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LECTURE NEPHROTIC SYNDROME KIDNEY DISORDERS – CLINICAL : A Asymptomatic hematuria/proteinuria N Nephrotic syndrome N Nephritic syndrome U Urolithiasis R Rapidly progressive glomerulonephritis I Interstitial and tubular diseases C Chronic renal disease KIDNEY DISORDERS – CLINICAL Slide 3: NEPHRITIC Hematuria Proteinuria Hypoalbuminemia Oliguria (GFR, Cr, BUN) Edema (salt and water retention) Hypertension NEPHROTIC Proteinuria (“nephrotic range” >3.5g/24h) Hypoalbumimenia Edema Hyperlipidemia Lipiduria Slide 4: NEPHROTIC SYNDROME The nephrotic syndrome is a clinical complex characterized by a number of renal and extra renal features the most prominent of which are: heavy proteinuria (in practice >3.0 to 3.5 g/1.73 m2 per 24 hours), which leads to hypoproteinemia decreased levels of serum albumin (albumin < 3 g/dl -hypoalbuminemia), severe edema, elevated serum lipids (hyperlipidemia), lipiduria, and hypercoagulability 2 Slide 5: NEPHROTIC SYNDROME It is important to realize that the NS is not a disease; it is a syndrome caused by many different renal diseases When a clinician encounters a patient with the NS it is important for him to determine the underlying condition, because the course and prognosis will depend on the underlying disease 3 NB! Slide 6: DISEASES ASSOCIATED WITH THE NEPHROTIC SYNDROME 4 Slide 7: SECONDARY DISEASE ASSOCIATED WITH THE NEPHROTIC SYNDROME 5 Slide 8: NEPHROTIC SYNDROME Nephrotic syndrome is 15 times more common in children than in adults. Most cases of primary nephrotic syndrome are in children and are due to minimal-change disease. The age at onset varies with the type of nephrotic syndrome. In adults, the most common form of glomerulopathy causing nephrotic syndrome is membranous glomerulonephritis, followed by FSGS. In certain countries and in certain regions of the same country, diabetic nephropathy is emerging as a major cause of nephrotic syndrome 6 NB! Slide 9: COMPONENTS OF THE NORMAL NEPHRON 7 Slide 11: Sodium/water retention GLOMERULAR DAMAGE Reduced GFR Protein loss Activation of the renein-angiotensin system Increased aldosterone Proteinuria Hypoalbuminemia Reduced blood oncotic pressure Systemic edema Hepatic lipoprotein synthesis Hyper-lipidemia Hyper-coaguability NEPHROTIC SYNDROME 8 Slide 12: 9 Slide 13: Glomerular filtration – size barrier – charge barrier Re-absorption at proximal tubule – 98% of filtered protein reabsorbed REGULATION OF PROTEIN EXCRETION BY THE NORMAL KIDNEY 10 Slide 14: Abnormal glomerular filter – Selective proteinuria (“loss of charge barrier”) – Non-selective proteinuria (“loss of size barrier”) • Proximal tubular dysfunction • Overload proteinuria MECHANISMS OF INCREASED PROTEIN EXCRETION ASSOCIATED WITH DISEASE 11 Slide 15: CLASSIFICATION OF PROTEINURIA 12 Slide 16: CAUSE OF PROTEINURIA AS RELATED TO QUANTITY Tubular proteinuria never exceeds 2 g per 24 h and never causes NS Urinary excretion of more than 3.5 g per 24 hours is always glomerular disease 13 Slide 17: Orthostatic proteinuria – typically in healthy teens and young adults – occurs upon assuming upright position – usually less than 2g/24 h Functional proteinuria – patients with normal kidneys but experiencing: - high fever - congestive heart failure - exposure to cold - resolves with resolution of precipitating event NON-PATHOLOGIC FORMS OF PROTEINURIA Persons younger than 30 years who excrete less than 2 g of protein per day and who have a normal creatinine clearance should be tested for orthostatic proteinuria NB! 14 Slide 18: Proteinuria (albuminuria) results from injury to glomerular circulation Increased proteinuria (albuminuria) is associated with progressive kidney disease In diabetes and hypertension, proteinuria (albuminuria) is also an indicator of injury in the systemic circulation Proteinuria (albuminuria) is associated with increased cardiovascular risk THE DUAL SIGNIFICANCE OF PROTEINURIA 15 Slide 19: most common clinical correlate of severe proteinuria with almost always associated with hypoalbumemia relationship between proteinuria and hypoalbuminia is variable variability partly depends on liver’s capacity to synthesize albumin 6-10 percent of albumin pool normally catabolized daily HYPOALBUMINEMIA 16 Slide 20: 1. Increased loss (in urine) or catabolism (filtered albumin increased tubular reabsorption enhanced catabolism by tubular cells; increased renal catabolism in part offset by decreased extrarenal catabolism) 2. Decreased synthesis of albumin (hepatic synthesis in nephrotic syndrome is normal or increased, but below maximal rate achieved in other hypoalbuminemic states) 3. Changes in albumin distribution (some evidence for redistribution into other capillary beds) HYPOALBUMINEMIA IN NEPHROTIC SYNDROME MAY RESULT FROM: 17 Slide 21: THE CYCLE OF EDEMA FORMATION 18 Slide 22: In a steady state, the flux of water across the capillary wall can be expressed by the following formula: 19 Qw = K ([Pc - Pi] - [p - [i] IN THIS FORMULA: Qw- is net flux of water, K - is the capillary filtration coefficient, Pc - is plasma fluid hydrostatic pressure, Pi - is the interstitial fluid hydrostatic pressure. p - is the plasma oncotic pressure, i - is the interstitial fluid oncotic pressure. When the fall of -is wide, the amount of fluid filtered exceeds the maximal lymphatic flow, and edema occurs. Slide 23: High glomerular permeability leads to hyperalbuminuria and, eventually, to hypoalbuminemia. Hypoalbuminemia lowers the plasma colloid osmotic pressure, causing greater transcapillary filtration of water and the development of edema. Capillary hydrostatic pressure and the gradient of plasma to interstitial fluid oncotic pressure determine the movement of fluid from the vascular compartment to the interstitium. Fluid that is not absorbed back into the vascular system until it has reached the venous end of the capillary bed is usually absorbed by the lymphatics and returned back to the vascular space. THE CYCLE OF EDEMA FORMATION 20 Slide 24: Responses to decreased blood volume Decreased renal perfusion, renin release, sequential generation of angiotensin II, aldosterone, and subsequent sodium reabsorption ADH release and resultant water retention at collecting duct Decreased atrial naturetic peptide release and resultant decreased sodium excretion Edema is result of salt and water retention THE CYCLE OF EDEMA FORMATION (II) 21 Slide 25: increase in total plasma and LDL cholesterol with a normal or reduced HDL cholesterol increased risk of premature atherosclerosis Clinical correlate of severe proteinuria (nephrotic syndrome) Total plasma cholesterol levels increase as proteinuria becomes heavy Levels of triglycerides only mildly increased HYPERLIPIDEMIA 22 loss of albumin & associated hypoalbuminemia directly or indirectly stimulates hepatic protein synthesis reduced colloid osmotic pressure results in increased albumin and lipoprotein synthesis and decreased catabolism of lipoproteins in nephrotic syndrome Pathogenesis Slide 26: 23 Slide 27: Patients can develop spontaneous peripheral arterial or venous thrombosis, renal vein thrombosis, and pulmonary embolism. Clinical features of acute renal vein thrombosis include sudden onset of flank or abdominal pain, gross hematuria, a left-sided varicocele (the left testicular vein drains into the renal vein), increased proteinuria, and an acute decline in glomerular filtration rate. Chronic renal vein thrombosis is asymptomatic. HYPERCOAGULABILITY 24 Slide 28: 25 Metabolic complications of NS include protein malnutrition and iron-resistant microcytic hypochromic anemia due to transferrin loss. High glomerular permeability causes the excretion of vitamin