Minimal change glomerular disease associated with solid neoplasms: a systematic review.

BACKGROUND: Paraneoplastic minimal change disease (MCD) has been associated with hematological malignancies, whereas solid malignancies are commonly associated with membranous glomerulonephritis. In this systematic review of the literature, we describe the clinical features, treatment and outcome of MCD associated with solid neoplasms. METHODS: We performed a systematic review of the MEDLINE, COCHRANE, EMBASE and SCOPUS databases, including case reports of adult patients with biopsy-proven MCD and solid malignancy, without language or time restrictions. RESULTS: Sixty-seven papers were included, presenting 86 cases with a mean age of 57.8 ± 14.7 years; 41.0% were women. Nephrotic syndrome was the initial presentation in 96.2% of patients; 67.2% had kidney function impairment, and 21.2% required kidney replacement therapy. The most frequent malignancies were malignant thymoma (34.9%), kidney (14.0%), lung (12.8%), and gastrointestinal tumors (12.8%). In 40.7% of cases, the neoplasm diagnosis preceded MCD by 33.8 ± 46.1 months, while in 31.4%, it followed diagnosis of MCD by 12.4 ± 22.6 months. In 27.9%, the neoplasm and kidney disease were diagnosed simultaneously. Immunosuppressive therapy was started in 79.1% of cases and tumor-specific treatment in 83.7%. Remission of MCD was achieved in 80.2% of patients: 38.2% responded to immunosuppressive treatment alone and 29.6% to oncological treatment alone. CONCLUSIONS: The association between MCD and solid neoplasms is well-documented. Immunosuppressive therapy alone induced nephrotic syndrome remission in over one-third of cases; most others responded to tumor-specific treatment. Solid tumor screening should be considered in MCD independently of the steroid response, though more data on solid tumor-associated MCD prevalence are needed for a definitive statement. PROSPERO TRIAL REGISTRATION NUMBER: CRD42024521854.

Semaglutide-associated kidney injury.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are multipurpose agents effective in improving glycemic control in patients with type 2 diabetes while also achieving weight loss and risk reduction of major cardiovascular (CV) events and chronic kidney disease progression. With their increased utility in diabetes, obesity, CV health and renal protection, the use of GLP-1RAs has increased. However, with this increased use, there have also been increased reports of associated kidney adverse events, including case reports of acute interstitial nephritis (AIN) associated with GLP-1RA use. We report the data from the Food and Drug Administration adverse event reporting system (FAERS) in relation to GLP-1RA use and adverse kidney events, with acute kidney injury being the most common. In addition, we report two cases of semaglutide-associated biopsy-proven AIN and one with associated podocytopathy. To our knowledge, this is the first case of biopsy-proven AIN with podocytopathy associated with semaglutide use. Both patients experienced complete remission shortly after discontinuing semaglutide and undergoing immunosuppressive therapy. Further analysis of the FAERS database revealed 17 cases of proteinuria and 1 case of glomerulonephritis associated with semaglutide in the FAERS database, however no further information was available. While further research is needed to establish causality, this case series adds to the growing body of literature that semaglutide is associated with AIN and adds a new association, semaglutide with AIN and podocytopathies. While the overall clinical and mortality benefits of GLP-1RAs may outweigh the rarer risks, prescribers need to be aware of these associations, particularly as the use of GLP-1RAs continues to expand.

To biopsy or not to biopsy a teenager with typical idiopathic nephrotic syndrome? Start steroids first.

It is well known that minimal change disease (MCD) and focal segmental glomerulosclerosis are the most common histopathology findings in children with idiopathic nephrotic syndrome. Moreover, several studies demonstrated that MCD is associated with high steroid-responsiveness and a low incidence of kidney failure, suggesting that routine kidney biopsy is not warranted. Over time, the indications for performing a kidney biopsy have become increasingly stringent, aiming to limit unnecessary invasive procedures in the paediatric population. The most recent guidelines state that a kidney biopsy is not usually necessary at disease onset. Still, it should be performed in case of atypical features suggestive of systemic diseases or glomerulonephritis and in case of steroid-resistance, to assess the different differential diagnoses, regardless of patient age. Moreover, it has been shown that the best prognostic marker in childhood nephrotic syndrome is response to treatment and that kidney histology is not accurate in predicting prognosis. Furthermore, a kidney biopsy is not necessary to predict the relapsing course. Notably, kidney biopsy is an invasive procedure and may lead to significant complications. Finally, novel non-invasive biomarkers have been validated or are in the process of being approved to guide differential diagnoses and thus limit the need for kidney biopsies in patients with typical nephrotic syndrome. In the following sections, we aim to explain why initiating steroid treatment as the initial approach in teenagers with typical nephrotic syndrome is a reasonable strategy. Additionally, we explore how kidney biopsy indications may be alleviated in this population.

