Role of medication in the level of aluminium in the blood of chronic renal patients

Transcription

1 NDT Advnce Access published November 21, 28 Nephrol Dil Trnsplnt (28) 1 of 5 doi:.93/ndt/gfn631 Originl Article Role of mediction in the level of luminium in the blood of chronic renl ptients Denise Bohrer 1, Denise C. Bertgnolli 1,SndrM.R.deOliveir 1, Pulo C. do Nscimento 1, LendroM.deCrvlho 1, Solnge C. Grci 2,LuizC.Arntes 3 nd Elvino J. G. Brros 4 1 Deprtment of Chemistry, 2 Deprtment of Toxicology, Federl University of Snt Mri, 3 Hospitl of the Federl University of Snt Mri, Snt Mri nd 4 Clinicl Hospitl of Porto Alegre, Federl University of Rio Grnde do Sul, Porto Alegre, Brzil Abstrct Bckground. Although dilysis fcilities provide highqulity wter, bnorml luminium levels mong ptients on hemodilysis hve still been reported. Since ptients with chronic kidney disese re often on multiple medictions, medicines my be n extr source of luminium for them. The degree to which ingesting contminted mediction influenced the level of luminium in the ptients blood ws investigted. Methods. All medictions consumed by group of ptients on regulr dilysis tretment were nlysed nd the totl luminium ingested by ech ptient ws clculted. At the sme time, the ptients blood ws collected nd luminium ws mesured. The nlyses were crried out by tomic bsorption spectrometry. Results. For ll drugs consumed, the mount of luminium ingested versus the blood luminium level presented no correltion. Since high level of contmintion ws presented by injectble iron, insulin nd erythropoietin (EPO), nother group of ptients tht received reduced mount of orl mediction ws selected. Among them, eight did not receive ny injectble drug, five received only EPO nd seven injectble iron, EPO nd insulin. With these restricted groups, it ws possible to show tht the injectble dministrtion of contminted mediction incresed the Al level in the ptients blood, minly in reltion to iron formultions. Conclusion. Among the medictions investigted, the injectbles re the most significnt source of luminium for ptients with renl insufficiency. This extr luminium intke is reflected in higher luminium levels in the ptients blood. Key words: luminium; elevted serum luminium; erythropoietin; insulin; iron Correspondence nd offprint requests to: Denise Bohrer, Deprtment of Chemistry, Federl University of Snt Mri, Snt Mri, RS, Brzil. Tel/Fx: ; E-mil: ndenise@quimic.ufsm.br Introduction Ptients with chronic kidney disese on regulr hemodilysis tretment re theoreticlly exposed to Al minly through the wter used to prepre the dilyste. This ssumption is due to the enormous volume of wter to which the ptients re usully exposed, 36 l/week [1]. However, with the dvent of the reverse osmosis for wter purifiction, wter contmintion is no longer problem. Since the previously used luminium-bsed phosphte binder [2 4] hs been replced by clcium-bsed binders or Sevelmer, polymeric mine tht binds phosphte, no other significnt Al sources for the ptients re considered. Nevertheless, ptients on regulr hemodilysis tretment present bnorml plsm/serum Al levels [5]. In the United Kingdom [6], plsm Al ws udited over the period of Jnury 2 Jnury 24, resulting in collection of results for 1626 ptients. The rnge ws µg/l,with men vlue of 12.7 µg/l. In the United Sttes, survey retrospectively exmined 14 mesurements of serum Al from Jnury 2 to April 23 [7]. Although Al serum vlues were stisfctory considering the evolution of the tretment conditions, they could not be considered within the norml rnge for ll ptients. In n erlier work [8], we showed tht the regulr mediction dministered to the ptients is contminted by Al. Formultions contining iron nd clcium presented the highest Al levels followed by clcitriol nd vitmins of B complex. Moreover, injectbles present much greter contmintion thn orl formultions, nd considering the wy of dministrtion, their role in incresing the Al level in ptient s blood my be significnt. Iron, besides being one of the most contminted formultions, might indirectly enhnce Al bsorption. Fe my be dministered long with the so-clled supplementry gents, scorbic cid, succinic cid nd citrte, being the ltter lso used to prevent nuse cused by iron. These gents used to improve the bsorption of iron stores my lso promote or enhnce Al bsorption, since the sme complexing effect these species hve on Fe is displyed with regrd to Al. It hs been shown tht citrte C The Author [28]. Published by Oxford University Press on behlf of ERA-EDTA. All rights reserved. For Permissions, plese e-mil: journls.permissions@oxfordjournls.org

