Focal Segmental Glomerulosclerosis Research Articles

Proteomic Analysis of Idiopathic Nephrotic Syndrome Triggered by Primary Podocytopathies in Adults: Regulatory Mechanisms and Diagnostic Implications.

Idiopathic nephrotic syndrome (NS) is a heterogeneous group of glomerular disorders which includes two major phenotypes: minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). MCD and FSGS are classic types of primary podocytopathies. We aimed to explore the molecular mechanisms in NS triggered by primary podocytopathies and evaluate diagnostic value of the selected proteomic signatures by analyzing blood proteome profiling. Totally, we recruited 90 participants in two cohorts. The first cohort was analyzed using label-free quantitative (LFQ) proteomics to discover differential expressed proteins and identify enriched biological process in NS which were further studied in relation to clinical markers of kidney injury. The second cohort was analyzed using parallel reaction monitoring-based quantitative proteomics to verify the data of LFQ proteomics and assess the diagnostic performance of the selected proteins using receiver-operating characteristic curve analysis. Several biological processes (such as immune response, cell adhesion, and response to hypoxia) were found to be associated with kidney injury during MCD and FSGS. Moreover, three proteins (CSF1, APOC3, and LDLR) had over 90% sensitivity and specificity in detecting adult NS triggered by primary podocytopathies. The identified biological processes may play a crucial role in MCD and FSGS pathogenesis. The three blood protein markers are promising for diagnosing adult NS triggered by primary podocytopathies.

Association of Preterm Birth with Adverse Glomerular Disease Outcomes in Children and Adults.

While some studies of children with nephrotic syndrome have demonstrated worse outcomes in those born preterm compared with term, little data exists on associations of preterm birth with outcomes in adult-onset glomerular disease. Cardiovascular outcomes in those born preterm with glomerular disease are unknown. We performed a cross-sectional and longitudinal analysis of participants in the Cure Glomerulonephropathy (CureGN) cohort. Preterm (<37 weeks' gestation) was compared to term (≥37 weeks' gestation). A survival analysis and adjusted Cox proportional hazards model were used to examine a composite outcome of 40% decline in estimated glomerular filtration rate (eGFR) or progression to kidney failure. An adjusted logistic regression model was used to examine remission of proteinuria. There were 2,205 term and 235 preterm participants. APOL1 risk alleles were more common in those born preterm. More pediatric than adult participants in CureGN were born preterm: 12.8% vs. 7.69% (P<0.001). Adults born preterm as compared to term had a higher prevalence of Focal Segmental Glomerulosclerosis (FSGS) (35% vs. 25%, P=0.01) and APOL1 high-risk genotype (9.4% vs 4.2%, P=0.01). Participants born preterm had a shorter time interval to a 40% eGFR decline/kidney failure after biopsy (P=0.001). In adjusted analysis, preterm participants were 28% more likely to develop 40% eGFR decline/kidney failure (Hazard Ratio: 1.28 [1.07, 1.54], P=0.008) and 38% less likely to attain complete remission of proteinuria (Odds Ratio: 0.62 [0.45, 0.87], P=0.006). There was no significant difference in cardiovascular events. Preterm birth was a risk factor for adverse outcomes in this heterogenous cohort of children and adults with glomerular disease. Adults born preterm were more likely to have an APOL1 high-risk genotype and FSGS. In analyses adjusted for FSGS and APOL1 risk status, there was less remission and faster progression of kidney disease in those born preterm.

