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Reduction of toxicity of corticosteroid therapy after renal transplantation
Reduction of Toxicity of Corticosteroid Therapy After Renal Transplantation
R
R SIEGEL,
R G. LUKE, A
A
M D M.6,
HELLEBUSCH,
Lexmgton,
Ch
B
M D.
Kentucky
From the Department of Medicine, College of Medicme. Untversrty of Kentucky Medrcal Kentucky ‘40506. ReCenter, Lexington, quests for reprints should be addressed to Dr R R Siegel, Renal Drvision. Department of Medicine. University of Kentucky Medical Center, Lexrngton, Kentucky 40506 Manuscrrpt received June 15, 1971
Twenty-eight patients were begun on single morning rather than divided doses of prednisone shortly after renal transplantation; in ten of these conversion to alternate-day therapy was accomplished from nine to thirty-two months after transplantation (group A), and in eighteen the conversion was completed immediately after transplantation (group 6). In no patient did peptic ulcer or gastrointestinal bleeding develop. Deaths from infection occurred in two patients while receiving daily steroid therapy. Severe infections and hypertension were infrequent and controllable on single morning or alternate-day therapy, and Cushingism regressed on alternate-day therapy. Conversion to alternate-day steroid therapy was successful in nine of ten patients in group A and in fourteen of sixteen surviving patients in group B. During a total of 823 patient-months of spaced steroid therapy, despite twenty-three rejection reactions, renal function was well maintained, and no graft was irretrievably rejected. It is concluded that steroid complications can be minimized by dose-spacing without harming graft function. Successful clinical renal homotransplantation requires suppression of the persistent tendency to allograft rejection while minimizing the risks of broad-spectrum immunosuppression. The inability of corticosteroid to control rejection adequately in man was apparent before the introduction of azathioprine, an immunosuppressive agent which could suppress the development of allograft rejection [1,2]. Nevertheless, in patients being treated with azathioprine as the primary immunosuppressive agent, corticosteroid is used widely [l-6] beginning either at the time of transplantation [2,3] or upon the first manifestation of rejection [4,5]. Even in the latter instance, most patients are receiving steroids soon after transplantation because of the frequency of early rejection. The undesirable effects of continued steroid therapy are among the most dangerous complications of post-transplant rmmunosuppressive therapy. A recent analysis of sixty deaths of post-transplant patients [7] incriminated prednisone as “the most important causative factor in the development of infection,” which had directly caused forty-eight of the sixty fatalities. Gastrointestinal ulceration and bleeding, also attributable to steroid therapy, has been a prominent cause of deaths in other series [3,6,8]. Disability may occur from necrosis of the femoral head [9] and, in our own experience, from psychologically crippling facial Cushingism. The potentially serious consequences of long-continued steroid therapy require circumspect evaluation of the precise role of such treatment and strenuous efforts to reduce the associated hazards.
August 1972
The American Journal of Medicine
Volume 53
159
CORTICOSTEROID
TOXICITY
AFTER
RENAL
TRANSPLANTATION-SIEGEL
Our efforts to find less toxic ways of employing corticosteroids have utilized two approaches, single daily doses rather than divided doses, and alternate-day rather than daily steroid administration. In 1966, following a report [lo] that single daily doses of triamcinolone caused less adrenal suppression than divided doses, we began to administer prednisone in single daily doses within a few weeks after renal transplantation to minimize adrenal suppression and possibly to avoid other steroid side-effects. No apparent increase in the incidence of rejection among these patients was noted; in 1967 we converted this regimen in several patients surviving more than nine months post-transplantation to one dose of prednisone given on alternate days (alternate-day prednisone therapy). Since 1968, the conversion of therapy in newly grafted patients from divided doses to a single daily dose and thence to alternate-day prednisone administration has been a uniform therapeutic goal. Our purpose here is to record our experience in converting the steroid regimens of twenty-eight patients to alternate-day schedules at various intervals after transplantation and to present evidence that steroid toxicity in such patients may be reduced by dose-spacing without any increase in the incidence of rejection. We believe that this experience may have relevance to the management of patients with other conditions requiring longterm corticosteroid therapy. CASE MATERIAL Twenty-eight Medical Service patients, ten of whom had received renal allografts prior to the beginning of the study, and eighteen of whom subsequently received transplants, were candidates for alternate-day prednisone therapy. There was no patient selection, all ten survivors as of August 1967 and all eighteen who received allografts between then and the end of June 1970 were included. Each study patient served as his own control, utihzing the renal function of the preceding period on daily prednisone therapy as a baseline. The group included sixteen male and twelve female patients. The mean age was 29.6 years, ranging from fourteen to fifty. In nineteen patlents the primary disease was glomerulonephritls (in one Instance associated with Goodpasture’s syndrome [li]), in six chronic pyelonephritis, in two polycystic disease and in one medullary cystic disease. Twenty-three patients received their grafts from living related donors and five from cadaveric donors. Lymphocyte antigen matching, performed in the laboratory of Dr. Paul Terasaki at the University of California in Los Angeles, was available In most of the live donor pairs and in two of the cadaverlc donor pairs. Matching results are included in Tables I and I I. All transplant surgery was performed using the
160
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The American Journal of Medicine
ET AL
standard technic with the donor ureter implanted through a uretero-neocystostomy. Bilateral nephrectomy was performed before or at the time of transplantation in all but six patients. IMMUNOSUPPRESSIVE~
DRUG MANAGEMENT
Azathioprine therapy was started in all patients at the time of transplantation and contmued in a dosage of 1.5 to 2 5 mg/kg/ day as tolerated without causing leukopenia. The parenteral administration of prednisolone was begun at the time of transplantation in every patient in a dosage of 25 mg four times a day. When oral administration became possible, prednisone was given in comparable dosage, with gradual reduction from 100 to 60 mg daily, and around-the-clock antacid therapy was begun. In the meantime, prednisone doses were consolidated so that the entire amount was finally taken as a single morning dose (Figure 1). Prophylactic antacid therapy was continued indefinitely. Between August 1967 and June 1969, the steroid regimen in ten surviving patients who had received renal allografts from nine to thirty-two months (mean of twenty months) previously, and whose prednisone dosage had been reduced to 10 or 20 mg a day, was converted to the alternate-day prednisone schedule. These patients (group A, Table I) had stable renal function for many months preceding change of therapy “Classic” alternate-day therapy, in which the dose given on alternate days IS twice the dose previously given daily [13], was used in three patients (Cases 1,5 and 9, Table I). In the remaining seven patients, therapy was changed to the alternate-day schedule by maintaining alternate-day dose at one to one and a half times the previous daily dose and reducing the intervening day’s dose gradually to zero. In early 1968, a protocol was developed whereby steroid therapy in allograft recipients was converted to alternate-day administration beginning shortly after transplantation. The conversion protocol outlined herein and shown graphically in Figure 1 was utilized in eighteen unselected patients receiving allografts between February 1968 and June 1970 (group B, Table II). (1) As described for group A patients, high dose around-the-clock parenteral steroid therapy was begun at surgery, and the succeeding oral prednisone regimen was modified and consolidated to a single 60 mg morning dose. (2) The administration of 60 mg prednisone was continued on alternate days while the intervening day’s dose was reduced until 60 and’ 30 mg were being given on alternate days. Between 60 and 40 mg, the downward steps were 5 mg (1 tablet) and 2.5 mg (l/z tablet) for all succeeding reductions. (3) The 60 mg dose of the SO/SO mg alternate-day schedule was reduced until the patient was taking 30 mg prednisone daily. (4) The intervening day’s dosage was reduced generally at a slower rate, until eliminated, leaving the patient on 30 mg every other day. The alternate-day dos-
Volume 53
19,M
38,M
18,M
33,M
32,F
50,M
17,M
18,F
43.M
18,F
1
2
3
4
5
6
7
8
9
10
Donor
NM
B
NM
NM
B
15
10
15
20
15
30
30
10
30
20
20
WI
15
10
15
Wt
D
15
15
B
15
15
NM
15
15
(mg) i
10
7.5
(m&W*
NM
c-
Match
12
26
27
36
28
20
32
36
9
19
14
9
po&)S
2.0 f
2.0 f
60 i
48f
50 i
60+4
49* (6 mo, n = 6)
0.2
(9 mo, n = 6)
43zt3
(17 mo, n = 17)
0.05
(6 mo, n = 8)
0.2
(5 mo, n = 9)
0.1
(16 mo, n = 9)
0.0
1.7+0.1
1.3 f
44 f
rejectIon
(14 mo, n = 10)
0.1
during
1.35 f
9
15
(8 mo, n = 8)
7
2
9
6
4
76 zk 11
Ccreat fell to -58
2.2 f
14
61+
5
72+ 13
(12 mo, n = 10) 1.85 + 0.1
1.9 f
30
0.15 (13 mo, n = 6)
2.0 z!z 0.2
1.5zt
70 zt 5
51 i
60f9
4
12
75 dz 7 (5 mo, n = 7)
0.1
(13 mo, n = 8)
1.8zt 0.2
(11 mo, n = 8)
44 f
(8 mo, n = 6) 0.1
7
9
49dz 3 (7 mo, n = 8) 2.2 It 0.5
1.3 f
54+ (15 mo, n = 10)
0.1
1.9 * 0.2**
1.6 f
44 f (23 mo, n = 11)
1.9 + 0.2
10
94 zt 4
(10 mo, n = 6)
1.95 zt 0.1
1.9 f
80 f
(22 mo, n = 11)
0.1**
10
60 dz 10
(11 mo, n = 7)
2.1 zt 0.1
1.95 f
75 f
(10 mo, n = 7)
1.5rtO.l
(14 mo, n = 8)
0.1
Ccreat
(7 mo, n = 6)
1.4 i
Pcreat
Before Alternate-Day Therapy
9
28
30
10
22
12
39
39
0-G
Durmg Alternate-Day Therapy ___Ccreat Pcreat ~ ___~_ __~ 1.4 i 0.1 58 zk 11
Renal Allograft Functlon#
130 95
120
190
75
125
...
