Renal Week 2

Factors affecting renal phosphate excretion.

Sodium: Saline infusion increases renal phosphate excretion. Calcium:Hypercalcemiaincreases phosphate excretion. Phosphate: Low dietary phosphate decreases phosphate excretion. Proton: Acute acidosis increases phosphate excretion. Parathyroid hormone, calcitiol, and phosphatonin(FGF23) are the major regulators for phosphate homeostasis. Glomerular filtration rate: Decreased glomerular filtration rate is the major cause of hyperphosphatemiafor chronic kidney disease.

membranous nephropathy (histo 8)

Light Microscopy Thick GBM with "spikes" Immunofluorescence Diffuse fine granular deposits on capillary walls Usually IgG, C3 Electron Microscopy Numerous, small subepithelial immune deposits Reactive "spikes" of GBM Effacement of podocyte foot processes

Recognize a mixed acid-base disorder

Look for clues in patient history, amount of compensation (inadequate or excessive), and from serum electrolytes and anion gap. If the numbers don't add up, check the pH using the Henderson- Hasselbach equation.

focal segmental glomerulosclerosis (FSGS) (histo 4)

Light Microscopy Focal glomeruli with scarring/sclerosis of a segment of the glomerular capillary tuft Immunofluorescence Trapping of C3 and/or IgM in areas of sclerosis (non-specific) Electron Microscopy Accumulation of matrix material, cells, plasma protein in sclerotic area No immune deposits Primary: Diffuse effacement of podocyte foot processes Secondary: Patchy or variable effacement of foot processes

Diabetic nephropathy (histo 1)

Light Microscopy Glomerular nodules of matrix material, thickened GBM Thick tubular basement membranes, fibrosis of interstitium, vascular sclerosis Immunofluorescence No immune deposits Pseudolinear staining of glomerular and tubular BM with IgG and albumin due to "stickiness" of basement membranes Electron Microscopy Diffuse thickening of GBM Expansion of mesangium with increased matrix No immune deposits Variable foot process effacement More severe in advanced disease

Diabetic nephropathy (histo 2)

Light Microscopy Glomerular nodules of matrix material, thickened GBM Thick tubular basement membranes, fibrosis of interstitium, vascular sclerosis Immunofluorescence No immune deposits Pseudolinear staining of glomerular and tubular BM with IgG and albumin due to "stickiness" of basement membranes Electron Microscopy Diffuse thickening of GBM Expansion of mesangium with increased matrix No immune deposits Variable foot process effacement More severe in advanced disease

Discuss the risk factors for progression of CKD to end-stage-renal-disease (ESRD)

1. Proteinuria > 1.0 grams per day 2. Hypertension 3. Type of underlying disease (i.e. diabetes mellitus, polycystic kidney disease) 4. African-American race 5. Male gender 6. Obesity a. Increases glomerular capillary pressure 7. Hyperlipidemia a. High lipid levels are associated with a faster rate of progression 8. Smoking 9. Hyperphosphatemia 10. Metabolic acidosis a. Bicarbonate supplementation appears to slow progression of CKD b. Mechanism thought to be due to reduction in tubulointerstitial inflammation 11. High protein diet a. Increases glomerular capillary pressure 12. Hyperuricemia a. Data emerging that treatment to reduce uric acid levels may slow the rate of GFR loss

Diabetic nephropathy (histo 3)

Light Microscopy Glomerular nodules of matrix material, thickened GBM Thick tubular basement membranes, fibrosis of interstitium, vascular sclerosis Immunofluorescence No immune deposits Pseudolinear staining of glomerular and tubular BM with IgG and albumin due to "stickiness" of basement membranes Electron Microscopy Diffuse thickening of GBM Expansion of mesangium with increased matrix No immune deposits Variable foot process effacement More severe in advanced disease

Identify complications of nephrotic syndrome.

A. Altered coagulation 1. Thromboembolism - Typically seen with >10 grams of proteinuria/24 hrs. a. Increased hepatic production of procoagulation factors. b. Anticoagulant factors lost through glomerular capillaries (anti-thrombin III). c. Concomitant volume depletion from diuretic therapy + reduced oncotic pressure in the vasculature leads to hemoconcentration and increased platelet aggregation. d. Thrombus formation i. Predilection for renal vein thrombosis (likely due to loss of fluid across the glomerulus and ensuing hemoconcentration in the postglomerular circulation). B. Infection 1. Due to immunoglobulin loss in the urine. 2. Common infections: Staphylococcus and Streptococcus pneumoniae

Identify the consequences of CKD and understand the relationship to cardiovascular disease

A. Cardiovascular disease 1. Majority of patients with CKD will die from cardiovascular disease rather than progressing to end-stage-renal-disease (ESRD) 2. Although CKD and cardiovascular disease share many of the same risk factors; even when these variables are factored out, there is an independent risk for developing cardiovascular disease in CKD patients 3. Both decreased GFR and increase in proteinuria increase the risk of cardiovascular disease 4. In this study, patients with stage 2-4 CKD were followed over 5 years. Most patients ended up dying from cardiovascular death rather than progressing to ESRD. The bulk of patients die from cardiovascular cause, particularly stage 3 CKD. B. Hypertension 1. Present in 80-85% of patients with CKD 2. Multifactorial including a. Sodium retention b. Increased activity of the renin-angiotensin system c. Enhanced activity of the sympathetic nervous system d. Secondary hyperparathyroidism (raises intracellular calcium --> vasoconstriction) e. Impaired nitric oxide synthesis and endothelium mediated vasodilitation C. Mineral-Bone Disorder (covered in your last lecture) 1. Decreased urinary phosphorus excretion 2. Compensatory increase in FGF-23 (phosphatonin) increases phosphate excretion in an attempt to maintain normal serum phosphorus concentrations 3. Decrease in 1,25 Vitamin D (FGF-23 inhibits 1-alph-OH'lase), decrease in serum calcium -->increase in PTH and secondary hyperparathyroidism 4. Can lead to osteomalacia (soft bones due to defective mineralization), osteitis fibrosa (high bone turnover), and vascular calcification D. Anemia 1. Decreased erythropoietin production from the kidney Hemoglobin (Hgb) < 13g/dL for men and post-menopausal women Hgb <12g/dL for pre-menopausal women ~ 90% of patients with GFR <30ml/min have anemia Due to decreased erythropoeitin (Epo) production

Distinguish 2 types of amyloid in renal disease and identify the treatment for each.

A. Definition and epidemiology 1. Group of diseases characterized by extracellular deposition of beta-sheet fibrils (abnormally folded protein) within kidney and other organs. 2. Cause of nephrotic syndrome in adults. B. Pathophysiology 1. Many different types, most important for renal disease are Primary (AL) and Secondary (AA). a. AL (primary) - Seen in patients with plasma cell myeloma; the abnormal protein consists of monoclonal immunoglobulin light chains (often lambda). b. AA (systemic reactive) - Seen in patients with chronic inflammatory diseases (i.e. rheumatoid arthritis, inflammatory bowel disease, hepatitis, chronic pyogenic infections including IV drug users). i. Protein - Serum amyloid A protein C. Renal Biopsy Findings 1. Light Microscopy a. Amorphous, pale eosinophilic material irregularly distributed in mesangium and along glomerular capillary loops. b. Also can be present in vessels and interstitium. c. Special stain: Congo red - Amyloid stains salmon or red color and shows apple green birefringence under polarized light. 2. Immunofluorescence a. Variable; may see light chain restriction if AL type (i.e. staining only for kappa without lambda, if the amyloid consists of kappa light chains). 3. Electron Microscopy a. Deposition of haphazardly arranged fibrils within the mesangium and glomerular basement membrane. b. Variable podocyte foot process effacement. D. Clinical course and treatment 1. Poor prognosis, progression to end stage renal disease is common. 2. Treatment - Nonspecific therapy outlined in Section VII should be initiated in primary and secondary amyloidosis. a. Primary - Chemotherapy, peripheral blood stem cell transplant. b. Secondary - Treat the underlying disease.