D–binding protein and complexes in the urine, leading to (1) malabsorption of calcium and development of bone disease (eg, osteitis fibrosa cystica) because of enhanced parathyroid hormone production and (2) osteomalacia because of impairment in mineralization. METABOLIC COMPLICATIONS Slide 29: 26 SYMPTOMS AND SIGNS Slide 30: Symptoms and signs include anorexia, malaise, puffy eyelids, retinal sheen, abdominal pain, wasting of muscles, and edema. Focal edema may be the reason for seeking help for such complaints as: difficulty breathing (pleural effusion or laryngeal edema), substernal chest pain (pericardial effusion), scrotal swelling, swollen knees (hydroarthrosis), swollen abdomen (ascites), and (in children) abdominal pain from edema of the mesentery. SYMPTOMS AND SIGNS 27 An early sign of NS is frothy urine. At presentation, proteinuria is usually > 2 gm/m2/day, or a urine protein/creatinine ratio is > 2 Slide 31: Most often, the edema is mobile - detected in the eyelids in the morning and in the ankles after ambulation. Orthostatic hypotension and even shock may develop in children. Adults may be hypo-, normo-, or hypertensive. Oliguria and even acute renal failure may develop because of hypovolemia and diminished perfusion. SYMPTOMS AND SIGNS 28 Slide 32: Patients present with increasing edema over a few days or weeks, lethargy, poor appetite, weakness, and occasional abdominal pain. The initial episode and the subsequent relapses may follow an apparent viral upper respiratory tract infection. Edema is the predominant feature and initially develops around the eyes and lower extremities. PHYSICAL: With time, the edema becomes generalized and may be associated with an increase in weight, the development of an ascitic or pleural effusion, and a decline in urine output. Hematuria and hypertension are unusual but manifest in a minority of patients. 29 Slide 33: Prolonged NS may result in nutritional deficiencies, including protein malnutrition resembling kwashiorkor, brittle hair and nails, alopecia, stunted growth, demineralization of bone, glucosuria, hyperaminoaciduria of various types, K+ depletion, myopathy, decreased total Ca, tetany, and hypometabolism. Spontaneous peritonitis may occur, and opportunistic infections are prevalent. The high incidence of infection is thought to be due to the urinary loss of immunoglobulins. Coagulation disorders, with decreased fibrinolytic activity and episodic hypovolemia, are a serious thrombotic risk (notably, renal vein thrombosis). Hypertension with cardiac and cerebral complications is most likely in patients with diabetes or collagen vascular disease. COMPLICATIONS 30 Slide 34: LABORATORY FINDINGS: URINE The initial urinalysis shows marked proteinuria > 2 g/m2/day or a random urinary protein/creatinine ratio > 2. The urine sediment usually contains hyaline, granular, fatty, waxy, and epithelial cell casts. Lipiduria is determined by performing Sudan staining of casts containing lipid granules, identifying macrophages and renal tubular cells containing fatty droplets (oval fat bodies), and finding anisotropic crystals (doubly refractile fat bodies) with polarized light microscopy. Microscopic hematuria and RBC casts also may be present depending on the cause of the glomerular disease. WBCs are prominent in exudative diseases and SLE. Amyloid fibrils may be seen on electron microscopy with amyloid nephropathy. 