Targeting complement activation in brain-dead donors improves renal function after transplantation

Abstract Background and Aims Ischemia-reperfusion (I/R) damage is a relevant cause of delayed graft function (DGF). Complement activation is involved in experimental I/R injury, but few data are available about the expression of the complement cascade final component -membrane attack complex (MAC)- and I/R injury in KT patients. We studied the dynamics of membrane attack complex (MAC) as plasma fraction (pMAC) and the histological deposit pattern of C3b, complement factor H (FH) and MAC in DGF patients. Method We evaluated pMAC levels in 59 recipients, 38 with immediate graft function and 21 without serum creatinine decreased at day 7 (DGF). pMAC was measured at admission for KT (day 0) and 7 days after KT (day 7). Sandwich ELISAs were used to measure MAC. Additionally, we performed imunohistoquimical stained for MAC, C3b and kidney biopsies (KB) with DGF (n=12) and a control group of one-year protocol biopsies without damage (n=4) Results Patients in the DGF group were older, more frequently diabetics and received kidneys from older donors and more frequently controlled cardio-circulatory death type. Day0 and day7 post-KT pMAC levels were similar in non-DGF patients 5902±3049 mAu/L vs 6178±2882 mAu/L; p=0.686). However, patients with DGF showed a significant increase of pMAC levels between day0 and day7 (6621±2202 mAu/L vs 9625±4142 mAu/L; p=0.006. Figure 1 Percentage pMAC levels increase (Δ0-7 pMAC%) discriminative assessment analyzed by ROC curve showed a good discriminative value for DGF with an AUC of 0.78; p<0.001 (sensitivity 81%, specificity 66% by cut-off point of 5%). In patients with DGF longer than ten days, we found more frequently patients with a Δ0-7 pMAC >5% (83% vs 17% Δ0-7 pMAC <5% ; p=0.003).Patients with DGF showed renal function at 3 and 6 months, but worse renal function 1 year after KT (serum creatinine 1.78±0.61 vs 1.35±0.30 mg/dl in non-DGF patients). DGF patients with Δ0-7 pMAC >5% displayed worse renal function 1 and 2 year after KT compared to DGF patients with Δ0-7 pMAC <5%. MAC, C3b and FH stains were observed in tubular epithelial cells basal membrane. DGF-kidney biopsies showed more frequently high-intensity stain for MAC and FH than controls, without differences to C3b stain. DGF-kidney biopsies also showed a higher number of tubules with positive stain and larger perimeter of tubules with positive stains for MAC, C3b and FH than the controls. Figure 2. Among the 12 patients with DGF-biopsies, three (25%) never recovered renal function, all of them presented Δ0-7 pMAC >5% and intense, diffuse and positive staining in more than 50% of tubular perimeter for MAC, FH and C3b Conclusion Complement activation during peritrasplant period could be related with the severity of graft injury and the presence of DGF. Therefore, the determination of MAC levels could be useful to identify patients with possible complement dependent graft injury that might benefit from complement inhibitor therapies

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Donor dopamine treatment in brain dead rats is associated with an improvement in renal function early after transplantation and a reduction in renal inflammation

Transplant International ◽

10.1111/j.1432-2277.2008.00725.x ◽

2008 ◽

pp. ???-??? ◽

Cited By ~ 4

Author(s):

Simone Hoeger ◽

Anke Reisenbuechler ◽

Uwe Gottmann ◽

Fabian Doyon ◽

Claude Braun ◽

...

Keyword(s):

Renal Function ◽

Renal Inflammation ◽

Brain Dead

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SERUM ANGIOPOIETIN 1 AND 2 ARE ELEVATED IN DECEASED BRAIN DEAD DONORS AND PREDICT RENAL FUNCTION AFTER TRANSPLANTATION.

