Objectives: Cardiovascular disease is the most common cause of sickness and death for long-term kidney transplant recipients, and dyslipidemia is an important risk factor for developing cardiovascular disease. Lipid-lowering strategies, with the use of statins, have been shown to reduce the cardiovascular risks related to dyslipidemia, but concomitant use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and immunosuppressive agents may increase the risk of rhabdomyolysis owing to a drug-drug interaction. We report a case of simvastatin-induced rhabdomyolysis and acute kidney injury triggered by addition of sirolimus and cisplatin-based chemotherapy to a kidney transplant recipient who had previously tolerated chronic statin therapy.
Key words : Simvastatin, Sirolimus, Cisplatin, Rhabdomyolysis, Kidney transplant
Kidney transplant is a critical treatment option for appropriate candidates that improves survival compared with maintenance dialysis. Despite the benefits of transplant, graft loss, and cardiovascular mortality may occur over time, and cardiovascular disease is now the most common cause of death after kidney transplant. Dyslipidemia is an independent risk factor for chronic cardiovascular disease in kidney transplant recipients and in the general population as well. The lipid-lowering agents, particularly 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are appropriate and well-tolerated first-line agents for dyslipidemia.
Simvastatin is among the most commonly prescribed statins because of its favorable lipid-lowering potential and its availability. Sirolimus is a new immunosuppressant with antiproliferative properties, which may be a substitute to transitional calcineurin inhibitors. Sirolimus and statins are major substrates of the cytochrome P450 3A4 enzyme (CYP 3A4) in the liver.1,2 Thus, concurrent use of these drugs can increase their serum levels, potentially leading to adverse effects. Clinically significant statin-induced rhabdomyolysis is an uncommon but life-threatening disorder. We describe the first case of a kidney transplant recipient, a 64-year-old woman, who developed severe rhabdomyolysis after concurrent administration of simvastatin and sirolimus after cisplatin-based chemotherapy for lung cancer.
A 64-year-old woman with lupus nephritis was diagnosed as having end-stage renal disease, and she underwent a kidney transplant in 1994. Her immunosuppressive regimen consisted of cyclosporine and corticosteroids, and she had stable graft function. She had been continually treated with simvastatin (20 mg/d) owing to dyslipidemia for the preceding 5 years.
On April 2011, she visited our hospital because of chest discomfort and exertional dyspnea. A pulmonary nodule was detected in her right middle lung field by computed tomography and a chest radiograph, and a computed tomography-guided lung biopsy was performed. She finally received a diagnosis of stage IV adenocarcinoma of the lung with multiple brain and bone metastases. Calcineurin inhibitors, such as cyclosporine, have been known to enhance tumor development through mechanisms independent of the host’s immunity. Conversely, mammalian target of rapamycin inhibitors have demonstrated potentials as immunosuppressive and anticancer agents. We switched the patient’s main immunosuppressive agent from cyclosporine to sirolimus (2 mg/d). Ten days after changing her immunosuppressive agent, the first chemotherapy was started. Gemcitabine 1250 mg/m2 plus cisplatin 75 mg/m2 every 3 weeks was scheduled. The serum creatinine was 128.18 μmol/L (1.45 mg/dL) at the time of chemotherapy initiation.
Two weeks after the first chemotherapy was given, she was readmitted to the hospital owing to poor oral intake, general myalgia, and severe diarrhea. A physical examination showed she had a blood pressure of 112/74 mm Hg. Peripheral pitting edema was not seen in her lower extremities. Her creatinine level was 275.81 μmol/L (3.12 mg/dL), and model of end-stage renal disease estimated glomerular filtration rate was 15.959 mL/min/1.73 m2. Urinalysis showed 3+ leukocyte, 2+ occult blood by urinary dipstick, with 20 to 29 red blood cells per high-power field on microscopic examination, and 1+ proteinuria with a spot urine protein creatinine ratio of 2.850 g/d level. The serum albumin was 26 g/L (2.6 g/dL), total protein was 53 g/L (5.3 g/dL), aspartate transferase was 720 U/L, alanine transferase was 303 U/L, creatine phosphokinase was 29 940 U/L, lactate dehydrogenase was 3544 U/L, and her serum myoglobin was 47.10 nmol/L (825 ng/mL) (normal range, < 3.997 nmol/L [70 ng/mL]). The sirolimus drug level was 10.2 ng/mL (normal trough level 8 to 12 ng/mL). Ultrasonographic findings of the transplanted kidney showed no evidence of acute rejection or hydronephrosis (Figure 1).
Simvastatin, sirolimus, and chemotherapy were all discontinued because of rhabdomyolysis and acute kidney injury. We performed forced alkaline diuresis and hydration. Urine and blood culture demonstrated Escherichia coli sepsis. Symptomatic therapy and use of antibiotics were performed. Despite treatment, the serum urea nitrogen and creatinine concentrations increased to 35.70 mmol/L (100.2 mg/dL) and 362.44 μmol/L (4.1 mg/dL). Pulmonary edema deteriorated, and urine output decreased to 165 cc/d. Hemodialysis began on hospital day 19.
After dialysis, her creatine phosphokinase levels gradually declined from 12 970 U/L to 313 U/L, and her serum creatinine concentration decreased to 72.488 μmol/L (0.82 mg/dL). Her general weakness and myalgia gradually improved. Nevertheless, septic shock caused by the urinary tract infection and disseminated intravascular coagulation did not improve, and the patient died 30 days after admission (Figure 2).
