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BackgroundSphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a recently recognized inborn error of metabolism associated with steroid-resistant nephrotic syndrome as well as adrenal insufficiency and immunological, neurological, and skin manifestations. SPLIS is caused by inactivating mutations in SGPL1, encoding the pyridoxal 5'phosphate-dependent enzyme sphingosine-1-phosphate lyase, which catalyzes the final step of sphingolipid metabolism. Some SPLIS patients have undergone kidney transplantation, and others have been treated with vitamin B6 supplementation. In addition, targeted therapies including gene therapy are in preclinical development. In anticipation of clinical trials, it will be essential to characterize the full spectrum and natural history of SPLIS. We performed a retrospective analysis of 76 patients in whom the diagnosis of SPLIS was established in a proband with at least one suggestive finding and biallelic SGPL1 variants identified by molecular genetic testing. The main objective of the study was to identify factors influencing survival in SPLIS subjects.ResultsOverall survival at last report was 50%. Major influences on survival included: (1) age and organ involvement at first presentation; (2) receiving a kidney transplant, and (3) SGPL1 genotype. Among 48 SPLIS patients with nephropathy who had not received a kidney transplant, two clinical subgroups were distinguished. Of children diagnosed with SPLIS nephropathy before age one (n = 30), less than 30% were alive 2 years after diagnosis, and 17% were living at last report. Among those diagnosed at or after age one (n = 18), ~ 70% were alive 2 years after diagnosis, and 72% were living at time of last report. SPLIS patients homozygous for the SPL R222Q variant survived longer compared to patients with other genotypes. Kidney transplantation significantly extended survival outcomes.ConclusionOur results demonstrate that SPLIS is a phenotypically heterogeneous condition. We find that patients diagnosed with SPLIS nephropathy in the first year of life and patients presenting with prenatal findings represent two high-risk subgroups, whereas patients harboring the R222Q SGPL1 variant fare better than the rest. Time to progression from onset of proteinuria to end stage kidney disease varies from less than one month to five years, and kidney transplantation may be lifesaving.

Background: Podocytopenia refers to a decrease in the number of podocytes. When podocytes are injured, they may detach leading to podocytopenia, which represents a critical step in the development of podocytopathy and subsequently deterioration of renal functions. Pathological assessment of podocytopenia plays a crucial role in diagnosing underlying kidney diseases. Aim: To assess detached podocytes and evaluate their diagnostic role in the development of focal segmental glomerulosclerosis. Materials and methods: This is a retrospective study, conducted on 67 archival renal biopsies with the clinical diagnosis of steroid-resistant or steroid-dependent nephrotic syndrome (SRNS) and diagnosed as focal segmental glomerulosclerosis (FSGS) and podocytopathy with detached podocytes by electron microscopy (EM). Colloidal iron stain and Desmin immunohistochemical stain were performed. Assessment of the mean percent of stained pixels in relation to the surface tuft area of the glomerulus, i.e., mean percent of stained area (PSA) was done using image analysis system (ImageJ 1.52a) software. Results: Podocytopathy with detached podocytes was diagnosed in 35 (52.24%) cases, while FSGS was diagnosed in 32 (47.76%) cases. Regarding detached podocytes, 27 (49.3%) cases showed no detached podocytes by light microscopy (LM), while only 4 (6%) showed severe podocyte detachment. There was a statistically significant difference between control cases and both podocytopathy with detached podocytes and FSGS regarding mean PSA (p ≤ 0.001). Conclusion: Standardized reporting of detached podocyte cells is becoming mandatory as they have a high positive predictive value for the expected EM picture. [ABSTRACT FROM AUTHOR]

Background: This study investigated the factors influencing the prognosis of children with steroid-resistant nephrotic syndrome (SRNS) in patients from the Guangxi region. Methods: We retrospectively analyzed clinical and pathological data of 279 patients with SRNS from six tertiary hospitals in Guangxi. Clinical data were compared between initial (I-SRNS) and secondary (S-SRNS) steroid resistance subgroups and Cox regression analysis was used to determine risk factors for chronic kidney disease (CKD) and CKD stage 5 (CKD5) in patients with SRNS. Results: The median age of onset was 54 months. Thirty-three patients had extra-kidney manifestations. Fifty-two, 24, 57, 33, and 41 patients had hypertension, acute kidney injury, vitamin D deficiency, high intraocular pressure, and dwarfism, respectively. One hundred eighty-two and 92 patients had I-SRNS and S-SRNS, respectively. There were significant differences in sex, ethnicity, family history, incidence of hematuria, clinical classification, efficacy of immune agents, and prognosis between groups (P < 0.05). Among the 279 cases of SRNS, 239 had normal kidney function, 37 developed CKD, and 16 had CKD5. An increase in serum creatinine level (HR = 1.003) was significantly associated with CKD in children with SRNS, and effective immunosuppressant therapy decreased the CKD risk (HR = 0.168). Patients with increased serum creatinine levels (HR = 1.003) and acute kidney injury (HR = 4.829) were more likely to progress to CKD5. Conclusions: Children with S-SRNS showed a higher response to immunosuppressants than those with I-SRNS. Effective immunosuppressant therapy was found to protect against CKD, whereas increased acute kidney injury was an independent risk factor for CKD5. [ABSTRACT FROM AUTHOR]

