observed acute renal failure in 7.4% 32/435 of patients with HELLP syndrome, and approximately one - third of these patients required hemodialysis [32].. HELLP syndrome associated with a
Trang 1fl exion and then compresses the bladder [19,20] Other risk factors for urinary obstruction in pregnancy include pyelonephri-tis, renal calculi, ureteral narrowing, and low abdominal wall compliance [21]
Renal ultrasound is the fi rst step in the evaluation of possible urinary tract obstruction, although results may be inconclusive due to the physiologic dilation of the collecting system often seen
in pregnancy due to both the effects of progesterone and the mechanical pressure of the gravid uterus Thus, anterograde or retrograde pyelography may be necessary for defi nitive diagnosis Relief of the obstruction may be accomplished by ureteral stent placement, percutaneous nephrostomy, manual reduction of an incarcerated uterus, or amnioreduction in the case of polyhy-dramnios If the fetus is signifi cantly premature, correcting the obstruction should allow for a substantial delay in delivery
as well as recovery of renal function If the patient is near term, however, delivery may be indicated to remove both the mechani-cal and hormonal causes of the obstruction It should be noted that the fetal mortality rate for reversible obstructive uropathy with associated renal failure has been reported to be as high as 33% [22]
Pyelonephritis
Pyelonephritis is an important cause of ARF during pregnancy
As a result of the normal physiologic changes that accompany pregnancy, the urinary collecting system is prone to dilation and urinary stasis In addition, there is an increased sensitivity to bacterial endotoxin - induced tissue damage These normal changes result in an increased incidence in both upper and lower tract infections The incidence of pyelonephritis in pregnancy is approximately 2% and it is one of the most common causes of sepsis during pregnancy [23] Presenting symptoms generally include fever, fl ank pain, nausea, vomiting, and possibly urinary frequency, dysuria, and urgency The most common causative
organism is E coli , which accounts for nearly 75% of cases [24] Other potential pathogens include Proteus mirabilis , Klebsiella pneumoniae , group B streptococci, enterococci, and Pseudomonas aeruginosa Prompt and appropriate antibiotic treatment is
gen-erally very effective in treating pyelonephritis during pregnancy, with improvement seen in the fi rst 24 – 48 hours After resolution
of the initial infection, suppressive antibiotic treatment through-out pregnancy should be considered as the recurrence rate is as high as 20%
Although pyelonephritis rarely results in a signifi cant decline
in renal function in non - pregnant patients, Gilstrap and col-leagues demonstrated a substantial decrease in creatinine clear-ance among gravidas with pyelonephritis, with a return to normal
or near normal renal function in the majority of women re -evaluated following antibiotic therapy [25,26] As mentioned previously, it has been postulated that this decline in renal func-tion is related to an increased vascular sensitivity to bacterial endotoxins and vasoactive mediator release in pregnancy [1] It
ATN may occur in cases of rhabdomyolysis or massive hemolysis
More commonly in pregnancy, however, ATN is ischemic in
nature, as a result of a hemodynamic insult with hypotension and
impaired renal perfusion This is commonly due to a hemorrhage
during pregnancy, which may be the result of either placental
abruption or a postpartum hemorrhage which complicates
approximately 1% and 4 – 6% of pregnancies respectively [16]
In those patients with pre - eclampsia who develop renal failure,
ATN appears to be the underlying renal lesion Clinically, it may
be diffi cult to distinguish between severe prerenal azotemia and
ATN, although urinary indices and urinalysis may be helpful
(Table 28.2 ) Urinalysis typically reveals muddy brown granular
casts and renal tubular epithelial cells In light of impaired renal
tubular function, laboratory evaluation reveals a high urinary
sodium excretion as well as urine that is neither concentrated nor
dilute Acute tubular necrosis may be either oliguric (urine
output < 400 mL/day) or non - oliguric ( > 400 mL/day), depending
on the mechanism of injury and the severity Treatment of ATN
is supportive and necessitates optimization of hemodynamics,
avoidance of potential nephrotoxin exposure, nutritional support
with careful monitoring of fl uids and electrolytes and,
occasion-ally, dialysis Renal function typically recovers in 7 – 14 days with
appropriate treatment
Urinary o bstruction
Although urinary obstruction is a relatively uncommon cause of
ARF in pregnancy, it is readily reversible and, therefore, must be
considered in the differential Obstruction may occur at any level
of the urinary tract due to a wide variety of causes, many of which
are not unique to pregnancy (Table 28.6 ) Additionally, gravidas
with an abnormally confi gured or overdistended uterus, such as
those with uterine leiomyomata, polyhydramnios, or multiple
gestations, may be particularly susceptible Ureteral compression
by the gravid uterus, with resultant ARF and hypertension, has
been reported [17] and large leiomyomata have even been
reported to cause ureteral obstruction in the fi rst trimester [18]
Another cause unique to pregnancy is an incarcerated uterus,
which may cause urinary retention as the gravid uterus enlarges
but becomes trapped in the pelvis secondary to signifi cant
Table 28.6 Causes of urinary obstruction
Blood clots Blood clots
