Objectives: We report our experience in treating Mongolian patients transferred to our center in Korea to undergo kidney transplants, including immunologically high-risk patients.

Materials and Methods: Between September 2009 and February 2013, thirty-three Mongolian patients underwent kidney transplants at our center with the approval of the Korean Network for Organ Sharing. Their clinical data were retrospectively collected and analyzed.

Results: The mean age of the transplant recipients was 38.8 ± 10.5 years, and the causes of end-stage renal disease were glomerulonephritis (5), diabetes mellitus (2), hypertension (3), and unknown (25). These cases included ABO incompatibility, high levels of sensitization, and retransplant, at fre­quencies of 9, 12, and 9. Basiliximab (30) or antithymocyte globulin (2) was administered as the induction therapy, and combination regimens of plasmapheresis with or without intravenous immunoglobulins and/or rituximab were used in some high-risk patients. The mean follow-up after kidney transplant was 12.87 ± 11.7 months. During the follow-up, antibody-mediated rejection and graft failure occurred in 2 patients. In addition, cytomegalovirus infection, calcineurin inhibitor toxicity, and BK viremia developed in 1 patient each. The mean estimated glomerular filtration rates at 1, 6, and 12 months after kidney transplant were 88.2 ± 26.9 mL/min/1.73 m2, 67.5 ± 14.9 mL/min/ 1.73 m2, and 63.9 ± 21.1 mL/min/1.73 m2. In addition, subgroup analysis revealed that ABO-incompatible and immunologically high-risk recipients had comparable renal function status during the follow-up

Conclusions: We found that an overseas kidney transplant program in Korea could be conducted safely, even in high-risk patients. Therefore, a proper cooperation and transfer system for these high-risk patients between neighboring countries might help in providing improved medical care in this setting.

Key words : ABO-incompatible, High-risk kidney transplant, Overseas kidney transplant, Sensitization

Introduction

Although kidney transplant (KT) is the best treatment option to enhance the quality of life of patients with end-stage renal disease (ESRD), severe global inequalities in access to transplant surgery still exist because, in the transplant health care system, developing countries have not adopted essential legislation and established governmental support. To improve transplant systems in such countries, it would be of great help to network with experienced centers that can share their systems and protocols. Especially in countries with insufficient experience with performing KT in high-risk patients, a transfer system between neighboring countries could be a reasonable alternative for patients with ESRD and incompatibility with a live donor.

In Mongolia, chronic kidney disease is common. Recently, researchers reported that 13.9% of the Mongolian population have proteinuria or an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m² as calculated with the Modified Diet in Renal Disease Study equation.^1,2 In addition, approximately 200 people in Mongolia are newly diagnosed with ESRD every year, despite the country’s having a small population of about 3 million people.^3,4 However, owing to a limited number of functioning dialysis units, many patients in Mongolia with ESRD cannot be maintained on dialysis therapy, which leads to difficulty in management and more frequent requirement for KT. Although KT has been conducted successfully in Mongolia since 2006, little attention has been paid to KT for high-risk patients there.^3,4 Therefore, in Mongolia, more experience with ABO-incompatible and highly sensitized cases is required to achieve an enhanced KT program. Since 2009, our center in Korea has operated an overseas KT program for Mongolian patients, including those who are at risk immunologically. In this article, we report our experience with this program.

Materials and Methods

Between September 2009 and February 2013, thirty-three KTs were performed on Mongolian patients at the Korea University Anam Hospital. We retrospectively analyzed the medical records of these patients. All procedures were carried out with living donors and conducted with the approval of the national allocation system (Korea Network for Organ Sharing [KONOS]). KONOS evaluates the relation strictly between the donor and recipient to prevent any kind of commercial donation. The study was approved by the Ethical Review Committee of the Institute. All of the protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration. Written informed consent was obtained from all subjects.

