Therapeutic implications and pathophysiological role of calprotectin in acute kidney injury
Final Report Abstract
TP7 aimed at a characterization of calprotectin as a novel biomarker for acute kidney injury (AKI). In the first funding period we performed a proof of concept trial showing that urinary calprotectin is concentrations are substantially increased in intrinsic AKI, whereas they resembled healthy controls in prerenal AKI. This finding was confirmed in a second cohort (validation trial). In the second funding period we demonstrated that urinary calprotectin is able to distinguish prerenal and intrinsic AKI in pediatric populations as well. With regard to the effects of immunosuppression, it remained unclear whether calprotectin had a discriminatory potency in AKI after renal transplantation as well. A further clinical trial addressed this question and revealed a diagnostic potency in this setting. Moreover, urinary calprotectin concentrations obtained early after transplantation demonstrated a predictive value for graft function of the following 12 months. Immunohistochemistry studies identified monocytes and granulocytes as the primary source of calprotectin in the renal interstitium. To determine the timecourse of urinary calprotectin secretion after ischaemia/reperfusion-induced kidney injury in comparison to neutrophil gelatinase-associated lipocalin, we performed a trial in subjects undergoing nephron sparing surgery for kidney tumours. Calprotectin concentrations started rising within 2 hours after ischaemia/reperfusion-induced kidney injury and remained increased for several days. An interesting collateral finding was that urothelial tumours are associated with increased calprotectin concentrations as well. This finding was separately addressed in a consecutive confirmatory trial including immunohistochemical analyses.8 Pyuria was identified as a further alternative source of urinary calprotectin and has to be taken into account in the interpretation of calprotectin concentrations in AKI. In summary, these findings identified calprotectin as a sensitive but not a specific marker in AKI. Since AKI may also occur in pre-established chronic kidney disease (“acute on chronic AKI“), a further clinical trial investigated urinary calprotectin in different forms of CKD. Only inflammatory kidney diseases, e. g. vasculitis, were consistently associated with increased calprotectin concentrations. Noninflammatory diseases were associated with low calprotectin concentrations thereby allowing a diagnostic use in the setting of acute on chronic AKI. A prognostic value for a future deterioration of renal function could not be demonstrated. This aspect was additionally investigated in the international multicenter randomized controlled ”STOP-IgAN“ trial. In accordance with the above mentioned data calprotectin did neither demonstrate a predictive value for a deterioration of renal function, nor for a response to immunosuppressive therapy in IgA nephropathy. In the meantime other groups confirmed our central finding and moreover indicated that calprotectin plays a pathophysiological role in AKI. Very recently, the clinical trials on the use of urinary calprotectin for the discrimination of intrinsic and prerenal AKI were summarized in a first meta-analysis. The findings of the first funding period led to an international patent application. Currently, the following projects are ongoing: We investigated the pathophysiological role of calprotectin in acute ischemia/reperfusion injury using S100A9 -/- mice. The experiments have been successfully finished. Moreover, we performed a clinical trial on the diagnostic use of calprotectin to identify subjects at increased risk for contrast induced nephropathy. In summary, the two funding periods were used to successfully perform an in-depth characterization of the diagnostic use, the dynamics and the source of urinary calprotectin in acute and chronic kidney injury in different populations.
Publications
- Urinary calprotectin and the distinction between prerenal and intrinsic acute kidney injury. Clin J Am Soc Nephrol 6: 2347-2355, 2011
Heller F, Frischmann S, Grunbaum M, Zidek W, Westhoff TH
(See online at https://doi.org/10.2215/cjn.02490311) - Calprotectin and neutrophil gelantinase-associated lipocalin in the differentiation of pre-renal and intrinsic acute kidney injury. Acta Physiol (Oxf) 207: 700-708, 2013
Seibert FS, Pagonas N, Arndt R, Heller F, Dragun D, Persson PB, Schmidt-Ott, Zidek W, Westhoff
(See online at https://doi.org/10.1111/apha.12064) - Urinary calprotectin and posttransplant renal allograft injury. PLoS One 9: e113006, 2014
Tepel M, Borst C, Bistrup C, Marcussen N, Pagonas N, Seibert FS, Arndt R, Zidek W, Westhoff TH
(See online at https://doi.org/10.1371/journal.pone.0113006) - Urinary calprotectin: a new diagnostic marker in urothelial carcinoma of the bladder. World J Urol 32: 1485-1492, 2014
Ebbing J, Mathia S, Seibert FS, Pagonas N, Bauer F, Erber B, Günzel K, Kilic E, Kempkensteffen C, Miller K, Bachmann A, Rosenberger C, Zidek W, Westhoff TH
(See online at https://doi.org/10.1007/s00345-013-1227-8) - Dynamics of urinary calprotectin after renal ischaemia. PLoS One 11: e0146395, 2016
Ebbing J, Seibert FS, Pagonas N, Bauer F, Miller K, Kempkensteffen C, Günzel K, Bachmann A, Seifert HH, Rentsch CA, Ardelt P, Wetterauer C, Amico P, Babel N, Westhoff TH
(See online at https://doi.org/10.1371/journal.pone.0146395) - Urinary biomarkers for the differentiation of prerenal and intrinsic pediatric acute kidney injury. Pediatr Nephrol 31: 2553-2563, 2016
Westhoff JH, Fichtner A, Waldherr S, Pagonas N, Seibert FS, Babel N, Tönshoff B, Bauer F, Westhoff TH
(See online at https://doi.org/10.1007/s00467-016-3418-1) - Urinary calprotectin differentiates between prerenal and intrinsic acute renal allograft failure. Transplantation 101: 387-394, 2017
Seibert FS, Rosenberger C, Mathia S, Arndt, R, Arns W, Andrea H, Pagonas N, Bauer F, Zidek W, Westhoff TH
(See online at https://doi.org/10.1097/TP.0000000000001124) - Urinary calprotectin, kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin for the prediction of adverse outcome in pediatric acute kidney injury. Eur J Pediatr 176: 745-755, 2017
Westhoff JH, Seibert FS, Waldherr S, Bauer F, Tönshoff B, Fichtner A, Westhoff TH
(See online at https://doi.org/10.1007/s00431-017-2907-y) - Prognostic value of urinary calprotectin, NGAL and KIM-1 in chronic kidney disease. Kidney Blood Press Res 43: 1255-1262, 2018
Seibert FS, Sitz M, Passfall J, Haesner M, Laschinski P, Buhl M, Bauer F, Babel N, Pagonas N, Westhoff TH
(See online at https://doi.org/10.1159/000492407) - Urinary biomarkers in the prediction of prognosis and treatment response in IgA nephropathy. Kidney Blood Press Res 43: 1563-1572, 2018
Neuhaus J, Bauer F, Fitzner C, Hilgers RD, Seibert F, Babel N, Doevelaar A, Eitner F, Floege J, Rauen T, Westhoff TH
(See online at https://doi.org/10.1159/000494442)
