Chronic Kidney Diseasedrtedwilliams.net/cop/762/762ESRD.pdf · · 2008-01-19NKF Definition of...

Chronic Kidney Chronic Kidney DiseaseDisease

Myrna Y. Munar, Pharm.D., BCPSMyrna Y. Munar, Pharm.D., BCPSAssociate ProfessorAssociate Professor

NKF Definition of Chronic NKF Definition of Chronic Kidney DiseaseKidney Disease

Kidney damage for 3 or more months, as Kidney damage for 3 or more months, as defined by structural or functional defined by structural or functional abnormalities of the kidney, with or without abnormalities of the kidney, with or without decreased GFR, manifested by pathologic decreased GFR, manifested by pathologic abnormalities or markers of kidney damage, abnormalities or markers of kidney damage, including abnormalities in the composition of including abnormalities in the composition of the blood or urine or abnormalities in imaging the blood or urine or abnormalities in imaging tests.tests.GFR < 60 ml/min/1.73mGFR < 60 ml/min/1.73m22 for 3 months or for 3 months or more, with or without kidney damage.more, with or without kidney damage.

–– K/DOQI guidelines Am J K/DOQI guidelines Am J KidnKidn Dis 2002;39(2 Dis 2002;39(2 supplsuppl 1):S181):S18

Staging of CKD Based on GFRStaging of CKD Based on GFR

< 15 need for RRT< 15 need for RRTKidney failureKidney failure55

15 15 –– 2929Severe Severe decdec. GFR. GFR44

30 30 –– 5959Moderate Moderate decdec. GFR. GFR33

60 60 –– 8989Kidney damage with mild Kidney damage with mild decdec. . GFRGFR

22

>> 9090Kidney damage w/normal or inc. Kidney damage w/normal or inc. GFRGFR

11

>> 90 w/risk factors90 w/risk factorsAt increased riskAt increased risk

GFR ml/min/1.73MGFR ml/min/1.73M22DescriptionDescriptionStageStage

NKF-K DOQI AJKD 2002;39:S1

GFR CalculatorsGFR Calculators

Available on Web site Available on Web site http://www.nephron.comhttp://www.nephron.com

DefinitionsDefinitionsESRDESRD

GFR <15 ml/min/1.73 mGFR <15 ml/min/1.73 m22; stage 5 CKD; stage 5 CKDPts require renal replacement therapyPts require renal replacement therapy

UremiaUremiaClinical syndromeClinical syndrome

EpidemiologyEpidemiology

Rate of growth of renal disease is 6Rate of growth of renal disease is 6--7% 7% per yearper year

Largest increase seen in:Largest increase seen in:Pts over 65 yrsPts over 65 yrsAfrican AmericanAfrican AmericanNative AmericanNative American

US Renal Data System (USRDS)US Renal Data System (USRDS)

EpidemiologyEpidemiology

Life expectancy has increased. Life expectancy has increased. Reflects:Reflects:

Improved dialysis equipment/proceduresImproved dialysis equipment/proceduresWider acceptance of dialysisWider acceptance of dialysisIncreased graft survival in tx ptsIncreased graft survival in tx pts

Causes of ESRDCauses of ESRD

DiabetesDiabetes39% of cases39% of cases

HTNHTN28%28%

DM & HTN account for largest increase DM & HTN account for largest increase in ESRD prevalencein ESRD prevalenceGlomerulonephritisGlomerulonephritis

11%11%

Causes of Death w/ESRDCauses of Death w/ESRD

Cardiac diseasesCardiac diseasesInfectionInfectionCerebrovascular diseaseCerebrovascular diseaseMalignancyMalignancy

Clinical ManifestationsClinical Manifestations

Derangement in Na & waterDerangement in Na & waterNa wasting & dehydrationNa wasting & dehydration

Inability to reabsorb NaInability to reabsorb Na

Fluid overloadFluid overload

Clinical Events as GFR DeclinesClinical Events as GFR Declines

65 ml/min (Stage 2 CKD)65 ml/min (Stage 2 CKD)Nocturia, decreased ability to concentrate Nocturia, decreased ability to concentrate urineurine


< 60 ml/min (Stage 3 CKD)< 60 ml/min (Stage 3 CKD)iPTHiPTH levels begin to riselevels begin to riseBegin to see evidence of bone disease at Stage 3 Begin to see evidence of bone disease at Stage 3 CKD (GFR 30CKD (GFR 30--59 ml/min/1.73m59 ml/min/1.73m22))

50 ml/min (Stage 3 CKD)50 ml/min (Stage 3 CKD)AnemiaAnemia

15 ml/min (Stage 4 CKD)15 ml/min (Stage 4 CKD)Decreased K excretion (F&E)Decreased K excretion (F&E)

K excretion is flow dependentK excretion is flow dependentDecreased aldosterone synthesis/effectivenessDecreased aldosterone synthesis/effectiveness


15 ml/min (Stage 4 CKD)15 ml/min (Stage 4 CKD)Acidosis (AcidAcidosis (Acid--Base)Base)

Cannot excrete H ions generated by Cannot excrete H ions generated by metabolism of dietary proteinmetabolism of dietary proteinDecreased GFR Decreased GFR --> decreased filtration of > decreased filtration of urinary buffersurinary buffersImpaired synthesis of ammonia to titrate H ionsImpaired synthesis of ammonia to titrate H ions

Management of Renal Disease Management of Renal Disease ComplicationsComplications

Renal OsteodystrophyRenal Osteodystrophy

Kidney plays impt role in POKidney plays impt role in PO44 excretion excretion and vitamin D activationand vitamin D activationClinical complicationsClinical complications

Early manifestation is pruritisEarly manifestation is pruritisBone painBone painIncreased propensity to fracturesIncreased propensity to fracturesDevelopment of metastatic calcificationsDevelopment of metastatic calcifications

L/T complicationL/T complication

Skeletal abnormalitiesSkeletal abnormalities

ProcessProcess

Hypocalcemia Hypocalcemia --> secretion of > secretion of parathyroid hormone (PTH)parathyroid hormone (PTH)Causes of hypocalcemiaCauses of hypocalcemia

HyperphosphatemiaHyperphosphatemiaDecreased production of 1,25 dihydroxyDecreased production of 1,25 dihydroxy--vitamin Dvitamin D33 aka calcitriolaka calcitriolPeripheral resistance to actions of PTHPeripheral resistance to actions of PTH

HypocalcemiaHypocalcemia

HyperphosphatemiaHyperphosphatemiaAs GFR falls, 30 ml/min, POAs GFR falls, 30 ml/min, PO44 is retained is retained because 70% of ingested PObecause 70% of ingested PO44 is excreted is excreted by kidneysby kidneysPOPO44 complexes with Ca complexes with Ca --> hypocalcemia> hypocalcemia

HypocalcemiaHypocalcemia

Kidneys are responsible for activation of Kidneys are responsible for activation of vitamin D to calcitriolvitamin D to calcitriol

Activation occurs in proximal tubule by Activation occurs in proximal tubule by mitochondrial Pmitochondrial P--450 system450 systemEnzyme involved in activation is 1Enzyme involved in activation is 1--alphaalpha--hydroxylasehydroxylaseDecreased renal mass/nephron loss Decreased renal mass/nephron loss --> > decreased ability to produce calcitrioldecreased ability to produce calcitriol

CalcitriolCalcitriol

Interacts with intestinal receptors to Interacts with intestinal receptors to increase Ca absorptionincrease Ca absorption2 effects in renal failure:2 effects in renal failure:

11stst effect of decreased calcitriol effect of decreased calcitriol --> > decreased Ca absorptiondecreased Ca absorption22ndnd effect of decreased calcitriol effect of decreased calcitriol --> > impaired bone mineralizationimpaired bone mineralization

Hypocalcemia Hypocalcemia --> HyperPTH> HyperPTH

Increased PTHSecondary

Hyperparathyoidism

Hypocalcemia

ImpairedPhospateExcretion

Impaired bonemineralizationOsteomalacia

more later


Hyperparathyroidism

Hypocalcemia

DecreasedProductionCalcitriol

Nephron Loss

Consequences of Consequences of HyperphosphatemiaHyperphosphatemia

IncreasedCa x P product:

Soft-tissue (metastatic)calcifications

Blocks calcitriol-effectto inhibit

PTH secretion

Direct effect ofincreased PTH

Hyperphosphatemia

Hyperphosphatemia and PTHHyperphosphatemia and PTH

Phosphate has a direct stimulatory Phosphate has a direct stimulatory effect on PTH glandeffect on PTH gland

