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The influence of donor age on graft survival in renal transplantation
The Influence of Donor Age on Graft Survival in Renal Transplantation By Suzanne T. Ildstad, David J. Tollerud, John Noseworthy, Frederick Ryckman, Curtis A. Sheldon, and Lester W. Martin
Cincinnati, Ohio 9 The current supply of kidneys from cadaver and living related donor sources is not sufficient to meet the demand. As a result, alternative sources of renal allografts are being explored, including very young donors and anencephalic newborns. However, data on the success of transplanting kidneys from very young donors are limited and conflicting. The purpose of this study was to determine w h e t h e r the function and survival of renal grafts obtained from newborns and very young donors is different from that for grafts obtained from older donors. Thirty-six cadaveric donors under the age of 3 years, including seven anencephalic newborns, w e r e evaluated. AIIograft recipients ranged in age from 12 months to 57 years. The clinical outcome for these donor organs was compared w i t h the graft survival for 136 kidneys transplanted from cadaver donors over age 3 years at our institution. There was a 65% 6-month and 64% 1-year graft survival in recipients of kidneys from donors greater than or equal to 3 years. Survival of grafts from donors under 12 months of age (n = 16) was significantly decreased compared w i t h donors age 3 years and older, w i t h a 31% 6-month (P < .01) and 19% 12-month survival (P < .001}. Grafts obtained from anencephalic donors did not differ in survival or function from kidneys obtained from other donors less than 12 months of age. Survival for renal allografts from donors age 13 months to 3 years was also decreased relative to older donors: 55% at 6 months (P > .1 ) and 40% at 1 year (P < .05). Graft survival from donors age 3 to 5 years was analyzed separately and was not significantly different from that of donors over age 5. AIIograft survival was similar for single kidney and en bloc duplex renal grafts, and was not influenced by the age or size of the recipient or by duration of cold ischemia. The most f r e q u e n t cause of graft loss was early nonfunction in the presence of anastomotic patency and was not influenced by recipient size and age. Mechanisms responsible for this process have not yet been characterized. These data indicate that increased efforts must be directed at defining the etiology of primary graft nonfunction and developing i m p r o v e d techniques for p r e s e r v a t i o n of allografts obtained from very young donors for this potential resource to be used w i t h efficiency. 9 1990 b y W,B. Saunders Company.
INDEX WORDS: Kidneys from small donors; pediatric renal allograft donors.
HE FIELD of renal transplantation has under-
T gone revolutionary advances in the past decade. The data are now clear that renal transplantation in adult and pediatric patients with end-stage renal failure is superior to chronic dialysis both financially~ and with respect to quality of life.2'3 Transplantation obviates the psychological and neurological impairment, growth retardation, and renal osteodystrophy associated with chronic dialysis.4s As a result, the number of renal transplants performed has increased dramatically over the past decade, and the current supply of cadaver kidneys is not adequate to meet the demand. To help meet this demand, alternative sources of renal allografts are being explored, including crossspecies transplantation, living unrelated donors and anencephalic newborns. Data on the efficacy of transplanting kidneys from very young donors are limited and conflicting913 occurring predominantly as case reports in the literature. This has prompted us to review our experience with the outcome of cadaveric renal allografts from donors under the age of 3 years. MATERIALS A N D METHODS
All patients who underwent a cadaver or living related donor renal transplant at the Children's Hospital of Cincinnati from 1976 to 1986 were identified from medical records, operative reports, and the local transplant center registry. In addition, all cadaver donors of age 3 and less were identified from the transplant center registry. Both adult and pediatric (less than 18 years) patients who were recipients of these grafts were identified and analyzed. There was 100% complete follow-up in all patients, with a minimum follow-up of 1 year. No patients were excluded from analysis. Calculations of allograft survival were performed using the lifetable survival method. ~4 Actuarial graft survival rates were computed at discrete time periods following allograft placement, and significance estimates for differences in survival between comparison groups were calculated using chi-square analysis. Is lmmunosuppressive therapy for kidneys obtained from very small donors was identical to that for renal allografts transplanted from older donors and consisted of azathioprine and steroids. Six of the 36 patients also received cyclosporine. RESULTS
Patient Characteristics
From the Department of Pediatric Surgery, Children's Hospital of Oncinnati, OH. Presented at the 20th Annual Meeting of the American Pediatric Surgical Association, Baltimore, Maryland, May 28-31, 1989. Address reprint requests to Suzanne T. Hdstad, MD, Assistant Professor, Department of Pediatric Surgery, Pittsburgh Children's Hospital, One Children's Place, Pittsburgh, PA 15213. 9 1990 by W.B. Saunders Company. 0022-3468/90/2501-0025503.00/
Thirty-six recipients of renal allografts from donors less than 3 years of age were identified and evaluated. They were compared with 136 recipients of allografts from donors age 3 years and older. Allografts from very young donors were transplanted into 31 pediatric recipients age 12 months to 18 years and 5 adult recipients ranging in age from 19 years to 57 years.
134
Journal of Pediatric Surgery, Vol 25, No 1 (January), 1990: pp 134-139
135
DONOR AGE IN RENAL TRANSPLANTATION
Table 1. Analysis of Immunosuppression
100 90
and F r e q u e n c y of
~8o
T r a n s p l a n t s Per Y e a r
No. of Transplants Performed From Donor <3 yr
Year of Transplant
No. of RecipientsTreated with Cyclosporine
No. of Grafts with Primary Nonfunction
1968 1970
1 1
0 0
0 0
1972 1973 1974 1975
2 1 2 3
0 0 0 0
2 0 0 1
1976 1977 1978 1979
2 2 2 2
0 0 0 0
2 1 1 1
1980 1981 1982 1983 1984 1985 1986 1987
1 4 10 1 0 1 1 1
0 0 2 1 0 1 1 1
O 1 3 0 0 1 1 1
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.
