International Uroloyy and Nephroloyy 19 (3), pp. 333--340 (1987)

Cyclosporine in the Treatment of Steroid Resistant Rejection Episodes in Living Donor Kidney Transplants

M. SOBH, F. EL-HUSSEINI, A. SHEBAB EL-DIN, M. GHONEIM

Urology and Nephrology Center, Mansoura University, Mansoura, Egypt

(Received May 17, 1986)

Cyclosporine had been used to treat steroid resistant rejection episodes in 24 living related donor kidney transplants. The rejection episodes as well as their response to cyclosporine were documented by graft biopsies and/or fine needle aspiration cytology.

Ten similar patients suffering from steroid resistant rejection episodes were not given cyclosporine. These cases were evaluated and their outcome was compared to those who received cyclosporine therapy.

In the 24 cases who received cyclosporine, there was complete reversal of the rejection episodes in 11, partial reversal in 6, arrest of the rejection crisis in 4 and failure in 3. In all the 10 cases without cyclosporine therapy the grafts were found to be lost.

It was concluded that cyclosporine can cure established rejection episodes even when severe and steroid resistant.

Introduction

The therapeutic value of cyclosporine as a prophylactic immunosuppressive drug in man has been established [1 ]. Experimental work in vitro has shown that cyclosporine acts mainly on the early stage of T-cell maturation, most probably through an effect on the synthesis and release of the mediator molecules of inter- leukin 1 and 2 [2].

Evidence was provided that the drug was unable to reverse established skin graft rejection in mice [3]. Wagner in 1983 proposed that cyclosporine may be used to prevent rather than to cure established graft rejection (cit. [4]).

Herein we report our experience in the use of cyclosporine for the treatment of established steroid resistant rejection episodes in patients previously maintained on azathioprine and prednisolone.

Material and methods

During a period of 18 months, out of our living related donor kidney trans- plants who were receiving conventional immunosuppressive treatment (predni- solone and imurane), 24 patients developed acute rejection episodes for which initiation of cyclosporine therapy was judged to be of potential benefit.

VNU Science Press, Utrecht Akad~miai Kiadr, Budapest

334 S o b h et al. : Cyc lospor ine

Ten cases, similar in respect of age, sex, source of the graft, degree of HLA matching, who had been exposed to steroid resistant acute rejecton episodes but were not given cyclosporine therapy were re-evaluated for comparison with cyclo- sporine-treated patients.

Acute rejection was diagnosed when there was a deterioration in graft function with variable combinations of fever, oliguria, hypertension and swelling of the graft. The clinical diagnosis was supported in every case by percutaneous needle biopsy of the graft and/or fine needle aspiration cytology (FNAC).

Rejection episodes were considered to be steroid resistant when there was no clinical, biochemical and histopathologic improvement following the adminis- tration of methylprednisolone (750 mg i.v.) and cyclophosphamide (400 mg i.v.) daily for five consecutive days.

Cyclosporine was initiated 3-5 days after the fifth bolus of methylpredni- solone when there was a progressive deterioration in the graft function.

Cyclosporine was given orally in a dose of 12.5 mg/kg/day. Prednisolone was tapered rapidly to an oral dose of 20 mg/day within 2 weeks. All other antirejec- tion drugs were completely stopped.

Results

Twenty-four patients (18 males and 6 females; age ranging between 13 and 42 years) received cyclosporine treatment. All of them had living related donor kidney transplants. The donors were brothers or sisters in 15 cases, one of the parents in 8 cases and offspring in one case; all were HLA-1 haplotype identical. Five out of the 24 cases had acute rejection on top of chronic. Two of the remaining 19 cases had acute tubular necrosis in association with the acute rejection.

Table 1 presents an analysis of the immediate outcome of the 24 cases follow- ing treatment with cyclosporine. The response to therapy became evident within 5-7 days following initiation of treatment. There was complete reversal of the rejection episodes in 11 cases. This was documented by needle biopsy and/or aspiration cytology (Figs 1 and 2). The mean serum creatinine in this group was 1.0 ___ 0.5 mg/100 ml.

