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Rationale & Objective: Novel approaches to the assessment of kidney disease risk during hypertension treatment are needed because of the uncertainty of how intensive blood pressure (BP) lowering impacts kidney outcomes. We determined whether longitudinal N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements during hypertension treatment are associated with kidney function decline., Study Design: Prospective observational study., Setting & Participants: 8,005 SPRINT (Systolic Blood Pressure Intervention Trial) participants with NT-proBNP measurements at baseline and 1 year., Exposure: 1-year change in NT-proBNP categorized as a ≥25% decrease, ≥25% increase, or <25% change (stable)., Outcome: Annualized change in estimated glomerular filtration rate (eGFR) and ≥30% decrease in eGFR., Analytical Approach: Linear mixed-effect and logistic regression models were used to evaluate the association of changes in NT-proBNP with subsequent annualized change in eGFR and ≥30% decrease in eGFR, respectively. Analyses were stratified by baseline chronic kidney disease (CKD) status., Results: Compared with stable 1-year NT-proBNP levels, a ≥25% decrease in NT-proBNP was associated with a slower decrease in eGFR in participants with CKD (adjusted difference, 1.09%/y; 95% CI, 0.35-1.83) and without CKD (adjusted difference, 0.51%/y; 95% CI, 0.21-0.81; P = 0.4 for interaction). Meanwhile, a ≥25% increase in NT-proBNP in participants with CKD was associated with a faster decrease in eGFR (adjusted difference, -1.04%/y; 95% CI, -1.72 to -0.36) and risk of a ≥30% decrease in eGFR (adjusted odds ratio, 1.44; 95% CI, 1.06-1.96); associations were stronger in participants with CKD than in participants without CKD (P = 0.01 and P < 0.001 for interaction, respectively). Relationships were similar irrespective of the randomized BP arm in SPRINT (P > 0.2 for interactions)., Limitations: Persons with diabetes and proteinuria >1 g/d were excluded., Conclusions: Changes in NT-proBNP during BP treatment are independently associated with subsequent kidney function decline, particularly in people with CKD. Future studies should assess whether routine NT-proBNP measurements may be useful in monitoring kidney risk during hypertension treatment., Plain-Language Summary: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker in the blood that reflects mechanical stress on the heart. Measuring NT-proBNP may be helpful in assessing the risk of long-term losses of kidney function. In this study, we investigated the association of changes in NT-proBNP with subsequent kidney function among individuals with and without chronic kidney disease. We found that increases in NT-proBNP are associated with a faster rate of decline of kidney function, independent of baseline kidney measures. The associations were more pronounced in individuals with chronic kidney disease. Our results advance the notion of considering NT-proBNP as a dynamic tool for assessing kidney disease risk., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Genes underneath signals from genome-wide association studies (GWAS) for kidney function are promising targets for functional studies, but prioritizing variants and genes is challenging. By GWAS meta-analysis for creatinine-based estimated glomerular filtration rate (eGFR) from the Chronic Kidney Disease Genetics Consortium and UK Biobank (n = 1,201,909), we expand the number of eGFRcrea loci (424 loci, 201 novel; 9.8% eGFRcrea variance explained by 634 independent signal variants). Our increased sample size in fine-mapping (n = 1,004,040, European) more than doubles the number of signals with resolved fine-mapping (99% credible sets down to 1 variant for 44 signals, ≤5 variants for 138 signals). Cystatin-based eGFR and/or blood urea nitrogen association support 348 loci (n = 460,826 and 852,678, respectively). Our customizable tool for Gene PrioritiSation reveals 23 compelling genes including mechanistic insights and enables navigation through genes and variants likely relevant for kidney function in human to help select targets for experimental follow-up., (© 2021. The Author(s).)

