Acute Kidney Injury

Acute tubular necrosis/ATN

-Clinical history is crucial to ascertain the possible etiology of ATN, but not helpful in diagnosing ATN itself. -Also, knowing the possible etiologies of ATN is important because there is no specific test to prove one etiology or another - no drug level and no biopsy would indicate that a specific toxin caused ATN.

INTRINSIC AKI

-Most pathologies affecting the kidneys bilaterally may potentially lead to AKI. -Unilateral kidney disease does not cause AKI because the unaffected kidney is perfectly capable to work on its own. -Thus, people with one kidney - like transplant recipients and donors - have normal UO, sCr and eGFR. -But if that single kidney is affected, those patients are at risk of developing AKI. The etiologies of intrinsic AKI can be grouped according to the site of pathology as follows: a. Glomerulopathies: acute glomerulonephritis; crystallopathies b. Tubulopathies: acute tubular necrosis (ATN) c. Interstitium: acute allergic interstitial nephritis (AIN) d. Micro-angiopathies: HUS/TTP; renal artery emboli e. Analgesic nephropathy.

from case 7 The patient responds well to the acute management and is started on the appropriate treatment for SLE and hypertension. After 6 months her symptoms improve, however her GFR remains at around 50 mL/min/BSA. What is the diagnosis at this point?

Chronic kidney disease The BP is now 122/64 mmHg. What is the treatment of this condition that best controls the BP and at the same time controls the proteinuria and renal structure remodeling? ACE inhibitor

case 4 A 45-year-old man with cirrhosis due to a chronic hepatitis C infection develops oliguria and a sudden increase in BUN and creatinine levels, with a BUN:creatinine ratio of 26:1. Imaging of this patient's kidney's is most likely going to reveal which of the following? A. Horseshoe kidney B. Enlarged kidneys with severe hydronephrosis C. Kidneys of normal size with "flea-bitten" appearance D. Kidneys of normal size and shape E. Enlarged, polycystic kidneys

D. Kidneys of normal size and shape

Hepatorenal syndrome

- = A prerenal AKI picture as above because kidneys are intrinsically normal. - But there is severe liver disease (cirrhosis) with hypoalbuminemia, leading to decreased plasma oncotic pressure, which will cause the H2O to diffuse in the extracellular spaces. Thus, the patient becomes virtually hypovolemic.

Henoch-Schonlein purpura

- = leukocytoclastic generalized vasculitis - Predominant in children (rare and more severe in adults)

Renal artery thrombosis/Renal infarction/cardioembolic disease

- AKI may be caused by large thrombi that obstruct both RAs => wedge-shaped necrosis of the renal parenchyma. - Kidneys are predisposed because of their increased perfusion rate and limited RA collaterals. Risk factors: HTN, obesity, atrial fibrillation. - Presentation: acute onset flank pain, CVA tenderness, frank hematuria. - Characteristic increase in LDH due to necrosis.

Bilateral renal artery stenosis (RAS)

- Causes: atherosclerosis; fibromuscular dysplasia - Manifesting by resistant HTN secondary to continuous stimulation of the reninangiotensin-aldosterone system (RAAS). Diagnosis: symptoms and signs of multiorgan ischemia, including CNS involvement (headaches, TIAs, stroke, aneurysms); mesenteric ischemia (with abdominal pain after eating); extremity claudication). - Once added an ACE-I to the treatment of hypertension caused by RAS => AKI - Because in bilateral RAS GFR is maintained by PG-induced vasodilation of afferent arteriole and the RAAS-induced vasoconstriction of efferent arteriole => if RAAS inhibited by ACE-I => glomerular filtration pressure decreases => GFR and filtration fraction decrease, while at the same time sCr increases. - If the patient is also on a diuretic, this needs to be stopped, because in the setting of fluid depletion there is an increased dependence on RAAS to maintain GFR. Radiology: U/S small kidneys, CT/MR angiography (in FMD characteristic "string-ofbeads")

Toxin-induced ATN

- Characteristic focal epithelial necrosis Etiology: • Exogenous nephrotoxins: medications, contrast media (contrast-induced nephropathy), synthetic cannabinoids (SPICE, K2), ethylene glycol (oxalate precipitates Ca in tubules -> ATN in ~ 3 d). • Endogenous nephrotoxins: crystal nephropathies (pigment nephropathy caused by myoglobin, hemoglobin, tumor lysis syndrome), Bence-Jones proteins (multiple myeloma), hypercalcemia. Other things under toxin-induced ATN: - Ethylene glycol poisoning - Gentamicin - Light chain cast nephropathy (multiple myeloma, gammopathies)

Crystallopathies/crystal nephropathies

- Crystallopathy = associated with the formation and aggregation of crystals in the tubuli, promoting tissue inflammation and scarring. - Caused by crystal-forming intrinsic minerals, metabolites, and proteins or extrinsic dietary components and drug metabolites. - Common causes of drug-induced crystal nephropathies: uric acid, acyclovir; sulfonamides. Other things associated with this: -Pigment nephropathy -Acute tumor lysis syndrome -Renal athero-embolism/cholesterol crystal embolism (CCE)

Renal athero-embolism/cholesterol crystal embolism (CCE)

- Emboli of cholesterol crystals arising from the rupture of an atherosclerotic plaque from aortic or other major arteries block smaller arteries (150-200 μm in diameter) -> affect kidneys, skin, gastrointestinal system, eyes, muscles, bones, brain, nerves, internal organs, and limbs. - Kidneys are located near the abdominal aorta => most frequent target organ of CCE Pathology: o Obstruction of arcuate and interlobar arteries by CCs causes cortical and medullary infarcts o Passive (physical) or regulated necrosis of the endothelial cells. - Diagnosis of AKI caused by CCE difficult -> based history of a precipitating event (catheterization, vascular surgery, angiography) and other organ involvement (skin => livedo reticularis, "blue-toe syndrome).

Microangiopathic nephropathy: Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP)

- HUS & TTP are different diseases, despite some clinical similarities. - TTP: abnormal protease = the von Willebrand factor (vWF)-cleaving metalloprotease ADAMTS13 = disintegrin and metalloprotease with a thrombo-spondin type 1 motif, member 13) = reduced activity to < 10% - HUS: Normal ADAMTS13 (except in idiopathic HUS, when it is <10%) Etiology: Shiga-like toxin (Stx)- associated : • E coli (70% in US, mainly serotype O157:H7) • S disenteriae type 1 Non-Stx HUS: • Sporadic • Non-enteric bacteria & viruses • Drugs etc.

