Combined liver-kidney transplantation in polycystic disease: Our experience and literature review

Abstract

Combined liver-kidney transplantation (CLKT) is lifesaving for patients with end-stage liver disease and underlying chronic kidney disease. Kidney injury is common, and CLKT accounts for 10% of all liver transplants, reflecting the physiological changes caused by portal hypertension in patients with end-stage liver disease. The increasing number of CLKT procedures has resulted in a large cohort of patients who should be studied in detail to identify factors (both donor- and recipient-related) that are associated with better outcomes. Evidence is emerging on the safety and efficacy of delaying the kidney component of CLKT and on the immunological benefits of multiorgan transplantation involving the liver. In this article, we review the most recent analyses and provide our perspectives on best practices in CLKT, integrating the literature with our single-centre retrospective series of 20 adult polycystic disease patients who underwent CLKT at the Department of Abdominal Center IRCCS ISMETT between 2008 and 2025. Simultaneous liver-kidney transplantation has been a major advance in the management of patients with dual-organ disease. The development of new modalities of organ preservation should be encouraged in order to optimise the identification and selection of patients for CLKT and to increase the use of extended criteria donors.

Key Words: Combined liver-kidney transplantation; Liver transplant; Hypothermic machine perfusion; Polycystic disease; End-stage renal disease; Chronic liver disease; Cirrhosis

Core Tip: Polycystic liver-kidney disease is a rare but debilitating condition requiring combined liver-kidney transplantation. This evidence review integrates contemporary data with our single-centre series (ISMETT, 2008-2025) of 20 combined liver-kidney transplantations for polycystic disease. The results show 95% patient survival (95% confidence interval: 86%-100%) at 1 year, 3 years, and 5 years after transplant and two kidney graft losses. We summarise actionable selection and technical considerations, such as symptom-driven liver listing, renal trajectory, and selective native nephrectomy, and emphasise innovations including liver-mediated immunoprotection and hypothermic machine perfusion, which enable delayed kidney implantation and the safer use of extended criteria donors.

INTRODUCTION

Polycystic disease is an inherited disorder characterised by the presence of large numbers of diffuse cysts in the liver and kidneys. The mechanisms underlying the formation of cysts in polycystic liver disease (PLD) and polycystic kidney disease (PKD) are complex. It may occur as an isolated PLD or as a feature of autosomal dominant PKD (ADPKD) or autosomal recessive PKD[1]. Both PLD and PKD are associated with primary cilia of the biliary epithelial cells and with key proteins involved in ciliary function and are therefore classified as fibrocystic or ciliary diseases. Clinically, isolated PLD was first recognised as a distinct disorder in the 1950s, with its genetic basis confirmed in 2003 by analysing eight Finnish families[2].

Many patients with PLD are asymptomatic, and the diagnosis is often made incidentally during an imaging study. However, a subset of patients may have significant symptoms, including abdominal pain, bloating and organ compression, which can have a significant impact on quality of life[2].

Clinical manifestations are primarily due to the presence of multiple liver cysts and an increase in liver volume, which can lead to systemic complications. These include gastro-oesophageal reflux and respiratory distress due to compression of the oesophagus and diaphragm and, in severe cases, symptoms of end-stage liver disease (ESLD). While clinical management is the first line of treatment for symptomatic polycystic disease, liver transplantation (LT) is often the preferred option for patients with hepatomegaly and persistent symptoms.

PKD is characterized by the progressive growth of cysts resulting in significantly enlarged kidneys. High blood pressure and flank pain are common complications, along with urinary tract infections, haematuria, kidney stones, heart valve defects, and intracranial aneurysms.

Combined liver-kidney transplantation (CLKT) offers a therapeutic option for patients with ESLD and concomitant chronic kidney disease (CKD), persistent acute kidney injury, or metabolic diseases that affect kidney function. First successfully performed 40 years ago in Innsbruck, Austria, CLKT has become an important treatment modality, offering curative potential for hereditary conditions and improving survival in patients with advanced chronic disease[3-5].

In this review, we summarise the current evidence on the clinical evaluation and management of polycystic disease, with particular emphasis on liver-kidney transplantation strategies, perioperative considerations, and our institutional experience in adult patients with polycystic liver and kidney disease (PLKD).