CARE OF CHRONIC KIDNEY DISEASE PATIENT

A. Early referral to a Nephrologist: a. Patients should be referred to a Nephrologist early in their course of disease b. GFR <60 ml/min or albuminuria > 300mg per day c. Early referral may be associated with lower health-care costs and decreased morbidity and mortality B. Cardiovascular risk factor modification: a. Given increased risk for cardiovascular disease, aggressive modification of cardiovascular risk factors is paramount 1. HMG-CoA reductase inhibitors (statins) for hyperlipidemia 2. Exercise, weight loss, tobacco cessation C. Preparation for renal replacement therapy a. Despite our best efforts at employing measure to halt or slow progression of disease (as outlined above), patients will progress to the need of renal replacement therapy b. Renal replacement therapy is typically needed when GFR drops to ~ 8-15ml/min c. If symptoms of uremia (nausea, vomiting, anorexia, dysgusia, pruritis or itching, altered sleep habits, impaired cognition, or pericardial effusion), renal replacement therapy should be started regardless of GFR d. Types of renal replacement therapy (Dr. Logan will be going over this in detail) 1. In-center hemodialysis 2. Home hemodialysis 3. Peritoneal dialysis 4. Kidney transplant e. Patients need to be educated about options for renal replacement early f. Pre-emptive transplant (transplant prior to dialysis) offers the best survival advantage (not always possible) g. If choosing hemodialysis, a permanent vascular access should be placed at least 12 weeks prior to the need of replacement therapy (i.e. arteriovenous fistula or arteriovenous graft) in order to avoid the use of catheters which carry a higher infectious risk Arteriovenous fistula (AVF) - connection between artery and vein in efforts to "arterialize" the vein. This will allow cannulation with large bore needles in order to access high blood flows (i.e. 500ml/min) during dialysis Performed when vasculature not able to permit AVF creation Higher rate of thrombosis Higher rate of infection vs. AVF Arteriovenous graft (AVG) Performed when vasculature not able to permit AVF creation Higher rate of thrombosis Higher rate of infection vs. AVF Tunneled vascular catheters Least desirable Highest infection rate Increased risk of great vessel stenosis

Identify the epidemiology, etiology, pathogenesis, clinical course and treatment of focal segmental glomerulosclerosis (FSGS), and understand that minimal change disease and FSGS are part of the same disease continuum.

A. Epidemiology 1. Most common cause of nephrotic syndrome in adults (~ 35% of all biopsies for nephrotic syndrome). 2. Second most common to minimal change disease in children. 3. Increased incidence in African-Americans and males. B. Etiology 1. Primary - Idiopathic and genetic/familial a. Familial forms are associated with genes encoding slit diaphragm proteins in the foot process of the podocyte, including nephrin, podocin, TRPC6, alpha-actinin-4. 2. Secondary - Heterogeneous, occurs in many forms of renal injury and systemic disease. a. Special associations: Loss of renal mass, obesity, HIV, Sickle Cell disease, drugs. C. Pathogenesis 1. Primary - Mechanisms of podocyte injury: a. Immune dysregulation - Systemic T-cell dysfunction, similar to MCD (same disease continuum but reduced responsiveness to therapy). b. Genetic mutations of podocyte proteins (as above) c. May involve presence of a circulating toxin which is supported by the rapidity of recurrent disease following renal transplant. 2. Secondary - Mechanisms of podocyte injury: a. Hyperfiltration and increased glomerular capillary hypertension (in reduced renal mass, obesity, Sickle Cell disease). b. Direct injury to the podocyte from virus (HIV). D. Renal Biopsy Findings 1. Light Microscopy a. Focal glomeruli show sclerosis (scarring) of a segment of the glomerular capillary tuft. b. Sclerotic lesions may have accumulation of collagen/matrix material, foam cells and/or proteinaceous material (hyaline). 2. Immunofluorescence a. No specific immune complex deposition. b. Non-specific trapping of immunoglobulins and complement (usually IgM and C3) in areas of sclerosis. 3. Electron Microscopy a. No immune deposits. b. Obliteration of a segment of the glomerulus by accumulation of matrix, cells and plasma protein material (hyaline). c. Diffuse podocyte foot process effacement in primary FSGS; variable/patchy effacement in secondary FSGS. E. Clinical course 1. Primary FSGS may present with acute or insidious onset. a. Hematuria in 30% of patients, hypertension, variable degrees of reduced function. 2. Secondary FSGS always presents with insidious onset. a. Presents more often with nephrotic range proteinuria (>3.5 g) rather than full nephrotic syndrome. 3. Untreated primary FSGS follows a progressive course to ESRD, rate of spontaneous remission <10%. a. 50% of patients have end stage renal disease in 10 years. b. Better prognosis for children than adults. 4. Risk factors for progression include high level proteinuria (i.e. >10g), reduced renal function (elevated creatinine), and presence of tubulointerstitial fibrosis. 5. Primary FSGS may recur after transplant, sometimes within days. a. See diffuse podocyte injury by EM first; then sclerotic lesions appear by light microscopy as recurrent disease progresses. F. Treatment: 1. Primary FSGS - Treatment similar to MCD a. All should receive nonspecific therapy outlined above (section VII). b. High dose prednisone. a. Less likely to respond vs MCD. c. Cyclophosphamide or cyclosporine in patients who are steroid dependent and/or resistant. d. If no response to above therapies, may have familial FSGS with mutations in slit diaphragm proteins. 2. Secondary FSGS a. Nonspecific therapy - ACE inhibitors and angiotensin receptor blockers. b. Treatment of underlying disease (i.e. HIV)

Identify the epidemiology, etiology, pathogenesis, clinical course and treatment of minimal change disease (MCD).

A. Epidemiology 1. Most common cause of nephrotic syndrome in children; (90% in children <5 years, 50% in children >10 years with increased percentage typically FSGS). 2. Accounts for 10-15% of nephrotic syndrome in adults. B. Etiology 1. Idiopathic 2. Drugs - NSAIDs 3. Neoplasm - Hodgkin's disease, lymphoma, leukemia C. Pathogenesis 1. Exact cause unknown; key feature: Podocyte injury a. Systemic T cell dysfunction thought to result in production of a glomerular permeability factor that injures podocytes leading to foot process effacement and proteinuria. 2. May follow respiratory infection or viral illness. D. Renal Biopsy Findings 1. Light Microscopy a. Normal appearance (i.e. "minimal" changes) 2. Immunofluorescence - Negative 3. Electron Microscopy a. Diffuse effacement of podocyte foot processes b. No immune complexes; normal glomerular basement membrane E. Clinical course 1. Historically, untreated MCD was associated with risk of mortality due to infection and risk of thromboembolism. 2. Generally responsive to steroid therapy (90% of children respond) with good prognosis; no progression to chronic renal disease. 3. Patients may have acute renal failure due to tubular injury (acute tubular necrosis). F. Treatment 1. All should receive nonspecific therapy outlined above (section VII). 2. High dose steroids (prednisone). 3. Cyclophosphamide in patients who are steroid-dependent (i.e. steroids cannot be stopped without relapse in nephrotic syndrome). 4. Cyclosporine in patients who are resistant (no or poor response) to steroids; consider re-biopsy as diagnosis may be FSGS.

Identify the epidemiology, etiology, pathogenesis, clinical course and treatment of membranous nephropathy.

A. Epidemiology 1. Second most common cause of nephrotic syndrome in adults. 2. Occurs in all ethnic groups, most common in men >40 yrs. B. Etiology 1. Primary/idiopathic (70%) and secondary (30%) forms. 3. Associations in secondary membranous: a. Drugs (penicillamine, captopril, gold, NSAIDs) b. Malignancy (carcinomas, melanoma) c. Systemic lupus erythematosus d. Infections (Hepatitis B, lesser extent Hepatitis C) C. Pathogenesis 1. Immune complex mediated disease a. Primary - Often due to circulating IgG antibodies directed against antigen expressed on the podocyte foot process (antigen = Type-M phospholipase A2 receptor). b. Secondary - Antigens = Viral proteins, tumor proteins, drug related substances, etc. 2. Immune complex formation activates complement cascade. a. Assembly of C5b-9 (membrane attack complex) inserts into podocyte plasma membrane resulting in complement-mediated podocyte injury. 3. Proteinuria - Due to podocyte foot process effacement (dysfunction of slit diaphragm) and loss of podocytes (apoptosis, necrosis, and detachment from the underlying basement membrane). D. Renal Biopsy Findings 1. Light Microscopy a. Diffuse thickening of the glomerular capillary loops. b. Small "spikes" of glomerular basement membrane material sometimes visible by Jones silver stain. 2. Immunofluorescence a. Fine granular immune deposits along the glomerular capillary walls. b. Usually IgG, C3, kappa and lambda. 3. Electron Microscopy a. Numerous, small electron dense immune deposits along the subepithelial aspect of glomerular basement membrane. b. Reactive "spikes" of glomerular basement membrane material form between deposits. c. Diffuse podocyte foot process effacement. E. Clinical course 1. Spontaneous remission occurs in up to 30% patients at 5 years; spontaneous partial remission (<2 grams proteinura/day) occurs in up to 40% patients at 5 years. 2. Progression to ESRD in 40% at 15 years if untreated. 3. Risk factors for progression: a. Older age of onset, male > females, increased serum creatinine, >8 grams of proteinuria at presentation, presence of tubulointerstitial fibrosis on biopsy. F. Treatment 1. All should receive nonspecific therapy outlined above (Section VII). 2. Immune-targeted therapy if there are risk factors for progression or patient remains symptomatic on ACEi/ARB/loops/diet. b. Cyclophosphamide + prednisone administered over 6 months. c. Cyclosporine + low dose prednisone as an alternative to those who fail or cannot tolerate cyclophosphamide.

