Immunoglobulin G4-related disease presenting with nephrotic syndrome due to minimal change disease: a case report.

BACKGROUND: Immunoglobulin G4-related disease is an inflammatory disease affecting multiple organs including the kidney. Immunoglobulin G4-related kidney disease most commonly manifests as a tubulointerstitial nephritis and is associated with glomerular disease in a proportion of cases. Membranous nephropathy is the most frequent glomerular lesion. Herein, we report the first documented case of immunoglobulin G4-related disease presenting with nephrotic syndrome owing to minimal change disease. CASE PRESENTATION: A 67-year-old South Asian male presented to our service with systemic upset and leg swelling. He had heavy proteinuria (urine protein:creatinine ratio 1042 mg/mmol) and was hypoalbuminemic (17 g/L) and hypercholersterolemic (9.3 mmol/L), consistent with the nephrotic syndrome. His serum creatinine was 140 µmol/L, and he was hypocomplementemic (C3 0.59 g/L, C4 < 0.02 g/L) with raised immunoglobulin G4 subclass levels (5.29 g/L). Kidney biopsy demonstrated minimal change disease alongside a plasma-cell-rich tubulointerstitial nephritis with strong positive staining for immunoglobulin G4. A diagnosis of minimal change disease in the setting of immunoglobulin G4-related disease was made. He was commenced on oral prednisolone at 60 mg daily but suffered infectious complications, including necrotizing fasciitis within 3 weeks of starting treatment, ultimately resulting in his death 52 days after initial presentation. CONCLUSION: This case highlights the potential for immunoglobulin G4-related disease to be associated with a spectrum of glomerular pathologies including minimal change disease. It adds to the differential diagnosis of secondary causes of minimal change disease, and moreover, aids as an important reminder of the potential complications of high-dose steroids used in its treatment.

Evaluation of C4d expression and staining patterns by immunohistochemistry in renal biopsy samples with focal segmental glomerulosclerosis and minimal change disease.

INTRODUCTION: C4d is an activation product of lectin pathway of complement. Glomerular deposition of C4d is associated with poor prognosis in different types of immune-related glomerulonephritis. The present study was conducted to investigate expression level of C4d and its staining pattern in renal biopsy of patients with focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) by immunohistochemistry method. MATERIALS AND METHODS: In this retrospective cross-sectional study, renal biopsy specimens from 46 samples of MCD, 47 samples of FSGS, and 15 samples without glomerular disease as the controls, were subjected to immunohistochemistry staining with C4d. Demographic characteristics and information obtained from light and electron microscopy (EM) of patients were also extracted from their files. RESULTS: C4d positive staining was observed in 97.9 % of FSGS and 43.5 % of MCD samples, which showed a statistically significant difference (P < 0.001). The sensitivity and specificity of C4d expression for diagnosing FSGS were 97.9 % and 56.5 %, respectively. There was no significant correlation between C4d expression and any of the light and electron microscopy findings, including presence of foam cells, mesangial matrix expansion, interstitial fibrosis and tubular atrophy, and basement membrane changes in MCD patients. Also, no significant correlation was observed between C4d expression and clinical symptoms of proteinuria or prolonged high level of creatinine in patients with MCD. DISCUSSION AND CONCLUSION: The expression of C4d marker had a good sensitivity and negative predictive value in the diagnosis of FSGS.

Rationale and design of the Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study.

INTRODUCTION: Disease subtyping and monitoring are essential for the management of nephrotic syndrome (NS). Although various biomarkers for NS have been reported, their clinical efficacy has not been comprehensively validated in adult Japanese patients. METHODS: The Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study is a nationwide, multicenter, and prospective cohort study in Japan, enrolling adult (≥18 years) patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), and lupus nephritis (LN). Baseline clinical information and plasma and urine samples will be collected at the time of immunosuppressive therapy initiation or biopsy. Follow-up data and plasma and urine samples will be collected longitudinally based on the designated protocols. Candidate biomarkers will be measured: CD80, cytotoxic T-lymphocyte antigen 4, and soluble urokinase plasminogen activator receptor for MCD and FSGS; anti-phospholipase A2 receptor and thrombospondin type-1 domain-containing protein 7A antibodies for MN; fragment Ba, C3a, factor I, and properdin for MPGN/C3G; and CD11b, CD16b, and CD163 for LN. Outcomes include complete and partial remission, relapse of proteinuria, a 30% reduction in estimated glomerular filtration rate (eGFR), eGFR decline, and initiation of renal replacement therapy. The diagnostic accuracy and predictive ability for clinical outcomes will be assessed for each biomarker. RESULTS: From April 2019 to April 2023, 365 patients were enrolled: 145, 21, 138, 10, and 51 cases of MCD, FSGS, MN, MPGN/C3G, and LN, respectively. CONCLUSION: This study will provide valuable insights into biomarkers for NS and serve as a biorepository for future studies.

