Acute Kidney Injury in Pregnancy—Current Status

Anjali Acharya, Jolina Santos, Brian Linde, and Kisra Anis

Pregnancy-related acute kidney injury (PR-AKI) causes significant maternal and fetal morbidity and mortality. Management of
PR-AKI warrants a thorough understanding of the physiologic adaptations in the kidney and the urinary tract. Categorization of
etiologies of PR-AKI is similar to that of acute kidney injury (AKI) in the nonpregnant population. The causes differ between de-
veloped and developing countries, with thrombotic microangiopathies (TMAs) being common in the former and septic abortion
and puerperal sepsis in the latter. The incidence of PR-AKI is reported to be on a decline, but there is no consensus on the exact
definition of the condition. The physiologic changes in pregnancy make diagnosis of PR-AKI difficult. Newer biomarkers are be-
ing studied extensively but are not yet available for clinical use. Early and accurate diagnosis is necessary to improve maternal
and fetal outcomes. Timely identification of ‘‘at-risk’’ individuals and treatment of underlying conditions such as sepsis, pre-
eclampsia, and TMAs remain the cornerstone of management. Questions regarding renal replacement therapy such as modal-
ity, optimal prescription, and timing of initiation in PR-AKI remain unclear. There is a need to systematically explore these
variables to improve care of women with PR-AKI.
Q 2013 by the National Kidney Foundation, Inc. All rights reserved.
Key Words: Pregnancy, Acute kidney injury, Preeclampsia, Thrombotic microangiopathy

I ntroduction velop obstruction because of mechanical compression of

Although the incidence of pregnancy-related acute kid-
ney injury (PR-AKI) is reported to have decreased, espe-
cially in the developed nations, it is associated with
significant maternal and fetal morbidity and mortality.1
Acute kidney injury (AKI) is reported in approximately
1% of women with severe preeclampsia and 3% to 15%
of women with hemolysis, elevated liver enzymes,
and low platelets (HELLP) syndrome.2,3 Although
decreasing in developing countries, PR-AKI continues
to be a significant problem and is due to septic abortion
and puerperal sepsis. This difference in incidence be-
tween nations arises from legalization of abortion in the
developed countries and variation in patient demograph-
ics, standard of care, and access to prenatal care. There
are many definitions of PR-AKI in the literature. This
lack of consensus is a major limitation to our understand-
ing of PR-AKI. Questions as to the best method to mea-
sure estimated glomerular filtration rate (GFR) and
proteinuria in pregnancy still remain. With these caveats,
we summarize adaptive changes in the kidney during
pregnancy, etiologies of PR-AKI, current diagnostic crite-
ria, and treatment options.
Kidney Adaptive Changes during Pregnancy
A full review of the physiologic changes of pregnancy is
detailed in ‘‘Renal Physiology of Pregnancy’’ in this issue.
Our focus is on changes relevant to the management of
PR-AKI. In pregnancy, the length of the kidney increases
by 1 to 1.5 cm and the volume increases up to 30% from
changes in the vascular and interstitial spaces. The uri-
nary collecting system is dilated with hydronephrosis
in up to 80% of pregnant women. Although usually
asymptomatic, this dilatation predisposes women to as-
cending urinary tract infections resulting in maternal
and fetal complications. Pregnant women may rarely de-
the ureters between the gravid uterus and the linea termi-
nalis.4 Within weeks of conception, glomerular filtration
increases by 40% to 60% and kidney blood flow by
80%, persisting until the middle of the third trimester. To-
tal body water increases by 6 to 8 L, 4 to 6 L of which are
extracellular, and accounts for the edema of pregnancy.5
This volume expansion is dependent on activation of
the renin-aldosterone-angiotensin system and accumula-
tive sodium retention of up to 950 mmol on average. In-
creased kidney interstitial compliance may also play
a role in elevation of GFR.6 In addition to systemic vaso-
dilatation, relaxin, a 6-kDa peptide produced by the cor-
pus luteum, causes a decrease in kidney afferent and
efferent resistance, which contributes to an increase in
kidney blood flow, GFR, and solute clearance. This leads
to a physiologic decrease in circulating creatinine, urea,
and uric acid. The average serum creatinine (SCr) during
pregnancy is 0.5 to 0.6 mg/dL, and a SCr of 1.0 mg/dL is
reflective of kidney impairment. Blood urea nitrogen de-
creases to approximately 8 to10 mg/dL. An increase in
secretion of uric acid along with a decrease in reabsorp-
tion is also seen in normal pregnancy. As a result, serum
uric acid level nadirs at 2.0 to 3.0 mg/dL between 22 and
24 weeks of pregnancy.
An increase in protein excretion from 60 to 90 mg/24
hours to 180 to 250 mg/24 hours is seen in the third tri-
mester because of an increase in filtered load combined
From Jacobi Medical Center, Bronx, NY; Jacobi Medical Center, Bronx, NY;
Yale University School of Medicine, New Haven, CT.
The authors report no financial conflicts of interest.
Address correspondence to Anjali Acharya, MBBS, Jacobi Medical Center,
Building 1, Room 6E-23B, 1400 South Pelham Parkway, Bronx, NY 10461.
E-mail: anjali2526@gmail.com
Ó 2013 by the National Kidney Foundation, Inc. All rights reserved.
1548-5595/$36.00
http://dx.doi.org/10.1053/j.ackd.2013.02.002

