PREGNANCY AND CHRONIC KIDNEY DISEASE

1. Chronic Kidney Disease

Chronic kidney disease (CKD) is a pathophysiological progressive process of the loss of
nephron number and function that will results in end-stage renal disease (ESRD). t can
be cause by multiple etiologies mainly by diabetes, hypertension, glomerulonephritis and
polycystic kidney disease [1]. The symptoms of renal dysfunction must be present for at
least 3 months for it to be considered chronic. The symptoms include gastrointestinal
tract symptoms such as anorexia, nausea, vomiting, diarrheae; skin manifestations such
as pruritus, dry skin, ecchymosis; fatique, increased somnolence, failure to thrive,
malnutrition and many more [2]. Generally, these disturbances become clinically
manifest with CKD stage 4-5 with glomerular filtration rate of < 30mL/min.
For young women with renal insufficiency, it is important to have a counselling regarding
fertility and pregnancy outcome. Successful pregnancy prognosis can be estimated by
considering arbitrary categories of renal function that include normal or mild impairment,
defined as serum creatinine of less than 1.5mg/dL; moderate impairment, defined as a
serum creatinine of 1.5-3.0mg/dL and severe renal insufficiency, defined as a serum
creatinine greater than 3.0mg/dL.

. RenaI Changes in NormaI Pregnancy
n pregnancy, dramatic changes occur with respect to both renal plasma flow and
glomerular filtration. By the second trimester, renal plasma flow increases approximately
75% above baseline, and then decreases by the end of the third trimester. The
glomerular filtration rate is increased almost 50% by the end of the first trimester, and
this rate is maintained throughout gestation. Glomerular filtration is clinically assessed by
creatinine clearance, and because creatinine is also secreted by the renal tubules, the
actual glomerular filtration rate is less than the measured creatinine clearance [3]. The
overall effect of the increase in both renal plasma flow and glomerular filtration rate
causes a decrease in the filtration fraction until the third trimester, when renal plasma
flow falls slightly.
Changes to the kidney during normal pregnancies are summarized in the table below:
Table 1. Renal Changes in Normal Pregnancy [4]
AIteration CIinicaI ReIevance
ncreased
renal size
Renal length
approximately 1 cm
greater on radiographs
Postpartum decreases in size should not
be mistaken for parenchymal loss
Dilatation of
pelves,
calyces, and
ureters

Resembles
hydronephrosis on
ultrasound or VP (more
marked on right)

Not to be mistaken for obstructive
uropathy; retained urine leads to
collection errors; upper urinary tract
infections are more virulent; may be
responsible for "distention syndrome"
elective pyelography should be deferred
to at least 12 weeks postpartum
ncreased
renal
hemodynamics

Glomerular filtration rate
and renal plasma flow
increase ~50%

Serum creatinine and urea nitrogen
values decrease during normal gestation;
>0.8mg/dL (> 72 mol/L) creatinine
already suspect; protein, amino acid, and
glucose excretion all increase
Changes in
acidbase
metabolism

Renal bicarbonate
threshold decreases;
progesterone stimulates
respiratory center

Serum bicarbonate and Pco
2
are 45
mEq/L and 10 mm Hg lower, respectively,
in normal gestation; a Pco
2
of 40 mm Hg
already represents CO
2
retention
Renal water
handling
Osmoregulation altered:
osmotic thresholds for
AVP release and thirst
decrease; hormonal
disposal rates increase

Serum osmolality decreases 10 mOsm/L
(serum Na ~ 5 mEq/L) during normal
gestation; increased metabolism of AVP
may cause transient diabetes insipidus in
pregnancy

