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BACKGROUND The accuracy of estimation of kidney function with the use of routine metabolic tests, such as measurement of the serum creatinine level, has been controversial. The European Kidney Function Consortium (EKFC) developed a creatinine-based equation (EKFC eGFRcr) to estimate the glomerular filtration rate (GFR) with a rescaled serum creatinine level (i.e., the serum creatinine level is divided by the median serum creatinine level among healthy persons to control for variation related to differences in age, sex, or race). Whether a cystatin C-based EKFC equation would increase the accuracy of estimated GFR is unknown. METHODS We used data from patients in Sweden to estimate the rescaling factor for the cystatin C level in adults. We then replaced rescaled serum creatinine in the EKFC eGFRcr equation with rescaled cystatin C, and we validated the resulting EKFC eGFRcys equation in cohorts of White patients and Black patients in Europe, the United States, and Africa, according to measured GFR, levels of serum creatinine and cystatin C, age, and sex. RESULTS On the basis of data from 227,643 patients in Sweden, the rescaling factor for cystatin C was estimated at 0.83 for men and women younger than 50 years of age and 0.83 + 0.005 x(age-50) for those 50 years of age or older. The EKFC eGFRcys equation was unbiased, had accuracy that was similar to that of the EKFC eGFRcr equation in both White patients and Black patients (11,231 patients from Europe, 1093 from the United States, and 508 from Africa), and was more accurate than the Chronic Kidney Disease Epidemiology Collaboration eGFRcys equation recommended by Kidney Disease: Improving Global Outcomes. The arithmetic mean of EKFC eGFRcr and EKFC eGFRcys further improved the accuracy of estimated GFR over estimates from either biomarker equation alone. CONCLUSIONS The EKFC eGFRcys equation had the same mathematical form as the EKFC eGFRcr equation, but it had a scaling factor for cystatin C that did not differ according to race or sex. In cohorts from Europe, the United States, and Africa, this equation improved the accuracy of GFR assessment over that of commonly used equations. (Funded by the Swedish Research Council.) [ABSTRACT FROM AUTHOR]

In clinical practice, the glomerular filtration rate (GFR), a measurement of kidney functioning, is normally calculated using equations, such as the European Kidney Function Consortium (EKFC) equation. Despite being the most general equation, EKFC, just like previously proposed approaches, can still struggle to achieve satisfactory performance, limiting its clinical applicability. As a possible solution, recently machine learning (ML) has been investigated to improve GFR prediction, nonetheless the literature still lacks a general and multi-center study. Using a dataset with 19,629 patients from 13 cohorts, we investigate if ML can improve GFR prediction in comparison to EKFC. More specifically, we compare diverse ML methods, which were allowed to use age, sex, serum creatinine, cystatin C, height, weight and BMI as features, in internal and external cohorts against EKFC. The results show that the most performing ML method, random forest (RF), and EKFC are very competitive where RF and EKFC achieved respectively P10 and P30 values of 0.45 (95% CI 0.44;0.46) and 0.89 (95% CI 0.88;0.90), whereas EKFC yielded 0.44 (95% CI 0.43; 0.44) and 0.89 (95% CI 0.88; 0.90), considering the entire cohort. Small differences were, however, observed in patients younger than 12 years where RF slightly outperformed EKFC., (© 2024. The Author(s).)

International consensus supports the development of standardized protocols for measured glomerular filtration rate (mGFR) to facilitate the integration of mGFR testing in both clinical and research settings. To this end, the European Kidney Function Consortium convened an international group of experts with relevant experience in mGFR. The working group performed an extensive literature search to inform the development of recommendations for mGFR determination using 1-compartment plasma clearance models and iohexol as the exogenous filtration marker. Iohexol was selected as it is non-radio labeled, inexpensive, and safe, can be assayed at a central laboratory, and the other commonly used non-radio-labeled tracers have been (inulin) or are soon to be (iothalamate) discontinued. A plasma clearance model was selected over urine clearance as it requires no urine collection. A 1 compartment was preferred to 2 compartments as it requires fewer samples. The recommendations are based on published evidence complemented by expert opinion. The consensus paper covers practical advice for patients and health professionals, preparation, administration, and safety aspects of iohexol, laboratory analysis, blood sample collection and sampling times using both multiple and single-sample protocols, description of the mGFR mathematical calculations, as well as implementation strategies. Supplementary materials include patient and provider information sheets, standard operating procedures, a study protocol template, and support for mGFR calculation., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Introduction: Subclinical kidney dysfunction may contribute to salt-sensitive hypertension. We assessed the association between the urinary sodium-potassium ratio (Na/K ratio) and blood pressure (BP) in a general population cohort without diabetes, chronic kidney disease, cardiovascular disease, or treated hypertension. We investigated whether any such association was mediated by the kidney function markers measured glomerular filtration rate (mGFR), urinary albumin-creatinine ratio (ACR), and urinary epidermal growth factor-creatinine ratio (EGF-Cr)., Methods: The Tromsø Study is a population-based study of inhabitants of the municipality of Tromsø, Northern Norway. Participants aged 50-62 years, without diabetes, chronic kidney disease, or cardiovascular disease, were invited to the substudy Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6; 2007-09). For the present study, we excluded participants reporting the use of 1 or more antihypertensive agents, leaving 1,311 RENIS-T6 participants for a cross-sectional analysis. We measured office BP, 24-h ambulatory blood pressure (ABP), and mGFR using iohexol clearance. Na/K ratio, ACR, and EGF-Cr were measured in morning urine samples., Results: Urinary Na/K ratio was significantly associated with systolic office BP and ABP independently of cardiovascular risk factors and kidney function markers. A one-standard deviation unit increase in the Na/K ratio was associated with increased systolic ABP by 1.0 (0.3-1.6) mm Hg. Urinary Na/K ratio showed a stronger association with office BP than ABP. EGF-Cr, ACR, and mGFR did not mediate the relationship between urinary Na/K ratio and systolic BP., Conclusions: In a representative sample of the middle-aged North-European population without diabetes, chronic kidney disease, cardiovascular disease, or treated hypertension, there was a consistent association between urinary Na/K ratio and BP. The association with BP was not mediated through kidney function measures, suggesting a relationship between a diet with high sodium and low potassium and higher BP regardless of kidney function., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The results of randomized controlled trials are unclear about the long-term effect of blood pressure (BP) on kidney function assessed as the glomerular filtration rate (GFR) in persons without chronic kidney disease or diabetes. The limited duration of follow-up and use of imprecise methods for assessing BP and GFR are important reasons why this issue has not been settled. Since a long-term randomized trial is unlikely, we investigated the association between 24-h ambulatory BP (ABP) and measured GFR in a cohort study with a median follow-up of 11 years. The Renal Iohexol Clearance Survey (RENIS) cohort is a representative sample of persons aged 50 to 62 years without baseline cardiovascular disease, diabetes, or kidney disease from the general population of Tromsø in northern Norway. ABP was measured at baseline, and iohexol clearance at baseline and twice during follow-up. The study population comprised 1589 persons with 4127 GFR measurements. Baseline ABP or office BP components were not associated with the GFR change rate in multivariable adjusted conventional regression models. In generalized additive models for location, scale, and shape (GAMLSS), higher daytime systolic, diastolic, and mean arterial ABP were associated with a slight shift of the central part of the GFR distribution toward lower GFR and with higher probability of GFR < 60 mL/min/1.73 m 2 during follow-up (p < 0.05). The use of a distributional regression method and precise methods for measuring exposure and outcome were necessary to detect an unfavorable association between BP and GFR in this study of the general population., (© 2023. Springer Nature Limited.)

