Review of dialysate calcium concentration in hemodialysis

12 Pages·2006·0.13 MB·English

by  Hemodialysis International 2006

Hemodialysis International2006; 10:326–337
Trainee Forum
Review of dialysate calcium concentration in
hemodialysis
Nigel TOUSSAINT, Patrick COONEY, Peter G. KERR
DepartmentofNephrology,MonashMedicalCentre,Clayton,Vic.,Australia
Abstract
Thedialysatecalcium(Ca)concentrationforhemodialysis(HD)patientscanbeadjustedtomanage
moreoptimallythebody’sCaandphosphatebalance,andthusimprovebonemetabolismaswellas
reduceacceleratedarteriosclerosisandcardiovascular mortality.TheappropriatedialysateCacon-
centration allowing this balance should be prescribed to each individual patient depending on a
multitude of variable factors relating to Ca load. A lower dialysate Ca concentration of 1.25 to
1.3mmol/LwillpermittheuseofvitaminDsupplementsandCa-basedphosphatebindersinclinical
practice, with much less risk of Ca loading and resultant hypercalcemia and calcification. Low Ca
bathsareusefulinthesettingofadynamicbonediseasewhereanincreasein boneturnoverisre-
quired. However, low Ca levels in the dialysate may also predispose to cardiac arrhythmias and
hemodynamically unstable dialysis sessions with intradialytic hypotension. Higher Ca dialysate is
useful to sustain normal serum Ca levels where patients are not taking Ca-based binders or if Ca
supplements are not able to normalize serum levels. Suppression of hyperparathyroidism is also
effective with dialysate Ca of 1.75mmol/L, but hypercalcemia, metastatic calcification, and over-
suppression of parathyroid hormone are risks. Dialysate Ca of 1.5mmol/L may be a compromise
betweenboneprotectionandreductionincardiovascularriskforconventionalHDandisacommon
concentration used throughout the world. The increase in longer, more frequent dialysis such as
short-dailyandnocturnalHD,however,providesanotherchallengewithregardtooptimaldialysate
Calevelsandhigherlevelsof1.75mmol/Lareprobablyindicatedinthissetting.Difficultiesinde-
terminingtheidealdialysateCaoccurbecauseofthecomplexpathophysiologyofboneandmineral
metabolisminHDpatientsandthereneedstobeabalancebetweendialysisprescriptionandother
treatment modalities. To optimize management of the abnormal Ca balance, other aspects of this
disorder need to be more fully clarified and, with evolving medications for phosphate control and
treatment of secondary hyperparathyroidism, as well as the emergence of a multitude of different
HDregimes,furtherstudiesarerequiredtomakedefinitiverecommendations.Atpresent,weneed
tomaintainflexibilitywithHDtreatmentsandsodialysateCaneedstobeindividualizedtomeetthe
specificrequirementsofpatientsbyoptimizingmanagementofrenalbonediseaseandsimultane-
ouslyreducingmetastaticcalcificationandcardiovasculardisease.
Key words: Dialysate calcium, hemodialysis, calcium balance, vascular calcification, mineral me-
tabolism,calcium(cid:1)phosphateproduct
Correspondence to: P. G.Kerr, Department ofNephrology, Monash Medical Centre, 246 ClaytonRd, Clayton, Vic. 3168,
Australia.
E-mail: [email protected]
326 r 2006 The Authors. Journal compilation r 2006 International Society for Hemodialysis
Dialysatecalciumconcentration
CLINICAL TRAINING AT MONASH drop-inclinics.Allclinicsarefollowedbyadiscussionof
MEDICAL CENTRE, CLAYTON, the patients seen, with all attendees at the clinic (con-
MELBOURNE, VIC., AUSTRALIA sultants, registrars, and residents)—this usually takes up
to an hour. There is a weekly department meeting with
The training pathway for medical specialties in Australia presentations of renal histology, scientific work, or other
is governed by the Royal Australasian College of Physi- nephrology topics and there is a second weekly journal
cians (covering Australia and New Zealand). After a club.Thehospitalhasaweeklygeneralmedicinemeeting
compulsory intern year, trainees typically enter ‘‘basic as well (similar to a grand round). In addition, all ad-
training’’ that incorporates exposure to all medical spe- vancedtraineesmustcompletea‘‘project’’ineachyearof
cialtiesandgeneralmedicine.Thisoccurspredominantly training—this is usually a small clinical research topic,
in teaching hospitals with some secondment to smaller many of which have been published.
suburbanandruralhospitals.Basictrainingtakes3years, The department also has 5 nephrology PhD students
wherein trainees progress through working as a resident who have completed their advanced training but who
doctor(similartoaHouseOfficer)toregistrarlevelwhere have elected to pursue research. Three are involved in
theysuperviseresidents.Inthethirdyearofthistraining, laboratory research (glomerulonephritis, diabetes, and
thereare2examinations.Firstly,thereisthewrittenexam peritoneal membrane pathobiology) and 2 in clinical re-
(multiplechoice format), which incorporates clinical sci- search (dialysis nutrition and vascular disease). The De-
ences and clinical medicine in all internal medical disci- partmentiscurrentlyinvolvedin23clinicaltrialsandhas
plines. If successful at this examination, candidates may anactivebasicsciencelaboratory,including14scientists.
