Glomerular Diseases

Nephritic vs nephrotic

Nephritic syndrome: inflamed glomeruli bleed. Inflammatory, hypercellular glomeruli damage the capillary wall, so red cells leak and GFR falls: hematuria with RBC casts (the hallmark), hypertension, oliguria, azotemia, and sub-nephrotic proteinuria (under 3.5 g/day). Salt and water retention drives the hypertension and periorbital edema.

Nephrotic syndrome: injured podocytes leak. Podocyte or GBM injury lets protein through: proteinuria over 3.5 g/day, hypoalbuminemia, edema from low oncotic pressure, hyperlipidemia (the liver ramps up lipoprotein synthesis), and lipiduria with fatty casts and Maltese-cross oval fat bodies. Urinary loss of antithrombin III causes hypercoagulability, and loss of immunoglobulins raises infection risk.

Nephritic diseases

Post-streptococcal GN (PSGN). Children, 2–4 weeks after group A strep pharyngitis or impetigo with a nephritogenic strain: cola-colored urine, periorbital edema, hypertension, and LOW C3 from complement consumption. Immune complexes give granular "lumpy-bumpy" (starry sky) IgG and C3 on IF and subepithelial "humps" on EM. Usually self-limited in children.

IgA nephropathy (Berger disease). The most common GN worldwide. Mesangial IgA deposits cause episodic gross hematuria CONCURRENT with a URI or GI infection (within 1–2 days, "synpharyngitic"), unlike PSGN's 2–4 week lag, and C3 is normal. It is the renal lesion of IgA vasculitis (Henoch-Schönlein purpura), which adds palpable purpura, arthralgia, and abdominal pain.

Rapidly progressive GN (RPGN). Renal function is lost over days to weeks, and light microscopy shows crescents in Bowman space (fibrin, macrophages, proliferating parietal cells). Immunofluorescence sorts the cause:

• Linear: anti-GBM disease (Goodpasture), with antibodies to type IV collagen causing hematuria plus hemoptysis.
• Granular: immune complex disease, such as PSGN and lupus.
• Pauci-immune (negative IF): ANCA vasculitis: c-ANCA in granulomatosis with polyangiitis (GPA); p-ANCA in microscopic polyangiitis (MPA) and EGPA.

Alport syndrome. A hereditary type IV collagen defect (COL4A5, most often X-linked) that affects eye, kidney, and ear: eye problems (e.g., anterior lenticonus), nephritic hematuria that progresses to renal failure, and sensorineural deafness. EM shows "basket-weave" splitting and lamellation of the GBM lamina densa.

Membranoproliferative GN (MPGN). Straddles nephritic and nephrotic presentations. Mesangial ingrowth splits the GBM, so PAS or silver stains show "tram-track" double contours. Type I has subendothelial immune-complex deposits (HBV, HCV). Type II, dense deposit disease, is driven by C3 nephritic factor, an autoantibody that stabilizes C3 convertase, causing persistently low C3 and intramembranous deposits.

Nephrotic diseases

Minimal change disease. The most common nephrotic syndrome in children. LM is normal and IF negative; only EM reveals diffuse foot process effacement. Loss of the charge barrier causes selective albuminuria, and the response to corticosteroids is excellent. Associations: recent infection, Hodgkin lymphoma, and NSAIDs.

Focal segmental glomerulosclerosis (FSGS). The most common primary nephrotic syndrome in adults, especially Black and Hispanic patients (APOL1 risk variants). LM shows sclerosis in SOME glomeruli and only part of each; IF is often negative; EM shows foot process effacement. Associations: HIV (collapsing variant), heroin, sickle cell disease, and obesity. It responds poorly to steroids and can progress to CKD.

Membranous nephropathy. A leading cause of primary nephrotic syndrome in white adults; primary disease has antibodies to the podocyte phospholipase A2 receptor (anti-PLA2R). Secondary causes: SLE (class V lupus nephritis), HBV, solid tumors, and drugs (NSAIDs, penicillamine, gold). LM shows diffuse GBM thickening, IF granular IgG and C3, and EM subepithelial deposits with a "spike-and-dome" pattern. Renal vein thrombosis risk is especially high.

Diabetic nephropathy. The most common cause of ESRD in the US. Nonenzymatic glycation thickens the GBM and expands the mesangium, forming Kimmelstiel-Wilson nodules (nodular glomerulosclerosis). Hyalinosis of the efferent arteriole raises intraglomerular pressure, so hyperfiltration comes first, followed by microalbuminuria and then overt proteinuria. ACE inhibitors/ARBs dilate the efferent arteriole and slow progression.

Renal amyloidosis. The kidney is the most commonly involved organ, and deposits cause nephrotic-range proteinuria. Congo red shows apple-green birefringence under polarized light. AL amyloid derives from plasma-cell light chains (multiple myeloma); AA amyloid from chronic inflammation.

Reading the biopsy: where deposits sit

Deposit location on EM. The position of immune deposits often clinches the diagnosis:

• Subepithelial (between GBM and podocyte): PSGN humps; membranous spike-and-dome.
• Subendothelial (between endothelium and GBM): MPGN type I; diffuse proliferative lupus nephritis, which thickens capillaries into "wire loops."
• Intramembranous (within the GBM): dense deposit disease (MPGN type II).
• Mesangial: IgA nephropathy.

Deposits on the blood side of the GBM (subendothelial) are exposed to circulating leukocytes and tend to cause proliferative, nephritic injury; deposits beyond it (subepithelial) tend to injure podocytes and cause proteinuria, with PSGN as the notable exception.