Review Article
Combined Liver Kidney Transplantation in Pediatrics: Indications, Special Considerations, and Outcomes
David Cha1, Katherine Concepcion2, Amy Gallo1 and Waldo Concepcion1*
1Department of Multi Organ Transplantation, Stanford University School of Medicine, USA
2Department of Surgery, Loma Linda University School of Medicine, USA
*Corresponding author: Waldo Concepcion, Department of Multi-Organ Transplantation, Stanford University School of Medicine, Palo Alto, CA 94304, USA
Published: 07 Mar, 2017
Cite this article as: Cha D, Concepcion K, Gallo A,
Concepcion W. Combined Liver
Kidney Transplantation in Pediatrics:
Indications, Special Considerations, and
Outcomes. Clin Surg. 2017; 2: 1352.
Abstract
Combined liver and kidney transplants (CLKTs) are not commonly performed in pediatric
patients. Advancing the medical community’s understanding of when these procedures may be the
optimal choice for pediatric patients and when other options may be preferable is crucial. There are
three main pediatric groups who may be considered candidates for CLKT: (1) those who suffer a
disease that leads to irreversible liver and kidney damage‒including autosomal recessive polycystic
kidney disease; (2) those with end-stage renal disease caused by a liver-based metabolic disease‒
including primary hyperoxaluria types 1 and 2, methylmalonic acidemia, and atypical hemolytic
uremic syndrome; and (3) those who present with concomitant liver and kidney failure‒including
patients with Boichis syndrome (nephronophthisis plus congenital hepatic fibrosis) or with liver
tumor plus nephrotoxicity. We review here the indications and special considerations related to
CLKT for patients in each of these groups and the outcomes seen to date in these pediatric patient
groups. With the appropriate donor selection, family education, and medical team commitment
CLKT has been shown to be and, we believe, will continue to be an outstanding option for medical
management in this select group of patients. Continued advances pre-transplant, intra-operatively
and post-transplant will be required to optimize success.
Keywords: Combined liver kidney transplantation; Simultaneous liver kidney transplantation;
Autosomal recessive polycystic kidney disease; Primary hyperoxaluria, methylmalonic acidemia;
Atypical hemolytic uremic syndrome; Boichis syndrome, Concomitant liver and kidney failure
Introduction
Since the first combined liver and kidney transplant (CLKT) was performed at Innsbruck
University in 1983 [1], 7,255 such procedures have been performed in the U.S. through September
30, 2016 [2]. However, the vast majority of these (6,958) have been in adults, with only 297 CLKTs
performed in pediatric recipients, 124 in children aged 11-17, 77 in those 6-10 years, 88 in those 1-5
years, and only eight in children < 1 year. Worldwide, only 10-30 pediatric CLKTs are performed
annually [3]. Advancing the medical community’s understanding of when these procedures may be
the optimal choice for pediatric patients and when other options may be preferable is crucial.
There are three main groups of pediatric patients who may be considered candidates for CLKT:
(1) those who suffer a disease that leads to irreversible liver and kidney damage‒including autosomal
recessive polycystic kidney disease (ARPKD); (2) those with end-stage renal disease (ESRD) caused
by a liver-based metabolic disease‒including primary hyperoxaluria type 1 (PH1) and type 2 (PH2),
methylmalonic acidemia (MMA), and atypical hemolytic uremic syndrome (aHUS); and (3) those
who present with concomitant liver and kidney failure‒including patients with Boichis syndrome
(nephronophthisis plus congenital hepatic fibrosis) or with liver tumor plus nephrotoxicity [3,4].
We review here the indications and special considerations related to CLKT for patients in each of
these groups and the outcomes seen to date with CLKT in these pediatric patient groups.
