Evaluation of the Efficacy and Safety of Conversion to Sirolimus in 85 Renal Transplant Recipients

Evaluation of the Efficacy and Safety of Conversion to Sirolimus in 85 Renal Transplant Recipients E. Sola, V. Lopez, C. Gutierrez, M. Cabello, D. Burgos, M. Gonzalez Molina, and D. Hernandez ABSTRACT Objective. Treatment with sirolimus (SRL) is a potential therapeutic option for renal transplant recipients, especially those who have developed chronic graft nephropathy (CGN) or a neoplasm. Our aim was to analyze the efficacy and safety of conversion to SRL in renal transplant recipients. Materials and Methods. We undertook a retrospective study of 85 patients converted to SRL, 47% for tumors, 39% for CGN, and 14% for other causes. The follow-up period was 34 months (range, 1–93 months). Results. Baseline creatinine was 1.8 ⫾ 0.69 mg/dL (1.6 ⫾ 0.59 for tumors and 2.3 ⫾ 0.6 for CGN). At 1 year, the creatinine was the same in both groups: 1.8 mg/dL (P ⫽ NS). Graft survival at 12 months was 89% (81% for tumors, 81% for CGN, and 100% for other causes). SRL was withdrawn in 34% of patients: 18% for severe side effects, 7% for patient death, and 9% for graft loss. The serum creatinine and proteinuria were significantly increased among those subjects who returned to dialysis because of CGN compared with those with conserved renal function. Patients who developed pneumonitis showed a lower baseline aMDRD, but no difference in SRL levels. Side effects occurred in 40% of patients, with no difference in renal function, proteinuria, or SRL levels. Renal function showed a significant improvement in the patients who continued SRL (aMDRD 45.7 vs 50.7 mL/min/1.73 m2 at 12 months; P ⫽ .08), more marked among those who converted due to CGN. Increases were seen in levels of serum lipids, as well as in the percentage of patients treated with statins. Proteinuria increased significantly, as did the percentage of patients treated with ACE inhibitors/ARA2. Conclusions. Conversion to SRL in patients with CGN was safe when renal function had not undergone marked worsening and there was no proteinuria. Patients who were converted experienced an improvement in renal function. HE INCIDENCE OF neoplasms in organ transplant patients has increased over recent years. In some countries, it now surpasses infections as the cause of death in this population. Several factors have contributed to this situation, notably the use of certain immunosuppressive regimens and the increasing age of the recipients, enhancing the likelihood of developing a tumor. The last complication undermines patient and graft survivals, due to the process itself and the changes in immunosuppressive therapy. Graft survival during the first year posttransplantation has increased significantly, whereas long-term results have hardly changed. Chronic graft nephropathy (CGN) is the most prevalent cause of late kidney transplant failure, characterized by progressive loss of graft function combined with proteinuria and hypertension.

T

Sirolimus (SRL), a potent, new, nonnephrotoxic immunosuppressive agent, possesses antiproliferative properties and exerts antitumor activity by various mechanisms.1,2 Conversion from a nephrotoxic to a nonnephrotoxic, antiproliferative drug like SRL might be a useful approach to prevent or treat CGN. PATIENTS AND METHODS We undertook a retrospective study of all patients converted to SRL between July 2002 and October 2008. We studied a total of 85 From the Nephrology Department, Carlos Haya Hospital, Malaga, Spain. Address reprint requests to Dr E. Sola, Nephrology Department, Carlos Haya Hospital, Avenida Carlos Haya, 29010 Malaga, Spain. E-mail: [email protected]

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0041-1345/09/$–see front matter doi:10.1016/j.transproceed.2009.06.101

Transplantation Proceedings, 41, 2137–2138 (2009)

2137

2138 patients, including 47% converted because of a neoplasm (T), the most common type of which was a nonmelanoma skin tumor (42%), followed by posttransplant lymphoproliferative syndromes (5%). An additional 39% of the patients were converted because of CGN, 8% because of hyperglycemia, and 6% for other reasons, eg, alopecia or hemolytic uremic syndrome. The mean follow-up period was 34 months (range, 1–93 months). The mean transplant time prior to conversion was 34.4 ⫾ 20 months; 52% of patients were being treated with cyclosporine and 48% with tacrolimus, mostly in association with steroids and mycophenolate mofetil.

