Ulcerative colitis and nephrotic syndrome: a two-sample Mendelian randomization study.

To investigate the potential causal relationship between ulcerative colitis and nephrotic syndrome. We obtained the whole-genome association study data of ulcerative colitis in the European population from the GWAS database. Relevant single nucleotide polymorphisms (SNPs) were selected for analysis. We employed the inverse variance-weighted meta-analysis of multiplicative random effects models to obtain SNP-specific Wald ratio estimates, which assume horizontal pleiotropy. In addition, we performed sensitivity analyses using MR-Egger, weighted median, and IVW. Our findings suggest a strong association between ulcerative colitis and nephrotic syndrome (P < 0.05). After conducting sensitivity analyses, we found no evidence of horizontal pleiotropy or heterogeneity (P > 0.05). This study provides evidence for an association between ulcerative colitis and nephrotic syndrome, which may help us better understand the conditions of ulcerative colitis and nephropathy.

Effect of proteinuria at relapse on shear wave velocity assessed using ultrasound elastography in children with idiopathic nephrotic syndrome.

PURPOSE: Shear wave velocity (SWV) is an ultrasound elastography technique that provides much information for kidney disease assessment. However, the factors that alter SWV are not fully understood; it is unclear whether the variation in SWV seen in proteinuria associated with disease progression is due to tissue or proteinuria. This study investigated the effect of proteinuria on SWV. METHODS: This prospective observational study compared SWV at remission with SWV at relapse in children treated for idiopathic nephrotic syndrome (INS) between April 2020 and December 2023. All relapses without oral steroids during the observation period were measured. SWV at remission was defined as the date closest to relapse during which repeated measurements were taken approximately every 3 months after steroid discontinuation. RESULTS: Eight patients were treated for INS with a median observation period of 21.9 months (11.8-27.1). Of the 15 relapses, five that met the definition were considered for the study. The median interval between the measurement at relapse and remission was 40 days (11-55). SWV was significantly lower at relapse than remission (2.40 ± 0.20 m/s vs. 2.14 ± 0.15 m/s, P < 0.01). CONCLUSIONS: SWV decreased in the presence of severe proteinuria at relapse compared to the remission measurements. Although more cases need to be studied, the decrease in SWV may reflect the mechanism by which protein leaks into the urine, not just a direct change caused by the presence of proteinuria.

A prospective cohort study of rituximab in the treatment of refractory nephrotic syndrome.

OBJECTIVE: To explore the efficacy and safety of rituximab (RTX) in the treatment of autoimmune nephropathy manifested as refractory nephrotic syndrome (RNS). METHODS: A single-center prospective cohort study was conducted on RNS patients treated with RTX between March 2017 and December 2019. The subjects were divided into the primary nephropathy (PN) group and the secondary nephropathy (SN) group. Based on the estimated glomerular filtration rate (eGFR) before RTX treatment, the SN group was then divided into the SN-1 group (eGFR ≥ 30 ml/min) and the SN-2 group (eGFR < 30 ml/min). Biochemical parameters and clinical data were recorded during follow-up. RESULTS: Fifty-four patients were followed up for at least 6 months. The overall remission rates were 65%, 66.7%, 27.3% in the PN, SN-1, and SN-2 groups, respectively (P = 0.022). Kaplan-Meier analysis showed a significant difference of the renal survival among the three subgroups (P < 0.001). Multivariate Cox regression analysis showed that eGFR value before treatment was an independent predictor (HR 0.919, 95%CI 0.863-0.979) for renal survival. In terms of adverse events, infection accounted for 56.6%. The incidence of severe infection was 10%, 25% and 50% in PN group, SN-1 group and SN-2 group, respectively. CONCLUSIONS: RTX may be a promising option in RNS patients with eGFR ≥ 30 ml/min/1.73m2. However, it has little effect on prognosis in patients with secondary RNS with eGFR < 30 ml/min/1.73m2, but with a high risk of severe infection.

Analysis and Study on Epidemiological Features and Prognosis of Nephrotic Syndrome in Xinjiang and Heilongjiang.