High phosphate diet High phosphate diet --> increased mRNA > increased mRNA expression per cell and PTH cell expression per cell and PTH cell hyperplasiahyperplasiaLow phosphate diet Low phosphate diet --> post transcriptional > post transcriptional decrease in PTH mRNA levelsdecrease in PTH mRNA levelsLow phosphate diet decreases serum PTHLow phosphate diet decreases serum PTH

Observed in rats, dogsObserved in rats, dogsObserved in ESRD patientsObserved in ESRD patients

Normal Effects of PTHNormal Effects of PTHPhysiologic attempt to restore normal Physiologic attempt to restore normal [Ca] and [PO[Ca] and [PO44]]

Stimulates 1Stimulates 1--alpha alpha hydroxylasehydroxylase activity activity --> > increased calcitriolincreased calcitriolIncreased GI absorption of CaIncreased GI absorption of CaIncreased renal Ca reabsorption; Increased renal Ca reabsorption; decreased renal CL of Cadecreased renal CL of CaDecreased renal tubular reabsorption of Decreased renal tubular reabsorption of POPO44; increased renal PO; increased renal PO44 excretionexcretion

Maintains Ca & POMaintains Ca & PO44 homeostasis until homeostasis until GFR fall to < 25GFR fall to < 25--30% of normal30% of normal…….then.then

Secondary Secondary HyperparathyroidismHyperparathyroidism

As renal fxn worsens,As renal fxn worsens,Sufficient production of calcitriol can no Sufficient production of calcitriol can no longer be maintained longer be maintained --> PTH biosynthesis > PTH biosynthesis increasesincreasesPeripheral resistance (1Peripheral resistance (1oo) renal to PTH) renal to PTH……Persistent hypocalcemiaPersistent hypocalcemia……Leads to REDIRECTION OF PTH TO BONELeads to REDIRECTION OF PTH TO BONE

Sacrifice the integrity of bone in an effort to Sacrifice the integrity of bone in an effort to maintain normal [Ca]maintain normal [Ca]Increased bone resorption Increased bone resorption

22oo HyperparathyroidismHyperparathyroidism

Increasedrenal Ca

reabsorption

Decreased renaltubular

reabsorption ofphosphate

IncreasedCa mobilization

from bone


Hyperparathyroidism

Classification of Renal Bone Classification of Renal Bone DiseaseDisease

High turnover lesionsHigh turnover lesionsOsteitis fibrosa cysticaOsteitis fibrosa cysticaDue to persistently elevated PTHDue to persistently elevated PTHPTH & ILPTH & IL--1, IL1, IL--6, IL6, IL--11, TNF, GM11, TNF, GM--CSF, & CSF, & MM--CSF recruit & differentiate CSF recruit & differentiate osteoclastosteoclastprecursorsprecursorsActive bone resorptionActive bone resorption

Increase in number & size of osteoclastsIncrease in number & size of osteoclastsIncrease in osteoblastic activity, but normal Increase in osteoblastic activity, but normal bone is replaced by fibrous tissuebone is replaced by fibrous tissue

OsteitisOsteitis FibrosaFibrosa CysticaCystica

Clinical consequences:Clinical consequences:FracturesFracturesSkeletal deformitiesSkeletal deformitiesTendon ruptureTendon ruptureBone painBone pain


Low turnover lesionsLow turnover lesionsOsteomalacia 2Osteomalacia 2oo to:to:

Calcitriol deficiencyCalcitriol deficiency–– Mineralization of bone depends on an Mineralization of bone depends on an

adequate supply of calcitrioladequate supply of calcitriol–– Impaired formation of calcitriol Impaired formation of calcitriol --> decreased > decreased

Ca Ca --> impaired mineralization> impaired mineralization

Persistent metabolic acidosisPersistent metabolic acidosis–– Bone bufferingBone buffering

Aluminum accumulationAluminum accumulation–– Aluminum bone diseaseAluminum bone disease


Low turnover lesionsLow turnover lesionsOsteomalacia contOsteomalacia cont’’dd

Decreased bone formation & turnoverDecreased bone formation & turnoverFurther impairment in the mineralization Further impairment in the mineralization of newly formed bone of newly formed bone --> unmineralized > unmineralized bone collagen (osteoid)bone collagen (osteoid)Accumulation of Accumulation of osteoidosteoidPrevention of Prevention of osteomalaciaosteomalacia w/calcium w/calcium supplementation, calcitriol, correction of supplementation, calcitriol, correction of acidosisacidosis


Adynamic bone diseaseAdynamic bone diseaseOveruse/overtxmt of vitamin D Overuse/overtxmt of vitamin D analogues or calciumanalogues or calcium--containing containing phosphate bindersphosphate binders

Bone LesionsBone Lesions

A=normal boneA=normal boneB=osteitis B=osteitis fibrosafibrosa cysticacysticaC=osteomalaciaC=osteomalacia

Unmineralized Unmineralized bonebone

D=mixed dzD=mixed dzE=adynamic E=adynamic bone diseasebone disease

Manifestations of Renal Manifestations of Renal OsteodystrophyOsteodystrophy

PruritisPruritisCalcium deposits in the skinCalcium deposits in the skin

OsteomalaciaOsteomalaciaSoftening of the bonesSoftening of the bones

OsteoporosisOsteoporosisBone lossBone loss

OsteosclerosisOsteosclerosisAbnormal bone Abnormal bone density/hardening/depositiondensity/hardening/deposition

Manifestations of Renal Manifestations of Renal OsteodystrophyOsteodystrophy

CalciphylaxisCalciphylaxisCalcifications leading to ischemic necrosis Calcifications leading to ischemic necrosis of tips of fingers & toesof tips of fingers & toes

Red eyesRed eyesCalcifications of the conjunctivaeCalcifications of the conjunctivae

Band keratopathyBand keratopathyCalcifications of the corneaCalcifications of the cornea

Metastatic CalcificationMetastatic CalcificationOccurs when CaxPOOccurs when CaxPO44product > 55 mgproduct > 55 mg22/dl/dl22

Hyperphosphatemia plays a Hyperphosphatemia plays a major rolemajor roleCurrent K/DOQI Current K/DOQI recommendations are to recommendations are to maintain product < 55 maintain product < 55 mgmg22/dl/dl22

Can occur in visceral & Can occur in visceral & nonvisceral tissuesnonvisceral tissuesVisceral: heart lungsVisceral: heart lungsNonvisceral: joints, Nonvisceral: joints, muscle, SQ tissue, tissue muscle, SQ tissue, tissue near tendonsnear tendons

Massive softMassive soft--tissue tissue calcification of the calcification of the foot of a patient on foot of a patient on longlong--term term hemodialysishemodialysis

Archives of Archives of Orthopedic & Trauma Orthopedic & Trauma Surgery Surgery 2003;123(1):512003;123(1):51--33

Cardiac calcificationCardiac calcification

Occurs when CaxPOOccurs when CaxPO44 product > 70 product > 70 mgmg22/dl/dl22

Cardiac calcifications have been Cardiac calcifications have been reported in 60% of dialysis pts upon reported in 60% of dialysis pts upon autopsy autopsy (AJKD 1996;27:394(AJKD 1996;27:394--401; Nephrol Dial Transplant 401; Nephrol Dial Transplant 1998;13:20371998;13:2037--40)40)

Found in myocardium, pericardium, conduction Found in myocardium, pericardium, conduction system, aortic & mitral valves, myocardial & system, aortic & mitral valves, myocardial & coronary arteriescoronary arteriesMay lead to arrhythmia, LV dysfxn, aortic & mitral May lead to arrhythmia, LV dysfxn, aortic & mitral stenosis & stenosis & regurgregurg, heart block, ischemia, CHF, , heart block, ischemia, CHF, deathdeath

Vascular calcificationVascular calcification

Phosphorus may enter smooth muscle cells of Phosphorus may enter smooth muscle cells of blood vesselsblood vesselsPhosphorus alters the phenotype of smooth Phosphorus alters the phenotype of smooth muscle cells causing them to change into muscle cells causing them to change into osteoblastsosteoblasts (bone(bone--laying cells)laying cells)This begins the process of blood vessel This begins the process of blood vessel calcificationcalcificationCalcification of coronary arteries is associated Calcification of coronary arteries is associated with increased CV mortality in patients with increased CV mortality in patients w/Stage 5 CKD (GFR < 15)w/Stage 5 CKD (GFR < 15)

