A Rare Case of Membranous Nephropathy Complicated by Chylothorax.

Background: Chylothorax can be classified into traumatic and nontraumatic based on the etiology. Nephrotic syndrome is a very rare cause of nontraumatic chylothorax in adults. Case presentation: A 66-year-old woman with membranous nephropathy who was non-compliant with her management, presented with dyspnea, and was found to have a large right sided chylothorax. Her chylothorax was secondary to membranous nephropathy after excluding other causes, which has been rarely reported in literature. Conclusion: This case highlights the possibility of nephrotic syndrome causing chylothorax, especially in patients with undiagnosed nephrotic syndrome or patients non-compliant with their management. When evaluating a patient with chylothorax, providers should consider nephrotic syndrome in the differential diagnosis. LEARNING POINTS: Chylothorax can be secondary to nephrotic syndrome which has been rarely reported in literature.Providers should be aware of nephrotic syndrome as a cause of chylothorax especially in patients with undiagnosed nephrotic syndrome or non-compliance with their management.Treatment of underlying cause is usually sufficient for spontaneous resolution of chylothorax with or without pleural fluid evacuation.

The Association of Lower Levels of Baseline Proteinuria With Earlier Remission in Primary Membranous Nephropathy.

Aim To study the clinical profile and course and to assess the outcome of patients with biopsy-proven primary membranous nephropathy (MN). Methods This study was carried out in a tertiary care hospital between December 2017 and December 2021 on four-year retrospective biopsy-proven patients with membranous nephropathy (MN). Urinary proteins, serum albumin, and serum creatinine were the baseline investigations that were performed. Special tests were done whenever necessary. Patients were treated with a modified Ponticelli (MP) regimen whenever needed. Patients were followed up after treatment administration for a minimum of a year. Results The study was done in 48 biopsy-proven MN patients. Thirty-six patients had primary MN with a mean age of 47+/-11.7 years. The male-female ratio was 2.6:1. Hypertension was present in 39% (14 patients), microscopic hematuria in 28% (10 patients), and acute kidney injury in 22% (8 patients). The mean 24-hour urinary protein was 11.2+/-2.9 g/day. PLA2R was positive in 78% (28 patients) of primary MN patients. Spontaneous remission was noted in 13.8% (5 patients) who were treated conservatively. Spontaneous remission was associated with lower baseline proteinuria (p<0.001), higher baseline serum albumin (p<0.001), and PLA2R negativity (p=0.04). Complete or partial treatment response was noted in 74.2% (23 patients). Treatment remission was associated with lower baseline proteinuria (p=0.018). Secondary membranous nephropathy (secondary MN) was diagnosed in 12 patients. Eleven were class V lupus nephritis, all women, and one male person living with HIV/AIDS (PLHA). Conclusions The majority of our primary MN patients were PLA2R positive on renal biopsy. Statistically significant factors associated with spontaneous remission were lower proteinuria, higher serum albumin at baseline, and PLA2R negativity. Treatment response was associated with lower proteinuria at presentation. The most common cause of secondary MN was lupus nephritis.

Effect of finerenone on nephrotic syndrome in patients with diabetic kidney disease.

