Challenging Cases in Immunosuppression for Kidney Transplantation

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 2 of a 2-part series

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

Overview

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 second part of this activity, Dr. Donald E. Hricik addresses challenging cases submitted by US nephrologists and transplant specialists in a recent survey.


Disclosures

This activity is supported by an educational grant from Novartis Pharmaceuticals Corporation. Additional support provided by Penn State College of Medicine and Answers in CME.

Course Director
Donald E. Hricik, MD, has a financial interest/relationship or affiliation in the form of:
Consultant for Astellas Pharma US, Inc.
Speakers Bureau participant with Genentech, Inc.- Hoffmann-La Roche Inc. and Novartis Corporation.
Medical Director
Annette Wiggins
Answers in CME, Inc.
Annette Wiggins has no financial interests/relationships or affiliations in relation to this activity.

Answers in CME staff who may potentially review content for this activity have disclosed no relevant financial relationships.

Penn State College of Medicine staff and faculty involved in the development and review of this activity have disclosed no relevant financial relationships.

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Case 1: This is an 18-year-old female with history of end-stage renal disease (ESRD) secondary to lupus; she is status post-deceased donor renal transplant in 2010 and has a history of intermittent nonadherence to medications and frequent episodes of acute kidney injury secondary to pyelonephritis.

She has been recently admitted to the hospital with elevated creatinine. A transplant biopsy was performed, confirming humoral rejection with C4D staining and elevated levels of donor-specific antibodies (DSAs). She was started on therapeutic plasma exchange followed by intravenous immunoglobulin (IVIg) x 5. Her DSA levels are still elevated, although her creatinine is improving. What are her options?

Dr. Hricik: This is one of the most problematic areas in kidney transplantation—how to manage the patient with acute or chronic antibody-mediated rejection. Of course, this case is a little more complicated because of the multiple episodes of pyelonephritis—not on the basis of immune injury, but on the basis of scarring from recurrent episodes. But it's also common to see acute humoral rejection emerge in the setting of noncompliance. We're pretty good at treating acute humoral rejection, and the mainstays of therapy now have become plasma exchange and treatment with IVIg, as she received. Now, it's encouraging to note that her creatinine is currently improving, but the DSA [levels], they're still elevated. I think the concern in the long run is that she may lose this kidney from chronic antibody damage.

So what can we do? Repeating plasma exchange and IVIg is a fairly expensive modality, and if her creatinine is improving, I don't think many would accept that. The other therapeutic options that can be considered are the use of rituximab, the anti-CD20 antibody, which has some utility in treating at least acute humoral rejection, but I'm not so sure of a benefit in the chronic picture.1 And of course, the other category of drugs that are being used experimentally are the proteosome inhibitors—the main one being bortezomib. But I believe that the group in Cincinnati has shown pretty convincingly that that class of agents may be helpful in early cases of acute humoral rejection,2 but are not very helpful in patients with late acute humoral rejection or chronic humoral rejection.3

So we are really stumped here, and unfortunately, it remains true that antibody-mediated chronic rejection is now emerging as one of the most common causes of late graft loss. The only other thing I would say about this case is that I've seen some noncompliant patients who improve just by improving adherence,4-7 and in some cases, increasing the maintenance doses of drugs. So, for example, if the patient is on tacrolimus, we would probably increase our target levels for that drug, at least over the short term, in an effort to get some control.

But this is a big problem in the field of kidney transplantation—studies have shown that DSAs emerge in [approximately] 10% to 15% of patients within the first year or two after transplantation.6,8-10 And it's important to know that those de novo DSAs don't always take their toll in terms of an acute event, but most studies have shown that three- and five-year graft survival are poor in patients with de novo DSAs.6,8,10 And they develop even in patients who are completely adherent with their regimens.

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Case 2: A 56-year-old woman who received a deceased donor kidney transplant four years ago has developed melanomas on the back and thigh. She has been maintained on low-dose cyclosporine, low-dose mycophenolate mofetil (MMF), and prednisone. Should she be switched from a calcineurin inhibitor (CNI) to an mTOR inhibitor? Should the CNI be stopped or is some other strategy preferred?

