Nephrol Dial Transplant (2004) 19 [Suppl 3]: iii26 iii31 DOI: 10.1093/ndt/gfh1011 Non-heart donors Ana Sánchez-Fructuoso 1, Dolores Prats Sánchez 1, María Marqués Vidas 1, Eduardo Lo pez de Novales 2 and Alberto Barrientos Guzmán 1 1 Nephrology Department, Hospital Clı nico San Carlos, Madrid, Spain and 2 Nephrology Service, Hospital Regional Carlos Haya, Ma laga, Spain Abstract Background. Several groups have demonstrated that non-heart donation is a viable source of organs for transplantation. However, the theoretically worse graft function and survival of the kidneys obtained from non-heart donors (NHBDs) is still a matter of debate that has led to consider them as marginal donors for kidney transplantation. Methods. In this report, we compare the outcome and course of 83 kidney transplants from NHBDs with those corresponding to 3177 adult cadaveric heart donor (HBD) transplants performed over the same period in our country. Graft and patient survival were estimated by means of Kaplan Meier analysis. In addition, groups were compared using Cox proportional regression. Results. The delayed graft function (DGF) rate was higher on NHBD transplants than in HBD kidneys (58.8 vs 28.9%, P<0.0001). However, in 1998, where the highest number of NHBD transplants was performed, graft function estimated by serum creatinine levels at 3 months and 1 year, was significantly better in the NHBD transplant group (1.42±0.45 vs 1.66±0.66 and 1.45±0.59 vs 1.62±0.64, respectively, P ¼ 0.01 and 0.07). Graft survival at 2 years was 97%, 95% at 4 years and 84% at 6 years for NHBDs and 97, 90 and 84%, respectively, for HBDs. Interestingly, DGF was a risk factor for worse graft survival in HBDs but not on NHBDs. Conclusions. We conclude that, in our study, both graft function and graft survival of NHBD kidney transplants are at least similar to those from HBD transplants. Therefore, NHBDs should be considered as a viable source of non-marginal kidneys for transplant. Correspondence and offprint requests to: Ana Sánchez-Fructuoso, MD, Nephrology Department Hospital, Clínico San Carlos, Madrid, Spain. Email: asanchez.hcsc@salud.madrid.org Keywords: graft function; heart donor; kidney transplantation; non-heart donor; patient survival Introduction Owing to an ever-increasing number of patients receiving treatment for end-stage renal disease and the adoption of less restrictive criteria for inclusion in the kidney transplant waiting list, there is a growing need for cadaveric kidney donors. Numerous efforts have been made to increase organ donation, and cadaveric kidney donations in Spain have risen, particularly among the older age groups [1]. These measures have led to reduced waiting times as the waiting list gets shorter [1]. At different centres, the shortage of kidneys has prompted the use of non-heart donors (NHBDs). The aim of this paper was both to compare the survival of transplant kidneys from NHBDs with those of kidneys procured from heart donors (HBDs) and to conduct a study of the survival and renal function of transplant kidneys from NHBDs and HBDs, taking into consideration the inter-relationship with delayed graft function (DGF). Subjects and methods In this report, we compare the outcome and course of 83 kidney transplants from NHBDs with those corresponding to 3177 adult cadaveric HBD transplants performed over the same period in our country. Graft and patient survival were estimated by means of Kaplan Meier analysis. In addition, groups were compared using Cox proportional hazards regression. Results Table 1 provides the incidence of HBDs/NHBDs for each year of transplantation (no significant differences were found). Nephrol Dial Transplant Vol. 19 Suppl 3 ß ERA EDTA 2004; all rights reserved
Risk factors for chronic allograft nephropathy iii27 Table 1. Incidence of NHBDs for each year of transplantation Non-heart Table 2 describes creatinine evaluated at 3 months and 1 year post-transplantation, and creatinine changes from 3 months to 1 year in HBDs and NHBDs. In 1998, the highest number of NHBD transplants was performed; there was a trend for better serum creatinine at 1 year in the NHBD transplant group (P ¼ 0.07). When analysing only patients with DGF (Table 3), both creatinine at 3 months and 1 year were significantly higher for HBDs. The proteinuria values at 1 year post-transplantation were significantly lower in NHBD transplants (0.23±0.31 vs 0.35±0.88 g/24 h in the HBD transplants, P ¼ 0.05) The NHBD transplants showed DGF rates of 58.8 vs 28.9% in the HBD transplants (P<0.0001). Multiple regression analysis of risk factors for DGF is provided in Table 4. As can be seen, the NHBD transplant is an independent risk factor for a DGF of 4.3 (95% CI 2.6 7.0). Comparison of graft survival between HBDs and NHBDs Overall Kaplan Meier estimates of graft survival for HBDs and NHBDs are shown in Figure 1. Cox regression showed no significant differences. Graft survival at 2 years was 97%, 95% at 4 years and 84% at 