AVP =vasopressin; VP = intravenous pyelography.
Maternal posture may also have influence on several aspects of renal function. n
example, late in pregnancy, urinary flow and sodium excretion average less than half
the excretion rate in the supine position compared with that in the lateral recumbent
position. The impact of posture on glomerular filtration and renal plasma flow is much
more variable.
The amounts of various nutrients such as amino acids and water soluble vitamins
excreted in the urine of pregnant women is in much greater amounts than in
nonpregnant women
The physiological changes in renal hemodynamics induced during normal pregnancy
have several implications for the interpretation of tests of renal function. Serum
creatinine and urea nitrogen levels decrease from a mean of 0.7 and 1.2 mg/dL to 0.5
and 0.9 mg/dL, respectively, whereas values of 0.9 and 1.4 mg/dL suggest underlying
renal disease and should prompt further evaluation. Creatinine clearance in pregnancy
should be 30 percent higher than the 100 to 115 mL/min normally measured in non
pregnant women.
Creatinine clearance is a useful test to estimate renal function in pregnancy provided
that complete urine collection is made during an accurately timed period. During the
day, pregnant women tend to accumulate water in the form of dependent edema, and at
night, while recumbent, they mobilize this fluid and excrete it via the kidneys. This
reversal of the usual nonpregnant diurnal pattern of urinary flow causes nocturia, and
the urine is more dilute than in the nonpregnant state. Failure of a pregnant woman to
excrete concentrated urine after withholding fluids for approximately 18 hours does not
signify renal damage. The kidney in these circumstances functions perfectly normally by
excreting mobilized extracellular fluid of relatively low osmolality.
Glucosuria during pregnancy is not necessarily abnormal. The appreciable increase in
glomerular filtration, together with impaired tubular reabsorptive capacity for filtered
glucose, accounts in most cases for glucosuria. Even though glucosuria is common
during pregnancy, the possibility of diabetes mellitus should not be ignored when it is
identified.
Proteinuria normally is not evident during pregnancy except occasionally in slight
amounts during or soon after vigorous labor. Albumin excretion is minimal and ranges
from 5 to 30 mg/day. Hematuria if not the result of contamination during collection, most
often suggests a diagnosis of urinary tract disease. Difficult labor and delivery, of
course, can cause hematuria because of trauma to the lower urinary tract.
. Water MetaboIism in NormaI Pregnancy
ncreased water retention is a normal physiological alteration of pregnancy. This
retention is mediated by a fall in plasma osmolality induced by a resetting of osmotic
thresholds for thirst and vasopressin secretion.
At term, the water content of the fetus, placenta, and amnionic fluid amounts to about
3.5 L. Another 3.0 L accumulates as a result of increases in the maternal blood volume
and in the size of the uterus and the breasts. Thus, the minimum amount of extra water
of an average women during normal pregnancy is about 6.5 L. Demonstrable pitting
oedema of the ankles and legs is seen in most pregnant women, especially at the end of
the day. This accumulation of fluid, which may amount to a litre or so, is caused by an
increase in venous pressure below the level of the uterus as a consequence of partial
occlusion of the vena cava. A decrease in interstitial colloid osmotic pressure induced by
normal pregnancy also favours oedema late in pregnancy.
. EIectroIytes and MineraIs MetaboIism in NormaI Pregnancy
n normal pregnancy, plasma osmolality is decreased approximately 10 mOsm/kg H
2
O
due to a decrease in the concentration of sodium. Despite the decreased serum
concentration, there is an overall increase of almost 1000 mEq of sodium in the maternal
intravascular and interstitial fluids, fetus, and placenta. Sodium loss is increased by the
elevated glomerular filtration rate and by progesterone that promotes natriuresis. This is
offset by a dramatic increase in renal tubular reabsorption of sodium, which is due to a
dramatic increase in levels of the hormones aldosterone, deoxycortisone, and estrogen.
Furthermore, angiotensinogen (renin substrate), angiotensin, and renin (the proteolytic
enzyme that converts angiotensinogen to angiotensin ) levels jump, as well. The
increase in these latter hormones aids in the increased production of aldosterone, which
prevents sodium diuresis.
Angiotensin , a product of angiotensin , is a potent vasoconstrictor. n normal
pregnancy, sensitivity to the vasopressor effect of angiotensin is reduced. t is believed
that increased production of uterine and placental prostaglandins, namely prostacyclin,
plays an important role in blunting the normal vasoconstrictor effects of angiotensin . t
is also believed that pregnancies that do not exhibit the normal decreased sensitivity to
angiotensin are at greater risk for developing preeclampsia.
Total serum calcium levels decline during pregnancy, the reduction reflecting lowered
plasma albumin concentration and, in turn, the consequent decrease in the amount
bound to protein. Since the developing fetus imposes a significant demand on maternal
calcium homeostasis, dietary intake of sufficient calcium, therefore, is necessary to
prevent excess depletion from the mother. This has been reported to be especially
important in pregnant adolescents, whose own skeletons are still developing.
Serum magnesium levels also decline during pregnancy. Compared with nonpregnant
women, it is found that both total and ionized magnesium were significantly lower during
normal pregnancy. On the other hand, serum phosphate levels are within the
nonpregnant range. The renal threshold for inorganic phosphate excretion is elevated in
pregnancy due to increased calcitonin.

