Bjørn Odvar Eriksen

Cystatin C is not a better estimator of GFR than plasma creatinine in the general population.

Accurate measurement of glomerular filtration rate (GFR) is complicated and costly; therefore, GFR is commonly estimated by assessing creatinine or cystatin C concentrations. Because estimates based on cystatin C predict cardiovascular disease better than creatinine, these estimates have been hypothesized to be superior to those based on creatinine, when the GFR is near the normal range. To test this, we measured GFR by iohexol clearance in a representative sample of middle-aged (50-62 years) individuals in the general population, excluding those with coronary heart or kidney disease, stroke or diabetes mellitus. Bias, precision (median and interquartile range of estimated minus measured GFR (mGFR)), and accuracy (percentage of estimates within 30% of mGFR) of published cystatin C and creatinine-based GFR equations were compared in a total of 1621 patients. The cystatin C-based equation with the highest accuracy (94%) had a bias of 3.5 and precision of 18 ml/min per 1.73 m², whereas the most accurate (95%) creatinine-based equation had a bias of 2.9 and precision of 15 ml/min per 1.73 m² The best equation, based on both cystatin C and creatinine, had a bias of 7.6 ml/min per 1.73 m², precision of 15 ml/min per 1.73 m², and accuracy of 92%. Thus, estimates of GFR based on cystatin C were not superior to those based on creatinine in the general population. Hence, the better prediction of cardiovascular disease by cystatin C than creatinine measurements, found by others, may be due to factors other than GFR.

An estimated glomerular filtration rate equation for the full age spectrum

BACKGROUND Glomerular filtration rate (GFR) is accepted as the best indicator of kidney function and is commonly estimated from serum creatinine (SCr)-based equations. Separate equations have been developed for children (Schwartz equation), younger and middle-age adults [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation] and older adults [Berlin Initiative Study 1 (BIS1) equation], and these equations lack continuity with ageing. We developed and validated an equation for estimating the glomerular filtration rate that can be used across the full age spectrum (FAS). METHODS The new FAS equation is based on normalized serum creatinine (SCr/Q), where Q is the median SCr from healthy populations to account for age and sex. Coefficients for the equation are mathematically obtained by requiring continuity during the paediatric-adult and adult-elderly transition. Research studies containing a total of 6870 healthy and kidney-diseased white individuals, including 735 children, <18 years of age, 4371 adults, between 18 and 70 years of age, and 1764 older adults, ≥70 years of age with measured GFR (inulin, iohexol and iothalamate clearance) and isotope dilution mass spectrometry-equivalent SCr, were used for the validation. Bias, precision and accuracy (P30) were evaluated. RESULTS The FAS equation was less biased [-1.7 (95% CI -3.4, -0.2) versus 6.0 (4.5, 7.5)] and more accurate [87.5% (85.1, 89.9) versus 83.8% (81.1, 86.5)] than the Schwartz equation for children and adolescents; less biased [5.0 (4.5, 5.5) versus 6.3 (5.9, 6.8)] and as accurate [81.6% (80.4, 82.7) versus 81.9% (80.7, 83.0)] as the CKD-EPI equation for young and middle-age adults; and less biased [-1.1 (-1.6, -0.6) versus 5.6 (5.1, 6.2)] and more accurate [86.1% (84.4, 87.7) versus 81.8% (79.7, 84.0)] than CKD-EPI for older adults. CONCLUSIONS The FAS equation has improved validity and continuity across the full age-spectrum and overcomes the problem of implausible eGFR changes in patients which would otherwise occur when switching between more age-specific equations.

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.

Predictors of change in estimated GFR: a population-based 7-year follow-up from the Tromsø study

BACKGROUND Chronic kidney disease is associated with increased cardiovascular mortality, and even mild impairment of renal function is a cardiovascular risk factor. Several studies have investigated the risk factors for the development of end-stage renal disease, but little is known about predictors of change in renal function in the general population. METHODS The present study included 2249 men and 2192 women without signs of kidney disease at baseline who were followed for 7 years from 1994 to 1995 in the Tromsø Study. Estimated glomerular filtration rate (eGFR) was calculated from the Modification of Diet in Renal Disease study equation. Gender-specific multiple linear regression analyses were used to assess predictors of change in eGFR (DeltaGFR). RESULTS Change in eGFR, measured in ml/min/1.73 m(2)/year, was associated with systolic blood pressure (SBP) [beta-value for a 10-mmHg increase in SBP, men = -0.14, 95% confidence interval (CI) = -0.18 to -0.09; women = -0.07, 95% CI = -0.11 to -0.03] and fibrinogen [beta-value for 1 SD increase in fibrinogen, men (1 SD: 0.85 g/L) = -0.12, 95% CI -0.20 to -0.03; women (1 SD: 0.80) = -0.11, 95% CI -0.20 to -0.02]. High alcohol consumption in men and high physical activity in women predicted an increase in eGFR. Higher albumin/creatinine ratio was associated with a decline in eGFR in men only. CONCLUSIONS Some risk factors for change in GFR seem to be gender specific but both high SBP and high levels of fibrinogen contribute to a more rapid decline in GFR for both men and women.

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.

Uric acid is a risk factor for ischemic stroke and all-cause mortality in the general population: a gender specific analysis from The Tromsø Study.

