Discovery of Autoantibodies Targeting Nephrin in Minimal Change Disease Supports a Novel Autoimmune Etiology.

BACKGROUND: Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease. The etiology remains unknown. The efficacy of B cell-targeted therapies in some patients, together with the known proteinuric effect of anti-nephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease. METHODS: We evaluated sera from patients with minimal change disease, enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort and from our own institutions, for circulating nephrin autoantibodies by indirect ELISA and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. We also evaluated renal biopsies from our institutions for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence. RESULTS: In two independent patient cohorts, we identified circulating nephrin autoantibodies during active disease that were significantly reduced or absent during treatment response in a subset of patients with minimal change disease. We correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies from our institutions. We also identified a patient with steroid-dependent childhood minimal change disease that progressed to end stage kidney disease; she developed a massive post-transplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies. CONCLUSIONS: Our discovery of nephrin autoantibodies in a subset of adults and children with minimal change disease aligns with published animal studies and provides further support for an autoimmune etiology. We propose a new molecular classification of nephrin autoantibody minimal change disease to serve as a framework for instigation of precision therapeutics for these patients.

Minimal Change Disease Following the Pfizer-BioNTech COVID-19 Vaccine.

We report on the development of minimal change disease (MCD) with nephrotic syndrome and acute kidney injury (AKI), shortly after first injection of the BNT162b2 COVID-19 vaccine (Pfizer-BioNTech). A 50-year-old previously healthy man was admitted to our hospital following the appearance of peripheral edema. Ten days earlier, he had received the first injection of the vaccine. Four days after injection, he developed lower leg edema, which rapidly progressed to anasarca. On admission, serum creatinine was 2.31 mg/dL and 24-hour urinary protein excretion was 6.9 grams. As kidney function continued to decline over the next days, empirical treatment was initiated with prednisone 80 mg/d. A kidney biopsy was performed and the findings were consistent with MCD. Ten days later, kidney function began to improve, gradually returning to normal. The clinical triad of MCD, nephrotic syndrome, and AKI has been previously described under a variety of circumstances, but not following the Pfizer-BioNTech COVID-19 vaccine. The association between the vaccination and MCD is at this time temporal and by exclusion, and by no means firmly established. We await further reports of similar cases to evaluate the true incidence of this possible vaccine side effect.

Clinical and morphologic spectrum of renal involvement in idiopathic hypereosinophilic syndrome.

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.

IgM mesangial deposition as a risk factor for relapses of adult-onset minimal change disease.

BACKGROUND: Immunoglobulin M (IgM) mesangial deposition in pediatric minimal change disease (MCD) has been reported to be associated with steroid dependence and poor renal outcomes. However, the evidence linking the impacts of IgM mesangial deposition to the treatment prognosis in adult-onset MCD is still elusive. METHODS: In this retrospective cohort study, 37 adult patients with MCD received kidney biopsies from January 2010 to May 2020. Immunofluorescence microscopy was performed and the patients dichotomized according to IgM mesangial deposition (12 patients with positive IgM deposition; 25 patients with negative IgM deposition). We analyzed the clinical features, the dosage of immunosuppressive agents, and the response to treatment for 2 years between the two groups. RESULTS: Analysis of the clinical symptoms, the dosage of immunosuppressive treatment, and the time to remission revealed no statistical difference between the groups. However, compared to the negative IgM group, the frequency of relapses was significantly higher in the positive IgM group during the two-year follow-up period (the negative IgM group 0.25 episodes/year; the positive IgM group 0.75 episodes/year, p = 0.029). Furthermore, multivariate linear regression revealed that the positivity of IgM mesangial deposition is independently associated with the frequency of relapses (regression coefficient B 0.450, 95% CI 0.116-0.784, p = 0.010). CONCLUSIONS: Our findings indicated that adult-onset MCD patients with IgM mesangial deposition have a high risk of relapses. Therefore, intensive monitoring of disease activity should be considered in MCD adults with IgM mesangial deposition.

Parallel disease activity of Behçet's disease with renal and entero involvements: a case report.

