Approximately 20% of patients undergoing liver transplantation (LTx) demonstrate acute or chronic renal insufficiency, and 2% of patients undergoing LTx are deemed to require a simultaneous renal transplant. Since the introduction of the model for end-stage liver disease (MELD) in the United States in 2002 as the sole criteria for donor liver allocation, simultaneous liver-kidney transplants (LKTx) have risen dramatically (Fig. 1). There is little published data and no controlled data to guide transplant programs in regard to appropriate indications for LKTx both in acute and chronic kidney diseases (CKDs). However, in 2008, a summary of the proceedings of an American consensus conference was published, and this has served to guide practice and stimulate research in regards to LKTx (1). It seems that different programs have different thresholds for performing LKTx (2–5). It has even been suggested that kidneys are being “wasted” in combination transplants (6). It is critically important to ensure that this double resource is being used effectively since alternatively, the two organs could be used separately to benefit two transplant recipients. The purpose of this review was to summarize currently available data and to propose algorithms in an attempt to stimulate discussion and move toward a unified approach.
CURRENT STATUS OF LKTx
The Canadian Institute for Health Information reported 63 LKTx were completed between 1999 and 2008, the last year for which data are available (7). The United Network for Organ Sharing (UNOS) database (www.unos.org) records a steady increase in LKTx over the last decade (Fig. 1). The majority of these patients are 50 to 64 years of age. There is considerable variation by region; however, the reasons are not clear (Table 1).
THE MELD FACTOR
The MELD score was implemented to help delegate livers to recipients in greatest need and to help deal with increasing waitlist mortality. It is a logarithmic equation incorporating serum bilirubin, serum creatinine, and the prothrombin time (international normalized ratio) to predict mortality and thereby choose candidates most in need of LTx. Relatively heavy weighting of the serum creatinine in this equation has resulted in greater priority for patients with renal dysfunction and accordingly, an increased proportion of patients are being transplanted with acute or chronic renal disease (8). This lead to concern because renal failure before LTx has been reported to predict an increased risk of postoperative renal failure, infection, and death (2).
Kanwal et al. (9) has compared two cohorts undergoing LTx in the pre-MELD (n=3857) and post-MELD (n=4245) eras. No significant differences were observed in patient or graft survival up to 12 months posttransplantation. Although the post-MELD era patients were sicker, patient and graft survival were comparable to the pre-MELD era. Nevertheless, worse pretransplant renal function translates to worse renal function posttransplant.
ESTIMATING RENAL FUNCTION IN LIVER DISEASE
It is widely recognized that using serum creatinine to estimate renal function is unreliable in patients with liver disease (2, 10). Cirrhotic individuals have a lower muscle mass, decreased hepatic synthesis of creatine, the precursor of creatinine, and increased tubular secretion of creatinine, all of which serve to overestimate renal function. Furthermore, an elevated serum bilirubin can interfere with the creatinine determination, if a colorimetric (as opposed to an enzymatic) assay is used leading to spuriously low values. It is also important to realize that women will have a lower MELD score than men because of a smaller muscle mass and yet the score does not adjust for gender (11).
RENAL DISEASE IN PATIENTS WITH LIVER DISEASE
Renal indications for LKTx include both acute kidney injury (AKI) and CKD. The most common causes of AKI in these patients are hepatorenal syndrome (HRS) type 1 and acute tubular necrosis. CKD is most commonly secondary to glomerulonephritis, polycystic kidney disease, and primary hyperoxaluria. In this latter metabolic condition, a liver graft can correct the underlying enzyme deficiency (alanine-glyoxylate aminotransferase) to prevent recurrent renal failure, which invariably follows renal transplants alone.
ACUTE RENAL FAILURE IN LIVER DISEASE PATIENTS
HRS has been a particularly challenging condition given the somewhat unpredictable potential for spontaneous improvement with liver transplant alone. The International Ascites Club has defined HRS type 1 as a rapid impairment of renal function, specifically characterized by a serum creatinine level greater than 2.5 mg/dL (>220 μM/L) or a 24-hr creatinine clearance less then 40 mL/min; the lack of renal recovery despite plasma volume expansion by 1.5 L isotonic saline, proteinuria less then 500 mg/day, no evidence of ureteral obstruction or intrinsic renal disease or prerenal causes. HRS type 1 has rapid onset and progressive course with a mean survival of only 15 days without treatment, whereas type 2 is less severe (creatinine >1.5 mg/dL [132 μM/L]) and more slowly progressive with a mean survival of 6 months. Randomized controlled trials have shown improvement in HRS type 1 using vasoconstrictors such as terlipressin (12); however, definitive treatment of HRS is LTx. The challenge continues to be an inconsistent ability to discriminate between patients who will recover renal function after LTx and those who will not and therefore require LKTx.
