Pregnancy in CKD

Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e18
Contents lists available at ScienceDirect
Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn
11
Pregnancy in CKD: Questions and answers in a

changing panorama
Giorgina Barbara Piccoli, MD a, *, Gianfranca Cabiddu, MD b,
Rossella Attini, MD c, Federica Vigotti, MD a,
Federica Fassio, MD c, Alessandro Rolfo, PhD c,
Domenica Giuffrida, MD c, Antonello Pani, MD b,
Piero Gaglioti, MD c, Tullia Todros, PhD c
a
SS Nefrologia, Department of Clinical and Biological Sciences, ASOU San Luigi Gonzaga, University of
Torino, Turin, Italy
b
SCDU Nephrology, Brotzu Hospital, Cagliari, Italy
c
Materno-Foetal Unit, Department of Obstetrics, ASOU OIRM S Anna, University of Torino, Turin, Italy
Keywords:
pregnancy
chronic kidney disease (CKD)
proteinuria
hypertension
glomerulonephritis and interstitial
nephropathies
dialysis and transplantation
Chronic kidney disease (CKD) is increasingly encountered in

pregnancy because of greater diagnostic awareness, which is a
reection of the newer, broader denitions (i.e., any changes in
blood or urine composition or at imaging, or a glomerular ltration
rate (GFR) of <60 mL/min lasting at least 3 months) and of
increased incidence (higher maternal age and better outcomes of
several kidney diseases).
CKD is extremely heterogeneous and may be described by the
degree of GFR reduction (CKD stages), the presence of proteinuria
and hypertension and the type of kidney disease; the risk of
adverse pregnancy-related events increases as GFR decreases and
it is affected by proteinuria and hypertension. Specic risks are
reported in various diseases such as lupus nephropathy or diabetic
nephropathy. While transplantation at least partially restores
fertility in end-stage kidney disease, pregnancy on dialysis is
increasingly reported.
This chapter deals with the available evidence on the management
of CKD patients in pregnancy.
2015 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: 39 3475514005.

E-mail addresses: gbpiccoli@yahoo.it, giorgina.piccoli@unito.it (G.B. Piccoli).
http://dx.doi.org/10.1016/j.bpobgyn.2015.02.005
1521-6934/ 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Piccoli GB, et al., Pregnancy in CKD: Questions and answers in a
changing panorama, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://
dx.doi.org/10.1016/j.bpobgyn.2015.02.005
G.B. Piccoli et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e18
Introduction
Chronic kidney disease: a matter of denition
Almost 20 years ago, the National Kidney Foundation started a campaign entitled The Fight against
the Silent Killers [1]. These silent killers were chronic kidney diseases (CKD), and they were dened as
silent because they were frequently asymptomatic until renal failure occurred, and they were killers
as kidney disease affects survival [1e3]. Presently, after acknowledging the risks in elderly patients, the
denition of silent killer may be applied to CKD in pregnancy, as these often undiagnosed diseases are
a main cause of morbidity in pregnancy [4,5].
CKD is currently broadly dened as any alteration in renal morphology, imaging or function, or by a
glomerular ltration rate (GFR) <60 mL/min for at least 3 months [1,6,7]. Despite the revisions and
criticisms, the advantage of this denition is that it focuses on the earlier CKD stages, when kidney
function is still normal and the potential for recovery is higher [1].
Serum creatinine, which is derived from muscle mass, is physiologically lower in women and in
small body size; furthermore, in pregnancy physiological hyperltration may mask an initial GFR
reduction, thus leading to underestimation of CKD in pregnancy [6,7]. Changes in GFR are not an early
marker of disease, as it starts decreasing when >50% of the renal parenchyma is damaged; hence, it is
important to identify CKD in stage 1, when kidney function is normal and CKD is revealed by proteinuria, haematuria, electrolyte derangements, tubulo-interstitial diseases, single kidney (including
kidney donation) or even simple kidney scars due to previous acute pyelonephritis [1].
On the basis of these broad denitions, the prevalence of CKD reaches 3% in women in childbearing
age, a signicant difference as compared to previous denitions, which were based upon high creatinine levels that probably identied <10% of cases [5,6].
Pregnancy is a very important opportunity to diagnose kidney disease in an apparently healthy
woman. In our experience, CKD is diagnosed or acknowledged as a risk factor in pregnancy in at least
40% of cases [8]. The physiological increase in GFR, the lack of validated formulae for GFR assessment in
pregnancy and the clinical and laboratory overlap with pre-eclampsia (PE) are important challenges for
early diagnosis as discussed below [9e11]. We also discuss how CKD bears a risk of adverse pregnancyrelated outcomes starting from the early stages, and even minor signs of CKD should be taken into
consideration [8,12e15].
In the following paragraphs, we summarise the available evidence and its limits, sharing our points
of view on the diagnosis and care of CKD in pregnancy.
What is inside CKD?
Regardless of how it is dened, CKD is a syndrome and not a disease; its main descriptors are kidney
function, kidney disease, proteinuria and hypertension (Fig. 1).
Kidney function, which is subdivided by the Kidney Disease Outcomes Quality Initiative (K-DOQI)
denition into ve stages, is probably the most powerful descriptor of the severity of the disease and of
the risk of complications [1,12e21].
As a rule, immunologic and systemic diseases (such as glomerulonephritis, or diabetic or lupus
nephropathies) are more frequently associated with adverse pregnancy-related events; conversely,
interstitial kidney diseases share a higher risk of upper urinary tract infection (UTI), unexplained
oedema or stone disease [22e27].
Hypertension and proteinuria are independently correlated with CKD progression and with adverse
pregnancy-related events, and, when present, PE may be difcult or impossible to diagnose [28,29].
Limits of the currently reported evidence
Despite the increased interest, evidence regarding CKD in pregnancy is scant and heterogeneous.
There are several reasons for this, including fragmented literature that lacks a common language, the
involvement of various diseases, the fact that it is subject to referral biases and that it is inuenced by
the study setting [12,13].
Fig. 1. The relationship among CKD, proteinuria and hypertension is complex: proteinuria persisting >3 months (from microalbuminuria to nephrotic proteinuria) is by denition a marker of CKD; hypertension may occur in the absence of CKD, but hypertension is a risk factor for CKD and its prevalence increases with CKD stage; kidney disease is the most common cause of
secondary hypertension in young women. CKD: chronic kidney disease is dened as either kidney damage or GFR <60 mL/min
1.73 m2 for 3 months. Kidney damage is dened as pathologic abnormalities or markers of damage, including abnormalities in
blood or urine tests or imaging studies [1]. Proteinuria: microalbuminuria, albumin excretion below 300 mg/day. Nephrotic proteinuria 3 g/day. Nephrotic syndrome: nephrotic proteinuria plus hypoalbuminaemia, oedema and/or hypercholesterolaemia.
There are at least four reasons for these limitations. Firstly, the changes in denitions that have only
recently been integrated into obstetric nephrology make pooling of data difcult. Secondly, CKD is
heterogeneous as it is made up of several families of diseases. Thirdly, progression of CKD differs from
patient to patient, and the role of disease modulators (including proteinuria, hypertension, nutritional
status and lifestyle) is still unknown. Fourthly, the lack of low-risk pregnancy control groups in many
studies hinders contextualization of the results as the baseline risks vary widely around the world, and
they depend on genetic background, lifestyle and health-care systems.
Risks for the mother and child
There are three main risks for CKD mothers: worsening of kidney function, development of the
hypertensive disorders of pregnancy with possible persistence of hypertension after delivery and death
[4e6,12e20].
There are four main risks for the child: prematurity (with all its sequelae), inheritance of maternal
diseases, malformations and side effects of maternal therapies [4e6,12e20].
Main risks for the child
The main risks for the foetus are linked to prematurity. A detailed discussion is beyond the scope of
this review; however, it must be mentioned that an increase in CKD in adulthood has been reported in
small babies, even if this term was often employed ambiguously, overlapping small, small-for
gestational-age (SGA) and intrauterine growth-restricted babies [30e33].
Children of CKD mothers are not reported as being at a higher risk of malformations [5,6,12,13,34].
The only exception is one study that reported a higher incidence of malformations in children of
mothers with nephropathy and diabetes as compared to diabetes alone [35].
The genetics of kidney diseases is only partially known. Besides the most common Mendelian
diseases, such as autosomal dominant polycystic kidney disease (ADPKD) and Alport syndrome (heterogeneous, usually X-linked), many genes have not been identied: this is the case with immunoglobulin A (IgA) nephropathy, probably the most common form of glomerulonephritis in young adults,
with 30% positive family history [36,37]. Inheritance is often multifactorial, as in vesico-ureteral reux,
while other malformations of the urinary tract are linked to various genes [38e40]. Hence, the possibility that kidney diseases recur in the offspring cannot be excluded and should probably be
mentioned in counselling [41].
Commonly used drugs in CKD and potential effects on the foetus
CKD therapy is often complex and multiple drugs are routinely needed in advanced CKD, systemic
diseases and kidney transplantation. Tables 1 and 2 summarise some information on the most
commonly used drugs in CKD, that is, antihypertensive and immunosuppressive drugs with particular
regard to CKD patients [42e60].
While the advantages of universal treatment for mild to moderate hypertension are controversial in
the general population, nephrologists usually prefer normal or lowenormal blood pressure targets.
However, to the best of our knowledge, no randomised trials have ever been performed involving
hypertensive CKD patients in pregnancy, thus leaving each group free to individually dene the choice
of the treatment policy [44].
An important point regards the discontinuation of potentially dangerous drugs. Contrary to the
guidelines on hypertension and pregnancy, many nephrologists, including our group, prefer to discontinue angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor inhibitors on the
occasion of a positive pregnancy test, at least in compliant, reliable patients, with a regular menstrual
cycle agreeing to perform the test immediately after missing menstruation. This is motivated by the
absence of a carry-over effect (meaning that once stopped, they do not have any lingering teratogenic
effect) and by the fact that, in particular in patients with proteinuric diseases, this policy allows us to
maximize nephroprotection and to start a pregnancy with minimal proteinuria (Table 1).
On the contrary, preventive discontinuation and/or switch to a different type of drugs may be
indicated for several immunosuppressors, because of the risk of are-ups of immunologic diseases,
such as systemic lupus erythematosus (SLE) or of rejection after kidney transplantation if the changes
are performed during pregnancy (Table 2).
Pregnancy in the various CKD stages
Renal function impairment is a major determinant not only of pregnancy outcomes but also of
fertility, which is progressively lost across CKD stages and only partially restored after transplantation
[61,62]. As mentioned, the risk of adverse pregnancy-related events increases with renal function
impairment [6,8e21]. Quantifying the risk is difcult due to the heterogeneity of the studies. In a recent
meta-analysis, a combined outcome was analysed (merging the risks of gestational hypertension, PE,
eclampsia and maternal mortality), and the risk was found to range from 2 to >10 times that of the
control population [12]. Fig. 2 reports the risk pattern across stages obtained in a large series of CKD
patients observed in two Italian settings (the ToCOS cohort, Torino Cagliari Observational Study).
Special considerations: stages 1e2
Renal function is normal in stage 1 CKD (GFR >90 mL/min) and in the grey area of mildly reduced
kidney function in stage 2 (90e60 mL/min), with persistent signs of disease, including proteinuria,
haematuria, kidney scars, electrolyte disorders or kidney stones. Interestingly, a baseline risk of adverse
Drug
Main features
Usually considered rst-choice drugs [42e44]

