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Case Report

Gynecol Obstet Invest 2007;63:3944


DOI: 10.1159/000094942

Received: December 14, 2004


Accepted: June 10, 2006
Published online: August 10, 2006

Proximal Renal Tubular Acidosis in


Pregnancy
A Case Report and Literature Review

C.J. Firmin a T.F. Kruger a R. Davids b


Departments of a Obstetrics and Gynaecology, and b Internal Medicine, Renal Unit,
Tygerberg Hospital, University of Stellenbosch, Cape Town, South Africa

Key Words
Renal tubular acidosis  Proximal tubular acidosis  Type 2
renal acidosis  Metabolic acidosis  Acid-base balance

Abstract
Renal tubular acidosis is usually associated with chronic renal conditions and is rarely encountered in pregnancy. It may
be inherited causing osteomalacia and rickets in children or
acquired following autoimmune diseases or following exposure to nephrotoxic agents. It is known to worsen during
pregnancy and if left untreated may cause maternal and foetal morbidity or death. We report a 28-year-old woman,
gravida 3 para 2, who presented at 30 weeks gestation with
lethargy, weakness and generalized myalgia. Investigation
revealed severe hypokalaemia and a systemic metabolic acidosis due to proximal renal tubular acidosis. Her previous
pregnancies were both complicated by foetal losses at term.
Following prompt correction of her electrolyte disturbance
and metabolic acidosis, she went on to deliver a healthy female infant at term. Regular evaluation up to 1 year post-partum revealed mild persistence of her hypokalaemia. At 1
year, the infant showed no signs of the disorder and is growing normally.
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Introduction

Renal tubular acidosis (RTA) causes a relative or absolute acid build-up in the blood and manifests as a metabolic acidosis. It may be inherited, acquired or idiopathic.
When it occurs in the general population it is usually associated with chronic renal conditions which may be
caused by an autoimmune disease such as systemic lupus
erythematosis (SLE), or following the ingestion of nephrotoxic substances. Hereditary RTA may present in childhood with rickets and failure to thrive [1]. RTA is rarely
encountered in pregnancy where it is commonly associated with maternal toluene abuse [2]. Most of the cases
reported in the literature occurred following chronic renal disease and persisted after delivery [38]. The renal
disease was usually associated with a systemic disorder
such as diabetes mellitus, chronic active hepatitis or SLE.
RTA may also be transient with no obvious aetiology and
show complete resolution following delivery [9]. RTA due
to maternal substance abuse has been associated with
foetal growth retardation, pre-term labour, dysmorphic
features and perinatal death [10, 11]. This may be related
to the direct toxic effect these agents have on foetal tissue.
RTA, due primarily to underlying renal disease, may be
asymptomatic in pregnancy and little is known of the effect it has on the embryology and growth of the foetus.

C.J. Firmin
Department of Obstetrics and Gynaecology
Tygerberg Hospital, University of Stlelenbosch
Cape Town (South Africa)
Tel. +27 21 938 9209, Fax +27 21 933 3084 , E-Mail hkr@sun.ac.za

RTA occurs when the renal tubules fail to excrete excess dietary acid or when there is a defect in the re-absorption of filtered bicarbonate. This acid-base disturbance produces a systemic or metabolic acidosis with
raised or low levels of potassium. The overall renal filtration ability is usually preserved and renal failure is uncommon. Patients require oral bicarbonate and potassium supplementation according to the degree and type of
RTA. RTA has been classified according to the biochemical abnormality found in the kidney as well as the site of
the disorder. Type 1 RTA is encountered most often and
occurs in the distal tubules. It results in the retention of
hydrogen ions. Type 2 RTA occurs in the proximal tubules and results in the loss of bicarbonate. Both types
result in hypokalaemic, hyperchloraemic metabolic acidosis with a normal an-ion gap. Other biochemical abnormalities may co-exist, such as hypocalcaemia and hypercalciuria which may lead to osteopaenia and kidney
stone formation. Type 3 RTA is rarely described and is
thought to be a combination of type 1 and type 2 RTA.
Most sources no longer use this term. Type 4 RTA presents with hyperkalaemic metabolic acidosis.
We report a case of proximal RTA (type 2) as it presented in the pregnancy of a woman who previously had
an unexplained intra-uterine death.