Sloughed papillae Neuropathic bladder
Ureteral stricture or ligation Urethral stricture
Retroperitoneal fi brosis
Extrinsic compression by tumor, gravid uterus
Trang 2of underlying chronic renal disease, presumably unmasked by pregnancy and/or pre - eclampsia [5]
HELLP s yndrome
HELLP is an acronym used to describe a constellation of fi ndings,
including h emolysis, e levated l iver enzymes, and l ow p latelets
Nausea, epigastric or right upper quadrant pain, and tenderness may be present at the time of diagnosis, as well as proteinuria and renal dysfunction Coagulation studies including fi brinogen, pro-thrombin time, and partial thromboplastin time may be useful in distinguishing this disorder from others associated with dissemi-nated intravascular coagulation (DIC), in that they are often normal in patients with HELLP syndrome in the absence of pla-cental abruption
HELLP syndrome has been described in 4 – 12% of patients with severe pre - eclampsia [30] and is considered to represent
a variant of severe pre - eclampsia However, in a small study
by Krane, in which patients with HELLP syndrome underwent renal biopsy, less than half had the glomerular endotheliosis classic for pre - eclampsia [31] Sibai et al observed acute renal failure in 7.4% (32/435) of patients with HELLP syndrome, and approximately one - third of these patients required hemodialysis [32] Evidence of disseminated intravascular coagulation was present in 84% of these patients, and 44% had abruptio placen-tae HELLP syndrome associated with acute renal failure in this study carried a maternal mortality rate of 13% and perinatal mortality rate of 34% The poor prognoses described by Sibai likely refl ect the severity of disease seen in his patient population
Generally, treatment of HELLP syndrome consists of expeditious delivery once the diagnosis is established, as well as magnesium sulfate for seizure prophylaxis as discussed earlier, with rapid recovery of renal function expected In a group of 23 patients with HELLP syndrome who were normotensive prior to pregnancy, no residual renal impairment was observed following delivery However, 40% of patients with chronic hypertension and subsequent HELLP syndrome eventually required chronic dialysis [32,33]
Acute f atty l iver of p regnancy
Acute fatty liver of pregnancy is another uncommon cause of ARF
in pregnancy, with an incidence reported as between 1 in 6700 and 1 in 13 000 deliveries [34,35] The disease exhibits a slight predominance in nulliparas; it has been diagnosed as early as 24 weeks of gestation and as late at 7 days postpartum [4,35] , but usually occurs in the last few weeks of gestation Initial manifesta-tions are non - specifi c, including nausea, vomiting, headache, malaise, and abdominal pain Laboratory evaluation reveals mild elevation of serum transaminase levels, hyperbilirubinemia, and leukocytosis as well as hypoglycemia Renal failure develops in
is this sensitivity to endotoxin that may account for the greater
incidence of septic shock and adult respiratory distress syndrome
from pyelonephritis during pregnancy
Pre - e clampsia
Among those causes of ARF unique to pregnancy, pre - eclampsia/
eclampsia accounts for the majority One study of ARF in
preg-nancy performed in Uruguay, which included patients from 1976
to 1994, reported that pre - eclampsia was the cause of ARF in
approximately 47% of cases [27] Another retrospective study
conducted at an inner city hospital in Georgia described pre
eclampsia in more than one - third of 21 cases of ARF diagnosed
at their institution from 1986 to 1996 [7]
Classically, pre - eclampsia is defi ned as the development of
hypertension, proteinuria, and edema after the 20th week of
ges-tation (It should be noted, however, that severe pre - eclampsia
may occur earlier than 20 weeks in the presence of gestational
trophoblastic disease, also called a molar pregnancy.) Elevated
liver enzymes, coagulation abnormalities, and microangiopathic
hemolytic anemia may be seen in severe pre - eclampsia as well
The diagnosis is established clinically and rarely confi rmed by
renal biopsy
Pathologically, pre - eclampsia is characterized by swollen
glo-merular capillary endothelial cells or gloglo-merular endotheliosis,
with resultant capillary obstruction and glomerular ischemia
[28] Importantly, the extent of the morphologic lesion does
not necessarily correspond to the degree of renal functional
impairment [4] In addition, the presence of subtle volume
depletion and enhanced sensitivity of the renal vasculature to
vasoconstriction may contribute to superimposed ATN, which
many believe to be the lesion associated with signifi cant ARF in
pre - eclampsia
Treatment of severe pre - eclampsia and the associated renal
failure ultimately depends on delivery of the infant and seizure
prophylaxis with magnesium sulfate during the delivery and for
at least 24 hours postpartum This is accomplished regardless of
the gestational age of the fetus, though consultation with a
mater-nal - fetal medicine specialist is recommended with a premature
fetus to determine if it is possible to delay delivery long enough
to administer corticosteroids in an attempt to improve fetal lung
maturity It is important to monitor fl uid administration closely
while magnesium sulfate is given as patients with impaired renal
function will not clear the medication as well and dose reductions
may be necessary
Recovery of renal function is usually seen within days to weeks
after delivery with isolated pre - eclampsia, although up to 20%
may have some degree of residual impairment [29] In contrast,
