Professional Documents
Culture Documents
Pre-Eclampsia Is A Valuable Opportunity To Diagnose Chronic Kidney Disease - A Multicentre Study
Pre-Eclampsia Is A Valuable Opportunity To Diagnose Chronic Kidney Disease - A Multicentre Study
Gianfranca Cabiddu1, Claudia Mannucci2,3, Antioco Fois2, Stefania Maxia1, Antoine Chatrenet2,
Sarah Osadolor2,4, Emily Kimani2,4, Massimo Torreggiani 2, Rossella Attini5, Bianca Masturzo5,
Marie Thérèse Cheve6 and Giorgina Barbara Piccoli2,7
1
Department of Nephrology, Brotzu Hospital, University of Cagliari, Cagliari, Italy, 2Department of Nephrology, Centre Hospitalier, Le Mans,
France, 3Department of Nephrology, University of Pisa, Pisa, Italy, 4Medical School of Alberta, Alberta, Canada, 5Department of Obstetrics,
University of Turin, Turin, Italy, 6Department of Obstetrics, Centre Hospitalier Le Mans, Le Mans, France and 7Department of Clinical and
Biological Sciences, University of Turin, Turin, Italy
experienced an episode of PE [3, 10]. The first study was aimed (560 000 inhabitants). Patients with severe PE, haemolysis,
at quantifying common risk factors in end-stage kidney disease elevated liver enzymes and low platelets (HELLP) or other
and PE, matching two cohorts of patients, one derived from the relevant obstetric pathology are routinely referred to CHM.
US Renal Data System, and one of the women who gave birth According to the hospital management system, in 2017–19, the
in Olmsted County, Minnesota. In a small cohort of 44 women estimated annual incidence of PE was 3–3.5%.
that started renal replacement therapy on average 17 years after The Azienda Ospedaliera Brotzu, Cagliari, is the largest hos-
pregnancy, the incidence of previous PE was 18%; overall in pital in Sardinia, an Italian island with 1.6 million inhabitants.
21% of the cases CKD was evident before the first pregnancy; The obstetric ward follows 800–1000 deliveries per year,
no data were, however, available on pre-existing CKD and PE offering care for high-risk pregnancies (thalassaemia, diabetes,
[3]. kidney and autoimmune diseases). Since 1995, a nephrology
In a pilot study of our group, the records of 99 women who outpatient service is dedicated to kidney diseases in pregnancy.
had experienced an episode of PE in our hospital in 2017 were According to the hospital data, the annual incidence of PE was
examined; in this initial study, we did not exclude multiple 5% in 2017–19.
pregnancies, and divided the evaluation into CKD versus no-
CKD [10]. Definitions employed
To overcome the limitations of a single-centre study, with CKD was defined according to the 2002 Kidney Disease
small sample size, and to try to adjust for confounders, such as Outcomes Quality Initiative classification and stratification:
multiple pregnancies, we undertook the present multicentre kidney damage for 3 months as defined by structural or
study. We gathered data in the same period (2017–19) in two functional anomalies of the kidney, with or without decreased
nephrology centres (Le Mans, France and Cagliari, Italy). glomerular filtration rate (GFR), manifest by either pathological
The study’s primary objective was to assess the prevalence and abnormalities or markers of kidney damage, including abnor-
the characteristics of the newly diagnosed CKD in women who malities in the composition of blood or urine, or abnormalities
had experienced an episode of PE; furthermore, we tried to in imaging tests; or GFR <60 mL/min/1.73 m2 for 3 months
identify the characteristics, if any, of PE occurring in the context with or without kidney damage [11].
of CKD. In the cases that attended one or more consultations in ne-
We named the study with the acronym PRE-Eclampsia phrology, CKD staging was confirmed at least once, at a dis-
Early CKD Diagnosis, to underline the possibility of profiting tance of at least 3 months, after the initial evaluation.
from the occurrence of PE to allow early CKD diagnosis. Otherwise, cases waiting for confirmation of CKD, or
with unclear data, were classified as unclear diagnosis-ongoing
MATERIALS AND METHODS work-up.
