Prevention of acute rejection with antithymocyte globulin, avoiding corticosteroids, and delaying cyclosporin after renal transplantation
Diego Cantarovich1,,
Magali Giral-Classe1,
Maryvonne Hourmant1,
Jacques Dantal1,
Gilles Blancho1,
Lydie Lerat1,
Anne Moreau2 and
Jean-Paul Soulillou1
1 Department of Nephrology and Clinical Immunology, Institut de Transplantation et de Recherche en Transplantation (ITERT),
2 Department of Pathology, Nantes University Hospital, Nantes, France
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Abstract
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Background. Despite their well-known side-effects, corticosteroids (Cs) are currently used after kidney transplantation. Avoidance of Cs may improve patient quality of life and eventual long-term survival. We report on a regimen using antithymocyte globulin (ATG) and mycophenolate mofetil (MMF) for induction, and cyclosporin (CsA) plus MMF for maintenance treatment of recipients of primary kidney transplantation.
Methods. We studied 11 consecutive, non-sensitized renal transplant patients (nine cadaver and two living donors). Initial immunosuppression consisted of ATG (1.5 mg/kg/day, i.v.) given for 10 days and MMF (1.0 g/b.i.d.). CsA (8 mg/kg, in two divided doses) was started on post-operative day 11. Cs were only allowed in the case of MMF discontinuation, for the treatment of acute rejection, and in the event of recurrence of the primary glomerulonephritis.
Results. All patients completed the entire 10-day ATG course. Main side-effects included fever (>38°C) and serum sickness, observed in 73 and 27% of the patients respectively. The incidence of acute rejection was 27% (three of 11 patients). In two patients with acute rejection, serum sickness was concomitantly diagnosed and renal histology was partially compatible with immune-complex disease. The remaining patient had two episodes of low-grade rejection. All rejection episodes were rapidly reversed. Two patients (18%) were treated with ganciclovir for cytomegalovirus (CMV) infection. Two patients (18%) are currently receiving Cs for recurrence of the native glomerulonephritis and two rejection episodes respectively. All patients are currently alive with functioning kidneys (average follow-up of 8.4 months; average creatinine level of 128 µmol/l).
Conclusion. This pilot study suggests that ATG induction in combination with MMF and delayed introduction of CsA, in the absence of Cs, is not well tolerated in recipients of kidney transplants. An earlier introduction of calcineurin inhibitors and/or a shorter course of ATG may reduce the incidence of fever and serum sickness secondary to ATG.
Keywords: antithymocyte globulin; corticosteroids; cyclosporin; immunosuppression; mycophenolate mofetil; side-effects
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Introduction
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The number of patients experiencing an acute rejection after kidney transplantation has decreased considerably during recent years. This is due to the effectiveness of novel associations of immunosuppressive drugs. Despite the well known side-effects of corticosteroids (Cs), these drugs continue to be included in such new combinations. We have previously reported on the effectiveness of an immunosuppressive regimen based on rabbit antithymocyte globulin (ATG), cyclosporin microemulsion (CsA), and mycophenolate mofetil (MMF), without Cs, in recipients of simultaneous kidneypancreas transplants, in whom Cs administration had potentially detrimental effects [1]. Based on the very low (7%) incidence of acute kidney rejection in our first study, the aim of the present study was to extend our observation to kidney transplant recipients. In addition, we investigated whether delaying the introduction of CsA to the end of the ATG course would further improve outcome, since both Cs and CsA could interfere with the mechanism of action of polyclonal and monoclonal antilymphocyte globulins [2,3].
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Subjects and methods
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This study was approved by the Committee for Research on Human Subjects at the University Hospital of Nantes. Between November 1998 and April 1999, we enrolled 11 consecutive patients (nine women and two men) between 39 and 64 years of age (average 48 years), who received a primary (nine cadaver, one living unrelated, and one living related) kidney transplant. For cadaveric transplantations, the cold ischaemic time was 23 h, ranging between 14 and 35 h. None of the patients was sensitized before transplantation. Mean HLA-A, -B, and -DR mismatch between donor and recipient was 5 (ranging from 3 to 6). Primary disease was chronic glomerulonephritis in seven patients, chronic interstitial nephritis in two patients, and hypertension and polycystic kidney disease in one patient each. All patients were on chronic dialysis at the time of transplantation.