La glomérulonéphrite fibrillaire (GNF) est une pathologie glomérulaire décrite depuis 1977, rare, ayant une prévalence inférieure à 1 % des prélèvements de biopsies rénales. Elle se présente par une insuffisance rénale, une protéinurie, une hématurie et une hypertension artérielle chez l'adulte d'âge moyen. Sa définition est histologique, passant par la microscopie optique, qui retrouve des dépôts organisés de fibrilles d'environ 20 nm négatives pour la coloration au rouge Congo. La microscopie électronique, premier gold standard du diagnostic, est désormais supplantée par l'immunohistochimie avec l'anticorps anti-DNAJB9. La découverte de cette molécule a permis une révolution dans le diagnostic de la GNF grâce à ses excellentes sensibilité et spécificité (respectivement 98 et 99 %). L'association au virus de l'hépatite C, aux maladies auto-immunes et aux néoplasies ou hémopathies est débattue. Le pronostic rénal est réservé, avec une évolution vers l'insuffisance rénale terminale chez 50 % des patients dans les 2 à 4 ans après le diagnostic. Le traitement recommandé, faute d'étude randomisée contrôlée, repose sur les mesures de néphroprotection, une corticothérapie et éventuellement un immunosuppresseur en seconde ligne comme le rituximab. Après transplantation rénale, la guérison ou la récidive sont possibles. La physiopathologie est encore mal connue et des études supplémentaires seraient nécessaires. Fibrillary glomerulonephritis (FGN) is a glomerular disease described since 1977, with a prevalence in renal biopsies of less than 1%. It presents as renal failure, proteinuria, haematuria and hypertension in middle-aged adults. It is defined histologically, using light microscopy, which reveals organised deposits of fibrils measuring around 20 nm, which are negative for Congo red staining. Electron microscopy, the first gold standard for diagnosis, has now been superseded by immunohistochemistry using the anti-DNAJB9 antibody. The discovery of this molecule has revolutionised the diagnosis of GNF, thanks to its excellent sensitivity and specificity (98% and 99% respectively). The association of GNF with hepatitis C virus, autoimmune diseases, neoplasia or haemopathy is debated. Renal prognosis is guarded, with 50% of patients progressing to end-stage renal failure within 2 to 4 years of diagnosis. In the absence of randomised controlled trials, the recommended treatment is based on nephroprotective measures, corticosteroid therapy and possibly a second-line immunosuppressant such as rituximab. After renal transplantation, recovery or recurrence is possible. The pathophysiology of the disease is still poorly understood, and further studies are needed. [ABSTRACT FROM AUTHOR]

• DSS significantly improves NS treatment outcomes compared to western medicine alone. • Network pharmacology analysis identifies multiple active compounds and pathways targeted by DSS. • DSS regulates key targets involved in inflammation, immunity, and renal fibrosis. • Study provides evidence for DSS as a promising treatment option for NS. The purpose of this study was to investigate the efficacy and mechanism of DSS in treating nephrotic syndrome through meta-analysis and network pharmacology methods. To conduct a comprehensive search for randomized controlled trials on the efficacy of Danggui Shaoyao San (DSS) in the treatment of nephrotic syndrome, we searched across eight electronic databases from their establishment to May 1, 2023. The Cochrane Collaboration's Risk of Bias 2 tool was used to evaluate the quality of evidence regarding bias risk and outcomes. Statistical analysis was performed using RevMan software (version 5.4). Furthermore, network pharmacology was employed to validate the underlying mechanism. This study included 14 articles that involved 1256 patients with nephrotic syndrome. The clinical efficacy of DSS against nephrotic syndrome was significantly higher than that of Western medical treatment alone. In comparison with the control groups, which were administered Western medicines alone, the use of DSS significantly increased plasma albumin levels (mean difference [MD] = 4.32, 95 % confidence interval [CI] [2.37, 6.24], p < 0.00001) and reduced 24 h urinary protein excretion (MD = −0.92, 95 % CI [−1.11, −0.73], p < 0.00001), total cholesterol levels (MD = −1.23, 95 % CI [−1.76, −0.70], p < 0.00001), triglyceride levels (MD = −0.37, 95 % CI [−0.54, −0.20], p < 0.00001). Furthermore, the combination of DSS with Western medicines achieved better control of adverse reactions in comparison with the control groups (relative risk = 0.37, 95 % CI [0.29, 0.49], p < 0.00001). Network pharmacology analysis identified 39 important active compounds and 18 core target genes involved in the treatment of primary nephrotic syndrome by DSS. Gene Ontology enrichment analysis identified 2126 biological processes, 64 cellular components, and 115 molecular functions, while Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis identified 149 signaling pathways. Key active compounds include ginsenoside Rg5, ginsenoside Rg1, schisandrin A, berberine, gallic acid, quercetin, and β-sitosterol, while potential core target genes include IL6, AKT1, TNF, VEGFA, IL1B , and TP53. KEGG pathway analysis indicated that DSS is involved in multiple mechanisms, such as neural development, synaptic plasticity, programmed cell death, inflammation, and immunity. DSS has higher efficacy and safety in the treatment of nephrotic syndrome and acts on nephrotic syndrome via mechanisms that involve multiple targets, components, and pathways. [ABSTRACT FROM AUTHOR]