Computed Computed tomography tomography (CT) sections (CT) sections from a 27 year from a 27 year old male old male hemodialysis pt hemodialysis pt showing showing calcification in calcification in all 3 coronary all 3 coronary arteries and arteries and aortaaorta

aorta Circulation 2002; 106:100-105

Metastatic pulmonary calcification after renal transplantationCXR showing numerous diffuse confluent nodular opacities.Ref: Eur Respir J 1997;10:1025-7

Metastatic pulmonary calcification after renal transplantationComputed tomography (CT) scan of the chest.Ref: Eur Respir J 1997;10:1025-7

Metastatic calcificationsMetastatic calcifications

FactorsFactorsElevated PTHElevated PTHHyperphosphatemiaHyperphosphatemiaHypercalcemiaHypercalcemiaElevated Ca x P productElevated Ca x P product

Hip FracturesHip Fractures

Incidence of hip fractures in the dialysis Incidence of hip fractures in the dialysis population is 4 x general populationpopulation is 4 x general populationAssociated with 1 year mortality 2x that Associated with 1 year mortality 2x that of dialysis patient without hip fractureof dialysis patient without hip fracture

Ref: Ref: LeinauLeinau L et al, L et al, SeminSemin Dialysis Dialysis 2006;19(1):752006;19(1):75--99

DetectionDetection

Q monthQ monthQ 3 monthsQ 3 months<15 or <15 or dialysisdialysis

55

Q 3 monthsQ 3 monthsQ 3 monthsQ 3 months1515--292944

Q 12 Q 12 monthsmonths

Q 12 Q 12 monthsmonths

3030--595933

Ca & POCa & PO44iPTHiPTHGFR GFR ml/min/1.73 ml/min/1.73 mm22

CKD StageCKD Stage

ManagementManagement

HyperphosphatemiaHyperphosphatemia

Need to maintain serum [PONeed to maintain serum [PO44] within the ] within the near near normal normal rangerange

CKD Stage 3 & 4 goal POCKD Stage 3 & 4 goal PO44 = 2.7 = 2.7 –– 4.6 mg/dl4.6 mg/dlCKD Stage 5 goal POCKD Stage 5 goal PO44 = 3.5 = 3.5 –– 5.5 mg/dl5.5 mg/dl

In healthy pts w/ good renal fxn: 2.2In healthy pts w/ good renal fxn: 2.2--4.2 mg/dl4.2 mg/dl

Avoid hypophosphatemia to decrease the risk of Avoid hypophosphatemia to decrease the risk of osteomalacia (softening of the bones)osteomalacia (softening of the bones)

2 methods: dietary restriction, PO2 methods: dietary restriction, PO44 bindersbinders

Dietary RestrictionDietary Restriction

Limit intake to 800Limit intake to 800--1000 mg/d in pts on 1000 mg/d in pts on dialysisdialysis

HD removes 500HD removes 500--700 mg PO700 mg PO44/session/sessionPD removes 300 mg/dayPD removes 300 mg/day

Use more severe restrictions in pts not Use more severe restrictions in pts not yet on HDyet on HD

Note: Usual daily intake in healthy pts is Note: Usual daily intake in healthy pts is 10001000--1800 mg/d1800 mg/d

High POHigh PO44 FoodsFoods

Dairy foodsDairy foodsMilk, eggs, butter, Milk, eggs, butter, ice cream, cheeseice cream, cheese

MeatsMeatsChocolateChocolateCarbonated Carbonated beveragesbeverages

Beer, colaBeer, cola

NutsNuts

LegumesLegumesBeans, lentils, peas, Beans, lentils, peas, soybeans, soy foodssoybeans, soy foods

Breads & cerealsBreads & cerealsBarley, bran, Barley, bran, cornbread, wholecornbread, whole--grain breadsgrain breads

Phosphate BindersPhosphate BindersUsed when pts cannot control [POUsed when pts cannot control [PO44] ] with diet and dialysis alonewith diet and dialysis aloneMajority of pts require phosphate Majority of pts require phosphate bindersbinders

CalciumCalcium--containing binders (L/T use)containing binders (L/T use)CaCOCaCO33 or Ca acetateor Ca acetate

Polymer: sevelamer (L/T use)Polymer: sevelamer (L/T use)AluminumAluminum--containing binders (S/T use)containing binders (S/T use)

AlOHAlOH: : AmphojelAmphojel, , AlternagelAlternagel, , AluAlu--Tabs/Caps, Tabs/Caps, BasaljelBasaljel

GuidelinesGuidelinesBind dietary POBind dietary PO44 in the GI tractin the GI tract

Decreased PODecreased PO44 absorptionabsorptionIncreased fecal elimination of bound POIncreased fecal elimination of bound PO44

Administer immediately before or with Administer immediately before or with mealsmealsAdjust dose to size/timing of mealsAdjust dose to size/timing of mealsAvoid longAvoid long--term use of aluminumterm use of aluminum--containing binderscontaining binders

Aluminum accumulation & toxicityAluminum accumulation & toxicity

Calcium Carbonate (CaCOCalcium Carbonate (CaCO33))

Carbonate salt may correct acidosisCarbonate salt may correct acidosisInexpensiveInexpensiveContains a high % of elemental CaContains a high % of elemental CaProvides Ca supplementationProvides Ca supplementation

May help correct hypocalcemia May help correct hypocalcemia –– dec. PTH dec. PTH BUT may cause hypercalcemiaBUT may cause hypercalcemia

Generic products may have poor Generic products may have poor dissolution characteristicsdissolution characteristics

CalciumCalcium--Containing ProductsContaining Products

Abdominal Abdominal roentgenogram roentgenogram showing dialysis pt showing dialysis pt w/poor dissoln of w/poor dissoln of generic Cageneric Ca--containing bindercontaining binder

Calcium AcetateCalcium Acetate

Claim to fame:Claim to fame:It has twice the binding capacity for POIt has twice the binding capacity for PO44per Ca compared to CaCOper Ca compared to CaCO33

Phoslo 667 mg 2Phoslo 667 mg 2--3 tabs with meals3 tabs with meals167 mg of elemental Ca167 mg of elemental Ca

Contains Ca, so can also cause Contains Ca, so can also cause hypercalcemiahypercalcemia

Calcium CitrateCalcium Citrate

Disadvantages:Disadvantages:Citrate may enhance aluminum absorptionCitrate may enhance aluminum absorption

Risk aluminum toxicityRisk aluminum toxicity

Do not use with aluminumDo not use with aluminum--containing containing binders (incl. Sucralfate)binders (incl. Sucralfate)AluminumAluminum--citrate complexes may inhibit citrate complexes may inhibit bone growth & exacerbate aluminum bone bone growth & exacerbate aluminum bone dzdz

CalciumCalcium--containing Binderscontaining Binders

Total dosage of elemental calcium should not Total dosage of elemental calcium should not exceed 1500 mg/dayexceed 1500 mg/dayTotal intake of elemental calcium (including Total intake of elemental calcium (including dietary calcium) should not exceed 2000 dietary calcium) should not exceed 2000 mg/daymg/dayShould not be used in HD pts who are Should not be used in HD pts who are hypercalemichypercalemic (corrected serum Ca >10.2 (corrected serum Ca >10.2 mg/dl or whose iPTH < 150 pg/ml)mg/dl or whose iPTH < 150 pg/ml)Pts who have vascular and/or softPts who have vascular and/or soft--tissue tissue calcifications should use noncalcifications should use non--calcium calcium containing binderscontaining binders

55300 mg300 mg750 mg750 mgTums EXTums EX

3.753.75400 mg400 mg1000 mg1000 mgTums UltraTums Ultra

33500 mg500 mg1250 mg1250 mgTums 500Tums 500

7.57.5200 mg200 mg500 mg500 mgTumsTums

Number of Number of Pills to Pills to Equal about Equal about 1500 mg 1500 mg Elemental Elemental CaCa

Elemental Elemental CaCa

ContentContentBrand NameBrand Name

7.57.5200 mg200 mg500 mg500 mgChoozChooz(gum)(gum)

33500 mg500 mg1250 mg1250 mgCalciChewCalciChew

Not RecommendedNot RecommendedCitraCalCitraCal(citrate)(citrate)

99167 mg167 mg667 mg667 mgPhosLoPhosLo

Number of Number of Pills to Pills to Equal about Equal about 1500 mg 1500 mg Elemental Elemental CaCa

