Renal & Urinary

Nephrotic syndrome: workup and differential

Clinical Overview and When to Suspect Nephrotic Syndrome

— Proteinuria ≥3.5 g/day (or UPCR ≥3.5 g/g) — the cardinal feature

— Hypoalbuminemia (<3.0 g/dL, often <2.5)

— Edema (peripheral, periorbital, anasarca)

— Hyperlipidemia with lipiduria (oval fat bodies, "Maltese cross")

— Adult with new-onset bilateral leg edema, frothy urine, weight gain

— Incidental dipstick 3+/4+ protein on routine visit or insurance physical

— Diabetic with worsening edema, declining albumin, and rising UPCR

— Patient with known SLE, HIV, hepatitis B/C, or multiple myeloma developing edema

— Child 2–8 yrs old with periorbital edema misdiagnosed as "allergies"

— Nephrotic = bland sediment, heavy proteinuria, edema dominant

— Nephritic = active sediment (RBC casts, dysmorphic RBCs), HTN, AKI, sub-nephrotic proteinuria

— Overlap exists (e.g., lupus nephritis, MPGN can present with both)

— UPCR >3.5 g/g, eGFR <60, hematuria + proteinuria, or systemic features

— Same-day workup if AKI, gross hematuria, hypertensive urgency, or anasarca

— Children: minimal change disease (MCD) ~90% → empiric steroids before biopsy

— Adults: FSGS, membranous, diabetic nephropathy, amyloid → biopsy usually required

Step 3 management: In an ambulatory adult with new nephrotic-range proteinuria, the first three orders are UPCR, serum albumin, and basic metabolic panel, followed by nephrology referral within 1–2 weeks — not empiric steroids.

Definition: Glomerular disease with the tetrad of:

Pathophysiology snapshot: Injury to the glomerular filtration barrier (podocyte, basement membrane, or endothelium) → loss of size/charge selectivity → massive albuminuria → ↓oncotic pressure → edema + hepatic compensatory lipoprotein synthesis → hyperlipidemia.

When to suspect in clinic:

Distinguish from nephritic syndrome:

Initial outpatient triggers for nephrology referral:

Adult vs pediatric pretest probability:

Presentation Patterns and Key History

— "Swelling around my eyes in the morning" (periorbital edema, gravity-dependent shift)

— "My shoes don't fit anymore" / pitting lower extremity edema

— "Foamy or bubbly urine that doesn't flush away" — high specificity for proteinuria

— Rapid weight gain (5–15 kg) over weeks without dietary change

— Scrotal/labial edema, abdominal distention from ascites, dyspnea from pleural effusions

— Acute/subacute (days–weeks): minimal change disease, drug-induced (NSAIDs), post-infectious

— Insidious (months): membranous nephropathy, diabetic nephropathy, amyloidosis, FSGS

— Diabetes duration ≥10 yrs + retinopathy → diabetic nephropathy is the leading adult cause

— Hepatitis B → membranous; Hep C → MPGN, cryoglobulinemia

— HIV → collapsing FSGS (especially in patients of African descent, APOL1 risk alleles)

— Recent NSAID, lithium, pamidronate, interferon, anti-VEGF, checkpoint inhibitors → drug-induced

— Solid tumor (lung, colon, breast, prostate) in adult >60 with membranous pattern

— Hodgkin lymphoma → minimal change; non-Hodgkin/CLL → membranous or MPGN

— IV drug use → secondary FSGS (heroin), HCV

— Constitutional symptoms, macroglossia, easy bruising, carpal tunnel → amyloidosis

— Malar rash, arthralgias, oral ulcers, photosensitivity → lupus nephritis

— Recent strep/viral URI in child → post-infectious GN (nephritic, but overlap)

Board pearl: A 55-year-old smoker with new nephrotic syndrome and a membranous pattern on biopsy mandates age-appropriate cancer screening (CT chest, colonoscopy, mammogram, PSA) before labeling it primary — malignancy-associated membranous changes management entirely.

Classic chief complaints:

Tempo clues:

Targeted history — chase secondary causes:

Family history: Alport, Fabry, congenital nephrotic syndrome (Finnish type), APOL1-associated FSGS

Medication and supplement review: Including herbal/Chinese herbs (aristolochic acid), gold, penicillamine — historical but still tested.

Physical Exam Findings and Volume Assessment

— Pitting, symmetric, gravity-dependent — starts periorbital (loose tissue), progresses to legs, sacrum, scrotum/labia

— Worse in morning (face) and evening (legs) — distinguishes from cardiac edema (constant LE pattern)

— Anasarca in severe cases with serositis (pleural effusions, ascites, pericardial effusion)

— Nephrotic patients can be hypovolemic, euvolemic, or hypervolemic despite obvious edema

— "Underfill" pattern: ↓effective arterial volume, cool extremities, orthostasis, ↑BUN/Cr ratio, FENa <1% — common in MCD, kids

— "Overfill" pattern: HTN, elevated JVP, primary renal Na retention — common in FSGS, diabetic, membranous

— Assess JVP, capillary refill, orthostatic vitals, mucous membranes before diuresing

— Pleural effusions (dullness, decreased breath sounds at bases) in 20–30%

— S3 only if concurrent volume overload or cardiac disease — not typical of pure nephrosis

— Shifting dullness, fluid wave from ascites

— Spontaneous bacterial peritonitis can occur in nephrotic ascites — fever + abdominal pain → paracentesis

— Muehrcke lines (paired white transverse bands on nails) from hypoalbuminemia

— Xanthelasma, eruptive xanthomas from hyperlipidemia

— Periorbital purpura, macroglossia, waxy plaques → AL amyloidosis

— Malar rash, oral ulcers → lupus

— Track marks → IV drug-related FSGS/HCV

— Carpal tunnel signs (Tinel/Phalen) bilateral → amyloid

— Asterixis if uremic

— Asymmetric leg swelling + calf tenderness → DVT (nephrotic = hypercoagulable)

— Flank pain, gross hematuria → renal vein thrombosis (classic with membranous)

Key distinction: Bilateral pitting edema with periorbital involvement and frothy urine = nephrotic; unilateral leg swelling in a nephrotic patient is DVT until proven otherwise — order Doppler ultrasound same visit.

