17th european society on hypertension meeting milan, 2007 ingenious hypercare: renal phenotype josep...
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17th European Society on Hypertension Meeting
Milan, 2007
INGENIOUS HYPERCARE:
RENAL PHENOTYPE
Josep Redon. MD, PhD, FAHAHypertension Clinic. Internal MedicineHospital Clinico. University of Valencia
Spain
HO
ME B
PJRP B2: Genetics, genomics and proteomics on chronic kidney disease in hypertension
• Investigating the genetic, genomic and proteomic basis of susceptibility to renal damage (urinary albumin excretion and renal damage) in HTN patients
• Creating a large database of several thousand patients in different European countries
• Cross-sectional and follow-up investigations
HO
ME B
PJRP B2: Genetics, genomics and proteomics on chronic kidney disease in hypertension: Objectives
• To analyse genetic factors associated with renal phenotypes in hypertensive subjects: elevated urinary albumin excretion (microalbuminuria, proteinuria), reduced GFR, end-stage renal disease
• To detect novel early markers of renal damage in hypertension by using proteomics and to examine their association with genetic markers
HO
ME B
PJRP B2: Genetics, genomics and proteomics on chronic kidney disease in hypertension: Types of studies
• Family-based association study of renal phenotypes, conducted simultaneously in the A2, B2 and B3
• Case-control studies of renal phenotypes in previously recruited hypertensives
• Follow-up studies of renal phenotypes in preexisting cohorts and in the family study
HO
ME B
PPhenotypes for renal damage in hypertension:
yearsyears monthsmonths
UA
EU
AE
FG m
l/min
FG m
l/min
HO
ME B
PPrevalence of renal damage in hypertension. I-Demand project (927 subjects)
122(13.2%)
99(10.7%)
134(14.5%)
renal dysfunction: 38.5% of pts
microalbuminuria
N=233(25.3%)
eGFR 60 ml/min
N=221(24.0%)
HO
ME B
PSeven-year incidence of ESRD according baseline creatinine clearance and proteinuria in general population
Creatinine Clearance (ml/min)
Proteinuria (+) Proteinuria (-)
0 15 30 45 60 75 90 105 120 135
1000
100
10
1
0.1
0.01
Cu
mu
lati
ve I
ncid
en
ce o
f ES
RD
p
er
1.0
00 s
cre
en
ed
in
7 y
rs
From Iseki et al., 2004
HO
ME B
PPhenotypes for renal damage in hypertension: GFR
Cockroft-Gault Formula (140- age) x body weight
(serum creatinine * 72)
* x 0.85 (if female)
MDRD Formula 186 * serum creatinine -1.154 * age -0.203
* 0.742 (if female) * 1.210 (if AA)
eGFReGFR
HO
ME B
PStages of chronic renal disease
Stage Description GF ml/min/ 1.73 m2
Prevalence
- On risk -
1 Renal lesion with GF normal or increased
>90 3.3 %
2 Renal lesion with GF slightly reduced
60-89 3.0 %
3 GF moderately reduced 30-59 4.3 %
4 GF severely reduced 15-29 0.2 %
5 Renal failure <15 o dialysis 0.1 %
HO
ME B
PPrevalence of chronic renal failure in hypertension
Serum Cr eCrCl> 1.4-1.5 mg/dl < 60 ml/min
HOT 18790 2.5% 12.3%
INSIGHT 6321 3.1 % 29.1%
HOPE 9173 10.5 % 36.4% **
H Clinico 1539 5.3 % 17.5 % *
(n)
HO
ME B
PCreatinine and cardiovascular morbidity and mortality. HOPE study
Mann et al. Ann Intern Med 2001
0
10
20
30
40
50
60
Primary
outcome
CV
mortality
Creatinine <1,4 mg/dl Creatinine >1,4mg/dl
Myocardial
infarction
Total
mortality
HO
ME B
PCardiovascular risk and creatinine values >1.5 mg/dl. HOT study
Adapted from Ruilope et al, JASN 2001
CV eventsMI
StrokeCV mortality
Total mortality0
1
2
3
4RR
HO
ME B
PCardiovascular disease and probability of GFR decline. The ARIC study
Elsaved et al. Arch Intern Med 2007
HO
ME B
PRelationship between serum levels of creatinine and creatinine clearance
Miravalles, Rodicio (data on file)
HO
ME B
PFormulans to estimate the GFR
Cockroft-Gault Formula (140- age) x body weight
(serum creatinine * 72)
* x 0.85 (if female)
MDRD Formula 186 * serum creatinine -1.154 * age -0.203
* 0.742 (if female) * 1.210 (if AA)
eGFReGFR
HO
ME B
PRelationship between MDRD and Cockcroft-Gault formulas to estimate renal function
Miravalles, Rodicio (data on file)
eG
FR
(m
l/m
in/1
.73
m2
)
Creatinine clearance (ml/min)
HO
ME B
PRelationship between two methods to estimate GFR: MDRD formula and I-talamate
MDRD
Iodo-talamate
Rule et al. Ann Intern Med 2004
HO
ME B
PGFR and standarized rates of hospitalization and cardiovascular events
Kaiser Permanent Renal RegistryKaiser Permanent Renal Registry
Go, A. S. et al. N Engl J Med 2004
HO
ME B
PAssociation of eGFR, and cystatin C with risk for death in elderly without chronic kidney disease
Shlipak et al. Ann Intern Med 2006
HO
ME B
PRelationship between serum cystatin C and creatinine clearance
Miravalles, Rodicio (data on file)
