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doi: 10.1093/ndt/gfs573
Advance Access publication 12 January 2013
ORIGINAL ARTICLE
Marilisa Biolcati2
and Tullia Todros2
Correspondence and offprint requests to: Giorgina Keywords: chronic kidney disease, echo-Doppler, placenta
B. Piccoli; E-mail: gbpiccoli@yahoo.it pre-eclampsia, proteinuria, ultrasounds
1199
The Author 2013. Published by Oxford University Press on
behalf of ERA-EDTA. All rights reserved.
typically present with hypertension and proteinuria. Both may GFR below 60 mL/min for the same time period. As the most
have a stormy course with high risks for mother and child. widely used formulae (Cockcroft and Gault and MDRD) have
Both have a high prevalence in Western countries: CKD is esti- serious limits in pregnancy, GFR calculation was based, when-
mated as high as 3% in women in childbearing age and pre- ever possible, on preconception data, within 3 months prior to
eclamptic manifestations complicate 25% of all pregnancies conception, as elsewhere specied [9].
[17]. Hypertension was dened as systolic blood pressure 140
The availability of preconception data should allow the and/or diastolic blood pressure 90 or anti-hypertensive
differential diagnosis between PE and CKD in most cases; therapy; patients on anti-hypertensive therapy prior to con-
however, pregnancy is often the rst occasion in which a ception were classied as affected by chronic hypertension
woman undergoes biochemical tests [1, 2, 4, 5]. Furthermore, even when therapy had been discontinued in pregnancy; they
renal diseases may occur or are up in pregnancy, favoured by were not included in the study unless CKD was present [17].
the hormonal milieu [8, 9]. PE was dened as the appearance of hypertension with sys-
The relationship between PE and CKD is entangled: PE tolic blood pressure 140 mmHg or diastolic blood pressure
affects kidney function, causing proteinuria and hypertension; 90 mmHg accompanied by proteinuria 300 mg/24 h after
a link between PE and CKD has been identied in large-popu- 20 weeks of gestational age in a previously normotensive
lation studies [1, 2, 58]. Conversely, CKD, hypertension and woman; alterations should resolve within 3 months after deliv-
proteinuria are independent risk factors for unfavourable preg- ery [9, 1719].
nancy outcomes and PE [610]. A mixed clinical pattern was identied when a previously
The differential diagnosis between CKD and PE is difcult: normotensive, non-proteinuric patient with known kidney
It has been shown that abnormal FVWs in the uterine ar- CKD patients were selected from the database of the Out-
teries after 2224 weeks of gestation reect abnormal tro- patient Unit dedicated to kidney diseases in pregnancy, pro-
phoblast invasion of the spiral arteries, which is thought to spectively updated since 2000.
contribute to the pathogenesis of PE [1, 2, 1215]. This To mimic the PE patterns, patients with proteinuria 300
pattern is often associated with abnormal Doppler FVWs in mg/day and hypertension, at the time of the Doppler study
the umbilical arteries, indicating abnormal development of and who had undergone at least one Doppler study in our
the vascular villous tree, which in turn is associated with Unit, were selected. If a patient was proteinuric and hyperten-
foetal growth restriction [1316]. sive before pregnancy, she was considered as CKD; the diag-
The present study aimed at testing the working hypothesis nosis of PE on CKD was done on the case of new onset of
that Doppler FVWs in the umbilical and uterine arteries are proteinuria and hypertension on a previously non-proteinuric
different in PE and CKD. Considering PE as a primary dis- non-hypertensive woman with known CKD.
order of placental implantation, we expected the uterine and Only patients observed since 2005 were included for hom-
umbilical arteries FVWs to be altered in PE patients. In con- ogeneity with the other two archives.
trast, FVWs were expected to be normal in CKD patients, at PE patients were selected from the database of the
least until the late phase of pregnancy. In cases in which PE is Materno-Foetal Unit, gathering all hospitalized patients in the
superimposed over CKD, the pattern was expected to reect Unit since 2005. The diagnosis of PE, as supplied on the clini-
the prevalent disease. cal charts, was reviewed by one nephrologist and two obstetri-
cians.