Both duration and degree of renal impairment before LTx have been linked with incidence and progression of kidney dysfunction postoperatively (2, 4, 13). Pretransplant renal function has remained an independent predictor of posttransplant mortality (14). Northup et al. (15) recently reviewed the largest series to date of 1041 liver transplant recipients from the UNOS database who were on dialysis for AKI at the time of their transplant. Of these, 707 patients (68%) ultimately recovered their renal function and were removed from dialysis. This group suggested LKTx be considered in patients who had been on renal replacement for greater than 90 days. Marik et al. (4) reported 28 patients (13 on dialysis) with type 1 HRS who underwent LTx in whom renal dysfunction resolved in 16 (57%). Ruiz et al. (3) have reported a retrospective analysis of 22 patients with HRS as part of their experience of 99 LKTx and concluded that LKTx should be done if a patient had been on dialysis for greater then 60 days. Work from other investigators supports the concept of using duration of pretransplant dialysis as the major factor to implicate need for LKTx (2, 11), and the multidisciplinary American consensus conference suggested 6 weeks as a threshold after which LKTx should be considered (1). However, there remains a significant gray zone between 6 and 12 weeks wherein some patients still recover renal function post-LTx: the UNOS data showed 24% of patients on dialysis for 8 to 12 weeks pre-LTx came off dialysis post-LTx (15). This uncertainty about renal recovery and different time on dialysis thresholds reported by different studies is reflected in Figure 2 by suggesting additional assessment and in some cases, intraoperative renal biopsy. Careful assessment by nephrology is critical, including duplex Doppler blood flow, urinary sodium, urinalysis and renal biopsy (see below), but this will continue to be a difficult management decision with an important impact on utilization of kidneys from deceased donors. In particular, patients with ongoing urinary sodium >20 mM/L, fractional excretion of sodium >2%, urinary osmolarity <350 mOsm/kg, and/or proteinuria or urinary sediment showing red blood cell casts or oval fat bodies should be considered for kidney biopsy. Additional factors predicting lack of renal recovery post-LTx include donor and recipient age and the presence of diabetes (15). Those patients who fail to recover renal function post-LTx have reduced survival (15), highlighting the need for better discriminatory tools to predict recovery.
In general, renal biopsy has been invaluable to determine the cause of renal dysfunction or proteinuria or both (2). Clinicians have been understandably reluctant to perform percutaneous biopsies in cirrhotic patients particularly those with coagulopathy or low platelets or both. Jouet et al. (10) investigated the safety and usefulness of transjugular renal biopsy in 70 cirrhotic patients, with successful acquisition of tissue in 55. The biopsies showed glomerular changes in 41 patients, interstitial abnormalities in 7, and end-stage processes in 2; 5 patients had normal biopsies. Based on the biopsy findings, five patients underwent LKTx. Complications associated with biopsy included persistent hematuria (four patients) and perinephric hematoma (four patients). Three required transfusion. No deaths occurred. Pichler et al. (16) performed renal biopsies (mainly transjugular) in 26 patients awaiting LTx with renal failure. They proposed histologic guidelines to guide the decision for LKTx: more than or equal to 30% interstitial fibrosis, at least 40% glomerulosclerosis, or severe glomerular injury. The accurate predictors of irreversibility have not been well studied, but many programs use similar criteria (17). Percutaneous biopsies have also been reported to be useful in liver transplant candidates with renal failure of unknown cause and often provided discordant results from the serum and urine biochemistry and renal ultrasound (18). Patients were identified for liver transplant alone who would likely otherwise have had LKTx. There were bleeding complications in 8 of 44 patients of whom 5 required radiologic intervention. A role for intraoperative renal biopsy has been suggested (2), and we would propose it be considered in those cases where noninvasive, pretransplant assessment was equivocal. The upper pole of the right kidney could be biopsied after hepatectomy, and although this is likely to be safe, this will need prospective assessment. The surgeons could then proceed with LTx alone or LKTx depending on the result (Fig. 2). A limitation of this approach is the difficulty in assessing interstitial fibrosis, which generally requires additional staining. As well, this delay would add cold ischemic time to the kidney in the cases where (on the basis of favorable recipient renal histology) it was decided to give the donor kidney to the backup renal recipient. Prospective assessment will be required to determine the utility of intraoperative renal biopsy to guide these crucial transplant decisions.
