A polygenic score for reduced kidney function and adverse outcomes in a cohort with chronic kidney disease.
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ABSTRACT:
SUBMITTER: Steinbrenner I
PROVIDER: S-EPMC9868068 | biostudies-literature | 2023 Feb
REPOSITORIES: biostudies-literature
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A polygenic score for reduced kidney function and adverse outcomes in a cohort with chronic kidney disease.
Steinbrenner Inga I Yu Zhi Z Jin Jin J Schultheiss Ulla T UT Kotsis Fruzsina F Grams Morgan E ME Coresh Josef J Wuttke Matthias M Kronenberg Florian F Eckardt Kai-Uwe KU Chatterjee Nilanjan N Sekula Peggy P Köttgen Anna A
Kidney international 20221205 2
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Project description:Chronic kidney disease (CKD) is a common complex condition associated with high morbidity and mortality. Polygenic prediction could enhance CKD screening and prevention; however, this approach has not been optimized for ancestrally diverse populations. By combining APOL1 risk genotypes with genome-wide association studies (GWAS) of kidney function, we designed, optimized and validated a genome-wide polygenic score (GPS) for CKD. The new GPS was tested in 15 independent cohorts, including 3 cohorts of European ancestry (n = 97,050), 6 cohorts of African ancestry (n = 14,544), 4 cohorts of Asian ancestry (n = 8,625) and 2 admixed Latinx cohorts (n = 3,625). We demonstrated score transferability with reproducible performance across all tested cohorts. The top 2% of the GPS was associated with nearly threefold increased risk of CKD across ancestries. In African ancestry cohorts, the APOL1 risk genotype and polygenic component of the GPS had additive effects on the risk of CKD.
| S-EPMC9329233 | biostudies-literature
Project description:We sought to determine the relationship between age-related clonal hematopoiesis (CH) and chronic kidney disease (CKD). CH, defined as mosaic chromosome abnormalities (mCA) and/or driver mutations was identified in 5449 (2.9%) eligible UK Biobank participants (n = 190,487 median age = 58 years). CH was negatively associated with glomerular filtration rate estimated from cystatin-C (eGFR.cys; β = -0.75, P = 2.37 × 10-4), but not with eGFR estimated from creatinine, and was specifically associated with CKD defined by eGFR.cys < 60 (OR = 1.02, P = 8.44 × 10-8). In participants without prevalent myeloid neoplasms, eGFR.cys was associated with myeloid mCA (n = 148, β = -3.36, P = 0.01) and somatic driver mutations (n = 3241, β = -1.08, P = 6.25 × 10-5) associated with myeloid neoplasia (myeloid CH), specifically mutations in CBL, TET2, JAK2, PPM1D and GNB1 but not DNMT3A or ASXL1. In participants with no history of cardiovascular disease or myeloid neoplasms, myeloid CH increased the risk of adverse outcomes in CKD (HR = 1.6, P = 0.002) compared to those without myeloid CH. Mendelian randomisation analysis provided suggestive evidence for a causal relationship between CH and CKD (P = 0.03). We conclude that CH, and specifically myeloid CH, is associated with CKD defined by eGFR.cys. Myeloid CH promotes adverse outcomes in CKD, highlighting the importance of the interaction between intrinsic and extrinsic factors to define the health risk associated with CH.
