Model-based estimation of iohexol plasma clearance for pragmatic renal function determination in the renal transplantation setting

Background Iohexol plasma clearance-based glomerular filtration rate (GFR) determination provides an accurate method for renal function evaluation. This technique is increasingly advocated for clinical situations that dictate highly accurate renal function assessment, as an alternative to conventional serum creatinine-based methods with limited accuracy or poor feasibility. In the renal transplantation setting, this particularly applies to living renal transplant donor eligibility screening, renal transplant function monitoring and research purposes. The dependency of current iohexol GFR estimation techniques on extensive sampling, however, has limited its clinical application. We developed a population pharmacokinetic model and limited sampling schedules, implemented in the online InsightRX precision dosing platform, to facilitate pragmatic iohexol GFR assessment. Methods Iohexol concentrations (n = 587) drawn 5 min to 4 h after administration were available from 67 renal transplant recipients and 41 living renal transplant donor candidates with measured iohexol GFRs of 27-117 mL/min/1.73 m(2). These were split into a model development (n = 72) cohort and an internal validation (n = 36) cohort. External validation was performed with 1040 iohexol concentrations from 268 renal transplant recipients drawn between 5 min and 4 h after administration, and extended iohexol curves up to 24 h from 11 random patients with impaired renal function. Limited sampling schedules based on one to four blood draws within 4 h after iohexol administration were evaluated in terms of bias and imprecision, using the mean relative prediction error and mean absolute relative prediction error. The total deviation index and percentage of limited sampling schedule-based GFR predictions within +/- 10% of those of the full model (P-10) were assessed to aid interpretation. Results Iohexol pharmacokinetics was best described with a two-compartmental first-order elimination model, allometrically scaled to fat-free mass, with patient type as a covariate on clearance and the central distribution volume. Model validity was confirmed during the internal and external validation. Various limited sampling schedules based on three to four blood draws within 4 h showed excellent predictive performance (mean relative prediction error 97%). The best limited sampling schedules based on three to four blood draws within 3 h showed reduced predictive performance (mean relative prediction error = 85%), but may be considered for their enhanced clinical feasibility when deemed justified. Conclusions Our online pharmacometric tool provides an accurate, pragmatic, and ready-to-use technique for measured GFR-based renal function evaluation for clinical situations where conventional methods lack accuracy or show limited feasibility. Additional adaptation and validation of our model and limited sampling schedules for renal transplant recipients with GFRs below 30 mL/min is warranted before considering this technique in these patients.Nephrolog

The influence of a cooked-meat meal on estimated glomerular filtration rate

<b>Background:</b> Chronic kidney disease (CKD) is an important but under-recognized condition. Recent national guidelines have recommended that biochemistry laboratories report estimated GFR (eGFR) to improve diagnosis of CKD and facilitate disease staging and management. Previous reports have suggested that intake of large amounts of cooked meat can lead to a significant increase in serum creatinine concentration.<p></p> <b>Methods:</b> Participants (n = 32), consisting of 17 healthy volunteers and 15 outpatients, were recruited. Measurement of serum creatinine (kinetic Jaffe method, enzymatic, isotope-dilution mass spectrometry [IDMS]) and cystatin C, and calculation of eGFR were carried out before (i) and after a meal containing cooked meat (ii) and a meat-free meal (iii).<p></p> <b>Results:</b> Following intake of cooked meat, median serum creatinine concentration (kinetic Jaffe) increased from 80.5 µmol/L preprandially to 101.0 µmol/L 1-2 h postprandially (P<0.0001), and 99.0 µmol/L 3-4 h postprandially (P<0.0001). Median eGFR decreased from 84.0 mL/min/1.73 m2 preprandially to 59.5 mL/min/1.73 m2 1-2 h postprandially (P<0.0001), and 64.0 mL/min/1.73m2 3-4 h postprandially (P<0.0001). Consumption of non-meat-containing meals had little impact on serum creatinine (kinetic Jaffe) and eGFR. Changes in serum creatinine were similar using all three methods, and cystatin C concentration was generally uninfluenced by food intake.<p></p> <b>Conclusions:</b> Intake of cooked meat has a significant effect on serum creatinine concentration and eGFR. Misclassification of CKD is possible if measurements are made after meals containing cooked meat. Clinicians should ensure that CKD classification is based on samples taken in the appropriate conditions: either fasting or after avoidance of cooked meat on the day of sampling. National guidelines which overlook this factor should be revisited

Supplementary Material for: Investigating the Role of Cardiovascular Biomarkers in Children with Pre-Dialysis Chronic Kidney Disease: A Substitute to Echocardiography to Detect Increased Left Ventricular Mass?

