pregnancy in ckd

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

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Best Practice & Research ClinicalObstetrics and Gynaecology

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11

Pregnancy in CKD: Questions and answers in achanging 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 ofTorino, Turin, Italyb SCDU Nephrology, Brotzu Hospital, Cagliari, Italyc Materno-Foetal Unit, Department of Obstetrics, ASOU OIRM S Anna, University of Torino, Turin, Italy

Keywords:pregnancychronic kidney disease (CKD)proteinuriahypertensionglomerulonephritis and interstitialnephropathiesdialysis and transplantation

* Corresponding author. Tel.: þ39 3475514005.E-mail addresses: [email protected], giorgina.p

http://dx.doi.org/10.1016/j.bpobgyn.2015.02.0051521-6934/© 2015 Elsevier Ltd. All rights reserved

Please cite this article in press as: Piccochanging panorama, Best Practice & Redx.doi.org/10.1016/j.bpobgyn.2015.02.005

Chronic kidney disease (CKD) is increasingly encountered inpregnancy because of greater diagnostic awareness, which is areflection of the newer, broader definitions (i.e., any changes inblood or urine composition or at imaging, or a glomerular filtrationrate (GFR) of <60 mL/min lasting at least 3 months) and ofincreased incidence (higher maternal age and better outcomes ofseveral kidney diseases).CKD is extremely heterogeneous and may be described by thedegree of GFR reduction (CKD stages), the presence of proteinuriaand hypertension and the type of kidney disease; the risk ofadverse pregnancy-related events increases as GFR decreases andit is affected by proteinuria and hypertension. Specific risks arereported in various diseases such as lupus nephropathy or diabeticnephropathy. While transplantation at least partially restoresfertility in end-stage kidney disease, pregnancy on dialysis isincreasingly reported.This chapter deals with the available evidence on the managementof CKD patients in pregnancy.

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Introduction

Chronic kidney disease: a matter of definition

Almost 20 years ago, the National Kidney Foundation started a campaign entitled ‘The Fight againstthe Silent Killers’ [1]. These silent killers were chronic kidney diseases (CKD), and they were defined 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, thedefinition of ‘silent killer’may be applied to CKD in pregnancy, as these often undiagnosed diseases area main cause of morbidity in pregnancy [4,5].

CKD is currently broadly defined as any alteration in renal morphology, imaging or function, or by aglomerular filtration rate (GFR) <60 mL/min for at least 3 months [1,6,7]. Despite the revisions andcriticisms, the advantage of this definition is that it focuses on the earlier CKD stages, when kidneyfunction 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 insmall body size; furthermore, in pregnancy physiological hyperfiltration may mask an initial GFRreduction, 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 isimportant to identify CKD in stage 1, when kidney function is normal and CKD is revealed by pro-teinuria, haematuria, electrolyte derangements, tubulo-interstitial diseases, single kidney (includingkidney donation) or even ‘simple’ kidney scars due to previous acute pyelonephritis [1].

On the basis of these broad definitions, the prevalence of CKD reaches 3% in women in childbearingage, a significant difference as compared to previous definitions, which were based upon high creat-inine levels that probably identified <10% of cases [5,6].

Pregnancy is a very important opportunity to diagnose kidney disease in an apparently healthywoman. In our experience, CKD is diagnosed or acknowledged as a risk factor in pregnancy in at least40% of cases [8]. The physiological increase in GFR, the lack of validated formulae for GFR assessment inpregnancy and the clinical and laboratory overlapwith pre-eclampsia (PE) are important challenges forearly diagnosis as discussed below [9e11]. We also discuss how CKD bears a risk of adverse pregnancy-related outcomes starting from the early stages, and even ‘minor’ signs of CKD should be taken intoconsideration [8,12e15].

In the following paragraphs, we summarise the available evidence and its limits, sharing our pointsof view on the diagnosis and care of CKD in pregnancy.

What is ‘inside CKD’?

Regardless of how it is defined, CKD is a syndrome and not a disease; its main descriptors are kidneyfunction, kidney disease, proteinuria and hypertension (Fig. 1).

Kidney function, which is subdivided by the Kidney Disease Outcomes Quality Initiative (K-DOQI)definition into five stages, is probably the most powerful descriptor of the severity of the disease and ofthe risk of complications [1,12e21].

As a rule, immunologic and systemic diseases (such as glomerulonephritis, or diabetic or lupusnephropathies) are more frequently associated with adverse pregnancy-related events; conversely,interstitial kidney diseases share a higher risk of upper urinary tract infection (UTI), unexplainedoedema or stone disease [22e27].

