Come stimare il filtrato glomerulare in gravidanza: la creatininemia

Come stimare il filtrato
glomerulare in gravidanza:
la creatininemia ed oltre
Francesca Mallamaci
La morte della madre e del bambino alla nascita è uno degli eventi più drammatici e dolorosi.. ..
Morire di parto
Semmelweiss
“savior of mothers”
i primi tentativi di dare sistematizzazione razionale al
dramma della morte da parto attraverso la descrizione
dell’evento risalgono alla medicina egizia….
…contribuendo a una drammatica riduzione della
mortalità da parto….

600.000 donne/anno muoiono per cause connesse alla gravidanza
Almeno 50.000 di questi decessi sono attribuibili alla pre-eclampsia /eclampsia
99% di questi eventi sono nei paesi in via di sviluppo
Changes in renal function during healthy pregnancy
GFR (ml/min/1.73 m2)
190
170
150
130
110
90
Before
First
Second
pregnancy trimester trimester
Third
trimester
Gestational hyperfiltration is accompanied by a relative decrease in concentrations
of serum creatinine and urea, so values considered normal in non pregnant state
may be abnormal in pregnancy….
Davison J et al, Medical disorders in obstetric practice. 3rd edition 1995; 226-305
How common is CKD in pregnancy ?
20-39 year-old pregnant women
Prevalence (%)
5
4
3%
3
2
0.7%
1
0
I-II
III-V
CKD Stages
Williams D et al, BMJ, 2008; 26: 211-215
E’ noto che la gravidanza è un fattore di rischio per la progressione delle
nefropatie........la malattia renale cronica è un fattore di rischio per gli eventi maternofetali....
Preterm delivery
(%) 50
44%
40
30
20
10
5%
0
Low risk
pregnancies
CKD
Pregnancies
Neonatal intensive care
Single center, case control study
358 pregnancies (91 CKD vs. 267 “low risk”)
Follow-up: 9 years
26%
1%
Low risk
pregnancies
CKD
Pregnancies
Piccoli GB, CJASN 2010; 5: 844-855
Preterm delivery
(%) 60
50
33%
40
30
20
10
5%
Neonatal intensive care
…Outcomes in low risk pregnancies vs. stage 1 CKD pregnancies
18%
1%
0
Low risk
pregnancies
CKD (stage 1)
Pregnancies
Low risk
pregnancies
CKD (stage 1)
Pregnancies
Piccoli GB, CJASN 2010; 5: 844-855
Risk factors for adverse outcomes in CKD pregnancies
delivery care
Pretermintensive
Neonatal
(logistic regression analysis)
Odds
ratioratio
Odds
15
Hypertension
was
to the risk
of
Proteinuria did
notunrelated
predict preterm
delivery
neonatal intensive care
10
5
Reference
Reference
0
Without
Proteinuria
Hypertension
< 1g/day
With
Proteinuria
Hypertension
> 1g/day
CKD is a challenge for pregnancy from early stages.
Strict follow-up is needed for CKD patients, even when there is a
“normal” renal function.
Piccoli GB, CJASN 2010; 5: 844-855
Longitudinal study
49 non-diabetic pregnant women with a preconception GFR < 60 mL/min
Outcome: GFR decrease before conception versus after
delivery
Imbasciati E et al, AJKD 2007, 49:753-762.
Proteinuria < 1
Proteinuria ≥ 1
Rate of GFR decline
(ml/min/month)
2.0
1.5
1.0
0.5
0.0
GFR
≥ 40
GFR
< 40
Before
Conception
GFR
≥ 40
GFR
< 40
After
Delivery
In women with renal insufficiency the presence of both GFR less
than 40 and proteinuria greater than 1 g /d before conception
predicts poor outcomes.
Imbasciati E et al, AJKD 2007, 49:753-762.
La malattia renale cronica è un importante
fattore di rischio per la madre e per il feto
anche negli stadi più iniziali
Una stima corretta della funzione renale è di
primaria importanza per un monitoraggio più
stretto delle gravidanze a rischio.
Quale è il modo migliore per determinare la
funzione renale in gravidanza?
