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Critical evaluation of the association of acute with chronic graft rejection in kidney and heart transplant recipients
TISSUE COMPATIBILITY AND ALLORECOGNITION
ELSEVIER
Critical Evaluation of the Association of Acute With Chronic Graft Rejection in Kidney and Heart Transplant Recipients G. Opelz for the Collaborative
W
Transplant
Study
ITH THE USE of modern
immunosuppressive regimens, acute transplant rejection during the early posttransplant period has become less common. The longterm attrition rate from chronic rejection, however, is of increasing concern. It was pointed out in recent publications that episodes of acute rejection usually precede chronic rejections.‘*2 Because of this association of acute with subsequent chronic rejection, it has been suggested that the much feared chronic rejection process might be prevented if early acute rejections could be avoided altogether by means of aggressive immunosuppressive induction treatment. We report herein on an analysis of the Collaborative Transplant Study kidney and heart transplant data with respect to the association of acute with chronic graft rejection.
METHODS
Transplants performed from 1983 to 1994 were included in this analysis. All patients analyzed were on a cyclosporine-based immunosuppressive induction regimen and had a functioning graft 1 year after transplantation. The transplants were reported to the Collaborative Transplant Study by 305 kidney and 104 heart transplant centers.’ Background medical data and information on immunosuppressive treatment regimens were reported to the study center shortly after transplantation. Clinical follow-up data were reported at 3, 6. and 12 months, and yearly thereafter. No exclusions were made and patients dying with functioning grafts were counted as graft failures. Graft survival rates were computed according to the method of Kaplan and Meier. Statistical significance was estimated using the log-rank test.
0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
RESULTS
AND
DISCUSSION
Not surprisingly, cadaver kidney recipients treated for rejection during the first posttransplant year had a significantly lower graft outcome during the subsequent 5 years than recipients who did not require rejection treatment (Fig 1). We investigated whether all acute rejections were an indicator of subsequent chronic rejection, or whether successfully reversed rejections had to be viewed differently. The patients were separated into those who, following rejection treatment, attained a l-year serum creatinine value of ~130 wmol/L and those with a higher l-year serum creatinine value. As shown in Fig 2, patients treated for rejection whose serum creatinine returned to a level usually considered as “normal” in transplant recipients had only a slightly lower long-term graft survival rate compared to patients who experienced no rejection during the first year. Only when graft function did not return to normal after rejection treatment, as indicated in the current analysis by a l-year serum creatinine value of ~130 pmol/L, did these patients have a clearly inferior long-term outcome (Fig 2). In transplants performed during the most recent 5-year period from 1990 to 1994, the influence of rejections on long-term graft outcome was negligible in patients with a l-year creatinine of ~130 pmol/L (Fig 3).
From the Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Heidelberg, Germany. Address reprint requests to Gerhard Opel& MD, Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany.
0041-l 345/97/$17.00 PII SO041 -1345(96)00013-9
73
Transplantation
Proceedings,
29, 73-76 (1997)
OPELZ
74
100
--------c-c
100
--._*_
“...,. ‘y
-._* =.._
%_
*.
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90
*-..
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-.
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--““Y;.z ....... .-.:;.;...., ._ “W... -. . . :”....... -REJ TR -.__;...,. -..‘:‘; ..... _,_“...
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70
80
- REJTR
“,., + REJ TR
50
50
0 0
1
2
3 Years
4
5
6
Fig 1. Survival rates of first cadaver kidney grafts according to whether the patients were treated for rejection during the first posttransplant year (+REJ TR, n = 10,212) or not (-REJ TR, n = 24,208). All patients analyzed had a functioning graft l-year posttransplantation. The subsequent survival rate was significantly higher in patients without rejection treatment during the first year (f < .OOOl).