Elemental Elemental CaCa

ContentContentBrand NameBrand Name

AluminumAluminum--containing Binderscontaining Binders

Use aluminumUse aluminum--containing binders when:containing binders when:POPO44 is markedly elevated (>7 mg/dl)is markedly elevated (>7 mg/dl)Double product is elevated > 60Double product is elevated > 60--75 mg/dl75 mg/dl……Minimize risk of metastatic calcificationsMinimize risk of metastatic calcifications

Pts who cannot be controlled w/CaPts who cannot be controlled w/Ca--containing binders alonecontaining binders alonePts who develop hypercalcemia from CaPts who develop hypercalcemia from Ca--containing bindercontaining binder

AluminumAluminum--containing Binderscontaining Binders

3030--60 ml po with meals60 ml po with meals3030--60 ml po with meals60 ml po with meals11--3 tabs with meals3 tabs with meals11--3 tabs with meals3 tabs with meals

AmphojelAmphojelAlternagelAlternagelAluAlu--Tab 500 mgTab 500 mgAluAlu--Cap 400 mgCap 400 mg

Usual Daily DoseUsual Daily DoseOTC ProductOTC Product

AluminumAluminum--containing Binderscontaining BindersSwitch to a CaSwitch to a Ca--containing binder when containing binder when serum [POserum [PO44] ] << 6 mg/dl6 mg/dlUse S/T (4 weeks) Use S/T (4 weeks) Avoid L/T useAvoid L/T useSituations of aluminum toxicity:Situations of aluminum toxicity:

Concurrent use of aluminumConcurrent use of aluminum-- & citrate& citrate--containing productscontaining productsHigh [aluminum] in dialysateHigh [aluminum] in dialysateRare nowadays: use of Rare nowadays: use of deionizeddeionized water & water & reverse osmosis to clear aluminumreverse osmosis to clear aluminum

Aluminum Toxicity Aluminum Toxicity –– Acute Acute Aluminum NeurotoxicityAluminum Neurotoxicity

Features:Features:Altered consciousnessAltered consciousnessSeizuresSeizuresComaComaUsually progresses to deathUsually progresses to death

Hi mortalityHi mortality

Aluminum Toxicity Aluminum Toxicity –– Dialysis Dialysis EncephalopathyEncephalopathy

Features – Subacute syndrome:Speech abnormalitiesAltered consciousnessSeizuresOften intermittent and worsens transiently after HDUsually slowly progressive

Aluminum Toxicity Aluminum Toxicity –– Bone Bone DiseaseDisease

Impaired bone mineralization Impaired bone mineralization --> > osteomalaciaosteomalaciaAltered bone cell proliferation Altered bone cell proliferation --> > adynamic bone diseaseadynamic bone diseaseFeatures:Features:

Bone painBone painFracturesFracturesMuscle weaknessMuscle weakness

Aluminum Toxicity Aluminum Toxicity –– MicrocyticMicrocyticAnemia & Anemia & EpoEpo ResistanceResistance

Aluminum competes with Fe for the Aluminum competes with Fe for the same absorption and cellular uptake same absorption and cellular uptake pathwayspathwaysDecreased Decreased erythropoiesiserythropoiesisFeatures:Features:

MicrocyticMicrocytic anemiaanemiaNo evidence of iron deficiencyNo evidence of iron deficiencyNo response to iron therapyNo response to iron therapy

Aluminum ToxicityAluminum Toxicity

Difficult to treatDifficult to treatPREVENTION IS KEYPREVENTION IS KEYHD does not remove aluminumHD does not remove aluminum

Highly bound to transferrinHighly bound to transferrin

Pts with Sx of organ dysfxn should receive Pts with Sx of organ dysfxn should receive chelation therapy (DFO)chelation therapy (DFO)

DFO DFO chelateschelates aluminum, then hi flux or hi aluminum, then hi flux or hi efficiency is used to remove efficiency is used to remove chelatedchelated productproduct

MagnesiumMagnesium--containing POcontaining PO44BindersBinders

Recommended in textbook BUT NOT Recommended in textbook BUT NOT USEDUSED

Risk of hypermagnesemiaRisk of hypermagnesemiaEgs Maalox, MylantaEgs Maalox, MylantaDo not use magnesium laxative eg MOMDo not use magnesium laxative eg MOM

NonNon--calcium, noncalcium, non--aluminum, aluminum, nonnon--magnesiummagnesium--containing containing

phosphate bindersphosphate binders

Sevelamer (RenaGel)Sevelamer (RenaGel)Nonabsorbable polymerNonabsorbable polymer--based PObased PO44binding agent; forms ionic & to a lesser binding agent; forms ionic & to a lesser extent H bonds w/POextent H bonds w/PO44

Does not contain Ca, Al, or Mg so no Does not contain Ca, Al, or Mg so no accumulation of these ionsaccumulation of these ions

No risk of hypercalcemiaNo risk of hypercalcemia400, 800 mg tabs400, 800 mg tabs

TID w/mealsTID w/mealsNo studies, but manufacturer No studies, but manufacturer recommends no other meds 1hr before recommends no other meds 1hr before or 3 hrs after sevelamer doseor 3 hrs after sevelamer dose

Sevelamer vs Ca AcetateSevelamer vs Ca Acetate

N=83 adult HD pts (age 54.4 N=83 adult HD pts (age 54.4 ++ 15 yrs)15 yrs)OpenOpen--label, randomized, crossover studylabel, randomized, crossover study22--week POweek PO44 binder washout periodbinder washout periodRandomized to: sevelamer 465 mg cap 2Randomized to: sevelamer 465 mg cap 2--4 4 caps tid wm or Ca acetate 667 mg tabs 1caps tid wm or Ca acetate 667 mg tabs 1--3 3 tabs tid wm to achieve serum [POtabs tid wm to achieve serum [PO44] 2.5] 2.5--5.5 5.5 mg/dl x 8 wksmg/dl x 8 wks22--week washout, then crossed over to other week washout, then crossed over to other txmttxmt

Ref: Am J Kidn Dis 1999;33(4):694Ref: Am J Kidn Dis 1999;33(4):694--701701

HypercalcemiaHypercalcemia

Ca acetateCa acetate--treated pts had a higher incidence of treated pts had a higher incidence of hypercalcemia during treatmenthypercalcemia during treatment

Serum [POSerum [PO44]]

Observed a similar decrease in [POObserved a similar decrease in [PO44] ] between sevelamer & Ca acetatebetween sevelamer & Ca acetate

L/T Effects of Sevelamer on L/T Effects of Sevelamer on CaxPOCaxPO44 Product & LipidsProduct & Lipids

Premise:Premise:NonNon--aluminumaluminum--, non, non--calciumcalcium--containing containing binder so should have no effects on CaxPObinder so should have no effects on CaxPO44productproductMay also have favorable effect on lipid May also have favorable effect on lipid profilesprofiles

Binds bile acids, resulting in increased Binds bile acids, resulting in increased fecal bile acid excretion & reduction in fecal bile acid excretion & reduction in LDLLDL

N=192 adult HD ptsN=192 adult HD ptsReceived openReceived open--label sevelamerlabel sevelamer

Nephrol Dial Transplant 1999;14(12):2907Nephrol Dial Transplant 1999;14(12):2907--1414

ResultsResults

+0.15 +0.15 ++ 0.290.29HDL mmol/LHDL mmol/L

--0.81 0.81 ++ 0.750.75LDL mmol/LLDL mmol/L

--1.46 1.46 ++ 1.781.78CaxPOCaxPO4 4 productproduct

0.08 0.08 ++ 0.220.22Serum [Ca] mmol/LSerum [Ca] mmol/L

--0.71 0.71 ++ 0.770.77Serum [POSerum [PO44] mmol/L] mmol/L

Mean Change in:Mean Change in:SevelamerSevelamer--treated ptstreated pts

P < 0.0001, all comparisons

Lanthanum carbonateLanthanum carbonate

FosrenolFosrenol (Shire)(Shire)NonNon--aluminumaluminum--, non, non--calciumcalcium--containing binder so should have no containing binder so should have no effects on CaxPOeffects on CaxPO44 productproductTrivalent Trivalent cationcation found in the environment and found in the environment and seawaterseawaterBinds phosphate in the gutBinds phosphate in the gutF < 0.002%F < 0.002%250 250 –– 1000 mg chewable tablets1000 mg chewable tablets

