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Current Experience With Renal Transplantation in Older Patients
Current Experience With Renal Transplantation in Older Patients Bharat Shah, MD, M. Roy First, MD, Rino Munda, MD, Israel Penn, MD, James P. Fidler, MD, and J. Wesley Alexander, MD • Older patients (>50 years old) are generally considered to be at high risk in renal transplantation, particularly those receiving cadaveric kidneys. The outcome in 53 older patients (mean age, 54 years; range, 50 to 64 years) receiving transplants between January 1,1980 and December 31, 1986 and followed through June 30,1987 were analyzed. Before 1984, immunosuppression consisted of azathioprine and prednisone (AP); thereafter, triple therapy (TT)-Iow-dose cyclosporine, azathioprine, and prednisone-was used. The overall 1-, 3-, and 5-year actuarial patient survival was 87%, 84%, and 84%, respectively. Survival for living related donor (LRD) transplant recipients was 100%, 92%, and 92%; survival for cadaveric (CAD) transplant recipients was 81%,81%, and 81%. The overall graft survival was 74%, 66%, and 66% at 1, 3, and 5 years, respectively; graft survival was 88%, 81 %, and 81% for LRD transplant recipients and 68%, 58%, and 58%, for CAD recipients. The patient and graft survival rates were better in the TT group than in the AP group. Eight patients died after transplantation; six within the first year. The causes of patient death were infection (50%), cardiac (25%), and malignancy (25%). Rejection (56%) and patient death (38%) accounted for most of the grafts lost. Patient and graft survival rates in diabetic patients were not significantly different from survival rates in nondiabetic patients. Results in recipients of ten secondary and one tertiary transplant were poor, with only four of 11 grafts functioning at 1 year. Infectious complications were common, and steroid-induced diabetes occurred in 16% of patients whose grafts functioned >1 month. It was concluded that results of primary renal transplantation in older patients have significantly improved in recent years. Transplantation should be the preferred modality of treatment for end-stage renal disease in patients aged 50 to 64 years in the absence of obvious contraindications. © 1988 by the National Kidney Foundation, Inc. INDEX WORDS: Transplantation; older patients; survival.
I
N THE PAST, patients aged > 50 years have been considered to be at high risk in renal transplantation, particularly when kidneys were obtained from cadaveric donors. 1-4 In recent years, with growing experience and judicious use of immunosuppression, results of renal transplantation have improved in this group of patients. 1.5.6 Addition of cyclosporine to the immunosuppressive regimen has further improved the outcome following transplantation. 7-9 In the light of current experience, it appears that transplantation should be the preferred form of treatment even in patients > 50 years old because of improved quality of life after transplantation. 1O We reviewed our experience with transplantation in older patients to see how the results in this group compared with those obtained in younger patients. We further analyzed the outcome according to donor type, immunosuppressive protocol, and complications after transplantation.
From the Departments of Internal Medicine and Surgery, University of Cincinnati Medical Center, Cincinnati_ Address reprint requests to M_ Roy First, MD, Division of Nephrology, University of Cincinnati Medical Center, 5363 MSB, 231 Bethesda Ave, Cincinnati, OH 45267-0585. © 1988 by the National Kidney Foundation, Inc. 0272-6386/66/1206--0008$3.00/0
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MATERIAL AND METHODS Three hundred sixty-five renal transplants were performed between January 1, 1980 and December 31, 1986 at the University of Cincinnati Medical Center and followed through June 30, 1987. Of these, 64 transplants were performed in 53 patients 50 to 64 years old at the time of transplantation, with a mean age of 54.3 years, including 53 primary transplants, ten secondary transplants, and one tertiary transplant. There were 33 male and 20 female recipients. Racial distribution was 29 whites, 18 blacks, 5 Arabs, and 1 Oriental. Donor source in the 53 primary transplants was cadaveric (CAD) in 36, and living related donor (LRD) in 17 (five human lymphocyte antigen [HLA] identical, 12 haploidentical)_ Over the same period, 221 primary transplants were performed in recipients aged 17 to 49 years (mean age, 34.0 years). Outcomes were compared between the older and younger patients groups_ Table 1 shows the characteristics of the patients in the two age groups. In recent years, our criteria for accepting older patients for renal transplantation have been liberalized. This is reflected in the fact that only 16 transplants were performed in this age group between January I, 1980 and December 31, 1983, whereas 48 transplants were performed between January 1, 1984 and December 31, 1986. This increase in the number of older patients was partly due to introduction of cyc\osporine in 1984_ Figure 1 shows the percentage of older patients receiving transplants each year from 1980 to 1986 and the donor sources. All patients had pretransplant barium enemas and gallbladder ultrasound_ Localized diverticular disease was treated by segmental colonic resection before 1983, but thereafter this procedure was performed only if the patient had experienced acute diverticulitis; if gallstones were present, cholecystectomy
American Journal of Kidney Diseases, Vol XII, No 6 (December), 1988: pp 516-523
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RENAL TRANSPLANTATION IN OLDER PATIENTS Table 1. Characteristics of Patients Receiving First Kidney Transplant in the Age Groups > 50 Years and 17 to 49 Years Age Group >50 yr
Age Group 17 to 49 yr
53
221
33 (62%) 20 (38%)
133 (60%) 88 (40%)
N Sex Male Female Age, yr (mean
±
SO)
54.3
±
3.0
34.0
± 8 .6
Donor CAD LRD
36 (68%) 17 (32%)
151 (68%) 70 (32%)
Immunosuppression AP TT
20 (38%) 33 (62%)
125 (56%) 97 (44%)
Etiology of ESRD CGN DGS HTNS CIN PKD Other
17 (32%) 13 (25%) 11 (21%) 4(7%) 3(6%) 5(9%)
113 51 8 13 11 25
(51%) (24%) (4%) (5%) (5%) (11%)
Abbreviations: Ap, azathioprine, prednisone; TT, triple therapy (cyclosporine, azathioprine, prednisone); CGN, chronic glomerulonephritis; DGS, diabetic glomerulosclerosis; HTNS, hypertensive nephrosclerosis; CIN, chron ic interstitial nephritis; PKD, polycystic kidney disease. was performed. Bilateral nephrectomy for control of hypertension was not performed in any of the patients.
Transfusion Protocol Recipients of CAD transplants each received a total of five units of blood. Patients were activated on the cadaveric waiting list 2 weeks after the fifth transfusion. Serum for crossmatch and panel-reactive antibody (PRA) was obtained before the initial transfusion, at the time of listing, and monthly thereafter.
50
40
30
% 20
10
0
~~ 1980
1981
1982
~
1983 1984
1985
1986
Fig 1. Percentage of patients aged > 50 years receiving renal transplants each year from 1980 to 1986. (.), cadaveric donor; (0), living related donor.
Recipients of haploidentical LRD kidneys were given three donor-specific transfusions (DST) of 150 mL whole blood at 2week intervals. Transplantation was performed 3 to 4 weeks after the third transfusion if the T-warm cross match (performed at 37°C) was negative. Only one recipient of an "LA-identical LRD kidney received DST.
