Genetic testing for kidney disease of unknown etiology.
Ontology highlight
ABSTRACT:
SUBMITTER: Hays T
PROVIDER: S-EPMC7784921 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
Publications
Genetic testing for kidney disease of unknown etiology.
Hays Thomas T Groopman Emily E EE Gharavi Ali G AG
Kidney international 20200424 3
In many cases of chronic kidney disease, the cause of disease remains unknown despite a thorough nephrologic workup. Genetic testing has revolutionized many areas of medicine and promises to empower diagnosis and targeted management of such cases of kidney disease of unknown etiology. Recent studies using genetic testing have demonstrated that Mendelian etiologies account for approximately 20% of cases of kidney disease of unknown etiology. Although genetic testing has significant benefits, incl ...[more]
Similar Datasets
Project description:Genetic testing is increasingly used in the workup and diagnosis of kidney disease and kidney-related disorders of undetermined cause. Out-of-pocket costs for clinical genetic testing have become affordable, and logistical hurdles overcome. The interest in genetic testing may stem from the need to make or confirm a diagnosis, guide management, or the patient's desire to have a more informed explanation or prognosis. This poses a challenge for providers who do not have formal training in the selection, interpretation, and limitations of genetic tests. In this manuscript, we provide detailed discussion of relevant cases in which clinical genetic testing using a kidney gene panel was applied. The cases demonstrate identification of pathogenic variants for monogenic diseases-contrasting them from genetic risk alleles-and bring up diagnostic limitations and diagnostic utility of these tests in nephrology. This review aims to guide clinicians in formulating pretest conversations with their patients, interpreting genetic variant nomenclature, and considering follow-up investigations. Although providers are gaining experience, there is still risk of testing causing more anxiety than benefit. However, with provider education and support, clinical genetic testing applied to otherwise unexplained kidney-related disorders will increasingly serve as a valuable diagnostic tool with the potential to reshape how we consider and treat many kidney-related diagnoses.
| S-EPMC9528385 | biostudies-literature
Project description:IntroductionPrevious studies have suggested that genetic kidney diseases in adults are often overlooked, representing up to 10% of all cases of chronic kidney disease (CKD). We present data obtained from exome sequencing (ES) analysis of patients with biopsy-proven undetermined kidney disease (UKD).MethodsES was proposed during routine clinical care in patients with UKD from January 2020 to December 2021. We used in silico custom kidney genes panel analysis to detect pathological variations using American College of Medical Genetics guidelines in 52 patients with biopsy-proven UKD with histological finding reassessment.ResultsWe detected 12 monogenic renal disorders in 21 (40.4%) patients. The most common diagnoses were collagenopathies (8/21,38.1%), COL4A3 and COL4A4 accounting for 80% of these diagnoses, and ciliopathies (5/21, 23.8%). The diagnostic yield of ES was higher in female patients and patients with a family history of kidney disease (57.1% and 71%, respectively). Clinical nephropathy categories matched with the final genetic diagnoses in 72.7% of cases, whereas histological renal lesions matched with the final diagnoses in 92.3% of cases. The genetics diagnoses and histopathological findings were in complete agreement for both glomerular and tubulointerstitial cases. Interstitial inflammation without tubulitis was only observed in tubulopathies or ciliopathies. Isolated CKD, CKD with proteinuria or hematuria, and isolated proteinuria or hematuria yielded the highest diagnostic yields (54.6%, 52.6%, and 42.9%, respectively).ConclusionES done in patients with biopsy-proven UKD should be considered as a first-line tool for CKD patients with a family history of kidney disease. Combination of ES and kidney biopsy may have major impacts on kidney disease ontology.
| S-EPMC10577324 | biostudies-literature
Project description:The main causes of chronic kidney disease (CKD) globally are diabetes and hypertension but epidemics of chronic kidney disease of unknown etiology (CKDu) occur in Central America, Sri Lanka, India and beyond. Althoug also being observed in women, CKDu concentrates among men in agricultural sectors. Therefore, suspicions fell initially on pesticide exposure, but currently chronic heat stress and dehydration are considered key etiologic factors. Responding to persistent community and scientific concerns about the role of pesticides, we performed a systematic review of epidemiologic studies that addressed associations between any indicator of pesticide exposure and any outcome measure of CKD. Of the 21 analytical studies we identified, seven were categorized as with low, ten with medium and four with relatively high explanation value. Thirteen (62%) studies reported one or more positive associations, but four had a low explanation value and three presented equivocal results. The main limitations of both positive and negative studies were unspecific and unquantified exposure measurement ('pesticides'), the cross-sectional nature of most studies, confounding and selection bias. The four studies with stronger designs and better exposure assessment (from Sri Lanka, India and USA) all showed exposure-responses or clear associations, but for different pesticides in each study, and three of these studies were conducted in areas without CKDu epidemics. No study investigated interactions between pesticides and other concommittant exposures in agricultural occupations, in particular heat stress and dehydration. In conclusion, existing studies provide scarce evidence for an association between pesticides and regional CKDu epidemics but, given the poor pesticide exposure assessment in the majority, a role of nephrotoxic agrochemicals cannot be conclusively discarded. Future research should procure assessment of lifetime exposures to relevant specific pesticides and enough power to look into interactions with other major risk factors, in particular heat stress.
