Renal & Urinary

IgA nephropathy: diagnosis and management

Clinical Overview and When to Suspect IgA Nephropathy

— Pathogenesis: galactose-deficient IgA1 (Gd-IgA1) → autoantibody binding → immune complex deposition in mesangium → mesangial proliferation, hematuria, proteinuria

— Peak incidence: 2nd–3rd decade; M:F ~2:1; higher prevalence in East Asians and Whites, lower in African Americans

— Young adult with gross hematuria within 1–3 days of an upper respiratory or GI infection ("synpharyngitic" hematuria) — contrast with post-strep GN where latency is 1–3 weeks

— Asymptomatic microscopic hematuria + proteinuria found on routine urinalysis or pre-employment/military physical

— Slowly progressive CKD in a young patient with bland hypertension and red cells/casts on UA

— Rapidly progressive GN picture with crescents (uncommon but board-favorite)

— IgA vasculitis (Henoch-Schönlein purpura) — same renal lesion plus palpable purpura, arthralgias, abdominal pain

— Cirrhosis (secondary IgAN from impaired hepatic IgA clearance)

— Celiac disease, HIV, ankylosing spondylitis, dermatitis herpetiformis

IgA nephropathy (IgAN, Berger disease) is the most common primary glomerulonephritis worldwide and a leading cause of CKD/ESRD in young adults

When to suspect on Step 3:

Key distinction: Synpharyngitic (IgAN, within days) vs. post-infectious GN (latency 1–3 weeks after pharyngitis or 3–6 weeks after impetigo, low complements). IgAN has normal C3/C4.

Associated conditions to flag:

Board pearl: A 24-year-old man with recurrent episodes of tea-colored urine occurring during URIs, normal complements, and 1+ proteinuria → think IgAN even before biopsy. Differentiating features from thin basement membrane disease and Alport syndrome (family history, sensorineural hearing loss, lenticonus) are tested heavily.

Step 3 management: Initial outpatient workup includes confirming hematuria with phase-contrast microscopy (dysmorphic RBCs, acanthocytes), quantifying proteinuria with spot UPCR, BMP for eGFR, and BP measurement — biopsy decisions follow these results.

Presentation Patterns and Key History

— Recurrent gross hematuria (40–50%): episodes coinciding with mucosal infection (URI, gastroenteritis, UTI) or vigorous exercise; urine clears in days; between episodes microscopic hematuria persists

— Asymptomatic microscopic hematuria ± proteinuria (30–40%): incidental finding; often discovered on routine screening (military induction, insurance physical, pregnancy)

— Chronic kidney disease with hypertension (slowly progressive): subnephrotic proteinuria, rising creatinine; sometimes the initial presentation in adults >40

— Acute kidney injury from a crescentic/rapidly progressive GN course (<10%)

— AKI from tubular obstruction by RBC casts during a gross hematuria episode — usually reversible

— Nephrotic syndrome with minimal-change-like features (rare overlap)

— Malignant hypertension as presenting sign

— Timing of hematuria relative to infection (synpharyngitic = same day to ~3 days)

— Family history of hematuria, renal failure, deafness (rule out Alport), or hematuria-only phenotype (thin basement membrane)

— Skin rash, joint pain, abdominal pain → IgA vasculitis

— Liver disease, alcohol use, IVDU, hepatitis → secondary IgAN

— GI symptoms, dermatitis → celiac disease/dermatitis herpetiformis

— NSAID use, exercise intensity, menstrual contamination (women)

— IgAN: synpharyngitic, normal C3, recurrent episodes, no edema usually

— PSGN: 1–3 week latency, low C3, single episode, edema/HTN prominent, ASO/anti-DNase B positive

Three classic clinical phenotypes on the boards:

Less common but tested presentations:

High-yield history questions:

Key distinction: IgAN vs. post-streptococcal GN

Board pearl: A college athlete with hematuria after a hard workout and a sore throat 2 days ago — classic synpharyngitic IgAN. Don't anchor on exercise-induced hematuria (which is transient and isolated).

Step 3 management: Document baseline BP, weight, and a 24-hour or first-morning UPCR before any therapeutic decision; have the patient log episodes for the renal consultant.

Physical Exam Findings and Hemodynamic Assessment

— Hypertension in 30–40% at diagnosis; may be the only exam clue

— Measure BP with proper technique; document orthostatics if on diuretics or ACEi

— Edema is usually absent unless nephrotic-range proteinuria or advanced CKD

— Tachycardia/fluid overload suggests AKI with oliguria — escalate

— Palpable purpura on buttocks/lower extremities → IgA vasculitis (HSP); diagnostic gestalt shift

— Dermatitis herpetiformis (grouped vesicles on extensor surfaces) → celiac-associated

— Stigmata of chronic liver disease (spider angiomas, palmar erythema, caput medusae) → secondary IgAN

— Malar rash, photosensitivity → push toward lupus nephritis differential

— Erythematous pharynx or tonsillar exudate confirms recent URI trigger

— Sensorineural hearing loss + anterior lenticonus → Alport, not IgAN

— Conjunctival pallor in advanced CKD

— S4 gallop or LVH apex suggests longstanding HTN

— RUQ tenderness, hepatomegaly → cirrhotic IgAN

— Costovertebral angle tenderness — think pyelonephritis or stones as alternate hematuria source

— Symmetric arthralgias (knees, ankles) with purpura → HSP

— Sacroiliac tenderness → ankylosing spondylitis association

— Check for oligo-anuria, uremic signs (asterixis, pericardial rub), hyperkalemic ECG changes

— These mandate inpatient admission and urgent nephrology consult

IgAN is largely a "lab-diagnosed" disease — exam is often unremarkable, but targeted findings drive workup:

Vital signs and volume:

Skin and mucocutaneous:

HEENT and pharynx:

Cardiopulmonary and abdominal:

Musculoskeletal:

Hemodynamic assessment in suspected RPGN/crescentic IgAN:

Key distinction: Edema dominates PSGN and lupus nephritis; IgAN exam is typically clean except for HTN — exam findings often reframe the differential more than confirm IgAN.