Immunosuppressive Protocol The 16 patients who received transplants before 1984 were treated with conventional immunosupression consisting of azathioprine and prednisone (AP). Azathioprine, 4 mg/kg intravenous (IV), was administered on the day of surgery, followed by a maintenance dose of 2 mg/kg/d. The maintenance dose was reduced in the presence of WBC count < 5,000/"L. On the day of surgery, 250 mg IV methylprednisolone was administered. The day after surgery, 200 mg prednisone was administered orally. The prednisone was then reduced rapidly to reach a level of 1.0 mg/kg/d by day 14 and 0.5 mg/kg/d by day 28. The prednisone was reduced gradually thereafter. Acute rejection episodes (ARE) were diagnosed on clinical and biochemical parameters (an increase in the serum creatinine >0.3 mg/dL) and confirmed by percutaneous allograft biopsy in all instances. ARE were treated with IV methylprednisolone, 250 mg daily, for four days. In the event of a poor response to corticosteroids, antilymphocyte globulin (ALG) , 15 mg/kg/d for seven days, and/or graft irradiation, 150 rad/d for three days , was used. After 1984 a major change in immunosuppressive protocol was introduced, with use of low doses of cyclosporine, azathioprine, and prednisone (triple therapy [TID. This therapy has been described in detail by First et al. II Briefly, all patients received azathioprine, 4 mg/kg IV, and methyiprediosolone,
518
SHAH ET AL
250 mg IV, on the day of transplantation. On day I, if the urine output was good and serum creatinine already falling, oral cyclosporine was added in a dose of 10 mg/kg/d. If the urine output was poor and serum creatinine rising, horse antithymocyte globulin (ATG-Atgam) was added instead of cyclosporine. ATG was continued either until serum creatinine fell to < 4 mg/dL or for 14 days. Cyclosporine was introduced in a dose of 10 mg/kg/d when renal function had improved. The dose of cyclosporine was reduced to 8 mg/kg/d after I week and further reduced to 6 mg/kg/d on day 30. Beyond 6 months, the dose of cyclosporine was maintained at 4 to 6 mg/kg/d. AREs were treated in one of three ways: (I) IV methylprednisolone, 250 mg daily for three to four days; (2) ATG, 10 to 15 mg/kg/d for ten days; or (3) OKT3, 5 mg IV daily for ten days.
53)(36)( 17) 100
(19)
(S)
(3)
(14)
(11)
~
(/)
80
(7)
(15)
(10)
(7)
(6)
(4)
~
60
0
1
,
,
I
I
I
12
24
36
48
60
Months After Transplantation
A
5;l}(36}( 17)
Patient survival and kidney survival statistics were calculated by actuarial techniques. 12 Patients dying of any cause while their grafts were still functioning were considered transplant deaths. Death occurring any time after transplantation has been considered transplant death even if the graft failed and the patient returned to dialysis. A graft was considered lost when any of the following events occurred: (I) nephrectomy; (2) return to dialysis; (3) death of any cause; (4) retransplantation without a return to dialysis. A comparison between different groups was achieved by calculating:
100 (15)
iii
.~
~
(/)
80
1(10)
(7)
(5)
(4)
J(19)
(12)
(8)
(7)
1(9)
(S)
(3)
(3)
(32)
~
(17) 60
of 8
=
(7)
.~
Data Analysis
Z
(13) (23)
(34)
iii
I
I
I
24
I
I
12
36
48
60
Months After Transplantation
Pn - P'n [SE(pn)]2 + [SE(P 'n)]2
where Pn is the percentage survival and SE standard error.13
RESULTS
Patient and Graft Survival Rates after Primary Renal Transplantation Of 53 patients, 45 were alive 6 to 87 months after transplantation. As shown in Fig 2A, 1-, 3-, and 5-year actuarial survival was 87 %, 84 %, and 84% (96%, 88%, and 85% in younger patients). The corresponding figures were 100%, 92 %, and 92 % for LRD transplant recipients (98 %, 98 %, and 96 % in younger patients) and 81 %, 81 %, and 81 % for CAD recipients (95 %, 84 %, and 78 % in younger patients). As shown in Fig 2B, overall graft survival was 74%,66%, and 66% at 1, 3, and 5 years, respectively (73%,65%, and 60% in younger patients). Graft survival was 88 %, 81 %, and 81 % for LRD transplant recipients (88 %, 84 %, and 78 % in younger patients) and 68%, 58%, and 58% for CAD recipients (66%,53%, and 51 % in younger patients). Overall patient survival in older patients was lower at 1 year (P < 0.05) compared with younger patients, but there was no significant difference in survival at 3 and 5 years. This dif-
Fig 2. (A) Patient and (8) graft survival after primary renal transplantation in patients aged >50 years. (_ _), overall (n = 53); (6-6), living related donor (n = 17); (0-0), cadaver donor (n = 36). Figures in parenthesis indicate number of patients being followed at each time interval.
ference in overall patient survival at 1 year was largely due to the difference in survival in CAD recipients (P < 0.05) because the survival in LRD recipients was similar in the older and younger patients. There was no significant difference (P > 0.05) in graft survival between the two groups at any period after transplantation. In interpreting these results it must be pointed out that the number of older patients followed beyond 3 years was very small (Fig 2). Moreover, a greater proportion of patients in the older age group received TT than in the younger age group (Table 1). Impact of Cyclosporine in Primary Transplants Analysis of patient and graft survival rates according to the donor type (CAD/LRD) and immunosuppressive therapy (AP/TT) resulted in small subgroups and limited periods of follow-up (because cyclosporine was only introduced in 1984). The patient survival at 2 years in the LRD recipients was 100% in the TT group (n = 7) and 88% in the AP group (n = 10). In CAD recipients the 2-year patient survival was 82 % in the TT
519
RENAL TRANSPLANTATION IN OLDER PATIENTS
group (n = 26) and 80% in the AP group (n 10). These differences were not statistically significant (P > 0.05). On the other hand, the graft survival in both LRD transplant recipients and CAD recipients was significantly better in the TT groups (P < 0.05). The 2-year LRD graft survival in the TT patients was 100 %, compared with 77 % in the AP group. For CAD recipients the 2-year graft survival in the two groups was 65 % and 30%, respectively. The AP-treated CAD transplant group included four patients who lost the grafts in the early posttransplant period and never achieved renal function to the level required to introduce cyc1osporine according to our protocol. This obviously biases the results strongly against this group of patients. If these four patients are excluded, the 2-year graft survival of 50% is still inferior to that obtained with TT (P < 0.05). Causes of Patient Death and Graft Loss
Table 2 shows the causes of patient death and graft loss according to donor type and immunosuppressive treament. Eight patients died after transplantation. Six of the deaths occurred within the first year after transplantation, all in recipients of primary CAD transplants. Two deaths occurred in recipients of LRD kidneys; both of these patients rejected the first (LRD) graft and received CAD kidneys. One patient died of sepsis 17 months after the first transplant but within 1 month of the second kidney transplant, which was combined with a pancreas transplant. The second patient died 69 months after the first transplant; this Table 2.
