| Abstract|| |
Kidney transplantation is the treatment of choice for most uremic patients. However, organ shortage remains the central problem in kidney transplantation. To deal with the widening gap between supply and demand of organs for renal transplantation, efforts to expand the organ donor pool have received increased attention. To solve this problem, we have initiated a living unrelated donor (LURD) program using emotionally related persons, friends and well-motivated volunteers as organ donors. A controlled transplant program, now known as the "Iran model", supported by the government for LURD renal transplantation was launched, which resulted in eliminating the waiting list. A charity founded by patients with end-stage renal disease, acts as a liaison agency and the altruistic volunteers have to register with the foundation for being introduced to the potential recipient referred by transplant centers. This review deals with the history of renal transplantation in Iran and describes the "Iran model" protocol and our experience of the non-related renal transplantation. Our results indicate that proper selection and pre-operative management of potential living donors lead to promising results in kidney transplantation. The health of the living donors is not impaired by the donation. The rate of early post-operative complications is low. Living donor kidney transplantation, in our geographical area with a low-rate of cadaveric donor transplants, is an alternative to expand the donor pool, yielding better results in terms of patient and graft survival.
Keywords: Kidney transplantation, Unrelated living donor, Iran model, Patient and graft survival.
|How to cite this article:|
Einollahi B. Iranian Experience with the Non-Related Renal Transplantation. Saudi J Kidney Dis Transpl 2004;15:421-8
| Introduction|| |
Kidney transplantation is generally accepted as the treatment of choice for most patients with end-stage renal disease (ESRD).  Successful kidney transplantation improves both patient survival and quality of life, and relieves the burden of dialysis in patients suffering from ESRD.  In addition, transplantation is also associated with markedly decreased cost of health care for the society and government.
The rapidly increasing incidence of renal failure and the inadequate supply of kidneys, especially from cadavers, have created a wide gap between kidney supply and demand, which has resulted in very long waiting times to receive an organ as well as an increasing number of deaths during this waiting period. For example, between 1988 and 1995, the number of patients awaiting renal transplantation in the United States grew from 11,909 to 17,635 and due to the organ shortage, the median waiting time for cadaveric kidney increased from 400 to 842 days.  At present, one patient is added to the transplant waiting list every 15 minutes and 16 patients die every day while waiting for a transplant. In the year 2000, over 6250 patients died while waiting for a transplant. 
Efforts have been made to extend donor criteria in order to expand the donor pool. , One way to meet the growing demand for kidneys is by increasing living donor renal transplantations. This has been increasingly practiced in the United States, where in the year 2000, the number of living donor renal transplantations almost equaled that from cadaver donors. The use of emotionally related donors, the most obvious pioneering approach to expand the living donor pool, renders extending donor eligibility to include individuals who are not genetically related to the recipient.
The first successful kidney transplantation was carried out by Murray and Merrill in 1954 between living identical twin brothers.  In accordance with their idea of a voluntary donor for a specific recipient, the concept of "living-unrelated" or "emotionally related" donor emerged. Spouses or close friends, who were willing to donate, underwent psychiatric and medical evaluation to determine their motivation and absence of coercion. Ultimately, motivation in this group of donors proved easy to document, and recipient outcomes were found to be superior than for patients receiving cadaveric organs. 
More recently, efforts have moved beyond the original paradigm of Murray and Merrill. The growing public awareness of the shortage of transplantable kidneys has led some people with no personal relationship to an ESRD patient to seek ways of donating an organ. Previously, transplant centers discouraged such volunteers, but the number of transplant centers that are willing to accept living unrelated donors has grown from 74 centers in 1990 to 176 centers in 1994.  Currently, living unrelated donors, including emotionally related and friends as well as donors who want to give their kidneys for altruistic reasons, have been increasing within United States, Canada, Europe, and other countries. The rate of complications in the donor after kidney donation is extremely small and the reported mortality rate after donor nephrectomy is 1 in 5000. On the other hand, there are many psychological and spiritual benefits, and most donors express an increased sense of pride and satisfaction and the joy of giving a gift of life to a relative, a friend or to another fellow human being. Another justification is that the success rate of living donor kidney transplantation is considerably higher than that of cadavers. 
