Search

Background: Membranoproliferative glomerulonephritis is a rare entity which can be a result from autoimmune diseases, caused by various medications and infections., Case Presentation: We herein present the case of a 62-year-old male patient who presented with fatigue and was found to have severe anemia, impaired renal function, and nephrotic syndrome. A renal biopsy revealed membranoproliferative glomerulonephritis (MPGN) of the immune complex type with activation of the classical complement pathway. Further investigations led to the diagnosis of a chronic Coxiella burnetii-infection (Q fever), likely acquired during cycling trips in a region known for intensive sheep farming. Additionally, the patient was found to have a post endocarditic destructive bicuspid aortic valve caused by this pathogen. Treatment with hydroxychloroquine and doxycycline was administered for a duration of 24 months. The aortic valve was replaced successfully and the patient recovered completely., Conclusions: Early detection and targeted treatment of this life-threatening disease is crucial for complete recovery of the patient., (© 2024. The Author(s).)

BACKGROUND The incidence of glomerular disease recurrence in kidney transplant patients varies according to type of glomerulopathy; therefore, it is important to know the primary chronic kidney disease etiology. C3 glomerulopathy (C3G) is characterized by deposits of C3 in immunofluorescence and its pathogeny is based on the dysregulation of the alternative complement pathway. C3G has a high recurrence rate and, given its low prevalence, only case series have been published. A higher rate of recurrence and a more aggressive course have been described in association with monoclonal gammopathy (MG). CASE REPORT We describe the case of a 78-year-old man with chronic kidney disease of unknown etiology (no significant proteinuria) and monoclonal IgGl gammopathy with low risk of progression, who received a kidney transplant, presenting accelerated deterioration of kidney function. Histopathology showed predominant C3 deposits in immunofluorescence, compatible with C3 glomerulonephritis (C3GN). He was treated with eculizumab during 4 weeks while the study was completed. The response to treatment was not favorable and the patient remained in the dialysis program. CONCLUSIONS Further studies are needed to explain the pathogenic mechanisms of complement alternative pathway dysregulation mediated by monoclonal component in patients with C3GN and MG. Patients older than 50 years who are on a waiting list for kidney transplantation should have an MG detection study. The information provided to patients with MG on a waiting list for kidney transplantation should include not only the possibility of hematologic progression but also the recurrence/de novo appearance of associated kidney pathology.

Recently, the comprehensive concept of "infection-related glomerulonephritis (IRGN)" has replaced that of postinfectious glomerulonephritis (PIGN) because of the diverse infection patterns, epidemiology, clinical features, and pathogenesis. In addition to evidence of infection, hypocomplementemia particularly depresses serum complement 3 (C3), with endocapillary proliferative and exudative GN developing into membranoproliferative glomerulonephritis (MPGN); also, C3-dominant or co-dominant glomerular immunofluorescence staining is central for diagnosing IRGN. Moreover, nephritis-associated plasmin receptor (NAPlr), originally isolated from the cytoplasmic fraction of group A Streptococci , is vital as an essential inducer of C3-dominant glomerular injury and is a key diagnostic biomarker for IRGN. Meanwhile, "C3 glomerulopathy (C3G)", also showing a histological pattern of MPGN due to acquired or genetic dysregulation of the complement alternative pathway (AP), mimics C3-dominant IRGN. Initially, C3G was characterized by intensive "isolated C3" deposition on glomeruli. However, updated definitions allow for glomerular deposition of other complement factors or immunoglobulins if C3 positivity is dominant and at least two orders of magnitude greater than any other immunoreactant, which makes it challenging to quickly distinguish pathomorphological findings between IRGN and C3G. As for NAPlr, it was demonstrated to induce complement AP activation directly in vitro, and it aggravates glomerular injury in the development of IRGN. A recent report identified anti-factor B autoantibodies as a contributing factor for complement AP activation in pediatric patients with PIGN. Moreover, C3G with glomerular NAPlr deposition without evidence of infection was reported. Taken together, the clinico-pathogenic features of IRGN overlap considerably with those of C3G. In this review, similarities and differences between the two diseases are highlighted.

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Systemic mastocytosis is characterised by tissular infiltration and a cytokine storm due to mast cells excessive proliferation and activation. Herein, we report an extraordinary case of AH1N1 influenza post-viral glomerulonephritis occurring in the course of an aggressive systemic mastocytosis with an associated hematological neoplasm. Because of a multisystemic involvement including the liver and lungs, we treated mastocytosis with midostaurin (multiple inhibitor of kinase protein), anti H1/H2 blockers and dexamethasone as first line treatment. One month later and despite vaccination, he developed a severe acute lung injury with respiratory distress due to AH1N1 influenza in association with the nephrotic syndrome. Kidney biopsy disclosed a membranoproliferative glomerulonephritis that was successfully treated with mycophenolate mofetil. Only a few cases of influenza post-viral or post-vaccination glomerulonephritis are documented in the medical literature. This is an exceptional association of uncommon conditions occurring within only a few months in the same patient., (Copyright © 2021 Société francophone de néphrologie, dialyse et transplantation. Published by Elsevier Masson SAS. All rights reserved.)