Hypertension and proteinuria are independently correlated with CKD progression and with adversepregnancy-related events, and, when present, PE may be difficult 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, theinvolvement of various diseases, the fact that it is subject to referral biases and that it is influenced bythe study setting [12,13].

Please cite this article in press as: Piccoli GB, et al., Pregnancy in CKD: Questions and answers in achanging panorama, Best Practice & Research Clinical Obstetrics and Gynaecology (2015), http://dx.doi.org/10.1016/j.bpobgyn.2015.02.005

Fig. 1. The relationship among CKD, proteinuria and hypertension is complex: proteinuria persisting >3 months (from micro-albuminuria to nephrotic proteinuria) is by definition a marker of CKD; hypertension may occur in the absence of CKD, but hy-pertension is a risk factor for CKD and its prevalence increases with CKD stage; kidney disease is the most common cause ofsecondary hypertension in young women. CKD: chronic kidney disease is defined as either kidney damage or GFR <60 mL/min1.73 m2 for �3 months. Kidney damage is defined as pathologic abnormalities or markers of damage, including abnormalities inblood or urine tests or imaging studies [1]. Proteinuria: microalbuminuria, albumin excretion below 300 mg/day. Nephrotic pro-teinuria �3 g/day. Nephrotic syndrome: nephrotic proteinuria plus hypoalbuminaemia, oedema and/or hypercholesterolaemia.

G.B. Piccoli et al. / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e18 3

There are at least four reasons for these limitations. Firstly, the changes in definitions that have onlyrecently been integrated into obstetric nephrology make pooling of data difficult. Secondly, CKD isheterogeneous as it is made up of several ‘families’ of diseases. Thirdly, progression of CKD differs frompatient to patient, and the role of disease modulators (including proteinuria, hypertension, nutritionalstatus and lifestyle) is still unknown. Fourthly, the lack of ‘low-risk pregnancy’ control groups in manystudies hinders contextualization of the results as the baseline risks vary widely around the world, andthey 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 thehypertensive disorders of pregnancywith 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 maternaldiseases, 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 ofthis 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-forgestational-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 ofmothers with nephropathy and diabetes as compared to diabetes alone [35].

The genetics of kidney diseases is only partially known. Besides the most common Mendeliandiseases, such as autosomal dominant polycystic kidney disease (ADPKD) and Alport syndrome (het-erogeneous, usually X-linked), many genes have not been identified: this is the case with immuno-globulin 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 reflux,while other malformations of the urinary tract are linked to various genes [38e40]. Hence, the pos-sibility that kidney diseases recur in the offspring cannot be excluded and should probably bementioned 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, systemicdiseases and kidney transplantation. Tables 1 and 2 summarise some information on the mostcommonly used drugs in CKD, that is, antihypertensive and immunosuppressive drugs with particularregard to CKD patients [42e60].

While the advantages of universal treatment for mild tomoderate hypertension are controversial inthe 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 involvinghypertensive CKD patients in pregnancy, thus leaving each group free to individually define the choiceof the treatment policy [44].

An important point regards the discontinuation of potentially dangerous drugs. Contrary to theguidelines on hypertension and pregnancy, many nephrologists, including our group, prefer to dis-continue angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor inhibitors on theoccasion of a positive pregnancy test, at least in compliant, reliable patients, with a regular menstrualcycle agreeing to perform the test immediately after missing menstruation. This is motivated by theabsence of a ‘carry-over effect’ (meaning that once stopped, they do not have any lingering teratogeniceffect) and by the fact that, in particular in patients with proteinuric diseases, this policy allows us tomaximize 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 beindicated for several immunosuppressors, because of the risk of flare-ups of immunologic diseases,such as systemic lupus erythematosus (SLE) or of rejection after kidney transplantation if the changesare 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 offertility, 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 functionimpairment [6,8e21]. Quantifying the risk is difficult due to the heterogeneity of the studies. In a recentmeta-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 thecontrol population [12]. Fig. 2 reports the risk pattern across stages obtained in a large series of CKDpatients 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 reducedkidney 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


Table 1Main antihypertensive drugs in pregnant patients with CKD.

Drug Main features FDA SOGC

Usually considered first-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.B 1-A

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.