CLINICAL EVALUATION AND PATIENT SELECTION

Liver volume increases by 1.8% every 6 to 12 months in patients with PLD. Most patients remain asymptomatic, regardless of the type of PLD[6]. However, approximately 20% of patients experience significant clinical signs such as dyspnoea, early satiety, abdominal distension, malnutrition, gastro-oesophageal reflux, and back pain, often because of hepatomegaly and cyst complications. These symptoms can have a significant impact on quality of life. PLD can also cause hepatic venous outflow obstruction, leading to portal hypertension, ascites, variceal haemorrhage, or splenomegaly. In addition, hormonal effects, especially due to oestrogen, may increase the growth of liver cysts in women, probably due to the expression of oestrogen receptors alpha and beta[7,8].

Most patients with PLD have normal liver function tests. This is because the liver parenchyma is typically not extensively damaged. However, in severe cases, γ-glutamyltransferase, alkaline phosphatase, aspartate aminotransferase, and total bilirubin may be elevated. Elevation of γ-glutamyltransferase and alkaline phosphatase is often associated with the activation of biliary cells due to the mass effect of the enlarged cysts, while an increase in total bilirubin may be due to the cysts compressing the bile ducts, leading to cholestasis[9,10].

Waanders et al[11] found that 45% of patients with PLD had elevated levels of carbohydrate antigen 19-9, with the degree of elevation being positively correlated with the volume of polycystic liver cysts. A significant increase in carbohydrate antigen 19-9 levels should raise concerns about the possibility of cyst infection, and the levels will typically decline following effective anti-infective treatment. Currently, two primary clinical classifications for PLD are widely used: The Gigot classification and the Schnelldorfer classification, which are frameworks for the assessment of disease severity and clinical management[2,12,13]. Both the Gigot and Schnelldorfer classifications of PLD consider the number, size and volume of the cysts, together with the residual liver parenchyma, as the key criteria for classification. The Schnelldorfer classification, which also includes an assessment of the inflow and outflow of the remaining liver segments, is more useful in guiding decisions about possible surgical intervention. The Qian classification, which is based solely on the number of cysts and the presence of symptomatic hepatomegaly, is now rarely used because it is overly simplistic and has limited value in guiding treatment[8,14].

MEDICAL MANAGEMENT OF POLYCYSTIC DISEASE

Somatostatin analogues

Currently, there are no approved treatments for PLD. A review of the literature suggests that octreotide has been used with some success. For example, in 2010, Caroli et al[15] administered 40 mg of octreotide monthly and observed a significant reduction in liver volume, with a mean reduction of 71 ± 57 mL over six months. Similarly, Hogan et al[16] evaluated the effects of the same dose in patients with severe PLKD. They reported a mean liver volume reduction of 4.95% ± 6.77% over one year (P = 0.048).

Mechanistic target of rapamycin: Key driver of cellular growth and emerging therapeutic target

The mechanistic target of rapamycin (mTOR) is a serine/threonine protein kinase belonging to the phosphatidylinositol 3-kinase family. A key regulator of diverse cell signalling pathways, mTOR orchestrates fundamental processes, such as growth, metabolism and survival[17]. Two mTOR inhibitors, namely sirolimus and everolimus, have been proposed as therapeutic options for PLD; for example, sirolimus monotherapy after kidney transplantation (KT) was associated with a modest 11.9% reduction in liver volume (P = 0.009)[18]. Despite providing an early, hypothesis-generating signal that sirolimus might reduce polycystic liver volume, this study was small and retrospective. In contrast, larger randomised controlled trials investigating sirolimus and everolimus over two years did not demonstrate a statistically significant effect on renal cyst progression (P = 0.26 and P = 0.06, respectively), and failed to improve renal function[19,20].

As immunosuppressants, mTOR inhibitors can increase the risk of infections, malignancies and other adverse effects such as dyslipidaemia, thrombosis and lung disease. Although most of the side effects are moderate and can be resolved with dose reduction, they are unpredictable and idiosyncratic, and require careful monitoring in the clinical setting[21,22]. To conclude, despite having an acceptable safety profile, there is insufficient evidence to support the use of mTOR inhibitors to treat PLD; therefore, they are not recommended for PLD patients until more robust, comprehensive data are available.

