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Marginal donors: A viable solution for organ shortage
ELSEVIER
Marginal Donors: A Viable Solution for Organ Shortage G.M. Abouna
T
HE DEMAND for organ transplantation has been increasing very rapidly because of increasing success and the rising incidence of end-stage failure of many vital organs, including the kidney, the liver, and the heart, while the supply of organs from optimal donors has remained low and insufficient to meet the increasing demand. Indeed, over the period 1988 to 1996, the number of patients on the transplant waiting list in the USA has increased from 15,000 to more than 50,000, while the number of transplants performed each year increased from 12,000 to only 20,000. In addition, the number of patients dying on the waiting list each year, varies from about 9% for kidney recipients to 24% for liver and 32% for heart recipients. Many of these patients can be saved if marginal organs are used for transplantation instead of being discarded.‘” CL4SSlFlCATlON
OF MARGINAL DONORS
Suboptimal and marginal donors that have been used by ourselves and by other centres during the past 16 years include: elderly donors; paediatric donors; diabetic donors; cadaver organs with long cold ischemia times; non-heartbeating donors; organs with vascular and anatomic anomalies; ABO-incompatible donors; and donors with elevated serum creatinine, hypertension, or infection. THE OLDER DONOR
There are well-known age-associated changes in most vital organs, including glomerular sclerosis, tubular atrophy, and interstitial fibrosis in the case of kidneys; coronary artery disease in the case of hearts; steatosis in the case of livers, and an increase in sensitivity to ischemic damage in all.‘-” It has been observed during the past decade that, while the number of elderly donors has increased, the rate of discard of such donors has also increased, because many centres are still reluctant to use organs from such donors under the pressure of the recent managed care system and the fear that they will have a negative effect on their own centre-specific data, which is published by UNOS in the USA. On the other hand, many centres, including our own, have been utilizing most of these donors because of acute organ shortage and with very acceptable results.“,8Z9,13-‘5 In cadaveric renal transplantation, Sautner et al’” have reported similar graft survival rates at 1 and 3 years for kidneys taken from donors older than 60 years, compared with kidneys from younger donors. At our centre we also 0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation
Proceedings,
29, 2759-2764
(1997)
reported similar l- and 2-year graft survival in 30 kidneys taken from donors aged 56 to 73 years compared with 64 kidneys from younger donors.’ However, the serum creatinine in the recipients of older donors was significantly higher than in recipients of younger ones. Llovera? compared the Spanish results of 250 kidneys from donors aged 55 to 72 years with younger donors and they too found no difference in graft survival at 2 to 5 years, but the serum creatinine was significantly higher in the older kidneys. In our own series, renal biopsies of older kidneys, which were performed before transplantation, showed some degree of glomerular sclerosis, interstitial fibrosis, and arterial thickening in some 83% of the kidneys used. Similar results have been reported in kidneys transplanted from living related older donors compared as with younger one from India, Korea, and Japan.‘6-‘8 In liver transplantation, Adam and Bismuth” reported no difference in graft function and patient survival when the liver donor was aged 53 +- 3 years compared with younger donors, whereas a more recent report by Emre and Miller” demonstrated excellent survival results in 36 liver grafts from donors aged 70 to 84 years at 3 months and at 1 year. In cardiac and lung transplantation. reports from several centres have shown comparable graft survivals at 1 and 5 years in recipients from donors aged 41 to 59 years as compared with younger donors. “,19.‘0 Two other important observations in the use of older donors were recently reported. Cecka and Terasaki analyzed the results of some 45,000 cadaver donor transplants carried out in the USA between 1987 and 1994 and showed that survival of kidney grafts from donors older than 60 years of age was the highest at 1 to 10 years, when these kidneys were transplanted in recipients of the same age.‘i Mizutani et al showed that kidneys from older donors had a significantly higher survival when the weight of the recipient was less than 55 kg as compared with larger recipients.‘2 Both these studies indicate that older kidneys will have better survival when they are transplanted into From the College of Medicine & Medical Sciences, Arabian Gulf University, Manama, Bahrain; and the Department of Surgary, Allegheny University of Hea.ith Sciences, Philadelphia, Pennsylvania. Address reprint requests to Dr George M. Abouna, MD, Dean, College of Medicine & Medical Sciences, Professor & Chairman, Department of Surgery, Arabian Gulf University, P.O. Box: 22979, Manama, Bahrain.
