ckd-mbd:messages from clinical trials

CKD-MBD Messages from Clinical Trials

Alaa Sabry, MD, FACP.Mansoura University

AGENDA

•CKD MBD A Over View

•Vascular calcification and Mortality Review Literature.

•Medical Management of CKD

CKD-Mineral and Bone Disorder

A systemic disorder of mineral and bone metabolism due to CKD manifested by either one or a combination of the following:– Abnormalities of calcium,

phosphorus, PTH, or vitamin D metabolism

– Abnormalities in bone turnover, mineralization, volume, linear growth, or strength

– Vascular or other soft tissue calcification

Moe S, et al. Kidney Int 69: 1945, 2009

Types of Renal Bone Disease

• Traditionally classified according to degree of abnormal bone turnoverHigh Turnover (osteitis fibrosa)

– Hyperparathyroidism (bone turnover is increased)Low turnover

– Adynamic - OsteomalaciaOsteoporosis/ osteomalcia:(bone turnover is also low in combination with an increased volume of

unmineralized bone (osteoid))

– Post-menopausal - Post-transplant

Mixed uremic osteodystrophyelements of both high and low bone turnover This is also characterized by marrow fibrosis and increased unmineralized

osteoid.

KI (2007) 71, 31-38. Levin et. al.

Prevalence of Abnormal Mineral Metabolism in CKD

>4.6

Associations between elevations in phosphorus, calcium, calcium-phosphorus product, and parathyroid hormone (PTH) with risk for mortality.

Chertow G M et al. CJASN 2007;2:898-905

©2007 by American Society of Nephrology

METHODS

• A systematic and comprehensive database search of MEDLINE (1948 to December 2010) and EMBASE (1947 to December 2010).

• RESULTS• A systematic search yielded 47 eligible studies

(N = 327 644) in 49 cohorts of adults with chronic kidney disease

• The risk of death was higher with increasing levels of serum phosphorus (5.5 mg/dL).

• For every 1-mg/dL increase in serum phosphorus, the risk of mortality increased by 18% (RR, 1.35)

No evidenc for association between parathyroid hormone and cardiovascular mortality.

There was weak evidence of association between serum calcium level and cardiovascular death (RR, 1.15; 95% CI, 1.08-1.23)

First Message

• The evidentiary basis for a strong, consistent, and independent association between serum levels of calcium and parathyroid hormone and the risk of death and cardiovascular events in chronic kidney disease is poor.

• There appears to be an association between higher serum levels of phosphorus and mortality in this population.

Patho-physiology

The factors involved in the pathogenesis of secondary hyperparathyroidism

Martin K J , González E A JASN 2007;18:875-885 (5)


FGF23 in CKD

• Levels rise early with decline of GFR.

• Become significant by stage II

• A 1000 folds normal levels at stage V

Pereira et al. Bone 45: 1161–1168, 2009

AGENDA




Cardiovascular Disease (CVD) MortalityGeneral Population versus ESRD Patients

Foley RN, Parfrey PS, Sarnak MJ. Am J Kidney Dis. 1998;32(suppl):S112-S119. GP=General PopulationESRD=End-Stage Renal Disease

Annual CVD mortality (%)

Age (years)

0.001

0.01

0.1

1

10

100

25-34 35-44 45-54 55-64 65-74 75-84 >85

GP maleGP female

GP blackGP white

Dialysis maleDialysis femaleDialysis blackDialysis white

Vascular calcification in CKD

Calcification of Coronary Arteries is Highly Prevalent Among CKD Patient Populations

22

CKD = chronic kidney disease; RIND=Renagel in New Dialysis; TTG=treat-to-goal.1. Russo D et al. Am J Nephrol. 2007;27:152-158.2. Spiegel DM et al. Hemodial Int. 2004;8:265-272.3. Chertow GM et al. Kidney Int. 2002;62:245-252.

Percentage of CKD Patients With Coronary Artery Calcification Across 3 Studies in Different CKD Populations

5164

83

0

20

40

60

80

100

CKD Patients Not onDialysis

Incident Dialysis Prevalent Dialysis

Patie

nts

(%)

(Russo1)

(Spiegel, RIND2)

(Chertow, TTG3)

Probability of all-cause survival according to calcification score.

Jacques Blacher et al. Hypertension. 2001;38:938-942

Copyright © American Heart Association, Inc. All rights reserved.