.
.
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1
I 3
2
J 4
I 5
I 6
I 7
P 8
I 9
I 10
YEARS POST RENAL ALLOGRAFT Fig 2. Survival of allografts f r o m donors a g e n e w b o r n to 12 months (C~O), 13 m o n t h s t o 3 y e a r s ( H ) , 3 to 5 years (&--&), and g r e a t e r t h a n or equal t o 5 y e a r s ( A - - A ) as calculated by life table.
To evaluate the outcome of renal allografts from very young donors, the survival and function of 36 cadaveric renal allografts from donors under the age of 3 years was compared with the 65% 6-month and 64% 12-month survival for 136 kidneys transplanted from donors age 3 years or greater (Fig 1). A separate
analysis comparing survival of grafts from donors 3 to 5 years of age (n = 14) with donors over age 5 revealed no significant differences in 6- or 12-month survival rates (P > .1) (Fig 2). Survival of allografts from very young donors was significantly inferior compared with grafts from older donors. There was only a 50% 6-month and 31% 12-month graft survival for kidneys from donors less than 3 years of age (Fig 1). Graft survival for donors under 13 months of age (n = 16) was especially decreased when compared with donors over age 3 years, with a 31% 6-month (P < .01) and 16% 12month ( P < .001) survival (Fig 2). This group included seven anencephalic newborn infants. Graft survival for anencephalic donors was not significantly different from that for other donors under 13 months of age (Fig 3). For donors under 13 months of age, allograft survival was similar for single kidney (n = 7) and en bloc duplex renal grafts (n = 9), and was not influenced by recipient age or size. Survival for renal allografts obtained from donors age 13 months to 3 years was also significantly decreased relative to donors aged 3 years and older, with a 55% 6-month ( P > .1) and 40% 12-month survival (P < .05). 100
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Influence of Pediatric Donor Age on Graft Survival in Cadaveric Renal Transplantation
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The mean age for children who were recipients of small grafts was 7 years, and the median age was 9 years. For adult recipients of kidneys from small donors, the mean age was 48, and the median age 39. Table 1 represents the number of transplants from very young donors performed each year. Immunosuppression for the majority of the patients consisted of azathioprine and prednisone. When cyclosporine became clinically available, patients received cyclosporine in combination with the other two agents.
>
50 40
I 1
I 2
I 3
I 4
I 5
t 6
I 7
I 8
I I ( I I L I I I I 9 10 11 12 13 14 15 16 17 18
YEARS POST RENAL ALLOGRAFT Fig 1. Survival of allografts f r o m donors less t h a n 3 y e a r s of a g e ( O - - - O } c o m p a r e d w i t h grafts f r o m donors a g e 3 y e a r s and older ( H | as calculated by t h e life table m e t h o d .
* 1
2
3
4i
I lll 112 13 I ll4 115 lu/ 117 118 5i 6i 7I 8I 9I ' 10 YEARS POST RENAL ALLOGRAFT
Fig 3. Survival of allografts from anencephalic donors (0----0) w a s not significantly d i f f e r e n t f r o m t h o s e o b t a i n e d f r o m o t h e r donors a g e n e w b o r n to 13 m o n t h s ( H ) .
136
ILDSTAD ET AL
Analysis of Early Graft Loss
Influence of Recipient Age on Graft Outcome
The most frequent cause of graft loss in allografts obtained from donors less than 3 years was early nonfunction in the presence of anastomotic patency as determined by operative inspection, doppler ultrasound, angiography, or by gross and histologic inspection after removal of the failed graft. Graft loss was not influenced by recipient size or age, but was directly related to the age of the donor (Table 2). The rate of primary nonfunction of allografts obtained from donors less than 3 years was significantly higher when compared with that for donors age 3 years or older. The rate of primary nonfunction in the presence of anastomotic patency was 63% for renal allografts obtained from donors less than the age of 1 year and 30% for grafts obtained from donors aged 13 months to 3 years, compared with only 2% in grafts obtained from donors greater than or equal to 3 years of age ( P < . 0 1 ; Table 2). This did not appear to be a cyclosporine effect, since only 6 of 36 patients who received a renal allograft from donors less than 3 years of age received cyclosporine. When analyzed separately, there was a 57% (4/7) rate of primary nonfunction for renal allografts harvested from anencephalic donors (Table 2). Of the functioning kidneys obtained from anencephalic donors, one graft has functioned for 18 years (most recent serum creatinine, 1.1), one for 12 years (most recent serum creatinine, 1.9), and the third was rejected at 1 year posttransplant secondary to patient noncompliance. This rate of function in kidneys from anencephalic donors is not significantly different from that for grafts harvested from other donors under 13 months of age (P > . 1).
The rate of primary graft nonfunction was also not significantly influenced by the age of the recipient in those patients who were transplanted with renal allografts from donors less than 3 years. The frequency of primary graft nonfunction was 47% in recipients 1 to 10 years of age, 54% in those 11 to 19 years of age, and 34% in those age 20 or older.
Influence of Duration of Cold Ischemia on Allograft Function and Outcome The average duration of cold ischemia time was 21 hours for all grafts transplanted from donors less than age 3 years. For grafts that exhibited primary nonfunction, the average cold ischemic time was 23.8 hours, compared with 21.6 hours in grafts that exhibited early function. This difference was not significantly different. Table 2. Frequency of Primary Graft Nonfunction in Renal AIIografts Obtained From Very Smalls Donors Frequencyof PrimaryGraft Donor Age Anencephalic newborns Age 5 d to 12 mo Age 13 to 35 mo Age 3 yr and older
N 7 9 20 136
Nonfunction 4 6 6 3
(57%) (67%) (30%) (2%)
Significance Estimate* (P) <.001 <.001 <.001
*Comparison made with outcome of renal allografts obtained from donors 3 years of age and older.