Clinical features and genetic analysis of 15 Chinese children with dent disease

Objective The clinical characteristics, genetic mutation spectrum, treatment strategies and prognoses of 15 children with Dent disease were retrospectively analyzed to improve pediatricians’ awareness of and attention to this disease. Methods We analyzed the clinical and laboratory data of 15 Chinese children with Dent disease who were diagnosed and treated at our hospital between January 2017 and May 2023 and evaluated the expression of the CLCN5 and OCRL1 genes. Results All 15 patients were male and complained of proteinuria, and the incidence of low-molecular-weight proteinuria (LMWP) was 100.0% in both Dent disease 1 (DD1) and Dent disease 2 (DD2) patients. The incidence of hypercalciuria was 58.3% (7/12) and 66.7% (2/3) in DD1 and DD2 patients, respectively. Nephrocalcinosis and nephrolithiasis were found in 16.7% (2/12) and 8.3% (1/12) of DD1 patients, respectively. Renal biopsy revealed focal segmental glomerulosclerosis (FSGS) in 1 patient, minimal change lesion in 5 patients, and small focal acute tubular injury in 1 patient. A total of 11 mutations in the CLCN5 gene were detected, including 3 missense mutations (25.0%, c.1756C > T, c.1166T > G, and c.1618G > A), 5 frameshift mutations (41.7%, c.407delT, c.1702_c.1703insC, c.137delC, c.665_666delGGinsC, and c.2200delG), and 3 nonsense mutations (25.0%, c.776G > A, c.1609C > T, and c.1152G > A). There was no significant difference in age or clinical phenotype among patients with different mutation types (p > 0.05). All three mutations in the OCRL1 gene were missense mutations (c.1477C > T, c.952C > T, and c.198A > G). Conclusion Pediatric Dent disease is often misdiagnosed. Protein electrophoresis and genetic testing can help to provide an early and correct diagnosis.

A Novel COL4A5 Pathogenic Variant Joins the Dots in a Family with a Synchronous Diagnosis of Alport Syndrome and Polycystic Kidney Disease

Alport Syndrome (AS) is the most common genetic glomerular disease, and it is caused by COL4A3, COL4A4, and COL4A5 pathogenic variants. The classic phenotypic spectrum associated with AS ranges from isolated hematuria to chronic kidney disease (CKD) with extrarenal abnormalities. Atypical presentation of the disorder is possible, and it can mislead the diagnosis. Polycystic kidney disease (PKD), which is most frequently associated with Autosomal Dominant PKD (ADPKD) due to PKD1 and PKD2 heterozygous variants, is emerging as a possible clinical manifestation in COL4A3-A5 patients. We describe a COL4A5 novel familial frameshift variant (NM_000495.5: c.1095dup p.(Leu366ValfsTer45)), which was associated with AS and PKD in the hemizygous proband, as well as with PKD, IgA glomerulonephritis and focal segmental glomerulosclerosis (FSGS) in the heterozygous mother. Establishing the diagnosis of AS can sometimes be difficult, especially in the context of misleading family history and atypical phenotypic features. This case study supports the emerging genotypic and phenotypic heterogeneity in COL4A3-A5-associated disorders, as well as the recently described association between PKD and collagen type IV (Col4) defects. We highlight the importance of the accurate phenotyping of all family members and the relevance of next-generation sequencing in the differential diagnosis of hereditary kidney disease.

Single-Cell Transcriptional Signatures of Glomerular Disease in Transgenic Mice with APOL1 Variants.

APOL1 high-risk variants contribute to kidney disease among African-ancestry individuals. We sought to describe cell-specific APOL1 variants-induced pathways using two mouse models. We characterized bacterial artificial chromosome (BAC)/APOL1 transgenic mice crossed with HIV-associated nephropathy (HIVAN) Tg26 mice and BAC/APOL1 transgenic mice given interferon-γ. Both mouse models showed more severe glomerular disease in APOL1-G1 compared to APOL1-G0 mice. Bulk RNA-seq of HIVAN model-glomeruli identified synergistic podocyte-damaging pathways activated by APOL1-G1 and by the HIV transgene. Single-nuclear RNA-seq revealed podocyte-specific patterns of differentially-expressed genes as a function of APOL1 alleles. Shared activated pathways, e.g. mTOR, and differentially-expressed genes, e.g. Ccn2, in podocytes in both models suggest novel markers of APOL1-associated kidney disease. HIVAN mouse-model podocyte single-nuclear RNA-seq data showed similarity to human focal segmental glomerulosclerosis glomerular RNA-seq data. Differential effects of the APOL1-G1 variant on the eukaryotic Initiation factor-2 pathway highlighted differences between the two models. These findings in two mouse models demonstrated both shared and distinct cell type-specific transcriptomic signatures induced by APOL1 variants. These findings suggest novel therapeutic opportunities for APOL1 glomerulopathies.