Additional proposals to enhance availability of live donor kidneys include non-directed donation and paired-kidney-exchange programs. The former situation is when the transplant team is approached by persons to donate a kidney to any patient on the waiting list for a cadaveric organ.  The latter has been used since 1991 in Korea. ABO blood group compatibility is required for most successful renal transplantations; thus, several altruistic emotionally related donations may be rendered impossible because of incompatible blood groups. In such circumstances, exchange of kidneys is being practiced. 
This review deals with the history of renal transplantation in Iran and describes our experience with non-related renal transplantation.
| History of Renal Transplantation in Iran|| |
Kidney transplantation is being performed in Iran for the last 38 years, initiated by surgeons in Shiraz university in 1967  ; however, no real progress was made since very limited resources were provided. Between 1967 and 1979, 500 kidneys were transplanted among Iranian citizens, 112 were performed in Iran and the remaining abroad. For four years after 1979, transplantation was virtually stopped.
Due to Western sanctions and limitations on Iran during the Iran-Iraq war, dialysis equipment and dialysate ran out and massive civilian and military casualties saturated the hospitals, and many patients requiring renal replacement therapy died. In 1984, two renal transplant teams were organized and they set up a living related donor (LRD) transplant program. In 1987, the first wife-to-husband transplant was carried out. The demand for kidney transplantation was rapidly growing, but in view of the lack of a permissive law, cadaver donation remained insignificant. On the other hand, the number of patients having suitable or motivated relatives for donation was low. Despite the positive official fatwa, the Iranian parliament passed no law regarding cadaveric transplantation. In 1990, therefore, a controlled living unrelated donor (LURD) renal transplantation program was launched and the government agreed to pay some money as "rewarded donation" or "altruistic gift" to the unrelated kidney donors. The program of Iranian model developed at great speed and the government provided the funds in vies of the large demand, lack of cadaver donors, the high cost of transplantation abroad, safety of kidney donation and availability of volunteers (altruistic or incentive driven unrelated). As a result, the number of renal transplants gradually increased to almost 16,000 from June 1984 up to March 2004. In 1999, the national renal transplant waiting list dropped to zero, an achievement that was based on the development of transplantation with living unrelated donors. 
Until April 2000, when the parliament passed the law justifying cadaveric donor organ transplantation after brain-death, less than one percent of kidney transplants came from cadavers. Despite the religious permission, especially Imam Khomeini's fatwa, there were only sporadic cadaveric transplantations before passing the law. At the present time, cadaveric kidney transplantations account for 10% of the annual transplantation in Iran (approximately 166 cases in 2003).
| Iran Model|| |
The transplant program, now known as the "Iran Model", supported by the government for LURD transplantation, has several important characteristics [Table - 1].
Patients with ESRD are confirmed officially, by nephrologists, as suffering from end-stage renal disease (ESRD) after appropriate examination and tests. If a patient is suitable for a transplant, the nephrologist refers him/her to the Society for Supporting Dialysis and Transplantation Patients (SSDTP). The SSDTP, a charity founded in 1978 by ESRD patients, acts as a liaison agency between potential donors and recipients. The altruistic volunteers have to register with the SSDTP, and undergo evaluation in the foundation's clinics. Donors are all 18-35 years old; permission from the parents or the spouse to register is mandatory. The potential donors should be in complete health and consents are obtained prior to introduction to the potential recipients. The SSDTP receives no financial incentives for finding a LURD or for referring the recipient and the donor to a transplant center. There is no role for a middle-man or agency in this model. The donor and recipient are introduced together at the SSDTP and agree upon the center to be referred to. All kidney transplant centers are university hospitals and are licensed by the government. Unfortunately, more than 50% of the recipients are poor 2 and would have died without this program. We, however, hope to see progress being made in cadaver donor transplantation in the near future.
