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DETECTION OF CKD IN EALRY STAGESDETECTION OF CKD IN EALRY STAGESLONG TERM FOLLOWLONG TERM FOLLOW--UP UP
FROM CHILDREN TO ADULT AGEFROM CHILDREN TO ADULT AGE
Rosanna CoppoTurin, Italy
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short-term outcome(childhood):dialysis, transplantation
CKDCKDin childrenin children
long-term outcomein adult life
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ESRF in children
30-40% CAKUT: congenital abnormalities of the kidney and urinary tract
10-20% CONGENITAL RENAL DISEASES: tubular, cystic, metabolic diseases, hereditary nephritis
20% acquired glomerular diseases
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Renal congenital hypodysplasia
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CAKUT: congenital abnormalities of the kidney and urinary tract
British Association Pediatric Nephrology (BANP) report, Lewis,2008
• Renal dysplasia with /without VU reflux is the most common cause of ESRF in the childhood population.
• There are overlaps between CAKUT and VUR nephropathy and the distinction is quite arbitrary.
• Joining the two groups, they account for 32% of childhood ESRF
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Renal dysplasia/reflux Renal dysplasia/reflux nephropathynephropathy
Renal hypodysplasiaCongenital VURObstructive uropathy
renal massrenal massreduction reduction
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Hypothesis for the development of pyelonephritic scarring
Acute pyelonephritisHigh grades of VUR
Delays in treatment Recurrent pyelonephritis
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Progression of CKD in children Neild G
CAKUT progression:GFR improves from 0 to 3 years of age
is stable between 3 and 11 y;
slowly decreases in 50% of the caseswhen baseline GFR is < 40 ml/min/1.73 m2.
We expect that several subjects with CAKUT will reach ESRF in adult life
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Causes of ESFR in children in Europe and in USA
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Renal disease
UK in Children
UKRena lReg.
USRDS
Age y. 0-15 18-21 22-31 32-39 0-19 20-29 30-39
N.cases 913 397 1447 2089 1112 2521 5575
Dysplasia and/or VUR
32% 14% 10% 8% 19% 4% 1%
Obstructive nephropath
15% 12% 7% 6% 12% 1% 1%
Tubulo/inter diseases
8% 6% 3% 2% 4% 3% 3%
UK Renal Registry adults
USRDS USA Renal RegistryChildren Adults
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ESRF in children
30-40% CAKUT: congenital abnormalities of the kidney and urinary tract
10-20% CONGENITAL RENAL DISEASES: tubular diseases, nephronophthysis, cystic nephropathy(recessive PKCD) metabolic diseases (primary hyperoxaluria) hereditary nephritis (Alport’s s) and congenital nephrotic syndrome.
primary glomerular diseases?
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Renal disease
BAPNchildren
UKRenalReg.
USRDS
Age y. 0-15 18-21 22-31 32-39 0-19 20-29 30-39
N.cases 913 397 1447 2089 1112 2521 5575
Dysplasia and/or VUR
32% 14% 10% 8% 19% 4% 1%
Obstructive nephropathy
15% 12% 7% 6% 12% 1% 1%
Tubulo/inter stdiseases
8% 6% 3% 2% 4% 3% 3%
Glomerular diseases
23% 39% 32% 28% 32% 32% 18%
Congenital NS
5% 0 0 0 2% 0 0
UK Renal Registry adults
USRDS USA Renal RegistryChildren Adults
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ITALIAN REGISTRY OF CHILDREN IN CKD TREATED WITH DIALYSIS mean age 8.7±6 years old
0
1
2
3
4
5
6
7
8
9
10
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
età anni
num
ero
pazi
enti
DP HDacquired renal
diseasescongenital renal
diseases
children age
N o
f chi
ldre
n
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BAPNUK
BAPNUK
NAPRTCSUSA
NAPRTCSUSA
Age y. 8-11 12-15 6-12 13-20
Glomerular diseases
27% 26% 8% 19%
Glomerular disease so severe to progress to ESRF within childhood
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Age y 0-15IgA nephropathy 1 %Primary FSGS 10 %
Mesangiocapillary GN 1 %Alport’s Syndrome 1 %Systemic lupus erythemathodes 1 %Henoch-Schoenlein purpura GN 2 %
Unspecified GN 1%
TOTAL 22 % of all causes of ESRF
Glomerular diseaseleading to ESFR in childhood
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Glomerular disease
0-15 18-21 22-31
IgA nephropathy 1 6 10
Primary FSGS 10 4 3
Mesangiocapillary GN 1 3 2
Alport’s Syndrome 1 7 2
Systemic lupus erythemat.
