**2. The history of surgical techniques in pancreas transplantation**

The first pancreas transplantation performed by W. Kelly and R. Lillehei on December 17, 1966 at the University of Minnesota was a duct ligated segmental graft which was implanted in the left iliac fossa along with a kidney coming from the same cadaver donor in a 28 year old female uremic recipient with type 1 diabetic nephropathy [4]. It was the first ever SPK (Fig 1). The recipient was insulin-free for six days; later she needed exogenous insulin, the need being attributed to the high doses of steroids given to prevent rejection. However, she also developed graft pancreatitis, that was most likely related to duct ligation, and for which she received 950 Rads graft irradiation. On February 14, 1967, Kelly and Lillehei removed the pancreas and rejected kidney. The recipient died from pulmonary embolism 13 days after pancreas graft removal [4]. This first case exemplified many of the problems that were associated with TP over the following 2 decades: surgical complications, wound infections, and graft rejection.

**Figure 1.** Drawing of the first segmental pancreas transplant (from Kelly et al.) [4].

Lillehei was the lead surgeon in the second pancreas transplant, also done with a kidney (Fig 2). He went on to do a total of 13 cases between the first case of Kelly and 1973, 9 with a kidney and 4 without [5, 6]. Significant changes in surgical techniques were made between the first and the second transplant pertaining to graft size (whole organ versus segmental) and duct management (cutaneous duodenostomy versus duct ligation). Lillehei transplanted the donor's whole pancreas and attached duodenum extraperitoneally to the 32-Year-old recipi‐ ent's left iliac fossa (Fig 2). This transplant achieved a more prolonged state of graft function, but rejection treatment had to be instituted three and eight weeks post-transplant. Both rejection episodes affected the graft duodenum. The recipient was on insulin when she died four months post transplant from sepsis.

compatible graft is available [1]. By contrast, the number of PTA remains limited in non uremic recipients with life-threatening complications of diabetes, in whom one might hope to avoid the hypoglycaemic events with a successful graft. That can also be achieved with IT. But except for rare cases, insulin independence with IT requires more than a single human pancreas and is limited over time [1]. Moreover, IT needs costly materials, chambers and rooms for prepa‐

The first pancreas transplantation performed by W. Kelly and R. Lillehei on December 17, 1966 at the University of Minnesota was a duct ligated segmental graft which was implanted in the left iliac fossa along with a kidney coming from the same cadaver donor in a 28 year old female uremic recipient with type 1 diabetic nephropathy [4]. It was the first ever SPK (Fig 1). The recipient was insulin-free for six days; later she needed exogenous insulin, the need being attributed to the high doses of steroids given to prevent rejection. However, she also developed graft pancreatitis, that was most likely related to duct ligation, and for which she received 950 Rads graft irradiation. On February 14, 1967, Kelly and Lillehei removed the pancreas and rejected kidney. The recipient died from pulmonary embolism 13 days after pancreas graft removal [4]. This first case exemplified many of the problems that were associated with TP over the following 2 decades: surgical complications, wound infections, and graft rejection.

ration. That's why IT will not be included in the present report.

250 Current Issues and Future Direction in Kidney Transplantation

**Figure 1.** Drawing of the first segmental pancreas transplant (from Kelly et al.) [4].

Lillehei was the lead surgeon in the second pancreas transplant, also done with a kidney (Fig 2). He went on to do a total of 13 cases between the first case of Kelly and 1973, 9 with a kidney and 4 without [5, 6]. Significant changes in surgical techniques were made between the first and the second transplant pertaining to graft size (whole organ versus segmental) and duct management (cutaneous duodenostomy versus duct ligation). Lillehei transplanted the

**2. The history of surgical techniques in pancreas transplantation**

After that series of 13 Pancreas Transplants, R. Lillehei concluded that most complications were associated with kidney graft rejection without pancreas rejection and recipient death [5, 6, 7].

After the first four pancreas transplants at the University of Minnesota, the next four trans‐ plants were performed in South America in 1968; [8, 9, 10]; three were performed in Brazil and one in Argentina at the Buenos Aires Hospital. Only one functioned sufficiently to induce insulin-independence and was subsequently lost to rejection at 4 months. [10].