when patients with chronic hypertension and underlying renal
disease experience ARF in pregnancy, approximately 80% will
require long - term renal replacement therapy [15] Histologic
evaluation in those patients with persistent renal impairment,
proteinuria, or hypertension postpartum has revealed evidence
Trang 3those receiving such treatment Additional therapeutic interven-tions varied, including aspirin, dipyridamole, and corticosteroids Greater than 50% of all patients had evidence of renal dysfunc-tion, although those with severe ARF or anuria were excluded from the Canadian multicenter trial
Delivery in cases of TTP/HUS is not necessarily indicated, especially at very early gestational ages, which is why care must be taken to differentiate this disease from severe pre - eclampsia
Nine of the 76 women seen at Johns Hopkins presented in their third trimester of pregnancy, although there was no comment as
to the degree of renal impairment in this subset of patients A recent report of three patients with postpartum HUS at the Rhode Island hospital who were treated with frequent plasma exchange and prednisone reported survival in all three patients [41] Additionally, Hayward and colleagues described nine preg-nant women presenting between the fi rst trimester of gestation and 1 month postpartum with TTP - HUS [42] Of these 21 women from three institutions, all but one survived, and none required renal replacement therapy With respect to future preg-nancies, one recent report cites only an 18% recurrence risk in subsequent pregnancies in patients with a history of postpartum TTP/HUS [43]
Postpartum r enal f ailure
Idiopathic postpartum renal failure, also referred to as postpar-tum HUS, is a unique cause of pregnancy - associated ARF that typically develops in the puerperium following an uncomplicated pregnancy and delivery Women may present up to several months following delivery with severe hypertension, microangio-pathic hemolytic anemia, and oliguric renal failure, often with congestive heart failure and CNS manifestations A prodromal
fl u - like illness or initiation of oral contraceptives may be associ-ated with postpartum renal failure as well as with idiopathic HUS, suggesting a toxic or hormonal infl uence
Pathologically, the disease is often indistinguishable from the thrombotic microangiopathies, idiopathic HUS and TTP, with arteriolar injury, fi brin deposition, and microvascular (arteriolar and glomerular capillary) thrombosis The major pathologic involvement is renal, as opposed to CNS involvement seen in TTP The pathogenesis of the thrombotic microangiopathies remains unclear, although intravascular coagulation, disordered platelet aggregation, endothelial damage, and alterations in pros-taglandins have been suggested [44] Therapies have been chosen
in an attempt to intervene in one or more of these processes, including plasma exchange, plasma infusion, antiplatelet agents, and anticoagulation In addition, acute and long - term dialytic support is often necessary, with approximately 12 – 15% of patients developing end - stage renal disease The maternal mortal-ity rate was estimated at between 46% and 55% in the 1980s [45,46] but appears to be improving with the use of plasma exchange and other treatments
the majority of cases and, left untreated, patients may progress to
fulminant hepatic failure with jaundice, encephalopathy,
dis-seminated intravascular coagulopathy, gastrointestinal
hemor-rhage, and death Maternal and fetal mortality rates as high as
85% were seen in the past, although with earlier diagnosis and
treatment a recent analysis of 28 consecutive cases reported no
maternal deaths [35]
Diagnosis of fatty liver may be established by liver biopsy
revealing microvesicular fatty infi ltration Computed
tomogra-phy (CT) may reveal decreased hepatic attenuation A report by
Usta and colleagues described their experience with 13 patients
(14 cases) of AFLP over an 8 - year period, all of whom had ARF
on presentation [36] They reported 100% maternal survival,
with 13% perinatal mortality Although nine of 14 cases were
initially diagnosed as pre - eclampsia, the diagnosis of AFLP was
subsequently confi rmed either by liver biopsy (10/14), CT of the
liver (2/14), or clinically One patient experienced a recurrence
of AFLP in a subsequent pregnancy Although CT revealing
hepatic density below the normal range of 50 – 70 Hounsfi eld
units has been reported as suggestive of AFLP, Usta ’ s study
dem-onstrated a high false - negative rate with only two of 10 abnormal
scans, including nine biopsy - proven cases [36] Contributing to
the diagnostic dilemma in these women is the frequent
occurrence of hypertension, edema, and proteinuria suggestive of pre
eclampsia, although renal pathology has failed to reveal evidence
of glomerular endotheliosis As is the case with severe pre
-eclampsia, expeditious delivery is warranted, with prompt
improvement in both hepatic and renal failure noted in nearly all
cases [34,35]
Thrombotic t hrombocytopenic
p urpura/ h emolytic u remic s yndrome
Thrombotic thrombocytopenic purpura/hemolytic uremic
syn-drome (TTP/HUS) is an uncommon disorder during pregnancy
with an incidence of approximately 1 in 25 000 births [37] It is
characterized by the classic pentad of thrombocytopenia,
hemo-lytic anemia, fever, neurologic abnormalities, and some degree of
renal dysfunction During pregnancy, the disorder tends to
present earlier than pre - eclampsia, with a median gestational age
of onset of 23 weeks [38] The underlying pathophysiology of the
