[Precision diagnosis and therapeutic intervention of Alport syndrome].

Alport syndrome is one of the most common inherited kidney diseases caused by mutations in the type Ⅳ collagen genes. It has a complex pattern of inheritance and diverse clinical manifestations, and severe cases will rapidly progress to end-stage kidney disease. With the rapid development of genetic testing technology, there is a deeper understanding of the genetic spectrum of Alport syndrome, the effectiveness of clinical therapies, and the prediction of disease prognosis. Therefore, the purpose of the article is to introduce the advances in the diagnosis and treatment of Alport syndrome, aiming to improve the early diagnosis and standardized treatment of this disease.

T cell expressions of aberrant gene signatures and Co-inhibitory receptors (Co-IRs) as predictors of renal damage and lupus disease activity.

BACKGROUND: Systemic lupus erythematosus (SLE) is distinguished by an extensive range of clinical heterogeneity with unpredictable disease flares and organ damage. This research investigates the potential of aberrant signatures on T cell genes, soluble Co-IRs/ligands, and Co-IRs expression on T cells as biomarkers for lupus disease parameters. METHODS: Comparative transcriptome profiling analysis of non-renal and end-stage renal disease (ESRD) phenotypes of SLE was performed using CD4 + and CD8 + cDNA microarrays of sorted T cells. Comparing the expression of Co-IRs on T cells and serum soluble mediators among healthy and SLE phenotypes. RESULTS: SLE patients with ESRD were downregulated CD38, PLEK, interferon-γ, CX3CR1, FGFBP2, and SLCO4C1 transcripts on CD4 + and CD8 + T cells simultaneously and NKG7, FCRL6, GZMB/H, FcγRIII, ITGAM, Fas ligand, TBX21, LYN, granulysin, CCL4L1, CMKLR1, HLA-DRß, KIR2DL3, and KLRD1 in CD8 T cells. Pathway enrichment and PPI network analyses revealed that the overwhelming majority of Differentially Expressed Genes (DEGs) have been affiliated with novel cytotoxic, antigen presentation, and chemokine-cell migration signature pathways. CD8 + GZMK + T cells that are varied in nature, including CD161 + Mucosal-associated invariant T (MAIT) cells and CD161- aged-associated T (Taa) cells and CD161-GZMK + GZMB + T cells might account for a higher level of GZMK in CD8 + T cells associated with ESRD. SLE patients have higher TIGIT + , PD1 + , and lower CD127 + cell percentages on CD4 + T cells, higher TIM3 + , TIGIT + , HLA-DR + cell frequency, and lower MFI expression of CD127, CD160 in CD8 T cells. Co-IRs expression in T cells was correlated with soluble PD-1, PDL-2, and TIM3 levels, as well as SLE disease activity, clinical phenotypes, and immune-therapy responses. CONCLUSION: The signature of dysfunctional pathways defines a distinct immunity pattern in LN ESRD patients. Expression levels of Co-IRs in peripheral blood T cells and serum levels of soluble PD1/PDL-2/TIM3 can serve as biomarkers for evaluating clinical parameters and therapeutic responses.

People with genetic kidney diseases on kidney replacement therapy have different clinical outcomes compared to people with other kidney diseases.

Despite increasing awareness of genetic kidney disease prevalence, there is limited population-level information about long term outcomes of people with genetic kidney disease receiving kidney replacement therapy. This analysis included people who commenced kidney replacement therapy between 1989 and 2020 as recorded in the Australian and New Zealand Dialysis and Transplant registry. Genetic kidney diseases were subclassified as majority and minority monogenic. Non-genetic kidney diseases were included as the comparator group. Primary outcome measures were 10-year mortality and 10-year graft failure. Cox proportional hazard regression were used to calculate unadjusted and adjusted hazard ratios (AHRs) for primary outcomes. There were 59,231 people in the dialysis subgroup and 21,860 people in the transplant subgroup. People on dialysis with genetic kidney diseases had reduced 10-year mortality risk (majority monogenic AHR: 0.70, 95% CI 0.66-0.76; minority monogenic AHR 0.86, 95% CI 0.80-0.92). This reduced 10-year mortality risk continued after kidney transplantation (majority monogenic AHR: 0.82, 95% CI 0.71-0.93; minority monogenic AHR 0.80, 95% CI 0.68-0.95). Majority monogenic genetic kidney diseases were associated with reduced 10-year graft failure compared to minority monogenic genetic kidney diseases and other kidney diseases (majority monogenic AHR 0.69, 95% CI 0.59-0.79). This binational registry analysis identified that people with genetic kidney disease have different mortality and graft failure risks compared to people with other kidney diseases.

