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Targeted blood levels of cyclosporine for cardiac transplantation
J
THORAC CARDIOVASC SURG
88:952-957, 1984
Targeted blood levels of cyclosporine for cardiac transplantation Forty-nine patients bave undergone cardiac tramplantation since July, 1982, and bave been treated with maintenance cycIosporine and low~ prednisone, 15 to 20 mg. Cyclosporine dose bas been targeted to a whole-blood level of 1,000 ng/ml as measured by radioimmune assay. The actuarial survival rate in this group of patients bas been 79% at 12 months and 71 % at 21 months. Histologic rejection bas occurred at all blood levels of cyclosporine, as bas significant nephrotoxicity. The hepatic toxicity encountered bas been more a clinicalnuisance tban significant problem. The administereddose of cyclosporine required to reach a target of 1,000 ng/ml bas varied between 2 and 30 mg/kg/day. The average perioperative and late serum creatinine levels were 1.2 and 1.49 mg/ell and occurred with cyclosporine levels of 1,078 and 1,068 ng/ml, respectively. Late CYClosporine toxicity bas persisted despite reduction in the dose of cyclosporine below the targeted 1,000 ng/ml. Some method of blood level monitoring is necessary in patients receiving cyclosporine immune suppression to assure adequacy of the administered dose. The 1,000 ng/ml target bas provided adequate immune suppression. Significant nephrotoxicity bas not correlated with the blood level measured.
Bartley P. Griffith, M.D. (by invitation), Robert L. Hardesty, M.D. (by invitation), Alfredo Trento, M.D. (by invitation), Ann Lee, M.S.N. (by invitation), and Henry T. Bahnson, M.D., Pittsburgh. Pa.
Major cardiac transplantation centers are reporting superior results with the use of cyclosporine for immune suppression.I. 2 One and 2 year survival rates approaching 80% have been possible. These results are better than the 1 year survival rates of 50% to 66% obtained in patients treated with conventional immune suppression with azathioprine.' The clinical use of cyclosporine has been complicated in an attempt to balance its therapeutic immunosuppressive threshold against its significant renal and hepatic toxicity.vv' A whole-blood level of cyclosporine has been sought which would ensure maximal immune suppressionand minimal toxicity.Previous clinical data accrued in our institution for heart and heart-lung transplant recipients suggested that a wholeblood trough level of cyclosporine of 1,000 ng/ml was comparable to the plasma trough level of 200 ng/rnl suggested by Kahan" to be an immunosuppressive level above which renal and hepatic toxicity would be likelyto From the University of Pittsburgh School of Medicine, Department of Surgery, 1084 Scaife Hall, Pittsburgh, Pa. Read at the Sixty-fourth Annual Meeting of The American Association for Thoracic Surgery, New York, N. Y, May 7-9, 1984. Address for reprints: Bartley P. Griffith, M.D., Department of Surgery, University of Pittsburgh, 1084 Scaife Hall, Pittsburgh, Pa. 15261.
952
occur. Most cyclosporine is distributed outside the plasma; thus, whole-blood levels of the drug rather than plasma levels have been measured, as the latter include excess drug not bound to lymphocytes and erythrocytes.' Methods Since June, 1982, 57 cardiac transplant recipients have received cyclosporine, low-maintenance dose prednisone (0.2 mg/kg/day), and rabbit antithymocyte globulin immune suppression. The third drug was not used prophylactically but rather as a rescue from severe or chronic moderate histologic rejection. A dose of 200 mg of prednisone, or its equivalent in methylprednisolone, was given on the first postoperatively day and was tapered to 20 mg within 10 days. Mild and acute moderate rejection was managed with intravenous methylprednisolone, usually 1 gm daily for 3 days. Cyclosporine(10 to 17.5 mgjkg) was given orally 1 to 4 hours preoperatively and continued orally, or by nasagastric tube, every 12 hours postoperatively. As a result of convenience, cyclosporine was given usually every 12 hours at a dose of 5 mgjkg without a determination of the blood level for the initial two postoperative doses. The dose of cyclosporine was then adjusted three to five times weekly by targeting it to a whole-blood level of
Volume 88 Number 6 December, 1984
1,000 ng/rnl as determined by radioimmune assay (Sandoz Pharmaceuticals, E. Hannover, N. J.). In the event of rejection, the targeted level for cyclosporine was not changed, but a level between 1,000 and 1,500 ng/rnl was accepted unless renal or hepatic toxicity occurred. Elevations in serum creatinine or bilirubin were treated in the absence of rejection by gradually reducing the dose to obtain blood levels between 500 and 1,000 ng/ml. Cyclosporine was continued even if acute anuria occurred, but doses were adjusted to achieve levels less than 1,000 ng/ml,
Cyclosporine
30
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The radioimmune assay for cyclosporine generally gave consistent results, but there was considerable variability in the dose of cyclosporine required to obtain the target blood level (range 2 to 30 mg/kg/day) (Fig. 1, A). The average dose of 8 rug/kg/day resulted in a blood level of 1,089 ng/ml in the first 6 weeks postoperatively. Although the same average dose (7.5 mg/kg/day) was effective after 6 weeks, the trend at 6 months was a lower dose to achieve the same level (Fig. 1, B). Between July, 1982, and March, 1984, 49 patients underwent cardiac transplantation with cyclosporine targeted to the 1,000 ng/ml blood level. The cumulative survival rate at 12 and 21 months was 79% and 71%. There were three deaths related to rejection. One patient with sarcoidosis died of hyperacute rejection of two hearts transplanted within 20 hours. Trypan blue and ethidium bromide crossmatches were negative, but an endothelial antibody was detected retrospectively. Another patient died of precipitous rejection 5 days postoperatively, and the third died of rejection and mediastinal infection 4 months postoperatively. Histologic rejection was noted at a wide range of cyclosporine levels.The average cyclosporine level obtained prior to a recipient's first episode of moderate rejection (3+) varied between 600 and 1,700 ng/ml (Fig. 2, A). The first episode of significant rejection was chosen to evaluate the effects of blood-level targeting, as subsequent biopsy results were modified by augmented immune suppression. The difference in the degree of rejection noted between levels grouped 501 to 1,000, 1,001 to 1,500, and greater than 1,500 ng/ml was insignificant (Fig. 2, B). Less rejection was found in those biopsy specimens (26) obtained when blood levels of cyclosporine were less than 500 ng/ml, However, this was not unanticipated, as only those recipients without antecedent rejection, but with significant toxicity, were dosed to obtain these low levels. Cyclosporine nephrotoxicity presented with increasing blood urea nitrogen and creatinine levels. Nephro-
_
8.07 ± 3.1 1189 ± 421
7.53 ± 4.1 1096 ± 508
•
.. ........... . .._- .... . .. . ... ... .... ..