DISCUSSION
Recent improvements in immunosuppressive agents have led to revolutionary advances in the field of renal transplantation. Consequently, the number of transplants has increased dramatically, resulting in a severe shortage of kidneys available for transplantation. This is especially true for the pediatric transplant recipient, where size limitations create an additional obstacle in donor selection. Alternative sources of renal allografts are now being explored, including very young donors and anencephalic newborns. 9"1~ Until recently, most centers have avoided renal allografts obtained from donors less than 5 years of age. Data on the efficacy of transplanting kidneys from very young donors are limited and conflicting, and has consisted primarily of case reports in the literature. 9"13 Our experience with 36 donors under the age of 3 years, including 7 anencephalic newborns, has provided a large series from which to analyze the influence of donor age on graft outcome and function. Our data indicate that the survival of allografts obtained from donors less than 3 years of age was significantly inferior to that of grafts obtained from donors greater than 3 years of age. This effect was highly correlated with age of donor but was not influenced by age of recipient. One-year graft survival for kidneys obtained from donors less than 13 months of age was 31% at 6 months and 16% at 12 months. This was significantly inferior to the graft survival observed in patients who received an allograft from donors age 3 years of age or greater, where survival was 65% at 6 months and 64% at 12 months (P < .01 and P < .001, respectively). There was a 55% 6-month and 40% 12-month survival for renal allografts obtained from donors aged 13 months to 3 years, again significantly inferior to the outcome for that of allografts from donors greater than or equal to 3 years. These results are at variance with other reports in the literature. However, our large series has allowed us to compare outcome by age stratification while other centers have combined all donors less than 5 years of age for overall comparison because of small sampling size. 15J6
In our series, the most common cause of graft loss in kidneys obtained from donors less than 3 years was
DONOR AGE IN RENAL TRANSPLANTATION
137
primary nonfunction in the presence of anastomotic patency. Mechanisms responsible for this graft loss may include blood flow discrepancy, pulse pressure differences in children in comparison with adults, the effects of ischemia in immature kidneys, and other technical considerations attendant with small blood vessel anastomoses. Cold ischemia time was not a significant factor in our series. Perfusion and preservation techniques have been developed and characterized for renal allografts obtained from adult donors, but little attention has been focused on potential differences in requirements for the preservation and perfusion of kidneys from the very young, or even fetal donors. In spite of the current high early failure rate of kidneys transplanted from very young donors, our data indicate that the long-term function of surviving kid-
neys appears to be normal. Therefore, additional efforts must be directed at defining the optimum conditions for perfusion and preservation during harvesting of these grafts, although this alone may not result in an improved graft outcome. Young donors are a potential source of kidney allografts for our current acute shortage of donor organs. However, until details specific to the perfusion and preservation of kidneys from young donors have been better defined, the authors recommend that renal allografts from donors under the age of 3 years be used with caution. ACKNOWLEDGMENT The authors thank Micheile Waters for manuscript preparation, Jean Loos for technical assistance, and Dr Marc Rowe for manuscript review.
REFERENCES 1. Eggers PW: Effect of transplantation on the medicare end stage renal disease program. N Engl J Med 318:223, 1988 2. Kahan BJ: Pediatric renal transplantation (letter). Transplant Immunol 4:1-11, 1987 3. So SKS, Simmons RL, Fryd DS, et al: Improved results of multiple renal transplantation in children. Surgery 98:729, 1985 4. Avner ED, Harmon WE, Crupe WE, et al: Mortality of chronic hemodialysis and renal transplantation in pediatric end stage renal disease. Pediatrics 67:412, 1981 5. Bale JF Jr, Sieger RL, Bray FF: Encephalopathy in young children with moderate chronic renal failure. Am J Dis Child 134:581, 1980 6. Grushkin CM, Fine RN: Growth in children following renal transplantation. Am J Dis Child 125:514, 1973 7. Rizzoni G, Malikoazek M, Pennisi A, et al: Renal transplantation in children less than 5 years of age. Arch Dis Child 55:532-536, 1980 8. Potter D, Feduska N, Melzer J, et al: Twenty years of renal transplantation in children. Pediatrics 77:465-470, 1986
9. Lum CT, Fryd DS, Polta TA, et al: Results of kidney transplantation in the young child. Transplantation 34:167, 1982 10. Holzgreve W, Belier FK, Buchholz B, et al: Kidney transplantation from anencephalic donors. N Engl J Med 316:1069, 1987 11. Martin LW, McEnery PT, Rosenkrantz JG, et al: Renal homotransplantation in children. J Pediatr Surg 14:571, 1979 12. Hayes JM, Novick AC, Streem SB, et al: The use of single pediatric cadaver kidneys for transplantation. Transplantation 45:106, 1988 13. Trompeter RS, Bewick M, Haycock GB, et al: Renal transplantation in very young children. Lancet 1:373, 1983 14. Gehan EA: A generalized Wileoxon test for comparing arbitrary singly-censored samples. Biometrika 52:203, 1965 15. Daniel WW: Biostatistics: A Foundation for Analysis in the Health Sciences, ed 3. New York, NY, Wiley, 1983 16. Wengerter K, Matas A J, Tellis VA, et al: Transplantation of pediatric donor kidneys to adult recipients: Is there a critical donor age? Ann Surg 204:172, 1986
Discussion E.P. Wood (Omaha, NE): This study confirms the impression that those of us that perform renal transplantation have had that donors less than 2 years of age probably should not be used for cadaveric donation. I have a couple of questions in that you did not discuss patient survival. I think it is important in renal transplantation that this is a quality of life operation as opposed to a life saving operation and I think it is important that if we are using very small donors with the idea that a number of them will not function adequately, what is your survival rate in patients who undergo these procedures. Second, I wonder if you are going to continue to use these very small donors and how you would advise us to modify our techniques as far as organ procurement and whether there is any indication that it will help lower the incidence of
