Phosphate Salivary Secretion in Hemodialysis Patients: Implications for the Treatment of Hyperphosphatemia

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1 Originl Pper Nephron Physiol 2007;105:p52 p55 DOI: / Received: My 31, 2006 Accepted: October 31, 2006 Published online: Jnury 12, 2007 Phosphte Slivry Secretion in Hemodilysis Ptients: Implictions for the Tretment of Hyperphosphtemi Vincenzo Svic, c Lorenzo A. Clò d Rento Cldrer c Adelide Cvleri c Antonio Grnt Domenico Sntoro Rodolfo Svic Ugo Murc b Agostino Mllmce Guido Bellinghieri Deprtments of Nephrology nd b Physiology, University of Messin, c Nephrology nd Dilysis Units, Pprdo Hospitl, Messin, d Deprtment of Clinicl nd Experimentl Medicine, Clinic Medic 4, University of Pdu, Pdu, Itly Key Words Hyperphosphtemi Phosphte, slivry Abstrct Bckground/Aims: Hyperphosphtemi is recognized s contributing to the incresed risk of crdic deth in endstge renl disese (ESRD) nd hemodilysis (HD) ptients. Currently vilble phrmcologic tretment for hyperphosphtemi is bsed on phosphte binders but, despite tretment, only hlf of the ptients fll within the rnge for serum phosphorus of the K/DOQI guidelines. Therefore, there is need to identify other therpeutic pproches in order to reduce serum phosphte. Slivry fluid contins phosphte which, if relted to the dily slivry secretion (1,000 1,880 ml), my rise interest in order to identify further dditive pproches to phosphorus removl in uremic ptients, while dt bout slivry phosphte secretion in ESRD ptients re controversil. Methods: This study evlutes slivry phosphte secretion in 68 HD ptients compred with 30 helthy subjects. Sxon s test confirmed norml slivry function in ptients nd controls. Slivry clcium nd serum phosphte, clcium nd PTH were lso mesured. Results: HD ptients hd significntly higher slivry phosphorus levels compred with helthy controls: ( ) vs ( ) mg/dl (p! ), nd this significntly cor- relted (p! ) with serum phosphorus. Multiple regression nlysis confirmed serum phosphorus s the only predictor (p! ) of slivry phosphorus. Conclusions: Given the functionl secretive similrity between slivry glnds nd the kidneys, this incresed slivry phosphte secretion might be interpreted s being compenstory in the presence of renl filure. Absorption of the incresed slivry phosphte secretion, however, my worsen hyperphosphtemi; therefore, the binding of slivry phosphte might be considered s further therpeutic pproch to hyperphosphtemi in ESRD. Copyright 2007 S. Krger AG, Bsel Introduction The mortlity risk of crdiovsculr disese in ptients with end-stge renl disese (ESRD) nd in those under renl replcement tretment with dilysis is known to be 30 times higher thn in the generl popultion [1]. Hyperphosphtemi is recognized fctor contributing minly to the incresed risk of crdic deth in these ptients [2, 3]. In fct, in ptients with renl disese, the well-known reltionship between hyperphosphtemi, secondry hyperprthyroidism, bone turnover nd extr-osseous clcifictions hs recently led to the recogni- Fx E-Mil krger@krger.ch S. Krger AG, Bsel /07/ $23.50/0 Accessible online t: Lorenzo A. Clò, MD, PhD Deprtment of Clinicl nd Experimentl Medicine Clinic Medic 4, University of Pdu, Vi Giustinini, 2 IT Pdu (Itly) Tel , Fx , E-Mil renzclo@unipd.it

2 tion of the mjor role plyed by elevted serum phosphte levels in the induction of vsculr clcifiction [4 6], crdic interstitil fibrosis nd rteril thickening [7], therefore highly incresing the risk of crdic deth [2, 3]. Pssive mechnisms responsible for vsculr clcifictions re thought to be due to the elevted phosphte plsm levels nd high clcium phosphte ion product resulting in supersturted plsm [8, 9]. In ESRD ptients nd in those under renl replcement tretment with dilysis, much ttention hs therefore been focused on therpeutic interventions for their bnormlities in minerl nd phosphte metbolism in order to reduce the impct of these importnt determinnts of vsculr clcifictions on the incresed risk of crdic deth [10]. With regrd to hyperphosphtemi, other thn reduction in dietry phosphorus intke nd dilysis tretment, the currently vilble phrmcologic therpy for hyperphosphtemi is bsed on phosphte binders, including the recently introduced lnthnum crbonte nd sevelmer [11]. However, despite this tretment, only 45% of the ptients fell within