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.

Development of quantitative assay for simultaneous measurement of purine metabolites and creatinine in biobanked urine by liquid chromatography-tandem mass spectrometry.

Purine metabolism is essential for all known living creatures, including humans in whom elevated serum concentration of purine break-down product uric acid (UA) is probably an independent risk factor for mortality, type 2 diabetes and cardiovascular events. An automated multiplex assay that measures several purine metabolites could therefore prove useful in many areas of medical, veterinary and biological research. The aim of the present work was to develop a sensitive LC-MS/MS method for simultaneous quantitation of xanthine, hypoxanthine, UA, allantoin, and creatinine in biobanked urine samples. This article describes details and performance of the new method studied in 55 samples of human urine. Archival sample preparation and effect of storage conditions on stability of the analytes are addressed. The intra-day and inter-day coefficients of variation were small for all the analytes, not exceeding 1% and 10%, respectively. Measurements of UA and creatinine in biobanked urine showed good agreement with values obtained using routine enzymatic assays on fresh urine. Spearman's correlation coefficients were 0.869 (p < .001) for creatinine and 0.964 (p < .001) for UA. Conclusion: the newly developed LC-MS/MS method allows reliable quantitative assessment of xanthine, hypoxanthine, allantoin, UA and creatinine. The proposed pre-analytical processing makes the method suitable for both fresh and biobanked urine stored frozen at -80 °C for at least 5.5 years.

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.

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 and Measured GFR Associate Differently with Retinal Vasculopathy in the General Population.

BACKGROUND/AIMS: Estimated glomerular filtration rate (eGFR) is used extensively in epidemiological research. Validations of eGFR have demonstrated acceptable performance, but the dependence of creatinine and cystatin C on non-GFR factors could confound associations with disease. Few studies have investigated this issue in direct comparison with measured GFR (mGFR). We compared the associations between eGFR and mGFR and retinal vasculopathy, a marker of systemic microvasculopathy. METHODS: Iohexol clearance and retinal photography were examined in the Renal Iohexol Clearance Survey in Tromsø 6, which consists of a representative sample of middle-aged persons from the general population. A total of 1,553 persons without self-reported kidney disease, cardiovascular disease or diabetes were investigated. Three eGFR equations based on creatinine and/or cystatin C from the Chronic Kidney Disease Epidemiology Collaboration were studied. Differences between eGFR and mGFR were analyzed with seemingly unrelated regression methods. RESULTS: mGFR in the lowest quartile was associated with an increased multivariable-adjusted odds ratio of retinopathy (OR 1.86, 95% CI 1.16-2.97), but not with retinal artery or vein diameters. eGFR based on cystatin C (eGFRcys) was consistently biased relative to mGFR in its associations with retinal vessel diameters across different models. eGFR based on creatinine (eGFRcrea) and eGFR based on both creatinine and cystatin C were also biased in several of these models (p < 0.05). For retinopathy, the differences between the 3 eGFR and mGFR measurements were not statistically significant. CONCLUSIONS: Low mGFR is associated with retinopathy in the general population. eGFR based on creatinine and/or cystatin C are not valid substitutes for mGFR in studies of the relationship between the retina and kidney function in healthy persons.

Analgesic use in a Norwegian general population: change over time and high-risk use--The Tromsø Study.

