CONTEXT

In recent years, chronic kidney disease has received increased attention as a leading public health problem. Indeed, the adjusted incidence of end-stage renal disease is 100-200 per million population in the European region, leading to an incremental prevalence of respectively 800-1200 per million people in Europe in 2009.

For these patients with end-stage renal disease, despite the increased short-term peri-operative risk of death, transplantation has become the preferred treatment, now providing better patient survival than prolonged dialysis therapy, in both adults and children. This success of kidney transplantation is attributed to improvements in surgical techniques, donor selection and organ allocation procedures, prevention, identification and treatment of acute rejection episodes, management of post-transplant complications and better knowledge of immunosuppressive drug pharmacokinetics and pharmacodynamics.

In 2010, 18,246 renal transplantation procedures were performed in the European member states, 19.8% of which from living donors. Worldwide, the respective figures are 71,418 kidney transplantations and 46% from living donors.

Graft survival

In renal allograft recipients, graft survival at one year post-transplantation has improved to more than 95%. However, at 10 years, graft survival is only approximately 65-70%, with no major improvement with regards to the previous decade. Also, although acute rejection (AR) is a major risk factor for the development of chronic allograft nephropathy leading to graft loss, decreases in the incidence of AR in recent years have not translated into improved long-term outcomes. Both immune mechanisms (T-cell mediated and antibody-mediated rejection, de novo or recurrent glomerular disease, etc.) and non-immune mechanisms (nephrotoxicity of calcineurin inhibitors, accelerated aging, epithelial-mesenchymal transition, etc.) contribute to the progression of chronic histological damage and scarring of renal allografts. These injury processes jeopardize graft function and long-term graft survival. Because only a subset of patients develop chronic injury and because at present physicians do not have the ability to reverse chronic fibrotic kidney damage, it is essential that the transplant community develops reliable and noninvasive approaches to predict which patients are most likely to develop graft failure, so that appropriate interventions can be instituted before it becomes clinically apparent.

For many years, histological examination of kidney graft biopsies has been the gold standard to identify rejection and chronic tubular and interstitial lesions in transplanted patients. The Banff classification has been established to describe and classify elementary lesions leading to the diagnosis of borderline lesions, T-cell mediated rejection (TCMR), antibody-mediated rejection (AMR), interstitial fibrosis and tubular atrophy (IFTA). It is worth nothing that no clearly defined cause can be attributed to the majority of cases of IFTA. Indication biopsies are performed when there are clinical signs in favour of graft lesions, such as an increase in serum creatinine. Systematic biopsies at predefined post-transplantation periods, called protocol biopsies, have been developed since the 1980s to monitor the graft more closely and detect subclinical lesions. They are now used systematically in many transplantation centres worldwide. In fact, subclinical rejection has been identified in more than 30% and up to 45.7% of protocol biopsies at 3 months post-transplantation. The presence of subclinical lesions is associated with more intense interstitial fibrosis at 1 year and a worse graft function at 24 months. Protocol biopsies also allow monitoring the progression of IFTA lesions, CNI toxicity, BK virus infection or chronic antibody-mediated rejection, and identifying the recurrence of glomerulonephritis.

However, Banff histological grading needs adequate graft sampling, which is not achieved in up to 27 % of the biopsies. Moreover, about 25% of the biopsies cannot be classified properly (14). The characterization of borderline lesions represents an even greater problem, since up to 33% of the borderline lesions may be reclassified as TCMR and atrophy scarring may interfere with the assessment of inflammation and tubulitis. Studies on Banff scoring also showed that inter-operator reproducibility is weak (10), with a particular difficulty in grading tubulitis and interstitial fibrosis (16). Finally, this method is invasive and uncomfortable for the patients.

Currently, non-invasive monitoring of the transplanted kidney is based on the measurement of serum creatinine to estimate the glomerular filtration rate (GFR). However, patients with normal serum creatinine can undergo subclinical rejection, as it is only detectable after substantial injury of the graft. Also, the evolution of serum creatinine can be hectic in the long term.

Why is BioMargin important ?

There is an unmet need for better understanding of the mechanisms driving acute and chronic alloimmune injury, immunological quiescence, operational tolerance and tissue injury. There is also a need for robust, non-invasive methods to predict and diagnose acute and chronic graft lesions, to help avoid or diminish the use of invasive biopsies and/or to detect graft lesions earlier and with more accuracy, and thus improve patient treatment, quality of life and graft survival in the long term. Such methods will also diminish the need for second or third transplantations, thus reducing the number of patients on the waiting lists and/or the cost of end-stage renal disease treatment.
The different levels of biomolecular organization and control, such as regulation of the transcriptome, proteome and metabolome are interdependent and greatly affected by environmental events and stresses throughout life. Several teams have searched for biomarkers of renal graft lesions, but there has been no cross-fecundation of these different “omics” approaches, nor any consolidation of the different clusters of biomarkers discovered using different technologies. An analysis of these different omics levels based on the principles of systems biology, combined with biomarker localisation in the graft is therefore necessary to gain insight into the disease mechanisms and will help to develop predictors at the individual level. More specifically, the combination of validated biomarker clusters together with clinical and biological data should make it possible, through the use of disease-progression models, to stratify kidney graft recipients before 1 year post-transplantation, with regard to the risk of severe renal function deterioration or graft loss at 3 or 5 years. The prediction will be refined with every new individual data as time goes on. Early therapeutic interventions based on the anticipated risk and personalized pathway modulation should then be able to actually improve long-term graft survival and patients’ quality of life.