Significance Statement: eGFR from creatinine, cystatin C, or both has been primarily used in search of biomarkers for GFR decline. Whether the relationships between biomarkers and eGFR decline are similar to associations with measured GFR (mGFR) decline has not been investigated. This study revealed that some biomarkers showed statistically significant different associations with eGFR decline compared with mGFR decline, particularly for eGFR from cystatin C. The findings indicate that non-GFR-related factors, such as age, sex, and body mass index, influence the relationship between biomarkers and eGFR decline. Therefore, the results of biomarker studies using eGFR, particularly eGFRcys, should be interpreted with caution and perhaps validated with mGFR., Background: Several serum protein biomarkers have been proposed as risk factors for GFR decline using eGFR from creatinine or cystatin C. We investigated whether eGFR can be used as a surrogate end point for measured GFR (mGFR) when searching for biomarkers associated with GFR decline., Methods: In the Renal Iohexol Clearance Survey, GFR was measured with plasma iohexol clearance in 1627 individuals without diabetes, kidney, or cardiovascular disease at baseline. After 11 years of follow-up, 1409 participants had one or more follow-up GFR measurements. Using logistic regression and interval-censored Cox regression, we analyzed the association between baseline levels of 12 serum protein biomarkers with the risk of accelerated GFR decline and incident CKD for both mGFR and eGFR., Results: Several biomarkers exhibited different associations with eGFR decline compared with their association with mGFR decline. More biomarkers showed different associations with eGFRcys decline than with eGFRcre decline. Most of the different associations of eGFR decline versus mGFR decline remained statistically significant after adjustment for age, sex, and body mass index, but several were attenuated and not significant after adjusting for the corresponding baseline mGFR or eGFR., Conclusions: In studies of some serum protein biomarkers, eGFR decline may not be an appropriate surrogate outcome for mGFR decline. Although the differences from mGFR decline are attenuated by adjustment for confounding factors in most cases, some persist. Therefore, proposed biomarkers from studies using eGFR should preferably be validated with mGFR., (Copyright © 2023 by the American Society of Nephrology.)

Introduction: One-quarter of adults worldwide meet the criteria of metabolic syndrome (MetS). MetS increases the risk of diabetes, chronic kidney disease (CKD), and cardiovascular disease. However, the association between MetS, hyperfiltration, and long-term glomerular filtration rate (GFR) decline in the general population is unknown., Methods: In the Renal Iohexol Clearance Survey (RENIS), we investigated 1551 people aged 50 to 63 years; representative of the general population without diabetes, cardiovascular disease, or kidney disease. The GFR was measured using iohexol clearance at baseline and twice during 11 years of follow-up. Hyperfiltration at baseline was defined as an absolute GFR (ml/min) above the 90th percentile adjusted for sex, age, and height, because these variables correlate with nephron number. MetS was defined as increased waist circumference and 2 risk factors among hypertension, hyperglycemia, elevated triglycerides, and low high density lipoprotein (HDL)-cholesterol levels. The GFR decline rate was calculated using linear mixed models., Results: MetS was associated with hyperfiltration at baseline (odds ratio [OR] 2.4; 95% CI: 1.7-3.5, P  < 0.001) and a steeper GFR decline rate during follow-up (-0.30 [-0.43 to -0.16] ml/min per 1.73 m 2 /yr). Compared to those without MetS, GFR decline was -0.83 (95% CI: -1.13 to -0.53) ml/min per 1.73 m 2 /yr in those with MetS and baseline hyperfiltration and -0.15 (-0.30 to 0.00) in those MetS without hyperfiltration, P  = 0.2 for interaction., Conclusions: In the nondiabetic general population, those with MetS had an increased OR of hyperfiltration and steeper long-term GFR decline. Randomized controlled trials are needed to explore whether treatment of hyperfiltration can prevent loss of GFR in persons with MetS., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: Renal functional response (RFR) is the acute increase in glomerular filtration rate (GFR) after a protein load. Low RFR is a marker of single nephron hyperfiltration. Low birth weight (LBW) is associated with reduced number of nephrons, lower kidney function, and smaller kidneys in adults. In the present study, we investigate the associations among LBW, kidney volume, and RFR., Methods: We studied adults aged 41 to 52 years born with either LBW (≤2300 g) or normal birth weight (NBW; 3500-4000 g). GFR was measured using plasma clearance of iohexol. A stimulated GFR (sGFR) was measured on a separate day after a protein load of 100 g using a commercially available protein powder, and RFR was calculated as delta GFR. Kidney volume was estimated from magnetic resonance imaging (MRI) images using the ellipsoid formula., Results: A total of 57 women and 48 men participated. The baseline mean ± SD GFR was 118 ± 17 ml/min for men and 98 ± 19 ml/min for women. The overall mean RFR was 8.2 ± 7.4 ml/min, with mean RFR of 8.3 ± 8.0 ml/min and 8.1 ± 6.9 ml/min in men and women, respectively ( P  = 0.5). No birth-related variables were associated with RFR. Larger kidney volume was associated with higher RFR, 1.9 ml/min per SD higher kidney volume ( P  = 0.009). Higher GFR per kidney volume was associated with a lower RFR, -3.3ml/min per SD ( P  < 0.001)., Conclusion: Larger kidney size and lower GFR per kidney volume were associated with higher RFR. Birth weight was not shown to associate with RFR in mainly healthy middle-aged men and women., (© 2023 Published by Elsevier Inc. on behalf of the International Society of Nephrology.)

Background: A new Chronic Kidney Disease Epidemiology Collaboration equation without the race variable has been recently proposed (CKD-EPIAS). This equation has neither been validated outside USA nor compared with the new European Kidney Function Consortium (EKFC) and Lund-Malmö Revised (LMREV) equations, developed in European cohorts., Methods: Standardized creatinine and measured glomerular filtration rate (GFR) from the European EKFC cohorts (n = 13 856 including 6031 individuals in the external validation cohort), from France (n = 4429, including 964 Black Europeans), from Brazil (n = 100) and from Africa (n = 508) were used to test the performances of the equations. A matched analysis between White Europeans and Black Africans or Black Europeans was performed., Results: In White Europeans (n = 9496), both the EKFC and LMREV equations outperformed CKD-EPIAS (bias of -0.6 and -3.2, respectively versus 5.0 mL/min/1.73 m², and accuracy within 30% of 86.9 and 87.4, respectively, versus 80.9%). In Black Europeans and Black Africans, the best performance was observed with the EKFC equation using a specific Q-value (= concentration of serum creatinine in healthy males and females). These results were confirmed in matched analyses, which showed that serum creatinine concentrations were different in White Europeans, Black Europeans and Black Africans for the same measured GFR, age, sex and body mass index. Creatinine differences were more relevant in males., Conclusion: In a European and African cohort, the performances of CKD-EPIAS remain suboptimal. The EKFC equation, using usual or dedicated population-specific Q-values, presents the best performance in the whole age range in the European and African populations included in this study., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Introduction: Nitric oxide (NO) deficiency is associated with endothelial dysfunction, hypertension, atherosclerosis, and chronic kidney disease (CKD). Reduced NO bioavailability is hypothesized to play a vital role in kidney function impairment and CKD. We investigated the association of serum levels of endogenous inhibitors of NO, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), and precursors of NO, arginine, citrulline, and ornithine, with a decline in glomerular filtration rate (GFR) and new-onset CKD., Methods: In a prospective cohort study of 1407 healthy, middle-aged participants of Northern European origin in the Renal Iohexol Clearance Survey (RENIS), GFR was measured repeatedly with iohexol clearance during a median follow-up time of 11 years. GFR decline rates were analyzed using a linear mixed model, new-onset CKD (GFR < 60 ml/min per 1.73 m 2 ) was analyzed with interval-censored Cox regression, and accelerated GFR decline (the 10% with the steepest GFR decline) was analyzed with logistic regression., Results: Higher SDMA was associated with slower annual GFR decline. Higher levels of citrulline and ornithine were associated with accelerated GFR decline (odds ratio [OR], 1.43; 95% confidence interval [CI] 1.16-1.76 per SD higher citrulline and OR 1.23; 95% CI 1.01 to 1.49 per SD higher ornithine). Higher citrulline was associated with new-onset CKD, with a hazard ratio of 1.33 (95% CI 1.07-1.66) per SD higher citrulline., Conclusions: Associations between NO precursors and the outcomes suggest that NO metabolism plays a significant role in the pathogenesis of age-related GFR decline and the development of CKD in middle-aged people., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Objectives . Urinary albumin excretion is a risk marker for cardiovascular disease (CVD). Studies suggest that urinary orosomucoid may be a more sensitive marker of general endothelial dysfunction than albuminuria. The aim of this population-based cross-sectional study was to examine the associations between urinary orosomucoid to creatinine ratio (UOCR), urinary albumin to creatinine ratio (UACR) and subclinical CVD. Design . From the Tromsø Study (2007/2008), we included all men and women who had measurements of urinary orosomucoid ( n  = 7181). Among these, 6963 were examined with ultrasound of the right carotid artery and 2245 with echocardiography. We assessed the associations between urinary markers and subclinical CVD measured as intima media thickness of the carotid artery, presence and area of carotid plaque and diastolic dysfunction (DD). UOCR and UACR were dichotomized as upper quartile versus the three lowest. Results . High UOCR, adjusted for UACR, age, cardiovascular risk factors and kidney function, was associated with presence of DD in men (OR: 3.18, 95% CI [1.27, 7.95], p  = .013), and presence of plaque (OR: 1.20, 95% CI [1.01, 1.44], p  = .038) and intima media thickness in women (OR: 1.34, 95% CI [1.09, 1.65], p  = .005). Analyses showed no significant interaction between sex and UOCR for any endpoints. UACR was not significantly associated with DD, but the associations with intima media thickness and plaque were of magnitudes comparable to those observed for UOCR. Conclusions . UOCR was positively associated with subclinical CVD. We need prospective studies to confirm whether UOCR is a clinically useful biomarker and to study possible sex differences.

