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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2011  |  Volume : 22  |  Issue : 4  |  Page : 662-669
Desensitization protocol for highly sensitized renal transplant patients: A single-center experience


1 Department of Nephrology and Transplantation Medicine, IKDRC-ITS, Ahmedabad, India
2 Department of Pathology, Laboratory Medicine and Transfusion Services and Immunohematology, IKDRC-ITS, Ahmedabad, India
3 Department of Urology and Transplantation, IKDRC-ITS, Ahmedabad, India

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Date of Web Publication9-Jul-2011
 

   Abstract 

Highly sensitized patients are destined to remain untransplanted for long. Early transplantation results in cost-saving, reduced morbidity/mortality and improved quality of life. We carried out a prospective study to evaluate the efficacy and safety of desensitization protocol vis-à-vis patient/graft survival in living donor renal transplantation in highly sensitized patients. Between December 2008 and April 2010, 34 renal transplant (RTx) patients underwent desensitization protocol. An anti-human globulin-enhanced lymphocytotoxicity crossmatch assay (AHG-CDC) ≥25% and T-cell median channel shift (MCS) >50, B-cell MCS >100 [flow crossmatch (FXM)] were considered crossmatch (XM) positive. All patients were administered bortezomib (1.3 mg/m 2 , days 1, 4, 8, 11), plasmapheresis, rabbit-anti-thymocyte globulin (r-ATG), mycophenolate mofetil (MMF) and intravenous immunoglobulins (IVIg). LCXM and FXM were repeated post-protocol. In the event of persistent sensitization, additional bortezomib cycle was repeated along with plasmapheresis, IVIg, calcineurin inhibitors (CNI) and rituximab. If the cross match (CMX) was negative or acceptable, patients underwent RTx. Post-transplant immunosuppression consisted of prednisone, CNI and MMF. Biopsy was performed in the event of graft dysfunction and treated accordingly. There were 18 males and 16 females, with a mean age of 37.4 years. Mean dialysis duration was 14.9 ± 17.6 months. Average third party transfusions were 6.2 ± 4.5, 17.6% had autoimmune diseases, 20.6% were multi-para. Pre-protocol AHGXM was 55.3 ± 24.5%, T-cell crossmatch (TCXM) was 122.4 ± 91.4 MCS and B-cell crossmatch (BCXM) was 279 ± 142.9 MCS. Totally, 85.3% responded within 1 month with reduction in AHG-CDC to 19.9 ± 5.2%, TCXM to 24.7 ± 19.4 MCS and BCXM to 74.7 ± 34.8 MCS. Side effects noted in 38.2% were manageable. Over follow-up of 0.92 ± 0.8 years, patient/graft survival was 100%/88.2% and mean serum creatinine was 1.27 ± 0.32 mg/dL. Acute rejections were noted in 24.1%, who responded to steroids + rabbit antithymocyte globulin (rATG). Five (14.7%) patients were transplanted after changing donors. Our desensitization protocol seems to be safe and effective. Bortezomib may offer new possibilities in desensitization protocols.

How to cite this article:
Kute VB, Vanikar AV, Trivedi HL, Shah PR, Goplani KR, Patel HV, Gumber MR, Patel RD, Kanodia KV, Suthar KS, Trivedi VB, Modi PR. Desensitization protocol for highly sensitized renal transplant patients: A single-center experience. Saudi J Kidney Dis Transpl 2011;22:662-9

How to cite this URL:
Kute VB, Vanikar AV, Trivedi HL, Shah PR, Goplani KR, Patel HV, Gumber MR, Patel RD, Kanodia KV, Suthar KS, Trivedi VB, Modi PR. Desensitization protocol for highly sensitized renal transplant patients: A single-center experience. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2019 Sep 21];22:662-9. Available from: http://www.sjkdt.org/text.asp?2011/22/4/662/82641

   Introduction Top


Patients with high levels of preformed human leukocyte antigen (HLA) antibodies are at a high risk of losing their grafts due to rejections. Hence, they are destined to remain on the waiting list of deceased donor organ transplantation (DDOT) for a long time till these harmful antibodies are deleted or removed to make them "transplantable". Various desensitization protocols using rituximab, intravenous immunoglobulins (IVIg) and plasmapheresis have been tried with variable success. [1],[2],[3],[4],[5],[6] We carried out a prospective study in living donor renal transplantation in highly sensitized patients to evaluate the efficacy and safety of desensitization protocol vis-à-vis patient/graft survival and rejection episodes in which we used combination of anti-T, anti-B cell antibodies, IVIg and plasmapheresis along with proteasome inhibitor bortezomib.


