Renal & Urinary

Lupus nephritis: classification and immunosuppression

Clinical Overview and When to Suspect Lupus Nephritis

— New proteinuria ≥0.5 g/day (or UPCR ≥0.5), especially with active urine sediment (dysmorphic RBCs, RBC/cellular casts)

— Unexplained rise in creatinine

— New hypertension, peripheral edema, or nephrotic syndrome

— Falling complements (C3, C4) with rising anti-dsDNA titers — serologic flare often precedes clinical flare by weeks

— Young woman (peak 15–45 years) with hypocomplementemic GN

— Malar rash, oral ulcers, arthritis, serositis, cytopenias, Raynaud's

— Positive ANA (>95% sensitive) — confirm with anti-dsDNA and anti-Smith

— Immune complex deposition (anti-dsDNA, anti-nucleosome) in mesangium, subendothelial, or subepithelial space

— Location of deposits drives the ISN/RPS class and clinical phenotype

— Subendothelial = proliferative (Class III/IV, "nephritic"); subepithelial = membranous (Class V, "nephrotic")

Lupus nephritis (LN) is immune complex–mediated glomerulonephritis in patients with systemic lupus erythematosus (SLE), affecting up to 50% of SLE patients within 10 years of diagnosis.

Higher prevalence and severity in Black, Hispanic, and Asian patients; African American women have ~2× risk of progression to ESKD.

When to suspect LN in a known SLE patient:

When to suspect SLE in a patient presenting first with nephritis:

Pathophysiology essentials:

Step 3 management: Any SLE patient with new proteinuria, hematuria, or rising creatinine needs prompt renal biopsy unless contraindicated — biopsy dictates immunosuppression intensity. Do not treat empirically based on serologies alone.

Board pearl: Lupus nephritis can occur with normal ANA in disease flare if the patient has previously been ANA-positive — never exclude LN on a single negative ANA in an established SLE patient with active sediment.

Presentation Patterns and Key History

— Class I (minimal mesangial): Normal urinalysis, normal creatinine — usually incidental

— Class II (mesangial proliferative): Microscopic hematuria ± mild proteinuria (<1 g/day), preserved GFR

— Class III (focal, <50% glomeruli) / Class IV (diffuse, ≥50%): Active sediment, proteinuria often nephrotic-range, hypertension, rising creatinine; may present as RPGN

— Class V (membranous): Nephrotic syndrome — heavy proteinuria, edema, hypoalbuminemia, hyperlipidemia; often normal sediment and creatinine

— Class VI (advanced sclerosis, ≥90% globally sclerotic): Chronic kidney disease, minimal active inflammation

— Prior SLE diagnosis, current medications, adherence (especially hydroxychloroquine)

— Recent flare triggers: UV exposure, infection, pregnancy, drug withdrawal, sulfa drugs

— Constitutional symptoms: fatigue, fever, weight loss, arthralgias

— Skin (malar/discoid rash, photosensitivity), mucosal ulcers, alopecia, serositis (pleuritic chest pain)

— Neuropsychiatric symptoms, Raynaud's, sicca

— Thrombotic events, miscarriages → screen for antiphospholipid syndrome (co-occurs in ~30% of SLE)

— NSAIDs can confound creatinine and BP

— ACEi/ARB status (renoprotective baseline)

— Prior cyclophosphamide exposure (cumulative toxicity, fertility implications)

Clinical presentation tracks closely with histologic class:

Key historical features to elicit:

Medication history matters:

Family history: SLE, other autoimmune disease, CKD

Social: Reproductive plans (drives induction choice), contraception (teratogenic regimens), insurance access (biologics cost), tobacco/alcohol

Key distinction: Pure Class V mimics primary membranous nephropathy — nephrotic syndrome without sediment, normal complements possible — but PLA2R antibody is negative in lupus membranous. Always check PLA2R when membranous picture appears without clear SLE.

Board pearl: Hydroxychloroquine nonadherence is one of the strongest predictors of LN flare — verify it at every visit.

Physical Exam Findings and Volume Assessment

— Malar (butterfly) rash sparing nasolabial folds; discoid lesions on scalp/ears

— Photosensitive rashes on sun-exposed areas

— Painless oral or nasopharyngeal ulcers (often on hard palate)

— Non-scarring alopecia, "lupus hair" (fragile frontal hairline)

— Hypertension is common in proliferative LN (Class III/IV) and worsens with declining GFR

— Tachycardia may reflect anemia, pericardial effusion, or volume overload

— Weigh patient; trend daily weights in admitted patients

— Pericardial rub or muffled heart sounds → lupus pericarditis or effusion

— Pleural rub, dullness to percussion → pleural effusion (serositis)

— Crackles, S3, elevated JVP → volume overload from nephrotic state or AKI

— Libman-Sacks endocarditis: nontender, sterile valvular vegetations (especially mitral); often clinically silent

— Symmetric, nonerosive polyarthritis (Jaccoud's arthropathy — reducible deformities)

— Tenosynovitis; avascular necrosis (especially femoral head in chronic steroid users)

— Raynaud's phenomenon, livedo reticularis (think APS)

— Periorbital and peripheral pitting edema (nephrotic) or dependent edema

— Digital ulcers, splinter hemorrhages

— JVP, lung exam, peripheral edema, orthostatics

— In nephrotic patients: intravascular depletion can coexist with peripheral edema — diurese cautiously

General appearance:

Vital signs and volume status:

Cardiopulmonary:

Musculoskeletal:

Skin/extremities:

Neurologic: Cognitive dysfunction, seizures, focal deficits (lupus cerebritis or stroke from APS)

Volume assessment is critical for management:

CCS pearl: Order daily weights, strict I/O, orthostatic vitals, and BP every 4 hours on the admission orders for any patient admitted with active LN — these track response and prevent over-diuresis.

