1. Background
Renal transplantation is the best available renal replacement therapy for end-stage renal disease. Kidney transplant recipients have a better quality of life and consume fewer health care resources compared with patients on dialysis (1). The number of patients with end-stage renal disease is rising rapidly, while those who can undergo a kidney graft are limited because of the donor organ shortage. The organs supplied by living donors are superior to those from cadaveric sources (2). Therefore, much effort has been made to increase the supply of living donors. Improvements in the use of immunosuppression and advances in tissue typing have been associated with better patient and graft survivals in recent years (3). Despite studies that compared the outcome of related and unrelated living donation worldwide, an evaluation of the impact of live unrelated kidney donor (LURD) as a source for renal transplantation has not been adequately studied in Egypt (4). Thus, we conducted the present study.
2. Objectives
Concerning this hypothesis, we decided to study the donor-recipient relationship and its impact on both graft and patient survival among Egyptian patients. In Egypt, there are no cadaveric kidney transplantations and the only source for renal transplantation is through living donation. So, we tried to encourage all types of living donation participants to answer the question whether unrelated donation is inferior to related donation.
3. Patients and Methods
This study was comprised of 2,485 kidney transplant recipients who received their grafts between March 1976 and December 2013 at our center. Out of this total, 2,075 received their grafts from living related donors (related group a parent, a child, or a sibling of the recipient), while 410 received their grafts from live unrelated kidney donors (unrelated group-spouses, friends, or altruistic individuals). The recipients shared at least one HLA haplotype with their donors. The mean follow-up time was 7.72 ± 6.15 years. We compared demographic characteristics, acute rejection episodes, chronic rejection, complication rates and long-term graft, and patient survivals among the groups. Rejection was diagnosed on the basis of an increase in serum creatinine, confirmed by examination of a graft biopsy sample. All donors and recipients were evaluated by standard biochemical, serological, and radiological evaluation and they received immunosuppressive therapy. Demographic characteristics were compared using the chi-square test. Graft and patient survivals were calculated using the Kaplan-Meier method. All analyses were performed using SPSS 16.0. P values, less than 0.05 were considered to be statistically significant. The study was approved by our ethics committee.
4. Results
A total of 2,075 living related donor (LRD) and 410 living unrelated donor (LURD) transplants were performed during the period. Demographic characteristics of the recipients and donors are shown in Table 1. Our results showed high statistical significance regarding both donor and recipient age (P < 0.001); the mean age of donors was higher in the related group (LRD 36.2 ± 10.5 years versus LURD 31.4 ± 6.4 years), while the mean age of recipients was higher in the unrelated group (LURD 34.8 ± 11.1 years versus LRD 28.8 ± 9.8 years). The percentage of male donors was significantly higher in the unrelated group (P < 0.001). Hematological workup showed that blood grouping had a high statistical significance (P = 0.002), however, no significant difference regarding blood transfusion could be observed between both groups (P = 0.71). The percentage of couples with one DR matched locus was higher in the unrelated group (LURD 94.9% versus LRD 85.5%), while the percentage of couples with two DR matched loci was higher in the related group (LRD 14.5% versus LURD 5.1%). The percentages of couples with zero, one, and two HLA matching were higher in the related group (8.8%, 12.8%, 64.5%), respectively, while the percentages of couples with three and four HLA matching were higher in the unrelated group (39.8% and 21.9%) (Table 1).
