Recurrent C3 glomerulopathy after kidney transplantation.

The complement system is part of innate immunity and is pivotal in protecting the body against pathogens and maintaining host homeostasis. Activation of the complement system is triggered through multiple pathways, including antibody deposition, a mannan-binding lectin, or activated complement deposition. C3 glomerulopathy (C3G) is a rare glomerular disease driven by complement dysregulation with high post-transplantation recurrence rates. Its treatment is mainly based on immunosuppressive therapies, specifically mycophenolate mofetil and glucocorticoids. Recent years have seen significant progress in understanding complement biology and its role in C3G pathophysiology. New complement-tergeting treatments have been developed and initial trials have shown promising results. However, challenges persist in C3G, with recurrent post-transplantation cases leading to suboptimal outcomes. This review discusses the pathophysiology and management of C3G, with a focus on its recurrence after kidney transplantation.

Manejo de glomerulonefritis membranoproliferativa secundaria a infección por virus de hepatitis C / Management of membranoproliferative glomerulonephritis secondary to infection by hepatitis C virus

Las glomerulonefritis membranoproliferativas son ne-fropatías glomerulares poco frecuentes cuya prevalencia ha disminuido en nuestro medio. Presentan una histología característica y pueden asociarse a diferentes enfermeda-des. La presentación clínica es variada y su diagnóstico de-finitivo requiere realizar una biopsia renal. El tratamiento viene condicionado por la enfermedad de base, tratándose con inmunosupresores cuando existe una disminución del filtrado glomerular.Presentamos el caso de una mujer de 47 años con glo-merulonefritis membranoproliferativa secundaria a infec-ción por de virus de hepatitis C para describir el manejo de este tipo de pacientes, dado que se trata de una patología con una baja prevalencia (AU)

Membranoproliferative glomerulonephritis is an un-common condition that affects the glomeruli of the kid-neys; its prevalence has decreased in our environment. Membranoproliferative glomerulonephritis has a charac-teristic histology that can be associated to different diseas-es. The clinical presentation varies, and to achieve a defin-itive diagnosis a renal biopsy must be done. Treatment is based on the underlying disease; when a drop in glomer-ular filtration rate is detected, immunosuppressants are prescribed.We describe the management of a 47-year-old female with membranoproliferative glomerulonephritis second-ary to hepatitis C virus infection, a condition with very low prevalence (AU)

[Management of membranoproliferative glomerulonephritis secondary to infection by hepatitis C virus].

Membranoproliferative glomerulonephritis is an uncommon condition that affects the glomeruli of the kidneys; its prevalence has decreased in our environment. Membranoproliferative glomerulonephritis has a characteristic histology that can be associated to different diseases. The clinical presentation varies, and to achieve a definitive diagnosis a renal biopsy must be done. Treatment is based on the underlying disease; when a drop in glomerular filtration rate is detected, immunosuppressants are prescribed. We describe the management of a 47-year-old female with membranoproliferative glomerulonephritis secondary to hepatitis C virus infection, a condition with very low prevalence.

[Diagnosis and treatment of glomerular diseases with a membranoproliferative glomerulonephritis (MPGN) pattern of injury]. / Diagnose und Therapie glomerulärer Erkrankungen mit einem membranoproliferativen Läsionsmuster (MPGN) ­ 2023.

