Transplantation: Desensitization and transplantation for sensitized patients?

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Nature Reviews Nephrology 7, 682-683 (December 2011) | doi:10.1038/nrneph.2011.148

Subject Category: Transplant

Transplantation: Desensitization and transplantation for sensitized patients?
J. Michael Cecka About the author

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Abstract
For patients who undergo desensitization treatment to reduce or neutralize circulating donor-specific anti-HLA antibodies prior to transplantation, survival is lower than for unsensitized patients. However, a new study suggests that for sensitized patients, desensitization and transplantation might be better than remaining on dialysis or waiting for a compatible kidney transplant.

Approximately one-third of candidates for kidney transplantation in the US have circulating antibodies directed against HLA antigens, the major barriers to successful organ transplantation. Sensitization can result from exposure to foreign HLA antigens primarily through pregnancies, previous organ transplants or blood transfusions. When antibodies are directed against the HLA antigens of the donated kidney, the patient is at risk of a variety of problems, ranging from catastrophic hyperacute rejection to accelerated acute rejection and other difficult to manage events. A crossmatch test to identify donor-specific HLA antibodies is performed prior to transplantation to avoid these complications. The result of this test often precludes kidney transplantation from a willing and otherwise suitable living donor, but a patient's sensitized status can also be a clear obstacle to receiving a deceased donor kidney, depending on the breadth of reactivity of the antibodies.

A recent study by Montgomery et al.,1 reported in the New England Journal of Medicine, showed that 211 patients who underwent desensitization with plasmapheresis and low-dose treatment with intravenous immunoglobulin (IVIG; 100 mg/kg body weight) before living donor renal transplantation fared better than carefully matched control patients. The control patients were on the United Network for Organ Sharing (UNOS) kidney transplant waiting list and either remained on dialysis or waited for a compatible deceased donor kidney transplant. Patient survival after 8 years was 80.6% in the desensitized group compared with 30.5% in the dialysis–only control group and 49.1% in the dialysis–or–transplantation control group.

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An important consideration when interpreting desensitization results is the original degree of sensitization, which can vary considerably between patients and different transplant centers. Advances in the technologies used to identify and characterize anti-HLA antibodies2 have led to very sensitive and precise methods of identification. However, some controversy exists about the clinical relevance of weak antibodies that can only be detected by the most sensitive techniques. Montgomery and colleagues addressed this concern by dividing their patients into three groups according to the relative strength of the crossmatch test that initially precluded transplantation with their donor: those with a positive complement-dependent cytotoxicity crossmatch (the least sensitive test that detects only the strongest antibodies); those with a more sensitive positive flow cytometry crossmatch; and those whose donor-reactive antibodies could only be detected with the most sensitive solid-phase tests. Long-term survival decreased with increasing antibody strength, but even patients with the strongest and most dangerous antibodies had better survival after desensitization and transplantation than did the control groups.

These results should encourage more transplant centers to consider desensitization as an alternative to a prolonged wait for a compatible transplant, particularly for patients who have a willing living donor. The team from Johns Hopkins developed the low-dose IVIG protocol and has been desensitizing patients for more than a decade. This desensitization procedure removes antibodies by plasmapheresis and interferes with residual antibodies using low-dose IVIG. Other programs have used high-dose IVIG (2 g/kg) protocols to achieve a somewhat more durable desensitization that enables patients to wait for up to a few months for a deceased donor kidney.3 However, desensitization is not guaranteed by either procedure, and the effect is often only temporary when antibody levels are reduced. In addition, not all patients can be desensitized. Those with very high titer antibodies require multiple desensitization cycles that are not always successful4 and treatment is costly (both for individual and multiple cycles). Indeed, the Johns Hopkins group does not attempt to desensitize every sensitized patient. After transplantation, desensitized patients must be monitored carefully to detect the return of antibodies, and the incidence of antibody-mediated rejection is higher in these patients than in unsensitized patients. Therefore, desensitized patients often require more hospital resources than recipients who have an uneventful post-transplantation course. In fact, the careful follow-up of recipients who were desensitized in the Johns Hopkins' study was probably more intensive than the follow-up of their control patients (who underwent surgery and monitoring at a number of transplant centers), which might have contributed to the superior survival Montgomery et al. observed for their desensitized patients.

Desensitization enables patients to reduce their risk of early graft failure...

Sensitized patients are less likely to find a compatible donor than are unsensitized patients. The strength and specificities of their anti-HLA antibodies provide an accurate estimate of the percentage of donors who will be incompatible.5 Candidates for a kidney transplant who are on the UNOS waiting list and are sensitized to >20% of potential deceased donors have access to HLA-matched kidneys from anywhere in the US. Those sensitized to ≥80% of donors receive additional priority points when a compatible local donor kidney becomes available to increase their chances of receiving a transplant. Improved technology for identifying and characterizing anti-HLA antibodies permits accurate 'virtual' crossmatches based on the specific antibodies identified in the patient's serum and the HLA type of the donor. Increased utilization of virtual crossmatching for sensitized patients has increased access to deceased donor kidneys by streamlining the UNOS allocation process.6 For patients who have a willing living donor, paired kidney exchanges enable patients to swap incompatible kidneys for compatible ones.7 However, for most broadly sensitized patients, none of these options offers much hope of transplantation. Desensitization enables patients to reduce their risk of early graft failure with an incompatible donor and it can be combined with these other approaches to identify less risky donor kidneys that can be safely transplanted.8 Transplanting compatible kidneys is the best option,9 but the study by Montgomery et al. shows that time is an important element and waiting for a compatible kidney might not be the right choice for many sensitized patients. Desensitization provides an option for those who are not likely to find a compatible donor anytime soon.

Competing interests statement

The author declares no competing interests.

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References

Montgomery, R. A. et al. Desensitization in HLA-incompatible kidney recipients and survival. N. Engl. J. Med. 365, 318–326 (2011).
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Cecka, J. M. Current methodologies for detecting sensitization to HLA antigens. Curr. Opin. Organ Transplant. 16, 398–403 (2011).
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Vo, A. A. et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N. Engl. J. Med. 359, 242–251 (2008).
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Cecka, J. M., Kucheryavaya, A. Y., Reinsmoen, N. L. & Leffell, M. S. Calculated PRA: initial results show benefits for sensitized patients and a reduction in avoidable positive crossmatches. Am. J. Transplant. 11, 719–724 (2011).
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Cecka, J. M. Calculated PRA (CPRA): the new measure of sensitization for transplant candidates. Am. J. Transplant. 10, 26–29 (2010).
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Warren, D. S. & Montgomery, R. A. Incompatible kidney transplantation: lessons from a decade of desensitization and paired kidney exchange. Immunol. Res. 47, 257–264 (2010).
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Blumberg, J. M., Gritsch, H. & Veale, J. L. Kidney paired donation: advancements and future directions. Curr. Opin. Organ Transplant. 16, 380–384 (2011).
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Montgomery, R. A. Renal transplantation across HLA and ABO antibody barriers: integrating paired donation and desensitization protocols. Am. J. Transplant. 10, 449–457 (2010).
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Bradley, J. A. et al. Antibody-mediated rejection—an ounce of prevention is worth a pound of cure. Am. J. Transplant. 11, 1131–1139 (2011).
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Author affiliations

J. M. Cecka
University of California Los Angeles, Pathology and Laboratory Medicine, UCLA Immunogenetics Center, 1000 Veteran Avenue 15–20, Los Angeles, CA 90095, USA.
mcecka@ucla.edu

Published online 4 October 2011

http://www.nature.com/nrneph/journal/v7/n12/full/nrneph.2011.148.html