primary nonfunction. In addition, you gave several possible mechanisms of why these kidneys do not work. Could you perhaps speculate a bit more on what the mechanism may be to the primary nonfunction of these kidneys? P. Guzzetta (Washington, DC): In our experience in Washington, DC, we found that if we use a kidney that is larger than 40 g, and for relative size that is about the size of a grade A large egg, we have not had any problems with those kidneys in patients. That kidney correlates with a donor age of approximately 18 months. We do specifically use kidneys smaller than that in patients who are quite small and we have only had one primary nonfunction in six patients transplanted less than 1 year of age. I think that the message that you are giving is that you should not use
138
the kidneys from patients who are less than 3 years of age. In those centers that do use very small kidneys specifically for very small patients, unfortunately I think that they might be doing a disservice, and it is just up to the responsibility of the people using those kidneys to make sure that they are not all thrown in the basket. I do have one specific question related to that. Does this mean that at Cincinnati they no longer harvest kidneys from patients less than 3 years of age? You didn't mention in the presentation the microscopic evaluation of the kidneys that were taken out and as you probably know the group in Alabama feel very strongly that primary nonfunction in the adult is related to rejection. Do you have some information about the microscopic evaluation of these kidneys? D. Tapper (Seattle, WA): I think that the national data absolutely supports the information presented. I am surprised that Dr Guzzetta's institution has not also confirmed this; however, the national data kept at the UCLA Registry as well as all the bulletins that are sent around absolutely confirm primary nonfunction is significantly higher when kidneys less then 2 years of age are used. I would like to ask Dr Ildstad whether or not it would be possible from this long experience to go back and see exactly who harvested these kidneys and whether or not there is a difference between those organs that were harvested by pediatric surgeons or harvested in your own institution versus the ones that were shipped you. It seems simplistic to say that this is technical, but you wonder if the kidney was working in an 1 t-month-old child with a normal creatinine why does the kidney not work after transplantation. Your slide indicates that there was no significant difference due to cold storage. You wonder why the kidney would not immediately work and why was the nonfunction so high. I wonder as to whether or not our colleagues who are doing the bulk of the harvesting do not have the same appreciation for the tiny vasculature of these kidneys.
J.C. Molenaar (Rotterdam, The Netherlands): I have two short questions. Extensive reduction of renal tissue in animals leads to renal function deterioration due to glomerular hypertension and subsequent microvascular injury. Has the pathology of the nonfunctioning kidneys been studied in this respect? Transplantation of very young donor kidneys in animals leads to rapid increase of the glomerular infiltration rate and also to a rapid growth of the transplanted the kidney. Have you looked into these phenomena in the surviving kidneys of your series? L. Martin (CincinnatL OH): Dr Ildstad insisted that I show you the slide of one very special patient included in her report. This is a young man who received a set of kidneys from an anencephalic donor when he weighed
ILDSTAD ET AL
17 pounds. He could not talk and could not walk. He was thought to be retarded. He has, 22 years later, finished college. He is 25 years old and this is a photograph of him with his fiance. He still has the kidneys from the anencephalic donor. He has never had a flicker of rejection. S. lldstad (closing): Dr Wood, with regard to the long-term outcome of the recipients of small kidneys, our data indicate that if the kidney survives that the long-term function of the kidney is similar to that of kidneys obtained from donors greater than 2 years of age. In some of the patients we have followed for up to 18 to 20 years, the creatinines have remained normal. Dr Guzzetta indicated that in their experience they have encountered one nonfunctioning allograft in six patients. However, in small numbers of patients it is difficult to make statistically significant analyses of the recipients of small kidneys. One additional nonfunctioning kidney would change the percentage of nonfunction significantly. Larger numbers would be required to reduce sampling error. Our data indicate that there is only a 43% chance of function in the kidneys obtained from donors less than 12 months of age. In effect, one is playing the odds. That is an issue that each transplant surgeon must address because if the kidney obtained from a donor greater than 3 years of age has less than a 2% rate of primary nonfunction and one obtained from a donor less than 12 months of age has a 57% to 67% rate of primary nonfunction, the surgeon has to decide whether the patient needs that kidney so badly that he or she is are willing to accept such a high chance of failure if a kidney from a donor less than 3 years of age is used. With the current availability of dialysis to temporize until a suitable donor is found, I would recommend avoiding the kidney obtained from donors less than 3 years until the mechanism responsible for the primary nonfunction is understood. Dr Tapper's question with regard to the harvesting of the kidneys is an interesting one. In our institution, until the cooperative transplant center was formed, the pediatric surgeons harvested all of the kidneys. All of the anencephalic donor kidneys in this study were harvested by a pediatric surgeon at the Children's Hospital. The majority of the other kidneys come from our institution and were therefore also harvested by a pediatric surgeon. The criteria that we used for brain death in the anencephalic donors was the same criteria that our institution uses for brain death, and that has been an evolving criteria because this study spans 18 years. Dr Mollenar's question regarding the histologic appearance of these kidneys that had initial nonfunction is interesting. The pathology was examined and there was no evidence for cellular infiltrates that would be compatible with
DONOR AGE IN RENAL TRANSPLANTATION
rejection. In addition, the vascular anastomoses were patent. It seemed to be more of a cellular or parenchymai level of nonfunction. However, some of the kidneys obtained from donors less than 3 years of age did undergo immunologic failure from rejection. The issue of antigenicity of fetal versus newborn versus adult
139
tissues has not been characterized and although we assume that newborn tissue is less antigenic, this has not been proven. Studies in animals have shown that fetuses are competent to reject foreign tissues after the first trimester. I would like to thank the discussants for their thoughtful questions.
