51Cr-EDTA Clearance Research Articles

Accuracy of estimating equations for the assessment of glomerular filtration rate in critically ill patients versus outpatients.

Estimating equations for the assessment of glomerular filtration rate (GFR) have been poorly investigated in the critical care setting. We evaluated the agreement between the GFR measured with 51CrEDTA/iohexol (mGFR) and four estimating equations based on serum concentrations of creatine and/or cystatin C (eGFR) in two cohorts: critically ill patients and outpatients with normal-to-moderately reduced GFR. Forty-three patients in the critical care group and 48 patients in the outpatient group were included. GFR was measured (mGFR) by plasma infusion clearance of 51Cr-EDTA/iohexol (critical care group) and the single injection, one-sample plasma 51Cr-EDTA clearance technique (outpatients). The following estimating equations (eGFR) were used: the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for creatinine (CKD-EPICr), cystatin C (CKD-EPICys C), creatinine+cystatin C (CKD-EPICr + Cys C) and the Lund-Malmö creatinine+cystatin C equation (LMCr + Cys C). Agreement between mGFR and eGFR was assessed by the Bland-Altman method and accuracy by calculating P30 and P10. In the critically ill group, the bias between the estimating equations and mGFR was -3.6 to 2.8 mL/min/1.73 m2, while the error was 121%-127% and the accuracy (P30) 33%-40%. In the outpatients, the bias between the estimating equations and mGFR was -13.0 to 7.6 mL/min/1.73 m2, while the error was 31%-41% and the accuracy (P30), 67%-96%. All four equations performed poorly in assessing GFR in the critically ill cohort with an unacceptably high error and low accuracy in contrast to the outpatient group. To accurately assess GFR in critically ill patients, GFR must be measured not estimated. For the assessment of glomerular filtration rate (GFR), it can be measured directly, but is frequently estimated using a point measure of serum creatinine concentration. In this study, ICU case GFR estimations, by different adjusted equations, done also for a cohort of outpatients, showed that these serum creatinine-based estimations for ICU cases are not highly precise or reliable.

#2929 Plasma levels of brain injury markers NfL and GFAP are independently predicted by glomerular filtration rate in patients with chronic kidney disease

Abstract Background and Aims Patients with chronic kidney disease (CKD) have a high prevalence of cerebrovascular disease and cognitive impairment. The aim of the present study was to measure brain injury biomarkers in plasma in a cohort of patients with CKD stages 3 and 4, without a diagnosis of cerebrovascular disease, and to determine factors that independently predicted plasma levels of these biomarkers. Method This was a cross-sectional cohort study including 110 patients with CKD stages 3 and 4, and 55 healthy, matched, controls, recruited from the outpatient clinic at Sahlgrenska university hospital, Gothenburg, Sweden. None of the included study subjects had a diagnosis of cerebrovascular disease, cognitive impairment, or any other neurological disease. Plasma concentrations of neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and phosphorylated Tau (p-Tau231) were analyzed with ultrasensitive single molecule array (SIMOA). Measured GFR (mGFR) was determined by plasma clearance of ⁵¹Cr-EDTA. Values are medians [interquartile range]. For linear regression analyses standardised beta coefficients (β) are presented. Results Characteristics of CKD patients and healthy controls are presented in Table 1. Plasma concentrations of NfL (37.5 [22.1-47.5] vs. 13.4 [10.5-16.7] ng/L, p < 0.001), p-Tau231 (25.7 [19.1-38.7] vs. 13.9 [10.5-16.3] ng/L, p < 0.001) and GFAP (190 [140-281] vs. 153 [116-211] ng/L, p = 0.001) were significantly elevated in patients with CKD vs. controls. In CKD patients, mGFR showed statistically significant inverse correlations to plasma concentrations of NfL, p-Tau231, and GFAP (Table 2). In multiple regression analyses, mGFR was associated with plasma levels of NfL (β = −0.457, p < 0.001) and GFAP (β = −0.322, p < 0.001) independently of diabetes, age, troponin-T, b-hemoglobin, and aortic pulse-wave velocity. However, mGFR was not significantly associated with plasma levels of p-Tau231 in a multiple regression analysis. Conclusion Plasma levels of brain injury markers NfL, p-Tau231 and GFAP were elevated in patients with CKD stages 3 and 4, without a history of cerebrovascular disease, compared to healthy controls. Furthermore, mGFR independently predicted plasma concentrations of NfL and GFAP in multiple regression models. These results raise the possibility that reduced GFR per se may be associated with subclinical brain injury.

