A multi-source data integration approach reveals novel associations between metabolites and renal outcomes in the German Chronic Kidney Disease study.
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ABSTRACT:
SUBMITTER: Altenbuchinger M
PROVIDER: S-EPMC6764972 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundHypothyroidism and low free triiodothyronine (FT3) syndrome [low FT3 levels with normal thyroid-stimulating hormone (TSH)] have been associated with reduced kidney function cross-sectionally in chronic kidney disease (CKD) patients with severely reduced estimated glomerular filtration rate (eGFR) or end-stage kidney disease (ESKD). Results on the prospective effects of impaired thyroid function on renal events and mortality for patients with severely reduced eGFR or from population-based cohorts are conflicting. Here we evaluated the association between thyroid and kidney function with eGFR (cross-sectionally) as well as renal events and mortality (prospectively) in a large, prospective cohort of CKD patients with mild to moderately reduced kidney function.MethodsThyroid markers were measured among CKD patients from the German Chronic Kidney Disease study. Incident renal endpoints (combined ESKD, acute kidney injury and renal death) and all-cause mortality were abstracted from hospital records and death certificates. Time to first event analysis of complete data from baseline to the 4-year follow-up (median follow-up time 4.04 years) of 4600 patients was conducted. Multivariable linear regression and Cox proportional hazards models were fitted for single and combined continuous thyroid markers [TSH, free thyroxine (FT4), FT3] and thyroid status.ResultsCross-sectionally, the presence of low-FT3 syndrome showed a significant inverse association with eGFR and continuous FT3 levels alone showed a significant positive association with eGFR; in combination with FT4 and TSH, FT3 levels also showed a positive association and FT4 levels showed a negative association with eGFR. Prospectively, higher FT4 and lower FT3 levels were significantly associated with a higher risk of all-cause mortality (N events = 297). Per picomole per litre higher FT3 levels the risk of reaching the composite renal endpoint was 0.73-fold lower (95% confidence interval 0.65-0.82; N events = 615). Compared with euthyroid patients, patients with low-FT3 syndrome had a 2.2-fold higher risk and patients with hypothyroidism had a 1.6-fold higher risk of experiencing the composite renal endpoint.ConclusionsPatients with mild to moderate CKD suffering from thyroid function abnormalities are at an increased risk of adverse renal events and all-cause mortality over time.
| S-EPMC8328092 | biostudies-literature
Project description:Mitochondrial dysfunction is increasingly recognized as a critical determinant of both hereditary and acquired kidney diseases. However, it remains poorly understood how mitochondrial metabolism is regulated to support normal kidney function and how its dysregulation contributes to kidney disease. Here, we show that the nuclear receptor estrogen-related receptor gamma (ERR?) and hepatocyte nuclear factor 1 beta (HNF1?) link renal mitochondrial and reabsorptive functions through coordinated epigenomic programs. ERR? directly regulates mitochondrial metabolism but cooperatively controls renal reabsorption via convergent binding with HNF1?. Deletion of ERR? in renal epithelial cells (RECs), in which it is highly and specifically expressed, results in severe renal energetic and reabsorptive dysfunction and progressive renal failure that recapitulates phenotypes of animals and patients with HNF1? loss-of-function gene mutations. Moreover, ERR? expression positively correlates with renal function and is decreased in patients with chronic kidney disease (CKD). REC-ERR? KO mice share highly overlapping renal transcriptional signatures with human patients with CKD. Together these findings reveal a role for ERR? in directing independent and HNF1?-integrated programs for energy production and use essential for normal renal function and the prevention of kidney disease.
| S-EPMC6003475 | biostudies-literature
Project description:The Chronic Renal Insufficiency Cohort (CRIC) Study was established to examine risk factors for the progression of chronic kidney disease (CKD) and cardiovascular disease (CVD) in patients with CKD. We examined baseline demographic and clinical characteristics.Seven clinical centers recruited adults who were aged 21 to 74 yr and had CKD using age-based estimated GFR (eGFR) inclusion criteria. At baseline, blood and urine specimens were collected and information regarding health behaviors, diet, quality of life, and functional status was obtained. GFR was measured using radiolabeled iothalamate in one third of participants.A total of 3612 participants were enrolled with mean age +/- SD of 58.2 +/- 11.0 yr; 46% were women, and 47% had diabetes. Overall, 45% were non-Hispanic white, 46% were non-Hispanic black, and 5% were Hispanic. Eighty-six percent reported hypertension, 22% coronary disease, and 10% heart failure. Mean body mass index was 32.1 +/- 7.9 kg/m(2), and 47% had a BP >130/80 mmHg. Mean eGFR was 43.4 +/- 13.5 ml/min per 1.73 m(2), and median (interquartile range) protein excretion was 0.17 g/24 h (0.07 to 0.81 g/24 h). Lower eGFR was associated with older age, lower socioeconomic and educational level, cigarette smoking, self-reported CVD, peripheral arterial disease, and elevated BP.Lower level of eGFR was associated with a greater burden of CVD as well as lower socioeconomic and educational status. Long-term follow-up of participants will provide critical insights into the epidemiology of CKD and its relationship to adverse outcomes.