Before KT, each patient was evaluated by performing a series of laboratory and radiologic tests, including human leukocyte antigen (HLA) typing, HLA cross-matching, anti-HLA antibody testing, ABO blood typing, abdominal computed tomography, and echocardiography. Anti-HLA antibodies were assessed by performing Luminex assays (Tepnel Lifecodes, Stamford, CT, USA) using class I and class II panel reactive antibody (PRA) identification kits, and highly sensitized recipients were defined as having a PRA level ≥ 50%.

In ABO-incompatible cases, we used rituximab and multiple sessions of plasmapheresis (double-filtration plasmapheresis or total plasma exchange) according to the level of ABO antibody titer before KT and obtained an isoagglutinin titer ≤ 1:8 on the day of the KT.

For the initial immunosuppressant, basiliximab (90.9%) or antithymocyte globulin (6.1%) (1.5 mg/kg/d for 4 or 5 days) was used to induce immunosuppression with triple-maintenance drugs (prednisolone, calcineurin inhibitor, and an antimetabolite). In the combination regimens, plasmapheresis, with or without intravenous immunoglobulins and/or rituximab, was also used in some cases. All patients were periodically followed by both transplant centers in Mongolia and at our center every 3 to 6 months. They were also in constant contact with our medical staff via e-mail.

Kidney biopsies were performed in our center when renal function decreased after KT, and they were analyzed using the Banff 07 classification.⁵

Results

Baseline patient characteristics
The baseline patient characteristics are summarized in Table 1. Among the 33 KT cases, 9 were retransplants (27.3%), 12 involved highly sensitized recipients (36.4%), 10 had 4 or more HLA mismatches (30.3%), and 9 involved an ABO-incompatible donor (27.3%). Although the causes of ESRD were unknown in 75.8% of the cases, the most common primary renal disease was glomerulonephritis. Four patients (12.1%) were hepatitis B surface antigen (HBsAg)-positive, and 12 were hepatitis C antibody (36.4%) (HCVAb)-positive. All transplant recipients who were hepatitis virus-positive had normal liver function and showed no evidence of liver cirrhosis before undergoing KT. In addition, all HBsAg-positive recipients were administered antiviral prophylaxis after KT. Donors who were hepatitis C virus (HCV)-positive donors were matched with recipients who were HCV-positive, and donors who were hepatitis B virus (HBV)-positive were involved when their DNA test was negative for HBV and the recipient displayed a high HBV antibody titer (> 10 mIU/mL).

Clinical patient outcomes
All recipients were followed for a minimum of 3 months after KT (mean follow-up 12.87 ± 11.7 mo). In the early posttransplant period, delayed graft function occurred in 1 patient. The mean eGFRs at 1, 6, and 12 months after KT were 88.2 ± 26.9 mL/min/1.73 m², 67.5 ± 14.9 mL/min/1.73 m², and 63.9 ± 21.1 mL/min/1.73 m². The renal function of the Mongolian patients was not significantly different from that of the Korean patients in the same period. In addition, in ABO-incompatible cases, the mean eGFRs at 1, 6, and 12 months were 79.2 ± 38.1 mL/min/1.73 m², 67.8 ± 20.9 mL/min/ 1.73 m², and 62.1 ± 27.4 mL/min/1.73 m², showing similar short-term outcomes compared to those of ABO-compatible cases (Figure 1A). Patients were defined as “high risk” if they had 1 or more of the following characteristics: second transplant, PRA > 50%, 4 or more HLA mismatches, and ABO incompatibility. A total of 22 patients were included in the high-risk group, and their mean eGFRs at 1, 6, and 12 months were 85.4 ± 30.3 mL/min/1.73 m², 68.7 ± 16.8 mL/min/1.73 m², and 63.2 ± 22.5 mL/min/ 1.73 m² (Figure 1B).