Glomerular Filtration Rate Estimation Using β2-Microglobulin and β-Trace Protein in Adults With Solid Tumors: A Prospective Cross-Sectional Study

β2-Microglobulin (B2M) and β-trace protein (BTP) are novel endogenous filtration markers that may improve the accuracy of estimated glomerular filtration rate (eGFR) beyond creatinine and cystatin C (eGFRcr-cys), but they have not been assessed in patients with cancer. Cross-sectional analysis. Prospective cohort of 1,200 patients with active solid tumors recruited between April 2015 and September2017. CKD-EPI equations without race combining B2M and/or BTP with creatinine with or without cystatin C (2-, 3-, or 4-marker panel eGFR). Performance of equations compared with eGFRcr-cys and non-GFR determinants of serum B2M and BTP (SB2M, and SBTP, respectively). Measured GFR (mGFR) was determined using the plasma clearance of chromium-51 labeled ethylenediamine tetraacetic acid (51Cr-EDTA). Bias was defined as the median of the differences between mGFR and eGFR, and 1-P30 was defined as the percentage of estimates that differed by more than 30% from the mGFR (1-P30). Linear regression was used to assess association of clinical and laboratory variables with SB2M, and SBTP after adjustment for mGFR. Mean age and mGFR were 58.8±13.2 SD years and 78.4±21.7 SD mL/min/1.73m2, respectively. Performance of the 3-marker and 4-marker panel equations was better than eGFRcr-cys (lesser bias and 1-P30). Performance of 2-marker panel equations was as good as eGFRcr-cys (lesser bias and similar 1-P30). SB2M and SBTP were not strongly influenced by cancer site. Participants may have had better clinical performance status than the general population of patients with solid tumors. B2M and BTP can improve the accuracy of eGFR and may be useful as confirmatory tests in patients with solid tumors, either by inclusion in a multimarker panel equation with creatinine and cystatin C, or by substituting for cystatin C in combination with creatinine. The most accurate method to assess estimate kidney function is estimated glomerular filtration rate (eGFR) using creatinine and cystatin C (eGFRcr-cys). We studied whether using β2-microglobulin (B2M) and/or β-trace protein (BTP) with creatinine with or without cystatin C (2-, 3-, or 4-marker panel eGFR) might be useful in patients with active solid tumors. The performance of the 3-marker and 4-marker panel equations was better than eGFRcr-cys. Performance of 2-marker panel equations was as good as eGFRcr-cys. We conclude that B2M and BTP can improve the accuracy of eGFR and may be useful as a confirmatory test in patients with solid tumors either by inclusion in multimarker panel equation with creatinine and cystatin C or by substituting for cystatin C in combination with creatinine.

Rescaling creatinine makes GFR estimation equations generally applicable across populations - validation results for the Lund-Malmö equation in a French cohort of sub-Saharan ancestry.

To make glomerular filtration rate (GFR) estimating equations applicable across populations with different creatinine generation by using rescaled serum creatinine (sCr/Q) where sCr represents the individual creatinine level and Q the average creatinine value in healthy persons of the same population. GFR measurements (mGFR, plasma clearance of 51Cr-EDTA) were conducted in 964 adult Black Europeans. We established the re-expressed Lund-Malmö revised equation (r-LMR) by replacing serum creatinine (sCr) with rescaled creatinine sCr/Q. We evaluated the r-LMR equation based on Q-values of White Europeans (r-LMRQ-white; Q-values females: 62 μmol/L, males: 80 μmol/L) and Black Europeans (r-LMRQ-Black; Q-values females: 65 μmol/L, males: 90 μmol/L), and the European Kidney Function Consortium equation (EKFCQ-White and EKFCQ-Black) regarding bias, precision (interquartile range, IQR) and accuracy (percentage of estimates within ±10 % [P10] and ±30 % [P30] of mGFR). Median bias of r-LMRQ-White/r-LMRQ-Black/EKFCQ-White/EKFCQ-Black were -9.1/-4.5/-6.3/-0.9 mL/min/1.73 m2, IQR 14.7/14.5/14.5/15.6 mL/min/1.73 m2, P10 25.1 %/34.8 %/30.3 %/37.2 % and P30 74.2 %/84.1 %/80.6 %/83.6 %. The improvement of bias and accuracy when using proper Q-values was most pronounced in men. Similar improvements were obtained above and below mGFR 60 mL/min/1.73 m2 and at various age and BMI intervals, except for BMI<20 kg/m2 where bias increased, and accuracy decreased. GFR estimating equations may be re-expressed to include rescaled creatinine (sCr/Q) and used across populations with different creatinine generation if population-specific average creatinine concentrations (Q-values) for healthy persons are established.

