Multi-organ transplantation is the transplant of two or more organs from a single donor into a single recipient. While the incidence of multi-organ transplantation has been steadily rising among adult recipients, it remains rare among pediatric recipients, with only 50–60 cases performed each year in the USA (Fig. 1). The majority of adult multi-organ transplants involve a kidney—in 2022, 9.2% of all donor kidneys were allocated as part of a multi-organ transplant [1]—but over half of pediatric multi-organ transplants are intestinal multivisceral transplants that typically do not include a kidney. In 2022, there were 12 liver-kidney transplants, 4 heart-kidney transplants, 2 kidney-pancreas transplants, and 1 liver-kidney-intestine-pancreas transplant among pediatric recipients in the USA [1]. Due to the small number of pediatric multi-organ transplants, evidence to guide listing and management is limited. In this review, we aim to summarize existing data and best practices while identifying areas of needed research.

Fig. 1
figure 1

Incidence of pediatric multiorgan transplant in the USA 2013–2022, overall and by organ type [1]

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Multi-organ allocation

In the US Organ Procurement and Transplantation Network (OPTN) and European Eurotransplant network, multi-organ candidates are prioritized above kidney-alone recipients, with allocation driven primarily by the non-kidney organ. Therefore, a candidate for multi-organ transplant who is allocated a heart, liver, or pancreas based on those allocation policies will automatically be allocated a kidney from the same donor, regardless of the individual’s position on the kidney waiting list. Importantly, this does not work in reverse; if a multi-organ candidate is at the top of the kidney waiting list, they are not entitled to a liver or liver from the same donor. Multi-organ allocation in other transplant systems can vary widely by locality. For example, in the UK, only one kidney per donor may be allocated to a multiorgan candidate, [2] while in Ontario, Canada, adult multi-organ and kidney-pancreas candidates are given priority after pediatric candidates with similar levels of HLA sensitization [3].

In recent years, the US OPTN has established kidney listing criteria for adult heart-kidney (Policy 5.10.E) and liver-kidney candidates (Policy 9.9) [4]. To be eligible for multi-organ listing that includes a kidney, adult candidates must report either chronic kidney disease for 90 days, with an estimated glomerular filtration rate (eGFR) < 30 ml/min at the time of listing, or sustained acute kidney injury, defined as an eGFR < 25 ml/min or dialysis at least once per week. Adult kidney-pancreas candidates must meet the same listing criteria as adult kidney-alone transplants. However, none of these listing policies applies to candidates < 18 years of age. There are currently no listing criteria for pediatric multi-organ candidates.

Both the US OPTN [4] and European Eurotransplant Network [5] also include a “safety net” that gives priority to those who are listed for a kidney transplant within 12 months of receiving a heart-alone or liver-alone transplant [4]. In Eurotransplant, this takes the form of additional points. In the USA, there is an additional allocation classification for “safety net” candidates that gives priority allocation for kidneys with a kidney donor profile index (KDPI) > 20%. Additionally, in the USA “safety net” candidates are lower on the wait list (allocation classification 27) than candidates registered prior to age 18 years old (allocation classification 6). Therefore, current safety net policies may not significantly affect or benefit pediatric candidates.

As multi-organ allocation is driven by the non-kidney organ, a knowledge of non-kidney organ allocation is important to understand eligibility criteria and estimated wait times. In the USA, pediatric liver allocation is based on either the Pediatric End-Stage Liver Disease (PELD; < 12 years old) or Model for End-Stage Liver Disease (MELD; ≥ 12 years old) score, both of which aim to estimate the risk of 90-day waitlist mortality using common liver function test values, including creatinine (for MELD score only) [4]. Patients who meet criteria for fulminant hepatic failure or primary non-function of a liver allograft may qualify for Pediatric Status 1A listing. Children with hepatoblastoma, metabolic liver disease, or with specific criteria of acute-on-chronic liver disease decompensation can be listed as Status 1B. Status 1A and 1B receive liver offers in priority over children listed with a PELD or MELD score. Many children with common indications for combined liver-kidney transplantation, including metabolic disorders, will have a low PELD or MELD score due to preserved liver synthetic function. For these patients, there are exception pathways, written into policy, to provide a higher MELD/PELD score. For example, pediatric candidates with primary hyperoxaluria type 1 can have their MELD/PELD score changed to the “median MELD/PELD at transplant plus 3 points” if they provide documentation of alanine:glycoxylate aminotransferase (AGT) deficiency and have an eGFR < 25 ml/min (OPTN Policy 9.5.H). Individuals with urea cycle disorders or organic acidemias can apply for the “median MELD/PELD at transplant” and will be moved to status 1B if they do not receive a transplant within 30 days of listing, while those with rare disorders that do not have written exception policies can apply to the National Liver Review Board requesting additional points. The Review Board application must document how liver transplant addresses the disease complications and mortality risk, reference other MELD/PELD exception categories to justify the additional points, and present documented experience of other, similar cases that were treated with liver transplant.

