azathioprine were combined and CsA was introduced icoid and azathioprine in selected compliant recipients with low immunological risk, follow-up time post-.
Nephrol Dial Transplant ( 1997) 12: 1956–1960
Nephrology Dialysis Transplantation
Original Article
Maintenance cyclosporin monotherapy after renal transplantation— clinical predictors of long-term outcome G. Touchard, T. Hauet, F. Cogny Van Weydevelt, B. Hurault de Ligny, P. Peyronnet, Y. Lebranchu, O. Toupance, P. N’Doye and M. Busson Departments of Nephrology, University Hospitals of Poitiers , Angers, Caen, Limoges, Tours, Reims, and INSERM U93, France
Abstract Background. There is considerable debate about whether maintenance cyclosporin (CsA) monotherapy is advisable or not in renal transplantation. Methods. Between August 1984 and December 1989, 463 adult patients received a first cadaver graft. Initial immunosuppression was sequential: antilymphocyte or antithymocyte globulins (10–14 days), prednisone and azathioprine were combined and CsA was introduced ( 6–8 mg/kg/day) when the antilymphocyte or antithymocyte globulins were discontinued. When the graft function was stable and the peak of preformed lymphocytotoxic antibodies was ∏25% and/or the number of rejection episodes was ∏1, the steroid therapy was stopped within 1.5–3 months after transplantation, and azathioprine within 3–12 months. Patients with both anti HLA antibodies >25% and more than one rejection episode were excluded. Cyclosporin doses were adapted for whole-blood trough levels between 100 and 200 ng/ml (monoclonal antibody radioimmunoassay or high-performance liquid chromatography). Cyclosporin monotherapy was attempted in 234 of the 463 patients. Results. At the end of the investigation in January 1993 (follow-up time >36 months, mean 60.5±4.5 months), 135 patients were receiving CsA without steroids or azathioprine. The 99 CsA monotherapy failures were due to rejection episodes in 48 cases, CsA A nephrotoxicity in 26 cases, and other causes in 25 cases, including five deaths and four with poor compliance. Renal function was stable in patients with successful CsA monotherapy: mean creatininaemia was 124±10 mmol/l at the time of CsA monotherapy inclusion and 129±10 mmol/l at the end of follow-up (mean time of CsA monotherapy 52±6 months). The parameters for predicting monotherapy success were age ( 43.2 versus 37.8, P=0.0014), timing of trial inclusion 6 months post-transplant (7.9±3 versus 5.3±3.1 months, P=0.04), and excellent and stable renal funcCorrespondence and oprint requests to: Dr G. Touchard, Department of Nephrology, CHU, BP 577, F 86021 Poitiers France.
tion at the time of inclusion (124±10 versus 145±32 mmol/l, P6 months, and stable creatininaemia levels. Key words: CsA monotherapy; CsA toxicity; immunosuppression; long-term outcome; low immunological risk
Introduction Maintenance treatment of first cadaver renal graft is a matter of controversy. There is no ideal immunosuppression. The majority of centres administer long-term maintenance therapy using low doses of two or three drugs regardless of the characteristics of the recipients or the course of renal transplantation. A few teams have proposed CsA monotherapy as the maintenance regimen in patients with a stable renal function after initial double or triple therapy, with good patient and graft survivals [1–5]. The potential advantages of maintenance CsA monotherapy are numerous. It avoids complications caused by long-term steroid administration and overimmunosuppression and hence decreases the incidence of infections and de novo cancers. These advantages should be potentially hampered by the risks of progressive renal damage due to CsA monotherapy, i.e. the risks of acute and chronic rejection [6,7]. Long-term use of CsA by itself does not adversely impact on clinical outcomes following renal transplantation [8,9]. To date there are no defined prognostic parameters to predict monotherapy success or failure because the number of patients reported in
© 1997 European Renal Association–European Dialysis and Transplant Association
Long-term CsA monotherapy after renal transplantation
previous studies was too small and the duration of follow-up was too short. We therefore designed an open study of maintenance CsA monotherapy in first cadaver kidney transplant adult recipients after sequential triple drug initial immunosuppression to specifically answer the following questions : ( 1) What percentage of first cadaver kidney recipients defined as low immunological risk could be successfully maintained on CsA monotherapy? and (2 ) Which criteria could be used as reliable predictors for the outcome of CsA monotherapy? Cyclosporin monotherapy was attempted in a large cohort of informed patients with a good and stable graft function (creatininaemia 25%) were excluded. The resumption of prednisone and/or azathioprine (i.e. failure of CsA monotherapy)
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was discussed when creatininaemia level increased 20% above the baseline level at the time of conversion to monotherapy.