BACKGROUND: Increased use of analgesics in the population is a cause for concern in terms of drug safety. There is a paucity of population-based studies monitoring the change in use over time of both non-prescription (OTC) analgesics and prescription (Rx) analgesics. Although much is known about the risks associated with analgesic use, we are lacking knowledge on high-risk use at a population level. The purpose of this study was to estimate the prevalence of non-prescription and prescription analgesic use, change over time and the prevalence in the presence of potential contraindications and drug interactions in a general population. METHODS: A repeated cross-sectional study with data from participants (30-89 years) of the Tromsø Study in 2001-02 (Tromsø 5; N = 8039) and in 2007-08 (Tromsø 6; N = 12,981). Participants reported use of OTC and Rx analgesics and regular use of all drugs in the preceding four weeks. Change over the time period was analyzed with generalized estimating equations. The prevalence of regular analgesic use in persons with or without a clinically significant contraindication or drug interaction was determined in the Tromsø 6 population, and differences were tested with logistic regression. RESULTS: Analgesic use increased from 54 to 60% in women (OR = 1.24, 95% CI 1.15-1.32) and from 29 to 37% in men (OR = 1.39, 95% CI 1.27-1.52) in the time period; the increase was due to sporadic use of OTC analgesics. There was substantial regular use of analgesics in several of the contraindication categories examined; the prevalence of non-steroidal anti-inflammatory drugs was more than eight per cent among persons with chronic kidney disease, gastrointestinal ulcers, or high primary cardiovascular risk. About four per cent of the study population demonstrated at least one potential drug interaction with an analgesic drug. CONCLUSIONS: The use of analgesics increased in the time period due to an increase in the use of OTC analgesics. Analgesic exposure in the presence of contraindications or drug interactions may put patients at risk. Public and prescriber awareness about clinically relevant contraindications and drug interactions with analgesics need to be increased.

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.

Physical exercise, fasting glucose, and renal hyperfiltration in the general population: the Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6).

BACKGROUND AND OBJECTIVES: Abnormally elevated GFR, or hyperfiltration, is a proposed mechanism for kidney injury in diabetes, prediabetes, and obesity. This study investigated whether lack of physical exercise is associated with hyperfiltration and whether exercise modifies the positive association between fasting glucose and measured GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Renal Iohexol Clearance Survey in Tromsø 6 measured GFR as single-sample plasma iohexol clearance in 1506 members of the general population (age 50-62 years) without diabetes, cardiovascular disease, or kidney disease. Leisure-time physical exercise was assessed by a self-administered questionnaire. Hyperfiltration was defined as GFR above the 90th percentile after adjustment for sex, age, weight, height, and use of renin-angiotensin system inhibitors. RESULTS: High-intensity exercise was associated with lower adjusted odds of hyperfiltration in men (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.28-0.80) but not in women (OR, 1.02; 95% CI, 0.60-1.72). In both sexes, high-intensity exercise modified the association between fasting glucose and GFR. A fasting glucose level 1 mmol/L higher was associated with a GFR that was 7.3 (95% CI, 4.0-10.6) and 6.2 (95% CI, 3.4-9.0) ml/min per 1.73 m(2) higher in men and women who never exercised or exercised with low intensity. There was no association between fasting glucose and GFR in men and women who exercised with high intensity (interaction, P<0.001). CONCLUSIONS: High-intensity exercise was associated with lower odds of hyperfiltration in men and modified the association between glucose and GFR of both sexes in a population without diabetes.

The role of cystatin C in improving GFR estimation in the general population.

