**2.2. The whole pancreas transplantation reign (from mid 80's)**

**Figure 7.** Exocrine secretion of segmental grafts drained directly into the bladder, as first described by Sollinger et al. [26].

256 Current Issues and Future Direction in Kidney Transplantation

**Figure 8.** Enteric drainage of a segmental pancreas graft to a Roux-en-Y limb of recipient jejunum. The temporary external drainage of the pancreatic duct secretions to the catheter brought to the Roux-en-Y loop and the abdominal

wall is illustrated [28].

Thus, in the mid 80's, whole pancreas transplantation with a duodenal segment became the gold standard surgical procedure.

In 1987, Nghiem and Corry at the University of Iowa described the technique of bladder drainage via a graft-to-recipient duodeno-cystostomy for whole pancreaticoduodenal grafts (Fig 9) [33]. Most U.S. and European centers quickly adopted bladder drainage via the graft duodenum. For SPK transplants, the dominant reason to use bladder-drainage was to reduce the risk of anastamotic leaks, since rejection could be monitored by serum creatinine. For solitary pancreas transplants, bladder-drainage had the advantage of urine amylase monitor‐ ing for rejection.

**Figure 9.** Pancreaticoduodenal transplantation with bladder drainage. A side-to-side anastomosis of the duodenal segment is made to the dome of the bladder [33].

In the mid 80's, Starzl [34] and associates reintroduced in U.S.the technique of enteric-drained whole-organ pancreaticoduodenal transplants, as originally described by Lillehei while the Stockholm group continued to do enteric drainage by direct duodeno-enterostomy [35]. Nearly everyone was convinced that whole pancreaticoduodenal transplants were preferable for PT from cadaver donors, and after en – bloc liver and pancreas procurement (Fig 11), transplant surgeons designed methods for reconstructing the vasculature to both organs (Fig 12) [36 - 39].

**Figure 11.** Maneuvers for en-bloc removal of a whole pancreas and a liver from a cadaver donor with normal vascular anatomy.The gastroduodenal artery must be divided so that the common and proper hepatic arteries can remain in continuity and be retained with the liver. The portal vein is divided just superior to the entrance of the splenic vein. Then, the pancreatic portion is lengthened by an iliac vein graft. The celiac and superior mesenteric arteries can re‐

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**Figure 12.** Whole-pancreas procurement and reconstruction of its arterial supply in a donor with a replaced / accesso‐

main with the pancreas with a Carrel aortic patch. [38]

LHA = left hepatic artery. GDA = gastroduodenal artery

SMA = superior mesenteric artery.[39]

ry right hepatic artery (R / A RHA).

SA = splenic artery

a: drawing of the procedure.

b: the segmental pancreas graft.

c: the end-to-end pancreas graft anastomosis to the Roux-en-Y loop.

d: the anastomosis suture was protected by a catheter inserted into the pancreas duct.

**Figure 10.** Segmental pancreatic transplant in the first Belgian recipient with enteric diversion of the exocrine secre‐ tion, in a Roux-en-Y loop.

From the mid-80s to the mid-90s, bladder drainage became the most common technique worldwide (Fig 9). However, because of chronic complications of bladder drainage (urinary tract infections, cystitis, urethritis (Fig 13), reflux pancreatitis, hematuria, metabolic acidosis and dehydration from fluid and bicarbonate losses), leading to conversion to enteric drainage in approximately a quarter of the recipients, in the mid-1990s, surgeons began to shifted to primary enteric drainage (Fig 14), not only for SPK transplants, but at some institutions also for solitary pancreas transplants [40].

