emergent early markers of renal progression in autosomal dominant

Emerging Early Markers of Renal Progression in Autosomal-Dominant Polycystic Kidney Disease

Patients: Implications for Prevention and Treatment

Imed HELAL, MDCharles Nicolle Hospital

Tunis - Tunisia

Introduction • ADPKD is the most common life-threatening single-gene

disease.• It affects over 15 million people worldwide.• 5 to 9 % of the etiologies of ESRD (Fourth leading cause

of ESRD). • Currently no treatment that can stop ADPKD progression• An important clinical variability , especially in age at

ESRD .• Therefore, markers to distinguish ADPKD patients with a

poor versus a good prognosis will be helpful

The cystic degeneration of the kidneys, once it reaches the point where it can be recognized or suspected during life, is an illness without cure.

Rayer, 1841

Hypothethical scheme relating GFR and age.

Jared J. Grantham et al. CJASN 2006;1:148-157

©2006 by American Society of Nephrology

Total Kidney Volume

Alabama Emory Kansas Mayo

CRISP Cohort

Kidney Int 2003;64:1035–1045

CRISP Cohort

Relationship between glomerular filtration rate (GFR) and age-adjusted mean renal volume

Kidney Int 2003;64:1035–1045

PKD 1 mutationPKD 2 mutation

Age (yr)

Tota

l Kid

ney

Volu

me

(ml)

Total Kidney VolumeTotal Kidney VolumeOptimal Population to Study Renal Volume: Optimal Population to Study Renal Volume:

Based on NIH-CRISP DataBased on NIH-CRISP Data

J.J. Grantham 2006 NEJM 354:2128

Hypertension

0102030405060708090

100

0-19 20-34 35-44 45-54

Perc

enta

ge w

ith h

yper

tens

ion

Age (years)

Prevalence of Hypertension in ADPKD Males and Females

NS P < 0.001 P < 0.0005 NS

Males FemalesKelleher, Schrier, et al., Am J Hypertension, 17:1029-34, 2004.

The Progression of Renal Disease in Hypertensive and Normotensive

ADPKD Patients

Age (years)

15 20 25 30 35 40 45 50 55 60 65 70 75

1.5

1

0.5

0

0.67

1.0

2.0

Normotensive

Hypertensive

P<0.001

1/Sc

rScr (m

g/dl)

Gabow, Schrier, et al. KI,41:1311-1319,1992

800

600

400

200

0

800

600

400

200

0

Males Females

HBP NBP

HBP NBP

P < 0.0005

P < 0.002

Gabow, Schrier, et al: KI,38:1177-1180,1990.

Mean Renal Volume is Significantly Higher in Hypertensive versus Normotensive ADPKD Patients

cm3

cm3

Parameter NBP (N=30) BBP (N=27) HBP (N=28) P-value for ANOVA

Male/female 13/17 15/12 17/11 NSAge (years) 12.0 ± 0.8 11.8 ± 0.8 13.6 ± 0.8 NSHeight (cm) 151 ± 5 151 ± 5 160 ± 4 NSSerum creatinine (mg/100 ml) 0.66 (0.57–0.70) 0.69 (0.62–0.77) 0.74 (0.68–0.81) NS

24-h creatinine clearance (ml/min/1.73 m2)

135 (127–145) 127 (117–138) 130 (120–141) NS

Urine microalbumin excretion (mg/day) 31 (19–51) 22 (14–35) 23 (16–33) NS

Systolic blood pressure (mm Hg) 109 ± 2 119 ± 2 130 ± 3 <0.0001

Diastolic blood pressure (mm Hg) 64 ± 1 68 ± 1 72 ± 2 0.0005

Note. SBP: NBP vs BBP (P=0.0122), NBP vs HBP (P<0.0001), BBP vs HBP (P=0.0022); DBP: NBP vs BBP (P=NS), NBP vs HBP (P=0.0003), BBP vs HBP (P=NS). Data presented as mean ± s.e. or geometric mean (95% CI).