Identify diabetic nephropathy as the most common cause of nephrotic syndrome in the US, and discuss the treatment of diabetic nephropathy.

A. Epidemiology and clinical presentation 1. Most common systemic illness to cause nephrotic syndrome and most common cause of ESRD in the US. 2. Occurs in both Type I and Type II diabetes, often with genetic susceptibility. 3. Common in Hispanic, Native American and Black populations. B. Pathogenesis 1. Metabolic - Hyperglycemia and pro-inflammatory mediators cause biochemical derangements of glomeruli leading to increased synthesis of matrix proteins and pro-fibrotic growth factors. a. Nonenzymatic glycosylation (covalent binding of glucose) to proteins in glomerulus contributes to glomerulopathy. 3. Hemodynamic - Hyperfiltration leading to increased glomerular capillary pressure and glomerular hypertrophy. C. Renal Biopsy Findings 1. Light Microscopy a. Glomeruli - Diffusely thickened glomerular basement membranes, increased mesangial matrix leads to formation of large nodules comprised of matrix material (Kimmelstiel-Wilson nodules). b. Tubules/interstitium - Thick tubular basement membranes, progressive fibrosis. c. Vessels - Intimal sclerosis of arteries (arteriosclerosis); hyalinosis of arterioles. 2. Immunofluorescence a. No specific immunoglobulin or complement deposition. b. Pseudolinear staining of glomerular and tubular basement membranes with IgG and albumin. i. Due to "stickiness" of basement membranes. 3. Electron Microscopy a. Diffuse thickening of glomerular basement membranes due to increased amount of lamina densa. b. No immune deposits. c. Increased mesangial matrix and mesangial cells, often forming nodules of matrix material. d. Variable podocyte foot process effacement (more severe in advanced disease). D. Clinical course 1. Patients present with proteinuria: a. Early - Leakage of small amounts of albumin (microalbuminuria), often asymptomatic. b. Late - Overt proteinuria with development of nephrotic syndrome. May take 10-20 years to develop. 2. Progression depends on blood sugar control. In many patients, progressive scarring leads to ESRD. E. Treatment 1. Nonspecific treatment outlined above (section VII). 2. Strict blood sugar control - Oral hypoglycemics and/or insulin. 3. Kidney-pancreas transplant - Definitive treatment for type I DM.

Identify the 4 clinical findings in nephrotic syndrome and understand how these findings develop (pathophysiology of nephrotic syndrome).

A. Glomerular proteinuria 1. Increased filtration of macromolecules across the glomerular capillary wall due to abnormalities in the glomerular epithelial cells (podocytes). a. Albumin is principal urinary protein, others include clotting inhibitors, transferrin, and vitamin D binding protein. B. Hypoalbuminemia 1. Consequent to urinary albumin losses. 2. Hepatic albumin synthesis increases; however, it is unable to sufficiently replete serum levels. - Serum albumin levels Usually <2 g/dl (nl 3.5-5.5 g/dL) C. Edema 1. Hypoalbuminemia causes egress of fluid into the interstitial space resulting in decreased plasma oncotic pressure. 2. Stimulation of the Renin-Angiotensin system resulting in aldosterone release, causing marked sodium retention, sympathetic stimulation, and reduced natiuretic peptide release. a. Causes dependent, pitting edema D. Hyperlipidemia and lipiduria 1. Decreased oncotic pressure stimulates hepatic lipoprotein synthesis. a. Manifests as hypercholesterolemia, hypertriglyceridemia. 2. In lipiduria, lipid becomes entrapped in casts, enclosed by the cytoplasmic membrane of a degenerated renal tubular epithelial cell = oval fat body. a. The cholesterol in oval fat bodies appear as maltese crosses under polarized light.

Review the normal anatomy of the glomerulus, and identify the glomerular basement membrane (GBM), mesangium (matrix and cells), endothelial cells, and epithelial cells (podocytes and parietal epithelial cells).

A. Glomerulus - Anastomosing capillaries lined by fenestrated endothelium, supported by mesangium, surrounded by Bowman's capsule, with two layers of epithelium (visceral and parietal). B. Glomerular capillary wall 1. Thin layer of fenestrated endothelium. 2. Glomerular basement membrane (lamina densa, lamina rara interna and lamina rara externa), composed mostly of Type IV collagen. 3. Visceral epithelial cells (podocytes) - Interdigitating "foot" processes, separated by slit diaphragm (filtration slit). C. Mesangium 1. Supports the capillary loops. 2. Consists of cells and matrix. D. Bowman's capsule - Lined by parietal epithelial cells. Resident Glomerular Cells 1. Endothelial cells Lines inner aspect of capillary loops 2. Mesangial cells Provides structural support Makes extracellular matrix 3. Epithelial cells - Podocytes -- Lines outer aspect of capillary loops Maintains loop shape Provides size and charge barrier to filtrate Synthesizes/maintains glomerular basement membrane (GBM)

Describe the three modalities for examination of renal biopsy tissue.

A. Light Microscopy 1. Multiple level sections of formalin-fixed tissue cut and mounted on glass slides. 2. Basic stain: Hematoxylin and Eosin (H&E) 3. Special stains: Periodic Acid Schiff (PAS), trichrome, Jones silver stain Formalin fixed tissue H&E - General stain, good for inflammatory cells PAS (periodic acid schiff) - Mesangium, basement membranes Jones silver - Basement membranes Trichrome - Fibrosis, necrosis B. Immunofluorescence Microscopy 1. Used to detect presence of immunoglobulin and complement proteins. 2. Multiple level sections of frozen tissue cut and mounted on glass slides. 3. Proteins detected: IgG, IgM, IgA, C3, C4, C1q, fibrinogen, albumin, kappa light chain, and lambda light chain. Frozen tissue Immunoglobulins: - Heavy chains: IgA, IgG, IgM - Light chains: kappa, lambda Complement: C3, C4, C1q Fibrin/fibrinogen -Marker of severe injury (necrosis, crescents) Albumin -Good barometer for background staining - "Stickiness" factor C. Electron Microscopy 1. Transmission electron microscope is used to examine ultrastructure of renal tissue. 2. Tissue fixed and embedded in hard epoxy resin; ultrathin sections cut using diamond blade; sections mounted on a grid and examined using electron microscope. Gluteraldehyde/formalin mix Structures examined: Glomerular basement membrane Cells - Podocytes, endothelial cells, mesangial cells Mesangial matrix Tubular basement membranes Interstitium

Identify the four most common clinical presentations resulting in a renal biopsy.

A. Nephrotic syndrome: Clinical condition related to dysfunction of glomerular podocyte. Four key components: 1. Proteinuria > 3.5 gm/24 hours. 2. Hypoalbuminemia 3. Hyperlipidemia and lipiduria 4. Edema B. Acute nephritic syndrome: Clinical condition associated with glomerular capillary dysfunction/inflammation (active glomerulonephritis). 1. Main clinical features: Hematuria, proteinuria, increased blood pressure, edema, increased serum creatinine, and active urinary sediment. a. Active urinary sediment - Red blood cells and casts (made of red blood cells, white blood cells and/or epithelial cells) detected in the urine; indicates active glomerulonephritis 2. Rapidly progressive glomerulonephritis - Severe form of acute nephritic syndrome with rapid rise in serum creatinine (renal emergency). C. Persistent asymptomatic urine abnormality: Usually subnephrotic range proteinuria (< 3.5 gm/24 hours) or persistent/recurrent microscopic hematuria. D. Renal failure: Elevated serum creatinine. 1. Acute - Glomerular, vascular or tubulointerstitial disease. 2. Chronic - Advanced renal disease, usually irreversible, due to a variety of primary diseases.

Identify the 5 clinical clues that suggest the presence of secondary hypertension.

A. Pathogenesis is related to the underlying condition B. Clinical Manifestations a. The clinical features of secondary hypertension are, often times, indistinguishable to that of essential hypertension in the majority of cases b. There are some clinical clues, however, that may suggest the presence of a secondary cause as outlined below: i. Young age of onset (before 3rd decade) ii. Sudden onset of hypertension iii. Uncontrolled/refractory hypertension iv. Hypokalemia in association with metabolic alkalosis (without the use of diuretics) v. Features of a recognized underlying cause (i.e. hyperglycemia in the setting of Cushing's syndrome) -i.e. New onset of hyperglycemia in the setting of weight gain characterized by truncal obesity and "moon facies" --> Cushing's syndrome

Distinguish primary glomerular diseases that cause nephrotic syndrome from systemic diseases.