thensitaclinicalexamination,whichhasaformatoflong
andshortcasesextendingoverawholeday(2longcases
Training in dialysis
and 4 short cases)—again, cases are drawn from all as-
pects of internal medicine. As mentioned, Monash Medical Centre cares for about
Once successful at the examinations, candidates com- 485 dialysis patients, including 135 patients on perito-
plete the 3 years of basic training and enter ‘‘advanced neal dialysis (PD), and there are about 70 to 90 new di-
training.’’ This is usually discipline specific—in the case alysis patients entering the program each year. Dialysis
inpoint,innephrology.Advancedtrainingspansafurther educationforadvancedtraineesoccursatavarietyoflev-
3 years and incorporates at least 2 clinical years as a Ne- els,includingtreatingin-hospital patientsandambulato-
phrology Registrar but may include a third elective year, rycarepatients.PeritonealdialysisisofferedasCAPDand
either in another specialty or in research. Many candi- APD; hemodialysis (HD) is offered as satellite and home
dates overlap a PhD year at this point. There are no exit (in-center tends to be a transit zone only). Home HD
examinations but there are annual reports on progress, includes conventional and nocturnal dialysis, and the
submitted toaSpecialistAdvisoryCommittee thatisdis- department currently has 31 patients on nocturnal HD.
cipline specific. The registrar covering dialysis at any one time is re-
AtMonashMedicalCentre,werunalargeprogramby sponsible for ambulatory management of outpatient HD
Australian standards. The Nephrology Department cares and PD patients. As with all nephrology units in Mel-
for485dialysispatientsandover500transplantpatients, bourne, training in ambulatory dialysis for the advanced
including kidney–pancreas transplantation. There are 3 trainee at Monash Medical Centre occurs throughout the
clinicalregistrarswhorotatethroughcareoftheinpatient duration of the 3 years of clinical practice as a registrar,
ward, dialysis, and transplantation (transplant patients andisintegraltotheoverallefficiencyofHDpatientcare
are cared for by the Physicians in Australia). There are inthedepartment.Thereisoneco-ordinateddialysisout-
usuallyabout25to30inpatientsatanyonetimebutre- patient clinic per week with regular attendance by Con-
nalbiopsiesandmanysurgicalproceduresareperformed sultants and registrars, as well as allied health staff in-
as day cases. We perform around 300 renal biopsies per cludingadietician,socialworker,anddialysiseducators.
year(nativeandtransplant),andthereareabout40to45 Thereare20to25HDinpatientsatanyonetimecared
transplants per year (including 8–10 kidney-pancreas). for by the ward registrar, but with good clinical practice
Educationalactivitiesincludeformalroundingwiththe most management of patients will occur in the commu-
consultant 3 times/week, separately in general nephro- nity with regular out-patient review. In-patient HD
logy and transplantation, and attendance at a dialysis training involves regular ward rounds with the consult-
clinic weekly and a glomerulonephritis clinic weekly. ant,anddirectcommunicationwithdialysisnursingstaff
There are 2 formal transplant clinics weekly, plus daily and between registrars. There would typically be about
Hemodialysis International2006; 10:326–337 327
Toussaintetal.
10 to 15 acute HD patient admissions per month, and centrationwasusedasthismostcloselymatchednormal
review of patients in the intensive care setting, especially serum ionized Ca. It was soon discovered that higher
of those requiring support with hemofiltration, is also levelsofCawererequiredtosustainserumCalevelsand
crucialtooptimaltrainingofadvancedtraineesatMonash to increase Ca load, therefore preventing hypocalcemia
Medical Centre. and renal bone disease.3
The administration of active vitamin D (calcitriol) in
the 1970s eliminated the need for the dialysate to im-
DIALYSATE CALCIUM
prove Ca load and a higher dialysate Ca concentration,
with a net flux of Ca into the patient, was not required.
Clinical scenerio
With the introduction of Ca-based phosphate binders in
A54-year-oldmalehasbeenmanagedwithHDfor3years. the late 1980s, in association with calcitriol use, hyper-
Hisdialysisparametersinclude—4hr,3times/week,using calcemiabecameamorecommonpotentialproblem,and
a1.6m2polysulfonehigh-fluxdialyzer,achievingaspKt/V alowerCadialysatewasre-introduced.Slatapolskyetal.,
of 1.5. He has always struggled with phosphate control. in1986,reportedonHDpatientsreceivingCacarbonate
Owing to regulatory restrictions, sevelemar hydrochloride asphosphatebindersinassociationwithdialysiscontain-
is unavailable. His phosphate control includes calcium ing 1.75mmol/L Ca dialysate revealing the complication
carbonate, 2 tablets 3 times daily with meals, and alumi- of hypercalcemia.4 A repeat analysis of patients reported
numhydroxide,1tablet3timesdailywithmeals.Healso in 1989, with lower Ca dialysate (1.25mmol/L) and as-
takes calcitriol 0.25mcg daily. His serum calcium is sociated Ca carbonate administration, at an average dose
2.6mmol/L, phosphate 2.1mmol/L, intact parathyroid of10.5g/day,demonstratednohypercalcemia.5Theben-
hormone (iPTH) level is 53pmol/L, and albumin is 38g/ efitsoflowCadialysateinassociationwithCa-containing
L.OneisconcernedabouthisiPTHlevelandwouldliketo bindersandalsowithcalcitriolhavealsobeenconfirmed
increase his calcium carbonate to 9 tablets daily but are in many early studies, with the active vitamin D compo-
concerned about his serum calcium. nent effective in treating patients with secondary hyper-
Whatoptionsinthedialysatecalciumconcentrationareavail- parathyroidism (HPT).6,7
able? What is the ‘‘correct’’ dialysate calcium? However, the more recent introduction of non-Ca,
nonaluminum-basedphosphatebinders,noncalcemicvi-
tamin D analogues, as well as the emergence of calcimi-
REVIEW
meticagentsintoclinicalpracticeimprovingmanagement
of mineral metabolism, have made the current choice of
Introduction dialysate Ca even more difficult, and also more crucial.