Case report: A novel R246L mutation in the LMX1B homeodomain causes isolated nephropathy in a large Chinese family.

BACKGROUND: Genetic factors contribute to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Advances in genetic testing have enabled the identification of hereditary kidney diseases, including those caused by LMX1B mutations. LMX1B mutations can lead to nail-patella syndrome (NPS) or nail-patella-like renal disease (NPLRD) with only renal manifestations. CASE PRESENTATION: The proband was a 13-year-old female who was diagnosed with nephrotic syndrome at the age of 6. Then she began intermittent hormone and drug therapy. When she was 13 years old, she was admitted to our hospital due to sudden chest tightness, which progressed to end-stage kidney disease (ESRD), requiring kidney replacement therapy. Whole-Exome Sequencing (WES) results suggest the presence of LMX1B gene mutation, c.737G > T, p.Arg246Leu. Tracing her family history, we found that her father, grandmother, uncle and 2 cousins all had hematuria, or proteinuria. In addition to the grandmother, a total of 9 members of the family performed WES. The members with kidney involved all carry the mutated gene. Healthy members did not have the mutated gene. It is characterized by co-segregation of genotype and phenotype. We followed the family for 9 year, the father developed ESRD at the age of 50 and started hemodialysis treatment. The rest patients had normal renal function. No extra-renal manifestations associated with NPS were found in any member of the family. CONCLUSIONS: This study has successfully identified missense mutation, c.737G > T (p.Arg246Leu) in the homeodomain, which appears to be responsible for isolated nephropathy in the studied family. The arginine to leucine change at codon 246 likely disrupts the DNA-binding homeodomain of LMX1B. Previous research has documented 2 types of mutations at codon R246, namely R246Q and R246P, which are known to cause NPLRD. The newly discovered mutation, R246L, is likely to be another novel mutation associated with NPLRD, thus expanding the range of mutations at the crucial renal-critical codon 246 that contribute to the development of NPLRD. Furthermore, our findings suggest that any missense mutation occurring at the 246th amino acid position within the homeodomain of the LMX1B gene has the potential to lead to NPLRD.

HLA-B*51 Frequency in Transplant Patients and Donors.

OBJECTIVES: HLA molecules play a crucial role in transplantation. The best treatment modality in patients with end-stage renal disease is renal transplant. HLA mismatches between patients and donors can prolong time for renal transplant therapy, reduce graft survival, and increase mortality. HLA region is the most polymorphic genetic region and is essential for antigen presentation. The main target of the recipient's immune system is HLA molecules on the surface of donor cells. HLA-B*51 is associated with Behcet disease, a rare multisystemic disease characterized by autoimmunity and inflammatory processes. In transplant recipients, inflammation and vasculitis are immunologic mechanisms that are responsible for damage of graft tissue. In this retrospective study, we aimed to investigate the frequency of HLA-B*51 in patients diagnosed with end-stage renal disease and in controls and to investigate correlations with rejection episodes. MATERIALS AND METHODS: Patients who applied to Baskent University Adana Dr. Turgut Noyan Research and Medical Center (between 2010 and 2022) with end-stage renal disease (n = 1732) and a control group (n = 5277) received HLA typing for class I (HLA-A, HLA-B). Sequence-specific primers or sequencespecific oligonucleotides were used. Among patients diagnosed with end-stage renal disease, 321 had kidney transplant. RESULTS: Frequency of HLA-B*51 was 25.92% in patients and 25.22% in controls. No significant differences were found between patients and controls in the frequency of HLA-B*51. Among kidney transplant recipients with HLA-B*51 (n = 72), 38.89% had rejection episodes and 61.11% had no rejection. No significant association was found between HLA-B*51 allele positivity and rejection. CONCLUSIONS: No significant relationship was shown between patients diagnosed with end-stage renal disease and HLA-B*51 positivity. Previous studies support frequency of the HLA-B*51 allele in the control group. Although Behçet disease is known to cause renal vasculitis, HLA-B*51 positivity alone was not associated with vasculitis or inflammation.

