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.).

New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race.

BACKGROUND: Current equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a social and not a biologic construct. METHODS: We developed new eGFR equations without race using data from two development data sets: 10 studies (8254 participants, 31.5% Black) for serum creatinine and 13 studies (5352 participants, 39.7% Black) for both serum creatinine and cystatin C. In a validation data set of 12 studies (4050 participants, 14.3% Black), we compared the accuracy of new eGFR equations to measured GFR. We projected the prevalence of chronic kidney disease (CKD) and GFR stages in a sample of U.S. adults, using current and new equations. RESULTS: In the validation data set, the current creatinine equation that uses age, sex, and race overestimated measured GFR in Blacks (median, 3.7 ml per minute per 1.73 m2 of body-surface area; 95% confidence interval [CI], 1.8 to 5.4) and to a lesser degree in non-Blacks (median, 0.5 ml per minute per 1.73 m2; 95% CI, 0.0 to 0.9). When the adjustment for Black race was omitted from the current eGFR equation, measured GFR in Blacks was underestimated (median, 7.1 ml per minute per 1.73 m2; 95% CI, 5.9 to 8.8). A new equation using age and sex and omitting race underestimated measured GFR in Blacks (median, 3.6 ml per minute per 1.73 m2; 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m2; 95% CI, 3.4 to 4.4). For all equations, 85% or more of the eGFRs for Blacks and non-Blacks were within 30% of measured GFR. New creatinine-cystatin C equations without race were more accurate than new creatinine equations, with smaller differences between race groups. As compared with the current creatinine equation, the new creatinine equations, but not the new creatinine-cystatin C equations, increased population estimates of CKD prevalence among Blacks and yielded similar or lower prevalence among non-Blacks. CONCLUSIONS: New eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

Extending the cystatin C based EKFC-equation to children - validation results from Europe.

BACKGROUND: A new cystatin C based European Kidney Function Consortium (EKFCCysC) equation was recently developed for adults, using the same mathematical form as the previously published full age spectrum creatinine based EKFC-equation (EKFCCrea). In the present study the cystatin C based EKFC-equation is extended to children, by defining the appropriate cystatin C rescaling factor QCysC. METHODS: Rescaling factor QCysC for cystatin C was defined as: a) 0.83 mg/L, exactly as it was defined for young adults in the adult equation, and b) a more complex QCysC-age relationship based on 4th degree cystatin C-age polynomials after evaluation of data from Uppsala, Stockholm and Canada and aggregated data from Germany. The EKFCCysC equation was then validated in an independent dataset in European children (n = 2,293) with measured GFR, creatinine, cystatin C, age, height and sex available. RESULTS: The EKFCCysC with the simple QCysC-value of 0.83 had a bias of -7.6 [95%CI -8.4;-6.5] mL/min/1.73 m2 and a P30-value of 85.8% [95%CI 84.4;87.3] equal to the EKFCCysC with the more complex 4th degree QCysC-value. The arithmetic mean of the EKFCCrea and EKFCCysC with the simple QCysC of 0.83 had a bias of -4.0 [95%CI -4.5;-3.1] mL/min/1.73 m2 and P30 of 90.4% [95%CI 89.2;91.6] similar to using the more complex 4th degree QCysC-polynomial. CONCLUSION: Using exactly the same QCysC of 0.83 mg/L, the adult EKFCCysC can easily be extended to children, with some bias but acceptable P30-values. The arithmetic mean of EKFCCrea and EKFCCysC results in bias closer to zero and P30 slightly over 90%.

A study of size-selective renal elimination using a novel human model.

The recently discovered selective glomerular hypofiltration syndromes have increased interest in the actual elimination of molecules in the human kidney. In the present study, a novel human model was introduced to directly measure the single-pass renal elimination of molecules of increasing size. Plasma concentrations of urea, creatinine, C-peptide, insulin, pro-BNP, ß2-microglobulin, cystatin C, troponin-T, orosomucoid, albumin, and IgG were analysed in arterial and renal venous blood from 45 patients undergoing Transcatheter Aortic Valve Implantation (TAVI). The renal elimination ratio (RER) was calculated as the arteriovenous concentration difference divided by the arterial concentration. Estimated glomerular filtration rate (eGFR) was calculated by the CKD-EPI equations for both creatinine and cystatin C. Creatinine (0.11 kDa) showed the highest RER (21.0 ± 6.3%). With increasing molecular size, the RER gradually decreased, where the RER of cystatin C (13 kDa) was 14.4 ± 5.3% and troponin-T (36 kDa) was 11.3 ± 4.6%. The renal elimination threshold was found between 36 and 44 kDa as the RER of orosomucoid (44 kDa) was -0.2 ± 4.7%. The RER of creatinine and cystatin C showed a significant and moderate positive linear relationship with eGFR (r = 0.48 and 0.40). In conclusion, a novel human model was employed to demonstrate a decline in renal elimination with increasing molecular size. Moreover, RERs of creatinine and cystatin C were found to correlate with eGFR, suggesting the potential of this model to study selective glomerular hypofiltration syndromes.

