Guillen-Anaya, Miguel-Angel

Jadoul, Michel

Marti, Hans-Peter

Uehlinger, Dominik

Wauters, Jean-Pierre

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et al. [8] reported that inﬂammation is associated withhypoalbuminaemia and increased mortality in HD patients.These studies and many others suggest that inﬂammationplays a central role in the development of malnutrition andcardiovascular mortality in patients with chronic kidneydisease. On the other hand, more recently, Pupim et al. [7]showed that surrogate markers of nutritional status (S-albumin, pre-albumin and serum creatinine) were, indeed,signiﬁcantly related to all-cause mortality in HD patients,even after adjustment for serum CRP. Although in our studywe could not conﬁrm a negative correlation betweenS-albumin and CRP, taking into account only the baselinemeasurements, it should be noted that in patients who werepersistently inﬂamed in our study, a negative correlation was,indeed, found between S-albumin and CRP in the fourconsecutive measurements preceding the study, demonstrat-ing the inﬂuence of inﬂammation on S-albumin levels. Wecould speculate why this ﬁnding could not be veriﬁed in thepatients who were not persistently inﬂamed. One reasoncould be the high prevalence of malnutrition, veriﬁed bySGA, in the Brazilian HD population, which differs fromAmerican and European HD populations where the majorityof earlier studies on these relationships were done. Anotherreason is that we excluded patients with clinically signiﬁcantinﬂammatory events, which in turn could be reﬂected by theabsence of correlation in the whole studied HD population.In summary, we agree with Tsirpanlis and colleagues that(i) clinically signiﬁcant inﬂammatory events modify the levelsof S-albumin, (ii) this effect is not immediate and (iii) thesefactors should be taken into account when analysing therelationship between S-albumin and short acute-phasereactants, such as CRP. We therefore advocate [9] sequentialmeasurements of CRP, which may provide a better approachin the interpretation of decreasing S-albumin levels. On theother hand, it seems reasonable to assume that the S-albuminwill remain as a valuable predictor of uraemic malnutrition,inﬂammation and increased risk for mortality.Conﬂict of interest statement. None declared.1Renal, Diabetes and Marcelo Mazza do Nascimento1Hypertension Research Peter Stenvinkel2Center Miguel Riella1Pro´-Renal Foundation Bengt Lindholm2Brazil2Karolinska UniversityHuddinge HospitalDivisions of Renal Medicine and Baxter NovumKarolinska InstitutetSweden1. Nascimento MM, Pecoits-Filho R, Qureshi AR et al.The prognostic impact of ﬂuctuating levels of C-reactiveprotein in Brazilian haemodialysis patients: a prospective study.Nephrol Dial Transpl 2004; 19: 2803–28092. Tsirpanlis G, Bagos P, Ioannou D et al. Exploring inﬂamma-tion in hemodialysis patients: persistent and superimposedinﬂammation. Kidney Blood Press Res 2004; 27: 63–703. Kaysen GA, Dubin JA, Mu¨ller HG, Rosales L, Levin NW,Mitch WE and the HEMO Study Group. Inﬂammation andreduced albumin synthesis associated with stable decline inserum albumin in hemodialysis patients. Kidney Int 2004; 65:1408–14154. Kaysen GA, Chertow GM, Adillkarla R et al. Inﬂammationand dietary protein intake exert competing effects on serumalbumin and creatinine in haemodialysis patients. Kidney Int2001; 60: 333–3405. Stenvinkel P, Heimburger O, Paultre F et al. Strong associationbetween malnutrition, inﬂammation, and atherosclerosis inchronic renal failure. Kidney Int 1999; 55: 1899–19116. Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C.Inﬂammation enhances cardiovascular risk and mortality inhemodialysis patients. Kidney Int 1999; 55: 648–6587. Pupim LCK, Hakim RM, Shiyr Y, Ikitzler TA. Uremicmalnutrition is a predictor of death independent of inﬂamma-tory status. Kidney Int 2004; 66: 2054–20608. Stenvinkel P, Heimbu¨rger O, Lindholm B, Kaysen GA,Bergstro¨m J. Are there two types of malnutrition in chronicrenal failure? Evidence for relationships between malnutrition,inﬂammation and atherosclerosis (MIA-syndrome). NephrolDial Transplant 2000; 15: 953–9609. Stenvinkel P and Lindholm B. CRP in end-stage renaldisease – are there reasons to measure it? Blood Purif 2005;23: 72–78doi:10.1093/ndt/gfh663Drug interaction between sevelamer and cyclosporinThis letter was originally published in NDT volume 19,issue 7, but without the Reply. The publisher would liketo apologise for this error and would now like to publish thepaper again to include the Reply.Sir,We read with interest the original report made byMiguel-Angel Guillen-Anaya and Michel Jadoul [1] ofa drug interaction between sevelamer and cyclosporin(CsA) occurring in a liver transplant patient treated alsoby chronic haemodialysis. After sevelamer was started,the CsA trough levels reached values as low as 35 ng/mland they dropped again after rechallenge. As potentialexplanation, the authors suggest that CsA absorption,which is bile-dependent [2], could be hampered by thefact that sevelamer binds bile acids in the gastrointestinal(GI) tract. Interestingly, in the clinical study performedby Jensen et al. [3], the bile-acid sequestrant cholestyr-amine, 4 g given at noon, did not interfere with CsAabsorption.We would like to mention that sevelamer is a poly(allyl-aminehydrochloride) polymer that may bind not onlyphosphate and bile acids, as the authors point out, butalso cholesterol, vitamins D, E and K and folic acid [4].A direct binding of a lipophilic substance such as CsA – andby extension also tacrolimus – appears, therefore, as anadditional and more likely explanation.This observation points to the distinction to be madebetween the two types of phosphate binding in the GI tract:a speciﬁc one achieved by aluminium hydroxide and calciumsalts and a non-speciﬁc binding attained by polymerssuch as sevelamer. This absence of speciﬁcity might beof less importance for vitamins or folic acid absorption,but may put the patient at risk when lipophilic agents, suchas immunosuppressive and/or other drugs (lipophilicstatins?), are prescribed. Under those circumstances, itappears that sevelamer should be used with caution,i.e. at least at a time distant of potentially interferingdrugs and only when speciﬁc (and less expensive) phosphatebinders are contraindicated.660 Nephrol Dial Transplant (2005) 20: 660Conﬂict of interest statement. None declared.Division of Nephrology – Jean-Pierre WautersHypertension Dominik UehlingerUniversity Hospital Hans-Peter MartiBernSwitzerlandEmail: jean-pierre.wauters@insel.ch1. Guillen-Anaya MA, Jadoul M. Drug interaction betweensevelamer and cyclosporin. Nephrol Dial Transplant 2004; 19: 5152. Trull AK, Tan KKC, Tan L et al. Absorption of cyclosporinfrom conventional and new micro-emulsion oral formulationsin liver transplant recipients with external bile diversion. Br JClin Pharmacol 1995; 39: 627–6313. Jensen RA, Lal SM, Diaz-Arias A et al. Does cholestyramineinterfere with cyclosporine absorption? Prospective study inrenal transplant patients. ASAIO J 1995; 41: 704–7064. Product Information Brochure USA and Summary of ProductCharacteristics of the EMEA.doi:10.1093/ndt/gfh788ReplySir,We thank Jean-Pierre Wauters and colleagues for theirhelpful comments. The lower level of cyclosporin A (CsA)under sevelamer may indeed be due to a direct binding ofCsA by sevelamer, rather than to an indirect impact ofsevelamer on bile acids. Thus, the recommendation of a delaybetween the intake of sevelamer and that of drugs such asCsA is fully warranted. We disagree, however, on the claimthat calcium-based binding