ANCA-associated glomerulonephritis

- Includes: Granulomatosis with polyangiitis / Wegener granulomatosis (associated with PR3- ANCA); microscopic polyangiitis (MPO-ANCA); Churg-Strauss syndrome (MPO-ANCA); druginduced ANCA-associated glomerulonephritis (MPO-ANCA). - Rapid progression to RPGN unless start immediately Rx.

Pre-renal AKI~ Labs

- Urinalysis: increased urine specific gravity (sg) > 1.020; hyaline casts; "BLAND" - BUN/sCr > 20/1 due to the following mechanisms: o Increase in passive of transfer of urea in PCT, following enhanced reabsorption of Na and H2O. o Increased urea reabsorption mediated by ADH, which increases the permeability of the inner medullary collecting ducts to H2O and urea, allowing for maximal free H2O retention. o At the same time creatinine continues to be secreted FENa: % of filtered Na excreted in the urine -> is < 1%. o Note that if the patient is on a diuretic, FENa is falsely high (>2%) due to the Na loss, thus it is not reliable and should be replaced by fractional excretion of urea = FEUrea (typically < 35%). 8 o FENa may also falsely indicate pre-renal AKI (<1%) in ATN caused by pigment damage (myoglobinuria or hemoglobinuria), because pigment injury causes intense vasoconstriction and thus reduces Na filtration and excretion. - Urine Na: <20 mEq/dL

Pigment nephropathy

- May be caused by: o hemoglobin (from hemolysis) or o myoglobin (rhabdomyolysis - following: heat injury; "crush injury"; strenuous exercise; seizures; tetanus; alcohol or cocaine; severe hypokalemia; Rx) - When overwhelming concentrations of pigment are filtered by glomeruli and reabsorbed by renal tubules - Pigmented casts may form => obstruction of the DCT => intrarenal vasoconstriction => ATN - Myoglobinuria = a severe oxidant stress on tubular cells (damage is worse when urine flow slow) Presentation: o Hemolysis: pallor, jaundice; tachycardia; splenomegaly, dark urine. o Rhabdomyolysis: muscle pain; bruising; symptoms of the underlying cause, colacolored urine. Labs: o As opposed to other causes of ATN, FENa <1%; o Urinalysis: - dipstick positive for blood - but sediment NEGATIVE for RBCs = PSEUDOHEMATURIA; urinary hemoglobin or myoglobin; brown granular casts (but absence does not exclude diagnosis); o Increased LDH and haptoglobin in hemolysis; o Increased creatine-phosphokinase (5X upper level of normal); o Hyperkalemia; o Hyperphosphatemia o Hypocalcemia.

Post-infectious glomerulonephritis

- Most cases resolve spontaneously within 1 week, but adults are more likely than children to develop AKI or CKD. - See Hematuria and Proteinuria lecture.

PRE-RENAL AKI

- Most common cause of AKI - Characterized by a decrease in eGFR due to a decrease in renal perfusion pressure, without damage to the renal parenchyma - Maintaining a normal GFR is dependent on adequate renal perfusion: kidneys receive up to 25% of the cardiac output => failure of the general circulation or isolated failure of the intrarenal circulation => profound impact on renal perfusion. - Reversible: no damage to the nephrons, fixing the cause will restore the renal function - If untreated => ischemia and necrosis of the tubuli = acute tubular necrosis/ATN (most common cause of ATN).

IgA nephropathy/Berger disease

- Most common cause of glomerulonephritis in the US - Clinical presentation: gross hematuria concomitant with URI or flu-like illness; NO latent period; usually normal BP (if high BP -> poor prognosis)

Pre-renal AKI~ Clinical presentation

- Most patients - asymptomatic, normal physical examination. - Symptoms of azotemia: fatigue, nausea, vomiting, oliguria, confusion, shortness of breath - Manifestations of hypovolemic shock/volume depletion: hypotension, orthostatic hypotension, tachycardia, reduced skin turgor, dry mucosae. - Manifestations of volume overload: pleural effusion, pericardial effusion, tamponade.

Goodpasture syndrome

- Rapid progression to RPGN and AKI -> ESRD/CKD

Acute tumor lysis syndrome

- Soon after chemotherapy initiation (as soon as 48h!), massive destruction of malignant cells will lead to the release of uric acid and monosodium urate/MSU (break down products of nucleic acids), LDH, K (hyperkalemia). - MSU crystals precipitate inside the tubular lumen, especially in the most acidic parts - DCT and collecting ducts (note that pKa of uric acid is 5.4, thus it is soluble if urine pH > 5.5 - within physiologic range). - Precipitation of uric acid crystals => obstruction of DCT and collecting ducts => AKI

The way you discriminate between prerenal AKI (simple hypoperfusion) and ATN (ischemia and necrosis) is

-by looking at the time-lapse between the onset of hypoperfusion, by looking at the response to the correction of hypoperfusion, and by looking at urinalysis. -Pre-renal AKI will be reversed promptly by simply restoring appropriate blood supply to the kidney. -ATN will have a protracted phase, since the damaged cells need to be replaced. In simple hypoperfusion: prerenal~ hyaline casts -The hyaline casts have no cells - nephrons are still ok. ATN~ brown granular casts. -The brown casts are actually the dead cells that get incorporated into the precipitated protein - a sign that the nephrons are damaged.

case 9 • A 40-year-old male with substance use disorder (IV heroin) is admitted to the hospital for right-sided endocarditis. He is started on nafcillin and gentamicin intravenously. On the 3rd day post-admission, his laboratory results are as follows: • Serum: BUN 40 mg/dL and Cr 4.8 mg/dL • Urinalysis: protein excretion 400 mg/24h; numerous casts as in the attached photograph. • What is the most likely cause of the patient's condition?