Advances in Chronic Kidney Disease, Vol 20, No 3 (May), 2013: pp 215-222 215
216 Acharya et al

with less efficient tubular reabsorption.7 Normal protein It can cause microabsesses and is associated with
excretion in pregnancy is less than 260 mg per 24 hours, incomplete resolution of kidney function. All of the
with 11 protein on urine dipstick being considered ab- conditions that lead to acute tubular necrosis (ATN) can
normal.8 Women with preexisting proteinuria exhibit an cause ACN. ACN, which consists of patchy or diffuse
exaggeration of protein excretion in the second and third ischemic damage of the cortex, occurs in 2% to 7% of PR-
trimesters. Microscopic hematuria usually indicates kid- AKI cases.16 Conditions associated with ACN are massive
ney pathology. Occasionally, it can be seen in women hemorrhage due to abruptio placentae or other severe
with placenta percreta, in which the placenta invades complications such as placenta previa, prolonged intra-
through the myometrium into neighboring viscera. Gross uterine fetal death, or amniotic fluid embolism. Although
hematuria is rare in pregnancy and can be seen in the set- endothelial damage secondary to fibrin deposition from
ting of acute cortical necrosis (ACN). primary disseminated intravascular coagulation (DIC)
Another change, which is considered physiologic, and severe kidney ischemia have been proposed in the
is mild respiratory alkalosis that results in a compensa- pathogenesis, the increased susceptibility to ACN during
tory increase in kidney bicarbonate excretion.9 This is im- pregnancy remains poorly understood.
portant to take into account during treatment of TMAs of pregnancy traditionally include preeclamp-
metabolic acidosis. Vasopressinase, which is secreted by sia, HELLP syndrome, and acute fatty liver of pregnancy
the placenta, renders antidiuretic hormone inactive and (AFLP) and are difficult to distinguish from thrombotic
may result in nephrogenic diabetes insipidus with poly- thrombocytopenic purpura (TTP) and hemolytic uremic
uria, polydipsia, and hypernatremia.10 The resultant vol- syndrome (HUS). Preeclampsia is defined by new-onset
ume depletion rarely leads to the development of hypertension with systolic blood pressure of 140 mmHg
a prerenal state and AKI. These physiologic changes, in- or greater or diastolic blood pressure of 90 mmHg or
cluding those in GFR, revert greater after 20 weeks gesta-
back to a prepregnancy state tion together with protein-
CLINICAL SUMMARY
within a few weeks postpar- uria (0.3 g or more protein
tum. in a 24-hour specimen). Pre-