Lanthanum carbonate vs Lanthanum carbonate vs standard therapy: HD ptsstandard therapy: HD pts

n=1359 chronic HD ptsn=1359 chronic HD pts11--3 week washout period3 week washout periodPts were randomized to receive lanthanum carbonate Pts were randomized to receive lanthanum carbonate initial dose of 750 or 1500 mg/day DD after meals initial dose of 750 or 1500 mg/day DD after meals (n=682) or standard therapy w/pre(n=682) or standard therapy w/pre--study phosphate study phosphate binder (n=277)binder (n=277)Doses were titrated to achieve serum PODoses were titrated to achieve serum PO44 level level << 5.9 5.9 mg/dl (before the DOQI mg/dl (before the DOQI quidelinesquidelines of <5.5 mg/dl)of <5.5 mg/dl)66--week dose titration followed by 24 month week dose titration followed by 24 month maintenance phasemaintenance phasePrimary goal: L/T safety of lanthanum vs standard Primary goal: L/T safety of lanthanum vs standard therapy; Secondary goal: efficacy of lanthanum vs therapy; Secondary goal: efficacy of lanthanum vs standard therapystandard therapy

Clin Nephrol 2006;65(3):191-202

Adverse EventsAdverse Events

Treatment related AE occurred in Treatment related AE occurred in >> 15% of 15% of total ptstotal ptsMost common were GI both groups (N/V/D, Most common were GI both groups (N/V/D, abdominal pain)abdominal pain)HypercalcemiaHypercalcemia::

lanthanum 4.3% vs standard lanthanum 4.3% vs standard txtx 8.4%8.4%

Low incidence of Low incidence of biliarybiliary/liver disorder:/liver disorder:lanthanum 4% vs standard therapy 7%lanthanum 4% vs standard therapy 7%

No No pp values reportedvalues reported

Serum PhosphateSerum Phosphate

% Pts w/Controlled Phosphate% Pts w/Controlled Phosphate

Serum CalciumSerum Calcium

Serum PTHSerum PTH

Shaded area = desired range

ConclusionsConclusions

Similar tolerabilitySimilar tolerabilitySimilar efficacySimilar efficacyLanthanum carbonate maintains serum Lanthanum carbonate maintains serum calcium levels at a lower level than calcium levels at a lower level than standard therapystandard therapy

Calcium SupplementationCalcium Supplementation

Once POOnce PO44 has been controlled, achieve has been controlled, achieve normocalcemianormocalcemiaTarget serum [Ca] 8.4Target serum [Ca] 8.4--10.2 mg/dl; 8.410.2 mg/dl; 8.4--9.5 mg/dl in CKD stage 59.5 mg/dl in CKD stage 5Achieved by administering Ca Achieved by administering Ca supplements supplements betweenbetween mealsmeals

Treatment Failure of POTreatment Failure of PO44 BindersBinders

Poor compliancePoor complianceGI upsetGI upsetOTC products advertised as antacids or Ca OTC products advertised as antacids or Ca supplements supplements --> confusion> confusion

Educate pt that it is a phosphate binderEducate pt that it is a phosphate binder

Poor dissolnPoor dissolnPresence of severe hyperparathyroidismPresence of severe hyperparathyroidism

Questions (not a clicker question)Questions (not a clicker question)

How would you prescribe POHow would you prescribe PO44 binders in binders in the following situations?the following situations?

NPONPOContinuous enteral tube feedingsContinuous enteral tube feedingsTPNTPNNo breakfast, regular lunch, big supperNo breakfast, regular lunch, big supperPt receiving po Fe supplementsPt receiving po Fe supplements

22oo HyperparathyroidismHyperparathyroidismInitiated by hypocalcemiaInitiated by hypocalcemia

Recall, Recall, decreased calcitrioldecreased calcitriol & increased PO& increased PO44contribute to hypocalcemia contribute to hypocalcemia --> increased > increased PTHPTH

Shift in Ca set pointShift in Ca set pointSerum [Ca] necessary to suppress PTH is Serum [Ca] necessary to suppress PTH is higher (recall, target serum [Ca] 9higher (recall, target serum [Ca] 9--11 11 mg/dl)mg/dl)

Parathyroids are insensitive to negative Parathyroids are insensitive to negative feedback controlsfeedback controls

Set Point Set Point –– SigmoidalSigmoidal PTHPTH--Ca Ca Relationship Relationship n=5 ptsn=5 pts

1 = [PO1 = [PO44] 8.5 mg/dl ] 8.5 mg/dl --> > set point [Ca] 5.1set point [Ca] 5.12 = [PO2 = [PO44] 7.0 mg/dl ] 7.0 mg/dl --> > set point [Ca] 4.8set point [Ca] 4.81 = [PO1 = [PO44] 5.4 mg/dl ] 5.4 mg/dl --> > set point [Ca] 4.6set point [Ca] 4.6Q: What happens to the Q: What happens to the set point as [POset point as [PO44] ] increases?increases?

Abstract JASN 1997; Abstract JASN 1997; 8:556; Kidney 8:556; Kidney IntInt1999;suppl 73:S311999;suppl 73:S31--S37S37

123

Set Point Set Point –– SigmoidalSigmoidal PTHPTH--Ca Ca Relationship Relationship n=5 ptsn=5 pts

Q: What happens to Q: What happens to the set point as the set point as [PO[PO44] increases?] increases?

Shifted to right Shifted to right --> > need higher [Ca] to need higher [Ca] to suppress PTHsuppress PTHControl of POControl of PO44results in lower results in lower [PTH][PTH]

Abstract JASN 1997; Abstract JASN 1997; 8:556; Kidney 8:556; Kidney IntInt1999;suppl 73:S311999;suppl 73:S31--S37S37

123

CalcitriolCalcitriolSuppresses the Suppresses the synthesis & release of synthesis & release of PTHPTH

Binds to target cells (VDR Binds to target cells (VDR = vitamin D receptor) & = vitamin D receptor) & inhibits PTH gene inhibits PTH gene transcriptiontranscriptionDirectly interacts Directly interacts w/receptors on the PTH w/receptors on the PTH gland to inhibit PTH gland to inhibit PTH secretionsecretion

Interacts with intestinal Interacts with intestinal receptors receptors --> increased > increased Ca absorption Ca absorption decdec. . PTHPTH

When to start therapyWhen to start therapy

Achieve normophosphatemia firstAchieve normophosphatemia firstSerum [POSerum [PO44] <5.5 mg/dl (stage 5 CKD)] <5.5 mg/dl (stage 5 CKD)Serum [POSerum [PO44] <4.6 mg/dl (stages 3] <4.6 mg/dl (stages 3--4 CKD)4 CKD)HyperphosphatemiaHyperphosphatemia

Causes resistance to the PTHCauses resistance to the PTH--suppressing suppressing effects of vita D analogseffects of vita D analogsDirectly stimulates PTH releaseDirectly stimulates PTH releaseIf Ca increases with vita D analog, then If Ca increases with vita D analog, then increased risk of metastatic calcificationsincreased risk of metastatic calcifications

When to start therapyWhen to start therapy

<5.5<5.5<9.5<9.5>150>150(target 150(target 150--300)300)

Stage 5 CKDStage 5 CKDGFR <15GFR <15

<4.6<4.6<9.5<9.5>110>110(target 70(target 70--110)110)

Stage 4 CKDStage 4 CKDGFR 15GFR 15--2929

<4.6<4.6<9.5<9.5>70>70(target 35(target 35--70)70)

Stage 3 CKDStage 3 CKDGFR 30GFR 30--5959

Serum POSerum PO44Serum Ca Serum Ca mg/dlmg/dl

iPTH pg/mliPTH pg/ml

Vitamin D AnalogsVitamin D Analogs

Use agents that do not require kidney Use agents that do not require kidney activation such asactivation such as

1,251,25--dihydroxy vitamin Ddihydroxy vitamin D33 (calcitriol)(calcitriol)11--alphaalpha--hydroxy vitamin Dhydroxy vitamin D22 (paricalcitol)(paricalcitol)

CalcitriolCalcitriol

2 products2 productsRocaltrol (oral): 0.25, 0.5 mcg capsRocaltrol (oral): 0.25, 0.5 mcg capsCalcijex (IV): 1 mcg/mlCalcijex (IV): 1 mcg/ml

?Daily vs Pulse Dosing?Daily vs Pulse Dosing

Calcitriol po: QD, TIW, or Calcitriol po: QD, TIW, or QWK QWK (Ref: Clin Nephrol 1998:49(4):245(Ref: Clin Nephrol 1998:49(4):245--250)250)

N=16 adult CRF pts (51 N=16 adult CRF pts (51 ++ 16 yrs)16 yrs)Randomized crossover study:Randomized crossover study:

A: 0.5 mcg po qamA: 0.5 mcg po qamB: 2.0 mcg po TIWB: 2.0 mcg po TIWC: 2.0 mcg po q weekC: 2.0 mcg po q week

3 months of each txmt; 1 month wash3 months of each txmt; 1 month wash--out periodout periodLow POLow PO44 diet; CaCOdiet; CaCO33 for POfor PO44 > > 2mmol/L; AlOH for PO2mmol/L; AlOH for PO44 > 5.5 mmol/L> 5.5 mmol/L

Calcitriol po: QD, TIW, or Calcitriol po: QD, TIW, or QWKQWK

1.18 1.18 ++0.040.04

1.15 1.15 ++0.060.06

1.22 1.22 ++0.060.06

1.16 1.16 ++0.050.05

1.19 1.19 ++0.050.05

1.15 1.15 ++0.060.06

iCa iCa mM/LmM/L

165 165 ++121*121*

274 274 ++111111

135 135 ++76*76*

283 283 ++148148

275 275 ++168168

270 270 ++136136

[iPTH] [iPTH] pg/mlpg/ml

C (q C (q week)week)

BasalBasalB B (TIW)(TIW)

BasalBasalA (qd)A (qd)BasalBasal

P 0.05

Calcitriol po: QD, TIW, or Calcitriol po: QD, TIW, or QWKQWK

TIW pulse dosing significantly reduced TIW pulse dosing significantly reduced [iPTH][iPTH]First data to show efficacy of single po First data to show efficacy of single po once a week pulse doseonce a week pulse dose

No significant modulations in [iCa] or [PONo significant modulations in [iCa] or [PO44] ] were observedwere observed

L/T Effect of IV CalcitriolL/T Effect of IV CalcitriolIncludes Bone Density StudiesIncludes Bone Density Studies

N=15 HD patients (age 18N=15 HD patients (age 18--70 yrs); [iPTH] 70 yrs); [iPTH] 10x normal10x normal2 week washout period; calcitriol IV 1 mcg 2 week washout period; calcitriol IV 1 mcg TIW x 3 wks, then dose adjusted per [iPTH] TIW x 3 wks, then dose adjusted per [iPTH] & serum [Ca]& serum [Ca]BMD: femoral neck, lumbar spine (baseline & BMD: femoral neck, lumbar spine (baseline & after 1 yr)after 1 yr)Study duration: 1 yearStudy duration: 1 year

–– Ref: Am J Nephol 1997;17:118Ref: Am J Nephol 1997;17:118--123123

L/T Effect of IV CalcitriolL/T Effect of IV Calcitriol

XX--axis = time axis = time (months)(months)Significant Significant reduction in reduction in [PTH] [PTH] associated associated w/increased w/increased [Ca][Ca]

Dual Photon Densitometry Dual Photon Densitometry g/cmg/cm22

7.43 7.43 ++6.806.80

0.89 0.89 ++0.090.09

0.834 0.834 ++0.0020.002

Femur**Femur**

9.3 9.3 ++ 8.98.91.159 1.159 ++0.220.22

1.071 1.071 ++0.230.23

Spine*Spine*

% increase% increasePostPost--txmttxmtPrePre--txmttxmtSiteSite

* p < 0.003; ** p < 0.001

Pulse Oral vs IV CalcitriolPulse Oral vs IV Calcitriol

N=20 chronic HD patientsN=20 chronic HD patients4 month run4 month run--in phase with no calcitriolin phase with no calcitriolRandomized to receive calcitriol 0.5 Randomized to receive calcitriol 0.5 mcg TIW, then adjusted q 2 wks per mcg TIW, then adjusted q 2 wks per [iCa][iCa]

pulse po (n=10) or IV (n=10)pulse po (n=10) or IV (n=10)Study txmt duration = 4 monthsStudy txmt duration = 4 months

–– Ref:Nephron 1997;77:267Ref:Nephron 1997;77:267--7272


4 mo4 mo2 mo2 mo004 mo4 mo2 mo2 mo00

1. 31 1. 31 ++0.100.10

1.35 1.35 ++0.090.09

1.24 1.24 ++0.050.05

1.38 1.38 ++0.080.08

1.34 1.34 ++0.080.08

1.25 1.25 ++0.060.06

iCa iCa mM/LmM/L

60*60*123123330330144*144*200200344344[iPTH] [iPTH] pg/mlpg/mlmedianmedian

IV n=10IV n=10Pulse oral n=10Pulse oral n=10

P < 0.001, 0 vs 4 mo.


Pulse calcitriol (po or IV) significantly reduced Pulse calcitriol (po or IV) significantly reduced [iPTH] in pts w/mild to moderate [iPTH] in pts w/mild to moderate hyperparathyoidismhyperparathyoidismPulse calcitriol (po or IV) did not significantly Pulse calcitriol (po or IV) did not significantly reduce [iPTH] in pts w/severe reduce [iPTH] in pts w/severe hyperparathyroidismhyperparathyroidism

1157 1157 ++ 156 vs 807 156 vs 807 ++ 228 pg/ml, p=0.09228 pg/ml, p=0.09

IV calcitriol produced the effect sooner (p 1IV calcitriol produced the effect sooner (p 1stst

mo) vs po calcitriol ( p 2mo) vs po calcitriol ( p 2ndnd mo)mo)

Pulse DosingPulse DosingHas a direct effect on PTH glandHas a direct effect on PTH gland

May be due to supratherapeutic peakMay be due to supratherapeutic peakGreater reductions in PTH Greater reductions in PTH concentrationsconcentrationsLess intestinal Ca absorptionLess intestinal Ca absorption

Lesser incidence of hypercalcemiaLesser incidence of hypercalcemiaTypical starting doses for pulse (po or Typical starting doses for pulse (po or IV):IV):

0.50.5--2 mcg, with 0.52 mcg, with 0.5--1.0 mcg increase 1.0 mcg increase based upon [PTH] obtained q 6 monthsbased upon [PTH] obtained q 6 months

HypercalcemiaHypercalcemia

Hold calcitriolHold calcitriolRisk development of adynamic bone dzRisk development of adynamic bone dz

Restart at a lower dose once Restart at a lower dose once hypercalcemia is controlledhypercalcemia is controlled

Hold/adjust doses of CaHold/adjust doses of Ca--containing containing binders/supplements; use/switch to binders/supplements; use/switch to sevelamersevelamerUse lowest [Ca] in dialysateUse lowest [Ca] in dialysate

Paricalcitol (Zemplar)Paricalcitol (Zemplar)

Associated with a low incidence of Associated with a low incidence of hypercalcemia with pulse dosinghypercalcemia with pulse dosing

Decreased intestinal absorption of Ca; Decreased intestinal absorption of Ca; decreased Ca mobilization from bonedecreased Ca mobilization from bone

Efficacious alternative to calcitriol w/less Efficacious alternative to calcitriol w/less hypercalcemiahypercalcemia

No prospective studies have compared the No prospective studies have compared the agentsagents

Paricalcitol (Zemplar)Paricalcitol (Zemplar)

IV: 0.04 IV: 0.04 –– 0.1 mcg/kg given as a bolus 0.1 mcg/kg given as a bolus dose no more frequently than qod at dose no more frequently than qod at any time during HDany time during HDInjection: 5 mcg/ml (1 ml, 2 ml, 5 ml)Injection: 5 mcg/ml (1 ml, 2 ml, 5 ml)Oral Capsule, Liquid Filled: 1, 2, 4 mcg Oral Capsule, Liquid Filled: 1, 2, 4 mcg

Suppression of PTH by Suppression of PTH by ParicalcitolParicalcitol

N=71 original pts N=71 original pts --> n=35 randomized to > n=35 randomized to study txmts (22 paricalcitol; 13 placebo)study txmts (22 paricalcitol; 13 placebo)

chronic HD patients; age 50 chronic HD patients; age 50 ++ 16 yrs16 yrs

PlaceboPlacebo--controlled, randomized, multicenter controlled, randomized, multicenter trialtrial4 weeks of paricalcitol 0.04 4 weeks of paricalcitol 0.04 –– 0.24 mcg/kg 0.24 mcg/kg TIW or placeboTIW or placebo

Different dosing groups: 0.04,0.08,0.16,0.24 Different dosing groups: 0.04,0.08,0.16,0.24 mcg/kgmcg/kg

Am J Kidn Dis 1998;32(2 suppl 2):S48Am J Kidn Dis 1998;32(2 suppl 2):S48--5454


Study endpoint: at least a 30% Study endpoint: at least a 30% reduction from maximum baseline reduction from maximum baseline [iPTH] for 75% of pts receiving [iPTH] for 75% of pts receiving paricalcitol per dosing groupparicalcitol per dosing group