Autosomal Recessive Polycystic Kidney Disease
Occurring in an estimated one in 20,000 live births [5], ARPKD is rare but is the most common
renal cystic/ciliopathy disease in childhood. In ARPKD there is a mutation in PKDHD1, a gene
located on chromosome 6p12 that encodes fibrocystin (also known as polyductin), a signaling
molecule in kidney tubuli and liver bile ducts that functions to maintain the 3-dimensional tubular
architecture [6]. Because the fibrocystin signaling defect is variable, there are substantial variations
in the manifestations of kidney and liver injury. Death occurs in 25-30% of neonates with the most severe disease, most commonly from sepsis or respiratory
failure from associated pulmonary hypoplasia. However, substantial
improvements in survival rates are being seen with antihypertensive
therapy and improved neonatal care [7,8]. Both kidney and liver
disease are progressive in most patients, with nearly 50% progressing
to ESRD in the first decade of life. Renal involvement ranges from
a urinary concentration defect in apparently normal kidneys to
fusiform dilatations of the renal collecting ducts leading to the
formation of cysts and renal insufficiency [8-10]. Liver involvement
includes defective remodeling of the ductal plate, abnormal portal
veins and progressive fibrosis of the portal tract [8]. Although all
ARPKD patients have congenital hepatic fibrosis (CHF), not all
develop liver dysfunction. However, hepatic defects often become
progressively more severe with age, with liver disease a major cause
of morbidity and mortality. The histological changes in the liver can
lead to severe portal hypertension, splenomegaly with hypersplenism,
and esophageal varices resulting in bleeding complications [9].
The CHF commonly predisposes to recurrent cholangitis [9]. In
approximately a third of ARPKD patients, Caroli syndrome develops,
characterized by segmental non-obstructive cystic dilatation of
the intrahepatic biliary ducts with conserved association with the
intrahepatic biliary system [11]. In patients with Caroli syndrome,
congenital hepatic fibrosis is always present; in the most advanced
stage, there is hepatomegaly, portal hypertension, cholangitis and
variceal bleeding [9]. Treatment strategies for ARPKD are challenging
due to the fact that the kidney and liver disorders progress differently
and the variability of organ involvement is not completely understood.
In children with early presentation and a need for nephrectomy
secondary to respiratory compromise, dialysis is started in the first
days of life and isolated kidney transplant is done in the first years of
life. Complications from liver disease (portal hypertension, cholangitis
and hypersplenism) after isolated kidney transplant are common and
would then require sequential liver transplant evaluation. In one
study of 14 ARPKD patients who underwent kidney transplant, five
patients died, four from complications of hepatic disease; of the nine
patients who survived, CHF-related complications were present in
56% at a mean of 6.3 years post-transplant [12]. CLKT is indicated in
older children with ESRD and evidence of CHF with hypersplenism
and cholangitis [13]. Isolated liver transplant is indicated in older
children with progressive complications of liver disease and stable
kidney disease.
Primary Hyperoxaluria Types 1 and 2
PH1 is a rare autosomal recessive metabolic disorder, with
an estimated incidence of only one case in 120,000 live births
[14], but is the most common indication for CLKT in children.
The cause of PH1 is deficiency or mislocalization of the liverspecific
peroxisomal enzyme alanine-glyoxylateaminotransferase
(AGT) [11]. Because AGT is required to catalyze the conversion of
glyoxylate to glycine, the enzyme deficiency results in the conversion
of glyoxylate to oxalate which forms insoluble calcium salts which
can collect in the kidney and other organs [15]. This can result in
recurrent nephrocalcinosis (deposition of calcium oxalate in the renal
parenchyma), nephrolithiasis (deposition of calcium oxalate in the
renal pelvis/urinary tract), or ESRD with a history of renal stones or
calcinosis [11-15]. There is substantial variation in the presentation
of PH1, with the age at onset of symptoms ranging from birth to
the sixth decade, with a median age of 5-6 years [16]. In the more
severe, infantile form of PH1, 80% develop ESRD by the age of three
years [17]. Data from a 1990 German study had indicated that by
age 15 approximately 50% of patients develop ESRD [18]. However,
later surveys performed in Switzerland and France found that ESRD
occurred in only 20% of patients by the age of 15 but in 50% of patients
by the age of 25 [19-20]. When the glomerular filtration rate (GFR)
drops below 40 mL/min/1.73m2, oxalate is deposited systemically into
bone and soft tissue including the retina, the blood vessels, the nerves
and the heart [13]. Because some infants are pyridoxine sensitive and
will show improvement in renal function with high-dose vitamin
B6 [14], responsiveness to pyridoxine should be evaluated prior to
transplantation. The specific pathogenic variants p.Gly170Arg and
p.Phe152Ile are associated with a positive response to pyridoxine
supplementation, especially for homozygotes, so testing for these may
have predictive value [14,21,22].
