Renal disease in pregnancy

REVIEW

Renal disease in pregnancyMatt Hall

Nigel J Brunskill

AbstractKidney disease in pregnancy is rare but associated with considerable risks

of adverse maternal and foetal outcomes, and considerable anxiety on

the part of the clinician. Evidence based strategies for management are

limited. In this review we will discuss current trends in monitoring, treat-

ment and prognosis for patients with chronic kidney disease, end-stage

kidney disease and acute kidney injury in pregnancy.

Keywords chronic kidney disease; dialysis; pregnancy; transplant

National Kidney Federation K/DOQI classification ofchronic kidney disease

CKD stage Estimated GFR Comment

1 >90 ml/min Only classified as CKD if

associated with renal structural

or urinary dipstick abnormalities

2 60e89 ml/min

3 30e59 ml/min May be subclassified into:

Introduction

During normal pregnancy, the maternal cardiovascular system

undergoes important changes. Blood volume and red cell mass

increase by up to 50%, systemic vascular resistance falls and

cardiac output increases by up to 30%. Given the central role of

the kidney in maintaining fluid and blood pressure homeostasis,

these cardiovascular adaptations have the following profound

effects on renal function:

� renal blood flow increases by 50%

� glomerular filtration rate (GFR) increases by 30%

� serum creatinine decreases by 20%.

Reciprocal changes in cardiac output and vascular resistance

minimize alteration in blood pressure, however blood pressure

falls in the first two trimesters and gradually returns to baseline as

the pregnancy approaches term. In normal pregnancy, increased

GFR, changes in glomerular haemodynamics and possibly alter-

ations in renal tubular function lead to an increase in urine

protein excretion. In the general female population an upper limit

of normal urine protein excretion is 150 mg/d whereas in normal

pregnancy it is 260 mg/d.

Increased renal blood flow and generalized vascular dilatation

increases renal size by approximately 1 cm in length during

normal pregnancy. Smooth muscle relaxation and compression

of the ureters by the gravid uterus commonly lead to pelvicaly-

ceal dilatation, more prominently on the right than the left.

The magnitude of these changes makes it unsurprising that

limitation to adaptation by chronic kidney disease (CKD) leads to

adverse pregnancy outcomes.

Matt Hall MA MB MRCP(UK) is a Specialist Registrar in Renal Medicine at

John Walls Renal Unit, Leicester General Hospital, Leicester, UK.

Conflicts of interest: none declared.

Nigel J Brunskill MB PhD FRCP is Professor of Renal Medicine at the John

Walls Renal Unit, Leicester General Hospital, Leicester, UK. Conflicts of

interest: none declared.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 20:5 131

Chronic kidney disease

Definition

The National Kidney Foundation K/DOQI classification of

chronic kidney disease (CKD) has been embraced internationally

(Table 1). Progression through these stages of disease correlates

with the risk of developing end-stage renal disease (ESRD), the

development of CKD-related complications (erythropoietin defi-

ciency, renal mineral and bone disorder) and increasing cardio-

vascular risk. Classification of an individual as having CKD is

dependent on abnormalities in serum biochemistry, urinary

constituents or renal structure that are persistent for 3 months or

more.

Measuring renal function

Glomerular filtration rate: in the general population, serum

creatinine has been supplemented as a marker of renal function

by estimated glomerular filtration rate (eGFR). Formulaic esti-

mations of eGFR depend on the serum creatinine and other

variables such as patient age and gender. In the United Kingdom,

eGFR is usually calculated using the four-variable Modification of

Diet in Renal Disease (MDRD) formula although importantly this

is not validated for use in pregnancy. The equation is inaccurate

at values greater than 60 ml/min. The Cockcroft and Gault

formula is less accurate at estimating GFR than the MDRD

formula, particularly with more severe CKD but requires input of

the patient’s weight.

An alternative method of measuring renal function is by

calculation of the creatinine clearance. Calculated creatinine

clearance has similar accuracy to the MDRD formula but requires

a 24-h urine collection which is inconvenient and therefore often

incomplete. The ‘gold standard’ for measuring GFR is inulin

clearance or radiolabelled-EDTA clearance. This is highly

reproducible but labour intensive, expensive and invasive.