Alpha-methyldopa
Widely used in pregnancy, with no reported negative effects on the foetus or on
its subsequent development. May not be able to correct severe hypertension in CKD.
Nifedipine
The long-acting drug is most commonly used in hypertension in pregnancy.
The increase in peripheral oedema may be a relevant side effect in CKD patients.
Labetalol
Usually well tolerated, should be avoided in subjects with asthma. In an RCT, it was
shown to be comparable to alpha-methyldopa [45]
Usually considered second-choice drugs [42,43]
Beta blockers
The main drawback in older studies was foetal growth restriction, possibly as an effect
of overzealous correction [44]. Beta1-selective beta blockers (atenolol) are more often
involved. Beta blockers may be more effective than alpha-methyldopa in severe hypertension,
alone or in combined therapy. At delivery, they may induce hypoglycaemia, hypotension and
bradycardia (usually mild and transient)
Clonidine
The effect is similar to alpha-methyldopa; side effects may be more common and hypertensive
rebounds at discontinuation are common; slowing foetal growth is occasionally reported [46]
Diuretics
They are usually avoided in pregnancy except for nephrological or cardiological indications.
Thiazides may be continued in patients previously on treatment [47]. In selected cases with
Gitelman syndrome, amiloride may be employed [48].
To be avoided [42,43]
Short-acting nifedipine
Contraindicated by the FDA, RCOG and AIPE due to the risk of severe sudden hypotension
with detrimental effects on placental ows
ACE-i
Both drugs are contraindicated in all phases of pregnancy because of the risk of several
ARB and related drugs
major malformations, including cardiovascular, central nervous system, renal and bone
malformations [49]. See text on pre-emptive discontinuation.
FDA
SOGC
1-A
1-A
1-A
D atenolol
B pindolole
C metoprolol.
1-B
C
B hydrochlorothiazide amiloride
D
C 1st
D 2nde3rd trimester
II 2E
Notes: FDA, site of the Food and Drug Administration [42]; FDA rating: A, controlled human studies show no risk; B, no evidence of risk in studies; C, risk cannot be ruled out; D, positive
evidence of risk; and X, contraindicated in pregnancy.
SOGC: Society of Obstetrics and Gynaecology of Canada: guidelines 2014 [43].
Table 1
Main antihypertensive drugs in pregnant patients with CKD.
Drug
Main features
Usually considered as relatively safe, when absolutely needed [50e52]

