In contrast to isolated liver transplantation (L-Tx) or isolated renal transplantation (R-Tx), combined liver–kidney transplantation (CLKT) is a procedure in which a whole or partial liver and a kidney from the same donor are transplanted during the same surgical procedure. Although pediatric CLKT is a rare practice, with 10–30 pediatric procedures per year worldwide [1▪], the knowledge of experienced tertiary centers has improved since 1984, the year of the first CLKT ; this surgery is currently feasible, even for patients with low body weight [3–5].
CLKT can be proposed in case of inherited inborn errors of metabolism in which the primary defect corresponds to an hepatic enzyme, such as the peroxisomal alanine:glyoxylate aminotransferase in primary hyperoxaluria type one (PH-1) [6▪▪], or the vitamin B12-dependent enzyme methylmalonyl-CoA mutase in methylmalonic academia (MMA) [7▪]. CLKT can also be proposed in atypical hemolytic uremic syndrome (aHUS) [8▪], and in case of genetic diseases with severe damage to the kidneys and the liver, for example autosomal recessive polycystic kidney disease (ARPKD) and other ciliopathies . Last, even though it remains exceptional in pediatrics, CLKT can be also discussed in patients presenting with severe liver disease and chronic kidney disease (CKD) or end-stage renal disease (ESRD) .
Results of pediatric data are globally promising [10,11]; recent reports demonstrated that pediatric CLKT can be performed even in children less than 15 kg body weight [4,5]. The immediate postoperative course is important for both patient survival and long-term outcomes. The main questionable issues are the safety of the procedure in the smallest children, the specific management after CLKT that should be applied in patients with PH-1 in order to prevent disease recurrence on the renal graft and the timing of CLKT, namely whether it is better to perform a combined or a sequential transplantation in PH-1 and ARPKD [12▪,13]. The aim of this review was therefore to provide a 2015 update on pediatric CLKT.
Combined liver–kidney transplantation for primary hyperoxaluria type one
PH-1 induces oxalate overproduction and massive urinary excretion of calcium oxalate [6▪▪]. Besides the oxalate accumulation in the kidney leading to CKD and further ESRD, insoluble oxalate accumulates in the skeleton and vessels. As the metabolic defect is in the liver, isolated R-Tx cannot correct the primary metabolic defect. In such a case, the high rate of urinary oxalate excretion originates from both ongoing oxalate production from the native liver and oxalate deposits in tissues will induce a rapid recurrence on the renal graft.
In Europe, poor results of isolated R-Tx were reported 20 years ago, the 3-year graft survival ranging from 17 to 23% (and a 5-year graft survival of only 14% in children), with a risk of recurrence up to 90–100% in the absence of L-Tx . Therefore, this strategy cannot be recommended any longer. Isolated R-Tx, however, remains a possible temporary solution in developing countries before transferring the child in a specialized center for further CLKT procedure .
Thus, CLKT will be required in most patients with PH-1. In that setting, most teams use cadaveric donors, but a living related donor may be considered . DNA analysis must confirm the diagnosis before discussing any Tx procedure, because some patients present with PH without alanine:glyoxylate aminotransferase deficiency. A diagnosis of PH-type 2 (PH-2), PH-type 3 or another unidentified type of PH will therefore be made; in these non PH-1 types of PH, the Tx strategy is not completely delineated yet . Indeed, isolated R-Tx could be the preferable treatment in patients with PH-2: a more favorable course after isolated R-Tx was reported in this group , but others challenged this observation, by reporting failure of isolated R-Tx in a pediatric PH-2 patient because of recurrence . Responsiveness to pyridoxine should also be evaluated before transplantation, as some patients may benefit from isolated R-Tx if pyridoxine is maintained; however, the rationale for such an approach relies only on case reports or small series .
In case of PH-1, the 2009 KDIGO guidelines suggest preventing oxalate deposition after CLKT until plasma and urine oxalate levels are normal with the following supportive measures: first, increased oral fluid intake, second, potassium or sodium citrate, and third, intensive hemodialysis to remove oxalate if necessary . It remains debatable to perform systematic hemodialysis after CLKT to clear oxalate so as to avoid an early release of oxalate deposits on the renal graft; it should be limited to patients with significant systemic involvement . In all patients, hyperhydration (2–3 l/m2 per day), often requiring a gastro-intestinal tube (G-tube) or a gastrostomy, is a cornerstone because of the progressive oxalate release from the skeleton [12▪].
