Combined Liver, Pancreas-Duodenum, and Kidney Transplantation for Patients with Hepatitis B Cirrhosis, Uremia, and Insulin-Dependent Diabetes

Background

Abdominal multiorgan transplantation is effective for patients with multiple organ failure (MOF). Combined liver-kidney transplantation (CLKT), simultaneous kidney-pancreas transplantation (SKPT) with enteric drainage of pancreatic exocrine secretions, and simultaneous orthotopic liver and heterotopic pancreas-duodenum transplantation (SLPT) can be indicated for patients with failure of both organs. All of these combinations have been reported in the literature [1].

Combined liver, pancreas-duodenum, and kidney transplantation (LPDKT) has only been performed in a few cases as a therapeutic approach for patients with end-stage liver disease combined with insulin-dependent diabetes mellitus with renal failure. Such patients are rare, and there is no causal connection among end-stage liver disease, diabetes, and chronic renal failure. Patients with simultaneous failure of 3 organs often have difficulty tolerating surgery due to their poor physical condition [2]. LPDKT is complex because the perioperative hemodynamics are unstable, and it is difficult to adjust the use of drugs during and after surgery, which makes successfully combined transplantation challenging. According to statistics, the 5-year survival rates of diabetic patients after liver transplantation are significantly lower than those of nondiabetic patients, so diabetic patients must strictly control their blood glucose level after organ transplantation to keep it in the normal range [3,4]. Herein, we discuss a case where 1 patient with end-stage liver disease, post-chronic hepatitis B cirrhosis, uremia, and insulin-dependent diabetes mellitus (IDDM) was successfully transplanted and recovered, the details of surgical techniques, and immunosuppressive treatment regimens.

Case Report

ETHICS STATEMENT:

The study was approved by the Institutional Ethics Committee for Clinical Research and Animal Trials of the First Affiliated Hospital of Sun Yat-sen University, and an informed consent waiver was granted by the IEC given the retrospective nature and minimal risk of the study. The patient gave consent for his details and accompanying images to be published.

Discussion

Classic orthotopic liver transplantation combined with heterotopic pancreas transplantation is the standard treatment for chronic hepatitis B cirrhosis, IDDM, and uremia. There are few reports (Table 3 [7–11]) on the treatment of combined LPDKT in patients with end-stage liver disease, renal disease, and IDDM because patients with all these conditions are rare. There is no conclusive evidence yet to suggest an internal causative relationship among end-stage liver disease, chronic renal failure, and diabetes.

Surgical treatment of patients with multiple organ failure is often difficult because of the patients’ poor physical condition. The complex surgical process, unstable hemodynamic changes [12], and many contradictions regarding the adjustments of medication during and after the operation increase the difficulty of a successful combined LPDKT. However, this type of surgery will reduce the complications of pancreas transplantation affecting a previously transplanted liver, such as vascular embolism, pancreatitis, or a local abscess. Moreover, it can also reduce the damage to the liver produced by pancreatic complications when reoperation is required, and it will facilitate the operation, but this technique is very difficult [13]. Some studies have shown that combined liver transplantation can reduce the recipient’s rejection of the transplanted organs, while the insulin and glucagon produced by the pancreas have nutritional protective effects on the liver [14,15]. The pancreas relies on portal vein reflux, which makes the metabolism of insulin more stable [16].

Therefore, combined pancreas transplantation should be considered for patients with organ failure complicated with diabetes. The grafts should all be taken from the same donor with a similar genetic background and antigenicity. This will produce fewer donor-specific antibodies than grafts from different donors. The symptoms of diabetes can be corrected at the same time as uremia and liver failure. Combined en bloc liver-pancreas transplantation has been proven to be effective in treating end-stage liver disease with IDDM [17,18]. Zhang et al [7] reported the long-term effects of liver-kidney-pancreas transplant for patients with advanced liver disease, hepatitis B cirrhosis, chronic renal failure, and chronic pancreatitis caused by insulin-dependent diabetes, and achieved satisfactory long-term effects after 14 years of follow-up, without any rejection or other complications. Kornberg et al [19] reported SLPT for 14 liver cirrhosis and IDDM patients. All recipients could discontinue insulin therapy shortly after the operation. The 7-year survival rate of the recipients was as high as 64.2%, and only 1 patient experienced diabetes relapse. Li et al [9] reported simultaneous LPDKT in a patient with hepatitis B cirrhosis, uremia, and IDDM. The patient was hospitalized for 47 days and did well with normalization of transplanted organ function. Therefore, combined LPDKT is effective in the treatment of diabetes with liver and kidney failure and has better long-term effects than combined liver-kidney transplantation.

Like the original technique of pancreas graft exocrine drainage, the bladder-drained grafts always had to be revised to enteric drainage owing to complications such as urinary tract infections, metabolic acidosis, and reflux pancreatitis from urinary retention. Bladder drainage may have a selective benefit to allow for an earlier diagnosis of graft rejection by allowing monitoring of urinary amylase levels, but its status has been questioned because of improvements in immunosuppression. Subsequently, enteric drainage becomes another most physiologic approach for drainage of exocrine secretions.