[Long-term auditory monitoring in children with Alport syndrome based on different degrees of renal injury].

Objective:To investigate long-term auditory changes and characteristics of Alport syndrome（AS） patients with different degrees of renal injury. Methods:Retrospectively analyzing clinical data of patients diagnosed AS from January 2007 to September 2022, including renal pathology, genetic detection and hearing examination. A long-term follow-up focusing on hearing and renal function was conducted. Results:This study included 70 AS patients, of which 33（25 males, 8 females, aged 3.4-27.8 years） were followed up, resulting in a loss rate of 52.9%.The follow-up period ranged from 1.1to 15.8 years, with 16 patients followed-up for over 10 years. During the follow-up, 10 patients presenting with hearing abnormalities at the time of diagnosis of AS had progressive hearing loss, and 3 patients with new hearing abnormalities were followed up, which appeared at 5-6 years of disease course. All of which were sensorineural deafness. While only 3 patients with hearing abnormalities among 13 patients received hearing aid intervention. Of these patients,7 developed end-stage renal disease（ESRD）, predominantly males （6/7）. The rate of long-term hearing loss was significantly different between ESRD group and non-ESRD group（P=0.013）. There was no correlation between the progression of renal disease and long-term hearing level（P>0.05）. kidney biopsies from 28 patients revealed varying degrees of podocyte lesion and uneven thickness of basement membrane. The severity of podocyte lesion was correlated with the rate of long-term hearing loss（P=0.048）, and there was no correlation with the severity of hearing loss（P>0.05）. Among 11 cases, theCOL4A5mutationwas most common （8 out of 11）, but there was no significant correlation between the mutation type and hearing phenotype（P>0.05）. Conclusion:AS patients exhibit progressive hearing loss with significant heterogeneity over the long-term.. THearing loss is more likely to occur 5-6 years into the disease course. Hearing abnormalities are closely related to renal disease status, kidney tissue pathology, and gene mutations, emphasizing the need for vigilant long-term hearing follow-up and early intervention.

G Protein Coupled Receptor 87 (GPR87) in End Stage Kidney and Associated Tumors.

BACKGROUND/AIM: End-stage renal disease (ESRD) and acquired cystic renal disease (ACRD) are characterized by progressive inflammation, structural remodeling and by development of unique cancer types. Eosinophilic-vacuolated and chromophobe-like renal cell carcinoma develop exclusively in ACRD kidney. The aim of the study was to investigate the molecular mechanism of ESRD/ACRD carcinogenesis. MATERIALS AND METHODS: Our previous Affymetrix array analysis detected GPR87 as one of the highly and specifically expressed genes in ESRD/ACRD kidneys. In this study we analyzed normal and ESRD/ACRD kidneys and related tumors for GPR87 expression by PCR, RT-PCR, and immunohistochemistry. RESULTS: Immunohistochemistry revealed a strong GPR87 expression in proliferating epithelial cells in ESRD/ACRD kidneys and in cells of eosinophilic-vacuolated and chromophobe-like renal cell carcinoma. CONCLUSION: GPR87 signaling plays an important role in the structural remodeling of ESRD/ACRD kidney and development of ACRD-associated tumors with unique histology.

Investigation of APE1 and OGG1 expression in chronic hemodialysis patients.

