Trimethylamine N-oxide (TMAO) is a gut microbial metabolite derived from dietary phosphatidylcholine and carnitine. Recently, we have shown that TMAO accumulates in patients with chronic kidney disease (CKD), not only due to impaired kidney clearance, but also due to altered microbial production. Increasing evidence points to TMAO as an emerging contributor to cardiovascular disease. However, the prognostic impact of TMAO on adverse kidney outcomes in patients with established CKD remains unclear. Thus, the aim of this study was to determine the prevalence and prognostic implications of TMAO in patients with CKD. We analyzed data from 4724 participants of the German Chronic Kidney Disease (GCKD) cohort, a prospective observational cohort of CKD patients with an eGFR of 30-60 mL/min/1.73 m2 or overt proteinuria in the presence of an eGFR>60 mL/min/1.73 m2 at enrollment. TMAO levels were quantified in plasma at baseline using proton nuclear magnetic resonance spectroscopy. Creatinine and cystatin C measurements were obtained up to four times during follow-up, enabling the calculation of eGFR trajectories. The primary outcomes were all-cause mortality as well as the incidence of composite kidney endpoint (CKE), defined as eGFR decline >40% from baseline, eGFR <15 ml/min/1.73 m², initiation of kidney replacement therapy (dialysis or transplantation), or renal death, within 6.5 years. Time-to-event analyses were conducted using multivariate proportional hazards regression models. Median TMAO levels increased with higher CKD GFR and albuminuria categories. Over a median follow-up of 6.5 years, 479 deaths were recorded. Elevated TMAO concentrations at baseline (fourth versus first quartile) were significantly associated with increased all-cause mortality risk. This association remained robust after adjustment for traditional risk factors, history of cardiovascular disease, high-sensitivity C-reactive protein, and eGFR as well as albuminuria. Further, higher TMAO levels were consistently associated with increased incidence of CKE and after multivariate analyses independently predicted CKE risk, underscoring its potential as a prognostic kidney biomarker in CKD. Among patients with CKD, TMAO levels were increased progressively with lower GFR and higher albuminuria. Elevated TMAO levels were independently associated with a greater risk of all-cause mortality and CKE. These findings emphasize the critical role of gut microbiota-derived metabolites in the progression and outcomes of CKD, highlighting TMAO as a potential biomarker for risk stratification and as a potential target for therapeutic intervention.

Introduction:The rate of decline in estimated glomerular filtration rate (GFR, eGFR) is increasingly recognized as a quantitative marker of chronic kidney disease (CKD) progression. However, data on eGFR slopes have mainly been reported in cohorts enriched for fast progression and the heterogeneity of eGFR slopes across the spectrum of CKD remains poorly defined. Methods:In 5214 participants of the German CKD (GCKD) study, we modeled eGFR slopes using per-protocol and clinical measurements. We used linear-mixed effects models, with eGFR slope as the outcome and baseline demographics as independent variables to (i) describe eGFR slope heterogeneity; (ii) assess differences by CKD etiology, eGFR and urinary albumin-to-creatinine ratio (UACR) categories, sex, and age; and (iii) determine associations of slopes with estimated eGFR decline (30%, 40%, and 57%) and observed end points (kidney failure with replacement therapy, mortality). Results:On average, 9 eGFR values per participant (interquartile range: 7-12) over 6.5 years were used for slope calculation. The adjusted mean annual eGFR slope was -1.43 ml/min per 1.73 m2. Slopes were similar across eGFR categories, but steeper with higher UACR. Faster eGFR decline was observed in participants of younger age and in those with polycystic kidney disease or diabetic kidney disease (DKD). Although eGFR slopes did not consistently differ by sex, women with diabetes as the leading cause of CKD had lower slopes than their male counterparts. A rapid annual decline (> 5 ml/min per 1.73 m2) occurred in 4.3%, with variation in frequency by CKD cause and UACR. Conclusion:In conclusion, though the average eGFR slope was low, it varied considerably, depending on CKD etiology and UACR. This data may help to put slope estimates in individual patients and defined subpopulations into perspective.