BACKGROUND: Behçet's disease (BD) is a systemic inflammatory vasculitis with both autoimmune and autoinflammatory properties. Renal involvement in BD and its spontaneous remission have been rare. We herein describe a case of parallel disease activity of BD with entero and renal involvements, followed by a spontaneous remission without corticosteroid treatment. CASE PRESENTATION: A 54-year-old woman who had a 4-year history of BD, maintained with colchicine treatment, suffered abdominal pain, hemorrhagic stool and diarrhea. Physical examination revealed strong tenderness in the entire abdomen. Laboratory test results showed increased levels of inflammation, and a computed tomography scan revealed edematous intestinal wall thickening with ascites. Blood and stool cultures showed no specific findings. Since she was suspected to have developed panperitonitis with acute enterocolitis, she started treatment with an antibacterial agent under bowel rest. Her abdominal symptoms gradually improved, while diarrhea and high levels of inflammatory reaction persisted. Colonoscopy revealed discontinuous abnormal mucosal vascular patterns and ulcerations in the whole colon except for the rectum, and histological analyses of the intestine demonstrated transmural mucosal infiltration of inflammatory cells without epithelioid granuloma or amyloid deposition. Based on these findings, she was diagnosed with entero BD. Meanwhile, pedal edema appeared during her hospitalization. Urinalysis results were consistent with nephrotic syndrome, thus a renal biopsy was performed. Light microscopy showed no obvious glomerular and interstitial abnormalities, whereas electron microscopy revealed foot process effacement without immune complex deposition or fibrillary structure, compatible with minimal change disease (MCD). Only with conservative therapy, her proteinuria decreased, followed by a complete remission in 3 weeks from the onset of edema. The coincident episode of MCD was finally diagnosed as renal BD that paralleled disease activity to entero BD. She started adalimumab administration, resulting in the further improvement of diarrhea and inflammatory levels. CONCLUSIONS: This is the first report to demonstrate MCD as renal involvement of BD along with the disease activity of entero BD.

Efficacy of rituximab in thymoma associated minimal change disease: case report.

BACKGROUND: Thymomas have been associated with a broad spectrum of autoimmune diseases. Minimal change disease (MCD) is the most frequent pathological lesion reported. Pathophysiological mechanisms involved in secondary MCD, and linking MCD to thymoma are not yet fully explained, although the hypothesis of T cell dysfunction has been suggested. The fundamental therapeutic principles are steroids and surgical treatment of thymoma, but failures and relapses often require immunosuppressant combinations. CASE PRESENTATION: A 62-year-old female was admitted in our unit for a nephrotic syndrome associated with a thymoma. The diagnosis of thymoma associated MCD was confirmed by kidney biopsy. After surgical resection of the thymoma and steroid therapy, no remission was observed. Immunosuppressive therapy was then intensified with introduction of rituximab. Here, we report a steroid-resistant nephrotic syndrome secondary to MCD associated thymoma, which achieved complete remission after rituximab therapy. To the best of our knowledge, this is the first report of the use and efficacy of rituximab therapy in this pathology. CONCLUSIONS: Our case report suggests that primary and secondary MCD may share similar pathophysiological mechanisms. It does not allow us to draw any conclusions about the mechanism of action of rituximab, but we believe this report argues for the safety and efficacy of rituximab use in thymoma-associated MCD, and therefore constitutes a rationale for future studies.

New-onset Nephrotic Syndrome after Janssen COVID-19 Vaccination: a Case Report and Literature Review.

Various coronavirus disease 2019 (COVID-19) vaccines are being developed, which show practical preventive effects. Here, we report a 51-year-old healthy man with nephrotic syndrome secondary to minimal change disease (MCD) after Ad26.COV.2 (Janssen) vaccination. He had no comorbid disease and received Ad26.COV.2 on April 13, 2021. Seven days after vaccination, he developed edema and foamy urine. Edema rapidly aggravated with decreased urine volume. He was admitted to the hospital 28 days after vaccination, and his body weight increased by 21 kg after vaccination. His serum creatinine level was 1.54 mg/dL, and 24-h urinary protein excretion was 8.6 g/day. Kidney biopsy revealed no abnormality in the glomeruli and interstitium of the cortex and medulla under the light microscope. Electron microscopy revealed diffuse effacement of the podocyte foot processes, thus, he was diagnosed with MCD. High-dose steroid therapy was applied, and his kidney function improved three days after steroid therapy. Three weeks after steroid use, his serum creatinine decreased to 0.95 mg/dL, and spot urine protein-to-creatine decreased to 0.2 g/g. This case highlights the risk of new-onset nephrotic syndrome secondary to MCD after vectored COVID-19 vaccination. Although the pathogenesis is uncertain, clinicians need to be careful about adverse renal effects of COVID-19 vaccines.

Increased number and activation of peripheral basophils in adult-onset minimal change disease.

