Saudi Journal of Kidney Diseases and Transplantation

ORIGINAL ARTICLE
Year
: 1996  |  Volume : 7  |  Issue : 3  |  Page : 291--296

Is There an Advantage in Adding Azathioprine to Prednisone and Cyclosporine in Kidney Transplant Recipients?


Magdi Hussein, Jacob Mooij, Haysam Roujouleh 
 Department of Nephrology and Dialysis, Al Hada Armed Forces Hospital, Taif, Saudi Arabia

Correspondence Address:
Magdi Hussein
Department of Nephrology and Dialysis, Al Hada Armed Forces Hospital, PO Box 1347 Taif
Saudi Arabia

Abstract

Some recent studies have raised doubts about the advantage of adding azathioprine to cyclosporine and prednisone («DQ»triple therapy«DQ») in kidney transplant patients. We reviewed the charts of 53 patients followed at our center after they received a living non-related kidney transplant in India. Thirty-eight patients used «DQ»triple therapy«DQ» (cyclosporine, prednisone and azathioprine) and 15 patients «DQ»double therapy«DQ» (cyclosporine and prednisone). A multi-variate analysis was used to study the differences in gender, age, follow-up period, number of patients with at least one acute rejection episode, number of significant infections, cyclosporine dosage and trough levels, prednisone dosage, transplant function, and graft loss due to rejection. There was no difference in the number of acute rejections or graft loss due to rejection in both treatment groups. Although the mean cyclosporine levels at 6, 12 and 24 months and the mean dosage at 6 and 12 months were significantly lower in the triple therapy group, there was no significant differences in these parameters between the patients with and without rejection. The cyclosporine levels at the time of rejection were also not different from the levels in the patients without rejection. The results support other reports suggesting that azathioprine does not seem to add to the immunosuppressive effect, as it is not associated with a lower incidence of acute rejections or an improved graft survival.



How to cite this article:
Hussein M, Mooij J, Roujouleh H. Is There an Advantage in Adding Azathioprine to Prednisone and Cyclosporine in Kidney Transplant Recipients?.Saudi J Kidney Dis Transpl 1996;7:291-296


How to cite this URL:
Hussein M, Mooij J, Roujouleh H. Is There an Advantage in Adding Azathioprine to Prednisone and Cyclosporine in Kidney Transplant Recipients?. Saudi J Kidney Dis Transpl [serial online] 1996 [cited 2020 Oct 22 ];7:291-296
Available from: https://www.sjkdt.org/text.asp?1996/7/3/291/39492


Full Text

 Introduction



Since the introduction of cyclosporine for the treatment of renal transplant recipients, there has been no general consensus regarding the most optimal dosage of this drug that would assure adequate immunosuppression and yet avoid its potential nephrotoxicity. addition of azathioprine as in "triple therapy" (the combination of cyclosporine, prednisone and azathioprine) would theoretically aim to achieve that goal by allowing a reduced cyclosporine dose [1] . However, some recent studies have reported no advantages of adding azathioprine to a "double drug" (prednisone and cyclosporine) therapy regimen [2],[3],[4],[5],[6],[7],[8] . Since 1984 we have followed at our center patients who received living non-related kidney transplants in India. All these patients sought renal transplantation in India, despite our efforts to discourage them against commercial transplantation, which is not allowed in the Kingdom of Saudi Arabia. The early complications in patients after living non­-related kidney transplantation and the ethical aspects have been discussed extensively elsewhere [9],[10],[11],[12],[13],[14],[15] . For the purpose of this study we concentrated on the differences in outcome between patients receiving double or triple immunosuppresive therapy.