Pediatric heart allocation is based on a series of categorical “statuses,” Status 1A, Status 1B, and Status 2, which are defined by the level of cardiac support required by the patient. While exceptions are less commonly needed in pediatric heart-kidney transplantation, providers can apply to the National Heart Review Board to have their patient’s status upgraded if the transplant physician “believes, using acceptable medical criteria, that a heart candidate has an urgency and potential benefit comparable to that of other candidates at the requested status” [4].

Simultaneous liver-kidney transplant

Certain clinical situations or specific pathologies may require simultaneous liver-kidney (SLK) transplantation. According to the 2021 OPTN/SRTR report, only 13 pediatric SLK were performed that year, accounting for 1.6% of all pediatric kidney transplant recipients [6]. An immunological benefit of simultaneously transplanting a liver and a kidney has been reported, which positively impacts kidney graft survival by decreasing the occurrence of both acute cellular and antibody-mediated rejection [7, 8]. The protective mechanisms are not fully elucidated, but include hepatic elimination of preformed lymphocytotoxic antibodies as well as the presence of donor-type soluble HLA class 1 antigens that neutralize HLA antibodies [9, 10]. There are no recommendations regarding immunosuppression choice or drug levels for pediatric SLK patients. Management is center-specific, with variable use of induction and maintenance suppression reported [11].

On the other hand, SLK is a long and challenging surgical procedure, where hemodynamic instability and severe blood loss at the time of liver transplant may preclude proceeding with the kidney transplant. Even in the absence of complications during liver transplant, the inevitable longer cold ischemia time of the kidney allograft when compared with kidney transplant alone can affect postoperative graft performance, leading to acute tubular necrosis and a higher incidence of delayed graft function (DGF) requiring post-transplant kidney replacement therapy. In the adult population, reported DGF rates after SLK vary widely from 16 to 49%. While certain risk factors are not as applicable to the pediatric population (donor factors including hepatitis C virus, hypertension, diabetes), the duration of delay of kidney after liver transplantation and a longer cold ischemia time were significant independent predictors of DGF [12]. Transplanting two organs in a small child poses technical challenges related to the size of the recipient, who may not be able to accommodate 2 grafts simultaneously, but also raises the question of donor quality, which might be suboptimal for organs recovered in an age- and size-matched donor, especially from the kidney standpoint. A higher rate of postoperative complications has been noted after SLK [13]. SLK should therefore be reserved for very specific situations. A last concern to voice with SLK lies in medical conditions that may or may not absolutely require a liver transplant given the preserved synthetic hepatic function but need a kidney transplant. In these situations, SLK may deprive patients listed for a kidney transplant alone from being transplanted, subjecting them to ongoing complications from kidney replacement therapy.

Pathologies requiring an SLK transplant can be classified in diseases affecting the liver and the kidney simultaneously, kidney disease caused by liver disorders, kidney dysfunction in chronic liver disease, or kidney disease following liver transplantation. Van Hoeve et al. published an extensive review presenting the various situations of liver involvement in kidney disease and vice versa [14]. Therefore, only a few selected pathologies will be discussed here.