Vasopressin-2 receptor antagonist

The vasopressin-2 receptor (V2R), expressed in renal tubular epithelial cells, promotes cystogenesis by increasing intracellular cyclic adenosine monophosphate and stimulating epithelial proliferation and fluid secretion. Accordingly, V2R antagonism has shown a clear biological and clinical rationale in ADPKD: Preclinical studies demonstrated slower renal cyst growth and improved renal function in PCK rat models, and randomised clinical evidence showed that tolvaptan significantly reduced the rate of kidney cyst growth compared with controls (P < 0.001)[23]. In addition, tolvaptan has been shown to preserve renal function in patients with advanced ADPKD.

However, the applicability of this mechanism to PLD is biologically less straightforward. V2R is not expressed in biliary epithelial cells, which weakens the mechanistic rationale for a direct effect on liver cysts. Thus, although recent reports suggest that V2R antagonism may reduce liver volume in PLD[24], the available evidence remains limited.

TRANSPLANT STRATEGIES IN POLYCYSTIC DISEASE

LT in PLD

LT remains the primary treatment for PLD and is indicated primarily for patients with severe symptoms that significantly impair quality of life or with untreated complications such as portal hypertension and malnutrition. LT is typically recommended for patients with advanced forms of PLD. The survival rate of PLD patients is significantly higher than that of patients with diseases such as hepatocellular carcinoma and chronic liver failure[12].

Patients with PLD are at increased risk of perioperative mortality due to the complexity of hepatectomy, particularly when the liver is significantly enlarged[25]. In order to reduce the risk of bleeding and torsion of the inferior vena cava (IVC) during liver mobilisation, we routinely use the standard technique of IVC replacement and veno-venous bypass. However, primary abdominal closure is usually performed, as the risk of abdominal compartment syndrome is considered to be low in these patients. Survival at 5 years is reported to be 92.3%[12,26,27].

Immunological benefits of CLKT

Improved survival, avoidance of unpredictable waiting times, and potential immunological protection are among the potential benefits of CLKT. Clinical and experimental evidence suggests that the liver allograft may exert a protective effect on the kidney graft, with lower rates of both T-cell-mediated and antibody-mediated rejection compared with kidney-only transplantation in selected settings[28].

In the early post-transplant phase, the large endothelial and sinusoidal surface of the liver allograft may contribute to partial adsorption/clearance of circulating donor-specific antibodies and modulation of complement activation, thereby attenuating early antibody-mediated injury to the renal allograft. This early buffering phenomenon is commonly referred to as the “sink effect”, and has been successfully exploited to protect the kidney in crossmatch-positive patients by transplanting a partial replacement liver from the same donor. Initial studies identified the sink effect and chimerism as key mechanisms of immunological tolerance. In the majority of patients undergoing CLKT, the pre-formed donor-specific antibodies are cleared within four months. This may in part explain the reduced expression of genes associated with endothelial cell activation and inflammation in kidney biopsies one year after CLKT compared with patients who underwent a kidney-only transplant with a similar level of pre-sensitisation[29,30].

However, liver-mediated immunoprotection in CLKT is likely broader than the sink effect alone. Although these mechanisms are not specific to polycystic disease biology, they are particularly relevant in PLKD cohorts, in whom prolonged dialysis exposure, repeated procedures, and occasional transfusions may result in variable sensitisation risk before transplantation.

The mechanisms underlying the immunomodulatory effect of the liver can be better understood from recent studies, which demonstrate a reduced frequency of activated CD4 T cells and donor-specific T-cell hyporesponsiveness, and a higher frequency of CD19⁺CD24⁺CD38^- memory B cells and FOXP3⁺Helios⁺regulatory T cells after CLKT, all associated with a tolerogenic profile[31-33].

Innovative techniques: Organ preservation methods

Major challenges in combined LT include patient selection, organ shortage, prolonged cold ischaemia and a lack of reliable biomarkers to predict recovery of organ function. The use of biomarkers to refine patient selection and the implementation of machine perfusion (MP) techniques to reduce time constraints and improve graft viability are emerging strategies to address these challenges[34].