Case Report
A 28-year-old woman gravida 3, para 2 presented at 30 weeks
gestation with complaints of lethargy, thirst, muscle weakness
and generalized body pains. Her serum potassium level was
1.6 mmol/l. She was not in labour.
Her two previous pregnancies were both complicated by foetal
losses at term. Her first pregnancy resulted in an early neonatal
death following a term home delivery when she was 18 years old.
The cause of death was given as meconium aspiration syndrome.
Her second pregnancy was complicated by polyhydramnios and
a sudden intra-uterine death at 40 weeks gestation. No foetal
anomalies were noted on ultrasound and screening tests for diabetes mellitus, toxoplasmosis, rubella, cytomegalovirus and herpes simplex virus were negative in that pregnancy. Labour was
induced and she delivered a fresh stillborn. The foetus showed no
dysmorphic features and the placenta was considered normal. A
post-mortem examination was not performed and the exact cause
of death was not established. Her post-partum course was uncomplicated. The patient then suffered a form of muscle weakness 6
months following this pregnancy. She gave the history of a flu-like
illness that was associated with malaise and weakness for which
she received antibiotics following consultation with a general
practitioner. She did not experience any urinary or renal symptoms and a random urine analysis performed did not show any
abnormalities. Before completing her course of antibiotics her
clinical condition worsened and she was admitted to a secondary

40

Gynecol Obstet Invest 2007;63:3944

level hospital for severe lethargy and weakness. Limited investigations done during this admission revealed a serum potassium level of 1.4 mmol/l. Other serum biochemistry results obtained from
past records showed a corrected calcium level of 2.16 mmol/l
(2.052.56 mmol/l), magnesium of 1.04 mmol/l (0.651.10 mmol/
l), phospate of 0.48 mmol/l (0.81.40 mmol/l) and a serum albumin level of 33 g/l (3552 g/l). Her full blood count haemoglobin
was 6.8 g/dl (1116 g/dl). Her thyroid function tests were normal
and an ELISA retroviral (HIV) antibody test was negative. She
was discharged a week later following a blood transfusion and
potassium supplementation. A follow up serum potassium level
taken a month later revealed a level of 2.1 mmol/l. Clinically, the
patient felt well and did not complain of any symptoms. She was
given a month supply of potassium supplementation. No other
results could be obtained from her past medical records. The patient had no family history of a similar condition and she denied
the use of any substances such as nicotine, alcohol or any illicit
drugs.
For her current problem, she was admitted at a referring hospital and given intravenous potassium chloride which raised her
serum potassium level from 1.6 to 3.5 mmol/l. On admission at
our centre 24 h later, her serum potassium level had dropped to
2.9 mmol/l. Other serum urea and electrolyte values were as follows: sodium 138 mmol/l (135147 mmol/l), chloride 116 mmol/l
(99113 mmol/l), ureum 2.4 mmol/l (2.67.0 mmol/l) and creatinine 86 mol/l (60100 mol/l). Her arterial blood gas revealed
a pH of 7.25 (7.377.43), pCO2 of 3.36 kPa (4.506.10 kPa), pO2 of
12.10 kPa (11.0015.00 kPa), total bicarbonate of 11.1 mmol/l
(21.025.0 mmol/l) and a base excess of 13.7 mmol/l (4.0 to
2.0 mmol/l). Physical examination of the patient revealed no
anaemia, pyrexia or hypertension. There was mild renal angle
tenderness. Foetal evaluation showed a normal singleton foetus
appropriate for 30 weeks gestation. Results obtained from her antenatal booking investigations revealed a haemoglobin value
above 10 g/dl, a negative (VDRL) syphilis serology and O positive
blood grouping. Her urine culture showed no bacterial growth.
This was following 2 weeks therapy with oral nitrofurantoin for
a urinary tract infection by Klebsiella species at 28 weeks gestation. The patient was HIV negative. Her full blood count, liver
function tests, serum glucose, calcium, phospate and magnesium
levels were all within normal limits. Lupus anticoagulant and
anti-cardiolipin antibody tests were negative and thyroid function tests were normal. No glucose or proteins were detected in
a random urine sample. A provisional assessment of hyperchloraemic metabolic acidosis with severe hypokalaemia was made
and her therapy was changed to oral potassium and bicarbonate
supplementation once her serum potassium level was above
3.5 mmol/l. The serial growth pattern of the foetus was normal
and an antenatal non-stress test at 30 weeks gestation was reactive. Ultrasound revealed no gross foetal abnormalities and umbilical artery Doppler waveforms were within normal limits. Foetal kidney, bladder and liquor volume was normal. The patients
subsequent ECG showed no evidence of cardiac conduction disturbances and her chest X-ray and skeletal detail was normal. Ultrasound of her liver was normal. Renal ultrasonography revealed
moderate right hydronephrosis and mild left hydronephrosis.
Kidney architecture and differentiation were intact and there was
no evidence of nephrocalcinosis.
These results were evaluated in consultation with the renal
unit. The patients serum electrolyte and arterial blood gas mea-