Nowadays, the pathogenesis of minimal change disease (MCD) is still not well-known, and the current understanding on MCD is mainly based on data derived from children, and very few adults. Here, we comprehensively analysed the correlation between the changes of peripheral basophils and the incidence rate and relapse of adult-onset MCD. The results showed that in patients at the onset of MCD, the ratio and activation of basophils were all higher than those of healthy controls (all P < .05). In vitro test results showed that basophils from healthy controls can be activated by the serum taken from patients with MCD. Among 62 patients at the onset of MCD, with complete remission after treatment and 1 year of follow-up, the relative and absolute basophil counts before treatment were higher in the long-term remission group (n = 33) than that of the relapse group (n = 29). The basophil counts were significantly higher in the infrequent relapse group (n = 13) than that of the frequent relapse group (n = 16; P < .05). These findings suggested that basophil may play a pathogenic role in adult-onset MCD, and the increased number and activation of peripheral basophils could predict recurrence in adult MCD.

Approach to Diagnosis and Management of Primary Glomerular Diseases Due to Podocytopathies in Adults: Core Curriculum 2020.

Podocyte injury is the initiating step in the pathway toward clinically evident forms of nephrotic syndrome known as podocytopathies, represented as either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). There are hallmark differences in the histologic appearances of MCD and FSGS, which in turn represent distinct pathogenic models after initial podocyte injury (eg, no change in podocyte number in MCD vs podocyte detachment and death in FSGS). However, MCD and FSGS also share a number of common causes, supporting the theory that these diseases lie along a shared podocytopathy spectrum. In this installment of AJKD's Core Curriculum in Nephrology, we demonstrate how the podocytopathies can be classified according to pathogenesis and treatment response as an alternative to histologic description. Using case examples, we show how these alternative classification schemes can assist not only diagnosis, but also long-term management of podocytopathies.

Spectrum of podocytopathies in new-onset nephrotic syndrome following COVID-19 disease: a report of 2 cases.

BACKGROUND: Coronavirus disease-2019 (COVID-19) is an ongoing pandemic which has affected over 12 million people across the globe. Manifestations in different organs systems are being reported regularly. Renal biopsy findings in hospitalized COVID-19 patients presenting solely with acute kidney injury (AKI) have recently been described in published literature in few case reports. The findings include diffuse acute tubular injury (ATI) along with the glomerular lesion of collapsing glomerulopathy (CG). However, nephrotic syndrome as the presenting complaint of COVID-19 has not been reported widely, neither has any other glomerular lesion other than CG. CASE PRESENTATION: We describe the kidney biopsy findings of two patients who had recent diagnoses of COVID-19 and presented with new-onset nephrotic syndrome. Renal biopsy in both patients showed ATI (as in previous reports) and distinct glomerular findings on light microscopy - that of minimal change disease (MCD) initially in one patient followed by CG in a subsequent biopsy and CG at the outset in the other patient. The electron microscopic findings in both patients were that of severe podocytopathy (diffuse and severe podocyte foot process effacement). CONCLUSION: Our cases highlight a novel clinical presentation of COVID-19 renal disease, not described before, that of new-onset nephrotic syndrome. While all published case reports describe CG as the glomerular pathology, we describe a non-CG pathology (MCD) in one of our cases, thereby adding to the repertoire of renal pathology described in association with COVID-19 patients. However, the exact mechanism by which podocyte injury or podocytopathy occurs in all such cases is still unknown. Optimal treatment options for these patients also remains unknown at this time.

Management and treatment of glomerular diseases (part 2): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

In November 2017, the Kidney Disease: Improving Global Outcomes (KDIGO) initiative brought a diverse panel of experts in glomerular diseases together to discuss the 2012 KDIGO glomerulonephritis guideline in the context of new developments and insights that had occurred over the years since its publication. During this KDIGO Controversies Conference on Glomerular Diseases, the group examined data on disease pathogenesis, biomarkers, and treatments to identify areas of consensus and areas of controversy. This report summarizes the discussions on primary podocytopathies, lupus nephritis, anti-neutrophil cytoplasmic antibody-associated nephritis, complement-mediated kidney diseases, and monoclonal gammopathies of renal significance.

Primary glomerulonephritides.