Membranoproliferative glomerulonephritis (MPGN) is the most typical Hepatitis C virus (HCV)-associated glomerulopathy, and the available data about the utilization of direct-acting antivirals (DAA) in HCV-associated glomerulonephritis is inadequate. We evaluated the renal and viral response in two cases of HCV-related MPGN; the first caused by cryoglobulinemia while the second was cryoglobulin-negative. Both patients received immunosuppression besides DAA in different regimens. They achieved partial remission but remained immunosuppression-dependent for more than 6 months after DAA despite sustained virological response, which enabled safer but incomplete immunosuppression withdrawal. Both patients were tested for occult HCV in peripheral blood mononuclear cells and found to be negative. Hence, the treatment of HCV-related MPGN ought to be according to the clinical condition and the effects of drug therapy. It is important to consider that renal response can lag behind the virological response.

Introduction:  Type I cryoglobulinemia is a rare disease which affects the skin, central nervous system and kidneys. It is usually associated with lymphoproliferative disorders such as multiple myeloma, lymphoma and monoclonal gammopathy of renal significance. Proteinuria and membranoproliferative glomerulonephritis are the most common renal manifestations; Case presentation: Here we report the case of a female patient in her late 40 s who had proteinuria accompanied by Raynaud's phenomenon, high blood and plasma viscosity, hearing loss, and cardiac and central nervous system involvement. Monoclonal immunoglobulin G-λ protein was detected and serum was positive for cryoglobulin. Renal biopsy revealed massive cryo-plugs with unique ultrastructural appearance in the glomerular and peritubular capillary lumina. Immunofluorescence showed predominant IgG3/λ deposition in cryo-plugs. As reported, the clinical manifestations of this patient resulted from cryoprecipitate and hyperviscosity syndrome; Conclusion: Cryoglobulinemia should be considered as a possible diagnosis in patients with Raynaud's phenomenon, hyperviscosity syndrome and monoclonal immunoglobulin., (© 2021. Japanese Society of Hematology.)

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., (Copyright © 2021 by the American Society of Nephrology.)

Background: Factor H-related protein 5 (FHR-5) is a member of the complement Factor H protein family. Due to the homology to Factor H, the main complement regulator of the alternative pathway, it may also be implicated in the pathomechanism of kidney diseases where Factor H and alternative pathway dysregulation play a role. Here, we report the first observational study on CFHR5 variations along with serum FHR-5 levels in immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) and C3 glomerulopathy (C3G) patients together with the clinical, genetic, complement, and follow-up data., Methods: A total of 120 patients with a histologically proven diagnosis of IC-MPGN/C3G were enrolled in the study. FHR-5 serum levels were measured in ELISA, the CFHR5 gene was analyzed by Sanger sequencing, and selected variants were studied as recombinant proteins in ELISA and surface plasmon resonance (SPR)., Results: Eight exonic CFHR5 variations in 14 patients (12.6%) were observed. Serum FHR-5 levels were lower in patients compared to controls. Low serum FHR-5 concentration at presentation associated with better renal survival during the follow-up period; furthermore, it showed clear association with signs of complement overactivation and clinically meaningful clusters., Conclusions: Our observations raise the possibility that the FHR-5 protein plays a fine-tuning role in the pathogenesis of IC-MPGN/C3G., Competing Interests: Author VJ was employed by company Medimpax. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Garam, Cserhalmi, Prohászka, Szilágyi, Veszeli, Szabó, Uzonyi, Iliás, Aigner, Schmidt, Gaggl, Sunder-Plassmann, Bajcsi, Brunner, Dumfarth, Cejka, Flaschberger, Flögelova, Haris, Hartmann, Heilos, Mueller, Rusai, Arbeiter, Hofer, Jakab, Sinkó, Szigeti, Bereczki, Janko, Kelen, Reusz, Szabó, Klenk, Kóbor, Kojc, Knechtelsdorfer, Laganovic, Lungu, Meglic, Rus, Kersnik Levart, Macioniene, Miglinas, Pawłowska, Stompór, Podracka, Rudnicki, Mayer, Rysava, Reiterova, Saraga, Seeman, Zieg, Sládková, Stajic, Szabó, Capitanescu, Stancu, Tisljar, Galesic, Tislér, Vainumäe, Windpessl, Zaoral, Zlatanova, Józsi and Csuka.)

The rare and heterogeneous kidney disorder C3 glomerulopathy (C3G) is characterized by dysregulation of the alternative pathway (AP) of the complement system. C3G is often associated with autoantibodies stabilizing the AP C3 convertase named C3 nephritic factors (C3NeF). The role of classical pathway (CP) convertase stabilization in C3G and related diseases such as immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) remains largely unknown. Here, we investigated the CP convertase activity in patients with C3G and IC-MPGN. Using a refined two-step hemolytic assay, we measured the stability of CP convertases directly in the serum of 52 patients and 17 healthy controls. In four patients, CP convertase activity was prolonged compared to healthy controls, i.e. the enzymatic complex was stabilized. In three patients (2 C3G, 1 IC-MPGN) the convertase stabilization was caused by immunoglobulins, indicating the presence of autoantibodies named C4 nephritic factors (C4NeFs). Importantly, the assay also enabled detection of non-immunoglobulin-mediated stabilization of the CP convertase in one patient with C3G. Prolonged CP convertase activity coincided with C3NeF activity in all patients and for up to 70 months of observation. Crucially, experiments with C3-depleted serum showed that C4NeFs stabilized the CP C3 convertase (C4bC2a), that does not contain C3NeF epitopes. All patients with prolonged CP convertase activity showed clear signs of complement activation, i.e. lowered C3 and C5 levels and elevated levels of C3d, C3bc, C3bBbP, and C5b-9. In conclusion, this work provides new insights into the diverse aspects and (non-)immunoglobulin nature of factors causing CP convertase overactivity in C3G/IC-MPGN., Competing Interests: JW has received grants from Achillion and Chemocentryx, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Michels, van de Kar, van Kraaij, Sarlea, Gracchi, Engels, Dorresteijn, van der Deure, Duineveld, Wetzels, van den Heuvel and Volokhina.)

