Rituximab (RTX) is non-inferior to cyclophosphamide (CYC) followed by azathioprine (AZA) for remission-induction in severe ANCA-associated vasculitis (AAV), but renal outcomes are unknown. This is a post hoc analysis of patients enrolled in the Rituximab for ANCA-Associated Vasculitis (RAVE) Trial who had renal involvement (biopsy proven pauci-immune GN, red blood cell casts in the urine, and/or a rise in serum creatinine concentration attributed to vasculitis). Remission-induction regimens were RTX at 375 mg/m(2) × 4 or CYC at 2 mg/kg/d. CYC was replaced by AZA (2 mg/kg/d) after 3-6 months. Both groups received glucocorticoids. Complete remission (CR) was defined as Birmingham Vasculitis Activity Score/Wegener's Granulomatosis (BVAS/WG)=0 off prednisone. Fifty-two percent (102 of 197) of the patients had renal involvement at entry. Of these patients, 51 were randomized to RTX, and 51 to CYC/AZA. Mean eGFR was lower in the RTX group (41 versus 50 ml/min per 1.73 m(2); P=0.05); 61% and 75% of patients treated with RTX and 63% and 76% of patients treated with CYC/AZA achieved CR by 6 and 18 months, respectively. No differences in remission rates or increases in eGFR at 18 months were evident when analysis was stratified by ANCA type, AAV diagnosis (granulomatosis with polyangiitis versus microscopic polyangiitis), or new diagnosis (versus relapsing disease) at entry. There were no differences between treatment groups in relapses at 6, 12, or 18 months. No differences in adverse events were observed. In conclusion, patients with AAV and renal involvement respond similarly to remission induction with RTX plus glucocorticoids or CYC plus glucocorticoids.
Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) has been described as a new entity resembling immune-complex glomerulonephritis (GN). The recurrence of proliferative GN with monoclonal IgG in the renal allograft has been reported. However, recurrence of proliferative GN with monoclonal IgA after renal allograft is undefined. We previously reported a case of a 35-year-old woman with proliferative glomerulonephritis with monoclonal lambda (lambda) with mesangial and subendothelial paracrystalline deposits in the native kidney and initially undetectable circulating monoclonal protein or clone by bone marrow biopsy or flow cytometry. Despite immunosuppressive therapy, her renal disease progressed to end-stage of renal disease (ESRD) and the patient ultimately received a renal allograft. Transplantation was followed by recurrence of IgA-lamba PGNMID 4 months after renal transplantation and was associated the diagnosis of multiple myeloma. To the best of our knowledge recurrence of IgA PGNMID with paracrystalline deposits has not been previously reported.
Atypical hemolytic uremic syndrome (aHUS) is a relatively rare disorder described by the triad of hemolytic anemia, thrombocytopenia, and renal failure. Atypical HUS could be genetic, acquired, or idiopathic (without known genetic changes or environmental triggers). Monoclonal protein has uncommonly been reported as a cause of microangiopathic hemolytic anemia (MAHA). We report a 59-year-old white man who presented with acute kidney injury (AKI) with MAHA and was given a diagnosis of aHUS with monoclonal gammopathy. His kidney function and proteinuria worsened with persistent hemolysis despite eculizumab and later cyclophosphamide and prednisone treatment. He responded well to VRD (bortezomib, lenalidomide, and dexamethasone) regimen. Renal function, proteinuria, and hemolysis all improved, and he was been in remission for more than 15 months. To our knowledge, this is the first report of successful treatment with bortezomib-based regimen for a patient with aHUS and monoclonal protein refractory to eculizumab therapy.
Monoclonal Ig deposition disease (MIDD) is a rare complication of monoclonal gammopathy characterized by deposition of monoclonal Ig light chains and/or heavy chains along the glomerular and tubular basement membranes. Here, we describe a unique case of IgD deposition disease. IgD deposition is difficult to diagnose, because routine immunofluorescence does not detect IgD. A 77-year-old man presented with proteinuria and renal failure, and kidney biopsy analysis showed a nodular sclerosing GN with extensive focal global glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Immunofluorescence was negative for Ig deposits, although electron microscopy showed deposits in the glomeruli and along tubular basement membranes. Laser microdissection of glomeruli and mass spectrometry of extracted peptides showed a large spectra number for IgD, and immunohistochemistry showed intense glomerular and tubular staining for IgD. Together, these findings are consistent with IgD deposition disease. Bone marrow biopsy analysis showed 5% plasma cells, which stained for IgD. The patient was treated with bortezomib and dexamethasone, which resulted in improvement of hematologic parameters but no improvement of renal function. The diagnosis of IgD deposition disease underscores the value of laser microdissection and mass spectrometry in further evaluating renal biopsies when routine assessment fails to reach an accurate diagnosis.
Dysfunction of the alternative pathway of complement in the fluid phase results in deposition of complement factors in the renal glomeruli. This results in glomerular injury and an ensuing proliferative response. The term "C3 glomerulopathy" is used to define such an entity. It includes both C3 glomerulonephritis and dense deposit disease (DDD). Both C3 glomerulonephritis and DDD are characterized by a proliferative glomerulonephritis and bright glomerular C3 mesangial and capillary wall staining with the absence or scant staining for immunoglobulins (Ig). The two conditions are distinguished based on electron microscopy findings: mesangial and capillary wall deposits are noted in C3 glomerulonephritis, while ribbon-shaped dense osmiophilic intramembranous and mesangial deposits are noted in DDD. On the contrary, uncontrolled activation of the alternative pathway of complement on endothelial cell surface results in endothelial injury with an ensuing thrombotic microangiopathy, termed atypical hemolytic uremic syndrome (aHUS). Kidney biopsy in aHUS is often indistinguishable from other forms of thrombotic microangiopathy including enterohemorrhagic Escherichia coli-induced HUS and thrombotic thrombocytopenic purpura and shows thrombi in glomerular capillaries, mesangiolysis, and endothelial injury as evidenced by swelling and double contour formation along the glomerular capillary walls, with negative immunofluorescence studies for Ig and complement factors and no deposits on electron microscopy.
Redux: brought back, resurgent (Wikipedia free dictionary). This essay traces the history of the concepts that led to the usage of the term 'nephrotic syndrome' beginning ?90 years ago. We then examined the various definitions used for this syndrome and modified them to conform to contemporary standards. Remarkably, only minor modifications were required. This analysis of a common clinical entity may be helpful in ensuring appropriate evaluation of patients suffering from nephrotic syndrome and nephrotic-range proteinuria.