Relapse of minimal change disease following the third mRNA COVID-19 vaccination: a case report and literature review.

Mass vaccination is the most important strategy to terminate the coronavirus disease 2019 (COVID-19) pandemic. Reports suggest the potential risk of the development of new-onset or relapse of minimal change disease (MCD) following COVID-19 vaccination; however, details on vaccine-associated MCD remain unclear. A 43-year-old man with MCD, who had been in remission for 29 years, developed nephrotic syndrome 4 days after receiving the third dose of the Pfizer-BioNTech vaccine. His kidney biopsy revealed relapsing MCD. Intravenous methylprednisolone pulse therapy followed by oral prednisolone therapy was administered, and his proteinuria resolved within 3 weeks. This report highlights the importance of careful monitoring of proteinuria after COVID-19 vaccination in patients with MCD, even if the disease is stable and no adverse events occurred during previous vaccinations. Our case report and literature review of COVID-19 vaccine-associated MCD indicated that MCD relapse tends to occur later after vaccination and slightly more often following the second and subsequent vaccine doses than new-onset MCD.

A pilot study of anti-nephrin antibodies in podocytopaties among adults.

AIM: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are podocytopathies characterized by damage to the glomerular filtration barrier, leading to proteinuria and nephrotic syndrome. The production of anti-podocyte antibodies has been proposed as potential circulating factors contributing to the development of these conditions. The aim of the study is to evaluate the levels of anti-nephrin antibodies in patients with podocytopathies and healthy subjects. METHODS: In this study, a total of 77 patients with active glomerulopathy and 11 healthy subjects were included. Forty one patients were diagnosed with FSGS, 11 with MCD, and 25 with MN. To measure the levels of anti-nephrin antibodies, enzyme-linked immunosorbent assay was used. RESULTS: The levels of antibodies to nephrin were significantly higher in patients with MCD 61.2 [28.9-66.3] ng/mL and FSGS 32.5 [17.2-58.4] ng/mL compared to MN 20.3 [14.4-38.4] and healthy individuals 15.3 [12-18.9] ng/mL, p < .05. In patients with primary FSGS, the levels of antibodies to nephrin were significantly higher 45.2 [20-64.3] ng/mL compared to patients with secondary FSGS 26.7 [11.2-44.1] ng/mL, p < .05. There were no significant differences in the remission rate between the anti-nephrin antibodies positive and negative groups (log-rank test: p = .158). CONCLUSION: The level of anti-nephrin antibodies was found to be significantly higher in patients with MCD and pFSGS compared to those with sFSGS, MN, and healthy subjects. Anti-nephrin antibodies in MCD and primary FSGS may be associated with the severity of podocytopathies, however they did not have an impact on the response to therapy.

Exacerbation of Minimal Change Disease Following mRNA COVID-19 Vaccination.

