Browsing by Author "Stajic, Natasa (6602606131)"

Individuals with congenital anomalies of the kidney and urinary tract (CAKUT) show a broad spectrum of malformations. CAKUT can occur in an isolated fashion or as part of a syndromic disorder and can lead to end-stage kidney failure. A monogenic cause can be identified in ~12% of affected individuals. This study investigated a single-center CAKUT cohort analyzed by exome sequencing (ES). Emphasis was placed on the question whether diagnostic yield differs between certain CAKUT phenotypes (e.g., bilateral kidney affection, unilateral kidney affection or only urinary tract affection). 86 unrelated individuals with CAKUT were categorized according to their phenotype and analyzed by ES to identify a monogenic cause. Prioritized variants were rated according to the recommendations of the American College of Medical Genetics and Genomics and the Association for Clinical Genomic Science. Diagnostic yields of different phenotypic categories were compared. Clinical data were collected using a standardized questionnaire. In the study cohort, 7/86 individuals had a (likely) pathogenic variant in the genes PAX2, PBX1, EYA1, or SALL1. Additionally, in one individual, a 17q12 deletion syndrome (including HNF1B) was detected. 64 individuals had a kidney affection, which was bilateral in 36. All solved cases (8/86, 9%) had bilateral kidney affection (diagnostic yield in subcohort: 8/36, 22%). Although the diagnostic yield in CAKUT cohorts is low, our single-center experience argues, that, in individuals with bilateral kidney affection, monogenic burden is higher than in those with unilateral kidney or only urinary tract affection. © 2023, The Author(s).

Individuals with congenital anomalies of the kidney and urinary tract (CAKUT) show a broad spectrum of malformations. CAKUT can occur in an isolated fashion or as part of a syndromic disorder and can lead to end-stage kidney failure. A monogenic cause can be identified in ~12% of affected individuals. This study investigated a single-center CAKUT cohort analyzed by exome sequencing (ES). Emphasis was placed on the question whether diagnostic yield differs between certain CAKUT phenotypes (e.g., bilateral kidney affection, unilateral kidney affection or only urinary tract affection). 86 unrelated individuals with CAKUT were categorized according to their phenotype and analyzed by ES to identify a monogenic cause. Prioritized variants were rated according to the recommendations of the American College of Medical Genetics and Genomics and the Association for Clinical Genomic Science. Diagnostic yields of different phenotypic categories were compared. Clinical data were collected using a standardized questionnaire. In the study cohort, 7/86 individuals had a (likely) pathogenic variant in the genes PAX2, PBX1, EYA1, or SALL1. Additionally, in one individual, a 17q12 deletion syndrome (including HNF1B) was detected. 64 individuals had a kidney affection, which was bilateral in 36. All solved cases (8/86, 9%) had bilateral kidney affection (diagnostic yield in subcohort: 8/36, 22%). Although the diagnostic yield in CAKUT cohorts is low, our single-center experience argues, that, in individuals with bilateral kidney affection, monogenic burden is higher than in those with unilateral kidney or only urinary tract affection. © 2023, The Author(s).

Acute kidney injury caused by ischemia and subsequent reperfusion is associated with a high rate of mortality and morbidity. Ischemia/reperfusion injury in kidney transplantation causes delayed graft function and is associated with more frequent episodes of acute rejection and progression to chronic allograft nephropathy. Alloantigen-independent inflammation is an important process, participating in pathogenesis of injurious response, caused by ischemia and reperfusion. This innate immune response is characterized by the activity of classical cells belonging to the immune system, such as neutrophils, macrophages, dendritic cells, lymphocytes, and also tubular epithelial cells and endothelial cells. These immune cells not only participate in inflammation after ischemia exerting detrimental influence but also play a protective role in the healing response from ischemia/reperfusion injury. Delineating of complex mechanisms of their actions could be fruitful in future prevention and treatment of ischemia/reperfusion injury. Among numerous so far conducted experiments, observed immunomodulatory role of adenosine and adenosine receptor agonists in complex interactions of dendritic cells, natural killer T cells, and T regulatory cells is emphasized as promising in the treatment of kidney ischemia/reperfusion injury. Potential pharmacological approaches which decrease NF-κB activity and antagonize mechanisms downstream of activated Toll-like receptors are discussed. © 2017 Aleksandra Kezić et al.