<p><b><i>Background:</i></b> Children with chronic kidney disease (CKD) are at increased risk of future cardiovascular (CV) events. Our aim in this prospective single-centre cross-sectional analysis was to assess the relationship of a novel panel of CV biomarkers with left ventricular hypertrophy (LVH). <b><i>Methods:</i></b> A panel of five CV biomarkers (asymmetric dimethyl arginine, high sensitivity C-reactive protein, homocysteine, N-terminal pro-B type natriuretic peptide and uric acid) were measured on the same day as an echocardiogram assessment, in paediatric patients with pre-dialysis stages 3-5 of CKD. <b><i>Results:</i></b> Of 73 children aged 5-18 years, LVH, all eccentric, was identified in 38%. Systolic blood pressure (BP), glomerular filtration rate (GFR) and higher intake of calcium-based phosphate binders were significantly worse in children with LVH. In multivariate models analysing each biomarker one at a time with confounders [GFR, systolic BP z-score, anti-hypertensive medication (yes/no) and elemental calcium intake], clinic systolic BP z-score and elemental calcium intake consistently displayed a significant relationship with indexed left ventricular mass (LVMI). None of the evaluated CV biomarkers displayed a significant relationship with LVMI. <b><i>Conclusions:</i></b> In our cohort of children with moderately severe pre-dialysis CKD we have identified no suitable biomarkers to detect LVH. We would therefore recommend that echocardiographic determination of LVMI remains the technique of choice for detection of LVH in children with CKD.</p

Urinary albumin/creatinine ratio tertiles predict risk of diabetic retinopathy progression: a natural history study from the Adolescent Cardio-Renal Intervention Trial (AdDIT) observational cohort

Aims/hypothesis We hypothesised that adolescents with type 1 diabetes with a urinary albumin/creatinine ratio (ACR) in the upper tertile of the normal range (high ACR) are at greater risk of three-step diabetic retinopathy progression (3DR) independent of glycaemic control. Methods This was a prospective observational study in 710 normoalbuminuric adolescents with type 1 diabetes from the nonintervention cohorts of the Adolescent Cardio-Renal Intervention Trial (AdDIT). Participants were classified as ‘high ACR’ or ‘low ACR’ (lowest and middle ACR tertiles) using baseline standardised log10 ACR. The primary outcome, 3DR, was determined from centrally graded, standardised two-field retinal photographs. 3DR risk was determined using multivariable Cox regression for the effect of high ACR, with HbA1c, BP, LDL-cholesterol and BMI as covariates; diabetes duration was the time-dependent variable. Results At baseline mean ± SD age was 14.3 ± 1.6 years and mean ± SD diabetes duration was 7.2 ± 3.3 years. After a median of 3.2 years, 83/710 (12%) had developed 3DR. In multivariable analysis, high ACR (HR 2.1 [1.3, 3.3], p=0.001), higher mean IFCC HbA1c (HR 1.03 [1.01, 1.04], p=0.001) and higher baseline diastolic BP SD score (HR 1.43 [1.08, 1.89], p=0.01) were independently associated with 3DR risk. Conclusions/interpretation High ACR is associated with greater risk of 3DR in adolescents, providing a target for future intervention studies. Trial registration isrctn.org ISRCTN91419926.Paul Z. Benitez-Aguirre, M. Loredana Marcovecchio, Scott T. Chiesa, Maria E. Craig, Tien Y. Wong, Elizabeth A. Davis, Andrew Cotterill, Jenny J. Couper, Fergus J. Cameron, Farid H. Mahmud, H. Andrew W. Neil, Timothy W. Jones, Lauren A. B. Hodgson, R. Neil Dalton, Sally M. Marshall, John Deanfield, David B. Dunger, Kim C. Donaghu

A new strategy for vascular complications in young people with type 1 diabetes mellitus

Diabetes vascular complications, including cardiovascular disease, diabetic nephropathy and retinopathy, have a negative effect on the long-term prognosis of young people with type 1 diabetes mellitus (T1DM). Poor glycaemic control and consequent increased HbA1c levels are major risk factors for the development of vascular complications. HbA1c levels are the main focus of current management strategies; however, the recommended target is rarely achieved in adolescents. Thus, a clear need exists for improved biomarkers to identify high-risk young people early and to develop new intervention strategies. Evidence is accumulating that early increases in urinary albumin excretion could be predictive of adolescents with T1DM who are at an increased risk of developing vascular complications, independent of HbA1c levels. These findings present an opportunity to move towards the personalized care of adolescents with T1DM, which takes into consideration changes in albumin excretion and other risk factors in addition to HbA1c levels.M. Loredana Marcovecchio, R. Neil Dalton, Denis Daneman, John Deanfield, Timothy W. Jones, H. Andrew W. Neil ... et al. (on behalf of the Adolescent type 1 Diabetes cardio-renal Intervention Trial (AdDIT) study group