CHRONIC RENAL FAILURE IN LIVER TRANSPLANT
Patients with CKD may or may not have been on dialysis before their LTx. Gonwa et al. (19) have demonstrated that individuals with the best renal function pre-LTx lose the most renal function, whereas those with low pretransplant glomerular filtration rate (GFR; mean 47±13 mL/min) may preserve their renal function postoperatively. This suggests that renal sparing immunosuppressive protocols have been effectively used. Because of ongoing renal toxicity from calcineurin inhibitors posttransplantation, it has been recommended that patients with a GFR less then 35 to 40 mL/min should undergo combined transplantation. Other investigators have looked at delaying renal transplantation approximately 1 year after liver transplant because much of the improvement in GFR should manifest within this time (20). Tanriover et al. (21) have proposed an algorithm based on duration of renal failure, GFR measured by the iodine-125 iothalamate test, and renal biopsy (Fig. 3). There were two bleeding complications among the 20 patients both of whom had percutaneous biopsies.
A difficult question has been whether LTx candidates with borderline kidney function should have LKTx or LTx alone and possible future kidney transplant. Rejection-free graft survival is superior at 1 and 3 years for LKTx (85% and 78%, respectively) as compared with kidney after liver transplant (77% and 67%, respectively) (13). Chronic changes leading to kidney graft loss has also been shown to be significantly less. This may indicate an immunologic advantage of LKTx when both organs are from the same donor. It has been proposed that major histocompatibility complex class 1 and 2 molecules produced in the liver neutralize alloantibodies and inhibit cytotoxic T lymphocyte activity (2, 16). These anti-human leukocyte antigen antibodies may also be absorbed by the liver protecting against an effect on the renal allograft. Another proposed mechanism is the development of molecular chimerism inhibiting cell-mediated and antibody-mediated rejection of the renal transplant (2, 13).
A large retrospective analysis of the UNOS database compared LKTx with kidney after liver transplant and reported longer renal graft half-life and reduced chronic renal rejection in the LKTx group (22). The LKTx had higher early death rates as expected, but these were similar to the kidney after liver transplant group by year 3. However, these were likely different patient groups at the time of the liver transplant in renal function. Furthermore, at the time of transplant, the LKTx patients were younger and received grafts from younger donors but were more likely to be in the intensive care unit. The decision of LKTx vs. liver transplant alone in a patient with renal disease is therefore a complex one and must take into account numerous factors including probability of renal recovery, recipient stability (renal grafts do poorly in hemodynamically unstable patients), and overall graft and patient survival. This must be balanced against uniformly long kidney transplant waiting lists and becomes an ethical and a medical decision.
Factors predicting nonrecovery of renal function or progressive CKD after liver transplant include preexisting diabetes mellitus, hypertension, and coronary artery disease (13). Ischemic or toxic insults to the kidneys as a result of hypotension, sepsis, and nephrotoxin use are also associated with post-LTx renal dysfunction (2). In those patients progressing to end-stage renal failure, there was only 20% survival at 5 years in those not having a subsequent renal transplant (23).
THE PROGRESSION OF LIVER DISEASE
Liver disease progresses from chronic liver disease to cirrhosis, and then to portal hypertension, and finally to hepatic decompensation which includes any of ascites, encephalopathy, or variceal hemorrhage. LTx has become the treatment of choice in carefully selected patients with end-stage decompensated liver disease, without which, the prognosis is poor. The MELD score will be higher in individuals with any degree of renal failure, apart from the status of their liver. Therefore, it is a concern that patients may be getting their liver transplanted prematurely and independently of their chronic liver failure.