Design of a User-Centered Electronic Health Tool for Glomerular Disease Management

Introduction Patients with primary glomerular disease (GN) have unique management needs. We describe the design of a user-centered, patient-facing electronic health (eHealth) tool to support GN management. Methods We surveyed patients and GN expert nephrologists on disease management tasks, educational needs, and barriers and facilitators of eHealth tool use. Results were summarized and presented to patients, nephrologists, engineers, and a behavioral and implementation science expert in stakeholder meetings to jointly design an eHealth tool. Key themes from the meetings are described using rapid qualitative analysis. Results Sixty-six patients with minimal change disease, focal segmental glomerulosclerosis, IgA nephropathy, and membranous nephropathy responded to the survey, as well as 25 nephrologists from the NIH-funded Cure Glomerulonephropathy study network. Overall, patients performed fewer management tasks and acknowledged fewer informational needs than recommended by nephrologists. Patients were more knowledgeable about eHealth tools than nephrologists. Nine patient stakeholders reflected on the survey findings and noted a lack of awareness of key recommended management tasks and receiving little guidance from nephrologists on using eHealth. Key themes and concepts from the stakeholder meetings about eHealth tool development included the need for customizable design, trustworthy sources, seamless integration with other apps and clinical workflow, and reliable data tracking. The final design of our eHealth tool, the UrApp System, has 5 core features: “Profile” generates personalized data tracking, educational information, facilitation with provider discussions and inputting other preferences; “Data Tracking” displays patient health data with the ability to communicate important trends to patients and nephrologists; “Resources” provides trusted education information in a personalized manner; “Calendar” displays key events and generate reminders; and “Journal” facilitates information documentation using written or audio notes. Conclusion Our theory- and evidenced-based, stakeholder-engaged design process created designs for an eHealth tool to support the unique needs of patients with GN, optimized for effectiveness and implementation.

WIP1 inhibition as a new therapeutic strategy for collapsing glomerulopathy

Collapsing glomerulopathy (CG) is an aggressive variant of focal and segmental glomerulosclerosis. Understanding the diverse mechanisms that can drive CG promises to uncover new therapeutic strategies. In this issue, Duret etal. identify WIP1 phosphatase as a therapeutic target for CG. Using genetic ablation and pharmacologic inhibition, they show that blockade of WIP1 activity is protective in 2 different mouse models of CG. This study highlights the complex interplay of glomerular signaling pathways in CG and offers hope for targeted therapies.

Hydralazine use can be associated with IgM-dominated immune complex-mediated glomerulonephritis

ABSTRACT Context IgM-dominant immune complex-mediated glomerulonephritis (IgM-dominant ICMGN) is a rare renal entity, characterized by a membranoproliferative pattern by light microscopy, dominant IgM staining by immunofluorescent staining, and subendothelial deposits by electron microscopy. This study was to investigate if some of IgM-ICMGN were associated with autoimmune disorders induced by hydralazine. Design Seven IgM-dominant ICMGN cases were identified over 8 years. Their pathologic phenotypes and clinical scenarios were analyzed in detail. Results Patients’ ages ranged from 47 to 87 years old with 5 women and two men. Six of seven patients had drug-induced autoimmune phenomenon (hydralazine-induced positive ANCA and ANA). All of them had renal dysfunction and some proteinuria. Most pathologic features showed a membranoproliferative pattern of glomerulonephritis with dominant IgM deposits at subendothelial spaces. IgM nephropathy (a variant of focal segmental glomerulosclerosis), chronic thrombotic microangiopathy, and cryoglobulinemic glomerulopathy were ruled out in the cases. Conclusion The hydralazine-induced autoimmune phenomenon can be seen in IgM-dominant ICMGN, which should be classified as a subtype of membranoproliferative glomerulonephritis.