Static cold storage (SCS), the conventional method for preservation and transport of donor organs on ice, has long been considered the gold standard in organ transplantation due to its practicality and ability to sufficiently preserve high-quality donor allografts. However, the growing demand for organ transplants and the shortage of available donors have led to an increase in the acceptance of extended criteria donation (ECD) allografts, such as those from older donors or organs with longer preservation times. Although the use of ECD allografts has contributed to a reduction in the mortality rate on the waiting list and has resulted in acceptable clinical outcomes, ischaemia-reperfusion injury after SCS remains a significant challenge, particularly with regard to postoperative function of ECD organs[35-38].

Preoperative MP has been shown to be associated with improved postoperative outcomes and prolongation of organ preservation. The use of both hypothermic oxygenated perfusion (HOPE) and normothermic MP to reduce early allograft dysfunction, particularly in LT, has been supported by several randomised controlled trials. The protective mechanism of HOPE involves restoring mitochondrial oxygen levels during hypothermic preservation, helping to prevent mitochondrial injury during reperfusion[39].

For renal allograft, hypothermic MP (HMP) has been shown to reduce delayed graft function (DGF). In marginal renal allografts, however, the benefits of end-ischaemic MP, including both HOPE and normothermic MP, have not been consistently demonstrated. This suggests that their potential impact in this setting needs to be investigated further[40].

Simultaneous liver-kidney transplantation

The clinical indications for simultaneous liver-kidney transplantation (SLKT) can be broadly divided into three categories: (1) ESLD with CKD, including: Glomerulonephritis, interstitial nephritis, polycystic renal syndrome and calcineurin inhibitor toxicity; (2) ESLD with acute kidney injury, including: Hepatorenal syndrome and acute tubular necrosis; and (3) Metabolic disorders, including: Primary hyperoxaluria I, alpha-1-antitrypsin deficiency, glycogen storage disease type I, sickle cell disease, amyloidosis, haemolytic uraemic syndrome, and methylmalonic acidaemia.

Currently, SLKT is indicated for ESLD associated with chronic renal or metabolic disease, but it remains controversial for ESLD associated with acute renal failure, including hepatorenal syndrome[41-43].

Delayed kidney transplantation

SLKT requires careful attention to surgical logistics and perioperative management of both the liver and kidney allografts. LT recipients often present with severe disease, including significant coagulopathy, and typically require vasopressor and inotropic support during the procedure. Therefore, the haemodynamic conditions during LT are not ideal for the newly implanted kidney allograft. While hepatic allograft function benefits from low central venous pressure and balanced fluid status to prevent graft congestion, these conditions are suboptimal for renal allograft function. Renal perfusion is compromised by low central venous pressure and systolic blood pressure or the use of vasopressors to stabilise blood pressure. Hepatic reperfusion injury and elevated bilirubin levels can lead to renal tubular injury, acute tubular necrosis and DGF, which can further compromise the renal allograft[44,45].

Ekser and Goggins[45] introduced the “Indiana approach” to SLKT in order to meet the physiological requirements of both transplanted organs. In this technique, LT is performed first, while the kidney allograft is maintained using HMP. This method allows for a delayed implantation of the kidney allograft, typically up to 2-3 days after LT has been performed[45]. To better contextualise the Indiana approach within the broader literature, we provide a narrative comparison of kidney implantation and preservation strategies reported in CLKT (Table 1).

Table 1 Comparison of kidney implantation and preservation strategies reported in combined liver-kidney transplantation.

Strategy/protocol	Kidney implantation timing and preservation	Main reported findings (qualitative)	Key limitations
Standard SLKT	Simultaneous/SCS	Widely used and feasible	Not specifically designed to protect kidney during immediate post-LT instability
		However renal graft may be exposed to unfavorable hemodynamics during/after LT	Heterogeneous outcomes depending on recipient severity
End-ischemic renal MP in marginal kidneys[40]	Simultaneous/end ischemic HOPE/NMP/HMP	Benefits not consistently demonstrated across studies, especially in marginal graft settings	Heterogeneous donor types/protocols/endpoints
		HMP associated with lower DGF in some analyses, despite longer CIT	Limited CLKT-specific evidence
		No clear effect on PNF
Delayed KT after LT with machine perfusion[46]	Delayed (timing variable)/HMP	Demonstrates technical feasibility and potential benefit in selected high-risk cases	Very small numbers
			Case-based evidence
			No standardized protocol
			Limited comparability across reports
Delayed KT after LT with HMP (“Indiana approach”)[43]	Continuous HMP during delay (typically 1-3 days after LT)	Reported improved renal outcomes (lower DGF/better eGFR) despite prolonged CIT in selected CLKT recipients	Primarily single-center experience
			Retrospective design
		Physiologically attractive strategy	Limited external validation

