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Acute renal failure in pregnancy Hilary S. Gammill, MD; Arundhathi Jeyabalan, MD, MSCR Objectives: To provide an evidence-based, up-to-date review of the literature regarding the assessment and management of acute renal failure that may affect women during pregnancy and the postpartum period. Design: A review of the current literature was performed. Results: Acute renal failure is a rare complication of pregnancy but is associated with significant morbidity and mortality. Management requires knowledge of the renal physiologic changes occurring in pregnancy and the relevant diagnoses, both pregnancy-specific and those that may coincidentally occur with pregnancy. In addition, fetal effects must be taken into consideration. A cute renal failure in the setting of pregnancy presents an important clinical challenge. While pregnancy-related acute renal failure (PR-ARF) has become a rare occurrence in the developed world, it continues to be associated with significant mortality and long-term morbidity. The societal impact of this is particularly pronounced given the young and productive status of these women as a whole. The care of women with PR-ARF is challenging because there are two patients to consider: the mother and her fetus. A multidisciplinary approach to care is essential, with a team including critical care specialists, maternal-fetal-medicine specialists, nephrologists, and neonatology specialists. Incidence of Acute Renal Failure in Pregnancy Different definitions of acute renal failure (which have ranged from serum creatinine levels of ⬎0.8 mg/dL to dialysis requirement) render comparison across epidemiologic studies difficult. Furthermore, populations vary signifi- From Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences (HSG, AJ), University of Pittsburgh Medical Center, Pittsburgh, PA. Copyright © 2005 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000183155.46886.C6 S372 Conclusions: Ideal care for women with acute renal failure in pregnancy or postpartum requires a multidisciplinary approach that may include maternal-fetal medicine, critical care medicine, nephrology, and neonatology specialists.(Crit Care Med 2005; 33[Suppl.]:S372–S384) KEY WORDS: renal failure; pregnancy; pregnancy complications; acid-base homeostasis; prerenal ischemia; tubular necrosis; hemodialysis; renal replacement therapy; hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome; preeclampsia cantly in their demographics, referral base, and standard of care. Accepting these limitations, we can assess general trends in the epidemiology and impact of PR-ARF. Since the 1960s, the overall incidence of PR-ARF has decreased from 1/3000 to 1/15,000 –1/20,000. Similarly, the proportion of total cases of PR-ARF pregnancy has fallen from 20 – 40% in the 1960s to 2–10% in the 1980s (1–3). Coincident with these declines, there has been little change in the overall mortality and long-term morbidity rates. From the 1950s through the 1990s, overall mortality rates have ranged from 0 –30% with no clear trend over time (2–5). The consistency of mortality may be attributable to increased efficiency in the developed world at prevention of cases of straightforward ARF; the patients who continue to develop renal failure are sicker— often with multiple system organ failure (3). Long-term prognosis has also remained fairly consistent over time, with full renal recovery rates of 60 –90% (2, 4, 5). The overall decrease in incidence has been attributed to two main trends—the legalization of abortion in most developed countries and the resulting decrease in septic abortion, and the improvement in accessible prenatal care with the attendant surveillance for preeclampsia and other obstetrical complications, which together account for a substantial portion of PR-ARF (2, 3). In the developing world, and in other populations with limited access to prenatal care and to abortion services, PR-ARF continues to be a significant problem, with associated higher mortality and morbidity. Epidemiologic data from India suggest that PR-ARF continues to account for 20% of total ARF cases and that mortality rates remain as high as 50% (6, 7). In an inner-city population in Atlanta, a low renal recovery rate of approximately 50% raises concerns about access to care in certain populations even in the United States (8). In addition to the estimated impact of PR-ARF in previously healthy patients, it is well-known that in women with underlying chronic renal dysfunction (baseline serum creatine ⬎1.4 mg/dL), there is a significantly increased risk of pregnancyrelated loss of renal function (43%), and an estimated 10% of patients experience rapid deterioration in renal function (9). Prevention To affect the overall incidence of disease, primary prevention via improved access to prenatal care is key. On the other hand, affecting mortality and long-term renal recovery is the focus of acute care for these patients, since early and appropriate management can prevent or limit irreversible change. This will be our focus in this presentation. To optimize acute care for pregnant women, it is crucial to build on an understanding of the physiologic changes to Crit Care Med 2005 Vol. 33, No. 10 (Suppl.) the renal system in pregnancy. We will therefore review the renal physiology of pregnancy, the evidence regarding efficacy and suitability of diagnostic and therapeutic options for PR-ARF , and etiologies of ARF both specific to and coincident with pregnancy. We will also discuss fetal considerations in the setting of maternal ARF. Renal Physiology: Alterations in Pregnancy Physiologic changes to the renal system associated with pregnancy fall into several categories of alterations: anatomical, hemodynamic, substrate handling, and acid-base status. From as early as the first trimester, there is dilation of the renal collecting system as well as enlargement of the kidneys overall. There is a laterality to these changes, with more dramatic and ubiquitous effects seen on the right side, particularly with advancing gestation (10, 11). These alterations are thought to be related to hormonal effects on ureteral smooth muscle and to external compression of the ureters at the pelvic brim (right greater than left) (12). The hemodynamic changes affecting renal blood flow are coincident with and partially causative of some of the general cardiovascular changes of pregnancy. Very early decreases in peripheral vascular resistance in pregnancy are due in large part to decreased renal vascular resistance that may be related to the effects of maternal hormones such as relaxin. This arteriolar underfilling is thought to lead to a systemic response including marked increases in cardiac output (approximately 50% above nonpregnant baseline) and plasma volume (approximately 40% above baseline). Although this increase in plasma volume is also accompanied by an increase in red cell mass, the former is more substantial of the two, thus leading to a mild relative anemia in pregnancy. The decrease in peripheral vascular resistance also results in lower blood pressure, with a nadir around midgestation and a gradual return to baseline by term (12, 13). There are also changes in glomerular filtration rate (GFR) and renal plasma flow. Both increase during the first half of pregnancy and subsequently level off, with increases on the order of 40 – 65% for GFR and 50 – 85% for renal plasma flow (Fig. 1). These changes predict the decreases in serum creatinine levels that Crit Care Med 2005 Vol. 33, No. 10 (Suppl.) Figure 1. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) during pregnancy. Schematic based on data from Ref. 13. are seen throughout gestation (12, 13). Table 1 shows normal values for creatinine and other parameters in pregnancy. There is a physiologic decrease in plasma osmolality beginning in early gestation, reaching its nadir around the 10th week of pregnancy and remaining stable for the duration of pregnancy. This has been attributed to a “resetting of the osmostat,” with an appropriate vasopressin response around an altered threshold in pregnancy (14). Potential causes for all of these changes have been hypothesized, including volume expansion; hormonal factors including progesterone, prolactin, and relaxin; and endothelial factors including endothelin and nitric oxide (12, 13). In terms of substrate handling, some degree of proteinuria (⬍300 mg/24 hrs) is normal in advancing gestation and does not indicate renal compromise. This may be due to increased GFR and to an alteration in the charge of the glomerular membrane that increases membrane permeability to negatively charged proteins. It is also common in pregnancy to have a mild degree of glucosuria. Normally, glucose is freely filtered at the glomerulus and reabsorbed in the proximal tubule. In pregnancy, there is increased glucose filtration overall as GFR is increased, and there seems to be some impairment in resorption as well (12, 13). The kidney plays an important role in acid-base homeostasis. The primary acidbase alteration of pregnancy results from an increase in minute ventilation, which causes a relative respiratory alkalosis. Resulting from this, there develops a compensatory metabolic acidosis with a decline in serum bicarbonate levels as noted in Table 1. This decrease in serum bicarbonate may limit the buffering capacity in pregnancy (12, 13). Table 1. Normal laboratory variables in pregnancy Variable Normal Value in Pregnancy HCO3 Urinary protein Plasma osmolality 9.0 mg/dL (average) 0.5 mg/dL (average) 1 ⬃40% over baseline 1 ⬃25% over baseline 2 ⬃10 mm Hg below baseline 18–20 mEq/L Maximum 300 mg/24 hrs 2 ⬃10 mOsm/kg H2O BUN Cr GFR CrCl PCO2 BUN, blood urea nitrogen; Cr, creatinine; GFR, glomerular filtration rate; CrCl, creatinine clearance. From Refs. 13 and 108. General Diagnostic Principles Defining Acute Renal Failure. Conceptually, ARF has been described as “a deterioration of renal function over a period of hours to days, resulting in the failure of the kidney to excrete nitrogenous waste products and to maintain fluid and electrolyte homeostasis” (15). Specific diagnostic criteria have remained nebulous, and, as mentioned previously, this has clouded the literature regarding ARF, particularly weakening the generalizability of study conclusions and rendering the translation of research to bedside care more problematic. Recent attempts to standardize these definitions account for the limitations of commonly used measures of renal function (serum creatinine, urine output, GFR) including their variability by patient age, gender, size, and underlying renal function (16). The Acute Dialysis Quality Initiative developed a model for diagnosis of ARF, as shown in Figure 2 (17). Categorizing Acute Renal Failure. Traditionally, ARF has been divided into S373 Figure 2. Diagnostic scheme for acute renal failure (ARF). The classification system includes separate criteria for creatinine and urine output. The criteria that lead to the worst classification should be used. Note that RIFLE-F is present even if the increase in serum creatinine (SCreat) is less than three-fold so long as the new SCreat is ⱖ4.0 mg/dL (350 mol/L) in the setting of an acute increase of ⱖ0.5 mg/dL (44 mol/L). The designation RIFLE-FC should be used in the case to denote “acute on chronic” disease. Similarly, when RIFLE-F classification is reached by urine output (UO) criteria, a designation of RIFLE-FO should be used to denote oliguria. The shape of the figure denotes the fact that more patients (high sensitivity) will be included in the mild category, including some who do not actually have renal failure (less specificity). In contrast, at the bottom, the criteria are strict and therefore specific, but some patients will be missed. GFR, glomerular filtration rate; ARF, acute renal failure. Reprinted with permission from Ref. 16. three etiologies: prerenal, intrarenal, and postrenal (15). Prerenal ARF occurs as a result of decreased renal perfusion. This can occur because of hypovolemia (as in severe blood loss), hypotension (as in septic shock), or low cardiac output. If uncorrected, prerenal ARF can lead to intrinsic renal damage and intrarenal ARF. Adequate and immediate correction of renal perfusion is the crucial therapeutic intervention that can prevent this transition and ameliorate long-term damage. Intrarenal ARF can also occur due to specific effects on the renal parenchyma via toxin-mediated or immunologic mechanisms. Postrenal ARF reflects downstream obstruction of the genitourinary tract. This can occur from obstruction of both renal outflow tracts (as in urethral obstruction) or of a unilateral tract if the unobstructed kidney is nonfunctional. As we understand more of the physiology of ARF and of the complexity of multiple organ disease, it becomes evident that this system represents an oversimplification. However, until we can develop classification schemes more relevant to physiology and outcomes, this general approach can be useful in guiding clinical management (16). Every patient presenting with PR-ARF should undergo a detailed history, physical examination, and laboratory assessment. Urine electrolyte analysis can be particularly useful in the categorization of the type of renal failure (Table 2). As renal perfusion diminishes, a functioning kidney responds by increasing sodium resorption and decreasing sodium excretion. If intrinsic renal damage has occurred, however, this process is impaired. The Role for Renal Biopsy. In a general population of nonpregnant patients with ARF, those with less straightforward presentations can benefit from renal biopsy. One study found that in approximately 70% of ARF cases, management was altered by histology (18). In a nonpregnant population, the serious complication rate of renal biopsy is also reassuringly low at ⬍1% (19). In pregnancy, we expect diagnoses to be clinically discernable in the large majority of cases; therefore, we would anticipate that there would be a smaller role for renal biopsy. Furthermore, theoretical concerns have been raised regarding possible increased morbidity of the procedure in pregnancy. The primary utility of renal biopsy in pregnancy is the identification of etiologies other than preeclampsia when patients present