Amboss Nephrology

Diabetic nephropathy

A major cause of end stage renal disease (ESRD) Pathophysiology: chronic hyperglycemia → non-enzymatic glycosylation (NEG) of the basement membrane (protein glycation) → increased permeability and thickening of the basement membrane and stiffening of the efferent arteriole→ hyperfiltration (increase in GFR) → increase in intraglomerular pressure → progressive glomerular hypertrophyand increased renal size → worsening of filtration capacity PathologyThree major histological changes occur: Mesangial expansionGlomerular basement membrane thickeningGlomerulosclerosis (later stages): may be diffuse (most common) or pathognomonic nodular glomerulosclerosis(Kimmelstiel-Wilson nodules) Clinical findingsOften asymptomatic; patients may complain of foamy urineProgressive diabetic kidney disease with signs of renal failure and risk of uremia (e.g., uremic polyneuropathy)Arterial hypertension Urine analysisProteinuriaInitially moderately increased albuminuria (microalbuminuria) ,Eventually significantly increased albuminuria (macroalbuminuria): nephrotic syndrome may develop. Differential diagnoses: other causes of chronic kidney disease (e.g., hypertensive nephropathy) and nephrotic syndrome Prevention and managementStringent glycemic control Antihypertensive treatment: ACE inhibitors OR angiotensin-receptor blockers are the first-line antihypertensive drugs in diabetic patients. Second line agents to be added to ACE inhibitors or ARBs to further control hypertension include diuretics or calcium channel blockersDietary modification: daily salt intake < 5-6 g/day; phosphorus and potassium intake restriction in advanced nephropathy; protein restriction Microalbuminuria is the earliest clinical sign of diabetic nephropathy. The extent of albuminuria correlates with the risk of cardiovascular disease! Early antihypertensive treatment delays the progression of diabetic nephropathy!

Tubulointerstitial diseases Tubulointerstitial diseases are characterized by acute or chronic inflammation of the renal tubules and interstitium. Acute interstitial nephritis is commonly caused by allergic reactions to drugs, but infection or systemic disease may also precipitate the disease. Common causes of chronic nephritis include drug toxicity (especially analgesics), metabolic disease (e.g., uric acid nephropathy), and other underlying conditions (e.g., multiple myeloma). Typical symptoms in both acute and chronic nephritis are painless hematuria (without RBC casts!) and pyuria. Depending on the underlying disease, nephritis may present with additional symptoms such as rash, arthralgias, and fever in the case of allergic interstitial nephritis. The most important diagnostic modalities are lab tests (increased blood urea nitrogen and creatinine) and urinalysis, although a kidney biopsy may be indicated in select cases. Treatment usually consists of supportive measures and addressing the underlying cause (e.g., discontinuing medication). All diseases affecting the renal tubules can ultimately lead to chronic renal failure.

Acute tubulointerstitial nephritis Acute tubulointerstitial nephritis is most commonly caused by a hypersensitivity reaction to drugs (allergic interstitial nephritis). Some drugs may also lead to crystal-induced acute kidney injury. Allergic interstitial nephritis Antibiotics (rifampin, penicillins, cephalosporins, sulfonamides) , NSAIDs, diuretics, allopurinol, PPIs, phenytoin. Drugs, particularly antibiotics and NSAIDs, act as haptens, inducing a hypersensitivity reaction. Painless hematuria Flank pain Sterile pyuria Peripheral eosinophilia Rash Fever Arthralgias Pyuria, Eosinophiluria Histology: diffuse interstitial inflammatory infiltrate (T lymphocytes, monocytes) Crystal-induced acute kidney injury E.g, acyclovir, indinavir, ciprofloxacin, methotrexate Drugs with low urine solubility precipitate within the renal tubules→ tubular obstruction & toxicity to tubules Patients are usually asymptomatic Renal colic Crystals on brightfield microscopy TherapyDiscontinue drugs and administer IV fluidsPrognosisAcute interstitial nephritis generally has a good prognosis. Other etiologies Infectious: staphylococci, streptococci, Brucella, Legionella, hantaviruses Systemic diseases: Sjögren's syndrome, systemic lupus erythematosus (SLE), sarcoidosis Autosomal dominant tubulointerstitial kidney disease: A rare genetic disorder that causes progressive renal dysfunction. Chronic tubulointerstitial nephritis The most common cause of chronic interstitial nephritis is analgesic nephropathy. Multiple myeloma can also be the cause. Analgesic nephropathy EtiologyNSAIDs and acetaminophen Formerly associated with phenacetin intake (no longer FDA-approved) PathophysiologyInhibition of prostacyclin synthesis → vasoconstrictionof the medullary blood vessels → papillary ischemia and papillary necrosis Possible colicky pain due to papillary necrosis Myeloma kidney (myeloma cast nephropathy) Multiple myeloma Excessive amounts of light chains are produced and filtered into the primary urine → precipitation of light chains in renal tubules → tubular obstruction & toxicity to renal tissue Painless hematuria Pyuria Fatigue Nausea Forced diuresis If necessary, plasmapheresis/dialysis Chronic tubulointerstitial nephritis usually progresses to end-stage renal disease. It is associated with an increased risk of urothelial carcinoma. Other etiologies Drugs MesalazineCadmium, lithium, lead Systemic diseases: Sjögren's syndrome, SLE Metabolic diseases: hyperuricemia, hypercalcemia, hyperoxaluria Renal papillary necrosis Definition: coagulative necrosis of the renal medullary pyramids and papillae Etiology (often multifactorial) PyelonephritisObstruction of the urinary tractSickle cell disease and sickle cell traitTuberculosisCirrhosis of the liverAnalgesic abuse: due to inhibition of prostaglandin-mediated vasodilation in the vasa rectaRenal transplant rejectionDiabetes mellitusSystemic vasculitis PathophysiologyUsually occurs bilaterallyIschemia → necrosis and sloughing of the papillae → ureteral obstruction → possibly scarring Clinical features (can be acute or chronic) Patients with a chronic course are usually asymptomatic or only present with mild symptomsFlank pain, colicky painHematuria (microscopic or macroscopic)Fever, chillsAcute kidney injury (rare) Diagnostics: see "Diagnostics" below and in pyelonephritis Therapy: see "Treatment" below and in pyelonephritis Causes of renal papillary necrosis: POSTCARDS (pyelonephritis, obstruction, sickle cell disease, tuberculosis, cirrhosis, analgesics, renal transplant rejection, diabetes mellitus, systemic vasculitis) Diagnostics ↑ BUN and creatinine UrinalysisTubular proteinuria (usually < 2 g/24 h)Hematuria: tubulointerstitial diseases show no RBC casts or acanthocytes (in contrast to glomerulonephritis)Sterile pyuriaWBC casts Kidney biopsy (often nonspecific histological findings) UltrasoundAcute nephritis: The kidneys appear edematous and enlarged.Chronic nephritis: The kidneys often appear shrunken. CT: may show bilateral calcifications of the renal papilla, filling defects in papillary necrosis, and small kidneys in chronic nephritis[4] Intravenous urography: test of choice for renal papillary necrosis; findings include: Irregular papillaeRing shadows Filling defects in the renal pelvisSmall contrast-containing cavities in the papillary regions Treatment For all tubulointerstitial diseases: Treat underlying disease Monitor kidney function Consider glucocorticoids In select cases, (temporary) dialysis

Chronic kidney disease Chronic kidney disease (CKD) is defined as an abnormality of the kidney structure or function for ≥ 3 months. The most common causes of CKD in the United States are diabetes mellitus, hypertension, and glomerulonephritis. Since the kidneys have exceptional compensatory mechanisms, most patients remain asymptomatic and are unaware of their condition until their kidney function is significantly impaired. Patients typically present with symptoms of fluid overload (e.g., peripheral edema) and uremia. Laboratory evaluation shows hyperkalemia, hyperphosphatemia, and hypocalcemia, as well as metabolic acidosis. Management focuses mainly on treating the underlying disease and preventing possible complications, e.g., treating hypertension, avoiding nephrotoxic substances, and maintaining adequate hydration. If chronic kidney disease progresses to end-stage renal disease (ESRD), renal replacement therapy (dialysis) or a kidney transplant is necessary.

Definition Chronic kidney disease is defined as an abnormality of the kidney structure or function for ≥ 3 months. Associated with an irreversible reduction of the excretory (glomerular, tubular) and the endocrine functions of the kidney Epidemiology About 10% of adults in the US suffer from chronic kidney disease. African Americans are at increased risk of developing chronic kidney disease. Diabetic nephropathyMost common cause, accounts for 44% of cases in the USHypertensive nephropathy28%Glomerulonephritis8%Polycystic kidney disease/hereditary2%Urological disease0.5%Other causes: amyloidosis, toxins, chronic inflammation Clinical features Patients are often asymptomatic until later stages. Hypertension Peripheral edema Pulmonary edema (usually interstitial pulmonary edema) Clinical features of uremia Fatigue, weakness, loss of appetite, headaches Uremic fetorPigmented spotsPruritus AnemiaUremic pericarditisFriction rub on auscultationDiagnostics: Uremic pericarditis does not show typical ECG changes such as diffuse ST-segment elevation. PleuritisAsterixisEncephalopathy: seizures, somnolence, comaPeripheral neuropathy: paresthesiasGastrointestinal symptoms: nausea, vomiting↑ Risk of infection: leukocyte dysfunction↑ Bleeding tendency secondary to platelet dysfunction Chronic kidney disease-mineral and bone disorder (CKD-MBD): abnormalities of mineral or bone metabolism in the setting of chronic renal disease Etiology: mostly due to secondary hyperparathyroidism → high-turnover renal osteodystrophy or osteitis fibrosa cysticaClinical features: weakness, fractures, bone pain, avascular necrosis Patients develop secondary hyperparathyroidism and subsequent renal osteodystrophy due to hyperphosphatemia, hypocalcemia, and the insufficient production of vitamin D! StageGlomerular filtration rate (GFR) (mL/min/1.73 m2)Description1> 90Normal or high260 to 89Mildly decreased330 to 59Moderately decreased415 to 29Severely decreased5< 15Kidney failure StageUrinary albumin excretion (mg/day)DescriptionA1< 30NormalA230 to 300Mildly increased (microalbuminuria)A3> 300Severely increased (macroalbuminuria) Diagnostics Blood↑ Creatinine and BUNElectrolytes: hyperkalemia, hyperphosphatemia, hypocalcemia Monitor blood pH for metabolic acidosis ↓ Calcitriol levels↑ Parathyroid hormone (PTH)Coagulation testing: ↔︎ PT, PTT, platelet count, ↑ bleeding time caused by uremic coagulopathyAnemia of chronic kidney disease: ↓ hemoglobin, ↔︎ MCVPathophysiology: ↓ erythropoietin → decreased stimulation of RBC production → normocytic, normochromic anemia Urinalysis: possibly abnormal urine sediment (see nephritic sediment, nephrotic sediment) Ultrasound: shrunken kidneys and fibrotic parenchyma Renal biopsy: sometimes indicated to determine the underlying cause In chronic renal disease, close surveillance of serum potassium values as well as calcium and phosphate values is essential! Treatment DietSalt restriction in patients with edema or hypertensionSee treatment of hyperkalemia.See treatment of acid-base disorders. Nephrotoxic substances avoidance NSAIDsNicotineSulfonamide antibiotics, aminoglycosides, vancomycinAcyclovirCisplatinOthers (e.g., lead, amphetamines, amphotericin B, radiographic contrast material) Strict blood pressure controlWell-controlled blood pressure is essential to prevent disease progression.See treatment of hypertension. VaccinationsAll patients with CKD Pneumococcal vaccine every 5 yearsInfluenza vaccine annuallySusceptible patients: hepatitis B vaccine (see high-risk groups for HBV infection) Special patient groupsEnd-stage renal diseaseDialysis until a renal transplant is availableAnemia of chronic kidney diseaseAdminister synthetic EPO, possibly in conjunction with iron replacement depending on serum ferritin and transferrin values. Adverse effects: increased risk of thrombosis, increase in blood pressureRBC transfusion may be needed in cases of EPO resistance Metabolic diseasesHyperlipidemia: statinsDiabetes mellitus: Insulin dose may have to be decreased. Restrict protein intake to 0.8-1.0 g/kg/dayActively bleeding or about to undergo a surgical procedureDesmopressin (DDAVP): first-line therapyCryoprecipitate: life-threatening bleeding resistant to treatment with desmopressinConjugated estrogens: for chronic control of bleeding Correction of anemia Dialysis

Hypercalcemia Hypercalcemia is a condition of high calcium levels (total Ca2+> 10.5 mg/dL or ionized Ca2+> 5.25 mg/dL) in the blood serum. For information regarding the physiology and homeostasis of calcium, please see the hypocalcemia learning card. The most common causes of hypercalcemia are primary hyperparathyroidism and malignancy with paraneoplasticproduction of parathyroid hormone-related protein (PTHrP). Symptoms of hypercalcemia include nephrolithiasis, bone pain, abdominal pain, and polyuria. Management depends on the severity of calcium imbalance. Mild and asymptomatic moderate hypercalcemia is treated with oral rehydration and low calcium intake, while symptomatic moderate cases and severe cases require IV rehydration and calcitonin administration. Hypercalcemic crisis is a life-threatening complication that manifests with dehydration, oliguria, and altered consciousness and requires immediate forced diuresis.

Definition Hypercalcemia = total serum calcium concentration > 10.5 mg/dL (> 2.62 mmol/L), or ionized (free) calcium concentration > 5.25 mg/dL (> 1.31 mmol/L) [ PTH-mediatedPrimary hyperparathyroidismAdenoma (sporadic or in multiple endocrine neoplasia)Excess PTH → increased active vitamin D (calcitriol) production via stimulation of 1-alpha-hydroxylasesynthesis in the kidneysSecondary hyperparathyroidismRenal insufficiency → ↓ production of 1,25-dihydroxyvitamin D → ↑ PTH May also be caused by vitamin D deficiency or hypocalcemiaTertiary hyperparathyroidismRenal failure → chronic secondary hyperparathyroidism → autonomous activation of one or more parathyroid glandsFamilial hypocalciuric hypercalcemia (FFH)See FFH in subtypes and variants section below.Non-PTH-mediatedHypercalcemia of malignancyMost common cause: paraneoplastic production of PTHrP (e.g., squamous cell carcinomas of the lung, head, and neck; breast, ovarian, bladder, and renal cancer; lymphoma and leukemia)Osteolytic metastases (e.g., multiple myeloma, breast cancer, lymphoma and leukemia, renal and prostate cancer)Paraneoplastic production of 1,25-dihydroxyvitamin D (calcitriol): e.g., lymphoma, ovarian dysgerminomaGranulomatous disorders (e.g., sarcoidosis) Hydroxylase activity in activated mononuclear cells produces 1,25-dihydroxyvitamin D (calcitriol) outside of the kidneys. OtherMedicationsThiazide diuretics: reduce renal calcium excretionExcess vitamin D: increases intestinal calcium absorptionCalcium supplementsHyperthyroidism↑ Thyroid hormone → increased osteoclastic activity → increased bone resorptionLong periods of immobilizationLack of weight-bearing activities → osteoclast activation → bone demineralization → hypercalcemiaMilk-alkali syndromeExcessive consumption of calcium carbonatePresents with hypercalcemia, metabolic alkalosis, and acute kidney injuryPaget disease of the boneIncreased rate of bone remodelingAdrenal insufficiencyThe exact pathophysiology is unknown; several mechanisms are proposed. [2]Hypovolemia → ↓ GFR → ↓ Ca2+ excretion → ↑ blood concentration of Ca2+↑ 1α-hydroxylase → ↑ calcitriol → ↑ Ca2+ intestinal absorption↓ Stanniocalcin Primary hyperparathyroidism and hypercalcemia of malignancy account for > 90% of cases of hypercalcemia. Compared to primary hyperparathyroidism, serum calcium is typically higher in hypercalcemia of malignancy (> 13 mg/dL, or > 3.25 mmol/L), and patients, therefore, exhibit more severe symptoms. Clinical features The clinical presentation is variable and may be asymptomatic. Nephrolithiasis, nephrocalcinosis (calcium oxalate > calcium phosphate stones) Bone pain, arthralgias, myalgias, fractures Constipation Abdominal pain Nausea and vomiting Anorexia Peptic ulcer disease [5] Pancreatitis Neuropsychiatric symptoms such as anxiety, depression, fatigue, and cognitive dysfunctionSomnolenceObtundation and coma indicate progression to hypercalcemic crisis Diminished muscle excitability Cardiac arrhythmiasMuscle weakness, paresis Polyuria and dehydration Hypercalcemic crisis: life-threatening condition that should be suspected at total calcium levels > 14 mg/dL(3.5 mmol/L) or ionized calcium > 12 mg/dL (3 mmol/L); patients present with Dehydration (due to ADH resistance and vomiting)Oliguria/anuriaAltered consciousnessPsychosis Hypercalcemia can cause pancreatitis. Hypocalcemia in patients with pancreatitis suggests pancreatic necrosis. The presentation of hypercalcemia includes stones (nephrolithiasis), bones (bone pain, arthralgias), thrones (increased urinary frequency), groans (abdominal pain, nausea, vomiting), and psychiatric overtones (anxiety, depression, fatigue). Note that these are also the findings of vitamin D overdose! Subtypes and variants Familial hypocalciuric hypercalcemia (FHH) [6] Etiology: autosomal dominant inactivating mutation in the CaSR gene → decreased sensitivity of G-coupledCa2+-sensing receptors in the kidneys and parathyroid glands → higher levels of Ca2+ required to suppress PTH →higher reabsorption of Ca2+ in the kidney → hypocalciuria with mild hypercalcemia and normal or increased PTH levels Clinical featuresUsually asymptomatic (incidental finding) Neonatal hypocalcemia in children of mothers with FHH (e.g., paresthesias, muscle spasms, seizures) DiagnosisHypercalcemia and inappropriately normal or increased PTHHypocalciuria↓ 24-hour urinary calcium excretion (< 200 mg/ day)↓ Calcium/creatinine clearance ratio (< 0.01 ) Therapy: no treatment necessary Diagnostics Approach [7] Evaluate calcium imbalance Initial test: serum calcium concentration Confirm true hypercalcemia: measure ionized calcium or use serum albumin to calculate corrected calcium. Corrected calcium (mg/dL) = measured total Ca2+ (mg/dL) + [0.8 x (4.0 - albumin concentration in g/dL)] Increased ionized calcium, regardless of total calcium levels → true hypercalcemia (potentially symptomatic)Increased total calcium with normal ionized (active) calcium → factitious hypercalcemia (asymptomatic finding) Differentiate between low PTH and high PTH: to determine the underlying cause of hypercalcemiaPTH: the most important test for patients with disorders of calcium balanceFurther laboratory tests to confirm the diagnosis (e.g., creatinine in suspected CKD) Further testsECGQT interval shorteningIn severe hypercalcemia: J waveFurther evaluation of bone disorders: See laboratory evaluation of bone diseases. The corrected calcium concentration calculated using serum albumin may not be accurate when major pH changes have taken place in the body (e.g., following surgery). In these cases, it is better to measure ionized calcium directly. Low PTHHypercalcemia of malignancy ↑ PTHrPVitamin D intoxication↑ Calcidiol (25-hydroxyvitamin D)Sarcoidosis or other granulomatous disease, lymphoma↑ Calcitriol (1,25-dihydroxyvitamin D)Milk-alkali syndromeMetabolic alkalosisHigh to normal PTHPrimary hyperparathyroidism↓ Phosphate↔︎/↑ Urine calciumFamilial hypocalciuric hypercalcemia (FHH)↓ Urine calcium Treatment Treatment of any underlying disorder (e.g., glucocorticoids in sarcoidosis or any other granulomatous disease → reduction in activity of mononuclear cells producing calcitriol) Mild or asymptomatic hypercalcemia: total calcium < 12 mg/dL (< 3 mmol/L) or ionized calcium < 8 mg/dL(< 2 mmol/L) Encourage adequate oral hydrationReduce dietary intake of calciumAvoid thiazide diuretics, lithium, high-calcium diet Moderate hypercalcemia: total calcium 12-14 mg/dl (3-3.5 mmol/L)Asymptomatic: same treatment as for mild hypercalcemia (see above)Symptomatic: same treatment as described for severe hypercalcemia (see below) Severe or symptomatic hypercalcemia: total calcium > 14 mg/dL (> 3.5 mmol/L) or ionized calcium > 19 mg/dL(> 2.5 mmol/L)Immediate therapy [8]IV hydration with isotonic saline Calcitonin [9]In hypercalcemic crisis: immediate forced diuresis (following volume replacement!)Cause-based therapy Excessive bone resorption (e.g., hypercalcemia of malignancy, immobilization): bisphosphonates (zoledronic acid, pamidronate) Renal insufficiency or heart failure: loop diuretics (with monitoring of serum potassium) to avoid volume overload Dialysis in very severe cases (total calcium > 18 mg/dL; ionized calcium > 4.5 mmol/L) or concomitant renal failure Thiazide diuretics enhance Tubular calcium resorption → Discontinue them in hypercalcemia. Loop diuretics Lose calcium → Administer them in hypercalcemia.

Hypocalcemia Hypocalcemia is a state of low calcium levels (total Ca2+< 8.5 mg/dL or ionized Ca2+< 4.65 mg/dL) in the blood serum. Total calcium comprises the ionized calcium, which is the physiologically active ion, as well as protein-bound, physiologically inactive calcium. Calcium plays an important role in various cellular processes in the body, such as stabilizing the resting membrane potential of cells, cell signaling, coagulation, and hormone release. In addition to hormonal control by parathyroid hormone (PTH) and calcitriol, calcium homeostasis is also influenced by serum proteinlevels and acid-base status, both of which impact the ratio of protein-bound Ca2+ to ionized Ca2+ in the serum. Symptoms of hypocalcemia include tetany, which indicates neuromuscular excitation (e.g., carpopedal spasm, "pins and needles" sensation, other paresthesias) as well as prolongation of the QT interval, and abdominal pain. Management consists primarily of treating the underlying disorder and, if necessary, calcium supplementation.

Definition Hypocalcemia: total serum calcium concentration < 8.5 mg/dL (< 2.12 mmol/L), or ionized (free) calcium concentration < 4.65 mg/dL (< 1.16 mmol/L) [1] Calcium homeostasis and calcium physiology Total and ionized calcium concentrations Total calcium: the total amount of calcium circulating in the serum, comprising protein-bound, anion-bound, and ionized calciumApprox. 40% of the total serum calcium is bound to proteins (mostly albumin) and is physiologically inactive. Hypoproteinemia (due to, e.g., nephrotic syndrome, liver cirrhosis, severe malnutrition, malabsorption) →↓ total Ca2+ level but ionized Ca2+ level is unaffected → factitious hypocalcemiapH influences the binding of calcium to serum proteins. ↑ pH → ↓ H+ in serum binding to proteins → ↑ Ca2+ binding to proteins → ↓ ionized Ca2+ concentration compensatory ↑ PTH↓ pH → ↑ H+ in serum binding to proteins → ↓ Ca2+ binding to proteins → ↑ ionized Ca2+ concentration compensatory ↓ PTH Ionized calcium: the calcium fraction that is not bound to any proteins but is physiologically active Approx. 45% of the total serum calciumFunctions as the main regulator of PTH secretionPTH secretion is influenced by pH variations but not by changes in albumin levels.An excess causes true hypercalcemia whereas a deficiency causes true hypocalcemia To remember the changes in PTH depending on pH, think: ↑ pH = ↑ PTH and ↓ pH = ↓ PTH The physiological role of calcium [2] Ionized Ca2+ is responsible for stabilizing the resting membrane potential of cells. ↓ Serum Ca2+ → ↑ membrane excitability↑ Serum Ca2+ → ↓ membrane excitability Acts as a second messenger in signaling pathways Cofactor for several enzymes (e.g., phospholipase A, gamma-glutamyltransferase) Required for the promotion of coagulation pathways Calcium homeostasis Calcium homeostasis is a complex process, involving many organs (kidneys, gastrointestinal tract, bones, liver, and skin) and hormones (PTH, calcitonin, vitamin D). The acronym "PTH" describes the action of parathyroid hormone → P = Phosphate T = Trashing H = Hormone To remember that calcitonin keeps the calcium in the bones, think: Calci-bone-in! Low PTHHypoparathyroidismSurgical removal of the parathyroid glands (thyroidectomy, parathyroidectomy)Autoimmune destruction of the parathyroid glands (e.g., in autoimmune polyglandular syndrome)Congenital disorders of the parathyroid gland (e.g., DiGeorge syndrome)High PTH (secondary hyperparathyroidism)Vitamin D deficiencyMalnutrition and malabsorption (e.g., alcoholism, chronic IBD, cystic fibrosis, gastric-bypass)Lack of sunlight exposureDecreased enzymatic hydroxylation to active form (e.g., cirrhosis/liver disease, chronic kidney disease)Vitamin D-dependent rickets (type 1 and type 2)PseudohypoparathyroidismPTH resistanceHyperphosphatemia (see phosphate)↓ Renal excretion of phosphate (e.g., impaired renal function)Increased phosphate intake (e.g., oral supplements, enemas)Increased tissue breakdown (e.g., tumor lysis syndrome, rhabdomyolysis, crush injury)Acute necrotizing pancreatitis (see acute pancreatitis) Calcium soap precipitation in the abdomen OtherMedicationsLoop diuretics increase renal calcium excretion.Calcitonin Bisphosphonates GlucocorticoidsDenosumabFoscarnetPhosphateL-asparaginaseDoxorubicinCisplatinKetoconazolePentamidineCytosine arabinosideGallium nitratePlicamycinMultiple blood transfusions and hemolysisCitrate in blood products chelates serum calciumHypomagnesemia (see magnesium) Hypomagnesemia → ↓PTH secretion or induces PTH resistance → hypocalcemiaHyperventilationRedistribution of calcium Osteoblastic metastasesMetastases of primary malignancies (e.g., prostate cancer, small cell lung cancer) in the bone with rapid new bone formationRenal tubular disordersSee RTA type 1 and Gitelman syndromePseudohypocalcemiaDue to gadolinium contrast agent or hypoalbuminemiaNeonatal hypocalcemiaDue to cessation of placental Ca2+ transfer at birthHungry bone syndromeHypoparathyroidism following parathyroidectomy or thyroidectomy despite normal or increased PTH Hypocalcemia is most often due to hypoparathyroidism or vitamin D deficiency (e.g., malabsorption, chronic kidney disease). Clinical features Tetany: increased neuromuscular excitability (when caused by respiratory alkalosis = hyperventilation-induced tetany) Paresthesias: typically tingling or pins-and-needles sensation in extremities and/or in the perioral areaMuscle spasms, such as carpopedal spasm and cramps (possible in any muscle)Maneuvers to elicit tetany in physical exam Chvostek sign: short contractions (twitching) of the facial muscles elicited by tapping the facial nerve below and in front of the ear (approx. 2 cm ventral to the ear lobe)Trousseau sign: ipsilateral carpopedal spasm occurring several minutes after inflation of a blood pressure cuffto pressures above the systolic blood pressure Seizures Cardiac arrhythmias (typically ventricular tachyarrhythmias) [10] Hypotension Myocardial depression Biliary colic Abdominal cramping and diarrhea Suspect hypocalcemia in the postoperative thyroidectomy patient with new-onset paresthesias and muscle spasms or cramping. Diagnostics Approach [12] Evaluate calcium imbalance Initial test: serum calcium concentration Confirm true hypocalcemia: Measure ionized calcium or use serum albumin to calculate corrected calcium. Particularly important in patients with hypoalbuminemia to rule out factitious hypocalcemia: an asymptomatic decrease in total calcium with a normal ionized Ca2+ level that typically occurs due to low serum protein levels. Differentiate between low PTH and high PTH: to determine the underlying cause of hypocalcemia (see differential diagnosis of hypocalcemia above) PTH: the most important test for patients with disorders of calcium balanceFurther laboratory tests to confirm the diagnosis (e.g., creatinine in suspected CKD) Further testsECG: prolonged QT interval PTH levels in hypocalcemia Low PTHHypoparathyroidism (e.g., postsurgical)↑ PhosphateHigh PTHVitamin D deficiency↓ Or normal phosphate↓ Calcidiol (25-hydroxyvitamin D)↓ Or normal or ↑ calcitriol (1,25-dihydroxyvitamin D) [13]Chronic kidney disease↑ Phosphate↑ CreatininePseudohypoparathyroidism↑ PhosphateHyperphosphatemia↑ PhosphateMalabsorption or alcoholism↓ Magnesium Treatment Calcium supplementation (see calcium repletion)IV calcium (1-2 g calcium gluconate in 50 mL of 5% dextrose infused over 10-20 mins): indicated in severely symptomatic patients (e.g., tetany, seizures), those with a prolonged QT interval, and asymptomatic patients with an acute decrease in serum corrected calcium to ≤ 7.5 mg/dL (≤ 1.9 mmol/L) Oral calcium: indicated in patients with mild neuromuscular irritability (e.g., paresthesias), and those with serum corrected calcium > 7.5 mg/dL (> 1.9 mmol/L) Treat any underlying conditionsHypoparathyroidism or vitamin D deficiency: vitamin D supplementationLoop diuretics intake: medication change to thiazides Hypomagnesemia-induced hypocalcemia: magnesium supplementation Because of adverse cardiac effects, cardiac monitoring is recommended in patients receiving simultaneous cardiac glycosides(digoxin and digitoxin) and IV calcium. Loop diuretics Lose calcium. Discontinue them in hypocalcemia.

