Measurement Of GFR Research Articles

Agreement between Creatinine and Cystatin C-Based Equations in the Estimation of Glomerular Filtration Rate among Malaysian Patients with Renal Impairment

Abstract: Background: Cystatin C-based equations have been proposed as an alternative for creatinine-based equations in the estimation of Glomerular Filtration Rate (eGFR). Limited studies were available with regards to the Asian population to evaluate the agreement of eGFR measured based on both biomarkers. This study aimed to evaluate the agreement between various cystatin C- and creatinine-based eGFR equations. Methods: Patients were recruited from the Nephrology Clinic Universiti Kebangsaan Malaysia Medical Centre. Serum cystatin C and creatinine levels were analysed by particle-enhanced immunoturbidimetry assay and kinetic alkaline picrate method, respectively. Various cystatin C-based (Hoek, Larsson, Grubb, Flodin, cystatin C-based Chronic Kidney Disease Epidemiology (CKD-EPI)) and creatinine-based eGFR equations (Cockcroft-Gault, Modification of Diet in Renal Disease, creatinine-based CKD-EPI) were compared by using the Pearson’s correlation and Bland-Altman plot. Results: A total of 118 patients included in this study have a mean age of 61±15 years and 57.6% were female. The mean serum cystatin C and creatinine levels were 2.00±1.06 mg/L and 2.21±1.63 mg/dL, respectively. The correlation between serum cystatin C and creatinine level was significant (r=0.78, P<0.01). All cystatin C-based eGFR correlated significantly with the creatinine-based eGFR equations. The strongest correlation was between creatininebased and cystatin C-based CKD-EPI equation (r=0.93, P<0.01). The Bland-Altman plot shows that cystatin C-based CKD-EPI equation had the least mean difference when compared with creatinine-based CKD-EPI equation. Conclusion: Significant correlation and good agreement were demonstrated between various cystatin C-based and creatininebased eGFR equations. The cystatin C-based equations are appropriate alternative for GFR measurement among Malaysian patients with renal impairment. Key words: Cystatin C, Creatinine, Estimated Glomerular Filtration Rate, Renal Function, Renal Elimination, Chronic Kidney Disease.

A comparison between 2017 FAS and 2012 CKD-EPI equations: a multi-center validation study in Chinese adult population.

The recent guidelines recommend using the estimated glomerular filtration rate (eGFR) to evaluate renal function. There are two reported full-age-spectrum (FAS) equations in 2017, which are based on serum cystatin C concentrations with or without accompanying serum creatinine level (FASCr-Cys or FASCys). We compared the performance and assessed the applicability of the new FAS equation with the 2012 CKD-EPI (CKD-EPICys and CKD-EPICr-Cys) equation in Chinese subjects. A total of 1184 patients, mean aged 55.06year who underwent 99mTc-DTPA GFR measurements (rGFR) from four hospitals were enrolled. The bias (eGFR-rGFR), precision (interquartile range of difference [IQR]), and accuracy (the proportion of eGFR within 30% of rGFR [P30]) of eGFR and rGFR calculated by four equations were compared. Generally, the equation based on the combination of Cys and Scr performed superior to that on the basis of Cys alone, either the CKD-EPICr-Cys or the FASCr-Cys. Detailedly, referred to rGFR (67.33ml/min/1.73m2), the CKD-EPICys, CKD-EPICr-Cys, FASCys, and the FASCr-Cys estimated GFR 56.46ml/min/1.73m2, 62.79ml/min/1.73m2, 56.45ml/min/1.73m2, and 61.04ml/min/1.73m2, gave ROCAUC0.944, 0.954, 0.943, and 0.953, respectively. Another comparison as to bias, precision, P30, and RMSE with FASCr-Cys were - 2.87ml/min/1.73m2, 19.01ml/min/1.73m2, 74.16%, and 17.84ml/min/1.73m2 showed that FASCr-Cys performed approximately more accurate than other equations, as well as the diagnostic consistency of GFR staging. In the rGFR < 60ml/min/1.73m2 subgroup, the FASCr-Cys equation showed the best performance. In older subjects, compared with FASCys, CKD-EPICr-Cys, and CKD-EPICys, the FASCr-Cys equation had relatively less bias (- 8.09 vs. - 9.63, - 7.52, - 11.04, P < 0.05), most precise (15.18 vs. 16.32, 15.22, 16.63), and most accuracy, P30 was statistically different from the other equations, and achieved a ideal value > 70%. The performance of the FASCr-Cys equation is better than that of the CKD-EPICr-Cys equation in the Chinese population, particularly in the elderly. Yet, further modification of FAS equations from a large-scale study could be more suitable for the Chinese population, particularly in older people.