Recent European guidelines suggest using the kidney failure risk equation (KFRE) and mortality risk equation for kidney disease (MREK) to guide decisions on whether elderly patients with chronic kidney disease should be referred early for dialysis preparation. However, the concurrent use of the two risk equations has not been validated. To do so we evaluated 1,188 individuals over five years with estimated glomerular filtration rate (eGFR) under 45ml/min/1.73m 2 and age over 65 years from the Norwegian population based HUNT study. Forty-two patients started renal replacement therapy and 462 died as their first clinical event. The KFRE was well calibrated (mean risk estimate 4.9% vs observed 3.5%) with high diagnostic accuracy (C-statistics 0.93). The MREK underestimated death risk in those with lower risk (mean risk estimate 30.1% vs observed 38.9%) and had moderate diagnostic accuracy (C-statistics 0.71). Only 31 individuals had estimated end stage kidney disease (ESRD) risk greater than death risk, and most experienced ESRD before death. Only two of 598 patients over 80 years old, and ten of 1,063 with eGFR 25-45ml/min/1.73m 2 at baseline experienced ESRD. Decision curve analysis demonstrated that for risk adverse patients, deferring ESRD preparation may be appropriate until predicted ESRD risk exceeds predicted death risk. For those preferring a more aggressive approach, referral when eGFR is under 25 ml/min/1.73m 2 may be beneficial if age remains under 80 years. Thus, the risk of ESRD is low compared to the risk of death in many older patients with chronic kidney disease stage 3b or worse, and combination of predicted ESRD and death risks, eGFR levels, age, and the patient`s valuations of harm and benefit can be helpful for deciding when to start dialysis preparations., (Copyright © 2019 International Society of Nephrology. All rights reserved.)

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.

Rationale & Objective: Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework., Study Design: Cross-sectional individual participant-level analyses in a global consortium., Setting & Study Populations: 17 CKD and 38 general population and high-risk cohorts., Selection Criteria for Studies: Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension., Data Extraction: Data were obtained and analyzed between July 2015 and January 2018., Analytical Approach: We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses., Results: The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m 2 ), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g)., Limitations: Variations in study era, health care delivery system, typical diet, and laboratory assays., Conclusions: Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

The incidence of renal replacement therapy varies across countries. However, little is known about the epidemiology of chronic kidney disease (CKD) outcomes. Here we describe progression and mortality risk of patients with CKD but not on renal replacement therapy at outpatient nephrology clinics across Europe using individual data from nine CKD cohorts participating in the European CKD Burden Consortium. A joint model assessed the mean change in estimated glomerular filtration rate (eGFR) and mortality risk simultaneously, thereby accounting for mortality risk when estimating eGFR decline and vice versa, while also correcting for the measurement error in eGFR. Results were adjusted for important risk factors (baseline eGFR, age, sex, albuminuria, primary renal disease, diabetes, hypertension, obesity and smoking) in 27,771 patients from five countries. The adjusted mean annual eGFR decline varied from 0.77 (95% confidence interval 0.45, 1.08) ml/min/1.73m 2 in the Belgium cohort to 2.43 (2.11, 2.75) ml/min/1.73m 2 in the Spanish cohort. As compared to the Italian PIRP cohort, the adjusted mortality hazard ratio varied from 0.22 (0.11, 0.43) in the London LACKABO cohort to 1.30 (1.13, 1.49) in the English CRISIS cohort. These results suggest that the eGFR decline showed minor variation but mortality showed the most variation. Thus, different health care organization systems are potentially associated with differences in outcome of patients with CKD within Europe. These results can be used by policy makers to plan resources on a regional, national and European level., (Copyright © 2018 International Society of Nephrology. All rights reserved.)

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 Author 2015. Published by Oxford University Press on behalf of ERA-EDTA.)