ROC curves to detect patients with GFR 60 – 90 mL/min
Cystatin C 0.671 (0.576 – 0.756)
Creatinine0.578 (0.481 – 0.675)
HO
ME B
PMeasuring GFR in the JRP A2, B2 and B3 (I)
• MDRD formula in each of the centres
• Creatinine will be measured in the coordinating centre with a standarized method and GFR will be recalculated
• Cystatin C will be measured in the coordinating centre
HO
ME B
PPhenotypes for renal damage in hypertension: Urinary albumin excretion
UAEUAE
HO
ME B
PPrevalence of microalbuminuria according BP categories. NAHNES III
80
70
60
50
40
30
20
10
0
Pre
vale
nce o
f alb
um
inu
ria,
%
optimal normal high normal stage 1 stage 2 stage 3
men women
5 8 712 12
1416
21
3135
56 55
from Jones, et al. 2003
HO
ME B
PNatural history of microalbuminuria
Redon et al. Curr Hypertens Rep 2007
0
10
20
30
40
50
60
Time x BP
Insulin-resistant
Non-insulin resistant
Nephrosclerosis
Mic
roalb
um
inu
ria
perc
en
tag
e (
%)
60
HO
ME B
PChanges in UAE categories according the UAE level and the presence of treatment at the begining
Group of patients Number subjects
(%) Rate100
patientes/year
Microalbuminurics
Regresion untreated 61 59 27.8
Regresion treated 191 40 18.0
Progresion 11 7.3
Proteinurics
Regresion untreated 12 33 17.4
Regresion treated 46 54 20.7
from Pascual, et al. J Hypertens 2006
HO
ME B
PUAE and risk of cardiovascular and non-cardiovascular mortality
Hillege et al Circulation 2000
60
HO
ME B
PUrinary albumin excretion and cardiovascular mortality. NAHNES II
Muntner et al. JASN 2002
<30 mg/dL, n=852830-299 mg/dL, n=196300 mg/dL, n=62
1.00
0.75
0.50
0.25
0.0050 55 60 65 70 75 80 85
Age (yr)
Cu
mu
lati
ve C
V d
isease
mort
ality
HO
ME B
PMicroalbuminuria and GFR changes overtime. The PREVEND study
Microalbuminuria
Delt
a c
reati
nin
e c
leara
nce
(m
l/m
in p
er
4 y
ear)
Urinary albumin excretion (mg/24hr)
1 10 100 1000-15
-10
-5
0
5
10
Verhave et al. JASN 2003
HO
ME B
PPassage, metabolization and excretion of albumin in the urine
Total albumin (IMRA and non-IMRA), fragments
Tubular cells
Reabsorption
Degradation
Back-leak
Back-leak
Filtration
HO
ME B
PMethods to measure albumin in urine
• Antibody recognisable albumin Immunoassays (RIA, nephelometry)
• Albumin not detected by immunoassays HPLC, precipitation
• Peptide fragments Spectrophotometry
HO
ME B
PCircadian variability of UAE in essential hypertensionCircadian variability of UAE in essential hypertension
1
10
100
1000N
igh
t U
AE (
µg
/min
)
1 10 100 1000
Day UAE (µg/min)
Redón et al, Med Clin, 1995
HO
ME B
PIntraindividual variability of UAE measurementsIntraindividual variability of UAE measurements
1
10
100
1000Fir
st
day
24-h
ou
rs (
µg
/min
)
1 10 100 1000
Second day 24 hours (µg/min)
DM tipo 1
HTA
Redón et al, Med Clin 1995
HO
ME B
PUAE: samples and units of measurementUAE: samples and units of measurement
Spot Night 24 hour
mg/24 h
mg/min
mg/mmol Cr
mg/g Cr
Urine sample
Un
its
HO
ME B
PUAE: samples and units of measurementUAE: samples and units of measurement
Spot Night 24 hour
mg/24 h 30-299
mg/min 20-199
mg/mmol Cr 3-29
mg/g Cr 30-299
Urine sample
Un
its
HO
ME B
PUrinary albumin stability over timein ideal conditions: 4ºC and protected from light
DayPercentageof negatives
who still negative
Percentageof positives
who still positiveAgreement
Correlationcoefficient
HO
ME B
PUrinary albumin measurement by using RIA and HPLC
HO
ME B
PBland-Altman plot of two methods for measuring urinary albumin: RIA and HPLC
HO
ME B
PMeasuring UAE in the JRP A2, B2 and B3 (I)
• First voiding urine in the morning
• 3 different days
• Measurements with nephelometrie and simultaneous examination of sediment (or disptick) in each of the centres
• 5 aliquots to store frozen at -20º at least (maintain at 4º out of light until frozen , recomendable no more than 4 hours)
• Samples frozen should be sent to the coordinating center (each 3 or 6 months)
HO
ME B
PMeasuring UAE in the JRP A2, B2 and B3 (and the others) (II)
• Measurements of albumin (nephrelometrie, HPLC) and creatinine
• UAE will be analyzed as qualitative and quantitative traits
• Measurement of other markers (oxidative stress)
• Proteomics in a small sample (with special requirements for urine collection and storage)
HO
ME B
PRisk for ESRD according BP categories in the Kaiser Permanent Register (21-year follow-up)
men women
120-129/80-84130-139/85-89
140-159/90-99
160-179/100-109
180-209/110-119≥210/120
70
60
50
40
30
20
10
0
Ag
e-a
dju
ste
d E
SR
D r
ate
s
per
100000 p
ers
on
-yrs
Blood pressure categoryfrom Hsu, et al. 2005
aRR 1.62aRR 1.98
aRR 2.59
aRR 3.86aRR 3.88
aRR 4.25
<120/80