Membranoproliferative glomerulonephritis (MPGN) represents a heterogeneous group of diseases. The common feature of a membranoproliferative lesion pattern in the kidney biopsy can either be idiopathic/primary or-much more frequently-have a secondary cause. The historical classification into MPGN types I to III has largely been abandoned and replaced in recent years by a pathogenesis-oriented classification. A MPGN with C1q, C3 and/or C4 deposits on light microscopy is referred to as immune complex GN (IC-GN), while a MPGN with dominant C3 deposits is referred to as C3 glomerulopathy (C3G). C3G is further divided into C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). These diagnoses can only be made by a kidney biopsy. Possible causes of MPGN are chronic infections (especially hepatitis B and C, bacterial infections, infections with protozoa), autoimmune diseases (especially lupus, rheumatoid arthritis) or malignancies (especially hematological malignancies). Particularly in the case of C3G a comprehensive analysis of the complement system components is strongly recommended. Due to the low incidence and the heterogeneous clinical appearance of MPGN therapeutic decisions must be made individually; an optimal general therapy is unknown, except that supportive treatment as with other glomerular diseases should be optimized. In the case of a secondary MPGN it is generally recommended to treat the potential cause of the MPGN. If significant proteinuria persists and eGFR remains > 30 ml/min/1.73 m2, treatment with systemic steroids and mycophenolate mofetil is recommended. Other treatment options on an individual level after evaluation and discussion of the risk-benefit ratio with the patient are rituximab and eculizumab. Rapidly progressive MPGN should be treated like ANCA-associated vasculitis. The recurrence rates after kidney transplantation are very high and treatment is challenging.

Liver factor B silencing to cure C3 glomerulopathy: Evidence from a mouse model of complement dysregulation.

Uncontrolled activation of the alternative pathway (AP) of complement, due to genetic and/or acquired defects, plays a primary pathogenetic role in C3 glomerulopathy (C3G), a rare and heterogeneous disease characterised by predominant C3 fragment deposition within the glomerulus, as well as glomerular damage. There are currently no approved disease-specific treatments for C3G, but new drugs that directly counteract AP dysregulation, targeting components of the pathway, have opened promising new perspectives for managing the disease. Complement factor B (FB), which is primarily synthesised by hepatocytes, is a key component of the AP, as it drives the central amplification loop of the complement system. In this study we used a GalNAc (N-Acetylgalactosamine)-conjugated siRNA to selectively target and suppress liver FB expression in two mouse models characterised by the complete (Cfh-/- mice) or partial (Cfh+/-) loss of function of complement factor H (FH). Homozygous deletion of FH induced a severe C3G phenotype, with strong dysregulation of the AP of complement, glomerular C3 deposition and almost complete C3 consumption. Mice with a heterozygous deletion of FH had intermediate C3 levels and exhibited slower disease progression, resembling human C3G more closely. Here we showed that FB siRNA treatment did not improve serum C3 levels, nor limit glomerular C3 deposition in Cfh-/- mice, while it did normalise circulating C3 levels, reduce glomerular C3 deposits, and limit mesangial electron-dense deposits in Cfh+/- mice. The present data provide important insights into the potential benefits and limitations of FB-targeted inhibition strategies and suggest RNA interference-mediated FB silencing in the liver as a possible therapeutic approach for treating C3G patients with FH haploinsufficiency.

Poor outcomes of proliferative glomerulonephritis with monoclonal IgG deposits in renal allografts: a retrospective multicenter study.

BACKGROUND: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) in renal allografts is a rare, renal-limited disease. No study has reported the long-term outcomes and prognostic features of PGNMID in renal allografts in the Chinese population. METHODS: We retrospectively included transplant patients diagnosed with PGNMID who underwent renal allograft biopsy at three transplant centers from April 2012 to July 2020. We observed the clinicopathologic features, explored the long-term graft survival, and investigated the characteristics associated with the prognosis. RESULTS: A total of 13 transplant patients with PGNMID were included, out of 3821 biopsies. The mean follow-up time was 55 months since kidney transplantation (KTx). At diagnosis, all patients presented with proteinuria (100%) and most of them with hematuria (92%). IgG3κ (69%) was the main immunofluorescence (IF) subtype. The median graft survival of the total cohort was 17 months from diagnosis and 49 months from kidney transplantation. During follow-up, 9 patients needed dialysis and 2 out of 9 patients who progressed to dialysis died of infection. Primary membranoproliferative glomerulonephritis (MPGN) (P = 0.014) and MPGN pattern at diagnostic biopsy (P < 0.001) were associated with a higher risk of graft loss. CONCLUSIONS: The long-term outcome of allograft PGNMID was relatively poor in the Chinese population. Primary MPGN and MPGN pattern in renal allograft were associated with  poor outcomes.