the rnge for serum phosphorus of the K/DOQI guidelines [12]. Tretment with phosphte binders is essentilly used to limit dietry phosphorus bsorption by binding dietry phosphorus during pssge through the intestinl trct. No other wy for phosphorus removl, except dilysis, hs been found. Norml slivry secretion is known to be in the rnge of 1,000 1,800 ml/dy [13]. Slivry fluid contins electrolytes including phosphte [13] which, if relted to the mount of slivry secretion per dy, my rise interest in identifying nother possible pproch to phosphorus removl in uremic ptients. There is, however, little informtion on the phosphorus content of slivry secretions nd the slivry phosphte secretion in ESRD ptients. This study ws set up to evlute the slivry phosphte secretion in group of ESRD ptients under chronic dilysis tretment compred with helthy subjects used s control group. The results of this study nd, in prticulr, the reltionship between incresed slivry phosphte nd phosphtemi, shown for the first time by this study, might open the wy for n dditionl therpeutic pproch to the tretment of hyperphosphtemi in these ptients through the removl of excess slivry phosphte. Ptients nd Methods Sixty-eight ESRD ptients from the Dilysis Unit t the Pprdo Hospitl, Messin (47 mles nd 29 femles, men ge yers) on 240-min three times week bicrbonte dilysis with polysulfone dilyzers (HD ptients) were enrolled in the study. Thirty helthy subjects (18 mles nd 12 femles, men ge yers) from the medicl nd prmedicl stff of our division were used s controls. Inclusion criteri were ge older thn 18 yers nd minimum of 1 yer of hemodilysis tretment. Exclusion criteri were cute infections, mlignncy, inflmmtory processes, dry mouth symptoms nd the presence of clinicl signs of utonomic nervous system impirment ccording to our previously reported protocol [14] s well s ptients with Sjögren s syndrome. All ptients nd controls were checked for norml slivry function using the Sxon test [15] t enrollment, nd ll ptients were treted with the phosphte binder, sevelmer, t dose of g/dy. All ptients gve n informed consent before prticiption nd the study ws pproved by our institutionl uthorities. Serum phosphorus, clcium nd prthyroid hormone (PTH) were mesured from fsting predilysis blood smples in HD ptients. In control subjects, blood smples were collected from n ntecubitl vein. Before the hemodilysis session, 2 ml of sliv were collected by direct suction from the orl vestibule using n utomtic pipette. After centrifugtion of the smple, clcium nd phosphorus concentrtions were evluted. The sme determintions were performed in the control subjects. After centrifugtion of the smple, serum nd slivry clcium nd phosphorus levels were determined in spectrophotometric ssy using flex regent crtridge (Dde Behring Inc., Newrk, N.J., USA). The serum PTH concentrtion ws evluted using the Immulite 2000 intct PTH, solid-phse, two-site chemiluminescent enzyme-lbeled immunometric ssy (Dignostic Product Corportion, Los Angeles, Clif., USA), with norml vlues rnging between 7.0 nd 53.0 pg/ml. Sttisticl Anlysis Dt were evluted on Mcintosh G5 computer (Apple Computer, USA) using the Sttview II sttisticl pckge (Brin- Power Inc., USA). The distribution of the dt ws estblished with the Kolmogorov-Smirnov test. A norml distribution resulted only for PTH. Given the skewed distribution of serum nd slivry clcium nd phosphorus in HD ptients, logrithmic trnsformtion ws performed before sttisticl nlysis. Dt re expressed s geometric mens with 95% confidence intervls, nd were nlyzed using the non-prmetric Wilcoxon-Mnn-Whitney rnk sum test. Vlues t the 5% level or less (p! 0.05) were considered sttisticlly significnt. Regression nlysis ws used for HD ptients to identify relevnt reltions between levels of slivry phosphte nd other prmeters while multiple regression nlysis ws performed in order to verify independent predictors. R e s u l t s In HD ptients, the serum nd slivry clcium levels were 8.73 ( ) nd 7.21 ( ) mg/dl, respectively. In these ptients the serum nd slivry phos- Slivry Phosphte in HD Ptients Nephron Physiol 2007;105:p52 p55 p53

