The effect of genetic polymorphism in complement proteins on clinical renal transplant outcome

Lead Research Organisation: Newcastle University
Department Name: Institute of Cellular Medicine

Abstract

The number of people with kidney failure is increasing, with a 7% per year rise in patients on dialysis. For the majority of these patients the best treatment is kidney transplantation. Unfortunately the demand for transplant kidneys exceeds the number available and the transplant waiting list increases yearly. This situation is made worse by a steady rate of transplant failure requiring a return to dialysis or another transplant.
There is increasing evidence that modifying drug treatment can slow the progression of damage to a transplanted kidney. Unfortunately we are often late to recognise that damage is occurring at which point there may already be significant irreversible renal damage. Ideally we would be able to identify patients at risk at an early stage, prior to the development of significant damage, and alter treatments at this point. The main objective of this proposal is to develop a method by which risk of later problems can be predicted at the time of transplantation.
Studies have shown that differences between individuals at a genetic level can influence the outcome after transplantation. However, this work has yet to translate into improvements in patient care. We plan to use these genetic differences to predict the course of patients following kidney transplantation and to identify those patients at high or low risk of problems leading to graft damage. This would allow us to alter the intensity of monitoring and even use drug treatments to prevent damage developing. The work proposed in this application will define how powerful this type analysis can be and therefore form the basis of future clinical trials in this area.

Technical Summary

Transplantation is the best treatment for patients with stage 5 chronic kidney disease, but is limited by the availability of donor organs and by failure of the kidney after transplantation. Chronic allograft injury (CAI) is the main cause of kidney loss after the first year. The aetiology of CAI is incompletely understood but is likely to be multifactorial including immune and non-immune factors. There is increasing recognition that complement activation causes graft injury at several stages post transplant and that complement proteins synthesised within the kidney may be most important.
We have recently shown in a study of over 600 kidney transplant donor?recipient pairs that a single polymorphism of C3, the pivotal component of the complement cascade, strongly influences the incidence of CAI and long-term transplant outcome. The polymorphism C364G, designated C3F, when present in the donor kidney, is associated both with better graft function and survival. The next phase of this work is to translate this important observation into a clinically useful system that can screen donor and recipient DNA pre-transplantation to help predict long term graft outcome. In this way risk of CAI could be stratified, identifying high-risk individuals allowing treatment regimes to be altered to increase graft survival.
Specifically we propose to:
1. Develop a robust system for screening for multiple SNPs complement genes that can be applied to clinical material.
2. Use this system to identify other SNPs and SNP haplotypes in the main complement proteins that independently affect kidney allograft outcome. These may modify the predictive value of C345G allowing more accurate stratification of CAN risk. This may also increase our understanding of the mechanism by which these SNPs alter graft outcome.
3. Combine this data with other factors known to influence graft outcome to further stratify patients into levels of risk of graft loss.
4. Establish a prospective study to use the screening system developed to demonstrate the feasibility of grouping transplants into risk categories that may influence graft outcome.
At the end of this study period we would expect to have a method for identifying complement SNPs that influence graft outcome, know the magnitude of their effect and be able to use this data to predict clinical outcome. We would expect to demonstrate that this can be used in clinical transplantation and form the basis of a major prospective study including alteration of treatment regimes.

Publications

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Brown JH (2012) Postpartum aHUS secondary to a genetic abnormality in factor H acquired through liver transplantation. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

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Hernandez-Fuentes MP (2018) Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

 
Title Multiplex system to type complement gene SNPs 
Description Rapid, high throughput method to type 505 SNPs spanning complement genes 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact Ongoing research collaboration. Has been used in other populations/cohorts. 
 
Title Renal transplant DNA collection 
Description Approximately 1000 donor and recipient DNA samples. his is already being used in one other collaborative project 
Type Of Material Biological samples 
Provided To Others? No  
Impact DNA samples to be supplied to WTCCC3 study. Paper now in preparation. led to further input into WTCCC3 
 
Title Statistical analysis of the effect of interaction between SNPs in transplant donor and recpient 
Description Statistical technique development 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Ongoing analysis of SNP analysis data 
 
Description Investigation of complement polymorphism in atypical haemolytic uraemic syndrome 
Organisation European Hopital Georges Pompidou
Country France 
Sector Hospitals 
PI Contribution Use of the method of multiplex typing complement gene SNPs
Collaborator Contribution Identification of genes that contribute to susceptibility to atypical HUS
Impact Identification of new polymorphisms. Validation of results in progress.
Start Year 2009
 
Description UK & Ireland Renal Transplant Consortium (UKIRTC) 
Organisation King's College London
Department MRC Centre for Transplantation
Country United Kingdom 
Sector Academic/University 
PI Contribution Group of transplant centres within the UK assembled to co-ordicnate and develop genetic studies in transplantation in the UK. Partner.
Collaborator Contribution Ongoing research collaboration.
Impact WTCCC genome wide association study on transplant outcome.
Start Year 2009
 
Description Presentation to Kidney Patients Association 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Informal visit and presentations

Increaing patient awareness of research.
Year(s) Of Engagement Activity 2009