-heroin -main cause of toxic ATN the urine microscopy shows muddy brown granular casts

Acute tubular necrosis/ATN~ Clinical presentation evolves in 3 stages

1. Initiation = tubular injury stage: • 24-36h 2. Maintenance = oliguric phase: • 1-3 weeks • Decreased UO and eGFR, fluid overload, increased BUN and creatinine (BUN/sCr < 10-15), hyperkalemia, metabolic acidosis 3. Recovery = polyuric phase: • After 3-4 weeks • Gradual increase in UO with polyuria • There is continued impairment of renal function with electrolyte wasting => hypokalemia (life-threatening); hypomagnesemia, hypophosphatemia, hypocalcemia.

Acute tubular necrosis: renal medulla

1. Patchy or diffuse denudation of the renal tubular cells with loss of brush border (blue arrows) 2. Flattening of the renal tubular cells due to tubular dilation (orange arrows) 3. Intratubular cast formation (yellow arrows) 4. Sloughing of cells => granular casts (red arrow). 5. Intratubular obstruction due to the denuded epithelium and cellular debris is evident (green arrow); denuded tubular epithelial cells clump together via intercellular adhesion molecules.

Glomerulopathies

= Both a cause and a risk factor for AKI - Any type of glomerulopathy may lead to AKI - but most are usually chronic - Pediatric PSGN, IgA nephropathy, TBMN, Alport's, minimal change NS unlikely to develop into AKI/CKD. - Most severe form, often with acute progression: crescentic GN - RPGN

case 6 • A 65-y-o man with well-controlled HTN presents with a 2-day history of shaking chills followed by a fever, and a cough productive of rusty coloured sputum. He feels lethargic. Five years ago he underwent radiation therapy for prostate cancer and 6 months ago his PSA was within normal limits. His current medications are hydrochlorothiazide and lisinopril. He smokes a 3-5 cigarettes/d and has 1 drink per week. • Vitals: temp 38.6°C; BP 90/60 mm Hg; pulse 110 bpm; RR 24 breaths/min. Lung auscultation reveals decreased breath sounds and crackles at the right lung base. Abdomen is soft, not painful, and no masses palpable. Extremities are warm and the capillary refill time is 4 seconds. Laboratory findings • CBC: WBC, 16,000/mcL (70% PMNs, 20% bands, 10% lymphocytes); Hb 10.2 g/dL; Hct 32%; MCV 88 mcm3; • Electrolytes: Na 140 mEq/L; K 5.4 mEq/L; Cl 100 mEq/L; HCO3 19 mEq/L; • Renal function testing: BUN 40 mg/dL; creatinine 3.8 mg/dL (a month ago was 1.4 mg/dL). • Urinalysis: hyaline casts What is the most likely explanation for this presentation? A. Hypovolemia B. Septic shock C. Drug toxicity D. Obstructive uropathy due to BPH E. Post-streptococcal glomerulonephritis

A. Hypovolemia septic shock- vasodilation -renal hypofusion hyaline casts: suggest pre-renal

case 1 A 35-year-old woman is brought to the emergency room after a motor-vehicle accident in which she suffered a fractured femur. The accident occurred 1h prior to the patient being found by the side of the road, still trapped in her severely damaged car. On the scene her pulse rate was 120 pulsations/min, her BP was 90/50 mmHg and she appeared confused. She was transported at a tertiary center for further management. • After 2 hours from admission, it was noted that her urinary output was < 0.5 mL/Kg/h. • What findings are expected to be revealed on laboratory investigations? (more options may be true) A. Urine output < 0.5 mL/Kg/h B. Urinary Na < 20 mEq/L C. K+ 6 mEq/L D. Urea 19 mg/dL E. Creatinine > 1.2 mg/dL F. Urea : creatinine ratio > 20:1 G. FENa < 1 mEq/L H. Urine osmolality > 450 mOsmol/L I. Metabolic alkalosis

A. Urine output < 0.5 mL/Kg/h B. Urinary Na < 20 mEq/L C. K+ 6 mEq/L E. Creatinine > 1.2 mg/dL F. Urea : creatinine ratio > 20:1 G. FENa < 1 mEq/L H. Urine osmolality > 450 mOsmol/L I. Metabolic alkalosis

case 17 A 59-year-old woman with multiple myeloma is started on chemotherapy. Her baseline creatinine is 1.1 mg/dL. Three days later she is admitted in the Emergency Department with a urine output of 400 mL in the past 24h. Her creatinine is now 8.2 mg/dL. What is the explanation for this patient's condition? A. Bence-Jones proteinuria B. Hyperuricemia C. Side effects of cisplatin D. Hypercalcemia E. Hyperoxaluria

B. Hyperuricemia -ATN b/c of chemotherapy

case 10 • A 36-year-old previously healthy woman c/o shortness of breath for 1 week. She also reports that her legs are swollen. She had a bad sore throat 4 weeks ago - now resolved. • Vitals: pulse 80/min, BP 150/90; 1+ pedal edema; auscultation of lungs: few bilateral basal crackles. • BUN 40 mg/dL; Creatinine 5.0 mg/dL; Na =145 mEq/L; K 6 mEq/L • Anti-streptolysin O positive • Anti-DNAse positive. Urine: • Urine Cr =50 mg/kg body weight/day; Urine Na =30 mEq/L • Protein excretion 900 mg/24h What is the most likely cause of the patient's condition? A. Hemolytic uremic syndrome B. Post-infectious glomerulonephritis C. Allergic acute interstitial nephritis D. Acute tubular necrosis E. Prerenal azotemia

B. Post-infectious glomerulonephritis Microscopy: red cell casts

case 2 A 60-year-old man with a history of mild hypertension has a heart attack in the parking lot and is brought to the emergency department. On arrival, he is pale, cold, diaphoretic, and his BP is 80/40 mmHg supine. The ECG and troponins confirm an inferior myocardial infarction. He receives appropriate treatment, but during the resuscitation he is noted to be oliguric. BUN:creatinine ratio is 24:1 and urinalysis reveals hyaline casts. Which of the following is best explaining this presentation? A. Acute tubular necrosis B. Pre-renal azotemia C. Stress reaction D. Allergic interstitial nephritis E. Urinary tract obstruction

B. Pre-renal azotemia ~b/c hyaline casts, history, BUN:Cr ratio Dx: cardiogenic shock

from case 1 Prompt management of this condition prevents lesions most likely located in which areas of the nephron? A. Glomerulus B. Straight segment of PCT C. Convoluted segment of PCT D. Macula densa E. Distal convoluted tubule F. Collecting duct