Membranoproliferative glomerulonephritis: no longer the same disease and may need very different treatment.

Membranoproliferative glomerulonephritis (MPGN) is a pattern of glomerular injury that may be primary or secondary to infections, autoimmune diseases and haematological disorders. Primary C3G and IC-MPGN are rare and the prognosis is unfavourable. Based on immunofluorescence findings, MPGN has been classified into complement-mediated C3 glomerulopathy (C3G) and immune complex-mediated MPGN (IC-MPGN). However, this classification leaves a number of issues unresolved. The finding of genetic and acquired complement abnormalities in both C3G and IC-MPGN indicates that they represent a heterogeneous spectrum rather than distinct diseases. An unsupervised hierarchical clustering in a cohort of patients with primary C3G and IC-MPGN identified four distinct pathogenetic patterns, characterized by specific histologic and clinical features, and genetic and acquired complement abnormalities. These results provide the groundwork for a more accurate diagnosis and the development of targeted therapies. The drugs that are currently used, such as corticosteroids and immunosuppressants, are frequently ineffective in primary C3G and IC-MPGN. Eculizumab, an anti-C5 monoclonal antibody, has been used occasionally in single cases or small series. However, only a few patients have achieved remission. This heterogeneous response could be related to the extent of terminal complement activation, which may vary substantially from patient to patient. Several drugs that target the complement system at different levels are under investigation for C3G and IC-MPGN. However, clinical trials to test new therapeutics will be challenging and heavily influenced by the heterogeneity of these diseases. This creates the need to characterize each patient to match the specific complement abnormality with the type of intervention.

A Guide for Adult Nephrologists and Hematologists to Managing Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy in Teens Transitioning to Young Adults.

Atypical hemolytic uremic syndrome and C3 glomerulopathy/immune complex membranoproliferative glomerulonephritis are ultra-rare chronic, complement-mediated diseases with childhood manifestation in a majority of cases. Transition of clinical care of patients from pediatric to adult nephrologists-typically with controlled disease in native or transplant kidneys in case of atypical hemolytic uremic syndrome and often with chronic progressive disease despite treatment efforts in case of C3 glomerulopathy/immune complex membranoproliferative glomerulonephritis-identifies a challenging juncture in the journey of these patients. Raising awareness for the vulnerability of this patient cohort; providing education on disease pathophysiology and management including the use of new, high-precision complement antagonists; and establishing an ongoing dialog of patients, families, and all members of the health care team involved on either side of the age divide will be inevitable to ensure optimal patient outcomes and a safe transition of these patients to adulthood.

C3 glomerulopathy: Understanding an ultra-rare complement-mediated renal disease.

C3 glomerulopathy (C3G) describes a pathologic pattern of injury diagnosed by renal biopsy. It is characterized by the dominant deposition of the third component of complement (C3) in the renal glomerulus as resolved by immunofluorescence microscopy. The underlying pathophysiology is driven by dysregulation of the alternative pathway of complement in the fluid-phase and in the glomerular microenvironment. Characterization of clinical features and a targeted evaluation for indices and drivers of complement dysregulation are necessary for optimal patient care. Autoantibodies to the C3 and C5 convertases of complement are the most commonly detected drivers of complement dysregulation, although genetic mutations in complement genes can also be found. Approximately half of patients progress to end-stage renal disease within 10 years of diagnosis, and, while transplantation is a viable option, there is high risk for disease recurrence and allograft failure. This poor outcome reflects the lack of disease-specific therapy for C3G, relegating patients to symptomatic treatment to minimize proteinuria and suppress renal inflammation. Fortunately, the future is bright as several anti-complement drugs are currently in clinical trials.

An Interdisciplinary Diagnostic Approach to Guide Therapy in C3 Glomerulopathy.