2 2 D. Bohrer et l. is mjor fctor in the toxicity of orlly dministrted Al [9 13]. We cn lso notice tht Al nd Fe ply not fully explined role in nephrogenic systemic fibrosis [14]. This is disbling disese tht occurs in ptients with kidney filure exposed to gdolinium-contining contrst gents used for mgnetic resonnce ngiogrphy. The study hs shown tht Al, Fe nd gdolinium re ccumulted in the hert, blood vessels nd skin of ptients who hve been exposed to gdolinium-bsed contrst mteril. The uthors believe tht some of the excess Al in the tissue, long with Fe, prticiptes in the trnsmetlltion of the gdolinium contrst. Al ccumultion cn only occur if it is delivered into the ptient s body; therefore, it is importnt to know its sources. We believe tht our study, using the primry lbortory record of Al intoxiction, i.e. the serum level, my help to evlute the role of the mediction in Al intke. The influence of the mediction on the level of Al ws investigted in the blood (serum) of ptients with end-stge renl disese on regulr dilysis tretment. In the first stge of the investigtion, group of ptients ws selected nd the medictions tht ech ptient ws consuming were nlysed for Al quntifiction; t the sme time, Al ws lso mesured in the blood of these ptients. In the second stge, nother group of ptients, who were tking reduced quntity of orl medictions, ws selected. This group included both those ptients who consumed injectbles nd who did not consume injectbles, nmely, iron supplements, EPO nd insulin. Agin, the medictions nd the ptients blood were nlysed for Al quntifiction. Mteril nd methods Ptients nd blood smples Twenty ptients on regulr hemodilysis tretment t the Cs de Súde Hospitl (Snt Mri, Brzil) nd 2 ptients on CAPD t the University Hospitl (t the Federl University of Snt Mri) were selected for the study. The blood ws collected during the hemodilysis session following protocol previously estblished [15]. Blood smples were centrifuged for serum seprtion. Before the mesurement, smples were deproteinized by the combined ction of trichlorocetic cid nd microwve irrdition [15]. All steps of smple preprtion were conducted under lminr flow (clss ). Aluminium ws mesured by grphite furnce tomic bsorption spectrometry (GF AAS) under the conditions described in Tble 1 in the supplementry dt vilble online. The dilysis concentrte used to prepre the dilyste ws the sme (from the sme lot) for ll ptients, s well s the dilysis solution used by ptients on CAPD. Since the mediction tken by the ptients, with the exception of clcium crbonte, ws furnished by the hospitl, it ws simple to collect smples from the sme lot tht ws given to the ptients for ech medicine. Apprtus A Vrin SpectrAA-2 tomic bsorption spectrometer equipped with GTA- grphite furnce nd n uto smpler (Vrin, Melbourne, Austrli), Trox clss clen bench (Trox, Curitib, Brzil), domestic microwve oven (Philips, São Pulo, Brzil), Joun C412 centrifuge (Joun, St Herblin, Frnce) nd Berghof BSB 939- IR sub-boiling distilltion pprtus (Berghof, Eningen, Germny) were used. Regents The wter used throughout ws distilled, deionized nd further purified by Milli-Q high-purity wter device (Millipore, Bedford, MA, USA). An luminium stndrd solution contining mg/l Al (Merck, Germny) ws used to prepre the working stndrd solutions. HNO 3 [65% (m/m), 1.17 g/ml] from Merck ws further purified by subboiling distilltion. Contmintion control To void contmintion, only plstic mterils were used. All lbortory wre (pipette tips, volumetric flsks, etc.) were immersed for t lest 48 h in % (v/v) HNO 3 /ethnol solution nd, shortly before use, wshed with Milli-Q purified wter. To void contmintion from the ir, ll steps in the smple nd regent preprtion were crried out in clss clen bench. Anlysis of medictions Becuse the Al level in these smples cn vry from microgrm to milligrm per grm, the mesurement ws crried out by tomic bsorption spectrometry either using flme (FAAS) or grphite furnce (GF AAS) ccording to the Al concentrtion. All smples were processed ccording to procedure described elsewhere [8]. For ll products, t lest three smples of the sme lot were nlysed, nd the results reported correspond to the men vlue. Clcultion of luminium ingestion Bsed on the results of the mediction nlysis, it ws possible to clculte the Al mount in ech dose of medicine. The Al ingested by ech ptient, ws clculted by multiplying the mount of Al present in the medicine by the dose given to the ptient. Since the frequency of dministrtion vries from drug to drug nd from ptient to ptient, the clcultion ws done on weekly bsis. Results nd discussion The first step ws to clculte the Al ingested by ech ptient through mediction. The most consumed medicines were nlysed. Knowing the Al level in the products consumed by the ptients nd the dose dministered to ech one, the clcultion ws crried out on weekly bsis, in order to include ll the medictions tken by the ptient. Tble 1 presents this clcultion, crried out for 2 ptients, including the Al present in ech dosge nd the totl mount ingested. Besides the totl mount, Tble 1 lso presents the mount of Al tken orlly nd intrvenously.

