Aust. N.Z. J. Med. (1977). 7. vv. 16-19
Carcinoembryonic Antigen in Renal Allograft Recipients and Immunosuppressed Renal Patient%* J. B. Myerst, Margaret Frostf, A. S. Coates**, J. D. Mathewst? and Priscilla Kincaid-Smith$$
From the Department of Medicine, University of Melbourne, Clinical Research Unit, Walter and Eliza Hall Institute of Medical Research and the Royal Melbourne Hospital, and the Department of Nephrology, Royal Melbourne Hospital
Summary: Carcinoembryonic antigen in renal allograft recipients and immunosuppressed renal patients. J. B. Myers, Margaret Frost, A. S. Coates, J. D. Mathews, Priscilla Kincaid-Smith, Aust. N.Z. J. Med., 1977, 7. pp. 16-1 9. Carcinoembryonic antigen (CEA) was estimated in plasma from 70 patients with a renal transplant, 105patients with glomerulonephritis w h o had received immunosuppressive therapy, and 124 healthy controls. There were raised levels in 30% of those with a renal transplant, 10% of those with glomerulonephritis and 2% of controls, and levels were higher in current smokers. CEA levels did not correlate with pre- transplant dialysis time nor with serum creatinine levels, but tended to fall with increasing time after transplantation, especially in non-smokers. CEA levels did not correlate with prednisolone dosage nor with number of rejection episodes, after allowing for time after transplantation and smoking habit. Nine of 70 patients with a renal transplant and three of 105 with glomerulonephritis had cancer, of skin in seven, cervix uteri in four, and colon in one. CEA was raised in all four transplant recipients with a visceral cancer (cervix three and colon one), but in none of the five with cutaneous cancer. Raised CEA levels occurring late after a renal allograft should prompt a careful search for visceral cancer. 'Supported by grants from the University of Melbourne Medical Research Committee and the Joseph Herman Trust, and the National Health and Medical Research Council of Australia. This is publication No. 2163 from The Walter and Eliza Hall Institute of Medical Research. ?Research Fellow, Departments of Medicine and Nephrology. $Research Assistant, Clinical Research Unit. '"First Assistant Research PhSSrcian, Clinical Research Unit. ttResearch Fellow, Department of Medicine. $$Professor in Medicine, Director of Department of Nephrology. Correspondence: Dr. A. S. Coates, The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Victoria 3050 Accepted for publication: 1 September, 1976
An increased incidence of malignant disease has been reported in immunosuppressed recipients of organ transplants.', Immunosuppressive agents3 and uraemia" have been suggested as factors contributing to the development of malignancy in these patients. The value of the circulating level of CEA as a diagnostic marker of cancer has been extensively studied.5-11 Hansen and his coworkers have found elevated CEA levels in renal transplant recipient^.^ We therefore measured CEA in patients with renal allografts. For comparison, a group of patients with glomerulonephritis who had been treated with immunosuppressive agents and a group of healthy controls were also studied. Patients, Materials and Methods
Putients Of 104 renal allograft recipients attending our transplant outpatient clinic, 70 who attended during the period of this study were included. There were 37 males and 33 females; ages ranged from 8-60 years (mean 35 years). Sixty-eight patients had cadaver grafts and two had living related donor grafts. Five of the 68 have received a second cadaver transplant. The mean duration of immunosuppressive treatment was 31 months (range 1-112) and the mean interval since commencing such treatment was 33 months (range 1-138). No patient had received antilymphocyte globulin. One hundred and five patients with glomerulonephritis who had received or who%ere currently receiving immunosuppressive agents (i.e. cyclophosphamide, azathioprine or prednisolone) and who were currently attending the hospital were also studied. There were 58 males and 47 females; ages ranged from 16-67 years (mean 36 years). Seventy-three of these patients had received cyclophosphamide in the past. Fourteen were taking cyclophosphamide alone ; two were taking cyclophosphamide together with prednisolone and one was taking cyclophosphamide and azathioprine; ten were taking azathioprine and prednisolone ; three were taking only azathioprine and 16 were taking only prednisolone. Fifty-nine glomerulonephritis patients were not currently receiving treatment and treatment had been stopped one to 88 months before this study. The mean duration of immunosuppressive therapy was 39 months (range 1-118) and the mean interval since commencing such therapy was 54 months (range 2-204).