10
Results
>6WKS
~61fKS
Mean CyA Dose Mean CyA Level
953
900
•
.'"
.
1700
2500
WHOLE BLOOD CyA LEVEL ( ng/ml RIA)
12
I I I I I II j
I
I
Fig. 1. A. Relationship between oral cyclosporine (mgjkg) and whole-blood cyclosporine levels (ngjml) by radioimmune assay (RIA). B. The change in oral cyclosporine (mgjkg) with time after transplantation. The bars represent standard error of the mean.
toxicity did not correlate with the whole-blood levels of cyclosporine; however, the dose of cyclosporine was adjusted so that patients would not be repeatedly exposed to excessively high levels (Fig. 3, A). The average perioperative and late creatinine levels were 1.2 and 1.49 mg/dl and occurred with cyclosporine levels of 1,178 and 1,068 ng/rnl, respectively. The most significant rise in serum creatinine to an average of 1.8 mg/dl was noted 4 months postoperatively (Fig. 3, B). This degree of late toxicity has persisted despite reduction of the dose of cyclosporine below 1,000 ng/rnl. Beyond 6 months postoperatively, four of 16 recipients had creatinine values above 2 mg/dl, In this subgroup the mean creatinine level was 3.1 mg/dl and the cyclosporine level, 718 ng/ml. Hepatic toxicity, determined by an elevation of the total bilirubin value, could not be related to the wholeblood cyclosporine level (Fig. 4, A). Again, the intent to target the whole-blood levels at 1,000 ng/ml determined
The Journal of
954
Griffith et al.
Thoracic and Cardiovascular Surgery
1800
.
..
AVIlIlAGE CyA
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124
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Fig. 2. A, The average cyclosporine level compiled prior to moderate (3+) rejection associated with mild cytolysis. D, Average grade of histologic rejection as related to whole-blood cyclosporine levels (ng/rnl) by radioimrnune assay (RIA). The bars represent standard error of the mean.
that no patient was exposed to levels substantially above the target. There was a decline in the hepatic toxicity with time as the mean bilirubin level fell from 2.26 mg/dl at 6 weeks to 1.17 mg/dl late postoperatively (Fig. 4, B). Hepatic toxicity was more of a nuisance than a serious toxicity, and early elevations were tolerated without reduction of the cyclosporine dose. Four weeks postoperatively, 14 of 40 patients had an elevated total bilirubin level ranging from 2 to 8 tug]dl, and the corresponding cyclosporine levels ranged from 542 to 1,700 ng/ml. Statistical analysis of the hepatic and concomitant renal toxicity indicated no correlation. Discussion The principal message is the lack of correlation between the dose of cyclosporine and the whole-blood level. Monitoring of the blood level is necessary to ensure that the administered dose provides a significant level of circulating cyclosporine. Cyclosporine predominates outside the blood volume, and the in-blood distribution is concentration dependent. Approximately 32% to 47% of
1.25
II 1
j
Fig. 3. Renal toxicity. A. Serum creatinine (CR. mg/dl) related to whole-bloodcyclosporine levels (ng/rnl) by radioimmune assay (RIA). D. Mean change in serum creatinine (mg/dl) with time after cardiac transplantation. The bars represent standard error of the mean.