**Figure 11.** Maneuvers for en-bloc removal of a whole pancreas and a liver from a cadaver donor with normal vascular anatomy.The gastroduodenal artery must be divided so that the common and proper hepatic arteries can remain in continuity and be retained with the liver. The portal vein is divided just superior to the entrance of the splenic vein. Then, the pancreatic portion is lengthened by an iliac vein graft. The celiac and superior mesenteric arteries can re‐ main with the pancreas with a Carrel aortic patch. [38]

LHA = left hepatic artery. GDA = gastroduodenal artery SA = splenic artery SMA = superior mesenteric artery.[39]

(a) (b)

258 Current Issues and Future Direction in Kidney Transplantation

(c) (d)

c: the end-to-end pancreas graft anastomosis to the Roux-en-Y loop.

d: the anastomosis suture was protected by a catheter inserted into the pancreas duct.

a: drawing of the procedure. b: the segmental pancreas graft.

tion, in a Roux-en-Y loop.

for solitary pancreas transplants [40].

)

**Figure 10.** Segmental pancreatic transplant in the first Belgian recipient with enteric diversion of the exocrine secre‐

From the mid-80s to the mid-90s, bladder drainage became the most common technique worldwide (Fig 9). However, because of chronic complications of bladder drainage (urinary tract infections, cystitis, urethritis (Fig 13), reflux pancreatitis, hematuria, metabolic acidosis and dehydration from fluid and bicarbonate losses), leading to conversion to enteric drainage in approximately a quarter of the recipients, in the mid-1990s, surgeons began to shifted to primary enteric drainage (Fig 14), not only for SPK transplants, but at some institutions also

**Figure 14.** Pancreaticoduodenal transplantation with enteric drainage. A side-to-side anastomosis of the duodenal segment is made to the distal ileon, or the proximal jejeunum. It can also be performed on a Roux-en-Y loop [35].

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Either enteric or bladder drainage is now done for virtually all pancreas transplants using a whole pancreas graft with a duodenal segment. The other techniques are virtually never used unless for salvage of a technical situation (e.g., duct injection might be used to manage a leak). With regard to the venous drainage of pancreas grafts, portal would be the most physiological but the systemic venous system was only accessed during the first two decades. Later on, the use of portal drainage at the junction of the recipient's superior mesenteric and splenic vein was favored in recipients of enteric drained whole-organ pancreaticoduodenal transplants (Fig 15). Surgeons reported on its metabolic and possible immunologic advantage, features also noted at the University of Maryland, where a large program existed of conversion to almost exclusive portal drainage [41]. By the end of the 1990's, almost 20 % of pancreas transplants in U.S. and in Europe were being done with portal drainage but the proportion did not increase nearly as much as the proportion of pancreas grafts that were enteric drained, reaching over 80 % for solitary in U.S. and over 90 % for SPK transplants in Europe (Fig 16). Early diagnosis of pancreas rejection had been difficult from the beginning, in particular for solitary pancreas transplants where serum creatinine could not be used as a surrogate marker

**2.3. The modern era of surgical techniques**

(b)

**Figure 13.** Chemical urethritis in a pancreas recipient with bladder drainage of the exocrine secretion (Panel (a)). CT scan: same recipient (Panel (b)).

**Figure 14.** Pancreaticoduodenal transplantation with enteric drainage. A side-to-side anastomosis of the duodenal segment is made to the distal ileon, or the proximal jejeunum. It can also be performed on a Roux-en-Y loop [35].

#### **2.3. The modern era of surgical techniques**

(a)

260 Current Issues and Future Direction in Kidney Transplantation

(b)

scan: same recipient (Panel (b)).

**Figure 13.** Chemical urethritis in a pancreas recipient with bladder drainage of the exocrine secretion (Panel (a)). CT