The Doppler studies were obtained from the archives of the
METHODS Materno-Foetal Unit where all tests have been stored since
2005. Only studies since the 26th gestational week were con-
Clinical denitions sidered, for the sake of standard reference values. If more were
Three referral clinical categories were dened: CKD, PE available for the same patient, the rst one after the 26th gesta-
and mixed (PE on CKD). tional week was selected. Only singletons were included.
CKD patients were either referred from a nephrology unit, Out of 78 patients, initially identied from the 3 different
were they were followed for different types of kidney diseases, archives, 61 cases were selected for the nal evaluation (5 PE
diagnosed according to the usual criteria or diagnosed as with patients were excluded, reclassied as pregnancy-induced hy-
CKD during pregnancy; all these patients were referred to a pertension; 1 patient was excluded because of twin pregnancy;
nephrology unit after delivery and the diagnosis of CKD was 2 patients because of incomplete data; 9 patients because the
conrmed in all cases. ow measurement was performed before 26 weeks of gesta-
CKD was classied according to K-DOQI guidelines as tional age, when the results are not yet standardized). One
every anomaly of blood and urine composition, or imaging or patient (two pregnancies) initially in the PE group was reclas-
pathological data, lasting for at least three months or with a sied as affected by a mixed pattern.
1200
G.B. Piccoli et al.
Table 1. Baseline data of the 61 cases
Clinical Patients Maternal age Race Parity (rst BMI Proteinuria before
subset at start pregnancy delivery: g/day
of pregnancy %) (median)
(years)
CKD 17 29.9 5.7 Caucasian 12 9 (52.9%) 22.8 4.0 2.05 (0.3317.29)
(70.6%)
Asian 3
(17.6%)
African 1
(5.9%)
Other 1
(5.9%)
PE 39 32 4.8 Caucasian 34 31 (79.5%) 24.8 5.2 1.52 (0.326)
(87.2%)
African 4
ORIGINAL ARTICLE
All cases 61 32 5.1 Caucasian 51 43 (70.5%) 24 4.8 2 (0.317.29)
(83.6%)
Asian 3
(4.9%)
African 5
(8.2%)
Other 2
(3.3%)
Note: no signicant difference in baseline data among groups.
Doppler ow studies data proposed by Todros et al. [16]. Abnormal patterns of um-
The evaluation of the uterine arteries took into account the bilical artery Doppler waveforms, especially absence or rever-
resistance index (RI) or Pourcelot ratio, dened as peak systo- sal of end-diastolic velocities, were also recorded.
lic ow minus peak end diastolic ow divided by peak systolic Flow denitions. Three major simplied ow patterns
ow. were identied: alteration of both FVWs (uterine and umbili-
According to the literature, an abnormal uterine artery cal arteries), hypothesized as predictive of PE; normal FVWs
Doppler FVW was dened as a mean (of the two uterine ar- at both levels, hypothesized as predictive of CKD; altered
teries) RI of 0.58; a further more restrictive cut-point (0.62) FVW in either artery, considered mixed. The studies were
was also tested. Both cut-points are standardized references, performed by the same small team of operators, working to-
and are applied to gestational ages of at least 26 weeks. The gether for over 10 years.
uterine ows are not physiologically variable with the gesta-
tional age thereafter, and not age adjusted [1316]. Statistical analysis
The presence of early diastolic notching in the waveform of
the main uterine arteries was underlined, especially if bilateral A descriptive analysis was performed as appropriate (mean
[1316]. and standard deviation for parametric and median and range
Umbilical artery Doppler waveforms were analysed using for non-parametric data). Students t-test and log rank (when
the Pulsatility index (PI), dened as peak systolic ow minus appropriate), Chi-square test and ANOVA were used for com-
end diastolic ow divided by mean ow. Normal values of PI parisons between cases and controls and among groups. Sig-
were adjusted for gestational age, after the 26th gestational nicance was set at <0.05. Both RI cut-points (0.58 and 0.62)
week, and were dened according to gestational age-adjusted were tested. The tests were also stratied by operator of the
study.