70
120
92
78
110
80
115
66
108
70
110
115 70
125 78
84 130
118 72
X
125
74
134
<90
130
SF
125
-108 74
Day Therapy
On Alternate-
116
135 85
3
150
100
150
96
140
3
110
Day Therapy ___-
Before Alternate-
(mm W
Mean Blood Pressure
NOTE: Donors: P, parent; S, sibling; C, cadaver; Son (to father) in one case. Match: HL-A and Te lymphocyte antigen matchmg, graded A-D; NM, no match secured. * Daily prednisone dose prror to conversion to alternate-day therapy, mg/day smgle AM dose. t mg prednisone/aIternate day during observation period. 1 Months post-transplant when alternate-day steroid admimstration begun. 0 Total duration (months) of alternate-day therapy. creatinlne clearance In ml/minute k standard devlatlon, months of observation # Pcreat = serum creatlnine in mg/lOO ml + standard deviation. Ccreat = endogenous and (n=) number of observations m parentheses. During alternate-day therapy refers to function during latest portion of treatment period. ** Function until rejection episode.
~
Age (Yr) and Sex
Case No.
Alternate- Duration of Day Alternate- Therapy AlternatePrror Begun Day Day Therapy Dose Dadv Dose (mo
CORTICOSTEROID
TABLE
II
TOXICITY
AFTER
RENAL
TRANSPLANTATION-SIEGEL
Group B. Clinical and Laboratory
ET AL
Data Before and During Alternate-Day
Prednisone
Therapy
Predmsone Therapy Alternate-
Case No.
Age (yr) and Sex
Donor
Match
-
Day
Alternate-Day Tnal (mo postop)*
Stable (me postop)f
-
Duration of AlternateDay (me)S
Rejections
AlternateDay Dose (m8)Q
Daily Dose (m8)#
Before Alternate-Day Therapy
During Alternate-Day Therapy
1
43,M
s
NM
5%
8
20
30
...
...
2
37,M
C
NM
6
6
14
20
...
...
...
3
31,F
S
A
1
1
16
40--L 15
...
...
...
4
19,M
P
c-
8
8
10
40+ 30
...
5
28,M
s
A
5
5
10
30+ 20
...
...
...
6
20,M
P
D
5
5
9
30+ 25
...
...
...
7
14,F
P
D
7
7
6
30+ 20
...
l-4 mo
*. .
8
40,M
C
D
5
5
6
554 40
...
5 days
...
9
28,F
P
B
8
8
5
30
...
3wk
...
10
17,M
P
C
5
5
4
30
...
5 days
...
11
33,F
S
C
5
5
3
30
...
5 days
...
12
23,M
P
c-
6%
6%
3
30
...
...
..*
13
40,F
S
A
8
8
4
Off
14
37,F
S
D
59
28
5
15
23,F
P
C
...
...
16
44,F
Dau.
c-
...
17
19,M
C
NM
18
39,M
C
B
-
...
6wk
12 mo
25
...
5 days
5,9mo
...
...
20/10
...
.*.
...
...
...
>40
1,6,5 mo
...
7
...
l/P
...
30/15
5wk
7 mo
...
..*
...
...
30+60
4mo
...
age was later reduced further in some patients. Reductions were generally made every second day for recipients of well matched grafts from related donors, particularly in descending from 60 mg daily to 60/30 mg dn alternate days and every fourth day for further reductions. Slower reduction rates were used routinely for recipients of cadaveric grafts and after rejektion episodes. If there was any question of the stability of homograft function, steroid administration was main-
August 1972
7wk
30
NOTE: Abbrevrations as in Table I. Dau. = daughter. * Indicates timing of first penod on alternate-day prednisone (months postoperatrve). f Coincides with alternate-day trial if rejection did not quickly follow alternate-day trial, otherwise stable, tolerated alternate-day therapy began.
162
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The American Journal of Medicine
months
postoperative
when
tained for a period at one of the stages (60 mg daily, SO/SO mg on alternate days, 30 mg daily or 30/15 mg on alternate days). For all patients (groups A and B) alternate-day steroid therapy was interrupted in favor of conventional anti-rejection therapy with large doses of steroids daily and other agents whenever rejection was recognized. Rejection was diagnosed when definite reductions in renal function occurred that were inexplicable by any
Volume 53
CORTICOSTEROID
TOXICITY
AFTER RENAL
TRANSPLANTATION-SIEGEL
ET AL
RenalAllograft Functron Before Alternate-Day Therapy
Pcreat
DunngAlternate-Day#Therapy Pcreat
Ccreat
1.4 f 0.2 3oi 4 (2.5 mo, n = 10)
1.4 f 0.1 48zt 3 (9 mo, n = 6)
1.2 f 0.1 65+ 6 (3 mo, n=14)
1.8 f 0.1 88 f 12 (10 mo, n = 8)
1.1 zt 0.05 (5 wk, n = 2.0 i 0.2 (5 mo, n =
45rt 8 11) 50 f 6 7)
1.3 I!= 0.1 (11 mo, n = 1.7 f 0.2 (9 mo, n =
68 f 8 13) 64 f 7 8)
2.2 f- 0.1 (4 mo, n = 1.4 + 0.2 (3 mo, n =
71* 2 6) 70f 4 8)
1.8 I!= 0.2 (10 mo, n = 1.55 4 0.1 (9 mo, n =
86zt 9 8) 79f 6 9)
1.7 f 0.1 (2 mo, 1.9It 0.1 (4 mo, 2.2 It 0.1 (3 mo, 2.1 If 0.1 (3 mo, 1.4 f 0.1 (2 mo, 1.6 f 0.1 (4 mo, 1.6 f 0.2 (3 mo, 3.5 It 0.1 (6 mo, 0.9 f 0.2 (2 mo, 2.9 zt 0.4 (7 mo, 3.0f 0.3 (5 mo, 3.6-3.8 (2 mo,
46 zt 4 5) 69 xt 10 6) 40 f 6 7) 65 f 12 6) 63dz 9 8) 66 * 5 12) 601-t 8 7) 24zt 3 6) 53zt 3 6) 23 zt 4 17) 44zt6 7) 41-48 30)
2.1 f 0.2 (6 mo, 2.1 f 0.2 (5 mo, 2.35 f 0.3 (5 mo, 2.2 * 0.2 (4 mo, 1.4 f
61 f 6 10) 66 f 8 11) 38 f 6 6) 7Odz 6 4) 691 3 3) 7oIt 7 3) 64x!= 6 5) 25+ 1 8)
$ lndrcates 8 Indicates # lndrcates 11Function
n = n = n = n = n = n = n = n = n = n = n = n =
n = n = n = n = n = n = n = n =
...
...
...
...
...
...
...
other process after suitable investigations The use of single daily morning doses of steroid was continued in treating most rejectron reactions No attempt was made to use high dose-alternate day steroid therapy to control rejections
Serial serum
EVALUATION
determinations of blood urea nitrogen creatinine, endogenous creatinme and
Early rejection on alternate-day steroid therapy; resumed to control hypertensron; blood pressure 205/120-w 115/80 mm Hg Retropentoneal (hematoma) rnfectron cleared on alternate-day steroid therapy; blood pressure 135/90-H 120/80 mm Hg Steroid dose reduced very rapidly to control accelerated Cushingism Membr. G-N-like rejection early on 40 mg/day, on alternate-day therapy, blood pressure 150/90-lOO++ 130/85 mm Hg Reductron of steroid delayed by suspected rejectron (see Frg. 1) Uro-cutaneous fistula healed on alternate-day therapy, Cushingism gone, blood pressure 150/100+-+135/80 mm Hg Recurrent rejection over 3 mo (see Fig. 2) decreasing Cushrngrsm on alternate-day therapy Early acute rejectron, no further problems, Cushrngism decreased on 55 mg prednisone on alternate-day therapy Tolerated alternate-day therapy after serious early rejection; Cushrngism, blood pressure decreased Tolerated alternate-day therapy after early acute rejection, reduced very slowly Pyelonephritrs and abscess on daily steroid, drainage stopped on alternate-day therapy Hypertension, blood pressure 135/102-+130/80 mm Hg and marked Cushrngrsm gone on alternate-day therapy Rejection, Ccr 64435 after 4 mo alternate-day therapy, alternate-day therapy being resumed with good function Rejection at 5 and 9 mo on alternate-day trials, steroid diabetes and cataracts better on alternate-day therapy Died of cytomegalovrrus sepsis and cytomegalovirus + Pseudomonas pneumonia at 4 mo Recurrent rejection on <40 mg/day prednrsone, died cryptococcosis ReJeCtIOn at 5 wk with low WBC and Klebsiella pneumonia,
functron stable on 30/15 mg daily Rejection at 4 mo, Ccr 60440, persists with severe high blood pressure on daily prednrsone
duration of alternate-day therapy In months. the tolerated steroid dosage. necessary daily steroid dose if alternate-day therapy until rejectron episode.
