Nephrotic Syndrome

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Contents 1 More Specific Terms 2 Introduction 3 Etiology 4 Pathology 5 Clinical-manifestations 6 Laboratory 7 Diagnostic-procedures 8 Radiology 9 Complications 10 Management 11 More General Terms 12 Additional Terms 13 References

More Specific Terms

• familial nephrotic syndrome
• isolated diffuse mesangial sclerosis (IDMS)
• steroid-resistance nephrotic syndrome

Introduction

• Defined as > 3.5 grams of protein in 24 hour urine, hypo- albuminemia, hyperlipidemia, & edema.

Etiology

• mechanism:

• increased permeability of the glomerular capillary basement membrane
• nephrotic syndrome produces a hypercoagulable state

• causes of glomerular proteinuria

• diabetic nephropathy (most common cause)#
• minimal change disease (children, adults)
• membranous nephropathy (elderly, white)*
• focal segmental glomerulosclerosis ( African Americans)%
• amyloidosis
• post- infectious glomerulonephritis ( GN)

• post-streptococcal glomerulonephritis

• IgA nephropathy
• membranoproliferative glomerulonephropathy
• systemic lupus erythematosus ( SLE)
• multiple myeloma
• hepatitis B, hepatitis C
• HIV
• syphilis
• other causes: endocarditis, Wegener's granulomatosis, lymphoma, malignancy

• pharmacologic causes:
• captopril
• gold salts
• penicillamine
• probenecid
• NSAIDs
• interferon-alpha
• pamidronate
• drugs of abuse

• heroin
• cocaine

• also see causes of nephrotic syndrome

• * most common cause of idiopathic nephrotic syndrome in elderly & in white Americans [6,7]
•  % most common cause in African Americans [6]
• # nephrotic syndrome is a late manifestation [7]

Pathology

• loss of glomerular basement membrane barriers to protein passage

• minimal change disease - loss of glycosaminoglycans
• membranous glomerulonephritis - loss of porous structure

• Na+ retention

• intrascular volume depletion stimulates renin-angiotensin-aldosterone axis
• increased distal tubular resorbtion of Na+
• impaired response to atrial natriuretic factor ( ANF)

• edema
• hypercoagulable state associated with:

• decrease in plasma

• antithrombin 3 (loss of antithrombin 3 in urine)
• factor IX & factor XI
• plasminogen

• increase in plasma

• fibrinogen
• protein C, protein S
• alpha-2 antiplasmin

• increased platelet reactivity

• thrombocytosis
• increased factor IV & thromboglobulin
• altered endothelial function

• venous thrombosis more common than arterial thrombosis

• susceptibility to infection

• loss of complement factor B
• loss of immunoglobulins

• hyperlipidemia

• impaired catabolism of apo-B containing lipoproteins
• alpha-1 acid glycoprotein may play role

Clinical-manifestations

• edema/ anasarca

• periorbital edema, pedal edema
• ascites

• increased serum cholesterol (usually)
• thromboemboli & renal vein thrombosis are common
• hypertension may be present
• signs & symptoms of systemic lupus erythematosus
• signs & symptoms of diabetes mellitus

• diabetic retinopathy on fundoscopic exam

• hepatosplenomegaly associated with:

• amyloidosis
• lymphoma
• hepatitis
• malignancy
• endocarditis

• gross hematuria may be present

Laboratory

• urinalysis

• microscopy:

• evidence of glomerular disease: RBC, RBC casts

• glucosuria with diabetes
• proteinuria: albuminuria (dipstick detects albumin)
• lipiduria: maltese cross fat droplets seen with polarized microscopy

• urine protein > 300 mg/dL
• 24 hour urine protein > 3.5 grams
• urine protein electrophoresis

• albumin in glomerular disease
• Bence Jones protein in myeloma

• urine immunofixation electrophoresis
• serum chemistries

• serum glucose
• serum albumin: low

• HIV testing: HIV is associated with focal segmental glomerulosceloris
• urine toxicology: IV drug abuse is associated with amyloidosis
• serologies

• antinuclear antibody ( ANA)
• anti glomerular basement membrane ( anti-GBM)
• complement C3 & complement C4: diminished in:

• lupus nephritis
• membranoproliferative GN
• post- streptococcal GN
• proliferative GN secondary to endocarditis

• cryoglobulins
• anti neutrophil cytoplasmic antibody ( ANCA)

• elevated in Wegener's granulomatosis

• streptozyme & antistreptolysin O ( ASO)

• post streptococcal glomerulonephritis

• hepatitis serologies

• hepatitis B surface antigen ( HBsAg)
• hepatitics C antibody

• serum transaminases & hepatitis profile

• hepatitis may be associated with glomerular proteinuria

• lipid panel:

• hyperlipidemia
• increased total cholesterol, LDL cholesterol & Lp<a>

• age- & sex-appropriate screening for cancer

Diagnostic-procedures

• renal biopsy

• relatively safe
• indications

• abnormal serologic studies
• azotemia
• distinguish from nephritic syndrome

• contraindications:

• small kidneys: suggests scarring & fibrosis

Radiology

• renal ultrasound

• size of kidneys
• chronicity of disease
• evaluates obstruction
• renal vein doppler for renal vein thrombosis
• reflux nephropathy
• polycystic kidney disease
• often required for biopsy
• if kidneys are markedly diseased or scarred & small, aggressive workup should not be pursued [6]

Complications

• deep vein thrombosis, pulmonary embolism, especially associated with membranous glomerulonephritis

Management

• general measures

• ACE inhibitors or ARBs reduce proteinuria
• edema

• despite edema, patients are at risk for intravascular volume depletion
• loop diuretic ( furosemide)

• +/- metolazone to mobilize edema
• combined with albumin infusion or addition of spironolactone for severe albuminuria [6]

• salt restriction 2-3 g sodium/day

• HMG CoA reductase inhibitor to reduce cholesterol
• heparin & warfarin to prevent emboli
• dietary protein titered to urinary losses

• immunosuppressive therapy

• in adults, obtain renal biopsy prior to intiating immunosuppressive therapy [6]
• glucocorticoids

• idiopathic nephrotic synrome frequently responds to glucocorticoids
• minimal change disease is the most responsive [6]
• prednisolone 1 mg/kg QD for 8 weeks

• cyclophosphamide ( Cytoxan) 1-2 mg/kg QD for 8 weeks
• azathiaprine ( Imuran)
• cyclosporine ( Sandimmune)
• chlorambucil ( Leukeran)

• pentoxyfylline ( Trental)

• decreases hyperfiltration
• may be useful in diabetics
• adenosine receptor antagonist

• gel-foam ablation

• if proteinuria is so severe as to impair viabilility, the kidney may be infarcted with gel-foam by radiologic procedure

• hemodialysis: GFR < 30 mL/min [6]
• renal transplantation

More General Terms

• nephrosis
• syndrome

Additional Terms

• causes of nephrotic syndrome
• nephritis
• proteinuria

References

1. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook, Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 829-39.
2. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 270-71
3. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 520-522
4. Orth SR, Ritz E The nephrotic syndrome. NEJM 338:1202-10, 1998 PMID: [1]
5. Navarro JE et al Urinary protein excretion and serum tumor necrosis factor in diabetic patients with advanced renal failure: effects of pentoxifylline administration. Am J Kidney Disease 33:458 1999 PMID: [2]
6. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, American College of Physicians, Philadelphia 1998, 2006, 2009
7. Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004
8. Nephrotic Syndrome: NIH Institute and Center Resources [3]

nephrotic syndrome