Long-term outcomes of adults with focal segmental glomerulosclerosis (FSGS) in the GCKD cohort

Abstract Background Focal segmental glomerulosclerosis (FSGS) can lead to kidney failure in adults. This study examines the progression of FSGS in the German Chronic Kidney Disease (GCKD) cohort. Methods The GCKD study (N = 5217), a prospective cohort, included 159 patients with biopsy-confirmed FSGS recruited from 2010 to 2012. Baseline was defined as first study visit. Adjudicated endpoints included a composite kidney endpoint (CKE), including an eGFR decline &amp;gt; 40%, eGFR &amp;lt; 15 ml/min/1.73 m2 or initiation of kidney replacement therapy (KRT), and combined major adverse cardiovascular events (MACE), including non-fatal myocardial infarction or stroke and all-cause mortality. Associations between baseline demographics, laboratory data, comorbidity, and CKE and MACE were analyzed using the Cox proportional hazards regression model. Results The mean age at baseline was 52.1 ± 13.6 years, with a disease duration of 4.7 2 (Q1: 1; Q3: 6) years before joining the study. Median urinary albumin to creatinine ratio (UACR) at baseline was 0.7 g/g (IQR 1.7), while mean eGFR was 55.8 ± 23 mL/min/1.73m². Based on clinical and pathological features, 69 (43.4%) patients were categorized as primary FSGS, 55 (34.6%) as secondary FSGS and 35 (22%) as indeterminate. Over a follow-up of 6.5 years, 44 patients reached the composite kidney endpoint, and 16 individuals had at least one MACE. UACR ≥ 0.7 g/g was strongly associated with both the composite kidney endpoint (HR 5.27; 95%; CI: 2.4–11.5), and MACE (HR 3.37; 95% CI: 1.05–10.82) compared to &amp;lt; 0.7 g/g, whereas higher eGFR at baseline (per 10 ml/min) was protective for both endpoints (HR of 0.8; 95% CI: 0.68–0.95 and HR 0.63; 95% CI: 0.46–0.88 respectively). Patients with secondary FSGS experienced a greater rate of eGFR decline than patients with primary FSGS. Conclusions Lower eGFR and higher albuminuria are key risk factors for kidney disease progression and cardiovascular events in patients with FSGS.

Dexamethasone promotes renal fibrosis by upregulating ILT4 expression in myeloid-derived suppressor cells.

Studies have shown that adoptive transfer of myeloid-derived suppressor cells (MDSCs) can alleviate various inflammatory diseases, including glomerulonephritis, but the long-term effects of the transferred MDSCs are still unclear. In addition, although glucocorticoids exert immunosuppressive effects on inflammatory diseases by inducing the expansion of MDSCs, the impact of glucocorticoids on the immunosuppressive function of MDSCs and their molecular mechanisms are unclear. In this study, we found that adoptive transfer of MDSCs to doxorubicin-induced focal segmental glomerulosclerosis (FSGS) mice for eight consecutive weeks led to an increase in serum creatinine and proteinuria and aggravation of renal interstitial fibrosis. Similarly, 8 weeks of high-dose dexamethasone administration exacerbated renal interstitial injury and interstitial fibrosis in doxorubicin-induced mice, manifested as an increase in serum creatinine and proteinuria, collagen deposition and α-SMA expression. On this basis, we found that dexamethasone could enhance MDSC expression and secretion of the fibrosis-related cytokines TGF-β and IL-10. Mechanistically, we revealed that dexamethasone promotes the expression of immunoglobulin-like transcription factor 4 (ILT4), which enhances the T-cell inhibitory function of MDSCs and promotes the activation of STAT6, thereby strengthening the expression and secretion of TGF-β and IL-10. Knocking down ILT4 alleviated renal fibrosis caused by adoptive transfer of MDSCs. Therefore, our findings demonstrate that the role and mechanism of dexamethasone mediate the expression and secretion of TGF-β and IL-10 in MDSCs by promoting the expression of ILT4, thereby leading to renal fibrosis.

Non-diabetic nephropathy in diabetic patients: incidence, HbA1c variability and other predictive factors, and implications.

Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD) in the population. In patients with diabetes mellitus, the incidence of non-diabetic nephropathy (NDNP) has been estimated to range from 3% to 69.5%. Personal judgment is frequently employed while deciding whether or not to do a kidney biopsy(KB) on diabetic patients. NDNP alters the prognosis and course of treatment for people with DM. In our study, we examined the incidence of NDNP concurrent with the progression of diabetes mellitus, as well as the laboratory and clinical indicators that could be utilized to forecast it. A retrospective analysis of 76 diabetic patients who underwent KB was conducted. Based on the pathological diagnoses of these patients, they were categorized as DNP (diabetic nephropathy) or NDNP. The definition of HbA1c variability was determined by calculating the mean HbA1c and the average value of the HbA1c measurements, as well as the standard deviation (SD) for each participant. NDNP was detected in 50% of 76 patients. Among patients with NDNP, 36.8% had focal segmental glomerulosclerosis (FSGS), 23.6% had membranous glomerulonephritis, and 7.8% had IgA nephritis. The NDNP group exhibited significantly higher rates of female gender, absence of diabetic retinopathy, shorter time to diagnosis of diabetes mellitus, chronic kidney disease, and proteinuria, less intensive medication for diabetes mellitus, presence of hematuria and leukociduria, immunological serological marker positivity, and non-HbA1C variability. Risk factors for predicting non-diabetic nephropathy, as determined by multivariate analysis, included female gender, the absence of diabetic retinopathy, non-HbA1c variability and a positive immunological serological test. In this study, a significant number of diabetic patients with chronic kidney disease were diagnosed with NDNP. Identifying these patients allows for treatment of the specific underlying disease. Factors such as the absence of DR, non-HbA1c variability, female gender, and immunological serological test positivity can predict NDNP and guide the clinician's decision on kidney biopsy. Further prospective studies are warranted to validate the efficacy of potential predictive factors like HbA1c variability.

Incorporating genetic testing into a routine kidney clinic.

Incorporating genetic testing in routine outpatient nephrology clinic can improve on chronic kidney disease (CKD) diagnosis and utilization of precision medicine. We sent a genetic test on patients with atypical presentation of common kidney diseases, electrolytes derangements, and cystic kidney diseases. We were able to identify a gene variant contributing to patients' kidney disease in more than half of our cohort. We then showed that patients with ApoL1 risk allele have likely worse kidney disease, and we were able to confirm genetic focal segmental glomerulosclerosis (FSGS) in 2 patients and avoid unnecessary immunosuppression. Genetic testing has also improved our operation to establish a polycystic kidney disease excellence center by confirming our diagnosis, especially in patients without a well-defined family history. In conclusion, utilizing genetic testing in a routine outpatient renal clinic did not cause any burden to either patients or nephrologists, with minimal administrative effort and no financial cost to our patients. We expect that genetic testing in the right setting should become routine in nephrology to achieve a patient-centered precision medicine with less invasive means of kidney disease diagnosis.

E018 Prophylactic co-trimoxazole prescribing practice in patients who received rituximab therapy: comparison across indications and specialties

Abstract Background/Aims Rituximab is a chimeric anti-CD20 monoclonal antibody targeting B-cells used as part of treatment algorithms for malignancy and autoimmune diseases. As is the case of other immunosuppressive agents, rituximab increases the risk of infections. Primary prophylaxis with co-trimoxazole may be considered in high-risk cohort of patients to prevent opportunistic infection, particuarly Pneumocystis jerovecii pneumonia (PJP). To investigate the prescribing practice for prophylactic co-trimoxazole in patients who received rituximab infusion in a large tertiary referral centre. To compare practices between rheumatology and nephrology department. To compare the incidence of hospitalisation for infection (particularly PJP) between those prescribed prophylactic co-trimoxazole and those who did not. Methods This was a single centre retrospective observational study over a 3 year period assessing prophylactic co-trimoxazole prescribing practice in 185 patients attending rheumatology or renal services in Cork University Hospital (CUH) and receiving rituximab. Co-trimoxazole prophylactic treatment was defined as prophylaxis dose of co-trimoxazole (either 480mg daily or 960mg three times per week) received during rituximab treatment and at least 6 months post completion of treatment. Results 185 patients’ medical charts were reviewed. Only 28 patients received prophylaxis with co-trimoxazole. The majority of patients (n = 24, 85%) who received prophylaxis with co-trimoxazole had an underlying diagnosis of small vessel vasculitis (SVV). Co-trimoxazole was more commonly prescribed by nephrologists (n = 17, 71% primarily for SVV) as compared to rheumatologist (n = 7, 29% primarily for SVV). 156 patients were not prescribed prophylactic co-trimoxazole. The primary indication for rituximab in these patients was inflammatory arthropathy (IA) (n = 72,46%), SVV (n = 26, 16%), systemic lupus erythematosus (n = 19, 12%), with the remainder accounted for by scleroderma, undifferentiated connective tissue disease, membranous nephropathy (MN), myositis, focal segmental glomerulosclerosis and amyloid renal disease. No patient was admitted over the course of the study period with PJP. 59 patients required hospital admissions due to other infections, most commonly patients with SVV. The most common infections were respiratory tract and urinary tract infections. Overall infections requiring hospitalization were more common in the group receiving prophylaxis, perhaps highlighting the vulnerable nature and greater prednisolone prescribing in the SVV cohort. No difference was seen between groups in the prevalence of UTIs. Conclusion In this cohort co-trimoxazole prophylaxis was more commonly prescribed for patient with small vessel vasculitis and differences in prescribing patterns were seen between nephrologists and rheumatologists. With greater awareness of the heightened risk of PJP in patents receiving rituximab consideration should be given to use of antibiotic prophylaxis for other indications. Disclosure S. Tio: None. J. Morrow: None. S. Cowley: None. M. Clarkson: None. G. Murphy: None.