Board pearl: New murmur + stroke in SLE = Libman-Sacks until proven otherwise; get TEE and antiphospholipid antibodies.

Diagnostic Workup — Initial Labs, Urine Studies, and Serologies

— Urinalysis with microscopy: dysmorphic RBCs, RBC casts, WBC casts, granular casts — manual microscopy by nephrologist often outperforms automated

— Urine protein-to-creatinine ratio (UPCR) on spot sample — >0.5 g/g is significant; >3.5 g/g = nephrotic-range

— 24-hour urine collection if spot UPCR is discordant with clinical picture

— BMP: creatinine, BUN, electrolytes, bicarbonate (look for metabolic acidosis of CKD)

— Estimate GFR (CKD-EPI 2021, race-free)

— Albumin (low in nephrotic syndrome), total protein, lipid panel (hyperlipidemia of nephrosis)

— CBC with diff: anemia (chronic disease, hemolytic, or CKD), leukopenia, lymphopenia, thrombocytopenia

— Reticulocyte count, haptoglobin, LDH, peripheral smear if hemolysis suspected (rule out TMA)

— Coombs test if AIHA suspected

— ANA (sensitive, not specific) — get titer and pattern

— Anti-dsDNA — specific; titers correlate with renal activity

— Anti-Smith — specific but less sensitive

— Complement: C3, C4, CH50 — low levels suggest active immune complex disease

— Anti-Ro/La, anti-RNP, anti-chromatin

— Hepatitis B (HBsAg, anti-HBc, anti-HBs), Hepatitis C, HIV

— Quantiferon or PPD for latent TB

— VZV serology if rituximab/belimumab planned

— Strongyloides serology in patients from endemic areas

Urine studies (the cornerstone):

Serum chemistry:

Hematology:

SLE-specific serologies:

Antiphospholipid panel: Lupus anticoagulant, anti-cardiolipin IgG/IgM, anti–β2-glycoprotein I IgG/IgM — critical for risk stratification and pregnancy planning

Infection screen before immunosuppression:

Pregnancy test in all reproductive-age women before cytotoxic therapy

Step 3 management: Order urinalysis with microscopy + UPCR + C3/C4 + anti-dsDNA + CBC + BMP + albumin as the initial LN workup panel — these are the labs that get repeated at every flare visit.

Diagnostic Workup — Renal Biopsy and ISN/RPS Classification

— Establish histologic class (I–VI)

— Quantify activity index (AI, 0–24) and chronicity index (CI, 0–12)

— Identify concurrent lesions (TMA, podocytopathy, tubulointerstitial disease, vascular involvement)

— Proteinuria ≥0.5 g/day (spot UPCR ≥0.5)

— Unexplained rise in creatinine

— Active urinary sediment (RBC casts, dysmorphic hematuria)

— Repeat biopsy if treatment failure, relapse, or to assess remission/chronicity before changing therapy

— Class I: Minimal mesangial — normal LM, mesangial deposits on IF/EM

— Class II: Mesangial proliferative — mesangial hypercellularity

— Class III: Focal LN — <50% glomeruli involved; subdivide A (active), A/C, C (chronic)

— Class IV: Diffuse LN — ≥50% glomeruli; subdivide A, A/C, C (segmental vs global no longer required in 2018 revision)

— Class V: Membranous LN — subepithelial deposits, thickened GBM with "spikes"; can coexist with III or IV (reported as III+V or IV+V)

— Class VI: Advanced sclerosis — ≥90% globally sclerotic glomeruli, no residual activity

Renal biopsy is the diagnostic and management cornerstone of LN — required to:

Indications for biopsy in known/suspected SLE:

Contraindications: uncontrolled BP, uncorrected coagulopathy, single kidney (relative), active UTI

2018 ISN/RPS Classification (revised):

Immunofluorescence: "Full-house" pattern (IgG, IgA, IgM, C3, C1q) is highly suggestive of LN

Electron microscopy: Tubuloreticular inclusions ("interferon footprints") in endothelial cells; subendothelial deposits in proliferative; subepithelial in membranous

Key distinction: Class III/IV (proliferative) drives aggressive induction immunosuppression; pure Class V is treated more like membranous nephropathy with proteinuria-directed therapy ± moderate immunosuppression; Class VI is not treated with immunosuppression — focus on CKD/ESKD care.

Board pearl: High chronicity index (>3) predicts poor response to immunosuppression and progression to ESKD — repeat biopsy guides whether to escalate or de-escalate.

Risk Stratification and Treatment Goals

— Complete renal response (CRR): UPCR <0.5 g/g, stable or improved creatinine (within 10–25% of baseline), inactive sediment — target by 12 months (ideally sooner)

— Partial renal response (PRR): ≥50% reduction in proteinuria to subnephrotic levels, stable creatinine — target by 6 months

— Early proteinuria reduction (≥25% by 3 months, ≥50% by 6 months) predicts long-term renal survival

— Black or Hispanic ethnicity

— Male sex

— Baseline creatinine elevation or low GFR

— Nephrotic-range proteinuria

— High activity AND chronicity index on biopsy

— Crescents, fibrinoid necrosis, TMA on biopsy

— Hypertension at diagnosis

— Delay in starting immunosuppression

— Nonadherence to hydroxychloroquine

— Induction (3–6 months): Aggressive immunosuppression to achieve remission — Class III/IV ± V

— Maintenance (≥3 years, often longer): Lower-intensity immunosuppression to prevent relapse

— Adjunctive (lifelong): Hydroxychloroquine, RAAS blockade, BP control, statin if indicated, bone/cardiovascular risk reduction

— Hydroxychloroquine 5 mg/kg/day (max 400 mg) — reduces flares, improves renal outcomes, lowers thrombosis risk; annual ophtho exam after 5 years

