The kidneys integrate information from continuous systemic processes related to the absorption, distribution, metabolism and excretion (ADME) of metabolites. To identify underlying molecular ...mechanisms, we performed genome-wide association studies of the urinary concentrations of 1,172 metabolites among 1,627 patients with reduced kidney function. The 240 unique metabolite-locus associations (metabolite quantitative trait loci, mQTLs) that were identified and replicated highlight novel candidate substrates for transport proteins. The identified genes are enriched in ADME-relevant tissues and cell types, and they reveal novel candidates for biotransformation and detoxification reactions. Fine mapping of mQTLs and integration with single-cell gene expression permitted the prioritization of causal genes, functional variants and target cell types. The combination of mQTLs with genetic and health information from 450,000 UK Biobank participants illuminated metabolic mediators, and hence, novel urinary biomarkers of disease risk. This comprehensive resource of genetic targets and their substrates is informative for ADME processes in humans and is relevant to basic science, clinical medicine and pharmaceutical research.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Pressure ulcer prophylaxis is a central topic in clinical care. Pressure-relieving repositioning is strongly recommended for all pressure-sensitive patients. The Mobility Monitor (MoMo) is a ...technical device that records a patient's movements and transmits the data to a monitor. This study investigated the extent to which the MoMo sensor system, which records and visualises patients' movements in bed, supports nurses in performing pressure-relieving repositioning in neurological and neurosurgical intensive care units (ICU).
This stepped-wedge cluster-randomised trial involved two clusters: one neurological and one neurosurgical ICU. The study was carried out in two steps over three periods between November 2018 and May 2019, with a two-month interval between each step. At the beginning of the study, we equipped 33 beds across the two ICUs with a MoMo system. Our primary endpoint was the immobility rate, which is defined as the patient's inactive time in bed exceeding two hours without pressure-relieving movements divided by the time the MoMo was in the bed. The immobility rate ranges from 0 to below 1, with higher values indicating lower mobility. Secondary endpoints were the rate of new pressure ulcers and the rate of relevant pressure-relieving repositionings. Relevant repositionings are defined as the number of repositionings identified by the MoMo as a pressure-relieving repositioning divided by the total number of repositionings, RESULTS: 808 patients were included in the study, of whom 403 were in the control group and 405 were in the intervention group. The mean immobility rate was 0.171 during the control phase and 0.144 during the intervention phase. The estimated intervention effect was -0.0018 (95% confidence interval -0.0471, 0.0436, p=0.94). The number of new pressure ulcers was 5/405 in the intervention phase and 15/403 in the control phase. We noted a small difference in the mean rate of relevant repositioningswith an estimated intervention effect of 0.046 (95% confidence interval -0.018, 0.110, p=0.16).
Our results are insufficient to recommend the standardised use of mobility monitors in neurological or neurosurgical ICUs.
The primary analysis was prespecified and the trial was registered in the German Clinical Trials Register (DRKS) under the reference number DRKS00015492 (31/10/2018).
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IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UL, UM, UPUK, VSZLJ
Chronic kidney disease (CKD) is highly connected to inflammation and oxidative stress. Both favour the development of cancer in CKD patients. Serum apolipoprotein A-IV (apoA-IV) concentrations are ...influenced by kidney function and are an early marker of kidney impairment. Besides others, it has antioxidant and anti-inflammatory properties. Proteomic studies and small case-control studies identified low apoA-IV as a biomarker for various forms of cancer; however, prospective studies are lacking. We therefore investigated whether serum apoA-IV is associated with cancer in the German Chronic Kidney Disease (GCKD) study.
These analyses include 5039 Caucasian patients from the prospective GCKD cohort study followed for 6.5 years. Main inclusion criteria were an eGFR of 30-60 mL/min/1.73m
or an eGFR > 60 mL/min/1.73m
in the presence of overt proteinuria.
Mean apoA-IV concentrations of the entire cohort were 28.9 ± 9.8 mg/dL (median 27.6 mg/dL). 615 patients had a history of cancer before the enrolment into the study. ApoA-IV concentrations above the median were associated with a lower odds for a history of cancer (OR = 0.79, p = 0.02 when adjusted age, sex, smoking, diabetes, BMI, albuminuria, statin intake, and eGFR
). During follow-up 368 patients developed an incident cancer event and those with apoA-IV above the median had a lower risk (HR = 0.72, 95%CI 0.57-0.90, P = 0.004). Finally, 62 patients died from such an incident cancer event and each 10 mg/dL higher apoA-IV concentrations were associated with a lower risk for fatal cancer (HR = 0.62, 95%CI 0.44-0.88, P = 0.007).