 Patients and Methods



We followed 53 patients in our hospital after they received a living non-related kidney transplant in India. Of them 22 were females and 31 were males. The patients had been on dialysis for 0-60 months (mean: 16 + 16 months) and the age at transplantation ranged from 16-74 years (mean: 42 + 14 years). Most of the patients started follow-up in our hospital 1-2 weeks after the transplantation. Information about histocomptability typing results of donors and recipients were not available in most of the cases. Cross matching was negative according to the brief medical reports. The immunosuppressive treatment the patients were receiving at the start of follow­up arrival consisted of cyclosporine and prednisone in 15 cases (28%), and of triple therapy (cyclosporine, prednisone and azathioprine) in 38 patients (72%). Our policy was not to change the immunosuppressive treatment unless medically indicated. In eight out of 38 patients on triple therapy azathioprine was discontinued within 1-2 months after transplantation. The reasons for discontinuing this drug were severe pneumonia (n = 3), pulmonary tuberculosis (n= 2), malaria (n=l), wound infection (n=l), diabetic foot ulcer (n=l).

Cyclosporine blood levels were measured with polyclonal fluorescence polarization on TDx Analyzer (Abbott Laboratories, Chicago, ILL, USA) [16] . The mean cyclosporine trough levels at the start of the follow-up were 700 + 477 ng/ml in whole blood. The dosage of cyclosporine was adjusted aiming for a trough level of 400-800 ng/ml in whole blood during the first three months, and subsequently a whole blood level of 200-500 ng/ml (polyclonal assay). During the start of follow­up, the prednisone dosage was gradually reduced to reach 10 mg daily. Episodes of acute rejection were diagnosed on clinical, laboratory and sonographic criteria. There was a need to confirm diagnosis by a core-needle biopsy in 40% of the cases. Acute rejection episodes were treated with pulse doses of 750­-1000 mg of methylprednisolone on three consecutive days. Antithymocyte globulin was used in one case for a steroid-resistant rejection. The follow-up period for the patients ranged from 2-100 months (mean: 35 ± 26 months).

The patients were divided according to the immunosuppressive treatment protocol (double or triple therapy) they received at the start of the study following the "intention to treat" principle [17] . Alternatively, the patients were also divided into one group in which the patients had at least one acute rejection episode, and another in which there was no history of acute rejection. Both groups were analyzed with the same statistical method regarding the impact of the following factors: gender, age, immunosuppressive protocol (double or triple therapy at the start of the study), number of significant infections, mean cyclosporine trough level and dosage at 6, 12 and 24 months.

In addition, the cyclosporine dosage and level at the time of rejection, in the patients who had one episode, were compared with the mean values of these parameters in the patients without rejection. In the patients who had two or more acute rejection episodes, the mean cyclosporine dosage and level of the first two rejection episodes were used for such comparison. As only two patients had three acute rejection episodes, the third rejection episodes was not included in this analysis.

 Statistical Analysis



Differences between individual parameters were analyzed with an independent t-test and X2 - test. Values are given as mean ± standard deviation (SD). The differences between the two groups in gender, age, follow-up period, number of patients with at least one acute rejection episode, number of significant infections (requiring hospitalization), mean cyclosporine whole blood trough level and dosage (mg/kg body weight) at 6, 12 and 24 months, mean prednisone dosage and mean serum creatinine level at 6, 12 and 24 months, and graft failure due to rejection were analyzed with (forward stepwise) logistic regression (SPSS/ PC, Advanced Statistics TM; SPSS Inc, Chicago, USA) [18] .

 Results



Seventeen of the 53 patients (32%) had at least one rejection episode, of which five had two and two had three rejection episodes. The first rejection episodes occurred within a period of 1-70 months of follow-up (median: 10 months) with 10 of them within one year and seven after one year, of which five were after two years. Thirteen of these patients were in the triple therapy and four in the double therapy group, the difference not reaching statistical significance (logistic regression; [Table 1]).

The mean cyclosporine level and dosage at 6, 12 and 24 months were significantly lower in the triple therapy than those in the double therapy group by both logistic regression and independent t-test. The cyclosporine dosage at 24 months was also lower in the triple therapy patients, but the difference was not statistically significant. There was no difference in the prednisone dosage between the two groups.

When the influence of different factors (gender, age, immunosuppressive protocol, number of infections, mean cyclosporine level and dosage at 6, 12 and-24 months) on the occurrence of rejections was analyzed, there were no differences between the two groups. There was also no significant difference between the cyclosporine levels and dosage at the time of the rejection compared to the mean values of these parameters in the patients without rejection [Table 2]. Five patients had the first rejection after 2 years (range 31-70 months). The cyclosporine level of these patients at the time of the rejection ranged from 217­-680 ng/ml.

