RPGN is a nephrology emergency. If creatinine is rising rapidly + active urine sediment (RBC casts, dysmorphic RBCs) - consult nephrology IMMEDIATELY for urgent biopsy. Untreated crescentic GN leads to irreversible ESRD within days to weeks. Do not wait for serologies to return before consulting.
Common Causes
Nephrotic
Nephritic
Minimal change disease (children #1)
IgA nephropathy (#1 worldwide)
FSGS (adults #1, especially AA)
Post-streptococcal GN (children)
Membranous nephropathy (PLA2R antibody)
Lupus nephritis (class III/IV)
Diabetic nephropathy
ANCA vasculitis (GPA, MPA)
Amyloidosis
Anti-GBM (Goodpasture)
Nephrotic Causes - Detailed
Cause
Association
Biopsy Finding
Minimal Change Disease
Children (#1), NSAIDs, lymphoma (Hodgkin)
Normal on light microscopy; podocyte foot process effacement on EM
FSGS
HIV, obesity, heroin, African Americans
Focal and segmental sclerosis of glomeruli
Membranous Nephropathy
PLA2R antibody, cancer (lung, colon), hepatitis B
Subepithelial deposits ("spike and dome" on silver stain)
Diabetic Nephropathy
#1 secondary cause in adults, long-standing DM
Kimmelstiel-Wilson nodules, mesangial expansion
Amyloidosis
AL (myeloma) or AA (chronic inflammation)
Congo red stain โ apple-green birefringence
Nephritic Causes - Detailed
Cause
Key Features
Biopsy / Diagnosis
IgA Nephropathy
Most common GN worldwide (Berger disease). Episodic gross hematuria with URI.
Mesangial IgA deposits on IF
Post-Streptococcal GN
Children 1โ3 wk after pharyngitis. ASO titer โ, low C3.
Subepithelial "humps" on EM, granular IF ("lumpy-bumpy")
Lupus Nephritis
Class III (focal) and IV (diffuse) are most severe. Low C3/C4, dsDNA+.
"Full house" IF (IgG, IgA, IgM, C3, C1q)
ANCA Vasculitis
GPA (c-ANCA/PR3) or MPA (p-ANCA/MPO). Pauci-immune GN.
Crescentic GN with few/no immune deposits (pauci-immune)
Anti-GBM / Goodpasture
Pulmonary hemorrhage + GN. Anti-GBM antibodies.
Linear IgG staining along GBM on IF
MPGN
Low C3 and C4. Hepatitis C association.
Mesangial and subendothelial deposits, "tram-tracking" of GBM
๐จ Management
Nephrotic Syndrome Management
ACEi/ARB -reduce proteinuria (first-line for ALL proteinuric kidney disease)
Diuretics -loop diuretics for edema. May need albumin co-infusion if severe hypoalbuminemia.
Statin -hyperlipidemia management
Anticoagulation -consider if albumin < 2.5 (loss of antithrombin III โ hypercoagulable state โ renal vein thrombosis)
Key Evidence: Rituximab is now first-line for primary membranous nephropathy MENTOR, 2019. For ANCA vasculitis, rituximab is noninferior to cyclophosphamide for induction RAVE, 2010 and superior for maintenance MAINRITSAN, 2014. For lupus nephritis class III/IV, add mycophenolate or cyclophosphamide to steroids ALMS, 2009. Voclosporin added to standard therapy improves renal response in lupus nephritis AURORA, 2021.
Nephritic Syndrome Management
Treat underlying cause -immunosuppression for lupus nephritis, ANCA vasculitis
BP control -ACEi/ARB preferred
Supportive -fluid/salt restriction, diuretics if edema
Urgent nephrology + renal biopsy -rapidly progressive GN (RPGN) is an emergency
Anticoagulation in nephrotic syndrome: Membranous nephropathy has the highest thrombotic risk. Consider prophylactic anticoagulation when albumin < 2.5 g/dL. Renal vein thrombosis presents as flank pain, hematuria, and sudden worsening of proteinuria. Diagnose with CT venography or Doppler ultrasound Lionaki, 2012.
The kidney leaks antithrombin III (a key anticoagulant) in the urine along with other proteins. Loss of ATIII โ uninhibited thrombin activity โ hypercoagulable state. Clinical significance: renal vein thrombosis (especially in membranous nephropathy), DVT, PE. Consider prophylactic anticoagulation when albumin < 2.5 g/dL.
What is the most common cause of nephrotic syndrome in adults vs children?