Rationale & Objective: Afamin is a vitamin Ebinding glycoprotein primarily expressed in the liver and kidney. This study investigated whether serum afamin concentrations are associated with kidney function and incident kidney failure. Study Design: Prospective cohort study with 6.5 years follow-up. Setting & Participants: 5,041 White patients enrolled in the German Chronic Kidney Disease (GCKD) study with measured afamin concentrations and either an estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m2 or an eGFR > 60 mL/min/1.73 m2 with a urinary albumin-creatinine ratio (UACR) of >= 300 mg/g at study entry. Exposure: Serum afamin concentrations (mg/L). Outcome: Incident kidney failure (initiation of kidney replacement therapy or kidney-related death). Analytical Approach: Generalized linear regression and quantile regression models fit to investigate the association of afamin concentrations with eGFR and UACR. Adjusted Cox regression analysis to examine the association of afamin concentrations with incident kidney failure. Results: The mean +/- SD afamin concentration at study entry was 73.2 +/- 17.6 mg/L. Higher afamin concentrations were associated with better kidney function with a 2.60 mL/min/1.73 m2 higher eGFR (95% CI, 2.30-2.8 9) and a 5.97 mg/g lower UACR (95% CI, 3.04-8.9 0) for each 10 mg/L higher level of afamin concentration in adjusted analysis. During the follow-up period, each 10 mg/L higher level of afamin concentration was associated with a 14% lower risk of kidney failure (HR, 0.86 [95%CI, 0.810.92], P < 0.001). Limitations: Residual confounding, and potential limited generalizability to non-White populations and people with mild stages of chronic kidney disease (CKD) or no CKD. Conclusions: Higher serum afamin concentrations appear to be associated with a higher eGFR, less albuminuria, and a lower risk for future kidney failure in patients with CKD.

Genetic studies of the metabolome can uncover enzymatic and transport processes shaping human metabolism. Using rare variant aggregation testing based on whole-exome sequencing data to detect genes associated with levels of 1,294 plasma and 1,396 urine metabolites, we discovered 235 gene–metabolite associations, many previously unreported. Complementary approaches (genetic, computational (in silico gene knockouts in whole-body models of human metabolism) and one experimental proof of principle) provided orthogonal evidence that studies of rare, damaging variants in the heterozygous state permit inferences concordant with those from inborn errors of metabolism. Allelic series of functional variants in transporters responsible for transcellular sulfate reabsorption (SLC13A1, SLC26A1) exhibited graded effects on plasma sulfate and human height and pinpointed alleles associated with increased odds of diverse musculoskeletal traits and diseases in the population. This integrative approach can identify new players in incompletely characterized human metabolic reactions and reveal metabolic readouts informative of human traits and diseases. Gene-based rare variant aggregation study with the levels of 1,294 plasma and 1,396 urine metabolites from paired specimens of 4,737 participants reveals graded effects of rare, putatively damaging variants on gene function and human traits.

