Membranoproliferative Glomerulonephritis over 20 Years at a Tertiary Referral Center in the UK

Membranoproliferative glomerulonephritis (MPGN) is a histological pattern of injury found on kidney biopsy. It is named because of the classical appearance of mesangial hypercellularity and thickening of the glomerular basement membrane. Internationally, it accounts for between 1 and 3% of kidney biopsy diagnoses [1]. Traditionally, MPGN was classified as type I, II, and III based on the appearances on electron microscopy [2]. The modern classification is based instead on immunofluorescence findings and related to the underlying pathogenesis [3‒7]. This has reclassified MPGN into three main categories: immune complex-mediated MPGN (IC MPGN), complement-mediated MPGN, and an MPGN pattern negative for immune complexes and complement [3‒7]. IC MPGN is caused by the deposition of immune complexes or by circulating immunoglobulins and can be seen with chronic infections, autoimmune disease, and monoclonal gammopathies [7, 8]. The less common complement-mediated MPGN is predominantly accounted for by C3 glomerulopathy (C3G), although there is also the rarer entity of C4 glomerulopathy. C3G is caused by dysregulation and persistent activation of the alternative complement pathway, which can be caused by inherited or acquired defects, and is further subdivided into C3 glomerulonephritis (C3GN) and dense deposit disease (DDD) [7, 9]. As the name indicates, C3Gs are characterized by dominant staining for C3 and must be immunoglobulin negative [9, 10]. DDD is distinct from C3GN with a characteristic electron microscopy appearance, with the presence of electron-dense sausage-shaped deposits along the glomerular basement membrane and mesangium [9]. An MPGN pattern which is negative for immune complexes or complement is mostly attributable to an underlying thrombotic microangiopathy.

Presentations are typical of glomerulonephritis, with varying degrees of hematuria and proteinuria. Approximately a third of patients are reported as presenting with nephrotic syndrome [11, 12]. Hypocomplementemia is not always present and may be seen in MPGN regardless of the classification. The prognosis is variable, with the degree of proteinuria and kidney function at presentation, and biopsy chronicity associated with poorer outcomes [12, 13]. The finding of MPGN necessitates investigation for underlying etiologies including infection, autoimmune disease, monoclonal gammopathy, and malignancy. Due to the heterogenous nature and relative rarity of the conditions, clinical trials have been difficult, but a number are ongoing. Best supportive kidney care is the cornerstone of all conditions, including the use of RAAS inhibition. An individualized approach should be adopted thereafter depending on the determined underlying etiology. Immunosuppression is often utilized, particularly in C3G, with evidence to date including for the use of steroids and mycophenolate mofetil, and complement inhibition, and further studies ongoing [5, 14‒16].

Longitudinal retrospective data have been published from cohorts with C3G, including in the USA from the Mayo Clinic and Columbia and the Spanish group for the study of glomerular disease in Europe and recently of MPGN in a large North American Pediatric cohort [11‒13, 17, 18]. Our study presents long-term real-world data on MPGN from the UK, describing the epidemiology, treatments, and outcomes of all biopsy cases of MPGN at our renal center over a 20-year period.

Salford Royal Hospital, Northern Care Alliance (NCA) NHS Foundation Trust, UK, is a tertiary renal center serving a catchment population of 1.55 million. This study presents a review of over 20 years of biopsy data from January 2000 through to December 2020, conducted using the organization’s biopsy database and electronic patient record. All patients with an MPGN pattern on kidney biopsy were included. Patients with new MPGN posttransplant, MPGN documented on biopsy based on the old classification but subsequently diagnosed as IgA, and those with an MPGN pattern but a known lupus diagnosis were excluded. Data collected included patient demographics, details of the renal histology from the kidney biopsy, baseline laboratory results, treatments received, and clinical outcomes including renal replacement therapy (RRT) and death. The pathology reports of all patients were reviewed in detail, as well as the patient records and laboratory results to ensure accurate diagnosis and attribution of underlying causes. Proteinuria measurements were using spot urine protein:creatinine ratio (uPCR), measured as mg/mmol.