Dr. Hricik: Well, malignancy, of course, is one of the dreaded complications of chronic immunosuppression. Melanomas are probably overrepresented in the transplant population; however, hardly as common as the more common skin cancers, particularly squamous cell cancer of the skin, and even basal cell cancer of the skin. Those are the most common of all cancers that are seen in transplant recipients.

There's been the notion that the [mammalian target of rapamycin, or [m]TOR inhibitors have antineoplastic effects in a general way, but specifically for kidney cancer, for Kaposi's sarcoma, and for the skin cancers. There are now two randomized studies that convincingly show that patients with multiple squamous cell and basal cell carcinomas and patients with multiple warts (which are related to HPV [human papillomavirus] infection) appear to benefit from a strategy of switch from a CNI to an [m]TOR inhibitor.11-13 In those studies, patients were randomized to do one or the other, and after a long period of follow-up, there were fewer squamous cell or non–melanoma skin cancers [NMSC] in the groups that were converted to [m]TOR inhibitors.

There would be some temptation to switch this patient, but I don't think based on scientific evidence. We would certainly consider minimizing some of the other drugs that she's taking, particularly if the melanomas keep cropping up or if she develops other malignancies.

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Case 3: This is a 60-year-old patient with ESRD who will be receiving an expanded criteria donor (ECD) kidney. If using a CNI-sparing regimen is preferred, what are the best options?

Dr. Hricik: Well, I presume the basis for this question is the evidence that ECD kidneys exhibit higher rates of delayed graft function,14 and may be a risk for acute rejection.

Does it help to use a CNI-sparing regimen? I guess the best evidence that this might be helpful is the BENEFIT-EXT trial of belatacept that ended up bringing that drug to FDA approval.15 The BENEFIT-EXT trial was limited to recipients of ECD kidneys, and comparing a cyclosporine-based regimen to a belatacept-based regimen, there was improved [glomerular filtration rate, or] GFR after long-term follow-up in the group that never saw cyclosporines [and] that was treated with belatacept. So I have some enthusiasm for that regimen, but we need more evidence to show that that benefit is true.

Now, in many centers not yet using belatacept, I think there's kind of a convention to withhold CNIs in patients with delayed graft function or administer them at reduced doses. It's a common practice; I don't think there's been any proven benefit, and some centers have shown that using full doses of CNIs from the get-go result in outcomes that are exactly the same or similar to patients where initial CNI-sparing is practiced. In our own center, we do hold our tacrolimus for a couple of days in the patients with delayed graft function. Does this provide any long-term benefit to the patient receiving the ECD kidney? I don't think we know.

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References

  1. Barnett AN et al. Transpl Int. 2013;26:563-575.
  2. Walsh RC et al. Transplantation. 2010;89:277-284.
  3. Sadaka B et al. Semin Hematol. 2012;49:263-269.
  4. Morath C et al. Transpl Int. 2012;25:633-645.
  5. Prendergast MB, Gaston RS. Clin J Am Soc Nephrol. 2010;5:1305-1311.
  6. Wiebe C et al. Am J Transplant. 2012;12:1157-1167.
  7. Sellarés J et al. Am J Transplant. 2012;12:388-399.
  8. Huang Y et al. 2013 American Transplant Congress. Abstract D1590.
  9. Rebellato LM et al. Clin Transpl. 2011:337-340.
  10. Lan J et al. Transplantation. 2010;89:178-184.
  11. Schena FP et al. Transplantation. 2009;87:233-242.
  12. Stallone G et al. N Engl J Med. 2005;352:1317-1323.
  13. Salgo R et al. Am J Transplant. 2010;10:1385-1393.
  14. Hassanain M et al. Transplant Proc. 2009;41:133-134.
  15. Durrbach A et al. Am J Transplant. 2010;10:547-557.

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Novartis Pharmaceuticals Corporation

This activity is supported by an educational grant from Novartis Pharmaceuticals Corporation.

Additional support provided by Penn State College of Medicine and Answers in CME.

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