1 3 3
HS purpura GN 2 2 1Unspecified GN 1 4 5
TOTAL 22 39 32
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BAPNchildren
BANPadolesc
UK young adults
NAPRTCS NAPRTCS
Age y. 8-11 12-15 18-21 6-12 13-20
Glomerular diseases
27% 26% 28% 8% 19%
Uncertainetiology
2% 65 28% 2% 2%
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In adults in 2007 28%
CRF without diagnosis in children in UK registries
UK Pediatric Registry. In 1976: 39%
In 2008: 3%
Underdiagnosed CAKUT or Glomerular diseases?
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0
10
20
30
40IgA nephropahy:
the commonest glomerulonephritis in the world
Adults
Children
ASIA AUSTR EUR NORTH AMERICA
In about 25-30% of children by screening
Japan, South Korea, Taiwan
20%
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Patient A: detected by screening : survival 12 years
0102030405060708090
100110
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Dispers. (XY) 2
Patient B: proteinuria : survival 7 years
Patient C: hypertension, reduced GFR: survival 2.5 years
years
GFR
Geddes et al NDT 2003
Children detected by screening
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The ERA-EDTA Registry reported that 67% of IgAN patients who enter dialysis are aged between 25 and 55
(22% < 30 years )
Since the decline of IgAN is slow
(25% of the cases need dialysis in 20 years)
IgA Nephropathy in children
it is clear that
several progressive IgAN begin in the childhood
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Chronic kidney disease perspectives in Japan and the importance of urinalysis screening Japanese Society of Nephrology
Yamagata K et al Clin Exp Nephrol 2008
Screening program in Japan:Since 1972 in childrenSince 1983 in workers and resident > 40 y.o.
In Japanese population High prevalence of dialysis and high prevalence of proteinuria
Non diabetic, non hypertensive proteinuric patients.In Japan 0.9% in USA 0.4%
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Clinical manifestation of IgAN
0
50
100
150
200
250
300
350
microh/prot acute NS
IgAN
othersAsymtomatic microscopic hematuria/proteinuria
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IgAN is the most common glomerular disease in the world and has often its origin in childhood
• IgAN in the young: often defected by chance
• In several cases the disease manifests as hypertension with minimal urinary abnormalitiesor in reduced GFR and no renal biopsy is performed
In Japan in the last decade the frequency of ESFR due to GN changed from 10,000 to 9,000/yeardue to early screening programme
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The late referral to dialysis is dangerous:there is a need to identify the condition of CKD
in adult subjects before complete loss of kidney function
Conditions at risk for CKDmust be detected as early as possible
to establish a correct management of CKD complications
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Cardiovascular risk is increased in CKD
Go, New Engl J Med (2004) 351:1296
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Treat the kidney to protect your heart ! de Zeeuw, 2004
Treating kidney diseasemeans
decrease morbility and mortalitydue to cardiovascolar disease
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How early should we start the search for CKD How early should we start the search for CKD and related factors favouring and related factors favouring
cardiocardio--vascolar disease?vascolar disease?
In the pediatric age In the pediatric age several CKD can be unidentified several CKD can be unidentified
Conditions favouring CKD Conditions favouring CKD may be operating in lifemay be operating in life
very early, even prenatalyvery early, even prenataly
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PREVIOUS OBSERVATIONS
1965 Rose:ISCHEMIC CARDIAC DISEASE IN ADULTS WAS ASSOCIATED
WIT HIGH MORTALITY RATE IN THE SAME FAMILY
PRENATAL CONDITIONING PRENATAL CONDITIONING OF RENAL AND CARDIOVASCULAR DISEASEOF RENAL AND CARDIOVASCULAR DISEASE
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In Norway : 2.183.317 born in 1967-2004.526 ESRD526 ESRD..
