nephrotic syndrome

Introduction

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

Etiology

• causes of glomerular proteinuria
  • diabetic nephropathy (most common cause)#
  • minimal change disease (children, adults)
  • membranous nephropathy (elderly, white)*
  • focal segmental glomerulosclerosis (African Americans)%
  • renal amyloidosis -> AA-amyloidosis -> rheumatoid arthritis
  • post-infectious glomerulonephritis (GN)
    • post-streptococcal glomerulonephritis
  • IgA nephropathy
  • membranoproliferative glomerulonephropathy
  • systemic lupus erythematosus (SLE)
  • malignancy
    • multiple myeloma, lymphoma, other
  • hepatitis B, hepatitis C
  • HIV
  • syphilis
  • endocarditis
  • Wegener's granulomatosis
• 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

% most common cause in African Americans

# nephrotic syndrome is a late manifestation

• nephrotic range proteinuria in a diabetic without microvascular disease (retinopathy) or macrovascular disease (cardiovascular disease) is not due to diabetes mellitus; obtain kidney biopsy

Pathology

• loss of glomerular basement membrane barriers to protein passage
  • increased permeability of the glomerular capillary basement membrane
  • 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
  • loss of albumin
  • insufficient synthesis of albumin
    • healthy liver can synthesis 30 g of albumin/day
• nephrotic syndrome produces a hypercoagulable state associated with:
  • decrease in plasma antithrombin 3 (loss of antithrombin 3 in urine)
  • decrease in plasma factor IX & plasma factor XI
  • decrease in plasma plasminogen
  • increase in plasma fibrinogen (increased synthesis)
  • increase in plasma protein C, plasma protein S
  • increase in plasma alpha-2 antiplasmin
  • increase in plasma factor V, plasma factor VII, plasma factor VIII, plasma factor X
  • increased platelet reactivity
    • thrombocytosis
    • increased plasma factor IV & plasma 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
• atherosclerosis
  • loss of high-density lipoprotein
  • loss of heparan sulfate
  • loss of alpha-1 acid glycoprotein
  • increased synthesis of apolipoprotein B & LDL
• anemia
  • loss of erythropoietin
  • loss of transferrin
• osteomalacia
  • loss of vitamin D-binding protein
• hypothyroidism
  • loss of thyroxine
  • loss of thyroid hormone-binding proteins
• unknown effects
  • increase in plasma alpha2-globulins & beta-globulins
  • increase in plasma IgM

Clinical manifestations

• edema/anasarca
  • periorbital edema, pedal edema
  • abdominal distension, ascites
• increased serum cholesterol (usually)
• venous thromboembolism common
  • deep vein thrombosis
    • renal vein thrombosis is common
  • pulmonary embolism
• hypertension may be present
• signs & symptoms of systemic lupus erythematosus
• signs & symptoms of diabetes mellitus
  • diabetic retinopathy on funduscopic 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 > 350 mg/dL (3500 mg/L)
  • urine protein/creatinine > 3.5 (g/g) (3500 mg/g)
• 24 hour urine protein > 3.5 grams (3500 mg)
• urine protein electrophoresis
  • albumin in glomerular disease
  • Bence Jones protein in myeloma
• urine immunofixation electrophoresis
• serum chemistries
  • serum glucose
  • serum albumin: hypoalbuminemia
• 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
    • postinfectious 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>
• thyroid function testing
  • free thyroxine may be low (lost in urine)
  • serum TSH may be elvated (low free thyroxine)
• 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
• CT angiography if suspected renal vein thrombosis

Complications

• deep vein thrombosis, pulmonary embolism, especially associated with membranous glomerulonephritis
  • renal vein thrombosis is common (flank pain, worsening renal function)
• excessive urine thyroxine causing hypothyroidism in patients on thyroxine-replacement therapy
• hyperlipidemia

• disease interaction(s) of hypothyroidism with nephrotic syndrome

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
    • 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 initiating immunosuppressive therapy
  • glucocorticoids
    • idiopathic nephrotic synrome frequently responds to glucocorticoids
    • minimal change disease is the most responsive
    • 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 is not an indication
  • evidence of uremic encephalopathy
• renal transplantation
• treat complications
  • statin for hyperlipidemia
  • anticoagulation for venous thromboembolism due to urinary loss of antithrombin
  • low salt diet & loop diuretics for edema

More general terms

• nephrosis
• glomerulonephropathy; glomerulopathy
• syndrome

More specific terms

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

Additional terms

• causes of nephrotic syndrome
• nephritis
• proteinuria

Patient information

nephrotic syndrome patient information