the drug is found in plasma; 4% to 9% in lymphocytes; 5% to 12% in granulocytes; and 41% to 50% in erythrocytes.' At therapeutic doses, blood levels of cyclosporine may be two to ten times higher than plasma levels. In this study, whole-blood levelshave been monitored in preference to plasma levels since the latter include the excess drug that is not bound to lymphocytes and erythrocytes. It has been noted that an individual recipient's requirements for the drug vary after transplantation and that frequent incremental and decremental adjustments in the oral dose are necessary to achieve the target level. The variability in the dose represents a variation in gastrointestinal absorption and hepatic metabolism. After 3 months the levels have been less variable, and by 6 months the average dose of cyclosporine was 7.3 mg/kg to achieve an average level of 1,033 ng/ml, In an effort to test the adequacy of the 1,000 ng/ml
Volume 88 Number 6 December. 1984
whole-blood level of cyclosporine, we explored its relative effect upon suppression of rejection and renal plus hepatic toxicity. The value of this test is weakened to a certain extent by the initial presumption that a blood level of 1,000 ng/ml would provide a therapeutic immunosuppressive level without exposing recipients to excessive dose-related toxic effects. Using simultaneous samples, we found the whole-blood cyclosporine target of 1,000 ng/ml to be similar to a plasma level of 200 ng/rnl, as measured by Kahan. It has been suggested that plasma trough levels of 200 and below might limit drug toxicity," It was not deemed appropriate to experiment initially with lower target levels that might expose the heart transplant recipient to the risk of inadequate immune suppression and morbid rejection. However, some comment may be made regarding the adequacy of the 1,000 ng/ml target, because often considerably lower and higher levels were measured. Again, individual variation to the oral dose of cyclosporine was responsible for most of the off-target values, although in some instances levels were purposely lowered because of cyclosporine toxicity at the target level. Rejection occurred at all levels, and the first episode of serious histologic rejection (3+) was associated with average levels between 600 and 1,800 ng/ml. Less rejection was seen for the few patients with low levels (less than 500 ng/ml), but these patients had not experienced previous rejection, and their dose of cyclosporine had been lowered because of toxicity. When rejection occurred, the prejudice of the proposed 1,000 ng/ml target prevailed, and the dose of cyclosporine was consistently altered to assure an adequate blood level. As the 1 year actuarial survival rate has been 79% and because there have been only three rejection-related deaths, we considered the 1,000 ng/ml level to be therapeutic. Renal and hepatic toxicity occurred at all blood levels of cyclosporine, and those toxicities were not interdependent. Hepatic toxicity was a clinical nuisance and not a serious problem. Mild toxicity appeared to be more time-dependent than dose-related. Consistently, renal toxicity occurred and was managed by reducing the dose of cyclosporine only when the creatinine value rose above 2 tng] dl. Even though the dose was reduced below the target, nephrotoxicity rarely resolved in patients with creatinine values in excess of 2 mg/dl; an increase in the creatinine level above 3 mg/dl occurred in only one patient. An inexplicable deterioration of this patient's graft occurred 11 months postoperatively, and associated with that deterioration was a rapid rise in the creatinine value from a stable level of 2.5 to 9 mg/dl, This patient has recently undergone successful retrans-
Cyclosporine 9 5 5
,,;6 lfKS >6 WKS
12
Mean Bilirubin
2.26
1.17
Mean CyA Level
1177
1072
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Fig. 4. Hepatic toxicity. A, Total bilirubin (mg/dl) compared to whole-blood cyclosporine level (ng/ml) by radioimmune assay (RIA). B, The average total bilirubin (mg/dl) as compared to time after cardiac transplantation. The bars represent one standard error of the mean.
plantation of the heart with a concomitant kidney transplant. Our experience of persistent nephrotoxicity at varied levels of cyclosporine is consistent with reported series of renal allografts treated with cyclosporine and monitored by plasma or whole-blood levels.r" It would appear that some recipients will not tolerate cyclosporine and will require a switch to azathioprine immune suppression. 10 Monitoring of the blood level of cyclosporine is essential in the presence of significant acute or chronic renal failure. Variability in the absorption and metabolism also necessitates monitoring to assure an adequate level for immunesuppression. Its measurement is valuable in ascertaining whether or not acute perioperative renal failure is due to cyclosporine toxicity. Renal failure occurs postoperatively without clinical circumstances suggesting the likelihood of acute tubular necrosis. It has been treated successfully by reduction in the cyclospo-
The Journal of
9 5 6 Griffith et al.
rine dose if the blood level is greater than 1,000 ng/ml. Occasionally a dose or two of cyclosporine has been withheld in patients with refractory renal failure, and this has generally prompted a diuresis without increased risk of rejection. In conclusion, we cannot be sure whether lower levels of cyclosporine would produce a similar degree of immune suppression but with less toxicity of the drug.
2
3
4
5
6 7
8
9
10
REFERENCES Griffith BP, Hardesty RL, Bahnson HT: Powerful but limited immune suppression for cardiac transplantation with cyclosporine A and low-dose steroid. J THoRAc CARDIOVASC SURG 87:35-42, 1984 Jamieson SW, Oyer PE, Bieber CP, Hunt SA, Billingham M, Miller J, Gamberg P, Stinson EB, Shumway NE: Cardiac transplantation at Stanford. Heart Transplant 2:243-244, 1983 Baumgartner WA, Reitz BA, Oyer PE, Stinson EB, Shumway NF: Cardiac homotransplantation. Curr Probl Surg 16:6-61, 1979 Egel J, Greenberg A, Thompson ME, Hardesty RL, Griffith BP, Bahnson HT, Bernstein RL, Psuchett 18: Renal failure in heart transplant patients receiving cyclosporine. Transplant Proc 15:2706-2707, 1983 Schade RR, Guglielmi A, Van Thiel DH, Thompson ME, Warty V, Griffith B, Sanghvi A, Bahnson HT, Hardesty RL: Cholestasis in heart transplant recipients treated with cyclosporine. Transplant Proc 15:2757-2760, 1983 Kahan BD: Cyclosporin A. A selective anti-T cell agent. Clin Haematol 2:743-761, 1982 Beveridge T: Pharmacokinetics and metabolism of cyclosporin A, Cyclosporin A: Proceedings of an International Conference on Cyclosporin A, DJG White, ed., Amsterdam, 1982, Elsevier Biomedical Press, pp 35-44 Duggin GG, Willis N, Baxter C, Hall B, Horvath J, Tiller 0: Nephrotoxicity of cyclosporine and plasma and RBC concentrations, First International Congress on Cyclosporine, Houston, Texas, 1983, p 103 Castro LA, Hillebrand G, Hiner W, Land W: Cyclosporine in patients with oligoanuria after kidney transplantation, First International Congress on Cyclosporine. Houston, Texas, 1983, p 104 Flechner SM, Van Buren CT, Kahan BD: Effect of conversion from cyclosporine to azathioprine (Az) immunosuppression on renal allograft function, First International Congress on Cyclosporine. Houston, Texas, 1983, p 105
Discussion PROFESSOR ROLAND HETZER Hannover, Federal Republic of Germany
We fully agree with this important and timely presentation by Dr. Griffith on the basis of our experiences with 10 patients who have undergone orthotopic heart transplantation at our institution since July, 1983. The patients were treated with a