COMPARISON STUDY OF CYSTATIN C &amp; CREATININE-BASED GFR FORMULAS WITH 51CR-EDTA CLEARANCE IN PATIENTS WITH CIRRHOSIS

This study aimed to compare cystatin C and Creatinine based GFR equations with 51Cr-EDTA clearance as the gold standard in cirrhotic patients. A prospective study was conducted in the Hepatology &amp; Medicine Departments of Tertiary Care Hospitals. A total of 140 patients were included in the study. 66 cirrhotic patients correlated with cystatin C with creatinine and 74 patients correlating 51Cr-EDTA glomerular filtration rate to adjustments of diet in renal disease and Larsson and Hoek formulas for Cystatin C were selected for the study. Bland-Altman plots and concordance correlation coefficients were used to evaluate agreements. The correlation between cystatin C and bilirubin was poor, and the correlation between bilirubin and creatinine was strong. The medium values of creatinine and cystatin C were greater in a group with a GFR of more than 70 ml (27 patients), and their difference was significant (p &lt;0.0001). The new GFR obtained by the creatinine formula was more accurate than GFR obtained by the cystatin C formula. With a 50% change in GFR, the creatinine formula provided a 90% GFR estimate. CysC formulas are not better for estimating glomerular filtration rate than creatinine formulas.

#5465 RACE-FREE EGFR EQUATION IN KIDNEY RECIPIENTS: A DEVELOPMENT AND VALIDATION STUDY

Abstract Background and Aims To assess the performances of the current eGFR equations, including the race-free CKD-EPI-2021, in the kidney transplant population, and compare these performances to a race-free kidney-recipient-specific (KRS) GFR equation. Method We included adult kidney recipients transplanted between 01/01/2000 and 01/01/2021 in 17 academic cohorts in Europe, the USA and Australia comprising 14 transplant centres and three clinical trials. Measured GFRs (mGFR) were assessed using 51Cr-EDTA, 99Tc-DTPA, inulin, iothalamate or iohexol clearance, according to the local practice. A KRS GFR equation was developed using additive and multiplicative stepwise linear regressions and its performance was compared to those of the current GFR equations. The performances were assessed with the P30 and the correct classification of chronic kidney disease (CKD) stage metrics. Results The study included 15 489 patients, having 50 464 GFR values both measured and estimated by creatinine-based equations. Among the current GFR equations, race-free CKD-EPI-2021 equation showed the lowest performance compared with MDRD and CKD-EPI-2009 equations. We then built a race-free KRS GFR equation based on an additive model including creatinine, age, and sex. We showed that using race did not increase the performance of the equation. We found that the race-free KRS GFR equation showed significantly improved performance compared with the race-free CKD-EPI-2021 equation and performed well in the external validation cohorts (P30 ranging from 73.0% to 91.3%). Finally, we showed that the race-free KRS GFR equation performed well in a series of kidney transplant recipient subpopulations stratified by race, sex, age, body mass index, donor type, therapeutics, creatinine and GFR measurement methods and timing. Based on these results we developed an online application that estimates GFR based on recipient age, sex and creatinine: https://transplant-prediction-system.shinyapps.io/eGFR_equation_KTX/ Conclusion Using multiple, international cohorts of kidney recipients, we developed and validated a new race-free KRS GFR equation that demonstrated high accuracy and outperformed the race-free CKD-EPI-2021 equation developed in individuals with native kidneys.

#2948 β-2-MICROGLOBULIN AND β-TRACE-PROTEIN DO NOT IMPROVE ESTIMATION OF GFR IN KIDNEY TRANSPLANT RECIPIENTS COMPARED TO CREATININE AND CYSTATIN C

Abstract Background and Aims Precise estimates of glomerular filtration rate (eGFR) are important in kidney transplant recipients (KTRs). Current eGFR formulas based on plasma creatinine and/or cystatin C are associated with significant bias. We investigated whether race free formulas based on plasma values of β-trace-protein and β-2-microglobulin performed better than formulas based on creatinine and cystatin C in a Scandinavian cohort of KTRs. Method We included samples and data from the randomised, controlled trial CONTEXT. GFR was measured by plasma clearance of 51Cr-EDTA or iodothalamate. eGFR was calculated using the new race-free CKD-EPI eGFR-creatinine and/or cystatin C(2021) formulas as well as the CKD-EPI eGFR-β-trace-protein and/or eGFR-β-2-microglobulin formulas. GFR estimates were evaluated at 3 (n = 82) and 12 (n = 64) months post-transplant using mean bias, precision, and accuracy. Also, formulas were analysed for their ability to correctly classify changes in measured GFR from 3 to 12 months. Results At 12 months eGFR-creatinine-cystatin C performed best according to mean bias (−4.54 ml/min/1.73 m2), precision (SD = 8.18 ml/min/1.73 m2) and accuracy (P10 = 47%) among creatinine and cystatin C based formulas (Table 1). Among the β-trace-protein and β-2-microglobulin based formulas, eGFR-β-trace-protein-β-2-microglobulin performed best according to precision (SD = 7.64 ml/min/1.73 m2) and accuracy (P10 = 36%) (Table 1). eGFR-β-trace-protein-β-2-microglobulin and eGFR-creatinine-cystatin C performed similar when comparing residuals (p = 0.481). eGFR-β-trace-protein, eGFR-β-trace-protein-β-2-microglobulin and eGFR-creatinine-cystatin C performed best in correctly classifying changes in mGFR from 3 to 12 months. Conclusion β-trace-protein and β-2-microglobulin do not improve the measurement of GFR compared to creatinine and cystatin C based formulas in KTRs.