Edema characteristics:

Volume status — the critical exam:

Cardiopulmonary:

Abdominal:

Skin and mucosa:

Neuro/MSK:

Vascular:

Diagnostic Workup — Initial Labs and Urine Studies

— Urinalysis with microscopy: dipstick ≥3+ protein, look for oval fat bodies, fatty casts, "Maltese cross" under polarized light; bland sediment expected

— Spot urine protein-to-creatinine ratio (UPCR): ≥3.5 g/g = nephrotic range; replaces 24-hr collection in most settings

— 24-hr urine protein: still used to confirm and trend; >3.5 g/24h diagnostic

— Urine albumin-to-creatinine ratio (UACR): useful in diabetics; >2200 mg/g roughly nephrotic

— Serum albumin <3.0 g/dL (often <2.5); degree correlates with edema and thrombosis risk

— Total protein, A/G ratio — low albumin with elevated globulins → suspect myeloma/amyloid

— BMP: Creatinine, BUN, eGFR, Na (pseudohyponatremia from hyperlipidemia possible), K, HCO₃

— Calcium: often low (binds albumin); correct for albumin; check ionized if symptomatic

— Fasting lipid panel: ↑LDL, ↑total cholesterol, ↑triglycerides; statin indicated if persistent

— CBC for anemia (CKD, myeloma), thrombocytosis

— PT/INR, PTT; antithrombin III often low (urinary loss) → hypercoagulable

— LFTs, HBsAg, anti-HBc, anti-HCV, HIV — mandatory before immunosuppression

— RPR/syphilis if risk factors (membranous association)

— Renal ultrasound: kidney size, echogenicity, rule out obstruction, confirm two kidneys before biopsy

— CXR for pleural effusions if dyspneic

CCS pearl: On the CCS case, order "urine protein/creatinine ratio," "serum albumin," "BMP," "lipid panel," "HBsAg/anti-HCV/HIV," and "renal ultrasound" on the same screen — advancing the clock without this baseline workup loses points.

Step 1 — Confirm and quantify proteinuria:

Step 2 — Confirm hypoalbuminemia and assess severity:

Step 3 — Renal function and electrolytes:

Step 4 — Lipids:

Step 5 — CBC and coagulation:

Step 6 — Hepatic and infectious panel:

Step 7 — Imaging:

Diagnostic Workup — Serologies and Renal Biopsy

— ANA, anti-dsDNA, complement C3/C4 → lupus nephritis (low C3/C4)

— ANCA (MPO, PR3) → pauci-immune (more nephritic, but overlap)

— Anti-GBM → Goodpasture (nephritic)

— Cryoglobulins, rheumatoid factor, HCV RNA → cryoglobulinemic MPGN (low C4, normal/low C3)

— SPEP, UPEP, serum free light chains, immunofixation → multiple myeloma, AL amyloid, MGRS — mandatory in adults >40

— Anti-PLA2R antibody → primary membranous nephropathy (70–80% sensitive, highly specific); can sometimes spare biopsy

— Anti-thrombospondin type-1 domain-containing 7A (THSD7A) → less common membranous marker

— Complement panel: C3 low in post-infectious, MPGN, lupus; both low in lupus/cryo

— HbA1c, fundoscopy in diabetics — retinopathy supports diabetic nephropathy without biopsy

— Indications in adults: virtually all new nephrotic syndrome unless clear diabetic nephropathy with retinopathy and typical course, or PLA2R-positive membranous with stable function

— Indications in children: steroid-resistant, atypical age (<1 or >12 yrs), hematuria, HTN, ↓complement, ↓renal function — otherwise empiric steroids first

— Pre-biopsy checklist: BP <140/90, INR ≤1.4, platelets >100k, hold antiplatelets/anticoagulants, confirm two kidneys, type and screen

— Post-biopsy: bedrest 4–6 hr, monitor for hematuria, perinephric hematoma, AV fistula

— Light microscopy (architecture)

— Immunofluorescence (Ig and complement deposits)

— Electron microscopy (podocyte foot process effacement, deposit location)

Board pearl: An adult with nephrotic syndrome, positive anti-PLA2R antibody, preserved eGFR, and no secondary cause may be diagnosed with primary membranous nephropathy and treated without biopsy per KDIGO 2021 — a high-yield testable update.