In 6 cases there was partial re~)ersal of the rejection episodes. The serum creatinine did not return to its basal values and its mean value was

Table 1

Early results of cyclosporine therapy

Complete Partial Arrested Failure Total

reversal episodes

11 6 4 3 24

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Sobh et al.: Cyclosporine 335

Fig. la. Severe form of cellular rejection with vascular involvement. Biopsy taken a few days following high dose steroid therapy. There are dense interstitial lymphocytic infiltrate and

arterial changes in the form of intimal oedema and infiltration by lymphocytes. HE, • 250

Fig. lb . The same case two weeks after initiation of cyclosporine therapy. There is complete resolution of the rejection crisis. HE, • 100

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Fig. 2a. F N A C (May-Gr t inwa ld -Giemsa stain, x 1000) of a case with severe form of rejection showing aggregates of macrophages dominating the aspirate. The total corrected increment

was 13 Fig. 2b. F N A C (May-Gr i inwa ld -Giemsa stain, x 1000) of the same case one week after starting cyclosporine therapy. There is change in the character of the cellular infiltrate to

lymphocyte. Total corrected increment was 3

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Fig. 3. Biopsy from a case with partial clinical response. There are complete resolution of lymphocytic infiltrate and persistent structural changes in the form of tubular atrophy, inter-

stitial fibrosis and arterial intimal thickening. HE, • 100

Fig. 4. Case of acute rejection on top of chronic. Three weeks after initiation of cyclosporine therapy there was resolution of the dense lymphocytic infiltrates but persistence of the stigmata

of chronic rejection

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338 Sobh et al. : Cyclosporine

Fig. 5. Case of haemolytic uraemic syndrome showing massive vascular thrombosis and arterial wall fibrinoid necrosis. Phosphotungstenic acid haematoxylin, X 40

2.5 -t- 0.5 mg/100 ml. Residual histopathologic changes were evident in the biopsy samples (Fig. 3).

In four cases, there was further deterioration of the graft function after cyclosporine therapy. This was accompanied by resolution of the interstitial infiltrate and oedema, but the graft functions were unsatisfactory, with a mean serum creatinine value of 3.5 _+ 0.5 mg/100 ml. In all these cases stigmata of chronic rejection were observed (Fig. 4).

Three out of the 24 cases did not show any response to cyclosporine therapy. There was one patient who had a concomitant chronic rejection and died f rom ventricular fibrillation. Two grafts were lost, one due to development of chronic rejection and the other to haemolytic uraemic syndrome (Fig. 5).

In 10 cases with steroid resistant rejection episodes occurring in the period before introduction of cyclosporine therapy in our Center, when re-evaluated, loss of all the grafts was observed.

The 21 functioning grafts were followed up for a period ranging between 12 and 18 months after cyclosporine treatment. There was stabilization of the graft function in 11 cases which were completely reversed, in 3 out of the 6 cases which were incompletely reversed and in 3 out of the 4 cases with arrested rejection.

Late treatment failures were due to graft loss in one case and patient mortality in 3. The graft loss was due to extensive progressive fibrosis. Patient mortality was due to acute pancreatitis in one case and to acute pulmonary oedema in two cases.

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Discussion

Experimental data on the efficacy of cyclosporine in controlling the immune response are conflicting. Leapman et al. [5] suggested that cyclosporine could inhibit secondary responses of primed T-cells in mixed lymphocytic cultures. Lindsey et al. [6] could not show any effect of cyclosporine in preventing secondary antibody responses to bovine serum albumin in BSA-immunized rabbits. Borel and Mtsz/tros [3] were unable to reverse established skin graft rejection in mice. On the other hand, Homan et al. [7] reported a reversal of acute rejection episodes by cyclosporine in dogs.