RENAL FUNCTION
ClrnrcalCourse and Compkcatrons; Effects of Alternate-Day PrednrsoneTherapy
Ccreat
and urea
not begun or not tolerated.
clearances, and twenty-four hour sodium and protein excretion were performed daily while the patients were in the hospital, once or twice weekly upon their discharge and at gradually increasing Intervals up to every SIX weeks thereafter. Analyses were performed using standard Autoanalyzere methods. Clearance values were not corrected to bodv surface area or weiaht. Renal allograft function in Tables I and II ig expressed in terms of mean serum creatinine and mean
August 1972
The American Journal of Medicine
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163
CORTICOSTEROIO
TOXICITY
AFTER
RENAL TRANSPLANTATION-SIEGEL
endogenous creatrnine clearance, f standard deviation (SD), for periods before and after beginnmg alternate-day therapy. For group A patients, the baseline periods are from six to seventeen months. In those begun on alternate-day steroid therapy soon after transplantation (group B), the baseline period represents function from the trme it first stabilized after transplantation, or after rejection episodes, until the beginning of the current episode of alternate-day steroid therapy and is not less than two and a half months, except in one patient who was receiving sterords on alternate days five weeks after transplantation. In any case, the baseline period contains not less than six measurements of serum creatinine and of creatinine clearance. Except for three patients In Table I I (Cases 11, 12 and 13), in whom conversion to alternate-day therapy was recently accomplished, the “after” periods are not less than four months and include a minimum of four measurements of creatinine and creatimne clearance. RESULTS
Two of the patients in group A (Table I) had rejection reactions prior to the institution of alternate-day steroid therapy, one (Case 7) four months before and one (Case 10) eleven months before. In all ten patients therapeutic conversion was accomplished .without immediate incident. Only two rejection episodes occurred, at twelve and twenty-two months after adoption of the alternate-day schedule. In one patient (Case 4) rejection was mild and was fully reversed by increasing the prednisone dose from 30 mg on alternate days to 60 mg in a single daily dose. Steroid dosage was subsequently reduced rapidly by the protocol outlined for group B patients so that the patient was again receiving 30 mg prednisone every other day five months after treatment for rejection. This appears as a second experience for this patient in Table I. The second rejection episode that occurred during alternate-day steroid therapy was in a patient (Case 3) who had received an unmatched cadaveric kidney nineteen months before the therapeutic conversion and in whom graft function had subsequently been stable for twelve months. Function was reduced to 25 per cent of previous values during rejection and never returned to more than 50 per cent. This patient is discussed under “Problems.” In a third patient (Case 8) there was some loss of renal function during alternate-day steroid therapy, but this is attributed to the effects of well documented chronic urinary tract infection rather than rejection. Over-all, group A patients, who were generally receiving small (10 to 15 mg) daily doses of prednisone when alternate-day therapy was instituted, maintained good function. During a total
164
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1972
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Journal
of Medicine
Volume
ET AL
of 257 months of such therapy in ten patients, the mean change in serum creatinine was not significant, being +0.03 f 0.033 mg/lOO ml (mean f standard error of the mean; p < 0.30). The mean change in creatinine clearance was also not significant (+1.6 f 4.0 ml/minute; p < 0.70). Experience with group B (Table II) covers 135 patient-months of steroid-reduction efforts in eighteen patients and 115 patient-months after the substitution of alternate-day regimens in fifteen of them. There were sixteen rejection reactions in eleven patients prior to the introduction of alternate-day therapy; four of these occurred five days after transplantation, and the remaining twelve occurred in seven patients at intervals from three weeks to five months after transplantation. After conversion of the therapeutic regimen, which was at least begun in fifteen of the eighteen patients, there were five rejection episodes in four patients. Four occurred within three weeks of beginning alternate-day therapy, and one occurred four months after conversion. Of the eighteen patients in group B two ,(Cases 15 and 16) died four and eleven months postoperatively because of opportunistic infections (disseminated cytomegalovirus and cryptococcosis, respectively) before alternate-day therapy could be attempted. Thirteen (Cases 1-13, Table II) of the remaining sixteen patients were receiving alternate-day therapy within eight months (mean six months) after transplantation. Conversion in the fourteenth patient (Case 14) was not accomplished until twenty-eight months after operation because of rejection on two occasions soon after the institution of alternate-day therapy. However her renal function has now been stable for five months after conversion. In the two remaining patients (Cases 17 and 18) conversion has not yet been attempted because of rejection problems. There has been no evidence of deterioration in renal function in the fourteen patients in whom conversion to an alternate-day dosage schedule was successful; comparison of renal function before and after such therapy shows a change in serum creatinine of i-O.08 f 0.10 mg/lOO ml (mean f SEM; P <0.50) and a change in creatinine clearance of +9 f 2.4 ml/minute (P < 0.005). The sum total of experience with the patients in group B is that the steroid regimen in most graft recipients, despite prior rejection episodes, can be converted to alternate-day prednisone administration. Rejection reactions beginning within the first two months after transplantation, or suspicion of rejection, delayed advancement to alternate-day steroid schedules beyond the theoretically possi-
53
CORTlCOSTEROlD
TOXICITY
AFTER RENAL
TRANSPLANTATION-SIEGEL
ET AL
90
THEORET PREDNIS REDUCT’N60 RATE w 30
SERUM 9
CREATININE 1
CONC w
60 PREDNIS mg
30
DAYS
OCT
NOV
DEC
JAN
FE0
MAR
AFU
MAY
JUN
Figure 1. Renal allograft fonchon and schedule of prednisone therapy I/) Case 5 (Table II) contrasted with theoretically possrble rate of steroid reducbon (at top of chart). The unmarked arrows mdrcate apparent decreases in function interpreted as possible refecbon, resulting in return to hrgher dally doses of prednrsone. Lines lorning points on curves of serum creatinine and creatinine clearance represent interpretations of data upon which therapy was based. The first thick bar indicates the period of divided dose parenteral steroid adminrstration and the segmented thin bars the dose consolrdation phase leading to single mormng dose steroid administration (step 1 in text). Each thin bar in the upper and lowermost graphs indicates single mornrng dose on one day. Reduction steps 2,3,4 are represented by the progressively diminishing bar heights. 60130 means 60 and 30 mg on successive days, similarly for 30115; 30 or 60 alone indicates that daily dosage; 30/O, 20/O, 15/O indicate that alternate-day dosage. Time scales are compressed after 30/O dosage on each graph Azathroprine dosage was from 175 to 200 mglday (2 mglkg) throughout
ble three months’ time (Figure 1) in all but one instance, so that by the time of full conversion most patients were five to eight months beyond transplantation. Twelve of the fourteen patients who tolerated alternate-day therapy had received kidneys from related donors, whereas only two of the four recipients of cadaveric grafts tolerated conversion. EFFECT OF DOSAGE-SPACING ON COMPLICATIONS OF STEROID THERAPY
No one of the twenty-eight patients in this study had any symptoms or signs of gastritis, ulcer or gastrointestinal bleeding after the introduction of
single morning doses for daily prednisone therapy or during alternate-day treatment. During the course of the study there were only two fatalities from infection among the twentyeight patients. Three other serious infections were Pneumocystis carinii pneumonitis (Case 7), perirenal abscess and pyelonephritis (Case 11) and Klebsiella pneumonia (Case 17). All of these infections occurred in patients receiving intensive daily steroid treatment either for rejection or shortly after transplantation. Recovery from infection in a retroperitoneal hematoma and from an infected uretero-cutaneous fistula followed conversion to alternate-day therapy in two additional
August 1972
The American Journal of Medicine
Volume 53
165
CORTICOSTEROID
Figure 2. conversion
TOXICITY
AFTER
RENAL
TRANSPLANTATION-SIEGEL
Case 10 (Table I). Appearance to 15 mg on alternate days (right).
of patient
patients. No serious infections occurred in any patient in whom the regimen was fully changed to alternate-day prednisone administration. The facial and trunkal distortions of Cushing’s syndrome uniformly remitted in group A patients, irrespective of whether total steroid dose was altered. A striking example is shown in Figure 2. In group B patients, the cosmetic changes of Cushing’s syndrome were not generally prevented by the reduction program, which still involved five to eight months of daily steroid therapy, but these stigmata did regress rapidly after starting true alternate-day therapy. Facial Cushingism, obesity and steroid-related hypertension were seen to regress on as much as 55 mg prednisone every other day (Case 8, Table I I), and the administration of 30 mg on -alternate days appeared to permit substantial resolution of all the undesirable manifestations of hypercorticism. Remission of the facial and bodily distortions of Cushing’s syndrome was often of great psychological benefit to patients who had become withdrawn and depressed because of their appearance. After conversion, hypertension was uniformly ameliorated or controlled in both group A and
166
August 1972
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ET AL.
