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Saudi Journal of Kidney Diseases and Transplantation
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SCOT FORUM Table of Contents   
Year : 2006  |  Volume : 17  |  Issue : 1  |  Page : 97-102
Renal Allograft Antibody Mediated Rejection in Highly Sensitized Patient


King Faissal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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How to cite this article:
Abdulbaki A. Renal Allograft Antibody Mediated Rejection in Highly Sensitized Patient. Saudi J Kidney Dis Transpl 2006;17:97-102

How to cite this URL:
Abdulbaki A. Renal Allograft Antibody Mediated Rejection in Highly Sensitized Patient. Saudi J Kidney Dis Transpl [serial online] 2006 [cited 2019 Jul 21];17:97-102. Available from: http://www.sjkdt.org/text.asp?2006/17/1/97/32454

   Case Presentation Top


F.Q is a 49-year-old female with a history of end-stage renal disease secondary to unknown etiology. She was started on regular hemodialysis in 1996. Her other medical history included hypertension and chronic hepatitis C viral (HCV) infection (Grade 2 Stage 1). In January of 2000 she was cleared for receiving a living related kidney from her son with a one haplotype match. She had 0% cytotoxic antibodies (CTA). However, the crossmatch with her son was incompatible due to positive T-cell IgG by flow cytometry. Her B-cell IgG flow cytometry crossmatch was negative. Since the patient had no other available donor, she was waitlisted to receive a cadaver kidney. In April 2004, desensitization protocol was established at our institution and the couple was called for reassessment. The repetition of the initial crossmatch was this time compatible and the couple was cleared for the transplant surgery. The planned immunosup­pression was tacrolimus (FK506), myco­phenolate mofetil (MMF) and prednisone with anti CD 20 monoclonal antibody induction (basiliximab). However, when the final crossmatch was performed it proved to be again positive for T-cell both by flow cytometry (85 channel shift) and complement dependent cytotoxicity (CDC). The B-cell crossmatch remained negative and the CTA performed by the CDC method remained at 0%. No history of blood transfusion or other sensitizing events were detected between the different crossmatch procedures. The patient was deemed highly sensitized and the decision was made to proceed with the transplant­tation. Desensitization was performed with the administration of intravenous immunoglobulin (IVIG) 2 gm/kg over 36 hours, MMF one gm twice/day (bid) and rabbit anti-human thymocyte polyclonal antibody (ATG). The desensitization was successful as was evident by the conversion of the crossmatch to negative both by the flow cytometry and the CDC methods. The surgical procedure was uneventful.

On the operative day, the patient received 500 mg of intravenous (I.V.) methylpred­nisolone along with 1.5 mg/kg of I.V. ATG intraoperatively, and 500 mg of I.V. rituximab administered immediately postoperatively as a part of the desensitization regimen.

Following the operation, the patient sustained good primary graft function with a remarkable decrease in serum creatinine from the preoperative value of 704 µmol/L to the first postoperative day value of 259 µmol/L. The renal ultrasound showed good perfusion without evidence of any perinephric or pelvic collection. The renal nuclear scan revealed prompt perfusion with delayed excretion suggestive of a picture of acute tubular necrosis (ATN). The patient was then maintained on an immunosuppressive regimen consisting of tapered dose of prednisone to 20 mg per day, MMF 1 gm orally bid. The introduction of tacrolimus was delayed to the 15th postoperative day to avoid further possible tubular injury. The ATG was continued till the tacrolimus was started; the frequency of the dosing was determined by body weight, the absolute lymphocyte and CD3 counts.

On the 6th postoperative day, a decrease in urine output was noted and the drop in serum creatinine stopped at 220 µmol/L for two consecutive days. A renal allograft biopsy was performed and confirmed the presence of ATN [Figure - 1]. The repetition of crossmatch was positive by flowcytometry but negative for both T and B-cell crossmatch by CDC. The patient was clinically managed with I.V. fuorsemide and fluid restriction.

On the 9th postoperative day, due to lack of improvement, the patient had another allograft biopsy [Figure - 2],[Figure - 3]. There was morphological evidence of acute tissue injury with positive peritubular capillary C4d staining. In addition to the biopsy findings, the positive cross­match confirmed the presence of donor specific antibody (DSA). All these findings were compatible with the diagnosis of antibody mediated rejection (AMR).

Treatment for AMR was initiated with five sessions of plasma exchange over five days, 100 mg/kg of IVIG administered at the end of the first four sessions and 1 gm/kg at the end of the fifth. During the treatment of the AMR, the urine output was between 1000-1500 ml/day and serum creatinine ranged between 220-250 µmol/L. Following the end of treatment serum creatinine started to steadily decrease from 232 µmol/L on the 15th postoperative day to 125 µmol/L on the 19th postoperative day at which point the patient was discharged in stable condition. At discharge, the immuno­suppressive regimen consisted of prednisone 20 mg /day, tacrolimus 4 mg bid, MMF 750 mg bid and sirolimus 3 mg /day. The sirolimus was added to augment the patient's immuno­suppression over the first six month post transplant.