3 Tble 1. Aluminium ingested together with the mediction by different ptients in 1 week Ptient Al present in the weekly dose (µg) Al intke per week (µg) Totl (µg) B complex CCO 3 Clcitriol Cptopril Clonidine Digoxin Enlpril EPO Furosemide Insulin Iron Nifedipine Propnolol Orl Intrvenous Intrdermic The vlues were clculted considering the Al present s impurity in ech formultion nd the dose dministrted to the ptient. Hidden luminium 3 Downloded from t Pennsylvni Stte University on My 8, 216

4 4 D. Bohrer et l. Al serum (ug/l) Totl Al ingested Al serum (ug/l) b Al dministrted intrvenously Al intke (ug) Al intke (ug) Fig. 1. Serum Al of ptients on dilysis tretment s function of the Al ingested vi mediction in 1 week. () Totl Al ingested; (b) Al dministrted intrvenously Al (ug/l) men ± SD = 6.7 ± 2.4 men ± SD = 16.4 ± ptient men ± SD = 22.1 ± 9. no injectbles EPO insulin iron + insulin iron + EPO Fig. 2. Serum Al of ptients on dilysis tretment s function of the Al ingested vi mediction in 1 week. Sttisticlly different (P <.5) by one-wy ANOVA. The grphics presented in Figure 1 correlte the serum Al level to the mount of Al tken with the mediction. When the totl mount ws considered, no correltion ws observed (Figure 1); however, when only injectble Al ws considered, it ws observed tht n increse in the Al ingested corresponded to n increse in the Al serum level (Figure 1b). This result my be explined by the fct tht when Al ingested orlly is to be considered, Al present in food nd wter should lso be computed, which is clcultion not esy to do [16]. Moreover, becuse orlly ingested Al is mostly eliminted through the intestinl trct, the frction rebsorbed into the circultory system is difficult to clculte. In order to hve better control of the vribles, nother group of ptients tht received reduced mount of orl mediction ws selected. Only the Al received intrvenously by the ptients ws computed. Among these ptients, eight received no intrvenous mediction, five only EPO, one only insulin, one iron nd insulin nd five iron Tble 2. Aluminium dministrted together with the injectble mediction to different ptients in 1 week Dosge Al intke (µg) Ptient EPO (UI) Insulin (UI) Iron (ml) EPO Insulin Iron Totl The vlues were clculted considering the Al present s impurity in the formultions nd the dose dministrted to the ptient.