Purpose: Subclinical chronic kidney disease is known to exacerbate hypertension and progression of kidney damage. In order to initiate timely interventions, early biomarkers for this vicious circle are needed. Our aim was to describe the cross-sectional associations of urinary orosomucoid and urinary N-acetyl-β-D-glucosaminidase (NAG) with blood pressure and the longitudinal associations of urinary orosomucoid and NAG to hypertension after 7 years, and to compare the strength of these associations to the urinary albumin excretion (UAE). Material and methods: The Tromsø Study is a population-based, prospective study of inhabitants of the municipality of Tromsø, Northern Norway. Morning spot urine samples were collected on three consecutive days in the Tromsø 6 survey (2007-2008). We assessed the cross-sectional associations of urinary orosomucoid, NAG and UAE with blood pressure in Tromsø 6. In a cohort of participants attending Tromsø 6 and Tromsø 7 (2015-2016), we studied whether urinary biomarkers were longitudinally associated with hypertension. Results: A total of 7197 participants with a mean age of 63.5 years ( SD 9.2), and a mean blood pressure of 141/78 mmHg ( SD 23.0/10.6), were included in the study. Orosomucoid and UAE, but not NAG, was significantly associated with systolic and diastolic blood pressure in all the crude and multivariable cross-sectional analyses. Orosomucoid had consistently, although marginally, stronger associations with blood pressure. Incident hypertension at follow-up (Tromsø 7) was consistently significantly associated with urinary orosomucoid, but not urinary NAG or UAE. However, the standardized regression coefficients for orosomucoid were only marginally stronger than the standardized regression coefficients for ACR. Conclusion: In a cohort from the general population urine orosomucoid had a stronger cross-sectional association with blood pressure than UAE. After 7 years, urine orosomucoid showed the strongest association with incident hypertension. There were varying and weak associations between U-NAG, blood pressure and hypertension.

Hyperfiltration is a state of high glomerular filtration rate (GFR) observed in early diabetes that damages glomeruli, resulting in an iterative process of increasing filtration load on fewer and fewer remaining functional glomeruli. To delineate underlying cellular mechanisms of damage associated with hyperfiltration, transcriptional profiles of kidney biopsies from Pima Indians with type 2 diabetes with or without early-stage diabetic kidney disease were grouped into two hyperfiltration categories based on annual iothalamate GFR measurements. Twenty-six participants with a peak GFR measurement within two years of biopsy were categorized as the hyperfiltration group, and 26 in whom biopsy preceded peak GFR by over two years were considered pre-hyperfiltration. The hyperfiltration group had higher hemoglobin A1c, higher urine albumin-to-creatinine ratio, increased glomerular basement membrane width and lower podocyte density compared to the pre-hyperfiltration group. A glomerular 1240-gene transcriptional signature identified in the hyperfiltration group was enriched for endothelial stress response signaling genes, including endothelin-1, tec-kinase and transforming growth factor-β1 pathways, with the majority of the transcripts mapped to endothelial and inflammatory cell clusters in kidney single cell transcriptional data. Thus, our analysis reveals molecular pathomechanisms associated with hyperfiltration in early diabetic kidney disease involving putative ligand-receptor pairs with downstream intracellular targets linked to cellular crosstalk between endothelial and mesangial cells., (Copyright © 2022 International Society of Nephrology. All rights reserved.)

Background: CKD is more prevalent in women, but more men receive kidney replacement therapy for kidney failure. This apparent contradiction is not well understood., Methods: We investigated sex differences in the loss of kidney function and whether any sex disparities could be explained by comorbidity or CKD risk factors. In the Renal Iohexol Clearance Survey (RENIS) in northern Europe, we recruited 1837 persons (53% women, aged 50-62 years) representative of the general population and without self-reported diabetes, CKD, or cardiovascular disease. Participants' GFR was measured by plasma iohexol clearance in 2007-2009 ( n =1627), 2013-2015 ( n =1324), and 2018-2020 ( n =1384). At each study visit, healthy persons were defined as having no major chronic diseases or risk factors for CKD. We used generalized additive mixed models to assess age- and sex-specific GFR decline rates., Results: Women had a lower GFR than men at baseline (mean [SD], 90.0 [14.0] versus 98.0 [13.7] ml/min per 1.73 m 2 ; P <0.001). The mean GFR change rate was -0.96 (95% confidence interval [CI], -0.88 to -1.04) ml/min per 1.73 m 2 per year in women and -1.20 (95% confidence interval [CI], -1.12 to -1.28) in men. Although the relationship between age and GFR was very close to linear in women, it was curvilinear in men, with steeper GFR slopes at older ages (nonlinear effect; P <0.001). Healthy persons had a slower GFR decline, but health status did not explain the sex difference in the GFR decline., Conclusion: Among middle-aged and elderly individuals in the general population, decline in the mean GFR in women was slower than in men, independent of health status., (Copyright © 2022 by the American Society of Nephrology.)

Background: Age-related reduction of glomerular filtration rate (GFR) is a major contributor to the global chronic kidney disease (CKD) epidemic. We investigated whether baseline serum levels of the pro-fibrotic matrix metalloproteinase 2 (MMP2), MMP7 and their inhibitor, tissue inhibitor of metalloproteinase 1 (TIMP1), which mediates fibrosis development in aging animals, were associated with GFR decline in a general non-diabetic population., Methods: In the Renal Iohexol Clearance Survey, we measured GFR using iohexol clearance in 1627 subjects aged 50-64 years without self-reported diabetes, kidney or cardiovascular disease. After a median of 5.6 years, 1324 had follow-up GFR measurements. Using linear mixed models and logistic regression analyses, we evaluated the association of MMP7, MMP2 and TIMP1 with the mean GFR decline rate, risk of accelerated GFR decline (defined as subjects with the 10% steepest GFR slopes: ≥1.8 mL/min/1.73 m2/year) and incident CKD [GFR <60 mL/min/1.73 m2 and/or urinary albumin to creatinine ratio (ACR) ≥3.0 mg/mmol]., Results: Higher MMP7 levels (per standard deviation increase of MMP7) were associated with steeper GFR decline rates [-0.23 mL/min/1.73 m2/year (95% confidence interval -0.34 to -0.12)] and increased risk of accelerated GFR decline and incident CKD [odds ratios 1.58 (1.30-1.93) and 1.45 (1.05-2.01), respectively, in a model adjusted for age, sex, baseline GFR, ACR and cardiovascular risk factors]. MMP2 and TIMP1 showed no association with GFR decline or incident CKD., Conclusions: The pro-fibrotic biomarker MMP7, but not MMP2 or TIMP1, is associated with increased risk of accelerated GFR decline and incident CKD in middle-aged persons from the general population., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA.)