Urinary proteins are valuable biomarkers for physiological processes and early detection and moni-toring of systemic and kidney diseases. However, comprehensive quantification and characterization of the urine proteome using high-throughput platforms remains limited. Using an affinity-based assay for large-scale proteomics, the Olink Explore 3072 platform, we quanti-fied 2,868 proteins in urine samples from 1,268 participants of the German Chronic Kidney Disease (GCKD) study. Protein detectability in urine, defined as the percentage of samples with measurements above the limit of detection, showed a bimodal distribution: 659 (23%) proteins had high (>80%) and 1,336 proteins (47%) had low (<20%) detectability. Over 95% of highly detectable proteins were confirmed as present in urine by mass spectrometry. They were enriched for extracellular, exosomal, and cell-surface localization, and showed tissue-specific expression in hepatocytes, immune cells, and prox-imal tubule cells. Significant associations of protein levels with sex (921 proteins), BMI (367 proteins) and age (157 proteins) showed plausible relationships such as prostate-specific antigen and male sex. Unsuper-vised correlation analysis of protein levels detected multiple biologically meaningful protein clus-ters, reflecting shared cellular compartments (e.g., lysosomal origin), tissue of origin (e.g., liver), and molecular interactions (e.g., receptor-ligand or chaperone-transporter complexes). In conclusion, the Olink Explore 3072 platform is well-suited for large-scale urine proteomics and identifies biologically plausible representations of ongoing processes in health and disease. Our comprehensive characterization provides a valuable resource for biomarker discovery and future targeted studies of urine proteins. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The work of M.M., S.H., O.B., and A.K. was funded by German Research Foundation (DFG) project ID 431984000 (SFB 1453). Germany's Excellence Strategy (CIBSS, EXC-2189, project ID 390939984) supported the work of Y.L. and A.K. The GCKD study was and is supported by the BMBF (FKZ 01ER 0804, 01ER 0818, 01ER 0819, 01ER 0820 and 01ER 0821) and the KfH Foundation for Preventive Medicine. Unregistered grants to sup-port the study were provided by corporate sponsors (listed at https://gckd.org). We are grateful for the willingness of the patients to participate in the GCKD study. The enormous effort of the study personnel of the various regional centers is highly appreciated. We thank the large number of neph-rologists who provide routine care for the patients and collaborate with the GCKD study. The GCKD investigators are listed in the Supplementary Note. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All Ethics Committees of all participating institutions gave ethical approval for this work. The study centers include: Friedrich-Alexander-University Erlangen-Nuremberg, Medical Faculty of the Rheinisch-Westfaelische Technische Hochschule Aachen, Charite-University Medicine Berlin, Medical Center-University of Freiburg, Medizinische Hochschule Hannover, Medical Faculty of the University of Heidelberg, Friedrich-Schiller-University Jena, Medical Faculty of the Ludwig-Maximilians-University Munich, Medical Faculty of the University of Wuerzburg). The GCKD study is listed in the German Clinical Trials Register (DRKS 00003971). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Comprehensive summary data are provided in the supplementary materials, including: protein de-tectability values in urine overall and by batch, as well as stratified by sex (Supplementary Tables 3 and 10), protein variability measures (Supplementary Table 6), associations with demographic fac-tors (Supplementary Table 8), and correlation/network analyses (Supplementary Table 9). Data underlying the results and figures presented in this manuscript are available in the supplementary tables. Code used for statistical analyses is available from the corresponding author upon reasona-ble request. Information on publicly available external datasets used in this study is provided in the Methods and Supplementary Methods sections. Individual-level data from the GCKD study can be made available to approved collaborators upon request to the GCKD data access committee, in ac-cordance with German data protection laws and participant consent agreements. Details are availa-ble at https://www.gckd.org/.

Introduction The rate of decline in eGFR is increasingly recognized as a quantitative marker of chronic kidney disease (CKD) progression. However, data on eGFR slopes have mainly been reported in cohorts enriched for fast progression and the heterogeneity of eGFR slopes across the spectrum of CKD remains poorly defined. Methods In 5,214 participants of the German CKD (GCKD) study, we modeled eGFR slopes using per-protocol and clinical measurements. We used linear-mixed effects models, with eGFR slope as the outcome and baseline demographics as independent variables, to (i) describe eGFR slope heterogeneity, (ii) assess differences by CKD etiology, eGFR and UACR categories, sex and age, and (iii) determine associations of slopes with estimated eGFR decline (30%, 40%, and 57%) and observed endpoints (kidney failure with replacement therapy, mortality). Results On average 9 eGFR values/participant (IQR 7-12) over 6.5 years were used for slope calculation. The adjusted mean annual eGFR slope was -1.43mL/min/1.73m2. Slopes were similar across eGFR categories, but steeper with higher UACR. Faster eGFR decline was observed in participants of younger age and in those with polycystic or diabetic kidney disease. While eGFR slopes did not consistently differ by sex, women with diabetes as the leading cause of CKD had lower slopes than their male counterparts. A rapid annual decline (> 5 mL/min/1.73m2) occurred in 4.3%, with variation in frequency by CKD cause and UACR. Conclusion In conclusion, while the average eGFR slope was low, it varied considerably, depending on CKD etiology and UACR. This data may help to put slope estimates in individual patients and defined subpopulations into perspective.

