**3. The history of immunosuppression in pancreas transplantation**

Advances in immunosuppressive protocols and the introduction of new immunosuppres‐ sants have had a major impact on and improved outcome after PT. As already mentioned, in 1979, Calne and associates first reported the successful use of cyclosporine in two pancreas recipients [22]. Due to the large dose of CsA used as a single agent and its nephrotoxicity, Starzl et al. proposed to combined reduced doses of CsA with steroids [43]. Further decreased in CsA dosages by using the synergistic effect of combining CsA to Aza was proposed by Squifflet et al. based on animals experiments [29, 44]. Triple drugs combining CsA, Aza and Steroids and later on quadruple drugs regimen with a short course induction of polyclonal Antibodies was the mainstay IS regimen during the next decade [21]. Starzl and his team first reported the use of Tacrolimus (Tac) in pancreas allograft recipients during the investigative period in 1989. [45] After approval, the first report on the use of Tac for pancreas transplantation was by D. Shaffer and associates, successfully reversing ongoing acute rejection in two SPK recipients. [46].

A major topic of the 4th Spitzingsee Workshop (January 30 – February 02, 1997; Kühtai, Austria) was the IS therapy in PT [25]. At that time, the newly introduced agent mycophenolate mofetil (MMF) was proved to be superior to azathioprine (Aza) for the prevention of acute rejection in kidney transplantation patients [47]. Data comparing Tac with the old (oil-based) formula‐ tion of CsA were also available in kidney transplantation, but there were some concerns about Tac having a diabetogenic effect [48], specially for pancreas. A preliminary study investigating the use of Tac in pancreatic transplantation, which was published by Gruessner et al., showed that pancreatic graft survival at 6 months post transplant was higher with Tac (79%) than in a historical group of SPK recipients treated with the oil-based formulation of CsA (65%; p = 0.04) [49]. During the same era, the new micro-emulsion (Me) formulation of CsA (CsA – Me) had been introduced into clinical practice.

PTA hand-made (n=7):

266 Current Issues and Future Direction in Kidney Transplantation

PTA stapler (n=0)

SPK stapler (n=3)

rejection in two SPK recipients. [46].

 Graft thrombosis (1)\* Pancreatitis + peri-pancreas fluid collection due to partial necrosis of pancreas (1)\*

SPK hand-made (n=1): no.

Peri-pancreas fluid

syndrome (1)\*

collection + inflammatory

 Digestive hemorrhage due to ulcers of the donor duodenal stump (1)

**Table 1.** Complications and outcome in 11 recipients of whole pancreas grafts with duodeno-duodenostomy, at the University of Liege, CHU Sart Tilman. The D-D anastomosis was hand-made (n=7) or using a stapler device (n=4)

Advances in immunosuppressive protocols and the introduction of new immunosuppres‐ sants have had a major impact on and improved outcome after PT. As already mentioned, in 1979, Calne and associates first reported the successful use of cyclosporine in two pancreas recipients [22]. Due to the large dose of CsA used as a single agent and its nephrotoxicity, Starzl et al. proposed to combined reduced doses of CsA with steroids [43]. Further decreased in CsA dosages by using the synergistic effect of combining CsA to Aza was proposed by Squifflet et al. based on animals experiments [29, 44]. Triple drugs combining CsA, Aza and Steroids and later on quadruple drugs regimen with a short course induction of polyclonal Antibodies was the mainstay IS regimen during the next decade [21]. Starzl and his team first reported the use of Tacrolimus (Tac) in pancreas allograft recipients during the investigative period in 1989. [45] After approval, the first report on the use of Tac for pancreas transplantation was by D. Shaffer and associates, successfully reversing ongoing acute

A major topic of the 4th Spitzingsee Workshop (January 30 – February 02, 1997; Kühtai, Austria) was the IS therapy in PT [25]. At that time, the newly introduced agent mycophenolate mofetil (MMF) was proved to be superior to azathioprine (Aza) for the prevention of acute rejection in kidney transplantation patients [47]. Data comparing Tac with the old (oil-based) formula‐ tion of CsA were also available in kidney transplantation, but there were some concerns about Tac having a diabetogenic effect [48], specially for pancreas. A preliminary study investigating the use of Tac in pancreatic transplantation, which was published by Gruessner et al., showed that pancreatic graft survival at 6 months post transplant was higher with Tac (79%) than in a historical group of SPK recipients treated with the oil-based formulation of CsA (65%; p = 0.04)

**3. The history of immunosuppression in pancreas transplantation**

 Peri-pancreas hematoma + inflammatory syndrome (1)\* Surgical exploration +

Surgical exploration +

treatment+transfusion

drainage Transplantectomy Surgical exploration +

drainage

drainage

Conservative

At that period, all European participants to the meeting were performing a limited number of SPK per centre. All realized that local studies would not aim solving the IS problems. Therefore W. Land took the opportunity to propose them the first large international prospective multicentre study in the field of PT, comparing Tac to the new CsA – Me, along with MMF, corticosteroids and a short course of induction therapy with Rabbit – antithymocyte globulines (R-ATG, Fresenius, Germany).

