Chronic Kidney Disease Perspectives for the Internist:

Focus on Anemia and Bone Management

Vinod K. Bansal, MDProfessor of Medicine Division of Nephrology and HypertensionDecember 19, 2008

ObjectivesCKD staging and prevalenceBarriers to careCKD as chronic care modelKey complications of CKDManagement of complications with focus on anemia and bone disorders

CKD=chronic kidney disease

National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI)Stages of Chronic Kidney Disease

StageDescriptionGFR(ml/min/1.73 m2)1Kidney Damage with Normal or GFR>902Kidney Damage with Mild GFR60-893Moderate GFR30-594Severe GFR15-295Kidney Failure

MDRD Equation to Predict of GFRPrediction based on age, gender, race and serum creatinine

GFR/1.73 m2 = 186 x [Pcr]-1.154 x [age]-.203 x [.299 if female] x [1.192 if black]

www.kidney.orgnephron.com/cgi-bin/MDRD.org

MDRD Equation Predicts GFRR2=90.3%91% Within 30% of GFR

Prevalence of ESRD has been rising steadilyUSRDS ADR, 2008

Incidence varies widely by race and ethnicityIncident ESRD patients; rates adjusted for age & gender.USRDS ADR, 2007

Challenges to improving CKD careCKD remains underdiagnosedInadequate screening of at-risk patientsMisinterpretation of test resultsImplementation of recommended care is poorUnderutilization of ACE inhibitors and ARBs Poor achievement of BP goalsMany people poorly prepared for dialysis (poor nutritional status, little understanding of dialysis choices)Many clinicians feel inadequately educated Perception that CKD is a specialist diseaseUncertain about how to interpret diagnostic testsUnclear about clinical recommendationsLow confidence in their ability to successfully manage CKD

The Chronic Care Model (CCM)Summarizes basic elements for improving care in health systems (community, organization, practice, patient levels)Originated from a synthesis of scientific literature done by MacColl Institute for Healthcare Innovation in early 1990sExtensively reviewed by advisory panel of experts; compared with features of leading U.S. chronic illness management programsRefined and published in its current form in 1998Improving Chronic Illness Care, a national program of RWJF, launched in 1998 with CCM at its coreICIC and Institute for Healthcare Improvement developed the Chronic Care Breakthrough Series Collaboratives, which gave rise to HSRAs Health Disparities Collaboratives

The Chronic Care Model

What it Means for CKDCCM provides a much-needed paradigm for how to improve CKD detection and managementOffers a systematic way to identify needs and set prioritiesA convenient shorthand to use in communicating with a variety of audiencesMakes it clear which elements we need to addressAligning CKD initiatives with established CCM change concepts helps us demonstrate their broader value

CKD ComplicationsHypertensionAnemiaBone and mineral disordersMalnutritionCardiovascular risk and mortality

CKD=chronic kidney disease

Anemia ObjectivesTo recognize that anemia is a common complication of CKDTo understand that anemia is associated with an increased risk of morbidity and mortalityTo update information regarding the clinical use of ESAs for treatment of anemiaTo understand important clinical considerations during ESA therapy

CKD=chronic kidney disease; ESA=erythropoietin-stimulating agent

Anemia OverviewPrevalence and clinical consequences of anemia in CKDReview of ESAs as treatment for anemia in CKDClinical considerations during initial correction of anemiaClinical relevance of short vs long dosing intervalsChallenges of ESA therapyHb variability/stabilityLack or loss of responseInflammationCKD=chronic kidney disease; ESA=erythropoietin-stimulating agent; Hb=hemoglobin

Anemia Overview

Review of ESAs as treatment for anemia in CKDClinical considerations during initial correction of anemiaClinical relevance of short vs long dosing intervalsChallenges of ESA therapyHb variability/stabilityLack or loss of responseInflammation

CKD=chronic kidney disease; ESA=erythropoietin-stimulating agent; Hb=hemoglobin.

