Kidney transplantation in children and adolescents with C3 glomerulopathy or immune complex membranoproliferative glomerulonephritis: a real-world study within the CERTAIN research network.

BACKGROUND: Complement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare chronic kidney diseases with an overall poor prognosis, with approximately 40-50% of patients progressing to kidney failure within 10 years of diagnosis. C3G is characterized by a high rate of disease recurrence in the transplanted kidney. However, there is a lack of published data on clinical outcomes in the pediatric population following transplantation. METHODS: In this multicenter longitudinal cohort study of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, we compared the post-transplant outcomes of pediatric patients with C3G (n = 17) or IC-MPGN (n = 3) with a matched case-control group (n = 20). RESULTS: Eleven of 20 children (55%) with C3G or IC-MPGN experienced a recurrence within 5 years post-transplant. Patients with C3G or IC-MPGN had a 5-year graft survival of 61.4%, which was significantly (P = 0.029) lower than the 5-year graft survival of 90% in controls; five patients with C3G or IC-MPGN lost their graft due to recurrence during this observation period. Both the 1-year (20%) and the 5-year (42%) rates of biopsy-proven acute rejection episodes were comparable between patients and controls. Complement-targeted therapy with eculizumab, either as prophylaxis or treatment, did not appear to be effective. CONCLUSIONS: These data in pediatric patients with C3G or IC-MPGN show a high risk of post-transplant disease recurrence (55%) and a significantly lower 5-year graft survival compared to matched controls with other primary kidney diseases. These data underscore the need for post-transplant patients for effective and specific therapies that target the underlying disease mechanism.

Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy.

Introduction: Complement 3 glomerulopathy (C3G) is a rare inflammatory kidney disease mediated by dysregulation of the alternative complement pathway. No targeted therapy exists for this aggressive glomerulonephritis. Efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) (measured by complement biomarkers) of iptacopan were assessed in patients with C3G. Methods: In this phase 2, multicenter, open-label, single-arm, nonrandomized study, adults with biopsy-proven, native kidney C3G (native cohort) and kidney transplant recipients with C3G recurrence (recurrent kidney transplant [KT] cohort) received iptacopan twice daily (bid) for 84 days (days 1-21: 10-100 mg; days 22-84: 200 mg). The primary end point was the urine protein-to-creatinine ratio (UPCR; native cohort) and the change in the C3 deposit score of kidney biopsy (recurrent KT cohort). The complement pathway measures included Wieslab assay, soluble C5b9, and serum C3 levels. Results: A total of 27 patients (16 native cohort and 11 recurrent KT cohort) were enrolled and all completed the study. In the native cohort, UPCR levels decreased by 45% from baseline to week 12 (P = 0.0003). In the recurrent KT cohort, the median C3 deposit score decreased by 2.50 (scale: 0-12) on day 84 versus baseline (P = 0.03). Serum C3 levels were normalized in most patients; complement hyperactivity observed pretreatment was reduced. Severe adverse events (AEs) included post-biopsy hematuria and hyperkalemia. No deaths occurred during the study. Conclusion: Iptacopan resulted in statistically significant and clinically important reductions in UPCR and normalization of serum C3 levels in the native cohort and reduced C3 deposit scores in the recurrent KT cohort with favorable safety and tolerability. (ClinicalTrials.gov identifier: NCT03832114).

Expert Discussion on Challenges in C3G Diagnosis: A Podcast Article on Best Practices in Kidney Biopsies.

Complement 3 glomerulopathy (C3G) is an ultra-rare, progressive kidney disease resulting from dysregulation of the alternative complement pathway. Clinical presentation of C3G is heterogeneous and definitive diagnosis relies on kidney biopsy and immunofluorescence staining. The term C3G encompasses two subgroups, dense deposit disease and C3 glomerulonephritis, distinguished via electron microscopy. In this podcast article, the authors discuss the challenges associated with C3G diagnosis and the central role of kidney biopsy. Using an illustrative case study, key histological observations are described, and best practices are discussed from the perspectives of a nephrologist and a nephropathologist. Podcast Audio (MP4 141866 KB).

Selective Binding of Heparin/Heparan Sulfate Oligosaccharides to Factor H and Factor H-Related Proteins: Therapeutic Potential for C3 Glomerulopathies.