Most glomerulonephritides, even the more common types, are rare diseases. They are nevertheless important since they frequently affect young people, often cannot be cured, and can lead to chronic kidney disease, including end-stage renal failure, with associated morbidity and cost. For example, in young adults, IgA nephropathy is the most common cause of end-stage renal disease. In this Seminar, we summarise existing knowledge of clinical signs, pathogenesis, prognosis, and treatment of glomerulonephritides, with a particular focus on data published between 2008 and 2015, and the most common European glomerulonephritis types, namely IgA nephropathy, membranous glomerulonephritis, minimal change disease, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and the rare complement-associated glomerulonephritides such as dense deposit disease and C3 glomerulonephritis.

Chronic Lyme borreliosis associated with minimal change glomerular disease: a case report.

BACKGROUND: There are only few cases of renal pathology induced by Lyme borreliosis in the literature, as this damage is rare and uncommon in humans. This patient is the first case of minimal change glomerular disease associated with chronic Lyme borreliosis. CASE PRESENTATION: A 65-year-old Caucasian woman was admitted for an acute edematous syndrome related to a nephrotic syndrome. Clinical examination revealed violaceous skin lesions of the right calf and the gluteal region that occurred 2 years ago. Serological tests were positive for Lyme borreliosis and skin biopsy revealed lesions of chronic atrophic acrodermatitis. Renal biopsy showed minimal change glomerular disease. The skin lesions and the nephrotic syndrome resolved with a sequential treatment with first ceftriaxone and then corticosteroids. CONCLUSION: We report here the first case of minimal change disease associated with Lyme borreliosis. The pathogenesis of minimal change disease in the setting of Lyme disease is discussed but the association of Lyme and minimal change disease may imply a synergistic effect of phenotypic and bacterial factors. Regression of proteinuria after a sequential treatment with ceftriaxone and corticosteroids seems to strengthen this conceivable association.

Regulatory T cells and minimal change nephropathy: in the midst of a complex network.

Minimal change nephrosis (MCN) is an important cause of morbidity in children. In spite of successful therapies having been developed in the last three decades, most aspects related to pathogenesis still remain poorly defined. Evolution in basic immunology and results deriving from animal models of the disease suggest a complex interaction of factors and cells starting from activation of innate immunity and continuing with antigen presentation. Oxidants, CD80 and CD40/CD40L have probably a relevant role at the start. Studies in animal models and in human beings also suggest the possibility that the same molecules (i.e. CD80, CD40) are expressed by podocytes under inflammatory stimuli, representing a direct potential mechanism for proteinuria. B and T cells could play a relevant role this contest. Implication of B cells is suggested indirectly by studies utilizing anti-CD20 monoclonal antibodies as the main therapy. The role of regulatory T cells (Tregs ) is supported mainly by results in animal models of nephrotic syndrome (i.e. adriamycin, puromycin, lipopolysaccharide), showing a protective effect of direct Treg infusion or stimulation by interleukin 2 (IL-2). Limited studies have also shown reduced amounts of circulating Tregs in patients with active MCN cells. The route from bench to bedside would be reduced if results from animal models were confirmed in human pathology. The expansion of Tregs with recombinant IL-2 and new anti-CD20 monoclonal antibodies is the beginning. Blocking antigen-presenting cells with cytotoxic T lymphocyte antigen (CTLA-4)-Ig fusion molecules inhibiting CD80 and/or with blockers of CD40-CD40 ligand interaction represent potential new approaches. The hope is that evolution in therapies of MCN could fill a gap lasting 30 years.

Renal pathology in hematopoietic cell transplant recipients: a contemporary biopsy, nephrectomy, and autopsy series.

Renal injury in hematopoietic cell transplant recipients may be related to a combination of factors including chemotherapy, radiation, infection, immunosuppressive agents, ischemia, and graft-versus-host disease, and can involve glomerular, tubulointerstitial, and vascular structures. We reviewed renal pathology from 67 patients at a single institution (2009-2014), including 14 patients with biopsy for clinical dysfunction, 6 patients with surgical kidney resection for other causes, and 47 autopsy patients. Kidney specimens frequently contained multiple histopathologic abnormalities. Thrombotic microangiopathy, membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis were the most common glomerular findings. Pathologies not previously reported in the hematopoietic cell transplant setting included collapsing glomerulopathy, antiglomerular basement membrane disease, fibrillary glomerulonephritis, and in the case of two surgical resections distinctive cellular segmental glomerular lesions that defied classification. Kidney specimens frequently demonstrated acute tubular injury, interstitial fibrosis, arteriolar hyaline, and arteriosclerosis. Other kidney findings at autopsy included leukemia and amyloid (both recurrent), diabetic nephropathy, bacterial infection, fungal invasion, and silver deposition along glomerular and tubular basement membranes. Also in the autopsy cohort, C4d immunohistochemistry demonstrated unexpected membranous nephropathy in two patients, yet C4d also colocalized with arteriolar hyaline. This retrospective hematopoietic cell transplant cohort illustrates multifaceted renal injury in patients with renal dysfunction, as well as in patients without clinically recognized kidney injury.