during
15 mg daily prednisone
therapy
(/eft) and after
group B patients. Two patients had aseptic necrosis of the femoral head, which developed before the change to alternate-day steroid therapy was made. This may be an unusually low incidence [9]. Alternate-day therapy had no effect on the course of the diseqse. Two of the twenty-eight patients had steroid-induced diabetes mellitus, which remitted on alternate-day therapy. Four patients had lenticular cataracts which improved symptomatically on alternate-day steroid therapy. PROBLEMS IN MANAGING STEROID THERAPY The only likely major ill effect of not administering steroid on a daily basis would be an increased incidence of rejection. Among the ten group A patients there were two rejection reactions over 257 patient-months of alternate-day steroid therapy. In one there was full recovery; the second rejection occurred in a long stable recipient of a cadaveric allograft (Case 3, Table I) and may have gone untreated for two months. There was 75 per cent reduction in renal function and only partial recovery. Alternate-day prednisone therapy was resumed three times up to six months after maximum postrejection improvement because of the patient’s
Volume 53
CORTICOSTEROID
depressive reaction to reappearance of Cushing’s facies; decrease in function followed each resumption The graft has survived well enough over the intervening two years to prevent symptoms despite slowly declining function apparently associated with maintaining alternate-day steroid therapy. This experience suggests that after rejection there may be no safe time to resume alternateday steroid therapy in some patients. In a total of ten patients, nine of whom had re: ceived kidneys from related donors, resumption or assumption of alternate-day steroid therapy two to six months after rejection episodes caused no recurrence. In fact, no graft from a related donor in the entire serves, with one exception, showed persistent impairment from rejection reactions during the course of decreasing prednisone dosage as descrrbed under “Methods.” That excepnon occurred In a woman (Case 16, Table II) who had received a graft from her own daughter; rejection was inexorable, requiring maintained high daily steroid dosage, and death occurred from disseminated cryptococcosis. Only two patients have had symptoms that might be directly attributable to omitting steroid every other day One, (Case 2, Table II) had symptoms suggestive of postural hypotension and hypoglycemia, which could not be documented objectively, for about two weeks after finally omitting steroid on alternate days. Another (Case 5, Table II) had mild arthralgia for two or three weeks after achieving a fully alternate-day schedule. COMMENTS It IS possible that steroid therapy could have been eliminated altogether in some of these patients, particularly in those receiving small doses and long past transplantation (group A). However, a reported gradual withdrawal of prednisone from five patients whose renal function had been stable for at least a year on 5 to 10 mg of prednisone/ day was associated with acute rejection reactions in three [12]. Because there was virtually no evidence of steroid toxicity on stable low alternateday dosage we chose not to attempt to terminate steroid therapy entirely. Several lanes of evidence favor the use of corticosteroid in well spaced doses. Single daily doses do not suppress adrenocortical secretory activity as much as divided doses [lo], probably because the susceptibility of the pituitary-adrenal axis to suppression by exogenous steroid varies diurnally, being least in the morning and maximal at midnight [13]. The metabolic effects of glucocorticoid associated with protein catabolism and gluconeo-
TOXICITY
AFTER
RENAL
TRANSPLANTATION-SIEGEL
ET AL
genesis vary during alternate-day adminrstration in a way that indicates nearly complete disappearance twenty-four hours after each dose [14]. Continuous high blood levels of corticosterord may not be required for anti-inflammatory effects, single doses of cortisol can provide twenty-four hour suppression of inflammation, possibly because of sequestration in inflamed tissues [15]. These findings suggest that some of the advantages of alternate-day steroid administration can be realized by administering steroid in single morning doses even when daily steroid therapy is thought to be required The technic of reducing steroid dosage on every other day until the patient is receiving steroid only on alternate days differs from the approaches used previously, both in renal transplant recipients [3,16] and in various diseases [17-201, in which either double the total of prior divtded daily doses is given on alternate days or the daily dose is increased stepwise one day and the intervening day’s dose is decreased until eliminated [3] Our attempt to provide at least some of the advantages of alternate-day steroid therapy to all patients beginning shortly after transplantation also differs from previously reported efforts, which were generally begun three [3] or six months [16] later. Alternate-day therapy has proved effective in the treatment of a variety of diseases requiring long-term corticosteroid therapy [17-201 Our method of establishing spaced-dose therapy in progressive stages may facilitate the application of such treatment, with its documented benefits. The precise role of corticosterord in managing allograft rejection and whether “anti-inflammatory” or “immunosuppressive” effects are more important are unresolved questions. In the clinical situation in which azathioprine provides the primary immunosuppression, the fact that alternate-day steroid therapy does less harm to cellular immune mechanisms [17] may be a positive advantage, leaving the patient with better resistance to the opportunistic infections which complicate immunosuppressive therapy [7]. The foregoing may be the reason for the comparatively low incidence of deaths from infection in our series Among a total of 164 recipients of kidneys from living related donors in the Denver [7], Richmond [8] and Chicago series [3], there were a total of thirty-two deaths from infection (20 per cent). Deaths from infection among the recipients of cadaveric grafts were twice as frequent. Since adoption of single morning dose and alternate-day dose prednisone therapy there have
August 1972
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167
CORTICOSTEROID
TOXICITY
AFTER
RENAL
TRANSPLANTATION-SIEGEL
been only two fatalities among twenty-three recipients of live donor grafts (8.7 per cent incidence) in this series, both of which occurred in patients exposed to large daily doses of steroids (Cases 15 and 16, Table I I). Four patients receiving single morning doses survived serious infections, and no patient receiving alternate-day steroid therapy had a serious infection. Gram-negative septicemias, as reported by Reeve [3], have been conspicuously absent. The absence of gastrointestinal ulceration and bleeding in our series also contrasts with the experience of others [3,6,8]. Moore and Hume [8] described four patients with gastrointestinal ulceration and hemorrhage who required surgery (two of whom died) among seventy-seven recipients of living donor grafts, and ten such patients (only two of whom survived) among thirty-six recipients of cadaver kidneys. In another series [3] three each of fifty live donor and fifty cadaver recipients had bleeding peptic ulcer, requiring gastrectomy in one. There were few, if any, ill effects of alternateday steroid therapy and the conversion process leading towards it. Although rejection reactions occurred, they were readily controlled, with few exceptions. In the combined group of twenty-three live related donor (LRD) and five cadaveric kidney recipients, there were two deaths (in LRD recipients) over the three year period, for a gross survival of 91 per cent in the group receiving live related donor kidneys. This compares with an 87 per cent one year survival for recipients of kidneys from related donors in the seventh and latest report of the kidney transplant registry [21]. Information on the frequency of rejection episodes with conventional steroid usage is scanty. In one series [22], sixty-five recipients of live related donor grafts incurred eighteen episodes with 61 per cent kidney survival at up to five years
ET AL
after transplantation. In another series [3], fifty recipients of live related donor grafts had five acute rejections with loss of four grafts, and four grafts were lost from chronic rejection. Among our eighteen patients advanced toward alternateday steroid therapy from time of transplant there were sixteen rejection episodes in eleven patients before the institution of alternate-day therapy and five afterward, without loss of any grafts. In most patients reduction of steroid therapy toward alternate-day regimens has seemed to serve as a test of allograft tolerance, with no permanent damage apparent from promptly treated rejection reactions. Many more problems were encountered in converting to alternate-day steroid regimens among the patients in group B than in group A patients, presumably because of the temporal proximity to transplantation and the magnitude and rapidity of the changes in steroid dosage; in two of sixteen surviving patients the regimen could not be fully changed over. Nevertheless, once alternate-day regimens were reached, about six months after transplantation, tolerance of such steroid administration was almost complete. Frequent and careful evaluation of the patients is the critical requirement for utilization of this reduction scheme, particularly while the larger changes are being made. Those patients whose prednisone dose was reduced to 30 mg daily without crisis during the four months after transplantation or rejection, readily tolerated the next stage reduction to 30 mg on alternate days. Our experience indicates that it may not be necessary to reduce steroid dosage to less than 30 mg prednisone on alternate days in order to obtain full benefit of alternate-day therapy. Steroid has an indispensable role in treating rejection reactions, but intercurrent use of steroid can be modified to reduce hazards, without compromising graft function.
REFERENCES 1.
2.
3.
4.
5
6
166
Manmck JA, Egdahl RH: Endocrinologrcal agents (In transplant immunosuppression), chap 29, Human Transplantation (Rapaport FT. Dausset J, eds), New York and London, Grune & Stratton, 1968 Hume DM, Magee JH, Kauffman MH Jr, et al Renal homotransplantation rn man in modrfied recipients. Ann Surg 158. 608, 1983. Reeve CE, Martin DC, Gonik HC, et al. Kidney transplantation, a comparison of results using cadaver and related Irving donors Amer J Med 47.410. 1969. Marchioro TL. Current clinical results of renal transplantation. Arch Intern Med (Chicago) 123 485, 1989. Arsenberg AC: Drugs employed for the suppression of rmmunologrc responsiveness New Eng J Med 272 1114.1965. Ginn HE. Late medical complications of renal transplantation. Arch Intern Med (Chicago) 123. 537, 1969.
August 1972
The American Journal of Medicine
7.
8.
9
10
11
12
Volume 53
Hill RB, Dahrlrng BE II, Starzl TE, et al Death after transplantation, an analysts of sixty cases. Amer J Med 42. 327,1967. Moore TC, Hume DM The period and nature of hazard in clrnical renal transplantation. I. The hazard to patrent survival Ann Surg 170 1, 1969. Cruess RL. Blennerhassett J. MacDonald FR, et al Aseptic necrosis following renal transplantation. J Bone Joint Surg 50-A: 1577, 1988 Grant SD, Forsham PH, DiRaimondo VC Suppressron of 17-hydroxycorhcosterords rn plasma and urrne by single and divided doses of triamcinolone. New Eng J Med273 11151965. Siegel RR: The basis of pulmonary disease resolutron after nephrectomy in Goodpasture’s syndrome. Amer J Med Sci 259’ 201.1970. Kuss R, Legrarn M, Porsson J, et al Human renal homotransplantation. acute late rejection after com-
CORTICOSTEROID
13
14
15
16
17
plete withdrawal of steroid therapy (abstract) 4th lnternatlonal Congress on Nephrology, 1969 (Stockhelm), p 447 Nichols T, Nugent CA, Tyler FH Diurnal vartatlon In suppression of adrenal functton by glucocorttcotds J Endocr 25 343,1965 Walton J, Watson ES, Ney RL Alternate-day vs shorter-Interval steroid admlntstratton Arch Intern Med (Chtcago) 127 601,197O Dougherty TF. Brown HE, Berltner DL Metabolism of hydrocortlsone durmg Inflammation Endocrinology 62 455, 1958 Reed WP, Lucas ZJ, Cohn R Alternate-day prednisone admInIstration after renal transplantation Lancet I 747,197o MacGregor RR, Sheagren JN. Lipsett MB, et al Alternate-day prednisone therapy, evaluation of delayed hypersensltivlty responses, control of disease and
TOXICITY
18
19
20
21 22
August 1972
AFTER
RENAL
TRANSPLANTATION-SIEGEL
ET AL
steroid side effects New Eng J Med 280 1427, 1969 Ackerman GL, Nolan CM Adrenocortlcal tesponslveness after alternate-day cortlcosterold therapy New Eng J Med 278 405, 1968 Cocco AE, Mendeloff Al Evaluation of Intermittent cortlcosterold therapy In ulceratwe colltls Johns Hopkins Med J 120 162, 1967 Soyka LF Treatment of nephrotic syndrome tn children use of alternate-day prednisone regimen Amer J DIS Child 113 693, 1967 Editorial, Results of kidney transplantation Lancet 1 179, 1970 (a) Moore TC, Hume DM The period and nature of hazard rn clinical renal transplantation II The hazard to transplant kidney function Ann Surg 170 12, 1969 (b) Ibid II I The hazard to transplant kidney survival. Idem. p 25
The American Journal of Medicine
Volume 53
169
R
R SIEGEL,
R G. LUKE, A
A
M D M.6,
HELLEBUSCH,
Lexmgton,
Ch
B
M D.