BACKGROUND Minimal change disease is a common cause of nephrotic syndrome in adults. There are few reported cases of vaccine-related podocytopathy with nephrotic-range proteinuria in the setting of a minimal change disease history. There have been rare reports of acute renal damage following vaccination to prevent COVID-19 and some cases of exacerbation of ongoing nephropathy. This report is a 33-year-old man with a 22-year history of nephrotic syndrome due to minimal change disease which exacerbated following a third dose of an mRNA SARS-CoV-2 vaccine for COVID-19. CASE REPORT We report a case of nephrotic syndrome after the third dose of the BNT162b2 mRNA COVID-19 vaccine. The patient presented with mild edema in the bilateral lower extremities and sacrum. Laboratory investigations confirmed nephrotic-range proteinuria and hypoalbuminemia. A kidney sonogram demonstrated mild renal parenchymal disease and a small non-obstructing right renal calculus. Renal biopsy revealed diffuse podocyte foot process effacement, punctuate IgG podocyte cytoplasmic staining, and minimal global glomerulosclerosis, consistent with a diagnosis of a diffuse podocytopathy with a minimal change disease phenotype. The patient was started on oral prednisone treatment, which led to remission of his symptoms and normalization of lab test results with normal BUN and Cr and resolution of proteinuria. Treatment was tapered off over the course of 28 weeks. CONCLUSIONS We presents a case of longstanding minimal change disease that showed exacerbation following a third dose of an mRNA vaccine for SARS-CoV-2. Although this may be a rare association, this case supports that patients with chronic glomerulonephritis need to be monitored.

Mild mesangial proliferative IgA nephropathy with and without minimal change disease.

Mild mesangial proliferative IgA nephropathy with minimal change disease (MCD-IgAN) and mild mesangial proliferative IgA nephropathy without minimal change disease (Non-MCD-IgAN) have similar characteristics on light microscopy. Nevertheless, their discrepancies in clinicopathological features and prognosis remain unknown. A total of 589 patients with biopsy-proven mild mesangial proliferative IgA nephropathy (M-IgAN) combined with light microscopy and immunofluorescence were enrolled. Firstly, the diagnoses of the patients by electron microscopy were recorded and used as the gold standard. We calculated the sensitivity and specificity using nephrotic syndrome (NS) as the diagnostic criteria to identify MCD-IgAN. Then, excluding patients with a 24-h urinary total protein less than 0.5 g/day, incomplete clinical data, or less than the six-month follow-up, we included 184 cases of non-MCD-IgAN and 98 cases of MCD-IgAN. The patients' clinicopathological and outcome data were collected and compared. Among the 589 patients, according to electron microscopy, 381 were diagnosed with non-MCD-IgAN, 167 with MCD-IgAN, and 41 with M-IgAN complicated by other glomerular diseases. Using NS as the diagnostic criteria to distinguish non-MCD-IgAN and MCD-IgAN, the sensitivity and specificity were 83.8% and 99.5%, respectively. The patients in the MCD-IgAN group tended to be younger, hypotensive, with lower urinary erythrocytes, and more likely to achieve complete remission, and fewer patients progressed to the endpoint than those in the non-MCD-IgAN group (all P < 0 .05). NS appears to be an objective indicator for differentiating MCD-IgAN from non-MCD-IgAN. Non-MCD-IgAN varies greatly from MCD-IgAN in clinicopathology and treatment response, with a poorer prognosis.

[Diagnosis and treatment of Minimal Change Disease in adults-2023]. / Diagnostik und Therapie der Minimal Change Glomerulopathie beim Erwachsenen ­ 2023.

Minimal change disease is a glomerulopathy that clinically manifests as acute onset nephrotic syndrome. A diagnosis is made by renal biopsy, implying the absence of glomerular lesions on light microscopy but detection of extensive podocyte foot process effacement on electron miscroscopy. Considering the typically excellent response to immunosuppressive measures (especially to glucocorticoids), an autoimmune pathogenesis is assumed. Although general prognosis is overall beneficial, steroid-dependent, steroid-resistant and frequently-relapsing disease courses may complicate the management of these patients and necessitate the use of alternative immunosuppressive treatment strategies. Here, the Austrian Society of Nephrology (ÖGN) provides a consensus on how to best diagnose and manage adult patients with minimal change disease.

Nephrotic syndrome with Minimal Change Disease and Atopy in NorthAfrican adults.

