Kidney allograft outcomes in combined kidney with other solid organ transplantation

Abstract

With advances in solid organ transplantation, the option of combined kidney with other solid organ transplantation is an enticing option for patients with advanced kidney disease and concomitant other solid organ failure. Kidney allograft dysfunction is well known to be associated with increased adverse outcomes post solitary kidney transplant however, outcomes for patients and the kidney allograft are somewhat understudied in the setting of kidney transplantation when combined with other solid organ transplantation such as in a simultaneous liver-kidney transplant. We will provide an overview of the current literature available on kidney allograft clinical outcome measures in combined solid organ transplant recipients such as delayed kidney allograft function, kidney allograft rejection, kidney allograft and patient survival metrics and how they compare to patients with kidney transplants alone. Worse kidney allograft survival outcomes were noted in most combined other organ with kidney transplantation (liver-kidney, heart-kidney, and lung-kidney) due to comorbidities attributed to non-renal organ dysfunction whereas improved kidney allograft survival outcomes were noted for pancreas-kidney transplantation.

Key Words: Kidney allograft outcomes; Simultaneous heart-kidney transplant; Simultaneous pancreas-kidney transplant; Simultaneous liver-kidney transplant; Simultaneous lung-kidney transplant

Core Tip: Combined kidney with other solid organ transplantation has emerged as an enticing option for patients suffering from advanced kidney disease in addition to other advanced non-renal solid organ disease. The increased risk of early kidney allograft failure with most such simultaneous organ transplantation of liver-kidney, heart-kidney, and lung-kidney competes with the overall improved all-cause mortality risk for select patients compared to those receiving their other non-renal organ transplant alone. As recipients of multi-organ transplants often receive priority for quality kidney allografts before waitlisted recipients for a kidney transplant alone, special care must be taken to minimize renal allograft futility.

INTRODUCTION

Thanks to improvements in patient survival in patients suffering from advanced and end-organ non-renal diseases in the setting of also having advanced kidney disease, a subtype transplantation of combined kidney with other organ transplantation has emerged[1]. This is permitted as some organ donors can donate several organs, and in the United States, the Organ Procurement and Transplantation Network (OPTN) and United Network for Organ Sharing (UNOS) policies dictate when some organs need to be offered together to one candidate. This has been established as the preferred modality of transplantation for these select patients, given that chronic kidney failure continues to be a recognized complication of transplantation of nonrenal organs[2]. Current OPTN/UNOS policies support combined other organ and kidney transplantation for heart, lung, and liver when pre-transplant estimated glomerular filtration rate (EGFR) is less than 30 mL/minute/1.73 m² or pre-transplant dialysis due to reductions in mortality compared to another organ transplant alone[3-5]. Additionally, the safety-net policy permitting priority listing status for follow up kidney transplants after other organ transplants in patients that went without combined other organ-kidney transplantation yet have persistent kidney dysfunction requiring either dialysis or EGFR < 20 mL/minute/1.73 m² is available. The following will be a look into the data available for the kidney allograft specific outcomes for these simultaneous multi-organ transplant recipients.

To provide an up-to-date picture of the current state of kidney allograft outcomes in combined kidney with other non-renal organ transplantation, the PubMed database was searched for articles on kidney specific outcomes of delayed graft function, acute rejection rates, and survival outcomes including death with a functioning graft rate for the respective iterations of combined organ transplant compared with kidney transplant alone (KTA). Keywords included in the search included “kidney allograft outcomes” combined with “liver-kidney transplantation”, “heart-kidney transplantation”, “lung-kidney transplantation”, or “kidney-pancreas transplantation”, with preference for inclusion of more recently published studies ideally published within the last 5-10 years. These findings are summarized in Table 1 and detailed in the following text.

Table 1 Summary of kidney allograft outcomes in combined solid organ transplantation based on major published studies.