Presence of Carotid Artery Plaque Is Associated with Rapid Renal Function Decline in Patients with Type 2 Diabetes and Normal Baseline Renal Function

Background: Recent clinical evidences indicate that early rapid renal function decline is closely associated with the development of diabetic kidney disease. We have investigated the incidence and baseline clinical predictors of rapid renal function decline in patients with type 2 diabetes and normal baseline renal function. Methods: A total of 967 type 2 diabetic patients from the Korean National Diabetes Program (KNDP), a prospective, multicenter, observational cohort study, with serial GFR measurement for 5 years and normal renal function were included for the analysis. Rapid renal function decline was defined as an eGFR decline &amp;gt;3.3% per year. Carotid ultrasonography was used to assess carotid intima-media thickness (IMT) and the presence of plaque. Results: The mean age was 53.7 years with body mass index of 25.4 kg/m2. Rapid renal function decline developed in 158 participants (16.3%) and average GFR decline was -5.2 ± 1.9% /year in rapid decliners and -0.4 ± 1.9% /year in non-decliners. There were no differences in the presence of albuminuria or retinopathy between the rapid decliners and non-decliners at baseline. Multivariable logistic regression analyses revealed that female sex (odds ratio (OR) 4.80 [95% CI 2.69-8.56], p&amp;lt;0.0001), higher urine albumin/creatinine ratio (OR 1.26 [1.03-1.55], p=0.024), presence of carotid artery plaque (OR 2.58 [1.47-4.53], p=0.001), and previous history of hypertension (OR 1.93 [1.09-3.44], p=0.025) and CVD (OR 2.53 [1.24-5.15], p=0.011) were the independent clinical predictors for rapid renal function decline. Conclusions: Our study suggests the need for close monitoring of renal function and early intensive management in patients with type 2 diabetes and carotid atherosclerosis. Disclosure D. Seo: None. S. Kim: None. S. Ahn: None. S. Hong: None. M. Nam: None. J. Woo: None. S. Baik: None. K. Lee: None. Y. Kim: None. Y. Park: None.

Estimated glomerular filtration rate in stable older kidney transplant recipients-are present algorithms valid? A national cross-sectional cohort study

Several equations have been developed for estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease (CKD), but none were developed based on data from elderly kidney transplant recipients (KTR). The primary aim of this study was to evaluate different creatinine-based equations in stable elderly KTR. A national cross-sectional study was performed using data from 263 consecutive kidney transplant recipients 60 years or older who performed a routine GFR measurement one year after engraftment. GFR was measured by iohexol clearance calculation based on two samples. eGFR was calculated from a range of different creatinine-based equations using information obtained at the time of GFR measurement. Bias, precision, and accuracy were evaluated for each equation. All equations apart from Nankivell had accuracy (P30) > 80%. The BIS1, FAS, LMRCR , and Cockcroft & Gault equations in recipients older than 70 years and the FAS, LMRCR , and MDRD in recipients 60-69 years old had nonsignificant bias. The CKD-EPI had significant bias in both groups. If one should choose a single equation for follow-up of individual CKD progression in all recipients ≥ 60 years, the FAS or LMRCR equations are probably the best alternatives.