BACKGROUND: The role of DNA repair mechanisms is of significant importance in diseases characterized by elevated oxidative DNA damage, such as chronic kidney disease. It is imperative to thoroughly understand the functions of molecules associated with DNA repair mechanisms, not only for assessing susceptibility to diseases but also for monitoring disease progression. In this research, we investigated the APE1 and OGG1 gene expression levels, both of which are involved in the base excision repair (BER) mechanism in chronic hemodialysis patients with malignancy (HPM; n = 8) and without malignancy (HP; n = 36) in pre- and post-dialysis period and 37 healty persons. We also assessed how these values correlate with the clinical profiles of the patients. METHODS AND RESULTS: We conducted gene expression analysis using real-time polymerase chain reaction (qRT-PCR). No significant differences in APE1 gene expression levels were observed in pre-dialysis when comparing the HP and HPM groups to the control group. The expression levels of the OGG1 gene were significantly lower in both the HP and HPM groups in pre- and post-dialysis periods compared to the control group. Dialysis procedures led to a reduction in APE1 and OGG1 gene expression levels in both HP and HPM groups. CONCLUSIONS: The findings of our study elucidate the impact of alterations in the base excision repair (BER) mechanism, including the hemodialysis process, in end-stage renal disease (ESRD).

Familial focal segmental glomerulosclerosis associated with a WT1 gene missense mutation: A case report.

Focal s egmental glomerulosclerosis (F SGS) can cause protei nuria and loss o f k idney fun ction, leading to e ndstage renal di s ease (ESRD). Podocyte injury is the ce ntral pathophysiologi cal mechanis m of hereditary FSGS. Numerous mutations in genes e ncoding or affe cting the transcriptional regulation of podocyte cell compar tments have been detected in patients with genetic FSGS. Herein, we report a rare case of familial FSGS with an autosomal dominant WT1 mutation. A 63-year- old man developed pro teinuri a; his reading showed over 1g prote in/day. A pa thological diagn osis of FSG S was made after rena l biops y. H is elder brother an d a 36-year- old son also had ESRD. Heterozygous variant of WT1 (NM_024426.4) c.1373G>A (p.Arg458Gln ) mi s sense was dete cted in the patient a nd his son , by whole-exome sequen cing. Although genetic screening is not a par t of routine practice, it s hould be per for med in such cases to a id a ppropriate tre atment options sel ecting, revealing extra ren al symptoms, and family planning.

lncRNA FAS-AS1 served as a diagnostic biomarker of end-stage renal disease and mediated vascular calcification via regulating oxidative stress and inflammation.

PURPOSE: Vascular calcification is a frequently occurring complication of end-stage renal disease (ESRD). This study focused on the significance of long non-coding RNA Fas cell surface death receptor-antisense 1(lncRNA FAS-AS1) in ESRD-related vascular calcification aiming to explore a potential biomarker for the detection. METHODS: The study enrolled 65 healthy individuals, 79 ESRD patients (48 patients with vascular calcification), and 93 early-stage (I-IV) chronic kidney disease (CKD) patients. The expression of FAS-AS1 in serum was evaluated by real-time quantitative polymerase chain reaction (PCR). The diagnostic potential of FAS-AS1 was assessed in discriminating ESRD patients, vascular calcification, and the severity of vascular calcification. In vitro, the vascular smooth muscle cells (VSMCs) were treated with a hyperphosphatemia medium to evaluate the effect of FAS-AS1 on VSMCs calcification. RESULTS: Elevated serum FAS-AS1 was observed in ESRD patients, which could discriminate from healthy individuals and early-stage CKD patients. FAS-AS1 was associated with the development of ESRD and the occurrence of vascular calcification. FAS-AS1 was also upregulated in vascular calcification patients, especially the patients with severe calcification, which showed diagnostic significance in evaluating vascular calcification degrees. Calcified VSMCs showed significantly increased levels of Ca2+, reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6), which was attenuated by silencing FAS-AS1. CONCLUSIONS: FAS-AS1 discriminated ERSD patients and was associated with the occurrence of vascular calcification. The knockdown of FAS-AS1 suppressed hyperphosphatemia-induced vascular calcification via alleviating oxidative stress and inflammation.

