controversies in nephrology pth—a particularly...

Controversies in Nephrology

PTH—A Particularly Tricky Hormone: Why Measure Itat All in Kidney Patients?

Giorgia Garrett,* Sunita Sardiwal,* Edmund J. Lamb,* and David J.A. Goldsmith†

SummaryPlasma parathyroid hormone (PTH) concentrations are commonly measured in the context of CKD, as PTHconcentration elevation is typical in this clinical context. Much has been inferred from this raised PTHconcentration tendency, both about the state of skeletal integrity and health and also about the potential clinicaloutcomes for patients. However, we feel that reliance on PTH concentrations alone is a dangerous substitute forthe search for, and use of, more precise and reliable biomarkers. In this article, we rehearse these arguments,bringing together patient-level and analytical considerations for the first time.

Clin J Am Soc Nephrol 8: 299–312, 2013. doi: 10.2215/CJN.09580911

IntroductionIn the many efforts to conquer Mount Everest, thename of George Herbert Leigh Mallory (1886–1924),an English mountaineer who took part in the firstthree British expeditions in the early 1920s, standsapart. Mallory and his mountain-climbing partner,Andrew Irvine, disappeared during the 1924 expedi-tion somewhere high on the Northeast ridge. Malloryis best known for having replied to the question “Whydo you want to climb Mount Everest?” with “Becauseit’s there.” These without doubt are the best-knownthree words in that field (1).

If instead we ask of nephrologists, “Why wouldyou want to make a blood measurement of parathy-roid hormone (PTH) concentration in your CKD pa-tients?”, we wonder what their replies might be? Inthis reviewwe take a careful look at why we do what wedo today with respect to PTH measurements; the evi-dence on which this decision is based; the implicationsfor patients, physicians, and payers alike; and, finally,why persisting with our current practice may be prevent-ing us from adopting a better approach to the manage-ment of CKD–mineral bone disorder (CKD-MBD).

PTH: Origins and PhysiologyPTH is a single-chain hormone of 84 amino acids

that is encoded by a gene on chromosome 11p. Inresponse to a change in the extracellular concentra-tion of plasma ionized calcium, a decrease in plasmacalcium concentration is accompanied by an increasein production of PTH by the parathyroid glands.PTH is cleaved from pre-pro-PTH, where it is stored(together with fragments) in the parathyroid glandsfor later release in secretory granules. The half-life ofendogenous PTH is very short indeed, at 2–4 minutes.It is cleaved in two situations: within the parathyroidgland and after secretion. The cleavage pattern can beclassified by site into N-terminal, carboxy (C)-terminal,and mid-region fragments. These are then eventually

metabolized by the kidney and in the liver. The mainrole of PTH is to increase plasma calcium concentrationby stimulating the release of calcium from the skeleton,while also increasing calcium reabsorption by the renaldistal tubule (2).PTH also stimulates the synthesis of vitamin D in its

active double-hydroxylated form—calcitriol—whosesynthesis occurs in the proximal renal tubule andwhose action in turn causes an increase in intestinalcalcium absorption. Finally, PTH stimulates bone for-mation (as an anabolic effect), and this property is nowincreasingly exploited in clinical practice for treatmentof osteoporosis (3).This mechanistic complexity makes the assay of the

true, “biologically active” PTH important but fraughtwith technical challenges (4). All of these challengesare further compounded by the presence of CKD.

Why Did/Do We Want to Measure PTH in theFirst Place?A Brief History of PTH MeasurementsThe importance of cardiovascular abnormalities in

patients undergoing dialysis was noted in the pio-neering period of the 1960s; because of its ability toact on cardiomyocytes by increasing their cytosoliccalcium, PTH was considered a “uremic toxin” (5,6).Measurements of PTH slowly became more accessi-ble, available, and affordable and by the 1980s be-came routine in the clinical care of patients with CKD.

Skeletal Integrity, Health, and Bone TurnoverConsiderationsAbnormal skeletal structure and function are rela-

tively common findings in patients with CKD (depend-ing on the precision of the techniques used to interrogatethe skeleton). This is especially so in patients requiringdialysis (7). Extraskeletal “soft tissue” calcification isoften a feature of CKD-MBD (with some evidence of

*East Kent HospitalsUniversity, NHSFoundation Trust,Canterbury, Kent,United Kingdom;and †King’s HealthPartners AHSC, Guy’sHospital, London,United Kingdom

Correspondence: Dr.David J.A. Goldsmith,King’s Health PartnersAHSC, Guy’s HospitalCampus, Great MazePond, London SE19RT, United Kingdom.Email: [email protected]

www.cjasn.org Vol 8 February, 2013 Copyright © 2013 by the American Society of Nephrology 299

mailto:[email protected]

mailto:[email protected]

reciprocity between skeletal and soft tissue calcium content).It is likely that vitamin D has bimodal concentration-dependentpropensities to retard or advance soft tissue calcium depo-sition (8,9). This important interplay between skeleton, ves-sels, and outcomes was recognized by the Kidney DiseaseImproving Global Outcomes (KDIGO) initiative in itsCKD-MBD position paper of 2006 (10).The “gold standard” for diagnosis of the skeletal compo-

nent of the CKD-MBD triad is biopsy-based histomorpho-metric analysis of bone biopsy specimens. However, bonebiopsy, a painful and invasive procedure, is now muchless commonly performed in clinical practice, and clinicaland laboratory support for these procedures has wanedsubstantially as a result. There are four significant “bonediseases” (defined from bone biopsy findings) that we rec-ognize as occurring in CKD: osteitis fibrosa cystica, low-turnover or adynamic bone disease, osteomalacia, andmixed uremic osteodystrophy (7,11). Hyperparathyroid-ism, due to progressive phosphate retention and lack ofvitamin D activity, is the major promotor of the develop-ment of osteitis fibrosa. Near-universal sustained eleva-tion of PTH concentrations is seen by the time dialysistherapy begins (12).Adynamic bone disease, or state, is best defined by

low or absent bone formation in the context of a markedreduction in osteoblast and osteoclast numbers (13). Oneimportant understanding to consider is the change in thesubstrate of dialysis patients over the last three decades.Three important patient-level factors seem most stronglyto underpin low bone formation: aging of the patient pop-ulation, the presence of diabetes, and the use of increasedcalcium loading in the context of oral phosphate binding.All of these factors have increased between 1990 and 2010,explaining the current major predominance of adynamicbone disease in biopsy series (14).PTH has become the lingua franca of bone disease man-

