Critical Care Obstetrics part 40 docx

Acute Renal Failure 379 fl 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 retro- Table 28.6 Causes of urinary obstruction. Upper tract Lower tract Stones Stones Blood clots Blood clots Tumor Tumor Sloughed papillae Neuropathic bladder Ureteral stricture or ligation Urethral stricture Retroperitoneal fi brosis Extrinsic compression by tumor, gravid uterus Chapter 28 380 of 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 glomerular 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 Acute Renal Failure 381 those 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 occur- rence 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 Chapter 28 382 tion 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 func- 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 Leukocytosis CNS involvement HTN, hypertension; LFTs, liver function tests; MAHA, microangiopathic hemolytic anemia; RUQ, right upper quadrant. Acute Renal Failure 383 13 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 . 2 8 A n t o n o v y c h T T , M o s t o fi 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: an update . Semin Nephrol 1984 ; 3 : 232 – 239 . 2 Gammill HS , Jeyabalan A . Acute renal failure in pregnancy . Crit Care Med 2005 ; 33 (Suppl): S372 – S384 . 3 Stratta P , Besso L , Canavese C , et al. Is pregnancy - related acute renal failure a disappearing clinical entity? Ren Fail 1996 ; 18 ( 4 ): 575 – 584 . 4 Lindheimer MD , Katz AI , Ganeval D , et al. Acute renal failure in pregnancy . In: Brenner BN , Lazarus JM , eds. Acute Renal Failure . New York : Churchill Livingstone , 1988 : 597 – 620 . 5 Stratta P , Canavese C , Dogliani M , et al. Pregnancy - related renal failure . Clin Nephrol 1989 ; 32 : 14 – 20 . 6 Turney JH , Ellis CM , Parsons FM . Obstetric acute renal failure 1956 – 1987 . Br J Obstet Gynaecol 1989 ; 96 : 679 – 687 . 7 Nzerue CM , Hewan - Lowe K , Nwawka C . Acute renal failure in preg- nancy: a review of clinical outcomes at an inner - city hospital from 1986 – 1996 . J Natl Med Assoc 1998 ; 90 : 486 – 490 . 8 Thadhani R , Pascual M , Bonventre JV . Acute renal failure . N Engl J Med 1996 ; 334 : 1448 – 1460 . 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 . 10 Gordon M , Landon MB , Samuels P , et al. Perinatal outcome and long - term follow - up associated with modern management of diabetic nephropathy . Obstet Gynecol 1996 ; 87 : 401 – 409 . 11 Gonzalez M , Chew W , Soltero L , Gamba G , Correa R . Percutaneous kidney biopsy, analysis of 26 years: complication rate and risk factors . Rev Invest Clin 2000 ; 52 : 125 – 131 . 12 Kuller JA , D ’ Andrea NM , McMahon MJ . Renal biopsy and preg- nancy . Am J Obstet Gynecol 2001 ; 184 ( 6 ): 1093 – 1096 . Chapter 28 384 42 Hayward CPM , Sutton DMC , Carter WH , et al. Treatment outcomes in patients with adult thrombotic thrombocytopenic purpura - hemolytic uremic syndrome . Arch Intern Med 1994 ; 154 : 982 – 987 . 43 Vesely SK , Li X , McMinn JR , Terrell DR , George JN . Pregnancy out- comes after recovery from thrombotic thrombocytopenic purpura - hemolytic uremic syndrome . Transfusion 2004 ; 44 ( 8 ): 1149 – 1158 . 44 Hayslett JP . Postpartum renal failure . N Engl J Med 1985 ; 312 : 1556 – 1559 . 45 Weiner CP . Thrombotic microangiopathy in pregnancy and the post- partum period . Semin Hematol 1987 ; 24 : 119 – 129 . 46 Li PK , Lai FM , Tam JS , Lai KN . Acute renal failure due to postpartum hemolytic uremic syndrome . Aust NZ J Obstet Gynaecol 1988 ; 28 ( 3 ): 228 – 230 . 47 Donohoe JF . Acute bilateral cortical necrosis . In: Brenner BM , Lazarus JM , eds. Acute Renal Failure . Philadelphia : WB Saunders , 1983 : 252 – 269 . 48 Prakash J , Tripathi K , Pandey LK , Gadela SR . Renal cortical necrosis in pregnancy - related acute renal failure . J Indian Med Assoc 1996 ; 94 ( 6 ): 227 – 229 . 49 Francois M , Tostivint I , Mercadal L , Bellin M , Izzedine H , Deray G . MR imaging features of acute bilateral renal cortical necrosis . Am J Kidney Dis 2000 ; 35 ( 4 ): 745 – 748 . 35 Castro MA , Fassett MJ , Reynolds TB , Shaw KJ , Goodwin TM . Reversible peripartum liver failure: a new perspective on the diagno- sis, treatment, and cause of acute fatty liver of pregnancy, based on 28 consecutive cases . Am J Obstet Gynecol 1999 ; 181 ( 2 ): 389 – 395 . 36 Usta IM , Barton JR , Amon EA , et al. Acute fatty liver of pregnancy: an experience in the diagnosis and management of fourteen cases . Am J Obstet Gynecol 1994 ; 171 ( 5 ): 1342 – 1347 . 37 Dasche JS , Ramin SM , Cunningham FG . The long - term consequences of thrombotic microangiopathy (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) in pregnancy . Obstet Gynecol 1998 ; 91 : 662 – 668 . 38 Elliott MA , Nichols WL . Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome . Mayo Clin Proc 2001 ; 76 : 1154 – 1162 . 39 Bell WR , Braine HG , Ness PM , Kickler TS . Improved survival in thrombotic thrombocytopenic purpura - hemolytic uremic syndrome . N Engl J Med 1991 ; 325 : 398 – 403 . 40 Rock GH , Shumak KH , Buskard NA , et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic throm- bocytopenic purpura . N Engl J Med 1991 ; 325 : 393 – 397 . 41 Shemin D , Dworkin LD . Clinical outcome in three patients with postpartum hemolytic uremic syndrome treated with frequent plasma exchange . Ther Apher 1998 ; 2 ( 1 ): 43 – 48 . 385 Critical Care Obstetrics, 5th edition. Edited by M. Belfort, G. Saade, M. Foley, J. Phelan and G. Dildy. © 2010 Blackwell Publishing Ltd. 29 Acute Fatty Liver of Pregnancy 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 Chapter 29 386 ops 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, head- ache, 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 FADH 2 3-hydroxyacyl-CoA Enoyl-CoA hydratase NADH + H + NAD + OH C O S CoACCH 2 H 2 O O RSCoACCH 3 CH 2 O RSCoACCHCH O C O S CoACH 3 RC O CoA S R CH S CoACCH 2 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 Acute Fatty Liver of Pregnancy 387 by 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.) Chapter 29 388 lutely 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 adequate maternal 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 abso- Table 29.2 Differential diagnosis of acute fatty liver of pregnancy. Acute fatty liver of pregnancy Acute hepatitis Cholestasis of pregnancy Severe pre - eclampsia Trimester Third Variable Third Third 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 Recurrence Reported No Yes Yes . outcome in three patients with postpartum hemolytic uremic syndrome treated with frequent plasma exchange . Ther Apher 1998 ; 2 ( 1 ): 43 – 48 . 385 Critical Care Obstetrics, 5th edition. Edited. 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. 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,