Cystatin C-Based Equation to Estimate GFR without the Inclusion of Race and Sex.

BACKGROUND: The accuracy of estimation of kidney function with the use of routine metabolic tests, such as measurement of the serum creatinine level, has been controversial. The European Kidney Function Consortium (EKFC) developed a creatinine-based equation (EKFC eGFRcr) to estimate the glomerular filtration rate (GFR) with a rescaled serum creatinine level (i.e., the serum creatinine level is divided by the median serum creatinine level among healthy persons to control for variation related to differences in age, sex, or race). Whether a cystatin C-based EKFC equation would increase the accuracy of estimated GFR is unknown. METHODS: We used data from patients in Sweden to estimate the rescaling factor for the cystatin C level in adults. We then replaced rescaled serum creatinine in the EKFC eGFRcr equation with rescaled cystatin C, and we validated the resulting EKFC eGFRcys equation in cohorts of White patients and Black patients in Europe, the United States, and Africa, according to measured GFR, levels of serum creatinine and cystatin C, age, and sex. RESULTS: On the basis of data from 227,643 patients in Sweden, the rescaling factor for cystatin C was estimated at 0.83 for men and women younger than 50 years of age and 0.83 + 0.005 × (age - 50) for those 50 years of age or older. The EKFC eGFRcys equation was unbiased, had accuracy that was similar to that of the EKFC eGFRcr equation in both White patients and Black patients (11,231 patients from Europe, 1093 from the United States, and 508 from Africa), and was more accurate than the Chronic Kidney Disease Epidemiology Collaboration eGFRcys equation recommended by Kidney Disease: Improving Global Outcomes. The arithmetic mean of EKFC eGFRcr and EKFC eGFRcys further improved the accuracy of estimated GFR over estimates from either biomarker equation alone. CONCLUSIONS: The EKFC eGFRcys equation had the same mathematical form as the EKFC eGFRcr equation, but it had a scaling factor for cystatin C that did not differ according to race or sex. In cohorts from Europe, the United States, and Africa, this equation improved the accuracy of GFR assessment over that of commonly used equations. (Funded by the Swedish Research Council.).

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

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.

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

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 > .05) but significantly different from the CRIC [females 1.13 ± 0.23 (P < .0001), males 1.42 ± 0.31 (P < .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.

Performance of creatinine-based equations to estimate glomerular filtration rate with a methodology adapted to the context of drug dosage adjustment.

AIM: The Cockcroft-Gault (CG) creatinine-based equation is still used to estimate glomerular filtration rate (eGFR) for drug dosage adjustment. Incorrect eGFR may lead to hazardous over- or underdosing. METHODS: In a cross-sectional analysis, CG was validated against measured GFR (mGFR) in 14 804 participants and compared with the Modification-of-Diet-in-Renal-Diseases (MDRD), Chronic-Kidney-Disease-Epidemiology (CKD-EPI), Lund-Malmö-Revised (LMR) and European-Kidney-Function-Consortium (EKFC) equations. Validation focused on bias, imprecision and accuracy (percentage of estimates within ±30% of mGFR, P30), overall and stratified for mGFR, age and body mass index at mGFR <60 mL/min, as well as classification in mGFR stages. RESULTS: The CG equation performed worse than the other equations, overall and in mGFR, age and BMI subgroups in terms of bias (systematic overestimation), imprecision and accuracy except for patients ≥65 years where bias and P30 were similar to MDRD and CKD-EPI, but worse than LMR and EKFC. In subjects with mGFR <60 mL/min and at BMI 18.5-25 kg/m2 , all equations performed similarly, and for BMI < 18.5 kg/m2 CG and LMR had the best results though all equations had poor P30-accuracy. At BMI ≥ 25 kg/m2 the bias of the CG increased with increasing BMI (+17.2 mL/min at BMI ≥ 40 kg/m2 ). The four more recent equations also classified mGFR stages better than CG. CONCLUSIONS: The CG equation showed poor ability to estimate GFR overall and in analyses stratified for mGFR, age and BMI. CG was inferior to correctly classify the patients in the mGFR staging compared to more recent creatinine-based equations.

Development and Validation of a Modified Full Age Spectrum Creatinine-Based Equation to Estimate Glomerular Filtration Rate : A Cross-sectional Analysis of Pooled Data.

