The Association Between Metabolic Syndrome, Hyperfiltration, and Long-Term GFR Decline in the General Population

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 2 /yr). Compared to those without MetS, GFR decline was 0.83 (95% CI: 1.13 to 0.53) ml/min per 1.73 m2 /yr in those with MetS and baseline hyperfiltration and 0.15 ( 0.30 to 0.00) in those MetS without hyperfiltration, P ¼ 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

Low-grade impairments in cognitive and kidney function in a healthy middle-aged general population: a cross-sectional study

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

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 middleaged people

Estimated Glomerular Filtration Rate (eGFR) based on cystatin C was associated with increased risk of hip and proximal humerus fractures in women and decreased risk of hip fracture in men, whereas eGFR based on creatinine was not associated with fracture risk in both sexes: The Tromsø Study

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

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; P2 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 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. CKD is projected to become the fifth leading cause of years of life lost in 2040. In most countries, more women than men develop CKD stage G3, which is defined as a reduced GFR, whereas more men start RRT. This apparent contradiction is poorly understood, but proposed explanations include gender disparities in access to health care and RRT, biologic differences between women and men leading to different GFR decline rates, bias in creatinine-based formulas to estimate the GFR, and overestimation of the CKD prevalence in women. In addition, sex and gender disparities in health status could cause differences in GFR loss. For example, women have a lower prevalence of myocardial infarction and a longer life expectancy than men. However, although cross-sectional population studies have found a higher mean GFR in healthy than in unhealthy persons, it is unknown whether good health is associated with preserved GFR during aging at the individual level, and whether this can explain the sex difference in CKD prevalence. Population-based longitudinal studies with repeated assessments of GFR in the same individuals are necessary to investigate the associations between sex, health status, and age-related GFR decline. The few existing studies on GFR change rates were not population based, did not investigate the association with health status, or used equations to calculate the eGFR on the basis of endogenous substances. These eGFR equations are biased by non–GFR-related factors, such as muscle mass, affecting men and women differently, particularly during aging. Measurements of GFR by an exogenous filtration marker, e.g., iohexol, avoid these methodologic problems. Accordingly, we investigated age- and sex-specific GFR decline rates in the Renal Iohexol Clearance Survey (RENIS), which is the only general population cohort with repeated measurements of GFR.The aim of the study was to report a reference range for age-related GFR decline in the general population and to investigate possible sex disparities in GFR decline rates by health status

Iohexol plasma clearance for measuring glomerular filtration rate in clinical practice and research: a review. Part 1: How to measure glomerular filtration rate with iohexol?

Published version. Source at http://dx.doi.org/10.1093/ckj/sfw070 While there is general agreement on the necessity tomeasure glomerular filtration rate (GFR) inmany clinical situations, there is less agreement on the bestmethod to achieve this purpose.As the gold standardmethod for GFR determination, urinary (or renal) clearance of inulin, fades into the background due to inconvenience and high cost, a diversity of filtrationmarkers and protocols compete to replace it. In this review, we suggest that iohexol, a non-ionic contrast agent, is most suited to replace inulin as the marker of choice for GFR determination. Iohexol comes very close to fulfilling all requirements for an ideal GFRmarker in terms of low extra-renal excretion, low protein binding and in being neither secreted nor reabsorbed by the kidney. In addition, iohexol is virtually non-toxic and carries a low cost. As iohexol is stable in plasma, administration and sample analysis can be separated in both space and time, allowing access to GFR determination across different settings. An external proficiency programme operated by Equalis AB, Sweden, exists for iohexol, facilitating interlaboratory comparison of results. Plasma clearance measurement is the protocol of choice as it combines a reliable GFR determination with convenience for the patient. Single-sample protocols dominate, butmultiple-sample protocolsmay bemore accurate in specific situations. In lowGFRs one ormore late samples should be included to improve accuracy. In patients with large oedema or ascites, urinary clearance protocols should be employed. In conclusion, plasma clearance of iohexol may well be the best candidate for a common GFR determination method

Comparability of Plasma Iohexol Clearance Across Population-Based Cohorts.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadRationale & 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 Cb (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. Keywords: Renal clearance; accuracy; agreement; concordance correlation; glomerular filtration rate (GFR); iohexol; kidney function tests; measured GFR; measurement error; multiple-sample; single-sample.United States Department of Health & Human Services National Institutes of Health (NIH) - USA National Institute on Aging, United States Hjartavernd, Iceland (Icelandic Heart Association) Icelandic Parliament (Althingi) KfH-Foundation of Preventive Medicine, Germany Dr. Werner Jackstadt Foundation, Germany Northern Norway Regional Health Authority Boehringer Ingelhei

Standardization of serum creatinine is essential for accurate use of unbiased estimated GFR equations: evidence from three cohorts matched on renal function

peer reviewedABSTRACT 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/m2) and renal function (mGFR ± 3 ml/min/1.73 m2). 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 &gt; .05) but significantly different from the CRIC [females 1.13 ± 0.23 (P &lt; .0001), males 1.42 ± 0.31 (P &lt; .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

Iohexol plasma clearance measurement protocol standardization for adults: a consensus paper of the European Kidney Function Consortium.

peer reviewedInternational 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

Performance of creatinine-based equations to estimate glomerular filtration rate in White and Black populations in Europe, Brazil and Africa.

peer reviewed("[en] 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.","[en] ",""