Background: To explore the clinical and pathological features of renal lesions in patients with kidney involvement in idiopathic hypereosinophilic syndrome (IHES)., Methods: The demographic, clinical, and pathological characteristics and the treatment and follow-up data were analyzed., Results: We identified 18 patients with IHES and renal involvement. Eleven patients presented with nephrotic syndrome, and 6 patients had impaired renal function. 15 patients underwent renal biopsy, and the pathological findings included the following: membranoproliferative glomerulonephritis in 3 patients; minimal-change disease in 3; mesangial proliferative nephritis in two; IgA nephropathy in 2; membranous nephropathy in two; chronic interstitial nephritis in two; focal segmental sclerosis in one; and eosinophil infiltration into the renal interstitium in 11 and into the glomerulus in 3. After treatment with glucocorticoids, the eosinophil count decreased. 15 patients were followed up, and 14 showed a decrease in urinary protein or renal function recovery. When glucocorticoids were discontinued, eosinophil increased (8 cases), urine protein increased (1 case), and 1 patient progressed to end-stage renal disease., Conclusions: Nephrotic syndrome with or without renal insufficiency is the main clinical manifestation. A wide spectrum of renal lesions can be observed in patients with IHES. Eosinophil infiltration into the renal interstitium was common in these patients. Most patients have a good prognosis after glucocorticoid therapy.

In several cases with IgA nephropathy (IgAN), differential diagnosis is difficult due to the complication with other systemic diseases which can induce secondary IgAN. Recently, we demonstrated that immunostaining with galactose-deficient IgA1-specific monoclonal antibody (KM55 mAb) specifically showed positive in primary IgAN cases. Here, we report four cases which we could make definitive diagnosis by immunohistological analysis using KM55 mAb. The underlying systemic diseases are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), hepatitis C (HCV) and Crohn's disease (CD). Renal pathological findings in the four cases revealed mesangial proliferative glomerulonephritis with IgA and C3 deposits. Immunostaining with KM55 mAb was positive for three cases complicated with RA, SLE and CD, respectively. Thus, these three cases were diagnosed as primary IgAN and treated with tonsillectomy and steroid pulse therapy. These three cases finally achieved clinical remission. On the other hand, the case with HCV showed negative for KM55. Finally, we diagnosed as HCV-related nephropathy and successfully treated by antiviral agents. These cases suggested KM55 mAb is a strong tool to differentiate primary IgAN from secondary IgAN.

A 74-year-old man presented with nephrotic syndrome and kidney insufficiency. Laboratory tests revealed monoclonal gammopathy of immunoglobulin A-lambda. Renal biopsy revealed diffuse mesangial proliferation and double-contoured basement membranes. Immunofluorescent analyses showed granular deposition of immunoglobulin A and C3 at the capillary walls and mesangial regions. Immunohistochemistry suggested monoclonal deposition of immunoglobulin A1-lambda. Electron microscopic analyses showed finely granular electron-dense deposits at mesangial and subendothelial areas. These findings suggested immunoglobulin A-type proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Based on the results of bone marrow aspiration, multiple myeloma was diagnosed. Because the renal manifestation was considered to be affected by monoclonal gammopathy, chemotherapy was initiated rather than immunomodulatory therapy. Although bortezomib and dexamethasone proved ineffective, second chemotherapy with elotuzumab, lenalidomide, and dexamethasone was successful, and kidney function recovered. Effective treatments for proliferative glomerulonephritis with monoclonal immunoglobulin deposits have not been established. This represents the first description of a patient successfully treated for proliferative glomerulonephritis with monoclonal immunoglobulin deposits by chemotherapy using elotuzumab.