1201
Pre-eclampsia or chronic kidney disease, Doppler criteria
Accuracy of both normal ows in predicting CKD and of
termination
both abnormal ows in predicting PE was summarized
through sensitivity, specicity, positive predictive value (PPV),
Death-
negative predictive value (NPV), positive likelihood ratio (LH
2.6%
1.6%
NS
+) and negative likelihood ratio (LH), with their 95% con-
dence intervals (95% CI); signicance of differences was tested
with Chi-square test.
31 (79.5%)
40 (65.6%)
6 (35.3%)
NICU (%)
The analysis was performed with the SPSS software
3 (60%)
Need for
0.0013
(version 18.0).
NICU, Neonatal Intensive Care Unit; SGA, small for gestational age baby, according to the Italian reference standards; week, gestational week; NS, non-signicant
R E S U LT S
38 (97.4%)
54 (88.5%)
11 (64.7%)
5 (100%)
Caesarean
Baseline characteristics and outcome data
section
0.0030
The main clinical data of the 61 cases are reported in
(%)
Table 1, according to the three main clinical categories. No sig-
nicant difference was observed for demographic data in the
different subsets.
The CKD group consisted of 17 patients; 7 in stage 1; 2 in
4 (10.2%)
score (50 )
4 (6.6%)
<7 (%)
Apgar
were: glomerulonephritis [6], kidney malformation [1], pre-
NS
vious acute pyelonephritis, with scars, [1], interstitial nephro-
pathy [4], Adult dominant polycystic kidney disease
(ADPKD) [1], kidney transplant [1], solitary kidney [1] and
17.6% (23.5%)
15.6% (28.1%)
16.7% (27.8%)
diabetic nephropathy [2].
20% (40%)
The ve patients with a mixed pattern of PE on CKD were
ORIGINAL ARTICLE
SGA: <5th
centile %
(% < 10)
two in stage 1 and three in stage 2 CKD, and were affected by
glomerulonephritis [3], ADPKD [1] and nephrolithiasis [1].
NS
The overall prognosis was better in the CKD patients than
in the PE patients, with a signicantly lower incidence of
preterm babies (deliveries <37 weeks: 76.5 versus 97.4%,
2028.4 682.1
1362.9 609.5
1416 373.6
1552.7 676.6
P = 0.0434; deliveries 34 weeks: 47.1 versus 92.3%,
Birth weight
0.0006
Table 2. Perinatal outcome data in the study population
91.8% (78.7%)
100% (80%)
Preterm % <37
32.1 3.3
0.0003
61
n
pattern
Mixed
versus
CKD)
P (PE
CKD
cases
All
PE
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G.B. Piccoli et al.
F I G U R E 1 : Comparison between clinical diagnosis and ow pattern.
ORIGINAL ARTICLE
ows, n (%) abnormal pattern, n (%) normal ows in the abnormal ows in the
ows, n (%) prediction of CKD prediction of PE
All cases
All 18 (29.5) 24 (39.3) 19 (31.2) CKD versus PE + PE PE versus CKD + PE
patients on CKD; P = 0.0018 on CKD; P = 0.0233
CKD 10 (58.8) 1 (5.9) 6 (35.3)
PE 7 (17.9) 20 (51.3) 12 (30.8)
PE on 1 (20) 3 (60) 1 (20)
CKD
Either both normal or both abnormal ows (mixed ow pattern excluded)
All 18 (42.9) 24 (57.1) CKD versus PE + PE PE versus CKD + PE
patients on CKD; P = 0.0007 on CKD; P = 0.0081
CKD 10 (90.9) 1 (9.1)
PE 7 (25.9) 20 (74.1)
PE on 1 (25) 3 (75)
CKD
PE versus CKD only: all cases
All 17 (30.4) 21 (37.5) 18 (32.1) CKD versus PE; PE versus CKD;
patients P = 0.0022 P = 0.0034
CKD 10 (58.8) 1 (5.9) 6 (35.3)
PE 7 (17.9) 20 (51.3) 12 (30.8)
PE versus CKD only: either both normal or both abnormal ows (mixed ow pattern excluded)
All 17 (44.7) 21 (55.3) CKD versus PE; PE versus CKD;
patients P = 0.0010 P = 0.0010
CKD 10 (90.9) 1 (9.1)
PE 7 (25.9) 20 (74.1)
1203
Pre-eclampsia or chronic kidney disease, Doppler criteria
Table 4. Accuracy of both normal ows in predicting CKD and of both abnormal ows in
predicting PE (mixed ow pattern and PE on CKD excluded)
Test disease Sensitivity Specicity PPV NPV LH + (IC95%) LH P-value
(IC95%) (IC95%) (IC95%) (IC95%) (IC95%)
Both normal 0.91 0.74 0.59 0.95 3.51 0.12 0.001
ows: (0.620.98) (0.550.87) (0.360.78) (0.770.99) (1.806.81) (0.020.81)
prediction of
CKD
Both 0.74 0.91 0.95 0.59 8.15 0.27 0.001
abnormal (0.550.86) (0.620.98) (0.770.99) (0.360.78) (1.2453.51) (0.150.55)
ows:
prediction of
PE
F I G U R E 2 : Summary suggestions according to the ow pattern in patients presenting with proteinuria and hypertension in pregnancy. Basic
nephrological evaluation includes clinical history, as recorded by the nephrologist, renal clearances, GFR assessment by the common formulae,
24 h proteinuria, kidney and urinary tract ultrasounds. Extensive evaluation includes all of the above plus serum and urinary electrolytes, acid
base balance, basic immunological data and further tests tailored to the most likely clinical hypothesis.