CCS pearl: On the CCS, order BP, weight, UA, BMP, and a thorough skin exam on the first screen for any young adult with hematuria — advancing the clock without these costs you points.

Diagnostic Workup — Initial Labs, Imaging, and Urinalysis

— Urinalysis with microscopy: dysmorphic RBCs, acanthocytes (>5%), RBC casts = glomerular hematuria

— Spot urine protein-to-creatinine ratio (UPCR) or albumin-to-creatinine ratio (UACR) — preferred over dipstick for quantification

— 24-hour urine if borderline or research-quality data needed

— BMP for serum creatinine and eGFR (CKD-EPI 2021, no race coefficient)

— CBC (anemia of CKD), albumin

— Lipid panel if proteinuria >1 g/day

— C3 and C4: normal (low complements → PSGN, lupus, MPGN, cryoglobulinemia)

— ANA, anti-dsDNA — exclude lupus

— ANCA (PR3, MPO) — exclude pauci-immune GN

— Anti-GBM — exclude Goodpasture

— Hepatitis B, hepatitis C, HIV — exclude infection-related GN

— SPEP/UPEP with free light chains in older adults — exclude paraprotein disease

— ASO / anti-DNase B if recent pharyngitis suspected (rules in PSGN)

— Renal ultrasound: assess kidney size, echogenicity, hydronephrosis; rules out stones, masses, polycystic disease as hematuria sources

— Small echogenic kidneys → chronicity; biopsy yield drops

— Cystoscopy/CT urogram only if >40 yo, smoker, or atypical features to exclude urothelial cancer per AUA microhematuria guidelines

— Elevated in ~50% — not diagnostic (low sensitivity/specificity); don't anchor on it

— Gd-IgA1 assays exist but are not routine clinical practice

First-tier outpatient labs (every suspected IgAN patient):

Serologies to exclude mimics — all should be NEGATIVE/NORMAL in primary IgAN:

Imaging:

Serum IgA level:

Key distinction: Normal complements + glomerular hematuria + elevated IgA = supportive but not diagnostic; biopsy remains the gold standard.

Board pearl: Dipstick-positive blood with no RBCs on microscopy = myoglobinuria or hemoglobinuria, not glomerular disease — redirect workup.

Step 3 management: In a young patient with isolated microhematuria, normal BP, eGFR ≥60, and UPCR <0.3 g/g, observe with q6–12 month UA/BP/creatinine rather than rushing to biopsy.

Diagnostic Workup — Renal Biopsy and Confirmatory Studies

— Proteinuria >0.5–1 g/day (especially persistent)

— Declining eGFR or unexplained AKI

— Hypertension with hematuria in a young adult

— Hematuria plus features suggesting alternative diagnosis (low complements, positive serologies)

— Not typically biopsied: isolated microhematuria with normal BP, eGFR, and UPCR <0.3 g/g

— Light microscopy: mesangial hypercellularity and matrix expansion; segmental sclerosis, endocapillary proliferation, or crescents in severe forms

— Immunofluorescence (DIAGNOSTIC): dominant or codominant mesangial IgA deposits, often with C3 and IgG/IgM; C1q typically absent (its presence suggests lupus)

— Electron microscopy: electron-dense deposits in the mesangium ± paramesangial regions

— M — Mesangial hypercellularity

— E — Endocapillary hypercellularity

— S — Segmental glomerulosclerosis

— T — Tubular atrophy/interstitial fibrosis (strongest predictor of progression)

— C — Crescents (added 2017)

— Higher MEST-C scores → worse renal survival, may guide immunosuppression

Renal biopsy is the definitive diagnostic test — IgAN cannot be diagnosed without tissue

Indications for biopsy in suspected IgAN:

Histology — three lenses:

Oxford MEST-C classification (prognostic and tested):

International IgAN Prediction Tool: integrates clinical (eGFR, BP, proteinuria, race) and MEST-C variables to estimate 5-year risk of 50% eGFR decline or ESRD — used in shared decision-making

Key distinction: IgAN vs. lupus nephritis on biopsy — both can have mesangial IgA, but lupus shows "full house" staining (IgA, IgG, IgM, C3, C1q) and tubuloreticular inclusions on EM.

Board pearl: Mesangial IgA deposition + palpable purpura + arthralgia = IgA vasculitis (same renal histology as IgAN, systemic disease) — clinical context distinguishes them.

Step 3 management: Hold anticoagulants/antiplatelets, document platelets >50k, BP <140/90, and obtain INR before percutaneous biopsy; observe ≥6 hours post-procedure for hematoma/gross hematuria.