Transplantation Journal ◽

10.1097/01.tp.0000332316.08432.6d ◽

2008 ◽

Vol 86 (Supplement) ◽

pp. 174

Author(s):

H Leuvenink ◽

L Koudstaal ◽

M Nijboer ◽

H Burgerhof ◽

V Nieuwenhuijs ◽

...

Keyword(s):

Renal Function ◽

Brain Dead ◽

Angiopoietin 1

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Prednisolone has a positive effect on the kidney but not on the liver of brain dead rats: a potencial role in complement activation

Journal of Translational Medicine ◽

10.1186/1479-5876-12-111 ◽

2014 ◽

Vol 12 (1) ◽

pp. 111 ◽

Cited By ~ 15

Author(s):

Rolando Rebolledo ◽

Bo Liu ◽

Mohammed Z Akhtar ◽

Petra J Ottens ◽

Jian-ning Zhang ◽

...

Keyword(s):

Complement Activation ◽

Brain Dead ◽

Positive Effect

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Urinary properdin excretion is associated with intrarenal complement activation and poor renal function

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfp630 ◽

2009 ◽

Vol 25 (4) ◽

pp. 1157-1161 ◽

Cited By ~ 18

Author(s):

M. A. Siezenga ◽

R. N. van der Geest ◽

M. J. K. Mallat ◽

T. J. Rabelink ◽

M. R. Daha ◽

...

Keyword(s):

Renal Function ◽

Complement Activation ◽

Poor Renal Function

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Effects of Terlipressin on Management of Hypotensive Brain-Dead Patients Who are Potential Organ Donors: A Retrospective Study

Frontiers in Pharmacology ◽

10.3389/fphar.2021.716759 ◽

2021 ◽

Vol 12 ◽

Author(s):

Donghua Zheng ◽

Genglong Liu ◽

Li Chen ◽

Wenfeng Xie ◽

Jiaqi Sun ◽

...

Keyword(s):

Renal Function ◽

Retrospective Study ◽

Liver Function ◽

Estimated Glomerular Filtration Rate ◽

Organ Procurement ◽

Venous Pressure ◽

Organ Donors ◽

Hemodynamic Stability ◽

Norepinephrine Dose ◽

Brain Dead

Background: Administration of terlipressin can reverse hypotension in potential organ donors with norepinephrine-resistance. The aim of this study was to determine the effects of terlipressin on the hemodynamics, liver function, and renal function of hypotensive brain-dead patients who were potential organ donors.Methods: A retrospective study was conducted by using the ICU database of one hospital. 18 patients in a total of 294 brain-dead cases were enrolled and administered terlipressin intravenously. All physiological parameters of recruited patients were obtained at baseline, 24 and 72 h after administration, and immediately before organ procurement.Results: Terlipressin induced significant increases in mean arterial pressure (MAP) from 69.56 ± 10.68 mm Hg (baseline) to 101.82 ± 19.27 mm Hg (immediately before organ procurement) and systolic blood pressure (SBP) from 89.78 ± 8.53 mm Hg (baseline) to 133.42 ± 26.11 mm Hg (immediately before organ procurement) in all patients. The increases in MAP were accompanied by significant decreases in heart rate (HR) from 113.56 ± 28.43 bpm (baseline) to 83.89 ± 11.70 bpm (immediately before organ procurement), which resulted in the decrease of norepinephrine dose over time from 0.8 ± 0.2 μg/kg/min (baseline) to 0.09 ± 0.02 μg/kg/min (immediately before organ procurement). There were no changes in central venous pressure, liver function including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin. Renal function, assessed by serum creatinine (SCr), urine output (UOP), creatinine clearance rate (CCr), and estimated glomerular filtration rate (eGFR), improved significantly.Conclusion: Our analysis of brain-dead patients with hypotension indicates that administration of terlipressin can significantly increases MAP, SBP, UOP, CCr, and eGFR, while decreases HR and Scr. Terlipressin appears to help maintain hemodynamic stability, reduce vasoactive support, and improve renal function.

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