BACKGROUNDS: The pathogenesis of nephrotic syndrome (NS) is complex, and there are differences between regions. This study attempted to collect clinicopathological data of patients diagnosed with NS in Xinjiang and Heilongjiang in the past 2 years, so as to explore the onset features of NS and treatment and prognosis of patients in the two regions. METHODS: Clinical data of 375 patients diagnosed with NS using renal biopsy in Xinjiang and Heilongjiang from March 2019 to March 2021 were collected. Clinical data of patients before treatment were collected, and the chi-square test was utilized to compare the differences in the sex distribution of two groups. The U test was utilized to compare abnormal distribution continuous data between two groups, such as age, hemoglobin, plasma albumin, proteinuria, and triglycerides. Independent sample t-test was utilized to compare normal distribution continuous data between two groups, such as serum total protein, serum creatinine, blood urea nitrogen, glomerular filtration rate, and total cholesterol. The independent sample t-test was also used to compare the immunoglobulin levels and complement levels between the two groups after treatment, including IgA, IgG, IgM, C3, and C4. Kaplan-Meier method was used to analyze and plot the cumulative curves of complete remission rate and partial remission rate. RESULTS: For 275 NS patients from Xinjiang, the male-to-female ratio was 0.81 : 1. For 84 patients from Heilongjiang, the male-to-female ratio was 1.05 : 1. The onset ages of patients in Xinjiang and Heilongjiang were 22-45 years old and 22-47 years old, respectively. Respectively, there were 221 cases (80.36%) and 66 cases (78.57%) of primary NS in Xinjiang and Heilongjiang. There were 54 cases (19.64%) and 18 cases (21.43%) of secondary NS in Xinjiang and Heilongjiang, respectively. There was no statistically significant difference in cause distribution between the two regions (p = 0.756). After treatment, immunoglobulin levels (IgA (p = 0.009), IgG (p = 0.002), IgM (p < 0.001)) and complement C3 (p < 0.001) and C4 (p < 0.001) levels in Xinjiang and Heilongjiang were statistically significant. 129 cases in Xinjiang (46.91%) and 55 cases in Heilongjiang (65.48%) were treated with glucocorticoid (GC) combined with immunosuppressive therapy, respectively. After receiving treatment, 67 (24.36%) of 275 patients in Xinjiang achieved complete remission, 166 (60.36%) achieved partial remission, 22 (26.19%) of 84 patients in Heilongjiang achieved complete remission, and 56 (66.67%) achieved partial remission, and there was no statistically significant difference in remission rate between the two regions (p = 0.159). Patients in Xinjiang and Heilongjiang achieved complete remission at an average of 10.34 weeks (9.98-10.70) and 9.95 weeks (9.26-10.65), respectively. There was no significant difference in complete remission rates between the two regions (p = 0.663). Patients in Xinjiang and Heilongjiang achieved partial remission at an average of 8.76 weeks (8.38-9.14) and 7.99 weeks (7.33-8.65), respectively. There was no significant difference in the partial remission rate between the two regions (p = 0.065). CONCLUSION: The causes of NS in Xinjiang and Heilongjiang were similar. After treatment, there were differences in immunoglobulin levels (IgA, IgG, IgM) and complement levels (C3, C4) in the two regions. The main treatment methods used in the two regions were GC combined with immunosuppressive therapy. The prognosis of patients in the two regions was similar. The complete remission rate and partial remission rate after treatment in the two regions were similar, and the average time required to achieve complete remission and partial remission was also similar.

Horseshoe kidney with PLA2R-positive membranous nephropathy.

