TITLE

ACUTE KIDNEY INJURY IN THE PREGNANT PATIENT

Rosemary Nwoko, Darko Plecas and Vesna D. Garovic

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ABSTRACT

Acute kidney injury (AKI) is costly and associated with increased mortality and

morbidity. An understanding of the renal physiologic changes that occur during

pregnancy is essential for proper evaluation, diagnosis, and management of AKI.

As in the general population, AKI can occur from pre-renal, intrinsic, and post-

renal causes. Major causes of pre-renal azotemia include hyperemesis

gravidarum and uterine hemorrhage in the setting of placental abruption. Intrinsic

etiologies include infections from acute pyelonephritis and septic abortion,

bilateral cortical necrosis, and acute tubular necrosis. Particular attention should

be paid to specific conditions that lead to AKI during the second and third

trimesters, such as preeclampsia, HELLP syndrome, acute fatty liver of

pregnancy, and TTP-HUS. For each of these disorders, delivery of the fetus is

the recommended therapeutic option, with additional therapies indicated for each

specific disease entity. An understanding of the various etiologies of AKI in the

pregnant patient is key to the appropriate clinical management, prevention of

adverse maternal outcomes, and safe delivery of the fetus. In pregnant women

with pre-existing kidney disease, the degree of renal dysfunction is the major

determining factor of pregnancy outcomes, which may further be complicated by

a prior history of hypertension.

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KEY WORDS

Acute kidney injury (AKI) - TTP-HUS (thrombotic thrombocytopenic purpura-

Hemolytic uremic syndrome) - HELLP (hemolysis, elevated liver enzymes, low

platelets) - TMA (thrombotic microangiopathy) - aHUS (atypical hemolytic uremic

syndrome).

INTRODUCTION

Acute kidney injury (AKI) can be defined as the sudden loss of renal

function associated with a rise in creatinine levels above a known baseline.

In this setting, clearance of nitrogenous wastes, as well as extracellular

volume and electrolyte regulation are impaired. AKI in the general

population is associated with increased mortality, increased length of

hospital stay and financial costs . In the pregnant population the incidence

of all AKI cases, including dialysis dependence, is less than 1% in the

Western world, with reduced frequency and improved mortality since the

1960s. It is important to note that epidemiologic data on the incidence and

prevalence of AKI in pregnancy may vary due to different diagnostic

criteria and variable cut-off values for serum creatinine levels that define

kidney injury, the lack of creatinine data in this young, healthy population,

and the variability in ethnicity and socioeconomic class. New cases of

pregnancy-related AKI have declined from approximately 1/3000 to 1/15,000

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– 20,000 since the 1960s . Two main factors may be responsible for the

overall decline in the incidence of pregnancy-related AKI: improvement in

pre-natal care and a decrease in the rate of illegal, septic abortions in

developed countries. It is possible that the use of antiprogesterone drugs,

such as mifepristone, might have contributed to the declining septic

abortion rates, although there is a paucity of data regarding this

association.

During pregnancy, AKI can be due to any of the same disorders that affect

the general population, such as pre-renal, intrinsic and post-renal causes.

In the text that follows, we will review AKI in pregnancy in the context of

pre-renal, intrinsic and post-renal etiologies, and will address its

presentation and onset with respect to gestational age (i.e., trimester of

pregnancy), as this may help to facilitate making a differential diagnosis.

Finally, AKI may occur as a new condition, a pre-existing, albeit

unrecognized condition, or as a pre-existing condition in patients with

normal or impaired renal function. Among conditions that may lead to AKI,

and which commonly occur during the second and/or third trimester,

special attention will be given to those disease processes that are unique

to the pregnancy state.

