Does More Serum Creatinine Really Just Mean Less Volume?

where M5molarity (concentration) and V5volume. Reconfigured, it calculates a new concentration (M2) in response to increases or decreases in volume. Far from the bounds of a chemistry textbook, a version of this principle is applied to clinical discussions and research of patients with AKI (1,2). Changes in GFR are often paralleled by changes in volume status. In this context, serum creatinine may reflect filtration and/or changes in total body volume (TBV) (concentration/dilution). Studies in critically ill adults found that correcting serum creatinine to account for potential dilution secondary to volume overload improved recognition of AKI and association with adverse outcomes (1–3). Similarly, studies of pediatric AKI have repeatedly found that volume-adjusting serum creatinine before applying creatinine-based AKI definitions resulted in a stronger association between AKI and mortality (4–6). However, the human body is not a simple static and closed system, suggesting the need for a methodologic examination of the relationship between creatinine concentration and volume-related effects. In this issue of Kidney360, Maulion et al. elegantly took on the problem of creatinine dilution by performing secondary analysis of the ROSE-AHF trial (7). Participants in ROSE-AHF included 360 individuals with acute decompensated heart failure (ADHF) and at least one symptom and clinical sign of volume overload on history and physical (8). ROSE-AHF randomized participants to treatment with dopamine, nesiritide, or placebo. For 72 hours after admission, fluid balance, urine output, and body weight were closely monitored. Serum creatinine was measured every 24 hours. The primary end points were total diuresis and changes in cystatin C. No significant difference was noted in these end points between treatment arms. The use of the ROSE-AHF study population is one of the key strengths of the analysis by Maulion et al. Loop-diuretic dosing was protocolized at 2.53 of home dosing, reducing the heterogeneity in dosing often encountered in clinical practice. Second, research has shown that assessments of body weight, fluid intake, and fluid output recorded as part of routine inpatient care are prone to error and poorly reflect true measurements (9). Intensive monitoring of input and output in ROSE-AHF participants greatly increased the validity of their data. Studying this problem in the context of ADHF was relevant because individuals hospitalized with ADHF have rapid changes in volume status and kidney function. Both have been associated with adverse outcomes (10). Using serum creatinine and fluid balance data from the 72-hour study period, Maulion et al. calculated the expected change in serum creatinine in response to changes in TBV using three models. The models primarily differ in their assumption of serum creatinine as a reflection of generation and kidney clearance. The first model (eCRInstant VD) estimated how serum creatinine would change if the difference in TBV observed over 72 hours happened instantaneously. In this setting, the body is a container, and the creatinine mass is fixed. Not surprisingly, calculated changes in serum creatinine poorly estimated observed values. The second model (eCr72HR VD) estimated GFR and creatinine generation using the baseline serum creatine value. Next, they assumed that volume shift observed over 72 hours occurred at a linear rate. Finally, they incorporated these steady rates of creatinine generation, filtration, and observed 72-hour fluid balance to estimate changes in serum creatinine. The third model is most complex and uses creatinine at baseline and 72 hours to integrate kinetic eGFR into estimates of volume-dependent changes in creatinine. The 72-hour estimated creatinine is calculated assuming creatinine enters a steady state at that time and using the kinetic eGFR along with the MDRD formula to calculate estimated serum creatinine. Model 3 (eCR72HR Kinetic) best approximates observed changes in creatinine—somewhat expected because it incorporates the 72-hour creatinine in the equation. Yet, volume effects only accounted for a median of 3% of estimated changes in serum creatinine. The eCR72HR Kinetic model emphasizes that volume-related effects on serum creatinine concentrations are minimal. The key takeaway from this study is that the volume effects on creatinine in clinical practice cannot be simplified to a basic dilution equation. In patients with ADHF, volume effects may in fact be nonconsequential