Context: Chronic kidney disease (CKD) is prevalent in older individuals, but the risk implications of low estimated glomerular filtration rate (eGFR) and high albuminuria across the full age range are controversial., Objective: To evaluate possible effect modification (interaction) by age of the association of eGFR and albuminuria with clinical risk, examining both relative and absolute risks., Design, Setting, and Participants: Individual-level meta-analysis including 2,051,244 participants from 33 general population or high-risk (of vascular disease) cohorts and 13 CKD cohorts from Asia, Australasia, Europe, and North/South America, conducted in 1972-2011 with a mean follow-up time of 5.8 years (range, 0-31 years)., Main Outcome Measures: Hazard ratios (HRs) of mortality and end-stage renal disease (ESRD) according to eGFR and albuminuria were meta-analyzed across age categories after adjusting for sex, race, cardiovascular disease, diabetes, systolic blood pressure, cholesterol, body mass index, and smoking. Absolute risks were estimated using HRs and average incidence rates., Results: Mortality (112,325 deaths) and ESRD (8411 events) risks were higher at lower eGFR and higher albuminuria in every age category. In general and high-risk cohorts, relative mortality risk for reduced eGFR decreased with increasing age; eg, adjusted HRs at an eGFR of 45 mL/min/1.73 m2 vs 80 mL/min/1.73 m2 were 3.50 (95% CI, 2.55-4.81), 2.21 (95% CI, 2.02-2.41), 1.59 (95% CI, 1.42-1.77), and 1.35 (95% CI, 1.23-1.48) in age categories 18-54, 55-64, 65-74, and ≥75 years, respectively (P <.05 for age interaction). Absolute risk differences for the same comparisons were higher at older age (9.0 [95% CI, 6.0-12.8], 12.2 [95% CI, 10.3-14.3], 13.3 [95% CI, 9.0-18.6], and 27.2 [95% CI, 13.5-45.5] excess deaths per 1000 person-years, respectively). For increased albuminuria, reduction of relative risk with increasing age was less evident, while differences in absolute risk were higher in older age categories (7.5 [95% CI, 4.3-11.9], 12.2 [95% CI, 7.9-17.6], 22.7 [95% CI, 15.3-31.6], and 34.3 [95% CI, 19.5-52.4] excess deaths per 1000 person-years, respectively by age category, at an albumin-creatinine ratio of 300 mg/g vs 10 mg/g). In CKD cohorts, adjusted relative hazards of mortality did not decrease with age. In all cohorts, ESRD relative risks and absolute risk differences at lower eGFR or higher albuminuria were comparable across age categories., Conclusions: Both low eGFR and high albuminuria were independently associated with mortality and ESRD regardless of age across a wide range of populations. Mortality showed lower relative risk but higher absolute risk differences at older age.

Background: Cardiovascular risk prediction is particularly important in the primary prevention of cardiovascular disease (CVD). Yet, data on whether the combined addition of albuminuria and estimated glomerular filtration rate (eGFR) improves cardiovascular risk prediction in individuals without CVD in the community is scarce., Methods: We investigated associations between urinary albumin excretion rate (UAER), cystatin C-based eGFR and cardiovascular mortality in a community-based cohort of elderly men (ULSAM study; n = 1113, mean age 71 years, 208 cardiovascular deaths, median follow-up 12.9 years) with prespecified analyses in participants without CVD (n = 649, 86 cardiovascular deaths)., Results: Using multivariable Cox regression, higher UAER and lower eGFR were associated with increased risk for cardiovascular mortality independently of established cardiovascular risk factors in the whole sample and in men without CVD at baseline [subsample without CVD: UAER; hazard ratio (HR) per 1 SD 1.26, 95% confidence interval (CI) 1.05-1.51, P = 0.01; eGFR: HR per 1 SD 0.74, 95% CI 0.59-0.92, P = 0.007]. Analyses of model discrimination, calibration, reclassification and global fit suggested that UAER and eGFR also add relevant prognostic information beyond established cardiovascular risk factors in participants without prevalent CVD. Interestingly, established cutoffs used to diagnose microalbuminuria (UAER > 20 μg/min) and chronic kidney disease Stage 3 (eGFR < 60 mL/min/1.73 m(2)), appeared less suitable for cardiovascular risk prediction [integrated discrimination improvement (IDI) 0.006, P = 0.11], while cutoffs UAER > 6 μg/min and eGFR < 45 mL/min/1.73 m(2) significantly improved IDI (0.047, P < 0.001)., Conclusions: UAER and eGFR improved cardiovascular risk prediction beyond established cardiovascular risk factors, suggesting that these kidney biomarkers may be useful in predicting cardiovascular death in elderly men.

