|Year : 2021 | Volume
| Issue : 5 | Page : 1289-1299
|Pretransplant donor-specific anti-human leukocyte antigen antibodies despite a negative complement-dependent lymphocytotoxicity crossmatch: Is it wise to desensitize before kidney transplant?
Mohamed Abdel Monem1, Torki Al Otaibi1, Amin Roshdy Soliman2, Merfat Elansary3, Mona Aziz Ibrahim4, Bahaa-Eldin Zayed2, Osama Ashry Gheith5, Ayman Maher Nagib5, Khaled Abdel Tawab1, Yahya Makkeyah6, Zakaria Elsayed Zakaria1, Medhat A Halim1, Tarek Mahmoud1, Prasad Nair1
1 Department of Nephrology, Hamed Al-Essa Organ Transplant Center, Ibn Sina Hospital, Sabah Area, Kuwait
2 Department of Internal Medicine and Nephrology, Faculty of Medicine, Cairo University, Egypt
3 Clinical Pathology Department, Faculty of Medicine, Cairo University, Egypt
4 Clinical Pathology Department, Faculty of Medicine, Cairo University, Egypt; Department of Immunology, Behbehani Center, Kuwait
5 Department of Nephrology, Hamed Al-Essa Organ Transplant Center, Ibn Sina Hospital, Sabah Area, Kuwait; Department of Dialysis and Transplantation, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
6 Nephrology Department, North West Anglia NHS Foundation Trust, Peterborough City Hospital, Peterborough, UK
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|Date of Web Publication||4-May-2022|
| Abstract|| |
The significance of pretransplant donor-specific antibodies (DSAs) despite negative complement-dependent lymphocytotoxicity crossmatch (CDC-XM) would be useful for clinical decision-making. Hence, we aimed to determine the impact of pretransplant DSA despite negative crossmatch on the outcome of kidney transplantation. One hundred and eleven kidney recipients were prospectively enrolled in this study after being transplanted at Hamed Al-Essa Organ Transplant Center of Kuwait between January 2011 and December 2013. Of them, 50 recipients with positive DSA at the time of transplant were subjected to desensitization (Group 1). Three local protocols were utilized; first included plasma exchange, high-dose intravenous immunoglobulin (IVIG), and rituximab; second included immunoadsorption plus RTX, and the third included high-dose IVIG and rituximab. The second group included 61 recipients with negative DSA. All recipients had negative CDC-XM and flow cytometry crossmatch at the time of transplant. Panel-reactive antibody (±DSA) levels with mean fluorescence intensity and graft function were monitored along the first 24 months for all patients. There were no statistically significant differences between the two groups regarding early posttransplant graft function, patient and graft survivals. Pretransplant DSA with negative CXM carries a minimal clinical risk with optimized immunosuppression.
|How to cite this article:|
Monem MA, Al Otaibi T, Soliman AR, Elansary M, Ibrahim MA, Zayed BE, Gheith OA, Nagib AM, Tawab KA, Makkeyah Y, Zakaria ZE, Halim MA, Mahmoud T, Nair P. Pretransplant donor-specific anti-human leukocyte antigen antibodies despite a negative complement-dependent lymphocytotoxicity crossmatch: Is it wise to desensitize before kidney transplant?. Saudi J Kidney Dis Transpl 2021;32:1289-99
|How to cite this URL:|
Monem MA, Al Otaibi T, Soliman AR, Elansary M, Ibrahim MA, Zayed BE, Gheith OA, Nagib AM, Tawab KA, Makkeyah Y, Zakaria ZE, Halim MA, Mahmoud T, Nair P. Pretransplant donor-specific anti-human leukocyte antigen antibodies despite a negative complement-dependent lymphocytotoxicity crossmatch: Is it wise to desensitize before kidney transplant?. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 May 25];32:1289-99. Available from: https://www.sjkdt.org/text.asp?2021/32/5/1289/344748
| Introduction|| |
Preformed anti-human leukocyte antigens (HLA) antibodies have a major negative impact on allograft survival, forming a significant barrier in renal transplantation. Binding of such anti-HLA antibodies to antigens on endothelial cells results in alloantibody-mediated tissue injury and subsequently allo-graft rejection. Several immunological tests are carried out to reduce this risk in renal transplant recipients.
