Abstract
Acute kidney injury (AKI) is an abrupt deterioration of renal function often caused by severe clinical disease such as sepsis, and patients require intensive care. Acute-phase parameters for systemic inflammation are well established and used in routine clinical diagnosis, but no such parameters are known for AKI and inflammation at the local site of tissue damage, namely the nephron. Therefore, we sought to investigate complement factors C3a/C3 in urine and urinary sediment cells. After the development of a C3a/C3-specific mouse monoclonal antibody (3F7E2), urine excretion from ICU sepsis patients was examined by dot blot and immunoblotting. This C3a/C3 ELISA and a C3a ELISA were used to obtain quantitative data over 24 hours for 6 consecutive days. Urine sediment cells were analyzed for topology of expression. Patients with severe infections (n = 85) showed peak levels of C3a/C3 on the second day of ICU treatment. The majority (n = 59) showed C3a/C3 levels above 20 μg/ml at least once in the first 6 days after admission. C3a was detectable on all 6 days. Peak C3a/C3 levels correlated negatively with peak C-reactive protein (CRP) levels. No relationship was found between peak C3a/C3 with peak leukocyte count, age, or AKI stage. Analysis of urine sediment cells identified C3a/C3-producing epithelial cells with reticular staining patterns and cells with large-granular staining. Opsonized bacteria were detected in patients with urinary tract infections. In critically ill sepsis patients with AKI, urinary C3a/C3 inversely correlated with serum CRP. Whether urinary C3a/C3 has a protective function through autophagy, as previously shown for cisplatin exposure, or is a by-product of sepsis caused by pathogenic stimuli to the kidney must remain open in this study. However, our data suggest that C3a/C3 may function as an inverse acute-phase parameter that originates in the kidney and is detectable in urine.
Highlights
The complement system with the central component C3 represents a member of the innate immune system
We sought to evaluate whether C3a/C3 is involved in urinary tract infections (UTI) often associated with such disease conditions
Acute phase proteins in the serum are represented by C-reactive protein (CRP), fibrinogen, ferritin, complement factor C3 and others
Summary
The complement system with the central component C3 represents a member of the innate immune system. Thereby the tubular epithelial cells alter their gene transcription leading to changes in the regulation of autophagy [9] This is of importance in order to balance and counteract stressing factors such as reactive oxygen species [10] which could result in AKI. As the result of such an ongoing process it has to be assumed that upregulated gene products, of which some represent secreted [13] or cleaved protein fragments [14, 15], might be detectable in urine and can serve as biomarkers [13, 16, 17] In this line it is of note that at the kidney glomerular mesangial cells [18], glomerular epithelial cells [19] and tubular epithelia the complement factor C3 gene is induced for transcription upon pathogenic stimuli [2, 20, 21] given by interferon gamma (INFγ), immunocomplexes [22] and interleukin (IL)-1α [23]. We sought to evaluate whether C3a/C3 is involved in urinary tract infections (UTI) often associated with such disease conditions
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