Background Persons with chronic kidney disease (CKD) are at increased risk of adverse events, early mortality and multimorbidity. A detailed overview of adverse event types and rates from a large CKD cohort under regular nephrological care is missing. We generated an interactive tool to enable exploration of adverse events and their combinations in the prospective, observational German CKD (GCKD) study. Methods The GCKD study enrolled 5217 participants under regular nephrological care with an estimated glomerular filtration rate of 30-60 or >60 mL/min/1.73 m2 and an overt proteinuria. Cardiovascular, cerebrovascular and peripheral vascular, kidney, infection, and cancer events, as well as deaths were adjudicated following a standard operation procedure. We summarized these time-to-event data points for exploration in interactive graphs within an R shiny app. Multivariable adjusted Cox models for time to first event were fitted. Cumulative incidence functions, Kaplan-Meier curves and intersection plots were used to display main adverse events and their combinations by sex and CKD etiology. Results Over a median of 6.5 years, 10 271 events occurred in 2947 participants (56.5%), of which 680 participants (13.0%) died. The new publicly available interactive platform enables readers to scrutinize adverse events and their combinations as well as mortality trends as a gateway to better understand multimorbidity in CKD: incident rates per 1000 patient-years varied by event type, CKD etiology and baseline characteristics. Incidence rates for the most frequent events and their recurrence were 113.6 (cardiovascular), 75.0 (kidney) and 66.0 (infection). Participants with presumed diabetic kidney disease and men were more prone to experiencing events. Conclusion This comprehensive explorative tool to visualize adverse events (https://www.gckd.org/studienhintergrund/previous-study-results/event-analysis/), their combination, mortality and multimorbidity among persons with CKD may serve as a valuable resourec for patient care, identification of high-risk groups, health services and public health policy planning.

Background 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. Methods 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 2 or an eGFR > 60 mL/min/1.73m 2 in the presence of overt proteinuria. Results 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 creatinine ). 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). Conclusions 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. Graphical Abstract

Rationale & Objective: Copeptin and Midrange pro-atrial natriuretic peptide (MR-pro-AN P) are associated with outcomes independently of N -termi-nal pro-brain natriuretic peptide (NT-pro-BNP) patients with heart failure (HF). The value of these markers in patients with chronic kidney disease (CKD) has not been studied. Study Design: Prospective cohort study. Setting & Participants: A total of 4,417 patients enrolled in the German Chronic Kidney Disease (GCKD) study with an estimated glomerular filtra-tion rate of 30-60 mL/min/1.73m2 or overt pro-teinuria (urinary albumin-creatinine ratio >3 00mg/g or equivalent). Exposures: Copeptin, MR-pro-ANP, and NT-pro-BNP levels were measured in baseline samples. Outcomes: Noncardiovascular death, cardiovas-cular (CV) death, major adverse CV event (MACE), and hospitalization for HF. Analytical Approach: HRs for associations of Copeptin, MR-pro-ANP, and NT-pro-BNP with outcomes were estimated using Cox regression analyses adjusted for established risk factors. Results: During a maximum follow-up of 6.5 years, 413 non-CV deaths, 179 CV deaths, 519 MACE, and 388 hospitalizations for HF were observed. In Cox regression analyses adjusted for established risk factors, each one of the 3 markers were associated with all the 4 outcomes, albeit the highest HRs were found for NT-pro-BNP. When models were extended to include all the 3 markers, NT-pro-BNP remained associated with all 4 outcomes. Conversely, from the 2 novel markers, associations remained only for Copeptin with non-CV death (HR, 1.62; 95% CI, 1.04-2.54 for highest vs lowest quintile) and with hospitalizations for HF (HR, 1.73; 95% CI, 1.0 8-2.75). Limitations: Single-point measurements of Copeptin, MR-pro-ANP, and NT-pro-BNP. Conclusions: In patients with moderately severe CKD, we confirm NT-pro-BNP to be strongly associated with all outcomes examined. As the main finding, the novel marker Copeptin demonstrated independent associations with non-CV death and hospitalizations for HF, and should therefore be evaluated further for risk assessment in CKD.