Azathioprine
This is the most widely used immunosuppressive drug. It is teratogenic in animal models, but not in humans, possibly because
the foetal liver is not able to activate the drug. K-DIGO and European Best Practice Guidelines
suggest switching from mycophenolate to azathioprine before pregnancy [50e52]
Cyclosporine A
This calcineurin inhibitor has not been associated with increased teratogenicity; however, small-for-gestational-age
babies and preterm delivery have been reported, possibly due to the maternal disease and not specically to the drug;
levels may vary in pregnancy and the hypertensive, hyperglycaemic and nephrotoxic effects should be mentioned [53]
Tacrolimus
The drug has similar effects and side effects to Cyclosporine A; as it is a relatively new drug, experience is more limited
than with the previous drug [54]
Steroids
Together with azathioprine, these are the most often employed and best-known drugs. The most frequently used
short-acting corticosteroids include prednisone, methylprednisolone and prednisolone, while betamethasone and
dexamethasone are among the long-acting drugs. No major malformations have been reported, and the issue of
labio-palatoschisis is debated. A higher risk of premature rupture of membranes has been reported. Other relevant side
effects include infectious risk and the increased risk of gestational diabetes [55]
Hydroxychloroquine
This synthetic antimalarial agent crosses the placenta but was not found to be associated with foetal toxicity [56]
To be avoided [50e52]
Cyclophosphamide
This alkylating agent is contraindicated in pregnancy; a few reports suggest that pregnancy termination is common in the
case of inadvertent use or need for life-saving therapy. A few positive reports, mainly in women with SLE are also available [57]
Methotrexate
This teratogenic agent is also employed for extrauterine pregnancy termination. Discontinuation for one to three menstrual
cycles is usually indicated [50e52]
Mycophenolate
Severe foetal malformations are reported, mainly involving cardiovascular and cranial malformations. Discontinuation for at least
6 weeks, to stabilize kidney function, is usually indicted after kidney transplantation [58,59]
m-Tor inhibitors
Very few studies considered their use in pregnancy. They are teratogenic in animals and discontinuation in humans is a matter
of debate; KDIGO guidelines suggest discontinuation in anticipation of pregnancy [58,60]
FDA
D
C
C
N
D
X
D
C
Notes: FDA site of the Food and Drug Administration [42]; FDA rating: A, controlled human studies show no risk; B, no evidence of risk in studies; C, risk cannot be ruled out; D, positive
evidence of risk; N, not classied; and X, contraindicated in pregnancy.
Table 2
Main immunosuppressive drugs in pregnant CKD patients.
Fig. 2. Risk patterns in the various CKD stages in the ToCOS cohort (Torino Cagliari Observational Study), data collection on 504 liveborn singleton deliveries in CKD patients followed up in the two largest facilities for CKD in pregnancy in Italy.
pregnancy outcomes persists also in subjects without hypertension, proteinuria or systemic diseases:
in three large series of kidney donors, the risk of adverse pregnancy-related events, mainly PE, was
about twice as high after donation than before, even if the odds of PE remained low due to careful
donor selection [63e65]. A study on a Saudi Arabian population showed that even in these early stages
of CKD, the risk of prematurity as well as the need for neonatal intensive care unit (NICU) and caesarean
sections increased by two- to sixfold from CKD stage 1 to stage 2 [66]. Progression of kidney disease is
rare in these disease stages, as suggested by a large series of IgA nephropathy and early diabetic nephropathy; analogous data were found in our stage 1e2 CKD patients [8,14,25,67].
Therapeutic approaches: Therapeutic interventions are mainly linked to the baseline disease, proteinuria and hypertension (see the following paragraphs). In their absence, the only therapeutic tool is
close clinical surveillance, with attention to the signs heralding hypertensive disorders of pregnancy
[8,14,68].
Counselling hints: There is still little evidence on the outcome of early CKD in pregnancy. In most
series, preterm delivery is two- to fourfold higher (in our experience mainly late preterm); the odds of
needing NICU or of having a small baby are consequently increased. The reasons for this increase, in the
absence of hypertension and proteinuria, are not known. Hence, counselling should underline the
uncertainties and the need for close surveillance of all pregnancies in CKD patients [8,14,68].
Special considerations: stage 3
CKD stage 3 is dened by a GFR of 60e30 mL/min. This implies a decrease in kidney parenchyma
ranging from 15% to 30%, following the rule of thumb that the amount of renal tissue is about half of
the renal function. While in elderly patients this may be the result of vascular ageing, in young patients
it is mainly the result of progressive disease; consequently, the prevalence of glomerular and systemic
diseases is higher in this subset [8,14,25,67].
Therapeutic approaches: Besides treatment for the underlying disease and, when needed, the
metabolic correction described for CKD stages 4e5, in our experience a moderate decrease in dietary
protein intake with veganevegetarian diets may be of help, most likely by counterbalancing the
effects of hyperltration on the remnant nephrons [69e71]. Strict clinical surveillance is recommended (Table 3).
Counselling hints: The reported risk of kidney function worsening varies in the literature (20e50% of
cases) [12e18]. The prevalence of prematurity increases as kidney function worsens, becoming almost
the rule in stages CKD 4e5 (in our experience >75% of children of CKD stage 3 mothers are born
preterm and about half are delivered before the 34th gestational week). This is closely connected to the
need for NICU that occurred in >40% of the babies in our series (Fig. 2). To our knowledge, there are
currently no studies examining the psychological impact of this need for special care in CKD mothers.
Special considerations: stages 4 and 5 (not on renal replacement therapy)
Kidney function is severely reduced (stage 4: GFR 30e15 mL/min, stage 5: GFR <15 mL/min), and
hypertension and proteinuria are increasingly encountered in CKD stage 4 and 5 patients. Although the
recent guidelines on the start of dialysis have shifted towards lower GFR, some centres prefer to start
renal replacement therapy early in younger patients [72]. Where available, patients in CKD stages 4e5
are frequently wait-listed for pre-emptive transplantation.
Therapeutic approaches: Strict clinical surveillance is fundamental. The importance of the baseline
disease may decrease when CKD progresses as the end stage involves all of the kidney structures.
Therapy is aimed at correcting the four main metabolic derangements: malnutrition, anaemia, calciumephosphate parathyroid hormone (PTH) balance and acidosis. Malnutrition is frequently reported
as an effect of both the hyper-catabolic effect of advanced CKD and the decreased appetite induced by
acidosis and correlated with urea levels. Malnutrition is a constant threat in advanced CKD, and
attention should be paid to reaching the caloric target of 30e35 kcal/kg/day to reduce protein wasting.
The diet issue is, however, discussed. In our experience, veganevegetarian diets may be used for
counterbalancing the hyperltration of pregnancy, in particular in patients with advanced CKD or
proteinuria, in whom ACE inhibitors and angiotensin receptors inhibitors have to be discontinued. At
least in our single-centre pioneer experience, vegan diets, with a protein intake of 0.7e0.8 g of proteins
kilograms of body weight, strictly controlled for the risk of malnutrition, were safe in pregnancy and
were associated with a lower incidence of SGA babies and possibly with a stabilizing effect on kidney
function and proteinuria [70,71]. However, these promising data need conrmation on a larger scale.
Anaemia, due to erythropoietin decit, is a common threat, and it is associated with impaired intrauterine growth. Erythropoietin does not cross the placenta, and it is considered safe in pregnancy.
The need for erythropoietin usually increases in pregnancy and the optimal response is attained at
ferritin levels of 200e400 ng/mL, thus enhancing the need for iron supplementation [73]. CKD patients
are also at a risk of B12 deciency, in particular when on protein-restricted diets. The calciumephosphate balance is frequently impaired due to the lack of hydroxylation of 25-OH vitamin D in the
kidney. Recently, attention has been drawn to the importance of 25-OH vitamin D [74]. Low vitamin D
levels have been (albeit non-consistently) associated with an increased risk of PE and other pregnancyrelated adverse events. As baseline levels are often already low in CKD patients, we suggest correcting
at least the main deciencies.
The lack of regeneration of bicarbonates in the failing kidney is the basis of acidosis, another progression factor for CKD [75]. Acidosis may cause hyperkalaemia, a potential threat in advanced CKD.
Bicarbonate therapy has no contraindications in pregnancy; oral bicarbonate is preferable as intravenous (i.v.) bicarbonate is associated with an acute water and sodium overload.
Counselling hints: Reports on both the risk of GFR worsening and the need for dialysis during or
immediately after pregnancy differ, but they may be estimated as occurring in 50e75% of cases
[18e21]. Our results show a lower incidence (22% CKD 4e5 shifted by one CKD stage or started dialysis), but they are based on a small number of cases (Fig. 2). Proteinuria and hypertension may either
appear or worsen during pregnancy in up to 70e80% of cases.
Disease or condition
Minimal follow-up
Main biochemical tests prescribed
Imaging
Other
Stage 1 CKD [not otherwise

specied (nos)]
4e6 weeks
Renal ultrasounds if not

performed in the
previous year
Stage 2 CKD (nos)
4 weeks
Every 4e6 weeks: urinalysis, urinary culture,

Na, K, Ca, P, albumin, creatinine, urea, uric
acid; clearance and proteinuria on 24-h urine
collection every 10e12 weeks;
Like stage 1, frequency increased to 4 weeks
Same as above
Stage 3 CKD (nos)
3 weeks
Same as above; monthly 24-h urine collection
Same as above
Stages 4e5 CKD (nos)
1e2 weeks
Same as above
Hypertension
According to stage; at least weekly

in the case of non-controlled BP
Same as above; 24-h urine collection twice

monthly
According to stage.
Glomerulonephritis in remission
(CKD stage 1, proteinuria <0.3 g/day)
According to stage; at least monthly

in SLE
Urinalysis every 1e2 weeks, checking for

proteinuria
Proteinuria >0.3 to <3 g/day
According to stage; minimum 4

weeks
Proteinuria>3 g/day
According to stage; minimum 2

weeks
According to stage; if no infection
every 4e6 weeks
24-h proteinuria, clearances and serum

albumin at least monthly; IgG, IgA and IgM;
coagulation with antithrombin III every
10e12 weeks
Same as above; proteinuria at least twice
monthly
According to stage plus urinalysis and urinary
cultures every 1e2 weeks; calciuria in the
case of kidney stones
Nutritional parameters
at start: ferritin, vit D,
B12, folates, albumin,
total proteins
Like stage 1, every
10e12 weeks
Same as above; monthly
in on-diet patients
Same as above; monthly
in on-diet patients
Home BP prole; 24-h
BP monitoring in the
case of doubts
Other tests
according to the type
of glomerulonephritis
(i.e., autoantibodies
in SLE); immunological
prole at start and end
of pregnancy.
Same as above
(glomerulonephritis)
Previous acute pyelonephritis and

diseases at risk of UTI including
malformations and ADPKD
Echocardiography if not
performed in the
previous year
Same as above
Same as above
Same as above
Same as above
Renal ultrasounds every