Estimated glomerular filtration rate (eGFR) and albuminuria are among the most important cardiovascular risk factors, but the optimal cutoff for predicting mortality may not yet have been agreed upon. Foley et al. analyzed data from the population-based NHANES III study with classification tree methodology. They found that an eGFR of 94 ml/min per 1.73 m(2) and an albumin-creatinine ratio of 9 mg/g were the optimal cutoff values, that is, more 'normal' values than are used to define chronic kidney disease.

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.

Decreased glomerular filtration rate (GFR) and albuminuria are used in combination to define chronic kidney disease, but their separate and combined effects on cardiovascular and all-cause mortality have not been studied in the general population. The linked mortality file of the Third National Health and Nutrition Examination Survey includes data from 13 years of follow-up (1988-2000) for 14,586 US adults. The authors estimated GFR from standardized serum creatinine levels. Albuminuria was defined by the urinary albumin:creatinine ratio. Incidence rate ratios (IRRs) were adjusted for major cardiovascular disease risk factors and C-reactive protein. Lower estimated GFR was associated with higher risks of cardiovascular and all-cause mortality overall and within every albuminuria category. Likewise, increasing albuminuria was associated with higher risk of estimated GFR overall and within every category. When estimated GFR and albuminuria were examined simultaneously, a 10-ml/minute/1.73 m(2) lower estimated GFR (among persons with estimated GFR <60 ml/minute/1.73 m(2)) was associated with an IRR of 1.29 (95% confidence interval: 1.06, 1.55) for cardiovascular mortality and a doubling of albuminuria was associated with an IRR of 1.06 (95% confidence interval: 1.04, 1.08) for cardiovascular mortality. The authors conclude that moderately decreased estimated GFR and albuminuria independently predict cardiovascular and all-cause mortality in the general population. These data support recent recommendations defining chronic kidney disease and stratifying subsequent risks based on both decreased GFR and albuminuria.

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.

Background: Guidelines recommend the modification of diet in the renal disease (MDRD) formula or the Cockcroft-Gault formula for estimating the glomerular filtration rate (GFR). However, there is an ongoing discussion whether the MDRD formula should be used in the general population as several studies have found a large underestimation of its GFR estimates., Methods: In this study, 1,029 low-risk subjects, eligible for kidney donation according to internationally accepted criteria were selected from the population-based second Health Survey of Nord-Trondelag (HUNT II). Serum creatinine values traceable to isotope dilution mass spectrometry were used with the re-expressed MDRD formula recently published. The 2.5th, 50th and 97.5th percentiles of GFR by age were calculated and compared to reference values from the literature, which are based on GFR measured with gold standard methods in potential kidney donors., Results: The difference between the 50th percentiles for MDRD estimates and measured GFR in the literature was small and constant over age: +0.5 ml/min/1.73 m(2) at age 20 and -2.0 ml/min/1.73 m(2) at age 80. Bias for Cockcroft-Gault estimates varied from 0.0 ml/min/1.73 m(2) to -21.4 ml/min/1.73 m(2). Other formulae also had a too steep age correction, and bias among the elderly varied from -10 to -30 ml/min/1.73 m(2). Hence, 30-80% of the general population above age 60 had GFR estimates below their age-specific 2.5th percentile of normal kidney function, while the MDRD formula was much more conservative (13.3%)., Conclusion: The MDRD formula gave nearly unbiased estimates for normal GFR. All other formulae tested had, especially in the elderly, a much larger negative bias and cannot be recommended for use in the general population.

