Objectives: Kidney transplant is the treatment of choice for end-stage renal disease. Because of the insufficient supply of donor organs for transplant, the number of patients on the transplant wait list is increasing. We analyzed demographic and clinical factors including sensitization status of patients on the kidney transplant wait list in our center.
Materials and Methods: Patients on the kidney transplant wait list at Ankara University School of Medicine by July 2018 were evaluated. Data on demographics, comorbidities, treatment characteristics, and immunologic properties were collected.
Results: The study included 528 kidney transplant candidates whose mean time on the deceased donor organ wait list was 57 ± 47 months. Enlisted patients were aged 53 ± 13 years, and 95% of them were on dialysis. Dialysis vintage was longer and percentage of patients who had anti-HLA antibodies was higher in women than men (P = .004 and P < .001, respectively). Levels for median fluorescence intensity were higher in women compared with men (class I, P < .001; and class II, P = .011). Transfusion (P < .001), pregnancy (P = .001), transplant (P < .001), longer dialysis vintage (P = .021), and longer time on wait list (P = .001) were associated with anti-HLA antibody positivity. Multiple regression analysis revealed that a history of transplant and blood transfusion were independent risk factors of a positive panel reactive antibodies.
Conclusions: In our kidney transplant candidates on the wait list, sensitization by transplant has a significant impact on development of anti-HLA antibodies. Updates of the organ allocation system to consider sensitized candidates and strategies to expand the deceased donor organ pool and donation rates are needed to increase the rate of deceased donor kidney transplant in Turkey.
Key words : Anti-HLA antibodies, End-stage renal disease, Sensitization events, Solid-organ transplant
Kidney transplant (KTx) is the treatment of choice for patients with end-stage renal disease (ESRD) because of improved quality of life and reduced mortality risk compared with maintenance dialysis.1 The first successful KTx took place in Turkey in 1975. Deceased donor organ allocation policies and the national wait list for deceased donor organs were constituted in 2000.2 Since then, kidneys have been allocated to patients on the wait list against whom the donor has no incompatible antigens at either the HLA-A,HLA-B, or HLA-DR loci. If there were no zero-antigen mismatch patients, then kidneys were allocated according to a point score calculated for each ABO-compatible patient. In such a case, one of the kidneys is given to the donor center, and the other is offered to a transplant center determined according to matching and scoring processes. Point scores are calculated according to HLA matching score (for each HLA-DR match, 150 points; HLA-B, 50 points; HLA-A, 25 points), region (1000 points), center (250 points), dialysis vintage (3 points for each month), and recipient age (HLA matching score ×2.5 for ≤11 years, ×1.5 for 12-17 years). According to the Registry Report, the number of patients who underwent KTx in 2018 was 3817 in Turkey, only 20% of whom received organs from deceased donors.3 The total number of patients awaiting KTx is 22 800 in Turkey, and every year new patients are added to the wait list.4 As in other countries with a low number of deceased donor KTx, efforts for expansion of the donor pool and avoidance of the inequities in access to KTx are needed in our country.
Pretransplant anti-HLA antibody positivity, which is associated with increased risk of antibody-mediated rejection and reduced graft survival, is a significant obstacle in KTx.5 The wait time for a suitable donor is longer for presensitized patients, dependent on the percentage of panel reactive antibodies (PRA), and longer wait time on dialysis is associated with poor graft and patient survival.6,7 The sensitization events, such as blood transfusions, previous transplants, and pregnancy are responsible for higher prevalence of anti-HLA antibodies.8-11 Evaluation of the KTx candidate’s clinical and sensitization status is important to decide the appropriate renal replacement treatment. In this study, we analyzed demographic and clinical factors including sensitization status of patients with ESRD on KTx wait list and aimed to discover sensitization risk factors in our center.
Materials and Methods
We evaluated 528 patients who were on deceased donor KTx wait list of Ankara University School of Medicine, Ibni Sina Hospital by July 2018. Patients’ demographic and clinical features and laboratory and transplant data were collected. Screen for PRA and identification tests were performed with Luminex assay kits (Luminex Corporation) according to the manufacturer’s guidelines. Screening tests for PRA were performed in all candidates, with the use of sera collected every 6 months while on wait list. Positivity for PRA was defined as >5%, with identification of only IgG anti-HLA isotype-positive cases after dithiothreitol treatment. Positive samples from the screen were further tested for the identification of class I (A, B, and C) and class II (DRB1, DQA1, and DQB1) antibodies. For single antigen assays, cutoff level was defined as a raw median fluorescence intensity (MFI) of ≥500. Antibody strength was also graded into weak (500-2999 MFI) and moderate-strong (≥3000 MFI). In the present study, patients with PRA >5% and antibody strength >500 MFI were considered as positive for anti-HLA antibody. HLA alloimmunization was analyzed according to different sensitization events.
