MOLECULAR MECHANISMS OF DELAYED KIDNEY GRAFT FUNCTION

D.K. Abendroth¹, M. Marzinzig¹, J. Kaden^2
1Zentrum Für Chirurgie, Universitätsklinik Ulm, Ulm/GERMANY, ²Renal Transplant Centre, Friedrichshain Hospital (formerly), Berlin/GERMANY

Body: Brain death is associated with cytokine release indicating inflammation, tissue injuries, hypoxia and immune activation. This initial immunoactivation is counterregulated by immunosuppressive acting metabolites of tryptophane via activation of Indoleamine 2,3 dioxygenase (IDO). High mobility group box 1 (HMGB1) is a nuclear factor (NF) released as an early mediator of repair, inflammation and destruction. IDO suppresses T-cell reactivity upregulated by the proinflammatory cytokines IFN-γ and TNF-α. In a retrospective study, we compared results of IDO and HMGB1 in renal transplantation to estimate their impact on immediate and long-term graft-function. Furthermore we evaluated the differences and effects concerning a polyclonal induction treatment (in the recipient) with ATG. Patients and Methods In a consecutive group of patients after renal transplantation (n=397) treated either with quadruple drug induction (QDT, n= 285; ATG-F, CsA, AZA, MP; mean age 42+11 y., duration of dialysis 41+23 months ) or triple drug (TDT, n=112; CsA, AZA, MP; mean age 43+13 y., duration of dialysis 24+14 months ) as immunosuppressive therapy were included in this analysis. Furthermore sera from 109 organ donors ( mean age 38,4+12 y.) could be evaluated. Results HMGB-1 was higher in donors with delayed renal function (DGF). HMGB1 was also higher in the first 3 weeks in patients showing DGF and was positive correlated (r²=0,718) to the days until creatinine felt < 200µmol/l (9,66+10 (PF) vs. 25,8+14 (DGF); p<.001). ATG-induction treatment decreased HMGB-1 significantly (p<.001) by - 87% (+11) compared to TDT with an increase of + 24% (+9). In 17 % of the donors IDO was elevated (+3s) indicating an inflammatory activation (brain death / infection). In contrast to IL-6 and CRP, IDO values rose permanently in relation to donor´s stay at the ICU. IDO showed excellent predictive values for rejection far prior increase of creatinine (median >4 days) as the gold standard. Furthermore, if IDO values were < 3s in the early postoperative period between 3 and 7 weeks, long-term function (10years) was significantly better (71% vs. 31%). Conclusion IDO elevation in brain death organ donors are indicating a functional counter-regulation of innate immune response without impact on postoperative graft function. In the recipient, there was an excellent correlation to rejection and long term-function. Elevated HMGB-1 in the donor as well as in the recipient might indicate the activated innate immune response and the grade of injury. Treatment of this activation is of benefit either concerning DGF or long-term function. These results are the proof of concept for the role of HMGB-1 as a predictive marker concerning graft injury and for IDO as a very important marker for rejection and long-term function. Donor (pre-) treatment should be the next step.

Disclosure: All authors have declared no conflicts of interest.