eGFR at diagnosis was not considered, due to its variable
Settings of study
behaviour in PE, and only data available for at least 3 months
This study was undertaken in France (Le Mans, Sarthe after delivery were considered for definition of persistent micro-
district in Central France) and Italy (Cagliari, Sardinia Island). albuminuria or reduced eGFR. Furthermore, while severe PE
The Centre Hospitalier Le Mans (CHM), one of the largest may reduce the eGFR, hyperfiltration is common in pregnancy
non-university hospitals in France, has an obstetric service with and data recorded shortly after delivery may still reflect this
3500 deliveries per year; dedicated consultations for women physiological adaptation. In this context, to avoid overestima-
experiencing an episode of PE have been available since 2017 tion of the prevalence of CKD, we chose to risk the bias of un-
[10]. The Obstetric Unit is the only tertiary care in the Sarthe derestimation, considering as without CKD the women who
Patients with PE Patients with PE Patients Patients with PE Patients with PE Patients
superimposed on confirmed on without PE superimposed on confirmed on without PE
CKD, followed by clinical chart (unconfirmed CKD, followed by clinical chart (unconfirmed
a nephrologist assessment: diagnosis): a nephrologist assessment: diagnosis):
in pregnancy: 123 519 in pregnancy: 172 89
18 1
1 1
Hospital discharge codes: preeclampsia, eclampsia, HELLP, Hospital discharge codes: preeclampsia, eclampsia, HELLP
hypertensive disorders of pregnancy
FIGURE 1: Study flowchart. In Le Mans, the codes relative to PE, eclampsia and HELLP were analysed (262 codes, 89 miscoded—hypertensive
disorders of pregnancy without proteinuria or other markers of PE; one patient followed-up conjointly with the nephrologist), since a previous
study showed misclassification of PE as hypertensive disorders of pregnancy in <5% of the cases [10], while the code PE was commonly chosen
in the case of other hypertensive disorders of pregnancy. In Cagliari, all the codes of hypertensive disorders of pregnancy were assessed, since
at a preliminary random sampling of the data, both coding errors were found to be present.
separately, since microalbuminuria may be a consequence of PE The comparison of proportions was made with the chi-
and a marker of the increased risk of CKD after PE. squared or the Fisher’s exact test according to the subsampling
size involved.
The outcome ‘no evidence of CKD’ was tested against ‘evi-
Statistical evaluation
dence of kidney involvement or possible kidney involvement’
The statistical analysis was performed with SPSS version 14 (including in this definition the three categories of: CKD; ongo-
(IBM Corp., Armonk, NY, USA). ing diagnostic work-up and microalbuminuria) by means of
Results were displayed with the median and the interquartile multiple logistic regression, after testing for collinearity. The
range (IQR). choice of the covariates to include in the multivariate model
With respect to the diagnosis of CKD, patients were divided was based on either the statistical significance at the univariate
into four groups: evidence of CKD diagnosis; no evidence of analysis, or the well-acknowledged clinical relevance (for in-
CKD diagnosis; unclear CKD diagnosis (e.g. intermittent pro- stance, age and week of delivery).
teinuria; possible kidney scars, waiting for imaging confirma- In the regression model, we tested the relationship with age
tion; unexplained early-onset hypertension and family history (dichotomized at the median, i.e. 34 years), week of delivery (di-
of CKD); isolated microalbuminuria following the PE episode. chotomized at 37 weeks), BMI before pregnancy (dichotomized
The continuous series were tested for normality using the at 25 kg/m2), small for gestational age (<10th centile) and pri-
Shapiro–Wilk test, and homoscedasticity with Leven’s test. miparity. The model employed a backward deletion method
According to the conditions of application, for comparing two and standardized residuals were verified.