Kidney outcomes in children with primary focal segmental glomerulosclerosis from a low- and middle- income country.

Limited data exists regarding the clinical course and outcomes of children with primary focal segmental glomerulosclerosis (FSGS) from low- and middle- income countries. Children aged 1-18years with biopsy-proven primary FSGS followed from January 2010-June 2023 in a tertiary-care center were enrolled and their clinical profile, histological characteristics, kidney outcomes, and predictors of adverse outcomes were determined. Over 13years, 73 (54.8% boys) children with median (IQR) age at FSGS diagnosis 6.7 (3,10) years were recruited and followed up for median 4 (2.5,8) years. FSGS-not otherwise specified (NOS) was the most common histological subtype, in 64 (87.6%) children, followed by collapsing variant in 5 (6.8%) children. At last follow-up, 43 (58.9%), 2 (2.7%) and 28 (38.3%) children were in complete remission (CR), partial remission (PR), and no remission (NR) respectively. Calcineurin inhibitors led to CR or PR in 39 (62%) children. Overall, 21 (28.7%) children progressed to chronic kidney disease (CKD) stage 2-5 (19 from NR vs. 2 from PR group; p = 0.03); with 41% of those NR at 12months progressing to CKD 4-5 by last follow-up. On multivariable analysis, collapsing variant [adjusted HR 2.5 (95%CI 1.5, 4.17), p = 0.001] and segmental sclerosis > 25% [aHR 9.9 (95%CI 2.2, 45.2), p = 0.003] predicted kidney disease progression. In children with FSGS, response to immunosuppression predicts kidney survival as evidenced by nil to lower progression to CKD 2-5 by median follow-up of 4 (2.5,8) years in children with CR and PR, comparedto those with no remission at 12months from diagnosis. Segmental sclerosis > 25% and collapsing variant predicted progression to advanced CKD.

Recurrent disease after pediatric renal transplantation.

Recurrent disease after kidney transplant remains an important cause of allograft failure, accounting for 7-8% of graft loss and ranking as the fifth most common cause of allograft loss in the pediatric population. Although the pathophysiology of many recurrent diseases is incompletely understood, recent advances in basic science and therapeutics are improving outcomes and changing the course of several of these conditions. Review of the literature. We discuss the diagnosis and management of recurrent disease. We highlight new insights into the pathophysiology and treatment of post-transplant primary hyperoxaluria, focal segmental glomerulosclerosis, immune complex glomerulonephritis, C3 glomerulopathy, lupus nephritis, atypical hemolytic uremic syndrome, and IgA nephropathy.

Identification of Plasma hsa_circ_0001230 and hsa_circ_0023879 as Potential Novel Biomarkers for Focal Segmental Glomerulosclerosis and circRNA-miRNA-mRNA network analysis.