RESULTS

The mean creatinine before conversion was 1.8 ⫾ 0.69 mg/dL. Significant differences were observed between the preconversion creatinine in the group converted because of neoplasms and those converted due to CGN (1.6 ⫾ 0.59 vs 2.3 ⫾ 0.6 mg/dL; P ⬍ .001). One year after conversion the mean creatinine was 1.8 ⫾ 1.17 mg/dL, with no difference between the 2 groups. One-year graft survival was 89% (81% for T, 81% for CGN, and 100% for other causes). Censoring for death with a functioning graft, 1-year graft survival was 94% for T vs 92% for CGN. SRL treatment was interrupted in 34% of patients: 9% due to graft loss; 7%, patient death; and 18%, severe adverse effects. Forty percent of patients experienced side effects: 20% diarrhea, 17% edema, 23% buccal aphthae, 10% pneumonitis, and 14% skin alterations (patients can experience more than one side effect). No relation was observed between the occurrence of side effects and the reason for conversion or renal function. However, the patients who developed pneumonitis showed a lower baseline creatinine clearance (aMDRD), but no difference in SRL levels. Those patients who lost their graft had worse baseline renal function, more marked among those converted due to CGN. In this group, those who lost their renal function displayed a significantly higher baseline creatinine and proteinuria than those in the group who retained graft function: creatinine 2.2 ⫾ 0.5 vs 2.8 ⫾ 0.7 mg/dL and proteinuria 135 ⫾ 130 vs 1517 ⫾ 1500 mg/24 h. The 26 patients who continued SRL for at least 1 year experienced an improvement in renal function (aMDRD 46.2 vs 50.8 mL/min/1.73 m2; P ⫽ .02) that was more marked among those who were converted because of CGN (30.7 vs 42.7 mL/min/1.73 m2; P ⫽ .02). The proteinuria rose significantly (301 ⫾ 292 vs 816 ⫾ 793 mg/24 h). The percentage of hypertensive patients (those who required at least one drug for control of hypertension) fell significantly, although the percentage of patients receiving ACE inhibitors or ARA2 rose significantly in relation to the increase in proteinuria. The lipid levels of cholesterol, low-density lipoprotein (LDL), and triglycerides rose significantly, as did the percentage of patients taking statins, with 70% of patients who were previously taking statins requiring increased doses or the addition of another agent (ezetimibe or fibrates). No important difference was observed in the mean hemoglobin level, although there were differences in the per-

SOLA, LOPEZ, GUTIERREZ ET AL Table 1. Baseline Versus Postconversion to SRL Values in Renal Transplant Recipients

Creatinine (mg/dL) aMDRD (mL/min/1.73 m2) Hemoglobin (g/dL) Epo (%) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglycerides (mg/dL) Statins (%) Hypertension (%) ACE inhibitors/ARA2 (%) DM (%)

Baseline

Postconversion (12 Months)

P

1.8 ⫾ 0.69 43.18 ⫾ 18.4 12.7 ⫾ 2 14.9 179.7 ⫾ 35 102.1 ⫾ 26 123 ⫾ 41 41.9 69.7 59.4 24.2

1.8 ⫾ 1.17 50.7 ⫾ 20.4 12.9 ⫾ 1.9 43.3 211.29 ⫾ 40 120 ⫾ 39 181 ⫾ 34 54.8 64.6 76.9 13.6

NS .08 NS .01 .01 .01 .01 .01 .01 .01 .01

Epo, percentage of patients on treatment with erythropoiesis stimulators; statins, percentage of patients on treatment with statins; hypertension, percentage of patients on treatment for hypertension; ACE inhibitors/ARA2, percentage of patients on treatment with ACE inhibitors or ARA2; DM, percentage of patients on insulin treatment for diabetes mellitus; NS, not significant.

centage of patients requiring treatment with erythropoiesisstimulating factors or an increase in their doses (Table 1). DISCUSSION

This study observed that conversion to SRL was safe and effective in most patients. Organ transplant patients treated with calcineurin inhibitors who developed a tumor may thus benefit from conversion to SRL.3 In agreement with other reports,4 patients with less worsening of renal function and low-grade proteinuria benefit more from the change than those with impaired renal function at baseline. We detected a high percentage of side effects, mostly controllable, although SRL had to be withdrawn in 18% of cases. Most cases corresponded to pneumonitis. A relation was observed between worse baseline renal function and development of interstitial pneumonitis. There was a general increase in urinary protein excretion, which resulted in a greater percentage of patients treated with ACE inhibitors/ ARA2, although the overall percentage of patients requiring hypotensive agents fell. The lipid profile generally worsened, with an increased percentage of patients requiring lipid-lowering agents. REFERENCES 1. Dieckmann F, Campistol JM: Conversion from calcineurin inhibitors to sirolimus in chronic allograft nephropathy: benefits and risks. Nephrol Dial Transplant 21:562, 2006 2. Campistol JM, Albanell J, Arns W, et al: Use of proliferation signal inhibitors in the management of post-transplant malignancies— clinical guidance. Nephrol Dial Transplant 22(suppl 1):i36, 2007 3. Lopez V, Gutierrez C, Cabello M, et al: Conversion to sirolimus in posttransplant renal neoplasms. Transplant Proc 39: 2264, 2007 4. Mulay AV, Cockfield S, Stryker R, et al: Conversion from calcineurin inhibitors to sirolimus for chronic renal allograft dysfunction: a systematic review of the evidence. Transplantation 82:1153, 2006