10e12 weeks, increased
frequency in the case of
dilatation or colic
Table 3
Main indications for nephrological follow-up in the ToCOS units (Torino and Cagliari, Italy); the tests are in addition to routine antenatal assessment.
10
Foetal risks: The prematurity risk is high, being almost the rule in most series [12e17]. The need for
drug therapy may expose the foetus to iatrogenic consequences (Tables 1e2).
Pregnancy on dialysis
Although it was once considered impossible, successful pregnancy on dialysis is now increasingly
reported [76e81]. Most reports involve haemodialysis (HD), but pregnancy may also be successful on
peritoneal dialysis (PD) or haemodialtration [76e83]. Pregnancy occurs on a background of markedly
reduced fertility: the odds of having a live-born baby are reduced by about 100-fold on dialysis and by
about 10-fold after transplantation [82,83]. The probability of delivering a live-born baby once pregnancy is started has risen from about 25% in the 1960se1970s to about 50% in the 1980se1990s and to
>75% in the new millennium. More than 90% of live-born babies are reported in selected settings in
which quotidian and long (overnight) dialysis schedules are applied, thus raising issues on the meaning
of adequate dialysis [78].
Details on dialysis management are beyond the scope of this review. However, a few general rules
are now relatively well established: in the absence of residual kidney function, HD should be planned
6/7 days per week and PD should be intensied. There is a strict relationship between dialysis hours per
week, dialysis efciency, success of pregnancy and duration of gestation. Success is higher in the
presence of residual renal function, in particular when long-hour dialysis is not available. The indications for dialysis start in pregnancy are not dened, but early dialysis start is not incompatible with
a successful pregnancy [81,84].
Counselling hints
A woman on dialysis who undertakes or desires a pregnancy should be advised that experience in
this eld is limited, although it is increasing and improving. She should be told that she has at least a
75% chance of success provided that dialysis is intensied and kept under strict clinical control. While
the risk of malformations is probably the same as it is in the overall population, premature birth has to
be expected, with the need for hospitalization in the intensive care unit and possible short and longterm sequelae related to the degree of prematurity. A mild increase in hypertension and microalbuminuria has been reported in the offspring [82,85].
Pregnancy after kidney transplantation
Kidney transplantation is usually considered the best approach to restoring fertility on renal
replacement therapy [51,86e90]. Pregnancy after kidney transplantation shares the same disease
modulators as pregnancy in CKD (kidney function, hypertension and proteinuria), while the underlying
kidney disease is probably less relevant than the co-morbidities (such as diabetes or cardiovascular
disease). Two points are more specic: the need for immunosuppressive therapy that is shared by
glomerular and systemic diseases, and the risk of rejection. The issue of kidney graft loss during or after
pregnancy has been extensively, although never conclusively, discussed. The guidelines for pregnancy
after kidney transplantation suggest planning pregnancy in the presence of good kidney function,
without proteinuria or hypertension, 1e2 years after transplantation and at least 6 weeks after discontinuing mycophenolic acid or m-Tor inhibitors [51,89,90]. These conditions are optimal, but the
problems related to unplanned pregnancy and to suboptimal renal function remain unsolved, thus
raising clinical and ethical issues and highlighting the need for patient education. According to a recent
systematic review, in the face of a high probability of a live-born baby, the risks are high for PE (27.0%),
gestational diabetes (8.0%), caesarean section (56%) and preterm delivery (46% vs. 12.5% in the US
population) [86].
Counselling hints
Overall, the success rate of pregnancy after kidney transplantation is high, albeit differently
calculated (>90% of cases overcoming the rst trimester, with an overall success rate of 70e80%). The
11
decline in kidney function has been estimated from 0% to about 20%, but patient selection plays a
crucial role. The risk of prematurity, SGA babies and worsening of kidney function are shared by CKD;
conversely, infectious complications are more specically linked to immunosuppression [51,86e90].
The long-term effect of in utero exposure to immunosuppressive drugs is not known and this should
probably be mentioned, together with the other areas of uncertainty [91,92].
Proteinuria
Proteinuria is a hallmark of kidney disease, and when it is above 3 g/day, it is almost invariably
associated with acute or chronic glomerular damage. Conversely, hypertension is frequently associated
with CKD and its prevalence rises as renal function worsens to >90% in CKD stage 5. Whatever the
cause, proteinuria and hypertension are associated with the risk of all adverse pregnancy-related
outcomes in all CKD stages [4e6]. There is no specic therapy for proteinuria in pregnancy besides
treatment of the underlying kidney disease; the most common antiproteinuric agents (ACE inhibitors
and angiotensin II receptor inhibitors) are contraindicated in pregnancy due to their teratogenicity
(Tables 1e2). The risk of massive proteinuria has two main aspects: low maternal plasma protein levels
may induce foetal growth impairment, similarly to malnutrition. A rapid drop in plasma proteins may
reduce utero-placental ows, thus resulting in placental hypoperfusion, a particular threat in subjects
with impaired placentation. Evidence on i.v. albumin administration in pregnancy is scant; albumin
infusion may theoretically temporarily restore plasma volume, but this is counterbalanced by a rise in
proteinuria [93].
As pregnancy is a prothrombotic state, if a woman is nephrotic, we would pragmatically recommend thrombo-prophylaxis with low molecular weight heparin, which is safe in pregnancy.
Hypertension
Unlike hypertension not being associated with CKD, target blood pressure values in hypertensive
CKD pregnancies have not been established. It is presumably wise to avoid overcorrection because of
the risk of reducing utero-placental ows and of foetal growth impairment [43,94]. However, strict
blood pressure control is a precious tool in CKD, and it is effective in reducing proteinuria and slowing
CKD progression. Hence, our group implements strict blood pressure control (ideal target <130/
80 mmHg, acceptable <140/90 mmHg), under careful clinical surveillance [8,14]. This advice is in
keeping with the most recent Control of Hypertension In Pregnancy Study (CHIPS) trial [95].
Differential diagnosis between CKD and PE
PE shares proteinuria and hypertension with CKD [27,28]. The relationship between PE and CKD is
far from being unravelled, and the diseases are mutually related: CKD increases the risk of PE,
pregnancy-induced hypertension and proteinuria; conversely, PE is a risk factor for subsequent CKD
[96e98]. According to the usual denition of PE, proteinuria and hypertension antedating 20 gestational weeks are presumably due to kidney disease. This may not be true in twin pregnancies in which
early and severe PE has been described, and in which the combination with CKD may have explosive
clinical features [99,100].
The denition of PE superimposed on CKD is unclear; worsening of blood pressure control may be
difcult to dene, in particular after an initial blood pressure drop; likewise, an increase in proteinuria
may be a reection of hyperltration, as well as a sign of immunologic are.
There are at least three situations in which the differential diagnosis between CKD and PE may be
impossible on clinical grounds: when CKD ares or develops in pregnancy or in the absence of data
antedating the 20th gestational week.