PTH, mean % change from PTH, mean % change from baselinebaseline

-100

-80

-60

-40

-20

0

20

0 2 4 6 8 10

Weeks

Placebo0.04 mcg/kg0.08 mcg/kg 0.16 mcg/kg0.24 mcg/kg

% Pts Achieving 30% Reduction in [iPTH] % Pts Achieving 30% Reduction in [iPTH] from Baselinefrom Baseline

0102030405060708090

Placebo 0.04mcg/kg

0.08mcg/kg

0.16mcg/kg

0.24mcg/kg

% Pts


68% of pts receiving paricalcitol achieved 68% of pts receiving paricalcitol achieved efficacy endpoint regardless of doseefficacy endpoint regardless of dose

83% of pts in the 0.16 83% of pts in the 0.16 –– 0.24 mcg/kg group 0.24 mcg/kg group attained efficacy endpointattained efficacy endpoint2% in the placebo group attained efficacy 2% in the placebo group attained efficacy endpointendpoint

No clinically significant differences in [Ca] No clinically significant differences in [Ca] or [POor [PO44] between paricalcitol and placebo ] between paricalcitol and placebo groupsgroups

ParicalcitolParicalcitol Capsule (Capsule (ZemplarZemplar))

To test the safety and efficacy of oral To test the safety and efficacy of oral paricalcitolparicalcitolcapsules (F = 0.80) in pts w/ stage 3 and 4 CKD with capsules (F = 0.80) in pts w/ stage 3 and 4 CKD with secondary HPTsecondary HPTCombined results of 3 prospective, randomized, Combined results of 3 prospective, randomized, doubledouble--blind, placeboblind, placebo--controlled, multicenter studiescontrolled, multicenter studiesn=220 ptsn=220 ptsInitial dose 1Initial dose 1--2 mcg QD or 22 mcg QD or 2--4 mcg thrice weekly 4 mcg thrice weekly depending on depending on iPTHiPTH << 500 pg/ml (lower doses or > 500 pg/ml (lower doses or > 500 pg/ml higher doses)500 pg/ml higher doses)Study treatment duration: 24 weeksStudy treatment duration: 24 weeks

–– Coyne D, et al. Am J Coyne D, et al. Am J KidnKidn DisDis 2006;47(2):2632006;47(2):263--7676

Achievement of Achievement of iPTHiPTH TargetsTargets

Absolute Absolute iPTHiPTH Values from Values from BaselineBaseline

Mean + SEP < 0.001 found from week 3 thru end of study

Serum Ca & PO4 LevelsSerum Ca & PO4 Levels

Mean + SE

ParicalcitolParicalcitol--Treated PatientsTreated Patients

ConclusionsConclusions

TxmtTxmt with po with po paricalcitolparicalcitolObserved significant and sustained Observed significant and sustained iPTHiPTHlevel reduction in patients with stages 3 level reduction in patients with stages 3 and 4 CKDand 4 CKDObserved minimal or no effect on calcium Observed minimal or no effect on calcium and phosphorus metabolismand phosphorus metabolism

DoxercalciferolDoxercalciferol ((HectorolHectorol))

Intravenous Solution: 2 mcg/mlIntravenous Solution: 2 mcg/mlEnd of dialysis dosingEnd of dialysis dosing

Oral Capsule: 0.5 mcg, 2.5 mcg Oral Capsule: 0.5 mcg, 2.5 mcg Oral Capsule, Liquid Filled: 0.5 mcg, 2.5 mcgOral Capsule, Liquid Filled: 0.5 mcg, 2.5 mcg

PreHD po dosing PreHD po dosing –– QDQDHD po dosing HD po dosing -- TIWTIW

Dosing based upon Dosing based upon iPTHiPTH levelslevelsNo headNo head--toto--head trials head trials w/paricalcitolw/paricalcitol

NKF K/DOQI Goal Conc.NKF K/DOQI Goal Conc.

150 150 –– 30030070 70 –– 11011035 35 -- 7070iPTH iPTH (pg/ml)(pg/ml)

<15 or <15 or dialysisdialysis

1515--29293030--5959GFR GFR (ml/min/1.73 (ml/min/1.73 mm22))

CKD Stage CKD Stage 55



iPTH = intact PTH

New Assay New Assay –– BiointactBiointact PTHPTH

BiointactBiointact PTH (PTH (biPTHbiPTH))Assays different part of PTH moleculeAssays different part of PTH moleculeTarget range is 50% that for iPTHTarget range is 50% that for iPTH


150 150 –– 30030070 70 –– 11011035 35 -- 7070iPTH iPTH (pg/ml)(pg/ml)

75 75 -- 15015035 35 -- 555517.7 17.7 -- 3535biPTHbiPTH(pg/ml)(pg/ml)

<15 or <15 or dialysisdialysis

1515--29293030--5959GFR GFR (ml/min/1.73 (ml/min/1.73 mm22))




iPTH = intact PTH; biPTH = biointact PTH


<55<55<55<55<55<55Ca x POCa x PO44

8.4 8.4 –– 9.59.58.4 8.4 –– 10.210.28.4 8.4 –– 10.210.2Ca mg/dlCa mg/dl

3.5 3.5 –– 5.55.52.7 2.7 –– 4.64.62.7 2.7 –– 4.64.6POPO44 mg/dlmg/dl




Corrected Serum [Ca]Corrected Serum [Ca]

Corrected Serum [Ca] in mg/dl= total serum Corrected Serum [Ca] in mg/dl= total serum Ca (mg/dl) + 0.0704 x [34 minus serum Ca (mg/dl) + 0.0704 x [34 minus serum albumin (g/L)]albumin (g/L)]

Most closely approximates corrected total Ca in Most closely approximates corrected total Ca in CKD pts; R = 0.84 (no p value reported in CKD pts; R = 0.84 (no p value reported in K/DOQI)K/DOQI)

Corrected Serum [Ca] in mg/dl = total serum Corrected Serum [Ca] in mg/dl = total serum Ca (mg/dl) x [4 Ca (mg/dl) x [4 –– serum albumin (g/L)]serum albumin (g/L)]

““For routine clinical interpretation needed for For routine clinical interpretation needed for appropriate care of pts w/kidney diseasesappropriate care of pts w/kidney diseases””K/DOQIK/DOQI

Nephrol Dial Transplant 2000;15:1841-6

Monitoring Vitamin D TherapyMonitoring Vitamin D Therapy

Serum Ca & POSerum Ca & PO44 every month for the 1every month for the 1stst

3 months, then every 3 months 3 months, then every 3 months (opinion)(opinion)PTH every 3 months (opinion)PTH every 3 months (opinion)

Vitamin D Dose AdjustmentsVitamin D Dose Adjustments

If iPTH below target i.e risk of adynamic If iPTH below target i.e risk of adynamic bone disease (or if serum Ca >9.5 bone disease (or if serum Ca >9.5 mg/dl):mg/dl):

Hold vitamin D until iPTH increase to above Hold vitamin D until iPTH increase to above target range (or serum Ca returns to < 9.5 target range (or serum Ca returns to < 9.5 mg/dl), then resume half the dose of mg/dl), then resume half the dose of vitamin D. If the lowest dose is being vitamin D. If the lowest dose is being used, then reduce to alternateused, then reduce to alternate--day dosing day dosing (opinion)(opinion)

Vitamin D Dose AdjustmentsVitamin D Dose Adjustments

If serum POIf serum PO44 increases to >4.6 mg/dl, increases to >4.6 mg/dl, hold vitamin D therapy, begin or hold vitamin D therapy, begin or increase dose of phosphate binder until increase dose of phosphate binder until serum POserum PO44 decreases to < 4.6 mg/dl, decreases to < 4.6 mg/dl, then resume prior dose of vitamin D then resume prior dose of vitamin D (opinion)(opinion)

Mortality risk among HD patients Mortality risk among HD patients receiving different vitamin D analogsreceiving different vitamin D analogs

Mortality rates were Mortality rates were similar for similar for paricalcitolparicalcitol vs vs doxercalciferoldoxercalciferolMortality was lower in Mortality was lower in paricalcitolparicalcitol and and doxercalciferoldoxercalciferol vs vs calcitriol (calcitriol (PP < 0.05)< 0.05)Mortality was higher in Mortality was higher in pts not on vita D pts not on vita D analogs vs pts on vita D analogs vs pts on vita D analogs (analogs (PP < 0.05)< 0.05)

data not showndata not shown

Kidney Int 2006:70:1858-1865

WhatWhat’’s new?s new?Calcimimetic agentsCalcimimetic agents

CalciumCalcium--Sensing ReceptorSensing ReceptorFound in high concentrations on the Found in high concentrations on the surface of PTH cellssurface of PTH cells