Usingtheappropriatedialysatecalcium(Ca)concentration
Current management of mineral
in HD patients has important management implications
with regard to the prevention of renal bone disease and metabolism
also, more importantly, the reduction of vascular calcifi-
Patients with end-stage kidney disease (ESKD) have a
cation. Manipulations of the dialysate Ca concentration
disruptioninsystemicCaandphosphatehomeostasis.As
enable alterations in Ca load as dialysate Ca impacts on
a result of limited excretion of phosphate, diminished
serum Ca, phosphate, and parathyroid hormone (PTH)
hydroxylationof25-hydroxyvitaminDtocalcitriol(1,25-
and,mostlikely,softtissuecalcification.Concentrationsin
dihydroxyvitaminD)andresultinghypocalcemia,thereis
thedialysatecanbecustomizeddependingonthecurrent
an effect on bone, the gut, and the parathyroid glands.
andtargetedserumCalevelsaswellasthedesiretomain-
HypersecretionofPTHisinitiallyappropriatebyincreas-
tain hemodynamic stability during dialysis.1
ing Ca phosphate release from bone and enhancing uri-
nary phosphate excretion (via a decrease in proximal
Historical perspective
reabsorption). PTH can, in early stages, correct both the
Dialysate in general, with its electrolyte and acid-base hypocalcemia and the hyperphosphatemia. With declin-
components, has evolved specifically and scientifically ing kidney function, worsening phosphate retention is
throughstudiestoprovidethebestoutcomemeasuresfor intimately related to the common development of sec-
patients on HD, but the optimal dialysate Ca concentra- ondary HPT. The latter is a major cause for concern be-
tion is yet to be delineated.2 When dialysis was initially causethehighcirculatinglevelsofPTHplayanimportant
introduced in the 1960s, 1.25mmol/L dialysate Ca con- roleinthedevelopmentofrenalosteodystrophyandpos-
328 Hemodialysis International2006; 10:326–337
Dialysatecalciumconcentration
sibly in other uremic complications as well. Increased Worldwide practice
levels of PTH are also closely associated with cardiovas-
cular disease in dialysis patients. WorldwideuseofdialysateCavariesthroughoutdifferent
CurrentmanagementofmineralmetabolisminESKDin- countries.Themostrecentclinicalpracticeguidelinesby
volvesthecontrolofhyperphosphatemiaandtheuseofac- the National Kidney Foundation (New York, United
tivevitaminDcompoundstosuppressPTH,withanaimto States) Kidney Disease Outcome Quality Initiative (K/
obtainnormalizationofserumCaandphosphate.Phosphate DOQI) guidelines recommend a dialysate Ca concentra-
controlindialysispatientsisdifficultandmanagementrelies tion of 1.25mmol/L rather than 1.5mmol/L to avoid
ondietaryrestriction,theuseofphosphatebinders,manyof excessCaloadandpreventvascularcalcification,2where-
whichareCa-based,anddialysis.8Dialysishaslimitedabil- as in Japan and Australia a dialysate of 1.5mmol/L is
ity for phosphate control although phosphate removal by common.ThereisnorecommendationfordialysateCain
HD is very much a time-dependent process.9 the European Best Practice Guidelines (EBPG). The first
Aluminum hydroxide was initially thought to be the Dialysis Outcomes and Practice Patterns Study (DOPPS)
ideal phosphate binder, especially being the most cost involved 307 HD centers with participants from Japan,
effective;however,ithaslargelybeenabandonedbecause United States, and Europe, and revealed that the average
of the risks of aluminum toxicity with osteomalacia and dialysate Ca concentration was 1.45mmol/L, 60% of
encephalopathy.10 If aluminum-based binders are need- patients exceeding the K/DOQI recommendation.19
ed, certain guidelines recommend against their use for Lower dialysate Ca in general was more predominantly
longer than 4 weeks.2 Ca carbonate and Ca acetate sub- used in the United States. Interestingly, from the DOPPS
sequently replaced aluminum hydroxide as the most data there was a significantly increased all-cause (but
commonly used phosphate binders but their use is asso- notcardiovascular)mortalityriskassociatedwithahigher
ciated with hypercalcemia, especially in association with Ca dialysate.
the use of vitamin D metabolites or higher dialysate Ca Despiteallstudiessofar,recommendationsworldwide
concentrations.11 Although patients were previously di- arebasedmostlyonopinion,withmortalityandmorbid-
alyzedagainst1.5or1.75mmol/LCabathstopreventCa ity data currently lacking, to answer the question of
depletion, as mentioned with the widespread use of Ca- which dialysate Ca is the safest and most effective. Rec-
salts,asphosphatebinders,reducedCadialysatebecame ommendationsfromLocatellietal.,basedonaconsensus
standard.MorephysiologicaldialysatewithalowerCaof fromthethird‘‘AccordWorkshop,’’heldinParisin2000
1.25mmol/L allowed for increased intestinal Ca absorp- and published in 2002, suggested that the dialysate Ca
tionwithCa-basedmedication,withoutapositivedialysis content should be 1.5 to 1.75mmol/L, with 1.5mmol/L
Ca balance and resultant hypercalcemia.12,13 preferredinpatientstakingCasupplementsorvitaminD
With thischange, however, thereisanassociationwith analoguestoavoidapositiveCabalance.20Theconsensus
worsening secondary HPT, as a result of negative dialysis recommendedadialysateCaconcentrationof1.75mmol/
Ca balances, and the use of Ca-containing binders is L if patients were not on these medications, and it sug-
perhaps only more likely to accelerate the process of Ca gestedthat1.25mmol/Lshouldbeavoidedforprolonged
deposition and vascularcalcification.12,14–17 Also, a lower periods due to risks of aggravating secondary HPT.