Neither the four-factor MDRD equation, nor the Cockcroft and

Gault equation is valid in pregnancy due to alterations in renal

haemodynamics together with changes in interstitial fluid distri-

bution and consequently the volume of distribution of creatinine.

Therefore most centres continue to rely on the serum creatinine

concentration to identify potential renal dysfunction.

3a: 45e59 ml/min

3b: 30e44 ml/min

4 15e29 ml/min

5 <15 ml/min or on

dialysis

GFR; glomerular filtration rate, Estimated GFR calculations are not valid

during pregnancy.

Table 1

� 2010 Elsevier Ltd. All rights reserved.

REVIEW

Proteinuria: for routine clinical use, urine reagent dipstick tests

are a simple and cheap semi-quantitative method for measuring

proteinuria, but are subject to inaccuracy due to changes in urine

concentration, acidity and the presence of bacteruria and various

drugs. Dipstick tests are useful for screening for proteinuria and

should be supplemented by quantitative measurement if

abnormal.

Traditionally, protein excretion is quantified by measurement

of a 24-h collection of urine. This is inconvenient for the patient

and collections are often incomplete. Nevertheless, if performed

correctly, this remains the most accurate method available.

In general nephrological practice, the protein:creatinine ratio

(PCR) or albumin:creatinine ratio (ACR) are accepted as surro-

gates for 24-h collections. They are also included in international

diagnostic guidelines for pre-eclampsia. Assuming steady

production and excretion of creatinine, this method corrects for

variations in urine concentration and correlates closely with

complete 24-h urine collection data. PCR or ACR should be used

for quantitative monitoring of proteinuria during pregnancy.

Epidemiology and aetiology

CKD is rare in pregnant patients, affecting 0.15% of pregnancies,

and most patients have early stages of CKD. In the general

population, diabetes mellitus and hypertension are the com-

monest causes of CKD. In a prospective data series from three

specialist renal-obstetric services in the UK, chronic pyelone-

phritis and primary glomerulonephritis are more common in

pregnancy and CKD (Figure 1). These differences in aetiology are

predominantly a result of patients’ age and that more aggressive

or severe CKD leads to impaired fertility.

For some patients, pregnancy is the first time that their blood

pressure and urine are monitored; hypertension, proteinuria or

haematuria detected at booking may uncover previously undi-

agnosed CKD. The development of hypertension and urinary

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Figure 1


dipstick abnormalities later in pregnancy can represent de novo

renal disease but must be differentiated from pre-eclampsia.

Investigation

Pre-existing CKD: by definition, isolated measurements of blood

pressure, serum creatinine or proteinuria are of limited value in

CKD. Establishing baseline level of renal function and protein-

uria, and identifying changing trends in values in the knowledge

of on-going treatment are of crucial importance.

At thebookingvisit, serum creatinine, andeitherurinePCR/ACR

or 24-h urine collection should be performed to determine baseline

renal function and urine protein excretion. A repeat 24-h urine

collection is indicated when precise quantification of proteinuria is

required, for example, in diagnosing pre-eclampsia when the PCR is

equivocal or if nephrotic syndrome is suspected (see below).

Patients should have the following recorded at every subse-

quent visit:

� blood pressure

� urine dipstick

� urine PCR or ACR, and/or urine culture, if dipstick positive.

Depending on the level of renal function at baseline. The

following should be measured every 6e8 weeks during

pregnancy:

� serum creatinine, urea and urate

� haemoglobin.

More frequent measurement is required if renal function is

abnormal or deteriorating.

For patients with renal transplants, trough serum levels of the

calcineurin inhibitors tacrolimus or cyclosporine should be

measured at every visit. Altered pharmacodynamics during

pregnancy necessitate careful titration of doses of these drugs to

maintain adequate levels whilst avoiding toxicity.

A renal ultrasound is required during pregnancy if:

� there is a sudden decline in renal function

� there are signs or symptoms suggestive of obstruction or renal

stone disease

� a new diagnosis of CKD is suspected following booking visit

investigations.

Functional ureteric obstruction should only be suspected if there

are progressive changes on serial renal ultrasound scans,

suggestive signs and symptoms, or worsening renal function.