PHYSIOLOGIC CHANGES IN PREGNANCY

Most organ systems in a pregnant female undergo changes in order to

accommodate the growing fetoplacental unit. There are considerable

changes that occur in the urinary tract system: both kidneys and ureters

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increase in size by 1 to 1.5 cm , accompanied by dilation of the renal pelvis

and calyx. This dilation of the urinary system is due to the hormonal effects

of progesterone, external compression by the gravid uterus and

morphologic changes in the ureteral wall . Progesterone also reduces

ureteral peristalsis, contraction and tone. Decreased bladder tone, bladder

hyperemia and edema potentiate asymptomatic bacteruria, while bladder

flaccidity may affect the vesicoureteral valve, leading to vesicoureteral

reflux . The result of these physiological changes are increased risks for

urinary stasis, urinary tract infection, and, ultimately, pyelonephritis. The

systemic vasodilatory state, typical of pregnancy, increases renal

perfusion and glomerular filtration rate (GFR). Due to the rise in GFR,

hypouricemia and increased urine protein excretion occur. Systemic

vasodilation leads to the stimulation of anti-diuretic hormone (ADH) release

and increased thirst, resulting in a decrease in plasma osmolality and

plasma sodium concentration by 4 to 5 mEq/L . Minute ventilation

increases due to progesterone-induced stimulation of the central

respiratory center in the brain. This results in a decrease in pCO2 and a

mild chronic respiratory alkalosis, which is compensated for by renal

excretion of bicarbonate.

PRE-RENAL AZOTEMIA

This is defined as a decrease in the effective intravascular volume leading to

decreased renal perfusion. Causative factors seen in the non-pregnant

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population, such as vomiting, diarrhea, congestive heart failure, nephrotic

syndrome and diuretic use, are possible etiologies in the pregnant patient .

Pre-renal azotemia during pregnancy may be due to hypovolemia resulting from

hyperemesis gravidarum, diuresis, and hemorrhage from trauma, placental

previa, placental abruption, a ruptured or atonic uterus or intra-operative

bleeding. It may also result from decreased cardiac output in the setting of pre-

existing valvular heart disease, ischemia or cardiomyopathy from any cause.

Finally, decreased renal perfusion may also occur in the settings of anaphylaxis,

sepsis, and the use of non-steroidal anti-inflammatory drugs/

cyclooxygenase-2 inhibitors (NSAIDs/COX-2 inhibitors).

The most common causes of prerenal azotemia in pregnancy include

hyperemesis gravidarum and hemorrhage. Hyperemesis gravidarum is defined

as severe and persistent nausea and vomiting leading to weight loss, exceeding

5 percent of the pre-pregnancy body weight, and ketonuria . These patients

present in the first trimester of pregnancy with acute renal failure

associated with a hypokalemic, metabolic alkalosis. Conceivably,

metabolic alkalosis may be compensated by a respiratory response, i.e,

hypoventilation, but clinical studies supporting this compensatory

response are limited. As this occurs in the setting of preexisting

respiratory alkalosis, which is a known physiological consequence of the

direct progesterone effect on the respiratory center in pregnant women,

further evaluation with a blood gas may be necessary in order to evaluate

the respiratory and metabolic components and diagnose the underlying

acid-base disorder. Other laboratory abnormalities can include an increase in

hematocrit (hemoconcentration), mild elevations in aminotransferases , as well

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as mild hyperthyroidism. The hyperthyroidism is thought to be due to the thyroid

stimulating activity of human chorionic gonadotropin . Treatment with antiemetics

and intravenous fluids usually corrects the acid-base, electrolyte and renal

abnormalities .

The differential diagnoses of hemorrhage during the first trimester of pregnancy

differ from the second or third trimesters. Specifically, in the third trimester,

placenta previa, abruptio placenta (preeclampsia and prior hypertension are risk

factors), uterine rupture and vasa previa may occur.

INTRINSIC KIDNEY INJURY

Damage to the tubulo-interstitium, glomerulus, or cortex can lead to intrinsic

kidney damage during pregnancy. Causes of intrinsic AKI include tubular and

interstitial damage from acute tubular necrosis (ATN), contrast-induced

nephropathy, infections, nephrotoxic drugs and myoglobinuria. The usual causes

of glomerulonephritis (GN) in the non-pregnant patient, such as lupus nephritis,

post-infectious GN, and focal segmental glomerulosclerosis (FSGS) may occur.

The renovascular system can be affected in conditions such as HUS/TTP, anti-

phospholipid syndrome, scleroderma renal crisis, HELLP and pre-eclampsia/

eclampsia.

INFECTION

Urinary tract infections are very common in pregnancy, but rarely cause AKI,

except when accompanied by septicemia or hypotension. However, acute

pyelonephritis, without signs of sepsis or hypotension, may result in abscess

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formation and kidney injury , although it is unclear why these patients develop

significant renal dysfunction.

