Chronic kidney disease and risk of bloodstream infections and sepsis: a 17-year follow-up of the population-based Trøndelag Health Study in Norway.

PURPOSE: Bloodstream infections (BSI) and sepsis are important causes of hospitalization, loss of health, and death globally. Targetable risk factors need to be identified to improve prevention and treatment. In this study, we aimed to evaluate the association of chronic kidney disease (CKD) and risk of and mortality from BSI and sepsis in the general population during a 22-year period. METHODS: We conducted a prospective cohort study among participants in the population-based Norwegian HUNT Study, where 68,438 participated. The median follow-up time was 17.4 years. The exposures were estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR) in urine. The outcomes were hazard ratios (HR) of hospital admission or death due to BSI or sepsis. The associations were adjusted for age, sex, diabetes, obesity, systolic blood pressure, smoking status, and cardiovascular disease. RESULTS: Participants with eGFR < 30 ml/min/1.732 had HR 3.35 for BSI (95% confidence intervals (CI) 2.12-5.3) and HR 2.94 for sepsis (95% CI 1.82-4.8) compared to normal eGFR (≥ 90 ml/min/1.732). HRs of death from BSI and sepsis were 4.2 (95% CI 1.71-10.4) and 4.1 (95% CI 1.88-8.9), respectively. Participants with severely increased albuminuria (ACR > 30 mg/mmol) had HR 3.60 for BSI (95% CI 2.30-5.6) and 3.14 for sepsis (95% CI 1.94-5.1) compared to normal albumin excretion (ACR < 3 mg/mmol). HRs of death were 2.67 (95% CI 0.82-8.7) and 2.16 (95% CI 0.78-6.0), respectively. CONCLUSION: In this large population-based cohort study, CKD was clearly associated with an increased risk of BSI and sepsis and related death.

Anxiety and depression symptoms, albuminuria and risk of acute myocardial infarction in the Norwegian HUNT cohort study.

BACKGROUND: Studies suggest increased risk for an outcome in people with joint exposures that share common causal pathways. The objective of this study was to determine the risk of incident acute myocardial infarction (AMI) following exposure to both albuminuria and/or anxiety and depression symptoms. METHODS: Participants who provided urine samples to the HUNT2 (1995-97) or HUNT3 (2007-2009) surveys were followed until the end of 2016. Albuminuria was measured by Albumin Creatine Ratio (ACR) and participants self-reported mood and anxiety symptoms on the Hospital Anxiety and Depression scale. We used Cox regression to estimate hazard ratios (HRs) for first incident AMI considering interaction between exposures and additive models to calculate the proportion of AMI that were attributable to the synergy of both exposures, adjusted for the Framingham variables. RESULTS: Eleven thousand fourteen participants free of previous AMI were eligible for participation, with 1234 incident AMIs occurred during a mean 13.7 years of follow-up. For participants who had a healthier CVD risk profile, the HR for AMI of having both albuminuria (3-30 mg/mmol) and depression (≥8) was 2.62 (95% 1.12-6.05) compared with a HR 1.34 (95% CI 1.04-1.74) with raised ACR only (Likelihood Ratio-test 0.03). Adding anxiety (≥8) to albuminuria (3-30) tripled the risk (HR 3.32 95% CI 1.43-7.17). The additive models suggest that these risks are not higher than expected based on each risk factor alone. CONCLUSIONS: This study indicate that the risk of AMI in persons with elevated albuminuria but with an otherwise healthy CVD profile might be amplified by anxiety and depression symptoms. The increased risk with joint risk factors is not higher than expected based on each risk factor alone, which indicate that the risk factors do not share causal pathways.

The HUNT study: Association of comorbidity clusters with long-term survival and incidence of exacerbation in a population-based Norwegian COPD cohort.

BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease often viewed as part of a multimorbidity complex. There is a need for better phenotyping of the disease, characterization of its interplay with other comorbidities and its association with long-term outcomes. This study aims to examine how clusters of comorbidities are associated with severe exacerbations and mortality in COPD. METHODS: Participants with potential COPD were recruited from the second (1995-1997) and third (2006-2008) survey of the HUNT Study and followed up until April 2020. Ten objectively identified comorbidities were clustered using self-organizing maps. Severe COPD exacerbations requiring hospitalization were assessed using hospital data. All-cause mortality was collected from national registries. Multivariable Cox regression was used to calculate hazard ratios (HRs) with 95% CIs for the association between comorbidity clusters and all-cause mortality. Poisson regression was used to calculate incidence rate ratios (IRRs) with 95% CI for the cumulative number of severe exacerbations for each cluster. RESULTS: Five distinct clusters were identified, including 'less comorbidity', 'psychological', 'cardiovascular', 'metabolic' and 'cachectic' clusters. Using the less comorbidity cluster as reference, the psychological and cachectic clusters were associated with all-cause mortality (HR 1.23 [1.04-1.45] and HR 1.83 [1.52-2.20], adjusted for age and sex). The same clusters also had increased risk of exacerbations (unadjusted IRR of 1.24 [95% CI 1.04-1.48] and 1.50 [95% CI 1.23-1.83], respectively). CONCLUSION: During 25 years of follow-up, individuals in the psychological and cachectic clusters had increased mortality. Furthermore, these clusters were associated with increased risk of severe COPD exacerbations.

Low grade albuminuria as a risk factor for subtypes of stroke - the HUNT Study in Norway.

BACKGROUND AND PURPOSE: Albuminuria is a marker for endothelial dysfunction and knowledge on its association with stroke and stroke subtypes are limited. METHODS: Corresponding data from 7261 participants of the population-based HUNT2 study (1995-1997) was linked with hospital records, identified all patients registered and diagnosed with a first-time stroke. Each diagnosis was validated by reviewal of the medical record appertaining to the individual. We then applied Cox proportional hazard models to estimate the hazard ratios (HRs) for the association between albuminuria (measured as albumin-to-creatinine-ratio, ACR) and diagnosis of stroke and stroke subtypes. RESULTS: 703 (9.7%) participants developed a first ischemic stroke during a median follow-up of 15 years. Higher albuminuria was associated with a higher rate for ischemic stroke and the risk rose steadily with increasing ACR (15% increment per unit increase in ACR concentration in mg/mmol). In the fully adjusted model, the HR for all ischemic strokes was 1.56 (95% CI 1.24-1.95) for those with an ACR ≥3 mg/mmol compared to participants with an ACR < 1 mg/mmol. Overall, increasing ACR was associated with a higher risk of all ischemic stroke subtypes. This was seen to be strongest for lacunar stroke (HR 1.75, CI 1.12-2.72, p = 0.019), and also for stroke of undetermined etiology (HR 1.53, CI 1.11-2.11, p = 0.009) and those caused by atherosclerosis in the large arteries (HR 1.51, CI 0.78-2.94, p = 0.186) than for cardio-embolic stroke (HR 1.22, CI 0.64-2.3, p = 0.518). CONCLUSIONS: Albuminuria is an important risk factor, potentially already at low grade, for ischemic stroke especially for lacunar subtype. Measuring albuminuria is both cheap and readily available. This offers the opportunity to evaluate the risk for endothelial dysfunction and thus the subsequent risk for stroke and cerebral small vessel disease.

Moderately increased albuminuria, chronic kidney disease and incident dementia: the HUNT study.