disorder is apparently due to intravascular thrombi that result in
fragmentation of red blood cells, platelet consumption, and
varying degrees of systemic ischemia
Although treatment guidelines are not well established, plasma
exchange is recommended due to an apparent benefi t in survival
in a small number of patients Due to the continuum of disease,
both HUS and TTP have been considered together in most
clini-cal trials The Canadian Apheresis Study Group and a group at
Johns Hopkins University examined therapeutic outcomes in
TTP and TTP/HUS, respectively [39,40] Both reported the
supe-riority of plasma exchange therapy in terms of clinical response
and survival, with mortality rates of 22% and 9% respectively, in
Trang 4tion recovers Close attention to fl uid balance is critical because either superimposed volume depletion or fl uid overload may exacerbate ARF or necessitate earlier dialytic intervention In addition, magnesium sulfate administration in cases of pre eclampsia may also increase the patient ’ s risk for fl uid overload
or toxicity from the medication and should be monitored closely Correction of the metabolic acidosis seen with ARF may require bicarbonate therapy or dialysis, if it remains refractory to medical therapy or occurs in the setting of congestive heart failure Prevention of hyperphosphatemia includes dietary phosphate restriction and non - absorbable or calcium - containing phosphate binders given with meals Dietary potassium restriction also is imperative to avoid potentially life - threatening hyperkalemia A cation - exchange resin, such as kayexalate, can be used for mild hyperkalemia or until dialysis is available For hyperkalemia with associated electrocardiographic changes, acute therapy includes intravenous calcium gluconate to stabilize the cardiac membrane, infusion of glucose and insulin or inhaled β - agonists to transiently shift potassium intracellularly, and acute dialysis Additional conservative measures include avoiding further neph-rotoxic exposure and hypotension, control of hypertension, and medication dose adjustment according to the degree of renal impairment
In patients with severe metabolic abnormalities that are unre-sponsive to conservative medical management, volume overload and pulmonary congestion that cannot be corrected with diuret-ics, or signs and symptoms of uremia including pericarditis and encephalopathy, dialysis is indicated
As discussed previously, if the underlying etiology is deter-mined to be severe pre - eclampsia, then delivery may be indicated, even at very early gestational ages as there is no other way to prevent progression of the disease
Prognosis
The prognosis for return of renal function depends on multiple variables, including baseline renal status, duration of renal failure,
Bilateral r enal c ortical n ecrosis
Acute, bilateral renal cortical necrosis is a pathologic entity
con-sisting of partial or complete destruction of the renal cortex, with
sparing of the medulla While not unique to pregnancy, this rare
and catastrophic form of ARF occurs most commonly in
preg-nancy, with obstetric causes accounting for 50 – 70% of cases [47]
Although BRCN represents less than 2% of cases of ARF in the
non - pregnant population, it has been reported to account for
10 – 38% of obstetric cases of renal failure, perhaps secondary to
the hypercoagulable state and altered vascular sensitivity of
preg-nancy [31,48] Patients typically present between 30 and 35 weeks
of gestation in association with profound shock and renal
hypo-perfusion, such as that seen with abruptio placentae, placenta
previa, and other causes of obstetric hemorrhage Acute BRCN has
also been observed early in pregnancy associated with septic
abor-tion Abruption placentae, with either overt or concealed
hemor-rhage, appears to be the most common antecedent event [47]
Patients with BRCN present with severe and prolonged
oliguria or anuria (urine output < 50 mL/day), fl ank pain, gross
hematuria, and urinalysis demonstrating RBC and granular casts
Diagnosis is established by renal arteriogram demonstrating
virtual absence of cortical blood fl ow (interlobular arteries),
despite patency of the renal arteries Diagnosis may also be
estab-lished by ultrasonography, contrast - enhanced CT demonstrating
areas of cortical lucency, and MRI [49] The prognosis for patients
with BRCN is extremely poor, again likely related to the severity
of illness, with one study of 15 cases during pregnancy reporting
a mortality rate of 93% [48]
Management of a cute r enal f ailure
Management of ARF in pregnancy is similar to that in the non
pregnant patient, including supportive therapy as well as dialysis
General principles include treating the underlying cause,
preven-tion of further renal injury, and supportive care until renal
Table 28.7 Classifi cation of pregnancy - associated acute renal failure
Pre - eclampsia HELLP syndrome Acute fatty Postpartum Pyelonephritis Bilateral renal
liver of pregnancy (HUS) renal failure cortical necrosis
Proteinuria RUQ pain Elevated LFTs Occurring postpartum Positive urine culture Hemorrhage
Hypertension Proteinuria Hyperbilirubinemia MAHA Fever Hypotension/shock
Edema Hemolysis Coagulopathy Oliguria Oliguria/anuria
Elevated LFTs Oliguria Severe HTN Flank pain Thrombocytopenia Nausea Prodromal illness Gross hematuria Normal coags Abdominal pain Thrombocytopenia
HTN, hypertension; LFTs, liver function tests; MAHA, microangiopathic hemolytic anemia; RUQ, right upper quadrant
Trang 513 Turton P , Hughes P , Bolton H , Sedgwick P Incidence and demo-graphic correlates of eating disorder symptoms in a pregnant