0041-1345/97/$17.00 PII SO041 -1345(97)00667-2
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recipients with lower functional demand, due to age or low body weight. Finally, from our own experience and that of others, it has been shown that there is higher morbidity in older kidneys when they are subjected to longer cold ischemia time and when renal biopsy shows marked histologic changes of the aging process.6,8,9 On the basis of current experience and available data, it can be safely recommended that kidneys from older donors can be successfully used if: frozen section renal biopsy shows <25% glomerulosclerosis; the kidneys are given to older recipients whenever possible; ischemia time is reduced to minimum and, when it exceeds 24 hours, pulsatile perfusion is used. Older hearts should undergo bench coronary angiography and older livers should undergo biopsy before transplantation to determine that the degree of macrovesicular steatosis is less than 30%. PAEDIATRIC DONORS
Kidneys from donors aged less than 5 years have certain inherent risk factors that have made many centres reluctant to using them for transplantation into adults. These include: small nephron mass, leading to poor initial function; small vessels and ureters, causing technical difficulties; higher rate of vascular thrombosis; higher incidence of posttransplant hypertension; and increased sensitivity to cyclosporine and to prolonged cold ischemia. 23 Because of these problems many centres have been reluctant to use paediatric kidneys for transplantation, whereas a few others have resorted to enbloc transplantation of two kidneys into one recipientz4 However, because of the increasing shortage of donors, we and others have resorted to transplantation of single kidneys into adult recipients with excellent results.23,25 Vander Vliet et al compared the rate of graft survival and function in 25 single paediatric kidneys (~3 years) transplanted in adults with 28 pairs of kidneys transplanted enbloc, and graft survival and the mean highest creatinine clearance were similar at 1 and 5 yearsz6 Sutherland reported the results of 98 single paediatric kidneys (Cl0 years of age) and 33 enbloc double kidneys into adult recipients and again showed that, except for retransplantation, graft survival and function were comparable in the two groups.27 During the period from 1992 to 1994 we transplanted 76 paediatric kidneys into adult recipients. Ten pairs were transplanted enbloc, the remainder as single grafts in adults. Of these 55 kidneys came from donors aged 0.5 to 5 years. We showed that graft survival at 1, 5, and 10 years was 83%, 56%, and 46% respectively, which is similar to that seen in adult kidneys. It was also shown that graft hypertrophy and improvement in function were completed by 6 months, with a creatinine clearance rising from 15 2 8 mL/min at 1 month to 50 5 11 at 6 months. Graft loss due to vascular thrombosis was only 4% and ureteric complications occurred in 6%, but all were salvaged.23 From this experience, and in view of the severe shortage of organs, we strongly recommend that all paediatric kidneys from donors >6 months should be transplanted as single organs in
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children and in adults and that such kidneys should be matched with a smaller sized and nonhypertensive adult recipient to the extent possible and that percutaneous heparin should be used for the first 72 hours followed by oral aspirin and persantime long term. It is also recommended that interrupted vascular suture and temporary stenting of the ureter should be carried out at operation and that induction immunosuppression with delayed cyclosporine therapy is advisable. KIDNEY GRAFTS FROM DIABETIC DONORS
In 1983, we showed, for the first time, that the transplantation of kidneys from a diabetic donor with good renal function into nondiabetic recipients was successful and resulted in improvement in early diabetic nephropathy, which had existed in the donor.28 In a subsequent report we showed that, in one of the recipients who became diabetic and required insulin, diabetic nephropathy in the grafted kidney returned, confirming that uncontrolled hyperglycemia is the primary cause of diabetic nephropathy, rather than any intrinsic predisposition of the kidney.29 Since that time other centres have began to use diabetic donors for kidney transplantation, with similar good results, as recently reported by Spees et al.” GRAFTS WITH PROLONGED ISCHEMIA TIME
Until recently, many centres were reluctant to utilize kidney grafts that had been preserved for longer than 30 hours, whether by cold storage or hypothermic perfusion. This policy was based on the fact that there are adverse consequences following prolonged ischemia, which include increased incidence of primary nonfunction, increased rate of delayed graft function requiring haemodialysis, and reduced graft survival, particularly when marginal donors were used. While working in Kuwait in the early 1980s where cadaveric organs were not available, we adopted the policy of accepting kidneys with long preservation times of 30 to 76 hours, which had been turned down by other centres in Europe and the USA. A total of 61 such kidneys were transplanted after cold preservation in 47 and pulsatile perfusion in 14.” It was shown in that trial that the rate of primary nonfunction and long-term graft survival at 1 and 2 years were similar, regardless of the period of ischemia. The only difference seen was that when the period of ischemia exceeded 50 hours there was a higher incidence of delayed function and the need for posttransplant dialysis. It was also shown that hypothermic perfusion significantly reduced the incidence of delayed graft function and the need for dialysis and that both early and late graft function were significantly improved if cyclosporine was withheld until full diuresis was established. These results were recently confirmed by Light and colleagues who showed that, during preservation for up to 45 hours, pulsatile perfusion significantly increased the rate of immediate graft function, thus reducing hospital stay and transplant costs. 32 Similarly, Tesi and colleagues have recently shown that the use of pulsatile perfusion allows the
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identification of certain parameters that can help in the elimination of high-risk marginal donors and result in a much reduced rate of delayed function without compromising patient outcome. 33 Matsuno and colleagues have also shown that the use of machine perfusion preservation as a viability determinant is an effective method in preservation of kidneys procured from non-heart-beating donors.34 From these data the following recommendations can thus be made regarding the graft with prolonged cold ischemia: (1) good graft preservation is possible with the use of pulsatile perfusion, which also helps in predicting graft viability. (2) In the case of marginal donors, (eg, the elderly, paediatrics, and hypertensives), cold ischemia time should be kept as brief as possible, regardless of the method of preservation, and induction immunosuppression should be carefully selected and administration of cyclosporine delayed until graft diuresis has been established. NON-HEART-BEATING
DONORS