Anemia Is a Common Complication of CKDAnemia often develops early in the course of CKD and worsens as CKD progresses.*Anemia defined as at least two Hct values below the gender-specific norm (Hct value

Effect of Diabetes on Anemia* Prevalence (KEEP)With DiabetesWithout DiabetesAnemia develops earlier in CKD patients with diabetes, and at any given level of GFR, the prevalence of anemia is greater in patients with diabetes.7050402010 0603040 54.252.2P =0.038P =0.00940.4 20.823.5 10.116.2 4.87.55.75.9 4.5 8.7 6.2P =0.00180Estimated GFR (mL/min/1.73 m)*Anemia defined as Hb 50 years of age) and

Untreated Anemia Is Associated With Increased HospitalizationsRetrospective analysis of pre-dialysis patients with CKDHolland DC, et al. Nephrol Dial Transplant. 2000;15:650-658. N=362Hb 9.5 g/dLHb >9.5 g/dL Anemia Associated With Decreased Number of Hospital-Free Months P=0.059313.321.5Median Number of Hospital-Free Months25201510 5 0CKD=chronic kidney disease; Hb=hemoglobin.

Anemia OverviewPrevalence and clinical consequences of anemia in CKD

Clinical considerations during initial correction of anemiaClinical relevance of short vs long dosing intervalsChallenges of ESA therapyHb variability/stabilityLack or loss of responseInflammation

CKD=chronic kidney disease; ESA=erythropoietin-stimulating agent; Hb=hemoglobin

Benefits of Treatment With ESAsTreatment with ESAs to achieve partial correction of Hb levels is associated withImproved quality of life1Reduced risk for mortality2Reduced risk of hospitalization31. Eschbach JW, et al. Ann Intern Med. 1989;111:992-1000. 2. Collins AJ, et al. Semin Nephrol. 2000;20:345-349. 3. Collins AJ, et al. J Am Soc Nephrol. 2001;12:24652473.ESAs=erythropoietin-stimulating agents; Hb=hemoglobin

EpoetinRecombinant human erythropoietin; rHuEPO Forms: epoetin alfa, epoetin beta, epoetin delta*, epoetin omega*Acts by stimulating the proliferation, survival, and differentiation of erythroid progenitors into reticulocytes1-4Approved for either intravenous (IV) or subcutaneous (SC) administration 2 to 3 times per week (often given less frequently in clinical practice)5Frequency of administration dictated partly by the short biologic half-life (~68 hours following a single IV injection)1-41. Egrie JC, et al. Immunobiology. 1986;172:213-224; 2. Graber SE, et al. Ann Rev Med. 1978;29:51-66; 3. Eschbach JW, et al. N Eng J Med. 1987;316:73-78; 4. Eschbach JW, et al. Ann Intern Med. 1989;111:992-1000.; 5. Papatheofanis FJ, et al. Curr Med Res Opin. 2006;22:837-842.* Not available in the US..

Darbepoetin alfa2 more carbohydrate chains and up to 8 more sialic acid residues than epoetinThis extends the half-life by at least three fold and allows for decreased frequency of administration

Egrie JC, et al. Nephrol Dial Transplant. 2001;16 Suppl 3:3-13. Macdougall IC, et al. J Am Soc Nephrol. 1999;10:23922395.

Anemia OverviewPrevalence and clinical consequences of anemia in CKDReview of ESAs as treatment for anemia in CKD

Clinical relevance of short vs long dosing intervalsChallenges of ESA therapyHb variability/stabilityLack or loss of responseInflammationCKD=chronic kidney disease; ESA=erythropoietin-stimulating agent; Hb=hemoglobin

HypertensionUp to 80% of patients with CKD have a history of hypertension1,2During the early phase of treatment when the hematocrit is increasing, ~25% of patients on dialysis may require Initiation of antihypertensive therapy3orIncreases in antihypertensive therapy3Blood pressure should be controlled adequately before initiation of ESA therapy3,4 Kerr DN. In: Beeson PB, McDermott W, Wyngaarden JB, eds. Cecil Textbook of Medicine. 1979:1351-1367. Agarwal R, et al. Am J Med. 2003;115: 291-297. 3. National Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S146. 4. Agarwal R. Kidney Int Suppl. 2006;(101):S9-12. Macdougall IC, et al. Lancet. 2006;368:947-953.CKD=chronic kidney disease; ESA=erythropoietin-stimulating agent.

Iron Deficiency in CKD In patients beginning ESA treatment, iron deficiency occurs due to increased iron consumption during erythropoiesisIron deficiency will develop in most dialysis patients receiving ESAs Iron deficiency is the most common reason for resistance to the effect of ESAsNational Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S146. CKD=chronic kidney disease; ESA=erythropoietin-stimulating agent.