Genetic Markers Among the Israeli Druze Minority Population With End-Stage Kidney Disease.

RATIONALE & OBJECTIVE: Genetic etiologies have been identified among approximately 10% of adults with chronic kidney disease (CKD). However, data are lacking regarding the prevalence of monogenic etiologies especially among members of minority groups. This study characterized the genetic markers among members of an Israeli minority group with end-stage kidney disease (ESKD). STUDY DESIGN: A national-multicenter cross-sectional study of Israeli Druze patients (an Arabic-speaking Near-Eastern transnational population isolate) who are receiving maintenance dialysis for ESKD. All study participants underwent exome sequencing. SETTING & PARTICIPANTS: We recruited 94 adults with ESKD, comprising 97% of the total 97 Druze individuals throughout Israel being treated with dialysis during the study period. PREDICTORS: Demographics and clinical characteristics of kidney disease. OUTCOME: Genetic markers. ANALYTICAL APPROACH: Whole-exome sequencing and the relationship of markers to clinical phenotypes. RESULTS: We identified genetic etiologies in 17 of 94 participants (18%). None had a previous molecular diagnosis. A novel, population-specific, WDR19 homozygous pathogenic variant (p.Cys293Tyr) was the most common genetic finding. Other monogenic etiologies included PKD1, PKD2, type IV collagen mutations, and monogenic forms of noncommunicable diseases. The pre-exome clinical diagnosis corresponded to the final molecular diagnosis in fewer than half of the participants. LIMITATIONS: This study was limited to Druze individuals, so its generalizability may be limited. CONCLUSIONS: Exome sequencing identified a genetic diagnosis in approximately 18% of Druze individuals with ESKD. These results support conducting genetic analyses in minority populations with high rates of CKD and for whom phenotypic disease specificity may be low. PLAIN-LANGUAGE SUMMARY: Chronic kidney disease (CKD) affects many people worldwide and has multiple genetic causes. However, there is limited information on the prevalence of genetic etiologies, especially among minority populations. Our national-multicenter study focused on Israeli Druze patients. Using exome-sequencing, we identified previously undetected genetic causes in nearly 20% of patients, including a new and population-specific WDR19 homozygous pathogenic variant. This mutation has not been previously described; it is extremely rare globally but is common among the Druze, which highlights the importance of studying minority populations with high rates of CKD. Our findings provide insights into the genetic basis of end-stage kidney disease in the Israeli Druze, expand the WDR19 phenotypic spectrum, and emphasize the potential value of genetic testing in such populations.

A nationwide survey of MYH9-related disease in Japan.

BACKGROUND: MYH9-related disease (MYH9-RD) is characterized by congenital macrothrombocytopenia, Döhle body-like granulocyte inclusions, and nephropathy, which may progress to end-stage kidney disease (ESKD). However, information on the effects of renin-angiotensin system (RAS) inhibitors on kidney survival is currently lacking and the outcomes of kidney replacement therapy (KRT) in MYH9-RD are largely unknown. METHODS: We conducted a cross-sectional nationwide survey by sending questionnaires to 145 institutions in Japan and analyzed data for 49 patients. RESULTS: The median patient age was 27 years. Genetic analysis was performed in 37 (76%) patients. Twenty-four patients (65%) had MYH9 variants affecting the motor domain of non-muscle myosin heavy chain-IIA, and these patients had poorer kidney survival than those with variants affecting the tail domain (P = 0.02). There was no significant difference in kidney survival between patients treated with and without RAS inhibitors. Hemodialysis and peritoneal dialysis were performed in 16 and 7 patients, respectively. There were no major bleeding complications during the perioperative period or during follow-up, except for one patient. Most of the 11 patients who underwent kidney transplantation required perioperative red cell concentrate transfusions, but there was no graft loss during the median posttransplant observational period of 2.0 (interquartile range, 1.3-6.8) years. CONCLUSION: Our study demonstrated no beneficial effect of RAS inhibitors on kidney function in patients with MYH9-RD, indicating the need for further studies with more patients. All modalities of KRT are feasible options for MYH9-RD patients who progress to ESKD, with adequate attention to bleeding complications.