Development and validation of a new equation based on plasma creatinine and muscle mass assessed by CT scan to estimate glomerular filtration rate: a cross-sectional study.

Inter-individual variations of non-glomerular filtration rate (GFR) determinants of serum creatinine, such as muscle mass, account for the imperfect performance of estimated GFR (eGFR) equations. We aimed to develop an equation based on creatinine and total lumbar muscle cross-sectional area measured by unenhanced computed tomography scan at the third lumbar vertebra. The muscle mass-based eGFR (MMB-eGFR) equation was developed in 118 kidney donor candidates (iohexol clearance) using linear regression. Validation cohorts included 114 healthy subjects from another center (51Cr-EDTA clearance, validation population 1), 55 patients with chronic diseases (iohexol, validation population 2), and 60 patients with highly discordant creatinine and cystatin C-based eGFR, thus presumed to have atypical non-GFR determinants of creatinine (51Cr-EDTA, validation population 3). Mean bias was the mean difference between eGFR and measured GFR, precision the standard deviation (SD) of the bias, and accuracy the percentage of eGFR values falling within 20% and 30% of measured GFR. In validation population 1, performance of MMB-eGFR was not different from those of CKD-EPICr2009 and CKD-EPICr2021. In validation population 2, MMB-eGFR was unbiased and displayed better precision than CKD-EPICr2009, CKD-EPICr2021 and EKFC (SD of the biases: 13.1vs 16.5, 16.8 and 15.9mL/min/1.73 m2). In validation population 3, MMB-eGFR had better precision and accuracy {accuracy within 30%: 75.0% [95% confidence interval (CI) 64.0-86.0] vs 51.5% (95% CI 39.0-64.3) for CKD-EPICr2009, 43.3% (95% CI 31.0-55.9) for CKD-EPICr2021, and 53.3% (95% CI 40.7-66.0) for EKFC}. Difference in bias between Black and white subjects was -2.1mL/min/1.73 m2 (95% CI -7.2 to 3.0), vs -8.4mL/min/1.73 m2 (95% CI -13.2 to -3.6) for CKD-EPICr2021. MMB-eGFR displayed better performances than equations based on demographics, and could be applied to subjects of various ethnic backgrounds.

Hypotonicity-Induced Increase in Duodenal Mucosal Permeability Is Regulated by Cholinergic Receptors in Rats

BackgroundThe role of cholinergic receptors in the regulation of duodenal mucosal permeability in vivo is currently not fully described.AimsTo elucidate the impact of nicotinic and muscarinic acetylcholine receptor signaling in response to luminal hypotonicity (50 mM NaCl) in the proximal small intestine of rat.MethodsThe effect on duodenal blood-to-lumen clearance of 51Cr-EDTA (i.e., mucosal permeability) and motility was studied in the absence and presence of nicotinic and muscarinic receptor agonists and antagonists, a sodium channel blocker (tetrodotoxin), and after bilateral cervical vagotomy.ResultsRats with duodenal contractions responded to luminal hypotonicity by substantial increase in intestinal permeability. This response was absent in animals given a non-selective nicotinic receptor antagonist (mecamylamine) or agonist (epibatidine). Pretreatment with tetrodotoxin reduced the increase in mucosal permeability in response to luminal hypotonicity. Further, the non-selective muscarinic receptor antagonist (atropine) and agonist (bethanechol) reduced the hypotonicity-induced increase in mucosal permeability, while vagotomy was without an effect, suggesting that local enteric reflexes dominate. Finally, neither stimulating nor blocking the α7-nicotinic receptor had any significant effects on duodenal permeability in response to luminal hypotonicity, suggesting that this receptor is not involved in regulation of duodenal permeability. The effect of the different drugs on mucosal permeability was similar to the effect observed for duodenal motility.ConclusionsA complex enteric intramural excitatory neural reflex involving both nicotinic and muscarinic receptor subtypes mediates an increase in mucosal permeability induced by luminal hypotonicity.