H.P. Acthar(®) Gel is currently the only Food and Drug Administration therapy approved for the treatment of nephrotic syndrome. Active drug ingredients include structurally related melanocortin peptides that bind to cell surface G-protein-coupled receptors known as melanocortin receptors, which are expressed in glomerular podocytes. In animal models of membranous nephropathy, stimulation has been demonstrated to reduce podocyte injury and loss. We hypothesized that H.P. Acthar(®) Gel would improve symptoms of the nephrotic syndrome in patients with idiopathic membranous nephropathy.
Prior to the 1970s, severe cases of antineutrophil cytoplasmic antibody associated vasculitis (AAV) were thought to be invariably fatal. However, the use of cyclophosphamide-based treatment regimens fundamentally altered disease outcomes, transforming AAV into a manageable, chronic illness. Despite the tremendous success of cyclophosphamide in the treatment of AAV, there remained a need for alternative therapies, due to high rates of treatment failures and significant toxicities. In recent years, with the introduction of targeted biologic response modifiers into clinical practice, many have hoped that the treatment options for AAV could be expanded. Rituximab, a chimeric monoclonal antibody directed against the B-lymphocyte protein CD20, has been the most successful biologic response modifier to be used in AAV. Following the first report of its use in AAV in 2001, experience with rituximab for treatment of AAV has rapidly expanded. Rituximab, in combination with glucocorticosteroids, is now well established as a safe and effective alternative to cyclophosphamide for remission induction for severe manifestations of granulomatosis with polyangiitis and microscopic polyangiitis. In addition, initial experiences with rituximab for remission maintenance in these diseases have been favorable, as have experiences for remission induction in eosinophilic granulomatosis with polyangiitis.
Focal and segmental glomerulosclerosis (FSGS) is a common histopathological lesion that can represent a primary podocytopathy, or occur as an adaptive phenomenon consequent to nephron mass reduction, a scar from a healing vasculitic lesion, direct drug toxicity or viral infection among other secondary causes. Thus, the presence of an FSGS lesion in a renal biopsy does not confer a disease diagnosis, but rather represents the beginning of an exploratory process, hopefully leading ultimately to identification of a specific etiology and its appropriate treatment. We define primary FSGS as a 'primary' podocytopathy characterized clinically by the presence of nephrotic syndrome in a patient with an FSGS lesion on light microscopy and widespread foot process effacement on electron microscopy (EM). Secondary FSGS is commonly characterized by the absence of nephrotic syndrome and the presence of segmental foot process effacement on EM. Failure to accurately differentiate between the primary and secondary forms of FSGS has resulted in many patients undergoing unnecessary immunosuppressive treatment. Here, we review some key points that may assist the practicing nephrologist to distinguish between primary and secondary FSGS.
The Nephrology Quiz and Questionnaire (NQ&Q) remains an extremely popular session for attendees of the Annual Meeting of the American Society of Nephrology. As in past years, the conference hall of the 2013 meeting was overflowing with interested audience members. Topics covered by expert discussants included electrolyte and acid-base disorders, glomerular disease, ESRD/dialysis, and transplantation. Complex cases representing each of these categories, along with single best answer questions, were prepared by a panel of experts. Before the meeting, program directors of United States nephrology training programs answered questions through an Internet-based questionnaire. A new addition to the NQ&Q was participation in the questionnaire by nephrology fellows. To review the process, members of the audience test their knowledge and judgment on a series of case-oriented questions prepared and discussed by experts. Their answers are compared in real time using audience response devices with the answers of nephrology fellows and training program directors. The correct and incorrect answers are then briefly discussed after the audience responses and the results of the questionnaire are displayed. This article recapitulates the session and reproduces its educational value for CJASN readers. Enjoy the clinical cases and expert discussions.
Membranoproliferative glomerulonephritis (MPGN) has been classified based on its pathogenesis into immune complex-mediated and complement-mediated MPGN. The immune complex-mediated type is secondary to chronic infections, autoimmune diseases or monoclonal gammopathy. There is a paucity of data on MPGN associated with autoimmune diseases. We reviewed the Mayo Clinic database over a 10-year period and identified 12 patients with MPGN associated with autoimmune diseases, after exclusion of systemic lupus erythematosus. The autoimmune diseases included rheumatoid arthritis, primary Sjögren's syndrome, undifferentiated connective tissue disease, primary sclerosing cholangitis and Graves' disease. Nine of the 12 patients were female, and the mean age was 57.9 years. C4 levels were decreased in nine of 12 patients tested. The serum creatinine at time of renal biopsy was 2.2 ± 1.0 mg/dl and the urinary protein was 2,850 ± 3,543 mg/24 h. Three patients required dialysis at the time of renal biopsy. Renal biopsy showed an MPGN in all cases, with features of cryoglobulins in six cases; immunoglobulin (Ig)M was the dominant Ig, and both subendothelial and mesangial electron dense deposits were noted. Median follow-up was 10.9 months. Serum creatinine and proteinuria improved to 1.6 ± 0.8 mg/dl and 428 ± 677 mg/24 h, respectively, except in 3 patients with end-stage renal disease. In summary, this study describes the clinical features, renal biopsy findings, laboratory evaluation, treatment and prognosis of MPGN associated with autoimmune diseases.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small-vessel vasculitis that primarily comprises 2 clinical syndromes: granulomatosis with polyangiitis and microscopic polyangiitis. Cyclophosphamide and glucocorticoids have traditionally been used for induction of remission. However, more recent studies have shown that rituximab is as effective as cyclophosphamide for induction therapy in patients with newly diagnosed severe AAV and superior for patients with relapsing AAV. There is also accumulating evidence indicating a potential role of rituximab for maintenance therapy in AAV. In this article, we will review the evidence supporting the various treatment choices for patients with AAV.
C3 glomerulonephritis (C3GN) results from abnormalities in the alternative pathway of complement, and it is characterized by deposition of C3 with absent or scant Ig deposition. In many patients, C3GN progresses to ESRD. The clinical features, pathology, and outcomes of patients with C3GN receiving kidney transplantation are unknown. Between 1996 and 2010, we identified 21 patients at our institution who received a kidney transplant because of ESRD from C3GN. The median age at the time of initial diagnosis of C3GN at kidney biopsy was 20.8 years. The median time from native kidney biopsy to dialysis or transplantation was 42.3 months. Of 21 patients, 14 (66.7%) patients developed recurrent C3GN in the allograft. The median time to recurrence of disease was 28 months. Graft failure occurred in 50% of patients with recurrent C3GN, with a median time of 77 months to graft failure post-transplantation. The remaining 50% of patients had functioning grafts, with a median follow-up of 73.9 months. The majority of patients had hematuria and proteinuria at time of recurrence. Three (21%) patients were positive for monoclonal gammopathy and had a faster rate of recurrence and graft loss. Kidney biopsy at the time of recurrence showed mesangial proliferative GN in eight patients and membranoproliferative GN in six patients. All allograft kidney biopsies showed bright C3 staining (2-3+), with six biopsies also showing trace/1+ staining for IgM and/or IgG. To summarize, C3GN recurs in 66.7% of patients, and one half of the patients experience graft failure caused by recurrence.