B. Straight segment of PCT What is the next best step in the management of this patient? -fluids

Case 8 • A 34-year-old previously well man presents with malaise, nausea and anorexia. The previous week he was seen in Urgent Care for an episode headaches, nausea, abdominal pain and diarrhea, after cleaning his boat engine with a carbon tetrachloride - based agent in his small and poorly ventilated garage. He was diagnosed with diarrhea and was discharged on supportive treatment. Diarrhea resolved, however the other symptoms persisted, and he noted that he is passing dark urine in very small amounts. • Vitals: apyrexial, BP 190/110 mmHg, PR 100/min, RR 23/min. He is pale and periorbital edema is noted. There is no jaundice. Cardiopulmonary examination does not reveal any abnormalities. His liver span is 14 cm. • Investigations: CBC: Hb 7 mg/dL; MCV 76; WBC 19200; Serum: BUN 80 mg/dL; Creatinine 8.9 mg/dL; Na 125 mEq/L; K 7.1 mEq/dL; Cl 90 mEq/dL; Urine: Total urine output in 24h: 150ml, with sg 1015. Urine sediment: numerous granular casts What is (are) the cause(s) of the patient's condition? A. Acute pyelonephritis B. Acute interstitial nephritis C. Acute tubular necrosis D. Papillary necrosis E. Prerenal azotemia F. Rapidly-progressing glomerulonephritis

C. Acute tubular necrosis The ECG is hyperkalemia what to do for this patient? 1. calcium gluconate 2. K+ lowering drugs

case 13 • You are asked to consult on a 25-year-old female patient hospitalized for osteomyelitis following an open fracture of her femur in a ski accident. She is treated with methicillin, ibuprofen and morphine PDA. • Recently she started to be feverish (100.9oF) and developed a rash on her arms. Her examination is otherwise normal. Her attending orthopedic surgeon is most concerned about a rapid rise in the creatinine over the past 24 hours. BUN 25 mg/dL, creatinine 3.5 mg/dL. • CBC shows mild eosinophilia. • Urine sediment shows 5 RBC/hpf, 50 WBC/hpf, WBC with some eosinophils and scanty eosinophil casts. Proteinuria of 400 mg/day on the 24-h collection specimen. U-Na is 50 mEq/L and FENa > 2%. What is the most likely diagnosis? A. Prerenal acute kidney injury B. Acute tubular necrosis C. Acute tubulo-interstitial nephritis D. Post-infectious glomerulonephritis E. Hemolytic uremic syndrome

C. Acute tubulo-interstitial nephritis -Methicillin is the main culprit in this case

Case 7 • A previously well 23-yr-old female with a recent history of recurrent headaches, which she has been treating with a magnesium-containing herbal medication, presents to her primary care physician with diarrhea for 1 week and cola-colored urine for 3 days. Her mother is 47 years old and is on treatment for Hashimoto's thyroiditis. No other significant FH. • Vitals: temp 100.6oF, BP 220/120 mmHg, pulse 55 beats/min, RR 14/min, SpO2 98%. She is alert and fully oriented. She has mild periorbital edema and fundoscopy reveals grade 2 hypertensive changes. The cardiopulmonary examination is within normal limits. Few petechiae and a blotchy erythematous, non-blanching, nonpruritic rash on her lower extremities. Neurologic examination is normal. Investigations • CBC: WCC normal at 7.9 × 103/μL, hemoglobin 11.7 g/dL, and hematocrit 36%, platelets 100 x 103/μL. • Urinalysis: gross hematuria with numerous dysmorphic RBCs (including acanthocytes) and RBC casts; numerous white blood cells; • Proteinuria 200 mg/24h. • Electrolytes: Na 133 mEq/L, K 4.9 mEq/L, Cl 102 mEq/L, HCO3 21 mEq/L, Ca 7.5 mg/dL, and Mg 2.2 mg/dL • Renal function: BUN 46 mg/dL, creatinine 3.4 mg/dL, GFR 49 mL/min/BSA. • Stool: negative for leukocytes and blood; cultures for Clostridium difficile were negative, and ova and parasite exams were pending. • Reveals a history of early morning stiffness of her finger joints. • Complains of occasional ulcers in mouth. • Often develops a butterfly rash over her face on exposure to sun. The investigations results are shown below: • Hepatitis B and C serologies: negative. • Rheumatoid factor: weakly positive. • C3: low. • Antinuclear antibody (ANA): positive at 1:320. • Anti-double-stranded DNA and anti-SCL-70 studies: pending. • Renal biopsy: pending Hospital admission • The patient is admitted to the nephrology ward and her elevated BP is managed successfully with intravenous nicardipine. • After 24h the patient develops a three-component friction rub on cardiac auscultation, and the urine output is 0.5 mL/Kg/day • Renal function evaluation: BUN 62 mg/dL, creatinine 6.4 mg/dL, GFR 38 mL/min/BSA • K+ 6.5 mEq/L Why would IV nicardipine be preferred over IV nitroprusside in the management of this patient's hypertensive emergency? A. Nicardipine has a faster onset of action compared to nitroprusside. B. Nitroprusside is delivered as a potassium salt and the potassium level is high. C. Nitroprusside can be toxic in patients with renal insufficiency. D. Nicardipine is more effective than nitroprusside in patients of AfroCaribbean descent. E. Nicardipine has a greater effect on reducing venous tone.

