Research Daniel Abramowicz

Abstract

Kidney transplantation is the treatment of choice for patients with end-stage renal disease. However 15% of the transplanted patients develop acute kidney rejection: T-cell mediated rejection (TCMR) or antibody-mediated rejection (ABMR). At the other end of this spectrum, exceptional patients maintain a prolonged allograft function without rejection after the discontinuation, either through noncompliance or medically-driven, of all immunosuppressive drugs. These patients are designated as "operationally tolerant" in reference to the lack of immune allo-reponse. This condition is extremely rare, as only 0.03% of kidney recipients was proven to be tolerant in a recent European-wide survey. MicroRNAs (miRNA) are non-coding RNAs with a central role in cell biology by binding to complementary target mRNAs, resulting in translational inhibition or degradation. Furthermore miRNAs form complexes with RNA binding proteins protecting them from RNAse-dependent degradation. As a consequence, miRNAs are highly stable in both plasma and urine. Several miRNAs have been suggested to be involved in the pathophysiology of TCMR, ABMR and tolerance. Given their role in pathophysiology, in vivo modulation of miRNA expression as a therapeutic strategy is widely explored in chronic kidney disease (CKD), like autosomal dominant polycystic disease and Alport syndrome. Currently, trials with miRNA targeting therapy in the field of transplantation have not entered the clinical phase yet. However, recent work on miRNA in kidney transplantation in humans, both in the pathophysiology and biomarker field, provides evidence for the therapeutic potential of miRNA targeting therapies. In this prospective, longitudinal observational clinical study we will investigate the role of miRNA in the development of acute rejection (both TCMR and ABMR) as well as the induction of tolerance after kidney transplantation. Pilot experiments with 28 kidney transplant patients confirmed the feasibility of isolating miRNA from plasma and kidney tissue. miRNA was sequenced with a NGS approach at Oxford Genome Centre. Unravelling the clinically relevant pathophysiological pathways might represent novel preventive and therapeutic targets. Besides, the comparison of miRNA profiles in both tolerogenic patients and rejection adds a scientifically interesting perspective at the extremes of the immune reaction towards a graft. In this project, we start from clinically relevant miRNA profiles in three groups of kidney transplant patients: rejection, matched stable graft patients and tolerant patients. Therefore, we intend to expand the discovery cohort data firstly and confirm the profiles found in a validation cohort secondly; while in parallel we will try to unravel the pathophysiological pathways involved in an experimental set-up.

Researcher(s)

• Promoter: Abramowicz Daniel

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

Kidney transplantation is the treatment of choice for patients with end-stage renal disease. Rejection of the transplant organ remains a major obstacle in organ survival. Histological evaluation of a kidney biopsy remains the gold-standard diagnostic tool in the detection of a rejection episode but is an invasive, costly and labour-intensive procedure. Therefore, there is a critical need for non-invasive detection and prediction methods. Donor-derived cell free DNA (ddccfDNA), present in the blood and urine of the recipient after transplantation, is a potential biomarker of allograft health. An increase in the ddccfDNA fraction might point to damage to the graft. In a prospective, longitudinal clinical trial with renal transplant recipients, we will investigate whether ddccfDNA can be used as a routine marker of allograft health by measuring the ddccfDNA fraction in blood and urine with a novel, cost effective and universal technique (non-invasive organ transplant test, NIOTT). Preliminary analysis from plasma samples of 28 recipients demonstrate the feasibility of the study protocol, the cfDNA extraction and the NIOTT methodology. In this project we will further optimise the NIOTT accuracy by use of donor DNA and the protocol to extract ddccfDNA from urine samples. After inclusion of all patients, we will investigate the ddccfDNA kinetics after transplantation in recipients with stable graft function and in transplant recipients with graft associated pathologies.

Researcher(s)

• Promoter: Abramowicz Daniel
• Co-promoter: Bosmans Jean-Louis
• Co-promoter: Ledeganck Kristien
• Fellow: Gielis Els

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

More than half of the patients with chronic renal failure decease from cardiovascular disease. Since prevention of end-stage renal failure and its concomitant vascular damage remains one of the main goals in the search for methods to improve the outcome of these patients, it is important to define biomarkers for early diagnosis of vascular damage in end stage renal failure, and to identify components that can slow down and/or stop the evolution towards end stage renal failure. Therefore at the time of the identification of the candidate (predictive) biomarkers, samples of patients in the different stages of renal failure (CKD 2 to 5), of patients with renal replacement therapy (hemodialysis (HD) and peritoneal dialysis (PD) should be available, The individual patient can act as his own control in the progression of renal failure. Therefore, we wish to collect an additional blood sample, together with an additional sample from the 24h urine collection and/or the dialysate/PD-effluent in all patients who present themselves at the service of nephrology. This additional sampling will be performed as follow-up, yearly for three years. By the creation of a biobank with data of our own patients will enable us in the future be able to respond quickly to new developments in the field of new biomarkers for the progression of kidney failure and early diagnosis of vascular disease, and whether or not to confirm their value in an independent patient population. The currently routinely collected clinical data (regardless of participation in the study) will be collected in parallel in a central database.

Researcher(s)

• Promoter: Abramowicz Daniel

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project