SLKT: Simultaneous liver-kidney transplantation; SCS: Static cold storage; KT: Kidney transplantation; LT: Liver transplantation; HOPE: Hypothermic oxygenated perfusion; NMP: Normothermic machine perfusion; HMP: Hypothermic machine perfusion; DGF: Delayed graft function; CIT: Cold ischemia time; PNF: Primary non-function; eGFR: Estimated glomerular filtration rate.

Delayed KT offers several advantages. It allows haemodynamic stabilisation and correction of coagulopathy in the immediate post-LT period, thereby reducing potential damage to the renal allograft. Delayed transplantation also facilitates the decompression of varices, reducing intraoperative blood loss during KT and potentially improving renal allograft outcomes. In addition, the planned delay allows for complete withdrawal of vasopressors prior to KT, thereby minimising the risk of vasopressor-induced DGF. Supporting the recipient with continuous veno-venous haemodialysis (CVVHD) during this interim period helps to maintain stable central venous pressure and fluid balance while clearing post-liver reperfusion debris and elevated bilirubin levels from the circulation. This further reduces the risk of renal tubular injury and DGF[46,47].

Using a larger cohort and a comparative analysis of SLKT vs delayed KT in CLKT, the Indiana group confirmed that DGF is the most significant negative predictor of patient survival in CLKT. Furthermore, their results showed that prolonged cold ischaemia time (CIT), which typically contributes to renal allograft injury and a higher incidence of DGF, is not a concern in the context of the Indiana approach.

Ekser and Goggins[45] reported that despite an average CIT of more than 50 hours for delayed renal allografts in CLKT, the rates of DGF and estimated glomerular filtration rate (eGFR) were superior to those in SLKT. Kidney allografts were preserved by continuous HMP at 4 °C for 45 hours and 46 hours, respectively, until implantation. During this period, the recipients were supported with CVVHD. The recipients were completely weaned off vasopressors before KT. Delayed KT was performed extraperitoneally in the right pelvic fossa through a separate incision, and native nephrectomy was not required in any of the recipients[45,46].

It is essential to evaluate and adopt strategies to minimise renal allograft futility in CLKT, particularly in the rare context of PLKD. The timely documentation and reporting of novel approaches, such as the Indiana approach, will facilitate their wider adoption and provide critical insights into their efficacy. Specifically, the potential synergy between HMP and delayed KT merits further investigation to determine its role in the optimisation of renal allograft function in CLKT. Furthermore, by incorporating extended donor criteria, including kidneys donated after circulatory death, this approach may support the safe expansion of the donor pool[28,48].

Simultaneous or delayed KT, using HMP after LT

Studies have shown that recipients of a SLKT with a Model for End-stage Liver Disease (MELD) score above 30 have significantly poorer survival and greater rates of primary failure than those with a MELD score below 30[29].

The reduction in KT survival observed in recipients of a SLKT with a MELD score of more than 30 is mainly attributed to the physiological disturbances induced by the LT. Recipients of LT often require the use of vasopressors to treat perioperative hypotension, which can adversely affect renal allograft function and lead to reduced survival of the transplanted kidney. In order to mitigate these adverse effects, a number of studies have investigated the strategy of delaying KT. These approaches allow delayed transplantation until the recipient's coagulopathy and haemodynamic status have stabilised by preserving the renal allograft using HMP[48].

Ekser and Goggins[45] compared the results of SLKT with those of delayed KT in a cohort of 69 recipients of simultaneous KT and 61 recipients of delayed KT. As expected, the median renal CIT was longer in the delayed KT group (50 hours vs 10 hours). Most importantly, the delayed KT group had significantly lower rates of DGF, lower one-year eGFR, and improved one- and five-year patient survival compared with the SLKT group[45].