Table 1. Characteristics of Live Kidney Donors and Kidney Transplants at the Time of Transplantationa
| Variable | Related Group (n = 2,075) | Unrelated Group (n = 410) | P Value |
|---|---|---|---|
| Recipient age, y | 28.8 ± 9.8 | 34.8 ± 11.1 | < 0.001 |
| Recipient gender | < 0.001 | ||
| Male | 1,554 (74.9) | 297 (72.4) | |
| Female | 521 (25.1) | 113 (27.6) | |
| Donor age, y | 36.2 ± 10.5 | 31.4 ± 6.4 | < 0.001 |
| Donor gender | < 0.001 | ||
| Male | 906 (43.7) | 297 (72.4) | |
| Female | 1,169 (56.3) | 113 (27.6) | |
| Hematological characteristics | |||
| Blood groups | 0.002 | ||
| Same | 1,689 (81.4) | 299 (72.9) | |
| Different compatible | 386 (18.6) | 111 (27.1) | |
| Blood transfusion | 0.71 | ||
| No | 1500 (72.3) | 300 (73.2) | |
| Yes | 575 (27.7) | 110 (26.8) | |
| Immunological work up | |||
| A) HLA class I matching | < 0.05 | ||
| Zero | 183 (8.8) | 4 (0.9) | |
| One | 264 (12.8) | 15 (3.7) | |
| Two | 1,339 (64.5) | 138 (33.7) | |
| Three | 189 (9.1) | 163 (39.8) | |
| Four | 100 (4.8) | 90 (21.9) | |
| B) HLA class II (DR) matching | < 0.05 | ||
| One | 1,775 (85.5) | 389 (94.9) | |
| Two | 300 (14.5) | 21 (5.1) | |
aValues are expressed as No. (%) or mean ± SD.
The most common causes of end-stage kidney disease (ESKD) in the LURD group were glomerulonephritis and polycystic kidney disease (n = 66, 16.1% and n = 43, 10.5%), while in the LRD were due to unknown causes and obstructive uropathy (n = 1,406, 67.7% and n = 98, 4.7%) (Table 2).
Table 2. Pre-Transplant Medical Comorbiditya
| Variable | Related Group (n = 2,075) | Unrelated Group (n = 410) | P Value |
|---|---|---|---|
| Hypertension | 0.84 | ||
| No | 174 (42.4) | 891 (42.9) | |
| Yes | 236 (57.6) | 1,184 (57.1) | |
| Schistosomiasis | < 0.001 | ||
| No | 315 (76.8) | 1,430 (68.9) | |
| Yes | 95 (23.2) | 645 (31.1) | |
| Original kidney disease | |||
| Glomerulonephritis | < 0.001 | 66 (16.1) | 238 (11.4) |
| Chronic pyelonephritis | 0.865 | 47 (11.5) | 232 (11.3) |
| Hypoplasia | 0.936 | 3 (0.7) | 16 (0.8) |
| Polycystic kidney disease | < 0.001 | 43 (10.5) | 36 (1.7) |
| Nephrosclerosis | 0.841 | 9 (2.2) | 49 (2.4) |
| Obstructive uropathy | 0.005 | 7 (1.7) | 98 (4.7) |
| Unknown | 0.005 | 235 (57.3) | 1,406 (67.7) |
aValues are expressed as No. (%).
In regards to induction and maintenance immunosuppressive protocols, ATG induction had the highest percentage in the unrelated group (LURD 16.4% versus LRD 6.9%) (Table 3). The percentages of recipients maintained on steroid-azathioprine or mycophenolate mofteil (MMF) and tacrolimus (Tac)-MMF were significantly higher in the related group (LRD 13.5% versus LURD 7.1%, and LRD 17.1% versus LURD 11.4%), respectively, while the percentages of recipients maintained on Steroid-cyclosporine Azathioprine or MMF were significantly higher in the unrelated group (LURD 61.2% versus LRD 52.2%) with comparable percentages in both groups regarding other protocols (Table 4).