Analyses were performed using IBM SPSS software registered with the University of Manchester. In the descriptive part of the analysis, continuous variables were expressed as median and interquartile range after checking for normality of the distribution, with between-group differences (IC MPGN and C3G) tested using Mann-Whitney U test. Categorical variables were expressed as number and percentage and p values obtained by Fisher’s exact test. Kaplan-Meier charts were used to demonstrate the survival difference between the groups. A p value of <0.05 was taken as being statistically significant throughout the analysis.

This study was registered with the NCA research and innovation committee (ID: 22HIP13). As a retrospective observational study with complete anonymization of patient details, the need for individual consent was waived by the committee. There were no data protection or ethical concerns.

Figure 1 shows patient inclusion in the study. We identified 67 patients with a histological finding of MPGN on kidney biopsy. Of these, 41 remained following application of the exclusion criteria. Of the 41 remaining, 28 had IC MPGN, 10 had C3G (8 with C3GN and 2 with DDD), and 3 were of unknown classification due to insufficient available information.

Baseline features of the overall cohort, and the IC MPGN and C3G subgroups are presented in Table 1. The overall median age was 61 years, and the majority of patients were female (60.5%) and white (92.1%). At presentation, median creatinine was 164 μmol/L, estimated glomerular filtration rate 31.5 mL/min/1.73 m², and uPCR 394 mg/mmol. Median follow-up was 72 months (range 45–126), with no significant difference in follow-up between the IC MPGN and C3G groups. Nephrotic range proteinuria was the presenting feature in 14/28 (50%) patients with IC MPGN and 7/10 (70%) patients with C3G. C3 and C4 levels were reduced in 12 patients (29.3%) and 8 patients (19.5%), respectively.

MPGN was associated with infections in 8 patients (19.5%), connective tissue disease in 3 patients (7.3%), monoclonal gammopathies or hematological malignancies in 8 patients (19.5%), and 2 had identified complement deficiencies (4.9%). In the IC MPGN group, 2 patients had lymphoma, 3 had leukemia, 1 had light chain disease, 2 had hepatitis C, 4 were attributed to other infection, 2 had lupus nephritis, 1 had mixed connective tissue disease, 1 had C4 deficiency, 1 had a factor H and factor I deficiency, and the remaining 11 did not have an identified etiology. In the C3G group, 2 patients had leukemia, 1 patient had tuberculosis, and 1 patient had hepatitis C.

The medical therapies utilized are summarized in Table 2. Overall, 78.9% received renin-angiotensin-aldosterone system inhibitors and 71.1% received any immunosuppression, of whom 51.7% received more than one immunosuppressive agent. The most common agent was prednisolone, received by 31.7% of patients, and the most common combination was that of mycophenolate mofetil and prednisolone. No eculizumab or other complement inhibitors were used in these patients during this period.

Outcomes are presented in Table 3. Median follow-up was 72 (range 45–126) months. Over the study period, 47.4% progressed to end-stage kidney disease (ESKD), and at the end of the study, 50% of the population were alive. Progression to ESKD requiring RRT was seen in 42.9% of the IC MPGN group and 60% of the C3G group. This includes 2 patients who received a kidney transplant (both in the C3G group), one of which developed recurrence during the available follow-up. Totally, 53.6% of the IC MPGN group and 40% of the C3G group died during the study period. Kaplan-Meier curves of overall survival and survival without RRT are presented in Figure 2.

There was no difference in renal function (estimated glomerular filtration rate) at the beginning or end of the study period in either group (Fig. 3a) (p = 0.94 C3G, p = 0.53 IC MPGN). There was no difference between the starting proteinuria (uPCR) and proteinuria at the end of follow-up in the C3G group (p = 0.45), but there was a significant difference in the IC MPGN group (p = 0.006).

