Kidney and Pancreas Transplantation and Organ Procurement Unit
Université Catholique de Louvain
What is the best immunosuppressive treatment in simultaneous pancreas–kidney transplantation (SPK)? Currently, SPK is the gold-standard therapy for type 1 diabetic patients with endstage nephropathy.(1) Vascularised pancreas transplantation is now widely performed in many major centres throughout Europe and the USA. Both the number of centres performing pancreas transplantation and the total number of pancreas grafts transplanted continue to increase with time. This article reviews the current status of immunosuppression in SPK and focuses on the best regimen used.
Over the past 40 years, the introduction of new agents and more effective immunosuppressive regimens and improvements in the diagnosis and treatment of rejection have resulted in a better short-term graft survival. The results in pancreas transplantation, as reported by the International Pancreas Transplant Registry (IPTR), have continued to improve since the first pancreas transplant was performed in 1966. In 1980, before the ciclosporin era, the IPTR reported a one-year graft survival of 21% for all pancreas transplants performed between 1966 and 1980. In the most recent data presented by the IPTR, one-year pancreas graft survival in the SPK group approached 85%. The one-year patient and kidney graft survival rate for this time period were respectively 95% and 92%, which is similar to the one-year cadaver kidney graft survival in nondiabetic recipients.(2)
Various groups have used different approaches with regard to induction and maintenance immunosuppressive therapy. Ideally, we should be able to give a specific immunosuppressive therapy for each patient based on his/her immune reactivity and on the toxic effects encountered from the different immunosuppressive agents.
Induction immunosuppressive therapy
Within the transplantation field, pancreas transplantation uses the most antilymphocyte antibodies. According to the IPTR report, the percentage of induction therapy with one or more of these agents each year from 1994 to 2003 in the SPK category ranged from 62% to 82%.(2)
The choice of which antilymphocyte antibody to use remains controversial. Currently, antilymphocyte antibodies are T-cell-depleting polyclonal (rabbit antithymocyte globulin: ATG-Fresenius(®) [Fresenius Biotech GmbH, Germany]; rabbit antithymocyte globulin: Thymoglobulin(®) [Genzyme, USA]; and horse antithymocyte globulin: Atgam [Pharmacia & Upjohn Company, USA]) or T-cell-depleting monoclonal (murine anti-CD3: Orthoclone OKT3(®) [Ortho Biotech Inc, USA]; Alemtuzumab: Campath-1H(®) (Genzyme, USA]) antibodies and nondepleting monoclonal antibodies (daclizumab: Zenapax(®) [F Hoffmann-La Roche Ltd, Switzerland]; and basiliximab: Simulect(®) [Novartis AG, Switzerland]).
A variety of studies comparing induction therapy with polyclonal and monoclonal antibodies have provided varying results, but overall the use of an induction therapy significantly diminishes the rejection rate.(3,4) Even if no prospective randomised study demonstrated an emerging treatment for induction, some works have recently focused on induction therapy (see Table 1).
A prospective, randomised, open-label, multicentre study focused on the effect of antibody induction therapy in SPK recipients.(5) The study, conducted in 18 US pancreas transplant centres, randomised 174 SPK recipients to induction (n=87) or non‑induction (n=87) groups. In the induction group, either T-cell-depleting (Thymoglobulin®) or -nondepleting antibodies (interleukin-2 receptor antibodies) were used. Maintenance therapy in both groups was with tacrolimus (Prograf(®) [Astellas Pharma Inc, Japan]), mycophenolate mofetil (MMF, Cellcept(®) [F Hoffmann-La Roche Ltd, Switzerland]) and steroids. At three years, actual patient survival rate (94% vs 90%) and pancreas graft survival rate (76% vs 76%) were similar between the two groups, but actual kidney survival rate was significantly higher in the induction group (92% vs 82%; p=0.04). Significantly higher rates of CMV infection occurred in the T-cell-depleting antibody induction subgroup (36%) compared with the anti-interleukin-2 receptor antibodies subgroup (2%) and the noninduction group (8%; p<0.0001). Therefore, this study concluded that decisions regarding the use of induction therapy must weigh the risk of kidney graft loss or rejection against the risk of infection.
Another prospective, randomised, multicentre study compared the safety and efficacy of two dosing regimens of daclizumab versus no antibody induction in SPK recipients maintained on tacrolimus, MMF and prednisone.(6,7) The study involved 24 US pancreas transplant centres and one Canadian centre. One group of 107 pancreas recipients received daclizumab at 1mg/kg every 14 days for five doses; one group (n=112) received 2mg/kg every 14 days for two doses, and another 78 recipients did not receive daclizumab.
At three years, no differences were noted in patient, pancreas and kidney graft survival rates among the three groups. The mean time to first acute rejection (AR) was delayed in groups 2 (288 days) and 1 (245 days) compared with group 3 (145 days, p=0.07). The cumulative incidences of AR were not statistically different. The alternative two-dose regimen of daclizumab was as safe and effective as the conventional five-dose regimen compared with no antibody induction in SPK patients, but no long-term benefits were noted.
