Hot-topic debate on kidney function: Renal-sparing approaches are ineffective

Abstract

Key Points

1. Both acute kidney injury and chronic renal disease are common in patients undergoing liver transplantation. The etiologies are mixed.

2. The incidence of chronic renal failure after liver transplantation is unacceptable, and it has a significant impact on long-term outcomes after liver transplantation.

3. The role of calcineurin inhibitors (CNIs) in the development of posttransplant chronic renal failure is likely overrated.

4. The use of CNIs in the early posttransplant period is currently essential.

5. Whether new agents will be able to provide effective immunosuppression as primary immunosuppressives remains to be proven. Liver Transpl, 2011. © 2011 AASLD.

The development of chronic renal failure has emerged as one of the most important complications experienced after liver transplantation. The development of chronic kidney disease after liver transplantation reflects the frequency with which both acute kidney injury and chronic kidney disease occur before liver transplantation and the impact of various posttransplant events on the subsequent development of chronic kidney disease.

It has long been believed that the use of calcineurin inhibitors (CNIs) is the most important factor related to the development of chronic kidney disease after transplantation. Thus, there have been efforts to develop CNI-free regimens for more than 20 years. However, I will try to make the case that these efforts have been largely unsuccessful and that the frequency of posttransplant chronic kidney disease is increasing.

ACUTE KIDNEY INJURY AND CHRONIC KIDNEY DISEASE IN LIVER TRANSPLANT CANDIDATES

Both acute kidney injury and chronic kidney disease occur frequently in liver transplant recipients. In its purest form, hepatorenal syndrome represents a functional form of renal dysfunction, which theoretically is reversible.1 However, as we know, most patients experiencing what has been called hepatorenal syndrome do not recover normal function after liver transplantation.2 For this reason, after a recent meeting between members of the International Ascites Club and representatives from the kidney community, it was agreed that the progression of renal dysfunction occurring in the setting of cirrhosis and ascites should be called acute kidney injury.3 This now acknowledges that many patients with this syndrome experience actual injury to the kidneys.

Abbreviations: CNI, calcineurin inhibitor; GFR, glomerular filtration rate.

Chronic kidney disease is also common in patients awaiting liver transplantation.4 There are a number of kidney diseases that are associated with specific causes of liver disease. For example, membranous glomerulonephritis is associated classically with hepatitis B. It also, however, occurs at an increased frequency in patients with hepatitis C. The classic kidney disease associated with hepatitis C is membranoproliferative glomerulonephritis, which is often associated with the presence of cryoglobulinemia. Immunoglobulin A nephropathy can occur with any cause of cirrhosis. Finally, diabetes mellitus occurs at an increased frequency in patients with hepatitis C and in patients with nonalcoholic fatty liver disease. It is also worth mentioning that simultaneous liver-kidney transplantation is the treatment of choice for patients with hereditary oxaluria and for some patients with polycystic liver and kidney disease.

With the introduction of liver allocation by Model for End-Stage Liver Disease scores,5 more patients with significant renal dysfunction are undergoing transplantation.6 In fact, in the United States, more than 10% of patients undergoing liver transplantation either are on renal replacement therapy or receive a simultaneous liver-kidney transplant.7 This is because the Model for End-Stage Liver Disease score is heavily influenced by serum creatinine. In fact, if an individual is simply on dialysis with normal liver function, the Model for End-Stage Liver Disease score is already 20.

INCIDENCE OF CHRONIC KIDNEY DISEASE AFTER LIVER TRANSPLANTATION

Everyone involved in liver transplantation should have been mortified by Ojo et al.'s publication in New England Journal of Medicine.8 In that analysis of data from the Scientific Registry of Transplant Recipients, liver transplant recipients had an incidence of chronic renal failure [which was defined as a glomerular filtration rate (GFR) <29 cc/minute] of almost 20% by 10 years. This was second only to the rate for intestinal transplant recipients and was greater than the rates for heart, lung, and heart-lung recipients. Most importantly, Ojo et al. showed that patients who develop chronic renal failure after transplantation have a 4.5-fold increased rate of mortality. A recent study using the liver transplantation database of the National Institute of Diabetes and Digestive and Kidney Diseases showed that beyond 5 years, chronic kidney disease is second only to liver disease as a cause of death after liver transplantation.9 This study highlights not only the frequency with which chronic kidney disease occurs but also its clinical importance. These patients also consume greater resources after transplantation.

Several studies have identified the risk factors for developing posttransplant chronic renal failure.8, 10 These include the development of acute kidney injury in the early posttransplant period. The pretransplant or posttransplant development of diabetes mellitus is also an important risk factor. Hypertension, age, and female sex also have been identified as risk factors for chronic renal failure.

Several studies have examined whether there is a difference in the frequency of chronic kidney disease in patients receiving cyclosporine-based immunosuppression versus those receiving tacrolimus-based immunosuppression. Thus far, it is not clear that there is a major difference between these 2 CNIs.