Shortly following discharge the patient's serum creatinine reached a nadir of 85 µmol/L and remained stable ever since.


   Discussion Top


In 1969, Patel and Terasaki published a landmark study in which they unequivocally demonstrated that the presence of recipient antibodies to antigens expressed on donor white cells were a major risk factor for immediate graft loss.[1] The data were so compelling that the author asserted '…the ethics of transplanting kidneys without the prior knowledge of the result of the lympho­cyte crossmatch test can reasonably be expected to be questioned. Since then, prospective crossmatching has been perfor­med routinely on all transplant patients.

Although hyperacute allograft rejection has not been completely eliminated, its incidence has been significantly reduced, as patients with positive crossmatch with their prospective donors were not transplanted. This practice on the other hand enlarged the population of patients on the transplant waiting list, frequently crossmatched but rarely transplanted.

Recently, advances in immunosuppressive therapy have directed clinicians to reopen the case for this "highly sensitized" population of patients resulting in the development of desensitizing protocols using IVIG and or plasmapheresis. As many of these patients were successfully transplanted, it was evident that a toll had to be paid with an increase in the incidence of AMR. In the context of desensitization, the AMR has become even more versatile and sometimes hard to discern and manage.

During the past few decades, multiple terms have been used to describe rejection that may have a humoral component (i.e., vascular rejection and accelerated acute rejection), recently, however, the term AMR was coined by the consensus opinion from the antibody working group [2] to describe all rejections involving DSA or reactive antibody (e.g., anti-HLA, ABO iso­agglutinin, and antiendothelial antibodies).

De novo AMR (acute or chronic) occurs in patients who lack DSA, by sensitive assays, and have a negative crossmatch with their donor before transplant but develop AMR after the transplantation.[3] As antibody-reducing protocols have become available and more commonly utilized, AMR is increasingly seen in the context of preconditioning for a positive crossmatch or ABO incompatibility. There is some early evidence that post-desensitization AMR may behave differently than the de novo form. [3],[4] It tends to be more rapidly responsive to therapy, and patients usually return to their baseline renal function after treatment. However, the role of anticipation in the favorable clinical outcome cannot be ignored especially that these patients tend to be more carefully monitored after receiving the preconditioning regimens.

Technologic advances in the histo­compatibility tests and immunohistology have considerably assisted the diagnosis of AMR. The increased sensitivity of assays and the ability to distinguish between the antibodies specific for the donor versus a third party HLA antigens or non-HLA antigens have been tremendous advance­ments. [5],[6] Likewise, the emergence of C4d staining as a sensitive indicator of comple­ment activation that occurs in the setting of AMR has provided an additional important diagnostic criterion. [7],[8] A firm diagnosis of AMR can be made when there is a coalescence of allograft dysfunction, characteristic features of histology and immunohistology, and the presence of DSA. However, all these data are not always available, and there can be a time lag between each of these elements.

If graft dysfunction is present, then the next step is to assess the level of risk associated with the clinical setting in which the transplantation has occurred. High-risk criteria include husband to wife or child to mother donor-recipient pairs, history of sensitizing event (pregnancy, transfusion, or previous transplantation), and known produ­ction of HLA-specific antibody, presently or historically. If the transplantation has occurred in a low-risk setting, then the burden of proof for the diagnosis of AMR is greater and must include both the classic biopsy findings and the presence of DSA. In the high-risk patient, the presence of the characteristic features of AMR on light microscopy and the positive C4d staining represent sufficient diagnostic criteria. Even without DSA or characteristic biopsy features, one must still maintain a high index of suspicion among patients who have graft dysfunction and significant risk factors for AMR.

The light microscopy features consistent with the AMR can appear on protocol biopsy in the presence of stable renal function, this represent a subclinical or preclinical antibody-mediated process that may or may not evolve into frank AMR. If DSA is detectable and there is evidence of injury on the allograft biopsy in the acute setting, graft function will likely occur, and these patients may benefit from early or preemptive treatment with the endpoint being eradication of DSA or resolution of injury. Anti HLA DSA may persist in the presence of a normal biopsy and graft function. This could represent an adjust­ment or a latent antibody response. In the early post-transplant period this may be an appropriate trigger for more therapy. In most cases anti-HLA DSA can be durably suppressed. [9],[10]


   Questions Top


Dr. Souqiyyeh (Saudi Center for Organ Transplantation): Do we have long-term patient and graft survival data available on AMR?

