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. 2019 Oct 27;8(6):95-108.
doi: 10.5527/wjn.v8.i6.95.

Complement activation and long-term graft function in ABO-incompatible kidney transplantation

Marit S van Sandwijk  1 , Astrid Klooster  2 , Ineke Jm Ten Berge  3 , Arjan Diepstra  2 , Sandrine Florquin  4 , Joris J Hoelbeek  4 , Frederike J Bemelman  3 , Jan-Stephan Sanders  5
Affiliations

Complement activation and long-term graft function in ABO-incompatible kidney transplantation

Marit S van Sandwijk et al. World J Nephrol. .

Abstract

Background: ABO-incompatible and ABO-compatible kidney transplantation are equivalent in terms of short-term graft and patient survival. This is thought to be the result of ABO-incompatible graft accommodation, which occurs when anti-blood group antibodies re-occur after transplantation but somehow do not yield their detrimental effect. The underlying mechanism is unclear, but one of the hypotheses is that this is the result of complement inhibition. Since virtually all ABO-incompatible graft biopsies are C4d positive, this complement inhibition must occur somewhere in the complement cascade after the formation of C4d has already taken place, but where exactly is unclear. It is also unclear whether complement inhibition is complete. Incomplete accommodation could explain why recent studies have shown that long-term graft function in ABO-incompatible transplantation is somewhat inferior to ABO-compatible kidney transplantation.

Aim: To unravel the relationship between pre-transplant anti-ABO antibodies, complement activation, and long-term graft function.

Methods: We included all 27 ABO-incompatible transplantations that were performed between 2008 and 2013 at the Academic Medical Center Amsterdam and the University Medical Center Groningen. For each ABO-incompatible transplantation, we included four ABO-compatible controls matched by age, sex, and transplantation date.

Results: Graft and patient survival were not significantly different. The slope of kidney function during five-year follow-up was also not significantly different, but ABO-incompatible recipients did have a lower kidney function at three months (creatinine clearance 58 vs 69 mL/min, P = 0.02, Modification of Diet in Renal Disease 46 vs 52 mL/min/1.73 m2, P = 0.08), due to a high rate of early rejection (33% vs 15%, P = 0.03), mostly T-cell mediated. Pre-transplant anti-ABO IgG titers were positively correlated with C5b-9 staining, which itself was positively correlated with the occurrence of T-cell mediated rejection. This may be the result of concurrent C5a formation, which could function as a costimulatory signal for T-cell activation.

Conclusion: Co-stimulation of T-cell activation by ongoing complement activation by anti-ABO antibodies may be responsible for an impaired long-term graft function in ABO-incompatible kidney transplantation.

Keywords: ABO-incompatible; Complement; Graft function; Kidney transplantation; Rejection.

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Conflict of interest statement

Conflict-of-interest statement: All authors declare no potential conflicts of interest.

Figures

Figure 1
Figure 1
Tacrolimus trough levels. Tacrolimus trough levels at 2 wk, 6 wk, 3 mo, and 1 year after transplantation.
Figure 2
Figure 2
Kidney function. A: Estimated glomerular filtration rate (Modification of Diet in Renal Disease) without imputation in case of graft loss; B: Estimated glomerular filtration rate (Modification of Diet in Renal Disease) with imputation of 10 mL/min/1.73 m2 in case of graft loss; C: Creatinine clearance without imputation in case of graft loss; D: Creatinine clearance with imputation of 10 mL/min/1.73 m2 in case of graft loss. Curves were estimated using linear mixed models. The dots indicate point estimates at 3, 6, 12, 24, 36, 48 and 60 months. CrCl: Creatinine clearance; MDRD: Modification of Diet in Renal Disease.
Figure 3
Figure 3
Patient and graft survival. A: Patient survival; B: Death-censored graft survival.
Figure 4
Figure 4
Rejection-free survival and kidney function split by occurrence of rejection. A: Rejection-free survival; B: Estimated glomerular filtration rate (Modification of Diet in Renal Disease). P value calculated for intercept of ABO-i recipients with rejection (black line) compared to all other groups.
Figure 5
Figure 5
Complement activation in ABO-incompatible. A: Complement activation in ABO-incompatible indication biopsies; B: Complement activation in ABO-incompatible protocol biopsies; C: Digital photographs of complement activation. Intensity of staining ranges from 0-3. Figures indicate the percentage of biopsies with each intensity score. Glom: Glomerular; PTC: Peritubular capillaries; BMt: Basal membrane of the tubuli.
See this image and copyright information in PMC

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