Table 3. Induction Immunosuppressive Protocolsa
| Induction Therapy | Related Group (n = 2,075) | Unrelated Group (n = 410) | P Value |
|---|---|---|---|
| Anti-thymocyte globulin (ATG) | 144 (6.9) | 67 (16.4) | < 0.001 |
| Basiliximab (SIMULECT) | 908 (43.8) | 162 (39.5) | 0.111 |
| Others [Muromonab-CD3 (OKT3), Daclizumab (ZENAPAX), Alemtuzumab (CAMPATH)] | 85 (4.1) | 12 (2.9) | 0.262 |
| No induction | 938 (45.2) | 169 (41.2) | 0.138 |
Table 4. Maintenance Immunosuppressive Protocolsa
| Immunosuppressive Protocols | Related Group, (n = 2,075) | Unrelated Group, (n = 410) | P Value |
|---|---|---|---|
| Steroid-Azathioprine or MMFb | 280 (13.5) | 29 (7.1) | < 0.001 |
| Steroid-cyclosporine or Tac-Azathioprinec or MMF | 1,296 (62.5) | 306 (74.6) | < 0.001 |
| Steroid-cyclosporine or Tac-mTORd or MMF | 145 (6.9) | 28 (6.9) | 0.904 |
| Tac-MMF | 354 (17.1) | 47 (11.4) | 0.004 |
aValues are expressed as No. (%).
bMycophenolate mofteil (MMF).
cTacrolimus (Tac).
dMammalian target of rapamycin (mTOR).
Post-transplant medical complications were analyzed. There were no significant differences between both groups regarding hypertension, diabetes mellitus, hepatic problems, infections, or malignancy (Table 5). The rate of acute vascular rejection was significantly higher in the unrelated group (LURD n = 26, 6.3% versus LRD n = 71, 3.41%), while the rate of cases without acute rejection was significantly higher in the related group (LRD n = 960, 46.3% versus LURD n = 167, 40.7%) (Table 6).
Table 5. Post-Transplantation Medical Complicationsa
| Variable | Related Group (n = 2,075) | Unrelated Group (n = 410) | P Value |
|---|---|---|---|
| Hypertension | 0.84 | ||
| Yes | 1,228 (59.3) | 245 (59.8) | |
| No | 847 (40.7) | 165 (40.2) | |
| Diabetes mellitus | 0.07 | ||
| Yes | 343 (16.5) | 106 (25.8) | |
| No | 1,732 (83.5) | 304 (74.2) | |
| Hepatic problems | 0.82 | ||
| Yes | 129 (5.7) | 23 (5.4) | |
| No | 1,946 (94.3) | 387 (94.6) | |
| Infections | 0.88 | ||
| Yes | 378 (17.8) | 75 (18.1) | |
| No | 1,697 (82.2) | 335 (81.9) | |
| Malignancy | 0.15 | ||
| Yes | 97 (4.7) | 26 (6.3) | |
| No | 1,978 (95.3) | 384 (93.7) |
aValues are expressed as No. (%).
Table 6. Number and Type of Rejection Episodesa
| Variable | Related Group (n = 2,075) | Unrelated Group (n = 410) | P Value |
|---|---|---|---|
| Number of acute rejections | |||
| No rejection | 960 (46.3) | 167 (40.7) | 0.03 |
| One episode | 614 (29.6) | 129 (31.5) | 0.447 |
| ≥ Two episodes | 501 (24.1) | 114 (27.8) | 0.116 |
| Type of rejection | |||
| Acute cellular | 728 (35.1) | 156 (38.1) | 0.25 |
| Acute vascular | 71 (3.41) | 26 (6.3) | 0.005 |
| Chronic rejection | 490 (23.6) | 80 (19.5) | 0.07 |
| Rejection free | 786 (37.9) | 148 (36.1) | 0.496 |
aValues are expressed as No. (%).
There was no statistical significance between both groups in regards to creatinine clearance and serum creatinine for one, three, and five years post transplantation (P = 0.684, 0.579, 0.201, and 0.107), respectively (Table 7). The graft and patient survival of each group is shown in Tables 8 and 9.
Kaplan-Meier graft and patient survival curves for each group are shown in Figures 1 and 2. There were no significant differences regarding graft and patient survival between both groups (P = 0.071 and P = 0.386, respectively).