Kentucky
From the Department of Medicine, College of Medicme. Untversrty of Kentucky Medrcal Kentucky ‘40506. ReCenter, Lexington, quests for reprints should be addressed to Dr R R Siegel, Renal Drvision. Department of Medicine. University of Kentucky Medical Center, Lexrngton, Kentucky 40506 Manuscrrpt received June 15, 1971
Twenty-eight patients were begun on single morning rather than divided doses of prednisone shortly after renal transplantation; in ten of these conversion to alternate-day therapy was accomplished from nine to thirty-two months after transplantation (group A), and in eighteen the conversion was completed immediately after transplantation (group 6). In no patient did peptic ulcer or gastrointestinal bleeding develop. Deaths from infection occurred in two patients while receiving daily steroid therapy. Severe infections and hypertension were infrequent and controllable on single morning or alternate-day therapy, and Cushingism regressed on alternate-day therapy. Conversion to alternate-day steroid therapy was successful in nine of ten patients in group A and in fourteen of sixteen surviving patients in group B. During a total of 823 patient-months of spaced steroid therapy, despite twenty-three rejection reactions, renal function was well maintained, and no graft was irretrievably rejected. It is concluded that steroid complications can be minimized by dose-spacing without harming graft function. Successful clinical renal homotransplantation requires suppression of the persistent tendency to allograft rejection while minimizing the risks of broad-spectrum immunosuppression. The inability of corticosteroid to control rejection adequately in man was apparent before the introduction of azathioprine, an immunosuppressive agent which could suppress the development of allograft rejection [1,2]. Nevertheless, in patients being treated with azathioprine as the primary immunosuppressive agent, corticosteroid is used widely [l-6] beginning either at the time of transplantation [2,3] or upon the first manifestation of rejection [4,5]. Even in the latter instance, most patients are receiving steroids soon after transplantation because of the frequency of early rejection. The undesirable effects of continued steroid therapy are among the most dangerous complications of post-transplant rmmunosuppressive therapy. A recent analysis of sixty deaths of post-transplant patients [7] incriminated prednisone as “the most important causative factor in the development of infection,” which had directly caused forty-eight of the sixty fatalities. Gastrointestinal ulceration and bleeding, also attributable to steroid therapy, has been a prominent cause of deaths in other series [3,6,8]. Disability may occur from necrosis of the femoral head [9] and, in our own experience, from psychologically crippling facial Cushingism. The potentially serious consequences of long-continued steroid therapy require circumspect evaluation of the precise role of such treatment and strenuous efforts to reduce the associated hazards.
August 1972
The American Journal of Medicine
Volume 53
159
CORTICOSTEROID
TOXICITY
AFTER
RENAL
TRANSPLANTATION-SIEGEL
Our efforts to find less toxic ways of employing corticosteroids have utilized two approaches, single daily doses rather than divided doses, and alternate-day rather than daily steroid administration. In 1966, following a report [lo] that single daily doses of triamcinolone caused less adrenal suppression than divided doses, we began to administer prednisone in single daily doses within a few weeks after renal transplantation to minimize adrenal suppression and possibly to avoid other steroid side-effects. No apparent increase in the incidence of rejection among these patients was noted; in 1967 we converted this regimen in several patients surviving more than nine months post-transplantation to one dose of prednisone given on alternate days (alternate-day prednisone therapy). Since 1968, the conversion of therapy in newly grafted patients from divided doses to a single daily dose and thence to alternate-day prednisone administration has been a uniform therapeutic goal. Our purpose here is to record our experience in converting the steroid regimens of twenty-eight patients to alternate-day schedules at various intervals after transplantation and to present evidence that steroid toxicity in such patients may be reduced by dose-spacing without any increase in the incidence of rejection. We believe that this experience may have relevance to the management of patients with other conditions requiring longterm corticosteroid therapy. CASE MATERIAL Twenty-eight Medical Service patients, ten of whom had received renal allografts prior to the beginning of the study, and eighteen of whom subsequently received transplants, were candidates for alternate-day prednisone therapy. There was no patient selection, all ten survivors as of August 1967 and all eighteen who received allografts between then and the end of June 1970 were included. Each study patient served as his own control, utihzing the renal function of the preceding period on daily prednisone therapy as a baseline. The group included sixteen male and twelve female patients. The mean age was 29.6 years, ranging from fourteen to fifty. In nineteen patlents the primary disease was glomerulonephritls (in one Instance associated with Goodpasture’s syndrome [li]), in six chronic pyelonephritis, in two polycystic disease and in one medullary cystic disease. Twenty-three patients received their grafts from living related donors and five from cadaveric donors. Lymphocyte antigen matching, performed in the laboratory of Dr. Paul Terasaki at the University of California in Los Angeles, was available In most of the live donor pairs and in two of the cadaverlc donor pairs. Matching results are included in Tables I and I I. All transplant surgery was performed using the
160
August 1972
The American Journal of Medicine
ET AL
standard technic with the donor ureter implanted through a uretero-neocystostomy. Bilateral nephrectomy was performed before or at the time of transplantation in all but six patients. IMMUNOSUPPRESSIVE~
DRUG MANAGEMENT
Azathioprine therapy was started in all patients at the time of transplantation and contmued in a dosage of 1.5 to 2 5 mg/kg/ day as tolerated without causing leukopenia. The parenteral administration of prednisolone was begun at the time of transplantation in every patient in a dosage of 25 mg four times a day. When oral administration became possible, prednisone was given in comparable dosage, with gradual reduction from 100 to 60 mg daily, and around-the-clock antacid therapy was begun. In the meantime, prednisone doses were consolidated so that the entire amount was finally taken as a single morning dose (Figure 1). Prophylactic antacid therapy was continued indefinitely. Between August 1967 and June 1969, the steroid regimen in ten surviving patients who had received renal allografts from nine to thirty-two months (mean of twenty months) previously, and whose prednisone dosage had been reduced to 10 or 20 mg a day, was converted to the alternate-day prednisone schedule. These patients (group A, Table I) had stable renal function for many months preceding change of therapy “Classic” alternate-day therapy, in which the dose given on alternate days IS twice the dose previously given daily [13], was used in three patients (Cases 1,5 and 9, Table I). In the remaining seven patients, therapy was changed to the alternate-day schedule by maintaining alternate-day dose at one to one and a half times the previous daily dose and reducing the intervening day’s dose gradually to zero. In early 1968, a protocol was developed whereby steroid therapy in allograft recipients was converted to alternate-day administration beginning shortly after transplantation. The conversion protocol outlined herein and shown graphically in Figure 1 was utilized in eighteen unselected patients receiving allografts between February 1968 and June 1970 (group B, Table II). (1) As described for group A patients, high dose around-the-clock parenteral steroid therapy was begun at surgery, and the succeeding oral prednisone regimen was modified and consolidated to a single 60 mg morning dose. (2) The administration of 60 mg prednisone was continued on alternate days while the intervening day’s dose was reduced until 60 and’ 30 mg were being given on alternate days. Between 60 and 40 mg, the downward steps were 5 mg (1 tablet) and 2.5 mg (l/z tablet) for all succeeding reductions. (3) The 60 mg dose of the SO/SO mg alternate-day schedule was reduced until the patient was taking 30 mg prednisone daily. (4) The intervening day’s dosage was reduced generally at a slower rate, until eliminated, leaving the patient on 30 mg every other day. The alternate-day dos-
Volume 53
19,M
38,M
18,M
33,M
32,F
50,M
17,M
18,F
43.M
18,F
1
2
3
4
5
6
7
8
9
10
Donor
NM
B
NM
NM
B
15
10
15
20
15
30
30
10
30
20
20
WI
15
10
15
Wt
D
15
15
B
15
15
NM
15
15
(mg) i
10
7.5
(m&W*
NM
c-
Match
12
26
27
36
28
20
32
36
9
19
14
9
po&)S
2.0 f
2.0 f
60 i
48f
50 i
60+4
49* (6 mo, n = 6)
0.2
(9 mo, n = 6)
43zt3
(17 mo, n = 17)
0.05
(6 mo, n = 8)
0.2
(5 mo, n = 9)
0.1
(16 mo, n = 9)
0.0
1.7+0.1
1.3 f
44 f
rejectIon
(14 mo, n = 10)
0.1
during
1.35 f
9
15
(8 mo, n = 8)
7
2
9
6
4
76 zk 11
Ccreat fell to -58
2.2 f
14
61+
5
72+ 13
(12 mo, n = 10) 1.85 + 0.1
1.9 f
30
0.15 (13 mo, n = 6)
2.0 z!z 0.2
1.5zt
70 zt 5
51 i
60f9
4
12
75 dz 7 (5 mo, n = 7)
0.1
(13 mo, n = 8)
1.8zt 0.2
(11 mo, n = 8)
44 f
(8 mo, n = 6) 0.1
7
9
49dz 3 (7 mo, n = 8) 2.2 It 0.5
1.3 f
54+ (15 mo, n = 10)
0.1
1.9 * 0.2**
1.6 f
44 f (23 mo, n = 11)
1.9 + 0.2
10
94 zt 4
(10 mo, n = 6)
1.95 zt 0.1
1.9 f
80 f
(22 mo, n = 11)
0.1**
10
60 dz 10
(11 mo, n = 7)
2.1 zt 0.1
1.95 f
75 f
(10 mo, n = 7)
1.5rtO.l
(14 mo, n = 8)
0.1
Ccreat
(7 mo, n = 6)
1.4 i
Pcreat
Before Alternate-Day Therapy
9
28
30
10
22
12
39
39
0-G
Durmg Alternate-Day Therapy ___Ccreat Pcreat ~ ___~_ __~ 1.4 i 0.1 58 zk 11
Renal Allograft Functlon#
130 95
120
190
75
125
...