Methylmalonic acidemia (MMA) is an autosomal recessive disorder caused by a complete or partial deficiency of the enzyme methylmalonyl-CoA mutase, a defect in the transport/synthesis of its cofactor, or a deficiency in the methylmalonyl-CoA epimerase enzyme in the liver [15]. Patients develop accumulation of methymalonic acid in their tissues and fluids, leading to metabolic acidosis and hyperammonemia, presenting as vomiting, lethargy, and coma. Kidney disease presents as tubular damage. Management consists of medical and nutritional treatments, but despite these measures, metabolic crises can occur and lead to neurological and kidney insults. Liver transplant can provide enzyme activity to improve the metabolic situation. Following liver alone or SLK transplant, the plasma methylmalonic acid levels decrease. Levels are especially lower in patients also receiving a kidney transplant due to a lower enzymatic activity provided by the kidney transplant. A large multicenter European study as well as a French national study both demonstrated that SLK transplant was associated with better metabolic outcomes and should be therefore recommended in children and teenagers with MMA [16, 17].

Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy leading to chronic kidney disease stage V. Loss of function mutations affecting complement factor H (CFH), complement factor I (CFI), complement factor 3 (C3), or others lead to an overactivation and dysregulation of the alternative complement pathway [18]. Most of the complement-regulated factors (CFH, CFI, C3) are synthesized by hepatocytes, and the liver is not usually affected by aHUS. SLK was previously performed to restore the abnormal complement factor to prevent recurrence of disease in the newly transplanted kidney. However, since the introduction of anti-C5 antibody (eculizumab), SLK has been more rarely performed for aHUS given higher rates of morbidity and mortality related to liver transplantation. However, eculizumab prophylaxis is currently a lifelong costly therapy, while liver transplant can provide definitive cure of the disease [19].

Primary hyperoxaluria (PH) is caused by rare autosomal recessive inborn errors of oxalate metabolism. An enzymatic defect occurring within the liver, alanine:glyoxylate aminotransferase (AGT), leads to an overproduction of oxalate with large urinary excretion of calcium oxalate, further leading to the development of chronic kidney disease [14]. Extra-kidney oxalate deposition is also observed. Severe forms of PH manifesting in infancy require initiation of dialysis, and a liver transplant is required to restore the enzymatic deficiency. However, SLK is often not possible in small infants due to size concerns, and in those instances, liver transplant followed by kidney transplant is most often performed. Oxalate levels may not resolve rapidly post-transplant, and the kidney allograft from an SLK could be further injured by circulating oxalate molecules, which can lead to kidney graft injury [20, 21]. A sequential liver-kidney transplant (liver first followed by kidney transplant when the oxalate levels have near normalized) is therefore recommended in this specific situation. If an SLK is performed in older patients with sufficient space, postoperative hemodialysis is often required to clear circulating oxalate until achieving optimal graft function [22]. However, a recent multicenter European study showed comparable outcomes after SLK and sequential liver-kidney transplant for PH type 1, and the surgical option should be based on the individual patient’s characteristics and availability of organs [23]. The recent development of lumasiran, a small interfering RNA that inhibits an enzyme upstream of AGT and leads to rapid reduction in urine oxalate levels, could theoretically substantially reduce or eliminate the need for SLK in children with PH type 1; however, data proving this is not yet available. The effect of lumasiran on SLK incidence may also be affected by limited data supporting use in patients with an eGFR < 30 ml/min/1.73 m2, patients on dialysis, and children less than 1 year old [24].

Autosomal recessive polycystic kidney disease (ARPKD), although rare, is the most common form of cystic kidney disease occurring in childhood. It is caused by a mutation in the polycystic kidney and hepatic disease 1 (PKHD1) gene [25]. Diagnosis may occur prenatally or in the neonatal period due to severely enlarged kidneys and organomegaly. In addition to causing chronic kidney disease in the setting of non-obstructive dilatation of the collecting tubules, it can be associated with non-obstructive dilatation of the intrahepatic bile ducts (Caroli’s disease) or can present with congenital hepatic fibrosis and a ductal plate malformation (Caroli syndrome). Nearly 50% of patients progress to chronic kidney disease stage V within the first decade of life. Liver involvement often presents as recurrent cholangitis or portal hypertension. However, the liver synthetic function remains preserved, and therefore a simultaneous liver transplant can often be avoided. If the hepatic cystic burden of disease is located preferentially in one lobe of the liver, a hepatectomy can be performed, while if a ductal plate malformation is identified, a choledochal cyst excision can be performed instead. Lastly, portal hypertension occurring in patients with preserved liver function or compensated cirrhosis can be treated with selective portosystemic shunting (such as a distal splenorenal shunt) [26]. Patients can then undergo a kidney transplant alone. However, in the setting of Caroli’s disease with severe bilobar hepatic cystic involvement, SLK will better prevent recurrent cholangitis in an immunosuppressed patient.