On the basis of studies by our group, normal utero-placental ow correlated with CKD while
impaired utero-placental ow was linked to PE in patients with proteinuria and/or hypertensive patients in pregnancy [27]. Along the same lines, the ratio between soluble Fms-like tyrosine kinase 1
(sFlt-1) and placental growth factor (PlGF) maternal serum levels may distinguish PE from CKD: in a
small study of our group, normal levels have been associated with CKD but not with PE [28]. While
12
waiting for larger studies, a practical suggestion might be to undertake a diagnostic pathway for CKD in
a pregnant woman with proteinuria and hypertension and normal utero-placental ows and/or in the
case of a normal angiogeniceantiangiogenic prole, at least where these markers are available [27,28].
Kidney biopsy in pregnancy
The best way to differentiate between PE and CKD and the only way to dene the kidney disease is a
kidney biopsy. Kidney biopsy in pregnancy is still a matter of controversy; the pros of the diagnostic
yield have to be balanced with the risks of major bleeding that, according to a systematic review, may
be increased, with a peak of major complications at 23e26 gestational weeks. The relevant complications were observed in 7% of subjects during pregnancy and in 1% after delivery.
While each choice has to be discussed individually, other diagnostic tools such as the analysis of the
selectivity of proteinuria, suggesting minimal change disease or focal glomerular sclerosis and Pla2r in
the diagnosis of membranous nephropathy, may support a non-invasive clinical diagnosis [101]. In
such a context, a therapeutic trial of steroids for new-onset proteinuria in pregnancy that does not have
other features of PE may be a good option, in particular in patients with selective proteinuria (i.e.,
proteinuria mainly constituted by albumin, as minimal change nephropathy, focal segmental glomerulosclerosis and, more rarely, initial membranous nephropathy potentially respond, at least
partially, to steroids).
Pregnancy in the most common renal diseases
Each kidney disease has peculiarities in pregnancy, and a detailed analysis of these peculiarities is
beyond the general scope of this review. Highlighting a few aspects may be of interest, also to underline
the great heterogeneity of CKD and the need for an integrated approach as well as multidisciplinary
obstetrical and nephrological management.
Primary glomerular diseases
The hallmarks of glomerular disease are proteinuria with or without hypertension and haematuria.
IgA nephropathy is the most common glomerulonephritis in the young; in the presence of normal
renal function, the risk of functional impairment is minor, if any. Some authors suggest employing
acetylsalicylic acid since the early phases of pregnancy to favour placentation, in IgA as well as in other
primary and secondary glomerulonephritides, including lupus nephritis [67,102,103].
Ideally, pregnancy should be undertaken in the presence of normal renal function, no or low-grade
proteinuria and normal blood pressure. However, many glomerulonephritides have a progressive
course, and in the presence of chronically impaired renal function, counselling should include discussing the possibility of a further decline, the problems of pregnancy on dialysis and the fact that
transplantation may not solve all problems because of the long waiting lists and, after transplantation,
the need for many drugs and the risk of suboptimal kidney function. Furthermore, with regard to IgA
nephropathy, family clustering is observed in about 30% of patients [104]. This gure should be provided to the patients, and it should lead to periodic testing in the children.
SLE and other systemic autoimmune disorders
SLE may be considered the prototype of a severe and protean autoimmune disease. The literature on
SLE and pregnancy is enormous, and extensive reviews are available [22,23,105].
Four main points should be kept in mind when counselling patients: lupus nephropathy encompasses all the primary glomerular and interstitial morphologic lesions; the overlap with antiphospholipid syndrome is consistent; maternal deaths are now rare in CKD, and almost all the
recently reported ones are associated with SLE; and lupus nephropathy and diabetic nephropathy are
the main causes of perinatal deaths in CKD [13,106,107]. The risk is highest in active SLE, and it is lowest
in patients in clinical remission, who have normal kidney function, normal blood pressure and no
relevant proteinuria. The causes of maternal death vary and encompass the main risks in SLE patients,
13
that is, cardiovascular diseases and infection. Neonatal deaths are associated with disease activity and
with specic autoantibodies, but they may occur in the absence of any known risk factors and also in
term pregnancies [105].
Tubulo-interstitial disorders and chronic pyelonephritis
Tubulo-interstitial disorders encompass several elusive diseases with non-specic histological
pictures, mainly characterised by electrolyte disturbances and renal stone disease e nephrocalcinosis.
Their occurrence may be suspected in the case of early onset of kidney stones, recurrent renal colic and
nephrocalcinosis. The clinically complex nephrocalcinosis-tubular disorders are commonly associated
with hypercalciuria, which often increases in pregnancy, with the intensication of renal colics and
with oedema, which is important in the differential diagnosis with PE [27].
Chronic pyelonephritis, once linked to chronic kidney infections, is now commonly the result of
subsequent episodes of acute pyelonephritis, with the formation of kidney scars. Renal infections may
occur in the presence of several predisposing factors including vesico-ureteral reux, renal malformations, ADPKD and renal stones. The risk of UTIs is higher in pregnancy; however, only one randomized controlled trial (RCT) was carried out on the prevention of recurrent UTI [108]. In agreement
with the trial, we suggest urinalysis and urinary cultures every 1e2 weeks in patients at risk considering the frequent lack of UTI symptoms in pregnancy and the usual time lag of 1e2 weeks after lower
UTI to kidney involvement. In our experience, this was feasible, with good compliance from the patients who had experience of pyelonephritis, and who are followed up as high-risk pregnancies.
However, where this is not feasible, we suggest at least monthly tests of urinary cultures and urinalysis.
Prompt treatment of infections and preventive therapy, usually with low-dose antibiotics, should
be tailored according to germ sensitivity in the patient and in the population. In the last gestational
weeks, discontinuation of nitrofurantoin (otherwise considered safe) may be indicated in the presence
of history or suspicion of G6PD deciency and of clavulanate-containing agents for the risk of neonatal
enterocolitis [109,110].
Autosomal dominant polycystic kidney disease
ADPKD is one of the most common monogenic disorders worldwide (1:500e1000 live births). In
about 90% of cases, a mutation in either the PKD1 gene on chromosome 16 or the PKD2 gene on
chromosome 4 is found. Penetrance is complete, and virtually all carriers develop kidney cysts, but
expressivity is highly variable and only partially understood. The clinical manifestations increase with
age, and ADPKD may be asymptomatic in the childbearing age. Besides the non-specic signs of CKD
(hypertension, proteinuria and renal function impairment), cysts have a risk of infection and bleeding;
hence, we follow the same surveillance policy as in UTI [111,112]. Some authors consider the risk of
intracystic bleeding an indication for caesarean section on account of the increased abdominal pressure
at parturition [112]. Other groups, including ours, limit the indication for caesarean section to cases
with large cysts and recent or massive bleeding.
Counselling may be challenging: prenatal diagnosis is feasible in about 90% of the cases (PKD1 and
PKD2 mutations). However, clinical manifestations are usually delayed to the third to fourth decade,