There is no consensus on the definition of PR-AKI.
eclampsia can also present

The incidence of PR-AKI is reported to be on a decline. up to 4 to 6 weeks postpar-
Etiologies of PR-AKI

The normal physiological changes during pregnancy must tum.17 Severe preeclampsia
As in the general popula- be kept in mind when using the traditional diagnostic is diagnosed when one of
tion, etiologies of PR-AKI approach and laboratory parameters in the diagnosis and the following are seen: sys-
treatment of PR-AKI.
can be divided into prerenal, tolic blood pressure greater
renal, and postrenal cate-
Proteinuria increases during pregnancy, but the normal than 160 mmHg, diastolic
gories. They can be further range of protein excretion and the best method to blood pressure greater than
measure proteinuria are still under debate.
grouped into pregnancy- 100 mmHg, proteinuria
related and -unrelated con- greater than 5 g/24 hours,
ditions (Table 1). Risk or other signs and symptoms
factors known to predispose to the development of PR- of end-organ injury. HELLP syndrome, which may occur
AKI are the presence of hypertension, preeclampsia, ges- in up to 10% to 20% of women with severe preeclampsia,
tational hypertension, CKD with SCr of greater than 1.5 often between 28 and 36 weeks gestation, is characterized
mg/dL, presence of proteinuria, and thrombotic microan- by hemolysis, aspartate aminotransferase greater than 70
giopathy (TMA).11 Diabetes mellitus not only quadruples U/L, and a platelet count less than 100 3 109.18 Approxi-
the risk of preeclampsia, but also predisposes to PR-AKI mately 40% of PR-AKI cases in the developed nations are
in the presence of microalbuminuria despite normal base- due to severe preeclampsia complicated by HELLP syn-
line SCr.12,13 Kidney involvement in systemic lupus drome, with the likelihood of AKI increasing with the se-
erythematosis, especially World Health Organization verity of HELLP.2,18-21 On the other hand, 3% to 15% of
Class III and IV and the presence of antiphospholipid women with HELLP syndrome develop AKI. Fifty
antibodies, are also risk factors for PR-AKI. percent of patients with AFLP, a rare condition seen in
Sepsis and hypotension leading to PR-AKI continue to the third trimester, develop preeclampsia. Overlap of
be important causes, especially in developing nations. AFLP with HELLP syndrome is common.
Bacteriuria, which is seen in 2% to 7% of pregnancies, if Recently, TMAs have been reclassified based on their
untreated, has a greater propensity to progress to pyelone- pathogenetic mechanisms into ADAMTS13- (a disintegrin
phritis (in up to 40%) than in nonpregnant women.14,15 and metalloproteinase with a thrombospondin type 1 mo-
This increased risk is due to the hormonal and anatomic tif, member 13) deficient TMA, complement dysregulation
changes of pregnancy. It is worth mentioning that TMA, and TMAs secondary to other mechanisms. These
pyelonephritis, which generally does not cause AKI in secondary TMAs include those due to vascular endothe-
the nonpregnant state, can do so during pregnancy. lial growth factor deficiency, verotoxin-induced TMA,
 Acute Kidney Injury and Pregnancy 217

Table 1. Etiologies of PR-AKI and pregnancy TMA (P-TMA).22 ADAMTS13-deficient

Prerenal Causes* TMA arises from autoantibodies against ADAMTS13,
, Pregnancy-related conditions a protease that cleaves large von willebrand factor multi-
- Hyperemesis gravidarum
mers. Deficiency of ADAMTS13 results in accumulation
- Vomiting due to preeclampsia, HELLP, and AFLP
of ultralarge von willebrand factor multimers and forma-
- Hemorrhage

