IMPACT OF OBSERVATION PERIOD ON OUTCOMES OF PRIMARY MEMBRANOUS NEPHROPATHY

Membranous nephropathy (MN) is the leading cause of primary nephrotic syndrome in adults and is characterized by a kidney-specific autoimmune response mediated by circulating autoantibodies targeting podocytes. Approximately 80% of primary MN cases are associated with anti-phospholipase A2 receptor (PLA2R) antibodies. The prognosis of MN is highly variable; about one-third of patients experience spontaneous remission, while 20-40% may progress to end-stage renal disease within a decade. Although administering immunosuppressive ((IS) therapy can reduce the likelihood of progressive kidney function decline, it is associated with significant adverse effects, including infections and metabolic disturbances. Given the potential for spontaneous remission and the toxicity of IS regimens, the KDIGO guidelines recommend a 6-month observation period with supportive care before considering IS therapy for patients with preserved kidney function and non-severe nephrotic syndrome. However, it remains unclear whether this watchful waiting strategy might lead to missed therapeutic opportunities and irreversible kidney injury. Therefore, this study aimed to evaluate the impact of the observation period on clinical outcomes in patients with primary MN.

We included adult patients diagnosed with MN by renal biopsy or positive serum PLA2R antibody, with 24-hour urinary protein ≥3.5g, and estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73m², who were treated at Huashan Hospital, Fudan University between January 2012 and December 2024. Exclusion criteria included secondary MN, immunosuppressive therapy at baseline, or rapid renal function decline (defined as ≥30% reduction in eGFR within 6 months and eGFR <60 mL/min/1.73 m²). The primary endpoint was a composite outcome of doubling of serum creatinine, ≥50% decline in eGFR, eGFR <15 ml/min/1.73m², initiation of renal replacement therapy, or death related to renal disease. The secondary endpoint was remission of nephrotic syndrome, including partial remission and complete remission. Complete remission was defined as proteinuria of <0.3 g/day or a uPCR of <0.3 g/g, along with a serum albumin level of at least 3.5 g/dL and a stable or improved eGFR. Partial remission was defined as proteinuria between 0.3 and 3.5 g/day or uPCR between 0.3 and 3.5 g/g, with a reduction of ≥50% from baseline, accompanied by improvement in the serum albumin concentration and stable eGFR. Propensity score matching was used to balance baseline characteristics. Survival analyses were performed to compare outcomes using Kaplan–Meier curves and log-rank tests. A Cox proportional hazards model was used to identify independent prognostic factors. The exposure-adjusted event rate was used to assess the risk of adverse events during treatment.

A total of 440 patients with primary MN were initially identified. After excluding 27 patients with baseline urinary protein <3.5 g/24h and 55 patients with eGFR <60 ml/min/1.73m², 358 patients were finally included. The median age was 52.85 years (IQR 40.52-61.81), 72.3% were male, the baseline eGFR was 103.2 ± 27.3 ml/min/1.73m², serum albumin was 26.0 ± 6.1 g/L, and median urinary protein level was 5.9 g/24h (IQR 4.5-8.4). PLA2R-associated membranous nephropathy accounted for 83% of cases, with a median PLA2R antibody level of 52.5 Ru/ml (IQR 1.00-168.3). According to the duration of observation period, patients were categorized into an early treatment group (n = 171), who received IS within 6 months of diagnosis, and a delayed treatment group (n = 187), who underwent ≥6 months of observation. Compared to the delayed treatment group, the early treatment group had higher baseline urinary protein (6.3 g/24h [IQR 4.7-8.8] vs. 5.7 g/24h [IQR 4.3-7.8], P<0.05) and lower serum albumin (24.2 ± 5.9 g/L vs. 27.7 ± 5.8 g/L, P<0.001), indicating more severe nephrotic syndrome at presentation, while renal function was similar between groups.

After propensity score matching (123 patients per group), baseline characteristics were well balanced, though anti-PLA2R antibody levels differed. The delayed treatment group had a longer follow-up (37 months [IQR 20.7-59.2] vs. 36 months [IQR 23-52]). Within the delayed group, 57 patients eventually received IS therapy (delayed IS group) while 66 continued supportive care only (delayed non-IS group). Immunosuppressive regimens did not differ between the early and delayed IS groups. At the last follow-up, no significant difference were observed in the primary composite endpoint or remission rates between the early and delayed treatment groups. However, the duration of nephrotic syndrome was longer in the delayed treatment group (17.2 months [IQR 11.9-24.3] vs. 14.0 months [IQR 7.4-29.3], P<0.001). The 3-year cumulative remission rate and 5-year renal survival rate did not differ significantly between the two groups. A three-way comparison including the early, delayed IS, and delayed non-IS subgroups also showed no differences in these outcomes. Subgroup analysis of 162 PLA2R-associated MN patients with available baseline PLA2R antibody levels yielded conclusions similar to the overall population.

Safety analysis revealed that both the early and delayed IS groups had a higher proportion of patients experiencing adverse events during follow-up (46.8% and 39.6%, respectively) compared to the delayed non-IS group (12.5%, P < 0.001). The exposure-adjusted event rates were also higher in the early and delayed IS groups groups (9.0 and 8.4 vs. 4.0 per 100 patient-years, P < 0.05).

Univariate Cox regression analysis indicated that for patients with primary membranous nephropathy, older age, elevated baseline serum creatinine, failure to achieve remission, and prolonged duration of nephrotic syndrome were risk factors for poor renal outcomes. After multivariate adjustment, failure to achieve remission remained the only independent risk factor (HR 0.017, 95% CI 0.003-0.115), while the duration of observation period had no significant effect on long-term renal outcomes (HR 1.000, 95% CI 0.999-1.000).

For patients with primary membranous nephropathy and normal renal function, an initial observation period of at least 6 months was not associated with reduced remission rates or increased risk of progression. Failure to achieve remission was the independent risk factor for poor renal outcome, while the duration of observation period had no significant effect.