INF2 and ROBO2 gene mutation in an Indian family with end stage renal failure and follow-up of renal transplantation.

BACKGROUND: Accurate genetic diagnosis of end-stage renal disease patients with a family history of renal dysfunction is very essential. It not only helps in proper prognosis, but becomes crucial in designating donor for live related renal transplant. We here present a case of family with deleterious mutations in INF2 and ROBO2 and its importance of genetic testing before preparing for kidney transplantation. CASE PRESENTATION: We report the case of a 29-year-female with end-stage renal disease and rapidly progressive renal failure. Mutational analysis revealed an Autosomal Dominant inheritance pattern and mutation in exon 4 of the INF2 gene (p. Thr215Ser) and exon 26 of the ROBO2 gene (p. Arg1371Cys). Her mother was diagnosed for CKD stage 4 with creatinine level of 4.3 mg/dL. Genetic variants (INF2 and ROBO2) identified in proband were tested in her sisters and mother. Her elder sister was positive for both heterozygous variants (INF2 and ROBO2). Her mother was positive for mutation in INF2 gene, and her donor elder sister did not showed mutation in INF2 gene and had mutation in ROBO2 gene without any clinical symptoms. CONCLUSION: This case report emphasize that familial genetic screening has allowed us in allocating the donor selection in family where family member had history of genetic defect of Chronic Kidney Disease. Information of the causative renal disorder is extremely valuable for risk-assessment and planning of kidney transplantation.

LncRNA H19: a novel player in the regulation of diabetic kidney disease.

Diabetic kidney disease (DKD), one of the most severe complications of diabetes mellitus (DM), has received considerable attention owing to its increasing prevalence and contribution to chronic kidney disease (CKD) and end-stage kidney disease (ESRD). However, the use of drugs targeting DKD remains limited. Recent data suggest that long non-coding RNAs (lncRNAs) play a vital role in the development of DKD. The lncRNA H19 is the first imprinted gene, which is expressed in the embryo and down-regulated at birth, and its role in tumors has long been a subject of controversy, however, in recent years, it has received increasing attention in kidney disease. The LncRNA H19 is engaged in the pathological progression of DKD, including glomerulosclerosis and tubulointerstitial fibrosis via the induction of inflammatory responses, apoptosis, ferroptosis, pyroptosis, autophagy, and oxidative damage. In this review, we highlight the most recent research on the molecular mechanism and regulatory forms of lncRNA H19 in DKD, including epigenetic, post-transcriptional, and post-translational regulation, providing a new predictive marker and therapeutic target for the management of DKD.

Histone deacetylase 9 exacerbates podocyte injury in hyperhomocysteinemia through epigenetic repression of Klotho.

Although hyperhomocysteinemia (hHcys) has been recognized as an important independent risk factor in the progression of end-stage renal disease and the development of cardiovascular complications related to end-stage renal disease, the mechanisms triggering pathogenic actions of hHcys are not fully understood. The present study was mainly designed to investigate the role of HDACs in renal injury induced by hHcys. Firstly, we identified the expression patterns of HDACs and found that, among zinc-dependent HDACs, HDAC9 was preferentially upregulated in the kidney from mice with hHcys. Deficiency or pharmacological inhibition of HDAC9 ameliorated renal injury in mice with hHcys. Moreover, podocyte-specific deletion of HDAC9 significantly attenuated podocyte injury and proteinuria. In vitro, gene silencing of HDAC9 attenuated podocyte injury by inhibiting apoptosis, reducing oxidative stress and maintaining the expressions of podocyte slit diaphragm proteins. Mechanically, we proved for the first time that HDAC9 reduced the acetylation level of H3K9 in the promoter of Klotho, then inhibited gene transcription of Klotho, finally aggravating podocyte injury in hHcys. In conclusion, our results indicated that targeting of HDAC9 might be an attractive therapeutic strategy for the treatment of renal injury induced by hHcys.

