Nephrotic syndrome

BASICS
DESCRIPTION: A syndrome comprising glomerular proteinuria (3.5 g per 1.73m2 body-surface area/day), hypoalbuminemia, lipiduria, hypercholesterolemia and edema as a result of a primary renal disease or secondary to another disease process. System(s) affected: Renal/Urologic, Endocrine/Metabolic Genetics: N/A Incidence/Prevalence in USA: Children - 2:100,000 new cases/year Adults - 3:100,000 new cases/year Predominant age: Children - 1.5-6 years (MCD) Adults - all ages (FGS, MGN more common USA; IgG-IgA worldwide) Predominant sex: Male = Female

SIGNS AND SYMPTOMS: Fluid retention: abdominal distention, ascites, edema, puffy eyelids, scrotal swelling, weight gain, shortness of breath Anorexia Hypertension Oliguria Orthostatic hypotension Retinal sheen Skin striae

CAUSES: Primary renal disease Fibrillary glomerulopathy (primary) Focal glomerulonephritis Focal glomerulosclerosis (FGS) IgA nephropathy Membranoproliferative glomerulonephritis (MPGN) Membranous glomerulonephritis (MGN) Mesangial proliferative glomerulonephritis Minimal change disease (MCD) Rapidly progressive glomerulonephritis (RPGN) Congenital nephrotic syndrome Secondary renal disease. Associated primary renal disease shown in brackets: Allergens (snake venoms, antitoxins, poison ivy, insect stings) Carcinoma (bronchogenic, breast, colon, stomach, kidney) [MGN, etc] Diabetes mellitus (most common) Erythema multiforme Fibrillary glomerulopathy (secondary: amyloid, cryoglobulins, multiple myeloma, chronic lymphocytic leukemia [CLL]

Henoch-Schnlein purpura Heredofamilial (Alport's syndrome, Fabry's disease) HIV infection Hodgkin's lymphoma [MCD] Infections: ventriculoatrial shunt infection, bacterial endocarditis [MPGN], viral (hepatitis B [MPGN, mesangial, MGN]) other viral (hepatitis C), protozoal and helminthic Leukemias Lymphomas [MGN] Non-Hodgkin's lymphoma Focal glomerulosclerosis (reflux nephropathy, heroin abuse, nephron ablation, extensive glomerular scarring in acute glomerulonephritis, chronic renal allograft rejection, end stage kidney, morbid obesity, a thromboembolism) Malignant hypertension Melanoma Nephrotoxins and drugs (gold penicillamine, mercury [MGN]) Nonsteroidal anti-inflammatory drug induced nephrotic syndrome [MCD] and interstitial nephritis. Polyarteritis nodosa Post streptococcal glomerulonephritis [PSGN] - 20% are nephrotic Sarcoid Serum sickness Sjgren's syndrome Systemic lupus erythematosus (SLE) [MGN, FGS, focal, mesangial, diffuse, proliferative] Toxemia of pregnancy

RISK FACTORS: Drug addiction (e.g. heroin [FGS]) Hepatitis B and C, HIV, other infections Immunosuppression Nephrotoxic drugs Vesicoureteral reflux (FGS) Cancer (usually MGN, may be nil disease (MCD) Chronic analgesic abuse

DIAGNOSIS
DIFFERENTIAL DIAGNOSIS: See Causes. Is the disease predominantly nephrotic (protein without hematuria) such as MCD or MGN; or predominantly nephritic (protein plus blood) such as MPGN or FGS?

LABORATORY: Hypoalbuminemia Hyperlipidemia Lipiduria Low complement in some diseases Azotemia Hypercholesterolemia Increased serum beta-globulin Increased serum IgG Urine Proteinuria (> 3 gm/24 hr) Glycosuria Hematuria Aminoaciduria RBC casts

Granular casts Proteinuria Hyaline casts Fatty casts Foamy appearance Drugs that may alter lab results: See description Disorders that may alter lab results: Many

PATHOLOGICAL FINDINGS: Light microscopy May see nothing (e.g., MCD) Disease specific: sclerosis (e.g., FGS in diabetes) Immunofluorescence: Mesangial IgA (Schnlein-Henoch, IgG-IgA nephropathy). Other specific for disease. Electron microscopy (specific for disease as in sub -epithelial deposits of IgG in MGN)

SPECIAL TESTS: Complement levels Antinuclear antibody Serum protein electrophoresis/quantitative immunoglobulins Urine immune electrophoresis Blood cultures Renal venogram for thrombosis

IMAGING: X-ray Ultrasound CT MRI or venography for renal vein thrombosis

DIAGNOSTIC PROCEDURES: History, physical, basic laboratory including electrolytes, renal biopsy with light, immunofluorescence, electron microscopy for definitive diagnosis