Either enteric or bladder drainage is now done for virtually all pancreas transplants using a whole pancreas graft with a duodenal segment. The other techniques are virtually never used unless for salvage of a technical situation (e.g., duct injection might be used to manage a leak). With regard to the venous drainage of pancreas grafts, portal would be the most physiological but the systemic venous system was only accessed during the first two decades. Later on, the use of portal drainage at the junction of the recipient's superior mesenteric and splenic vein was favored in recipients of enteric drained whole-organ pancreaticoduodenal transplants (Fig 15). Surgeons reported on its metabolic and possible immunologic advantage, features also noted at the University of Maryland, where a large program existed of conversion to almost exclusive portal drainage [41]. By the end of the 1990's, almost 20 % of pancreas transplants in U.S. and in Europe were being done with portal drainage but the proportion did not increase nearly as much as the proportion of pancreas grafts that were enteric drained, reaching over 80 % for solitary in U.S. and over 90 % for SPK transplants in Europe (Fig 16). Early diagnosis of pancreas rejection had been difficult from the beginning, in particular for solitary pancreas transplants where serum creatinine could not be used as a surrogate marker like in SPK. That's why there is still room for improvement in surgical techniques. In order to have easy access to the graft for performing biopsies, De Roover et al. [42] proposed recently a technical modification and a side-to-side duodeno-duodenal (D-D) anastomosis while using a whole pancreaticoduodenal transplant with the venous effluent drained into the portal system of the recipient (Fig 17, 18). It offers serial sampling of the duodenal transplant mucosa by simple fibroscopies, a useful tool for monitoring rejection (Fig 18, Panel B). The duodenal anastomosis can be hand-made or performed using a stapler device. But the major drawback of both techniques could be the management of duodenal leaks on graft thrombosis. Our experience in 11 pancreas recipients at the University of Liege, CHU Sart Tilman is summarized in table 1. Peri-pancreatic collections, with or without pancreatitis were managed by surgical exploration and drainage. So far, only one graft thrombosis (PTA) needed prompt removal but was followed by a duodenal leak with cutaneous fistula which required weeks before healing (table 1). Therefore, prospective studies will be useful to specify the place of the D-D and each particular surgical suturing technique.

**IPTR/UNOS**

**PTA SPK** 263

*Duct Management Technique* **USA DD Primary Pancreas Transplants 1/ 1/ 1988 –12/ 31/ 2011**

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**% ED drained PAK**

**IPTR/UNOS**

**PTA SPK**

2/12

*Portal Drainage in ED Txs* **USA DD Primary Pancreas Transplants, 1/ 1/ 1988 – 12/ 31/ 2011**

(a) (b)

**<sup>60</sup>** % **PAK**

(c)

**Figure 16.** International Pancreas Transplant Registry \* Panel (a): US Pancreas Transplants per year, between 12/16/1966 and 12/31/2011. Panel (b): Duct management techniques (urinary versus enteric drainage) in US primary pancreas transplants, between 1/1/1988 and 12/31/2011. Panel (c): Portal Drainage in enteric drained (ED) trans‐

2/12

\*By courtesy from A.E. Gruessner Department of Surgery,

University of Arizona, Tucson, USA.

plants. US primary pancreas transplants, between 1/1/1988 and 12/31/2011.

Kidney and Pancreas Transplantation: The History of Surgical Techniques and Immunosuppression

**Figure 15.** Pancreaticoduodenal transplantation with enteric drainage and portal drainage at the junction of the re‐ cipient's superior mesenteric and splenic veins [41].

like in SPK. That's why there is still room for improvement in surgical techniques. In order to have easy access to the graft for performing biopsies, De Roover et al. [42] proposed recently a technical modification and a side-to-side duodeno-duodenal (D-D) anastomosis while using a whole pancreaticoduodenal transplant with the venous effluent drained into the portal system of the recipient (Fig 17, 18). It offers serial sampling of the duodenal transplant mucosa by simple fibroscopies, a useful tool for monitoring rejection (Fig 18, Panel B). The duodenal anastomosis can be hand-made or performed using a stapler device. But the major drawback of both techniques could be the management of duodenal leaks on graft thrombosis. Our experience in 11 pancreas recipients at the University of Liege, CHU Sart Tilman is summarized in table 1. Peri-pancreatic collections, with or without pancreatitis were managed by surgical exploration and drainage. So far, only one graft thrombosis (PTA) needed prompt removal but was followed by a duodenal leak with cutaneous fistula which required weeks before healing (table 1). Therefore, prospective studies will be useful to specify the place of the D-D and each

**Figure 15.** Pancreaticoduodenal transplantation with enteric drainage and portal drainage at the junction of the re‐

particular surgical suturing technique.