Factors Associated With Coronary Calcification* in Young Dialysis Patients

FactorCoronary Calcification

(N=14)No Calcification

(N=25) P Value†

Dose of oral calcium (mg/day) 6456 ± 4278 3325 ± 1490 0.02

Serum P (mg/dL) 6.9 ± 0.9 6.3 ± 1.2 0.06

Serum Ca (mg/dL) 9.5 ± 1.0 9.1 ± 0.9 0.25

Age (y) 26 ± 3 15 ± 5 <0.001

Duration of dialysis (y) 14 ± 5 4 ± 4 <0.001

24

Ca = calcium; P = phosphorus.*Determined by electron beam computed tomography (EBCT); †Determined using unpaired t-tests; Data are presented as means ± standard deviations.Goodman WG et al. N Engl J Med. 2000;342:1478-1483.

Second Message

• Coronary artery calcification is significant and progressive in a majority of patients with early chronic kidney disease

• There is an association between arterial calcification and increased risk of all-cause mortality in chronic kidney disease patients on dialysis

• Daily calcium intake is one modifiable risk factor associated with calcification of coronary arteries

AGENDA




Treatment of CKD-MBD

• A) Medical:• Dietary phosphate restriction• Calcitriol or other Vit D analogues • Phosphate binders• Calcimimetics

• B) Surgical:• Parathyroidectomy

Clinical Outcomes

Clinical Outcomes

Cinacalcet HCl

PTHCalcium

PhosphorusAsso

ciated

PTHCalcium

Phosphorus

“improves”

Vitamin Dcalcimimetic

Pi binder ?Intervention

Surrogatemarker

Modified from: Moe SM, et al. Kidney Int. 2005;67:760-771.Block GA, et al. J Am Soc Nephrol. 2004;2208-2218.

Active Vitamin D Sterols

Teng M et al. N Engl J Med 2003;349:446-456.

Kaplan–Meier Analysis of Survival According to the Type of Vitamin D Therapy.

Cavaetes

• Emerging observational data support an association between vitamin D therapy and improved patient-level outcomes in adults with CKD

• limitations ;• Unmeasured confounders (for example, baseline comorbid

conditions, nutritional status, or concomitant therapy) .• Selection bias • These large-scale studies suggest a clinical advantage for

vitamin D therapy in people with CKD that demands exploration through adequately powered RCTs.

Vitamin D

Established Vit D

• Established vitamin D compounds were not associated with a statistically significant reduction in PTH levels (weighted mean difference, 17.16 pmol/L [CI, 36.32 to 2.00 pmol/L])

Established Vit D

Compared with placebo, established vitamin D sterols were associated with an increased risk for hypercalcemia (RR, 2.37 [95% CI, 1.16 to 4.85]) and hyperphosphatemia (RR, 1.77 [CI, 1.15 to 2.74])

Newer Vitamin D

• Compared with placebo, newer vitamin D compounds were associated with hypercalcemia (RR, 5.15 and were not associated with increased episodes of hyperphosphatemia (RR, 0.89 [CI, 0.42 to 1.91])

• Newer vitamin D compounds also have a mixed effect on surrogate end points; overall, they significantly reduce PTH levels (by about 11 pmol/L)

• Trials directly comparing newer vitamin D analogues with established compounds were rare and small and did not demonstrate important differences in any outcome Ca , ph, iPTH

Vitamin D

• We found no significant difference for any patient-level outcome (including fracture) between vitamin D and placebo, vitamin D and another vitamin D sterol, or vitamin D and a different route of administration.

Vitamin D conclusion

Third Message

• No evidence of superiority of newer vitamin D analogues over established vitamin D compounds for any outcome when these agents were compared directly in RCTs.

• The lack of direct head-to-head trials comparing newer with established agents makes it difficult to assess whether newer vitamin D agents have similar or different effects, even on biochemical outcomes, than established compounds.

Phosphate binders

Does Phosphate binders decreases Vascular calcification ?

Renagel in New Dialysis (RIND)

Renagel in New Dialysis (RIND) Study

• To examine the relationship between phosphate binder choice and CAC assessed by EBCT in new hemodialysis patients– sevelamer HCl vs. calcium-based binder

Block GA, Spiegel DM, Ehrlich J, et al. Kidney Int. 2005;68:1815-1824.