BACKGROUND: The equations used to estimate glomerular filtration rate (GFR) based on serum creatinine level are limited by their dependence on muscle mass. Although cystatin C level predicts clinical outcomes better than creatinine level in the general population, its role in estimating GFR in the reference range is unclear. Cystatin C level is not influenced by muscle mass, but by several other non-GFR determinants. We investigated whether regression models using cystatin C level alone or in combination with creatinine level in principle would improve GFR estimation in the general population compared with models using creatinine level alone. STUDY DESIGN: Study of diagnostic accuracy. SETTING & PARTICIPANTS: A representative sample (n = 1,621; aged 50-62 years) of the general population in Tromsø, Norway, without coronary heart disease, stroke, diabetes mellitus, or kidney disease. Individuals had participated in the Renal Iohexol Clearance Survey (RENIS-T6), part of the sixth Tromsø Study. INDEX TEST: Performance of multiple linear and fractional polynomial regression models with plasma creatinine and/or cystatin C levels as independent variables and measured GFR as a dependent variable. REFERENCE TEST: Plasma iohexol clearance. OTHER MEASUREMENTS: Creatinine measured with an enzymatic method. Cystatin C measured with a particle-enhanced turbidimetric immunoassay. RESULTS: In internal validation of models with cystatin C, creatinine, or both levels, percentages of GFR estimates within 10% of measured GFR were 61% (95% CI, 58%-63%), 62% (95% CI, 59%-64%), and 68% (95% CI, 65%-70%), respectively. Models with either cystatin C or creatinine level had very similar precision and ability to detect GFR <90 mL/min/1.73 m(2), whereas models based on both markers performed better. LIMITATIONS: Only middle-aged individuals of European ancestry were investigated. Lack of standardization between cystatin C assays. No external validation of regression models. CONCLUSIONS: Models based on cystatin C alone are not superior to those based on creatinine, but models based on both markers can improve GFR estimation in the reference range.

Impaired fasting glucose is associated with renal hyperfiltration in the general population.

OBJECTIVE: Increased glomerular filtration rate (GFR), also called hyperfiltration, is a proposed mechanism for renal injury in diabetes. The causes of hyperfiltration in individuals without diabetes are largely unknown, including the possible role of borderline hyperglycemia. We assessed whether impaired fasting glucose (IFG; 5.6-6.9 mmol/L), elevated HbA1c, or hyperinsulinemia are associated with hyperfiltration in the general middle-aged population. RESEARCH DESIGN AND METHODS: A total of 1,560 individuals, aged 50-62 years without diabetes, were included in the Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6). GFR was measured as single-sample plasma iohexol clearance. Hyperfiltration was defined as GFR>90th percentile, adjusted for sex, age, weight, height, and use of renin-angiotensin system inhibitors. RESULTS: Participants with IFG had a multivariable-adjusted odds ratio of 1.56 (95% CI 1.07-2.25) for hyperfiltration compared with individuals with normal fasting glucose. Odds ratios (95% CI) of hyperfiltration calculated for a 1-unit increase in fasting plasma glucose (FPG) and HbA1c, after multivariable-adjustment, were 1.97 (1.36-2.85) and 2.23 (1.30-3.86). There was no association between fasting insulin levels and hyperfiltration. A nonlinear association between FPG and GFR was observed (df=3, P<0.0001). GFR increased with higher glucose levels, with a steeper slope beginning at FPG≥5.4 mmol/L. CONCLUSIONS: Borderline hyperglycemia was associated with hyperfiltration, whereas hyperinsulinemia was not. Longitudinal studies are needed to investigate whether the hyperfiltration associated with IFG is a risk factor for renal injury in the general population.

Estimated GFR associates with cardiovascular risk factors independently of measured GFR.

Estimation of the GFR (eGFR) using creatinine- or cystatin C-based equations is imperfect, especially when the true GFR is normal or near-normal. Modest reductions in eGFR from the normal range variably predict cardiovascular morbidity. If eGFR associates not only with measured GFR (mGFR) but also with cardiovascular risk factors, the effects of these non-GFR-related factors might bias the association between eGFR and outcome. To investigate these potential non-GFR-related associations between eGFR and cardiovascular risk factors, we measured GFR by iohexol clearance in a sample from the general population (age 50 to 62 years) without known cardiovascular disease, diabetes, or kidney disease. Even after adjustment for mGFR, eGFR associated with traditional cardiovascular risk factors in multiple regression analyses. More risk factors influenced cystatin C-based eGFR than creatinine-based eGFR, adjusted for mGFR, and some of the risk factors exhibited nonlinear effects in generalized additive models (P<0.05). These results suggest that eGFR, calculated using standard creatinine- or cystatin C-based equations, partially depends on factors other than the true GFR. Thus, estimates of cardiovascular risk associated with small changes in eGFR must be interpreted with caution.