Targeted serologies (driven by history):

Renal biopsy — the diagnostic gold standard:

Biopsy interpretation needs three views:

Risk Stratification and General Management Logic

— Low risk: normal eGFR, proteinuria <3.5 g/day, albumin >3.0, stable

— Moderate risk: proteinuria 3.5–8, eGFR borderline

— High risk: proteinuria >8 g/day, ↓eGFR, high anti-PLA2R titer, or life-threatening complications (severe AKI, thromboembolism)

— ACE inhibitor or ARB — antiproteinuric, BP target <130/80; start low and titrate, monitor K and Cr (allow up to 30% Cr rise)

— Sodium restriction <2 g/day; fluid restriction if hyponatremic

— Loop diuretic for edema (furosemide 40–80 mg PO BID, often need high doses or IV due to albumin binding loss); add thiazide or metolazone for resistance

— Statin for persistent dyslipidemia (LDL goal individualized)

— Anticoagulation if albumin <2.0–2.5 g/dL with membranous, or any DVT/PE history — prophylactic warfarin or DOAC (membranous-specific)

— Vaccinate before immunosuppression: pneumococcal (PCV15→PPSV23 or PCV20), influenza, COVID, shingles, HBV

— Vitamin D repletion (urinary loss of D-binding protein)

— Dietary protein 0.8–1.0 g/kg/day (not high-protein — accelerates loss)

— Smoking cessation, BMI optimization, exercise as tolerated

Step 3 management: Even before biopsy results return, you can and should start ACEi/ARB, low-salt diet, loop diuretic for edema, and statin — these are renoprotective and not contraindicated. Hold immunosuppression until histology guides therapy.

First, classify primary vs secondary — secondary causes (diabetes, lupus, HBV/HCV/HIV, malignancy, drugs, amyloid) are treated by addressing the underlying disease; immunosuppression is reserved for primary disease.

Estimate progression risk (KDIGO membranous risk model example):

Universal supportive therapy (the "nephrotic bundle"):

Lifestyle:

Disease-specific immunosuppression (covered in chunk 7) only after diagnosis confirmed.

Pharmacotherapy — Disease-Specific First-Line Regimens

— Prednisone 1 mg/kg/day (max 80 mg) × 4–16 weeks, then taper over 6 months

— ≥80% of children and ~75% of adults respond; relapses common

— Frequent relapse/steroid dependence → cyclophosphamide, calcineurin inhibitor (tacrolimus, cyclosporine), or rituximab

— Primary FSGS: prednisone 1 mg/kg/day × up to 16 weeks; slow taper; CNI if steroid-resistant

— Secondary FSGS (obesity, reflux, HIV, heroin): treat underlying cause + ACEi/ARB; no immunosuppression

— Low risk: ACEi/ARB, observe 6 months

— Moderate/high risk: Rituximab (preferred per KDIGO 2021), or cyclophosphamide + steroids (modified Ponticelli), or CNI-based regimen

— Anti-PLA2R titer trends guide response

— ACEi or ARB (never combine), SGLT2 inhibitor (dapagliflozin/empagliflozin) regardless of A1c if eGFR ≥20, finerenone (nonsteroidal MRA), GLP-1 agonist, glycemic control (A1c ~7%)

— Hydroxychloroquine + induction with mycophenolate mofetil or cyclophosphamide + steroids; belimumab or voclosporin add-on

— Daratumumab + CyBorD (bortezomib/cyclophosphamide/dex), autologous stem cell transplant in eligible patients

— ATTR amyloid: tafamidis, patisiran, inotersen

Board pearl: In adult primary membranous with high-risk features, rituximab has supplanted cyclophosphamide as first-line in KDIGO 2021 — expect a stem testing this update. Cyclophosphamide remains preferred for rapidly progressive or life-threatening disease.

Minimal change disease (MCD):

Focal segmental glomerulosclerosis (FSGS):

Membranous nephropathy:

Diabetic nephropathy:

Lupus nephritis (class V membranous lupus):

Amyloidosis (AL):

HBV-membranous: entecavir/tenofovir; HCV-MPGN: direct-acting antivirals (sofosbuvir-based)

HIV-associated nephropathy (collapsing FSGS): ART is first-line therapy, plus ACEi/ARB

Adjunctive Pharmacology — Diuretics, Anticoagulation, Lipids

— Loop diuretics are first-line; oral furosemide bioavailability is erratic (10–90%) — torsemide or bumetanide have more reliable absorption

— Hypoalbuminemia → less drug delivery to tubule → need higher doses, often IV bolus or continuous infusion for inpatients

— Sequential nephron blockade: add metolazone or HCTZ 30 min before loop for diuretic resistance

— Avoid albumin infusions routinely — transient effect, no mortality benefit; reserve for severe hypotension with anasarca

— Goal: 0.5–1 kg/day weight loss; faster risks AKI and orthostasis

— Monitor daily weights, I/Os, BMP every 1–3 days when titrating

— Hypercoagulability mechanisms: urinary loss of antithrombin III, protein S; increased fibrinogen, platelet activation

— Highest risk: membranous nephropathy with albumin <2.5–2.8 g/dL

— Prophylactic anticoagulation indicated when albumin <2.0–2.5 in membranous (use validated risk tools weighing bleeding)

— Therapeutic for confirmed DVT, PE, or renal vein thrombosis — typically warfarin (INR 2–3) continued until remission and albumin >3.0

— DOACs increasingly used but data strongest in non-membranous settings

— Statin for persistent LDL elevation; nephrotic dyslipidemia is atherogenic and increases CV mortality

— Avoid combining with cyclosporine (rhabdo risk); use rosuvastatin or pravastatin at lower doses

— ACEi/ARB reduce proteinuria 30–50%; check K and Cr at 1–2 weeks

— Hold if Cr rises >30%, K >5.5, or symptomatic hypotension

— Avoid in pregnancy (teratogenic)

CCS pearl: For a hospitalized anasarcic patient not responding to oral furosemide 80 mg BID, the next CCS move is IV furosemide drip + metolazone PO, not albumin infusion — and start prophylactic anticoagulation if albumin <2.5 and membranous biopsy.