Background: Differences in the performance of estimated glomerular filtration rate (eGFR) equations have been attributed to the mathematical form of the equations and to differences between patient demographics and measurement methods. We evaluated differences in serum creatinine (SCr) and eGFR in cohorts matched for age, sex, body mass index (BMI) and measured GFR (mGFR)., Methods: White North Americans from Minnesota ( n  = 1093) and the Chronic Renal Insufficiency Cohort (CRIC) ( n  = 1548) and White subjects from the European Kidney Function Consortium (EKFC) cohort ( n  = 7727) were matched for demographic patient characteristics (sex, age ± 3 years, BMI ± 2.5 kg/m 2 ) and renal function (mGFR ± 3 ml/min/1.73 m 2 ). SCr was measured with isotope dilution mass spectrometry (IDMS)-traceable assays in the Minnesota and EKFC cohorts and with non-standardized SCr assays recalculated to IDMS in the CRIC. The Minnesota cohort and CRIC shared a common method to measure GFR (renal clearance of iothalamate), while the EKFC cohort used a variety of exogenous markers and methods, all with recognized sufficient accuracy. We compared the SCr levels and eGFR predictions [for Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and EKFC equations] of patients fulfilling these matching criteria., Results: For 305 matched individuals, mean SCr (mg/dL) was not different between the Minnesota and EKFC cohorts (females 0.83 ± 0.20 versus 0.86 ± 0.23, males 1.06 ± 0.23 versus 1.12 ± 0.37; P  > .05) but significantly different from the CRIC [females 1.13 ± 0.23 ( P  < .0001), males 1.42 ± 0.31 ( P  < .0001)]. The CKD-EPI equations performed better than the EKFC equation in the CRIC, while the opposite was true in the Minnesota and EKFC cohorts., Conclusion: Significant differences in SCr concentrations between the Minnesota and EKFC cohorts versus CRIC were observed in subjects with the same level of mGFR and equal demographic characteristics and can be explained by the difference in SCr calibration., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Aim: The Cockcroft-Gault (CG) creatinine-based equation is still used to estimate glomerular filtration rate (eGFR) for drug dosage adjustment. Incorrect eGFR may lead to hazardous over- or underdosing., Methods: In a cross-sectional analysis, CG was validated against measured GFR (mGFR) in 14 804 participants and compared with the Modification-of-Diet-in-Renal-Diseases (MDRD), Chronic-Kidney-Disease-Epidemiology (CKD-EPI), Lund-Malmö-Revised (LMR) and European-Kidney-Function-Consortium (EKFC) equations. Validation focused on bias, imprecision and accuracy (percentage of estimates within ±30% of mGFR, P30), overall and stratified for mGFR, age and body mass index at mGFR <60 mL/min, as well as classification in mGFR stages., Results: The CG equation performed worse than the other equations, overall and in mGFR, age and BMI subgroups in terms of bias (systematic overestimation), imprecision and accuracy except for patients ≥65 years where bias and P30 were similar to MDRD and CKD-EPI, but worse than LMR and EKFC. In subjects with mGFR <60 mL/min and at BMI 18.5-25 kg/m 2 , all equations performed similarly, and for BMI < 18.5 kg/m 2 CG and LMR had the best results though all equations had poor P30-accuracy. At BMI ≥ 25 kg/m 2 the bias of the CG increased with increasing BMI (+17.2 mL/min at BMI ≥ 40 kg/m 2 ). The four more recent equations also classified mGFR stages better than CG., Conclusions: The CG equation showed poor ability to estimate GFR overall and in analyses stratified for mGFR, age and BMI. CG was inferior to correctly classify the patients in the mGFR staging compared to more recent creatinine-based equations., (© 2021 British Pharmacological Society.)

Background: Lower urinary excretion of the kidney tubule-specific biomarker epidermal growth factor (uEGF) is associated with increased risk of renal function [glomerular filtration rate (GFR)] loss in diabetes and in patients with established chronic kidney disease (CKD). We investigated whether uEGF is associated with rapid GFR decline or incident CKD in the general population., Methods: Subjects without CKD or diabetes were recruited from the general population in Tromso, Norway [Renal Iohexol Clearance Survey (RENIS); N = 1249] and Groningen, the Netherlands [Prevention of REnal and Vascular END-stage disease (PREVEND); N = 4534], with a median follow-up of 5.6 and 7.4 years, respectively. GFR was measured by iohexol clearance in the RENIS and estimated using the CKD Epidemiology Collaboration creatinine-cystatin C equation in the PREVEND study. Rapid GFR decline was defined as an annual GFR loss >3.0 mL/min/1.73 m2 and in sensitivity analyses as subjects with the 10% steepest GFR slope within each cohort., Results: Lower baseline uEGF excretion was associated with rapid GFR loss in both cohorts {RENIS, odds ratio [OR] per 1 μg/mmol lower uEGF 1.42 [95% confidence interval (CI) 1.06-1.91], P = 0.02; PREVEND, OR 1.29 [95% CI 1.10-1.53], P < 0.01}, adjusted for baseline GFR, albumin:creatinine ratio and conventional CKD risk factors. Similar results were obtained using the outcome of the 10% steepest GFR slope in each cohort. Lower uEGF levels were associated with incident CKD in the combined analysis of both cohorts., Conclusions: Lower uEGF levels are associated with increased risk of rapid GFR loss and incident CKD in the general population. This finding, together with previous findings in CKD and high-risk populations, supports that uEGF may serve as a broadly applicable biomarker representing the tubular component of the current glomerulus-centric clinical risk assessment system., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Purpose: Patients with end-stage kidney disease have an increased fracture risk. Whether mild to moderate reductions in kidney function is associated with increased fracture risk is uncertain. Results from previous studies may be confounded by muscle mass because of the use of creatinine-based estimates of the glomerular filtration rate (eGFRcre). We tested the hypothesis that lower eGFR within the normal range of kidney function based on serum cystatin C (eGFRcys) or both cystatin C and creatinine (eGFRcrecys) predict fractures better than eGFR based on creatinine (eGFRcre)., Methods: In the Tromsø Study 1994-95, a cohort of 3016 women and 2836 men aged 50-84 years had eGFRcre, eGFRcys and eGFRcrecys estimated using the Chronic Kidney Disease Epidemiology Collaboration equations. Hazard ratios (HRs) (95% confidence intervals) for fracture were calculated in Cox's proportional hazards models and adjusted for age, height, body mass index, bone mineral density, diastolic blood pressure, smoking, physical activity, previous fracture, diabetes and cardiovascular disease., Results: During a median of 14.6 years follow-up, 232, 135 and 394 women and 118, 35 and 65 men suffered incident hip, proximal humerus and wrist fractures. In women, lower eGFRcre did not predict fracture, but the risk for hip and proximal humerus fracture increased per standard deviation (SD) lower eGFRcys (HRs 1.36 (1.16-1.60) and 1.33 (1.08-1.63)) and per SD lower eGFRcrecys (HRs 1.25 (1.08-1.45) and 1.30 (1.07-1.57)). In men, none of the eGFR estimates were related to increased fracture risk. In contrast, eGFRcys and eGFRcrecys were inversely associated with hip fracture risk (HRs 0.85 (0.73-0.99) and 0.82 (0.68-0.98))., Conclusions: In women, each SD lower eGFRcys and eGFRcrecys increased the risk of hip and proximal humerus fracture by 25-36%, whereas eGFRcre did not. In men, none of the estimates of eGFR were related to increased fracture risk, and each SD lower eGFRcys and eGFRcrecys decreased the risk of hip fracture by 15-18%. The findings particularly apply to a cohort of generally healthy individuals with a normal kidney function. In future studies, the association of measured GFR using the gold standard method of iohexol clearance with fractures risk should be examined for causal inference. More clinical research is needed before robust clinical inferences can be made., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Although lower high-density lipoprotein cholesterol (HDL-C) levels are considered a risk factor for cardiovascular disease (CVD), experimental evidence suggest that aging, inflammation, and oxidative stress may remodel HDL-C, leading to dysfunctional HDL-C. Population studies on HDL-C and loss of the glomerular filtration rate (GFR) reported inconsistent results, but they used inaccurate estimates of the GFR and may have been confounded by comorbidity., Methods: We investigated the association of HDL-C levels with risk of GFR loss in a general population cohort; the participants were aged 50-62 years and did not have diabetes, CVD, or chronic kidney disease (CKD) at baseline. The GFR was measured using iohexol-clearance at baseline ( n =1627) and at the follow-up ( n =1324) after a median of 5.6 years. We also investigated any possible effect modification by low-grade inflammation, physical activity, and sex., Results: Higher HDL-C levels were associated with steeper GFR decline rates and increased risk of rapid GFR decline (>3 ml/min per 1.73 m 2 per year) in multivariable adjusted linear mixed models and logistic regression (-0.64 ml/min per 1.73 m 2 per year [95% CI -0.99, -0.29; P  < 0.001] and odds ratio 2.7 [95% CI 1.4, 5.2; P  < 0.001] per doubling in HDL-C). Effect modifications indicated a stronger association between high HDL-C and GFR loss in physically inactive persons, those with low-grade inflammation, and men., Conclusion: Higher HDL-C levels were independently associated with accelerated GFR loss in a general middle-aged nondiabetic population., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Background: The Chronic Kidney Disease in Children Study (CKiD) equation for children and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for adults are recommended serum creatinine (SCr)-based calculations for estimating glomerular filtration rate (GFR). However, these equations, as well as their combination, have limitations, notably the problem of implausible changes in GFR during the transition from adolescence to adulthood and overestimation of GFR in young adults. The full age spectrum (FAS) equation addresses these issues but overestimates GFR when SCr levels are low., Objective: To develop and validate a modified FAS SCr-based equation combining design features of the FAS and CKD-EPI equations., Design: Cross-sectional analysis with separate pooled data sets for development and validation., Setting: Research and clinical studies ( n  = 13) with measured GFR available., Patients: 11 251 participants in 7 studies (development and internal validation data sets) and 8378 participants in 6 studies (external validation data set)., Measurements: Clearance of an exogenous marker (reference method), SCr level, age, sex, and height were used to develop a new equation to estimate GFR., Results: The new European Kidney Function Consortium (EKFC) equation is a FAS equation with low bias (-1.2 mL/min/1.73 m 2 [95% CI, -2.7 to 0.0 mL/min/1.73 m 2 ] in children and -0.9 mL/min/1.73 m 2 [CI, -1.2 to -0.5 mL/min/1.73 m 2 ] in adults) across the FAS (2 to 90 years) and SCr range (40 to 490 µmol/L [0.45 to 5.54 mg/dL]) and with fewer estimation errors exceeding 30% (6.5% [CI, 3.8% to 9.1%] in children and 3.1% [CI, 2.5% to 3.6%] in adults) compared with the CKiD and CKD-EPI equations., Limitation: No Black patients were included., Conclusion: The new EKFC equation shows improved accuracy and precision compared with commonly used equations for estimating GFR from SCr levels., Primary Funding Source: Swedish Research Council (Vetenskapsrådet).