| Transplantation Activities in Iran|| |
The prevalence of patients on renal replacement therapy was 292 per million population (pmp) in the year 2003; 47% had a functioning renal graft, 51% were on hemodialysis and one percent was on peritoneal dialysis. We have recently shown that the prevalence of chronic renal failure (CRF) in Iran was much more than reported data.  The problem is, as CRF usually has no prominent symptom(s) until ESRD develops, the majority of patients do not get referred to physicians. Thus, they remain unrecognized in early stages and consequently are not recorded in any charts of the organizations responsible for public health care in different countries.
Approximately 16,000 kidney transplantations were performed in 23 centers until March 2004 (24 renal transplants pmp). The annual number of kidney transplantations increased from fewer than 100 in 1986 to 1640 in 2003. Almost 24% of the kidney transplantations (3754 cases) were performed in our centers (Labbafi Nejad and Baghiatollah hospitals) until March 2004. For living kidney transplantation, the rate increased from 2.7 pmp in 1986 to 24 pmp in 2003, and the proportion of cadaveric donors increased from less than 1% by the end of year 2000 to almost 10% of kidney transplantations in 2003.
| The Results of Living Donor Kidney Transplantation|| |
A prospective national report showed the short-term results of all living donor renal transplants carried out in the country.  The overall one- and three-year patient survival rates were 94.23% and 92.90%, respectively. One- and three-year overall graft survival rates were 90.80% and 85.93%, respectively. A marked center effect with respect to graft survival has been observed among different transplantation units. Despite this variation, a significant improvement was seen in most centers in one- and three-year graft survival rates. Unfortunately, there is no national study to report long-term results in Iran, and most centers report their own results as single center experiences. The reports of our centers will be discussed below as they constitute the largest cohort of renal transplants (24% of the all recipients) in Iran.
Our centers (Labbafi Nejad and Baghiatollah hospitals) have extensive experience in transplantation of kidneys from living donors (LD). From 1984, we have performed more than 3700 such transplantations. Based on our policy, when any potential donor is referred by the SSDTP to our transplantation centers, a complete medical history, physical examination, laboratory tests and radiological studies are performed. Most donors, however, have thorough tests in advance which are rechecked by our nephrologists. The purpose of this evaluation is to ensure that the donor does not have any risk factors for organ donation. We also do an outpatient evaluation to ensure that the potential recipient is medically ready for a transplant. We also make sure that the potential recipient realizes that the transplantation could be cancelled at any time (e.g. because of the donor's decision to withdraw from the program).
More recently, usage of laparoscopic techniques to procure the kidney from the donor has been carried out at the Labbafi Nejad hospital. Laparoscopic nephrectomy was proposed as an alternative to the standard open approach to minimize short-term risk to the kidney donor, decreasing the duration of hospital stay and convalescence period with time away from the job as well as peri-operative pain, because of the small incision. Since June 2000, laparoscopic nephrectomy has been performed in 309 cases with no significant impact on graft survival and an obvious positive outcome for the donor. Simforoosh has reported the results of the first prospective randomized study of laparoscopic versus open living nephrectomy confirming that both techniques are equally safe and successful. 
In 2003, we reported our experience in 2822 patients who received LD transplants with more than 15 years of follow-up.  Recipients were generally young (mean age 34 years) and most donors were less than 35 years old at the time of transplantation (mean age 28 years). The majority of patients received a kidney from LURDs (80.8%). The results of LRD renal transplantations are as good as those who underwent LURD renal transplantations. The results were also comparable with the USRDS reports  and long-term graft survival of LD kidneys was encouraging [Table2],[Table3]. Nafar has recently reported that patient and graft survivals in 2117 recipients after 19 years of follow-up were promising (76.30% and 50.10%, respectively) (unpublished data). In our study, living unrelated donors were significantly younger than living related donors (P < 0.05). The patients who received grafts from donors under 30 years of age had significantly better patient and graft survival compared to recipients whose donors were 30 years and older (P = 0.01 and P = 0.02, respectively). Thus, our findings show a superior patient and graft survival outcome for those who receive kidneys from younger donors. Old kidneys have relatively decreased numbers of functioning nephrons, and survive less when transplanted. 
