Polymorphism in the GATM Locus Associated with Dialysis-Independent Chronic Kidney Disease but Not Dialysis-Dependent Kidney Failure.
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SUBMITTER: Salamon S
PROVIDER: S-EPMC8228672 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure.Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations.Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death.Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.
| S-EPMC6050927 | biostudies-literature
Project description:This article presents a dataset of body composition in chronic kidney disease (CKD) non-dialysis-dependent (NDD), hemodialysis (HD) and peritoneal dialysis (PD) (for at least 3 months), and kidney transplantation (KTx) (for at least 6 months) patients. The data were collected as part of a PhD research project, an observational cross-sectional study followed by a prospective analysis (about 6 months later). Adult CKD patients (18≤age≤60 years old) from a tertiary hospital were recruited: CKD in stages 3b to 5 for NDD patients; PD patients without peritonitis in the last 30 days; HD patients in 4-hour dialysis session, 3 times per week, through an arteriovenous fistula; and KTx patients with CKD in stages 1 to 3a. Patients with presence of amputated limbs or an electronic implant, wheelchair user or inpatient, body weight above 140 kg or BMI higher than 40 kg/m2, acute infections, cancer diagnosis, acquired immunodeficiency syndrome, and others that could alter body composition were excluded. The dataset in this publication consist of some clinical measurements for characterization of the sample, body composition measurements by dual-energy X-ray absorptiometry and by bioelectrical impedance spectroscopy in tetra-polar whole-body wrist to ankle (BISWB) and segmental (BISSEG) protocols of 266 CKD patients, being 137 men and 129 women; 81 in NDD treatment, 83 in HD, 24 in PD, and 80 in KTx. Measurements were performed consecutively by the same professional after an 8-hour fast, empty urinary bladder, drainage of the peritoneal dialysate, and just after the midweek hemodialysis session. To analyze differences among subgroups according to sex and CKD treatment, unpaired T test or ANOVA and Chi-square, adjusted by Bonferroni post-test, were applied. Agreement in fat free mass and fat mass measurements between BISWB and BISSEG, for cross-sectional data and for body composition changes (prospective measurement - cross-sectional measurement), was checked using intraclass correlation coefficient and 95% confidence intervals. Agreement on individual level was evaluated using the Bland-Altman method with limits of agreement. The data can be valuable in the study of body composition in CKD under all types of treatment and also for agreement analysis among body composition measurements by different instruments and techniques. The data are analysed and interpreted in the research article Bellafronte et al., 2020 [1].
| S-EPMC7721620 | biostudies-literature
Project description:BackgroundThe need for dialysis after kidney allograft failure (DAGF) is among the top five reasons for dialysis initiation, making this an important topic in clinical nephrology. However, data are scarce on dialysis choice after transplantation and clinical outcomes for DAGF in children.MethodsPatients receiving chronic dialysis < 18 years were recorded from January 1991 to January 2019 by the Italian Registry of Pediatric Chronic Dialysis (IRPCD). We investigated factors influencing choice of dialysis modality, patient outcome in terms of mortality, switching dialysis modality, and kidney transplantation.ResultsAmong 118 patients receiving DAGF, 41 (35%) were treated with peritoneal dialysis (PD), and 77 (65%) with haemodialysis (HD). Significant predictors for treatment with PD were younger age at dialysis start (OR 0.85 per year increase [95%CI 0.72-1.00]) and PD use before kidney transplantation (OR 8.20 [95%CI 1.82-37.01]). Patients entering DAGF in more recent eras (OR 0.87 per year increase [95%CI 0.80-0.94]) and with more than one dialysis modality before kidney transplantation (OR 0.56 for being treated with PD [0.12-2.59]) were more likely to be initiated on HD. As compared to patients on HD, those treated with PD exhibited increased but non-significant mortality risk (HR 2.15 [95%CI 0.54-8.6]; p = 0.28) and higher prevalence of dialysis-related complications during DAGF (p = 0.002) CONCLUSIONS: Patients entering DAGF in more recent years are more likely to be initiated on HD. In this specific population of children, use of PD seems associated with a more complicated course. A higher resolution version of the Graphical abstract is available as Supplementary information.