INTRODUCTION: In adults, minimal change disease (MCD) accounts for 15 to 25% of nephrotic syndrome (NS). Numerous reports have suggested a link between NS and atopy. However, data on treatment and prognosis of NS associated with allergy are limited. AIM: To examine the presenting characteristics, treatments and outcomes of adults with allergic MCD in a North African center. METHODS: This was an observational study using retrospectively collected data. Patients were recruited from the Nephrology department of Sahloul Hospital (Sousse, Tunisia) from January 2006 to December 2020. Adults with a biopsy proved MCD, which was associated with atopy, were included. RESULTS: Fifteen patients (eight males, age mean±SD: 34±13 years) were included. High eosinophil and immunoglobulin E (IgE) levels were noted in three and twelve patients respectively. The IgE mean level at the initial presentation was 1431 IU/ml. Allergic skin tests were positive in nine patients. All patients were treated with corticosteroids, five had anti-histamine therapy and five had hyposensitization therapy, which was successful in two patients. Thirteen patients had relapsed during follow-up. Mean eosinophil level was significantly higher in patients with frequent relapses compared to those with infrequent relapses (5415/mm³ vs. 239.12/mm³, respectively, p=0.022). Two patients had progressed to chronic renal failure. CONCLUSION: It is important to search for atopic disorders in patients with MCD to better control this disease and use specific treatments. However, the efficacy of anti-allergic therapies has to be proven.

Glomerular parietal epithelial expression of CD44 in minimal change nephrotic syndrome and primary focal segmental glomerulosclerosis: A clinico-pathological study.

Introduction: Minimal change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS) are the two common causes of nephrotic syndrome (NS) in both children and adults with overlapping clinical features, but with distinct prognostic and therapeutic implications. The distinction between these relies entirely on histopathology, which can sometimes be difficult. CD44 is expressed by activated parietal epithelial cells, plays a role in matrix deposition and thus in the pathogenesis of FSGS. Aims: To assess the expression of CD44 in MCNS and FSGS and to evaluate its association with the known clinical and histopathological prognostic factors. Materials and Methods: Thirty cases each of MCNS and FSGS were studied. The clinical, laboratory, histopathological, and CD 44 immunohistochemical data were recorded. The findings were analyzed and correlated. A P value of < 0.05 was considered statistically significant. Results: Statistical association was noted between CD44 positivity and serum creatinine (p = 0.031), estimated glomerular filtration rate (p = 0.040), segmental sclerosis (p < 0.001), tubular atrophy (p = 0.027), interstitial fibrosis (p = 0.027), and histological diagnosis (p < 0.001). The sensitivity, specificity, positive predictive, and negative predictive values were 90%, 76.67%, 79.41% and 88.46%, respectively. Conclusions: CD44 immunostain can effectively distinguish MCNS from FSGS. The congruent results of CD44 positivity with known prognostic factors support the possibility of using the CD44 marker as a predictive tool in selecting high-risk patients and offering appropriate therapeutic measures.

[Clinical presentation and prognosis in children over 10-year-old with primary nephrotic syndrome].

Objective: To summary the clinical presentation and prognosis of primary nephrotic syndrome (PNS) in teenagers. Methods: The clinical data, renal pathological types and prognosis of 118 children over 10-year-old with PNS treated in the Department of Nephrology of the Children's Hospital Affiliated to Capital Institute of Pediatrics from January 2010 to December 2020 were retrospectively analyzed, with 408 children ≤10-year-old as control group synchronously. Chi-square test was used to compare the difference of clinical types, pathologic types, response to steroids and tubulointerstitial changes between the groups. The teenagers with steroid resistant nephrotic syndrome (SRNS) were divided into initial non-responder group and late non-responder group. Kaplan-Meier method was used to compare the difference of persistent proteinuria, and Fisher's exact test for the histological types. Results: There were 118 children >10-year-old, including 74 males and 44 females, with the onset age of 12.1 (10.8, 13.4) years; and 408 children ≤10-year-old with the onset age of 4.5 (3.2, 6.8) years. The proportion of SRNS was significantly higher in patients >10-year-old than those ≤10-year-old (24.6% (29/118) vs. 15.9% (65/408), χ2=4.66, P=0.031). There was no statistical difference in the pathological types between >10-year-old and ≤10-year-old (P>0.05), with minimal change disease the most common type (56.0% (14/25) vs. 60.5% (26/43)). The percentage of cases with renal tubulointerstitial lesions was significantly higher in children >10-year-old compared to those ≤10-year-old (60.0% (15/25) vs. 23.3% (10/43), χ2=9.18, P=0.002). There were 29 cases presented with SRNS in PNS over 10-year-old, including 19 initial non-responders and 10 late non-responders. Analyzed by Kaplan-Meier curve, it was shown that the percentage of persistent proteinuria after 6 months of immunosuppressive treatments was significantly higher in initial non-responders than those of the late non-responders ((22±10)% vs. 0, χ2=14.68, P<0.001); the percentage of minimal change disease was significantly higher in patients of late non-responders than those of the initial non-responders (5/6 vs. 3/13, P=0.041). Of the 63 >10-year-old with steroid-sensitive nephrotic syndrome followed up more than one year, 38 cases (60.3%) had relapse, and 14 cases (22.2%) were frequent relapse nephrotic syndrome and steroid dependent nephrotic syndrome. Among the 45 patients followed up over 18-year-old, 22 cases (48.9%) had recurrent proteinuria continued to adulthood, 3 cases of SRNS progressed to kidney insufficiency, and one of them developed into end stage kidney disease and was administrated with hemodialysis. Conclusions: Cases over 10-year-old with PNS tend to present with SRNS and renal tubulointerstitial lesions. They have a favorable prognosis, but are liable to relapse in adulthood.