3 Slivry phosphorus (log mg/dl) e phorus levels were 5.56 ( ) nd ( ) mg/dl, respectively. PTH ws pg/ml. In control subjects the slivry phosphorus level ws 12.1 ( ) mg/dl. Considering the upper limit of the confidence intervls for the men slivry phosphte s the cutoff in control subjects (14.73 mg/dl), 62 of 68 subjects (91.17 %) hd n incresed slivry phosphte level. In HD ptients, slivry phosphorus ws significntly higher compred with helthy controls: ( ) vs ( ) mg/dl (p! ). The slivry phosphorus levels of HD ptients correlted significntly (p! ) with the serum phosphorus levels ( fig. 1 ). Multiple regression nlysis confirmed tht only serum phosphorus ws significntly nd independently correlted (p! ) with slivry phosphorus ( tble 1 ). Discussion n=68 r 2 = 0.29 p = log slivry phosphorus = * log serum phosphorus Serum phosphorus (log mg/dl) e Fig. 1. Reltionship between serum nd slivry phosphorus in HD ptients. Decresing the excess morbidity nd mortlity from crdiovsculr disese is trget of primry importnce in the therpeutic strtegies for ESRD nd HD ptients. Crdiovsculr clcifictions re known to contribute gretly to the incresed morbidity nd mortlity of ESRD Tble 1. Independent predictors of log e slivry phosphorus (P) in 68 subjects on hemodilysis Vrible Coefficient Stndrd error p Intercept Serum log e P ~ Serum log e C ~0.70 Slivry log e C ~0.16 PTH ~0.19 nd HD ptients [1, 2] nd hyperphosphtemi is recognized s plying custive role in the induction of these complictions [2 7]. To dte, phrmcologic therpeutic pproches to hyperphosphtemi in ESRD ptients re bsed only on phosphte binders which, together with reduced dietry phosphte intke, join dilysis to remove excess phosphorus from the blood. Despite these therpeutic mesures, however, more thn hlf of the ptients still hve serum phosphte levels bove the rnge recommended by the K/DOQI guidelines [9]. Therefore, it is very importnt to identify new methods of intervention nd other possible therpeutic pproches to reduce phosphte levels in blood. Slivry secretion rnges between 1,000 nd 1,800 ml/ dy nd is considerble source of electrolytes including phosphte [13]. The results of our study show tht in our HD ptients the slivry glnds produce relevnt mount of phosphte. In fct, we observed tht, compred with helthy controls, the slivry phosphorus rtio in HD ptients is more thn doubled nd slivry phosphorus is five times higher thn serum phosphorus. In ddition, in HD ptients, slivry phosphorus correlted with serum phosphorus, nd multivrite nlysis confirmed tht serum phosphorus ws the only independent fctor predicting incresed slivry phosphorus secretion. In our ptients we did not mesure the totl mount of sliv secreted; however, in considertion of the norml slivry function of the ptients enrolled in our study given their norml vlues on the Sxon test, we cn rtionlly ssume tht the slivry secretions of our ptients rnge between the vlues for norml slivry secretion reported bove. Therefore, bsed on our dt nd ccording to the mount of dily sliv secretion, the slivry glnds seem ble to secrete relevnt mount of phosphte, which my rnge between nd mg. In ddition, this incresed slivry phosphte secretion ws found in lmost ll (91.73%) of our HD ptients, further vlidting our results. p54 Nephron Physiol 2007;105:p52 p55 Svic et l.

4 Recent studies hve considered the function of slivry glnds in dilysis ptients with contrsting results [15 17]. Ko et l. [16] showed significntly poorer slivry function in ESRD ptients with orl mnifesttions compred with ESRD ptients without orl mnifesttions nd helthy controls. Postorino et l. [15] reported reduced slivry function in HD ptients nd ttributed this to the presence of fibrosis of the slivry glnds. In contrst, Blum et l. [17] reported incresed slivry phosphte levels in ESRD ptients, nd relted this to the secondry hyperprthyroidism of uremic ptients. All the ptients evluted in our study were free of orl mnifesttions nd hd norml slivry function s confirmed by the Sxon test, therefore ruling out the presence of fibrosis of the slivry glnds. In greement with the dt of Blum et l. [17] our ptients hd incresed slivry phosphte; however, no reltionship ws found between the incresed slivry phosphte secretion nd PTH, which mkes ny influence of secondry hyperprthyroidism on slivry phosphte secretion unlikely. It must be noted tht in 1979, t the time the report by Blum et l. [17] ws published, mesurements of PTH were bsed on the less sensitive evlution of PTH frgments which, compred with the