Rationale: Infection is a major trigger or pathogenic origin in a substantial proportion of glomerulonephritis (GN) patients, typically manifesting infection-related GN (IRGN). Various microorganisms, infection sites, and clinical and histopathological features are involved in IRGN. Once an infectious origin is identified and successfully eradicated, nephrotic syndrome or kidney dysfunction is spontaneously resolved. However, if patients are asymptomatic and the origin is undetermined, the diagnosis and treatment of GN is challenging. This case presentation reported on an IRGN case manifesting steroid-resistant nephrotic syndrome associated with asymptomatic sinusitis as a pathogenic origin., Patient Concerns: A 68-year-old male presented with severe kidney dysfunction and edema in both extremities., Diagnosis: The patient was clinically diagnosed with hypocomplementemic nephrotic syndrome and kidney dysfunction and histopathologically with diffuse proliferative GN and a focal pattern of membranoproliferative GN. The findings suggested that idiopathic membranoproliferative glomerulonephritis type I was more likely than IRGN, given a critical lack of apparent infection., Interventions: Combined intravenous methylprednisolone, oral prednisolone, and cyclosporin did not improve the patient's condition. Thus, IRGN associated with inapparent infectious origin was suspected. Repeated thorough and careful examinations including CT scan showed sinusitis in his left maxillary sinus. Moreover, reanalysis of kidney specimen revealed positive nephritis-associated plasmin receptor in glomeruli, a typical finding for IRGN, supporting a pathogenic significance of his sinusitis. Medical treatment was initiated with 200 mg oral clarithromycin daily., Outcomes: Oral clarithromycin gradually improved proteinuria and hypocomplementemia and resulted in nephrotic syndrome remission in parallel with opacification resolution of sinuses shown on CT., Lessons: This case presentation showed that asymptomatic sinusitis is potentially a pathogenic IRGN origin. A gold standard therapy for idiopathic GN, corticosteroid could be damaging in uncontrolled or underdiagnosed infection. In asymptomatic patients, a thorough screening of infectious diseases, including sinusitis, together with a renal histological evaluation of glomerular nephritis-associated plasmin receptor deposition is also essential in treating a wide spectrum of GN.

Background: In Brazil, schistosomiasis is caused only by Schistosoma mansoni , occurring in the northeastern and southeastern regions. Schistosomiasis primarily affects the liver and gastrointestinal tract, although the kidneys can also be affected, mainly in the form of glomerulopathies. Here, we describe the characteristics of patients with schistosomiasis-associated glomerulopathies, including treatment and renal outcomes., Materials and Methods: This was a retrospective analysis of patients diagnosed with schistosomiasis-associated glomerulopathy between 2002 and 2017. Clinical, biochemical, and histopathological (kidney biopsy) data were evaluated., Results: Of the 24 patients evaluated, 19 (79.1%) were male and 16 (66.4%) were White. The mean age was 38.58 ± 9.83 years. We observed the hepatosplenic form of schistosomiasis in 15 patients (68.1%), nephrotic-nephritic syndrome in 13 (54.1%), hematuria in 20 (83.3%), and hypertension in 18 (75.0%). Renal histology showed a predominance of membranoproliferative pattern (n = 17/70.8%). On immunofluorescence, 19 patients (82.6%) showed immunoglobulin M (IgM) expression, 10 (43.4%) showed IgM+IgG expression, and 1 (4.3%) showed a "full house" pattern. The median follow-up time was 59.70 months, by the end of which 9 patients (37.5%) had developed end-stage renal disease (ESRD). Baseline serum creatinine was higher among the patients who developed ESRD than among those who did not (1.99 ± 1.08 vs. 1.34 ± 0.46 mg/dL, p = 0.05)., Conclusion: Our study is one of the rare clinical studies on schistosomiasis-associated glomerulopathy with a long follow-up and renal endpoints, showing that one third of our patients, independent of their histological form, progress to dialysis.
.

Background: IgA deficiency associated with glomerulonephritis is rare. In particular, there is no prior report regarding the association between IgA deficiency and membranoproliferative glomerulonephritis (MPGN) in children. Herein, we describe the case of a 5-year-old girl with selective IgA deficiency and MPGN., Case Presentation: The patient presented with persisting urinary abnormality and hypocomplementemia following a group A treptococcal infection. Renal biopsy revealed the presence of diffuse mesangial hypercellularity, endocapillary proliferation, and focal thickening of the walls of the glomerular capillaries using light microscopy, with IgG and moderate C3 deposits observed using immunofluorescence. Electron microscopy images revealed nodular deposits in the subendothelial areas, with hump-shaped subepithelial deposits. The pathological diagnosis was confirmed as MPGN. Treatment using oral prednisolone (PSL), mizoribine (MZR), and angiotensin-converting enzyme inhibitors reduced the proteinuria. The PSL dose was gradually tapered, with the low dose of PSL and MZR continued for 4 years. Histological findings were improved on repeated renal biopsy, and PSL and MZR administration was discontinued., Conclusions: We report a rare case of MPGN related to a streptococcal infection in a child. The clinical presentation included selective IgAD, with several pathological findings and a clinical course typical of glomerulopathy. The patient was successfully treated using multidrug therapy.

We performed a renal biopsy for nephrotic syndrome in a patient with squamous cell lung carcinoma, which can worsen the prognosis. Chemoradiation therapy was effective for the cancer and proteinuria; we thus inferred that the nephrotic syndrome had been closely associated with the carcinoma. A pathological analysis of the kidney showed monoclonality for λ chain, satisfying the diagnostic criteria of proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID); however, conspicuous mesangial proliferation was not observed. This is the first case of PGNMID complicated with lung carcinoma; furthermore, our findings underscore the importance of examining renal lesions and assessing monoclonality in cancer patients.

Background: Primary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN., Methods: We analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource-Rare Diseases Study. We examined copy number, rare, and common variants., Results: Our analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significant enrichment of rare variants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) ( P =3.29×10 -8 ; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01, and DRB1*03:01 ( P =1.21×10 -8 ; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis of HLA serotypes in 338 individuals with membranoproliferative GN and 15,614 individuals with nonimmune renal failure., Conclusions: We found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causing primary membranoproliferative GN and implicate an underlying autoimmune mechanism in most cases., (Copyright © 2020 by the American Society of Nephrology.)