A case report of minimal change disease associated with Kimura disease complicated by optic neuritis.

Kimura disease (KD) is a rare chronic inflammatory disease that typically presents with soft subcutaneous granulomas in the head and neck regions characterized by elevated blood eosinophils and immunoglobulin E (IgE) level, whose aetiology remains poorly elucidated. Minimal change disease (MCD) has been reported as one of the renal manifestations that KD can present with, indicating that they may share a common pathology. Herein we describe a case of recurrent MCD associated with KD. During a follow-up period of 15 years, MCD recurred three times with increased disease activity of KD as reflected by flares of skin lesions and elevated peripheral eosinophils, and responded well to increased doses of prednisolone and cyclosporin. Notably, visual field defects in his right monocular vision appeared at the time of third recurrence of MCD, leading to the diagnosis of optic neuritis (ON). Optic nerve involvement associated with KD is extremely rare, and this case is noteworthy in that inflammation in the optic nerve was observed at the time of MCD recurrence with increased disease activity of KD, suggesting the existence of a common pathology between KD, MCD, and ON. In patients with KD, an imbalance of T helper (Th) cells with Th2 cells predominating over Th1 cells is observed, which results in hyperIgEemia and eosinophilia. This Th2-predominant immunological status in KD considered to predispose to MCD may also predispose to ON. MCD with a background of Th2-predominant immune state may require attention to the possibility of complication of ON.

To biopsy or not to biopsy a teenager with idiopathic nephrotic syndrome? Biopsy first.

Kidney biopsy plays a crucial role in the diagnosis and management of several glomerular diseases. While it is generally considered a routine and safe procedure in children, it should be conducted with the primary objective of addressing the following question: do the prognosis and treatments vary based on the findings of kidney biopsy? In children presenting with idiopathic nephrotic syndrome (INS), guidelines suggest to consider kidney biopsy for individuals older than 12 years, primarily due to the possible increased incidence of different glomerulonephritis compared to younger patients, who predominantly manifest with minimal change disease. However, these guidelines also advocate for uniform therapeutic strategies, typically steroids, irrespective of the age or histological findings. Whether the age of more than 12 years may be a recommendation for performing kidney biopsy at presentation of INS is debatable. Instead, kidney biopsy could be reserved for steroid-resistant cases. On the other hand, when kidney biopsy is performed in INS, particularly in focal segmental glomerulosclerosis, histology may reveal additional lesions, that are strongly associated with a poorer response to treatment and worse clinical outcomes. Therefore, current guidelines on treatments of nephrotic syndrome may appear overly restrictive, despite the relevant findings provided by kidney biopsy. Therefore, in the present manuscript, which is part of a pro-con debate on the management of nephrotic syndrome in adolescents, we emphasize the potential role of performing a kidney biopsy before initiating corticosteroid treatment.

The compositional and functional imbalance of the gut microbiota in CKD linked to disease patterns.