Since the re-classification of membranoproliferative glomerulonephritis the new disease entity C3 glomerulopathy is diagnosed if C3 deposition is clearly dominant over immunoglobulins in immunohistochemistry or immunofluorescence. Although this new definition is more orientated at the pathophysiology as mediated by activity of the alternative complement pathway C3 glomerulopathy remains a heterogenous group of disorders. Genetic or autoimmune causes are associated in several but not in all patients with this disease. However, prognosis is poorly predictable, and clinicians cannot directly identify patients that might benefit from therapy. Moreover, therapy may range from supportive care alone, unspecific immune suppression, plasma treatment, or plasma exchange to complement inhibition. The current biopsy based diagnostic approaches sometimes combined with complement profiling are not sufficient to guide clinicians neither (i) whether to treat an individual patient, nor (ii) to choose the best therapy. With this perspective, we propose an interdisciplinary diagnostic approach, including detailed analysis of the kidney biopsy for morphological alterations and immunohistochemical staining, for genetic analyses of complement genes, complement activation patterning in plasma, and furthermore for applying novel approaches for convertase typing and complement profiling directly in renal tissue. Such a combined diagnostic approach was used here for a 42-year-old female patient with a novel mutation in the Factor H gene, C3 glomerulopathy and signs of chronic endothelial damage. We present here an approach that might in future help to guide therapy of renal diseases with relevant complement activation, especially since diverse new anti-complement agents are under clinical investigation.

Clinically Different Presentations of Family Members With the Same Homozygote Diacylglycerol Kinase Epsilon Mutation: Case Report.

Membranoproliferative glomerulonephritis and renal microangiopathies may manifest similar clinical presentations and histology. Many genetic mutations that cause these diseases have been reported. Studies on mutations in the gene encoding diacylglycerol kinase epsilon identified a novel pathophysiologic mechanism leading to atypical hemolytic uremic syndrome and/or membranoproliferative glomerulonephritis. Here, we present the different clinical presentations and treatments in 4 family members who carried the same homozygous diacylglycerol kinase epsilon mutation. The first patient (age 5 years, 3 months old at diagnosis) had nephrotic syndrome. The kidney biopsy was membranoproliferative glomerulonephritis; partial remission was achieved with cyclophosphamide, cyclosporine, and mycophenolate mofetil treatment. The second patient (age 5 years, 7 months at diagnosis) presented with overlapping atypical hemolytic uremic syndrome and membranoproliferative glomerulonephritis. Remission could not be achieved with cyclophosphamide, cyclosporine, and mycophenolate mofetil, and hemodialysis treatment was started. At 10 years from first admission, the patient had end-stage kidney disease, and kidney transplant was performed successfully. The third patient was admitted with the diagnosis of nephrotic syndrome at 13 months of age, kidney biopsy showed membranoproliferative glomerulonephritis, and spontaneous remission developed during followup. He presented with hemolytic uremic syndrome 15 months after the first admission, and dialysis was started. Remission was achieved with plasma infusion and eculizumab treatment. The fourth patient (a 7-month-old boy and brother of patient 3) had no clinical or laboratory findings. All patients had genetic analysis, and mutation in exon 2:c.473G>A(p. W158*) was detected. Our related patients with the same mutation showed different clinical and histological findings. However, we did not observe a clear genotype-phenotype correlation in patients with diacylglycerol kinase epsilon nephropathy, suggesting additional factors mediating phenotypic heterogeneity.

A CHILD WITH DENSE DEPOSIT DISEASE AND DECREASED CLASSIC COMPLEMENT PATHWAY ACTIVITY.

We report a rare case of nephritic syndrome underlying dense deposit disease (DDD) with alternative complement pathway dysfunction explained with both C3 nephritic factor (C3NeF) antibodies and DDD associated polymorphism of factor H. An 8-year-old boy presented with macroscopic hematuria, hypertension and periorbital edema followed by persistently low C3 during the 8-week follow-up. Positive C3 staining on immunofluorescence microscopy, supported by dense deposits within the glomerular basement membrane on electron microscopy, confirmed the diagnosis of DDD. Preliminary tests for complement activation showed decreased classic pathway and deficient alternative complement pathway, as well as slightly positive C3NeF, supporting the diagnosis of DDD. Genetic analysis revealed a polymorphism of the complement factor H gene with an increased risk of developing DDD. Supportive therapy led to satisfactory recovery of renal function and normalization of C3. Given the poor prognosis of the disease, proper approach to such specific glomerulopathy is important to avoid or at least slow down progression to end-stage renal disease.