Thoracic and Cardiovascular Surgery
cyclosporine-prednisolone regimen with pulsed methylprednisolone doses for rejection treatment and antithymocyte globulin for the second rejection treatment course. Whole-blood trough levels of cyclosporine were monitored daily immediately after the operation. After a preoperative oral dose of cyclosporine, 14 to 18 mg/kg, cyclosporine levels inadvertently rose to more than 1,000 ng/ml during the first 4 postoperative days. Transient renal dysfunction was observed in all patients during the first postoperative week, with complete anuria. in two patients who required two and five courses of hemodialysis, These two patients, in contrast to the others, however, had additional conditions which limited renal function: chronic thrombotic occlusion of the suprarenal inferior vena cava in one and cardiac arrest with resuscitation in the other, The renal dysfunction was eventually controlled in all patinets when cyclosporine levels fell below 800 ng/mI. We assumed that renal failure results from the addition of cyclosporine nephrotoxicity to preexisting renal damage when the cyclosporine level exceeds 1,000 ng/rnl, As a consequence, the nephrotoxic effects of cyclosporine may become manifest in diseased kidneys at blood levels that are tolerated by kidneys with normal function. Significant rejection of myocytolysis was independent of cyclosporine levels. However, these were never allowed to drop below 300 ng/ml, In agreement with the concept followed by our colleagues of the Hannover renal and liver transplant program, blood levels in our heart transplant patients are not kept at between 600 and 800 ng/mI during the first six postoperative weeks and between 300 and 600 ng/rnl in the later course. This latter level was obtained by daily doses of 3 to 6 ng/kg body weight. Daily monitoring of cyclosporine levels appears to be mandatory in the first postoperative period, and in particular in patients with other factors predisposing to renal failure. I would like to ask Dr. Griffith to comment on the lowest cyclosporine level that he considers tolerable in his heart transplant patients and on the conditions under when he would change from cyclosporine to another immunosuppressive regimen. DR. CHRISTIAN CABROL Paris, France
Our experience with 100 heart transplants performed over on 11 year period confirms the dramatic change in the mid-term results wrought by the use of cyclosporin. In our initial series, before December, 1980, we used the conventional treatment. Despite some long-term survivors, one of whom is living and well 10 years after operation, the results were rather disappointing. They do not compare with the results obtained in our last 50 patients operated upon after December, 1980, and treated with cyclosporine. In these patients the actuarial survival rate is 83% at 2 and 3 years. However, our experience also confirms that cyclosporine has important drawbacks-systemic hypertension and, most of all, renal toxicity being responsible for two early deaths in our series. It was necessary to find a compromise between the conventional and the cyclosporine regimens. Our present
Volume 88 Number 6 December, 1984
protocol is somewhat different from that of the Pittsburgh group. Immediately before and for 2 or 3 days after the operation, we use the conventional drugs-high doses of corticosteroids, azathioprine, and antilymphocyte globulin. Then, when the hemodynamic situation of those previously very sick patients improves and when hepatic and renal functions become better, azathioprine and antilymphocyte globulin are discontinued, corticosteroids are reduced, and cyclosporine is started and progressively increased until an adequate serum level is obtained. This level is not changed during the rejection episodes, which are managed again by high doses of corticosteroids and, if necessary, by antilymphocyte globulin. Because of the variability in absorption and metabolism of cyclosporine, its serum levels must be checked frequently, especially during the first weeks, along with regular control of rejection, infection, and hepatic and renal toxicity. Careful adjustment of the treatment and meticulous control of the patient still remain the major factors of long-term success in cardiac transplantation. I have two questions for the authors. Why did you use whole blood levels of cyclosporine rather than the serum level, as recommended by the furnishing company? Also, did you use a correction for the variation of the hematocrit value? DR. KEITH REEMTSMA New York. N. Y.
We can certainly confirm the effectiveness of cyclosporine in the early management of cardiac transplant recipients. For example, in our program at Columbia-Presbyterian Medical Center in New York, we have done cardiac transplants in the first 4 months of 1984 on nine patients, with nine survivors and minimal problems with rejection or infection. I believe we may use somewhat lower doses of cyclosporine, and we treat rejection with a pulse dose of steroids but with rapid reduction of steroids to maintenance levels. We would emphasize the importance of frequent biopsies, as patients receiving cyclosporine do not show the signs seen in patients receiving azathioprine. I would close on a cautionary note. Although the early results with cyclosporine are promising, the long-term consequences are unknown. Most patients show impaired renal
Cyclosporine
9 57
function, many have arterial hypertension, and a few are developing severe coronary artery lesions as early as the second year after transplantation. For these reasons I believe we should remain cautious as we try to understand these late problems following cardiac transplantation. DR. GRIFFITH (Closing) I would like to thank the discussants for their kind words. Dr. Hetzer, we do not have a feel for the lowest therapeutic level. It is difficult to probe with cardiac recipients, as a mistake would be a morbid one. We have used much lower doses of cyclosporine, around I to 2 mg/kg/day, in four patients who have developed Iymphoproliferative disorders. These doses have given whole-blood levels of less than 500 ng/rnl, These patients have not shown rejection. What would make me switch from cyclosporine? It is very difficult to improve on the survival rates that cyclosporine has produced. The best conventional survival rates with azathioprine and prednisone alone have been 66% I year postoperatively. So I think that we have some room to experiment with cyclosporine. However, I believe that serious chronic renal toxicity will cause us to make some adjustments, as Dr. Cabrol has pioneered, i.e., a switch to azathioprine or some combination of lesser amounts of both drugs. With respect to Professor Cabrol's questions, we use whole blood because we believe there is less of a temperature-related change in the samples. We have not corrected specifically for hematocrit, and yet we do keep close watch on the hematocrit values. Most patients have frequent phlebotomies and require some transfusion during their first 6 weeks, and most hematocrit values have been between 30% and 35%. Dr. Reemtsma, we agree that there should be a red flare of caution with respect to cardiac transplantation. We are concerned about a general resumption of what has been shown to be a therapeutic operation. It is not without its great difficulties, and we are currently just probing the way with new and powerful suppressants. Dr. Reemtsma, I believe you are measuring serum troughs as opposed to whole-blood troughs, and the conversion factor is somewhere between 2 and 3 to 1. I believe that our levels are commensurate.