Cincinnati, Ohio 9 The current supply of kidneys from cadaver and living related donor sources is not sufficient to meet the demand. As a result, alternative sources of renal allografts are being explored, including very young donors and anencephalic newborns. However, data on the success of transplanting kidneys from very young donors are limited and conflicting. The purpose of this study was to determine w h e t h e r the function and survival of renal grafts obtained from newborns and very young donors is different from that for grafts obtained from older donors. Thirty-six cadaveric donors under the age of 3 years, including seven anencephalic newborns, w e r e evaluated. AIIograft recipients ranged in age from 12 months to 57 years. The clinical outcome for these donor organs was compared w i t h the graft survival for 136 kidneys transplanted from cadaver donors over age 3 years at our institution. There was a 65% 6-month and 64% 1-year graft survival in recipients of kidneys from donors greater than or equal to 3 years. Survival of grafts from donors under 12 months of age (n = 16) was significantly decreased compared w i t h donors age 3 years and older, w i t h a 31% 6-month (P < .01) and 19% 12-month survival (P < .001}. Grafts obtained from anencephalic donors did not differ in survival or function from kidneys obtained from other donors less than 12 months of age. Survival for renal allografts from donors age 13 months to 3 years was also decreased relative to older donors: 55% at 6 months (P > .1 ) and 40% at 1 year (P < .05). Graft survival from donors age 3 to 5 years was analyzed separately and was not significantly different from that of donors over age 5. AIIograft survival was similar for single kidney and en bloc duplex renal grafts, and was not influenced by the age or size of the recipient or by duration of cold ischemia. The most f r e q u e n t cause of graft loss was early nonfunction in the presence of anastomotic patency and was not influenced by recipient size and age. Mechanisms responsible for this process have not yet been characterized. These data indicate that increased efforts must be directed at defining the etiology of primary graft nonfunction and developing i m p r o v e d techniques for p r e s e r v a t i o n of allografts obtained from very young donors for this potential resource to be used w i t h efficiency. 9 1990 b y W,B. Saunders Company.
INDEX WORDS: Kidneys from small donors; pediatric renal allograft donors.
HE FIELD of renal transplantation has under-
T gone revolutionary advances in the past decade. The data are now clear that renal transplantation in adult and pediatric patients with end-stage renal failure is superior to chronic dialysis both financially~ and with respect to quality of life.2'3 Transplantation obviates the psychological and neurological impairment, growth retardation, and renal osteodystrophy associated with chronic dialysis.4s As a result, the number of renal transplants performed has increased dramatically over the past decade, and the current supply of cadaver kidneys is not adequate to meet the demand. To help meet this demand, alternative sources of renal allografts are being explored, including crossspecies transplantation, living unrelated donors and anencephalic newborns. Data on the efficacy of transplanting kidneys from very young donors are limited and conflicting913 occurring predominantly as case reports in the literature. This has prompted us to review our experience with the outcome of cadaveric renal allografts from donors under the age of 3 years. MATERIALS A N D METHODS
All patients who underwent a cadaver or living related donor renal transplant at the Children's Hospital of Cincinnati from 1976 to 1986 were identified from medical records, operative reports, and the local transplant center registry. In addition, all cadaver donors of age 3 and less were identified from the transplant center registry. Both adult and pediatric (less than 18 years) patients who were recipients of these grafts were identified and analyzed. There was 100% complete follow-up in all patients, with a minimum follow-up of 1 year. No patients were excluded from analysis. Calculations of allograft survival were performed using the lifetable survival method. ~4 Actuarial graft survival rates were computed at discrete time periods following allograft placement, and significance estimates for differences in survival between comparison groups were calculated using chi-square analysis. Is lmmunosuppressive therapy for kidneys obtained from very small donors was identical to that for renal allografts transplanted from older donors and consisted of azathioprine and steroids. Six of the 36 patients also received cyclosporine. RESULTS
Patient Characteristics
From the Department of Pediatric Surgery, Children's Hospital of Oncinnati, OH. Presented at the 20th Annual Meeting of the American Pediatric Surgical Association, Baltimore, Maryland, May 28-31, 1989. Address reprint requests to Suzanne T. Hdstad, MD, Assistant Professor, Department of Pediatric Surgery, Pittsburgh Children's Hospital, One Children's Place, Pittsburgh, PA 15213. 9 1990 by W.B. Saunders Company. 0022-3468/90/2501-0025503.00/
Thirty-six recipients of renal allografts from donors less than 3 years of age were identified and evaluated. They were compared with 136 recipients of allografts from donors age 3 years and older. Allografts from very young donors were transplanted into 31 pediatric recipients age 12 months to 18 years and 5 adult recipients ranging in age from 19 years to 57 years.
134
Journal of Pediatric Surgery, Vol 25, No 1 (January), 1990: pp 134-139
135
DONOR AGE IN RENAL TRANSPLANTATION
Table 1. Analysis of Immunosuppression
100 90
and F r e q u e n c y of
~8o
T r a n s p l a n t s Per Y e a r
No. of Transplants Performed From Donor <3 yr
Year of Transplant
No. of RecipientsTreated with Cyclosporine
No. of Grafts with Primary Nonfunction
1968 1970
1 1
0 0
0 0
1972 1973 1974 1975
2 1 2 3
0 0 0 0
2 0 0 1
1976 1977 1978 1979
2 2 2 2
0 0 0 0
2 1 1 1
1980 1981 1982 1983 1984 1985 1986 1987
1 4 10 1 0 1 1 1
0 0 2 1 0 1 1 1
O 1 3 0 0 1 1 1
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YEARS POST RENAL ALLOGRAFT Fig 2. Survival of allografts f r o m donors a g e n e w b o r n to 12 months (C~O), 13 m o n t h s t o 3 y e a r s ( H ) , 3 to 5 years (&--&), and g r e a t e r t h a n or equal t o 5 y e a r s ( A - - A ) as calculated by life table.
