Evaluation of trial outcomes in acute kidney injury by creatinine modeling

Abstract

Background and objectives: Clinical trials of acute kidney injury (AKI) use changes in creatinine as outcome metrics. This study investigated how outcome metrics and baseline creatinine affect trial outcome.

Design, setting, participants, & measurements: A one-compartment pharmacokinetic model of creatinine change resulting from a decrease in GFR was applied to a population of 10,000 simulated virtual inpatients. Treatment was simulated as an amelioration of GFR decrease by a specified percentage, the treatment efficacy, in 50%. Three categorical and two continuous outcome metrics were calculated and compared. Outcomes were compared for measured and estimated baseline creatinine levels that were back-calculated assuming a GFR of 100 or 75 ml/min.

Results: The continuous metrics, the average value of creatinine and the average value of creatinine relative to baseline decreased approximately linearly with increase in treatment efficacy. The categorical metrics displayed a sigmoidal decrease and erroneously suggested perfect treatment when GFR decrease was ameliorated by only 60 to 80%. Using an estimate of baseline creatinine increased the number of patients who were classified as having AKI.

Conclusions: When used to determine clinical trial outcome, continuous metrics correctly detected the extent of intervention. At low treatment efficacy, categorical metrics underestimated and at high treatment efficacy overestimated the effect of treatment. These effects were exaggerated when the population contained a high proportion of patients with more severe AKI. An estimated baseline creatinine level will overestimate AKI prevalence compared with a measured baseline value. Clinical trials of AKI should use a continuous outcome metric and a measured baseline and report baseline median and interquartile range.

Figure 1.

Derivation of the AVC and the RAVC for the period 0 to t.

Figure 2.

Histogram of a population of 10,000 initial plasma creatinine values (C_0n) that were randomly chosen according to the probability distribution Table 2 and binned into 100 equal bins of width 0.035 mg/dl each.

Figure 3.

Histogram of a population of 10,000 initial plasma GFR decreases (Δg_n) randomly chosen according to the probability distribution Table 2 and binned into 100 equal bins of width 1% each.

Figure 4.

Distribution of 10,000 VIP population showing the relative (%) increase in plasma creatinine from baseline at each time point, t. Box plots show 25 and 75% quartiles with median. Upper whiskers are 1.5 times the interquartile range; lower whiskers show the minimum. X = mean values.

Figure 5.

Prevention trial (n = 10,000). The proportion (%) of VIPs categorized in each categorical outcome metric for total RIFLE, total AKIN, total W&B, severity stage metrics RIFLE R and AKIN I, and the value of the continuous outcome metric mean RAVC (%) at 48 h after GFR decrease (A) and 144 h after GFR decrease (B) are shown as a function of the treatment efficacy. C and D show the corresponding effect size as a function of treatment efficacy. Note that W&B is not defined beyond 48 h and is therefore not represented in the 144-h graphs.

Figure 6.

Intervention trial VIP-33 (initial GFR decrease >33.3%; n = 2286). The proportion (%) of VIPs categorized in each categorical outcome metric for total RIFLE, total AKIN, total W&B, severity stage metrics RIFLE R and AKIN I, and the value of the continuous outcome metric mean RAVC (%) at 48 h after GFR decrease (A) and 144 h after GFR decrease (B) are shown as a function of the treatment efficacy. C and D show the corresponding effect size as a function of treatment efficacy. Note that W&B is not defined beyond 48 h and is therefore not represented in the 144-h graphs.

Figure 7.

Intervention trial VIP-67 (initial GFR decrease >66.7%; n = 427). The proportion (%) of VIPs categorized in each categorical outcome metric for total RIFLE, total AKIN, total W&B, severity stage metrics RIFLE R and AKIN I, and the value of the continuous outcome metric mean RAVC (%) at 48 h after GFR decrease (A) and 144 h after GFR decrease (B) are shown as a function of the treatment efficacy. C and D show the corresponding effect size as a function of treatment efficacy. Note that W&B is not defined beyond 48 h and is therefore not represented in the 144-h graphs.

Figure 8.

High-risk patients (initial creatinine >1.5 mg/dl; n = 710). The proportion (%) of VIPs categorized in each categorical outcome metric for total RIFLE, total AKIN, total W&B, severity stage metrics RIFLE R and AKIN I, and the value of the continuous outcome metric mean RAVC (%) at 48 h after GFR decrease (A) and 144 h after GFR decrease (B) are shown as a function of the treatment efficacy. C and D show the corresponding effect size as a function of treatment efficacy. Note that W&B is not defined beyond 48 h and is therefore not represented in the 144-h graphs.

Figure A1.