patient developed a cardiac arrhythmia 41 months after a third transplant. For purposes of analysis these two deaths were included in the LRD survival group (see Methods); however, from a practical point of view no recipient of an LRD kidney died within 1 year of the primary transplant. Infection was the cause of death in four cases (three bacterial sepsis, one Pneumocytis carinii pneumonia) . There were two cardiac deaths (one of acute myocardial infarction on the third posttransplant day, the other of cardiac arrhythmia 69 months after primary transplantation) . Malignancy accounted for two deaths (one disseminated carcinoma of the colon 92 days posttransplant, one bronchogenic carcinoma of the lung 9 months after transplantation) . Of the 16 primary grafts lost, nine (56%) were lost from rejection: two from early rejection (hyperacute and accelerated rejection) , three from acute rejection, and four from chronic rejection. Patient death accounted for the loss of six (38 %) grafts, and one (6%) graft was lost when an attempt to perform an angioplasty for transplant renal artery stenosis resulted in tear of the vessel, requiring emergency nephrectomy. Results in Diabetic Patients
Fifteen transplants were performed in 13 diabetic patients. Among the 13 primary transplants performed in diabetic patients, seven were LRD transplants and six were CAD transplants; seven were treated with TT and six with AP. Patient and graft survival following primary renal
Causes of Patient Death and Graft Loss Following Primary Transplantation CAD (n = 36) AP (n = 10)
Patient death Bacterial sepsis (n = 3) Pneumocystis (n = 1) Malignancy (n = 2) Cardiac (n = 2) Graft loss Death (n
= 6)
Rejection Hyperacute (n = 1) Accelerated (n = 1) Acute (n = 3) Chronic (n = 4)
LAD (n = 17)
TT (n = 26)
AP (n = 10)
TT (n = 7)
1
2
2
4
1 2
2
Technical (n = 1) Total number of patients: n = 53. Abbreviations: AP, azathioprine, prednisone; TT, triple therapy (cyclosporine, azathioprine, prednisone).
520
SHAH ET AL
transplantation was 92 %, 79% , and 79 % and 75% , 63%, and 63% at 1, 3, and 5 years, respectively. The results in this small subgroup were not significantly different from the results in nondiabetic recipients. However, outcome in this group was biased by the fact that the majority received LRD transplants. Two diabetic recipients died; one of acute myocardial infarction on the third posttransplant day and one of sepsis following a second kidney transplant, which was combined with pancreas transplant. Four grafts failed following primary transplantation (one patient death , one recurrent acute rejection, and two chronic rejections) .
a tertiary transplant. Four grafts were lost from rejection, three from hyperacute rejection, and one from recurrent acute rejection . The three patients who lost grafts from hyperacute rejection had high PRA at the time of transplantation (100%, 97 %, and 73 %); in one case this occurred when a kidney was inadvertently transplanted into a patient with a positive crossmatch because of an administrative error. Only four of the 11 grafts were functioning 1 year after transplantation. Analysis of HLA matching in the regrafted patients revealed poor tissue compatibility (average A-B locus match, 0.91 antigens; average DR locus match, 0.27 antigens) .
Results of Retransplantation
Posttransplant Complications
Ten second transplants and one third transplant were performed in ten patients. All were retransplanted with CAD kidneys; six received TT and five received AP In this group, two patients died of sepsis within 1 month of transplantation, and one patient died of a cardiac cause 41 months after
Table 3 lists the complications after primary renal transplantation. Infections were more common in recipients of CAD transplants. The bacterial infections encountered were urinary infection (n = 6), pneumonia Cn = 6), Gram-negative septicemia Cn = 3) , wound infection (n = 3), perirec-
Table 3.
Complications Following Primary Transplantation CAD (n AP (n = 10)
Infections Bacterial Urinary infection (n = 6) Pneumonia (n = 6) Septicemia (n = 3) Wound infection (n = 3) Perirectal abscess (n = 2) Goretex graft (n = 1) Infected foot (n = 1) Otitis media (n = 1) Pulmonary TB (n = 1)
4 1 1
= 36)
LAD (n
IT (n = 26)
1
Protozoal Pneumocystis (n = 3)
3
Technical Urologic urinary leak (n = 3)
2
=
6)
2
1)
HypertenSion (n = 29) Diabetes (n
IT(n = 7)
2 2
2 4
=
= 17)
1 3
Viral Cytomegalovirus (n = 5) Herpes zoster (n = 4)
Vascular Renal artery stenosis (n
AP (n = 10)
4
16 3
4
5 2
Total number of patients: n = 53. Abbreviations: AP, azathioprine, prednisone; TT, triple therapy (cyclosporine, azathioprine, prednisone); TB, tuberculosis.
RENAL TRANSPLANTATION IN OLDER PATIENTS
tal abscess (n = 2) , infected goretex graft (n 1), infected foot ulcer in a diabetic patient (n 1), otitis media (n = 1) , and pulmonary tuberculosis (n = 1). There were five cases of cytomegalovirus infection and four cases of herpes zoster infection. Pneumocystis carinii pneumonia occurred in three patients , all on TT. Three patients developed urinary leaks in the early posttransplant period; all were successfully treated by reimplantation of the ureter. One patient developed renal artery stenosis 9 months posttransplant; angioplasty resulted in a tear in the vessel, requiring emergency nephrectomy. Thirtyeight of the 40 nondiabetic patients who received transplants had functioning grafts at 1 month; six (16 %) of these patients developed steroid-induced diabetes. Hypertension was present in 29 (63%) of 46 patients with functioning kidneys beyond 3 months . DISCUSSION
There has been a progressive increase in the number of older patients accepted for transplantation at our center. Currently most of these patients undergo CAD transplantation, unlike the early period in which LRD transplants predominated. At present, older patients constitute 25 % to 30 % of our renal transplant recipients with a CAD-toLRD transplant ratio of 3: 1. The Medical Information System of the Health Care Financing Administration (HCFA) reported higher mortality rates in the first year after transplantation in the older patients than in younger patients, and in older recipients of CAD kidneys than in older LRD recipients. 7. 14 Six of the eight deaths in our study occurred within the first year after transplantation; all occurred in recipients of CAD kidneys. Two of the deaths were caused by cardiac causes and two by malignancy ; this emphasizes the need for more intensive pretransplant screening for diseases occurring with a higher frequency in older patient population . On the other hand, graft survival in older patients at 1 year was no different from that observed in younger patients. In a large study reported by the UCLA Transplant Registry,15 graft survival rates were better in recipients aged 41 to 60 years than in younger recipients. This could be attributed to a more vigorous allograft response in younger than in older patients , resulting in a higher graft loss from rejection. Aging is associated with a generalized decline in
521
immunologic function , particularly the T cell immune response. 16 18 The addition of immunosuppressive drugs after transplantation further compromises immune responses in older patients. Thus, infections are more common in older patients after transplantation and account for the higher mortality rate. A high incidence of infectious complications in older recipients of cadaveric kidneys has been reported by others,4.19 in agreement with the observations in this series. In our patients, graft loss from death accounted for 38 % of primary grafts lost. This was in contrast to only 16.7% of grafts lost from death in our younger patients. Similar observations have been reported in other series.7.19.20 With growing experience in transplantation and judicious use of immunosuppressive therapy, the results of renal transplantation have improved in older patients in recent years even with conventional immunosuppressive therapy. \.5.6 The addition of cyclosporine to the immunosuppressive regiment has further improved outcome in these patients. We observed improved patient and graft survival rates in patients treated with TT compared to Ap, although the number of patients followed long-term in each of our groups was small. This is consisent with reports from other centers. 7.8.16 Patient survival in our recipients of both LRD and CAD kidneys was superior to that reported in patients of similar age treated by dialysis. 7.14 In the HCFA report 1- and 3-year survival rates in almost 36 ,000 patients aged >50 years treated by dialysis were 77 % and 48 %, respectively.14 However, comparisons of patient survival between those treated by dialysis and those treated by transplantation are not strictly valid , as it is highly likely that many of the older patients treated by dialysis were suffering from diseases that would have made them unacceptable candidates for transplantation . Patient and graft survival rates in a small group of diabetic patients in this series were not different from those in nondiabetic patients. However, these results were biased by the fact that seven of 13 (54 %) primary renal transplants in diabetic patients were performed from a LRD, while only ten of 40 (25 %) nondiabetic patients received LRD transplants . The results of secondary transplantation were extremely poor, with only four of 11 grafts functioning at 1 year. The bad results in these patients