Missed abortion
tion of platelet thrombi.23 P-TMA is considered a second-

Septic abortion ary TMA that can be due to ADAMTS13 deficiency,

Placental abruption a complement alternate pathway dysregulation, or an-

Placenta previa other mechanism.24 Lastly, whether HELLP and pre-

Uterine atony eclampsia are truly TMAs is now questioned because the

Bleeding during surgery

Uterine laceration
main lesion seen here is not TMA but glomerular endothe-

Uterine perforation liosis. A full review of these conditions is beyond the scope
, Pregnancy-unrelated conditions of this discussion, but such a regrouping of TMAs will
- Vomiting due to infections such as UTI or sepsis, gas-
help simplify approaches to treatment. For an in-depth
troenteritis discussion of this subject, we refer you to recently pub-
- Pyelonephritis

- Diuretic use
lished reviews of this topic.25,26
- Congestive heart failure Lastly, iatrogenic injuries to the bladder and ureter are
Renal causes extremely rare causes of PR-AKI with a reported incidence
, Pregnancy-related conditions
of 0.006% to 0.94%.27 They can occur during cesarean sec-
- ATN, ACN
tion, especially in an emergency setting. Common causes

Preeclampsia

HELLP
are inadvertent injury to the urinary bladder and ureteral

AFLP damage or transection. Such injuries are more often asso-

Amniotic fluid embolism ciated with developmental abnormalities in the mother

Pulmonary embolism such as an ectopic kidney or duplication of the ureters.27
- TMA

HUS

Preeclampsia Diagnosis of AKI in Pregnancy

HELLP

AFLP Definitions of PR-AKI vary from an increase in SCr level

DIC to the need for dialysis. Some authors have used the risk,

Worsening of existing glomerular disease
, Pregnancy-unrelated conditions
injury, failure, loss, and end stage (RIFLE) criteria focus-
- ATN
ing on the change in SCr or GFR and urine output.1,28
- De novo glomerular diseases However, there has been no validation of the RIFLE
- Acute interstitial nephritis criteria in pregnant women. The Acute Kidney Injury
Postrenal causes Network criteria, which use urine output and a change
, Pregnancy-related conditions

- Bilateral hydronephrosis in rare cases

- Trauma to the ureters and bladder during cesarean
section
, Pregnancy-unrelated conditions
- Bilateral ureteral obstruction due to stones or tumor
- Tubular obstruction (calcium or uric acid crystal in-
duced)
- Obstruction at the bladder outlet
AKI in kidney allograft
- Acute rejection
- ATN
- Acute interstitial nephritis, calcineurin inhibitor toxicity,
recurrent disease, infections such as cytomegalovirus,
BK virus
- Postinfectious glomerulonephritis
Abbreviations: ACN, acute cortical necrosis; AFLP, acute fatty liver of
pregnancy; AKI, acute kidney injury; ATN, acute tubular necrosis;
DIC, disseminated intravascular coagulation; HELLP, hemolysis, el-
evated liver enzymes, and low platelets; HUS, hemolytic uremic syn-
drome; TMA, thrombotic microangiopathies; UTI, urinary tract
infection.
*Can cause ATN and ACN.
in SCr ($26.2 mmol/L or 0.3 mg/dL) to define the
presence of AKI, have not been used in pregnancy.29
Guo and colleagues have shown serum cystatin C to
have the best negative correlation with 24-hour urine cre-
atinine clearance when compared with SCr and uric acid
in normal pregnancies and severe preeclampsia.30 How-
ever, a recent study has shown no parallel between cysta-
tin C and inulin clearances in healthy pregnant women.31
At this time, the use of cystatin C for measurement of
GFR in pregnancy cannot be recommended.
In our opinion, because of an increased solute clear-
ance and the plasma volume expansion seen during
pregnancy, a significant decline in GFR or a greater rise
in the absolute SCr value will be required to satisfy the
current Acute Kidney Injury Network criteria of a 0.3-
mg/dL increase in SCr. Therefore, the current SCr criteria
used in the general population are unreliable for diagnos-
ing PR-AKI and underestimate its occurrence. We
propose that in addition to the traditional urine output
218 Acharya et al

