Liver‐Kidney: Indications, Patient Selection, and Allocation Policy

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Abbreviations

ABDRmm

ABDR mismatch

AKI

acute kidney injury

CKD

chronic kidney disease

CrCl

creatinine clearance

eGFR

estimated GFR

EPTS

estimated post transplant survival

ESRD

end‐stage renal disease

GFR

glomerular filtration rate

HRS

hepatorenal syndrome

HUS

hemolytic uremic syndrome

KDPI

Kidney Donor Profile Index

LT

liver transplantation

MELD

Model for End‐Stage Liver Disease

MDRD

modification of diet in renal disease

NKF

National Kidney Foundation

OPTN

Organ Procurement and Transplantation Network

SLK

simultaneous liver and kidney

SLKT

simultaneous liver and kidney transplantation

Adoption of Model for End‐Stage Liver Disease (MELD) score was a game changer for liver transplantation (LT) listing and allocation practices. It transformed the allocation to be more objective and transparent while maintaining optimal patient and graft survival and being in line with the “Final Rule.” The Final Rule, issued by Department of Health and Human Services in 1999, established a regulatory framework for the structure and operations of the Organ Procurement and Transplantation Network (OPTN). Despite all these advantages, MELD‐based allocation policy has a few unintended consequences, such as an increased risk for new‐onset posttransplant end‐stage renal disease (ESRD) and higher rates of simultaneous liver and kidney transplantation (SLKT) compared with the pre‐MELD era (Fig. 1).1, 2 This has engendered controversy within the transplant community because SLKTs draw deceased donor kidneys from the kidney transplant candidate pool.

Figure 1.

Percentage of SLKTs performed in the United States from 2000 to 2017.

PREDICTORS OF RENAL NONRECOVERY AFTER LT ALONE

SLKT is an important option for LT candidates with acute or chronic renal dysfunction deemed unlikely to recover after LT alone. The guidance to list for SLKT is data driven for LT candidates with ESRD and inherited metabolic disorders. However, this guidance is based on expert opinion for LT candidates with acute kidney injury (AKI) because of the paucity of data to accurately predict renal recovery after LT alone. Two studies with similar study populations but different definition of renal nonrecovery examined the predictors of renal nonrecovery after LT alone.3, 4 One study (N = 2112) reported the cumulative incidence rate of renal nonrecovery, defined as transition to chronic dialysis within 6 months of LT alone, as 8.9% among those who were receiving pre‐LT acute dialysis (<90 days) and survived for 6 months after LT,3 whereas another study (N = 1041) reported that 32% of LT recipients had ESRD who were receiving pre‐LT dialysis (regardless of duration) and survived more than 30 days after LT.4 The predictors of renal nonrecovery were longer duration of pre‐LT dialysis, diabetes, previous LT, and older age. The post‐LT mortality was very high in both of these studies.3, 4

EVOLUTION OF SLKT LISTING PRACTICES: 2002 TO 2017

Previous OPTN policy for SLKT did not specify medical eligibility criteria for assessing kidney function when a deceased donor kidney was allocated to a SLKT candidate. The policy simply stated that if the donor and the candidate are local, then the kidney will be allocated with the liver. These practices were not only contrary to the “Final Rule” but also led to wide variation and inequity in the SLKT listing and transplant practices across the country.5, 6, 7

Early guidance did not recommend SLKT listing for AKI not requiring dialysis.5 In 2009, OPTN put forth the formal SLKT listing criteria decreasing the duration of sustained AKI with or without dialysis (glomerular filtration rate [GFR] ≤ 25 mL/min) to ≥6 weeks (Table 1). This duration was further relaxed to 4 weeks based on the 2012 consensus conference (Table 1).7

Table 1.

Published Guidance and Previous OPTN Policy for SLKT Allocation

Authors	Recommendations
Davis et al.5 (2007)	CKD and CrCl ≤30 mL/min AKI and/or HRS on dialysis for ≥6 weeks Prolonged AKI with kidney biopsy showing fixed renal damage SLK not recommended in patients with AKI not requiring dialysis
Eason et al.6 (2008) Consensus Report	ESRD with cirrhosis and symptomatic portal hypertension or hepatic vein portal gradient ≥10 mm Hg CKD with GFR ≤30 mL/min AKI/HRS with Cr ≥2 mg/dL and dialysis ≥8 weeks Evidence of CKD and kidney biopsy showing >30% glomerulosclerosis or interstitial fibrosis Other criteria: diabetes, hypertension, age >65 years, other preexisting renal disease with proteinuria, renal size, and duration of elevated Cr
OPTN Policy11 (3.5.10) (2009)	CKD requiring dialysis with documentation of the Centers for Medicare and Medicaid Services form 2728 CKD (GFR ≤ 30 mL/min by MDRD‐6/iothalamate measurement and proteinuria > 3 g/day) Sustained AKI with dialysis ≥6 weeks at least twice per week for 6 consecutive weeks Sustained AKI without dialysis (GFR ≤ 25 mL/min ≥6 weeks by MDRD‐6/direct measurement) Sustained AKI: a combination of time in categories above for a total of 6 weeks Inherited metabolic disorders
Nadim et al.7 (2012) Consensus Report	Persistent AKI for ≥4 weeks with one of the following: Stage 3 AKI: modified RIFLE (Risk, Injury, Failure, Loss, and End‐Stage Kidney Disease) criteria eGFR ≤35 mL/min (MDRD‐6 equation) or GFR ≤25 mL/min (iothalamate) CKD for 3 months, defined by the NKF with one of the following: eGFR ≤40 mL/min (MDRD‐6 equation) or GFR ≤30 mL/min (iothalamate) Proteinuria ≥2 g/day Kidney biopsy: >30% global glomerulosclerosis or >30% interstitial fibrosis Inherited metabolic disorders