Risk Stratification and Management Logic

— Proteinuria >1 g/day sustained (strongest modifiable risk)

— Hypertension, particularly uncontrolled

— eGFR <60 at presentation

— High MEST-C scores (especially T1–T2 tubular atrophy)

— Crescents on biopsy (C1/C2)

— Older age at diagnosis (paradoxically worse than childhood-onset)

— Isolated microhematuria with normal BP, eGFR, and proteinuria <0.5 g/day → ~10-year renal survival approaches 100%

— Single episode of gross hematuria, complete resolution, no proteinuria

— Step 1 — Optimize supportive care for ALL patients ≥3–6 months:

— Maximally tolerated RAAS inhibition (ACEi or ARB)

— BP target <120/80 (SPRINT-aligned in IgAN)

— SGLT2 inhibitor added if proteinuria persists ≥0.5 g/day despite RAAS (per DAPA-CKD/EMPA-KIDNEY)

— Sodium restriction (<2 g/day), smoking cessation, weight optimization, statin per ASCVD risk

— Hydroxychloroquine in some Asian protocols — not yet standard US practice

— Step 2 — Reassess at 3–6 months. If proteinuria remains >0.75–1 g/day despite optimized supportive care AND high risk of progression:

— Consider targeted-release budesonide (Nefecan/TRF-budesonide) — gut-directed, addresses mucosal IgA source

— Or systemic glucocorticoids (controversial post-TESTING trial — toxicity burden)

— Newer agents: sparsentan (dual endothelin/angiotensin receptor antagonist, FDA-approved 2023 for IgAN)

— Step 3 — Crescentic/RPGN IgAN: cyclophosphamide + steroids (analogous to ANCA vasculitis)

Risk stratification drives every treatment decision in IgAN — therapy is tiered, not one-size-fits-all

Predictors of progression:

Favorable features:

2021 KDIGO management framework (updated by 2024 guidance):

Key distinction: Supportive care first, immunosuppression only for high-risk persistent proteinuria — TESTING and STOP-IgAN trials tempered enthusiasm for routine steroids due to infection and metabolic toxicity.

Step 3 management: Schedule the 3–6 month reassessment visit at the time supportive care is initiated — proteinuria, BP, and eGFR at that visit determine escalation.

Pharmacotherapy — First-Line Drug Regimens

— Indicated for all IgAN patients with proteinuria >0.5 g/day OR hypertension

— Start lisinopril 10 mg or losartan 50 mg daily; titrate every 2–4 weeks to max tolerated dose (lisinopril up to 40 mg, losartan up to 100 mg) targeting BP <120/80 and proteinuria <0.5 g/day

— Check BMP and potassium 1–2 weeks after initiation/titration; tolerate up to 30% creatinine rise

— Do not combine ACEi + ARB (ONTARGET — increased AKI/hyperkalemia)

— Counsel women of childbearing age — teratogenic in 2nd/3rd trimester; use reliable contraception or switch to labetalol/nifedipine if pregnant

— Add when proteinuria ≥0.5 g/day persists despite max RAAS, regardless of diabetes status

— Dapagliflozin 10 mg daily or empagliflozin 10 mg daily

— Reduces proteinuria ~25–40%, slows eGFR decline (DAPA-CKD, EMPA-KIDNEY)

— Watch for euglycemic DKA (especially perioperative — hold 3 days pre-op), genital mycotic infections, modest initial eGFR dip

— FDA-approved 2021 (full approval 2023) for IgAN with proteinuria ≥1.5 g/day at high progression risk

— 16 mg daily × 9 months, then taper

— Acts on gut Peyer's patches (source of Gd-IgA1), minimizing systemic steroid toxicity

— Still monitor BP, glucose, weight, mood, infection

— Dual ETA/AT1 receptor antagonist; 400 mg daily (PROTECT trial)

— Replaces ARB, not added to it

— REMS due to hepatotoxicity and teratogenicity — monthly LFTs first year, contraception required

— Statin per ASCVD primary prevention guidelines

— Sodium <2 g/day, protein 0.8 g/kg/day in advanced CKD

— Influenza, pneumococcal, COVID-19, hepatitis B vaccinations before immunosuppression

Foundation — RAAS blockade (ACEi or ARB):

SGLT2 inhibitors (dapagliflozin, empagliflozin):

Targeted-release budesonide (Tarpeyo):

Sparsentan:

Adjuncts:

Board pearl: Combining ACEi + ARB or ACEi + direct renin inhibitor is contraindicated — high-yield wrong answer.

Step 3 management: Document baseline LFTs, pregnancy test, and lipid panel before sparsentan; schedule monthly LFTs × 12 months as part of the REMS protocol.

Advanced and Procedural Management

— Systemic glucocorticoids (controversial):

— Prednisone 0.6–0.8 mg/kg/day tapered over 6–8 months (or methylprednisolone pulse) for persistent proteinuria >1 g/day after optimized supportive care

— TESTING trial showed renal benefit but doubled serious infections (especially in Asian patients); reduced-dose regimen plus PJP prophylaxis now standard

— Required adjuncts: TMP-SMX for PJP, calcium/vitamin D, PPI, bone density screening, glucose monitoring

— Cyclophosphamide + steroids for crescentic/RPGN IgAN (>25–50% glomeruli with crescents and rapidly rising creatinine)

— IV pulse cyclophosphamide × 3–6 months, then maintenance azathioprine or MMF

— Counsel re: infertility, bladder toxicity, malignancy; consider gamete preservation

— MMF: modest evidence; sometimes used in Asian populations or as steroid-sparing

— Sparsentan — see prior chunk

— Iptacopan (factor B complement inhibitor) — FDA-approved 2024 for IgAN

— Atrasentan (selective endothelin antagonist) — approved 2024 for IgAN proteinuria

— Anti-APRIL/BAFF agents (sibeprenlimab, atacicept) — in late-phase trials, target B-cell IgA production

— Patients on complement inhibitors need meningococcal, pneumococcal, H. influenzae vaccination before starting

— Practiced in Japan; not recommended in US/European guidelines outside trials

— Progressive CKD → discuss modalities (HD, PD, transplant) when eGFR <30

— Pre-emptive transplant when eGFR <20; living donor preferred

— Post-transplant recurrence ~30%, graft loss in 5–10% — recipients need surveillance UPCR

Immunosuppression — reserved for high-risk or crescentic disease:

Emerging/specialty therapies (high-yield 2024–2025):

Tonsillectomy:

Renal replacement therapy:

Key distinction: Crescentic IgAN with RPGN behaves like ANCA vasculitis — treat aggressively with cyclophosphamide + steroids; do not rely on RAAS alone.