CKD-EPI and EKFC GFR Estimating Equations: Performance and Other Considerations for Selecting Equations for Implementation in Adults.

SIGNIFICANCE STATEMENT: New eGFR equations from Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and European Kidney Function Consortium (EKFC) using creatinine (eGFRcr), cystatin C (eGFRcys), and both (eGFRcr-cys) have sufficient accuracy for use in clinical practice, leading to uncertainty in selecting equations for implementation. The authors evaluated performance of equations in an independent population of 4050 adults and evaluated other considerations important for implementation. They found that CKD-EPI and EKFC equations are approaching convergence, with better performance of eGFRcr-cys equations in the overall group and fewer differences among race, sex, and age subgroups than eGFRcr equations. Larger differences among eGFRcr equations reflect regional population differences in creatinine, forcing a trade-off between accuracy and uniformity in global implementation of eGFRcr equations. More widespread use of cystatin C could avoid this trade-off. BACKGROUND: New CKD-EPI and EKFC eGFR equations using eGFRcr, eGFRcys, and both (eGFRcr-cys) have sufficient accuracy for use in clinical practice. A better understanding of the equations, including their performance in race, sex and age subgroups, is important for selection of eGFR equations for global implementation. METHODS: We evaluated performance (bias and P 30 ) of equations and methods used for equation development in an independent study population comprising 4050 adults pooled from 12 studies. The mean (SD) measured GFR was 76.4 (29.6) ml/min per 1.73 m 2 and age 57.0 (17.4) years, with 1557 (38%) women and 579 (14%) Black participants. RESULTS: Coefficients for creatinine, cystatin C, age, and sex in the CKD-EPI and EKFC equations are similar. Performance of the eGFRcr-cys equations in the overall population (bias <±5 ml/min per 1.73 m 2 and P 30 >90%) was better than the eGFRcr or eGFRcys equations, with fewer differences among race, sex, and age subgroups. Differences in performance across subgroups reflected differences in diversity of source populations and use of variables for race and sex for equation development. Larger differences among eGFRcr equations reflected regional population differences in non-GFR determinants of creatinine. CONCLUSION: CKD-EPI and EKFC equations are approaching convergence. It is not possible to maximize both accuracy and uniformity in selecting one of the currently available eGFRcr equations for implementation across regions. Decisions should consider methods for equation development in addition to performance. Wider use of cystatin C with creatinine could maximize both accuracy and uniformity of GFR estimation using currently available equations.

The complexity of kidney disease and diagnosing it - cystatin C, selective glomerular hypofiltration syndromes and proteome regulation.

Estimation of kidney function is often part of daily clinical practice, mostly done by using the endogenous glomerular filtration rate (GFR)-markers creatinine or cystatin C. A recommendation to use both markers in parallel in 2010 has resulted in new knowledge concerning the pathophysiology of kidney disorders by the identification of a new set of kidney disorders, selective glomerular hypofiltration syndromes. These syndromes, connected to strong increases in mortality and morbidity, are characterized by a selective reduction in the glomerular filtration of 5-30 kDa molecules, such as cystatin C, compared to the filtration of small molecules <1 kDa dominating the glomerular filtrate, for example water, urea and creatinine. At least two types of such disorders, shrunken or elongated pore syndrome, are possible according to the pore model for glomerular filtration. Selective glomerular hypofiltration syndromes are prevalent in investigated populations, and patients with these syndromes often display normal measured GFR or creatinine-based GFR-estimates. The syndromes are characterized by proteomic changes promoting the development of atherosclerosis, indicating antibodies and specific receptor-blocking substances as possible new treatment modalities. Presently, the KDIGO guidelines for diagnosing kidney disorders do not recommend cystatin C as a general marker of kidney function and will therefore not allow the identification of a considerable number of patients with selective glomerular hypofiltration syndromes. Furthermore, as cystatin C is uninfluenced by muscle mass, diet or variations in tubular secretion and cystatin C-based GFR-estimation equations do not require controversial race or sex terms, it is obvious that cystatin C should be a part of future KDIGO guidelines.

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.

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.

Large difference but high correlation between creatinine and cystatin C estimated glomerular filtration rate in Mesoamerican sugarcane cutters.