is fully speciﬁc for phosphate.Indeed, the co-administration of either calcium acetate orsevelamer with ciproﬂoxacin recently has been shown toreduce the oral bioavailability of the latter drug by some 50%[1].Conﬂict of interest statement. None declared.Miguel-Angel Guillen-AnayaMichel Jadoul1. Kays MB et al. Effects of sevelamer hydrochloride and calciumacetate on the oral bioavailability of ciproﬂoxacin. Am JKidney Dis 2003; 42: 1253–1259doi:10.1093/ndt/gfh788Sevelamer and pharmacokinetics of cyclosporin Aafter kidney transplantationSir,In their interesting article, Pieper et al. analysed prospectivelythe effect of sevelamer on the pharmacokinetics of cyclo-sporin (CsA) and mycophenolate mofetil (MMF) in kidneytransplanted patients [1]. They provide the reassuringmessage that, in contrast to MMF, CsA kinetics are notsigniﬁcantly modiﬁed by the intake of sevelamer. Theseresults are in sharp contrast to the observation and potentialmechanisms that we reported recently [2,3].The short duration (4 days) and limited statistical power(10 adults and eight children) of the study of Pieper et al.make such a strong message rather questionable [4]. Indeed,only 4 days after starting sevelamer, none of the CsAparameters (measured by Cedia and FPIA assays) wascompletely stable: the area under the curve (AUC) decreasedfrom 3547±660 to 3230±612 ng/h/ml, Cmax decreased from955±193 to 855±272 ng/ml and Tmax increased from 1.3to 1.5 h. In addition, when measured with polyclonal anti-bodies, the CsA levels decreased signiﬁcantly and, amongits primary metabolites determined by HPLC, the AUC andCmax of AM1—which also has an immunosuppressive action[5]—decreased signiﬁcantly by 30 and 25%, respectively.Despite these observations, the authors conclude that‘sevelamer intake for several days does not signiﬁcantlyinﬂuence CsA kinetics’. Based on their data, this conclusionappears at least premature, especially if the risk of transplantrejection due to insufﬁcient immunosuppression is considered[6]. Great caution in the use of sevelamer in transplantedpatients is still warranted until a careful long-term, largesize study on the potential interaction of sevelamer with CsAsolves the question.Conﬂict of interest statement. None declared.1Division of Dominik Uehlinger1Nephrology-Hypertension Hans-Peter Marti2University Hospital Michel Jadoul3Bern Jean-Pierre Wauters12Division of NephrologyUniversity HospitalZurichSwitzerland3Division of NephrologyCliniques Universitaires Saint-LucBrusselsBelgiumEmail: jean-pierre.wauters@insel.ch1. Pieper AK, Buhle F, Bauer S et al. The effect of sevelameron the pharmacokinetics of cyclosporin A and mycophenolatemofetil after renal transplantation. Nephrol Dial Transplant2004; 19: 2630–26332. Guillen-Anaya MA, Jadoul M. Drug interaction betweensevelamer and cyclosporin. Nephrol Dial Transplant 2004; 19: 5153. Wauters JP, Uehlinger D, Marti HP. Drug interaction betweensevelamer and cyclosporin. Nephrol Dial Transplant 2004; 19:1939–19404. Felipe CR, Silva HT, Pinheiro Machado PG, Garcia R, da SilvaMoreira SR, Medina Pestana JO. Time-dependent changes incyclosporine exposure: implications for achieving target concen-trations. Transplant Int 2003; 16: 494–5035. Copeland KR, Yatscoff RW, McKenna RM.Immunosuppressive activity of cyclosporine metabolites com-pared and characterized by mass spectrometry and nuclearmagnetic resonance. Clin Chem 1990; 36: 225–2296. Waiser J, Slowinski T, Brinker-Paschke A et al. Impact ofthe variability of cyclosporin A trough levels on long-termrenal allograft function. Nephrol Dial Transplant 2002; 17:1310–1317doi:10.1093/ndt/gfh700Nephrol Dial Transplant (2005) 20: 661 661

Drug interaction between sevelamer and cyclosporin [V. Varia Letter and Reply]

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