Sodium disorders Sodium is the most important extracellular cation and plays an important role in maintaining the body's extracellular fluidvolume. Sodium imbalances typically reflect a dilution or concentration of extracellular fluid rather than an actual loss or gain of sodium. These changes in extracellular fluid volume are mainly due to an increase or decrease in ADH serum levels (which causes the retention and loss of free water respectively). In certain cases, however, sodium imbalances may be the direct result of sodium loss (e.g., following diarrhea, vomiting, or the use of antidiuretics) or excessive sodium intake. Treating sodium imbalances involves careful correction of the sodium deficit/excess and treating the underlying cause. A rapid correction of sodium imbalance can have damaging osmotic effects such as central pontine myelinolysis.

Definition Hyponatremia: serum concentration < 135 mEql/L Hypernatremia: serum concentration > 145 mEql/L Etiology Hyponatremia Hypotonic hyponatremia (↓ serum osmolality) Hypovolemic hyponatremiaRenal causes: diuretics, aldosterone deficiency (Addison's disease)Extrarenal causes: pancreatitis, vomiting, diarrhea, burns, bleeding Euvolemic hyponatremiaSyndrome of inappropriate ADH secretion (SIADH)Psychogenic polydipsiaHypothyroidism Rarely alcoholism Hypervolemic hyponatremiaCongestive heart failureLiver cirrhosisNephrotic syndrome Isotonic hyponatremia (↔︎ serum osmolality) Pseudohyponatremia HyperlipidemiaParaproteinemia (e.g., multiple myeloma) Hypertonic hyponatremia (↑ serum osmolality) Hyperglycemia Use of mannitol AldosteroneEffect: Aldosterone causes sodium and water reabsorptionRelease of aldosterone: decreased renal perfusion → RAAS activation → aldosterone release ADHEffect: ADH causes water reabsorption and increases thirst.Release of ADHPrimary stimulus: increase in serum osmolality (very sensitive even to a 1% change in serum osmolality).Non-osmotic stimulus: A change in extracellular fluid volume by more than 10% (which is sensed by carotid baroreceptors) can also stimulate ADH release. Hypernatremia Hypovolemic hypernatremia Dehydration (e.g., due to poor oral fluid intake, diarrhea) Diuretics Osmotic diuresis (e.g., hyperglycemia, uremia, high-protein tube feeding) Euvolemic hypernatremia Diabetes insipidus (central or renal) Lack of access to water Hypervolemic hypernatremia Primary hyperaldosteronism Cushing's syndrome Iatrogenic: excessive infusion of NaCl or sodium bicarbonate solutions Drinking sea water Clinical features Clinical features are primarily neurological and depend on the severity of the sodium imbalance. Mild symptoms AnorexiaNauseaVomitingHeadacheMuscle crampsModerate symptoms Muscle weaknessLethargyConfusionSevere symptoms SeizuresAltered consciousnessComa Symptoms also depend on the onset of sodium imbalanceAcute onset (< 48 hours): usually symptomatic event even with mild sodium derangementsSubacute or chronic onset (> 48 hours): usually asymptomatic unless severe derangements are present Diagnostics Blood testsSerum sodium concentrationSerum osmolality to assess volume status is always the first step in evaluation HyponatremiaHypotonic hyponatremia (most common): serum osmolality < 280 mOsmol/kgHypertonic hyponatremia: serum osmolality > 295 mOsmol/kgIsotonic hyponatremia: serum osmolality 280-295 mOsmol/kgHypernatremia: ↑ serum osmolalityHematocrit↓ Hematocrit: possibly fluid overload↑ Hematocrit: hypovolemia, dehydration Urine examination Hyponatremia: urine sodium concentration > 20 mEq/L implies renal sodium loss < 20 mEq/L implies extrarenal sodium loss Hypernatremia: urine osmolality > 800 mOsmol/kg implies extrarenal water loss < 800 mOsmol/kg implies renal water loss The kidneys continue to excrete water despite a water deficit. Treatment General principles Treat underlying cause Patients with serum sodium values < 120 mEq/L or >160 mEq/L require intensive care. Careful correction of sodium levels: maximum correction within 24 hours is 10 mEq/L (rate of correction: 0.5-1 mEq/L per hour)Effects of rapid correctionRapid increase in sodium levels → risk of central pontine myelinolysisRapid fall in serum sodium → risk of cerebral edema Hyponatremia Hypovolemic hyponatremiaMild to moderate symptoms: normal saline Severe symptoms: hypertonic saline Euvolemic hyponatremiaMild to moderate symptoms: fluid restrictionSevere symptoms: hypertonic saline Hypervolemic hyponatremia: Mild to moderate symptoms: fluid restriction ± loop diureticSevere symptoms: isotonic saline Hypernatremia Correct free water deficit Mild hypernatremia in non-hospitalized patients: oral rehydration Moderate to severe hypernatremia, or hypernatremia in hospitalized patients: IV routeAcute hypernatremia (< 48 hours): hypotonic saline (e.g., ½ NS ) or 5% dextrose (D5W) orSubacute or chronic hypernatremia (> 48 hours): 5% dextrose in 0.45% NS (D5½NS) Hypovolemic hypernatremiaFluid resuscitationOnce adequately resuscitated: correct free water deficit Euvolemic hypernatremia: correct free water deficit Hypervolemic hypernatremia: loop diuretic + 5% dextrose The cornerstone of the management of hypernatremia is correcting the free water deficit. Slow correction to prevent osmotic cell damage! Complications Osmotic myelinolysis Definition: Damage to the myelin sheath of nerves in the CNS caused by a sudden rise in the osmolarity of blood. Central pontine myelinolysis Most common type of osmotic myelinolysisAffects central region of the ponsExtrapontine myelinolysisAffects cerebellum, lateral geniculate body, thalamus, putamen, cortical, and subcortical white matter CausesRapid correction of chronic hyponatremia Clinical featuresAltered level of consciousness, comaLocked-in syndromeImpaired cranial nerve function: dysarthria, dysphagia , diplopiaWorsening quadriparesis Treatment: supportive care The symptoms of pontine myelinolysis appear 2 to 6 days after the correction of hyponatremia! Others Intracranial hemorrhage Cerebral edema Noncardiogenic pulmonary edema Rhabdomyolysis Bone fractures

Nephritic syndrome Nephritic syndrome is characterized by glomerular damage leading to hematuria, pyuria, water retention, and subsequent hypertension and edema. It can be caused by a variety of conditions including autoimmune, hereditary, and infectious diseases. This learning card provides an overview of nephritic syndrome; underlying conditions are discussed in more detail in other learning cards. Nephritic diseases can present in varying degrees of severity, ranging from asymptomatic hematuria to systemic involvement as in rapidly progressive glomerulonephritis. The urine sediment is typically characterized by red blood cell (RBC) casts, mild to moderate proteinuria (< 3.5 g/day), and sterile pyuria. Diagnosis of the underlying disease is often based on presentation and laboratory values, although renal biopsy may be indicated for confirmation.

Definition Nephritic syndrome consists of a combination of some or all of the following signs: Hematuria with acanthocytes RBC casts in urine Proteinuria (< 3.5 g/24h) Hypertension Mild to moderate edema Sterile pyuria Oliguria Azotemia Poststreptococcal glomerulonephritisOccurs weeks after group A β-hemolyticstreptococci infectionsPharyngitis/tonsillitis (most common): 1-2 weeksSkin infections: 3-4 weeksUsually affects children between the ages of 3-12 yearsCan lead to RPGN in some casesPositive antistreptococcal antibodies (ASO, ADB)↓ Serum C3 complement levelsTea- or cola-colored urineLM: glomeruli appear enlarged and hypercellularIM: granular subepithelial immune complexdepositions (IgG, IgM, C3) → "lumpy-bumpy" appearanceEM: dome-shaped, subepithelial deposits ("humps")Usually self-limitingSupportive therapy (see "Treatment" below)IgA nephropathy(Berger's disease)Most common idiopathic glomerulonephritisworldwideEpisodic gross hematuria during or directly after upper respiratory tract (URT), gastrointestinal (GI) infections, or strenuous exercise Occurrence: ♂ > ♀Peak incidence: 2nd to 3rd decade of life∼ 25-30% of the patients progress to end-stage renal disease (ESRD) within 20-25 yearsAsymptomatic microhematuria with intermittent gross hematuria↑ Serum IgANormal C3 complement levelsLM: mesangial proliferationIM: mesangial IgA depositsEM: mesangial immune complex depositsSupportive therapy (see "Treatment" below)Glucocorticoids in severe cases Small vessel vasculitisGranulomatosis with polyangiitis(Wegener's)Pulmonary and nasopharyngeal involvement is common → hemoptysis, nasal ulcersc-ANCARenal biopsy: segmental necrotizing glomerulonephritisEM: immune complex depositionsSupportive therapy (see "Treatment" below)Immunosuppressive therapyMicroscopic polyangiitisUsually only mild respiratory symptomsp-ANCAChurg-Strauss syndromePatients present with: AsthmaAllergic rhinitisPurpuraPeripheral neuropathyp-ANCA (∼ 50% of cases)Peripheral eosinophiliaFocal segmental necrotizing glomerulonephritis Goodpasture syndrome (Anti-GBM antibody disease) Two peaks of occurrence: 3rd decade of life (♂ > ♀) and ≥ 60 years of age (♀ > ♂) Caused by antibodies against type IV collagen Antibodies can cross-react with basement membrane of pulmonary capillaries and lead to pulmonary hemorrhage and hemoptysis Can lead to RPGN Pulmonary infiltrates on chest x-ray IM: linear deposition of immunoglobulin(IgG) along the glomerular basement membrane Immunosuppressive therapy Plasmapheresis Thin basement membrane disease Hereditary disorder Abnormalities of type IV collagen Good prognosis Persistent microhematuria Possible episodic gross hematuria, typically occurring during or directly after an upper respiratory tract infection or exercise EM: diffuse thinning of glomerular basement membrane Renal function monitoring Supportive therapy (see "Treatment" below) Alport syndrome X-linked (usually affects males) Mutation in gene for type IV collagen Often leads to ESRD Persistent microhematuria with intermittent gross hematuria Associated with sensorineural hearing loss and abnormalities of the eye EM: splitting and alternating thickening and thinning of the glomerular basement membrane Supportive therapy (see "Treatment" below) Renal transplant can lead to development of Goodpasture syndrome Lupus nephritisComplication of systemic lupus erythematosusCan be nephritic or nephroticCan lead to RPGN in some casesANA, anti-dsDNA antibodiesHistologic changes are very variableSupportive therapy (see "Treatment" below)Immunosuppressive therapy Rapidly progressive glomerulonephritis (RPGN) Glomerular diseases that progress to ESRDwithin weeks to months Can be caused by a variety of diseases: Goodpasture syndrome(anti-GBM disease)Poststreptococcal glomerulonephritisSystemic lupus erythematosus (SLE)Microscopic polyangiitisGranulomatosis with polyangiitis(Wegener's) LM, IM, EM: crescent formation, monocytes, macrophages Immunosuppressive therapy Plasmapheresis Pathophysiology Inflammation → cytokine release → glomerular capillary damage Porous glomerular basement membrane → leakage of proteins and RBCs → nephritic sediment (all blood components are detectable on urinalysis)Proteinuria (< 3.5 g/24h): leakage of proteinsHematuria: leakage of RBCs, which stick together and form red blood cell casts in the renal tubulesOliguria: inflammatory infiltrates reduce fluid movement across the membrane (↓ GFR)Azotemia: inflammation prevents sufficient filtering and excretion of ureaSalt retention → intravascular volume expansion → hypertension and edema Clinical features Intermittent gross hematuria (red or brown urine"cola-colored urine"), Hypertension Pitting edema If ↓GFR: oliguria and uremic symptoms (see uremia) For a comparison of nephrotic and nephritic syndrome see nephrotic vs. nephritic syndrome Diagnostics Urinalysis: Nephritic sedimentHematuria (either micro- or intermittent macrohematuria)Dysmorphic red blood cells (acanthocytes) Red blood cell casts Mild to moderate proteinuria of > 150 mg/24h but < 3.5 g/24h (non-selective glomerular proteinuria) Sterile pyuria and sometimes WBC casts Renal biopsy: sometimes indicated in patients with a nonspecific disease pattern to confirm diagnosis Blood tests↑ Creatinine, ↓ GFRAzotemia with ↑ BUN Glomerular hematuria is a typical finding in nephritic syndrome. It is characterized by acanthocytes, RBC casts, and mild to moderate proteinuria! (Nonglomerular hematuria is characterized by bright red or pink urine, the occurrence of blood clots, normal RBC morphology, and the absence of RBC casts.) Treatment Supportive therapy Low-sodium dietWater restriction Medical therapy If proteinuria and/or hypertension: angiotensin-converting enzyme inhibitors or angiotensin-receptor blockersIf severe hypertension and/or edema: diureticsSometimes immunosuppressive therapy is indicated. If severe renal insufficiency or kidney failure: renal replacement therapy (e.g., hemodialysis, possibly transplantation) For management of specific diseases: See the "Therapy" sections of the respective learning cards.

Proteinuria Proteinuria is defined as a urinary protein excretion of > 150 mg/day. It has many possible causes, which may be benign (e.g., fever, intense exercise, dehydration) or more serious (e.g., glomerulonephritis, multiple myeloma). There are three different pathophysiological mechanisms that may lead to proteinuria: damage to the glomeruli (glomerular), damage to the tubules (tubular), or overproduction of low-molecular-weight proteins (overflow). If proteinuria is detected, patients should be further evaluated (e.g., additional urinalyses) to determine the underlying cause. The detection of microalbuminuria is of particular importance, as it suggests early diabetic or hypertensive nephropathy.

Definition Proteinuria = urinary protein excretion of > 150 mg/day [1] Diagnosis Urinalysis Urine dipstick → repeat to rule out transient proteinuria (primarily detects albumin) Sulfosalicylic acid test: sulfosalicylic acid is added to urine to measure total urine proteins (not specific for albumin) 24-hour urine collection or urine protein-to-creatinine ratio in a spot urine sample to rule out orthostatic proteinuria Urine sediment to rule out glomerular disease Electrophoresis to rule out tubulointerstitial diseases and multiple myeloma Proteinuria can cause foamy urine! Diagnosis of underlying disease Differential diagnoses of nephrotic syndrome See diabetes mellitus. See multiple myeloma. Classification According to quantity Microalbuminuria Urine albumin excretion of 30-300 mg/day Diagnosis is made if two out of three tests are positive. Early symptom of diabetic nephropathy and hypertensive nephropathy Specific urine dipstick tests, radioimmunoassay, or ELISA required for detection Overt proteinuria (formerly "macroalbuminuria") Urine albumin excretion > 300 mg/day Standard urine dipstick tests can be used for detection. Nephrotic syndrome: massive proteinuria (> 3.5 g/24 h), hypoalbuminemia, edema, and hyperlipidemia According to origin Glomerular proteinuria Damage to the glomeruli → increased permeability of the glomerular filtration barrier → urinary protein excretion Characteristic finding: appearance of large proteins in the urineSelective glomerular proteinuriaLoss of negative charge of glomerular basement membraneOnly small- to medium-sized proteins can be found in the urine (primarily albumin) Can be found in diseases with mild damage to the glomeruli (e.g., minimal change disease, IgA nephropathy)Non-selective glomerular proteinuriaDamage to the glomerular basement membraneAll types of protein of any size can be found in the urine (albumin, transferrin, and IgG are commonly detected)Can be found in diseases with severe damage to the glomeruli and subsequent permeability to all components of the blood (e.g., rapidly progressive glomerulonephritis, lupus nephritis, amyloid nephropathy) Tubular proteinuria Damage to the tubules → failure to reabsorb small proteins in the tubules → urinary protein excretion The detection of beta-2 microglobulin without large proteins is typical. Can be found in tubulointerstitial nephritis, analgesics nephropathy, acute renal failure Mixed proteinuria Found in diseases that affect both the glomeruli and the tubules (e.g., chronic renal failure) Prerenal proteinuria (or overflow proteinuria) Increased production of low-molecular-weight proteins → The reabsorption capacity of the tubules is exceeded.Light chains or Bence-Jones protein (see myeloma kidney)Hemoglobinuria (in hemolysis)Myoglobinuria (in rhabdomyolysis) Postrenal proteinuria Proteins that are being produced in the tubules (Tamm-Horsfall protein) Proteins that reach the urine in the lower urinary tract (e.g., trauma or inflammation) Benign proteinuria Defined as isolated proteinuria < 3.5 g/day Important, benign differential diagnosis in the evaluation of proteinuria Very common; mostly affects younger individuals Types of benign proteinuriaOrthostatic proteinuria (postural proteinuria): increased protein excretion only in the upright positionTransient proteinuriaMost common cause of isolated proteinuria in childrenCauses: Heavy exertion/stressFeverSeizuresExposure to cold temperaturesWomen can present with mild proteinuria due to vaginal discharge. A dipstick test should be repeated to exclude underlying disease. No treatment necessary; excellent prognosis

Rhabdomyolysis and crush syndrome Rhabdomyolysis is the breakdown of skeletal muscle tissue caused by either traumatic or nontraumatic injury (e.g., seizures, ischemia, drug reactions). Traumatic rhabdomyolysis is often due to a crush injury resulting from a prolonged crushing force on skeletal muscle, for example, after being trapped under a collapsed building or following a car accident. Symptoms may be caused by an overabundance of intracellular substances (e.g., myoglobin, potassium, phosphate) following their release from destroyed muscle cells or by third spacing. Rhabdomyolysis classically presents with myalgia, generalized weakness, and darkened urine (myoglobinuria). Complications include acute kidney injury and crush syndrome, the systemic manifestation of traumatic rhabdomyolysis. Crush syndrome is also often associated with acute kidney injury; additionally, it typically presents with signs of volume depletion (hypovolemia, shock) and compartment syndrome of the affected extremity (usually the lower legs). Treatment is generally conservative and includes fluid resuscitation and correction of metabolic abnormalities. In the case of renal failure, dialysis may be indicated.

Definition Rhabdomyolysis: breakdown of skeletal muscle tissue Crush injury: localized injury to the skeletal muscle by a crushing force Crush syndrome: systemic manifestation of crush injury Etiology Causes of rhabdomyolysis TraumaticCrush injuryDirect injury NontraumaticSeizuresOverexertion (e.g., ultramarathon)Intoxication (e.g., cocaine, heroin, alcohol, carbon monoxide, phencyclidine)Skeletal muscle ischemiaInfectionAdverse drug reactions (e.g., neuroleptics, statins)Malignant hyperthermia Pathophysiology Rhabdomyolysis → release of the following substances:Creatinine phosphokinase (CPK) and serum myoglobin → pigment nephropathy → acute tubular necrosis → acute kidney injury (intrinsic)Potassium → cardiac arrhythmiaLactic acid → metabolic acidosis Hypovolemia → decreased renal perfusion → acute kidney injury (prerenal) Reperfusion syndrome → compartment syndrome Clinical features Rhabdomyolysis Classic triad MyalgiaGeneralized weaknessDarkened urine (red to brown) Nonspecific symptoms: fever, nausea, vomiting ComplicationsAcute kidney injury: oliguria or anuriaCompartment syndrome: may develop after fluid resuscitationCrush syndrome Crush syndrome In addition to signs of rhabdomyolysis: Hypovolemia and shock Diagnostics Blood↑ Creatine kinase↑ Potassium, ↑ phosphate,↓ calcium↑ Lactate dehydrogenase↑ Myoglobin In the case of acute kidney injury: ↑ blood urea nitrogen, ↑ creatinine UrineMyoglobinuriaLow fractional excretion of sodium Contrary to other causes of intrinsic renal failure, in pigment-induced acute kidney injury, the fractional excretion of sodium usually remains low, possibly as a result of concomitant renal vasoconstriction. Treatment IV fluid administration Monitor fluid output and electrolyte levels Correct electrolyte imbalances as necessary (see treatment of hypocalcemia and hyperkalemia) In the case of renal failure: consider hemodialysis

Glomerular diseases Renal glomeruli excrete urinary substances and excess water as an ultrafiltrate into the urine by selectively filtering the blood. Any damage to the glomeruli disrupts the filtration process and results in the appearance of blood components (proteins and red blood cells) in the urine. Glomerular damage is commonly caused by immune-mediated processes, which often lead to glomerulonephritis. Non-inflammatory causes, such as metabolic disease (e.g., diabetes, amyloidosis), can also result in significant damage to the glomeruli. The pathophysiology of glomerular diseases is complex; most patients present with either nephritic syndrome (low-level proteinuria, microhematuria, oliguria, and hypertension) or nephrotic syndrome (high-level proteinuria and generalized edema). All glomerular diseases can progress to acute or chronic renal failure. Thus, quick diagnosis and immediate initiation of immunosuppressive therapy are required to prevent irreversible kidney damage.

Definition Terminology of glomerular diseasesDiffuse: all glomeruli are affectedFocal: only a number of glomeruli are affectedGlobal: the entire glomerulus is affectedSegmental: only part of the glomerulus is affectedProliferative: an increased number of cells in the glomerulusSclerosing: scarring of the glomerulusNecrotizing: cell death within the glomerulisCrescentic: accumulation of cells such as macrophages, fibroblasts, and epithelial cells in Bowman's space Pathophysiology The glomerular filtration barrier consists of 3 parts Initial segment: Fenestrated glomerular capillary endothelium prevents large proteins from passing through.Second segment: The glomerular basement membrane (GBM) contains a negative charge produced by heparan sulfate. Final segment: Visceral epithelial cells produce/maintain the GBM and contain intercellular junctions created by podocytes that prevent further protein loss. Damage to the glomeruli → disruption of the glomerular filtration barrier → can lead to nephritic or nephroticsyndromeSee pathophysiology of nephritic syndromeSee pathophysiology of nephrotic syndrome Nephritic syndrome Proteinuria (< 3.5 g/day) Hematuria with acanthocytes Mild to moderate edema RBC casts in urine Oliguria Azotemia Hypertension Sterile pyuria Inflammatory response within glomeruli → GBMdisruption Poststreptococcal glomerulonephritis IgA nephropathy (Berger's disease) Granulomatosis with polyangiitis (Wegener's) Microscopic polyangiitis Churg-Strauss syndrome Goodpasture syndrome (anti-GBM disease) Alport syndrome (hereditary nephritis) Thin basement membrane disease Rapidly progressive glomerulonephritis (RPGN) Lupus nephritis Nephrotic syndrome Heavy proteinuria (> 3.5 g/day) Hypoalbuminemia Generalized edema Hyperlipidemia and fatty casts in urine Hypertension ↑ Risk of thromboembolism and infection Structural damage of glomerular filtration barrier → massive renal loss of protein Minimal change disease Focal segmental glomerulosclerosis Membranous nephropathy Membranoproliferative glomerulonephritis Diabetic nephropathy Amyloid light-chain (AL) amyloidosis, light chain deposition disease Lupus nephritis All glomerular diseases can lead to acute and chronic kidney failure!