Similarly, about 25% of patients presenting with Joubert syndrome, an autosomal recessive ciliopathy, will develop kidney disease [27]. Other features include facial dysmorphia, polydactyly, endocrine anomalies, and hepatic disease manifesting as congenital hepatic fibrosis. Some patients may develop features of portal hypertension with preserved synthetic function that can be successfully treated with a selective portosystemic shunt, avoiding liver transplant, and proceed to kidney transplant alone.

Alagille’s syndrome is an autosomal dominant disorder caused by a mutation in the JAG1 or NOTCH2 genes affecting multiple organs. The liver histology is characterized by a paucity of bile ducts and presents with cholestasis. Cardiac (most often peripheral pulmonary stenosis), skeletal (butterfly vertebrae), and ocular (posterior embryotoxon) anomalies are commonly identified [28]. Kidney involvement can present as dysplasia, vesicoureteral reflux, and renovascular hypertension. Liver transplant alone can be required in childhood.

Lastly, hepatorenal syndrome (HRS) can occur in patients with advanced liver disease, where kidney impairment occurs in the absence of any other kidney abnormality. Its pathophysiology is not well understood but involves renovascular vasoconstriction [29]. Severe HRS cases require kidney replacement therapy support. Liver transplant is curative treatment, but SLK is rarely required as the recovery rate is high [30].

From a technical standpoint, an SLK transplant can be performed either using a single incision with both organs being placed intraperitoneally or through 2 separate incisions, allowing the kidney to be placed retroperitoneally [21] (Fig. 2). This decision is obviously influenced by the recipient’s size and weight. With an intended SLK transplant, the liver transplant is performed first as it is the life-saving organ. However, massive bleeding and hemodynamic instability may occur during liver transplant which may preclude proceeding with the kidney transplant. Options then include keeping the kidney allograft on ice or pump for up to 24 h (if the extended cold ischemia time is deemed acceptable for a given recipient) or returning the graft to the kidney-alone pool for reallocation. If conditions allow for proceeding with the kidney transplant during the same procedure, the kidney vascular anastomoses are performed after the liver reperfusion is completed and may be performed before proceeding with the biliary anastomosis to decrease the kidney cold ischemia time. The ureteral anastomosis may be performed immediately after finishing the kidney reperfusion, and the biliary anastomosis is completed last. Hemostasis of the kidney allograft surgical field is checked and closed last, as ongoing coagulopathy from liver disease and/or administration of anticoagulation may lead to an increased risk of bleeding and hematoma around the kidney.

Fig. 2
figure 2

Combined liver-kidney transplantation includes an orthotropic transplantation of a whole, reduced size, or split liver depending on the donor/recipient size match as well as isolated kidney transplantation from the same donor. The kidney graft is implanted in the right or left iliac fossa or intraperitoneally. From Jalanko et al. Pediatr Nephrol 2014, reprinted with permission from Springer [21]

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Postoperatively, the overall management is dictated by the liver allograft. Fluid management may be more conservative (central venous pressure (CVP) 5–10 mmHg), especially with segmental grafts, which may be more prone to bleeding from the cut surface and for which graft edema from high CVP is therefore avoided. This may impact the kidney allograft early after transplant and lead to slower graft recovery. Conversely, low CVP is avoided after liver transplant due to concern for thrombosis. Therefore, early use of diuretics is often avoided unless ventilation concerns were to occur. This may also change kidney transplant management, especially in the setting of slow graft function/acute tubular necrosis where diuretics may otherwise be used. Many pediatric liver centers routinely use prophylactic anticoagulation after liver transplant, which may lead to an increased incidence of perinephric hematomas. Bleeding after liver transplant is a frequent complication that can lead to a low circulating blood volume and can impact kidney function recovery. Lastly, immunosuppression with calcineurin inhibitors is often started on the first postoperative day after liver transplant, which may also impact early kidney allograft function.