First series reporting multicenter European pediatric experience of CLKT in PH-1 were published in 1991, from 14 centers having performed 22 CLKT . Ten years ago, Shapiro et al. showed high mortality rate in PH-1 patients undergoing CLKT, with 50% of death after 9 years of follow-up. More recent studies have demonstrated improved survival rates, for example a 100%-patient survival at 6.7 years in Millan's cohort , and a 75%-patient survival with a mean follow-up of 7.4 years in Gagnadoux's cohort . In Europe, CLKT remains the preferred approach in PH-1. The European PH-1 Transplant Registry reported 127 liver Tx including more than 100 CLKT in 117 patients between 1984 and 2004 . Results were encouraging with patient survival rates of 86, 80, and 69% at 1 year, 5 years, and 10 years, respectively; there were 13 kidney graft failures. Comparable results have been reported from the USRDS, with a patient survival above 80% at 5 years and a death-censored graft survival of 76% at 8-year post Tx . Experience indicates that once perioperative mortality has been avoided, CLKT is an acceptable treatment for PH-1 , even in infants .
In PH-1, the strategy of CLKT should, however, also be influenced by the stage of the disease: patients who are transplanted after a long period of time on dialysis may rather benefit from a sequential L- and R-Tx in order to clear systemic oxalate by dialysis before a send-step R-Tx , as discussed below. As a consequence, if simultaneous CLKT is logical in patients with a GFR between 15 and 40 ml/min per 1.73 m2, a sequential procedure (L-Tx first, then dialysis until sufficient oxalate has been cleared from the body, followed by R-Tx) may be proposed to ESRD patients with a long waiting time undergoing dialysis .
Last, bone fractures in PH-1 patients appear to occur mainly at the femoral neck ; the fracture risk persists after CLKT, but the relative risk in comparison to other patients undergoing pediatric R-Tx for another primary disease is hard to determine . One can hypothesize that the excess risk is observed as long as urine oxalate excretion remains abnormal after CLKT. Therefore, sustained hyperhydration after CLKT seems completely mandatory to protect the renal graft and vessels against oxalate deposition. It could be withdrawn when urinary oxalate/creatinine ratio has normalized, provided its close follow-up afterwards [12▪].
Combined liver–kidney transplantation for methylmalonic academia
Classical (or isolated) MMA is a heterogeneous inborn error of metabolism . Patients may develop complications despite medical treatment, notably severe central nervous system (CNS) damage and CKD. With improved survival of MMA patients, CKD has become recognized as part of the disease, renal biopsies showing extensive interstitial fibrosis, chronic inflammation and tubular atrophy, with progressive renal impairment; additional analyses revealed a defect in electron transport chain, namely a ‘megamitochondrial’ disorder .
A single-centre retrospective study on 14 patients undergoing isolated L-Tx (n = 6) or CLKT (n = 8) at a mean age of 8.2 years (range 0.8–20.7) was recently published by Niemi et al.[7▪]. Eleven (79%) patients were diagnosed during the neonatal period (six neonatal screenings). All underwent a deceased donor Tx; 12 (86%) received a whole liver graft. Of the patients who underwent CLKT, seven underwent preoperative hemodialysis. Postoperative survival was 100%. At a mean follow-up of 3.3 ± 4.2 years, patient survival was 100%, liver allograft survival 93%, and kidney allograft survival 100%. After Tx, no episodes of hyperammonemia, acidosis, or metabolic decompensation were observed. The mean serum MMA levels at the time of Tx were 1648 ± 1492 μmol/l (normal < 0.3, range 99–4420); 3 days post-Tx, levels fell on average by 87% (mean 210 ± 154 μmol/l), and at 4 months, they were 83% below pre-Tx levels (mean 305 ± 108 μmol/l). A more substantial decrease was observed after CLKT in comparison to isolated L-Tx [7▪]. Developmental delay was present in 12 patients (86%) before Tx, but all patients maintained neurodevelopmental abilities or exhibited improvements in motor skills, learning abilities, and social functioning post-Tx.