OBJECTIVES: To explore the relationship between creatinine and cystatin C based estimated glomerular filtration rate (eGFR) in actively working sugarcane cutters. METHODS: This cohort study included 458 sugarcane cutters from Nicaragua and El Salvador. Serum samples were taken before and at end of harvest seasons and analysed for creatinine and cystatin C. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas were used to calculate eGFRs based on creatinine (eGFRcr), cystatin C (eGFRcys) and both creatinine and cystatin C (eGFRcrcys) at each time point. Bland-Altman plots and paired t-tests were used to compare the difference between eGFRcr and eGFRcys, and the difference in eGFRs between before and at end of the harvest seasons. RESULTS: The mean eGFRcr was higher than eGFRcys in both cohorts; absolute difference 22 mL/min/1.73 m2 (95% CI 21 to 23) in Nicaragua and 13 mL/min/1.73 m2 (95% CI 11 to 15) in El Salvador. Correlations between eGFRcr and eGFRcys were high, with r=0.69, 0.77 and 0.67 in Nicaragua at pre-harvest, end-harvest and cross-harvest, and r=0.89, 0.89 and 0.49 in El Salvador. CONCLUSIONS: Creatinine increases among heat-stressed workers reflect reduced glomerular filtration as estimated using eGFRcys, a marker independent of muscle mass and metabolism. The discrepancy between eGFRcr and eGFRcys may indicate reduced glomerular filtration of larger molecules and/or systemic bias in CKD-EPI performance in this population.

Cystatin C-based equations for estimating glomerular filtration rate do not require race or sex coefficients.

Estimation or measurement of glomerular filtration rate (GFR) is generally required for optimal treatment of patients. Plasma creatinine has been used for estimation of GFR since 1926 and plasma cystatin C since 1979. The creatinine level is strongly dependent upon muscle mass and as the average muscle mass of different populations may vary, creatinine-based GFR-estimating equations have since 1999 used more than 10 different race coefficients to improve the diagnostic performance of such equations. But 'race' cannot be determined by biological measurements and is thus an ill-defined biological entity and controversial as it involves self-reporting and social considerations. In contrast, cystatin C-levels are virtually independent of muscular mass and cystatin C-based GFR-estimating equations do not require race coefficients for reliable estimation of GFR. The use of cystatin C-based GFR-estimating equations, alone or in conjunction with creatinine-based GFR-estimating equations, is therefore highly recommended to eliminate the use of race coefficients in estimating GFR. Although sex is a more biology-oriented parameter than race, sex terms may in some cases be controversial, involving self-reporting and social considerations. However, sex terms are not required for adequate estimation of GFR using cystatin C-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).

Markers of renal function at admission and mortality in hip fracture patients - a single center prospective observational study.

Plasma cystatin C and shrunken pore syndrome (SPS) are associated with increased mortality in older adults. The objective was to assess the association between these markers of kidney function at admission and mortality in hip fracture patients. Hip fracture patients presenting at Lund University Hospital were eligible for inclusion. Cox regression was used to assess association between plasma cystatin C, creatinine, cystatin C- or creatinine-based estimations of glomerular filtration rate (eGFRCYS and eGFRCREA), or SPS (defined as eGFRCYS/eGFRCREA < 0.7) and mortality during one year follow up. Improvement in discrimination relative to the Nottingham Hip fracture score was assessed by Receiver Operational Characteristics (ROC) analysis and calculation of Net Reclassification Index (NRI). 996 patients were included in the study. Cystatin C, creatinine, eGFRCYS and eGFRCREA were associated with one-year mortality in both unadjusted and adjusted analyses. The association with mortality was stronger for cystatin C and for eGFRCYS than for creatinine and eGFRCREA. Patients with SPS had doubled mortality compared with patients without SPS (43.7 and 20.2%, respectively, p < .001). Hazard ratio for SPS in the adjusted analysis was 1.66 (95%CI; 1.16-2.39, p = .006). None of the markers improved discrimination compared to the Nottingham Hip Fracture Score using ROC analysis whereas eGFRCYS and eGFRCREA improved NRI. Our conclusion is that plasma concentrations of creatinine or cystatin C, eGFRCYS or eGFRCREA or SPS at admission in hip fracture patients are associated with mortality when known risk factors are accounted for. Identification of high risk patients may be improved by eGFRCYS or eGFRCREA.

Glomerular filtration and shrunken pore syndrome in children and adults.