In a more recent study, Chang et al[48] analysed renal outcomes from the United Network for Organ Sharing database and compared HMP with SCS for KT in SLKT. While renal CIT was longer in the HMP group (12.8 hours vs 10.0 hours), the study found that HMP was associated with a reduction in DGF, although it did not affect the incidence of primary non-function[48].

INSTITUTIONAL EXPERIENCE

Since the start of our transplant programme, 69 combined solid-organ transplants have been performed in adult recipients at IRCCS ISMETT, including 37 liver-kidney, 25 kidney-pancreas, 4 heart-kidney, and 3 liver-lung procedures. From this overall experience, we extracted a retrospective cohort of adult patients with polycystic hepatorenal disease who underwent CLKT.

Surgical and perioperative management

In accordance with standard practice at our centre, all patients were recruited and listed following a careful multidisciplinary review, which included radiology-assisted assessment of tomographic imaging. All evaluated patients had polycystic disease complicated by “clutter syndrome”, and symptomatic adult PLKD has consistently been the primary indication for transplantation, defined by clinically relevant compressive (“mass-effect”) symptoms, including dyspnoea when supine and impaired oral intake/early satiety due to abdominal discomfort.

Preoperative dialysis was performed to avoid the need for CVVHD, and postoperative haemodialysis was performed as required.

All patients received basiliximab 20 mg intravenously at induction and on postoperative day (POD) 4. The immunosuppressive regimen consisted of tacrolimus (0.10-0.20 mg/kg/day), mycophenolate mofetil (500 mg every 12 hours), and steroids. Thymoglobulin was only used in one patient for hyperimmunity. It was avoided in the other patients to prevent worsening of pancytopenia.

Renal transplantation was performed via an extraperitoneal approach with vascular anastomosis to the external iliac vessels and a ureter-bladder anastomosis. Heparin was not administered during clamping the external iliac vessels; however, a continuous heparin drip was administered based on the international normalised ratio trend.

Nephrectomy was considered in the presence of a urinary tract infection linked to infected or haemorrhagic cysts causing sepsis or anaemia.

Over the study period, the core surgical technique and implantation strategy remained unchanged at our centre (extraperitoneal kidney implantation and standard orthotopic LT). The main practice change was the progressive introduction of MP technologies which were initially prioritised for higher-risk grafts. While donor after circulatory death (DCD) donation has become increasingly relevant in Italy, no CLKT from DCD donors was performed in this series.

Study methods

All consecutive adult patients with polycystic disease undergoing CLKT between 2008 and 2025 were included; paediatric recipients were excluded. Quantitative variables are summarised as median and interquartile range (IQR), and categorical variables as frequency and percentage. Graft and patient survival were estimated using Kaplan-Meier methods. Data were collected within the MetabOLiKT study, approved by the Institutional Review Board (IRRB/18/23) and by the local Ethics Committee on November 20, 2023.

Study findings

Between 2008 and 2025, a total of 20 adult patients affected by polycystic disease underwent CLKT (Table 2). Sixty percent of them were female and the mean age was 52.0 years (median 52.5, IQR 48.0-58.5). The median MELD score was 21.0 (IQR 16.8-23.2), and serum creatinine at transplant was 6.8 mg/dL (IQR 3.7-8.0). Haemodialysis was ongoing at the time of transplantation in 15 patients (75.0%, Table 2). CLKT was always performed using grafts from donors after brain death, and both grafts were always from the same donor. All patients underwent standard orthotopic LT after hepatectomy. Biliary end-to-end anastomosis was performed in all recipients.

Table 2 Baseline and perioperative characteristics of 20 adult recipients undergoing combined liver-kidney transplantation, n (%)/median (interquartile range).

Variable	Value
Male sex	8 (40)
Recipient age	52.5 (48.0-58.5)
Model for end-stage liver disease	21.0 (16.8-23.2)
Serum creatinine at transplant, mg/dL	6.8 (3.7-8.0)
Hemodialysis at transplant	15 (75.0)
Machine-perfused liver graft	0 (0)
Machine-perfused kidney graft	4 (20)
Split liver	1 (5)
Post transplant outcomes
Dialisis at transplant	15 (75.0)
Delayed liver graft function	2 (10.0)
Delayed renal graft function	6 (30.0)
Occurrence of acute renal rejection	1 (5.0)

In five of the 20 polycystic patients (25.0%), a pre-emptive kidney transplant was performed. In five patients (25.0%), a simultaneous right nephrectomy was performed due to the large size of the right kidney.