criteria, even an acute increase of 0.1 mg/dL of SCr or
a failure of SCr to decrease from baseline should be con-
sidered abnormal and indicative of AKI. This concept
needs further investigation. Often there is a lack of infor-
mation on baseline prepregnancy SCr values in this pop-
ulation, which further confounds the diagnosis.
Therefore, it is imperative to obtain baseline SCr values
on all women early in pregnancy. This strategy has two
advantages: (1) It aids in early identification of those
at risk for PR-AKI, and (2) it helps in making an accurate
diagnosis.
Evaluation of a pregnant patient for prerenal, intrare-
nal, and postrenal causes of AKI is based on history,
physical exam, urinalysis, and urine electrolytes using
the general principles of evaluating AKI.1 These parame-
ters, particularly the use of urine electrolytes, need explo-
ration in pregnancy because there are many physiologic
mechanisms promoting sodium reabsorption and natri-
uresis at different stages of pregnancy.32
Proteinuria plays an important role in the diagnosis of
primary glomerulonephritis and severe preeclampsia.
There is a recent debate regarding proteinuria as a requi-
site diagnostic criterion for preeclampsia. Opponents ar-
gue that proteinuria is unreliable and that unwanted
outcomes occur even in the absence of proteinuria.33,34
Proteinuria can be assessed by using the urinary
dipstick method, 24-hour urine collection, and protein:
creatinine (P/C) ratio on a random sample. The ideal
method for measurement of proteinuria and the cutoff
level for abnormal protein excretion in preeclampsia are
far from settled.35 Twenty-four-hour urine collection, al-
though most accurate for quantifying urinary protein, is
cumbersome for the patient and has the possibility of in-
complete collection. Obstetric caregivers are using the
P/C ratio more frequently. A recent meta-analysis showed
a pooled sensitivity of 83.6% and a specificity of 76.3%
when a P/C ratio cutoff of greater than 30 mg/mmol
was compared with the gold standard of 300 mg/day in
a 24-hour urine collection in hypertensive pregnant
women. This meta-analysis concluded that the P/C ratio
had a better negative predictive value in this population.36
Because of a decrease in tubular secretion, there is an ele-
vation of serum uric acid level in preeclampsia. Tradition-
ally, uric acid has been used as a marker in preeclampsia,
but its predictive value for diagnosis and prognosis of this
condition has been mixed.37 However, a recent study look-
ing at uric acid in patients with gestational hypertension
found it to be an accurate predictor of presence and sever-
ity of preeclampsia.38 The utility of the angiogenic factors
soluble fms-like tyrosine kinase-1, placental growth factor,
and soluble endoglin as diagnostic and predictive
markers for preeclampsia is detailed in ‘‘Emerging Bio-
markers of Preeclampsia’’ in this issue.
P-TMAs can be difficult to differentiate from one an-
other because of similarities in their presentation.
Table 2 succinctly summarizes the differences. HELLP

Table 2. Differential Diagnosis TMA in Pregnancy1,26,39,40,48,62

Disease Manifestations and Management Severe Preeclampsia/HELLP AFLP TTP/HUS SLE/APLS aHUS
Timing of onset
2nd trimester 1 1 11 1 1
3rd trimester 11 11 1 1 1
Postpartum 1 - 1 1 11
Signs and symptoms
Fever - - 1 1 1
HTN 111 11 1 11 1
Neurological symptoms 1 1 11 1 -
Purpura - - 11 1 11
Laboratory abnormalities
AKI 1 11 111 11 111
Hemolytic anemia 11 1 111 11 111
Thrombocytopenia 11 1 111 1 111
Transaminitis 11 111 1 - 1
DIC 1 11 - 1 -
Elevated PT 11 111 - - -
Hypoglycemia - 11 - - -
ADAMTS13 deficiency 1 - 11 - 1
Treatment
Delivery/supportive 111 111 - - -
Plasmapheresis - - 111 1 111
Steroids 1* 1* 1/- 111 -