British Journal of Obstetrics and Gynaecology,
2008;115:109–112
Population: 24 healthy pregnant volunteers (age 22-35 years)
10 women with pre-eclampsia were similarly studied in late
pregnancy and postpartum.
GFR (by inulin clearance)
early pregnancy (10–16 wks of gestation)
late pregnancy (33–39 wks of gestation)
postpartum (>8 wks following delivery)
A third group of 10 pregnant women with chronic renal impairment were studied
on one or two occasions during pregnancy.
How to assess the agreement between
two methods of measurement ?
+ 2 SD
Individual “bias”
Average “bias”
Differences between
individual measurements
0
provided by the 2
methods
Perfect agreement
95% levels of
agreement
- 2 SD
Average values of
individual measurements
provided by the 2
methods
Bland-Altman plot
Smith MC et al, British Journal of Obstetrics and Gynaecology, 2008;115:109–112
Normal Pregnancy (n=48 observations in 24 women)
Difference between
Inulin Cl and MDRD
120
+ 96 ml/min
100
80
60
40
Average
Bias: + 41 ml/min
20
0
-20
-13 ml/min
-40
40
60
80
100 120 140 160 180
Average value between
Inulin Cl and MDRD
Post partum (n=24 women)
Difference between
Inulin Cl and MDRD
120
100
80
+ 50 ml/min
60
40
Average
Bias: + 12 ml/min
20
0
-20
-25 ml/min
-40
40
60
80
100 120 140 160 180
Average value between
Inulin Cl and MDRD
Pre-eclampsia (n=10)
Difference between
Inulin Cl and MDRD
120
100
+ 66 ml/min
80
60
Average
Bias: + 23 ml/min
40
20
0
-19 ml/min
-20
-40
40
60
80
100 120 140 160 180
Average between
Inulin Cl and MDRD
Pregnant women with
pre-existing renal impairment (n=15)
Difference between
Inulin Cl and MDRD
120
100
+ 86 ml/min
80
60
Average
Bias: + 27 ml/min
40
20
0
-20
-31 ml/min
-40
40
60
80
100 120 140 160 180
Average between
Inulin Cl and MDRD
This study indicates that in all situations, MDRD substantially underestimates glomerular
filtration rate during pregnancy and cannot be recommended for use in clinical practice.
Alper AB et al, American Journal of Perinatology, 2007, 24: 569-574

209 pre-eclamptic patients recruited from 5 large hospitals
To compare
eGFR
Cockcroft-Gault
MDRD170
MDRD186
Vs
Creatinine clearance
(24-hour urine collection)
Additionally, a set of new equations that more accurately estimate GFR in
preeclamptic patients based on ethnicity, preeclampsia GFR, was created.
Performance of Cockcroft-Gault, MDRD170, MDRD186 and Pre-eclampsia
GFR formulas for predicting creatinine clearance
50
+42 ml/min
Bias
(ml/min)
25
0
- 3 ml/min
-25
- 20 ml/min
Cockcroft
MDRD170
Perfect
agreement
- 13 ml/min
MDRD186
Pre-eclampsia
Estimation formulas
Current GFR estimation equations based on serum
creatinine values in nonpregnant patients are not reliable
measures of renal function in patients with preeclampsia. The
use of a new (PGFR) formula is recommended.
Alper AB et al, American Journal of Perinatology, 2007, 24: 569-574
Pregnancy in chronic kidney disease.
Need for a common language
Piccoli GB et al - Ahead of print 2011
REVIEW
“…there is a strong need to unify definitions and
stratifications to allow quantitative evidence-based
counseling in CKD in pregnant women.
…further analysis is highly needed in this complex field…
planning new prespective studies.”
S
&
C
Chronic Kidney Disease is an important risk factor in pregnancy
both for maternal and fetal outcomes.
A correct assessment of renal function in pregnant women is of
paramount importance.
eGFR formulas commonly used in non pregnant women seem not to
be helpful in pregnant women.
To date Creatinine Clearance seems to be the most appropriate
method.
Multicentric studies on this issue would be welcome.
