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Abstract :
[en] Kidney transplant long-term outcome relies on numerous factors out of which several occur during the first year after transplantation. It is also during this phase that most of the treatment options are decided. With progresses of immunosuppression, a lot of the immune related injuries have become clinically silent which, nowadays, still implies that a surveillance biopsy (SB) is performed for the diagnosis of subclinical rejection (SCAR). Moreover those improvements in controlling the alloimmune response together with less stringent criteria for acceptance of both recipients and donors have led to a growing complexity of performing the diagnosis for acute transplant kidney dysfunction. Here also, obtaining a transplant biopsy remains the gold standard for evaluating the causes of acute renal dysfunction, but the diagnostic yield of this procedure has decreased due to a raising proportion of those for-cause biopsies (fcB) revealing no signs of rejection (defining what is called acute dysfunction with non rejection or ADNR).
This work concentrates on the lessons learned from both the SB and the fcB during the first year post kidney transplantation under modern immunosuppression.
In the first part of this analysis, we have evaluated the incidence, causes and consequences of ADNR. We have shown that this polymorphic entity is quite frequent in our practice with an incidence rate of 72%. As a group, ADNR is associated with lower estimated glomerular filtration rate (eGFR) at one year post-transplantation. Moreover a higher proportion of patients with ADNR present with fast declining eGFR from 12 to 24 months post transplantation (a surrogate marker for future graft loss).
The second part of this thesis is a critical evaluation of our clinical protocol of SB driven-steroid withdrawal concentrating on safety, efficiency and usefulness of the process. The serious adverse event-rate post-SB was 2.8%, out of which 0.4% necessitating invasive procedures. Out of an initial cohort of 502 kidney transplants, 481 were analyzed. SB revealed signs of SCAR (including borderline changes) in 27% of cases. Per-protocol SW was achieved in 35% of patients, an extra 10% of SW were performed either without SB (8%) or despite a SCAR (2%). Late biopsy proven acute rejection (BPAR) rates were respectively of 6%, 8% and 22% in these 3 groups. We have also identified sub-clinical antibody-mediated rejection as an independent risk factor for late BPAR in this cohort. The SB-driven SW strategy was associated with both total and death-censored long-term outcome; the per-protocol SW group showing one of the best kidney transplants longevity.
There is a need non-invasive markers of acute rejection because kidney biopsy is an invasive procedure with relatively low yield both in the settings of acute dysfunction or as part of a systematic surveillance strategy. The last part of this work was dedicated to the validation of 18F-FDG PET-CT as a non-invasive marker of acute rejection. In a first pilot study on 32 patients, it was compared to the results of a concomitant fcB. The standardized mean uptake value (SUV) was shown to correlate with the inflammation within the kidney as scored by the Banff classification. Moreover, a mean SUV above a threshold of 1.6 had a negative predictive value (NPV) of 100% for BPAR, thereby providing an attractive tool to rule out the necessity of performing a biopsy when faced with acute renal dysfunction. In a second analysis, the ability of 18F-FDG PET-CT to pick-out SCAR was tested in a cohort of 92 SB with similar encouraging results, the NPV reaching 98% in this case.
In conclusion, we have shown that individualized adaptation of immunosuppression taking into account the degree of alloimmune response is feasible and safe. However, it necessitates an invasive procedure that could frequently be avoided provided we could rely on non-invasive markers of rejection. Based on our work, 18F-FDG PET-CT stands out as a potential candidate for such an “iconomarker” to guide decision-making prior to biopsy. As a future perspective of this work, we propose to confirm these findings in a prospective randomized controlled trial comparing our current protocol of SB-driven SW with an iconomarker-based strategy of SW.