agement, although we think that the evidence supportingthis practice is weak. It is important to consider just howreliable plasma PTH concentrations are in informing nephrol-ogists about skeletal health, integrity, and turnover.Fundamentally, PTH is much more reflective of para-

thyroid activity than of bone remodeling (15). Although ithas high sensitivity for detecting hyperparathyroid renalbone disease, its specificity is poor (16). We believe that thedisease and treatment paradigm shift from the “high turn-over”/high PTH osteitis fibrosa lesions predominating inthe 1960s to 1980s has great significance for the bone abnor-malities we must be able to detect using current biomarkers,and the treatments we need to use to help today’s patients,rendering sole reliance on PTH concentrations a flawed andrisky strategy.This paradigm shift, allied with the intrinsically low

specificity, are two reasons for the lack of a good correlationbetween PTH and bone formation rate (shown in many ofthe studies cited in Table 1), except at extremes of PTHvalues (e.g., .600 ng/L and ,100 ng/L). This PTH concen-tration range is of course similar to the KDIGO recommen-dations for the desirable PTH ranges in patients with CKDstage 5D (10). Table 1 details studies comparing bone his-tomorphometry with several different bone turnover mark-ers from 1996 to 2010. The table demonstrates in particularthat when PTH concentrations are in the KDIGO “desirable

range” of two to nine times the upper limit of normal (17),reliance on single plasma PTH measurement alone pro-vides little useful predictive information about underlyingbone histology. Moreover, the ability of plasma PTH con-centrations maintained in the previously desired KidneyDisease Outcomes Quality Initiative (KDOQI) range (150–300 ng/L) to discriminate between adynamic bone andmixed bone lesions was poor.

Patient Outcome ConsiderationsMore recently there has been a realization that the vas-

culature can become heavily calcified, substantially alteringvessel properties by decreasing arterial compliance, andprobably also contributing to cardiovascular disease (CVD)and outcomes (18). There has been a broader appreciationof the potential importance of the relationship betweenplasma phosphate, calcium, PTH, alkaline phosphatase(ALP), and vitamin D and overall survival in CKD.Many cross-sectional studies in diverse populations have

hinted at relationships between abnormal mineral and bonemeasures and adverse overall and cardiovascular outcomes.In general, these associations are most convincing for plasmaphosphate and, more recently, plasma fibroblast growthfactor-23 concentrations (19). This clinical topic has been re-viewed recently by Goldsmith and Cunningham (20).Descriptions of myocardial hypertrophy, myocardial

fibrosis, myocardial calcium (micro)deposition, atheroscle-rosis, often abnormally heavily calcified lesions, vascularstiffening, and raised BP have been cardinal features ofthe cardiovascular response to CKD for many decades. Onefactor that has also consistently been linked to these changesis higher plasma PTH concentrations. These structural andfunctional changes referred to in the cardiovascular systemmay directly contribute to morbidity and mortality fromcardiovascular causes (21). Arrhythmias, ischemia, and de-creased left ventricular function are all clinically challeng-ing, are common in CKD, and might be promoted by bothplasma phosphate and PTH elevations (22).The best evidence to date of PTH involvement with CVD

among patients with CKD who have not started dialysiscomes from work by Bhuriya and colleagues (23) withthe Kidney Early Evaluation Program (KEEP) dataset. Inthis report, patients with PTH concentrations .70 ng/Lhad a .50% increased risk for cardiovascular events com-pared with patients with PTH ,35 ng/L. In this samepopulation, however, and contrary to many other cohortassociations, there was no relationship between CVD andplasma calcium or phosphate concentrations (23). This isinteresting because a reasonably strong relationship betweenplasma PTH concentrations and outcomes in healthy menhas been demonstrated (24). Recently, however, the Cardio-vascular Health Study reported 14-year follow-up data on2312 persons free of CVD at the outset. PTH concentrationsdid not predict all-cause or cardiovascular outcomes, al-though low vitamin D levels did (25).However, the KEEP study has many limitations. Because

of its cross-sectional design, a causal relationship betweenplasma PTH concentrations and CVD cannot be reliablydefined. Its conclusions may not be generalizable to pop-ulations younger than the study cohort (which had a meanage of 68 years). Vitamin D concentrations, treatments, andplasma lipid concentrations were not measured and could

300 Clinical Journal of the American Society of Nephrology

Tab

le1.

Studiesco

mparingbonehistomorphometry

andplasm

abiomarke

rsofboneturnoverin

adultswithCKD

(1995–2

010)

Author

(Referen

ce)

Date

Bon

eBiops

ySa

mples

(n)

Other

Bon

eMarke

rsPT

HAssay

PTH

Ran

geStud

ied

CKD

Stag

eCon

clus

ion

Ure~ na

etal.(65

)19

9642

Total

PTH,iPT

H,

bone

ALP

Alle

grointact

PTH

(San

Juan

Cap

istran

o,CA)

Ave

rage

iPTH

was

753

inhigh

bone

turnov

eran

d12

8in

norm

alor

low

bone

turnov

er(P=0.00

5)

5Pa

tientswith

high

-turnov

erbo

nelesion

sha

dsign

ificantly

high

erplasmabA

LPlevelsthan

patientswith

norm

alor

low

turnov

er.B

one

form

ationan

dresorptio

nwerehigh

lycorrelated

inthesepa

tients,an

dplasmabA

LPlevelswere

positiv

elycorrelated

with

bone

resorptio

nmeasures,includ

ingosteoclastsurface(r=0

.39;

P,0.0001)a

ndosteoclastnu

mber(r=0

.36;

P,0.001),and

with

bone

form

ationmeasures,

osteob

lastsurface(r=0

.50;P,

0.005)

andbo

neform

ationrate(r=0

.91;P,

0.001).

Gerak

isetal.

(76)

1996

114

iPTH,o

steo

calcin

Immun

orad

iometric

assay(N

icho

lsAllegro)

MeaniPTH

levels:621

inHPD

,397

inROD,

152in

adyn

amicbo

ne,

139in

osteom

alacia

5Serum

iPTH

andosteocalcincorrelated

with

mosthistom

orph

ometricindices

ofbo

neform

ation,

mineralization,

andresorption

(r.0.5).iPT

Hleve

ls.

200pg

/mla

ndBGP

leve

ls.

50ng

/mlind

icated

hype

rparathy

roid

bone

disease,w

hile

iPTH

leve

ls,

65an

dBGP

,20

indicated

adyn

amicbo

ne.