CAC=Coronary Artery CalcificationEBCT=Electron Beam Computed Tomography

Renagel in New Dialysis (RIND) Study DesignScreened (N=385)

Declined/Screen failures (N=237) Randomized (N=148)

Calcium (N=75) Sevelamer HCl (N=73)

Adverse Event (N=1)Transplanted (N=3)

Death (N=1)Other (N=4)

Lost to Follow-Up (N=1)Transferred to PD (N=2)

Adverse Event (N=1)Transplanted (N=2)

Death (N=1)Other (N=2)

Transferred to PD (N=2)

Available for Analysis (N=55)(at Least 1 Post Baseline EBCT)

Available for Analysis (N=54)(at Least 1 Post Baseline EBCT)

Baseline EBCT (N=67) Baseline EBCT (N=62)

109 patients EBCT=Electron Beam Computed Tomography


Effects of Sevelamer HCl and Calcium on Coronary Artery Calcification

N=54 N=55 N=51 N=53 N=45 N=47 N=40 N=45

CACS=Coronary Artery Calcification Score


0

50

100

150

200

250

300

350

Baseline 6 months 12 months 18 months

Median CACS Sevelamer HCl Calcium

Treat-to-Goal Study

Treat-to-Goal Study Study Design

BL EBCT

Titrate dose:PO4=3.0-5.0 mg/dL

Ca <10.5 mg/dL

26 week EBCT

Titrate dose:PO4=3.0-5.0 mg/dL

Ca <10 mg/dLPTH 150-300 pg/mL

Vitamin D if PTH >300 pg/mLIf P>5.5 mg/dL

2 weeks200 patients

12 weeks 40 weeks

52 week EBCT

Extended treatmentSevelamer HCl HD: 2.9 Years

Calcium binderHD; 3.6 Years

Extended treatment

BL=BaselineEBCT=Electron Beam Computed TomographyPTH=Parathyroid Hormone

Chertow GM, Burke SK, Raggi P. Treat to Goal Working Group. Kidney Int. 2002;62:245-252.

RANDOMIZEWashoutPeriod

Between group comparisons: P=0.03 (coronary), P=0.01 (aorta)

Sevelamer HCl (S)Calcium (C)Coronary

artery

Med

ian

chan

ge in

calc

ifica

tion

scor

e (%

)

-7%N=16

0

10

20

30

40

60

70

90

20%N=17

83%N=24

66%N=25

-10

-5

50

80 Aorta

P=NS

P=NS

P<0.0001

P<0.0001

Treat-to-Goal Study: 2-Year European Data Coronary Artery and Aortic Calcification


Treat-to-Goal StudySummary

• Control of serum phosphorus was equivalent between calcium-based phosphate binders and sevelamer

• Patients receiving calcium as a phosphate binder experienced significantly more hypercalcemia and iPTH levels below the targeted range

• Both coronary artery and aortic calcification progressed significantly in the calcium group but not in the sevelamer group


CARE2

• After 1 year of treatment, LDL-C levels decreased in both groups

CARE 2

Fourth Message

• Although the data are not consistent, there appears to be relatively less progression of vascular calcification with sevelamer versus calcium-containing phosphate binders among patients with CKD.

• With intensive lowering of LDL-C levels for 1 year, hemodialysis patients treated with either calcium acetate or sevelamer experienced similar progression of CAC.

Mortality

Independent study(ND patients)

Independent• 12 nephrology clinics in South Italy were

evaluated.• 6 months of follow-up before the enrollment

(stage 3–4 CKD ). Follow up 36 months.• Methods:• Patients were randomized to receive either

open-label calcium carbonate or sevelamer.• A total of 212 patients ( stage 3-4 CKD)were

considered the efficacy analyses.

IndependentMortality

All-cause mortality and the composite end point were lower in patients receiving sevelamer. Dialysis inception was lower in patients

receiving sevelamer (NS).

Independent

All-cause mortality by phosphate binder: randomized trials (11 Trials 936/4622 )

Published online July 19, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60897-1

Study or Subgroup1.12.1 RCTBarreto 2008Block 2007Chertow 2002Di Iorio 2012Kakuta 2011Qunibi 2008Russo 2007Sadek 2003Suki 2008Takei 2008Wilson 2009Subtotal (95% CI)Total eventsHeterogeneity: Tau² = 0.03; Chi² = 12.35, df = 7 (P = 0.09); I² = 43%Test for overall effect: Z = 2.09 (P = 0.04)

1.12.2 Non-Randomized StudiesBorzecki 2007Jean 2011Panichi 2010Subtotal (95% CI)Total eventsHeterogeneity: Tau² = 0.00; Chi² = 1.57, df = 2 (P = 0.46); I² = 0%Test for overall effect: Z = 1.90 (P = 0.06)