| S-EPMC8807385 | biostudies-literature
Project description:ObjectivesTo investigate whether partner bereavement is associated with adverse cardiovascular and kidney-related events in people with reduced kidney function.DesignTwo parallel matched cohort studies using linked routinely collected health data.SettingEngland (general practices and hospitals using linked Clinical Practice Research Datalink, Hospital Episode Statistics, and Office of National Statistics) and Denmark (hospitals and community pharmacies using the Danish National Patient, Prescription and Education Registries and the Civil Registration System).ParticipantsBereaved people with reduced kidney function (estimated glomerular filtration rate (eGFR) <60mL/min/1.73m2 (England) or hospital-coded chronic kidney disease (Denmark)) and non-bereaved people with reduced kidney function similarly defined, matched on age, sex, general practice (England), and county of residence (Denmark) and followed-up from the bereavement date of the exposed person.Main outcome measuresCardiovascular disease (CVD) or acute kidney injury (AKI) hospitalization, or death.ResultsIn people with reduced kidney function, we identified 19,820 (England) and 5,408 (Denmark) bereaved individuals and matched them with 134,828 (England) and 35,741 (Denmark) non-bereaved individuals. Among the bereaved, the rates of hospitalizations (per 1000 person-years) with CVD were 31.7 (95%-CI: 30.5-32.9) in England and 78.8 (95%-CI: 74.9-82.9) in Denmark; the rates of hospitalizations with AKI were 13.2 (95%-CI: 12.5-14.0) in England and 11.2 (95%-CI: 9.9-12.7) in Denmark; and the rates of death were 70.2 (95%-CI: 68.5-72.0) in England and 126.4 (95%-CI: 121.8-131.1) in Denmark. After adjusting for confounders, we found increased rates of CVD (England, HR 1.06 [95%-CI: 1.01-1.12]; Denmark, HR 1.10 [95%-CI: 1.04-1.17]), of AKI (England, HR 1.20 [95%-CI: 1.10-1.31]; Denmark HR 1.36 [95%-CI: 1.17-1.58]), and of death (England, HR 1.10 [95%-CI: 1.05-1.14]; Denmark HR 1.20 [95%-CI: 1.15-1.25]) in bereaved compared with non-bereaved people.ConclusionsPartner bereavement is associated with an increased rate of CVD and AKI hospitalization, and death in people with reduced kidney function. Additional supportive care for this at-risk population may help prevent serious adverse events.
| S-EPMC8460004 | biostudies-literature
Project description:BACKGROUND:In studies including the general population, the presence of non-malignant monoclonal gammopathy (MG) can be causally associated with kidney damage and shorter survival. We assessed whether the presence of an MG is associated with a higher risk of kidney failure or death in individuals with chronic kidney disease (CKD). METHODS AND FINDINGS:Data were used from 3 prospective cohorts of individuals with CKD (not on dialysis or with a kidney transplant): (1) Renal Impairment in Secondary Care (RIISC, Queen Elizabeth Hospital and Heartlands Hospital, Birmingham, UK, N = 878), (2) Salford Kidney Study (SKS, Salford Royal Hospital, Salford, UK, N = 861), and (3) Renal Risk in Derby (RRID, Derby, UK, N = 1,739). Participants were excluded if they had multiple myeloma or any other B cell lymphoproliferative disorder with end-organ damage. Median age was 71.0 years, 50.6% were male, median estimated glomerular filtration rate was 42.3 ml/min/1.73 m2, and median urine albumin-to-creatinine ratio was 3.4 mg/mmol. All non-malignant MG was identified in the baseline serum of participants of RIISC. Further, light chain MG (LC-MG) was identified and studied in participants of RIISC, SKS, and RRID. Participants were followed up for kidney failure (defined as the initiation of dialysis or kidney transplantation) and death. Associations with the risk of kidney failure were estimated by competing-risks regression (handling death as a competing risk), and associations with death were estimated by Cox proportional hazards regression. In total, 102 (11.6%) of the 878 RIISC participants had an MG. During a median follow-up time of 74.0 months, there were 327 kidney failure events and 202 deaths. The presence of MG was not associated with risk of kidney failure (univariable subhazard ratio [SHR] 0.97 [95% CI 0.68 to 1.38], P = 0.85; multivariable SHR 1.16 [95% CI 0.80 to 1.69], P = 0.43), and although there was a higher risk of death in univariable analysis (hazard ratio [HR] 2.13 [95% CI 1.49 to 3.02], P < 0.001), this was not significant in multivariable analysis (HR 1.37 [95% CI 0.93 to 2.00], P = 0.11). Fifty-five (1.6%) of the 3,478 participants from all 3 studies had LC-MG. During a median follow-up time of 62.5 months, 564 of the 3,478 participants progressed to kidney failure, and 803 died. LC-MG was not associated with risk of kidney failure (univariable SHR 1.07 [95% CI 0.58 to 1.96], P = 0.82; multivariable SHR 1.42 [95% CI 0.78 to 2.57], P = 0.26). There was a higher risk of death in those with LC-MG in the univariable model (HR 2.51 [95% CI 1.59 to 3.96], P < 0.001), but not in the multivariable model (HR 1.49 [95% CI 0.93 to 2.39], P = 0.10). An important limitation of this work was that only LC-MG, rather than any MG, could be identified in participants from SKS and RRID. CONCLUSIONS:The prevalence of MG was higher in this CKD cohort than that reported in the general population. However, the presence of an MG was not independently associated with a significantly higher risk of kidney failure or, unlike in the general population, risk of death.