Introduction Focal segmental glomerulosclerosis (FSGS) is a common glomerulopathy with unclear mechanism. The demand for FSGS clinical diagnostic biomarkers has not yet been met. Circular RNA (circRNA) is a novel non-coding RNA with multiple functions, but its diagnostic value for FSGS remains unexplored. This study aimed to identify circRNAs that could aid in early clinical diagnosis and to investigate their mechanisms in podocyte injury. Methods The signature of plasma circRNAs for FSGS was identified by circRNA microarray. The existence of circRNAs was confirmed by qRT-PCR, RNase R assay, and DNA sequencing. Plasma levels of circRNAs were evaluated by qRT-PCR. The diagnostic value was appraised by receiver operating characteristic curve. The circRNA-miRNA-mRNA network was built with Cytoscape 7.3.2. Statistically significant differences were calculated by the Mann-Whitney U-test. Results A total of 493 circRNAs (165 upregulated, 328 downregulated) were differentially expressed in the plasma of FSGS patients (n = 3) and normal controls (n = 3). Eight candidate circRNAs were demonstrated to be circular and stable transcripts. Among them, hsa_circ_0001230 and hsa_circ_0023879 were significantly upregulated in FSGS patients (n = 29) compared to normal controls (n = 51). The areas under the curve value of hsa_circ_0001230 and hsa_circ_0023879 were 0.668 and 0.753, respectively, while that of two-circRNAs panel was 0.763. The RNA pull-down analysis revealed that hsa_circ_0001230 and hsa_circ_0023879 could sponge hsa-miR-106a. Additionally, hsa_circ_0001230 and hsa_circ_0023879 positively regulated hsa-miR-106a target genes phosphatase and tensin homolog (PTEN) and Bcl-2-like protein 11 (BCL2L11) in podocytes. Conclusion Hsa_circ_0001230 and hsa_circ_0023879 are novel blood biomarkers for FSGS. They may regulate podocyte apoptosis by competitively binding to hsa-miR-106a.

Mutations in the NUP93, NUP107 and NUP160 genes cause steroid-resistant nephrotic syndrome in Chinese children

BackgroundThe variants of nucleoporins are extremely rare in hereditary steroid-resistant nephrotic syndrome (SRNS). Most of the patients carrying such variants progress to end stage kidney disease (ESKD) in their childhood. More clinical and genetic data from these patients are needed to characterize their genotype–phenotype relationships and elucidate the role of nucleoporins in SRNS.MethodsFour patients of SRNS carrying biallelic variants in the NUP93, NUP107 and NUP160 genes were presented. The clinical and molecular genetic characteristics of these patients were summarized, and relevant literature was reviewed.ResultsAll four patients in this study were female and initially presented with SRNS. The median age at the onset of the disease was 5.08 years, ranging from 1 to 10.5 years. Among the four patients, three progressed to ESKD at a median age of 7 years, ranging from 1.5 to 10.5 years, while one patient reached stage 3 chronic kidney disease (CKD3). Kidney biopsies revealed focal segmental glomerulosclerosis in three patients. Biallelic variants were detected in NUP93 in one patient, NUP107 in two patients, as well as NUP160 in one patient respectively. Among these variants, five yielded single amino acid substitutions, one led to nonsense mutation causing premature termination of NUP107 translation, one caused a single nucleotide deletion resulting in frameshift and truncation of NUP107. Furthermore, one splicing donor mutation was observed in NUP160. None of these variants had been reported previously.ConclusionThis report indicates that biallelic variants in NUP93, NUP107 and NUP160 can cause severe early-onset SRNS, which rapidly progresses to ESKD. Moreover, these findings expand the spectrum of phenotypes and genotypes and highlight the importance of next-generation sequencing in elucidating the molecular basis of SRNS and allowing rational treatment for affected individuals.

[Expansion of the genotypic and phenotypic spectrum and treatment of four children with Steroid-resistant nephrotic syndrome due to variants of TRPC6 gene].

To summarize the clinical and genetic characteristics, treatment and prognosis of four children with Steroid-resistant nephrotic syndrome (SRNS) due to variants of TRPC6 gene. Clinical data of four children with SRNS admitted to Children's Hospital Affiliated to Zhengzhou University between May 2020 and August 2022 were collected. Peripheral blood samples were collected from the children and their parents, and whole exome sequencing was carried out. Sanger sequencing was used to verify the pathogenicity of the candidate variants among the children and their parents. All of the four children were found to harbor heterozygous variants of the TRPC6 gene, including c.523C>T (p.R175W), c.1327T>A (p.F443I), c.430G>C (p.E144Q) (unreported previously), and c.523C>T (p.R175W), which were all missense variants. Two of the children have shown a simple type, whilst two have shown a nephritis type, none had extrarenal phenotype. Comprehensive renal pathology of three children revealed focal segmental glomerulosclerosis (FSGS). Two children were treated with steroids combined with calcineurin inhibitors (CNIs), among whom one showed significant improvement in symptoms. Discoveries of the novel c.430G>C variant and the new SRNS phenotype of the c.1327T>A variant have expanded the mutational and phenotypic spectrum of the TRPC6 gene, which has provided a reference for clinical diagnosis and genetic counseling for the families.

