How nephrotic syndrome is tested on Step 1

Expect a child with periorbital edema after an infection, or an adult with edema and a systemic disease, plus a biopsy description.

PodocyteinjuryFiltrationbarrier leaksProteinloss> 3.5 g/dayin urineLowalbumin↓ OncoticpressureEdemaPeriorbital,dependentLiverresponse↑Lipoproteins
Mechanism. The liver increases lipoprotein synthesis in response to low oncotic pressure, causing hyperlipidemia.

Complications of protein loss

Each complication reflects a lost plasma protein.

Lost plasma proteinsAntithrombinIIIThrombosis, renalveinImmunoglobulinsInfections(encapsulated)AlbuminEdema; drug bindingchangesBindingproteinsVitamin D andthyroid
Complications. Children with nephrotic syndrome are at risk of spontaneous bacterial peritonitis from encapsulated organisms.

Primary podocytopathies

Minimal change disease and FSGS both injure podocytes but differ in prognosis.

Minimal change diseaseMost common in childrenNormal light microscopyFoot-process effacement on EMSelective (albumin) proteinuriaSteroid-responsiveFSGSCommon in adultsSegmental sclerosis of some glomeruliEffacement plus scarringNonselective proteinuriaOften steroid-resistant; can progressvs
Minimal change vs FSGS. Minimal change disease is associated with Hodgkin lymphoma, NSAIDs, and recent infection or immunization.

Causes compared

The patient and the biopsy findings point to the cause.

DiseaseLight microscopyEM / IFAssociations
Minimal changeNormalEffaced foot processes; IF negativeChildren; Hodgkin lymphoma; NSAIDs
FSGSSegmental sclerosis and hyalinosisEffacement; IF usually negativeHIV, heroin, sickle cell, obesity, APOL1
MembranousDiffuse GBM thickeningSubepithelial deposits, "spike and dome"; granular IgGAnti-PLA2R; lupus (class V), hepatitis B, solid tumors, NSAIDs, penicillamine
Diabetic nephropathyMesangial expansion; Kimmelstiel-Wilson nodulesGBM thickeningLong-standing diabetes
AmyloidosisCongo red-positive depositsApple-green birefringencePlasma-cell dyscrasia, chronic inflammation

Hyperfiltration in early diabetes is followed by albuminuria; ACE inhibitors or ARBs and SGLT2 inhibitors slow progression.

Treatment and a worked example

Treat the cause, reduce proteinuria, and manage complications.

  • Glucocorticoids for minimal change disease (most children remit).
  • ACE inhibitor or ARB to reduce proteinuria; loop diuretics for edema; statins for hyperlipidemia.
  • Immunosuppression for selected FSGS and membranous nephropathy.
  • Anticoagulation when thrombosis occurs (and sometimes prophylactically in high-risk membranous disease).
functions Worked example — adult with edema

A 58-year-old has edema and 6 g/day proteinuria. Biopsy shows diffuse GBM thickening, subepithelial deposits, and silver-stain "spikes." Serum anti-PLA2R antibody is positive. He develops sudden flank pain and hematuria. What happened?

  1. GBM thickening with subepithelial deposits and spikes = membranous nephropathy.
  2. Anti-PLA2R positivity indicates primary (autoimmune) disease.
  3. Membranous nephropathy carries a high risk of thrombosis from urinary loss of antithrombin III.
  4. Sudden flank pain and hematuria suggest renal vein thrombosis.

Answer. Renal vein thrombosis, a hypercoagulable complication of membranous nephropathy.