Table 7. Serum Creatinine and Creatinine Clearance at Last Follow-upa
| Variable | Related Group (n = 2,075) | Unrelated Group (n = 410) | P Value |
|---|---|---|---|
| Serum creatinine, mg/dL | |||
| After one year | 1.38 ± 0.69 | 1.35 ± 0.61 | 0.579 |
| After three years | 1.62 ± 0.95 | 1.54 ± 0.88 | 0.201 |
| After five years | 1.71 ± 1.04 | 1.59 ± 0.89 | 0.107 |
| Creatinine clearance at last follow-up, mL/min | |||
| Creatinine clearance | 63.45 ± 33.75 | 61.61 ± 33.46 | 0.384 |
aValues are expressed as mean ± SD.
Table 8. Graft and Patient Survival of the Related Group
| Years | Survival Rate | SE | Hazard Ratio | Confidence Interval (95% CI) |
|---|---|---|---|---|
| Graft survival | ||||
| 1 year | 0.97 | 0.004 | 0.03 | (0.9622, 0.9778) |
| 5 years | 0.866 | 0.008 | 0.13 | (0.8503, 0.8817) |
| 10 years | 0.679 | 0.013 | 0.32 | (0.6535, 0.7045) |
| Patient survival | ||||
| 1 year | 0.971 | 0.004 | 0.03 | (0.9622, 0.9778) |
| 5 years | 0.951 | 0.005 | 0.05 | (0.9402, 0.9598) |
| 10 years | 0.808 | 0.011 | 0.192 | (0.7864, 0.8296) |
Table 9. Graft and Patient Survival of the Unrelated Group
| Years | Survival Rate | SE | Hazard Ratio | Confidence Interval (95% CI) |
|---|---|---|---|---|
| Graft survival | ||||
| 1 year | 0.954 | 0.011 | 0.046 | (0.9314, 0.9755) |
| 5 years | 0.836 | 0.02 | 0.164 | (0.7968, 0.875) |
| 10 years | 0.667 | 0.029 | 0.333 | (0.6101, 0.7238) |
| Patient survival | ||||
| 1 year | 0.95 | 0.011 | 0.05 | (0.9284, 0.9716) |
| 5 years | 0.888 | 0.017 | 0.112 | (0.8547, 0.9213) |
| 10 years | 0.76 | 0.027 | 0.24 | (0.7071, 0.8129) |
Figure 1.
Graft Survival in LRD and LURD
Figure 2.
Patient Survival in LRD and LURD
5. Discussion
Kidney donation by biologically unrelated persons has been attempted in different areas of the world, including the Middle and Far East (5). These donations have received adverse publicity because of multiple factors, including the following: unresolved ethical issues like donor payment and possible coercion, unacceptably high donor and recipient morbidity and mortality, and poor allograft survival rates (6). With these points in mind, our center allows transplantation from living unrelated donors under certain circumstances, like hereditary nephritis, polycystic renal diseases and in the case of re-transplantation. Renal transplantation from living unrelated donors is successful, but has been met with some opposition due to poor tissue antigen compatibility and fear of commercialization.
In the present study, we note several important demographic differences between the two groups. Living unrelated recipients tend to be more elderly with younger donors, and a high percentage of male donors; however, in the living related group there are a high percentage of female donors, which was observed in live-donor programs in most countries, including the United States and Australia (7, 8). In Australia, female donors accounted for 53% and 62% of overall LRD and LURD donors, respectively; the latter likely reflects the growth in spousal donation (9). The reason for the greater proportion of female donors remains unclear, although some contributing factors could be medical (higher rates of cardiovascular disease in men) or psychosocial (financial issues and differing perception towards donation between genders) (10, 11). Our immunological work agrees with Fuller TF et al. and Humar A et al. (12, 13), since the number of live related transplants (LRT) with 3 & 4 HLA & 2DR matching are significantly higher than in the live unrelated transplants (LURT).
