Acute kidney injury biomarkers and hydration assessments following prolonged mild hypohydration in healthy young adults

Abstract

The high prevalence of inadequate hydration (e.g., hypohydration and underhydration) is concerning given that extreme heat increases excess hospitalizations for fluid/electrolyte disorders and acute kidney injury (AKI). Inadequate hydration may also be related to renal and cardiometabolic disease development. This study tested the hypothesis that prolonged mild hypohydration increases the urinary AKI biomarker product of insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinase-2 ([IGFBP7·TIMP-2]) compared with euhydration. In addition, we determined the diagnostic accuracy and optimal cutoffs of hydration assessments for discriminating positive AKI risk ([IGFBP·TIMP-2] >0.3 (ng/mL)²/1,000). In a block-randomized crossover design, 22 healthy young adults (11 females and 11 males) completed 24 h of fluid deprivation (hypohydrated group) or 24 h of normal fluid consumption (euhydrated group) separated by ≥72 h. Urinary [IGFBP7·TIMP-2] and other AKI biomarkers were measured following the 24-h protocols. Diagnostic accuracy was assessed via receiver operating characteristic curve analysis. Urinary [IGFBP7·TIMP-2] [1.9 (95% confidence interval: 1.0-2.8) vs. 0.2 (95% confidence interval: 0.1-0.3) (ng/mL)²/1,000, P = 0.0011] was markedly increased in hypohydrated versus euhydrated groups. Urine osmolality (area under the curve: 0.91, P < 0.0001) and urine specific gravity (area under the curve: 0.89, P < 0.0001) had the highest overall performance for discriminating positive AKI risk. Optimal cutoffs with a positive likelihood ratio of 11.8 for both urine osmolality and specific gravity were 952 mosmol/kgH₂O and 1.025 arbitrary units. In conclusion, prolonged mild hypohydration increased urinary [IGFBP7·TIMP-2] in males and females. Urinary [IGFBP7·TIMP-2] corrected to urine concentration was elevated in males only. Urine osmolality and urine specific gravity may have clinical utility for discriminating positive AKI risk following prolonged mild hypohydration.NEW & NOTEWORTHY This study found that prolonged mild hypohydration in healthy young adults increased the Food and Drug Administration approved acute kidney injury (AKI) biomarker urinary insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinase-2 [IGFBP7·TIMP-2]. Urine osmolality and specific gravity demonstrated an excellent ability to discriminate positive AKI risk. These findings emphasize the importance of hydration in protecting renal health and lend early support for hydration assessment as an accessible tool to assess AKI risk.

Keywords: NephroCheck; dehydration; heat wave; kidney injury molecule-1; neutrophil gelatinase-associated lipocalin.

Graphical abstract

Figure 1.

Prolonged mild hypohydration elicited by 24-h fluid deprivation protocol. Healthy males (n = 11) and females (n = 11) underwent 24-h fluid deprivation (hypohydrated group) or 24-h normal fluid consumption (euhydrated group). Change in 24-h nude body mass (A), urine specific gravity (B), urine color (C), serum osmolality (D), and urine osmolality (E) were analyzed using two-way ANOVA with factors of sex and hydration and post hoc Holm–Šídák tests for multiple comparisons. P values from main effects (sex and hydration) and interaction (sex × hydration) reported are shown at the top, and exact P values from multiple-comparison adjustments are shown above a given comparison. Data are presented as means with 95% confidence intervals and individual values. a.u., arbitrary units.

Figure 2.

Elevated urinary acute kidney injury biomarkers following prolonged mild hypohydration. Healthy males (n = 11) and females (n = 11) underwent 24-h fluid deprivation (hypohydrated group) or 24-h normal fluid consumption (euhydrated group). A: product of insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinase (TIMP)-2 ([IGFBP7·TIMP-2]). B: IGFBP7. C: TIMP-2. D: kidney injury molecule-1 (KIM-1). E: neutrophil gelatinase-associated lipocalin (NGAL). Data were analyzed with two-way ANOVA with factors of sex and hydration and post hoc Holm–Šídák tests for multiple comparisons. P values from main effects (sex and hydration) and interaction (sex × hydration) are shown at the top, and exact P values from multiple-comparison adjustments are shown above a given comparison. Data are presented as means with 95% confidence intervals and individual values.

Figure 3.

Urine osmolality-corrected (A, C, E, G, and I) and urine creatinine-corrected (B, D, F, H, and J) corrected acute kidney injury biomarker responses to prolonged mild hypohydration. Healthy males (n = 11) and females (n = 11) underwent 24-h fluid deprivation (hypohydrated group) or 24-h normal fluid consumption (euhydrated group). A and B: product of insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinase (TIMP)-2 ([IGFBP7·TIMP-2]). C and D: IGFBP7. E and F: TIMP-2. G and H: kidney injury molecule-1 (KIM-1). I and J: neutrophil gelatinase-associated lipocalin (NGAL). Data were analyzed with two-way ANOVA with factors of sex and hydration and post hoc Holm–Šídák tests for multiple comparisons. P values from main effects (sex and hydration) and interaction (sex × hydration) are shown at the top, and exact P values from multiple-comparison adjustments are shown above a given comparison. Data are presented as means with 95% confidence intervals and individual values.

Figure 4.

Criterion hypohydration values vs. urinary product of insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinase-2 ([IGFBP7·TIMP-2]) > 0.3 (ng/mL)²/1,000. Individual values of urinary [IGFBP7·TIMP-2] plotted as a function of the percent change in body mass over 24 h (A), urine color (B), urine specific gravity (C), urine osmolality (D), serum osmolality (E), and serum Na⁺ (F). Healthy males and females underwent 24-h fluid deprivation (hypohydrated group) or 24-h normal fluid consumption (euhydrated group). A positive acute kidney injury risk score was identified as urinary [IGFBP7·TIMP-2] > 0.3 (ng/mL)²/1,000. Areas in the shaded zone represent the criterion range for hypohydration. Fisher’s exact test was used as a conservated method to determine an association of the data. Body mass loss over 24 h (Δbody mass) and all urine data are n = 44 (11 males and 11 females in two conditions; A–D), whereas serum data are n = 42 (11 males and 10 females in two conditions; E and F). a.u., arbitrary units.

Figure 5.

Receiver operating characteristic curves for hypohydration measures in discriminating positive acute kidney injury (AKI) risk. Positive AKI risk was determined as urinary product of insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinase-2 ([IGFBP7·TIMP-2]) > 0.3 (ng/mL)²/1,000. The line of identify represents random chance. Area under the curve (AUC) values are reported as means with 95% confidence intervals and P values from statistical comparison with random chance. AUC was compared using the nonparametric method of Delong et al. (63). AUCs for all hypohydration measures were statistically different from random chance (P ≤ 0.0240). *AUC different from the change in body mass (Δbody mass) (P ≤ 0.0097); †AUC different from serum osmolality (P = 0.0240); ‡AUC different from serum Na⁺ (P ≤ 0.0193). A–F: body mass (A), urine color (B), urine specific gravity (C), urine osmolality (D), serum osmolality (E), and serum sodium (F).