Minimal change disease with papillary thyroid carcinoma: a report of two adult cases.

BACKGROUND: Minimal change disease (MCD), a pathological type of nephrotic syndrome (NS), can occur in patients with tumors. We report two adult cases of MCD associated with papillary thyroid carcinoma (PTC), known to be extremely rare in adults. CASE PRESENTATION: A 35-year-old female patient was simultaneously diagnosed with MCD and PTC. The MCD was effectively treated with thyroidectomy and prednisone.In addition, a 50-year-old male patient, who had been diagnosed with PTC three years prior, had MCD confirmed by renal biopsy. The patient achieved complete remission following treatment with tacrolimus and rituximab. CONCLUSIONS: The present case report describes and discusses the diagnostic and treatment processes employed in these two patients. Clinicians need to be aware of the renal effects of treating patients with solid tumors.

IgA nephropathy with minimal change disease associated with primary Sjögren's syndrome: A case report.

RATIONALE: Only 1 case of IgA nephropathy (IgAN) with minimal change disease (MCD) associated with primary Sjögren's syndrome (SS) has been reported. We additionally describe IgAN with MCD associated with primary SS. PATIENT CONCERNS: A 80-year-old woman visited our hospital complaining of generalized edema that had started 4 weeks prior. She reported a sense of thirst and dry eye for the last 5 years. DIAGNOSES: Her initial laboratory findings were compatible with nephrotic syndrome; both the antinuclear antibody (1:80) and anti-SS-A (Ro) antibody (200 U/mL) tests were positive. A salivary gland scan revealed markedly decreased uptake for both the parotid and submandibular glands. The Schirmer test was positive. The random urine protein/creatinine ratio was 10 mg/mg. Renal biopsy was compatible with IgAN with superimposed MCD. INTERVENTIONS: Furosemide was intravenously administered with intermittent albumin infusion for her edema control. She was started on prednisone 40mg daily for 6 weeks, which was tapered to 5 mg for another 6 months after starting prednisolone. OUTCOMES: Over the next 6 months, her edema improved and the proteinuria decreased significantly. LESSONS: Physician should suspect IgA with MCD when patient with SS clinically showed nephrotic syndrome, and perform renal biopsy for pathologically diagnosis and appropriate treatment.

Japanese clinical practice patterns of primary nephrotic syndrome 2021: a web-based questionnaire survey of certified nephrologists.