Suspected new diagnosis of CKD: in a suspected new case of

CKD, large kidneys on ultrasound may reflect polycystic kidney

disease, diabetic nephropathy or chronic obstruction. Focal

scarring of kidneys may reflect a congenital abnormality of the

kidney and urinary tract (CAKUT) in the mother, most commonly

vesicoureteric reflux. Small kidneys may be the result of any

chronic process and further diagnosis may be difficult. Renal

biopsy tends to show non-specific scarring and inflammation only

and is generally not performed.

Renal biopsy can be performed during pregnancy by experi-

enced radiologists or nephrologists but should be reserved for:

� unexplained decline in kidney function in CKD or acute

kidney injury

� newly diagnosed nephrotic syndrome

� features suggestive of systemic disease or vasculitis.

A renal biopsy is not indicated to investigate stable CKD, non-

nephrotic range proteinuria or pre-eclampsia, and not after 32


REVIEW

weeks’ gestation when the pregnancy should be brought to an

end prior to renal investigation.

Immunological investigation should be requested if there is

suspicion of intrinsic renal disease e haematuria, proteinuria,

decreased renal function and/or hypertension (Table 2).

Foetal outcomes

Adverse foetal outcomes occur in 18% of pregnancies in mothers

with CKD compared to 9% in those without CKD.

Renal function: mothers with a baseline serum creatinine greater

than 180 mmol/l are faced with risks of developing pre-eclampsia

of 60%, intrauterine growth restriction 65%, preterm delivery

90% and perinatal mortality 10%. Even early CKD (preconception

estimated GFR > 60 ml/min) is associated with increased risk of

prematurity and intrauterine growth restriction as compared to

the general population, predominantly due to an increased risk of

developing pre-eclampsia.

Aetiology of CKD: the aetiology of CKD, rather than the level of

renal function, has minimal impact on foetal outcome with the

exception that asymptomatic bacteruria and overt urinary tract

infection are associated with an increased risk of preterm

delivery. Diabetes mellitus and SLE may lead to adverse foetal

outcome independently of concurrent CKD.

Hypertension: in numerous studies, uncontrolled hypertension in

patients with CKD prior to conception or in early pregnancy is

a key independent predictor of adverse foetal outcome. Blood

pressure increases in the second half of pregnancy in patients with

CKD due to limitations in vascular relaxation and increasing

circulating volume as a result of relative over-activity of the renin-

angiotensin system. Elevated blood pressure predicts the occur-

rence of pre-eclampsia, prematurity, intrauterine growth restric-

tion and neonatal mortality.

When to treat maternal high blood pressure to optimize foetal

outcome is controversial. Foetal outcomes are similar in those with

mild to moderate high blood pressure (<160/100 mmHg) and in

patients treated forhypertension.Aggressive treatment of maternal

hypertension during pregnancy (less than 120/80 mmHg) may lead

to intrauterine growth restriction. In patients with CKD it is

recommended to target a blood pressure of <140/90 mmHg,

predominantly to reduce maternal complications (see below).

Immunological investigation of suspected intrinsic renal dise

Test Comments

Anti-nuclear antibodies (ANA) Found in connecti

(anti-dsDNA) and

Anti-neutrophil cytoplasmic antibodies (ANCA) Associated with sm

polyangiitis).

Complement components C3 and C4 Decreased levels a

mesangiocapilliary

cryoglobulinaemia

Serum and urine immunoglobulins and light chains Plasma cell dyscra

Other tests Rheumatoid factor

Table 2


Proteinuria: elevated urine protein excretion is associated with

intrauterine growth restriction however this effect can be almost

wholly accounted for by concurrent comorbidity (predominantly

hypertension, diabetes mellitus or pre-eclampsia). It is uncertain

whether proteinuria per se is an independent risk factor.

Nephrotic syndrome (proteinuria greater than 3 g/d, serum

albumin less than 30 g/l and oedema) occurs rarely in pregnancy

and is almost always a result of pre-eclampsia. Case series prior

to 2000 report perinatal mortality of greater than 40% if

nephrotic syndrome develops in the first trimester but more

recent anecdotal reports suggest that outcomes are much more

favourable.