The current shortage of organs has lead to the reintroduction of the old and accepted concept of non-heart-beating donors with greater understanding and clarification of the different classes of this type of donor, the method of in situ preservation of the organs before removal, and the application of improved methods of preservation before transplantation. According to the Maastricht classification there are four categories of non-heart-bearing donors (NHBD): (1) dead on arrival; (2) unsuccessful resuscitation; (3) awaiting cardiac arrest with diagnosed brain death; and (4) sudden cardiac arrest in a brain dead donor.3” Maastricht category 3 is also called controlled NHBD, which is the ideal situation, whereas the other categories are uncontrolled types of NHBD. There are now considerable data to show that the results of kidney, liver, and pancreas transplantation from controlled non-heart-beating donors are excellent, providing that the warm ischemia time is less than 30 to 45 minutes, which is followed by in situ perfusion cooling of the organs using a three- or a four-lumen catheter.36,“7 To increase the organ supply, many centres throughout the world are now using controlled and uncontrolled non-heart-beating donors for kidney, liver, and other organ transplants. However, there are a number of important issues that must be considered when a non-heart-beating cadaver programme is used. These include: ethical issues; family consent; and method of in situ cooling to reduce warm ischemia time, such as employing peritoneal cooling or intraarterial cooling by aortofemoral cannula or hypothermic cardiopulmonary bypass. Also, the method of organ preservation, whether by simple cooling or hypothermic perfusion, are important. In most reports, the results of long-term graft survival of kidneys from NHBD cases are comparable to those of brain dead donors, although there is greater primary graft nonfunction or delayed graft function especially with elderly donors and after long cold storage.36-39 The latter are considerably reduced by using pulsatile
perfusion preservation.40 It is estimated that, by using NHBD, the number of available organs for transplantation can be increased by 20% to 50%. In the case of liver and pancreas, it is generally agreed upon that only controlled NHBDs should be used.4’ ABO-INCOMPATIBLE
GRAFTS
Because ABO antigens are represented on the vascular endothelium of the graft, the use of ABO incompatible grafts may result in antibody-mediated hyperacute or accelerated rejection. 42 However, if the AI30 antibody is removed, and particularly if further production of antibody is halted by splenectomy, successful transplantation across the ABO barrier becomes possible.43-46 Starzl was the first to report a successful renal transplant across the ABO barrier in 1964.47 With recent technological developments of plasmapheresis and immunoadsorption, many centres have embarked on the use of ABO-incompatible kidney and liver grafts with excellent results.43,44,46”’ It has been shown that successful transplantation can be carried out assuming that the level of preformed antibody is sufficiently lowered by plasmapheresis or immunoadsorption 1 to 2 weeks prior to transplantation and then quadruple immunosuppression is employed. The importance of splenectomy has been emphasized by Alexander et a143and also by Toma, who obtained 84% l-year graft survival when both immunoadsorption or plasmapheresis with splenectomy were carried out. In 1984, Brynger et al and, more recently, Nelson et al, have shown that, when A2 donors are used, successful transplantation can be carried out without resorting to plasmapheresis or immunoadsorption, particularly when the anti-IgG titer for the A2 antigen in the recipient is 10w.~~These results have been confirmed by others as it has been shown that the A2 antigen is very weak compared with Al or B antigens.44,4s*5” It can be concluded that successful transplantation is possible with ABO-incompatible grafts when the preformed antibody is removed by plasmapheresis or immunoadsorption to a titer of less than 1:4, when splenectomy is carried at the time of transplantation, and when quadruple immunosuppression with steroids, ATG, MMF, or azathioprine and cyclosporine is used. In the A2 subgroup of donors recipient preparation may not be necessary if the anti-A, IgG titer is less than 1:s. MULTIPLE RENAL ARTERIES AND VASCULAR ANOMALIES
Until recently, many centres have been reluctant to use kidneys with multiple arteries, especially when other suboptimal conditions exist, such as donor age, long cold ischemia time, etc, for fear of technical complication and graft loss. Theoretically, multiple renal arteries are more likely to lead to technical complications during anastomosis with increased incidence of arterial stenosis and thrombosis, increased operating time, prolonged relative cold isch-
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emia time, and ischemic damage to the ureter and decreased graft survival. 54-56 Because approximately 30% of kidneys have multiple renal arteries, and in 10% of these this is bilateral, many good grafts are lost if such kidneys are discarded.54 Recent experience by several centres, including our own, has shown that the aforementioned theoretical problems can be avoided with good surgical techniques and excellent graft survival can be obtained. In this way all available kidneys can be utilized. Kidneys with more than one artery can be safely and effectively used by employing the following technical modifications, either at the time of transplantation or at “bench surgery” before transplantation. Methods used to deal with bilateral renal arteries at transplantation include: (1) both arteries are anastomosed end-to-side to the external iliac artery with or without an arterial patch; (2) each artery is anastomosed end-to-end to the two branches of the internal iliac; (3) one artery is anastomosed end-to-side to the external iliac artery and the other end-to-end to the internal iliac artery; and (4) one artery is anastomosed end-to-side to the external iliac artery, and the other, usually a lower pullout, is anastomosed end-to-end to the inferior hypogastric artery. With bench surgery prior to transplantation, while the kidney is still in ice, the following techniques have been employed: (1) the smaller of the two arteries is anastomosed end-toside to the larger artery; (2) side-to-side anastomosis of the two arteries is done to form one common trunk; (3) an autologous bifurcating artery with a large common trunk is connected to the two renal arteries end-to-end; and (4) the upper polar artery is ligated if the area of ischemia is less than 1 cm*. By employing these techniques, several large series have been reported, where the incidence of vascular and ureteric complications has been very similar to that obtained with kidneys having single renal arteries.“’ Indeed, we have used a right kidney from a Syear-old child with five renal arteries and five veins, with one of these arteries, to the inferior pole, having been accidentally divided. The kidney was rejected by all the transplant centres in Pennsylvania. Using the bench surgery techniques the divided artery was successfully repaired and the aortic cuff was split into two segments, one bearing two and the other three vessels. The kidney was then transplanted into an adult patient with the two arterial and venous cuffs anastomosed end-to-side to the iliac artery and iliac vein, respectively. This patient continues to have normal renal function 5 years later (Figs 1 and 2) Clearly, when multiple vascular procedures have to be carried out, there may be an increased incidence of ATN. In a very large series of some 998 kidneys at the University of Minnesota, recently reported by Benedetti et al, there was no significant difference in graft survival, nor in the rate of vascular and urologic complications, at 1 and 5 years, between kidneys with single and multiple renal arteries5” Therefore, it is recommended that kidneys with multiple renal arteries should be used, either by direct anastomosis
Fig 1. Paediatric right kidney with five renal arteries with inferior polar branch accidentally divided.
of the two arteries at the time of transplantation or by performing appropriate bench surgery. At all times, the lower polar artery must be preserved while the upper polar artery may be ligated if it supplies less than 1 cm* of cortex. During anastomosis, interrupted sutures of 6/O or 7/O should be used or a “growth factor” should be employed if the anastomosis is carried out with continuous suture. In our center, we employ subcutaneous heparin for the first 72 hours followed by oral aspirin and persentin long term. OTHER
TYPES
OF MARGINAL
DONORS
Donors with hypertension or higher serum creatinine, and those with positive serology for CMV, constitute suboptima1 grafts and are rejected by many centres. Chou et al showed that, although the l-year graft survival for cadaver
Fig 2. Same kidney as in Fig 1. The inferior polar artery having been repaired. The aortic cuff was then divided into two segments: one bearing three and the other two of the arterial branches that were separately anastomosed to the external iliac artery.