70
120
92
78
110
80
115
66
108
70
110
115 70
125 78
84 130
118 72
X
125
74
134
<90
130
SF
125
-108 74
Day Therapy
On Alternate-
116
135 85
3
150
100
150
96
140
3
110
Day Therapy ___-
Before Alternate-
(mm W
Mean Blood Pressure
NOTE: Donors: P, parent; S, sibling; C, cadaver; Son (to father) in one case. Match: HL-A and Te lymphocyte antigen matchmg, graded A-D; NM, no match secured. * Daily prednisone dose prror to conversion to alternate-day therapy, mg/day smgle AM dose. t mg prednisone/aIternate day during observation period. 1 Months post-transplant when alternate-day steroid admimstration begun. 0 Total duration (months) of alternate-day therapy. creatinlne clearance In ml/minute k standard devlatlon, months of observation # Pcreat = serum creatlnine in mg/lOO ml + standard deviation. Ccreat = endogenous and (n=) number of observations m parentheses. During alternate-day therapy refers to function during latest portion of treatment period. ** Function until rejection episode.
~
Age (Yr) and Sex
Case No.
Alternate- Duration of Day Alternate- Therapy AlternatePrror Begun Day Day Therapy Dose Dadv Dose (mo
CORTICOSTEROID
TABLE
II
TOXICITY
AFTER
RENAL
TRANSPLANTATION-SIEGEL
Group B. Clinical and Laboratory
ET AL
Data Before and During Alternate-Day
Prednisone
Therapy
Predmsone Therapy Alternate-
Case No.
Age (yr) and Sex
Donor
Match
-
Day
Alternate-Day Tnal (mo postop)*
Stable (me postop)f
-
Duration of AlternateDay (me)S
Rejections
AlternateDay Dose (m8)Q
Daily Dose (m8)#
Before Alternate-Day Therapy
During Alternate-Day Therapy
1
43,M
s
NM
5%
8
20
30
...
...
2
37,M
C
NM
6
6
14
20
...
...
...
3
31,F
S
A
1
1
16
40--L 15
...
...
...
4
19,M
P
c-
8
8
10
40+ 30
...
5
28,M
s
A
5
5
10
30+ 20
...
...
...
6
20,M
P
D
5
5
9
30+ 25
...
...
...
7
14,F
P
D
7
7
6
30+ 20
...
l-4 mo
*. .
8
40,M
C
D
5
5
6
554 40
...
5 days
...
9
28,F
P
B
8
8
5
30
...
3wk
...
10
17,M
P
C
5
5
4
30
...
5 days
...
11
33,F
S
C
5
5
3
30
...
5 days
...
12
23,M
P
c-
6%
6%
3
30
...
...
..*
13
40,F
S
A
8
8
4
Off
14
37,F
S
D
59
28
5
15
23,F
P
C
...
...
16
44,F
Dau.
c-
...
17
19,M
C
NM
18
39,M
C
B
-
...
6wk
12 mo
25
...
5 days
5,9mo
...
...
20/10
...
.*.
...
...
...
>40
1,6,5 mo
...
7
...
l/P
...
30/15
5wk
7 mo
...
..*
...
...
30+60
4mo
...
age was later reduced further in some patients. Reductions were generally made every second day for recipients of well matched grafts from related donors, particularly in descending from 60 mg daily to 60/30 mg dn alternate days and every fourth day for further reductions. Slower reduction rates were used routinely for recipients of cadaveric grafts and after rejektion episodes. If there was any question of the stability of homograft function, steroid administration was main-
August 1972
7wk
30
NOTE: Abbrevrations as in Table I. Dau. = daughter. * Indicates timing of first penod on alternate-day prednisone (months postoperatrve). f Coincides with alternate-day trial if rejection did not quickly follow alternate-day trial, otherwise stable, tolerated alternate-day therapy began.
162
6mo
The American Journal of Medicine
months
postoperative
when
tained for a period at one of the stages (60 mg daily, SO/SO mg on alternate days, 30 mg daily or 30/15 mg on alternate days). For all patients (groups A and B) alternate-day steroid therapy was interrupted in favor of conventional anti-rejection therapy with large doses of steroids daily and other agents whenever rejection was recognized. Rejection was diagnosed when definite reductions in renal function occurred that were inexplicable by any
Volume 53
CORTICOSTEROID
TOXICITY
AFTER RENAL
TRANSPLANTATION-SIEGEL
ET AL
RenalAllograft Functron Before Alternate-Day Therapy
Pcreat
DunngAlternate-Day#Therapy Pcreat
Ccreat
1.4 f 0.2 3oi 4 (2.5 mo, n = 10)
1.4 f 0.1 48zt 3 (9 mo, n = 6)
1.2 f 0.1 65+ 6 (3 mo, n=14)
1.8 f 0.1 88 f 12 (10 mo, n = 8)
1.1 zt 0.05 (5 wk, n = 2.0 i 0.2 (5 mo, n =
45rt 8 11) 50 f 6 7)
1.3 I!= 0.1 (11 mo, n = 1.7 f 0.2 (9 mo, n =
68 f 8 13) 64 f 7 8)
2.2 f- 0.1 (4 mo, n = 1.4 + 0.2 (3 mo, n =
71* 2 6) 70f 4 8)
1.8 I!= 0.2 (10 mo, n = 1.55 4 0.1 (9 mo, n =
86zt 9 8) 79f 6 9)
1.7 f 0.1 (2 mo, 1.9It 0.1 (4 mo, 2.2 It 0.1 (3 mo, 2.1 If 0.1 (3 mo, 1.4 f 0.1 (2 mo, 1.6 f 0.1 (4 mo, 1.6 f 0.2 (3 mo, 3.5 It 0.1 (6 mo, 0.9 f 0.2 (2 mo, 2.9 zt 0.4 (7 mo, 3.0f 0.3 (5 mo, 3.6-3.8 (2 mo,
46 zt 4 5) 69 xt 10 6) 40 f 6 7) 65 f 12 6) 63dz 9 8) 66 * 5 12) 601-t 8 7) 24zt 3 6) 53zt 3 6) 23 zt 4 17) 44zt6 7) 41-48 30)
2.1 f 0.2 (6 mo, 2.1 f 0.2 (5 mo, 2.35 f 0.3 (5 mo, 2.2 * 0.2 (4 mo, 1.4 f
61 f 6 10) 66 f 8 11) 38 f 6 6) 7Odz 6 4) 691 3 3) 7oIt 7 3) 64x!= 6 5) 25+ 1 8)
$ lndrcates 8 Indicates # lndrcates 11Function
n = n = n = n = n = n = n = n = n = n = n = n =
n = n = n = n = n = n = n = n =
...
...
...
...
...
...
...
other process after suitable investigations The use of single daily morning doses of steroid was continued in treating most rejectron reactions No attempt was made to use high dose-alternate day steroid therapy to control rejections
Serial serum
EVALUATION
determinations of blood urea nitrogen creatinine, endogenous creatinme and
Early rejection on alternate-day steroid therapy; resumed to control hypertensron; blood pressure 205/120-w 115/80 mm Hg Retropentoneal (hematoma) rnfectron cleared on alternate-day steroid therapy; blood pressure 135/90-H 120/80 mm Hg Steroid dose reduced very rapidly to control accelerated Cushingism Membr. G-N-like rejection early on 40 mg/day, on alternate-day therapy, blood pressure 150/90-lOO++ 130/85 mm Hg Reductron of steroid delayed by suspected rejectron (see Frg. 1) Uro-cutaneous fistula healed on alternate-day therapy, Cushingism gone, blood pressure 150/100+-+135/80 mm Hg Recurrent rejection over 3 mo (see Fig. 2) decreasing Cushrngrsm on alternate-day therapy Early acute rejectron, no further problems, Cushrngism decreased on 55 mg prednisone on alternate-day therapy Tolerated alternate-day therapy after serious early rejection; Cushrngism, blood pressure decreased Tolerated alternate-day therapy after early acute rejection, reduced very slowly Pyelonephritrs and abscess on daily steroid, drainage stopped on alternate-day therapy Hypertension, blood pressure 135/102-+130/80 mm Hg and marked Cushrngrsm gone on alternate-day therapy Rejection, Ccr 64435 after 4 mo alternate-day therapy, alternate-day therapy being resumed with good function Rejection at 5 and 9 mo on alternate-day trials, steroid diabetes and cataracts better on alternate-day therapy Died of cytomegalovrrus sepsis and cytomegalovirus + Pseudomonas pneumonia at 4 mo Recurrent rejection on <40 mg/day prednrsone, died cryptococcosis ReJeCtIOn at 5 wk with low WBC and Klebsiella pneumonia,
functron stable on 30/15 mg daily Rejection at 4 mo, Ccr 60440, persists with severe high blood pressure on daily prednrsone
duration of alternate-day therapy In months. the tolerated steroid dosage. necessary daily steroid dose if alternate-day therapy until rejectron episode.