Diuretic strategy:

Anticoagulation in nephrotic syndrome:

Lipid management:

RAAS blockade pearls:

SGLT2 inhibitors: now indicated in non-diabetic CKD with proteinuria (DAPA-CKD, EMPA-KIDNEY) — added on top of ACEi/ARB

Special Populations — Elderly and Renal/Hepatic Impairment

— Membranous nephropathy is the most common primary cause; always evaluate for occult malignancy (lung, colon, breast, prostate, GI) — age-appropriate screening + symptom-driven imaging

— AL amyloidosis rises in incidence — low threshold for SPEP/UPEP/free light chains, fat pad or marrow biopsy

— Minimal change disease in elderly: often associated with NSAIDs or hematologic malignancy; AKI more common at presentation than in children

— Drug-induced (NSAIDs, bisphosphonates, anti-VEGF, immune checkpoint inhibitors) is increasingly common — careful med rec

— Diuretics → falls, AKI, hyponatremia, hypokalemia

— ACEi/ARB → hyperkalemia, AKI; start low, monitor weekly initially

— Steroids → hyperglycemia, osteoporosis, infection, delirium — co-prescribe calcium, vitamin D, bisphosphonate, PJP prophylaxis (TMP-SMX) when prednisone ≥20 mg/day >4 weeks

— Cyclophosphamide → bladder cancer, infertility, infection; rituximab often preferred in elderly

— Dose-adjust enoxaparin, DOACs, many antibiotics

— Avoid metformin if eGFR <30; SGLT2i now approved down to eGFR 20

— Avoid gadolinium (NSF risk) and IV contrast where feasible

— Diuretic-induced encephalopathy risk; monitor mental status, ammonia

— Adjust statin (avoid in decompensated cirrhosis)

— Use entecavir or tenofovir alafenamide for HBV with renal disease; direct-acting antivirals dose-adjusted for HCV

Key distinction: New nephrotic syndrome in a patient >60 = search hard for malignancy and monoclonal gammopathy before labeling primary; missing AL amyloid or paraneoplastic membranous is a classic Step 3 board trap.

Elderly (>65 yrs) presentation:

Pharmacologic caution in elderly:

CKD with nephrotic features (advanced):

Hepatic impairment (e.g., HBV/HCV cirrhosis with nephrotic membranous/MPGN):

Polypharmacy review: stop nephrotoxins (NSAIDs, aminoglycosides, IV contrast where possible).

Special Populations — Pediatrics, Pregnancy, and Genetic Subgroups

— Peak age 2–8 yrs, more common in boys; ~90% minimal change disease

— Classic presentation: periorbital edema after URI, frothy urine

— Empiric prednisone 60 mg/m²/day × 4–6 weeks, then 40 mg/m² alternate-day taper — biopsy NOT required initially

— Indications for biopsy in kids: age <1 yr or >12 yr, gross hematuria, HTN, ↓C3, ↓eGFR, steroid resistance after 4–8 weeks

— Complications unique to kids: SBP (Streptococcus pneumoniae most common — pneumococcal vaccination essential), cellulitis, hypovolemic shock during aggressive diuresis

— Congenital nephrotic syndrome (<3 mo) — Finnish type (NPHS1 nephrin mutation), often requires nephrectomy/transplant

— Distinguish nephrotic syndrome from preeclampsia — preeclampsia: HTN + proteinuria after 20 weeks, often with elevated LFTs, low platelets, headache, visual changes

— Pre-existing nephrotic disease (lupus, membranous, FSGS) increases preeclampsia, preterm birth, fetal loss risk

— Stop ACEi/ARB, statins, MMF, cyclophosphamide before conception or as soon as pregnancy detected

— Pregnancy-compatible agents: hydroxychloroquine (continue in lupus), azathioprine, tacrolimus, low-dose steroids, labetalol/nifedipine for BP

— Aspirin 81 mg from 12 weeks for preeclampsia prevention in high-risk renal patients

— Anticoagulation with LMWH (warfarin teratogenic; DOACs avoided)

— APOL1 risk alleles (G1/G2) — high FSGS, HIVAN, hypertensive nephrosclerosis risk in African ancestry; testable on Step 3

— Alport syndrome (COL4A3/4/5) — hematuria + proteinuria + sensorineural hearing loss, lenticonus

— Fabry disease (α-galactosidase A) — angiokeratomas, neuropathy, cardiac/renal disease; enzyme replacement

— NPHS1/NPHS2 mutations in steroid-resistant pediatric FSGS

Step 3 management: A pregnant patient with lupus nephritis on MMF should be transitioned to azathioprine + hydroxychloroquine preconception, with low-dose aspirin from 12 weeks — testable transition-of-care scenario.

