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.

Office and Ambulatory Heart Rate as Predictors of Age-Related Kidney Function Decline.

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.

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.

Urinary Markers of Oxidative Stress Are Associated With Albuminuria But Not GFR Decline.

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 m2 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.

Metabolic syndrome but not obesity measures are risk factors for accelerated age-related glomerular filtration rate decline in the general population.

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.

Blood pressure and age-related GFR decline in the general population.

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.

Association of TNF Receptor 2 and CRP with GFR Decline in the General Nondiabetic Population.

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 m2 per year. There were 133 participants with rapid mGFR decline, defined as an annual mGFR loss >3.0 ml/min per 1.73 m2, and 26 participants with incident CKD, defined as mGFR<60 ml/min per 1.73 m2 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 m2 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 m2 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.

High Ambulatory Arterial Stiffness Index Is an Independent Risk Factor for Rapid Age-Related Glomerular Filtration Rate Decline in the General Middle-Aged Population.

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.

Central obesity associates with renal hyperfiltration in the non-diabetic general population: a cross-sectional study.

BACKGROUND: Obesity is a risk factor for end-stage renal disease. Renal hyperfiltration, defined as an abnormally high glomerular filtration rate (GFR), is a link in the causal chain between diabetes and chronic kidney disease. Whether obesity is associated with hyperfiltration in the non-diabetic general population, remains unresolved due to a lack of consensus regarding the definition of hyperfiltration and the limited precision of high-range GFR estimations with creatinine and/or cystatin C. METHODS: 1555 middle-aged participants without diabetes, renal or cardiovascular disease were enrolled from the general population in the Renal Iohexol Clearance Survey from the 6th Tromsø Study (RENIS-T6) between 2007 and 2009. Obesity was assessed using the body mass index (BMI), waist circumference (WC) and the waist-hip ratio (WHR). GFR was measured by iohexol clearance. Dichotomous variables for hyperfiltration were based on two alternative definitions using unadjusted GFR (mL/min) above the 90th percentile. The 90th percentile was age-, sex- and height-specific in one definition and age-, sex-, height- and weight-specific in the other. RESULTS: In multivariable adjusted logistic regression models, only WHR was consistently associated with hyperfiltration based on both definitions. For the definition based on the age-, sex-, height- and weight-specific 90th percentile, the association with the WHR (odds ratios (95 % confidence intervals)) for hyperfiltration was 1.48 (1.08-2.02) per 0.10 WHR increase. CONCLUSIONS: Central obesity is associated with hyperfiltration in the general population. The WHR may serve as a better indicator of the renal effects of obesity than BMI or WC.

Association of Increasing GFR with Change in Albuminuria in the General Population.

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 ratiofollow-up-to-albumin-to-creatinine ratiobaseline 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.

Elevated blood pressure is not associated with accelerated glomerular filtration rate decline in the general non-diabetic middle-aged population.

Although hypertension is a risk factor for end-stage renal disease, this complication develops in only a minority of hypertensive patients. Whether non-malignant hypertension itself is sufficient to cause reduced glomerular filtration rate (GFR) is unclear. Therefore, we investigated whether elevated blood pressure (BP) was associated with accelerated GFR decline in the general population. The study was based on the Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6), which included a representative sample of 1594 individuals aged 50 to 62 years from the general population without baseline diabetes or kidney or cardiovascular disease. GFR was measured as iohexol clearance at baseline and follow-up after a median observation time of 5.6 years. BP was measured according to a standardized procedure. The mean (SD) GFR decline rate was 0.95 (2.23) ml/min/yr. In multivariable adjusted linear mixed regressions with either baseline systolic or diastolic BP as the independent variable, there were no statistically significant associations with GFR decline. Thus, elevated BP is not associated with accelerated mean GFR decline in the general middle-aged population. Hence, additional genetic and environmental factors are probably necessary for elevated BP to develop manifest chronic kidney disease in some individuals.

Prediabetes and Risk of Glomerular Hyperfiltration and Albuminuria in the General Nondiabetic Population: A Prospective Cohort Study.