BACKGROUND: Horseshoe kidney (HSK) is a common congenital defect of the urinary system. The most common complications are urinary tract infection, urinary stones, and hydronephrosis. HSK can be combined with glomerular diseases, but the diagnosis rate of renal biopsy is low due to structural abnormalities. There are only a few reports on HSK with glomerular disease. Here, we have reported a case of PLA2R-positive membranous nephropathy occurring in a patient with HSK. CASE PRESENTATION: After admission to the hospital due to oedema of both the lower extremities, the patient was diagnosed with nephrotic syndrome due to abnormal 24-h urine protein (7540 mg) and blood albumin (25 g/L) levels. Abdominal ultrasonography revealed HSK. The patient's brother had a history of end-stage renal disease due to nephrotic syndrome. Therefore, the patient was diagnosed with PLA2R-positive stage II membranous nephropathy through renal biopsy under abdominal ultrasonography guidance. He was administered adequate prednisone and cyclophosphamide, and after 6 months of treatment, urinary protein excretion levels significantly decreased. CONCLUSION: The risk and difficulty of renal biopsy in patients with HSK are increased due to structural abnormalities; however, renal biopsy can be accomplished through precise positioning with abdominal ultrasonography. In the literature, 20 cases of HSK with glomerular disease have been reported thus far. Because of the small number of cases, estimating the incidence rate of glomerular diseases in HSK is impossible, and the correlation between HSK and renal pathology cannot be stated. Further studies should be conducted and cases should be accumulated to elucidate this phenomenon.

Vascular Endothelial Growth Factor (VEGF) and Neopterin Levels in Children with Steroid-sensitive and Steroid-resistant Nephrotic Syndrome.

BACKGROUND: The most common glomerular disease in children is nephrotic syndrome. Steroid-resistant nephrotic syndrome tends to have a worse disease course, which bears a significant risk of chronic kidney disease in children. OBJECTIVE: To compare VEGF and neopterin levels between children with steroid-sensitive nephrotic syndrome (SSNS), steroid-resistant nephrotic syndrome (SRNS), and also healthy (control) children. METHODS: This cross-sectional study was conducted at H. Adam Malik General Hospital, Indonesia from January to December 2018. There were 160 children aged 1 to 8 years with confirmed nephrotic syndrome and without end-stage renal disease and systemic diseases, divided into SSNS, SRNS, and control groups. Data regarding age, gender, urine albumin creatinine ratio (UACR), serum albumin, total cholesterol, urea, creatinine, VEGF, and neopterin levels were collected. A p-value of less than 0.05 is considered statistically significant. RESULTS: There were no differences between groups in gender (p = 0.269) and age (p = 0.375), but there was significant difference of UACR, albumin level, total cholesterol level, and VEGF level between groups, (all p< 0.001). There was a moderate positive correlation between VEGF level and UACR (r(158) = 0.439, p< 0.001) and a moderate negative correlation between neopterin level and albumin level (r(158)= -0.312, p = 0.005). CONCLUSION: There were no differences in serum VEGF and neopterin levels between steroid-sensitive and steroid-resistant nephrotic syndrome groups. Serum VEGF level was positively correlated with UACR while serum neopterin level was negatively correlated with serum albumin level.

A Novel Model for Nephrotic Syndrome Reveals Associated Dysbiosis of the Gut Microbiome and Extramedullary Hematopoiesis.

Glomerular kidney disease causing nephrotic syndrome is a complex systemic disorder and is associated with significant morbidity in affected patient populations. Despite its clinical relevance, well-established models are largely missing to further elucidate the implications of uncontrolled urinary protein loss. To overcome this limitation, we generated a novel, inducible, podocyte-specific transgenic mouse model (Epb41l5fl/fl*Nphs1-rtTA-3G*tetOCre), developing nephrotic syndrome in adult mice. Animals were comprehensively characterized, including microbiome analysis and multiplexed immunofluorescence imaging. Induced knockout mice developed a phenotype consistent with focal segmental glomerular sclerosis (FSGS). Although these mice showed hallmark features of severe nephrotic syndrome (including proteinuria, hypoalbuminemia and dyslipidemia), they did not exhibit overt chronic kidney disease (CKD) phenotypes. Analysis of the gut microbiome demonstrated distinct dysbiosis and highly significant enrichment of the Alistipes genus. Moreover, Epb41l5-deficient mice developed marked organ pathologies, including extramedullary hematopoiesis of the spleen. Multiplex immunofluorescence imaging demonstrated red pulp macrophage proliferation and mTOR activation as driving factors of hematopoietic niche expansion. Thus, this novel mouse model for adult-onset nephrotic syndrome reveals the significant impact of proteinuria on extra-renal manifestations, demonstrating the versatility of this model for nephrotic syndrome-related research.

Iron deficiency in proteinuric children with nephrotic syndrome: A cross-sectional pilot study.