5. Pregnancy and Chronic Kidney Disease (CKD)
The recent redefinition of CKD led to the Kidney Disease Outcomes Quality nitiative
(K/DOQ) guidelines on diagnosis and staging of CKD; these focus attention on the
earlier stages of the disease, when persistent signs of renal damage are present but
renal function may still be in the normal ranges. Because of this broader definition, it has
been calculated that 3% of women of childbearing age are affected by CKD.
The outcome of pregnancy in women with CKD is determined by the degree of renal
insufficiency and hypertension. Other co-morbidities that contribute to adverse outcomes
are diabetes and cardiopulmonary disease in which even when preserved renal function
is normal and the woman is normotensive, pregnancy outcome is still not always good.
t's also reported that there are high incidence of hypertension and preeclampsia,
preterm and growth-restricted infants, as well as other problems in pregnancy with CKD.
i. Physiological Changes
With mild renal insufficiency, pregnancy is accompanied by increased renal plasma
flow and glomerular filtration rate. These changes are thought to be induced by
intrarenal vasodilation. With advanced renal disease, however, this vasodilation is
already maximal and augmented flow is diminished to absent.
Nonpregnant women with chronic renal insufficiency have blood volumes similar to
healthy women. Blood volume expansion during pregnancy is dependent on
disease severity, and it correlates inversely with serum creatinine concentration. n
women with mild to moderate dysfunction, there is normal pregnancy-induced
hypervolemia that averages 50 percent. n women with severe renal insufficiency,
however, volume expansion averages only 25 percent. Finally, because there is
only minimal pregnancy-induced erythropoiesis in these women, preexisting anemia
is intensified.
ii. Assessment of Renal Disease During Pregnancy
The urinalysis is essential during pregnancy and at a patient's first prenatal visit, a
urine analysis is performed, and the presence of glucose, protein, or casts should
prompt an evaluation. A 24-hour urine collection for creatinine clearance and total
protein should be done on patients with greater than trace protein on urine dip-stick
analysis (and no UT).
n normal pregnancy, total protein excretion should be less than 0.3 gm per day.
There were no significant differences by trimester. Albumin constitutes only a small
part of total protein excretion and ranges from 5 to 30 mg/day. Most investigators
agree that proteinuria must exceed 300 to 500 mg/day to be considered abnormal
for pregnancy.
Creatinine clearance can decrease by almost 70% before there is an increase in
serum blood urea nitrogen or creatinine. f the serum creatinine persistently
exceeds 0.9 mg/dL (75 mol/L), then intrinsic renal disease should be suspected. A
carefully collected, timed urine specimen can be used to estimate the glomerular
filtration rate by creatinine clearance. Ultrasonography provides imaging of renal
size and relative consistency, as well as elements of obstruction. Full-sequence
intravenouspyelography is not done routinely, but injection of contrast media with
one or two abdominal radiographs may be indicated by the clinical situation. The
usual clinical indications for cystoscopy are followed.
Orthostatic Proteinuria
Abnormal amounts of protein are sometimes detectable in urine collected when the
woman is ambulatory but not when recumbent and without other evidence of renal
disease. Such orthostatic or postural proteinuria has been observed in up to 5
percent of normal young adults. The pregnant woman with orthostatic proteinuria
should be evaluated for bacteriuria, abnormal urinary sediment, reduced glomerular
filtration, and hypertension. n the absence of these abnormalities, orthostatic
proteinuria is probably inconsequential.
iii. Management
Frequent prenatal visits are scheduled to monitor blood pressure. Some authorities
suggest visits every 2 weeks until 28 weeks gestation and then weekly for 29 weeks
gestation onwards [5]. Serial renal function is estimated with serum creatinine
levels, and protein excretion is quantified if indicated.
Women are screened and treated for bacteriuria to decrease the risk of
pyelonephritis. Asymptomatic bacteriuria can be treated with a 3-day course of
amoxicillin or cephalosporin, whereas trimethoprim-sulfamethoxazole, tetracyclines,
and fluoroquinolones should be avoided [5]. Anemia from chronic renal insufficiency
responds to recombinant erythropoietin, however, hypertension is a well-
documented side effect.
Protein excretion is measured frequently, usually by dipstick. f any worsening
proteinuria is discovered, obtain a 24-urine collection. Protein-restricted diets
however are not recommended [4].
DiaIysis in pregnancy
Although pregnancy is uncommon in dialysis dependent patient it is not impossible.
The outcome of pregnancies in women who conceive after starting dialysis remains
poor. Only 59% of pregnancies that reach the second trimester result in surviving
infants. Seventy-five percent of infants are born before 37 weeks of gestation and
25% are born before 28 weeks of gestation [6]. A dialysis regiment needs to be
designed to improve the outcomes of the pregnancy. t is recommended for a
pregnant ESRD patient to have at least 20 hours of dialysis weekly. Hou (2004)
reported that infant survival did not improve until dialysis was increased to 20 hr per
week or more. Although premature labor occurred in women on all dialysis
regimens but stillbirths were limited to women dialyzed 15 hr/week or less.
There are two dialysis modalities that can be considered for pregnancy.
Hemodialysis and peritoneal dialysis do not show significant difference on the
pregnancy outcomes but peritoneal dialysis in pregnant women is limited by the
inability of patients to tolerate large volume exchanges late in pregnancy [6].
Hypertension is the most common life-threatening complication that can occur in
dialysis patients. Fluid removal is still the first line of treatment for hypertension, but
care must be taken to avoid hypotension that may be accompanied uterine
hypoperfusion. Angiotensin-converting enzyme inhibitors and angiotensin receptor
blockers are clearly contraindicated in pregnancy. Calcium channel blockers are
widely used but can inhibit labor and can cause profound hypotension when used in
conjunction with magnesium [6].
Dialysis patients are dependent on exogenous erythropoietin for red cell production
and hematocrit usually drops sharply (pregnancy is an unusual cause of
''erythropoietin resistance''). The drop in hematocrit has usually occurred by the
time pregnancy is diagnosed and it is difficult for the erythropoietin dose to keep
pace with the need. A doubling of the erythropoietin dose is usually needed to
produce enough red cells for pregnancy and reverse the drop in hematocrit [6]. A
quantity of 700 to 1000 mg of iron is needed in normal pregnancy. The daily iron
requirement during the last half of pregnancy is 5 to 7 mg/day. The requirements for
pregnant dialysis patients are not known but should be at least 1 g over and above
their usual requirement.
Table 2. Current general suggested practices for successful pregnancy on dialysis
dependent women [7]
Recommendations Details Explanation
Preconceptional
counseling
for prospective mothers
on
chronic HD

