HBs Antigenemia in Renal Allograft Recipients RICHARD N. FINE, M.D., MOHAMMAD H. MALEKZADEH, M.D., ALFRED J. PENNISI, M.D., CHRISTEL H. UITTENBOGAART, M.D., ROBERT B. ETTENGER, M.D., BENJAMIN H. LANDING, M.D., HARRY T. WRIGHT, JR., M.D.
Serial HBs Ag determinations were performed on 98 renal allograft recipients with functioning grafts for 6 to 108 months, 85 of whom were followed from the initiation of dialysis. Twenty-six (27%) recipients had HBs antigenemia following transplantation. Thirteen (50o) of the 26 recipients were HBs Ag positive during the period of dialysis and 13 developed HBs antigenemia 1 to 44 months following transplantation. Seventeen (65%) of the 26 HBs Ag positive patients had hepatic dysfunction which was detected by biochemical surveillance and not associated with clinical symptomatology. There was no evidence of progressive hepatic insufficiency. HBs Ag persisted in 24 (92%) recipients for 6 to 49 months. Clearing of antigenemia occurred in only two patients, both of whom ultimately rejected their grafts. The presence of HBs Ag had no adverse effect on graft function. Temporary reduction in azathioprine dosage with hepatic dysfunction was not associated with rejection episodes. The major hazard posed by the HBs Ag positive recipient is the potential reservoir for spread to the general population because of the persistence of antigenemia.
I NCREASED INCIDENCE of hepatitis in patients with end-stage renal disease undergoing hemodialysis
was first noted in 1965.8 After the establishment of the connection between HBs Ag and hepatitis B,5 the frequent occurrence of HBs Ag in hemodialysis patients was observed. Although HBs Ag was at times associated with clinical hepatitis, many dialysis patients were noted to be persistent asymptomatic carriers. In a previous report," we documented that 45% of the patients in a pediatric hemodialysis unit over a 31/2 year period developed HBs antigenemia. Two thirds of those affected developed hepatic dysfunction (HD), and antigenemia persisted for as long as 3 years. Similarly, hepatic disease has been observed frequently in renal allograft recipients.21 2325 Both drug toxicity and viral infection have been implicated etiologically. In an earlier report,19 we described 9 (14%) cases of HD in children following renal transplantation. The etiology was considered to be azathioprine toxicity in 8 recipients and cytomegalovirus (CMV) in one. Reprint Address: Richard N. Fine, M.D., Dialysis and Transplant Program, Childrens Hospital of Los Angeles, 4650 Sunset Blvd., Los Angeles, California 90027.
411
From the Departments of Pediatrics and Pathology, University of Southern California School of Medicine and the Department of Pathology, and the Division of Infectious Diseases and the Dialysis and Transplant Program, Childrens Hospital of Los Angeles, Los Angeles, California
Subsequently, the occurrence of HBs Ag in renal allograft recipients has been noted.18'24'29'37 Although HBs Ag usually persisted in the graft recipient, the association between HBs Ag and HD was variable. Since June, 1970 all patients undergoing hemodialysis at Childrens Hospital of Los Angeles have been followed serially with HBs Ag determinations during the period of dialysis. In November, 1973 such surveillance was continued following transplantation and, in addition, all patients with functioning grafts as of November, 1973 were subsequently followed with serial HBs Ag determinations. The purpose of this report is to detail our experience with HBs antigenemia in renal allograft recipients.
Materials Between February, 1967 and August, 1975, 127 patients received 165 renal allografts from 33 live related, 3 live unrelated and 129 cadaver donors. All live related and live unrelated donor grafts were first transplants, whereas, 87 cadaver donor grafts were first, 34 were second, 6 were third and two were fourth transplants. From November, 1973 to February, 1976, 98 recipients (74 first, 23 second and one third transplant) with functioning grafts for >6 months were tested serially for HBs Ag. Of the 98 recipients, 85 had at least one HBs Ag determination prior to transplantation and 37 had serial HBs Ag determinations from the initiation of dialysis and to the time of, and following, transplantation. Immunosuppressive therapy consisted of azathioprine and prednisone exclusively as previously described.9 No patient received anti-lymphocytic serum, actinomycin C or x-irradiation and no patient under-
412 PATIENT #
FINE AND OTHERS
I 4
I,I I
-I = R .