Complement-dependent lymphocytotoxicity (CDC) crossmatch (XM) has been routinely used to detect preformed, donor-specific complement-fixing antibodies. However, antibody-mediated rejection does occur in some patients with a negative crossmatch, signifying that the standard CDC assay lacks sensitivity in detecting clinically significant antibodies. Recent new tests which utilized purified HLA molecules coated on microbeads, Luminex single-antigen beads, are being used widely. It is highly sensitive that can detect very low levels of HLA antibodies, and it is highly specific that can determine antibody specificities more accurately.
Anti-HLA antibodies developed in the recipient’s immune system as a result of a sensitization event pretransplant (blood transfusion, previous transplant, or pregnancy). Monitoring of posttransplant clinically relevant antibodies directed against donor-specific HLA Class I and Class II mismatches has been a significant area of interest within the transplant community.
The presence of untreated donor-specific antibody (DSA) HLA antibodies results in an immune attack on the transplanted organ, and increases risk of graft loss and/or acute antibody-mediated rejection (ABMR) by attacking the vascular endothelium of the allograft.,,,
Routine monitoring of DSA may provide early detection of patients at risk for rejection due to inadequate immunosuppression as a result of their poor compliance. The introduction of solid-phase assays to assess anti-HLA antibodies as well as C4d staining for evaluation of allograft biopsies has reformed the current era of assessing acute and chronic DSA-mediated rejection in the field of transplantation. Preformed, DSA HLA antibodies are responsible for some renal allograft rejections. Their detection prior to transplantation is an important step to exclude incompatible donors. The significance of pretransplant DSA despite a negative XM remains controversial.,, Assessment of the impact of DSA on allograft outcome in a prospective trial will be unethical as it will carry high risk.
During the past 10 years, the development of desensitization protocols has explored the possibility of renal transplantation across DSA and has demonstrated encouraging short-term outcomes in highly-sensitized transplant candidates. Desensitization regimens including the use of intravenous immunoglobulin (IVIG) and rituximab have been shown to overcome DSA and ABMR. In 2003, Jordan et al reported that an IVIG treatment could inhibit crossmatch positivity and allow for successful transplantation. In addition, Gloor et al developed a desensitization regimen, including pretransplant plasma exchange, IVIG, rituximab, and splenectomy to overcome live donor kidney transplantation with positive crossmatches. However, chronic ABMR after renal transplantation remains a serious concern, and the risk of infectious and neoplastic complications after desensitization, such as BK virus-associated nephropathy and urothelial carcinoma, need to be properly addressed.,,, With success of ABO-incompatible renal transplantation following rituximab use instead of splenectomy, our transplant center developed a desensitization protocol for live donor renal transplantation with DSA in 2007 that included plasmapheresis, IVIG, and rituximab.
| Aim|| |
The aim of our study was to determine the impact of pretransplant donor-specific HLA antibodies detected by Luminex, despite a negative CDC-XM, on the outcomes of kidney transplantation up to 24 months.
| Patients and Methods|| |
This prospective open-label study was conducted in Hamed Al-Essa Organ Transplant Center between January 2011 and December 2013. The study comprised 111 kidney transplant recipients who were categorized into two groups. Patients with positive DSA at the time of transplantation and were subjected to desensitization protocol represented Group I (n = 50), while those who had negative panel-reactive antibody (PRA) at the time of transplantation represented Group II (n = 61). We excluded patients with positive CDC-XM and/or flow cytometry crossmatch (FCXM), unfit patients for renal transplantation, patients with ejection fraction <40%, and those who refused to participate in the study.
All patients had negative CDC-XM and FCXM with their donors for both T-cell and B-cell at the time of transplantation. All patients were subjected to detailed history taking, clinical examination, and laboratory investigations with special stress on baseline PRA and DSA (for all the patients and at the time of transplantation and at 3, 6, 12, and 24 months intervals (MFI above 1500 was considered positive). Moreover, serum creatinine and proteinuria were checked at the same time intervals.