CCS pearl: For inpatient AKI from IgAN with crescents, order urgent biopsy, methylprednisolone pulse 500–1000 mg × 3 days, IV cyclophosphamide, PJP prophylaxis, and stress-dose calcium/PPI — all on day 1.

Special Populations — Elderly and Renal/Hepatic Impairment

— IgAN at older age is often more aggressive — higher proteinuria, more sclerosis on biopsy, faster progression to ESRD

— Biopsy risk-benefit shifts: weigh small kidneys, vascular disease, anticoagulation

— Comorbid HTN, diabetes, and atherosclerotic kidney disease confound proteinuria interpretation

— RAAS inhibitors: start low (lisinopril 5 mg), titrate slowly; monitor potassium and creatinine more frequently (every 1–2 weeks)

— Glucocorticoid toxicity is amplified: osteoporosis, hyperglycemia, infection, delirium, cataracts — strongly favor budesonide or non-steroid agents

— Cyclophosphamide carries higher infection and malignancy risk in elderly — dose-reduce by 25% for age >70 and by eGFR

— Immunosuppression yields diminishing returns when fibrosis is extensive (high T-score on MEST-C); focus on CKD complications and transplant planning

— RAAS inhibitors: continue even at low eGFR if hyperkalemia controlled (STOP-ACEi trial: stopping does not improve eGFR, may worsen CV outcomes)

— Hyperkalemia management: dietary K restriction, loop diuretic, patiromer or sodium zirconium cyclosilicate to allow RAAS continuation

— SGLT2 inhibitors: dapagliflozin can be initiated down to eGFR 25 and continued thereafter; empagliflozin down to eGFR 20

— Metabolic acidosis: sodium bicarbonate to keep HCO3 >22

— Anemia: iron repletion, ESA when Hgb <10

— CKD-MBD: vitamin D, phosphate binders as indicated

— Secondary IgAN from impaired hepatic clearance of IgA

— Treat the underlying liver disease (alcohol cessation, antiviral for HBV/HCV); renal disease often improves with liver transplantation

— Avoid nephrotoxins; dose-adjust drugs cleared hepatically

— Budesonide caution — significant first-pass metabolism in liver disease can increase systemic exposure

Elderly patients (>65):

Advanced CKD (eGFR <30):

Hepatic impairment / cirrhotic IgAN:

Key distinction: Primary IgAN responds to immunosuppression; secondary (cirrhotic) IgAN responds to treating the liver.

Step 3 management: In any elderly IgAN patient starting prednisone, simultaneously initiate calcium 1200 mg, vitamin D 800 IU, PJP prophylaxis (TMP-SMX SS daily), and order a DEXA scan within 6 months.

Special Populations — Pregnancy and Pediatrics

— Most common GN encountered in pregnancy; outcomes depend on pre-conception eGFR, BP control, and proteinuria

— Favorable predictors: eGFR ≥60, BP normal, proteinuria <1 g/day → usually uncomplicated

— Risks if eGFR <40 or uncontrolled HTN: preeclampsia, preterm delivery, IUGR, accelerated maternal CKD progression

— Pre-conception counseling: optimize BP <130/80, switch teratogenic agents, ensure folic acid, vaccinate (avoid live vaccines later)

— Stop ACEi/ARB/sparsentan (teratogenic — renal dysgenesis, oligohydramnios); switch to labetalol, nifedipine, methyldopa, or hydralazine

— Stop SGLT2 inhibitors, MMF, cyclophosphamide (teratogenic)

— Continue/switch to azathioprine or hydroxychloroquine if immunosuppression needed

— Steroids: prednisone preferred (placental 11β-HSD2 inactivates it); minimize dose

— Combined nephrology + maternal-fetal medicine care

— BP every 2 weeks, monthly UPCR and creatinine, fetal growth scans q4 weeks from 24 weeks

— Low-dose aspirin 81 mg from 12 weeks for preeclampsia prevention (CKD is high-risk indication)

— Resume RAAS inhibitors — enalapril and captopril are lactation-compatible

— Contraception counseling; avoid estrogen-containing methods if HTN uncontrolled

— Often presents as recurrent gross hematuria; generally milder course than adults

— Overlap with IgA vasculitis (HSP) — palpable purpura, abdominal pain, arthralgias, nephritis

— Management mirrors adult algorithm: RAAS for proteinuria, supportive care; steroids for nephrotic-range proteinuria or crescentic disease

— Track growth, school performance, BP percentiles

IgAN in pregnancy:

Drug switches before/during pregnancy:

Antenatal monitoring:

Postpartum:

Pediatric IgAN:

Key distinction: IgA vasculitis nephritis in children — usually self-limited but biopsy if nephrotic, RPGN, or persistent proteinuria >3 months.

Board pearl: A pregnant patient on losartan with IgAN — stop losartan immediately, switch to labetalol or nifedipine, start ASA 81 mg, refer to MFM. Failing to discontinue is a frequent wrong answer.

