Combined Liver and Kidney Transplantation

Indications

There are only a few established indications for CLKT in children and adolescents, and globally, less than 100 procedures are performed per annum. The main one is primary hyperoxaluria type I (PH1), a very rare disease caused by deficiency or mislocalization of the alanine-glyoxylate aminotransferase, an enzyme mainly expressed in the liver. Different mutations in the alanine-glyoxylate aminotransferase ( AGXT) gene are responsible for this disease, with the c.731T > C (p.Ile244Thr) mutation the most frequent. This autosomal recessive condition leads to an overproduction of oxalate, which is massively excreted via the kidneys, leading to severe nephrocalcinosis, causing end-stage renal disease (ESRD) early in childhood. Additionally, oxalate is stored in all other organs, leading to severe systemic oxalosis with oxalate deposits in soft tissues, retina, bones, myocardium, and endothelium of blood vessels. The phenotype can be quite variable but is often related to the mutation type. Therefore direct measurement of enzyme activity of the alanine-glyoxylate aminotransferase in the liver biopsies is no longer needed for the diagnosis of PH1. Sequencing of the AGXT gene, in combination with measurement of serum oxalate and detection of oxalate crystals in the retina, is sufficient for the diagnosis. Untreated PH1 could often lead to early mortality in infancy. There are also milder, genetically distinct forms of hyperoxaluria (PH type 2 and PH type 3). PH2 progresses much slower and may only lead to ESRD later in life, whereas patients with PH3 have only mild hyperoxaluria and no progression of renal disease.

Autosomal recessive polycystic kidney disease (ARPKD) is also a rare autosomal recessive disease caused by mutations of the polycystic kidney and hepatic disease 1 ( PKHD1 ) gene leading to ESRD in early infancy, childhood, or even during pregnancy. This disease is most often diagnosed prenatally during routine ultrasound evaluations of the kidneys, with microcysts developing in the kidneys, liver, and pancreas. In most, but not all, cases, development of liver cysts follows that of kidney cysts by many years. In children with ARPKD, mainly those with early ESRD, isolated KT is required. Progression to clinically significant liver disease usually occurs later and may include a segmental nonobstructive cystic dilatation of the intrahepatic biliary ducts (Caroli disease), hepatic fibrosis with portal hypertension, and/or polycystic liver disease. LT is only indicated in a minority of patients with complications from portal hypertension, or even less frequently from recurrent life-threatening cholangitis. In selected cases, CLKT can be the therapy of choice. In autosomal dominant polycystic kidney disease, a disease that is more frequent in adults, isolated KT is frequently indicated, whereas LT is rare, especially in childhood and adolescence.

Patients with nephronophthisis (i.e., with NPHP1 and NPHP2 gene mutations) most often suffer from primary renal phenotypes that become clinically symptomatic in the second decade of life, so isolated KT is indicated. However, some of these patients (those with mutations in the NPHP3 and NPHP22 genes) could develop hepatic involvement including Caroli disease, liver fibrosis, and/or polycystic liver disease. In such patients with severe hepatic involvement including impaired liver function, recurrent cholangitis, or portal hypertension with uncontrolled gastrointestinal bleeding and therapy-refractory ascites, CLKT could be considered as a therapeutic option.

In methyl-malonic aciduria (MMA), the metabolic defect can be partially corrected by LT, thereby reducing the risk of metabolic stroke and stabilizing neurocognitive development by reducing episodes of hyperammonemia. Therefore, some authors recommend early LT, once MMA is diagnosed, for example, following neonatal screening. In MMA, children with late diagnosis who also progressively develop chronic renal failure, CLKT could be considered. The decision to transplant must be carefully assessed by a multidisciplinary team, including the individual metabolic situation and renal and neurological involvement. It is noteworthy that transplantation only partially corrects the defect and is not a complete cure of the disease. The irreversibility of preexisting, especially neurological, symptoms must be discussed in detail with families.

Complement-mediated hemolytic uremic syndrome (HUS, formerly called atypical HUS) in most patients can be adequately treated with a complement blockade, which leads to a normal kidney function if administered early enough. Currently, the only approved medication for this indication is the C5 monoclonal antibody eculizumab. In those patients with progressive ESRD, KT with the protection of eculizumab is possible, preventing relapse of HUS in the graft. Therefore, complement blockade is the treatment of choice in these patients. In countries where eculizumab is not available, an indication for CLKT could be considered. LT corrects the complement defect in the liver. Several successful reports on combined transplantation have been published, using either perioperative fresh-frozen plasma infusions or plasmapheresis to temporarily correct the complement defect.