— ACEi or ARB for proteinuria and BP control (target BP <130/80, proteinuria <0.5 g/day)

— SGLT2 inhibitor (dapagliflozin/empagliflozin) increasingly recommended for proteinuric CKD, including LN with eGFR ≥20 — avoid in active immunosuppressive induction until stable

— Vaccinations updated before immunosuppression: pneumococcal, influenza, COVID-19, HPV, zoster (recombinant), HBV

Goals of therapy (KDIGO 2024 / ACR 2024):

Adverse prognostic factors:

Phases of treatment:

Universal background therapy for ALL LN patients:

Step 3 management: A patient with new Class IV LN gets simultaneous orders for hydroxychloroquine + ACEi + high-dose steroids + induction immunosuppressant + PCP prophylaxis + bone protection + vaccination review — think of LN as a bundle, not a single drug.

Pharmacotherapy — Induction Regimens

— Glucocorticoids:

— IV methylprednisolone pulses 250–500 mg/day × 3 days for severe disease (lower than historical 1 g due to infection risk)

— Then oral prednisone 0.6–1 mg/kg/day (max ~60 mg), rapid taper to ≤7.5 mg/day by month 3–6

— PLUS one of the following steroid-sparing agents (preferred regimens):

— Mycophenolate mofetil (MMF) 2–3 g/day (or mycophenolic acid equivalent) — preferred in Black/Hispanic patients (better response than cyclophosphamide); preferred when fertility preservation matters

— Low-dose IV cyclophosphamide (Euro-Lupus): 500 mg IV every 2 weeks × 6 doses — total dose 3 g; preferred in white European patients, severe disease, or when adherence to oral MMF is a concern

— High-dose cyclophosphamide (NIH regimen): 500–1000 mg/m² monthly × 6 — reserved for severe/crescentic disease; more toxicity

— Triple therapy (add-on) options now first-line per 2024 guidelines:

— Belimumab (anti-BLyS monoclonal) added to MMF or cyclophosphamide — BLISS-LN trial showed improved renal response

— Voclosporin (calcineurin inhibitor) added to MMF + steroids — AURORA trials showed faster, deeper proteinuria reduction; monitor BP and creatinine

— Induction with MMF + glucocorticoids if nephrotic-range proteinuria or worsening renal function

— Alternative: calcineurin inhibitor (tacrolimus or voclosporin) + low-dose steroid

— Subnephrotic Class V: RAAS blockade alone may suffice

— PCP prophylaxis (TMP-SMX) when prednisone ≥20 mg/day for >4 weeks

— Calcium + vitamin D; bisphosphonate if steroids >3 months at ≥7.5 mg/day

— PPI if high GI risk

Class I/II: No specific immunosuppression for renal disease; treat extrarenal SLE manifestations; hydroxychloroquine + RAAS blockade

Class III/IV (± V) — Induction (first 3–6 months):

Class V (pure membranous):

Refractory disease: Switch MMF ↔ cyclophosphamide; add rituximab (off-label but supported); obinutuzumab in trials

Prophylaxis with induction:

Board pearl: MMF is teratogenic (pregnancy category D) — counsel contraception and switch to azathioprine before conception. Cyclophosphamide causes premature ovarian failure — give GnRH agonist (leuprolide) for fertility preservation in young women.

Pharmacotherapy — Maintenance and Refractory Disease

— MMF 1–2 g/day — preferred maintenance agent; superior to azathioprine in ALMS maintenance trial for preventing relapse

— Azathioprine 2 mg/kg/day — alternative; preferred when pregnancy planned (compatible with conception/pregnancy); check TPMT activity before starting to avoid severe myelosuppression

— Low-dose prednisone ≤5 mg/day or off completely if possible

— Belimumab continued from induction if used

— Voclosporin continued if used in induction

— Minimum 3 years after complete renal response

— Longer if persistent serologic activity, prior relapse, or high chronicity index

— Taper slowly; abrupt withdrawal triggers relapse

— UPCR, urinalysis with microscopy, BMP, CBC, LFTs

— C3/C4 and anti-dsDNA (trend, not absolute)

— Drug levels: tacrolimus/voclosporin trough; MMF level not routine

— Mild relapse (proteinuria rise without GFR decline): increase current regimen, optimize hydroxychloroquine adherence

— Moderate/severe relapse: re-biopsy if class transition suspected, then re-induce

— Class switch (e.g., proliferative → membranous) changes therapy

— Re-biopsy to confirm active disease (not chronicity)

— Switch induction agent (MMF ↔ cyclophosphamide)

— Add rituximab (1 g IV × 2, two weeks apart)

— Obinutuzumab (anti-CD20) in trials with promising results

— Anifrolumab (anti–type I IFN receptor) — approved for SLE, LN data emerging

— Plasmapheresis only for concurrent TTP-like TMA or pulmonary-renal syndrome

— Cyclophosphamide: monthly CBC, urinalysis (hemorrhagic cystitis), MESNA with IV doses, lifetime cumulative dose limit

— MMF: GI side effects, leukopenia, infections (CMV reactivation)

— Voclosporin: BP, creatinine within 2 weeks of start; avoid with strong CYP3A4 inhibitors

— Belimumab: depression/suicidality screening, infusion reactions

Maintenance phase (start after induction, continue ≥3 years; often 5+ years):

Duration of maintenance:

Monitoring during maintenance (every 3 months when stable):

Managing relapse:

Refractory disease (no response by 6 months or progression):

Drug-specific monitoring pearls:

CCS pearl: When ordering induction immunosuppression, simultaneously order CBC weekly × 4, then monthly; UA monthly; BMP every 2 weeks × 1 month then monthly; lipid panel; pregnancy test; PCP prophylaxis; calcium/vitamin D.