Finally, as the LR+ is the likelihood of a given result in a attention over follow-up, a potentially relevant suggestion in
patient with the target disorder, both normal ows display a clinical practice (Figure 2).
3.5 times higher likehood to be found in CKD than in PE and In our study, there was no difference, or gradation, in arter-
both abnormal ows are 8 times more likely in PE, when com- ial ow patterns in patients with or without GFR loss or ac-
pared with CKD (Table 4). cording to proteinuria; minor differences linked to the
diseases as well as to ethnicity or to other factors may,
however, be evident only in much larger cohorts.
Our data support the concept that proteinuria and hyper-
DISCUSSION tension in CKD and PE do not share the same pathogenesis
and that they may not have the same effect on the foetus
The main results of our study identify two main ow patterns, (Table 3). In PE, a primary defect of placentation is presently
one highly suggestive of CKD (both normal ows) and one considered the trigger for a series of events ultimately resulting
highly suggestive of PE (both altered ows) (Table 3, Figures 1 in generalized endothelial dysfunction via oxidative stress; the
and 2). The differences were statistically signicant (normal highly signicant correlation with the presence of altered
ows in discriminating CKD versus PE: P = 0.0018; abnormal ows, mirroring the presence of an abnormal placental vascu-
ows identifying PE versus CKD: P = 0.0233). The intermedi- lar tree, supports this interpretation [1, 2, 12]. Conversely, the
ate patterns (mixed ows, grouping cases with one normal presence of normal uterine and placental ows, highly predic-
and one abnormal ow) can be interpreted as needing further tive of CKD, supports the hypothesis that in CKD the
1204
G.B. Piccoli et al.
endothelial dysfunction is limited to the kidney and does not
affect placental development. ETHICAL COMMITTEE
The strength of this paper is its novelty: it represents the
rst attempt to apply Doppler criteria to differentiate between The study was approved by the Ethics Committee of the San-
CKD and PE, indeed showing a highly signicant correlation tAnna Hospital, University of Torino. No test was performed
between the ow pattern and the two diseases. The correlation for the sake of the present analysis, which relied on routine
is highly relevant from the clinical point of view, strongly clinical assessments.
suggesting the presence of either PE or CKD in patients with
both abnormal or both normal uterine and umbilical ow
patterns and identifying an intermediate pattern, mainly con- AC K N O W L E D G E M E N T S
sisting in normal umbilical and altered uterine ows, requiring
further clinical attention (Figure 2). To Dr. Peter Christie for his careful language revision.
This study has several limitations, partly shared by retro-
spective studies: it relies on clinical denitions, which are
qualitative and with a degree of approximation; it evaluates the FUNDING
data according to the clinical charts and the different archives,
No nancial support was obtained for this study. The results
built for different purposes; the numbers are not high enough
presented in this paper have not been published previously in
to allow stratication by important parameters, such as gesta-
whole or part, except in abstract format.
tional age at test, level of proteinuria, CKD stage and type of
ORIGINAL ARTICLE
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