Immediate post-transplantation immunosuppression consisted of ATG and MMF. A 10-day ATG course (Thymoglobuline®, IMTIX-Sangstat, Lyon, France), at a starting intravenous dose of 1.5 mg/kg/day, was scheduled. Doses of ATG were then monitored and adjusted according to daily E-rosette test. ATG dose was adjusted to maintain the level of rosetting lymphocytes below 10% of the peripheral mononucleated cells. MMF (CellCept®, Hoffman La Roche, Neuilly-sur-Seine, France) was started orally at a dose of 1.0 g/b.i.d. This dose was decreased or discontinued in the case of adverse clinical or haematological events. CsA (Neoral®, Novartis, Rueil-Malmaison, France) was introduced on day 11 (after the end of the ATG course) at an oral dose of 8 mg/kg, in two divided doses. Doses of CsA were adjusted according to CsA blood trough levels, aiming for 150 ng/ml (Cyclo-Trac SP, Sorin, France). Cs were started only in case of MMF discontinuation following the ATG course, and in the case of acute rejection or recurrence of the primary glomerulonephritis. In patients suspected of experiencing an acute kidney rejection episode, a core renal biopsy was obtained to confirm the diagnosis and to graduate the histological features in accordance with the Banff classification [4]. Rejection episodes were treated with high-dose intravenous Cs (5, 5, 4, 3 and 2 mg/kg/day, over 5 consecutive days). Antiviral (herpes, cytomegalovirus (CMV)) prophylaxis was not given and no patient received granulocyte colony-stimulating factor to treat leukopenia.
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Results
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Follow-up ranged from 6 to 11 months (average 8.4). Despite delaying CsA administration to day 11, two patients (18%) required transient haemodialysis because of delayed graft function. The scheduled 10-day ATG course was given to all patients (an average of 24 vials per patient, ranging from 17 to 31). Low-grade fever was observed in all patients during ATG therapy with 73% having a temperature
38°C. Three patients (27%) developed a typical acute serum sickness and in two of them, renal impairment was involved. CMV infection was diagnosed in five patients (45%); however, only two patients required ganciclovir because of CMV disease. Three of the patients developed herpes labialis before CMV infection. One patient presented with a bacterial urinary tract infection. No other bacterial or fungal infections were observed. No patient experienced gastrointestinal side-effects, diabetes or malignancy.
Three patients (27%) received an anti-rejection treatment; two of these also had serum sickness (on post-operative day 10). Kidney lesions at the time of serum sickness and renal dysfunction were compatible with Banff 2b and Banff 2a rejection grade respectively (Figures 1
and 2
). A rapid and complete normalization of renal function was observed in both patients after ATG withdrawal and OKT3/plasma exchange therapy. The patient with grade 2b rejection also required transient haemodialysis. As shown in Figure 1
, a significant improvement of renal lesions was noted after anti-rejection treatment. No control biopsy was performed in the remaining patient. The third patient developed a borderline and grade 1a acute rejection episodes on post-transplant days 16 and 80 respectively. Both episodes were reversible with high-dose Cs.

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Fig. 1. Renal transplant biopsy sections of a patient with clinical acute serum sickness and severe renal dysfunction. (a) Post-transplant day 10 renal transplant biopsy section (trichrome stainx400), showing extensive interstitial haemorrhage. No glomerular thrombi were observed. Unfortunately, no artery was observed in this first biopsy specimen. (b) Two days later, severe intima arteritis in one arterial cross-section was observed. Infarction accounted for 2/3 of the biopsy specimen (periodic acid-Schiff stainx400). Banff grade 2b (i1, t1, g0, ah0 and v2*) rejection was diagnosed. (c) Three weeks later, after the anti-rejection treatment, only focal interstitial fibrosis was noted. No infarction was observed. Unfortunately, no artery was observed in this third biopsy specimen (trichrome stainx200). At this time, serum creatinine level returned to pre-rejection levels (150 µmol/l) and no proteinuria was observed.
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Fig. 2. Post-transplant day 14 renal transplant biopsy of a patient with clinical acute serum sickness and renal dysfunction. A Banff 2a (t1, i2, g2, v1 and ah1) rejection was diagnosed. (a) Glomerulitis and no thrombi (trichrome stainx400). (b) Mild arteritis in one arterial cross-section (periodic acid-Schiff stainx400).