MARGINAL DONORS
kidneys is very similar, regardless of presence of hypertension in the donor, the long-term survival was significantly reduced.57 Busson showed that the l- and 2-year survival of kidney and cardiac grafts was significantly reduced when donors with positive CMV serology are used.58 CONCLUSION
There are considerable data and experience to support the policy that no marginal or suboptimal graft should be discarded due to donor age, diabetes, or presence of multiple arteries, providing that renal function in the donor is normal. Kidney grafts from non-heart-beating cadavers or those with long ischemia tinies can all be used successfully, especially if the kidney is preserved by pulsatile perfusion rather than by simple hypothermia. ABO-incompatible grafts can be used successfully, providing that adequate removal of preformed anti-Al30 antibody is carried out prior to transplantation and at the time of transplantation a splenectomy is performed. It is estimated that, by using such suboptimal donors, the current organ supply can be increased by another 25% to 30%, thus making successful transplantation therapy available to a larger number of patients currently on the rapidly expanding national transplant recipient waiting list all over the world. REFERENCES 1. Alexander JW, Vaughn WK: Transplantation 51:135, 1991 2. UNOS Bulletin, Vol 1, Dee 1996 3. UNOS Update, July/August 1996, p 28 4. Douzdjian V, Gugliuzza KG, Fish JC: Transplant Proc 27: 3128, 1995 5. Roels L, Christiaens MR, Waer M, et al: Transplant Proc 27:795, 1995 6. Cofan F, Oppenheimer F, Campistol JM, et al: Transplant Proc 28:2248, 1995 7. Gonzalez SC: Transplant Proc 27~2409, 1995 8. Lloveras J, Arias M, Puig JM, et al: Transplant Proc 25:3175, 1993 9. Kumar MS, Stephan R, Chui J, et al: Transplant Proc 25:3097, 1993 10. Albrechtsen D, Leivestad T, Soda1 G, et al: Transplant Proc 27~986, 1995 11. Milan0 A, Livi U, Casula R, et al: Transplant Proc 25:3158, 1993 12. Orlowski JP, Spees EK: Transplant Proc 25:3101, 1993 13. Sautner T, Gotzinger P, Wamser P, et al: Transplant Proc 23:2598, 1991 14. Cantarovich D, Giral-Classe M, Le Sam JN, et al: Clin Transplant 8:237, 1994 15. Adam R, Astarcioglu I, Azoulay D, et al: Transplant Proc 23:2602, 1991 16. Kumar A, Kumar RV, Srinadh ES, et al: Clin Transplant 8:523, 1994 17. Emre S, Myron E, Schwartz E, et al: Transplantation 62:62, 1996 18. Hayashi T, Koga S, Higashi Y, et al: Transplant Proc 27:984, 1995
2763 19. Ladowski JS, Beatty L, Sullivan M, et al: J Thorac Cardiovast Surg 106:1236, 1993 20. Sundaresan S, Semenkovich J, Ochoa L, et al: J Thorac Cardiovasc Surg 109:1075, 1995 21. Cecka JM, Terasaki PI: Transplant Proc 27:801, 1995 22. Mizutani N, Kotoh S, Yamada Y, et al: Transplant Proc 28:1589, 1996 23. Abouna GM, Kumar MSA, Chvala R, et al: Transplant Proc 28:2564, 1995 24. Nghiem DD, Hsia S, Carpenter BJ, et al: Clin Transplant 8:213, 1994 25. Gourlay W, Stothers L, McLaughlin MG, et al: J Urol 153:322, 1995 26. Vander Vliet JA, Persijin GG, Cohen M: In Abouna GM (ed): Clinical Organ Transplantation, Amsterdam-Martinus Nijhoff; 1984, p 115 27. Sutherland DER, Rainer QG, Grussmer WG, et al: Dordrecht-Kluwer; p 201, 1991 28. Abouna GM, Adnani MS, Kremer GM, et al: Lancet ii:1274, 1983 29. Abouna GM, Adnani MS, Kumar MSA, et al: Lancet i:622, 1986 30. Spees EK, Orlouski JP, Fitting KM, et al: Transplant Proc 22:378, 1990 31. Abouna GM, Samham MS, Kumar MSA, et al: Transplant Proc 19:2051, 1987 32. Light JA, Kowalski AE, Gage F, et al: Transplant Proc 28:2962-4, 1995 33. Tesi RJ, Elbhammas EA, Davies EA, et al: Clin Transplant 8:134, 1994 34. Matsuno N, Sakurai E, Tamaki I, et al: Transplant Proc 26~2421, 1994 35. Kootstra G: Transplant Proc 28:2965, 1995 36. Heineman E, Daemen JHC, Kootstra G: Transplant Proc 28:2895, 1995 37. Lloveras J, Puig JM, Cerda M, et al: Transplant Proc 27:2909, 1995 38. Bell P, Dibekoglu M, Gonzalez C, et al: Transplant Proc 28:2951, 1995 39. Daemen JW, Kootstra G, Wijnen RM, et al: Clin Transplant 8:303, 1994 40. Daemen JHC, Heineman E, Kootstra G: Transplant Proc 28:2906, 1995 41. D’Allesandro A, Hoffman R, Knechtle SJ, et al: Abstracts of ASTS Annual Scientific Meeting, Chicago, IL, 1995, p 115 42. Alexander GPJ, Latinne D, Gianello P, et al: Clin Transplant 5:583, 1991 43. Alexander GPJ, Latinne D, Carlier M, et al: Transplant Rev 5:230, 1991 44. Toma H: Urol Clin N Am 21:299, 1994 45. Takahashi K, Yagisawa T, Sonda K, et al: Transplant Proc 25:271, 1993 46. Boudreaux JP, Hayes DH, Mizrahi S, et al: Transplant Proc 25:1874, 1993 47. Starzl TF, Morchioro TL, Holmer JH, et al: Surgery 55:195, 1964 48. Nelson PW, Helling TS, Shield CF, et al: Am J Surg 164:541, 1992 49. Slapak M, Digard N, Ahmed M: Transplant Proc 22:1425, 1990 50. Tanabe K, Takahashi K, Sonda K. et al: Transplant Proc 27: 1020, 1995
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51. Toma Y, Tanaba K, Fujita S, et al: Transplant Int 6:313, 1993 52. Yamazaki Y, Kawaguchi H, Ito K, et al: .I Ural 154:914,1995 53. Brynger H, Rydberg L, Samuelsson B, et al: Transplant Proc 16:1175, 1984
55. Benedetti E, Troppmann C, Gillingham K, et al: Ann Surg 221:406, 1995
54. Ganesan KS, Huilgol AK, Sundar S, et al: Transp Proc 26:2101, 1994