For patients in Group 1, desensitization methods included three local protocols: protocol 1 included plasma exchange, high-dose IVIG, and rituximab; protocol 2 included immune-adsorption and rituximab; while protocol 3 included high-dose IVIG and rituximab.
Protocol 3 was used in patients with DSA against only one HLA locus. While the choice between protocols 1 and 2 were randomly adjusted to local logistics. The ratio was 2:1, i.e., two cases using protocol 1 followed by one case using protocol 2.
Immunosuppressive medications were started seven days prior to renal transplant, in the form of mycophenolate mofetil (MMF) 500 mg twice daily and tacrolimus 0.05 mg/kg per day on two divided doses. One volume plasma exchange was performed using Fresenius multifiltrate machine (total 8 sessions: 4 pretransplant and 4 posttransplant). Fresh frozen plasma or human albumin was used as replacement based upon daily coagulation profile of the patient. Similarly, immuno-adsorption (used in the 2nd protocol) was performed using the Fresenius immuno-adsorption system (total 8 sessions: 4 pretransplant and 4 posttransplant).
A single dose of rituximab was given postoperatively on day 0 (375 mg/m2). Routine investigations before giving rituximab included complete blood picture, kidney function tests, blood culture and sensitivity, urine culture and sensitivity, chest X-ray, and electrocardiograph. The premedications in the form of injection methylprednisolone 250 mg in 100 mL normal saline over 30 min, injection hydrocortisone 100 mg intravenous, chlorpheniramine maleate 2 mg tablet, and tablet paracetamol 1 g. The total dose was added to 450 mL normal saline (1 mL = 1 mg). Infusion was given slowly as follows: in the 1st h 50 mL/h; next 30 min 75 mL/h, and then increased by 25 mL each 30 min till the end of the infusion. High-dose IVIG (2 g/kg with maximum 120 g) was given on two divided doses on days 2 and 1.
Our immunosuppression protocol consisted of five doses of antithymocyte globulin (Sanofi US, Bridgewater, NJ, USA) or 2 doses of IL-2 receptor blocker (Basiliximab; Novartis, Inc., Switzerland) based on immuno-logical risk stratification. Also, maintenance therapy consisted of prednisolone, MMF, and a calcineurin inhibitor (CNI). The dose of CNI was gradually decreasing till the lowest dose by the end of the 1st year guided by 12-h trough level. All patients were given cytomegalovirus (CMV) and Pneumocystis pneumonia prophylaxis for six months in an adjusted dose according to estimated glomerular filtration rate.
Diagnosis and treatment of rejection
T-cell mediated rejection (TCMR) was treated with intravenous methylprednisolone sodium succinate (1 g/day for 3 days) and or thymoglobulin (1 mg/kg for 7–10 days) for steroid-resistant rejection. Acute antibody-mediated rejection was treated with plasma exchange (10 sessions), IVIG (2 g/kg), and single dose of rituximab (375 mg/m2). All rejection episodes were biopsy-proven according to Banff 2013 criteria.
Pretransplant donor-specific CXM was performed by the standard CDC technique using dithiothreitol (DTT) to inactivate immunoglobulin M antibodies. FCXM was performed using BD FACS Canto II system. Detection of PRA, DSA, and HLA typing was performed using Luminex® 100™ IS system. Luminex 100 IS technology is based on flow cell fluorometry with Luminex-developed innovations. The fluidics, optics, robotics, temperature control, software, and xMAP microspheres work together to enable simultaneous analysis of up to 100 analytes in a single test sample.
| Statistical Analysis|| |
Data were analyzed on an IBM personal computer, using IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, USA. Data were described as mean ± standard deviation (SD) for quantitative (Numerical) variables and as frequency and percentage for qualitative (categorical) variables. T-test was used to compare the continuous data between the two groups, while noncontinuous data were compared using Mann–Whitney U-test. Categorical data were compared using Chi-square test. Qualitative data were displayed in cross-tabulation and quantitative data were described in terms of arithmetic mean SD. Bivariate techniques were used for initial evaluation of contrasts. P <0.05 was considered statistically significant.