Perioperative complication rates are higher in SLK than other isolated transplants [6]. A higher initial rate of morbidity and mortality related to the procedure is associated with a higher incidence of graft loss [31]. A recent multicenter European study comparing kidney transplant alone vs. SLK for ARKPD showed a higher mortality rate and was not associated with improved 5-year kidney transplant survival [32]. However, despite a more complex medical and surgical history, as well as an often more complicated post-transplant course, the quality of life of pediatric SLK recipients was not perceived as inferior to isolated liver or kidney transplant, either by the transplant recipient or their parent [33].

Simultaneous heart-kidney transplantation

Simultaneous heart-kidney transplantation (sHKTx) is rare, and the majority are performed in North America. Between January 1990 and June 2017, the International Thoracic Organ Transplant Registry recorded 50 pediatric heart-kidney transplants worldwide [34]. The main indication is heart disease that leads to secondary kidney dysfunction via mechanisms including chronic or intermittent low cardiac output, nephrotoxic medications, and concomitant kidney anomalies. As more patients with heart disease are delaying transplant longer, and more heart transplant recipients are surviving to re-transplantation, the incidence of simultaneous heart-kidney transplant has been slowly rising, from 1–2 cases per year to 3–6 cases per year [35]. Between 1995 and 2017, 32.7% of pediatric heart-kidney transplants were heart re-transplants compared to only 5% of heart-alone transplants [35].

There is no consensus on the degree of kidney dysfunction that warrants a simultaneous heart-kidney transplant. In 2023 the US Organ Procurement and Transplant Network implemented new listing criteria for adults seeking sHKTx, including chronic kidney diseases with an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 or sustained acute kidney injury with an eGFR < 25 ml/min/1.73 m2 [36]; however, these criteria do not apply to pediatric candidates. Choudhry et al. reviewed 9245 pediatric heart transplant recipients and 63 pediatric sHKTx recipients in the USA between 1992 and 2017. Among patients requiring pre-transplant dialysis, the risk of death for patients receiving a sHKTx was substantially lower than those receiving heart transplant alone; however, there was no improvement in survival with sHKTx for patients who did not require pre-transplant dialysis. In patients with an eGFR ≤ 35 ml/min/1.73 m2, heart-alone recipients had worse survival than those receiving a sHKTx [37]. Complicating matters, radionucleotide studies have shown that kidney function can improve with improved hemodynamics after transplant [38], and a review of infants with kidney failure at the time of cardiac surgery showed high mortality but no requirement for dialysis at hospital discharge [39]. When evaluating an individual patient for potential sHKTx, there is typically a level of uncertainty about the possibility of kidney recovery and the need for multi-organ transplant.

A significant debate in heart-kidney transplant is the relative benefits and utility of a simultaneous versus sequential approach. Data shows that heart recipients with a high risk of kidney dysfunction who receive a simultaneous heart-kidney transplant have improved survival compared to those who receive a heart transplant alone; hemodialysis appears to be especially detrimental to the transplanted heart [40]. However, sHKTx recipients also have higher rates of primary kidney allograft nonfunction (14–42%), shorter kidney allograft survival, and fewer total life-years gained compared to kidney-alone recipients [41]. In the International Society of Heart and Lung Transplant registry, 20% of sHKT survivors had a creatinine greater than 2.5 mg/dl at 5-year post-transplant [34]. Due to these concerns, some advocate for an alternative management plan of sequential kidney-after-heart transplant, in which a patient receives a heart transplant, is hemodynamically stabilized and observed for recovery of kidney function and then is evaluated for a living- or deceased-donor kidney transplant from a different donor [41]. OPTN policy now encourages sequential kidney-after-heart transplant via a “safety net” kidney allocation policy that gives priority to recipients of a heart transplant who develop kidney failure within 1 year after transplant [36]. Sequential transplant may be necessary for infants and other small children. Heart allografts are matched to patients based on size, but kidneys from donors less than 5 years of age have increased rates of vascular thrombosis and primary nonfunction [39]. Therefore, the youngest pediatric patients may have benefit from a sequential kidney-after-heart approach, ideally with a living donor allograft [34].