Special Populations — Elderly, Renal Impairment, and Hepatic Disease

— Less common but more aggressive when present; higher chronicity at diagnosis

— Confirm SLE serologically — rule out paraproteinemia, vasculitis, drug-induced lupus

— Lower thresholds for infection — reduce steroid doses, prefer MMF over cyclophosphamide

— Address polypharmacy, falls risk (steroid myopathy, osteoporosis)

— Vaccinate aggressively before immunosuppression: recombinant zoster, PCV20, RSV, annual influenza

— Screen for comorbidities driving CV risk: DM, HTN, hyperlipidemia

— eGFR-based dose adjustments:

— MMF: generally no dose adjustment but lower starting dose if GI intolerance

— Cyclophosphamide: reduce by 25–50% if eGFR <30; high risk of myelosuppression

— Voclosporin: contraindicated if eGFR <45 (relative; per current labeling, caution <45, contraindicated <30 in trial criteria)

— Belimumab: no renal adjustment

— Rituximab: no renal adjustment

— Avoid NSAIDs entirely

— Hyperkalemia risk with ACEi/ARB + low GFR — monitor K closely

— Anemia of CKD: iron studies, consider ESA when eGFR <30 and Hb <10

— Phosphate/PTH/vitamin D management starts when eGFR <45

— Immunosuppression for LN itself usually unnecessary if renal disease is "burned out" (Class VI) and no extrarenal activity

— Continue therapy if extrarenal SLE flares

— Hydroxychloroquine continues at reduced dose (200 mg every other day to daily based on weight) — still reduces flares and thrombosis

— Transplant eligibility: good outcomes; defer transplant until SLE quiescent ≥6 months and serologies stable

— Azathioprine: hepatotoxicity, dose-reduce or avoid

— MMF: caution but generally safe

— Cyclophosphamide: hepatically metabolized to active form — caution

— Voclosporin: dose-reduce in moderate hepatic impairment; avoid in severe

— Check hepatitis B status before all immunosuppression — prophylactic entecavir/tenofovir if HBsAg+ or anti-HBc+ with detectable DNA

Elderly patients (>65) with new LN:

CKD considerations:

ESKD on dialysis:

Hepatic impairment:

Step 3 management: Elderly patient with new nephrotic syndrome and "lupus" serologies — biopsy is essential to distinguish LN from age-related diagnoses (amyloid, paraprotein-related, membranous from malignancy) before committing to immunosuppression.

Special Populations — Pregnancy and Pediatrics

— Plan pregnancy when SLE/LN quiescent ≥6 months — active LN at conception → high risk of preeclampsia, preterm birth, fetal loss, maternal flare, renal decline

— Pre-conception counseling: medication review, antiphospholipid screen, anti-Ro/La (neonatal lupus, congenital heart block risk)

— Continue: Hydroxychloroquine (reduces flares, lowers congenital heart block in anti-Ro+), azathioprine, tacrolimus, low-dose prednisone, low-dose aspirin (preeclampsia prevention from 12 weeks)

— Stop pre-conception: MMF (teratogenic — orofacial clefts, microtia), cyclophosphamide, methotrexate, leflunomide, ACEi/ARB (switch to labetalol/nifedipine), warfarin if APS (switch to LMWH)

— Voclosporin and belimumab: limited data, generally discontinued

— Switch MMF → azathioprine at least 3 months before conception with confirmed disease stability

— Prior thrombosis: therapeutic LMWH + low-dose aspirin

— Prior pregnancy loss without thrombosis: prophylactic LMWH + aspirin

— Triple-positive aPL: high-risk monitoring

— Monthly UPCR, BMP, CBC, complements, anti-dsDNA

— Fetal surveillance: serial growth ultrasounds; fetal echo at 16–28 weeks if anti-Ro/La positive (CHB surveillance)

— Distinguishing LN flare vs preeclampsia is critical and difficult: LN flare → active sediment, low complements, rising dsDNA, often <34 weeks; preeclampsia → after 20 weeks, often >34 weeks, no sediment, normal complements, elevated uric acid, sFlt-1/PlGF ratio

— More aggressive than adult disease; higher rates of Class IV and ESKD

— Same biopsy-driven approach; MMF and cyclophosphamide both used

— Growth, puberty, bone health, vaccinations, school performance must be addressed

— Adolescent adherence is the major treatment barrier — transition-of-care planning critical

Pregnancy in lupus nephritis:

Medications and pregnancy:

Antiphospholipid syndrome co-management:

Monitoring during pregnancy:

Pediatric lupus nephritis:

Board pearl: A pregnant SLE patient with worsening proteinuria after 20 weeks — check complements and uric acid. Low complements + rising dsDNA + active sediment → LN flare (treat). Normal complements + high uric acid + hypertension → preeclampsia (deliver).

Key distinction: MMF must be stopped 6 weeks before conception; cyclophosphamide 3 months. Document counseling in the chart.