The study was approved by the Ethical Review Committee of the Ankara University. All of the protocols conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Informed consent was obtained from all participants included in the study.
Statistical analysis was performed with SPSS software (version 16). Continuous data are described as mean values ± SD, and categorical data are expressed as number of patients and percent of total patients. The Pearson chi-square or the Fisher exact test was used to compare the nonparametric data, and a t test was used for comparison of parametric variables. Binary logistical regression tests were performed to determine the association with positivity of PRA. A value of P < .05 was considered statistically significant.
Patients’ clinical features according to sex
We evaluated 528 potential KTx recipients on the deceased donor organ wait list. Enlisted patients were aged 53 ± 13 years, and most of them were male (55.7%) (Table 1). The most common causes of ESRD were hypertensive renal disease, diabetic kidney disease, and glomerulonephritis, and in 12% of candidates the ESRD cause was unknown. Prevalence of hypertension was high, followed by diabetes and cardiovascular disease. Cardiovascular diseases were more frequent in men than in women (P = .010). Most of the candidates were on dialysis (95%), and the most preferred modality was hemodialysis (HD). Primary arteriovenous fistula was used for HD access in 89% of patients. Mean dialysis vintage was 70 months and significantly longer in women than men (P = .004). Mean time on wait list was 57 ± 47 months. As no statistically significant difference was established according to sex, women had remarkably longer wait times than men (P = .087).
Sensitization events and status according to sex
There was a history of transfusion in 273 patients (51.0%), and the prevalence was higher in women than men (P = .003) (Table 1). The mean red blood cell transfusion units were comparable (3.9 vs 4.1 units, respectively; P = .742). There were 53 patients who had a history of transplant (10.0%), and no significant difference was established according to the sex (P = .562). Of the women, 80% (n = 187) had a history of pregnancy.
Class I and/or II anti-HLA antibody positivity was detected in half of our patients. In anti-HLA antibody-positive patient group, the number of women (52.3%) was higher than the number of men (47.7%) (P < .001). Mean MFI levels were higher in women compared with men in patients of whom anti-HLA antibody strength was >500 MFI (means ± SE: class I, 5005 ± 549 vs 2223 ± 294 [P < .001]; class II, 5618 ± 639 vs 3513 ± 504 [P = .011], respectively). Levels of class I and/or class II anti-HLA antibodies ≥3000 MFI were more frequent in women than in men (26.2% vs 9.9%, respectively; P < .001). Anti-HLA antibody positivity rates were significantly higher in patients with a history of transplant (86.8%), pregnancy (58.3%), and blood transfusion (57.1%) than patients without each sensitization event (44.2%, 43.1%, and 39.2%, respectively). After the anti-HLA antibody status was evaluated in 4 groups (negative, class I positive, class II positive, and class I and II positive), the effect of sensitization events on anti-HLA positivity remained significant (P < .001, P = .004, and P < .001, respectively) (Table 2). Age, maintenance on dialysis, number of pregnancies, and number of transfusions were not associated with sensitization status. Dialysis vintage and mean time on wait list were longer in patients who had anti-HLA antibody positivity (negative vs positive for class I and/or II: mean dialysis vintage, 65 ± 55 vs 77 ± 61 months [P = .021]; mean time on wait list, 51 ± 44 vs 65 ± 50 months [P = .001], respectively).
The logistic regression model included sex, dialysis vintage, time on wait list, history of blood transfusion, organ transplant, and pregnancy and revealed that previous transplant and transfusion history were independent risk factors of a positive PRA (Table 3).
We described clinical characteristics and immunologic profile of our patients on KTx wait list in this cross-sectional study, which can be helpful to interpret the properties of candidates in Turkey. We demonstrated that women had longer dialysis vintage and longer wait time on the list and higher prevalence of anti-HLA antibody positivity and mean MFI levels than men. Although female sex, blood transfusion, pregnancy, organ transplant, longer dialysis vintage, and longer wait time were associated with anti-HLA antibody positivity in our candidates on the wait list, previous transplant and transfusion history were the independent factors.
According to US and United Kingdom registries, nearly half of KTx wait list patients were aged 50 to 64 years.12,13 In addition, the average age of enlisted candidates in Canada, Europe, and the Far East has been reported to be between 48 and 52 years.8,14-16 In Turkey, 40% of HD patients and 42% of peritoneal dialysis patients were aged 45 to 64 years.3 Compatible with this data, we determined that the mean age of our KTx wait list patients was 53 years.
