Isolated C3 Deposits Research Articles

Atypical Presentation of Infantile Bullous Pemphigoid with Isolated C3 Deposits

Bullous pemphigoid is an acquired autoimmune bullous disorder with autoantibodies targeting distinctive antigenic components of the skin and mucous membrane. It occurs mostly in the elderly, with the incidence of disease increasing with age and rare in children and infants. The clinical features are extremely polymorphous characterized by tense blisters and intense itching. The disease in pediatric population usually has a favorable outcome with appropriate treatment. Here, we present a case of infantile bullous pemphigoid with a rare presentation, triggered by vaccination and showing only linear C3 deposits.

Bacterial infection-related glomerulonephritis in patients with diabetes.

Diabetic patients are prone to infections, thus making them a unique cohort at risk of developing bacterial infection-related glomerulonephritis (IRGN). In total, 1693 adult diabetic patients underwent kidney biopsy between 2005 and 2021 at our tertiary care hospital in South India. Of these, 121 consecutive cases which met criteria of bacterial IRGN were included in this study. The mean age of the cohort was 53.1 ± 10.1 years and 83/121 (68.5%) were males. Majority (98.3%) had type 2 diabetes for a median duration of 6 (IQR, 2-12) years. The most common sites of infection were skin (47/121, 38.8%) and urinary tract (15/121, 12.4%). Fifty percent (58/121) of patients had underlying advanced diabetic kidney disease (DKD). Isolated C3 deposits (without immunoglobulin) occurred in 66/121 (54.5%) patients predominantly in advanced DKD patients. IgA-dominant glomerulonephritis occurred in only 9/121 (7.4%) patients. Short-course oral steroid was given to 86/121 (71.1%) patients. Steroid related dysglycemia and immunosuppression related infections occurred in 9/61 (14.8%) and 16/61 (26.2%) patients respectively. Of the 90 patients with follow up details >3 months, 46 (51.1%) progressed to kidney failure over a median period of 0.5 (IQR, 0-7.2) months. Patients diagnosed in the latter half of our study period (2013-2021) were older, less commonly presented with fever, had more pronounced hypocomplementemia and severe renal histology predominantly with a 'starry sky' immunofluorescence pattern. Superimposed bacterial IRGN on underlying DKD is associated with poor renal outcomes. Use of short course steroid was associated with significant toxicity.

Current concepts in C3 glomerulopathy.

Complement component 3 glomerulopathy (C3G) is a recently defined entity comprising of dense deposit disease and C3 glomerulonephritis. The key histological feature is the presence of isolated C3 deposits without immunoglobulins. Often masqueradng as some of the common glomerulonephritides this is a prototype disorder occurring from dysregulated alternate complement pathway with recently identified genetic defects and autoantibodies. We review the pathophysiology, clinical features, and diagnostic and treatment strategies.

Molecular genetics of familial hematuric diseases

The familial hematuric diseases are a genetically heterogeneous group of monogenic conditions, caused by mutations in one of several genes. The major genes involved are the following: (i) the collagen IV genes COL4A3/A4/A5 that are expressed in the glomerular basement membranes (GBM) and are responsible for the most frequent forms of microscopic hematuria, namely Alport syndrome (X-linked or autosomal recessive) and thin basement membrane nephropathy (TBMN). (ii) The FN1 gene, expressed in the glomerulus and responsible for a rare form of glomerulopathy with fibronectin deposits (GFND). (iii) CFHR5 gene, a recently recognized regulator of the complement alternative pathway and mutated in a recently revisited form of inherited C3 glomerulonephritis (C3GN), characterized by isolated C3 deposits in the absence of immune complexes. A hallmark feature of all conditions is the age-dependent penetrance and a broad phenotypic heterogeneity in the sense that subsets of patients progress to added proteinuria or proteinuria and chronic renal failure that may or may not lead to end-stage kidney disease (ESKD) anywhere between the second and seventh decade of life. In addition to other excellent laboratory tools that assist the clinician in reaching the correct diagnosis, the molecular analysis emerges as the gold standard in establishing the diagnosis in many cases of doubt due to equivocal findings that complicate the differential diagnosis. Recent work led to the description of candidate genetic modifiers which confer a variable risk for progressing to chronic renal failure when co-inherited on the background of a primary glomerulopathy. Finally, more families are still waiting to be studied and more genes to be mapped and cloned that are responsible for other forms of heritable hematuric diseases. The study of such genes and their protein products will likely shed more light on the structure and function of the glomerular filtration barrier and other important glomerular components.

