Primary membranoproliferative glomerulonephritis (MPGN) is an ultrarare disease characterized by immunofluorescence microscopy as either immune-complex mediated (IC-MPGN) or C3 glomerulopathy (C3), the latter subdivided by electron microscopy to C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Both IC-MPGN and C3G typically have obvious C3 staining differentiating them from other causes of MPGN histology. Secondary causes must be excluded, including infections, autoimmune disease, and neoplasia. Clinical presentations are variable, including urinary sediment abnormalities, nephrotic syndrome, or a rapidly progressive course. The prognosis is unfavorable with about 50% reaching kidney failure by 10 years. Recurrence following transplantation is frequent, and allograft survival is shortened. The pathogenesis involves dysregulation of the alternate pathway (AP) of complement. Possibly 20% of patients harbor pathogenic mutations in AP proteins or their regulators, and up to 80% have autoantibodies impairing normal regulation. Paraproteins are found in 20 - 40% of otherwise primary MPGN, either directly detectable on biopsy (IC-MPGN) or as dysregulators of the AP. Therapy of MPGN begins with supportive care as for all glomerulopathies. Paraproteins require clone-directed therapy. When immunosuppression is considered, complement inhibition should be first line. Two agents are now FDA approved for C3G, the oral Factor B inhibitor iptacopan and the subcutaneous C3-inhibitor pegcetacoplan, the latter also approved for IC-MPGN. If complement inhibition is unavailable, MMF/steroids may be considered. Following transplantation, protocol biopsies are needed to detect early recurrence with the intent of complement inhibition.

Primary membranoproliferative glomerulonephritis (MPGN) is a rare progressive kidney disease that often leads to end-stage kidney disease. Our previous nationwide registry study (Report 1, 2015-2018) characterized initial demographics and treatment patterns. In this study (Report 2), we aimed to update these findings, focusing on newly registered cases (2017-2021). Personal clinical records of patients with primary MPGN between 2017 and 2021 were obtained from the national registry organized by the Japanese Ministry of Health, Labour and Welfare. Characteristics of primary MPGN throughout Japan were investigated. A total of 210 patients (median age, 49 years; male, 51%) with newly registered primary MPGN were identified. Nephrotic syndrome was present in 83.8% of patients at enrollment. Initial treatment frequently included corticosteroids (63.8%), with a modest increase in intravenous methylprednisolone pulse therapy (41.4%) compared with that in Report 1. The incidence of hemodialysis was 7.1%. Compared with those in Report 1, the demographic patterns were similar; however, nephrotic presentations were more common. Cyclosporine and mizoribine usage were significantly higher in the pediatric group (< 18 years, n = 44) compared to the corresponding usage in the older adult group (≥ 65 years, n = 75). The mean dosage of oral prednisolone and other immunosuppressants during initial treatment did not differ among the four age groups. Compared with the earlier report (Report 1), patients with newly registered primary MPGN presented with nephrotic syndrome more often, highlighting the continued risk of poor prognosis and the need for more refined therapeutic approaches.

In primary membranoproliferative glomerulonephritis (MPGN), mesangial and capillary proliferation manifests as a diffuse, spherical change; in secondary MPGN, lesions are predominantly focal and segmental. A 52-year-old woman with a 2-year history of primary Sjögren's Syndrome (pSS) and no prior renal involvement developed fever, nephrotic syndrome, and acute kidney injury with oliguria after a pulmonary infection. Her highest recorded serum creatinine level was 327.3 µmol/L, and the lowest serum albumin level was 22.1 g/L. Laboratory findings included an antinuclear antibody titer of 1:320, anti-SSA/52KD antibody positivity, complement C3 of 0.468 g/L, complement C4 of 0.0107 g/L, and rheumatoid factor (RF) 678 IU/mL. The highest 24-hour urinary protein quantification reached 9.78 g/24h. After anti-infective treatment, urine output gradually increased, and edema resolved. Cryoglobulin testing showed type II cryoglobulin positivity. Light microscopy revealed MPGN-like lesions in 66.7% of glomeruli and mesangial proliferative glomerulonephritis-like lesions in 25%. Final diagnosis was MPGN. Cyclophosphamide and methylprednisolone were administered. After 30 months follow-up, the patient's serum creatinine level was 82.1 µmol/L; proteinuria was negative. This case represents the first reported instance of non-diffuse MPGN with cryoglobulinemic GN secondary to pSS. Infection may serve as a key factor in exacerbating cryoglobulinemia and triggering cryoglobulinemic GN onset.