Background: Recurrence of focal segmental glomerulosclerosis (FSGS) or steroid-resistant nephrotic syndrome (SRNS) after kidney transplant leads to significant morbidity and potentially earlier allograft loss. To date however, reported rates, risk factors and treatment outcomes have varied widely. Methods: We applied computational phenotypes to a multicenter aggregation of electronic health records data from 7 large pediatric health systems in the USA, to identify recurrence rates, risk factors, and treatment outcomes. We refined the data collection by chart review. Results: From > 7 million patients, we compared children with primary FSGS/SRNS who received a kidney transplant between 2009 and 2020 and who either developed recurrence (n = 67/165; 40.6%) or did not (n = 98/165). Serum albumin level at time of transplant was significantly lower and recipient HLA DR7 presence was significantly higher in the recurrence group. By 36 months post-transplant, complete remission occurred in 58.2% and partial remission in 17.9%. Through 6 years post-transplant, no remission after recurrence was associated with an increased risk of allograft loss over time (p < 0.0001), but any remission showed similar allograft survival and function decline to those with no recurrence. Since treatments were used in non-random fashion, using spline curves and multivariable non-linear analyses, complete + partial remission chance was significantly higher with greater plasmapheresis sessions, CTLA4-Ig doses or LDL-apheresis sessions. Only treatment with anti-CD20, CTLA4-Ig agents, or LDL-apheresis sessions were associated with complete remission. Excluding 25 patients with mutations did not significantly change our results. Conclusions: Our contemporary high-risk cohort had higher favorable response rates than most prior reports, from combinations of agents. [ABSTRACT FROM AUTHOR]

Background: Alport syndrome is a genetically heterogenous disorder resulting from variants in genes coding for alpha-3/4/5 chains of Collagen IV, which results in defective basement membranes in the kidney, cochlea and eye. The syndrome has different inheritance patterns and historically, was thought of as a disease affecting solely males. Case: A 15-year-old female presented with pedal oedema, hypertension and proteinuria. She underwent a kidney biopsy which showed findings in keeping with focal segmental glomerulosclerosis. Her condition was refractory to steroids. Steroid-resistant nephrotic syndrome genetics were sent, revealing a rare pathogenic variant in the COL4A5 gene. Conclusion: Heterozygous females with X-linked Alport syndrome can develop chronic kidney disease and hearing loss. Clinicians should be mindful when reviewing kidney histology to include Alport syndrome as a differential for female patients. COL4A3-5 genes should be included in all steroid-resistant nephrotic syndrome genetic panels. [ABSTRACT FROM AUTHOR]

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Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors in nephrotic patients on immunosuppression are underexplored. We evaluated dapagliflozin's impact in non-diabetic primary nephrotic syndrome. Methods: Randomized controlled clinical trial was conducted on 60 non-diabetic primary nephrotic syndrome patients, equally assigned to dapagliflozin and control groups. All patients received the standard of care medication and the Dapagliflozin group received 10 mg dapagliflozin in addition. Demographic data, nephrotic syndrome etiology, proteinuria levels, eGFR, and immunosuppression doses, were well-matched. After 6 months of follow up primary outcomes included changes in and eGFR. Results: Both groups exhibited significant reductions in proteinuria after 6 months, with the dapagliflozin group achieving a mean UPCR reduction of – 94.7%, and the control group – 86.7% (p < 0.001). However, the comparative change in proteinuria between both groups did not reach statistical significance (p = 0.158). Dapagliflozin initially led to a transient eGFR decline. Dapagliflozin also resulted in a significant mean body weight reduction (p < 0.001) and notable improvements in triglyceride levels compared to the control group (p = 0.045). Conclusion: In primary nephrotic syndrome patients, adjunct dapagliflozin may enhance the standard of care. While notable, the reduction in proteinuria was comparable to that of the control group by the study's end. Furthermore, after 6 months, eGFR remained stable in both groups. However, significant weight loss and serum triglyceride reduction were particularly pronounced in the dapagliflozin group. Further long-term investigations are necessary to address potential immunosuppression-related confounding effects in patients with primary glomerular disease. [ABSTRACT FROM AUTHOR]