58. Busson M, N’Doye P, Benoit G, et al: Transplant 27:1662, 1995
56. Khauli R: Ural Clin N Am 2~321, 1994 57. Chou SW, Norman DJ: Transplantation
46:89, 1988 Proc
Marginal Donors: A Viable Solution for Organ Shortage G.M. Abouna
T
HE DEMAND for organ transplantation has been increasing very rapidly because of increasing success and the rising incidence of end-stage failure of many vital organs, including the kidney, the liver, and the heart, while the supply of organs from optimal donors has remained low and insufficient to meet the increasing demand. Indeed, over the period 1988 to 1996, the number of patients on the transplant waiting list in the USA has increased from 15,000 to more than 50,000, while the number of transplants performed each year increased from 12,000 to only 20,000. In addition, the number of patients dying on the waiting list each year, varies from about 9% for kidney recipients to 24% for liver and 32% for heart recipients. Many of these patients can be saved if marginal organs are used for transplantation instead of being discarded.‘” CL4SSlFlCATlON
OF MARGINAL DONORS
Suboptimal and marginal donors that have been used by ourselves and by other centres during the past 16 years include: elderly donors; paediatric donors; diabetic donors; cadaver organs with long cold ischemia times; non-heartbeating donors; organs with vascular and anatomic anomalies; ABO-incompatible donors; and donors with elevated serum creatinine, hypertension, or infection. THE OLDER DONOR
There are well-known age-associated changes in most vital organs, including glomerular sclerosis, tubular atrophy, and interstitial fibrosis in the case of kidneys; coronary artery disease in the case of hearts; steatosis in the case of livers, and an increase in sensitivity to ischemic damage in all.‘-” It has been observed during the past decade that, while the number of elderly donors has increased, the rate of discard of such donors has also increased, because many centres are still reluctant to use organs from such donors under the pressure of the recent managed care system and the fear that they will have a negative effect on their own centre-specific data, which is published by UNOS in the USA. On the other hand, many centres, including our own, have been utilizing most of these donors because of acute organ shortage and with very acceptable results.“,8Z9,13-‘5 In cadaveric renal transplantation, Sautner et al’” have reported similar graft survival rates at 1 and 3 years for kidneys taken from donors older than 60 years, compared with kidneys from younger donors. At our centre we also 0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation
Proceedings,
29, 2759-2764
(1997)
reported similar l- and 2-year graft survival in 30 kidneys taken from donors aged 56 to 73 years compared with 64 kidneys from younger donors.’ However, the serum creatinine in the recipients of older donors was significantly higher than in recipients of younger ones. Llovera? compared the Spanish results of 250 kidneys from donors aged 55 to 72 years with younger donors and they too found no difference in graft survival at 2 to 5 years, but the serum creatinine was significantly higher in the older kidneys. In our own series, renal biopsies of older kidneys, which were performed before transplantation, showed some degree of glomerular sclerosis, interstitial fibrosis, and arterial thickening in some 83% of the kidneys used. Similar results have been reported in kidneys transplanted from living related older donors compared as with younger one from India, Korea, and Japan.‘6-‘8 In liver transplantation, Adam and Bismuth” reported no difference in graft function and patient survival when the liver donor was aged 53 +- 3 years compared with younger donors, whereas a more recent report by Emre and Miller” demonstrated excellent survival results in 36 liver grafts from donors aged 70 to 84 years at 3 months and at 1 year. In cardiac and lung transplantation. reports from several centres have shown comparable graft survivals at 1 and 5 years in recipients from donors aged 41 to 59 years as compared with younger donors. “,19.‘0 Two other important observations in the use of older donors were recently reported. Cecka and Terasaki analyzed the results of some 45,000 cadaver donor transplants carried out in the USA between 1987 and 1994 and showed that survival of kidney grafts from donors older than 60 years of age was the highest at 1 to 10 years, when these kidneys were transplanted in recipients of the same age.‘i Mizutani et al showed that kidneys from older donors had a significantly higher survival when the weight of the recipient was less than 55 kg as compared with larger recipients.‘2 Both these studies indicate that older kidneys will have better survival when they are transplanted into From the College of Medicine & Medical Sciences, Arabian Gulf University, Manama, Bahrain; and the Department of Surgary, Allegheny University of Hea.ith Sciences, Philadelphia, Pennsylvania. Address reprint requests to Dr George M. Abouna, MD, Dean, College of Medicine & Medical Sciences, Professor & Chairman, Department of Surgery, Arabian Gulf University, P.O. Box: 22979, Manama, Bahrain.