Complications and Adverse Outcomes

— Progressive CKD → ESRD: 20–40% within 20 years of diagnosis; major cause of dialysis/transplant in young adults

— AKI: during gross hematuria episodes (RBC cast obstruction, ATN) — usually reversible with hydration and supportive care

— RPGN/crescentic transformation: rare but devastating; rapid creatinine doubling, oligo-anuria

— Recurrence in renal allograft: ~30% histologic, ~10% clinical graft loss

— Accelerated atherosclerosis from CKD, HTN, dyslipidemia, proteinuria

— LVH, heart failure with preserved EF

— Sudden cardiac death risk rises with eGFR <45

— Manage with statin (per KDIGO: statin or statin + ezetimibe in adults ≥50 with CKD not on dialysis), BP control, antiplatelet per ASCVD risk

— Glucocorticoid toxicity: infection (PJP, herpes zoster), hyperglycemia/new-onset DM, osteoporosis/fragility fracture, AVN of femoral head, cataracts, mood changes, weight gain, adrenal suppression

— Cyclophosphamide: hemorrhagic cystitis (use mesna), bladder cancer (lifelong surveillance), infertility, secondary malignancy, myelosuppression

— RAAS inhibitors: hyperkalemia, AKI, angioedema (ACEi >> ARB), cough (ACEi)

— SGLT2i: euglycemic DKA, Fournier gangrene (rare), volume depletion, mycotic genital infections

— Sparsentan/atrasentan: fluid retention, hepatotoxicity, teratogenicity

— Anemia, secondary hyperparathyroidism/CKD-MBD, metabolic acidosis, hyperphosphatemia, uremic pruritus

— Vascular access planning when eGFR <20–25

— Chronic disease burden in young adults — depression screening, work/school accommodations

Renal complications:

Cardiovascular complications (leading cause of death in CKD):

Treatment-related complications:

CKD-related complications:

Psychosocial:

Key distinction: AKI from RBC cast obstruction during a hematuria flare = supportive care only; AKI from crescentic transformation = urgent biopsy and immunosuppression. Don't conflate them.

Step 3 management: Annual cystoscopy + urine cytology for life after cyclophosphamide exposure (bladder cancer surveillance), and lifetime fracture risk assessment after long-term steroids.

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

— Any patient with biopsy-confirmed IgAN

— Proteinuria >500 mg/day, persistent hematuria with HTN, or unexplained eGFR <60

— Failure to achieve proteinuria <0.5–1 g/day after 3–6 months of optimized supportive care

— Consideration of immunosuppression, sparsentan, or budesonide

— Pregnancy planning in a known IgAN patient

— Rapidly rising creatinine (doubling over days to weeks)

— New nephrotic-range proteinuria (UPCR >3.5 g/g)

— Refractory hypertension or hypertensive urgency/emergency

— Suspected crescentic GN on clinical grounds — high WBC casts, anemia, systemic symptoms

— Pulmonary-renal syndrome features (hemoptysis, infiltrates) — broaden to anti-GBM, ANCA vasculitis

— AKI with creatinine ≥1.5× baseline plus oliguria

— Volume overload requiring IV diuresis

— Hyperkalemia >6.0 with ECG changes

— Uremic symptoms (pericarditis, encephalopathy)

— Severe HTN requiring IV therapy

— Initiation of pulse methylprednisolone or cyclophosphamide

— Hyperkalemia with arrhythmia

— Hypertensive emergency with end-organ damage

— Acute pulmonary edema requiring NIPPV

— RPGN requiring emergent dialysis access placement

— Severe sepsis on immunosuppression

— Pathology (biopsy interpretation)

— Interventional radiology or nephrology for biopsy

— MFM for pregnancy

— Transplant nephrology when eGFR approaches 20

— Vascular surgery for AV fistula when eGFR <20–25

Outpatient nephrology referral indicated for:

Urgent/same-day nephrology consultation:

Inpatient admission criteria:

ICU triage:

Multidisciplinary consults:

Key distinction: Microhematuria + normal renal function in a 22-year-old = outpatient with PCP follow-up; same patient with creatinine rising from 1.0 to 2.5 over 3 weeks = admit and biopsy now.

CCS pearl: On CCS, escalate location appropriately — moving an RPGN patient from "office" to "ward" and ordering renal biopsy, methylprednisolone pulse, and TMP-SMX prophylaxis on day 1 captures critical management actions.

Key Differentials — Other Glomerular Diseases

— 1–3 week latency after pharyngitis, 3–6 weeks after impetigo

— Low C3, normal C4 (alternative pathway)

— Positive ASO, anti-DNase B; humped subepithelial deposits on EM

— Self-limited in children; supportive care

— Persistent microhematuria, family members affected

— Normal BP, normal eGFR, no/minimal proteinuria

— EM: diffusely thin GBM (<250 nm)

— Excellent prognosis; reassure, monitor

— X-linked or autosomal — type IV collagen mutation (COL4A3/4/5)

— Sensorineural hearing loss + anterior lenticonus + progressive nephritis

— EM: lamellated, "basket-weave" GBM

— Treat with RAAS inhibitor early; progresses to ESRD in males

— Young woman, multisystem (rash, arthritis, serositis, cytopenias)

— ANA, anti-dsDNA, anti-Sm positive; low C3 and C4

— Biopsy: "full-house" immunofluorescence including C1q, tubuloreticular inclusions

— Class-directed therapy (steroids + MMF or cyclophosphamide)

— Nephritic + nephrotic features; low C3 ± C4

— Associated with HCV/cryoglobulinemia, monoclonal gammopathy, complement dysregulation (C3 glomerulopathy)

— Biopsy: tram-track GBM, subendothelial deposits

— Pauci-immune crescentic GN; scant immune deposits on IF

— Positive c-ANCA/PR3 or p-ANCA/MPO

— Systemic features: sinusitis, hemoptysis, neuropathy

— Linear IgG along GBM; rapidly progressive renal failure ± pulmonary hemorrhage

— Plasmapheresis + cyclophosphamide + steroids

Post-infectious (post-streptococcal) glomerulonephritis (PSGN):

Thin basement membrane nephropathy (benign familial hematuria):

Alport syndrome:

Lupus nephritis:

Membranoproliferative GN (MPGN):

ANCA-associated vasculitis (GPA, MPA, EGPA):

Anti-GBM disease (Goodpasture):

Key distinction: Complement status is the fastest screen — IgAN, anti-GBM, ANCA vasculitis, and minimal change have normal complements; PSGN, lupus, MPGN, cryoglobulinemic, and endocarditis-associated GN have low complements.