In 1969, two other U.S. institutions performed one SPK transplant each: one at the University of Colorado (Fred Merkel and Thomas Starzl) and one at the University of California, Irvine Medical Center (John Connolly). [8, 11]. The first pancreas transplant in Europe, along with a kidney transplant, was performed in 1972 at Guys Hospital, in London, U.K. (Mick Bewick). [8].

By the 1970s, only 25 pancreas transplants had been performed at six institutions worldwide. Two-thirds of those early pancreas transplants were done along with a simultaneous kidney transplant. Exocrine secretions had been drained by duct ligation, cutaneous duodenostomy, or enteric drainage using a Roux-en-Y loop. Of these 25 grafts, only one, from Lillehei's original series, functioned for almost one year, and none for more than one year.

On November 24, 1971, Marvin Gliedman at Montefiore Hospital and Medical Center in New York performed the first pancreas transplant using urinary drainage via the native ureter [12]. Gliedman and associates performed a total of 11 ureteral pancreas transplants in the early 1970s (Fig 3) with one graft functioning for 22 months and another for 50 months – at that point the longest pancreas graft survival recorded. [13, 14]. However, ureteral drainage did not find widespread application because of tenuous leakage-prone duct-to-ureter anastomosis; leakage from the pancreas cut surface; and the potential need for ipsilateral native nephrectomy. The main conclusion drawn from that original and historical series was the probable evidence of a hierarchy in rejection, the pancreas being less antigenic than the kidney the latter being less antigenic than the duodenum [15]. Therefore, surgical techniques using a segmental pancreatic graft (body and tail) were developed during the next decade.

**Figure 4.** Technique for revascularization in the recipient of a segmental pancreas graft. The celiac axis (on a Carrel patch) and portal vein of the graft are anastomosed to the commun iliac vessels of the recipient through the meso-

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

http://dx.doi.org/10.5772/55347

253

**Figure 5.** Injection of a synthetic polymer into the duct of a segmental pancreas graft following revascularization. Ap‐

proximately 4-6 ml of the polymer is injected, followed by ligation of the duct [17-20].

sigmoid [16].

**Figure 3.** Ureteral pancreas transplant according to Gliedman et al [12] end-to-end distal ureter to pancreatic duct anastomosis.

#### **2.1. The segmental pancreas transplantation reign (from mid 70's to mid's 80's)**

In the mid 70's, the segmental pancreas while avoiding the duodenal segment was the most popular technique used for PT [6, 7]. Various procedures were proposed to drain the exocrine secretion: the duct could be left opened with the segmental graft placed intraperitoneally (Fig 4) [16] or blocked by an intraductal injection (Fig 5) of either Neoprene (J.M. Dubernard) [17] or Prolamine (W. Land) [18] or Polyisoprene (P. Mc Master) [19] or Silicone (D.E.R. Sutherland) [20]. Kidney and Pancreas Transplantation: The History of Surgical Techniques and Immunosuppression http://dx.doi.org/10.5772/55347 253

the longest pancreas graft survival recorded. [13, 14]. However, ureteral drainage did not find widespread application because of tenuous leakage-prone duct-to-ureter anastomosis; leakage from the pancreas cut surface; and the potential need for ipsilateral native nephrectomy. The main conclusion drawn from that original and historical series was the probable evidence of a hierarchy in rejection, the pancreas being less antigenic than the kidney the latter being less antigenic than the duodenum [15]. Therefore, surgical techniques using a segmental pancreatic

**Figure 3.** Ureteral pancreas transplant according to Gliedman et al [12] end-to-end distal ureter to pancreatic duct

In the mid 70's, the segmental pancreas while avoiding the duodenal segment was the most popular technique used for PT [6, 7]. Various procedures were proposed to drain the exocrine secretion: the duct could be left opened with the segmental graft placed intraperitoneally (Fig 4) [16] or blocked by an intraductal injection (Fig 5) of either Neoprene (J.M. Dubernard) [17] or Prolamine (W. Land) [18] or Polyisoprene (P. Mc Master) [19] or Silicone (D.E.R. Sutherland) [20].

**2.1. The segmental pancreas transplantation reign (from mid 70's to mid's 80's)**

anastomosis.

graft (body and tail) were developed during the next decade.

252 Current Issues and Future Direction in Kidney Transplantation

**Figure 4.** Technique for revascularization in the recipient of a segmental pancreas graft. The celiac axis (on a Carrel patch) and portal vein of the graft are anastomosed to the commun iliac vessels of the recipient through the mesosigmoid [16].