Megaureter Megaureter is defined as ureteral dilation > 7 mm. Primary megaureter is due to obstructed or refluxing vesicoureteral junction, while secondary megaureter is caused by bladder outlet obstruction. Although rare, primary megaureter is responsible for up to 20% of hydronephrosis cases in neonates. About half of the patients with megaureter are asymptomatic. The other half may present with a urinary tract infection, abdominal pain, or features of uremia. Ultrasound (prenatal and postnatal) shows ureteral dilation, which may be accompanied by hydronephrosis. CT or MRurography shows a constricted terminal ureter with proximal dilation, while voiding cysticrogram detects vesicoureteral reflux in refluxing megaureter. Prophylactic antibiotics and regular follow-ups are sufficient in patients with primary megaureter and preserved renal function. Surgery (terminal ureter resection and re-implantation into the bladder) is indicated in patients with deteriorating renal parameters. Patients with secondary megaureter require treatment of the underlying cause. Those who do not receive treatment can develop recurrent urinary tract infections, hydronephrosis, and obstructive nephropathy with permanent kidney damage.

Definition Ureteral dilation > 7 mm in children Epidemiology Incidence : rare (<0.5 cases per 1000 births) Sex : ♂> ♀ (4: 1) Second most common cause of hydronephrosis in newborns (20% of cases) The most common cause of hydronephrosis in newborns is ureteropelvic junction obstruction. Etiology Primary megaureter Primary obstructed megaureterCongenital developmental defect of the muscular layer of the terminal ureterDistal aperistaltic segment of ureter causing functional obstructionIncreased intraureteral pressure in dilation Primary refluxing megaureter: dilation of the ureter secondary to primary vesicoureteral reflux (VUR) Secondary megaureter Secondary obstructed megaureterBladder outlet obstruction High intracystic pressureFunctional obstruction of the vesicoureteral junction (VUJ)Urine can not pass into the bladderUreteral dilation Secondary refluxing megaureter : bladder outlet obstruction with ureteral dilation caused by secondary vesicoureteral reflux Clinical features Prenatal detection of hydronephrosis and dilated ureter on antenatal ultrasonography Postnatal presentation ∼ 50% are asymptomatic, with normal renal parameters; Often an incidental finding on ultrasoundSymptoms of urinary tract infectionAbdominal / flank painFeatures of uremia Diagnostics Ultrasound (best initial and confirmatory test)HydronephrosisUreteral dilation > 7 mm Further evaluationVoiding cystourethrography (VCUG): to identify retrograde reflux of urine into the ureters Radionuclide renal scanning : to identify obstruction and evaluate renal function Treatment Primary megaureter Conservative therapyIndicated in children with preserved renal functionProphylactic antibiotics Regular follow-up SurgeryIndicated in children with deteriorating renal functionProcedure: resection of the distal segment of the ureter and re-implantation into the bladder(ureteroneocystostomy) Secondary megaureter Treatment of the underlying disease Complications Urinary tract infections Hydronephrosis Obstructive nephropathy

Renal artery stenosis Renal artery stenosis is the narrowing of one or both renal arteries. It is most commonly caused by atherosclerosis. In young women, fibromuscular dysplasia is an important underlying cause. Decreased renal blood flow due to renal arterystenosis causes activation of the renin-angiotensin-aldosterone system, which in turn results in secondary hypertension. Physical examination may reveal an abdominal bruit. Patients with progressive renal artery stenosis develop renal insufficiency and progressive renal atrophy. Hypokalemia in a newly diagnosed case of hypertension or an abrupt increase in creatinine after initiating ACE inhibitors or angiotensin receptor blockers is suggestive of renal artery stenosis. The diagnosis is confirmed by duplex ultrasonography or angiography. Treatment of mild renal artery stenosis primarily consists of antihypertensive therapy. The antihypertensives of choice are paradoxically ACE inhibitors and angiotensin receptor blockers; calcium channel blockers or beta blockers can also be used. Patients on ACE inhibitors or angiotensin receptor blockers should be closely monitored for an increase in serum creatinine, especially if they have bilateral renal artery stenosis. Patients with severe renal artery stenosis will require renal angioplasty.

Epidemiology Accounts for 1-10% of all hypertension cases. 5-25% of pediatric cases of secondary hypertension cases have a renovascular etiology. Age and sex preponderance depend on the underlying cause (see "Etiology" below). Etiology Atherosclerosis (∼ 90% of cases): occurs more often in men > 50 years of age Fibromuscular dysplasia (∼ 10% of cases): mostly affects women < 50 years of age Pathophysiology Narrowing of one or both renal arteries → obstruction of renal blood flow → ischemia → renin release and activation of the renin-angiotensin-aldosterone system → hyperreninemic hyperaldosteronism → increased sodium retention and peripheral vascular resistance → renovascular hypertension (secondary hypertension) Prolonged renal hypoperfusion → chronic stimulation of the juxtaglomerular apparatus to secrete renin → hyperplasiaof the juxtaglomerular apparatus No improvement in renal blood flow → ischemic renal injury → renal insufficiency and progressive renal atrophy Clinical features Abdominal bruits heard over the flank or epigastrium; present during both systole and diastole Hypertension that is often resistant to therapy Features of renal insufficiency (e.g., nausea, edem Diagnostics Laboratory findings Decreased kidney function (see " Diagnostics" in acute kidney injury) ↑ Serum creatinine > 30% after antihypertensive treatment with ACE inhibitors or angiotensin-receptor blockers is a strong indication of renal artery stenosis. Hypokalemia Imaging (confirmatory test) Indications [12][13]Onset of hypertension before the age of 30 years or after 55 yearsNew onset renal dysfunction or worsening of renal function with ACEi or ARBsUnexplained renal atrophy or asymmetry of > 1.5 cm between kidneysHypertension that is resistant to a 3-drug antihypertensive regimen Imaging modality [12][14][13]First-line: non-invasive imaging Duplex ultrasonographyORCT or MR angiographySecond-line: invasive catheter angiography FindingsTubular stenosis of the proximal renal artery segment → typically atherosclerotic diseaseStenosis of the distal renal artery segment with a "string-of-beads" appearance → typically fibromuscular dysplasia[4][5]Significant renal artery stenosis: > 60% reduction in the diameter of the renal arteryIncreased systolic flow velocity in the renal artery (Duplex) Decrease in kidney size Treatment Patients with atherosclerosis: reduce risk factors by statin therapy and lifestyle modification Antihypertensive therapy: ACE inhibitors, angiotensin receptor blockers, calcium channel blocker, beta blockers [12] Closely monitor serum creatinine especially in patients with bilateral renal artery stenosis. ACE inhibitor or ARB treatment should be terminated if rapid and/or severe worsening of kidney function occurs. Revascularization procedures [12][16]Indications> 60% unilateral stenosis with any of the following: Patients with heart failure who have recurrent acute decompensationsUnexplained acute pulmonary edemaUnstable anginaFailure of, or intolerance to antihypertensive treatmentAccelerated hypertensionSingle functioning kidney> 60% bilateral stenosisProgressive renal insufficiencyProceduresFirst-line: percutaneous transluminal renal angioplastyAtherosclerotic disease: with stentingFibromuscular dysplasia: typically without stentingSecond-line: aortorenal bypass surgery

Fibromuscular dysplasia Fibromuscular dysplasia (FMD), a disease that primarily affects young to middle-aged women, is characterized by the proliferation of connective tissue and muscle fibers within the arterial vessel walls. The resulting stenosis impairs perfusion of the affected organ, causing ischemia. The symptoms of fibromuscular dysplasia vary depending on the site and the degree of stenosis of FMD. The renal, internal carotid, and vertebral arteries are predominantly involved. Carotid and vertebral artery involvement may present with transient ischemic attack (TIA) and/or stroke, while patients with renal FMD usually present with secondary hypertension and chronic renal insufficiency. Bruits at the costovertebral angle and the carotid region are characteristic findings of renal and carotid artery involvement respectively. In rare cases, patients may present with mesenteric ischemia and/or peripheral artery disease as a result of splanchnic or peripheral arterial involvement. The "string of beads" sign, a characteristic finding on angiography, distinguishes FMD from other causes of arterial occlusion. All patients with renal FMD should be treated with ACE inhibitors and/or ARBs, while those with carotid artery involvement should be placed on stroke prophylaxis (low-dose aspirin therapy). Balloon angioplastywithout stenting is the definitive treatment.

Epidemiology Age of onset: typically 30-50 years, but can manifest at any age Sex: ♀ > ♂ (8:1)Among children: ♀ ≈ ♂ Ethnicity: increased prevalence among the white population Pathophysiology Fibromuscular dysplasia (FMD) is an idiopathic, non-inflammatory, non-atherosclerotic, developmental condition that primarily affects small and medium-sized muscular arteries. Histopathology The most commonly encountered histology is medial fibroplasia. Pathophysiology FMD results in ischemia by one or more of the following mechanisms: StenosisFormation of saccular aneurysms → aneurysmal ruptureArterial dissection → arterial occlusionFormation of intravascular thrombi → embolization Renal artery stenosis → ↓ renal perfusion → compensatory activation of the renin-angiotensin-aldosterone system → secondary hypertension Disease localization Renal artery (renal FMD; ∼ 75-80% of cases)Usually bilateral renal artery stenosisSecond most common cause of renal artery stenosis after atherosclerosis.Accounts for 30-50% of cases of renal artery stenosis among children and 5-10% of cases among adults. Carotid and vertebral artery involvement (extracranial cerebrovascular FMD; ∼ 65-75% of cases and often bilateral) Clinical features The symptoms of fibromuscular dysplasia are nonspecific and vary depending on the site of FMD, the degree of stenosis, and the underlying pathology (e.g., arterial dissection). Renal FMDClinical features of renal artery stenosisSecondary hypertension Abdominal bruitSymptoms of chronic kidney diseaseFlank or abdominal pain Cerebrovascular FMDHeadache, neck pain, pulsatile tinnitusTIA, amaurosis fugax, stroke, Horner's syndromeCervical bruit Diagnostics ImagingImaging modalities Best initial tests for renal FMD: duplex ultrasonography and/or CT angiography (see "Diagnostics" in renal artery stenosis)Best initial tests for cerebrovascular FMD: CT angiography Gold standard: digital subtraction angiography (DSA) Finding Common finding: "string of beads" sign Less commonly: a single, circumferential/tubular stenotic lesion Laboratory tests: serum creatinine Differential diagnoses AtherosclerosisPatients with atherosclerosis are usually older, male, and have risk factors such as obesity and/or cigarette smoking.On angiography, atherosclerosis affects the proximal segments and ostia of arteries, while FMD affects middle and distal segments of the artery. Vasculitis (e.g., giant cell/temporal arteritis) Treatment Renal artery FMD: see "Therapy" in renal artery stenosis Cerebrovascular FMDAntiplatelet drugs (e.g., aspirin) for stroke prophylaxis is recommended for all patients.Patients who are symptomatic: percutaneous transluminal angioplasty

IgA nephropathy IgA nephropathy (Berger disease) is the most common primary glomerulonephritis worldwide. It most frequently affects males in the second to third decades of life. Clinical manifestations are usually triggered by upper respiratory tract or gastrointestinal infections and include gross hematuria and flank pain. In some cases, it may present as rapidly progressive glomerulonephritis (RPGN). Urinalysis of asymptomatic patients often shows persistent microhematuria and minor proteinuria, while more severe cases may manifest with recurrent episodes of nephritic syndrome. A kidney biopsyis indicated in patients with signs of severe or progressive disease to make a definitive diagnosis. Treatment consists of measures to slow the progression of the disease (e.g., ACE inhibitors) as well as immunosuppressive therapy in more severe cases. Even with the appropriate treatment, up to 50% of patients progress to end-stage renal disease within 20-25 years.

Epidemiology IgA nephropathy is the most common primary glomerulonephritis in adults. Peak incidence: second to third decades of life Sex: ♂ > ♀ (2:1) Ethnicity: more common in the Asian population (worldwide) Pathophysiology The cause is still not entirely understood. Most likely mechanism: an increased number of defective, circulating IgA antibodies are synthesized (often triggered by mucosal infections, i.e., upper respiratory tract and gastrointestinal infections) → IgA antibodies form immune complexes that deposit in the kidney → glomerulonephritis (type III hypersensitivity reaction) [1] Clinical features The course of the disease is highly variable and can manifest in the following forms: Asymptomatic Recurring episodes of:Gross or microscopic hematuriaFlank painLow-grade feverAnd/or nephritic syndrome (including hypertension)Usually during or immediately following a respiratory or gastrointestinal infection [2] Can progress to RPGN and/or nephrotic syndrome (< 10% of patients) Up to 50% of patients progress to end-stage renal disease within 20-25 years. IgA nephropathy and Henoch-Schonlein purpura (HSP) are both IgA-mediated vasculitides triggered by a mucosal infection. HSP most commonly occurs in children < 10 years of age and affects multiple organ systems (palpable purpura, abdominal pain, arthralgia). IgA nephropathy is limited to the kidneys and typically affects adults. Diagnostics Diagnosis is based on clinical presentation and laboratory results. In some cases, renal biopsy may be indicated to confirm the diagnosis. [9] UrinalysisSigns of nephritic sediment, including persistent microhematuria and possibly minor proteinuria Episodic flare-ups of gross hematuria in 50% of patients [3]In rare cases, nephrotic sediment Laboratory testsSerum IgA level is elevated in 50% of patients. [10]Complement levels (e.g., C3 level) are generally normal. [11] Renal biopsy Usually only indicated if there are signs of severe or progressive disease, including: [8]Urinary protein > 0.5-1 g/24 h↑ Serum creatinineHypertensionFindingsLight microscopy: mesangial proliferationImmunofluorescent microscopy: mesangial IgA depositsElectron microscopy: mesangial immune complex deposits The renal manifestation of Henoch-Schönlein purpura is pathologically the same as IgA nephropathy. Differential diagnoses Poststreptococcal glomerulonephritisAssociated with low complement levelsTypically occurs 10-20 days following an infection Lupus nephritis Membranoproliferative glomerulonephritis Treatment Patients with isolated hematuriaRegularly monitor kidney function and initiate treatment if disease progresses (e.g., occurrence of proteinuria).Symptoms resolve spontaneously in 30% of patients. [10] Patients with proteinuria or hypertension : ACE inhibitors/angiotensin II receptor blockers For severe/rapidly progressive disease: glucocorticoids PLUS possibly cyclophosphamide/azathioprine

Polycystic kidney disease Polycystic kidney disease (PKD) is an inherited disorder in which multiple cysts develop in the kidneys. The WHO classification recognizes two distinct disorders: autosomal recessive PKD (ARPKD), which is associated with a short life expectancy that rarely surpasses childhood, and autosomal dominant PKD (ADPKD), which is associated with a reduced life expectancy in adulthood. The severity of symptoms varies significantly depending on the underlying disorder. Onset of ARPKD is usually in infancy or childhood, with patients presenting with pulmonary insufficiency and progressive renal failure. Patients with ADPKD, on the other hand, typically present with flank pain, arterial hypertension, and progressive kidney disease in adulthood. Early diagnosis and treatment may prevent or delay end stage renal disease. Kidney transplantation is the only curative treatment option.

Epidemiology IncidenceADPKD: ∼ 1/1,000; one of the most common inherited kidney diseases in humansARPKD: ∼ 1/20,000 Overview of the WHO classification Autosomal recessive polycystic kidney disease(ARPKD)Inherited: mutation on chromosome 6Bilateral Equally sized cystsObligate hepatic involvementBirth to childhood Autosomal dominant polycystic kidney disease(ADPKD)Inherited: mutation on chromosome 16 (85% of cases) or 4 (15% of cases) with an alteration of polycystin-1 or 2 (the gene products of PKD1 and PKD 2 respectively) [3]BilateralCysts vary in sizeMultiple extrarenal manifestationsAdulthood(typically age > 30 years) Clinical features Autosomal recessive polycystic kidney disease (ARPKD) Chronic renal failure: frequently hematuria, proteinuria Protruding abdomen due to renal enlargement or hepatomegaly Extrarenal manifestationsSevere in-utero renal impairment → maternal oligohydramnios → Potter sequenceCraniofacial abnormalities (retrognathia, low-set ears, flat nose) and clubbed feet Pulmonary hypoplasia → respiratory insufficiency in neonates Obligate liver involvement: portal fibrosis → portal hypertension and progressive liver failureHypertension (unknown cause), which is difficult to control and can result in congestive heart failure Autosomal dominant polycystic kidney disease (ADPKD) Chronic renal failure Flank or abdominal pain Recurrent urinary tract infections Nephrolithiasis Extrarenal manifestationsMultiple hepatic cysts (in up to 70% of cases) ; cysts may also occur in the pancreas, spleen, ovary, and testiclesCardiovascular Signs of arterial hypertension (e.g., morning headaches)Heart valve defects (particularly mitral valve prolapse)Left ventricular hypertrophyColon diverticula, abdominal or inguinal herniasCerebral berry aneurysm (5-20%) Diagnostics Positive family history Physical examination: palpable, bilateral upper abdominal masses that are not tender to touch UltrasoundAutosomal recessive polycystic kidney disease (ARPKD)Enlarged kidneys with multiple cysts bilaterally; diffuse increased echogenicity despite the presence of liquid-filled cysts (anechoic) Hepatic cysts; fibrosisAutosomal dominant polycystic kidney disease (ADPKD) In adults: enlarged kidneys with multiple cysts bilaterally of varying sizes (anechoic masses)In children: evidence of cysts in combination with a positive family historyHepatic, pancreatic, splenic cysts may be visible. Computer tomography (CT) Further diagnostic testsEvaluate and monitor renal function and blood pressure Intravenous pyelogram (IVP) to evaluate the presence of obstructions in the renal pelvis and urinary tract caused by renal cystsLiver biopsy in ambiguous casesGenetic testing: DNA linkage analysis to identify ADPKD1 and ADPKD2 [3] Pathology ARPKD: cystic dilatation of the collecting ducts (other nephron segments are usually not affected) and hepatic fibrosis ADPKD: progressive cystic dilatation of the tubular system; hepatic cysts; gastrointestinal, CNS, and cardiovascular involvement (see also "Symptoms/Clinical findings" above) Differential diagnoses Multicystic dysplastic kidneys Definition: renal dysplasia with multiple cystic dilatation of nephrons during embryonic development Etiology: unclear; sporadic occurrence during embryonic development of the ureter and nephrons (rarely with a positive family history) Clinical featuresOnset: birth to childhoodRarely symptomatic; large cysts might impair urinary output Renal insufficiency is rare. Ultrasound: unilateral (rarely bilateral) cysts of varying size Treatment: See "Therapy" below. Obstructive cystic dysplasia Definition: renal dysplasia and cystic dilatation secondary to fetal obstructions (e.g., ureteral stenosis) in the urinary tract Clinical featuresOnset: birth-childhoodAsymptomatic in mild cases; acute renal failure in severe cases During pregnancy: oligohydramnios Ultrasound: unilateral or bilateral cysts of varying size Treatment: elimination of the obstruction as a curative approach Medullary sponge kidney Definition: calcified cysts originating from the papillary collecting tubules Etiology: congenital, sporadic Clinical featuresUsually asymptomatic; incidental findingHypercalciuriaRecurrent urinary tract infections, nephrolithiasis, and chronic renal insufficiency may occur in the case of bilateral manifestation (∼ 75% of cases). Diagnosis: ultrasound and intravenous pyelogram (IVP) Treatment: prophylactic treatment of nephrolithiasis with thiazide diuretics Renal cysts Definition: solitary or multiple renal cysts Diagnosis: usually benign incidental finding during CT or ultrasound examinationsRound or oval anechoic cysts (black = fluid) and dorsal sound amplification If ultrasound findings are unusual (e.g., internal echoes, poorly delimited or thickened cyst wall), malignant diseases should be considered as a differential diagnosis. TreatmentNot indicated in most casesIndication for surgery: symptomatic cysts (e.g., impaired urinary flow, pain) or risk of further complications Rare complications: ruptured cysts, cyst infection, and compression of adjacent tissue Treatment Prevent or delay progression to end stage renal disease (ESRD)Regular sonographic monitoring and laboratory evaluation of renal functionAvoid nephrotoxic substancesEarly treatment of arterial hypertension: ACE-inhibitors or Angiotensin receptor blockers (ARBS)Early treatment of urinary tract infections Monitor and treat liver failure Genetic counseling Hemodialysis or peritoneal dialysis for ESRD Kidney transplantation is the only curative option (see also end stage renal disease). Prognosis ARPKDNeonates with severe cystic dilatation have a poor life expectancy; rarely survive > 1 month after birth The majority of children who survive infancy have a life expectancy > 15 years; the prognosis depends on the extent of renal and hepatic impairment. ADPKD50% of ADPKD patients have ESRD requiring dialysis by the age of 60. Chronic hypertension and cerebral aneurysms in particular are associated with a poor prognosis.

Renal cell carcinoma Renal cell carcinoma (RCC), which arises from renal tubular epithelium, is the most common cause of renal malignancy in adults. While a fraction of cases of RCC occur in association with hereditary disorders, most cases are sporadic. Important risk factors for RCC include smoking, acquired cystic disease of the kidney, nephrolithiasis, and chronic acetaminophenuse. Clinical features of RCC include hematuria, flank pain, a flank mass, anemia, and weight loss. Patients may also present with paraneoplastic manifestations such as hypercalcemia and hypertension. The most important initial test is a contrast CT of the abdomen. The treatment of choice is surgical resection. RCC is notoriously resistant to classical chemotherapeutic agents. Early stage RCC with tumor growth limited to the kidney has a very good prognosis.

Epidemiology Most common malignancy of the renal parenchyma (85% of renal cancers in adults are RCC) Sex: ♂ > ♀ (∼ 2:1) Age of onset: 60-80 years Etiology Most renal cell carcinomas occur sporadically. However, approx. 4% of renal cell carcinomas are associated with hereditary factors. In both forms, sporadic and hereditary RCCs, structural alterations of the short arm of chromosome 3 (3p) and subsequent alterations of the VHL gene are commonly found. Risk factors for sporadic renal cell carcinoma Smoking Certain pre-existing conditionsAcquired cystic kidney disease as a result of ESRD Renal pelvic stonesObesityHypertensionImmunodeficiencyChronic hepatitis C infectionSickle cell disease Exposure to certain toxinsOccupational exposure to cadmium, asbestos, and/or petroleum by-products such as trichloroethylene (a degreasing agent)Chemotherapeutic agents (e.g., cisplatin) during childhood Chronic analgesic use (especially acetaminophen, and aspirin) Hereditary renal cell carcinomas Von Hippel-Lindau syndrome Hereditary papillary renal cell carcinoma (HPRCC) Tuberous sclerosis Hereditary leiomyomatosis and renal cancer syndrome (HLRCC, Reed's syndrome) Hereditary renal cell carcinomas are autosomal dominant and tend to affect patients at a younger age than sporadic renal cell carcinomas! Pathophysiology Renal cell carcinomas are adenocarcinomas that usually arise from the epithelial cells of the proximal convoluted tubule. Clear cell RCC is the most common histological variant (∼ 80% of all cases). Due to a mutation of the VHL gene on chromosome 3pHistologyPolygonal cells with a clear, glycogen and/or lipid-filled cytoplasm that are arranged as cords or tubules (clear cells)Unifocal, unilateral growth Clear cell RCC∼ 80%Proximal convoluted tubuleMutation of the VHL gene on chromosome 3pPolygonal cells with a clear, glycogen and/or lipid-filled cytoplasm that are arranged as cords or tubules (non-papillary growth)Unifocal, unilateral growth Measured prognosis Papillary(chromophilic) RCC∼ 10%Trisomy 7, trisomy 17, and loss of Y chromosomeCuboidal, low columnar cells that grow in papillary formationsBilateral, multifocal growth may occur.Type 1 papillary RCC: measured prognosis Type 2 papillary RCC: aggressive tumor with a poor prognosis Chromophobic RCC∼ 5%Intercalated cells of the cortical collecting ductHypodiploidyLarge polygonal cells with a prominent cell membrane, eosinophilic cytoplasm, and a perinuclear haloExcellent prognosis Oncocytic RCC∼ 5%UnknownOriginate from oncocytomas Similar to chromophobic RCC except that there is no perinuclear halo and the cells occur as tumor nestsExcellent prognosis Collecting duct carcinoma (Bellini duct carcinoma)∼ 1%Medullary collecting ductUnknownMalignant glandular cells that are arranged as irregular within a fibrous stroma (hobnail pattern)Medullary duct carcinoma: a variant of a collecting duct carcinoma which is associated with sickle cell disease Aggressive tumorwith a poor prognosis Spread of renal cell carcinomaSpread beyond the renal capsule → lymph nodes of the renal hilum → para-aortic nodesGrowth into the renal vein and the inferior vena cava (IVC)Metastatic spread to the lung and bone Clinical features Renal cell carcinomas are asymptomatic in the early stages. Patients become symptomatic when the tumor has reached a large size (usually > 10 cm) and/or if metastases are present. Hematuria is the most common presenting symptom. Anemia (common): pallor, lethargy Dragging/colicky flank pain Potentially palpable renal mass Constitutional symptoms: weight loss , fatigue, night sweats, fever The classical triad of renal cell carcinoma consists of hematuria, flank pain, and a palpable flank mass. However, only 5-10% of patients present with all three components of the triad and > 25% present with one or more atypical symptoms related to paraneoplastic syndromes and/or disseminated disease. Paraneoplastic syndromesHypertension Hypercalcemia Polycythemia , leukemoid reaction Secondary hypercortisolism Stauffer's syndrome: non-metastatic hepatic dysfunction characterized by elevated liver enzymes (esp. alkaline phosphatase) and clotting abnormalities Limbic encephalitis: memory loss, psychosis, depression Reactive amyloidosis Symptoms of local spreadVaricocele Budd-Chiari syndrome: lower limb edema, ascites, hepatic dysfunction Symptoms of metastatic disease Pulmonary metastases: dyspnea, hemoptysisBone metastases: bone pain, pathological fractures T1Tumor is limited to the kidneyTumor size is ≤ 7 cm in greatest dimensionT2Tumor is limited to the kidneyTumor size is > 7 cm in greatest dimensionT3Tumor extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland or beyond the Gerota fasciT4Tumor extends beyond the Gerota fascia (including contiguous extension into the ipsilateral adrenal gland)N0No metastasis in regional lymph node(s)N1Metastasis in regional lymph node(s)M0No distant metastasisM1Distant metastasis Stage IT1; N0Stage IIT2; N0Stage IIIT1 or T2; N1T3; N0 or N1Stage IVT4; Any N2; M0Any T; Any N; M1 Imaging Evaluation of RCCBest initial test: abdominal CT scan with contrast Distorted renal outline and stretched renal calycesRenal lesion(s) with thickened irregular walls, variable enhancement, and calcificationRenal ultrasound : renal lesion(s) with variable echogenicity Evaluation of metastatic diseaseCT/MRI of the thorax: cannonball metastases and/or enlarged mediastinal lymph nodesBone scan is indicated for patients with bone pain and ↑ ALP Laboratory tests Urinalysis: hematuria Hb levels and CBC Hypercalcemia ↑ AST, ALT, and/or ALP BUN/creatinine Percutaneous renal biopsy is generally not recommended. Differential diagnoses Differential diagnoses for renal masses in adults The most common renal tumor in children is a nephroblastoma (Wilm's tumor)! Common differential diagnoses for renal masses in adults include: Malignant massesRenal cell carcinomaUrothelial carcinoma of the renal pelvis (∼ 8% of renal tumors)Metastasis from extrarenal tumorsOther rare primary malignancies: lymphomas, soft tissue sarcomas, carcinoid tumors Benign massesAngiomyolipomaOncocytomaMetanephric adenomaRenal abscessGranulomatous renal disease (e.g., renal tuberculosis, xanthogranulomatous pyelonephritis)Renal cysts (e.g., polycystic kidney disease) Angiomyolipoma Definition: benign renal tumors that arise from perivascular epithelioid cells and consist of blood vessels, smooth muscle, and mature fat cells EpidemiologyMean age of onset: 43 yearsSex: ♀ > ♂ (4:1) EtiologySporadic May be associated with the following syndromes: Tuberous sclerosis (TSC). Sporadic lymphangioleiomyomatosis PathologyClassic angiomyolipomas Epithelioid angiomyolipomas: greater number of epithelioid cells with acidophilic and granular cytoplasm, less fat Clinical featuresMostly asymptomaticLarge angiomyolipomas may present with hematuria, retroperitoneal hemorrhage, and impaired renal function.Symptoms of tuberous sclerosis may be present. DiagnosticsImaging usually provided the diagnosis Abdominal ultrasound: round, well-circumscribed, highly echogenic (similar echogenicity to renal pelvis) renal tumor often located near the renal capsuleAbdominal CT: tumor with macroscopic fat deposits , no calcificationPercutaneous biopsy may be required if imaging is inconclusive Treatment: Surgical resection of the tumor is indicated for angiomyolipomas that measure more than 4 cm in diameter. Oncocytoma Oncocytoma is a benign epithelial tumor. Histologically, an oncocytoma consists of large, acidophilic, mitochondria-richtumor cells (so-called oncocytes) without perinuclear clearing (vs. chromophobic RCC). An oncocytoma is not confined to the kidneys and may develop in the thyroid gland, pancreas, or the pituitary gland. Definition: benign tumor arising from the intercalated tubular cells PathologyMacroscopy: brown tumor with central radial scarMicroscopy: excessive amount of mitochondria → acidophilic, granular cytoplasm TherapySurveillanceIf tumor increases in size → suspicious for malignant transformation in RCC → nephrectomyOften resected in order to exclude RCC Prognosis: Oncocytomas are not invasive, but they may transform into a malignant oncocytic RCC. Treatment Treatment of choice: surgical resection of the tumor via open, robotic, or laparoscopic surgery . Depending on the extent of the tumor (see RCC staging), the following surgical procedures are performed: Stage I: cryoablation, thermal ablation, partial nephrectomy , or simple nephrectomy Stage II-IV: radical nephrectomy Patients who are unfit for surgery should be monitored for tumor growth and may be treated palliatively with: Arterial embolizationExternal beam radiotherapy Immunomodulatory and/or targeted therapyInterferon-α (immunotherapy)Recombinant cytokines (e.g., interleukin-2)Tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, pazopanib) Chemotherapy is not used to treat RCC because RCC is highly resistant to chemotherapeutic agents, with a response rate of only 15-30%! This occurs because tumor cells express MDR-1 (multidrug resistance protein-1). Prognosis The overall prognosis is determined by the anatomic extent of the disease (stage of cancer at diagnosis) and the histopathology of the tumor. Early stage RCC with tumor growth limited to the kidney generally has a good prognosis. Histopathology: Collecting duct carcinomas and RCC with a sarcomatoid appearance on histology are associated with a poor prognosis. Increased awareness and screening (e.g., ultrasound) of high-risk patients in recent years has led to earlier tumor detection and improved the prognosis of RCC!

