emergent early markers of renal progression in autosomal dominant
TRANSCRIPT
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
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
Cadnapaphornchai, Schrier, et al. Kidney Int 74; 1192-96, 2008
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
Cadnapaphornchai, Schrier, et al. Kidney Int 74; 1192-96, 2008
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
Helal I, Schrier R et al. CJASN 2011;6:2439-2443
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.
Helal I, Schrier R et al. CJASN 2011;6:2439-2443
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
Helal I, Schrier R et al. Nephrol Dial Transplant. 2013 Feb;28(2):380-5
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
Helal I, Schrier R et al. Nephrol Dial Transplant. 2013 Feb;28(2):380-5
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