German Chronic Kidney Disease Study Research Articles

Associations of Urine and Plasma Metabolites With Kidney Failure and Death in a Chronic Kidney Disease Cohort

Rationale & ObjectiveBiomarkers that enable better identification of persons with chronic kidney disease (CKD) who are at higher risk for disease progression and adverse events are needed. This study sought to identify urine and plasma metabolites associated with progression of kidney disease. Study DesignProspective metabolome-wide association study. Setting & ParticipantsPersons with CKD enrolled in the German CKD Study (GCKD) with metabolite measurements; with external validation within the Atherosclerosis Risk in Communities Study. Exposures1,513 urine and 1,416 plasma metabolites (Metabolon, Inc.) measured at study entry using untargeted mass spectrometry. OutcomesMain endpoints were kidney failure (KF), and a composite endpoint of KF, eGFR <15 mL/min/1.73m2, or 40% decline in eGFR (CKE). Death from any cause was a secondary endpoint. After a median of 6.5 years follow-up, 500 persons experienced KF, 1,083 experienced CKE and 680 died. Analytical ApproachTime-to-event analyses using multivariable proportional hazard regression models in a discovery-replication design, with external validation. Results5,088 GCKD participants were included in analyses of urine metabolites and 5,144 in analyses of plasma metabolites. Among 182 unique metabolites, 30 were significantly associated with KF, 49 with CKE, and 163 with death. The strongest association with KF was observed for plasma hydroxyasparagine (hazard ratio: 1.95, 95% confidence interval: 1.68-2.25). An unnamed metabolite measured in plasma and urine was significantly associated with KF, CKE, and death. External validation of the identified associations of metabolites with KF or CKE revealed direction-consistency for 88% of observed associations. Selected associations of 18 metabolites with study outcomes have not been previously reported. LimitationsUse of observational data and semi-quantitative metabolite measurements at a single time point. ConclusionsThe observed associations between metabolites and KF, CKE or death in persons with CKD confirmed previously reported findings and also revealed several associations not previously described. These findings warrant confirmatory research in other study cohorts.

Long-term outcomes of adults with FSGS in the German Chronic Kidney Disease cohort.

Focal segmental glomerulosclerosis (FSGS) can lead to kidney failure in adults. This study examines the progression of FSGS in the German Chronic Kidney Disease (GCKD) cohort. The GCKD study (N=5217), a prospective cohort, included 159 patients with biopsy-confirmed FSGS recruited from 2010 to 2012. Baseline was defined as the first study visit. Adjudicated endpoints included a composite kidney endpoint (CKE), including an estimated glomerular filtration rate (eGFR) decrease >40%, eGFR <15ml/min/1.73m2 or initiation of kidney replacement therapy and combined major adverse cardiovascular events (MACE), including non-fatal myocardial infarction or stroke and all-cause mortality. Associations between baseline demographics, laboratory data, comorbidity and CKE and MACE were analysed using the Cox proportional hazards regression model. The mean age at baseline was 52.1±13.6years, with a disease duration of 4.72years (quartile 1: 1; quartile 3: 6) before joining the study. The median urinary albumin:creatinine ratio (UACR) at baseline was 0.7g/g (IQR 0.1;1.8), while mean eGFR was 55.8±23ml/min/1.73m2. Based on clinical and pathological features, 69 (43.4%) patients were categorized as primary FSGS, 55 (34.6%) as secondary FSGS and 35 (22%) as indeterminate. Over a follow-up of 6.5years, 44 patients reached the composite kidney endpoint and 16 individuals had at least one MACE. UACR ≥0.7g/g was strongly associated with both the composite kidney endpoint {hazard ratio [HR] 5.27 [95% confidence interval (CI) 2.4-11.5]} and MACE [HR 3.37 (95% CI 1.05-10.82)] compared with <0.7g/g, whereas a higher eGFR at baseline (per 10ml/min) was protective for both endpoints [HR 0.8 (95% CI 0.68-0.95) and HR 0.63 (95% CI 0.46-0.88), respectively]. Patients with secondary FSGS experienced a greater rate of eGFR decline than patients with primary FSGS. Lower eGFR and higher albuminuria are key risk factors for kidney disease progression and cardiovascular events in patients with FSGS.

Interactive exploration of adverse events and multimorbidity in CKD.