BACKGROUND: Epidemiologic studies has shown an association of albuminuria and low estimated glomerular filtration rate (eGFR) with dementia, but the findings are inconsistent. This study examines the association between eGFR, MA with dementia and its subtypes: AD, VaD, a mixture of AD/VaD, and other dementias. METHODS: Data from the second wave of the HUNT 2 Study (1995-1997) were linked with a dementia register known as the Health and Memory Study (HMS) collected during 1995-2011 in Nord-Trøndelag County, Norway. Dementia was ascertained using World Health Organization's ICD-10 criteria into subtypes: AD,VaD, mixed AD/VaD, and other dementia. eGFR and its association with dementia was examined in 48,508 participants of the HUNT Study, of which 668 were diagnosed with all-cause dementia. Association between MA and dementia were studied in a subset of 7024 participants, and 214 were diagnosed with all-cause dementia. Cox regression models were conducted analyzing the association between dementia and MA using albumin creatine ratio (ACR). Cox regression models and Fine-Gray models were used to examine the association between dementia and eGFR. RESULTS: A positive association was found between increasing ACR and dementia. ACR in the fourth quartile (> 1.78 mg/mmol) with increased hazard ratio of VaD, 3.97 (1.12 to 14.07), compared with ACR in the first quartile (<.53 mg/mmol). There was no association between eGFR and dementia or its subgroups. CONCLUSIONS: Our results strengthens the hypothesis that vascular mechanisms may affect both kidney and brain as an association between MA and dementia was found. However, eGFR was not significantly associated with dementia independent of diabetes mellitus or hypertension.

CKD Prevalence Varies across the European General Population.

CKD prevalence estimation is central to CKD management and prevention planning at the population level. This study estimated CKD prevalence in the European adult general population and investigated international variation in CKD prevalence by age, sex, and presence of diabetes, hypertension, and obesity. We collected data from 19 general-population studies from 13 European countries. CKD stages 1-5 was defined as eGFR<60 ml/min per 1.73 m(2), as calculated by the CKD-Epidemiology Collaboration equation, or albuminuria >30 mg/g, and CKD stages 3-5 was defined as eGFR<60 ml/min per 1.73 m(2) CKD prevalence was age- and sex-standardized to the population of the 27 Member States of the European Union (EU27). We found considerable differences in both CKD stages 1-5 and CKD stages 3-5 prevalence across European study populations. The adjusted CKD stages 1-5 prevalence varied between 3.31% (95% confidence interval [95% CI], 3.30% to 3.33%) in Norway and 17.3% (95% CI, 16.5% to 18.1%) in northeast Germany. The adjusted CKD stages 3-5 prevalence varied between 1.0% (95% CI, 0.7% to 1.3%) in central Italy and 5.9% (95% CI, 5.2% to 6.6%) in northeast Germany. The variation in CKD prevalence stratified by diabetes, hypertension, and obesity status followed the same pattern as the overall prevalence. In conclusion, this large-scale attempt to carefully characterize CKD prevalence in Europe identified substantial variation in CKD prevalence that appears to be due to factors other than the prevalence of diabetes, hypertension, and obesity.

Long-term trends in the prevalence of chronic kidney disease and the influence of cardiovascular risk factors in Norway.

Surveillance of chronic kidney disease (CKD) prevalence over time and information on how changing risk factors influence this trend are needed to evaluate the effects of general practice and public health interventions. Because very few studies addressed this, we studied the total adult population of a demographically stable county representative of Norway using cross-sectional studies 10 years apart (Nord-Trøndelag Health Study (HUNT)2 and Nord-Trøndelag Health Study (HUNT)3, 65,237 and 50,586 participants, respectively). Thorough quality-control procedures and comparisons of methods over time excluded analytical drift, and multiple imputations of missing data combined with nonattendance weights contributed to unbiased estimates. CKD prevalence remained stable in Norway from 1995 through 1997 (11.3%) to 2006 through 2008 (11.1%). The association of survey period with CKD prevalence was modified by a strong decrease in blood pressure, more physical activity, and lower cholesterol levels. Without these improvements, a 2.8, 0.7, and 0.6 percentage points higher CKD prevalence could have been expected, respectively. In contrast, the prevalence of diabetes and obesity increased moderately, but the proportion of diabetic patients with CKD decreased significantly (from 33.4% to 28.6%). A CKD prevalence of 1 percentage point lower would have been expected without these changes. Thus, CKD prevalence remained stable in Norway for more than a decade in association with marked improvements in blood pressure, lipid levels, and physical activity and despite modest increases in diabetes and obesity.

A 15-Year Follow-Up Study of Sense of Humor and Causes of Mortality: The Nord-Trøndelag Health Study.