and they may never occur; hence, several groups, including ours, do not systematically offer genetic
screening in pregnancy. Considering the progress that has been made in the treatment of kidney
diseases, forecasting what life with ADPKD will be like in the next 40 years is almost impossible. This
lag in prevision leaves ample room for distinct approaches, from no genetic testing to preimplantation
selection, which is a matter of intense controversy [111,112].
Diabetic nephropathy
The improvements in maternalefoetal and diabetic care allow pregnancy in an increasing number
of type 1 diabetic women with end organ damage. In the presence of scattered evidence, the risk of
pregnancy-related adverse events did not substantially decrease over time, except for stillbirth (from
>10% to about 5% in severe diabetic nephropathy); the newly reported increase in malformations in
14
diabetic nephropathy highlights the need for further studies. Multidisciplinary management is needed,
and the possibility of rapid development of proteinuria and hypertension, both of which are clinically
challenging and of difcult pathophysiological interpretation, should be kept in mind [24,25,35,113].
Summary
CKD in pregnancy may be described through four main elements: stage (stage 1: normal renal
function; stage 5: end-stage disease), renal disease (such as: glomerular, interstitial and polycystic
kidney disease; systemic diseases and diabetic nephropathy), the presence of hypertension and the
presence and degree of proteinuria.
The prognosis of pregnancy is the result of a combination of these elements, and this makes
counselling complex as the available evidence does not sufce to allow us to dene risk in individual
patients. Notwithstanding these limits, pregnancy is possible in all CKD stages and is increasingly
reported also on dialysis. The risk of adverse outcome is already higher in the rst CKD stage and
increases in proportion to renal function impairment. CKD is often asymptomatic and pregnancy is an
opportunity for diagnosis. Differential diagnosis with PE may be difcult; however, the presence of
normal utero-placental ows and, whenever available, angiogeniceantiangiogenic prole suggests
taking into consideration a diagnosis of CKD.
The main risks for the mother include worsening of kidney function, hypertension and proteinuria.
Maternal death is rare and almost exclusively reported in systemic diseases, such as lupus nephropathy, while perinatal death is mainly reported in lupus nephritis, diabetic nephropathies and on
dialysis. Besides these rare, severe outcomes, the main risks for the foetus are linked with prematurity,
whose incidence increases as kidney function impairment worsens. The risk of malformations does not
increase, with the possible exception of diabetic nephropathy; however, the genetics of kidney diseases
is complex and should be discussed in counselling. Multidisciplinary management and strict clinical
follow-up are the basis for maternalefoetal care.
Practice points
CKD is associated with an increased risk of adverse pregnancy-related outcomes (i.e., prematurity, need for neonatal intensive care unit and SGA babies) starting in the early stages,
when kidney function is within the normal range.
The risk of maternal death in CKD is very low, and it is mainly reported in systemic immunologic diseases, first of all systemic lupus erythematosus (SLE).
SLE, diabetic nephropathy and chronic dialysis are correlated with perinatal death, whose
incidence is also correlated with prematurity.
The risk of adverse pregnancy-related outcomes increases as kidney function worsens, in the
presence of hypertension and/or proteinuria at the start of pregnancy and in systemic diseases, dialysis and transplantation.
The risk of kidney function worsening increases in proportion to kidney function impairment
and may involve >50% of patients with advanced CKD.
In the last CKD stages, metabolic derangements (anaemia, calciumephosphate derangement, acidosis and malnutrition) are common and need prompt correction.
Control of hypertension, low-protein diets and attention to weight gain may help control
hyperfiltration, a challenge for kidney function.
Differential diagnosis in pregnancy between CKD and PE may be impossible; CKD should be
taken into consideration in the presence of normal utero-placental flows, foetal growth and
(when available) normal angiogeniceantiangiogenic pattern
No increases in malformations have been reported in children of CKD mothers, with the
possible exception of diabetic nephropathy, which requires further study.
15
Research agenda
Pathophysiology of the increase in risk of adverse pregnancy-related events in stage 1 CKD in
the absence of hypertension and proteinuria (baseline risk);
Multicentre studies to assess the risks of specific kidney diseases in pregnancy;
Long-term effect of in utero exposure to immunosuppressors and other drugs in CKD;
Assessment of follow-up policy and blood pressure target in hypertensive pregnant women;
and
Differential diagnosis of CKD and PE in pregnancy.
Conict of interest
No nancial disclosure or conict of interest for any of the authors.
Acknowledgements
We are grateful to Frances Perricone for her careful language editing.
References
[1] www.kidney.org, last accessed 30.06.14.
[2] Coresh J, Turin TC, Matsushita K, et al. Decline in estimated glomerular ltration rate and subsequent risk of end-stage
renal disease and mortality. JAMA 2014 Jun 25;311(24):2518e31.
[3] Fox CS, Matsushita K, Woodward M, et al. Associations of kidney disease measures with mortality and end-stage renal
disease in individuals with and without diabetes: a meta-analysis. Lancet 2012;380:1662e73.
[4] Smyth A, Radovic M, Garovic VD. Women, kidney disease, and pregnancy. Adv Chronic Kidney Dis 2013;20:402e10.
[5] Davison JM, Lindheimer MD. Pregnancy and chronic kidney disease. Semin Nephrol 2011;31:86e99.
*[6] Williams D, Davison J. Chronic kidney disease in pregnancy. BMJ 2008;33:211e5.
[7] Winearls CG, Glassock RJ. Dissecting and rening the staging of chronic kidney disease. Kidney Int 2009;75:1009e14.
[8] Piccoli GB, Fassio F, Attini R, et al. Pregnancy in CKD: whom should we follow and why? Nephrol Dial Transplant 2012;
27(Suppl. 3):iii111e8.
n E, Olofsson P, B
[9] Krutze
ack SE, et al. Glomerular ltration rate in pregnancy: a study in normal subjects and in patients
with hypertension, preeclampsia and diabetes. Scand J Clin Lab Invest 1992;52:387e92.
[10] Ahmed SB, Bentley-Lewis R, Hollenberg NK, et al. A comparison of prediction equations for estimating glomerular
ltration rate in pregnancy. Hypertens Pregnancy 2009;28:243e55.
[11] Smith MC, Moran P, Ward MK, et al. Assessment of glomerular ltration rate during pregnancy using the MDRD
formula. BJOG 2008;115:109e12.
*[12] Nevis IF, Reitsma A, Dominic A, et al. Pregnancy outcomes in women with chronic kidney disease: a systematic review.
Clin J Am Soc Nephrol 2011;6:2587e98.
[13] Piccoli GB, Conijn A, Attini R, et al. Pregnancy in chronic kidney disease: need for a common language. J Nephrol 2011;
24:282e99.
*[14] Piccoli GB, Attini R, Vasario E, et al. Pregnancy and chronic kidney disease: a challenge in all CKD stages. Clin J Am Soc
Nephrol 2010;5:844e55.
[15] Hou SH, Grossman SD, Madias NE. Pregnancy in women with renal disease and moderate renal insufciency. Am J Med
1985;78:185e94.
[16] Jungers P, Forget D, Henry-Amar M, et al. Chronic kidney disease and pregnancy. Adv Nephrol Necker Hosp 1986;15:
103e41.
[17] Jones DC, Hayslett JP. Outcome of pregnancy in women with moderate or severe renal insufciency. N Engl J Med
1996;335:226e32.
[18] Epstein FH. Pregnancy and renal disease. N Engl J Med 1996;335:277e8.
[19] Bramham K, Briley AL, Seed PT, et al. Pregnancy outcome in women with chronic kidney disease: a prospective cohort
study. Reprod Sci 2011;18:623e30.
[20] Imbasciati E, Gregorini G, Cabiddu G, et al. Pregnancy in CKD stages 3 to 5: fetal and maternal outcomes. Am J Kidney
Dis 2007;49:753e62.