0041-1345/97/$17.00 PII SO041 -1345(97)00667-2
2759
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recipients with lower functional demand, due to age or low body weight. Finally, from our own experience and that of others, it has been shown that there is higher morbidity in older kidneys when they are subjected to longer cold ischemia time and when renal biopsy shows marked histologic changes of the aging process.6,8,9 On the basis of current experience and available data, it can be safely recommended that kidneys from older donors can be successfully used if: frozen section renal biopsy shows <25% glomerulosclerosis; the kidneys are given to older recipients whenever possible; ischemia time is reduced to minimum and, when it exceeds 24 hours, pulsatile perfusion is used. Older hearts should undergo bench coronary angiography and older livers should undergo biopsy before transplantation to determine that the degree of macrovesicular steatosis is less than 30%. PAEDIATRIC DONORS
Kidneys from donors aged less than 5 years have certain inherent risk factors that have made many centres reluctant to using them for transplantation into adults. These include: small nephron mass, leading to poor initial function; small vessels and ureters, causing technical difficulties; higher rate of vascular thrombosis; higher incidence of posttransplant hypertension; and increased sensitivity to cyclosporine and to prolonged cold ischemia. 23 Because of these problems many centres have been reluctant to use paediatric kidneys for transplantation, whereas a few others have resorted to enbloc transplantation of two kidneys into one recipientz4 However, because of the increasing shortage of donors, we and others have resorted to transplantation of single kidneys into adult recipients with excellent results.23,25 Vander Vliet et al compared the rate of graft survival and function in 25 single paediatric kidneys (~3 years) transplanted in adults with 28 pairs of kidneys transplanted enbloc, and graft survival and the mean highest creatinine clearance were similar at 1 and 5 yearsz6 Sutherland reported the results of 98 single paediatric kidneys (Cl0 years of age) and 33 enbloc double kidneys into adult recipients and again showed that, except for retransplantation, graft survival and function were comparable in the two groups.27 During the period from 1992 to 1994 we transplanted 76 paediatric kidneys into adult recipients. Ten pairs were transplanted enbloc, the remainder as single grafts in adults. Of these 55 kidneys came from donors aged 0.5 to 5 years. We showed that graft survival at 1, 5, and 10 years was 83%, 56%, and 46% respectively, which is similar to that seen in adult kidneys. It was also shown that graft hypertrophy and improvement in function were completed by 6 months, with a creatinine clearance rising from 15 2 8 mL/min at 1 month to 50 5 11 at 6 months. Graft loss due to vascular thrombosis was only 4% and ureteric complications occurred in 6%, but all were salvaged.23 From this experience, and in view of the severe shortage of organs, we strongly recommend that all paediatric kidneys from donors >6 months should be transplanted as single organs in
ABOUNA
children and in adults and that such kidneys should be matched with a smaller sized and nonhypertensive adult recipient to the extent possible and that percutaneous heparin should be used for the first 72 hours followed by oral aspirin and persantime long term. It is also recommended that interrupted vascular suture and temporary stenting of the ureter should be carried out at operation and that induction immunosuppression with delayed cyclosporine therapy is advisable. KIDNEY GRAFTS FROM DIABETIC DONORS
In 1983, we showed, for the first time, that the transplantation of kidneys from a diabetic donor with good renal function into nondiabetic recipients was successful and resulted in improvement in early diabetic nephropathy, which had existed in the donor.28 In a subsequent report we showed that, in one of the recipients who became diabetic and required insulin, diabetic nephropathy in the grafted kidney returned, confirming that uncontrolled hyperglycemia is the primary cause of diabetic nephropathy, rather than any intrinsic predisposition of the kidney.29 Since that time other centres have began to use diabetic donors for kidney transplantation, with similar good results, as recently reported by Spees et al.” GRAFTS WITH PROLONGED ISCHEMIA TIME
Until recently, many centres were reluctant to utilize kidney grafts that had been preserved for longer than 30 hours, whether by cold storage or hypothermic perfusion. This policy was based on the fact that there are adverse consequences following prolonged ischemia, which include increased incidence of primary nonfunction, increased rate of delayed graft function requiring haemodialysis, and reduced graft survival, particularly when marginal donors were used. While working in Kuwait in the early 1980s where cadaveric organs were not available, we adopted the policy of accepting kidneys with long preservation times of 30 to 76 hours, which had been turned down by other centres in Europe and the USA. A total of 61 such kidneys were transplanted after cold preservation in 47 and pulsatile perfusion in 14.” It was shown in that trial that the rate of primary nonfunction and long-term graft survival at 1 and 2 years were similar, regardless of the period of ischemia. The only difference seen was that when the period of ischemia exceeded 50 hours there was a higher incidence of delayed function and the need for posttransplant dialysis. It was also shown that hypothermic perfusion significantly reduced the incidence of delayed graft function and the need for dialysis and that both early and late graft function were significantly improved if cyclosporine was withheld until full diuresis was established. These results were recently confirmed by Light and colleagues who showed that, during preservation for up to 45 hours, pulsatile perfusion significantly increased the rate of immediate graft function, thus reducing hospital stay and transplant costs. 32 Similarly, Tesi and colleagues have recently shown that the use of pulsatile perfusion allows the
MARGINAL DONORS
2761
identification of certain parameters that can help in the elimination of high-risk marginal donors and result in a much reduced rate of delayed function without compromising patient outcome. 33 Matsuno and colleagues have also shown that the use of machine perfusion preservation as a viability determinant is an effective method in preservation of kidneys procured from non-heart-beating donors.34 From these data the following recommendations can thus be made regarding the graft with prolonged cold ischemia: (1) good graft preservation is possible with the use of pulsatile perfusion, which also helps in predicting graft viability. (2) In the case of marginal donors, (eg, the elderly, paediatrics, and hypertensives), cold ischemia time should be kept as brief as possible, regardless of the method of preservation, and induction immunosuppression should be carefully selected and administration of cyclosporine delayed until graft diuresis has been established. NON-HEART-BEATING
DONORS
