Long-term outcomes of patients with end-stage kidney disease due to membranoproliferative glomerulonephritis: an ANZDATA registry study

Data were obtained from patients enrolled in the ANZDATA registry. All patients with ESKD from January 1, 1996 to December 31, 2016 in Australia and New Zealand were included (Additional file 1: Figure S1). Patients with ESKD caused by glomerulonephritis were selected from this group. These patients were then categorized into two cohorts: patients with ESKD caused by MPGN and patients with ESKD caused by any other form of glomerulonephritis (all other GN). Only patients with a diagnosis of a primary GN were included in the all other GN group. Data on MPGN subtype was not available. Patients with missing demographic or co-morbidity data were excluded from the study. These patients represented less than 1% of the selected patient cohort.

Baseline characteristics were evaluated at the initiation of dialysis or, if pre-emptively transplanted, at the time of transplantation. They included age, sex, ethnicity, smoking status, hepatitis C antibody status, diabetes mellitus, chronic lung disease, coronary artery disease, peripheral vascular disease, cerebrovascular disease and any previous diagnosis of cancer. Dialysis and transplant details were also obtained including the commencement date of dialysis, date of transplantation, date of kidney function recovery if applicable, and whether the patient was a late referral for KRT (defined as referral to a nephrologist within 3 months of KRT commencement). Patients were categorized into two dialysis or transplant eras: from 1996 to 2006 or 2007–2016, based on the date of commencement of dialysis or transplantation.

The primary outcome was patient survival. Secondary outcomes evaluated included cause of death, kidney function recovery on dialysis, time to transplantation, allograft survival, cause of allograft loss and disease recurrence post-transplant.

Categorical variables were expressed as numbers and percentages and continuous variables as mean with standard deviations or median with interquartile range based on distribution. Differences between MPGN and all other GN groups were assessed with Chi squared or Fisher’s exact test for categorical variables, and students t-test for continuous variables.

Propensity score matching was utilized to compare primary and secondary outcomes between MPGN and all other GN patients for both dialysis and transplantation cohorts using the MatchIt software package [12]. Propensity scores were calculated using a logistic regression model for the likelihood of developing MPGN using patient age, sex, ethnicity, all available co-morbidities, late referral for KRT, and dialysis or transplantation era. A 1:1 nearest-neighbor matching algorithm was used with no replacement. A maximum matching caliper distance of 0.25 standard deviations of the logit of the propensity score was permitted and, if no match was possible, the patient was excluded from matching. Standardized mean differences were calculated for each variable used in matching.

Patient survival on dialysis, patient survival following kidney transplantation, kidney function recovery on dialysis, kidney allograft survival and death censored kidney allograft survival were assessed by Kaplan Meier analysis, multivariable Cox proportional hazards regression and competing risk analysis (Fine and Gray method) [13] using the survival and survminer packages [14, 15]. For patients with multiple kidney transplants, outcomes following their first transplant only were considered. Covariates included in the Cox models were age, sex, ethnicity, dialysis or transplantation era, hepatitis C antibody status, smoking status, presence of diabetes, coronary artery disease, peripheral vascular disease, cerebrovascular disease, previous diagnosis of cancer, KRT type and late referral for KRT. Schoenfeld residuals were used to assess proportional hazards assumptions. Patient survival on dialysis was censored for kidney function recovery, loss to follow-up, kidney transplantation and end of study. Kidney function recovery was censored for death, loss to follow-up, kidney transplantation and end of study. Patient survival following kidney transplantation was censored for allograft failure, loss to follow-up and end of study. Death-censored kidney allograft survival was censored for death, loss to follow-up and end of study. Competing-risk for patients with and without MPGN were calculated. Kidney transplantation was a competing risk for death on dialysis, patient death was the competing risk for death censored allograft failure, and allograft failure was the competing risk for death following kidney transplantation. Data processing and analysis was performed using R [16]. P values less than 0.05 were deemed statistically significant.

Between 1996 and 2016, a total of 56,481 patients received dialysis in Australia and New Zealand; 13,462 of these received a kidney transplant. Within this group, 456 (0.8%) patients had ESKD secondary to MPGN (441 requiring dialysis and 15 with pre-emptive transplants) and 12,660 (22.4%) had any other form of glomerulonephritis as the cause of their ESKD (all other GN) (Table 1). All patients with MPGN had a renal biopsy confirming their diagnosis while 74.6% of patients with all other GN were biopsy confirmed. The most common GN in patients with any other GN was IgA nephropathy (3196, 27%; Additional file 1: Table S1). Compared with all other GN patients, those with ESKD from MPGN were more likely to be Maori or Pacific Islander (15% vs. 7%) or have a positive Hepatitis C antibody (10% vs. 1%). There was no difference in the incidence of a positive Hepatitis C antibody between different ethnicities. The incidence of MPGN as a cause of ESKD became less frequent over the two dialysis eras, with 274 patients (1.1% of all patients on KRT) developing ESKD due to MPGN between 1996 and 2006 compared to 182 (0.6%) between 2007 and 2016. The prevalence of Hepatitis C antibody positive MPGN patients remained similar across the two dialysis eras (10.2% in 96–06 vs. 10.4% in 07–16). The ethnicity of patients with MPGN also did not differ between the two dialysis eras (Additional file 1: Table S2). Rates of cancer were higher in patients with MPGN compared to those with GN (10.0% vs 7.3%).