Coe

netal.(77

)19

9841

(37dou

ble-

labe

led)

iPTH

,osteocalcin,

ALP

,b-A

LP,

TRAP,

ICTP

,DPD

Dou

ble-an

tibo

dy

RIA

(Inc

star,

Stillwater,M

N)

9pa

tientswith

low

turnov

er(A

BD)h

ada

PTH

of71,9

with

MUO

hadaPT

Hof

178,an

d23

with

high

turnov

er(H

PT)h

adaPT

Hof

917

5So

meutility

inmeasu

remen

tofthe

biom

arke

rs.

bALPsu

periorto

PTH

inthisseries.B

iased

series

becaus

epo

pulation

was

pred

ominan

tly

HPT

patien

ts,w

ithalargesp

read

ofPT

Hva

lues

andbo

nebiop

syfind

ings.T

ypical

ofthe19

90sera.

Carmen

Sánc

hez

etal.(78

)200

057

ALP,o

steo

calcin

IRMA

47%

(PTH

was

88.58in

patien

tswithad

ynam

icbo

nelesion

,390

inthose

withhigh

-turnov

erlesion

s,41

2in

those

withosteitisfibrosa,

and20

8in

those

withmild

HPT

)

5Meanba

selin

ePT

Hleve

lsfrom

prev

ious

year

andPT

Hleve

lsat

timeof

bone

biop

sywere

greaterin

patien

tswithhigh

turnov

erthan

thosewithABD

(P,0.05

).PT

Hleve

ls,

150in

patien

tswithABD

show

edsens

itivityof

91.6%,spe

cificity

of95

.2%,

andPP

Vof

97%.Inthehigh

-turnov

ergrou

p,PT

Hleve

ls.

450pg

/mlh

adasp

ecificity

andPP

Vof

100%

.Coe

netal.(79

)20

0218

6Non

eIRMA

Not

specified

3,4,

5In

pred

ialysispa

tien

ts,b

onebiop

syshow

ed9casesof

ABD,8

casesof

osteom

alacia,

50casesof

MUO,a

nd2casesof

HPT

.Amon

ghe

mod

ialysispa

tien

ts,1

2ha

dABD,

3ha

dosteom

alacia,3

0ha

dMUO,

and61

hadHPT

.

Clin J Am Soc Nephrol 8: 299–312, February, 2013 Rationale for PTH Measurements, Garrett et al. 301

Tab

le1.(Continued

)

Author

(Referen

ce)

Date

Bon

eBiops

ySa

mples

(n)

Other

Bon

eMarke

rsPT

HAssay

PTH

Ran

geStud

ied

CKD

Stag

eCon

clus

ion

Coe

netal.(80

)20

0235

PTH

1-84

,PTH

7-84

,bALP,

calcium

and

phosph

ate

IRMA

MeanPT

HforHPT

,776

;forMO,2

62;for

low

turnov

er,1

04.P

TH

1–84

forHPT

,434

;forMO,2

62;for

low

turnov

er,1

04.P

TH

totalfor

HPT

,833

;forMO,2

62;for

low

turnov

er,1

12(P

,0.01

forall)

5Twoassays

ofsimila

rva

luein

osteod

ystrop

hy.

PTH

7–84

may

inhibitP

TH

andcaus

ePT

Hbo

neresistan

cein

chronicrena

lfailure.

PTH

1–84

/7–

84isprop

osed

asago

odassay

forpred

icting

bone

turnov

erin

chronicrena

lfailu

re.T

hePT

H1–

84-to-7–

84ratioisno

tamarke

rof

low

turnov

eran

disof

nous

ein

noninv

asivehistolog

icdiagn

osis.

Bervo

etsetal.

(81)

2003

84iPTH,tAP,

bALP,

osteoc

alcin,

seru

mcalcium

IRMA

128in

ABD,2

27in

norm

al,

200in

HPT

,309

inmix,

376in

osteom

alacia.

Correlation

matrixof

bioche

mical

and

histolog

icmeasu

res:

iPTH

versus

tAP,

0.45

;iPTH

versus

BAP,0

.55;

iPTH

versus

osteocalcin,

0.39

;iPT

Hve

rsus

PYD,

0.35

;iPT

Hve

rsus

DPY

D,

0.49

;tAPve

rsus

bALP,

0.76

;PYD

versus

DPY

D,

0.93;P

YD

versus

creatin

ine,0.54;D

PYD

versus

creatin

ine,0.51

(refer

toTa

ble3of

the

stud

yformorede

tail)

Pred

ialysis

PPVforpo

pulation

under

stud

ywas

47%.

Fordiagn

osisof

bone

disease,o

steo

calcin

leve

l,41

ng/Lha

dasens

itivityof

83%

andsp

ecificity

of67

%.T

hecombina

tion

ofan

osteocalcinleve

l#41

ng/Lwith

bALP#

23U/Lincreasedthesens

itivity,

specificity,a

ndPP

Vto

72%,8

9%,a

nd77

%,

resp

ective

ly.A

BD

andno

rmal

bone

take

nas

onegrou

pcouldbe

detectedbe

stby

bALP

leve

ls#25

U/Lan

dtA

Pleve

l#84

U/L,

show

ingsens

itivitiesof

72%

and88

%an

dsp

ecificities

of76

%an

d60

%,

correspo

ndingwithPP

Vsof

89%

and85

%,respe

ctively.

Spasov

skietal.

(82)

2003

84iPTH,

osteoc

alcin

IRMA

227in

norm

albo

ne,1

28in

ABD,2

01in

HPT

,37

6in

osteom

alacia,

309in

mixed

osteod

ystrop

hy

5Ofthe

serand

omly

selected

patien

ts,

62%

presen

tedwithan

abno

rmal

bone

histolog

icresu

lt,a

ndABD

was

themost

prev

alen

ttyp

eof

ROD

inthispo

pulation

.Pa

tien

tch

aracteristicsassociated

withABD

includ

edmalege

nder,latereferral,a

nddiabe

tes,while

osteom

alacia

was

associated

witholder

patien

tag

e(.

58yr)an

dserum

calcium

leve

ls,

8mg/

dl.

Coe

netal.(83

)20

0510

4ALP,2

5-OHD,

calcitriol

IRMA

Thisstud

yus

ed25

-OHD

asfocu

srather

than

PTH

5Vitam

inD

defi

cien

cyaffectsbo

neturnov

erin

CKD

patien

ts.N

ocorrelationbe

tween

PTH

and25

-OHD

inCKD

patien

ts.N

ocorrelationbe

tweencalcitriol

and25

-OHD.