groups (e.g. seen in nephrology versus not seen in nephrology), Temporal series (e.g. weeks of delivery) were visually ana-
the independent Student’s t-test and Wilcoxon rank-sum test lysed with the inversed Kaplan–Meier curves and the differen-
were used. To compare three or more groups, one-way analysis ces were tested through the log-rank test. Cox regression
of variance and Kruskal–Wallis test were used. analysis was performed through a backward deletion method to
Le Mans Cagliari
All cases Le Mans Evaluation in Evaluation on P-value Cagliari Evaluation in Evaluation on P-value P-value
all cases nephrology clinical charts (evaluation) all cases nephrology clinical charts (Evaluation) (Le Mans—
Cagliari)
N 282 162 72 90 120 39 81
Baseline data and risk factors
Age, median (IQR), years 33 (9) 30 (8) 31 (11) 29 (7) 0.097 36 (6) 36 (7) 36 (6) 0.747 <0.001
Age 40 years, n (%) 43 (15.2) 15 (9.3) 11 (15.3) 4 (4.4) 0.018 28 (23.3) 9 (23.1) 19 (23.5) 0.963 0.001
Parity (first), n (%) 145 (51.6) 81 (50.3) 36 (50.0) 45 (50.6) 0.943 64 (53.3) 18 (46.2) 46 (56.8) 0.274 0.616
Known HTA, n (%) 52 (18.4) 29 (17.9) 12 (16.7) 17 (18.9) 0.714 23 (19.2) 13 (33.3) 10 (12.3) 0.006 0.786
Known diabetes, n (%) 13 (4.6) 2 (1.2) 1 (1.4) 1 (1.1) 0.999 11 (9.2) 5 (12.8) 6 (7.4) 0.336 0.002
History of PE, n (%) 52 (18.4) 26 (16.0) 14 (19.4) 12 (13.3) 0.292 26 (21.7) 11 (28.2) 15 (18.5) 0.228 0.344
Week of delivery 28 to • (14.2) 32 (19.9) 19 (26.8) 13 (14.4) 0.052 8 (6.7) 2 (5.1) 6 (7.4) 0.999 0.002
<34, n (%) • 59
Week of delivery 34 (21.0) 31 (19.3) 12 (16.9) 19 (21.1) 0.501 28 (23.3) 12 (30.8) 16 (19.8) 0.181 0.406
to <37, n (%)
Week of delivery 37, n (%) 170 (60.5) 88 (54.7) 32 (45.1) 56 (62.2) 0.030 82 (68.3) 24 (61.5) 58 (71.6) 0.267 0.020
Proteinuria, median (IQR), 0.90 (2.67) 1.70 (3.61) 2.75 (4.36) 1.30 (2.57) 0.037 0.41 (0.79) 0.60 (1.47) 0.34 (0.75) 0.003 <0.001
g/24 h
Caesarian, n (%) 203 (72.0) 105 (64.8) 48 (66.7) 57 (63.3) 0.106 98 (81.7) 33 (84.6) 65 (80.2) 0.562 0.005
HELLP, n (%) 40 (14.2) 26 (16.0) 14 (19.4) 12 (13.3) 0.149 14 (11.7) 8 (20.5) 6 (7.4) 0.036 0.263
ICU maternal, n (%) 14 (5.0) 12 (7.4) 5 (6.9) 7 (7.8) 0.726 2 (1.7) 1 (2.6) 1 (1.2) 0.546 0.001
Offspring data
Weight (g), median (IQR) 2670 (1125) 2378 (1232) 2127 (1490) 2553 (940) 0.010 2915 (681) 2950 (810) 2900 (660) 0.931 <0.001
Weight <2500 g, n (%) 115 (40.8) 85 (52.5) 44 (61.1) 41 (45.6) 0.027 30 (25.0%) 10 (25.6) 20 (24.7) 0.910 <0.001
Weight <1500 g, n (%) 13 (13.5) 30 (18.5) 22 (30.6) 8 (8.9) <0.001 8 (6.7%) 1 (2.6) 7 (8.6) 0.272 0.007
Centiles, median (IQR) 20 (53) 10 (40) 9 (25) 14 (47) 0.261 32 (50) 31 (56) 32 (46) 0.181 <0.001
Centiles <10, n (%) 99 (35.1) 77 (47.5) 38 (52.8) 39 (43.3) 0.313 22 (18.3) 5 (12.8) 17 (21.0) 0.279 <0.001
Centiles <5, n (%) 67 (23.8) 55 (34.0) 22 (30.6) 28 (31.1) 0.476 12 (10.0) 1 (2.6) 11 (13.6) 0.101 <0.001
NICU, n (%) 80 (28.5) 37 (22.8) 21 (29.2) 16 (17.8) 0.151 43 (35.8) 14 (35.9) 29 (35.8) 0.992 0.023
NICU, median (IQR), days 8.5 (15) 7 (29) 31 (35) 5.5 (4) 0.180 9 (11) 12 (10) 8 (11) 0.320 0.607
n, cohort size; HTA, arterial hypertension; ICU, intensive care unit; NICU, neonatal intensive care unit. In bold: statistically significant differences.
