Urinary neprilysin in the critically ill patient

Sahra Pajenda, Karl Mechtler, Ludwig Wagner

Critically ill patients in intensive care face hazardous conditions. Among these, acute kidney injury (AKI) is frequently seen as a result of sepsis. Early diagnosis of kidney injury is of the utmost importance in the guidance of interventions or avoidance of treatment-induced kidney injury. On these grounds, we searched for markers that could indicate proximal tubular cell injury. Urine samples of 90 patients admitted to the intensive or intermediate care unit were collected over 2 to 5 days. The biomarker neprilysin (NEP) was investigated in urine using several methods such as dot blot, ELISA and immunofluorescence of urinary casts. Fifty-five healthy donors acted as controls. NEP was highly significantly elevated in the urine of patients who suffered AKI according to the KDIGO criteria in comparison to healthy controls. It was also found to be elevated in ICU patients without overt signs of AKI according to serum creatinine changes, however they were suffering from potential nephrotoxic insults. According to our findings, urinary NEP is indicative of epithelial cell alterations at the proximal tubule. This was elaborated in ICU patients when ghost fragments and NEP(+) microvesicles were observed in urinary sediment cytopreparations. Furthermore, NEP(+) immunofluorescence of healthy kidney tissue showed staining at the proximal tubules. NEP, a potential marker for proximal tubular epithelia, can be measured in urine. This does not originate from leakage of elevated serum levels, but indicates proximal tubular cell alterations such as brush border severing, which can heal in most cases.