Complement dysregulation is characteristic of the renal diseases atypical hemolytic uremic syndrome (aHUS) and complement component 3 glomerulopathy (C3G). Complement regulatory protein Factor H (FH) inhibits complement activity, whereas FH-related proteins (FHRs) lack a complement regulatory domain. FH and FHRs compete for binding to host cell glycans, in particular heparan sulfates (HS). HS is a glycosaminoglycan with an immense structural variability, where distinct sulfation patterns mediate specific binding of proteins. Mutations in FH, FHRs, or an altered glomerular HS structure may disturb the FH : FHRs balance on glomerular endothelial cells, thereby leading to complement activation and the subsequent development of aHUS/C3G. In this study, we aimed to identify specific HS structures that could specifically compete off FHRs from HS glycocalyx (HSGlx), without interfering with FH binding. FH/FHR binding to human conditionally immortalized glomerular endothelial cells (ciGEnCs) and HSGlx purified from ciGEnC glycocalyx was assessed. HS modifications important for FH/FHR binding to HSGlx were analyzed using selectively desulfated heparins in competition with purified HSGlx. We further assessed effects of heparinoids on FHR1- and FHR5-mediated C3b deposition on ciGEnCs. In the presence of C3b, binding of FH, FHR1 and FHR5 to ciGEnCs was significantly increased, whereas binding of FHR2 was minimal. FHR1 and 5 competitively inhibited FH binding to HSGlx, leading to alternative pathway dysregulation. FHR1 and FHR5 binding was primarily mediated by N-sulfation while FH binding depended on N-, 2-O- and 6-O-sulfation. Addition of 2-O-desulfated heparin significantly reduced FHR1- and FHR5-mediated C3b deposition on ciGEnCs. We identify 2-O-desulfated heparin derivatives as potential therapeutics for C3G and other diseases with dysregulated complement.

C3 glomerulopathy and atypical hemolytic uremic syndrome: an updated review of the literature on alternative complement pathway disorders.

The complement system plays a significant role within the pathological process of C3 glomerulopathy (C3GP) and atypical hemolytic uremic syndrome (aHUS). In daily practice, clinicians should differentiate the subgroups of C3GP because of they should apply different treatment modalities. In the past, C3GP was considered as a part of membranoproliferative glomerulonephritis (MPGN). MPGN is defined as glomerular capillary thickening secondary to the synthesis of the new glomerular basement membrane and mesangial cellular hyperplasia with mesangial matrix expansion. Atypical hemolytic uremic syndrome is an ultra-rare disease that can be outlined by the triad of Coombs negative microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Recent advances demonstrated that these diseases share common abnormalities of the control of the alternative complement system. Therefore, nowadays, most researchers advocate that there may be overlap in the pathogenesis of C3GP and aHUS. This review will provide recent novel mechanisms and treatment options in these diseases. For the purposes that we mentioned above and to help clinicians, we aimed to describe the etiology, pathophysiology, and treatment of C3GP and aHUS in this comprehensive review.

Multimodal imaging of retinal pigment epithelial detachments in patients with C3 glomerulopathy: case report and review of the literature.

BACKGROUND: To describe the optical coherence tomography angiograhy (OCTA) of drusenoid pigment epithelial detachments (PEDs) in a woman affected by Complement 3 (C3) glomerulopathy, which represents a spectrum of glomerular diseases characterized on fluorescent microscopy by C3 accumulation with absent, or scanty, immunoglobulin deposits. It is due to acquired or genetically defective alternative pathway control and is generally associated with drusen-like deposits in Bruch's membrane, as well as choriocapillaris. These retinal lesions can be associated with choroidal neovascularization and central serous chorioretinopathy (CSCR). OCTA is useful to detect neovascularization without injecting a contrast product, particularly in these patients who may have renal insufficiency. CASE PRESENTATION: A 28-year-old woman affected by C3 glomerulpathy was diagnosed with asymptomatic multiple bilateral PEDs during a routine ophthalmologic consultation. To better characterize the lesions, multimodal imaging was performed and included: optic coherence tomography (OCT), en-face OCT, OCTA, fluorescence and indocyanine angiography. The OCTA clearly identified vascular network rarefaction with decreased choriocapillary vascularization. It confirmed that PEDs associated with C3 glomerulonephritis are not vascularized, but rather of serous type. CONCLUSIONS: Patients affected by C3 glomerulopathy can develop neovascular membranes as retinal complications of pigment epithelial detachments. Optical coherence angiography may be indicated to identify this complication, without injecting any contrast product that could produce further kidney damage.