| S-EPMC5442867 | biostudies-literature
Project description:2 mL of preserved urine samples were precipitated overnight with 5 mL of ice-cold acetone, pellets were washed 70% acetone resuspended in 5% SDS followed by trypsin digestion of up to 100 ugs of each sample using an S-trap. One-third of tryptic peptides were microflow LC-MS/MS using an ACQUITY UPLC interfaced to an Exploris 480 high resolution mass spectrometer. After direct injection, peptides were separated on a 1 mm x 10 mm 1.7 micron ACQUITY Premier charged surface hybrid (CSH) C18 column (Waters Corp) using a flow rate of 100 microliters/min, and the DIA analysis was performed using a staggered, overlapping window method with a MS2 mass range of 400-1000, 30,000 resolution and 45 x 28 m/z windows. Direct-DIA searches and peptide/protein quantification was performed using Spectronaut 15.
2022-10-11 | MSV000090513 | MassIVE
Project description:(1) Background: Despite ample research, the factors, specific causes, and pathways associated with chronic kidney disease of unknown etiology (CKDu) remain elusive. Therefore, we performed a systematic review to explore the potential etiologies for the development of CKDu globally. (2) Methods: A systematic literature review was conducted using databases CINAHL, Cochrane Library, Embase, Google Scholar, MEDLINE, and PsycINFO on the specific causes and pathophysiology related to CKDu from inception until April 2021. Study selection, data extraction of included articles, and quality appraisal were assessed. The narrative approach was used to summarize and comprehend the findings. (3) Results: Our study included 25 studies, considering 38,351 participants. Twelve studies were case-control, ten were cross-sectional, and three were cohort designs. All articles were from low-and middle-income countries (LMICs). The findings suggest 12 factors are associated with CKDu. Most studies (n = 8) identified farming and water sources as the factors related to CKDu, with heavy metal toxicity coming in second (n = 7). (4) Conclusion: The systematic review reported various factors associated with CKDu, from which most studies reported farming, water sources, and heavy metal poisoning. Considering the findings, the study recommends future strategies and public health initiatives to prevent the epidemiological/environmental factors contributing to CKDu.
| S-EPMC9956943 | biostudies-literature
Project description:Gut dysbiosis and changes in short-chain fatty acids (SCFAs) occur in end-stage chronic kidney disease (CKD); however, the degree of these changes in the gut microbiome and serum SCFA profiles in the early stages of CKD, particularly in CKD of unknown etiology (CKDu), is unclear. We herein investigated the gut microbiome and SCFA profiles of early-stage CKD patients (CKD stages 1-3) in a community in Khon Kaen Province, Thailand. Seventy-two parasite-free participants were distributed among a healthy control group (HC, n=18) and three patient groups (an underlying disease group [UD, n=18], early-stage CKD with underlying disease [CKD-UD, n=18], and early-stage CKD of unknown etiology, [CKDu, n=18]). Fecal DNA was individually extracted and pooled for groups of six individuals (three pools in each group) to examine the composition of the gut microbiome using next-generation sequencing. A SCFA ana-lysis was performed on serum samples from each individual using gas chromatography-mass spectrometry. The results revealed that microbial abundance differed between the healthy group and all patient groups (UD, CKD-UD, and CKDu). [Eubacterium]_coprostanoligenes_group was more abundant in the CKDu group than in the HC and CKD-UD groups. Furthermore, serum concentrations of acetate, a major SCFA component, were significantly lower in all patient groups than in the HC group. The present results indicate that minor changes in the gut microbiome and a significant decrease in serum acetate concentrations occur in early-stage CKDu, which may be important for the development of prevention strategies for CKD patients.
| S-EPMC10522841 | biostudies-literature
Project description:Chronic kidney disease (CKD) is a global health problem with a genetic component. Genome-wide association studies have identified variants associated with specific CKD etiologies, but their genetic overlap has not been well studied. This study examined SNP associations across different CKD etiologies and CKD stages using data from 5,034 CKD patients of the German Chronic Kidney Disease study. In addition to confirming known associations, a systemic lupus erythematosus-associated risk variant at TNXB was also associated with CKD attributed to type 1 diabetes (p = 2.5 × 10-7), a membranous nephropathy-associated variant at HLA-DQA1 was also associated with CKD attributed to systemic lupus erythematosus (p = 5.9 × 10-6), and an IgA risk variant at HLA-DRB1 was associated with both CKD attributed to granulomatosis with polyangiitis (p = 2.0 × 10-4) and to type 1 diabetes (p = 4.6 × 10-11). Associations were independent of additional risk variants in the respective genetic regions. Evaluation of CKD stage showed a significant association of the UMOD risk variant, previously identified in population-based studies for association with kidney function, for advanced (stage ≥G3b) compared to early-stage CKD (≤stage G2). Shared genetic associations across CKD etiologies and stages highlight the role of the immune response in CKD. Association studies with detailed information on CKD etiology can reveal shared genetic risk variants.