The mean serum creatinine level was not significantly different between the two immunosuppressive treatment groups over the observation period [Table 1]. Concerning the outcome, five of the triple therapy patients (13%) lost their graft due to rejection versus two in the double therapy group (13%) [Table 1].

 Discussion



The theoretical background for adding azathioprine to cyclosporine and prednisone is to increase the immunosuppressive effect without enhancing the side effects inherent to each drug. Triple therapy is now being used worldwide and "has become almost standard therapy" [19] . However, some recent studies have reported no advantage of adding azathioprine to double drug regimen [2],[3],[4],[5],[6],[7],[8] . Hardie, et al (1992) found, in a controlled study of 395 cadaver kidney transplant patients, no significant differences in graft or patient survival at one year between triple and double immunosuppressive therapy, although the graft survival at 24 and 36 months was lower in the triple therapy group [6] .

Lindholm et al (1994) found in a prospective, randomized trial of 195 living donor renal transplants, no significant differences between the outcome in patients on triple versus double therapy [8] . Opelz reported in the Collaborative Transplant Study lower graft survival rates in patients on triple therapy compared to patients on double therapy [20] . According to Burke, et al late first rejections (occurring after one year) are associated with noncompliance with therapy (in 34 percent) and with blood cyclosporine concentrations that are marginally lower than those of patients who had no episodes of rejections [21] . In our study population the cyclosporine levels at the time of rejection were not significantly different from the mean levels of the patients without rejection. In addition, the mean cyclosporine levels at 6, 12 and 24 months in the patients with rejection were not significantly different from those in the patients without rejection. The cyclosporine levels at the time of rejection in the five patients who had the first rejection after 24 months, were in the desired range, making non-compliance also less likely in these patients.

In our study, we found no differences in gender, age, follow-up period, number of acute rejections, number of infections and mean serum creatinine level at 6, 12 and 24 months, and number of graft loss due to rejection between the two immunosuppressive treatment groups. Wrenshall, et al [4] and Bowman, et al [7] found in patients on triple therapy more acute rejections episodes com­pared to double therapy, possibly related to lower cyclosporine dosage. In addition, some studies have reported a high correlation between the occurrence of chronic rejections and the dosage of cyclosporine, with a higher frequency of rejections being found in patients with lower levels of cyclosporine [1],[21],[22] .

In our study group, the cyclosporine levels and dosage were significantly lower in the patients on triple therapy. Although the patients on triple therapy were aimed for the same range of cyclosporine trough levels as the patients on double therapy, there was a tendency to reduce the cyclosporine dosage in patients on triple therapy, which significantly resulted in cyclosporine levels at the lower side of the desired range.

However, when comparing the patients with and without acute rejection, there was no significant difference in cyclosporine dosage and levels. Also the cyclosporine level at the time of the rejection was not significantly lower than the mean cyclosporine levels in the patients who had no rejection. This might be the reason that we, contrary to Wrenshall, et al [4] and Bowman, et al [7] , did not find an increased number of acute rejection in the patients on triple therapy despite the overall lower cyclosporine levels in these patients. Our study tends to support other studies reporting that the addition of azathioprine to double therapy does not seem to be of advantage as it is not associated with a lower incidence of rejections or an improved graft survival [2],[3],[4],[5],[6],[7],[8] . As indicated in other reports, azathioprine also does not allow lowering of the cyclosporine dosage, thus reducing cyclosporine-associated nephrotoxi-city, which is one of the main claimed advantages of triple therapy [1],[4],[7],[21],[22] . However, there was a limitation in our study by the nonavailability of HLA typing in most of our patients, which might have affected our results due to the relatively small number of the studied patients.

In fact, despite the overall cyclosporine dosage and levels being higher in the double therapy group, the mean serum creatinine level was in the same range as in the triple therapy patients, which is in accordance with other reports suggesting that there is no evidence of cyclosporine toxicity when targeting for the standard therapeutic trough levels [1],[22] .