31 Slide 35: SIGNIFICANCE OF SPECIFIC URINARY CASTS 32 Concentrated urine, febrile diseases, after strenuous exercises, in the course of diuretic therapy (not indicative of renal disease) This section of renal cortex reveals tubules containing hyaline casts that are bile stained in a patient with hyperbilirubinemia. HYALYNE CASTS Hyaline casts, which appear very pale and slightly refractile, are common findings in urine. Slide 36: 33 SIGNIFICANCE OF SPECIFIC URINARY CASTS Nonspecific, can represent acute tubular necrosis These are granular casts, with a roughly rectangular shape GRANULAR CASTS, COARSE Casts which persist may break down, so that the cells forming it are degenerated into granular debris, as has occurred in this granular cast. Slide 37: 34 SIGNIFICANCE OF SPECIFIC URINARY CASTS Glomerulonefritis The presence of this red blood cell cast in on urine microscopic analysis suggests a glomerular or renal tubular injury RED BLOOD CELL CAST This histologic section at medium power with trichrome stain highlights red blood cells grouping together in tubules to form casts. The tubular epithelium is also damaged, with a foamy appearance, and is the basis for the appearance of oval fat bodies in urine in this case. Slide 38: 35 SIGNIFICANCE OF SPECIFIC URINARY CASTS RENAL TUBULAR CELL CASTS Acute tubular necrosis, interstitial nephritis This renal tubular cell cast suggests injury to the tubular epithelium Slide 39: 36 SIGNIFICANCE OF SPECIFIC URINARY CASTS WHITE BLOOD CELL CAST Pyelonephritis, interstitial nefritis ( indicative of infection or inflammation) This white blood cell cast suggests an acute pyelonephritis Slide 40: 37 SIGNIFICANCE OF SPECIFIC URINARY CASTS BROAD, WAXY CAST Chronic renal failure (indicative of stasis in collecting tubule) This is a broad, waxy cast. Note that the edges are sharp and there are "cracks" in this cast. Slide 41: OVAL FAT BODIES Standard light microscopy and polarized light microscopy) shows the appearance of these in the urine as so-called oval fat bodies. Oval fat bodies can be seen quite nicely with polarized microscopy because of the birefringence of the lipid, which produces maltese cross configurations Oval fat bodies are markers for nephrotic range proteinuria but not for any particular disease. These lipid droplets also can become incorporated into casts, i.e., fatty casts 38 Slide 42: 39 SIGNIFICANCE OF SPECIFIC URINARY CASTS FATTY CASTS AND OVAL FAT BODIES In summary, fatty casts and oval fat bodies are characteristic of the nephrotic syndrome and derived from epithelial cells that have engorged themselves with the lipoproteins and proteins spilled during nephrosis. This is a fatty casts and oval fat bodies Slide 43: LABORATORY FINDINGS: URINE Urine K+ usually is high in the accumulation phase of nephrotic edema; urine Na+ concentration often is < 1 mmol/L (K+/Na+ ratio > 1). Aldosterone secretion is elevated during this stage but may be normal at other times despite continued edema. Serum urea nitrogen or creatinine concentrations vary according to the degree of renal impairment. 40 Slide 44: LABORATORY FINDINGS: BLOOD: HYPOALBUMINEMIA is detected by chemical measurement or quantitative electrophoresis. Albumin often is < 2.5 g/dL and, in children, is sometimes < 1 g/dL. Levels of - and -globulins, other immunoglobulins, adrenocortical and thyroid hormones, ceruloplasmin, transferrin, ASO protein, and C are usually low. Lipemia is documented by increased total cholesterol and triglyceride levels. Lipid levels > 10 times normal are associated with severe hypoalbuminemia due to increased lipid production and decreased elimination. Coagulopathies are common, perhaps because of the urinary loss of factors IX and XII and thrombolytic factors (urokinase and antithrombin III) and increased serum levels of factor VIII, fibrinogen, and platelets 41 Slide 45: GLOMERULAR DISORDERS ASSOCIATED WITH NEPHROTIC SYNDROME PRIMARY RENAL DISORDERS ASSOCIATED WITH NEPHROTIC SYNDROME 42 NEPHROTIC SYNDROME – CLINICAL CASE : NEPHROTIC SYNDROME – CLINICAL CASE AM 23 year old man from Egham. Presented at age 3 with nephrotic syndrome, never biopsied. Numerous relapses (~15). Normal serological investigations. Rarely off steroids Cushingoid Relapse 2003 whilst on 5mg prednisolone. Attends clinic