CLKT is the procedure of choice for PH1 patients [23-27] in order
to protect the transplanted kidney from the same damage experienced
by the native kidneys. Data from the United States Renal Data System
shows patient survival above 80% at 5 years, with graft survival of
76% eight years post-transplant [28]. Data from the European PH1
Transplant Registry on 100 CLKT procedures performed from 1984
to 2004 has shown patient survival rates of 86%, 80%, and 69% at
one, five, and ten years, respectively, with 13 kidney graft failures [29].
Small studies have pointed to important therapeutic considerations
with patient and graft survival rates of 75% (at 5 years) in children
with early CLKT in whom high hydration was maintained for 6
months to 5 years as long as oxaluria exceeded 0.5 mmol/day [30] and
100% (at 6.7 years) in infants with early diagnosis and early CLKT,
aggressive pre-transplant dialysis, and avoidance of post-transplant
renal dysfunction [31].
Because of the high risk of postoperative renal dysfunction due to
mobilization of oxalate from other tissues, experts in the field suggest
that sustained hyperhydration post-CLKT should be considered
mandatory to protect the renal graft and vessels from oxalate
deposition, with discontinuation only when the urinary oxalate/
creatinine ratio has normalized [11,13]. Postoperative crystallization
inhibitors are also recommended to prevent disease recurrence in
the new kidney [11]. In addition, both intensive dialysis prior to
transplantation and postoperative hemodialysis post-transplant
until urine oxalate levels are normal are recommended to reduce the
oxalate pool, preventing deposition of oxalate in the kidney graft [11].
Sequential transplantation beginning with the liver can be considered
when a kidney is not available [27] and in PH1 patients with stage 5
chronic kidney disease (estimated GFR less than 15 ml per minute
per 1.73 m2) [27] so that the new liver can allow aggressive dialysis
to mobilize some of the systemic oxalate burden prior to the kidney
transplantation, thus protecting the kidney graft [32-33]. DNA
analysis should always be done to confirm the diagnosis of PH1
prior to consideration of CLKT [13]. With PH1, isolated kidney
transplant is no longer recommended [13]. It cannot correct the
primary metabolic defect since it is in the liver, and multiple studies
have shown very poor renal graft survival due to the continuing high
level of urinary oxalate excretion that results from both ongoing
oxalate production by the native liver and oxalate deposits in tissues
[13,33]. Only in developing countries where isolated renal transplant
might provide a temporary solution until a child can be brought to a
specialized center for CLKT is kidney transplant alone still considered
[23].
Primary hyperoxaluria type 2 (PH2) is an autosomal recessive metabolic disorder that is thought to be less common than PH1 but
for which there is currently no prevalence data [34]. The cause of PH2
is deficiency of the enzyme glyoxylate reductase-hydroxypyruvate
reductase (GRHPR), the lack of which results in substantial
overproduction of oxalate and, thus, hyperoxaluria [11]. PH2
onset is most commonly in childhood with presenting symptoms
typically those associated with renal stones, including renal colic,
hematuria, and urinary tract obstruction [35-36]. In comparison to
PH1, the clinical course of PH2 is generally more benign but there
may be recurrent nephrolithiasis (deposition of calcium oxalate in
the renal pelvis/urinary tract) and nephrocalcinosis (deposition of
calcium oxalate in the renal parenchyma) [34], as well as ESRD in
approximately 20% of cases [11]. In PH2 patients with ESRD, oxalosis
(widespread tissue deposition of calcium oxalate) is common [34].