Introduction: Diabetic kidney disease (DKD) is an important complication of diabetes as it results in end-stage renal disease; hence, several drugs have been developed for its treatment. However, even with treatment with renin-angiotensin system inhibitors and sodium-glucose cotransporter-2 inhibitors, the residual risk of DKD remains. While this risk is an issue, the renoprotective effects of finerenone, a novel non-steroidal mineralocorticoid receptor antagonist, are becoming evident. High proteinuria increases the risk of cardiovascular death as well as renal failure. Hence, it is especially important to address cases of urine protein to nephrotic levels in DKD, however, no previous studies have assessed the safety and efficacy of finerenone in patients with DKD and nephrotic syndrome. Therefore, this study aimed to assess whether finerenone has a renoprotective effect in advanced DKD complicated by nephrotic syndrome. Methods: Nine patients with DKD and nephrotic syndrome who received 10-20 mg/day of finerenone were retrospectively analyzed. The average observation period was 9.7 ± 3.4 months. Patients with serum potassium levels greater than 5.0 mEq/L at the start of finelenone were excluded. Changes in urinary protein levels, estimated glomerular filtration rate (eGFR), and serum potassium levels were studied before and after finerenone administration. Results: The mean changes in the urinary protein creatinine ratio (UPCR) at baseline were 6.6 ± 2.0. After finerenone treatment, the mean UPCR decreased to -0.6 ± 3.9; however, this change was not statistically significant.The eGFR decline slope also tended to decrease with finerenone treatment (before vs. after: 3.1 ± 4.9 vs. -1.7 ± 3.2 mL/min/1.73 m2. Furthermore, finerenone did not increase serum potassium levels. Conclusions: Patients treated with finerenone showed decreased UPCR; hence, it is suggested that finerenone may be effective in treating nephrotic syndrome in patients with DKD. These findings may be applicable to real-world clinical settings. Nonetheless, it is important to note that this study was a retrospective analysis of a single-center cohort and had a limited sample size, highlighting the need for additional large-scale investigations.

A case of membranous nephropathy complicated by Cronkhite-Canada syndrome successfully treated with mizoribine.

Cronkhite-Canada syndrome (CCS) is a non-hereditary disorder characterized by non-neoplastic hamartomatous gastrointestinal polyposis, hair loss, nail atrophy, hyperpigmentation, and diarrhea. While the relationship between CCS and nephritis remains unclear, seven cases of nephritis complicated by CCS have been reported to date, all of which were membranous nephropathy (MN). A 57-year-old man presented with taste disturbance, hair loss, nail plate atrophy, skin pigmentation, and frequent diarrhea. Endoscopic findings showed multiple polyposis of the stomach and large intestine. Given the above, he was diagnosed with CCS. The symptoms gradually improved with prednisolone treatment, although urinary protein and hypoproteinemia appeared during the tapering of prednisolone. He was diagnosed with MN using a renal biopsy, and immunofluorescence microscopy with IgG subclass staining showed predominantly diffuse granular capillary wall staining of IgG4. The cause of secondary MN was not found, including malignant tumors. Nephrotic-range proteinuria persisted despite treatment with prednisolone and cyclosporine. Additional treatment with mizoribine resulted in incomplete remission type 1 of nephrotic syndrome, suggesting that mizoribine may be a treatment option for patients with CCS with steroid-resistant MN. Considering a high prevalence of hypoproteinemia due to chronic diarrhea and protein-losing enteropathy in patients with CCS, proteinuria might be overlooked; thus, follow-up urinalysis would be recommended in patients with CCS.

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.

Nephrotic syndrome associated with solid malignancies: a systematic review.

BACKGROUND: Nephrotic syndrome (NS) can occur as a paraneoplastic disorder in association with various types of carcinoma. However, paraneoplastic nephrotic syndrome (PNS) is often misdiagnosed as idiopathic nephrotic syndrome or as an adverse effect of oncology treatment, leading to delayed diagnosis and suboptimal treatment. The characteristics of NS associated with solid malignancies are not yet elucidated. We systematically summarized the clinical data for 128 cases of NS combined with solid malignancies with the aim of informing the clinical management of PNS. METHODS: We searched the PubMed database for articles published from the date of inception through to October 2023 using the following keywords: "cancer" or "malignant neoplasms" or "neoplasia" or "tumors" and "nephrotic syndrome", "nephrotic" or "syndrome, nephrotic". All data were extracted from case reports and case series, and the extraction included a method for identifying individual-level patient data. RESULTS: A literature search yielded 105 cases of PNS and 23 of NS induced by cancer therapy. The median age at diagnosis was 60 years, with a male to female ratio of 1.8:1. In patients with PNS, manifestations of NS occurred before, concomitantly with, or after diagnosis of the tumor (in 36%, 30%, and 34% of cases, respectively). Membranous nephropathy (49%) was the most prevalent renal pathology and found particularly in patients with lung, colorectal, or breast carcinoma. Regardless of whether treatment was for cancer alone or in combination with NS, the likelihood of remission was high. CONCLUSION: The pathological type of NS may be associated with specific malignancies in patients with PNS. Prompt identification of PNS coupled with suitable therapeutic intervention has a significant impact on the outcome for patients.