Idealran

geof

25-O

HD

shou

ldbe

20–40

ng/ml.


Tab

le1.(Continued

)

Author

(Referen

ce)

Date

Bon

eBiops

ySa

mples

(n)

Other

Bon

eMarke

rsPT

HAssay

PTH

Ran

geStud

ied

CKD

Stag

eCon

clus

ion

Gal-M

oscovici

etal.(84)2

005

96,b

ut52

serum

PTH

leve

lsat

the

timeof

biop

sy

PTH

N-tactP

TH

SPIRMA-kit

23%

540

%of

patien

tsha

dosteitisfibrosacystica.

The

remaining

60%

hadva

riou

sform

sof

low-turno

verbo

nediseases.Nocorrelation

betw

eenPT

Han

dbo

neform

ationrate

inall

patien

ts(r=0.28

)orin

subg

roup

swithPT

Hl

150–

550an

d50

0–12

00pg

/ml(r=0.27

and0.21

,resp

ective

ly).Close

correlationbe

tweenPT

Han

dbo

neform

ationrate

foun

don

lyin

subg

roup

withPT

Hleve

lind

icating

low-turno

verbo

nedisease.

Leh

man

netal.

(85)

2005

132

iPTH,b

io-

intact

PTH

Nicho

lsAdv

antage

Autoana

lyzer

iPTH

sens

itivityan

dsp

ecificity

forlow

bone

turnov

er,4

0%an

d10

0%;b

io-intact

PTH,1

00%

and81

%.

iPTH

sens

itivityan

dsp

ecificity

forhigh

bone

turnov

er,2

7%an

d18

%;

bio-intact

PTH,7

3%an

d91

%

3,4,

5Pa

tien

tswithCKD

stag

e3/

4an

dlow-turno

ver

skeletal

lesion

sha

dBI-PTH

values

of35

pg/ml

andiPTH

values

of59

pg/ml.Corresp

onding

values

forbio-intact

PTH

andiPTH

inthose

withhigh

turnov

erwere14

1an

d22

1pg

/ml.

Patien

tswithCKD

stag

e5an

dlow-turno

ver

skeletal

lesion

sha

dbio-intact

PTH

andiPTH

leve

lsof

52an

d90

pg/ml,resp

ective

ly;

correspo

ndingleve

lsforthosewith

high

-turno

verlesion

swere23

7an

d46

1pg

/ml.AUCsfordisting

uishinglow-from

high

-turno

verlesion

swere0.94

pg/mlfor

bio-intact

PTH

and0.91

pg/mlfor

iPTH

inCKD

stag

e5.

Barreto

etal.(86

)20

0897

Second

-gen

eration

5Association

betw

eenlow

turnov

eran

dbe

ing

white

andatren

dtowardan

association

witholder

age(P=0.07

)and

diabe

tes(P=0.07

)wereno

ticed.T

hese

resu

ltssu

ggestthat

KDOQItarget

rang

eof

iPTH

isno

tnecessarily

asafe

target

rang

eforbo

ne.F

urthermore,

even

foran

iPTH

of43

00pg

/ml,low

turnov

erwas

observed

inon

ethirdof

patien

ts.

Yam

adaetal.

(87)

2008

98TRACP5

B,N

TX,

ALP,

PTH

Two-site

IRMA

for

who

lePT

Hassay;

second

-gen

eration

Elecsys

PTH

IRMA

foriPTH

Meanva

lues

6SD

:iPTH,1

12.7684

.2;

who

lePT

H,

68.1657

.3

Pred

ialysis

Log

serum

TRACP5

Ban

dothe

rbo

nemarke

rsweresign

ificantly

nega

tive

lycorrelated

with

GFR

(r=20.58

;P,0.00

01)a

ndALP(r=0.41

0;P,0.00

01)a

ndpo

sitive

lycorrelated

withPT

H(r=0.62

6foriPTH;r=0.64

0forwho

lePT

H).

TRACP5

Bwas

sign

ificantly

correlated

tologiPTH

(r=0.51

2;P,0.00

01)a

ndlogwho

lePT

H(r=0.53

5;P,0.00

01).Ren

aldysfunc

tion

doe

sno

tinflue

nceserum

TRACP5

Ban

dbo

neALPbu

tdoe

sinflue

nceNTXan

dosteocalcin.

Serum

TRACP5

Bmay

beago

odmarke

rfor

serum

bone

resorption

inpred

ialysisCKD.


Tab

le1.(Continued

)

Author

(Referen

ce)

Date

Bon

eBiops

ySa

mples

(n)

Other

Bon

eMarke

rsPT

HAssay

PTH

Ran

geStud

ied

CKD

Stag

eCon

clus

ion

Ferreira

etal.

(88)

2008

91(44given

sevelamer,47

givencalcium-

basedbind

ers)

bALP

Ana

lyzedat

bone

diagno

stican

dresearch

labo

ratory

inKentucky

Med

ianiPTH

inseve

lamer

patien

ts,

167(ran

ge,3

–19

58);

med

ianiPTH

incalcium

patien

ts,

113(ran

ge,4

–13

69)

5The

freq

uent

observationof

ABD

withmed

ian

PTH

150–

400pg

/mlreaffirm

theva

lue

ofbo

nebiop

sies

duringdialysisin

patien

tswithinterm

ediate

PTH

values.

Leh

man

netal.

(89)

2008

132

PTH,o

steo

calcin,

vitamin

D,serum

ALPan

dbA

LP,

pyrind

olinean

ddesox

ypyrindoline

Che

milu

minescenc

emetho

don

the

Nicho

lsAdva

nced

Autoa

nalyzer

Med

ianPT

Hin

low-turno

verCKD

3an

d4,56;m

edianPT

Hin

low-turno

verCKD

3,104(PPV

,0.79;NPV

,0.82;sen

sitiv

ity,0.91;

specificity,0.36).M

edian

PTH

inhigh

-turno

ver

CKD

4an

d5,210;

med

ianPT

Hin

high

-turnov

erCKD

5,295

(PPV

,0.89;NPV

,0.55;sen

sitiv

ity,0.91;

specificity,0.36).

3–5

Osteitisfibrosawas

themostcommon

histom

orph

ometricform

:47%

ofCKD

stag

e3an

d4pa

tien

tsan

d61

%of

those

inCKD

stag

e5.