Kidney failure has traditionally been categorised as mild, moderate or severe. Other poorly defined terms like uraemia and end-stage kidney disease have commonly been applied. During the last few years, an international consensus has emerged staging chronic kidney disease into 5 stages: stage 1 being glomerular filtration rate (GFR) > 90 ml/min and signs of kidney damage, stage 2 GFR 60-89 ml/min and signs of kidney damage, stage 3 being GFR 30-59 ml/min, stage 4 being GFR 15-29 ml/min, and stage 5 GFR < 15 ml/min. Kidney function should be calculated from creatinine-based formulas, or measured by isotope or iohexol clearances rather than as renal clearance of creatinine in timed urine samples. We address the importance and implications of these new definitions.

Background: The Modification of Diet in Renal Disease (MDRD) formula is recommended by European and American guidelines for estimating glomerular filtration rate (GFR). However, the accuracy of the formula has been questioned in several studies. Our objective is to evaluate the performance of the MDRD formula with special emphasis on the possibility that interlaboratory calibration differences for serum creatinine reduce the accuracy of the formula., Methods: The MDRD and 7 other commonly used formulae were evaluated regarding bias, precision, and accuracy. The 215 adults included were patients with chronic kidney disease, potential kidney donors, and patients referred before nephrotoxic chemotherapy. Serum creatinine was measured by means of a kinetic Jaffé method (Hitachi 917, Hitachi, Tokyo, Japan; reagents from Roche Diagnostics, Mannheim, Germany). GFR, measured as plasma clearance of chromium 51-labeled EDTA (Cr-EDTA), ranged from 3 to 162 mL/min/1.73 m2., Results: The MDRD formula was heavily biased, but it still had significantly better accuracy than the other formulae tested. After recalibrating our serum creatinine values (serum creatinine [mg/dL] = -0.215 + 1.08 * serum creatinine), systematic bias was greatly reduced and better accuracy was achieved: 45.6% of results differed less than 15% from Cr-EDTA, 64.2% differed less than 30%, and 81.4% differed less than 50%. The equation for recalibrating creatinine values was based on data with traceability to reference methods and on sensitivity analysis., Conclusion: The MDRD formula seems to be the best formula available for GFR estimating, but it is based on a serum creatinine method calibrated to give much lower values than most laboratories, leading to underestimation of GFR in mild renal insufficiency.

Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis.

BACKGROUND: Urine biomarkers of kidney tubule health may distinguish aspects of kidney damage that cannot be captured by current glomerular measures. Associations of clinical risk factors with specific kidney tubule biomarkers have not been evaluated in detail. METHODS: We performed a cross-sectional study in the Systolic Blood Pressure Intervention Trial among 2,436 participants with a baseline estimated glomerular filtration rate (eGFR)

ObjectiveTo evaluate the associations between adiposity measures (body mass index, waist circumference, and waist-to-height ratio) with decline in glomerular filtration rate (GFR) and with all cause mortality.DesignIndividual participant data meta-analysis.SettingCohorts from 40 countries with data collected between 1970 and 2017.ParticipantsAdults in 39 general population cohorts (n=5 459 014), of which 21 (n=594 496) had data on waist circumference; six cohorts with high cardiovascular risk (n=84 417); and 18 cohorts with chronic kidney disease (n=91 607).Main outcome measuresGFR decline (estimated GFR decline ≥40%, initiation of kidney replacement therapy or estimated GFR

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. [ABSTRACT FROM AUTHOR]