Firmin /Kruger /Davids

surements were promptly corrected on oral potassium and bicarbonate supplementation and further management occurred on a
two weekly outpatient basis with a view to inducing labour at term
for a previously bad obstetric history. At 38 weeks gestation the
patient had no biochemical abnormality and foetal evaluation was
normal. Her cervix was favourable for surgical induction and labour was induced with artificial rupture of membranes. Contractions progressed steadily without the need for augmentation. Labour was uncomplicated and there were no signs of maternal electrolyte abnormalities or foetal distress. She delivered a healthy
female infant by vaginal route. The baby weighed 2,706 g with
good APGAR scores. There were no dysmorphic features. Paediatric investigation showed no serum electrolyte abnormalities or
acid-base disturbance in the baby.
The patient was discharged on oral potassium and bicarbonate
supplementation as well as intramuscular medroxyprogesterone
acetate and seen again at 6 weeks post-partum. She had no new
complaints and her baby was breastfeeding well. Her serum electrolyte levels were within normal limits except for a potassium
level of 3.3 mmol/l. Further investigation of her urine at follow up
showed a raised urinary bicarbonate level of 6.9 mmol/l and a
urine pH of 7.1. Twenty four hour urine analysis showed no increased excretion of calcium, phospate, magnesium or amino acids. No ammonium was found in the urine. Three weeks later
following improved compliance on supplements, her serum potassium level was within normal range and all other electrolyte
investigations were within normal limits. She was once again reviewed at 8 months post-partum and again admitted to taking her
supplements on an ad hoc basis. Serum urea and electrolyte levels
were as follows: sodium 141 mmol/l (135147 mmol/l), potassium
2.8 mmol/l (3.35.3 mmol/l), ureum 7.0 mmol/l (2.67.0 mmol/l)
and creatinine 108 mol/l (60100 mol/l). At 1 year post-partum, the patient and baby were evaluated at her local referring
centre. For the two preceding months she had stopped using her
oral supplementation altogether as she felt well and no longer
thought it was necessary. Her serum potassium was 3.2 mmol/l
and urea 7.9 mmol/l. Her blood pressure was normal. At 1 year
her baby was growing well and had achieved all neurological and
motor milestones for her age.