Pediatric nephrotic syndrome:

Pregnancy:

Genetic subgroups:

Complications and Adverse Outcomes

— Incidence 10–40% in adults; highest in membranous and severe hypoalbuminemia (<2.5)

— Renal vein thrombosis — classic with membranous; presents with flank pain, hematuria, sudden ↑Cr, LDH elevation; diagnose with CT venography or MRV

— DVT, PE, arterial events (stroke, MI) also occur

— Lifelong anticoagulation may be needed if recurrent

— Loss of immunoglobulins, complement (factor B), and immunosuppressant use → ↑risk

— Spontaneous bacterial peritonitis — especially pediatric ascites; S. pneumoniae, E. coli; paracentesis if fever/abdominal pain, treat with ceftriaxone

— Cellulitis, pneumonia, urinary infections

— Vaccinate pre-immunosuppression; PJP prophylaxis on high-dose steroids

— Pre-renal from aggressive diuresis or sepsis

— Intrinsic from interstitial nephritis (NSAIDs, drugs), renal vein thrombosis, collapsing FSGS, AIN from antibiotics

— Bilateral renal vein thrombosis can cause sudden anuric AKI

— Accelerated atherosclerosis from dyslipidemia, HTN, oxidative stress

— MI, stroke risk elevated — statin and BP control essential

— Loss of transferrin, erythropoietin precursors; iron studies often misleadingly normal

— Hypothyroidism from urinary loss of thyroxine-binding globulin and free T4 — check TSH, replace as needed

— Vitamin D deficiency from urinary D-binding protein loss → secondary hyperparathyroidism, osteopenia

— Hypocalcemia, hypocalciuria

— Variable by histology: MCD usually preserves function; FSGS and membranous more progressive; amyloid often relentless

— Track eGFR, UPCR, and BP every 3 months

Board pearl: Sudden flank pain + gross hematuria + rising creatinine + LDH spike in a known membranous patient = renal vein thrombosis — order CT/MR venography and start anticoagulation.

Thromboembolism (signature complication):

Infection:

Acute kidney injury:

Cardiovascular:

Anemia:

Endocrine and metabolic:

Progression to ESRD:

When to Escalate Care — ICU, Consult, and Inpatient Triage

— Anasarca with respiratory compromise (pleural effusions, pulmonary edema)

— Severe hypoalbuminemia (<1.5) with hypotension or hypovolemic shock

— AKI (Cr >2× baseline) or oliguria

— Confirmed or suspected thromboembolism (DVT, PE, RVT) requiring anticoagulation initiation

— Sepsis, SBP, cellulitis with systemic signs

— Hypertensive urgency/emergency

— Need for urgent biopsy in unstable patient

— Severe electrolyte disturbances (Na <125, K >6, symptomatic hypocalcemia)

— Massive PE with hemodynamic instability → consider thrombolysis or thrombectomy

— Septic shock — broad-spectrum antibiotics, source control, vasopressors

— Respiratory failure from large pleural effusions — thoracentesis, possibly intubation

— Severe AKI requiring RRT — uremic encephalopathy, refractory hyperkalemia, acidosis, volume overload

— Nephrology: all new nephrotic syndrome, for biopsy planning and immunosuppression

— Rheumatology: lupus, vasculitis, cryoglobulinemia

— Hematology/Oncology: monoclonal gammopathy, amyloid, lymphoma-associated cases

— Infectious Diseases: HIV, HBV/HCV co-management before/during immunosuppression

— Interventional Radiology: for kidney biopsy if percutaneous; for catheter-directed thrombolysis of RVT

— Cardiology: if cardiac amyloid suspected (low-voltage EKG, septal thickening)

— Stabilize hemodynamics → quantify proteinuria and renal function → secure diagnosis (serologies, biopsy) → initiate supportive bundle → start disease-specific therapy → arrange follow-up

— Stable weight trend, controlled BP, no AKI progression, anticoagulation plan in place, follow-up scheduled within 1–2 weeks, vaccinations updated

CCS pearl: On a CCS case of nephrotic syndrome with new dyspnea, order D-dimer + CT-PA (or V/Q if AKI) and lower extremity Doppler in parallel — do not wait for sequential testing. Empirically anticoagulate while imaging pending if high pretest probability.

Indications for hospital admission:

ICU triage:

Consultations to obtain:

Inpatient priorities (CCS-style):

Discharge readiness criteria:

Key Differentials — Primary Glomerular Causes

— Most common cause in children; ~10–15% in adults

— LM: normal; IF: negative; EM: diffuse foot process effacement

— Triggers: idiopathic, NSAIDs, Hodgkin lymphoma, recent viral illness

— Highly steroid-responsive

— Leading cause of primary nephrotic syndrome in Black adults in the US

— LM: focal, segmental sclerosis; IF: nonspecific; EM: foot process effacement

— Variants: classic, collapsing (HIV, parvovirus, severe disease), tip lesion (better prognosis), perihilar, cellular

— Primary (podocyte injury, often APOL1) vs secondary (obesity, reflux, single kidney, heroin, HIV) — distinguish by EM (diffuse vs segmental effacement) and clinical context

— Most common primary cause in older White adults

— LM: thickened GBM, "spike and dome" on silver stain; IF: granular IgG and C3 along GBM; EM: subepithelial deposits

— Anti-PLA2R antibody in ~70–80% of primary cases

— Secondary: HBV, lupus (class V), solid tumors, drugs (NSAIDs, gold, penicillamine)

— Often mixed nephrotic-nephritic; low complement

— Classified by IF: immune-complex mediated (HCV, cryoglobulins, lupus, monoclonal Ig), C3 glomerulopathy (alternative complement dysregulation)

— LM: lobular hypercellularity, double contours ("tram-tracks")

— Usually nephritic, but can reach nephrotic range in 5–10%

— Synpharyngitic hematuria 1–3 days after URI; mesangial IgA on IF

— Most common cause of nephrotic-range proteinuria in US adults

— Nodular glomerulosclerosis (Kimmelstiel-Wilson), retinopathy usually concomitant in type 1; less consistent in type 2

Key distinction: Membranous = subepithelial deposits with spikes and PLA2R; MPGN = subendothelial deposits with tram-tracks and low complement; MCD = no deposits, only foot process effacement on EM.