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. The GCKD study enrolled 5217 participants under regular nephrological care with an estimated glomerular filtration rate of 30-60 or >60mL/min/1.73m2 and an overt proteinuria. Cardio-, cerebro- 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. Over a median of 6.5 years, 10271 events occurred in total and 680 participants (13.0%) died while 2947 participants (56.5%) experienced any event. 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 diabetic kidney disease and men were more prone to experiencing events. This comprehensive explorative tool to visualize adverse events (https://gckd.diz.uk-erlangen.de/), their combination, mortality, and multimorbidity among persons with CKD may manifest as a valuable resource for patient care, identification of high-risk groups, health services, and public health policy planning.

Apolipoprotein A-IV concentrations and cancer in a large cohort of chronic kidney disease patients: results from the GCKD study

BackgroundChronic 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.MethodsThese 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/1.73m2 or an eGFR > 60 mL/min/1.73m2 in the presence of overt proteinuria.ResultsMean 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 eGFRcreatinine). 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).ConclusionsOur 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

Copeptin, Natriuretic Peptides, and Cardiovascular Outcomes in Patients With CKD: The German Chronic Kidney Disease (GCKD) Study

Copeptin and Midrange pro-atrial natriuretic peptide (MR-pro-ANP) are associated with outcomes independently of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in patients with heart failure (HF). The value of these markers in patients with chronic kidney disease (CKD) has not been studied. Prospective cohort study. A total of 4,417 patients enrolled in the German Chronic Kidney Disease (GCKD) study with an estimated glomerular filtration rate of 30-60mL/min/1.73m2 or overt proteinuria (urinary albumin-creatinine ratio>300mg/g or equivalent). Copeptin, MR-pro-ANP, and NT-pro-BNP levels were measured in baseline samples. Noncardiovascular death, cardiovascular (CV) death, major adverse CV event (MACE), and hospitalization for HF. 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. 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, 1.08-2.75). Single-point measurements of Copeptin, MR-pro-ANP, and NT-pro-BNP. 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. A blood sample-based biomarker that indicates high cardiovascular risk in a patient with kidney disease would help to guide interventions and has the potential to improve outcomes. In 4,417 patients of the German Chronic Kidney Disease study, we assessed the relationship of Copeptin, pro-atrial natriuretic peptide, and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) with important outcomes over a follow-up period of 6.5 years. NT-pro-BNP was strongly associated with all of the 4 outcomes, including death unrelated to cardiovascular disease, death because of cardiovascular disease, a major cardiovascular event, and hospitalization for heart failure. Copeptin was associated with death unrelated to cardiovascular disease and hospitalization for heart failure. NT-pro-BNP and Copeptin are, therefore, promising candidates for a blood sample-based strategy to identify patients with kidney disease at high cardiovascular risk.

Cardiovascular risk due to diabetes mellitus in patients with chronic kidney disease-prospective data from the German Chronic Kidney Disease cohort.

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. The multicenter, prospective, observational German Chronic Kidney Disease study comprises 5217 participants (1868 with DM) with a baseline mean estimated glomerular filtration rate of 30-60mL/min/1.73 m2 and/or proteinuria >0.5g/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). 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). 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.