IDEAL IMMUNOSUPPRESSIVE REGIMEN

The ideal immunosuppressive regimen should possess several qualities. First, it should prevent both acute and chronic rejection. Second, it should decrease the risk of recurrent disease. Third, it should have minimal side effects. Finally, it should maximize the quality of life. With respect to point 1, the current expectation is that acute rejection rates should be less than 20% and that chronic rejection rates should be less than 5%. The major issue for point 2 is the recurrence of hepatitis C. However, at this time, it is not clear that any immunosuppressive regimen is particularly favorable for the recurrence of hepatitis C. The issue at hand is particularly influenced by point 3. As mentioned previously, chronic kidney disease is a very important posttransplant complication. Thus, it is important that the relative nephrotoxicity of an immunosuppressive regimen be factored into its relative efficacy. This also affects point 4 with respect to the quality of life.

CNIS ARE LIKELY OVERRATED IN TERMS OF NEPHROTOXICITY

The intent of every renal-sparing immunosuppressive regimen is to limit the exposure to CNIs. The assumption is that the major cause of posttransplant kidney injury is CNI nephrotoxicity. Thus, it is important to test whether this premise is true.

There is little doubt that CNIs can lead to an acute decrease in the GFR. However, this is largely due to renovascular effects and not to true injury to the kidneys. If CNIs are withdrawn at this point, there is generally a 30% improvement in the GFR. The evidence that this reflects or will lead to histological damage or a lack of histological progression is lacking. In liver transplant recipients, there is very little information about renal histology after transplantation. To more carefully examine this issue, one needs to examine the data from kidney transplant recipients. In the recent Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppression Trial,11 long-term kidney biopsy samples showed no differences in mild, moderate, or severe chronic allograft nephropathy between the group receiving cyclosporine and the groups receiving high-dose or low-dose belatacept. The interstitial fibrosis and tubular atrophy that define the presence of chronic allograft nephropathy have generally been attributed to CNI toxicity. However, these data suggest that this is an oversimplification.

It is also critical to point out that the use of CNIs was not a risk factor for the development of chronic renal failure in liver transplant recipients in Ojo et al.'s article.8 In a similar study of heart transplant recipients, the use of CNIs was also not found to be a risk factor for the development of chronic renal failure.

Thus, data showing that CNIs are responsible for all or even most histological damage to the kidneys after liver transplantation are lacking.

CNI-FREE IMMUNOSUPPRESSIVE REGIMENS

The experience to date with CNI-free immunosuppressive regimens in liver transplantation has been universally disappointing. In general, they are associated with unacceptable rates of acute cellular rejection and poor outcomes. Almost invariably, the studies have been stopped before a determination could be made about their long-term effects on renal function or renal histology.

Two of the better examples of CNI avoidance are the recent Spare the Nephron study12 and the liver belatacept study.13 In the Spare the Nephron study, either cyclosporine or tacrolimus was withdrawn early and replaced by sirolimus.12 This large study was stopped early because of a high rate of sirolimus intolerance and poorer outcomes. In fact, this study managed to get a black-box warning for sirolimus in liver transplant recipients. The liver belatacept trial included 5 arms.13 The 3 belatacept arms did not include a CNI. Although these arms were associated with improved renal function, the study was again stopped early because of worse outcomes in the belatacept arms. Again, there was no opportunity to study the long-term effects on renal function or renal histology.

Several large studies have looked at the long-term outcomes of complete CNI avoidance in kidney transplant recipients. I have already mentioned the kidney belatacept trial.11 The Efficiency Limiting Toxicity Elimination (ELITE)-Symphony trial was a study in which CNI replacement was compared with a lower dose CNI or full-dose cyclosporine.14 The best results were obtained for a low-dose tacrolimus group. An unacceptably high rate of rejection was seen in the CNI-free group.

It seems quite clear at this time that the use of a CNI is required to achieve good outcomes after liver transplantation.

REDUCED-DOSE CNI IMMUNOSUPPRESSIVE REGIMENS

Several studies have looked at reducing the doses of CNIs through the inclusion of antibody induction or the use of mycophenolate mofetil.15-17 Several conclusions can be drawn from these experiences. First, the rates of acute cellular rejection are acceptable with immunosuppressive regimens in which the doses of CNIs are reduced. Second, these regimens are associated with modest improvements in renal function in comparison with full-dose CNI regimens. Third, no study has looked at renal histology after liver transplantation, and no study has reported the impact of lower dose CNI regimens on long-term renal function. Finally, in each of these studies, there was still an impressive decrease in the posttransplant GFRs of the reduced-dose CNI arms.

FUTURE

Chronic kidney disease is an important cause of long-term morbidity and mortality after liver transplantation. Although great efforts have been made to identity renal-sparing immunosuppressive regimens, they have largely failed. New immunosuppressive agents that target relatively unique parts of the immune activation cascade, such as Janus kinase 3 and protein kinase C, are currently under development.18 Whether these agents will be potent enough to allow for CNI avoidance is not clear. However, when such regimens are developed and tested in the future, it will be imperative that more sophisticated studies of renal function and renal injury be built into the protocols.

Perhaps too much effort has been focused on eliminating CNIs from our immunosuppressive regimens. It is quite clear that there are other determinants of posttransplant chronic kidney disease that deserve as much attention, if not more.