Diagnosis of rejection and CsA renal toxicity The diagnosis of acute rejection episodes was based on the classical clinical criteria (fever, graft swelling and tenderness, oliguria, weight gain) and on a rapid rise in serum creatinine levels with normal or subtherapeutic trough CsA levels, haematocrit drop, and normal graft appearance by ultrasonography. A graft biopsy was performed when the diagnosis was not obvious. The diagnosis of CsA renal toxicity relied on clinical history, donor age, prolonged graft preservation or anastomosis time, CsA trough level >200 ng/ml by monoclonal antibody immunoassay or high-pressure liquid chromatography or >600 ng/ml by polyclonal antibody assay, gradual rise in serum creatinine with no significant change in haematocrit and a decrease of serum creatinine levels to the initial value after reduction of CsA dosage. The interval for checking on the patients after conversion had been weekly if the conversion was initiated before the 6th month and 2-weekly if the conversion was initiated after the 6th month post-transplantation.
Statistical analysis All data are expressed as mean±SD. Patients with CsA monotherapy success (group Ia) were compared to patients with CsA monotherapy failure (group Ib). Statistical comparisons between value were performed using chi-square analyses for categorical variables and equality of means tests (Student’s t test) for comparing groups of continuous variables. Graft and patient survival in the dierent groups were evaluated by the Kaplan–Meier method [10]. All cases of allograft loss were included in the survival analysis. Statistical significance was defined as a P∏0.05.
Results In the whole series of 463 patients, graft and patient survival 6 years after first graft were 73 and 90% respectively ( Figure 1). Cyclosporin monotherapy was attempted in 234 patients i.e. 51% of cases (group I ). The 229 remaining patients were given two- or threedrug combination therapy. Main features of the patients under study are summarized in Table 1. The mean follow-up time of patients undergoing CsA monotherapy (group I ) was 60.5±4.5 months. At the end of follow up, 201 patients were alive with a functioning graft. Nine patients (4%) died, including four patients in haemodialysis and one patient who received a second graft. Six-year actuarial graft and patient survival was 80 and 91% respectively. At the end of the study 135 patients had functioning grafts and had receiving neither steroids nor Aza (group Ia). They accounted for 58% of the patients enrolled in the CsA monotherapy trial and 29% of our recipients of primary allografts. The mean follow-up time after transplantation and after CsA monotherapy onset was respectively 59±4.5 months and 52±6 months. Seventy-five patients (55.5%) entered CsA monotherapy before the 6th month post-
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G. Touchard et al. Table 2. Causes of CsA monotherapy failure (including deaths) Rejection Cyclosporin toxicity renal other side-eects poor compliance Other causes relapse of glomerulonephritis lymphoproliferative disorder arterial thrombosis autoimmune anaemia undetermined Deaths with functioning graft and cyclosporin monotherapy Total
Fig. 1. Patient and graft actuarial survival overall results. ( N= number of patients under risk.).
48 26 4 4 3 2 2 1 4 5 99
month post-transplantation in 59 patients ( 60%). Mean creatininaemia was 145±32 mmol/l at the time of CsA monotherapy onset and 187±20 mmol/l at the time of CsA monotherapy discontinuation. Only three patients (3%) with no preformed anti-HLA antibodies experienced more than one rejection episode before CsA monotherapy was tried.
Table 1. Main features of the patients under study
Number of patients Recipient age (years) mean±SD Patients aged more than 50 (%) Panel lymphocyte reactivity (% patients) >0 ∏25% >25% Donor age ( years) mean±SD Cold ischaemia time (h) mean±SD Serum creatinine level±SD (mmol/litre at time of CsA monotherapy start) Serum creatinine level mean±SD (mmol/litre) at end of follow-up ( patients with functioning graft) Timing of CsA monotherapy onset (months after transplantation)
Group I
Group Ia
234 39.2±12 23.5
135 43.2±12.1 35.5
99 37.8±12.6 23.7
=0.0014 =0.03
22.2 10.7 11.5 29.4±11.3 21.6±9 133±20
18.5 9.6 8.9 29.2±11.2 21.7±8.9 124±10
27.3 12.1 15.2 29.6±11.2 21.6±9.3 145±32
NS NS NS NS NS