A comparison of four established GFR formulas to estimate measured GFR and changes in GFR in adult kidney transplant recipients

The accurate assessment of glomerular filtration rate (GFR) is important in the follow-up of kidney transplant recipients in order to identify graft dysfunction. A number of formulas have been proposed to calculate GFR from endogenous plasma markers such as creatinine or cystatin C since measuring GFR using exogenous markers is troublesome. This study compares and evaluates the ability of four different GFR formulas to estimate kidney graft function and to detect changes in GFR in kidney transplant recipients. The study included patients from the prospective, multicenter CONTEXT trial in kidney transplant recipients. GFR was measured using plasma clearance of 51Cr-EDTA and estimated using the MDRD, CKD-EPI Creatinine, CKD-EPI Cystatin C and CKD-EPI Cystatin C + Creatinine equations at three (n = 83) and twelve (n = 65) months post-transplantation. For each formula mean bias, precision, and accuracy were evaluated. The MDRD equation had the lowest mean bias (0.2 ml/min/1.73 m2), whereas the CKD-EPI Cystatin C + Creatinine equation had the highest precision (8 ml/min/1.73 m2). Accuracy at three months were similar for all equations (P30 > 80%) except for the CKD-EPI Cystatin C equation, which performed poorer (P30 = 55%). None of the formulas evaluated avoided misclassification of changes in GFR. The most optimal combination of precision and accuracy suggests the use of CKD-EPI Creatinine + Cystatin C equation in kidney transplant recipients.

Performance of the 2021 CKD-EPI equations without a race coefficient in a multi-racial population of adults with solid tumors: A prospective cross-sectional study.

12064 Background: We previously showed that estimated glomerular filtration rate (eGFR) based on serum creatinine (Scr)(eGFRcr) using the 2009 CKD-EPI equation performed better than Cockroft-Gault equation (CG) in solid tumor patients in Brazil (Onco-GFR Study). In that study, eGFR based on Scr and cystatin C (Scys)(eGFRcr-cys) using the 2012 CKD-EPI was the most accurate equation and suitable for use as a confirmatory test. The CKD-EPI 2009 eGFRcr and 2012 eGFRcr-cys equations include a term for race (Black vs. non-Black). The 2021 CKD-EPI eGFRcr and eGFRcr-cys equations do not include race and are now recommended in the US, but have not been assessed in a multi-racial population or in cancer patients. The aim of this study is to evaluate the performance of the 2021 CKD-EPI equations in the Onco-GFR Study. Methods: Measured GFR (mGFR) was determined using the plasma clearance of 51Cr-EDTA. Scr and Scys assays were traceable to international standards. Results: A group of 1,200 patients recruited between April 2015 and September 2017 were included for analysis. Patients were 58.8±13.2 years, 50.8% male. Race distribution was Black participants 12.8% and non-Black participants 81.2%. Mean (SD) mGFR was 78.5±21.7 ml/min/1.73 m2. For eGFRcr, the overestimation of mGFR was larger for the 2021 vs. 2009 equation -10.0 vs. 8.1 ml/min/1.73m2, resulting in lesser accuracy 1-P30 of 22.3 vs. 19.1, but still more accurate than CG equation (1-P30 of 24.9, P = 0.05). For eGFRcr-cys, the overestimation of mGFR was larger for the 2021 vs. 2012 equation (-4.1 vs. -2.0 ml/min/1.73m2). eGFRcr-cys using the 2021 equation was more accurate than eGFRcr using the 2021 equation and eGFRcys using the 2012 equation (1-P30 9.8 vs. 22.3 and 12.3, p-values &lt; 0.001 and 0.01, respectively) (Table). Conclusions: 2021 CKD-EPI eGFRcr equation race performed better than CG. 2021 CKD-EPI eGFRcr-cys performed better than 2021 eGFRcr and 2012 eGFRcys equations. Removing race from eGFR equations represents an advance and should be incorporated in cancer care. [Table: see text]

Impaired renal clearance among Swedish adolescents born preterm.

AimTo determine whether adolescents born before 28 gestational weeks have an increased risk for renal impairment.MethodsSwedish infants, born before 28 gestational weeks in 2001 and 2002, were identified from a local register. A total of 16 children, 12 females and 4 males, were examined at 16–17 years of age with 51Cr‐EDTA clearance. A comparison group (n = 26) was used.ResultsMost study participants (n = 13) had normal blood pressure; one individual had hypertension stage 1. All study participants had results within the reference interval for ionised calcium, parathyroid hormone, intact fibroblast growth factor‐23 and for urinary albumin‐to‐creatinine ratio. Four out of 16 participants (25%) had a 51Cr‐EDTA clearance less than 90 ml/min/1.73 m2, indicating a reduced kidney function. Measured 51Cr‐EDTA clearance values were significantly lower in the study group than in the comparison group (p = 0.0012). Five study participants (31%) were referred for further investigations.ConclusionSwedish children born before 28 gestational weeks have an increased risk of renal impairment later in life, suggesting that the kidney function in these individuals should be assessed, at least once, during adolescence.