Adults: FSGS (#1 overall, especially in African Americans) and membranous nephropathy (#1 primary cause in Caucasians). Diabetic nephropathy is the #1 secondary cause. Children: Minimal change disease (#1, ~80%). MCD responds dramatically to steroids -> 90% achieve remission within 4โ8 weeks.
What is PLA2R antibody and why is it important?
Phospholipase A2 receptor antibody is positive in ~70% of primary membranous nephropathy. It distinguishes primary from secondary causes (cancer, lupus, hepatitis B). Titers correlate with disease activity and treatment response. MENTOR, 2019 showed rituximab is superior to cyclosporine for PLA2R+ MN.
What complement pattern helps distinguish nephritic causes?
Low C3 + C4: lupus nephritis, cryoglobulinemia (both activate classical pathway). Low C3 only (normal C4): post-streptococcal GN, C3 glomerulopathy, atypical HUS (alternative pathway). Normal complement: IgA nephropathy, ANCA vasculitis, anti-GBM disease (no complement consumption).
What is the significance of RBC casts on urinalysis?
RBC casts are pathognomonic for glomerulonephritis. They form when RBCs become trapped in Tamm-Horsfall protein casts within the tubules. Their presence confirms glomerular origin of hematuria (vs bladder, ureter, or kidney stone). Dysmorphic RBCs also suggest glomerular origin but are less specific.
When is renal biopsy indicated in nephrotic syndrome?
Adults: almost always indicated to guide treatment (except diabetic nephropathy with typical features - long-standing DM, retinopathy, no hematuria). Children: NOT needed for first episode with typical MCD presentation - empiric steroids. Biopsy if steroid-resistant, atypical features, or adult onset.
What is RPGN and why is it a nephrology emergency?
Rapidly Progressive Glomerulonephritis: loss of > 50% renal function over days to weeks. Characterized by crescents on biopsy (> 50% of glomeruli). Three categories: anti-GBM (type I), immune complex (type II: lupus, IgA, post-infectious), pauci-immune (type III: ANCA). Untreated leads to ESRD within weeks. Needs urgent biopsy and immunosuppression.
What is the MENTOR trial and what did it change?
MENTOR, 2019 (NEJM): Rituximab was noninferior to cyclosporine for inducing remission in membranous nephropathy at 12 months, and SUPERIOR at 24 months (60% vs 20% complete/partial remission). Rituximab is now first-line for primary MN. Less toxic than prior cyclophosphamide-based regimens.
Why do nephrotic patients develop hyperlipidemia?
Liver compensates for albumin loss by increasing protein synthesis, which includes increased lipoprotein (VLDL, LDL) production. Simultaneously, urinary loss of lipoprotein lipase cofactors reduces lipid clearance. Both mechanisms lead to marked hyperlipidemia. Treat with statins. Lipids normalize when nephrotic syndrome remits.
Clinical Examples
๐ Case 1 - Minimal Change Disease
Patient: 5-year-old boy presents with periorbital edema for 3 days. UA: 4+ protein, no blood. Labs: albumin 1.8 g/dL, cholesterol 380, Cr 0.4.
Diagnosis: Minimal change disease (most common nephrotic syndrome in children).
Key findings:
Nephrotic range proteinuria (4+) with severe hypoalbuminemia (1.8)
Periorbital edema - classic early sign in children (gravitational pooling while sleeping)
No hematuria - confirms nephrotic (not nephritic) pattern
Age 5 - MCD accounts for ~80% of nephrotic syndrome in children
Treatment: Prednisone 2 mg/kg/day (max 60 mg). Patient achieves complete remission within 4 weeks. No biopsy needed for first episode in children with typical presentation.
๐ Case 2 - ANCA Vasculitis (Nephritic)
Patient: 45M with gross hematuria, HTN (168/98), lower extremity edema. Labs: Cr 2.8 (baseline 1.0), UA with RBC casts. ANCA positive (p-ANCA/MPO).
Nephrotic range proteinuria (UPCR 8.2) with hypoalbuminemia and hyperlipidemia
PLA2R antibody positive - confirms primary membranous (~70% of cases)
Age-appropriate cancer screening needed - membranous can be paraneoplastic (lung, colon, breast)
High risk for renal vein thrombosis - membranous has the highest thrombotic risk of all nephrotic causes
Treatment: Started on rituximab (first-line immunosuppression for primary MN per MENTOR trial). ACEi for proteinuria reduction. Anticoagulation given albumin < 2.5. Monitor PLA2R titers for treatment response.