BACKGROUND: The Chronic Kidney Disease in Children Study (CKiD) equation for children and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for adults are recommended serum creatinine (SCr)-based calculations for estimating glomerular filtration rate (GFR). However, these equations, as well as their combination, have limitations, notably the problem of implausible changes in GFR during the transition from adolescence to adulthood and overestimation of GFR in young adults. The full age spectrum (FAS) equation addresses these issues but overestimates GFR when SCr levels are low. OBJECTIVE: To develop and validate a modified FAS SCr-based equation combining design features of the FAS and CKD-EPI equations. DESIGN: Cross-sectional analysis with separate pooled data sets for development and validation. SETTING: Research and clinical studies (n = 13) with measured GFR available. PATIENTS: 11 251 participants in 7 studies (development and internal validation data sets) and 8378 participants in 6 studies (external validation data set). MEASUREMENTS: Clearance of an exogenous marker (reference method), SCr level, age, sex, and height were used to develop a new equation to estimate GFR. RESULTS: The new European Kidney Function Consortium (EKFC) equation is a FAS equation with low bias (-1.2 mL/min/1.73 m2 [95% CI, -2.7 to 0.0 mL/min/1.73 m2] in children and -0.9 mL/min/1.73 m2 [CI, -1.2 to -0.5 mL/min/1.73 m2] in adults) across the FAS (2 to 90 years) and SCr range (40 to 490 µmol/L [0.45 to 5.54 mg/dL]) and with fewer estimation errors exceeding 30% (6.5% [CI, 3.8% to 9.1%] in children and 3.1% [CI, 2.5% to 3.6%] in adults) compared with the CKiD and CKD-EPI equations. LIMITATION: No Black patients were included. CONCLUSION: The new EKFC equation shows improved accuracy and precision compared with commonly used equations for estimating GFR from SCr levels. PRIMARY FUNDING SOURCE: Swedish Research Council (Vetenskapsrådet).

Prospects for improved glomerular filtration rate estimation based on creatinine-results from a transnational multicentre study.

BACKGROUND: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation is routinely used to assess renal function but exhibits varying accuracy depending on patient characteristics and clinical presentation. The overall aim of the present study was to assess if and to what extent glomerular filtration rate (GFR) estimation based on creatinine can be improved. METHODS: In a cross-sectional analysis covering the years 2003-17, CKD-EPI was validated against measured GFR (mGFR; using various tracer methods) in patients with high likelihood of chronic kidney disease (CKD; five CKD cohorts, n = 8365) and in patients with low likelihood of CKD (six community cohorts, n = 6759). Comparisons were made with the Lund-Malmö revised equation (LMR) and the Full Age Spectrum equation. RESULTS: 7In patients aged 18-39 years old, CKD-EPI overestimated GFR with 5.0-16 mL/min/1.73 m2 in median in both cohort types at mGFR levels <120 mL/min/1.73 m2. LMR had greater accuracy than CKD-EPI in the CKD cohorts (P30, the percentage of estimated GFR within 30% of mGFR, 83.5% versus 76.6%). CKD-EPI was generally the most accurate equation in the community cohorts, but all three equations reached P30 above the Kidney Disease Outcomes Quality Initiative benchmark of 90%. CONCLUSIONS: None of the evaluated equations made optimal use of available data. Prospects for improved GFR estimation procedures based on creatinine exist, particularly in young adults and in settings where patients with suspected or manifest CKD are investigated.

Hospital admission with pneumonia and subsequent persistent risk of chronic kidney disease: national cohort study.

BACKGROUND: Although acute onset kidney complications associated with severe infections including pneumonia are well characterized, little is known about possible subsequent delayed risk of chronic kidney disease (CKD). PATIENTS AND METHODS: Associations between hospital admission with pneumonia in adulthood and raised risks of subsequent CKD were evaluated in a cohort of all male residents in Sweden born from 1952 to 1956 (n=284,198) who attended mandatory military conscription examinations in late adolescence (n=264,951) and were followed up through 2009. CKD and pneumonia were identified using Swedish national registers, and their associations were evaluated using Cox regression. Excluding the first year, the subsequent period was divided into ≤5, >5-≤15, and >15 years after hospital admission with pneumonia. Follow-up ended on the date of first incident diagnosis of kidney disease, death, emigration, or December 31,2009, whichever occurred first. RESULTS: During a median follow-up of 36.7 (interquartile range 35.3-37.9) years from late adolescence, 5,822 men had an inpatient pneumonia diagnosis without contemporaneous kidney disease. Among exposed men, 136 (2.3%) were later diagnosed with CKD compared with 2,749 (1.2%) of the unexposed. The adjusted hazard ratio for CKD in the first year after the first episode of pneumonia was 14.55 (95% confidence interval, 10.41-20.32), identifying early onset kidney complications and possibly pre-existing undiagnosed CKD. Starting follow-up 1 year after pneumonia to reduce the potential influence of surveillance bias and the risk of reverse causation, the adjusted hazard ratio for CKD in the first 5 years of follow-up was 5.20 (95% confidence interval, 3.91-6.93) and then attenuated with increasing time. CONCLUSION: Pneumonia among inpatients is associated with a persistently increased risk for subsequent CKD, with the highest risk during the years immediately after pneumonia. Health care professionals should be aware of this period of heightened risk to facilitate early diagnosis and secondary preventive interventions.

Measured glomerular filtration rate does not improve prediction of mortality by cystatin C and creatinine.