Cadnapaphornchai, Schrier, et al. CJASN, 4;820-829, 2009

Normotensive (NBP), borderline hypertensive (BBP), and hypertensive (HBP) subjects

Correlation between systolic blood pressure and renal volume in 85 ADPKD children

Cadnapaphornchai, Schrier, et al. Kidney Int 74; 1192-96, 2008

3

4

5

6

7

8

75 100 125 150 175Systolic blood pressure (mm Hg)

Ln[R

enal

Vol

ume]

(ml)

Borderline Hypertensive Normotensive

r = 0.70P<0.0001

Correlation between diastolic blood pressure and renal volume in 85 ADPKD children


33.5

44.5

55.5

66.5

77.5

50 60 70 80 90 100Diastolic blood pressure (mm Hg)

Ln[R

enal

Vol

ume]

(ml)

r = 0.52P<0.0001

Borderline Hypertensive Normotensive

Renal volume was markedly increased in hypertensive (HBP) as compared to borderline hypertensive (BBP) and normotensive

(NBP) children with ADPKD


300

200

100

P<0.002

P<0.0002

NS

NBP HBPBBP

Ren

al v

olum

e (g

eom

etric

mea

n w

ith 9

5% C

I)

0

Helal I, Schrier R et al. CJASN 2011;6:2439-2443

Glomerular HyperfiltrationParameter GH Without GH P-valueN 32 148Age (years) 11.4 ± 3.6 10.8 ± 3.9 0.27Male/Female 19/13 63/85 0.08Mean follow-up (years) 4.74 ± 3.56 5.06 ± 4.14 0.68(Kg/ m2 ) 20.4 ± 5.2 20.0 ± 5.9 0.40(mmHg) 120 ± 18 114 ± 14 0.09DBP (mmHg) 72 ± 12 71 ± 11 0.70Symptoms and complications of ADPKDHypertensionRecurrent flank painHistory of macrohematuriaHistory of cyst infection

17 (53.13%)4 (12.5%)8 (25.0%)5 (15.63%)

51 (34.46%)24 (16.44%)18 (12.16%)38 (25.85%)

0.100.080.150.35

Serum Creatinine (mg/dl) 0.58 ± 0.18 0.69 ± 0.19 0.0049CrCl (ml/min/1.73m2) 158.9 ± 17.1 107.7 ± 20.5 < 0.0001Total kidney volume (cm3) 431.9 ± 196.0 400.1 ± 317.1 0.03MedicationACEINSAID

0 (0%)3 (9.38%)0 (0%)1 (3.23)

1 (0.68%)13 (8.9%)0 (0%)10 (6.94%)

0.821.000.69


Glomerular Hyperfiltration

Incremental rate of TKV/ BSA

growth per year

GH Without GH P-value

Adjusted for age, gender +19.26 ± 10.82 cm3 - 4.30 ± 7.74 cm3 0.008

Adjusted for age, gender, ACEI/

use, hypertension

+37.21 ± 7.79 cm3 +15.27 ± 4.05 cm3 0.005

% increase in TKV (year) 9.25 ± 9.10% 8.78 ± 10.40% 0.45

Annual total kidney volume in ADPKD patients without and with GH in Relation to Time.


Creatinine clearance (ml/min per 1.73 m2) in autosomal dominant polycystic kidney disease patients with (A) and without (B) glomerular hyperfiltration in relation to time.

Helal I , Schrier R et al. CJASN 2011;6:2439-2443

©2011 by American Society of Nephrology

Uric Acid

Helal I, Schrier R et al. Nephrol Dial Transplant. 2013 Feb;28(2):380-5

Parameter No hypertension or hypertension onset >30 years of age

Hypertension onset ≤30 years of age P-value

NumberAge (years)Male/femaleBMI (kg/m2) Hypertension (%)SBP (mmHg)DBP (mmHg)Geometric mean proteinuria (mg/24 h)Geometric mean CrCl (mL/min/1.73 m2) Mean uric acid (mg/dL)a