Poststreptococcal glomerulonephritis Poststreptococcal (or postinfectious) glomerulonephritis (PSGN) refers to acute glomerular inflammation that results from a preceding infection with nephritogenic strains of streptococci. Although most commonly seen in children following group A streptococcal tonsillopharyngitis, skin infections such as impetigo may trigger PSGN as well. Deposition of immune complexes containing the streptococcal antigen within the glomerular basement membrane results in complement activation and subsequent damage to the glomeruli. PSGN typically presents as a nephritic syndrome with hematuria, mild proteinuria, edema, and hypertension. Elevated antistreptolysin O titers (ASO), low complement levels, and elevated creatinine support the diagnosis. In children, close monitoring and supportive therapy facilitate the recovery process. While most children recover fully, the prognosis in adults is typically less favorable.

Epidemiology Mostly affects children (between the ages of 3-12 years) and patients > 60 years of age The incidence has decreased in developed countries due to the systematic use of antibiotics and improved hygienic standards. Etiology Occurs approximately 10-30 days following an acute infectionThe most common cause is a prior infection with group A beta-hemolytic streptococci Infection of the mouth and pharynx (tonsillitis, pharyngitis) Soft tissue infections (erysipelas, impetigo) OsteomyelitisIt occurs less frequently following other bacterial, viral infections, or malaria. Immune complex glomerulonephritis can also manifest during an acute infection (e.g., in endocarditis or soft tissue abscesses)! Pathophysiology Infection with nephritogenic strains of group A beta-hemolytic streptococci → immune complexes containing the streptococcal antigen deposit within the glomerular basement membrane (likely involves molecular mimicry) → complement activation → destruction of the glomeruli → immune complex-mediated glomerulonephritis and nephritic syndrome (see glomerular diseases for more information) Clinical features Approx. 50% of cases remain asymptomatic Nephritic syndromeHematuria: tea- or cola-colored urineHypertension: can lead to headachesEdema; may be associated with dyspnea and neurologic symptoms (e.g., seizures) Oliguria Influenza-like symptoms Flank pain Diagnostics Laboratory testsNormocytic, normochromic anemiaPossibly elevated BUN and creatinine (often transient)↑ Antistreptolysin-O titer (ASO) (particularly following streptococcal infection of the pharynx)↑ Anti-DNase B antibody (ADB) titer (particularly following streptococcal infection of the soft tissue)↓ C3 complement Urinalysis: nephritic sediment (e.g., hematuria and RBC casts, mild proteinuria) Ultrasound: enlarged kidneys Renal biopsy (not performed in most cases) Indication: suspected rapidly progressive glomerulonephritis Findings Light microscopy: glomeruli appear enlarged and hypercellular (infiltration of monocytes and polymorphonuclear cells)Immunofluorescent microscopy: granular deposits (IgG, IgM, C3 complement), which create a "lumpy-bumpy"appearanceElectron microscopy: "humps" = subepithelial immune complexes (between epithelial cells and the glomerular basement membrane) Differential diagnoses IgA nephropathy Thin basement membrane disease See "Etiology" of nephritic syndrome Treatment In most cases the disease is self-limiting and only supportive treatment focused on the complications of volume overload is necessary. Monitor electrolytes, renal function parameters, and blood pressure For edema: low-sodium and low-protein diet, loop diuretics For hypertension: ACE-inhibitors/ARBs, calcium channel blockers (see "Treatment" in the learning card on hypertension) If persisting streptococcal infection: antibiotic therapy (penicillin G benzathine) If severe course/complications: glucocorticoids, temporary need for dialysis Complications Complications are more common in adults: Acute renal failure Rapidly progressive glomerulonephritis Nephrotic syndrome later in the course of the disease Prognosis Recovery usually occurs within 6-8 weeks.In children: restitution of kidney function in > 90% of casesIn some cases, urinalysis may remain abnormal for extended periods. Follow-ups are therefore important! In adults, about 50% of patients suffer from persistently reduced renal function.

Diabetes insipidus Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. Central DI, the most common form of diabetes insipidus, is caused by insufficient levels of circulating antidiuretic hormone (ADH); nephrogenic DI, however, is characterized by defective renal ADH receptors in the kidneys. Patients with DI excrete large quantities of diluted urine (polyuria), which causes excessive thirst (polydipsia) in response to fluid loss. Additionally, patients develop the need to urinate at night (nocturia), leading to sleep deprivation and daytime sleepiness. Desmopressin, a synthetic ADH analog, is the treatment of choice in central DI. In nephrogenic DI, hereditary forms are treated with thiazide diuretics or NSAIDs, while acquired forms are first managed by treating the underlying disease.

Epidemiology Prevalence in the US: 3:100,000 Sex: ♀=♂ Etiology Central diabetes insipidus (CDI); most common form: caused by insufficient or absent hypothalamic synthesis or secretion of antidiuretic hormone (ADH) from the posterior pituitaryPrimary (∼ ⅓ of cases)Most cases are idiopathic. The hereditary form is rare. Autoimmune etiology of primary CDI has been suggested [2][3]Secondary (∼ ⅔ of cases)Brain tumors (especially craniopharyngioma) and cerebral metastasis (most common: lung cancer and leukemia/lymphoma) Neurosurgery: usually after the removal of large adenomasTraumatic brain injury, pituitary bleeding, subarachnoid hemorrhagePituitary ischemia (e.g., Sheehan syndrome, ischemic stroke)Infection (e.g., meningitis) Nephrogenic diabetes insipidus (NDI); rare: caused by defective ADH receptors in the distal tubules and collecting ductsHereditary (mutation in ADH receptor; very rare) AcquiredAdverse effect of medications (lithium, demeclocycline) Hypokalemia, hypercalcemia Renal disease (e.g., autosomal dominant polycystic kidney disease, renal amyloidosis)Pregnancy Pathophysiology ADH enables the integration of aquaporins into the plasma membrane of collecting duct cells → reabsorption of free water Either ↓ ADH (central DI) or defective renal ADH receptors (nephrogenic DI) → impaired ability of the kidneys to concentrate urine (hypotonic collecting ducts) → dilute urine (low urine osmolarity) Urine osmolality changesNormal: 500-800 mOsmol/kgComplete DI (< 300 mOsmol/kg, often < 100 mOsmol/kg)Partial DI (300-500 mOsmol/kg) Hyperosmotic volume contraction [12]Loss of fluid with urine → increased extracellular fluid osmolarity → passage of fluid from the intracellular to the extracellular space → equalization of the osmolarities of the extracellular and intracellular fluidDue to the loss of fluid, the osmolarities of intracellular and extracellular compartments are now higher (hyperosmotic) than the initial values.The fluid volume is redistributed between the two compartments to equalize the osmolarities and remains lower than the initial values in each of them (volume contraction) Note that in central DI, ADH levels are decreased, while in nephrogenic DI, they are normal or increased to compensate for the high urine output. Clinical features Polyuria with dilute urine Nocturia → restless sleep, daytime sleepiness Polydipsia (excessive thirst) In cases of low water intake → severe dehydration (altered mental status, lethargy, seizures, coma) and hypotension In the absence of nocturia, diabetes insipidus is very unlikely! Diagnostics Approach If DI is suspected, sodium, plasma osmolality, and urine osmolality values are tested (see expected lab values in the table below). A water deprivation test then allows DI to be differentiated from primary polydipsia. The patient's response to the administration of desmopressin, furthermore, distinguishes CDI from NDI. If CDI is diagnosed, a CT scan or MRI of the head should be conducted to rule out brain tumors (especially craniopharyngioma). Water deprivation test (confirmatory test) After obtaining baseline lab values, patients stop drinking water for 2-3 hours before the first measurement After 2-3 hours without drinking water Test urine volume and osmolality every hourTest sodium and plasma osmolality every two hours Water deprivation continues until one of the following occurs: Urine osmolality rises and reaches a normal value (> 600 mOsmol/kg) → DI ruled out and primary polydipsiaconfirmedNo change in urine osmolality despite a rising plasma osmolality (> 290 mOsmol/kg)Plasma osmolality > 295-300 mOsmol/kg or sodium ≥ 145 meq/L In the latter two situations → administer desmopressin (a synthetic ADH analog)Monitor urine osmolality testing every 30 minutes for 2 hoursIn CDI: Urine osmolality rises after desmopressin administration (renal ADH receptors are intact).In NDI: Urine osmolality remains low after desmopressin administration (defective renal ADH receptors). Primary polydipsia (psychogenic polydipsia) Sodium Hyponatremia (< 137 meq/L) ADHlevelsNormal or decreased Plasma osmolalityLow-normal (255-280 mOsmol/kg) UrineosmolalityVery low (< 250 mOsmol/kg) Water deprivation test resultsPlasma osmolality: does not raise above normal level (275-290 mOsmol/kg) Urine osmolality: rises, reaches normal value (> 600 mOsmol/kg) Desmopressin administration resultsWater deprivation test results confirm diagnosis; no need to administer desmopressin Central diabetes insipidus Mild hypernatremia (> 150 mEq/L) ADH Decreased Plasma osm High-normal or slightly elevated (280-290 mOsmol/kg) Urine Osm Low Partial DI: 300-500 mOsmol/kgComplete DI: < 300 mOsmol/kg Urine specific gravity < 1.006 Water Dep Plasma osmolality: rises (> 290 mOsmol/kg) Urine osmolality: remains low Desmopressin Plasma osmolality: normalizes (275-290 mOsmol/kg) Urine osmolality risesIn partial CDI: ∼ 10%In complete CDI: by > 50% Nephrogenic diabetes insipidus Mild hypernatremia (> 150 mEq/L) ADH Increased Plasma osm High-normal or slightly elevated (280-290 mOsmol/kg) Urine Oms Low Partial DI: 300-500 mOsmol/kgComplete DI: < 300 mOsmol/kg Urine specific gravity < 1.006 Water Dep Plasma osmolality: rises (> 290 mOsmol/kg) Urine osmolality: remains low Desmopressin Plasma osmolalityremains elevated Urine osmolalityremains lowIn partial NDI: ∼ 10%In complete NDI: no change Differential diagnoses Primary polydipsia Diabetes mellitus Beer potomania: Dilutional hyponatremia secondary to limited renal free water excretion caused by intake of large amounts of beer. Treatment Treat the underlying condition, ensure sufficient fluid intake, and initiate a low-sodium, low-protein diet. Central diabetes insipidusDesmopressin: synthetic vasopressin without vasoconstrictive effects Administration: intranasal, subcutaneous, or oralImportant side effect: hyponatremia (→ see syndrome of inappropriate antidiuretic hormone secretion)Other indications besides central diabetes insipidus include:Hemophilia AVon Willebrand diseaseSleep enuresisAlternative medication: chlorpropamide Nephrogenic diabetes insipidusDiscontinuation of the causative agent (e.g., lithium, demeclocycline) in medication-induced NDIThiazide diuretics NSAIDs (e.g., indomethacin) Amiloride : Indicated in patients with lithium-induced NDI; amiloride blocks lithium entry through the sodium channel.

Thin basement membrane nephropathy Thin basement membrane nephropathy is a primary glomerulonephritis caused by abnormalities of type IV collagen and thinning of the glomerular basement membrane. Patients typically present with episodes of intermittent gross hematuriaand flank pain, often triggered by upper respiratory tract (URT) infections or exercise. Urinalysis shows persistent microhematuria and sometimes proteinuria. Kidney biopsy is required for diagnosis, showing diffuse thinning of the glomerular basement membrane. While the disease generally has an excellent prognosis and often does not require treatment, patients with proteinuria should be treated with ACE inhibitors to slow progression.

Epidemiology Prevalence: 5-9% Etiology Hereditary (usually autosomal dominant) or sporadic Pathophysiology Abnormalities of type IV collagen cause thinning of the glomerular basement membrane → transient ruptures of glomerular capillary wall → hematuria Clinical features Usually asymptomatic Episodic gross hematuria, possibly in combination with flank pain may occur, typically following an upper respiratory tract infection or exercise. Other symptoms of nephritic syndrome (e.g., hypertension) can occur (especially in adults). Very rarely progresses to end-stage renal disease Diagnostics Diagnosis is usually assumed in patients based on the presentatation and a family history of benign hematuria. Renal biopsy is reserved for cases in which signs of progression (e.g., proteinuria, hyperkalemia) occur or if the family history is unclear. UrinalysisUsually only persistent microhematuriaPossible episodic gross hematuria, potentially associated with hypercalciuria and hyperuricosuriaMinor proteinuria is possible, especially in adults Renal biopsy Light microscopy: no abnormalitiesElectron microscopy: diffuse thinning of the glomerular basement membrane Treatment Isolated hematuria does not require treatment. ACE inhibitors/AT-II antagonists in patients with proteinuria > 500-1000 mg/day

Retroperitoneal fibrosis Retroperitoneal fibrosis (RPF, Ormond's disease) is a rare disease of unknown etiology, characterized by inflammation and fibrosis of the retroperitoneum resulting in compression and encasement of the ureter, and/or the retroperitoneal blood vessels. RPF may be primary/idiopathic (most common) or secondary (e.g., drug-induced, inflammatory, iatrogenic). Patients often present with non-specific symptoms (e.g., fever, malaise, weight loss, flank pain, etc.). Bilateral ureteral obstruction, with subsequent hydronephrosis and obstructive nephropathy, is common. Diagnosis is often suspected in patients who present with bilateral hydronephrosis of unknown etiology. Contrast CT is the diagnostic test of choice and reveals a retroperitoneal mass encasing and obstructing the ureters and/or the aorta and IVC. Diagnosis is confirmed on CT-guided biopsy of the mass. High-dose glucocorticoids are the mainstay of treatment of primary RPF. Secondary RPF is managed by treating the underlying cause (stopping the offending drug, treating the infection, etc.). Symptomatic/severe obstruction of the retroperitoneal structures require treatment (ureteric stenting, ureterolysis, arterial stenting, etc.). Prognosis of non-malignancy-induced RPF is good, but recurrence rates are high (70%).

Epidemiology PrevalenceRare (1 per 200,000-500,000 of the general population) Primary/idiopathic RPF: most common (70% of the cases) Peak age of incidence: 40-60 years Sex: ♂ > ♀ (2:1) Etiology Primary/idiopathic retroperitoneal fibrosis Immune reaction to antigens within aortic atherosclerotic plaques Systemic autoimmune disease: RPF may be a systemic autoimmune disease of large arteries → periaortic inflammation → inflammation and fibrosis in the periaortic region IgG4-related disease (immunoglobulin G4 related disease): characterized by an infiltration of various organs by IgG4-bearing plasma cells which cause inflammation and fibrosis Secondary retroperitoneal fibrosis Drugs: ergot alkaloids (methysergide, ergotamine) ; Dopamine agonists (pergolide, methyldopa), β-blockers, analgesics (phenacetin), hydralazine, etc. Biological agents: infliximab, etanercept, etc. Malignancies: primary retroperitoneal malignancies , Retroperitoneal metastases , carcinoid tumors Infections: mycobacterium tuberculosis, actinomycosis, histoplasmosis Iatrogenic: surgery or radiation therapy to the retroperitoneum Trauma: retroperitoneal hemorrhage Tobacco use Exposure to asbestos Malignancies and exposure to methysergide are the most common causes of secondary RPF! Pathophysiology The etiological factors incite an immune response in the retroperitoneum. → inflammation of the retroperitonealtissue → healing by fibrosis Fibrosis can entrap and obstruct retroperitoneal structures. Clinical features Pain in the lower back/flanks (most common symptom) Constitutional symptoms: fever, anorexia, weight loss, nausea, etc. Specific symptoms Ureters → upper urinary tract obstruction → hydronephrosis and features of chronic renal failure (obstructive nephropathy: uremia, hypertension, etc.) Infrarenal aorta/iliac arteries → chronic mesenteric ischemia, lower limb and gluteal claudication pain, etc. Inferior vena cava/iliac veins →deep vein thrombosis, renal vein thrombosisGonadal vessels → hydrocoele, varicocoele, testicular painLymphatic channels → lymphedema Diagnostics Laboratory testsRaised inflammatory markers: elevated CRP and ESR Renal parameters: blood urea nitrogen, serum creatinine, and serum electrolyte levels Autoantibodies: e.g., ANA (antineutrophilic antibody), ANCA (antineutrophilic cytoplasmic antibody) ImagingContrast-enhanced CT scanInvestigation of choice to diagnose RPFFindings: Para-aortic mass extending from the renal arteries to the common iliac arteries. Encasement and/or compression of the ureters, IVC, and/or aorta May identify malignanciesCT-guided biopsy of the mass MRI and MRA: useful in patients in whom contrast administration is contraindicated Intravenous urography and retrograde pyelography Renal ultrasonography: useful in assessing response to therapy Biopsy: (confirmatory test)CT-guided/laparoscopic biopsy of the retroperitoneal massEarly stage: hypervascular tissue with perivascular lymphocytic infiltrate and lipid-laden macrophagesLate stage: avascular fibrous tissue which is devoid of cells Treatment Medical therapy Primary RPFOral high-dose glucocorticoids: first line therapy with high dose prednisone (1 mg/kg/day for the first month) Tamoxifen: indicated as monotherapy in patients with contraindications to glucocorticoid therapy Immunosuppressants : indicated in glucocorticid-resistant disease Secondary RPFTreatment of the underlying etiology: e.g., discontinue the causative drug, treat chronic infections, treatment of lymphoma, etc.Oral high-dose glucocorticoids: Indicated in symptomatic/severe drug-induced cases of secondary RPF Decompression of obstructed retroperitoneal structures Kidneys and ureters (see treatment of upper urinary tract obstruction) Conservative therapy: Patients with mild hydronephrosis and normal renal parameters: respond well to medical therapy aloneMild hydronephrosis with abnormal renal parameters: cystoscopy-guided ureteric stentingObstructive nephropathy: urgent decompression with percutaneous nephrostomy, followed by surgerySurgical decompression: open/laparoscopic ureterolysis (release of the ureter from fibrotic tissue) Aorta or iliac arteries: see "Revascularization" in peripheral arterial disease IVC or iliac veins: see "Treatment" in deep vein thrombosis Prognosis Prognosis of non-malignancy induced RPF is good, with symptomatic and clinical improvement obvious within a few weeks of initiating therapy. High recurrence rates of idiopathic RPF (70%) Poor prognosis of malignancy-incduced RPF (∼ 6 months)

Alport syndrome Alport syndrome is a genetic disorder that is characterized by glomerulonephritis, often in combination with sensorineural hearing loss and sometimes eye abnormalities. It is caused by a genetic defect of type IV collagen, which is usually inherited in an X-linked pattern and therefore mostly affects boys. Patients typically present with intermittent gross hematuria during infancy. In adolescence, patients classically start to develop more serious signs of chronic kidney disease (e.g., proteinuria), and may experience hearing loss or, in rare cases, vision problems. In milder forms, patients may remain asymptomatic and only require monitoring. In classic Alport syndrome, diagnostic evaluation shows persistent microhematuria on urinalysis and splitting of the glomerular basement membrane on kidney biopsy. The classic form usually leads to end-stage renal disease (ESRD) between the second and third decade of life, and the only definitive treatment is a kidney transplant.

Epidemiology Rare disorder (but it is the most common hereditary nephritis) Age of onset Hematuria may present in infancySevere disease typically presents during adolescence, although some milder forms may have late onset or remain subclinical. Etiology Usually X-linked inheritance (the disease tends to be more severe in males) Autosomal dominant, autosomal recessive, and digenic inheritance is also possible. Pathophysiology Genetic defect of type IV collagen chains (component of the basement membrane of the kidneys, eye, and cochlea) → kidney damage, sensorineural hearing loss, and ocular abnormalities Clinical features Often asymptomatic Initially intermittent gross hematuria As glomerular damage progresses → symptoms of nephritic syndrome and chronic kidney disease (usually leads to ESRD between the ages of 16 and 35) Sensorineural hearing loss (∼ 60% of cases) Ocular findings (lenticonus) (∼ 25% of cases) Patients with Alport syndrome can't pee, can't see, can't hear a bee! Diagnostics Laboratory testsUrinalysis: best initial test, signs of nephritic syndrome (e.g., hematuria, minor proteinuria)BUN and creatinine to assess severity of renal disease Skin biopsy: confirmatory test, absence of collagen type IV alpha-5 chains Kidney biopsy Light microscopy: mesangial cell proliferation and sclerosisElectron microscopy: splitting and alternating thickening and thinning of the glomerular basement membrane("basket-weave appearance")Immunostaining: absence of the type IV collagen alpha-3, alpha-4, and/or alpha-5 chains in the basement membrane Molecular genetic testing: can confirm and distinguish subtypes Patients diagnosed with Alport's should regularly undergo: Audiometry: may detect high-frequency sensorineural hearing lossOphthalmic evaluation: may detect anterior lenticonus, perimacular flecks, or other eye abnormalities Treatment Monitor renal function regularly In patients with proteinuria : ACE inhibitors/angiotensin II receptor blockers As disease progresses to renal failure: see management of chronic kidney disease (e.g., sodium restriction, diuretics) A kidney transplant is the only definitive treatment of Alport syndrome.Complication: Goodpasture disease (anti-GBM antibody disease) can occur due to newly developed collagentype IV antigens following a kidney transplant. Hearing aids in patients with hearing loss Consider surgery in patients with lenticonus

Granulomatosis with polyangiitis Granulomatosis with polyangiitis (GPA, previously known as Wegener's granulomatosis) is a systemic vasculitis that affects both small and medium-sized vessels. Patients typically initially suffer from a limited form that may consist of constitutional symptoms and localized manifestations such as chronic sinusitis, rhinitis, otitis media, ocular conditions, and/or skin lesions. In later stages, more serious manifestations may arise, including pulmonary complications and glomerulonephritis, although the skin, eyes, and heart may also be involved. Diagnosis is based on laboratory testing (positive for PR3-ANCA/c-ANCA), imaging, and biopsy of affected organs, which demonstrate necrotizing granulomatous inflammation. GPA is treated with immunosuppressive drugs, typically consisting of glucocorticoids combined with methotrexate, cyclophosphamide, or rituximab. Relapses are common.