A. Primary glomerular diseases 1. Also known as "immune podocytopathies"; due to immune-mediated injury to the podocyte. a. Membranous nephropathy b. Minimal change disease c. Primary focal segmental glomerulosclerosis (FSGS) d. Idiopathic/autoimmune membranoproliferative glomerulonephritis (MPGN) B. Secondary - Systemic diseases 1. Diseases whereby podocyte injury plays a prominent role, but is consequent to a systemic disease process. a. Diabetic nephropathy b. Amyloidosis c. Systemic lupus erythematosis

Describe the generalized treatment of nephrotic syndrome (nonspecific therapy).

A. Renin-angiotensin system: All should be treated with ACE inhibitors (ACEi) and or angiotensin receptor blockers (ARB) to reduce intraglomerular capillary pressure and reduce proteinuria. B. Diuresis: Loop diuretics for edema, low sodium diet (<2g/day). C. Strict blood pressure control: Goal <130/80 mm/Hg. D. Statin: Treatment of hyperlipidemia (Statin = HMG-CoA reductase inhibitor).

Describe three proposed mechanisms for the pathogenesis of immune-complex mediated renal disease.

A. Some forms of renal disease are caused by antigen-antibody complexes. B. Three proposed mechanisms of immune complex formation 1. Antigen-antibody complexes form in the blood, circulate to the kidney and are then deposited into renal tissue. 2. A circulating antigen is first deposited into the kidney, and the recognizing antibody then binds to the planted antigen. 3. A protein normally present in renal tissue acts as an auto-antigen, and the recognizing antibody binds to this intrinsic renal protein. C. Mechanisms of renal injury 1. Antigen-antibody complexes activate the complement cascade. 2. Some results of complement activation: a. Elaboration of cytokines and chemokines. b. Recruitment of inflammatory cells. c. Damage to renal tissues from cell lysis, actions of inflammatory mediators, activation of digestive enzymes, etc. 3. Inflammatory type of injury more severe in diseases that cause acute nephritis vs nephrotic syndrome. -Activation of complement cascade--> Elaboration of cytokines, chemokines --> Recruitment of inflammatory cells --> Damage to renal tissue Cell lysis, disruption of mesangium or capillary walls --> Actions of inflammatory mediators, proteolytic enzymes, etc. - Inflammatory injury more severe in diseases that cause NEPHRITIC syndrome than nephrotic syndrome

Identify the stages of CKD based on GFR

A. The purpose of staging is to identify patients who are at the highest risk for progression and having complications from CKD Stage 3 has been recently modified to 3a (GFR 46-59) and 3b (31-45) given association with higher mortality at GFR <45ml/min (particularly with cardiovascular events) CKD is becoming an epidemic! The prevalence of Stage 5 CKD (GFR <15ml/min) was 700,000 in 2010 and is projected to reach 2.2 million by 2030

Diabetic nephropathy (histo 4)

Light Microscopy Glomerular nodules of matrix material, thickened GBM Thick tubular basement membranes, fibrosis of interstitium, vascular sclerosis Immunofluorescence No immune deposits Pseudolinear staining of glomerular and tubular BM with IgG and albumin due to "stickiness" of basement membranes Electron Microscopy Diffuse thickening of GBM Expansion of mesangium with increased matrix No immune deposits Variable foot process effacement More severe in advanced disease

Diabetic nephropathy (histo 5)

Light Microscopy Glomerular nodules of matrix material, thickened GBM Thick tubular basement membranes, fibrosis of interstitium, vascular sclerosis Immunofluorescence No immune deposits Pseudolinear staining of glomerular and tubular BM with IgG and albumin due to "stickiness" of basement membranes Electron Microscopy Diffuse thickening of GBM Expansion of mesangium with increased matrix No immune deposits Variable foot process effacement More severe in advanced disease

minimal change disease (MCD) histo zoom in

Light Microscopy Normal Immunofluorescence Negative Electron Microscopy Diffuse effacement of podocyte foot processes No immune complexes; normal GBM

minimal change disease (MCD) histo zoom out

Light Microscopy Normal Immunofluorescence Negative Electron Microscopy Diffuse effacement of podocyte foot processes No immune complexes; normal GBM

Describe different interventions available that slow progression of chronic kidney disease

Although progressive nephron loss cannot be avoided, there are interventions that can slow the rate of progression 1. Blood pressure control: The most important intervention is adequate BP control! a. Aim for a goal of <130/80 b. Lower goals have been proposed for patients with overt proteinuria (>1g per day) - i.e. <125/75, but there is no convincing data to support this c. Recent data suggests lowering BP <140/90 in African Americans has no further beneficial effect 2. Renin-angiotensin-aldosterone antagonism: a. Inhibition of angiotensin II and aldosterone (ACE inhibitors, angiotensin receptor blockers) slows progression of CKD in proteinuric diseases (>30mg or albuminuria) b. Independent of BP lowering effect c. Decrease glomerular capillary pressure, reduce hyperfiltration, and mitigates tubulointerstitial fibrosis 3. Control phosphorus levels: a. Dietary discretion b. Phosphorus binders (taken with meals binds phosphorus and eliminates through stool) 4. Treat metabolic acidosis: a. Sodium bicarbonate supplementation (has been shown to slow GFR loss) 5. Stop smoking (a no brainer!) 6. Correct anemia: a. Erythrocyte stimulating agent (ESA) or erythropoietin 7. Use of an HMG-CoA reductase inhibitor (statin): a. Associated with slowing of GFR 8. Low protein diet: a. Benefit primarily in proteinuric diseases (>1g per day) - slows GFR loss b. Goal ~ 0.6-0.8g/Kg protein per day c. Should be followed by a nutritionist to avoid malnutrition 9. Treat underlying disease! a. Strict glycemic control in diabetes mellitus 1. Tight control of blood glucose (Hemoglobin A1c <7%) results in improved renal outcomes b. Immunosuppression therapy for primary glomerular diseases (will be discussed in the nephritic and nephrotic lectures)

Polycystic kidney disease

Autosomal dominant - presents in adulthood Associated with PKD 1 and PKD 2 mutations Most common cause of genetic kidney disease Most patients will progress to the need of renal replacement therapy (dialysis or transplant) Autosomal recessive - presents in childhood Infantile polycystic kidney disease Cystic dilitations of the collecting duct and congenital hepatic fibrosis

A 29 year-old woman is noted to have microscopic hematuria and 2+ positive dipstick proteinuria (no proteinuria on dipstick is normal) on screening labs for a life insurance policy. It was confirmed on a repeat urinalysis 2 weeks later. Her serum creatinine is normal. A 52 year-old man with a history of hypertension is noted to have a serum creatinine of 1.9mg/dL (normal 0.5-1.2mg/dL). His urinalysis is unremarkable. In review of his past records, his serum creatinine was elevated to 1.7mg/dL 6 months prior. Which one of these patients has chronic kidney disease?

BOTH Presence of either: Kidney damage or Decreased kidney function for >3 months with a decreased glomerular filtration rate (GFR)

membranous nephropathy (histo 1)

Light Microscopy Thick GBM with "spikes" Immunofluorescence Diffuse fine granular deposits on capillary walls Usually IgG, C3 Electron Microscopy Numerous, small subepithelial immune deposits Reactive "spikes" of GBM Effacement of podocyte foot processes

CKD consequence: MBD

C. Mineral-Bone Disorder (covered in your last lecture) 1. Decreased urinary phosphorus excretion 2. Compensatory increase in FGF-23 (phosphatonin) increases phosphate excretion in an attempt to maintain normal serum phosphorus concentrations 3. Decrease in 1,25 Vitamin D (FGF-23 inhibits 1-alph-OH'lase), decrease in serum calcium --> increase in PTH and secondary hyperparathyroidism 4. Can lead to osteomalacia (soft bones due to defective mineralization), osteitis fibrosa (high bone turnover), and vascular calcification Vascular calcification Renal osteodystrophy Osteomalacia (defective mineralization) High turnover bone disease (osteitis fibrosa - peritrabecular fibrosis) Mixed uremic bone disease (features of both osteitis fibrosa and osteomalacia) Adynamic bone disease (iatrogenic --> oversuppression of PTH typically with active vitamin D analogues --> decreased bone formation and turnover Trochanteric fractures Subperiosteal bone resorption at the radial aspect of the phalanges from osteoclast activity in secondary hyperparathyroidism

membranous nephropathy (histo 2)

Light Microscopy Thick GBM with "spikes" Immunofluorescence Diffuse fine granular deposits on capillary walls Usually IgG, C3 Electron Microscopy Numerous, small subepithelial immune deposits Reactive "spikes" of GBM Effacement of podocyte foot processes

Describe the renal manifestations of diabetes mellitus and discuss how it manifests clinically (i.e. hyperfiltration, microalbuminuria, etc.)