| S-EPMC7048272 | biostudies-literature
Project description:It remains unclear whether infection events before entering end stage renal disease (ESRD) have a long-term negative impact on patients with advanced chronic kidney disease (CKD) who survive to permanent dialysis. We enrolled 62,872 patients with advanced CKD who transitioned to maintenance dialysis between January 1, 2004 and December 31, 2013. We used multivariable Cox as well as Fine and Gray models to determine the association of pre-dialysis infection exposure with all-cause mortality after starting dialysis. Compared with no infection during advanced CKD, the presence of infection exposure during that period was independently associated with a higher risk of all-cause mortality in the first year of dialysis (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.27-1.42) and also during the entire follow-up period (HR 1.19, 95% CI 1.16-1.22). The increased risks of all-cause mortality increased incrementally with higher annual number of infections during advanced CKD. Similar results were found for all other adverse outcomes, e.g. post-ESRD infection-related hospitalization and major cardiac and cerebrovascular events. In conclusion, infection events during advanced CKD was associated with increased risks of adverse outcomes after dialysis has been started. Timely interventions in such a vulnerable group may help attenuate these risks.
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Project description:ImportanceThe risk of airflow limitation and chronic obstructive pulmonary disease (COPD) is influenced by combinations of cigarette smoking and genetic susceptibility, yet it remains unclear whether gene-by-smoking interactions are associated with quantitative measures of lung function.ObjectiveTo assess the interaction of cigarette smoking and polygenic risk score in association with reduced lung function.Design, setting, and participantsThis UK Biobank cohort study included UK citizens of European ancestry aged 40 to 69 years with genetic and spirometry data passing quality control metrics. Data was analyzed from July 2020 to March 2021.ExposuresPRS of combined forced expiratory volume in 1 second (FEV1) and percent of forced vital capacity exhaled in the first second (FEV1/FVC), self-reported pack-years of smoking, ever- vs never-smoking status, and current- vs former- or never-smoking status.Main outcomes and measuresFEV1/FVC was the primary outcome. Models were used to test for interactions with models, including the main effects of PRS, different smoking variables, and their cross-product terms. The association between pack-years of smoking and FEV1/FVC were compared for those in the highest vs lowest decile of estimated genetic risk for low lung function.ResultsWe included 319 730 individuals, of whom 24 915 (8%) had moderate-to-severe COPD cases, and 44.4% were men. Participants had a mean (SD) age 56.5 of (8.02) years. The PRS and pack-years were significantly associated with lower FEV1/FVC (PRS: β, -0.03; 95% CI, -0.031 to -0.03; pack-years: β, -0.0064; 95% CI, -0.0064 to -0.0063) and the interaction term (β, -0.0028; 95% CI, -0.0029 to -0.0026). A stepwise increment in estimated effect sizes for these interaction terms was observed per 10 pack-years of smoking exposure. The interaction of PRS with 11 to 20, 31 to 40, and more than 50 pack-years categories were β (interaction) -0.0038 (95% CI, -0.0046 to -0.0031); -0.013 (95% CI, -0.014 to -0.012); and -0.017 (95% CI, -0.019 to -0.016), respectively. There was evidence of significant interaction between PRS with ever- or never- smoking status (β, interaction; -0.0064; 95% CI, -0.0068 to -0.0060) and current or not-current smoking (β, interaction; -0.0091; 95% CI, -0.0097 to -0.0084). For any given level of pack-years of smoking exposure, FEV1/FVC was significantly lower for individuals in the tenth decile (ie, highest risk) than the first decile (ie, lowest risk) of genetic risk. For every 20 pack-years of smoking, those in the tenth decile compared with the first decile of genetic risk showed nearly a 2-fold reduction in FEV1/FVC.Conclusions and relevanceCOPD is characterized by diminished lung function, and our analyses suggest there is substantial interaction between genome-wide PRS and smoking exposures. While smoking was associated with decreased lung function across all genetic risk categories, the associations were strongest in individuals with higher estimated genetic risk.