Total (95% CI)Total eventsHeterogeneity: Tau² = 0.01; Chi² = 13.88, df = 10 (P = 0.18); I² = 28%Test for overall effect: Z = 2.40 (P = 0.02)Test for subgroup differences: Chi² = 0.92, df = 1 (P = 0.34), I² = 0%

Events

1116

120301

2670

135

436

1486274

284

720

Total

526099

10791

1002721

105322

6802312

608247242

1097

3409

Events

8235

220703

2750

157

500

228109170

507

1007

Total

4967

10110592

1032821

105020

6742310

769432515

1716

4026

Weight

0.3%3.2%1.0%3.0%

0.8%

0.3%24.5%

17.9%50.9%

20.6%12.7%15.9%49.1%

100.0%

M-H, Random, 95% CI

0.12 [0.02, 0.91]0.53 [0.28, 1.00]1.22 [0.39, 3.88]0.54 [0.28, 1.03]

Not estimable0.44 [0.12, 1.66]

Not estimable0.33 [0.04, 2.95]0.97 [0.84, 1.12]

Not estimable0.85 [0.70, 1.05]0.78 [0.61, 0.98]

0.82 [0.69, 0.98]0.99 [0.76, 1.30]0.93 [0.74, 1.16]0.89 [0.78, 1.00]

0.87 [0.77, 0.97]

Non-Calcium Binders Calcium Binders Risk Ratio Risk RatioM-H, Random, 95% CI

0.02 0.1 1 10 50Favours Non-Calcium Favours Calcium

22 % reduction in moratlity in favor of non-CBBs

All-cause mortality by phosphate binder: non-randomized trials(3 trials 791/2381)


Non-randomized trials –11% reduction in mortality in favor of non-CBBs

Results – Coronary artery calcification (CAC)


Difference in calcium score from baseline to longest follow up: -95.26 (95% CI: -146.68 -- -43.84)

DCOR study

DCOR Mortality

• All-Cause and Cause-Specific Mortality During the follow-up period, 431 deaths were recorded for the sevelamer group, and 426 for the calcium group.

• The all-cause mortality rate was not significantly different between the sevelamer and calcium

DCOR Morbidity

• However none of the differences was statistically significant.

Sevelamer hydrochloride versus calcium salts

There was no significant reduction in the risk of all-cause mortality with sevelamer hydrochloride in comparison to calcium salts .

There were significantly higher phosphorus levels with sevelamer hydrochloride in

comparison to calcium salts

There were significantly lower calcium levels with sevelamer hydrochloride in

comparison to calcium salts


There were significantly higher PTH levels with sevelamer hydrochloridein comparison to calcium salts


Conclusion

Fourth Message

• Limited data suggest that sevelamer compared with calcium carbonate may decrease mortality among CKD patients who are not on dialysis.

• There are insufficient data to establish the comparative superiority of novel non-calcium binding agents over calcium-containing phosphate binders for patient-level outcomes such as all-cause mortality and cardiovascular end-points in CKD.

Calcimimetics

EVOLVE

Methods

• Study Design• Multicenter• Prospective • Randomized • Placebo-controlled

trial • Compared cinacalcet

with placebo in 3883 adults undergoing dialysis.

• Primary End Points• The time to death or

the first nonfatal cardiovascular event (myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event).

EVOLVE Results

• Primary Composite End Point Was reached in (48.2%) in the cinacalcet group (49.2%) in the placebo group (p=0.11).

Evolve

EVOLVE

Post Hoc Evolve• Cardiovascular Events• A) Atherosclerotic disease : first

occurrence of myocardial infarction, nonhemorrhagic stroke, hospitalization for unstable angina, peripheral vascular event (including nontraumatic amputation),

• death associated with a cardiovascular procedure, or death due to aneurysm dissection or rupture.

• B) nonatherosclerotic cardiac or vascular pathological processes:

• Heart failure, hemorrhagic stroke, sudden death, fatal pulmonary embolism, or death due to other or unknown cardiovascular cause .

Evolve post Hoc

• The cumulative incidence o nonatherosclerotic events was marginally lower in the cinacalcet than in the placebo group (P=0.062).• there was a 16% lower hazard of nonatherosclerotic events in patients randomized to cinacalcet.• The number needed to treat for 1 year to prevent 1 sudden death was 145.