1493
their presence was not associated with a specific pattern of PE
(Le Mans—
(Supplementary data, Table S3).
Cagliari)
0.995
0.383
0.906
0.166
P-value
Multiple regression analysis and Cox analysis
In the multiple regression analysis, the outcome ‘any kind of
(evaluation)
kidney involvement’ (including CKD diagnosis, microalbumi-
P-value
<0.001
<0.001
<0.001
0.819
nuria and ongoing work-up) was confirmed as significantly as-
sociated with preterm delivery (adjusted odds ratio: 1.761;
P ¼ 0.035, unadjusted odds ratio: 1.797; P ¼ 0.027), whereas
age, centile <10, BMI and parity were not (Table 5).
Evaluation on
clinical charts
5 (6.2)
ated with CKD (higher probability of earlier delivery in the
81
0
presence of signs of kidney involvement), after adjustment for
age, BMI and parity (Table 6). No difference was found after ad-
justment for centre.
Evaluation in
nephrology
18 (46.2)
12 (30.8)
Cagliari
7 (17.9)
DISCUSSION
2 (5.1)
39
83 (69.2)
all cases
Cagliari
7 (5.8)
7 (5.8)
120
0.001
0.093
75 (83.3)
3 (3.3)
2 (2.2)
90
21 (29.2)
29 (40.3)
15 (20.8)
Le Mans
7 (9.3)
Italic P-values in the case of one cell equal 0. In bold: statistically significant differences.
17 (10.5)
Le Mans
all cases
10 (6.2)
the age group 25–44 years has been estimated around 5% in the
162
24 (8.5)
282
CKD, n (%)
Overall P-value
Of note, only about two-thirds of patients diagnosed with CKD small for gestational age was not different. The difference in the
were in Stage 1, while 13/54 were in Stage 2 (24.1%) and 6/54 duration of pregnancy is significant in the univariate and multi-
(11.1%) in Stage 3 (Supplementary data, Table S1). variate logistic regressions, results also from the analysis of the
While in most of the cases the diagnostic clues were based delivery curve (Kaplan–Maier) and is confirmed in the Cox
on imaging and/or clinical history (imaging data were funda- analysis, after adjustment for age, BMI and parity (Tables 5 and
mental for diagnosis in 32/54 cases), we cannot exclude that in 6; Figure 2). No centre effect was likewise detected.
some cases diagnosed upon persistence of proteinuria or reduc- The differences in timing of delivery are not fully explained
tion of the kidney function this might be the result of the PE ep- by the presence of other clinical features of PE: patients with
isode in itself; only eight cases were diagnosed solely upon and without CKD have similar BMI, and weight gain, while
biochemical data. Of note, one patient was later diagnosed with patients with diagnosis of CKD are significantly older and with
membranous nephropathy and two had persistent haematuria higher prevalence of previous hypertension than patients with-
and proteinuria, while CKD was in Stage 3 in two further cases out sign of CKD. The differences are, however, of limited value
(Supplementary data, Table S1). To try to limit the bias of con- for allowing a clear clinical discrimination (hypertension: 23.3%
sidering as CKD those cases whose renal derangements result versus 14.4%; age 37 versus 31 years; Table 3). This lack of
from PE, patients with persistent microalbuminuria were con- highly specific features supports a policy of nephrology evalua-
sidered as a separate category. tion for all patients having experienced a PE episode.
The second main result is that, when PE is associated with a The reasons why a pregnancy in which PE is superimposed
previously undiagnosed CKD, it is characterized by a gestation on CKD should be shorter than a pregnancy not in the context
time 1 week shorter. The duration of pregnancy is the only of CKD are not clear. While in many of the cases the diagnostic
difference in the features of PE in patients with or without signs hints suggest that CKD was already present [small kidneys, kid-
of CKD found in our study, while the risk of having a child ney scars and autosomal dominant polycystic kidney disease
All cases
Week of delivery
1.0
suggestions of a higher incidence of ‘late maternal’ PE in CKD
CKD status patients [25–27]. A different signature of placental biomarkers
No CKD
Evidence of CKD has been described in known CKD, PE without known CKD
0.8 and superimposed PE on CKD [28–30]. Prospective studies
Overall [Log-rank]: 0.007
should be addressed at combining these suggestions, by propos-
Cumulative delivery