D
12 13 14
*
=
Initid Pbs-Trapknt Determ
_
O1 HBs og negative _ HBrs ag positiv R Reected D Died
15
16 17
18
a
19
20 21 22 23 24 25 26
II
-I 1 R
L
D
R
-5
0 5
1 0l5
202530354045505560
MONTHS
o
April 1977
inhibition method (40). A HBs Ag titer > 1/8 was considered positive. Blood specimens were obtained for serum glutamic oxalic transaminase (SGOT), glutamic pyruvic transaminase (SGPT) determinations and bilirubin levels monthly during the period of dialysis, at least monthly during the first posttransplant year and at one to 6 month intervals thereafter. An SGOT and/or SGPT of >100 IU or a serum bilirubin of >2.0 mg/dl was considered biochemical evidence of HD.
TRANSPLANT
2 3
5 6 7 8 9 10 I1
Ann. Surg.
POSTTRANSPLANT
FIG. 1. Persistence of HBs Ag Posttransplant.
went thymectomy. Only two patients, both with polycystic kidney disease and congenital hepatic fibrosis,
underwent splenectomy. Methods At the initiation of dialysis 85 of the 98 patients were tested for the presence of HBs Ag. Subsequently, monthly blood specimens were obtained for HBs Ag determinations until the patient received a renal allograft. Since November, 1973, serial HBs Ag determinations have been continued following transplantation. These were performed at monthly intervals during the first post-transplant year and at one to 6 month intervals thereafter depending upon the frequency of followup clinic visits. In addition, HBs Ag determinations were performed at one to 6 month intervals on all recipients who had functioning grafts as of November, 1973, but who had been transplanted previously. The presence of HBs Ag was determined by both complement fixation (CF) (28) and hemagglutination
Results Incidence of HBs Ag following transplantation Of the 98 patients with functioning grafts for 6 to 108 months, 26 (27%) had HBs antigenemia following transplantation. An additional two patients, whose grafts functioned for less than one month also had HBs antigenemia following transplantation. Both were HBs Ag positive prior to transplantation. Acquisition of HBs Ag (Fig. 1)
Thirteen (50%) of the 26 patients were HBs Ag positive during the period of dialysis. The onset of HBs antigenemia prior to transplantation varied from one to 22 months. Ten patients were positive at the time of transplantation. Two (Nos. 6 and 9) were negative although they had been positive 2 to 6 months previously, and for one patient (No. 1), who was positive 2 months prior to transplantation, no determination was available at the time of transplantation. The 13 patients who were negative during dialysis developed HBs Ag antigenemia one to 44 months following transplantation. In 7 patients (Nos. 7, 11, 13, 15, 16, 23 and 25), the initial positive determination was obtained 1 to 7 months posttransplant and in three patients (Nos. 24, 22 and 18), at 14, 20 and 44 months respectively after transplantation. Three patients (Nos. 4, 3 and 2), who were negative prior to transplantation, were found to be HBs Ag positive at 22, 24 and 27 months, respectively, posttransplant, when the initial posttransplant determinations were obtained. Of the 13 patients who had HBs antigenemia during the period of dialysis, 6 (Nos. 6, 8, 9, 10, 17 and 20), had evidence of HD within a 3 month period prior to transplantation. In addition, one patient (No. 16) who was HBs Ag negative both prior to and at the time of transplantation, had biochemical evidence of HD prior to transplantation. HBs Ag and hepatic dysfunction Seventeen (65%) of the 26 HBs Ag positive patients had HD following transplantation. In all instances HD
Vol. 185 * No. 4
413
HBs ANTIGENEMIA TABLE 1. HB, ag and Hepatic Dysfunction Posttransplant Highest Posttransplant
Patient Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Current Status*
Onset H.D. Post-tx. Month
SGOT
SGPT (IU)
Bilirubin mg/dl
HB, ag
(IU)
1 13 6 20 3 1 11 1 1 1 1 1 11 16 4 1 1 -
135 136 140 128 180 300 496 660 120 790 94 209 159 70 106 113 94
280 193 180 199 154 400 255 1150 390 1850 334 273 68 120 115 105 242
Serial HBs Ag determinations were performed on 98 renal allograft recipients with functioning grafts for 6 to 108 months, 85 of whom were followed from the initiation of dialysis. Twenty-six (27%) recipients had HBs antigenemia following transplantation. Thirteen (50o) of the 26 recipients were HBs Ag positive during the period of dialysis and 13 developed HBs antigenemia 1 to 44 months following transplantation. Seventeen (65%) of the 26 HBs Ag positive patients had hepatic dysfunction which was detected by biochemical surveillance and not associated with clinical symptomatology. There was no evidence of progressive hepatic insufficiency. HBs Ag persisted in 24 (92%) recipients for 6 to 49 months. Clearing of antigenemia occurred in only two patients, both of whom ultimately rejected their grafts. The presence of HBs Ag had no adverse effect on graft function. Temporary reduction in azathioprine dosage with hepatic dysfunction was not associated with rejection episodes. The major hazard posed by the HBs Ag positive recipient is the potential reservoir for spread to the general population because of the persistence of antigenemia.