Importance of Iron Sufficiency During ESA InitiationAdapted from Macdougall IC, et al. Kidney Int. 1996;50:1694-1699.WeekHb (g/dL)****P

Evaluating Iron Status in Anemic Patients With CKDIron status test results reflect either the Level of iron in tissue storesor Adequacy of iron for erythropoiesisSerum ferritin is an indicator of storage iron Tests that reflect adequacy of iron for erythropoiesis include: TSATPHRCCHrNational Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S146. CKD=chronic kidney disease; TSAT=transferrin saturation; PHRC=percentage of hypochromic red blood cells; CHr=content of hemoglobin in reticulocytes.

Avoiding Iron Deficiency2006 KDOQI guidelines recommend the following goals of iron therapy during administration of ESAsFor HD patients:TSAT >20% ANDSerum ferritin concentration >200 ng/mLFor non-HD patients:TSAT >20% ANDSerum ferritin concentration >100 ng/mL National Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S146. KDOQI=Kidney Disease Outcomes Quality Initiative; ESAs=erythropoietin-stimulating agents; HD=hemodialysis; TSAT=transferrin saturation.

Avoiding Iron OverloadAccording to the 2006 KDOQI guidelines, when serum ferritin is >500 ng/mL, decisions regarding IV iron administration should weigh: ESA responsivenessHb and TSAT levelsPatients clinical statusNational Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S146. KDOQI=Kidney Disease Outcomes Quality Initiative; IV=intravenous; ESA=erythropoietin-stimulating agent; Hb=hemoglobin; TSAT=transferrin saturation.

How to Initiate ESA Therapy Epogen (epoetin alfa) prescribing information, Amgen, Inc, Thousand Oaks, Calif.; 2. Procrit (epoetin alfa) prescribing information, Ortho Biotech Products, L.P., Raritan, New Jersey. 3. Provenzano R, et al. Clin Nephrol. 2005;64:113-123; 4. Provenzano R, et al. Clin Nephrol. 2004;61:392-405. 5. Aranesp (darbopoetin alfa) prescribing information, Amgen, Inc., Thousand Oaks, Calif. 6. Suryani MG, et al. Am J Kidney Dis. 2003;23:106-111; 7. Ling B, et al. Clin Nephrol. 2005;63:327-334. 8. IV=intravenous; SC=subcutaneous.

Monitoring Rate of Hb ResponseIt is recommended that the dose of ESA be decreased if the Hb increase exceeds 1.0 g/dL in any 2-week period In clinical trials, increases in Hb >1.0 g/dL during any 2-week period were associated with increased incidence of Cardiac arrestNeurologic events (including seizures and stroke)Exacerbations of hypertensionCongestive heart failureVascular thrombosis/ischemia/infarctionAcute myocardial infarctionFluid overload/edema Epogen (epoetin alfa) prescribing information, Amgen, Inc, Thousand Oaks, Calif. Procrit (epoetin alfa) prescribing information, Ortho Biotech Products, L.P., Raritan, New Jersey. Aranesp (darbopoetin alfa) prescribing information, Amgen, Inc., Thousand Oaks, Calif.Hb=hemoglobin; ESA=erythropoietin-stimulating agent.

Target Hb LevelKDOQI 2001 Anemia Guidelines: 11-12 g/dL1KDOQI 2006 Anemia Guidelines: 11 g/dL1Use caution when intentionally maintaining Hb >13 g/dL1FDA Label: Hb 10-12 g/dL 2-4Current area of controversy5,6Optimal Hb?1. National Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S146. 2. Epogen (epoetin alfa) prescribing information, Amgen, Inc, Thousand Oaks, Calif. 3. Procrit (epoetin alfa) prescribing information, Ortho Biotech Products, L.P., Raritan, New Jersey. 4. Aranesp (darbopoetin alfa) prescribing information, Amgen, Inc., Thousand Oaks, Calif. 5. Drueke TB, et al. N Engl J Med. 2006;355:2071-2084.6. Singh AK, et al. N Engl J Med. 2006;355:2085-2098.Hb=hemoglobin; KDOQI=Kidney Disease Outcomes Quality Initiative.

Hemoglobin EffectChanges over time between group 1 (Hgb 13.0-15.0) and group 2 (Hgb 10.5-11.0) for patients with stage 3 or 4 CKD (n=603). Primary end point was composite of eight CVD events.

Drueke et al. NEJM 2006;355:2071

Correction of AnemiaPrimary Composite End-Point of death, MI, CHF hospitalization, stroke.

