CLINICAL OBSTETRICS AND GYNECOLOGY Volume 57, Number 4, 851–861 r 2014, Lippincott Williams & Wilkins
Acute Kidney Injury During Pregnancy JAMES W. VAN HOOK, MD Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, Ohio Abstract: Acute kidney injury complicates the care of a relatively small number of pregnant and postpartum women. Several pregnancy-related disorders such as preeclampsia and thrombotic microangiopathies may produce acute kidney injury. Prerenal azotemia is another common cause of acute kidney injury in pregnancy. This manuscript will review pregnancyassociated acute kidney injury from a renal functional perspective. Pathophysiology of acute kidney injury will be reviewed. Specific conditions causing acute kidney injury and treatments will be compared. Key words: acute kidney injury, thrombotic microangiopathy, acute tubular necrosis, pregnancy
Introduction Acute kidney injury (AKI) is generally defined as a wide range of abrupt changes to kidney function, with severity varying from mild changes in kidney function (elevated serum creatinine) to overt renal failure necessitating renal replacement therapy (RRT) (dialysis). Classification of AKI in nonpregnant individuals has been recently standardized by the Acute Dialysis Quality Initiative work group into a severity continuum of Risk-Injury-Failure-Loss-End stage (RIFLE) Correspondence: James W. Van Hook, MD, Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, OH. E-mail: [email protected] The authors declare that they have nothing to disclose. CLINICAL OBSTETRICS AND GYNECOLOGY
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classification format.1 AKI in pregnancy has no current uniform agreed-upon definition. Subsequently, historical comparison of AKI is challenging. Over the last 50 years, the rate of AKI has decreased from 1/3000 to 1/15,000. The likely causes of this decrease have been both a worldwide improvement in prenatal care and a reduction in AKI from illegal septic abortion.2 AKI necessitating dialysis is very uncommon during pregnancy. Like many infrequent yet serious medical disorders, AKI may serve to markedly increase both maternal and fetal mortality and morbidity. An understanding of the origin and classification of AKI may serve to provide the provider insight into effective treatment and management.
Pathophysiology and Diagnosis of AKI RENAL PHYSIOLOGY OF PREGNANCY
Several important renal system changes occur during pregnancy.3 The overriding basis of these changes is to promote an increased intravascular volume through increased antidiuretic hormone and renin-angiotensin-aldosterone (RAA)-mediated reduction in renal excretion of sodium. VOLUME 57
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Through several mechanisms, including resistance of vascular smooth muscle to the vasoconstrictive effects of RAA activation and nitric oxide-mediated and relaxin-mediated afferent and efferent vasodilatation, glomerular blood flow increases. The renal collecting system undergoes smooth muscle relaxation and dilation, with physiological hydronephrosis and hydroureter. Relative stasis of urine is common in pregnancy. Increased cardiac output directly increases renal plasma blood flow and glomerular filtration rate (GFR) during pregnancy. GFR is normally increased by approximately 30% to 50% by late pregnancy. Serum creatinine levels decrease. Consequently, protein excretion is increased by a similar amount. Normal protein excretion during pregnancy is increased, and may be up to 300 mg/24 h. Uric acid excretion is normally increased as well. Plasma osmolality and plasma sodium levels decline by approximately 10 mOsm/L and 5 mEq/L, respectively. During pregnancy, an increase in serum progesterone serves to increase minute ventilation. A respiratory alkalosis is typically seen by late pregnancy, with compensatory renal excretion of bicarbonate. Serum bicarbonate in the normal third trimester gravida is typically lower than in nonpregnant subjects (18 to 21 mEq/L). Renal changes unique to the pregnant state must be considered during diagnosis, treatment, and management of pregnant women with renal disorders. Diagnostic criteria used for AKI in the nonpregnant state may not be valid or useful during pregnancy. DEFINITION OF AKI
As noted previously in this text, there is no uniform consensus recommendation for AKI during pregnancy. The American College of Obstetrics and Gynecology addresses the diagnosis of acute renal www.clinicalobgyn.com
failure in the context of its recent Task Force on Hypertensions in Pregnancy Executive Summary addressing preeclampsia classification.4 Renal insufficiency in defined as a serum creatinine level of >1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease. This working classification is essentially advocated by other authorities.5,6 Lack of uniformity in diagnosis and a paucity of evidence-based guidance suggesting that nonpregnant criteria have good utility in pregnancy make the diagnosis still elusive and imprecise. A better way to consider AKI during pregnancy is to recognize why the diagnostic criteria are different for pregnant patients than for nonpregnant women with AKI. The normally seen enhanced renal function inherent in the pregnant state may seemingly mask AKI early in its disease course. Practitioners unfamiliar with renal physiology of pregnancy may be slow to recognize AKI. Prompt recognition may theoretically reduce permanent injury. Two additional corollaries relating to the assessment of renal function during pregnancy must also be addressed. The first is that the true estimation of GFR during pregnancy is not reliable until a timed urine creatinine excretion (24 h urine creatinine clearance is used). Estimates used for nonpregnant individuals are not reliable in pregnancy.7 The second involves the clinical utility of measurement or estimation of urinary protein excretion. As outlined previously, normal protein excretion during pregnancy may be up to 300 mg/24 h. Urine protein to plasma protein ratio (U/P>0.3 defined as abnormal) estimation of protein excretion has recently been advocated to supplant or replace the more cumbersome 24-hour protein collection method.4 It is important to note that one of the reasons that the easier and less precise U/P test is advocated is because the presence and the degree of proteinuria are not directly
Acute Kidney Injury During Pregnancy predictive of outcome in the case of preeclampsia. ETIOLOGY OF AKI IN PREGNANCY
AKI in pregnancy is somewhat unique in that both typical and pregnancy-related etiologies must be considered. AKI during pregnancy in women without underlying renal disease may present early or late in pregnancy. Early in pregnancy, infectious etiologies (urosepsis from pyelonephritis; septic abortion) and the renal consequences of hypovolemia are most common. Presentation in the late second trimester, entire third trimester, and postpartum may be due to pregnancy-related disorders such as preeclampsia or they may be due to consequences of pregnancy or labor (abruptio placenta, blood loss anemia from postpartum hemorrhage). However, it is important to note that pregnancy-related disorders may by multimodal in their causation of AKI. Consequently, it is often quite challenging to unravel the cause of AKI. Recognition of both the gestational age and any pregnancy comorbidities is very important in the understanding of an individual patient’s AKI etiology. The best pathophysiological approach to AKI in any patient is an attempt to classify renal failure as prerenal, intrinsic, or postrenal. Table 1 lists common prerenal, intrinsic, and postrenal causes of AKI. Prerenal causes may be secondary to hemorrhage, hypovolemia (such as from hyperemesis gravidarum), sepsis, or congestive heart failure. Intrinsic AKI may be from acute tubular necrosis (ATN), renal cortical necrosis, thrombotic microangiopathy, preeclampsia spectrum disorders, acute fatty liver of pregnancy (AFLP), glomerulonephritis, or acute interstitial nephritis (AIN) from medication exposure. Postrenal etiologies include mechanical obstruction (postsurgical obstruction), neoplasm, or uteropelvic obstruction from pregnancy. The latter is a very uncommon cause of bilateral postrenal AKI. Such cases are typically only seen in conjunction with a
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TABLE 1. Acute Kidney Injury Classification Prerenal
Intrinsic
Postrenal
Hemorrhage Hypovolemia
Ischemia Acute interstitial nephritis Medications* Preeclampsia
Obstruction Sulfonamide use Acyclovir use Mechanical obstruction
Preeclampsia Dehydration Diuretic use Diarrhea
Microangiopathy Radiocontrast agents
NSAID use Shock or Sepsis *Most medications cause intrinsic kidney injury. Examples of exceptions are depicted (adapted from text). NSAID indicates nonsteroidal anti-inflammatory drug.
