Reduced Production of Creatinine Limits Its Use as Marker of Kidney Injury in Sepsis

Abstract

Serum creatinine is used clinically to detect and evaluate acute kidney injury (AKI) and chronic kidney disease (CKD), 1,2 although the limitations of serum creatinine for the early detection and accurate estimation of renal injury are widely known. In AKI, serum creatinine does not accurately reflect the GFR because the patient is not in steady state. 3 Furthermore, serum creatinine is also influenced by tubular creatinine secretion and by nonrenal factors such as muscle mass, liver function, and nonrenal (gastrointestinal) elimination.Sepsis remains a serious problem in critically ill patients, and mortality from sepsis is increased dramatically when complicated by AKI; therefore, early detection and accurate evaluation of AKI is important in patients with sepsis. We modified the cecal ligation and puncture (CLP) mouse sepsis model to make it more clinically relevant, and our model developed sepsis-induced AKI. 4 -6 We found that serum creatinine increased to a lesser extent in CLP (approximately 0.5 mg/dl) than ischemia/reperfusion or cisplatin administration (Ͼ1 mg/dl) within 24 h of injury. To explore nonrenal factors that might account for this disparity, we used bilateral nephrectomy (BNx), a technique used recently by others to study the contribution of the kidney to cytokine metabolism and acute lung injury. 7 First, we evaluated sepsis in bilaterally nephrectomized mice. We induced sepsis by CLP surgery with 8-mm cecal ligation, which causes modest sublethal sepsis in normal outbred CD-1 mice. 8 All animals survived until they were killed at 18 h after surgery. CLP surgery in non-nephrectomized mice caused a numerically small, but not significant increase of serum creatinine (sham BNx ϩCLP group). As expected, we found large increases of serum creatinine in the BNxϩsham CLP group; however, induction of sepsis at the time of BNx significantly decreased serum creatinine (BNxϩCLP group) compared with nonseptic BNx alone (BNxϩsham CLP group; Figure 1A), raising doubt about whether serum creatinine accurately reflects impaired kidney function during sepsis. In contrast, nonrenal organ injury markers (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and lactate dehydrogenase [LDH]) and serum TNF-␣ were higher in the BNxϩCLP group than in the BNxϩsham CLP group, confirming the presence of severe sepsis (Figure 1, ABSTRACTAlthough 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-␣. 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 decrease...

The Use of Plasma and Urine Neutrophil Gelatinase Associated Lipocalin (NGAL) and Cystatin C in Early Diagnosis of Septic Acute Kidney Injury in Critically Ill Patients

“…In contrast to our study Nejad et al identified no difference in urine Cystatin C levels of patients with sepsis and septic AKI. They explained their findings with the possibility of masking of urine Cystatin C increase in AKI with the increased levels in sepsis and as it was shown in an experimental study of Doi et al sepsis can decrease creatinin levels; if AKI definition was made according to an increase in creatinine level the sensitivity of urine Cystatin C decreases [9]. The authors suggested that a new threshold for urine Cystatin C can be defined for the prediction of AKI in these septic patients.…”

“…Furthermore serum creatinine is also influenced by tubular creatinine secretion and nonrenal factors such as muscle mass, liver function and non-renal gastrointestinal elimination [6][7][8]. Besides, Doi et al, found in their animal study that sepsis dramatically reduces the production of creatinine without changes in body weight, hematocrit and extracellular fluid volume [9].…”

Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

“…This approach has limitations, however, and loss of muscle mass, changes in volume of distribution, changes in renal reserve, and hyperfiltration can confound the assessment of functional recovery [54][55][56][57][58][59][60] . The limitations of using serum creatinine to assess recovery are supported by observational data indicating that AKI is associated with an increased risk of CKD, even when accompanied by an apparent complete return of serum creatinine to baseline levels 61,62 .…”

Serum Creatinine Changes Associated with Critical Illness and Detection of Persistent Renal Dysfunction after AKI

“…However, large improvements in GFR from baseline after critical illness would seem implausible, whereas large and sustained falls in creatinine generation have been shown in animal models of sepsis (14), patients with advanced CKD (15), and critically ill humans (16)(17)(18), with greatest decrease occurring in the sickest patients (16). Skeletal muscle is the major source of creatinine production, and critical illness is associated with profound loss of skeletal muscle protein (10,19,20), with muscle thickness steadily decreasing over time after ICU admission (10,21,22).…”