dialysateCahasnotbeenshowntoproducepositiveeffects Given the interplay between dialysate Ca concentra-
in a study ofhealth-relatedquality-of-life parameters.17 tionsandmedicationadministrationwithregardtoserum
The more recent introduction of Ca-free binders, with Ca and phosphate control, changes in the practice of
a decrease in the overall intestinal Ca absorption, phosphatebinderprescriptionareimportantinproviding
nowaltersthebalancetowardanoverallnegativeCaload theoptimalCadialysateconcentration.Morethan80%of
with the potential to stimulate PTH production. There- alldialysispatientsaremanagedwithphosphatebinders,
fore, a trend toward the use of higher concentrations Ca-based agents previously being the most predominant
of dialysate Ca has been recommended to avoid Ca worldwide;19 however, the most recent DOPPS data
depletion and 1.5mmol/L Ca bath has subsequently (2002–2004) revealed that 25.9% of patients were tak-
become more accepted for the majority of HD patients. ingtheCa-freebindersevelamer,comparedwith0.1%of
This level seems to be suitable because the moderately patients using sevelamer during the initial observation
negative dialysis balances can be easily counterbalanced period (1996–2001).21 Phosphate binder usage differs
by the administration of mild doses of Ca-containing across countries, with currently over half of patients in
binders, if necessary, in order to ensure a neutral total the United States and some Western European countries
body Ca balance.18 being managed with non-Ca-based binders, although Ca
Hemodialysis International2006; 10:326–337 329
Toussaintetal.
acetate may still be more cost effective.10 In some coun- Cardiovascular morbidity and vascular
tries,non-Ca-basedphosphatebinderssuchassevelamer calcification
andlanthanumarenotreadilyavailableduetoregulatory
and cost issues. The leading cause of mortality in patients with ESKD is
cardiovascular disease.32,33 Compared with the general
population,dialysispatientshavea3-to30-foldincrease
Dialysis Ca physiology
in mortality, depending on the age group examined.33
The diffusion of Ca in HD depends on the Ca gradient This excess in mortality compared with the general pop-
between the serum concentration and the dialysate ulation is not explained by the presence of traditional
concentration. Studies have shown that when the dialy- cardiovascular riskfactors, anda largecomponentofthe
sate Ca is greater than 1.5mmol/L, there is an expected vascular calcification is likely due to the chemical prob-
gain in Ca.11,22,23 Losses by convective transport, lem of Ca and phosphate excess. Precipitation of Ca and
however, can exceed the amount of Ca gained by diffu- phosphate may be responsible for much of the medial
sion22 so ultrafiltration is also an important factor in the arterial calcification and the Ca(cid:1)phosphate product
overall Ca balance. Ca mass balance studies have dem- (Ca(cid:1)P) is an independent risk factor for vascular calci-
onstrated that generally, providing the patient is norm- ficationandcardiovasculardeath.34Ithasalsobeendem-
ocalcemic, a dialysate Ca concentration of 1.75mmol/L onstrated that phosphate levels are linearly and
produces a positive Ca balance and a negative balance independentlyassociatedwithall-causeandcardiovascu-
is obtained with a dialysate Ca of 1.25mmol/L.23–25 lar mortality in dialysis and predialysis patients.34
Dialysate free of Ca has been shown in one early human Vascularcalcification is not, however, as simple as ‘‘Ca
study to produce symptomatic hypocalcemia within the loading’’ with passive precipitation of Ca and phosphate
first 60min of dialysis for chronic HD patients 26 when one or more of these minerals are in excess. It is
and hypotension can also result from inadvertent use of now recognized that this extra-osseous calcification in
a Ca-free dialysate.27 ESKD is an active process involving vascular smooth
Ca ions are extremely important in the contractile muscle cell transformation to osteoblast-like cells with
process of both vascular smooth muscle cells and cardi- elevated phosphate levels and other as yet unidentified
ac myocytes and changes can have significant effects on uremic toxins inducing this differentiation. Only once
hemodynamics.28Whetherthiseffectisaresultofchang- mineralization is initiated will alterations in Ca and
es in myocardial contractility or mediated through vas- phosphate balance accelerate this process via multiple
cular reactivity is unclear. Serum ionized Ca increases mechanisms.35–37 In recent years, several mechanisms
duringsessionswithdialysateCaof1.5and1.75mmol/L have been identified to explain vascular calcification in-
anddecreasestothelowerlimitsofnormalafterHDwith cluding loss of inhibition, induction of bone formation,
1.25mmol/L. Van Kuijk et al., reported that with the circulating nucleational complexes, and cell death.