We started our transplantation program in the Mansoura urology and nephrology center (UNC) moving from one immunosuppressive protocol to another by starting with steroid and azathioprine and moving to the use of MMF, TAC, and sirolimus. Our study revealed no significant differences between LRT and LURT regarding immunosuppressive protocols, apart from the protocols Steroid-Azathioprine or MMF and Tac-MMF where a higher percentage of LRD group (P < 0.001) and (P = 0.004) respectively and this correlated with better HLA matching that encouraged less immunosuppressive drugs, like a steroid-free regimen (Tac and MMF protocol), while the protocols Steroid-cyclosporine Azathioprine or MMF were significantly higher in the unrelated group (P < 0.001). For induction immunosuppression, we considered the poorer HLA matching in the unrelated group and used anti-thymocyte globulin (ATG) and this correlated with the KDIGO guidelines that recommend the use of ATG, which is a potent immunosuppressive agent, rather than interleukin-2 receptor antibodies principally for groups at high-risk for allograft rejection (14).
Although the incidence of early graft loss because of acute rejection has decreased steadily over the past decades, acute rejection is considered a major risk factor for chronic rejection and a strong predictor of long-term graft survival in both cadaveric and living donor kidney transplants (15, 16). In the present study, the percentages of patients with acute vascular rejection were significantly higher in the unrelated group (P = 0.005). This is not in agreement with Humar A et al. (13), who reported that the incidence of acute rejection was not higher for LURD recipients after comparing 595 LRDs with 116 LURDS; these mismatching results could be explained by the difference in immunosuppression protocols or the difference in HLA matching. Surprisingly in our study, there was no difference in the biopsy proved chronic rejection between both groups (P = 0.07), despite the higher incidence of acute vascular rejection in LURD. We found a higher incidence of early rejection in LURD compared to LRD and this agrees with Fuller et al. and Matas AJ et al. (12, 16), who reported higher percentages of early and severe rejections in LURT than LRT. There are some important factors that might impede the use of LURD sources, such as the elderly age of donors and the higher number of HLA mismatches compared with LRD (12). Our study is not in agreement with previous studies, since the LURD ages were significantly younger than LRD ages; this may be due to most LURD recipients in that study being friends and spouses, which is not the same as in our study. We reported no significant differences in regards to creatinine clearance and serum creatinine for one, three, and five years post transplantation between the two groups.
The one-, five-, and ten-year graft survival rates were 97%, 86.6%, and 67.9%, respectively, for recipients of LRD, while that for recipients of LURD were 95.4%, 83.6%, and 66.7%, respectively (Figure 1) (Tables 8 and 9). The one-, five-, and ten-year patient survival rates were 97.1%, 95.1%, and 80.8%, respectively, for recipients of LRD, while that for recipients of LURD were 95%, 88.8%, and 67%, respectively (Figure 2) (Tables 8 and 9). Worldwide, long-term graft survival of LURD kidneys is also encouraging. For example, in the 2008 annual report of the scientific registry of transplant recipients, the unadjusted five-year survival of LURD kidneys was the same as that of living related donor kidneys (approximately 80 %) (17). In Italy, graft survival rates of 172 LURT recipients were 87% in one year, 79% in five years, and 69% in nine years (18). On the other hand, D’Alessandro AM et al. (19), reported that patient survival in LURD recipients was worse than in LRD recipients; however, this study included a high percentage of diabetic patients.
5.1. Limitations
There are potential limitations associated to our study. First, it is a retrospective single center study. Second, there were many changes in immunosuppressive protocols over the last few decades, but we should consider that the study was comprised of live matched donors and the majority were related donors with insignificant immunological risks in the unrelated group.
5.2. Conclusions
Graft survival is affected by factors like age of the donor, degree of HLA compatibility, original kidney disease, number and severity of acute rejection episodes, despite that kidney transplant recipients who received their grafts either from live related donors or live unrelated donors had a comparable patient and graft survival. Kidney donation by volunteers who are genetically unrelated to their recipients is medically successful, socially valuable, and ethically acceptable provided that donors are healthy, competent, and well-informed.
