Minimal change disease following COVID-19 vaccination: A systematic review.

BACKGROUND: The newly developed COVID-19 vaccines are highly effective and safe. However, a small portion of vaccine recipients experience a wide range of adverse events. Recently, glomerular disease, including the development of Minimal Change Disease (MCD), has been observed after administration of different COVID-19 vaccines, although causality remains a matter of debate. AIM: The aim of this systematic review was to comprehensively examine the available literature and provide an overview of reported cases of MCD following vaccination against SARS-CoV-2. RESULTS: We identified 46 eligible articles which included 94 cases with MCD following COVID-19 vaccination of which one case was reported twice due to a second relapse. Fifty-five participants were males (59.1%, 55/93) and 38 (40.9%, 38/93) were females with a mean age of 45.02 years (SD:20.95). From the included patients 50 (50/94, 53.1%) were described as new-onset and 44 (46.9%, 44/94) as relapse. On average, symptomatology developed 16.68 days (SD: 22.85) after the administration of the vaccine irrespective of the dose. Data about symptoms was reported in 68 cases with the most common being oedema (80.8%, 55/68), followed by weight gain (26.5%, 18/68) and hypertension (16.1%, 11/68). In terms of outcome, more than half of the patients went into remission (61%, 57/94), while 18 recovered or improved post treatment (19.1%, 18/94). Two people relapsed after treatment (2.1%, 2/94) and two cases (2.1%, 2/94) were reported as not recovered. CONCLUSION: MCD is possibly a condition clinicians may see in patients receiving COVID-19 vaccines. Although this adverse event is uncommon, considering the limited published data and the absence of confirmed causality, increased clinical awareness is crucial for the early recognition and optimal management of these patients.

ß1-Integrin blockade prevents podocyte injury in experimental models of minimal change disease.

INTRODUCTION: Activation of the focal adhesion kinase (FAK) in podocytes is involved in the pathogenesis of minimal change disease (MCD), but the pathway leading to its activation in this disease is unknown. Here, we tested whether podocyte ß1 integrin is the upstream modulator of FAK activation and podocyte injury in experimental models of MCD-like injury. METHODS: We used lipopolysaccharide (LPS) and MCD sera to induce MCD-like changes in vivo and in cultured human podocytes, respectively. We performed functional studies using specific ß1 integrin inhibitors in vivo and in vitro, and integrated histological analysis, western blotting, and immunofluorescence to assess for morphological and molecular changes in podocytes. By ELISA, we measured serum LPS levels in 35 children with MCD or presumed MCD (idiopathic nephrotic syndrome [INS]) and in 18 healthy controls. RESULTS: LPS-injected mice showed morphological (foot process effacement, and normal appearing glomeruli on light microscopy) and molecular features (synaptopodin loss, nephrin mislocalization, FAK phosphorylation) characteristic of human MCD. Administration of a ß1 integrin inhibitor to mice abrogated FAK phosphorylation, and ameliorated proteinuria and podocyte injury following LPS. Children with MCD/INS in relapse had higher serum LPS levels than controls. In cultured human podocytes, ß1 integrin blockade prevented cytoskeletal rearrangements following exposure to MCD sera in relapse. CONCLUSIONS: Podocyte ß1 integrin activation is an upstream mediator of FAK phosphorylation and podocyte injury in models of MCD-like injury.

Efficacy of Rituximab for Minimal Change Disease and Focal Segmental Glomerulosclerosis with Frequently Relapsing or Steroid-Dependent Nephrotic Syndrome in Adults: A Chinese Multicenter Retrospective Study.