Iohexol Plasma Clearance in Animal Models: The Clear Choice for Measuring Early Renal Dysfunctio

Glomerular filtration rate is a measure of the kidney’s ability to filter blood. In animal models of early kidney failure, there is no routine method to accurately measure GFR. The expensive gold standard of GFR measurement is exogenous inulin clearance. The commonly used method, endogenous plasma creatinine concentration, is unreliable and insensitive, especially at normal levels of renal function. This study investigates the utility of iohexol, an inexpensive radio-contrast agent as a promising exogenous marker for plasma clearance kidney function evaluation in rats. Early stages of progressive kidney failure were induced with a 0.25% adenine diet in male Sprague Dawley rats (N=8) over 5 weeks. Both plasma clearance of iohexol and inulin and creatinine concentration were evaluated following weekly venous injections and blood sampling. Plasma iohexol clearance and plasma inulin clearance strongly correlate (R2=0.95). However, plasma creatinine concentration correlated weakly with iohexol(R2=0.53) and inulin(R2=0.58). Iohexol plasma clearance accurately measures changes in kidney function, especially in in comparison to creatinine analysis. The data demonstrates creatinine is an inappropriate marker for renal function in early adenine-induced CKD rat models. Ongoing analysis of this data suggests refinement of the protocol will yield a simple method for routine measure of kidney function in murine lab animals. This tool will facilitate advancement in kidney disease onset and allow for more accurate interpretation of kidney function in the various animal models.

Progressive kidney disease may not alter the association of hyponatremia with mortality.

Hyponatremia is a common electrolyte disorder and a prognostic marker for mortality. We hypothesize that in advanced chronic or acute kidney disease, hyponatremia is not independently associated with mortality because of the contribution of kidney failure to its pathophysiology. Clinical Looking Glass, Montefiore's clinical database, was used to build a cohort of all patients hospitalized between January of 2009 and December of 2011. A chronic kidney disease (CKD) group and an acute kidney injury (AKI) group were defined based on GFR measurements during and before index hospitalization. Cox regression models assessed the hazard for death for those with community acquired hyponatremia as compared to those without hyponatremia, stratified by stage of kidney disease within each cohort. Forty-four thousand four hundred and seventy-six patients were studied. Forty six percent (46.2%) of subjects were in the CKD cohort and 53.8% were in the AKI cohort. Hyponatremic patients were older, and had a higher prevalence of CKD and AKI. A total of 7,934 subjects died (17.8%) during 22months of follow-up. In CKD and AKI cohorts, hyponatremia, age, race, illness severity and Charlson score were associated with mortality. Hyponatremia had similar hazard ratios (HR) across kidney disease stages despite loss of statistical significance in later stages due to smaller sample size. The association between community acquired hyponatremia and mortality showed consistent HRs across progressive stages of CKD and AKI suggesting that the contribution of tubular dysfunction to hyponatremia in advanced kidney disease does not alter this association.

Modification of a two blood sample method used for measurement of GFR with 99mTc-DTPA.

Measurements of GFR may be performed with a slope/intercept method (S/I), using only two blood samples taken in strictly defined time points. The aim of the study was to modify this method in order to extend time intervals suitable for blood sampling. Modification was based on a variation of a Russel et al. model parameter, selection of time intervals suitable for blood sampling and assessment of uncertainty of calculated results. Archived values of GFR measurements of 169 patients with different renal function, from 5.5 to 179 mL/min, calculated with a multiple blood sample method were used. Concentrations of a radiopharmaceutical in consecutive minutes, from 60th to 190th after injection, were calculated theoretically, using archived parameters of biexponential functions describing a decrease in 99mTc-DTPA concentration in blood plasma with time. These values, together with injected activities, were treated as measurements and used for S/I clearance calculations. Next, values of S/I clearance were compared with the multiple blood sample method in order to calculate suitable values of exponent present in a Russel's model, for every combination of two blood sampling time points. A model was considered accurately fitted to measured values when SEE ≤ 3.6 mL/min. Assessments of uncertainty of obtained results were based on law of error superposition, taking into account mean square prediction error and also errors introduced by pipetting, time measurement and stochastic radioactive decay. The accepted criteria resulted in extension of time intervals suitable for blood sampling to: between 60 and 90 minutes after injection for the first sample and between 150 and 180 minutes for the second sample. Uncertainty of results was assessed as between 4 mL/min for GFR = 5-10 mL/min and 8 mL/min for GFR = 180 mL/min. Time intervals accepted for blood sampling fully satisfy nuclear medicine staff and ensure proper determination of GFR. Uncertainty of results is entirely acceptable and for high GFR values even comparable with uncertainty of multi-sample measurements.

Educational review: measurement of GFR in special populations.