Occurrenc

eof

ABD

did

notd

iffer.Correlation

coefficien

tsbe

tween

bone

marke

rsan

dhistom

orph

ometric

measu

reswerehigh

erforCKD

5pa

tien

tswithhigh

turnov

erbo

nelesion

s.Pred

ictive

valueforhigh

versus

low/no

rmal

bone

turnov

erstatus

was

simila

rforAPH

,BAP,

pyridinoline,desox

ypyrindoline,

tartrate-resistant

acid

phosph

atase,

andPT

Hin

CKD

5.

Coe

netal.(90

)20

0932

Seru

mcalcium,

phosph

ate,ALP,

andiPTH

IRMA

Mean6

SD,

916.46

751.97

5Sign

ificantly

high

correlationbe

tween

PTH

andhistod

ynam

icmeasu

rebo

neform

ationrate

perbo

nesu

rface(r=0.70

7;P,0.00

001).Inv

erse

correlationbe

tween

agean

dbo

neform

ationrate,p

ositive

correlationbe

tweenag

ean

dcard

iac

andcorona

ryAga

tstonlogscores.

Bon

eturnov

ermeasu

reswererelated

toPT

H,corrobo

rating

theclose

dep

enden

ceof

themeasu

redbo

nemeasu

res.

Fehm

ieta

l.(91)

2009

43Seru

mcalcium,

phosph

ate,an

dbo

ne-spe

cificALP

Bio-intactP

TH

(Nicho

ls),Total

intact

PTH

and

1–84

who

lePT

H(Scantibod

ies)

Protocol

A:m

ean

bio-intact

PTH

6SD

,612

636

.2Protocol

B:total

PTH,7

32;w

hole

PTH,4

24;P

TH

ratio,

1.66

5Ave

rage

leve

lofiPT

Hishigh

erin

African

-American

patien

tswithpred

ialysis

CKD

andthosewithCKD

undergo

ing

dialysis.Current

KDOQIgu

idelines

dono

tdisting

uish

African

American

sfrom

whites.

Thiscalls

foran

alternativerang

eof

iPTH

forAfrican

American

s.


be additional sources of unmeasured and therefore uncor-rected confounding: A link between PTH and lipids is wellrecognized (26). There was no confirmation of major adversecardiac events by electrocardiographic or echocardiographicreadings or clinical record confirmation of myocardial in-farction, stroke, or abnormal heart rhythm, which obviouslybrings accuracy limitations to the definition of endpoints inthis report.Alternatively, Kalantar-Zadeh and colleagues suggest

that there is a U-shaped relationship between PTH andoverall adverse endpoints in CKD (higher mortality withlow and high PTH concentrations) (27). However, data tosupport this interpretation mainly come from dialysischains where we believe that many residual undetectedor unmeasured confounders are likely to still be operating.Pertinent findings from the 4D Study in Germany (28,29)have shown a modest linear relationship between all-causeand CVD outcomes and PTH concentrations. However, thiswas seen only in patients without substantial malnutritionor inflammation (implying that the comorbid phenotype ofthe patients included in case series, and data output fromdialysis chains, can influence outcomes). Moreover, epide-miologic findings for patients with CKD stage 5D fre-quently translate badly to patients with CKD stage 3 or 4.The largest and most comprehensive meta-analysis of

this topic was published recently by Palmer et al. (30) fromStrippoli’s Cochrane research group. Forty-seven cohortstudies (involving 327,644 patients) met the authors’ inclu-sion criteria. The relative risk for death increased 18% forevery 0.33-mmol/L (1-mg/dl) increase in plasma phosphate.There was no significant association between all-cause mor-tality and plasma concentrations of PTH (relative risk per100-ng/L increase, 1.01) or calcium (relative risk per 1-mg/dl[0.25-mM] increase, 1.08).Therefore, in the largest and probably the most reliable

studies, there appears to be only a weak association betweenhigher plasma concentrations of phosphate (and no consis-tent relationship for PTH) and overall or CVD mortality inthe CKD population. One must also point out that no inter-vention study has targeted plasma PTH concentrations (orplasma phosphate, calcium, or vitamin D), in any CKD pop-ulation, with CVD and mortality endpoints.

Measurement of PTH in Real Life: It’s Just Not asSimple as Checking a Box or Pressing a ButtonIn requesting and interpreting laboratory investigations,

we must always ask the questions: (1) What is the result ofthis test going to do for the betterment of the patient’shealth, and (2) is the test itself reliable as a marker of illnessor outcomes? The dangers of believing that test result “num-bers” equate to illness or health, or that an automatic responseto “normalize” these numbers is appropriate, have now beenmasterfully spelled out in relation to both anemia (31) andCKD-MBD (20). If there is no obvious utility, there is futility.However, for PTH we must also understand important

inherent potential biases and inaccuracies relating to numer-ous analytic and preanalytic factors.

Evolution of PTH AssaysIncreasingly specific PTH assays have been developed

over the years (Figure 1) (32). Between the 1960s and the

Tab

le1.(Continued

)

Author

(Referen

ce)

Date

Bon

eBiops

ySa

mples

(n)

Other

Bon

eMarke

rsPT

HAssay

PTH

Ran

geStud

ied

CKD

Stag

eCon

clus

ion

Herbe

rthetal.

(92)

2010

141

iPTH,P

TH

1-84

,an

dPT

Hratio

Third

-gen

eration

Average

totalP

TH,525;

PTH

1–84,286;P

THratio

,1.5.Serum

iPTH

high

erwith

high

bone

turnov

er;

PTH

ratio

lower

with

low

bone

turnov

er(P=0

.01).

Forblackpa

tients,

sign

ificant

associations

werefoun

dbetw

een

iPTH

andbo

neturnov

er(P=0

.01)

5Stud

yad

dressed

addingthePT

Hratioto

iPTH

andPT

H1–

84fordiagn

osingtheleve

loflow

bone

turnov

erin

thispa

tien

tpo

pulation

.Histologically

,patientspresen

tedwithabroa

drang

eof

bone

-turnov

erab

norm

alities.In

white

patien

ts(n=40

),iPTH

cutoff(.

420)

resu

lted

incorrectlyclassifying84

%as

high

turnov

er.

PTH

ratio,1whe

nad

ded

toiPTH

,42

0increasedPP

Vforlow

bone

turnov

erfrom

74%

to90

%in

thesepa

tien

ts.Inblack

patien

ts(n=71

).

