Deceased vs living donor grafts for pediatric simultaneous liver‐kidney transplantation: A single‐center experience

Abstract Introduction In conditions of limited experience of pediatric simultaneous liver‐kidney transplantation (SLKT) using grafts from living and deceased donors, there is a certain need to validate the approach. Patients The retrospective study of 18 pediatric patients who received SLKT between 2008 and 2019. Results Grafts were obtained from both living and deceased donors. The patients’ age ranged from 2 to 16 years (9 years ±4). The body weight of the children varied from 9.5 to 39 kg (22 kg ±9). The follow‐up period lasted from 1 to 109 months (median 38 months ±35). The various graft combinations were used in both groups. There was no mortality during the follow‐up. There was no significant difference in baseline parameters in recipients who received grafts from living and deceased donors except age (7.5 years ±2.2 vs 11.8 years ±4.1; P = .038). Rate of complications > grade II was higher among recipients of deceased donor SLKT (7.7% vs 60%; OR, 7.8; 95% CI, 1.04‐58.48; P = .044). All the patients are alive with both grafts functioning. All the living donors returned to the normal life. Conclusion SLKT is a safe and effective procedure for children with both simultaneous end‐stage liver disease and end‐stage renal disease. Both living donor partial liver and kidney transplantation and deceased donor liver‐kidney transplantation can be considered as safe and feasible options.


| INTRODUC TI ON
The first successful simultaneous liver and kidney transplantation (SLKT) was performed at the University of Innsbruck in 1983 by R. Margreiter. Since that time, SLKT has been established as the treatment of choice for the pediatric and adult patients with simultaneous end-stage liver and end-stage kidney disease. 1,2 In standard clinical practice, the MELD (model for end-stage liver disease) scoring system is used as a disease severity index to help prioritize the allocation of organs for transplantation. Currently, more than 400 SLKT are performed annually in Europe and the United States. Most of the patients are adults. 2 In contrast, SLKT is still an extremely rare procedure in children and adolescents. Only approximately thirty pediatric SLKT procedures are performed every year worldwide, and SLKT accounts for 1%-2% of all pediatric liver transplants.
Approximately 1/3 of the recipients are under 5 years of age, and 2/3 of the recipients are between 6 and 17 years old. 3 Both simultaneous and sequential combined liver-kidney transplants from the same living donor have been described. 4 The first successful combined kidney and liver transplantation from a living donor was reported by Marujo et al in 1999. 5 The first case of laparoscopic partial liver and kidney procurement was described by our transplant team recently. 6 Combined liver and kidney transplantation can be indicated in pediatric patients for one of the following several reasons: (a) A patient has a disease leading to irreversible hepatic and renal failure, such as an autosomal recessive polycystic kidney disease (ARPKD) with associated congenital hepatic fibrosis; (b) a patient has end-stage renal failure caused by impaired substance metabolism in the liver, such as in primary type 1 hyperoxaluria (PH1) or atypical hemolytic-uremic syndrome (aHUS) with mutation of complement factor H 7 (liver transplantation is performed to correct the underlying defect and prevent disease recurrence in the renal graft 8 ); or (c) a patient has acute combined liver and kidney injury (such as drug toxicity or vascular damage). Of note, this final indication is much more commonly observed in adults rather than in children. 9 For the particular case of children with ARPKD, the indications for liver transplantation include the following: liver failure (with portal hypertension or without), recurrent cholangitis, cirrhosis (verified by biopsy), or "acute" mutations of polycystic kidney disease. 9,10 The ethical aspect of related organ donation remains controversial, especially in the case of multiorgan living donation. 11 In pediatric practice, one of the parents of the recipient usually volunteers to become a living donor. Thus, the close emotional relationship normally observed between parents and children can make ethical issues easier to solve. 12 While several groups have published their limited experiences in pediatric SLKT, more publications are certainly needed to validate the approach across multiple centers.
In the present series, we provide and discuss the results of 18 pediatric patients that underwent combined liver and kidney transplantation at our center.