A major function of the kidney is to, by glomerular filtration, maintain the overall steady-state of 5-30 kDa proteins, many of which are signalling molecules. This function of the kidney has been overlooked, since predominantly low-molecular-mass substances <1 kDa have been used to measure or estimate glomerular filtration rate (GFR). The use of cystatin C (13 kDa) as a marker of GFR has allowed the discovery that the filtration of 5-30 kDa molecules can be selectively impaired defining the shrunken pore syndrome. The discovery, pathophysiology, morbidity (mainly cardiovascular manifestations) and mortality of this syndrome are described.

A novel method for creatinine adjustment makes the revised Lund-Malmö GFR estimating equation applicable in children.

The aim of this study was to establish creatinine growth curves separately for males and females that can be used to adjust childhood levels of serum creatinine to corresponding adult levels. Linear regression with fractional polynomials of age as independent variable was used to construct creatinine growth curves for a reference cohort (n = 83,157 samples from Belgium and Sweden, age 2-40 years). Adjusted creatinine obtained from the growth curves was used to improve accuracy of estimated glomerular filtration rate (eGFR) based on the Lund-Malmö revised (LMR) equation in children. The LMR equation based on creatinine values adjusted to age 18 years was validated against measured GFR (mGFR) in a separate cohort of 4005 children from four different European countries. Validation metrics included median bias, precision, and accuracy expressed as percentage of estimates within ±30% (P30) of mGFR. Remarkable improvements in bias and accuracy were observed; P30 increased from 56% to 74% after creatinine adjustments in children with mGFR <75 mL/min/1.73 m2 (n = 932), while P30 was relatively unchanged (89-90%) at mGFR ≥75 mL/min/1.73 m2 (n = 3073). The suggested approach with adjusted creatinine makes LMR applicable in children irrespective of their renal function.

Shrunken pore syndrome and mortality: a cohort study of patients with measured GFR and known comorbidities.

Shrunken pore syndrome (SPS) is defined by a cystatin C-based estimation of glomerular filtration rate (eGFRCYS) being less than 60% or 70% of a creatinine-based GFR estimation (eGFRCR) in the absence of extrarenal influences on cystatin C or creatinine concentrations. SPS has been associated with a substantial increase in mortality or morbidity in all investigated populations. However, in these studies, neither the diagnoses, nor causes of death were described, and only estimated GFR was available. The present study concerns 2781 individuals with measured GFR (mGFR), known diagnoses, and known causes of death during 5.6 years in median. Cox multivariate proportional hazards regression model was used to estimate hazard ratios (HR) for all-cause and cancer, cardiovascular, diabetes or chronic kidney disease (CKD) as cause-specific mortality among patients with SPS. At an eGFRCYS/eGFRCR-ratio <0.70, the adjusted SPS death risk in the total cohort (HR 3.0, 95% CI 2.4-3.7) was clearly higher than that for the other diagnosis groups. In a sub-cohort of 1300 persons with or without diagnosis, but with normal mGFR, the all-cause mortality of SPS was markedly increased (HR 4.1, 95% CI 2.6-6.5). In a sub-cohort of 567 persons with normal mGFR and no diagnosis, the all-cause mortality of SPS was even more increased (HR 7.3, 95% CI 2.3-23). The prevalence of SPS in the total cohort was 23% and in the sub-cohorts 17 and 12%, respectively. As SPS is associated with a high mortality, occurs in the absence of reduced mGFR and albuminuria, it expands the spectrum of kidney disorders.

CKD: A Call for an Age-Adapted Definition.

Current criteria for the diagnosis of CKD in adults include persistent signs of kidney damage, such as increased urine albumin-to-creatinine ratio or a GFR below the threshold of 60 ml/min per 1.73 m2 This threshold has important caveats because it does not separate kidney disease from kidney aging, and therefore does not hold for all ages. In an extensive review of the literature, we found that GFR declines with healthy aging without any overt signs of compensation (such as elevated single-nephron GFR) or kidney damage. Older living kidney donors, who are carefully selected based on good health, have a lower predonation GFR compared with younger donors. Furthermore, the results from the large meta-analyses conducted by the CKD Prognosis Consortium and from numerous other studies indicate that the GFR threshold above which the risk of mortality is increased is not consistent across all ages. Among younger persons, mortality is increased at GFR <75 ml/min per 1.73 m2, whereas in elderly people it is increased at levels <45 ml/min per 1.73 m2 Therefore, we suggest that amending the CKD definition to include age-specific thresholds for GFR. The implications of an updated definition are far reaching. Having fewer healthy elderly individuals diagnosed with CKD could help reduce inappropriate care and its associated adverse effects. Global prevalence estimates for CKD would be substantially reduced. Also, using an age-specific threshold for younger persons might lead to earlier identification of CKD onset for such individuals, at a point when progressive kidney damage may still be preventable.