When analyzing patients whose rejections had been treated either with steroid pulses or with polyclonal or monoclonal antibodies, the long-term outcome in patients with a l-year creatinine level of ~130 pmol/L was similar (Fig 4). One may assume that patients who received polyclonal or monoclonal antibodies for rejection treatment had, on average, more severe rejections than those treated with steroids only. The results depicted in Fig 4 therefore indicate that even severe rejections have no marked dele-
0 0
1
2
4
3
5
Years Fig 3. Same analysis as shown in Fig 2A, here for transplants performed during the latest 5year period analyzed (1990 to 1994). The difference between patients with or without rejection treatment was negligible. Dotted line: -REJ TR, n = 6563; dashed line: +REJ TR, n = 1448 (P = NS).
terious effect on long-term outcome, provided they are completely reversible. Whether the patients received induction treatment with polyclonal or monoclonal antibodies, or whether they were immunosuppressed without antibody induction, had no significant influence on subsequent outcome. Patients who 100
50 t 0-f 0
0 0
1
A Fig 2. Graft survival from One-year creatinine Cl30 2130 pmol/L. Dotted line: influence of early rejections (A).
2
3 Years
4
5
6
B
1
2
3 Years
4
5
6
1 to 6 years in patients with (+REJ TR) or without (-REJ TR) rejection treatment during the first year. (A) Fmol/L. Dotted line: -REJ TR (n = 13,319); dashed line: +REJ TR (n = 3221). (B) One-year creatinine -REJ TR (n = 10,713); dashed line +REJ TR (n = 6905). Although statistically significant (P < .OOi), the on chronic graft loss was comparatively small in patients with a l-year serum creatinine of ~130 pmol/L
ACUTE AND CHRONIC
KIDNEY GRAFT REJECTION
75
+ POLYCLONAL - REJ TR + oKT3 + STEROIDS
0
1
2
3 Years
4
5
6
0
Fig 4. Influence of rejections treated during the first year on long-term outcome. Rejection treatment with different immunosuppressive protocols is indicated. All patients had a l-year creatinine of ~130 PmollL. -REJ TR (n = 13,319) = no rejection treatment during the first year. +POLYCLONAL (n = 396) = rejection treatment with polyclonal antibodies. +OKT3 (n = 351) = rejection treatment with monoclonal 0KT3. +STEROIDS (n = 2192) = rejection treatment with steroid bolus.
required rejection treatment during the first year had a lower long-term graft survival rate, regardless of whether antibody induction was administered or not (Fig 5). The fraction of patients requiring rejection treatment during the first year was only marginally smaller among patients who received antibody induction (28%) than among those without antibody induction (30%). The result was not significantly different if the patients received antibody induction with monoclonal OKT3 or with polyclonal antibodies.
loo-
+INDUCT -REJ -INDUCT -REJ
+INDUCT +REJ -INDUCT +REJ
1
0
1
2
3 Years
4
5
6
Fig 5. Influence of rejections treated during the first year on long-term graft outcome in patients with or without induction therapy with polyclonal or monoclonal 0KT3 antibodies. Whether or not antibody induction was carried out had little effect on the rate of rejections requiring treatment during the first year or on the subsequent survival rate. Polyclonal: +INDUCT -REJ, n = 6411; -INDUCT -REJ, n = 17,797. OKT3: +INDUCT +REJ, n = 2430; -INDUCT +REJ, n = 7782).
3 Years
4
5
6
Fig 6. Influence of rejections treated during the first year on long-term graft outcome in patients with a l-year serum creatinine of <130 kmol/L. +INDUCT = with antibody induction; -INDUCT = without antibody induction. +REJ = with rejection treatment during first year; -REJ = without rejection treatment during first year. +INDUCT -REJ, n = 3394; -INDUCT -REJ, n = 9925; +INDUCT +REJ, n = 691; -INDUCT +REJ, n = 2530.
When the analysis of patients with antibody induction was restricted to those who had a l-year serum creatinine of ~130 Fmol/L, there was again only a small advantage for patients without rejection treatment over those who required rejection treatment during the first year (Fig 6).
100 ----------=:;;;>.,, ‘.-_‘.....,,, . . “‘... ‘_.__:‘..‘...,.,, “.........(., go. ..-_._ .. ” ....... . ..__‘_._;;.;‘....., *_._“(.x. 60.-F .z ._.__ 2 s $
70-
g &?
60-
0
0-I
2
1
2
3
4
5
_RE J -f-R +REJ TR
6
Years Fig 7. Influence of rejection treatment during the first posttransplant year on long-term outcome of first orthotopic heart transplants. Although patients without rejection treatment (-REJ TR, n = 3343) had a statistically significantly higher survival rate than patients with rejection treatment (+REJ TR, n = 3314) (P < .Ol), the graft survival difference was relatively small (compare with kidney graft results shown in Fig 1). Note that approximately one half of the heart transplant recipients received rejection treatment during the first year.