Successful Use of Plasma Exchange to Prevent Recurrence of C3 Glomerulonephritis after Kidney Transplantation: A Case Report

Background: Complement-mediated glomerulonephritis relapses in about 80% of patients with a history of disease recurrence in a previous graft. There is so far no efficient treatment to prevent recurrence. Methods: Case report on the use of intermittent plasma exchange to prevent recurrence of C3 glomerulonephritis (C3GN) in a second kidney transplant, after loss of a previous graft due to disease recurrence. Results: Our 26 year-old patient was initially diagnosed with type 1 membranoproliferative glomerulonephritis with isolated C3 deposits. She developed end stage renal disease and received a first kidney transplant in 2007. The post-transplant course was complicated by an early graft loss due to biopsy proven recurrence of C3GN (after 9 months). Persistent activation of the alternative complement pathway (low C3, high C3d and normal C4) was noted before, during and after transplantation. Thus far no underlying pathogenic mechanism has been found despite extensive evaluation of the complement pathway. Because of specific anti-HLA antibodies against more than 85% of the donor panel the patient was admitted to the Eurotransplant Acceptable Mismatch program. A second kidney transplantation was performed in January 2011. We combined standard triple immunosuppression with plasma exchange (40mL/kg body weight per treatment) at decreasing frequency, with a maintenance schedule of 1 exchange every two weeks after the first month. One year after transplantation no rejection has occurred and the patient maintains good graft function (creatinine 1.3 mg/dL) without signs of complement activation, microscopic hematuria and proteinuria. A protocol biopsy 3 months after transplantation showed no signs of disease recurrence on immunofluorescence and electron microscopy. Conclusion: Prophylactic plasma exchange might correct the underlying pathogenic mechanism in patients with C3 glomerulonephritis, thereby preventing uncontrolled complement activation and recurrence of disease after kidney transplantation. Plasma exchange could be a cost-effective and widely available alternative to the recently developed C5 inhibitor Eculizimab in this indication.

Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies

Dense deposit disease and glomerulonephritis with isolated C3 deposits are glomerulopathies characterized by deposits of C3 within or along the glomerular basement membrane. Previous studies found a link between dysregulation of the complement alternative pathway and the pathogenesis of these diseases. We analyzed the role of acquired and genetic complement abnormalities in a cohort of 134 patients, of whom 29 have dense deposit disease, 56 have glomerulonephritis with isolated C3 deposits, and 49 have primary membranoproliferative glomerulonephritis type I, with adult and pediatric onset. A total of 53 patients presented with a low C3 level, and 65 were positive for C3 nephritic factor that was significantly more frequently detected in patients with dense deposit disease than in other histological types. Mutations in CFH and CFI genes were identified in 24 patients associated with a C3 nephritic factor in half the cases. We found evidence for complement alternative pathway dysregulation in 26 patients with membranoproliferative glomerulonephritis type I. The complement factor H Y402H variant was significantly increased in dense deposit disease. We identified one at-risk membrane cofactor protein (MCP) haplotype for glomerulonephritis with isolated C3 deposits and membranoproliferative glomerulonephritis type I. Thus, our results suggest a critical role of fluid-phase alternative pathway dysregulation in the pathogenesis of C3 glomerulopathies as well as in immune complex-mediated glomerular diseases. The localization of the C3 deposits may be under the influence of MCP expression.