pelvic pathology (uterine fibroids, higherorder multiple gestation, or marked polyhydramnios). A review of the distribution of AKI categorization in the general adult population offers some insight into the multimodal nature that is frequently seen in the patient with renal failure. Many practitioners think in a singular manner when considering the etiology of AKI. As outlined in preceding paragraphs, acute renal insufficiency is often multimodal in nature. In the general adult population with AKI, it is estimated that approximately 70% of community-acquired cases of acute renal insufficiency are classified as prerenal. Forty percent of hospitalized patients with AKI are initially classified as prerenal. Sustained prerenal azotemia results in ATN. Therefore, ATN is the most common cause of intrinsic AKI.5,8,9 Interestingly, in hospital admission–associated AKI, >1 insult is often present. An important conclusion is therefore to understand that AKI, when recognized, may be the result of >1 injury etiology. In pregnancy, hypovolemia may be a hemodynamic consequence of preeclampsia. Abruptio placenta may result in obstetric hemorrhage with hypovolemia as an overlay of disseminated intravascular www.clinicalobgyn.com
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coagulation–mediated intrinsic renal injury. A patient with hypovolemia may also be exposed to an aminoglycoside antibiotic. An important key to both diagnosis and therapy in AKI is to recognize the clinical context of presentation. CLINICAL APPROACH TO THE DIAGNOSIS OF AKI
As outlined previously, the definition of AKI during pregnancy is not uniformly agreed upon. Although AKI can present with or without oliguria, in obstetrical patients AKI is often initially seen in conjunction with oliguria. Two definitions of oliguria are applicable to pregnant patients. The general definition of oliguria is a urine output 1 300-500
>1.020
1.010-1.020
*Hyaline casts and/or absence of other tubular or glomerular elements. w Granular or red cell casts. FENa indicates fractional excretion of sodium.
factors and preeclampsia lends credence to the premise that preeclampsia is a systemic disease. Preeclampsia typically is not associated with AKI that would necessitate dialysis. In 1 series, all AKI patients with preeclampsia who needed dialysis also had postpartum hemorrhage and/or abruptio placenta. HELLP syndrome is associated with a 7% risk of AKI.13 Preeclampsia is associated with both oliguria and transient elevation of serum creatinine.14 Impaired excretion of uric acid is the cause of the commonly observed finding of elevated serum uric acid. Up to 20% of women diagnosed with preeclampsia associated with severe features of disease are subsequently found to have underlying chronic renal disease. The hemodynamic consequences of preeclampsia are somewhat complex and were originally described by Clark et al15 many years ago. In patients with oliguria, most commonly the cause of oliguria is secondary to reduced intravascular volume resulting in a prerenal kidney perfusion state. Less commonly, renal afferent arteriolar vasospasm or depressed myocardial function causes the underlying pathophysiological process. It is important to note that, during management of the 3 different types of oliguria, all 3 causes are prerenal from the standpoint of glomerular function.
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Clinical management of oliguria uses an empiric ‘‘least harm’’ strategy. As prerenal perfusion is often the cause of oliguria in preeclamptic patients with oliguria and reduced intravascular volume is the most common subset, empiric intravascular volume resuscitation is the first recommended treatment of oliguria. Although invasive hemodynamic monitoring is now generally not recommended for treatment of oliguria, the use of continuous oxygen saturation monitoring and careful volume resuscitation on a limited basis is often effective at restoration of intravascular volume. Although oliguria is generally seen in association with AKI, AKI and oliguria are not synonymous. But what is important is to recognize and treat intravascular volume depletion to potentially prevent renal ischemia that would cause AKI. Finally, as preeclampsia is in the differential diagnosis of other causes of AKI, an understanding of the disorder is important in the exclusion of those other causes. THROMBOTIC MICROANGIOPATHIES
Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenia purpura (TTP) are similar in presentation and often are referred to as 1 entity—HUS/TTP, with subcharacterization based on predominance of renal or thrombogenic organ involvement. The mechanism of disease in TTP is probably different than in HUS. Clinical presentation of HUS/TTP is often strikingly similar to that of HELLP. All 3 disorders may exhibit microangiopathic hemolytic anemia.16,17 HUS/TTP is uncommon. HUS/TTP is relatively more common in women (70% of cases), with 1/7 cases diagnosed during pregnancy. TTP is characterized by fever, severe thrombocytopenia, neurological symptoms, and usually what is relatively mild renal insufficiency. Serum creatinine may be normal or only somewhat elevated. TTP is usually seen with an identified deficiency in the ADAMTS-13 plasma metalloprotease www.clinicalobgyn.com
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that normally cleaves von Willebrand multimers. Deficiency can be congenital or acquired by circulating autoantibodies.5 Deficiency causes multimer-mediated microthrombosis. Pregnancy may predispose to the effects of ADAMTS-13 deficiency, as the enzyme normally decreases progressively during pregnancy. The pathophysiological mechanism of HUS is less clear. Atypical HUS (not associated with Shiga verotoxin exposure) is sometimes associated with dysregulation of the alternate complement pathway by constitutional factors that lead to inactivating mutations of the genes that affect activation of C3 and factor B complement. Deficit of factor H (a complement inhibitor) results in diffuse endothelial injury with resultant diffuse microthrombosis. Pregnancy may be a triggering factor for HUS.18 HUS is frequently seen in conjunction with marked intrinsic AKI: Serum creatinine levels are frequently >2.3 mg/ dL. Need for dialysis is frequent. Presentation may be immediately postpartum. As TTP/HUS may represent a common clinical presentation of a spectrum of disorders, a pathophysiology-based classification mechanism may ultimately be the best way to classify HUS/TTP. It has been proposed that HUS/TTP is classified into 3 categories according to underlying pathogenesis. The proposed categories are complement dysregulation HUS/TTP, ADAMTS-13 HUS/TTP, and
TABLE 3.
other mechanism (Verotoxin, etc.) HUS/ TTP. Mechanism overlap does occur and the validity of this proposed classification is still uncertain. However, the important point for clinicians is that HUS/TTP may represent a spectrum of disorders rather than 2 distinct entities.16 The exclusion of HELLP syndrome from the differential diagnosis in the pregnant or postpartum patient who presents with microangiopathic hemolytic anemia, hypertension, and renal insufficiency is challenging. Table 3 outlines differences in presentation of HELLP, TTP, HUS, and AFLP (discussed subsequently).2,4,16–18 Two important clinical caveats are that, whereas preeclampsia can present and worsen postpartum, delivery is not directly therapeutic in gravidas with HUS/TTP. Plasmapheresis allows clearance of thrombogenic multimers. HUS is usually associated with marked AKI, whereas HELLP, in the absence of a second diagnosis such as hypovolemia-mediated prerenal AKI, rarely leads to significant renal injury. AFLP
AFLP occurs in approximately 1:5000 to 1:10,000 pregnancies.19 Acute liver failure is causes by an underlying defect in the longchain mitochondrial fatty acid b-oxidation metabolism. A fetal autosomal recessive defect in the production of long-chain 3hydroxyacyl-CoA dehydrogenase causes
Comparison of Microangiopathies With Preeclampsia
Parameter
HUS
TTP
Preeclampsia
Presentation Typical onset
Acute Peripartum
Acute Throughout pregnancy
Renal impairment Neurologic sequelae Thrombocytopenia ADAMTS-13 deficiency Recovery
Significant Uncommon Possible Possible Unaffected by delivery
Mild to moderate Common Present Present Unaffected by delivery
Acute of subacute Usually 3rd trimester of peripartum Mild or transient Possible Possible Uncommon After delivery
ADAMTS-13 indicates disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenia.