C. Nitroprusside can be toxic in patients with renal insufficiency. BP 220/120 mmHg (malignant hypertension) *dont want to use nitroprusside b/c it will cause cyanoide intravenous nicardipine~ vasodilator

case 19 A 65-year-old man is brought in by his wife with a 3 days history of malaise, anorexia, and confusion for the past 3 days. Generally healthy and independent, he had been well, except for a cold several days ago, for which he was treated with a decongestant. Over the last 3 days, he has seemed tired and a little confused. He has been drinking liquids but not eating much. He has had a couple of episodes of urinary incontinence, which he he had never had before. On examination, his temperature is 36.5oC, his abdomen is soft, non-tender, and his prostate is mildly enlarged, without nodules. Initial laboratory test results include Na 138 mEq/L; K 4.8 mEq/L; Cl 100 mEq/L; HCO3 20 mEq/L; BUN 90 mg/dL; creatinine 7.2 mg/dL. Urinalysis shows RBC 10/hpf. What is the leading hypothesis in this case? A. Acute tubular necrosis B. Acute interstitial nephritis C. Postrenal AKI D. Prerenal azotemia E. Urinary tract infection

C. Postrenal AKI

case 5 A 22-year-old male with sickle cell anemia and abdominal pain has been vomiting nonstop for 2 days. Vitals: pulse 100/min, BP 90/70. PE: Dehydrated 10% Labs: BUN 50 mg/dL, S Cr 2.0 mg/dL. What is the most likely cause of this patient's condition? A. Renal infarction B. Acute interstitial nephritis C. Prerenal azotemia D. Acute tubular necrosis

C. Prerenal azotemia ~hyaline cast

~FENa ~BUN : creatinine ratio

FENa • % of Na excreted adjusted for urine volume • Prerenal: < 1% (intact tubuli => most filtered Na reabsorbed) • Intrinsic AKI: > 2% (Na wasting) • Postrenal AKI: may start with <1% and progress to >2% BUN : creatinine ratio • Prerenal: > 20 • Intrinsic AKI: < 20 (10-15) • Post-renal AKI: unreliable

case 16 A 40-year-old man is hospitalized after a motor vehicle accident. He is noted to be hypotensive and is given a transfusion with packed red blood cells, after which he is transferred to ICU. On the second day from admission, the patient develops edema and oliguria. His FENa is 4% and urinalysis shows numerous muddy brown epithelial and granular casts. What is the most likely cause of this presentation? A. Acute pyelonephritis B. Cortical necrosis C. Acute interstitial nephritis D. Acute tubular necrosis E. Prerenal azotemia

D. Acute tubular necrosis

case 3 A 63-year-old woman with a history hypertension, mild heart failure and osteoarthritis presents for follow up after being started on ibuprofen for severe shoulder pain 3 weeks ago. Her usual medications are atenolol, lisinopril and acetaminophen. Her serum creatinine was checked 6 months ago, and it was 1.1 mg/dL. Today her laboratory test results show: Na 141 mEq/24 h; K 5.0 mEq/24 h; Cl 100 mEq/24 h; HCO3 20 mEq/L; BUN 32 mg/dL; creatinine 2.5 mg/dL; FENa 0.9%; urine sediment 3 RBCs/hpf, 5-10 WBCs/hpf, no casts. What is the most likely diagnosis? A. Acute tubular necrosis B. SLE nephritis C. Hypertensive nephrosclerosis D. Acute interstitial nephritis E. Renal hypoperfusion

E. Renal hypoperfusion

from case 8 What is your management plan for this patient? A. Continue with supportive therapy. B. Calcium gluconate, then insulin and glucose to decrease potassium levels. C. Insulin and glucose, followed by kayexalate and inhaled albuterol. D. Magnesium, then 5% dextrose/water together with insulin. E. Calcium gluconate, followed by insulin and glucose, kayexalate and inhaled albuterol. F. Magnesium, followed by insulin and glucose, as well as kayexalate and inhaled albuterol.

E. Calcium gluconate, followed by insulin and glucose, kayexalate and inhaled albuterol.

case 14 A 62-year-old woman is admitted with acute left lower quadrant abdominal pain. She also has fever, chills and noticed blood in her stool. Blood cultures identify E Coli and Candida albicans. The non-contrast and contrast CT scan on admission is consistent with acute diverticulitis. The patient's renal function indicates a BUN of 15 mg/dL and sCr of 0.9 mg/dL. The patient is immediately started on intravenous vancomycin, gentamicin, metronidazole and amphotericin B. After 36 hours, BUN is 20 mg/dL and sCr is 2 mg/dL. Which of the following is the most likely cause of the patient's renal function change? A. Vancomycin B. Gentamicin C. Metronidazole D. Amphotericin B E. Contrast media

E. Contrast media -give a ton of fluids so the kidney can get rid of it

case 15 A 40-year-old woman undergoes a reduction of an open humeral fracture under general anesthetic, which is complicated by fat embolism. The next day the patient develops anuria, flank pain and gross hematuria. On physical examination, a new cardiac friction rub is noted. Laboratory tests show an abrupt increase in creatinine, to three times the baseline values. The ultrasound demonstrates hypodensities within the renal cortex, and on this basis the patient is diagnosed diffuse cortical necrosis. What is the most appropriate management in this case? A. Broad-spectrum antibiotics B. Renal biopsy C. Active monitoring D. Aggressive fluid support E. Hemodialysis

E. Hemodialysis

case 12 • An 18-year-old girl presents with fever, vomiting, abdominal pain, diarrhea that lasted for 4 days. She also noticed blood in the stool. Now diarrhea is resolved, but she is feeling weak and for about 12 hours passed only a cupful of red urine. • Physical examination: • Vitals: temperature 100.8oF, RR 18, PR 110, BP130/90mmHg • Pale, lethargic, about 5% dehydrated • Abdomen diffusely painful but soft, normal bowel sounds • Neurological examination within normal limits Bedside tests: • Urine dipstick: • Blood 4+ • Protein 3+ • Hb 8g/dL • Urinalysis: proteinuria 500 mg/24h, red blood cells (RBCs) and RBC casts may be present Serum chemistry: • BUN 30 mg/dL, creatinine 3.4 mg/dL, Na 132 mEq/l, K 5 mEq/L • Hematology: • Hb 7.8 g/dL, WBC 20000/mm3; platelets 70000/mm3; • Peripheral blood smear: corrected reticulocyte count 5.4%; schizocytes 15% • Clotting profile normal Hemolytic workup: • Bilirubin: Total 1.31 mg/dL; Direct 0.19 mg/dL; • LDH 2500 U/L; • Haptoglobin 10 mg/dL (normal 41 - 165 mg/dL); • Coombs negative Stool culture: positive E coli 0157:H7 • ADAMTS-13 activity: 70% of normal What is the most likely cause of the patient's condition? A. Acute tubular necrosis B. Acute interstitial nephritis C. Post-streptococcal glomerulonephritis D. HIV-induced nephritis E. Hemolytic uremic syndrome

