Assessment of Iothalamate Plasma Clearance: Duration of Study Affects Quality of GFR

Background and objectives: Measurement of GFR is important for the management of chronic kidney disease (CKD). Although bolus administration of radiocontrast agents is commonly used to measure GFR, the optimal duration of sampling to assess their plasma clearance is unknown. The purpose of this study was to evaluate whether the duration of plasma sampling influences precision and estimation of GFR.Design, setting, participants, & measurements: GFR was measured by sampling plasma 12 times over 5 h in 56 patients with CKD (mean age 64 yr, 98% men, 79% Caucasian, 34% diabetics, estimated GFR 31.8 ± 14.2 ml/min/1.73 m²). In a subset of 12 patients we measured GFR by sampling plasma 17 times over 10 h.Results: Short sampling intervals considerably overestimated GFR measured using total plasma iothalamate clearance, especially in larger patients. In the higher estimated GFR group (>30 ml/min/1.73m²), the 5-h GFR was 17% higher and 2-h GFR 54% higher compared with the 10-h GFR, which averaged 40.3 ml/min/1.73 m². In the lower estimated GFR group (<30 ml/min/1.73m²), the 5-h GFR was 36% higher and 2-h GFR 126% higher compared with the 10-h GFR, which averaged 22.2 ml/min/1.73 m². Short sampling duration also reduced the precision of the estimated GFR from 1.67% for 10-h GFR, to 3.48% for 5-h GFR, and to 7.07% for 2-h GFR.Conclusions: GFR measured over a longer duration with multiple plasma samples spanning the distribution and elimination phases may improve precision and provide a better measure of renal function.The clinical manifestations of chronic kidney disease (CKD) are heterogenous, but it is generally accepted that the staging of CKD rests upon an accurate knowledge of GFR (1). Although urinary clearance of radioactive iothalamate has been used as the reference method to measure GFR (2), many clinical and research laboratories now use plasma clearance of nonradioactive radiocontrast dyes instead (3–7). Plasma clearance of iothalamate can be measured either after continuous infusion of iothalamate to achieve steady state and measuring plasma iothalamate (4,5,7), or after an intravenous bolus (3,6,8). The latter technique involves administering a bolus dose of iothalamate or another radiocontrast dye and sampling blood at timed intervals to study its pharmacokinetics. We and others have reported that plasma iothalamate clearance provides improved precision over urinary clearances (8,9). Because of improved precision, the plasma iothalamate clearance technique appears attractive for longitudinal studies in which sample size can be reduced to detect a given change in GFR (9).The optimal duration of plasma sampling to best ascertain GFR remains undefined—no minimum duration of sampling is recommended. Accordingly, uncertainty exists when planning the optimal duration of GFR studies for the long-term follow-up renal function. Review of published work reveals that the duration of plasma iothalamate clearances measurement has varied anywhere between 2 to 10 h (8,10–12). In a study that measured plasma iothalamate concentration time profile over 10 h (12), plasma clearance was noted to be log-linear in all instances after 120 min, whereas another study reported that a 2-h time frame was perfectly adequate (10). A more recent multicenter study in children in the United States suggested 5 h as an adequate time frame for sampling (6).We sought to evaluate the optimal duration of measurement of plasma iothalamate clearance in a cohort of patients with CKD. We hypothesized that short studies would overestimate GFR and that longer studies would reduce this error. We reasoned that short studies in patients with lower GFR would be associated with greater discrepancy compared with studies with longer sampling duration and tested the hypothesis that shorter duration studies would sacrifice precision compared with longer studies.