popula-tion Int J Eat Disord 1999 ; 26 : 448 – 452
14 Grunfeld JP , Ganeval D , Bournerias F Acute renal failure in
preg-nancy Kidney Int 1980 ; 18 : 179 – 191
15 Sibai BM , Villar MA , Mabie BC Acute renal failure in hypertensive disorders of pregnancy Pregnancy outcome and remote prognosis in
thirty - one consecutive cases Am J Obstet Gynecol 1990 ; 162 ( 3 ):
777 – 783
16 Ovelese Y , Ananth CV Placental abruption Obstet Gynecol 2006 ; 108 :
1005 – 1016
17 Satin AJ , Seiken GL , Cunningham FG Reversible hypertension in
pregnancy caused by obstructive obstetric uropathy Obstet Gynecol
1993 ; 81 : 823 – 825
18 Courban D , Blank S , Harris MA , Bracy J , August P Acute renal failure
in the fi rst trimester resulting from uterine leiomyomas Am J Obstet Gynecol 1997 ; 177 ( 2 ): 472 – 473
19 Myers DL , Scotti RJ Acute urinary retention and the incarcerated,
retroverted, gravid uterus A case report J Reprod Med 1995 ; 40 ( 6 ):
487 – 490
20 Nelson MS Acute urinary retention secondary to an increased gravid
uterus Am J Emerg Med 1986 ; 4 ( 3 ): 231 – 232
21 Brandes JC , Fritsche C Obstructive acute renal failure by a gravid uterus: a case report and review Am J Kidney Dis 1991 ; 18 :
398 – 401
22 Khanna N , Nguyen H Reversible acute renal failure in association with bilateral ureteral obstruction and hydronephrosis in pregnancy
Am J Obstet Gynecol 2001 ; 184 ( 2 ): 239 – 240
23 Cunningham FG , Lucas MJ Urinary tract infections complicating
pregnancy Bailli è re ’ s Clin Obstet Gynaecol 1994 ; 8 : 353 – 373
24 Davison JM , Lindheimer MD Renal disorders In: Creasy RK , Resnick
R , eds Maternal Fetal Medicine , 4th edn Philadelphia : WB Saunders ,
1999 : 873 – 894
25 Whalley PJ , Cunningham FG , Martin FG Transient renal dysfunction
associated with acute pyelonephritis of pregnancy Obstet Gynecol
1975 ; 46 : 174 – 177
26 Gilstrap LC , Cunningham FG , Whalley PJ Acute pyelonephritis
during pregnancy: an anterospective study Obstet Gynecol 1981 ; 57 :
409 – 413
27 Ventura JE , Villa M , Mizraji R , Ferreiros R Acute renal failure in
pregnancy Ren Fail 1997 ; 19 ( 2 ): 217 – 220
28 Antonovych TT , Mostofi FK Atlas of Kidney Biopsies Washington,
DC : Armed Forces Institute of Pathology , 1981 : 266 – 275
29 Suzuki S , Gejyo F , Ogino S Post - partum renal lesions in women
with pre - eclampsia Nephrol Dial Transplant 1997 ; 12 : 2488 –
2493
30 Martin JN , Blake PG , Perry KG , et al The natural history of HELLP
syndrome: patterns of disease progression and regression Am J Obstet Gynecol 1991 ; 164 : 1500 – 1513
31 Krane NK Acute renal failure in pregnancy Arch Intern Med 1988 ;
148 : 2347 – 2357
32 Sibai BM , Ramadan MK Acute renal failure in pregnancies
compli-cated by hemolysis, elevated liver enzymes, and low platelets Am J Obstet Gynecol 1993 ; 168 : 1682 – 1690
33 Nakabayashi M , Adachi T , Itoh S , Kobayashi M , Mishina J , Nishida
H Perinatal and infant outcome of pregnant patients undergoing
chronic hemodialysis Nephron 1999 ; 82 : 27 – 31
34 Kaplan MM Acute fatty liver of pregnancy N Engl J Med 1985 ; 313 :
367 – 370
and the etiology of the ARF For instance, if the patient had
normal renal function before ARF from an acute obstructive
process that is relieved in a timely manner, then a full recovery
should be expected On the other hand, as previously discussed,
studies have demonstrated that, of patients with compromised
renal function who develop pre - eclampsia with ARF, up to 80%
may require long - term dialysis [15]
Summary
Evaluation of the pregnant patient with ARF encompasses a
broad range of disorders, some of which are unique to pregnancy
Prerenal azotemia, intrinsic renal disease, including ATN, GN,
and interstitial nephritis, and urinary obstruction should be
con-sidered based on clinical presentation Evaluation of ARF during
pregnancy is similar to that in the non - pregnant patient,
includ-ing urinalysis and urinary diagnostic indices, and in some cases,
renal biopsy In addition, diseases unique to pregnancy and those
more common during pregnancy must be considered, including
pre - eclampsia, HELLP syndrome, AFLP, postpartum renal
failure, and BRCN (Table 28.7 ) Treatment may necessitate
prompt delivery of the infant, even at early gestational ages when
issues of prematurity may exist
References
1 Pertuiset N , Ganeval D , Grunfeld JP Acute renal failure in pregnancy:
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2 Gammill HS , Jeyabalan A Acute renal failure in pregnancy Crit Care
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4 Lindheimer MD , Katz AI , Ganeval D , et al Acute renal failure in
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5 Stratta P , Canavese C , Dogliani M , et al Pregnancy - related renal
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6 Turney JH , Ellis CM , Parsons FM Obstetric acute renal failure 1956 –
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7 Nzerue CM , Hewan - Lowe K , Nwawka C Acute renal failure in
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8 Thadhani R , Pascual M , Bonventre JV Acute renal failure N Engl J
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9 Jones DC , Hayslett JP Outcome of pregnancy in women with
moder-ate or severe renal insuffi ciency N Engl J Med 1996 ; 335 : 226 – 232
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Reversible peripartum liver failure: a new perspective on the
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Trang 7Critical Care Obstetrics, 5th edition Edited by M Belfort, G Saade,
M Foley, J Phelan and G Dildy © 2010 Blackwell Publishing Ltd.
