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17th European Society on Hypertension Meeting Milan, 2007. INGENIOUS HYPERCARE : RENAL PHENOTYPE. Josep Redon. MD, PhD, FAHA Hypertension Clinic. Internal Medicine Hospital Clinico. University of Valencia Spain.

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17th European Society on Hypertension Meeting Milan, 2007

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17th european society on hypertension meeting milan 2007 l.jpg

17th European Society on Hypertension MeetingMilan, 2007

INGENIOUS HYPERCARE:

RENAL PHENOTYPE

Josep Redon. MD, PhD, FAHA

Hypertension Clinic. Internal Medicine

Hospital Clinico. University of Valencia

Spain


Jrp b2 genetics genomics and proteomics on chronic kidney disease in hypertension l.jpg

JRP 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


Jrp b2 genetics genomics and proteomics on chronic kidney disease in hypertension objectives l.jpg

JRP 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


Jrp b2 genetics genomics and proteomics on chronic kidney disease in hypertension types of studies l.jpg

JRP 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


Phenotypes for renal damage in hypertension l.jpg

Phenotypes for renal damage in hypertension:

UAE

FG ml/min

years

months


Prevalence of renal damage in hypertension i demand project 927 subjects l.jpg

Prevalence of renal damage in hypertension. I-Demand project (927 subjects)

renal dysfunction: 38.5% of pts

microalbuminuria

N=233(25.3%)

eGFR 60 ml/min

N=221(24.0%)

134(14.5%)

99(10.7%)

122(13.2%)


Slide7 l.jpg

Seven-year incidence of ESRD according baseline creatinine clearance and proteinuria in general population

Proteinuria (+) Proteinuria (-)

1000

100

Cumulative Incidence of ESRD

per 1.000 screened in 7 yrs

10

1

0.1

0.01

0 15 30 45 60 75 90 105 120 135

Creatinine Clearance (ml/min)

From Iseki et al., 2004


Phenotypes for renal damage in hypertension gfr l.jpg

Phenotypes for renal damage in hypertension: GFR

eGFR

  • 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)


Stages of chronic renal disease l.jpg

Stages of chronic renal disease


Prevalence of chronic renal failure in hypertension l.jpg

Prevalence of chronic renal failure in hypertension

Serum Cr eCrCl

> 1.4-1.5 mg/dl < 60 ml/min

(n)

HOT 18790 2.5% 12.3%

INSIGHT 6321 3.1 % 29.1%

HOPE 9173 10.5 % 36.4% **

H Clinico1539 5.3 % 17.5 % *


Creatinine and cardiovascular morbidity and mortality hope study l.jpg

Creatinine and cardiovascular morbidity and mortality. HOPE study

60

50

40

30

20

10

0

Primary

Myocardial

CV

Total

outcome

infarction

mortality

mortality

Creatinine <1,4 mg/dl

Creatinine >1,4mg/dl

Mann et al. Ann Intern Med 2001


Cardiovascular risk and creatinine values 1 5 mg dl hot study l.jpg

RR

4

Cardiovascular risk and creatinine values >1.5 mg/dl. HOT study

3

2

1

0

Stroke

Total mortality

CV events

MI

CV mortality

Adapted from Ruilope et al, JASN 2001


Cardiovascular disease and probability of gfr decline the aric study l.jpg

Cardiovascular disease and probability of GFR decline. The ARIC study

Elsaved et al. Arch Intern Med 2007


Relationship between serum levels of creatinine and creatinine clearance l.jpg

Relationship between serum levels of creatinine and creatinine clearance

Miravalles, Rodicio (data onfile)


Formulans to estimate the gfr l.jpg

Formulans to estimate the GFR

eGFR

  • 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)


Relationship between mdrd and cockcroft gault formulas to estimate renal function l.jpg

Relationship between MDRD and Cockcroft-Gault formulas to estimate renal function

eGFR (ml/min/1.73m2)

Creatinine clearance (ml/min)

Miravalles, Rodicio (data onfile)


Relationship between two methods to estimate gfr mdrd formula and i talamate l.jpg

Relationship between two methods to estimate GFR: MDRD formula and I-talamate

Iodo-talamate

MDRD

Rule et al. Ann InternMed 2004


Gfr and standarized rates of hospitalization and cardiovascular events l.jpg

GFR and standarized rates of hospitalization and cardiovascular events

Kaiser Permanent Renal Registry

Go, A. S. et al. N Engl J Med 2004


Association of egfr and cystatin c with risk for death in elderly without chronic kidney disease l.jpg

Association of eGFR, and cystatin C with risk for death in elderly without chronic kidney disease

Shlipak et al. Ann InternMed 2006


Relationship between serum cystatin c and creatinine clearance l.jpg

Relationship between serum cystatin C and creatinine clearance

ROC curves to detect patients with GFR 60 – 90 mL/min

Cystatin C

0.671 (0.576 – 0.756)

Creatinine

0.578 (0.481 – 0.675)

Miravalles, Rodicio (data onfile)


Measuring gfr in the jrp a2 b2 and b3 i l.jpg

Measuring GFR in the JRP A2, B2 and B3 (I)

  • MDRD formula in each of the centres

  • Creatininewillbemeasured in thecoordinating centre with a standarizedmethod and GFR willberecalculated