To evaluate the outcome of renal allografts from very young donors, the survival and function of 36 cadaveric renal allografts from donors under the age of 3 years was compared with the 65% 6-month and 64% 12-month survival for 136 kidneys transplanted from donors age 3 years or greater (Fig 1). A separate
analysis comparing survival of grafts from donors 3 to 5 years of age (n = 14) with donors over age 5 revealed no significant differences in 6- or 12-month survival rates (P > .1) (Fig 2). Survival of allografts from very young donors was significantly inferior compared with grafts from older donors. There was only a 50% 6-month and 31% 12-month graft survival for kidneys from donors less than 3 years of age (Fig 1). Graft survival for donors under 13 months of age (n = 16) was especially decreased when compared with donors over age 3 years, with a 31% 6-month (P < .01) and 16% 12month ( P < .001) survival (Fig 2). This group included seven anencephalic newborn infants. Graft survival for anencephalic donors was not significantly different from that for other donors under 13 months of age (Fig 3). For donors under 13 months of age, allograft survival was similar for single kidney (n = 7) and en bloc duplex renal grafts (n = 9), and was not influenced by recipient age or size. Survival for renal allografts obtained from donors age 13 months to 3 years was also significantly decreased relative to donors aged 3 years and older, with a 55% 6-month ( P > .1) and 40% 12-month survival (P < .05). 100
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Influence of Pediatric Donor Age on Graft Survival in Cadaveric Renal Transplantation
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The mean age for children who were recipients of small grafts was 7 years, and the median age was 9 years. For adult recipients of kidneys from small donors, the mean age was 48, and the median age 39. Table 1 represents the number of transplants from very young donors performed each year. Immunosuppression for the majority of the patients consisted of azathioprine and prednisone. When cyclosporine became clinically available, patients received cyclosporine in combination with the other two agents.
>
50 40
I 1
I 2
I 3
I 4
I 5
t 6
I 7
I 8
I I ( I I L I I I I 9 10 11 12 13 14 15 16 17 18
YEARS POST RENAL ALLOGRAFT Fig 1. Survival of allografts f r o m donors less t h a n 3 y e a r s of a g e ( O - - - O } c o m p a r e d w i t h grafts f r o m donors a g e 3 y e a r s and older ( H | as calculated by t h e life table m e t h o d .
* 1
2
3
4i
I lll 112 13 I ll4 115 lu/ 117 118 5i 6i 7I 8I 9I ' 10 YEARS POST RENAL ALLOGRAFT
Fig 3. Survival of allografts from anencephalic donors (0----0) w a s not significantly d i f f e r e n t f r o m t h o s e o b t a i n e d f r o m o t h e r donors a g e n e w b o r n to 13 m o n t h s ( H ) .
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ILDSTAD ET AL
Analysis of Early Graft Loss
Influence of Recipient Age on Graft Outcome
The most frequent cause of graft loss in allografts obtained from donors less than 3 years was early nonfunction in the presence of anastomotic patency as determined by operative inspection, doppler ultrasound, angiography, or by gross and histologic inspection after removal of the failed graft. Graft loss was not influenced by recipient size or age, but was directly related to the age of the donor (Table 2). The rate of primary nonfunction of allografts obtained from donors less than 3 years was significantly higher when compared with that for donors age 3 years or older. The rate of primary nonfunction in the presence of anastomotic patency was 63% for renal allografts obtained from donors less than the age of 1 year and 30% for grafts obtained from donors aged 13 months to 3 years, compared with only 2% in grafts obtained from donors greater than or equal to 3 years of age ( P < . 0 1 ; Table 2). This did not appear to be a cyclosporine effect, since only 6 of 36 patients who received a renal allograft from donors less than 3 years of age received cyclosporine. When analyzed separately, there was a 57% (4/7) rate of primary nonfunction for renal allografts harvested from anencephalic donors (Table 2). Of the functioning kidneys obtained from anencephalic donors, one graft has functioned for 18 years (most recent serum creatinine, 1.1), one for 12 years (most recent serum creatinine, 1.9), and the third was rejected at 1 year posttransplant secondary to patient noncompliance. This rate of function in kidneys from anencephalic donors is not significantly different from that for grafts harvested from other donors under 13 months of age (P > . 1).
The rate of primary graft nonfunction was also not significantly influenced by the age of the recipient in those patients who were transplanted with renal allografts from donors less than 3 years. The frequency of primary graft nonfunction was 47% in recipients 1 to 10 years of age, 54% in those 11 to 19 years of age, and 34% in those age 20 or older.
Influence of Duration of Cold Ischemia on Allograft Function and Outcome The average duration of cold ischemia time was 21 hours for all grafts transplanted from donors less than age 3 years. For grafts that exhibited primary nonfunction, the average cold ischemic time was 23.8 hours, compared with 21.6 hours in grafts that exhibited early function. This difference was not significantly different. Table 2. Frequency of Primary Graft Nonfunction in Renal AIIografts Obtained From Very Smalls Donors Frequencyof PrimaryGraft Donor Age Anencephalic newborns Age 5 d to 12 mo Age 13 to 35 mo Age 3 yr and older
N 7 9 20 136
Nonfunction 4 6 6 3
(57%) (67%) (30%) (2%)
Significance Estimate* (P) <.001 <.001 <.001
*Comparison made with outcome of renal allografts obtained from donors 3 years of age and older.
