We included patients with idiopathic MN who were treated at two medical centers of the Catholic University of Korea (Seoul and Daejeon St. Mary’s Hospitals) from September 1998 to August 2016. Patients with histologically proven MN were screened and those with potential secondary causative factors were excluded by: clinical history with regard to possible drug use; serologic tests for both infectious and connective tissue diseases including serum autoantibodies, such as antinuclear antibody, anti-double-stranded DNA antibody, anti-neutrophil cytoplasmic antibody, and rheumatoid factor and complement; and screening for hepatitis B and hepatitis C viruses. Patients who had associated malignancies at presentation were also excluded from the study. Thorough clinical examination and appropriate laboratory screening excluded those with secondary causes for MN, leaving 135 patients diagnosed with idiopathic MN. We classified the study participants into ‘older’ and ‘younger’ groups, where ‘older’ was defined as 60 years of age or older at the time of the renal biopsy [9,10].

Data for age, sex, laboratory test results, treatment modalities, clinical responses to treatment, progression to ESRD, occurrence of infection, and patient survival were collected. Body mass index was calculated as the ratio of weight in kilograms divided by the square of the height in meters. Estimated glomerular filtration rate (eGFR) was determined from serum creatinine concentration, age, sex, and race using the abbreviated Modification of Diet in Renal Disease (MDRD) formula [12]. Protein concentration in a 24-hour urine sample or the protein-creatinine ratio of spot urine was used to estimate the amount of proteinuria. Treatment modalities were classified into four groups: conservative treatment, corticosteroids alone (at least 50 mg prednisone/day), cyclophosphamide with or without steroids (less than 15 mg prednisone/day), or cyclosporine with or without steroids (less than 15 mg prednisone/day).

Renal biopsy specimens were examined by light microscopy, immunofluorescence microscopy, and electron microscopy. Sections (2 μm) stained with hematoxylin and eosin, Masson’s trichrome, periodic acid-Schiff, and periodic acid-silver methenamine were examined by light microscopy. The number of global or segmental sclerotic glomeruli is presented as the percentage of the total number of glomeruli in the biopsy specimen. The degree of tubular atrophy was graded from 0 to 3 (mild, moderate, and severe). Interstitial fibrosis was graded as follows: grade 0, none; grade 1, < 25%; grade 2, 26% to 50%; and grade 3, > 50%. Cryosections (4 μm) were stained with fluorescein isothiocyanate-conjugated rabbit anti-human immunoglobulin G (IgG), IgA, IgM, κ and λ light chains, and complement 3 (C3), C4, and C1q.

The primary endpoint was treatment response, which was assessed as CR, partial remission (PR), or no response (NR). CR was defined as urinary protein excretion less than 300 mg/day and stable serum creatinine level. PR was defined as urine protein excretion less than 3.5 g/day or less than 50% of baseline proteinuria with stable serum creatinine level. NR was defined when urinary protein excretion remained at over 50% of the baseline value or serum creatinine level progressively increased [4,13,14]. The secondary endpoints were progression to ESRD, the occurrence of infection and patient death. Development of infection was defined as such that required hospitalization. ESRD was considered a prerequisite for renal replacement therapies such as maintenance dialysis and kidney transplantation.

Variables are presented as the mean ± SD or as frequencies (percentage). Continuous variables were compared using Student’s t test, and categorical variables were compared using a chi-square test or Fisher’s exact test. To test for an independent association of older age and the occurrence of endpoints, a Cox proportional hazards model was used. Such variables that were deemed clinically significant (i.e., the presence of hypertension, proteinuria, treatment modality, and hemoglobin level) were entered into multivariate Cox regression analyses along with variables of p value less than 0.1 in univariate analyses. The cumulative event rates for the prespecified endpoint were estimated by the Kaplan-Meier method and compared using log-rank tests. A p < 0.05 was considered significant. Statistical analysis was performed using SPSS software version 20.0 (IBM Corp., Armonk, NY, USA).

The study was approved by the Institutional Review Board at College of Medicine, the Catholic University of Korea (XC15RIMI0071K). Informed consent was waived due to the retrospective nature of the study.

A total of 135 patients included 77 men (57%) and 58 women (43%). The mean age was 53.7 ± 14.4 years. Eighteen (13%) and 41 patients (30%) had diabetes and hypertension, respectively. The mean eGFR was 99.0 ± 41.9 mL/min/1.73 m² and 19 patients (14.1%) had eGFR less than 60 mL/min/1.73 m². The amount of proteinuria ranged from 0.02 to 18.02 g/day and patients with nephrotic range proteinuria (> 3 g/day) accounted for 103 (76%). Of these patients, 48 (36%) were treated conservatively with the use of ARBs, while 87 patients (64%) were assigned to treatment with immunosuppressive agents.

A greater proportion of older patients than of younger patients had hypertension. Compared with younger patients, older patients presented with lower eGFR. There were no significant differences in serum albumin level, lipid profiles, and the amount of proteinuria. The proportion of those with nephrotic range proteinuria was more prevalent in the older group. The biopsy findings in older patients demonstrated unfavorable histologic changes (Table 1).

In the older patient group, 18 (33.3%) achieved CR, 14 (25.9%) had PR, and 22 (40.7%) had NR. Younger patients had significantly more favorable responses to treatment than older patients did (CR 61.7%, PR 11.1%, NR 27.2%, p = 0.004). The cumulative event rate for achieving CR was significantly inferior in older patients compared with younger patients (p = 0.012) (Fig. 1A). Compared to younger patients, older patients with nephrotic range proteinuria achieved less CR (30.4% vs. 54.4%, p = 0.013) and those with non-nephrotic range proteinuria had more NR (50.0% vs. 8.3%, p = 0.026).

Two deaths (3.7%) occurred in the older patient group (p = 0.158 vs. younger patients). The cumulative event rate for requiring renal replacement therapy was significantly higher in older patients (p = 0.015) (Fig. 1B). Older patients had a greater risk of infection and a significant difference was observed between the age groups in the development of infection (p = 0.005) (Fig. 1C).

Univariate Cox proportional hazard models showed that older age and male sex decreased the odds ratio (OR) for CR and an increased eGFR was positively associated with CR from proteinuria (Table 2). After adjusting for clinically relevant factors, older age and male sex remained as significant predictors of a reduced chance of CR from proteinuria. Both univariate and multivariate models revealed older age as a robust predictor of the development of infection. In univariate models, older patients had a significantly greater risk of progression to ESRD (OR, 10.91; 95% confidence interval [CI], 2.11 to 56.36; p = 0.004), but this association was not significant in multivariate models (adjusted OR, 2.08; 95% CI, 0.26 to 16.47; p = 0.486).

The effectiveness of different treatment strategies in older and younger patients was analyzed in terms of CR attainment, development of ESRD, and infection. Conservative treatment was associated with a significantly lower remission rate in older patients (Fig. 2A). No significant differences were observed between the age groups in terms of renal progression and occurrence of infectious complications in patients managed with conservative treatment. Corticosteroid treatment was less effective in the older patient group (n = 18) in achieving CR and preventing progression to ESRD, and moreover was associated with a greater frequency of infectious complications (Fig. 2B) than in the younger patient group (n = 22). Cyclosporine showed comparable effectiveness for achieving CR and in preventing renal functional deterioration and infectious complications between older and younger patients (n = 12 and n = 24, respectively) (Fig. 2C). The number of patients treated with cyclophosphamide was limited, but this treatment was associated with comparable rates of CR (50.0% vs. 80.0%, p = 0.545) and infectious complications (16.7% vs. 0.0%, p = 1.00) in older and younger patients (n = 6 and n = 5, respectively).