AimsBoth hypo- and hyperkalaemia can have immediate deleterious physiological effects, and less is known about long-term risks. The objective was to determine the risks of all-cause mortality, cardiovascular mortality, and end-stage renal disease associated with potassium levels across the range of kidney function and evaluate for consistency across cohorts in a global consortium.Methods and resultsWe performed an individual-level data meta-analysis of 27 international cohorts [10 general population, 7 high cardiovascular risk, and 10 chronic kidney disease (CKD)] in the CKD Prognosis Consortium. We used Cox regression followed by random-effects meta-analysis to assess the relationship between baseline potassium and adverse outcomes, adjusted for demographic and clinical characteristics, overall and across strata of estimated glomerular filtration rate (eGFR) and albuminuria. We included 1 217 986 participants followed up for a mean of 6.9 years. The average age was 55 ± 16 years, average eGFR was 83 ± 23 mL/min/1.73 m2, and 17% had moderate- to-severe increased albuminuria levels. The mean baseline potassium was 4.2 ± 0.4 mmol/L. The risk of serum potassium of >5.5 mmol/L was related to lower eGFR and higher albuminuria. The risk relationship between potassium levels and adverse outcomes was U-shaped, with the lowest risk at serum potassium of 4-4.5 mmol/L. Compared with a reference of 4.2 mmol/L, the adjusted hazard ratio for all-cause mortality was 1.22 [95% confidence interval (CI) 1.15-1.29] at 5.5 mmol/L and 1.49 (95% CI 1.26-1.76) at 3.0 mmol/L. Risks were similar by eGFR, albuminuria, renin-angiotensin-aldosterone system inhibitor use, and across cohorts.ConclusionsOutpatient potassium levels both above and below the normal range are consistently associated with adverse outcomes, with similar risk relationships across eGFR and albuminuria.

BackgroundSome evidence suggests that chronic kidney disease is a risk factor for lower-extremity peripheral artery disease. We aimed to quantify the independent and joint associations of two measures of chronic kidney disease (estimated glomerular filtration rate [eGFR] and albuminuria) with the incidence of peripheral artery disease.MethodsIn this collaborative meta-analysis of international cohorts included in the Chronic Kidney Disease Prognosis Consortium (baseline measurements obtained between 1972 and 2014) with baseline measurements of eGFR and albuminuria, at least 1000 participants (this criterion not applied to cohorts exclusively enrolling patients with chronic kidney disease), and at least 50 peripheral artery disease events, we analysed adult participants without peripheral artery disease at baseline at the individual patient level with Cox proportional hazards models to quantify associations of creatinine-based eGFR, urine albumin-to-creatinine ratio (ACR), and dipstick proteinuria with the incidence of peripheral artery disease (including hospitalisation with a diagnosis of peripheral artery disease, intermittent claudication, leg revascularisation, and leg amputation). We assessed discrimination improvement through c-statistics.FindingsWe analysed 817 084 individuals without a history of peripheral artery disease at baseline from 21 cohorts. 18 261 cases of peripheral artery disease were recorded during follow-up across cohorts (median follow-up was 7·4 years [IQR 5·7-8·9], range 2·0-15·8 years across cohorts). Both chronic kidney disease measures were independently associated with the incidence of peripheral artery disease. Compared with an eGFR of 95 mL/min per 1·73 m2, adjusted hazard ratios (HRs) for incident study-specific peripheral artery disease was 1·22 (95% CI 1·14-1·30) at an eGFR of 45 mL/min per 1·73 m2 and 2·06 (1·70-2·48) at an eGFR of 15 mL/min per 1·73 m2. Compared with an ACR of 5 mg/g, the adjusted HR for incident study-specific peripheral artery disease was 1·50 (1·41-1·59) at an ACR of 30 mg/g and 2·28 (2·12-2·44) at an ACR of 300 mg/g. The adjusted HR at an ACR of 300 mg/g versus 5 mg/g was 3·68 (95% CI 3·00-4·52) for leg amputation. eGFR and albuminuria contributed multiplicatively (eg, adjusted HR 5·76 [4·90-6·77] for incident peripheral artery disease and 10·61 [5·70-19·77] for amputation in eGFR

