Updates in Immunosuppressive Therapy for Kidney Transplantation: Implications of the Latest Data for Practice

Course Director

Donald E. Hricik, MD

Donald E. Hricik, MD
Professor of Medicine
Chief of the Division of Nephrology and Hypertension
Division of Nephrology and Hypertension
Department of Medicine
School of Medicine
Case Western Reserve University
Cleveland, Ohio

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Part 1 of a 2-part series

Dr. Hricik provides expert feedback to the questions submitted by your peers during a recent survey on this topic.


Despite advances in transplantation medicine, acute and long‐term organ rejection remains a significant challenge. New developments in immunosuppressive therapies may provide better management options with a decreased risk of adverse renal or cardiovascular events that are common with standard calcineurin inhibitors (CNIs), but the promise of CNI‐free immunosuppressive strategies has yet to be fully realized. Accordingly, nephrologists and transplant specialists need to be able to use available regimens for optimal outcomes in their patients undergoing kidney transplantation, and to understand the clinical impact of emerging strategies. In the first part of this activity, Dr. Donald E. Hricik answers questions on modern immunosuppressive strategies from a recent survey of US nephrologists and transplant specialists.

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What is the best next step for those patients who develop chronic allograft nephropathy while on a calcineurin inhibitor (CNI)?

Dr. Hricik: So I think the answer to that question has become a moving target in the past 10 years or so, in part because the very term chronic allograft nephropathy, I think, is increasingly becoming obsolete—and the reason for that is we now recognize that there are various histologies that constitute that very broad definition. So we now know, for example, that some patients have so-called transplant glomerulopathy, which was once a component of chronic allograft nephropathy. Now we know that transplant glomerulopathy is probably a form of antibody-mediated rejection.1 There are some patients who have pure interstitial fibrosis and tubular atrophy, or IFTA, on their biopsies. Some of these patients may have true calcineurin inhibitor toxicity, which could warrant conversion to another agent.

But data have now convincingly shown that fibrosis alone is probably not as harmful to long-term graft survival as we once thought it was—if you have fibrosis associated with inflammation, that tends to be a harbinger for poor graft survival.2 So if anything, eliminating CNIs in patients who have transplant glomerulopathy or fibrosis with inflammation is probably not a good idea.

Narrator: In addition to glomerular filtration rates >40 mL/min, other parameters that are needed prior to the switch is made in order to have a benefit, as per this study, are protein excretion <800 mg/day and creatinine <2.5 mg/dL.

Dr. Hricik: Now, for patients with pure IFTA, there are some conversion regimens that can be considered. I think some patients benefit from conversion to an [m]TOR inhibitor [or mammalian target of rapamycin], but results of the CONVERT study showed us that most of the benefit occurs in patients who already have glomerular filtration rates >40 mL/min and who have minimal proteinuria.3 Otherwise, conversion to [m]TOR inhibitors is not very successful. And of course, the newest drug that some are considering is belatacept. But right now I would say the scientific evidence for converting patients with chronic renal dysfunction to belatacept is not robust,4,5 and further studies are needed.

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How should we manage patients with recognized adverse reactions to immunosuppressive therapies such as new-onset diabetes or difficult-to-control hyperlipidemia?

Dr. Hricik: These are, of course, very common problems that we deal with in the transplant clinic. Data show that new-onset diabetes mellitus occurs in up to 25% of our patients after a few years,6-8 and hyperlipidemia is also common, probably occurring in 70% to 80% of our patients.9,10 There's no doubt that the calcineurin inhibitors play some role in both of these metabolic abnormalities. The bulk of the data suggest that of the two available calcineurin inhibitors, tacrolimus clearly is a cause of new-onset diabetes more often than is cyclosporin. But the other side of the coin is that cyclosporin is almost certainly more of a problem when it comes to causing hyperlipidemia, where[as] probably hyperlipidemia is not that commonly seen with tacrolimus.11

Certainly, there have been some studies looking at conversion from one calcineurin inhibitor to another.12 Again, this may be of benefit to a patient with new-onset diabetes, converting them from tacrolimus to cyclosporin, for example, but you may end up finding that your patient now has new hyperlipidemia that they haven't before. So in our own practice, we're reluctant to make those switches, and rely instead on careful dose reductions if we really believe that we can help a patient with their metabolic problem. Transplant centers monitor lipid profiles probably three or four times a year.