Minimal change disease (MCD):

Focal segmental glomerulosclerosis (FSGS):

Membranous nephropathy:

Membranoproliferative glomerulonephritis (MPGN):

IgA nephropathy:

Diabetic nephropathy:

Key Differentials — Secondary and Systemic Causes

— Type 1: ~10–15 years after diagnosis, with retinopathy (>90% concordance)

— Type 2: timing variable, retinopathy concordance ~60% — atypical features (rapid onset, hematuria, no retinopathy) warrant biopsy

— Mainstays: ACEi/ARB, SGLT2i, finerenone, GLP-1 RA, glycemic control

— ANA+, anti-dsDNA+, low C3/C4, multisystem features

— Treat with HCQ + MMF/cyclophosphamide ± rituximab/belimumab/voclosporin

— AL (monoclonal light chain): myeloma, MGRS — Congo red apple-green birefringence, fat pad biopsy

— AA (serum amyloid A): chronic inflammation (RA, IBD, chronic infections, FMF)

— ATTR: hereditary or wild-type; cardiac dominant but can cause renal disease

— HBV → membranous (children especially)

— HCV → MPGN, cryoglobulinemic vasculitis

— HIV → collapsing FSGS (HIVAN), immune-complex disease

— Syphilis, malaria, schistosomiasis, parvovirus, EBV, CMV — varied glomerular patterns

— Solid tumors (lung, colon, breast, prostate, GI) → membranous

— Hodgkin lymphoma → minimal change

— Non-Hodgkin, CLL, multiple myeloma → membranous, MPGN, AL amyloid, light/heavy chain deposition disease

— NSAIDs → MCD, membranous, AIN with nephrotic features

— Gold, penicillamine → membranous (historical)

— Bisphosphonates (pamidronate) → collapsing FSGS

— Interferon-α → FSGS

— Immune checkpoint inhibitors → AIN, MCD, lupus-like nephritis

— Heroin, anabolic steroids → FSGS

— Lithium → minimal change, FSGS

Board pearl: A 30-year-old IV heroin user of African ancestry with rapid-onset edema and 12 g/day proteinuria → collapsing FSGS (consider HIV/APOL1); a 65-year-old smoker with insidious membranous → search for lung or colon cancer.

Diabetes mellitus:

Lupus nephritis (class V membranous lupus):

Amyloidosis:

Infections:

Malignancy:

Drugs:

Genetic: Alport (often nephritic), Fabry, congenital nephrotic syndrome (NPHS1, NPHS2, WT1, LAMB2)

Preeclampsia/HELLP — pregnancy-specific, resolves postpartum

Secondary Prevention and Long-Term Plan

— ACEi or ARB maximally tolerated, BP target <130/80 mmHg, ideally <125/75 if proteinuria persists

— SGLT2 inhibitor in diabetic and non-diabetic CKD with proteinuria (eGFR ≥20)

— Finerenone in diabetic CKD with albuminuria, K ≤4.8

— Statin for atherogenic dyslipidemia and CV risk reduction

— Smoking cessation, weight optimization, exercise 150 min/week

— Dietary sodium <2 g/day, protein 0.8 g/kg/day, plant-forward pattern

— Continue therapeutic anticoagulation until remission and serum albumin >3.0 g/dL sustained

— Reassess prophylaxis if albumin rebounds

— Steroid taper over months, never abrupt

— Monitor for relapse with UPCR and albumin

— Bone health: DEXA at baseline, calcium 1000–1200 mg/day, vitamin D 800–1000 IU/day, bisphosphonate if T-score < –1.5 on chronic steroids

— PJP prophylaxis (TMP-SMX) on prednisone ≥20 mg/day for >4 weeks or other heavy immunosuppression

— Annual influenza, COVID-19 boosters

— Pneumococcal (PCV20 or PCV15→PPSV23)

— HBV series if non-immune

— Zoster recombinant for ≥50 yrs or immunosuppressed ≥19

— Avoid live vaccines (MMR, varicella, yellow fever, LAIV) on active immunosuppression

— Age-appropriate screening; lower threshold for symptom-driven workup in membranous patients

— Aspirin only for established ASCVD (not primary prevention generally)

— Manage diabetes, lipids, BP aggressively

Step 3 management: At every nephrotic syndrome visit, document the "ABCDES" — ACEi/ARB & Anticoagulation; BP & Bone health; Cholesterol (statin) & Cancer screen; Diabetes/SGLT2i; Edema/diuretic titration; Salt restriction & Screenings/vaccines.