BackgroundDiabetes mellitus and hypertension are risk factors for acute kidney injury (AKI). Whether estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (ACR) remain risk factors for AKI in the presence and absence of these conditions is uncertain.Study designMeta-analysis of cohort studies.Setting & population8 general-population (1,285,045 participants) and 5 chronic kidney disease (CKD; 79,519 participants) cohorts.Selection criteria for studiesCohorts participating in the CKD Prognosis Consortium.PredictorsDiabetes and hypertension status, eGFR by the 2009 CKD Epidemiology Collaboration creatinine equation, urine ACR, and interactions.OutcomeHospitalization with AKI, using Cox proportional hazards models to estimate HRs of AKI and random-effects meta-analysis to pool results.ResultsDuring a mean follow-up of 4 years, there were 16,480 episodes of AKI in the general-population and 2,087 episodes in the CKD cohorts. Low eGFRs and high ACRs were associated with higher risks of AKI in individuals with or without diabetes and with or without hypertension. When compared to a common reference of eGFR of 80mL/min/1.73m(2) in nondiabetic patients, HRs for AKI were generally higher in diabetic patients at any level of eGFR. The same was true for diabetic patients at all levels of ACR compared with nondiabetic patients. The risk gradient for AKI with lower eGFRs was greater in those without diabetes than with diabetes, but similar with higher ACRs in those without versus with diabetes. Those with hypertension had a higher risk of AKI at eGFRs>60mL/min/1.73m(2) than those without hypertension. However, risk gradients for AKI with both lower eGFRs and higher ACRs were greater for those without than with hypertension.LimitationsAKI identified by diagnostic code.ConclusionsLower eGFRs and higher ACRs are associated with higher risks of AKI among individuals with or without either diabetes or hypertension.

BackgroundAcute kidney injury (AKI) is a serious global public health problem. We aimed to quantify the risk of AKI associated with estimated glomerular filtration rate (eGFR), albuminuria (albumin-creatinine ratio [ACR]), age, sex, and race (African American and white).Study designCollaborative meta-analysis.Setting & population8 general-population cohorts (1,285,049 participants) and 5 chronic kidney disease (CKD) cohorts (79,519 participants).Selection criteria for studiesAvailable eGFR, ACR, and 50 or more AKI events.PredictorsAge, sex, race, eGFR, urine ACR, and interactions.OutcomeHospitalized with or for AKI, using Cox proportional hazards models to estimate HRs of AKI and random-effects meta-analysis to pool results.Results16,480 (1.3%) general-population cohort participants had AKI over a mean follow-up of 4 years; 2,087 (2.6%) CKD participants had AKI over a mean follow-up of 1 year. Lower eGFR and higher ACR were strongly associated with AKI. Compared with eGFR of 80mL/min/1.73m(2), the adjusted HR of AKI at eGFR of 45mL/min/1.73m(2) was 3.35 (95% CI, 2.75-4.07). Compared with ACR of 5mg/g, the risk of AKI at ACR of 300mg/g was 2.73 (95% CI, 2.18-3.43). Older age was associated with higher risk of AKI, but this effect was attenuated with lower eGFR or higher ACR. Male sex was associated with higher risk of AKI, with a slight attenuation in lower eGFR but not in higher ACR. African Americans had higher AKI risk at higher levels of eGFR and most levels of ACR.LimitationsOnly 2 general-population cohorts could contribute to analyses by race; AKI identified by diagnostic code.ConclusionsReduced eGFR and increased ACR are consistent strong risk factors for AKI, whereas associations of AKI with age, sex, and race may be weaker in more advanced stages of CKD.