References

1Ben-Maimon CS, Burke JF, Besarab A, Jarrel BE, Francos GC, Moyer SS. Evidence against chronic progressive cyclosporine nephrotoxicity. Transplant Proc 1991;23:1260-2.
2Ponticelli C, Tarantino A, Montagnino G, et al. Arandomized trial comparing triple-drug and double-drug therapy in renal transplantation. Transplantation 1988;45:913-8.
3Brinker KR, Dickerman RM, Gonwa TA, et al. Arandomized trial comparing double-drug and triple-drug therapy in primary cadaveric renal transplantation. Transplants 1990;50:43-9.
4Wrenshall LE, Matas AJ, Canafax DM, et al. An increased incidence of late acute rejection episodesin cadaver renal allograft recipients given azathioprine, cyclosporine and prednisone. Transplantation 1990;50:233-7.
5Lindholm A, Albrechtsen D, Tufveson G, Karl-berg I, Persson NH, Groth CG. A randomized trial of cyclosporine and prednisolone versuscyclosporine, azathioprine, and prednisolone in primary cadaveric enal transplantation. Trans­plantation 1992;54:624-31.
6Hardie IR, Tiller DJ, Mahony JF, et al. First report of an Australian randomized trial comparing cyclosporine + prednisolone with cyclosporine+ azathioprine and cyclosporine + azathioprine+ prednisolone in renal transplantation. Transplant Proc 1992;24:2241-2.
7Bowman JS 3d, Angstadt JD, Waymack JP, Jaffers GJ. A comparison of triple­ therapy with double-therapy immunosuppression in cadaveric renal transplantation. Transplantation 1992;53:556-9.
8Lindholm A, Albrechtsen D, Flatmark A, et al. Arandomized multicenter trial of cyclosporin andprednisolone versus cyclosporin, azathioprine, and prednisolone following primary living donor renal transplantation. Transplant Int 1994;7:207-15.
9Al-Khader AA, Abomelha MS, Saltissi D, Chang R, Jawdat M, Otaibi K. Our experience in live non-related renal transplantation performed in Bombay and followed up in Saudi Arabia. Proceedings of the XI th International Congress of the Transplantation Society, Helsinki 1986; 11:4.
10Salahudeen AK, Woods HF, Pingle A, et al. High mortality among recipients of bought living-unrelated donor kidneys. Lancet 1990;336:725-8.
11Al-Khader AA, Al-Sulaiman M, Dhar JM. Living non-related kidney transplanta­tion in Bombay. Lancet 1990;33 6:1002.
12Mohamed AS, Velasco N. Kidneys for sale. Lancet1990;336:1384.
13Daar AS. Organ donation-world experience; theMiddle East. Transplant Proc 1991;23(5):2505-7.
14Onwubalili JK, Obineche EN, Assuhaimi S, Bassiouni M. Outcome of bought living non-related donor kidneys followed up at a single center. Transplant Int 1994;7:27-32.
15Hussein MM. Mooij JM, Roujouleh H, El-Sayed H. Commercial living-non­ related renal transplantation observations on early complications. Transplant Proc 1996 in press.
16Shaw LM. Advances in cyclosporine pharmacology, measurement, and therapeutic monitoring. Clin Chem 1989;35:1299-308.
17Pocock SJ. Protocol deviations. In: Clinical trials a practical approach. Chicester, U.K. John Wileyand Sons 1983;176-86.
18Norusis MJ. Logistic regression. In: SPSS/PC +advanced statistics version 5.0 SPSS Inc., Chicago, U.S.A. 1992;28S-301.
19Suranyi MG, Halloran PF, Hall BM. Recent developments in renal transplantation. In: Gonick HC (ed) Current Nephrology Volume 17. ST. Louis, USA: Mosay year book 1994;385-464.
20Opelz G. Collaborative transplant study-10-yearreport. Transplant Proc 1992;24:2342-55.
21Burke JF Jr, Pirsch JD, Ramos EL, et al. Long-term efficacy and safety of cyclosporine in renal transplant recipients. Engl J Med 1994;331:358-­63.
22Almond PS, Matas A, Gillingham K, et al. Risk factors for chronic rejection in renal allograft recipients. Transplantation 1993;55:752-6.