Low birth weight increases risk for ESRD
Risk for ESRDincreased by 70%when birth weight
<2.500 g
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The association remains significant even after adjustement for congenital malformations,
multiple births, maternal age, maternal pre-eclampsia
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The risk does not involveThe risk does not involvehereditary or congenital renal diseases only, hereditary or congenital renal diseases only,
but also acquired glomerular diseasesbut also acquired glomerular diseases
Low birt weight increases risk for ESRD
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Also experimental models of immune mediated acquired glomerulaAlso experimental models of immune mediated acquired glomerular diseases are r diseases are worse in animals with low birth weight induced by uterine acrteworse in animals with low birth weight induced by uterine acrterial ligationrial ligation
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Developing programming
several diseases in adult age have their origin in a dysegulated developing programming during the in utero life due to defective nutritional apports or noxious agents exposure
Pregnancy and prenatal life are critical for the renal function and the cardiovascular risk
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• The nefrogenesis is not complete till the 36° weeks of gestation.
• The growth after a preterm birth (even in intensive care units) allows < 10% only of the expected renal growth in respect to in utero growth in regular term infants
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Low birth weight
Placental Placental malfunctionmalfunction
Environmental conditioning of genetical factors:the mather acts as the organogenesis conditioning environment
NutritionNutrition(low proteins(low proteinshigh sodium) high sodium)
hyperglicemiahyperglicemia
smoking in pregnancysmoking in pregnancy
EPIGENETICSEPIGENETICS
GENETICGENETICFACTORSFACTORS
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Low neonatal birth weight
Hypertrophic glomeruli Hypertrophic glomeruli Glomerular hypertensionGlomerular hypertension
riduced GFRriduced GFR increased increased albuminuriaalbuminuria
Brenner’s hypothesis in the ’80s:low nephron number,
glomerular hyperfiltration,genic activation
birth weight <2.5 Kgincreases by 40-70% the ESRD
in adult life
renal renal sclerosissclerosis
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To rule out the possibility of maternal confounding factors (smoking,hypertension, etc)
• Monozygous or dizygous twins differing from their birth weight were followed up :
a reduced intrauterine growth conditions CKD e and hypertension in adult age, independently from genetic and
environmental factors• At multivariate analysis the low birth weight remains the
only independent risk factor
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•• 30 studies30 studies•• Informations from 39.559 subjectsInformations from 39.559 subjects
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Odd Ratio:1.73 (1.44Odd Ratio:1.73 (1.44-- 2.08) p< 0.001)2.08) p< 0.001)
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CARDIOCARDIO--RENALRENALPREVENTION PREVENTION
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High maternal sodium intake
Reduced nephron number
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Riduced number of glomeruli
Increased Na reabsorption from distal tubuli (NCC and E-NaC)
RAS
cortisol-mineralcorticoid receptor
sympatic activity: HIF is activatedrby hypoxia, Na is reabsorbed
Increased Na sensitivity Increased Na sensitivity
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• eNOS decrease
• ADMA increase
• Reactive oxygen species production
• Endothelial proliferation
Exaggerated maternal sodium intake is an epigenetic conditioning factor
for hypertension
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hypertensionhypertension
increased risk for children with low birth weight
CVCVdiseasedisease accelerated accelerated
ESFRESFR
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several adults have a certain degree of CKD derived from congenital causes,
which will never end in dialysis need but represent a severe risk for
cardiovascular acidents
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Lurbe J Hypertension 2007
• Cildren with low neonatal birth weight present with a normal BP at birth ,
• But at adolescence they have 2-3 mmHg BP higher than controls
• If they become obese, hypertension is further enhanced
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1818--26 yers old 26 yers old 15,000 subjects15,000 subjects
6 years oof follow6 years oof follow--upup
Obesity, albuminuria and urinalysis findings in USyoung adults from the add health wave III study