BACKGROUND: Associations between the sense of humor and survival in relation to specific diseases has so far never been studied. METHODS: We conducted a 15-year follow-up study of 53,556 participants in the population-based Nord-Trøndelag Health Study, Norway. Cognitive, social, and affective components of the sense of humor were obtained, and associations with all-cause mortality, mortality due to cardiovascular diseases (CVD), infections, cancer, and chronic obstructive pulmonary diseases were estimated by hazard ratios (HRs). RESULTS: After multivariate adjustments, high scores on the cognitive component of the sense of humor were significantly associated with lower all-cause mortality in women (HR = 0.52, 95% confidence interval [CI] = 0.33-0.81), but not in men (HR = 0.88, 95% CI = 0.59-1.32). Mortality due to CVD was significantly lower in women with high scores on the cognitive component (HR = 0.27, 95% CI = 0.15-0.47), and so was mortality due to infections both in men (HR = 0.26, 95% CI = 0.09-0.74) and women (HR = 0.17, 95% CI = 0.04-0.76). The social and affective components of the sense of humor were not associated with mortality. In the total population, the positive association between the cognitive component of sense of humor and survival was present until the age of 85 years. CONCLUSIONS: The cognitive component of the sense of humor is positively associated with survival from mortality related to CVD and infections in women and with infection-related mortality in men. The findings indicate that sense of humor is a health-protecting cognitive coping resource.

Methodology used in studies reporting chronic kidney disease prevalence: a systematic literature review.

BACKGROUND: Many publications report the prevalence of chronic kidney disease (CKD) in the general population. Comparisons across studies are hampered as CKD prevalence estimations are influenced by study population characteristics and laboratory methods. METHODS: For this systematic review, two researchers independently searched PubMed, MEDLINE and EMBASE to identify all original research articles that were published between 1 January 2003 and 1 November 2014 reporting the prevalence of CKD in the European adult general population. Data on study methodology and reporting of CKD prevalence results were independently extracted by two researchers. RESULTS: We identified 82 eligible publications and included 48 publications of individual studies for the data extraction. There was considerable variation in population sample selection. The majority of studies did not report the sampling frame used, and the response ranged from 10 to 87%. With regard to the assessment of kidney function, 67% used a Jaffe assay, whereas 13% used the enzymatic assay for creatinine determination. Isotope dilution mass spectrometry calibration was used in 29%. The CKD-EPI (52%) and MDRD (75%) equations were most often used to estimate glomerular filtration rate (GFR). CKD was defined as estimated GFR (eGFR) <60 mL/min/1.73 m(2) in 92% of studies. Urinary markers of CKD were assessed in 60% of the studies. CKD prevalence was reported by sex and age strata in 54 and 50% of the studies, respectively. In publications with a primary objective of reporting CKD prevalence, 39% reported a 95% confidence interval. CONCLUSIONS: The findings from this systematic review showed considerable variation in methods for sampling the general population and assessment of kidney function across studies reporting CKD prevalence. These results are utilized to provide recommendations to help optimize both the design and the reporting of future CKD prevalence studies, which will enhance comparability of study results.

The accuracy of predicting cardiovascular death based on one compared to several albuminuria values.

Albuminuria is a well-documented predictor of cardiovascular (CV) mortality. However, day-to-day variability is substantial, and there is no consensus on the number of urine samples required for risk prediction. To resolve this we followed 9158 adults from the population-based Nord-Trøndelag Health Study for 13 years (Second HUNT Study). The predictive performance of models for CV death based on Framingham variables plus 1 versus 3 albumin-creatinine ratio (ACR) was assessed in participants who provided 3 urine samples. There was no improvement in discrimination, calibration, or reclassification when using ACR as a continuous variable. Difference in Akaike information criterion indicated an uncertain improvement in overall fit for the model with the mean of 3 urine samples. Criterion analyses on dichotomized albuminuria information sustained 1 sample as sufficient for ACR levels down to 1.7 mg/mmol. At lower levels, models with 3 samples had a better overall fit. Likewise, in survival analyses, 1 sample was enough to show a significant association to CV mortality for ACR levels above 1.7 mg/mmol (adjusted hazard ratio 1.37; 95% CI 1.15-1.63). For lower ACR levels, 2 or 3 positive urine samples were needed for significance. Thus, multiple urine sampling did not improve CV death prediction when using ACR as a continuous variable. For cutoff ACR levels of 1.0 mg/mmol or less, additional urine samples were required, and associations were stronger with increasing number of samples.

