Reduced production of creatinine limits its use as marker of kidney injury in sepsis

Abstract

Although diagnosis and staging of acute kidney injury uses serum creatinine, acute changes in creatinine lag behind both renal injury and recovery. The risk for mortality increases when acute kidney injury accompanies sepsis; therefore, we sought to explore the limitations of serum creatinine in this setting. In mice, induction of sepsis by cecal ligation and puncture in bilaterally nephrectomized mice increased markers of nonrenal organ injury and serum TNF-alpha. Serum creatinine, however, was significantly lower in septic animals than in animals subjected to bilateral nephrectomy and sham cecal ligation and puncture. Under these conditions treatment with chloroquine decreased nonrenal organ injury markers but paradoxically increased serum creatinine. Sepsis dramatically decreased production of creatinine in nephrectomized mice, without changes in body weight, hematocrit, or extracellular fluid volume. In conclusion, sepsis reduces production of creatinine, which blunts the increase in serum creatinine after sepsis, potentially limiting the early detection of acute kidney injury. This may partially explain why small absolute increases in serum creatinine levels are associated with poor clinical outcomes. These data support the need for new biomarkers that provide better measures of renal injury, especially in patients with sepsis.

Figure 1.

BNx and subsequent sepsis induced by CLP. (A through E) Serum creatinine (A), AST (B), ALT (C), LDH (D), and serum TNF-α (E) were measured at 18 h after surgery (n = 5 to 6 per group). Data are means ± SEM. *P < 0.05 versus Sham BNx/Sham CLP; #P < 0.05 versus BNx.

Figure 2.

Effects of chloroquine treatment on BNx+CLP. (A through E) Serum creatinine (A), AST (B), ALT (C), LDH (D), and serum TNF-α (E) were measured at 18 h after surgery (n = 8 to 9 per each BNx group; n = 5 per sham group). Sham is Sham BNx/Sham CLP. Data are mean ± SEM. #P < 0.05 versus BNx+CLP.

Figure 3.

Volume of distribution (Vd) and estimated creatinine production. (A) Vd of creatinine and FITC-inulin were measured from 14 to 18 h after surgery. (B) Estimated creatinine production was measured at 0 to 14 h after surgery. Data are means ± SEM (n = 5 to 6 per group). #P < 0.05 versus BNx.