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Acute Kidney Injury During Pregnancy excessive fetal long-chain fatty acids to be transported across the placenta into the maternal circulation. Fetal long-chain fatty acids are then deposited into the maternal liver, resulting in hepatic dysfunction and, if not recognized and treated by delivery of the fetus, fulminant maternal liver failure.20 Definitive diagnosis of AFLP is via liver biopsy, although decreased long-chain 3hydroxyacyl-CoA dehydrogenase activity in the newborn of a patient with hepatorenal insufficiency suggests the diagnosis.19 Table 3 outlines typical differences in AFLP from HELLP or HUS/TTP. AKI occurs in approximately 60% of patients with the diagnosis of AFLP. The etiology is multifactorial, and may result from prerenal and/or intrinsic mechanisms. As with HELLP syndrome, delivery of the fetus is necessary for maternal recovery. ATN
ATN is mechanistically the end result of renal glomerular ischemia. The incidence of ATN during pregnancy is not accurately characterized. ATN has been associated with abruptio placenta, preeclampsia, hemorrhage, and some medications. Nonsteroidal anti-inflammatory agents used for postpartum pain relief or tocolysis alter tubular perfusion with ATN as the resulting consequence.21 The hallmark of ATN is tubular cell damage resulting in cell death. AKI secondary to ATN is intrinsic in classification. Recovery is based upon severity of insult and degree of unaffected residual nephron volume.8 ATN has 3 phases: initiation, maintenance, and recovery. The recovery phase is typically marked by diuresis with eventual return of renal function.8,9 Maintenance of urine output throughout the course of AKI is a general indicator of a milder presentation. Current understanding of ATN reveals a much more complex etiology and disease process than formerly recognized. Renal injury involves both primary and secondary injury, with the complex
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interrelationship between tubular and glomerular injury.22 Sublethal injury to the nephron may not result in cell death, but may cause organ failure. In effect, the response of the human kidney to ischemia and cellular injury mimics pathophysiology in other organ systems. A stress or injury predisposition may cause alteration in normal function, diminished renal filtration, disruption in tubular function, and ultimately cessation of renal function. Injury may be transient or permanent. Operationally, a general understanding of the spectrum of renal ischemia and injury is very important in the prevention and limitation of renal disease. ATN is a natural consequence of untreated prerenal AKI. In pregnancy most cases of ATN involve underlying prerenal azotemia. Recognition of prerenal AKI offers the possibility of limitation of injury. Renal cortical necrosis is an end-stage lesion secondary to renal ischemia. Cortical necrosis is rarely seen in societies with access to health care. Unfortunately, 50% to 70% of new cases are secondary to pregnancy-related etiologies.2 Massive necrosis of the renal cortex produces anuria and severe renal failure. Most patients with renal cortical necrosis require dialysis. Up to 90% of survivors are dialysis dependent upon hospital discharge.2 Those who recover typically exhibit some degree of renal insufficiency. GLOMERULONEPHRITIS
Approximately 4% of pregnant women have preexisting chronic renal disease. Diabetic renal disease is the most common diagnosis.2 Many patients with chronic renal disease develop preeclampsia or have other pregnancy-related renal comorbidities. AKI as a result of glomerulonephritis or acute non–pregnancy-related renal disease may occur during pregnancy. Etiologies include primary glomerular disease such as membranoproliferative glomerulonephritis or poststreptococcal glomerulonephritis, as well as secondary glomerular causes such as systemic lupus www.clinicalobgyn.com
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nephritis.23 Treatment and diagnosis are disease specific. A challenge that clinicians often face is that the overlap of or misdiagnosis of preeclampsia in the patient with chronic or acute glomerular disease is frequently present. Hypertension and proteinuria are hallmarks of preeclampsia and are often seen in patients with primary or secondary glomerular disease as well. The acute presentation of hypertension and proteinuria at a preterm or previable gestational age is often a diagnostic and therapeutic dilemma if the diagnosis is not clear. The diagnosis of preeclampsia with severe features may ultimately require delivery. Primary or secondary renal disease is not directly treated by delivery. Underlying renal disease may increase the chance that a secondary diagnosis of preeclampsia as an overlay of another renal disorder may occur. Clinical suspicion, presence or absence of other disease-related signs or symptoms, and examination of urinary sediment may provide clinical guidance. Patients with glomerulonephritis typically have urinary sediment analysis showing red blood cell casts and other cellular signs of direct renal injury. The urinary sediment of patients with preeclampsia typically does not exhibit an active urinary sediment.21 OBSTRUCTIVE AKI
Renal obstruction is an uncommon cause of AKI during pregnancy. Physiological urinary stasis is common in pregnancy. In addition, mechanical compression of the urinary collecting system typically results in maternal hydronephrosis and hydroureter.2 Although urinary stasis and pregnancy-related partial obstruction usually are not a cause of AKI, both changes likely are contributory to the increased incidence of pyelonephritis in pregnant women.19,23 AKI and chronic renal insufficiency have both been reported in pregnancies complicated by polyhydramnios, uterine anomalies, uterine fibroids, or www.clinicalobgyn.com
prior pelvic surgery. A more common association is that of renal nephrolithiasis. Unilateral nephrolithiasis in a patient with underlying renal disease or bilateral obstruction have both been reported in association with AKI.2,24 In the general adult population, posttubular obstruction is another cause of obstructive AKI. Medications such as acyclovir and sulfonamide antibiotics may result in tubular obstruction.8 Except for medication-induced posttubular obstruction, management of obstructive AKI is generally based on relief of obstruction. Cystoscopy, placement of ureteral stents, and percutaneous nephrostomy may be necessary to relieve obstructive AKI. Delivery is very infrequently needed as a therapeutic measure. AIN
AIN is the etiology of AKI in approximately 10% to 15% of hospitalized US patients.24,25 Inflammatory infiltration within the renal interstitial parenchyma and peritubular architecture histologically defines AIN. As the disorder involves the renal tubular architecture, a more correct descriptive term for the disorder is acute tubulointerstitial nephritis. AIN has been associated to exposure to medications (nonsteroidal anti-inflammatory agents, diuretics, b-lactamic antibiotics, antiacids), infections, and autoimmune disorders. The overall incidence of AIN during pregnancy is not known. Drug exposure–mediated AIN is possible in pregnant or postpartum women because they frequently receive medications for treatment of a variety of conditions. There is no direct association with medication dose and disease development, although the risk for development of AIN increases after 2 weeks of medication use.24 Nonsteroidal anti-inflammatory agents may produce both AIN and ATN by drug reaction and ischemia-mediated tubular dysfunction,
Acute Kidney Injury During Pregnancy respectively. Pyelonephritis occurs in approximately 0.5% of pregnant women who receive prenatal care.26 Pyelonephritis also may cause AKI by AIN or ATN, the latter in the setting of hypovolemia and prerenal azotemia.