I NCREASED INCIDENCE of hepatitis in patients with end-stage renal disease undergoing hemodialysis
was first noted in 1965.8 After the establishment of the connection between HBs Ag and hepatitis B,5 the frequent occurrence of HBs Ag in hemodialysis patients was observed. Although HBs Ag was at times associated with clinical hepatitis, many dialysis patients were noted to be persistent asymptomatic carriers. In a previous report," we documented that 45% of the patients in a pediatric hemodialysis unit over a 31/2 year period developed HBs antigenemia. Two thirds of those affected developed hepatic dysfunction (HD), and antigenemia persisted for as long as 3 years. Similarly, hepatic disease has been observed frequently in renal allograft recipients.21 2325 Both drug toxicity and viral infection have been implicated etiologically. In an earlier report,19 we described 9 (14%) cases of HD in children following renal transplantation. The etiology was considered to be azathioprine toxicity in 8 recipients and cytomegalovirus (CMV) in one. Reprint Address: Richard N. Fine, M.D., Dialysis and Transplant Program, Childrens Hospital of Los Angeles, 4650 Sunset Blvd., Los Angeles, California 90027.
411
From the Departments of Pediatrics and Pathology, University of Southern California School of Medicine and the Department of Pathology, and the Division of Infectious Diseases and the Dialysis and Transplant Program, Childrens Hospital of Los Angeles, Los Angeles, California
Subsequently, the occurrence of HBs Ag in renal allograft recipients has been noted.18'24'29'37 Although HBs Ag usually persisted in the graft recipient, the association between HBs Ag and HD was variable. Since June, 1970 all patients undergoing hemodialysis at Childrens Hospital of Los Angeles have been followed serially with HBs Ag determinations during the period of dialysis. In November, 1973 such surveillance was continued following transplantation and, in addition, all patients with functioning grafts as of November, 1973 were subsequently followed with serial HBs Ag determinations. The purpose of this report is to detail our experience with HBs antigenemia in renal allograft recipients.
Materials Between February, 1967 and August, 1975, 127 patients received 165 renal allografts from 33 live related, 3 live unrelated and 129 cadaver donors. All live related and live unrelated donor grafts were first transplants, whereas, 87 cadaver donor grafts were first, 34 were second, 6 were third and two were fourth transplants. From November, 1973 to February, 1976, 98 recipients (74 first, 23 second and one third transplant) with functioning grafts for >6 months were tested serially for HBs Ag. Of the 98 recipients, 85 had at least one HBs Ag determination prior to transplantation and 37 had serial HBs Ag determinations from the initiation of dialysis and to the time of, and following, transplantation. Immunosuppressive therapy consisted of azathioprine and prednisone exclusively as previously described.9 No patient received anti-lymphocytic serum, actinomycin C or x-irradiation and no patient under-
412 PATIENT #
FINE AND OTHERS
I 4
I,I I
-I = R .