BACKGROUND: With the publication of the "Evidence-Based Clinical Practice Guideline for Nephrotic Syndrome 2020," we examined nephrologists' adherence to the recommendations of four of its clinical questions (CQs). METHODS: This was a cross-sectional web-based survey conducted between November and December 2021. The target population comprised nephrologists certified by the Japanese Society of Nephrology who were recruited using convenience sampling. The participants answered six items regarding the four CQs about adult patients with nephrotic syndrome and their characteristics. RESULTS: In total, 434 respondents worked in at least 306 facilities, of whom 386 (88.9%) provided outpatient care for primary nephrotic syndrome. Of these patients, 179 (41.2%) answered that they would not measure anti- phospholipase A2 receptor antibody levels in cases of suspected primary membranous nephropathy (MN) in which kidney biopsy was not possible (CQ1). Regarding immunosuppressants as maintenance therapy after relapse of minimal change nephrotic syndrome (CQ2), cyclosporine was the most common choice (290 [72.5%] and 300 [75.0%] of 400 respondents after the first and second relapses, respectively). The most common treatment for steroid-resistant cases of primary focal segmental glomerulosclerosis (CQ3) was cyclosporine (323 of 387, 83.5%). For the initial treatment of primary MN with nephrotic-range proteinuria (CQ4), corticosteroid monotherapy was the most common choice (240 of 403, 59.6%), followed by corticosteroid and cyclosporine (114, 28.3%). CONCLUSION: Gaps in recommendations and practices regarding serodiagnosis and treatment of MN (i.e., CQ1 and 4) are observed, suggesting the need to address the barriers to their insurance reimbursement and the lack of evidence behind them.

Combination of the gut microbiota and clinical indicators as a potential index for differentiating idiopathic membranous nephropathy and minimal change disease.

Objectives: Membranous nephropathy (MN) and minimal change disease (MCD) are two common types of nephrotic syndrome that have similar clinical presentations but require different treatment strategies. Currently, the definitive diagnosis for these conditions relies on invasive renal biopsy, which can be limited in clinical practice.Methods: In this study, we aimed to differentiate idiopathic MN (IMN) from MCD using clinical data and gut microbiota. We collected clinical data and stool samples from 115 healthy individuals, 115 IMN, and 45 MCD at the onset of disease and performed 16S rRNA sequencing. Through machine learning methods including random forest, logistic regression, and support vector machine, a classifier to differentiate IMN from MCD was constructed.Results: Baseline clinical data comparing the IMN and MCD groups showed that the MCD had higher levels of hemoglobin, uric acid, cystatin C, ß2-microglobulin, α1-microglobulin, total cholesterol, and low-density lipoprotein and lower levels of albumin and CD4+ T-cell counts. The gut microbiota of the two groups differed at all levels of the phylum and genus. Differential gut microbiota may disturb the integrity of the intestinal wall and lead to the passage of inflammatory mediators through the intestinal barrier, causing kidney injury. We constructed a noninvasive classifier with a discrimination efficacy of 0.939 that combined the clinical data and gut microbiota information to identify IMN and MCD.Conclusions: The classifier of the gut microbiota combined with clinical indicators has achieved good performance in identifying IMN and MCD, which provides a new approach for the noninvasive discrimination of different pathological types of kidney disease.

A Case of Lupus Nephritis Preceded by Minimal Change Disease and Membranous Glomerulonephritis.

BACKGROUND Lupus nephritis (LN) is the most common and serious complication of systemic lupus erythematosus (SLE). Minimal change disease (MCD) and primary membranous nephropathy (PMN) are the 2 most common causes of primary nephrotic syndrome. Our purpose in publishing this case report is to introduce an unusual clinical course and initial renal biopsy revealed MCD and then PMN in second renal biopsy. Subsequently, a third renal biopsy resulted in a final diagnosis of LN. To the best of our knowledge, this is the first such report. CASE REPORT The 31-year-old male patient was initially diagnosed with MCD after the first renal biopsy in 2004. He improved with initial management and had a complete remission for 9 years. After 9 years, the patient again presented with heavy proteinuria without systemic lupus erythematous finding and he was diagnosed with MN following the second renal biopsy. Seven years later, he again developed proteinuria alone with concurrent systemic symptoms of systemic lupus erythematosus, and a third biopsy was performed, leading to final diagnosis as LN. He was well managed with the methylprednisolone and cyclophosphamide (CTX) regimen, which improved renal function and spared the patient from continuous hemodialysis. CONCLUSIONS In rare case, MCD may represent an early phase of lupus nephritis, which may subsequently develop into severe lupus nephritis.