In MMA, both L-Tx , R-Tx , and CLKT  have been advocated in the past. No guidelines are, however, available to identify the most suitable organ to transplant. As such, Brassier et al. recently reported on four patients with MMA receiving isolated R-Tx, at a mean age of 7.9 years. R-Tx improved the relevant metabolic parameters in all patients. Plasma and urinary MMA levels immediately decreased and remained normal or subnormal, and no further acute metabolic decompensation was observed. One patient died from hepatoblastoma 2 years after R-Tx. One patient presented with CNS impairment before R-Tx that stabilized after R-Tx. These authors concluded that isolated R-Tx is an interesting alternative therapeutic option in MMA, nevertheless highlighting that further CNS impairment remains possible after R-Tx .
Combined liver–kidney transplantation for atypical hemolytic uremic syndrome
Most pediatric HUS are ‘typical’, inducing ESRD in 5–10% of cases, with no risk of disease recurrence after R-Tx. Conversely, 5–10% of children suffer from aHUS, with a more than 50% risk of ESRD, and subsequent high risk of disease recurrence after R-Tx .
The knowledge of genetics and pathophysiology of aHUS has dramatically improved during the last 10 years, the deregulation of the alternative complement pathway being a cornerstone of this disease [36,37]. Because most complement factors are synthesized in the liver (CFH, CFB, and C3), CLKT in association with plasmatherapy before and after Tx has been proposed in the past: indications for such an aggressive and risky option are currently very limited because of the efficacy of the anti-C5 antibody eculizumab, but the option of CLKT with a protective effect of eculizumab periprocedure might represent an option to cure aHUS [8▪,38]. Isolated L-Tx in aHUS patients with functioning kidneys should no longer be recommended as the risks associated with the procedure and the long-term immunosuppression outweigh the possible risks associated with eculizumab therapy [8▪].
Recent pediatric guidelines have reviewed thoroughly the current evidence for diagnosis and management of pediatric aHUS [39▪▪]. The authors wonder what could be the place of CLKT in pediatric aHUS in 2015. Part of the answer may be in the recent review of 20 patients with CFH, CFB, and C3 mutations who received CLKT (N = 19) or L-Tx (N = 1): 16 patients were cured from aHUS with both grafts functioning; however, three patients died in the early postoperative period from vascular complications after years on dialysis . Although most groups would take the option of R-Tx in association with eculizumab, the experts recommend not to completely discard CLKT in these patients, and to discuss all options with patients and families [39▪▪]. Last, eculizumab may not be available in all countries on a long-term basis, and this should also be taken into account [39▪▪].
Combined liver–kidney transplantation for autosomal recessive polycystic kidney disease
ARPKD is a rare entity but the most common renal cystic disease in childhood with an estimated incidence of 1/20 000 live births. It is generally diagnosed in utero or at birth and occurs as a result of mutations in a single gene, Polycystic Kidney and Hepatic Disease 1 (PKHD1) on chromosome 6p12 . ARPKD has multisystem manifestations and is a significant cause of renal and liver-related morbidity and mortality in children, with nonobstructive fusiform dilatation of the renal collecting tubules and congenital hepatic fibrosis . Progresses in neonatal medical care and renal replacement therapy (RRT) have improved the long-term survival of ARPKD patients. Nearly 50% of the patients surviving the neonatal period, however, progress to ESRD within the first decade of life requiring R-Tx. Besides the renal outcomes, hepatic complications such as cholestasis, cholangitis, portal hypertension (hypersplenism, variceal bleeding) are life-threatening and frequently require L-Tx.
The Tx strategies in ARPKD are challenging; there is currently no consensus for the optimal decision. As kidney and liver manifestations progress differently and since the variability of organ involvement is not completely understood, the decision of Tx strategy becomes more difficult. Most often R-Tx is performed first, followed by L-Tx or CLKT later in childhood or adulthood [43,44▪]. CLKT has been suggested as the first treatment option in selected patients who require R-Tx given that immunosuppression is already performed. This approach is mainly based on the fact that 64–80% of the mortality occurring in ARPKD patients with R-Tx is attributed to cholangitis/sepsis related to liver disease; moreover, the liver allograft may be immunologically protective to the kidney graft, specifically if the same donor is used for both kidney and liver. A paradigm for patients selection has been suggested including the Pediatric/Model for End-Stage Liver Disease scores associated with the recurrence and severity of cholangitis and/or the treatment resistance of portal hypertension . It has, however, to be validated in a large cohort. Last, a rapid worsening of CKD represents also a concern in ARPKD patients with liver-predominant phenotype who will first undergo L-Tx.