Ferris M et al clin JASN 2007; 2: 1207-1214
BMI >35 kg/m2 or increase in BMI during BMI >35 kg/m2 or increase in BMI during followfollow--upup
Is associated with proteinuria OR 1.76 (1.02Is associated with proteinuria OR 1.76 (1.02--3.04)3.04)
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BMI >35
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1818--26 yo;26 yo;15,000 subjects15,000 subjects
Observation over 6 years Observation over 6 years
Obesity, albuminuria and urinalysis findings in USyoung adults from the add health wave III study
Ferris M et al clin JASN 2007; 2: 1207-1214
27:100027:100027.000/milion subjects have hematuria 27.000/milion subjects have hematuria
without urinary tract infectionwithout urinary tract infection
6:10006:10006000/milion joung subject 6000/milion joung subject
have proteinuria (in 1/6 associated with hematuria)have proteinuria (in 1/6 associated with hematuria)
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Figura 1
0.6% 0.6% proteinuriaproteinuria2.7%2.7%hematuriahematuria
0.1% 0.1% proteinuria proteinuria andandhematuriahematuria
Is young adult Is young adult underdiagnosed forunderdiagnosed for
Glomerular diseases ?Glomerular diseases ?
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short-term outcome(childhood):dialysis, transplantation
CKDCKDin childrenin children
renal mass reductionrenal mass reduction
chronicchronicglomerularglomerulardiseasesdiseases
long-term outcomein adult and and elderly patients
unsuspectedlyunsuspectedlyreduced renal massreduced renal mass
undiagnosedundiagnosedglomerularglomerulardiseasesdiseases
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account for about 30% of all patients entering dialysis
CRF without diagnosis in all the renal registries
we need an early diagnosis starting from a very early time
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Basso peso neonatale
Rischio di Rischio di malattia CVmalattia CV
Rischio di Rischio di CKDCKD
sia nel bambino che nell’adulto
identificazioneidentificazioneprecoceprecoce
di soggetti a rischio:di soggetti a rischio:sorveglianzasorveglianza
attenta attenta
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In adults in 2007 28%
CRF without diagnosis UK registries
Underdiagnosed CAKUT or Glomerular diseases?
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Considerando la progressione generale della IgAN
(25% dei casi necessitano dialisi entro 20 anni)
67% dei casi di IgAN che arrivano alla dialisi hanno età di 25- 55 anni
(25% hanno < 30 anni all’inizio del RDT)
èè evidente cheevidente che
Origini e Progressione della IgAN
molte IgAN che progrediscono alla dialisi molte IgAN che progrediscono alla dialisi nellnell’’adultoadulto
cominciano nellcominciano nell’’ etetàà pediatricapediatrica
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Primary IgAN++Hb
macroscopichematuria
Chronicrenal failure
ProteinuriaProteinuria
andmicroscopic
hematuria
nourinary signs
years0
102030405060708090
100110
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Dispers. (XY) 2
Normalrenal function
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Patient A: hematuria children detected by screening
0102030405060708090
100110
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Dispers. (XY) 2
Patient B: proteinuria
Patient C: hypertension, reduced GFR
years
CrCl
Geddes NDT 2003
Start of IgA deposition
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Italian Registry of Pediatric Renal Biopsies (432 cases) Children with isolated microscopic hematuria (A) or with hematuria associated with proteinuria (B)
Coppo et al Nephrol Dial Transplant 1998; 13: 293-297
0
5
10
15
20
25
30
35
TN IgAN Al MCH MPGN FSG SLE HSP MP GN otherGN
%
0
5
10
15
20
25
30
35
TN IgAN Al MCH MPGN FSG SLE HSP MP GN otherGN
A B
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La IgAN è la più comune glomerulonefrite in Italia ed ha spesso radici nell’età pediatrica
IgAN nel giovane: reperto orinario è spesso modesto, microematuria e proteinuria in tracce(che talora restano, note, per tutta la vita ma senza adeguato follow-up)
Molti casi non sono diagnosticati per le loro minime manifestazioni cliniche(che spesso restano, non note, per tutta la vita)
Nella ricerca di fattori di rischio per CKD e CVDNon trascuriamo il più banale: microematuria e GN cronica
non diagnosticata
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RIDT 2008 : malattia causale ingresso in dialisi22% senza diagnosi di malattia causale,23% con diagnosi generica di malattia vascola 20% nefropatia diabetica, senza biospia renaleIn RECORD-IT 30 % glomerulonefriti croniche in CKD In ERA-EDTA Registry 32% glomerulonefriti Il 30% dei trapiantati ha una malattia glomerulare.