INTRODUCTION: Rituximab has been proven effective and safe in pediatric patients with frequently relapsing or steroid-dependent nephrotic syndrome (FR/SDNS). We aimed to analyze the efficacy and safety of rituximab in adult FR/SDNS patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). METHODS: A retrospective cohort study at three nephrology centers in China included adult FR/SDNS patients with biopsy-proven MCD or FSGS. Primary outcomes were relapse frequency and first relapse-free survival time. Adverse events were well recorded, and logistic regression analyses were used to investigate the risk factors of relapse. RESULTS: Eighty-one patients (age, 25.0 years; interquartile range, 20.0-40.5; 67% males; 82.7% MCD) received an average rituximab dose of 1,393.8 ± 618.7 mg/2 years during the 2-year follow-up period. The relapse frequency, calculated as the ratio of relapse times to follow-up years, significantly decreased after rituximab treatment (0.04 [0.00, 0.08] vs. 1.71 [1.00, 2.45], p < 0.001). The first relapse-free survival time was 16.7 ± 8.0 months. Fifty-seven patients (70.4%) achieved cessation of corticosteroids and immunosuppressants within 3 months after the first rituximab infusion. Adverse events were mostly mild, and no severe treatment-related adverse events were observed. Low serum albumin level before rituximab and high CD56+CD16+ natural killer cell count after rituximab were independent risk factors of relapse within 2 years after rituximab treatment. CONCLUSION: Rituximab was proven an effective and safe treatment option for adult FR/SDNS patients with MCD or FSGS in maintaining disease remission and minimizing corticosteroid exposure.

Histological transition from minimal change disease to THSD7A-associated membranous nephropathy in a patient receiving long-term steroid treatment: A case report.

RATIONALE: A predominant Th2 immune response is suggested in the pathogenesis of both minimal change disease (MCD) and membranous nephropathy (MN); however, consecutive development of the 2 diseases in a patient is extremely rare. PATIENT CONCERN: A Japanese man, who developed nephrotic syndrome in his 50s and was diagnosed with MCD by renal biopsy, experienced a relapse of proteinuria approximately 3 years later during long-term steroid treatment. Since the proteinuria was resistant to increase in steroid dosage, repeat renal biopsy was performed, which revealed a small amount of glomerular subepithelial immune deposits containing immunoglobulin (Ig)G (dominantly IgG4). Immunostaining for thrombospondin-type-1-domain-containing-7A (THSD7A) was positive on the glomerular capillary walls, whereas that for other causative antigens of MN, such as phospholipase A2 receptor or neural epidermal growth factor-like 1 protein, was negative. Detailed examination found no associated condition, including malignancies and allergic diseases. DIAGNOSIS: The diagnosis of THSD7A-associated idiopathic MN was made. INTERVENTIONS AND OUTCOMES: He received further increased dose of steroids. Thereafter he maintained clinical improvement because his urinary protein level was decreased. LESSONS: The present case suggested that histological transition from MCD to MN is possible and repeat biopsy would be crucial for accurate diagnosis.

Efficacy of low-dose rituximab in minimal change disease and prevention of relapse.

BACKGROUND: Minimal change disease (MCD) is a major cause of nephrotic syndrome (NS) in children and a minority of adults. The higher tendency to relapse put patients at risk for prolonged exposure to steroids and other immunosuppressive agents. B cell depletion with rituximab (RTX) may be beneficial to the treatment and prevention of frequently relapsing MCD. Therefore, this study aimed to verify the therapeutic/preventive effects of low-dose RTX on the relapse in adult with MCD. METHODS: A total of 33 adult patients were selected for the study, including 22 patients with relapsing MCD in relapse treatment group who were treated with low-dose RTX (200 mg per week × 4 following by 200 mg every 6 months) and 11 patients in relapse prevention group with complete remission (CR) after steroid therapy were treated with RTX (200 mg ×1 every 6 months) for preventing the relapse of MCD. RESULTS: Of the 22 patients with MCD in relapse treatment group, there were 21 cases (95.45%) of remission [2 (9.09%) partial remission (PR), 19 (86.36%) CR], 1 (4.56%) no remission (NR) and 20 (90.90%) relapse-free. The Median duration of sustained remission was 16.3 months (3, 23.5 months, inter quartile range (IQR)). 11 patients in the relapse prevention group during a follow-up of 12 months (9-31 months) had no relapse. The average dose of prednisone in two groups after RTX treatment was significantly lower than before treatment. CONCLUSION: The results of this study suggested low-dose RTX can significantly reduce relapse rate and steroid dose in adults with MCD with fewer side effects. Low-dose RTX regimens may be beneficial for the treatment of relapsing MCD in adults and may be the preferred regimen for patients at high risk for the development of adverse events from corticosteroids.