Once a decision is made to pursue a simultaneous heart-kidney transplant, the team must develop a plan for the timing of these procedures. In a traditional simultaneous heart-kidney transplant, the patient undergoes the heart transplant procedure first, followed by the kidney transplant, in one anesthesia event. This minimizes the cold ischemia time for the kidney, but also results in increased kidney exposure to the hypotension, cardiopulmonary bypass inflammatory cascade, and vasoconstrictor medications that are typical during heart transplant [42]. An alternative strategy is to perform a staged procedure, in which the heart is transplanted first, the patient recovers for up to 24 h, and then the team returns to the operating room for the kidney transplant [43]. This results in longer cold ischemia time for the kidney and requires two anesthesia events in quick succession; however, this also allows for hemodynamic stabilization of the patient prior to kidney vascular anastomosis. A staged procedure also allows for reallocation of the kidney if the heart transplant is not successful. The kidney can also be kept on pump to reduce the impact of a prolonged cold ischemia time.

Peri- and postoperative fluid management can be challenging in sHKT. Kidney allografts often benefit from a high CVP (8–15 mmHg) and robust intravascular volume, while heart transplant recipients may not be able to tolerate this volume. In the denervated heart allograft, there is no baroreceptor reflex; therefore, the patient will not become tachycardic with hypovolemia. The left ventricle also has decreased compliance, lower filling pressure, and lower cardiac output. Ionotropes may be needed, but there is no evidence that any particular ionotrope is better for kidney perfusion [42]. In patients with high pulmonary artery pressures, the right ventricle is also preload dependent, but excessive preload and high CVP can cause acute right ventricular failure. Frequent monitoring, including routine use of transesophageal echocardiography for volume status assessment, may be necessary to balance the needs of both new allografts [44], though in practice the heart-kidney recipient may not be able to achieve the same beneficial hydration as a kidney-alone recipient due to the needs of the heart.

There are no established recommendations for immunosuppression in pediatric sHKT, and protocols are center-specific. In the USA, currently, over 80% of pediatric heart transplant cases receive induction immunosuppression compared to nearly 100% of pediatric kidney transplant recipients. Maintenance immunosuppression regimens are similar and primarily based on a combination of tacrolimus and mycophenolate mofetil, with prednisone prescribed to approximately 40%; however, goal tacrolimus trough levels may vary [45, 46]. Successful sHKT requires early and frequent communication between the cardiac and kidney transplant teams regarding prescription and adjustment of immunosuppression medications. Joint clinic visits may be especially beneficial for these patients to ensure coordination of care for both organs.

Outcomes for pediatric heart-kidney transplant recipients are similar to those of heart-alone patients, with a 5-year patient survival of approximately 80% reported in the International Society of Heart and Lung Transplant registry and 81.5% reported in US cohorts [35, 37]. However, pediatric heart-kidney recipients are much more likely to have evidence of kidney disease; 10% are on chronic dialysis at 5-year post-transplant compared to 0.4% of heart-alone recipients [34] (Fig. 3). Incidence of heart (11%) and kidney (7.9%) rejection within 1-year post-transplant is also similar to those reported in pediatric heart-alone and kidney-alone recipients [37].

Fig. 3
figure 3

Cumulative morbidity rates in survivors within 5 years after transplant for pediatric heart transplants performed from January 1, 1994, to June 30, 2012. a Defined as creatinine >2.5 mg/dl (221 μmol/liter), dialysis, or kidney transplant. From International Society of Heart and Lung Transplantation Registry, Rossano et al. J Hea Lung Transplant 2018, reprinted with permission from Elsevier [34]

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Simultaneous pancreas-kidney transplant

In the adult population, most pancreatic transplants are performed as simultaneous pancreas-kidney (SPK) transplants to treat type 1 diabetes and its systemic complications, although the proportion of SPK performed for type 2 diabetes is increasing [47]. In the pediatric population, most pancreatic allografts are transplanted as part of multivisceral (liver-pancreas-intestine) transplants for intestinal failure due to short gut syndrome, congenital enteropathies, or intestinal motility disorders, complicated by intestinal failure associated liver disease (IFALD).