THORAC CARDIOVASC SURG
88:952-957, 1984
Targeted blood levels of cyclosporine for cardiac transplantation Forty-nine patients bave undergone cardiac tramplantation since July, 1982, and bave been treated with maintenance cycIosporine and low~ prednisone, 15 to 20 mg. Cyclosporine dose bas been targeted to a whole-blood level of 1,000 ng/ml as measured by radioimmune assay. The actuarial survival rate in this group of patients bas been 79% at 12 months and 71 % at 21 months. Histologic rejection bas occurred at all blood levels of cyclosporine, as bas significant nephrotoxicity. The hepatic toxicity encountered bas been more a clinicalnuisance tban significant problem. The administereddose of cyclosporine required to reach a target of 1,000 ng/ml bas varied between 2 and 30 mg/kg/day. The average perioperative and late serum creatinine levels were 1.2 and 1.49 mg/ell and occurred with cyclosporine levels of 1,078 and 1,068 ng/ml, respectively. Late CYClosporine toxicity bas persisted despite reduction in the dose of cyclosporine below the targeted 1,000 ng/ml. Some method of blood level monitoring is necessary in patients receiving cyclosporine immune suppression to assure adequacy of the administered dose. The 1,000 ng/ml target bas provided adequate immune suppression. Significant nephrotoxicity bas not correlated with the blood level measured.
Bartley P. Griffith, M.D. (by invitation), Robert L. Hardesty, M.D. (by invitation), Alfredo Trento, M.D. (by invitation), Ann Lee, M.S.N. (by invitation), and Henry T. Bahnson, M.D., Pittsburgh. Pa.
Major cardiac transplantation centers are reporting superior results with the use of cyclosporine for immune suppression.I. 2 One and 2 year survival rates approaching 80% have been possible. These results are better than the 1 year survival rates of 50% to 66% obtained in patients treated with conventional immune suppression with azathioprine.' The clinical use of cyclosporine has been complicated in an attempt to balance its therapeutic immunosuppressive threshold against its significant renal and hepatic toxicity.vv' A whole-blood level of cyclosporine has been sought which would ensure maximal immune suppressionand minimal toxicity.Previous clinical data accrued in our institution for heart and heart-lung transplant recipients suggested that a wholeblood trough level of cyclosporine of 1,000 ng/ml was comparable to the plasma trough level of 200 ng/rnl suggested by Kahan" to be an immunosuppressive level above which renal and hepatic toxicity would be likelyto From the University of Pittsburgh School of Medicine, Department of Surgery, 1084 Scaife Hall, Pittsburgh, Pa. Read at the Sixty-fourth Annual Meeting of The American Association for Thoracic Surgery, New York, N. Y, May 7-9, 1984. Address for reprints: Bartley P. Griffith, M.D., Department of Surgery, University of Pittsburgh, 1084 Scaife Hall, Pittsburgh, Pa. 15261.
952
occur. Most cyclosporine is distributed outside the plasma; thus, whole-blood levels of the drug rather than plasma levels have been measured, as the latter include excess drug not bound to lymphocytes and erythrocytes.' Methods Since June, 1982, 57 cardiac transplant recipients have received cyclosporine, low-maintenance dose prednisone (0.2 mg/kg/day), and rabbit antithymocyte globulin immune suppression. The third drug was not used prophylactically but rather as a rescue from severe or chronic moderate histologic rejection. A dose of 200 mg of prednisone, or its equivalent in methylprednisolone, was given on the first postoperatively day and was tapered to 20 mg within 10 days. Mild and acute moderate rejection was managed with intravenous methylprednisolone, usually 1 gm daily for 3 days. Cyclosporine(10 to 17.5 mgjkg) was given orally 1 to 4 hours preoperatively and continued orally, or by nasagastric tube, every 12 hours postoperatively. As a result of convenience, cyclosporine was given usually every 12 hours at a dose of 5 mgjkg without a determination of the blood level for the initial two postoperative doses. The dose of cyclosporine was then adjusted three to five times weekly by targeting it to a whole-blood level of
Volume 88 Number 6 December, 1984
1,000 ng/rnl as determined by radioimmune assay (Sandoz Pharmaceuticals, E. Hannover, N. J.). In the event of rejection, the targeted level for cyclosporine was not changed, but a level between 1,000 and 1,500 ng/rnl was accepted unless renal or hepatic toxicity occurred. Elevations in serum creatinine or bilirubin were treated in the absence of rejection by gradually reducing the dose to obtain blood levels between 500 and 1,000 ng/ml. Cyclosporine was continued even if acute anuria occurred, but doses were adjusted to achieve levels less than 1,000 ng/ml,
Cyclosporine
30
• •••• • • • • • •
20
~5
s
-~
_.--~.-
~ ·~fI":"·
~.