Changes in kidney function are typically followed by the sequential estimation of glomerular filtration rate (eGFR). Formulae for eGFR work well on a population basis, but there are well-known conditions where they do not work. The purpose of this review is to summarize the existing literature on special populations in the pediatric age range and provide recommendations on how to estimate GFR in these populations. The reliability of creatinine depends on muscle mass, while cystatin C (not widely available) is limited by inflammation and changes in protein catabolism. Various dietary factors can alter eGFR. Renal function in neonates changes drastically every day, and there are currently no satisfactory reference intervals for routine pediatric use. Gender effects and conditions such as wasting disease and obesity require alternative ways to obtain eGFR. In oncology patients, chemotherapy may negatively affect renal function, and nuclear GFR measurements may be necessary. For body builders, high muscle mass may lead to underestimation of eGFR using creatinine. Clinicians should be aware of special populations that may yield misleading eGFRs with conventional creatinine-based formulae, and that the alternative methods may be more appropriate for some populations.

MDRD vs. CKD-EPI in comparison to 51Chromium EDTA: a cross sectional study of Malaysian CKD cohort

BackgroundAccurate measurement of renal function is important: however, radiolabelled gold standard measurement of GFR is highly expensive and can only be used on a very limited scale. We aim to compare the performance of Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations in the multi-ethnic population attending University Malaya Medical Centre (UMMC).MethodsThis is a cross-sectional study recruiting patients, who attend UMMC Nephrology clinics on voluntary basis. 51-Chromium EDTA (51Cr-EDTA) plasma level was used to measure the reference GFR. The serum creatinine was determined by IDMS reference modified Jaffe kinetic assay (CrJaffe). The predictive capabilities of MDRD and CKD-EPI based equations were calculated. Data was analysed using SPSS version 20 and correlation, bias, precision and accuracy were determined.ResultsA total of 113 subjects with mean age of 58.12 ± 14.76 years and BMI of 25.99 ± 4.29 kg/m2 were recruited. The mean reference GFR was 66.98 ± 40.65 ml/min/1.73m2, while the estimated GFR based on MDRD and CKD-EPI formula were 62.17 ± 40.40, and 60.44 ± 34.59, respectively. Both MDRD and CKD-EPI were well-correlated with reference GFR (0.806 and 0.867 respectively) and statistically significant with p < 0.001. In the overall cohort, although MDRD had smaller bias than CKD-EPI (4.81 vs. 6.54), CKD-EPI was more precise (25.22 vs. 20.29) with higher accuracy within 30% of measured GFR (79.65 vs. 86.73%).ConclusionThe CKD-EPI equation appeared to be more precise and accurate than the MDRD equation in estimating GFR in our cohort of multi-ethnic populations in Malaysia.

GFR estimation based on standardized creatinine and cystatin C: a European multicenter analysis in older adults.

Although recommended by the Kidney Disease Improving Global Outcomes, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPICR) creatinine equation was not targeted to estimate glomerular filtration rate (eGFR) among older adults. The Berlin Initiative Study (BIS1CR) equation was specifically developed in older adults, and the Lund-Malmö revised (LMRCR) and the Full Age Spectrum (FASCR) equations have shown promising results in older adults. Our aim was to validate these four creatinine equations, including addition of cystatin C in a large multicenter cohort of Europeans ≥70 years. A total of 3226 individuals (2638 with cystatin C) underwent GFR measurement (mGFR; median, 44 mL/min/1.73 m2) using plasma iohexol clearance. Bias, precision (interquartile range [IQR]), accuracy (percent of estimates ±30% of mGFR, P30), eGFR accuracy diagrams and probability diagrams to classify mGFR<45 mL/min/1.73 m2 were compared. The overall results of BIS1CR/CKD-EPICR/FASCR/LMRCR were as follows: median bias, 1.7/3.6/0.6/-0.7 mL/min/1.73 m2; IQR, 11.6/12.3/11.1/10.5 mL/min/1.73 m2; and P30, 77.5%/76.4%/80.9%/83.5% (significantly higher for LMR, p<0.001). Substandard P30 (<75%) was noted for all equations at mGFR<30 mL/min/1.73 m2, and at body mass index values <20 and ≥35 kg/m2. LMRCR had the most stable performance across mGFR subgroups. Only LMRCR and FASCR had a relatively constant small bias across eGFR levels. Probability diagrams exhibited wide eGFR intervals for all equations where mGFR<45 could not be confidently ruled in or out. Adding cystatin C improved P30 accuracy to 85.7/86.8/85.7/88.7 for BIS2CR+CYS/CKD-EPICR+CYS/FASCR+CYS/MEANLMR+CAPA. LMRCR and FASCR seem to be attractive alternatives to CKD-EPICR in estimating GFR by creatinine-based equations in older Europeans. Addition of cystatin C leads to important improvement in estimation performance.