MO422: Strong Positive Association Between GFR and the Urine-To-Plasma Urea Concentration Ratio in Patients With Sickle Cell Disease. Possible Functional Meaning

Abstract BACKGROUND AND AIMS Sickle cell disease (SCD) induces a decline in urine concentration and progressive deterioration of kidney (K) function. Hyperfiltration is often observed before this decline, and plasma urea is low. Oral urea or hydroxyurea improves the condition of these patients (pts). These observations draw the attention to renal urea handling in SCD. Studies suggest that addition of urea into the loop of Henle may indirectly modify NaCl concentration at the macula densa and induce a rise in glomerular filtration rate (GFR) by depressing the tubule-glomerular feedback (TGF) [1]. The urine-to-plasma urea concentration ratio (U/P urea) is a novel marker associated with GFR and the progression of disease in ADPKD [2]. The present study addresses the relationship of U/P urea with GFR in SCD pts. METHOD A total of 184 homozygous SCD pts referred to our department were included. They underwent extensive evaluation including measured GFR (mGFR) (51Cr EDTA clearance) and plasma and 24-h urine chemistries. The association between mGFR and U/P urea was tested using univariate, and multivariate stepwise regression analyses. RESULTS Mean age was 35.6 ± 2.8 years (mean ± SD) and body mass index (BMI) 22.2 ± 0.3 kg/m2. Mean mGFR was 107 ± 3 ml/min x 1.73m2. Hyperfiltration was observed in 37% of pts. Urine volume (UV) 1.71 ± 0.75 L/24h. Urea excretion 267 ± 151 mmol/24h. In 13% of pts fractional excretion of urea (FEurea) exceeded 50%. U/P urea (42 ± 20) varied from 6 to 112. It was not associated with 24-h urea excretion but showed a negative association with UV (P &amp;lt; 0.007). mGFR was strongly and positively associated with U/P urea (r = 0.58, P &amp;lt; 0.0001) but not with U/P osmolarity (see Figure and Table). mGFR was also associated with U/P creatinine although more weakly (r = 0.266, p &amp;lt; 0.0001) and with BMI and negatively associated with age, MAP and serum creatinine (creat). After adjustment for U/P creat, the association between mGFR and U/P urea remained highly significant, whereas, after adjustment for U/P urea, the association between mGFR and U/P creat disappeared. In multivariate regression, mGFR remained strongly associated with U/P urea. CONCLUSION Our data show a strong association between mGFR and U/P urea that remains highly significant after multivariate analysis. i) This suggests that a specific estimated GFR equation for SCD patients including the U/P urea ratio could be clinically more relevant than CKD-EPI equations. ii) A specific mechanism may link GFR and intrarenal urea handling, as U/P urea but not U/P osmolarity appears to be involved. Urea could play a role, indirectly, in the regulation of GFR [1]. In SCD, the longer transit time of the blood in vasa recta may favour countercurrent exchanges and lead to a greater addition of urea in loops of Henle (increasing the U/P urea ratio) and thus increasing GFR by reducing TGF. Sickled red cells and resulting in slower blood flow in the medulla may selectively influence urea handling, participating in high FEurea and GFR often observed in SCD pts. iii) As is the case in ADPKD, more attention should be given to longitudinal studies to the relationship between U/P urea and kidney disease progression in SCD pts.

The trajectory of renal function following mechanical circulatory support and subsequent heart transplantation.

AimPatients with advanced heart failure (HF) frequently suffer from renal insufficiency. The impact of durable mechanical circulatory support (MCS) and subsequent heart transplantation (HTx) on kidney function is not well described.Methods and resultsWe studied patients with advanced HF who received durable MCS as bridge to transplantation (BTT) and underwent subsequent HTx at our centre between 1996 and 2018. Glomerular filtration rate (GFR) was measured by 51Cr‐EDTA or iohexol clearance during heart failure work‐up; 3–6 months after MCS; and 1 year after HTx. Chronic kidney disease (CKD) was classified according to KDIGO criteria based on estimated GFR. A total of 88 patients (46 ± 15 years, 84% male) were included, 63% with non‐ischaemic heart disease. The median duration of MCS‐treatment was 172 (IQR 116–311) days, and 81 subjects were alive 1 year after HTx. Measured GFR increased from 54 ± 19 during HF work‐up to 60 ± 16 mL/min/1.73 m2 after MCS (P < 0.001) and displayed a slight but nonsignificant decrease to 57 ± 22 mL/min/1.73 m2 1 year after HTx (P = 0.38). The trajectory of measured GFR did not differ between pulsatile and continuous flow (CF) pumps. Among patients 35–49 years and those who were treated in the most recent era (2012–2018), measured GFR increased following MCS implantation and subsequent HTx. Estimated GFR displayed a similar course as did measured GFR.ConclusionsIn patients with advanced heart failure, measured GFR improved after MCS with no difference between pulsatile and CF‐pumps. The total study group showed no further increase in GFR following HTx, but in certain subgroups, including patients aged 35–54 years and those treated during the latest era (2012–2018), renal function appeared to improve after transplant.