The 18-month efficacy of a single course of rituximab as compared with conventional immunosuppression with cyclophosphamide followed by azathioprine in patients with severe (organ-threatening) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is unknown.
A young male is evaluated for nephrotic-range proteinuria, hypercalciuria, and an elevated serum creatinine. A renal biopsy is performed and shows focal global glomerulosclerosis. The absence of nephrotic syndrome suggest that glomerulosclerosis was a secondary process. Further analysis of the proteinuria showed it to be due mainly to low-molecular weight proteins. The case illustrates the crucial role of electron microscopy as well as evaluation of the identity of the proteinuria that accompanies a biopsy finding of focal and global or focal and segmental glomerulosclerosis.
Immunosuppressive treatment of patients with idiopathic membranous nephropathy (iMN) is heavily debated. The controversy is mainly related to the toxicity of the therapy and the variable natural course of the disease-spontaneous remission occurs in 40-50% of patients. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis provides guidance for the treatment of iMN. The guideline suggests that immunosuppressive therapy should be restricted to patients with nephrotic syndrome and persistent proteinuria, deteriorating renal function or severe symptoms. Alkylating agents are the preferred therapy because of their proven efficacy in preventing end-stage renal disease. Calcineurin inhibitors can be used as an alternative although efficacy data on hard renal end points are limited. In this Review, we summarize the KDIGO guideline and address remaining areas of uncertainty. Better risk prediction is needed to identify patients who will benefit from immunosuppressive therapy, and the optimal timing and duration of this therapy is unknown because most of the randomized controlled trials were performed in low-risk or medium-risk patients. Alternative therapies, directed at B cells, are under study. The discovery of anti-M type phospholipase A2 receptor-antibodies is a major breakthrough and we envisage that in the near future, antibody-driven therapy will enable more individualized treatment of patients with iMN.
Recently, serum soluble urokinase receptor (suPAR) has been proposed as a cause of two thirds of cases of focal segmental glomerulosclerosis (FSGS). It was noted to be uniquely elevated in cases of primary FSGS, with higher levels noted in cases that recurred after transplantation. It is also suggested as a possible target and marker of therapy.
Presentation of the Nephrology Quiz and Questionnaire (NQQ) has become an annual tradition at the meetings of the American Society of Nephrology. It is a very popular session, judged by consistently large attendance. Members of the audience test their knowledge and judgment on a series of case-oriented questions prepared and discussed by experts. They can also compare their answers in real time, using audience response devices, to those of program directors of nephrology training programs in the United States, acquired through an Internet-based questionnaire. The topic presented here is GN. Cases representing this category, along with single best answer questions, were prepared by a panel of experts (Drs. Fervenza, Glassock, and Bleyer). The correct and incorrect answers were then briefly discussed after the audience responses and the results of the questionnaire were displayed. This article recapitulates the session and reproduces its educational value for a larger audience--that of the readers of the Clinical Journal of the American Society of Nephrology. Have fun.
C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition. This meeting report represents the current consensus view of the group.
The value of classification systems applied to the examination of renal biopsies is based on several factors: first, on the ability to provide efficient communication between pathologists and between pathologists and clinicians; second, on the possibility to implement diagnostic information with prognostic indication. Even more important, the practical value of a classification is proved by the ability of providing elements that guide therapeutic decisions and can be used in the follow-up of the patient. With these aims, new histologic classification systems have been proposed in the last decade for lupus nephritis and IgA nephropathy under the leadership of the Renal Pathology Society and the International Society of Nephrology. These classifications have gained a significant level of worldwide acceptance and have been the subject of multiple single-center and multicenter validation studies, which have underpinned their clinical benefits and limitations and served to highlight remaining questions and difficulties of interpretation of the biopsy sample. More recently, a classification system has also been proposed for ANCA-associated crescentic glomerulonephritis (ANCA-GN), although the validation process for this is still in an early stage. In this review, we examine in some detail the ISN/RPS classification for lupus nephritis and the Oxford classification for IgA nephropathy, with emphasis on clinicopathologic correlations, their value for and evolving impact on clinical studies and clinical practice, and their significant limitations in this regard as exposed by validation studies. We also suggest possible ways by which these classifications might be modified to make them more applicable to clinical practice. Finally, we more briefly discuss the newly proposed classification for ANCA-GN.Kidney International advance online publication, 2 October 2013; doi:10.1038/ki.2013.375.
C3 glomerulonephritis (GN) is a proliferative GN resulting from glomerular deposition of complement factors due to dysregulation of the alternative pathway of complement. Dysregulation of the alternative pathway of complement may occur as a result of mutations or functional inhibition of complement-regulating proteins. Functional inhibition of the complement-regulating proteins may result from a monoclonal gammopathy.
The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multicenter collaborative consortium established to develop a translational research infrastructure for nephrotic syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary study program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy for detailed clinical, histopathological, and molecular phenotyping at the time of clinically indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and biannually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histological data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for nephrotic syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.
In the kidney, immunoglobulin light chain amyloidosis (AL) can be deposited in vascular-limited AL (V-AL) or diffuse (D-AL) pattern. These patterns are associated with different clinical presentations. A nested case study was performed to describe these differences. V-AL was defined by the vascular-limited deposits. Cases were matched for age, sex and date of renal biopsy. There were 12 cases of V-AL (mean age 61 ± 11 years) and 24 cases of D-AL. Median follow-up was 26 months for V-AL and 38 months for D-AL, P = 0.14. Lambda was more common in D-AL (83.3%) than V-AL (50%, P = 0.04). Cardiac function was similar between the two groups. V-AL patients presented with lower renal function (serum creatinine = 2.1 versus 1.3 mg/dL, P = 0.02; estimated glomerular filtration rate 31 versus 59 mL/min/1.73m(2), P = 0.01 and creatinine clearance 38.5 versus 64 mL/min/1.73m(2), P = 0.02, respectively). Proteinuria was low grade in V-AL [0.4 (0.09-0.98) g/day] compared to nephrotic range in D-AL patients [8.0 (0.2-22) g/day, P < 0.001]. Stem cell transplantation was performed on 62.5% of the D-AL but on only 25% of the V-AL, P = 0.08. Median survival was longer in patients with D-AL (77.2 months) versus V-AL (40.6 months, log-rank P = 0.02). Our study found that V-AL patients presented with more severe renal insufficiency and less proteinuria than D-AL. There was a preference for ? light chain in the D-AL that was not noted in the V-AL. Patients with D-AL in this study had a longer median survival but most of them were stem cell transplantation candidates.