522
appear to have been related to the poor HLA compatibility and high levels of sensitization, both of which have been associated with poor outcome after retransplantation. 21 -24 In three of these patients the graft was lost due to hyperacute rejection; all three patients had high PRA, and in one case the kidney was inadvertently transplanted into a patient with positive crossmatch. Thus, two of ten kidneys were lost to hyperacute rejection, a rate similar to the reported 18 % of kidneys that never function in secondary transplant recipients with cytotoxic antibodies. This phenomenon may occur either because there may be antibody undetected by the complement-dependent cytotoxicity test or because the current crossmatching techniques are not sensitive enough. 21 The incidence of diverticular disease in the general population increases significantly after the age of 50 years. 25 In earlier reports, perforation of colonic diverticuli following transplantation resulted in a high mortality rate 26 ; however, much better results have been reported more recently. 27 Our current policy is to reserve prophylactic colectomy for patients with symptomatic diverticulitis. Pretransplant cholecystectomy was performed in those patients with gallstones; this approach has been advocated in this age group to prevent acute cholecystitis after transplantation. 28 Because atherosclerotic vascular disease occurs with increasing frequency after the age of 40 years, one might expect a higher incidence of anastomotic vascular complications in older patients.29 However, this did not appear to be the case in our patients. Of the 46 patients whose graft functioned beyond the third month after transplantation, 29 (63 %) were hypertensive. This incidence was similar to the 60 % reported in adult renal transplant recipients. 3o Corticosteroid-induced diabetes occurred in 16% of our nondiabetic patients whose grafts functioned beyond 1 month; this was higher than the overall reported incidence of 5 % to 10%.31 Corticosteroid-induced diabetes has been reported more frequently in older patients after renal transplantation,32 and is probably caused by an unmasking effect of corticosteroids in patients who have the potential to develop maturity-onset diabetes. This complication was observed more frequently in recipients of CAD kidneys. In summary, the results of renal transplantation in older patients have improved significantly in re-
SHAH ET AL
cent years, particularly since the introduction of cyclosporine. Although there is a higher mortality rate in the early period after transplantation, longterm results are not much different from those obtained in younger patients. Infection constitutes a significant posttransplant complication but can be minimized by using lower doses of immunosuppressive agents and by pretransplant screening for and eradication of any potential sources of infection. In addition, patients in this age group should be more rigorously screened for diseases occurring with a higher frequency in this population, such as coronary artery disease and malignancy. Transplantation should no longer be considered a high-risk procedure in patients aged 50 to 65 years, and should be offered to all such patients unless an obvious contraindication exists. ACKNOWLEDGMENT We wish to thank Violet Henry for her expert secretarial assistance.
REFERENCES 1. Najarian JS, Sutherland DER, Morrow CE, et al: Kidney transplantation for high-risk patients. Kidney Int 23:s1O-s15, 1983 (suppl 14) 2. Delmonico FL, Cosimi AB, Russel PS: Renal transplantation in the older age group. Arch Surg 110:1107-1109,1975 3. Sommer BG, Sutherland DER, Simmons RL, et al: Prognosis after renal transplantation: Cumulative influence of combined risk factors. Transplantation 27:4-7, 1979 4. Sommer BG, Ferguson RM, Davin TD, et al: Renal transplantation in patients over 50 years of age. Transplant Proc 13:33-35, 1981 5. Okiye SE, Engen DE, Sterio FS, et al: Primary renal transplantation in patients 50 years of age and older. Transplant Proc 15: 1046-1053, 1983 6. Jordan ML, Novick AC, Steinmuller D, et al: Renal transplantation in the older recipient. J UroI134:243-246, 1985 7. Krakauer H, Spees EK, Hodges JF, et al: The current experience with cyclosporine in the United States: Recipient age considerations. Transplant Proc 17:2808-2810, 1985 8. Hunsicker LG: Impact of cyclosporine on cadaveric renal transplantation: A summary statement. Am J Kidney Dis 5:335-341, 1985 9. Taube D, Cameron JS, Challah S: Renal transplantation in older patients, in Nunez JFM, Cameron JS (eds): Renal Function and Disease in the Elderly. London, Butterworth, 1987, pp 529-537 10. Evans RW, Manninen DL, Garrison LP, et al: Quality of life of patients with end-stage renal disease. N Engl J Med 312:553-559, 1985 11. First MR, Alexander JW, Wadhwa N, et al: The use of low doses of cyclosporine, azathioprine and prednisone in renal transplantation. Transplant Proc 18: 132-135, 1986 (suppl 1) 12. Merrell M, Schulman LE: Determination of prognosis
RENAL TRANSPLANTATION IN OLDER PATIENTS in chronic diseases, illustrated by systemic lupus erythematosus. J Chron Dis 1: 12-32, 1955 13. Colton T: Statistics in Medicine: Longitudinal Studies and the Use of Life Table. Boston, Little, Brown, 1974, pp 237-250 14 . Krakauer H, Grauman JS , McMullan MR, et al: The recent U.S. experience in the treatment of end stage renal disease by dialysis and transplantation. N Engl J Med 308: 15581563, 1983 15. Lee PG, Terasaki PI: Effect of age on kidney transplants, in Terasaki PI (ed): Los Angeles, UCLA Tissue Typing Laboratory, 1985, pp 123-137 16. Roberts-Thompson IC, Youngchaiyud LL, Whittingham S, et al: Aging, immune response and mortality. Lancet 2:368370, 1974 17. Fox RA: Immunology and aging, in Brocklehurst JC (ed) : Textbook of Geriatric Medicine and Gerontology. New York, Churchill Livingstone, 1985, pp 82-105 18. Renlund DG, Gilbert EM, O'Connell JB, et al: Ageassociated decline in cardiac allograft rejection. Am J Med 83:391-398, 1987 19. Ost L, Groth CC , Lindholm B, et al: Cadaver renal transplantation in patients of 60 years and above. Transplantation 30:339-340, 1980 20. Ringden 0, Ost L , Klintmalm G, et al: Improved outcome in renal transplant recipients above 55 years of age treated with cyclosporine and low doses of steroids. Transplant Proc 15:2407-2412, 1983 (suppl I) 21 . Iwaki Y, Iguro T, Terasaki PI: Effect of sensitization on kidney allografts, in Terasaki PI (ed): Los Angeles, UCLA Tissue Typing Laboratory, 1985, pp 139-145
523 22. Perdue ST: Risk factors for second transplants, in Terasaki PI (ed): Los Angeles , UCLA Tissue Typing Laboratory, 1985, pp 191-203 23. Iwaki Y, Terasaki PI: Sensitization effect, in Terasaki PI (ed): Los Angeles, UCLA Tissue Typing Laboratory, 1986, pp 257-265 24. Cicciarelli J, Cho YC : Regraft kidney transplant survival, in Terasaki PI (ed): Los Angeles, UCLA Tissue Typing Laboratory, 1986, pp 285-297 25. Colcock BP: Recent experience in the surgical treatment of diverticulitis. Surg Gynecol Obstet 121:63-69, 1965 26. Misra MK, Pinkus GS , Birtch G, et al : Major colonic diseases complicating renal transplantation. Surgery 73 :942948, 1973 27. Church JM, Braun WE, Novick AC, et al: Perforation of the colon in renal hemograft recipients. Ann Surg 203:6976, 1986 28. Okiye SE, Engen DE, Sterioff S, et al : Primary renal transplantation in patients 50 years of age and older. Transplant Proc 15: 1046-1053, 1983 29. Geis pw, Giacchino JL, Jacobi RJ, et al: Technical considerations in elderly renal allograft recipients . Am J Surg 132:332-335, 1976 30. Bachy C, Van Ypersele de Strihou C, Alexandre GPJ, et al: Hypertension after renal transplantation. Proc Eur Dial Transplant Assoc 12:461-470, 1976 31. Strom TB, Tilney NL: Renal transplantation: clinical aspects, in Brenner BM, Rector FC (eds): The Kidney. Philadelphia, Saunders, 1986, pp 1941-1976 32. Ruis JO, Simmons RL, Callender CO, et al: Steroid diabetes in renal transplant recipients: Pathogenetic factors and prognosis. Surgery 73:759-765 , 1973
I
N THE PAST, patients aged > 50 years have been considered to be at high risk in renal transplantation, particularly when kidneys were obtained from cadaveric donors. 1-4 In recent years, with growing experience and judicious use of immunosuppression, results of renal transplantation have improved in this group of patients. 1.5.6 Addition of cyclosporine to the immunosuppressive regimen has further improved the outcome following transplantation. 7-9 In the light of current experience, it appears that transplantation should be the preferred form of treatment even in patients > 50 years old because of improved quality of life after transplantation. 1O We reviewed our experience with transplantation in older patients to see how the results in this group compared with those obtained in younger patients. We further analyzed the outcome according to donor type, immunosuppressive protocol, and complications after transplantation.