PTH,p

arathy

roid

horm

one;ABD,adyn

amicbo

nedisease;M

UO,m

ixed

urem

icosteod

ystrop

hy;H

PD,h

omepe

ritone

aldialysis;iPTH,intactp

arathy

roid

horm

one;ALP,

alka

lineph

osph

atase;

bALP,

bone

-spe

cificalka

lineph

osph

atase;tA

P,totalalkalineph

osph

atase;ROD,ren

alosteod

ystrop

hy;B

GP,

bone

Glaprotein;

TRAP,tartrate-resistan

tacidph

osph

atase;IC

TP,typ

eIcollage

ncarbox

yterm

inal

prop

eptide;DPD

,deo

xypy

ridinoline;HPT

,hyp

erpa

rathyroidism;IRMA,immun

orad

iometricassay;

PPV,p

ositivepred

ictive

value;25

-OHD,2

5-hy

droxy

vitamin

D;A

UC,

area

under

thereceiver-operatingch

aracteristiccu

rve;KDOQI,Kidne

yDisease

Outco

mes

Qua

lityInitiative

;TRACP5

B,tartrate-resistan

tacidph

osph

atase5B

;NTX,collage

ntype

1cross-lin

ked

N-telop

eptide;NA,n

otav

ailable;BMI,bo

dymassindex

;NPV

,neg

ativepred

ictive

value.

a ProtocolA

:KDOQIg

uide

lines

appliedtothebio-intactPT

Hassay.ProtocolB:follo

wingK7D

OQIg

uide

lines

forintactP

THan

d/or

theratio

ofPT

H-(1-84)/N-terminallytrun

catedfrag

ments(PTH

ratio

).


1980s, (inclusive) radioimmunoassays (RIAs) were used;these are now considered “first-generation” PTH assays.Such RIA-based techniques involved a single antibody di-rected toward epitopes found mainly in the mid-region orC-terminal regions of the PTH molecule. These assays provedto be of significantly limited reliability for two main reasons:first, the different characteristics of the antisera used, and sec-ond, the increasing realization that PTH can circulate in dif-ferent forms (not only in the form of the intact 84–amino acidpeptide but also as many hormone fragments, particularlyfrom the mid- and C-terminal regions). Cross-reactivity with,and detection of, a variety of C-terminal PTH fragments aswell as full-length PTH (1–84) was a feature of most PTH RIAtechniques, which tended to produce a wide variety of results.Measurements of PTH concentrations in patients with

CKD using these C-terminal RIAs were unsatisfactory andinaccurate as a result of reduced renal excretion of suchfragments, resulting in marked PTH concentration eleva-tion compared with persons who did not have CKD.Amino-terminal RIAs frequently had greater accuracy andpredictive utility than the contemporary mid- or C-terminalRIAs in the assessment of patients with CKD-MBD, but theywere still significantly inaccurate (4,32).The next important technical development was of second-

generation PTH assays, starting in about 1987. These two-site immunoradiometric assays helped to mitigate many ofthe inadequacies of the single-antibody RIAs (33,34). In thisnewer method, a capture antibody is used to bind near theN-terminus and a second solid phase-coupled antibodythen can bind to the C-terminus. Such assays were moreintrinsically considerably more reproducible than RIAs,particularly for patients requiring treatment with dialysis.These so-called intact PTH assays were reputed to detectjust full-length PTH (1–84). They remain the most widelyused methods for measuring PTH in clinical use today,although they commonly now involve nonradioactive de-tection systems. But we must also admit it is now clearerthat even intact PTH assays detect more than one species ofPTH when plasma is fractionated by HPLC (35).More recently, PTH assays have achieved a third itera-

tion, or generation. These newest PTH assays appear to havesubstantially improved specificity for full-length PTH (1–84)(36). These “whole” or “bioactive” PTH assays appear toprovide results that are approximately 50%–60% of those

achieved with the intact assays in patients with CKD andabout 15% lower than those in persons without CKD. Spe-cific information on the available assays and their character-istics has recently been published (37).One vexing but important question is whether C-terminal

fragments (often called 7–84 [although the exact compositionis unknown]), once accumulated, could be active biologi-cally. To date this has best been shown only in animals,and the prospect remains controversial in humans. PTH(7–84) is reputed to be able to antagonize the calcemicresponse to PTH (1–84) using in vivo experimental protocols.Studies in vitro have shown that PTH (7–84) can induce re-duction in bone resorption, which has previously been stim-ulated by different agonists (38,39). Thus, C-terminal PTHfragments in high concentrations may modulate the actionsof PTH on the skeleton. Malluche and Monier-Faugere havesuggested that the ratio of PTH (1–84)/PTH (7–84) can aid indetecting adynamic bone disease (40), but other groups havefailed to replicate these results.

Intermethod VariabilityClinically relevant variability exists among PTH assays.

Souberbielle and colleagues (41,42) compared PTH concentra-tions measured using 15 commercial immunoassays from 47samples of plasma pooled from patients undergoing dialy-sis. Their reference standard was the Nichols Allegro PTHassay because the KDOQI guidelines were predominantlybased on this assay; however, this assay is no longer avail-able. The median bias in their study ranged from 245% to123%. Similar results have been observed by others (43,44).Intermethod variability may be explained in part by

problems of antibody specificity and standardization.Commercially available assays show differing recovery ofPTH (1–84) and differing cross-reactivity with PTH (7–84).This reflects differences in antibody specificities and affinitiesof the assays, which are individual to each manufacturer. Theproblem is further compounded by the differential and pos-sibly variable retention and therefore accumulation of PTH(7–84) and other fragments in CKD. There is also no agreed-upon common standard between PTH assays (i.e., the humanPTH [1–84] calibrators used in these assays differ betweencommercial companies). D’Amour and colleagues suggestedthat after adjustment for differences in human PTH (1–84)calibrators, this adjustment can lead to a useful improvementin interassay agreement (45). A newly established First In-ternational Standard for PTH (World Health OrganizationInternational Standard 95/646) has been prepared, and itscommutability between assays is being established (46). It ishoped that the introduction of this material will lead to sub-stantial improvement in assay comparability (47).