Type of combined transplant	Delayed graft function	Acute rejection	Kidney graft failure/survival	Patient survival
SLK	(1) 39% of cases (Lunsford et al[11]); (2) Higher with high MELD, vasopressor use, or poor hemodynamic status; and (3) Delayed kidney implantation (up to 48 hours) reduces DGF	Possible lower rejection rates vs KTA thought to be due to an immunomodulatory mechanism conferred by liver	(1) Renal allograft futility in 20.7% (death or dialysis by 3 months, Lunsford et al[11]); and (2) Early graft loss linked to hemodynamic instability and high MELD	Early mortality higher in high-MELD SLK recipients, but long-term survival similar to KTA once stabilized
SHKT	(1) 27%-37% of cases (Swanson et al[1], Grupper et al[16]); (2) Linked to pre-transplant mechanical circulatory support and RV pressure elevation; and (3) Delayed kidney implantation (up to 69 hours) can reduce risk	No significant difference vs KTA	5-year-graft survival 72% (vs 73% in KTA, Choudhury et al[9])	5-year patient survival lower (75% vs 84%) due to cardiac comorbidities (Choudhury et al[9])
SLKT	(1) Higher DGF risk than kidney-after-lung (3 vs 0 cases; Mesnard et al[31]); and (2) Often due to circulatory shock during lung transplant	Insufficient data on rejection rates	(1) > 3 times high hazard of kidney graft loss (HR = 3.27, P < 0.001, Chen et al[4]); and (2) Primarily from death with functioning graft	Overall survival lower than KTA due to lung-related mortality, not renal factors
SPK	(1) Lower DGF incidence vs KTA (Israni et al[41]); and (2) Improved ischemia times metabolic milieu from normoglycemia	No significant difference vs KTA	Superior long term graft year survival. 10-year survival 78% (vs 60%-65% for KTA, Reddy et al[36], Esmeijer et al[37])	Improved patient survival and reduced cardiovascular mortality (3.3% vs 19%, Lange et al[39])

SLK: Simultaneous liver-kidney; SHKT: Simultaneous heart and kidney transplantation; SLKT: Simultaneous lung and kidney transplant; SPK: Simultaneous pancreas-kidney; MELD: Model for end-stage liver disease; DGF: Delayed graft function; RV: Right ventricle; KTA: Kidney transplant alone; HR: Hazard ratio.

KIDNEY TRANSPLANT IN THE SETTING OF A SIMULTANEOUS LIVER-KIDNEY TRANSPLANT COMPARED TO A KIDNEY TRANSPLANT ALONE

The practice of simultaneous liver-kidney (SLK) transplant has seen a drastic increase in utilization over the years due to the concerted effort to prevent the development of post-liver transplant mortality, given studies demonstrating increased survival among transplant candidates with chronic kidney disease who undergo SLK transplant compared to liver transplant alone[6]. The most commonly performed multi-organ transplant in the United States has been SLK, accounting for nearly 10 percent of all deceased liver transplants performed in 2020[7]. To formalize the criteria for SLK transplantation, UNOS approved a policy regulating SLK transplantation in 2016 and implemented it in 2017, and also enacted the “safety net” for patients that may benefit from kidney transplantation but did not meet the initial criteria at the time of their liver transplant[8]. This Safety Net afforded priority for these patients with ongoing kidney dysfunction at 60-365 days after their liver transplant for a kidney transplant. These UNOS/OPTN policies for SLK transplantation and safety net provided a framework for combined kidney and other organ transplantation policies in subsequent years[9].

When discussing kidney allograft outcomes in SLK transplant recipients, there has been variation depending on which specific kidney allograft metrics are being reported. Given the substantially sicker patient population of SLK transplant recipients, it would be expected that the specific physiological needs of the kidney allograft would be negatively impacted. Cullaro et al[10] found just that with SLK transplant recipients with increasing model for end-stage liver disease scores had much higher rates of 90-day and 1-year kidney failure when compared to kidney after liver transplantation. Additionally, Lunsford et al[11] conducted a retrospective single-center multivariate regression analysis of 145 SLK transplant recipients, finding that 39% experienced delayed graft function and 20.7% had renal allograft futility (i.e., patient death or need for dialysis at 3 months post-transplant). Given that delayed graft function portends to most significant negative predictor in SLK transplant recipients, a delayed strategy for implanting the corresponding kidney allograft up to 48 hours after the liver to permit hemodynamic stabilization and weaning of vasopressor support was utilized by groups such as Ekser et al[7], finding reduced rates of delayed graft function and improved short and long-term kidney allograft EGFR. Interestingly, some investigators have observed that SLK transplantation may offer an immunologic advantage due to decreased rates of acute rejection if both organs are transplanted simultaneously, compared to a KTA or kidney after liver, potentially mediated by a systemic immunomodulatory mechanism[12-15].