Abbreviations: AFLP, acute fatty liver of pregnancy; aHUS, atypical hemolytic uremic syndrome; AKI, acute kidney injury; DIC, disseminated
intravascular coagulation; HELLP, hemolysis, elevated liver enzymes, and low platelets; HTN, hypertension; PT, prothombin time; SLE/APLS,
systemic lupus erythematosis/antiphospholipid syndrome; TMA, thrombotic microangiopathy; TTP/HUS, thrombotic thrombocytopenic pur-
pura/hemolytic uremic syndrome.
1 ¼ mild/occasionally; 11 ¼ moderate/sometimes; 111 ¼ severe/always; 1/- ¼ Limited data.
*Indicated for fetal lung maturation.
 Acute Kidney Injury and Pregnancy
and TTP present predominantly with microangiopathic
hemolytic anemia and thrombocytopenia. TTP occurs
late in pregnancy, whereas atypical HUS (aHUS) occurs
in the postpartum period. AFLP presents with oliguria,
clinical and laboratory findings of liver dysfunction
with elevations in serum transaminase levels (to .1000
IU/L), an elevation in conjugated bilirubin concentration,
and a prolongation of prothrombin time.
Data on the role and timing of kidney biopsy are lim-
ited. Kidney biopsy is not frequently performed during
pregnancy, but it may be necessary if PR-AKI is as-
sociated with proteinuria, hematuria, and/or positive
serologies (ie, when glomerulonephritis is suspected).
Another compelling reason is to differentiate glomerulo-
nephritis from preeclampsia after the second trimester to
avoid premature delivery. Performing a kidney biopsy
can be technically difficult after the 28th week of gesta-
tion because of the inability of the patient to lie in a prone
position.39 A kidney biopsy after 28 to 30 weeks of gesta-
tion is avoided, especially in light of improved neonatal
care available for premature infants should early delivery
be necessary.1,40 In a series of 18 kidney biopsies
performed in women between 11 weeks of gestation
and 19 days postpartum, the most common procedure-
related complication was a perirenal hematoma (38% of
the patients).41
Treatment
Treatment of PR-AKI poses special challenges because of
the risks to the mother and the fetus. Randomized trials
are lacking, and treatment is based on expert opinion
and small case series. Management of PR-AKI is best pro-
vided by a multidisciplinary team that involves obstetri-
cians, nephrologists, neonatologists, and other specialists
as needed, along with the patient. Good prenatal care
with early recognition of ‘‘at-risk’’ women for prompt
identification is paramount. In established PR-AKI, treat-
ment includes supportive measures, prevention of fur-
ther injury, identification and management of the
underlying cause, initiation of renal replacement therapy
(RRT) when indicated, and prompt delivery of the fetus
in some instances.
Intravascular volume depletion can occur early in
pregnancy because of nausea and vomiting. It can be
severe, especially in hyperemesis gravidarum, and may
result in PR-AKI.42 Intravenous fluids to ensure hemody-
namic stability to maintain kidney and uteroplacental
perfusion are crucial. Invasive hemodynamic monitoring
is occasionally needed to guide treatment.
If untreated, sepsis is associated with high maternal
and fetal morbidity and mortality.1 The general princi-
ples of antibiotic treatment and AKI management apply.
Careful review of the drugs in terms of its U.S. Food and
Drug Administration Pregnancy Category (see Guest Ed-
itorial) is mandatory. Removal of the underlying focus of
219
infection and evacuation of uterine contents may be nec-
essary. In established ACN or ATN, treating the compli-
cations and providing RRT are the only therapeutic
options.
Complications of PR-AKI include metabolic acidosis,
electrolyte abnormalities, anemia, volume overload, and
hypertension. Alkali therapy for metabolic acidosis
with sodium bicarbonate can be used with an aim to in-
crease the arterial pH close to 7.2, at which level the ad-
verse effects of acidemia are minimal43-45; a pH less
than 7.0 is considered as critical acidemia in the
fetus.46,47 Hyperkalemia can be treated with insulin,
glucose, and cation exchange resin. Because of its local
action, the exchange resin is felt to have no harmful