Diabetic kidney disease, hypertensive kidney disease, and glomerulonephritis have been the most common causes of ESRD.3,12,17,18 The prevalence of diabetic kidney disease in candidates on the wait list increased from 31% to 37% within the previous decade.13 In contrast, diabetes as a cause of kidney disease was seen less frequent in our study (21%). In the United Kingdom and Europe, the proportion of patients with glomerulonephritis (approximately 20%) was reported to be higher than in the US and Turkey. Country-based differences in the prevalence of primary renal disease could be seen as a result of renal biopsy preference variations. Dialysis Outcomes and Practice Patterns Study demonstrated that hypertension, diabetes, and coronary artery disease were the most common concomitant comorbidities in patients.19 As the distribution of comorbidities in our patients on the wait list was similar, cardiovascular diseases were more frequently observed in men than in women. Ningyan and colleagues showed that male sex was associated with cardiovascular events among KTx patients on the wait list without preexisting cardiovascular disease.20 Prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) was low, similar to the general population in the world. Although the prevalence of hepatitis, especially HCV, had been higher in HD patients, the development of new antiviral therapies and anti-HBV vaccine dramatically reduced viral hepatitis in the past decade. Between 2007 and 2018, the prevalence of HCV declined from 13% to 4% and HBV from 5% to 3% among HD patients in Turkey.3
Globally, approximately 85% of ESRD patients are on HD as renal replacement treatment modality, which is similar to our study population.17,18 In our study, 5% of our patients were awaiting preemptive KTx. Indeed, Turkish Registry reported lower percentage of HD (79%) in incident renal replacement treatment patients in 2018, and KTx ratio (14%) was higher than in other registries (Europe 4%, US 3%). Primary arteriovenous fistula was the vascular access choice for HD in 89% of our patients, which was higher than shown in the Turkish and US Registries of patients on HD (77% and 63%, respectively). Turkey has been one of the countries in which percentage of primary arteriovenous fistula use was highest. Dialysis vintage was long in our candidates on the wait list (mean 70 months). In addition, more than one-fifth of patients on the American KTx wait list had been on HD for more than 6 years.
Mean wait time of our enlisted patients was approximately 5 years. In a Canadian study, mean wait time was reported as 2.1 years.14 Although nearly half of KTx candidates had been on the list for less than 2 years in the US, it is noteworthy that the number of patients waiting ≥5 years for transplant increased in the past decade from 11.6% to 16.6%.13 The longer wait time in our study is associated with the shortage of deceased donor organ donations in Turkey.
Similar to our data, the dominance of men (approximately 60%) has been evident for KTx wait lists worldwide.8,12-16 In addition, we found that mean wait time for transplant was longer for women. Sex inequity in access to KTx wait list and transplant has been shown in many studies.12,19,21,22 Women had 13% lower chance of wait-listing within 2 years and 16% lower chance to receive KTx within the first 2 years after wait-listed compared with men in the United Kingdom.12 In addition, median time from dialysis initiation to wait list was longer for women.23 Segev and colleagues demonstrated that sex disparity has become more distinctive against women, with increased age and associated comorbidities, such as diabetes and cardiovascular disease.24 With every decade of age increase, women had 7% less access to transplant than men of the same age. The primary reason that candidates remained unlisted was a medical contraindication (approximately 50%) for both sexes, but patient refusal was slightly higher in women compared with men.23 Women had less interest in transplant and were less likely to complete the pretransplant workup.25 Although the reasons for sex inequities in access to KTx wait list are not well understood, this may be associated with socioeconomic status, educational level, social support, employment status, insurance systems, and discrimination by health professionals.21
Enlisted patients in our center had higher prevalence of anti-HLA antibody positivity (50.5%) than other studies reported in the literature. Presently, 40% of candidates awaiting KTx in the US are sensitized against HLA antigens (PRA ≥1%), and approximately 15% of patients are highly sensitized with PRA levels >80%.13 Prevalence of PRA positivity is 20% to 33% in different Turkish KTx centers.9,26 In a study of 674 transplant recipients, it was reported that class I and/or II anti-HLA antibody positivity was higher in patients with a history of transfusion (33.0%), pregnancy (71.4%), or transplant (76.9%).10 Lopes and colleagues showed higher prevalence of class I and II anti-HLA antibody positivity in patients with these sensitization events (class I, 18.9%, 38.3%, and 75.0%; class II, 11.1%, 39.5%, and 71.2%, respectively).11 In a comprehensive Turkish study, anti-HLA class I, II, and I and II positivity rates were 13.1%, 6.3%, and 14.1% in patients sensitized only by blood transfusion, 35.5%, 29.0%, and 45.2% in patients sensitized by pregnancy, and 15.6%, 34.4%, and 38.9% in patients with previous transplant sensitization, respectively.9 Similar to these studies, we found class I and/or II anti-HLA antibody positivity was higher in patients with a history of transfusion, pregnancy, and transplant. Although Akgul and colleagues were able to identify a correlation between HLA allo-immunization and increased number of pregnancies and transfusions, we did not detect such an association.