T Flint Porter
Department of Obstetrics and Gynecology, University of Utah Health Science UT, and Maternal - Fetal Medicine, Urban Central
Region, Intermountain Healthcare, Salt Lake City, UT, USA
Introduction
Acute fatty liver of pregnancy (AFLP) is a rare, yet potentially
fatal complication of late pregnancy Also known as acute fatty
metamorphosis or acute yellow atrophy, the incidence ranges
between 1 in 7000 and 1 in 15 000 depending on the population
studied [1 – 3] Older published series reported maternal and
peri-natal mortality rates as high as 75 and 85%, respectively [4]
However, more recent experience suggests that both morbidity
and mortality can be reduced by early recognition and prompt
treatment [1,2,5]
Epidemiology
The majority of cases of AFLP occur during the third trimester
[1,5,6] , usually between 30 and 38 weeks of gestation [3] ; some
do not become clinically evident until after delivery [7] Rare
mid - trimester cases have also been reported [8,9] There are no
clear epidemiologically distinct risk factors for AFLP Neither
maternal age nor ethnicity appears to affect risk Most affected
women are in their fi rst pregnancy [7] though AFLP has been
diagnosed in multiparous women with otherwise normal
obstet-ric histories Recurrence in subsequent pregnancy has also been
reported [10,12] Additional suggested risk factors include the
presence of a male fetus [13] , and multiple gestation [7,14]
Pathogenesis
The pathogenesis of AFLP has not been fully elucidated but
abnormalities in mitochondrial fatty acid oxidation likely play an
important role Fatty acid oxidation (FAO) is the major source
of energy for skeletal and heart muscle, a process that occurs primarily in the liver during conditions of prolonged fasting, illness, and increased muscular activity [3] Hepatic FAO also plays an essential role in intermediary liver metabolism and syn-thesizes alternative sources of energy for the brain when blood glucose levels are low [13]
Mitochondrial FAO functions via a protein complex known as mitochondrial trifunction protein (MTP) It is composed of three enzymes, one of which is long - chain 3 - hydroxyacyl - CoA dehy-drogenase (LCHAD) Human defects in MTP have emerged as
an important group of metabolic errors because of their serious clinical implications (Figure 29.1 ) They are recessively inherited and result in either isolated LCHAD defi ciency or dramatically reduced functionality of all three of the MTP enzymes Most reported cases involve children with isolated LCHAD defi ciency who present within the fi rst few hours to months of life with non - ketotic hypoglycemia and hepatic encephalopathy, which progresses to coma and death if untreated [15,16] Cardiomyopathy, slowly progressing peripheral neuropathy, skeletal myopathy, or sudden, unexpected death are also reported [17,18]
Schoeman [11] and colleagues were the fi rst group to suggest
an association between recurrent maternal AFLP and a fetal fatty acid oxidation disorder in two siblings, both whom died at 6 months of age [16] Other reports of a potential causative rela-tionship followed [15,19 – 22] In one series of 12 affected preg-nancies, several offspring delivered of mothers with AFLP were diagnosed postnatally with a homozygous form of LCHAD [19,23] Parental heterozygosity was subsequently confi rmed LCHAD defi ciency was later reported in three families in associa-tion with pregnancies complicated by AFLP [20] Ibdah [15] reported that 80% of mothers who delivered babies with
con-fi rmed MTP defects developed either AFLP or HELLP during their pregnancy Three of them had a history of AFLP in a previ-ous pregnancy In a subsequent prospective study, the same group [24,25] found that in approximately 1 in 5 pregnancies complicated by AFLP, the fetus is LCHAD - defi cient These fi nd-ings support the potentially life - saving role of screening for MTP defects in children born to women with AFLP Prenatal diagnosis
Trang 8ops and leads to oliguria and acute tubular necrosis [1] In turn, damage to the proximal renal tubules results in decreased sensi-tivity to vasopressin and transient diabetes insipidus [27,28] Laboratory evidence of renal dysfunction is evident early in the disease with increased serum creatinine levels Uric acid and blood urea nitrogen concentrations are also elevated, and with the onset of jaundice, urobilinogen appears in the urine Serum electrolytes may refl ect metabolic acidosis and plasma glucose is often below 60 mg/dL suggesting reduced hepatic glycogenolysis [29] It is not uncommon for mild hypoglycemia to be masked
in subsequent pregnancies has also been performed using
chori-onic villus sampling in an effort to identify at - risk pregnancies
[26]
Clinical p resentation
The clinical presentation of AFLP is non - specifi c and most
com-monly includes nausea, vomiting, anorexia, tachycardia, and
abdominal pain (Table 29.1 ) [1,3,5,7] Symptoms may develop
suddenly or over a 2 – 3 week period Though liver size is usually
normal or small, 50% of women with AFLP are jaundiced and
complain of right upper quadrant or epigastric pain Fever,
headache, and pruritus are not uncommon [1,3] Symptoms of pre
eclampsia are present in 50% of women with AFLP including
hypertension, proteinuria, and edema [7] Some women present
with isolated obstetric complaints including contractions,
decreased fetal movement, and vaginal bleeding [1]
Systemic complications of AFLP are due to fulminant hepatic
failure and include encephalopathy, acute renal failure, infection,
pancreatitis, gastrointestinal hemorrhage, coagulopathy, and at
least mild hypoglycemia Neurological dysfunction begins early