lower dialysate Ca concentration, there is a significantly An elevated Ca(cid:1)P combination is likely to be a pre-
larger decline in blood pressure compared with higher dominant risk factor and Ca alone may also be problem-
dialysate Ca in patients with normal cardiac function.29 atic because, in general, a positive Ca balance may
This is perhaps related to decreased left ventricular con- promote or accelerate soft-tissue and vascular calcifica-
tractility using the lower dialysate Ca. Stable blood pres- tionevenintheabsenceofhypercalcemia.38Duringcon-
sureisalsoachievedwiththeuseofhigherdialysateCain ventional HD, a positive Ca balance and a concomitant
those patients with impaired cardiac function.30 inflammatory state probably act as co-factors in the
HD with a dialysate Ca bath of 1.75mmol/L therefore development of calcifications.39
seems to be a possible strategy for improving hemody- Studies using electron-beam computed tomography
namic stability in patients, especially for those with (EBCT)haveaccuratelyand quantitatively assessed coro-
cardiac impairment.31 This therapy, however, is limited nary artery calcification with total calcification scores
bytheconcernsofdevelopinghypercalcemiawithresult- proven to be strongly predictive of coronary artery athe-
antexcessiveCaloadsexacerbatingvascularcalcification. rosclerosis and of major future adverse cardiac events in
The recent introduction of calcimimetics, as well as thegeneralpopulation.40,41InthosepatientswithESKD,
the widespread use of Ca-free phosphate binders, may calcificationscoresarealsomarkedlyincreased,especially
providetheopportunitytouseahigherdialysateCacon- atayoungerage,andprogressmorerapidly,althoughthe
centration without the effect of predisposing cardiovas- prognostic significance of EBCT in this population has
cular mortality (Table 1). only recently been investigated.16,42–45
330 Hemodialysis International2006; 10:326–337
Dialysatecalciumconcentration
The presence and extent of vascular calcification in cluded that the effect of serum Ca on blood pressure was
ESKDisconsistentlylinkedtoanincreasedriskofdeath. through left ventricular(LV) stroke volume and output.
Modalitiesfordeterminingthedegreeofcalcification,in- It has been postulated that an increase in serum-ion-
cluding plain radiography,45 ultrasound,46 and EBCT,44 izedCaduringHDcouldalsopotentiallyleadtoimpaired
haveallcorrelatedgreatercalcificationwith poorerprog- LV relaxation. However, using a dialysate Ca concentra-
nosisandshownthatvascularcalcificationisastrongand tion of 1.75mmol/L one study showed that perhaps this
independent predictor of cardiovascular and all-cause wasnotnecessarilythecase,revealingnochangeinDop-
mortality in HD patients. The administration of Ca-con- plermeasuresofLVdiastolicfunctionwithanincreasein
taining phosphate binders is associated with progressive serum Ca after 1hr of HD without ultrafiltration.55 In-
coronary calcification but correlation between dialysate stead,changesintheseLVparameterswerethoughtmore
Ca levels and EBCTis yet to be determined. likely to be related to preload.
Hemodynamic stability on dialysis Renal bone disease
Serum-ionizedCalevelsareadeterminantofvasoconstric- AllpatientswithESKDwillhaverenalbonediseasebythe
tion; therefore, alterations in dialysate Ca concentration time they require dialysis. On dialysis, this does not im-
may impact on arterial compliance. One study looking at provebutprogressesandinHDpatientsrenalbonedisease
the effect of treatment with lower dialysate Ca revealed isaseriouscomplicationthatcanresultinfractures,bone
favorable changes in blood pressure and arterial compli- pain, and extraosseous calcification. Several different fac-
ance as well as a reduction in serum aldosterone levels torscontributetobonediseaseandaspectrumexistsfrom
(amarkerofvasoactivity).47However,cardiacarrhythmias high bone turnover disease, related to secondary HPT, to
are also more likely to occur in HD patients with lower low bone turnover disease due to osteomalacia or ady-
dialysateCaassociatedwiththepotentialforworseningof namicbonedisease,thelatteraresultofaluminumtoxicity
QT prolongation.48,49 ormorecommonlyovertreatmentofHPTwithvitaminD.
Intradialytic hypotension remains a problem in HD Clinically, the distinction between these pathological
andtheetiologyismultifactorial.Asoutlinedearlier,one diagnoses is often based on the serum PTH level. Para-
predisposition has been low dialysate Ca and one study, thyroid hormone levels of less than 11pmol/L (100pg/
whereHDpatientsunderwentalternatedialysiswith1.25 mL) are suggestive of adynamic bone disease and levels
and 1.75mmol/L dialysate Ca, revealed a minor but sta- greater than 33pmol/L (300pg/mL) are indicative of
tistically significant reduction in mean blood pressure overstimulatingPTHandhighturnoverbonedisease.Di-
with the use of the lower Ca bath.50 Manipulations have alysate Ca has been shown to consistently correlate in-
showntoimproveefficacywiththisregardbyusinghigh- versely with PTH and therefore higher Ca dialysate will
er Ca dialysate.51,52 More hemodynamically stable dialy- suppress HPTand lower Ca levels will improve turnover
sis sessions, without intradialytic hypotension, may be and increase PTH.
achievedwithadialysateCaof1.75mmol/Landresultin The diagnostic value of serum PTH levels to predict
subsequent improved morbidity. For patients with cardi- accurately the nature of renal bone disease, however, is
ac impairment and reduced life-span, the benefits of re- debatable. Levels between 11pmol/L (100pg/ml) and
duction in dialysis events could be weighed against the 55pmol/L (500pg/ml) are probably insufficiently sensi-
potential long-term effects of a higher dialysate Ca con- tive or specific to diagnose either low or high turnover
centration with increases in vascular calcification that bone disease.2 The K/DOQI guidelines suggest that if a
may not affect life expectancy. Increasing the magnesium patient with ESKD and serum levels of intact PTH be-
dialysate concentration to 0.75mmol/L may also be of tween 11 and 55pmol/L develops unexplained hyper-
benefit for a lower (1.25mmol/L) dialysate Ca to reduce calcemia, bone pain, or an increase in bone alkaline
the incidence of intradialytic hypotension.53 phosphatase (ALP) activity, a bone biopsy can be useful.