Although experience with organ transplantation in PH2 patients is
limited, isolated kidney transplantation has been suggested as the
possible procedure of choice [27,37]. However, the failure of this
procedure in a pediatric PH2 patient because of disease recurrence has
led others to question this and suggest that CLKT might be preferable
[38]. Bacchetta et al. [13] suggest that responsiveness to pyridoxine
should be assessed in PH2 patients prior to transplantation since it
is possible that some may benefit from isolated kidney transplant if
pyridoxine is maintained but note that only case reports and small
series support such an approach.
Atypical Hemolytic Uremic Syndrome
Atypical hemolytic uremic syndrome (aHUS) is a rare progressive
disease most commonly the result of complement alternative
pathway (AP) dysregulation, the cause of 60-70% of cases [39-
42]. In aHUS there is impaired synthesis or function of factor H, a
complement control protein that normally controls complement
activation through the alternative pathway, resulting in deposition
of complement, destruction of microvasculature, and severe renal
and neurological involvement [43]. The disease is characterized by
microangiopathic hemolytic anemia, thrombocytopenia, and renal
impairment [39]. CLKT is no longer commonly recommended for
aHUS because eculizumab (Soliris, Alexion Pharmaceuticals, New
Haven, Connecticut), a recombinant humanized monoclonal IgG2/4
antibody that binds to the terminal complement component 5 (C5),
has been shown to be an effective treatment for most patients with
aHUS, combined with isolated kidney transplant, if necessary. Studies
to date have shown that eculizumab yields sustained inhibition of
complement-mediated thrombotic microangiopathy (TMA) and
allows improved or preserved renal function in the majority of
patients with aHUS, including both children and adults [44-46].
However, certain gene mutations are associated with altered response
to eculizumab. Mutations in multiple genes have been associated
with increased aHUS susceptibility, including CFH, CFI, MCP,
C3, CFB and THBD (thrombomodulin). In addition, mutations in
DGKE have recently been shown to be associated with complementindependent
forms of aHUS in which aHUS develops before age one
and results in hypertension, hematuria and proteinuria (sometimes
in the nephrotic range), with chronic kidney disease developing with
age [47]. In patients with isolated DGKE mutation, no benefit was
observed from eculizumab treatment [47]; in a patient with both
DGKE mutations and an associated C3 variant, eculizumab treatment
was associated with clinical improvement but persistent proteinuria
[48]. In addition, a C5 variant that prevents eculizumab from binding
to C5 has been identified in Asian-origin patients who were resistant
to eculizumab [49].
Because the only other approach used in the past, plasma
exchange/plasma infusion had limited efficacy with a high rate of
complications [50] and considerable morbidity in children, isolated
kidney transplant had been tried. However, post-transplant aHUS
recurrence occurred in 60% of patients [39,51], with five-year
graft survival of only 30% in patients with recurrence and 68%
in patients without recurrence [51]. Prophylactic eculizumab has
been successfully used to prevent post-transplant recurrence in
patients in whom previous grafts had been lost due to recurrence
or who had high-risk genetic abnormalities (CFH, C3, and CFB +
CFI mutation) [52]. Patients treated with eculizumab after posttransplant
recurrence have most often not reached full return of
graft function [52]. In a 2016 international consensus statement
by experts from Europe, Canada, Turkey, and the United States
prophylactic eculizumab is recommended for patients at high risk
of post-transplant recurrence; additional research will be required
to determine when or if eculizumab withdrawal might be possible
[52]. In the consensus statement these experts also note that liver
transplantation or CLKT is the only way to cure aHUS in patients
with severe aHUS and mutations of complement factors synthesized
in the liver (CFH, CFB and C3) [52]. They recommend that CLKT
should still be considered an option that should be discussed with
patients and families, with full consideration of risks and benefits, and
factoring in whether the cost of long-term eculizumab treatment after
isolated kidney transplantation can be covered. There is currently
substantial variation in eculizumab availability due to the extremely
high cost of the drug; it is currently one of the most expensive drugs
in the world. With any consideration of transplant, there should be
meticulous pre-transplant multidisciplinary evaluation to assure that
there is no metabolic crisis, infection or precipitating factor. Pre- and
intra- operative plasma exchange can be used to inhibit unregulated
complement deposition.