ABSTRACT Background Diabetes mellitus (DM) and chronic kidney disease (CKD) are well-known cardiovascular and mortality risk factors. To what extent they act in an additive manner and whether the etiology of CKD modifies the risk is uncertain. Methods The multicenter, prospective, observational German Chronic Kidney Disease study comprises 5217 participants (1868 with DM) with a baseline mean estimated glomerular filtration rate of 30–60 mL/min/1.73 m2 and/or proteinuria >0.5 g/day. We categorized patients whose CKD was caused by cardiovascular or metabolic diseases (CKDcvm) with and without DM, as opposed to genuine CKD (CKDgen) with and without DM. Recorded outcomes were first events of non-cardiovascular and cardiovascular death, 4-point major adverse cardiovascular events (4-point MACE) and hospitalization for heart failure (HHF). Results During the 6.5-year follow-up 603 (12%) non-cardiovascular and 209 (4%) cardiovascular deaths, 645 (12%) 4-point MACE, and 398 (8%) HHF were observed, most frequently in patients with DM having CKDcvm. DM increased the risk of non-cardiovascular [hazard ratio (HR) 1.92; 95% confidence interval (CI) 1.59–2.32] and cardiovascular (HR 2.25; 95% CI 1.62–3.12) deaths, 4-point MACE (HR 1.93; 95% CI 1.62–2.31) and HHF (HR 1.87; 95% CI 1.48–2.36). Mortality risks were elevated by DM to a similar extent in CKDcvm and CKDgen, but for HHF in CKDcvm only (HR 2.07; 95% CI 1.55–2.77). In patients with DM, CKDcvm (versus CKDgen) only increased the risk for HHF (HR 1.93; 95% CI 1.15–3.22). Conclusions DM contributes to cardiovascular and mortality excess risk in patients with moderate to severe CKD in both, CKDcvm and CKDgen. Patients with DM and CKDcvm are particularly susceptible to HHF.

Objective: Adipose tissue contributes to adverse outcomes in chronic kidney disease (CKD), but there is uncertainty regarding the prognostic relevance of different adiposity measures. We analyzed the associations of neck circumference (NC), waist circumference (WC), and body mass index (BMI) with clinical outcomes in patients with mild to severe CKD.Methods: The German Chronic Kidney Disease study isa prospective cohort study, which enrolled Caucasian adults with mild to severe CKD, defined as estimated glomerular filtration rate : 30-60 mL/min/1.73 m2, or .60 mL/min/1.73 m2 in the presence of overt proteinuria. Associations of NC, WC, and BMI with all-cause death, major adverse cardiovascular events (MACE: a composite of nonfatal stroke, nonfatal myocardial infarction, peripheral artery disease intervention, and cardiovascular death), and kidney failure (a composite of dialysis or transplantation) were analyzed using multivariable Cox proportional hazards regression models adjusted for confounders and the Akaike information criteria were calculated. Models included sex interactions with adiposity measures.Results: A total of 4537 participants (59% male) were included in the analysis. During a 6.5-year follow-up, 339 participants died, 510 experienced MACE, and 341 developed kidney failure. In fully adjusted models, NC was associated with all-cause death in women (hazard ratio 1.080 per cm; 95% CI 1.009-1.155) but not in men. Irrespective of sex, WC was associated with all-cause death (hazard ratio 1.014 per cm; 95% CI 1.005-1.038). NC and WC showed no association with MACE or kidney failure. BMI was not associated with any of the analyzed outcomes. Models of all-cause death, including WC offered the best (lowest) Akaike information criteria.Conclusion: In Caucasian patients with mild to severe CKD, higher NC (in women) and WC were significantly associated with increased risk of death from any cause but BMI was not.