DISCUSSION
Recent improvements in immunosuppressive agents have led to revolutionary advances in the field of renal transplantation. Consequently, the number of transplants has increased dramatically, resulting in a severe shortage of kidneys available for transplantation. This is especially true for the pediatric transplant recipient, where size limitations create an additional obstacle in donor selection. Alternative sources of renal allografts are now being explored, including very young donors and anencephalic newborns. 9"1~ Until recently, most centers have avoided renal allografts obtained from donors less than 5 years of age. Data on the efficacy of transplanting kidneys from very young donors are limited and conflicting, and has consisted primarily of case reports in the literature. 9"13 Our experience with 36 donors under the age of 3 years, including 7 anencephalic newborns, has provided a large series from which to analyze the influence of donor age on graft outcome and function. Our data indicate that the survival of allografts obtained from donors less than 3 years of age was significantly inferior to that of grafts obtained from donors greater than 3 years of age. This effect was highly correlated with age of donor but was not influenced by age of recipient. One-year graft survival for kidneys obtained from donors less than 13 months of age was 31% at 6 months and 16% at 12 months. This was significantly inferior to the graft survival observed in patients who received an allograft from donors age 3 years of age or greater, where survival was 65% at 6 months and 64% at 12 months (P < .01 and P < .001, respectively). There was a 55% 6-month and 40% 12-month survival for renal allografts obtained from donors aged 13 months to 3 years, again significantly inferior to the outcome for that of allografts from donors greater than or equal to 3 years. These results are at variance with other reports in the literature. However, our large series has allowed us to compare outcome by age stratification while other centers have combined all donors less than 5 years of age for overall comparison because of small sampling size. 15J6
In our series, the most common cause of graft loss in kidneys obtained from donors less than 3 years was
DONOR AGE IN RENAL TRANSPLANTATION
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primary nonfunction in the presence of anastomotic patency. Mechanisms responsible for this graft loss may include blood flow discrepancy, pulse pressure differences in children in comparison with adults, the effects of ischemia in immature kidneys, and other technical considerations attendant with small blood vessel anastomoses. Cold ischemia time was not a significant factor in our series. Perfusion and preservation techniques have been developed and characterized for renal allografts obtained from adult donors, but little attention has been focused on potential differences in requirements for the preservation and perfusion of kidneys from the very young, or even fetal donors. In spite of the current high early failure rate of kidneys transplanted from very young donors, our data indicate that the long-term function of surviving kid-
neys appears to be normal. Therefore, additional efforts must be directed at defining the optimum conditions for perfusion and preservation during harvesting of these grafts, although this alone may not result in an improved graft outcome. Young donors are a potential source of kidney allografts for our current acute shortage of donor organs. However, until details specific to the perfusion and preservation of kidneys from young donors have been better defined, the authors recommend that renal allografts from donors under the age of 3 years be used with caution. ACKNOWLEDGMENT The authors thank Micheile Waters for manuscript preparation, Jean Loos for technical assistance, and Dr Marc Rowe for manuscript review.
REFERENCES 1. Eggers PW: Effect of transplantation on the medicare end stage renal disease program. N Engl J Med 318:223, 1988 2. Kahan BJ: Pediatric renal transplantation (letter). Transplant Immunol 4:1-11, 1987 3. So SKS, Simmons RL, Fryd DS, et al: Improved results of multiple renal transplantation in children. Surgery 98:729, 1985 4. Avner ED, Harmon WE, Crupe WE, et al: Mortality of chronic hemodialysis and renal transplantation in pediatric end stage renal disease. Pediatrics 67:412, 1981 5. Bale JF Jr, Sieger RL, Bray FF: Encephalopathy in young children with moderate chronic renal failure. Am J Dis Child 134:581, 1980 6. Grushkin CM, Fine RN: Growth in children following renal transplantation. Am J Dis Child 125:514, 1973 7. Rizzoni G, Malikoazek M, Pennisi A, et al: Renal transplantation in children less than 5 years of age. Arch Dis Child 55:532-536, 1980 8. Potter D, Feduska N, Melzer J, et al: Twenty years of renal transplantation in children. Pediatrics 77:465-470, 1986
9. Lum CT, Fryd DS, Polta TA, et al: Results of kidney transplantation in the young child. Transplantation 34:167, 1982 10. Holzgreve W, Belier FK, Buchholz B, et al: Kidney transplantation from anencephalic donors. N Engl J Med 316:1069, 1987 11. Martin LW, McEnery PT, Rosenkrantz JG, et al: Renal homotransplantation in children. J Pediatr Surg 14:571, 1979 12. Hayes JM, Novick AC, Streem SB, et al: The use of single pediatric cadaver kidneys for transplantation. Transplantation 45:106, 1988 13. Trompeter RS, Bewick M, Haycock GB, et al: Renal transplantation in very young children. Lancet 1:373, 1983 14. Gehan EA: A generalized Wileoxon test for comparing arbitrary singly-censored samples. Biometrika 52:203, 1965 15. Daniel WW: Biostatistics: A Foundation for Analysis in the Health Sciences, ed 3. New York, NY, Wiley, 1983 16. Wengerter K, Matas A J, Tellis VA, et al: Transplantation of pediatric donor kidneys to adult recipients: Is there a critical donor age? Ann Surg 204:172, 1986
Discussion E.P. Wood (Omaha, NE): This study confirms the impression that those of us that perform renal transplantation have had that donors less than 2 years of age probably should not be used for cadaveric donation. I have a couple of questions in that you did not discuss patient survival. I think it is important in renal transplantation that this is a quality of life operation as opposed to a life saving operation and I think it is important that if we are using very small donors with the idea that a number of them will not function adequately, what is your survival rate in patients who undergo these procedures. Second, I wonder if you are going to continue to use these very small donors and how you would advise us to modify our techniques as far as organ procurement and whether there is any indication that it will help lower the incidence of