with mother, Oedema, low JVP Creatinine 88mmol/l; Alb 18g/dl, 24 hr protein 5g. MINIMAL CHANGE DISEASE : MINIMAL CHANGE DISEASE MINIMAL CHANGE DISEASE : MINIMAL CHANGE DISEASE 90% childhood nephrotic syndrome Common in young adults 15% total adult cases Steroid responsive (80%) ‘steroid sensitive’ 2nd line therapy Associations NSAIDs Paraneoplastic Hodgkin’s disease MINIMAL CHANGE GN: : Introduction Synonyms: Incidence: Etiology: Clinical Features: Lab Features: Pathology: Clinical Course: Nil disease, lipoid nephrosis, foot process disease Idiopathic. Loss of net negative charge on capillary basement membrane. Nephrotic syndrome. History of recent URI in 30%. Association with Hodgkin’s lymphoma. Overlap with FSGS patients. Selective proteinuria. No specific laboratory findings. Spontaneous remission in 25-40%. Complete remission in 65-70% of patients. Steroid resistant patients may progress to FSGS. LM - Normal. IF - Negative. EM - Focal fusion/loss of foot processes. 80% of nephrotic syndrome in children (1-8 yrs.), mostly male. Adults in 2nd-3rd decade. MINIMAL CHANGE GN: Slide 50: A. MINIMAL CHANGE DISEASE (lipoid nephrosis) 44 Slide 51: A. MINIMAL CHANGE DISEASE (syn. "nil" disease; lipoid nephrosis) Most frequent cause of nephrotic syndrome in children (70% or more of cases in children) Clinically, patients have generalized edema with normal renal function tests and selective proteinuria Hematuria is usually absent and patients are normotensive Morphologically, the glomeruli are normal by light microscopy and negative by immunofluorescence (IF) Electron microscopy (EM) reveals generalized foot process fusion Minimal change disease responds readily to steroids, although relapses when therapy is discontinued are common The long term prognosis is excellent 43 CLINICAL CASE -2 : CLINICAL CASE -2 SH 76 lady Rapid onset oedema and dyspnoea Gross oedema; Proteinuria 13g/day Urinalysis Prot 4+, blood –trace Creatinine 176mmol/l, Alb 22g /dl FSGS : FSGS Mild Moderate Collapsing ASSOCIATIONS Idiopathic Morbid obesity Heroin abuse HIV infection NSAID (Minimal change disease) FSGS : FSGS Most common idiopathic nephrotic syndrome in adults (33%) Increasing incidence More common in blacks Treatment very difficult Slide 55: B. FOCAL SCLEROSIS (syn. focal segmental glomerulosclerosis; focal sclerosing glomerulopathy with hyalinosis). Occurs in children and adults, representing about 5-10% of all cases of nephrotic syndrome. Clinical findings often mimic minimal change disease although hematuria, hypertension, and nonselective proteinuria may be present. By light microscopy focal segmental glomerular sclerosis (hyalinosis) is seen, especially in juxtamedullary glomeruli. IF reveals IgM and C3 in these sclerotic areas. EM shows massive subendothelial deposits of proteins. (Note: these are not immune complexes). Often poorly responsive to steroids. Prognosis is guarded with renal failure occurring in at least 30% of patients and permanent renal impairment in another 50%. Children may respond more favorably than adults. Focal sclerosis recurs in renal transplants. 45 Slide 56: С. MEMBRANOUS GLOMERULONEPHRITIS (syn. membranous nephropathy; membranous glomerulopathy) Most common cause of primary nephrotic syndrome in adults (40% of cases) Usually idiopathic, but may be associated with infectious agents (syphilis, hepatitis virus, malaria), neoplasms, drugs (gold, penicillamine), and autoimmune disorders (SLE, rheumatoid arthritis, mixed connective tissue disease). By light microscopy the glomerular basement membrane is uniformly thickened. Cell proliferation is minimal. By IF granular deposits of IgG and C3 are uniformly distributed along the basement membrane. EM reveals thickening of basement membrane, "spikes", subepithelial deposits, and foot process fusion. The prognosis is variable. Spontaneous remissions occur in some cases whereas others progress slowly to chronic renal failure. Steroids and other immune suppressive agents may be effective in retarding the progression to renal failure, but the effect on proteinuria is unpredictable. 