E. Hemolytic uremic syndrome

case 11 A 30 y-o man is admitted with recurrent, prolonged, ongoing generalized tonic-clonic convulsions that were terminated with intravenous lorazepam in the emergency department. He has no chronic illnesses, but he has a long history of amphetamine use, currently under therapy. The patient is transferred to high care and monitored closely. Within the next 24 h, it is noted that his urine output is 0.4 mL/kg/h. His vitals show a temperature of 37.1oC, BP 140/90, pulse 80/min, respiratory rate of 16/min. He has bibasilar lung crackles on auscultation, and mild pitting pedal edema. Serum chemistry results are as follows: BUN 40 mg/dL, creatinine 6.4 mg/dL, K 6.2 mEq/L. Urinalysis shows +2 protein, +3 blood, but no RBCs or WBCs on microscopy. Which of the following is the most likely cause of this patient's observed abnormalities? A. Renal infarction due to arterial obstruction B. Glomerular injury due to immune complexes C. Tubular injury due to light-chain deposition D. Tubular injury due to interstitial inflammation E. Tubular injury due to released myoglobin F. Tubular injury due to released hemoglobin

E. Tubular injury due to released myoglobin -myoglobin cause a false 3+ blood dipstick tonic-clonic~ when mm. contract they release myoglobin, K+, creatinine

case 18 A 23-year-old man is beginning chemotherapy for leukemia when he develops severe intermittent left flank pain that soon migrates to the pelvis. Three days later, the patient's creatinine level to 6.8 mg/dL and his urea is 23 mg/dL. His FENa is > 4% with urinary osmolality of <350 mOsm/kg. Blood and urine cultures are negative for bacteria and eosinophilia. An abdominal X-Ray fails to locate any pathology. Which of the following is the most likely location of the lesion causing this patient's presentation? A. Glomeruli B. Renal interstitium C. Renal tubules D. Left ureter E. Urethra

E. Urethra

Prerenal azotemia

ETIOLOGY -Hypovolemia - ↓ cardiac output - ↓ effective circulating volume (eg, HF, liver failure) PATHOPHYSIOLOGY ↓ RBF → ↓ GFR → ↑ reabsorption of Na+/H2O and urea URINE OSMOLALITY (mOsm/kg) >500 URINE Na+ (mEq/L) <20 FENa <1% SERUM BUN/Cr >20

Postrenal azotemia

ETIOLOGY -Stones -BPH -Neoplasm -Congenital anomalies PATHOPHYSIOLOGY Outflow obstruction (bilateral) URINE OSMOLALITY (mOsm/kg) varies URINE Na+ (mEq/L) varies FENa varies SERUM BUN/Cr varies

Intrinsic renal failure

ETIOLOGY Tubules and interstitium: -Acute tubular necrosis (ischemia, nephrotoxins) -Acute interstitial nephritis Glomerulus: -Acute glomerulonephritis Vascular: -Vasculitis -Hypertensive emergency -TTP-HUS PATHOPHYSIOLOGY In ATN, patchy necrosis → debris obstructing tubules and fluid backflow → ↓ GFR URINE OSMOLALITY (mOsm/kg) <350 URINE Na+ (mEq/L) >40 FENa >2% SERUM BUN/Cr <15

Acute interstitial nephritis

Etiology: • Drugs (70-75%) • Virtually any drug can cause AIN, but mostly if drugs likely to cause type I (IgE mediated) allergy and those causing Stevens-Johnson syndrome, toxic epidermal necrolysis, hemolysis. • Common causes of AIN: NSAIDs, beta-lactam antibiotics, sulfa drugs (furosemide, thiazides, antibiotics), quinolones, rifampicin, cimetidine, proton pump inhibitors, allopurinol, phenytoin Autoimmune or systemic disease (10-20%): • SLE, Sjogren, sarcoidosis, Wegener granulomatosis Non-renal infections (4-10%): • Legionella, strep B, leptospirosis, mycobacteria, E Coli, Candida, adenovirus, EBV • Tubulo-interstitial nephritis with uveitis (5-10%)

case 20 A 71-year-old male patient with a past medical history of hypertension and diabetes mellitus presents with aching chest pain on exertion and difficulty passing urine. On abdominal examination, a mildly tender mass is palpable about 1 in/2 cm above the pubic symphysis, in the midline. On rectal examination, the prostate is smooth and enlarged. The patient's creatinine is 6 mg/dL. A Foley catheter is placed, and about 1300 mL of straw-colored urine is passed over 10 minutes. Subsequently, the patient's creatinine is found to be 1.2 mg/dL. Which is the most likely cause of this patient's presentation? A. Pre-renal azotemia B. Ischemic acute tubulo-necrosis C. Toxin-induced tubulo-necrosis D. Allergic acute tubulo-interstitial nephritis E. Papillary necrosis F. Post-renal AKI G. Prostate cancer

F. Post-renal AKI

from case 7 Immunofluorescence

Glomerulus stained for C1q: • granular mesangial and capillary wall staining. • segmental confluent granular capillary wall staining (arrow) corresponding to large subendothelial deposits (wire loop lesions).

Microangiopathic nephropathy: Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) ~Labs

Labs: - Picture of hemolytic anemia with schizocytes in peripheral blood smear and evidence of hemolysis with a negative anti-globulin test. - Unlike DIC, PT and PTT are normal.

criteria differentiating between papillary necrosis vs acute pyelonephritis

Papillary necrosis Onset: Few hours Symptoms: Passed necrotic material in urine Urine culture: Negative CT scan: Bumpy contour of the structure where the papillae were lost Treatment: No treatment Acute pyelonephritis Onset: Few days Symptoms: Dysuria Urine culture: Positive CT scan: Diffusely swollen kidney Treatment: Antibiotics (anti-Gramnegative bacilli)

Analgesic nephropathy

Prolonged and excessive use of analgesics, and especially NSAIDs, causes renal damage through multiple mechanisms: • ATN: direct toxicity to tubuli • AIN: allergic interstitial infiltrate • Membranous GN • Vascular insufficiency: inhibits PG => constriction of afferent arteriole => decreased renal perfusion • Papillary necrosis due to direct toxicity and sudden vascular insufficiency in patients at risk: o DM o Sickle cell disease o Obstructive nephropathy o Chronic pyelonephritis