From the Departments of Internal Medicine and Surgery, University of Cincinnati Medical Center, Cincinnati_ Address reprint requests to M_ Roy First, MD, Division of Nephrology, University of Cincinnati Medical Center, 5363 MSB, 231 Bethesda Ave, Cincinnati, OH 45267-0585. © 1988 by the National Kidney Foundation, Inc. 0272-6386/66/1206--0008$3.00/0
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MATERIAL AND METHODS Three hundred sixty-five renal transplants were performed between January 1, 1980 and December 31, 1986 at the University of Cincinnati Medical Center and followed through June 30, 1987. Of these, 64 transplants were performed in 53 patients 50 to 64 years old at the time of transplantation, with a mean age of 54.3 years, including 53 primary transplants, ten secondary transplants, and one tertiary transplant. There were 33 male and 20 female recipients. Racial distribution was 29 whites, 18 blacks, 5 Arabs, and 1 Oriental. Donor source in the 53 primary transplants was cadaveric (CAD) in 36, and living related donor (LRD) in 17 (five human lymphocyte antigen [HLA] identical, 12 haploidentical)_ Over the same period, 221 primary transplants were performed in recipients aged 17 to 49 years (mean age, 34.0 years). Outcomes were compared between the older and younger patients groups_ Table 1 shows the characteristics of the patients in the two age groups. In recent years, our criteria for accepting older patients for renal transplantation have been liberalized. This is reflected in the fact that only 16 transplants were performed in this age group between January I, 1980 and December 31, 1983, whereas 48 transplants were performed between January 1, 1984 and December 31, 1986. This increase in the number of older patients was partly due to introduction of cyc\osporine in 1984_ Figure 1 shows the percentage of older patients receiving transplants each year from 1980 to 1986 and the donor sources. All patients had pretransplant barium enemas and gallbladder ultrasound_ Localized diverticular disease was treated by segmental colonic resection before 1983, but thereafter this procedure was performed only if the patient had experienced acute diverticulitis; if gallstones were present, cholecystectomy
American Journal of Kidney Diseases, Vol XII, No 6 (December), 1988: pp 516-523
517
RENAL TRANSPLANTATION IN OLDER PATIENTS Table 1. Characteristics of Patients Receiving First Kidney Transplant in the Age Groups > 50 Years and 17 to 49 Years Age Group >50 yr
Age Group 17 to 49 yr
53
221
33 (62%) 20 (38%)
133 (60%) 88 (40%)
N Sex Male Female Age, yr (mean
±
SO)
54.3
±
3.0
34.0
± 8 .6
Donor CAD LRD
36 (68%) 17 (32%)
151 (68%) 70 (32%)
Immunosuppression AP TT
20 (38%) 33 (62%)
125 (56%) 97 (44%)
Etiology of ESRD CGN DGS HTNS CIN PKD Other
17 (32%) 13 (25%) 11 (21%) 4(7%) 3(6%) 5(9%)
113 51 8 13 11 25
(51%) (24%) (4%) (5%) (5%) (11%)
Abbreviations: Ap, azathioprine, prednisone; TT, triple therapy (cyclosporine, azathioprine, prednisone); CGN, chronic glomerulonephritis; DGS, diabetic glomerulosclerosis; HTNS, hypertensive nephrosclerosis; CIN, chron ic interstitial nephritis; PKD, polycystic kidney disease. was performed. Bilateral nephrectomy for control of hypertension was not performed in any of the patients.
Transfusion Protocol Recipients of CAD transplants each received a total of five units of blood. Patients were activated on the cadaveric waiting list 2 weeks after the fifth transfusion. Serum for crossmatch and panel-reactive antibody (PRA) was obtained before the initial transfusion, at the time of listing, and monthly thereafter.
50
40
30
% 20
10
0
~~ 1980
1981
1982
~
1983 1984
1985
1986
Fig 1. Percentage of patients aged > 50 years receiving renal transplants each year from 1980 to 1986. (.), cadaveric donor; (0), living related donor.
Recipients of haploidentical LRD kidneys were given three donor-specific transfusions (DST) of 150 mL whole blood at 2week intervals. Transplantation was performed 3 to 4 weeks after the third transfusion if the T-warm cross match (performed at 37°C) was negative. Only one recipient of an "LA-identical LRD kidney received DST.
Immunosuppressive Protocol The 16 patients who received transplants before 1984 were treated with conventional immunosupression consisting of azathioprine and prednisone (AP). Azathioprine, 4 mg/kg intravenous (IV), was administered on the day of surgery, followed by a maintenance dose of 2 mg/kg/d. The maintenance dose was reduced in the presence of WBC count < 5,000/"L. On the day of surgery, 250 mg IV methylprednisolone was administered. The day after surgery, 200 mg prednisone was administered orally. The prednisone was then reduced rapidly to reach a level of 1.0 mg/kg/d by day 14 and 0.5 mg/kg/d by day 28. The prednisone was reduced gradually thereafter. Acute rejection episodes (ARE) were diagnosed on clinical and biochemical parameters (an increase in the serum creatinine >0.3 mg/dL) and confirmed by percutaneous allograft biopsy in all instances. ARE were treated with IV methylprednisolone, 250 mg daily, for four days. In the event of a poor response to corticosteroids, antilymphocyte globulin (ALG) , 15 mg/kg/d for seven days, and/or graft irradiation, 150 rad/d for three days , was used. After 1984 a major change in immunosuppressive protocol was introduced, with use of low doses of cyclosporine, azathioprine, and prednisone (triple therapy [TID. This therapy has been described in detail by First et al. II Briefly, all patients received azathioprine, 4 mg/kg IV, and methyiprediosolone,
518
SHAH ET AL
250 mg IV, on the day of transplantation. On day I, if the urine output was good and serum creatinine already falling, oral cyclosporine was added in a dose of 10 mg/kg/d. If the urine output was poor and serum creatinine rising, horse antithymocyte globulin (ATG-Atgam) was added instead of cyclosporine. ATG was continued either until serum creatinine fell to < 4 mg/dL or for 14 days. Cyclosporine was introduced in a dose of 10 mg/kg/d when renal function had improved. The dose of cyclosporine was reduced to 8 mg/kg/d after I week and further reduced to 6 mg/kg/d on day 30. Beyond 6 months, the dose of cyclosporine was maintained at 4 to 6 mg/kg/d. AREs were treated in one of three ways: (I) IV methylprednisolone, 250 mg daily for three to four days; (2) ATG, 10 to 15 mg/kg/d for ten days; or (3) OKT3, 5 mg IV daily for ten days.