51Cr-EDTA plasma clearance in children: One, two, or multiple samples?

Plasma disappearance curves using multiple blood samples are a recognized reference method for measuring glomerular filtration rate (GFR). However, there is no consensus on the protocol for this type of measurement. A two-compartment model is generally considered acceptable for the mathematical description of the concentration–time decay curve. The impact of the fitting procedure on the reported GFR has not been questioned.We defined 8 different fitting procedures to calculate the area under the curve, and from this area under the curve, the GFR. We applied the 8 fitting methods (all considering a full concentration–time curve) on the multiple sample data (8 samples) of 20 children diagnosed with Duchenne muscular dystrophy. We evaluated the effect (variability) on the reported GFR from the different fitting methods and compared these results with GFR-values calculated from late samples only (samples after 120 minutes) and from one-sample methods.In 6 out of 20 cases, the fitting methods on the full concentration–time curve resulted in very different reported GFR-values, mainly because some methods were not able to fit the data, or methods resulted in GFR-values ranging from 0 to 120 mL/min. The reported GFR-result therefore strongly depends on the fitting method, making the full concentration–time method less robust than expected. Compared with a consensus reference GFR, the late sample models did not show fitting issues and may therefore be considered as more robust. Also the one-sample methods showed acceptable accuracy.The late sample methods (using 3 time-points) provide robust and reliable methods to determine GFR.

A prospective cross-sectional study estimated glomerular filtration rate from creatinine and cystatin C in adults with solid tumors

Current guidelines recommend estimating glomerular filtration rate (eGFR) using creatinine (eGFRcr) with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation as the first test for GFR evaluation, but the Cockcroft-Gault (CG) equation is still commonly used in oncology practice and clinical trials despite increasing evidence of its inaccuracy compared to measured GFR (mGFR). Guidelines recommend eGFR using cystatin C (eGFRcys) or both markers (eGFRcr-cys) as a confirmatory test, but neither was carefully evaluated in cancer patients. Therefore, we compared performance of the CKD-EPI equations and others to the CG equation in adults with a variety of solid tumors. The mGFR was determined by plasma clearance of 51Cr-EDTA. Bias was defined as the median of the differences between mGFR and eGFR while accuracy was defined as the percentage of estimates that differed by more than 30% from the measured GFR (1-P30). We prospectively recruited 1,200 patients between April 2015 and September 2017 with a mean age and mGFR of 58.8 years and 78.4 ml/min/1.73m2, respectively. Bias among eGFRcr equations varied from -8.1 to+6.1 ml/min/1.73 m2. CG was the least accurate, 1-P30 (95% confidence interval) was 24.9 (22.4- 27.3)%; CKD-EPI had 1-P30 of 19.1 (16.8-21.2)% while eGFRcr-cys had the best performance: bias -2.0 (-2.6 to -1.1) ml/min/1.73m2 and 1-P30 7.8 (6.3-9.4)%. Thus, the CG equation should not be preferred over CKD-EPI equation, and eGFRcr-cys can be used as a confirmatory test in adults with solid tumors. Hence, a major policy implication would be to adopt general practice guideline-recommended methods for GFR evaluation in oncology practice and clinical trials.

Measurement of glomerular filtration rate and its current status in African countries GFR measurement and its status in Africa

Glomerular filtration rate (GFR) is usually estimated rather than measured as this only requires measurement of an endogenous filtration marker. In certain clinical settings a more accurate measure of GFR is essential. The most commonly used endogenous filtration marker is creatinine. Exogenous filtration markers include nonradiopharmaceuticals such as inulin, iohexol and unlabelled iothalamate, or radiopharmaceuticals such as 51Crethylenediaminetetraacetic acid (51Cr-EDTA) and 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA). Inulin is considered an ideal filtration marker but the clearance of iothalamate, 99mTc-DTPA, 51Cr-EDTA and iohexol have all been shown to have sufficient accuracy for measuring GFR. For radiopharmaceuticals, a well counter is required to measure the amount of activity in patient samples. Iohexol or unlabelled iothalamate require samples to be measured using high performance liquid chromatography with ultraviolet detection (HPLC-UV), liquid chromatography-tandem mass spectrometry (LC-MS/MS) or x-ray fluorescence (XRF). Due to the practical challenges of measuring urinary clearance, measurement of GFR in clinical settings is almost exclusively based on plasma clearance of a filtration marker. This can follow a long-established approach based on the ratio of the tracer administered to the area under the plasma concentration curve. Alternatively, a single plasma sample giving an apparent volume of distribution at a given time point can be used to accurately measure GFR. While techniques exist for the measurement of GFR in a number of African countries, preliminary evidence suggests that facilities are very limited. There is a need for support for both equipment and training to establish GFR measurement facilities in several centres on the continent. Keywords: measured glomerular filtration rate;, mGFR;, Africa

The Impact of α-Adrenoceptors in the Regulation of the Hypotonicity-Induced Increase in Duodenal Mucosal Permeability In Vivo.