Structural Characterization of Covalently Stabilized Human Cystatin C Oligomers.

Human cystatin C (HCC), a cysteine-protease inhibitor, exists as a folded monomer under physiological conditions but has the ability to self-assemble via domain swapping into multimeric states, including oligomers with a doughnut-like structure. The structure of the monomeric HCC has been solved by X-ray crystallography, and a covalently linked version of HCC (stab-1 HCC) is able to form stable oligomeric species containing 10-12 monomeric subunits. We have performed molecular modeling, and in conjunction with experimental parameters obtained from atomic force microscopy (AFM), transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) measurements, we observe that the structures are essentially flat, with a height of about 2 nm, and the distance between the outer edge of the ring and the edge of the central cavity is ~5.1 nm. These dimensions correspond to the height and diameter of one stab-1 HCC subunit and we present a dodecamer model for stabilized cystatin C oligomers using molecular dynamics simulations and experimentally measured parameters. Given that oligomeric species in protein aggregation reactions are often transient and very highly heterogeneous, the structural information presented here on these isolated stab-1 HCC oligomers may be useful to further explore the physiological relevance of different structural species of cystatin C in relation to protein misfolding disease.

Validation of standardized creatinine and cystatin C GFR estimating equations in a large multicentre European cohort of children.

BACKGROUND: Most validations of paediatric glomerular filtration rate (GFR) estimating equations using standardized creatinine (CR) and cystatin C (CYS) assays have comprised relatively small cohorts, which makes accuracy across subgroups of GFR, age, body mass index (BMI) and gender uncertain. To overcome this, a large cohort of children referred for GFR determination has been established from several European medical centres. METHODS: Three thousand four hundred eight measurements of GFR (mGFR) using plasma clearance of exogenous substances were performed in 2218 children aged 2-17 years. Validated equations included Schwartz-2009CR/2012CR/CYS/CR+CYS, FASCR/CYS/CR+CYS, LMRCR, Schwartz-LyonCR, BergCYS, CAPACYS, CKD-EPICYS, AndersenCR+CYS and arithmetic means of the best single-marker equations in explorative analysis. Five metrics were used to compare the performance of the GFR equations: bias, precision and three accuracy measures including the percentage of GFR estimates (eGFR) within ± 10% (P10) and ± 30% (P30) of mGFR. RESULTS: Three of the cystatin C equations, BergCYS, CAPACYS and CKD-EPICYS, exhibited low bias and generally satisfactory accuracy across all levels of mGFR; CKD-EPICYS had more stable performance across gender than the two other equations. Among creatinine equations, Schwartz-LyonCR had the best performance but was inaccurate at mGFR < 30 mL/min/1.73 m2 and in underweight patients. Arithmetic means of the best creatinine and cystatin C equations above improved bias compared to the existing composite creatinine+cystatin C equations. CONCLUSIONS: The present study strongly suggests that cystatin C should be the primary biomarker of choice when estimating GFR in children with decreased GFR. Arithmetic means of well-performing single-marker equations improve accuracy further at most mGFR levels and have practical advantages compared to composite equations.

The mortality increase in cardiac surgery patients associated with shrunken pore syndrome correlates with the eGFRcystatin C/eGFRcreatinine-ratio.

Shrunken pore syndrome (SPS) is a condition in which estimated glomerular filtration rate (eGFR) based upon cystatin C is lower than eGFR based upon creatinine. It has been associated with increased mortality even in the presence of normal GFR in both a cardiac surgical population and a general population. No systematic studies of the variation in eGFRcystatin C/eGFRcreatinine-ratio used for SPS diagnosis have been published. This study aims to evaluate whether early and midterm mortality following elective cardiac surgery varies with the ratio used to identify SPS. Preoperative levels of cystatin C and creatinine were analysed in 4007 patients undergoing elective coronary artery bypass grafting (CABG) and/or surgical aortic valve replacement (sAVR). The eGFRcystatin C/eGFRcreatinine-ratio was calculated based on the equation pairs CKD-EPIcystatin C/CKD-EPIcreatinine and CAPA/LMrev. The overall 1- and 3-year all-cause mortality was 2.9 and 6.8%, respectively. Mean follow-up time was 3.6 years. Mortality markedly and progressively increased with a decrease in the eGFRcystatin C/eGFRcreatinine-ratio for both equation pairs. An increase in mortality was noted already when the ratio decreased from 1.0 to 0.90. To facilitate the clinical decisions based upon the SPS-defining eGFRcystatin C/eGFRcreatinine-ratio, we calculated both the ratios defining the highest combined sensitivity and specificity and the ratios producing a high specificity of 95%, finding different cut-off for these scenarios.