| S-EPMC8678715 | biostudies-literature
Project description:Objective Although an association between serum inorganic phosphorus levels and a poor prognosis has been noted in dialysis patients, these associations have been insufficiently reported in non-dialysis-dependent chronic kidney disease (NDD-CKD) patients. This study attempted to determine the association between serum inorganic phosphorus levels and adverse outcomes in Japanese NDD-CKD patients. Methods We investigated the relationships between serum inorganic phosphorus levels and adverse outcomes, such as kidney events, cardiovascular events, and all-cause death, in Japanese NDD-CKD patients using longitudinal data from the Fukushima CKD Cohort Study with a median follow-up period of 2.8 years. The study evaluated 822 patients with NDD-CKD enrolled between June 2012 and July 2014. A kidney event was defined as a combination of doubling of the baseline serum creatinine or end-stage renal disease. Cox regression was performed to analyze the relationships of the quartile of the serum inorganic phosphorus with kidney events, cardiovascular events, and all-cause death. Results The frequency of kidney events per 1,000 person-years exhibited a U-shaped distribution based on serum inorganic phosphorus levels, with these levels not significantly associated with an increased risk of cardiovascular events and all-cause death. A multivariable Cox regression analysis showed an increased risk of kidney events for the highest quartile of the serum inorganic phosphorus levels (≥3.7 mg/dL) versus the second quartile (2.9-3.2 mg/dL, hazard ratio, 3.30; 95% confidence interval, 1.50-7.28; p=0.003). There were no significant associations between the serum calcium levels and adverse outcomes. Conclusion Serum inorganic phosphorus levels were associated with an increased risk of CKD progression in Japanese NDD-CKD patients.
| S-EPMC9259314 | biostudies-literature
Project description:BackgroundSome observational studies have shown the relationships between hyperuricemia and chronic kidney disease (CKD); however, the threshold of serum uric acid (SUA) for deterioration of kidney function and the association between SUA and kidney injury by baseline kidney function remains unclear. This study aimed to clarify the relationships between SUA and reduced kidney function.MethodsWe analyzed a historical cohort of male Japanese individuals who underwent medical checkup between 1998 and 2007. Participants with baseline data and who were followed up for at least one year were included and stratified according to baseline kidney function. Kidney function was classified as normal [estimated glomerular filtration rate (eGFR) ≥ 90 ml/min/1.73 m2] or mildly reduced (eGFR 60-89 ml/min/1.73 m2). The outcome measured was kidney impairment defined as a decrease in eGFR to < 60 ml/min/1.73 m2. Associations between SUA and risk for outcome and eGFR slopes were assessed.ResultsA total of 41632 subjects with mean age 45.4 years were included. During a mean follow-up of four years, 3186 (7.6%) subjects developed kidney dysfunction. Subjects with SUA ≥ 6.0 mg/dL had a significantly increased risk for kidney impairment compared with subjects with SUA of 4-4.9 mg/dL. SUA threshold levels were different according to baseline kidney function; SUA ≥ 7.0 and ≥ 6.0 mg/dL for normal and mildly reduced kidney function, respectively. Approximately the same trends were observed for eGFR slopes.ConclusionIn the general population, hyperuricemia appears to be a risk factor for kidney impairment in males. For participants with mild kidney dysfunction, even a slight elevation of SUA can be a risk factor.