Sample StabilityPTH assay results can differ to an important degree if

samples are measured in plasma or serum and depending onthe temperature and speed of processing. Many studies havefound that at room temperature, PTH ismore stable in plasmaderived from blood samples collected into EDTA-preservedtubes than in tubes containing no preservative (48,49). PTHalso seems to be more stable in EDTA-preserved whole bloodthan plain clotted blood samples (50). Conversely, Cavalieret al. reported improved stability in serum compared with

Figure 1. | Different areas of the PTH molecule that are detectedwith the three “generations” of PTH assay used historically to thepresent day. These assays do not detect the same PTH species. PTH,parathyroid hormone; RIA, radioimmunoassay; N-PTH, N-terminalPTH; C-PTH, C-terminal PTH.


EDTA plasma under frozen storage conditions (51). Joly et al.observed relatively stable PTH concentrations in EDTAplasma after 18 hours at room temperature with five differentassay systems but a 12% increase in measured concentrationwith the Immulite assay (42). Changes in measured PTHconcentrations as a result of different storage conditionswere potentially sufficient to affect clinical decision-making in many cases (42).

Biologic VariabilityInvestigators of a recent pragmatic “real-life” study reported

the intrinsic biologic variability of plasma calcium, phos-phate, ALP, and PTH concentrations in patients undergoinghemodialysis (52). In 22 stable patients, these analytes weremeasured twice weekly over a 6-week period. Researcherscould then calculate intraindividual coefficients of variationand the reference change value, defined as the value re-quired to allow 95% certainty that a true change in valuehad occurred. With PTH, this was 72% for patients undergo-ing dialysis; in other words, a PTH value of 300 ng/L and asubsequent value of 500 ng/L would not necessarily be trulydifferent from each other. These studies have led to the no-tion that 26 specimens should ideally be measured over ashort time period to estimate a dialysis patient’s PTH homeo-static set point (52). This clearly is a long way from currentstandard clinical practice.

Other VariablesOther contributions to PTH variability exist but are also

poorly appreciated. For example, Vulpio et al. (53) observedcentral venous catheter PTH concentrations in patients un-dergoing hemodialysis to be 30% higher than concentrationsin peripheral blood samples. The reasons for this differenceremain obscure.

PTH or ALP: Combine for the Best of Both WorldsThe pitfalls of relying on PTH alone as a marker of

underlying bone activity in patients with renal failureare increasingly recognized. These pitfalls include (1)standardization-related interassay variation (4); (2) assay non-specificity (approximately 50% of measured PTH is of abiologically inactive form) (54); (3) skeletal resistance (55);(4) poor histologic correlation to target ranges (Table 1);(5) racial variation in the PTH-histology relationship (56);(6) profound effects of venous sampling site on concentra-tion (53); (7) strong relationship between PTH and bodymass index (57) and nutritional and inflammatory status(29); and (8) high biologic variation (52). These issues raiseimportant concerns over the validity of specific target con-centrations of PTH and the use of PTH alone in monitor-ing response to treatment (4,11,17).We therefore advocate a blended approach, using PTH

especially where the plasma concentrations are “extreme”(,100 ng/L or .600 ng/L), combined with total (we be-lieve better), bone-specific ALP (bALP) concentrations. Asrecommended by KDIGO, we suggest looking at trendsover time and rolling averages, not at individual values.There are many potential biomarkers of skeletal health

and integrity, some difficult to use and to interpret in CKDbecause renal function affects the plasma concentrations.One of the best-known, and best-established, potential

biomarkers is the plasma concentration of ALP—especiallybALP—which has a good relationship with both bone turn-over and patient-level outcomes (58,59). ALP and PTH aspotential bone-specific biomarkers are compared and con-trasted in Table 2; we believe the table shows that bALPhas much as-yet unfulfilled promise in this regard. Precisecutoff values for bALP will require more prospective studieson decent-sized heterogeneous cohorts of patients undergo-ing dialysis, but the available literature indicates that plasmaconcentrations , 20 IU/L are reliably associated with low-turnover bone disease states (positive predictive value. 80%).Although serum total ALP is still routinely measured as

part of biochemical analyte panels, it is often considered justas an adjunct to PTH measurement, with no clearly definedmanagement targets. Despite this, ALP is more sensitive tothe effects of vitamin D replacement than is PTH (60,61) andhas a strong independent linear positive association withmortality in patients with kidney disease (62) and in thenon-CKD population (58). This association is possibly linkedthrough vascular calcification (63). Shantouf et al.observed a significant association between serum ALP activ-ity and coronary artery calcification in hemodialysis pa-tients, with serum ALP .120 U/L being a robust predictorof calcification (63).Concentrations of bALP correlate with PTH concentrations

in patients undergoing hemodialysis (64): They are increasedin high-turnover bone disease and are more specific for thiscondition than PTH or total ALP (16, 65). Furthermore, un-like PTH, concentration of bALP directly reflects osteoblasticactivity, does not accumulate in blood with declining renalfunction (66), and is strongly and independently related tobone mineral density (67,68). It is also a good predictor, withdual-energy x-ray absorptiometry–derived bone mineraldensity values, of future fracture risk in patients undergoingdialysis (69). Biologic variation of bALP is approximatelyhalf that of PTH (70). bALP effectively provides a “livingbiopsy” of osteoblastic activity, without the problems of re-sistance and nonspecificity that bedevil interpretation ofPTH. Of course, it remains the case that bone biopsy is thedesirable but rarely achievable diagnostic maneuver, althougheven the much-vaunted accuracy of bone biopsy must be setaside for the increasing lack of histomorphometric interpre-tative expertise and the known skeletal metabolic heteroge-neity seen in CKD. Despite histologic studies demonstratingbALP as a good marker of bone turnover in patients under-going hemodialysis (Table 1) (71,72), its use has not becomewidespread, probably reflecting difficulties of measurementand concerns over cross-reaction with liver-derived ALP.

Measurement of PTH in Current Clinical Practice:Quo Vadis?The short half-life of PTH is perfect in helping surgeons

understand what they have achieved by parathyroidec-tomy because intraoperative PTH values can determine theneed for further neck exploration (73). If we adopt thecurrent recommended surveillance policy of four PTHmeasurements a year, this allows us to assess the concen-tration of this hormone for 0.003% of the patient’s “clini-cal” year. Given the fluctuations, cyclicity, and many otherinfluences on PTH, most notably plasma calcium concen-tration, it is an act of optimism (or folly) to imagine thatthese precious 16 minutes of comprehension will guide us


Tab

le2.