| PATIENTS AND ME THODS
A retrospective review and analysis was performed on prospectively collected data from an institutional database of surgeries, which oc-

| Patients
During the study period, 816 liver transplants were performed at our center, and 18 of them were combined liver and kidney transplants (in eight boys and 10 girls).
When a patient with ARPKD with CHF is listed for CLKT, the following principles are taken into account: liver function (PELD score), presence of portal hypertension, quality of life (skin itching), and repeating severe biliary infections.
In 13 cases, the liver and kidney transplants were procured from living donors, and in five cases, they were procured from deceased donors. The first pediatric SLKT using the grafts from a deceased donor in our center was performed in August 2017. In two cases, liver and kidney grafts were procured from the same living donor using a purely laparoscopic approach.

| Selection of the living donors
According to Russian law, only genetic relatives may be considered as living donors. Primary assessment of all donors included estimation of general health and obtaining informed consent. Next, a potential donor underwent laboratory, instrumental, and functional examination. Finally, liver and kidney anatomy and function assessments were carried out. In particular, preoperative evaluation included the analysis of the vascular anatomy (via CT scan), the biliary anatomy (via MR cholangiography), and the tissue suitability (via liver biopsy).
Furthermore, the inclusion criteria for the laparoscopic procedure additionally included the presence of standard arterial (Michaelis types I-III) and venous anatomy.

| Split-liver procedure (deceased donors)
Donors with brain death younger than 45 y.o. without limitations (hemodynamically stable with the use of ≤2 vasopressors, <5 days in ICU, serum sodium level <160 mmol/L, liver ultrasound without evidence of steatosis, normal or subnormal total serum bilirubin and transaminases) were considered for split-liver transplantation.
The final decision was made after gross liver examination as well as arterial anatomy evaluation. In situ liver resection was applied as a method of choice in order to reduce the graft cold ischemia time.
Conversion to ex situ splitting on the back bench was performed if hemodynamical instability developed during the resection.

| Surgical technique
At least a day before the surgery, all the patients undergoing renal replacement therapy (RRT) had been given a hemodialysis session.
The surgical technique of SLKT does not significantly differ from an isolated liver or kidney transplantation. Depending on the anthropometric characteristics of the recipient, the following graft combinations were applied: left lateral section and kidney, left lobe and kidney, right lobe and kidney, or whole liver and kidney.
An appropriate graft type was chosen based on the weight of the patient, the abdominal cavity size of the recipient, the availability of the organ for transplantation, and the severity of the underlying disease.
All procedures were done using our institution's stepwise SLKT surgical approach included consequential steps: vascular reconstruction of the liver graft (caval anastomosis, portal anastomosis, followed by reperfusion and arterial anastomosis), vascular reconstruction of the kidney graft (followed by kidney reperfusion and ureterocystoanastomosis), and biliary reconstruction. This particular series of steps reduces both hepatic warm ischemia and renal cold ischemia to the minimal time necessary.
Bilateral nephrectomy was performed in all of the recipients in order to prevent infection and malignancy of the native kidneys in the future.
Ureterocystoanastomosis was accompanied by routine stent placement. The biliary reconstruction was performed as a Rouxen-Y choledochojejunostomy in 14 cases (77.8%) and as duct-to-duct anastomosis in four cases (22.2%). Stent drainage was applied occasionally based on the diameter of the duct.
Methylprednisolone (5 mg/kg) was administrated twice during the surgery: first after liver reperfusion and again after kidney reperfusion. The basic immunosuppressive protocol included tacrolimus, low-dose methylprednisolone, and mycophenolate mofetil (MMF). During the first 3 months after SLKT, the concentration of tacrolimus in the blood was maintained at the level of 7-12 ng/mL.
Individual side effects of MMF such as diarrhea or leukopenia were considered outcomes, which triggered consideration for discontinuation of the drug.

