Prospective monitoring of BK polyomavirus infection early posttransplantation in nonrenal solid organ transplant recipients.

BACKGROUND: BK virus-associated nephropathy is an important cause of renal dysfunction in renal transplant recipients. Renal dysfunction after nonrenal solid organ transplantation (NRSOT) is common; however, the impact of BK virus remains uncertain. METHODS: Sixty (7 heart, 25 liver, and 28 lung) NRSOT recipients were enrolled in this single center prospective longitudinal study. Urine and plasma were collected for detection of BK viral load using a real-time quantitative polymerase chain reaction assay at transplantation and at 3, 6, and 9 months posttransplantation. Demographic and clinical data including serum creatinine and immunosuppressive therapy were also collected. RESULTS: BK viruria was detected in 16 of 193 (8.3%) samples corresponding to 9 of 60 (15%) subjects. The median BK viral load was 1.12 x 10 (range, 1.1 x 10-2.66 x 10) copies per milliliter. No viremia was detected. In seven of nine, viruria occurred by 3 months posttransplantation. At 9 months of posttransplantation, the median Modification of Diet in Renal Disease-estimated glomerular filtration rate in those with BK viruria on at least one sample was similar to those without viruria (58.0 [IQR 43.1-60.7] mL/min/1.73 m vs. 61.4 [IQR 50.6-74.4] mL/min/1.73 m; P=0.39). CONCLUSIONS: Although BK infection was common in this NRSOT population, BK viremia was not observed and there was no association between BK viruria and renal dysfunction. Our data suggest that routine surveillance for BK virus early posttransplantation in NRSOT may not be warranted but should be further examined in a larger multicenter trial.

Clopidogrel-precipitated rhabdomyolysis in a stable heart transplant patient.

OBJECTIVE: To report the case of an orthotopic heart transplant recipient who developed rhabdomyolysis precipitated by the addition of clopidogrel to the existing regimen of cyclosporine and atorvastatin, which had been tolerated for more than 3 years without adverse effects or laboratory evidence of myositis. CASE SUMMARY: Fourteen years after cardiac transplantation, a 58-year-old woman began a planned 4 week course of clopidogrel 75 mg/day following coronary angioplasty and placement of a stent in the left circumflex coronary artery. Almost 4 weeks later, she presented with severe muscle pain and weakness and laboratory evidence of rhabdomyolysis, with marked elevations of plasma creatine kinase (96,000 U/L) and urine myoglobin (332,872 microg/L) as well as early acute renal failure (serum creatinine 2.9 mg/dL). Symptoms and laboratory abnormalities resolved with cessation of cyclosporine, atorvastatin, and clopidogrel. Clopidogrel was not restarted, while atorvastatin and cyclosporine were; the patient had no recurrence of symptoms up to 15 months later. DISCUSSION: Both atorvastatin and cyclosporine, as well as clopidogrel's active thiol derivative, are metabolized by the cytochrome P450 3A4 isoenzyme. Cyclosporine is also a moderate inhibitor of this isoenzyme. We postulate that competition between atorvastatin and clopidogrel for CYP3A4 receptors, already partially inhibited by cyclosporine, led to increased atorvastatin concentrations, resulting in the acute onset of rhabdomyolysis. This theory is further supported by the patient's continued ability to tolerate the combination of atorvastatin and cyclosporine, without clopidogrel, on rechallenge. Use of the Naranjo probability scale revealed that rhabdomyolysis was probably precipitated by the addition of clopidogrel to the stable baseline regimen of cyclosporine and atorvastatin. CONCLUSIONS: Practitioners must be conscious of the potential for adverse effects when prescribing clopidogrel to heart transplant patients who are concomitantly receiving cyclosporine and a statin. If concomitant administration is required, careful clinical and laboratory monitoring of the patient is necessary.

Supratherapeutic response to ezetimibe administered with cyclosporine.

OBJECTIVE: To report the case of a patient who underwent orthotopic heart transplant (OHT) and demonstrated a supratherapeutic response to ezetimibe when administered with cyclosporine. CASE SUMMARY: Ezetimibe 10 mg/day was added to the lipid-lowering regimen (atorvastatin 40 mg/day) of a 64-year-old male patient after OHT to achieve a target low-density lipoprotein cholesterol (LDL-C) level < or = 97 mg/dL, as recommended by national guidelines. After 2 months of ezetimibe, the patient's LDL-C level had decreased by 60% to 51 mg/dL. Subsequently, the dose of ezetimibe was reduced to 5 mg/day and, after another 2 months, a repeat lipid panel revealed LDL-C 57 mg/dL. DISCUSSION: Hyperlipidemia is a common problem among heart transplant recipients. Combination therapy using a statin plus ezetimibe appears to be an attractive option to achieve target lipid levels in this population. However, the manufacturer warns that ezetimibe should be administered cautiously in patients concomitantly receiving cyclosporine. Unpublished data suggest a pharmacokinetic interaction between ezetimibe and cyclosporine that results in a significant 2.3- to 12-fold increase in exposure to total ezetimibe. An objective causality assessment in this case revealed that this supratherapeutic LDL-C reduction was probably related to coadministration of ezetimibe and cyclosporine. A potential mechanism to explain this interaction might be an alteration in glucuronidation induced by cyclosporine. CONCLUSIONS: When ezetimibe is prescribed for patients concomitantly receiving cyclosporine, it should be initiated at a lower than recommended dose (> or = 5 mg/day) and titrated upward. Careful and consistent monitoring of patients on this combination is also advised.