OPEL2
76
“._‘;c...._,, ‘.__:‘>.__, -_.> .__., . .._“....... “_..._ ......(. ‘._l’<...._., “_;“..__:” ‘.._._
90
.-!? .z 2
80
i 2
70
s
60
-REJ TR
. +REJTR I
50 1/ 0
1
2
3 Years
4
5
clonal antibodies does not appear to result in a marked reduction in the rate of chronic rejection (Fig 5). The results obtained in an analysis of heart transplants differed from those obtained in kidney transplant recipients. Even in the overall analysis, there was only a small difference in long-term outcome between patients who did or did not require rejection treatment during the first year (Fig 7). Moreover, if patients were analyzed who were reported to have “excellent graft outcome” at 1 year, the subsequent success rate was nearly identical regardless of whether the patients had been treated for rejection or not (Fig 8). Thus, there is very little evidence in heart transplantation that acute rejection episodes are a predictor of chronic rejection.
6
Fig 8. Influence of rejection treatment during the first year on subsequent heart transplant survival in patients who were reported to have “excellent graft outcome” at 1-year posttransplantation. The difference in subsequent survival between patients with (+REJ TR, n = 3203) or without (-REJ TR, n = 2848) rejections during the first year was only marginally significant (P = .04).
These results suggest that effective strategies for the successful treatment of acute rejection need to be developed to reduce the incidence of chronic kidney graft rejection. Aggressive induction treatment with monoclonal or poly-
ACKNOWLEDGMENT
The contributions of the kidney and heart transplant centers participating in the Collaborative Transplant Study are gratefully acknowledged.
REFERENCES
1. Almond PS, Matas A, Gillingham K, et al: Transplantation 55:752, 1993 2. Sumrani N, Cacciarelli TV, Georgi B, et al: Transplant Proc 25~2259, 1993 3. Collaborative Transplant Study, Newsletter 3, University of Heidelberg, July 1, 1996
ELSEVIER
Critical Evaluation of the Association of Acute With Chronic Graft Rejection in Kidney and Heart Transplant Recipients G. Opelz for the Collaborative
W
Transplant
Study
ITH THE USE of modern
immunosuppressive regimens, acute transplant rejection during the early posttransplant period has become less common. The longterm attrition rate from chronic rejection, however, is of increasing concern. It was pointed out in recent publications that episodes of acute rejection usually precede chronic rejections.‘*2 Because of this association of acute with subsequent chronic rejection, it has been suggested that the much feared chronic rejection process might be prevented if early acute rejections could be avoided altogether by means of aggressive immunosuppressive induction treatment. We report herein on an analysis of the Collaborative Transplant Study kidney and heart transplant data with respect to the association of acute with chronic graft rejection.
METHODS
Transplants performed from 1983 to 1994 were included in this analysis. All patients analyzed were on a cyclosporine-based immunosuppressive induction regimen and had a functioning graft 1 year after transplantation. The transplants were reported to the Collaborative Transplant Study by 305 kidney and 104 heart transplant centers.’ Background medical data and information on immunosuppressive treatment regimens were reported to the study center shortly after transplantation. Clinical follow-up data were reported at 3, 6. and 12 months, and yearly thereafter. No exclusions were made and patients dying with functioning grafts were counted as graft failures. Graft survival rates were computed according to the method of Kaplan and Meier. Statistical significance was estimated using the log-rank test.
0 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
RESULTS
AND
DISCUSSION
Not surprisingly, cadaver kidney recipients treated for rejection during the first posttransplant year had a significantly lower graft outcome during the subsequent 5 years than recipients who did not require rejection treatment (Fig 1). We investigated whether all acute rejections were an indicator of subsequent chronic rejection, or whether successfully reversed rejections had to be viewed differently. The patients were separated into those who, following rejection treatment, attained a l-year serum creatinine value of ~130 wmol/L and those with a higher l-year serum creatinine value. As shown in Fig 2, patients treated for rejection whose serum creatinine returned to a level usually considered as “normal” in transplant recipients had only a slightly lower long-term graft survival rate compared to patients who experienced no rejection during the first year. Only when graft function did not return to normal after rejection treatment, as indicated in the current analysis by a l-year serum creatinine value of ~130 pmol/L, did these patients have a clearly inferior long-term outcome (Fig 2). In transplants performed during the most recent 5-year period from 1990 to 1994, the influence of rejections on long-term graft outcome was negligible in patients with a l-year creatinine of ~130 pmol/L (Fig 3).