   Methods Top


Histocompatibility testing

We routinely perform the flow cytometry crossmatch (FCXM) and complement-dependent cytotoxicity crossmatches (CDC) on all allograft recipients. [7] These tests were performed on samples obtained before treatment and after treatment.

Flow cytometry crossmatch

Three-color FCXMs were performed according to the method of Bray et al, [7] using a FACScan cytometer. T and B lymphocytes were stained with phycoerythrin-conjugated mouse monoclonal antibody specific for human CD3 and CD19, respectively. The presence of bound antibody was determined using a fluorescein isothiocyanate-conjugated (FITC) anti-human IgG. T-cell flow crossmatch results were expressed as mean channel shift (MCS) over background. T-cell crossmatches were considered positive at more than 50 MCS and B-cell flow crossmatches were considered positive at more than 100 MCS. [8] Pronase pre-treatment was used to treat the lymphocytes used in the FCXM to prevent a false-positive result due to the presence of anti-CD20 anti-body as previously described. [9]

Lymphocytotoxicity assay

An anti-human globulin-enhanced lymphocytotoxicity crossmatch assay (AHG-CDC) was performed by combining 1 μL of donor cells with recipient serum in a tray. The components were mixed and allowed to incubate for 30 min at room temperature. Following the incubation, the contents of the tray were washed three times with 10 μL 0.9% saline. 1 μL of anti-globulin was then added to the tray, followed by 5 μL of rabbit complement. The components were mixed and allowed to incubate at room temperature for 60 min. Following the incubation, 5 μL of ethidium bromide/acridine orange stain was added to the tray wells. Cell death was identified by penetration of the fluorescent dye into the cell. The lymphocyte cross-matching (LCXM) using AHG-CDC method ≥25% was considered positive, which is an absolute contraindication for transplantation. Autocross-matching was performed for all donors and recipients to exclude autoantibody as a cause of any positive crossmatch.

Recipient serum was also treated with dithioerythritol to exclude IgM antibodies when appropriate.

Panel reactive antibody

Panel reactive antibody (PRA) screening for anti-HLA antibodies pretransplant was also performed in the setting of any high-risk case for presensitization (patients with a history of blood transfusion, pregnancy, previous transplantation, child to mother or husband to wife donation). [10] PRA was done by the commercially available enzyme-linked immunosorbent assay (ELISA) technique for the detection of both HLA class I-and class II-specific antibodies. Because of the limited specificity of the B-cell flow crossmatch, PRA testing was also used to confirm the presence of class II antibodies in the serum. PRA detected by ELISA is more sensitive than the CDC assay. [11],[12],[13] The PRA results per se did not influence our decision whether or not to proceed with a specific living donor transplant; however, we assumed that high sensitization was associated with a higher risk of acute antibody-mediated rejection (AMR).

This was a prospective, open labeled, single-armed study carried out between December 2008 and April 2010. The study and written informed consent forms were approved by the Institutional Review Board. The higher risk of severe rejection and allograft loss was specifically discussed with all living donors and recipients. The risks associated with plasmapheresis, IVIg and a higher cumulative dose of immunosuppressant were discussed with all recipients. Patients who had a positive cross-match only by either T-or B-cell flow cytometric techniques but a negative cytotoxic cross-match were excluded from this analysis. Similarly, patients whose primary donor-specific anti-HLA antibody (DSA) was directed against class II [positive B-cell crossmatch (BCXM) combined with a negative T-cell crossmatch (TCXM)] also were excluded from this analysis. After these exclusions, 34 patients who were identified as having a positive AHG-CDC crossmatch (CMX) against their living donor and positive flow crossmatch were included in this analysis. Before transplantation, all patients were AHG-CDC crossmatch negative. Transplantation is performed when a negative or acceptable CMX is achieved which is defined as a negative CDC CMX with flow CMX positivity <200 channel shifts for T cells and B cells. [6]

Out of 390 renal transplant (RTx) patients, 8.7% (n = 34) were sensitized and were on the waiting list for transplantation since 0.92 ± 0.8 (range: 0.2-3.98) years. Out of these, 18 were males and 16 were females, with a mean age of 37.4 ± 12.2 years. Basic diseases were chronic glomerulonephritis (n = 18), lupus nephritis (n = 6), chronic tubulointerstitial nephritis (n = 4), autosomal dominant polycystic kidney disease (n = 3), diabetic nephropathy (n = 2) and Alport's syndrome (n = 1). Donors were 12 parents, eight extended family members, eight spouses and six sibs. Mean donor age was 43.7 ± 11.9 years; 16 were males and 18 were females. Mean HLA haplo-mismatch was 2.2 ± 1.4.