AKI etiology

There are 3 types of AKI: 1. Pre-renal: the main abnormality is decreased blood delivery to the kidney; 2. Intrinsic: the abnormality is within the kidney; 3. Post-renal: the abnormality is obstruction in the urine flow

Pre-renal AKI~ Pathogenesis

a. Decreased intravascular volume ("true" intravascular volume depletion) i. Hypovolemia (dehydration, hemorrhage) ii. Hypo-albuminemia iii. "Third spacing" (ascites) iv. Diuretics b. Reduced cardiac output: i. Cardiogenic shock ii. CHF iii. Tamponade iv. Cirrhosis (hepato-renal syndrome) c. Changes in vascular resistance - systemic vasodilatation i. Sepsis ii. Anaphylaxis iii. Anti-HTN Rx (eg: ACE inhibitors, ARBs) d. Local renal hypoperfusion i. Renal artery stenosis, embolism, thrombosis (especially bilateral) ii. NSAID's iii. ACE-inhibitors, ARB's

Most common cause of toxic drug-induced ATN =

contrast media o High urine osmolality despite very low urine [Na]. o Why: constriction afferent arteriole => tubular dysfunction => massive resorption of Na and H2O. o Very rapid rise in creatinine (~24h post-exposure -> peak 3 d -> baseline 10 d) o Note here that vancomycin, gentamicin and amphotericin B may all cause AKI but never after only one dose and usually take 5-10 days to cause tubular damage.

Tubulopathies

i. Acute tubular necrosis/ATN ii. Crystallopathies o Pigment nephropathy o Uric acid nephropathy o Renal cholesterol embolism

Extra-renal vascular disease:

i. Bilateral renal artery stenosis (RAS) ii. Renal artery thrombosis/Renal infarction/cardioembolic disease

Intrarenal vascular disease

i. Microangiopathic nephropathy: Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) ii. AKI in patients with hypertension and CKD iii. Papillary necrosis

Ischemic ATN~ Pathophysiology:

i. Renal hypoperfusion due to decreased blood flow to the kidney results initially in prerenal AKI (reduced blood flow to the afferent artery means decreased GFR - thus AKI). ii. If prolonged, the prerenal AKI caused by hypoperfusion leads to ATN due to renal ischemia and even necrosis iii. Note that "hypoperfusion" is in fact a stage where the decreased blood flow through the kidney did not yet cause real damage to the glomerulus, while "ischemia" and "necrosis" are terms used for the stages where there is already reversible damage (ischemia) or irreversible damage (necrosis) to the nephron. Thus, simple "hypoperfusion" is only the initial event in the development of ischemia and necrosis. iv. If ischemia is not addressed and it is prolonged => local release of inflammatory mediators => vasoconstriction and damage to the glomerulus => decreased eGFR. 12 v. Also, there is significant tubular damage with shedding of tubular epithelial cells. These cells become embedded in the hyaline casts and will cause them to appear brown and granular ("muddy-brown" granular casts). The casts will block the tubular lumen and lead to a backflow of urine ultrafiltrate back into the Bowmann's capsule, with a corresponding increase in the glomerular hydrostatic pressure, which will further decrease the eGFR. vi. Inflammatory elements accumulate in the interstitium, perpetuating the cycle of tubular destruction.

There are 2 major causes of ATN

ischemic and toxin-induced

Ischemic ATN

o Most common o Prolonged, untreated prerenal AKI => patchy loss of tubular epithelial cells with tubular dilatation; flattened tubular cells with loss of brush border and subsequent necrosis and denudation of tubular basement membrane o Most affected = most metabolically-active epithelial cells in the terminal (straight) part of PCT and thick part of loop of Henle (medulla)

Light chain cast nephropathy (multiple myeloma, gammopathies)

o Pathophysiology: neoplastic plasma cell producing monoclonal Ig chains = paraproteins; osteoclast activation leading to osteopenia and lytic lesions in bones. o Presentation: bone pain (often lower back ache due to lytic lesions in the vertebral bodies); constitutional symptoms (weight loss, fatigue); recurrent infections (impaired immunity); constipation and muscle weakness (due to hypercalcemia). o Labs: normocytic anemia; AKI/CKD; hypercalcemia, monoclonal proteinemia (the M-spike); proteinuria with a gamma-gap (= total protein minus albumin) of at least 4 g/dL. o Note that urine dipstick may be negative for protein because most commercial kits only detect albumin, not small molecular-weight proteins.

Pre-renal AKI~ Pathophysiology

o The normal response of the kidney to poor perfusion = concentrate the urine maximally and avidly reabsorb sodium, in an effort to maintain/increase intravascular volume and normalize renal perfusion Mechanism: ▪ Decreased renal blood supply → failure of renal vascular autoregulation to maintain renal perfusion → decreased GFR → activation of RAAS (reninangiotensin-aldosterone system) → increased aldosterone release → increased reabsorption of Na+ , H2O → increased urine osmolality → secretion of ADH → increased reabsorption of H2O and urea. ▪ However, creatinine is still secreted in PCT => sBUN/sCr increases. Effects of reduced local renal perfusion of medications: ▪ In normal individuals who are not on any medications, a reduced renal perfusion by itself may not lead to AKI due to the increased vasodilatory PGs that dilate the afferent arteriole and the RAAS activation that constricts the efferent arteriole. ▪ But in elderly patients and in patients on Rx with NSAIDs and ACE-I/ARBs, the reduced renal perfusion leads to AKI.

Microangiopathic nephropathy: Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) ~Pathology ~Presentation

presentation: • Prodromal diarrhea in Stx-HUS • HUS = TRIAD: AKI, microangiopathic hemolytic anemia, thrombocytopenia with purpuric rash • TTP = PENTAD: fever, thrombocytopenia with purpuric rash, microangiopathic hemolytic anemia, neuro impairment, AKI • Neuro disturbances typical for TTP (less in HUS - when usually associated with azotemia) • AKI typical for HUS (less in TTP) • Diagnosis = initially based on clinical presentation - this is an emergency and treatment should not be delayed while waiting for investigations

~Urinalysis ~Urine [Na] ~Urine osmolality

~Urinalysis Prerenal causes: • <10 cellular casts/hpf (often none or hyaline casts: parenchyme intact) Intrinsic AKI: • > 10 cellular casts/hpf • Type of casts depends on etiology ~Urine [Na] • Prerenal AKI (normal reabsorptive capacity): fluid depletion causes H2O retention => Na retention => low U-[Na] < 20 mEq/L • Intrinsic AKI due to tubular injury: Na not reabsorbed => lost in urine => increased U-[Na] > 40-50 mEq/L ~Urine osmolality • Prerenal: (tubules not damaged): If dehydration => increased AD => H2O reabsorbtion => Uosmol > 500 (high sg) • Intrinsic AKI: loss of concentrating ability => U osmol < 450 mOsmol/kg (similar to blood osmol = 300 = isosthenuria => inappropriately high losses of H2O and Na.