Sequence and copy number variations in the human CFHR-Factor H gene cluster comprising the complement genes CFHR1 , CFHR2 , CFHR3 , CFHR4 , CFHR5 , and Factor H are linked to the human kidney diseases atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy. Distinct genetic and chromosomal alterations, deletions, or duplications generate hybrid or mutant CFHR genes, as well as hybrid CFHR-Factor H genes, and alter the FHR and Factor H plasma repertoire. A clear association between the genetic modifications and the pathologic outcome is emerging: CFHR1 , CFHR3 , and Factor H gene alterations combined with intact CFHR2 , CFHR4 , and CFHR5 genes are reported in atypical hemolytic uremic syndrome. But alterations in each of the five CFHR genes in the context of an intact Factor H gene are described in C3 glomerulopathy. These genetic modifications influence complement function and the interplay of the five FHR proteins with each other and with Factor H. Understanding how mutant or hybrid FHR proteins, Factor H::FHR hybrid proteins, and altered Factor H, FHR plasma profiles cause pathology is of high interest for diagnosis and therapy., (Copyright © 2020 by the American Society of Nephrology.)

In April 2012, a group of nephrologists organized a consensus conference in Cambridge (UK) on type II membranoproliferative glomerulonephritis and decided to use a new terminology, "C3 glomerulopathy" (C3 GP). Further knowledge on the complement system and on kidney biopsy contributed toward distinguishing this disease into three subgroups: dense deposit disease (DDD), C3 glomerulonephritis (C3 GN), and the CFHR5 nephropathy. The persistent presence of microhematuria with or without light or heavy proteinuria after an infection episode suggests the potential onset of C3 GP. These nephritides are characterized by abnormal activation of the complement alternative pathway, abnormal deposition of C3 in the glomeruli, and progression of renal damage to end-stage kidney disease. The diagnosis is based on studying the complement system, relative genetics, and kidney biopsies. The treatment gap derives from the absence of a robust understanding of their natural outcome. Therefore, a specific treatment for the different types of C3 GP has not been established. Recommendations have been obtained from case series and observational studies because no randomized clinical trials have been conducted. Current treatment is based on corticosteroids and antiproliferative drugs (cyclophosphamide, mycophenolate mofetil), monoclonal antibodies (rituximab) or complement inhibitors (eculizumab). In some cases, it is suggested to include sessions of plasma exchange., Competing Interests: The authors declare no conflict of interest. The sponsor had no role in the design, execution, interpretation or writing of the study.

Multicentric Castleman disease is a rare polyclonal lymphoproliferative disorder mainly associated with two renal manifestations: thrombotic microangiopathy and amyloidosis. Nevertheless, we report here a case of human herpes virus-8 negative multicentric Castleman disease with membranous proliferative glomerulonephritis and extracapillary proliferation. A patient was successfully treated with corticosteroids, anti-CD20 and cyclophosphamide therapy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Previous reports of glomerular disease in adult patients with autosomal dominant dystrophic epidermolysis bullosa (EB) are limited and include post-infectious glomerulonephritis, IgA nephropathy, amyloidosis, and leukocytoclastic vasculitis. To our knowledge, membranoproliferative glomerulonephritis (MPGN) has not been described before. We report a case of a 39-year-old male with autosomal dominant dystrophic EB, presenting with bilateral leg swelling of one-week duration. There was no other significant past medical history. The physical examination was remarkable for scars and erosions over all body areas, with all extremities with blisters and ulcers covered, absent finger and toenails and bilateral lower extremity edema. Serum creatinine was 0.9 mg/dL, albumin 1.3 g/dL and urine protein excretion 3.7 g/24 h. Viral markers (hepatitis-B, C, and HIV), complement c3 and c4 levels and auto-immune antibody profile all remained negative or within normal limits. Renal ultrasound and echocardiogram were normal. Renal biopsy recovered 14 glomeruli, all with proliferation of mesangial and endothelial cells as well as an expansion of the mesangial matrix, focal segmental sclerosis and amorphous homogeneous deposits demonstrating apple-green birefringence under polarized light with Congo red stain. Our observation emphasizes the importance of recognizing MPGN and secondary amyloidosis in patients with EB, especially with the availability of newer treatment modalities.

Background: Kimura's disease is a rare disease and its etiology is still unclear. Here we reported a case with lymphadenopathy complicated with secondary membranoproliferative glomerulonephritis., Case Presentation: A 46-year-old Chinese man presented with bilateral tumor-like nodules over his neck during the past 6 months and developed edema for 15 days. His blood pressure was 145/90 mmHg, multiple 1 × 1 cm masses were found over bilateral post-auricular and submandibular areas, along with trace edema of the lower extremities. Laboratory data showed an increased peripheral eosinophil count at 3.66 × 10 9 /L (50% of total leukocytes), with a 24-hour urine total protein of 8 g and a serum albumin of 19 g/L, and serum IgE of 2930 IU/ml (<100 IU/ml). The patient underwent renal biopsy, which revealed membranoproliferative glomerulonephritis with eosinophilic infiltration of the interstitium. Lymph node biopsy showed eosinophilic lymphoid follicular granuloma. Bone marrow biopsy showed no abnormalities. A diagnosis of Kimura's disease was then established. We started him on prednisone 60 mg/day (1 mg/kg), and tapered the dose to 55 mg/day 2 months later, followed by a gradual reduction of 2.5 mg every 2 weeks. Valsartan was given for blood pressure control. His neck nodules shrank after 2 weeks of treatment and complete renal remission was achieved 3 months later. No relapse occurred after follow-up for 31 months., Conclusion: Kimura's disease can present with bilateral neck nodules and nephrotic syndrome (membranoproliferative glomerulonephritis), and prednisone can be a suitable choice of treatment.