Sources of HLA sensitization

Mean dialysis duration was 14.9 ± 7.6 months. Two patients were candidates for second transplant. Average third party transfusions were 6.2 ± 4.5, 17.6% (n = 6) had autoimmune diseases and seven women (20.6%) were multi-para.

Desensitization protocol

All patients were subjected to desensitization protocol [Table 1] using bortezomib (1.3 mgm 2 , days 1, 4, 8, 11) with plasmapheresis, followed by hemodialysis and infusion of low-dose IVIg (5 g/day) on days 13, 16, 19, 22, followed by rabbit anti-thymocyte globulin (rATG) (1.5 mg/kg BW) on day 23. All patients were administered mycophenolate mofetil (MMF) (500 mg 2-3 times a day) to decrease the neoantigen response and it was continued post-transplant. Plasmapheresis (Cobe Spectra Version 7, Gambro, China) was performed by exchanging 60-80% of total plasma volume with 20% human albumin and normal saline (while maintaining replacement proportion of 40% colloid, 60% crystalloid). rATG (1.5 mg/kg BW) was given on day 23. LCXM and FCXM (T/B-CXM) were performed on day 24. If the CMX was negative or acceptable, patients were transplanted. If unacceptable, further desensitization protocol was carried out by administering Rituximab [375 mg/m 2 body surface area (BSA)] for persistent B-cell positivity (>200 MCS) on day 26, followed by bortezomib (1.3 mg/m 2 , days 29.33, 37, 40), and plasmapheresis followed by hemodialysis and infusion of low-dose IVIg (5 g/day) on days 43, 46, 49, 52. Calcineurin inhibitors (CNI) [cyclosporine (CsA) 3-5 mg/kg BW/day] or tacrolimus (0.05-0.08 mg/kg BW/day) were started in the event of TCXM positivity (>100 MCS) on day 26. (T/B-CXM) was once again repeated on day 53. If CMX was negative or acceptable, patients underwent RTx on day 54/55. If CMX was unacceptable, living donors were changed and deceased donor (DD) was considered. Complete blood counts and liver function tests were monitored.
Table 1: Algorithm for desensitization protocol.

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Immunosuppressive regimen

Induction immunosuppression consisted of r-ATG (1.5 mg/kg, single dose), and methylprednisolone (MP) 500 mg intravenously. MP was continued for three days postoperatively. [14] Maintenance immunosuppression consisted of prednisolone (30 mg/day tapered to 10 mg/day at 3 months post-transplant and continued thereafter) and CNI (tacrolimus 0.05-0.08 mg/kg BW/day or CsA 3-5 mg/kg/day) and MMF (1.5-2 g/day). MMF dose was adjusted according to CBC. Doses of CNI were adjusted as per trough levels. All patients received perioperative ceftriaxone 1 g twice a day × 3 days, prophylaxis against cytomegalovirus (CMV) infection (gancyclovir 1 g thrice a day × 3-6 months), fungal infections (fluconazole 100 mg once a day × 6 months) and Pneumocystis carinii pneumonia (trimethoprim/sulfamethaxazole 60/800 mg, once a day × 9 months post-transplant).

Diagnosis and treatment of rejection

In the event of unexplained rise in serum creatinine (SCr) or evidence of acute graft dysfunction, graft biopsy was performed and treated as per the requirement. Acute rejection: Increase in SCr to ≥20% above baseline SCr with histologic evidence of acute rejection defined by Banff 1997 criteria (update 2005). [15] AMR - As per Banff criteria, [16] biopsies consistent with AMR required two out of the three following characteristics: presence of DSA, histologic changes consistent with AMR, positive C4D staining in peritubular capillaries with or without structures. Acute cellular rejection (ACR): Defined by Banff 1997 criteria (update 2005). [15] Renal biopsies were reported using the Banff 1997 criteria (update 2005). [15] C4D immunohistochemical staining was performed on each biopsy, and all histological evaluations were performed by a single renal transplant pathologist. ACR was treated with three doses of MP 500 mg IV followed by r-ATG 1.5 mg/kg BW (single dose) in the absence of clinical response. AMR was treated with three doses of MP 500 mg IV, followed by plasmapheresis as per the response (in 4-8 sessions) alternating with IVIg 5 g/day for 5-10 doses. Rituximab (375 mg/m 2 BSA) as a single dose was given if patients did not respond to the above treatment. LCXM and flow crossmatch (FCM) were performed in the event of graft dysfunction and treated accordingly.