RENAL FUNCTION
ClrnrcalCourse and Compkcatrons; Effects of Alternate-Day PrednrsoneTherapy
Ccreat
and urea
not begun or not tolerated.
clearances, and twenty-four hour sodium and protein excretion were performed daily while the patients were in the hospital, once or twice weekly upon their discharge and at gradually increasing Intervals up to every SIX weeks thereafter. Analyses were performed using standard Autoanalyzere methods. Clearance values were not corrected to bodv surface area or weiaht. Renal allograft function in Tables I and II ig expressed in terms of mean serum creatinine and mean
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endogenous creatrnine clearance, f standard deviation (SD), for periods before and after beginnmg alternate-day therapy. For group A patients, the baseline periods are from six to seventeen months. In those begun on alternate-day steroid therapy soon after transplantation (group B), the baseline period represents function from the trme it first stabilized after transplantation, or after rejection episodes, until the beginning of the current episode of alternate-day steroid therapy and is not less than two and a half months, except in one patient who was receiving sterords on alternate days five weeks after transplantation. In any case, the baseline period contains not less than six measurements of serum creatinine and of creatinine clearance. Except for three patients In Table I I (Cases 11, 12 and 13), in whom conversion to alternate-day therapy was recently accomplished, the “after” periods are not less than four months and include a minimum of four measurements of creatinine and creatimne clearance. RESULTS
Two of the patients in group A (Table I) had rejection reactions prior to the institution of alternate-day steroid therapy, one (Case 7) four months before and one (Case 10) eleven months before. In all ten patients therapeutic conversion was accomplished .without immediate incident. Only two rejection episodes occurred, at twelve and twenty-two months after adoption of the alternate-day schedule. In one patient (Case 4) rejection was mild and was fully reversed by increasing the prednisone dose from 30 mg on alternate days to 60 mg in a single daily dose. Steroid dosage was subsequently reduced rapidly by the protocol outlined for group B patients so that the patient was again receiving 30 mg prednisone every other day five months after treatment for rejection. This appears as a second experience for this patient in Table I. The second rejection episode that occurred during alternate-day steroid therapy was in a patient (Case 3) who had received an unmatched cadaveric kidney nineteen months before the therapeutic conversion and in whom graft function had subsequently been stable for twelve months. Function was reduced to 25 per cent of previous values during rejection and never returned to more than 50 per cent. This patient is discussed under “Problems.” In a third patient (Case 8) there was some loss of renal function during alternate-day steroid therapy, but this is attributed to the effects of well documented chronic urinary tract infection rather than rejection. Over-all, group A patients, who were generally receiving small (10 to 15 mg) daily doses of prednisone when alternate-day therapy was instituted, maintained good function. During a total
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of 257 months of such therapy in ten patients, the mean change in serum creatinine was not significant, being +0.03 f 0.033 mg/lOO ml (mean f standard error of the mean; p < 0.30). The mean change in creatinine clearance was also not significant (+1.6 f 4.0 ml/minute; p < 0.70). Experience with group B (Table II) covers 135 patient-months of steroid-reduction efforts in eighteen patients and 115 patient-months after the substitution of alternate-day regimens in fifteen of them. There were sixteen rejection reactions in eleven patients prior to the introduction of alternate-day therapy; four of these occurred five days after transplantation, and the remaining twelve occurred in seven patients at intervals from three weeks to five months after transplantation. After conversion of the therapeutic regimen, which was at least begun in fifteen of the eighteen patients, there were five rejection episodes in four patients. Four occurred within three weeks of beginning alternate-day therapy, and one occurred four months after conversion. Of the eighteen patients in group B two ,(Cases 15 and 16) died four and eleven months postoperatively because of opportunistic infections (disseminated cytomegalovirus and cryptococcosis, respectively) before alternate-day therapy could be attempted. Thirteen (Cases 1-13, Table II) of the remaining sixteen patients were receiving alternate-day therapy within eight months (mean six months) after transplantation. Conversion in the fourteenth patient (Case 14) was not accomplished until twenty-eight months after operation because of rejection on two occasions soon after the institution of alternate-day therapy. However her renal function has now been stable for five months after conversion. In the two remaining patients (Cases 17 and 18) conversion has not yet been attempted because of rejection problems. There has been no evidence of deterioration in renal function in the fourteen patients in whom conversion to an alternate-day dosage schedule was successful; comparison of renal function before and after such therapy shows a change in serum creatinine of i-O.08 f 0.10 mg/lOO ml (mean f SEM; P <0.50) and a change in creatinine clearance of +9 f 2.4 ml/minute (P < 0.005). The sum total of experience with the patients in group B is that the steroid regimen in most graft recipients, despite prior rejection episodes, can be converted to alternate-day prednisone administration. Rejection reactions beginning within the first two months after transplantation, or suspicion of rejection, delayed advancement to alternate-day steroid schedules beyond the theoretically possi-
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90
THEORET PREDNIS REDUCT’N60 RATE w 30
SERUM 9
CREATININE 1
CONC w
60 PREDNIS mg
30
DAYS
OCT
NOV
DEC
JAN
FE0
MAR
AFU
MAY
JUN
Figure 1. Renal allograft fonchon and schedule of prednisone therapy I/) Case 5 (Table II) contrasted with theoretically possrble rate of steroid reducbon (at top of chart). The unmarked arrows mdrcate apparent decreases in function interpreted as possible refecbon, resulting in return to hrgher dally doses of prednrsone. Lines lorning points on curves of serum creatinine and creatinine clearance represent interpretations of data upon which therapy was based. The first thick bar indicates the period of divided dose parenteral steroid adminrstration and the segmented thin bars the dose consolrdation phase leading to single mormng dose steroid administration (step 1 in text). Each thin bar in the upper and lowermost graphs indicates single mornrng dose on one day. Reduction steps 2,3,4 are represented by the progressively diminishing bar heights. 60130 means 60 and 30 mg on successive days, similarly for 30115; 30 or 60 alone indicates that daily dosage; 30/O, 20/O, 15/O indicate that alternate-day dosage. Time scales are compressed after 30/O dosage on each graph Azathroprine dosage was from 175 to 200 mglday (2 mglkg) throughout
ble three months’ time (Figure 1) in all but one instance, so that by the time of full conversion most patients were five to eight months beyond transplantation. Twelve of the fourteen patients who tolerated alternate-day therapy had received kidneys from related donors, whereas only two of the four recipients of cadaveric grafts tolerated conversion. EFFECT OF DOSAGE-SPACING ON COMPLICATIONS OF STEROID THERAPY
No one of the twenty-eight patients in this study had any symptoms or signs of gastritis, ulcer or gastrointestinal bleeding after the introduction of
single morning doses for daily prednisone therapy or during alternate-day treatment. During the course of the study there were only two fatalities from infection among the twentyeight patients. Three other serious infections were Pneumocystis carinii pneumonitis (Case 7), perirenal abscess and pyelonephritis (Case 11) and Klebsiella pneumonia (Case 17). All of these infections occurred in patients receiving intensive daily steroid treatment either for rejection or shortly after transplantation. Recovery from infection in a retroperitoneal hematoma and from an infected uretero-cutaneous fistula followed conversion to alternate-day therapy in two additional
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Figure 2. conversion
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Case 10 (Table I). Appearance to 15 mg on alternate days (right).