Nowadays, there is insufficient evidence for the recommendation of management patients with a primary membranoproliferative glomerulonephritis (MPGN). A better understanding of the pathogenesis has led to the reclassification of primary MPGN and distinction into the two main entities of either primary immune complex-MPGN or C3 glomerulopathy. Both entities share overlapping pathophysiological features with complement alternative pathway (AP) dysregulation. Iptacopan is an oral inhibitor of the complement factor B that effectively blocks the complement AP. We report the first successful treatment of a 47-year-old man suffering from a primary immune complex-MPGN with iptacopan. So far established immunosuppressive therapies with prednisone and mycophenolate mofetil failed to control the current flare of the disease, mainly presenting with impaired kidney function and proteinuria within the nephrotic range. However, 3 months after starting the treatment with iptacopan urine protein-creatinine ratio decreased impressively to a level of 100-150 mg/mmol. Thereafter, low-level proteinuria and kidney function remained stable during follow-up. Do date, the treatment with iptacopan is continued as a monotherapy and is well tolerated. To the best of our knowledge, this is the first case report which suggests that iptacopan may be an interesting treatment option for primary immune complex-MPGN.

Primary membranoproliferative glomerulonephritis (MPGN) is a rare kidney disease with poor prognosis and no specific therapies. The disease heterogeneity and the difficulty of performing repeated kidney biopsies pose big challenges. This study investigates the correlation between non-contrast enhanced magnetic resonance imaging (MRI) and histologic and clinical findings in patients with primary MPGN. Patients with primary MPGN underwent baseline and 1-year kidney MRI in addition to biopsy and laboratory testing as part of a prospective MRI subproject of a clinical trial (<ext-link ext-link-type="uri" xlink:href="http://ClinicalTrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">ClinicalTrials.gov</ext-link> identifier NCT03723512). Diffusion-weighted and phase-contrast MRI were used to investigate kidney diffusivity and perfusion. Peritubular interstitial volume and fibrosis were quantified on kidney biopsies. Seven patients with primary MPGN (18[17-21] years, 43% females) were included. Kidney biopsies showed variable degree of global and segmental glomerular sclerosis ([5-30]% and [10-60]%), mild interstitial fibrosis (&lt;10%), and increased peritubular interstitial volume ([19-40]%). MRI and laboratory parameters changed very differently from patient to patient over 1 year. Peritubular interstitial volume and glomerular sclerosis negatively associated with renal blood flow (RBF) (rho = -0.81 and -0.77), and positively with renal vascular resistance (RVR) (rho = 0.65 and 0.73). Urinary albumin to creatinine ratio (uACR) negatively associated with RBF and filtration fraction (FF) (rho = -0.86 and -0.6), while positively with RVR (rho = 0.88). uACR decrease was associated with kidney diffusivity increase (rho = -0.5). Measured glomerular filtration rate (GFR) positively associated with kidney diffusivity, RBF, and FF (rho = 0.87, 0.85, and 0.59), while negatively with RVR (rho = -0.89); GFR increase was associated with kidney diffusivity, RBF, and FF increase (rho = 0.77, 0.7, and 0.7) and RVR decrease (rho = -0.7). The strong correlation found between MRI and histologic and clinical findings, despite the rather limited number of patients, highlights MRI potential to monitor disease progression in patients with rare kidney disease.