Management GENERAL PRINCIPLES
Treatment of AKI involves specific management of the underlying condition. Specific measures may also be indicated to limit renal damage and restore renal function. An important point to reiterate is that to reach renal failure, often >1 specific cause or pathophysiological mechanism is responsible for AKI. In addition, the contribution of prerenal azotemia secondary to hypovolemia cannot be underemphasized.8,19 Thus prevention of AKI may be potentially accomplished by recognition and treatment of hypovolemia. RENAL-SPECIFIC THERAPY
Specific treatments of AKI have focused on restoration of urine output, prevention of secondary injury, and restoration renal perfusion so as to allow repair of cellular injury. At the present time, goal-directed pharmacological treatment of perfusion or urinary output is not associated with improvement in outcome. Low-dose (1 to 3 mg/kg/min) dopamine infusion was formerly thought to improve outcome because the surrogate outcome of increased urine output was incorrectly assumed to reflect restoration of renal function. ‘‘Conversion’’ of oliguric to nonoliguric ATN was thought to result in improved outcome and survival. In fact, ‘‘conversion’’ does not occur. Continued urine production in a patient with AKI simply reflects a lower degree of renal injury and may also reflect less additional hypoperfusion from prerenal AKI. A recent meta-analysis of dopamine use in the setting of AKI refutes the benefit of dopamine as a therapy in the
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setting of AKI.26 Loop diuresis theoretically reduces tubular oxygen consumption and increases urinary output. However, the use of furosemide for prevention or treatment of AKI does not reduce the inhospital mortality or need for RRT in adults undergoing loop diuresis with the agent. The use of furosemide for the treatment of oliguric AKI is not recommended unless signs of pulmonary congestion are clinically evident. Atrial natriuretic peptide augments GFR by afferent arteriolar vasodilatation. Although several randomized and observational cohort trials have been undertaken studying the use of atrial natriuretic peptide to treat AKI, no clinical benefits have been observed, although some data suggest that atrial natriuretic peptide may reduce contrast-induced nephropathy in patients with chronic renal failure.26 Other promising but unproven medical therapies for AKI include fenoldopam, N-acytylcysteine, and albumin. None of the medications used for treatment of AKI are specifically approved for use in pregnancy. Each of the agents mentioned in this section have been used in pregnancy. Inconclusive results, similar to that observed in the nonpregnant population have been seen in pregnant patients treated in a similar manner. The use of balanced crystalloids such as Lactated Ringers and Plasmalyte is associated with less kidney injury as compared with normal saline, as high chlorine concentrations are associated with renal vasoconstriction and renal ischemia. DIALYSIS—RRT
In nonpregnant critically ill patients, there is no uniform agreement or consensus on the timing of RRT initiation, the timing of discontinuation of RRT, or the optimal choice of the RRT technique used.26 The 2 main types of RRT used in critically ill patients are continuous renal replacement therapy (CRRT) and intermittent hemodialysis (IHD). Conclusive evidence as to the superiority of one www.clinicalobgyn.com
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modality over the other is currently lacking. A third technique (sustained low efficiency dialysis) was developed to overcome inherent disadvantages with CRRT and IHD. In general, IHD removes large amounts of fluid and solutes in short periods of time. The latter is not tolerated in hemodynamically unstable patients rendering good candidates for CRRT in which fluid and solute removal is more gradual over 24 hours every day. Information exists on the conduct and outcome of RRT during pregnancy. The majority of available information pertaining to the use of RRT during pregnancy focuses on ongoing treatment of chronic renal insufficiency. Very little information is published about the acute use of RRT for AKI. In a recent South American case series of AKI of mixed etiology, RRT therapy during pregnancy was associated with a maternal mortality of 30.9%.27 In general, it is felt that earlier institution of dialysis during pregnancy, with greater intensity of dialysis and careful optimization of intravascular volume, results in optimization of outcome.2 Other measures used in the management of AKI are similar in pregnant and in nonpregnant patients. Management of serum potassium and phosphate is approached in a similar manner. Oral administration of calcium acetate (Phoslo) and sevelamer will decrease phosphate levels. Correction of intravascular volume, thromboembolic prophylaxis, and other subsidiary therapies are generally unchanged. PLASMAPHERESIS
Plasmapheresis is not universally used in the treatment of AKI. Plasmapheresis is used therapeutically in patients with thrombotic microangiopathies. The probable mechanism of action is likely that plasmapheresis removes large von Willebrand multimers or ADAMTS-13 autoantibodies. TTP survival is now approximately 80% when plasmapheresis is www.clinicalobgyn.com
used.16 The replacement fluid should be fresh frozen plasma (as opposed to albumin), as it is a source of ADAMTS-13. Plasmapheresis is probably not directly effective in the treatment of preeclampsia and is not generally effective for most other causes of AKI. PREGNANCY MANAGEMENT
Fetal effects from AKI are to a large degree influenced by the underlying etiology. Data regarding chronic renal insufficiency and pregnancy outcome may not reflect the specifics of a pregnant patient with AKI. Any benefits from delivery are more due to the underlying cause, an example of which would be delivery planning and management in the patient with severe preeclampsia (improvement in maternal renal function) as compared with HUS/TTP (delivery not specifically helpful). Care of the pregnant patient with AKI can be multifaceted and challenging, both from a disease standpoint and from the complexities involved in the care of the fetus and pregnancy itself. Multidisciplinary care is advisable in most cases.
Conclusions AKI is relatively infrequent in pregnant and postpartum women. Many cases of AKI during or after pregnancy involve the continuum between prerenal AKI and intrinsic renal disease. Many of the abnormal pregnancy conditions that are associated with AKI in pregnancy are conditions that may exhibit both prerenal and intrinsic pathophysiology. Other causes of AKI during pregnancy occur at similar rates in nonpregnant age and sex-matched women. Therapy of AKI involves limitation of disease progression by attenuation of secondary injury. Therapy is otherwise supportive. Prevention of disease progression in patients with mild renal insufficiency potentially may reduce the chance that AKI will develop.
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References 1. Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure- definition, outcome measures, animal models, fluid therapy, and information technology needs: the second international consensus conference of the acute dialysis quality initiative (ADQI) group. Crit Care. 2004;8: R204–R212. 2. Nwoko R, Pilecas D, Garovic VD. Acute kidney injury in the pregnant patient. Clin Nephrol. 2012;78:478–486. 3. Norwitz ER, Robinson JN. Pregnancy-induced physiologic alterations. In: Belfort M, Saade G, Foley M, Phelan J, Dildy G III. eds. Critical Care Obstetrics. Oxford: Wiley-Blackwell; 2011: 30–52. 4. American College of Obstetricians and Gynecologists: Task Force on Hypertension in Pregnancy. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ task force on hypertension in pregnancy. Obstet Gynecol. 2013;122:1122–1131. 5. Machado S, Figueiredo N, Borges A, et al. Acute kidney injury in pregnancy: a clinical challenge. J Nephrol. 2012;25:19–30. 6. Lafayette R. AKI in pregnant patient: two lives at stake. Nephrol Times. 2010;3:9–10. 7. Alper AB, Yi Y, Webber LS, et al. Estimation of glomerular filtration rate in preeclamptic patients. Am J Perinatol. 2007;24:569–574. 8. Thadani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med. 1996;334:1448–1460. 334. 9. Needham E. Management of acute renal failure. Am Fam Physician. 2005;72:1739–1746. 10. Mehta RL, Kellum JA, Shah SV, et al. Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11:R31. 11. Albright RC Jr. Acute renal failure: a practical update. Mayo Clin Proc. 1996;334:1448–1460. 12. Singri N, Ahya SN, Levin ML. Acute renal failure. JAMA. 2003;289:747–751. 13. Sibai BM, Ramadan MK, Usta I, et al. Maternal morbidi and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets. Am J Obstet Gynecol. 1993;169:1000–1006. 14. Drakeley AJ, Le Roux PA, Anthony J, et al. Acute renal failure complicating severe preeclampsia requiring admission to an obstetric intensive care unit. Am J Obstet Gynecol. 2002;186: 253–256.
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15. Clark SL, Greenspoon JS, Aldahl D, et al. Severe preeclampsia with persistent oliguria: management of hemodynamic subsets. Am J Obstet Gynecol. 1988;159:604–607. 16. Fakhouri F, Vercel C, Fremeaux-Bacchi V. Obstetric nephrology: AKI and thrombotic microangiopathies in pregnancy. Clin J Am Soc Nephrol. 2012;7:2100–2106. 17. George J. The thrombotic thrombocytopenia purpura and hemolytic uremic syndrome: evaluation and management and long term experiences of the Oklahoma TTP-HUS registry, 1989-2007. Kidney Int. 2009;112:S52–S54. 18. Fakhouri F, Roumenina L, Provot F, et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol. 2010;21:859–867. 19. Thadhani RI, Maski MR. Renal disorders. In: Creasy RK, Resnik R, Iams JD, Lockwood CJ, Moore TR, Greene MF eds. Creasy & Resnik’s Maternal-Fetal Medicine Principals and Practice, 7th ed. Philadelphia: Elsevier Saunders; 2014: 949–964. 20. Wei Q, Zhang L, Liu X. Clinical diagnosis and treatment of acute fatty liver of pregnancy: a literature review and 11 new cases. J Obstet Gynaecol Res. 2010;36:751–756. 21. Podymow T, August P, Akbari A. Management of renal disease in pregnancy. Obstet Gynecol Clin N Am. 2010;37:195–210. 22. Heyman SN, Rosenberger C, Rosen S. Acute kidney injury: lessons from experimental models. Contrib Nephrol. 2011;169:286–296. 23. Deering SH, Seiken GL. Acute renal failure. In: Belfort M, Saade G, Foley M, Phelan J, Dildy G III. eds. Critical Care Obstetrics. Oxford: Wiley-Blackwell; 2011:376–384. 24. Kodner CM, Kuprimoti A. Diagnosis and management of acute interstitial nephritis. Am Fam Physician. 2003;67:2527–2534. 25. Wing DA, Fassett MJ, Getahun D. Acute pyelonephritis in pregnancy: an 18 year retrospective analysis. Am J Obstet Gynecol. 2014;210: 219; e1-6. 26. Negi S, Shigematsu T. Current therapeutic strategies for acute kidney injury. Clin Exp Nephrol. 2012;16:672–678. 27. Silva GB Jr, Monteiro FA, Mota RM, et al. Acute kidney injury requiring dialysis in obstetric patients: a series of 55 cases in Brazil. Arch Gynecol Obstet. 2009;279:131–137.