The duodenal mucosa is regularly exposed to a low osmolality, and recent experiments suggest that hypotonicity increases mucosal permeability in an osmolality-dependent manner. The aim was to examine whether the sympathetic nervous system, via action on α-adrenoceptors, affects the hypotonicity-induced increase in duodenal mucosal permeability. The duodenum of anaesthetised rats was perfused in vivo with a 50 mM NaCl solution in the presence of adrenergic α-adrenoceptor drugs. Studied were the effects on mucosal permeability (blood-to-lumen clearance of 51Cr-EDTA), arterial blood pressure, luminal alkalinisation, transepithelial fluid flux, and motility. Hypotonicity induced a six-fold increase in mucosal permeability, a response that was reversible and repeatable. The α2-adrenoceptor agonist clonidine abolished the hypotonicity-induced increase in mucosal permeability, reduced arterial blood pressure, inhibited duodenal motility, and decreased luminal alkalinisation. The α2-adrenoceptor antagonists, yohimbine and idazoxan, prevented the inhibitory effect of clonidine on the hypotonicity-induced increase in mucosal permeability. The α1-agonist phenylephrine or the α1-antagonist prazosin elicited their predicted effect on blood pressure but did not affect the hypotonicity-induced increase in mucosal permeability. None of the α1- or α2-adrenoceptor drugs changed the hypotonicity-induced net fluid absorption. In conclusion, stimulation of the adrenergic α2-adrenoceptor prevents the hypotonicity-induced increase in mucosal permeability, suggesting that the sympathetic nervous system has the capability to regulate duodenal mucosal permeability.

Comparison of 51Cr-EDTA and 99mTc-DTPA for glomerular filtration rate measurement.

The production of 51Cr-labelled ethylenediaminetetraacetic acid (51Cr-EDTA), a validated and widely used radio-isotopic tracer for glomerular filtration rate (GFR) measurement in Europe, was recently halted by the manufacturer. Technetium-99m-diethylenetriaminepentaacetic acid (99mTc-DTPA) clearance has so far mostly been restricted to assessment of separate renal function by scintigraphy, but scarcely used and validated for GFR measurement. We compared the performances of 51Cr-EDTA and 99mTc-DTPA for GFR and extracellular fluid measurement. In a multi-centre prospective study, 51Cr-EDTA and 99mTc-DTPA were simultaneously injected into 88 patients, and their urinary and plasma clearances, as well as their volumes of distribution, were measured during seven 30-min periods after a 90-min equilibrium time. Mean age was 52.2 ± 14.5years, 59% were men. Urinary clearances of 51Cr-EDTA and 99mTc-DTPA were 64.1 ± 27.6 and 66.1 ± 28.0mL/min, respectively, with a mean bias of 2.00 ± 2.25mL/min, an accuracy within 10% of 95% [95% CI 91-99], and a coefficient of determination (R2) of 0.994. Plasma clearances of 51Cr-EDTA and 99mTc-DTPA were 66.1 ± 25.8 and 68.1 ± 26.6mL/min, respectively, with a mean bias of 1.96 ± 3.32mL/min, an accuracy within 10% of 91% [95% CI 85-97] and a R2 of 0.985. Distribution volumes were 17.3 ± 4.6 L for 51Cr-EDTA and 16.6 ± 4.6 L for 99mTc-DTPA (R2 0.930). The accuracy and precision of 99mTc-DTPA clearance, compared to 51Cr-EDTA clearance, was excellent for both urinary and plasma clearance methods, despite an approximate 2mL/min overestimation, showing that the tracer is a reliable alternative to 51Cr-EDTA for GFR measurement.

Effect of obesity, age and gender on glomerular filtration rate measured in normal adults

This was a retrospective study of 120live kidney donors (75females, 45males). GFR was evaluated from 51Cr-EDTA plasma clearance using blood samples taken at 3, 4 and 5hours. The slope-intercept GFR was corrected for body surface area using the Dubois & Dubois and for the fast exponential using the Brochner-Mortensen equation. Scatter plot of DFG against age in live kidney donors was plotted and the 98% range limits have been defined. The median GFR obtained for kidney donors was 88mL/min/1.73m2 [68-130]. No significant difference with gender was found. 51Cr-EDTA clearance was strongly correlated with patient age (r =-0.62, P <0,0001). GFR decreased by approximately 8mL/min/1.73m2 per decade. Based on these results, a nomogram for GFR is presented. The interpretation of GFR requires age-adjusted normal values. These standards need not be adjusted to the patient's sex or BMI.