Gentamicin

• = most common cause of drug-induced ATN • Filtered across glomerulus, concentrates in PCT => impairs lysosomal function, protein synthesis and mitochondrial activity => ATN with focal lesions => loss of resorptive capacity of PCT => secondary Fanconi syndrome. • Dose dependent (after more than 2-3 doses) • Onset after 5-10 days (like most drug-induced non-oliguric ATN). - Other drugs causing toxic ATN: cisplatin, acyclovir, vancomycin and amphotericin B.

Papillary necrosis

• = sloughing off of the renal papillae caused by drugs (NSAIDs) and toxins, or by sudden vascular obstruction with ischemia => death of the cells in papillae and their shedding off in the collecting system of the kidney. - There is always a background of underlying, pre-existing renal damage - even though sometimes baseline BUN and creatinine seem normal (remember that creatinine only starts rising when a patient has already lost 60-70% renal function) - Patients complain of sudden onset flank pain, fever, hematuria - quite difficult to distinguish from acute pyelonephritis, so you need to look for a history of drug use and prior kidney disease (chronic pyelonephritis, urinary obstruction), sickle cell disease or diabetes mellitus.

AKI in patients with hypertension and CKD

• AKI = form of acute target organ dysfunction in patients with baseline chronic kidney disease (CKD). Any degree of AKI in patients with severe acute BP elevations ("malignant hypertension") and CKD is associated with a greater risk of morbidity and mortality. • Malignant hypertension causes severe damage to tiny arteries called arterioles. Arterioles anywhere in the body can be affected, but it is the eyes, the brain and the kidneys that are most commonly worst affected. • Symptoms: severe, frequent and persistent headache (uncommon with HTN unless BP is very high). Brain involvement sometimes causes hypertensive encephalopathy with seizures and altered level of consciousness. Eyesight may be blurred, and scotomas are noted. • Damaged retinal arteries and arterioles can be seen on fundoscopy, and the optic disk evidences papilledema. • Kidney damage can occur rapidly, and it may cause complete severe AKI/ESRD with anuria.

Ethylene glycol poisoning

• Common exogenous toxin - high yield topic in the board exams! • Causes ATN by: direct tubular injury via its metabolite glycolic acid; and also tubular obstruction due to precipitation of oxalic acid. • Affects mainly PCT • Characteristic high-anion gap metabolic acidosis with high osmolar gap.

Post-renal AKI~ Pathophysiology

• Initially the blockage of the urinary tract will cause a back-flow of ultrafiltrate into the Bowman capsule that will slow down the glomerular filtration and decrease the GFR, hence you see raised creatinine, hence the patient has AKI. • Remember that filtration pressure is roughly the difference between the hydrostatic pressure in the capillary that pushes the fluid out of the capillary on one hand, and the oncotic pressure in the capillary (which keep the fluid inside) as well as the hydrostatic pressure in the Bowman's capsule. • If the there is a back-flow of ultrafiltrate, the hydrostatic pressure will increase in the capsule with a decrease in the overall filtration pressure, and thus filtration will be slowed down or even stopped. Initially, the glomerulus is not damaged, thus in the first stages FENa will be 1% or even less. • In time however, if the blockage is not relieved (eg. by catheterizing the bladder), filtration stops. Also, the glomerulus and the tubuli will be damaged due to the raised pressure of the urine back-flow. The result will be irreversible renal damage, where the post-renal AKI manifests itself as intrinsic AKI, with FENa > 2%. This happens for instance in acute hydronephrosis. • Therefore, in post-renal AKI initially FENa may be 1% or less, and later, when it causes intrinsic renal damage, FENa will become 2%. • Thus, FENa is not so useful to diagnose UT obstructions - you need to rely more on your clinical skills for your differential, than just looking at FENa.

Dx. Lupus nephritis: Active global diffuse proliferative GN (class IV-G A)

• Presentation: diffuse and global hypercellularity where >50% of the glomeruli are involved (in fact, all glomeruli), with each glomerulus having more than half of the profile involved. • Characteristic infiltrate: leukocytes with karyorrhexis (big nucleus that are diffuse) • Immunofluorescence: subendothelial deposits in the form of hyaline thrombi => wire loop lesions that stain with "full-house" immunofluorescence, all features of diffuse proliferative lupus nephritis.

from case 7 The following chest x-ray is obtained. What is your diagnosis?

• The patient was later ordered a chest CT scan, which showed mild pericardial effusion and bilateral pleural effusions. • How do you manage this presentation? -hemodialysis -then calcium gluconate

Post-renal AKI

• This type of AKI may be suspected when there is a history of anuria/oliguria, full bladder sensation, and a suprapubic fullness, which corresponds on abdominal palpation to a suprapubic mass. • Note that the obstruction must cause bilateral blockage of the urine flow. Thus, obstruction of one of the ureters in a patient who has both kidneys may cause hydronephrosis on the obstruction site, but no AKI.

. Acute interstitial nephritis~ DIAGNOSTIC

• Typically -> non-specific symptoms and signs of AKI => must be distinguished from other AKI causes. • Distinguishing clinical features of drug-induced AIN = fever, rash, arthralgia in a patient with AKI, 3-5 days after exposure. Tests: Urine: • WBC and WBC casts • Eosinophiluria - eosinophils and eosinophil casts on Hansel stain - confirms AIN, but not present in all patients • Other conditions with eosinophiluria: UTI (cystitis, pyelonephritis) and prostatitis • Imaging: U/S • Biopsy: gold standard. The only definitive method to distinguish AIN from other causes of AKI = renal biopsy. However, biopsy used only when diagnosis is unclear, or the patient does not improve after removal of possible causes and there are no contraindications.