preterm with renal failure. This is because the only cure for preeclampsia is delivery. Finding lesions other than those associated with preeclampsia has the potential to identify patients who can be managed by therapies other than delivery, thereby minimizing iatrogenic preterm birth and optimizing maternal treatment. A review of the literature on renal biopsy in pregnancy shows complication rates of approximately 1.6 – 4.4%, including perirenal bleeding requiring nephrectomy and perirenal hematoma; as many Table 2. Categorization of acute renal failure Prerenal Proteinuria Hemoglobinuria Leukocyturia Sediment UNa, mEq/L Fractional excretion of sodium,a (%) Urine osmolality, mOsm/kg Trace to none — — Few hyaline casts ⬍20 ⬍1 ⬎500 Intrarenal Mild to moderate ⫾ ⫾ Granular or cellular casts; WBCs; RBCs ⬎40 ⬎2 ⬍350 Postrenal Trace to none ⫾ ⫾ No casts; WBCs; RBCs Early appears prerenal, later postrenal WBC, white blood cell; RBC, red blood cell; UNa, urine sodium; PCr, phosphocreatinine; PNa, plasma sodium; UCr, urine creatinine. The fractional excretion of sodium is the fraction of sodium filtered at the glomerulus that is excreted in the urine. It is calculated by the formula (UNa)(PCr)/(PNa)(UCr) 䡠 100. a S374 Crit Care Med 2005 Vol. 33, No. 10 (Suppl.) as 17% of women had gross hematuria (20). Most studies reported 0% mortality rates, but one study did describe a maternal death (21). Packham and Fairley (22), in 1987, addressed the safety and utility of renal biopsy in pregnancy; their indications for biopsy included new-onset hematuria, proteinuria, or impaired renal function in the first or second trimesters. In a series of 111 biopsies in 104 women, they reported a 97% tissue procurement rate, one patient with a serious perirenal hematoma, and four patients with transient hematuria or pain that resolved spontaneously. In 80% of the patients biopsied, a specific glomerulonephritis was identified (22). Lindheimer and Davidson (23) reviewed these conflicting data in 1987 and suggested that whereas the overall safety profile of renal biopsy in pregnancy is probably not significantly greater than outside of pregnancy, the procedure does have attendant risks, and the indications for biopsy should be limited to situations “when there is sudden deterioration in renal function before 32 wks gestation and no obvious cause is apparent.” This philosophy, which intends to maximize the clinical relevance of biopsy results, has since been adopted. More recent series of renal biopsies performed using the current method of ultrasound guidance suggest that in a well-selected population, histology specifically directs management in 66 –100% of patients. Complication rates in these studies ranged from perirenal hematoma rates of 0 – 40%, with up to 25% of those cases requiring transfusion, and there were no maternal deaths (24,25). These recent studies substantiate Lindheimer and Davidson’s suggestion that renal biopsy has a role in pregnancy and that the invasiveness of the procedure should be factored into the decision whether to biopsy. The current state of neonatal care, with excellent outcomes beyond 30 wks, should perhaps lead us to reassess the gestational age threshold for biopsy, considering when the implications of iatrogenic prematurity are most significant. General Therapeutic Principles Once an assessment of the type and degree of ARF is made, the general principles of management involve the following: a) treatment of underlying causes; b) prevention of further damage; and c) supportive measures until recovery may occur. Therapeutic measures directed at specific pregnancy-related diagnoses are Crit Care Med 2005 Vol. 33, No. 10 (Suppl.) detailed in the next section. Here, we will focus on the management of ARF and renal replacement therapy (RRT) by summarizing the general medical literature and then discussing pregnancy-specific considerations of each intervention. Medical Management. General management of ARF begins with correction of underlying etiological factors and removal of renal toxins (most commonly aminoglycoside antibiotics and radiocontrast agents). Care must also be taken to adjust the dosing of medications that are renally cleared; one such agent commonly used in pregnancy is magnesium sulfate, which is used for seizure prophylaxis in preeclampsia and for inhibition of preterm labor. Prevention and treatment of infection are crucial in this population, as sepsis is the most common cause for mortality in ARF. Following these measures, the single most important intervention is fluid management. The goal is to restore and maintain renal perfusion to reverse preischemic changes; even after tubular necrosis has ensued, the extent of further damage can be limited by adequate perfusion. In most cases, clinical assessment can guide this therapy; however, in more complicated cases, invasive hemodynamic monitoring may be necessary (15). Pharmacologic measures remain secondary therapies for the treatment or amelioration of ARF. Low-dose dopamine infusion has traditionally been used because of its vasodilatory effect on renal arterioles and resultant increase in renal blood flow. However, the current evidence suggests that this does not translate into any difference in clinical outcome. A large placebo-controlled trial comparing low-dose dopamine to placebo showed no differences in serum creatinine, need for renal replacement therapy, or length of intensive care unit/hospital stay (26). Meta-analyses of smaller studies have found similar results (27, 28). Dopamine can trigger tachyarrhythmias, pulmonary shunting, and gastrointestinal or digital necrosis (15). A particular concern in pregnancy is the effect of vasoactive medications on uterine blood flow and therefore the effects on the fetoplacental unit. There is evidence in animal models that dopamine infusion reduces uterine artery blood flow in both normotensive and hypotensive settings. Furthermore, dopamine may also inhibit prolactin release and therefore has the potential to negatively affect lactation (29). Based on the lack of clinical benefit and associated risks, there is no clear role for dopamine infusion in the treatment of ARF in pregnancy. Loop diuretics increase renal intratubular flow rates, which may decrease intratubular obstruction and ameliorate resulting cellular damage. This has been the rationale for the use of loop diuretics in ARF. Furthermore, since nonoliguric ARF has an overall better prognosis than oliguric ARF, it seemed plausible that converting an oliguric state to a nonoliguric one with the use of pharmacologic diuresis might positively affect prognosis (15). The published evidence in this regard is conflicting. There are data suggesting that diuretic therapy does not decrease the need for RRT or positively affect mortality. A recent review points out that although several observational cohort studies suggest that diuretics may be associated with an increased risk of death or renal death, these results are difficult to interpret due to their lack of randomization (30). In a large, multiplecenter international cohort study, multivariate analyses showed no difference in mortality rates