Given the relative rarity of the conditions, this study adds to the literature by presenting the real-world experience of MPGN in a tertiary center in the UK. This study describes the demographics, associated conditions, treatments, and outcomes of 38 patients with MPGN from 2000 to 2020 with a median follow-up of over 5 years. C3G accounted for approximately one-quarter of the MPGN cases, with C3GN being 4 times more common than DDD reflecting the literature [11, 19]. The study found an older patient population (median age 61 years) than is typically reported, and particularly in contrast to a previous publication from the UK and Ireland on C3G where the median age was 21 years [19]. It also found a predominantly white ethnic cohort despite the ethnically diverse population of the NCA catchment area and which reflects what has been reported elsewhere. A total of 50% of patients had nephrotic range proteinuria at presentation, and significant renal impairment was also common at presentation with a median creatinine of 164 μmol/L, with no significant difference between the IC MPGN or C3G groups. As would be expected, a variety of associated conditions were found, with the most common triggers identified including infection and the presence of a hematological malignancy or monoclonal gammopathy, each accounting for 19.5% of cases. Poor outcomes were observed in the overall cohort with progression to ESKD and mortality both at almost 50%. This may be influenced by the older patient population in this study.

High rates of supportive treatment were seen, with 78.9% taking RAAS blockade. High rates of immunosuppression use were also seen in both subgroups: 75% in the IC MPGN subgroup and 60% in the C3G group. Prednisolone was the most frequently used immunosuppressant agent in both groups (31.7%), with the combination therapy of prednisolone and mycophenolate mofetil seen in 24.4% of patients. Low numbers of diagnoses of complement abnormalities were identified, and no patients received eculizumab, likely representing the historical nature of this review. Significantly reduced proteinuria was seen in the IC MPGN group at the end of follow-up despite similar rates of RAAS inhibitors and immunosuppression to the C3G group, although this may reflect survivor bias.

Limitations include those of a retrospective observational study, as well as the small numbers. Given this study design, the results may not be generalizable to a broader population and there is a risk of selection bias. Additionally, the change in the classification and management of MPGN over the period of the study may mean there are cases which are unaccounted for, or where there was under-appreciation of complement abnormalities or monoclonal gammopathies as the cause of MPGN earlier in the study timeframe.

This paper provides an updated UK perspective on real-world MPGN management and outcomes, albeit in a single center. The UK and Irish perspective was last reported by Medjeral-Thomas and colleagues [19] a decade ago. Unfortunately, the outcomes of patients in this study do not show an improvement. There is hope that new treatments on the horizon, such as the early results with iptacopan [20, 21], will deliver improvements in care and outcomes for these patients.

Individualized management of patients with an MPGN biopsy finding is paramount, with comprehensive evaluation for triggers and complement abnormalities required. Going forward, registry enrolment and collaborative studies such as has been seen in other rare kidney diseases may increase the growing evidence base to inform management of patients with IC MPGN and C3G.

This study protocol was reviewed and approved by the Northern Care Alliance (NCA) Research and Innovation Committee, Approval No. 22HIP13. As a retrospective observational study which was fully anonymized and using data routinely collected as part of patient care, full research ethics approval was deemed not required by this committee in accordance with local and national guidance. The need for individual patient consent was waived by the Research and Innovation Committee of the NCA.

S.S. has received honoraria from AstraZeneca, Bayer, Sanofi-Genzyme, Novartis, CSL Vifor, GSK, Menarini, and Boehringer Ingelheim. PK has received honoraria from AstraZeneca, Bayer, Lilly, Napp, Novartis, CSL Vifor, Pharmacosmos, and Boehringer Ingelheim, has participated in advisory boards and clinical consultancy for Astellas, AstraZeneca, Bayer, Otsuka, Unicyte, and CSL Vifor, and has received grants from Astellas, Vifor, BerGenBio, and Evotec. CC has received honoraria from Boyer and Sanofi-Genzyme. H.O.K., J.S., C.R., and S.M. have no conflicts of interest to declare. None of these have been related to this study or had any impact on its writing or results.

This study received no funding support.

Data curation: H.O.K., J.S., C.R., and S.M. Formal analysis: H.O.K. and R.C. Methodology: H.O.K., J.S., R.C., and S.S. Supervision: C.C., R.C., S.S., and P.A.K. Writing – original draft: H.O.K. Writing – review and editing: all authors.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.