Chronic graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT). Chronic GVHD may have atypical manifestations affecting non-classical organs. The diagnosis in patients with atypical manifestations of chronic GVHD is particullarly challenging, and there is a lack of knowledge regarding their pathogenesis and treatment. We reported a case who developed post-HSCT nephrotic syndrome and portal hypertensive ascites, which are both rare and atypical manifestations of chronic GVHD. Kidney biopsy revealed membranous nephropathy and renal thrombotic microangiopathy with glomerular immune deposits, suggesting antibody-mediated kidney injury. Treatment with ruxolitinib resulted in remission of both nephrotic syndrome and ascites, suggesting a role of cytokines in the pathogenesis. This case highlighted the awareness of nephrotic syndrome and portal hypertensive ascites as atypical manifestations of chronic GVHD, and the efficacy of ruxolitinib for the two manifestations. [ABSTRACT FROM AUTHOR]

Background: TRIM8-related neuro-renal syndrome (NRS), caused by pathogenic variants of the TRIM8 gene, is characterized by epilepsy, developmental delay (DD) and renal disorders. The severity of the neurological effects as well as the presence of renal disorders is variable among patients. Here, we report three additional patients with clinical features compatible with NRS and summarize the association between the variants’ loci and phenotype of TIRM8-related NRS. Methods: A retrospective analysis was conducted for three Chinese children with NRS due to TRIM8 variants identified through whole-exome sequencing (WES). Previous reports of patients with TRIM8-related NRS were reviewed systematically. Demographic and clinical data were collected from these patients Results: Two de novo TRIM8 truncating variants in three NRS patients were identified in our study, including c.1327_c.1328delCCinsTG (p. Arg443*) and c.1375C>T (p.Gln459*). Our three patients all exhibited drug-resistant epilepsy and early-onset DD, and two of whom developed electrical status epilepticus during sleep (ESES). Brain magnetic resonance imaging (MRI) showed periventricular leukomalacia in one patient and normal in the other two. All three patients demonstrated nephrotic range proteinuria (NRP) or nephrotic syndrome (NS) with normal renal function during follow-up. There was a total of 27 patients with TRIM8-related NRS have been identified to date. The most common clinical features are renal diseases (89%), DD (89%), followed by epilepsy (78%). 67% of patients eventually progressed to end-stage renal disease (ESRD). Focal seizure was the most frequent seizure type (57%). 52% of patients presented drug-resistant epilepsy. 64% of patients exhibited non-specific brain MRI abnormalities. Brain atrophy was the most common change (50%). Two patients with TRIM8 variants closer to the N-terminal had neurological diseases without renal damage. Five patients with TRIM8 variants closer to the C-terminal had no severe neurological diseases. Seven patients had Gln459* variant which is the most common variant (7/27, 25.9%). The severity of the renal and neurological damage of the seven patients was variable. Conclusion: This study expands the number of individuals with confirmed NRS due to pathogenic variants in TRIM8. Neurological and renal phenotype with the same variant locus differed in their severity. Further research is needed to explore the relationship between genotype and phenotype of TRIM8 variants. [ABSTRACT FROM AUTHOR]

Introduction: Fibrillary glomerulonephritis (FGN) is a rare form of glomerular disease that accounts for less than 1 percent of all renal biopsies. It is characterized by pathognomonic electron microscopy findings of fibrillar deposits in the mesangium and glomerular capillary walls. FGN was initially considered to be an idiopathic disorder. However, approximately 30–50 percent of patients have a secondary cause, including a history of malignancy in up to 23% of cases. Chronic lymphocytic leukemia (CLL) is a rare cause of FGN, with limited data and poor prognosis. Case Presentation: In this report, we present the case of a 69-year-old male who was diagnosed with CLL in 2013 and was initially managed conservatively. In 2016, he developed nephrotic syndrome and renal impairment. Renal biopsy showed FGN, and treatment was targeted to the CLL with bendamustine and rituximab, which led to partial remission of nephrotic syndrome and improvement in renal function. After 3 years of clinical remission, the nephrotic syndrome relapsed, and he underwent a repeat renal biopsy confirming ongoing FGN. A bone marrow biopsy confirmed CLL relapse, and the patient was treated with ibrutinib (a tyrosine kinase inhibitor). The patient achieved a significant organ response and sustained remission. Conclusion: This case highlights the success of treating a potentially identifiable cause of FGN and highlights that even at relapse, treatment can confer benefits and help prevent end-stage renal failure. [ABSTRACT FROM AUTHOR]