Blood pressure may be altered by changes in Ca either The bone biopsy will allow more accurate assessment of
through alterations in systemic vascular resistance or the rate of bone formation and bone mineralization and
changes in cardiac output, or both. A study of 8 HD pa- will help guide therapy.2
tients with variable dialysate Ca from 0.5 to 2.5mmol/L For patients with adynamic bone disease (low or low-
showed changes in blood pressure with alterations in Ca normalboneturnover),theuseoflowerdialysatemaybe
levels.54 Higher Ca dialysate augmented cardiac output beneficial. These patients are at a higher risk of cardio-
whileleavingvascularresistanceunchanged,soitwascon- vascularmortalityandoftenhavehighCa(cid:1)Pasaresult
Hemodialysis International2006; 10:326–337 331
Toussaintetal.
Table1 Potential advantages and disadvantages of different dialysate calcium concentrations
Dialysate calcium Advantages Disadvantages
Lower (1.25–1.5mmol/L) Reduces risk of hypercalcemia Potentialfor negative calcium balance
Allows greateruse of vitamin D and and stimulation of PTH
calcium-containing phosphate binders Increasein intra-dialytic hypotension
Benefitin adynamicbone disease
Higher (1.5–1.75mmol/L) Improves hemodynamic stability Greaterrisk of hypercalcemia
Suppression of PTH Limits use of vitamin D and calcium
Beneficial for bone protection in based binders
nocturnal hemodialysis Possible risk of vascularcalcification
PTH=parathyroidhormone.
ofhighserumCalevels.56InoneprospectivestudyofHD ofalternate1.25and1.75mmol/LdialysateCa(2hreach),
patientswithbiochemicalmarkerssuggestiveofadynam- there was a significant reduction in intra-dialytic events,
ic bone disease, dialysate Ca was reduced from 1.75 to describedtoberelatedtoanincreaseincardiacoutputwith
1.25mmol/L in patients to assess bone metabolism.57 an ionized Ca-inducedincreasein myocardialcontractility.
This demonstrated a significant reduction in Ca(cid:1)P The authors concluded that with the use of profiling, by
(5.62–3.95) and an increase in PTH. Parameters of bone individualizing the dialysate Ca concentrations used and
resorption (pyridinoline) and formation (bone ALP) alternatingbetween them, there may bean improvement
were significantly increased, peaking after 12 months. inhemodynamic stability,while simultaneously reducing
Treatment with a lower dialysate Ca may therefore be potential problems with hypercalcemia.
potentially advantageous in this clinical setting to stimu- Despite only a small sample size, this study demon-
late bone turnover. stratedapossiblestrategytohelp ameliorateintradialytic
Anotherstudyreviewing67patients,withthedialysate hypotension,asignificantcauseofpatientmorbidity,but
Careducedfrom1.5to1.25mmol/L,alsoanalyzedbone longer-term cardiovascular morbidity and mortality as
metabolism and revealed an initial increase in PTH and wellaseffectsonrenalbonediseasehavenotbeenanaly-
osteocalcin.58InasubgroupwithinitiallylowPTHlevels zed with Ca profiling.
(o11pmol/L), there was an improvement in adynamic
bone disease. In those patients with PTH 433pmol/L,
Differing dialysis modalities
lowering the dialysate Ca also allowed an increase in the
dose of vitamin D without consequent hypercalcemia, Nocturnal hemodialysis (NHD) provides longer and po-
and a subsequentreduction in PTH. Therefore, reducing tentially more frequent dialysis and has definitely been
dialysateCaallowsmoreflexibleadjustmentofvitaminD proven to provide superior phosphate control compared
tocorrectmetabolicabnormalitiesofbonerelatedtosec- withconventionalhemodialysis(CHD),9,60withNHDpa-
ondary HPT. tients even being able to discontinue phosphate binders.
TheeliminationofCa-containingphosphatebindersatthe
commencementofNHDhaspreviouslybeenshown,how-
Dialysis Ca profiling
ever,toleadtoalossofupto8gofelementalCaperweek
OnepossibilityofutilizingthebenefitsoflowdialysateCa in oral intake, and so exacerbate Ca deficiency and sec-
topreventhypercalcemiabutatthesametimeavoidingin- ondary HPT.61 Increasing the dialysate Ca concentration
tra-dialytichypotensiveepisodesiswiththeuseofCapro- correctsthisproblem,withanoverallnetgainofCatothe
filing. In a randomized crossover trial, Kyriazis et al., patientwhen using a 1.75mmol/L Ca bath.
studied 18 HD patients undertaking 4-hr dialysis with ei- The effects of daily dialysis on Ca balance may differ
ther1.25mmol/LCadialysateorwith1.25mmol/Lforthe dependingonwhetherthemodalityisNHDorshortdaily
first2hrand1.75mmol/Lfortheremaining2hr,followed (SDHD).61–65 The London Daily/NHD Study examined
by a 4-hr session with 1.5mmol/L bath.59 Hemodynamic the effect of dialysate Ca concentration on Ca and phos-
effects were comparable between dialysis with either phate metabolism, comparing daily HD (including NHD
1.25mmol/L or 1.5mmol/L, with hypotension toward the and SDHD) with CHD.61 Patients on NHD were initially
endoftreatmentsessions.WithHDusingthecombination dialyzingagainsta1.25mmol/LCabathwithdemonstra-
332 Hemodialysis International2006; 10:326–337
Dialysatecalciumconcentration
tion of increases in ALP and PTH; predialysis serum Ca serumCalevelsandthereforethiswastherecommended
levelsbecamelowerinpatientsonNHDwithinamonth. dialysatetoreduceaccelerationofboneturnoverandsub-
This observational study showed that increasing the di- sequent development of renal osteodystrophy. Another
alysate Ca concentration in NHD prevented HPT and Japanese study of HD patients also confirmed the neces-
bone disease. Those patients on CHD and SDHD still sityofahigherdialysateCatopreventworseningsecond-
required phosphate binders and did not become Ca ary HPTwhen sevelamer is used as a phosphate binder,
deficienton 1.25mmol/L Cadialysate. Concerns still ex- even with additional active vitamin D supplements.72
ist, though, that higher Ca baths in NHD, however, may Lanthanum carbonate is another newer phosphate
potentially contribute to hypercalcemia, vascular calcifi- binder, although initial concerns with its use surround-
cation, and subsequently more cardiovascular mortality. edthepotentialabsorptionofthiselementandlong-term
Despite the higher Ca levels with increased dialysate accumulationintissues.73Invitro,ithasanticalcification
Ca,theCa(cid:1)PisreducedonNHDbecauseofmuchbet- and antiatherosclerotic properties and may be another
ter phosphate control and although long-term mortality alternative to Ca-based binders but long-term studies
data are not yet available, this mode of dialysis certainly are pending.
