Genetics in kidney disease in 2013: Susceptibility genes for renal and urological disorders.
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ABSTRACT:
SUBMITTER: Divers J
PROVIDER: S-EPMC4003456 | biostudies-literature | 2014 Feb
REPOSITORIES: biostudies-literature
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Project description:Purpose of reviewThis paper reviews recent efforts to identify genetic variants conferring risk for chronic kidney disease. A brief overview of methods for identifying gene variants is provided, along with genetic associations and new avenues under exploration.Recent findingsThe role of renal failure susceptibility genes, including MYH9, ELMO1, UMOD and ACTN4, has become clearer over the past 18 months. The spectrum of MYH9-associated kidney disease, including focal segmental glomerulosclerosis, global glomerulosclerosis and collapsing glomerulopathy, related entities contributing to approximately 43% of end-stage renal disease in African-Americans, has come to light.SummaryMYH9 will re-categorize focal segmental glomerulosclerosis and related disorders, and has clarified the relationship between hypertension and kidney disease. MYH9 polymorphisms account for much of the excess risk of HIV-associated nephropathy and nondiabetic kidney disease in African-Americans. Kidney disease associations with ELMO1 and UMOD have been replicated and applications of genome-wide association studies based on expression data are providing novel insights on renal protein expression. These breakthroughs will alter our approach to kidney disease surveillance and lead to new therapeutic options.
| S-EPMC2883259 | biostudies-literature
Project description:Nephronophthisis (NPHP) is a renal ciliopathy and an autosomal recessive cause of cystic kidney disease, renal fibrosis, and end-stage renal failure, affecting children and young adults. Molecular genetic studies have identified more than 20 genes underlying this disorder, whose protein products are all related to cilia, centrosome, or mitotic spindle function. In around 15% of cases, there are additional features of a ciliopathy syndrome, including retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders. Alongside, gene identification has arisen molecular mechanistic insights into the disease pathogenesis. The genetic causes of NPHP are discussed in terms of how they help us to define treatable disease pathways including the cyclic adenosine monophosphate pathway, the mTOR pathway, Hedgehog signaling pathways, and DNA damage response pathways. While the underlying pathology of the many types of NPHP remains similar, the defined disease mechanisms are diverse, and a personalized medicine approach for therapy in NPHP patients is likely to be required.
| S-EPMC5770800 | biostudies-other
Project description:BACKGROUND:Urological malignancy (UM) in patients with chronic kidney disease (CKD) is an added burden to their overall morbidity and mortality. UM is itself a common cause of CKD. Understanding the associations of UM with outcomes in advanced CKD can help in optimisation of the management of these patients. This study investigates the distribution and association of urological malignancy with outcomes (renal progression and mortality) in patients with advanced non-dialysis dependent CKD. METHODS:The study was conducted in 2637 of 3115 patients recruited in the Salford Kidney Study between the years 2002 and 2016. A comparative analysis was performed between 160 patients with UM (at baseline and incident) and 2477 patients with no malignancy. Cox-regression models and Kaplan-Meir estimates were used to explore the association between the presence of UM with mortality and renal outcome. Linear regression analysis was used to calculate the rate of progression of CKD in the groups. A 1:3 propensity score matched cohort of 640 patients was generated and utilised in the above analyses. RESULTS:4.4% had a history of UM at baseline with the annual incident rate being 0.37%. The site of malignancy was the kidney in 40% with comparable numbers for prostatic malignancy (39%). 70% (111/160) of UM patients had a medical cause as their primary diagnosis for CKD. Over a median follow up of 4?years, 34% (905) patients died. In the matched sample, the proportion of deaths was similar between the groups (UM 44% versus no malignancy 48%, p?=?0.36). 30% reached end-stage renal disease (ESRD) with no difference between the groups. In the Cox-regression model, UM did not prove to be a risk factor associated with either all-cause mortality (HR:1.03; CI: 0.79-1.35; p?=?0.81) or reaching ESRD (HR:1.12; CI: 0.80-1.58; p?=?0.49). The rate of decline in estimated glomerular filtration rate (eGFR) was similar between the groups (-?1.05 vs -?1.25?mL/min/1.73m2/year, p?=?0.31). CONCLUSIONS:There was no correlation observed between UM and all-cause mortality or ESRD. Medical causes of CKD have a significant influence on the outcomes in patients with UM, whereas the UM did not. Hence, a coordinated approach with early liaison between the urology and nephrology teams is needed in the management of UM patients with CKD.
| S-EPMC7257121 | biostudies-literature
Project description:Preterm birth results in low nephron endowment and increased risk of acute kidney injury (AKI) and chronic kidney disease (CKD). To understand the pathogenesis of AKI and CKD in preterm humans, we generated potentially novel mouse models with a 30%-70% reduction in nephron number by inhibiting or deleting Ret tyrosine kinase in the developing ureteric bud. These mice developed glomerular and tubular hypertrophy, followed by the transition to CKD, recapitulating the renal pathological changes seen in humans born preterm. We injected neonatal mice with gentamicin, a ubiquitous nephrotoxic exposure in preterm infants, and detected more severe proximal tubular injury in mice with low nephron number compared with controls with normal nephron number. Mice with low nephron number had reduced proliferative repair with more rapid development of CKD. Furthermore, mice had more profound inflammation with highly elevated levels of MCP-1 and CXCL10, produced in part by damaged proximal tubules. Our study directly links low nephron endowment with postnatal renal hypertrophy, which in this model is maladaptive and results in CKD. Underdeveloped kidneys are more susceptible to gentamicin-induced AKI, suggesting that AKI in the setting of low nephron number is more severe and further increases the risk of CKD in this vulnerable population.