At the University of Minnesota, a prospective nonrandomised observational study was conducted, using a combination of a depleting antibody (alemtuzumab) with an antimetabolite (MMF), avoiding calcineurin inhibitors (CNIs) and steroids altogether.(8,9) Seventy-five patients (20 SPK, 23 pancreas after kidney [PAK] and 32 pancreas transplant alone [PTA]) received alemtuzumab (four doses for induction, up to 12 doses within the first year) and MMF (>2g/day) for induction and maintenance therapy. Those recipients were compared with a historical control group comprising 67 SPK, 112 PAK and 87 PTA recipients on Thymoglobulin(®) (induction) and tacrolimus (maintenance). At six months, no differences in patient, pancreas and kidney graft survival rates or in graft loss from rejection were noted between the study group and the historical control group. The incidence of a first reversible rejection episode was higher in the study group (alemtuzumab and MMF) for SPK recipients (41%) than the historical control group (9%; p<0.0003) but not for PAK and PTA recipients. The authors concluded that this combination eliminates undesired CNI- and steroid-related side-effects, but a longer follow-up will be warranted before expanded application can be recommended.
At the Northwestern University of Chicago, a nonrandomised, retrospective, sequential study compared the efficacy of alemtuzumab (n=50) or Thymoglobulin(®) (n=38) induction in combination with a prednisone-free, tacrolimus and sirolimus (Rapamune(®) [Wyeth, USA])-based immunosuppression protocol.(10) Patient and graft survival rates did not significantly differ between patients treated with alemtuzumab and antithymocyte globulin. Rejection rates were also not different at one and two years. CMV infection rate was statistically significantly lower in the alemtuzumab group (6.5% versus 28%).
Maintenance immunosuppressive therapy
At present, maintenance immunosuppressive therapy consists a combination of either tacrolimus, the microemulsion formulation of ciclosporin (Neoral(®) [Novartis AG, Switzerland]), sirolimus, MMF and steroids. Long-term management schemes show more variation than short-term regimens.
Some authors advocate CNI-only: tacrolimus or ciclosporin, CNI–MMF, CNI–sirolimus, sirolimus–MMF, with or without prednisone, strategies. Although no data suggest a difference in outcome, there have been few randomised trials (see Table 1).
Corticosteroids were the first immunosuppressive agents used in solid organ transplantation, and they remain a cornerstone of many immunosuppressive regimens. A number of randomised, prospective trials of steroid withdrawal or avoidance have been performed.(10–13) However, the long-term benefits of steroid withdrawal protocols are still under scrutiny.
Almost all steroid regimens include a perioperative massive (250–1,000mg) dose of methylprednisolone to dampen graft tissue injury and reduce T-cell activation. During the immediate postoperative period, steroid doses are rapidly tapered from 200mg to 20–30mg per day, followed by a more gradual taper to 10–5mg between 30 and 90 days. With the advent of improved maintenance immunosuppression provided by the new drugs, it is likely that, in the future, safe steroid withdrawal will be possible in a greater proportion of patients.(10–13)
The introduction of ciclosporin in 1983 allowed the emergence of pancreas transplantation programmes. The development of the microemulsion formulation (Neoral(®)) resulted in a non-bile-dependent formulation with less intra- and interpatient variability and improved bioavailability.(14) The most popular strategy starts with 6–10mg/kg ciclosporin given as a twice-a-day regimen. The dose is adjusted on the basis of measured trough levels to achieve the target levels of 175–350ng/ml, measured with specific monoclonal antibodies.
The major disadvantage of tacrolimus has been a significantly higher incidence of new-onset insulin-dependent diabetes mellitus.(15) Nevertheless, although post-transplant diabetes mellitus was associated with an increased risk of graft failure, tacrolimus was associated with a significantly reduced risk for graft failure (RR 0.70, p<0.0001), death-censored graft failure (RR 0.72, p<0.01) and mortality (RR 0.65, p<0.001) compared with non-tacrolimus treatment.(16)
A large European multicentre study (EuroSPK 001 study with 10 European and one Israeli centres) compared the efficacy and safety of tacrolimus versus the microemulsion formulation of ciclosporin in 205 SPK recipients (103 recipients were randomised to tacrolimus and 102 to ciclosporin).(17,18) All recipients received four doses of rabbit anti-T-cell induction therapy, MMF and short-term corticosteroids. This study, which compared tacrolimus with ciclosporin, did not show any disadvantage of tacrolimus on the occurrence of post-transplant diabetes mellitus. Throughout the study, glycated haemoglobin and fasting C peptide levels were within the normal range in the two groups. Fasting blood glucose was higher during the first two months post-transplant in the tacrolimus group than in the ciclosporin group, but no differences were seen thereafter.(19) Concerning glucose metabolism and secretory capacity of the pancreas graft, no significant differences were found comparing tacrolimus- versus ciclosporin-treated graft recipients.(20)
That study showed a significantly higher pancreas graft survival rate with tacrolimus (91%) than ciclosporin (74%; p<0.0005). The difference in graft survival was caused by a significantly higher rate of graft thrombosis in the ciclosporin group. This finding can be attributed to high levels of ciclosporin within the first week post-transplant, a higher rate of biopsy-proven pancreas or kidney rejection for ciclosporin (38%) versus tacrolimus (27%; p<0.09) recipients, or a combination thereof. In addition, the conversion rate from ciclosporin to tacrolimus was significantly higher (33%) than from tacrolimus to ciclosporin (6%). In summary, that study showed better results with tacrolimus than ciclosporin.(17–20) The most popular strategy starts with 0.2mg/kg tacrolimus given as a twice-a-day regimen. The dose is adjusted on the basis of measured trough levels to obtain a whole blood concentration of 8–15ng/ml.