Monitoring for viral infections after transplantation

For all highly sensitized patients who received a kidney transplant, polymerase-chain-reaction assays for CMV, and polyomavirus BK were performed on whole-blood specimens monthly for the first 3-6 months after transplantation and then every 3 months until the end of the first post-transplant year, or whenever there is an unexplained rise in SCr, and after treatment for acute rejection, with appropriate clinical features. The methods used for monitoring viral replication have been described previously. [17],[18],[19]


   Results Top


Mean AHG-CDC was 55.3 ± 24.5% (range: 25-90%), TCXM, 122.4 ± 91.4 MCS (range: 0-295), BCXM, 279 ± 142.9 MCS (range: 0-529). PRA was 80-100% in all patients. Totally, 29 (85.3%) patients responded; 23 (67.7%) responded to first desensitization protocol of 30 days in which four doses of bortezomib, plasmapheresis, and IVIg were used along with r-ATG and MMF; and 6 (17.6%) patients responded after extended second protocol using additional four doses of bortezomib, IVIg, plasmapheresis, single dose of rituximab and CNI. In responders to post-desensitization protocol, AHG-CDC dropped to 19.9 ± 5.2% (range: 17-25%), TCXM to 24.7 ± 19.4 MCS, (range: 0-50) and BCXM to 74.7 ± 34.8 MCS (range: 0-100).

Profile of non-responders: Five (14.7%) patients with mean age 27.5 ± 7.5 years (3 males, 2 females) did not respond to desensitization. Cause of end-stage renal diseases was lupus nephritis in three patients. There were high-risk cases for pre-sensitization, being patients with history of blood transfusion, pregnancy, previous transplantation, and husband to wife donation.

These were highly sensitized patients with PRA of 80-100% in all of them. They had persistent high median BCXM >400 MCS, TCXM >240 MCS and AHG-CDC crossmatch ≥90%. They were transplanted after changing the living donors and using DDs, placing them on a priority list of DD transplantation.

Adverse effects of bortezomib were noted in the form of neuropathy in 2 (5.9%), gastrointestinal disturbance in 8 (23.5%), thrombocytopenia in 5 (14.7%), herpes in 2 (5.8%), and disturbed liver function tests in 2 (5.8%) patients. These were grade 1 as per National Cancer Institute Common Toxicity Criteria, and were manageable and reversible. [20],[21],[22] Urinary tract infection and pulmonary tuberculosis developed in two patients each at mean follow-up of 30 ± 10 days. CMV infection in one patient was noted at seven months post-transplant and none of the patients developed BK polyoma virus infection/malignancy.

Over a follow-up of 0.92 ± 0.8 (range: 0.22-2.64) years, mean SCr was 1.27 ± 0.32 (range: 0.9-1.95) mg/dL. Patient survival was 100% and graft survival was 88.2% (n = 25). The reasons for graft loss (biopsy proven) in four patients were acute hemolytic uremic syndrome in two patients (7 and 9 months after transplant), out of whom one also contracted CMV infection and the other HCV infection with associated complications; third patient had unexplained acute patchy cortical necrosis at one month and in the fourth patient pseudoaneurysm of graft artery occurred at three months after the transplant. ACR was noted in 6.9% (n = 2), AMR in 10.3% (n = 3) and both combined in 6.9% (n = 2) patients. All of them received IV MP 500 mg × 3 doses. T-cell rejection responded to IV MP, 500 mg × 3 doses + rATG. Two patients with AMR required plasmapheresis and IVIg.