Discussion

The normal kidney maintains acidbase balance by


bicarbonate re-absorption and acid excretion in the form
of ammonium (NH4+). Loss of tubular function prevents
the kidney from excreting hydrogen ions or re-absorbing
filtered bicarbonate, causing a metabolic acidosis. The
term RTA refers to a diverse group of tubular disorders,
usually in the absence of glomerular damage, characterized by impairment of urinary acidification without increased serum urea levels and an-ion retention. Most
sources describe only 3 types of RTA, namely: distal RTA
(type 1), proximal RTA (type 2) and distal RTA (type 4).
An earlier designation, type 3 RTA referred to a combination of type 1 and type 2 disorders, however, it is rarely
Proximal RTA in Pregnancy

encountered and this term is no longer in use. Distal RTA


(type I) or classical RTA is encountered more often and
is associated with the inability of the distal renal tubules
to secrete/excrete endogenous hydrogen ions. It can be
inherited as a primary autosomal dominant condition.
Distal RTA (type 1) is, more often, a complication of diseases that also affect other organ systems, such as Sjgrens
syndrome, chronic active hepatitis and SLE. Other conditions which result in distal RTA (type 1) include analgesic
nephropathy, rejection of a transplanted kidney, renal
medullary cystic disease, obstructive uropathy and
chronic urinary tract infections. Excessive loss of urinary
calcium which is frequently seen in distal RTA (type 1)
disorders may lead to osteopaenia, osteomalacia, nephrocalcinosis and secondary hyperparathyroidism. Recent
genetic studies have associated some forms of familial
distal RTA with a polymorphic marker adjacent to the
SLC4A1 gene [12].
Proximal RTA (type 2) is associated with urinary loss
of bicarbonate due to failure of the proximal tubules to
re-absorb filtered bicarbonate. This type of RTA is often
congenital and may include various other defects in tubular function, as seen in, Fanconis syndrome in which
there is also tubular loss of glucose, calcium, phosphate,
other electrolytes and amino acids. All types of RTA may
be associated with failure to thrive and/or rickets when it
occurs in children. As with distal RTA (type 1), adults
may present with osteomalacia and osteopaenia together
with muscular weakness. This is due to low serum calcium levels as a result of tubular loss of the electrolyte as
well as compensatory mechanisms in bone aimed at buffering retained hydrogen ions. Proximal RTA (type 2) is
usually self limiting in the absence of chronic renal disease and in such cases when serum bicarbonate levels fall
below 15 mmol/l, filtered bicarbonate is actively reabsorbed in the proximal tubule. Urine pH will usually fall
below pH 5.5 indicating efficient reabsorption of bicarbonate. Alternatively, urine pH will be greater than 6 in
the presence of metabolic acidosis due to proximal tubular pathology. Another feature of proximal RTA (type 2)
is that the urine pH can be lowered to less than 5.5 with
acid loading. This test is not required to make the diagnoses of proximal RTA (type 2) and may be dangerous in
pregnancy. Distal RTA (type 4) presents with hyperkalaemic metabolic acidosis. Hyperkalaemic distal RTA may
result from sickle cell disease, urinary tract obstruction,
lupus, amyloidosis, or renal transplantation. It may also
be associated with low levels of circulating aldosterone or
renal resistance to aldosterone.