Rationale & Objective: Glomerular filtration rate (GFR) estimation based on creatinine or cystatin C level is currently the standard method for assessing GFR in epidemiologic research and clinical trials despite several important and well-known limitations. Plasma iohexol clearance has been proposed as an inexpensive method for measuring GFR that could replace estimated GFR in many research projects. However, lack of standardization for iohexol assays and the use of different protocols such as single- and multiple-sample methods could potentially hamper comparisons across studies. We compared iohexol assays and GFR measurement protocols in 3 population-based European cohorts., Study Design: Cross-sectional investigation., Setting & Participants: Participants in the Age, Gene/Environment Susceptibility-Kidney Study (AGES-Kidney; n=805), the Berlin Initiative Study (BIS, n=570), and the Renal Iohexol Clearance Survey Follow-up Study (RENIS-FU; n=1,324)., Tests Compared: High-performance liquid chromatography analyses of iohexol. Plasma iohexol clearance calculated using single- versus multiple-sample protocols., Outcomes: Measures of agreement between methods., Results: Frozen samples from the 3 studies were obtained and iohexol concentrations were remeasured in the laboratory at the University Hospital of North Norway. Lin's concordance correlation coefficient ρ was>0.96 and C b (accuracy) was>0.99 for remeasured versus original serum iohexol concentrations in all 3 cohorts, and Passing-Bablok regression did not find differences between measurements, except for a slope of 1.025 (95% CI, 1.006-1.046) for the log-transformed AGES-Kidney measurements. The multiple-sample iohexol clearance measurements in AGES-Kidney and BIS were compared with single-sample GFRs derived from the same iohexol measurements. Mean bias for multiple-sample relative to single-sample GFRs in AGES-Kidney and BIS were-0.25 and-0.15mL/min, and 99% and 97% of absolute differences were within 10% of the multiple-sample result, respectively., Limitations: Lack of comparison with an independent gold-standard method., Conclusions: Agreement between the iohexol assays and clearance protocols in the 3 investigated cohorts was substantial. Our findings indicate that plasma iohexol clearance measurements can be compared across these studies., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Population mean GFR is lower in older age, but it is unknown whether healthy aging is associated with preserved rather than lower GFR in some individuals., Methods: We investigated the cross-sectional association between measured GFR, age, and health in persons aged 50-97 years in the general population through a meta-analysis of iohexol clearance measurements in three large European population-based cohorts. We defined a healthy person as having no major chronic disease or risk factors for CKD and all others as unhealthy. We used a generalized additive model to study GFR distribution by age according to health status., Results: There were 935 (22%) GFR measurements in persons who were healthy and 3274 (78%) in persons who were unhealthy. The mean GFR was lower in older age by -0.72 ml/min per 1.73 m 2 per year (95% confidence interval [95% CI], -0.96 to -0.48) for men who were healthy versus -1.03 ml/min per 1.73 m 2 per year (95% CI, -1.25 to -0.80) for men who were unhealthy, and by -0.92 ml/min per 1.73 m 2 per year (95% CI, -1.14 to -0.70) for women who were healthy versus -1.22 ml/min per 1.73 m 2 per year (95% CI, -1.43 to -1.02) for women who were unhealthy. For healthy and unhealthy people of both sexes, both the 97.5th and 2.5th GFR percentiles exhibited a negative linear association with age., Conclusions: Healthy aging is associated with a higher mean GFR compared with unhealthy aging. However, both the mean and 97.5 percentiles of the GFR distribution are lower in older persons who are healthy than in middle-aged persons who are healthy. This suggests that healthy aging is not associated with preserved GFR in old age., (Copyright © 2020 by the American Society of Nephrology.)

Background: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation is routinely used to assess renal function but exhibits varying accuracy depending on patient characteristics and clinical presentation. The overall aim of the present study was to assess if and to what extent glomerular filtration rate (GFR) estimation based on creatinine can be improved., Methods: In a cross-sectional analysis covering the years 2003-17, CKD-EPI was validated against measured GFR (mGFR; using various tracer methods) in patients with high likelihood of chronic kidney disease (CKD; five CKD cohorts, n  = 8365) and in patients with low likelihood of CKD (six community cohorts, n  = 6759). Comparisons were made with the Lund-Malmö revised equation (LMR) and the Full Age Spectrum equation., Results: 7In patients aged 18-39 years old, CKD-EPI overestimated GFR with 5.0-16 mL/min/1.73 m 2 in median in both cohort types at mGFR levels <120 mL/min/1.73 m 2 . LMR had greater accuracy than CKD-EPI in the CKD cohorts (P 30 , the percentage of estimated GFR within 30% of mGFR, 83.5% versus 76.6%). CKD-EPI was generally the most accurate equation in the community cohorts, but all three equations reached P 30 above the Kidney Disease Outcomes Quality Initiative benchmark of 90%., Conclusions: None of the evaluated equations made optimal use of available data. Prospects for improved GFR estimation procedures based on creatinine exist, particularly in young adults and in settings where patients with suspected or manifest CKD are investigated., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m 2 This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m 2 , whereas in elderly people it is increased at levels <45 ml/min per 1.73 m 2 Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable., (Copyright © 2019 by the American Society of Nephrology.)