effects on the fetus.48 Prompt treatment of other electro-
lyte abnormalities such as hypokalemia and hypophos-
phatemia, which complicate PR-AKI in conditions such
as hyperemesis gravidarum, is essential. Human re-
combinant erythropoietin has been used safely in preg-
nancy, although severe anemia may require blood
transfusions. In women with congestive heart failure or
peripartum cardiomyopathy, the hemodynamic changes
of pregnancy can have disastrous maternal and fetal con-
sequences from fluid overload and hypoxia. Therefore,
the use of loop diuretics is indicated in these conditions,
as well as in PR-AKI with oliguria, despite their undesir-
able effect on uteroplacental perfusion and electrolyte
balance. Please see ‘‘Management of Hypertension in
Pregnancy’’ in this issue for treatment of hypertension
in pregnancy.
In biopsy-proven glomerulonephritis, steroid and
immunosuppressive therapy may be warranted. Cyclo-
phosphamide, an alkylating agent used in treating
biopsy-proven glomerulonephritis or vasculitis, causes
fetal toxicity. Its use in pregnancy is only indicated for
life-threatening maternal illness. A detailed review of im-
munosuppression in pregnancy is covered in ‘‘Pregnancy
in Renal Transplant Recipients’’ in this issue.
The mainstay of treatment in pregnancies compli-
cated by preeclampsia/eclampsia, HELLP syndrome,
and AFLP is delivery of the fetus.49 This decision is
guided by the gestational age, maternal and fetal con-
dition, and the severity of preeclampsia; prompt deliv-
ery is indicated when gestational age is 34 weeks or
more or if there is evidence of fetal or maternal dis-
tress. When gestational age is less than 34 weeks, the
use of glucocorticoids is indicated for 48 hours to ac-
celerate fetal pulmonary maturity. This should be fol-
lowed by delivery within 48 hours provided there is
no fetal or maternal distress. The other crucial therapy
is the use of magnesium sulfate with an aim to prevent
and treat seizures. Dosing regimens for magnesium
sulfate vary widely. Treatment with magnesium sulfate
is usually initiated at the start of induction of labor or
before cesarean section. It has also been used in the ex-
pectant management of preeclampsia, generally for 48
220 Acharya et al
to 72 hours while awaiting fetal lung maturity.50 It is
crucial to know that the kidneys excrete magnesium
and dose adjustment is necessary in kidney in-
sufficiency. Patients should be evaluated clinically
for evidence of magnesium toxicity. When there is kid-
ney impairment, additional serum magnesium level
monitoring every 6 hours is recommended. A level ex-
ceeding 4.8 mg/dL or 2 mmol/L results in neuromus-
cular and cardiovascular toxicity. The obstetric and
fetal evaluation in preeclampsia will be covered in
other articles in this issue.
The initial management of ADAMTS13-deficient TMA
during pregnancy is not different from that of the non-
pregnant patient, and delivery does not result in resolu-
tion of the condition. Plasma exchange, which is the
most effective therapy, restores enzymatic activity
through clearance of antibodies and should be initiated
as soon as possible.51 Daily plasma exchange is per-
formed until a platelet count of greater than 150 3 109/L
is achieved for at least 3 days and until the serum lactate
dehydrogenase level normalizes. This is followed by a ta-
per of plasma exchange over a 2-week period.25 Plasma
exchange is also recommended if it is not possible to dif-
ferentiate between preeclampsia/HELLP/AFLP and
TTP/aHUS. For TTP presenting in the first trimester, reg-
ular plasma exchange with close monitoring may allow
for continuation of pregnancy. Delivery is recommended
for women who do not respond to plasma exchange.52
Concern for fetal toxicity as well as long-term effects on
the neonates limits the use of rituximab, a B-cell-deplet-
ing antibody that is a second-line agent for TTP in the
nonpregnant patient. A recent retrospective review of
153 pregnancies in which rituximab was used showed
a live birth rate of 60%, a first trimester abortion rate of
21%, and congenital anomalies of 2.3%.53 Although the