BACKGROUND: Cystatin C may add explanatory power for associations with mortality in combination with other filtration markers, possibly indicating pathways other than glomerular filtration rate (GFR). However, this has not been firmly established since interpretation of associations independent of measured GFR (mGFR) is limited by potential multicollinearity between markers of GFR. The primary aim of this study was to assess associations between cystatin C and mortality, independent of mGFR. A secondary aim was to evaluate the utility of combining cystatin C and creatinine to predict mortality risk. METHODS: Cox regression was used to assess the associations of cystatin C and creatinine with mortality in 1157 individuals referred for assessment of plasma clearance of iohexol. RESULTS: Since cystatin C and creatinine are inversely related to mGFR, cystatin C - 1 and creatinine - 1 were used. After adjustment for mGFR, lower cystatin C - 1 (higher cystatin C concentration) and higher creatinine - 1 (lower creatinine concentration) were independently associated with increased mortality. When nested models were compared, avoiding the potential influence of multicollinearity, the independence of the associations was supported. Among models combining the markers of GFR, adjusted for demographic factors and comorbidity, cystatin C - 1 and creatinine - 1 combined explained the largest proportion of variance in associations with mortality risk ( R 2 = 0.61). Addition of mGFR did not improve the model. CONCLUSIONS: Our results suggest that both creatinine and cystatin C have independent associations with mortality not explained entirely by mGFR and that mGFR does not offer a more precise mortality risk assessment than these endogenous filtration markers combined.

Predictors in adolescence of ESRD in middle-aged men.

BACKGROUND: Identification of predictors of end-stage renal disease (ESRD) in adolescence could provide intervention targets and improve understanding of the cause. STUDY DESIGN: Register-based nested case-control study. SETTING & PARTICIPANTS: A cohort of all Swedish male residents born from 1952 through 1956 who attended mandatory military conscription examinations in late adolescence was used to identify 534 cases and 5,127 controls matched by birth year, county, and vital status. PREDICTOR: Erythrocyte sedimentation rate (ESR), proteinuria, blood pressure, and body mass index (BMI) in late adolescence. OUTCOMES: ESRD (defined here as dialysis therapy, kidney transplantation, surgical procedures creating long-term access for dialysis therapy, or chronic kidney disease stage 5) from 1985 through 2009. MEASUREMENTS: Physical working capacity and cognitive function score in late adolescence. Head of household's occupation and household crowding measured as person-per-room ratio from the 1960 census when participants were children. RESULTS: Proteinuria is associated notably with future ESRD, with an adjusted OR of 7.72 (95% CI, 3.94-15.14; P<0.001) for trace or positive dipstick findings. ESR has a dose-dependent association with ESRD with an adjusted OR of 2.07 (95%CI, 1.14-3.75; P=0.02) for ESR >15mm/h. Hypertension is associated strongly with future ESRD with an OR of 3.97 (95%CI, 2.08-7.59; P<0.001) for grade 2 hypertension and higher. Elevated BMI is associated statistically significantly with increased ESRD risk with an OR of 3.53 (95%CI, 2.04-6.11; P<0.001) for BMI ≥30 compared with 18.5-<25kg/m(2). LIMITATIONS: The study was limited to men, with no initial estimation of glomerular filtration rate, and information on smoking was unavailable. CONCLUSIONS: ESR, proteinuria, BMI, and blood pressure in late adolescence are independent predictors of ESRD in middle-aged men. This highlights the long natural history and importance of adopting a life-course approach when considering the cause of chronic kidney disease.

Mortality following unemployment during an economic downturn: Swedish register-based cohort study.

OBJECTIVE: To investigate if unemployment during an economic downturn is associated with mortality, even among men with markers of better health (higher cognitive function scores and qualifications), and to assess whether the associations vary by age at unemployment. DESIGN: Longitudinal register-based cohort study. SETTING: Study entry was in 1990 and 2001 when Sweden was entering periods of significant economic contraction. PARTICIPANTS: A representative sample of men from the general population (n=234 782) born between 1952 and 1956 who participated in military conscription examinations. Men in receipt of disability or sickness benefit at study entry were excluded. MAIN OUTCOME MEASURE: All-cause mortality. RESULTS: Unemployment compared with employment in 1991 (ages 34-38 years) produced adjusted HRs (with 95% CIs) for all-cause mortality (3651 deaths) during follow-up to 2001 and after stratification by education of 2.35 (1.99 to 2.76) for compulsory education, 2.25 (1.97 to 2.58) for up to 3 years postcompulsory education and 1.90 (1.40 to 2.57) for more than 3 years postcompulsory education. When unemployment was compared with employment in 2001 (ages 45-49 years) with follow-up to 2010, the pattern of mortality risk (4271 deaths) stratified by education was reversed, producing adjusted HRs of 2.81 (2.47 to 3.21) for compulsory education, 2.87 (2.58 to 3.19) for up to 3 years postcompulsory education and 3.44 (2.78 to 4.25) for more than 3 years postcompulsory education. Interaction testing confirmed effect modification by age/period (p=0.003). The degree of gradient reversal was slightly less pronounced after stratification by cognitive function but produced a similar pattern of results (p=0.004). CONCLUSIONS: Unemployment at older ages is associated with greater mortality risk than at younger ages, with the greatest relative increase in risk among men with markers of better health, suggesting the greater vulnerability of all older workers to unemployment-associated exposures.