L’arrivo alla dialisi ed al trapianto senza diagnosi rappresenta un risultato molto povero,
accettabile solo se fossimo certi che l’intervento del nefrologo non sarebbe in ogni caso servito a nulla.
Questo è nichilismo inaccettabile, che si ribalta in una svalutazione della nostra Professione
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impariamo dai Diabetologi
Diagnosi precoceLegacy effect
Effetto memoria della terapia prococe
.
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Il rischio cardiovascolare aumenta con l’aumento della proteinuria anche per valori minimi di
microalbuminuria
Gerstein, JAMA (2001) 268:421
PERCHE’ HANNOMICROALBUMINURIA?
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MICROALBUMINURIA
glomerulonefritiglomerulonefritiprepre--clinichecliniche
riduzione cronicariduzione cronicadi parenchima renaledi parenchima renale
DiabeteDiabete IpertensioneIpertensione
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short-term outcome(childhood):dialysis, transplantation
CKDCKDin childrenin children
renal mass reductionrenal mass reduction
chronicchronicglomerularglomerulardiseasesdiseases
long-term outcomein adult and and elderly patients
unsuspectedlyunsuspectedlyreduced renal massreduced renal mass
undiagnosedundiagnosedglomerularglomerulardiseasesdiseases
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LINEE DI ATTIVITA’PROGRAMMA SIN 2010-2012
Migliorare l’immagine della Nefrologia Italiana
Migliorare la visibilità del lavoro del Nefrologo Migliorare la visibilità SIN attraverso i risultati Migliorare la cura dei pazienti con malattia di rene
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PROGRAMMA 2010-2012
PROGETTI SIN• La diagnosi precoce di malattia renale• Il paziente portatore di rene trapiantato• La dialisi come sistema integrato con la nefrologia
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Come si presenta secondo i data-base internazionaliINon sol
BassoN nefronicongenito
Basso peso neonatale
ipodisplasiarenale
Danno renaleacquisito
GNC
PNC
La prevenzione della CKD fin dalle prime età(il controllo dietetico-farmacologico dove possibile)
significa prevenzione didialisi e di rischio CV nell’adulto
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short-term outcome(childhood):dialysis, transplantation
CKDCKDin childrenin children
renal mass reductionrenal mass reduction
chronicchronicglomerularglomerulardiseasesdiseases
long-term outcomein adult and and elderly patients
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USRDS database (Medicare)1380 deaths over 130.000 patients at risk in 1990-1996
MORTALITY due to CVD in children with ESRF:
DIALYSIS: 1000 times more than general population
TRANSPLANT: 100 times more than general population of the same age
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Systolic dysfunction in 48% of the cases Systolic dysfunction in 48% of the cases with concentric LVH with concentric LVH
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LVMI is correlated with CKD
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Evolution of IMT in children
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Coronary artery calcifications in childrenwith end-stage renal disease
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short-term outcome(childhood):dialysis, transplantation
CKDCKDin childrenin children
renal mass reductionrenal mass reduction
chronicchronicglomerularglomerulardiseasesdiseases
long-term outcomein adult and and elderly patients
unsuspectedlyunsuspectedlyreduced renal massreduced renal mass
undiagnosedundiagnosedglomerularglomerulardiseasesdiseases
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LVMI correlato a CKD
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il rischio CV di un soggetto di 25 anni trapiantato di rene è simile a quello di uno di 55 anni senza
nefropatieil rischio di IMA in un soggetto di 18-30 anni è
2.7% nei primi 3 anni dopo il trapianto
RRisk factors for CVD in children and young adults after renal transplantation
Becker et al Clin JASN 2006; 1:1284-1292
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Treat the kidney to protect your heart ! de Zeeuw, 2004
Prevenire le malattie di rene significa ridurre
necessità di dialisi e trapianto ma anche
morbilità e mortalitàper danno cardiovascolare
cominciare quando tutto il
processo è avanzato
può essere tardi!