Diabetes Mellitus - A group of metabolic diseases that manifests as hyperglycemia either because the pancreatic beta cells do not produce enough insulin (Type I diabetes) or due to insulin resistance (cells do not respond to insulin - Type II diabetes) a. 20-30% of diabetics will develop diabetic nephropathy b. Accounts for ~ 55% of new dialysis patients a. Given the increase in prevalence of Type II diabetes compared to Type I, Type II diabetes accounts for the majority of cases of diabetic nephropathy b. The renal risk for progression of disease (CKD) is equivalent in both Type I and II diabetes B. Manifestations: a. Glomerulopathy characterized by mesangial expansion, thickening of the glomerular basement membrane, and glomerulosclerosis (the pathology will be covered in Nephrotic syndrome lecture) b. Clinical characteristics: 1. Hyperfiltration and glomerular capillary hypertension - this is the earliest clinical manifestation of disease 2. Microalbuminuria: (now referred to as high albuminuria) - urinary albumin between 30mg-300mg (remember normal <30mg per day) a. This predicts high risk for future overt nephropathy (>1 gram of proteinuria) b. Crucial for effective therapy to target glomerular capillary hypertension (i.e. ACE inhibitors and angiotensin receptor blockers), glycemic control, and weight control in order to slow or halt the progression of disease! 3. Macroalbuminuria: (now referred to as very high albuminuria) - urinary albumin >300mg per day a. In the absence of effective therapy, patients will have a progressive decline in GFR and ESRD (if they do not die from a cardiovascular related event first!) 4. Progressive disease with little or no albuminuria: a. Subset of diabetic patients that still have progressive CKD but decline in GFR is not related to albuminuria b. Thought to be due to intrarenal vascular disease c. Rate in decline of GFR is much slower compared to albuminuric patients

membranous nephropathy (histo 3)

Light Microscopy Thick GBM with "spikes" Immunofluorescence Diffuse fine granular deposits on capillary walls Usually IgG, C3 Electron Microscopy Numerous, small subepithelial immune deposits Reactive "spikes" of GBM Effacement of podocyte foot processes

membranous nephropathy (histo 4)

Light Microscopy Thick GBM with "spikes" Immunofluorescence Diffuse fine granular deposits on capillary walls Usually IgG, C3 Electron Microscopy Numerous, small subepithelial immune deposits Reactive "spikes" of GBM Effacement of podocyte foot processes

You are seeing a 61 year-old gentleman who has stage IIIb CKD due to diabetic nephropathy and hypertension. Labs: creatinine is 2.1 mg/dL (normal 0.5-1.0 mg/dL), eGFR 31ml/min (normal 90-120ml/min). Proteinuria is estimated at 490mg by spot ratio (normal <150mg). He is on an ACE inhibitor, but blood pressure is not controlled (140's/80's). What is the most likely outcome for this gentleman?

He will die from a cardiovascular event (i.e. acute coronary syndrome etc.) within the next 3 years.

Describe the approach to acid-base disorders

History and physical examination Check the pH. Is the patient acidemic or alkalemic? Look at pCO2 and HCO3-. Is the disorder respiratory or metabolic? Is there appropriate compensation? If the numbers don't make sense, check the pH with the Henderson-Hasselbach equation. Is there an elevated anion gap? (This may be the only clue to a mixed acid-base disturbance)

membranous nephropathy (histo 5)

Light Microscopy Thick GBM with "spikes" Immunofluorescence Diffuse fine granular deposits on capillary walls Usually IgG, C3 Electron Microscopy Numerous, small subepithelial immune deposits Reactive "spikes" of GBM Effacement of podocyte foot processes

membranous nephropathy (histo 6)

Light Microscopy Thick GBM with "spikes" Immunofluorescence Diffuse fine granular deposits on capillary walls Usually IgG, C3 Electron Microscopy Numerous, small subepithelial immune deposits Reactive "spikes" of GBM Effacement of podocyte foot processes

You are asked to see a 57 year-old African-American gentleman who is noted to have a serum creatinine of 2.1 mg/dL (normal 0.5-1.2 mg/dL). 7 years ago his creatinine was 1.2 mg/dL. He has a history of hypertension diagnosed 17 years ago, dyslipidemia, and uses tobacco. He has not always been compliant with taking his antihypertensives. Retinal exam - cotton wool spots due to retinal ischemia Labs: creatinine is 2.1 mg/dL (normal 0.5-1.2 mg/dL). UA 1+ dipstick positive proteinuria. Proteinuria estimated at 680mg by spot ratio. What is the most likely cause of this gentleman's chronic kidney disease?

HTN

Describe the relationship between African-American ethnicity and progression of hypertensive-related CKD. Discuss the role of the APOL1 allele variant

Hypertension 1. Chronic elevations in blood pressure can lead to vascular, glomerular, and tubulointerstitial disease --> hypertensive nephrosclerosis 2. African Americans - much higher risk of progressive CKD and end-stage-renal-disease (dialysis dependent) despite "adequate" blood pressure control a. Association with genetic polymorphisms involving chromosome 22 - apolipoprotein L1 (APOL1) gene b. APOL1 is a minor apoprotein component of HDL cholesterol c. When intracellular, APOL1 has the ability to kill Trympanosomes that cause African Sleeping Sickness d. It is presumed that APOL1 allelic variants confer a selective biological advantage - resistance against Trympanasoma brucei rhodesiense but when inherited in a recessive fashion is associated with both hypertensive CKD with high progression to ESRD (also associated with proteinuria and FSGS in African Americans) 3. Clinical manifestations: Patients with hypertensive nephrosclerosis typically have had a long history of hypertension accompanied by retinopathy (vascular changes in the retina due to high arterial pressures), left ventricular hypertrophy, and low-grade proteinuria (<1 g per day)

amyloidosis renal (histo 1)

Light Microscopy Amorphous, pale eosinophilic material in glomeruli Congo red stain positive Can also do amyloid immunohistochemistry Immunofluorescence Variable; can see light chain restriction if AL type Electron Microscopy Haphazardly arranged fibrils within mesangium and GBM Variable podocyte injury

amyloidosis renal (histo 2)

Light Microscopy Amorphous, pale eosinophilic material in glomeruli Congo red stain positive Can also do amyloid immunohistochemistry Immunofluorescence Variable; can see light chain restriction if AL type Electron Microscopy Haphazardly arranged fibrils within mesangium and GBM Variable podocyte injury

amyloidosis renal (histo 3)

Light Microscopy Amorphous, pale eosinophilic material in glomeruli Congo red stain positive Can also do amyloid immunohistochemistry Immunofluorescence Variable; can see light chain restriction if AL type Electron Microscopy Haphazardly arranged fibrils within mesangium and GBM Variable podocyte injury

amyloidosis renal (histo 4)

Light Microscopy Amorphous, pale eosinophilic material in glomeruli Congo red stain positive Can also do amyloid immunohistochemistry Immunofluorescence Variable; can see light chain restriction if AL type Electron Microscopy Haphazardly arranged fibrils within mesangium and GBM Variable podocyte injury

amyloidosis renal (histo 5)

Light Microscopy Amorphous, pale eosinophilic material in glomeruli Congo red stain positive Can also do amyloid immunohistochemistry Immunofluorescence Variable; can see light chain restriction if AL type Electron Microscopy Haphazardly arranged fibrils within mesangium and GBM Variable podocyte injury

amyloidosis renal (histo 6)

Light Microscopy Amorphous, pale eosinophilic material in glomeruli Congo red stain positive Can also do amyloid immunohistochemistry Immunofluorescence Variable; can see light chain restriction if AL type Electron Microscopy Haphazardly arranged fibrils within mesangium and GBM Variable podocyte injury

amyloidosis renal (histo 7)

Light Microscopy Amorphous, pale eosinophilic material in glomeruli Congo red stain positive Can also do amyloid immunohistochemistry Immunofluorescence Variable; can see light chain restriction if AL type Electron Microscopy Haphazardly arranged fibrils within mesangium and GBM Variable podocyte injury

focal segmental glomerulosclerosis (FSGS) (histo 1)

Light Microscopy Focal glomeruli with scarring/sclerosis of a segment of the glomerular capillary tuft Immunofluorescence Trapping of C3 and/or IgM in areas of sclerosis (non-specific) Electron Microscopy Accumulation of matrix material, cells, plasma protein in sclerotic area No immune deposits Primary: Diffuse effacement of podocyte foot processes Secondary: Patchy or variable effacement of foot processes

focal segmental glomerulosclerosis (FSGS) (histo 2)