| Results|| |
There was a significant difference between the two groups regarding recipients gender distribution as males were 16% in Group 1 vs. 67.2% in Group 2 (P <0.001), while the two groups were comparable regarding mean age of the recipients (44.16 ± 14.9 years in Group 1 vs. 40.62 ± 16.2 years in Group 2), original kidney disease, and pretransplant comorbidities (including hypertension, diabetes mellitus, ischemic heart disease, hepatitis C infection, and latent tuberculosis). There was no significant difference between the two groups regarding cases with chronic hepatitis C or early posttransplant graft function (P >0.05) [Table 1].
Only 10 patients in Group 2 received their grafts from cadavers (P <0.05), while other patients in the two groups were matched regarding the type of living donors (P >0.056) [Table 1]. Moreover, preemptive transplantation was accounting for 70% in Group 1 and 23% in Group 2, hemodialysis was accounting for 26% in Group 1 and 69% in Group 2 (P <0.05), while peritoneal dialysis was accounting for 4% in Group 1 and 8% in Group 2 (P >0.05).
Most patients of Group 1 (98%) received induction with thymoglobulin vs. 44.25% in Group 2, while basiliximab was accounting for 2% in Group 1 (allergic cases to thymoglobulin) versus 41% in Group 2. Also, the majority of patients were maintained on tacrolimus-based maintenance immunosuppression (96%) compared to cyclosporine-based regimen (36%) in Group 2 (P ≤0.001) [Table 1].
There was no statistically significant difference between the two groups regarding post-transplant diabetes mellitus (P = 0.13, [Table 2]).
Bacterial infections [urinary tract infection (UTI) and non-UTI] were significantly more common in Group 1 (26% and 12% vs. 14.7% and 3.2% in Group 2 respectively) (P <0.05, [Table 2]). It is worth mentioning that most of infection episodes developed among desensitized group of patients who received PE, IVIG and rituximab. However, there was no statistically significant difference between the two groups regarding posttransplant viral infections.
Regarding event graft biopsies, we found that ATN was significantly more common in Group 2 and ABMR (which developed in during the 1st 3 months’ posttransplant) was, significantly more prevalent in Group 1 (P <0.05, [Table 1]) in spite that the prerejection MFI level of DSA was below 3000 in all cases [Figure 1]. However, we found no significant difference between the two groups regarding TCMR or the mean number of acute rejection episodes (1.2 ± 0.56 episode in Group 1 and 1.125 ± 0.35 episode in Group 2) (P >0.052, [Table 2]).
|Figure 1: Posttransplant follow-up of MFI of DSA against HLA loci in Group I at different intervals.|
DSA: Donor-specific antibody, HLA: Human leukocyte antigen.
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We found no statistically significant difference between the two groups regarding the graft or patient outcomes at the end of 24-month follow-up (P >0.05, [Table 3]).
|Table 3: Follow-up of graft function and transplant outcome among studied groups of patients.|
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Moreover, analysis of Group 1 with different desensitization protocols revealed no statistically significant difference in the graft or patient outcomes at the end of 24-month follow-up (P >0.05, [Table 3]).
There was so statistically significant difference between the two groups concerning graft function as represented by serum creatinine at different time intervals (P >0.05, [Table 3]). Moreover, we found that the two groups were comparable regarding level of proteinuria at the same time intervals (P >0.05, [Table 3]).
There was no statistically significant difference between the two studied groups when comparing the mean number of HLA mismatches.
There was a statistically significant difference between the two studied groups when comparing the mean PRA positivity for both Class I and Class II anti-HLA antibodies at baseline and during follow-up intervals. Also, there was a statistically significant difference between the two studied groups when comparing the mean MFI against HLA (A, B, DR, DQ) at baseline and during follow-up.