According to data from the United Network for Organ Sharing (UNOS) and the International Pancreatic Transplant Registry (IPTR) [20,21], from 2006 to 2016, 8.4% of pancreases underwent bladder drainage, 18.5% underwent enteric drainage using a Roux limb, and 66.4% underwent enteric drainage without a Roux limb. The survival rates of recipients and grafts for all strategies were similar. Enteric drainage is preferred because it can drain pancreatic secretions into the dysfunctional intestine, thereby transferring the contents of the small intestine from the transplanted duodenal-jejunal anastomosis. However, it can be easier to achieve graft rescue if the duodenum-jejunum anastomosis leaks when perforation occurs [22].

To improve the surgical process, the donor’s superior mesenteric artery and celiac arteries were anastomosed to a Y graft of the internal iliac artery and external iliac artery from the same donor to allow for a single vascular anastomosis (the common iliac artery) (Supplementary Figure 1). The artery and the recipient’s hepatic artery were anastomosed in an end-to-end fashion. The procedure of single opening vascular reconstruction is completed during the pruning of the organ clusters, which can appropriately prolong the vascular pedicle and shorten the anhepatic phase to make the anastomosis operation more convenient. It has been reported [23] that a long anhepatic phase will aggravate the ischemia-reperfusion injury (IRI) of the graft, which is of great significance for the recovery of postoperative organ function. After reperfusion of the organ cluster, we performed a modified uncut jejunal loop anastomosis (a Warren anastomosis) between the graft duodenum and recipient’s jejunum for exocrine pancreatic and biliary drainage. Warren anastomosis is a new anastomosis method for choledochojejunostomy, performed behind the antrum pyloricum after lifting the jejunum 15–20 cm away from the ligament of Treitz to the hilar of the liver and anastomosed end-to-side with the bile duct stump, and then the proximal jejunum is anastomosed side-to-side with the bile-draining jejunal loops 40 cm from the bile-enteric anastomosis to form a loop [24,25]. Compared with patients undergoing Roux-en-Y choledochojejunostomy, this surgical procedure is performed without cutting off the jejunum. Only the intestinal tube is ligated, and its normal electrophysiological conduction is not disrupted. Therefore, it is more conducive to the drainage of pancreatic juice, bile, and intestinal contents, reducing the incidence of intestinal loop motility disorders. The patient’s anus exhausts faster, and gastrointestinal function is recovered faster after surgery.

Donor organs are easy to procure and trim for multiple organ transplantation. Only 4 to 5 vessels need to be anastomosed during transplantation to make a jejunal anastomosis without a biliary anastomosis. In addition, the bile and pancreatic juice enter the recipient directly through the duodenum, which is more in line with the normal physiological function. Therefore, classic orthotopic liver transplantation, pancreas-partial duodenal transplantation, and heterotopic kidney transplantation are the best choices. In this case, the patient had end-stage liver disease, post-chronic hepatitis B cirrhosis, uremia, and insulin-dependent diabetes mellitus. After combined transplantation, exogenous insulin was stopped. The function of the liver and kidney and blood glucose levels returned to normal and satisfactory results were achieved.

Allograft rejection is still one of the important factors affecting the efficacy of organ cluster transplantation [26]. There is no perfect immunosuppressive program for multiple organ transplantation due to the small number of cases. At present, many researchers advocate that a combined immunosuppressive regimen should be used after hepatopancreas-duodenal organ cluster transplantation. The quadruple immunosuppressive regimen of this patient was based on basiliximab, tacrolimus, MMF, and Pred, and no allograft rejection occurred within 47 days after transplantation. Basiliximab was used to induce immunity at the end of the operation and on POD 4. The concentration of tacrolimus was stabilized to 8–10 μg/L in the first 3 months. The application of hormones can easily induce postoperative hyperglycemia and diabetes recurrence, and it is recommended that postoperative hormones be quickly reduced and discontinued early for such patients. Our patient recovered and was discharged home after 47 days of hospitalization, insulin-independent, and maintaining a healthy diet and good physical condition 365 days after transplant.

Decompensated cirrhosis secondary to hepatitis B is an absolute indication for liver transplantation, but it is necessary to prevent hepatitis B virus reinfection in the early period after surgery. We used high-dose anti-hepatitis B immunoglobulin to prevent hepatitis B virus infection during and after surgery, checked his HsBAb and HBV DNA regularly, and adjusted the dosage of anti-hepatitis B immunoglobulin. Preventing the recurrence of hepatitis is key for long-term survival [27].

This article reports a rare case in which the patient was diagnosed with decompensated cirrhosis secondary to hepatitis B with chronic renal function failure and uremia, IDDM, and kidney stones. We discussed the necessity of choosing this technique. The main advantage of this technique is its rapidity because of rebuilding the vessels in ex vitro and simplicity since it involves only 4 large vascular anastomoses and 1 duodeno-jejunostomy with no separate biliary anastomosis. This new choledochojejunostomy anastomosis method promotes the postoperative recovery of patients. We used a quadruple immunosuppressive regimen, including basiliximab, tacrolimus, mycophenolate mofetil (MMF), and prednisone acetate (Pred), and gradually transitioned to maintenance therapy with tacrolimus alone. We hope that our center’s experience can provide a reference for the selection and perioperative management of clinical multiorgan transplantation.

Conclusions

Simultaneous classic orthotopic liver, pancreas-duodenum, and heterotopic renal transplantation is a promising therapeutic option for patients with insulin-dependent diabetes combined with end-stage hepatic and renal disease, and our center’s experience can provide a reference for clinical multiorgan transplantation.