Light Microscopy Focal glomeruli with scarring/sclerosis of a segment of the glomerular capillary tuft Immunofluorescence Trapping of C3 and/or IgM in areas of sclerosis (non-specific) Electron Microscopy Accumulation of matrix material, cells, plasma protein in sclerotic area No immune deposits Primary: Diffuse effacement of podocyte foot processes Secondary: Patchy or variable effacement of foot processes

focal segmental glomerulosclerosis (FSGS) (histo 3)

Light Microscopy Focal glomeruli with scarring/sclerosis of a segment of the glomerular capillary tuft Immunofluorescence Trapping of C3 and/or IgM in areas of sclerosis (non-specific) Electron Microscopy Accumulation of matrix material, cells, plasma protein in sclerotic area No immune deposits Primary: Diffuse effacement of podocyte foot processes Secondary: Patchy or variable effacement of foot processes

membranous nephropathy (histo 7)

Light Microscopy Thick GBM with "spikes" Immunofluorescence Diffuse fine granular deposits on capillary walls Usually IgG, C3 Electron Microscopy Numerous, small subepithelial immune deposits Reactive "spikes" of GBM Effacement of podocyte foot processes

Explain the role and magnitude of compensation for simple acid-base disturbance

Metabolic acidosis: to compensate for the decrease in pH, ventilation increases in an attempt to reduce pCO2 and raise the pH. This does not raise the pH all the way to normal but does raise it towards normal. pCO2 = last two digits of the pH, or 1.5*HCO3 + 8. Metabolic alkalosis: the respiratory compensatory response is variable and takes hours to develop. The response is hypoventilation in an attempt to raise pCO2 and lower the pH. The pCO2 can only rise to about 55-60 mmHg. Often patients have other disease states and symptoms that cause hyperventilation, thus counteracting the compensatory response. pCO2 has variable increase, or 0.7*HCO3 + 20 Respiratory acidosis: acute response is increase in plasma bicarbonate (from non-carbonic acid buffers). Chronic (~72 hours) response is an increased acid excretion from the kidneys due to increased ammoniagenesis, with bicarbonate retention. Acutely, HCO3 increases 1 mEq/L per 10 mmHg rise in pCO2. Chronically, HCO3 increases 3.5 mEq/L per 10 mmHg rise in pCO2. Respiratory alkalosis: acute response is due to H+ released from non carbonic acid biffers. Delayed response in the kidneys of increased HCO3- excretion, reduced excretion of ammonium and titratable acid. In chronic cases, the pH can return to within normal range. Acutely, HCO3 decreases 2 mEq/L per 10 mmHg decline in pCO2. Chronically, HCO3 decreases 5 mEq/L per 10 mmHg decline in pCO2.

Discuss which form of renal replacement therapy confers the best survival advantage

Pre-emptive transplant (transplant prior to dialysis) offers the best survival advantage (not always possible)

Reflux nephropathy (vesicoureteral reflux)

Reflux nephropathy Vesicoureteral reflux Passage of urine from the bladder into the upper urinary tract Typically due to inadequate closure of the ureterovesical junction Presents in childhood

Describe the pathophysiology of CKD in regards to nephron loss and how it leads to renal scarring

Regardless of underlying disease, it is thought that the final common pathway to progressive CKD is shared mechanism 1. Initial insult to the kidney (i.e. tubulointerstitial, vascular, glomerular, or obstructive uropathy) leads to nephron loss 2. Renal function is initially maintained as the remaining nephrons will hyperfilter (GFR will remain the same) 3. The ongoing hyperfiltration results in glomerular capillary hypertension (each remaining nephron is under higher pressure given the higher filtering demands) 4. Glomerular capillary hypertension leads to cytokine activation (cell-signaling proteins) and podocyte dysfunction (glomerular epithelial cells that help maintain capillary loop shape) resulting in: a. Proteinuria b. Glomerular sclerosis c. Tubulointerstitial fibrosis ====> Renal Scarring (a, b, c)

Describe the different methods of measuring and estimating GFR. What are the specific limitations of each?

Serum Creatinine (we briefly discussed this in AKI lecture) 1. Derived from the metabolism of creatine in skeletal muscle and from dietary meat intake 2. Released into the circulation at a relatively constant rate and has a stable plasma concentration 3. Freely filtered across the glomerulus and is neither reabsorbed nor metabolized. It is inversely proportional to GFR 4. Can only be used in patients with stable kidney function 5. Limitations: a. Not accurate in patients with little muscle mass (liver disease, malnourished patients, congenital dwarfism, etc) - may have a creatinine within normal range but have a significant reduction in GFR (generate less creatinine from decreased muscle mass) b. Also secreted by organic secretory pathway in the proximal tubule i. Certain medications can inhibit the secretion of creatinine (Trimetheprim-Sulfamathoxazole, Cimetadine) and increase serum creatinine despite no change in GFR c. Does not detect early changes in GFR (see below) • An initial small rise in serum creatinine reflects a marked change in GFR whereas a marked rise in serum creatinine with advanced disease reflects a small absolute reduction in GFR • i.e. A decline in GFR from 120 to 80mL/min per 1.73m2 (loss of 40mL/min) in a 70Kg gentleman is associated with only a small rise in serum creatinine from 0.9 to 1.0 (because of increased creatinine secretion* - more creatinine is secreted into the tubule with early changes in GFR) • A further elevation in serum creatinine to 1.5mg/dL represents the loss of at least 1/3 or 27mL/min of the remaining GFR (assuming there is no further creatinine secretion) Relationship between the cr and true gfr as measured by inulin clearance. 171 pateitns with glomerular disease. Closed circles are one patient, continuous line reflects idealized relationship between these paramteres if creatinine were excreted soley by glomerular filgration and dashed line respesnts upper limit of normal for PCr of 1.4. Differences in GFR from 120 to 60ml/min reflects little elevation in Cr due to enahnced tubular secretion. Once Cr is above 1.5 to 2mg/dl, tubular secretion becomes saturated and Cr rises as expected with further reductions in GFR. Once creatinine increased to 1.5-2, tubular secretion becomes saturated and cr rises as expected with further reductions in GFR Creatinine clearance: 1. Clearance = UV/P where U=urinary concentration of a substance, V=volume of urine per set time (in this case 24h), and P=plasma concentration of a substance 2. Because creatinine is filtered and not reabsorbed by the tubule, we can measure the clearance of creatinine to obtain the measurement of GFR 3. Limitations: a. Remember - creatinine is also secreted into the tubule. Therefore the urinary creatinine concentration will be higher than what was actually filtered --> creatinine clearance will exceed the true GFR by ~ 10-20% b. Inaccurate collection - patients notoriously will over-collect (>24h) or under-collect urine c. Because of these limitations, creatinine clearance is no longer recommended for routinely assessing GFR Estimated GFR (eGFR) - Modifications of Diet and Renal Disease (MDRD) equation* 1. Estimates GFR by incorporating known demographic and clinical variables as observed surrogates for unmeasured factors other than GFR that affect serum creatinine a. i.e. age, gender, ethnicity, in addition to creatinine b. Actual formula is long and complicated - you are not responsible for it! 2. Increasingly used not only to estimate GFR but follow changes in GFR 3. Becomes less accurate when GFR >60ml/min/1.73m2 Other: 1. Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) a. Also estimates GFR based on age, gender, ethnicity, and creatinine. b. Better accuracy than MDRD when GFR >60ml/min (may eventually replace MDRD; for now MDRD is used most often in the US) 2. Cystatin C a. Alternative endogenous filtration marker that may have advantages over creatinine for GFR estimation ( not ready for prime time yet) 13.3 kD protein produced by all nucleated cells Potent inhibitor of lysosomal proteinases Filtered by the kidney Not secreted nor reabsorbed Metabolized in the tubules - thus unable to use for clearance (UV/P) Inversely proportional to GFR (higher cystatin C level, lower GFR) Less dependent on age, sex, race, and muscle mass Limitations No current standard for serum cystatin C measurements (reference rage) Only limited in a small number of laboratories

Identify the two determinants that define chronic kidney disease and discuss why one can have chronic kidney disease with a normal glomerular filtration rate (GFR)

The presence of either kidney damage or decreased kidney function for > 3 months with or without decreased glomerular filtration rate (GFR) Kidney damage includes a. Pathological abnormalities: Documented on kidney biopsy (can include glomerular, vascular, or tubulointerstitial disease) b. Clinical markers of kidney damage: 1. Proteinuria: >150mg per day of protein in the urine a. Albumin is most prominent component of protein in the urine and is often measured in lieu of the total protein - >30mg of albuminuria per day is abnormal 2. Glomerular hematuria: dysmorphic red blood cells (RBCs) or red blood cell casts on urinary sediment review indicates glomerular origin - glomerular disease c. Imaging: Polycystic kidneys, hydronephrosis, or small kidneys with thinned cortex on ultrasound Decreased kidney function: a. GFR <60 ml/min/1.73 m2 for > 3 months (remember normal GFR is between 90-120ml/min) b. Need to document at least 2 measurements separated by at least 2 weeks Pathological abnormalities documented on kidney biopsy, tubulointerstitial, vascular, or glomerular. Proteinuria, normal to have <150mg in 24h. Normal constituents are albumin, transferrin, anti-coagulants like anti-thrombin III, immunoglobulins. Albumin makes up ~ 80% of protein and often times will measure albumin in lieu of total protein. A microalbumin is a more sensitive test and can measure small amounts of protein in the urine.