Massive proteinuria in nephrotic syndrome causes depletion of various proteins. Iron deficiency can occur due to urinary loss of iron, transferrin, and soluble transferrin receptors. We conducted this cross-sectional study of 52 children with proteinuric nephrotic syndrome, aged 1-12 years (mean 7.1±2.7 years). Hemoglobin (Hb), RBC indices (MCV, MCH, MCHC), percentage of hypochromic RBCs (Hypo-He), reticulocyte hemoglobin content (Ret-He), and serum ferritin were examined. Seven (13%) patients had iron deficiency anemia and another 10 (19%) exhibited iron deficiency. A higher proportion of children with steroid-resistant disease had anemia than did steroid-sensitive children (P=0.076). Thus, children with nephrotic syndrome may have iron deficiency (32.7%), which needs to be screened.

Salvianolic acid A attenuates steroid resistant nephrotic syndrome through suPAR/uPAR-αvß3 signaling Inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvianolic acid A (SAA) is extracted from traditional Chinese medicine Salvia miltiorrhiza and is the main water-soluble and the biologically active ingredient. SAA possesses a variety of pharmacological activities and has an excellent protective effect on kidney disease, especially steroid resistant nephrotic syndrome (SRNS), and has advantages in improving the efficacy of glucocorticoids, but its mechanism needs to be further explored. PURPOSE: The study was designed to explore the effect of suPAR and uPAR in SRNS patients and evaluate the potential effect of SAA in improving podocyte steroid resistance and explore its mechanism. METHODS AND MATERIALS: The ELISA kits were used to detect the levels of suPAR in the blood and urine of subjects. The levels of uPAR, GRα, and GRß expression in renal tissues of SRNS patients was detected by immunohistochemistry and analyzed using the Pearson method. In vitro studies, steroid resistance model was induced by the TNF-α and IFN-γ. The protein and mRNA expression of Nephrin, GR, GRα and GRß were analyzed using western blot and qRT-PCR. The activity of GR-DNA binding was detected by using TransAM™ GR kits. Adriamycin further induced steroid resistance podocyte. Flow cytometry was used to detect the effect of SAA on podocyte apoptosis. ELISA assay was used to detect the suPAR expression in the podocyte supernatant. Western blot and qRT-PCR were used to detect the protein and mRNA expression of uPAR and Nephrin in podocytes. RESULTS: The serum and urine levels of suPAR were conspicuously higher in SRNS patients than healthy volunteers and SSNS patients, and the expression of uPAR in renal tissue of SRNS patients is negatively correlated with GRα, but positively correlated with GRß. The combination of TNF-α and IFN-γ could conspicuously increase the GRß expression and reduce GRα/GRß, and induce steroid resistance in podocytes. Moreover, we found that SAA could reduce the apoptosis of podocytes and suppress the expression of suPAR/uPAR, and increase the expression of Nephrin. CONCLUSION: The level of suPAR and uPAR expression may have important value in predicting glucocorticoids resistance in patients with idiopathic nephrotic syndrome (INS). The combination of TNF-α and IFN-γ induce podocytes can establish steroid resistance model in vitro. SAA could improve glucocorticoids resistance of podocyte which can be attributed in part to regulate the suPAR/uPAR-αvß3 signaling pathway.

Pediatric idiopathic steroid-sensitive nephrotic syndrome: diagnosis and therapy -short version of the updated German best practice guideline (S2e) - AWMF register no. 166-001, 6/2020.

Idiopathic nephrotic syndrome is the most frequent glomerular disease in children in most parts of the world. Children with steroid-sensitive nephrotic syndrome (SSNS) generally have a good prognosis regarding the maintenance of normal kidney function even in the case of frequent relapses. The course of SSNS is often complicated by a high rate of relapses and the associated side effects of repeated glucocorticoid (steroid) therapy. The following recommendations for the treatment of SSNS are based on the comprehensive consideration of published evidence by a working group of the German Society for Pediatric Nephrology (GPN) based on the systematic Cochrane reviews on SSNS and the guidelines of the KDIGO working group (Kidney Disease - Improving Global Outcomes).