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Necessità di conoscenza del problema per - diagnosi precoce - terapia ottimale per rallentare l’evoluzione
La CKD aumenta il rischio CV Le malattie renali croniche iniziate in età pediatrica aumentano il rischio CV nell’adulto?
Le insufficienze croniche di organo sono in pediatria una patologia rara se si considera la fase terminale con necessità di trapianto.
Nell’adulto le insufficienze d’organo sono patologie gravi per frequenza e impegno economico-sociale.
Molte malattie croniche che conducono ad insufficienza d’organo nell’adulto hanno radici molto lontane, nel 20% dei casi nell’infanzia.
E’ possibile una prevenzione di rene e di vita che si inizi in età pediatrica?
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Task Force in USA NIH nelle malattie renali dei bambini in insufficienza renale cronica
Gennaio 2006
studio prospetticodei bambini in IRC
morbilità correlata alla IRC
Malattia cardiovascolaremalattia osseaIpertensione
AnemiaInflammazione
CrescitaFunzione neurocognitivaSviluppo neuro-psichico
Stato socio-economico familiare
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la prevenzione di CKD deve iniziare fin dall’età pediatrica: Il 20% della CKD dell’adulto ha origine in età pediatrica
diagnosi precocedelle malattie renali
Il rischio CV dell’adulto ha radici in età pediatrica
prevenzione della progressione delle malattie renali
prevenzione del rischio cardio-vascolare
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0
10
20
30
40
50
60
0-14 15-24 25-44 45-64 65-74 >=75
HD DP TX
% w
ithin
trea
tmen
t mod
aliti
esPazienti prevalenti suddivisi per classi di età e modalità di terapia sostitutiva (RIDT 31/12/2004)
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PREVALENZA: età 0-19
Aumentata da 22 (1980) a 62 (2000) pmarp
INCIDENZA: età 0-19
Aumentata da 7 (1980) a 9 (2000) pmarp
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Casistica Great Hormond Street Hospital, Londra 1984-1998
Casistica USA, USRDS
1976-1993
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PREVALENZA DI IRC IN ETA’ PEDIATRICA IN PIEMONTE
in press: Acta pediatrica 2008
96 casi per milione di soggetti della stessa età
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REGISTRO ITALIANO DI DIALISI CRONICA PEDIATRICA Nuovi pazienti in Italia suddivisi per fasce d’età
0
5
10
15
20
25
30
35
2000 2001 2002 2003 2004 2005
DP 0-15.9 anni DP 16-18 anni HD 0-15.9 anni HD 16-18 anni
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Bambini in insufficienza renale in dialisi ERA-EDTA Registry
Il numero prevalente di bambini ed adolescenti in dialisi o trapiantati è aumentato da 22 per milione di bambini nel 1980 a 62 Per milione di bambini nel 2000
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table 4
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La funzione sistolica La funzione sistolica èè alterata nonostante alterata nonostante ll’’aumento della massa VSaumento della massa VS
Reduced systolic myocardial function in children with chronic renal insufficiency
Chinali M et al JASN 2006; 18: 593-598
la disfunzione sistolica la disfunzione sistolica èè pipiùù comune nei bambini con comune nei bambini con ipertrofia VS concentrica ed associata ipertrofia VS concentrica ed associata
con valori di Hb minoricon valori di Hb minori
ESCAPE trial europeo. ESCAPE trial europeo. 156 bambini 3156 bambini 3--18 anni, CKD 218 anni, CKD 2--44
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Per evitare la dialisi a soggetti adulti:
Molte nefropatie in età pediatrica sono considerate benigne ma in realtà progrediscono decenni dopo
NecessitNecessitàà di identificare e curare le di identificare e curare le nefropatienefropatie
in etin etàà pediatricapediatrica
Rischio CV Questo è 20 volte maggiore del normale e causa la morte nel 25% dei bambini o ex bambini in dialisi enel 15% dei trapiantati in età pediatrica
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Disfunzione sistolica subclinica in bambini con CKD iniziale o moderata. Questa condizione è associata negli adulti a prognosi CV sfavorevole.