During the past decade, azathioprine was replaced progressively by MMF.(21–23) Early studies in kidney transplantation showed that the immunosuppressive effect of MMF was greatest at a dose of 3g/day, although the clinical benefit at this dose was offset by an increase in gastrointestinal toxicity and CMV tissue invasion. It has therefore been suggested that a starting dose of 2g/day is appropriate. The use of a more flexible regimen permitting dosage adjustments according to clinical status may enable the dose to be tailored to individual needs and thereby improve efficacy and tolerability in clinical practice.(24) In the European study, 67.7% of patients had a MMF dose decreased below 2g/day at three years.(24) MMF is started preoperatively and further given as soon as the patient is able to take oral medications.
No pertinent data are published concerning the use of mycophenolate sodium (Myfortic(®) [Novartis AG, Switzerland]).
Recently, sirolimus has been studied in pancreas transplantation, following the success of the Edmonton protocol for islet transplantation, and was associated with daclizumab and low-dose tacrolimus without steroids.(25,26) Sirolimus has shown a powerful immunosuppressive potency in the absence of nephrotoxicity and diabetogenicity. Multicentre and single-centre reports have demonstrated that both CNI withdrawal and avoidance were possible when sirolimus was used in a concentration-controlled fashion, with low-dose corticosteroids and MMF. Although the experience with sirolimus in pancreatic transplantation is still limited, the results are promising.(27)
A multicentre study was conducted at 12 European transplant centres and one Israeli centre (EuroSPK002).28 It compared the safety and efficacy of MMF (n=118) versus sirolimus (n=123) in 241 SPK recipients who were given a four-day course of polyclonal antibody induction therapy and then maintained on tacrolimus and steroids (withdrawal attempted at six weeks). The results at three months showed no statistically significant differences between the two groups in patient or kidney survival rates, in the incidence of acute rejection episodes or in graft loss from rejection. In addition, no statistically significant differences have been found in the rates of CMV infection, urinary tract infection or abdominal infection. Triglycerides were significantly lower in the MMF group than in the sirolimus group, with respective values of 112mg/dl and 163mg/dl (p=0.0001).
In SPK transplantation, sirolimus is given either in a fixed dose of 2mg/day or to achieve a whole- blood through level of 6–15ng/ml. But there are no data available showing the ideal type of administration. No data have currently been published concerning the use of everolimus (Certican(®) [Novartis AG, Switzerland]) in SPK.
Future directions in immunosuppressive therapy
With the plethora of new drugs available, it is difficult to speculate on the future directions of immunotherapy. We have already achieved a one-year pancreas graft survival rate in the range of 85−90%. Various directions for the future include studies focused on steroid withdrawal or elimination, reduced use and possible elimination of antibody induction therapy, and withdrawal or elimination of calcineurin inhibitors (ciclosporin and tacrolimus) because of their potential risk of acute and chronic nephrotoxicity. There is a general impression that drug dose can be reduced over time due to adaptation of the graft to the host. But it may be that the host rather than the donor adapts to the artificial transplantation situation.
Rapid advances in immunobiology and immunopharmacology over the past 40 years have led to the promise of an exciting future in pancreas transplantation. The introduction of new immunosuppressive drugs and monoclonal antibodies has the potential to improve results even further.
The most common and effective maintenance regimen in pancreatic transplantation still consists of triple therapy with a combination of corticosteroids, tacrolimus and MMF. According to the IPTR, for transplants from 1 January 2000 to 6 June 2004, recipients given anti-T-cell induction therapy and maintained on tacrolimus and MMF had the highest one- and three-year pancreas graft survival rates: SPK (n=2,500), 88% and 81%.(2)
The author is the recipient of research grants from the following pharmaceutical companies whose products are described in this review: Astellas Pharma Inc;
F Hoffmann-La Roche Ltd; Novartis AG; Wyeth; Fresenius Biotech GmbH; and Genzyme
The author acknowledges the editorial assistance of D Van Ophem in the preparation of this article
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