Board pearl: Mesangial IgA + low complements + multisystem disease → think lupus, not IgAN, until C1q is excluded on biopsy.

Key Differentials — Non-Glomerular Causes of Hematuria

— Urothelial carcinoma (bladder, ureter, renal pelvis):

— Risk factors: age >40, smoking, aniline dye/aromatic amine exposure, cyclophosphamide history, schistosomiasis

— Painless gross hematuria — classic

— AUA guideline: cystoscopy + CT urogram or MR urogram for hematuria in patients ≥40 or with smoking history

— Step 3 trap: Do not anchor on IgAN in a 65-year-old smoker with painless gross hematuria — work up malignancy first

— Renal cell carcinoma: flank pain, mass, hematuria triad (late); paraneoplastic features

— Nephrolithiasis: colicky flank pain radiating to groin; CT without contrast

— BPH / urethral varices: older men, terminal hematuria

— UTI / hemorrhagic cystitis: dysuria, frequency; pyuria, positive culture

— Polycystic kidney disease: family history, flank pain, hypertension, palpable kidneys; ultrasound diagnostic

— Loin pain–hematuria syndrome: rare, exclusion diagnosis

— Sickle cell trait/disease: papillary necrosis, isosthenuria, painless hematuria — especially left-sided

— Renal infarction: flank pain, elevated LDH, embolic source (AFib)

— Renal vein thrombosis: nephrotic syndrome (membranous), flank pain, hematuria

— Nutcracker syndrome: left renal vein compression between SMA and aorta — left flank pain, hematuria, varicocele in men

— AV malformation: post-biopsy or congenital

— Myoglobinuria (rhabdomyolysis — dipstick positive, no RBCs)

— Hemoglobinuria (intravascular hemolysis)

— Foods (beets, rhubarb), drugs (rifampin, phenazopyridine, senna), porphyria

Urologic causes (must exclude, especially in older patients):

Other renal parenchymal mimics:

Vascular:

Pseudohematuria:

Key distinction: Glomerular hematuria → dysmorphic RBCs, RBC casts, proteinuria; urologic hematuria → monomorphic RBCs, clots, no proteinuria. The microscopy answers the question.

Step 3 management: In any patient ≥40 or with smoking history presenting with hematuria, order cystoscopy and upper tract imaging in parallel with glomerular workup — do not delay urologic evaluation.

Secondary Prevention, Discharge Medications, and Long-Term Plan

— ACEi or ARB at maximum tolerated dose — target BP <120/80, proteinuria <0.5 g/day

— SGLT2 inhibitor (dapagliflozin 10 mg or empagliflozin 10 mg) if proteinuria ≥0.5 g/day persists

— Consider sparsentan as ARB replacement in high-risk persistent proteinuria

— Statin per ASCVD primary prevention (most CKD patients qualify)

— Sodium bicarbonate if HCO3 <22

— Sodium <2 g/day (single highest-impact dietary change for proteinuria)

— Protein 0.8 g/kg/day in CKD stage 3+ (avoid high-protein/keto diets)

— Tobacco cessation — accelerates CKD progression and CV risk

— Alcohol moderation; avoid in cirrhotic IgAN

— Regular aerobic exercise; weight loss if BMI >25

— NSAID avoidance — counsel that OTC ibuprofen/naproxen can precipitate AKI

— Annual influenza

— Pneumococcal (PCV20 or PCV15 + PPSV23) — all CKD patients

— Hepatitis B series with anti-HBs titer check

— Shingrix if ≥50 or immunocompromised

— COVID-19 per current guidance

— Meningococcal, H. flu, pneumococcal before complement inhibitors (iptacopan)

— Avoid live vaccines on immunosuppression

— Calcium 1000–1200 mg + vitamin D 800 IU

— DEXA at baseline and every 1–2 years; bisphosphonate if FRAX elevated or fragility fracture

— PJP prophylaxis (TMP-SMX SS daily) while on prednisone ≥20 mg ≥4 weeks

— Refer at eGFR <30; list at eGFR <20

— Living-donor preferred; pre-emptive transplant best outcomes

— Counsel on ~30% recurrence rate post-transplant

Maintenance regimen for stable outpatient IgAN:

Lifestyle and dietary plan:

Vaccinations (especially before immunosuppression):

Steroid-exposed patients:

Transplant planning:

Board pearl: SGLT2 inhibitors are now disease-modifying in IgAN regardless of diabetes status — a 2024-current Step 3 answer.

Step 3 management: At every visit, reconcile NSAID use, herbal supplements (aristolochic acid risk), and contrast exposures — these are reversible accelerators of CKD.