Correlazione fra disfunzione VS e velocità di progressione della IRC
(iperattività simpatica o del sistema RAS a livello tissutale?)
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Tutti gli indici sono maggiori del normale in CKD e peggiorano in dialisi.
Evolution of large-vessel arteriopathyLitwin M et al NDT 2008; 14
Parziale miglioramento dopo trapianto, Correlata alla durata della dialisi ed al danno pre-esistente
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La sopravvivenza del rene trapiantato nei giovani è aumentata ma il rischio CV di un giovane portatore di rene trapiantato è 100 volte quello dei coetanei sani
Fattori di rischio comuni: ipertensione, obesità, IVS, diabete, iperlipidemia, Fattori di rischio infiammatorio,CKD, Ca/P
RRisk factors for CVD in children and young adults after renal transplantation
Becker et al Clin JASN 2006; 1:1284-1292
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Basso peso neonatale
Rischio di Rischio di malattia CVmalattia CV
Rischio di Rischio di CKDCKD
tutti i fattori precedenti,sia in osservazioni umane che in modelli animali
intolleranzaintolleranzaglucosioglucosio
dislipemiadislipemia
Rischio di Rischio di ipertensioneipertensione
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Ipotesi di Brenner1988
Ipotesi di Brenner1988
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il rischio CV di un soggetto di 25 anni trapiantato di rene è simile a quello di uno di 55 anni senza
nefropatieil rischio di IMA in un soggetto di 18-30 anni è
2.7% nei primi 3 anni dopo il trapianto
RRisk factors for CVD in children and young adults after renal transplantation
Becker et al Clin JASN 2006; 1:1284-1292
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www.escape-trial.org
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LVH LVH èè il piil piùù importante indicatore di rischio CV nella importante indicatore di rischio CV nella popolazione generale ed in ESRD popolazione generale ed in ESRD
Nei bambini mancano i fattori confondenti degli adulti:Nei bambini mancano i fattori confondenti degli adulti:la malattia coronarica e la microangiopatia diabeticala malattia coronarica e la microangiopatia diabetica
ESCAPE trial europeo. ESCAPE trial europeo. 156 bambini 3156 bambini 3--18 anni, CKD 218 anni, CKD 2--44
Studiati con ECO cardioStudiati con ECO cardio
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Anomalie VS nel 43% dei bambini in CDK 2-4
22.3% alterazioni 22.3% alterazioni concentricheconcentriche di geometria VSdi geometria VS(ipertrofia o rimodellamento)(ipertrofia o rimodellamento)
21% ipertrofica VS 21% ipertrofica VS eccentrica.eccentrica.