Complications and Adverse Outcomes

— Progression to ESKD: 10–30% within 10 years despite therapy; worse in Black/Hispanic patients

— Acute kidney injury during flare or from drug toxicity (calcineurin inhibitors, NSAIDs)

— Renal vein thrombosis in nephrotic syndrome (especially membranous) — sudden flank pain, hematuria, worsening proteinuria

— Hypertensive emergency from poorly controlled LN

— SLE confers 2–4× risk of premature atherosclerosis — MI risk is 50× higher in young SLE women

— Accelerated by chronic inflammation, steroids, dyslipidemia of nephrosis, hypertension, CKD

— Statin therapy when LDL-C goals not met or per ASCVD risk

— Pericarditis, myocarditis, Libman-Sacks endocarditis

— Hypercoagulable state from nephrotic syndrome (loss of antithrombin III)

— Antiphospholipid syndrome → arterial and venous thromboses, miscarriages

— Consider prophylactic anticoagulation when albumin <2.0–2.5 g/dL and nephrotic

— Bacterial (pneumococcus, gram-negative), opportunistic (PCP, CMV, aspergillus, cryptococcus), reactivation (TB, HBV, VZV)

— Highest risk during first 6 months of induction

— Fever in immunosuppressed LN patient = inpatient workup

— Cyclophosphamide: hemorrhagic cystitis, bladder cancer (lifetime risk), infertility, leukemia/MDS

— MMF: leukopenia, GI intolerance, infection

— Steroids: weight gain, diabetes, osteoporosis, cataracts, avascular necrosis (especially femoral head), psychiatric effects

— Hydroxychloroquine: retinal toxicity (rare with weight-based dosing; annual screening after 5 years)

— Calcineurin inhibitors: HTN, AKI, hyperkalemia, neurotoxicity

— Increased risk of non-Hodgkin lymphoma, cervical cancer (HPV), bladder/skin cancers (cyclophosphamide)

— Age-appropriate cancer screening with attention to cervical (annual cytology in immunosuppressed)

— Steroid-induced osteoporosis, AVN

— Hypogonadism after cyclophosphamide

Renal complications:

Cardiovascular complications:

Thrombotic complications:

Infectious complications (top cause of mortality):

Drug toxicities:

Malignancy:

Bone and metabolic:

CCS pearl: Nephrotic LN patient develops sudden flank pain + drop in Hb + new hematuria → order renal vein Doppler or CT venography for renal vein thrombosis; anticoagulate.

Board pearl: Leading causes of death in LN follow a bimodal pattern — early (infection, active disease), late (cardiovascular disease).

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

— Rapidly progressive GN: doubling creatinine over days to weeks

— Nephrotic syndrome with severe edema, anasarca, or AKI

— Hypertensive urgency/emergency

— Suspected pulmonary-renal syndrome (hemoptysis, alveolar hemorrhage)

— Active sepsis or febrile neutropenia in immunosuppressed patient

— Need for pulse IV steroids, IV cyclophosphamide, plasmapheresis, or biologic initiation when not feasible outpatient

— Concern for thrombotic microangiopathy or catastrophic APS

— Diffuse alveolar hemorrhage requiring respiratory support

— Hemodynamic instability (sepsis, cardiac tamponade from lupus pericarditis)

— Hypertensive emergency with end-organ damage

— Severe acute neuropsychiatric SLE (status epilepticus, coma, severe psychosis)

— Catastrophic antiphospholipid syndrome (CAPS) — multiorgan thromboses

— Need for urgent plasmapheresis or hemodialysis

— Nephrology — every LN case for biopsy interpretation and immunosuppression planning

— Rheumatology — co-management of systemic disease, biologic selection

— Maternal-fetal medicine — pregnancy planning or active pregnancy

— Hematology — APS, TMA, refractory cytopenias

— Infectious disease — opportunistic infection workup, complex prophylaxis

— Ophthalmology — annual HCQ retinal screening after 5 years

— Cardiology — accelerated atherosclerosis assessment, pericardial disease, Libman-Sacks

— Dermatology — refractory skin disease

— Transplant nephrology — when approaching ESKD

Indications for hospitalization:

ICU criteria:

Consultations to obtain:

Catastrophic APS pearl: Triple therapy = anticoagulation + high-dose steroids + plasmapheresis ± IVIG; rituximab/eculizumab in refractory cases

Pulmonary-renal syndrome: Always rule out ANCA-associated vasculitis overlap and anti-GBM disease — check ANCA and anti-GBM in addition to lupus serologies

CCS pearl: When admitting a patient with new RPGN, simultaneously order: renal biopsy consult, nephrology consult, urinalysis with microscopy, ANA/dsDNA/Sm/C3/C4/ANCA/anti-GBM, hep B/C/HIV, quantiferon, pregnancy test, CXR, ECG, type & screen, IV access — don't wait for biopsy to start pulse steroids if clinical RPGN is severe.

Step 3 management: Empiric pulse methylprednisolone is acceptable while awaiting biopsy in severe RPGN; specific steroid-sparing agent waits for histology.

Key Differentials — Other Glomerular Diseases

— Synpharyngitic hematuria (within days of URI vs 2–3 weeks in PSGN)

— Normal complements

— Mesangial IgA-dominant deposits on IF

— No systemic autoimmune features

— Hematuria 2–3 weeks after pharyngitis or 4–6 weeks after skin infection

— Low C3, normal C4 (alternative pathway)

— Subepithelial "humps" on EM

— Self-limited; supportive care

— Low C3 and C4 (immune complex MPGN) or low C3 only (C3 glomerulopathy)

— Associated with hepatitis C, monoclonal gammopathy, complement dysregulation

— Tram-track GBM appearance

— Key distinction from LN: absence of full-house IF, absence of SLE serologies/clinical features

— Pauci-immune crescentic GN

— Normal complements (helps distinguish from LN)

— ANCA positive (PR3 or MPO)

— Often with pulmonary, sinus, neurologic involvement

— Linear IgG staining along GBM

— Pulmonary hemorrhage + RPGN

— Anti-GBM antibodies

— Normal complements

— PLA2R antibody positive in ~70% (negative in lupus membranous)

— IgG4-dominant subepithelial deposits (vs IgG1/2/3 in LN)

— No mesangial or subendothelial deposits (LN has both)

— No tubuloreticular inclusions

— Hepatitis C–associated most commonly

— Low C4 prominent, palpable purpura, neuropathy

— Cryocrit positive

— Schistocytes, thrombocytopenia, AKI

— Can coexist with LN (worse prognosis) or be primary (TTP, aHUS, drug-induced)

— Check ADAMTS13 if TTP suspected

Same-category differentials (other glomerulonephritides):

IgA nephropathy:

Post-infectious / post-streptococcal GN:

Membranoproliferative GN (MPGN):

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

Anti-GBM disease (Goodpasture):

Primary membranous nephropathy:

Cryoglobulinemic GN:

Thrombotic microangiopathy (TMA):

Board pearl: Full-house IF + tubuloreticular inclusions on EM is essentially pathognomonic for LN even before serologies return.