Converting patients to other drug categories—for example, to an [m]TOR inhibitor—makes little sense, because, if anything, the [m]TOR inhibitors are associated with more hyperlipidemia. And, at least in some patients, the [m]TOR inhibitors are actually a cause of diabetes.13 Again, there's only some minor evidence-based literature on conversion to belatacept for patients with these metabolic disorders, and there does appear to be some benefit in at least the one published study of conversion.4 But I think we need more evidence from larger trials before we recommend that as a routine strategy.

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What is the role of novel immunosuppressive agents and strategies for patients receiving kidney transplantation?

Dr. Hricik: So interestingly, I think most of the new agents (and there really aren't many that have reached FDA approval) have been developed as replacements for the calcineurin inhibitors, but I would say that we're actually probably farther away from enthusiasm for CNI-free regimens than we were a while back.

The data with belatacept in the two major trials that were performed looked positive, but most of us are still concerned that in those studies, there was more acute rejection in the belatacept arms than there were in the cyclosporin-treated arms.14,15 And although the patients in the experimental arms of those studies ended up with better glomerular filtration rates in the long run, it's still concerning to most transplant nephrologists that you have higher rates of rejection. So again, I think we need more data to assure us that a belatacept regimen is the way to go in order to avoid calcineurin inhibitors.

Of all the experiences with [m]TOR inhibitors, the one that I always come back to is the pivotal trial that was performed looking at patients who were initially treated with sirolimus and a calcineurin inhibitor, and who were randomized after three months to either stay on the calcineurin inhibitor or to be withdrawn from the calcineurin inhibitor.16 The data from that study was impressive because glomerular filtration rates clearly were better in the [m]TOR inhibitor arm than the CNI arm, even after five years.17

But that protocol required de novo use of [m]TOR inhibitors, and most centers have moved away from the de novo use of these agents because of concerns about wound healing and the many other side effects of that class of drugs.13 And in fact, the problem with the [m]TOR inhibitors is that in most studies, somewhere between 20% and 40% of patients end up switching back to the other regimen because of intractable side effects.18

So I'm not here to say that calcineurin inhibitor agents are all good—they certainly are nephrotoxic agents, and there probably are some patients who would benefit from CNI-free regimens when toxicity is intractable, or where there's convincing evidence that the nephrotoxicity is purely related to the calcineurin inhibitor. But these are probably the only drugs that we have available that are known to inhibit immune memory, and some immunologists believe that memory is the final hurdle to tolerance, and if we take away the drugs that inhibit memory, there is a concern that in the long run, we'll see more late rejection—and even possibly more humoral rejection, which is an important cause of graft loss in the long run. So I think we've changed from enthusiasm from these regimens to very cautious enthusiasm over the past five or 10 years.

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  1. Gaston RS et al. Transplantation. 2010;90:68-74.
  2. Gago M et al. Am J Transplant. 2012;12:1199-1207.
  3. Schena FP et al. Transplantation. 2009;87:233-242.
  4. Rostaing L et al. Clin J Am Soc Nephrol. 2011;6:430-439.
  5. Grinyo J et al. Transpl Int. 2012;25:1059-1064.
  6. Rodrigo E et al. Diabetes Care. 2012;35:471-473.
  7. Lane JT, Dagogo-Jack S. J Clin Endocrinol Metab. 2011;96:3289-3297.
  8. Gosmanov AR, Dagogo-Jack S. Minerva Endocrinol. 2012;37:233-246.
  9. Dumler F, Kilates C. J Ren Nutr. 2007;17:97-102.
  10. Pourmand G et al. Int J Organ Transplant Med. 2010;1:131-137. http://home.sums.ac.ir/~habibzaf/ojs/index.php/IJOTM/article/viewFile/39/76.
  11. Vincenti F et al. Am J Transplant. 2007;7:1506-1514.
  12. Ghisdal L et al. Transpl Int. 2008;21:146-151.
  13. Hernández D et al. Nefrologia. 2011;31:27-34. http://www.revistanefrologia.com/revistas/P1-E515/P1-E515-S2784-A10512-EN.pdf.
  14. Vincenti F et al. Am J Transplant. 2010;10:535-546.
  15. Durrbach A et al. Am J Transplant. 2010;10:547-557.
  16. Johnson RW et al. Transplantation. 2001;72:777-786.
  17. Campistol JM et al. J Am Soc Nephrol. 2006;17:581-589.
  18. Rostaing L, Kamar N. J Nephrol. 2010;23:133-142.

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