Our data indicate an association of high apoA-IV concentrations with reduced frequencies of a history of cancer as well as incident fatal and non-fatal cancer events in a large cohort of patients with CKD.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Higher serum 6-bromotryptophan has been associated with lower risk of chronic kidney disease (CKD) progression, implicating mechanisms beyond renal clearance. We studied genetic determinants of urine ...6-bromotryptophan and its association with CKD risk factors and incident end-stage kidney disease (ESKD) in 4,843 participants of the German Chronic Kidney Disease (GCKD) study. 6-bromotryptophan was measured from urine samples using mass spectrometry. Patients with higher levels of urine 6-bromotryptophan had higher baseline estimated glomerular filtration rate (eGFR, p < 0.001). A genome-wide association study of urine 6-bromotryptophan identified two significant loci possibly related to its tubular reabsorption, SLC6A19, and its production, ERO1A, which was also associated with serum 6-bromotryptophan in an independent study. The association between urine 6-bromotryptophan and time to ESKD was assessed using Cox regression. There were 216 ESKD events after four years of follow-up. Compared with patients with undetectable levels, higher 6-bromotryptophan levels were associated with lower risk of ESKD in models unadjusted and adjusted for ESKD risk factors other than eGFR (<median level: cause-specific hazard ratio HR 0.70, 95% confidence interval CI 0.51 to 0.97; ≥median level: HR 0.50, 95% CI 0.34 to 0.74). Upon adjustment for baseline eGFR, this association became attenuated, suggesting that urine 6-bromotryptophan may represent a correlated marker of kidney health.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Background
Hypothyroidism 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.
Methods
Thyroid 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.
Results
Cross-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 (Nevents = 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; Nevents = 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.
Conclusions
Patients 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.
Abstract
BACKGROUND AND AIMS
Over 10% of the adult population worldwide is affected by chronic kidney disease (CKD). CKD is associated with an increased risk of kidney failure (KF), cardiovascular ...events and mortality. CKD is defined and staged by estimated glomerular filtration rate (eGFR), the most common measure of kidney function. Genome-wide association studies enable the calculation of polygenic risk scores (PRSs), e.g. for eGFR. The aim of this study was to investigate if a polygenic predisposition to lower eGFR is associated with KF, cardiovascular events and mortality in people with CKD, and if the eGFR PRS carries predictive ability.
METHOD
A PRS for log(eGFR) was developed and tuned in independent, general population-based study samples consisting of European ancestry participants of the UK Biobank and the CKDGen Consortium via the LDpred algorithm 1. Using genetic information and follow-up data of 4873 participants with moderate CKD enrolled in the German Chronic Kidney Disease study, we calculated, standardized and evaluated the association of the PRS with adverse endpoints. Main endpoints included KF, a composite endpoint of myocardial infarction, cerebral haemorrhage and stroke (3P-MACE), and overall mortality. Cox proportional hazard regression was conducted to estimate (cause-specific) hazard ratios (HRs). Predictive performance of the PRS for KF and 3P-MACE was assessed using prediction error curves and time-dependent c-index. The statistical significance level was Bonferroni-corrected for three main endpoints (P < .05/3).
RESULTS
After a median follow-up time of 6.5 years, 619 patients died, 466 experienced KF, and 545 3P-MACE. Higher levels of the PRS, corresponding to a genetic predisposition to lower eGFR, were associated with higher risk for all three endpoints {KF: HR 1.23, 95% confidence interval (95% CI) 1.12–1.35, 3MACE: 1.15 (1.06–1.25), mortality: 1.12 (1.04;1.22)} after adjusting for baseline age, sex and two principal components. Across deciles of the eGFR PRS, participants in the highest decile, corresponding to the genetically lowest eGFR, had a >2-fold increased risk of KF compared with those in the lowest decile HR = 2.13 (1.39–3.27), Fig. 1. No distinct improvement in the prediction performance for KF was observed when adding the PRS to the well-established KF risk equation by Tangri et al. 2. This also held true for the added predictive ability of the PRS for 3P-MACE when compared with a model with established cardiovascular risk factors.
CONCLUSION
Our study revealed a significant association between a polygenic predisposition to lower eGFR and KF, cardiovascular events, and mortality among people with moderate CKD, emphasizing the importance of genetic background even after disease onset. The eGFR PRS carried no added predictive ability with regard to KF and 3P-MACE beyond established risk factors.
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