Rationale & Objective: An elevated glomerular filtration rate (GFR), or renal hyperfiltration, may predispose individuals to subsequent rapid GFR decline in diabetes, obesity, and metabolic syndrome. Although this hypothesis is supported by results of experimental studies, the importance of hyperfiltration at the population level remains controversial. We investigated whether higher baseline GFR predicts a steeper decline in GFR., Study Design: Longitudinal cohort studies., Setting & Participants: 1,594 middle-aged Norwegians without diabetes (the Renal Iohexol Clearance Survey [RENIS]) and 319 Pima Indians (83% with type 2 diabetes)., Predictor: Baseline measured GFR using exogenous clearance methods., Outcomes: Change in measured GFR over time., Analytical Approach: Linear mixed regression models fit to assess the correlation between the random intercept (reflecting baseline GFR) and random slope (change in GFR over time)., Results: Mean baseline GFRs were 104.0 ± 20.1 (SD) and 149.4 ± 43.3 mL/min, and median follow-up durations were 5.6 (IQR, 5.2-6.0) and 9.1 (IQR, 4.0-15.0) years in the RENIS and Pima cohorts, respectively. Correlation between baseline GFR (random intercept) and slope of GFR decline was -0.31 (95% CI, -0.40 to -0.23) in the RENIS cohort and -0.41 (95% CI, -0.55 to -0.26) in the Pima cohort, adjusted for age, sex, height, and weight, suggesting that higher baseline GFRs were associated with steeper GFR decline rates., Limitations: Different methods for measuring GFR in the 2 cohorts. Renal hyperfiltration may not reflect higher single-nephron GFR. GFR decline is assumed to be linear, which may not match the actual pattern; observed correlations may arise from natural variation., Conclusions: Higher baseline GFR is associated with faster decline in GFR over time. If this relationship were causal, elevated GFR would represent a potentially modifiable risk factor for medium- to long-term GFR decline., (Copyright © 2019 National Kidney Foundation, Inc. All rights reserved.)

Background: Although the relationship between manifest chronic kidney disease and reduced cognitive function is well established, limited data exists on GFR and cognitive function in the general population. Both the brain and kidneys have low-impedance vascular beds, rendering them susceptible to damage from pulsatile blood flow. An association between mildly reduced GFR and cognitive function in the healthy general population may reveal early disease mechanisms underlying low-grade impairment of both organs as well as the possibility for intervention. Our aim was to identify an early stage of low-grade impairments in both the brain and the kidneys in the general population., Methods: This investigation was a population-based cross-sectional study that included 1627 participants aged 50-62 years who were representative of the general population in the municipality of Tromsø, Norway. The associations between GFR, measured as iohexol clearance, the urinary albumin-creatinine ratio and performance on five tests of cognitive function-the Digit Symbol Substitution Test, the finger tapping test, the Mini-Mental State Examination and the 12-word test parts 1 and 2 - were examined. The data were adjusted for factors known to be associated with both GFR and cognitive function, including cardiovascular risk factors, medications and education level., Results: In multivariate adjusted linear regression analyses, we did not observe associations of the measured GFR or albumin-creatinine ratio with performance on any of the five cognitive tests. In an analysis without adjustment for the education level, an association of worse performance on the Digit Symbol Substitution Test with higher measured GFR (p = 0.03) was observed. An exploratory analysis revealed an inverse relationship between mGFR and a higher education level that remained significant after adjusting for factors known to influence mGFR., Conclusions: We did not find evidence of an association between low-grade impairments in either the kidneys or the brain in the middle-aged general population. A possible association between a high GFR and reduced cognitive function should be investigated in future studies.

Background and Aims: Cardiovascular disease is a common cause of morbidity and mortality, with gender differences in pathophysiology. The endothelial glycocalyx maintains vascular integrity, and glycocalyx shedding reflects endothelial dysfunction and early atherosclerosis. Syndecan-1 and -4 are components of the glycocalyx, and increased serum levels indicate glycocalyx damage. We hypothesised that increased serum syndecan-1 and -4 were independently associated with myocardial infarction (MI), ischaemic stroke and all-cause mortality in men and women from a general population., Methods: Using a case-cohort design, we included 1495 participants from the Tromsø Study 2001-02. Syndecan-1 and -4 were measured in serum. Baseline variables also included age, gender, cardiovascular risk factors and urinary albumin-creatinine ratio (ACR). Hazard ratios were assessed using multivariable Cox regression models., Results: Between baseline in 2001-02 and December 2007 fatal or non-fatal MI was experienced by 328 and ischaemic stroke by 191 subjects, and 423 participants died. Syndecan-4 was independently associated with MI (hazard ratio per 10 ng/mL increase 1.32; 95% confidence interval 1.06-1.63), but not ischaemic stroke and mortality, and the associations were unchanged by adjustment for urinary ACR. Interaction between syndecan-4 and sex was borderline significant, and in gender-specific analysis, syndecan-4 was associated with MI in women only. Syndecan-1 was not associated with any endpoint., Conclusions: Syndecan-4 was associated with incident MI, and the association was stronger in women than in men. This suggests a link between endothelial glycocalyx shedding and coronary heart disease in women. Use of syndecan-4 as a risk marker in clinical setting needs further investigation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The decline in glomerular filtration rate (GFR) associated with aging is one of the most important predisposing causes of kidney failure in old age. Identifying persons at risk for accelerated GFR decline is an essential first step in the development of preventive measures to preserve kidney function in the elderly. Heart rate (HR) has not yet been studied as a risk factor for GFR decline in the general population. In the RENIS-T6 (Renal Iohexol-Clearance Survey in Tromsø 6), we measured baseline ambulatory HR and GFR as iohexol clearance in a representative, middle-aged cohort of 1627 persons without self-reported diabetes mellitus, cardiovascular disease, or kidney disease. In the RENIS-FU (RENIS Follow-Up Study), we repeated the GFR measurements and calculated the rate of GFR decline in 81% of the participants after a median follow-up of 5.6 years. The unadjusted mean rate of GFR decline was 0.96 mL/min per year. In multivariable-adjusted linear mixed models, 10 bpm higher ambulatory 24-hour and daytime HRs and office HR were associated with steeper GFR decline rates of 0.20 to 0.21 mL/min per year ( P≤0.01). The odds ratio for predicting a rate of GFR decline twice that of the population mean in a fully adjusted model was 1.24 ( P=0.01) for ambulatory 24-hour HR. Office HR was also an independent predictor of a steeper rate of GFR decline. HR may be a useful biomarker to identify persons at risk of accelerated GFR decline.

