Treatment of Secondary Pulmonary Hypertension With Bosentan and Its Pharmacokinetic Monitoring in ESRD Lutz Liefeldt, MD, Paul L.M. van Giersbergen, PhD, Jasper Dingemanse, PhD, Birgit Rudolph, MD, Torsten Walde, MD, Klemens Budde, MD, Hans-H. Neumayer, MD, and Berthold Hocher, MD ● Pulmonary hypertension (PH) is a rare disease with a very poor prognosis. Certain pharmacologic approaches, which reduce pulmonary arterial pressure (PAP) and thereby prevent end-stage cardiopulmonary failure, have been used during recent years. Endothelin-1 has been found to be involved in the pathogenesis of PH. The dual endothelin-receptor antagonist, bosentan, was recently approved for the treatment of pulmonary arterial hyperten- sion. The drug is mainly cleared by hepatic elimination. Severe renal dysfunction does not affect the single-dose pharmacokinetics of bosentan to a clinically relevant extent. Whether renal replacement therapy, however, interferes with the pharmacokinetics of bosentan is unknown. The authors report on the use of bosentan (125 mg twice daily) and its pharmacokinetic monitoring in a 19-year-old woman with PH and end-stage renal disease secondary to scleroderma. Treatment was well tolerated without drug-specific adverse effects. After 12 months of treatment, pulmonary arterial pressure had normalized (48 mm Hg before start of treatment, 27 mm Hg at last follow-up). On the basis of analyzing samples from Genius-hemodialysis by a liquid chromatography assay with tandem mass spectrometry detection, the authors determined the bosentan dialysis clearance to be as low as 3.5 mL/min. Bosentan for the treatment of secondary PH seems to be safe as well as effective in end-stage renal disease patients and no adjustment of the bosentan dosing regimen appears necessary. Am J Kidney Dis 43:923-926. © 2004 by the National Kidney Foundation, Inc. INDEX WORDS: Scleroderma; pulmonary hypertension; endothelin; bosentan; end-stage renal disease (ESRD). P ULMONARY hypertension (PH) is a rare, life-threatening disease. In a prospective study by Raymond et al 1 on outcomes in primary PH during a mean follow-up period of about 36 months, 20 of 81 patients died, and 21 underwent lung transplantation. Besides other predictors in this study, pericardial effusion was associated with adverse outcomes. The poor prognosis for patients with PH led to the use of several pharmacologic approaches to reduce pulmonary arterial pressure (PAP) and, thereby, prevent end-stage cardiopulmonary fail- ure. Because endothelin-1 has been found to be implicated in the pathogenesis of primary and secondary PH, 2-5 a promising approach is the use of endothelin receptor antagonists. 6,7 In 2001, oral bosentan, a dual endothelin receptor antago- nist, was approved for the treatment of pulmo- nary arterial hypertension. Bosentan is exten- sively metabolized in the liver, with biliary excretion of the 3 identified metabolites as the main route of elimination. 8 Severe renal impair- ment seems to have no clinically significant effect on single-dose pharmacokinetic parame- ters of bosentan. 9 However, it is unknown whether renal replacement therapy interferes with the steady-state pharmacokinetics of bosentan. We report on the use of bosentan and its pharmacoki- netic monitoring in a patient with PH and end- stage renal disease (ESRD) secondary to sclero- derma. CASE REPORT A 19-year old woman suffered from scleroderma (anti- Scleroderma 70 antigen [Scl-70] positive) since 1993. At the age of 11 years, the disease presented with skin involvement with acral necroses (which led to amputations of left Digitus manus III and right Digitus manus II and III). Sicca- syndrome and impaired swallowing developed later in the course. Various immunosuppressive regimens containing continuous long-term steroids, azathioprine, cyclosporine A, cyclophosphamide, and mycophenolate mofetil have been tried over several years without any significant clinical improvement. Secondary PH has been evident since August 2001 when the patient was admitted to our hospital because of progressively worsening dyspnea. The clinical situation at this time consisted of polyserositis with pericardial effusion From the Divisions of Nephrology and Cardiology, Depart- ment of Pathology, Center for Cardiovascular Research (CCR), Charite ´, Humboldt-University, Berlin, Germany; and the Department of Clinical Pharmacology, Actelion Pharma- ceuticals Ltd, Allschwil, Switzerland. Received September 19, 2003; accepted in revised form December 29, 2003. Address reprint requests to Priv. Doz. Dr. Berthold Hocher, MD, Universita ¨tsklinikum Charite ´, Center for Cardiovascu- lar Research, Hessische Str. 3-4, D-10115 Berlin, Germany. E-mail: berthold.hocher@charite.de © 2004 by the National Kidney Foundation, Inc. 0272-6386/04/4305-0019$30.00/0 doi:10.1053/j.ajkd.2003.12.054 American Journal of Kidney Diseases, Vol 43, No 5 (May), 2004: pp 923-926 923