In our work it is clear that in the 24 cases treated with cyclosporine there was a reversal of acute rejection episodes, even when they were severe and steroid resistant. On the contrary, all grafts were lost when cyclosporine was not given. The reversal was complete when evaluated histopathologically, with definite resolution of the lymphocytic infiltrate of the interstitium as well as other mani- festations of acute rejection. Clinical and biochemical incomplete recovery was observed in 10 patients out of the 24. This was due to structural changes in the graft occurring as a sequela of repeated rejection episodes in six cases and as co- existent chronic rejection in four. Complete failure with subsequent loss of the graft or patient was observed among 3 recipients. One patient had chronic rejection changes before the development of the acute rejection and died from ventricular fibrillation one week after starting the treatment. In the other case, despite clearing of the pleomorphic infiltrate a few days after starting cyclosporine therapy, the graft ceased to function due to haemolytic uraemic syndrome. The third case showed concomitant chronic rejection changes.

Hayry et al. [4] reported successful treatment with cyclosporine in steroid resistant acute rejection episodes in 4 out of 6 cases, in all the four controlled cases blast cells dominated the cellular infiltrate. In one case there was a distinct number of macrophages in the aspirates at later stages of the rejection. Similar observations were noted among our cases that were diagnosed and followed up by FNAC. In one of these cases we observed complete reversal of rejection episodes, with macrophages dominating the cellular infiltrate.

Similarly, MacDonald et al. [8 ], treating 12 cases of steroid resistant rejection with cyclosporine, observed a reversal of the rejection episodes in 6 patients. In the other 6 cases with co-existent chronic rejection, favourable response had been achieved in only one case. Among our cases there were 5 patients having con- comitant chronic rejection. The outcome of these cases was unfavourable and even though the acute rejection episodes had been aborted in three cases, they showed slowly progressive deterioration in the graft function, with chronic rejection process.

Based on these findings, we concluded that cyclosporine A can cure estab- lished acute rejection episodes even when they are severe and steroid resistant. Co-existent chronic rejection and/or significant structural damage in the graft are limiting factors against the success of cyclosporine A therapy.

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Acknowledgements

We wish to thank Miss Nehad Abdel Malik and Miss Mervat Lofty for their excellent technical help, and Mrs Angel Yanni for her efficient secretarial work.

References

1. Calne, R., Rolles, K., Thiru, S.: Cyclosporine A initially as the only immunosuppressant in 34 recipients of cadaveric organs. Lancet, 2, 1033 (1979).

2. Hess, A., Tutschka, P., Santos, W. : Effect of cyclosporine on the induction of cytotoxic T lymphocytes: Role of interleukin-1 and interleukin-2. Transplant. Proc. Suppl. 1, 15, 32 (1983).

3. Borel, J., Mdszfiros, J.: Skin transplantation in mice and dogs: effect of cyclosporine A and dihydrocyclosporine C. Transplantation, 29, 161 (1980).

4. Hayry, P., Willebrand, F., Taskinen, E., Ahonen, J.: Cyclosporine treatment of cortico- steroid resistant episodes of rejection. Arch. Surg., 118, 750 (1983).

5. Leapman, S., Filo, R., Smith, E. : In vitro effects of cyclosporine A on lymphocyte subpopula- tion. I. Suppress or cell sparing by cyclosporine A. Transplantation, 30, 404 (1983).

6. Lindsey, N., Harris, K., Norman, H. : Effect of cyclosporine A on the primary and secondary immune response in the rabbit. Transplant. Proc., 12, 252 (1980).

7. Homan, W., French, M., Millard, P., Dention, T., Fabre, J., Morris, P.: Studies on the effect of cyclosporine A upon renal allograft rejection in the dog. Surgery, 88, 169 (1980).

8. MacDonald, A., Belitsky, P., Cohen, A., Corcke, J., Gupta, R., Lennon, S., White, J.: Cyclosporine for steroid resistant rejection in Azathioprine-treated renal allograft recipients. Transplant. Proc. Suppl. 1, 15, 319 (1983).

International Urology andNephrology 19, 1987