1996; 335:226-232
To investigate the frequency and types of maternal and obstetrical complications and the
outcomes of pregnancy in 67 women with primary renal disease (82 pregnancies in total).
Initial serum creatinine >1.4 mg/dl and gestations that continued beyond the first trimester.
Serum Creatinine
Creatinine >2.5 mg/dl
3
45
40
35
2
(mg/dl)
(%)
1
36%
30
25
20
17%
15
Among pregnant
women with moderate or severe
renal insufficiency, the
0
10
nd
rates of complications
and
1st or 2hypertension,
3rd
1st or 2nddue to3rdworsening renal function,
trimester are
trimester
trimester trimester
obstetrical complications
increased.
Pre-eclampsia severa
Insorgenza di ipertensione e proteinuria e almeno 1 delle seguenti condizioni
Ritardo crescita
Sintomi neurologici
Transaminasi x 2
Sistolica >160 mmHg
o
Diastolica >110 mmHg
almeno 2 volte a distanza di 6 ore
Piastrine < 100.000 mm3
Complicanze più gravi: Oliguria, edema
polmonare, incidente CV, coagulopatia
Proteinuria >5g/24 ore
o
+++ dipstick in 2
campioni separati
Madre: Trattamento Ipertensione e
Monitoraggio Clinico
Feto: Monitoraggio fetale
Trattamento Ipertensione
Prevenzione incidenti Cerebro-Vascolari
RR
10
Proteinuria
8
Obiettivo:
140-155 mmHg
Soglia di trattamento in
90-105
assenza di danno d’organo
IVS
Working Group High BP
o
pregnancy 2000 NIH
nefropatia
6
Creatinina, ac.urico
Emocromo &
Piastrine
4
2
Transaminasi & LDH
0
120
140
160
systolic mmHg
180
SOGLIA ALTA PERCHE’ IL
RISCHIO ASSOLUTO DI
INCIDENTE CEREBROVASCOLARE A 1 ANNO E’
BASSO (15 : 100.000)
A population-based study linking all women attending the Second Health Study in Nord-Trøndelag,
Norway (1995–97) and subsequent pregnancies registered in the Medical Birth Registry.
N=3405 women (GFR: 108±19 ml/min/1.73 m2)
Over a follow-up of 11 years they gave birth to 5655 singletons
30
20
17%
(%)
10
0
Pre-eclampsia, small for
gestational age
Preterm birth
2009; 24: 3744–3750
Preterm birth
10
P<0.004
8
6
*OR
(95% CI)
4
2
1
>90
75-89
60-74
GFR (ml/min/1.73 m2)
Data adjusted for maternal age, parity, follow-up time, previous preeclampsia, pre-term
birth or SGA, BP, BMI, diabetes, smoking, history of CVD, family history of CVD and
education.
Nephrol Dial Transplant 2009; 24: 3744–3750
Interaction between hypertension and renal function for predicting
pre-eclampsia, SGA or preterm birth
GFR> 90 ml/min/1.73 m2
6
P=0.015
GFR< 90 ml/min/1.73 m2
P<0.001
4
*OR
(95% CI) 2
1
<140/90
> 140/90
BP (mmHg)
<140/90
> 140/90
BP (mmHg)
Data adjusted for maternal age, parity, follow-up time, previous preeclampsia, pre-term
birth or SGA, BP, BMI, diabetes, smoking, history of CVD, family history of CVD and
education.
Nephrol Dial Transplant 2009; 24: 3744–3750
0.7
0.6
Probability for
Adverse Outcome
0.5
0.4
0.3
0.2
60
70
80
90
100
110
120
130
eGFR (ml/min/1.73m2)
Women with eGFR 60–89 ml/min/1.73 m2 were not at increased risk for
preeclampsia, SGAor preterm birth unless they were also hypertensive.
Adverse fetal outcomes
Data Source: Colorado birth and death certificate data (1989 to 2001).