Evaluation of children with steroid-sensitive nephrotic syndrome in terms of allergies.

BACKGROUND: The etiology of minimal-change disease is not fully known, it is believed to be mediated by the immune system. Minimal-change disease also reported as having association with atopy. In this study, atopy history, the levels of serum IgE, and skin prick test in children with steroid-sensitive nephrotic syndrome were investigated. METHODS: A group of 30 children (mean age 7.7 ± 2.2 years, 56.6% male) diagnosed with steroid-sensitive nephrotic syndrome were included in the study. Serum immunoglobulin E levels and eosinophil counts were evaluated in children with steroid-sensitive nephrotic syndrome both in relapse and remission. Skin prick test was performed in remission. RESULTS: Of the 30 children investigated, 11 (36.7%) had a history of atopy. The median serum total IgE levels in nephrotic children in relapse, with (445 IU/mL) and without atopy (310 IU/mL) were significantly higher than those in remission (respectively, 200 IU/mL, p = 0.021, and 42 IU/mL, p = 0.001). The skin prick tests for all the allergens were evaluated as negative in all the patients. CONCLUSION: It was thought that increased IgE may reflect the activation of immune mechanism following various stimuli rather than a direct association with atopy in children with steroid-sensitive nephrotic syndrome.

Is there an association of hepatitis B virus infection with minimal change disease of nephrotic syndrome? A clinical observational report.

The rate of hepatitis B virus (HBV) infection is high in the Chinese population, and the implications of HBV infection are widely recognized, and membranous nephropathy is the most common renal lesion to be associated with HBV infection. Minimal change disease (MCD) is one of the most important histopathological characteristics in patients with nephrotic syndrome. There is no any study to report that HBV infection is associated with the etiology of MCD. Herein, we report four MCD patients with HBV infection and speculate that there is an association of HBV infection with the pathological type of MCD. In this study, we also reported the treatment schedule for these four MCD patients, and found that the anti-virus alone and combination of anti-virus with immunosuppressive agent could obtain a benefit for MCD patients with HBV infection. However, a well-designed study should be performed to confirm this association.

The treatment of minimal change disease in adults.

Minimal change disease (MCD) is the etiology of 10%-25% of cases of nephrotic syndrome in adults. The mainstay of treatment for adult MCD, oral glucocorticoids, is based on two randomized controlled trials and extensive observational data in adults, and this treatment leads to remission in over 80% of cases. Relapses are common, and some patients become steroid-resistant (SR), steroid-dependent (SD), or frequently relapsing (FR). The data guiding the treatment of these patients are limited. Here, we review MCD in adults with particular focus on the evidence for immunosuppressive therapy in these patients.

[Significance of serum cholesterol and fibrinogen in evaluating the risk of glomerulosclerosis in children with nephrotic syndrome].

OBJECTIVE: To investigate the significance of serum cholesterol and fibrinogen (Fib) in evaluating the risk of glomerulosclerosis in children with nephrotic syndrome. METHODS: Sixty-three children with primary nephrotic syndrome were divided into two groups according to their pathological types: minimal change glomerulopathy (MCG) (n=39) and focal segmental glomerulosclerosis (FSGS) groups (n=24). Serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C and Fib and 24-hour urinary protein excretion were retrospectively analyzed. RESULTS: Serum levels of TC, non-HDL-C, and LDL-C were significantly higher in the FSGS group than in the MCG group (P<0.05), but there were no significant differences in HDL-C, Fib and 24-hour urinary protein excretion between the two groups (P>0.05). According to the results of logistic regression analysis, high levels of LDL-C, non-HDL-C and TC were risk factors for FSGS (P<0.05). In patients whose proteinuria did not disappear after taking enough glucocorticoid for 4 weeks, the level of non-HDL-C was significantly higher in the FSGS group than in the MCG group (P<0.05); there were no significant differences in TC, LDL-C, HDL-C, and Fib between the MCG and FSGS groups (P>0.05). CONCLUSIONS: Serum cholesterol, especially non-LDL-C, is of great significance in evaluating the risk of glomerulosclerosis in children with nephrotic syndrome. There is no sufficient evidence to support serum Fib as a marker for predicting glomerulosclerosis in these children.