BackgroundThe role of serum uric acid as an independent predictor of cardiovascular disease and death is uncertain in the general population. Adjustments for additional cardiovascular risk factors have not been consistent. We examined the association of serum uric acid with all-cause mortality, ischemic stroke and myocardial infarction in a prospective population based study, with several traditional and non-traditional risk factors for cardiovascular disease included in the model.MethodsA population-based prospective cohort study was performed among 2696 men and 3004 women. Endpoints were all-cause mortality after 15 years, and fatal or non-fatal myocardial infarction (MI) and ischemic stroke after 12 years.Results1433 deaths, 659 MIs and 430 ischemic strokes occurred during follow-up. Fully adjusted Cox regression analyses showed that per 1 SD (87 μmol/L) increase in serum uric acid level, the risk of all-cause mortality increased in both genders (hazard ratios, HR men; 1.11, 95% CI 1.02-1.20, women; 1.16, 1.05-1.29). HRs and 95% CI for stroke were 1.31, 1.14-1.50 in men, 1.13, 0.94-1.36 in women, and 1.22 (1.09, 1.35) in the overall population. No independent associations were observed with MI.ConclusionSerum uric acid was associated with all-cause mortality in men and women, even after adjustment for blood pressure, estimated GFR, urinary albumin/creatinine ratio, drug intake and traditional cardiovascular risk factors. After the same adjustments, serum uric acid was associated with 31% increased risk of stroke in men.

Albuminuria, metabolic syndrome and the risk of mortality and cardiovascular events.

AIM Increased urinary albumin-excretion is a cardiovascular risk-factor. The cardiovascular risk of the metabolic syndrome (MetS) is debated. The aim of the present prospective, population-based study of non-diabetic individuals was to examine the association between low-grade urinary albumin-excretion, MetS, and cardiovascular morbidity and all-cause mortality. METHODS 5215 non-diabetic, non-proteinuric men and women participating in the Tromsø Study 1994-1995 were included. Urinary albumin-creatinine ratio (ACR) was measured in three urine samples. The participants were categorized into four groups by the presence/absence of MetS (the International Diabetes Federation definition) and ACR in the upper tertile (>or=0.75 mg/mmol). RESULTS Median follow-up time was 9.6 years for first ever myocardial infarction, 9.7 years for ischemic stroke and 12.4 years for mortality. High ACR (upper tertile)/MetS was associated with increased risk of myocardial infarction (hazard ratio (HR) 1.75; 95% confidence interval (CI): 1.30-2.37, p<0.001), stroke (HR 2.48; 95% CI: 1.66-3.71, p<0.001), and all-cause mortality (HR 1.63; 95% CI: 1.32-2.01, p<0.001) compared to reference (low ACR/no MetS). Similar associations were found for the high ACR/no MetS group. Low ACR/MetS was associated with myocardial infarction only (HR 1.82; 95% CI: 1.39-2.37, p<0.001). MetS predicted neither stroke nor mortality. Adjusted for its individual components, MetS was not associated with any end-point. CONCLUSIONS ACR>or=0.75 mg/mmol was associated with cardiovascular morbidity and all-cause mortality independently of MetS. MetS was not associated with any end-point beyond what was predicted from its components. Thus, low-grade albuminuria, but not MetS, may be used for risk stratification in non-diabetic subjects.

Estimating glomerular filtration rate for the full age spectrum from serum creatinine and cystatin C

Background. We recently published and validated the new serum creatinine (Scr)‐based full‐age‐spectrum equation (FAScrea) 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 (QcysC = 0.82 mg/L for ages <70 years and QcysC = 0.95 mg/L for ages ≥70 years). By replacing Scr/Qcrea in the FAScrea equation with ScysC/QcysC, or with the average of both normalized biomarkers, we obtained new ScysC‐based (FAScysC) and combined Scr‐/ScysC‐based FAS equations (FAScombi). To validate the new FAScysC and FAScombi 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 FAScysC 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 FAScombi equation outperformed all equations with P30 = 92.1% (P < 0.0001). In adults, the FAScysC equation (P30 = 82.6%) performed equally as well as the Chronic Kidney Disease Epidemiology Collaboration equation (CKD‐EPIcysC) (P30 = 80.4%) and the FAScombi equation (P30 = 89.9%) was also equal to the combined CKD‐EPI equation (P30 = 88.2%). In older adults, FAScysC was superior (P30 = 88.2%) to CKD‐EPIcysC (P30 = 84.4%; P < 0.0001) and the FAScombi 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.

GFR Normalized to Total Body Water Allows Comparisons across Genders and Body Sizes

The normalization of GFR to a standardized body-surface area of 1.73 m(2) impedes comparison of GFR across individuals of different genders, heights, or weights. Ideally, GFR should be normalized to a parameter that best explains variation in GFR. Here, we measured true GFR by iohexol clearance in a representative sample of 1627 individuals from the general population who did not have diabetes, cardiovascular disease, or kidney disease. We also estimated total body water (TBW), extracellular fluid volume, lean body mass, liver volume, metabolic rate, and body-surface area. We compared two methods of normalizing GFR to these physiologic variables: (1) the conventional method of scaling GFR to each physiologic variable by simple division and (2) a method based on regression of the GFR on each variable. TBW explained a higher proportion of the variation in GFR than the other physiologic variables. GFR adjusted for TBW by the regression method exhibited less dependence on gender, height, and weight compared with the other physiologic variables. Thus, adjusting GFR for TBW by the regression method allows direct comparisons between individuals of different genders, weights, and heights. We propose that regression-based normalization of GFR to a standardized TBW of 40 L should replace the current practice of normalizing GFR to 1.73 m(2) of body-surface area.

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?

While there is general agreement on the necessity to measure glomerular filtration rate (GFR) in many clinical situations, there is less agreement on the best method to achieve this purpose. As the gold standard method for GFR determination, urinary (or renal) clearance of inulin, fades into the background due to inconvenience and high cost, a diversity of filtration markers 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 GFR marker 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, but multiple-sample protocols may be more accurate in specific situations. In low GFRs one or more 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.