We found that sensitization events were associated with positive PRA, but a history of transplant was the strongest risk factor (P < .001). Lopes and colleagues demonstrated that transplant had the strongest immunization effect, followed by pregnancy and then transfusion.11 El-Awar and colleagues detected anti-HLA antibodies in almost all patients (96.2%) who were awaiting retransplant.27 Candidates awaiting a regraft had significantly stronger antibody strength (MFI) than first transplant candidates and those with transfusion or pregnancy.8,10
Pretransplant anti-HLA antibody positivity is a known risk factor for antibody-mediated rejection and poor graft survival, and the risk for both correlates with peak anti-HLA antibody strength.28 In a study of 161 308 transplant recipients, all-cause mortality and cardiovascular mortality were both 1.21 times higher in PRA 80%-100% category compared with PRA 0%.14 It was shown that there was a stepwise increase in transplant wait time with higher PRA levels. In the United Kingdom, the median wait time to transplant for unsensitized patients was 788 days and for highly sensitized patients was 2232 days.7 We also determined that the mean time on wait list was shorter in anti-HLA antibody-negative enlisted patients. Wolfe and colleagues demonstrated that lower transplant rates in women can be explained by their high PRA levels compared with men, as transplant rates were not significantly different between the sexes after adjustment for PRA levels.22 Because both anti-HLA antibody positivity and prolonged pretransplant dialysis are strong risk factors for increased graft and patient loss, it is important to avoid sensitization and to prioritize highly sensitized patients in organ allocation.
After a new kidney allocation system that prioritizes highly sensitized candidates had been implemented in US in 2014, the proportion of deceased donor KTx among candidates with calculated PRA 98%-100% increased dramatically from 4.8% to 14.6%.13 Acceptable mismatch programs, ie, those programs in which HLA mismatches that most likely would not result a positive crossmatch have been identified and used for the allocation of highly sensitized patients (calculated PRA >85%), have the highest priority in the Eurotransplant KTx allocation system.29 The probability of transplant within 2 years for highly sensitized patients increased from 20% to 60%. The PRA status has not been considered a part of the standard criteria in the present Turkish KTx allocation system. As demonstrated in our study, sensitization is an important problem for patients on the wait list in Turkey, and therefore organ allocation system updates that account for sensitized candidates are mandatory to compensate for inequities in access to transplant in our country. However, not only changes in allocation system but also new strategies to increase deceased donor organ pool and donation rates are needed in countries with low numbers of deceased donor KTx like Turkey, to prevent inequity against non-highly sensitized patients. Education and enhanced knowledge about transplant and donation are important to relieve social, medical, and religious concerns and to increase organ donation rates. Use of expanded criteria donors, donation after cardiac death organs, HBV-infected or HCV-infected donors, old-to-old match programs, en bloc transplant, hypothermic machine perfusion, ABO-incompatible transplant, and kidney paired donation are some of the approaches applied in the world to expand the kidney donor pool and may improve the problem of KTx in highly sensitized patients.
Our study documented clinical characteristics and immunologic profiles of patients on KTx wait list in Turkey. As patients with ESRD often have significant comorbidities and immunologic risks, in the evaluation of a potential KTx recipient it is important to offer the best choice of renal replacement treatment to improve the survival rates for graft and patient. Sensitization is an important problem for KTx candidates, as we established in our patients. In accordance with the literature, we demonstrated that previous transplant had the highest immunization effect against HLA antigens. Organ allocation criteria in our country must be updated to account for sensitized patients.
DOI : 10.6002/ect.2020.0304
From the 1Ankara University Faculty of Medicine, Department of Nephrology,
Ankara, Turkey; the 2Ankara University Faculty of Medicine, Department of
Internal Medicine, Ankara, Turkey; and the 3Ankara University Faculty of
Medicine, Transplantation Unit, Ankara, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Siyar Erdogmus, Ankara University Faculty of Medicine, Ibni Sina Hospital, Department of Nephrology, Talatpasa Blv No:82, 06230, Altindag/Ankara, Turkey
(Present address: Baskent University Hospital Ankara, Department of Nephrology, Mareşal Fevzi Çakmak Cd. 10. Sk. No:45, 06490 Bahçelievler/Ankara, Turkey)
E-mail: +90 505 861 6410
Table 1. Demographic and Clinical Data of Patients on Kidney Transplant Wait List, According to Sex
Table 2. Comparisons Between Panel Reactive Antibody Groups in Patients