COPD and microalbuminuria: a 12-year follow-up study.

Chronic obstructive pulmonary disease (COPD), low lung function independent of diagnosis and markers of inflammation are all associated with increased morbidity and mortality. Microalbuminuria, reflecting endothelial dysfunction, could be a relevant inflammatory marker of potential systemic effects of COPD. We hypothesised that there was a positive association between microalbuminuria and mortality in individuals with COPD. We conducted a 12-year follow-up study of 3129 participants in the second survey of the Nord-Trøndelag Health Study (HUNT), Norway. At baseline, albuminuria was analysed in three urine samples and spirometry was performed. Among the participants, 136 had COPD and microalbuminuria, defined as a urinary albumin/creatinine ratio between 2.5 and 30.0 mg·mmol(-1). The main outcome measures were hazard ratio of all-cause mortality according to microalbuminuria. Compared to those with COPD without microalbuminuria, the adjusted hazard ratio for all-cause mortality in those with COPD and microalbuminuria was 1.54, 95% CI 1.16-2.04. This result was similar after excluding cardiovascular disease at baseline. Classifying COPD severity by Global Initiative for Chronic Obstructive Lung Disease, there was a positive association trend with increasing severity stages. Microalbuminuria is associated with all-cause mortality in individuals with COPD and could be a relevant tool in identification of patients with poor prognosis.

Association between depression symptoms and moderately increased levels of the inflammation marker albuminuria is explained by age and comorbidity.

The study aimed to examine whether there are associations between depression symptoms and levels of the inflammation marker albuminuria. The 8303 participants in this cross-sectional study were subjects from the second survey of the Trøndelag Health Study (HUNT, Norway). Depression symptoms were assessed by the Hospital Anxiety and Depression Scale (HADS). Logistic regression analysis was performed to estimate the odds ratio (OR) for moderately increased albuminuria (ACR ≥ 3.0 mg/mmol) according to different HADS-depression (D) subgroups and -scores. Unadjusted ORs for moderately increased albuminuria were significantly increased in those with HADS-D ≥ 8 (OR 1.27, 95% CI 1.05-1.54, p = 0.013) and HADS-D ≥ 11 (OR 1.59, 95% CI 1.19-2.14, p = 0.002). After adjusting for age and sex, only HADS-D ≥ 11 was significantly associated with ACR ≥ 3.0 mg/mmol (OR 1.46, 95% CI 1.08-1.98, p = 0.014), and after multivariable adjustments for cardiovascular risk factors and comorbidity, there were no significant associations. However, adjusting for the interaction between age and HADS-D strengthened the association in linear regression models. The positive and significant association between moderately increased albuminuria and symptoms of depression found in unadjusted analyses weakened and disappeared after adjustments. Although individuals with depressive symptoms had albuminuria more often than individuals without such symptoms, and the association seemed to change with age, albuminuria may reflect other comorbidity and inflammation conditions than the depression symptomatology measured in this study.

The bidirectional association between depressive symptoms, assessed by the HADS, and albuminuria-A longitudinal population-based cohort study with repeated measures from the HUNT2 and HUNT3 Study.