53)(36)( 17) 100
(19)
(S)
(3)
(14)
(11)
~
(/)
80
(7)
(15)
(10)
(7)
(6)
(4)
~
60
0
1
,
,
I
I
I
12
24
36
48
60
Months After Transplantation
A
5;l}(36}( 17)
Patient survival and kidney survival statistics were calculated by actuarial techniques. 12 Patients dying of any cause while their grafts were still functioning were considered transplant deaths. Death occurring any time after transplantation has been considered transplant death even if the graft failed and the patient returned to dialysis. A graft was considered lost when any of the following events occurred: (I) nephrectomy; (2) return to dialysis; (3) death of any cause; (4) retransplantation without a return to dialysis. A comparison between different groups was achieved by calculating:
100 (15)
iii
.~
~
(/)
80
1(10)
(7)
(5)
(4)
J(19)
(12)
(8)
(7)
1(9)
(S)
(3)
(3)
(32)
~
(17) 60
of 8
=
(7)
.~
Data Analysis
Z
(13) (23)
(34)
iii
I
I
I
24
I
I
12
36
48
60
Months After Transplantation
Pn - P'n [SE(pn)]2 + [SE(P 'n)]2
where Pn is the percentage survival and SE standard error.13
RESULTS
Patient and Graft Survival Rates after Primary Renal Transplantation Of 53 patients, 45 were alive 6 to 87 months after transplantation. As shown in Fig 2A, 1-, 3-, and 5-year actuarial survival was 87 %, 84 %, and 84% (96%, 88%, and 85% in younger patients). The corresponding figures were 100%, 92 %, and 92 % for LRD transplant recipients (98 %, 98 %, and 96 % in younger patients) and 81 %, 81 %, and 81 % for CAD recipients (95 %, 84 %, and 78 % in younger patients). As shown in Fig 2B, overall graft survival was 74%,66%, and 66% at 1, 3, and 5 years, respectively (73%,65%, and 60% in younger patients). Graft survival was 88 %, 81 %, and 81 % for LRD transplant recipients (88 %, 84 %, and 78 % in younger patients) and 68%, 58%, and 58% for CAD recipients (66%,53%, and 51 % in younger patients). Overall patient survival in older patients was lower at 1 year (P < 0.05) compared with younger patients, but there was no significant difference in survival at 3 and 5 years. This dif-
Fig 2. (A) Patient and (8) graft survival after primary renal transplantation in patients aged >50 years. (_ _), overall (n = 53); (6-6), living related donor (n = 17); (0-0), cadaver donor (n = 36). Figures in parenthesis indicate number of patients being followed at each time interval.
ference in overall patient survival at 1 year was largely due to the difference in survival in CAD recipients (P < 0.05) because the survival in LRD recipients was similar in the older and younger patients. There was no significant difference (P > 0.05) in graft survival between the two groups at any period after transplantation. In interpreting these results it must be pointed out that the number of older patients followed beyond 3 years was very small (Fig 2). Moreover, a greater proportion of patients in the older age group received TT than in the younger age group (Table 1). Impact of Cyclosporine in Primary Transplants Analysis of patient and graft survival rates according to the donor type (CAD/LRD) and immunosuppressive therapy (AP/TT) resulted in small subgroups and limited periods of follow-up (because cyclosporine was only introduced in 1984). The patient survival at 2 years in the LRD recipients was 100% in the TT group (n = 7) and 88% in the AP group (n = 10). In CAD recipients the 2-year patient survival was 82 % in the TT
519
RENAL TRANSPLANTATION IN OLDER PATIENTS
group (n = 26) and 80% in the AP group (n 10). These differences were not statistically significant (P > 0.05). On the other hand, the graft survival in both LRD transplant recipients and CAD recipients was significantly better in the TT groups (P < 0.05). The 2-year LRD graft survival in the TT patients was 100 %, compared with 77 % in the AP group. For CAD recipients the 2-year graft survival in the two groups was 65 % and 30%, respectively. The AP-treated CAD transplant group included four patients who lost the grafts in the early posttransplant period and never achieved renal function to the level required to introduce cyc1osporine according to our protocol. This obviously biases the results strongly against this group of patients. If these four patients are excluded, the 2-year graft survival of 50% is still inferior to that obtained with TT (P < 0.05). Causes of Patient Death and Graft Loss
Table 2 shows the causes of patient death and graft loss according to donor type and immunosuppressive treament. Eight patients died after transplantation. Six of the deaths occurred within the first year after transplantation, all in recipients of primary CAD transplants. Two deaths occurred in recipients of LRD kidneys; both of these patients rejected the first (LRD) graft and received CAD kidneys. One patient died of sepsis 17 months after the first transplant but within 1 month of the second kidney transplant, which was combined with a pancreas transplant. The second patient died 69 months after the first transplant; this Table 2.
patient developed a cardiac arrhythmia 41 months after a third transplant. For purposes of analysis these two deaths were included in the LRD survival group (see Methods); however, from a practical point of view no recipient of an LRD kidney died within 1 year of the primary transplant. Infection was the cause of death in four cases (three bacterial sepsis, one Pneumocytis carinii pneumonia) . There were two cardiac deaths (one of acute myocardial infarction on the third posttransplant day, the other of cardiac arrhythmia 69 months after primary transplantation) . Malignancy accounted for two deaths (one disseminated carcinoma of the colon 92 days posttransplant, one bronchogenic carcinoma of the lung 9 months after transplantation) . Of the 16 primary grafts lost, nine (56%) were lost from rejection: two from early rejection (hyperacute and accelerated rejection) , three from acute rejection, and four from chronic rejection. Patient death accounted for the loss of six (38 %) grafts, and one (6%) graft was lost when an attempt to perform an angioplasty for transplant renal artery stenosis resulted in tear of the vessel, requiring emergency nephrectomy. Results in Diabetic Patients
Fifteen transplants were performed in 13 diabetic patients. Among the 13 primary transplants performed in diabetic patients, seven were LRD transplants and six were CAD transplants; seven were treated with TT and six with AP. Patient and graft survival following primary renal
Causes of Patient Death and Graft Loss Following Primary Transplantation CAD (n = 36) AP (n = 10)
Patient death Bacterial sepsis (n = 3) Pneumocystis (n = 1) Malignancy (n = 2) Cardiac (n = 2) Graft loss Death (n
= 6)
Rejection Hyperacute (n = 1) Accelerated (n = 1) Acute (n = 3) Chronic (n = 4)
LAD (n = 17)
TT (n = 26)
AP (n = 10)
TT (n = 7)
1
2
2
4
1 2
2
Technical (n = 1) Total number of patients: n = 53. Abbreviations: AP, azathioprine, prednisone; TT, triple therapy (cyclosporine, azathioprine, prednisone).