C3 Glomerulopathy and Related Disorders in Children: Etiology-Phenotype Correlation and Outcomes.

BACKGROUND AND OBJECTIVES: Membranoproliferative GN and C3 glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific etiologic data for pediatric membranoproliferative GN/C3 glomerulopathy are lacking, and outcome data are based on retrospective studies without etiologic data. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 80 prevalent pediatric patients with membranoproliferative GN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-up within the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determined using a Cox proportional hazards model. Kidney and transplant graft survival was determined using the Kaplan-Meier method. RESULTS: Central histology review determined 39 patients with C3 glomerulopathy, 31 with immune-complex membranoproliferative GN, and ten with immune-complex GN. Patients were aged 2-15 (median, 9; interquartile range, 7-11) years. Median complement C3 and C4 levels were 0.31 g/L and 0.14 g/L, respectively; acquired (anticomplement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% of patients, respectively, across all groups, including those with immune-complex GN. Median follow-up was 5.18 (interquartile range, 2.13-8.08) years. Eleven patients (14%) progressed to kidney failure, with nine transplants performed in eight patients, two of which failed due to recurrent disease. Presence of >50% crescents on the initial biopsy specimen was the sole variable associated with kidney failure in multivariable analysis (hazard ratio, 6.2; 95% confidence interval, 1.05 to 36.6; P<0.05). Three distinct C3 glomerulopathy prognostic groups were identified according to presenting eGFR and >50% crescents on the initial biopsy specimen. CONCLUSIONS: Crescentic disease was a key risk factor associated with kidney failure in a national cohort of pediatric patients with membranoproliferative GN/C3 glomerulopathy and immune-complex GN. Presenting eGFR and crescentic disease help define prognostic groups in pediatric C3 glomerulopathy. Acquired abnormalities of the alternative pathway were commonly identified but not a risk factor for kidney failure.

C3 Glomerulopathy: Diagnosis of a Rare Entity in a Resource-Limited Setting.

C3 glomerulopathy (C3G) is a rare entity that is defined by glomerular pathology characterized by predominant deposition of C3 in the glomeruli, with absent or scant immunoglobulin deposition. The aim of this study was to diagnose this rare entity, using clinical features, light microscopy (LM) and direct immunofluorescence (DIF) findings. A retrospective study was done from January 2016 to December 2018. Out of 207 kidney biopsies, eight cases of C3G were included in the study. Clinical, laboratory, and demographic data of all patients were obtained. LM and DIF findings were further evaluated. Nephrotic syndrome was the predominant clinical presentation in this study. All eight cases showed a membranoproliferative pattern on LM. DIF showed predominant mesangiocapillary staining with C3 in all eight cases. DIF plays an important role in making the correct diagnosis, which is necessary to further perform appropriate complement investigations, as these patients respond well to complement inhibitor therapy.

Recurrent C3 Glomerulonephritis with an ADAMTS 13 Gene Variant: A Case Report and Literature Review.

C3 glomerulonephritis (C3GN) is a recently described form of GN that mainly occurs in children and young adults. It results from dysregulation of the alternative complement pathway. Studies have shown that dense deposit disease has a high recurrence rate; however, since C3GN is a recently described disorder, its recurrence rate is still variable. A 28-year-old male with end-stage renal disease caused by C3GN underwent renal transplantation. After 19 months, the patient experienced recurrent C3GN (rC3GN) that involved a variant of unknown significance in the ADAMTS13 gene. Over a short span of time, the patient suffered from rapid deterioration of the graft function that required renal replacement therapy. This is the first case of rC3GN that possibly involved genetic alteration, a variant within the ADAMTS 13 gene.