   Discussion Top


Patel and Terasaki demonstrated in 1969 that RTx across positive CM barrier resulted in poor graft survival. [23] The significance of DSA was realized after this paper and paved way for invention of newer modalities for detecting DSA. Presence of cytotoxic lymphocytes or binding HLA antibodies in the patient's serum/PRA led to higher risk of hyperacute and accelerated rejection and also restricted the number of compatible donors. Patients with history of multiple pregnancies/transfusions, autoimmune disorders and previous transplantation are vulnerable to the development of HLA antibodies, making them high-risk candidates for transplantation. About 14% patients get enrolled in the waiting list for DD organ transplantation in the USA due to these risks, out of whom about 6.5% get transplanted. [6] High-dose IVIg protocol was evolved by Cedars Sinai group since it led to decreased incidence of allosensitization, ischemia reperfusion injury and acute rejections which eventually resulted in longer cardiac and renal allograft survival. [6],[24],[25] For patients not responding to IVIg regime for four doses (once a month), they modified the protocol by adding plasmapheresis and rituximab to achieve success in all sensitized patients. [26] Johns Hopkins University group hospitals had individualized the protocol for sensitized patients in which they used IVIg with CMV-Ig and a cocktail of immunosuppressive agents ± plasmapheresis/ splenectomy. [6] National Institutes of Health conducted the IGO2 study that was a controlled, clinical, multicenter, double-blinded trial of IVIg versus placebo in highly sensitized patients waiting for kidney transplantation and showed that IVIg group was transplanted after four years versus ten years waiting period of placebo group. Rejections were also less and graft survival also improved. [27] However, all these studies have shown that desensitization still took very long time for making patients "transplantable". The sensitized patients received five plasmapheresis treatments over three weeks in Cedars-Sinai Medical Center and low-dose CMV-Ig (100 mg/kg) after each plasmapheresis in Johns Hopkins University Hospital. [6] Similarly, we used low-dose IVIg after each plasmapheresis in our protocol as IVIg is an expensive therapy and specific IVIg products have toxicity at high doses (i.e., sucrose and saline excipient products). [6] MMF has been shown to decrease the response to neoantigens in the transplant population. [28]

This pilot study presented by us shows encouraging results at least on short-term follow-up. We believe that addition of bortezomib to the gamut of desensitization protocol has proved more effective and safe since bortezomib acts on long-and short-living plasma cells of the memory bank which are resistant to other modes of deletion. [29],[30] Our study shows that addition of bortezomib to the desensitization protocol has rendered high success rate with acceptable patient and graft survival to otherwise non-transplantable patients and has shown minimal side effects. Bortezomib may offer new possibilities in desensitization strategies. [18],[31],[32],[33],[34] Data from the US Renal Data System (2003) also confirm that a considerable cost saving to Medicare is seen in highly sensitized patients who receive a transplant versus those who remain on dialysis. [35]

The PRA value is generally considered to represent a patient's "transplantability index". It is important not to rely on one method for the detection of PRA as each method has its own advantages and disadvantages. If PRA and antibody specificity are determined on a series of patient sera, this can greatly help in predicting the crossmatch results. [10] Even in patients who receive zero mismatches at HLA-A, -B and -DR benefit from regular screening and anti-body characterization. Antibodies specific to HLA Cw, DQ and even DP have been shown to influence graft outcome. PRA activity was associated with graft survival in that patients with low PRA had significantly superior graft survival than those with high PRA.[10],[11],[12],[13]

Lack of protocol biopsies due to unwillingness of patients, lack of DSA determinations and lack of routine post-transplant crossmatches due to high cost (solid-phase crossmatch assays), absence of comparison with non-sensitized controls and short follow-up are the limitations of this study. Multi-centric randomized and controlled clinical trials are required not only to firmly conclude the superiority of bortezomib containing desensitizing protocol in comparison with classical strategies including plasmapheresis, IVIg and/or rituximab, but also to evaluate the long-term safety regarding infections and cancers.

Our desensitization protocol is safe and effective. Bortezomib may offer new possibilities in desensitization protocol. This study can possibly usher in multi-centric randomized and controlled clinical trials.

 
   References Top

1.Jordan SC, Tyan D, Stablein D, et al. Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end stage renal disease: Report of the NIH IGO2 trial. J Am Soc Nephrol 2004;15:3256-62.  Back to cited text no. 1
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2.Montgomery RA, Zachary AA, Racusen LC, et al. Plasmapheresis and intravenous immunoglobulin provides effective rescue therapy for refractory humoral rejection an allows kidneys to be successfully transplanted into cross-match positive recipients. Transplantation 2000;70: 887-95.  Back to cited text no. 2
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3.Tyan DB, Li Va, Czer L, et al. Intravenous immunoglobulin suppression of HLA alloantibody in highly sensitized transplant candidates and transplantation with a histo-incompatible organ. Transplantation 1994;57:553-62.  Back to cited text no. 3
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20.Bladé J, Samson D, Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998;102(5):1115-23.  Back to cited text no. 20
    
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23.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. 23
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Correspondence Address:
Vivek B Kute
Department of Nephrology and Clinical Transplantation, IKDRC-ITS, Ahmedabad
India
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