To identify biomarkers that distinguish between active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and remission in a manner superior or complementary to established markers of systemic inflammation.
Presentation of the Nephrology Quiz and Questionnaire (NQQ) has become an annual "tradition" at the meetings of the American Society of Nephrology. It is a very popular session judged by consistently large attendance. Members of the audience test their knowledge and judgment on a series of case-oriented questions prepared and discussed by experts. They can also compare their answers in real time, using audience response devices, to those of program directors of nephrology training programs in the United States, acquired through an Internet-based questionnaire. As in the past, the topics covered were transplantation, fluid and electrolyte disorders, end-stage renal disease and dialysis, and glomerular disorders. Two challenging cases representing each of these categories along with single best answer questions were prepared by a panel of experts (Drs. Hricik, Palmer, Bargman, and Fervenza, respectively). The "correct" and "incorrect" answers then were briefly discussed, after the audience responses and the results of the questionnaire were displayed. The 2010 version of the NQQ was exceptionally challenging, and the audience, for the first time, gained a better overall correct answer score than the program directors, but the margin was small. Last month we presented the transplantation and fluid and the electrolyte cases; in this issue we present the remaining end-stage renal disease and dialysis and the glomerular disorder cases. These articles try to recapitulate the session and reproduce its educational value for a larger audience--that of the readers of the Clinical Journal of the American Society of Nephrology. Have fun.
Membranoproliferative glomerulonephritis (MPGN) is a pattern of injury that results from subendothelial and mesangial deposition of Igs caused by persistent antigenemia and/or circulating immune complexes. The common causes of Ig-mediated MPGN include chronic infections, autoimmune diseases, and monoclonal gammopathy/dysproteinemias. On the other hand, MPGN also can result from subendothelial and mesangial deposition of complement owing to dysregulation of the alternative pathway (AP) of complement. Complement-mediated MPGN includes dense deposit disease and proliferative glomerulonephritis with C3 deposits. Dysregulation of the AP of complement can result from genetic mutations or development of autoantibodies to complement regulating proteins with ensuing dense deposit disease or glomerulonephritis with C3 deposits. We propose a new histologic classification of MPGN and classify MPGN into 2 major groups: Ig-mediated and complement-mediated. MPGN that is Ig-mediated should lead to work-up for infections, autoimmune diseases, and monoclonal gammopathy. On the other hand, complement-mediated MPGN should lead to work-up of the AP of complement. Initial AP screening tests should include serum membrane attack complex levels, an AP functional assay, and a hemolytic assay, followed by tests for mutations and autoantibodies to complement-regulating proteins.
Autoantibodies to the M-type phospholipase A(2) receptor (PLA(2)R) are sensitive and specific for idiopathic membranous nephropathy. The anti-B cell agent rituximab is a promising therapy for this disease, but biomarkers of early response to treatment currently do not exist. Here, we investigated whether levels of anti-PLA(2)R correlate with the immunological activity of membranous nephropathy, potentially exhibiting a more rapid response to treatment than clinical parameters such as proteinuria. We measured the amount of anti-PLA(2)R using Western blot immunoassay in serial serum samples from a total of 35 patients treated with rituximab for membranous nephropathy in two distinct cohorts. Pretreatment samples from 25 of 35 (71%) patients contained anti-PLA(2)R, and these autoantibodies declined or disappeared in 17 (68%) of these patients within 12 months after rituximab. Those who demonstrated this immunologic response fared better clinically: 59% and 88% attained complete or partial remission by 12 and 24 months, respectively, compared with 0% and 33% among those with persistent anti-PLA(2)R levels. Changes in antibody levels preceded changes in proteinuria. One subject who relapsed during follow-up had a concomitant return of anti-PLA(2)R. In summary, measuring anti-PLA(2)R levels by immunoassay may be a method to follow and predict response to treatment with rituximab in membranous nephropathy.
Chronic kidney disease (CKD) is becoming a major public health issue worldwide, mainly due to the increasing prevalence of hypertension, diabetes and aging population. Chronic hepatitis C virus (HCV) infection commonly involves the kidneys, can be a cause of CKD, and significantly impacts morbidity and mortality in these patients. Prompt recognition and knowledge of how to best manage these patients are essential in order to have a successful renal outcome. Patients with HCV and kidney involvement can often be managed with a specific combination of antiviral drugs, immunosuppressants, plasmapheresis, and newer monoclonal antibodies. However, no large randomized controlled trials have been conducted in this patient population, optimal management of HCV-mediated kidney diseases is not well defined, and treatment itself can be associated with significant toxicity in patients with CKD. This article reviews the recent literature, discusses the limitations of current therapies, as well as toxicity associated with treatment, and suggests future areas for research.
Epidemiological studies have shown a relationship between hepatitis B virus (HBV) infection and development of proteinuria in some patients (most commonly children), with a predominance for male gender and histological findings of membranous nephropathy on renal biopsy. The presence of immune complexes in the kidney suggests an immune complex basis for the disease, but a direct relation between HBV and membranous nephropathy (or other types of glomerular diseases) remains to be proven. Clearance of HBV antigens, either spontaneous or following antiviral treatments results in improvement in proteinuria. Thus, prompt recognition and specific antiviral treatment are critical in managing patients with HBV and renal involvement. The present review focuses on treatment of HBV with special emphasis given to antiviral therapies, its complications, and dosing in patients with HBV-associated kidney disease.