Singh AK et al NEJM 2006:355:2085

Normalization of Hb Has Increased RiskAdapted from Phrommintikul A, et al. Lancet. 2007;369:381-388. 1. Besarab A, et al. N Engl J Med. 1998;339:584-590; 2. Foley RN, et al. Kidney Int. 2000;58:1325-1335; 3. Furuland H, et al. Nephrol Dial Transplant. 2003;18:353-361; 4. Levin A, et al. Am J Kidney Dis. 2005;46:799-811; 5. Parfrey PS, et al. J Am Soc Nephrol. 2005;16:2180-189; 6. Singh AK, et al. N Engl J Med. 2006;355:2085-2098; 7. Drueke TB, et al. N Engl J Med. 2006;355:2071-2084; 8. Rossert J, et al. Am J Kidney Dis. 2006;47:738-750.

StudyRisk Ratio(95% CI)% WeightBesarab 19981Foley 20002Furuland 20033Levin 20054Parfrey 20055CHOIR 20066CREATE 20067Rossert 20068Overall (95% CI)57.9 1.1 10.1 10.1 7.2 13.07.62.2Risk ratioIncreased risk in higher targetIncreased risk in lower target1.21 (1.02, 1.45)1.33 (0.31, 5.75)0.99 (0.61, 1.62)0.34 (0.04, 3.22)0.66 (0.33, 1.30)1.45 (0.96, 2.19)1.48 (0.87, 2.52)1.17 (1.01, 1.35) 0-1 1100.17 (0.02, 1.37)Hb=hemoglobin.

Anemia OverviewPrevalence and clinical consequences of anemia in CKDReview of ESAs as treatment for anemia in CKDClinical considerations during initial correction of anemiaChallenges of ESA therapyHb variability/stabilityLack or loss of responseInflammation

CKD=chronic kidney disease; ESA=erythropoietin-stimulating agent; Hb=hemoglobinChallenges of ESA therapy

Anemia SummaryAnemia is a common and early complication of CKDAnemia is associated with an increased risk of morbidity and mortalityClinical use of ESAs for treatment of anemia requires vigilance regarding Hgb level, complications such as hypertension and resistance to response such as iron deficiencyIncreasing Hgb to >12 g/dL in patients with CKD is not recommended

Bone ObjectivesOverview of bone and mineral disorder (BMD) in CKDPathogenesis of BMDTreatment considerations

CKD=chronic kidney disease

Definition of CKD-MBDA systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following:Abnormalities of calicium, phosphorus, PTH, or vitamin D metabolismAbnormalities in bone turnover, mineralization, volume, linear growth, or strengthVascular or other soft tissue calcification

CKD=chronic kidney disease; CKD-MBD=chronic kidney disease-mineral and bone disorder; PTH=parathyroid hormone

Definition of Renal OsteodystrophyRenal osteodystrophy is an alteration of bone morphology in patients with CKD

It is one measure of the skeletal component of the systemic disorder of CKD-MBD that is quantifiable by histomorphometry of bone biopsy.

CKD=chronic kidney disease; CKD-MBD=chronic kidney disease-mineral and bone disorder

CKD-BMD Treatment GoalControl serum phosphorusMaintain normal serum calciumControl PTHCKD=chronic kidney disease; BMD=bone mineral disorder; PTH=parathryoid hormone

Pathogenesis of Disordered Mineral Metabolism in Chronic Kidney DiseasePhosphorus retentionLow calcitriol levelsHyperparathyroidism and parathyroid gland hyperplasiaHypocalcemiaSkeletal resistance to PTH GFR PO41,25(OH)2D 7-84 PTH Renal mass FGF23HyperphosphatemiaP = PhosphorusPTH = Parathyroid HormoneFG23 = Fibroblastic Growth Factor 23GFR = Glomerular Filtration Rate

Serum Analyses (Vit D, PTH) Vary With Stage of Kidney DiseaseLLN = Lower Limit of NormalULN = Upper Limit of NormalCraver L, et al. Nephrol Dial Transplant. 2007;22:1171-1176.50403020100 CKD1 CKD2 CKD3 CKD4 CKD5

N = 15 87 221 156 431,25(OH)2D3 (pg/mL)iPTH (pg/mL) CKD1 CKD2 CKD3 CKD4 CKD5

N = 174 341 856 354 1110200100*P < 0.05LLNULNLLN

9.79.69.59.49.39.29.19.08.9Serum Analyses (Ca, P) Vary With Stage of Kidney DiseaseSerum Calcium (mg/dL)Serum Phosphate (mg/dL)5.55.04.54.03.53.0All calcium values within normal rangeULN*P < 0.05 CKD1 CKD2 CKD3 CKD4 CKD5

N = 174 341 856 354 111 CKD1 CKD2 CKD3 CKD4 CKD5

N = 174 341 856 354 111LLN = Lower Limit of NormalULN = Upper Limit of NormalCraver L, et al. Nephrol Dial Transplant. 2007;22:1171-1176.