Key distinction: Low complements + active sediment narrows the differential to LN, post-infectious GN, MPGN, cryoglobulinemic GN, and endocarditis-associated GN — serologies and clinical context distinguish them.

Key Differentials — Non-Glomerular and Mimickers

— Triggers: hydralazine, procainamide, isoniazid, minocycline, TNF inhibitors, methyldopa, quinidine

— Anti-histone antibodies positive

— Renal involvement rare — if prominent nephritis, reconsider idiopathic SLE

— Anti-dsDNA usually negative (positive in hydralazine and anti-TNF DIL)

— Resolves on drug withdrawal

— Anti-U1-RNP positive in high titer

— Features overlap SLE, scleroderma, polymyositis

— Renal disease less common and milder

— Tubulointerstitial nephritis more common than glomerular

— Type 1 distal RTA classic

— Anti-Ro/La positive

— Malignant hypertension + AKI + MAHA in patient with diffuse scleroderma

— Treat with ACE inhibitor (only setting where ACEi is started during AKI)

— Often anti-RNA polymerase III positive

— Endocarditis-associated GN: fever, murmur, embolic phenomena, low complements, immune complex GN — get blood cultures and echo

— HIV-associated nephropathy: collapsing FSGS, nephrotic proteinuria, normal complements; rule out with HIV testing

— Hepatitis B: membranous nephropathy or PAN-like vasculitis

— Hepatitis C: cryoglobulinemic MPGN

— Syphilis and malaria: membranous nephropathy

— Amyloidosis (Congo red apple-green birefringence)

— MIDD, light-chain cast nephropathy, fibrillary GN

— Especially in older patients with new "lupus-like" picture — check SPEP/UPEP/free light chains

— Long-standing diabetes, retinopathy, normal complements, no sediment

— May coexist with LN — biopsy if atypical (rapid progression, sediment, no retinopathy)

Other-category differentials:

Drug-induced lupus (DIL):

Mixed connective tissue disease (MCTD):

Sjögren syndrome:

Scleroderma renal crisis:

Infectious mimickers:

Paraprotein-related disease:

Diabetic nephropathy:

Preeclampsia: As discussed in pregnancy chunk

Step 3 management: Always rule out infection (especially endocarditis, hepatitis, HIV) before committing to immunosuppression in a patient with low complements and nephritis — immunosuppression in undiagnosed infection is catastrophic.

Board pearl: Drug-induced lupus from hydralazine can rarely cause ANCA-positive vasculitis with renal involvement — stop the drug and treat as vasculitis.

Secondary Prevention and Long-Term Outpatient Plan

— Hydroxychloroquine lifelong (5 mg/kg/day, max 400 mg) — reduces flares, thrombosis, mortality

— ACEi or ARB titrated to BP <130/80 and proteinuria <0.5 g/day

— SGLT2 inhibitor (dapagliflozin or empagliflozin) for proteinuric CKD with eGFR ≥20, when disease is stable

— Statin if LDL >100 with high CV risk, or per ASCVD calculator (recognize SLE adds risk not captured by standard tools)

— Low-dose aspirin if APS-positive or high cardiovascular risk

— Calcium 1000–1200 mg + vitamin D 800–2000 IU daily

— Bisphosphonate if chronic steroids ≥7.5 mg/day for >3 months (or denosumab if CKD limits bisphosphonate)

— Annual influenza

— PCV20 (or PCV15 + PPSV23 sequence)

— COVID-19 boosters per current guidance

— Recombinant zoster (Shingrix) — safe during immunosuppression

— HBV (especially before rituximab/biologics)

— HPV through age 45 if not vaccinated

— Tdap, RSV per age guidelines

— Avoid live vaccines (MMR, varicella, yellow fever, live zoster, intranasal flu) during significant immunosuppression

— Sunscreen and sun avoidance (UV triggers flares)

— Smoking cessation (worsens HCQ efficacy and CV risk)

— Mediterranean or DASH diet; sodium restriction

— Regular weight-bearing exercise

— Mental health screening — depression/anxiety common

— Avoid estrogen-containing contraceptives if APS-positive or active disease

— Progestin-only, copper IUD, or levonorgestrel IUD preferred

— Document contraception when on teratogenic regimens

— Annual cervical cytology (immunosuppression increases HPV persistence)

— Skin checks (especially after cyclophosphamide)

— Age-appropriate breast, colon, lung screening

— Annual urinalysis for cyclophosphamide-exposed patients (bladder cancer surveillance for years)

Universal long-term medications for all LN patients:

Vaccinations (inactivated only during active immunosuppression):

Lifestyle counseling:

Contraception counseling:

Cancer screening:

Step 3 management: At every visit ask three questions: "Are you taking hydroxychloroquine? When was your last eye exam? Are you on contraception?" These three questions catch the most preventable LN problems.