BACKGROUND: Both albuminuria and depression are associated with cardiovascular disease, reflecting low-grade systemic inflammation and endothelial dysfunction. They share risk factors including weight, blood pressure, smoking and blood glucose levels. This longitudinal study aimed to examine bidirectional associations between depression symptoms, indexed by the Hospital Anxiety and Depression scale (HADS), and the inflammation marker albuminuria. METHODS: 2909 persons provided urine samples in both the second (HUNT2, 1995-97) and third wave (HUNT3, 2006-2008) of the Trøndelag Health Survey, Norway. We used a generalized linear regression model (GLM) and ANOVA to assess the association between albuminuria levels (exposure HUNT2) with depression symptoms (outcome in HUNT3); and between depression symptoms (exposure HUNT2) with albuminuria (outcome HUNT3). Depression symptoms were measured with the HADS Depression Scale, analyzed utilising the full 7 items version and analyses restricted to the first 4 items (HADS-D and HADS-4). We accounted for confounders including baseline individual levels of the exposure variables. RESULTS: In this 10-years follow-up study, we found no statistical evidence for an association between baseline depression symptoms and subsequent albuminuria, nor between baseline albuminuria and subsequent depression symptoms. For albuminuria, only 0.04% was explained by prior depression, and for depression, only 0.007% was explained by previous albuminuria levels. The results were essentially the same for the shorter HADS-4 measure. CONCLUSION: There does not appear to be a longitudinal association between albuminuria and depression measured by the HADS.

The causal effects of serum lipids and apolipoproteins on kidney function: multivariable and bidirectional Mendelian-randomization analyses.

BACKGROUND: The causal nature of the observed associations between serum lipids and apolipoproteins and kidney function are unclear. METHODS: Using two-sample and multivariable Mendelian randomization (MR), we examined the causal effects of serum lipids and apolipoproteins on kidney function, indicated by the glomerular-filtration rate estimated using creatinine (eGFRcrea) or cystatin C (eGFRcys) and the urinary albumin-to-creatinine ratio (UACR). We obtained lipid- and apolipoprotein-associated genetic variants from the Global Lipids Genetics Consortium (n = 331 368) and UK Biobank (n = 441 016), respectively, and kidney-function markers from the Trøndelag Health Study (HUNT; n = 69 736) and UK Biobank (n = 464 207). The reverse causal direction was examined using variants associated with kidney-function markers selected from recent genome-wide association studies. RESULTS: There were no strong associations between genetically predicted lipid and apolipoprotein levels with kidney-function markers. Some, but inconsistent, evidence suggested a weak association of higher genetically predicted atherogenic lipid levels [indicated by low-density lipoprotein cholesterol (LDL-C), triglycerides and apolipoprotein B] with increased eGFR and UACR. For high-density lipoprotein cholesterol (HDL-C), results differed between eGFRcrea and eGFRcys, but neither analysis suggested substantial effects. We found no clear evidence of a reverse causal effect of eGFR on lipid or apolipoprotein traits, but higher UACR was associated with higher LDL-C, triglyceride and apolipoprotein B levels. CONCLUSION: Our MR estimates suggest that serum lipid and apolipoprotein levels do not cause substantial changes in kidney function. A possible weak effect of higher atherogenic lipids on increased eGFR and UACR warrants further investigation. Processes leading to higher UACR may lead to more atherogenic lipid levels.

Combining GFR and albuminuria to classify CKD improves prediction of ESRD.

Despite the high prevalence of chronic kidney disease (CKD), relatively few individuals with CKD progress to ESRD. A better understanding of the risk factors for progression could improve the classification system of CKD and strategies for screening. We analyzed data from 65,589 adults who participated in the Nord-Trøndelag Health (HUNT 2) Study (1995 to 1997) and found 124 patients who progressed to ESRD after 10.3 yr of follow-up. In multivariable survival analysis, estimated GFR (eGFR) and albuminuria were independently and strongly associated with progression to ESRD: Hazard ratios for eGFR 45 to 59, 30 to 44, and 15 to 29 ml/min per 1.73 m(2) were 6.7, 18.8, and 65.7, respectively (P < 0.001 for all), and for micro- and macroalbuminuria were 13.0 and 47.2 (P < 0.001 for both). Hypertension, diabetes, male gender, smoking, depression, obesity, cardiovascular disease, dyslipidemia, physical activity and education did not add predictive information. Time-dependent receiver operating characteristic analyses showed that considering both the urinary albumin/creatinine ratio and eGFR substantially improved diagnostic accuracy. Referral based on current stages 3 to 4 CKD (eGFR 15 to 59 ml/min per 1.73 m(2)) would include 4.7% of the general population and identify 69.4% of all individuals progressing to ESRD. Referral based on our classification system would include 1.4% of the general population without losing predictive power (i.e., it would detect 65.6% of all individuals progressing to ESRD). In conclusion, all levels of reduced eGFR should be complemented by quantification of urinary albumin to predict optimally progression to ESRD.

Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis.

Chronic kidney disease (CKD) is a growing health burden currently affecting 10-15% of adults worldwide. Estimated glomerular filtration rate (eGFR) as a marker of kidney function is commonly used to diagnose CKD. We analyze eGFR data from the Nord-Trøndelag Health Study and Michigan Genomics Initiative and perform a GWAS meta-analysis with public summary statistics, more than doubling the sample size of previous meta-analyses. We identify 147 loci (53 novel) associated with eGFR, including genes involved in transcriptional regulation, kidney development, cellular signaling, metabolism, and solute transport. Additionally, sex-stratified analysis identifies one locus with more significant effects in women than men. Using genetic risk scores constructed from these eGFR meta-analysis results, we show that associated variants are generally predictive of CKD with only modest improvements in detection compared with other known clinical risk factors. Collectively, these results yield additional insight into the genetic factors underlying kidney function and progression to CKD.

Change in albuminuria and subsequent risk of end-stage kidney disease: an individual participant-level consortium meta-analysis of observational studies.

BACKGROUND: Change in albuminuria as a surrogate endpoint for progression of chronic kidney disease is strongly supported by biological plausibility, but empirical evidence to support its validity in epidemiological studies is lacking. We aimed to assess the consistency of the association between change in albuminuria and risk of end-stage kidney disease in a large individual participant-level meta-analysis of observational studies. METHODS: In this meta-analysis, we collected individual-level data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC) with data on serum creatinine and change in albuminuria and more than 50 events on outcomes of interest. Cohort data were eligible if participants were aged 18 years or older, they had a repeated measure of albuminuria during an elapsed period of 8 months to 4 years, subsequent end-stage kidney disease or mortality follow-up data, and the cohort was active during this consortium phase. We extracted participant-level data and quantified percentage change in albuminuria, measured as change in urine albumin-to-creatinine ratio (ACR) or urine protein-to-creatinine ratio (PCR), during baseline periods of 1, 2, and 3 years. Our primary outcome of interest was development of end-stage kidney disease after a baseline period of 2 years. We defined an end-stage kidney disease event as initiation of kidney replacement therapy. We quantified associations of percentage change in albuminuria with subsequent end-stage kidney disease using Cox regression in each cohort, followed by random-effects meta-analysis. We further adjusted for regression dilution to account for imprecision in the estimation of albuminuria at the participant level. We did multiple subgroup analyses, and also repeated our analyses using participant-level data from 14 clinical trials, including nine clinical trials not in CKD-PC. FINDINGS: Between July, 2015, and June, 2018, we transferred and analysed data from 28 cohorts in the CKD-PC, which included 693 816 individuals (557 583 [80%] with diabetes). Data for 675 904 individuals and 7461 end-stage kidney disease events were available for our primary outcome analysis. Change in ACR was consistently associated with subsequent risk of end-stage kidney disease. The adjusted hazard ratio (HR) for end-stage kidney disease after a 30% decrease in ACR during a baseline period of 2 years was 0·83 (95% CI 0·74-0·94), decreasing to 0·78 (0·66-0·92) after further adjustment for regression dilution. Adjusted HRs were fairly consistent across cohorts and subgroups (ie, estimated glomerular filtration rate, diabetes, and sex), but the association was somewhat stronger among participants with higher baseline ACR than among those with lower baseline ACR (pinteraction<0·0001). In individuals with baseline ACR of 300 mg/g or higher, a 30% decrease in ACR over 2 years was estimated to confer a more than 1% absolute reduction in 10-year risk of end-stage kidney disease, even at early stages of chronic kidney disease. Results were generally similar when we used change in PCR and when study populations from clinical trials were assessed. INTERPRETATION: Change in albuminuria was consistently associated with subsequent risk of end-stage kidney disease across a range of cohorts, lending support to the use of change in albuminuria as a surrogate endpoint for end-stage kidney disease in clinical trials of progression of chronic kidney disease in the setting of increased albuminuria. FUNDING: US National Kidney Foundation and US National Institute of Diabetes and Digestive and Kidney Diseases.