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Acute Kidney Injury During Pregnancy JAMES W. VAN HOOK, MD Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, Ohio Abstract: Acute kidney injury complicates the care of a relatively small number of pregnant and postpartum women. Several pregnancy-related disorders such as preeclampsia and thrombotic microangiopathies may produce acute kidney injury. Prerenal azotemia is another common cause of acute kidney injury in pregnancy. This manuscript will review pregnancyassociated acute kidney injury from a renal functional perspective. Pathophysiology of acute kidney injury will be reviewed. Specific conditions causing acute kidney injury and treatments will be compared. Key words: acute kidney injury, thrombotic microangiopathy, acute tubular necrosis, pregnancy
Introduction Acute kidney injury (AKI) is generally defined as a wide range of abrupt changes to kidney function, with severity varying from mild changes in kidney function (elevated serum creatinine) to overt renal failure necessitating renal replacement therapy (RRT) (dialysis). Classification of AKI in nonpregnant individuals has been recently standardized by the Acute Dialysis Quality Initiative work group into a severity continuum of Risk-Injury-Failure-Loss-End stage (RIFLE) Correspondence: James W. Van Hook, MD, Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, OH. E-mail: [email protected] The authors declare that they have nothing to disclose. CLINICAL OBSTETRICS AND GYNECOLOGY
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classification format.1 AKI in pregnancy has no current uniform agreed-upon definition. Subsequently, historical comparison of AKI is challenging. Over the last 50 years, the rate of AKI has decreased from 1/3000 to 1/15,000. The likely causes of this decrease have been both a worldwide improvement in prenatal care and a reduction in AKI from illegal septic abortion.2 AKI necessitating dialysis is very uncommon during pregnancy. Like many infrequent yet serious medical disorders, AKI may serve to markedly increase both maternal and fetal mortality and morbidity. An understanding of the origin and classification of AKI may serve to provide the provider insight into effective treatment and management.
Pathophysiology and Diagnosis of AKI RENAL PHYSIOLOGY OF PREGNANCY
Several important renal system changes occur during pregnancy.3 The overriding basis of these changes is to promote an increased intravascular volume through increased antidiuretic hormone and renin-angiotensin-aldosterone (RAA)-mediated reduction in renal excretion of sodium. VOLUME 57
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Through several mechanisms, including resistance of vascular smooth muscle to the vasoconstrictive effects of RAA activation and nitric oxide-mediated and relaxin-mediated afferent and efferent vasodilatation, glomerular blood flow increases. The renal collecting system undergoes smooth muscle relaxation and dilation, with physiological hydronephrosis and hydroureter. Relative stasis of urine is common in pregnancy. Increased cardiac output directly increases renal plasma blood flow and glomerular filtration rate (GFR) during pregnancy. GFR is normally increased by approximately 30% to 50% by late pregnancy. Serum creatinine levels decrease. Consequently, protein excretion is increased by a similar amount. Normal protein excretion during pregnancy is increased, and may be up to 300 mg/24 h. Uric acid excretion is normally increased as well. Plasma osmolality and plasma sodium levels decline by approximately 10 mOsm/L and 5 mEq/L, respectively. During pregnancy, an increase in serum progesterone serves to increase minute ventilation. A respiratory alkalosis is typically seen by late pregnancy, with compensatory renal excretion of bicarbonate. Serum bicarbonate in the normal third trimester gravida is typically lower than in nonpregnant subjects (18 to 21 mEq/L). Renal changes unique to the pregnant state must be considered during diagnosis, treatment, and management of pregnant women with renal disorders. Diagnostic criteria used for AKI in the nonpregnant state may not be valid or useful during pregnancy. DEFINITION OF AKI
As noted previously in this text, there is no uniform consensus recommendation for AKI during pregnancy. The American College of Obstetrics and Gynecology addresses the diagnosis of acute renal www.clinicalobgyn.com
failure in the context of its recent Task Force on Hypertensions in Pregnancy Executive Summary addressing preeclampsia classification.4 Renal insufficiency in defined as a serum creatinine level of >1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease. This working classification is essentially advocated by other authorities.5,6 Lack of uniformity in diagnosis and a paucity of evidence-based guidance suggesting that nonpregnant criteria have good utility in pregnancy make the diagnosis still elusive and imprecise. A better way to consider AKI during pregnancy is to recognize why the diagnostic criteria are different for pregnant patients than for nonpregnant women with AKI. The normally seen enhanced renal function inherent in the pregnant state may seemingly mask AKI early in its disease course. Practitioners unfamiliar with renal physiology of pregnancy may be slow to recognize AKI. Prompt recognition may theoretically reduce permanent injury. Two additional corollaries relating to the assessment of renal function during pregnancy must also be addressed. The first is that the true estimation of GFR during pregnancy is not reliable until a timed urine creatinine excretion (24 h urine creatinine clearance is used). Estimates used for nonpregnant individuals are not reliable in pregnancy.7 The second involves the clinical utility of measurement or estimation of urinary protein excretion. As outlined previously, normal protein excretion during pregnancy may be up to 300 mg/24 h. Urine protein to plasma protein ratio (U/P>0.3 defined as abnormal) estimation of protein excretion has recently been advocated to supplant or replace the more cumbersome 24-hour protein collection method.4 It is important to note that one of the reasons that the easier and less precise U/P test is advocated is because the presence and the degree of proteinuria are not directly
Acute Kidney Injury During Pregnancy predictive of outcome in the case of preeclampsia. ETIOLOGY OF AKI IN PREGNANCY
AKI in pregnancy is somewhat unique in that both typical and pregnancy-related etiologies must be considered. AKI during pregnancy in women without underlying renal disease may present early or late in pregnancy. Early in pregnancy, infectious etiologies (urosepsis from pyelonephritis; septic abortion) and the renal consequences of hypovolemia are most common. Presentation in the late second trimester, entire third trimester, and postpartum may be due to pregnancy-related disorders such as preeclampsia or they may be due to consequences of pregnancy or labor (abruptio placenta, blood loss anemia from postpartum hemorrhage). However, it is important to note that pregnancy-related disorders may by multimodal in their causation of AKI. Consequently, it is often quite challenging to unravel the cause of AKI. Recognition of both the gestational age and any pregnancy comorbidities is very important in the understanding of an individual patient’s AKI etiology. The best pathophysiological approach to AKI in any patient is an attempt to classify renal failure as prerenal, intrinsic, or postrenal. Table 1 lists common prerenal, intrinsic, and postrenal causes of AKI. Prerenal causes may be secondary to hemorrhage, hypovolemia (such as from hyperemesis gravidarum), sepsis, or congestive heart failure. Intrinsic AKI may be from acute tubular necrosis (ATN), renal cortical necrosis, thrombotic microangiopathy, preeclampsia spectrum disorders, acute fatty liver of pregnancy (AFLP), glomerulonephritis, or acute interstitial nephritis (AIN) from medication exposure. Postrenal etiologies include mechanical obstruction (postsurgical obstruction), neoplasm, or uteropelvic obstruction from pregnancy. The latter is a very uncommon cause of bilateral postrenal AKI. Such cases are typically only seen in conjunction with a
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TABLE 1. Acute Kidney Injury Classification Prerenal
Intrinsic
Postrenal
Hemorrhage Hypovolemia
Ischemia Acute interstitial nephritis Medications* Preeclampsia
Obstruction Sulfonamide use Acyclovir use Mechanical obstruction
Preeclampsia Dehydration Diuretic use Diarrhea
Microangiopathy Radiocontrast agents
NSAID use Shock or Sepsis *Most medications cause intrinsic kidney injury. Examples of exceptions are depicted (adapted from text). NSAID indicates nonsteroidal anti-inflammatory drug.