| S-EPMC2723966 | 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:BackgroundDespite the potential demonstrated by targeted plasma metabolite modulators in halting the progression of chronic kidney disease (CKD), a lingering uncertainty persists concerning the causal relationship between distinct plasma metabolites and the onset and progression of CKD.MethodsA genome-wide association study was conducted on 1,091 metabolites and 309 metabolite ratios derived from a cohort of 8,299 unrelated individuals of European descent. Employing a bidirectional two-sample Mendelian randomization (MR) analysis in conjunction with colocalization analysis, we systematically investigated the associations between these metabolites and three phenotypes: CKD, creatinine-estimated glomerular filtration rate (creatinine-eGFR), and urine albumin creatinine ratio (UACR). In the MR analysis, the primary analytical approach employed was inverse variance weighting (IVW), and sensitivity analysis was executed utilizing the MR-Egger method and MR-pleiotropy residual sum and outlier (MR-PRESSO). Heterogeneity was carefully evaluated through Cochrane's Q test. To ensure the robustness of our MR results, the leave-one-out method was implemented, and the strength of causal relationships was subjected to scrutiny via Bonferroni correction.ResultsOur thorough MR analysis involving 1,400 plasma metabolites and three clinical phenotypes yielded a discerning identification of 21 plasma metabolites significantly associated with diverse outcomes. Specifically, in the forward MR analysis, 6 plasma metabolites were determined to be causally associated with CKD, 16 with creatinine-eGFR, and 7 with UACR. Substantiated by robust evidence from colocalization analysis, 6 plasma metabolites shared causal variants with CKD, 16 with creatinine-eGFR, and 7 with UACR. In the reverse analysis, a diminished creatinine-eGFR was linked to elevated levels of nine plasma metabolites. Notably, no discernible associations were observed between other plasma metabolites and CKD, creatinine-eGFR, and UACR. Importantly, our analysis detected no evidence of horizontal pleiotropy.ConclusionThis study elucidates specific plasma metabolites causally associated with CKD and renal functions, providing potential targets for intervention. These findings contribute to an enriched understanding of the genetic underpinnings of CKD and renal functions, paving the way for precision medicine applications and therapeutic strategies aimed at impeding disease progression.
| S-EPMC11310041 | biostudies-literature
Project description:INTRODUCTION:Chronic kidney disease (CKD) is a major public health challenge given its high global prevalence and associated risks of cardiovascular disease and progression to end stage renal disease. Although it is known that numerous metabolic changes occur in CKD patients, identifying novel metabolite associations with kidney function may enhance our understanding of the physiologic pathways relating to CKD. OBJECTIVES:The objective of this study was to elucidate novel metabolite associations with kidney function among participants of two community-based cohorts with carefully ascertained metabolomics, kidney function, and covariate data. METHODS:Untargeted ultrahigh-performance liquid chromatography-tandem mass spectrometry was used to detect and quantify blood metabolites. We used multivariate adjusted linear regression to examine associations between single metabolites and creatinine-based estimated glomerular filtration rate (eGFRcr) among 1243 Bogalusa Heart Study (BHS) participants (median eGFRcr: 94.4, 5th-95th percentile: 66.0-119.6 mL/min/1.73 m2). Replication, determined by statistical significance and consistent effect direction, was tested using gold standard measured glomerular filtration rate (mGFR) among 260 Multi-Ethnic Study of Atherosclerosis (MESA) participants (median mGFR: 72.0, 5th-95th percentile: 43.5-105.0 mL/min/1.73 m2). All analyses used Bonferroni-corrected alpha thresholds. RESULTS:Fifty-one novel metabolite associations with kidney function were identified, including 12 from previously unrelated sub-pathways: N6-carboxymethyllysine, gulonate, quinolinate, gamma-CEHC-glucuronide, retinol, methylmalonate, 3-hydroxy-3-methylglutarate, 3-aminoisobutyrate, N-methylpipecolate, hydroquinone sulfate, and glycine conjugates of C10H12O2 and C10H14O2(1). Significant metabolites were generally inversely associated with kidney function and smaller in mass-to-charge ratio than non-significant metabolites. CONCLUSION:The 51 novel metabolites identified may serve as early, clinically relevant, kidney function biomarkers.