*n = 6111723039635535820493

N = 1,814Adapted from: Levin A, et al. Kidney Int. 2007;71:31-38.With Progressive Chronic Kidney Disease (CKD), Serum PTH Increases in an Adaptive Response to Maintain Calcium LevelsData presented are median values.iPTH = intact PTH.GFR = glomerular filtration rate.iPTH 1,25 (OH)2D3

Chart4

33.378016085843.5656836461

31.769436997335.6568364611

37.39946380736.9973190348

41.420911528231.7694369973

50.268096514828.0160857909

61.52815013424.1286863271

82.439678284220.3753351206

127.077747989316.2198391421

iPTH

1,25 OH2 D3

GFR level (mL/min)

iPTH (pg/mL)

1,25-dihydroxyvitamin D (pg/mL)

Sheet1

> 803.34E+014.36E+013.00E+01

70793.18E+013.57E+013.20E+01

60693.74E+013.70E+013.00E+01

50594.14E+013.18E+012.91E+01

40495.03E+012.80E+012.69E+01

30396.15E+012.41E+012.71E+01

20298.24E+012.04E+012.40E+01

< 201.27E+021.62E+012.08E+01

Sheet1

000

000

000

000

000

000

000

000

iPTH

1,25(OH)2 D3

25(OH)D3

GFR level (mL/min)

Intact PTH (pg/mL)

1,25 dihydroxyvitamin D (pg/mL)25 hydroxyvitamin D (ng/mL)

High Serum Phosphorus Levels Are Associated With Increased MortalityBlock GA et al. J Am Soc Nephrol. 2004;15:2208-2218. Relative risk of deathSerum phosphorus concentration (mg/dL)9Reference group

High Serum Calcium Levels Are Associated With Increased Mortality11.0Multivariate analysis adjusted for age, gender, race, or ethnicity, diabetes, vintage, body weight, URR, serum albumin, creatinine, predialysis BUN, bicarbonate, cholesterol, hemoglobin, ferritin, and aluminum.Adapted from Block GA et al. J Am Soc Nephrol. 2004;15:2208-2218.

Relative Risk of Mortality by Serum Parathyroid HormoneBlock GA et al. J Am Soc Nephrol. 2004;15:2208-2218. Relative risk of deathPlasma PTH concentration (pg/mL)600Reference group

Spectrum of Renal OsteodystrophyCalcium, Vitamin D PTHHigh TurnoverLow TurnoverNormal bone formationAdynamicOsteomalaciaMildOsteitisfibrosaAl3+Mixed lesion 300-400 pg/mLFrom Goodman WG, with permission.Sherrard DJ, et al. Kidney Int. 1993;43:436-442.Wang M, et al. Am J Kidney Dis. 1995;26:836-844.

The Incidence of Hip Fracture in ESRD Is 17.4 Times Greater Than the General PopulationCoco M, Rush H. Am J Kidney Dis. 2000;36:1115-1121. Fracture-free survivalPTH subgroups (pg/dL)501+196-50066-195

Association of Alkaline Phosphatase and SurvivalAll-cause death hazard ratioAlkaline phosphatase (U/I)

Pathogenesis of Vascular CalcificationsHyperphosphatemiaExcess CalciumElevated Ca x PAbnormal Bone RemodelingMatrix DepositionElevatedUremic FactorsVascular SmoothMuscle CellOsteoblast-LikeCellPromotersCbfa-1BMP-2Decreased InhibitorsFetuin-AMatrix Gla ProteinVessel CalcificationLoss of Bone Buffering Capacity for Ca x P

Vascular Calcification Predicts MortalityCalcification score: 0Calcification score: 1Calcification score: 2Calcification score: 3Calcification score: 4Probability of SurvivalDuration of Follow-up (months)020406080Blacher J et al. Hypertension. 2001;38:938.1.000.750.000.250.50Comparison between curves was highly significant (x2 = 42.66, P < 0.0001)

