What is the initial treatment approach for exostosin positive membranous nephropathy?

Treatment of Exostosin-Positive Membranous Nephropathy

For exostosin-positive membranous nephropathy, begin with 6 months of conservative management including ACE inhibitors/ARBs, and if nephrotic syndrome persists with proteinuria >4 g/day, initiate immunosuppressive therapy with either rituximab or a 6-month alternating regimen of corticosteroids and cyclophosphamide. 1, 2

Initial Conservative Management Period

• All patients with exostosin-positive membranous nephropathy should receive at least 6 months of conservative supportive care before considering immunosuppression, which includes ACE inhibitors or ARBs for antiproteinuric effect, blood pressure control targeting <130/80 mmHg, diuretics for edema, and sodium restriction. 1, 3

• During this observation period, monitor for spontaneous remission, as approximately 30% of membranous nephropathy cases may achieve partial or complete remission without immunosuppression. 4

• Consider prophylactic anticoagulation with warfarin if serum albumin falls below 2.5 g/dL (or <2.0 g/dL by bromocresol green method) due to significantly elevated thromboembolism risk. 1, 3

Criteria for Initiating Immunosuppressive Therapy

Immunosuppression should only be started when the patient has nephrotic syndrome AND meets at least one of these conditions: 5, 1

• Urinary protein excretion persistently exceeds 4 g/day AND remains above 50% of baseline value despite 6 months of optimal conservative therapy. 5, 1

• Presence of severe, disabling, or life-threatening symptoms directly related to nephrotic syndrome (such as severe edema, recurrent infections, or thromboembolic events). 5, 1

• Serum creatinine has risen by ≥30% within 6-12 months from diagnosis, but eGFR remains ≥25-30 mL/min/1.73m². 5, 1

Do NOT use immunosuppression if: 5, 1

• Serum creatinine is persistently ≥3.5 mg/dL (or eGFR ≤30 mL/min/1.73m²) with reduced kidney size on ultrasound (<8 cm length). 5

• Active severe or life-threatening infections are present. 5

First-Line Immunosuppressive Options

Option 1: Rituximab (Preferred for Exostosin-Positive Disease)

• Rituximab represents a rational first-line choice for exostosin-positive membranous nephropathy given the autoantibody-mediated pathogenesis and successful case report evidence. 2

• The case report of EXT1-associated membranous lupus nephritis demonstrated complete remission using multiple low-dose rituximab (200 mg doses approximately every 2 months, guided by CD19+ cell counts), achieving remission within 8 months. 2

• Standard rituximab dosing is 1 g on days 1 and 15, which achieved complete or partial remission in 62% of patients at 12 months and 83% at 24 months in the RI-CYCLO trial. 6

• Rituximab has a more favorable safety profile compared to alkylating agents, avoiding risks of myelotoxicity, malignancy, and infertility. 7, 6

Option 2: Alternating Corticosteroids and Cyclophosphamide

• The modified Ponticelli regimen consists of 6-month alternating monthly cycles: months 1,3, and 5 with IV methylprednisolone 1 g daily for 3 days followed by oral prednisone 0.5 mg/kg/day for 27 days; months 2,4, and 6 with oral cyclophosphamide 2.5 mg/kg/day (adjusted for age and renal function). 5, 1

• This regimen reduces death or ESKD by 56% (RR 0.44) and increases complete or partial remission rates to 60% (RR 1.46) compared to conservative therapy alone. 4

• Cyclophosphamide is preferred over chlorambucil due to superior safety profile (RR 0.48 for adverse events). 4

• The cumulative cyclophosphamide dose should not exceed 36 g to minimize malignancy and infertility risks. 3

Assessment of Treatment Response

• After completing the initial 6-month immunosuppressive regimen, manage conservatively for at least another 6 months before declaring treatment failure, unless kidney function is actively deteriorating or severe nephrotic symptoms persist. 5, 1

• Monitor proteinuria and serum albumin monthly; a decline in proteinuria to 50% of baseline during the first year significantly predicts eventual remission even if still in nephrotic range. 1

• For rituximab-treated patients, monitor CD19+ B-cell counts to guide re-dosing decisions. 2

Second-Line Therapy for Resistant Disease

• For patients who fail initial alkylating agent therapy, switch to calcineurin inhibitors (cyclosporine 3-5 mg/kg/day in divided doses or tacrolimus with target trough levels 5-10 ng/mL) for at least 6 months. 5, 8

• For patients who fail rituximab with stable kidney function, consider switching to the cyclophosphamide-corticosteroid regimen. 3

• If kidney function is declining despite initial therapy, cyclophosphamide with corticosteroids is recommended as second-line treatment. 3

Critical Pitfalls to Avoid

• Do not use corticosteroid monotherapy as it is ineffective for membranous nephropathy and increases adverse effects without benefit. 5

• Avoid declaring treatment failure prematurely; proteinuria may persist for 6-12 months after immunologic remission has occurred. 1, 3

• Do not exceed cumulative cyclophosphamide doses of 36 g due to significantly increased malignancy risk. 3

• Calcineurin inhibitors have high relapse rates (up to 60%) after discontinuation and do not alter long-term outcomes of death or ESKD, making them less ideal as first-line therapy. 4, 7