KIDNEY TRANSPLANT OUTCOMES IN THE SETTING OF A SIMULTANEOUS HEART-KIDNEY TRANSPLANT COMPARED TO A KTA

Over the past two decades, simultaneous heart and kidney transplantation (SHKT) has continued to emerge as a viable and increasingly accepted therapeutic option for patients affected by advanced cardiac disease and simultaneous permanent renal dysfunction. Even though this combined organ procedure can potentially present additional perioperative and immunologic complexities, the current evidence indicates that numerous kidney transplant outcomes, including delayed graft function, acute rejection, allograft survival, and patient survival, are generally equivalent to those for KTA among strictly selected patients. In a matched kidney-transplant cadaver donor study by Choudhury et al[9], a similar five-year graft survival was noted in recipients of an SHKT compared to those patients who underwent KTA, with 72% survival in the SHKT group vs 73% survival in the KTA group, respectively. However, the five-year post-procedure patient survival was decreased in the SHKT group compared with the KTA group (75% vs 84%, P = 0.02). This difference in five-year post-procedure patient survival could be accounted for by this population’s higher burden of cardiovascular comorbidities. Furthermore, delayed graft function appears more common following the SHKT procedure. Swanson et al[1] reported in a comprehensive review that delayed graft function rates ranged from 27% to 37% among recipients of SHKT, which notably exceeded the incidence typically reported in isolated kidney transplant recipients. A similar range was confirmed in a single-center cohort by Grupper et al[16], where they found 37% of SHKT recipients with delayed graft function, with strong associations of delayed graft function with pretransplant mechanical circulatory support and right ventricular pressures. Expectedly, delayed graft function predicted worse renal function at 1 year and 3 years after transplantation. To counteract such adverse outcomes, Lutz et al[17] suggested a delayed implantation approach in which the kidney graft is kept ex vivo for up to 69 hours after cardiac transplantation. Among the first five patients, 100% achieved one-year post-procedure survival and graft survival, supporting the opportunity of using such a delayed implantation approach in high-risk patients[17].

Currently, there is insufficient compelling evidence to claim that acute kidney rejection occurs at higher rates in SHKT recipients than in KTA recipients, likely at least in part due to the higher baseline maintenance immunosuppression required for maintenance of the non-renal allografts including generally higher target tacrolimus levels early on compared to most KTA recipients balanced against the kidney toxicity of these high tacrolimus levels[18-20]. The available data indicate that patient survival following the SHKT procedure is generally intermediate compared to that observed with the KTA procedure. This difference is likely attributable to the severity of pre-existing cardiac disease rather than renal pathology. Although focused on isolated kidney transplantation, Ojo et al[21] reported that over 40% of long-term graft loss was attributable to death with a functioning and viable graft, which further underscores the impact of nonrenal comorbidities on patient survival. Even among older patients’ cohorts with simultaneous heart and kidney failure, the SHKT procedure may offer a survival advantage compared to isolated heart transplantation. Savla et al[22] examined a national cohort of patients with heart retransplants and described that patients receiving combined kidney transplant had superior survival compared with recipients of heart re-transplantation alone, particularly among dialysis-dependent patients at the time of listing. Additionally, Bhardwaj et al[23] noted that patients with an EGFR of less than 30 mL/minute/1.73 m² were more likely to benefit from concomitant SHKT. Consequently, their findings also agree with recent policy modifications incorporated by the OPTN that include implementing a safety net provision that ensures priority kidney transplantation for certain recipients of heart transplantation[23]. Procedure optimization continues to be the key to preventing renal injury in SHKT recipients. Notably, Ngai et al[24] described significant factors to consider during the procedure, including the timing of organ implantation and approaches for maintaining hemodynamic stability.