During the follow-up, a posttransplant biopsy was conducted a total of 11 times across a total of 5 recipients who experienced acute or sustained renal dysfunction. In those cases, acute tubular necrosis and acute rejection were found in 1 and 4 patients. Borderline acute T-cell–mediated rejection was present in 2 patients, and another 2 patients had acute antibody-mediated rejection. One case with acute antibody-mediated rejection occurred 17 months after KT in a highly sensitized recipient (PRA I/II > 50%), and the other occurred 3 weeks after KT in an ABO-incompatible recipient. Their renal function improved slightly after treatment; however, their clinical response was not sustained for long, and their renal function gradually deteriorated. A follow-up biopsy showed chronic active antibody-mediated rejection, and graft failure occurred in these 2 patients. In addition, cytomegalovirus infection, calcineurin inhibitor toxicity, and BK viremia developed in 1 patient each; however, their renal function stabilized after treatment. All recipients with hepatitis showed stable liver function during the follow-up.

Discussion

As reported previously, there has been an increasing burden of ESRD in Mongolia.² However, the management of patients with ESRD there has been limited by a lack of proper dialysis units. Korea and Mongolia are very close countries, both geo­graphically and culturally; therefore, in 2009, our hospital opened a KT program for Mongolian patients with ESRD. We provided transplant staff who speak Mongolian and tried to minimize the burden of high medical costs for these patients. We also visited Mongolia regularly for education and consultation with Mongolian medical staff and were in constant contact with the patients through e-mail. As a result of these efforts, a total of 33 patients underwent KT in our center during the study period. In our analysis, we found the following patient characteristics. They were relatively young (mean age 38.8 ± 10.5 y), and, although it was difficult to know the exact cause of ESRD in many cases, glomerulo­nephritis was the most common renal disease (immunoglobulin A nephropathy in 4 patients and suspicion of glomerulonephritis in 2 patients). These patients had especially high rates of HBV and HCV infection (42.4%).

Mongolia is known to have the highest rate of hepatocellular carcinoma in the world,⁶ and recent studies have shown that 10% to 15% of the general population have HBV or HCV infection.⁷ Therefore, hepatitis-associated glomerulonephritis might be a common cause of ESRD in Mongolia.⁸ In the past, hepatitis infection was a hurdle to successful KT, but, with the availability of more effective antiviral agents, successful viral suppression and better outcomes can be achieved for KT recipients with HBV.^9,10 We also used antiviral agents in HBV-positive recipients after KT to keep their liver function stable during the follow-up. In patients with HCV, because the safety and effectiveness of antiviral treatment after KT have not yet been verified, more careful evaluation is important, and antiviral treatment should be considered before performing the transplant.¹¹ However, there are complex factors to be considered in the selection of hepatitis-positive donors, owing to issues with viral transmission and donor safety. Recent organ shortages have led to active use of kidneys from HBV-positive donors, especially in geographic areas in which HBV infection is endemic.^12,13 We also performed KT only when donor DNA tests for HBV were negative and the recipient was immune to HBV. The recipients remained HBsAg-negative 11 months after KT.

Controversy remains regarding the use of kidneys from HCVAb-positive donors; however, their use could be considered for HCVAb-positive recipients. In a recent prospective study, researchers demon­strated the long-term safety of this strategy.¹⁴ In our study, the patients who were HCV-positive and received kidneys from donors who were HCV-positive also had stable renal function during the follow-up. Therefore, in Mongolia, where HBV and HCV are endemic, it is necessary to consider the use of organs from hepatitis-positive donors as one option to more actively decrease the current organ shortage.

In this study, approximately 66.7% of the recipients were immunologically at high risk. We used induction immunosuppressants in all high-risk cases and desensitization protocols in some, including ABO-incompatible KT. Although severe antibody-mediated rejection developed in 2 recipients and their responses to treatment were poor, most of the recipients had excellent short-term outcomes. In addition, subgroup analysis revealed that ABO-incompatible and immunologically high-risk recipients had comparable renal function during the follow-up.¹⁵