Maternal outcomes

Renal function: the risk of developing pre-eclampsia for mothers

with CKD is 20% for patients with mild renal dysfunction (serum

creatinine < 125 mmol/l) and 60% with severe impairment

(serum creatinine > 180 mmol/l), compared to approximately 5%

in the general population. These estimations vary between

studies as a result of heterogeneity between study cohorts and

variations in diagnostic criteria used. CKD is commonly associ-

ated with proteinuria and hypertension prior to conception and

the diagnosis of ‘superimposed pre-eclampsia’ relies on arbitrary

increases in these parameters with or without additional clinical

features of pre-eclampsia (Box 1).

Decline in renal function during pregnancy occurs rarely in

patients with mild impairment at baseline (serum creatinine

<125 mmol/l) and often reflects an episode of obstruction,

pyelonephritis or pre-eclampsia. In such cases, return to baseline

renal function almost always occurs within 3 months post-par-

tum. The increase in GFR normally seen in the second and third

trimester may occur in patients with moderate or severe CKD

(serum creatinine > 125 mmol/l) and serum creatinine may fall

accordingly. In some however GFR may be reduced in the setting

of worsening hypertension and glomerular endotheliosis associ-

ated with pre-eclampsia.

Patients with severe CKD at baseline (serum creatinine

>180 mmol/l) have a 70% risk of declining renal function during

pregnancy and most of these patients fail to return to baseline

renal function post-partum. Women with a preconception serum

creatinine greater than 180 mmol/l have a one in three chance of

requiring dialysis during pregnancy or within 6 months of

delivery.

ase

ve tissue diseases and SLE. Antibodies against double-stranded DNA

extractable nuclear antigens (ENA) should be performed if positive.

all vessel vasculitis (Wegener’s granulomatosus and microscopic

re found in active SLE, post-infectious glomerulonephritis,

glomerulonephritis, subacute bacterial endocarditis,

and heavy chain-deposition disease

sias may be identified by a monoclonal band on electrophoresis.

, cryoglobulins and C3 nephritic factor measurement may be indicated.


National High Blood Pressure Education ProgramReport on High Blood Pressure in Pregnancy criteriafor the diagnosis of superimposed pre-eclampsia

C Blood pressure > 160/110 mmHg

C Blood control suddenly worsening after a period of good

control

C Development of proteinuria > 2000 mg/d or abrupt worsening

of proteinuria

C Serum creatinine increasing to > 110 mmol/l

Box 1

Medications use in CKD and pregnancy

Anti-hypertensives

Commonly used Rarely used Contraindicated

Nifedipine Beta-blockers ACE inhibitors

Labetalol Alpha-blockers Angiotensin receptor

blockers

Methyldopa Amlodipine Aliskiren

Hydralazine Verapamil Spironolactone

Moxonidine

Minoxidil (3rd trimester)

Thiazide diuretics

Diltiazem

Immunosuppressants

Likely to be safe Likely to be harmful Contraindicated

Prednisolone Anti-thymocyte

globulin

Mycophenolate

Azathioprine Rituximab Sirolimus

Ciclosporin Methotrexate

Tacrolimus

ACE, angiotensin converting enzyme.

Table 3

REVIEW

Aetiology of CKD: the underlying aetiology of CKD has little

impact on maternal outcome. Pregnancies in patients with

systemic sclerosis or polyarteritis nodosum complicated by CKD

have been associated with particularly poor maternal outcome

although data are limited.

There is an increased risk of asymptomatic bacteruria pro-

gressing to overt infection and pyelonephritis during pregnancy.

Patients with recurrent urinary tract infection or vesicoureteric

reflux are at particular risk and should be screened for bacteruria

by dipstick analysis and urine culture. Asymptomatic bacteruria

should be actively treated to reduce the risk of potentially serious

sepsis and reduce the incidence of preterm delivery.

Lupus nephritis often enters a phase of quiescence during

pregnancy as a result of increased endogenous corticosteroid

production. Consequently, flares can often occur in the puerpe-

rium when increased vigilance is recommended.

If lupus flares do occur during pregnancy they can be difficult to

distinguish from pre-eclampsia e hypertension, proteinuria and

decline in renal function, often with thrombocytopaenia. The

presence of invisible haematuria, depressed serum complement

levels, a rise in anti-double-stranded DNA titre and cutaneous

manifestations of SLE support a diagnosis of a lupus flare and

should be treated promptly. Renal biopsy may be required if renal

function declines quickly, or if nephrotic syndrome develops, in

order to determine the most appropriate treatment for the renal

disease. In this case the outlook for the pregnancy is poor. Changes

in serum angiogenic factors (soluble fms-like tyrosine kinase,

endoglin and placental growth factor) may be useful in differen-

tiating pre-eclampsia from other conditions but this approach is

not yet in common clinical use. Patients with SLE and anti-phos-

pholipid antibodies are at greatly increased risk of thromboem-

bolic disease and pre-eclampsia.