A patient with Silver-Russell syndrome with multilocus imprinting disturbance, and Schimke immuno-osseous dysplasia unmasked by uniparental isodisomy of chromosome 2.

Silver-Russell syndrome (SRS) is a congenital disorder characterized by prenatal and postnatal growth failure and craniofacial features. Hypomethylation of the H19/IGF2:IG-differential methylated region (H19LOM) is observed in 50% of SRS patients, and 15% of SRS patients with H19LOM had multilocus imprinting disturbance (MLID). Schimke immuno-osseous dysplasia (SIOD), characterized by spondyloepiphyseal dysplasia and nephropathy, is an autosomal recessive disorder caused by mutations in SMARCAL1 on chromosome 2. We report a patient with typical SRS-related features, spondyloepiphyseal dysplasia, and severe nephropathy. Molecular analyses showed H19LOM, paternal uniparental isodisomy of chromosome 2 (iUPD(2)pat), and a paternally inherited homozygous frameshift variant in SMARCAL1. Genome-wide methylation analysis showed MLID in this patient, although it showed no MLID in another patient with SIOD without SRS phenotype. These results suggest that iUPD(2)pat unmasked the recessive mutation in SMARCAL1 and that the SMARCAL1 gene mutation may have no direct effect on the patient's methylation defects.

Five-Year Follow-Up and Successful Kidney Transplantation in a Girl with a Severe Phenotype of Pierson Syndrome.

Pierson syndrome (PIERSS) is a rare autosomal recessive disorder characterized by the combination of congenital nephrotic syndrome (CNS) and extrarenal symptoms including ocular malformations and neurodevelopmental deficits. PIERSS is caused by biallelic pathogenic variants in the LAMB2 gene leading to the defects of ß2-laminin, the protein mainly expressed in the glomerular basement membrane, ocular structures, and neuromuscular junctions. Severe complications of PIERSS lead to the fatal outcome in early childhood in majority of the cases. We report a case of 5-year-old girl with severe phenotype of PIERSS caused by biallelic functional null variants of the LAMB2 gene. Due to consequences of CNS, the patient required bilateral nephrectomy and peritoneal dialysis since early infancy. The course was additionally complicated by tubulopathy, life-threatening infections, severe hypertension, erythropoietin-resistant anemia, generalized muscular hypotonia, neurogenic bladder, profound neurodevelopmental delay, epilepsy, gastrointestinal problems, secondary hypothyroidism, and necessity of repeated ocular surgery due to microcoria, cataract, and nystagmus. Due to multidisciplinary efforts, at the age of 4 years, the kidney transplantation was possible. Currently, the renal graft has an excellent function; however, the girl presents severe neurodevelopmental delay. The report presents a unique long-term follow-up of severe PIERSS with a few new phenotypical findings. It highlights the clinical problems and challenges in management of this rare condition.

The Association of Syndecan-1, Hypercoagulable State and Thrombosis and in Patients With Nephrotic Syndrome.

The aim of this study is to investigate whether Syndecan-1 (SDC-1), an indicator of endothelial glycocalyx injury, would increase the risk of hypercoagulable state and thrombosis in patients with nephrotic syndrome (NS). The prospective study was conducted among patients undergoing renal biopsy in the Department of Nephrology in our hospital from May to September 2018. We enrolled in patients with NS as the experimental group and patients with normal serum creatinine and proteinuria less than 1 g as the control group. Patients' characteristics including age, sex, laboratory test results and blood samples were collected for each patient. The blood samples were taken before the renal biopsy. The samples were immediately processed and frozen at -80°C for later measurement of Syndecan-1. One hundred and thirty-six patients were enrolled in the study. Patients with NS and hypercoagulability had a higher level of SDC-1 compared with control group. Patients with membranous nephropathy occupied the highest SDC-1 level (P = 0.012). Logistic regression showed that highly increased level of SDC-1 (>53.18 ng/ml) was an independent predicator for predicting hypercoagulable state. The elevated level of SDC-1 indicated that endothelial injury, combined with its role of accelerating hypercoagulable state, might be considered of vital importance in the pathophysiological progress of thrombosis formation in patients with NS.