Methylmalonic Acidemia
Methylmalonic acidemia (MMA) is an autosomal recessive
disease of methylmalonic acid metabolism that results from either
complete (mut0) or partial (mut-) congenital deficiency of the vitamin
B12-dependent enzyme methylmalonyl-CoA mutase (MUT) or from
defective adenosylcobalamin (cblA, cblB, cblD variant 2) metabolism
[43]. Despite detection of MMA through newborn screening and the
use of medical therapies, it causes significant morbidity and mortality
in infancy and childhood and, for those who reach adulthood,
significant debilitating end-organ damage [53], with substantial risk
for metabolic decompensation and multiple long-term complications
[54]. Although dietary management with medical foods has long
been a major component of MMA therapy, it has been shown that
even well-controlled MMA patients are at high risk for renal, cardiac,
ophthalmological, growth, and neurological complications [53].
Patients commonly present with metabolic crisis, profound acidosis,
seizures, neurological impairment and developmental delay [55-57].
With improved survival of MMA patients, chronic kidney disease
due to tubule interstitial injury has become recognized as part of
the disease, with some renal insufficiency present in 100% of MMA
patients and progression to ESRD and need for transplant common
[53,58,59]. In adolescents with MMA, it is estimated that the
prevalence of ESRD is 20-60% [57]. In a study of long-term outcomes
it was found that ESRD develops in 61% of MMA mut0 patients and
66% of cblB patients [60]. The study found that patients with mut0 and
cblB defects had earlier symptom onset, as well as a higher frequency of complications and deaths and more pronounced MMA urinary
excretion compared to those with mut- and cblA defects [60].
Isolated renal transplant can partially correct the metabolic
defect of MMA since the kidney possesses approximately 18% of the
methylmalonyl-CoA mutase activity present in the liver [43], and
may contribute to stabilization of clinical conditions [61]. However,
urinary excretion of methylmalonic acid remains elevated, potentially
causing progressive injury to the renal allograft [43]. Isolated liver
transplant replaces the missing enzyme and decreases hepatic
production of methylmalonic acid [43] and has been shown to
improve both metabolic stability and quality of life in MMA patients
[53]. However, it only partially corrects the metabolic defect because
abnormal methylmalonic acid metabolism continues in other tissues,
including the muscles and skin [62], and injury to non regenerative
tissues may not be mitigated [53]. In comparison to isolated transplant
of either the kidney or liver, CLKT can improve the underlying
enzymatic defect, increase the clearance of methylmalonic acid, and
restore renal function [43].
In a Stanford University study we assessed biochemical, surgical,
and long-term outcomes in children with severe, early-onset MMA
who underwent either CLKT (n=8) or isolated liver transplantation
(n=6) at mean age 8.2 years (range 0.8-20.7) [54]. For patients who
received CLKT, the indication for transplantation was chronic
kidney disease (stage III or IV). The indication for patients who
received LT was a difficult clinical course with multiple admissions
per year for hyperammonemia and metabolic acidosis. At the time
of diagnosis, mean blood ammonia in the six patients for whom the
level was available was 611 ± 404 μmol/L (range 197-1200). Pretransplantation,
all patients had multiple hospitalizations yearly as
the result of hyperammonemia, metabolic acidosis, or both. Twelve
patients received a whole liver graft and two a reduced-size graft.