Heterogeneous pattern of renal disease associated with homozygous Factor H deficiency

Membranoproliferative glomerulonephritis type II is a rare renal disease, associated with uncontrolled activation of the complement alternative pathway because of C3 nephritic factor. Abnormalities in factor H have been rarely described in patients with membranoproliferative glomerulonephritis type II. We report the clinical history, molecular defect, and histologic description of 3 patients with factor H deficiency and various types of membranoproliferative glomerulonephritis. The 3 patients presented with severely decreased C3. Circulating factor H was undetectable. Complete factor H deficiency (CFH) was due to homozygous complement factor H mutations in short consesus repeat (SCR) 7, 10, and 11. Age at onset was 1 (patient 1), 17 (patient 2), and 33 years (patient 3). Symptoms at diagnosis included proteinuria of 0.5, 2.4, and 11 g/d, respectively, microhematuria, and normal renal function in all cases. The estimated glomerular filtration rate at last follow-up was 25, 43, and 112 mL/min per 1.73 m(2), at ages of 29, 24, and 37 years, respectively. Renal biopsies disclosed a membranoproliferative glomerulonephritis type II with atypical discontinuous dense deposits in patient 1; a membranoproliferative glomerulonephritis type I with immunoglobin G (IgG), C1q, and abundant C3 deposits in patient 2; and a membranoproliferative glomerulonephritis with isolated C3 deposits without dense deposits in patient 3. This report of factor H-deficient patients emphasizes the diversity of the histologic lesions associated with factor H deficiencies and the role of the alternative pathway in several subtypes of membranoproliferative glomerulonephritis.

Membranoproliferative Glomerulonephritis with Isolated C3 Deposits: Case Report and Literature Review

Membranoproliferative glomerulonephritis with isolated C3 deposits (MPGNC3) is an uncommon condition characterized by overt glomerular C3 deposits in the absence of immunoglobulins and intramembranous dense deposits. Here the authors describe the clinical and morphological features of primary MPGNC3 in a 13-year-old boy and critically review the previously published cases. The patient presented with nephrotic syndrome and microscopic hematuria. Blood tests revealed very low circulating C3 levels. The renal biopsy exhibited subendothelial, subepithelial, and mesangial deposits, with C3 but not immunoglobulins seen on immunofluorescence. This case and the review of the literature indicate that the serum complement profile with decreased levels of C3 and normal levels of classical pathway components together with glomerular deposits containing exclusively complement C3 is highly suggestive of alternative pathway activation. The diagnosis of acquired and/or genetic complement abnormalities in some cases supports that complement dysregulation is implicated in the pathogenesis of MPGNC3. Such data show great promise to provide new therapy strategies based on modulation of the complement system activity.

A paraneoplastic membranoproliferative glomerulonephritis with isolated C3 deposits associated with hairy cell leukaemia

We describe a 35-year-old woman who presented with proteinuria and microscopic haematuria. Blood tests revealed a low C3 complement level, with no evidence of cryoglobulin. Renal biopsy showed a Type 1 membranoproliferative glomerulonephritis (MPGN) with isolated C3 deposits on immunofluorescence study. Bone marrow aspirate, done for monocytopenia, was consistent with a diagnosis of hairy cell leukaemia (HCL). Both haematological and nephrological diseases completely responded to treatment with cladribine, strongly suggesting that the renal disease was a paraneoplastic syndrome. To our knowledge, this is the first report of a non-cryoglobulinaemic MPGN associated to HCL.

Complement Factor H Deficiency and Posttransplantation Glomerulonephritis With Isolated C3 Deposits

We report the first cases of atypical hemolytic and uremic syndrome associated with complement factor H (CFH) deficiency in native kidneys and glomerulonephritis with isolated C3 deposits after kidney transplantation. Two boys developed atypical hemolytic and uremic syndrome at 16 and 11 months of age, associated with low C3 and CFH levels. Both rapidly progressed to end-stage renal failure and received a kidney transplant. Patient 1 had combined CFH and complement factor I (CFI) heterozygous mutations and a membrane cofactor protein (gene symbol, CD46) gene polymorphism. Five years posttransplantation, an allograft biopsy specimen showed numerous mesangial and extramembranous C3 deposits, although the patient had no biological sign of glomerulopathy. Nine years after transplantation, he was well with stable kidney function. Patient 2, who had a homozygous CFH mutation, developed glomerulonephritis with isolated C3 deposits 5 months after kidney transplantation while he was treated for early recurrence of hemolytic anemia. Four years later, the second kidney transplant biopsy specimen showed recurrence of thrombotic microangiopathy. Six years posttransplantation, kidney function was stable and complete blood cell count was normal with regular plasma therapy. These observations suggest that constitutional dysregulation of the alternative pathway is associated with a wide spectrum of kidney diseases, and glomerulonephritis with isolated C3 deposits and thrombotic microangiopathy may be different expressions of the same condition. Several factors could influence the disease, such as degree of CFH haploinsufficiency and other complement alternative pathway regulator abnormalities, such as a membrane cofactor protein polymorphism.