262 Current Issues and Future Direction in Kidney Transplantation

cipient's superior mesenteric and splenic veins [41].

\*By courtesy from A.E. Gruessner Department of Surgery, University of Arizona, Tucson, USA.

**Figure 16.** International Pancreas Transplant Registry \* Panel (a): US Pancreas Transplants per year, between 12/16/1966 and 12/31/2011. Panel (b): Duct management techniques (urinary versus enteric drainage) in US primary pancreas transplants, between 1/1/1988 and 12/31/2011. Panel (c): Portal Drainage in enteric drained (ED) trans‐ plants. US primary pancreas transplants, between 1/1/1988 and 12/31/2011.

**Figure 17.** Pancreaticoduodenal transplantation with portal drainage and side-to-side recipient duodenal drainage of the exocrine secretion [23]: schematic representation and positioning.

(a)

3/12

pancreas transplants between 1/1/2007 and 12/31/2011

**%**

*HLA A,B,DR Mismatching* **USA Primary DD Pancreas Transplants 1/ 1/ 1988 – 12/ 31/ 2011**

% of 5 or 6 HLA Mismatch

\*By courtesy from A.E. Gruessner Department of Surgery,

University of Arizona, Tucson, USA.

**IPTR/UNOS**

2/12

*Major Immunosuppressive Protocols* **USA Primary DD Pancreas Transplants 1/ 1/ 2007 – 12/ 31/ 2011**

**PAK PTA SPK**

(c)

**Figure 19.** International Pancreas Transplant Registry\* Panel (a): Purcentage of 5 or 6 HLA A, B, Dr Mismatching in US primary pancreas transplants between 1/1/1988 and 12/31/2011. Panel (b): Anti-T-Cell induction in US primary pan‐ creas transplants between 1/1/1988 and 12/31/2011. Panel (c): Major immunosuppressive protocols in US primary

Kidney and Pancreas Transplantation: The History of Surgical Techniques and Immunosuppression

**IPTR/UNOS**

**PAK PTA SPK** 265

*Anti-T-Cell Induction* **USA DD Primary Pancreas Transplants 1/ 1/ 1988 – 12/ 31/ 2011**

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(b)

**IPTR/UNOS**

**MMF TAC/MMF TAC SRL based**

**PAK PTA SPK**

**Figure 18.** Pancreaticoduodenal transplantation with portal drainage and side-to-side recipient duodenal drainage of the exocrine secretion [23]: Panel (a): per operative view Panel (b): endoscopic view of the duodenum

\*By courtesy from A.E. Gruessner Department of Surgery, University of Arizona, Tucson, USA.

**Figure 17.** Pancreaticoduodenal transplantation with portal drainage and side-to-side recipient duodenal drainage of

**Figure 18.** Pancreaticoduodenal transplantation with portal drainage and side-to-side recipient duodenal drainage of

the exocrine secretion [23]: Panel (a): per operative view Panel (b): endoscopic view of the duodenum

the exocrine secretion [23]: schematic representation and positioning.

264 Current Issues and Future Direction in Kidney Transplantation

(a)

(b)

**Figure 19.** International Pancreas Transplant Registry\* Panel (a): Purcentage of 5 or 6 HLA A, B, Dr Mismatching in US primary pancreas transplants between 1/1/1988 and 12/31/2011. Panel (b): Anti-T-Cell induction in US primary pan‐ creas transplants between 1/1/1988 and 12/31/2011. Panel (c): Major immunosuppressive protocols in US primary pancreas transplants between 1/1/2007 and 12/31/2011

[49]. During the same era, the new micro-emulsion (Me) formulation of CsA (CsA – Me) had

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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

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 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

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

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 =

been introduced into clinical practice.

(R-ATG, Fresenius, Germany).

groups [58].

CsA-Me (p = 0.009).

the place of Campath®, still remains to be confirmed [57].

0.001) and in those not receiving ganciclovir prophylaxis [48, 58].

**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)