#4778 THE NATURAL HISTORY OF IGA NEPHROPATHY IN THE GERMAN CHRONIC KIDNEY DISEASE (GCKD) COHORT

Abstract Background and Aims Primary IgA nephropathy (IgAN) is the most common form of glomerulonephritis and a major cause of kidney failure. Here we describe the natural history of individuals with IgAN in the German Chronic Kidney Disease (GCKD) cohort. Method From 2010 to 2012, 421 patients with biopsy-proven IgAN have been enrolled into the GCKD study, a prospective observational cohort study (N = 5217). Inclusion criteria were an estimated glomerular filtration rate (eGFR) of 30-60 mL/min/1.73 m2 or overt proteinuria in the presence of an eGFR&amp;gt;60 mL/min/1.73 m2. The adjudicated composite renal endpoint (Major Adverse Kidney Events; MAKE) was defined as eGFR decline&amp;gt;40%, eGFR&amp;lt; 15 ml/min or initiation of kidney replacement therapy. The associations between the incidence of MAKE and baseline risk factors were analyzed using the Cox proportional hazards regression model. Data relating to baseline demographics, laboratory, comorbidity, and mortality were used. Results The mean age at baseline of IgAN patients was 51.6 years (±13.6) and 67% were male. Duration of disease at baseline was 5.9 ± 8.1 years. Baseline median UACR was 0.4 g/g (0.1-0.8) and mean eGFR was 52.5 ± 22.4 mL/min/1.73m2. Over a follow-up of 6.5 years, 53 (12.6%) initiated kidney replacement therapy, 64 (15.2%) experienced &amp;gt;40% eGFR decline and additional 3 (0.7%) reached eGFR&amp;lt; 15 ml/min, i.e. 28% of the patients experienced a MAKE. Albuminuria, with reference to &amp;lt; 0.1 g/g was most associated with MAKE. Hazard ratios at UACR 0.1-0.6 g/g, 0.6-1.4 g/g, 1.4-2.2 g/g and &amp;gt;2.2 g/g were 2.03 (1.02-4.05), 3.8 (1.92-7.5), 5.64 (2.58-12.33) and 5.02 (2.29-11-03), respectively. Relapse, defined as UACR &amp;gt;2.2g/g, after partial remission (defined as UACR ≥0.1 g/g to &amp;lt;0.6 g/g) or complete (defined as UACR &amp;lt; 0.1 g/g) remission developed in only 13 (3.1%) patients. Conclusion The GCKD study reflects a large cohort with long follow up allowing for a thorough analysis of the natural history of IgAN. More than every fourth patient experienced a MAKE event within 6.5 years. Our findings support the use of albuminuria as a surrogate for poor kidney outcomes.

#5142 THE NATURAL HISTORY OF FSGS IN THE GERMAN CHRONIC KIDNEY DISEASE (GCKD) COHORT

Abstract Background and Aims FSGS is a heterogenic glomerular disease and a common cause of kidney failure in adults. Here we describe the natural history of individuals with FSGS in the German Chronic Kidney Disease (GCKD) cohort. Method From 2010 to 2012, 159 patients with biopsy-proven FSGS have been enrolled into the GCKD study, a prospective observational cohort study (N = 5217). Inclusion criteria were an estimated glomerular filtration rate (eGFR) of 30–60 mL/min/1.73 m2 or overt proteinuria in the presence of an eGFR&amp;gt;60 mL/min/1.73 m2. Baseline date was defined as first study visit. Endpoints were the composite renal endpoint (MAKE); eGFR decline &amp;gt;40%, eGFR&amp;lt; 15ml/min/1.73 m2 or initiation of kidney replacement therapy. The associations between the incidence of MAKE and clinical parameters were analyzed using the Cox proportional hazards regression model. Data relating to baseline demographics, laboratory, comorbidity, and mortality were used. Results The mean age at baseline of patients with FSGS was 52.1 ± 13.6 years. Median proteinuria at baseline was 0.7 g/g (Q1 0.1; Q3 1.8), while mean eGFR was 55.8 ± 23 mL/min/1.73 m². Mean duration of the disease before enrollment was 4.7 ± 6.8 years. The majority (101;63.5%) were male; 69 (43.4%) were diagnosed as primary FSGS using clinical and pathological criteria, 55 (34.6%) as secondary FSGS and for 35 (22%) the etiology was uncertain. At baseline, 37 (23.3%) were under immunosuppressive treatment. Over a follow-up of 6.5 years, 44 reached MAKE, in detail 19 (12%) initiated kidney replacement therapy, an additional 25 (15.8%) experienced a &amp;gt;40% eGFR decline. Albuminuria &amp;gt;0.7 g/g was associated with MAKE, with a HR of 1.47 (95% CI: 1.27-1.7) compared to &amp;lt;0.7 g/g. Higher eGFR at baseline (per 10 ml/min) protected from MAKE with a HR of 0.8 (95% CI: 0.68-0.95). Conclusion The GCKD cohort represents a large study population with lengthy and adjudicated follow-up data. Lower eGFR and higher albuminuria are significant risk factors for progressive kidney disease and ESKD in patients with FSGS.

Differential Prognostic Utility of Adiposity Measures in Chronic Kidney Disease

ObjectiveAdipose 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. MethodsThe German Chronic Kidney Disease study is a 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. ResultsA 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. ConclusionIn 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.

Different roles of protein biomarkers predicting eGFR trajectories in people with chronic kidney disease and diabetes mellitus: a nationwide retrospective cohort study

BackgroundChronic 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.MethodsWe 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.ResultsThe model combining clinical and protein predictors had higher predictive performance than a clinical only model, with an 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.ConclusionsProtein 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.