Evolve post Hoc

Cinacalcet Metanalysis

57.7% of subjects treated with cinacalcet achieved mean iPTH concentrations at or below the upper limit of K/DOQI target range compared with 19.2% of conventional therapy group (P = 0.001)

Safety and tolerability

Conclusion

• Practice guidelines promote therapeutic strategies without sufficient evidence of effectiveness or harms, overtreatment and widespread inappropriate use of medications, services, or devices .

• Nephrology guidelines recommend targets and treatment strategies to correct serum levels of phosphorus, calcium, and parathyroid hormone because observational data suggest there is an association between these potential risk biomarkers and vascular disease and death.

• To date, randomized controlled trials have not shown that treating mineral levels with existing treatment options reduces cardiovascular events or mortality

• Relying on surrogate end points and nonrandomized studies to evaluate treatment efficacy for new interventions is likely to result in unreliable estimates of clinical effectiveness.

• This, in turn, leads to extensive use of interventions that do not improve population outcomes and unnecessarily increase healthcare expenditure.

• Questions will remain as to why prescribing costs became so high in the context of insufficient cumulated evidence over the last decade

Thanks You

• Cost:• Mimpara 30 1360 x 12= 16.320

60 2500 x12 = 30.000• Renagel 1104 X 12 = 13.248• One alpha 1ug 30 48 x12= 576

Vascular Calcification • The occurrence, progression, and prognostic importance of vascular

calcification remain important questions in CKD and the influence of calcium-based binders on the progression of vascular calcification is a matter of intense debate (Bushinsky 2006; Friedman 2006; Moe 2006; Silver 2007).

• Two studies in the current analysis reported a higher rate of progression of vascular calcification with calcium salts compared with sevelamer hydrochloride

• (Block 2005; CARE Study 2004), while another showed no difference in calcium scores between sevelamer hydrochloride and calcium salts (BRiC Study 2008).

• While vascular calcification is associated with an increased risk of mortality in haemodialysis patients, the impact of reducing vascular calcification on survival outcomes has not been demonstrated in RCTS in CKD and non-CKD populations (McCullough 2009; Silver 2007).

Mile stone of Therapy 1970s: Suppress PTH with oral vitamin D and control Serum P04 with aluminum Aluminum Toxicity lead to Calcium binders 1980s iv calcitriol lead to hypercalcemia 1990s vitamin D analogs P04 mortality and Vascular calcification

studies Late 1990s Sevelamer 2000s Lanthanum, Cinacalcet

the KDIGO CKD-MBD guidelines • have placed less emphasis on attaining restricted plasma calcium and PTH ranges [ 9 ]:

• Serum phosphate should be maintained in the normal range for patients with CKD stages 3 to 5 but not yet on dialysis, and phosphate levels should be lowered to the normal range in those on dialysis.

• Among dialysis patients, the desired range for PTH should be two to nine times the upper limit of normal reference laboratory range (this is a key change, as the previous K-DOQI range of two to four times normal values was both too low, and too narrow, almost certainly tending to produce adynamic bone states and possibly increased adverse consequences).

• Plasma calcium levels should be maintained in the normal range. • The calcium-phosphate product should not be used to help guide therapy, and its use should be abandoned. • Trends in biochemical parameters as well as absolute values should be closely followed. • The dose of calcium salts can be considered for restriction in patients with hypercalcemia, adynamic bone disease,

vascular calcification and/or low serum PTH levels. • Not routinely screening all patients for vascular calcification, and, if individual patients need to be assessed for this,

reminding clinicians that lateral X-ray of the lumbar spine and echocardiography are excellent tools to use to detect, if not quantify, vascular calcification. CT-based techniques remain best for research.

• Not routinely using bone densitometry (DXA) scans to assess bone mineral content in CKD stages 3 to 5. • In a lengthy passage dealing with binders, therapies, and outcomes, the consensus was that there was not enough

evidence of sufficiently robust quality, to make any preferential recommendation of one class or style of oral phosphate binder over any other, and that a slew of factors should be considered (such as clinical, patient preference, economic, etc.).

Vitamin D• Vitamin D therapy has historically been based on alfacalcidol

(1 -hydroxyvitamin D3) or calcitriol, both of which attenuate secondary hyperparathyroidism.

• Although these compounds may reduce PTH levels, they increase calcium and phosphorus levels .