pelvic pathology (uterine fibroids, higherorder multiple gestation, or marked polyhydramnios). A review of the distribution of AKI categorization in the general adult population offers some insight into the multimodal nature that is frequently seen in the patient with renal failure. Many practitioners think in a singular manner when considering the etiology of AKI. As outlined in preceding paragraphs, acute renal insufficiency is often multimodal in nature. In the general adult population with AKI, it is estimated that approximately 70% of community-acquired cases of acute renal insufficiency are classified as prerenal. Forty percent of hospitalized patients with AKI are initially classified as prerenal. Sustained prerenal azotemia results in ATN. Therefore, ATN is the most common cause of intrinsic AKI.5,8,9 Interestingly, in hospital admission–associated AKI, >1 insult is often present. An important conclusion is therefore to understand that AKI, when recognized, may be the result of >1 injury etiology. In pregnancy, hypovolemia may be a hemodynamic consequence of preeclampsia. Abruptio placenta may result in obstetric hemorrhage with hypovolemia as an overlay of disseminated intravascular www.clinicalobgyn.com
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coagulation–mediated intrinsic renal injury. A patient with hypovolemia may also be exposed to an aminoglycoside antibiotic. An important key to both diagnosis and therapy in AKI is to recognize the clinical context of presentation. CLINICAL APPROACH TO THE DIAGNOSIS OF AKI
As outlined previously, the definition of AKI during pregnancy is not uniformly agreed upon. Although AKI can present with or without oliguria, in obstetrical patients AKI is often initially seen in conjunction with oliguria. Two definitions of oliguria are applicable to pregnant patients. The general definition of oliguria is a urine output 1 300-500
>1.020
1.010-1.020
*Hyaline casts and/or absence of other tubular or glomerular elements. w Granular or red cell casts. FENa indicates fractional excretion of sodium.
factors and preeclampsia lends credence to the premise that preeclampsia is a systemic disease. Preeclampsia typically is not associated with AKI that would necessitate dialysis. In 1 series, all AKI patients with preeclampsia who needed dialysis also had postpartum hemorrhage and/or abruptio placenta. HELLP syndrome is associated with a 7% risk of AKI.13 Preeclampsia is associated with both oliguria and transient elevation of serum creatinine.14 Impaired excretion of uric acid is the cause of the commonly observed finding of elevated serum uric acid. Up to 20% of women diagnosed with preeclampsia associated with severe features of disease are subsequently found to have underlying chronic renal disease. The hemodynamic consequences of preeclampsia are somewhat complex and were originally described by Clark et al15 many years ago. In patients with oliguria, most commonly the cause of oliguria is secondary to reduced intravascular volume resulting in a prerenal kidney perfusion state. Less commonly, renal afferent arteriolar vasospasm or depressed myocardial function causes the underlying pathophysiological process. It is important to note that, during management of the 3 different types of oliguria, all 3 causes are prerenal from the standpoint of glomerular function.
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Clinical management of oliguria uses an empiric ‘‘least harm’’ strategy. As prerenal perfusion is often the cause of oliguria in preeclamptic patients with oliguria and reduced intravascular volume is the most common subset, empiric intravascular volume resuscitation is the first recommended treatment of oliguria. Although invasive hemodynamic monitoring is now generally not recommended for treatment of oliguria, the use of continuous oxygen saturation monitoring and careful volume resuscitation on a limited basis is often effective at restoration of intravascular volume. Although oliguria is generally seen in association with AKI, AKI and oliguria are not synonymous. But what is important is to recognize and treat intravascular volume depletion to potentially prevent renal ischemia that would cause AKI. Finally, as preeclampsia is in the differential diagnosis of other causes of AKI, an understanding of the disorder is important in the exclusion of those other causes. THROMBOTIC MICROANGIOPATHIES
Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenia purpura (TTP) are similar in presentation and often are referred to as 1 entity—HUS/TTP, with subcharacterization based on predominance of renal or thrombogenic organ involvement. The mechanism of disease in TTP is probably different than in HUS. Clinical presentation of HUS/TTP is often strikingly similar to that of HELLP. All 3 disorders may exhibit microangiopathic hemolytic anemia.16,17 HUS/TTP is uncommon. HUS/TTP is relatively more common in women (70% of cases), with 1/7 cases diagnosed during pregnancy. TTP is characterized by fever, severe thrombocytopenia, neurological symptoms, and usually what is relatively mild renal insufficiency. Serum creatinine may be normal or only somewhat elevated. TTP is usually seen with an identified deficiency in the ADAMTS-13 plasma metalloprotease www.clinicalobgyn.com
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that normally cleaves von Willebrand multimers. Deficiency can be congenital or acquired by circulating autoantibodies.5 Deficiency causes multimer-mediated microthrombosis. Pregnancy may predispose to the effects of ADAMTS-13 deficiency, as the enzyme normally decreases progressively during pregnancy. The pathophysiological mechanism of HUS is less clear. Atypical HUS (not associated with Shiga verotoxin exposure) is sometimes associated with dysregulation of the alternate complement pathway by constitutional factors that lead to inactivating mutations of the genes that affect activation of C3 and factor B complement. Deficit of factor H (a complement inhibitor) results in diffuse endothelial injury with resultant diffuse microthrombosis. Pregnancy may be a triggering factor for HUS.18 HUS is frequently seen in conjunction with marked intrinsic AKI: Serum creatinine levels are frequently >2.3 mg/ dL. Need for dialysis is frequent. Presentation may be immediately postpartum. As TTP/HUS may represent a common clinical presentation of a spectrum of disorders, a pathophysiology-based classification mechanism may ultimately be the best way to classify HUS/TTP. It has been proposed that HUS/TTP is classified into 3 categories according to underlying pathogenesis. The proposed categories are complement dysregulation HUS/TTP, ADAMTS-13 HUS/TTP, and
TABLE 3.
other mechanism (Verotoxin, etc.) HUS/ TTP. Mechanism overlap does occur and the validity of this proposed classification is still uncertain. However, the important point for clinicians is that HUS/TTP may represent a spectrum of disorders rather than 2 distinct entities.16 The exclusion of HELLP syndrome from the differential diagnosis in the pregnant or postpartum patient who presents with microangiopathic hemolytic anemia, hypertension, and renal insufficiency is challenging. Table 3 outlines differences in presentation of HELLP, TTP, HUS, and AFLP (discussed subsequently).2,4,16–18 Two important clinical caveats are that, whereas preeclampsia can present and worsen postpartum, delivery is not directly therapeutic in gravidas with HUS/TTP. Plasmapheresis allows clearance of thrombogenic multimers. HUS is usually associated with marked AKI, whereas HELLP, in the absence of a second diagnosis such as hypovolemia-mediated prerenal AKI, rarely leads to significant renal injury. AFLP
AFLP occurs in approximately 1:5000 to 1:10,000 pregnancies.19 Acute liver failure is causes by an underlying defect in the longchain mitochondrial fatty acid b-oxidation metabolism. A fetal autosomal recessive defect in the production of long-chain 3hydroxyacyl-CoA dehydrogenase causes
Comparison of Microangiopathies With Preeclampsia
Parameter
HUS
TTP
Preeclampsia
Presentation Typical onset
Acute Peripartum
Acute Throughout pregnancy
Renal impairment Neurologic sequelae Thrombocytopenia ADAMTS-13 deficiency Recovery
Significant Uncommon Possible Possible Unaffected by delivery
Mild to moderate Common Present Present Unaffected by delivery
Acute of subacute Usually 3rd trimester of peripartum Mild or transient Possible Possible Uncommon After delivery
ADAMTS-13 indicates disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; HUS, hemolytic uremic syndrome; TTP, thrombotic thrombocytopenia.