Postoperative survival was 100%; at mean follow-up of 3.25 ± 4.2
years (range 0.25-14 years), patient, kidney graft, and liver graft
survival were 100%, 100%, and 93%, respectively. In one case there
was successful re-transplantation after losing the first liver graft
because of hepatic artery thrombosis five days post-transplant. Mean
serum MMA levels were 83% below pre-transplantation levels at
four months post-transplant. Post-transplantation, there were no
episodes of hyperammonemia or metabolic acidosis. At baseline,
developmental delay had been present in 86% of patients; posttransplant,
all patients either exhibited improvements in motor
skills, learning abilities, and social functioning, or at least maintained
neuro-developmental abilities.
Data from the United Network for Organ Sharing showed that in
patients with urea cycle defects or organic acidemias who underwent
liver transplant at < two years of age, the five-year overall survival
was 88%, with 78% liver graft survival; in those who underwent liver
transplant at > two years of age, there was 99% overall survival and
88% liver graft survival [63]. Quality of life has been shown to improve
substantially post-CLKT in MMA patients, with improvements in
energy, decreased hospitalizations, and the ability to return to school
with discontinuation of dialysis [54,57,64]. Based on our outcomes
to date at Stanford University, we recommend early CLKT for MMA
patients with chronic kidney disease to prevent further neurological
injury, avoid metabolic crisis, and provide the ability to liberalize
nutritional support in order to enhance growth and development
[54]. The complexity with these patients and the multispecialty team
that is needed to manage their clinical care demands an experienced
group of subspecialists with vast experience in metabolic diseases
and transplantation. With this, it is possible to accomplish excellent
results with this complex group of children. Isolated liver transplant
can be considered in patients with preserved renal function.
Concomitant Liver and Kidney Failure
Pediatric patients with concomitant liver and kidney failure may
also be candidates for CLKT. There are multiple conditions which
may in some cases result in this combined organ failure. Included are
the following: (1) nephronophthisis (NPHP) with congenital hepatic
fibrosis (Boichis syndrome), (2) alpha-1-antitrypsin deficiency (α1-
AT), (3) glycogen storage disease type Ia (GSDIa), (4) hepatorenal
syndrome (HRS), and (6) liver tumor plus nephrotoxicity [3,4,13].
Nephronophthisis (NPHP) is an autosomal recessive cystic
kidney disease that is the most common genetic cause of ESRD in
children and young adults [65]. With NPHP there are mutations
in NPHP genes that result in defects in signaling mechanisms that
involve the non-canonical Wnt signaling pathway and the sonic
hedgehog signaling pathway [65]. In NPHP there is commonly
multiple organ involvement, which may include not only liver fibrosis,
but also retinal degeneration, cerebellar hypoplasia, situs inversus,
and intellectual disability [65]. There have been reports of successful
CLKT for children with NPHP and hepatic fibrosis [66]. In one study,
of three NPHP/hepatic fibrosis patients who underwent CLKT, there
was no loss of liver graft but in one patient the kidney graft was lost
5 years after CLKT from chronic rejection that resulted from an
over-reduction of immunosuppressive therapies (cyclosporine and
azathioprine) due to an EBV infection [66]. This patient went back on
hemodialysis and underwent a second renal transplant 4 years later
but died from cardiovascular disease one year after the second renal
transplant (10 years after the initial CLKT); at the time of death, both
the second renal graft and the liver were functioning correctly.
The most common genetic cause of liver disease in children is
alpha-1-antitrypsin deficiency (α1-AT) [67], an autosomal recessive
disorder caused by mutations in the SERPINA1 gene [3] which
is the most common genetic disorder for which pediatric liver
transplantation is performed [68]. In children with a homozygous
Z mutation (Glu342L; PiZZ), the variant most commonly associated
with liver disease, it is estimated that approximately 10% to 20%
will develop cholestatic liver disease, with a minority progressing
to cirrhosis and hepatic failure [3,67,69]. Mesangiocapillary
(membranoproliferative) glomerulonephritis develops in some
children with α1-AT, and may progress to ESRD [70]. There have
been some reports of isolated liver transplantation in α1-AT patients
achieving reversal of renal dysfunction. In patients who have already
progressed to ESRD and advanced liver disease CLKT may be
appropriate. There have been several reports of long-term survival
post-CLKT in children [69,74,72].