A more common infectious cause of renal failure associated with pregnancy is

septic abortion, which has a higher incidence in underdeveloped countries.

These patients present with signs and symptoms of septic shock and/or

disseminated intravascular coagulation (DIC). Renal failure may be due to

volume contraction, acute tubular necrosis or bilateral renal cortical necrosis.

Treatment includes supportive care with intravenous fluids and appropriate

antibiotics. Dilatation and curettage, as well as hysterectomy may be needed in

certain cases.

Thrombotic Microangiopathy (TMA)

Thrombotic microangiopathy is a pathologic diagnosis that may occur with

pregnancy, in the setting of severe preeclampsia, with HELLP (hemolysis,

elevated liver enzymes and low platelets) syndrome, TTP (thrombotic

thrombocytopenic purpura), HUS (hemolytic uremic syndrome), as well as

atypical variants of HUS. Although the term TTP-HUS will be used frequently

in the following text, it is important to note that both can and do occur as

separate disease processes (Table 1). The main feature of platelet thrombi

and/or fibrin in the microvasculature, can lead to multi-organ dysfunction. The

above differentials should be considered in patients who present in late

pregnancy with acute renal failure, microangiopathic hemolytic anemia and

thrombocytopenia.

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Preeclampsia is characterized by hypertension and proteinuria occurring after 20

weeks gestation. Renal failure is unusual in this setting. Pregnancy termination is

the recommended and effective therapy, with abnormalities resolving post-

partum, although microalbuminuria may persist for weeks post delivery.

It is widely accepted that preeclampsia occurs in the setting of placental hypoxia

and underperfusion. In contrast to normotensive pregnancies, placental spiral

arteries in preeclampsia fail to lose their musculoelastic layers, ultimately leading

to decreased placental perfusion . Placental hypoxia ensues, which is viewed

frequently as an early event that may cause placental production of soluble

factors leading to endothelial dysfunction. Recent studies have provided

evidence that preeclampsia is associated with elevated levels of the soluble

receptor for vascular endothelial growth factor (VEGF) of placental origin. This

soluble receptor, commonly referred to as sFlt-1 (from fms-like tyrosine kinase

receptor-1), may bind and neutralize VEGF, and thus decrease free VEGF levels

that are required for active fetal and placental angiogenesis in pregnancy.

Therefore, elevated sFlt-1 may be the missing link between placental ischemia

on one side and endothelial dysfunction, mediated by sFlt-1 neutralization of

vascular growth factors, on the other.

HELLP syndrome is associated with severe hypertension/preeclampsia during

pregnancy. Its overall incidence is 1 to 2 per 1000 pregnancies, and occurs in 10-

20 percent of severe preeclamptics/eclamptics. The underlying mechanism of

injury is not fully understood, as 15 to 20 percent of affected patients do not have

hypertension or proteinuria. In addition to sFlt-1, elevated levels of soluble

endoglin may contribute to maternal endothelial dysfunction in HELLP patients .

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Recent studies are elucidating the role of the dysfunctional complement

alternative pathway (CAP) as a risk factor for HELLP. Mutations can occur in

the major regulatory proteins of the CAP, factor H, membrane cofactor protein

and factor I. In a case series of 11 patients diagnosed with HELLP, 4 patients

were found to have missense mutations in 1 of 3 genes encoding for CAP

regulatory proteins, which were not found in 100 healthy controls from the same

ethnic background . Low C3 and factor B levels may also predispose to HELLP

syndrome, even when no specific mutations are found in these genes .

The clinical manifestations of HELLP syndrome include ), abdominal pain

(midepigastric, right upper quadrant or below the sternum) nausea, vomiting and

malaise. Hypertension (blood pressure > 140/90) and proteinuria may be either

present or absent in these patients . Renal failure also may be present, and the

frequency of CAP abnormalities may be higher in these patients compared to

patients who present without renal involvement . The presence of

microangiopathic hemolytic anemia with schistocytes on blood smear, low

platelets and elevated liver enzymes are the diagnostic criteria for HELLP. Other

indicators of hemolysis include an elevated lactate dehydrogenase (LDH) or

indirect bilirubin, and low haptoglobin. However, there is no consensus as to the

degree of laboratory abnormalities that are diagnostic of HELLP syndrome.