Contribution of IL-33/ILC2-mediated Th2 cytokines during the progression of minimal change disease.

Minimal change disease (MCD) is a common type of nephrotic syndrome with high recurrence rate. This study aims to explore the impacts of interleukin (IL)-33 in MCD and to discuss its potential mechanism. In adriamycin (ADM) and puromycin aminonucleoside (PAN)-induced MCD rat model, IL-33 was used for treatment. H&E staining was applied for detecting histological changes. Critical proteins were examined by western blot. Corresponding commercial kits tested oxidative stress- and inflammation-related factors. Cell apoptosis was measured by TUNEL assay. ADM-induced podocyte injury model was establish to mimic MCD in vitro. Cell proliferation and apoptosis were detected by CCK-8 and TUNEL assays. Finally, podocyte was stimulated by innate lymphoid type-2 cells-secreted Th2 cytokines (ILC2s: IL-13 and IL-5 respectively), with or without incubation with M1 macrophage medium to further explore the immune-regulation of ILC2s behind the inflammatory environment of MCD. It was found that PAN-induced kidney jury, inflammation, oxidative stress and apoptosis were severer than ADM, and IL-33 treatment significantly alleviated the above injuries in PAN and ADM-induced MCD rat model. Moreover, IL-33 reversed the reduced viability and increased oxidative stress and apoptosis in ADM-induced podocyte injury model. Further, the capacities of IL-13 alone in inducing M1/M2 macrophage polarization, apoptosis, inflammation, kidney injury and reducing cell viability are stronger than IL-5. However, IL-13 reversed reduced cell viability and stimulated apoptosis, inflammation, kidney injury mediated by co-incubation with M1-conditioned medium. Collectively, IL-33 might protect against immunologic injury in MCD via mediating ILC2s-secreted IL-13.

Nephrotic syndrome of minimal change disease following exposure to mercury-containing skin lightening cream: A case report and literature review.

Long-term exposure to mercury-containing skin lightening cream can cause mercury-related nephropathy, among which, membranous nephropathy (MN) and minimal change disease (MCD) are the main pathological types. In contrast to these two conditions, MCD with IgA deposition is not a common disease. In the present study, we report a 65-year-old Asian woman who developed nephrotic syndrome following long-term use of mercury-containing skin lightening cream. The urine mercury level of the patient was significantly increased, and the results of the renal biopsy indicated diagnosis of MCD with IgA deposition. Following three courses of treatment with sodium dimercaptopropane sulfonate (DMPS) alone and discontinuation of the skin cream, the symptoms of the patient were relieved without use of glucocorticoids, with proteinuria turning negative and a significant reduction in urine mercury levels. During the 6-month follow-up period, routine urinalysis remained normal. By reviewing relevant published literature, we summarized the pathological characteristics, possible mechanism of action, and treatment strategies of mercury poisoning-related MCD. The possibility of mercury poisoning should be considered for patients with nephropathy and history of use of skin lightening cosmetics. In these patients, the urine mercury levels should be measured in time so that mercury removal therapy can be implemented early.

Nephrotic syndrome with minimal change disease after the Pfizer-BioNTech COVID-19 vaccine: two cases.

We present two cases of nephrotic syndrome with minimal change disease after the Pfizer-BioNTech COVID-19 vaccine. We discuss the initial presentation, investigation and management of these patients along with a discussion around the current evidence base for vaccine-induced nephrotic syndrome.

Interventions for minimal change disease in adults with nephrotic syndrome.