**Figure 5.** Injection of a synthetic polymer into the duct of a segmental pancreas graft following revascularization. Ap‐ proximately 4-6 ml of the polymer is injected, followed by ligation of the duct [17-20].

Twelve intraperitoneal open-duct segmental pancreas transplants were performed at the University of Minnesota in a two-year period [16]; four were rejected within 4 months; 3 had to be removed because of peritonitis or ascites. The latter recipient lived insulin-independent for 18 years until in 1996 she died from a trauma, with a functioning graft, the longest duration of function at that time [21].

Firstly, in 1979, the clinical use of Cyclosporine A (CsA) by R. Calne et al. [22] as the single immunosuppressant in 36 recipients of cadaveric organs. CsA remained the basic immuno‐

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

http://dx.doi.org/10.5772/55347

255

Secondly, in 1980, the organization by J.M. Dubernard in Lyon, France, of the first pancreas transplantation meeting, launching the International Pancreas (and Islet) Transplant Registry (IPTR) which was handled by D.E.R. Sutherland at the University of Minneso‐

Thirdly and finally, in 1981, the first of a series of 5 workshops – called the Spitzingsee Meeting – organized by W. Land in Kühtai, Austria [24]. The characteristics of these workshops consisted in gathering the world pioneers in PT and allowing them to discuss on not only the successes but also the failures, finding ways to prevent them or improve the results [25]. These meetings were also the basis of creating the International Pancreas and Islet Association (IPITA) and later on, in Europ, the European Study Group in Simultaneous Pancreas and Kidney Transplantation (EuroSPK) [25]. More recently, was created the EPITA, the European

During one of these workshops, H. Sollinger [26] had the idea to renew an old technique and divert the exocrine secretion of the pancreas into the bladder (Fig 7), while G. Tyden [27] and C. Groth [28] were proposing the enteric drainage (Fig 8). Slowly, both groups moved from the segmental graft [28] to the whole pancreas graft along with a duodenal segment (Fig 9) [26, 27]. This announced the end of the segmental transplantation reign. In the mean time, on November 10, 1982, the first pancreas transplantation was per‐ formed in Belgium by J.P. Squifflet and G.P.J. Alexandre [7]. The recipient was a 29 year old female with a 26 year history of type 1 diabetes. She was on peritoneal dialysis since one year and switched to hemodialysis a month before. She received a simultaneous pancreas and kidney transplants from a 22 year old female cadaver donor who died in a car accident from a head trauma. The recipient did not share any HLA antigen with the donor. She received a segmental pancreas graft, anastomosed on a Roux-en-Y loop (Fig 10), according to the technique described by Groth et al. (Fig 8) [23]. The immunosuppres‐ sive therapy consisted in a short course of antilymphocytic globulins induction along with cyclosporine A and steroids. She was one of the first few patients who received cyclospor‐ ine A in Belgium, at a dose a 14 mgr/kg/day. Following an episode of delayed graft function of the kidney, she fully recovered and was insulin free for a period of 2 years. Than insulin resistance was noticed along with an increase of 15 kg in body weight. Despite Cyclospor‐ in and steroids dose reduction and the introduction of azathioprine, insulin therapy was resumed. She eventually went back on hemodialysis 8 years later and died in June 1992 while waiting for a second kidney transplant. The choice of the surgical technique and IS was based on animal experiments [29–32] but also on the fact that segmental pancreas

suppressive (IS) drug up to the early 90'S.

Pancreas and Islet Transplantation Association [25].

transplantation was more popular during that period.

ta [23].

By contrast the duct occlusion technique became more popular despite numerous leaks, pancreatic fistulae, graft pancreatitis and vascular thrombosis. For managing these complica‐ tions, Dubernard et al. [17, 7] proposed the omentoplasty in warping the duct-occluted segmental pancreas with the omentum, while Calne et al. [6, 7] was performing an A-V fistula at the distal end of the pancreas tail (Fig 6; panels A and B).

**Figure 6.** Panel (a): omentoplasty according to Dubernard et al.[7, 17]. Panel (b): AV fistula between the distal splenic artery and vein according to Calne et al. [6, 7].

During the late 70'S, three major events occurred that contributed to the development of PT.