Glomerulonephritis (GN) refers to a group of renal diseases affecting the glomeruli due to the damage mediated by immunological mechanisms. A large proportion of the disease manifestations are caused by disturbances in the complement system. They can be due to genetic errors, autoimmunity, microbes or abnormal immunoglobulins, like modified IgA or paraproteins. The common denominator in most of the problems is an overactive or misdirected alternative pathway complement activation. An assessment of kidney function, amount of proteinuria and hematuria are crucial elements to evaluate, when glomerulonephritis is suspected. However, the cornerstones of the diagnoses are renal biopsy and careful examination of the complement abnormality. Differential diagnostics between the various forms of GN is not possible based on clinical features, as they may vary greatly. This review describes the known mechanisms of complement dysfunction leading to different forms of primary GN (like IgA glomerulonephritis, dense deposit disease, C3 glomerulonephritis, post-infectious GN, membranous GN) and differences to atypical hemolytic uremic syndrome. It also covers the basic elements of etiology-directed therapy and prognosis of the most common forms of GN. Common principles in the management of GN include treatment of hypertension and reduction of proteinuria, some require immunomodulating treatment. Complement inhibition is an emerging treatment option. A thorough understanding of the basic disease mechanism and a careful follow-up are needed for optimal therapy., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Transplant failure requires the consideration of numerous potential causes including rejection, acute tubular necrosis, infection, and recurrence of the original kidney disease. Kidney biopsy is generally required to approach these differential diagnoses. However, the histopathological findings on their own do not always lead to a definite diagnosis. Consequently, it is crucial to integrate them with clinical findings and patient history when discussing histopathological patterns of injury. The histopathologic finding of a membranoproliferative glomerulonephritis (MPGN) is one of the most challenging constellations since it does not refer to a specific disease entity but rather reflects a pattern of injury that is the result of many different causes. Whilst MPGN is occasionally classified as immune complex mediated, careful evaluation usually reveals an underlying disorder such as chronic infection, plasma cell dyscrasia, complement disorders, and autoimmune disease., Case Presentation: We describe the case of a 43-year-old woman who was referred to us because of a slowly rising serum creatinine 4 years after kidney transplantation. As in the native kidney, the biopsy revealed an MPGN pattern of injury. The cause of this finding had not been established prior to transplantation leading to a classification as idiopathic MPGN in the past. Further workup at the time of presentation and allograft failure revealed chronic infection of a ventriculoatrial shunt as the most probable cause., Conclusion: This case underlines the fact that MPGN is not a disease but a histopathological description. Consequently, the causative disorder needs to be identified to avoid kidney failure and recurrence after transplantation.

The Schnitzler syndrome (SS) is a rare and underdiagnosed entity that associates a chronic urticarial rash, monoclonal IgM (or sometimes IgG) gammopathy and signs and symptoms of systemic inflammation. During the past 45 years the SS has evolved from an elusive, little-known disorder to the paradigm of a late-onset auto-inflammatory acquired syndrome. Though there is no definite proof of its precise pathogenesis, it should be considered as an acquired disease involving abnormal stimulation of the innate immune system, which can be reversed by the interleukin 1 (IL-1) receptor antagonist anakinra. Here we describe the case of a 56-year-old male Caucasian patient affected by SS and hospitalized several times in our unit because of relapsing episodes of acute kidney injury. He underwent an ultrasound-guided percutaneous kidney biopsy in September 2012, which showed the histologic picture of type I membranoproliferative glomerulonephritis. He has undergone conventional therapies, including nonsteroidal anti-inflammatory drugs, steroids and immunosuppressive drugs; more recently, the IL-1 receptor antagonist anakinra has been prescribed, with striking clinical improvement. Although the literature regarding kidney involvement in the SS is lacking, it can however be so severe, as in the case reported here, to lead us to recommend the systematic search of nephropathy markers in the SS., (Copyright by Società Italiana di Nefrologia SIN, Rome, Italy.)

Cryoglobulinemia is a rare cause of kidney disease that occurs in patients with various diseases. Renal involvement often occurs after appearance of various clinical manifestations dominated by purpura and neuropathy. The aim of this study is to describe clinical, biological, and pathological characteristics of cryoglobulinemic glomerulonephritis (GN), as well as treatment and outcome. This is a retrospective study including all patients with positive cryoglobulin test and biopsy-proven GN secondary to cryoglobulinemia. Fourteen patients with cryoglobulinemic GN were collected. Their mean age was 46.92 ± 15.82 years with male predominance (64.28%). Weight loss, fever (71.42%), and purpuric rash (57.14%) were the main extrarenal manifestations. Eight patients presented with nephrotic syndrome (NS), associated with renal impairment in three patients. Four patients had rapidly progressive GN and two patients had acute kidney injury. Renal biopsy, performed in all patients, revealed membranoproliferative GN with glomerular thrombi in all patients. Crescents and necrotizing vasculitis were present in four patients. Hepatitis C virus (HCV) infection was the most common etiology. Antivirals and steroids or other immunosuppressive agents were used in most of the patients. During follow-up, complete response was observed in three patients and partial response was observed in four patients. Five patients had no response with renal injury requiring hemodialysis. NS with hematuria and renal insufficiency were the main clinical manifestations of cryoglobulinemic GN. In our study, HCV infection dominated the etiologies, although not well described earlier. A half of our patients had poor outcome even after antiviral and immunosuppressive therapy.