drug seems to be safe in neonates in the short term, the
long-term effects remain unknown. In postpartum
P-TMAs, plasma exchange is recommended if thrombo-
cytopenia, hemolysis, or kidney failure continue to
worsen 48 to 72 hours after delivery of the fetus. Eculizu-
mab, a monoclonal humanized immunoglobulin G that
inhibits complement activation, is the most potent agent
available for use in aHUS or complement dysregulation
TMAs. It appears safe to use eculizumab in pregnant
women with paroxysmal nocturnal hemoglobinuria,
which is its other U.S. Food and Drug Administration
indication.54 However, because aHUS occurs in the post-
partum period, fetal toxicity is generally not a concern.
The risk of relapse of TTP in subsequent pregnancies
varies between 20% for acquired defects and 100% in
inherited disorders.55,56 Close monitoring of maternal
ADAMTS13 activity and evidence of ongoing hemolysis
is required. Prophylactic plasmapheresis may be
indicated.
The indications for starting RRT in PR-AKI are the
same as in the nonpregnant population: acidosis, uremia,
electrolyte disturbance, and fluid overload. The reported
use of RRT in PR-AKI ranges widely depending on the
population studied. One study from the developed world
reported less than 1 in 10,000 to 15,000 pregnancies need-
ing RRT; another from a developing nation showed that
up to 60% of their PR-AKI patients required RRT.57,58
Either intermittent hemodialysis or peritoneal dialysis
can be used with no significant differences reported in
the rate of successful delivery.59 Data on timing, modality,
and dose of RRT are lacking. A lower threshold for in-
itiating RRT has been proposed in PR-AKI, similar to
that in pregnant women with CKD. This is to decrease
the unwanted effects of uremia on the fetus, such as poly-
hydramnios, preterm birth, premature rupture of mem-
branes, and developmental delay.1,60–63 Additionally,
malnutrition due to uremia can lead to increased risk
for congenital anomalies.64
For patients who are critically ill and hemodynami-
cally unstable, continuous RRT modalities should be con-
sidered. Continuous RRT has theoretical benefits of
increased intensity of dialysis and minimization of hemo-
dynamic and volume shifts, but it needs exploration as
the modality of choice in PR-AKI.1
Outcomes
Persistent kidney dysfunction or need for long-term di-
alysis is unusual, but it can occur in women with pre-
existing hypertension or CKD. Of the patients with
HELLP syndrome and PR-AKI, 30% to 50% require di-
alysis.21,65 Kidney function typically improves in these
patients with complete recovery after delivery.66 Mater-
nal mortality of PR-AKI, especially in those with
HELLP syndrome, was reported to be high (13%) in
the 1980s, although more recent reports suggest a
much lower incidence.18,67 However, in a cohort of
PR-AKI requiring dialysis, a mortality of 30.9% was re-
ported in a case series of 55 patients.66 The high fetal
morbidity and mortality seen in PR-AKI could be due
to the underlying comorbid conditions as well as to iat-
rogenic early termination of pregnancy. When HELLP
syndrome is complicated by AKI, the risk of perinatal
death is as high as 26% and increases with the severity
of the kidney injury.
Conclusion
Although the incidence of PR-AKI is claimed to be de-
clining, the exact number remains unknown. PR-AKI is
associated with high maternal and fetal morbidity and
mortality. Women at high risk for developing AKI
should have prenatal counseling to identify those at
risk. At this point in time, prevention of AKI is the
best strategy to avoid the detrimental consequences of
PR-AKI. There is an urgent need for early and accurate
diagnosis of PR-AKI to improve maternal and fetal out-
comes. This will provide a framework for a standardized
 Acute Kidney Injury and Pregnancy
approach to the care of patients with PR-AKI. Other
pieces of the puzzle such as the choice of RRT, the opti-
mal dialysis prescription, and the ideal time to initiate
RRT remain an enigma. This needs to be systematically
studied on a global scale to optimize care for women
with PR-AKI.
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