The current shortage of organs has lead to the reintroduction of the old and accepted concept of non-heart-beating donors with greater understanding and clarification of the different classes of this type of donor, the method of in situ preservation of the organs before removal, and the application of improved methods of preservation before transplantation. According to the Maastricht classification there are four categories of non-heart-bearing donors (NHBD): (1) dead on arrival; (2) unsuccessful resuscitation; (3) awaiting cardiac arrest with diagnosed brain death; and (4) sudden cardiac arrest in a brain dead donor.3” Maastricht category 3 is also called controlled NHBD, which is the ideal situation, whereas the other categories are uncontrolled types of NHBD. There are now considerable data to show that the results of kidney, liver, and pancreas transplantation from controlled non-heart-beating donors are excellent, providing that the warm ischemia time is less than 30 to 45 minutes, which is followed by in situ perfusion cooling of the organs using a three- or a four-lumen catheter.36,“7 To increase the organ supply, many centres throughout the world are now using controlled and uncontrolled non-heart-beating donors for kidney, liver, and other organ transplants. However, there are a number of important issues that must be considered when a non-heart-beating cadaver programme is used. These include: ethical issues; family consent; and method of in situ cooling to reduce warm ischemia time, such as employing peritoneal cooling or intraarterial cooling by aortofemoral cannula or hypothermic cardiopulmonary bypass. Also, the method of organ preservation, whether by simple cooling or hypothermic perfusion, are important. In most reports, the results of long-term graft survival of kidneys from NHBD cases are comparable to those of brain dead donors, although there is greater primary graft nonfunction or delayed graft function especially with elderly donors and after long cold storage.36-39 The latter are considerably reduced by using pulsatile
perfusion preservation.40 It is estimated that, by using NHBD, the number of available organs for transplantation can be increased by 20% to 50%. In the case of liver and pancreas, it is generally agreed upon that only controlled NHBDs should be used.4’ ABO-INCOMPATIBLE
GRAFTS
Because ABO antigens are represented on the vascular endothelium of the graft, the use of ABO incompatible grafts may result in antibody-mediated hyperacute or accelerated rejection. 42 However, if the AI30 antibody is removed, and particularly if further production of antibody is halted by splenectomy, successful transplantation across the ABO barrier becomes possible.43-46 Starzl was the first to report a successful renal transplant across the ABO barrier in 1964.47 With recent technological developments of plasmapheresis and immunoadsorption, many centres have embarked on the use of ABO-incompatible kidney and liver grafts with excellent results.43,44,46”’ It has been shown that successful transplantation can be carried out assuming that the level of preformed antibody is sufficiently lowered by plasmapheresis or immunoadsorption 1 to 2 weeks prior to transplantation and then quadruple immunosuppression is employed. The importance of splenectomy has been emphasized by Alexander et a143and also by Toma, who obtained 84% l-year graft survival when both immunoadsorption or plasmapheresis with splenectomy were carried out. In 1984, Brynger et al and, more recently, Nelson et al, have shown that, when A2 donors are used, successful transplantation can be carried out without resorting to plasmapheresis or immunoadsorption, particularly when the anti-IgG titer for the A2 antigen in the recipient is 10w.~~These results have been confirmed by others as it has been shown that the A2 antigen is very weak compared with Al or B antigens.44,4s*5” It can be concluded that successful transplantation is possible with ABO-incompatible grafts when the preformed antibody is removed by plasmapheresis or immunoadsorption to a titer of less than 1:4, when splenectomy is carried at the time of transplantation, and when quadruple immunosuppression with steroids, ATG, MMF, or azathioprine and cyclosporine is used. In the A2 subgroup of donors recipient preparation may not be necessary if the anti-A, IgG titer is less than 1:s. MULTIPLE RENAL ARTERIES AND VASCULAR ANOMALIES
Until recently, many centres have been reluctant to use kidneys with multiple arteries, especially when other suboptimal conditions exist, such as donor age, long cold ischemia time, etc, for fear of technical complication and graft loss. Theoretically, multiple renal arteries are more likely to lead to technical complications during anastomosis with increased incidence of arterial stenosis and thrombosis, increased operating time, prolonged relative cold isch-
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2762
emia time, and ischemic damage to the ureter and decreased graft survival. 54-56 Because approximately 30% of kidneys have multiple renal arteries, and in 10% of these this is bilateral, many good grafts are lost if such kidneys are discarded.54 Recent experience by several centres, including our own, has shown that the aforementioned theoretical problems can be avoided with good surgical techniques and excellent graft survival can be obtained. In this way all available kidneys can be utilized. Kidneys with more than one artery can be safely and effectively used by employing the following technical modifications, either at the time of transplantation or at “bench surgery” before transplantation. Methods used to deal with bilateral renal arteries at transplantation include: (1) both arteries are anastomosed end-to-side to the external iliac artery with or without an arterial patch; (2) each artery is anastomosed end-to-end to the two branches of the internal iliac; (3) one artery is anastomosed end-to-side to the external iliac artery and the other end-to-end to the internal iliac artery; and (4) one artery is anastomosed end-to-side to the external iliac artery, and the other, usually a lower pullout, is anastomosed end-to-end to the inferior hypogastric artery. With bench surgery prior to transplantation, while the kidney is still in ice, the following techniques have been employed: (1) the smaller of the two arteries is anastomosed end-toside to the larger artery; (2) side-to-side anastomosis of the two arteries is done to form one common trunk; (3) an autologous bifurcating artery with a large common trunk is connected to the two renal arteries end-to-end; and (4) the upper polar artery is ligated if the area of ischemia is less than 1 cm*. By employing these techniques, several large series have been reported, where the incidence of vascular and ureteric complications has been very similar to that obtained with kidneys having single renal arteries.“’ Indeed, we have used a right kidney from a Syear-old child with five renal arteries and five veins, with one of these arteries, to the inferior pole, having been accidentally divided. The kidney was rejected by all the transplant centres in Pennsylvania. Using the bench surgery techniques the divided artery was successfully repaired and the aortic cuff was split into two segments, one bearing two and the other three vessels. The kidney was then transplanted into an adult patient with the two arterial and venous cuffs anastomosed end-to-side to the iliac artery and iliac vein, respectively. This patient continues to have normal renal function 5 years later (Figs 1 and 2) Clearly, when multiple vascular procedures have to be carried out, there may be an increased incidence of ATN. In a very large series of some 998 kidneys at the University of Minnesota, recently reported by Benedetti et al, there was no significant difference in graft survival, nor in the rate of vascular and urologic complications, at 1 and 5 years, between kidneys with single and multiple renal arteries5” Therefore, it is recommended that kidneys with multiple renal arteries should be used, either by direct anastomosis
Fig 1. Paediatric right kidney with five renal arteries with inferior polar branch accidentally divided.
of the two arteries at the time of transplantation or by performing appropriate bench surgery. At all times, the lower polar artery must be preserved while the upper polar artery may be ligated if it supplies less than 1 cm* of cortex. During anastomosis, interrupted sutures of 6/O or 7/O should be used or a “growth factor” should be employed if the anastomosis is carried out with continuous suture. In our center, we employ subcutaneous heparin for the first 72 hours followed by oral aspirin and persentin long term. OTHER
TYPES
OF MARGINAL
DONORS
Donors with hypertension or higher serum creatinine, and those with positive serology for CMV, constitute suboptima1 grafts and are rejected by many centres. Chou et al showed that, although the l-year graft survival for cadaver
Fig 2. Same kidney as in Fig 1. The inferior polar artery having been repaired. The aortic cuff was then divided into two segments: one bearing three and the other two of the arterial branches that were separately anastomosed to the external iliac artery.