In general, cirrhotic patients have been excluded from renal transplantation (24), but this is consensus rather than evidence based. Limited data suggest that renal transplantation alone in Child's class A or compensated cirrhosis may be associated with reasonable outcomes in some patients (25, 26), but poor outcomes have also been reported (27). This approach is most likely to be successful in patients where the cirrhosis is inactive (e.g., remote alcoholism) or in cases where disease activity is suppressed on therapy (e.g., hepatitis B). Other causes such as hepatitis C may continue to evolve toward liver failure. If portal hypertension has already developed, fluid loading after implantation of the kidney may lead to splanchnic pooling with or without the development of ascites but importantly, reduced perfusion of the renal graft, which may compromise its function. There is a subset of cirrhotic patients, therefore, who are well compensated but have portal hypertension and would not be served well by kidney transplantation alone. There may be clinical evidence of portal hypertension such as splenomegaly, reduced platelet counts, or portosystemic varices on endoscopy or abdominal imaging. If not, portal hypertension can only be confirmed by transvenous measurement of pressures via the hepatic veins, which is referred to as the hepatic venous pressure gradient. Although this is an invasive procedure, experienced liver centers perform these measurements frequently with minimal morbidity, most commonly related to bleeding at the internal jugular puncture site (28). The management of those with well compensated portal hypertension remains controversial, and these patients may find themselves caught between the liver and kidney transplant programs. The kidney program may want them considered for LKTx, but the liver program may find them too well for LTx in comparison to their other listed patients in overt liver failure. Furthermore, studies have shown that those cirrhotic patients with an hepatic venous pressure gradient less than 10 mm Hg have only a 10% risk of decompensation in the next 4 years (29). This hemodynamic data can be incorporated into an algorithm to guide transplant decisions in cirrhotic patients with end-stage renal disease (Fig. 4).
HOW TO SELECT APPROPRIATE CANDIDATES FOR COMBINED TRANSPLANTS
Summary and Suggestions
Consensus guidelines are not yet in place to clearly delineate indications for LKTx, but the Consensus Conference on Simultaneous Liver Kidney Transplantation Review Board has proposed the following indications (1): (1) end-stage renal disease and symptomatic portal hypertension or hepatic vein wedge pressure gradient more than 10 mm Hg; (2) liver failure and CKD with GFR less than 30 mL/min; (3) AKI or HRS with creatinine more than 2.0 mg/dL and on dialysis more than 8 weeks; and (4) liver failure and CKD with renal biopsy demonstrating more than 30% glomerulosclerosis or 30% fibrosis (22).
LKTx are best suited for advanced disease of both organs. It is important to ensure that the allocation of kidneys for LKTx only occurs when renal disease is likely to be irreversible. Equally, cirrhotic patients undergoing renal transplantation should only be put forward for LKTx if they have at least significant portal hypertension. These will be highly selected patients, and the cause of liver disease and its likelihood to progress need to be considered. Guidelines need to be founded on strong clinical data, which is still only preliminary. The presented algorithms are not validated approaches but rather possible approaches, which might be useful to take this field forward. Ongoing consensus will need to be a dynamic process that incorporates both the existing data as summarized here and new data. For example, a risk score to predict the need for LKTx has recently been reported, which incorporates the presence of hypertension, proteinuria, and the duration and degree of renal dysfunction; however, its sensitivity remains unknown (30). Such approaches hold promise, however, so that the greatest benefit can be obtained from our scarce organ supply.
1. Eason JD, Gonwa TA, Davis CL, et al. Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation (SLK). Am J Transplant
2008; 8: 2243.
2. Davis CL, Gonwa TA, Wilkinson AH. Identification of patients best suited for combined liver-kidney transplantation. Liver Transpl
2002; 8: 193.
3. Ruiz R, Kunitake H, Wilkinson AH, et al. Long-term analysis of combined liver and kidney transplantation at a single center. Arch Surg
2006; 141: 735.
4. Marik PE, Wood K, Starzl TE. The course of type 1 hepatorenal syndrome post liver transplantation. Nephrol Dial Transplant
2006; 21: 478.
5. Bloom RD, Bleicher M. Simultaneous liver-kidney transplantation in the MELD era. Adv Chronic Kidney Dis
2009; 16: 268.
6. Locke JE, Warren DS, Singer AL, et al. Declining outcomes in simultaneous liver-kidney transplantation in the MELD era: Ineffective usage of renal allografts. Transplantation
2008; 85: 935.
7. Canadian Organ Replacement Register (Canadian Institute for Health Information). Treatment of end stage organ failure in Canada, 1999 to 2008. 2010 Annual Report. Ottawa, ON, Canada: CIHI 2010.