Pediatric C3 glomerulopathy: a 12-year single-center experience.

BACKGROUND: Complement component 3 glomerulopathy (C3G) is a disease with limited data in children. We aimed to compare childhood C3G cases with adults. We also studied subgroups of pediatric C3G and predictors of poor outcome. METHODS: This is a 12-year retrospective, single-center cohort, observational study. All cases of C3G were defined based on the 2013 consensus guidelines. RESULTS: C3G was diagnosed in 162 patients (119 adults, 43 pediatric) predominantly affecting males. With varied light microscopic patterns, pediatric C3G cases were categorized as follows: 23 C3 glomerulonephritis (C3GN) and 11 dense deposit disease (DDD) on electron microscopy. The pediatric DDD patients were relatively younger with more severe disease at presentation (more crescents in biopsy) but with lesser chronicity in biopsy compared with pediatric C3GN patients; however, both had a similar outcome. On comparing pediatric and adult C3G cases, adults had lower median eGFR and a higher degree of chronicity in the biopsy. The prognosis of C3G was better in pediatric patients. Predictors of kidney failure in pediatric C3G were low eGFR (HR = 0.82, p = 0.05) and severe interstitial fibrosis/tubular atrophy (HR = 1.05, p = 0.02). CONCLUSIONS: Electron microscopy-based subgroups of pediatric C3G differ in clinical presentation and course of the disease but have similar prognosis and long-term outcomes. Pediatric C3G differs from adult C3G with respect to presentation, laboratory results, biopsy features, treatment, and outcome, and as such, it should be considered as a separate entity rather than a smaller version of adult C3G.

Systemic Bartonellosis Manifesting With Endocarditis and Membranoproliferative Glomerulonephritis.

Cat scratch disease caused by Bartonella species is mostly benign and self-limiting condition. Systemic infection is uncommon in immunocompetent host. We describe the case of a 66-year-old male who presented with sudden painless left eye blindness and brown-colored urine. Laboratory findings revealed progressively rising serum creatinine in association with nephrotic-range proteinuria at 7 g/day and glomerular hematuria on urinalysis. An echocardiogram demonstrated mitral and tricuspid valve vegetations despite multiple negative blood cultures. The left eye blindness was attributed to retinal artery occlusion from septic valvular embolus. Kidney biopsy showed membranoproliferative glomerulonephritis pattern of injury with "full house" pattern on immunofluorescent staining with subendothelial deposits on electron microscopy. Markedly elevated IgG (immunoglobulin G) titers for B henselae and B quintana were discovered. The patient had several cats at home. Kidney failure rapidly progressed to require hemodialysis. Once the diagnosis of systemic bartonellosis was confirmed, doxycycline (for 4 months) with rifampicin (for 3 months) were initiated. Repeat echocardiogram in 4 months demonstrated a resolution of valvular vegetations; however, the left eye blindness was permanent. In the present case the correct diagnosis of systemic bartonellosis allowed institution of appropriate antibiotic therapy and to also achieve a partial recovery of renal function and to discontinue hemodialysis.

C3 Glomerulopathy: Pathogenesis and Treatment.

C3 glomerulopathy (C3G) is a rare set of kidney diseases with 2 patterns: C3 glomerulonephritis (C3GN) and dense deposit disease. Pathogenesis of both diseases is due to complement dysregulation in the alternative pathway. Acquired or genetic alterations of the regulatory proteins of the complement pathway result in C3G. Although the disease is characterized by low C3 levels in serum and C3-dominant staining by immunofluorescence on biopsy, other disease entities such as infection-related glomerulonephritis and masked monoclonal deposits can present similarly. Both the C3GN and dense deposit disease variants of C3G are progressive and recur in transplanted kidneys. Although no direct treatment is available, complement blockers are either available or in the clinical trial phase. This review will survey the pathogenesis of C3GN and current treatment options.