Renoprotection pillars (universal):

Anticoagulation continuation:

Immunosuppression tapering:

Vaccinations:

Cancer surveillance:

Cardiovascular prevention:

Follow-Up, Monitoring, and Counseling

— Active disease/recent diagnosis: every 2–4 weeks until stable

— Stable remission: every 3 months × 1 year, then every 6 months

— Post-immunosuppression initiation: weekly to biweekly labs initially

— Weight, BP, edema exam (counsel patient on home daily weights)

— UPCR or 24-hr urine protein — primary remission marker

— Serum albumin — recovery to >3.0 g/dL marks resolution

— BMP — Cr, eGFR, K, Na

— Lipid panel every 3–6 months

— CBC, LFTs if on immunosuppression

— Anti-PLA2R titers for membranous response monitoring

— Drug-specific: tacrolimus/cyclosporine troughs, CBC for cyclophosphamide, anti-CD20 counts for rituximab

— Complete remission: UPCR <0.3 g/g, normal albumin, stable Cr

— Partial remission: ≥50% reduction in proteinuria to <3.5 g/g, stable albumin/Cr

— Relapse: return of nephrotic-range proteinuria after remission

— Steroid-resistant, dependent, or frequently relapsing — escalate therapy

— Daily morning weights; call for ≥2 kg gain in 2 days

— Low-sodium diet education, dietitian referral

— Medication adherence emphasis — premature steroid taper triggers relapse

— Recognize symptoms of DVT/PE, infection, AKI; come in immediately

— Avoid NSAIDs, contrast studies when possible, herbal nephrotoxins

— Discuss fertility/teratogenicity of cyclophosphamide; offer sperm/egg banking

— Mental health screening — chronic illness, body image (steroid side effects)

— Encourage low-impact exercise; manage protein-energy wasting

— Smoking cessation counseling at every visit (5 A's)

CCS pearl: Schedule "follow-up in nephrology clinic in 2 weeks" with labs (BMP, UPCR, albumin) on the CCS office case after discharging a nephrotic patient — missing follow-up scheduling costs management points.

Follow-up cadence:

Monitoring parameters at each visit:

Remission definitions:

Patient counseling:

Rehabilitation and lifestyle:

Ethical, Legal, and Patient Safety Considerations

— Discuss bleeding (~1% major, ~10% minor hematuria), perinephric hematoma, AV fistula, need for transfusion, very rare nephrectomy or death

— Document understanding; use teach-back

— Special case: Jehovah's Witness patient — preoperative discussion of acceptable blood products (often albumin, cell saver acceptable; PRBCs declined) — document the specific products accepted/refused

— Capacity assessment if confused/uremic; surrogate decision-maker if needed

— Cyclophosphamide: infertility, hemorrhagic cystitis, bladder cancer, secondary malignancies — discuss fertility preservation before first dose

— Rituximab: infusion reactions, hepatitis B reactivation (screen and prophylax), PML (rare)

— Steroids: weight gain, diabetes, osteoporosis, mood changes, AVN of hip, infection

— Discharge med reconciliation — anticoagulation duration, steroid taper schedule clearly written, PJP prophylaxis, supplements

— Send discharge summary to PCP and nephrologist within 24–48 hr

— Schedule labs and follow-up before discharge — avoids gaps that cause relapse or thrombosis

— Patient education on diuretic dose-adjustment and sick-day rules (hold ACEi/ARB and SGLT2i during vomiting/dehydration to prevent AKI)

— IV drug use → counsel on harm reduction, offer treatment; not mandatory reporting in most jurisdictions

— HIV/HBV/HCV positivity → counsel about partner notification; some states have public health reporting requirements

— Document refusal of live vaccines; recommend alternatives where possible

— APOL1-related FSGS overrepresented in Black patients — ensure equitable biopsy access, transplant evaluation, and clinical trial inclusion

— Rituximab, novel agents (voclosporin, finerenone, SGLT2i) may have prior-auth barriers — engage social work and pharmacy early

Board pearl: Before starting cyclophosphamide in a 28-year-old woman with FSGS, document fertility counseling and offer oocyte/embryo cryopreservation — failure to do so is both an ethical and medico-legal lapse high-yield on Step 3.

Informed consent for kidney biopsy:

Informed consent for immunosuppression:

Transition-of-care safety:

Mandatory reporting and disclosure:

Vaccination ethics:

Disparities and equity:

Cost-of-care discussion:

High-Yield Associations and Rapid-Fire Clinical Facts

Key distinction: Nephrotic syndrome = bland sediment, heavy proteinuria, hypoalbuminemia, edema; nephritic syndrome = RBC casts, dysmorphic RBCs, HTN, AKI, sub-nephrotic proteinuria — mixed pictures point to MPGN, lupus, or post-infectious GN.

"Spike and dome" on silver stain → membranous nephropathy

Anti-PLA2R antibody → primary membranous (~70–80%); can diagnose without biopsy in stable disease

Subepithelial deposits → membranous, post-infectious GN

Subendothelial deposits + tram-tracks → MPGN

Mesangial IgA on IF → IgA nephropathy

"Apple-green birefringence" with Congo red → amyloidosis

Kimmelstiel-Wilson nodules → diabetic nephropathy

Foot process effacement only (no deposits) → minimal change disease

Collapsing FSGS → HIV, parvovirus B19, pamidronate, IFN, APOL1 risk alleles

"Maltese cross" under polarized light → lipiduria of nephrotic syndrome

Muehrcke lines (paired white transverse nail bands) → hypoalbuminemia

Frothy urine + periorbital edema + 3+ proteinuria → classic nephrotic presentation

Renal vein thrombosis → membranous nephropathy (highest association)

Hodgkin lymphoma → minimal change disease

Solid tumors in adults >60 → membranous nephropathy

HBV → membranous; HCV → MPGN with cryoglobulinemia (low C4); HIV → collapsing FSGS

NSAIDs → MCD ± interstitial nephritis; pamidronate → collapsing FSGS; heroin → FSGS