Hypertension: chronic hypertension is common in patients with

CKD. Increasing blood pressure refractory to treatment is often

seen as an indication for delivery, even in the absence of overt

pre-eclampsia. Severe hypertension (blood pressure >180/110

mmHg) associated with retinopathy, acute kidney injury,

pulmonary oedema or ischaemic chest pain requires immediate

treatment in a high-dependency setting. Such a scenario is rare,

however, and the majority of cases can be managed by titration

of oral anti-hypertensive agents and timely delivery.

There are contradictory reports of the impact of blood pres-

sure during pregnancy on progression of maternal renal disease,


however, contemporary prospective data from our unit suggest

that baseline diastolic blood pressure greater than 75 mmHg or

use of anti-hypertensive agents is predictive of accelerated

decline in renal function post-partum.

Proteinuria: increased urine protein excretion is predictive of

progressive renal dysfunction in general nephrology where

proteinuria per se is believed to be nephrotoxic. During normal

pregnancy, where urinary protein excretion can double, the

impact of proteinuria on kidney function is less clear, certainly in

the short to medium term.

In patients with eGFR less than 40 ml/min before conception,

proteinuria greater than 1 g/d is associated with an increased rate

of renal decline post-partum compared with than those with less

proteinuria. No similar effect is seen in patients with preserved

renal function.

Mothers who develop nephrotic syndrome during pregnancy

are at increased risk of venous thromboembolism. Loss of anti-

thrombotic serum components in the urine leads to increased

thrombotic tendency and strong consideration should be given to

the use of prophylactic anti-coagulation with low molecular

weight heparin (see below).

In the absence of nephrotic syndrome or renal dysfunction,

proteinuria does not appear to have a prominent independent

effect on maternal outcomes.

Management

Preconception counselling: ideally, all patients with CKD should

be offered counselling prior to conception in order to evaluate the

risks of proceeding with pregnancy and the likely outcomes.

Medications known to be harmful to the developing foetus can be

discontinued or substituted for safer alternatives (Tables 3 and 4).

Patients with active lupus nephritis or vasculitis, and those

with poorly controlled blood pressure should be advised to wait


Medications used in CKD and breastfeeding

Anti-hypertensives

Likely to be safe Likely to be harmful Contraindicated

Hydralazine Most dihydropyridine

calcium channel

blockers

Aliskiren

Nifedipine Celiprolol, nebivolol Most ACE inhibitors

Methyldopa Alpha-blockers Angiotensin receptor

blockers

Most beta-blockers Moxonidine

Enalapril Spironolactone

Furosemide

Thiazide diuretics

Minoxidil

Immunosuppressants

Prednisolone Mycophenolate Sirolimus

Azathioprine Ciclosporin Rituximab

Tacrolimus Methotrexate

Anti-thymocyte

globulin

ACE, angiotensin converting enzyme.

Table 4

REVIEW

until these are optimized before trying to conceive. Similarly,

patients with significant renal dysfunction (serum creatinine >

180 mmol/l) may not accept the risks associated with proceeding

with pregnancy and may be better advised to wait until they have

received a renal transplant.

In the majority of cases, patients need not be discouraged

from trying to conceive as long as the potential risks are under-

stood and the pregnancy is closely monitored.

Anti-hypertensive treatment: methyldopa, labetalol, nifedipine

and hydralazine are the most frequently used agents to treat

hypertension in pregnancy. All appear to be safe and well-

tolerated in pregnancy. Methyldopa should be avoided in

patients with depression.

Angiotensin converting enzyme inhibitors and angiotensin

receptor blockers must be avoided throughout pregnancy as they

are associated with congenital malformations and foetal urinary

tract agenesis. Diuretics can exacerbate intravascular volume

depletion in hypertensive disorders of pregnancy and lead to

IUGR. Labetalol appears safe but other beta-blockers may be

associated with intrauterine growth restriction (IUGR).