Association of ACTN4 Gene Mutation with Primary Nephrotic Syndrome in Children in Guangxi Autonomous Region, China.

Objective: To investigate the association between ACTN4 gene mutation and primary nephrotic syndrome (PNS) in children in Guangxi Autonomous Region, China. Methods: The high-throughput sequencing technology was used to sequence ACTN4 gene in 155 children with PNS in Guangxi Autonomous Region in China, with 98 healthy children serving as controls. Twenty-three exon-specific capture probes targeting ACTN4 were designed and used to hybridize with the genomic DNA library. The targeted genomic region DNA fragments were enriched and sequenced. The protein levels of ACTN4 in both case and control groups were quantified using ELISA method. Results: Bioinformatics analysis revealed five unique ACTN4 mutations exclusively in patients with PNS, including c.1516G>A (p.G506S) on one exon in 2 patients, c.1442 + 10G>A at the splice site in 1 patient, c.1649A>G (p.D550G) on exon in 1 patient, c.2191-4G>A at the cleavage site in 2 patients, and c.2315C>T (p.A772V) on one exon in 1 patient. The c.1649A>G (p.D550G) and c.2315C>T (p.A772V) were identified from the same patient. Notably, c.1649A>G (p.D550G) represents a novel mutation in ACTN4. In addition, three other ACTN4 polymorphisms occurred in both case and control groups, including c.162 + 6C>T (1 patient in case group and 2 patients in control group), c.572 + 11G>A (1 patient in case group and 2 patients in control group), and c.2191-5C>T (4 patients in the case group and 3 patients in control group). The serum ACTN4 concentration in the case group was markedly higher, averaging 544.7 ng/mL (range: 264.6-952.6 ng/mL), compared with 241.20 ng/mL (range: 110.75-542.35 ng/mL) in the control group. Conclusion: Five ACTN4 polymorphisms were identified among children with PNS in Guangxi Autonomous Region, China, including the novel mutation c.1649A>G. The lower serum levels of α-actinin-4 in the case group suggest that this protein might play a protective role in PNS.

Relation between interleukin-13 and annexin-V levels and carotid intima-media thickness in nephrotic syndrome.

Background and aim: The aim of the current study is to assess the relation between carotid intima-media thickness (CIMT) measurements, renal Doppler resistive index (RI) and serum levels of interleukin-13 (IL-13) and annexin-V (An-V) in children with idiopathic nephrotic syndrome (INS). Materials and methods: The present case-control study was conducted on 60 children with INS and 60 age- and sex-matched healthy children. All participants were subjected to evaluation of serum levels of IL-13 and An-V and ultrasound Doppler measurement of CIMT and renal RI. Results: Patients expressed significantly higher An-V (5.9 ± 2.6 vs. 2.1 ± 0.8 ng/mL, p<0.001) and IL-13 (19.2 ± 7.6 vs. 3.4 ± 1.4 ng/L) levels when compared with healthy counterparts. Moreover, it was shown that patients had significantly higher CIMT (0.49 ± 0.06 vs. 0.35 ± 0.03, p<0.001) as compared to controls. No significant differences were noted between the studied groups regarding right or left RIs. Correlation analysis identified significant direct correlation between serum An-V levels and albumin/creatinine ratio (ACR) (r = 0.55), cholesterol (r = 0.48), triglycerides (r = 0.36), IL-13 (r = 0.92) and CIMT (r = 0.53). Similar correlations could be found between serum IL-13 levels and CIMT measurements and the corresponding parameters. Conclusions: The present study suggests an association between higher early atherosclerosis expressed as elevated CIMT measurements in children with INS and elevated serum levels of An-V and IL-13.