FEBRUARY,
1977
17
CEA IN RENAL ALLOGRAFTS /
Particulars regarding smoking habits were obtained by direct questioning. A rejection episode was defined as a rise of 0.02 mmol!/ in serum creatinine, and was treated with a single intravenous dose of 1 g methyl-prednisolone sodium succinate. Patients were examined clinically for evidence of cancer, and cervical smears and vaginal examinations were performed on all women. The "normal" control group of 124 included 98 blood donors and 26 healthy laboratory staff. There were 88 males and 36 females; ages ranged from 18-68 years (mean 35 years).
Materials and hlrthotls Venous blood was collected in glass tubes containing ethylenediamine tetr'iacetic acid (EDTA), (Vacutainer, Becton-Dickinson and Company. Rutherford, New Jersey, IJSA). Plasma was assayed by the Zirconyl phosphate gel method' using reagents supplied by HoRman La Roche Inc., Nutley, New Jersey, USA. A detailed description of the assay method has been given by Frost and Coates."
SMOKING Never Smoked-NS. Past Smoker-ExSM Current Smoker-SM
8
6.5
6
5.0 CEA nglml
a
41
IMMUNOSUPPRESSED GLOMERULONEPHRITIS 3.1 t 2.0
a
3.9
2
-NS
ALLOGRAFT RECIPIENTS 4 . 8 2 3.3 ( S 0 I
Renal Allograft Recipients
nmunosuppressed lomcrulonephritis
ExSM
SM
NS
ExSM
SM
FIGURE 2. By analysis of variance there w a s significant heterogeneity of CEA level with respect to smoking habit for both the glomerulonephritis group ( F = 5 , 2 4 9 on 2, 95 df, P = 0.007) and the allograft recipients ( F = 3 . 3 0 1 o n 2, 50 df, P = 0.044). Smoking habits were not available for several subjects, and the patient with carcinoma of the colon (a non-smoker, see Table 1 ) was excluded from the allograft group for this comparison.
Results
a 0
a CONTROLS 2.2 2 1.2
5 CEA nq/rnl
FIGURE 1 . Frequency distribution of CEA levels in the groups studied. Mean levels and standard deviations (SD) are shown. The single high level in the renal allograft group is excluded from the mean and SD. Difference of allograft recipients from controls P < 0~001. Difference of allograft recipients from patients with glomerulo-nephritis P < 0.005. Difference of patients with glomerulonephritis from controls P < 0 . 0 1 .
The frequency distribution of CkA levels in the control group, in patients with glomerulonephritis, and in renal allograft recipients are shown in Figure 1. The normal range, established from the control group, was 0-4.6 ng/ml (mean 2.2kstandard deviation, 1 . 2 ng/ml); only two of 124 healthy control subjects had CEA levels above this range. The mean CEA level amodg immunosuppressed glomerulonephritis patients was 3 . 1 ng/ml and 1 1 (lOo,,) of these patients had levels above the normal range (difference from controls: xf = 6.6, P < 0.01). The mean CEA level among renal allograft recipients was 4 . 8 ng/ml, excluding one patient with an adenocarcinoma of the colon who had a very high level (50 ng/ml). Twenty-one (30",) of the renal allograft recipients had levels above the normal range as defined above. (Difference from control P < 0.001 ; difference from glomerulonephritis group P < 0.005.)
18
MYERS ET AL.
VOL.
7,
NO.
1
\ 0
SO?
(20 mg or more per day) 17 were within six months of transplantation. CEA levels tended to be higher in this group of patients than in patients on lower prednisolone dosage at more than six months after transplantation. This difference was more marked for the sub-group of patients who were ex-smokers than for patients who had never smoked or who were current smokers. Inspection of the data suggested that CEA level was related to time since transplantation, smoking habit and cancer (Fig. 3) more closely than to the dose of prednisolone ( r = -0.122, P > 0.10) or the number of rejection episodes ( r = 0.075, P > 0.10). CEA level was not related to pre-transplant dialysis time ( r = 0.150. P > 0.10), degree of HLA incompatibility of the allograft ( F = 0.722, P = 0.581), serum creatinine ( r = 0.064, P < 0.10) blood group ( F = 1.12, P = 0.350) or sex ( F = 0,931, P = 0,336). In the groups of patients studied we could not establish any significant relationship of CEA level to total doses of azathioprine, cyclophosphamide or prednisolone. Cancer was known or detected in three of 105 patients with glomerulonephritis and in nine of 70 allograft recipients (Table 1 ) but in two patients, one in each group, cancer was present before immunosuppressive therapy was
Renal Allografts Never smoked P a t snwkr x Current smoker o
201.