Follow-Up, Monitoring, and Counseling

— Active disease / induction: Every 2–4 weeks initially, then monthly

— Stable maintenance: Every 3 months

— Long-term remission (>2 years): Every 4–6 months, with rapid access for symptoms

— Symptoms: edema, joint pain, rash, fatigue, oral ulcers, chest pain, hair loss

— BP, weight, urine dipstick for proteinuria

— Medication adherence (especially HCQ — ask directly)

— Contraception status in reproductive-age women

— Every visit: CBC, BMP, UA with microscopy, UPCR, albumin, LFTs

— Every 3 months: C3/C4, anti-dsDNA

— Every 6–12 months: lipid panel, HbA1c if on steroids, 25-OH vitamin D

— Annual: TSH, urine for cyclophosphamide-exposed (bladder Ca surveillance)

— Nephrology: every 1–3 months during active disease, every 3–6 months stable

— Rheumatology: parallel schedule, often co-located visits

— Ophthalmology: baseline within 1 year of HCQ start, then annual after 5 years (or sooner with risk factors: renal disease, tamoxifen, dose >5 mg/kg)

— Dental cleanings every 6 months (immunosuppression risk)

— Repeat renal biopsy if relapse with suspected class transition, refractory disease, or to assess chronicity before stopping immunosuppression

— DEXA scan every 1–2 years if chronic steroids

— Echocardiogram if new murmur, dyspnea, or stroke

— Recognize flare symptoms: new edema, foamy urine, joint pain, rash, fatigue

— Sick-day rules: don't stop maintenance meds during infection; call clinic; stress-dose steroids if on chronic prednisone ≥5 mg/day and significantly ill

— Pregnancy planning timeline (6 months quiescence, switch off MMF 6 weeks pre-conception)

— Travel: avoid live vaccines, plan immunosuppression around endemic infections, carry medication list

— Pediatric → adult: formal transition program age 18–21

— Inpatient → outpatient: medication reconciliation, follow-up within 1–2 weeks of discharge, lab orders sent ahead

Monitoring frequency:

At each visit:

Laboratory monitoring schedule:

Specialty follow-up:

Imaging/procedures:

Patient counseling priorities:

Transition of care:

CCS pearl: On hospital discharge for LN flare, schedule nephrology follow-up within 2 weeks, send standing orders for BMP, UA, UPCR, CBC at 1 week, and ensure PCP prophylaxis is filled before discharge.

Ethical, Legal, and Patient Safety Considerations

— Patients must be counseled on infection risk, malignancy risk, infertility (cyclophosphamide), teratogenicity (MMF), and long-term steroid effects

— Document discussion of alternatives (MMF vs cyclophosphamide vs combination therapies)

— Special consent for off-label biologic use (rituximab)

— Young women receiving cyclophosphamide should be offered GnRH agonist (leuprolide) during therapy and referred to reproductive endocrinology for oocyte/embryo cryopreservation before treatment starts

— Failure to discuss fertility preservation is a documented source of malpractice claims

— Young men: sperm banking before cyclophosphamide

— MMF teratogenicity is severe (~25% pregnancy loss, ~25% major malformations)

— REMS-like counseling: document contraception method, plan, and follow-up for every prescription

— Two forms of contraception recommended on MMF

— Black and Hispanic patients have worse LN outcomes — systemic factors include access to specialty care, biologic cost, clinical trial underrepresentation

— Active outreach, language-appropriate education, addressing social determinants

— Hospital discharge without timely nephrology follow-up → flare and readmission

— Missed PCP prophylaxis prescription on discharge → fatal Pneumocystis pneumonia

— Failure to communicate medication changes to PCP → duplications or omissions

— Pediatric-to-adult transition: highest period of nonadherence and flare

— Confusion of mycophenolate mofetil (CellCept) vs mycophenolic acid (Myfortic) — not 1:1 dose equivalent (720 mg Myfortic ≈ 1000 mg CellCept)

— IV vs oral cyclophosphamide dose differences

— Tacrolimus formulation switches (IR vs ER) require trough rechecks

— Latent TB diagnosis triggers public health notification in some jurisdictions

— Hepatitis B/C/HIV reporting per state law

— Discuss with ESKD-transitioning patients: dialysis vs conservative management, transplant candidacy

— Address goals of care in refractory disease

Informed consent for immunosuppression:

Fertility preservation:

Contraception as a patient safety issue:

Vulnerable populations and disparities:

Transition-of-care risks (high Step 3 yield):

Medication errors:

Mandatory reporting and public health:

End-of-life and advanced care planning:

Step 3 management pearl: Before starting cyclophosphamide in a 28-year-old woman with LN, the correct next step is fertility preservation counseling and offering GnRH agonist — even if therapy is urgent, this discussion is mandatory and documentable.

High-Yield Associations and Rapid-Fire Clinical Facts

— Anti-dsDNA titers correlate with proliferative (Class III/IV) activity

— Low C3/C4 → active immune complex disease (Class III/IV)

— Anti-C1q antibody → highly associated with proliferative LN

— Anti-Sm → SLE-specific but doesn't predict class

— Anti-Ro/La → neonatal lupus, congenital heart block

— Lupus anticoagulant/anti-cardiolipin/anti-β2GP1 → APS

— "Wire loops" = subendothelial deposits (Class III/IV)

— "Spike and dome" or "holes" on silver stain = subepithelial deposits (Class V/membranous)

— "Full-house" IF = IgG + IgA + IgM + C3 + C1q

— Tubuloreticular inclusions = "interferon footprints" (also seen in HIV nephropathy)

— Crescents → severity marker, drives aggressive therapy

— Hydroxychloroquine: reduces flares ~50%, lowers thrombosis, improves lipids, lowers mortality

— MMF preferred over cyclophosphamide in Black/Hispanic patients

— Cyclophosphamide cumulative dose >36 g → significant bladder cancer risk

— Voclosporin: rapid proteinuria reduction; monitor BP and creatinine

— Belimumab: improves renal response when added to standard induction

— Rituximab: useful in refractory disease; deplete B cells, monitor IgG

— Anti-Ro+ pregnancy → fetal echo at 16–28 weeks for CHB

— MMF off 6 weeks pre-conception; cyclophosphamide 3 months

— Azathioprine, tacrolimus, HCQ, prednisone — all pregnancy-compatible

— Always check APS antibodies at diagnosis and before pregnancy

— Screen for cervical cancer annually if immunosuppressed

— Check vitamin D — frequently low

— Early: infection, active disease

— Late: cardiovascular disease, malignancy

Serology-class associations:

Histology pearls:

Drug pearls:

Pregnancy fast facts:

Co-existing disease screening:

Mortality patterns:

Board pearl: A patient with SLE, recurrent miscarriages, and a prolonged aPTT that doesn't correct with mixing study = lupus anticoagulant / antiphospholipid syndrome — paradoxical name (prolongs PTT in vitro, clots in vivo).