among those patients treated with diuretics (31). Based on this evidence, the use of loop diuretics in the treatment of ARF in a general medical population is reserved for treatment of volume overload, in an attempt to avoid RRT. Specific fetal risks of diuretic use have not been reported; however, any agent that alters maternal hemodynamics and has potential to affect uteroplacental perfusion must be used with care in pregnancy. Other agents that have been considered for use in ARF are listed in Table 3 (15, 29). Hyperkalemia, metabolic acidosis, and anemia are downstream effects of ARF that may require specific treatment short of RRT. Hyperkalemia can be treated with potassium binding resins (polystyrene sulfonate) or glucose and insulin (15). There are no published data on polystyrene sulfonate in pregnancy, but due to its mode of action and lack of absorption, there is no physiologic reason to believe that it would be harmful (32). Metabolic acidosis in the setting of ARF can be treated with sodium bicarbonate (15). There are no specific pregnancy-related contraindications to the use of glucose/ insulin or bicarbonate; however, the compensatory metabolic acidosis of pregnancy must be accounted for in the use of bicarbonate. Anemia related to ARF is due to both S375 Table 3. Other pharmacotherapeutics in acute renal failure (ARF) Agent Mechanism Clinical Utility Pregnancy Concerns Calcium channel blockers Renal vasodilation Dopamine receptor agonists Atrial natriuretic peptide Renal vasodilation Theophylline Adenosine antagonist May help prevent renal damage from radiocontrast agents in patients at risk N-acetylcysteine Free radical scavenger Osmotic agents, e.g. mannitol Diuresis May help prevent renal damage from radiocontrast agents in patients at risk Effective in the prevention of early myoglobinuric renal failure Renal vasodilation No clinical benefit; may cause hypotension and worsen ARF No clinical benefit; may cause hypotension and worsen ARF No clear clinical benefit; there may be subsets of patients who would benefit Hypotension, decreased UPBF No data; theoretic concern for hypotension and decreased UPBF No data; hemodynamically active, need to watch for hypotension and decreased UPBF Transient neonatal jitteriness and tachycardia immediately after delivery if recently exposed; no longterm risks Very limited data; appears safe Very limited data; hemodynamically active, need to watch for hypotension and decreased UPBF UPBF, uteroplacental blood flow. From Refs. 15 and 29. Table 4. Indications for the initiation of renal replacement therapy 1. Volume overload 2. Hyperkalemia refractory to medical management 3. Metabolic acidosis 4. Symptomatic uremia (including pericarditis, neuropathy, mental status changes) hemolysis (due to uremia-induced red blood cell membrane fragility) and decreased hematopoiesis (due to decreased erythropoietin levels) (33). Acute therapy is generally via transfusion; however, erythropoietin supplementation may play a role if the process is prolonged. Exogenous erythropoietin can be associated with hypertension (34), and increased dosing is often needed in pregnancy to attain therapeutic response (35–39). Renal Replacement Therapy. If these supportive measures are insufficient in the management of ARF, the next step in treatment is the initiation of RRT. The classic indications for initiation of RRT in ARF are listed in Table 4. There are several retrospective and a few prospective studies looking at early vs. late initiation of RRT in ARF which suggest that there may be a survival benefit to early-onset therapy (based on blood urea nitrogen levels), with survival estimates of 39 – 75% in the early-onset groups and 12– 75% in the late-onset groups (40). A definitive large randomized trial is yet to be done. Whether the threshold for initiation in pregnancy should be even lower remains undetermined. Fetal effects and S376 influences on uteroplacental blood flow should be accounted for in this decision. Once the decision has been made to initiate RRT, consideration turns to the method of its administration. Historically, the standard method has been intermittent hemodialysis. More recently, continuous hemofiltration, sometimes combined with hemodialysis, has become an alternative option in the intensive care unit. The technical differences in the modalities of dialysis and filtration are summarized in Figure 3. In general, hemodialysis works via diffusion. A semipermeable membrane is bathed in the patient’s blood on one side and a dialysate solution on the other. Small molecules diffuse across the membrane, resulting in normalization of the patient’s plasma solute concentrations. In contrast, hemofiltration makes use of convective flow. The patient’s blood is filtered along a highly permeable membrane, and water is filtered out, nonspecifically bringing with it all molecules of small molecular weight. After filtration, a replacement fluid is administered with physiologic concentrations of solutes (41). These techniques can be used alone or in combination. Each uses a circuit through a hemofilter or dialyzer via an efferent vessel (either artery or vein) and an afferent vessel (a vein). The techniques can be performed continuously or intermittently. The advantages of continuous RRT (CRRT) are the ability to maintain continuous control of volume and solute loads and to avoid the hemodynamic fluctuations inherent in intermittent dialysis (41,42). Whether these advantages of CRRT translate into decreased mortality and improved renal preservation remains in question. Available evidence supports the efficacy and safety of CRRT, but so far, no clear differences in overall outcomes have been shown in a general population. However, many of these trials were confounded by differences in overall health status (43– 45). In a recent meta-analysis that incorporated disease severity into a multivariate model, Kellum and colleagues (46) found an overall decreased risk of mortality with CRRT. These techniques may have particular benefit in specific populations, such as those who are hemodynamically compromised. Pregnant women represent one such potential patient group. Dialysis in Pregnancy. The medical literature reporting outcomes of dialysis in pregnancy is limited to retrospective reviews and case reports. The vast majority of these data are from patients with chronic renal disease. Our ability to translate medical evidence to the bedside of the pregnant patient with acute renal failure is, therefore, primarily extrapolative. There have been substantial improvements in both fertility and successful pregnancy rates in the CRF population over the past three decades. Since the first case report of a successful pregnancy on dialysis in 1971 (47) and an initial case series in the 1980s that suggested high rates of preterm birth, low birth weight, and refractory hypertension (48), the overall prognosis for these patients has improved significantly. However, these Crit Care Med 2005 Vol. 33, No. 10 (Suppl.) Figure 3. Methods of renal replacement therapy: Hemofiltration and hemodialysis. Schematic based on data from Refs. 41 and 42. pregnancies