Imaging, such as computed tomography (CT) or magnetic resonance imaging

(MRI), may be helpful in cases where complications such as hepatic hematoma,

infarction or rupture occur .

HELLP may be difficult to differentiate from TTP-HUS, as thrombocytopenia and

microangiopathic hemolysis occur with both conditions. However, the presence

of elevated liver enzymes strongly suggests HELLP syndrome (Table 1).

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TTP-HUS is a form of TMA that can be due to a deficiency in ADAMTS13 (TTP),

a von Willebrand factor (vWF) processing enzyme, or due to mutations in genes

that encode proteins responsible for regulating the CAP system (atypical HUS).

Deficiency in ADAMTS13 can be acquired or genetic, and patients have severe

thrombocytopenia and mild renal involvement. These patients commonly develop

neurological manifestations, and typically present in the second or third

trimesters of their pregnancies, when ADAMTS13 levels tend to fall . Atypical

HUS (non-Shiga toxin) is associated with mutations in genes coding for proteins

in the alternative complement pathway. This results in spontaneous and

excessive activation of CAP leading to endothelial cell damage. Complement

abnormalities occur due to acquired anti-Factor H antibodies, inactivating

mutations in factors H and I, or membrane co-factor protein, and activating

mutations in factor B or C3 coding genes. Patients predominantly have renal

involvement, and thrombocytopenia may not be as severe as seen in TTP-HUS.

The pregnancy state may trigger abnormal complement activation leading to

atypical HUS. In a recent series of 100 patients with atypical HUS, 21 percent

developed during pregnancy, with 79% occurring post-partum . Complement

abnormalities were detected in 18 of the 21 patients, and this patient group had

poor outcomes with respect to time to end stage renal disease (ESRD), as well

as risks of fetal loss and preeclampsia . The interactions among complement

components, angiogenic factors, and the clinical features of preeclampsia were

documented further using pregnant mouse models. Results of this study

demonstrated that complement activation targets the placenta, leading to

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endothelial dysfunction through the release of anti-angiogenic factors that have

been associated previously with hypertension and proteinuria

Renal biopsy is rarely needed for the diagnosis of these conditions, as clinical

and laboratory data are usually sufficient to distinguish and establish a diagnosis.

In addition, renal biopsy findings may be characteristic of TMA, but may not

differentiate among disease entities (e.g. HELLP versus atypical HUS). Light

microscopy typically shows double-contouring of the glomerular basement

membrane and mesangiolysis, with vascular changes such as arteriolar and

capillary thrombi

TTP-HUS may occur de novo with pregnancy, may relapse during pregnancy

and/or recur with subsequent pregnancies. The distinction among severe forms

of preeclampsia (and HELLP in particular), TTP, and HUS may be facilitated by

certain clinical and laboratory features, but it is not always possible (Table 1).

Renal biopsy should be considered if the laboratory evaluation is non-

diagnostic and/or in the presence of co-morbidities, such as systemic

lupus erythematosus, where the renal biopsy findings may have a major

impact on a patient’s treatment. For example, biopsy-proven lupus

nephritis optimally is managed with immunosuppression, whereas delivery,

even remote from term, is indicated for HELLP syndrome. In pregnant

patients with adequate blood pressure control and normal coagulation

parameters, renal biopsy can be safely performed . However, renal biopsy

is typically not advisable after 32 weeks of gestation.

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Finally, a thrombotic microangiopathy, similar to TTP, can occur in patients with

anti-phospholipid antibodies presenting with renal disease, thrombocytopenia,

and hemolytic anemia during pregnancy . In these patients, it is possible that a

hypercoagulable state, which is characteristic of pregnancy, may contribute to

the pre-existing subclinical thrombotic state due to the presence of anti-

phospholipid antibodies, resulting in a clinically apparent syndrome of thrombotic

microangiopathy during pregnancy (Figure 2). The role of anticoagulation in the

prevention/treatment of renal involvement in these patients is unclear.

ACUTE FATTY LIVER OF PREGNANCY

Fatty infiltration of hepatocytes may occur during pregnancy, and can be

associated with renal failure in 60% of cases . It should be suspected in women

with preeclampsia. This is a disease of the third trimester of pregnancy, and

patients present with elevated liver function tests, thrombocytopenia,

hypofibrinogenemia, hypoglycemia and coagulation abnormalities . In severe

cases, patients may present with encephalopathy. Renal failure may be due to

acute tubular necrosis and decreased renal perfusion.