Total number of 747.368 births: 911 from women with CKD and 4.606
from women without CKD
Adverse maternal outcomes
25
20
25
P<0.001
18%
20
15
10
P<0.001
14%
15
(%)
10%
10
5
5
0
0
Without
CKD
CKD
4%
Without CKD
CKD AJKD: 2004; 43: 415-423
Adverse fetal outcomes
4
3
OR and
95% CI 2
P<0.001
P<0.001
+ 76% excess odds for
adverse fetal outcomes
1
0
Crude *Adjusted
*Data adjusted for hypertension, anemia, diabetes lung and cardiac diseases,
education and ethnicity.
AJKD: 2004; 43: 415-423
Adverse maternal outcomes
5
No Kidney disease
Kidney disease
4
*Adjusted
OR (95% CI)
3
2
1
Reference
0
1999-2001
1992-1998
1989-1991
Birth year
* Data adjusted for hypertension, anemia, diabetes lung and cardiac diseases,
education and ethnicity,
AJKD: 2004; 43: 415-423
8
Serum Creatinine (mg/dl)
6
< 2.0 mg/dl
at the onset
of gestation
4
2
8
6
2.0 - 2.4 mg/dl
at the onset
of gestation
4
2
Women who had a
pregnancy-related
decline in renal
function
8
6
≥ 2.5 mg/dl
at the onset
of gestation
4
2
1st or
3rd
6 wk
6 mo
12 mo
2nd
Trimester
Post
Post
Post
pregnantTrimester
women with moderate
or
severe
Partum Partum
Partum
Among
renal insufficiency, the
rates of complications due to worsening renal function,
hypertension,
and
NEJM:1996;
335:226-232
obstetrical complications are increased, but fetal survival is high.
MAP> 105 mmHg
60
60
48%
50
40
(%) 30
Urinary protein > 3 g/L
50
41%
40
(% ) 30
28%
23%
20
20
10
10
0
0
1st or 2nd
trimester
3rd
trimester
1st or 2nd
3rd
trimester trimester
NEJM:1996; 335:226-232
%
40
Gradi di insufficienza renale da moderato a severo
In 70.000 individui seguiti dai medici di medicina generale (MMG)
30
20
SIN &
Collegio Italiano dei MMG
10 Donne
0
Minutolo R et al.
Uomini
35-44
45-54
AJKD 2008;52:444-53
55-64
anni
65-74
>75
2008; 359:800-809
To assess the association between pre-eclampsia in one or more pregnancies and the
subsequent development of ESRD.
The study population included women who had had a first singleton birth between 1967
and 1991.
Data sources:
- Medical Birth Registry of Norway, which contains data on all births in Norway since
1967:
-Norwegian Renal Registry, which contains data on all patients receiving a diagnosis of
end-stage renal disease (ESRD) since 1980.
During the follow-up (17±9 years after the first pregnancy), ESRD developed
in 477 out of 570.433 women (3.7 events per 100,000 women per year).
0.015
0.012
Cumulative risk
of ESRD
0.009
0.006
Pre-eclampsia
0.003
No Pre-eclampsia
0.000
0
10
20
30
40
Years after First Birth
Although the absolute risk of ESRD in women who have had pre-eclampsia is
low, preeclampsia is a marker for an increased risk of subsequent ESRD.
Perfect agreement
500
r = 0.76
400
300
Cockcroft-Gault
200
100
0
0
100
200
300
400
500
Creatinine clearance
Cockroft-Gault formula largely over-estimates creatinine clearance .
Identity line
400
r = 0.55
300
MDRD170
200
100
0
0
100
200
300
400
Creatinine clearance
MDRD170 under-estimates creatinine clearance
400
r = 0.55
300
MDRD186
200
100
0
0
100
200
300
400
Creatinine clearance
MDRD186 under-estimates creatinine clearance
400
r = 0.67
300
Pre-eclampsia
GFR
(PGFR)
200
100
0
0
100
200
300
400
Creatinine clearance
Pre-eclampsia
GFR estimation
provides a good
estimation ofbased
creatinineon
clearance
Current
GFR
equations
serum
creatinine values in nonpregnant patients are not reliable
measures of renal function in patients with preeclampsia. The
use of a new (PGFR) formula is recommended.