BACKGROUND: The prevalence of chronic kidney disease (CKD) is on the rise, posing a significant public health challenge. Although gut microbiome dysbiosis has been implicated in the impairment of kidney functions, the existence of pathological subtypes-linked differences remains largely unknown. We aimed to characterize the intestinal microbiota in patients with membranous nephropathy (MN), IgA nephropathy (IgAN), minimal change disease (MCD), and ischemic renal injury (IRI) in order to investigate the intricate relationship between intestinal microbiota and CKD across different subtypes. METHODS: We conducted a cross-sectional study involving 94 patients with various pathological patterns of CKD and 54 healthy controls (HCs). The clinical parameters were collected, and stool samples were obtained from each participant. Gut microbial features were analyzed using 16S rRNA sequencing and taxon annotation to compare the HC, CKD, MN, IgAN, MCD, and IRI groups. RESULTS: The CKD subjects exhibited significantly reduced alpha diversity, modified community structures, and disrupted microbial composition and potential functions compared to the control group. The opportunistic pathogen Klebsiella exhibited a significant enrichment in patients with CKD, whereas Akkermansia showed higher abundance in HCs. The study further revealed the presence of heterogeneity in intestinal microbial signatures across diverse CKD pathological types, including MN, IgAN, MCD, and IRI. The depression of the family Lachnospiraceae and the genus Bilophila was prominently observed exclusively in patients with MN, while suppressed Streptococcus was detected only in individuals with MCD, and a remarkable expansion of the genus Escherichia was uniquely found in cases of IRI. The study also encompassed the development of classifiers employing gut microbial diagnostic markers to accurately discriminate between distinct subtypes of CKD. CONCLUSIONS: The dysregulation of gut microbiome was strongly correlated with CKD, exhibiting further specificity towards distinct pathological patterns. Our study emphasizes the significance of considering disease subtypes when assessing the impact of intestinal microbiota on the development, diagnosis, and treatment of CKD.

Activation of the inflammasome and pyroptosis cascade in podocytes of patients with minimal change disease.

Background: In contrast to childhood minimal change disease (MCD), adult-onset MCD frequently recurs and requires prolonged immunosuppressive therapy. Accordingly, an investigation of the pathogenesis of adult MCD is required. MCD is usually accompanied by severe dyslipidaemia. Oxidized low-density lipoprotein (ox-LDL) is known to function in a damage-associated molecular pattern (DAMP) through CD36, triggering the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome and programmed cell death called pyroptosis. However, the relationship between MCD pathogenesis and NLRP3 inflammasome/pyroptosis activation via CD36 is not fully understood. Methods: We conducted comprehensive histological and clinical evaluations by analysing renal biopsy (RBx) specimens and urine samples obtained from 26 patients with MCD. These samples were compared with control kidneys from 15 transplant donors and urine samples from 15 healthy volunteers. Results: The number of podocytes was lower in the MCD group than in the control group. Urinary ox-LDL levels were higher in the MCD group than in the control group. Immunofluorescence staining revealed that NLRP3 and CD36 were upregulated in MCD podocytes. Urinary interleukin (IL)-18 levels increased in patients with MCD. Steroid therapy performed before RBx appeared to maintain the podocyte number and reduce urinary ox-LDL and IL-18 levels. Conclusion: In MCD, the NLRP3 inflammasome and pyroptosis cascade seem to be activated via upregulation of CD36 in podocytes, associated with increased urinary ox-LDL. Elevated urinary IL-18 levels suggest that pyroptosis may occur in MCD. Further research is required to confirm the significance of the podocyte NLRP3 inflammasome/pyroptosis in MCD.

A randomised, two-arm (1:1 ratio), double blind, placebo controlled phase III trial to assess the efficacy, safety, cost and cost-effectiveness of Rituximab in treating de novo or relapsing NS in patients with MCD/FSGS (TURING).

BACKGROUND: Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS) are a spectrum of disease causing the nephrotic syndrome (NS), characterised by proteinuria with debilitating oedema, as well as a high risk of venous thromboembolic disease and infection. Untreated, 50-60% patients with FSGS progress to end stage kidney disease after 5 years. These diseases respond to immunosuppression with high dose glucocorticoids, but 75% will relapse as the glucocorticoids are withdrawn, leading to significant morbidity associated with prolonged use. In children, the B cell depleting monoclonal antibody rituximab reduces relapse risk, but this drug has not been tested in randomised controlled trial in adults. METHODS: 130-150 adults with new or relapsing MCD/FSGS, from UK Renal Units, are being randomised to receive either rituximab (two 1 g infusions two weeks apart) or placebo. Partipicipants are recruited when they present with nephrosis, and all are treated with glucocorticoids as per KDIGO guidelines. Once in remission, prednisolone is withdrawn according to a pre-specified regimen. If in remission at 6 months, participants receive a further dose of trial drug. If they relapse, they are unblinded, and if they have received placebo, they are offered open label rituximab with protocolised prednisolone as in the main phase of the trial. The primary end point is time from remission to relapse. A number of secondary endpoints will be assessed including the effect of rituximab on: (1) NHS and societal resource use and hence cost: (2) safety: (3) other measures of efficacy, such as achievement of partial and complete remission of NS and the preservation of renal function: (4) health status of participant. TRIAL REGISTRATION: TURING received ethical approval on 14 Jun 2019 - REC reference: 19/LO/0738. It is registered on EudraCT, with ID number: 2018-004611-50, with a start date of 2019-06-14.