continue to be high risk, and outcomes remain quite variable. There is evidence to suggest that these improvements may be due to the recognition that increased dialysis dose may be beneficial. Okundaye and colleagues (39) in 1998 noted that an increase in the number of hours of dialysis per week (beyond a threshold of twenty hours per week) led to increasing survival and decreasing prematurity. Bagon and colleagues (49) found similar trends in their national survey of dialysis centers in Belgium in 1998. In an attempt to minimize the effects of uremia on pregnancy outcomes, they adjusted dialysis regimens with the goal to attain maximum predialysis urea levels of ⱕ100 mg/dL. In doing so, a positive correlation was noted between birth weight and “excess dialysis hours” (the number of hours of dialysis delivered minus the hours that would have been given if the patient were not pregnant) (49). These two publications have influenced the prescription of dialysis for these patients internationally, with the recommendation that an increased dialysis dose should be standard of care for pregnant women (50). There have been case reports since then of excellent perinatal outcome with intensive dialysis (38, 51). Although the majority of these studies assessed the role of hemodialysis, it should also be noted that peritoneal dialysis has been evaluated as well in the setting of CRF in pregnancy, remains a viable option, and may have the beneficial effect of minimizing maternal hemodynamic changes (52, 53). Other considerations for dialysis in pregnancy are summarized in Table 5 (35–37). Crit Care Med 2005 Vol. 33, No. 10 (Suppl.) As mentioned, the theoretical benefits of CRRT might particularly benefit women with PR-ARF. This is substantiated by the improved outcomes in the pregnant patient with CRF using more intensive dialysis. We also know that in pregnancy, the hemodynamic shifts inherent with intermittent dialysis may negatively affect uteroplacental perfusion and increase risk of placental oxidative stress with cyclic placental hypoperfusion and reperfusion. This has the potential to affect fetal growth and well-being. Furthermore, there has been concern that uremia, which results in increased delivery of urea to the fetus and increases fetal solute load, may lead to fetal diuresis and resultant polyhydramnios, thereby increasing risks of preterm birth and preterm rupture of membranes (35–37, 54). There has also been speculation that an “azotemic intrauterine environment” may contribute to the increased risk of developmental delay seen in the CRF population (39). Although it is impossible to separate out the relative contributions of underlying disease and specific treatments in the causality of these adverse outcomes, it is reasonable to speculate that, by minimizing fluctuations in both volume and solutes, CRRT could ameliorate these risks. However, there are no published data to directly substantiate any benefit of CRRT in pregnancy, nor do leaders in the field know of unpublished information (JA Kellum and R Bellomo, personal communication, 2005). Clearly, aggressive dialysis appears to be safe and beneficial in a pregnant population in general, and this must be factored in to an assessment of risk and benefit of early and intensive dialysis in pregnancy with ARF. Specific Etiologies of PR-ARF To identify the underlying etiology of ARF in pregnancy, it is important to consider both pregnancy-specific diagnoses as well as other etiologies relevant to reproductive age women that may be coincident with pregnancy. Several general categories of pregnancy-specific ARF can be delineated: hypertensive, thrombotic microangiopathic, infectious, hypovolemic, and obstructive. Other intrinsic ARF is generally associated with underlying disease coincident with pregnancy. In the following section, we review these categories and their component disease processes, with a focus on pathophysiology, prognosis, and specific therapies. Hypertension and Thrombotic Microangiopathy Preeclampsia/HELLP Syndrome. Preeclampsia is a pregnancy-specific condition diagnosed by new onset of hypertension and proteinuria after 20 wks of gestation. Although it is one of the most important causes of PR-ARF, the majority of preeclamptic patients do not develop renal failure. As we have come to better understand the pathophysiology of preeclampsia, it appears that hypertension is but a late clinical manifestation of the disorder. Other underlying processes such as endothelial dysfunction, inflammation, metabolic changes, enhanced pressor responsiveness and vasoconstriction, and activation of the clotting casS377 Table 5. Specific considerations for dialysis in pregnancy Variable Hemodynamics Serum urea levels Maternal weight Serum bicarbonate levels Contractions Vitamin and folate supplementation Anemia/erythropoietin levels Serum calcium levels Pregnancy-Specific Concern Careful attention to avoiding hypotension, fluid fluctuations, and volume changes in pregnancy; hypertension should also be treated if severe. Maintain ⬍60 mg/dL. Weight gain in pregnancy (baseline normal body mass index) should be 1–2.5 kg total in the first trimester and 0.3–0.5 kg/week in the second and third trimesters. Remember physiologic metabolic acidosis (compensatory for respiratory alkalosis) in pregnancy; bicarbonate is normally decreased 4–5 mEq/L. Scrutinize closely for preterm contractions and preterm labor associated with dialysis. Required in pregnancy and removed by dialysis; need to increase supplementation. If exogenous erythropoietin needed, therapeutic dosing is generally higher in pregnancy. Avoid hypercalcemia; calciferol doses often must be reduced. From Refs. 35–37 and 109. cade may play a more important role in the pathogenesis of this complex pregnancy-specific condition (55, 56). As mentioned previously, preeclampsia is often associated with specific changes in renal histology. The lesion pathognomonic of preeclampsia is glomeruloendotheliosis. This is characterized by a decrease in glomerular size with increased cytoplasmic volume (due to inclusion of electron-dense material) of the glomerular endothelial cells and resultant decrease in capillary lumen diameter, sometimes with complete capillary obliteration. These changes occur in up to 70% of patients with preeclampsia and persist in the immediate postpartum period (57), but they appear to reverse completely in the vast majority of cases (58, 59). Coincident with these histopathologic changes, there is an overall decrease in GFR and effective renal plasma flow in preeclampsia as compared with normal pregnancy. These decrements are approximately 32% and 24%, respectively, from normal late pregnancy levels (13).In addition to the primary effects of preeclampsia on renal function, preeclampsia can also predispose to PR-ARF through secondary effects of relative intravascular volume depletion, vasoconstriction, and activation of the inflammatory and coagulation cascades. In this setting, the superimposed insults of hemorrhage (e.g., abruption or postpartum hemorrhage) can have a more significant effect on renal perfusion, thus increasing risks of renal