Autosomal Recessive Adolescent Syndromic Nephronophthisis Caused by a Novel Compound Heterozygous Pathogenic Variant.

BACKGROUND Nephronophthisis, an autosomal recessive ciliopathy involving mutations in primary cilium genes, is characterized by chronic tubulointerstitial nephritis and a defective urine concentrating capacity. It accounts for about 5% of renal failure in children and adolescents and usually progresses to end-stage renal disease before the age of 30 years. Nephronophthisis is associated with extrarenal manifestations, including retinitis pigmentosa in Senior-Loken syndrome (SLS), and liver fibrosis in 10-20% of cases. While some presenting patterns could be characteristic, patients may have atypical presentation, making diagnosis difficult. Tubulointerstitial fibrosis is the predominant feature on histology and as such, diagnosis depends mostly on genetic testing. Despite advances in renal genomics over the years with a better understanding of primary cilia and ciliary theory, about 40% of nephronophthisis cases go undiagnosed. As the underlying genetic etiologies are not fully understood, morphologic pathologic findings are non-specific, and treatment options are limited to dialysis and transplantation. CASE REPORT We describe a unique case of a patient with adolescent nephronophthisis who presented with advanced chronic kidney disease and severe pancytopenia, who progressed to end-stage renal disease at the age of 19, and was found to have syndromic nephronophthisis with compound heterozygous inheritance. CONCLUSIONS This report highlights the atypical presentation patterns that can be seen in syndromic nephronophthisis, the importance of genetic diagnosis when there is a high index of suspicion, and the need to further study genetic variants to better understand and diagnose the disease and to develop targeted therapy.

Case series and literature review of primary hyperoxaluria type 1 in Chinese patients.

Based on the single-center case reports and all reported patients with primary hyperoxaluria type 1 (PH1) in China, this study discussed the clinical and genetic characteristics of this disease retrospectively. We reported and validated a novel genetic variation c.302 T > G: the clinical phenotypes of the two siblings were similar, in which both had onset in infancy, mainly manifested as renal insufficiency, and died within 6 months out of end-stage renal disease. The literature review is the first to summarize the Chinese patients with PH1 up to now. Forty-eight Chinese patients were included, containing 7 adults and 41 children. The median onset age was 51 months, and the ratio of male to female was 2.69:1. It showed a poor prognosis: 51.1% of Chinese primary hyperoxaluria type 1 patients suffered from end-stage renal disease, and 38.9% of patients died. Urolithiasis was the most common clinical manifestation both in adults and children, while infant-onset patients generally presented with renal insufficiency and had a higher mortality of 75.0%. One hundred and forty-nine AGXT mutant alleles are currently known in the Chinese population, c.33dupC and c.815_816insGA were the most common AGXT genes, accounting for 12.0% and 10.1% of allele frequencies, respectively. The exons 1, 2, 6, and 8 were the most common locations of gene variants, accounting for 78% of all variants, which will be promising targets of DNA sequencing for primary hyperoxaluria type 1.

APOL1 Gene Variants and Risk for Cardiovascular Disease.

INTRODUCTION: The association of APOL1 risk variants with cardiovascular risk and cardiovascular disease (CVD) in observational and clinical trials has had inconsistent results. We aim to assess the relationship between the presence of APOL1 risk variants and the CVD risk in Afro-descendant patients with end-stage renal disease (ESRD). METHODS: We performed an observational, cross-sectional study of Afro-descendant adult patients with ESRD who were on the waitlist for a kidney transplant. Associations of APOL1 genotypes (high-risk [HR] = 2 alleles; low-risk [LR] = 0 or 1 allele) with cardiovascular risk were the primary clinical endpoint. The relation was evaluated using univariate and multivariate analysis. RESULTS: We enrolled a total of 102 patients with ESRD; 37% (38 patients) had APOL1 HR status with two alleles in homozygous (G1/G1 = 21 and G2/G2 = 3) or compound heterozygote (G1/G2 = 14) form and 63% (64 patients) had APOL1 LR status. No significant association was found between HR APOL1 genotypes and high cardiovascular risk (in adjusted Colombia Framingham Risk Score). APOL1 HR versus LR variants were not independently associated with left ventricular hypertrophy or systolic dysfunction. No cardiovascular deaths occurred during the follow-up. CONCLUSION: In Afro-descendent patients with ESRD, APOL1 HR status is not associated with the increase in cardiovascular risk profile and metabolic disturbances.