[Role of distal nephron in the control of extracellular volume in physiology and in nephrotic syndrome]. / Rôle du néphron distal dans le contrôle du volume extracellulaire en condition physiologique et dans le syndrome néphrotique.

The kidney plays a major role to maintain the constancy of the "milieu intérieur" by adjusting the urinary excretion of water and solutes to the requirement of the body balance. This function is coordinated with elimination of waste products generated among others by the catabolism of proteins and nucleic acids. To cope with these two major functions, the human kidneys generate each day about 180 L of ultrafiltrate from plasma and reabsorbs the vast majority of filtered water and solutes to excrete daily about one-two liter(s) of urine containing concentrations of sodium, potassium and chloride ranging from 20 to 200 mM. The final adjustment of urine composition is finely tuned along the aldosterone-sensitive distal nephron (ASDN) which includes the distal convoluted tubule and the collecting system (connecting tubule and collecting duct). Sodium reabsorption is predominant along the distal tubule if potassium must be spared, or along the collecting system when large amounts of potassium must be secreted. Nephrotic syndrome is characterized by heavy proteinuria consecutive to a glomerular injury, associated with renal sodium and water retention taking initially place along ASDN and leading to edema.

TITLE: Rôle du néphron distal dans le contrôle du volume extracellulaire en condition physiologique et dans le syndrome néphrotique. ABSTRACT: Les reins jouent un rôle majeur dans le maintien de la composition du milieu intérieur. Cette fonction est coordonnée avec l'élimination des déchets du métabolisme, impliquant la production par les reins d'environ 180 litres de filtrat par jour et la réabsorption de la grande majorité de l'eau et des solutés filtrés. L'ajustement final de la composition de l'urine est réalisé dans le segment distal sensible à l'aldostérone (ASDN), qui inclut le tube contourné distal et le système collecteur. La réabsorption de sodium prédomine dans le tube distal si le potassium doit être épargné, ou dans le système collecteur si le potassium doit être sécrété. Le syndrome néphrotique est caractérisé par une protéinurie massive causée par des lésions glomérulaires, associée à une rétention hydrosodée prenant place dans l'ASDN et induisant chez le patient des œdèmes parfois volumineux.

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.

Efficacy of AAV9-mediated SGPL1 gene transfer in a mouse model of S1P lyase insufficiency syndrome.

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare metabolic disorder caused by inactivating mutations in sphingosine-1-phosphate lyase 1 (SGPL1), which is required for the final step of sphingolipid metabolism. SPLIS features include steroid-resistant nephrotic syndrome and impairment of neurological, endocrine, and hematopoietic systems. Many affected individuals die within the first 2 years. No targeted therapy for SPLIS is available. We hypothesized that SGPL1 gene replacement would address the root cause of SPLIS, thereby serving as a universal treatment for the condition. As proof of concept, we evaluated the efficacy of adeno-associated virus 9-mediated transfer of human SGPL1 (AAV-SPL) given to newborn Sgpl1-KO mice that model SPLIS and die in the first weeks of life. Treatment dramatically prolonged survival and prevented nephrosis, neurodevelopmental delay, anemia, and hypercholesterolemia. STAT3 pathway activation and elevated proinflammatory and profibrogenic cytokines observed in KO kidneys were attenuated by treatment. Plasma and tissue sphingolipids were reduced in treated compared with untreated KO pups. SGPL1 expression and activity were measurable for at least 40 weeks. In summary, early AAV-SPL treatment prevents nephrosis, lipidosis, and neurological impairment in a mouse model of SPLIS. Our results suggest that SGPL1 gene replacement holds promise as a durable and universal targeted treatment for SPLIS.

Immunopathogenesis of idiopathic nephrotic syndrome in children: two sides of the coin.