Diabetic kidney disease (DKD) develops over time due to a sustained continuous kidney exposure to hyperglycemia. The overall incidence of chronic kidney disease stage V is reported to be 4–17% at 20–30 years after T1DM diagnosis [48]. Therefore, the development of diabetic kidney complications that would justify a combined SPK transplant is unlikely in the pediatric population. Despite the increase in type 2 diabetes mellitus in the teenage population and associated kidney complications, the introduction of medical and surgical therapy such as SGLT-2 inhibitors and bariatric surgery may decrease kidney complications related to obesity and decrease the need for SPK in teenagers or young adults [49].

There were 11 pediatric SPK transplants performed in the USA between 2018 and 2022, four of which were performed in ages 11–17 years and three in ages 6–10 years. Among these transplants, only 3 were in diabetics (two patients with diabetes type 2 and one patient with diabetes type 1), all in teenagers; the indication for SPK in the other recipients is unknown [50]. A case report recently described an SPK transplant in a 15-year-old teenager with nail-patella syndrome who developed nephrotic syndrome at a young age, failed medical treatment, required bilateral nephrectomies and initiation of hemodialysis, and then further developed insulin-dependent diabetes [51]. He received a living donor kidney transplant that ultimately failed. Despite being highly sensitized (PRA 99%), he went on to receive an SPK at age 15 years. Although he developed mixed acute cellular and antibody-mediated rejection of his pancreatic allograft 8 months after transplant, his kidney and pancreatic functions were normal 12 months post-transplant. Similarly, a case series of two children receiving SPK for complications of diarrhea-associated HUS, one receiving deceased donor allografts and one from a living donor, reported good outcomes at 1 year of follow-up, though one of the two patients had multiple episodes of rejection [52]. These cases provide an example of how SPK transplant can be technically feasible and safe in selected patients, but indications overall remain rare.

Due to this rarity, information on management and outcomes of SPK transplant is primarily available for adults transplanted for type 1 diabetes. Surgery is complicated by the nature of pancreatic tissue; rare but serious complications include pancreatic pseudocyst, ductal leaks, hemorrhagic pancreatitis, and thrombosis [53, 54]. The pancreas is transplanted heterotopically at a site determined by surgeon preference, although often the pancreatic vessels are anastomosed to the inferior vena cava and/or the right common iliac vessels. The donor pancreas is kept en bloc with the donor duodenal C-loop. Anastomosis of the donor duodenum (and therefore pancreatic gland) is typically at the recipient’s jejunum close to the vascular anastomotic sites [53, 54]; the historic use of bladder anastomosis was associated with chronic metabolic acidosis and increased risk of urinary tract infections and is therefore rarely performed now [55]. The kidney allograft is placed in the left iliac fossa and anastomosed to the left iliac vessels. In the immediate postoperative period, patients require adequate volume resuscitation, but the goal CVP may be lower than for kidney-alone recipients. Post-transplant, glucose, and C-peptide levels are closely monitored as they reflect pancreas allograft function [54]. In adults, pancreatic allograft rejection is concordant with kidney graft rejection in 60% of cases [53]. Pancreas biopsy is technically difficult due to the intraperitoneal position of the graft and may be nondiagnostic in 12% of cases [53]. In adults, SPK has improved graft survival (> 90% at 1 year) compared to pancreas-alone (80%) or pancreas-after-kidney (82%) transplantation [54]. Long-term graft survival for SPK recipients also appears to be better than that of kidney-alone recipients (72% vs. 55% at 8 years) [53].