5 Hidden luminium 5 nd EPO. A new lot of ech mediction (those tht were being dministered to the ptients during the time of the blood collection) ws evluted for its Al level. These vlues, presented in Tble 2, re not very different from those obtined in the first prt of the study. Tble 2 shows the mount of Al ingested by ech ptient together with the selected mediction per week. The reltionship between Al ingested nd Al in serum cn be observed in Figure 2. Ptients not receiving intrvenous medictions presented Al serum levels < µg/l, nd for those tking only EPO or insulin, the Al level ws not significntly higher. On the other hnd, for ptients tking EPO, insulin nd iron, the Al serum level ws significntly higher, 22.1 ± 9. µg/l versus 6.7 ± 2.4 µg/l (men of the first group). The differences between the groups were evluted by one-wy ANOVA (P <.5). It is cler tht, mong the ptients tht received injectbles, the higher Al levels were presented by the ptients receiving iron, which is not only the most contminted formultion, but lso the one dministered in greter mounts. Conclusion Since the ptients were treted in the sme clinics, the dilystes were collective nd identicl Al source for ll ptients, nd could therefore be excluded from the sum of the Al ingested. Including gret number of ptients on different medictions hindered cler evlution of the influence of this source of Al in the ptients blood. Moreover, other sources such s drinking wter nd foodstuff my ply role when the intke of Al through mediction is not so high. The Al level found in ptients receiving the injectble drugs, iron, insulin nd EPO, three of the most importnt nd widely dministered medictions for dilysis ptients, is high in comprison to the ptients who do not receive these products. This shows tht these formultions my be significnt contribution to higher Al levels in blood. Aluminium exposure in chronic renl disese is wellrecognized problem nd is credited to the wter nd dilyste for ptients on regulr dilysis tretment. Medictions, however, re lso source of Al, minly those given intrvenously, which, similr to dilyste, fce no brriers to enter the ptients circultory system. Acknowledgements. We re thnkful to the nursery stff of both hospitls for their ssistnce in collecting the smples. Conflict of interest sttement. None declred. Supplementry dt Supplementry dt re vilble online t oxfordjournls.org. References 1. Dugirds JT, Blke PG, Ing TS. Hndbook of Dilysis, 4th edn. Boston, MA: Little, Brown nd Co., Persy VP, Behets GJ, Bervoets AR et l. Lnthnum: sfe phosphte binder. Semin Dil 26; 19: Storms LE, Chicell MF, Dice JE. Sevelmer therpy for peditric end-stge renl disese. Phrmcotherpy 26; 6: Coldonto JA. Control of hyperphosphtemi mong ptients with ESRD. J Am Soc Nephrol 25; 16(Suppl 2): S7 S Kusz AT, Antonsen JE, Hercz G et l. Screening plsm luminum levels in reltion to luminum bone disese mong symptomtic dilysis ptients. Am J Kidney Dis 1999; 34: Gult PM, Allen KR, Newton KE. Plsm luminium: still necessry for ptients on renl dilysis? Ann Clin Biochem 26; 43: Jffe JA, Liftmn C, Glickmn JD. Frequency of elevted serum luminium levels in dult dilysis ptients. Am J Kidney Dis 25; 46: Bohrer D, Bertgnolli DC, Oliveir SMR et l. Drugs s hidden source of luminium for chronic renl ptients. Nephrol Dil Trnsplnt 27; 22: Kirschbum BB, Schoolwerth AC. Acute luminum toxicity ssocited with orl citrte nd luminum-contining ntcids. Am J Med Sci 1989; 297: Gomez M, Domingo JL, Llobet JM. Developmentl toxicity evlution of orl luminum in rts: influence of citrte. Neurotoxicol Tertol 1991; 13: Coburn JW, Mischel MG, Goodmn WG et l. Clcium citrte mrkedly enhnces luminum bsorption from luminum hydroxide. Am J Kidney Dis 1991; 17: Tylor GA, Moore PB, Ferrier IN et l. Gstrointestinl bsorption of luminium nd citrte in mn. J Inorg Biochem 1998; 69: Sherrrd DJ. Aluminum much do bout something. New Engl J Med 1991; 324: Swminthn S, High WA, Rnville J et l. Crdic nd vsculr metl deposition with high mortlity in nephrogenic systemic fibrosis. Kidney Int 28; 73: Bohrer D, Nscimento PC, Pomblum SG. Deproteiniztion of blood serum by cid tretment nd microwve irrdition for the determintion of luminium by electrotherml tomicbsorption spectrometry. J Anl At Spectrom 1998; 13: Oliveir SMR, Bertgnolli DC, Bohrer D et l. Serum luminium: influence of wter nd food consumed by ptients with chronic renl insufficiency on regulr hemodilysis tretment. J Brs Nefrol 25; 27: 1 9 Received for publiction: Accepted in revised form: 2..8