Most unrelated donors were male (81% vs. 19%). In contrast with a previous study,  there was a greater proportion of male donors and a smaller proportion of female LURDs compared with the living related group. We did not find any significant differences between patient and graft survival rates with respect to donor sex.
Patient survival after renal transplantation varied according to the recipients' age. Older patients who underwent renal transplantation had a higher mortality rate than younger recipients (P<0.05). Rejection occurred less commonly in older recipients compared to younger patients (P<0.05). In our centers, immunosuppressive therapy is usually modified in the elderly recipient due to the increased risk of infection and death. We, however, suggest that transplantation should be offered as renal replacement therapy to elderly patients with ESRD, in the absence of contraindications.
Hepatitis B surface antigen (HBsAg) were positive in 3.1% of all our recipients. We observed that the presence of seropositivity to HBsAg was associated with lower patient survival (P < 0.01) with no impact on graft survival.
The prevalence of Hepatitis C virus (HCV) infection among kidney recipients in our study was 4.8% whereas in the population of a large study performed on 838 CRF patients undergoing hemodialysis in Tehran, antiHCV antibody was detected in the sera of 13.2% of patients.  This marked difference indicates that HCV-infected CRF patients probably should not be recommended to undergo renal transplantation. We observed that HCV infection had no impact on patient and graft survival in short and medium-term follow-up periods (less than 10 years). , We, however, found lower graft survival with no effect on patient survival among HCV Ab-positive recipients in long-term (15 years) follow-up.  Most previous studies have indicated similar patient and graft survival in HCV positive and negative recipients.  In contrast, studies which have extended the follow-up time to more than 10 years, have demonstrated lower patient and/or graft survival rate in HCV positive recipients. , Indeed, some studies have indicated that the difference in survival was significant only in the second decade after transplantation. s Our study also showed a longer time on hemodialysis in HCV positive patients  which has also been indicated in other reports. , These results confirm dialysis as a significant route of contaminating CRF patients. This could also explain why patients who have had more than one transplant are more likely to be anti-HCV positive. 
Infection after transplantation is the most serious complication that leads to patient's morbidity and mortality. Mycobacterium tuberculosis is one of the important organisms in developing countries. We found that its prevalence in our centers was not high (1.4%).  However, further studies in other transplant centers are required to know the exact prevalence of tuberculosis.
Post-transplant malignancy is a most important long-term complication. Skin Cancer is the most common malignancy after renal transplantation, especially squamous cell carcinoma.  Incidence of post-transplant malignancy in our experience was 1.6%, a figure which is less than reports from western countries. Skin cancer, predominantly Kaposi's sarcoma, was the most common neoplasm after transplantation followed by lymphoproliferative disorders. ,
Another aspect of particular relevance to Muslim recipients that is worth mentioning is fasting in the holy month of Ramadan. They are only allowed to eat and drink between sun set and dawn. Fasting during Ramadan is a religious duty for all healthy adult Muslims, but it is not mandatory for patients. We, however, prospectively studied 19 kidney transplant recipients who voluntarily chose to fast during the month of Ramadan and compared the results with 20 matched recipients who were not on fasting for three consecutive years. 
The results did not show any adverse effects of fasting in these recipients who had stable allograft renal function after one year of transplantation. A previous study has indicated similar results. 
| Acknowledgements|| |
I feel indebted to professor Simforoosh and Dr. Nafar for providing some of the data. I would like to thank Dr. Kazemeyni and Dr. Heydari for giving the data from Management Center for Transplantation and Special Diseases of Health Ministry.
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Department of Nephrology, Baghiatollah University of Medical Sciences, Tehran
[Table - 1], [Table - 2], [Table - 3]