provides greater improvements in well-being, cardiovas-
cular outcomes, and bone metabolism.61,62,66,67
Vitamin D analogs
IMPACTS OF NEWER TheprescriptionofactivevitaminDisamajortreatment
to correct hypocalcemia and suppress PTH levels in
PHARMACOLOGICAL MANAGEMENT
ESKD. According to the DOPPS data, 52% of patients
were treated with some form of vitamin D therapy.19
Sevelamer and Lanthanum
Calcitriol (1,25[OH] D ) and alfacalcidol (1a[OH] D )
2 3 2 2
Sevelamer hydrochloride is a newer phosphate binder have been predominantly used, administered by an oral
containing neither Ca nor aluminum. It is useful for oranintravenousroute,butconcernsregardingtherisks
patients requiring better phosphate control and who are of hypercalcemia and hyperphosphatemia have led to
also being administered vitamin D metabolites to reduce the emergence of vitamin D analogues that suppress
the potential for hypercalcemia. Sevelamer has been PTH without affecting serum Ca and phosphate levels.
demonstratedtostabilizecardiaccalcificationandreduce Maxicalcitol (22-oxacalcitriol) and doxercalciferol
the rate of progression by avoiding or reducing the need (1a[OH] D )havebeenstudiedalthoughnonehavebeen
2 2
for Ca-based phosphate binders, therefore providing completely successful in avoiding alterations of Ca and
areductioninCaload.68TheDialysisClinicalOutcomes phosphate and to date have not been proved superior to
Revisited (DCOR) study recently demonstrated that calcitriol and alfacalcidol.74
patientswhousedsevelamerexperienceda9%reduction Paricalcitol (19-nor-1,25[OH] D ) is being more com-
2 2
in risk of death from all causes relative to patients using monly used in the United States, perhaps following the
Ca-based phosphate binders over a 2-year period, with retrospective report of reduced mortality in North Amer-
mortality influenced by age and duration of treatment.69 ican HD patients taking paricalcitol rather than calci-
However, this study did not reveal a significant survival triol.75 No trials as yet have adequately addressed the
benefit for the non-Ca-based binder, failing to meet its implicationofthesenewervitaminDagentsinrelationto
primary or secondary endpoints and showing no signif- dialysate Ca levels.
icant difference in mortality or morbidity with sevelamer
compared with Ca-based phosphate binders.
Calcimimetics
Interestingly, following the initial published literature
revealing the advantages of sevelamer, it was emphasized Theintroductionofcalcimimeticagentsintoclinicalprac-
by Backenroth, in a letter to the editor, that dialysate Ca tice has also had beneficial effects on serum Ca, phos-
was not even included in the study.70 More recently, the phate, and Ca(cid:1)P and have brought increased focus on
effects of different dialysate Ca concentrations were as- the increased mortality risk associated with hyper-
sessed with the use of sevelamer hydrochloride.71 With calcemia.76CinacalcetbindstoandactivatestheCa-sens-
1.37mmol/LCadialysate,serumCalevelsdecreasedand ing receptor in the parathyroid glands, lowering the
PTH levels increased significantly and with 1.25mmol/L threshold for its activation by extra-cellular Ca and di-
Ca dialysate, there was even transient hypocalcemia. The minishing PTH release. Again, similar to the initial trials
group with a dialysate Ca of 1.5mmol/L had unchanged withsevelamer,dialysateCawasnotconsideredwiththe
Hemodialysis International2006; 10:326–337 333
Toussaintetal.
earlystudyinvolvingcinacalcetandthereforetheoptimal withLVdysfunctionorfrequentintra-dialytichypotension,
dialysate Ca bath to be prescribed in the setting of calci- but with reductions to 1.5mmol/L should hypercalcemia
mimetics has not been determined.77 The use of arise. Higher dialysate Ca concentrations of 1.75mmol/L
1.75mmol/L dialysate Cawasassessed ina smallsample mayalsobenecessaryforpatientswhosemedicationlistis
of7HDpatients,withadministrationofcinacalcetinpa- free of Ca-based binders and vitamin D supplements, as
tients with severe secondary HPT showing reduction in well as for patients with marked secondary HPTand also
serum PTH levels and without hypercalcemia.77 those undertaking NHD, although the long-term risk of
vascularcalcification needs exploration.