Recognize that acute kidney injury is a cause of chronic kidney disease

Tubulointerstitial Disease (affects tubules and interstitium of kidney) a. Polycystic kidney disease Autosomal dominant - presents in adulthood Associated with PKD 1 and PKD 2 mutations Most common cause of genetic kidney disease Most patients will progress to the need of renal replacement therapy (dialysis or transplant) Autosomal recessive - presents in childhood Infantile polycystic kidney disease Cystic dilitations of the collecting duct and congenital hepatic fibrosis b. Autoimmune diseases 1. Sjogren's disease, Sarcoidosis Sarcoidosis multisystem granulomatous disorder of unknown etiology characterized by noncaseating granulomas in involved organs, pulmonary, hilar LAN 2. Inflammatory infiltrate in the interstitium with associated tubular dysfunction c. Reflux nephropathy (vesicoureteral reflux) 1. Passage of urine from the bladder into the upper urinary tract 2. Typically due to inadequate closure of the ureterovesical junction 3. Presents in childhood Vascular Disease a. Hypertensive vasculopathy or benign nephrosclerosis (due to hypertension) b. Renovascular disease 1. Due to either bilateral or unilateral renal artery stenosis (atherosclerotic plaque or fibromuscular dysplasia that reduces renal arterial blood flow) c. Renal atheroembolic disease (cholesterol emboli) 1. We discussed this in AKI lecture - many patients do NOT recover full function after an event ultimately resulting in CKD Glomerular Disease a. Diabetic nephropathy (the most common cause of CKD in the United States) b. Primary glomerular diseases (we will discuss this in the Nephritic and Nephrotic disease lectures) Post-renal or Obstructive Uropathy a. If obstruction is prolonged without intervention, parenchymal loss will result (loss of nephron mass due to compression from reflux of urine) 1. Benign prostatic hyperplasia (most common) 2. Urethral strictures 3. Chronic obstructive calculi (nephrolithiasis) 4. Pelvic masses (external compression on ureters) Acute Kidney Injury a. Chronic sequelae from having either an initial or repeated episodes of AKI is increasingly recognized as a cause for CKD

CHRONIC KIDNEY DISEASE RELATED MINERAL BONE DISORDERS (CKD-MBD)

a. CKD-MBD is defined as a systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following: i. Abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism ii. Abnormalities in bone turnover, mineralization, volume, linear growth, or strength iii. Vascular or other soft tissue calcification b. Renal Osteodystrophy (ROD) is exclusively used to define the bone pathology associated with CKD.

Review normal calcium homeostasis.

a. Calcium is an important divalent ion for cellular function. b. Normal serum calcium is between 9.0 to 10.4 mg/dl. c. The serum calcium can be divided into three pools: ionized calcium (50%), complexed to phosphate, citrate, carbonate, and other anions (10%), and protein bounded (40%), which is not filtered by the glomerulus. d. Majority (99%) of total body calcium is store in bone. Only 1% in serum. e. Gastrointestinal calcium absorption is balanced by renal calcium excretion.

Renal Osteodystrophy

a. Classification i. High turnover bone disease or osteitis fibrosa. ii. Osteomalacia (defective mineralization). iii. Mixed uremic bone disease (a mixture of high turnover and osteomalacia). iv. Adynamic bone disease b. High turnover bone disease i. High PTH ii. Increased both osteoclasts and osteoblasts activities. iii. Resulted as disruption of the structure of bone. iv. Osteitis fibrosa is characterized by increased bone formation and resorption, increased osteoblast and osteoclast activation, and extensive peritrabecular fibrosis. c. Adynamic bone disease i. Low PTH ii. Low turnover iii. Decreased osteoclasts and osteoblasts activities. iv. No mineralization defect v. Very low rate of bone formation d. Osteomalacia. Similar to adynamic bone disease but with mineralization defect e. Mixed uremic bone disease Histologic features of both osteitis fibrosa and osteomalacia. f. Clinical manifestations. i. Bone pain ii. Muscle weakness iii. Skeletal deformities iv. Growth retardation in children

Identify the most common etiology of renovascular hypertension.

a. Defined: Hypertension caused by renal artery stenosis (unilateral or bilateral). i. The most common correctable cause of secondary hypertension b. Prevalence: Variable - depends on clinical circumstance i. Less than 1% in mild to moderate hypertension ii. 10-40% in patients with severe or refractory hypertension c. Etiology i. Atherosclerosis - 75-90% of renovascular hypertension 1. Typically in patients > 50 years old who have cardiovascular risk factors (tobacco use, dyslipidemia, peripheral vascular disease) ii. Fibromuscular dysplasia (FMD) - 10-25% of renovascular hypertension 1. Nonatherosclerotic, noninflammatory vascular disease presenting between the ages of 30-50 years old 2. Women > men iii. Other 1. Aortic/renal dissection 2. Takayasu's arteritis 3. Thrombotic/cholesterol emboli 4. Post-transplant renal artery stenosis (TRAS) 5. Post radiation PVD - obstruction of large arteries that are not within the coronary, aortic arch, or brain. Due to athersclerosis, or inflammatory state - leading to thrombus formation and narrowing of blood supply/ischemia Fibromuscular dysplasia is characterized by fibrous thickening of the intima, media, or adventitia of the artery. Up to 75% of all patients with FMD will have disease in the renal arteries. The lesions cause narrowing of the artery lumen. The second most common artery affected is the carotid artery, which is found in the neck and supplies the brain with blood. is a form of large vessel granulomatous vasculitis with massive intimal fibrosis and vascular narrowing affecting often young or middle-aged women of Asian decent. It mainly affects the aorta (the main blood vessel leaving the heart) and its branches, as well as the pulmonary arteries. Females are about 8-9 times more likely to be affected than males, can also affect renal arteries Ischemic ulcer and dependent rubor due to severe PVD (lack of blood flow to the capillary beds in the lower extremities and impaired autoregulation)

Management of CKD-MBD

a. Early prevention is the key b. Control hyperphosphatemia i. Control dietary intake ii. Phosphate binders iii. Adequate dialysis c. Control serum calcium level i. Calcium supplements for low Ca ii. Low Ca dialysate for high Ca d. Vitamin D analogs: i. Directly inhibit PTH synthesis and secretion, indirectly via vitamin-D receptors and hypercalcemia. e. Calcimimetic agent i. Cinacalcet (Sensipar) activates Ca sensing receptor and blocks PTH secretion f. Goal of intact PHT level i. stage 3 CKD (GFR 30 to 59), less than 70 ii. Stage 4 CKD (GFR15 to 29), less than 110 iii. stage 5 CKD (GFR < 15) or on dialysis, 150 to 300

Hypertension and its pathogenesis

a. Hypertension is the most common disease-specific reason for office visits of adults to physicians in the United States b. According to the 7th report of the Joint National Committee (JNC 7) based upon the average of 2 or more properly measured readings at each of 2 or more visits of an initial screen i. Normal blood pressure: Systolic < 120, diastolic < 80 ii. Prehypertension: Systolic 120-129, diastolic 80-89 iii. Hypertension: 1. Stage 1: Systolic 140-159, diastolic 90-99 2. Stage 2: Systolic > 160, diastolic > 100 c. The vast majority of physician visits for hypertension constitutes essential or idiopathic hypertension; however, ~ 10% of cases are due to secondary hypertension (ANg II, Catecholamines) that lead to an increase in peripheral resistance. There is augmentation in sympathetic tone leading to an increased HR, and activation of aldosterone, ADH leading to renal Na+ retention along with elevation in circulating catecholamine ultimately leading to increased SV -: Essential HTN arises from a complex interaction of genes and environmental factors. The pathogenesis is multifactorial involving several changes in local regulators and hormonal mediators that cause an increase in PR. There is augmentation in sympathetic tone and active of Aldosterone and ADH that leads to renal Na+ retention that affect HR and SV. The point of this slide is not to memorize these different factors at play but to illustrate the complex interplay between these local regulatory processes and hormonal mediators that result in essential HTN - this is in contrast to secondary HTN where there is an isolated underlying cause that can potentially be rectifiable.