Glycogen storage disease type I (GSDI) is an autosomal recessive
disorder caused by the accumulation of glycogen in certain organs
and tissues, especially the liver, kidneys, and small intestines.
The overall incidence of GSDI is 1 in 100,000 individuals; GSDIa
accounts for 80 percent of all GSDI cases. Glucose-6-phosphatasealpha
(G6PC) catalyzes the hydrolysis of glucose-6-phosphate to
glucose and phosphate in the terminal step of gluconeogenesis and
glycogenolysis [73]. The G6PC gene mutations that cause GSDIa
prevent this, resulting in excessive conversion to glycogen and
fat. The disease is characterized by hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, lactic academia,
and growth retardation leading to short stature [74]. Proteinuria,
hypertension, renal stones, nephrocalcinosis, and altered creatinine
clearance occur in some younger GSDI patients; with progression,
interstitial fibrosis becomes evident and some patients will progress
to ESRD requiring kidney transplant [75-77]. Most GSDI patients
will develop hepatic adenomas with the potential for intrahepatic
hemorrhage by the second or third decade of life; there is also the
potential for some adenomas to transform into hepatocellular
carcinoma (HCC) [76,78-80]. The standard treatment is nutrition
therapy aimed at preventing hypoglycemia and providing optimal
nutrition for growth and development. Other therapies that may be
used to address various disease manifestations include lipid-lowering
medications, allopurinol to prevent gout, citrate supplementation
to prevent nephrocalcinosis and urinary calculi development, and
ACE inhibitors to treat microalbuminuria [81]. Full guidelines for
management of GSDAa have been published by the American College
of Medical Genetics and Genomics [82]. Isolated liver transplantation
has been performed in GSDI patients with multiple unresectable
adenomas, poor metabolic control, and progressive liver failure with
resulting restoration of the liver glucoregulatory function and normal
metabolic balance, very significant catch-up growth and improved
quality of life; however, post-transplant complications included focal
segmental glomerulosclerosis with progressive renal insufficiency
[83-84]. There have been reports of a small number of CLKTs that
have been successfully performed in GSD1a patients [72,85-87];
physicians participating in these have recommended that CLKT be
considered for patients with ESRD secondary to GSDIa [84,86,87].
In hepatorenal syndrome (HRS) renal failure develops in patients
with advanced chronic liver disease and, in some cases, fulminant
hepatitis, who have ascites and portal hypertension. Approximately
40% of patients with cirrhosis and ascites will eventually develop
HRS. In most cases, HRS resolves with isolated liver transplantation
[88]. However, in some patients with lengthy HRS there can be
progression to irreversible renal failure. CLKT can be considered in
such patients [3,89,90]. There are currently no guidelines for CLKT
in pediatric HRS patients. CLKT is considered in adults with HRS
who have been on dialysis > 6 weeks. Jalanko and Pakarinen propose
that since the regenerative capacity of children’s kidneys is not very
different from that in adults, the recommendations for adults with
HRS may be valid for children [3].
In children with hepatoblastoma, renal failure may develop
because of the chemotherapy drugs used both before and after
tumor resection. Since the 1990’s most chemotherapy regimens for
hepatoblastoma have included cisplatin, doxorubicin, or both agents
[91,92]. Renal dysfunction develops in more than 70% of pediatric
patients receiving cisplatin [93], typically beginning within only a
few days of initiation of standard cisplatin treatment and shown by
increased serum creatinine and blood urea nitrogen levels [94,95].