Cancrr
0
@ I " r
I
I
m
I
I
90
120
.
60
MONTHS POST TRANSPLANTATION
FIGURE 3 CEA levels in individual allograft recipients in relation to the time since transplantation and smoking habits
In both patient groups CEA levels were higher in current smokers than in either past smokers or in patients who had never smoked (Fig. 2). CEA levels for individual patients with renal transplants are shown in Figure 3 in relation to the time since transplantation and smoking habits. Eleven of 21 patients studied in the first six months after transplantation had elevated levels whereas only ten of 49 patients studied more than six months after transplantation had elevated levels. Of 18 transplanted patients on high doses of prednisolone
TABLE 1 Patients with cancer ~
Glomerulonephritis patients - --.__
.__._
I.A.* G.B. C.W.
~
~
~
Allograft recipients _ _ ~ ~ _ ~~
__ -
D.B. E.D. K.H.
33 40 37
R.M.* M.U. G.G.
40
B.H. B.L. J.M.
~
~~
~~~
CEA (ng,ml) Age Biopsy, diagnosis and site __ __ __ ~~- -~ -~ -~__ 37 SCCtnose 1.4 67 BCC: face 1.0 25 Adenocarcinoma- . thyroid 1.0
.
-
~~~~
51 39 33 33 58
~
-
-.
- -
-
Treated surgically before CEA -~ _ _ - - --__ Ex-SM*" Yes EX-SM Yes EX-SM Yes
~-
-
2.4 3.0 3-8 3.0
3-9 7.7 9.1 11.8
50.0
**Ex-SM = past smoker f t N S = never smoked $$SM = current smoker
-
-
-~
SCC lip SCC hand SCC face and ear SCC forehead SCC leg and face Carcinoma cervix - i n sitir Carcinoma cervix- invasi\e Carcinoma cervix-invasive BCC and adenocarcinonia -colon
"Cancers occurred before immunosuppression YX'C = squamous cell carcinoma ::l3( ( = basal cell carcinoma
~
Smoking category
NStt NS NS SM$$ EX-SM SM SM
SM NS
- .-
- ~-
Yes Yes Yes Yes Yes Untreated a t time of CEA Yes Untreated at time of CEA Untreated at time of CEA
FEBRUARY,
1977
CEA IN RENAL ALLOGRAFTS
started. CEA levels were elevated in four of the 12 cancer patients but a very high level occurred in only one patient (J.M.) with adenocarcinoma of the colon. Discussion
We found elevated CEA levels in 30", of renal allograft recipients and in lo", of patients with glomerulonephritis ; this could be due to renal disease per se or to the effect of immunosuppressive therapy and/or to the presence of donor kidney tissue. The lack of any relationship of CEA tc: the serum creatinine level makes it unlikely that renal insufficiency was responsible for elevated CEA levels. Other evidence suggests that CEA levels are elevated in inflammatory disease', particularly during the active disease state. Inflammation in the kidney could be a factor contributing to elevations of CEA in both groups of patients within this study. Although it is possible that immunosuppressive therapy might contribute to elevated CEA levels as evidenced by the association of high CEA levels with high prednisolone dosage in the transplant group of patients, it is difficult to distinguish the possible effects of high prednisolone dosage on CEA from the possible effects of disease activity and rejection. The raised CEA levels in current smokers are consistent with previous reports suggesting that smoking may be a cause of elevated CEA levels.5, l 3 On balance, we suggest that CEA levels are related more to disease activity and smoking habit than they are to immunosuppressive therapy. Non-malignant diseases such as cirrhosis, pancreatitis and emphysema are associated with elevated CEA levels'. l 2 : if present in an allograft recipient, such diseases would naturally reduce the significance of elevated levels. The study was begun with the knowledge that immunosuppressed patients have a timerelated increase in predisposition to cancer, presumably due to impaired immune surveillance, and with the premise that developing
19
cancer would be revealed by rising levels of CEA in the blood. This premise was not altogether borne out in that early after grafting there were raised levels of CEA which were not associated with cancer. Of the nine cancers occurring in renal allograft recipients in this study, five were skin cancers, and were not associated with raised CEA levels. The remaining four were visceral cancers (cervix three, colon one) and all were associated with elevated CEA levels. These constituted 40", of elevated levels occurring more than ten months after renal allograft. Hence raised CEA levels occurring late after a renal allograft should prompt a careful search for visceral cancer. CEA estimations could be included in the routine monitoring after transplantation. Acknowledgements
We are grateful to Professor R. Lovell, Dr. 1. R. Mackay, Dr. S. Whittingham and Dr. D. Christie [or their help and interest, and t o Sister Durman and Irene lraay for help in the collection of blood specimens.