Accuracy Assessment of Five Equations Used for Estimating the Glomerular Filtration Rate in Korean Adults.

BackgroundWe aimed to assess the performance of the five creatinine-based equations commonly used for estimates of the glomerular filtration rate (eGFR), namely, the creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPIcr), Asian CKD-EPI, revised Lund–Malmö (revised LM), full age spectrum (FAS), and Korean FAS equations, in the Korean population.MethodsA total of 1,312 patients, aged 20 yr and above who underwent 51Cr-EDTA GFR measurements (mGFR), were enrolled. The bias (eGFR–mGFR) and precision (root mean square error [RMSE]) were calculated. The accuracy (P30) of four eGFR equations was compared to that of the CKD-EPIcr equation. P30 was defined as the percentage of patients whose eGFR was within±30% of the mGFR.ResultsThe mean bias (mL·min-1·1.73 m-2) of the five eGFR equation was as follows: CKD-EPIcr, -0.6; Asian CKD-EPI, 2.7; revised LM, -6.5; FAS, -2.5; and Korean FAS, -0.2. The bias of the Asian CKD-EPI, revised LM, and FAS equations showed a significant difference from zero (P<0.001). The RMSE values were as follows: CKD-EPIcr, 15.6; Asian CKD-EPI, 15.6; revised LM, 17.9; FAS, 16.3; and Korean FAS, 15.8. There were no significant differences in the P30 except for the Asian CKD-EPI equation: CKD-EPIcr, 76.6%; Asian CKD-EPI, 74.7%; revised LM, 75.8%; FAS, 76.0%; and Korean FAS, 75.8%.ConclusionsThe CKD-EPIcr and Korean FAS equations showed equivalent analytical and clinical performances in the Korean adult population.

The role of Atrial Natriuretic Peptide in the development of renal and cardiac damage in a Dahl SS rat model

Atrial natriuretic peptide (ANP), encoded by the Nppa gene, is an osmoregulatory hormone that promotes salt excretion. A GWAS identified ANP as a causative factor of blood pressure development, and in humans ANP levels are suggested as an indicator of salt‐sensitivity. Recently, Flister et al. (Genome Res, 2013) generated a knockout of Nppa in the Dahl Salt‐Sensitive (SS) rat background (further referred to as the SSNPPA−/− rat). The aim of the current study was to provide mechanistic insights into the effects of ANP deficiency on renal and cardiac function in the Dahl SS rats.In this study hypertension was induced in SSNPPA−/− and control Dahl SS rats by placing them on a high salt diet (HS, 4% NaCl) for 21 days. A combination of in vivo techniques (blood pressure monitoring and GFR measurements) with ex vivo imaging, electrophysiological, and biochemical methods were used to test the role of ANP deficiency in the development of SS hypertension. Immunohistochemical analysis was employed to assess renal and cardiac damage.Chronic i.v. infusion of ANP in wild type SS rats (100 ng/kg/day) attenuated the salt‐induced increase in blood pressure in the wild type SS rats, whereas SSNPPA−/− rats demonstrated a significantly higher mean arterial pressure compared to SS controls when the rats were fed a HS diet: on day 21 of diet MAP was 185.8 ± 9 mmHg in SSNPPA−/− rats compared to 144.6 ± 4 mmHg in SS controls. Additionally, SSNPPA−/− rats showed exacerbated kidney damage as revealed by intensified kidney hypertrophy, higher glomerular injury scores, and increased renal arterial hypertrophy. GFR was found to be reduced in the control SS rats fed a HS diet compared to LS diet, however significance was not reached in the SSNPPA−/− group. SSNPPA−/− rats did exhibit reduced diuresis, as well as a trend for lower sodium and chloride excretion when fed a HS diet. The activity of Epithelial Sodium Channel (an important contributor to the development of SS hypertension) was found to be increased in the cortical collecting ducts of the SSNPPA−/− rats. Additionally, SSNPPA−/− rats fed a HS diet showed intensified cardiac damage compared to SS controls, as demonstrated by higher heart to body weight ratio, and a dramatically elevated interstitial fibrosis. However, ultrasound echocardiography revealed that although SSNPPA−/− rats have cardiac remodeling, they do not exhibit heart failure.Therefore, ANP is major regulator in the development of SS hypertension, and its deficiency leads to more severe cardiac and kidney damage. Further work will be devoted to discovering specific ANP‐associated molecular pathways that mediate its effects in SS hypertension, and assessing the therapeutic benefits of ANP for treating cardiovascular diseases.Support or Funding InformationMCW RAC Pilot Grant (DVI) and NIH HL10880 (AS)