6 years for NHBDs and 97, 90 and 84%, respectively, for HBDs. The presence of DGF in the HBD organ recipients led to lower graft survival (P<0.0001) (Figure 2) but not in type I NHBD transplants (P ¼ 0.92). Cox regression showed that the presence of DGF is a risk factor for graft survival (Table 5) but not in NHBD transplants. Comparison of patient survival between HBDs and NHBDs Overall Kaplan Meier estimates of patient survival for HBDs and NHBDs are shown in Figure 3. No significant differences between both groups were found. Discussion 1990 1994 1998 Overall N % N % N % N % 14 1.8 27 2.6 42 2.9 83 2.5 773 98.2 1007 97.4 1397 97.1 3177 97.5 Chi-square test, P ¼ 0.2606. NHBDs were the primary source of kidney allografts in the early years of clinical transplantation, an era Table 2. Comparison of creatinine between heart/non-heart and years of transplantation 1990 1994 1998 Overall P Non-heart Creatinine at 3 months 1.87±1.03 1.59±0.64 0.3337 1.87±1.17 1.72±0.74 0.8902 1.42±0.45 1.66±0.66 0.0111 1.63±0.86 1.67±0.68 0.2194 Creatinine at 1 year 1.58±0.68 1.65±0.80 0.9948 1.78±1.11 1.73±0.75 0.8968 1.45±0.59 1.62±0.64 0.0650 1.58±0.82 1.66±0.72 0.1860 Creatinine change from 0.29±0.41 0.05±0.66 0.0139 0.09±0.44 0.01±0.55 0.2978 0.03±0.30 0.03±0.49 0.1140 0.06±0.38 0.00±0.55 0.5371 3 months to 1 year P-values were obtained from Kruskall Wallis tests.
iii28 A. Sa nchez-fructuoso et al. Table 3. Comparison of creatinine between heart/non-heart, only for patients with DGF 1990 1994 1998 Overall P Non-heart Creatinine at 3 months 2.18±1.39 1.79±0.72 0.6378 2.14±1.48 2.06±0.94 0.6317 1.49±0.50 1.92±0.83 0.0039 1.78±1.05 1.93±0.85 0.0312 Creatinine at 1 year 1.70±0.94 1.85±0.89 0.5007 2.05±1.39 2.04±0.87 0.4567 1.52±0.69 1.82±0.75 0.0178 1.72±1.00 1.90±0.83 0.0203 Creatinine change from 0.48±0.48 0.06±0.72 0.0179 0.06±0.47 0.02±0.72 0.7202 0.03±0.35 0.08±0.65 0.2060 0.07±0.44 0.03±0.69 0.7456 3 months to 1 year P-values were obtained from Kruskall Wallis tests. when death was defined as the moment when cardiac activity ceased. Because the period of warm ischaemia was often prolonged before revascularization, many grafts failed to function. The poor outcome of these grafts together with the later establishment of criteria for brain death in the 1960s resulted in the practical abrogation of non-heart donation on most transplantation programmes. The everincreasing number of patients undergoing dialysis, together with less restrictive transplant criteria, have led to a shortage of cadaveric kidneys for transplant. At the end of the year 2000, out of a total population approaching 39 million, 3986 patients were waiting for a kidney transplant in our country and the number of kidneys harvested from HBDs has stabilized [2]. Although there is a need to extend the use of brain-dead HBDs, there is still room for additional sources of organs, and this has prompted the use of NHBDs. It has been estimated that NHBDs permit a 7 40% increase in the number of transplants performed [3 10]. In accordance with the findings of others [5,8, 10 14], this series of renal transplants from NHBDs demonstrate an excellent long-term graft survival and renal function, although reduced NHBD graft survival rates have been previously reported by others [3,7,9]. Patients receiving NHBD kidneys underwent longer periods of oligoanuria and required longer periods of haemodialysis in accordance with data published by other authors [3 11,13,14]. Interestingly, delayed function of the NHBD graft was not associated with poorer graft outcome in our series, although due to the reduced number of subjects available, the analysis is not powered enough to ensure it. Moreover, it should be highlighted that renal function in 1998 when the highest number of NHBD transplants was performed was better at 1 year in the NHBD transplants with respect to HBD transplants. We considered the possibility that factors related to brain death might be detrimental for the outcome of HBD transplants. The kidney has a remarkable capacity to recover from an acute non-specific insult, such as the effects of donor brain death. If the insult is too severe, however, renal function may never return to baseline. Indeed, the damaged organ may develop progressive functional deterioration and irreversible chronic structural changes. Therefore, if DGF is interpreted as a possible mark for severe injury associated with brain death, it is not surprising that when renal function is compared only between patients that suffer DGF, HBD transplants achieve worse renal function than NHBD transplants. These clinical findings may support the accumulating evidence that severe brain lesions mediate detrimental effects on the graft. Severe injury of the brain is associated with a massive release of pro-inflammatory cytokines [15 17], and high-level expression of vascular and tubular adhesion molecules and MHC II is seen in kidneys from human cadaver donors as opposed to living-related grafts [18].