Efficacy of tacrolimus monotherapy in primary membranous nephropathy.

Objective: The aim of this study was to observe the remission of primary membranous nephropathy (PMN) and evaluate the efficacy of tacrolimus (TAC) monotherapy for PMN in comparison with TAC combined with a low-dose glucocorticoid (GC) protocol (TAC + GC). Methods: This was tested in a prospective monocentric observational trial of 70 patients with PMN, of whom 34 received TAC (0.05-0.075 mg/kg/day) or 36 received TAC (0.05-0.075 mg/kg/day) and GC (0.3-0.5 mg/kg/day of prednisone). Results: At 3, 6, 9, and 12 months of treatment, the effective rates in the TAC group and the TAC + GC group were similar (P > 0.05). The urinary protein quantification was reduced in patients under both therapeutic protocols, and the differences in the proteinuria quantification at 3, 6, 9, and 12 months of treatment were not statistically significant between the two groups (P > 0.05). The overall incidence of adverse reactions in the TAC group was lower than that in the TAC + GC group (23.5% < 36.1%), and the difference was statistically significant (P < 0.05). Conclusion: TAC monotherapy for PMN could effectively reduce urinary protein quantification and increase serum albumin levels. Compared with TAC + GC, TAC monotherapy for PMN had no difference in efficacy and fewer incidences of adverse reactions.

Therapeutic plasmapheresis in idiopathic membranous nephropathy anti-PLA2R-related: A case series.

Membranous nephropathy is the most common cause of nephrotic syndrome (NS) in non-diabetic adults; in 80% of patients it is idiopathic (PMN). PMN has an autoimmune pathogenesis, 70%-85% of patients have increased titer of antibodies to the podocyte membrane antigen PLA2R. The etiological, prognostic and predictive role of the Ab anti-PLA2R is demonstrated. Standard therapy consists in anti-CD20 monoclonal antibody rituximab (RTX) combined with steroids or immunosuppressants according to the risk of progressive loss of kidney function. The immunosuppressive therapies are potentially associated to severe adverse events that lead to protocol suspension. Given their pivotal pathogenetic role, serum clearance of anti-PLA2R with plasmapheresis could have a beneficial impact on NS, particularly in patients not requiring or tolerating standard therapies. In this series, we present three cases of PMN anti-PLA2R related treated with a RTX plus plasmapheresis approach and demonstrate its overall effective role on anti-PLA2R titer and clinical outcomes.

An Unusual Case of Immune Complex-Mediated Membranoproliferative Glomerulonephritis as Renal Manifestation of Idiopathic Hypereosinophilic Syndrome: A Case Report and Literature Review.

BACKGROUND: Idiopathic hypereosinophilic syndrome (IHES) is a disorder characterized by abnormal and persistent peripheral blood hypereosinophilia (eosinophil count ≥ 1.5 × 109/L and ≥10% eosinophils) with duration ≥ 6 months, associated organ damage, and/or dysfunction attributable to tissue eosinophilic infiltrate of unknown cause. IHES affects different organs such as the heart, lungs, nervous system, and skin, with renal involvement being rare in this condition. CASE PRESENTATION: We present a case of a young patient with IHES and immune complex-mediated membranoproliferative glomerulonephritis with nephrotic syndrome, as a rare renal manifestation. We discuss the clinical, analytical, and histopathologic renal and hematologic features, comparing them with other reported cases in the literature.

The Prevalence, Characteristics, and Putative Mechanisms of Dual Antigen-Positive Membranous Nephropathy: The Underestimated Condition.