46 MEMBRANOUS GN: : Synonyms: Incidence: Etiology: Clinical: Lab: Path: Clinical Course: Epimembranous, extramembranous GN Immune complex disease. Idiopathic in most patients, associated with infections, drugs, carcinomas, and heavy metals. Nephrotic syndrome in 80%, asymptomatic proteinuria in 20%. Microscopic hematuria. Non-selective proteinuria ± hematuria. Excellent prognosis in children. Some adults develop ESRD. Exclusion of other diseases is required. Diffuse, uniform BM thickening with subepithelial projections (“spikes”). Diffuse, coarsely granular IgG and C3 deposits along basement membranes. Electron-dense subepithelial deposits. 40-60 Years, 50% of adult nephrotic syndrome. MEMBRANOUS GN: Slide 58: С. MEMBRANOUS GLOMERULONEPHRITIS (membranous glomerulopathy) 49 Slide 59: MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (syn. lobular hypocomplementemic glomerulonephritis; mesangiocapillary proliferative glomerulonephritis) Occurs in children and adults, representing about 10% of all cases of nephrotic syndrome. Clinically, hematuria, hypertension, oliguria, and nonselective proteinuria are common. Serum complement levels are frequently depressed and C3 nephritic factor is present. By light microscopy the glomeruli are hypercellular and the basement membranes are thickened. Epithelial crescents may be seen. By IF and EM two distinct varieties of membranoproliferative glomerulonephritis are found. Type I: IF reveals immunoglobulins and classical complement pathway components distributed along the periphery of the glomerular lobules. EM shows subendothelial deposits. 47 Slide 60: MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS Type II: IF shows alternate pathway complement components deposited in the mesangium. EM reveals massive intramembranous deposits which are extremely electron dense (dense deposit disease). The prognosis for both types of disease is poor. Actuarial 5 year kidney survivals for Type I and Type II are 55% and 30% respectively. Recurrence of dense deposit disease (Type II) in renal transplants is well documented. 48 MEMBRANOPROLIFERATIVE GN : Introduction Etiology: Chronic immune complex GN. Associated with chronic infections, SLE, cancer, cirrhosis, heroin abuse, etc. Clinical: Nephrotic syndrome in 50%, acute nephritic syndrome in 20%. Recent history of URI in 50%. Hypertension and/or renal insufficiency. Lab: Hypocomplementemia of classic and alternate pathways. C3 nephritic factor (C3NEF). Circulating immune complexes. Clinical Course: Progressive deterioration of renal function ± short remissions. ESRD within 10 years in 50% of children and 80% of adults. Path: Diffuse proliferative GN with thickening of the glomerular capillary walls,, and GBM splitting (“tram-tracking”). Diffuse, coarsely granular C3 and IgG deposits along GBMs. Electron-dense subendothelial deposits. Incidence: Children and young adults (5-25 years). MEMBRANOPROLIFERATIVE GN Slide 62: MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (syn. lobular hypocomplementemic glomerulonephritis; mesangiocapillary proliferative glomerulonephritis) E. OTHER PROLIFERATIVE GLOMERULONEPHRITIDES: nephrotic syndrome may be observed in a proportion of individuals with post-streptococcal glomerulonephritis, IgA nephropathy, and Henoch-Schonlein (anaphylactoid) purpura. Nephrotic syndrome is very common in lupus nephritis (diffuse proliferative and membranous variants). 50 Slide 63: IgA IgA Nephropathy Focal mesangialproliferativeglomerulonephritis Immunofluorescence in the glomeruli:IgG +, IgA +++ (shown here), IgM Negative,and C3 ++. 