Epidemiology Sex: ♂ = ♀ Peak incidence: 65-74 years Affects white patients disproportionately; African-American patients are rarely affected. Etiology Idiopathic -GPA occurs more often after infections, especially those affecting the respiratory tract. Pathophysiology GPA is a type of ANCA-associated vasculitis The following processes play a key role in the pathophysiology of GPA: Aberrant epigenetic expression of proteinase-3 on the cell membrane of neutrophilsFormation of antibodies against proteinase-3 (PR3-ANCA) Binding of PR3-ANCA to PR3 activates neutrophils → release of neutrophilic inflammatory mediators, formation of neutrophil extracellular traps, complement activation → damage to endothelial cells of small blood vessels Clinical features Constitutional symptoms: fever, night sweats, weight loss, arthralgias ENT involvement(∼ 90% of cases): often the first clinical manifestationChronic rhinitis/sinusitis: nasopharyngeal ulcerations → nasal septum perforation → saddle nose deformity(depression of the nasal dorsum)In some cases, thick, purulent discharge, sometimes containing bloodOral ulcersChronic otitisGingival hyperplasia (strawberry gingivitis) Lower respiratory tract (∼ 95% of cases): potentially life-threateningTreatment-resistant, pneumonia-like symptoms with cough, dyspnea, hemoptysis, wheezing, hoarseness, or pleuritic painClinical features of pulmonary fibrosis, pulmonary hypertension, or pulmonary hemorrhage may occur. Renal involvement (∼ 80% of cases): potentially life-threateningPauci-immune glomerulonephritis (Pauci‑immune indicates that there is little evidence of immune complex/antibody deposits.) → rapidly progressive (crescentic) glomerulonephritis (RPGN), with possible pulmonary-renal syndrome Skin lesions (∼ 45% of cases) Papules, vesicles, ulcersPurpura of the lower extremities Ocular involvement (∼ 45% of cases) Conjunctivitis, episcleritis, retinal vasculitisCorneal ulcerations Cardiac involvement (∼ 33% of cases): potentially life-threateningPericarditis, myocarditisVasculitis of the coronary arteries; may lead to myocardial infarction and death Upper respiratory manifestations (i.e., purulent, sometimes bloody discharge; chronic nasopharyngeal infections; saddle nose deformity) are the most common chief complaints! GPA triad: necrotizing vasculitis of small arteries, upper/lower respiratory tract manifestations, and glomerulonephritis! Diagnostics Laboratory analysisBlood↑ Creatinine and ↑ BUN↑↑ ESR and ↑ CRPEvidence of PR3-ANCA/c-ANCA (anti-proteinase 3): highly sensitive and positive in ∼ 90% of patientsNormocytic normochromic anemia (in ∼ 50% of patients) UrineUrinalysis: microscopic hematuria, proteinuriaUrine sediment: dysmorphic RBC and RBC casts → nephritic sediment ImagingChest x-ray/CT: multiple bilateral cavitating nodular lesions PathologyDiagnosis should be confirmed by biopsy of affected tissueNecrotic, partially granulomatous vasculitis of small and medium-sized vesselsNecrotizing granulomas (intravascular and extravascular)Glomerulonephritis A biopsy is necessary to confirm the diagnosis! Granulomatosis with polyangiitis (GPA) Glomerulonephritis Localized necrotizing vasculitis Upper/lower respiratory tract manifestations with granulomas PR3-ANCA/c-ANCA (anti-proteinase 3) Microscopic polyangiitis Potentially palpable purpura Nasopharyngeal involvement less common No granulomatous inflammation MPO-ANCA/p-ANCA (anti-myeloperoxidase) Treatment Remission induction Mild: No evidence of active glomerulonephritis or other potentially lethal manifestations (e.g., lunghemorrhage, myocarditis) If mild disease → glucocorticoids + methotrexate (MTX) Patients who do not benefit from MTX may be switched to either cyclophosphamide or rituximab.If moderate to severe disease → glucocorticoids + either cyclophosphamide or rituximabPCP prophylaxis in patients receiving cyclophosphamide and corticosteroids: trimethoprim/sulfamethoxazole(TMP/SMX) Glucocorticoids should be tapered gradually as soon as the patient begins responding to the immunosuppressantagent. In the case of concurrent Goodpasture syndrome: plasmapheresis Remission maintenance : immunosuppressive drugs (e.g., azathioprine, rituximab or methotrexate). After remission, immunosuppressants should be continued for at least 18-24 months because of the high rate of relapse. Prognosis Without adequate treatment, the mortality rate is approx. 90% within 2 years. 5-year survival with adequate treatment is approx. 80%.

Nephrolithiasis Nephrolithiasis encompasses the formation of all types of urinary calculi in the kidney, which may deposit along the entire urogenital tract from the renal pelvis to the urethra. Risk factors include low fluid intake, high-sodium, high-purine, and low-potassium diets, which can raise the calcium, uric acid, and oxalate levels in the urine and thereby promote stone formation. Urinary stones are most commonly composed of calcium oxalate. Less common stones are made up of uric acid, struvite (due to infection with urease-producing bacteria), calcium phosphate, or cystine. Nephrolithiasis manifests as sudden onset colicky flank pain that may radiate to the groin, testes, or labia (renal/ureteric colic) and is usually associated with hematuria. Diagnostics include noncontrast spiral CT of the abdomen and pelvis or ultrasound to detect the stone, as well as urinalysis to assess for concomitant urinary tract infection and serum BUN/creatinine to evaluate kidney function. Small uncomplicated stones without concurrent infection or severe dilation of the urinary tract may be managed conservatively with hydration and analgesics to promote spontaneous stone passage. When the spontaneous passage appears unlikely or fails due to the stone's size or location, first-line urological interventions include shock wave lithotripsy, ureterorenoscopy, and, in case of large kidney stones, percutaneous nephrolithotomy. The most important preventive measure is adequate hydration. Collected stones should be sent for chemical analysis because in many cases specific lifestyle guidance, diet changes, and/or initiation of medical treatment (e.g, thiazide diuretics, urine alkalinization) can prevent future stone formation.

Epidemiology Sex: ♂ > ♀ Peak incidence: 30-60 years Risk factorsLow fluid intake, dehydrationPersonal or family historySee "Classification" below. Calcium oxalate stones ∼ 75%HypercalciuriaHyperoxaluriaHypocitraturia↓ Urine pHBiconcave dumbbells or bipyramidal envelopes RadiopacityUrine alkalinization Uric acid stones∼ 10%↓ Urine pHGout, hyperuricemia, and hyperuricosuriaRounded rhomboids or needle-shaped Urine alkalinization Struvite stones∼ 5-10%UTI with urease-producingbacteriaRectangular prisms (coffin lid-appearance) Radiopacity Urine acidification Calcium phosphate stones< 5%HyperparathyroidismType 1 renal tubular acidosisWedge-shaped prisms Radiopacity Urine acidification Cystine stonesCystinuriaHexagon-shaped crystals RadiopacityUrine alkalinization Calcium oxalate stones EtiologyHypercalciuria: presence of elevated calcium levels in the urine HyperoxaluriaIncreased intake of dietary oxalate Increased intestinal absorption of oxalate, e.g., due to fatty acid malabsorption in Crohn disease Vitamin C supplements Ethylene glycol poisoningPyridoxine deficiencyHypocitraturia: decreased level of citrate in the urine Hyperuricosuria: increased urinary excretion of uric acid Specific preventive measuresDietary modification Reduced intake of salt and animal protein Reduced intake of oxalate-rich foods and supplemental vitamin CThiazide diuretics Urine alkalinization Crohn disease leads to increased oxalate absorption via malabsorption of fatty acids, which can ultimately cause nephrolithiasis. Uric acid stones EtiologyPersistently acidic urineGout, hyperuricemia and hyperuricosuria Specific treatment: oral chemolitholysis via urine alkalinization Specific preventive measuresLow-purine dietAllopurinol Uricosuric agents (e.g., probenecid) increase the excretion of uric acid, which can accelerate the formation of stones! Struvite stones (triple phosphate stones/magnesium ammonium phosphate stones) EtiologyUpper UTI with urease-producing bacteria such as Proteus mirabilis, Klebsiella, and Pseudomonas : can form very large stones that fill the entire renal pelvis and calyces (staghorn calculi) Use of indwelling catheter increases risk Specific preventive measuresAntibiotic treatment of urinary tract infectionsUrine acidificationUsually require surgical stone removal Urinary tract infections can cause the formation of struvite stones, but struvite stones also increase the risk of urinary tract infections. It is important to break this vicious cycle! Less common stones Calcium phosphate stonesEtiology HyperparathyroidismType 1 renal tubular acidosisSpecific preventive measures Thiazide diureticsUrine acidification Cystine stonesEtiology: hereditary defect in renal tubular absorption of dibasic amino acids → cystinuriaClinical features: recurrent kidney stones starting in childhoodDiagnosis: can be made using a nitroprusside probe (cyanide nitroprusside test). Specific preventive measures: Urine alkalinization Clinical features Stones usually form in the collecting ducts of the kidneys but may be deposited along the entire urogenital tract from the renal pelvis to the urethra. Their localization and size determine the specific symptoms. Small kidney stones may also be asymptomatic and detected incidentally. Severe unilateral and colicky flank pain (renal colic) Radiates anteriorly to the lower abdomen, groin, labia, testicles, or perineum Paroxysmal or progressively worseningThe area around the kidneys may be tender on percussion (costovertebral angle tenderness) Hematuria Nausea, vomiting, and reduced bowel sounds Dysuria, frequency, and urgency Passage of gravel or a stone Depending on the location of the stone, nephrolithiasis may resemble conditions such as appendicitis or testicular torsion! Diagnostics Initial diagnostic workup includes imaging studies to locate the stone and laboratory tests to determine kidney function and assess for UTI. Laboratory tests↑ WBC: suggests concomitant UTI↑ Serum urea nitrogen and creatinine: suggests acute kidney injuryUrine dipstick and urinalysisGross or microscopic hematuria Pyuria, positive leukocyte esterase, positive nitrites, or bacteriuria (suggests UTI)Urine pH> 7 suggests urea-splitting organisms and struvite stones< 5 indicates uric acid stonesUrine microscopy: may detect crystalsDumbbell-shaped or octahedron-shaped crystals indicate calcium oxalate stones Rhomboid/needle-shaped crystals indicate uric acid stones Rectangular prisms (coffin lid-appearance) indicate struvite stones Urine culture: obtain in patients with clinical or laboratory signs of UTIStraining of urine: enables chemical analysis of stone composition and specific guidance on preventive treatment (see prevention section below)Metabolic evaluation: indicated in recurrent stones formers and high-risk first-time stone formers Serum calcium, phosphorus, uric acid, bicarbonate, PTH, albumin, and alkaline phosphate: to detect metabolic abnormalitiesTwenty-four-hour urine profile: to analyze urine compounds ImagingNonenhanced abdominopelvic CT scan: (gold standard) Demonstrates calculus size, site, density , and degree of obstruction Hydronephrosis: dilatation of the urinary tract proximal to the site of obstructionUltrasound: method of choice for patients in whom radiation exposure should be minimized (e.g., pregnant patients, children, recurrent stone formers) or if a gynecological or abdominal differential diagnosis is likely Kidney, ureter, and bladder (KUB) X-ray X-ray positive (radiopaque): calcium-containing stonesWeakly x-ray positive: struvite stones, cystine stonesX-ray negative (radiolucent): uric acid stonesIntravenous pyelogram (IVP) Noncontrast abdominopelvic CT scan or ultrasound are the tests of choice for diagnosis of nephrolithiasis! Differential diagnoses Causes of acute abdomen (see differential diagnosis of acute abdomen) Causes of hydronephrosis (see upper urinary tract obstruction) Causes of testicular pain (see differential diagnosis of scrotal pain) Urinary tract infection: cystitis or pyelonephritis Treatment Approach considerations Determine if it is a complicated case, including: high-grade or infected hydronephrosis, urosepsis, acute kidney injury, intractable pain, or vomiting Hemodynamically stable patients with uncomplicated stones ≤ 10 mm → a trial of observation with symptomatic treatment to enable spontaneous passage Urological intervention required for:Patients with stones > 10 mmComplicated stonesPaitents who decline conservative treatmentFailure to pass the stone spontaneously after 4-6 weeks For most patients with kidney or ureteral stones ≤ 20 mm, first-line interventional treatments include both ureterorenoscopy and shock wave lithotripsy. For patient with kidney stones > 20 mm, percutaneous nephrolithotomy is preferred. Medical therapy Uncomplicated stones ≤ 10 mm: offer observation with symptomatic treatment and, especially in case of distalureteral stones > 5 mm, medical expulsive therapy Hydration Analgesia (NSAIDs, IV morphine)Medical expulsive therapy: alpha blockers (e.g., tamsulosin) or calcium-channel blockers (e.g., nifedipine)Antibiotics: indicated in case of concomitant UTI Uric acid stones: dissolve with urine alkalinization Urological intervention IndicationsStones > 10 mmComplicated stones, i.e., concomitant high-grade obstruction, urosepsis, impending acute kidney injury, intractable pain vomitingAfter failed medical therapy, relapse, recurrent infection, or if preferred by patient ProceduresUreteral stenting or percutaneous nephrostomy : Surgical decompression in case of severely obstructed or infected pyelon; in those cases, definite stone treatment should be delayed until the infection has resolved.Extracorporeal shock wave lithotripsy (SWL) First-line treatment option for renal stones ≤ 20 mm and ureteral stonesLowest complication rate but often repeated SWL is necessary for patients with residual stone burdenStones have to be clearly visible on x-ray and/or ultrasoundContraindicated in case of untreated UTI, during pregnancy, and in patients with bleeding diathesis; not preferred in morbidly obese patients Ureterorenoscopy (URS) : First-line treatment option for renal stones ≤ 20 mm and ureteral stonesGreatest stone-free ratePercutaneous nephrolithotomy : first-line treatment for renal stones > 20 mmLaparoscopic or open stone removal (pyelolithotomy or ureterolithotomy): only considered in rare cases where other interventional methods have previously failed or are likely to do so (e.g., because of complex staghorn stones) Follow-up imaging is indicated after both conservative and operative treatment to ensure freedom of stones! Complications Recurrent urinary tract infections → risk of pyelonephritis, urosepsis, and perinephric abscess Urinary obstruction → inflammation of the kidney (hydronephrosis ) → permanent glomerular damage if left untreated Acute kidney injury Prognosis Stone size and location determines likelihood of spontaneous passage: Stones ≤ 0.5 cm tend to pass spontaneously, while stones ≥ 1 cm are unlikely to do so, especially if located in the pyelon or proximal ureter. 50% of patients may have a new episode of nephrolithiasis within 10 years. Prevention Sufficient fluid intake (≥ 2.5 L/day) For calcium stones: Reduced consumption of salt and animal protein Reduced consumption of oxalate-rich foods and supplemental vitamin C: for oxalate stones Thiazide diuretics for recurrent calcium-containing stones with idiopathic hypercalciuria (i.e., no hypercalcemia) For uric acid stones or high urinary uric acid levels in those with calcium stones: allopurinol Depending on urinary pH and stone composition: urine alkalinization or acidification (see specific measures in the classification section) Low calcium diets increase the risk of calcium-containing stone formation because they increase oxalate reabsorption!

Syndrome of inappropriate antidiuretic hormone secretion Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is an endocrine disorder caused by increased ADHsecretion in the pituitary gland (e.g., due to infection, drugs), ectopic production of ADH (e.g., small cell lung carcinoma), or enhanced stimulation of ADH in the kidneys as a result of a gene mutation. Hyponatremia develops as a result of increased water retention in the kidneys (not due to sodium deficiency) and systemic fluid overload. SIADH is usually asymptomatic and hyponatremia is often an incidental finding in laboratory results. In mild cases, symptoms include loss of appetite and nausea; in severe cases, seizures and altered consciousness can occur. Treatment depends on the severity of the disease and includes fluid restriction (asymptomatic patients) to hypertonic saline administration (severe cases).

Etiology Increased pituitary ADH secretionDiseases of the central nervous system (e.g., stroke, bleeding, infection, trauma)Pulmonary disease (pneumonia, COPD)Drugs (e.g., chlorpropamide, carbamazepine, cyclophosphamide, selective serotonin reuptake inhibitors)Endocrine disorders (glucocorticoid deficiency)Neurosurgery (especially: transsphenoidal pituitary surgery) Ectopic source of ADH secretion: paraneoplastic (particularly: small cell lung carcinoma) Enhanced stimulation of ADH receptors in the kidney: hereditary (mutation of vasopressin-2 receptor gene) Pathophysiology For more information regarding ADH secretion and regulation, see antidiuretic hormone. ↑ ADH secretion → receptor-mediated signaling cascade in the distal convoluted tubules and the collecting ducts of the kidneys → build-up of additional water canals (aquaporin-2) in the luminal cell membrane Water is drawn out of the urine and into the hyperosmolar kidney tissue → concentrates the urine and ↑ urine osmolality Water retention → ↓ serum osmolality → Euvolemic hyponatremia Osmotic fluid shifts → Cerebral edema and ↑ intracranial pressure Clinical features Symptoms of hyponatremia (see: "Sodium imbalance") Mild: anorexia, nausea, vomiting, headache, muscle crampsModerate: muscle weakness, lethargy, confusionSevere: seizures, altered consciousness Normotensive Symptoms of the underlying condition Diagnostics Blood↓ serum osmolality (< 280 mOsm/kg H2O) and ↓ sodium (< 135 mmol/L)Normal renal function (based on creatinine)Normal adrenal function (based on ACTH stimulation test)Normal thyroid function (based on thyroid hormones: TSH, T4, T3)Plasma ADH normal to elevatedFrequently ↓ uric acid values UrineUrine osmolality > 100 mOsm/kg H2O Urinary sodium excretion > 20 mmol/L SIADH patients are usually euvolemic, normotensive, and have no edema. An hyponatremic patient with edema should raise suspicion of other conditions (e.g. congestive heart failure). A high urine osmolality of > 300 mOsm/kg H2O is often cited, but SIADH is already possible at > 100 mOsm/kg H2O. Differential diagnoses See hyponatremia. Treatment Treatment of the underlying condition Asymptomatic patientsFluid restriction!Increased salt intake Symptomatic patientsHypertonic saline administration with ICU monitoring to impede osmotic demyelination syndromeIf severe: consider adding a loop diuretic (e.g., furosemide) to hypertonic saline Most effective if urine osmolality is > 2x the serum osmolality (typically urine osmolality > 500 mOsmol/kg)If initial measures fail, consider demeclocycline or vasopressin antagonists (vaptans): IV conivaptan and PO tolvaptan The sodium serum levels may increase by a maximum of 10 mmol/L within 24 hours or 0.5 mmol/L per hour. A rapid increase in serum sodium can lead to osmotic demyelination syndrome!

Dehydration Dehydration (exsiccosis) is a state of decreased total body water. This decrease in total body water occurs in excess of sodium (also called "free water loss"), resulting in a hypertonic and hypernatremic state. The terms "hypotonic" and "isotonic" are sometimes incorrectly used to describe dehydration, but these terms are only associated with hypovolemiaand hypovolemic shock. Dehydration most often affects children and the elderly. Treatment of dehydration involves correcting the free water deficit.

Etiology Insufficient water intake, particularly in elderly individuals and the critically ill Increased free water lossRenal loss: diuretics, hyperglycemia, polyuric phase of renal failure, diabetes insipidusExtrarenal loss: diarrhea , vomiting, burns, increased sweating, fever, inflammation, ascites See also hypovolemic hypernatremia and euvolemic hypernatremia. Clinical features Thirst Dry skin and mucous membranes Headache, dizziness, disorientation Weakness, fatigue, hemodynamic instability Dark circles around the eyes and frequent blinking (reduced tear fluid quantity) Children: no tears when crying Infants: sunken fontanelle, restlessness/lethargy Clinical featureMild dehydrationModerate dehydrationSevere dehydrationDecrease in body weight < 3%3-9%> 9%SymptomsMental statusAlertRestless, irritableLethargic, confusedThirst Slightly increasedThirsty; drinks eagerlyRefuses to drink Urine output Normal↓ (dark concentrated urine)↓↓Signs specific to dehydration EyesNormalSlightly sunkenSignificantly sunkenTears (especially children)NormalDecreasedAbsentTongueMoistDryParchedSkin turgor Instant recoilRecoil within 2 secondsRecoil after 2 seconds; significant skin tentingIn infants: anterior fontanelle NormalSlightly sunkenSignificantly sunkenSigns of hypovolemia and hypovolemic shock Pulse rateNormalMildly tachycardicInitially tachycardia → later bradycardia Blood pressureNormalNormal; postural hypotensionmay be presentHypotensionCapillary refill timeNormal (< 2 seconds)2-3 seconds> 3 secondsExtremitiesWarmCoolMottledBreathingNormalTachypneaTachypnea with deep breathing (Kussmaul breathing) Diagnostics Serum sodium: Hypernatremia Serum sodium levels can be used to determine the amount of free fluid needed to correct dehydration (see treatment of hypernatremia). ↑ Hematocrit ↓ Serum bicarbonate levels BUN to serum creatinine ratio > 20:1 → renal hypoperfusion due to hypovolemia Urine osmolality: See sodium imbalance for more information. < 800 mOmol/L → renal free water loss> 800 mOmol/L → extrarenal free water loss Blood glucose levels Hypoglycemia → decreased fluid intake as a possible cause of dehydrationHyperglycemia → osmotic diuresis as a possible cause of dehydration Treatment Patient who are hypovolemic as a result of severe dehydration require immediate fluid resuscitation with crystalloid solutions. Fluid resuscitationSevere hypovolemiaChildren: rapid infusion of 20 mL/kg of isotonic saline → reassess → repeat as neededAdults: rapid infusion of isotonic crystalloid → reassess → repeat as neededModerate hypovolemiaChildren: consider oral hydration therapy or 10 mL/kg of isotonic saline → reassess → repeat as needed Correction of electrolyte abnormalities Sodium imbalance should only be addressed once the patient is adequately resuscitated. Hypernatremia → Once volume resuscitated, free water deficit can be used to determine further management (see correct free water deficit). Hyponatremia → Once volume resuscitated, monitor closely, and consider hypotonic fluids to avoid rapid overcorrection (see sodium disorders). Complications Hypovolemic shock → prerenal renal failure Increased risk of infection, particularly of the urinary tract Thrombosis Osmotic demyelination syndrome Patients with diabetes mellitus: Dehydration can trigger diabetic ketoacidosis.

Acute kidney injury Acute kidney injury (AKI) is a sudden loss of renal function with a consecutive rise in creatinine and blood urea nitrogen(BUN). It is most frequently caused by decreased renal perfusion (prerenal) but may also be due to direct damage to the kidneys (intrarenal or intrinsic) or inadequate urine drainage (postrenal). In AKI, acid-base homeostasis, as well as the fluid and electrolyte balance, is disturbed, and the excretion of substances, including drugs, within the urine is impaired. The main symptom of AKI is oliguria or anuria; in some cases, polyuria may occur as a result of disturbed tubular reabsorption. Diagnosis of AKI requires an increase in serum creatinine concentration and/or decrease in urine output. Specific investigations are guided by the suspected cause. Rapid evaluation, diagnosis, and treatment are necessary to prevent irreversible loss of renal function.