BACKGROUND: The role of prediabetes as a risk factor for hyperfiltration and albuminuria in persons who do not develop diabetes is unclear. The lack of evidence is mainly due to the difficulty of accurately assessing the glomerular filtration rate (GFR) in the near-normal range of GFR. We investigated whether prediabetes is an independent risk factor for glomerular hyperfiltration and high-normal urinary albumin-creatinine ratio (ACR) using measured GFR (mGFR) rather than estimated GFR. STUDY DESIGN: Prospective cohort study based on the Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6) and the RENIS Follow-Up Study. Median observation time was 5.6 years. SETTING & PARTICIPANTS: A representative sample of 1,261 persons without diabetes mellitus (DM) from the general population aged 50 to 62 years. PREDICTOR: Prediabetes defined by fasting glucose and hemoglobin A1c according to levels suggested by the American Diabetes Association (preDMADA) and the International Expert Committee of 2009 (preDMIEC). OUTCOMES: Change in mGFR; hyperfiltration defined as mGFR>90th percentile adjusted for age, sex, weight, and height; and high-normal ACR (>10mg/g) at follow-up. MEASUREMENTS: GFR was measured with iohexol clearance. RESULTS: Baseline fasting glucose, hemoglobin A1c, and both definitions of prediabetes were predictors of higher mGFR at follow-up and lower annual mGFR decline in multivariable-adjusted regression analyses. Participants with preDMIEC had an OR for hyperfiltration of 1.95 (95% CI, 1.20-3.17) and for high-normal ACR of 1.83 (95% CI, 1.04-3.22) at follow-up. We adjusted for cardiovascular risk factors including ambulatory blood pressure at baseline and change in use of antihypertensive medication between baseline and follow-up. LIMITATIONS: Only middle-aged white patients participated. There is no consensus on how to define glomerular hyperfiltration. CONCLUSIONS: Our findings imply an independent role of prediabetes in the development of glomerular hyperfiltration and albuminuria. Prediabetes might be a target for early treatment to prevent chronic kidney disease in chronic hyperglycemia.

Residual Associations of Inflammatory Markers with eGFR after Accounting for Measured GFR in a Community-Based Cohort without CKD.

BACKGROUND AND OBJECTIVES: eGFR on the basis of creatinine (eGFRcre) associates differently with cardiovascular disease and mortality than eGFR on the basis of cystatin C (eGFRcys). This may be related to risk factors affecting the level of creatinine and cystatin C along non-GFR pathways, which may confound the association between eGFR and outcome. Nontraditional risk factors are usually not measured in epidemiologic studies of eGFR and cannot be adjusted for to reduce confounding. We examined whether the inflammatory markers soluble TNF receptor type 2 (sTNFR2), C-reactive protein (CRP), and fibrinogen associated differently with eGFR than with measured GFR (mGFR). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: GFR was measured by iohexol clearance in 1627 middle-aged participants without kidney disease, diabetes, or cardiovascular disease enrolled in the Renal Iohexol Clearance Survey Study from the Sixth Tromsø Study between 2007 and 2009. Generalized estimating equations were used to assess the residual associations between eGFR (eGFRcre, eGFRcys, and eGFR on the basis of creatinine and cystatin C) and the inflammatory markers relative to mGFR. RESULTS: sTNFR2, CRP, and fibrinogen were associated with a higher eGFRcre after accounting for mGFR in multivariable-adjusted models (2.63 ml/min per 1.73 m(2); 95% confidence interval [95% CI], 2.1 to 3.2 per SD increase in sTNFR2, 0.93 ml/min per 1.73 m(2); 95% CI, 0.3 to 1.5 per SD increase in log CRP, and 1.19 ml/min per 1.73 m(2); 95% CI, 0.6 to 1.8 per SD increase in fibrinogen). sTNFR2 and CRP were inversely associated with eGFRcys (-1.4 ml/min per 1.73 m(2); 95% CI, -2.1 to -0.6 per SD increase in sTNFR2, and -0.76 ml/min per 1.73 m(2); 95% CI, -1.4 to -0.1 per SD increase in log CRP). CONCLUSIONS: eGFRcre and eGFRcys are associated with inflammatory factors after accounting for mGFR but in opposite directions. These non-GFR-related associations may bias risk estimates by eGFR and, in part, explain the different risks predicted by eGFRcre and eGFRcys in longitudinal studies.

Estimated GFR is biased by non-traditional cardiovascular risk factors.

BACKGROUND: Estimated glomerular filtration rate (eGFR) based on either cystatin C or creatinine performs similarly in estimating measured GFR, but associate differently with cardiovascular disease (CVD) and mortality. This could be due to confounding by non-GFR-related traits associated with cystatin C and creatinine levels. We investigated non-GFR-related associations between eGFR and two types of nontraditional risk factors for CVD and death: L-arginine/dimethylarginine metabolism and insulin resistance. METHODS: GFR was measured via iohexol clearance in a cross-sectional study of 1,624 middle-aged persons from the general population without CVD, diabetes or chronic kidney disease. The dimethylarginines were measured using liquid chromatography tandem mass spectrometry (LC-MSMS). Insulin resistance was determined by the homeostasis model assessment (HOMA-IR). RESULTS: Asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), the L-arginine/ADMA ratio and insulin resistance were associated with creatinine-based eGFR after accounting for measured GFR in multivariable adjusted analyses. The cystatin C-based eGFR showed a similar residual association with SDMA; an oppositely directed, borderline significant association with ADMA; and a stronger residual association with insulin resistance compared with eGFR based on creatinine. CONCLUSION: Both creatinine- and cystatin C-based eGFR are influenced by nontraditional risk factors, which may bias risk prediction by eGFR in longitudinal studies.