Hypothermic pulsatile perfusion was used to support the renal allografts in 4 patients (20%), facilitating delayed implantation (Table 2). All patients underwent SLKT at the surgeon’s discretion.

Patients were retrospectively followed over a mean follow-up time of 85 months (median 71 months; IQR 23-138). Delayed liver graft function occurred in 2 patients (10.0%) and delayed renal graft function in 6 patients (30.0%).

Two patients experienced renal graft failure. In the first case, the kidney graft never achieved function, in the setting of sepsis secondary to infection of renal and hepatic cysts and severe malnutrition. In the second case, renal graft failure occurred on POD 15 due to renal artery thrombosis, which required graft nephrectomy and resumption of haemodialysis. One patient died on POD 72 from multiorgan failure secondary to sepsis, with concomitant liver and kidney graft dysfunction. Longitudinal renal function and patient and graft survival are reported in Table 3 and Figure 1. At 1 year, 3 years, and 5 years after CLKT, the median eGFR was 64.0 mL/minute/1.73 m², 62.0 mL/minute/1.73 m², and 64.0 mL/minute/1.73 m², respectively. Overall survival estimates were 95% (95% confidence interval: 86%-100%) at 1 years, 3 years, and 5 years, and graft survival estimates were 85% (95% confidence interval: 71%-100%) at the same time points (Table 3).

Figure 1  Kaplan-Meier estimates of overall patient survival and kidney graft survival after combined liver-kidney transplantation in 20 adult recipients with polycystic liver and kidney disease.

Table 3 Longitudinal observations of renal function and survival after combined liver-kidney transplantation, n (%).

	Time after combined liver-kidney transplant
	1 year	3 years	5 years
Patients in follow-up	16	11	11
Estimated glomerular filtration rate, mL/minute/1.73 m2
Median	64.0	62.0	64.0
IQR	53.8-73.5	44.5-69.0	43.5-73.5
eGFR ≥ 60	10 (62.5)	6 (55)	6 (55)
eGFR 30-59	6 (37.5)	5 (45)	4 (36)
eGFR < 30	0	0	1 (9)
Graft survival, KM-estimate (95%CI)	85% (71%-100%)	85% (71%-100%)	85% (71%-100%)
Overall survival, KM-estimate (95%CI)	95% (86%-100%)	95% (86%-100%)	95% (86%-100%)

IQR: Interquartile range; eGFR: Estimated glomerular filtration rate; KM: Kaplan-Meier; CI: Confidence interval.

FINAL CONSIDERATIONS

PLKD represents a distinctive indication for CLKT, in which transplant candidacy is frequently driven by the combined burden of disabling hepatomegaly, impaired quality of life, malnutrition, and progressive renal dysfunction rather than by classical biochemical liver failure alone. In this context, CLKT provides a definitive treatment strategy for both organ manifestations and may avoid the logistical and clinical drawbacks of sequential transplantation.

In our experience, PLKD accounted for more than half of all adult CLKTs performed at our institution, confirming the clinical relevance of this indication in a high-volume transplant setting. Outcomes were favourable, with 19 patients alive at follow-up, supporting the feasibility and safety of CLKT in carefully selected PLKD recipients despite the technical complexity of surgery in the presence of massive hepatomegaly and distorted anatomy. These findings are consistent with the literature reporting excellent post-transplant survival in PLKD recipients, often superior to other CLKT indications[49].

A key point that deserves emphasis is the dual-organ trajectory of polycystic disease. While hepatic symptoms and hepatomegaly often determine the indication for LT, the renal course in PKD is highly variable and substantially influences timing, perioperative risk, and long-term morbidity. Some patients progress slowly, whereas others develop advanced CKD, dialysis dependency, or require KT earlier in the disease course. This PKD-specific heterogeneity also affects candidacy pathways (including pre-emptive KT history), perioperative vulnerability to kidney injury during LT, and the expected benefit of kidney-protective strategies in CLKT.