Aims: To investigate the associations of cardiorespiratory fitness with cardiac, vascular, renal and cardiorenal characteristics in chronic heart failure in a telerehabilitation randomized clinical trial. Secondly, to evaluate the associations of cardiorenal syndrome with the effects of exercise. Methods and results: Sixty‐nine heart failure patients attended baseline examination, and 61 patients were randomly assigned 1:1 to 3‐month telerehabilitation or control. Data were collected at baseline and 3‐month post‐intervention, including echocardiography and vascular ultrasound, laboratory tests, exercise test with peak oxygen consumption (VO2peak) measurement and 6‐min walk test (6MWT). Baseline VO2peak and 6MWT distance was 0.85 mL*min−1*kg−1 lower and 20 m shorter per 10 mL/min/1.73m2 lower estimated glomerular filtration rate (both P < 0.001). Heart failure patients with cardiorenal syndrome had 3.5 (1.1) mL*min−1*kg−1 lower VO2peak and diastolic dysfunction grade 2–3, and elevated filling pressure was >50% more common compared with those without (all P < 0.05). At the 3‐month post‐intervention follow‐up, only the non‐CRS patients in the intervention group increased VO2peak (0.73 (0.51) mL*min−1*kg−1), whereas VO2peak in the CRS subpopulation of controls decreased (−1.34 (0.43) mL*min−1*kg−1). Cardiorenal syndrome was associated with a decrease in VO2peak in CRS patients compared with non‐CRS patients, −0.91 (0.31) vs. 0.39 (0.35) mL*min−1*kg−1 respectively, P = 0.013. Conclusions: Cardiorenal syndrome was negatively associated with VO2peak and 6MWT distance in chronic HF, and the associations were stronger than for heart failure phenotypes and other characteristics. The effect of exercise was negatively associated with cardiorenal syndrome. Exercise seems to be as important in heart failure patients with cardiorenal syndrome, and future studies should include CRS patients to reveal the most beneficial type of exercise. [ABSTRACT FROM AUTHOR]

The worldwide high prevalence of chronic kidney disease (CKD) and the increasing number of patients reaching end-stage renal disease (ESRD) are a matter of major concern. The most widely accepted classification system of CKD is that proposed by the Kidney Disease Outcomes Quality Initiative (KDOQI) in 2002. When applying this system, it has become apparent that the prevalence of CKD is particularly high in elderly subjects. The fact that this system is mainly based on estimated glomerular filtration rate (eGFR), subdividing the severity of CKD into five stages, is a matter of debate. A main issue is that although a reduced eGFR is often encountered in elderly subjects, most of these subjects do not have a renal disease leading to an increased risk of ESRD, i.e. the predictive power of ESRD is unsatisfactory. Recent advances have been put forward to improve (1) estimation of GFR and (2) prediction of ESRD. In this review, we discuss the currently available data with a focus on the elderly and propose an improved classification system of CKD which is characterized by a substantially better diagnostic accuracy for progression to ESRD. This is simply and cost-effectively accomplished by subdividing stage 3 CKD into two groups (eGFR 30-44 and 45-59 ml/min/1.73 m2) and by complementing all levels of eGFR with information about urinary albumin excretion, i.e. whether normoalbuminuria, microalbuminuria, or macroalbuminuria is present. The consequence should be a revision of the 2002 KDOQI CKD classification system according to these findings, which would be a significant step forward, particularly for elderly CKD patients. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The authors reflect on the classification of chronic kidney disease (CKD) from the Kidney Disease Outcomes Quality Initiative (KDOQI) which is based from the estimated glomerular filtration rate (eGFR). The authors mention that the CKD classification is created focusing on the improvement of early detection of CKD. They state that the CKD classification system was provided with suggestions to improve the system such as the subdivision of CKD Stage 3 into Stages 3a and 3b.

Background. Current knowledge on prepregnancy reduced kidney function and the risk of adverse pregnancy outcomes mainly relies on small studies in selected populations. We aim to investigate whether reduced kidney function is associated with the risk of adverse pregnancy-related outcomes in the general population. [ABSTRACT FROM PUBLISHER]