When activated by increased extracellular When activated by increased extracellular Ca, the calciumCa, the calcium--sensing receptor signals sensing receptor signals the cell by means of a Gthe cell by means of a G--protein protein transducingtransducing pathway to raise the pathway to raise the intracellularintracellular Ca concentrationCa concentrationModulates PTH secretionModulates PTH secretionActivation by small changes in extracellular Activation by small changes in extracellular [iCa] [iCa] --> steep > steep inverseinverse relationship w/PTHrelationship w/PTH

CalcimimeticsCalcimimetics

Acquired alterations in the expression of Acquired alterations in the expression of the calciumthe calcium--sensing receptor (sensing receptor (CaRCaR) may ) may play a role in the pathogenesis 2play a role in the pathogenesis 2oo

hyperPTHhyperPTHCalcimimeticsCalcimimetics

Modulate the calcium sensing receptor Modulate the calcium sensing receptor making it more sensitive to calcium making it more sensitive to calcium --> > suppression of PTH secretionsuppression of PTH secretionEnhances the affinity of Enhances the affinity of CaRCaR for Ca and for Ca and reduces PTH secretionreduces PTH secretion

CalcimimeticsCalcimimetics

In general,In general,Effects occur within 1Effects occur within 1--2 hours after 2 hours after administrationadministrationFall in [PTH] is doseFall in [PTH] is dose--dependentdependentPTH returns to baseline within 4PTH returns to baseline within 4--24 hours24 hoursObserve a decline in plasma Ca following Observe a decline in plasma Ca following decline in [PTH]decline in [PTH]

Can result in clinical symptomsCan result in clinical symptomsSeen with larger dosesSeen with larger doses

Achieving NKFAchieving NKF--K/DOQI Goals with K/DOQI Goals with Cinacalcet (Cinacalcet (SensiparSensipar))

Data were combined from 3 placeboData were combined from 3 placebo--controlled, doublecontrolled, double--blind, 26 wk studiesblind, 26 wk studiesn = 1136 HD pts w/secondary n = 1136 HD pts w/secondary hyperparathyroidismhyperparathyroidismRandomized to receive traditional therapy Randomized to receive traditional therapy with cinacalcet or placebowith cinacalcet or placebo

Initial cinacalcet dose 30 mg po daily (max 180 Initial cinacalcet dose 30 mg po daily (max 180 mg)mg)

Continued concomitant meds: Vitamin D, Continued concomitant meds: Vitamin D, phosphate binders, Ca supplementsphosphate binders, Ca supplements

Moe SM et al KI 2005;67:760Moe SM et al KI 2005;67:760--7171

iPTHiPTHiPTH = intact PTHiPTH = intact PTHBL = baselineBL = baselineShaded region = Shaded region = K/DOQI target rangeK/DOQI target range

Serum phosphorousSerum phosphorous

BL = baselineBL = baselineShaded region = Shaded region = K/DOQI target rangeK/DOQI target range

Serum calciumSerum calcium

BL = baselineBL = baselineShaded region = Shaded region = K/DOQI target rangeK/DOQI target range

Ca x PCa x P

Ca x P = calcium x POCa x P = calcium x PO44productproductBL = baselineBL = baselineShaded region = Shaded region = K/DOQI target rangeK/DOQI target range


<55<55<55<55<55<55Ca x POCa x PO44

8.4 8.4 –– 9.59.58.4 8.4 –– 10.210.28.4 8.4 –– 10.210.2Ca mg/dlCa mg/dl

3.5 3.5 –– 5.55.52.7 2.7 –– 4.64.62.7 2.7 –– 4.64.6POPO44 mg/dlmg/dl

150 150 –– 30030070 70 –– 11011035 35 -- 7070PTH PTH (pg/ml)(pg/ml)




Achievement of K/DOQI Targets:Achievement of K/DOQI Targets:Study A: 12 week dose titration; 14 week Study A: 12 week dose titration; 14 week efficacy assessment (US, Canada)efficacy assessment (US, Canada)

0%

10%

20%

30%

40%

50%

60%

70%

PTH Ca xPO4

Ca PO4 PTH &Ca xPO4

PlaceboCinacalcet

Achievement of K/DOQI Targets: Achievement of K/DOQI Targets: Study B: 12 week dose titration; 14 week Study B: 12 week dose titration; 14 week efficacy assessment (Europe, Australia)efficacy assessment (Europe, Australia)

0%

10%

20%

30%

40%

50%

60%

70%

PTH Ca xPO4

Ca PO4 PTH &Ca xPO4

PlaceboCinacalcet

Achievement of K/DOQI Targets: Achievement of K/DOQI Targets: Study C: 16 week dose titration; 10 week Study C: 16 week dose titration; 10 week efficacy assessment (US, Canada, Australia)efficacy assessment (US, Canada, Australia)

0%

10%

20%

30%

40%

50%

60%

70%

PTH Ca xPO4

Ca PO4 PTH &Ca xPO4

PlaceboCinacalcet

2 targets: PTH 2 targets: PTH < < & & CaxPCaxP < 55< 55

<1%<1%5%5%Serum Ca < 7.5 Serum Ca < 7.5 mg/dlmg/dlLow Ca rarely associated w/symptoms & returned to Low Ca rarely associated w/symptoms & returned to values > 8.0 w/adjustment of all medsvalues > 8.0 w/adjustment of all meds

19%19%31%31%NauseaNausea

15%15%27%27%VomitingVomiting

31% 31% pp > 0.05> 0.0529%29%Serious eventsSerious events

8%8%15%15%Study withdrawal Study withdrawal (N/V)(N/V)

3%3%2%2%Deaths (all not Deaths (all not related to drug)related to drug)

PlaceboPlaceboCinacalcetCinacalcetAdverse EventsAdverse Events

ParathyroidectomyParathyroidectomy

Indications:Indications:Persistent hypercalcemiaPersistent hypercalcemia

Serum [Ca] > 11.5 mg/dlSerum [Ca] > 11.5 mg/dlOccurs because of large doses of calcitriol Occurs because of large doses of calcitriol analogs needed to suppress PTHanalogs needed to suppress PTH

Persistently elevated Ca x POPersistently elevated Ca x PO44 product & product & progressive soft tissue calcification despite progressive soft tissue calcification despite agents to lower POagents to lower PO44

Progressive radiographic lesions & Sx of Progressive radiographic lesions & Sx of bone dz associated with hyperPTHbone dz associated with hyperPTH

ParathyroidectomyParathyroidectomy

IndicationsIndicationsUncontrolled bone dz associated with Uncontrolled bone dz associated with debilitating sxdebilitating sxIntractable pruritisIntractable pruritis

Calcifications under the skinCalcifications under the skin

Syndrome of calciphylaxis (rare)Syndrome of calciphylaxis (rare)Vascular calcification causing ischemic necrosis Vascular calcification causing ischemic necrosis of skin, muscle, and or subcutaneous fatof skin, muscle, and or subcutaneous fat

ProcedureProcedure

Subtotal parathyroidectomySubtotal parathyroidectomyResection of 3 Resection of 3 ½½ of 4 parathyroid glandsof 4 parathyroid glandsLeave 50 g of one viable gland in placeLeave 50 g of one viable gland in place

Total parathyroidectomy with forearm Total parathyroidectomy with forearm autograft Removal of all 4 parathyroid autograft Removal of all 4 parathyroid glandsglands

Autotransplanting 1 gland into the forearmAutotransplanting 1 gland into the forearmAccessible siteAccessible site

Post OpPost Op

Marked increase in bone productionMarked increase in bone production““Hungry bone syndromeHungry bone syndrome””HypocalcemiaHypocalcemiaHypophosphatemiaHypophosphatemiaHypomagnesemiaHypomagnesemia

Treatment with supplemental calcium Treatment with supplemental calcium and calcitriol may be necessary for and calcitriol may be necessary for weekweek--monthsmonths

Chronic Kidney Diseasedrtedwilliams.net/cop/762/762ESRD.pdf · · 2008-01-19NKF Definition of...

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Transcript of Chronic Kidney Diseasedrtedwilliams.net/cop/762/762ESRD.pdf · · 2008-01-19NKF Definition of...