BACKGROUND: Idiopathic nephrotic syndrome is a common form of glomerular nephropathy in children, with an incidence rate of 1.15-16.9/100,000 depending on different nationalities and ethnicities. The etiological factors and mechanisms of childhood idiopathic nephrotic syndrome have not yet been fully elucidated. This review summarizes the progress of the immunopathogenesis of idiopathic nephrotic syndrome in children. DATA SOURCES: We review the literature on the immunopathogenesis of idiopathic nephrotic syndrome in children. Databases including Medline, Scopus, and Web of Science were searched for studies published in any language with the terms "children", "idiopathic nephrotic syndrome", "immunopathogenesis", "T cells", "circulating permeability factors", and "B cells". RESULTS: Dysfunction in T lymphocytes and pathogenic circulatory factors were indicated to play key roles in the pathogenesis of idiopathic nephrotic syndrome. Recently, some studies have shown that cellular immune dysfunction may also be involved in the pathogenesis of idiopathic nephrotic syndrome. CONCLUSIONS: Both T- and B-cell dysfunction may play significant roles in the pathogenesis of idiopathic nephrotic syndrome, like two sides of one coin, but the role of B cell seems more important than T cells.

Use of angiotensin II receptor blocker during pregnancy: A case report.

BACKGROUND: Drugs that affect the renin-angiotensin system, such as angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors are not typically recommended for pregnant women because of their potential fetal toxicity. CASE STUDY: A 32-year-old pregnant woman with nephrotic syndrome lasting more than 5 years became pregnant for the first time. She had been taking losartan tablets before and during pregnancy. Ultrasound at 24+2 weeks of pregnancy showed oligohydramnios, and the maximum vertical depth of amniotic fluid volume was 1.4 cm. Follow-up ultrasound examinations every 2 weeks showed persistent oligohydramnios [amniotic fluid volume: 1.1-3.4 cm, amniotic fluid index 1.9-6.9 cm]. B-ultrasound at 30+2 weeks showed slightly enhanced fetal renal cortex echo. The patient was treated at 32+2 weeks of pregnancy at our hospital. DIAGNOSES: Nephrotic syndrome and oligohydramnios. INTERVENTIONS: Losartan was discontinued and replaced by nifedipine controlled-release tablets to lower blood pressure. The amount of amniotic fluid gradually increased to normal levels within 8 days. The patient was discharged at 33+2 weeks of pregnancy for follow-up. At 34+4 weeks, blood pressure had increased to 177/113 mm Hg and the patient was re-hospitalized with nephrotic syndrome complicated by preeclampsia. Due to progression of severe preeclampsia, elective cesarean section was performed at 35+3 weeks. After delivery, losartan and nifedipine were prescribed to continue lowering blood pressure. The patient was discharged 4 days after surgery. OUTCOMES: Losartan use was terminated at 32+2 weeks of pregnancy. Amniotic fluid returned to normal after 8 days and the baby was delivered after 22 days. At last follow-up, the infant was 24 months old and healthy. CONCLUSION: Although ARBs are effective for treating hypertension, they should be replaced by other classes of anti-hypertensive drugs in pregnant women. Pregnant women who elect to continue using ARBs should be informed about risks, they should be carefully monitored during pregnancy, and their pregnancy should be allowed to proceed as long as clinically feasible in order to optimize maternal and infant outcomes.

Impaired NEPHRIN localization in kidney organoids derived from nephrotic patient iPS cells.

Mutations in the NPHS1 gene, which encodes NEPHRIN, cause congenital nephrotic syndrome, resulting from impaired slit diaphragm (SD) formation in glomerular podocytes. We previously reported NEPHRIN and SD abnormalities in the podocytes of kidney organoids generated from patient-derived induced pluripotent stem cells (iPSCs) with an NPHS1 missense mutation (E725D). However, the mechanisms underlying the disease may vary depending on the mutations involved, and thus generation of iPSCs from multiple patients is warranted. Here we established iPSCs from two additional patients with different NPHS1 mutations and examined the podocyte abnormalities in kidney organoids derived from these cells. One patient had truncating mutations, and NEPHRIN was undetectable in the resulting organoids. The other patient had a missense mutation (R460Q), and the mutant NEPHRIN in the organoids failed to accumulate on the podocyte surface to form SD precursors. However, the same mutant protein behaved normally when overexpressed in heterologous cells, suggesting that NEPHRIN localization is cell context-dependent. The localization of another SD-associated protein, PODOCIN, was impaired in both types of mutant organoids in a cell domain-specific manner. Thus, the new iPSC lines and resultant kidney organoids will be useful resources for dissecting the disease mechanisms, as well as for drug development for therapies.