Etiology Prerenal (∼ 60% of cases) Any condition leading to decreased renal perfusion HypovolemiaVolume depletion: e.g., hemorrhage, vomiting, diarrhea, sweating, burns, diuretics, poor oral intake, acute pancreatitisDecreased circulating volume: e.g., hepatorenal syndrome, cirrhosis, nephrotic syndrome, congestive heart failure Hypotension: e.g., sepsis, dehydration, cardiogenic shock, anaphylactic shock Renal artery stenosis Drugs affecting glomerular perfusion: e.g., cyclosporine, tacrolimus, NSAIDs , ACE inhibitors Avoid co-administering ACE inhibitors and NSAIDs in patients with reduced renal perfusion (e.g., congestive heart failure, renal artery stenosis) because doing so can significantly decrease the glomerular filtration rate (GFR)! Intrinsic (∼ 35% of cases) Any disease causing severe direct kidney damage Acute tubular necrosis (causes ∼ 85% of intrinsic AKIs) Glomerulonephritis (e.g., rapidly progressive glomerulonephritis) VascularHemolytic uremic syndrome (HUS)Thrombotic thrombocytopenic purpura (TTP)Malignant hypertensionVasculitis Tubulointerstitial nephritisDrug-inducedInfectiousImmunological Prolonged prerenal failure leads to intrinsic failure because decreased renal perfusion causes tubular necrosis! Postrenal (∼ 5% of cases) Postrenal causes include any condition that results in obstruction of urinary flow from the renal pelvis to the urethra. Congenital malformations Acquired obstructions: benign prostatic hyperplasia (BPH), iatrogenic/catheter-associated tumors, stones, bleeding Neurogenic bladder (e.g., multiple sclerosis, spinal cord lesions, or peripheral neuropathy) As long as the contralateral kidney remains intact, patients with unilateral ureteral obstruction typically maintain normal serum creatinine levels. Pathophysiology Prerenal Decreased blood supply to kidneys (due to hypovolemia, hypotension, or renal vasoconstriction) → failure of renal vascular autoregulation to maintain renal perfusion → decreased GFR → activation of renin-angiotensin system → increased aldosterone release → increased reabsorption of Na+ and H2O → increased urine osmolality → secretion of antidiuretic hormone → increased reabsorption of H2O and urea Creatinine is still secreted in the proximal tubules, so the blood BUN:creatinine ratio increases. Intrinsic Damage to a vascular or tubular component of the nephron → necrosis or apoptosis of tubular cells → decreased reabsorption capacity of electrolytes, water, and/or urea (depending on the location of injury along the tubular system) Na+ has multiple reabsorption sites, so its reabsorption is often impaired, which leads to increased Na+ in the urineand increased urine osmolality. Acute tubular necrosis: necrotic debris obstructs tubules → decreased GFR → sequence of pathophysiological events similar to prerenal failure Postrenal Renal obstruction (e.g., stones, BPH, neoplasia, congenital anomalies) → increased retrograde hydrostatic pressurewithin tubuli → decreased GFR and compression of the renal vasculature → acidosis, fluid overload, and increased BUN, Na+, and K+. A normal GFR can be maintained if the other kidney's function is normal. Phases of AKI Kidney injury Symptoms of the underlying illness causing AKI may be present. Hours to days Oliguric or anuricphase Progressive deterioration of kidney function Reduced urine production (oliguria), < 50 ml/24 hrs = anuriaIncreased retention of urea and creatinine (azotemia) Complications: fluid retention (pulmonary edema), hyperkalemia, metabolic acidosis, uremia, lethargy, asterixis Generally < 2 weeks Polyuric phase Glomerular filtration returns to normal, which increases urine production (polyuria), while tubular reabsorption remains disturbed. Complications: loss of electrolytes and water (dehydration, hyponatremia, and hypokalemia) ∼ 3 weeks Recovery phase Kidney function and urine production normalize. Up to 2 years Clinical features May be asymptomatic. Oliguria or anuria Signs of volume depletion (in prerenal AKI caused by volume loss) Orthostatic or frank hypotension and tachycardiaReduced skin turgor Signs of fluid overload EdemaShortness of breath Signs of renal obstruction (in postrenal AKI) Distended bladderIncomplete voidingPain over the bladder or flanks Fatigue, confusion, and lethargy In severe cases: seizures or coma Affected individuals have a higher risk of secondary infection throughout all phases (most common reason for fatalities). Subtypes and variants Acute tubular necrosis Causes ∼ 85% of intrinsic AKIs LocationThe straight segment of the proximal tubule and the straight segment of the distal tubule (i.e., the thick ascending limb) are particularly susceptible to ischemic damage.The convoluted segment of the proximal tubule is particularly susceptible to damage from toxins. EtiologyIschemicProlonged hypovolemia/shockThromboembolismThrombotic microangiopathyCholesterol embolism (atheroemboli)ToxicContrast-induced nephropathyMedication: aminoglycosides, cisplatin, amphotericinPigment nephropathyMyoglobinuria due to rhabdomyolysis (crush syndrome)Hemoglobinuria associated with hemolysisAcute uric acid nephropathy Clinical features: same as for AKI (See "Clinical features" above.) Blood findings: azotemia, hyperkalemia, and metabolic acidosis Urinary sediment: muddy brown granular casts, epithelial cell casts, free renal tubular epithelial cells (due to denudation of the tubular basement membrane) Management: see "Treatment" section below. Prognosis: After 1-3 weeks, most patients with ATN will experience tubular re-epithelization and full recovery. Contrast-induced nephropathy Definition: AKI after IV administration of iodinated contrast medium Risk factorsChronic kidney disease (CKD): esp. in patients with diabetes mellitus, multiple myelomaCongestive heart failure, arterial hypotensionNephrotoxic drugs: esp. NSAIDsAnemiaDehydration Clinical features/diagnostics: See "Clinical features" above and "Diagnostics" below. CourseCreatinine is highest after 3-5 days after injury and usually falls back to the baseline level within 1 week.The course is typically mild because end-stage renal disease usually only occurs in patients with pre-existing CKD. PreventionAlways evaluate kidney function before administering a contrast agent.Use a low dose and low concentration of contrast medium.The patient should discontinue nephrotoxic substances before administration.Ensure hydration: isotonic NaCl before and after administration of contrast mediumAcetylcysteine (no clear recommendations .) Diagnostics Approach [11][12] The diagnosis of AKI requires an acute increase in serum creatinine and/or decrease in urine output (see the criteria for different stages in the table below); therefore, renal function tests should be done in every patient with suspected AKI Additional laboratory investigations and imaging should be guided by the suspected cause. Stages of AKI by Kidney Disease Improving Global Outcomes (KDIGO, 2012)StageSerum creatinineUrine output1Increase of 0.3 mg/dL (within 48 h) or1.5-1.9 times baseline (within 7 days)< 0.5 mL/kg/h for 6-12 h22-2.9 times baseline< 0.5 ml/kg/h for ≥12 h3≥ 3 times baseline orIncrease to ≥ 4 mg/dL orInitiation of renal replacement therapy orPatients < 18 years: decrease in eGFR to < 35mL/min/1.73m2< 0.3 mL/kg/h for ≥ 24 h orAnuria for ≥ 1 Prerenal Blood test findingsElevated serum creatinine concentrationSerum BUN:creatinine ratio > 20:1 Urine test findingsNormal urinalysisLow urine sodium concentration (< 20 mEq/L)Low fractional excretion of sodium (FeNa < 1%)The fractional excretion of sodium reveals how much filtered sodium is excreted in the urine.FENa= (V*UNa)/(GFR*PNa), using plasma and urine sodium concentrations (PNa and UNa), urine flow rate (V), and GFR orFENa= (SCr*UNa)/(SNa*UCr), using serum sodium (SNa), urine sodium (UNa), serum creatinine (SCr), and urinecreatinine (UCr).High urine osmolality (> 500 mosm/kg) and specific gravity (> 1.010)Hyaline casts due to hypovolemia resulting in concentrated urine: hyaline casts are a nonspecific finding that may also be seen in healthy individuals Intrinsic Blood test findingsElevated serum creatinine concentration and rapidly rising serum creatinine levelBUN:creatinine ratio < 15:1.Markedly elevated serum CPK level (10,000-100,000) in rhabdomyolysisHyperkalemia, metabolic acidosis, hyperphosphatemia, hypocalcemia, and hyperuricemia might be seen. Urine test findingsRenal tubular epithelial cells or granular, muddy brown, or pigmented castsUrine dipstick is positive for blood but negative for RBCs in rhabdomyolysis Biopsy: in suspected rapidly progressive glomerulonephritis Postrenal Blood test findingsElevated serum creatinine concentration in bilateral obstructionBUN:creatinine ratio varies. Urine test findingsNormal urinalysis (neurogenic bladder)Hematuria (stones, bladder cancer, clots) Imaging: high post-void residual volume and bilateral hydronephrosis on renal ultrasound or noncontrast CT scan Comparison of diagnostic findings in different types of AKI PrerenalIntrinsicPostrenalBUN/Cr ratio> 20:1< 15:1VariesFractional excretion of sodium< 1%> 2%Urine sodium concentration (mEq/L)< 20> 40Urine osmolality (mOsm/kg)> 500< 350< 350Urine sedimentsHyaline castsMuddy brown or granular casts (ATN)RBC casts (glomerulonephritis)Fatty casts (nephrotic syndrome)Absent Treatment General measuresTreat the underlying cause.Patient should discontinue nephrotoxic substance use.Adjust dosages of medications cleared by the kidney (e.g., amiodarone, digoxin, cyclosporin, tacrolimus, antibiotics, chemotherapeutic agents).Monitor and manage changes in pH, water, and electrolyte balance.Assess uremic signs and symptoms (e.g., anorexia, nausea, vomiting, metallic taste, altered mental status) dailyPerform dialysis if necessary. (See indications for acute dialysis.) PrerenalReplete volume with normal saline in patients with hypovolemiaAdminister diuretics in patients with hypervolemia who are hemodynamically stable and not anuric IntrinsicReplete volume with normal saline in suspected ATN or contrast-induced renal dysfunctionConsider corticosteroid or immunosuppressive therapy in RPGN or interstitial nephritis.Treat infection. Postrenal: Remove outflow obstructions with Foley catheter insertion, an indwelling bladder catheter, nephrostomy, or stenting. The longer the underlying cause, the greater the chance that AKI progresses to renal failure. Treat early! Consequences of renal failure (MAD HUNGER): Metabolic Acidosis, Dyslipidemia, High potassium, Uremia, Na+/H2O retention, Growth retardation, Erythropoietin failure (anemia), Renal osteodystrophy.

Rapidly progressive glomerulonephritis Rapidly progressive glomerulonephritis (RPGN) is an inflammatory disease of the kidneys characterized by rapid destruction of the renal glomeruli that often leads to end-stage renal disease. There are three different pathophysiological mechanisms that can result in RPGN: anti-glomerular basement membrane antibody disease (Goodpasture syndrome), immune complex glomerulonephritis (e.g., lupus nephritis), and glomerulonephritis associated with vasculitis (e.g., granulomatosis with polyangiitis). Patients may present with mild symptoms such as flank pain, edema, and decreased urine output. Laboratory tests show a sudden rise in serum BUN and creatinine as well as RBC casts and dysmorphic red blood cells on urinalysis. If the patient presents with hemoptysis, pulmonary-renal syndrome should be suspected. RPGN requires rapid diagnosis and immediate initiation of immunosuppressive therapy to prevent irreversible kidney damage.

Etiology Type I: anti-glomerular basement membrane antibody disease (Goodpasture syndrome) Type II: immune complex-mediated glomerulonephritisIgA nephropathy, membranoproliferative nephropathy, Henoch-Schönlein purpura (HSP)Lupus nephritisPoststreptococcal glomerulonephritis (PSGN) Type III: glomerulonephritis associated with vasculitis (pauci-immune GN, ANCA-associated)Granulomatosis with polyangiitis (Wegener granulomatosis)Microscopic polyangiitisEosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome, EGPA) Pathophysiology Breaks in the glomerular capillary wall and dysfunction of the glomerular basement membrane (GBM) → leakage of plasma proteins (e.g., coagulation factors) and passage of inflammatory cells (macrophages, T cells) into Bowman space → release of inflammatory cytokines → damage to the membrane of Bowman space → passage of cells from the interstitiuminto Bowman space → formation of fibrin clot and proliferation of cells (e.g., macrophages, fibroblasts, neutrophils, epithelial cells) → crescent moon formation → compression of the glomerulus → renal dysfunction Clinical features Nephritic syndrome Decrease in urine output within days to weeks → possibly anuria Fatigue Pulmonary symptoms (e.g., hemoptysis) may occur; see differential diagnosis of pulmonary-renal syndromes Characteristics of RPGNLaboratory findingsRapid rise of BUN and creatinine↑ Inflammatory markersNephritic sedimentMicrohematuria (acanthocytes, RBC casts)Non-selective glomerular proteinuria PyuriaBiopsy findings: The primary finding is a "crescent-moon shape": an extracapillary cell proliferation that displaces the glomerulusAnti-GBM disease Anti-glomerular basement membrane antibodies Biopsy: linear IgG deposits along the glomerular basal membrane Immune complex-mediated glomerulonephritis ↓ C3 complement Lupus nephritis: anti-dsDNA antibodies Poststreptococcal GN: ASO or ADB "Humps" seen on biopsy: antigen-antibody complexes between the capillary endothelium and the basal membrane Glomerulonephritis associated with vasculitis (pauci-immune GN) Granulomatosis with polyangiitis: c-ANCA Microscopic polyangiitis: p-ANCA Biopsy: few immunologic findings If serum creatinine rises rapidly due to renal damage, always suspect RPGN and initiate testing immediately. If urinalysis shows nephritic sediment, a renal biopsy is vital for quick diagnosis and initiation of appropriate treatment! Differential diagnosis of pulmonary-renal syndromes Goodpasture syndrome Auto-antibodies against collagentype IV in the renal and pulmonary capillary basement membrane Possibly triggered by viral infections, lymphomaHemoptysis, cough, dyspnea Anti-GBM antibodies Granulomatosis with polyangiitis (Wegener) Granulomatous vasculitisHistory of chronic sinusitis, nasal ulcers, perforation of the nasal septum c-ANCA Churg-Strausssyndrome Granulomatous vasculitis Palpable purpura Peripheral neuropathy Asthma, rhinitis p-ANCA Peripheral eosinophilia Microscopic polyangiitisNecrotizing vasculitis(no granulomas) Mild respiratory symptoms Palpable purpura p-ANCA Systemic lupus erythematosus CTD Pleuritis Malar rash Joint pain Anemia Anti-dsDNAantibodies Low complement Elevated renal function parameters and hemoptysis are a red flag for RPGN! Treatment Glucocorticoids and cyclophosphamide In the event of Goodpasture syndrome: plasmapheresis in addition to immunosuppression RPGN due to ANCA-associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis): combination therapy with glucocorticoids and rituximab is an effective alternative If therapy is initiated early: full recovery of renal function in > 50% of cases Without proper treatment, the prognosis is unfavorable: rapid progression to end-stage renal disease (requires renal replacement therapy) and high mortality

Disorders of potassium balance Potassium disorders may take the form of hyperkalemia (high serum potassium) or hypokalemia (low serum potassium). The most common cause of hyperkalemia is decreased kidney function. It may also be caused by endocrinological disturbances (e.g., hypoaldosteronism, hypocortisolism) or drugs such as potassium-sparing diuretics, angiotensin-converting enzyme (ACE) inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), and digoxin. Low serum potassium levels, on the other hand, can be caused by gastrointestinal losses (e.g., due to vomiting, diarrhea) or drugs such as non-potassium-sparing diuretics and laxatives. To determine the cause of a potassium disorder, it is essential to review the patient's medications and test for aldosterone and cortisol disturbances. Acute changes in serum potassium are very dangerous, as they influence the resting membrane potential and thus the electrical excitability of cells. These changes can lead to malignant cardiac arrhythmias. The management of hypokalemia and hyperkalemia includes dietary changes, medications, and, in the case of hyperkalemia, dialysis. The potassium serum concentration should be monitored closely until it is corrected. NOTES

Hyperkalemia Definition Serum potassium level > 5 mEq/L [1] Etiology Potassium excessReduced excretion: acute and chronic kidney disease [2]Endocrine causes: hypocortisolism, hypoaldosteronism Drugs: potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers, NSAIDs, and trimethoprim-sulfamethoxazole [3]GI absorption: increased intake of high-potassium foods (e.g., fresh fruits, dried fruits and legumes, vegetables, nuts, seeds, bran products, milk, and dairy products)Type IV renal tubular acidosisRelease from cells: myolysis, tumor lysis, hemolysis Extracellular shiftAcidosis → ↑ extracellular H+ → inhibition of the Na+/H+ antiporter → ↓ intracellular Na+ → ↓ sodium gradient inhibits the Na+/K+-ATPase → ↑ extracellular K+ concentrationHyperkalemia → ↑ extracellular K+ concentration → ↑ potassium gradient stimulates the Na+/K+-ATPase →↑ extracellular Na+ → ↑ sodium gradient stimulates the Na+/H+ antiporter → ↑ extracellular H+ → acidosisException: In renal tubular acidosis, findings include hypokalemia and metabolic acidosis.HyperosmolalityInsulin deficiency (manifests with hyperglycemia) Release from cells: rhabdomyolysis, tumor lysis syndrome, hemolysisDrugs Beta-blockers Succinylcholine: (esp. when given with preexisting burns and/or muscle trauma) ,Digoxin: inhibits the Na+/K+-ATPase → ↑ extracellular K+ concentration Pseudohyperkalemia: due to the release of potassium from red blood cell lysisBlood drawn from the side of IV infusion or a central line without previous flushingProlonged use of a tourniquetFist clenching during blood withdrawalDelayed sample analysis K+ acts like H+: Hyperkalemia leads to acidosis and vice versa! Errors in blood-drawing technique may lead to red blood cell lysis and a falsely elevated serum potassium concentration (pseudohyperkalemia)! When K+ shifts out of the cell, it's a BAD LOSS! - Beta-blockers, Acidosis, Digoxin, Lysis, hyperOsmolality, high Sugar, Succinylcholine Pathophysiology Potassium is an important factor in maintaining the resting membrane potential ↑ Extracellular K+concentration → ↓ resting membrane potential (less negative than -90 mV) → ↑ excitability Particularly acute extracellular changes in concentration influence excitability! Chronic changes lead to intracellular compensation! Clinical features Symptoms usually occur if serum potassium levels are > 7.0 mEq/L or they change rapidly. Cardiac arrhythmias (e.g., atrioventricular block, ventricular fibrillation) Muscle weakness, paralysis, paresthesia ↓ Deep tendon reflexes Nausea, vomiting, diarrhea Hyperkalemia (and hypokalemia) can cause cardiac arrhythmia and lead to ventricular fibrillation! Diagnostics Laboratory evaluationSerum potassium levels (always confirm abnormal serum potassium levels with a repeat blood draw)Creatinine, GFR to assess renal functionIn normal renal function: aldosterone level to rule out Addison diseaseArterial blood gas (ABG): influence of pH on the potassium homeostasisMetabolic acidosis: hyperkalemiaMetabolic alkalosis: hypokalemia ECG changesP-wave flattening, lengthening of the PR intervalLengthening of the QRS interval (wide QRS complex)Shortened QT intervalTall, peaked T waves Treatment Potassium level ≤ 6.5 mEq/L and no signs of cardiotoxicity: decrease intake/absorption (slow-acting option)Discontinue drugs that increase serum potassiumAvoid high-potassium foodsCation-exchange resins (e.g., sodium polystyrene sulfonate): bind potassium in the gut via the exchange of Na+ for K+Adverse effect (rare): intestinal necrosisLoop diuretics: promote excretion of potassium and lower total body potassium storesIntravenous, non potassium containing fluids: normal saline, dextrose 5% in water Potassium level > 6.5 mEq/L or cardiotoxicity: IV therapy for cardioprotection and to induce elimination/intracellular shift (rapid-acting option) Calcium gluconate: should be administered first! Insulin, preferably short-acting insulin, in combination with glucose Sodium bicarbonate: in acidemic patients Beta-2-adrenergic agonists Forced diuresis (loop diuretics with normal saline solution) Renal failure or ineffective initial treatmentHemodialysis: most effective and definitive treatment option Hypokalemia Definition Serum potassium level < 3.5 mEq/L [11] Etiology Potassium lossRenal lossEndocrine causes: hyperaldosteronism, hypercortisolism Drugs: diuretics, glucocorticoids, licorice (aldosterone-like action)Hypomagnesemia (1) Since magnesium serves as a cofactor in Na+/K+-ATPases, hypomagnesemia disrupts the Na+/K+-ATPasein the basolateral membrane of the cells of the proximal convoluted tubule and loop of Henle, leading to decreased Na+ reabsorption. This causes increased luminal sodium that, distally, leads to increased sodium reabsorption and potassium secretion by the principal cell; and(2) Apical ROMK channels in principal cells are inhibited by intracellular magnesium. With low levels of magnesium available, the ROMK channels are not inhibited, so K+ secretion increases. Type I and II renal tubular acidosisGastrointestinal loss: vomiting, diarrhea, laxatives (e.g., in bowel preparation prior to medical procedures) Intracellular shiftAlkalosis → ↓ extracellular H+ → stimulation of the Na+/H+ antiporter (transfers H+ out of the cells in exchange for Na+) → ↑ intracellular Na+ → ↑ sodium gradient stimulates the Na+/K+-ATPase (transfers K+ into the cells in exchange for Na+) → ↓ extracellular K+ concentrationHypokalemia → ↓ extracellular K+ concentration → ↓ potassium gradient inhibits the Na+/K+-ATPase → ↓ extracellular Na+ → ↓ sodium gradient inhibits the Na+/H+ antiporter → ↓ extracellular H+ → alkalosisException: In renal tubular, acidosis findings include hypokalemia and metabolic acidosis!HypoosmolalityDrugs Insulin: stimulation of the Na+/K+-ATPase pump, which moves potassium into the cell. Beta-2-adrenergic agonists: beta-2 receptor-mediated stimulation of the Na+/K+-ATPase pump Hypomagnesemia can lead to refractory hypokalemia! K+ acts like H+: Hyperkalemia leads to acidosis and vice versa! Potassium follows glucose INto the cells because of INsulin! Pathophysiology Potassium is an important factor in maintaining the resting membrane potential ↓ Extracellular K+ concentration → ↑ resting membrane potential (more negative than -90 mV) → ↓ excitability Particularly acute extracellular changes in concentration influence excitability! Chronic changes lead to intracellular compensation! Clinical features Symptoms usually occur if serum potassium levels are < 3.0 mEq/L or they change rapidly. Cardiac arrhythmias (e.g., premature atrial and ventricular complexes, ventricular fibrillation) Muscle weakness, paralysis Muscle cramps and spasms ↓ Deep tendon reflexes Nausea, vomiting, constipation Fatigue Polyuria In patients treated with digoxin: symptoms of digoxin toxicity Hypokalemia (and hyperkalemia) can cause cardiac arrhythmia and may lead to ventricular fibrillation! References:[6][14] Diagnostics Laboratory evaluationSerum potassium levels (always confirm abnormal serum potassium levels with a repeat blood draw)Urinary potassium level > 20 mEq/L: renal loss< 20 mEq/L: extrarenal lossArterial blood gas (ABG): influence of pH on the potassium homeostasisMetabolic alkalosis: hypokalemiaMetabolic acidosis: hyperkalemia ECG changesPresence of U waves: small waveform following the T wave that is often absent and becomes more pronounced in the context of hypokalemia or bradycardiaPossibly TU fusion; premature atrial and ventricular complexesST depressionT-wave flattening To remember that low potassium may result in a flattened T wave, recall: "No pot, no tea (T)!" References:[6][11] Differential diagnoses of hypokalemia Causes [15]GI lossesChronic diarrhea Villous adenoma of the colonBentonite ingestion Renal lossesHypomagnesemiaPrimary hyperaldosteronismCushing syndromeType 1 RTAType 2 RTAFanconi syndromeRenin-secreting tumorsCongenital adrenal hyperplasiaBartter syndromeGitelman syndromeLiddle syndromeIntracellular shiftIncreased glycogenesis (e.g., due to TPN)Increased insulinInsulin useRefeeding syndromeInsulinomaIncreased sympathetic tone Sympathomimetic usePheochromocytomaAlcohol withdrawalAcute myocardial infarctionHead traumaFamilial periodic paralysisThyrotoxicosisAlkalosisHypothermiaMedicationsDiuretics Thiazide diureticsLoop diureticsOsmotic diureticsLaxativesInsulinBeta-2 adrenergic receptor agonists (e.g., albuterol, terbutaline)CatecholaminesAntibiotics (e.g., penicillins, aminoglycosides, clindamycin)Antifungals (e.g., amphotericin B, azoles)Theophylline Treatment Treat the underlying cause or adjust an existing treatment; correct possible hypomagnesemiaIf diuretic-induced (e.g., loop or thiazide diuretics): Discontinue the diuretic or reduce the dose and combine with potassium-sparing diuretic spironolactone, ACE inhibitors, or beta blockers.Rehydrate with normal saline in the case of volume depletion and contraction alkalosis. Repletion Intake of high-potassium foodsPotassium chloride (KCl) Preferred route of administration: oralIn severe hypokalemia (< 2.5 mEq/L): IVOral or IV Magnesium for patients with hypomagnesemiaSee also Potassium repletion IV potassium may cause local irritation and lead to cardiac arrhythmias. Therefore, it should always be administered slowly (max. rate of 10 mEq/hour)! Periodic paralysis Definition Periodic paralyses comprises a group of muscle diseases that are characterized by weakness (proximal, symmetric, flaccid paralysis) with a simultaneous drop or rise in potassium levels. Etiology Mode of inheritance: autosomal-dominant inheritance with complete penetrance Pathophysiology Symptoms are triggered by hypo- or hyperkalemia: Hypokalemia: change in membrane permeability to potassium → extracellular potassium deficiency and intracellular sodium deficiency → refractory muscle tissueHyperkalemia: defect in sodium channels → sodium channels remain open → membrane repolarization is impaired Periodic paralysis may be associated with hyperkalemia or hypokalemia. Hyperkalemic periodic paralysis Hyperkalemic periodic paralysis is caused by a genetic defect affecting the voltage-gated sodium channel. Hypokalemic periodic paralysis Hypokalemic periodic paralysis may be caused by a genetic defect affecting one or all of the following three ion channels: Calcium channel (most common defect; 70% of cases) Voltage-gated sodium channel (less common) Inward rectifier potassium channel (rare defect) Clinical features Hypokalemic periodic paralysis Proximal, symmetric, flaccid paralysis and areflexia; Symptoms appear early in the morning hours and in the evening. Paralysis may last for hours to days and may involve respiratory muscles. Triggers: a carbohydrate-rich meal, a rise in insulin levels , hyperthyroidism Hyperkalemic periodic paralysis Hyperkalemic periodic paralysis is generally less severe than the hypokalemic form; respiratory muscles are spared while facial and pharyngeal muscles are often involved. Paralysis may last for minutes to hours Triggers: small fluctuations in potassium levels, exposure to cold, physical exertion Diagnostics Neurological examination: flaccid paralysis, areflexia EMG: low-amplitude muscle potentials EKG: U-wave in the case of hypokalemia, peaked T-wave in the case of hyperkalemia Laboratory findings: serum potassium levels < 3.5 mmol/L (hypokalemia) or > 5.5 mmol/L (hyperkalemia) Treatment During a spell of periodic paralysis: Hypokalemic periodic paralysis: potassium chloride, acetazolamide (an episode of hypokalemic periodic paralysis can be lethal!)Hyperkalemic periodic paralysis: calcium gluconate

Renal transplantation

Indication: patients with end-stage kidney disease (CKD 5) Technique: heterotopic implantation in the iliac fossa connecting donor ureter to recipient bladder ComplicationsAcute tubular necrosisGraft rejectionPost-transplant infectionVascular Early: renal artery thrombosis, renal vein thrombosis Late: renal artery stenosisUrological Urinary leakUrinary tract obstruction Lymphocele Calcineurin-induced nephrotoxicity Post-transplant carePost-transplant immunosuppressive therapyPrevention of post-transplant infectionsSerial monitoring of renal function testsDiagnostic algorithm in the case of renal dysfunction following renal transplantation Consider pre-renal causes of acute renal failure. Hypotension or normotensive patient → measure BUN:creatinine ratio to rule out dehydrationHypertension is present → consider renal artery stenosis → perform a doppler USGMeasure urine protein and perform a dipstick urine test for hematuria. Hematuria or proteinuria are present: Perform a renal biopsy directly.Hematuria and proteinuria are not present: If the patient is not on anticalcineurins → perform a renal biopsyIf the patient is on anticalcineurins → measure serum anticalcineurin levels ↑ Anticalcineurin levels: reduce anticalcineurin levels and remeasure creatinine↔︎ Anticalcineurin levels (i.e., within the target range): perform renal and bladder ultrasound to rule out obstruction If evidence of obstruction is present: perform renal scintigraphy↓ Anticalcineurin levels: perform a renal biopsy Prognosis: graft functions for approx. 14 years, longer if received from a living donor Renal transplantation is superior to dialysis in end-stage renal disease (ESRD)!