From the Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Heidelberg, Germany. Address reprint requests to Gerhard Opel& MD, Institute of Immunology, University of Heidelberg, Im Neuenheimer Feld 305, D-69120 Heidelberg, Germany.
0041-l 345/97/$17.00 PII SO041 -1345(96)00013-9
73
Transplantation
Proceedings,
29, 73-76 (1997)
OPELZ
74
100
--------c-c
100
--._*_
“...,. ‘y
-._* =.._
%_
*.
‘..,
90
*-..
‘k._
-.
“...
-.
“%,,,
T
--““Y;.z ....... .-.:;.;...., ._ “W... -. . . :”....... -REJ TR -.__;...,. -..‘:‘; ..... _,_“...
._‘:‘:‘2L
--.. *.._
‘..,
80
90
-...
-----------.-*
“Q...
+REJ TR
*.._
.._(
*...
.
“X.,,,
“._,_ “.___ x_“._. ..... ....... x.
70
80
- REJTR
“,., + REJ TR
50
50
0 0
1
2
3 Years
4
5
6
Fig 1. Survival rates of first cadaver kidney grafts according to whether the patients were treated for rejection during the first posttransplant year (+REJ TR, n = 10,212) or not (-REJ TR, n = 24,208). All patients analyzed had a functioning graft l-year posttransplantation. The subsequent survival rate was significantly higher in patients without rejection treatment during the first year (f < .OOOl).
When analyzing patients whose rejections had been treated either with steroid pulses or with polyclonal or monoclonal antibodies, the long-term outcome in patients with a l-year creatinine level of ~130 pmol/L was similar (Fig 4). One may assume that patients who received polyclonal or monoclonal antibodies for rejection treatment had, on average, more severe rejections than those treated with steroids only. The results depicted in Fig 4 therefore indicate that even severe rejections have no marked dele-
0 0
1
2
4
3
5
Years Fig 3. Same analysis as shown in Fig 2A, here for transplants performed during the latest 5year period analyzed (1990 to 1994). The difference between patients with or without rejection treatment was negligible. Dotted line: -REJ TR, n = 6563; dashed line: +REJ TR, n = 1448 (P = NS).
terious effect on long-term outcome, provided they are completely reversible. Whether the patients received induction treatment with polyclonal or monoclonal antibodies, or whether they were immunosuppressed without antibody induction, had no significant influence on subsequent outcome. Patients who 100
50 t 0-f 0
0 0
1
A Fig 2. Graft survival from One-year creatinine Cl30 2130 pmol/L. Dotted line: influence of early rejections (A).
2
3 Years
4
5
6
B
1
2
3 Years
4
5
6
1 to 6 years in patients with (+REJ TR) or without (-REJ TR) rejection treatment during the first year. (A) Fmol/L. Dotted line: -REJ TR (n = 13,319); dashed line: +REJ TR (n = 3221). (B) One-year creatinine -REJ TR (n = 10,713); dashed line +REJ TR (n = 6905). Although statistically significant (P < .OOi), the on chronic graft loss was comparatively small in patients with a l-year serum creatinine of ~130 pmol/L
ACUTE AND CHRONIC
KIDNEY GRAFT REJECTION
75
+ POLYCLONAL - REJ TR + oKT3 + STEROIDS
0
1
2
3 Years
4
5
6
0
Fig 4. Influence of rejections treated during the first year on long-term outcome. Rejection treatment with different immunosuppressive protocols is indicated. All patients had a l-year creatinine of ~130 PmollL. -REJ TR (n = 13,319) = no rejection treatment during the first year. +POLYCLONAL (n = 396) = rejection treatment with polyclonal antibodies. +OKT3 (n = 351) = rejection treatment with monoclonal 0KT3. +STEROIDS (n = 2192) = rejection treatment with steroid bolus.
required rejection treatment during the first year had a lower long-term graft survival rate, regardless of whether antibody induction was administered or not (Fig 5). The fraction of patients requiring rejection treatment during the first year was only marginally smaller among patients who received antibody induction (28%) than among those without antibody induction (30%). The result was not significantly different if the patients received antibody induction with monoclonal OKT3 or with polyclonal antibodies.