The Oxford classification of IgA nephropathy (IgAN) identified four pathological elements that were of prognostic value and additive to known clinical and laboratory variables in predicting patient outcome. These features are segmental glomerulosclerosis/adhesion, mesangial hypercellularity, endocapillary proliferation, and tubular atrophy/interstitial fibrosis. Here, we tested the Oxford results using an independent cohort of 187 adults and children with IgAN from 4 centers in North America by comparing the performance of the logistic regression model and the predictive value of each of the four lesions in both data sets. The cohorts had similar clinical and histological findings, presentations, and clinicopathological correlations. During follow-up, however, the North American cohort received more immunosuppressive and antihypertensive therapies. Identifying patients with a rapid decline in the rate of renal function using the logistic model from the original study in the validation data set was good (c-statistic 0.75), although less precise than in the original study (0.82). Individually, each pathological variable offered the same predictive value in both cohorts except mesangial hypercellularity, which was a weaker predictor. Thus, this North American cohort validated the Oxford IgAN classification and supports its utilization. Further studies are needed to determine the relationship to the impact of treatment and to define the value of the mesangial hypercellularity score.
Recent advances in the treatment of immunoglobulin light chain amyloidosis (AL) have dramatically improved survival. Kidney transplantation (KTx) has become more common but the long-term outcomes remain unknown and it is the objective of this study.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a common cause of rapidly progressive glomerulonephritis resulting in end-stage renal disease (ESRD). The optimal timing of kidney transplantation (KTX) for ESRD as a result of AAV and the risk of AAV relapse after KTX are not well defined. We report our experience with AAV patients who underwent KTX at our institutions between 1996 and 2010. Median follow-up was 64 months.
Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebo-controlled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m²). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (+3.3 ± 8.5 ml/min per 1.73 m²) whereas the mean eGFR decreased in the placebo group (-2.2 ± 4.8 ml/min per 1.73 m²; P = 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (-1.9 ± 6.7 ml/min per 1.73 m²). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P = 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy.
Fibrillary glomerulonephritis (FGN) is a rare primary glomerular disease. Most previously reported cases were idiopathic. To better define the clinical-pathologic spectrum and prognosis, we report the largest single-center series with the longest follow-up.
dense deposit disease (DDD) is the prototypical membranoproliferative glomerulonephritis (MPGN), in which fluid-phase dysregulation of the alternative pathway (AP) of complement results in the accumulation of complement debris in the glomeruli, often producing an MPGN pattern of injury in the absence of immune complexes. A recently described entity referred to as GN with C3 deposition (GN-C3) bears many similarities to DDD. The purpose of this study was to evaluate AP function in cases of GN-C3.
Primary focal segmental glomerulosclerosis (FSGS) is a disease with poor prognosis and high unmet therapeutic need. Here, we evaluated the safety and pharmacokinetics of single-dose infusions of fresolimumab, a human monoclonal antibody that inactivates all forms of transforming growth factor-? (TGF-?), in a phase I open-label, dose-ranging study. Patients with biopsy-confirmed, treatment-resistant, primary FSGS with a minimum estimated glomerular filtration rate (eGFR) of 25? ml/min per 1.73 ?m(2), and a urine protein to creatinine ratio over 1.8? mg/mg were eligible. All 16 patients completed the study in which each received one of four single-dose levels of fresolimumab (up to 4? mg/kg) and was followed for 112 days. Fresolimumab was well tolerated with pustular rash the only adverse event in two patients. One patient was diagnosed with a histologically confirmed primitive neuroectodermal tumor 2 years after fresolimumab treatment. Consistent with treatment-resistant FSGS, there was a slight decline in eGFR (median decline baseline to final of 5.85?ml/min per 1.73? m(2)). Proteinuria fluctuated during the study with the median decline from baseline to final in urine protein to creatinine ratio of 1.2 ?mg/mg with all three Black patients having a mean decline of 3.6? mg/mg. The half-life of fresolimumab was ?14 days, and the mean dose-normalized Cmax and area under the curve were independent of dose. Thus, single-dose fresolimumab was well tolerated in patients with primary resistant FSGS. Additional evaluation in a larger dose-ranging study is necessary.
Churg-Strauss syndrome (CSS) is a small vessel systemic vasculitis associated with asthma and eosinophilia that causes glomerulonephritis (GN) in ?25% of patients. Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody that depletes B cells and is effective in numerous autoimmune diseases including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We aim to evaluate the safety and efficacy of RTX in inducing remission of renal disease activity in patients with CSS.
We describe a 67-year-old woman who presented with significant proteinuria and hematuria. Kidney biopsy showed immunoglobulin G4 (IgG4)-related tubulointerstitial nephritis (TIN) with concurrent membranous nephropathy. IgG4-related TIN is a recently described entity that presents with progressive decreased kidney function and is characterized by a plasma cell-rich infiltrate that is positive for IgG4. It is associated with patchy, often well-localized, tubular atrophy and interstitial fibrosis. Workup for circulating anti-phospholipase A(2) receptor antibodies was negative, suggesting that the membranous nephropathy was not "primary" and may be linked to the IgG4-related disease. The presence of significant proteinuria and hematuria in the setting of IgG4-related TIN should raise suspicion of a glomerular disease. It is important to correctly diagnose IgG4-related TIN and concurrent membranous nephropathy because the lesion responds well to steroid therapy.
In patients with HIV, the use of highly active antiretroviral therapy has improved life expectancy. At the same time, this increase in life expectancy has been associated with a higher frequency of chronic kidney disease due to factors other than HIV infection. Besides HIV-associated nephropathy, a number of different types of immune complex and non-immune complex-mediated processes have been identified on kidney biopsies, including vascular disease (nephrosclerosis), diabetes, and drug-related renal injury. In this setting, renal biopsy needs to be considered in order to obtain the correct diagnosis in individual patients with HIV and kidney impairment. Many issues regarding the optimal treatment of the different pathological processes affecting the kidneys of these patients have remained unresolved. Further research is needed in order to optimize treatment and renal outcomes in patients with HIV and kidney disease.
A number of case reports and case series of patients with Wegeners granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome have supported the use of rituximab (RTX) for the treatment of refractory ANCA-associated vasculitis (AAV). Whether B cell depletion with RTX could replace cyclophosphamide as a first-line therapy for patients with severe AAV remains to be proven. Two studies, recently published in the New England Journal of Medicine, have examined the efficacy of RTX in inducing remission in patients with severe AAV.
It was postulated that in patients with membranous nephropathy (MN), four weekly doses of Rituximab (RTX) would result in more effective B cell depletion, a higher remission rate, and maintaining the same safety profile compared with patients treated with RTX dosed at 1 g every 2 weeks. This hypothesis was supported by previous pharmacokinetic (PK) analysis showing that RTX levels in the two-dose regimen were 50% lower compared with nonproteinuric patients, which could potentially result in undertreatment.
Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen.
Dense deposit disease (DDD) is a rare glomerular disease that typically affects children, young adults, and much less commonly, older patients. The pathophysiologic process underlying DDD is uncontrolled activation of the alternative pathway (AP) of complement cascade, most frequently secondary to an autoantibody to C3 convertase called C3 nephritic factor, although mutations in factor H and autoantibodies to this protein can impair its function and also cause DDD. Since 1995, we have diagnosed DDD in 14 patients aged 49 years or older; 10 of these patients (71.4%) carry a concomitant diagnosis of monoclonal gammopathy of undetermined significance (MGUS). In 1 of these 10 patients, the index case described here, we evaluated the AP and showed low serum AP protein levels consistent with complement activity, heterozygosity for the H402 allele of factor H, and low levels of factor H autoantibodies, which can affect the ability of factor H to regulate AP activity. In aggregate, these findings suggest that in some adults with MGUS, DDD may develop as a result of autoantibodies to factor H (or other complement proteins) that on a permissive genetic background (the H402 allele of factor H) lead to dysregulation of the AP with subsequent glomerular damage. Thus, DDD in some older patients may be a distinct clinicopathologic entity that represents an uncommon complication of MGUS.
To study the predictive value of biopsy lesions in IgA nephropathy in a range of patient ages we retrospectively analyzed the cohort that was used to derive a new classification system for IgA nephropathy. A total of 206 adults and 59 children with proteinuria over 0.5 g/24 h/1.73 m(2) and an eGFR of stage-3 or better were followed for a median of 69 months. At the time of biopsy, compared with adults children had a more frequent history of macroscopic hematuria, lower adjusted blood pressure, and higher eGFR but similar proteinuria. Although their outcome was similar to that of adults, children had received more immunosuppressants and achieved a lower follow-up proteinuria. Renal biopsies were scored for variables identified by an iterative process as reproducible and independent of other lesions. Compared with adults, children had significantly more mesangial and endocapillary hypercellularity, and less segmental glomerulosclerosis and tubulointerstitial damage, the four variables previously identified to predict outcome independent of clinical assessment. Despite these differences, our study found that the cross-sectional correlation between pathology and proteinuria was similar in adults and children. The predictive value of each specific lesion on the rate of decline of renal function or renal survival in IgA nephropathy was not different between children and adults.
Membranoproliferative glomerulonephritis (MPGN) is an immune complex-mediated glomerulonephritis characterized by subendothelial and mesangial deposition of immune complexes. Autoimmune diseases and chronic infections, such as hepatitis C, are commonly recognized causes of MPGN; however, monoclonal gammopathy is a less widely recognized cause of MPGN.
On examination of the records of 1321 patients following kidney transplant over an 11-year period, we found that 29 patients had recurrent membranoproliferative glomerulonephritis (MPGN). We excluded from this analysis patients who had MPGN type II, those with clear evidence of secondary MPGN, and those lacking post-transplant biopsies. During an average of 53 months of follow-up, we found using protocol biopsies that 12 of these patients had recurrent MPGN diagnosed 1 week to 14 months post-transplant. In 4 of the 12 patients this presented clinically, whereas the remaining had subclinical disease. The risk of recurrence was significantly increased in patients with low complement levels. Serum monoclonal proteins were found in a total of six patients; appeared to be associated with earlier, more aggressive disease; and were more common in recurrent than non-recurrent disease. The recurrence of MPGN was marginally higher in recipients of living-donor kidneys. Some patients developed characteristic lesions within 2 months post-transplant, whereas others presented with minimal, atypical histological changes that progressed to MPGN. Of 29 patients, 5 lost their allograft and 2 patients remain on chronic plasmapheresis. Our study shows the risk of MPGN recurrence and progression depends on identifiable pretransplant characteristics, has variable clinical impact, and can result in graft failure.
Microscopic polyangiitis (MPA) is a systemic small-vessel vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA), often targeting myeloperoxidase (MPO). Cyclophosphamide (CYC) plus corticosteroids (CS) is considered standard therapy for patients with renal involvement, but treatment response is not satisfactory in all patients and CYC has well recognized toxicity. This prospective pilot trial explored whether mycophenolate mofetil (MMF) represents an effective alternative to CYC for induction and maintenance of remission in MPA with mild to moderate renal involvement.
Renal dysfunction commonly occurs in multiple myeloma (MM) and is caused by deposition of abnormal light chain within various compartments of the kidney. Renal pathologic findings are diverse and include cast nephropathy (CN), amyloidosis and light-chain deposition disease (LCDD). We report a case of renal failure in a patient with MM caused by concurrent CN, amyloidosis and LCDD which has not been previously described.
Medications are a major source of acute kidney injury, especially in critically ill patients. Medication-induced renal injury can occur through a number of mechanisms. We present two cases of acute kidney injury (AKI) where inactive cytochrome P450 (CYP) polymorphism may have played a role. The first patient developed a biopsy-proven allergic interstitial nephritis following urethrotomy. Genetic testing revealed the patient to be heterozygous for an inactivating polymorphism CYP2C9*3 and homozygous for an inactivating polymorphism CYP2D6*4. Patient had received several doses of promethazine, which is metabolized by CYP2D6*4. Another patient developed AKI on several occasions after exposure to lansoprazole and allopurinol. CYP testing revealed the patient to be homozygous for inactivating polymorphism CYP2C19*2, which is responsible for the metabolism of lansoprazole. These are the first two cases of AKI associated with non-functional polymorphisms of cytochrome P450 superfamily. While the exact mechanism has not been worked out, it introduced the possibility of a new source of kidney injury.
IgA nephropathy is the most common glomerular disease worldwide, yet there is no international consensus for its pathological or clinical classification. Here a new classification for IgA nephropathy is presented by an international consensus working group. The goal of this new system was to identify specific pathological features that more accurately predict risk of progression of renal disease in IgA nephropathy, thus enabling both clinicians and pathologists to improve individual patient prognostication. In a retrospective analysis, sequential clinical data were obtained on 265 adults and children with IgA nephropathy who were followed for a median of 5 years. Renal biopsies from all patients were scored by pathologists blinded to the clinical data for pathological variables identified as reproducible by an iterative process. Four of these variables: (1) the mesangial hypercellularity score, (2) segmental glomerulosclerosis, (3) endocapillary hypercellularity, and (4) tubular atrophy/interstitial fibrosis were subsequently shown to have independent value in predicting renal outcome. These specific pathological features withstood rigorous statistical analysis even after taking into account all clinical indicators available at the time of biopsy as well as during follow-up. The features have prognostic significance and we recommended they be taken into account for predicting outcome independent of the clinical features both at the time of presentation and during follow-up. The value of crescents was not addressed due to their low prevalence in the enrolled cohort.