| S-EPMC7021455 | biostudies-literature
Project description:PurposeImpaired physical performance and frailty are common in older people with advanced chronic kidney disease but it is unclear which metabolic derangements contribute to these impairments. We, therefore, examined associations between renal biochemical markers and both physical performance and frailty in older people with advanced chronic kidney disease.MethodsSecondary analysis of data from the BiCARB trial, which enrolled non-dialysing patients aged 60 and over, with chronic kidney disease stage 4/5, with serum bicarbonate < 22 mmol/L. Participants undertook the Short Physical Performance Battery, maximum grip strength and six-minute walk test at baseline, 3, 6, 12 and 24 months. Renal biochemistry (serum creatinine, cystatin C, phosphate, and bicarbonate), haemoglobin, 25-hydroxyvitamin D and NT-pro-B-type natriuretic peptide were measured at baseline. Associations between baseline renal biochemistry and physical performance, and between baseline biochemistry and the monthly rate of change in physical performance were assessed.ResultsWe analysed data from 300 participants (mean age 74 years; 86 [29%] women). 148 (49%) were pre-frail, 86 (29%) were frail. In multivariable cross-sectional baseline analyses, only age and BMI were significantly associated with baseline short physical performance battery; age, sex, body mass index, NT-pro-BNP and 25-hydroxyvitamin D were significantly associated with baseline six-minute walk distance. No significant associations were found between biochemical markers and change in physical performance over time, except between baseline 25-hydroxyvitamin D concentration and change in six-minute walk distance.ConclusionsBiochemical markers associated with chronic kidney disease did not consistently associate with baseline physical performance or the rate of change of physical performance measures.Trial registrationISRCTN09486651.
| S-EPMC8463514 | biostudies-literature
Project description:1H Nuclear Magnetic Resonance (NMR)-based metabolic profiling is very promising for the diagnostic of the stages of chronic kidney disease (CKD). Because of the high dimension of NMR spectra datasets and the complex mixture of metabolites in biological samples, the identification of discriminant biomarkers of a disease is challenging. None of the widely used chemometric methods in NMR metabolomics performs a local exhaustive exploration of the data. We developed a descriptive and easily understandable approach that searches for discriminant local phenomena using an original exhaustive rule-mining algorithm in order to predict two groups of patients: 1) patients having low to mild CKD stages with no renal failure and 2) patients having moderate to established CKD stages with renal failure. Our predictive algorithm explores the m-dimensional variable space to capture the local overdensities of the two groups of patients under the form of easily interpretable rules. Afterwards, a L2-penalized logistic regression on the discriminant rules was used to build predictive models of the CKD stages. We explored a complex multi-source dataset that included the clinical, demographic, clinical chemistry, renal pathology and urine metabolomic data of a cohort of 110 patients. Given this multi-source dataset and the complex nature of metabolomic data, we analyzed 1- and 2-dimensional rules in order to integrate the information carried by the interactions between the variables. The results indicated that our local algorithm is a valuable analytical method for the precise characterization of multivariate CKD stage profiles and as efficient as the classical global model using chi2 variable section with an approximately 70% of good classification level. The resulting predictive models predominantly identify urinary metabolites (such as 3-hydroxyisovalerate, carnitine, citrate, dimethylsulfone, creatinine and N-methylnicotinamide) as relevant variables indicating that CKD significantly affects the urinary metabolome. In addition, the simple knowledge of the concentration of urinary metabolites classifies the CKD stage of the patients correctly.
| S-EPMC5115883 | biostudies-literature
Project description:BACKGROUND:Kidney renal clear cell carcinoma (KIRC) is the most common type of kidney cancer in adults, and it is responsible for approximately 90-95% of cases. Although extensive evidence has suggested that many immune- and inflammation-related genes could serve as effective biomarkers in KIRC, the potential associations among immune-, inflammation- and KIRC-related genes has not been sufficiently understood. METHODS:Here, we integrated multiple levels of data to construct an immune-, inflammation- or KIRC-directed neighbour network (IIKDN network) and a KIRC-related gene-directed network (KIRCD network). RESULTS:Our analysis suggested that immune- and inflammation-related genes in the network have special topological characteristics and expression patterns related to KIRC. We further identified five core clusters that showed a tighter network structure and stronger correlation of expression from the KIRCD network. Specifically, multiple-level molecular characteristics were systematically portrayed, including somatic mutation, copy-number variant and DNA methylation for the genes in five core clusters. We discovered that the genes showed strong correlation with respect to the expression and methylation levels in these five core clusters. These five core clusters could become special prognostic biomarkers for KIRC, and functional analysis showed that they were associated with activation of the immune and inflammation systems and cancer progression. CONCLUSIONS:Our findings highlighted the novel role of the immune and inflammation genes in KIRC.
| S-EPMC6537414 | biostudies-other
Project description:Hospital integration among rural districts to concentrate medical resources is one of the main projects of the Japanese government. In advance of this, we experienced hospital integration and screening for chronic kidney disease as definitive risk for end-stage kidney disease and cardiovascular mortality. After that, high-risk patients have been appropriately referred from generalists to nephrologists and/or cardiologists without acute deterioration of renal function or cardiac sudden death.
| S-EPMC7689234 | biostudies-literature