8. Freeman R. The impact of the model for end-stage liver disease on recipient selection for adult living donation. Liver Transpl
2003; 9: S54.
9. Kanwal F, Dulai GS, Spiegel BM, et al. A comparion of liver transplantation outcomes in the pre- vs. post-MELD eras. Aliment Pharmacol Ther
2005; 21: 169.
10. Jouet P, Meyrier A, Mal F, et al. Transjugular renal biopsy in the treatment of patients with cirrhosis and renal abnormalities. Hepatology
1996; 24: 1143.
11. Campbell MS, Kotlyar DS, Brensinger CM, et al. Renal function after orthotopic liver transplantation is predicted by duration of pretransplantation creatinine elevation. Liver Transpl
2005; 11: 1048.
12. Sanyal AJ, Boyer T, Garcia-Tsao G, et al. A Randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology
2008; 134: 1360.
13. Pham PT, Pham PC, Wilkinson AH. Renal function outcomes following liver transplantation and combined liver-kidney transplantation. Nat Clin Pract Nephrol
2007; 3: 507.
14. Gonwa TA, McBride MA, Anderson K, et al. Continued influence of preoperative renal function on outcome of orthotopic liver transplant (OLTX) in the US: Where will MELD lead us? Am J Transplant
2006; 6: 2651.
15. Northup PG, Argo CK, Bakhru MR, et al. Pretransplant predictors of recovery of renal function after liver transplantation. Liver Transpl
2010; 16: 440.
16. Pichler R, Dittrich M, Anderson AE, et al. Prediction of benefit from simultaneous liver-kidney transplantation versus liver-alone transplantation: Potential role for native kidney biopsy. J Am Soc Nephrol
2006; 17: 795A.
17. Davis CL, Feng S, Sung R, et al. Simultaneous liver-kidney transplantation: Evaluation to decision making. Am J Transplant
2007; 7: 1702.
18. Wadei HM, Geiger XJ, Cortese C, et al. Kidney Allocation to liver transplant candidates with renal failure of undetermined etiology: Role of percutaneous renal biopsy. Am J Transplant
2008; 8: 2618.
19. Gonwa TA, Klintmalm GB, Levy M, et al. Impact of pre-transplant renal dysfunction on survival after liver transplantation. Transplantation
1995; 59: 361.
20. Pawrode Al, Fine DM, Thuluvath PJ. Independent risk factors and natural history of renal dysfunction in liver transplant recipients. Liver Transpl
2003; 9: 741.
21. Tanriover B, Mejia A, Weinstein J, et al. Analysis of kidney function and biopsy results in liver failure patients with renal dysfunction: A new look to combined liver kidney allocation in the post-MELD Era. Transplantation
2008; 86: 1548.
22. Simpson N, Cho YW, Cicciarelli JC, et al. Comparison of renal allograft outcomes in combined liver-kidney transplantation versus subsequent kidney transplantation in liver transplant recipients: Analysis of UNOS database. Transplantation
2006; 82: 1298.
23. Al Riyami D, Alam A, Badovinac K, et al. Decreased survival in liver transplant patients requiring chronic dialysis: A Canadian experience. Transplantation
2008; 85: 1277.
24. Knoll G, Cockfield S, Blydt-Hansen T, et al. Canadian Society of Transplantation: Consensus guidelines on eligibility for kidney transplantation. CMAJ
2005; 173: S1.
25. Campbell MS, Constantinescu S, Furth EE, et al. Effects of hepatitis C-induced liver fibrosis on survival in kidney transplant candidates. Dig Dis Sci
2007; 52: 2501.
26. Gane E, Pilmore H. Management of chronic viral hepatitis before and after renal transplantation. Transplantation
2002; 74: 427.
27. Mouquet C, Mathurin P, Sylla C, et al. Hepatic cirrhosis and kidney transplantation outcome. Transplant Proc
1997; 29: 2406.
28. Bosch J, Abraldes JG, Berzigotti A, et al. The clinical use of HVPG measurements in chronic liver disease. Nat Rev Gastroenterol Hepatol
2009; 6: 573.
29. Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology
2007; 133: 481.
30. O'Riordan A, Donaldson N, Carins H, et al. Risk score predicting decline in renal function post liver transplant: Role in patient selection for combined liver kidney transplantation. Transplantation
2010; 89: 1378.