deterioration. Several studies have found that patients with pregnancy complications superimposed on S378 preeclampsia are at increased risk for the development of ARF, suggesting that processes that further reduce intravascular volume or that predispose to thrombotic microangiopathy may be pivotal (60). Entities specifically associated with preeclampsia-associated ARF include abruption, disseminated intravascular coagulation (DIC), HELLP syndrome (a variant of severe preeclampsia involving hemolysis, elevated liver enzymes, and low platelets which occurs in 4 –14% of cases of preeclampsia) (61, 62), and antiphospholipid antibody syndrome (63– 66). It follows that in preeclampsiarelated ARF, the primary pathologic process is acute tubular necrosis, with the most severe cases at risk for renal cortical necrosis (67). As in the general literature regarding ARF, studies evaluating the incidence of and prognosis for PR-ARF attributable to preeclampsia are greatly limited by lack of standard definitions, differences in standard of care, and difficulties in generalizability. Two of the most comprehensive recent studies suggest an overall incidence of ARF in preeclampsia of 1.5– 2%, although definitions have varied (63, 64). Another study suggested that this incidence increases significantly to ⬎7% in patients with HELLP syndrome (65). Maternal mortality rates in these studies were 0 –10%, and perinatal mortality rates were 34 – 41%. In terms of renal prognosis, short-term dialysis rates were 10 –50%. These three studies followed patients long-term, for an average of 4 yrs, and the need for long-term RRT de- pended on renal and hypertensive status entering pregnancy; none of the previously healthy preeclamptic patients required therapy. In contrast, of women with preexisting hypertension or renal disease, 40 – 80% required long-term dialysis, and several of these patients ultimately died of end-stage renal disease (63– 65). As with any case of ARF, treatment must first include treating underlying disorders. Preeclampsia is a progressive, multisystemic disease process, as mentioned previously. To date, there is no effective treatment strategy aside from delivery of the fetus and placenta. Therefore, in the case of preeclampsia-related ARF, delivery is indicated. The mode of delivery (vaginal vs. cesarean) depends on all clinical factors; beyond this, the principles of management are primarily supportive and include replacement of blood products as indicated, maintenance of intravascular volume, and renal replacement therapy as needed. Acute Fatty Liver of Pregnancy. Acute fatty liver of pregnancy (AFLP) is a disorder characterized by rapidly progressive hepatic failure in late gestation. It was initially described by Stander and Cadden (68) in 1934 and was considered extremely rare and frequently fatal for both mother and baby. The incidence of AFLP has increased (now possibly as high as 1/7,000 births), and maternal and perinatal mortality have decreased (in two recent series, there were no maternal deaths, and perinatal mortality was 7%) (69, 70). This is likely due to earlier diagnosis and intervention. Patients typically present with nausea, vomiting, malaise, and occasionally mental status changes. Laboratory evaluation frequently demonstrates hyperbilirubinemia, moderate elevations in transaminases, elevated ammonia levels, and hypoglycemia (67, 71).The diagnosis of AFLP is made after excluding other etiologies such as gall bladder disease and acute hepatitis. Many patients with AFLP have coincident diagnoses of preeclampsia or HELLP syndrome, and the metabolic abnormalities of AFLP can help to make this differentiation (69). Rarely, liver biopsy is needed to confirm the diagnosis, although the potential for clotting abnormalities in these patients should factor into the decision to biopsy. Other manifestations of AFLP include DIC (which is associated with decreased antithrombin III levels), major intraabdominal bleeding, central diabetes inCrit Care Med 2005 Vol. 33, No. 10 (Suppl.) Table 6. General principles in the differential diagnosis of preeclampsia, acute fatty liver of pregnancy (AFLP), thrombotic thrombocytopenic purpura (TTP), and hemolytic uremic syndrome (HUS) Onset Primary/unique clinical manifestation Purpura Fever Hemolysis Coagulation studies Hypoglycemia vWF multimers Preeclampsia/HELLP TTP HUS AFLP Usually third trimester Hypertension and proteinuria Median 23 wks Neurologic symptoms Often postpartum Renal involvement Absent Absent Mild Variable Absent Absent Present Present Severe Normal Absent Present Absent Absent Severe Normal Absent Present Close to term Nausea, vomiting, malaise Absent Absent Mild Prolonged abnormal Present Absent HELLP, hemolysis, elevated liver enzymes, and low platelets; vWF, von Willebrand factor. From Refs. 75–78, 82, and 86. sipidus, pancreatitis, and renal manifestations (67, 69 –71). The renal dysfunction seen in AFLP is likely multifactorial. One study suggested that modest elevations in serum creatinine levels indicative of mild insufficiency precede many of the clinical manifestations of the disease (69). Microvesicular fatty infiltration of hepatocytes occurs in some patients because of inherited defects in mitochondrial -oxidation of fatty acids. A particular mutation in long-chain 3-hydroxyacyl coenzyme A dehydrogenase causing an enzyme deficiency in both mother and fetus predisposes to AFLP (72). It is hypothesized that this abnormal fatty acid oxidation could lead to fatty infiltration of tissues other than the liver, including the kidney. Hepatorenal syndrome may also contribute, and in patients who experience hemorrhage and significant volume depletion, acute tubular necrosis can result. In all published series, renal recovery in survivors of AFLP was complete (67, 69, 70). As in preeclampsia, the only curative intervention for AFLP is delivery. Recovery tends to be more prolonged for AFLP; rarely are there any long-term sequelae. Additional supportive measures, including correction of coagulopathy, maintenance of intravascular volume, and treatment of superimposed infections, are crucial. RRT is rarely indicated (67, 69 – 71). Amniotic Fluid Embolism. Amniotic fluid embolism, a rare but dramatic clinical entity, can also be a cause of PR-ARF. Amniotic fluid embolism, which is also referred to as an anaphylactoid syndrome of pregnancy, is the acute onset of hypoxia, respiratory failure, cardiogenic shock, and DIC in pregnancy (73), occurring primarily during labor (70% of cases). The maternal mortality rate of amniotic fluid embolism is estimated to be ⬎60%, with a similar perinatal mortality rate, and Crit Care Med 2005 Vol. 33, No. 10 (Suppl.) most survivors (85%) suffer neurologic sequelae (74). Due to the syndrome’s associated DIC, cardiac dysfunction, and hemorrhage causing intravascular volume depletion, ARF is a factor to consider in all immediate survivors, and careful attention to volume resuscitation is crucial. Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and systemic ischemia and multiple organ failure (75–78). Although not specific to pregnancy, these disorders are often included in the differential diagnosis of preeclampsia/HELLP syndrome with ARF. Classically, TTP is identified by a pentad of clinical findings: thrombocytopenia, hemolytic anemia, fever, neurologic abnormalities, and renal dysfunction (79). HUS was noted to be similar, but with less dramatic neurologic involvement and more significant renal manifestations. Often difficult to differentiate from severe preeclampsia (Table 6) (80), these disorders occur in pregnancy at least as much as in the general population, (75) and some authors report that pregnancy-related TTP/ HUS accounts for 10 –25% of overall cases (76, 77). The overall incidence of TTP/HUS in pregnancy has been estimated to be 1/25,000 births (75).Pathophysiologically, TTP/HUS is thought to result from intravascular thrombi that cause consumption of platelets, fragmentation of red blood cells, and variable systemic ischemia (77). Large, multimeric forms of von Willebrand’s factor are found in these patients, and there is some evidence that a plasma protease that normally cleaves these multimers may be genetically absent, deficient or may be inhibited by an acquired autoantibody (81, 82). Acute renal failure occurs in two thirds of these patients (76). A number of retrospective reviews of TTP/HUS in pregnancy have been conducted. Maternal mortality has decreased over time and ranges between 8 – 44%; similarly perinatal mortality has also decreased but remains substantial, between 30 – 80% (75, 83, 80). One study reviewed the experience at Parkland Hospital between 1972 and 1997. Their overall mortality rates were fairly low; however, long-term morbidity and mortality were quite significant in the average 9-yr follow-up period. The majority of these patients had persistent renal insufficiency and hypertension, in the long term many of them required dialysis and transplantation, and at the time of their publication one had died of end-stage renal disease (75). Long-term neurologic sequelae are also possible with TTP/HUS (83). Other pregnancy-specific complications include fetal growth restriction, fetal distress and intrauterine demise, and recurrence with future pregnancy (75–77, 83). Although TTP/HUS can occur at any time during pregnancy or postpartum, the median gestational age at onset is about 23 wks, tending to occur earlier than in preeclampsia (77). Plasmapheresis is the cornerstone of therapy for TTP/HUS, associated with a decrease in mortality from 90% to 10 – 20% (84). Other modalities, albeit with less demonstrated benefit, include glucocorticoids, antiplatelet agents, and, for refractory cases, splenectomy or vincristine (76, 77). There is no clear benefit from delivery (75), and anticoagulation with heparin is potentially harmful (76). Supportive measures including fluids, blood transfusion (with caution in administration of platelets as this can exacerbate intravascular occlusion), and RRT are essential components of therapy as well (76, 77) Often, TTP/HUS is diagnosed in the S379 postpartum period, in patients with an initial diagnosis of severe preeclampsia who have worsening renal status, further hematologic decompensation, or multisystemic ischemia despite delivery (76). Postpartum Idiopathic ARF. Cases of PR-ARF confined to the postpartum period that do not meet specific criteria for TTP, HUS, preeclampsia, or AFLP have been grouped into a category of idiopathic postpartum ARF (67, 85). Recently, it seems clear that these patients fall along the spectrum of thrombotic microangiopathy with predominantly renal manifestations. There are no specific therapeutic principles regarding this entity; rather, patients should be treated according to their likely underlying etiology, with supportive care and plasmapheresis if clinically indicated (75, 86). Infection/Sepsis Sepsis from any cause can lead to hypotension and decreased renal perfusion, thus resulting in prerenal ischemia and potentially acute tubular necrosis. The most common causes of sepsis in pregnancy include pyelonephritis, chorioamnionitis, and pneumonia. Pyelonephritis is the most common infectious complication of pregnancy. Although the incidence of asymptomatic bacteriuria is not increased in pregnancy, there is a higher likelihood of ascending infection and pyelonephritis (87). In pregnancy, pyelonephritis is also associated with a higher risk of systemic inflammation and sepsis. These elevated risks can be attributed to several of the physiologic adaptations of the renal system to pregnancy, including ureteral dilation, bladder wall flaccidity, and increased sensitivity to bacterial endotoxin-induced tissue damage. Although pyelonephritis can lead to sepsis and ARF in both the pregnant and nonpregnant host, there is an increased risk of ARF due to pyelonephritis in pregnancy independent of the presence or absence of sepsis. One historical study showed that 25% of women with pyelonephritis in pregnancy demonstrated a significant decrement in GFR without sepsis (88). The most common organisms involved in pyelonephritis in pregnancy are Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. Pseudomonas aeruginosa, group B streptococci, and enterococci are also potential pathogens (89). As mentioned, septic abortion was once a significant contributor to ARF in pregnancy. With the legalization of abortion and subsequent decrease in inciS380 dence, this has become a less important contributor. However, cases of septic abortion associated with spontaneous and therapeutic abortion still occur. We have recently seen a case in our own institution of sepsis with ARF in a septic abortion possibly associated with chorionic villus sampling (an invasive procedure used for chromosomal assessment in cases of increased risk of fetal aneuploidy). There is some suggestion of a higher incidence of renal cortical necrosis in sepsis associated with septic abortion than would be expected with sepsis in general (90). These infections tend to be polymicrobial, often involving anaerobic species. The most common organisms involved in bacteremia due to ascending infection are E. coli, group B streptococci, anaerobic streptococci, Bacteroides species, Clostridium species, and enterococci (91). In terms of therapeutic considerations, in all of these cases, general supportive measures, including hydration and blood pressure support, should be accompanied by antibiotic therapy. The choice of antibiotic coverage should be governed by the organisms involved, either based on epidemiologic knowledge or documented by culture results. For the polymicrobial ascending infections of the genital tract, including septic abortion, antibiotic selection should be broadspectrum, ensuring adequate anaerobic coverage. For cases of septic abortion or chorioamnionitis, it should be noted that antibiotic penetration of the uterine cavity is suboptimal and that evacuation of the uterine contents is necessary for effective treatment. Volume Depletion Volume depletion can lead to ARF by causing prerenal ischemia. In pregnancy, the most common cause of volume depletion of this magnitude is obstetrical hemorrhage, which can occur at any gestational age. Severe cases of hyperemesis gravidarum leading to