Prevalence of hereditary tubulointerstitial kidney diseases in the German Chronic Kidney Disease study

Hereditary chronic kidney disease (CKD) appears to be more frequent than the clinical perception. Exome sequencing (ES) studies in CKD cohorts could identify pathogenic variants in ~10% of individuals. Tubulointerstitial kidney diseases, showing no typical clinical/histologic finding but tubulointerstitial fibrosis, are particularly difficult to diagnose. We used a targeted panel (29 genes) and MUC1-SNaPshot to sequence 271 DNAs, selected in defined disease entities and age cutoffs from 5217 individuals in the German Chronic Kidney Disease cohort. We identified 33 pathogenic variants. Of these 27 (81.8%) were in COL4A3/4/5, the largest group being 15 COL4A5 variants with nine unrelated individuals carrying c.1871G>A, p.(Gly624Asp). We found three cysteine variants in UMOD, a novel missense and a novel splice variant in HNF1B and the homoplastic MTTF variant m.616T>C. Copy-number analysis identified a heterozygous COL4A5 deletion, and a HNF1B duplication/deletion, respectively. Overall, pathogenic variants were present in 12.5% (34/271) and variants of unknown significance in 9.6% (26/271) of selected individuals. Bioinformatic predictions paired with gold standard diagnostics for MUC1 (SNaPshot) could not identify the typical cytosine duplication (“c.428dupC”) in any individual, implying that ADTKD-MUC1 is rare. Our study shows that >10% of selected individuals carry disease-causing variants in genes partly associated with tubulointerstitial kidney diseases. COL4A3/4/5 genes constitute the largest fraction, implying they are regularly overlooked using clinical Alport syndrome criteria and displaying the existence of phenocopies. We identified variants easily missed by some ES pipelines. The clinical filtering criteria applied enriched for an underlying genetic disorder.

PCSK9 and Cardiovascular Disease in Individuals with Moderately Decreased Kidney Function.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid homeostasis. Studies investigating the association between PCSK9 and cardiovascular disease in large cohorts of patients with CKD are limited. The association of PCSK9 concentrations with prevalent and incident cardiovascular disease was investigated in 5138 White participants of the German Chronic Kidney Disease study with a median follow-up of 6.5 years. Inclusion criteria were eGFR of 30-60 or >60 ml/min per 1.73 m2 in the presence of overt proteinuria (urine albumin-creatinine ratio >300 mg/g or equivalent). Prevalent cardiovascular disease was defined as a history of nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, carotid arteries interventions, and stroke. Incident major adverse cardiovascular disease events included death from cardiovascular causes, acute nonfatal myocardial infarction, and nonfatal stroke. Median PCSK9 concentration in the cohort was 285 ng/ml (interquartile range, 231-346 ng/ml). There was no association between PCSK9 concentrations and baseline eGFR and albuminuria. With each 100-ng/ml increment of PCSK9, the odds for prevalent cardiovascular disease (n=1284) were 1.22-fold (95% confidence interval, 1.12 to 1.34; P<0.001) higher in a model with extended adjustment for major confounders. This association was stronger in nonstatin than statin users (P value for interaction =0.009). During follow-up, 474 individuals experienced a major adverse cardiovascular disease event, and participants in PCSK9 quartiles 2-4 had a 32%-47% higher risk compared with those in quartile 1 (P<0.05). Subgroup analysis revealed that this association was restricted to those participants who already had cardiovascular disease at baseline (all hazard ratios >1.75; P=0.01). In addition, PCSK9 showed a valuable gain in classification accuracy for both prevalent cardiovascular disease (net reclassification index =0.27; 95% confidence interval, 0.20 to 0.33) and incident major adverse cardiovascular disease events during follow-up (net reclassification index =0.10; 95% confidence interval, 0.01 to 0.21) when added to an extended adjustment model. Our findings reveal no relation of PCSK9 with baseline eGFR and albuminuria but a significant association between higher PCSK9 concentrations and risk of cardiovascular disease independent of traditional risk factors, including LDL cholesterol levels.Clinical Trial registry name and registration number: German Chronic Kidney Disease Study (GCKD), DRKS 00003971.

Uromodulin and its association with urinary metabolites: the German Chronic Kidney Disease Study.

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. 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. 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. 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.

Association of osteopontin with kidney function and kidney failure in chronic kidney disease patients: the GCKD study.