The median follow up for all patients in the study was 2.74 years (IQR 0.68–4.8). For patients in the first dialysis era (1996–2006) it was 3.28 years (IQR 0.78–5.78) and for the second era (2007–2016) it was 2.31 years (IQR 0.63–3.99). Over the study period, 220 patients on dialysis with MPGN (50%) and 5234 patients with all other GN (44%) on dialysis died. The most common cause of death in both groups was cardiovascular disease (32% MPGN vs. 33% all other GN; Additional file 1: Table S3). In patients who underwent kidney transplantation, 37 patients with MPGN (19%) and 761 patients with all other GN died (14%; Additional file 1: Table S4). The most common cause of death in patients with MPGN was infection (32%) and in patients with all other GN cancer (26%).

The proportion of patients who received a kidney transplant was comparable amongst patients with MPGN (41.7%) and all other GN (43.6%; Table 2). Patients with MPGN who received a kidney transplant were more likely to be Maori or Pacific Islander (11% vs. 5%, respectively), and to have a positive Hepatitis C antibody (8% vs. 1%, respectively; Table 2).

Rates of kidney function recovery after commencing dialysis were similar between the two groups (3.2% for MPGN vs 2.3% for all other GN, p = 0.27). Using multivariable Cox proportional hazards model analysis, there was also no difference in recovery rates for patients with MPGN compared to patients with all other GN (Hazard Ratio [HR] 1.36, 95% confidence interval [CI] 0.79–2.35, p = 0.26, Additional file 1: Table S5).

Median duration from dialysis initiation to kidney transplantation was similar between the two groups (3.0 years for MPGN vs. 2.9 years for all other GN, p = 0.28; Additional file 1: Figure S4). Compared with kidney transplant patients with all other GN as their primary kidney disease, those with MPGN had higher rates of biopsy proven disease recurrence (18% vs. 5%, p = < 0.01). Recurrence rates were not significantly different across various ethnicities or for hepatitis C antibody status (Additional file 1: Tables S6 and S7). Rates of recurrence were similar for living vs. deceased donor (Additional file 1: Table S8). Rate of recurrence in patients with MPGN who received a pre-emptive kidney transplant recipients did not differ significantly (13%) compared to those who received a transplant once on dialysis (18%, p = 0.89).

Recurrence was the second most common cause of kidney allograft loss in patients with MPGN (32%) and the sixth most common cause in patients with all other GN (6%; Additional file 1: Table S9). In patients with MPGN who had allograft loss, the median time to allograft loss was significantly shorter in patients with MPGN recurrence (3.2 years, IQR 2.1–4.3 years) compared to patients with any other cause of allograft loss (4.4 years, IQR 1.8–7.0, p < 0.01). Five-year allograft survival rates were also significantly lower in patients with MPGN who had allograft loss due to disease recurrence compared to MPGN patients with allograft loss from any other cause (5% vs. 43%, p < 0.01; Fig. 1).

For each patient with MPGN, one patient with ESKD from all other GN was matched using PS matching for both dialysis and transplant patients. The characteristics of these matched cohorts were well balanced (standardized mean difference < 0.1 for all variables used for matching; Tables 1 and 2; Additional file 1: Tables S10 and S11, Figures S2 and S3). Patient survival on dialysis, following kidney transplantation, allograft survival and death censored allograft survival were analyzed in the matched cohort only.

Five-year survival on dialysis was 59% for patients with MPGN compared with 62% for patients with all other GN (p = 0.61; Fig. 2). Using multivariable Cox proportional hazards model analysis, patient survival on dialysis was not significantly different between patients with MPGN and those with all other GN (HR 1.03, 95% CI 0.85–1.27, p = 0.80; Table 3). Similar results were observed using competing risk regression analysis (Sub Hazard Ratio [SHR] 1.03, 95% CI 0.83 vs 1.17, p = 0.87; Additional file 1: Table S12).

Five-year patient survival following kidney transplantation was 93% in both MPGN and all other GN patients (p = 0.49; Fig. 3). Using multivariable Cox proportional hazards model analysis, patient survival was not significantly different between patients with MPGN and those with all other GN (HR 0.61, 95% CI 0.29–1.26, p = 0.18; Table 4). Similar findings were observed with competing risks analysis (SHR 0.61, 95% CI 0.33–1.1, p = 0.17; Additional file 1: Table S13).

During the study, kidney allograft loss occurred in 65 (34%) patients with ESKD due to MPGN and 934 (31%) patients with ESKD due to all other GN (p = 0.34). The most common cause of allograft loss for both groups was chronic allograft nephropathy (35% for MPGN and 53% for all other GN). Five-year allograft survival was 70% for patients with MGPN and 81% for patients with all other GN (p = 0.02; Fig. 4). Using multivariable Cox regression, allograft failure occurred significantly more frequently in patients with MPGN than in those with all other GN (HR 1.46, 95% CI 1.02–2.09, p < 0.01; Additional file 1: Table S14).

Five-year death censored allograft survival was also lower for patients with MPGN compared to patients with all other GN (74% vs. 87%, respectively, p < 0.01). Similar results were observed with Cox regression (HR 1.91, 95% CI 1.24–2.94, p < 0.01; Additional file 1: Table S15) and competing risks analysis (SHR 1.76, 95% CI 1.23–2.54, p = 0.01; Additional file 1: Table S16).