| Statistical analysis
Continuous variables were reported as mean ± standard deviation

| RE SULTS
The baseline perioperative parameters of the recipients such as age, gender, body weight, diagnosis, presence of renal replacement therapy before the transplantation, graft type, RRT before surgery, ABO compatibility with the donor, graft-to-recipient weight ratio, recipient surgery duration, and immunosuppressive regimen are summarized in Table 1. Baseline parameters of the donors such as age, sex, BMI, and relation to the recipient are reflected in Table 2.
The age of the patients ranged from 2 to 16 years (9 years ±4).
The weight varied from 10 to 38 kg ( In all cases, the kidney and liver transplants were procured from the same donor. In three cases of split-liver grafts, two were LLS grafts after the "classical" split and one was a right liver graft obtained by "full left/full right" splitting. No mortality occurred among the living liver donors. In 11 cases, the related donors were the mothers of the patients and in two cases the uncles. The age of the donors ranged from 25 to 47 years (35.5 ± 3.5), BMI from 20 to 26 kg/m 2 (22.7 ± 1.5).
After the surgery, all the patients were observed in the intensive care unit (ICU) while requiring mechanical ventilation (MV). The average time spent by recipient on MV in the ICU was 9 (±7.7) hours.
One patient required CVVH in the ICU due to delayed renal graft function, which resolved after the appropriate treatment. Other than age and follow-up (Table 1), there were no statistically significant relationships found between the perioperative parameters of the recipients and their respective donation source (living vs deceased).
Also, 1 (5.5%) patient developed hepatic artery steal syndrome, which was resolved by selective embolization of the splenic artery. During the time of the study, the readmission rate was 5.5% (n = 1) due to liver graft dysfunction caused by biliary stricture. Besides, four patients have been at least once admitted to a local hospital due to viral infection (n = 1; 5.5%), MMF-induced leukopenia (n = 1; 5.5%), seizures (n = 1; 5.5%), and motor vehicle collision (n = 1; 5.5%) with no long-term negative consequences. The overall rate of complications greater than Clavien-Dindo grade II was significantly higher in the group of deceased donor SLKT (OR, 7.8; 95% CI, 1.04-58.48; P = .04).
Complications greater than Clavien II have been found in three living donors (23.1%). Two of these cases were biliary leakage (ISGLS grade B), which were successfully resolved by placement of a percutaneous drain. In one case, a donor required a second operation to correct a non-resolving (>4 weeks) biliary fistula. All of the patients are alive and have achieved satisfactory function of both grafts (Figure 1).
All the related donors returned to their normal professional and recreational activities. No donor displayed evidence of abnormal liver or kidney functioning during the entire observation period.

| D ISCUSS I ON
Few recent studies have been published on this subject. 16 The combination of these two procedures can gain from the traditional benefits of minimal surgery (eg, reduced pain and blood loss, shorter duration of hospital stay, and enhanced rehabilitation) in particular. However, it is a subject for further investigations.
Our study, in agreement with others, confirmed that the most common indication for SLKT is the ARPKD associated with congenital hepatic fibrosis. [18][19][20][21] Indications for liver transplantation included evaluation of liver In summary, our work shows that SLKT can be successfully applied for ARKPD/CHF patients with promising long-term outcomes. [24][25][26][27][28] Both split-liver-kidney from deceased donors and living donor liver-kidney approaches are effective procedures with similar outcomes in the recipients. At the same time, we believe that living donor morbidity can be diminished and rehabilitation can be enhanced with the implementation of a laparoscopic minimally invasive approach.

| CON CLUS ION
Pediatric simultaneous liver and kidney transplantation is a safe and effective method of treatment for children with simultaneous endstage liver failure and end-stage renal failure. Living donors can be considered for simultaneous partial liver and kidney procurement. In addition, deceased donors can remain an important source of grafts for combined pediatric liver-kidney transplantation since both splitliver-kidney transplants from deceased donors and living donor liverkidney transplants have shown similar outcomes in the recipients.

CO N FLI C T O F I NTE R E S T
The authors declare no conflicts of interest.