Renal replacement therapy Renal replacement therapy is indicated when the kidney transiently or persistently loses its function to remove toxins, metabolites, and water from the body. It is also used in certain cases of poisoning/overdose when the kidney cannot clear the toxin fast enough. There are three main modalities used to replace the renal function: dialysis (either hemodialysis or peritoneal dialysis), hemofiltration, and kidney transplant (see "Renal transplantation" in transplantation). Dialysis is based on the diffusion of molecules across a semipermeable membrane, which separates blood on one side and the dialysate on the other. Hemofiltration is based upon the principles of filtration and convection, (as opposed to diffusion) and mimics the function of the glomerular system. An ultrafiltrate is excreted, and the replacement of electrolytes with a specific solution is essential. Kidney transplantation is indicated for patients with end-stage renal disease (ESRD). In those cases, it is associated with a greater long-term survival rate and a better quality of life than dialysis.

Indications Metabolic acidosis of pH < 7.1 Refractory hyperkalemia, hypercalcemia Toxic substances (e.g., lithium, toxic alcohols) Refractory fluid overload Signs of uremia, including pericarditis, encephalopathy, and asterixis on exam Mnemonic for indications for dialysis: A-E-I-O-U → Acidosis, Electrolyte abnormalities (hyperkalemia), Ingestion (of toxins), Overload (fluid), Uremic symptoms Hemodialysis and hemofiltration Preparation Large-bore venous catheter: insertion and catheter are similar to a central venous catheter Arteriovenous fistula: anastomosis of an artery and a vein as a safe, large-bore vascular access Preferred location: radiocephalic fistula (Cimino fistula; anastomosis between radial artery and cephalic vein in the distal forearm)Should be provided early to ensure availability when needed Usually constructed in the nondominant arm (less impairment)Indication: maintenance dialysis in chronic kidney disease Procedure/application HemodialysisMolecules diffuse across a semipermeable membrane down their concentration gradient and are removed from the blood.Superior at removing low-weight molecules (e.g., urea, protein-bound drugs, ammonia)Requires either a catheter (short-term option) or the creation and maturation of a fistula (long-term option)Common in the United States HemofiltrationMolecules are filtered out by a semipermeable membrane, whereas fluid passes through freely and re-enters the body (as "ultrafiltrate").Superior at removing middle-weight molecules (e.g., TNF, IL-8, IL-6)Replacement fluid is required because significant amounts of fluid are wasted in this process ("effluent").More common in Europe than the United States Complications Arteriovenous fistulasLocal: thrombosis, stenosis, aneurysm, infectionSystemic: steal syndrome , heart failure Hypotension Bleeding Rarely: amyloidosis, allergic reactions to the equipment Dialysis disequilibrium syndromePathophysiology: Because of the (rapid) extraction of osmotically active substances (e.g., urea, NaCl) during dialysis, patients (especially when they start on dialysis for the first time) can develop acute cerebral edema.Symptoms Nausea, vomitingDisorientation, seizuresPrevention: regular and slow hemodialysis Cardiovascular disease is the leading cause of death in dialysis patients and in kidney transplant recipients. Peritoneal dialysis Preparation A catheter is surgically placed into the peritoneal cavity. Procedure/application Similar to hemodialysis, but utilizes the patient's own peritoneal membrane as the semipermeable membrane Can be done at home (as opposed to a dialysis center) Preferred for highly adherent patients because of the potential complications which can occur if maintained incorrectly (see "Complications" below). Complications InfectionsExit-site infections and catheter tunnel infections Bacterial peritonitis Metabolic disturbances

Hypertensive Nephropathy

Kidneys Hypertensive nephrosclerosis Pathophysiology: chronic hypertension → narrowing of afferent arterioles and efferent arterioles → reduction of glomerular blood flow → glomerular and tubular ischemia → arteriolonephrosclerosis and fibrosis (focal segmental glomerulosclerosis) → end-stage renal disease Typical findingsInitially microalbuminuria and microhematuriaWith disease progression, nephrosclerosis with macroalbuminuria (usually < 1 g/day) and progressive renal failure occur.Biopsy: sclerosis in capillary tufts, arterial hyalinosis

Diagnostic evaluation of the kidney and urinary tract Diseases of the kidney and the urinary tract can present with a wide array of symptoms. In addition to flank or groin pain, referred pain may occur in other regions of the body, which can make diagnosis difficult. Therefore, acute abdominal painrequires consideration of the kidneys and urinary tract. Most chronic renal diseases are asymptomatic and are only detected through abnormal findings on urinalysis (erythrocytes, protein) or pathological changes of renal function parameters (increased serum creatinine, blood urea nitrogen). An ultrasound can be used for a quick evaluation of the kidney and urinary tract and is critical in diagnosing urinary tract obstructions and urinary retention.

Physical examination Changes in micturition (amount, appearance, discomfort) Flank painColicky pain with radiation to the groin or genitals is more commonly seen in urolithiasis.Persistent pain in inflammatory diseases Costovertebral angle tenderness (CVAT) Hematuria Hypertension: extrarenal manifestations that may indicate kidney injury Edema : See proteinuria. Acute appendicitis should be differentiated from right-sided renal colic! Appendicitis often presents with nausea, fever, and pain at McBurney's point! Terminology Quantity of urinePolyuria: urine output > 3 L/day in adultsOliguria: urine output < 500 mL/day Anuria: urine output < 50 mL/day Quality of urineIsosthenuria: loss of the ability to concentrate or dilute urine → urine osmolality approaching that of plasmaGlycosuria: glucose in the urineProteinuria: > 150 mg protein/day in the urineLeukocyturia/pyuria: white blood cells in the urine, sometimes with visible cloudinessBacteriuria: ≥ 105 organisms/mL organisms (in midstream collection)Hematuria (see below) Hemoglobinuria: hemoglobin in the urineMyoglobinuria: myoglobin in the urine GlycosuriaDiabetes mellitusBacteriuriaUrinary tract infectionHematuria in the first or last part of micturitionUrethral damagePersistent hematuriaVesical or supravesical originPainless hematuriaMalignancyHemoglobinuriaSevere intravascular hemolysisMyoglobinuriaRhabdomyolysisPolyuriaDiabetes mellitus, diabetes insipidus, drinking excessive amounts of water Urinalysis Gross urine assessmentTurbidity (how cloudy the urine is) Urine color Urine dipstickpH (urine pH usually ranges from 4.5-8)Specific gravity : Large molecules such as glucose or radiocontrast media may increase the urine specific gravitydespite a normal urine osmolality.Heme: > 90% sensitivity for hematuria; however, always confirm with microscopy for the presence of RBCs, as a dipstick cannot differentiate between hematuria, hemoglobinuria, or myoglobinuria! Leukocytes esterase: enzyme produced by WBC that indicates a UTIProtein (albumin) Glucose, ketones, urobilinogenNitrites Urine sedimentCellsErythrocytesLeukocytesAcanthocytes Urinary castsTubular structures formed in the distal convoluted tubule and collecting duct of the kidneysHyaline casts: nonspecific finding; can also be found in healthy individuals, often after exercise Structure: consist of a mucoprotein matrix of Tamm-Horsfall proteins Microscopy: homogeneous, transparent, and eosinophilicGranular casts: caused by degeneration of cells in RBC or WBC castsIndicate stasis in the nephronSeen in tubulointerstitial disease (glomerulonephritis, pyelonephritis, acute tubular necrosis) Structure: composed of a hyaline matrix with cellular debrisMicroscopy: usually bigger than hyaline casts; the droplets are refractiveWaxy casts: represent further degeneration of granular castsIndicate renal stasis and severe renal diseasenonspecific and may be seen in both acute and chronic kidney diseasesStructure: degenerating granular castMicroscopy: homogenous, sharp indentations; edges that appear more distinct and darker in colorRenal tubular epithelial cell casts: indication of glomerulonephritis or interstitial nephritis; can occasionally be found in healthy individuals Structure: consist of congregated tubular epithelial cellsMicroscopy: tubular casts; can contain multiple layers of cells; sometimes hard to differentiate from WBC castsWhite blood cell casts: strong indication of pyelonephritis; however, can also be seen in glomerulonephritisor interstitial nephritis Structure: accumulated white blood cells contained within a protein matrixMicroscopy: Casts usually have sharp margins and the central nuclei are seen. They can be hard to differentiate from renal tubular epithelial cell casts.Red blood cells casts: indication of glomerulonephritisStructure: accumulated RBCs in a mucoprotein matricMicroscopy: Cluster of biconcave shaped RBCs with darkly-staining hemoglobinBroad casts: usually seen with advanced chronic kidney disease; formed in dilated tubules with low flow Glomerular hematuria Red, smoky brown, "Coca-Cola" RBC morphologyDysmorphic Proteinuria> 500 mg/day Nonglomerular hematuria Red or pink urine no rbccasts, < 500 mg/day protien Blood values Urinary metabolitesSerum creatinine: used as an indirect indicator of the glomerular filtration rate Serum creatinine levels do not start rising until the GFR is reduced by at least 50% → If the GFR is > 60 mL/min, serum creatinine cannot be used to assess kidney function = "creatinine-blind" range! Additional interfering factors: Falsely elevated values: high-protein diet, high muscle mass, rigorous exercise Falsely decreased values: low muscle mass Blood urea nitrogen (BUN): metabolite of ammonia and proteins (also elevated in catabolic states)BUN/creatinine ratio≥ 20:1: Prerenal cause; urea reabsorption is increased. Typical for dehydration or hypoperfusion.≤ 10:1: Intrarenal cause; renal damage causes decreased urea reabsorption.10:1-20:1: Normal or postrenal cause. Uric acid: metabolite of purine bases Serum cystatin C : a more precise indicator of the glomerular filtration rate, though the analysis is more complex and expensive. Not routinely ordered. Creatinine clearance: equates approximately to the glomerular filtration rate (GFR) A more precise evaluation of creatinine clearance requires measuring creatinine in the urine over a 24-hour period (urine creatinine concentration x urine volume over 24 hours).Creatinine clearance or GFR can be estimated using the Cockcroft-Gault equation. Equation: CCr (mL/min) = ((140-age) x lean body weight(kg)) / (72 x serum creatinine (mg/dL))For women, the result should be multiplied by 0.85. Glomerular filtration rate (GFR): volume of primary urine that is filtrated by the kidneys over a certain amount of time per standardized body surface area (1.73 m2) Normal GFR: ≥ 90 mL/min/1.73m2 is considered normal.GFR is ∼ 120 mL/min/1.73m2 in young adults, decreases with age, and varies considerably between males and females. After the age of 29, a physiological decrease in the GFR of about 10 mL/min/1.73m2 occurs every ten years.The GFR can be estimated using the Cockcroft-Gault equation.Creatinine clearance approximates GFR but slightly overestimates it because of minimal creatinine secretion at the proximal tubule. Other parameters that should be evaluated in renal disease (particularly in chronic renal failure) are Na+, K+, Ca2+, phosphate, vitamin D, and parathyroid hormone (PTH). Autoantibodies (particularly antinuclear antibodies as an indication of glomerulonephritis) Renal biopsy Indications Evaluation of glomerulonephritis with no apparent underlying disease Suspected lupus nephritis or rapidly progressive glomerulonephritis Evaluation of renal transplant rejection Contraindications Anatomic abnormalities: abnormal position of the kidneys, atrophic kidneys, vascular malformations in the kidneyregion Coagulation disorders (thrombocytopenia, disorders of the platelet function, bleeding diathesis) Uncontrolled hypertension Infection of the kidneys Renal tumor Solitary kidney (relative contraindication) Hematuria Diagnostics Physical examInitial hematuria typically suggests a urethral cause.Terminal hematuria suggests damage to the bladder, prostate, or trigonal area.Total hematuria suggests damage in the kidneys or ureter.Microhematuria: hematuria that is not grossly visible Macrohematuria: hematuria that is grossly visible (see also red urine) Urinalysis: > 3 erythrocytes/HPF or > 5 erythrocytes/ μLIf normal → evaluate for coagulation disorders, kidney stones, and malignancy (see bladder cancer) If pyuria → urine culture (see urinary tract infection)If RBC casts and proteinuria → evaluate for glomerular diseases Differential diagnosis Nephritic syndrome Infection CystitisUrethritisProstatitis If asymptomatic, consider malignancy. Urothelial cancerRenal cell carcinomaProstate cancerIn children, Wilms tumor Urolithiasis Coagulation disorder (e.g., hemophilia) Polycystic kidney disease Myoglobinuria in professional athletes or crush syndrome Medication side effect Porphyrias

Nephrotic syndrome Nephrotic syndrome is characterized by a massive renal loss of protein (> 3.5 g/day) resulting in edema, hypercoagulability (antithrombin III deficiency), and an increased risk of infection (loss of immunoglobulins). Typical laboratory findings of nephrotic syndrome include hyperlipidemia and fatty casts on urinalysis. The most common causes of nephrotic syndrome in adults are focal segmental glomerulosclerosis and membranous nephropathy. Both diseases usually require immunosuppressive therapy. In children, nephrotic syndrome is most commonly caused by minimal change disease, a benign condition that responds well to corticosteroids. However, nephrotic syndrome can also be a manifestation of advanced renal disease (e.g., diabetic nephropathy, amyloidosis). These diseases are associated with a worse prognosis and are more difficult to treat.

Proteinuria > 3.5 g/24hHypoalbuminemiaEdemaHyperlipidemia Minimal change disease Most common cause of nephrotic syndrome in children Can be associated with tumors (e.g., Hodgkin lymphoma) LM: no changes EM: effacement of the foot processes Selective glomerular proteinuria [2] Responds well to corticosteroids Good prognosis Focal segmental glomerulosclerosisMost common cause of nephrotic syndrome in black populationsCan be associated with heroin abuse, HIV infection, obesity, and sickle cell diseaseLM: segmental sclerosis IM: IgM and C3 inside the sclerotic regionsEM: effacement of the foot processesUsually leads to ESRD if left untreatedImmunosuppressive treatment (but often shows poor response to corticosteroids) Membranous nephropathyMost common cause of nephrotic syndrome in white populationsPrimary: Anti-phospholipase A2 receptor antibodiesSecondary: can be associated with infections (hepatitis B and C), SLE, tumors, and medicationsLM: glomerular capillary loops and basement membraneappear thickened IM: subepithelial depositsEM: subepithelial dense deposits ("spike and dome appearance")Corticosteroids Membranoproliferative glomerulonephritis Immunoglobulin(IG)-mediatedmembranoproliferative glomerulonephritis: Associated with SLE, hepatitis C, monoclonal gammopathyComplement-mediatedmembranoproliferative glomerulonephritis: dense deposit disease and C3 glomerulonephritisIG-mediatedLow serum complement levelIM: IgG deposits on basement membraneComplement-mediatedLow serum C3 levels: patients with dense deposit disease often have IgG antibodies, so-called nephritic factor, against the C3 convertase, leading to persistent complement activation.IM: C3 deposits on basement membraneBoth: EM: basement membrane thickening, GBM splitting ("train-track" appearance)No single effective treatment Diabetic nephropathyLeading cause of ESRD in the industrialized worldLM: thickening of the glomerular basement membrane, nodules within glomeruli (Kimmelstiel-Wilson nodules) Treatment of underlying disease AmyloidosisMay also involve other tissues (e.g., heart)Can be associated with multiple myeloma or chronic inflammatory disease (e.g., rheumatoid arthritis)LM: Congo red stain shows apple green birefringenceunder polarized light Melphalan, corticosteroidsTreatment of underlying disease Lupus nephritisComplication of systemic lupus erythematosusCan be nephritic or nephroticANA, anti-DNA antibodies Immunosuppressive therapy Minimal change disease is the most common cause of nephrotic syndrome in children. In adults, nephrotic syndrome is most commonly caused by focal segmental glomerulosclerosis (black populations) and membranous nephropathy (white populations)! Pathophysiology Structural damage of glomerular filtration barrier → massive renal loss of protein → reactively increased hepatic protein synthesisLoss of negative charge of GBM → loss of selectivity of barrier (especially for negatively charged albumin)Podocyte damage and fusion (sign of nephrotic syndrome) → non-selective proteinuria (except minimal change disease, which presents with selective glomerular proteinuria) [2] If protein loss exceeds hepatic synthesis (usually with a loss of protein > 3.5 g/24hours) → hypoproteinemia/hypoalbuminemia, initially both normal GFR and creatinine Decreased serum albumin → ↓ colloid osmotic pressure → edema (especially if albumin levels < 2.5 g/dl) Elevated lipoproteins to compensate the loss of albumin→ ↑ cholesterol and triglycerides → lipiduria (fatty casts)Decreased levels of antithrombin III (AT III) and loss of fluid into the extravascular space ("thickening" of the blood) → hypercoagulability Loss of IGs → increased risk of infectionLoss of "transport proteins" → vitamin D deficiency, possible thyroxine deficiency, altered pharmacodynamics of drugs Clinical features Symptoms of nephrotic syndromeMarked edema: typically starting with periorbital edema and later pitting edema Weight gainPossibly frothy urineHypertensionHypercoagulable state with increased risk of thrombosis and embolic events (e.g., pulmonary embolism, renal vein thrombosis)Increased susceptibility to infectionSymptoms of hypocalcemia Symptoms of the underlying disease For a comparison of nephrotic and nephritic syndrome see nephrotic vs. nephritic syndrome Diagnostics UrinalysisDipstick (commonly used for screening) : usually shows ≥ 3+ protein24-hour urine collection or spot urine (confirmatory tests): Heavy proteinuria (> 3.5 g/24h) While 24-hour urine collection is more precise, a spot urine is usually more practical in a clinical setting.Urine sediment: Nephrotic sedimentProteinuriaLipiduria, fatty casts (hyaline casts with fat globule inclusions and proteins) appear as "Maltese cross" sign under polarized lightRenal tubular epithelial cell casts Blood↓ Total serum protein, albumin, IGs, AT III↑ Cholesterol, triglyceridesProtein electrophoresis: ↓ albumin and γ-zone, ↑ α2- and β-zone Possibly ↑ creatinine and/or BUN Ultrasound: possibly enlarged kidneys, increased echogenicity Renal biopsy (see "Pathology" below) Pathology Renal biopsy Indication: To confirm diagnosis or in patients with nonspecific disease pattern Minimal change diseaseBecause minimal change disease has a very good prognosis, a renal biopsy is generally not performed unless treatment fails.Structural defect of the podocytesLight microscopy: no changes (→ "minimal change")Electron microscopy: effacement of the foot processes Focal segmental glomerulosclerosis (FSGS): damage to the podocytesElectron microscopy: effacement of the foot processesImmunofluorescent microscopy: IgM and C3 inside sclerotic lesionsLight microscopy: segmental sclerosis and loss of podocytes Membranous nephropathy (MN): deposition of antibodies between podocytes and the basal membrane Electron microscopy: subepithelial dense deposits, also known as "spike and dome" appearanceImmunofluorescent microscopy: subepithelial deposits of immune complexes and complementLight microscopy: thickening of glomerular capillary loops and basal membrane Membranoproliferative glomerulonephritis: immune-mediated proliferation of the mesangiumElectron microscopy: thickening and splitting of the glomerular basement membrane ("train-track" appearance)Immunofluorescent microscopy: IgG deposits on basement membrane Treatment General measures Low-sodium and low-protein diet If necessary, antihypertensive therapy with ACE inhibitors or angiotensin II blockers/sartans Diuretics to reduce edema Treat hypercholesterolemia with statins Substitute vitamin D if patient has deficiency Consider thrombosis prophylaxis If the patient has an AT III deficiency, heparin is ineffective. Consider oral anticoagulants! Disease-specific Minimal change disease: patients usually respond well to at least 12 weeks of glucocorticoids (prednisone) Focal segmental glomerulosclerosis (FSGS): GlucocorticoidsCyclosporine or tacrolimus in steroid-resistant patients Membranous nephropathy (MN): glucocorticoids + cyclosporine/tacrolimus or cyclophosphamide Membranoproliferative glomerulonephritis:No clear recommendationsGlucocorticoids, cytotoxic agents, and calcineurin inhibitors can help Complications Thrombotic complicationsDeep vein thrombosisRenal vein thrombosisCause: hypercoagulable state (as in malignancies, antiphospholipid syndrome, nephrotic syndrome)Presentation: flank pain, hematuria, ↑ LDH, anuria/renal failure in bilateral thrombosisComplications: rupture of the renal capsule, pulmonary embolismTherapy: anticoagulation, if necessary substitute AT III Atherosclerotic complicationsCause: Abnormal lipid metabolism in combination with a hypercoagulable state lead to an increased risk of atherosclerotic complications.Presentation: myocardial infarction, stroke End-stage renal disease Prognosis Prognosis of minimal change disease is usually excellent With a wide variety of underlying diseases, the response to treatment can differ dramatically. Even patients receiving treatment commonly develop progressive renal failure and a need for dialysis.

Arterial blood gas analysis and pulse oximetry Arterial blood gas (ABG) analysis is a test regularly performed to measure oxygen saturation, carbon dioxide, and bicarbonate blood levels. It provides quick assessment of gas exchange processes and acid-base balance. Pulse oximetryis a non-invasive and quick way of measuring the oxygen saturation of peripheral arterial hemoglobin. The test relies on the fact that oxygenated and deoxygenated hemoglobin absorb different wavelengths of light. Physiological levels of oxygen saturation are generally above 95%.These tests provide vital information about a patient that is especially important in emergency and intensive care settings.

Pulse oximetry Technical backgroundOxygenated hemoglobin (O2Hb) and deoxygenated hemoglobin (HHb) exhibit different properties of light absorption O2Hb: ↑ infrared light absorption, allows ↑ red light pass through the measurement site (e.g., fingertip)HHb: ↑ red light absorption, allows ↑ infrared light pass through the measurement site An oximeter uses LEDs (light-emitting diodes) emitting both red and infrared light → a photodetector is positioned on the other side of the finger, opposite the LEDs, and detects the amount of light (and whether it is red or infrared light) passing through the measurement site → a processing unit calculates the amount of O2Hb → oximeter displays SpO2 Reference range: Resting Oxygen saturation > 95% is considered normal. A PaO2 of 100 mm Hg is necessary to reach a SpO2 level of ∼ 98%. Pulse oximetry provides falsely high values in cases of carbon monoxide poisoning, as complexes of hemoglobin and carbon monoxide are indistinguishable from oxygen-hemoglobin complexes! Arterial blood gas analysis Measured parametersPartial pressure of oxygen in arterial blood (PaO2) and partial pressure of carbon dioxide (PaCO2) in arterial bloodpHBase excess: Excess value of base in the blood. Used to identify whether an acid-base imbalance is predominantly a respiratory, metabolic, or a mixed acid-base disorder.Standard bicarbonateModern blood gas analyzers also measure: some electrolytes (i.e., sodium, potassium, chloride, calcium), blood glucose, hemoglobin, methemoglobin and carboxyhemoglobin concentrations Reference rangesPaCO2: 35-45 mm HgpH: 7.35-7.45HCO3-: 21 to 27 mEq/LBase excess: -2 to +3 mmol/LResting PaO2 > 80 mm Hg is considered normal. Procedure: A modified Allen test must be performed before the radial artery is punctured to assess collateral circulation in the hand. Manual pressure below the wrist is applied to both arteries, the hand is elevated, and the patient is asked to clench their fist for about 30 seconds to induce transient ischemia, leading to pallor of the hand.When the pressure is released from the ulnar artery, the patient's hand rapidly returns to normal color if collateral circulation is present.Interpretation: The test result is normal if the patient's hand rapidly returns to normal color. The test is negative and considered pathological if the patient's hand remains at least partially pale.Arterial blood can be drawn from radial arteries or an indwelling arterial catheter. Interpretation Hypoxemic respiratory failure (type 1 respiratory failure): ↓ PaO2Hypercapnic respiratory failure (type 2 respiratory failure): ↑ PaCO2 and ↓ PaO2See also "Diagnostics" in acid-base disorders. Mixed oxygen venous saturation DefinitionMixed oxygen venous saturation (SvO2) is the saturation of hemoglobin in the pulmonary artery.SvO2 is an indirect measure of the oxygen content in the venous system. Reference range: 65-70% InterpretationDecreased SvO2Increased tissue oxygen extraction due to decreased oxygen delivery to tissueDecreased hemoglobin concentrationLung diseaseDecreased alveolar oxygen concentrationDecreased alveolar oxygen diffusionIncreased right-to-left shuntingDecreased cardiac outputIncreased oxygen consumption by tissuesExerciseFeverSeizuresInability of hemoglobin to bind to oxygen (e.g., carbon monoxide poisoning)Increased SvO2Peripheral blood shunting (e.g., AV fistula)Decreased metabolic demand (e.g., hypothermia)

Renal tubular disorders Renal tubular disorders are a heterogeneous group of diseases that involve dysfunctions of transporters and channels in the renal tubular system. These dysfunctions may cause fluid loss and abnormalities in electrolyte and acid-basehomeostasis. The disorders are either primary (genetic) or acquired (e.g., drug adverse effects, renal disease). In renal tubular acidosis (RTA), there is normal anion gap (hyperchloremic) metabolic acidosis in a patient with normal or almost normal renal function. Types of RTA include distal tubular acid secretion (type 1), proximal tubular bicarbonate wasting (type 2), very rarely carbonic anhydrase deficiency (type III), and aldosterone deficiency/resistance (type 4). Type 2 can be further classified into isolated proximal tubular bicarbonate wasting and generalized proximal tubular wasting, known as Fanconi syndrome. X-linked hypophosphatemic rickets, the most common form of hereditary hypophosphatemic rickets, is caused by phosphate wasting and manifests with hypophosphatemia and symptoms of rickets. Bartter syndrome, Liddle syndrome, syndrome of apparent mineralocorticoid excess, and Gitelman syndrome are inherited disorders of tubular function characterized by hypokalemia and metabolic alkalosis. Because renal tubular disorders manifest in heterogeneous ways, diagnosis is often challenging; it is based on a combination of clinical features (e.g., rickets, impaired growth, symptoms of electrolyte deficiencies), laboratory analysis of blood and urine, and the results of investigations aimed at determining an underlying cause. The diagnosis of hereditary conditions is usually confirmed with genetic testing. Treatment of type 1 and type 2 RTA involves alkali therapy, while the treatment of type 4 RTA consists of furosemide therapy. X-linked hypophosphatemic rickets requires the supplementation of phosphate and vitamin D, while the mainstay of therapy for Bartter syndrome, Liddle syndrome, syndrome of apparent mineralocorticoid excess, and Gitelman syndrome involves lifelong oral potassium substitution with potassium-sparing diuretics.