[21] Chopra S, Suri V, Aggarwal N, et al. Pregnancy in chronic renal insufciency: single centre experience from North
India. Arch Gynecol Obstet 2009;279:691e5.
*[22] Lateef A, Petri M. Managing lupus patients during pregnancy. Best Pract Res Clin Rheumatol 2013;27:435e47.
[23] Stanhope TJ, White WM, Moder KG, et al. Obstetric nephrology: lupus and lupus nephritis in pregnancy. Clin J Am Soc
Nephrol 2012;7:2089e99.
16
*[24] Piccoli GB, Clari R, Ghiotto S, et al. Type 1 diabetes, diabetic nephropathy, and pregnancy: a systematic review and
meta-study. Rev Diabet Stud 2013;10:6e26.
[25] Bramham K, Rajasingham D. Pregnancy in diabetes and kidney disease. J Ren Care 2012;38(Suppl. 1):78e89.
[26] Semins MJ, Matlaga BR. Kidney stones during pregnancy. Nat Rev Urol 2014;11:163e8.
[27] Piccoli GB, Attini R, De Pascale A, et al. Protean presentation and multiple challenges of nephrocalcinosis in pregnancy
(six pregnancies in four patients). Nephrol Dial Transplant 2012;27:1131e8.
[28] Rolfo A, Attini R, Nuzzo AM, et al. Chronic kidney disease may be differentially diagnosed from preeclampsia by serum
biomarkers. Kidney Int 2013;83:177e81.
[29] Piccoli GB, Gaglioti P, Attini R, et al. Pre-eclampsia or chronic kidney disease? The ow hypothesis. Nephrol Dial
Transplant 2013;28:1199e206.
[30] Gubhaju L, Sutherland MR, Black MJ. Preterm birth and the kidney: implications for long-term renal health. Reprod Sci
2011;18:322e33.
[31] Sutherland MR, Gubhaju L, Moore L, et al. Accelerated maturation and abnormal morphology in the preterm neonatal
kidney. J Am Soc Nephrol 2011;22:1365e74.
[32] Hodgin JB, Rasoulpour M, Markowitz GS, et al. Very low birth weight is a risk factor for secondary focal segmental
glomerulosclerosis. Clin J Am Soc Nephrol 2009;4:71e6.
[33] Carmody JB, Charlton JR. Short-term gestation, long-term risk: prematurity and chronic kidney disease. Pediatrics
2013;131:1168e79.
[34] Blowey DL, Warady BA. Outcome of infants born to women with chronic kidney disease. Adv Chronic Kidney Dis 2007;
14:199e205.
[35] Bell R, Glinianaia SV, Tennant PW, et al. Peri-conception hyperglycaemia and nephropathy are associated with risk of
congenital anomaly in women with pre-existing diabetes: a population-based cohort study. Diabetologia 2012;55:
936e47.
[36] Paterson AD, Liu XQ, Wang K, et al. Genome-wide linkage scan of a large family with IgA nephropathy localizes a novel
susceptibility locus to chromosome 2q36. J Am Soc Nephrol 2007;18:2408e15.
[37] Kiryluk K, Li Y, Sanna-Cherchi S, et al. Geographic differences in genetic susceptibility to IgA nephropathy: GWAS
replication study and geospatial risk analysis. PLoS Genet 2012;8:e1002765.
[38] Feather SA, Malcolm S, Woolf AS, et al. Primary, nonsyndromic vesicoureteric reux and its nephropathy is genetically
heterogeneous, with a locus on chromosome 1. Am J Hum Genet 2000;66:1420e5.
[39] Sanna-Cherchi S, Reese A, Hensle T, et al. Familial vesicoureteral reux: testing replication of linkage in seven new
multigenerational kindreds. J Am Soc Nephrol 2005;16:1781e7.
m TJ, Schalling M, et al. How can genetics and epigenetics help the nephrologist improve the
[40] Witasp A, Ekstro
diagnosis and treatment of chronic kidney disease patients? Nephrol Dial Transplant 2014;29:972e80.
[41] Hildebrandt F. Genetic kidney diseases. Lancet 2010;375:1287e95.
[42] www.fda.gov, last accessed 20.06.14.
[43] Magee LA, Pels A, Helewa M, et al. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy:
executive summary. J Obstet Gynaecol Can 2014;36:416e38.
[44] Abalos E, Duley L, Steyn DW. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy.
Cochrane Database Syst Rev 2014;2:CD002252.
[45] Molvi SN, Mir S, Rana VS, et al. Role of antihypertensive therapy in mild to moderate pregnancy-induced hypertension: a prospective randomized study comparing labetalol with alpha methyldopa. Arch Gynecol Obstet 2012;285:
1553e62.
[46] Rothberger S, Carr D, Brateng D, et al. Pharmacodynamics of clonidine therapy in pregnancy: a heterogeneous
maternal response impacts fetal growth. Am J Hypertens 2010;23:1234e40.
[47] Collins R, Yusuf S, Peto R. Overview of randomised trials of diuretics in pregnancy. Br Med J 1985;290:17e23.
[48] Mascetti L, Bettinelli A, Simonetti GD, et al. Pregnancy in inherited hypokalemic salt-losing renal tubular disorder.
Obstet Gynecol 2011;117:512e6.
[49] Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after rst-trimester exposure to
ACE inhibitors. N Engl J Med 2006;354:2443e51.
[50] Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for
the care of kidney transplant recipients. Am J Transplant 2009;9(Suppl. 3):S1e155.
[51] EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Section IV:
long-term management of the transplant recipient. IV.10. Pregnancy in renal transplant recipients. Nephrol Dial
Transplant 2002;17(Suppl. 4):50e5.
[52] stensen M, Khamashta M, Lockshin M, et al. Anti-inammatory and immunosuppressive drugs and reproduction.
Arthritis Res Ther 2006;8:209.
[53] Bar Oz B, Hackman R, Einarson T, et al. Pregnancy outcome after cyclosporine therapy during pregnancy: a metaanalysis. Transplantation 2001;71:1051e5.
[54] Kainz A, Harabacz I, Cowlrick IS, et al. Review of the course and outcome of 100 pregnancies in 84 women treated with
tacrolimus. Transplantation 2000;70:1718e21.
[55] Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defects after maternal exposure to corticosteroids: prospective
cohort study and meta-analysis of epidemiological studies. Teratology 2000;62:385e92.
[56] Abarientos C, Sperber K, Shapiro DL, et al. Hydroxychloroquine in systemic lupus erythematosus and rheumatoid
arthritis and its safety in pregnancy. Expert Opin Drug Saf 2011;10:705e14.
[57] Pagnoux C, Mahendira D, Laskin CA. Fertility and pregnancy in vasculitis. Best Pract Res Clin Rheumatol 2013;27:
79e94.
[58] Sifontis NM, Coscia LA, Constantinescu S, et al. Pregnancy outcomes in solid organ transplant recipients with exposure
to mycophenolate mofetil or sirolimus. Transplantation 2006;82:1698e702.
[59] Anderka MT, Lin AE, Abuelo DN, et al. Reviewing the evidence for mycophenolate mofetil as a new teratogen: case
report and review of the literature. Am J Med Genet A 2009;149A:1241e8.
17
[60] Framarino-dei-Malatesta M, Derme M, Manzia TM, et al. Impact of mTOR-I on fertility and pregnancy: state of the art
and review of the literature. Expert Rev Clin Immunol 2013;9:781e9.
[61] Palmer BF. Sexual dysfunction in men and women with chronic kidney disease and end-stage kidney disease. Adv Ren
Replace Ther 2003;10:48e60.
[62] Holley JL, Schmidt RJ. Changes in fertility and hormone replacement therapy in kidney disease. Adv Chronic Kidney
Dis 2013;20:240e5.
[63] Ibrahim HN, Akkina SK, Leister E, et al. Pregnancy outcomes after kidney donation. Am J Transplant 2009;9:825e34.
[64] Reisaeter AV, Rislien J, Henriksen T, et al. Pregnancy and birth after kidney donation: the Norwegian experience. Am J
Transplant 2009;9:820e4.
[65] Garg AX, Nevis IF, McArthur E, et al. Gestational hypertension and preeclampsia in living kidney donors. N Engl J Med
2015;8(372):124e33.
[66] Alsuwaida A, Mousa D, Al-Harbi A, et al. Impact of early chronic kidney disease on maternal and fetal outcomes of
pregnancy. J Matern Fetal Neonatal Med 2011;24:1432e6.
[67] Limardo M, Imbasciati E, Ravani P, et al. Pregnancy and progression of IgA nephropathy: results of an Italian multicenter study. Am J Kidney Dis 2010;56:506e12.
[68] Bramham K, Lightstone L. Pre-pregnancy counseling for women with chronic kidney disease. J Nephrol 2012;25:
450e9.
[69] Piccoli GB, Ferraresi M, Deagostini MC, et al. Vegetarian low-protein diets supplemented with keto analogues: a niche
for the few or an option for many? Nephrol Dial Transplant 2013;28:2295e305.
[70] Piccoli GB, Leone F, Attini R, et al. Association of low-protein supplemented diets with fetal growth in pregnant
women with CKD. Clin J Am Soc Nephrol 2014;9:864e73.
[71] Piccoli GB, Attini R, Vasario E, et al. Vegetarian supplemented low-protein diets. A safe option for pregnant CKD