References 1 2 3
4
5
''9
h.
7.
8
Y,
10. I I.
I?. 13.
V. C. l I Y 7 3 l Skin tiimour\ in immunorupprcssed patients, A w l N Z J . Swg. 43, 214 Ptuu. I 11974): Occurrence 01 cancer in imiiiuiiedcficiencles. C'uIMw34,858 Ptuu. I . (1974). Chemical immunuruppression and human cancer. C'untw 34, 1474. MATAS.A. J . , SIMMOM,R.L , t i J t L L S l K A h 1 ) . C. L . Bl'StLMtitil, T J and N A J A R I ~ NJ , S. ( I V 7 5 ) Increased incidence 01malignant) during chronic renal failure. L u n w r I, X X 3 HAhsru. H J.. SuYl>tK, J J . . M i L u n . E , \ ' A N I ) I V O O K D i , J P , MI1 I t R . J. J (1974). Carcinoembryonic antigen 0 N , HINI'S, L. R. ,and BC~RUS, ICEA) a%ay A iahordtory adjunct in thc diagnosis and management 01 cancer, Hum Puih 5, 139. ~~HOO S . ti and MAI-KA>. E V. (1973): Carcinoernhryonic antigen in Cancer oftlie female reproductive .;!\tern. Scquentiai le\,cla and effects of treatment. .4uir N Z .I Ohsi?r. Gvnrrrc 13, I LAUKtNCF. D. I. R., STLYENS. u., BrTTiI.HLIM, R.. DARCS, D.. L~LSL. C., TLlRBtR~iLLt.C , ALt\ANIxK. P.. JIIIIVS. E W and Nrvii I I , A M. (1972). Role of plasma carcmormhr)onic antigen In the diagnovs ofgd\trointe\tinal mammary and hronchial ~arcinoma.Brri. nicd. .I. 3, 605. Lo GtRf.0, P . Knubrs. J. and H A M ~ NH., J . (19711: Demonstration of an antigcn commoii to several \arirtie\ of neoplasia A s a q u w g zirconyl phosphate gel, NM ,OR/. J. .k'd 285, 138. M A ~ S W E EJ.N b .l . WAKNtn, N L . BAhKtII KST, A. D. and M A C R A YI . R. llY72l: Carcinuemhryonic antigen in whole hcrum, Llrrr .I Cuitwr 26, 356. R r > u ( , s ~G~ ., CHII. T. M.. Hlll>OKL, D.,COHLN. k.,NFVATO,T.. WnNti, J J . . CHOA"~G, J.. G L I N A NP., and M m P t n . G. P. (19721: Carcinoemhryonic antigen in patient, w t h different cdncers. J Amer. nicd. A u . 220, 3bl ZAMCHLCL N, , M m i ~ r . T L , D i l A R , P and I
Carcinoembryonic Antigen in Renal Allograft Recipients and Immunosuppressed Renal Patient%* J. B. Myerst, Margaret Frostf, A. S. Coates**, J. D. Mathewst? and Priscilla Kincaid-Smith$$
From the Department of Medicine, University of Melbourne, Clinical Research Unit, Walter and Eliza Hall Institute of Medical Research and the Royal Melbourne Hospital, and the Department of Nephrology, Royal Melbourne Hospital
Summary: Carcinoembryonic antigen in renal allograft recipients and immunosuppressed renal patients. J. B. Myers, Margaret Frost, A. S. Coates, J. D. Mathews, Priscilla Kincaid-Smith, Aust. N.Z. J. Med., 1977, 7. pp. 16-1 9. Carcinoembryonic antigen (CEA) was estimated in plasma from 70 patients with a renal transplant, 105patients with glomerulonephritis w h o had received immunosuppressive therapy, and 124 healthy controls. There were raised levels in 30% of those with a renal transplant, 10% of those with glomerulonephritis and 2% of controls, and levels were higher in current smokers. CEA levels did not correlate with pre- transplant dialysis time nor with serum creatinine levels, but tended to fall with increasing time after transplantation, especially in non-smokers. CEA levels did not correlate with prednisolone dosage nor with number of rejection episodes, after allowing for time after transplantation and smoking habit. Nine of 70 patients with a renal transplant and three of 105 with glomerulonephritis had cancer, of skin in seven, cervix uteri in four, and colon in one. CEA was raised in all four transplant recipients with a visceral cancer (cervix three and colon one), but in none of the five with cutaneous cancer. Raised CEA levels occurring late after a renal allograft should prompt a careful search for visceral cancer. 'Supported by grants from the University of Melbourne Medical Research Committee and the Joseph Herman Trust, and the National Health and Medical Research Council of Australia. This is publication No. 2163 from The Walter and Eliza Hall Institute of Medical Research. ?Research Fellow, Departments of Medicine and Nephrology. $Research Assistant, Clinical Research Unit. '"First Assistant Research PhSSrcian, Clinical Research Unit. ttResearch Fellow, Department of Medicine. $$Professor in Medicine, Director of Department of Nephrology. Correspondence: Dr. A. S. Coates, The Walter and Eliza Hall Institute of Medical Research, PO Royal Melbourne Hospital, Victoria 3050 Accepted for publication: 1 September, 1976