POSTTRANSPLANT OUTCOMES OF SLKT RECIPIENTS

Locke et al.,8 based on the national data from 1987 to 2006, established superior patient and graft survival for SLKT recipients who were receiving pretransplant dialysis for more than 12 weeks. We demonstrated a small but significant gain (3.7 months) in 5‐year mean posttransplant survival time for SLKT recipients not receiving dialysis at transplantation in a propensity‐matched comparison between 1981 SLKT and 5470 LT‐alone recipients with serum creatinine concentration greater than 2.0 mg/dL who were transplanted between 2002 and 2009.9

Formica et al.,10 in their elegant review of the literature and OPTN database analysis, showed that 37% of SLKT recipients received no dialysis prior to transplantation. Out of those who were not receiving pre‐LT dialysis, 40% had a creatinine concentration less than 2.5 mg/dL at transplantation.10 An analysis of national data from 2002 to 2012 demonstrated that LT candidates with pre‐LT dialysis duration longer than 2 months or serum creatinine concentration greater than 2.5 mg/dL benefited from SLKT compared with LT alone. However, the outcomes with SLKT were inferior to LT alone without renal dysfunction. It is interesting that, of the 494 and 557 SLKTs performed in 2014 and 2015, respectively, 19% would not have been performed on the basis of the new medical eligibility criteria.10

CURRENT SLKT ALLOCATION POLICY: 2017 AND BEYOND

The new SLKT policy has two important components: medical eligibility criteria and the option of “safety net.” The medical eligibility criteria are based on the presence of chronic kidney disease (CKD), sustained AKI, or select inherited metabolic disorders11 (Table 2). The safety net is for those LT‐alone recipients who do not recover renal function after LT or subsequently develop advanced, persistent renal dysfunction within 60 to 365 days of transplant. Safety net candidates are assigned significant allocation priority in the kidney allocation system in order to receive an expedited kidney after LT, appearing ahead of other local adult candidates (Fig. 2).11

Table 2.

Current SLKT Medical Eligibility Criteria10, 11

Transplant Nephrologist to Confirm Candidate Has One of the Following	Transplant Center Must Document One of the Following in the Medical Record
CKD with measured/calculated GFR ≤60 mL/min for >90 days	Dialysis for ESRD Most recent eGFR/CrCl ≤30 mL/min at registration on kidney waiting list
Sustained AKI	Dialysis for 6 consecutive weeks eGFR/CrCl ≤25 mL/min for at least 6 consecutive weeks Any combination of the above for 6 consecutive weeks
Inherited metabolic disorders	Hyperoxaluria Atypical HUS: mutations in factor H and possibly factor I Familial nonneuropathic systemic amyloid Methylmalonic aciduria

Figure 2.

Allocation scheme for LT recipients eligible for safety net option for kidney transplantation. Reprinted with Permission.16

Studies suggest that multiorgan transplant recipients, including SLKT, draw high‐quality donor kidneys away from the kidney transplant candidate.9, 12 Donor kidney quality is measured using the Kidney Donor Profile Index (KDPI),13 which is a mapping of the kidney donor risk index from a relative risk scale to a cumulative percentage scale.14 The kidney graft survival of SLKT recipients is inferior compared with kidney transplant–alone recipients despite better donor kidney quality (KDPI 35%12), and despite that the OPTN prioritized allocation of deceased donor kidneys to multiorgan candidates before kidney‐alone candidates. Data suggest that any of the kidney allografts that failed after SLKT in the MELD era would have added a graft life span of 7.2 years if transplanted to a kidney transplant candidate.15

The kidney transplant community is concerned about access for highly sensitized and pediatric kidney candidates, and better utilization of kidneys through longevity matching. Therefore, the priority is limited within each kidney allocation sequence (Fig. 2).11 We believe that the new SLKT allocation policy may streamline the transplantation of high‐quality kidney allografts into patients who have waited as long as 10 years on the kidney‐alone transplantation waiting list.

POTENTIAL PITFALLS OF THE NEW SLKT POLICY

The potential pitfalls of the new SLKT allocation include a higher estimated GFR (eGFR) cutoff for initial listing for SLKT compared with kidney transplant–alone candidates, lack of inclusion of traditional risk factors of CKD progression, such as proteinuria and duration of diabetes, variability allowed in the methods of estimating eGFR, and a liberal definition of sustained AKI. Despite these pitfalls, this is a step forward in the SLKT allocation.

CONCLUSIONS

The key take‐home points are summarized (Table 3). Even though every SLKT drives a donor kidney away from a kidney‐alone candidate, the new SLKT allocation policy may strike an optimal balance between the principle of urgency and utility. It may reduce the variability in the SLKT listing and transplant practices by providing uniform medical eligibility criteria and by reducing the overutilization of SLKT through a safety net option. Finally, a careful monitoring and analysis of prospectively collected data will provide incremental evidence to further refine this policy over time.

Table 3.

Key Take‐Home Points

1. SLKT rates have increased significantly in the MELD era.

2. Low KDPI donor kidneys are allocated to multiorgan transplant recipients.

3. Evidence supporting defined criteria for SLKT other than for ESRD is weak.

4. Previous guidance for SLKT allocation lacked medical eligibility criteria.

5. The new SLKT allocation policy has two components: (1) medical eligibility criteria for SLKT, and (2) safety net option for those who experience stage 5 CKD within 60‐365 days of LT alone.

6. The new SLKT allocation criteria do not specify modalities for estimating GFR or kidney biopsy for eligibility criteria.

7. The new SLKT policy is a step toward streamlining the allocation of donor kidney for LT recipients and may reduce variability in the listing practices.