Association of kidney function and albuminuria with cardiovascular mortality in older vs younger individuals: The HUNT II Study.

BACKGROUND: The cardiovascular risk implications of a combined assessment of reduced kidney function and microalbuminuria are unknown. In elderly persons, traditional cardiovascular risk factors are less predictive, and measures of end organ damage, such as kidney disease, may be needed for improved cardiovascular mortality risk stratification. METHODS: The glomerular filtration rate was estimated from calibrated serum creatinine, and the urine albumin-creatinine ratio (ACR) was measured in 3 urine samples in 9,709 participants of the second Nord-Trøndelag Health Study (HUNT II), a Norwegian community-based health study, followed for 8.3 years with a 71% participation rate. RESULTS: An estimated glomerular filtration rate (EGFR) at levels of less than 75 mL/min/1.73 m(2) was associated with higher cardiovascular mortality risk, whereas a higher ACR was associated with higher risk with no lower limit. Low EGFR and albuminuria were synergistic cardiovascular mortality risk factors. Compared with subjects with an EGFR greater than 75 mL/min/1.73 m(2) and ACR below the sex-specific median who were at the lowest risk, subjects with an EGFR of less than 45 mL/min/1.73 m(2) and microalbuminuria had an adjusted incidence rate ratio of 6.7 (95% confidence interval, 3.0-15.1; P < .001). The addition of ACR and EGFR improved traditional risk models: 39% of subjects with intermediate risk were reclassified to low- or high-risk categories with corresponding observed risks that were 3-fold different than the original category. Age-stratified analyses showed that EGFR and ACR were particularly strong risk factors for persons 70 years or older. CONCLUSIONS: Reduced kidney function and microalbuminuria are risk factors for cardiovascular death, independent of each other and traditional risk factors. The combined variable improved cardiovascular risk stratification at all age levels, but particularly in elderly persons where the predictive power of traditional risk factors is attenuated.

Long-term changes in albuminuria: underlying causes and future mortality risk in a 20-year prospective cohort: the Nord-Trøndelag Health (HUNT) Study.

OBJECTIVE: Knowledge on how changing risk factors influence the progression of albuminuria over time is still limited. Furthermore, large population-based cohorts are needed to study the association between albuminuria change and mortality risk in nondiabetic study participants. METHODS: We evaluated changes of albuminuria in 6282 nondiabetic individuals from the Norwegian population-based Nord-Trøndelag Health study. Using three albumin/creatinine ratios (ACR), we studied the influence of cardiovascular risk factors on ACR change from baseline to follow-up 11 years later. We evaluated the next 8-year mortality risk by using flexible parametric methods to identify nonlinear main effects and their two-way interactions. RESULTS: Mean albuminuria increased significantly over 11 years (1.82-3.02 mg/mmol, P < 0.0001), but two-thirds of individuals had stable levels (ΔACR -1.40 to 1.40 mg/mmol). Higher age, ACR, and SBP as well as smoking and lower glomerular filtration rate at baseline were associated with increasing albuminuria. Study participants in the upper quartile of the increasing group had mean adjusted hazard ratio 1.31 (P = 0.004) for all-cause mortality compared with those with stable ACR. Those with decreasing ACR also had increased mortality, but the risk was strongly attenuated when adjusting for comorbidity. It also decreased the first 3 years before increasing. There was a strong interaction between baseline ACR and ΔACR. Increasing albuminuria had strongest effect on mortality in study participants with moderately increased baseline values. CONCLUSION: Both increasing and decreasing albuminuria are significant independent predictors of mortality in nondiabetic individuals, but must be interpreted in light of baseline values. Cutoffs and clinical usefulness in nondiabetic study participants should be further investigated.