Acute kidney injury caused by ischemia and subsequent reperfusion is associated with a high rate of mortality and morbidity. Ischemia/reperfusion injury in kidney transplantation causes delayed graft function and is associated with more frequent episodes of acute rejection and progression to chronic allograft nephropathy. Alloantigen-independent inflammation is an important process, participating in pathogenesis of injurious response, caused by ischemia and reperfusion. This innate immune response is characterized by the activity of classical cells belonging to the immune system, such as neutrophils, macrophages, dendritic cells, lymphocytes, and also tubular epithelial cells and endothelial cells. These immune cells not only participate in inflammation after ischemia exerting detrimental influence but also play a protective role in the healing response from ischemia/reperfusion injury. Delineating of complex mechanisms of their actions could be fruitful in future prevention and treatment of ischemia/reperfusion injury. Among numerous so far conducted experiments, observed immunomodulatory role of adenosine and adenosine receptor agonists in complex interactions of dendritic cells, natural killer T cells, and T regulatory cells is emphasized as promising in the treatment of kidney ischemia/reperfusion injury. Potential pharmacological approaches which decrease NF-κB activity and antagonize mechanisms downstream of activated Toll-like receptors are discussed. © 2017 Aleksandra Kezić et al.

Alport syndrome (AS) shows a broad phenotypic spectrum ranging from isolated microscopic hematuria (MH) to end-stage kidney disease (ESKD). Monoallelic disease-causing variants in COL4A3/COL4A4 have been associated with autosomal dominant AS (ADAS) and biallelic variants with autosomal recessive AS (ARAS). The aim of this study was to analyze clinical and genetic data regarding a possible genotype–phenotype correlation in individuals with disease-causing variants in COL4A3/COL4A4. Eighty-nine individuals carrying at least one COL4A3/COL4A4 variant classified as (likely) pathogenic according to the American College of Medical Genetics guidelines and current amendments were recruited. Clinical data concerning the prevalence and age of first reported manifestation of MH, proteinuria, ESKD, and extrarenal manifestations were collected. Individuals with monoallelic non-truncating variants reported a significantly higher prevalence and earlier diagnosis of MH and proteinuria than individuals with monoallelic truncating variants. Individuals with biallelic variants were more severely affected than those with monoallelic variants. Those with biallelic truncating variants were more severely affected than those with compound heterozygous non-truncating/truncating variants or individuals with biallelic non-truncating variants. In this study an association of heterozygous non-truncating COL4A3/COL4A4 variants with a more severe phenotype in comparison to truncating variants could be shown indicating a potential dominant-negative effect as an explanation for this observation. The results for individuals with ARAS support the, still scarce, data in the literature. © 2024 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.

Alport syndrome (AS) shows a broad phenotypic spectrum ranging from isolated microscopic hematuria (MH) to end-stage kidney disease (ESKD). Monoallelic disease-causing variants in COL4A3/COL4A4 have been associated with autosomal dominant AS (ADAS) and biallelic variants with autosomal recessive AS (ARAS). The aim of this study was to analyze clinical and genetic data regarding a possible genotype–phenotype correlation in individuals with disease-causing variants in COL4A3/COL4A4. Eighty-nine individuals carrying at least one COL4A3/COL4A4 variant classified as (likely) pathogenic according to the American College of Medical Genetics guidelines and current amendments were recruited. Clinical data concerning the prevalence and age of first reported manifestation of MH, proteinuria, ESKD, and extrarenal manifestations were collected. Individuals with monoallelic non-truncating variants reported a significantly higher prevalence and earlier diagnosis of MH and proteinuria than individuals with monoallelic truncating variants. Individuals with biallelic variants were more severely affected than those with monoallelic variants. Those with biallelic truncating variants were more severely affected than those with compound heterozygous non-truncating/truncating variants or individuals with biallelic non-truncating variants. In this study an association of heterozygous non-truncating COL4A3/COL4A4 variants with a more severe phenotype in comparison to truncating variants could be shown indicating a potential dominant-negative effect as an explanation for this observation. The results for individuals with ARAS support the, still scarce, data in the literature. © 2024 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.

Congenital anomalies of the kidney and urinary tract (CAKUT) account for approximately 40% of children with ESRD in the United States. Hitherto, mutations in 23 genes have been described as causing autosomal dominant isolated CAKUT in humans. However, .>90% of cases of isolated CAKUT still remain without a molecular diagnosis. Here, we hypothesized that genes mutated in recessive mouse models with the specific CAKUT phenotype of unilateral renal agenesis may also be mutated in humans with isolated CAKUT. We applied next-generation sequencing technology for targeted exon sequencing of 12 recessive murine candidate genes in574 individuals with isolated CAKUT from 590 families. In 15 of 590 families, we identified recessive mutations in the genes FRAS1, FREM2, GRIP1, FREM1, ITGA8, and GREM1, all of which function in the interaction of the ureteric bud and the metanephric mesenchyme. We show that isolated CAKUT may be caused partially by mutations in recessive genes. Our results also indicate that biallelic missense mutations in the Fraser/MOTA/BNAR spectrum genes cause isolated CAKUT, whereas truncating mutations are found in the multiorgan form of Fraser syndrome. The newly identified recessive biallelic mutations in these six genes represent the molecular cause of isolated CAKUT in 2.5% of the 590 affected families in this study. © 2014 by the American Society of Nephrology.