Key distinction: Anti-dsDNA = SLE activity; anti-histone = drug-induced lupus; anti-Sm = SLE specificity (rare); anti-Ro/La = Sjögren overlap and neonatal lupus.

Board Question Stem Patterns

— Next step: Renal biopsy (not empiric immunosuppression)

— After biopsy shows Class IV-A: Induction with MMF + glucocorticoids (preferred in this demographic); discuss adding belimumab or voclosporin

— Hydroxychloroquine, ACEi, vaccinations, PCP prophylaxis, contraception counseling

— Answer: Switch MMF → azathioprine, confirm 6 months stable disease, continue HCQ and prednisone ≤7.5 mg, add low-dose aspirin at 12 weeks

— Active sediment + low complements + rising dsDNA → LN flare

— No sediment + normal complements + elevated uric acid + sFlt-1/PlGF high → preeclampsia

— Next step: Repeat biopsy to confirm active disease vs chronicity; if active → switch to MMF + rituximab, or add belimumab

— Next step: GnRH agonist (leuprolide) for ovarian protection; reproductive endocrine referral

— Treatment: ACEi/ARB ± immunosuppression (MMF + steroids) if nephrotic-range

— Next step: Antiphospholipid antibody panel; lifelong warfarin if APS confirmed with thrombosis (avoid DOACs in triple-positive APS)

— Next step: Stop hydralazine; symptoms resolve

— Diagnosis: Pneumocystis pneumonia — confirms need for PCP prophylaxis with high-dose steroids

Classic stem 1 — New diagnosis: 28-year-old Black woman with malar rash, arthralgias, foamy urine; UA shows 3+ protein, RBC casts; UPCR 4.2; creatinine rising from 0.9 to 1.6; C3/C4 low; ANA 1:1280; anti-dsDNA high.

Classic stem 2 — Pregnancy planning: SLE patient with Class IV LN in remission on MMF asks about pregnancy.

Classic stem 3 — Distinguishing flare from preeclampsia: 32-week pregnant SLE patient with worsening proteinuria, BP 160/100.

Classic stem 4 — Refractory disease: Patient on cyclophosphamide induction 6 months with persistent proteinuria 2.5 g, rising creatinine.

Classic stem 5 — Fertility counseling: Young woman with new severe LN needing cyclophosphamide.

Classic stem 6 — Membranous LN: Nephrotic SLE patient with normal creatinine, no active sediment, normal complements, biopsy shows Class V.

Classic stem 7 — Co-morbid APS: SLE patient with stroke, livedo, prior miscarriages, prolonged aPTT.

Classic stem 8 — Drug-induced lupus: 65-year-old on hydralazine develops arthralgias, anti-histone +, anti-dsDNA −, no renal involvement.

Classic stem 9 — Hospital discharge: Recently discharged on prednisone 60 mg + MMF develops fever, dry cough, hypoxia.

Step 3 management pearl: When biopsy results aren't given but clinical and serologic picture screams proliferative LN with rising creatinine, the best initial step is empiric IV methylprednisolone pulse + arrange urgent biopsy — definitive immunosuppression then class-driven.

One-Line Recap

— Biopsy first, immunosuppress second — any SLE patient with proteinuria ≥0.5 g/day, active sediment, or rising creatinine needs a kidney biopsy before committing to an immunosuppressive regimen; the ISN/RPS class (I–VI) and activity/chronicity indices drive every subsequent decision.

— Induction for Class III/IV (± V): Glucocorticoids (pulse → oral taper) + MMF or low-dose cyclophosphamide (Euro-Lupus), with belimumab or voclosporin increasingly used as triple therapy per 2024 guidelines; MMF preferred in Black and Hispanic patients and when fertility matters.

— Maintenance with MMF (or azathioprine if pregnancy planned) for ≥3 years after complete renal response; lifelong hydroxychloroquine, ACEi/ARB, statin/SGLT2i when indicated, vaccinations, contraception counseling, and PCP prophylaxis are non-negotiable adjuncts.

— Special situations: Stop MMF 6 weeks before conception and switch to azathioprine; offer GnRH agonist with cyclophosphamide for fertility preservation; rule out infection (endocarditis, HBV, HCV, HIV, TB) before immunosuppression; repeat biopsy for refractory disease or suspected class transition; manage APS, accelerated atherosclerosis, and steroid-related bone/metabolic toxicity as parallel longitudinal priorities.

Lupus nephritis is biopsy-classified, induction-then-maintenance immunosuppression with universal hydroxychloroquine and RAAS blockade, where the histologic class (especially proliferative III/IV vs membranous V) dictates the intensity and choice of therapy, and outcomes hinge on early diagnosis, hydroxychloroquine adherence, and meticulous prevention of infection, thrombosis, and cardiovascular complications.

High-yield recap bullets:

Board pearl: When in doubt on a Step 3 LN question, the answer almost always involves biopsy, hydroxychloroquine, ACEi, MMF + steroids, contraception counseling, and PCP prophylaxis — assemble the bundle, not a single drug.