Renal tubular acidosis (RTA) In RTA, there is a normal anion gap metabolic acidosis in patients with normal or almost normal renal function. Renal tubular acidosis is caused by defects in the tubular transport of HCO3- and/or H+. Most forms of RTA are asymptomatic; rarely, life-threatening electrolyte imbalances may occur. Distal RTA (type 1) IncidenceRare auseSporadic type 1 RTA(idiopathic)Familial type 1 RTA(inherited genetic defects)Autoimmune diseases(e.g., systemic lupus erythematosus)Chronic obstructive uropathySickle cell nephropathyDrugs (e.g., ifosfamide, amphotericin B, lithium, NSAIDs)PathophysiologyThe α-intercalatedcells of the distaltubule are unable to secrete H+. Serum potassium levelsHypokalemia Urine pH ≥ 5.5 Urine anion gap Positive Calcium excretionIncreased Bone involvementBone demineralizationwithout overt ricketsor osteomalacia (due to increased bone turnover) NephrolithiasisUsually present TreatmentAlkali therapy with sodium bicarbonate or sodium citrate (Shohl solution) Proximal RTA (type 2) Very rare Sporadic type 2 RTA(idiopathic) Familial type 2 RTA(inherited genetic defects) Fanconi syndrome (see "Type 2 renal tubular acidosis" below) Drugs: acetazolamide Multiple myeloma The proximal convoluted tubulecells are unable to reabsorb HCO3-. Hypokalemia ≥ 5.5: an early finding of proximal RTA; attributed to continuous HCO3-excretion in the urine < 5.5: typical finding of proximal RTA; attributed to serum HCO3- depletion UAG Negative Vitamin D-resistanthypophosphatemicrickets/osteomalacia Alkali therapy with orally administered potassium citrate Mixed RTA (type 3) Extremely rare Carbonic anhydrase IIdeficiency (autosomal recessive disease) Type 1 RTA with HCO3- wasting Hypokalemia ≥ 5.5 UAG Positive Osteopetrosis Alkali therapy with orally administered sodium citrate(Shohl's solution) or potassium citrate Hyperkalemic RTA (type 4) Common HypoaldosteronismPrimary adrenal insufficiency (Addison disease)Diabetic nephropathy (diabetic hyporeninism)Drugs (e.g., NSAIDs, ACE inhibitors, heparin, cyclosporin, ARBs) Aldosterone resistanceChronic interstitial or obstructive nephropathyDrugs (e.g., Potassium-sparing diuretics, trimethoprim-sulfamethoxazole) Aldosterone deficiency and/or resistance cause hyperkalemia, which inhibits ammonia synthesis in the proximal convoluted tubule and decreases urinary ammonium excretion. Hyperkalemia < 5.5 UAG Positive Bone demineralization without overt rickets or osteomalacia Furosemide Mineralocorticoid replacement (fludrocortisone) Low-potassium diet Patients with uremic acidosis (metabolic acidosis due to renal failure) have a decreased glomerular filtration rate (increased serum creatinine) and increased anion gap metabolic acidosis. Patients with renal tubular acidosis have relatively normal glomerular filtration rates and normal anion gap metabolic acidosis! Distal renal tubular acidosis (type 1) Pathophysiology The α-intercalated cells of the distal tubule are unable to secrete H+ (apical) → ↓ intracellular production of HCO3- → ↓ HCO3-/Cl- exchanger activity (basolateral) → metabolic acidosis Etiology Sporadic type 1 RTA (idiopathic) Familial type 1 RTA (inherited genetic defects) Autoimmune diseasesSystemic lupus erythematosusSjogren syndromeRheumatoid arthritisPrimary biliary cirrhosisAutoimmune hepatitisHashimoto thyroiditis Nephrocalcinosis (e.g., hyperparathyroidism, vitamin D toxicity, sarcoidosis) Medullary sponge kidney Chronic obstructive uropathy (e.g., congenital anomalies) Sickle cell nephropathy Wilson disease Drugs: ifosfamide, amphotericin B, lithium, NSAIDs (analgesic nephropathy) Clinical features Nephrocalcinosis: calcium phosphate stones (due to an increase in urine pH ) Polyuria → polydipsia, dehydration Bone demineralization usually without overt rickets or osteomalacia (due to increased bone turnover) Impaired growth In some cases, features of hypokalemia (e.g., muscle weakness, hyporeflexia, paralysis, U waves and flattened T waveson ECG) Diagnostics SerumHyperchloremic metabolic acidosis (normal anion gap)Hypokalemia that improves with alkaline therapy UrineUrine pH ≥ 5.5Acid load test: Following oral administration of ammonium chloride, the urine does not acidify (pH remains > 5.3). Positive urine anion gapHypercalciuriaDecreased NH4+ excretionDecreased citrate excretion Treatment Alkalinization therapy with orally administered sodium bicarbonate or sodium citrate (Shohl solution) Renal tubular acidosis type 1 causes kidney stONEs. Proximal renal tubular acidosis (type 2) Type 2 renal tubular acidosis is characterized by a dysfunctional proximal convoluted tubule (PCT) that is unable to reabsorb HCO3-. The defect can either be isolated, affecting only the reabsorption of HCO3- or, more commonly, the PCT has a generalized dysfunction of the PCT, in which case the condition is referred to as Fanconi syndrome. Type 2 RTA syndrome PathophysiologyThe proximal convoluted tubule cells are unable to reabsorb HCO3- leading to increased HCO3- excretion in the urine. H+ secretion from α-intercalated cells in the collecting duct can acidify the urine, but cannot compensate for the excessive HCO3- excretion in the urine, thus resulting in distal tubular acidosis.Only HCO3- reabsorption is impaired. Isolated proximal RTA Only HCO3- reabsorption is impaired. Sporadic type 2 RTA (idiopathic) Familial type 2 RTA (inherited genetic defects) Autosomal recessive disease (more common)Autosomal dominant disease Drugs: acetazolamide Fanconi syndromeImpaired reabsorption of HCO3- and other compounds (e.g., potassium, glucose, phosphate, and amino acid reabsorption) in the PCT Inherited disorders CystinosisTyrosinemiaGalactosemiaType 1 glycogen storage diseaseWilson diseaseIschemia (acute tubular necrosis) Light chain nephropathy (e.g., multiple myeloma) Amyloidosis Vitamin D deficiency Paroxysmal nocturnal hemoglobinuria Drugs: ifosfamide, tenofovir, expired tetracyclines, aminoglycosides, cisplatin Heavy metal poisoning (e.g., lead, cadmium, mercury) Clinical features Vitamin D-resistant hypophosphatemic rickets/osteomalacia (individuals with Fanconi syndrome typically have more seevere symptoms) Short stature Polyuria → polydipsia, dehydration In some cases, features of hypokalemia (e.g., muscle weakness, hyporeflexia, paralysis, U waves and flattened T waveson ECG) Diagnostics SerumHyperchloremic metabolic acidosis (i.e., normal anion gap)Hypokalemia that worsens with alkali therapy Fanconi syndromeHypouricemiaHypophosphatemia UrineUrine pHIf serum HCO3- is higher than its reabsorption threshold: pH ≥ 5.5If serum HCO3- is depleted: pH < 5.5Bicarbonate infusion test: Urine pH rises to a level higher than 7.5 and the fractional excretion of bicarbonate is > 15% following administration of IV sodium chloride .Negative urine anion gapFanconi syndromeAminoaciduriaGlucosuria despite normal or low serum glucosePhosphaturia Treatment Alkali therapy with orally administered potassium citrate Thiazide diuretics if alkali therapy is not tolerated or effective Potassium citrate is required to correct the hypokalemia that occurs with the initiation of alkali therapy. Thiazide diuretics cause volume depletion and enhanced bicarbonate reabsorption. Renal tubular acidocis type 2 has two variants (isolated proximal RTA and Fanconi syndrome). Mixed renal tubular acidosis (type 3) A combination of type 1 and type 2 RTA. Etiology Carbonic anhydrase II deficiency (autosomal recessive disease) Pathophysiology Impaired H+ secretion by the distal convoluted tubule and HCO3- wasting by the proximal convoluted tubule Clinical features Guibaud-Vainsel syndromeOsteopetrosis Cerebral calcificationIntellectual disability Diagnostics SerumHyperchloremic (normal anion gap) metabolic acidosisHypokalemiaHypocalcemia UrineUrine pH ≥ 5.5Positive urine anion gapHypercalciuriaDecreased NH4+ excretionDecreased citrate excretion Treatment Alkali therapy with orally administered sodium citrate (Shohl solution) or potassium citrate Hyperkalemic renal tubular acidosis (type 4) Etiology HypoaldosteronismPrimary adrenal insufficiency (Addison disease)Hyporeninemic hypoaldosteronismAcute glomerulonephritis Diabetic nephropathy (diabetic hyporeninism) SLEAIDS nephropathyDrugs: NSAIDs, ACE inhibitors, heparin, cyclosporin, ARBsPseudohypoaldosteronism type 2 (Gordon syndrome) An autosomal dominant condition characterized by increased sodium reabsorption and decreased potassium secretion due to dysfunction of ion channels in the kidney.Manifestations include hypertension, hyperkalemia, hyperchloremia, and metabolic acidosis. Aldosterone resistanceChronic obstructive nephropathy or interstitial nephropathyDrugs: Potassium-sparing diuretics (e.g., spironolactone, amiloride, eplerenone, triamterene), trimethoprim-sulfamethoxazole, pentamidinePseudohypoaldosteronism type 1: A form of aldosterone resistance that is a caused by an autosomal dominantloss-of-function mutation in the gene encoding for mineralocorticoid receptor protein or autosomal recessiveloss-of-function mutations in the genes encoding the epithelial sodium channel. Pathophysiology Aldosterone deficiency and/or resistance → hyperkalemia and metabolic acidosis → inhibition of ammonia (NH3)synthesis in the proximal convoluted tubules → decreased urinary ammonium (NH4+) excretion Clinical features Polyuria → polydipsia, dehydration Impaired growth in children Features of hyperkalemia (e.g., muscle weakness, prolonged PR interval and peaked T waves on ECG) Diagnostics Serum Hyperchloremic metabolic acidosis (i.e., normal anion gap)Hyperkalemia UrineUrine pH < 5.5Positive urine anion gap (persistent sodium excretion)Decreased NH4+ excretionNormal or decreased calcium excretion Treatment Furosemide Mineralocorticoid replacement (fludrocortisone) Low-potassium diet Renal tubular acidosis type 4 leads to decreased NH4+ excretion. X-linked hypophosphatemic rickets Etiology X-linked dominant disease caused by a mutation in the PHEX gene Pathophysiology Mutation in the PHEX gene → increased levels of fibroblast growth factor 23 (FGF23) → indirect inhibition of the sodium-phosphate cotransporter in the proximal renal tubule → impaired reabsorption of phosphate → chronic hypophosphatemia → vitamin D-resistant rickets/osteomalacia Epidemiology X-linked hypophosphatemic rickets accounts for ∼ 80% of all familial causes of hypophosphatemia. Age of symptom onset: typically < 3 years Clinical features Features of rickets (e.g., short stature, bowing of legs) Dental abscesses Calcification of soft tissues (tendons, ligaments, and joint capsules) Deafness Arnold-Chiari malformation Diagnostics Laboratory tests Pronounced hypophosphatemiaIncreased alkaline phosphataseDecreased or normal 1,25-dihydroxyvitamin DNormal serum calcium, parathyroid hormone/parathyroid hormone-related peptide, and 25-dihydroxyvitamin D X-ray of the wrists, knees, ankles, and long bones, such as the femur (See "Diagnostics" in osteomalacia and rickets.) Treatment Phosphate substitution Calcitriol (1,25-dihydroxyvitamin D) substitution Complications of treatment: hyperparathyroidism, nephrocalcinosisAmiloride and hydrochlorothiazide are used to increase calcium reabsorption and thereby lower the risk of nephrocalcinosis. Bartter syndrome Definition A group of rare genetic disorders (autosomal recessive) that affect chloride reabsorption in the thick ascending limb of the loop of Henle Epidemiology Prevalence: 1/1,000,000 Pathophysiology Defective Na+-K+-2Cl- cotransporter in the thick ascending loop of Henle results in Loss of Cl-, Na+, and K+ in urine (as seen in chronic loop diuretic use) Failure to reabsorb Na+ leading to natriuresis (salt and water loss) and volume depletion, which activates the renin-angiotensin-aldosterone system (RAAS), leading to Renal vasoconstriction; however, a rise in prostaglandin E levels to counter renal vasoconstriction results in growth inhibitionElevated aldosterone levels, leading to increased K+ and H+ excretion and subsequent hypokalemia and metabolic alkalosis Decreased paracellular reabsorption of calcium → hypercalciuria → hypocalcemia, nephrocalcinosis, and renal stones Clinical features Antenatal symptoms: polyhydramnios, preterm delivery Severe polyuria and polydipsia → life-threatening volume depletion and hypotension Muscle atrophy, weakness, cramps, carpopedal spasm Failure to thrive, developmental delay Dysmorphic facies , strabismus, sensorineural deafness Symptoms of renal colic may occur as a result of calcium stones. Diagnostics Laboratory diagnosticsMetabolic alkalosisHypokalemiaHypercalciuria Hyperuricemia (∼ 50% of cases)Response to thiazide and loop diuretics Normal response to thiazide diuretics Blunted response to loop diuretics Confirmatory test: genetic testing Treatment Mainstay of therapy: lifelong oral potassium substitution with potassium-sparing diuretics (spironolactone, amiloride) The Na-K-2Cl cotransporter that is defective in Bartter syndrome is a target for loop diuretics! Gitelman syndrome Epidemiology Prevalence: 1/40,000 Age of symptom onset: ≥ 6 years; diagnosis is usually made in adolescence or adulthood Etiology Autosomal recessive defect in the SLC12A3 gene on chromosome 16p → impaired function of the thiazide-sensitivesodium-chloride cotransporter in the distal convoluted tubule → impaired Na+ and Cl-reabsorption → mild natriuresis → mild volume depletion → mild RAAS activation Clinical features Clinical features are similar to those of chronic thiazide diuretic use:Fatigue, muscle weaknessMuscle cramps and/or tetanyMild polyuriaChondrocalcinosisIn some cases, mild hypotension Diagnostics Metabolic alkalosis Severe hypokalemia Hypercalcemia and hypocalciuria Hypomagnesemia Response to thiazide and loop diuretics Normal response to loop diuretics Blunted response to thiazide diuretics Confirmatory test: genetic testing Treatment Mainstay of therapy: lifelong oral potassium substitution with potassium-sparing diuretics (spironolactone, amiloride) The effects of Gitelman syndrome are similar to those of a thiazide diuretic! Liddle syndrome Epidemiology Extremely rare Age of symptom onset: childhood Etiology Autosomal dominant gain-of-function mutation in the SCNN1B and SCNN1G genes on chromosome 16p → structural alteration in the β and γ subunits of the epithelial sodium channel (ENaC) in the collecting duct Pathophysiology Structural alteration in the ENaC subunits → inability of these subunits to bind with an intracellular ubiquitin-protein ligase (Nedd4) → decreased degradation of ENaC channels by ubiquitin proteasomes → increased number of ENaCs in the collecting duct → increased reuptake of water and sodium (pseudohyperaldosteronism) → hypertension with low renin production and hypokalemia Clinical features Hypertension Diagnostics Hypokalemia Metabolic alkalosis Decreased renin and aldosterone levels Confirmatory test: genetic testing Treatment Lifelong oral potassium substitution with potassium-sparing diuretics that directly block ENaCs in the collecting duct (e.g., amiloride, triamterene) The clinical features of Liddle syndrome are similar to those of hyperaldosteronism, except that Liddle syndrome manifests with decreased renin and aldosterone levels! Syndrome of apparent mineralocorticoid excess Epidemiology (hereditary disorder) [10] Extremely rare Age of symptom onset: infancy Etiology Autosomal recessive, loss-of-function mutations in the 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta-HSD2) gene on chromosome 16q → ↓ 11-beta-HSD2 enzyme. Acquired disorder from chronic exposure to glycyrrhetinic acid (e.g., from excessive consumption of black licorice), which inhibits the activity of the 11-beta-HSD2 enzyme. Pathophysiology With normal 11-beta-HSD2 activity: 11-beta-HSD2 converts cortisol into cortisone (cortisone, unlike cortisol, does not activate mineralocorticoid receptors). With 11-beta-HSD2 deficiency (or inhibition): ↓ cortisol conversion to cortisone → ↑ cortisol → ↑ mineralocorticoidreceptor activity. Clinical features Hypertension Low birth weight Failure to thrive Muscle weakness Polyuria and polydipsia due to nephrogenic diabetes insipidus Renal failure Diagnostics Best initial test: high ratio of urinary free cortisol to cortisone in a 24-hour urine collection Confirmatory test: genetic testing Additional findingsHypokalemiaMetabolic alkalosisDecreased renin and aldosterone levelsDecreased urinary free cortisone excretionHypercalciuria Treatment Cessation of licorice ingestion Lifelong oral potassium substitution with potassium-sparing diuretics (e.g., amiloride or eplerenone) to decrease the mineralocorticoid effects Thiazide in hypercalciuria or nephrocalcinosis Corticosteroids: Exogenous corticosteroid decreases endogenous cortisol production and subsequently reduces mineralocorticoid receptor activation. Spironolactone (an aldosterone receptor antagonist) is effective in treating the syndrome of apparent mineralocorticoid excessbut not Liddle syndrome! In Syndrome of Apparent Mineralocorticoid Excess, cortisol has the SAME action as aldosterone.

Acid-base disorders Acid-base disorders are a group of conditions characterized by changes in the concentration of hydrogen ions (H+) or bicarbonate (HCO3-), which lead to changes in the arterial blood pH. These conditions can be categorized as acidoses or alkaloses and have a respiratory or metabolic origin, depending on the cause of the imbalance. Diagnosis is made by arterial blood gas (ABG) interpretation. In the setting of metabolic acidosis, calculation of the anion gap is an important resource to narrow down the possible causes and reach a precise diagnosis. Treatment is based on identifying the underlying cause.

Respiratory acidosis Alveolar hypoventilation→ CO2 retention Airway obstruction (e.g., COPD exacerbation, bronchial asthma) Acute lung disease (e.g., pneumonia , pulmonary edema) Respiratory muscle weakness (e.g., myesthenia gravis, ALS) CNS depressionHead traumaPost-ictal stateDrug toxicity (e.g., opiates, barbiturates, and benzodiazepines) Respiratory alkalosis ↑ In respiratory rate and/or tidal volume → alveolar hyperventilation→ CO2 washout Pain, anxiety, panic attacks Pregnancy Hypoxemia (e.g., in high altitude) Drug toxicity (e.g., from salicylate , theophylline, progesterone) Hyperventilation while on mechanical ventilation Pulmonary disease (e.g., pneumonia, pulmonary embolism, pulmonary edema) Brainstem tumor (i.e., that causes central neurogenic hyperventilation) Metabolic acidosis ↑ Production/ingestion of H+ or loss of HCO3- High anion gap metabolic acidosisLactic acidosis: (e.g., severe tissue hypoxia, liver failure , metformin use)Ketoacidosis (e.g., diabetes mellitus, starvation, alcoholism)Renal insufficiency, uremiaIron tabletsIsoniazid (INH) treatmentAccumulation of exogenousorganic acidsMethanol (formic acid)Ethylene glycol (oxalic acid)Propylene glycol (lactic acid)Toluene Salicylate toxicity Normal anion gap metabolic acidosisRenal tubular acidosisGI loss of HCO3- (e.g., due to diarrhea, GI fistulas, intestinal stomas)Hyperchloremia (e.g., excess saline infusion)Addison diseaseDrugs (e.g., acetazolamide, spironolactone) Metabolic alkalosis Loss of H+ or ↑ production/ingestionof HCO3- Chloride-responsive(normal urinary chlorideof < 25 mmol/L)Vomiting or nasogastric suctionHypovolemia(contraction alkalosis)Loop or thiazide diuretics Chloride-resistant(increased urinary chloride of > 40 mmol/L)HyperaldosteronismCushing syndromeBartter syndromeGitelman syndromeLiddle syndromeHigh alkali loadantacid use, alkalization therapy) Metabolic acidosis↓ Arterial and CSF pH (with ↓ HCO3-) → ↑ stimulation of the medullary chemoreceptors → ↑ respiratory rate and/or tidal volume (hyperventilation) →↑ CO2 washout → ↓ PO2Winter formula:Expected PCO2 = (1.5 x HCO3-)+ 8 (+/- 2) Interpretation Measured PCO2 > expected PCO2: respiratory acidosis in addition to metabolic acidosisMeasured PCO2 < expected PCO2: respiratory alkalosisaddition to metabolic acidosis Metabolic alkalosis↑ Arterial and CSF pH (with ↑ HCO3-) → ↓ stimulation of the medullary chemoreceptors → ↓ respiratory rate and/or tidal volume (hypoventilation) →↑ CO2 retention → ↑ PO2 Expected pCO2 = (0.7 x HCO3-)+ 20 (+/- 5) Respiratory acidosisAcute compensationBuffers in bloodExpected HCO3- = 24 + [0.1 x (pCO2- 40)](+/- 3)Chronic compensation↓ Arterial pH (with ↑ PCO2) → ↑ HCO3- via: ↑ Reabsorption of HCO3- by the proximal convoluted tubule↑ Excretion of H+ as H2PO4- and NH4+ by the distal convoluted tubule and collecting ductExpected HCO3- = 24 + [0.4 x (pCO2 - 40)] (+/- 3) Respiratory alkalosisAcute compensationBuffers in bloodExpected HCO3- = 24 - [0.2 x (40 -pCO2)] (+/- 3)Chronic compensation↑ Arterial pH (with ↓ PCO2) → ↓ HCO3- via: ↓ Reabsorption of HCO3- by the proximal convoluted tubule↓ Renal excretion of H+Expected HCO3- = 24 - [0.5 x (40 -pCO2)] (+/- 3) Anion gap Definition: difference between the concentration of unmeasured anions and the concentration of unmeasured cations CalculationAnion gap = [Unmeasured cations] - [Unmeasured anions][Unmeasured cations] = [Total cations] - [Routinely measured cations] [Unmeasured anions] = [Total anions] - [Routinely measured anions] Since [Total cations] ≈ [Total anions] to maintain electrical neutrality, the formula can be rewritten as Anion gap =[Routinely measured cations] - [Routinely measured anions]If potassium concentration is normal, anion gap ≈ [Na+] - ([Cl-] + [HCO3-]) (Reference range: 6-12 mmol/L)In European countries, calculation of the anion gap usually also accounts for potassium, in which case the anion gap = ([Na+] + [K+]) - ([Cl-] + [HCO3-]) (Reference range: 10-16 mmol/L)In certain conditions (see "High anion gap metabolic acidosis" below), the unmeasured anions increase → ↑ anion gap InterpretationNormal anion gap metabolic acidosis (also known as hyperchloremic acidosis)Primary loss of HCO3- compensated with ↑ Cl- → unchanged anion gapEtiologyEndogenous: diarrhea, biliary or pancreatic fistula, renal tubular acidosis, Addison diseaseExogenous: drugs (e.g., carbonic anhydrase inhibitors), uptake of acids containing chloride ions (e.g., HCl)Further evaluation: measure urine anion gap = [Urine Na+] + [urine K+] - [urine Cl-]Positive urine anion gap → renal acidification (e.g., renal tubular acidosis)Negative urine anion gap → GI loss of bicarbonate (e.g., diarrhea)High anion gap metabolic acidosisIncreased concentration of organic acids such as lactate, ketoacids (beta-hydroxybutyrate, acetoacetate), oxalic acid, formic acid, or glycolic acid → no compensatory increase of Cl- → ↑ anion gapEtiologyEndogenous: lactic acidosis, ketoacidosis, renal insufficiency/uremiaExogenous: salicylate intoxication, ethanol intoxication, methanol intoxication, ethylene glycol intoxication(component of antifreeze products) Causes of normal anion gap acidosis (FUSEDCARS): F - Fistula (biliary, pancreatic), U - ureterogastric conduit, S - saline administration, E - endocrine Addison's disease, hyper-PTH), D - diarrhea, C - carbonic anhydrase inhibitor, A - ammonium chloride, R - renal tubular acidosis, S - spironolactone Causes of high anion gap acidosis (MUDPILES): M - methanol intoxication, U - uremia, D - diabetic ketoacidosis, P -paraldehyde, I - isoniazid or iron overdose, inborn error of metabolism, L - lactic acidosis, E - ethylene glycol intoxication, S - salicylate intoxication Treatment Treatment of acid-base disorders should always address the underlying cause. Some steps in urgent management are listed below. Respiratory acidosis: treat underlying cause (see "Treatment" of COPD, opioid intoxication, benzodiazepine overdose) Respiratory alkalosis: treat underlying cause; in the event of hyperventilation syndrome, patients benefit from reassurance and rebreathing into a paper bag. Metabolic acidosisAcute severe metabolic acidosis (pH < 7.1): intravenous sodium bicarbonate Chronic metabolic acidosis: oral sodium bicarbonate along with treatment of the underlying cause (e.g., diarrhea, renal tubular acidosis)Electrolyte disturbances: correct (e.g., hyperkalemia; see "Treatment" of potassium disorders)See individual learning cards for the management of diabetic ketoacidosis, salicylate toxicity. Metabolic alkalosisVolume depletion: isotonic saline to increase urinary bicarbonate excretion and correct extracellular volume lossBicarbonate excess: acetazolamide Electrolyte disturbances: correct (e.g., see "Treatment" of potassium disorders)