Following the discovery of podocyte phospholipase A2 receptor and thrombospondin type-1 domain-containing 7A, various potential target antigens for membranous nephropathy (MN) have been reported one after another. MN target antigens have now been identified in a significant proportion of patients, and a new classification framework classifies patients with MN based on the detected antigen and associated disease phenotype. A serology-based approach that does not require a histological diagnosis for patients suspected of having MN has also been proposed. However, there have been cases in which dual positivity for MN antigens and/or corresponding antibodies has been shown. Importantly, some of them showed a transition of the affected patient's immune responses to MN antigens, suggesting that serological diagnosis changes depending on the timing of the analysis. In this review, we provide detailed information on these cases and present an overview of our recent understanding of their putative mechanisms involved in these cases. Greater awareness is required to adequately recognize and develop appropriate therapeutic strategies for this condition.

Network Pharmacology and Molecular Docking Validation to Explore the Pharmacological Mechanism of Zhuling Decoction against Nephrotic Syndrome.

BACKGROUND: In recent years, the incidence and prevalence of Nephrotic Syndrome (NS) have been increasing. Zhuling decoction (ZLD), a classical Chinese medicine, has been clinically proven to be effective for the treatment of NS. However, its underlying mechanism and pharmacodynamic substances remain unclear. OBJECTIVE: This study aimed to explore the mechanism of action and chemical components of ZLD against NS using network pharmacology and molecular docking. METHODS: Traditional Chinese Medicine Systems Pharmacology (TCMSP), Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicines (BATMAN-TCM), and SwissTargetPrediction databases were used to screen the principal ingredients and the associated targets of ZLD. NS-related targets were obtained from the Online Mendelian Inheritance in Man (OMIM), GeneCards, Therapeutic Target Database (TTD), and Drugbank databases. Shared targets were derived by the intersection of ZLD- and NS-associated targets. Protein-interaction relationships were analyzed using the STRING database and Cytoscape. A visualized drug-active compound-target network of ZLD was established using Cytoscape. Analyses of gene enrichment were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) methods by the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database. Molecular docking was performed to assess the binding activity between active components and hub targets. RESULTS: Polyporusterone E, cerevisterol, alisol B, and alisol B 23-acetate were the primary potential ingredients of ZLD. HMGCR, HSD11B1, NOS2, NR3C1, and NR3C2 were the hub targets of ZLD against NS. Molecular docking showed that polyporusterone E, cerevisterol, and alisol B had high binding activities with targets HMGCR, HSD11B1, and NOS2. CONCLUSION: In summary, this study suggests that the main active compounds (polyporusterone E, cerevisterol, alisol B) may have important roles for ZLD acting against NS by binding to hub targets (HMGCR, HSD11B1, and NOS2) and modulating PI3K-Akt, Ras, MAPK, and HIF-1 signaling pathways.

Recessive variants in MYO1C as a potential novel cause of proteinuric kidney disease.

BACKGROUND: Steroid-resistant nephrotic syndrome is the second leading cause of chronic kidney disease among patients < 25 years of age. Through exome sequencing, identification of > 65 monogenic causes has revealed insights into disease mechanisms of nephrotic syndrome (NS). METHODS: To elucidate novel monogenic causes of NS, we combined homozygosity mapping with exome sequencing in a worldwide cohort of 1649 pediatric patients with NS. RESULTS: We identified homozygous missense variants in MYO1C in two unrelated children with NS (c.292C > T, p.R98W; c.2273 A > T, p.K758M). We evaluated publicly available kidney single-cell RNA sequencing datasets and found MYO1C to be predominantly expressed in podocytes. We then performed structural modeling for the identified variants in PyMol using aligned shared regions from two available partial structures of MYO1C (4byf and 4r8g). In both structures, calmodulin, a common regulator of myosin activity, is shown to bind to the IQ motif. At both residue sites (K758; R98), there are ion-ion interactions stabilizing intradomain and ligand interactions: R98 binds to nearby D220 within the myosin motor domain and K758 binds to E14 on a calmodulin molecule. Variants of these charged residues to non-charged amino acids could ablate these ionic interactions, weakening protein structure and function establishing the impact of these variants. CONCLUSION: We here identified recessive variants in MYO1C as a potential novel cause of NS in children.

The Protective Role of KANK1 in Podocyte Injury.

Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in KANK family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific Kank1 knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, Kank1 knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific Kank1 knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, KANK1-deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions.