For patients with CKD it is well-recognized that control of

hypertension is essential to abrogate decline in renal function.

Consensus guidelines derived from the RCOG Study Group on

renal disease and pregnancy recommend that a target blood

pressure of 140/90 mmHg is attained during pregnancy. Data to

support blood pressure treatment targets for patients with CKD

during pregnancy is lacking however. Mild to moderate hyper-

tension (<160/90 mmHg) for the limited duration of gestation is

unlikely to result in significant long-term cardiovascular damage

and aggressive treatment of hypertension may result in adverse


foetal outcome (see above). Severe hypertension (>160/100

mmHg) in the third trimester requires treatment to reduce the

risk of intracerebral haemorrhage in labour.

Other medication: recommendations on the use of medications

during pregnancy are based on experience and consensus

guidelines rather than evidence. Tables 3 and 4 list drugs

commonly prescribed in CKD and transplantation and their use

in pregnancy and breastfeeding.

In transplantation, a combination of prednisolone, azathio-

prine and tacrolimus or cyclosporine can be used during

pregnancy.

� At high doses (>20 mg/d) prednisolone can lead to foetal

adrenal insufficiency and risk of maternal infection. Mainte-

nance doses of less than 10 mg/d appear safe and well-

tolerated in pregnancy.

� Cyclosporine and tacrolimus may exacerbate hypertension

and limit renal adaptation to pregnancy. Foetal growth

restriction may be associated with these agents.

� Azathioprine is teratogenic in high doses in animal studies. In

humans it has been used without obvious teratogenicity. It

may be associated with foetal growth restriction.

Erythropoietin, vitamin D analogues and intravenous iron appear

safe in pregnancy.

Low molecular weight heparin: pregnancy is a pro-thrombotic

state and this is exacerbated by heavy proteinuria. Patients with

nephrotic range proteinuria (>3 g/d) should receive prophylactic

LMWH during pregnancy, particularly if there is hypo-

albuminaemia, obesity or other risk factors for venous thrombo-

embolism. Advice on thromboprophylaxis in pregnancy is

published by the Royal College of Obstetricians and Gynaecologists.

LMWH should be continued for at least 6 weeks following delivery.

Anti-microbial therapy: confirmed asymptomatic bacteruria

and symptomatic UTI during pregnancy should be treated with

antibiotics to reduce the risk of ascending infection and preterm

delivery. If more than one episode of bacteruria is confirmed

during pregnancy, prophylactic antibiotics should be prescribed.

The choice of antibiotic is determined by stage of pregnancy,

sensitivities of the cultured organisms and local practice. Ceph-

alosporins and penicillins are safe and well-tolerated throughout

pregnancy. Gentamicin may be used for severe pyelonephritis

with appropriate monitoring.

Trimethoprim is a folate antagonist and should be avoided in

the first trimester. Nitrofurantoin is associated with neonatal

haemolysis if used in the third trimester and should be avoided.

Quinolones should not be used throughout pregnancy.

Dialysis and pregnancy

End-stage renal failure reduces maternal fertility and conception

is rare in patients receiving dialysis. It is estimated that an

average sized renal unit in the United Kingdom will see one case

of dialysis and pregnancy per 4 years.

Approximately 25% of pregnancies in patients on dialysis end

with spontaneous abortion or termination in the first trimester. Of

those that progress to later pregnancy, adverse events are common:

� intrauterine growth restriction in 90%

� preterm delivery in 90%


REVIEW

� pre-eclampsia in 75%

� perinatal death in 50%.

Dialysis modality

Peritoneal dialysis: successful pregnancies can proceed in

patients using peritoneal dialysis (PD). The continuous nature of

the process limits uraemia and avoids rapid fluid shifts which

may compromise uteroplacental perfusion. As pregnancy prog-

resses the gravid uterus can reduce peritoneal blood flow and

prevent instillation of sufficient fluid to make PD effective. In the

absence of residual renal function, patients on PD may be unable

to control fluid status adequately during pregnancy, necessitating

transfer to haemodialysis (HD). Nevertheless, an elective change

from PD to HD is not mandatory for patients who are already

established on PD at the time of conception.