51 Slide 64: DIABETIC GLOMERULOSCLEROSIS 52 Slide 65: DIABETIC GLOMERULOSCLEROSIS Nephrotic syndrome is associated with both the diffuse and nodular forms of diabetic glomerulosclerosis. Renal functional abnormalities are usually associated with disease of at least 10 years duration. Arteriolonephrosclerosis and pyelonephritis may complicate the clinical and morphological findings. Light microscopy reveals diffuse thickening of the GBM, nodular expansion of the mesangium with mesangial hypercellularity, and hyalinization of arteriolar walls. IF may demonstrate immunoglobulins and complement in the glomeruli. EM regularly shows marked thickening of the GM and increased mesangial matrix material. There is no specific therapy which is beneficial in terms of improving kidney function. 53 Slide 66: 1. DIABETIC GLOMERULOSCLEROSIS 54 Nodular glomerulosclerosis characteristic of diabetes. The nodules tend to be unequal in size and somewhat irregularly distributed Later stage of nodular glomerulosclerosis in a patient with diabetes. The glomerulus is largely sclerosed but still shows characteristic features. Clinical case - 4 : Clinical case - 4 JH 76 year old lady noted to have impaired renal function by GP. Mild oedema, raised JVP 24 hr protein 3.2g Cr 188mmol/l; Alb 27g/dl IgG paraprotein Amyloidosis : Amyloidosis More common in elderly Two main types of renal amyloid AL amyloid AA amyloid Slide 69: AMYLOIDOSIS Nephrotic syndrome occurs in both primary and secondary amyloidosis. Although systemic amyloidosis is virtually always present, the diagnosis may be unsuspected without tissue biopsy. Light microscopy shows amyloid deposition in the glomeruli, interstitial tissue, and blood vessels. IF is usually negative. EM reveals typical amyloid fibrils in the GBM and the mesangium. Prognosis for the kidney is poor. Renal transplantation may be beneficial in some cases. 55 Slide 70: AMYLOIDOSIS Congo red stain from the renal biopsy of a patient with amyloid showing the characteristic green birefringence 56 Fully polarized Congo red stain showing blue-green birefringence characteristic of amyloid Slide 71: AMYLOIDOSIS 57 Periodic acid methenamine silver stain showing amyloid deposits in a glomerulus. The amyloid is an eosinophilic extracellular substance present in the glomerular mesangium. Slide 72: LUPUS NEPHRITIS Renal involvement occurs in about 70% of SLE patients. Most patients have anti-dsDNA antibodies and are hypocomplementemic. The histological changes in lupus nephritis vary from mild mesangial cell proliferation to diffuse proliferative glomerulonephritis. About half of the patients with lupus nephritis have the diffuse proliferative form (i.e. the most severe form). IF and EM reveal mesangial and subendothelial immune complex deposits containing IgG, IgM, IgA, and C3. These complexes often contain ss- and ds- DNA. 58 Slide 73: CLASSIFICATION OF LUPUS NEPHRITIS 59 Slide 74: Hypertension and proteinuria (albuminuria) are both independent variables that predict long-term decline in renal function Renal disease is both a cause and consequence of hypertension Reduction of blood pressure reduces cardiovascular risk and renal risk Reduction of proteinuria (albuminuria) may lower both cardiovascular risk and renal risk Renal Disease and HypertensionCore Concepts of Treatment 60 Slide 75: TREATMENT The treatment of NS involves (1) treatment of the underlying morphologic entity and, when possible, causative disease; (2) general measures to control proteinuria if remission is not achieved through immunosuppressive therapy; and (3) general measures to control nephrotic complications. 