Dr. Abdulbaki: There are some short term survival studies such as the study of Muaidi et al that showed the one year survival was worse for the C4d positive rejection than the negative C4d. However, it is still early to have long-term survival results such as five or ten years survival.

Dr. Quraishi (King Faisal Specialist Hospital and Research Center (KFSH-RC), Riyadh): We still see AMR despite the treatment of the AMR by anti thymoglobulin antibodies. Do you have an explanation for that?

Dr. Abdulbaki: Rejection can still occur with any anti rejection treatment. Further­more, the biologic agents such as ATG depend in their efficacy on the source of manufacturing and some batches may not be efficacious as claimed.

Dr. Al Kabawi (Yamama hospital): Do you perform follow-up biopsies for patients with AMR after clinical recovery?

Dr. Abdulbaki: Protocol biopsies are more sensitive tools for follow-up of the grafts with AMR than current serological or chemical parameters though the predictive value is still debatable.

Audience (KFSH-RC): In the desensitization protocol you presented, it appears that we expose the patients to heavy immuno­suppression. I am concerned about the side effects of such overpowered regimens such as malignancy.

Dr. Abdulbaki: It is of concern but the general outcome is still favorable in the majority of the patients. Such patients have no other option than dialysis if not transplanted this way.

Dr. Souqiyyeh (SCOT): It came to my knowledge that some transplantation programs in Saudi Arabia are attempting to start the application of the desensitization similar to your protocol. What is your advice to such attempts?

Dr. Abdulbaki: The application is possible if the means to apply it are available.

Dr. Khaled Shibani (KFSH-RC): I believe the cost is of concern for the application of such protocol and the long term results as well.

Dr. Abdulbaki: I agree that the notion about the cost. But the quality of life after transplantation is still better than dialysis.

Dr. Khaled Almishari (KFSH-RC): I want to allude to the question raised by Dr. Souqiyyeh about the wide application of the protocol by other centers in Saudi Arabia. The presence of the corporate team of dedicated medical staff, the well equipped serological laboratory (such as the availa­bility flow cytometry) and the available medications are crucial for the implementation of the protocol otherwise the results may be detrimental to the patients.

Dr. Alsunaid: Thank you all for attendance.

 
   References Top

1.Patel R, Terasaki PI. Significance of the positive crossmatch test in kidney trans­plantation. N Engl J Med 1969; 280: 735-9.  Back to cited text no. 1  [PUBMED]  
2.Montgomery RA, Hardy MA, Jordan SC, et al. Consensus opinion from the antibody working group on the diagnosis, reporting, and risk assessment for antibody-mediated rejection and desensitization protocols. Transplantation 2004; 78: 181-5.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Montgomery RA, Zachary AA, Racusen LC, et al. Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully trans­planted into cross-match-positive recipient. Transplantation 2000; 70(6): 887-95.  Back to cited text no. 3    
4.Sonnenday CJ, Ratner LE, Zachary AA, et al. Preemptive therapy with plasma­pheresis/intravenous immunoglobulin allows successful live donor renal transplantation in patients with positive crossmatch. Transplant Proc 2002; 34(5): 1614.  Back to cited text no. 4    
5.Lucas DP, Paparounis ML, Myers L, et al. Detection of HLA class I-specific antibodies by the QuickScreen enzyme­linked immunosorbent assay. Clin Diagn Lab Immunol 1997; 4: 252.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Zachary AA, Ratner LE, Graziani JA, et al. Chracterization of HLA class I-specific antibodies by ELISA using solubilized antigen targets: 2. Clinical relevance. Hum Immunol 2001; 62: 236-46.  Back to cited text no. 6    
7.Haas M, Ratner LE, Montgomery RA. C4d staining of perioperative renal transplant biopsies. Transplantation 2002; 74:711-11.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Racusen LC, Colvin RB, Solez K, et al. Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection Am J Transplant 2003; 3:708-14.  Back to cited text no. 8    
9.Zachary AA, Montgomery RA, Ratner LE, et al. Specific and durable elimination of antibody to donor HLA antigens in renal transplant patients. Transplantation 2003; 76(10): 1519-25.  Back to cited text no. 9    
10.Gebel HM, Bray RA, Nickerson P. Pre­transplant assessment of donor reactive, HLA-specific antibodies in renal transplan­tation: contraindication vs. risk. Am J Transplant 2003; 3(12): 1488-500.  Back to cited text no. 10    

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Correspondence Address:
Ammar Abdulbaki
Department of Medicine, Renal Transplantation Program, King Faissal Specialist Hospital and Research Center, P.O. Box 3054, Riyadh 11211
Saudi Arabia
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PMID: 17297547

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