GFR Evaluation in Living Kidney Donor Candidates.

Evaluation of GFR, required in the evaluation of living kidney donor candidates, is now receiving increasing emphasis because recent data demonstrate increased risk of kidney disease after donation, including a small increase in the risk of kidney failure. The international guideline development group, Kidney Disease Improving Global Outcomes, recently published a comprehensive set of recommendations for living donor evaluation, with three recommendations regarding GFR. (1) Donor candidacy is evaluated in light of long-term risk, in which GFR is one of many factors. ESRD is considered a central outcome, and a method for estimating long-term risk of ESRD in donor candidates is described. (2) Two GFR thresholds are used for decision-making: a high threshold (≥90 ml/min per 1.73 m2) to accept and a low threshold (<60 ml/min per 1.73 m2) to decline, with 60-89 ml/min per 1.73 m2 as an intermediate range in which the decision to accept or decline is made on the basis of factors in addition to GFR. (3) GFR is evaluated using several methods available at the transplant center, including estimating equations and clearance measurements. We review the rationale for the guideline recommendations, principles of GFR measurement and estimation, and our suggestions for implementation.

Accuracy diagrams: a novel way to illustrate uncertainty of estimated GFR

Most studies that validate GFR equations present accuracy results stratified by measured GFR (mGFR; diagnostic correctness) or by estimated GFR (eGFR; diagnostic predictiveness) only, without a clear distinction in interpretation. The accuracy of a GFR equation is normally reported in percent (e.g. P30), but is often misinterpreted when stratified by eGFR. The aim of the study was to develop new accuracy measures and diagrams that allow straightforward interpretations and illustrations of the uncertainty in eGFR in clinical practice. We applied quantile regression to the distribution of estimation errors for two creatinine-based GFR equations, LM-REV and CKD-EPI, in a clinical cohort (n = 3495) referred for GFR measurement (plasma clearance of iohexol). Measures of bias and precision and accuracy intervals (AIs) were expressed in mL/min/1.73 m2. Diagrams with AIs were chosen as a novel way to present the error margin in eGFR at a pre-specified certainty level. It was shown that creatinine-based equations are still quite inaccurate in that large estimation errors could not be ruled out with satisfactory certainty. As an example, the 75% AI for the most accurate equation, LM-REV, was approximately ±10 mL/min/1.73 m2 at eGFR = 45 mL/min/1.73 m2, whereas it ranged between −13 and +20 mL/min/1.73 m2 at eGFR = 90 mL/min/1.73 m2. Accuracy intervals presented in diagrams can be used to illustrate the uncertainty of eGFR. Future validation studies should assess the variability in the predictiveness of eGFR across populations and clinical settings using tools and performance measures that are easy to interpret.

Predictive performance of different kidney function estimation equations in lung transplant patients