Mena

Womena

Geometric mean TKV (cm3) TKV/BSA (cm3)Kidney calculi (%)ARBDiureticACEIAllopurinolESRDMedian age of onset of ESRD

45144.58 ± 12.30

152/29926.16 ± 5.74302 (66.96%)

128.84 ± 17.5582.78 ± 11.84

144.99 (131.92–159.36)57.52 (54.00–61.27)

5.77 ± 0.096.85 ± 0.135.22 ± 0.10

1162 (1085–1246)630 (588–674)

67 (14.92%)9 (2.00%)

112 (24.94%)133 (29.56%)

30 (6.65%)120 (26.73%)

64 (61–66) years

20635.65 ± 10.65

99/10727.21 ± 5.45206 (100%)

133.93 ± 17.8785.23 ± 13.52

201.76 (178.14–228.51)57.06 (51.62–63.07)

6.72 ± 0.137.40 ± 0.196.11 ± 0.16

1548 (1412–1697)800 (731–876)

32 (15.53%)10 (4.85%)

77 (37.38%)121 (59.02%)

7 (3.40%)63 (30.58%)

51 (48–56) years

<0.001<0.0010.0287<0.001<0.0010.0284<0.0010.8899<0.001<0.001<0.001<0.0010.00180.83240.04250.0011<0.0010.09330.3071<0.001

Relationship between uric acid and LnTKV, R2 = 0.1771, P < 0.001.

Helal I et al. Nephrol. Dial. Transplant. 2013;28:380-385

© The Author 2012. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: [email protected]

Serum uric acid, kidney volume and progression in ADPKD

Parameter Hazard ratio (95% CI) P-valueAgeSex (male)LnCrClARBDiureticACEIAllopurinolEarly onset of hypertensionBMISerum uric acid

0.725 (0.698–0.754)0.961 (0.669–1.381)0.165 (0.130–0.209)0.448 (0.061–3.292)1.148 (0.820–1.605)0.898 (0.635–1.271)1.800 (1.029–3.148)1.447 (1.020–2.053)1.008 (0.975–1.041)1.374 (1.240–1.523)

<0.0010.8301<0.0010.43030.42150.54410.03920.03860.6447<0.001


Multivariate HRs for the prediction of ESRD from the multivariate Cox regression using sex-specific quartiles

of serum uric acid Parameter Hazard ratio (95% CI) P-valueAgeSex (male)LnCrClARBDiureticACEIAllopurinolEarly onset of hypertension2nd quartile versus 1st quartile3rd quartile versus 1st quartile4th quartile versus 1st quartile

0.724 (0.696–0.753)1.621 (1.167–2.250)0.177 (0.140–0.225)0.389 (0.053–2.875)1.099 (0.783–1.543)0.847 (0.597–1.200)2.021 (1.187–3.442)1.267 (0.887–1.811)1.054 (0.547–2.029)2.931 (1.616–5.315)4.813 (2.613–8.866)

<0.0010.0039<0.0010.35470.58590.35030.00960.19340.8756<0.001<0.001


Renal Blood Flow (RBF)

Magnetic resonance (MR) angiogram of the renal arteries in a patient with ADPKD.

RBF- CRISP CohortSource F Value P Value R Value P Value

AgeGenderDiagnosis of hypertensionTotal kidney volumeTotal corrected renal blood flow

6.162.370.110.5027.80

0.01450.12600.73940.4827<0.0001

-0.39480.0733-0.1883-0.29180.5172

0.00010.38940.03470.00140.0001

Regression model predicting glomerular filtration rate (GFR): Effect of age, gender, physical kidney measures, and renal blood flow.

Kidney Int 2003;64:2214–2221

RBF- CRISP CohortBlood pressure

Number Ageyears Total kidney volumemL

Mean arterial pressuremm Hg

Systolic blood pressure-diastolic blood pressure mm Hg

Renal blood flowmL/min/1.73 m2

Renal vascular resistancedynes sec.cm-5

Glomerular filtration ratemL/min/1.73 m2

Normotensive

Hypertensive

P value

53

74

29.2± 7.7

34.5 ±7.6

<0.001

731± 406

1284± 673

<0.001

91.7± 9.4

99.6 ± 10.6

<0.001

38.8 ± 7.2

38.6 ± 8.3

NS

783 ± 205

732 ± 243

NS

9965± 2646

12135 ± 4383

0.002

104.2± 19.2

95.5± 24.9

0.035

Total kidney volumes and renal hemodynamic parameters in normotensive compared to hypertensive subjects and effects of antihypertensive medications.