| S-EPMC8599402 | biostudies-literature
Project description:BackgroundOlder adults with chronic kidney disease stage 5 may be offered a choice between dialysis and conservative management. Few studies have explored patients' reasons for choosing conservative management and none have compared the views of those who have chosen different treatments across renal units.Study designQualitative study with semistructured interviews.Settings & participantsPatients 75 years or older recruited from 9 renal units. Units were chosen to reflect variation in the scale of delivery of conservative management.MethodologySemistructured interviews audiorecorded and transcribed verbatim.Analytical approachData were analyzed using thematic analysis.Results42 interviews were completed, 4 to 6 per renal unit. Patients were sampled from those receiving dialysis, those preparing for dialysis, and those choosing conservative management. 14 patients in each group were interviewed. Patients who had chosen different treatments held varying beliefs about what dialysis could offer. The information that patients reported receiving from clinical staff differed between units. Patients from units with a more established conservative management pathway were more aware of conservative management, less often believed that dialysis would guarantee longevity, and more often had discussed the future with staff. Some patients receiving conservative management reported that they would have dialysis if they became unwell in the future, indicating the conditional nature of their decision.LimitationsRecruitment of older adults with frailty and comorbid conditions was difficult and therefore transferability of findings to this population is limited.ConclusionsOlder adults with chronic kidney disease stage 5 who have chosen different treatment options have contrasting beliefs about the likely outcomes of dialysis for those who are influenced by information provided by renal units. Supporting renal staff in discussing conservative management as a valid alternative to dialysis for a subset of patients will aid informed decision making. There is a need for better evidence about conservative management to support shared decision making for older people with chronic kidney failure.
| S-EPMC4339698 | biostudies-literature
Project description:BackgroundSarcopenia is a prevalent complication in patients with chronic kidney disease and is associated with poor quality of life, morbidity, and mortality. Several candidate biomarkers have been evaluated for this condition. This study assessed the serum cystatin C to creatinine (serum cystatin C/Cr) ratio as a potential biomarker for sarcopenia in patients with non-dialysis-dependent chronic kidney disease.MethodsThis study enrolled 517 outpatients. Muscle mass (lean tissue index) was measured using a bioimpedance spectroscopic device, and muscle strength (handgrip strength) was also measured. Sarcopenia was defined as a combination of low muscle strength and low muscle mass.ResultsSarcopenia was observed in 25.5% of patients, and the mean serum cystatin C/Cr ratio was significantly higher in patients with sarcopenia than in those without it (1.14 ± 0.26 vs. 1.01 ± 0.27, p < 0.001). The prevalence of sarcopenia and low lean tissue index increased as the cystatin C/Cr ratio increased. The negative predictive value of the cystatin C/Cr ratio for sarcopenia or low lean tissue index was ≥80%. Multivariate analyses revealed that when the serum cystatin C/Cr ratio increased by 1, the risk of sarcopenia, low lean tissue index, and low handgrip strength increased by 4.6-, 7.2-, and 2.6-fold, respectively (p = 0.003, p < 0.001, and p = 0.048). The association was maximized in patients with an estimated glomerular filtration rate of <30 mL/min/1.73 m2.ConclusionCalculating the serum cystatin C/Cr ratio could be helpful for detecting and managing sarcopenia in patients with chronic kidney disease.
| S-EPMC9576455 | biostudies-literature
Project description: Not available
| S-EPMC4230441 | biostudies-literature
Project description:IntroductionSarcopenia, the age-related loss of muscle mass and function, frequently accompanies chronic kidney disease. The aim of this study was to clarify the prevalence and the risk factors for sarcopenia among patients with non-dialysis-dependent chronic kidney disease (NDD-CKD), focusing on the use of drugs.MethodsWe conducted a cross-sectional analysis on a cohort of 260 patients with NDD-CKD in a university hospital, recruited between June 2016 and March 2017. We extracted data on patient gender, age, cause of chronic kidney disease, use of drugs, and comorbidities that could potentially affect the prevalence of sarcopenia. Sarcopenia was diagnosed using the criteria of the Asian Working Group for Sarcopenia. Logistic regression analysis was performed to analyze the association of each factor on the prevalence of sarcopenia.Results25.0% of our study subjects had sarcopenia. Multivariable analysis revealed that an increased risk of sarcopenia was significantly associated with age, male gender, body mass index, diabetes mellitus, and loop diuretic use (odds ratio, 4.59: 95% confidence interval, 1.81-11.61: P-value 0.001).ConclusionsIn our cohort, the prevalence of sarcopenia in patients with NDD-CKD was high, and diuretics use, particularly loop diuretic use, was suggested to be a risk factor of sarcopenia. Although loop diuretics are commonly used in patients with CKD, careful consideration of the risk of sarcopenia may be necessary.