Rapid age-related glomerular filtration rate (GFR) decline increases the risk of end-stage renal disease, and a low GFR increases the risk of mortality and cardiovascular disease. High body mass index and the metabolic syndrome are well-known risk factors for patients with advanced chronic kidney disease, but their role in accelerating age-related GFR decline independent of cardiovascular disease, hypertension and diabetes is not adequately understood. We studied body mass index, waist circumference, waist-hip ratio and metabolic syndrome as risk factors for accelerated GFR decline in 1261 middle-aged people representative of the general population without diabetes, cardiovascular disease or kidney disease. GFR was measured as iohexol clearance at baseline and repeated after a median of 5.6 years. Metabolic syndrome was defined as fulfilling three out of five criteria, based on waist circumference, blood pressure, glucose, high-density lipoprotein cholesterol and triglycerides. The mean GFR decline rate was 0.95 ml/min/year. Neither the body mass index, waist circumference nor waist-hip ratio predicted statistically significant changes in age-related GFR decline, but individuals with baseline metabolic syndrome had a significant mean of 0.30 ml/min/year faster decline than individuals without metabolic syndrome in a multivariable adjusted linear regression model. This association was mainly driven by the triglyceride criterion of metabolic syndrome, which was associated with a significant 0.36 ml/min/year faster decline when analyzed separately. Results differed significantly when GFR was estimated using creatinine and/or cystatin C. Thus, metabolic syndrome, but not the body mass index, waist circumference or waist-hip ratio, is an independent risk factor for accelerated age-related GFR decline in the general population., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Introduction: A minimal increase in the albumin-to-creatinine ratio (ACR) predicts cardiovascular disease and mortality, but whether it predicts kidney function loss in nondiabetic persons is unclear. We investigated the association between ACR in the optimal or high-normal range and the rate of glomerular filtration rate (GFR) decline in a cohort from the general population without diabetes, cardiovascular, or chronic kidney disease., Methods: In the Renal Iohexol Clearance Survey, we measured GFR using iohexol clearance in 1567 middle-aged nondiabetic individuals with an ACR <3.40 mg/mmol (30.0 mg/g) at baseline. The ACR was measured in unfrozen morning urine samples collected on 3 days before the GFR measurements. A total of 1278 (81%) participants had follow-up with GFR measurements after a median of 5.6 years., Results: The median ACR at baseline was 0.22 mg/mmol (interquartile range: 0.10-0.51 mg/mmol), the mean ± SD GFR was 104.0 ± 20.1 ml/min, and the mean ± SD GFR decline rate was -0.95 ± 2.23 ml/min per year. Higher baseline ACR levels were associated with a steeper GFR decline in adjusted linear mixed models. Study participants with ACR levels of 0.11 to 0.45 and 0.46 ± 3.40 mg/mmol had a 0.25 ml/min per year (95% confidence interval [95% CI]: -0.03 to 0.53) and 0.31 ml/min per year (95% CI: 0.02-0.60) steeper rate of decline than those with ACR ≤0.10 mg/mmol in multivariable-adjusted analyses. Among study participants with an ACR of <1.13 mg/mmol (defined as the optimal range), those with an ACR of 0.11 to 1.12 mg/mmol (n = 812) had a 0.28 ml/min per year (95% CI: 0.04-0.52) steeper rate of GFR decline than those with an ACR of ≤0.10 mg/mmol (n = 655)., Conclusion: A mildly increased ACR is an independent risk factor for faster GFR decline in nondiabetic individuals.

Introduction: Markers of oxidative stress increase with age and are prevalent with chronic kidney disease. However, the role of oxidative stress markers as predictors for kidney function decline in the general population is unclear., Methods: We investigated whether a baseline urinary excretion of oxidative DNA damage (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG]) and oxidative RNA damage (8-oxo-7,8-dihydroguanosine [8-oxoGuo]) was associated with the age-related glomerular filtration rate (GFR) decline or incident low-grade albuminuria during a median of 5.6 years of follow-up. In the Renal Iohexol Clearance Survey in the Sixth Tromsø Study, we measured GFR using iohexol clearance in 1591 participants without renal disease, diabetes, or cardiovascular disease. Low-grade albuminuria was defined as an albumin-creatinine ratio >1.13 mg/mmol., Results: The mean (SD) annual GFR change was -0.84 (2.00) ml/min per 1.73 m 2 per year. In linear mixed models, urinary 8-oxodG and 8-oxoGuo levels were not associated with the GFR change rate. In a multivariable adjusted logistic regression model, a baseline urinary 8-oxoGuo in the highest quartile was associated with an increased risk of low-grade albuminuria at follow-up (odds ratio: 2.64; 95% confidence interval: 1.50-4.65). When the highest quartile of urinary 8-oxoGuo was added to the baseline model, the area under the receiver operating characteristics curve for predicting low-grade albuminuria at follow-up improved from 0.67 to 0.71 ( P  = 0.002)., Conclusion: Oxidative stress measured as urinary 8-oxoGuo excretion was independently associated with incident low-grade albuminuria, but neither 8-oxoGuo nor 8-oxodG predicted an accelerated age-related GFR decline in a cohort representative of the middle-aged general population during almost 6 years of follow-up.

The data presented in this article are related to the research article entitled "The Diagnostic Value of Rescaled Renal Biomarkers Serum Creatinine and Serum Cystatin C and their Relation with Measured Glomerular Filtration Rate" (Pottel et al. (2017) [1]). Data are presented demonstrating the rationale for the normalization or rescaling of serum cystatin C, equivalent to the rescaling of serum creatinine. Rescaling biomarkers brings them to a notionally common scale with reference interval [0.67-1.33]. This article illustrates the correlation between rescaled biomarkers serum creatinine and serum cystatin C by plotting them in a 2-dimensional graph. The diagnostic value in terms of sensitivity and specificity with measured Glomerular Filtration Rate as the reference method is calculated per age-decade for both rescaled biomarkers. Finally, the interchangeability between detecting impaired kidney function from renal biomarkers and from the Full Age Spectrum FAS-estimating GFR-equation and measured GFR using a fixed and an age-dependent threshold is shown.

Background: Serum creatinine (Scr) is the major contributing variable in glomerular filtration rate (GFR) estimating equations. Serum cystatin C (ScysC) based GFR estimating (eGFR)-equations have also been developed. The present study investigates the relation between 'rescaled' levels of these renal biomarkers (with reference interval of [0.67-1.33]) and measured GFR (mGFR)., Methods: We evaluated the diagnostic ability to detect impaired kidney function of the rescaled renal biomarkers in 8584 subjects from 12 cohorts with measured GFR, standardized Scr and ScysC. We calculated sensitivity and specificity of the rescaled biomarkers to identify kidney disease, with reference to a fixed (60mL/min/1.73m 2 ) as well as an age-dependent threshold for mGFR., Results: The upper reference limit of 1.33 for rescaled renal biomarkers is closely related to the age-dependent threshold for defining kidney status by mGFR with sensitivity and specificity for the rescaled biomarkers close to 90% for all ages. If the fixed threshold of 60mL/min/1.73m 2 for mGFR is used, then lower specificity in children and sensitivity in older adults are observed., Conclusions: Impaired kidney function can be diagnosed by rescaled renal biomarkers instead of eGFR-equations using the fixed threshold of 1.33 for all ages, consistent with an age-dependent threshold of mGFR., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Objectives: Higher levels of inflammatory markers have been associated with renal outcomes in diabetic populations. We investigated whether soluble TNF receptor 2 (TNFR2) and high-sensitivity C-reactive protein (hsCRP) were associated with the age-related GFR decline in a nondiabetic population using measured GFR (mGFR)., Design, Setting, Participants, & Measurements: A representative sample of 1590 middle-aged people from the general population without prevalent kidney disease, diabetes, or cardiovascular disease were enrolled in the Renal Iohexol-Clearance Survey in Tromsø 6 (RENIS-T6) between 2007 and 2009. After a median of 5.6 years, 1296 persons were included in the Renal Iohexol-Clearance Survey Follow-Up Study. GFR was measured using iohexol clearance at baseline and follow-up., Results: The mean decline of mGFR during the period was -0.84 ml/min per 1.73 m 2 per year. There were 133 participants with rapid mGFR decline, defined as an annual mGFR loss >3.0 ml/min per 1.73 m 2 , and 26 participants with incident CKD, defined as mGFR<60 ml/min per 1.73 m 2 at follow-up. In multivariable adjusted mixed models, 1 mg/L higher levels of hsCRP were associated with an accelerated decline in mGFR of -0.03 ml/min per 1.73 m 2 per year (95% confidence interval [95% CI], -0.05 to -0.01), and 1 SD higher TNFR2 was associated with a slower decline in mGFR (0.09 ml/min per 1.73 m 2 per year; 95% CI, 0.01 to 0.18). In logistic regression models adjusted for sex, age, weight, and height, 1 mg/L higher levels of hsCRP were associated with higher risk of rapid mGFR decline (odds ratio, 1.03; 95% CI, 1.01 to 1.06) and incident CKD (odds ratio, 1.04; 95% CI, 1.00 to 1.08)., Conclusions: Higher baseline levels of hsCRP but not TNFR2 were associated with accelerated age-related mGFR decline and incident CKD in a general nondiabetic population., (Copyright © 2017 by the American Society of Nephrology.)