Follow-Up, Monitoring Parameters, and Counseling

— Low-risk (isolated microhematuria, no proteinuria, normal BP/eGFR):

— BP, UA, UPCR, creatinine every 6–12 months

— Reassure but do not discharge — IgAN can progress silently over decades

— Moderate-risk (proteinuria 0.3–1 g/day, controlled BP, eGFR ≥60):

— Every 3–4 months initially, then every 6 months if stable

— Track UPCR trend (single most important parameter)

— High-risk or on immunosuppression:

— Every 4–6 weeks with BMP, CBC, UA, UPCR

— Glucose monitoring on steroids; LFTs monthly on sparsentan first year

— UPCR or UACR — target <0.5 g/g (or <300 mg/g)

— Blood pressure — home BP log; target <120/80

— eGFR slope — decline >5 mL/min/year is concerning; <1 mL/min/year reassuring

— Potassium — keep <5.5; use binders if RAAS-limiting

— CBC, hemoglobin — anemia surveillance in CKD

— Ca, Phos, PTH, vitamin D when eGFR <60 (CKD-MBD)

— Lipid panel annually

— Disease is chronic and variable — most patients do well, but lifelong follow-up is essential

— Recognize and report gross hematuria episodes, edema, decreased urine output, severe headache (HTN)

— Family screening: first-degree relatives with hematuria should be evaluated (UA, BP, creatinine); familial IgAN exists but is uncommon

— Pregnancy planning — pre-conception nephrology visit, medication switches

— Mental health — chronic disease burden in young adults; screen with PHQ-2/9

— Hold ACEi/ARB/SGLT2i/diuretics during acute GI illness with dehydration ("DAMN" or "SADMANS" mnemonic) and resume after rehydration

— Avoid NSAIDs and IV contrast when possible

Monitoring cadence in stable IgAN:

Key monitoring parameters:

Counseling content:

Sick-day rules:

Key distinction: Sustained proteinuria <0.5 g/g portends excellent long-term prognosis; persistent >1 g/g despite optimization mandates escalation.

Step 3 management: Build a longitudinal care plan with annual flu vaccine, q3-month UPCR/BP/creatinine for the first year post-diagnosis, and a structured pregnancy-planning visit for women of reproductive age.

Ethical, Legal, and Patient Safety Considerations

— Discuss specific risks: gross hematuria (~5%), perinephric hematoma (15–20% on imaging, clinically significant <5%), need for transfusion (~1%), arteriovenous fistula, nephrectomy (rare), pain

— Confirm coagulation status (platelets ≥50k, INR <1.5, normal BP); document

— Use teach-back to confirm understanding; arrange interpreter for limited English proficiency

— Capacity assessment if cognitive impairment — surrogate decision-maker per state hierarchy

— Adolescent with new diagnosis — involve in decision (assent) per developmental capacity; parents provide consent

— Pregnant patient — biopsy is generally safe in 1st/early 2nd trimester if indicated; discuss with MFM

— Jehovah's Witness — pre-procedure discussion of blood product preferences; document advance directive

— High-risk discharge medication list: ACEi/ARB, SGLT2i, prednisone, cyclophosphamide, sparsentan

— Common transition-of-care error: failure to resume RAAS inhibitor after a hospitalization for AKI — document plan and timeline

— Sick-day rules must be written, not just verbalized

— Medication reconciliation at every visit — herbal supplements (especially aristolochic acid–containing Chinese herbs), NSAIDs, "kidney cleanses"

— Suspected gentamicin or other nephrotoxin exposure in occupational setting — occupational health referral

— ESRD requires CMS Form 2728 submission for Medicare coverage

— Pregnancy on teratogens (sparsentan REMS) — required reporting

— SGLT2 inhibitors, sparsentan, budesonide, iptacopan are expensive — verify coverage, apply for manufacturer assistance, document shared decision-making

— Transplant referral disparities — ensure equitable, timely referral

— Genetic considerations if Alport is on the differential — counsel re: implications for family

— Post-biopsy: 24-hour activity restriction, hematuria precautions, when to call

— Steroid taper instructions in writing — adrenal crisis risk if abruptly stopped

— Vaccination status verified before initiating immunosuppression (live vaccines contraindicated after)

Informed consent for renal biopsy:

Informed consent edge cases:

Medication safety and transitions of care:

Mandatory reporting and public health:

Equity and access:

Confidentiality:

Patient safety:

Step 3 management: A documented sick-day plan, written steroid taper, and a follow-up appointment scheduled before discharge are core patient-safety deliverables for every IgAN admission.

High-Yield Associations and Rapid-Fire Clinical Facts

— Gd-IgA1 (galactose-deficient IgA1) is the antigen → IgG autoantibodies form immune complexes → mesangial deposition

— Mucosal source: gut-associated lymphoid tissue (Peyer's patches) — rationale for targeted-release budesonide

— Polymeric IgA1 deposits in mesangium → complement activation via alternative and lectin pathways (C3 deposition without C1q)

— Most common primary GN worldwide

— Higher prevalence in East Asian populations; lower in African Americans

— Peak age 20–30; M:F 2:1

— URI, gastroenteritis, UTI, vigorous exercise, vaccination (occasionally)

— Normal C3 and C4 (key differentiator from PSGN, lupus, MPGN)

— Serum IgA elevated in ~50% — supportive, not diagnostic

— Microscopy: dysmorphic RBCs, acanthocytes, RBC casts

— IF: mesangial IgA dominant or codominant, often C3, IgG/IgM

— C1q absent (presence suggests lupus)

— EM: mesangial electron-dense deposits

— Oxford MEST-C: M, E, S, T, C — T (tubular atrophy) is the strongest prognostic factor

— IgA vasculitis (HSP): systemic IgA disease — purpura, arthralgia, abdominal pain, nephritis