and should immediately alert the physician to the possibility of
AFLP Symptoms may rapidly progress from restlessness,
confu-sion, and disorientation, to asterixis, seizures, psychosis, and
ulti-mately coma [1,3,5] Other systemic effects include respiratory
failure, sometimes requiring assisted ventilation [5] , ascites
[7] , and gastrointestinal bleeding from gastric ulceration and
Mallory – Weiss syndrome [2,7]
Renal insuffi ciency associated with AFLP is due to fatty infi
ltra-tion of the kidneys [1] Hepatorenal syndrome eventually
devel-3-ketoacyl-CoA thiolase
CoA
3-ketoacyl-CoA
Acetyl-CoA Acyl-CoA
2,3-enoyl-CoA R
3-hydroxyacyl-CoA
dehydrogenase
LCHAD deficiency block
Trifunctional protein defrciency block
Acyl-CoA dehydrogenase FAD
FADH2
3-hydroxyacyl-CoA
Enoyl-CoA hydratase
NADH + H+
NAD+ OH
C
O
S CoA C
CH2
H2O O
R CH2 CH3 C S CoA
O
R CH CH C S CoA
O
C O
S CoA
CH3
R C O
CoA S
R CH CH2 C S CoA
O
Acyl-CoA Figure 29.1 The biochemistry of mitochondrial trifunctional protein (MTP) defi ciencies
Mitochondrial fatty acid β - oxidation spiral where the MTP catalyzes long chain fatty acids substrates (see box) In isolated LCHAD defi ciency, the pathway is blocked after the enoyl Co - A hydratase reaction and before the 3 - hydroxyacyl Co - A dehydrogenase reaction, causing the accumulation of medium - and long - chain 3 - hydroxy fatty acids and their metabolites In complete MTP defi ciency, the pathway is blocked after the acyl Co - A dehydrogenase reaction and before the enoyl Co - A dehydrogenase reaction causing the accumulation of straight - chain fatty acids and their metabolites Adapted from Ibdah JA Acute fatty liver of pregnancy: an update on pathogenesis and clinical implications World J Gastroenterol 2006; 12(46):
7397 – 7404 [2]
Table 29.1 Signs and symptoms of acute fatty liver of pregnancy
Symptoms Nausea, vomiting Almost always Malaise Always Abdominal pain Almost always, may be variable in position
and severity
Physical signs Hypertension Almost always Edema Almost always Proteinuria Variable Jaundice Always Elevated liver transaminases Always Hypoglycemia Always, may be masked by administration of
glucose - containing intravenous fl uids Coagulopathy Common
Diabetes insipidus Common Encephalopathy Common, may correlate with ammonia levels
Trang 9by the administration of dextrose solutions which often routinely
occurs at the time of admission
Virtually all women with AFLP have laboratory evidence of
coagulopathy and at least 50% require replacement of blood
components [1,2,5,30] Impaired hepatic synthesis of coagulation
factors leads to prolongation of prothrombin time (PT) and
acti-vated partial thromboplastin time (aPTT) Hypofi brinogenemia,
profound antithrombin III defi ciency, and thrombocytopenia are
common Factor VIII levels most accurately refl ect the extent of
coagulopathy and their return toward normal signals recovery
Coagulopathy may worsen in the postpartum period, most likely
secondary to low antithrombin III levels [31]
Serum transaminase concentrations are typically mildly
increased, usually between 100 and 1000 U/L Bilirubin levels are
variable but generally exceed 5 mg/dL Alkaline phosphatase is
elevated but is not helpful in making the diagnosis because of
placental production Serum albumin is usually low Ammonia
levels are elevated, due to decreased utilization by urea cycle liver
enzymes and may predict the degree of altered sensorium
Elevated amylase and lipase should raise suspicions of
concomi-tant pancreatitis [32] Liver function tests usually return to
normal 4 – 8 weeks after delivery [4]
The gold standard used for confi rmation of AFLP remains the
liver biopsy However, it is rarely necessary when other clinical
and laboratory parameters are consistent with the diagnosis
Microscopic examination of fresh specimens stained with special
fat stains, most commonly oil red, demonstrate hepatocellular
cytoplasm distended by numerous fi ne vacuoles giving the cells a
distinct foamy appearance (Figure 29.2 ) The myriad of tiny
vacuoles are separated from each other by thin eosinophilic
cyto-plasmic strands and do not coalesce to form a single large vacuole
In contrast to the cytoplasm, the cell nucleus is located centrally
and is normal in size and appearance
Histologic changes are most prominent in the central portion
of the lobule with a thin rim of normal hepatocytes at the
periph-ery The lobular architecture is usually preserved and, with rare
exceptions, necrosis and infl ammation are absent [33] This is
distinct from the periportal fi brin deposition and hemorrhagic
necrosis reported in pre - eclampsia (Figure 29.3 ) Characteristic
histologic changes may be present up to 3 weeks after the onset
of jaundice
Diagnosis
A high index of suspicion based on clinical presentation
corre-lated with correct interpretation of laboratory testing is usually
suffi cient to make the diagnosis of AFLP [1,7] Liver biopsy is
usually not necessary or even possible because of coagulopathy
Most common among the differential diagnoses are pre -
eclampsia/HELLP syndrome, viral hepatitis, and cholestasis
(Table 29.2 ) Women with AFLP or pre - eclampsia/HELLP may
have elevated serum transaminases, thrombocytopenia or
coagu-lation defects However, liver failure and jaundice are rare in
(a)
(b)
Figure 29.2 (a) Acute fatty liver of pregnancy (H & E stain; magnifi cation 200 × ) Note diffuse fatty infi ltration and absence of necrosis and infl ammation (b) Higher magnifi cation demonstrates the fi ne cytoplasmic vacuoles and centrally placed nuclei (H & E stain; magnifi cation 1000 × ) (Courtesy of Dr Patricia Latham, University of Maryland Hospital.)