Review normal phosphate homeostasis.

a. Majority (85%) of total body calcium is stored in bone, 14% is intracellular(non-bone) and only 1% in serum. b. Serum phosphate is found in both organic and inorganic forms. Only inorganic form (Pi) presents in biologic solution and can be filtered by glomerulus. Organic forms include phospholopids and various organic esters. c. Normal serum phosphate is between 2.5 to 4.5 mg/dl. d. Gastrointestinal phosphate absorption is balanced by renal phosphate excretion.

Hormonal regulation of phosphate

a. PTH. i. PTH is the principal regulator of renal phosphate reabsorption. It reduces renal phosphate reabsorption by inhibition of type II sodium-dependent phosphate cotransporter. Therefore, it is phosphaturic. ii. PTH also increases phosphate release from bone. b. Calcitriol i. Calcitriol is the principal regulator in the GI. It increases intestinal phosphate absorption by stimulating type IIc sodium-dependent phosphate cotransporter in the brushborder membrane of small intestine. ii) Calcitriol increases renal phosphate reabsorption in proximal tubules. c. Phosphatonin i) A group of substances that initially appear to regulate serum P levels in tumor-induced osteomalacia, X-linked hypophosphatemic rickets, and autosomal dominant hypophosphatemic rickets ii) FGF 23 is one of the major phosphatonins iii) It inhibits NaPi2a synthesis in proximal tubule and inhibits calcitriol synthesis by inhibiting 1-OHase. iv) Calcitriol and high phosphate increases FGF23.

Hormonal regulation of calcium

a. PTH. PTH increase serum calcium level by increasing: i. Calcium release from bone. ii. Calcium reabsorption from the kidney (mainly DCT). iii. Conversion of vitamin D to calcitriol by stimulating 1-α hydroxylase, thus indirectly increases GI calcium absorption. b. Calcitiol i. Increases intestinal calcium absorption ii. Net effect of renal calcium excretion is unclear.

Vascular calcification

a. Pathogenesis. i. Vascular smooth muscle cells are capable of producing "bone"-like proteins in cell culture and forming mineralized nodules in vitro in the presence of phosphorus, identical to the requirements for bone nodule formation from osteoblasts in vitro. ii. Several nontraditional CKD cardiovascular risk factors can accelerate vascular calcification, including parathyroid hormone (PTH) and PTH- related peptide, calcitriol, advanced glycation end-products, alterations of lipoproteins, and homocysteine. iii. Inorganic phosphate is a signaling molecule with the ability to initiate both phenotypic change and mineralization in vascular smooth muscle cells. iv. Calcium phosphate deposition, in the form of bioapatite, is the hallmark of vascular calcification and can occur in the blood vessels, myocardium, and cardiac valves. v. In humans with CKD, there appears to be a relationship between disorders of mineral metabolism (abnormal levels of serum calciumand phosphorus), abnormal bone (renal osteodystrophy), and vascular calcification. b. Clinical Consequences of Vascular Calcification i. Vascular calcification can lead to devastating organ dysfunction depending on its extent and the organ affected. ii. In heart, calcification of cardiac valve leaflets is recognized as a major mode of failure of native as well as bioprosthetic valves iii. Calciphylaxis, a necrotizing skin caused by calcific uremic arteriolopathy. iv. Increased large vessels stiffening and therefore decreased compliance of these vessels v. Significantly increased cardiovascular mortality.

Know the common causes of secondary hypertension.

a. Renal i. Renovascular hypertension* ii. Renal parenchymal hypertension* b. Endocrine i. Primary hyperaldosteronism* ii. Cushing's syndrome* iii. Pheochromocytoma* iv. Hyperreninism v. Hypothyroidism vi. Hyperparathyroidism c. Cardiovascular causes i. Obstructive sleep apnea* ii. Coarctation of the aorta d. Drugs i. Glucocorticoids ii. Nonsteroidal anti-inflammatory drugs iii. Combined oral contraceptive medications iv. Calcineurin inhibitors v. Caffeine vi. Pseudoephedrine vii. Licorice (due to inhibition of 11-β hydroxysteroid dehydrogenase type 2 by glycerrhetinic acid*) e. Inherited causes i. Glucocorticoid-remediable aldosteronism ii. Syndrome of apparent mineralocorticoid excess (SAME) iii. Liddle's syndrome iv. Gordon's syndrome v. Congenital adrenal hyperplasia

Understand the pathogenesis of secondary hyperparathyroidism.

a. The pathogenesis of secondary hyperparathyroidism in chronic kidney disease is multifactorial, with a number of different processes contributing to disturbances in the regulation of PTH production and secretion. b. With the progressive loss of kidney function, active vitamin D production is diminished, phosphorus retention occurs, and levels of ionized extracellular calcium may also decline. c. The parathyroid gland is highly sensitive to even very small changes in ionized extracellular calcium and rapidly releases PTH in response to a decrease in calcium concentration. This response is mediated by the calcium-sensing receptor (CaR), the primary regulator of PTH secretion. d. Calcitriol inhibits gene transcription of precursors of PTH, and therefore a decline in calcitriol leads to increased PTH production. Decreased calcitriol has also been linked to decreased expression of calcium-sensing receptors in parathyroid tissue, which also contributes to increases in serum PTH levels. e)Elevated PTH is known to contribute to pathogenesis of renal osteodystrophy and has also been implicated in damage to other systems, including cardiac, cutaneous, endocrine, immunologic, and nervous systems. Associated imbalances in mineral homeostasis probably also contribute to organ system damage.

Renal handling of calcium transport

a. Urinary excretion of calcium is approximately 200 mg per day. b. The complexed and ionized calcium are freely filtered by the glomerulus. c. Less than 2% filtered calcium is excreted, and 98% filtered calcium is reabsorbed. d. The majority of calcium transport is passive. e. The major sites of calcium reabsorption are proximal tubules, thick ascending limbs, and distal tubules. i. Proximal tubule--Reabsorb 65% Ca, 90% passive; 10% active. Parallel to Na reabsorption, influenced by volume status: Depletion: increase Na and Ca reabsorption, Overload: decrease Na and Ca reabsorption. ii. TAL--Reabsorb 20% Ca, Mainly passive. Paracellular pathway mediated by paracellin-1. Lumen positive charge is the driving force (parallel to Na reabsorption), generated by Na,K,2Cl cotransporter and K channel. Transcellular pathway not identified. iii. DCT-- Reabsorb 10% Ca. Mainly transcellular transport. Active transport. Major regulatory site. Directions of Ca and Na transport tend to be opposite (through Na/Ca exchanger).

Renal handling of phosphate transport

a. Urinary excretion of phosphate is approximately 800 mg per day. b. About 12% filtered phosphate is excreted, and the remainder is reabsorbed. c. The renal phosphate reabsorption occurs by an active transcellular pathway in the proximal tubules. d. Filtered phosphate enter the apical brushborder membrane of proximal tubule via the sodium-dependent phosphate cotransporters (type II and Type I) and then cross the basolateral membrane into the blood via the type III sodium-dependent phosphate cotransporter. Phosphate transport in proximal tubule

You are asked to see a 49 year-old Latino gentleman who is noted to have a serum creatinine of 1.9 mg/dL (normal 0.5-1.0g/dL). 4 years ago his creatinine was 1.1 mg/dL. He has a history of diabetes, hypertension, and dyslipidemia. Labs: creatinine is 1.9 mg/dL (normal 0.5-1.0 g/dL). UA 2+ dipstick positive proteinuria. Proteinuria estimated at 1.2 g (1200 mg) by spot ratio. Hemoglobin A1c (measures blood glucose activity over a 3 month period of time) - high at 9.4% (normal <6.5%) What is the most likely cause of this gentleman's chronic kidney disease

diabetes

Understand the relationship between renal artery stenosis and the renin-angiotensin system (pathophysiology).

d. Pathophysiology i. Reduced renal perfusion pressure resulting from stenosis of the arterial vasculature in one of both kidneys ii. Decrease in renal perfusion pressure activates the renin-angiotensin-aldosterone system (RAAS) iii. Angiotensin II stimulation causes the following that results in sustained hypertension: 1. Increase in sympathetic nervous system activity 2. Vasoconstriction 3. Anti-diuretic hormone release (water retention) 4. Aldosterone release from the adrenal gland (sodium retention)

Factors affecting renal calcium excretion

i)Sodium. Saline infusion increases renal calcium excretion. ii)Calcium. Dietary calcium increases calcium excretion. iii)Phosphate. Dietary or IV phosphate increases calcium excretion. iv)Proton. Acidosis increases calcium excretion. v) PTH and calcitriol