Treatment of Nephritic Syndrome

I. General Supportive Management

1. Fluid and Sodium Management

• Dietary sodium restriction (60–80 mmol/24 h) combined with loop diuretics (e.g., furosemide) is the mainstay for edema control.
• Aim for fluid removal of no more than 1–2 kg/day in adults to avoid hypovolemia.
• In diuretic resistance: combine a loop diuretic with a thiazide or metolazone, or add amiloride (nephritic syndrome activates ENaC).
• In severe hypoalbuminemia, GI absorption of oral diuretics may be impaired — IV bolus or infusion may be needed.

2. Blood Pressure Control

• ACE inhibitors or ARBs are first-line — they reduce proteinuria and slow GFR decline.
• Target BP <130/80 mmHg (or lower if proteinuria is significant).
• NSAIDs should be avoided — they risk precipitating AKI, especially in the setting of pre-existing kidney impairment.

3. Dietary Protein

• Ensure adequate protein intake of 0.8–1 g/kg/day with high carbohydrate to minimize catabolism.

4. Lipid Management

• Statins or statin/ezetimibe combinations in adults >50 years with CKD stage 3–5, or younger adults with significant comorbidity.

5. Dialysis

• Indicated if severe, rapidly progressive renal failure (RPGN pattern) — serves as bridge while awaiting immunosuppressive response.

6. Avoidance of Nephrotoxins

• Caution with radiocontrast agents, aminoglycosides, and PPIs.

II. Disease-Specific Treatment

A. Post-Infectious (Post-Streptococcal) GN

• Treatment is supportive — control hypertension, manage edema, dialysis if needed.
• Antibiotics (e.g., penicillin) for active streptococcal infection in the patient and close contacts — but antibiotics do not reduce the occurrence of nephritis once established.
• No role for immunosuppressive therapy, even in the setting of crescents on biopsy.
• Prognosis in children is excellent; most cases resolve within weeks.
• Renal biopsy is not required unless atypical features are present.

Harrison's Principles of Internal Medicine 22E, 2025

B. IgA Nephropathy (IgAN)

Step 1: RAAS Blockade (All patients with proteinuria >500 mg/day)

• ARBs at escalating doses (e.g., losartan up to 200 mg/day) — shown superior to standard dosing for reducing proteinuria and preserving GFR.
• Target urinary protein <1 g/day.
• Dietary sodium restriction enhances effect.

Step 2: Glucocorticoids (if proteinuria persists >1–3.5 g/day despite RAAS blockade, with preserved GFR)

• 6-month course of IV + oral glucocorticoids — associated with reduced risk of doubling creatinine and improved renal survival (97% vs. 53% placebo at 10 years in one landmark RCT).
• Not beneficial if significant CKD/interstitial fibrosis is already present (STOP-IgAN, TESTING trials raised concerns about toxicity vs. benefit in CKD patients).

Step 3: Combined Immunosuppression (Progressive disease)

• Cytotoxic therapy (e.g., cyclophosphamide) reserved for documented progression despite above.
• Novel therapy: Targeted-release budesonide (Nefecon) — a KDIGO 2025-recognized option delivering corticosteroid to gut-associated lymphoid tissue, reducing galactose-deficient IgA1 production with less systemic toxicity.
• SGLT2 inhibitors (e.g., dapagliflozin) reduce proteinuria and slow progression; now incorporated in recent KDIGO guidance.
• Sparsentan (dual endothelin/angiotensin receptor blocker) approved for IgAN.

Brenner & Rector's The Kidney; Comprehensive Clinical Nephrology 7e; KDIGO 2025 IgAN Guideline

C. Lupus Nephritis (Class III/IV — Proliferative)

Induction Therapy

• High-dose corticosteroids (IV methylprednisolone pulses 500–1000 mg × 3 days, then oral prednisone 0.5–1 mg/kg/day tapered) PLUS one of:
  • Mycophenolate mofetil (MMF) 2–3 g/day — preferred in many centers (equivalent efficacy to cyclophosphamide, lower gonadotoxicity)
  • IV Cyclophosphamide (low-dose NIH or Euro-Lupus regimen)
• Triple therapy options now recommended by KDIGO/EULAR 2024:
  • Voclosporin (CNI) + MMF + glucocorticoids — AURORA-1 trial demonstrated superior complete renal response
  • Belimumab (anti-BLyS) + MMF/cyclophosphamide + glucocorticoids — BLISS-LN trial showed benefit
  • Hydroxychloroquine should be continued in all patients with lupus unless contraindicated.

Maintenance Therapy

• MMF 1–2 g/day (preferred) or azathioprine 1.5–2 mg/kg/day for at least 3–5 years.
• Continue hydroxychloroquine.
• RAS blockade for proteinuria reduction.

Harrison's Principles of Internal Medicine 22E; Comprehensive Clinical Nephrology 7e; NKF Primer 8e

D. ANCA-Associated Vasculitis (AAV) — Pauci-Immune GN

Induction Therapy

• Rituximab (375 mg/m² × 4 doses or 1g × 2 doses 14 days apart) + prednisone × 16 weeks
• Alternative: IV cyclophosphamide monthly × 3 months + prednisone × 16 weeks

• IV methylprednisolone pulses + IV cyclophosphamide monthly × 3–6 months + prednisone × 16 weeks
• Combination IV cyclophosphamide + rituximab reduces mortality, relapse, and ESKD vs. either agent alone

• PEXIVAS trial (2020) showed no overall reduction in mortality or ESKD with PLEX
• Still considered in: eGFR <30 mL/min without significant chronic fibrosis, or severe pulmonary hemorrhage requiring mechanical ventilation/O₂ supplementation
• NOT recommended as routine for all severe presentations

Maintenance Therapy

• After cyclophosphamide induction: switch to azathioprine at remission (12–18 months)
• After rituximab induction: close follow-up for early relapse; re-treat with rituximab at relapse
• Maintenance immunosuppression may be discontinued after 12–18 months of sustained remission

Comprehensive Clinical Nephrology 7e

E. Anti-GBM Antibody Disease (Goodpasture Syndrome)

Treatment

• IV methylprednisolone pulses (1 g/day × 3 days) → oral prednisolone 1 mg/kg/day
• Cyclophosphamide (age- and GFR-adjusted oral or IV)
• Plasma exchange — mandatory and urgent; 4L exchanges daily or every other day × 14 days or until anti-GBM antibodies are undetectable. Particularly vital with pulmonary hemorrhage.

• Serum creatinine <5.0 mg/dL at presentation → 90% kidney survival at 5 years
• Dialysis-dependent at presentation or 100% circumferential crescents → unlikely renal recovery; immunosuppression only indicated if concomitant pulmonary hemorrhage
• Transplantation after antibody disappearance — recurrence is rare

NKF Primer 8e; Comprehensive Clinical Nephrology 7e

F. Rapidly Progressive GN (RPGN) — General Approach

III. Summary Table