We report a case of simvastatin-induced rhabdomyolysis triggered by the addition of sirolimus and cisplatin-based chemotherapy to a kidney transplant recipient who previously tolerated chronic statin therapy. The patient consistently had been taking simvastatin and cyclosporine for several years and was in a tolerable state. However, she was diagnosed as having advanced stage lung cancer, and the immunosuppressive agent had to be changed from cyclosporine to sirolimus to inhibit growth of tumor cells. Concomitant use of HMG-CoA reductase inhibitors and sirolimus may result in severe rhabdomyolysis going to drug-drug interaction though the CYP 3A4 pathway.
Posttransplant dyslipidemia occurs in at least 60% of patients after kidney transplant.3 Immunosuppressive agents (eg, cyclosporine, sirolimus, and corticosteroids) have been associated with the development of posttransplant dyslipidemia.4,5 Statins are relatively safe first-line agents used in a setting of dyslipidemia associated with immunosuppressive therapy in subjects undergoing kidney transplant. Most statins are metabolized by the CYP 3A4 isoenzyme in the liver. Statin-induced rhabdomyolysis occurs more frequently when statins are used in combination with other pharmacologic agents metabolized by, or affecting, the activity of this enzyme such as the CYP 3A4. Known interacting medications are azole, antifungals, calcineurin inhibitors, fibrates, macrolide, and nondihydropyridine calcium channel blockers.6,7 Most of the reported rhabdomyolysis in kidney transplant recipients have been attributed to drug-drug interactions with calcineurin inhibitors, with the majority of interactions reported between cyclosporine and statins.8-10 Recently, Hurst and associates11 investigated the incidence and specific risk factors of rhabdomyolysis in kidney transplant recipients. They suggested that rhabdomyolysis in kidney transplant recipients was significantly more likely to occur with cyclosporine-based immunosuppression, not with either tacrolimus or sirolimus.
Sirolimus, a first-generation mammalian target of rapamycin inhibitor, inhibits cell cycle progression, and has proven to be a potent immunosuppressive agent for use in solid-organ transplant recipients.12 The beneficial effects for kidney function are shown by allowing calcineurin-inhibitor sparing, lower incidence of malignancies, and fewer viral infections. Sirolimus is extensively metabolized in the liver by CYP 3A4.2 We suggest the possibility of competition between sirolimus and simvastatin for their hepatic degradation via CYP 3A4. Competition for metabolic processing with sirolimus in the liver can result in increased statin drug levels, potentially enhancing simvastatin toxicity. Two cases of severe rhabdomyolysis after coadministration of statin and sirolimus have been reported in solid-organ transplant, and only 1 case has been reported in a kidney transplant recipient (Table 1).13,14 Our patient is the first case of severe rhabdomyolysis triggered by conversion of an immunosuppressive agent from cyclosporine to sirolimus in a kidney transplant who previously tolerated chronic statin therapy.
To improve long-term graft survival and reduce calcineurin-inhibitor toxicity, attempts are being made to change immunosuppressive regimens by reducing calcineurin inhibitor dosage and adding other agents in solid-organ transplant. The above reason has brought mammalian target of rapamycin inhibitors into light in kidney transplant. However, dyslipidemia, the most-common adverse effect of sirolimus,3 increases the need for concurrent use of sirolimus and a statin. As a result, the incidence of statin-induced rhabdomyolysis in kidney transplant recipients is expected to gradually increase in the future. Caution and awareness of potential drug interaction is required when coadministering these agents.
Other risk factors of rhabdomyolysis in our patient are female sex, Asian descent, impaired renal function, and concurrent infection. It is also possible that the acute renal injury owing to sepsis contributed to developing rhabdomyolysis that altered cytochrome P450 enzyme metabolism.15 Drug-induced rhabdomyolysis has been reported after administering chemotherapeutic drugs such as cytarabine,16 pemetrexed,17 5-azacytidine,18 and interferon alpha.19 The pathophysiology of these chemotherapy-induced rhabdomyolysis is idiosyncratic, and the contribution of the individual agents in developing rhabdomyolysis remains unclear. In our patient, cisplatin itself was not a risk factor for rhabdomyolysis. However, cisplatin-induced nephrotoxicity may be attributed indirectly to rhabdomyolysis.
In conclusion, the possibility of statin-induced rhabdomyolysis should be considered when evaluating kidney transplant recipients simultaneously receiving the above-mentioned chemotherapy regimens, sirolimus, and statins, which develop increased creatine kinase and creatinine levels. Clinicians should be aware of the risk of rhabdomyolysis during statin-sirolimus treatment to recognize it promptly and treat it successfully.
Volume : 12
Issue : 2
Pages : 152 - 155
DOI : 10.6002/ect.2013.0003
From the 1Division of Nephrology, Department of Internal Medicine,
College of Medicine, The Catholic University of Korea, Seoul; and the 2Division
of Nephrology, Department of Internal Medicine, Presbyterian Medical Center,
Acknowledgements: This study was supported by a grant of the Korea Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Corresponding author: Bum Soon Choi, MD, PhD, Division of Nephrology, Department of Internal Medicine, Seoul St. Mary’s Hospital, 222 Banpo-daero, Seocho-gu, Seoul, 137-701, Korea
Phone: +82 2 2258 6040
Fax: +82 2 599 3589
Figure 1. Ultrasonographic Findings of the Transplanted Kidney
Figure 2. Clinical Course of the Patient Before and After Concomitant Treatment With Statins, Sirolimus, and Chemotherapy
Table 1. Published Case Reports on Acute Rhabdomyolysis Potentially Associated With Concomitant Administration of Statin-Sirolimus in Solid-Organ Transplants