• Support for use of the newer vitamin D analogues (22- oxacalcitriol, doxercalciferol, paricalcitol, and falecalcitriol) is based on reports of similar or superior dose-equivalent suppression of PTH, less calcemic and phosphatemic activity, and the possibility of improved survival when compared with established vitamin D sterols (calcitriol or alfacalcidol)

Treat-to-Goal Study:Objective

• To compare the progression of coronary and aortic calcification in HD patients treated with sevelamer HCl


HD=Hemodialysis

CARE 2• study was conducted in 26 centers in the United

States.• Study Design and Randomization The study

included a washout period of up to 6 weeks, followed by 52 weeks of treatment.

• To be randomly assigned, patients had to have serum phosphorus levels greater than 5.5 mg/dL (1.78 mmol/L), LDL-C levels greater than 80 mg/dL (2.07 mmol/L), and baseline.

• Patients were randomly assigned in a 1:1 ratio to 2 treatment strategies: (1) calcium acetate (PhosLo, 667-mg capsules (2) sevelamer hydrochloride.

• Atorvastatin was given to calcium acetate–treated patients at randomization, but was added to sevelamer-treated patients at week 8 only if their LDL-C levels were not less than 70 mg/dL to achieve the LDL-C goal of less than 70 mg/dL (1.81 mmol/L).

• EBCT Imaging Protocol EBCT studies were performed at baseline and days 180 and 360

Difference between TTG, RIND and CARE2

• Our results clearly differ from those of the Treat to Goal and RIND Studies.17,18 In the Treat to Goal Study, Chertow et al17 reported that median percentage of increase in CAC score was 25% in prevalent HD patients treated with CBPB compared with a 6% increment in the sevelamer group. However, in their sevelamer-treated patients, plasma LDL-C levels decreased from 102 to 65 mg/dL (2.64 to 1.68 mmol/L) during the study period, but did not change in patients treated with CBPB.17 Similarly, in patients new to HD with evidence of CAC at baseline, Block et al18 showed that use of CBPB resulted in more rapid progression of CAC than use of sevelamer.

• Likewise, LDL-C levels were 25% lower in their sevelamer-treated patients.18 Fourth, the study duration of 12 months is relatively short. With longer follow-up, a difference in CAC progression between the 2 treatment groups possibly could have been observed.

• Alternatively, longer duration of treatment with atorvastatin may have shown a lower rate of CAC progression in both groups.

• Effect on calcification — Although the data are not consistent, there appears to be relatively less progression of vascular calcification with sevelamer versus calcium-containing phosphate binders among patients with CKD. However, it is unclear whether this benefit is associated with improvements in morbidity and mortality from cardiovascular disease.

• The prospective and randomized "Treat-to-Goal" and RIND trials both reported relatively less progression of coronary artery calcification with sevelamer versus calcium-containing phosphate binders [ 69,74,75,80 ]. By comparison, the Calcium Acetate Renagel Evaluation (CARE)-2 trial found similar progression of coronary artery calcification with sevelamer and calcium acetate [ 81 ].

• The differences observed between the "Treat-to-Goal", RIND, and the CARE-2 trial may be due, in part, to study limitations and the inclusion of a higher proportion of diabetic patients in the CARE-2 trial. This last finding may have resulted in a substantially greater progression of calcification.

• Over the past few decades, cardiovascular disease has accounted for over half of the deaths in people receiving dialysis (USRDS 2009).

Vascular calcification• Five studies reported the effects of sevelamer hydrochloride and calcium salts on

vascular calcification (BRiC Study 2008; Block 2005; Chertow 2002; Qunibi 2008; Russo 2007) (Table 1).

• 1) Chertow2002 reported slower progression of coronary, aortic, and heart valve calcification (measured by electron beam computed tomography) with the use of sevelamer hydrochloride in comparisonto calcium acetate, using the Agatston scoring system. Similarly,

• 2) Block 2005 showed decreased progression of coronary artery calcification with sevelamer hydrochloride compared to calcium salts in incident haemodialysis patients.

• 3) By contrast, Qunibi 2008 compared sevelamer hydrochloride plus atorvastatin to calcium acetate plus atorvastatin and reported similar coronary artery calcification progression in both groups.

• 4) BRiC Study 2008 recorded coronary artery calcium scores in 101 dialysis patients (using a modified Agatston scoring system) and reported no difference in coronary artery calcification progression between the sevelamer hydrochloride and calcium group (P = 0.59). The included studies used different scoring systems to assess vascular calcification and thus could not be pooled.