520
SHAH ET AL
transplantation was 92 %, 79% , and 79 % and 75% , 63%, and 63% at 1, 3, and 5 years, respectively. The results in this small subgroup were not significantly different from the results in nondiabetic recipients. However, outcome in this group was biased by the fact that the majority received LRD transplants. Two diabetic recipients died; one of acute myocardial infarction on the third posttransplant day and one of sepsis following a second kidney transplant, which was combined with pancreas transplant. Four grafts failed following primary transplantation (one patient death , one recurrent acute rejection, and two chronic rejections) .
a tertiary transplant. Four grafts were lost from rejection, three from hyperacute rejection, and one from recurrent acute rejection . The three patients who lost grafts from hyperacute rejection had high PRA at the time of transplantation (100%, 97 %, and 73 %); in one case this occurred when a kidney was inadvertently transplanted into a patient with a positive crossmatch because of an administrative error. Only four of the 11 grafts were functioning 1 year after transplantation. Analysis of HLA matching in the regrafted patients revealed poor tissue compatibility (average A-B locus match, 0.91 antigens; average DR locus match, 0.27 antigens) .
Results of Retransplantation
Posttransplant Complications
Ten second transplants and one third transplant were performed in ten patients. All were retransplanted with CAD kidneys; six received TT and five received AP In this group, two patients died of sepsis within 1 month of transplantation, and one patient died of a cardiac cause 41 months after
Table 3 lists the complications after primary renal transplantation. Infections were more common in recipients of CAD transplants. The bacterial infections encountered were urinary infection (n = 6), pneumonia Cn = 6), Gram-negative septicemia Cn = 3) , wound infection (n = 3), perirec-
Table 3.
Complications Following Primary Transplantation CAD (n AP (n = 10)
Infections Bacterial Urinary infection (n = 6) Pneumonia (n = 6) Septicemia (n = 3) Wound infection (n = 3) Perirectal abscess (n = 2) Goretex graft (n = 1) Infected foot (n = 1) Otitis media (n = 1) Pulmonary TB (n = 1)
4 1 1
= 36)
LAD (n
IT (n = 26)
1
Protozoal Pneumocystis (n = 3)
3
Technical Urologic urinary leak (n = 3)
2
=
6)
2
1)
HypertenSion (n = 29) Diabetes (n
IT(n = 7)
2 2
2 4
=
= 17)
1 3
Viral Cytomegalovirus (n = 5) Herpes zoster (n = 4)
Vascular Renal artery stenosis (n
AP (n = 10)
4
16 3
4
5 2
Total number of patients: n = 53. Abbreviations: AP, azathioprine, prednisone; TT, triple therapy (cyclosporine, azathioprine, prednisone); TB, tuberculosis.
RENAL TRANSPLANTATION IN OLDER PATIENTS
tal abscess (n = 2) , infected goretex graft (n 1), infected foot ulcer in a diabetic patient (n 1), otitis media (n = 1) , and pulmonary tuberculosis (n = 1). There were five cases of cytomegalovirus infection and four cases of herpes zoster infection. Pneumocystis carinii pneumonia occurred in three patients , all on TT. Three patients developed urinary leaks in the early posttransplant period; all were successfully treated by reimplantation of the ureter. One patient developed renal artery stenosis 9 months posttransplant; angioplasty resulted in a tear in the vessel, requiring emergency nephrectomy. Thirtyeight of the 40 nondiabetic patients who received transplants had functioning grafts at 1 month; six (16 %) of these patients developed steroid-induced diabetes. Hypertension was present in 29 (63%) of 46 patients with functioning kidneys beyond 3 months . DISCUSSION
There has been a progressive increase in the number of older patients accepted for transplantation at our center. Currently most of these patients undergo CAD transplantation, unlike the early period in which LRD transplants predominated. At present, older patients constitute 25 % to 30 % of our renal transplant recipients with a CAD-toLRD transplant ratio of 3: 1. The Medical Information System of the Health Care Financing Administration (HCFA) reported higher mortality rates in the first year after transplantation in the older patients than in younger patients, and in older recipients of CAD kidneys than in older LRD recipients. 7. 14 Six of the eight deaths in our study occurred within the first year after transplantation; all occurred in recipients of CAD kidneys. Two of the deaths were caused by cardiac causes and two by malignancy ; this emphasizes the need for more intensive pretransplant screening for diseases occurring with a higher frequency in older patient population . On the other hand, graft survival in older patients at 1 year was no different from that observed in younger patients. In a large study reported by the UCLA Transplant Registry,15 graft survival rates were better in recipients aged 41 to 60 years than in younger recipients. This could be attributed to a more vigorous allograft response in younger than in older patients , resulting in a higher graft loss from rejection. Aging is associated with a generalized decline in
521
immunologic function , particularly the T cell immune response. 16 18 The addition of immunosuppressive drugs after transplantation further compromises immune responses in older patients. Thus, infections are more common in older patients after transplantation and account for the higher mortality rate. A high incidence of infectious complications in older recipients of cadaveric kidneys has been reported by others,4.19 in agreement with the observations in this series. In our patients, graft loss from death accounted for 38 % of primary grafts lost. This was in contrast to only 16.7% of grafts lost from death in our younger patients. Similar observations have been reported in other series.7.19.20 With growing experience in transplantation and judicious use of immunosuppressive therapy, the results of renal transplantation have improved in older patients in recent years even with conventional immunosuppressive therapy. \.5.6 The addition of cyclosporine to the immunosuppressive regiment has further improved outcome in these patients. We observed improved patient and graft survival rates in patients treated with TT compared to Ap, although the number of patients followed long-term in each of our groups was small. This is consisent with reports from other centers. 7.8.16 Patient survival in our recipients of both LRD and CAD kidneys was superior to that reported in patients of similar age treated by dialysis. 7.14 In the HCFA report 1- and 3-year survival rates in almost 36 ,000 patients aged >50 years treated by dialysis were 77 % and 48 %, respectively.14 However, comparisons of patient survival between those treated by dialysis and those treated by transplantation are not strictly valid , as it is highly likely that many of the older patients treated by dialysis were suffering from diseases that would have made them unacceptable candidates for transplantation . Patient and graft survival rates in a small group of diabetic patients in this series were not different from those in nondiabetic patients. However, these results were biased by the fact that seven of 13 (54 %) primary renal transplants in diabetic patients were performed from a LRD, while only ten of 40 (25 %) nondiabetic patients received LRD transplants . The results of secondary transplantation were extremely poor, with only four of 11 grafts functioning at 1 year. The bad results in these patients
522
appear to have been related to the poor HLA compatibility and high levels of sensitization, both of which have been associated with poor outcome after retransplantation. 21 -24 In three of these patients the graft was lost due to hyperacute rejection; all three patients had high PRA, and in one case the kidney was inadvertently transplanted into a patient with positive crossmatch. Thus, two of ten kidneys were lost to hyperacute rejection, a rate similar to the reported 18 % of kidneys that never function in secondary transplant recipients with cytotoxic antibodies. This phenomenon may occur either because there may be antibody undetected by the complement-dependent cytotoxicity test or because the current crossmatching techniques are not sensitive enough. 21 The incidence of diverticular disease in the general population increases significantly after the age of 50 years. 25 In earlier reports, perforation of colonic diverticuli following transplantation resulted in a high mortality rate 26 ; however, much better results have been reported more recently. 27 Our current policy is to reserve prophylactic colectomy for patients with symptomatic diverticulitis. Pretransplant cholecystectomy was performed in those patients with gallstones; this approach has been advocated in this age group to prevent acute cholecystitis after transplantation. 28 Because atherosclerotic vascular disease occurs with increasing frequency after the age of 40 years, one might expect a higher incidence of anastomotic vascular complications in older patients.29 However, this did not appear to be the case in our patients. Of the 46 patients whose graft functioned beyond the third month after transplantation, 29 (63 %) were hypertensive. This incidence was similar to the 60 % reported in adult renal transplant recipients. 3o Corticosteroid-induced diabetes occurred in 16% of our nondiabetic patients whose grafts functioned beyond 1 month; this was higher than the overall reported incidence of 5 % to 10%.31 Corticosteroid-induced diabetes has been reported more frequently in older patients after renal transplantation,32 and is probably caused by an unmasking effect of corticosteroids in patients who have the potential to develop maturity-onset diabetes. This complication was observed more frequently in recipients of CAD kidneys. In summary, the results of renal transplantation in older patients have improved significantly in re-
SHAH ET AL
cent years, particularly since the introduction of cyclosporine. Although there is a higher mortality rate in the early period after transplantation, longterm results are not much different from those obtained in younger patients. Infection constitutes a significant posttransplant complication but can be minimized by using lower doses of immunosuppressive agents and by pretransplant screening for and eradication of any potential sources of infection. In addition, patients in this age group should be more rigorously screened for diseases occurring with a higher frequency in this population, such as coronary artery disease and malignancy. Transplantation should no longer be considered a high-risk procedure in patients aged 50 to 65 years, and should be offered to all such patients unless an obvious contraindication exists. ACKNOWLEDGMENT We wish to thank Violet Henry for her expert secretarial assistance.