Other indications: In children with glycogen storage disease type 1a and 1b, significant nephropathy can develop alongside the obligatory liver involvement and may indicate CLKT for selected patients; only two cases have been published. Alagille syndrome patients may also have renal involvement, such as renal dysplasia, in addition to severe cholestasis, and may exceptionally benefit from CKLT.

Absolute contraindications for CLKT in childhood are very rare–overwhelming infectious diseases, severe anatomical malformations where vascular anastomosis is not possible, malignant diseases that cannot be treated curatively, and serious underlying disorders that endanger the success of the transplant surgery. In severe physical or mental disability, a careful assessment of anticipated prognosis, quality of life, and family resources is mandatory. Portal hypertension with adequate liver function may be considered for repeated endoscopic procedures or a portosystemic shunt and do not necessarily represent an indication for additional LT in children with end-stage kidney disease. Regarding the recipients’ body weight or age, there are no generally accepted restrictions, but the limited abdominal capacity for a dual graft and the small vessel diameters must be considered. In our center, a CLKT was successfully carried out from a recipient body weight of 12 kg. To date, only a few case reports of an ABO-incompatible CLKT or CLKT from a living donor have been reported, so both procedures are still reserved for highly selected cases, and there is no general recommendation regarding an immunosuppressive regimen.

Timing of Transplantation

The timing of transplantation is primarily based on the natural course of the underlying disease. The choice of the right treatment option and the transplant timing in hyperoxaluria is difficult. Several transplantation modes, such as preemptive LT and sequential or simultaneous LT and KT, are possible. Isolated KT should be avoided because of the rapid recurrence of intrarenal oxalate depositions. In early-detected phenotypic PH1-patients, CLKT, in our view, should be performed as soon as possible to avoid systemic oxalosis. The timing is mainly based on the size of the child, as the diameter of aorta and vena cava could limit the KT. The second aspect of the decision-making is the availability of donor organs from infants or of split-liver grafts (see Surgical considerations and graft selection) and kidneys of appropriate size. Before transplantation, intensive combined hemodialysis and peritoneal dialysis have to be performed to keep the oxalate pool in the body low, with S-oxalate levels under 100 μg/L and minimal deposits in the eyes, bones, and the heart (as detected by speckled echocardiography). In cases of vitamin B6-responsive hyperoxaluria, this should be promptly administered. Experimental therapies, such as oral Oxalobacter perfringens , a bacterium that degrades oxalate and thereby reduces systemic oxalate load, are still mainly used in clinical trials. In infants with severe systemic oxalosis, primary LT followed by later KT, if required, can be the therapy of choice to avoid the consequences of oxalate overload. Because this procedure requires two separate, complex surgeries and increases the risk of sensitization, in our opinion, it should only be performed in selected cases.

In ARPKD and nephronophthisis, the decision as to whether the isolated liver or KT should be preferred depends on the severity of the liver disease and portal hypertension at the time of ESRD. In the majority of patients with normal liver function and no significant signs of portal hypertension at the start of dialysis, isolated KT is the therapy of choice. In patients where the indication for LT precedes the development of ESRD, a combined transplantation should be planned, even if glomerular filtration rate is only moderately decreased because the calcineurin inhibitor (CNI)–based immunosuppression will further impair kidney function after LT. In patients with ESRD and advanced liver disease such as recurrent cholangitis and portal hypertension with refractory ascites and uncontrolled gastrointestinal bleeding, a combined transplantation should be considered.

In MMA, early isolated LT is better for metabolic control, future kidney function, and the neurological prognosis of the child and therefore represents a therapy of choice. CLKT should be reserved for those patients with late diagnosis of MMA with chronic renal insufficiency secondary to chronic kidney disease grade 3 and above.

Box 11.1 A presents examinations required for CLKT assessment. Vaccinations should be administered at the earliest age possible (see Box 11.2 and Chapter 19 ). Before a formal placement on the transplant waiting list, additional specific procedures, potentially improving underlying conditions, such as bladder augmentation or ureteronephrectomy, should be performed.