MARGINAL DONORS
kidneys is very similar, regardless of presence of hypertension in the donor, the long-term survival was significantly reduced.57 Busson showed that the l- and 2-year survival of kidney and cardiac grafts was significantly reduced when donors with positive CMV serology are used.58 CONCLUSION
There are considerable data and experience to support the policy that no marginal or suboptimal graft should be discarded due to donor age, diabetes, or presence of multiple arteries, providing that renal function in the donor is normal. Kidney grafts from non-heart-beating cadavers or those with long ischemia tinies can all be used successfully, especially if the kidney is preserved by pulsatile perfusion rather than by simple hypothermia. ABO-incompatible grafts can be used successfully, providing that adequate removal of preformed anti-Al30 antibody is carried out prior to transplantation and at the time of transplantation a splenectomy is performed. It is estimated that, by using such suboptimal donors, the current organ supply can be increased by another 25% to 30%, thus making successful transplantation therapy available to a larger number of patients currently on the rapidly expanding national transplant recipient waiting list all over the world. REFERENCES 1. Alexander JW, Vaughn WK: Transplantation 51:135, 1991 2. UNOS Bulletin, Vol 1, Dee 1996 3. UNOS Update, July/August 1996, p 28 4. Douzdjian V, Gugliuzza KG, Fish JC: Transplant Proc 27: 3128, 1995 5. Roels L, Christiaens MR, Waer M, et al: Transplant Proc 27:795, 1995 6. Cofan F, Oppenheimer F, Campistol JM, et al: Transplant Proc 28:2248, 1995 7. Gonzalez SC: Transplant Proc 27~2409, 1995 8. Lloveras J, Arias M, Puig JM, et al: Transplant Proc 25:3175, 1993 9. Kumar MS, Stephan R, Chui J, et al: Transplant Proc 25:3097, 1993 10. Albrechtsen D, Leivestad T, Soda1 G, et al: Transplant Proc 27~986, 1995 11. Milan0 A, Livi U, Casula R, et al: Transplant Proc 25:3158, 1993 12. Orlowski JP, Spees EK: Transplant Proc 25:3101, 1993 13. Sautner T, Gotzinger P, Wamser P, et al: Transplant Proc 23:2598, 1991 14. Cantarovich D, Giral-Classe M, Le Sam JN, et al: Clin Transplant 8:237, 1994 15. Adam R, Astarcioglu I, Azoulay D, et al: Transplant Proc 23:2602, 1991 16. Kumar A, Kumar RV, Srinadh ES, et al: Clin Transplant 8:523, 1994 17. Emre S, Myron E, Schwartz E, et al: Transplantation 62:62, 1996 18. Hayashi T, Koga S, Higashi Y, et al: Transplant Proc 27:984, 1995
2763 19. Ladowski JS, Beatty L, Sullivan M, et al: J Thorac Cardiovast Surg 106:1236, 1993 20. Sundaresan S, Semenkovich J, Ochoa L, et al: J Thorac Cardiovasc Surg 109:1075, 1995 21. Cecka JM, Terasaki PI: Transplant Proc 27:801, 1995 22. Mizutani N, Kotoh S, Yamada Y, et al: Transplant Proc 28:1589, 1996 23. Abouna GM, Kumar MSA, Chvala R, et al: Transplant Proc 28:2564, 1995 24. Nghiem DD, Hsia S, Carpenter BJ, et al: Clin Transplant 8:213, 1994 25. Gourlay W, Stothers L, McLaughlin MG, et al: J Urol 153:322, 1995 26. Vander Vliet JA, Persijin GG, Cohen M: In Abouna GM (ed): Clinical Organ Transplantation, Amsterdam-Martinus Nijhoff; 1984, p 115 27. Sutherland DER, Rainer QG, Grussmer WG, et al: Dordrecht-Kluwer; p 201, 1991 28. Abouna GM, Adnani MS, Kremer GM, et al: Lancet ii:1274, 1983 29. Abouna GM, Adnani MS, Kumar MSA, et al: Lancet i:622, 1986 30. Spees EK, Orlouski JP, Fitting KM, et al: Transplant Proc 22:378, 1990 31. Abouna GM, Samham MS, Kumar MSA, et al: Transplant Proc 19:2051, 1987 32. Light JA, Kowalski AE, Gage F, et al: Transplant Proc 28:2962-4, 1995 33. Tesi RJ, Elbhammas EA, Davies EA, et al: Clin Transplant 8:134, 1994 34. Matsuno N, Sakurai E, Tamaki I, et al: Transplant Proc 26~2421, 1994 35. Kootstra G: Transplant Proc 28:2965, 1995 36. Heineman E, Daemen JHC, Kootstra G: Transplant Proc 28:2895, 1995 37. Lloveras J, Puig JM, Cerda M, et al: Transplant Proc 27:2909, 1995 38. Bell P, Dibekoglu M, Gonzalez C, et al: Transplant Proc 28:2951, 1995 39. Daemen JW, Kootstra G, Wijnen RM, et al: Clin Transplant 8:303, 1994 40. Daemen JHC, Heineman E, Kootstra G: Transplant Proc 28:2906, 1995 41. D’Allesandro A, Hoffman R, Knechtle SJ, et al: Abstracts of ASTS Annual Scientific Meeting, Chicago, IL, 1995, p 115 42. Alexander GPJ, Latinne D, Gianello P, et al: Clin Transplant 5:583, 1991 43. Alexander GPJ, Latinne D, Carlier M, et al: Transplant Rev 5:230, 1991 44. Toma H: Urol Clin N Am 21:299, 1994 45. Takahashi K, Yagisawa T, Sonda K, et al: Transplant Proc 25:271, 1993 46. Boudreaux JP, Hayes DH, Mizrahi S, et al: Transplant Proc 25:1874, 1993 47. Starzl TF, Morchioro TL, Holmer JH, et al: Surgery 55:195, 1964 48. Nelson PW, Helling TS, Shield CF, et al: Am J Surg 164:541, 1992 49. Slapak M, Digard N, Ahmed M: Transplant Proc 22:1425, 1990 50. Tanabe K, Takahashi K, Sonda K. et al: Transplant Proc 27: 1020, 1995
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