Very few data are available in long-term outcome of ARPKD and Tx ; hopefully, the recent initiation of a European register of ARPKD will help clinicians in such making-decision issues .
Combined liver/kidney transplantation for other diseases
Liver disease with an occasional kidney failure
Some cases of CLKT have been reported in these following indications, corresponding to primary liver diseases with renal impairment: alpha-1 antitrypsin deficiency, glycogen storage type 1, Alagille syndrome, biliary atresia, primary sclerotic cholangitis, liver disorder with a previous R-Tx and liver tumor with drug nephrotoxicity [1▪].
Ciliopathies and Boichis syndrome
An association of nephronophthisis (NPHP) and congenital hepatic fibrosis, also known as Boichis syndrome, was described in 1973 . Approximately 5% of patients with NPHP have hepatic fibrosis; in these patients, Otto identified homozygous or compound heterozygous missense mutations in the TMEM67 gene, which were not found in 105 NPHP patients without liver fibrosis . We have reported three cases of Boichis syndrome who underwent pediatric CLKT , and another case from Japan who underwent a sequential L- and R-Tx from a living donor .
Combined liver/kidney transplantation: liver and kidney during the same procedure, or liver first and kidney later?
This question is especially raised in PH-1, and the opposition between combined and sequential liver/kidney transplantation is still a matter of debate in 2015 . Indeed, the choice may be based on an immunological rationale, when using the same donor for both organs, but it can also be based on a biochemical rationale, when using a second-step procedure (liver transplantation first, clearance of oxalate burden from bone with hemodialysis, and secondary renal transplantation). The strategy of CLKT may be influenced by the stage of the disease: patients who are transplanted after a long period of time on RRT may rather benefit from a sequential L-and R-Tx in order to clear systemic oxalate by dialysis before a send-step kidney transplantation , but this strategy may also be of interest in case of living donors . Therefore, the option of a two-step procedure cannot be ruled out and should be kept in mind depending on local experience and patients’ characteristics, notably when the waiting time is supposed to be long enough to jeopardize both patient quality of life and survival [6▪▪].
In that setting, even though the mortality rate seems to be similar between combined and sequential transplantation, allograft rejection was described to increase in patients having undergone a sequential KLT . This question of combined versus sequential is therefore of the utmost importance in terms of immunology. Indeed, it has been described that adults with CLKT display lower rates of acute rejection episodes and improved renal allograft survival, when compared with patients receiving either isolated R-Tx in the international CTS registry , either R-Tx sometime after L-Tx in the UNOS database . A single-center retrospective case-control study compared 10 pediatric patients aged 10 ± 6 years having receiving a CLKT to a group of 20 R-Tx matched for age, era, and immunosuppression. A significant reduction in the incidence of acute rejection episodes was observed in the CLKT group. These results were further confirmed at a larger scale with an analysis of the 1995–2005 UNOS database . These findings support the concept that L-Tx is immunologically protective of the kidney allograft in CLKT, but these results have been challenged by others .
Surgical aspects and short-term outcomes of CLKT
CLKT usually includes an orthotopic transplantation of a whole, reduced-size, or split-liver (with a phase of hepatectomy) with an isolated R-Tx from the same donor, the renal graft being implanted in the iliac fossa or intraperitoneally [1▪]. The vascular and biliary anastomoses are critical for L-Tx, whereas the vascular and ureteral anastomoses are important for R-Tx.
As expected, the greater complexity of surgical procedures may jeopardize the short-term outcomes of CLKT. A retrospective series of 15 pediatric CLKT in children (median age 8 years, median body weight 17 kg, median follow-up 23 months) described in the early postoperative period six patients with bleeding complications and eight patients requiring hemodialysis; moreover, three patients presented with vascular complications, and one patient underwent a liver re-Tx 3 months after CLKT. One child underwent a CLKT re-Tx because of primary nonfunction of the liver associated with renal artery thrombosis. The authors also reported renal (N = 2), liver (N = 2), and combined (N = 1) acute rejection in the kidney; infectious complications were observed in two patients .