Gynecol Obstet Invest 2007;63:3944

41

A further subdivision of proximal RTA (type 2) is that


of a rare condition referred to as isolated proximal RTA.
It differs from generalized proximal tubular dysfunction
in that the multiple defects of tubular filtration, as is the
case in Fanconis syndrome, are not evident. Three categories of isolated proximal RTA have been identified:
(1) autosomal dominant proximal RTA; (2) autosomal recessive proximal RTA with ocular abnormalities; and
(3) sporadic isolated proximal RTA. Autosomal dominant and autosomal recessive proximal RTA is usually
permanent; life-long alkali therapy is needed. In contrast,
sporadic isolated proximal RTA is transient; alkali therapy can be discontinued after several years without reappearance of symptoms. Most case reports of isolated
proximal RTA are inherited and manifest early in childhood or puberty with short stature, neurological disturbances, cataracts, glaucoma and muscle paralysis leading
to paraplegia. Genetic studies have begun to elucidate the
molecular pathogenesis of inherited isolated proximal
RTA [13]. Patients with associated ocular abnormalities
have mutations in the gene SLC4A4 which encodes the
kidney type sodium-bicarbonate cotransporter (kNBC1)
membrane proteins [14]. The SLC9A3 gene which encodes the sodium-hydrogen exchanger isoform 3 (NHE3)
transporters is strongly associated with autosomal dominant proximal RTA. SLC9A3 knockout mice show lack of
transporter activity resulting in combined renal and intestinal defects of bicarbonate reabsorption [15].
There are several reports in the medical literature of
pregnant patients with RTA. The majority of these cases
were either secondary to ingestion of medications such as
dyazide, following toluene abuse, or associated with a
maternal systemic disorder, such as diabetes, chronic
hepatitis, alcoholism, and SLE [28]. Most cases were
chronic and persisted after delivery. RTA may also be
transient and completely disappear following delivery [9]
or following early cessation of nephrotoxic substances.
Szwed and Clarke [4] reported abrupt disappearance of
RTA in two pre-eclamptic females: one, following delivery of the foetus in a case possibly due to exacerbation of
SLE and another following discontinuance of Dyazide
therapy.
Our patient presented with a picture of proximal RTA
as indicated by her metabolic acidosis and alkaline urine.
Her hypokalaemia can be attributed to compensatory
mechanisms by the kidney to maintain acid-base balance
by eliminating potassium. In addition, she also had features of the rare sporadic isolated form of proximal RTA.
Her urine analysis revealed isolated tubular loss of filtered bicarbonate causing an alkaline urine pH of 7.1. We
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Gynecol Obstet Invest 2007;63:3944

could not detect increased excretion of substances such


as glucose, calcium or phosphates in her urine. No ammonium was excreted in her urine. She had none of the
childhood features of an inherited condition, nor any
family history. Her serum electrolytes showed predominant hypokalaemia but no associated hypocalcaemia or
hypercalciuria as is common in RTA. There were no clinical features of osteopaenia or nephrocalcinosis. Following prompt initiation of potassium and bicarbonate supplementation the patients clinical picture improved dramatically. We were careful not to over prescribe potassium
supplements as this could worsen her acidosis. Throughout pregnancy, her foetus showed no signs of growth retardation and her pregnancy outcome was good. We
could not, however, find any reversible cause for her RTA.
The patient was depended on chronic electrolyte supplementation and her electrolyte disturbance persisted many
months following delivery. Her raised serum urea level 1
year post-partum was in keeping with chronic pre-renal
dehydration due to a milder form of her condition. This
is a known feature of chronic tubular acidosis. At 1 year
post-partum the patient is no longer taking oral supplements and her serum potassium level is 3.2 mmol/l.
Pregnancy is known to worsen RTA due to its physiological effects on kidney function. It is known that pregnancy is associated with an increase in the maternal cardiac volume which causes an increase in renal glomerular
filtration and excretion of waste products. The excretion
of increased bicarbonate ion in pregnancy results in a loss
of base. Serum levels may fall from 34 to 20 mmol/l. This
fall in plasma bicarbonate may be due in part to pregnancy hormonal influences which cause a relative respiratory alkalosis following hyperventilation [16]. However, the pregnant woman adapts to these new levels of bicarbonate. The normal foetus is also well adapted to deal
with these minor changes affecting maternal plasma pH.
This is due primarily to the placental unit which allows
for efficient exchanges of oxygen and carbon dioxide between mother and foetus. However, chronic or untreated
maternal acidosis will eventually result in a reduction of
the maternal plasma oxygen carrying capacity which is
partly due to maternal haemoglobin acting as a buffer to
retained H+ ions during systemic acidosis. This will result
in less haemoglobin being available for oxygen transport
across the placenta which can eventually affect foetal oxygenation. Blechner et al. [17] also demonstrated that
blood flow to the pregnant uterus is decreased in maternal acidosis and may be associated with foetal distress. A
foetus with already reduced oxygen reserves, as may be
the case in advanced maternal diabetes or pre-eclampsia,
Firmin /Kruger /Davids