Evolve limitation

• In the placebo group, 384 of 1935 patients (19.8%) began receiving commercially available cinacalcet before the occurrence of aprimary event (corresponding to an annual rate of 7.4%).

• In the cinacalcet group, 1207 of 1948 patients (62.0%) discontinued the study drug, corresponding to an annual rate of 27.3%.

EVOLVE post HOC• Cardiovascular events in patients receiving hemodialysis may be

largely driven by nonatherosclerotic cardiovascular disease, perhaps resulting from long-term exposure to hypertension, fluid overload, and disorders of mineral and endocrine metabolism associated with CKD.

• Wheeler DC, Haynes R, Landray MJ, Baigent C. Cardiovascular aspects of

• kidney disease. In: Taal MW, Chertow GM, Marsden P, Skorecki K, Yu ASL,

• Brenner BM, eds. Brenner and Rector’s The Kidney. 9th ed. Philadelphia, PA:

• Elsevier Saunders; 2012:2059–2080.

Renagel in New Dialysis (RIND) Study Outcomes: Summary

• Baseline CAC score and choice of phosphate binder are independent predictors of mortality in subjects NEW to hemodialysis

• The severity of CAC at the time of initiation of hemodialysis is an important predictor of long-term survival

• Even after adjustment for age, race, gender, diabetes, albumin, Kt/V, history of

ASCVD, CRP and baseline CAC score, a baseline CAC >400 was associated with a 4-fold increase in mortality– Use of sevelamer HCl is associated with decreased mortality– Use of Ca-containing phosphate binder is associated with a 2-fold increase in

mortality

• Study supports KDOQI guidelines regarding preferential use of sevelamer HCl in the presence of cardiovascular calcification

Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int. 2007;71(5):438-441.

CARE2

• A prospective randomized clinical trial was to test the hypothesis that progression of calcification would be similar in HD patients treated with calcium- containing or calcium-free phosphate binders when LDL-C was decreased to a target level less than 70 mg/dL.

Vascular calcification

Treart to Goal

RIND

DCOR

• The present study comparison of sevelamer and calcium-based phosphate binders on mortality, hospitalization, and morbidity end points by using CMS data.

• Study Design• The DCOR trial was a multicenter, randomized,

openlabel, parallel-design trial. Subjects were enrolled from March 2001 through January 2002 and randomly assigned to Sevelamer or Ca acetate or carbonate.

• Trial was completed at the end of 2004.

Calcimimetics• Calcimimetic agents are small organic

molecules that act as allostersic activators of the calcium sensing receptors (CaSR) in the parathyroid gland and other tissues.

• Calcimimetics increase the threshold

sensitivity of the CaSR to extracellular calcium leading to activation of the CaSR at lower than normal levels of serum calcium.

• As a result, in the presence of these agents, even the low levels of ionized calcium typically present in patients with chronic kidney disease exert a suppressive effect on PTH secretion

Molecular targets regulating parathyroid gland function include, in rank order of importance, CASR, VDR, and a hypothetical phosphate sensing mechanism

EVOLVE

• The interpretation of this trial is limited by both a high drop-out rate in the cinacalcet group (62 percent), and a high rate of crossover in the placebo group: nearly 20 percent of patients in the placebo group ended up taking commercially available cinacalcet. The high rate of crossover may have diminished between group differences.

Vas. Calci

f.

lab

bone

LaboratoryCalciumPhosphorusAlkaline phosphatase.PTHVitamin D

Renal OsteodysdrophyTurnoverMineralizationVolumeLinear GrowthStrength

CalcificationX-rayEBCT

CKD-MBDThe broad syndrome that develops as asystemic disorder of mineral and bonemetabolism caused by CKD

Diagnosis of MBD

• The newer vitamin D analogues (22- oxacalcitriol, doxercalciferol, paricalcitol, and falecalcitriol).

• Established vitamin D sterols (calcitriol or alfacalcidol)

CARE2• Limitations: Treatment assignment was not blinded. The 1.8 a priori margin is large, CAC is

a surrogate• outcome, duration of treatment was short, and dropout rate was high (Forty-four patients

(42.7%) in the calciumacetate arm and 30 (30.0%) in the sevelamer arm dropped out of the study before 1 year.)

• Fifth, mean PTH levels generally were greater than the KDOQI-recommended level of 150 to 300 pg/mL (ng/L). Thus, it could be argued that high PTH levels, particularly in sevelamer-treated patients, may have contributed to the progression of CAC in these patients.