Ipertrofia VS indipendente daIpertrofia VS indipendente daValori di PAValori di PATerapia con ACEITerapia con ACEIMalattia renale di base Malattia renale di base
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LVMI correlato a CKD
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Ipertrofia VS concentrica ed eccentricaIpertrofia VS concentrica ed eccentricacome risultato di fattori emodinamici e noncome risultato di fattori emodinamici e non(CRP > 10mg/dl)(CRP > 10mg/dl)
Sesso maschile, anemia, sovraccarico idrico, Sesso maschile, anemia, sovraccarico idrico, MBI, microinfiammazione, MBI, microinfiammazione, concorrono alla ipertrofia VSconcorrono alla ipertrofia VSin bambini con IRC iniziale o moderatain bambini con IRC iniziale o moderata
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Disfunzione sistolica nel 48% dei casi con IVS concentricaDisfunzione sistolica nel 48% dei casi con IVS concentrica
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Evolution of large-vessel arteriopathyLitwin M et al NDT 2008; 14
Spessore intimaSpessore intima--media (IMT) media (IMT) area della sezione trasversa vasale (WCSA) area della sezione trasversa vasale (WCSA)
sezione trasversa del lume (LCSA) sezione trasversa del lume (LCSA) rapportate allrapportate all’’etetàà
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Correlazione fra PA diastolica e IMT
in bambini in CKD
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Correlazione IMT carotidea normalizzata per età e sesso con assunzione di chelanti del fosforo e con CaxP
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Il rischio CV in bambini in CKDIl rischio CV in bambini in CKD
E’causa la morte nel 25% dei bambini in dialisi
E’ causa di morte nel 15% dei soggetti trapiantati in età pediatrica
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Evoluzione di IMT in bambini
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Pulse wave velocity in end-stage renal disease:influence of age and body dimension
Kis E et al Pediatr Res 2008; 63: 95-98
PWV rapportata allPWV rapportata all’’altezza staturalealtezza staturaleèè aumentata in soggetti giovani in ESRDaumentata in soggetti giovani in ESRD
133 bambini e giovani 3-26 anni
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Coronary artery calcifications in childrenwith end-stage renal disease
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Coronary artery calcifications in childrenwith end-stage renal disease
Civiliban M et al Pediatr Nephrol 2006; 21: 1426-33
15% dei casi (1115% dei casi (11--21 anni)21 anni)correlazione con:correlazione con:
durata di dialisi, PTH, CaxP, Calcio per os, Vit D3durata di dialisi, PTH, CaxP, Calcio per os, Vit D3
TAC spirale per indagare calcificazioni coronariche (CAC)in 53 bambini –giovani in ESRD
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USRDS database (Medicare)1380 morti CV su 130.000 pazienti a rischio dal 1990- 1996
MORTALITA CV nei bambini con ESRF:
DIALISI: 1000 volte superiore alla popolazione generale
TRAPIANTO: 100 volte superiore alla popolazione generale della stessa età
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PROTEINURIAG
Afferent art
Efferent art
Angiotensin II
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HEMODINAMIC EFFECTSHEMODINAMIC EFFECTS
Vasoconstriction ( ET1, eNOS, ANP)Vasoconstriction ( ET1, eNOS, ANP)
Proteinuria Proteinuria
(due to hemdynamic effects and modification of glomerular (due to hemdynamic effects and modification of glomerular permeability)permeability)
Angiotensina IIAngiotensina II
Glomerulare hyperfiltrationGlomerulare hyperfiltration
HypertensionHypertension
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ATF-2
C-Jun
C-Fos C-Jun
Elk-1/Sap1
TARGET GENES
IkB
DNA
AP-1
Angiotensin II
p38 MAPKp38 MAPK
MEKMEK
JNKJNK
ERK 1/2ERK 1/2Elk-1/Sap1
NF-kBETS
Mitogen Activated Protein Kinases
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il rischio CV di un soggetto di 25 anni trapiantato di rene è simile a quello di uno di 55 anni senza
nefropatieil rischio di IMA in un soggetto di 18-30 anni è
2.7% nei primi 3 anni dopo il trapianto
Aspettativa di vita molto lunga: necessità della massime misure
di prevenzione possibili
RRisk factors for CVD in children and young adults after renal transplantation
Becker et al Clin JASN 2006; 1:1284-1292
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Causes of ESRF in incident population
0
5
10
15
20
25
30
35
40
45
Japan USA Germany Australia
GNdiab nephneph angoth
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• Often detected only by screening urine tests, or analysis to sporting, or chance analysis.
IgAN in children
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IgAN in childrenLinné, Berg, Levy, Hattori, Yoshikawa, Hogg, Wyatt
Estimated survival at 10 yearsin children:87- 93%
Severe clinical signs Severe clinical signs develop after 5develop after 5--15 years:15 years:
at longat long--term followterm follow--upupIgAN in children is aIgAN in children is aprogressive diseaseprogressive disease