Glomerular Disease & Proteinuria
Split nephrotic from nephritic, then let serologies and biopsy name the disease
Nephrotic vs nephritic
One clinical fork. Frothy urine and swollen ankles point toward podocyte injury (nephrotic); cola-colored urine and hypertension point toward glomerular inflammation (nephritic).
| Feature | Nephrotic | Nephritic |
|---|---|---|
| Mechanism | Podocyte injury | Glomerular inflammation |
| Proteinuria | >3.5 g/day | Subnephrotic |
| Urine sediment | Lipiduria: fatty casts, oval fat bodies, Maltese crosses | Dysmorphic RBCs and RBC casts |
| Other findings | Hypoalbuminemia, edema, hyperlipidemia, clots | Hypertension, oliguria, azotemia |
Workup. Quantify protein with a spot urine protein-to-creatinine ratio or a 24-hour collection. Send serologies: C3 and C4, ANA and anti-dsDNA, ANCA, anti-GBM, hepatitis B and C, HIV, ASO or anti-DNase B, and cryoglobulins. Renal biopsy gives the definitive diagnosis. A child with typical nephrotic syndrome is treated with steroids first, with biopsy reserved for steroid resistance or atypical features.
Nephrotic syndromes
| Disease | Typical patient and associations | Pathology | Course and therapy |
|---|---|---|---|
| Minimal change disease | Most common in children; Hodgkin lymphoma, NSAIDs | Normal light microscopy; foot-process effacement on EM | Dramatic corticosteroid response |
| FSGS | Leading primary cause in adults, especially Black patients; HIV, obesity, heroin | Segmental sclerosis; collapsing variant in HIV | Often steroid-resistant; progresses to ESRD |
| Membranous nephropathy | Older adults; secondary to solid tumors, hepatitis B, SLE, NSAIDs | Subepithelial deposits, spike-and-dome on EM | Anti-PLA2R in ~70% of primary cases; highest clot risk |
| Diabetic nephropathy | Most common cause of nephrotic-range proteinuria and ESRD | Mesangial expansion, Kimmelstiel-Wilson nodules | ACEi/ARB, SGLT2 inhibitor, glucose and BP control |
Minimal change. Selective albuminuria and a dramatic steroid response are the classic clues in a child with periorbital edema and normal complement.
FSGS. The collapsing variant is the classic lesion of HIV-associated nephropathy, and APOL1 risk variants explain much of the excess risk in Black patients.
Membranous. Anti-PLA2R antibodies mark primary disease. With a positive anti-PLA2R, preserved eGFR, and no atypical features, KDIGO 2021 allows the diagnosis without biopsy. A negative test in an older patient should prompt a search for a secondary cause, including age-appropriate cancer screening.
Nephrotic complications and management
Everything follows protein loss.
- Hypercoagulability: urinary loss of antithrombin III causes renal vein thrombosis and pulmonary embolism; membranous nephropathy carries the highest venous thrombosis risk.
- Infection: immunoglobulin loss increases infections, especially with encapsulated organisms such as S. pneumoniae.
- Edema and hyperlipidemia: low oncotic pressure drives edema, and the liver ramps up lipoprotein synthesis.
Sudden flank pain, hematuria, and a rising creatinine in a nephrotic patient suggest renal vein thrombosis.
Supportive care. ACE inhibitors or ARBs reduce proteinuria, loop diuretics and salt restriction control edema, statins treat hyperlipidemia, and anticoagulation is considered for high-risk patients such as membranous nephropathy with very low albumin.
Nephritic syndromes and complement
| Feature | IgA nephropathy | Post-streptococcal GN | Lupus nephritis (class IV) |
|---|---|---|---|
| Setting | Gross hematuria within 1–2 days of a mucosal (upper respiratory or GI) infection | 1 to 3 weeks after strep pharyngitis or 3 to 6 weeks after impetigo; cola urine, edema, hypertension | Active SLE |
| Complement | Normal | Low C3 | Low C3 and C4 |
| Serology | None specific | Elevated ASO or anti-DNase B (better marker after impetigo) | High anti-dsDNA |
| Biopsy | Mesangial IgA deposits | Subepithelial humps on EM; lumpy-bumpy IF | Wire-loop lesions; full-house IF |
| Treatment | Maximal ACE inhibitor or ARB plus SGLT2 inhibitor, proteinuria goal <0.5 g/day; add sparsentan, targeted-release budesonide, or steroids if proteinuria persists | Supportive; excellent prognosis in children | Glucocorticoids plus mycophenolate or low-dose cyclophosphamide, or triple therapy adding belimumab or a calcineurin inhibitor (voclosporin); hydroxychloroquine for all |
Timing separates IgA from PSGN. Hematuria arriving with the infection (synpharyngitic) is IgA nephropathy; hematuria weeks after it is PSGN. In PSGN, C3 normally recovers within about 8 weeks, and persistent hypocomplementemia suggests another diagnosis such as MPGN. IgA vasculitis (Henoch-Schönlein purpura) is the systemic counterpart of IgA nephropathy, with palpable purpura, arthralgia, and abdominal pain in children.
Complement sorts nephritic disease. Low: PSGN, lupus, MPGN, cryoglobulinemia. Normal: IgA nephropathy, anti-GBM disease, ANCA vasculitis.
Rapidly progressive GN
Crescents. RPGN loses renal function over days to weeks, with crescents on biopsy. It is an emergency: treat aggressively with high-dose steroids and immunosuppression, starting empirically if biopsy and serologies will be delayed.
- Anti-GBM (linear IF)Goodpasture disease: antibodies to type IV collagen in the glomerular and alveolar basement membranes cause hemoptysis plus hematuria. Treat with plasmapheresis, corticosteroids, and cyclophosphamide.
- Immune complex (granular IF)Lupus, PSGN, IgA nephropathy.
- Pauci-immune (no deposits)ANCA-associated vasculitis. Induce remission with steroids plus rituximab or cyclophosphamide.
ANCA patterns. c-ANCA (anti-PR3) marks granulomatosis with polyangiitis, which hits sinus, lung, and kidney (saddle nose, lung nodules). p-ANCA (anti-MPO) marks microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA), the latter with asthma and eosinophilia. Pauci-immune crescentic GN with c-ANCA in a patient with hemoptysis is GPA, whereas linear IgG staining with the same symptoms is anti-GBM disease.