The Association between Urinary Sodium-Potassium Ratio, Kidney Function, and Blood Pressure in a Cohort from the General Population.

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.

Nitric Oxide Precursors and Dimethylarginines as Risk Markers for Accelerated Measured GFR Decline in the General Population.

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 m2) 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.

Sex Differences in Age-Related Loss of Kidney Function.

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 m2; 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 m2 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.

Association of High-Density Lipoprotein Cholesterol With GFR Decline in a General Nondiabetic Population.

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 m2 per year) in multivariable adjusted linear mixed models and logistic regression (-0.64 ml/min per 1.73 m2 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.

Urinary excretion of epidermal growth factor and rapid loss of kidney function.

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.

Correlation Between Baseline GFR and Subsequent Change in GFR in Norwegian Adults Without Diabetes and in Pima Indians.

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.

Mild Albuminuria Is a Risk Factor for Faster GFR Decline in the Nondiabetic Population.

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.

Uric acid is associated with microalbuminuria and decreased glomerular filtration rate in the general population during 7 and 13 years of follow-up: The Tromsø Study.

BACKGROUND: The role of uric acid in development of renal dysfunction (RD) remains controversial. Earlier studies have reported inconsistent results, possibly because of their varying ability to adjust for confounding. The impact of longitudinal change in uric acid on renal outcome has not been assessed previously. We aimed to study the impact of change in serum uric acid (SUA) as well as baseline SUA on the development of RD. METHODS: In a prospective cohort study, we assessed the associations between change in SUA during follow-up, baseline SUA and RD (defined as albumin-creatinine-ratio (ACR) ≥1.13 mg albumin/mmol creatinine and/or eGFR < 60 ml/min/1.73 m(2)) in a large cohort from a general population participating in the Tromsø Study (n = 2637). Participants were stratified according to tertiles of change in SUA between baseline (1994/95) and follow-up 13 years later. (upper tertile: SUA increasing group, two lower tertiles: SUA non-increasing group). Logistic regression analysis was applied with RD and each component of RD after 7 and 13 years as the dependent variables. Adjustments were made for baseline eGFR, cardiovascular risk factors, and the use of antihypertensive drugs including diuretics. RESULTS: After excluding participants with RD at baseline, SUA increasers, compared to SUA non-increasers, had a doubled risk of RD after 7 years (odds ratio 2.00, (95 % CI 1.45, 2.75)). Odds ratio for RD in SUA increasers after 13 years was 2.18 (95 % CI 1.71, 2.79). The risk of developing ACR ≥1.13 mg/mmol alone was not significantly increased after 7 years (odds ratio 1.30 (95 % CI 0.90, 1.89), but after 13 years (odds ratio 1.43 (95 % CI 1.09, 1.86)). An increase in baseline SUA of 59 µmol/L (1 mg/dL) gave an odds ratio for RD after 13 years of 1.16 (95 % CI 1.04, 1.29). CONCLUSION: An increase in SUA during follow-up was associated with an increased risk of developing RD after 7 and 13 years.