Immunogenicity, Immunological Memory and monitoring of disease activity following an anamnestic immunization with the 13-Valent Pneumococcal Conjugate Vaccine (PCV13) in Children with Idiopathic Nephrotic Syndrome.

Anamnestic PCV13 immunization did not affect the relapse risk in pediatric Idiopathic Nephrotic Syndrome. PS-specific antibody titers increased significantly in all groups. Children receiving immunomodulatory treatments(IMTs) displayed significantly lower levels of PS-specific antibodies for 3/8 serotypes tested. PS-specific B-cell counts significantly increased only in healthy controls and patients receiving corticosteroids.

Efficacy of rituximab and risk factors for poor prognosis in patients with childhood-onset steroid-resistant nephrotic syndrome: a multicenter study.

BACKGROUND: The efficacy of rituximab in steroid-resistant nephrotic syndrome (SRNS) is controversial. We previously reported that rituximab in combination with methylprednisolone pulse therapy (MPT) and immunosuppressants was associated with favorable outcomes. We determined risk factors for poor response following rituximab treatment, which remains unknown. METHODS: This retrospective study included 45 patients with childhood-onset SRNS treated with rituximab across four pediatric kidney facilities. Treatment effects were categorized as complete remission (CR), partial remission (PR), and no remission (NR) at one year after rituximab treatment. The primary outcome was the rate of CR, PR, and NR. Risk factors for non-CR were calculated with multivariate logistic regression. Adverse events and the relationship between disease status at one year and long-term prognosis were also evaluated. RESULTS: The rates of CR, PR, and NR at one year were 69%, 24%, and 7%, respectively. The median time from rituximab administration to CR was 90 days. The median follow-up period after rituximab administration was 7.4 years. In multivariate analysis, significant risk factors for poor response were the pathologic finding of focal segmental glomerular sclerosis and a long interval between SRNS diagnosis and rituximab administration. The rates of CR were 90.3% and 21.4% in patients receiving rituximab within and after 6 months following SRNS diagnosis, respectively (p < 0.001). Five patients developed chronic kidney disease stage G5, including 2 of the 11 patients with PR and all 3 patients with NR, whereas none of the 31 patients with CR developed chronic kidney disease stage G5. CONCLUSION: Early administration of rituximab in combination with MPT and immunosuppressants might achieve favorable outcomes in patients with SRNS.

Pneumococcal carriage and serotype distribution in children with nephrotic syndrome.

BACKGROUND: Patients with nephrotic syndrome (NS) are at a higher risk of developing invasive pneumococcal disease (IPD). Pneumococcal carriage studies are helpful tools for detecting potentially infectious serotypes and guiding immunization efforts. Pneumococcal nasopharyngeal colonization is common, and IPD can easily occur in an immunosuppressed state. Limited information is available regarding the frequency of pneumococcal carriage in individuals with NS. The aim of this study was to evaluate pneumococcal carriage and serotype distribution in children with NS. METHODS: Pneumococcal carriage was detected by real-time PCR assays from nasopharyngeal swab samples from 98 children with NS, and 100 healthy controls. Isolates were serotyped by real-time PCR. RESULTS: The pneumococcal carriage rate was 44.9% in children with NS. Regarding the recommendation about pneumococcal immunization in children with NS, the vaccination rate was low. Also, non-PCV13 serotypes have been detected in at least 25% of PCV13-vaccinated children. There is no statistically significant difference in total pneumococcal carriage rate, PCV13 serotype carriage rate, or non-PCV13 serotype carriage rate between children with NS and healthy controls (p > 0.05 for all). CONCLUSIONS: The pneumococcal carriage rate was similar between children with NS and healthy controls. However, because children with NS have an increased risk for IPD, the serotype distribution of children with NS can demonstrate the improved protection offered by new pneumococcal vaccines. Regular monitoring for IPD is crucial for assessing the evolving sero-epidemiology of pneumococcal infections and evaluating the effectiveness of vaccines for children with NS.