Osteopontin (OPN), synthesized in the thick ascending limb of Henle's loop and in the distal tubule, is involved in the pathogenesis of kidney fibrosis, a hallmark of kidney failure (KF). In a cohort of chronic kidney disease (CKD) patients, we evaluated OPN's association with kidney markers and KF. OPN was measured from baseline serum samples of German Chronic Kidney Disease study participants. Cross-sectional regression models for estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) as well as Cox regression models for all-cause mortality and KF were evaluated to estimate the OPN effect. Additionally, the predictive ability of OPN and time-dependent population-attributable fraction were evaluated. Over a median follow-up of 6.5 years, 471 KF events and 629 deaths occurred among 4950 CKD patients. One-unit higher log(OPN) was associated with 5.5mL/min/1.73 m2 lower eGFR [95% confidence interval (95% CI) -6.4 to -4.6] and 1% change in OPN with 0.7% higher UACR (estimated effect 0.7, 95% CI 0.6-0.8). Moreover, higher OPN levels were associated with a higher risk of KF [hazard ratio (HR) 1.4, 95% CI 1.2-1.7] and all-cause mortality (HR 1.5, 95% CI 1.3-1.8). After 6 years, 31% of the KF events could be attributed to higher OPN levels (95% CI 3%-56%). In this study, higher OPN levels were associated with kidney function markers worsening and a higher risk for adverse outcomes. A larger proportion of KF could be attributed to higher OPN levels, warranting further research on OPN with regards to its role in CKD progression and possible treatment options.

MO517: A Polygenic Risk Score for Reduced EGFR is Associated With Adverse Events in a Chronic Kidney Disease Cohort —the German Chronic Kidney Disease Study

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 &amp;lt; .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 &amp;gt;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.

Genetics of osteopontin in patients with chronic kidney disease: The German Chronic Kidney Disease study.

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.

Telomere length and chronic kidney disease: cause or consequence?

Telomere length is considered as a clock mirroring aging and is influenced by oxidative stress and inflammation. Both conditions are highly prevalent in patients with chronic kidney disease and other degenerative disorders, such as cardiovascular disease. However, it is discussed controversially whether short telomeres are causally associated with chronic kidney disease or whether chronic kidney disease is contributing to an attrition of telomere length. Park etal., in this issue of Kidney International, use an extended 2-sample Mendelian randomization analysis with large data sets to shed new light on this research question.

Self-Reported Medication Use and Urinary Drug Metabolites in the German Chronic Kidney Disease (GCKD) Study.

Polypharmacy is common among patients with CKD, but little is known about the urinary excretion of many drugs and their metabolites among patients with CKD. To evaluate self-reported medication use in relation to urine drug metabolite levels in a large cohort of patients with CKD, the German Chronic Kidney Disease study, we ascertained self-reported use of 158 substances and 41 medication groups, and coded active ingredients according to the Anatomical Therapeutic Chemical Classification System. We used a nontargeted mass spectrometry-based approach to quantify metabolites in urine; calculated specificity, sensitivity, and accuracy of medication use and corresponding metabolite measurements; and used multivariable regression models to evaluate associations and prescription patterns. Among 4885 participants, there were 108 medication-drug metabolite pairs on the basis of reported medication use and 78 drug metabolites. Accuracy was excellent for measurements of 36 individual substances in which the unchanged drug was measured in urine (median, 98.5%; range, 61.1%-100%). For 66 pairs of substances and their related drug metabolites, median measurement-based specificity and sensitivity were 99.2% (range, 84.0%-100%) and 71.7% (range, 1.2%-100%), respectively. Commonly prescribed medications for hypertension and cardiovascular risk reduction-including angiotensin II receptor blockers, calcium channel blockers, and metoprolol-showed high sensitivity and specificity. Although self-reported use of prescribed analgesics (acetaminophen, ibuprofen) was <3% each, drug metabolite levels indicated higher usage (acetaminophen, 10%-26%; ibuprofen, 10%-18%). This comprehensive screen of associations between urine drug metabolite levels and self-reported medication use supports the use of pharmacometabolomics to assess medication adherence and prescription patterns in persons with CKD, and indicates under-reported use of medications available over the counter, such as analgesics.

Association of the metabolic syndrome with mortality and major adverse cardiac events: A large chronic kidney disease cohort.