Association between Human Leukocyte Antigen and End-Stage Renal Disease in Patients from Transylvania, Romania.

End-stage renal disease (ESRD) is the final stage of chronic kidney disease. This study explored the association between human leukocyte antigen (HLA) and ESRD. The interaction between genetic and environmental factors may also play a role in the development of ESRD. The study included 2392 ESRD patients who were awaiting renal transplantation. Blood samples were genotyped by SSOP and SSP-PCR methods. Multivariate logistic regression analysis showed that HLA-A*11 (p = 0.027), HLA-A*34 (p = 0.017), HLA-A*69 (p = 0.012), HLA-B*41 (p < 0.001), HLA-B*50 (p = 0.004), HLA-DRB1*10 (p = 0.027), and HLA-DRB1*14 (p = 0.004) were positively associated with ESRD (OR > 1); HLA-DRB1*07 (p < 0.001), HLA-DRB1*08 (p = 0.005), and HLA-DRB1*13 (p < 0.001) were protective against ESRD (OR < 1); and the three-locus haplotype HLA-A*02-B*41-DRB1*03, containing one susceptible allele, was strongly associated with ESRD (p < 0.001, OR = 3.15). In conclusion, this retrospective analysis of HLA typing in patients with ESRD of various etiologies suggests that molecular data on the HLA polymorphism should be collected in order to identify high-risk ESRD patients and to improve graft survival after kidney transplantation.

Puerarin alleviates chronic renal failure-induced pyroptosis in renal tubular epithelial cells by targeting miR-342-3p/TGF-ß/SMAD axis.

BACKGROUND: Chronic renal failure (CRF) is the result of kidney damage. Puerarin is a flavonoid with specific nephroprotective effect, but its effect on CRF needs further research. This study explored the effect of puerarin on CRF and the potential molecular mechanism. METHODS: Adenine was used to establish an in vivo CRF model in rats, and rats were intragastrically administered with puerarin at a dose of 400 mg/kg body weight once a day from day 1 to day 28. Hematoxylin and eosin (HE) and Masson staining were used to observe the morphology and fibrosis of kidney tissue. Lipopolysaccharide (LPS) (400 ng/mL)/H2O2 (200 µM) was applied to human kidney 2 (HK-2) cells to construct an in vitro CRF model. Enzyme-linked immunosorbent assay (ELISA) was performed to validate interleukin (IL)-1ß and IL-18 levels. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was performed to detect microRNA (miR)-342-3p levels. Transforming growth factor beta (TGF-ß)1, SMAD2, SMAD3, and pyroptosis marker proteins were detected by Western blot. The interaction between miR-342-3p and TGF-ß/SMAD was determined by a dual-luciferase reporter gene assay. Cell Counting Kit-8 (CCK-8) assay was utilized to determine cell viability. RESULTS: In the CRF model, puerarin alleviated renal injury and fibrosis and reduced creatinine (Cr) and blood urea nitrogen (BUN) levels. At the same time, miR-342-3p was downregulated, while the TGF-ß/SMAD axis was activated and levels of IL-1ß and IL-18 were increased. After treatment of CRF rats with puerarin, the expression level of miR-342-3p was increased, the TGF-ß/SMAD axis was inhibited, and the secretion of IL-1ß and IL-18 was decreased. MiR-342-3p directly bound to and negatively regulated the expression of TGF-ß1, SMAD2, and SMAD3. In the in vitro CRF model, miR-342-3p inhibited HK-2 cell pyroptosis by inhibiting the TGF-ß/SMAD axis. CONCLUSION: Puerarin reduced renal injury and pyroptosis in CRF rats by targeting the miR-342-3p/TGF-ß/SMAD axis.