BACKGROUND: Steroids have been used widely since the early 1970s for the treatment of adult-onset minimal change disease (MCD). Recently, newer agents have been used in adult MCD aiming to reduce the risk of adverse effects. The response rates to immunosuppressive agents in adult MCD are more variable than in children. The optimal agent, dose, and duration of treatment for the first episode of nephrotic syndrome, or for disease relapse(s) have not been determined. This is an update of a review first published in 2008. OBJECTIVES: We aimed to 1) evaluate the benefits and harms of different agents, including both immunosuppressive and non-immunosuppressive agents, in adults with MCD causing the nephrotic syndrome; and 2) evaluate the efficacy of interventions on 'time-to-remission' of nephrotic syndrome, in adults with MCD causing the nephrotic syndrome. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 21 July 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of any intervention for MCD with nephrotic syndrome in adults over 18 years were included. Studies comparing different types, routes, frequencies, and duration of immunosuppressive agents and non-immunosuppressive agents were assessed. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Statistical analyses were performed using the random-effects model and results were expressed as a risk ratio (RR) for dichotomous outcomes, or mean difference (MD) for continuous data with 95% confidence intervals (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Fifteen RCTs (769 randomised participants) were identified; four studies evaluated different prednisolone regimens, eight studies evaluated the calcineurin inhibitors (CNIs) (tacrolimus or cyclosporin), two studies evaluated enteric-coated mycophenolate sodium (EC-MPS) and one study evaluated levamisole. In all but two studies of non-corticosteroid agents, reduced-dose prednisolone was given with the treatment agent and the comparator was high-dose prednisolone. In the risk of bias assessment, 11 and seven studies were at low risk of bias for sequence generation and allocation concealment, respectively. No studies were at low risk of performance bias and eight studies were at low risk of detection bias. Thirteen, 10 and six studies were at low risk of attrition bias, reporting bias and other bias, respectively. Compared with no specific treatment, it is uncertain whether prednisolone increases the number with complete remission (1 study, 28 participants: RR 1.44, 95% CI 0.95 to 2.19), complete or partial remission (1 study, 28 participants: RR 1.38, 95% CI 0.98 to 1.95), subsequent relapse (1 study, 28 participants: RR 0.75, 95% CI 0.48 to 1.17), or reduces the adverse effects because the certainty of the evidence is very low. Compared with oral prednisolone alone, it is uncertain whether intravenous methylprednisolone and prednisolone increase the number with complete remission (2 studies, 35 participants: RR 1.76, 95% CI 0.17 to 18.32; I² = 90%), relapse (two studies, 19 participants. RR 1.18, 95% CI 0.65 to 2.15; I² = 0%) or adverse events because the certainty of the evidence is very low. Compared with prednisolone alone, CNIs with reduced-dose prednisolone or without prednisolone probably make little or no difference to the number achieving complete remission (8 studies; 492 participants: RR 0.99, 95% CI 0.93 to 1.05; I² = 0%), complete or partial remission (4 studies, 269 participants: RR 1.01, 95% CI 0.96 to 1.05; I² = 0%), or relapse (7 studies; 422 participants: RR 0.73, 95% CI 0.51 to 1.03; I² = 0%) (moderate certainty evidence), may reduce the risk of obesity or Cushing's Syndrome (5 studies; 388 participants: RR 0.11, 95% CI 0.02 to 0.59; I² = 45%) and the risk of acne (4 studies; 270 participants: RR 0.15, 95% CI 0.03 to 0.67; I² = 0%) (low certainty evidence); and had uncertain effects on diabetes or hyperglycaemia, hypertension, and acute kidney injury (AKI) (low certainty evidence). Compared with prednisolone alone, EC-MPS with reduced-dose prednisolone probably make little or no difference to the number undergoing complete remission at 4 weeks (1 study, 114 participants: RR 1.12, 95% CI 0.84 to 1.50), and at 24 weeks probably make little or no difference to the number undergoing complete remission (2 studies, 134 participants: RR 1.12, 95% CI 0.84 to 1.38; I² = 0%) (moderate certainty evidence), complete or partial remission (2 studies 134 participants: RR 0.92, 95% CI 0.75 to 1.12; I² = 0%), relapse (2 studies, 83 participants: RR 0.50, 95% CI 0.07 to 3.74; I² = 56%) (low certainty evidence); or to the adverse events of new-onset glucose intolerance, death, or AKI (low certainty evidence). One study (24 participants) compared levamisole and prednisolone with prednisolone in patients with relapsing disease. The authors identified no differences in mean relapse rate or adverse effects but no standard deviations were provided. AUTHORS' CONCLUSIONS: This updated review has identified evidence for the efficacy and adverse effects of CNIs and EC-MPS with or without reduced-dose prednisolone compared with prednisolone alone for the induction of remission in adults with MCD and nephrotic syndrome with some reductions in steroid-associated adverse events. RCT data on the efficacy and adverse effects of rituximab in adults with MCD are awaited. Further, adequately powered RCTs are required to determine the relative efficacies of CNIs and EC-MPS and to evaluate these medications in patients with relapsing or steroid-resistant disease.