D
12 13 14
*
=
Initid Pbs-Trapknt Determ
_
O1 HBs og negative _ HBrs ag positiv R Reected D Died
15
16 17
18
a
19
20 21 22 23 24 25 26
II
-I 1 R
L
D
R
-5
0 5
1 0l5
202530354045505560
MONTHS
o
April 1977
inhibition method (40). A HBs Ag titer > 1/8 was considered positive. Blood specimens were obtained for serum glutamic oxalic transaminase (SGOT), glutamic pyruvic transaminase (SGPT) determinations and bilirubin levels monthly during the period of dialysis, at least monthly during the first posttransplant year and at one to 6 month intervals thereafter. An SGOT and/or SGPT of >100 IU or a serum bilirubin of >2.0 mg/dl was considered biochemical evidence of HD.
TRANSPLANT
2 3
5 6 7 8 9 10 I1
Ann. Surg.
POSTTRANSPLANT
FIG. 1. Persistence of HBs Ag Posttransplant.
went thymectomy. Only two patients, both with polycystic kidney disease and congenital hepatic fibrosis,
underwent splenectomy. Methods At the initiation of dialysis 85 of the 98 patients were tested for the presence of HBs Ag. Subsequently, monthly blood specimens were obtained for HBs Ag determinations until the patient received a renal allograft. Since November, 1973, serial HBs Ag determinations have been continued following transplantation. These were performed at monthly intervals during the first post-transplant year and at one to 6 month intervals thereafter depending upon the frequency of followup clinic visits. In addition, HBs Ag determinations were performed at one to 6 month intervals on all recipients who had functioning grafts as of November, 1973, but who had been transplanted previously. The presence of HBs Ag was determined by both complement fixation (CF) (28) and hemagglutination
Results Incidence of HBs Ag following transplantation Of the 98 patients with functioning grafts for 6 to 108 months, 26 (27%) had HBs antigenemia following transplantation. An additional two patients, whose grafts functioned for less than one month also had HBs antigenemia following transplantation. Both were HBs Ag positive prior to transplantation. Acquisition of HBs Ag (Fig. 1)
Thirteen (50%) of the 26 patients were HBs Ag positive during the period of dialysis. The onset of HBs antigenemia prior to transplantation varied from one to 22 months. Ten patients were positive at the time of transplantation. Two (Nos. 6 and 9) were negative although they had been positive 2 to 6 months previously, and for one patient (No. 1), who was positive 2 months prior to transplantation, no determination was available at the time of transplantation. The 13 patients who were negative during dialysis developed HBs Ag antigenemia one to 44 months following transplantation. In 7 patients (Nos. 7, 11, 13, 15, 16, 23 and 25), the initial positive determination was obtained 1 to 7 months posttransplant and in three patients (Nos. 24, 22 and 18), at 14, 20 and 44 months respectively after transplantation. Three patients (Nos. 4, 3 and 2), who were negative prior to transplantation, were found to be HBs Ag positive at 22, 24 and 27 months, respectively, posttransplant, when the initial posttransplant determinations were obtained. Of the 13 patients who had HBs antigenemia during the period of dialysis, 6 (Nos. 6, 8, 9, 10, 17 and 20), had evidence of HD within a 3 month period prior to transplantation. In addition, one patient (No. 16) who was HBs Ag negative both prior to and at the time of transplantation, had biochemical evidence of HD prior to transplantation. HBs Ag and hepatic dysfunction Seventeen (65%) of the 26 HBs Ag positive patients had HD following transplantation. In all instances HD
Vol. 185 * No. 4
413
HBs ANTIGENEMIA TABLE 1. HB, ag and Hepatic Dysfunction Posttransplant Highest Posttransplant
Patient Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
Current Status*
Onset H.D. Post-tx. Month
SGOT
SGPT (IU)
Bilirubin mg/dl
HB, ag
(IU)
1 13 6 20 3 1 11 1 1 1 1 1 11 16 4 1 1 -
135 136 140 128 180 300 496 660 120 790 94 209 159 70 106 113 94
280 193 180 199 154 400 255 1150 390 1850 334 273 68 120 115 105 242