KIDNEY TRANSPLANT OUTCOMES IN THE SETTING OF A SIMULTANEOUS LUNG-KIDNEY TRANSPLANT COMPARED TO A KTA

Simultaneous lung and kidney transplant (SLKT) has been a quite rarely pursued therapeutic option since the first SLKT in the Unites States in 1995, with only 74 such patients being reported to the UNOS registry as of 2020[25,26]. Recipients of SLKT have been shown to have improved survival when compared to isolated lung transplant recipients with EGFR less than 30 mL/minute/1.73 m² or requiring dialysis prior to transplant[4]. It has been found that there is correlation between lower EGFR and worse early and late outcomes after lung transplantation[27]. Additionally, the most recent international consensus guidelines recommended against isolated lung transplant for patients with advanced baseline kidney dysfunction (glomerular filtration rate less than 40 mL/minute/1.73 m²), given the risks associated with immunosuppressive medications on kidney function post-transplant and potential need for dialysis and its associated impact on mortality[28,29].

Due to the relatively low number of registered SLKT recipients in the registry, there has been a relative paucity of data available comparing kidney allograft outcomes in combined SLKT vs kidney allograft alone. The retrospective cohort study conducted by Chen et al[4] found that the risk of kidney graft loss after SLKT was greater than 3 times higher (hazard ratio 3.27, P < 0.001) than that of KTA recipients using the contralateral kidney from the same deceased donor. This difference in graft loss in the study was attributed to the greater mortality of combined SLKT recipients with functioning allografts, thus suggesting that it was not kidney function specifically that was adversely affected by these combined SLKT, but rather that better care must be taken in avoiding futile SLKT to optimize the collective benefit of all transplant candidates. The 2013 randomized control study found SLKT with lower recipient survival than abdominal transplant alone[30]. The single-center retrospective cohort study by Mesnard et al[31] also supported the finding that kidney allograft prognosis for SLKT is mostly tied to patient survival in relation to their lung transplant complications, and in addition that the kidney after lung transplantation strategy had postoperative morbidity and kidney allograft function similar to those of kidney transplantation in non-lung transplanted patients. This study found numerically higher kidney delayed graft function in the SLKT cohort compared to the kidney after lung transplant cohort (3 vs 0, P-value of 0.18), which was attributed to circulatory shock of the lung transplant. Currently, there is insufficient data to comment on discrepancies in kidney acute rejection episodes in SLKT recipients compared to KTA recipients, likely due to in part from the increased baseline immunosuppression requirements for maintenance of the non-renal allograft including comparatively higher tacrolimus levels again balanced against the kidney toxicity of high tacrolimus levels[18,32,33].

KIDNEY TRANSPLANT OUTCOMES IN THE SETTING OF A SIMULTANEOUS PANCREAS-KIDNEY TRANSPLANT COMPARED TO A KTA

We will touch briefly on the practice of simultaneous pancreas-kidney (SPK) transplantation, which has now been established as the treatment of choice for patients with insulin-dependent diabetes mellitus and related end-stage kidney disease for acceptable candidates, as it not only provides quality of life by removing the need for exogenous insulin but also increases life expectancy when compared to remaining on dialysis[34]. The practice of SPK transplantation have traditionally been excluded from descriptions of combined organ transplants as the criteria for kidney transplant candidacy for SPK is the same for KTA compared to the other combined other organ transplantation discussed above with higher glomerular filtration rate thresholds for eligibility[35]. SPK promotes a 10-year survival rate of 78% on par with living donor kidney alone transplant and much better than the survival of deceased donor kidney-alone transplant recipients[36-38]. Investigators Lange et al[39] found SPK recipients had lower all-cause mortality and reduced cardiovascular mortality (3.3% compared to 19%) in addition to decreased major cardiovascular events (7% compared to 28%) compared to KTA recipients. However, Hedley et al[40] noted that this survival advantage of SPK over KTA is lost in pancreas allograft failure with no significant difference between the two in that situation. With regard to kidney-specific outcomes, it has long been established that SPK transplantation, when compared to KTA, was associated with longer kidney allograft survival as evidenced by the works of Israni et al[41], by means of improved glycemic control, decreased incidence of delayed graft function (11% for SPK compared to 25% for KTA), as well as shortened cold ischemia times[42,43]. The single-center retrospective study by Parajuli et al[44] found a kidney allograft delayed graft function rate in SPK recipients to be approximately 11% which is consistent with the findings in the registry. There was not a significant difference in acute rejection rates of the kidney allograft reported in SPK transplant recipients with comparable target tacrolimus levels of KTA recipients[41,45].