Metabolic syndrome with its key components insulin resistance, central obesity, dyslipidaemia, and hypertension is associated with a high risk for cardiovascular events and all-cause mortality in the general population. However, evidence that these findings apply to patients with chronic kidney disease (CKD) with moderately reduced estimated glomerular filtration rate and/or albuminuria is limited. We aimed to investigate the association between metabolic syndrome and its components with all-cause mortality and cardiovascular outcomes in CKD patients. Prospective observation of a cohort of 5110 CKD patients from the German Chronic Kidney Disease study with 3284 (64.3%) of them having a metabolic syndrome at baseline. During the follow-up of 6.5 years, 605 patients died and 650 patients experienced major cardiovascular events. After extended data adjustment, patients with a metabolic syndrome had a higher risk for all-cause mortality (hazard ratio [HR] = 1.26, 95% confidence interval [CI]: 1.04-1.54) and cardiovascular events (HR = 1.48, 95% CI: 1.22-1.79). The risk increased steadily with a growing number of metabolic syndrome components (increased waist circumference, glucose, triglycerides, hypertension and decreased HDL cholesterol): HR per component = 1.09 (95% CI: 1.02-1.17) for all-cause mortality and 1.23 (95% CI: 1.15-1.32) for cardiovascular events. This resulted in hazard ratios between 1.50 and 2.50 in the case when four or five components are present. An analysis of individual components of metabolic syndrome showed that the glucose component led to the highest increase in risk for all-cause mortality (HR = 1.68, 95% CI: 1.38-2.03) and cardiovascular events (HR = 1.81, 95% CI: 1.51-2.18), followed by the HDL cholesterol and triglyceride components. We observed a high prevalence of metabolic syndrome among patients with moderate CKD. Metabolic syndrome increases the risk for all-cause mortality and cardiovascular events. The glucose and lipid components seem to be the main drivers for the association with outcomes.

MO482URINE METABOLITE LEVELS OF CKD PATIENTS ARE ASSOCIATED WITH ADVERSE KIDNEY OUTCOMES AND MORTALITY*

Abstract Background and Aims Chronic kidney disease (CKD) affects &amp;gt;10% of the adult population worldwide and is associated with increased risk of kidney failure (KF) and mortality. Mechanisms underlying the variable course of disease progression are incompletely understood. This study aimed at identifying novel metabolite biomarkers of adverse kidney outcomes and overall mortality, which may offer insights into pathophysiological mechanisms. Method Using measurements of 1,487 metabolites in urine of 5,087 CKD patients enrolled in the German Chronic Kidney Disease study, we evaluated the association of urine metabolite levels with adverse events. Main endpoints include KF, a combined endpoint of KF and acute kidney injury (KF+AKI), and overall mortality. Statistical analysis was based on a discovery-replication design (ratio 2:1) and multivariable adjusted Cox regression models. We performed cause-specific hazard regression as well as subdistribution hazard analyses with death of other causes as a competing event for the endpoints KF and KF+AKI. Statistical significance was defined using a Bonferroni correction for the number of tested metabolites per stage. An association was considered replicated if effect estimates from both stages were significant and direction-consistent. Results Median follow-up time was 4 years. At time of analysis, 362 patients died, 241 experienced KF, and 382 KF+AKI. Overall, we identified 55 urine metabolites whose levels were significantly and reproducibly associated with adverse kidney outcomes and/or mortality. Cause-specific and subdistribution hazard analyses showed almost identical results. Higher levels of the amino acid C-glycosyltryptophan in urine were associated with higher risk for all three endpoints (KF: hazard ratio 1.43, 95% confidence interval [1.27;1.61], KF+AKI: 1.40 [1.27;1.55], mortality: 1.47 [1.33;1.63]). The cumulative incidence function of KF was higher for each quartile of urine C-glycosyltryptophan levels and the effect were most pronounced in the highest quartile (see Figure). The replicated metabolites belong to different biochemical classes, and those belonging to the phosphatidylcholines pathway showed enrichment. Members of this pathway contributed to the improvement of the prediction performance for KF observed when multiple metabolites were added to the well-established kidney failure risk equation by Tangri. Conclusion This comprehensive screen of the association between urine metabolite levels and adverse kidney outcomes and mortality identified and replicated 55 urine metabolites associated with adverse kidney events, potentially providing new insights into the mechanisms of kidney disease progression. The study represents a valuable resource for future experimental studies of biomarkers of CKD progression.