An increased incidence of malignant disease has been reported in immunosuppressed recipients of organ transplants.', Immunosuppressive agents3 and uraemia" have been suggested as factors contributing to the development of malignancy in these patients. The value of the circulating level of CEA as a diagnostic marker of cancer has been extensively studied.5-11 Hansen and his coworkers have found elevated CEA levels in renal transplant recipient^.^ We therefore measured CEA in patients with renal allografts. For comparison, a group of patients with glomerulonephritis who had been treated with immunosuppressive agents and a group of healthy controls were also studied. Patients, Materials and Methods
Putients Of 104 renal allograft recipients attending our transplant outpatient clinic, 70 who attended during the period of this study were included. There were 37 males and 33 females; ages ranged from 8-60 years (mean 35 years). Sixty-eight patients had cadaver grafts and two had living related donor grafts. Five of the 68 have received a second cadaver transplant. The mean duration of immunosuppressive treatment was 31 months (range 1-112) and the mean interval since commencing such treatment was 33 months (range 1-138). No patient had received antilymphocyte globulin. One hundred and five patients with glomerulonephritis who had received or who%ere currently receiving immunosuppressive agents (i.e. cyclophosphamide, azathioprine or prednisolone) and who were currently attending the hospital were also studied. There were 58 males and 47 females; ages ranged from 16-67 years (mean 36 years). Seventy-three of these patients had received cyclophosphamide in the past. Fourteen were taking cyclophosphamide alone ; two were taking cyclophosphamide together with prednisolone and one was taking cyclophosphamide and azathioprine; ten were taking azathioprine and prednisolone ; three were taking only azathioprine and 16 were taking only prednisolone. Fifty-nine glomerulonephritis patients were not currently receiving treatment and treatment had been stopped one to 88 months before this study. The mean duration of immunosuppressive therapy was 39 months (range 1-118) and the mean interval since commencing such therapy was 54 months (range 2-204).
FEBRUARY,
1977
17
CEA IN RENAL ALLOGRAFTS /
Particulars regarding smoking habits were obtained by direct questioning. A rejection episode was defined as a rise of 0.02 mmol!/ in serum creatinine, and was treated with a single intravenous dose of 1 g methyl-prednisolone sodium succinate. Patients were examined clinically for evidence of cancer, and cervical smears and vaginal examinations were performed on all women. The "normal" control group of 124 included 98 blood donors and 26 healthy laboratory staff. There were 88 males and 36 females; ages ranged from 18-68 years (mean 35 years).
Materials and hlrthotls Venous blood was collected in glass tubes containing ethylenediamine tetr'iacetic acid (EDTA), (Vacutainer, Becton-Dickinson and Company. Rutherford, New Jersey, IJSA). Plasma was assayed by the Zirconyl phosphate gel method' using reagents supplied by HoRman La Roche Inc., Nutley, New Jersey, USA. A detailed description of the assay method has been given by Frost and Coates."
