Projects / Programmes
Proteinuria and other noninvasive biomarkers for kidney allograft rejection
| Code |
Science |
Field |
Subfield |
| 3.06.00 |
Medical sciences |
Cardiovascular system |
|
| Code |
Science |
Field |
| B500 |
Biomedical sciences |
Immunology, serology, transplantation |
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
kidney transplantation, allograft rejection, urine protein excretion, noninvasive biomarkers of rejection
Researchers (13)
Organisations (2)
Abstract
Kidney allograft rejection undermines the full benefits of kidney transplantation. Rejection can be classified as T-cell-mediated (cellular) or antibody-mediated (humoral). Humoral rejection is becoming a leading cause of graft failure. A rejection episode is diagnosed by means of needle biopsy. This invasive procedure has become safer. Nevertheless, bleeding and subsequent graft loss still occurs, and inter-observer variability in biopsy reading remains problematic. The main indication for biopsy is allograft dysfunction. A noninvasive screening that foretells rejection before loss of kidney function is clinically detectable would be advantageous. In addition, noninvasive biomarkers should discriminate between cellular and humoral rejection that are associated with different treatment strategies and prognosis.
Epidemiological studies have suggested that increased urinary protein excretion (proteinuria) is associated with grater risk for graft failure. Greater permeability for plasma proteins in glomerular capillaries and tubular cell injury results in increased urinary protein excretion. Immune-mediated injury in allograft rejection can occur in the glomeruli, tubulo-interstitial and arterial compartment and would hypothetically result in subtle changes in urine protein excretion before substantial deterioration of kidney function occurs.
Previous studies showed that great majority of indication-based biopsies manifest phenotypic features of rejection. To differentiate between allograft rejection and other proteinuric conditions other potential biomarkers may be used. Major role in the pathogenesis of antibody-mediated rejection have donor-specific human leukocyte antibodies. These antibodies may activate complement and the terminal complement complex C5b-9 can be detected in the urine. Secondary to antibody-mediated injury, glomerular epithelial cells – podocytes may also appear in the urine. More recently, antibodies against angiotensin type II and endothelin receptors on endothelial cells have been implicated in humoral rejection.
The purpose of the research project is to assess diagnostic accuracy of proteinuria in association with other potential biomarkers of immune function in urine and serum to:
1. Noninvasively predict rejection episode before kidney graft dysfunction occurs.
2. Differentiate between cellular and humoral rejection that are associated with different treatment strategies and outcomes.
The predictive role and diagnostic accuracy of proteinuria in association with other noninvasive biomarkers of kidney allograft rejection will be assessed in a (1.) historic cohort and (2.) prospective validation study.
(1.) A historic cohort study is designed to retrospectively investigate whether spot urine protein excretion was predictive of allograft rejection in a national cohort of kidney transplant recipients between January 2000 and December 2012. We hypothesize that a sequential increase in proteinuria obtained in regular outpatient screening of kidney transplant recipients foretells allograft rejection and its phenotype.
(2.) The objective of a prospective part of the research project is to validate proteinuria in association with other biomarkers of immune function in urine and serum as predictors of kidney allograft rejection and its phenotype. A validation part of the research project is designed as a prospective controlled study in recipients of a kidney transplant since January 2014. We hypothesize that with regular screening of the transplant recipients for variations in proteinuria in association with other urine and serum biomarkers, allograft rejection and its phenotype can be diagnosed before significant loss of kidney allograft function occurs.
A noninvasive screening that foretells rejection before loss of kidney function is clinically detectable might reduce rejection-associated allograft damage, and ongoing characterization of the immune status could help minimize the effects of insufficient
Significance for science
Measurements of urine protein excretion offers a potential novel noninvasive means of diagnosing rejection in the kidney allograft. In addition, the amount and type of proteins excreted in the urine (glomerular vs. tubular proteinuria) may differentiate between different rejection phenotypes. This is important, because cellular and humoral rejections are associated with different treatment strategies and long-term prognosis.
Because contemporary immunosuppressive drugs can effectively treat rejection episode, a noninvasive means of diagnosing this reversible cause of allograft failure would be advantageous. Furthermore, noninvasive screening that foretells acute rejection before loss of kidney function is clinically detectable might reduce rejection-associated graft damage, and ongoing characterization of the immune status could help minimize the effects of insufficient or excess immunosuppression.
Early diagnosis and treatment of rejection may improve long-term kidney allograft survival that has not improved substantially over the last decades.
Significance for the country
Early diagnosis of kidney allograft rejection, rejection phenotype, and timely treatment of rejection episode before irreversible rejection-associated graft damage is clinically detectable may increase long-term graft survival that has not improved substantially over the last two decades. Early diagnosis of rejection can prevent hospital admission of the patient or may decrease the number or length of hospitalisations. Timely treatment of rejection episode is also more effective, shorter and therefore less expensive. Finally, improved long-term graft outcomes have a significant economic benefit for the national health care system, because kidney transplantation is cost-effective when compared with dialysis.
Most important scientific results
Interim report,
final report
Most important socioeconomically and culturally relevant results
Interim report,
final report