Importance:Type 2 diabetes increases the risk of progressive diabetic kidney disease, but reliable prediction tools that can be used in clinical practice and aid in patients' understanding of disease progression are currently lacking.Objective:To develop and externally validate a model to predict future trajectories in estimated glomerular filtration rate (eGFR) in adults with type 2 diabetes and chronic kidney disease using data from 3 European multinational cohorts.Design, Setting, and Participants:This prognostic study used baseline and follow-up information collected between February 2010 and December 2019 from 3 prospective multinational cohort studies: PROVALID (Prospective Cohort Study in Patients with Type 2 Diabetes Mellitus for Validation of Biomarkers), GCKD (German Chronic Kidney Disease), and DIACORE (Diabetes Cohorte). A total of 4637 adult participants (aged 18-75 years) with type 2 diabetes and mildly to moderately impaired kidney function (baseline eGFR of ≥30 mL/min/1.73 m2) were included. Data were analyzed between June 30, 2021, and January 31, 2023.Main Outcomes and Measures:Thirteen variables readily available from routine clinical care visits (age, sex, body mass index; smoking status; hemoglobin A1c [mmol/mol and percentage]; hemoglobin, and serum cholesterol levels; mean arterial pressure, urinary albumin-creatinine ratio, and intake of glucose-lowering, blood-pressure lowering, or lipid-lowering medication) were selected as predictors. Repeated eGFR measurements at baseline and follow-up visits were used as the outcome. A linear mixed-effects model for repeated eGFR measurements at study entry up to the last recorded follow-up visit (up to 5 years after baseline) was fit and externally validated.Results:Among 4637 adults with type 2 diabetes and chronic kidney disease (mean [SD] age at baseline, 63.5 [9.1] years; 2680 men [57.8%]; all of White race), 3323 participants from the PROVALID and GCKD studies (mean [SD] age at baseline, 63.2 [9.3] years; 1864 men [56.1%]) were included in the model development cohort, and 1314 participants from the DIACORE study (mean [SD] age at baseline, 64.5 [8.3] years; 816 men [62.1%]) were included in the external validation cohort, with a mean (SD) follow-up of 5.0 (0.6) years. Updating the random coefficient estimates with baseline eGFR values yielded improved predictive performance, which was particularly evident in the visual inspection of the calibration curve (calibration slope at 5 years: 1.09; 95% CI, 1.04-1.15). The prediction model had good discrimination in the validation cohort, with the lowest C statistic at 5 years after baseline (0.79; 95% CI, 0.77-0.80). The model also had predictive accuracy, with an R2 ranging from 0.70 (95% CI, 0.63-0.76) at year 1 to 0.58 (95% CI, 0.53-0.63) at year 5.Conclusions and Relevance:In this prognostic study, a reliable prediction model was developed and externally validated; the robust model was well calibrated and capable of predicting kidney function decline up to 5 years after baseline. The results and prediction model are publicly available in an accompanying web-based application, which may open the way for improved prediction of individual eGFR trajectories and disease progression.

Mineral and bone disorder (MBD) in chronic kidney disease (CKD) is tightly linked to cardiovascular disease (CVD). In this study, we aimed to compare the prognostic value of nine MBD biomarkers to determine those associated best with adverse cardiovascular (CV) outcomes and mortality. In 5 217 participants of the German CKD (GCKD) study enrolled with an estimated glomerular filtration rate (eGFR) between 30–60 mL·min −1 per 1.73 m 2 or overt proteinuria, serum osteoprotegerin (OPG), C-terminal fibroblast growth factor-23 (FGF23), intact parathyroid hormone (iPTH), bone alkaline phosphatase (BAP), cross-linked C-telopeptide of type 1 collagen (CTX1), procollagen 1 intact N-terminal propeptide (P1NP), phosphate, calcium, and 25-OH vitamin D were measured at baseline. Participants with missing values among these parameters ( n = 971) were excluded, leaving a total of 4 246 participants for analysis. During a median follow-up of 6.5 years, 387 non-CV deaths, 173 CV deaths, 645 nonfatal major adverse CV events (MACEs) and 368 hospitalizations for congestive heart failure (CHF) were observed. OPG and FGF23 were associated with all outcomes, with the highest hazard ratios (HRs) for OPG. In the final Cox regression model, adjusted for CV risk factors, including kidney function and all other investigated biomarkers, each standard deviation increase in OPG was associated with non-CV death (HR 1.76, 95% CI: 1.35–2.30), CV death (HR 2.18, 95% CI: 1.50–3.16), MACE (HR 1.38, 95% CI: 1.12–1.71) and hospitalization for CHF (HR 2.05, 95% CI: 1.56–2.69). Out of the nine biomarkers examined, stratification based on serum OPG best identified the CKD patients who were at the highest risk for any adverse CV outcome and mortality.