of patient
patients. No serious infections occurred in any patient in whom the regimen was fully changed to alternate-day prednisone administration. The facial and trunkal distortions of Cushing’s syndrome uniformly remitted in group A patients, irrespective of whether total steroid dose was altered. A striking example is shown in Figure 2. In group B patients, the cosmetic changes of Cushing’s syndrome were not generally prevented by the reduction program, which still involved five to eight months of daily steroid therapy, but these stigmata did regress rapidly after starting true alternate-day therapy. Facial Cushingism, obesity and steroid-related hypertension were seen to regress on as much as 55 mg prednisone every other day (Case 8, Table I I), and the administration of 30 mg on -alternate days appeared to permit substantial resolution of all the undesirable manifestations of hypercorticism. Remission of the facial and bodily distortions of Cushing’s syndrome was often of great psychological benefit to patients who had become withdrawn and depressed because of their appearance. After conversion, hypertension was uniformly ameliorated or controlled in both group A and
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during
15 mg daily prednisone
therapy
(/eft) and after
group B patients. Two patients had aseptic necrosis of the femoral head, which developed before the change to alternate-day steroid therapy was made. This may be an unusually low incidence [9]. Alternate-day therapy had no effect on the course of the diseqse. Two of the twenty-eight patients had steroid-induced diabetes mellitus, which remitted on alternate-day therapy. Four patients had lenticular cataracts which improved symptomatically on alternate-day steroid therapy. PROBLEMS IN MANAGING STEROID THERAPY The only likely major ill effect of not administering steroid on a daily basis would be an increased incidence of rejection. Among the ten group A patients there were two rejection reactions over 257 patient-months of alternate-day steroid therapy. In one there was full recovery; the second rejection occurred in a long stable recipient of a cadaveric allograft (Case 3, Table I) and may have gone untreated for two months. There was 75 per cent reduction in renal function and only partial recovery. Alternate-day prednisone therapy was resumed three times up to six months after maximum postrejection improvement because of the patient’s
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depressive reaction to reappearance of Cushing’s facies; decrease in function followed each resumption The graft has survived well enough over the intervening two years to prevent symptoms despite slowly declining function apparently associated with maintaining alternate-day steroid therapy. This experience suggests that after rejection there may be no safe time to resume alternateday steroid therapy in some patients. In a total of ten patients, nine of whom had re: ceived kidneys from related donors, resumption or assumption of alternate-day steroid therapy two to six months after rejection episodes caused no recurrence. In fact, no graft from a related donor in the entire serves, with one exception, showed persistent impairment from rejection reactions during the course of decreasing prednisone dosage as descrrbed under “Methods.” That excepnon occurred In a woman (Case 16, Table II) who had received a graft from her own daughter; rejection was inexorable, requiring maintained high daily steroid dosage, and death occurred from disseminated cryptococcosis. Only two patients have had symptoms that might be directly attributable to omitting steroid every other day One, (Case 2, Table II) had symptoms suggestive of postural hypotension and hypoglycemia, which could not be documented objectively, for about two weeks after finally omitting steroid on alternate days. Another (Case 5, Table II) had mild arthralgia for two or three weeks after achieving a fully alternate-day schedule. COMMENTS It IS possible that steroid therapy could have been eliminated altogether in some of these patients, particularly in those receiving small doses and long past transplantation (group A). However, a reported gradual withdrawal of prednisone from five patients whose renal function had been stable for at least a year on 5 to 10 mg of prednisone/ day was associated with acute rejection reactions in three [12]. Because there was virtually no evidence of steroid toxicity on stable low alternateday dosage we chose not to attempt to terminate steroid therapy entirely. Several lanes of evidence favor the use of corticosteroid in well spaced doses. Single daily doses do not suppress adrenocortical secretory activity as much as divided doses [lo], probably because the susceptibility of the pituitary-adrenal axis to suppression by exogenous steroid varies diurnally, being least in the morning and maximal at midnight [13]. The metabolic effects of glucocorticoid associated with protein catabolism and gluconeo-
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genesis vary during alternate-day adminrstration in a way that indicates nearly complete disappearance twenty-four hours after each dose [14]. Continuous high blood levels of corticosterord may not be required for anti-inflammatory effects, single doses of cortisol can provide twenty-four hour suppression of inflammation, possibly because of sequestration in inflamed tissues [15]. These findings suggest that some of the advantages of alternate-day steroid administration can be realized by administering steroid in single morning doses even when daily steroid therapy is thought to be required The technic of reducing steroid dosage on every other day until the patient is receiving steroid only on alternate days differs from the approaches used previously, both in renal transplant recipients [3,16] and in various diseases [17-201, in which either double the total of prior divtded daily doses is given on alternate days or the daily dose is increased stepwise one day and the intervening day’s dose is decreased until eliminated [3] Our attempt to provide at least some of the advantages of alternate-day steroid therapy to all patients beginning shortly after transplantation also differs from previously reported efforts, which were generally begun three [3] or six months [16] later. Alternate-day therapy has proved effective in the treatment of a variety of diseases requiring long-term corticosteroid therapy [17-201 Our method of establishing spaced-dose therapy in progressive stages may facilitate the application of such treatment, with its documented benefits. The precise role of corticosterord in managing allograft rejection and whether “anti-inflammatory” or “immunosuppressive” effects are more important are unresolved questions. In the clinical situation in which azathioprine provides the primary immunosuppression, the fact that alternate-day steroid therapy does less harm to cellular immune mechanisms [17] may be a positive advantage, leaving the patient with better resistance to the opportunistic infections which complicate immunosuppressive therapy [7]. The foregoing may be the reason for the comparatively low incidence of deaths from infection in our series Among a total of 164 recipients of kidneys from living related donors in the Denver [7], Richmond [8] and Chicago series [3], there were a total of thirty-two deaths from infection (20 per cent). Deaths from infection among the recipients of cadaveric grafts were twice as frequent. Since adoption of single morning dose and alternate-day dose prednisone therapy there have
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been only two fatalities among twenty-three recipients of live donor grafts (8.7 per cent incidence) in this series, both of which occurred in patients exposed to large daily doses of steroids (Cases 15 and 16, Table I I). Four patients receiving single morning doses survived serious infections, and no patient receiving alternate-day steroid therapy had a serious infection. Gram-negative septicemias, as reported by Reeve [3], have been conspicuously absent. The absence of gastrointestinal ulceration and bleeding in our series also contrasts with the experience of others [3,6,8]. Moore and Hume [8] described four patients with gastrointestinal ulceration and hemorrhage who required surgery (two of whom died) among seventy-seven recipients of living donor grafts, and ten such patients (only two of whom survived) among thirty-six recipients of cadaver kidneys. In another series [3] three each of fifty live donor and fifty cadaver recipients had bleeding peptic ulcer, requiring gastrectomy in one. There were few, if any, ill effects of alternateday steroid therapy and the conversion process leading towards it. Although rejection reactions occurred, they were readily controlled, with few exceptions. In the combined group of twenty-three live related donor (LRD) and five cadaveric kidney recipients, there were two deaths (in LRD recipients) over the three year period, for a gross survival of 91 per cent in the group receiving live related donor kidneys. This compares with an 87 per cent one year survival for recipients of kidneys from related donors in the seventh and latest report of the kidney transplant registry [21]. Information on the frequency of rejection episodes with conventional steroid usage is scanty. In one series [22], sixty-five recipients of live related donor grafts incurred eighteen episodes with 61 per cent kidney survival at up to five years
ET AL
after transplantation. In another series [3], fifty recipients of live related donor grafts had five acute rejections with loss of four grafts, and four grafts were lost from chronic rejection. Among our eighteen patients advanced toward alternateday steroid therapy from time of transplant there were sixteen rejection episodes in eleven patients before the institution of alternate-day therapy and five afterward, without loss of any grafts. In most patients reduction of steroid therapy toward alternate-day regimens has seemed to serve as a test of allograft tolerance, with no permanent damage apparent from promptly treated rejection reactions. Many more problems were encountered in converting to alternate-day steroid regimens among the patients in group B than in group A patients, presumably because of the temporal proximity to transplantation and the magnitude and rapidity of the changes in steroid dosage; in two of sixteen surviving patients the regimen could not be fully changed over. Nevertheless, once alternate-day regimens were reached, about six months after transplantation, tolerance of such steroid administration was almost complete. Frequent and careful evaluation of the patients is the critical requirement for utilization of this reduction scheme, particularly while the larger changes are being made. Those patients whose prednisone dose was reduced to 30 mg daily without crisis during the four months after transplantation or rejection, readily tolerated the next stage reduction to 30 mg on alternate days. Our experience indicates that it may not be necessary to reduce steroid dosage to less than 30 mg prednisone on alternate days in order to obtain full benefit of alternate-day therapy. Steroid has an indispensable role in treating rejection reactions, but intercurrent use of steroid can be modified to reduce hazards, without compromising graft function.
REFERENCES 1.
2.
3.
4.
5
6
166
Manmck JA, Egdahl RH: Endocrinologrcal agents (In transplant immunosuppression), chap 29, Human Transplantation (Rapaport FT. Dausset J, eds), New York and London, Grune & Stratton, 1968 Hume DM, Magee JH, Kauffman MH Jr, et al Renal homotransplantation rn man in modrfied recipients. Ann Surg 158. 608, 1983. Reeve CE, Martin DC, Gonik HC, et al. Kidney transplantation, a comparison of results using cadaver and related Irving donors Amer J Med 47.410. 1969. Marchioro TL. Current clinical results of renal transplantation. Arch Intern Med (Chicago) 123 485, 1989. Arsenberg AC: Drugs employed for the suppression of rmmunologrc responsiveness New Eng J Med 272 1114.1965. Ginn HE. Late medical complications of renal transplantation. Arch Intern Med (Chicago) 123. 537, 1969.
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12
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Hill RB, Dahrlrng BE II, Starzl TE, et al Death after transplantation, an analysts of sixty cases. Amer J Med 42. 327,1967. Moore TC, Hume DM The period and nature of hazard in clrnical renal transplantation. I. The hazard to patrent survival Ann Surg 170 1, 1969. Cruess RL. Blennerhassett J. MacDonald FR, et al Aseptic necrosis following renal transplantation. J Bone Joint Surg 50-A: 1577, 1988 Grant SD, Forsham PH, DiRaimondo VC Suppressron of 17-hydroxycorhcosterords rn plasma and urrne by single and divided doses of triamcinolone. New Eng J Med273 11151965. Siegel RR: The basis of pulmonary disease resolutron after nephrectomy in Goodpasture’s syndrome. Amer J Med Sci 259’ 201.1970. Kuss R, Legrarn M, Porsson J, et al Human renal homotransplantation. acute late rejection after com-
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13
14
15
16
17
plete withdrawal of steroid therapy (abstract) 4th lnternatlonal Congress on Nephrology, 1969 (Stockhelm), p 447 Nichols T, Nugent CA, Tyler FH Diurnal vartatlon In suppression of adrenal functton by glucocorttcotds J Endocr 25 343,1965 Walton J, Watson ES, Ney RL Alternate-day vs shorter-Interval steroid admlntstratton Arch Intern Med (Chtcago) 127 601,197O Dougherty TF. Brown HE, Berltner DL Metabolism of hydrocortlsone durmg Inflammation Endocrinology 62 455, 1958 Reed WP, Lucas ZJ, Cohn R Alternate-day prednisone admInIstration after renal transplantation Lancet I 747,197o MacGregor RR, Sheagren JN. Lipsett MB, et al Alternate-day prednisone therapy, evaluation of delayed hypersensltivlty responses, control of disease and
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19
20
21 22
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steroid side effects New Eng J Med 280 1427, 1969 Ackerman GL, Nolan CM Adrenocortlcal tesponslveness after alternate-day cortlcosterold therapy New Eng J Med 278 405, 1968 Cocco AE, Mendeloff Al Evaluation of Intermittent cortlcosterold therapy In ulceratwe colltls Johns Hopkins Med J 120 162, 1967 Soyka LF Treatment of nephrotic syndrome tn children use of alternate-day prednisone regimen Amer J DIS Child 113 693, 1967 Editorial, Results of kidney transplantation Lancet 1 179, 1970 (a) Moore TC, Hume DM The period and nature of hazard rn clinical renal transplantation II The hazard to transplant kidney function Ann Surg 170 12, 1969 (b) Ibid II I The hazard to transplant kidney survival. Idem. p 25
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