REFERENCES 1. Najarian JS, Sutherland DER, Morrow CE, et al: Kidney transplantation for high-risk patients. Kidney Int 23:s1O-s15, 1983 (suppl 14) 2. Delmonico FL, Cosimi AB, Russel PS: Renal transplantation in the older age group. Arch Surg 110:1107-1109,1975 3. Sommer BG, Sutherland DER, Simmons RL, et al: Prognosis after renal transplantation: Cumulative influence of combined risk factors. Transplantation 27:4-7, 1979 4. Sommer BG, Ferguson RM, Davin TD, et al: Renal transplantation in patients over 50 years of age. Transplant Proc 13:33-35, 1981 5. Okiye SE, Engen DE, Sterio FS, et al: Primary renal transplantation in patients 50 years of age and older. Transplant Proc 15: 1046-1053, 1983 6. Jordan ML, Novick AC, Steinmuller D, et al: Renal transplantation in the older recipient. J UroI134:243-246, 1985 7. Krakauer H, Spees EK, Hodges JF, et al: The current experience with cyclosporine in the United States: Recipient age considerations. Transplant Proc 17:2808-2810, 1985 8. Hunsicker LG: Impact of cyclosporine on cadaveric renal transplantation: A summary statement. Am J Kidney Dis 5:335-341, 1985 9. Taube D, Cameron JS, Challah S: Renal transplantation in older patients, in Nunez JFM, Cameron JS (eds): Renal Function and Disease in the Elderly. London, Butterworth, 1987, pp 529-537 10. Evans RW, Manninen DL, Garrison LP, et al: Quality of life of patients with end-stage renal disease. N Engl J Med 312:553-559, 1985 11. First MR, Alexander JW, Wadhwa N, et al: The use of low doses of cyclosporine, azathioprine and prednisone in renal transplantation. Transplant Proc 18: 132-135, 1986 (suppl 1) 12. Merrell M, Schulman LE: Determination of prognosis
RENAL TRANSPLANTATION IN OLDER PATIENTS in chronic diseases, illustrated by systemic lupus erythematosus. J Chron Dis 1: 12-32, 1955 13. Colton T: Statistics in Medicine: Longitudinal Studies and the Use of Life Table. Boston, Little, Brown, 1974, pp 237-250 14 . Krakauer H, Grauman JS , McMullan MR, et al: The recent U.S. experience in the treatment of end stage renal disease by dialysis and transplantation. N Engl J Med 308: 15581563, 1983 15. Lee PG, Terasaki PI: Effect of age on kidney transplants, in Terasaki PI (ed): Los Angeles, UCLA Tissue Typing Laboratory, 1985, pp 123-137 16. Roberts-Thompson IC, Youngchaiyud LL, Whittingham S, et al: Aging, immune response and mortality. Lancet 2:368370, 1974 17. Fox RA: Immunology and aging, in Brocklehurst JC (ed) : Textbook of Geriatric Medicine and Gerontology. New York, Churchill Livingstone, 1985, pp 82-105 18. Renlund DG, Gilbert EM, O'Connell JB, et al: Ageassociated decline in cardiac allograft rejection. Am J Med 83:391-398, 1987 19. Ost L, Groth CC , Lindholm B, et al: Cadaver renal transplantation in patients of 60 years and above. Transplantation 30:339-340, 1980 20. Ringden 0, Ost L , Klintmalm G, et al: Improved outcome in renal transplant recipients above 55 years of age treated with cyclosporine and low doses of steroids. Transplant Proc 15:2407-2412, 1983 (suppl I) 21 . Iwaki Y, Iguro T, Terasaki PI: Effect of sensitization on kidney allografts, in Terasaki PI (ed): Los Angeles, UCLA Tissue Typing Laboratory, 1985, pp 139-145
523 22. Perdue ST: Risk factors for second transplants, in Terasaki PI (ed): Los Angeles , UCLA Tissue Typing Laboratory, 1985, pp 191-203 23. Iwaki Y, Terasaki PI: Sensitization effect, in Terasaki PI (ed): Los Angeles, UCLA Tissue Typing Laboratory, 1986, pp 257-265 24. Cicciarelli J, Cho YC : Regraft kidney transplant survival, in Terasaki PI (ed): Los Angeles, UCLA Tissue Typing Laboratory, 1986, pp 285-297 25. Colcock BP: Recent experience in the surgical treatment of diverticulitis. Surg Gynecol Obstet 121:63-69, 1965 26. Misra MK, Pinkus GS , Birtch G, et al : Major colonic diseases complicating renal transplantation. Surgery 73 :942948, 1973 27. Church JM, Braun WE, Novick AC, et al: Perforation of the colon in renal hemograft recipients. Ann Surg 203:6976, 1986 28. Okiye SE, Engen DE, Sterioff S, et al : Primary renal transplantation in patients 50 years of age and older. Transplant Proc 15: 1046-1053, 1983 29. Geis pw, Giacchino JL, Jacobi RJ, et al: Technical considerations in elderly renal allograft recipients . Am J Surg 132:332-335, 1976 30. Bachy C, Van Ypersele de Strihou C, Alexandre GPJ, et al: Hypertension after renal transplantation. Proc Eur Dial Transplant Assoc 12:461-470, 1976 31. Strom TB, Tilney NL: Renal transplantation: clinical aspects, in Brenner BM, Rector FC (eds): The Kidney. Philadelphia, Saunders, 1986, pp 1941-1976 32. Ruis JO, Simmons RL, Callender CO, et al: Steroid diabetes in renal transplant recipients: Pathogenetic factors and prognosis. Surgery 73:759-765 , 1973