There was no statistically significant difference when comparing mean MFI of different DSAs against HLA A, B, DR, and DQ during follow-up period among different desensitization protocols [Figure 1].
| Discussion|| |
Acute renal allografts rejection is still considered a major problem, especially in sensitized patients, despite the potent immunosuppression. DSA represents one of the risk factors related to rejection. Luminex single-antigen beads with its high sensitivity were found to detect very low levels of HLA Abs. Moreover, it is capable of defining antibody specificities more accurately. However, the clinical significance of pretransplant DSA detected by Luminex despite negative CDC-XM was not investigated properly regarding its usefulness for clinical decision making.
In our study, we aimed to evaluate the risk-benefits of management of renal transplant recipients with pretransplant donor-specific HLA antibodies (DSA) – detected by Luminex despite a negative CDC-XM-compared to control group with negative DSA.
In Hamed Al-Essa Organ Transplant Center of Kuwait, cases with pretransplant DSA during the period between 2011 and 2013 represented 23.8% which was similar with the percentage (25%) reported by Adebiyi et al. However, such incidence was variable (5%–33%) in different reports,,,, possibly due to various factors, including the use of different MFI cutoffs for HLA antibody positivity, the sensitivity and specificity of different antibody detection methods, and the DSA HLA loci included in the analysis. Our DSA incidence (23.8%) is higher than the number of reports of pretransplant DSA formation, because we adopted lower threshold of 1500 MFI for positive results.
In addition, pretransplant DSA with a negative FCXM did not significantly impact acute rejection rates, graft function (GFR or proteinuria) or intermediate-term graft survival.
The studied groups were comparable regarding mean age (44.16 ± 14.9 years in Group 1 vs. 40.62 ± 16.2 years in Group 2). Females predominate in Group 1, while males predominate in Group 2 ([Table 1], P <0.05). This logic finding was matched with that reported by Yang and Yoo who observed significantly more female patients in the DSA group than in the non-DSA group (P = 0.005). This observation could be explained by the risk of sensitization with repeated pregnancies and possible blood transfusions.
In the current study, we used thymoglobulin in 27 patients versus basiliximab in 25 patients of the control group. In subgroup analysis, we found no significant difference between the subgroups regarding acute rejection, posttransplant DSA levels, and both graft and patient outcomes. Recent supporting data raise questions about the need for IL2-receptor blockers in kidney transplantation, as it may no longer be advantageous in standard-risk transplant patients and even may be lower to ATG in high-risk patients. Updated evidence-based guidelines are needed to support the decision concerning the induction therapy for transplant patients today.
From our study, we observed that the prevalence of acute antibody-mediated rejection (ABMR) was significantly higher in Group 1 (positive DSA and negative CXM group) but without significant negative impact on either the graft or the patient outcome. Similar observations were reported by David-Neto et al in 2012, who showed that patients with pretransplant DSA with a negative CDC crossmatch were associated with high risk for development of AMR, although survival rates were similar when patients transpose the 1st month after transplant. Also, they added that early posttransplant DSA monitoring should increase knowledge of antibody dynamics and their impact on the long-term graft outcome.
We also found that the incidence of acute rejection during 1st year was 38% in Group 1 versus 18% in Group 2 with significantly higher incidence of acute ABMR in the 1st group (22% vs. 8.1% respectively, P = 0.046).
This finding was observed by David-Neto et al, who reported comparable incidence of ABMR in their study. On the other hand, this was lower than that reported in other studies, particularly in patients with strongly positive DSA and a historic positive crossmatch. One explanation for this difference might be due to the low levels of DSA in our population, which were evidenced by the negative pre-transplant CDC-and flow crossmatches of the included patients. Moreover, we did not report any early graft loss due to acute ABMR – as that mentioned in the previous study by David-Neto et al – likely due to early and aggressive management.
The ABMR rates vary from one study to another; in one large retrospective study, the prevalence of ABMR was only 2%, and all patients with ABMR had at least one strong donor-specific DSA with an MFI value >6000. Patel et al reported ABMR in 50% (8/16 patients) of their patient cohort with recurrent pretransplant DSA. This difference in the incidence of ABMR could be due to different risk stratification in different transplant centers.