| S-EPMC4565699 | biostudies-literature
Project description:The KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) was launched in 2011 with the support of the Korea Disease Control and Prevention Agency. The study was designed with the aim of exploring the various clinical features and characteristics of chronic kidney disease (CKD) in Koreans, and elucidating the risk factors for CKD progression and adverse outcomes of CKD. For the cohort study, nephrologists at 9 tertiary university-affiliated hospitals participated in patient recruitment and follow-up. Biostatisticians and epidemiologists also participated in the basic design and structuring of the study. From 2011 until 2016, the KNOW-CKD Phase I recruited 2238 adult patients with CKD from stages G1 to G5, who were not receiving renal replacement therapy. The KNOW-CKD Phase II recruitment was started in 2019, with an enrollment target of 1500 subjects, focused on diabetic nephropathy and hypertensive kidney diseases in patients with reduced kidney function who are presumed to be at a higher risk of adverse outcomes. As of 2021, the KNOW-CKD investigators have published articles in the fields of socioeconomics, quality of life, nutrition, physical activity, renal progression, cardiovascular disease and outcomes, anemia, mineral bone disease, serum and urine biomarkers, and international and inter-ethnic comparisons. The KNOW-CKD researchers will elaborate a prediction model for various outcomes of CKD such as the development of end-stage kidney disease, major adverse cardiovascular events, and death.
| S-EPMC9371779 | biostudies-literature
Project description:BackgroundSecondary hyperparathyroidism (sHPT) develops frequently in patients with chronic kidney disease (CKD). However, the burden and long-term impact of sHPT on the risk of adverse health outcomes are not well studied.MethodsWe evaluated all adults receiving nephrologist care in Stockholm during 2006-11 who were not undergoing kidney replacement therapy and had not developed sHPT. Incident sHPT was identified by using clinical diagnoses, initiated medications or two consecutive parathyroid hormone (PTH) measurements ≥130 pg/mL. We characterized sHPT incidence by estimated glomerular filtration rate (eGFR) strata, evaluated clinical predictors and quantified the association between incident sHPT (time-varying exposure) and the risk of fractures, CKD progression, major adverse cardiovascular events (MACEs) and death.ResultsWe identified 2556 adults with CKD Stages 1-5 (mean age 66 years, 38% women), of whom 784 developed sHPT during follow-up. The incidence of sHPT increased with advancing CKD: from 57 cases/1000 person-years in CKD Stage G3 to 230 cases/1000 person-years in Stage G5. In multivariable analyses, low eGFR was the strongest sHPT predictor, followed by young age, male sex and diabetes. Incident sHPT was associated with a 1.3-fold (95% confidence interval 1.1-1.8) increased risk of death, a 2.2-fold (1.42-3.28) higher risk of MACEs, a 5.0-fold (3.5-7.2) higher risk of CKD progression and a 1.3-fold (1.5-2.2) higher risk of fractures. Results were consistent in stratified analyses and after excluding early events.ConclusionsOur findings illustrate the burden of sHPT in advanced CKD and highlight the susceptibility for adverse outcomes of patients developing sHPT. This may inform clinical decisions regarding pre-sHPT risk stratification, PTH monitoring and risk-prevention strategies post-sHPT development.
| S-EPMC8483675 | biostudies-literature