Figure 29.3 Liver section from a patient who died of complications of
pre - eclampsia (H & E stain; magnifi cation 40 × ) Note extensive hepatocellular infl ammation and necrosis (Courtesy of Dr James Kelley, Madigan AMC.)
Trang 10lutely contraindicated AFLP should not be considered an indication for cesarean, even though expeditious delivery is recommended Indeed, most hemorrhagic complications in women with AFLP occur as a result of surgical trauma [1] Attempts at induction of labor and vaginal delivery are appropri-ate as long as adequappropri-ate mappropri-aternal supportive care and fetal surveil-lance are possible Even so, fetal compromise during labor is common and cesarean delivery is often necessary [1] Women who are critically ill should not be subjected to long arduous induction of labor The ultimate decision regarding route of delivery should be individualized, based on the maternal and fetal conditions as well as the favorability of the cervical exam Anesthetic options in patients with AFLP are limited General anesthesia can further damage an already compromised liver and regional anesthetic poses a risk of hemorrhage when coagulopa-thy is present If general anesthesia must be used, inhalation agents with potential hepatotoxicity (e.g halothane ) should be avoided Isofl urane is a logical choice since it has little or no hepatotoxicity and may preserve liver blood fl ow [36,37] Epidural anesthesia is probably the best option under most circumstances because it preserves hepatic blood fl ow without hepatotoxic effects [37,38] Recognition and treatment of thrombocytopenia and coagulopathy is essential prior to neuraxial techniques
Supportive c are
Supportive care of patients with AFLP should include careful monitoring for evidence of progressive hepatic failure, hypogly-cemia, and coagulopathy This should occur in an intensive care setting and in consultation with physicians well - versed in the care
of critically ill patients Prevention of worsening hypoglycemia and reduction of endogenous production of nitrogenous wastes can be accomplished by providing approximately 2000 – 2500 calories per day, primarily in the form of glucose Most patients require solutions containing more than 5% dextrose, sometimes
as high as 25%, administered intravenously or through a
naso-pre - eclampsia/HELLP Some authorities believe that AFLP and
pre - eclampsia may occur concomitantly [1] The diagnosis of
viral hepatitis can be established quickly and with reasonable
certainty via specifi c serologic testing In addition, serum
trans-aminase levels in women with hepatitis are usually elevated well
beyond those typically seen in AFLP Women with cholestasis of
pregnancy are usually not as ill - appearing as those with AFLP,
pre - eclampsia, or viral hepatitis While liver function tests are
abnormal in cholestasis of pregnancy, concentrations of bilirubin
and transaminase are usually much lower compared to those of
AFLP or viral hepatitis and signs and symptoms typical of pre
eclampsia are rarely present
Ultrasonography, CT, and MRI are often performed as part of
the diagnostic work - up for jaundice during pregnancy Ultrasound
demonstrates echogenicities within the liver of women with AFLP
[7] While non - specifi c, ultrasound may also identify subcapsular
hematoma, cholecystitis, and/or cholangitis Both CT and MRI
may suggest AFLP based on lower density that occurs with fatty
infi ltration of the liver [34,35] However, both have high false
negative rates that limit their usefulness [30] In clinical practice,
imaging studies are complementary but not necessary to make
the diagnosis of AFLP and their performance should not delay
appropriate treatment Moreover, a normal study does not
exclude AFLP
Treatment
Women suspected of having AFLP should be hospitalized in an
intensive care setting where comprehensive supportive care can
be given and preparations for delivery can be made All published
series have reported improved maternal and perinatal outcome
when prompt delivery is accomplished [1,3 – 5,7] Most women
begin to show clinical improvement and resolution of laboratory
abnormalities by the second day postpartum [5] There are no
reported cases of AFLP resolving prior to delivery; Therefore,
once the diagnosis is established, expectant management is
Table 29.2 Differential diagnosis of acute fatty liver of pregnancy
Acute fatty liver of
pregnancy
Acute hepatitis Cholestasis of pregnancy Severe pre - eclampsia
Clinical manifestations Nausea, vomiting, malaise,
encephalopathy, abdominal pain, coagulopathy
Malaise, nausea, vomiting, jaundice, anorexia, encephalopathy
Pruritus, jaundice Hypertension, edema, proteinuria,
oliguria, CNS hyperexcitability
Bilirubin Elevated Elevated Elevated Normal or minimally elevated Transaminases Minimally elevated Markedly elevated Minimally elevated Normal or minimal to moderate
increase Alkaline phosphatase Usually normal for pregnancy Minimally elevated Moderately elevated Normal for pregnancy
Histology Fatty infi ltration, no infl ammation
or necrosis
Marked infl ammation and necrosis Biliary stasis, no infl ammation Infl ammation, necrosis, fi brin
deposition