Rituximab in Steroid-Dependent Podocytopathies.

Introduction: Rituximab (RTX) has been reported as an effective treatment alternative in primary forms of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) associated with steroid dependence and frequent relapses. However, the optimal RTX regimen and the outcomes of further doses of RTX remain unclear. This study aimed to evaluate the use of induction and maintenance RTX therapy for adults with primary podocytopathies. Methods: We performed a retrospective case series on adult patients with steroid-dependent podocytopathies who received an induction RTX therapy. Maintenance therapy was performed at physician's discretion. Remission and relapse rates, concomitant corticosteroids and immunosuppressants use, B-cell depletion and adverse events were analyzed. Results: Fourteen patients (mean age at start of RTX 29.1 ± 21.9 years) with MCD (n = 7) or FSGS (n = 7) were treated with 2 doses of 1,000 mg 2 weeks apart (n = 13) or four doses of 375 mg/m2 (n = 1) of RTX. At last follow-up (mean 47.3 ± 101.7 months), 10 patients were in complete remission and two remained in partial remission. A reduction in the number of relapses, number of patients under corticosteroids and immunosuppressants, and dose of prednisolone was observed when compared to baseline (14 [100%] vs. 5 [35.7%]; 8/14 [57.1%] vs. 4/12 [33.3%]; 13/14 [92.9%] vs. 7/12 [58.3%]; 20 mg/day vs. 5.25 mg/day, respectively). Maintenance RTX therapy was used in 6 patients, with sustained complete remission. Infusion reactions were observed in 4 patients (one required treatment withdrawal). Conclusions: Our findings support the use of RTX for a steroid-free remission in podocytopathies and suggest that maintenance RTX is well-tolerated and associated with prolonged remission. Further studies are needed to confirm its efficacy and safety and establish the optimal induction and maintenance RTX regimen in steroid-dependent podocytopathies.

Rituximab (RTX) seems to be an effective treatment alternative in primary forms of MCD and FSGS, particularly in cases of steroid dependence and frequent relapses. Our findings support the use of RTX for a steroid-free remission in podocytopathies and suggest that maintenance RTX is well-tolerated and associated with prolonged remission. Further studies are needed to confirm its efficacy and safety and establish the optimal induction and maintenance RTX regimen in steroid-dependent podocytopathies.

National Unified Renal Translational Research Enterprise: Idiopathic Nephrotic Syndrome (NURTuRE-INS) study.

Background: Idiopathic nephrotic syndrome (INS) is a heterogenous disease and current classification is based on observational responses to therapies or kidney histology. The National Unified Renal Translational Research Enterprise (NURTuRE)-INS cohort aims to facilitate novel ways of stratifying INS patients to improve disease understanding, therapeutics and design of clinical trials. Methods: NURTuRE-INS is a prospective cohort study of children and adults with INS in a linked biorepository. All recruits had at least one sampling visit collecting serum, plasma, urine and blood for RNA and DNA extraction, frozen within 2 hours of collection. Clinical histology slides and biopsy tissue blocks were also collected. Results: A total of 739 participants were recruited from 23 centres to NURTuRE-INS, half of whom were diagnosed in childhood [n = 365 (49%)]. The majority were white [n = 525 (71%)] and the median age at recruitment was 32 years (interquartile range 12-54). Steroid-sensitive nephrotic syndrome (SSNS) was the most common clinical diagnosis [n = 518 (70%)]. Of patients diagnosed in childhood who underwent a kidney biopsy, for SSNS (n =103), 76 demonstrated minimal change disease (MCD), whereas for steroid-resistant nephrotic syndrome (n =80), 21 had MCD. Almost all patients diagnosed in adulthood had a kidney biopsy [n = 352 (94%)]; 187 had MCD and 162 had focal segmental glomerulosclerosis. Conclusions: NURTuRE-INS is a prospective cohort study with high-quality biosamples and longitudinal data that will assist research into the mechanistic stratification of INS. Samples and data will be available through a Strategic Access and Oversight Committee.