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Acute Kidney Injury During Pregnancy excessive fetal long-chain fatty acids to be transported across the placenta into the maternal circulation. Fetal long-chain fatty acids are then deposited into the maternal liver, resulting in hepatic dysfunction and, if not recognized and treated by delivery of the fetus, fulminant maternal liver failure.20 Definitive diagnosis of AFLP is via liver biopsy, although decreased long-chain 3hydroxyacyl-CoA dehydrogenase activity in the newborn of a patient with hepatorenal insufficiency suggests the diagnosis.19 Table 3 outlines typical differences in AFLP from HELLP or HUS/TTP. AKI occurs in approximately 60% of patients with the diagnosis of AFLP. The etiology is multifactorial, and may result from prerenal and/or intrinsic mechanisms. As with HELLP syndrome, delivery of the fetus is necessary for maternal recovery. ATN
ATN is mechanistically the end result of renal glomerular ischemia. The incidence of ATN during pregnancy is not accurately characterized. ATN has been associated with abruptio placenta, preeclampsia, hemorrhage, and some medications. Nonsteroidal anti-inflammatory agents used for postpartum pain relief or tocolysis alter tubular perfusion with ATN as the resulting consequence.21 The hallmark of ATN is tubular cell damage resulting in cell death. AKI secondary to ATN is intrinsic in classification. Recovery is based upon severity of insult and degree of unaffected residual nephron volume.8 ATN has 3 phases: initiation, maintenance, and recovery. The recovery phase is typically marked by diuresis with eventual return of renal function.8,9 Maintenance of urine output throughout the course of AKI is a general indicator of a milder presentation. Current understanding of ATN reveals a much more complex etiology and disease process than formerly recognized. Renal injury involves both primary and secondary injury, with the complex
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interrelationship between tubular and glomerular injury.22 Sublethal injury to the nephron may not result in cell death, but may cause organ failure. In effect, the response of the human kidney to ischemia and cellular injury mimics pathophysiology in other organ systems. A stress or injury predisposition may cause alteration in normal function, diminished renal filtration, disruption in tubular function, and ultimately cessation of renal function. Injury may be transient or permanent. Operationally, a general understanding of the spectrum of renal ischemia and injury is very important in the prevention and limitation of renal disease. ATN is a natural consequence of untreated prerenal AKI. In pregnancy most cases of ATN involve underlying prerenal azotemia. Recognition of prerenal AKI offers the possibility of limitation of injury. Renal cortical necrosis is an end-stage lesion secondary to renal ischemia. Cortical necrosis is rarely seen in societies with access to health care. Unfortunately, 50% to 70% of new cases are secondary to pregnancy-related etiologies.2 Massive necrosis of the renal cortex produces anuria and severe renal failure. Most patients with renal cortical necrosis require dialysis. Up to 90% of survivors are dialysis dependent upon hospital discharge.2 Those who recover typically exhibit some degree of renal insufficiency. GLOMERULONEPHRITIS
Approximately 4% of pregnant women have preexisting chronic renal disease. Diabetic renal disease is the most common diagnosis.2 Many patients with chronic renal disease develop preeclampsia or have other pregnancy-related renal comorbidities. AKI as a result of glomerulonephritis or acute non–pregnancy-related renal disease may occur during pregnancy. Etiologies include primary glomerular disease such as membranoproliferative glomerulonephritis or poststreptococcal glomerulonephritis, as well as secondary glomerular causes such as systemic lupus www.clinicalobgyn.com
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nephritis.23 Treatment and diagnosis are disease specific. A challenge that clinicians often face is that the overlap of or misdiagnosis of preeclampsia in the patient with chronic or acute glomerular disease is frequently present. Hypertension and proteinuria are hallmarks of preeclampsia and are often seen in patients with primary or secondary glomerular disease as well. The acute presentation of hypertension and proteinuria at a preterm or previable gestational age is often a diagnostic and therapeutic dilemma if the diagnosis is not clear. The diagnosis of preeclampsia with severe features may ultimately require delivery. Primary or secondary renal disease is not directly treated by delivery. Underlying renal disease may increase the chance that a secondary diagnosis of preeclampsia as an overlay of another renal disorder may occur. Clinical suspicion, presence or absence of other disease-related signs or symptoms, and examination of urinary sediment may provide clinical guidance. Patients with glomerulonephritis typically have urinary sediment analysis showing red blood cell casts and other cellular signs of direct renal injury. The urinary sediment of patients with preeclampsia typically does not exhibit an active urinary sediment.21 OBSTRUCTIVE AKI
Renal obstruction is an uncommon cause of AKI during pregnancy. Physiological urinary stasis is common in pregnancy. In addition, mechanical compression of the urinary collecting system typically results in maternal hydronephrosis and hydroureter.2 Although urinary stasis and pregnancy-related partial obstruction usually are not a cause of AKI, both changes likely are contributory to the increased incidence of pyelonephritis in pregnant women.19,23 AKI and chronic renal insufficiency have both been reported in pregnancies complicated by polyhydramnios, uterine anomalies, uterine fibroids, or www.clinicalobgyn.com
prior pelvic surgery. A more common association is that of renal nephrolithiasis. Unilateral nephrolithiasis in a patient with underlying renal disease or bilateral obstruction have both been reported in association with AKI.2,24 In the general adult population, posttubular obstruction is another cause of obstructive AKI. Medications such as acyclovir and sulfonamide antibiotics may result in tubular obstruction.8 Except for medication-induced posttubular obstruction, management of obstructive AKI is generally based on relief of obstruction. Cystoscopy, placement of ureteral stents, and percutaneous nephrostomy may be necessary to relieve obstructive AKI. Delivery is very infrequently needed as a therapeutic measure. AIN
AIN is the etiology of AKI in approximately 10% to 15% of hospitalized US patients.24,25 Inflammatory infiltration within the renal interstitial parenchyma and peritubular architecture histologically defines AIN. As the disorder involves the renal tubular architecture, a more correct descriptive term for the disorder is acute tubulointerstitial nephritis. AIN has been associated to exposure to medications (nonsteroidal anti-inflammatory agents, diuretics, b-lactamic antibiotics, antiacids), infections, and autoimmune disorders. The overall incidence of AIN during pregnancy is not known. Drug exposure–mediated AIN is possible in pregnant or postpartum women because they frequently receive medications for treatment of a variety of conditions. There is no direct association with medication dose and disease development, although the risk for development of AIN increases after 2 weeks of medication use.24 Nonsteroidal anti-inflammatory agents may produce both AIN and ATN by drug reaction and ischemia-mediated tubular dysfunction,
Acute Kidney Injury During Pregnancy respectively. Pyelonephritis occurs in approximately 0.5% of pregnant women who receive prenatal care.26 Pyelonephritis also may cause AKI by AIN or ATN, the latter in the setting of hypovolemia and prerenal azotemia.