Coronary Artery Calcifications Increase With Dialysis DurationGoodman WG et al. N Engl J Med. 2000;343:1478.Proportion with calcificationDuration of dialysis (yrs)

Dialysis Patients Have Increased Cardiovascular Disease Mortality Compared to the General PopulationAge (years)0.010.110100253435444554556465747584> 85GP = general population; CVD = cardiovascular disease.Foley RN, et al. Am J Kidney Dis. 1998;32(suppl 3):S112-S119.Annual CVD Mortality (%)GP FemaleDialysis MaleDialysis FemaleDialysis BlackDialysis WhiteGP MaleGP BlackGP White1

Calcification in Secondary HPT59-year-old woman with ESRD began dialysis in 1997Whole-body bone scan shows active calcium uptake (dark areas):MyocardiumBreastsLower extremity soft tissuesSC uptake in the proximal upper extremities and left wristDiagnosis: Metastatic calcification resulting from ESRD Kok M et al. Clin Nucl Med. 2003;28:144-145.

Conventional Therapy in BMD

KDOQI Clinical Practice Guidelines For Bone Metabolism and Disease in ESRDCKD = chronic kidney disease; GFR = glomerular filtration rate; Ca x P = calcium-phosphorous product. Modified from National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI). Am J Kidney Dis. 2004;43:S1-S201.

Recommended Serum ValuesCKD StageGFR Range (mL/min/1.73 m2)Phosphorus (mg/dL)Calcium (corrected) (mg/dL)Ca x P (mg2/dL2)Intact PTH (pg/mL)330592.74.68.410.23570415292.74.68.410.2701105*

Goals of TherapyImmediate

Long-term

Maintain PTH within appropriate targets Prevent parathyroid gland hyperplasiaMaintain normal serum phosphorus levels Maintain normal serum calcium levelsMaintain normal skeletal functionReduce risk of renal osteodystrophyReduce risk of CV morbidity & mortality Cunningham J. Kidney Int. 1999;56(suppl 73):S59-S64.Goodman WG. Kidney Int. 2001;59:1187-1201.

Conventional Therapeutic ApproachesGoodman WG. Kidney Int. 2001;59:1187, with permission.Control PTH and CaVitamin D sterolsCa supplements/dialysate CaControl PDietary P restrictionPhosphate binders

Conventional Strategies to Achieve KDOQIBiochemical TargetsPTHCaPCalciumbinderPTHCaPNon calciumbinderPTHCaPVitamin DanalogueNKF. Am J Kidney Dis. 2003;42(suppl 3):S1-S201.Goodman WG. Kidney Int. 2001;59:1187-1201.Goodman WG. Semin Dial. 2004;17:209-216.

Unintended Effects of Conventional Treatment Are Reflected in KDOQI GuidelinesHold vitamin D when:iPTH 10.2 mg/dLSerum phosphorus >6.0 mg/dLDo not use calcium-based phosphate binders when:Serum calcium >10.2 mg/dLiPTH

Vitamin D Levels and Early Mortality Among Incident Hemodialysis Patients*P

Vitamin D Suppresses PTH but With Potential Trade-Offs in Phosphorous and Calcium Levels3 Months Following Initiation01236.05.85.65.45.25.04.64.8

Mean P (mg/dL) (95% CI)PhosphorusMonths After Initiation of IV Vitamin DCalcitriol (n = 2,667)Paricalcitol (n = 1,697)Doxercalciferol (n = 2,010)Tentori F, et al. Kidney Int. 2006;70:1858-1865. 0123400350300250200150100Mean iPTH (pg/mL) (95% CI)01239.69.49.29.08.88.28.08.68.4Mean Ca (mg/dL) (95% CI)iPTHCalcium

SummaryThe use of vitamin D and phosphate binders for the treatment of secondary HPT may involve trade-offs: their use to control one laboratory parameter may result in the unwanted increase in anotherCalcium-based phosphate binders are associated with progressive coronary artery and aortic calcification, especially when mineral metabolism is not well controlledLower serum levels of both 25-hydroxyvitamin D (25D) and 1,25 dihydroxyvitamin D (1,25D) were associated with increased mortality within 90 days of initiating hemodialysisAdditional studies are needed to prospectively address vitamin D therapy and its effect on mortality