currently used evlution of PTH through mesurement of the whole molecule, could hve overestimted the PTH concentrtion in those ptients nd were the bsis for the evidence of reltionship between PTH nd incresed slivry phosphte. The secretory units of slivry glnds re clusters of cells clled cini nd their function is similr to tht of renl tubules. The cini, in fct, secrete primry slivry fluid tht contins wter, electrolytes, mucus nd enzymes, which flow into the collecting ducts where the composition of sliv is mnged. Sodium is ctively rebsorbed while potssium nd phosphte re secreted. In HD ptients, the incresed slivry secretion, slivry phosphte in prticulr, could be rtionl explntion for the compenstory ctivity of the slivry glnds incresing their secretion in the presence of impired kidney function. The effect of this compenstory secretion is, however, bolished by the ingestion of sliv nd its following bsorption in the intestinl trct tht my become vicious circle between slivry phosphte secretion nd fsting phosphte bsorption, thereby worsening hyperphosphtemi. The demonstrtion tht slivry phosphte secretion in our HD ptients is incresed could open n importnt pth for possible dditionl therpeutic pproch to hyperphosphtemi by breking the vicious circle cused by the bsorption of the incresed slivry phosphte. In fct, by knowing the slivry phosphte blnce in HD ptients, it could be possible to bind slivry phosphte secretion, reducing its bsorption, nd therefore further reducing the serum phosphte concentrtion. This is prticulrly interesting when considering tht ll our study ptients were treted with sevelmer s phosphte binder nd, notwithstnding, they still hd hyperphosphtemi, there by confirming the need for further interventions. References 1 Prfrey PS: Crdic disese in dilysis ptients: dignosis, burden of disese, prognosis, risk fctors nd mngement. Nephrol Dil Trnsplnt 2000; 15(suppl 5): Guérin AP, London GM, Mrchis SJ, Metivier F: Arteril stiffening nd vsculr clcifictions in end-stge renl disese. Nephrol Dil Trnsplnt 2000; 15: Goodmn WG, Goldin J, Kuizon BD, Yoon C, Gles B, Sider D, Wng Y, Chung J, Emerick A, Greser L, Elshoff RM, Slusky IB: Coronry-rtery clcifiction in young dults with end-stge renl disese who re undergoing dilysis. N Engl J Med 2000; 342: Goldsmith D, Ritz E, Covic A: Vsculr clcifiction: stiff chllenge for the nephrologist. Kidney Int 2004; 66: Burke SK: Arteril clcifiction in chronic kidney disese. Semin Nephrol 2004; 24: Gichelli MC: Mechnism of vsculr clcifiction in uremi. Semin Nephrol 2004; 24: Amnn K, Tornig J, Kugel B, Gross ML, Tyrll K, El-Shkmk A, Szbo A, Ritz E: Hyperphosphtemi ggrvtes crdic fibrosis nd microvsculr disese in experimentl uremi. Kidney Int 2003; 63: Cozzolino M, Dusso AS, Sltopolsky E: Role of clcium-phosphte product nd bone-ssocited proteins on vsculr clcifiction in renl filure. J Am Soc Nephrol 2001; 12: Gnesh SK, Stck AG, Levin NW, Hulbert- Sheron T, Port FK: Assocition of elevted serum PO 4, C-PO4 product, nd prthyroid hormone with crdic mortlity risk in chronic hemodilysis ptients. J Am Soc Nephrol 2001; 12: Eknoyn G, Levin A, Levin NW; Ntionl Kidney Foundtion: Bone metbolism nd disese in chronic kidney disese. Am J Kidney Dis 2003; 42(suppl 3):S1 S Ritz E: Mnging minerl blnce in endstge renl disese. Nephrol Dil Trnsplnt 2004; 19(suppl 1):S1 S3. 12 Young EW, Akib T, Albert JM, McCrthy JT, Kerr PG, Mendelssohn DC, Jdoul M: Mgnitude nd impct of bnorml minerl metbolism in hemodilysis ptients in the Dilysis Outcomes nd Prctice Ptterns Study (DOPPS). Am J Kidney Dis 2004; 44: Lc G: Sliv ssys in clinicl nd reserch biology. Pthol Biol 2001; 49: Di Leo R, Vit G, Messin C, Svic V: Autonomic function in elderly uremics studied by spectrl nlysis of hert rte. Kidney Int 2005; 67: Postorino M, Ctlno C, Mrtorno C, Cutrupi S, Mrino C, Cozzupoli P, Scudo P, Zoccli C: Slivry nd lcriml secretion is reduced in ptients with ESRD. Am J Kidney Dis 2003; 42: Ko CH, Hsiek JF, Tsi SC, Ho YJ, Chng HR: Decresed slivry function in ptients with end-stge renl disese requiring hemodilysis. Am J Kidney Dis 2000; 36: Blum M, Zurkowsky S, Gilrd J, Avirm: Slivry phosphte nd clcium concentrtion in uremi. Clin Nephrol 1979; 12: Slivry Phosphte in HD Ptients Nephron Physiol 2007;105:p52 p55 p55

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