Pathological classifications in current use for the assessment of glomerular disease have been typically opinion-based and built on the expert assumptions of renal pathologists about lesions historically thought to be relevant to prognosis. Here we develop a unique approach for the pathological classification of a glomerular disease, IgA nephropathy, in which renal pathologists first undertook extensive iterative work to define pathologic variables with acceptable inter-observer reproducibility. Where groups of such features closely correlated, variables were further selected on the basis of least susceptibility to sampling error and ease of scoring in routine practice. This process identified six pathologic variables that could then be used to interrogate prognostic significance independent of the clinical data in IgA nephropathy (described in the accompanying article). These variables were (1) mesangial cellularity score; percentage of glomeruli showing (2) segmental sclerosis, (3) endocapillary hypercellularity, or (4) cellular/fibrocellular crescents; (5) percentage of interstitial fibrosis/tubular atrophy; and finally (6) arteriosclerosis score. Results for interobserver reproducibility of individual pathological features are likely applicable to other glomerulonephritides, but it is not known if the correlations between variables depend on the specific type of glomerular pathobiology. Variables identified in this study withstood rigorous pathology review and statistical testing and we recommend that they become a necessary part of pathology reports for IgA nephropathy. Our methodology, translating a strong evidence-based dataset into a working format, is a model for developing classifications of other types of renal disease.
To determine the outcome of kidney transplantation in patients with fibrillary glomerulonephritis (FGN), a rare glomerular disease, we followed 12 patients, 5 with FGN and 7 patients with monoclonal gammopathy and fibrillary deposits (MGFD), who underwent 15 kidney transplants since 1988 with a median follow-up of 52 months. Recurrent disease did not arise in any of the patients with FGN but developed in 5 patients with MGFD. Seven allografts failed: 1 in the FGN group and 6 in the MGFD group. Median allograft survival for patients with MGFD was 37 months but had not been reached in FGN patients. One patient with FGN had primary allograft failure secondary to graft thromboembolism. Three patients with MGFD were re-transplanted and one lost the second allograft to recurrent disease, but the other two died from hematological malignancy. Another patient was diagnosed with MPGN type III and did not have detectable fibrillary material 22 months after transplantation. One patient with MGFD had stable allograft function 6 months post-transplant but another, with recurrent disease, underwent peripheral blood stem cell transplantation and regained stable allograft function. Our study shows that kidney transplantation appears safe in patients with FGN with little risk of recurrence. However, patients with MGFD have a significant risk for disease recurrence. Whether the development of hematological malignancies following transplantation in this group is related to their original disease or was coincidental requires further studies.
Myeloperoxidase (MPO)-specific antineutrophil cytoplasmic antibodies have been proposed as pathogenic for microscopic polyangiitis. Supporting this hypothesis, a case report of transplacental anti-MPO antibody transfer presumably causing a vasculitis-like syndrome in the newborn is cited frequently. Here, we report a case of transplacental transfer of high levels of anti-MPO antibodies not resulting in clinical compromise in the newborn. The mother developed microscopic polyangiitis 5 years before the pregnancy. After induction therapy, remission was maintained with low-dose prednisone and azathioprine for 4.5 years despite high levels of anti-MPO antibodies (>100 U/mL). The patient elected to become pregnant, immunosuppression was maintained during pregnancy, and a normal-term neonate was delivered. The newborns venous blood anti-MPO antibody levels decreased gradually from greater than 100 U/mL at birth to undetectable by day 120. No clinical manifestation of vasculitis developed in the newborn. This case supports that anti-MPO antibodies alone are not pathogenic without additional cofactors.
Postinfectious glomerulonephritis is a common disorder that develops following an infection. In the majority of cases, there is complete recovery of renal function within a few days to weeks following resolution of the infection. In a small percentage of patients, however, the glomerulonephritis takes longer to resolve, resulting in persistent hematuria and proteinuria, or even progression to end-stage kidney disease. In some cases of persistent hematuria and proteinuria, kidney biopsies show findings of a postinfectious glomerulonephritis even in the absence of any evidence of a preceding infection. The cause of such atypical postinfectious glomerulonephritis, with or without evidence of preceding infection, is unknown. Here we show that most patients diagnosed with this atypical postinfectious glomerulonephritis have an underlying defect in the regulation of the alternative pathway of complement. These defects include mutations in complement-regulating proteins and antibodies to the C3 convertase known as C3 nephritic factors. As a result, the activated alternative pathway is not brought under control even after resolution of the infection. Hence, the sequela is continual glomerular deposition of complement factors with resultant inflammation and development of an atypical postinfectious glomerulonephritis.
Multiple myeloma is responsible for a wide variety of renal pathologies. Urinary protein and monoclonal spike cannot be used to diagnose cast nephropathy (CN). Because albuminuria is a hallmark of glomerular disease, this study evaluated the percentage of urinary albumin excretion (%UAE) as a tool to differentiate CN from Ig light chain amyloidosis (AL), light chain deposition disease (LCDD), and acute tubular necrosis (ATN).
Rituximab is a monoclonal antibody to the CD20 antigen on B-cells that was initially designed and approved for the treatment of non-Hodgkins B-cell lymphoma in 1997. In the last 15years, it has emerged as a potent immunosuppressant for many immune-mediated diseases, beginning initially with rheumatoid arthritis, and now extending into several other fields, including clinical nephrology. Based on recent large clinical trials, it is FDA-approved for the treatment of ANCA-associated vasculitis and continues to be studied in off-label usage for many glomerular diseases, including membranous nephropathy, lupus nephritis, and mixed cryoglobulinemia. It has been used as a treatment in nephrotic syndrome in children and adults, including both minimal change disease and focal segmental glomerulosclerosis. Given its efficacy, tolerability and safety profile in comparison to more conventional treatment regimens, RTX is rapidly emerging as a critical treatment modality in glomerular disease.
To identify circulating proteins that distinguish between active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and remission in a manner complementary to markers of systemic inflammation.