61 Initial Diet Therapy : Initial Diet Therapy For patients with modest renal insufficiency, reduce intake of high biological quality protein* intake of 1 gm/kg body weight/day For patients with marked renal insufficiency, reduce dietary protein intake to 0.8 gm/kg body weight/day Restrict dietary sodium intake to 4-6 gm/day Avoid foods rich in potassium *high biological quality proteins are those rich in essential amino acids 62 MANAGEMENT OF NEPHROTIC SYNDROME : MANAGEMENT OF NEPHROTIC SYNDROME New Definition of Renal Insufficiency Serum creatinine >1.4 mg/dL (men) Serum creatinine >1.2 mg/dL (women) Creatinine clearance <60 mL/min New Treatment Goal for Blood Pressure in Patients with Renal Insufficiency Blood pressure <130/80 mmHg 63 Initial Treatment Recommendations : Initial Treatment Recommendations Renal Insufficiency Clcr <60 mL/min CrSerum >1.4 mg/dL* Microalbuminuria (only Abnormality) Diabetes Mellitus ACE Inhibitor (or ARB) Start And Titrate To Maximum Tolerable Dose 130/80 130/80 Proteinuria *for women, CRSerum >1.2 mg/dL 64 Anti-Hypertensive Drugs: Sites of Action : Anti-Hypertensive Drugs: Sites of Action b-Blockers CCBs* Diuretics ACE Inhibitors AT1 Blockers a-Blockers a2-Agonists CCBs DA1 Agonists Diuretics Sympatholytics Vasodilators Blood Pressure Cardiac Output Total Peripheral Resistance = X 65 Slide 80: TREATMENT Measures that may reduce proteinuria include dietary protein restriction, ACE-inhibitors, and NSAIDs. The first two of these measures aim to reduce proteinuria and slow the rate of progression of renal failure by lowering intraglomerular pressure and preventing the development of hemodynamically mediated focal segmental glomerulosclerosis. Edema should be managed by moderate salt restriction (1 to 2 g/day), and use of loop diuretics. It is unwise to remove >1.0 kg of edema per day as more aggressive diuresis may precipitate intravascular volume depletion and prerenal azotemia. Anticoagulation is indicated for patients with deep venous thrombosis, arterial thrombosis, and pulmonary embolism. Hypertension should be treated with diuretics. Infections (especially bacteriuria, endocarditis, and peritonitis) are life-threatening. 66 Slide 81: TREATMENT Supportive therapy requires nutritional guidance to provide a diet that is normal in protein and K (1 mmol/kg/day) and low in saturated fat and Na (< 100 mmol/day). If hyponatremia is present, fluid intake is restricted. If a brisk diuresis occurs and edema remits, Na may need to be liberalized. If ascites is present, frequent small meals may be helpful. K+ intake should be about 1 mmol/kg/day. If hyponatremia is present, fluid intake is restricted. If a brisk diuresis occurs and edema remits, Na+ intake restrictions can be relaxed. If ascites is present, frequent small meals may be helpful. To control symptomatic edema, Na+ restriction (< 100 mmol/day) is recommended. Thiazide or loop diuretics may be used but may compromise renal function and predispose to thrombosis. 67 Slide 82: THE MANAGEMENT OF DYSLIPIDEMIA 68 Slide 83: PROGNOSIS Prognosis depends on the cause. Complete remissions may occur if NS is due to a treatable disorder, which occurs in about 50% of cases in childhood but fewer in adulthood. The prognosis generally is favorable in corticosteroid-responsive disorders . Some diseases causing NS remit spontaneously even after 5 yr. In all cases, prognosis may be worsened by infection, hypertension, significant azotemia, hematuria, or thromboses in cerebral, pulmonary, peripheral, or renal veins. The recurrence rate is high in kidney transplantation patients with FSGS, SLE, IgA nephropathy, and especially type II MPGN but less in those with type I MPGN. Recurrence also occurs in some transplantation patients with MGN and mesangial proliferative GN. 69 Slide 84: "View a negative experience in your life like you'd look at a photo negative. A single negative can create an unlimited number of positive prints."Gerhard GschwandtnerFounder of "Selling Power" magazine Slide 85: THANK YOU FOR ATTANTION! 70 You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.