C 1-A

Labetalol Usually well tolerated, should be avoided in subjects with asthma. In an RCT, it wasshown to be comparable to alpha-methyldopa [45]

C 1-A

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 ofteninvolved. Beta blockers may be more effective than alpha-methyldopa in severe hypertension,alone or in combined therapy. At delivery, they may induce hypoglycaemia, hypotension andbradycardia (usually mild and transient)

D atenololB pindololeC metoprolol.

1-B

Clonidine The effect is similar to alpha-methyldopa; side effects may be more common and hypertensiverebounds at discontinuation are common; slowing foetal growth is occasionally reported [46]

C

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 withGitelman syndrome, amiloride may be employed [48].

B hydrochlorothiazide amiloride

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 flowsD

ACE-iARB and related drugs

Both drugs are contraindicated in all phases of pregnancy because of the risk of severalmajor malformations, including cardiovascular, central nervous system, renal and bonemalformations [49]. See text on pre-emptive discontinuation.

C 1stD 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, positiveevidence of risk; and X, contraindicated in pregnancy.SOGC: Society of Obstetrics and Gynaecology of Canada: guidelines 2014 [43].

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Table 2Main immunosuppressive drugs in pregnant CKD patients.

Drug Main features FDA

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 Guidelinessuggest switching from mycophenolate to azathioprine before pregnancy [50e52]

D

Cyclosporine A This calcineurin inhibitor has not been associated with increased teratogenicity; however, small-for-gestational-agebabies and preterm delivery have been reported, possibly due to the maternal disease and not specifically to the drug;levels may vary in pregnancy and the hypertensive, hyperglycaemic and nephrotoxic effects should be mentioned [53]

C

Tacrolimus The drug has similar effects and side effects to Cyclosporine A; as it is a relatively new drug, experience is more limitedthan with the previous drug [54]

C

Steroids Together with azathioprine, these are the most often employed and best-known drugs. The most frequently usedshort-acting corticosteroids include prednisone, methylprednisolone and prednisolone, while betamethasone anddexamethasone are among the long-acting drugs. No major malformations have been reported, and the issue oflabio-palatoschisis is debated. A higher risk of premature rupture of membranes has been reported. Other relevant sideeffects include infectious risk and the increased risk of gestational diabetes [55]

C

Hydroxychloroquine This synthetic antimalarial agent crosses the placenta but was not found to be associated with foetal toxicity [56] NTo 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]D

Methotrexate This teratogenic agent is also employed for extrauterine pregnancy termination. Discontinuation for one to three menstrualcycles is usually indicated [50e52]

X

Mycophenolate Severe foetal malformations are reported, mainly involving cardiovascular and cranial malformations. Discontinuation for at least6 weeks, to stabilize kidney function, is usually indicted after kidney transplantation [58,59]

D

m-Tor inhibitors Very few studies considered their use in pregnancy. They are teratogenic in animals and discontinuation in humans is a matterof debate; KDIGO guidelines suggest discontinuation in anticipation of pregnancy [58,60]

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, positiveevidence of risk; N, not classified; and X, contraindicated in pregnancy.

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Fig. 2. Risk patterns in the various CKD stages in the ToCOS cohort (Torino Cagliari Observational Study), data collection on 504 live-born 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, wasabout twice as high after donation than before, even if the odds of PE remained low due to carefuldonor selection [63e65]. A study on a Saudi Arabian population showed that even in these early stagesof CKD, the risk of prematurity as well as the need for neonatal intensive care unit (NICU) and caesareansections increased by two- to sixfold from CKD stage 1 to stage 2 [66]. Progression of kidney disease israre in these disease stages, as suggested by a large series of IgA nephropathy and early diabetic ne-phropathy; 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, pro-teinuria and hypertension (see the following paragraphs). In their absence, the only ‘therapeutic tool’ isclose 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 mostseries, preterm delivery is two- to fourfold higher (in our experience mainly late preterm); the odds ofneeding NICU or of having a small baby are consequently increased. The reasons for this increase, in theabsence of hypertension and proteinuria, are not known. Hence, counselling should underline theuncertainties and the need for close surveillance of all pregnancies in CKD patients [8,14,68].

Special considerations: stage 3

CKD stage 3 is defined by a GFR of 60e30 mL/min. This implies a decrease in kidney parenchymaranging from 15% to 30%, following the ‘rule of thumb’ that the amount of renal tissue is about half ofthe 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 systemicdiseases is higher in this subset [8,14,25,67].

Therapeutic approaches: Besides treatment for the underlying disease and, when needed, themetabolic correction described for CKD stages 4e5, in our experience a moderate decrease in dietaryprotein intake with veganevegetarian diets may be of help, most likely by counterbalancing theeffects of hyperfiltration on the remnant nephrons [69e71]. Strict clinical surveillance is recom-mended (Table 3).