Glomerulonephropathy in ankylosing spondylitis

AbstractAim: Renal abnormalities have been reported in ankylosing spondylitis (AS). The purpose of this study was to elucidate the nature of glomerulonephropathy in AS.Methods: Two hundred and sixty‐six patients with definite AS diagnosed at Taipei Veterans General Hospital, Taiwan, were enrolled. Urinary analysis and renal biopsy were performed in this study. The nature of glomerulonephropathy in AS was analyzed.Results: Twelve out of 266 (4.5%) patients had AS‐associated nephropathy manifesting as haematuria alone (11 patients) or haematuria and proteinuria (1 patient). Renal biopsy in seven patients showed IgA nephropathy in two cases, mesangial nephropathy with isolated C3 deposits in three cases, and IgM nephropathy in two cases, one of which had accompanied infectious endocarditis.Conclusion: AS‐associated nephropathy is not uncommon and mesangial nephropathy is the most common form. Microscopic haematuria and proteinuria are the most common manifestations of renal involvement.

Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome

Introduction: Abnormal control of the complement alternative pathway (CAP) (factor H, factor I and membrane cofactor protein (MCP) deficiencies) is a well established risk factor for the occurrence of haemolytic...

Study of Asymptomatic Microscopic Hematuria in Potential Living Related Kidney Donors

Thirty potential living related kidney donors with asymptomatic microscopic hematuria of nonsurgical causes were entered in this study. They underwent thorough history taking, medical and ENT examination, laboratory and radiologic assessment and pure-tone audiometry. Family members were also subjected to urine analysis and audiometry. Moreover, the 30 donors were subjected to kidney biopsies which were examined by light microscopy, direct and indirect immunofluorescent microscopy, and electron microscopy. Hereditary nephritis (with or without sensorineural deafness) was found to be the most common cause of asymptomatic microscopic hematuria (25/30), followed by isolated C3 deposits disease (3/30), IgA nephropathy (1/30) and IgM nephropathy (1/30). Since these disease conditions are of a progressive nature, we have concluded that relatives of uremic patients with asymptomatic microscopic hematuria should not be considered for kidney donation even if they are strongly motivated.

Familial occurrence of primary glomerulonephritis: evidence for a role of genetic factors.

Chronic glomerulonephritis was diagnosed in 23 patients born in a small valley in Northern Italy and in five additional patients with one parent or a more remote ancestor born in the same area, all belonging to three potentially related families. Eighteen patients had biopsy-proven glomerulonephritis: 11 IgA nephropathy, 3 IgM nephropathy, 2 membranoproliferative type I, and 2 mesangial proliferative glomerulonephritis with isolated C3 deposits. Ten had clinical glomerulonephritis. A community screening programme discovered six additional related patients. Two underwent renal biopsy (1 IgA nephropathy; 1 focal glomerulosclerosis); four were diagnosed as having clinical glomerulonephritis. Genealogical investigation identified five deceased family members with diagnoses of chronic nephritis recorded on their death certificates. No environmental nephrotoxic factors were identified. Restriction fragment length polymorphism (RFLP) analysis of HLA-DR beta, HLA-DQ alpha and beta genes, and complement typing for C4A, C4B, and Bf polymorphisms were carried out for 29 patients, 168 healthy relatives, and 24 local controls. The frequency of HLA-Dw8.1 specificity, related to DR beta 8, DQ beta 3b, and DQ alpha 1a RFLPs, was significantly increased more in the affected and unaffected pedigree members than in Italian controls.