We recently reported our single-center experience of pediatric CLKT (N = 18 between 1992 and 2013, 14 PH-1, median age 6.7 years, median body weight 13 kg, median follow-up 6 years). In the early postoperative period, dialysis was required in seven patients and bleeding complications were observed in eight patients. Two renal grafts losses occurred early after CLKT in two small recipients (12 and 10 kg) . These results were similar to the ones found by Harps, who reported bleeding in 40% of the patients, and a normalization of plasma creatinine and liver enzymes within 1 month after CLKT .
Thus, bleeding and vascular complications early after CLKT should be anticipated, requiring a timely and interdisciplinary approach. With this management, long-term patient and graft survival is excellent .
Global prognosis of pediatric CLKT
The analysis of the 1995–2005 UNOS database reported 20% of patients in the CLKT group (as compared with 6% in the R-Tx group) who lost their renal graft within the 6 first months after transplantation (P < 0.001) . These apparent discrepancies between negative short-term outcomes and promising long-term outcomes are explained by the technical challenges induced by CLKT, the critically-ill nature of children requiring CLKT and the increased number of early complications because of the greater complexity of surgery [53,54]. The global outcome of CLKT is dependent on the primary cause of hepatic and kidney dysfunction as well as the clinical condition of the patient at the time of CLKT [1▪], but also on the surgeons’ and the center's experience.
A recent registry article from the American Scientific Registry of Transplant Recipients analyzed 152 primary pediatric CLKTs performed between 1987 and 2011, with a median follow-up of 98 months (16 lost to follow-up). All CLKT were performed with deceased donors, and the liver–kidney pair came from the same donor. Patient survival was 86.8, 82.1, and 78.9% at 1, 5, and 10 years, respectively, whereas liver graft survival was 81.9, 76.5, and 72.6%, respectively, and renal graft survival was 83.4, 76.5, and 66.8%, respectively . These results were compared in the American Scientific Registry of Transplant Recipients to pediatric patients receiving isolated L-Tx (N = 10 084) and isolated R-Tx (N = 14 800) during the same time frame: patients’ survival at 1, 5, and 10 years was 86.7, 81.2, and 77.4%, respectively, in patients having received L-Tx whereas it was 98.2, 95.4, and 90%, respectively, in patients having received R-Tx . Interestingly, in patients having undergone CLKT, PH-1 (N = 55 patients) was associated with reduced patient (P = 0.01), liver graft (P = 0.01), and kidney graft survival (P = 0.01) . Furthermore, graft outcome following CLKT improved over the past decade (P = 0.04 for liver, P = 0.02 for kidney), but this did not translate into improved patient survival (P = 0.2); no center performed more than 11 CLKT . This large and recent series confirmed that pediatric CLKT offers similar survival than L-Tx.
The immune-suppressive regimens in CLKT patients are center-dependent and usually associate induction with antiinterleukin-2 receptor, followed by calcineurin inhibitors, antimetabolites, and corticosteroids [1▪,4]. The prevalence of graft rejection is variable [1▪], Millan reporting 50% of renal acute rejection , whereas Gagnadoux did not report any acute rejection . In our experience, we observed five renal and six liver acute rejection .
Different series have confirmed the feasibility of pediatric CLKT with encouraging results in the long term, even in the youngest and smallest patients, provided that highly trained multidisciplinary teams are involved in this global management. The long-term outcomes after CLKT are currently comparable to that of isolated L- and R-Tx, even though the immediate postoperative period remains challenging.
The authors would like to thank all the physicians involved in the highly specialized care of these patients, and notably physicians from the Pediatric Nephrology Unit (Prof Pierre Cochat, Dr Bruno Ranchin, Dr Aurélia Bertholet-Thomas), from the Pediatric Hepatology and Gastro-Enterology Unit (Prof Alain Lachaux), from the Surgery Department (Prof Olivier Boillot, Dr Rémi Dubois, Dr Thomas Gelas, Prof Lionel Badet, Dr Frédéric Hameury, Prof Xavier Martin), and from the Pediatric Intensive Care Unit (Prof Etienne Javouhey).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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