Counselling hints: The reported risk of kidney functionworsening varies in the literature (20e50% ofcases) [12e18]. The prevalence of prematurity increases as kidney function worsens, becoming almostthe rule in stages CKD 4e5 (in our experience >75% of children of CKD stage 3 mothers are bornpreterm and about half are delivered before the 34th gestational week). This is closely connected to theneed for NICU that occurred in >40% of the babies in our series (Fig. 2). To our knowledge, there arecurrently 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), andhypertension and proteinuria are increasingly encountered in CKD stage 4 and 5 patients. Although therecent guidelines on the start of dialysis have shifted towards lower GFR, some centres prefer to startrenal replacement therapy early in younger patients [72]. Where available, patients in CKD stages 4e5are frequently wait-listed for pre-emptive transplantation.

Therapeutic approaches: Strict clinical surveillance is fundamental. The importance of the baselinedisease 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, cal-ciumephosphate parathyroid hormone (PTH) balance and acidosis. Malnutrition is frequently reportedas an effect of both the hyper-catabolic effect of advanced CKD and the decreased appetite induced byacidosis and correlated with urea levels. Malnutrition is a constant threat in advanced CKD, andattention should be paid to reaching the caloric target of 30e35 kcal/kg/day to reduce proteinwasting.

The diet issue is, however, discussed. In our experience, veganevegetarian diets may be used forcounterbalancing the hyperfiltration of pregnancy, in particular in patients with advanced CKD orproteinuria, in whom ACE inhibitors and angiotensin receptors inhibitors have to be discontinued. Atleast in our single-centre pioneer experience, vegan diets, with a protein intake of 0.7e0.8 g of proteinskilograms of body weight, strictly controlled for the risk of malnutrition, were safe in pregnancy andwere associated with a lower incidence of SGA babies and possibly with a stabilizing effect on kidneyfunction and proteinuria [70,71]. However, these promising data need confirmation on a larger scale.Anaemia, due to erythropoietin deficit, is a common threat, and it is associated with impaired intra-uterine 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 atferritin levels of 200e400 ng/mL, thus enhancing the need for iron supplementation [73]. CKD patientsare also at a risk of B12 deficiency, in particular when on protein-restricted diets. The calciume-phosphate balance is frequently impaired due to the lack of hydroxylation of 25-OH vitamin D in thekidney. Recently, attention has been drawn to the importance of 25-OH vitamin D [74]. Low vitamin Dlevels have been (albeit non-consistently) associated with an increased risk of PE and other pregnancy-related adverse events. As baseline levels are often already low in CKD patients, we suggest correctingat least the main deficiencies.

The lack of regeneration of bicarbonates in the failing kidney is the basis of acidosis, another pro-gression 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 intrave-nous (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 orimmediately 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 dial-ysis), but they are based on a small number of cases (Fig. 2). Proteinuria and hypertension may eitherappear or worsen during pregnancy in up to 70e80% of cases.


Table 3Main indications for nephrological follow-up in the ToCOS units (Torino and Cagliari, Italy); the tests are in addition to routine antenatal assessment.

Disease or condition Minimal follow-up Main biochemical tests prescribed Imaging Other

Stage 1 CKD [not otherwisespecified (nos)]

4e6 weeks Every 4e6 weeks: urinalysis, urinary culture,Na, K, Ca, P, albumin, creatinine, urea, uricacid; clearance and proteinuria on 24-h urinecollection every 10e12 weeks;

Renal ultrasounds if notperformed in theprevious year

Nutritional parametersat start: ferritin, vit D,B12, folates, albumin,total proteins

Stage 2 CKD (nos) 4 weeks Like stage 1, frequency increased to 4 weeks Same as above Like stage 1, every10e12 weeks

Stage 3 CKD (nos) 3 weeks Same as above; monthly 24-h urine collection Same as above Same as above; monthlyin on-diet patients

Stages 4e5 CKD (nos) 1e2 weeks Same as above; 24-h urine collection twicemonthly

Same as above Same as above; monthlyin on-diet patients

Hypertension According to stage; at least weeklyin the case of non-controlled BP

According to stage. Echocardiography if notperformed in theprevious year

Home BP profile; 24-hBP monitoring in thecase of doubts

Glomerulonephritis in remission(CKD stage 1, proteinuria <0.3 g/day)

According to stage; at least monthlyin SLE

Urinalysis every 1e2 weeks, checking forproteinuria

Same as above Other testsaccording to the typeof glomerulonephritis(i.e., autoantibodiesin SLE); immunologicalprofile at start and endof pregnancy.