Management GENERAL PRINCIPLES
Treatment of AKI involves specific management of the underlying condition. Specific measures may also be indicated to limit renal damage and restore renal function. An important point to reiterate is that to reach renal failure, often >1 specific cause or pathophysiological mechanism is responsible for AKI. In addition, the contribution of prerenal azotemia secondary to hypovolemia cannot be underemphasized.8,19 Thus prevention of AKI may be potentially accomplished by recognition and treatment of hypovolemia. RENAL-SPECIFIC THERAPY
Specific treatments of AKI have focused on restoration of urine output, prevention of secondary injury, and restoration renal perfusion so as to allow repair of cellular injury. At the present time, goal-directed pharmacological treatment of perfusion or urinary output is not associated with improvement in outcome. Low-dose (1 to 3 mg/kg/min) dopamine infusion was formerly thought to improve outcome because the surrogate outcome of increased urine output was incorrectly assumed to reflect restoration of renal function. ‘‘Conversion’’ of oliguric to nonoliguric ATN was thought to result in improved outcome and survival. In fact, ‘‘conversion’’ does not occur. Continued urine production in a patient with AKI simply reflects a lower degree of renal injury and may also reflect less additional hypoperfusion from prerenal AKI. A recent meta-analysis of dopamine use in the setting of AKI refutes the benefit of dopamine as a therapy in the
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setting of AKI.26 Loop diuresis theoretically reduces tubular oxygen consumption and increases urinary output. However, the use of furosemide for prevention or treatment of AKI does not reduce the inhospital mortality or need for RRT in adults undergoing loop diuresis with the agent. The use of furosemide for the treatment of oliguric AKI is not recommended unless signs of pulmonary congestion are clinically evident. Atrial natriuretic peptide augments GFR by afferent arteriolar vasodilatation. Although several randomized and observational cohort trials have been undertaken studying the use of atrial natriuretic peptide to treat AKI, no clinical benefits have been observed, although some data suggest that atrial natriuretic peptide may reduce contrast-induced nephropathy in patients with chronic renal failure.26 Other promising but unproven medical therapies for AKI include fenoldopam, N-acytylcysteine, and albumin. None of the medications used for treatment of AKI are specifically approved for use in pregnancy. Each of the agents mentioned in this section have been used in pregnancy. Inconclusive results, similar to that observed in the nonpregnant population have been seen in pregnant patients treated in a similar manner. The use of balanced crystalloids such as Lactated Ringers and Plasmalyte is associated with less kidney injury as compared with normal saline, as high chlorine concentrations are associated with renal vasoconstriction and renal ischemia. DIALYSIS—RRT
In nonpregnant critically ill patients, there is no uniform agreement or consensus on the timing of RRT initiation, the timing of discontinuation of RRT, or the optimal choice of the RRT technique used.26 The 2 main types of RRT used in critically ill patients are continuous renal replacement therapy (CRRT) and intermittent hemodialysis (IHD). Conclusive evidence as to the superiority of one www.clinicalobgyn.com
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modality over the other is currently lacking. A third technique (sustained low efficiency dialysis) was developed to overcome inherent disadvantages with CRRT and IHD. In general, IHD removes large amounts of fluid and solutes in short periods of time. The latter is not tolerated in hemodynamically unstable patients rendering good candidates for CRRT in which fluid and solute removal is more gradual over 24 hours every day. Information exists on the conduct and outcome of RRT during pregnancy. The majority of available information pertaining to the use of RRT during pregnancy focuses on ongoing treatment of chronic renal insufficiency. Very little information is published about the acute use of RRT for AKI. In a recent South American case series of AKI of mixed etiology, RRT therapy during pregnancy was associated with a maternal mortality of 30.9%.27 In general, it is felt that earlier institution of dialysis during pregnancy, with greater intensity of dialysis and careful optimization of intravascular volume, results in optimization of outcome.2 Other measures used in the management of AKI are similar in pregnant and in nonpregnant patients. Management of serum potassium and phosphate is approached in a similar manner. Oral administration of calcium acetate (Phoslo) and sevelamer will decrease phosphate levels. Correction of intravascular volume, thromboembolic prophylaxis, and other subsidiary therapies are generally unchanged. PLASMAPHERESIS
Plasmapheresis is not universally used in the treatment of AKI. Plasmapheresis is used therapeutically in patients with thrombotic microangiopathies. The probable mechanism of action is likely that plasmapheresis removes large von Willebrand multimers or ADAMTS-13 autoantibodies. TTP survival is now approximately 80% when plasmapheresis is www.clinicalobgyn.com
used.16 The replacement fluid should be fresh frozen plasma (as opposed to albumin), as it is a source of ADAMTS-13. Plasmapheresis is probably not directly effective in the treatment of preeclampsia and is not generally effective for most other causes of AKI. PREGNANCY MANAGEMENT
Fetal effects from AKI are to a large degree influenced by the underlying etiology. Data regarding chronic renal insufficiency and pregnancy outcome may not reflect the specifics of a pregnant patient with AKI. Any benefits from delivery are more due to the underlying cause, an example of which would be delivery planning and management in the patient with severe preeclampsia (improvement in maternal renal function) as compared with HUS/TTP (delivery not specifically helpful). Care of the pregnant patient with AKI can be multifaceted and challenging, both from a disease standpoint and from the complexities involved in the care of the fetus and pregnancy itself. Multidisciplinary care is advisable in most cases.
Conclusions AKI is relatively infrequent in pregnant and postpartum women. Many cases of AKI during or after pregnancy involve the continuum between prerenal AKI and intrinsic renal disease. Many of the abnormal pregnancy conditions that are associated with AKI in pregnancy are conditions that may exhibit both prerenal and intrinsic pathophysiology. Other causes of AKI during pregnancy occur at similar rates in nonpregnant age and sex-matched women. Therapy of AKI involves limitation of disease progression by attenuation of secondary injury. Therapy is otherwise supportive. Prevention of disease progression in patients with mild renal insufficiency potentially may reduce the chance that AKI will develop.
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15. Clark SL, Greenspoon JS, Aldahl D, et al. Severe preeclampsia with persistent oliguria: management of hemodynamic subsets. Am J Obstet Gynecol. 1988;159:604–607. 16. Fakhouri F, Vercel C, Fremeaux-Bacchi V. Obstetric nephrology: AKI and thrombotic microangiopathies in pregnancy. Clin J Am Soc Nephrol. 2012;7:2100–2106. 17. George J. The thrombotic thrombocytopenia purpura and hemolytic uremic syndrome: evaluation and management and long term experiences of the Oklahoma TTP-HUS registry, 1989-2007. Kidney Int. 2009;112:S52–S54. 18. Fakhouri F, Roumenina L, Provot F, et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol. 2010;21:859–867. 19. Thadhani RI, Maski MR. Renal disorders. In: Creasy RK, Resnik R, Iams JD, Lockwood CJ, Moore TR, Greene MF eds. Creasy & Resnik’s Maternal-Fetal Medicine Principals and Practice, 7th ed. Philadelphia: Elsevier Saunders; 2014: 949–964. 20. Wei Q, Zhang L, Liu X. Clinical diagnosis and treatment of acute fatty liver of pregnancy: a literature review and 11 new cases. J Obstet Gynaecol Res. 2010;36:751–756. 21. Podymow T, August P, Akbari A. Management of renal disease in pregnancy. Obstet Gynecol Clin N Am. 2010;37:195–210. 22. Heyman SN, Rosenberger C, Rosen S. Acute kidney injury: lessons from experimental models. Contrib Nephrol. 2011;169:286–296. 23. Deering SH, Seiken GL. Acute renal failure. In: Belfort M, Saade G, Foley M, Phelan J, Dildy G III. eds. Critical Care Obstetrics. Oxford: Wiley-Blackwell; 2011:376–384. 24. Kodner CM, Kuprimoti A. Diagnosis and management of acute interstitial nephritis. Am Fam Physician. 2003;67:2527–2534. 25. Wing DA, Fassett MJ, Getahun D. Acute pyelonephritis in pregnancy: an 18 year retrospective analysis. Am J Obstet Gynecol. 2014;210: 219; e1-6. 26. Negi S, Shigematsu T. Current therapeutic strategies for acute kidney injury. Clin Exp Nephrol. 2012;16:672–678. 27. Silva GB Jr, Monteiro FA, Mota RM, et al. Acute kidney injury requiring dialysis in obstetric patients: a series of 55 cases in Brazil. Arch Gynecol Obstet. 2009;279:131–137.
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