Macroglossia + periorbital purpura + carpal tunnel → AL amyloidosis

Hereditary nephritis + sensorineural hearing loss + lenticonus → Alport syndrome

Angiokeratomas + neuropathic pain + corneal whorls → Fabry disease

Anti-PLA2R titer trends → useful biomarker for membranous remission/relapse

Hypothyroidism in nephrotic patient → urinary loss of TBG and T4 — check TSH

Low complement in nephrotic-nephritic overlap → lupus, MPGN, post-infectious, cryoglobulinemic

Hypercoagulable triad: albumin <2.5 + membranous + immobilization → consider prophylactic anticoagulation

Pseudohyponatremia → from severe hyperlipidemia, not true hyponatremia

Vaccinate before immunosuppression — pneumococcal, influenza, HBV, COVID, shingles

Board Question Stem Patterns

A 58-year-old man has 6 weeks of leg swelling and frothy urine. UPCR 6.2 g/g, albumin 2.4, normal Cr, anti-PLA2R positive. → Diagnosis: primary membranous; first step: ACEi + statin + risk-stratify; biopsy may be deferred per KDIGO.

A 5-year-old boy has periorbital edema after URI, 4+ proteinuria, albumin 1.8, normal Cr/BP/complement. → Empiric prednisone, no biopsy; counsel on relapse risk and pneumococcal vaccination.

Known membranous nephropathy patient with sudden flank pain, gross hematuria, Cr 1.0 → 2.4, LDH elevated. → CT or MR venography; therapeutic anticoagulation.

Type 2 diabetic, 4 years duration, no retinopathy, abrupt onset of 8 g/day proteinuria with hematuria. → Biopsy is indicated; do not assume diabetic nephropathy.

65-year-old smoker with new nephrotic syndrome, membranous pattern. → Age-appropriate cancer screening (CT chest, colonoscopy).

35-year-old of African ancestry with newly diagnosed HIV, 10 g/day proteinuria, Cr 3.0. → Start ART (first-line therapy) + ACEi/ARB.

70-year-old with carpal tunnel, macroglossia, nephrotic proteinuria, low-voltage EKG. → SPEP/UPEP/free light chains; fat pad biopsy; refer to heme-onc.

Anasarcic patient on furosemide 80 mg PO BID, minimal urine output. → Switch to IV furosemide + add metolazone; consider continuous infusion.

Membranous patient, albumin 1.9, no thrombosis. → Start prophylactic anticoagulation (e.g., warfarin or DOAC).

Lupus nephritis patient on MMF wants to conceive. → Switch to azathioprine + HCQ; add aspirin 81 mg at 12 weeks.

HBsAg+ child with membranous nephropathy. → Antiviral therapy (entecavir/tenofovir), avoid immunosuppression initially.

Nephrotic patient, Na 128, triglycerides 1200. → Pseudohyponatremia from hyperlipidemia, no treatment for Na needed.

Step 3 management: When stems test "next best step," prioritize quantify proteinuria → start ACEi/ARB + supportive bundle → identify secondary causes → biopsy → disease-specific therapy — the algorithm rarely changes.

Stem 1 — Classic adult membranous:

Stem 2 — Pediatric MCD:

Stem 3 — Renal vein thrombosis:

Stem 4 — Diabetic nephropathy atypical:

Stem 5 — Paraneoplastic membranous:

Stem 6 — HIV-associated collapsing FSGS:

Stem 7 — AL amyloid:

Stem 8 — Diuretic resistance:

Stem 9 — Prophylactic anticoagulation:

Stem 10 — Pregnancy transition:

Stem 11 — Hepatitis B membranous:

Stem 12 — Pseudohyponatremia:

One-Line Recap

Nephrotic syndrome is defined by proteinuria ≥3.5 g/day, hypoalbuminemia, edema, and hyperlipidemia, demanding a stepwise workup that quantifies proteinuria, excludes secondary causes (diabetes, lupus, HBV/HCV/HIV, malignancy, drugs, amyloid), confirms histology by biopsy in nearly all adults, and applies a universal renoprotective bundle (ACEi/ARB, salt restriction, diuretic, statin, anticoagulation when indicated, vaccinations) before disease-specific immunosuppression.

Board pearl: When in doubt on a Step 3 stem, the safest "next step" in new nephrotic syndrome is UPCR + serum albumin + BMP + ACEi/ARB + nephrology referral — never empiric steroids in adults before histology.

Top three adult causes: diabetic nephropathy (overall), FSGS (Black adults), membranous (older White adults); #1 pediatric cause: minimal change disease — empiric steroids without biopsy.

Always rule out secondary: SPEP/UPEP/free light chains, HBV/HCV/HIV serologies, ANA, complement, age-appropriate malignancy screen in adults >60 with membranous.

The nephrotic bundle: ACEi/ARB to BP <130/80, sodium <2 g/day, loop diuretic ± metolazone, statin, anticoagulation prophylaxis if albumin <2.5 with membranous, SGLT2 inhibitor, vaccinations before immunosuppression, bone and PJP prophylaxis on steroids.

Highest-yield complication: renal vein thrombosis in membranous — flank pain, hematuria, rising Cr → CT/MR venography → anticoagulate.

KDIGO 2021 update: anti-PLA2R-positive primary membranous can be diagnosed without biopsy; rituximab is first-line for moderate-to-high-risk membranous.

Pregnancy: stop ACEi/ARB, statins, MMF, cyclophosphamide; continue HCQ, switch to azathioprine, add aspirin 81 mg from 12 weeks.