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

24-h proteinuria, clearances and serumalbumin at least monthly; IgG, IgA and IgM;coagulation with antithrombin III every10e12 weeks

Same as above Same as above(glomerulonephritis)

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

Same as above; proteinuria at least twicemonthly

Same as above Same as above

Previous acute pyelonephritis anddiseases at risk of UTI includingmalformations and ADPKD

According to stage; if no infectionevery 4e6 weeks

According to stage plus urinalysis and urinarycultures every 1e2 weeks; calciuria in thecase of kidney stones

Renal ultrasounds every10e12 weeks, increasedfrequency in the case ofdilatation or colic

e

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Foetal risks: The prematurity risk is high, being almost the rule in most series [12e17]. The need fordrug 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 increasinglyreported [76e81]. Most reports involve haemodialysis (HD), but pregnancy may also be successful onperitoneal dialysis (PD) or haemodiafiltration [76e83]. Pregnancy occurs on a background of markedlyreduced fertility: the odds of having a live-born baby are reduced by about 100-fold on dialysis and byabout 10-fold after transplantation [82,83]. The probability of delivering a live-born baby once preg-nancy 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 inwhich quotidian and long (overnight) dialysis schedules are applied, thus raising issues on themeaningof ‘adequate dialysis’ [78].

Details on dialysis management are beyond the scope of this review. However, a few general rulesare now relatively well established: in the absence of residual kidney function, HD should be planned6/7 days perweek and PD should be intensified. There is a strict relationship between dialysis hours perweek, dialysis efficiency, success of pregnancy and duration of gestation. Success is higher in thepresence of residual renal function, in particular when long-hour dialysis is not available. The in-dications for dialysis start in pregnancy are not defined, but early dialysis start is not incompatible witha successful pregnancy [81,84].

Counselling hints

A woman on dialysis who undertakes or desires a pregnancy should be advised that experience inthis field is limited, although it is increasing and improving. She should be told that she has at least a75% chance of success provided that dialysis is intensified and kept under strict clinical control. Whilethe risk of malformations is probably the same as it is in the overall population, premature birth has tobe expected, with the need for hospitalization in the intensive care unit and possible short and long-term sequelae related to the degree of prematurity. A mild increase in hypertension and micro-albuminuria has been reported in the offspring [82,85].

Pregnancy after kidney transplantation

Kidney transplantation is usually considered the best approach to restoring fertility on renalreplacement therapy [51,86e90]. Pregnancy after kidney transplantation shares the same diseasemodulators as pregnancy in CKD (kidney function, hypertension and proteinuria), while the underlyingkidney disease is probably less relevant than the co-morbidities (such as diabetes or cardiovasculardisease). Two points are more specific: the need for immunosuppressive therapy that is shared byglomerular and systemic diseases, and the risk of rejection. The issue of kidney graft loss during or afterpregnancy has been extensively, although never conclusively, discussed. The guidelines for pregnancyafter 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 dis-continuing mycophenolic acid or m-Tor inhibitors [51,89,90]. These conditions are optimal, but theproblems related to unplanned pregnancy and to suboptimal renal function remain unsolved, thusraising clinical and ethical issues and highlighting the need for patient education. According to a recentsystematic 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 USpopulation) [86].

Counselling hints

Overall, the success rate of pregnancy after kidney transplantation is high, albeit differentlycalculated (>90% of cases overcoming the first trimester, with an overall success rate of 70e80%). The



decline in kidney function has been estimated from 0% to about 20%, but patient selection plays acrucial role. The risk of prematurity, SGA babies and worsening of kidney function are shared by CKD;conversely, infectious complications are more specifically linked to immunosuppression [51,86e90].The long-term effect of in utero exposure to immunosuppressive drugs is not known and this shouldprobably 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 invariablyassociated with acute or chronic glomerular damage. Conversely, hypertension is frequently associatedwith CKD and its prevalence rises as renal function worsens to >90% in CKD stage 5. Whatever thecause, proteinuria and hypertension are associated with the risk of all adverse pregnancy-relatedoutcomes in all CKD stages [4e6]. There is no specific therapy for proteinuria in pregnancy besidestreatment of the underlying kidney disease; the most common antiproteinuric agents (ACE inhibitorsand angiotensin II receptor inhibitors) are contraindicated in pregnancy due to their teratogenicity(Tables 1e2). The risk of massive proteinuria has twomain aspects: lowmaternal plasma protein levelsmay induce foetal growth impairment, similarly to malnutrition. A rapid drop in plasma proteins mayreduce utero-placental flows, thus resulting in placental hypoperfusion, a particular threat in subjectswith impaired placentation. Evidence on i.v. albumin administration in pregnancy is scant; albumininfusion may theoretically temporarily restore plasma volume, but this is counterbalanced by a rise inproteinuria [93].