","
100
The radioimmune assay for cyclosporine generally gave consistent results, but there was considerable variability in the dose of cyclosporine required to obtain the target blood level (range 2 to 30 mg/kg/day) (Fig. 1, A). The average dose of 8 rug/kg/day resulted in a blood level of 1,089 ng/ml in the first 6 weeks postoperatively. Although the same average dose (7.5 mg/kg/day) was effective after 6 weeks, the trend at 6 months was a lower dose to achieve the same level (Fig. 1, B). Between July, 1982, and March, 1984, 49 patients underwent cardiac transplantation with cyclosporine targeted to the 1,000 ng/ml blood level. The cumulative survival rate at 12 and 21 months was 79% and 71%. There were three deaths related to rejection. One patient with sarcoidosis died of hyperacute rejection of two hearts transplanted within 20 hours. Trypan blue and ethidium bromide crossmatches were negative, but an endothelial antibody was detected retrospectively. Another patient died of precipitous rejection 5 days postoperatively, and the third died of rejection and mediastinal infection 4 months postoperatively. Histologic rejection was noted at a wide range of cyclosporine levels.The average cyclosporine level obtained prior to a recipient's first episode of moderate rejection (3+) varied between 600 and 1,700 ng/ml (Fig. 2, A). The first episode of significant rejection was chosen to evaluate the effects of blood-level targeting, as subsequent biopsy results were modified by augmented immune suppression. The difference in the degree of rejection noted between levels grouped 501 to 1,000, 1,001 to 1,500, and greater than 1,500 ng/ml was insignificant (Fig. 2, B). Less rejection was found in those biopsy specimens (26) obtained when blood levels of cyclosporine were less than 500 ng/ml, However, this was not unanticipated, as only those recipients without antecedent rejection, but with significant toxicity, were dosed to obtain these low levels. Cyclosporine nephrotoxicity presented with increasing blood urea nitrogen and creatinine levels. Nephro-
_
8.07 ± 3.1 1189 ± 421
7.53 ± 4.1 1096 ± 508
•
.. ........... . .._- .... . .. . ... ... .... ..
10
Results
>6WKS
~61fKS
Mean CyA Dose Mean CyA Level
953
900
•
.'"
.
1700
2500
WHOLE BLOOD CyA LEVEL ( ng/ml RIA)
12
I I I I I II j
I
I
Fig. 1. A. Relationship between oral cyclosporine (mgjkg) and whole-blood cyclosporine levels (ngjml) by radioimmune assay (RIA). B. The change in oral cyclosporine (mgjkg) with time after transplantation. The bars represent standard error of the mean.
toxicity did not correlate with the whole-blood levels of cyclosporine; however, the dose of cyclosporine was adjusted so that patients would not be repeatedly exposed to excessively high levels (Fig. 3, A). The average perioperative and late creatinine levels were 1.2 and 1.49 mg/dl and occurred with cyclosporine levels of 1,178 and 1,068 ng/rnl, respectively. The most significant rise in serum creatinine to an average of 1.8 mg/dl was noted 4 months postoperatively (Fig. 3, B). This degree of late toxicity has persisted despite reduction of the dose of cyclosporine below 1,000 ng/rnl. Beyond 6 months postoperatively, four of 16 recipients had creatinine values above 2 mg/dl, In this subgroup the mean creatinine level was 3.1 mg/dl and the cyclosporine level, 718 ng/ml. Hepatic toxicity, determined by an elevation of the total bilirubin value, could not be related to the wholeblood cyclosporine level (Fig. 4, A). Again, the intent to target the whole-blood levels at 1,000 ng/ml determined
The Journal of
954
Griffith et al.
Thoracic and Cardiovascular Surgery
1800
.
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Fig. 2. A, The average cyclosporine level compiled prior to moderate (3+) rejection associated with mild cytolysis. D, Average grade of histologic rejection as related to whole-blood cyclosporine levels (ng/rnl) by radioimrnune assay (RIA). The bars represent standard error of the mean.
that no patient was exposed to levels substantially above the target. There was a decline in the hepatic toxicity with time as the mean bilirubin level fell from 2.26 mg/dl at 6 weeks to 1.17 mg/dl late postoperatively (Fig. 4, B). Hepatic toxicity was more of a nuisance than a serious toxicity, and early elevations were tolerated without reduction of the cyclosporine dose. Four weeks postoperatively, 14 of 40 patients had an elevated total bilirubin level ranging from 2 to 8 tug]dl, and the corresponding cyclosporine levels ranged from 542 to 1,700 ng/ml. Statistical analysis of the hepatic and concomitant renal toxicity indicated no correlation. Discussion The principal message is the lack of correlation between the dose of cyclosporine and the whole-blood level. Monitoring of the blood level is necessary to ensure that the administered dose provides a significant level of circulating cyclosporine. Cyclosporine predominates outside the blood volume, and the in-blood distribution is concentration dependent. Approximately 32% to 47% of
1.25
II 1
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Fig. 3. Renal toxicity. A. Serum creatinine (CR. mg/dl) related to whole-bloodcyclosporine levels (ng/rnl) by radioimmune assay (RIA). D. Mean change in serum creatinine (mg/dl) with time after cardiac transplantation. The bars represent standard error of the mean.