  • Cystatin C willbemeasured in thecoordinating centre


Phenotypes for renal damage in hypertension urinary albumin excretion l.jpg

Phenotypes for renal damage in hypertension: Urinary albumin excretion

UAE


Prevalence of microalbuminuria according bp categories nahnes iii l.jpg

Prevalence of microalbuminuria according BP categories. NAHNES III

80

men women

70

60

56

55

50

Prevalence of albuminuria, %

40

35

31

30

21

20

16

14

12

12

8

10

7

5

0

optimal normal high normal stage 1 stage 2 stage 3

from Jones, et al. 2003


Natural history of microalbuminuria l.jpg

Natural history of microalbuminuria

Non-insulin resistant

60

60

Nephrosclerosis

50

40

Microalbuminuria

percentage (%)

30

Insulin-resistant

20

10

0

Time x BP

Redon et al. Curr Hypertens Rep 2007


Changes in uae categories according the uae level and the presence of treatment at the begining l.jpg

Changes in UAE categories according the UAE level and the presence of treatment at the begining

from Pascual, et al. J Hypertens 2006


Uae and risk of cardiovascular and non cardiovascular mortality l.jpg

UAE and risk of cardiovascular and non-cardiovascular mortality

60

Hillege et al Circulation 2000


Urinary albumin excretion and cardiovascular mortality nahnes ii l.jpg

Urinary albumin excretion and cardiovascular mortality. NAHNES II

1.00

0.75

0.50

0.25

0.00

50

55

60

65

70

75

80

85

<30 mg/dL, n=8528

30-299 mg/dL, n=196

300 mg/dL, n=62

Cumulative CV disease mortality

Age (yr)

Muntner et al. JASN 2002


Microalbuminuria and gfr changes overtime the prevend study l.jpg

Microalbuminuria and GFR changes overtime. The PREVEND study

Microalbuminuria

10

5

0

Delta creatinine clearance (ml/min per 4 year)

-5

-10

-15

1

10

100

1000

Urinary albumin excretion (mg/24hr)

Verhave et al. JASN 2003


Passage metabolization and excretion of albumin in the urine l.jpg

Filtration

Reabsorption

Degradation

Tubular cells

Back-leak

Back-leak

Passage, metabolization and excretion of albumin in the urine

Total albumin (IMRA and non-IMRA), fragments


Methods to measure albumin in urine l.jpg

Methods to measure albumin in urine

  • Antibodyrecognisablealbumin

    • Immunoassays (RIA, nephelometry)

  • Albuminnotdetectedbyimmunoassays

    • HPLC, precipitation

  • Peptidefragments

    • Spectrophotometry


  • Slide31 l.jpg

    Circadianvariability of UAE in essentialhypertension

    1000

    100

    Night UAE (µg/min)

    10

    1

    1

    10

    100

    1000

    Day UAE (µg/min)

    Redón et al, MedClin, 1995


    Slide32 l.jpg

    Intraindividualvariability of UAE measurements

    1000

    100

    First day

    24-hours (µg/min)

    10

    HTA

    DM tipo 1

    1

    1

    10

    100

    1000

    Second day 24 hours (µg/min)

    Redón et al, MedClin 1995


    Slide33 l.jpg

    UAE: samples and units of measurement

    Urine sample

    Units


    Slide34 l.jpg

    UAE: samples and units of measurement

    Urine sample

    Units


    Urinary albumin stability over time in ideal conditions 4 c and protected from light l.jpg

    Urinary albumin stability over timein ideal conditions: 4ºC and protected from light

    Percentage

    of positives

    who still positive

    Percentage

    of negatives

    who still negative

    Correlation

    coefficient

    Day

    Agreement


    Urinary albumin measurement by using ria and hplc l.jpg

    Urinary albumin measurement by using RIA and HPLC


    Bland altman plot of two methods for measuring urinary albumin ria and hplc l.jpg

    Bland-Altman plot of two methods for measuring urinary albumin: RIA and HPLC


    Measuring uae in the jrp a2 b2 and b3 i l.jpg

    Measuring UAE in the JRP A2, B2 and B3 (I)

    • Firstvoidingurine in themorning

    • 3 differentdays

    • Measurementswithnephelometrie and simultaneousexamination of sediment (ordisptick) in each of the centres

    • 5 aliquotstostorefrozen at -20º at least (maintain at 4º out of light untilfrozen , recomendable no more than 4 hours)

    • Samplesfrozenshouldbesenttothecoordinating center (each 3 or 6 months)


    Measuring uae in the jrp a2 b2 and b3 and the others ii l.jpg

    Measuring UAE in the JRP A2, B2 and B3 (and the others) (II)

    • Measurements of albumin (nephrelometrie, HPLC) and creatinine

    • UAE willbeanalyzed as qualitative and quantitativetraits

    • Measurement of othermarkers (oxidative stress)

    • Proteomics in a smallsample (withspecialrequirementsforurinecollection and storage)


    Risk for esrd according bp categories in the kaiser permanent register 21 year follow up l.jpg

    Risk for ESRD according BP categories in the Kaiser Permanent Register (21-year follow-up)

    70

    men women

    aRR 4.25

    60

    50

    aRR 3.88

    aRR 3.86

    Age-adjusted ESRD rates

    per 100000 person-yrs

    40

    30

    aRR 2.59

    20

    aRR 1.98

    aRR 1.62

    10

    0

    <120/80

    ≥210/120

    130-139/85-89

    140-159/90-99

    120-129/80-84

    180-209/110-119

    160-179/100-109

    Blood pressure category

    from Hsu, et al. 2005


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