Despite the use of preventive measures, progressive renal failure
can occur with successive cisplatin treatments, ultimately leading to
ESRD [96]. Doxorubicin can also cause significant nephrotoxicity
[97-100]. In some cases of hepatoblastoma, to meet the goal of
complete tumor resection with negative margins, total hepatectomy
with liver transplantation is required [101], particularly with large,
solitary PRETEXT IV tumors, multifocal PRETEXT IV tumors, and
unifocal centrally located tumors involving main hilar structures or
main hepatic veins (as with some PRETEXT II or III V+/P+ tumors)
[102]. For example, in the recent SIOPEL-4 study, total hepatectomy
with transplantation was required in 26% (16/62) of patients to
achieve complete macroscopic resection of the primary tumor [102].
In patients who will require liver transplantation and have suffered
kidney injury secondary to chemotherapy and/or intrinsic kidney
disease, CLKT offers the best option for long term success for several
reasons:
(1) The use of single donor for both organs offer immunological
advantages; (2) Immunosuppression management is improved with
the optimal renal function provided by the kidney transplant; (3)
Post-op chemotherapy can be administered in therapeutic doses
when renal function is improved.
CLKT Short and Long-Term Outcomes
CLKT is a complex surgical procedure in which technical complications are not uncommon. In a retrospective analysis of 15 CLKTs performed in 14 pediatric patients between 1998 and 2009, it was shown that postoperative bleeding occurred in six patients (40%), three of whom required operative revision for intraabdominal bleeding; postoperative hemodialysis was required in almost half of the infants (because of delayed kidney graft function or clearance of hyperoxaluria); two patients (13%) showed liver graft outflow complications; one patient developed renal artery thrombosis [103]. Despite these initial complications, the one- and five-year patient survival was 100%; one- and five-year graft survival was 80% for the liver and 93% for the kidney allograft. Because of small-sized anatomical structures and restricted space, CLKT in very young children presents technical challenges. However, in this study, subgroup analysis of the very small infants (age < 3 years and weight < 12 kg) showed both excellent short-term and long-term outcomes, with 100% survival of both grafts and patients at one and five years. Patient, liver graft and kidney graft survival rates have varied substantially in published pediatric CLKT series. Using the Scientific Registry of Transplant Recipients, Calinescu et al analyzed data to determine outcomes of 152 primary pediatric CLKTs performed from October 1987 to February 2011, the largest series to date [104]. Liver graft survival at one, five and ten years were 81.9%, 76.5%, and 72.6 %, and kidney graft survival was 83.4%, 76.5% and 66.8 %, respectively. Patient survival was 86.8% at one year, 82.1% at five years, and 78.9% at ten years, approximately equal to patient survival with isolated liver transplant at the same time points (86.7%, 81.2% and 77.4%) but inferior to survival with isolated kidney transplant at those points (98.2%, 95.4% and 90%). In PH1 patients, CLKT was associated with reduced patient, liver graft and kidney graft survival. However, liver graft survival improved after 2002.
Conclusion
As our understanding of liver-derived metabolic disorders increases, our indications for CLKT are potentially expanding as children with these diagnoses are outliving their historic cohort. Interestingly, aside from patients with concomitant liver and kidney failure, the population that makes up the smallest percentage of CLKTs being performed in pediatrics, none of the indications for CLKT include liver failure. In that setting, the liver transplant must be technically perfect as does the lifelong transplant care. Technical complications will add significant comorbidities that would not have been factored into disease prognosis prior to transplant. Hemodynamic instability from a prolonged operation can lead to delayed kidney graft function or primary graft non-function in a setting where correction of renal failure is the major goal of the operation. Chronic rejection can lead to liver failure which is a new entity in this patient population. Recent survival data suggest that we are tackling these issues but it remains imperative that these transplants be performed in experienced centers with full discussion and disclosure of potential risks and benefits to the patients and their families. With the appropriate donor selection, family education, and medical team commitment CLKT has been shown to be and, we believe, will continue to be an outstanding option for medical management in this select group of patients. Continued advances pre-transplant, intra-operatively and post-transplant will be required to optimize success.
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