In our study, desensitization protocol was applied to all DSA cases (50 patients). We found that pretransplant mean DSA MFI had ranged between 3276 to 3841 immediately before transplant with higher incidence of acute rejection during 1st year (38% in Group 1 vs. 18% in Group 2) and significantly higher incidence of acute ABMR in the same group but without significant impact on graft outcome. This finding was nearly similar to the levels detected at any time prior to transplant in the report by Adebiyi et al They denoted significantly higher AR risk in multivariable analysis but without inferior graft survival (n = 660, 162 with DSA) with negative T-cell and B-cell FCXM and none of them received desensitization therapy.
When taking the class of pretransplant DSA into consideration, Willicombe et al reported worse ABMR-free survival in patients with class II or mixed-class antibodies compared to those without pretransplant DSA. Patients with reported ABMR had higher MFI strength (mean 4089 vs. 2328 in those without, P = 0.046).
Our study shows an increased one-year risk of AR in patients with pretransplant DSA MFI ≥3000 without an impact on two-years death or graft survival. We did not find a significant association between DSA detection time in relation to transplant and graft outcomes. In contrast, Lefaucheur et al showed an increased risk of ABMR when DSA is present both historically and at the time of final crossmatch compared to historical DSA only (40% vs. 27%); however, the patients in this study did not undergo FCXM testing.
Two years graft outcome was comparable in both groups despite the use of deceased donors in Group 2 (16.3%) (P <0.05). This result was not similar to that reported in other studies which established superior outcomes of live-donor transplantation independently of HLA matching and donor or recipient characterristics.,, The comparable graft outcome in our study might be attributed to the desensitization programs for the patients in group.
However, our results were similar to the data reported by Ribeiro et al that showed that sensitized patients who received ATG had similar or lower incidence of acute rejection episodes when compared with non-sensitized patients not receiving ATG, these patients had similar safety profile, graft and patient survivals at one year. Brokhof et al reported – even in moderately sensitized renal transplant recipients – that induction with ATG was associated with a reduction in the occurrence of de novo DSA and ABMR when compared with basiliximab.
Among our patients, we found no significant difference between the sensitized and nonsensitized patients as regards graft and patient outcome possibly due to our desensitization and immunosuppression protocol in addition to close regular monitoring. These findings were comparable to many studies that denoted that tacrolimus-based regimens had superior allograft survival and rejections vs. cyclosporine-based regimens, however, significantly higher rates of PTDM developed in patients receiving low-dose tacrolimus compared to cyclosporine- and sirolimus-based regimens. Moreover; tacrolimus was associated with significantly lower rates of acute rejection and corticosteroid-resistant rejection, at two years found that the composite endpoint of allograft loss, patient death, and biopsyproven acute rejection was significantly lower with tacrolimus.
Finally, we observed that patients with bacterial infection (either UTI or non-UTI) were significantly higher in desensitized DSA group, especially those who received PE, IVIG, and rituximab. (38% vs. 18%, P = 0.046) and the majority of cases were UTI. This observation could be explained by the potent immunosuppression received by such group of patients. However, we found nonsignificant rise in the number of patients with posttransplant viral infections, especially CMV (32% vs. 16.3%) (P >0.05). The higher rate of viral infections in our desensitized patients despite prolonged CMV prophylaxis and comparable rate of acute rejection episodes to other studies could be explained by the aggressive desensitization protocol used among our patients (PP, high-dose IVIG, rituximab, and thymoglobulin in our study vs. IVIG alone or combined with PP). We did not report any case of malignancy among our patients over 24-month follow-up. This was similar with the results of previous three studies.,,
| Conclusion|| |
Pretransplant DSA with negative FCXM carries a minimal clinical risk-especially with optimized immunosuppression – for both graft and patient survival. We suggest desensitization therapy for those patients exhibiting higher levels of donor-specific immunologic risk.
Conflict of interest: None declared.
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Osama Ashry Gheith
Department of Dialysis and Transplantation, Urology and Nephrology Center, Mansoura University, Mansoura
Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3]
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