Kidney-intestinal transplantation

Composite visceral transplants—multi-organ transplants that involve the intestine—are the most common pediatric multi-organ transplants; however, they rarely involve a kidney [56]. Since 1988, there have been 61 composite visceral transplants including a kidney, 92% of which were liver-kidney-intestine-pancreas grafts [1]. The overall incidence of composite visceral transplants has been declining in recent years due to improvements in intestinal rehabilitation. Additionally, 5-year patient survival for a composite visceral transplant is 50–60%, lower than that for chronic parenteral nutrition. Therefore, the primary indication for composite visceral transplant is irreversible intestinal failure (often short bowel syndrome, congenital enteropathies, or intestinal motility disorders) complicated by end-stage liver disease from parenteral nutrition, recurrent catheter-related infections, or loss of vascular access [57]. A kidney may also be required if the patient has a congenital anomaly or has developed kidney failure due to recurrent infections or acute kidney injury.

Evaluation of the kidney-intestine candidate should pay special care to vascular patency, as many patients will have extensive venous thromboses caused by multiple line exchanges required for chronic parenteral nutrition that may complicate the procedure [58]. The surgical procedure is complex and individualized to the patient; the kidney may be transplanted en bloc with the intestine or separately. Small patients may not have adequate abdominal domain for the transplant, however abdominal wall closure at the time of transplant is preferred if possible to decrease the risk of infection, but potentially with an increased risk of compartment syndrome due to previous loss of domain from prior extensive bowel resection [59, 60]. Postoperatively, acute kidney injury is common (25% incidence reported in adult recipients), likely related to erratic intestinal absorption of tacrolimus and hypovolemia from fluid loss caused by a prolonged open abdomen and progressive abdominal closure or high-volume gastric output or diarrhea (a sign of acute rejection) [61]. Conversely, rejection of the intestinal allograft can also increase tacrolimus absorption [61]. Due to the high amount of lymphoid tissue in the intestine, 4–30% of composite visceral transplant recipients develop graft versus host disease [61, 62], and they have the highest rates of Epstein-Barr virus, DNAemia, and post-transplant lymphoproliferative disease among all pediatric transplant recipients [63, 64]. Despite the complications, quality of life is reportedly good after intestinal transplant although lower than the general population, especially regarding school functioning [65, 66].

Liver-kidney-pancreas transplant

There have been two reported cases of pediatric liver-kidney-pancreas transplant [67], both of which were performed for Wolcott-Rallison syndrome [68, 69]. Wolcott-Rallison syndrome is caused by mutations in EIF2AK, the gene encoding pancreatic endoplasmic reticulum kinase (PERK). In the absence of PERK function, the endoplasmic reticulum cannot handle accumulated unfolded proteins [69]. Symptoms include neonatal-onset insulin-dependent diabetes, skeletal dysplasia, short stature, and hepatic dysfunction [70]. When under stress due to infections, medications, or anesthesia, patients develop acute liver failure, often with acute kidney injury; the first episode is fatal in approximately 50% of cases.

Both cases of liver-kidney-pancreas transplant have been published in case reports. One involved a 4-year-old girl with known Wolcott-Rallison syndrome who developed multi-organ failure in the setting of a dry cough and low-grade fever [68]. The second case involved a 6-year-old girl without a prior diagnosis who presented in acute liver failure [69]. Both patients underwent liver-kidney-pancreas transplant; the 6-year-old girl received en bloc kidneys. Both had delayed closure of the abdominal wall but otherwise recovered well. Complications included urosepsis in one patient and acute rejection in the other, but both girls were alive with good graft function at 18-month follow-up.

Future directions

The medical complexity of pediatric transplant candidates continues to increase, but information on management and outcomes of multi-organ transplantation outcomes in pediatric patients remains limited. Existing data on the role of multi-organ transplantation versus single-organ transplant is often subject to confounding by indication, making it difficult to interpret, and national and international consensus on multi-organ transplant indications is lacking. Transplant management protocols are center-specific, driven by provider experience and opinion rather than evidence. There is a high need for increased reporting on pediatric multi-organ transplants, ranging from collection of international case numbers and assessment of varying listing requirements and allocation policies to perioperative management of fluids and immunosuppression and long-term outcomes, including quality of life. Case series as well as analyses of existing registries could provide significant additional information to improve the care provided to this small but vulnerable population.