SMOKING Never Smoked-NS. Past Smoker-ExSM Current Smoker-SM
8
6.5
6
5.0 CEA nglml
a
41
IMMUNOSUPPRESSED GLOMERULONEPHRITIS 3.1 t 2.0
a
3.9
2
-NS
ALLOGRAFT RECIPIENTS 4 . 8 2 3.3 ( S 0 I
Renal Allograft Recipients
nmunosuppressed lomcrulonephritis
ExSM
SM
NS
ExSM
SM
FIGURE 2. By analysis of variance there w a s significant heterogeneity of CEA level with respect to smoking habit for both the glomerulonephritis group ( F = 5 , 2 4 9 on 2, 95 df, P = 0.007) and the allograft recipients ( F = 3 . 3 0 1 o n 2, 50 df, P = 0.044). Smoking habits were not available for several subjects, and the patient with carcinoma of the colon (a non-smoker, see Table 1 ) was excluded from the allograft group for this comparison.
Results
a 0
a CONTROLS 2.2 2 1.2
5 CEA nq/rnl
FIGURE 1 . Frequency distribution of CEA levels in the groups studied. Mean levels and standard deviations (SD) are shown. The single high level in the renal allograft group is excluded from the mean and SD. Difference of allograft recipients from controls P < 0~001. Difference of allograft recipients from patients with glomerulo-nephritis P < 0.005. Difference of patients with glomerulonephritis from controls P < 0 . 0 1 .
The frequency distribution of CkA levels in the control group, in patients with glomerulonephritis, and in renal allograft recipients are shown in Figure 1. The normal range, established from the control group, was 0-4.6 ng/ml (mean 2.2kstandard deviation, 1 . 2 ng/ml); only two of 124 healthy control subjects had CEA levels above this range. The mean CEA level amodg immunosuppressed glomerulonephritis patients was 3 . 1 ng/ml and 1 1 (lOo,,) of these patients had levels above the normal range (difference from controls: xf = 6.6, P < 0.01). The mean CEA level among renal allograft recipients was 4 . 8 ng/ml, excluding one patient with an adenocarcinoma of the colon who had a very high level (50 ng/ml). Twenty-one (30",) of the renal allograft recipients had levels above the normal range as defined above. (Difference from control P < 0.001 ; difference from glomerulonephritis group P < 0.005.)
18
MYERS ET AL.
VOL.
7,
NO.
1
\ 0
SO?
(20 mg or more per day) 17 were within six months of transplantation. CEA levels tended to be higher in this group of patients than in patients on lower prednisolone dosage at more than six months after transplantation. This difference was more marked for the sub-group of patients who were ex-smokers than for patients who had never smoked or who were current smokers. Inspection of the data suggested that CEA level was related to time since transplantation, smoking habit and cancer (Fig. 3) more closely than to the dose of prednisolone ( r = -0.122, P > 0.10) or the number of rejection episodes ( r = 0.075, P > 0.10). CEA level was not related to pre-transplant dialysis time ( r = 0.150. P > 0.10), degree of HLA incompatibility of the allograft ( F = 0.722, P = 0.581), serum creatinine ( r = 0.064, P < 0.10) blood group ( F = 1.12, P = 0.350) or sex ( F = 0,931, P = 0,336). In the groups of patients studied we could not establish any significant relationship of CEA level to total doses of azathioprine, cyclophosphamide or prednisolone. Cancer was known or detected in three of 105 patients with glomerulonephritis and in nine of 70 allograft recipients (Table 1 ) but in two patients, one in each group, cancer was present before immunosuppressive therapy was
Renal Allografts Never smoked P a t snwkr x Current smoker o
201.
Cancrr
0
@ I " r
I
I
m
I
I
90
120
.
60
MONTHS POST TRANSPLANTATION
FIGURE 3 CEA levels in individual allograft recipients in relation to the time since transplantation and smoking habits
In both patient groups CEA levels were higher in current smokers than in either past smokers or in patients who had never smoked (Fig. 2). CEA levels for individual patients with renal transplants are shown in Figure 3 in relation to the time since transplantation and smoking habits. Eleven of 21 patients studied in the first six months after transplantation had elevated levels whereas only ten of 49 patients studied more than six months after transplantation had elevated levels. Of 18 transplanted patients on high doses of prednisolone
TABLE 1 Patients with cancer ~
Glomerulonephritis patients - --.__
.__._
I.A.* G.B. C.W.