The rationale for induction therapy using anti-T-cell agents was triple: minimizing the risks of early rejection episodes, accelerating recovery of renal and pancreatic allograft function (protection against the ischemic reperfusion injury) and perhaps, inducing a tolerogenic effect to donor alloantigens. Before 1994, choices of maintenance IS agents were limited to a "one size fits all" approach with the combined use of Cyclosporin A (CsA), azathioprine (Aza) and corticosteroids. But, with that regimen, rejection rates were about 75 % to 80 %, with a rate of 25 % to 30 % of recurrence. Therefore, during the early 90's anti-T-cell induction was auto‐ matically added in all 3 categories of pancreas transplantation (Fig 19, Panel B). The choice of the anti-T-Cell agent was based more on its accessibility than on any rationale or scientific approach; the anti-T-Cell agents which were used are: MALG®, OKT3®, ATGAM®, R-ATG®, Simulect®, Zenapax®, Thymoglobulin®, Campath®. During the CsA era, single centre studies emphasized the benefit of Quadruple over Triple therapies [50, 51]. Other comparative studies underlined the best efficacy of ATG over OKT3® and MALG® [52 - 54]. During the modern era, during which most centres were using Tacrolimus (Tac), Mycophenolate Mofetil (MMF) and corticosteroids for maintenance therapy, Kaufman et al. designed several multicenter studies [55, 56] in which they confirmed the usefulness of induction therapy in PT. By contrast, the place of Campath®, still remains to be confirmed [57].

The results of the first Euro-SPK study were encouraging [58]. The 1-year incidence of biopsyproven acute rejection of the kidney or pancreas was lower with Tac (27.2 %) than with CsA-Me (38.2 %; p = 0.09). Pancreatic graft survival at 1 year was significantly higher with Tac (91.3 %) than with CsA-Me (74.5 %; p = 0.0014). Kidney graft survival was similar in the two groups [58].

At 3 years, fewer patients receiving Tac (36.9 %) than CsA-Me (57.8 %) were discontinued from treatment (p = 0.003). The initial episodes of biopsy proven rejection were moderate or severe in just one out of 31 (3 %) Tac-treated patients compared with 11 of 39 (28 %) patients receiving CsA-Me (p = 0.009).

While 3-year patient and kidney survival rates were similar in the two treatment groups, pancreas survival was superior with Tac (89.2 vs 72.4 %; p = 0.002). Thrombosis resulted in pancreas graft loss in 10 patients receiving CsA-Me and in only 2 treated with Tac (p = 0.02). The overall incidence of adverse events was similar in both groups, but MMF intolerance was more frequent with Tac whereas hyperlipidaemia was more frequent with CsA-Me. Acute rejection was more common among CMV-infected patients (66 vs 41 % without infection; p = 0.001) and in those not receiving ganciclovir prophylaxis [48, 58].

There were no differences in 3-year kidney pancreas or patient survival between the 0-3 and 4-6 HLA antigen mismatch (MM) groups. Significantly more patients with 0-3 MM (66 %) were rejection-free at 3 years compared to those with 4-6 MM (41 %; p = 0.003). The relative risk of acute rejection was 2.6 times higher among patients with 4-6 MM than among those with 0-3 MM [48].

In summary the Euro-SPK study findings provided evidence to support the use of Tac in patients undergoing SPK transplantation.

A second SPK study addressed the issue of the choice of the antiproliferative agent which could be associated to Tac, either MMF or rapamycine (Rapa). Preliminary one and three year results demonstrated more frequent study withdrawal in the Rapa group, due to toxicity [59].

More than 60 % of those patients were rejection free at 1 year. Adequate kidney and pancreas functions were also achieved in both groups while the serum creatinine level was significantly lower in the Rapa group from month 2, the price to pay being hyperlipidemia, delayed wound healing, lymphocoele or hernia.

Corticosteroid withdrawal was possible in both studies in 70 % and 50 % of recipients respectively. Therefore, it can be concluded that steroid withdrawal is feasible in SPK trans‐ plantation but not in all patients; further studies must be designed to address that issue completely.