As pregnancy is a prothrombotic state, if a woman is nephrotic, we would pragmatically recom-mend 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 hypertensiveCKD pregnancies have not been established. It is presumably wise to avoid overcorrection because ofthe risk of reducing utero-placental flows and of foetal growth impairment [43,94]. However, strictblood pressure control is a precious tool in CKD, and it is effective in reducing proteinuria and slowingCKD 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 inkeeping 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 isfar 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 definition of PE, proteinuria and hypertension antedating 20 gesta-tional weeks are presumably due to kidney disease. This may not be true in twin pregnancies in whichearly and severe PE has been described, and in which the combination with CKD may have explosiveclinical features [99,100].

The definition of PE superimposed on CKD is unclear; worsening of blood pressure control may bedifficult to define, in particular after an initial blood pressure drop; likewise, an increase in proteinuriamay be a reflection of hyperfiltration, as well as a sign of immunologic flare.

There are at least three situations in which the differential diagnosis between CKD and PE may beimpossible on clinical grounds: when CKD flares or develops in pregnancy or in the absence of dataantedating the 20th gestational week.

On the basis of studies by our group, normal utero-placental flow correlated with CKD whileimpaired utero-placental flow was linked to PE in patients with proteinuria and/or hypertensive pa-tients 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 asmall study of our group, normal levels have been associated with CKD but not with PE [28]. While



waiting for larger studies, a practical suggestion might be to undertake a diagnostic pathway for CKD ina pregnant woman with proteinuria and hypertension and normal utero-placental flows and/or in thecase of a normal angiogeniceantiangiogenic profile, 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 define the kidney disease is akidney biopsy. Kidney biopsy in pregnancy is still a matter of controversy; the pros of the diagnosticyield have to be balanced with the risks of major bleeding that, according to a systematic review, maybe increased, with a peak of major complications at 23e26 gestational weeks. The relevant compli-cations 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 theselectivity of proteinuria, suggesting minimal change disease or focal glomerular sclerosis and Pla2r inthe diagnosis of membranous nephropathy, may support a non-invasive clinical diagnosis [101]. Insuch a context, a therapeutic trial of steroids for new-onset proteinuria in pregnancy that does not haveother 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 glo-merulosclerosis and, more rarely, initial membranous nephropathy potentially respond, at leastpartially, to steroids).

Pregnancy in the most common renal diseases

Each kidney disease has peculiarities in pregnancy, and a detailed analysis of these peculiarities isbeyond the general scope of this review. Highlighting a few aspects may be of interest, also to underlinethe great heterogeneity of CKD and the need for an integrated approach as well as multidisciplinaryobstetrical 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 employingacetylsalicylic acid since the early phases of pregnancy to favour placentation, in IgA as well as in otherprimary and secondary glomerulonephritides, including lupus nephritis [67,102,103].

Ideally, pregnancy should be undertaken in the presence of normal renal function, no or low-gradeproteinuria and normal blood pressure. However, many glomerulonephritides have a progressivecourse, and in the presence of chronically impaired renal function, counselling should include dis-cussing the possibility of a further decline, the problems of pregnancy on dialysis and the fact thattransplantation 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 IgAnephropathy, family clustering is observed in about 30% of patients [104]. This figure should be pro-vided to the patients, and it should lead to periodic testing in the children.

SLE and other systemic autoimmune disorders

SLEmay be considered the prototype of a severe and protean autoimmune disease. The literature onSLE 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 encom-passes all the primary glomerular and interstitial morphologic lesions; the overlap with anti-phospholipid syndrome is consistent; maternal deaths are now rare in CKD, and almost all therecently reported ones are associated with SLE; and lupus nephropathy and diabetic nephropathy arethemain causes of perinatal deaths in CKD [13,106,107]. The risk is highest in active SLE, and it is lowestin patients in clinical remission, who have normal kidney function, normal blood pressure and norelevant proteinuria. The causes of maternal death vary and encompass the main risks in SLE patients,



that is, cardiovascular diseases and infection. Neonatal deaths are associated with disease activity andwith specific autoantibodies, but they may occur in the absence of any known risk factors and also interm pregnancies [105].