BackgroundThere has been limited examination of the performance of glomerular filtration rate estimation (eGFR) equations in lung transplant populations. This study aimed to compare the performance of serum creatinine and cystatin C based eGFR equations with Tc-99m diethylenetriaminepentaacetic acid (DTPA) GFR measurements in individuals with end-stage lung disease, either prior to, or following, lung transplantation. MethodsIn this prospective observational study, participants underwent GFR measurements with Tc-99m Pentetate. Measured results were compared with GFR estimates derived from estimation equations [4-variable Modification of Diet in Renal Disease, Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine, cystatin C and creatinine-cystatin C combined equations]. ResultsNinety-seven individuals were studied (77 post- and 20 wait-listed for transplantation). Median (range) radionucleotide GFR was 56.7ml/min/1.73m2 (22.8–109.2ml/min/1.73m2). In the study cohort as a whole, the CKD-EPI creatinine-cystatin C combined equation showed the highest performance, but was only slightly superior to the CKD-EPI creatinine equation. However, in individuals with cystic fibrosis, low arm muscle mass and/or low body mass index, all of the creatinine-based equations showed unacceptable performance. In these subgroups, improved GFR estimation was seen with the CKD-EPI cystatin C equation, and predictions were better still using the CKD-EPI creatinine-cystatin C combined equation. ConclusionsThis study shows adequate predictive ability of CKD-EPI creatinine in the cohort as a whole, but unacceptable performance in patients with cystic fibrosis, low arm muscle mass and/or low body mass index. Our findings demonstrate that cystatin C may be a preferable filtration marker in these subgroups.

Testing Danegaptide Effects on Kidney Function after Ischemia/Reperfusion Injury in a New Porcine Two Week Model.

IntroductionIschemia/reperfusion injury (I/R-I) is a leading cause of acute kidney injury (AKI) and is associated with increased mortality. Danegaptide is a selective modifier of the gap junction protein connexion 43. It has cytoprotective as well as anti-arrhythmic properties and has been shown to reduce the size of myocardial infarct in pigs. The aim of this study was to investigate the ischemia-protective effect of Danegaptide in a porcine renal I/R-I model with two weeks follow up.MethodsUnilateral renal I/R-I was induced in pigs by clamping the left renal artery over a two hour period. The model allowed examination of renal blood flow by magnetic resonance imaging (MRI) and the measurement of single kidney GFR two weeks after injury. Eleven animals were randomized to Danegaptide-infusion while nine animals received placebo. Kidney histology and urinary neutrophil gelatinase-associated lipocalin (NGAL) excretion were included as markers of AKI.ResultsUnilateral kidney I/R-I resulted in an immediate ~50% GFR reduction, associated with a four-fold increase in urinary NGAL-excretion. Fourteen days after I/R-I, the total GFR was ~75% of baseline with a significantly lower GFR in the injured left kidney compared to the right kidney. No differences in GFR were observed between the treated and non-treated animals immediately after I/R-I or at Day 14. Furthermore, no differences were observed in the urinary excretion of NGAL, renal blood flow or other markers of renal function.ConclusionsAs expected this porcine renal I/R-I model was associated with reduced GFR two weeks after injury. Danegaptide did not improve renal function after I/R-I.

Improved kinetic model for the transcutaneous measurement of glomerular filtration rate in experimental animals

Transcutaneous measurement of the glomerular filtration rate (tGFR) is now frequently used in animal studies. tGFR allows consecutive measurements on the same animal, including multiple measurements on a daily basis, because no blood sampling is required. Here we derive and validatea novel kinetic model for the description of transcutaneously measured FITC-Sinistrin excretion kinetics. In contrast to standard 1- to 3-compartment models, our model covers the complete kinetic, including injection and distribution of the tracer in the plasma compartment. Because the model describes the complete progression of the measurement, it allows further refinement by correcting for baseline shifts observed occasionally during measurement. Possible reasons for shifts in the background signal include photo bleaching of the skin, autofluorescence, changes of physiological state of the animals during the measurements, or effects arising from the attachment of the measurement device. Using the new 3-compartment kinetic model with modulated baseline (tGFR3cp.b.m), tGFR measurements in rats can reach comparable precision as those from GFR measurements assessed using a gold standard technique based on constant infusion of a tracer. Moreover, the variability of simultaneous (parallel) measurements, as well as repeated tGFR measurements in the same animals, showed higher precision when tGFR3cp.b.m was compared with the 1-compartment tGFR1cp model.

Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in CKD

Unlike the case with creatinine, conditions affecting the non-glomerular filtration rate (GFR) determinants of low-molecular-weight serum proteins, β-trace protein (BTP), β2-microglobulin (B2M), and cystatin C, are not well characterized. Pooled cross-sectional analysis of 3 studies. 3,156 persons with chronic kidney disease from the MDRD (Modification of Diet in Renal Disease) Study, AASK (African American Study of Kidney Disease and Hypertension), and CRIC (Chronic Renal Insufficiency Cohort) Study. Demographic and clinical factors hypothesized to be associated with non-GFR determinants of the filtration markers, selected from literature review and physiologic and clinical considerations. Serum creatinine, BTP, B2M, and cystatin C levels. In multivariable-adjusted errors-in-variables regression models that included adjustment for measured GFR (mGFR) and mGFR measurement error, creatinine level had stronger associations with male sex, black race, and higher urine creatinine excretion than the other filtration markers. BTP was associated less strongly with age, similar in direction with sex, and opposite in direction with race than creatinine level. Like cystatin C, B2M level was associated less strongly with age, sex, and race than creatinine level. BTP, B2M, and cystatin C levels were associated more strongly than creatinine level with other factors, including urine protein excretion and weight for BTP, smoking and urine protein excretion for B2M, and smoking for cystatin C. Findings may not be generalizable to populations without chronic kidney disease, and residual confounding with GFR due to incomplete adjustment for GFR measurement error. Like creatinine, serum levels of low-molecular-weight proteins are affected by conditions other than GFR. Knowledge of these conditions can aid the interpretation of GFR estimates and risk using these markers and guide the use of these filtration markers in developing GFR estimating equations.

The Gomez' equations and renal hemodynamic function in kidney disease research.

Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease. A major challenge in preventing DKD is the difficulty in identifying high-risk patients at an early, pre-clinical stage. Albuminuria and eGFR as measures of renal function in DKD research and clinical practice are limited by regression of one-third of patients with microalbuminuria to normoalbuminuria and eGFR is biased and imprecise in the normal-elevated range. Moreover, existing methods that are used to assess renal function do not give detailed insight into the location of the renal hemodynamic effects of pharmacological agents at the segmental level. To gain additional information about the intrarenal circulation in-vivo in humans, mathematical equations were developed by Gomez et al in the 1950s. These equations used measurements of GFR, renal blood flow (RBF), effective renal plasma flow (ERPF), renal vascular resistance (RVR), hematocrit and serum protein to calculate afferent and efferent arteriolar resistances, glomerular hydrostatic pressure and filtration pressure. Although indirect and based on physiological assumptions, these techniques have the potential to improve researchers' ability to identify early pre-clinical changes in renal hemodynamic function in patients with a variety of conditions including DKD, thereby offering tremendous potential in mechanistic human research studies. In this review, we focus on the application of Gomez' equations and summarize the potential and limitations of this technique in DKD research. We also summarize illustrative data derived from Gomez' equations in patients with type 1 (T1D) and type 2 diabetes (T2D) and hypertension.

Measurement Error as Alternative Explanation for the Observation that CrCl/GFR Ratio is Higher at Lower GFR.

Overestimation of GFR by urinary creatinine clearance (CrCl) at lower levels of GFR has long been attributed to enhanced creatinine secretion. However, this does not take into consideration the contribution of errors in measured GFR (and CrCl) due to short-term biologic variability or test imprecision. We analyzed cross-sectional data among 1342 participants from the Chronic Renal Insufficiency Cohort study with baseline measurement of GFR by iothalamate clearance (iGFR) and CrCl by 24-hour urine collection. We examined the CrCl/iGFR ratio classified by categories of iGFR and also by categories of CrCl. Overall, mean CrCl/iGFR ratio was 1.13. CrCl/iGFR ratio was higher at lower iGFR categories. In contrast, this ratio was lower at lower CrCl levels. We hypothesize these relationships could be due to measurement error, which is bolstered by replicating these trends in a simulation and modeling exercise in which there was no variation in the ratio of CrCl/iGFR with true kidney function but taking into account the effect of measurement error in both CrCl and iGFR (of magnitudes previously described in the literature). In our simulated data, the observed CrCl/iGFR ratio was higher at lower observed iGFR levels when patients were classified by categories of observed iGFR. When the same patients were classified by categories of observed CrCl, the observed CrCl/iGFR ratio was lower at lower observed CrCl levels. The combined empirical and modeling results suggest that measurement errors (in both CrCl and iGFR) should be considered as an alternative explanation for the longstanding observation that the ratio of CrCl to iGFR gets larger as iGFR decreases.