Urine and Blood Emergent Early Markers

Correlation Between Mean Renal Volume and Maximal Urinary Osmolality in ADPKD

Subjects

Gabow, Schrier, et al. KI 35: 675-680, 1989

1200

800

600

400

1000

0 1000500 1500

Mean renal volume, cm3

Urin

e os

mol

ality

; mO

sm/k

g r = -0.50, P < 0.001

ADPKD Patients with Established Proteinuria have a Faster Loss of Renal

Function

Age (years)

15 20 25 30 35 40 45 50 55 60 65 70 75

1.5

1

0.5

0

0.67

1.0

2.0

No proteinuria

Established proteinuria

P<0.05

1/Sc

rScr (m

g/dl)

Chapman, Schrier, et al. JASN,5:1349-1354,1994

Others Urine and Blood Emergent Early Markers

• Urinary excretion of β2-microglobulin, neutrophil gelatinase-associated lipocalin (NGAL), and heart-type fatty acid-binding protein (H-FABP)

• Kidney injury molecule-1 (KIM-1), NGAL, and monocyte chemotactic protein-1 (MCP-1)

• Copeptin, Secreted frizzled-related protein 4 (sFRP4)• Angiogenic growth factors: Angiopoietin-1 and -2, and their

endothelial tyrosine kinase-2 receptor• Modifiable factors: Lower serum HDL-cholesterol, increased

urine sodium excretion and higher 24-hour urine osmolality

Traditional progression markers

PKD-1gene mutation , male gender , young age at diagnosis, HTN, gross hematuria, proteinuria,

young age at onset of HTN

Renal progression in ADPKD

Emerging progression markers

TKV, GH, RBFNGAL, H-FABP, KIM-1

MCP-1Serum HDL-

cholesterol, UNaV, 24-h urine osmolality

CopeptinAngiogenic growth

factors

Helal I and Schrier R. Am J Nephrol. 2012;36(2):162-7.

How Can Progression be Monitored and Quantified in

ADPKD?

CRISP Score

Patients fall into two general groups of kidney volume increase :

• Those with rapid rates of progression (>5% increase in total kidney volume per year)

• Those with rates of progression <5% per year

A new algorithm to predict renal outcome in ADPKD: The PRO-PKD score

Variable Category pts

Gender FemaleMale

01

Hypertension < 35 yrs No Yes

02

At least one urological complication < 35years

NoYes

02

Mutation PKD2PKD1/Non-Truncating

PKD1/Truncating

024

Total 0 to 9 points

Genetic Score

• PKD2: 1 point• PKD1, NTM: 2 points• PKD1, TM, Female: 3 points• PKD1, TM, Male: 4 points

Genetic Score or PRO-PKD Score?Age < 35 Age ≥ 35

Past or present history of urological event (s)

ANDPtient treated for HBP?

Are the clinical data required available (ie, age at first

treatment for HBP and age at first urological eveny?)

No Yes No Yes

Genetic score PRO-PKD score

Summary and Future Perspectives

• Several clinical, imaging, urine and blood markers have been associated with renal progression in ADPKD.

• Recognizing these emergent early markers may identify high-risk ADPKD patients and allow more intensive intervention.

Summary and Future Perspectives

• To date, however, it is not known whether these markers are primarily determined by renal function progression or whether these markers are factors in causing loss of renal function.

• Prospective, randomized studies in ADPKD will be necessary to determine whether these factors are merely markers of disease progression or are active pathogenetic factors in the progression of ADPKD.

Disclosure Statement

• None

emergent early markers of renal progression in autosomal dominant

Health & Medicine