the drug is found in plasma; 4% to 9% in lymphocytes; 5% to 12% in granulocytes; and 41% to 50% in erythrocytes.' At therapeutic doses, blood levels of cyclosporine may be two to ten times higher than plasma levels. In this study, whole-blood levelshave been monitored in preference to plasma levels since the latter include the excess drug that is not bound to lymphocytes and erythrocytes. It has been noted that an individual recipient's requirements for the drug vary after transplantation and that frequent incremental and decremental adjustments in the oral dose are necessary to achieve the target level. The variability in the dose represents a variation in gastrointestinal absorption and hepatic metabolism. After 3 months the levels have been less variable, and by 6 months the average dose of cyclosporine was 7.3 mg/kg to achieve an average level of 1,033 ng/ml, In an effort to test the adequacy of the 1,000 ng/ml
Volume 88 Number 6 December. 1984
whole-blood level of cyclosporine, we explored its relative effect upon suppression of rejection and renal plus hepatic toxicity. The value of this test is weakened to a certain extent by the initial presumption that a blood level of 1,000 ng/ml would provide a therapeutic immunosuppressive level without exposing recipients to excessive dose-related toxic effects. Using simultaneous samples, we found the whole-blood cyclosporine target of 1,000 ng/ml to be similar to a plasma level of 200 ng/rnl, as measured by Kahan. It has been suggested that plasma trough levels of 200 and below might limit drug toxicity," It was not deemed appropriate to experiment initially with lower target levels that might expose the heart transplant recipient to the risk of inadequate immune suppression and morbid rejection. However, some comment may be made regarding the adequacy of the 1,000 ng/ml target, because often considerably lower and higher levels were measured. Again, individual variation to the oral dose of cyclosporine was responsible for most of the off-target values, although in some instances levels were purposely lowered because of cyclosporine toxicity at the target level. Rejection occurred at all levels, and the first episode of serious histologic rejection (3+) was associated with average levels between 600 and 1,800 ng/ml. Less rejection was seen for the few patients with low levels (less than 500 ng/ml), but these patients had not experienced previous rejection, and their dose of cyclosporine had been lowered because of toxicity. When rejection occurred, the prejudice of the proposed 1,000 ng/ml target prevailed, and the dose of cyclosporine was consistently altered to assure an adequate blood level. As the 1 year actuarial survival rate has been 79% and because there have been only three rejection-related deaths, we considered the 1,000 ng/ml level to be therapeutic. Renal and hepatic toxicity occurred at all blood levels of cyclosporine, and those toxicities were not interdependent. Hepatic toxicity was a clinical nuisance and not a serious problem. Mild toxicity appeared to be more time-dependent than dose-related. Consistently, renal toxicity occurred and was managed by reducing the dose of cyclosporine only when the creatinine value rose above 2 tng] dl. Even though the dose was reduced below the target, nephrotoxicity rarely resolved in patients with creatinine values in excess of 2 mg/dl; an increase in the creatinine level above 3 mg/dl occurred in only one patient. An inexplicable deterioration of this patient's graft occurred 11 months postoperatively, and associated with that deterioration was a rapid rise in the creatinine value from a stable level of 2.5 to 9 mg/dl, This patient has recently undergone successful retrans-
Cyclosporine 9 5 5
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plantation of the heart with a concomitant kidney transplant. Our experience of persistent nephrotoxicity at varied levels of cyclosporine is consistent with reported series of renal allografts treated with cyclosporine and monitored by plasma or whole-blood levels.r" It would appear that some recipients will not tolerate cyclosporine and will require a switch to azathioprine immune suppression. 10 Monitoring of the blood level of cyclosporine is essential in the presence of significant acute or chronic renal failure. Variability in the absorption and metabolism also necessitates monitoring to assure an adequate level for immunesuppression. Its measurement is valuable in ascertaining whether or not acute perioperative renal failure is due to cyclosporine toxicity. Renal failure occurs postoperatively without clinical circumstances suggesting the likelihood of acute tubular necrosis. It has been treated successfully by reduction in the cyclospo-
The Journal of
9 5 6 Griffith et al.
rine dose if the blood level is greater than 1,000 ng/ml. Occasionally a dose or two of cyclosporine has been withheld in patients with refractory renal failure, and this has generally prompted a diuresis without increased risk of rejection. In conclusion, we cannot be sure whether lower levels of cyclosporine would produce a similar degree of immune suppression but with less toxicity of the drug.
2
3
4
5
6 7
8
9
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REFERENCES Griffith BP, Hardesty RL, Bahnson HT: Powerful but limited immune suppression for cardiac transplantation with cyclosporine A and low-dose steroid. J THoRAc CARDIOVASC SURG 87:35-42, 1984 Jamieson SW, Oyer PE, Bieber CP, Hunt SA, Billingham M, Miller J, Gamberg P, Stinson EB, Shumway NE: Cardiac transplantation at Stanford. Heart Transplant 2:243-244, 1983 Baumgartner WA, Reitz BA, Oyer PE, Stinson EB, Shumway NF: Cardiac homotransplantation. Curr Probl Surg 16:6-61, 1979 Egel J, Greenberg A, Thompson ME, Hardesty RL, Griffith BP, Bahnson HT, Bernstein RL, Psuchett 18: Renal failure in heart transplant patients receiving cyclosporine. Transplant Proc 15:2706-2707, 1983 Schade RR, Guglielmi A, Van Thiel DH, Thompson ME, Warty V, Griffith B, Sanghvi A, Bahnson HT, Hardesty RL: Cholestasis in heart transplant recipients treated with cyclosporine. Transplant Proc 15:2757-2760, 1983 Kahan BD: Cyclosporin A. A selective anti-T cell agent. Clin Haematol 2:743-761, 1982 Beveridge T: Pharmacokinetics and metabolism of cyclosporin A, Cyclosporin A: Proceedings of an International Conference on Cyclosporin A, DJG White, ed., Amsterdam, 1982, Elsevier Biomedical Press, pp 35-44 Duggin GG, Willis N, Baxter C, Hall B, Horvath J, Tiller 0: Nephrotoxicity of cyclosporine and plasma and RBC concentrations, First International Congress on Cyclosporine, Houston, Texas, 1983, p 103 Castro LA, Hillebrand G, Hiner W, Land W: Cyclosporine in patients with oligoanuria after kidney transplantation, First International Congress on Cyclosporine. Houston, Texas, 1983, p 104 Flechner SM, Van Buren CT, Kahan BD: Effect of conversion from cyclosporine to azathioprine (Az) immunosuppression on renal allograft function, First International Congress on Cyclosporine. Houston, Texas, 1983, p 105
Discussion PROFESSOR ROLAND HETZER Hannover, Federal Republic of Germany
We fully agree with this important and timely presentation by Dr. Griffith on the basis of our experiences with 10 patients who have undergone orthotopic heart transplantation at our institution since July, 1983. The patients were treated with a
Thoracic and Cardiovascular Surgery