Case report: Effective treatment of rituximab-resistant minimal change disease with obinutuzumab in an adult.

Background: Minimal change disease (MCD) is a common cause of adult nephrotic syndrome. Most adults with MCD achieve complete remission (CR) after initial steroid therapy. However, approximately 30% of adults who respond to steroids experience frequent relapses, becoming steroid-dependent and potentially developing refractory MCD. Treating refractory MCD in adults poses a significant challenge. Main body: A 37-year-old woman presented to the nephrology department with a 6-year history of MCD. The diagnosis of MCD was confirmed via renal biopsy. She initially achieved CR with steroid treatment but experienced relapse during steroid tapering. Subsequent CR was achieved with a regimen of steroids and tacrolimus although multiple relapses occurred. Rituximab led to another CR, but its maintenance lasted only 6 months. The response to subsequent rituximab treatments was unsatisfactory. Ultimately, obinutuzumab was selected, resulting in the induction and maintenance of CR for 12 months. Conclusions: This case demonstrates the successful treatment of frequently relapsed, steroid-dependent, and rituximab-resistant MCD with obinutuzumab. Obinutuzumab is a promising therapeutic option for rituximab-resistant MCD.

Canonical effects of cytokines on glomerulonephritis: A new outlook in nephrology.

Glomerulonephritis (GN) is an important cause of renal inflammation resulting from kidney-targeted adaptive and innate immune responses and consequent glomerular damage. Given the lack of autoantibodies, immune complexes, or the infiltrating immune cells in some forms of GN, for example, focal segmental glomerulosclerosis and minimal change disease, along with paraneoplastic syndrome and a special form of renal involvement in some viral infections, the likeliest causative scenario would be secreted factors, mainly cytokine(s). Since cytokines can modulate the inflammatory mechanisms, severity, and clinical outcomes of GN, it is rational to consider the umbrella term of cytokine GN as a new outlook to reclassify a group of previously known GN. We focus here, particularly, on cytokines that have the central "canonical effect" in the development of GN.

Relapsing nephrotic syndrome with acute renal failure following a unique episode of multiple bee stings: A case report.

The commonest renal involvement after bee stings is acute kidney injury due to rhabdomyolysis. Nephrotic syndrome combined with AKI is unusual complication of Hymenoptera stings. We diagnosed a minimal change disease and six-year follow up relapses.

Investigating quantitative histological characteristics in renal pathology using HistoLens.

HistoLens is an open-source graphical user interface developed using MATLAB AppDesigner for visual and quantitative analysis of histological datasets. HistoLens enables users to interrogate sets of digitally annotated whole slide images to efficiently characterize histological differences between disease and experimental groups. Users can dynamically visualize the distribution of 448 hand-engineered features quantifying color, texture, morphology, and distribution across microanatomic sub-compartments. Additionally, users can map differentially detected image features within the images by highlighting affected regions. We demonstrate the utility of HistoLens to identify hand-engineered features that correlate with pathognomonic renal glomerular characteristics distinguishing diabetic nephropathy and amyloid nephropathy from the histologically unremarkable glomeruli in minimal change disease. Additionally, we examine the use of HistoLens for glomerular feature discovery in the Tg26 mouse model of HIV-associated nephropathy. We identify numerous quantitative glomerular features distinguishing Tg26 transgenic mice from wild-type mice, corresponding to a progressive renal disease phenotype. Thus, we demonstrate an off-the-shelf and ready-to-use toolkit for quantitative renal pathology applications.

Role of Podocyte in Kidney Disease.