Calcium-Sensing Receptor (CaR)CaR is the primary regulator of PTH secretionDecrease in calcium increases PTH secretionIncrease in calcium suppresses PTH secretionCaR permits rapid response to changes in extracellular Ca2+ The discovery and cloning of the extracellular calcium-sensing receptor and the clarification of its role in calcium metabolism represent a major advance over the past 10 years.*

Available at: http://www.nature.com.Brown EM et al. Nature. 1993;366:575.*Coburn JW, Maung HM. Curr Opin Nephrol Hypertens. 2000;9:123.Conserved cysteineConservedAcidicConserved acidicPKC siteN-glycosylation

From Bench to Bedside: The Calcium-Sensing Receptor as a Therapeutic TargetAdapted from Nemeth EF, et al. J Pharmacol Exp Ther. 2004;308:627-635.Extracellular Ca, mM% Maximum fluorescenceControl (0.87 0.01 mM)10 nM (0.74 0.01 mM)100 nM (0.58 0.01 mM)Calcimimetics bind the CaR and lower the threshold of activation by extracellular calcium

Comparison of Calcimimetics With Vitamin D Analogues

Zeig S, et al. J Am Soc Nephrol. 2005;16:501A. Abstract F-PO757 and poster.Colloton M. Kidney Int. 2005;67:467-476.Tornig J. J Am Soc Nephrol. 2005;16:489-495.

CalcimimeticsVitamin D AnaloguesPTH axisDirectly suppresses PTH through CaRSuppresses PTH directly and indirectlycalcium, phosphateDecreases Ca and PIncreases Ca and P (GI effect)Vascular calcificationMay protect against vascular calcificationMay predispose to vascular calcificationSystemic effectsHigh selectivity for parathyroid gland, limited actions on other tissuesOther systemic effects that are potentially beneficial or harmful (excessive doses)

SummaryCalcium, directly acting through the CaR, is the major regulator of PTH transcription, secretion, and parathyroid gland hyperplasiaSignificantly more patients in phase 3 clinical trials were able to achieve the KDOQI biochemical targets with the addition of cinacalcet to conventional therapyPrimary therapy with cinacalcet to lower iPTH in conjunction with fixed low doses of vitamin D in phase 3b clinical trials resulted in more patients achieving the KDOQI biochemical targetsSecondary analyses of phase 3 clinical trials of cinacalcet compared with placebo and standard therapy conclude the risks of parathyroidectomy, skeletal fracture, and cardiovascular hospitalization were significantly lower with cinacalcet therapy

*Elevated:FGF-23PTHPhosphorus

Decreased:CalcitriolCalcium Coronary calcificationAortic calcificationCalciphylaxis

Abnormal bone histologyMineralizationTurnoverVolumeDecreased bone mineral density

KDIGO = Kidney Disease: Improving Global Outcomes.KDIGO is a registered trademark of Kidney Disease: Improving Global Outcomes, Inc.

Moe S, et al. Kidney Int. 2006;69:1945-1953.KDIGO Overview slide presentation at: http://www.kdigo.org/pdf/KDIGO%20Overview%20Slide%20Set.pptChronic Kidney DiseaseMineral and Bone Disorder (CKD-MBD)

Anemia Is a Common Complication of CKDKausz and colleagues published results of a study in 2002, which demonstrates that, as the level of serum creatinine increases, the prevalence of CKD patients defined as anemic increases. In this study, anemia was defined as at least two Hct values below the gender-specific norm (Hct value 1.0 g/dL during any 2-week period were associated with increased incidence of cardiac arrest, neurologic events (including seizures and stroke), exacerbations of hypertension, congestive heart failure, vascular thrombosis/ischemia/infarction, acute myocardial infarction, and fluid overload/edema.

ReferencesEpogen (epoetin alfa) prescribing information, Amgen, Inc, Thousand Oaks, Calif. Procrit (epoetin alfa) prescribing information, Ortho Biotech Products, L.P., Raritan, New Jersey. Aranesp (darbopoetin alfa) prescribing information, Amgen, Inc., Thousand Oaks, Calif.

Target Hb LevelThe KDOQI 2001 anemia guidelines recommended a target Hb range of 11-12 g/dL. The 2006 published anemia guidelines recommended Hb level of greater than or equal to 11 g/dL11 g/dL, but urged caution when intentionally maintaining Hb >13 g/dL. The prescribing information for the ESAs recommends a target Hb level of 10-12 g/dL. There is considerable controversy regarding the optimal hemoglobin level.