• EBCT studies were performed at baseline and days 180and 360• However, it is more difficult to conclude that intensive lowering of LDL-C levels influenced the

rate of progression of calcification in these patients because, despite excellent cholesterol level control in both treatment groups, there was significant within-group progression of calcification, indicating that other factors are driving the progression of calcification.

• Sixty percent of sevelamer-treated patients and 93% of CBPB-treated patients in the Renagel in New Dialysis (RIND) trial showed a true increase in CAC scores at 18 months.18 In that study, median percentages of increase in CAC scores were 38% and 52% in patients randomly assigned to sevelamer and CBPB, respectively.18

CARE 2• Treat to Goal and RIND Studies.17,18 In the Treat to Goal Study, Chertow et

al17 reported that median percentage of increase in CAC score was 25% in prevalent HD patients treated with CBPB compared with a 6% increment in the sevelamer group.

• However, in their sevelamer-treated patients, plasma LDL-C levels decreased from 102 to 65 mg/dL (2.64 to 1.68 mmol/L) during the study period, but did not change in patients treated with CBPB.

• 17 Similarly, in patients new to HD with evidence of CAC at baseline, Block et al18 showed that use of CBPB resulted in more rapid progression of CAC than use of sevelamer.

• Likewise, LDL-C levels were 25% lower in their sevelamer-treated patients.18• It is important to note that the dropout rate in our study is similar to that

encountered in the Treat to Goal Study.17

RIND• One hundred and twenty-nine patients new to Hemodialysis.• Subjects underwent electron beam computed tomography scanning (EBCT) at entry

into the study and again at 6, 12, and 18 months.• New hemodialysis patients with no evidence of coronary calcification showed little

evidence of disease development over 18 months independent of phosphate binder therapy.

• Investigators and clinicians were blinded to the EBCT results.• Patients in both treatment arms demonstrated similar control of serum phosphorus

and Ca × P. However, subjects treated with sevelamer had significantly lower mean corrected calcium (P<0.0001), higher iPTH (P = 0.05), higher PTH (1–84) (P = 0.03), lower total cholesterol (P = .003), and lower LDL-cholesterol (P=0.0003).

• At baseline, 37% of sevelamer treated subjects and 31% of calcium treated subjects had no detectable coronary artery calcium.

• No patient with a zero CACS at baseline progressed to a CACS >30.

RIND• The median increase in CACS at 18 months was 11-fold greater in the

calcium treated group compared to the sevelamer-treated group (127 points increase vs. 11 points increase, P = 0.01).

• Despite overall good control of the parameters of mineral metabolism, nearly all patients (93%) with baseline coronary calcification randomized to calcium containing phosphate binders demonstrated a true increase in CACS (>15%) at the end of 18 months, while 40% of patients randomized to sevelamer showed no progression.

• in the current study we found 36% of the patients (26% of diabetics) with a zero CACS.

• Limitations• The primary limitation of this study was the small number of patients

studied

Vitamin DStudy Selection

• Randomized and quasi-randomized• Controlled trials conducted in patients with CKD • Compared vitamin D compounds with placebo, different

vitamin D compounds directly, and different vitamin D dose and administration regimens.

• Studies enrolling patients with any stage of CKD and measuring the effect of these agents on surrogate biochemical end points at the end of treatment (for example, levels of PTH, calcium, phosphorus, and calcium phosphorus product) and hard patient-level end points (for example, all-cause and cardiovascular mortality, fracture, toxicity) were included.

Vitamin DIV VS Oral

• Intravenous administration of vitamin D was superior to oral administration in reducing PTH levels and levels of serum phosphorus at the end of treatment

A “stepped-care” approach to the prevention and treatment of secondary hyperparathyroidism in CKD.

Martin K J , González E A JASN 2007;18:875-885


2D

Pi binders in 5D (2B)

if <30ng/ml, (2C)

2B

*Multivariable adjusted40,538 end-stage renal disease (ESRD) patients on maintenance hemodialysis

Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. J Am Soc Nephrol. 2004;15:2208-2218.

Relative risk of death*

<3 3-4 4-5 5-6 6-7 7-8 8-9 >9

Serum phosphorous concentration (mg/dL)

Elevated Serum Phosphorus Increases Mortality Risk

0.00

1.0

1.4

1.6

2.0

2.2

0.08

1.2

1.8

N=40,538

Referent Range

? 60% risk reduction

Conclusion

ckd-mbd:messages from clinical trials

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