Risk factors for chronic allograft nephropathy Table 4. Risk factors for DGF (multiple logistic regression) iii29 % 95% CI OR 95% CI P HCVAb 0.0019 Negative 26.4 (24.6%, 28.3%) 1 Positive 33.9 (29.5%, 38.6%) 1.429 (1.141, 1.790) Donor age <0.0001 60 years 26.0 (24.2%, 27.9%) 1 >60 years 37.5 (32.7%, 42.5%) 1.704 (1.350, 2.151) Donor sex 0.0001 Male 30.0 (27.9%, 32.2%) 1 Female 23.0 (20.4%, 25.9%) 0.698 (0.581, 0.838) Cause of death <0.0001 ACV 32.5 (29.9%, 35.2%) 1 TCE 23.7 (21.6%, 26.0%) 0.645 (0.542, 0.769) Prior transplantation 0.0007 No 26.5 (24.7%, 28.3%) 1 Yes 35.6 (30.5%, 41.0%) 1.534 (1.197, 1.967) Donor type <0.0001 Non-heart 61.1% (49.4%, 71.7%) 1 26.7 (25.1%, 28.5%) 0.232 (0.143, 0.378) Immunosuppressive treatment <0.0001 Pre þ Aza þ CsA 11.8 (3.0%, 36.7%) 1.282 (0.802, 2.048) 0.2998 Pre þ Aza þ CsA þ Ab 29.4% (25.8%, 33.2%) 0.781 (0.473, 1.288) 0.3324 Pre þ CsA 40.6 (34.4%, 47.0%) 2.047 (1.239, 3.381) 0.0051 Pre þ CsA þ Ab 20.7 (16.5%, 25.5%) 1.459 (0.830, 2.564) 0.1889 Pre þ MMFþ CsA 26.8 (20.4%, 34.2%) 1.690 (1.053, 2.712) 0.0296 Pre þ MMF þ CsA þ Ab 24.0% (20.3%, 28.0%) 0.934 (0.540, 1.616) 0.8071 Pre þ MMFþ Tac (with/without Ab) 36.3 (28.6%, 44.9%) 1 Pre þ ANTIL þ Aza þ CsA 21.9 (17.7%, 26.8%) 3.988 (0.864, 18.412) 0.0763 Other 27.6 (25.9%, 29.3%) 1.898 (1.161, 3.104) 0.0106 Cold ischaemia time <0.0001 24 h 25.7 (24.0%, 27.6%) 1 >24 h 37.1 (32.7%, 41.7%) 1.703 (1.372, 2.113) Centre <0.0001 Table 5. Risk factors for graft survival RR 95% CI P HCVAb (ref. no ) 1.365 (1.103, 1.688) 0.0042 DGF (ref. no ) 1.747 (1.368, 2.230) <0.0001 Cause of death 0.782 (0.654, 0.935) 0.0070 (ref. ACV ) Donor age (ref. 1.504 (1.246, 1.816) <0.0001 <60 years ) Peak panel reactive Ab. 1.287 (1.053, 1.573) 0.0139 (ref. 15% ) Year of transplantation 0.0126 Centre <0.0001 Living donors were excluded from this analysis. Ref., reference. From our results, it may be concluded that the NHBDs represent a viable source of non-marginal kidneys for transplant. Although the use of brain-dead donors with hearts could be extended, there is still much need for additional sources. The authors feel that every effort should be made to encourage transplant centres that have not yet considered the use of NHBDs to do so. This may permit a substantial reduction in the ever-growing list of patients waiting for transplant. Fig. 1. Actuarial graft survival in NHBD and HBD transplants. HBD transplants (solid line), NHBD transplants (broken line). Survival rates were estimated by Kaplan Meier analysis. The logrank test was used to calculate the P-values.
