What is the prognosis of untreated membranous nephropathy (membranous glomerulonephritis)?

Prognosis of Untreated Membranous Nephropathy

Untreated membranous nephropathy follows a highly variable natural history: approximately 20–30% of patients achieve spontaneous complete remission, 20–40% develop persistent proteinuria (3–5 g/day) without progressive renal failure, and 40–50% progress to end-stage kidney disease, with the worst outcomes occurring in those with sustained nephrotic-range proteinuria. 1

Spontaneous Remission Rates

• Complete spontaneous remission occurs in 20–30% of untreated patients, with higher likelihood in women and those presenting with subnephrotic proteinuria (<3.5 g/day). 1
• Among patients followed for at least five years without immunosuppressive therapy, 65% achieved complete or partial remission of proteinuria. 2
• Only 38% of untreated patients in controlled studies experienced remission (complete or partial), compared to 83% of treated patients at 10-year follow-up. 1

Progression to End-Stage Kidney Disease

• Approximately 35–40% of untreated patients with nephrotic syndrome progress to end-stage kidney disease within 10 years. 3
• The probability of retaining adequate kidney function without dialysis is 88% at five years and 73% at eight years in untreated cohorts. 2
• In one series of patients who developed renal insufficiency, 65% of conservatively managed patients required chronic dialysis, 10% showed advanced renal failure, and 25% died during follow-up. 4
• Among 140 untreated patients, 20% developed end-stage renal disease, with 17 of 28 showing rapid progression within 2.5 years of diagnosis. 5

Risk Stratification by Proteinuria Severity

The Cattran risk stratification system identifies three prognostic categories based on proteinuria measured over a 6-month observation period: 1

• Low-risk patients (<4 g/day proteinuria) – most likely to spontaneously remit or maintain stable, subnephrotic proteinuria
• Medium-risk patients (consistently 4–8 g/day) – intermediate prognosis
• High-risk patients (>8 g/day or deteriorating proteinuria) – highest risk of progressive renal failure

Only 1 of 24 patients (4%) with nonnephrotic proteinuria at diagnosis progressed to end-stage renal disease, whereas baseline proteinuria ≥10 g/24 hours was strongly associated with renal progression. 5

Additional Prognostic Factors

Demographic Variables

• Male sex is associated with worse prognosis, with 15 of 17 patients showing rapid progression being male. 5
• Age >50 years predicts poorer outcomes. 2
• Asian populations (particularly Japanese) demonstrate significantly better long-term outcomes than Caucasians. 1

Histopathologic Features

• Superimposed focal segmental glomerulosclerosis (FSGS) lesions dramatically worsen prognosis, with remission rates of only 12.7% compared to 32% in patients with membranous nephropathy alone (pooled analysis of 282 patients). 6
• Patients with FSGS superimposed on membranous nephropathy show significantly lower renal survival (P <0.001) and more severe interstitial fibrosis, vascular lesions, and mesangial proliferation. 6

Clinical Parameters

• Hypertension at presentation correlates with worse outcomes, particularly when blood pressure control remains variable. 5, 6
• Impaired renal function at diagnosis predicts rapid progression. 5

Extrarenal Complications

Beyond renal outcomes, untreated membranous nephropathy carries significant morbidity: 1

• Accelerated vascular disease occurs more commonly than in other glomerular diseases
• Increased risk of thromboembolism, particularly when serum albumin falls below 2.9 g/dL
• Cardiovascular disease represents the leading cause of death (>60% of cases) in patients with cryoglobulinemic nephritis, though this applies to HCV-associated secondary forms. 1

Comparative Outcomes: Treated vs. Untreated

The stark contrast between treated and untreated outcomes underscores the importance of risk stratification: 1, 4

• Ten-year renal survival: 92% in treated patients versus 60% in untreated controls
• Four-year dialysis-free survival: 90% in treated versus 55% in untreated patients (P <0.001)
• Seven-year dialysis-free survival: 90% in treated versus 20% in untreated patients (P <0.001)

Critical Clinical Pitfall

The most common error is treating all patients with membranous nephropathy uniformly. The 6-month observation period with maximal conservative therapy (ACE inhibitor/ARB, blood pressure control <120 mmHg systolic, sodium restriction <2.0 g/day) allows identification of the 20–30% who will spontaneously remit, thereby avoiding unnecessary immunosuppression in patients who would improve without treatment. 1, 7

However, patients presenting with severely nephrotic proteinuria (>8–10 g/day), male sex, age >50 years, impaired renal function, or histologic FSGS lesions warrant earlier consideration of immunosuppressive therapy, as their natural history without treatment is progression to dialysis in the majority of cases within 2.5–7 years. 4, 5, 6