~
~
~
Allograft recipients _ _ ~ ~ _ ~~
__ -
D.B. E.D. K.H.
33 40 37
R.M.* M.U. G.G.
40
B.H. B.L. J.M.
~
~~
~~~
CEA (ng,ml) Age Biopsy, diagnosis and site __ __ __ ~~- -~ -~ -~__ 37 SCCtnose 1.4 67 BCC: face 1.0 25 Adenocarcinoma- . thyroid 1.0
.
-
~~~~
51 39 33 33 58
~
-
-.
- -
-
Treated surgically before CEA -~ _ _ - - --__ Ex-SM*" Yes EX-SM Yes EX-SM Yes
~-
-
2.4 3.0 3-8 3.0
3-9 7.7 9.1 11.8
50.0
**Ex-SM = past smoker f t N S = never smoked $$SM = current smoker
-
-
-~
SCC lip SCC hand SCC face and ear SCC forehead SCC leg and face Carcinoma cervix - i n sitir Carcinoma cervix- invasi\e Carcinoma cervix-invasive BCC and adenocarcinonia -colon
"Cancers occurred before immunosuppression YX'C = squamous cell carcinoma ::l3( ( = basal cell carcinoma
~
Smoking category
NStt NS NS SM$$ EX-SM SM SM
SM NS
- .-
- ~-
Yes Yes Yes Yes Yes Untreated a t time of CEA Yes Untreated at time of CEA Untreated at time of CEA
FEBRUARY,
1977
CEA IN RENAL ALLOGRAFTS
started. CEA levels were elevated in four of the 12 cancer patients but a very high level occurred in only one patient (J.M.) with adenocarcinoma of the colon. Discussion
We found elevated CEA levels in 30", of renal allograft recipients and in lo", of patients with glomerulonephritis ; this could be due to renal disease per se or to the effect of immunosuppressive therapy and/or to the presence of donor kidney tissue. The lack of any relationship of CEA tc: the serum creatinine level makes it unlikely that renal insufficiency was responsible for elevated CEA levels. Other evidence suggests that CEA levels are elevated in inflammatory disease', particularly during the active disease state. Inflammation in the kidney could be a factor contributing to elevations of CEA in both groups of patients within this study. Although it is possible that immunosuppressive therapy might contribute to elevated CEA levels as evidenced by the association of high CEA levels with high prednisolone dosage in the transplant group of patients, it is difficult to distinguish the possible effects of high prednisolone dosage on CEA from the possible effects of disease activity and rejection. The raised CEA levels in current smokers are consistent with previous reports suggesting that smoking may be a cause of elevated CEA levels.5, l 3 On balance, we suggest that CEA levels are related more to disease activity and smoking habit than they are to immunosuppressive therapy. Non-malignant diseases such as cirrhosis, pancreatitis and emphysema are associated with elevated CEA levels'. l 2 : if present in an allograft recipient, such diseases would naturally reduce the significance of elevated levels. The study was begun with the knowledge that immunosuppressed patients have a timerelated increase in predisposition to cancer, presumably due to impaired immune surveillance, and with the premise that developing
19
cancer would be revealed by rising levels of CEA in the blood. This premise was not altogether borne out in that early after grafting there were raised levels of CEA which were not associated with cancer. Of the nine cancers occurring in renal allograft recipients in this study, five were skin cancers, and were not associated with raised CEA levels. The remaining four were visceral cancers (cervix three, colon one) and all were associated with elevated CEA levels. These constituted 40", of elevated levels occurring more than ten months after renal allograft. Hence raised CEA levels occurring late after a renal allograft should prompt a careful search for visceral cancer. CEA estimations could be included in the routine monitoring after transplantation. Acknowledgements
We are grateful to Professor R. Lovell, Dr. 1. R. Mackay, Dr. S. Whittingham and Dr. D. Christie [or their help and interest, and t o Sister Durman and Irene lraay for help in the collection of blood specimens.
References 1 2 3
4
5
''9
h.
7.
8
Y,
10. I I.
I?. 13.
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