cyclosporine-prednisolone regimen with pulsed methylprednisolone doses for rejection treatment and antithymocyte globulin for the second rejection treatment course. Whole-blood trough levels of cyclosporine were monitored daily immediately after the operation. After a preoperative oral dose of cyclosporine, 14 to 18 mg/kg, cyclosporine levels inadvertently rose to more than 1,000 ng/ml during the first 4 postoperative days. Transient renal dysfunction was observed in all patients during the first postoperative week, with complete anuria. in two patients who required two and five courses of hemodialysis, These two patients, in contrast to the others, however, had additional conditions which limited renal function: chronic thrombotic occlusion of the suprarenal inferior vena cava in one and cardiac arrest with resuscitation in the other, The renal dysfunction was eventually controlled in all patinets when cyclosporine levels fell below 800 ng/mI. We assumed that renal failure results from the addition of cyclosporine nephrotoxicity to preexisting renal damage when the cyclosporine level exceeds 1,000 ng/rnl, As a consequence, the nephrotoxic effects of cyclosporine may become manifest in diseased kidneys at blood levels that are tolerated by kidneys with normal function. Significant rejection of myocytolysis was independent of cyclosporine levels. However, these were never allowed to drop below 300 ng/ml, In agreement with the concept followed by our colleagues of the Hannover renal and liver transplant program, blood levels in our heart transplant patients are not kept at between 600 and 800 ng/mI during the first six postoperative weeks and between 300 and 600 ng/rnl in the later course. This latter level was obtained by daily doses of 3 to 6 ng/kg body weight. Daily monitoring of cyclosporine levels appears to be mandatory in the first postoperative period, and in particular in patients with other factors predisposing to renal failure. I would like to ask Dr. Griffith to comment on the lowest cyclosporine level that he considers tolerable in his heart transplant patients and on the conditions under when he would change from cyclosporine to another immunosuppressive regimen. DR. CHRISTIAN CABROL Paris, France
Our experience with 100 heart transplants performed over on 11 year period confirms the dramatic change in the mid-term results wrought by the use of cyclosporin. In our initial series, before December, 1980, we used the conventional treatment. Despite some long-term survivors, one of whom is living and well 10 years after operation, the results were rather disappointing. They do not compare with the results obtained in our last 50 patients operated upon after December, 1980, and treated with cyclosporine. In these patients the actuarial survival rate is 83% at 2 and 3 years. However, our experience also confirms that cyclosporine has important drawbacks-systemic hypertension and, most of all, renal toxicity being responsible for two early deaths in our series. It was necessary to find a compromise between the conventional and the cyclosporine regimens. Our present
Volume 88 Number 6 December, 1984
protocol is somewhat different from that of the Pittsburgh group. Immediately before and for 2 or 3 days after the operation, we use the conventional drugs-high doses of corticosteroids, azathioprine, and antilymphocyte globulin. Then, when the hemodynamic situation of those previously very sick patients improves and when hepatic and renal functions become better, azathioprine and antilymphocyte globulin are discontinued, corticosteroids are reduced, and cyclosporine is started and progressively increased until an adequate serum level is obtained. This level is not changed during the rejection episodes, which are managed again by high doses of corticosteroids and, if necessary, by antilymphocyte globulin. Because of the variability in absorption and metabolism of cyclosporine, its serum levels must be checked frequently, especially during the first weeks, along with regular control of rejection, infection, and hepatic and renal toxicity. Careful adjustment of the treatment and meticulous control of the patient still remain the major factors of long-term success in cardiac transplantation. I have two questions for the authors. Why did you use whole blood levels of cyclosporine rather than the serum level, as recommended by the furnishing company? Also, did you use a correction for the variation of the hematocrit value? DR. KEITH REEMTSMA New York. N. Y.
We can certainly confirm the effectiveness of cyclosporine in the early management of cardiac transplant recipients. For example, in our program at Columbia-Presbyterian Medical Center in New York, we have done cardiac transplants in the first 4 months of 1984 on nine patients, with nine survivors and minimal problems with rejection or infection. I believe we may use somewhat lower doses of cyclosporine, and we treat rejection with a pulse dose of steroids but with rapid reduction of steroids to maintenance levels. We would emphasize the importance of frequent biopsies, as patients receiving cyclosporine do not show the signs seen in patients receiving azathioprine. I would close on a cautionary note. Although the early results with cyclosporine are promising, the long-term consequences are unknown. Most patients show impaired renal
Cyclosporine
9 57
function, many have arterial hypertension, and a few are developing severe coronary artery lesions as early as the second year after transplantation. For these reasons I believe we should remain cautious as we try to understand these late problems following cardiac transplantation. DR. GRIFFITH (Closing) I would like to thank the discussants for their kind words. Dr. Hetzer, we do not have a feel for the lowest therapeutic level. It is difficult to probe with cardiac recipients, as a mistake would be a morbid one. We have used much lower doses of cyclosporine, around I to 2 mg/kg/day, in four patients who have developed Iymphoproliferative disorders. These doses have given whole-blood levels of less than 500 ng/rnl, These patients have not shown rejection. What would make me switch from cyclosporine? It is very difficult to improve on the survival rates that cyclosporine has produced. The best conventional survival rates with azathioprine and prednisone alone have been 66% I year postoperatively. So I think that we have some room to experiment with cyclosporine. However, I believe that serious chronic renal toxicity will cause us to make some adjustments, as Dr. Cabrol has pioneered, i.e., a switch to azathioprine or some combination of lesser amounts of both drugs. With respect to Professor Cabrol's questions, we use whole blood because we believe there is less of a temperature-related change in the samples. We have not corrected specifically for hematocrit, and yet we do keep close watch on the hematocrit values. Most patients have frequent phlebotomies and require some transfusion during their first 6 weeks, and most hematocrit values have been between 30% and 35%. Dr. Reemtsma, we agree that there should be a red flare of caution with respect to cardiac transplantation. We are concerned about a general resumption of what has been shown to be a therapeutic operation. It is not without its great difficulties, and we are currently just probing the way with new and powerful suppressants. Dr. Reemtsma, I believe you are measuring serum troughs as opposed to whole-blood troughs, and the conversion factor is somewhere between 2 and 3 to 1. I believe that our levels are commensurate.