Pediatric Minimal Change Disease and AKI following the Pfizer-BioNTech COVID-19 Vaccine: causal or incidental correlation?

The global coronavirus 2019 (COVID-19) pandemic required vaccination even in children to reduce infection. We report on the development of acute kidney injury (AKI) and minimal change disease (MCD) nephrotic syndrome (NS), shortly after the first injection BNT162b2 COVID-19 vaccine (Pfizer-BioNTech). A 12-year-old previously healthy boy was referred to our hospital with complaints of peripheral edema and nephrotic range proteinuria. Nine days earlier he had received his first injection BNT162b2 COVID-19 vaccine (Pfizer-BioNTech). Seven days after injection, he developed leg edema, which rapidly progressed to anasarca with significant weight gain. On admission, serum creatinine was 1.3 mg/dL and 24-hour urinary protein excretion was 4 grams with fluid overload. As kidney function continued to decline over the next days, empirical steroid treatment and renal replacement therapy with ultrafiltration were started and kidney biopsy was performed. Seven days after steroid therapy, kidney function began to improve, gradually returning to normal. The association of MCD, nephrotic syndrome and AKI hasn't been previously described following the Pfizer-BioNTech COVID-19 vaccine in pediatric population, but this triad has been reported in adults. We need further similar case reports to establish the real incidence of this possible vaccine side effect.

Minimal change disease following the Moderna COVID-19 vaccine: first case report.

BACKGROUND: There have been cases of minimal change disease (MCD) reported following previous vaccines. During the COVID-19 era, only 3 cases of new-onset MCD and a case of MCD relapse were reported following the Pfizer-BioNTech COVID-19 vaccine. We herein report the first case of MCD after receiving the Moderna COVID-19 vaccine. CASE PRESENTATION: A 43-year-old man presented to hospital 3 weeks after receiving the first dose of the Moderna vaccine, with both bilateral lower extremities and scrotal edema. He initially developed a sudden-onset bilateral lower extremities swelling on day 7 post-vaccine. He, then, developed dyspnea and scrotal swelling over a time span of 2 weeks. On physical examination, his blood pressure was 150/92 mmHg. There was a decreased air entry at lung bases, bilateral lower extremities and scrotal edema. Labs revealed hypoalbuminemia, hyperlipidemia and 15 g of proteinuria. His immunologic and serologic work up was negative. Renal biopsy showed concomitant MCD and IgA nephropathy. Patient was treated with oral steroids and had a good response; his edema resolved, serum albumin improved, and proteinuria decreased to 1 g within 2 weeks of treatment. CONCLUSIONS: To the best of our knowledge, MCD has not been previously reported after receiving the Moderna COVID-19 vaccine. It remains unclear whether the COVID-19 mRNA vaccines are associated with the development of MCD, or it coincided with the mass vaccination. Further studies are needed to determine the incidence of MCD post COVID-19 vaccines and the underlying pathophysiology of glomerular injury post vaccination.

Minimal Change Disease With Severe Acute Kidney Injury Following the Oxford-AstraZeneca COVID-19 Vaccine: A Case Report.