From a surgical perspective, massive hepatomegaly remains the principal determinant of complexity during the hepatectomy phase, with increased risks of bleeding, difficult mobilisation, and haemodynamic instability. In our practice, routine use of IVC replacement and veno-venous bypass helped facilitate safe explantation and control intraoperative risk. In addition, primary abdominal closure was generally feasible, in line with the relatively low risk of abdominal compartment syndrome in this population despite major intra-abdominal volume changes after liver removal[12,26,27].

On the renal side, native nephrectomy may be required in selected PLKD recipients because of kidney size and space constraints. In our series, simultaneous right nephrectomy was performed in a subset of patients to allow safe graft placement. Although this adds technical complexity, it may be necessary to optimise implantation and reduce compressive complications. These decisions should therefore be individualised according to anatomy and operative risk.

Another critical issue is the timing of kidney implantation. Although SLKT remains the standard approach, the perioperative environment during LT is often suboptimal for the renal allograft because of vasopressor exposure, haemodynamic instability, reperfusion-related inflammatory injury, and coagulopathy[44,45]. These factors may contribute to DGF, which has been identified as a major negative predictor of survival after CLKT[45,46]. For this reason, kidney-protective strategies - particularly in recipients with high medical acuity - deserve increasing attention.

In this setting, delayed kidney implantation supported by HMP, as popularised by the “Indiana approach”, offers a physiologically sound strategy by allowing haemodynamic stabilisation, reduction of vasopressor requirements, and correction of coagulopathy before kidney reperfusion[45-47]. The available evidence suggests that prolonged renal CIT may be mitigated by continuous HMP, and that delayed implantation can improve renal outcomes in selected recipients, even in the context of CLKT[45,46]. Our experience with hypothermic pulsatile perfusion in a subset of patients supports the feasibility of this strategy and highlights the potential value of preservation technologies in complex combined transplantation.

More broadly, organ preservation is becoming increasingly relevant as transplant programmes expand the use of extended criteria donor organs. While SCS remains standard practice, MP techniques may improve graft utilisation and early function, especially when combined transplantation logistics require flexibility in implantation timing[34-36,39,40]. However, evidence remains heterogeneous - particularly for renal perfusion strategies in the CLKT setting - and prospective studies are needed to clarify which recipients benefit most and under which operative conditions.

CLKT may also confer immunological advantages, with the liver allograft exerting a tolerogenic effect that can reduce kidney allograft immune injury and rejection compared with kidney-only transplantation[28-33]. Although these mechanisms are not specific to polycystic disease biology, they may be clinically relevant in PLKD recipients, who may have variable sensitisation risk due to prolonged dialysis exposure, transfusions, or prior renal procedures. In liver-first CLKT sequencing, and potentially even more so when delayed kidney implantation is used, this immunomodulatory effect may contribute to favourable renal outcomes, although our study was not designed to evaluate immunological endpoints.

The present study has limitations, including its retrospective design, the limited sample size, and the long inclusion period, during which perioperative management and preservation strategies evolved. Nevertheless, these data provide meaningful real-world insight into a rare but clinically important indication for CLKT and support individualised surgical and perioperative planning in PLKD recipients.

CONCLUSION

In conclusion, CLKT is a safe and effective treatment option for selected patients with severe polycystic disease involving both the liver and the kidneys, with excellent survival and meaningful clinical benefit. In PLKD, candidate selection should be tailored to the disease phenotype, with listing criteria based primarily on symptoms and quality of life (including severe hepatomegaly, malnutrition, and compressive complications), rather than relying solely on conventional liver failure markers. In parallel, renal trajectory assessment in PKD and kidney-specific perioperative planning (including native nephrectomy when needed and kidney-protective implantation strategies) are essential to optimise outcomes and should be incorporated into future disease-specific CLKT pathways. Prospective multicentre PLKD registries should be developed to systematically collect disease-specific variables, including symptom burden, quality-of-life impairment, nutritional status, renal trajectory (CKD progression and dialysis burden), and both perioperative and longitudinal outcomes after CLKT.

ACKNOWLEDGEMENTS

We acknowledge the Italian Ministry of Health, which supports our research activity (Ministero della Salute, Ricerca corrente, Linea 1).