References1. National Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S146. 2. Epogen (epoetin alfa) prescribing information, Amgen, Inc, Thousand Oaks, Calif. 3. Procrit (epoetin alfa) prescribing information, Ortho Biotech Products, L.P., Raritan, New Jersey. 4. Aranesp (darbopoetin alfa) prescribing information, Amgen, Inc., Thousand Oaks, Calif.5. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071-2084.6. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085-2098.

Normalization of Hb Has Increased RiskTo determine whether targeting higher Hb concentrations when treating CKD patients with anemia puts them at increased risk of death, a meta-analysis of several studies examined the risk of all-cause mortality associated with a higher Hb target in the normal physiological range (defined here as between 12-16 g/dL) compared with a lower Hb target. Results showed that the risk ratio for the higher Hb target was 1.17 (95% CI 1.01-1.35), indicating that targeting higher Hb concentrations does put patients at increased risk. There was no heterogeneity between these studies and the data from the HD pataients and the non-HD patients were similar.

ReferencesPhrommintikul A, Haas SJ, Elsik M, et al. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet. 2007;369:381-388. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339:584-590.Foley RN, Parfrey PS, Morgan J, et al. Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy. Kidney Int. 2000;58:1325-35.Furuland H, Linde T, Ahlmen J, et al. A randomized controlled trial of haemoglobin normalization with epoetin alfa in pre-dialysis and dialysis patients. Nephrol Dial Transplant. 2003;18:353-361.Levin A, Djurdjev O, Thompson C, et al. Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD. Am J Kidney Dis. 2005;46:799-811.Parfrey PS, Foley RN, Wittreich BH, et al. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol. 2005;16:2180-2189.Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085-2098.Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071-2084.Rossert J, Levin A, Roger SD, et al. Effect of early correction of anemia on the progression of CKD. Am J Kidney Dis. 2006;47:738-750.*Key Points1,25-dihydroxyvitamin D (1,25(OH)2D3) levels start falling much earlier in CKD before the rise in PTH is observed. The changes in 1,25(OH)2D3 have not previously been described given the lack of data in this earlier population.1 Note that secondary HPT begins to occur at eGFR levels of approximately 45 mL/min/1.73 m2, similar to the point where the median value of 1,25(OH)2D3 begins to approach values deemed deficient (22 pg/mL) when using the values in the lowest tertile for this population.1BackgroundThe Study for the Evaluation of Early Kidney Disease (SEEK) was a prospective, observational, multicenter study.1 This was a cross-sectional analyses of baseline data. The primary objective was to determine the relationship of circulating vitamin D, PTH, calcium, and phosphorus in CKD patients who were not receiving prescribed vitamin D. This study was an initial attempt to help better define the role of vitamin D deficiency as it relates to eGFR and the development of hyperparathyroidism. Patients were enrolled from June to October 2004.5,255 patients were screened of which 1,903 were enrolled, and 1,814 were analyzed. A large number could not be enrolled due to eGFR levels or analyzed due to missing serum creatinine levels.

1Levin A, et al. Kidney Int. 2007;71:31-38.*Key PointsIn 2005, KDIGO proposed the term CKDMineral and Bone Disease (CKDMBD) to refer to a broad clinical syndrome due to CKD associated with abnormalities in bone and mineral metabolism, and extra-skeletal calcification.1 This Venn diagram illustrates how the consequences of CKD-MBD interact to produce poor outcomes for patients in the later stages of renal disease.2 BackgroundRecognizing that CKD is a worldwide public health problem, KDIGO sponsored a Controversies Conference on Renal Osteodystrophy, at which it was recommended that the term CKD-MBD should be used to describe the syndrome of biochemical, bone, and extra-skeletal calcification abnormalities that occur in CKD; these include abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and vascular or other soft tissue calcification.1 Chronic kidney disease involves disorders of both mineral and bone metabolism which are associated with significant morbidity, decreased quality of life, and extra-skeletal calcification that can lead to increased cardiovascular mortality. These disturbances have classically been termed renal osteodystrophy and classified based on bone biopsy.1

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1Moe S, et al. Kidney Int. 2006;69:1945-1953.2KDIGO Overview slide presentation at: http://www.kdigo.org/speaker_center.php. Accessed September 11, 2008.