Clinical Operational Tolerance and Immunosuppression Minimization in Kidney Transplantation: Where Do We Stand?

Background: The 20th century represents a breakthrough in the transplantation era, since the first kidney transplantation between identical twins was performed. This was the first case of tolerance, since the recipient did not need immunosuppression. However, as transplantation became possible, an immunosuppression-free status became the ultimate goal, since the first tolerance case was a clear exception from the hard reality nowadays represented by rejection. Methods: A plethora of studies was described over the past decades to understand the molecular mechanisms responsible for rejection. This review focuses on the most relevant studies found in the literature where renal tolerance cases are claimed. Contrasting, and at the same time, encouraging outcomes are herein discussed and a glimpse on the main renal biomarkers analyzed in this field is provided. Results: The activation of the immune system has been shown to play a central role in organ failure, but also it seems to induce a tolerance status when an allograft is performed, despite tolerance is still rare to register. Although there are still overwhelming challenges to overcome and various immune pathways remain arcane; the immunosuppression minimization might be more attainable than previously believed. Conclusion: Multiple biomarkers and tolerance mechanisms suspected to be involved in renal transplantation have been investigated to understand their real role, with still no clear answers on the topic. Thus, the actual knowledge provided necessarily leads to more in-depth investigations, although many questions in the past have been answered, there are still many issues on renal tolerance that need to be addressed.

R-DHA-Oxaliplatin Versus R-DHA-Cisplatin Regimen in B-Cell Nhl's Treatment: A Eight Years Retrospective Study

Background: R-DHAP regimen (rituximab, cisplatin, dexamethasone, high dose cytarabine) based on the 1988 Velasquez's study is a standard scheme used to treat relapsed Non-Hodgkin lymphomas (NHL). Cisplatin is frequently substituted with oxaliplatin to avoid nephrotoxicity, resulting in R-DHAX that is currently prescribed in first or second line treatment for aggressive NHL. However data are scarce. We compared the nephrotoxicity of cisplatine to oxaliplatine in R-DHA-platinum in this setting. Methods: All consecutive patients with NHL treated by R-DHAP or R-DHAX in Angers hospital between the 1st January 2007 and the 31th December 2014 were included. Either cisplatin 100 mg/m2 during 24 hours (R-DHAP) or oxaliplatin 130 mg/m2 during 2 hours (R-DHAX) were associated at d1 with cytarabine (2000 mg/m2 during 3 hours, two doses, d 2), dexamethasone (40 mg, d 1-4) and rituximab (375mg/m2, d 1) (Details on table 1). Cisplatin dosage were reduced from 25% to 50% according to individual renal tolerance. Up to 6 courses were delivered. Serum creatinine was recorded before each course of chemotherapy and was checked between d3 and d15 after administration, allowing to trace individual profiles of trajectories for their levels. These trajectories were clusterized in order to detect the existence of homogeneous patterns of evolution. This is a classical, semiparametric group-based statistical approach (Ref 1). Concomitant nephrotoxic drugs and events (sepsis…) were recorded to identify potential bias. Results: 21 patients received R-DHAP and 32 received R-DHAX. 6 patients switched from R-DHAP to R-DHAX due to nephrotoxicity. 2 different homogeneous clusters appeared. Cluster A included a majority of R-DHAX: 31 R-DHAX (88.6%), 3 R-DHAP (8.6%), 1 R-DHAP who changed to R-DHAX (2.9%). Cluster B contained a majority of R-DHAP: 11 R-DHAP (64.7%), 1 R-DHAX (5.9%), 5 R-DHAP to R-DHAX (29.4%) (p = 7.5.10-9). Cluster A graphic profile appeared less toxic than cluster B according to average serum creatinine level (mean cluster A: 70.2 µmol/L; mean cluster B: 99.5 µmol/L (p = 2.2.10-16)). Patients treated with R-DHAP experienced more severe renal failure than patients treated with R-DHAX (Chi-square test: p = 2.9.10-8, table 2). Nephrotoxic concomitant treatments have no significant discriminant effect. No differences were observed between either R-DHAP versus R-DHAX or cluster A versus B patients, as regards to age, sex, malnutrition status, histology, stage of the lymphoma, performans status, comorbidities including renal comorbidities and the history of nephrotoxic therapy. No significant difference was shown in OS and EFS (respectively, p = 0.463 and p = 0.290). Conclusions: Although R-DHAX is now widely used in NHL treatment, our study is one of the first to evaluate efficacy and renal tolerance of this treatment. R-DHAX nephrotoxicity is not significant whereas most patients receiving R-DHAP had significant acute renal impairment. We found no difference as regards to survival. A prospective study should compare these schedules in NHL to adapt future practices and improve morbidity. Table 1. Patients characteristics Caractéristics DHAP DHAX Total Sex M 14 (66.7%) 23 (71.9%) 37 (69.8%) F 7 (33.3%) 9 (28.1%) 16 (30.2%) Age (years) Median (min-max) 61 (34-80) 61 (39-77) 61 (34-80) BMI < 18 0 0 0 18 to 25 9 (42.9%) 17 (53.1%) 26 (49.1%) > 25 12 (57.1%) 15 (46.9%) 27 (50.9%) Performans Status (N=49) PS > = 2 3 (17.6%) 2 (6.3%) 5 (10.2%) PS < 2 14 (82.4%) 30 (93.8%) 44 (89.8%) Comorbidities Renal 1 (4.8%) 3 (9.4%) 4 (7.5%) Cardiovascular 8 (38.1%) 13 (40.6%) 21 (39.6%) Other 12 (57.1%) 16 (50%) 28 (52.8%) More than 2 comorbidities 6 (28.6%) 9 (28.1%) 15 (28.3%) Histologie NHL low grade 5 (23.8%) 5 (15.6%) 10 (18.9%) NHL High grade 15 (71.4%) 25 (78.1%) 40 (75.5%) CLL 1 (4.8%) 2 (6.3%) 3 (5.6%) Ann Arbor Stage I 0 0 0 II 2 (9.5%) 2 (6.3%) 4 (7.5%) III 2 (9.5%) 2 (6.3%) 4 (7.5%) IV 16 (76.2%) 26 (81.3%) 42 (79.2%) Previous chemotherapy Nephrotoxic 2 (9.5%) 3 (9.3%) 5 (9.4%) Non nephrotoxic 17 (80.9%) 21 (65.6%) 38 (71.7%) Albumine blood level < = 30 5 (23.8%) 5 (15.6%) 10 (18.9%) LDH > N 11 (52.4%) 12 (37.5%) 23 (43.4%) Total 21 32 53 Table 2. Renal Failures grade R-DHAP R-DHAX No renal failure 13 (27.7%) 100 (74.6%) Renal Failure 34 (72.3%) 34 (25.4%) (Reference 1: Group-based trajectory modeling in clinical research, Nagin et al. Annu Rev Clin Psychol. 2010) Disclosures No relevant conflicts of interest to declare.