loo-
+INDUCT -REJ -INDUCT -REJ
+INDUCT +REJ -INDUCT +REJ
1
0
1
2
3 Years
4
5
6
Fig 5. Influence of rejections treated during the first year on long-term graft outcome in patients with or without induction therapy with polyclonal or monoclonal 0KT3 antibodies. Whether or not antibody induction was carried out had little effect on the rate of rejections requiring treatment during the first year or on the subsequent survival rate. Polyclonal: +INDUCT -REJ, n = 6411; -INDUCT -REJ, n = 17,797. OKT3: +INDUCT +REJ, n = 2430; -INDUCT +REJ, n = 7782).
3 Years
4
5
6
Fig 6. Influence of rejections treated during the first year on long-term graft outcome in patients with a l-year serum creatinine of <130 kmol/L. +INDUCT = with antibody induction; -INDUCT = without antibody induction. +REJ = with rejection treatment during first year; -REJ = without rejection treatment during first year. +INDUCT -REJ, n = 3394; -INDUCT -REJ, n = 9925; +INDUCT +REJ, n = 691; -INDUCT +REJ, n = 2530.
When the analysis of patients with antibody induction was restricted to those who had a l-year serum creatinine of ~130 Fmol/L, there was again only a small advantage for patients without rejection treatment over those who required rejection treatment during the first year (Fig 6).
100 ----------=:;;;>.,, ‘.-_‘.....,,, . . “‘... ‘_.__:‘..‘...,.,, “.........(., go. ..-_._ .. ” ....... . ..__‘_._;;.;‘....., *_._“(.x. 60.-F .z ._.__ 2 s $
70-
g &?
60-
0
0-I
2
1
2
3
4
5
_RE J -f-R +REJ TR
6
Years Fig 7. Influence of rejection treatment during the first posttransplant year on long-term outcome of first orthotopic heart transplants. Although patients without rejection treatment (-REJ TR, n = 3343) had a statistically significantly higher survival rate than patients with rejection treatment (+REJ TR, n = 3314) (P < .Ol), the graft survival difference was relatively small (compare with kidney graft results shown in Fig 1). Note that approximately one half of the heart transplant recipients received rejection treatment during the first year.
OPEL2
76
“._‘;c...._,, ‘.__:‘>.__, -_.> .__., . .._“....... “_..._ ......(. ‘._l’<...._., “_;“..__:” ‘.._._
90
.-!? .z 2
80
i 2
70
s
60
-REJ TR
. +REJTR I
50 1/ 0
1
2
3 Years
4
5
clonal antibodies does not appear to result in a marked reduction in the rate of chronic rejection (Fig 5). The results obtained in an analysis of heart transplants differed from those obtained in kidney transplant recipients. Even in the overall analysis, there was only a small difference in long-term outcome between patients who did or did not require rejection treatment during the first year (Fig 7). Moreover, if patients were analyzed who were reported to have “excellent graft outcome” at 1 year, the subsequent success rate was nearly identical regardless of whether the patients had been treated for rejection or not (Fig 8). Thus, there is very little evidence in heart transplantation that acute rejection episodes are a predictor of chronic rejection.
6
Fig 8. Influence of rejection treatment during the first year on subsequent heart transplant survival in patients who were reported to have “excellent graft outcome” at 1-year posttransplantation. The difference in subsequent survival between patients with (+REJ TR, n = 3203) or without (-REJ TR, n = 2848) rejections during the first year was only marginally significant (P = .04).
These results suggest that effective strategies for the successful treatment of acute rejection need to be developed to reduce the incidence of chronic kidney graft rejection. Aggressive induction treatment with monoclonal or poly-
ACKNOWLEDGMENT
The contributions of the kidney and heart transplant centers participating in the Collaborative Transplant Study are gratefully acknowledged.
REFERENCES
1. Almond PS, Matas A, Gillingham K, et al: Transplantation 55:752, 1993 2. Sumrani N, Cacciarelli TV, Georgi B, et al: Transplant Proc 25~2259, 1993 3. Collaborative Transplant Study, Newsletter 3, University of Heidelberg, July 1, 1996