A new index for the outcome of focal segmental glomerulosclerosis

Focal segmental glomerulosclerosis (FSGS) is a common pathological form of nephrotic syndrome. This study analyzed the value of pathological lesions and clinical prognosis of different segmental glomerulosclerosis ratios in FSGS. Two hundred and six FSGS patients were collected from Dec 2013 to Apr 2016. The patients were divided into two groups according to the proportion of glomerular segmental sclerosis: F1 (SSR ≤ 15%, n = 133) and F2 (SSR > 15%, n = 73). The clinical and pathological data were recorded and analyzed, and statistical differences were observed between the serum uric acid level and the percentage of chronic renal failure. The pathological results showed significant differences in interstitial fibrosis and tubular atrophy (IFTA), degree of mesangial hyperplasia, vascular lesions, synaptopodin intensity, and foot process effacement between the two groups. Multivariate logistic regression analysis showed significant differences in creatinine (OR: 1.008) and F2 group (OR: 1.19). In all patients, the prognoses of urine protein and serum creatinine levels were statistically different. Multivariate Cox regression analysis revealed that F2 (hazard ratio: 2.306, 95% CI 1.022–5.207) was associated with a risk of ESRD (end stage renal disease). The proportion of segmental glomerulosclerosis provides a guiding value in the pathological diagnosis and clinical prognosis of FSGS.

Acute kidney injury in Hodgkin’s lymphoma, non-Hodgkin lymphoma/leukemia, and lymphoplasmacytic lymphoma: One center experience

Background: Acute kidney injury (AKI) is a common complication in patients with leukemia and lymphoma. In this single-center non-interventional retrospective study from 2010 to 2022, we aimed to evaluate causes, clinical features, and pathology finding in patients with Hodgkin lymphoma (HL), non-Hodgkin lymphoma/leukemia (NHL/CLL), or lymphoplasmacytic lymphoma (LPL) and AKI. Methods: We identified 101 patients with HL, NHL/CLL, and LPL. We analyzed AKI incidence and various clinical, laboratory, and pathology parameters and outcomes. Results: About 46.5% of patients with HL, NHL/CLL, and LPL presented with AKI. The incidence of AKI was the highest in the CLL setting (65.0%), it was lower and almost equal (48.0% and 47.0%) in NHL and HL, respectively, and the lowest (14.2%) in LPL. Study group comprised of 47 patients, M/F 31/16, median age was 64.0 [52.0; 71.0] years, and the patients with HL were significantly younger ( p = 0.022). The median disease duration prior to the AKI presentation was 14 [5; 44] months. Pre-renal AKI was diagnosed in 48.9% of cases: tumor lysis syndrome (TLS), specific lymphoid infiltration (LI), and post-renal AKI presented in 12.7% each. Kidney biopsy in 49% of patients revealed LI in 39.1% of cases. Focal segmental glomerulosclerosis presented in 21.7% of cases, proliferative glomerulonephritis with monoclonal immunoglobulin deposits in 13.0%, AA amyloidosis, IgA nephropathy, and AA amyloidosis in 8.6% each. AKI recovered in 63.8% of patients and 59.5% of patients were alive and dialysis-free at last evaluation: 100% with HL versus 58.3%, 46.1%, and 0% with NHL, LL, and LPL, respectively ( p = 0.025); and 8.5% remained alive on dialysis. About 25.5% of patients died after discontinuation or without need for dialysis; and 6.3% died on dialysis. Conclusion: AKI in patients with leukemia and lymphoma is heterogeneous and most commonly caused by volume depletion. AKI recovery, though not complete, occurred in 63.8% of cases with 68% survival.