patients: report of 12 pregnancies in 11 patients. Nephrol Dial Transplant 2011;26:196e205.
[72] Nesrallah GE, Mustafa RA, Clark WF, et al. Society of Nephrology 2014 clinical practice guideline for timing the
initiation of chronic dialysis. CMAJ 2014;186:112e7.
[73] Sienas L, Wong T, Collins R, et al. Contemporary uses of erythropoietin in pregnancy: a literature review. Obstet
Gynecol Surv 2013;68:594e602.
[74] De-Regil LM, Palacios C, Ansary A, et al. Vitamin D supplementation for women during pregnancy. Cochrane Database
Syst Rev 2012;2:CD008873.
[75] de Brito-Ashurst I, Varagunam M, Raftery MJ, et al. Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol 2009;20:2075e84.
[76] Hou SH. Pregnancy in women on haemodialysis and peritoneal dialysis. Baillieres Clin Obstet Gynaecol 1994;8:
481e500.
[77] Piccoli GB, Conijn A, Consiglio V, et al. Pregnancy in dialysis patients: is the evidence strong enough to lead us to
change our counseling policy? Clin J Am Soc Nephrol 2010;5:62e71.
*[78] Hladunewich MA, Hou S, Odutayo A, et al. Intensive hemodialysis associates with improved pregnancy outcomes: a
Canadian and United States cohort comparison. J Am Soc Nephrol 2014 May;25(5):1103e9.
[79] Toma H, Tanabe K, Tokumoto T, et al. Pregnancy in women receiving renal dialysis or transplantation in Japan: a
nationwide survey. Nephrol Dial Transplant 1999;14:1511e6.
[80] Luders C, Castro MC, Titan SM, et al. Obstetric outcome in pregnant women on long-term dialysis: a case series. Am J
Kidney Dis 2010;56:77e85.
[81] Jesudason S, Grace BS, McDonald SP. Pregnancy outcomes according to dialysis commencing before or after
conception in women with ESRD. Clin J Am Soc Nephrol 2014;9:143e9.
[82] Piccoli GB, Cabiddu G, Daidone G, et al. The children of dialysis: live-born babies from on-dialysis mothers in Italydan
epidemiological perspective comparing dialysis, kidney transplantation and the overall population. Nephrol Dial
Transplant 2014 Aug;29(8):1578e86.
[83] Shahir AK, Briggs N, Katsoulis J, et al. An observational outcomes study from 1966-2008, examining pregnancy and
neonatal outcomes from dialysed women using data from the ANZDATA Registry. Nephrology 2013;18:276e84.
[84] Cornelis T, Spaanderman M, Beerenhout C, et al. Antiangiogenic factors and maternal hemodynamics during intensive
hemodialysis in pregnancy. Hemodial Int 2013;17:639e43.
[85] Abou-Jaoude P, Dubourg L, Bessenay L, et al. What about the renal function during childhood of children born from
dialysed mothers? Nephrol Dial Transplant 2012;27:2365e9.
*[86] Deshpande NA, James NT, Kucirka LM, et al. Pregnancy outcomes in kidney transplant recipients: a systematic review
and meta-analysis. Am J Transplant 2011;11:2388e404.
*[87] McKay DB, Josephson MA. Pregnancy in recipients of solid organseeffects on mother and child. N Engl J Med 2006;
23(354):1281e93.
[88] Zachariah MS, Tornatore KM, Venuto RC. Kidney transplantation and pregnancy. Curr Opin Organ Transplant 2009;14:
386e91.
[89] Wyld ML, Clayton PA, Jesudason S, et al. Pregnancy outcomes for kidney transplant recipients. Am J Transplant 2013;
13:3173e82.
[90] Levidiotis V, Chang S, McDonald S. Pregnancy and maternal outcomes among kidney transplant recipients. J Am Soc
Nephrol 2009;20:2433e40.
[91] Tendron A, Gouyon JB, Decramer S. In utero exposure to immunosuppressive drugs: experimental and clinical studies.
Pediatr Nephrol 2002;17:121e30.
[92] Motta M, Tincani A, Meroni PL, et al. Follow-up of children exposed antenatally to immunosuppressive drugs.
Rheumatology 2008;47(Suppl. 3):iii32e4.
[93] Boldt J. Use of albumin: an update. Br J Anaesth 2010;104:276e84.
[94] American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Hypertension in
pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013;122:1122e31.
18
[95] Magee LA, von Dadelszen P, Rey E, et al. Less-tight versus tight control of hypertension in pregnancy. N Engl J Med
2015;372:407e17.
*[96] Vikse BE, Irgens LM, Leivestad T, et al. Preeclampsia and the risk of end-stage renal disease. N Engl J Med 2008;359:
800e9.
[97] McDonald SD, Han Z, Walsh MW, et al. Kidney disease after preeclampsia: a systematic review and meta-analysis. Am
J Kidney Dis 2010;55:1026e39.
[98] Wang IK, Muo CH, Chang YC, et al. Association between hypertensive disorders during pregnancy and end-stage renal
disease: a population-based study. CMAJ 2013;185:207e13.
[99] Piccoli GB, Arduino S, Attini R, et al. Multiple pregnancies in CKD patients: an explosive mix. Clin J Am Soc Nephrol
2013;8:41e50.
[100] Hladunewich MA, Steinberg G, Karumanchi SA, et al. Angiogenic factor abnormalities and fetal demise in a twin
pregnancy. Nat Rev Nephrol 2009;5:658e62.
[101] Piccoli GB, Daidola G, Attini R, et al. Kidney biopsy in pregnancy: evidence for counselling? A systematic narrative
review. BJOG 2013;120:412e27.
[102] North RA, Ferrier C, Gamble G, et al. Prevention of preeclampsia with heparin and antiplatelet drugs in women with
renal disease. Aust N Z J Obstet Gynaecol 1995;35:357e62.
[103] Dodd JM, McLeod A, Windrim RC, et al. Antithrombotic therapy for improving maternal or infant health outcomes in
women considered at risk of placental dysfunction. Cochrane Database Syst Rev 2013;7:CD006780.
[104] Kiryluk K, Novak J, Gharavi AG. Pathogenesis of immunoglobulin a nephropathy: recent insight from genetic studies.
Annu Rev Med 2013;64:339e56.
*[105] Smyth A, Oliveira GH, Lahr BD, et al. A systematic review and meta-analysis of pregnancy outcomes in patients with
systemic lupus erythematosus and lupus nephritis. Clin J Am Soc Nephrol 2010;5:2060e8.
[106] Ritchie J, Smyth A, Tower C, et al. Maternal deaths in women with lupus nephritis: a review of published evidence.
Lupus 2012;21:534e41.
[107] Unterscheider J, O'Donoghue K, Daly S, et al. Fetal growth restriction and the risk of perinatal mortality-case studies
from the multicentre PORTO study. BMC Pregnancy Childbirth 2014;14:63.
[108] Schneeberger C, Geerlings SE, Middleton P, et al. Interventions for preventing recurrent urinary tract infection during
pregnancy. Cochrane Database Syst Rev 2012;11:CD009279.
[109] Kenyon SL, Taylor DJ, Tarnow-Mordi W. Broad spectrum antibiotics for spontaneous preterm labour: the ORACLE II
randomised trial. Lancet 2001;357:989e94.
[110] Nordenq H, Luppatelli A, Romoren M, et al. Neonatal outcomes after gestational exposure to nitrofurantoin. Obstet
Gynecol 2013;121:306e13.
[111] Pei Y. Diagnostic approach in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2006;1:1108e14.
[112] Vora N, Perrone R, Bianchi DW. Reproductive issues for adults with autosomal dominant polycystic kidney disease. Am
J Kidney Dis 2008;5:307e518.
[113] Piccoli GB, Tavassoli E, Melluzza C, et al. Severe diabetic nephropathy in type 1 diabetes and pregnancyea case series.
Rev Diabet Stud 2013;10:68e78.

Pregnancy in CKD

Загружено:

Сведения о документе

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Pregnancy in CKD

Загружено:

Авторское право:

Доступные форматы

Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e18

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Pregnancy in CKD: Questions and answers in a

Chronic kidney disease (CKD) is increasingly encountered in

* Corresponding author. Tel.: 39 3475514005.

Usually considered rst-choice drugs [42e44]

Usually considered as relatively safe, when absolutely needed [50e52]

Main biochemical tests prescribed

Stage 1 CKD [not otherwise

Renal ultrasounds if not

Stage 2 CKD (nos)

Every 4e6 weeks: urinalysis, urinary culture,

Stage 3 CKD (nos)

Same as above; monthly 24-h urine collection

Stages 4e5 CKD (nos)

According to stage; at least weekly

Same as above; 24-h urine collection twice

According to stage; at least monthly

Urinalysis every 1e2 weeks, checking for

Proteinuria >0.3 to <3 g/day

According to stage; minimum 4

According to stage; minimum 2

24-h proteinuria, clearances and serum

Previous acute pyelonephritis and

Renal ultrasounds every

Вам также может понравиться