will not tolerate even the mildest fall in placental oxygen


delivery without developing tissue hypoxia or even death
in utero [18]. Foetal growth retardation, pre-term labour
and dysmorphic features associated with RTA and substance abuse are thought to be largely related to the primary effect these substances have on the foetal liver and
kidney. The low incidence of foetal abnormalities in reports of RTA due to chronic renal conditions supports
this notion [6].
The patients previous pregnancy ended in an unexplained intra-uterine death and we may have evidence to
postulate that it resulted from asymptomatic, untreated
proximal RTA resulting in undetected foetal distress and
intra-uterine death. The mechanism of foetal death may
be similar to that seen in gestational diabetes which is
thought to be due to the hypoxic effects of maternal-foetal acidosis. Polyhydramnios in diabetes is thought to be
due to the diuretic effect hyperosmolar foetal plasma has
on kidney excretion. The polyhydramnios which occurred in the above case is unclear as a post-mortem examination was not performed on the foetus. An inherited
renal condition known as Bartter syndrome which is also
due to tubular dysfunction, can present antenatal with
polyhydramnios [19]. However, in up to 60% of pregnancies presenting with polyhydramnios the cause is unknown. The patient suffered her first episode of severe
weakness and hypokalaemia necessitating hospital admission just 6 months after her stillbirth and this supports the notion of asymptomatic RTA in that pregnancy.
Rowe et al. proposed that pregnant woman with RTA
may have a higher risk of developing pregnancy induced
hypertension due to their underlying renal condition
which may be aggravated by the normal hypervolaemia
of pregnancy. He described three pregnancies in two
women with distal (type 1) RTA who developed persistent
diastolic hypertension in the third trimester. RTA is also
associated with an increase in the serum aldosterone secretion [20]. Gallery et al. prospectively studied 87 initially normotensive pregnant women, in whom 15 developed hypertension in the third trimester of pregnancy.
The hypertensive women differed from normotensive
women by failure to augment urinary ammonia excretion
in response to acid loading. This defect was similar to that
seen in distal RTA and may contribute to the development of pregnancy induced hypertension in these patients [21]. Our patient showed no evidence of hypertension in all her pregnancies. There are no other documented cases in the literature which associate RTA with
hypertension.

Maternal acidosis in pregnancy and the resultant negative effects on the foetus can be corrected, provided it is
diagnosed early and permanent damage has not yet occurred in the maternal-foetal circulation. Serum urea
and electrolytes as well as arterial blood gas measurements should be taken immediately on clinical suspicion.
Diabetic ketoacidosis must be excluded with initial investigation and a toxic screen for agents causing kidney
damage can be performed if substance abuse is suspected.
A family history may suggest an inherited condition. The
patients previous obstetric history can also provide important information. The foetus should be monitored
closely from an early gestation in a high-risk clinic setting
with attention to foetal growth, placental adequacy and
maternal renal function. Close liaison with medical physicians or nephrologists ensure proper work up and management of such patients. Spontaneous vaginal delivery
at term may be anticipated provided oral treatment results in the disappearance of the acidosis and electrolyte
disturbance. Urgent or elective delivery of the foetus may
be mandatory if the acidosis is associated with (1) worsening maternal renal function, (2) failure to respond to
medication or (3) signs of foetal distress. Immediate neonatal supervision should be directed toward foetal serum
biochemistry, acidbase disturbances and fluid balance.
Close attention must be given to infant growth, bony development and the attainment of neurological milestones.
Patients with persistence of their metabolic abnormality
may be maintained on chronic oral supplementation with
regular follow up of 6 months to 1 year to evaluate treatment compliance as well as the course of the disease.

Proximal RTA in Pregnancy

Gynecol Obstet Invest 2007;63:3944

Conclusion

In conclusion, we report a pregnant patient with features of sporadic isolated proximal RTA (type 2). She had
no other medical problems or history of substance abuse.
She responded well on treatment, despite poor compliance at home, and delivered a normal healthy infant of
appropriate weight for gestation. Following delivery, her
electrolyte disturbance persisted in a milder form up to 1
year post-partum and her infant is growing normally.

43

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