iii30 A. Sa nchez-fructuoso et al. Fig. 2. Actuarial graft survival in renal transplants according to the presence (solid line) or absence (broken line) of DGF. Right, HBD transplants; left, NHBD transplants. Survival rates were estimated by Kaplan Meier analysis. The log-rank test was used to calculate the P-values. Fig. 3. Actuarial patient survival in NHBD and HBD transplants. HBD transplants (solid line), NHBD transplants (broken line). Survival rates were estimated by Kaplan Meier analysis. The logrank test was used to calculate the P-values. Conflict of interest statement. None declared. References 1. Miranda B, Fernandez Lucas M, de Felipe C et al. Organ donation in Spain. Nephrol Dial Transplant 1999; 14 [Suppl 3]: 15 21 2. Miranda B, Fernández Zincke E, Can o n J, Cuende N, Naya MT, Garrido G. Características de los donantes renales en Espan a: factores de riesgo y o rganos desechados para trasplante. Nefrologı a 2001; 4: 111 118 3. Valero R, Sa nchez J, Cabrer C, Salvador L, Oppenheimer F, Manyalich M. Organ procurement from non-heart- donors through in situ perfusion or total body cooling. Transplant Proc 1995; 27: 2899 2900 4. Daemen JHC, de Wit RJ, Bronkhorst MWGA, Yin M, Heineman E, Kootstra K. Non-heart donor program contributes 40% of kidneys for transplantation. Transplant Proc 1996; 28: 105 106 5. Alonso A, Buitron JG, Go mez M et al. Short- and long-term results with kidneys from non-heart- donors. Transplant Proc 1997; 29: 1378 1380 6. Nicholson M, Dunlop P, Doughman T et al. Work-load generated by the establishment of a non-heart kidney transplant programme. Transplant Int 1996; 9: 603 606 7. Nicholson ML, Horsburgh T, Doughman TM et al. Comparison of the results of renal transplant from conventional and non-heart- cadaveric donors. Transplant Proc 1997; 29: 1386 1387 8. Sa nchez-fructuoso AI, Prats D, Naranjo P et al. Renal transplantation from non-heart donors: a promising alternative to enlarge the donor pool. J Am Soc Nephrol 2000; 11: 350 358 9. González Segura C, Castelao AM, Torras J et al. A good alternative to reduce kidney shortage. Transplantation 1998; 65: 1465 1470 10. Gok MA, Buckley PE, Shenton BK et al. Long-term renal function in kidneys from non-heart- donors: a single-center experience. Transplantation 2002; 74: 664 669 11. Wijnen RMH, Booster Mh, Stubenitsky BM, De Boer J, Heineman E, Kootstra K. Outcome of transplantation of nonheart donor kidneys. Lancet 1995; 345: 1067 1070 12. Schlumpf R, Weber M, Weinreich T, Klotz H, Zollinger A, Candinas D. Transplantation of kidneys from non-heart donors: an update. Transplant Proc 1995; 27: 2942 2944 13. Weber M, Dindo D, Demartines N, Ambuhl PM, Clavien PA. Kidney transplantation from donors without a heartbeat. N Engl J Med 2002; 347: 248 255
Risk factors for chronic allograft nephropathy 14. Cho YW, Terasaki PI, Cecka JM, Gjertson DW. Transplantation of kidneys from those donors whose hearts have stopped. N Engl J Med 1988; 338: 221 225 15. Takada M, Nadeau KC, Hancock WW et al. Effects of explosive brain death on cytokine activation of peripheral organs in the rat. Transplantation 1998; 65: 1533 1542 16. Van der Hoeven JA, Ploeg RJ, Postema F et al. Induction of organ dysfunction and up-regulation of inflammatory markers in the liver and kidneys of hypotensive brain dead rats: a model iii31 to study marginal organ donors. Transplantation 1999; 68: 1884 1890 17. Pratschke J, Wilhelm MJ, Kusaka M et al. Brain death and its influence on donor organ quality and outcome after transplantation. Transplantation 1999; 67: 343 348 18. Koo DD, Welsh KI, McLaren AJ et al. Cadaver versus living donor kidneys: impact of donor factors on antigen induction before transplantation. Kidney Int 1999; 56: 1551 1559