GFR measurement in patients with CKD: Performance and feasibility of simplified iohexol plasma clearance techniques

Abstract

Implementing shortened one-compartment iohexol plasma clearance models for GFR measurement is crucial since the gold standard inulin renal clearance technique and the reference two-compartment, 10-hour, 16-samplings iohexol plasma clearance method are clinically unfeasible. Inulin may precipitate anaphylactic shock. Four-hour and 8-hour one-compartment iohexol plasma clearance models with Bröchner-Mortensen correction provide accurate GFR measurements in patients with estimated GFR (eGFR) > or ≤40 mL/min/1.73m2, respectively. We compared the performance of the simplified 5-hour, 4-samplings, two-compartment population pharmacokinetic model (popPK) with the performance of the reference two-compartment 10-hour iohexol method in 16 patients with GFR 15.2 to 56.5 mL/min/1.73 m2. We also compared the performance of shortened (5, 6 and 7-hour) one-compartment models with the performance of the standard 8-hour one-compartment model in 101 patients with eGFR ≤40 mL/min/1.73 m2. The performance of popPK and shortened methods versus reference methods was evaluated by total deviation index (TDI), concordance correlation coefficient (CCC) and coverage probability (CP). TDI <10%, CCC ≥0.9 and CP >90% indicated adequate performance. TDI, CCC and CP of popPK were 11.11%, 0.809 and 54.10%, respectively. All shortened, one-compartment models overestimated the GFR (p <0.0001 for all) as compared to the 8-hour model. TDI, CCC and CP were 7.02%, 0.815, and 75.80% for the 7-hour model, 7.26%, 0.803, and 74.20% for the 6-hour model, and 8.85%, 0.729 and 64.70% for the 5-hour model. The agreement of popPK model was comparable to that obtained with the Chronic-Kidney-Disease-Collaboration-Epidemiology (CKD-Epi) and the Modification-of-Diet-in-Renal-Disease (MDRD) serum-creatinine based equations for GFR estimation. PopPK model is remarkably unreliable for GFR measurement in stage III-IV CKD patients. In patients with eGFR ≤40 mL/min/1.73m2, shortened one-compartment models, in particular the 5-hour model, are less performant than the reference 8-hour model. For accurate GFR measurements, the iohexol plasma clearance should be measured with appropriate protocols. Over-simplified procedures should be avoided.

Fig 1. Blood sampling scheme.

Blood samplings required for the standard 4-hour and 8-hour one-compartment models (Panels C and B), for the reference 10-hour two-compartment model (Panel A), and the simplified two-compartment popPK model (Panel D).

Fig 2. Mountain plot analysis.

Mountain plot analysis showing a percentile for each ranked difference between the standard 10-hour two-compartment model (reference GFR) and the simplified two-compartment popPK model (popPK GFR), MDRD (MDRD eGFR) and CKD-Epi (CKD-Epi eGFR) in the study group considered as a whole (Panel A, Overall, n = 40) and only first, baseline clearance studies available from each individual patient (Panel B, Baseline Analyses, n = 16).

Fig 3. Bland–Altman plots obtained with popPK model and the standard 10-hour two-compartment model.

Bland–Altman plots and limits of agreement between GFR obtained with the simplified two-compartment popPK model (popPK GFR) and the standard 10-hour two-compartment model (reference-GFR) in the study group considered as a whole (Panel A, Overall, n = 40) and only first, baseline clearance studies available from each individual patient (Panel B, Baseline Analyses, n = 16).

Fig 4. Intercept random model for Phase A.

Intercept random model based on standard 10-hour two-compartment model (reference GFR) versus the simplified two-compartment popPK model (popPK GFR), MDRD (MDRD eGFR) and CKD-Epi (CKD-Epi eGFR) (n = 40).

Fig 5. Bland–Altman plots with 8-hour vs. 7, 6 and 5 hours after iohexol infusion.

Bland–Altman plots and limits of agreement between GFR values obtained with the one-compartment models shortened to 7, 6, or 5 hours versus the GFR values obtained with the standard 8-hour procedure. Upper panels show data obtained from all available clearance measurements (Overall); Lower panels show data obtained from the first, baseline, clearance measurements available from each individual patient (Baseline Analyses).

Fig 6. GFRs measured with 8-hour vs. 7, 6 and 5 hours after iohexol infusion.

GFR values measured with the 8-hour standard one-compartment model versus GFR values obtained with shortened one-compartment protocols stopped at 7, 6 and 5-hours after iohexol infusion considering all available clearance studies (Panel A, Overall, n = 216) and only first, baseline clearance studies available from each individual patient (Panel B, Baseline Analyses, n = 101). Data are mean ± 95% confidence intervals.

Fig 7. Mountain plot with 8-hour vs. 7, 6 and 5 hours after iohexol infusion.

Mountain plot analysis showing a percentile for each ranked difference between the standard 8-hour one-compartment model (8-hour GFR) and different shortened protocols (7, 6 and 5-hours GFR) and Plot analysis was performed by using GFR data obtained from all available clearance measurements (Panel A, Overall, n = 216) and only from the first, baseline, clearance measurement available from each individual patient (Panel B, Baseline Analyses, n = 101).

Fig 8. Intercept random model for Phase B.

Intercept random model based on GFR values measured with the 8-hour standard one-compartment model versus GFR values obtained with 7, 6 and 5-hours models and CKD-Epi and MDRD formulas (n = 216).