Comparisonofplasm

abonealkalinephosphataseve

rsusplasm

aparathyroid

horm

oneas

bonebiomarke

rs

Adva

ntag

esof

usingbA

LP

Disad

vantag

esof

usingbA

LP

Disad

vantag

esof

usingPT

HAdva

ntag

esof

usingPT

H

Refl

ects

bone

form

ation(65)

Possible

interferen

cefrom

liver

isoe

nzym

ein

liver

disease

Refl

ects

parathyroidactivity

Filtered

bythekidne

ys;h

epatican

dFa

miliarityof

use

Hep

atic

deg

radation;

doe

sno

taccu

mulate

withprog

ressiveloss

ofGFR

(92)

Autom

ated

metho

dsno

twidely

available

rena

lmetab

olism

toC-terminal

frag

men

tsan

drena

lclearan

ceof

intact

PTH

Strong

correlationbe

tweenbA

LPan

dbo

nehistolog

y,as

wella

sothe

rbo

nemarke

rs(65,66

)W

eakcorrelationbe

tweenplasmaPT

Han

dbo

neform

ationrates—

skeletal

resistan

ceto

PTH

(Tab

le1)

Low

biolog

icva

riation(70)

Highbiolog

icva

riation(52)

Nodifferenc

ein

variationbe

tweena.m.

andp.m.d

ialysispa

tien

tsApp

aren

tdifferenc

ein

variationbe

tween

a.m.a

ndp.m.d

ialysispa

tien

ts(52)

Interm

etho

dva

riab

ility,con

tributed

to

Goo

dbe

tween-metho

dag

reem

ent(66

,67)

bymeasu

rand

heteroge

neity(43)

Anassociationwithcard

iova

scular

Linke

dto

vascular

calcification

and

card

iova

scular

disease

(63),w

ithhigh

conc

entrations

strong

lyassociated

with

short-term

mortalityin

dialysispa

tien

ts(59)

disease

buta

U-sha

pedassociation

withmortality(62)

Impo

rtan

tinter-raciald

ifferenc

es(highe

rva

lues

inAfrican

American

s)(56,91

)Sh

orth

alf-lifein

vivo

andex

vivo;h

ence

strict

preana

lyticalg

uidelines

Lon

gha

lf-life;stab

le(94)

need

ed(48)

Blood

samplingsite

variation(53)

Num

bers

inpa

renthe

sesarereferenc

ecitation

s.bA

LP,

bone

alka

lineph

osph

atase;PT

H,p

arathy

roid

horm

one.


adequately when making therapeutic decisions over theremainder of the year, even if PTH concentrations werereliable guides to clinical matters (which we question).However, in doing what we currently do as nephrolo-

gists, we are hoping that a highly labile hormone subject tocontinuous feedback control can offer guidance on the stateof chronic bone disease. Various bone-related therapies—these might include calcium, vitamin D (both native andsynthetic), calcimimetics, and bisphosphonates—whenused in the treatment of hyperparathyroidism, adynamicbone disease, osteomalacia, or osteoporosis, are all interven-tions whose biologic activity and outcomes are measured inmany weeks to many months, not just a few minutes. Tobelabor this point some more, PTH, with its short half-life, isoften used to “diagnose” the state of bone turnover; as wehave described, it is seriously defective in that role, but boneturnover itself can take months to years to alter spontane-ously or under therapeutic intervention. If we start a patientwith bone biopsy–proven high-turnover bone disease andan elevated PTH concentration on cinacalcet therapy, theplasma PTH concentration will decrease quickly (71,74),perhaps by 33%–50% in a few days to weeks. However,the underlying bone histology will not yet have changed.The clinical relevance and importance of assay-relatedvariabilities is also relevant here if one assumes that pa-tients will be treated according to their PTH concentrationif it exceeds a certain threshold (depending on whetherKDOQI, KDIGO, or National Center for Health and Clin-ical Excellence guidelines are being followed) (Figure 2).KDIGO correctly identified the overriding importance of

analyzing trends in blood PTH results rather than reflexivelyresponding to individual values (17). Although the currentwider KDIGO PTH acceptance range is beneficial to interas-say variability (75), the fundamental flaws inherent in reli-ance on PTH alone remain. The work of Lamb and colleagues

(52) shows, however, that even here this approach cannotwork with an infrequent or sparse sampling regimen; ininterpreting any “trend,” it is essential to be guided byknowledge of the large reference change value (72%) beforeaccepting one value as truly different from another.We believe that until intact PTH assays actually measure

intact PTH, until preanalytic conditions and assay calibra-tion are universally standardized, and until better evidencelinks PTH to skeletal or cardiovascular endpoints in CKD, itis hard to support continued measurement of PTH accordingto current recommended practice. This has recently beeneloquently and powerfully raised as a clinical governanceissue (47). Although extreme values of PTH probably doindicate adynamic or hyperparathyroid bone disease, mostresults will fall in an indefinite zone where biologic and an-alytical variability will preclude meaningful interpretation.We advocate a reappraisal of the evidence relating boneALP vis-à-vis PTH as markers of CKD-MBD and envisiona future in which both markers will be used in the routinemanagement of CKD-MBD, but for slightly different andmore clearly defined purposes.

DisclosuresD.J.A.G. has received speaking and consulting honoraria from

Abbott, Amgen, Genzyme, and Shire.

References1. Mallory Expedition. Available at: http://www.malloryexpedition.

com/george.htm. Accessed on March 9, 20112. Felsenfeld AJ, Rodrıguez M, Aguilera-Tejero E: Dynamics of

parathyroid hormone secretion in health and secondary hyper-parathyroidism. Clin J Am Soc Nephrol 2: 1283–1305, 2007

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4. Lamb EJ, Vickery S, Ellis AR: Parathyroid hormone, kidney disease,evidence and guidelines. Ann Clin Biochem 44(Pt 1): 1–4, 2007

Figure 2. | Potential clinical implications that may flow from interassay plasma PTH concentration differences. In some healthcare systems,andwithGuidelines Statements, different clinical interventions and actions can flow in response to different plasma PTHconcentrations. Theseinclude access to Cinacalcet in theUnited Kingdom (through theNICE guidance), potential parathyroidectomy, and continued use of vitaminDreceptor activators. This figure shows the potential differences in treatment decisions that might occur depending on assay-related PTHconcentration differences between different assays using the same patients’ samples. NICE,National Center for Health andClinical Excellence;PTH, parathyroid hormone. Reprinted with permission from ref. 44.


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Published online ahead of print. Publication date available at www.cjasn.org.

See related rebuttal, “Rebuttal: PTH—A Particularly TrickyHormone:WhyMeasure It at All in Kidney Patients?,” on page 321.


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