TREATMENT
APPROPRIATE HEALTH CARE: Outpatient

GENERAL MEASURES: Treat infections vigorously (especially bacteriuria, endocarditis, peritonitis) Anticoagulant (heparin and warfarin) if thromboses occur Vaccines: Pneumococcal, influenza and H. influenzae Avoid excess sunlight Avoid nephrotoxic drugs Judicious use of diuretics Severe anemia may be treated with erythropoietin Pneumococcal vaccine

SURGICAL MEASURES:

N/A

ACTIVITY: Bedrest as tolerated

DIET: Normal protein (1 g/kg/day) Low fat (cholesterol) Reduced sodium Liberal potassium (unless hyperkalemic) Supplemental multivitamins and minerals, especially D and iron Fluid restriction if hyponatremic Caloric restriction if obese or diabetic Hypercholesterolemia - low fat soy-protein diet, 7 g protein/kg/day

PATIENT EDUCATION: Printed material for patients: National Kidney Foundation, 30 E. 33rd Street, Suite 1100, NY, NY 10016, (800)622-9010 "Childhood Nephrotic Syndrome" (Order #02 -23NN) "Diabetes and Kidney Disease" (Order #02-09CP) and "Focal Glomerulosclerosis" (Order #02-28NN)

MEDICATIONS
DRUG(S) OF CHOICE: Treat underlying disorder (use decision analysis) For steroid-responsive disease: MCD and FGS Adults-MCD: prednisone 1.0-1.5 mg/kg/day for 4-6 weeks. After response, continue steroid for 2 additional weeks, then shift to maintenance dose of 2-3 mg/kg q od for 4 weeks. Taper to zero during the next 4-6 months, or 120 mg po qod same duration, same period of taper. FGS all adults should receive 3-4 months of glucocorticoids and a cumulative dose of 6 gm of prednisolone. Children: prednisone 60 mg/m2 or 2 mg/kg/day orally for 4 weeks. After response, continue steroid for 2 additional weeks, then shift to maintenance dose of 2-3 mg/kg q od for 4 weeks. Taper to zero during the next four months. MGN patients with a poor prognosis: persistent, heavy proteinuria > 8 gm/day for > 6 months; elevated serum creatinine; hypertension; male sex; over age 50 or have a biopsy with sclerosis. Probably benefit from cytotoxic therapy (chlorambucil or cyclophosphamide [Cytoxan]). For hepatitis B virus glomerular disease - interferon. There are initial data for the use of cyclosporine. For edema Most importantly salt restriction; then judicious thiazide, loop diuretics If resistant, a combination of loop and distal diluting segment diuretics, e.g., metolazone (Zaroxolyn) are synergistic It is possible that furosemide (Lasix) and albumin mixed and given IV may potentiate diuresis (eg, 150 mg furosemide plus 25 gm human serum albumin). Be wary of possible thromboses (especially renal vein thrombosis). Other nephrotic renal diseases: frequently relapsing MCD, RPGN, ?MGN, SLE Bolus steroids and/or immune suppression (cyclophospha mide, chlorambucil, cyclosporine) Consultation often required Hypercholesterolemia Diet and cholesterol lowering drugs (cholestyramine and/or HMG -CoA reductase inhibitors) Anticoagulants (heparin, followed by warfarin) for thromboti c events. There is data to suggest prophylactic oral anticoagulation in all cases of membranous GN (Kid Int. 1994;45:578-585). Hypocalcemia from vitamin D loss should be treated with oral vitamin D (dihydrotachysterol) 0.2 mg q day ACE inhibitors to reduce proteinuria even in normotensive patients and to control hypertension if also present. If the patient is intolerant of ACE I, angiotensin II receptor blockers should be utilized.

Contraindications: See manufacturer's literature Precautions: See manufacturer's literature Significant possible interactions: See manufacturer's literature

ALTERNATIVE DRUGS: N/A

FOLLOW UP
PATIENT MONITORING: Frequent monitoring for azotemia, hypertension, edema, nephrotoxicity, serum cholesterol, weight

PREVENTION/AVOIDANCE: Avoid causative factors whenever possible Detect and treat infections vigorously. Infections may involve the common (Pneumococcus) to the unusual (Strongyloides), especially with immunosuppression.

POSSIBLE COMPLICATIONS: Low levels of: 25-hydroxycholecalciferol, serum calcium, adrenocortical hormones, thyroid hormones Hypercoagulability, thrombosis Pulmonary emboli Hyperlipidemia/accelerated cardiovascular disease Acute renal failure Progressive renal failure Renal vein thrombosis Protein malnutrition Infection Pleural effusion Ascites Iron deficiency (uncommon)

EXPECTED COURSE AND PROGNOSIS: Varies with specific causes. Complete remission expected if basic disease is treatable (infection, malignancy, drug-induced). Otherwise may progress to dialysis dependence (e.g., diabetic glomerulosclerosis).