Podocytes are epithelial cells lining the outer surface of the renal glomerular capillaries and they play a pivotal role in maintaining the structural and functional integrity of the glomerular filtration barrier. Podocytes react to injury in various ways and any injury to these highly specialized cells can progress to podocyte dysfunction, resulting in a group of proteinuric renal diseases called podocytopathies. Podocytopathies include a wide spectrum of primary and secondary kidney diseases, including minimal change disease, diffuse mesangial sclerosis, focal segmental glomerulosclerosis, collapsing glomerulopathy, diabetic, membranous and lupus nephropathies. Etiologically, they can be idiopathic, genetic or secondary to infections and drugs, metabolic diseases, hemodynamic factors or associated with various immune and non-immune systemic diseases. This manuscript provides a basic understanding of podocyte structure, causes of podocyte injury, response to the injury and the subsequent progression to podocytopathies. The pathogenesis of these diseases is set around podocytes. The clinical and morphological manifestations, the commonality and heterogeneity of these podocytopathies are also discussed. As our knowledge of podocyte biology improves, so will our treatment avenues with a more podocyte-centric personalized approach.

Minimal Change Disease.

Minimal change disease represents a common cause of nephrotic syndrome in both pediatric and adult patients. Although much remains to be discovered, there have been significant recent advancements in our understanding of the pathophysiology of minimal change disease, including the discovery of antinephrin antibodies as a marker for diagnosis of disease. Here we will review what is known about the pathophysiology, treatment, and prognosis of minimal change disease and the differences between pediatric and adult patients. Recent advances in our understanding of the mechanisms of disease will be noted. We will discuss how this may change the treatment of minimal change disease going forward and what remains to be studied.

Advances in primary glomerulonephritis.

Primary glomerulonephritis comprises several renal-limited diseases that can cause haematoproteinuria, chronic kidney disease, nephrosis and end stage kidney disease. The most common of these are IgA nephropathy (IgAN), primary membranous nephropathy (PMN), Focal Segmental Glomerulosclerosis (FSGS) and Minimal Change Disease (MCD). Although rare, these diseases cause a significant burden to health care systems, given the high cost of treating End Stage Kidney Disease (ESKD) with dialysis or transplantation. Until recently, the pathogenesis of primary gloerulonephritis has remained obscure. However, recent advances in understanding of how these diseases evolve has led to the introduction of novel therapeutic agents. Trials are underway or have recently completed that have huge implications for the standard of care for the primary glomerulonephritidies, and should dramatically reduce the number of patients who progress onto end stage kidney disease. This article reviews the international Kidney Disease Improving Global Outcomes (KDIGO) guidelines for the treatment of IgAN, PMN, FSGS and MCD, as well as recent research on pathogenesis and treatment.

Minimal Change Disease Associated with SARS-CoV-2 (COVID-19) Infection among Adult Filipinos: A Report of Two Cases and Review of Related Literature.

A 40-year-old Filipino female with a history of right total mastectomy for a low-grade phyllodes tumor was admitted due to stillbirth. Her laboratory results revealed an incidental finding of a positive COVID-19 RT-PCR swab, serum creatinine 1.04 mg/dL, urine RBC 1/HPF, and a 24-hour urine protein of 9.22 grams with hypoalbuminemia and dyslipidemia. Serologic workup was noted to be negative. A kidney biopsy was performed which demonstrated unremarkable light microscopy (LM) and immunofluorescence (IF) with widespread podocyte-foot process effacement, consistent with minimal change disease. She was started on prednisone (1 mg/kg/day) and achieved complete remission after six weeks. A 61-year-old Filipino male with a history of Type 2 Diabetes Mellitus, Hypertension, Dyslipidemia, and mild COVID-19 infection four months prior, now presented with diarrhea. On admission, his COVID-19 RT-PCR swab revealed a reinfection. Workup demonstrated a serum creatinine 3.39 mg/dL, urine RBC 2/HPF, and urine ACR 2.6 g/g. Serologic tests were negative. He was diagnosed with Nephrotic Syndrome and underwent kidney biopsy. Findings showed an unremarkable LM and IF with widespread podocyte-foot process effacement, consistent with minimal change disease. He was started on prednisone (1 mg/kg/day) and achieved complete remission after eight weeks. SARS-CoV-2 (COVID-19) may present with a variety of kidney involvement which includes glomerulopathies such as MCD. An accurate diagnosis using the patient's clinical presentation, renal histopathology, and adjunct laboratory examinations, is essential to direct effective management and good outcomes.