The kidneys operate at the interface of plasma and urine by clearing molecular waste products while retaining valuable solutes. Genetic studies of paired plasma and urine metabolomes may identify underlying processes. We conducted genome-wide studies of 1,916 plasma and urine metabolites and detected 1,299 significant associations. Associations with 40% of implicated metabolites would have been missed by studying plasma alone. We detected urine-specific findings that provide information about metabolite reabsorption in the kidney, such as aquaporin (AQP)-7-mediated glycerol transport, and different metabolomic footprints of kidney-expressed proteins in plasma and urine that are consistent with their localization and function, including the transporters NaDC3 ( SLC13A3 ) and ASBT ( SLC10A2 ). Shared genetic determinants of 7,073 metabolite–disease combinations represent a resource to better understand metabolic diseases and revealed connections of dipeptidase 1 with circulating digestive enzymes and with hypertension. Extending genetic studies of the metabolome beyond plasma yields unique insights into processes at the interface of body compartments.

BACKGROUND AND AIMS:HDL-mediated cholesterol efflux capacity (CEC) may protect from cardiovascular disease. Thus, we aimed to identify its genetic and non-genetic determinants. METHODS:We measured CEC to 2% apolipoprotein B-depleted serum using BODIPY-cholesterol and cAMP-stimulated J774A.1 macrophages using serum samples from 4,981 participants in the German Chronic Kidney Disease (GCKD) study. Variance of CEC explained by clinical and biochemical parameters in a multivariable linear regression model was calculated by proportional marginal variance decomposition. A genome-wide association study with 7,746,917 variants was performed based on an additive genetic model. The main model was adjusted for age, sex and principal components 1-10. Further models were selected for sensitivity analysis and to reduce residual variance by known CEC pathways. RESULTS:Variables that explained 1% and more of the variance of CEC were concentrations of triglycerides (12.9%), HDL-cholesterol (11.8%), LDL-cholesterol (3.0%), apolipoprotein A-IV (2.8%), PCSK9 (1.0%), and eGFR (1.0%). The KLKB1 (chr4) and APOE/C1 (chr19) loci were genome-wide significantly (p < 5x10-8) associated with CEC in our main model (p = 8.8x10-10 and p = 3.3x10-10, respectively). KLKB1 remained significantly associated after additional adjustment for either kidney parameters, HDL-cholesterol, triglycerides or apolipoprotein A-IV concentrations, while the APOE/C1 locus was not significantly associated anymore after adjustment for triglycerides. Adjustment for triglycerides also revealed an association with the CLSTN2 locus (chr3; p = 6.0x10-9). CONCLUSIONS:We identified HDL-cholesterol and triglycerides as the main determinants of CEC. Furthermore, we newly found a significant association of CEC with the KLKB1 and the CLSTN2 locus and confirmed the association with the APOE/C1 locus, likely mediated by triglycerides.

Abstract Background Chronic kidney disease (CKD) is a common comorbidity in people with diabetes mellitus, and a key risk factor for further life-threatening conditions such as cardiovascular disease. The early prediction of progression of CKD therefore is an important clinical goal, but remains difficult due to the multifaceted nature of the condition. We validated a set of established protein biomarkers for the prediction of trajectories of estimated glomerular filtration rate (eGFR) in people with moderately advanced chronic kidney disease and diabetes mellitus. Our aim was to discern which biomarkers associate with baseline eGFR or are important for the prediction of the future eGFR trajectory. Methods We used Bayesian linear mixed models with weakly informative and shrinkage priors for clinical predictors (n = 12) and protein biomarkers (n = 19) to model eGFR trajectories in a retrospective cohort study of people with diabetes mellitus (n = 838) from the nationwide German Chronic Kidney Disease study. We used baseline eGFR to update the models’ predictions, thereby assessing the importance of the predictors and improving predictive accuracy computed using repeated cross-validation. Results The model combining clinical and protein predictors had higher predictive performance than a clinical only model, with an $$R^{2}$$ R 2 of 0.44 (95% credible interval 0.37–0.50) before, and 0.59 (95% credible interval 0.51–0.65) after updating by baseline eGFR, respectively. Only few predictors were sufficient to obtain comparable performance to the main model, with markers such as Tumor Necrosis Factor Receptor 1 and Receptor for Advanced Glycation Endproducts being associated with baseline eGFR, while Kidney Injury Molecule 1 and urine albumin-creatinine-ratio were predictive for future eGFR decline. Conclusions Protein biomarkers only modestly improve predictive accuracy compared to clinical predictors alone. The different protein markers serve different roles for the prediction of longitudinal eGFR trajectories potentially reflecting their role in the disease pathway.