| S-EPMC5814019 | biostudies-literature
Project description:BackgroundRoutine clinical evidence is limited on clinical outcomes associated with anemia in patients with severe chronic kidney disease (CKD).MethodsWe linked population-based medical databases to identify individuals with severe CKD (eGFR?<?30 mL/min/1.73 m2) in Northern Denmark from 2000 to 2016, including prevalent patients as of 1 January 2009 or incident patients hereafter into the study. We classified patients as non-anemic (??12/??13 g/dl hemoglobin (Hgb) in women/men), anemia grade 1 (10-12/13 g/dl Hgb in women/men), 2 (8-10 g/dl Hgb), and 3+?(<?8 g/dl Hgb), allowing persons to contribute with patient profiles and risk time in consecutively more severe anemia grade cohorts. Patients were stratified by dialysis status and followed for clinical outcomes.ResultsWe identified 16,972 CKD patients contributing with a total of 28,510 anemia patient profiles, of which 3594 had dialysis dependent (DD) and 24,916 had non-dialysis dependent (NDD) severe CKD. Overall, 14% had no anemia, 35% grade 1 anemia, 44% grade 2 anemia and 17% grade 3+?anemia. Compared to patients with no anemia, adjusted hazard ratios (HRs) for NDD patients with grade 3+?anemia were elevated for incident dialysis (1.91, 95% CI 1.61-2.26), any acute hospitalization (1.74, 95% CI 1.57-1.93), all-cause death (1.82, 95% CI 1.70-1.94), and MACE (1.14, 95% CI 1.02-1.26). Similar HRs were observed among DD patients.ConclusionsAmong NDD or DD patients with severe CKD, presence and severity of anemia were associated with increased risks of incident dialysis for NDD patients and with acute hospitalizations, death and MACE for all patients.
| S-EPMC7007417 | biostudies-literature
Project description:BackgroundInitiation of maintenance dialysis therapy for patients with chronic kidney failure is a period of high risk for adverse patient outcomes. Whether indications for dialysis therapy initiation are associated with mortality in this population is unknown.Study designRetrospective cohort study.Setting & participants461 patients who initiated dialysis therapy (hemodialysis, 437; peritoneal dialysis, 24) from January 1, 2004, through December 31, 2012, and were treated in facilities operated by a single dialysis organization. Follow-up for the primary outcome was through December 31, 2013.PredictorClinically documented primary indication for dialysis therapy initiation, as categorized into 4 groups: laboratory evidence of kidney function decline (reference category), uremic symptoms, volume overload or hypertension, and other/unknown.OutcomesAll-cause mortality.ResultsDuring a median follow-up of 2.4 years, 183 (40%) patients died. Crude mortality rates were 10.0 (95% CI, 6.8-14.7), 12.7 (95% CI, 10.2-15.7), 21.7 (95% CI, 16.4-28.6), and 12.2 (95% CI, 6.8-14.7) deaths/100 patient-years among patients initiating dialysis therapy primarily for laboratory evidence of kidney function decline, uremic symptoms, volume overload or hypertension, and other/unknown reason, respectively. Following adjustment for demographic variables, coexisting illnesses, and estimated glomerular filtration rate, initiation of dialysis therapy for uremic symptoms, volume overload or hypertension, or other/unknown reasons was associated with 1.12 (95% CI, 0.72-1.77), 1.69 (95% CI, 1.02-2.80), and 1.28 (95% CI, 0.73-2.26) times higher risk, respectively, for subsequent mortality compared to initiation for laboratory evidence of kidney function decline.LimitationsPossibility of residual confounding by unmeasured variables; reliance on clinical documentation to ascertain exposure.ConclusionsPatients initiating dialysis therapy due to volume overload may have increased risk for mortality compared with patients initiating dialysis due to laboratory evidence of kidney function decline. Further studies are needed to identify and test interventions that might reduce this risk.
| S-EPMC5182162 | biostudies-literature
Project description:Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk and have been shown to have beneficial effects in a broad range of patients. However, statins are associated with an increased risk, albeit small, of clinical myopathy and type 2 diabetes. Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy or toxicity, and have produced little information regarding mechanisms that modulate statin response. Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment. This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure, including rs9806699, a cis-eQTL for the gene glycine amidinotransferase (GATM) that encodes the rate-limiting enzyme in creatine synthesis. We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 0.60). Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy.
| S-EPMC3933266 | biostudies-literature