Membranoproliferative glomerulonephritis is known to recur after kidney transplantation and may lead to allograft loss. Although an optimal treatment has not been determined, B-cell targeted therapies are now increasingly used as first-line agents, based on growing data showing antibodies as key players in the pathogenesis of membranoproliferative glomerulonephritis. Here, we report a case of recurrent immune complex-mediated membranoproliferative glomerulonephritis 3 years after a living-donor kidney transplant. Treatment with plasmapheresis and rituximab resulted in immediate and sustained improvement in allograft function.
.

Rationale: Adult-onset hepatitis B virus-associated membranoproliferative glomerulonephritis (HBV-MPGN) is generally refractory, and an effective treatment for this condition has not been established. The indications for steroids in HBV-MPGN are an important clinical concern., Patient Concerns: A 28-year-old woman with a chronic hepatitis B virus infection developed nephrotic syndrome in her second month of pregnancy, with urinary protein levels of 3 to 10 g/d that continued into her postpartum period. She was a carrier of HBV with HBeAg seroconversion. As her renal impairment could have been a result of pregnancy, we observed her for 10 months postpartum without any intervention. However, spontaneous remission after childbirth was not achieved and urine protein levels were sustained at 1 to 3 g/d. About 10 months after delivery, elevated serum liver enzyme levels were observed., Diagnosis: Biopsies showed MPGN, with deposition of hepatitis B antigen in the glomeruli, and chronic B-type hepatitis with a severity grade of A1F0. She was diagnosed with HBV-MPGN., Interventions: The patient was started on entecavir 0.5 mg/d in March 2008. Within 1 month, serum HBV DNA became undetectable; within 3 months, her alanine aminotransferase levels normalized. However, urinary protein excretion did not decrease to <2 g/d. On a second renal biopsy, performed 7 months after entecavir treatment, proliferative lesions of the glomeruli were observed; therefore, prednisolone was started at an initial dose of 30 mg/d., Outcomes: Her proteinuria improved immediately and prednisolone was tapered over 10 months. A third renal biopsy showed a remarkable resolution of HBV-MPGN, with a significant decrease in mesangial proliferation and immune complex deposition. HBV reactivation was not observed during the prednisolone treatment., Lessons: Additional prednisolone therapy in combination with antiviral therapy should be considered for refractory HBV-MPGN, with sufficient care taken regarding HBV reactivation.

Aim: Analysis of etiology, clinical and morphological manifestations, approaches to therapy and prognosis of membranoproliferative glomerulonephritis (MPGN)., Materials and Methods: Cases of MPGN were retrospectively identified in the period 2000-2017 with subsequent analysis of etiology, clinical data and morphology (including deposits of immunoglobulins (Ig) and C3 complement fractions). The achievement of complete and partial remissions (PR, CR), overall survival, progression (by composite endpoint: decrease in the estimated GFR (eGFR) ≥50% from the baseline or eGFR &lt;15 ml/min/1.73 m2 or the onset of dialysis)., Results: 214 cases of MPGN entered the study with the average age of 44±16 years. Most patients had nephrotic syndrome and significant hematuria. In 58.4% of cases, eGFR was &lt;60 mL/min/1.73 m2, and every fifth patient had CKD 4 or 5 stages. The prevalence of MPGN among all biopsy-confirmed glomerulopathies was 9.3%. Idiopathic MPGN (iMPGN) was detected in 30.4% of cases, secondary MSGN (sMPGN) - in 69.6% (autoimmune diseases - 34.1%, infectious diseases - 16.4%, monoclonal gammopathies - 9.3%, complement-mediated damage - 9.8%). Ig+C3+MPGN was mainly associated with autoimmune diseases and infections; C3-glomerulopathy or thrombotic microangiopathy were most often causes of Ig-C3+MPGN; Ig-C3-/Ig+C3-MPGN had heterogeneous etiology. The median follow-up period was 28 [7; 37] months. The 10-year total cumulative patient and renal survival rates were 71 and 50%, respectively (without differences between sMPGN and iMPGN). The frequency of the PR/CR was 50% (iMPGN - 46.2%, sMPGN - 51.3%) depending on the etiology of the MPGN (p=0.049). The cumulative 10-year progression-free renal survival was nearly 100% in cases with PR/CR and 0% in non-responders., Conclusion: MPGN is a severe variant of glomerular damage with a heterogeneous etiological structure and an unfavorable prognosis. Targeted clinical and morphological diagnostics of MPGN allows to identify the cause of the disease in most cases. This approach is reliable for the adequate treatment choice and improvement of outcomes in MPGN.