Firstly, in 1979, the clinical use of Cyclosporine A (CsA) by R. Calne et al. [22] as the single immunosuppressant in 36 recipients of cadaveric organs. CsA remained the basic immuno‐ suppressive (IS) drug up to the early 90'S.

Twelve intraperitoneal open-duct segmental pancreas transplants were performed at the University of Minnesota in a two-year period [16]; four were rejected within 4 months; 3 had to be removed because of peritonitis or ascites. The latter recipient lived insulin-independent for 18 years until in 1996 she died from a trauma, with a functioning graft, the longest duration

By contrast the duct occlusion technique became more popular despite numerous leaks, pancreatic fistulae, graft pancreatitis and vascular thrombosis. For managing these complica‐ tions, Dubernard et al. [17, 7] proposed the omentoplasty in warping the duct-occluted segmental pancreas with the omentum, while Calne et al. [6, 7] was performing an A-V fistula

(a) (b)

**Figure 6.** Panel (a): omentoplasty according to Dubernard et al.[7, 17]. Panel (b): AV fistula between the distal splenic

During the late 70'S, three major events occurred that contributed to the development of

of function at that time [21].

254 Current Issues and Future Direction in Kidney Transplantation

artery and vein according to Calne et al. [6, 7].

PT.

at the distal end of the pancreas tail (Fig 6; panels A and B).

Secondly, in 1980, the organization by J.M. Dubernard in Lyon, France, of the first pancreas transplantation meeting, launching the International Pancreas (and Islet) Transplant Registry (IPTR) which was handled by D.E.R. Sutherland at the University of Minneso‐ ta [23].

Thirdly and finally, in 1981, the first of a series of 5 workshops – called the Spitzingsee Meeting – organized by W. Land in Kühtai, Austria [24]. The characteristics of these workshops consisted in gathering the world pioneers in PT and allowing them to discuss on not only the successes but also the failures, finding ways to prevent them or improve the results [25]. These meetings were also the basis of creating the International Pancreas and Islet Association (IPITA) and later on, in Europ, the European Study Group in Simultaneous Pancreas and Kidney Transplantation (EuroSPK) [25]. More recently, was created the EPITA, the European Pancreas and Islet Transplantation Association [25].

During one of these workshops, H. Sollinger [26] had the idea to renew an old technique and divert the exocrine secretion of the pancreas into the bladder (Fig 7), while G. Tyden [27] and C. Groth [28] were proposing the enteric drainage (Fig 8). Slowly, both groups moved from the segmental graft [28] to the whole pancreas graft along with a duodenal segment (Fig 9) [26, 27]. This announced the end of the segmental transplantation reign. In the mean time, on November 10, 1982, the first pancreas transplantation was per‐ formed in Belgium by J.P. Squifflet and G.P.J. Alexandre [7]. The recipient was a 29 year old female with a 26 year history of type 1 diabetes. She was on peritoneal dialysis since one year and switched to hemodialysis a month before. She received a simultaneous pancreas and kidney transplants from a 22 year old female cadaver donor who died in a car accident from a head trauma. The recipient did not share any HLA antigen with the donor. She received a segmental pancreas graft, anastomosed on a Roux-en-Y loop (Fig 10), according to the technique described by Groth et al. (Fig 8) [23]. The immunosuppres‐ sive therapy consisted in a short course of antilymphocytic globulins induction along with cyclosporine A and steroids. She was one of the first few patients who received cyclospor‐ ine A in Belgium, at a dose a 14 mgr/kg/day. Following an episode of delayed graft function of the kidney, she fully recovered and was insulin free for a period of 2 years. Than insulin resistance was noticed along with an increase of 15 kg in body weight. Despite Cyclospor‐ in and steroids dose reduction and the introduction of azathioprine, insulin therapy was resumed. She eventually went back on hemodialysis 8 years later and died in June 1992 while waiting for a second kidney transplant. The choice of the surgical technique and IS was based on animal experiments [29–32] but also on the fact that segmental pancreas transplantation was more popular during that period.

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

gold standard surgical procedure.

segment is made to the dome of the bladder [33].

ing for rejection.

Thus, in the mid 80's, whole pancreas transplantation with a duodenal segment became the

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

http://dx.doi.org/10.5772/55347

257

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‐

**Figure 9.** Pancreaticoduodenal transplantation with bladder drainage. A side-to-side anastomosis of the duodenal

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

**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].