The diagnosis is made clinically based upon presentation, laboratory and

imaging data. A liver biopsy is not necessary, but may be useful in atypical

presentations . Characteristic liver biopsy findings consist of microvesicular fatty

infiltration of hepatocytes in the central and mid-zonal lobular regions, with

sparing of the portal tracts .

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Primary treatment includes maternal stabilization, with correction of coagulation

abnormalities (with fresh frozen plasma, platelets, cryoprecipitate and red blood

cells) as needed and prompt delivery. Acute fatty liver of pregnancy may recur in

subsequent pregnancies, although the risk of recurrence is unknown.

RENAL CORTICAL NECROSIS

Renal cortical necrosis is a rare, but catastrophic process secondary to

ischemic necrosis of the renal cortex .It occurs as the end result of various

severe pregnancy complications, including abruptio placentae, placenta

previa, prolonged intrauterine fetal death or amniotic fluid embolism .

Obstetric etiologies account for approximately 50-70% of cases of renal

cortical necrosis . Patients present with the abrupt onset of oliguria or

anuria, gross hematuria, flank pain and hypotension . The diagnosis can be

made by ultrasonography or CT scan. There is no specific treatment

available and many patients will require dialysis, with 20-40 % of patients

having partial renal recovery . In one series, 42 of 45 patients (87.5%) with

biopsy-confirmed renal cortical necrosis were dialysis dependent upon

hospital discharge . In patients who recover partial renal function,

creatinine clearance stabilizes between 15 and 50 ml/min .

POST-RENAL KIDNEY INJURY

A common finding during the later stages of pregnancy is mild to moderate

dilatation of the collecting system from the gravid uterus, and relaxation of the

ureteral smooth muscle . While the majority of patients are asymptomatic

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and have normal renal function , this functional hydronephrosis, in rare

cases, may cause renal failure. Placing the patient in a lateral recumbent

position, thereby relieving uterine pressure on the ureter, may improve

urine output and creatinine. In contrast, patients with obstruction due to

either extrinsic (e.g. uterine fibroid), or intrinsic (e.g. renal stone) causes,

are commonly symptomatic and present with varying degrees of renal

insufficiency. Post-renal kidney injury occurs from obstruction of part or all of

the genitourinary system. Kidney stones, papillary necrosis, surgical ligation,

cervical cancer, and urethral obstruction by catheter malfunction, or blood clots

may be inciting factors. In the above cases, treatment involves relief of the

obstruction.

PREEXISTING RENAL DISEASE

Approximately 4% of childbearing-age women have chronic kidney disease, with

diabetic nephropathy being the most common cause found in pregnant women .

A variety of primary and/or systemic kidney diseases can occur in the pregnant

population and lead to an increased incidence of fetal prematurity, low birth

weight and fetal loss . Due to major obstetric and neonatologic advancements,

fetal outcomes in women with impaired renal function have improved in recent

years . However, the risk for fetal loss remained higher in pregnant patients with

preexisting renal insufficiency compared to a control group of women with

medical problems other than renal disease Factors predicting fetal loss included

severity of proteinuria and degree of renal dysfunction . Other risk factors for

complications include decreased GFR, nephrotic range proteinuria, advanced

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maternal age and the presence of underlying diseases, such as diabetes

mellitus, hypertension, and active systemic lupus nephritis.

Pregnancy likely does not contribute to the progression of renal insufficiency

when the maternal creatinine is less than 1.4 mg/dl and the blood pressure is

normal. There are increased risks of renal decline and pregnancy loss with a

creatinine ≥1.4 mg/dl,; women with creatinine values of 3 mg/dl or greater should

be strongly discouraged against pregnancy, due to the high risks for adverse

fetal outcomes and maternal events, including further renal decline . Other data

have shown an increased risk of deterioration of maternal renal function when

the creatinine clearance at conception is less than 25-30 ml/min .