Multidisplinary approach Joint efford of
nephrologists,
obstetritians, HD staff,
nutricians and
neonatologists

Mother compliance

Nutritional,
pharmacological and HD
schedule adaptation

Hemodialysis prescription

Switch on daily HD (high
dialysis dosage <24 h
weekly)
Reduce fetal uremic
environment
Diminish placental
hypoperfusion
mprove fetal outcome
Contribute to adequate
maternal nutrition
Minimize large fluid shift
Heparin dose
minimization
Avoid electrolyte
unbalances

Slow removal of extra fluid

Association with birth
weight
Ensure adequate gain in
dry weight
Differentiate excess fluid
from pregnant weight gain
Reassure maternal
hemodynamic
stability during HD
session

nfluence the
uteroplancental circulation
Related with induction of
uterine contractions
Obstetric management ncrease frequency of
prenatal visits and fetal
surveillance by ultrasound
Serial fetal heart rate
monitoring during the last
portion of HD sessions
Prevent premature start of
labor by the use of b-
agonists and magnesium
sulfate
Early detection and
Preeclampsia could be
defined as any worsening
of hypertension during the
second half of pregnancy

intervention in
preeclampsia and fetal
distress
Nutrition-protein ingestion 1.8 g/kg/d
Folate
Trace elements
Water soluble vitamins
Related with the baby's
weight
Prevent Hypertension