Adjustment to the dialysate Ca concentration can
Recommendations
change the overall Ca balance to maintain appropriate
Recent changes in the management of mineral metabo- serum levels of Ca and phosphate and therefore reduce
lism in patients with ESKD have placed more emphasis the risks of renal osteodystrophy and cardiovascular dis-
on the concentration of Ca in dialysate. A dialysate Ca ease.DialysateCaconcentrationshouldbemeasuredand
concentration of 1.25 to 1.5mmol/L is often the most taken into consideration in all studies analyzing serum
appropriateforHDpatients.ThenegativedialysisCabal- Ca,calcification,andmineralmetabolisminHDpatients,
ance is countered by the oral administration ofCa-based and as mentioned more research is warranted to deter-
phosphatebindersand,ifnecessary,theuseofvitaminD mine the optimal dialysate level.
analoguesformanagementofsecondaryPTH.Thisallows
an overall neutral total body Ca balance.78 A newer strat-
Response to clinical scenario
egyofre-emergingaluminum-basedphosphatebindersin
some countries andmoreimportantly aluminum-free and With regard to the initial clinical scenario, the predom-
Ca-freebinders,suchassevelamerandlanthanum,world- inant aim for this patient would be for better phosphate
wide, can be used for more optimal control of hyper- controlandgreatersuppressionofPTH.Atthesametime,
phosphatemia without the excessive Ca load and the risk carefulmonitoringofserumcalciumandCa(cid:1)Pisequal-
ofexacerbating vascularcalcification. With this strategy, it ly important to reduce the overall cardiovascular risk. If
maybenecessarytoadjustupwardsthe dialysate Cacon- sevelamerisnotavailable,areductioninphosphatecould
centration with the re-introduction of 1.75mmol/L be achieved through (i) the use of longer, more frequent
dialysate Ca to avoid problems with secondary HPT. The dialysis such as NHD, (ii) stricter dietary phosphate re-
useofnoncalcemicvitaminDanaloguesandcalcimimetics strictions,or(iii)theadditionofmorephosphatebinders,
also allows for higherdialysateCa baths. possibly extra aluminum hydroxide.
The decision to use a certain dialysate Ca should be Lanthanum would also be effective as a noncalcium-
made with results of Ca loading or depleting during di- based phosphate binder, although regulatory restrictions
alysis in association with information regarding the oral and cost issues in some countries may limit its use if
Ca intake allowing an even total-body Ca balance. The sevelamer is unattainable as well. If there are concerns
type and degree of renal bone disease and the associated about aluminum toxicity with aluminum-based binders,
cardiovascular co-morbidities should also influence the anincreaseinCa-containingphosphatebinders(increas-
individualizeddialysateCalevel. Biochemical markers of ing the currently prescribed calcium carbonate to 3 tab-
renal bone disease should be a consideration as a lower lets,3timesdaily)couldbeanoption;however,thereisa
dialysate Ca concentration may be an advantage to those further risk of exacerbating hypercalcemia. The dialysate
HDpatientswithadynamicbonediseasetoincreasebone calciumconcentrationinthissituationshouldbelowered
formation and resorption. Cardiovascular status should and a dialysate calcium level of 1.25 to 1.5mmol/L is
be appreciated when choosing dialysate Ca baths, both probablymostappropriate.Withtheuseofa1.25mmol/
with the attempt at reduction of accelerated arterioscle- L Ca bath, there may be an overall negative Ca balance
rosis as well as providing hemodynamic stability if there potentially worsening hyperparathyroidism (HPT).
is a degree of LV dysfunction. Reducing serum phosphate should also help manage
Recommendations are that patients taking Ca-based secondary HPT. Noncalcemic vitamin D analogues would
phosphate binders should be dialyzed against Ca of 1.25 probablynotprovideanyadditionaladvantagetothecur-
to1.5mmol/L.Lowerdialysateconcentrations(1.25mmol/ rentlyprescribedcalcitriol,althoughparicalcitolmayprove
L)shouldbeusedifadynamicbonediseaseexistswithlow in further studies to reduce hypercalcemia, vascularcalci-
PTH levels. Dialysate concentrations of 1.75mmol/L may fication, and subsequent mortality and therefore may be
beusedtoimprovehemodynamics,especiallyforpatients morebeneficial.Theadditionofacalcimimeticagent,like
334 Hemodialysis International2006; 10:326–337
Dialysatecalciumconcentration
cinacalcet,wouldbeanotherpossiblemanagementoption 11 Malberti F, Surian M, Poggio F, Minoia C, Salvadeo A.
tolowerPTHwithouttheriskofincreasingserumcalcium. Efficacy and safety of long-term treatment with calcium
Theoptimaldialysatecalciumconcentrationswiththeuse carbonateasaphosphatebinder.AmJKidneyDis.1988;
of cinacalcet and paricalcitol have not been determined 6:487–491.
12 Argiles A, Kerr P, Canaud B, Flavier J, Mion C. Calcium
although higher levels would most likely be necessary.
kinetics and the long term effects of lowering dialysate
If the dialysis modality was changed to NHD with an
calcium concentration.Kidney Int. 1993; 43:630–640.
improvement in hyperphosphatemia and withdrawal of
13 FernandezE,BorrasM,PaisB,MontoliuJ.Low-calcium
phosphate binders, then 1.75mmol/L dialysate calcium
dialysatestimulatesparathormonesecretionanditslong-
may be beneficial. This strategy would avoid total body
term use worsens secondary hyperparathyroidism. J Am
Ca depletion, and subsequent worsening HPT, but still Soc Nephrol. 1995; 6:132–135.
likelyreduceCa(cid:1)Pbecauseoftheimpressivereductions 14 Argiles A, Mion C. Low-calcium dialysate worsens sec-
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16 Chertow G, Burke S, Paolo R. Sevelamer attenuates the
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