Haemodialysis: the efficiency of haemodialysis (HD) in

removing toxic metabolites is affected by the duration of dialysis

session, the frequency of dialysis, the surface area of semi-

permeable membrane and the blood flow rate. As it is an inter-

mittent process, fluid and circulating uraemic toxins accumulate

between treatments.

Dialysis frequency should be increased to at least 20 h a week

during pregnancy to achieve:

� pre-dialysis urea less than 20 mmol/l (ideally less than

15 mmol/l)

� intradialytic fluid loss of less than 1000 ml per session.

Five times a week or even daily dialysis may be required.

Pre-eclampsia and dialysis

Pre-eclampsia occurs early and may be severe. Diagnosis of pre-

eclampsia is made in the context of worsening hypertension with

additional clinical features such as coagulopathy, liver dysfunc-

tion, intrauterine growth restriction or neurological symptoms.

Dialysis patients always display urinary dipstick abnormalities or

may be anuric, so testing for proteinuria is unhelpful.

Management

Blood pressure: intensive dialysis and fluid removal can accen-

tuate the haemodynamic changes in pregnancy causing blood

pressure instability and hypotension. However, many dialysis

patients have treated chronic hypertension prior to conception,

and medication may need to be reduced to maintain a diastolic

blood pressure greater than 80 mmHg. Lower blood pressure

may contribute to IUGR. Later in pregnancy blood pressure may

rise further due to pre-eclampsia necessitating further changes in

medication.

Fluid balance: the patient’s ‘‘dry weight’’ will increase by

approximately 1.5 kg in the first trimester and then 0.5 kg per

week until delivery. These changes should be supervised by

careful clinical evaluation of the patient’s fluid status.

Electrolyte balance: intensive dialysis can lead to excess loss of

potassium, calcium and over-repletion with bicarbonate. The

composition of dialysis fluid used should be adjusted to counter

this.

Nutrition: intensive dialysis leads to protein malnutrition

through loss of amino acids, and the pregnancy necessitates


increased protein intake. Dietetic input is crucial to maintain

input of at least 1.8 g protein/d.

Anaemia management: erythropoietin replacement during

pregnancy appears safe. Required doses may increase and

intravenous iron is usually requires to maintain stores. A target

haemoglobin of 10e11 g/dl is suggested.

Kidney transplantation and pregnancy

The first successful pregnancy in a recipient of a kidney trans-

plant occurred in March 1958. Over 15,000 children have been

born to mothers with renal transplants since then.

Maternal and foetal outcomes for pregnancies following renal

transplantation are far superior to those for mothers on dialysis.

The risks are predominantly related to the level of renal function

at conception and blood pressure control. Transplant rejection

and function are not affected by pregnancy assuming the

following are met:

� At least 12 months post-transplant.

� Stable renal function.

� Proteinuria <1 g/d.

� Minimal or well-controlled hypertension.

� No recent or on-going transplant rejection.

� Minimal levels of appropriate immunosuppression (seebelow).

For mothers with baseline creatinine less than 125 mmol/l,

successful pregnancy occurs in 97% of cases reaching the second

trimester. The incidence of preterm delivery, intrauterine growth

restriction and pre-eclampsia is greater than the general pop-

ulation and 30% of pregnancies may be affected.

With more severe baseline renal dysfunction, the incidence of

adverse foetal outcome increases. The likelihood of accelerated

maternal renal decline is also higher. In one study, all transplant

patients with creatinine greater than 200 mmol/l at conception

progressed to dialysis within 2 years.

There is no evidence of delayed development in children born

to mothers with a renal transplant, independent of complications

associated with preterm delivery.

Normal vaginal delivery is not contraindicated following renal

transplantation. If caesarean section is indicated then a lower

segment approach may be difficult due to the course of the

transplanted ureters.

Acute kidney injury in pregnancy

Definition

Acute kidney injury (AKI) is defined as a reduction in urine

output with biochemical evidence of decreased GFR. AKI in

pregnancy is rare.

Aetiology

AKI can be due to inadequate renal perfusion (pre-renal),

obstruction of the urinary tract (post-renal) or due to intrinsic

renal disease.

Pre-renal AKI in pregnancy follows sepsis, haemorrhage or

hypovolaemia (from hyperemesis or diarrhoea). This is the

commonest cause of AKI in pregnancy, particularly in developing

countries.