In Mongolia, data on KT for high-risk patients is insufficient.^3,4 Additionally, some of the important immunologic tests and treatment strategies, such as plasmapheresis, are not yet available. Therefore, an overseas transfer system between neighboring countries for high-risk patients, as well as the availability of KT for HLA- and ABO-incompatible patients in experienced centers, could be a reasonable alternative for patients with ESRD who have incompatibility with live donors.¹⁵ Moreover, the advent of the Internet and the smartphone has made it possible to easily contact patients remotely and respond to emergencies. In this study, we completed follow-up with most recipients via regular e-mails, and some of them visited us whenever they were asked to or wanted to. Our results suggest that an overseas transfer program for KT should be considered, especially for high-risk patients in countries where the experience in performing KT is not enough, although a long-term follow-up study is required to verify the safety of such programs. We also remain interested in and are continuing our efforts toward improving the transplant system by transferring our KT experience to a transplant team in Mongolia.

Conclusion

We found that an overseas transplant program in Korea for patients who need KT could be conducted safely, even in high-risk patients. Therefore, proper cooperation and a transfer system for those high-risk patients between neighboring countries might help in providing improved medical care in this setting.

References:

1. Li PK, Chow KM, Matsuo S, et al; and the Asian Forum for Chronic Kidney Disease Initiatives. Asian chronic kidney disease best practice recommendations: positional statements for early detection of chronic kidney disease from Asian Forum for Chronic Kidney Disease Initiatives (AFCKDI). Nephrology (Carlton). 2011;16(7):633-641.
2. Sharma SK, Zou H, Togtokh A, et al. Burden of CKD, proteinuria, and cardiovascular risk among Chinese, Mongolian, and Nepalese participants in the International Society of Nephrology screening programs. Am J Kidney Dis. 2010;56(5):915-927.
3. Jambaljav L, Nyamsuren D, Byambadash B, Ganbold L. Kidney transplantation achievements in Mongolia. Transplant Proc. 2010; 42(3):791-792.
4. Tumurbaatar B, Nyamsuren D, Byambadorj B, et al. Kidney transplantation in Mongolia using effective and economical immunosuppression - a three-year experience. Ann Transplant. 2012;17(1):132-139.
5. Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008;8(4):753-760.
6. Yang JD, Roberts LR. Hepatocellular carcinoma: A global view. Nat Rev Gastroenterol Hepatol. 2010;7(8):448-458.
7. Baatarkhuu O, Kim do Y, Bat-Ireedui P, Han KH. Current situation of hepatocellular carcinoma in Mongolia. Oncology. 2011;81(suppl 1):148-151.
8. Xu G, Huang T. Hepatitis B virus-associated glomerular nephritis in East Asia: progress and challenges. Eur J Intern Med. 2011;22(2):161-166.
9. Park KS, Han DJ, Park JB, Park JS, Park S. Long-term outcome of Hepatitis B-positive renal allograft recipients after development of antiviral treatment. Clin Nephrol. 2012;78(5):391-398.
10. Reddy PN, Sampaio MS, Kuo HT, Martin P, Bunnapradist S. Impact of pre-existing hepatitis B infection on the outcomes of kidney transplant recipients in the United States. Clin J Am Soc Nephrol. 2011;6(6):1481-1487.
11. Carbone M, Mutimer D, Neuberger J. Hepatitis C virus and nonliver solid organ transplantation. Transplantation. 2013;95(6): 779-786.
12. Berber I, Aydin C, Yigit B, Turkmen F, Titiz IM, Altaca G. The effect of HBsAg-positivity of kidney donors on long-term patient and graft outcome. Transplant Proc. 2005;37(10):4173-4175.
13. Natov SN, Pereira BJ. Transmission of viral hepatitis by kidney transplantation: donor evaluation and transplant policies (Part 1: hepatitis B virus). Transpl Infect Dis. 2002;4(3):117-123.
14. Morales JM, Campistol JM, Domínguez-Gil B, et al. Long-term experience with kidney transplantation from hepatitis C-positive donors into hepatitis C-positive recipients. Am J Transplant. 2010;10 (11):2453-2462.
15. Becker LE, Süsal C, Morath C. Kidney transplantation across HLA and ABO antibody barriers. Curr Opin Organ Transplant. 2013; 18(4):445-454.