primary nonfunction. In addition, you gave several possible mechanisms of why these kidneys do not work. Could you perhaps speculate a bit more on what the mechanism may be to the primary nonfunction of these kidneys? P. Guzzetta (Washington, DC): In our experience in Washington, DC, we found that if we use a kidney that is larger than 40 g, and for relative size that is about the size of a grade A large egg, we have not had any problems with those kidneys in patients. That kidney correlates with a donor age of approximately 18 months. We do specifically use kidneys smaller than that in patients who are quite small and we have only had one primary nonfunction in six patients transplanted less than 1 year of age. I think that the message that you are giving is that you should not use
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the kidneys from patients who are less than 3 years of age. In those centers that do use very small kidneys specifically for very small patients, unfortunately I think that they might be doing a disservice, and it is just up to the responsibility of the people using those kidneys to make sure that they are not all thrown in the basket. I do have one specific question related to that. Does this mean that at Cincinnati they no longer harvest kidneys from patients less than 3 years of age? You didn't mention in the presentation the microscopic evaluation of the kidneys that were taken out and as you probably know the group in Alabama feel very strongly that primary nonfunction in the adult is related to rejection. Do you have some information about the microscopic evaluation of these kidneys? D. Tapper (Seattle, WA): I think that the national data absolutely supports the information presented. I am surprised that Dr Guzzetta's institution has not also confirmed this; however, the national data kept at the UCLA Registry as well as all the bulletins that are sent around absolutely confirm primary nonfunction is significantly higher when kidneys less then 2 years of age are used. I would like to ask Dr Ildstad whether or not it would be possible from this long experience to go back and see exactly who harvested these kidneys and whether or not there is a difference between those organs that were harvested by pediatric surgeons or harvested in your own institution versus the ones that were shipped you. It seems simplistic to say that this is technical, but you wonder if the kidney was working in an 1 t-month-old child with a normal creatinine why does the kidney not work after transplantation. Your slide indicates that there was no significant difference due to cold storage. You wonder why the kidney would not immediately work and why was the nonfunction so high. I wonder as to whether or not our colleagues who are doing the bulk of the harvesting do not have the same appreciation for the tiny vasculature of these kidneys.
J.C. Molenaar (Rotterdam, The Netherlands): I have two short questions. Extensive reduction of renal tissue in animals leads to renal function deterioration due to glomerular hypertension and subsequent microvascular injury. Has the pathology of the nonfunctioning kidneys been studied in this respect? Transplantation of very young donor kidneys in animals leads to rapid increase of the glomerular infiltration rate and also to a rapid growth of the transplanted the kidney. Have you looked into these phenomena in the surviving kidneys of your series? L. Martin (CincinnatL OH): Dr Ildstad insisted that I show you the slide of one very special patient included in her report. This is a young man who received a set of kidneys from an anencephalic donor when he weighed
ILDSTAD ET AL
17 pounds. He could not talk and could not walk. He was thought to be retarded. He has, 22 years later, finished college. He is 25 years old and this is a photograph of him with his fiance. He still has the kidneys from the anencephalic donor. He has never had a flicker of rejection. S. lldstad (closing): Dr Wood, with regard to the long-term outcome of the recipients of small kidneys, our data indicate that if the kidney survives that the long-term function of the kidney is similar to that of kidneys obtained from donors greater than 2 years of age. In some of the patients we have followed for up to 18 to 20 years, the creatinines have remained normal. Dr Guzzetta indicated that in their experience they have encountered one nonfunctioning allograft in six patients. However, in small numbers of patients it is difficult to make statistically significant analyses of the recipients of small kidneys. One additional nonfunctioning kidney would change the percentage of nonfunction significantly. Larger numbers would be required to reduce sampling error. Our data indicate that there is only a 43% chance of function in the kidneys obtained from donors less than 12 months of age. In effect, one is playing the odds. That is an issue that each transplant surgeon must address because if the kidney obtained from a donor greater than 3 years of age has less than a 2% rate of primary nonfunction and one obtained from a donor less than 12 months of age has a 57% to 67% rate of primary nonfunction, the surgeon has to decide whether the patient needs that kidney so badly that he or she is are willing to accept such a high chance of failure if a kidney from a donor less than 3 years of age is used. With the current availability of dialysis to temporize until a suitable donor is found, I would recommend avoiding the kidney obtained from donors less than 3 years until the mechanism responsible for the primary nonfunction is understood. Dr Tapper's question with regard to the harvesting of the kidneys is an interesting one. In our institution, until the cooperative transplant center was formed, the pediatric surgeons harvested all of the kidneys. All of the anencephalic donor kidneys in this study were harvested by a pediatric surgeon at the Children's Hospital. The majority of the other kidneys come from our institution and were therefore also harvested by a pediatric surgeon. The criteria that we used for brain death in the anencephalic donors was the same criteria that our institution uses for brain death, and that has been an evolving criteria because this study spans 18 years. Dr Mollenar's question regarding the histologic appearance of these kidneys that had initial nonfunction is interesting. The pathology was examined and there was no evidence for cellular infiltrates that would be compatible with
DONOR AGE IN RENAL TRANSPLANTATION
rejection. In addition, the vascular anastomoses were patent. It seemed to be more of a cellular or parenchymai level of nonfunction. However, some of the kidneys obtained from donors less than 3 years of age did undergo immunologic failure from rejection. The issue of antigenicity of fetal versus newborn versus adult
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tissues has not been characterized and although we assume that newborn tissue is less antigenic, this has not been proven. Studies in animals have shown that fetuses are competent to reject foreign tissues after the first trimester. I would like to thank the discussants for their thoughtful questions.