| S-EPMC5655008 | biostudies-literature
Project description:A chronic kidney disease of unknown etiology (CKDu) has been killing workers in Central America. Occupational heat stress is thought to play an important role. Leptospirosis and hantavirus have been suggested as additional possible risk factors. In a case-control study in a Nicaraguan mining community, a structured survey was administered to adults, and biological measurements and specimens were taken. Serum was analyzed for antibodies to Leptospira and hantavirus. Before statistical analysis, a board-certified nephrologist determined final case and control status based on serum creatinine and other laboratory values. Multivariable analysis was by logistic regression. In sensitivity analyses, cases were restricted to those diagnosed with CKDu in the previous 3 years. Of 320 eligible participants, 112 were classified as presumptive cases, 176 as controls and 32 as indeterminant. The risk of CKDu in those ever having worked in mining or construction was 4.4 times higher than in other participants (odds ratio = 4.44, 95% CI: 1.96-10.0, P = 0.0003). Eighty-three (26%) of the 320 participants were seropositive for at least one tested strain of Leptospira. No evidence of a causal link between leptospirosis or hantavirus and CKDu was found. The sensitivity analyses provide some evidence against the hypotheses that leptospirosis or hantavirus leads to CKDu within a few years. A major limitation was the impossibility of determining the absolute or relative timing of infection and CKDu onset. A prospective cohort design, with repeated collection of specimens over several years, could yield clearer answers about infections as potential etiologic agents in CKDu.
| S-EPMC6726956 | biostudies-literature
Project description:Of the couples trying to conceive (had frequent, unprotected sexual intercourse for a year or longer) 15% will experience infertility with the annual incidence of infertility estimated at 1.2 couples per 1,000 total in the general population. Male factors contribute to over 50% of the cases with 7% of the male population experiencing infertility. Not being able to conceive a child is emotionally traumatic and frustrating and can affect the person's self esteem and the couple's relationship. Major progress has been achieved in identifying the etiology of male infertility and especially the genetic causes. However, in about 40% of the male infertility cases, the etiology remains unknown and both the diagnosis and/or treatment are a challenge. Genetic testing to determine the underlying genetic cause of infertility is not 100% and genes involved are still being discovered. Consequently, negative genetic test results do not rule out a genetic cause. Thus, genetic counselling should include information regarding the genetic etiology, if known, and the treatment options available. Furthermore, when the infertile couple/male is seeking assisted reproductive technology (ART) using intracytoplasmic sperm injection (ICSI), genetic counselling should include information regarding the risk of transmitting the genetic disorder, causing the male infertility, to the offspring. Therefore, the provision of genetic counselling is an integral component in the investigation and treatment of male infertility. This article will discuss the genetic counselling approach in cases with male infertility.
| S-EPMC8039627 | biostudies-literature
Project description:BackgroundIn Sri Lanka, there exists chronic kidney disease of both known (CKD) and unknown etiologies (CKDu). Identification of novel biomarkers that are customized to the specific causative factors would lead to early diagnosis and clearer prognosis of the diseases. This study aimed to find genetic biomarkers in blood to distinguish and identify CKDu from CKD as well as healthy populations from CKDu endemic and non-endemic areas of Sri Lanka.MethodsThe expression patterns of a selected panel of 12 potential genetic biomarkers were analyzed in blood using RT-qPCR. Fold changes of gene expressions in early and late stages of CKD and CKDu patients, and an apparently healthy population of a CKDu endemic area, Girandurukotte (GH) were calculated relative to apparently healthy volunteers from a CKDu non-endemic area, Kandy (KH) of Sri Lanka, using the comparative CT method.ResultsSignificant differences were observed between KH and early stage CKDu for both the insulin-like growth factor binding protein 1 (IGFBP1; p = 0.012) and kidney injury molecule-1 (KIM1; p = 0.003) genes, and KH and late stage CKD and CKDu for the glutathione-S-transferase mu 1 (GSTM1; p < 0.05) gene. IGFBP1 and KIM1 genes showed significant difference between the early and late stage CKDu (p < 0.01). The glutamate cysteine ligase catalytic subunit (GCLC) gene had significantly different expression between KH and all the other study groups (p < 0.01). The GH group was significantly different from the KH group for the oxidative stress related genes, G6PD, GCLC and GSTM1 (p < 0.01), and also the KIM1 gene (p = 0.003). IGFBP1, insulin-like growth factor binding protein 3 (IGFBP3), fibronectin 1 (FN1) and KIM1 showed significant correlations with serum creatinine, and IGFBP1, KIM1 and kallikrein 1 (KLK1) with eGFR (p < 0.05).ConclusionA panel consisting of IGFBP1, KIM1, GCLC and GSTM1 genes could be used in combination for early screening of CKDu, whereas these genes in addition with FN1, IGFBP3 and KLK1 could be used to monitor progression of CKDu. The regulation of these genes has to be studied on larger populations to validate their efficiency for further clinical use.
| S-EPMC5244589 | biostudies-literature