| S-EPMC9977438 | biostudies-literature
Project description:The complement-mediated renal diseases are a group of ultra-rare renal diseases that disproportionately affect children and young adults and frequently lead to irreversible renal failure. Genetic mutations in alternate pathway of complement genes are pathomechanistically involved in a significant number of these unique diseases. Here, we review our current understanding of the role of genetics in the primary complement-mediated renal diseases affecting children, with a focus on atypical hemolytic uremic syndrome and C3 glomerulopathy. Also, included is a brief discussion of the related diseases whose relationship to complement abnormality has been suspected but not yet confirmed. Advances in genetics have transformed both treatment and outcomes in these historically difficult to treat, highly morbid diseases.
| S-EPMC4918710 | biostudies-literature
Project description:Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
| S-EPMC3839542 | biostudies-literature
Project description:The spectrum of lipid disorders in chronic kidney disease (CKD) is usually characterized by high triglycerides and reduced high dense lipoprotein (HDL), associated with normal or slightly reduced low dense lipoprotein (LDL)-cholesterol. This dyslipidemia is associated with an increased risk for atherosclerotic cardiovascular disease. Keys for the cardiovascular risk reduction in these patients are lowering the number and modifying the composition of the cholesterol-carrying atherogenic lipoprotein particles. Statins have an important role in primary prevention of cardiovascular events and mortality in non-hemodialyzed CKD patients. The benefits in terms of progression of renal failure are contradictory. Patient education regarding dietary regimen should be part of the CKD clinical management.
| S-EPMC5644460 | biostudies-other
Project description:Studies have shown that as many as 1 in 10 adults with chronic kidney disease has a monogenic form of disease. However, genetic services in adult nephrology are limited. An adult Kidney Genetics Clinic was established within the nephrology division at a large urban academic medical center to increase access to genetic services and testing in adults with kidney disease. Between June 2019 and December 2021, a total of 363 patients were referred to the adult Kidney Genetics Clinic. Of those who completed genetic testing, a positive diagnostic finding was identified in 27.1%, a candidate diagnostic finding was identified in 6.7% of patients, and a nondiagnostic positive finding was identified in an additional 8.6% of patients, resulting in an overall yield of 42.4% for clinically relevant genetic findings in tested patients. A genetic diagnosis had implications for medical management, family member testing, and eligibility for clinical trials. With the utilization of telemedicine, genetic services reached a diverse geographic and patient population. Genetic education efforts were integral to the clinic's success, as they increased visibility and helped providers identify appropriate referrals. Ongoing access to genomic services will remain a fundamental component of patient care in adults with kidney disease.
| S-EPMC10360161 | biostudies-literature
Project description:Osteopontin (OPN), encoded by SPP1, is a phosphorylated glycoprotein predominantly synthesized in kidney tissue. Increased OPN mRNA and protein expression correlates with proteinuria, reduced creatinine clearance, and kidney fibrosis in animal models of kidney disease. But its genetic underpinnings are incompletely understood. We therefore conducted a genome-wide association study (GWAS) of OPN in a European chronic kidney disease (CKD) population. Using data from participants of the German Chronic Kidney Disease (GCKD) study (N = 4,897), a GWAS (minor allele frequency [MAF]≥1%) and aggregated variant testing (AVT, MAF<1%) of ELISA-quantified serum OPN, adjusted for age, sex, estimated glomerular filtration rate (eGFR), and urinary albumin-to-creatinine ratio (UACR) was conducted. In the project, GCKD participants had a mean age of 60 years (SD 12), median eGFR of 46 mL/min/1.73m2 (p25: 37, p75: 57) and median UACR of 50 mg/g (p25: 9, p75: 383). GWAS revealed 3 loci (p<5.0E-08), two of which replicated in the population-based Young Finns Study (YFS) cohort (p<1.67E-03): rs10011284, upstream of SPP1 encoding the OPN protein and related to OPN production, and rs4253311, mapping into KLKB1 encoding prekallikrein (PK), which is processed to kallikrein (KAL) implicated through the kinin-kallikrein system (KKS) in blood pressure control, inflammation, blood coagulation, cancer, and cardiovascular disease. The SPP1 gene was also identified by AVT (p = 2.5E-8), comprising 7 splice-site and missense variants. Among others, downstream analyses revealed colocalization of the OPN association signal at SPP1 with expression in pancreas tissue, and at KLKB1 with various plasma proteins in trans, and with phenotypes (bone disorder, deep venous thrombosis) in human tissue. In summary, this GWAS of OPN levels revealed two replicated associations. The KLKB1 locus connects the function of OPN with PK, suggestive of possible further post-translation processing of OPN. Further studies are needed to elucidate the complex role of OPN within human (patho)physiology.
| S-EPMC9015153 | biostudies-literature
Project description:A tight interplay of genetic predisposition and environmental factors define the onset and the rate of progression of chronic renal disease. We are seeing a rapid expansion of information about genetic loci associated with kidney function and complex renal disease. However, discovering the functional links that bridge the gap from genetic risk loci to disease phenotype is one of the main challenges ahead. Risk loci are currently assigned to a putative context using the functional annotation of the closest genes via a guilt-by-proximity approach. These approaches can be extended by strategies integrating genetic risk loci with kidney-specific, genome-wide gene expression. Risk loci-associated transcripts can be assigned a putative disease-specific function using gene expression coregulation networks. Ultimately, genotype-phenotype dependencies postulated from these associative approaches in humans need to be tested via genetic modification in model organisms. In this review, we survey strategies that employ human tissue-specific expression and the use of model organisms to identify and validate the functional relationship between genotype and phenotype in renal disease. Strategies to unravel how genetic risk and environmental factors orchestrate renal disease manifestation can be the first steps toward a more integrated, holistic approach urgently needed for chronic renal diseases.
| S-EPMC4224965 | biostudies-literature