We propose clonal deletion— immunization followed by deletion —as a "new" way to achieve tolerance. Immunization of a donor results in specific stimulation of a clone of cells, which can then be killed by various agents, leaving the patient otherwise immunologically normal. The theory of clonal deletion is supported by experimental evidence as well as earlier experiences with kidney transplants and donor - specific transfusions. To date, 22 patients who underwent clonal deletion have been surviving for 1.5 to 2.5 years with only low -dose prednisone. In addition, those patients who required conventional immunosuppressive drugs were treated with the new Drugs Added When Needed (DAWN) protocol. With DAWN as a tactic ready for intervention, and by using antibodies to monitor the completeness of clonal deletion, we assure that patients are subjected to the minimal amount of drugs on a personalized basis. We suggest that risks involved in testing this new procedure are small and the benefits immeasurable.
O'Leary JG, Kaneku H, Susskind BM, Jennings LW, Davis GL, Klintmalm GB, Terasaki PI
In the American Journal of Transplantation, Stegall and colleagues outline a new road to improving allograft survival in renal transplant patients. They make the argument that "rather than searching for new and better de novo immunosuppressive agents, we need to focus more on improving long term follow-up." Dr Stegall suggests "a combination of serum tests (DSA levels and polyoma virus testing) and protocol biopsies" should be used to identify the patients at highest risk of allograft loss. Once these highest risk patients are identified changes in immunosuppression and monitoring may be means to do something that hasn't been done in the 40+ year history of transplantation - significantly improve the rate of allograft loss after the first year post transplant.
Amico P, Hönger G, Mayr M, Steiger J, Hopfer H, Schaub S
The cumulative incidence of AMR (clinical and subclinical) at day 200 post-transplant in patients with preformed DSA was 55%, significantly higher compared to 6% in patients without preformed DSA. Five-year graft survival was significantly worse in patients with preformed DSA who also had AMR, compared to patients without preformed DSA and patients with preformed DSA without AMR (68% vs. 89% vs. 87%, p=0.002).
Fortheringham J, Angel C, Goodwin J, Harmer AW, McKane WS
Patients with de novo DSA after renal transplantation showed significantly higher rates of acute rejection (74% vs. 41%), more graft losses (29% vs. 9%), lower glomerular filtration rate (GFR) at the time of antibody detection (31.8 ml/min/1.73m2 vs. 44.1 ml/min/1.73m2) and lower 3-year allograft survival (69.5 vs. 91.1%) than patients with NDSA. The GFR decline was -5.85 ml/min/1.73m2/year in DSA patients, which was significantly higher than the -3.21 ml/min/1.73m2/year and the -0.08 ml/min/1.73m2/year for the control patients. In regards to proteinuria, 45% of DSA positive patients had more than 3 g/L of protein in urine at the time of antibody detection compared to only 3% in NDSA positive patients.
Lefaucheur C, Suberbielle-Boissel C, Hill GS, Nochy D, Andrade J, Antoine C, Gautreau C, Charron D, Glotz D
CDC-XM negative patients with preformed DSA detected by ELISA showed a 9-fold higher incidence of AMR than patients without DSA. Eight-year graft survival is significantly lower in patients with preformed DSA compared to patients without preformed DSA (67.9% vs. 77.3%, p=0.03), and this difference was even more significant if patients with DSA and AMR were analyzed separately from patients with DSA and no AMR (43.6% vs. 78.5%). Patients with DSA and no AMR have similar graft survival compared to patients without preformed DSA.
Loupy A, Suberbielle-Boissel C, Hill GS, Lefaucheur C, Anglicheau D, Zuber J, Martinez F, Thervet E, Mejean A, Charron D, Duong van Huyen JP, BrunevalP, Legendre C, Nochy D
CDC-XM negative patients with preformed DSA have significantly higher rates of AMR compared with DSA negative patients (19% vs. 0%, p<0.001), and also exhibit significantly lower 4-year graft survival (86.2% vs. 96.2%, p=0.01)
Gupta A, Iverson V, Varagunam M, Bodger S, Sinnott P, Thuraisingham RC
The presence of preformed DSA had no impact on delayed graft function, incidence of AMR or one-year graft survival, but a tendency toward lower 5-year graft survival was seen. A multivariate analysis demonstrated a six-fold increased risk of graft failure in DSA positive patients.
Singh N, Djamali A, Lorentzen D, Pirsch JD, Leverson G, Neidlinger N, Voss B, Torrealba JR, HofmannRM, Odorico J, Fernandez LA, Sollinger HW, Samaniego M
Sixty-seven percent of negative CDC-XM had detectable DSA using single antigen beads with a low cutoff and showed lower AMR-free survival compared to DSA negative patients.