We report a case of minimal change disease (MCD) with severe acute kidney injury (AKI) following the first injection of the ChAdOx1 nCoV-19 (AZD1222) vaccine from Oxford-AstraZeneca against coronavirus disease 2019 (COVID-19). A 71-year-old man with a history of dyslipidemia and a baseline serum creatinine of 0.7mg/dL presented with nephrotic syndrome, AKI, and severe hypertension 13 days after receiving the Oxford-AstraZeneca vaccine. Refractory hyperkalemia and hypervolemia with oligoanuria prompted initiation of hemodialysis. His serum albumin was 2.6g/dL and his urinary protein-creatinine ratio was 2,321mg/mmol. Given a high suspicion for rapidly progressive glomerulonephritis, empirical glucocorticoid treatment was initiated (3 methylprednisolone pulses followed by high-dose prednisone). A kidney biopsy showed MCD and acute tubular injury. Kidney function and proteinuria subsequently improved, and hemodialysis was discontinued 38 days after the start of therapy. This case describes de novo MCD after the Oxford-AstraZeneca vaccine. It adds to the few published case reports of MCD after the Pfizer-BioNTech COVID-19 vaccine. Further reports and studies will be needed to elucidate whether MCD is truly associated with COVID-19 vaccination.

Lithium toxicity and the kidney with special focus on nephrotic syndrome associated with the acute kidney injury: A case-based systematic analysis.

Despite the progress made in treating bipolar and unipolar affective disorders, lithium carbonate is still a common drug in psychiatric practice. Lithium-related renal side effects include nephrogenic diabetes insipidus, chronic tubulointerstitial nephropathy, and acute kidney injury (AKI). Nephrotic syndrome (NS) is an uncommon but severe complication of lithium treatment. We present a 49-year-old female treated with lithium carbonate due to a recurrent depressive disorder who developed NS during this therapy. NS spontaneously remitted after the drug withdrawal. Since her lithium serum levels were within the recommended values, we performed a retrospective analysis of lithium-induced NS cases trying to determine causes predisposing to the NS development, underlying histopathology, and preservation or irreversible loss of kidney function. This analysis revealed that in lithium-induced NS with AKI, lithium serum level was the key determinant of AKI development (the ß coefficient = 0.8499 with a confidence interval ranging from 0.7452 to 0.9546 and p value < 0.0001). In these cases, the underlying pathology was mainly minimal change disease (MCD), which was quickly reversible upon the drug withdrawal. The development of chronic kidney disease (CKD) seemed to be associated with lithium therapy duration. However, the multiple regression analysis for CKD as the dependent variable showed that the decisive factor was focal segmental glomerulosclerosis (FSGS) as the underlying pathology (the ß coefficient = 0.7866 with a confidence interval ranging from 0.600 to 0.9704 and the p value < 0.0001). Thus, we conclude that in lithium-induced NS/AKI, serum lithium levels contribute to these complications, while FSGS lesions are responsible for CKD's disease progression.

Minimal change disease concurrent with acute interstitial nephritis after long-term use of sorafenib in a patient with renal cell carcinoma.

Sorafenib is one of the multi-targeted tyrosine kinase inhibitors (TKI), mainly used for treating advanced renal cell carcinoma. Accumulated evidence indicates a minority of patients develop nephrotic syndrome (NS) as a high-grade nephrotoxic injury; however, evidence of NS after long-term use of sorafenib remains unclear. A 64-year-old man developed NS following 2-year use of sorafenib and his NS persisted even after sorafenib use was discontinued. Renal biopsy disclosed minimal change disease (MCD) concurrent with acute tubulointerstitial nephritis, indicating secondary MCD with which sorafenib may be involved. To prevent permanent renal insufficiency, we administered glucocorticoid and succeeded in achieving complete remission from NS. Nephrotoxic injuries could occur at any time with variable onset after sorafenib. Renal biopsy should be pursued in the case of NS associated with TKI therapy. To facilitate recovery of renal dysfunction, administration of prednisolone should be considered, particularly when NS does not disappear after cessation of TKIs.