A 76-year-old woman suddenly developed anasarca and a fever, and an examination revealed thrombocytopenia, reticulin fibrosis, and acute kidney injury, yielding the diagnosis of thrombocytopenia, anasarca, fever, reticulin fibrosis, organomegaly (TAFRO) syndrome. Renal replacement therapy and steroid treatment were soon started. Her proteinuria was minor at first; however, once the kidney function improved, nephrotic syndrome occurred. A kidney biopsy showed membranoproliferative glomerulonephritis-like glomerulopathy with massive macrophage infiltration. Although kidney dysfunction is often observed in TAFRO syndrome patients, its detailed mechanism is unclear. This case suggests that TAFRO syndrome involves both acute kidney injury with minor proteinuria and nephrotic syndrome, and these disorders can develop serially in the same patient.

We report the findings of an 18-year-old boy with immunoglobulin A vasculitis (IgAV) complicated with bowel perforation and nephritis. He presented with abdominal pain, arthralgia and palpable purpura. Massive proteinuria developed during his clinical course. The patient was treated successfully using combination therapy of glucocorticoid (GC), cyclosporine (CYA) and factor XIII (F XIII) replacement. A standard treatment strategy for severe IgAV patients has not been established due to its rarity. Combination therapy using GC, CYA and F XIII replacement should be considered for severe IgAV patients.

Membranoproliferative glomerulonephritis (MPGN) was recently classified as C3 glomerulopathies (C3G), and immune-complex (IC) mediated MPGN. Dysregulation of the complement alternative pathway, driven by acquired and/or genetic defects, plays a pathogenetic role in C3G. However, alternative pathway abnormalities were also found in IC-MPGN. The most common acquired drivers are the C3 nephritic factors (C3NeFs), heterogeneous autoantibodies that stabilize the C3 convertase, C3bBb. C3NeFs are traditionally detected by hemolytic assays based on sheep erythrocyte lysis, which however do not provide a direct molecular estimation of C3bBb formation and decay. We set up a microplate/western blot assay that specifically detects and quantifies C3bBb, and its precursor, the C3 proconvertase C3bB, to investigate the complex mechanistic effects of C3NeFs from patients with primary IC-MPGN ( n = 13) and C3G ( n = 13). In the absence of properdin, 9/26 patients had C3NeF IgGs stabilizing C3bBb against spontaneous and FH-accelerated decay. In the presence of properdin the IgGs of all but one patient had C3bBb-stabilizing activity. Properdin-independent C3NeFs were identified mostly in DDD patients, while properdin-dependent C3NeFs associated with either C3GN or IC-MPGN and with higher incidence of nephrotic syndrome. When we grouped patients based on our recent cluster analysis, patients in cluster 3, with highly electron-dense intramembranous deposits, low C3, and mostly normal sC5b-9 levels, had a higher prevalence of properdin-independent C3NeFs than patients in clusters 1 and 2. Conversely, about 70% of cluster 1 and 2 patients, with subendothelial, subepithelial, and mesangial deposits, low C3 levels and high sC5b-9 levels, had properdin-dependent C3NeFs. The flexibility of the assay allowed us to get deep insights into C3NeF mechanisms of action, showing that: (1) most C3NeFs bind strongly and irreversibly to C3 convertase; (2) C3NeFs and FH recognize different epitopes in C3 convertase; (3) C3NeFs bind rapidly to C3 convertase and antagonize the decay accelerating activity of FH on newly formed complexes; (4) C3NeFs do not affect formation and stability of the C3 proconvertase. Thus, our study provides a molecular approach to detecting and characterizing C3NeFs. The results highlight different mechanisms of complement dysregulation resulting in different complement profiles and patterns of glomerular injury, and this may have therapeutic implications.

Rationale: Membranoproliferative glomerulonephritis (MPGN) can be induced by autoimmune diseases, chronic infection, chronic hepatitis, and paraproteins (including cryoglobulinemia). In addition, the mixed cryoglobulinemic MPGN is reported to be highly correlated with hepatitis C virus (HCV) infection., Patient Concerns: We reported a rare case of a 61-year-old woman without a history of viral hepatitis infection; she presented with bilateral leg edema and proteinuria. Renal pathology revealed MPGN with multiple positive immunofluorescent staining. The consequent serum survey revealed positive cryoglobulin and monoclonal gammopathy of kappa type of immunoglobulin M. However, bone marrow study showed no obvious plasma cell proliferation, indicating that multiple myeloma was less likely., Diagnoses: This patient's cryoglobulinemic MPGN could be related to monoclonal gammopathy of undetermined significance., Interventions: Oral immunosuppressant., Outcomes: After steroid treatment, her renal function normalized and proteinuria kept in low level., Lessons: We demonstrated a rare cause of cryoglobulinemic MPGN without HCV infection, which led to a favorable prognosis after receiving steroid therapy. Moreover, the diagnosis of monoclonal gammopathy should be considered when facing such case and aggressive steroid therapy might be beneficial.

Dense deposit disease (DDD) is a very rare pathological finding associated with activation of the final complement pathway. DDD has been rarely found in association with multiple myeloma (MM). Here we report a patient with MM presenting with renal failure, anemia, and bone pain. The renal biopsy showed DDD. The patient received anti-myeloma treatment and responded well. The case is discussed and literature reviewed.
.