— Cirrhosis — secondary IgAN

— Celiac disease, dermatitis herpetiformis

— HIV, ankylosing spondylitis, IBD, psoriasis

— RAAS first (ACEi or ARB) — target BP <120/80, proteinuria <0.5 g/day

— SGLT2i add-on for persistent proteinuria

— Targeted-release budesonide for high-risk persistent proteinuria

— Sparsentan replaces ARB in high-risk patients

— Crescentic IgAN — steroids + cyclophosphamide

— ~20–40% progress to ESRD over 20 years

— Predictors: proteinuria >1 g/day, HTN, eGFR <60, MEST-C T1–T2, crescents

— Recurrence in transplant ~30%, graft loss in 5–10%

Pathophysiology pearls:

Epidemiologic pearls:

Classic triggers of hematuria episodes:

Lab pearls:

Biopsy pearls:

Associations:

Treatment pearls:

Prognosis:

Board pearl: "Synpharyngitic hematuria + normal complements" = IgAN until proven otherwise — fastest one-liner for the boards.

Key distinction: IgAN immune complexes contain IgA1, not IgA2; mucosal IgA is normally polymeric IgA1 — fits with the gut-mucosal pathogenesis model.

Board Question Stem Patterns

"A 22-year-old man develops tea-colored urine 1 day after onset of a sore throat. UA shows 50 RBCs/hpf with dysmorphic forms and RBC casts. BP 138/86. Cr 1.1. C3 and C4 normal. Best next step?" → Quantify proteinuria with UPCR, then refer for biopsy if >500 mg/g or HTN persists.

"A 24-year-old has hematuria 10 days after pharyngitis with C3 low, C4 normal, ASO positive." → PSGN, not IgAN. Supportive care.

"A 30-year-old with biopsy-proven IgAN has been on max-dose lisinopril for 6 months. BP 118/74, UPCR 1.2 g/g, eGFR 65. Next step?" → Add SGLT2 inhibitor (dapagliflozin); if proteinuria remains >0.75–1 g/g, consider targeted-release budesonide or sparsentan.

"A 35-year-old with known IgAN presents with creatinine rising from 1.2 to 3.8 over 3 weeks, oliguria, and many RBC casts. Biopsy: 40% crescents." → Pulse methylprednisolone + IV cyclophosphamide + PJP prophylaxis.

"A 68-year-old smoker with painless gross hematuria. UA: 30 RBCs/hpf, no proteinuria, no casts." → Cystoscopy + CT urogram (urothelial carcinoma workup), not biopsy.

"Microhematuria in a young man whose father is on dialysis and brother has hearing loss." → Alport syndrome — genetic testing, audiology, RAAS.

"A 28-year-old IgAN patient on losartan is now 8 weeks pregnant." → Stop losartan, switch to labetalol or nifedipine, start ASA 81 mg, co-manage with MFM.

"Five years after kidney transplant for IgAN-related ESRD, UPCR rises to 1.0 g/g." → Allograft biopsy — recurrence in ~30%.

"Palpable purpura on buttocks, abdominal pain, arthralgia, and hematuria." → HSP/IgA vasculitis — same renal histology, systemic disease, supportive ± steroids ± immunosuppression for severe nephritis.

Pattern 1 — Synpharyngitic hematuria:

Pattern 2 — Distinguishing from PSGN:

Pattern 3 — Treatment escalation:

Pattern 4 — RPGN:

Pattern 5 — Differential trap (older smoker with hematuria):

Pattern 6 — Familial hematuria:

Pattern 7 — Pregnancy:

Pattern 8 — Post-transplant:

Pattern 9 — IgA vasculitis:

Board pearl: When complement status is given, it's almost always the diagnostic linchpin. Memorize the low-complement vs. normal-complement GN list.

Key distinction: "Best next step" questions in IgAN almost always favor non-invasive optimization (RAAS, SGLT2i, BP, sodium) before immunosuppression — choose escalation only when proteinuria persists despite supportive care.

One-Line Recap

IgA nephropathy is a mesangial immune-complex glomerulonephritis defined by dominant IgA deposition on biopsy that classically presents in young adults with synpharyngitic hematuria and normal complements, and is managed in a stepwise fashion with maximal RAAS blockade and BP control first, SGLT2 inhibitors and targeted-release budesonide or sparsentan for persistent proteinuria, and cyclophosphamide plus steroids reserved for crescentic disease.

Diagnosis: Glomerular hematuria (dysmorphic RBCs, RBC casts) + proteinuria + normal C3/C4 + biopsy showing mesangial IgA dominance without C1q; MEST-C score (especially T) drives prognosis.

First-line therapy: ACEi/ARB titrated to BP <120/80 and proteinuria <0.5 g/day; add SGLT2 inhibitor if proteinuria persists ≥0.5 g/day regardless of diabetes status; sodium <2 g/day, smoking cessation, statin per ASCVD.

Escalation: Targeted-release budesonide, sparsentan, or systemic steroids for persistent high-risk proteinuria after 3–6 months of optimized supportive care; cyclophosphamide + pulse steroids for crescentic/RPGN IgAN.

Long-term: 20–40% progress to ESRD over 20 years; ~30% recurrence post-transplant; pregnancy requires switching off ACEi/ARB/SGLT2i/sparsentan to labetalol/nifedipine with low-dose aspirin; lifelong UPCR, BP, and eGFR monitoring at intervals matched to risk tier.

CCS pearl: For an outpatient IgAN visit, the high-value order set is BP measurement, UPCR, BMP, lipid panel, medication reconciliation (NSAIDs, herbals), vaccine review, and scheduling the 3-month reassessment — these actions capture nearly all the management points the case wants you to make.