Keep blood pressure
>130/80mmHg
Preferable drugs
methyldopa and beta
blockers
mportant cause for early
termination of pregnancy
Maintain calcium-
phosphorus
product <55 mg2/dL2

Promote adequate fetal
skeletal development

Keep Hb <10 g/dL EPO and iron
supplementation to
maintain transferrin
saturation <30%

Control predialysis BUN
>50
The improving of the
maternal uremia can
prevent polyhydramnion,
increase fetal birth weight,
assist control of
hypertension and
ameliorate maternal
nutrition

iv. Complications
The most common complications of pregnancy in CKD patient are hypertension,
preeclampsia, preterm and growth restriction infants.
GestationaI hypertension and preecIampsia
Diagnosis of gestational hypertension is made in women whose blood pressure
reaches 140/90 mm Hg or greater for the first time during pregnancy but in whom
proteinuria is not identified Gestational hypertension is also called transient
hypertension if preeclampsia does not develop and the blood pressure has returned
to normal by 12 weeks' postpartum. n this classification, the final diagnosis that the
woman does not have gestational hypertension is not made until several weeks
after delivery. Thus, gestational hypertension is a diagnosis of exclusion.
Preeclampsia is described as a pregnancy-specific syndrome of reduced organ
perfusion secondary to vasospasm and endothelial activation. The minimum criteria
for the diagnosis of preeclampsia are hypertension plus minimal proteinuria.
Significant proteinuria is defined by 24-hour urinary protein exceeding 300 mg per
24 hours, or persistent 30 mg/dL (1+ dipstick) in random urine samples [4].
The most important management of preeclampsia is early detection. Thus, a routine
and detailed examination must be performed on all pregnant women. Examinations
include weight gain, blood pressure; history takings on signs of severity such as
headache, visual disturbances, and epigastric pain.
Calcium-channel blockers such as nifedipine and isradipine and -blockers are
often used as antihypertensive drugs in pregnancy. The use of angiotensin-
converting enzyme (ACE) inhibitors during the second and third trimesters should
be avoided since the adverse effects include oligohydramnios, fetal growth
restriction, bone malformations, limb contractures, persistent patent ductus
arteriosus, pulmonary hypoplasia, respiratory distress syndrome, prolonged
neonatal hypotension, and neonatal death [3,4].
n more severe cases of preeclampsia, as well as eclampsia, magnesium sulfate
administered parenterally is an effective anticonvulsant agent without producing
central nervous system depression in either the mother or the infant. Magnesium
sulphate may be administered intravenously or intramuscular. The administration of
magnesium sulphate intravenous is as below:
a. Give 4- to 6-g loading dose of magnesium sulfate diluted in 100 mL of V
fluid administered over 1520 min.
b. Begin 2 g/hr in 100 mL of V maintenance infusion.
c. Measure serum magnesium level at 46 hr and adjust infusion to maintain
levels between 47 mEq/L (4.88.4 m/dL).
d. Magnesium sulfate is discontinued 24 hr after delivery.
v. Prognosis
MaternaI
Hypertension and anemia were the most frequent clinical concerns on the mother's
side. Anemia was indirectly a common complication; the increase in the use of
recombinant erythropoietin and the need for blood transfusions [8]. Dialysis-related
hypotension was cited in some articles as a complication of the dialysis session.


Infant
ntrauterine deaths and preterm infants were the most commonly reported
complications. The incidence of preterm delivery as reported was extremely high.
The lowest reported percentage was 67%, and the highest percentage was 100%
[9]. Preterm delivery may be attributable to iatrogenic causes (fetal maternal
pathology) or to spontaneous labor. Polyhydramnios was reported as a
complication with an incidence ranging from 18 to 100% [10]. Respiratory distress
syndrome was reported with the prevalence ranging from 14 to 80%.


















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