Tubulo-interstitial disorders and chronic pyelonephritis

Tubulo-interstitial disorders encompass several elusive diseases with non-specific histologicalpictures, 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 andnephrocalcinosis. The clinically complex nephrocalcinosis-tubular disorders are commonly associatedwith hypercalciuria, which often increases in pregnancy, with the intensification of renal colics andwith oedema, which is important in the differential diagnosis with PE [27].

Chronic pyelonephritis, once linked to chronic kidney infections, is now commonly the result ofsubsequent episodes of acute pyelonephritis, with the formation of kidney scars. Renal infections mayoccur in the presence of several predisposing factors including vesico-ureteral reflux, renal malfor-mations, ADPKD and renal stones. The risk of UTIs is higher in pregnancy; however, only one ran-domized controlled trial (RCT) was carried out on the prevention of recurrent UTI [108]. In agreementwith the trial, we suggest urinalysis and urinary cultures every 1e2 weeks in patients at risk consid-ering the frequent lack of UTI symptoms in pregnancy and the usual time lag of 1e2 weeks after lowerUTI to kidney involvement. In our experience, this was feasible, with good compliance from the pa-tients 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, shouldbe tailored according to germ sensitivity in the patient and in the population. In the last gestationalweeks, discontinuation of nitrofurantoin (otherwise considered safe) may be indicated in the presenceof history or suspicion of G6PD deficiency and of clavulanate-containing agents for the risk of neonatalenterocolitis [109,110].

Autosomal dominant polycystic kidney disease

ADPKD is one of the most common monogenic disorders worldwide (1:500e1000 live births). Inabout 90% of cases, a mutation in either the PKD1 gene on chromosome 16 or the PKD2 gene onchromosome 4 is found. Penetrance is complete, and virtually all carriers develop kidney cysts, butexpressivity is highly variable and only partially understood. The clinical manifestations increase withage, and ADPKD may be asymptomatic in the childbearing age. Besides the non-specific 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 ofintracystic bleeding an indication for caesarean section on account of the increased abdominal pressureat parturition [112]. Other groups, including ours, limit the indication for caesarean section to caseswith large cysts and recent or massive bleeding.

Counselling may be challenging: prenatal diagnosis is feasible in about 90% of the cases (PKD1 andPKD2 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 geneticscreening in pregnancy. Considering the progress that has been made in the treatment of kidneydiseases, 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 preimplantationselection, which is a matter of intense controversy [111,112].

Diabetic nephropathy

The improvements in maternalefoetal and diabetic care allow pregnancy in an increasing numberof type 1 diabetic women with end organ damage. In the presence of scattered evidence, the risk ofpregnancy-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



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 clinicallychallenging and of difficult 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 renalfunction; stage 5: end-stage disease), renal disease (such as: glomerular, interstitial and polycystickidney disease; systemic diseases and diabetic nephropathy), the presence of hypertension and thepresence and degree of proteinuria.

The prognosis of pregnancy is the result of a combination of these elements, and this makescounselling complex as the available evidence does not suffice to allow us to define risk in individualpatients. Notwithstanding these limits, pregnancy is possible in all CKD stages and is increasinglyreported also on dialysis. The risk of adverse outcome is already higher in the first CKD stage andincreases in proportion to renal function impairment. CKD is often asymptomatic and pregnancy is anopportunity for diagnosis. Differential diagnosis with PE may be difficult; however, the presence ofnormal utero-placental flows and, whenever available, angiogeniceantiangiogenic profile suggeststaking 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 nephrop-athy, while perinatal death is mainly reported in lupus nephritis, diabetic nephropathies and ondialysis. 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 notincrease, with the possible exception of diabetic nephropathy; however, the genetics of kidney diseasesis complex and should be discussed in counselling. Multidisciplinary management and strict clinicalfollow-up are the basis for maternalefoetal care.

Practice points

� CKD is associated with an increased risk of adverse pregnancy-related outcomes (i.e., pre-

maturity, 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 immu-

nologic 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 dis-

eases, 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 derange-

ment, 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.


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.