Abstract Background Chronic kidney disease (CKD), a major public health problem with differing disease etiologies, leads to complications, comorbidities, polypharmacy, and mortality. Monitoring disease progression and personalized treatment efforts are crucial for long-term patient outcomes. Physicians need to integrate different data levels, e.g., clinical parameters, biomarkers, and drug information, with medical knowledge. Clinical decision support systems (CDSS) can tackle these issues and improve patient management. Knowledge about the awareness and implementation of CDSS in Germany within the field of nephrology is scarce. Purpose Nephrologists’ attitude towards any CDSS and potential CDSS features of interest, like adverse event prediction algorithms, is important for a successful implementation. This survey investigates nephrologists’ experiences with and expectations towards a useful CDSS for daily medical routine in the outpatient setting. Methods The 38-item questionnaire survey was conducted either by telephone or as a do-it-yourself online interview amongst nephrologists across all of Germany. Answers were collected and analysed using the Electronic Data Capture System REDCap, as well as Stata SE 15.1, and Excel. The survey consisted of four modules: experiences with CDSS (M1), expectations towards a helpful CDSS (M2), evaluation of adverse event prediction algorithms (M3), and ethical aspects of CDSS (M4). Descriptive statistical analyses of all questions were conducted. Results The study population comprised 54 physicians, with a response rate of about 80–100% per question. Most participants were aged between 51–60 years (45.1%), 64% were male, and most participants had been working in nephrology out-patient clinics for a median of 10.5 years. Overall, CDSS use was poor (81.2%), often due to lack of knowledge about existing CDSS. Most participants (79%) believed CDSS to be helpful in the management of CKD patients with a high willingness to try out a CDSS. Of all adverse event prediction algorithms, prediction of CKD progression (97.8%) and in-silico simulations of disease progression when changing, e. g., lifestyle or medication (97.7%) were rated most important. The spectrum of answers on ethical aspects of CDSS was diverse. Conclusion This survey provides insights into experience with and expectations of out-patient nephrologists on CDSS. Despite the current lack of knowledge on CDSS, the willingness to integrate CDSS into daily patient care, and the need for adverse event prediction algorithms was high.

ABSTRACT Background The progression of chronic kidney disease (CKD), a global public health burden, is accompanied by a declining number of functional nephrons. Estimation of remaining nephron mass may improve assessment of CKD progression. Uromodulin has been suggested as a marker of tubular mass. We aimed to identify metabolites associated with uromodulin concentrations in urine and serum to characterize pathophysiologic alterations of metabolic pathways to generate new hypotheses regarding CKD pathophysiology. Methods We measured urinary and serum uromodulin levels (uUMOD, sUMOD) and 607 urinary metabolites and performed cross-sectional analyses within the German Chronic Kidney Disease study (N = 4628), a prospective observational study. Urinary metabolites significantly associated with uUMOD and sUMOD were used to build weighted metabolite scores for urine (uMS) and serum uromodulin (sMS) and evaluated for time to adverse kidney events over 6.5 years. Results Metabolites cross-sectionally associated with uromodulin included amino acids of the tryptophan metabolism, lipids and nucleotides. Higher levels of the sMS [hazard ratio (HR) = 0.73 (95% confidence interval 0.64; 0.82), P = 7.45e-07] and sUMOD [HR = 0.74 (95% confidence interval 0.63; 0.87), P = 2.32e-04] were associated with a lower risk of adverse kidney events over time, whereas uUMOD and uMS showed the same direction of association but were not significant. Conclusions We identified urinary metabolites associated with urinary and serum uromodulin. The sUMOD and the sMS were associated with lower risk of adverse kidney events among CKD patients. Higher levels of sUMOD and sMS may reflect a higher number of functional nephrons and therefore a reduced risk of adverse kidney outcomes.

Importance Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. Objective To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, Setting, and Participants Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. Exposures The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). Main Outcomes and Measures The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. Results Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m 2 (SD, 22 mL/min/1.73 m 2 ) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m 2 (SD, 22 mL/min/1.73 m 2 ) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m 2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m 2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). Conclusions and Relevance In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.