Some experts have suggested that patients with anti-phospholipid antibody

syndrome and a history of arterial thrombotic events (strokes, in particular),

should be advised against becoming pregnant . These women, despite adequate

anticoagulation, appear to be at risk for recurrent strokes. Poorly controlled

diabetes mellitus and active lupus nephritis are also relative contraindications to

pregnancy. Patients with preexisting renal disease should undergo

preconception counseling prior to attempting to conceive. Diabetic patients

should be closely monitored by an endocrinologist, with goals for tight

diabetic control before conception. A minimum of 6 consecutive months

without a flare, as well as stable renal function with a creatinine <1.4 mg/dL,

is required prior to conception in lupus patients In patients with lupus

nephritis, in remission, teratogenic anti-hypertensives and

immunosuppressives must be changed to safe alternatives prior to

conception.

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MANAGEMENT

An understanding of the physiologic changes occurring during pregnancy, as well

as early identification of women with pre-existing renal dysfunction, will enable

proper management of AKI that may occur during pregnancy. Therapy should be

directed at the underlying cause, and delivery of the fetus may be required in

certain instances, as discussed above. Severe renal failure may require dialysis,

and both hemodialysis and peritoneal dialysis can be safely used . Similar to

non-pregnant patients, plasma exchange should be considered for those with

peri-partum TTP-HUS. For patients with ESRD undergoing dialysis, it is crucial to

prevent intrauterine azotemia, manage anemia, provide adequate nutritional

support and avoid dialysis-associated hypotension.

Volume contraction from dehydration and hemorrhage from any cause can be

readily managed by resuscitation with intravenous fluids and blood products.

Urinary tract infections should be treated with appropriate antibiotic therapy that

is safe for both mother and fetus. Antibiotics should always be adjusted for the

level of GFR. Renal obstruction can be treated conservatively or with surgical

interventions.

CONCLUSION

In this review, we have discussed the different etiologies of AKI, in general, and

those unique to pregnancy. The management of AKI during pregnancy presents

a challenge that requires knowledge of potential causative factors, proper

evaluation and treatment, and consideration of both maternal and fetal well-

being. With respect to pregnancy-specific disorders, such as preeclampsia and

HELLP, their etiologies and pathogeneses remain elusive, resulting in a failure to

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develop specific preventive and treatment options. Future research may be

crucial in identifying the underlying pathogenetic mechanisms and related

therapeutic targets.

TABLE 1

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Preeclampsia HUS TTP

Time of onset Late 3rd trimester Post-partum 2nd and 3rd trimesters

Renal failure Unusual Common Minimal or absent

Renal prognosis Recovery 76% ESRD Fair

Neurological

findings

Present Minimal or absent Dominant

Low platelet count Present (HELLP) Present Present

DIC Present Absent Absent

Abnormal liver

enzymes

Present (HELLP) Absent Absent

Complement

alternative

pathway

Present (HELLP) Present Absent

Low ADAMTS13 Mild to moderate Absent Severe

FIGURE LEGENDS

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Table1. Differential diagnosis of TMA in pregnancy: the role of clinical and

laboratory findings

Figure 1. Flow diagram showing the differential diagnosis of thrombotic

microangiopathy.

Figure 2 Light (A) and electron microscopy (B) from a renal biopsy consistent

with TMA. A 43-year old admitted at 33 weeks gestation for increasing edema

and decreased urinary output. This was the patient’s first pregnancy (twins)

through in vitro fertilization. She presented in hemorrhagic shock, with elevated

liver enzymes, and LDH, thrombocytopenia and a creatinine of 2.7 mg/dl. A

diagnosis of HELLP was made and the patient underwent urgent Cesarean

section. Her kidney function further deteriorated post-partum and she required

hemodialysis. As her clinical course was not consistent with HELLP syndrome

(Table 1), additional work up was initiated. ADAMTS 13 levels ranged within 45-

68% of normal, with normal C3, C4, CH50, factor H and factor I levels. Factor H

antibody was negative. Lupus anticoagulant was positive. Her renal biopsy was

consistent with TMA.

2A: Light microscopy showing fibrin (yellow thin arrow) and a thrombus (green

thick arrow) within a vessel that propagates to the vascular pole of the

glomerulus. There is also evidence of endothelial cell swelling (dashed black

arrow) resulting from inflammation and injury.

2B: Electron microscopy showing foot process effacement (multiple short arrows)

and the formation of new glomerular basement membrane (thin long arrow), the

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process of double-contouring. She has remained on chronic hemodialysis and is

currently being evaluated for a renal transplant.

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