Urinary tract obstruction in pregnancy may be due to renal

stones, compression by the gravid uterus or exacerbation of


Indications for initiation of renal replacement therapyduring pregnancy

Absolute indications Relative indications

Refractory hyperkalaemia Moderate uraemia (urea >25 mmol/l)

Refractory fluid overload Resistant hypertension

Refractory metabolic acidosis

Severe uraemia causing

encephalopathy or pericarditis

Table 5

REVIEW

anatomical abnormalities (such as pelviuretic junction obstruc-

tion) by the morphological changes described above.

AKI due to intrinsic renal disease is commonly a result of

acute tubular necrosis following sustained hypoperfusion,

glomerular endotheliosis due to pre-eclampsia or acute lupus

nephritis. Primary renal disease may flare during pregnancy

(such as minimal change nephropathy or vasculitis) or, rarely, de

novo renal disease may develop.

Rare causes of AKI in pregnancy include ovarian hyperstim-

ulation syndrome, acute fatty liver of pregnancy and haemolytic

uraemic syndrome/thrombotic thrombocytopenic purpura

(HUS/TTP).

Investigation

A renal ultrasound is mandatory to exclude obstruction.

Hypoperfusion leading to pre-renal AKI is often self-evident

but imaging to identify covert sources of haemorrhage and

microbiological screening for sepsis may be necessary.

Immunological investigations should be requested if intrinsic

renal disease is suspected (Table 2). A renal biopsy may be

required if a diagnosis is not obvious and there is evidence of

severe or progressive renal impairment.

Management

Practice points

C Renal disease in pregnancy is a rare but important cause of

adverse maternal and foetal outcomes.

C Patient risk is proportional to their renal function and blood

pressure control prior to conception.

C Outcomes can be optimized by early identification of patients

at risk, close monitoring within a multidisciplinary team and

early treatment of urinary infection and blood pressure.

Successful management of AKI during pregnancy requires

frequent communication between nephrologist, obstetrician,

neonatologist and patient to optimize renal recovery, timing of

delivery and foetal viability.

Serial measurement of serum creatinine, urine output and

blood pressure is essential in AKI, ideally in a high-dependency

unit. Close attention to optimizing fluid status is crucial and this

may require invasive monitoring with central venous pressure

measurement. Nephrotoxic medications (including NSAIDs)

must be avoided.

The principles of therapy are:

1. To reduce or remove the underlying insult.

2. To optimize renal perfusion.

3. To identify the patient who, despite the above, requires renal

replacement therapy.

Indications for dialysis in pregnancy are similar to those in

general nephrology although a lower threshold for initiation has

been suggested to limit foetal uraemic exposure (Table 5). AKI in

pregnancy requiring dialysis is rare, occurring one in 20,000

pregnancies in developed countries. If renal replacement therapy

is required prior to 24 weeks gestation, foetal survival is poor.

Haemodialysis is generally preferred over peritoneal dialysis

as the modality of choice for initiating renal replacement therapy


in pregnancy as (a) the dose of dialysis can be titrated accurately,

(b) in can be initiated immediately and (c) it avoids the need for

insertion of a peritoneal catheter (see Dialysis and pregnancy).

Continuous venovenous haemofiltration is better tolerated in

patients with haemodynamic instability although the rate of

solute clearance is slower.

Specific therapy is indicated for some intrinsic renal diseases,

such as corticosteroids in lupus nephritis or plasmapheresis in

HUS/TTP. Urinary tract obstruction should be relieved by intra-

vesical catheter, ureteric stent insertion or a nephrostomy. AKI

secondary to pre-eclampsia requires timely foetal delivery. A

FURTHER READING

Davison JM, Nelson-Piercy C, Kehoe S, Baker P, eds. Renal disease in

pregnancy. London: RCOG Press, 2008.

Gammill HS, Jeyabalan A. Acute renal failure in pregnancy. Crit Care Med

2005; 33: S372e84.

McKay DB, Josephson MA. Pregnancy in recipients of solid organs e

effects on mother and child. N Engl J Med 2006; 354: 1281e93.

Williams D, Davison J. Chronic kidney disease in pregnancy. BMJ 2008;

336: 211e5.


Renal disease in pregnancy

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