The use of monoclonal antibodies in the treatment of malignancy and autoimmune diseases has rapidly expanded in the last decade. Rituximab, a monoclonal antibody to the CD20 antigen on B cells, was first approved by the US FDA in 1997 to treat non-Hodgkins B-cell lymphoma. It is now used, however, for a variety of diseases in both on- and off-label uses. It was approved by the FDA for use in refractory rheumatoid arthritis in 2007, and in April 2011 it was approved for the treatment of anti-neutrophil cytoplasmic antibody-associated vasculitides (including granulomatosis with polyangiitis [Wegeners granulomatosis] and microscopic polyangiitis), based on the promising results of the RAVE trial. Within the field of nephrology, in addition to its use in anti-neutrophil cytoplasmic antibody-associated vasculitides, it is has been used in the treatment of membranous nephropathy, membranoproliferative glomerulonephritis and lupus nephritis.
When membranoproliferative glomerulonephritis (MPGN) was first delineated as a discrete clinico-pathological entity more than a half-century ago, most cases were regarded as idiopathic (or primary) in nature. Advances in analysis of pathogenetic mechanisms and etiologies underlying the lesion of MPGN have radically altered the prevalence of the truly idiopathic form of MPGN. In addition, MPGN as a category among renal biopsies showing glomerulonephritis has diminished over time. In the modern era, MPGN is mainly classified morphologically on the basis of immunoglobulin (Ig; monoclonal or polyclonal) and complement (C3 only or combined with Ig) deposition and secondarily on the basis of its appearance on ultra-structural examination. Idiopathic MPGN is a diagnosis of exclusion, at least in many adults and a portion of children, and a systematic approach to evaluation will often uncover a secondary cause, such as an infection, autoimmune disease, monoclonal gammopathy, neoplasia, complement dysregulation or a chronic thrombotic microangiopathy. Idiopathic MPGN remains an endangered species after its separation from these known causes.
The discovery of different podocyte autoantibodies in membranous nephropathy (MN) raises questions about their pathogenetic and clinical meaning. This study sought to define antibody isotypes and correlations; to compare levels in MN, other glomerulonephritides, and controls; and to determine their association with clinical outcomes.
This study was conducted to evaluate the efficacy and safety of repeated and prolonged B cell depletion with rituximab (RTX) for the maintenance of long-term remission in patients with chronic relapsing granulomatosis with polyangiitis (Wegeners) (GPA).
C3 glomerulonephritis (C3GN) is a recently described disorder that typically results from abnormalities in the alternative pathway (AP) of complement. Here, we describe the clinical features, kidney biopsy findings, AP abnormalities, glomerular proteomic profile, and follow-up in 12 cases of C3GN. This disorder equally affected all ages, both genders, and typically presented with hematuria and proteinuria. In both the short and long term, renal function remained stable in the majority of patients with native kidney disease. In two patients, C3GN recurred within 1 year of transplantation and resulted in a decline in allograft function. Kidney biopsy mainly showed a membranoproliferative pattern, although both mesangial proliferative and diffuse endocapillary proliferative glomerulonephritis were noted. AP abnormalities were heterogeneous, both acquired and genetic. The most common acquired abnormality was the presence of C3 nephritic factors, while the most common genetic finding was the presence of H402 and V62 alleles of Factor H. In addition to these risk factors, other abnormalities included Factor H autoantibodies and mutations in CFH, CFI, and CFHR genes. Laser dissection and mass spectrometry of glomeruli from patients with C3GN showed accumulation of AP and terminal complement complex proteins. Thus, C3GN results from diverse abnormalities of the alternative complement pathway leading to subsequent glomerular injury.
Genetic causes of focal and segmental glomerulosclerosis (FSGS) typically involve mutations and allele variants of genes expressed in podocytes or, more rarely, glomerular basement membranes. In this report, we describe a 60-year-old woman with chronic kidney disease whose kidney biopsy showed FSGS. Immunoglobulins and C3 were undetectable in immunofluorescence studies. Electron microscopy showed subendothelial fluffy granular material with occasional double-contour formation suggestive of capillary wall injury and prompting work-up for a prothrombotic state. Evaluation of the alternative pathway of complement showed a novel polymorphism in short consensus repeat (SCR) 12 of complement factor H (CFH; c.2195C>T, p.Thr732Met) and a previously reported but largely uncharacterized polymorphism in complement factor C3 (c.463A>C, p.Lys155Gln). Dysregulation of the alternative pathway is associated with atypical hemolytic syndrome and dense deposit disease, but heretofore has not been associated with FSGS. This case highlights the expanding spectrum of complement-mediated glomerular disease and shows that FSGS with features of capillary wall injury should prompt evaluation for abnormalities in the alternative pathway. This case also expands the list of genetic polymorphisms that can be associated with an FSGS phenotype.
Severe crescentic and necrotizing glomerulonephritis typically is associated with anti-glomerular basement membrane or antineutrophil cytoplasmic antibodies. In this report, we describe a 23-year-old man with severe crescentic and necrotizing glomerulonephritis. Both anti-glomerular basement membrane and antineutrophil cytoplasmic antibody titers were negative. Kidney biopsy showed bright C3 staining in the mesangium and along capillary walls and no staining for immunoglobulins. Electron microscopy showed waxy deposits (many mesangial; few intramembranous or subendothelial), prompting evaluation of the alternative pathway of complement. Alternative pathway evaluation showed a novel mutation in short consensus repeat (SCR) 19 of complement factor H. In addition, the patient carried complement factor H and C3 risk alleles. Prompt treatment with intravenous steroids followed by oral steroids resulted in symptom alleviation and improved kidney function. This case shows what is to our knowledge a unique and previously unpublished cause of severe crescentic and necrotizing glomerulonephritis. Furthermore, the case demonstrates an expanding spectrum of complement-mediated glomerulonephritis and shows that crescentic and necrotizing glomerulonephritis with solely complement deposits should be evaluated for abnormalities in the alternative pathway of complement.
Accurate diagnosis and typing of renal amyloidosis is critical for prognosis, genetic counseling, and treatment. Laser microdissection and mass spectrometry are emerging techniques for the analysis and diagnosis of many renal diseases. Here we present the results of laser microdissection and mass spectrometry performed on 127 cases of renal amyloidosis during 2008-2010. We found the following proteins in the amyloid deposits: immunoglobulin light and heavy chains, secondary reactive serum amyloid A protein, leukocyte cell-derived chemotaxin-2, fibrinogen-? chain, transthyretin, apolipoprotein A-I and A-IV, gelsolin, and ?-2 microglobulin. Thus, laser microdissection of affected areas within the kidney followed by mass spectrometry provides a direct test of the composition of the deposit and forms a useful ancillary technique for the accurate diagnosis and typing of renal amyloidosis in a single procedure.
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