Conflict of interest

No financial disclosure or conflict 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 filtration 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 refining 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.[9] Krutz�en E, Olofsson P, B€ack SE, et al. Glomerular filtration 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

filtration rate in pregnancy. Hypertens Pregnancy 2009;28:243e55.[11] Smith MC, Moran P, Ward MK, et al. Assessment of glomerular filtration rate during pregnancy using the MDRD

formula. BJOG 2008;115:109e12.*[12] Nevis IF, Reitsma A, Dominic A, et al. Pregnancy outcomes in womenwith 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 inwomenwith renal disease and moderate renal insufficiency. 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 insufficiency. 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 womenwith 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 insufficiency: 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.


http://www.kidney.org

http://refhub.elsevier.com/S1521-6934(15)00024-3/sref1































































*[24] Piccoli GB, Clari R, Ghiotto S, et al. Type 1 diabetes, diabetic nephropathy, and pregnancy: a systematic review andmeta-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 flow 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 womenwith 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 novelsusceptibility 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: GWASreplication study and geospatial risk analysis. PLoS Genet 2012;8:e1002765.

[38] Feather SA, Malcolm S, Woolf AS, et al. Primary, nonsyndromic vesicoureteric reflux and its nephropathy is geneticallyheterogeneous, 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 reflux: testing replication of linkage in seven newmultigenerational kindreds. J Am Soc Nephrol 2005;16:1781e7.

[40] Witasp A, Ekstr€om TJ, Schalling M, et al. How can genetics and epigenetics help the nephrologist improve thediagnosis 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 hyperten-

sion: 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 heterogeneousmaternal 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 first-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 DialTransplant 2002;17(Suppl. 4):50e5.

[52] Østensen M, Khamashta M, Lockshin M, et al. Anti-inflammatory 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 meta-analysis. 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 withtacrolimus. Transplantation 2000;70:1718e21.

[55] Park-Wyllie L, Mazzotta P, Pastuszak A, et al. Birth defects after maternal exposure to corticosteroids: prospectivecohort 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 rheumatoidarthritis 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 exposureto 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: casereport and review of the literature. Am J Med Genet A 2009;149A:1241e8.






















































http://www.fda.gov




















































[60] Framarino-dei-Malatesta M, Derme M, Manzia TM, et al. Impact of mTOR-I on fertility and pregnancy: state of the artand review of the literature. Expert Rev Clin Immunol 2013;9:781e9.

[61] Palmer BF. Sexual dysfunction in men and womenwith chronic kidney disease and end-stage kidney disease. Adv RenReplace Ther 2003;10:48e60.

[62] Holley JL, Schmidt RJ. Changes in fertility and hormone replacement therapy in kidney disease. Adv Chronic KidneyDis 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, Røislien 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 multi-

center 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 im-

proves 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 DialTransplant 2014 Aug;29(8):1578e86.

[83] Shahir AK, Briggs N, Katsoulis J, et al. An observational outcomes study from 1966-2008, examining pregnancy andneonatal 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 intensivehemodialysis 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 fromdialysed mothers? Nephrol Dial Transplant 2012;27:2365e9.

*[86] Deshpande NA, James NT, Kucirka LM, et al. Pregnancy outcomes in kidney transplant recipients: a systematic reviewand 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 SocNephrol 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 Preg-nancy. Obstet Gynecol 2013;122:1122e31.














































































































[95] Magee LA, von Dadelszen P, Rey E, et al. Less-tight versus tight control of hypertension in pregnancy. N Engl J Med2015;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. AmJ Kidney Dis 2010;55:1026e39.

[98] Wang IK, Muo CH, Chang YC, et al. Association between hypertensive disorders during pregnancy and end-stage renaldisease: 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 Nephrol2013;8:41e50.

[100] Hladunewich MA, Steinberg G, Karumanchi SA, et al. Angiogenic factor abnormalities and fetal demise in a twinpregnancy. Nat Rev Nephrol 2009;5:658e62.

[101] Piccoli GB, Daidola G, Attini R, et al. Kidney biopsy in pregnancy: evidence for counselling? A systematic narrativereview. BJOG 2013;120:412e27.

[102] North RA, Ferrier C, Gamble G, et al. Prevention of preeclampsia with heparin and antiplatelet drugs in women withrenal 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 inwomen 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 withsystemic 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 studiesfrom 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 duringpregnancy. Cochrane Database Syst Rev 2012;11:CD009279.

[109] Kenyon SL, Taylor DJ, Tarnow-Mordi W. Broad spectrum antibiotics for spontaneous preterm labour: the ORACLE IIrandomised trial. Lancet 2001;357:989e94.

[110] Nordenq H, Luppatelli A, Romoren M, et al. Neonatal outcomes after gestational exposure to nitrofurantoin. ObstetGynecol 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.
























































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