PROPOSED CONTEMPORARY STRATEGIES FOR OPTIMIZING KIDNEY ORGAN ALLOCATION AND KIDNEY OUTCOMES IN MULTI-ORGAN TRANSPLANT

The current kidney allocation system policies explicitly prioritize deceased donor kidneys to multiorgan candidates over kidney alone candidates[35]. It follows then that since the new kidney allocation system has been implemented, there has been tremendous growth in the SLK, SHKT, and SLKT space compared to KTA or SPK candidates with disproportionate share of multi-organ transplant recipients having little to no pretransplant dialysis compared to less than 10% of KTA recipients[35].

Regarding potential means to balance utility with justice in multi-organ transplantation, there are various approaches to consider. We concur with the recommendation in OPTN/UNOS policies for pursuing simultaneous other solid organ with kidney transplantation for heart, lung, and liver when pre-transplant EGFR is less than 30 mL/minute/1.73 m² or requiring pre-transplant dialysis as well as following the established safety-net policy for prioritizing kidney-after-other organ allocation in patients who went without combined other organ-kidney transplantation but have persistent kidney dysfunction necessitating dialysis or EGFR < 20 mL/minute/1.73 m². Therefore, monitoring kidney function closely for native kidney function recovery of these solitary non-renal organ transplant recipients to permit timely referral for safety net evaluation and listing is essential as compared to routine monitoring strategy evidence of graft dysfunction in multi-organ transplant and KTA recipients.

Additionally, there have been interesting perspectives for delayed kidney transplantation for simultaneous other organ-kidney transplant to be considered for hemodynamically unstable patients following their non-renal organ transplant[46]. Contemporary advances in machine perfusion (hypothermic machine perfusion compared to static cold storage) show promise in permitting longer kidney preservation in such complicated situations as combined-organ transplantation to optimize kidney allograft outcomes and reducing delayed graft function[47,48]. These improvements in organ preservation so that the correct organ can go to the correct patient at the correct time can help mitigate the risk for these scarce kidneys being wasted either by permitting time for clinical stabilization of the intended recipient or for finding another suitable recipient should clinical stabilization be unattainable. As multiorgan transplantation outcomes are not currently included in reports on transplant center outcomes, additional efforts may be necessary to disincentivize renal allograft futility and realign transplantation practice with its foundational ethical principles[49].

CONCLUSION

Despite promising results, the retrospective design of the current studies, the heterogeneity of transplant center practices, and the diverse ranges of immunosuppressive protocols among patient cohorts make the direct comparison of the kidney outcomes of combined non-renal organ with kidney transplant and KTA challenging. Suffice it to say, from a utilitarian perspective, the common theme is of early kidney allograft failure in most combined other organ with kidney transplantation (SLK, SHKT, and SLKT) is due to comorbidities attributed to non-renal organ dysfunction. Efforts must be made to minimize the risk of renal allograft futility, with consideration for disincentivizing the practice via inclusion of multi-organ transplantation outcomes in transplant center specific reports. The utilization of strategies such as delayed transplantation of the kidney allograft, making use of Safety Net policies, as well as kidney after other organ transplantation, can be pursued. As the current OPTN/UNOS policies regulating the allocation of these kidney allografts prioritize these multi-organ recipients over those awaiting a KTA, care must be taken to optimally account for the scarcity of suitable kidney allografts and make best use of these organs for the collective benefit of the waitlisted population.