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All patients are currently alive and have functioning transplants. Only one patient has a serum creatinine level above 150 µmol/l. This patient has never experienced an acute rejection episode or acute serum sickness, but developed delayed graft function. The average serum creatinine of all patients is 128 µmol/l, ranging from 86 to 293. Only one patient has proteinuria >1 g/day, secondary to the recurrence of focal glomerular sclerosis. This last patient and the patient who was treated for two episodes of acute rejection are receiving Cs and tacrolimus treatment. Currently, two patients require treatment for hypertension. Throughout the follow-up period, MMF dosage was reduced in four patients because of leukopenia, it remained unchanged in six patients and was withdrawn in one patient.
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Discussion
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Despite not being aimed at efficacy, this pilot study suggests that the avoidance of Cs does not increase the incidence of acute rejection after primary renal transplantation. The need for anti-rejection treatment (27% of the patients) was similar (35%) to our historic controls receiving Cs, ATG induction, and delayed CsA [5]. None of these rejections impaired short-term renal function and/or induced permanent proteinuria. Similarly, the absence of Cs-induced anti-inflammatory effects was not associated with an increased incidence of delayed graft function (18%) or high levels of serum creatinine. On the other hand, patient clinical tolerance to ATG, without Cs and CsA, was poor (high incidence of fever and acute serum sickness) as compared to the pharmacovigilance profile of this drug when Cs and CsA are given concomitantly [6].
New immunosuppressive strategies have significantly reduced the incidence of acute rejection following kidney transplantation to as low as 20% [79]. Whether the actual primary end-point of these drug combinations must be 0% rejection remains unclear. Severe side-effects and adverse events such as diabetes and lymphoproliferative disorders seem to be more frequent than in the past. In addition, no true clinical tolerance has yet been achieved and chronic immunosuppression is still required for maintaining the function of most solid organ transplants.
Bacterial infections, gastrointestinal lesions, high blood pressure, lipid abnormalities, glucose intolerance, excessive weight gain, cataracts, and osteoporosis are some of the well-known complications related to Cs treatment. Hence, immunosuppressive protocols aimed at avoiding Cs use may reduce the incidence of side-effects and eventually ameliorate the short- and long-term quality of life of the patients. On the contrary, avoidance of Cs may impair renal function by enhancing the ischaemia/reperfusion injury syndrome and/or by increasing the incidence of acute and chronic rejection. Our preliminary results suggest that a Cs-free regimen did not have a detrimental effect on renal graft function and survival (100% functional grafts). Moreover, no patient experienced gastrointestinal complication, systemic bacterial infection, or diabetes, suggesting the negative impact of Cs on patient outcome. Several recent studies have confirmed that kidney [10], kidneypancreas [1] and liver [11] transplantation can be safely performed in the absence of Cs. Furthermore, in transplant animal models, Cs as well as CsA can block the immunosuppressive action of agents such as CTLA4-Ig [12] and anti-CD40L [13], and may have a similar effect on ATG. Moreover, in vitro, Cs and CsA impede ATG-induced apoptosis of activated T cells [2]. Whether ATG could be more efficacious in the absence of Cs and CsA after human renal transplantation remains to be determined. This pilot study cannot provide the answer to this question because of its inadequate statistical power and to the fact that patient clinical tolerance was poor, requiring the premature termination of the trial. A high proportion of patients developed fever and acute serum sickness (73 and 27% respectively). This unusually high incidence of serum sickness may be partially explained by the lack of Cs. As we previously reported, only 7% (two of 28) of kidney/pancreas transplant patients experienced serum sickness with a similar Cs-free, ATG/MMF protocol. However, CsA was given from the day of surgery [1].
In conclusion, because of increased toxicity, the results of this pilot study do not favour the recommendation of the avoidance of both Cs and CsA during the induction treatment with ATG (i.e. Thymoglobuline®) after renal transplantation. Further studies will be required to determine whether an earlier introduction of a calcineurin inhibitor and/or a shorter ATG course will allow, in a Cs-free regimen, better clinical tolerance, fewer type III hypersensitivity reactions, and optimal prevention of rejection.
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Acknowledgments
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The authors gratefully acknowledge Joanna Ashton for editing the manuscript and Marcelo Cantarovich MD for critical review.
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Notes
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Correspondence and offprint requests to: Diego Cantarovich MD, Department of Nephrology and Clinical Immunology, Institut de Transplantation et de Recherche en Transplantation (ITERT), Nantes University Hospital, 30 Boulevard Jean Monnet, F-44093 Nantes, France. 
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Received for publication: 6.12.99
Revision received 17. 5.00.