Arterial stiffness is a risk factor for cardiovascular and chronic kidney disease. However, the role of arterial stiffness as a predictor of the age-related glomerular filtration rate (GFR) decline in the general population remains unresolved because of difficulty in measuring GFR with sufficient precision in epidemiological studies. The ambulatory arterial stiffness index (AASI) is a proposed indicator of arterial stiffness easily calculated from ambulatory blood pressure. We investigated whether AASI could predict GFR decline measured as iohexol clearance in the general population. We calculated AASI from baseline ambulatory blood pressure and measured the iohexol clearance at baseline and follow-up in the RENIS-FU study (Renal Iohexol Clearance Survey Follow-Up). AASI was defined as 1 minus the regression slope of the diastolic blood pressure measurement over the systolic blood pressure measurement for each patient. The RENIS cohort included a representative sample of the general middle-aged population without baseline diabetes mellitus, cardiovascular disease, or kidney disease (n=1608). The participant age was 50 to 62 years old at baseline, and the median observation time was 5.6 years. The mean (SD) of the GFR decline rate was 0.95 mL/min per year (2.23) and that of the AASI was 0.38 mL/min per year (0.13). Baseline ambulatory blood pressure or the night/day systolic or diastolic ambulatory blood pressure ratios were not associated with GFR decline. In multivariable-adjusted linear mixed regression analysis, 1 SD of increase in the baseline AASI was associated with a 0.14 mL/min per year (95% confidence interval, -0.26 to -0.02) steeper GFR decline. We conclude that the AASI is an independent risk factor for accelerated age-related GFR decline in the general middle-aged population., (© 2017 American Heart Association, Inc.)

Background: We recently published and validated the new serum creatinine (Scr)-based full-age-spectrum equation (FAS crea ) for estimating the glomerular filtration rate (GFR) for healthy and kidney-diseased subjects of all ages. The equation was based on the concept of normalized Scr and shows equivalent to superior prediction performance to the currently recommended equations for children, adolescents, adults and older adults., Methods: Based on an evaluation of the serum cystatin C (ScysC) distribution, we defined normalization constants for ScysC ( Q cysC  =   0.82 mg/L for ages <70 years and Q cysC  =   0.95 mg/L for ages ≥70 years). By replacing Scr/ Q crea in the FAS crea equation with ScysC/ Q cysC , or with the average of both normalized biomarkers, we obtained new ScysC-based (FAS cysC ) and combined Scr-/ScysC-based FAS equations (FAS combi ). To validate the new FAS cysC and FAS combi we collected data on measured GFR, Scr, ScysC, age, gender, height and weight from 11 different cohorts including n  = 6132 unique white subjects (368 children, aged ≤18 years, 4295 adults and 1469 older adults, aged ≥70 years)., Results: In children and adolescents, the new FAS cysC equation showed significantly better performance [percentage of patients within 30% of mGFR (P30) = 86.1%] than the Caucasian Asian Paediatric Adult Cohort equation (P30 = 76.6%; P < 0.0001), or the ScysC-based Schwartz equation (P30 = 68.8%; P < 0.0001) and the FAS combi equation outperformed all equations with P30 = 92.1% (P < 0.0001). In adults, the FAS cysC equation (P30 = 82.6%) performed equally as well as the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI cysC ) (P30 = 80.4%) and the FAS combi equation (P30 = 89.9%) was also equal to the combined CKD-EPI equation (P30 = 88.2%). In older adults, FAS cysC was superior (P30 = 88.2%) to CKD-EPI cysC (P30 = 84.4%; P < 0.0001) and the FAS combi equation (P30 = 91.2%) showed significantly higher performance than the combined CKD-EPI equation (P30 = 85.6%) (P < 0.0001)., Conclusion: The FAS equation is not only applicable to all ages, but also for all recommended renal biomarkers and their combinations., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Hypertension is one of the most important causes of end-stage renal disease, but it is unclear whether elevated blood pressure (BP) also accelerates the gradual decline in the glomerular filtration rate (GFR) seen in the general population with increasing age. The reason may be that most studies have considered only baseline BP and not the effects of changes in BP, antihypertensive treatment and other determinants of GFR during follow-up. Additionally, the use of GFR estimated from creatinine or cystatin C instead of measurements of GFR may have biased the results because of influence from non-GFR related confounders. We studied the relationship between BP and GFR decline using time-varying variables in a cohort representative of the general population using measurements of GFR as iohexol clearance., Methods: We included 1594 subjects aged 50 to 62 years without baseline diabetes, kidney-, or cardiovascular disease in the Renal Iohexol-clearance Survey in Tromsø 6 (RENIS-T6). GFR, BP, antihypertensive medication and all adjustment variables were ascertained at baseline, and at follow-up after a median observation time of 5.6 years in 1299 persons (81%). The relationship between GFR decline and BP was analyzed in linear mixed models., Results: The mean (standard deviation) GFR decline rate was 0.95 (2.23) mL/min/year. The percentage of persons with hypertension (systolic BP ≥ 140 mmHg, diastolic BP ≥ 90 mmHg or antihypertensive medication) increased from 42 to 52% between baseline and follow-up. In multivariable adjusted linear mixed models using time-varying independent variables measured at baseline and follow-up, higher systolic and diastolic BP were associated with slower GFR decline rates by 0.10 and 0.20 mL/min/year/10 mmHg, respectively (p < 0.05). The association was stronger in persons on antihypertensive medication than in others (p < 0.05 for the interaction between BP and antihypertensive medication)., Conclusions: In the medium-term, elevated BP is not associated with accelerated GFR decline in the general middle-aged population. In persons using antihypertensive medication, elevated BP is associated with a paradoxical slower GFR decline. Studies with even longer observation periods are needed to evaluate the ultimate effect of BP on kidney function.

Background and Objectives: Hyperfiltration at the single-nephron level has been proposed as an early stage of kidney dysfunction of different origins. Evidence supporting this hypothesis in humans is lacking, because there is no method of measuring single-nephron GFR in humans. However, increased whole-kidney GFR in the same individual implies an increased single-nephron GFR, because the number of nephrons does not increase with age. We hypothesized that an increase in GFR would be associated with an increased albumin-to-creatinine ratio in a cohort of the general population., Design, Setting, Participants, & Measurements: We measured GFR by iohexol clearance at baseline in 2007-2009 and follow-up after 5.6 years in a representative sample of 1246 persons (aged 50-62 years) who were nondiabetic from the general population of Tromso, northern Norway. Participants were without cardiovascular disease, kidney disease, or diabetes at baseline. We investigated the association between change in GFR and change in albumin-to-creatinine ratio. Increased GFR was defined as a positive change in GFR (change in GFR>0 ml/min) from baseline to follow-up. An albumin-to-creatinine ratio >30 mg/g was classified as albuminuria., Results: Change in GFR was positively associated with a change in albumin-to-creatinine ratio in the entire cohort in the multiple linear regression. The albumin-to-creatinine ratio follow-up -to-albumin-to-creatinine ratio baseline ratio increased by 8.0% (95% confidence interval, 1.4 to 15.0) per SD increase in change in GFR. When participants with increased GFR (n=343) were compared with those with a reduced GFR (n=903), the ratio increased by 16.3% (95% confidence interval, 1.1 to 33.7). The multivariable adjusted odds ratio for incident albuminuria (n=14) was 4.98 (95% confidence interval, 1.49 to 16.13) for those with an increased GFR (yes/no)., Conclusions: Increasing GFR is associated with an increase in albumin-to-creatinine ratio and incident albuminuria in the general nondiabetic population. These findings support single-nephron hyperfiltration as a risk factor for albuminuria in the general population., (Copyright © 2016 by the American Society of Nephrology.)