refractory nausea and vomiting, if insufficiently treated, could also result in poor renal perfusion. Obstetrical hemorrhage can occur early in pregnancy due to spontaneous or induced abortion. More commonly, third trimester hemorrhage from placenta previa, placental abruption, or postpartum hemorrhage are contributors to significant blood loss, putting patients at risk of ARF. These processes can also be associated with consumptive coagulopathy, which can exacerbate the process, or disseminated intravascular coagulation, which can cause direct intrarenal damage. Treatment of hemorrhage sufficient to cause prerenal ischemia includes volume support, replacement of blood products, and correction of coagulopathy. In the antepartum setting, delivery is indicated, either vaginally or by cesarean section, depending on the clinical picture from an obstetric perspective. In the postpartum setting, the underlying problem must be addressed. For surgical bleeding, exploratory laparotomy and repair may be indicated. In cases of uterine atony leading to hemorrhage, medical therapy with uterotonics, or if refractory, surgical intervention may be necessary. Hyperemesis gravidarum is a common complication of pregnancy, with 70 – 85% of pregnant women experiencing some degree of nausea and vomiting (92) and 1–2% of women with severe symptoms, often including a loss of 5% of body weight (93). In general, hyperemesis can be managed with oral antiemetic medications. In a small subset of patients, aggressive management with enteral and/or parenteral nutrition and hydration may be required. In rare cases, severe hypovolemia can result in prerenal ischemia and ARF. A recent case report discusses one such patient, who required short-term RRT and supportive care and subsequently went on recover full renal function (94). Obstruction The gravid uterus can provide significant compression of the genitourinary system, particularly in settings of uterine overdistention such as polyhydramnios, multiple gestation, or uterine fibroids. Although rare, there have been several case reports of PR-ARF in these scenarios (95– 106). Maternal genitourinary anomalies or prior surgery can also increase susceptibility to such processes, particularly in the setting of a unilateral kidney or collecting system (106). Nephrolithiasis is another potential obstructive cause of ARF to consider, as the incidence of stones is the same as in a population of nonpregnant reproductive age women (107). Approaches to treatment of obstructive PR-ARF include cystoscopy and retrograde ureteral stent placement or percutaneous nephrostomy (95, 96, 106). If the clinical situation suggests Crit Care Med 2005 Vol. 33, No. 10 (Suppl.) Table 7. Differential diagnosis of intrinsic renal disease in reproductive-aged women Category/Location Mechanism/Subtype Specific Diagnoses Tubular necrosis Continuum with prerenal ischemia Vasculitis Systemic vascular inflammation with renal involvement Acute glomerulonephritis Ischemia Toxins Wegener’s granulomatosis Thromboembolic disease Scleroderma Immunoglobulin A nephropathy Thin basement membrane disease Lupus nephropathy Hereditary nephritis Mesangial proliferative glomerulonephritis Postinfectious glomerulonephritis Lupus nephropathy Rapidly progressive glomerulonephritis Fibrillary glomerulonephritis Membranoproliferative glomerulonephritis Focal glomerulosclerosis Minimal change disease Membranous nephropathy (including lupus) Diabetic nephropathy Late-stage postinfectious glomerulonephritis Drug/toxin (e.g. penicillins, cephalosporins, sulfonamides, rifampin, ciprofloxacin, NSAIDs, thiazide diuretics, furosemide, cimetidine, phenytoin, allopurinol) Autoimmune disease, e.g. lupus Infiltrative disease, e.g. sarcoidosis Infectious disease, e.g., legionnaire’s disease or hantavirus Focal glomerulonephritis Diffuse glomerulonephritis Nephrotic syndrome Acute interstitial nephritis Hypersensitivity response NSAIDs, nonsteroidal anti-inflammatory drugs. From Refs. 15 and 110 –112. Table 8. Differentiation of preeclampsia and acute glomerulonephritis Gestational age Hypertension Systemic manifestations Urine sediment Acute Glomerulonephritis Preeclampsia Any Present Collagen-vascular disease, preceding infection Hematuria, RBC casts, oval fat bodies Most third trimester Present Neurologic, hematologic, or hepatic involvement Isolated proteinuria or findings of ATN (brown granular casts, renal tubular cells) ⬎300 mg/24 hrs (mild), ⬎5 g/24 hrs (severe) 7 7 7 7 Proteinuria ⬎2 g/24 hrs Complement levels ANA Antistreptolysin-O titers Other autoantibodies 2 1 1 1 RBC, red blood cell; ATN, acute tubular necrosis; ANA, antinuclear antibody. From Ref. 113. that delivery would be appropriate, this may ameliorate genitourinary obstruction (97, 99, 102–105). Published case reports indicate excellent prognosis for general recovery and restoration of renal function once the obstruction is relieved (95, 97–99, 101–106). Rarely, hemodialysis has been suggested as a temporizing measure until more definitive treatment of the obstruction can be achieved (103). Crit Care Med 2005 Vol. 33, No. 10 (Suppl.) Other Intrinsic Renal Dysfunction As mentioned, the evaluation of a pregnant patient with ARF must take into consideration those etiologies that may occur coincident with gestation but may not be specific to pregnancy. Table 7 outlines this differential diagnosis in detail, with a focus on those diseases that are more common in reproductive-aged women. Differentiating glomerular dis- ease from preeclampsia and other forms of PR-ARF can be challenging. Some of the distinguishing characteristics are summarized in Table 8. Fetal Considerations The adverse perinatal outcomes associated with PR-ARF are typically due to altered uteroplacental hemodynamics. Intravascular support is a crucial component of management of these patients, both in limiting renal damage and in preserving uterine blood flow. Attention to volume status, the fetal effects of medications, and maternal solute load are key components of the treatment of PR-ARF. Fetal heart rate monitoring allows evaluation of fetal status and placental oxygen delivery. In viable gestations (⬎23–24 wks gestation), fairly frequent fetal heart rate monitoring may be indicated, with acceptable regimens ranging from periodic assessments with nonstress tests or biophysical profiles to continuous monitoring. The intensity of fetal heart rate monitoring should follow the acuity of the clinical situation, with those patients with hemodynamic instability most closely followed. Although fetal heart rate monitoring is an invaluable tool, it should be emphasized that maternal stability must be enS381 sured before an intervention specifically for fetal benefit should be undertaken. If preterm delivery is likely to be indicated for maternal benefit, the administration of glucocorticoids (betamethasone, e.g.) should be considered to minimize neonatal morbidity related to prematurity. In terms of neonatal management, the most common problems that these neonates face are those of prematurity. They also tend to have high intravascular solute loads, which puts them at risk for osmotic diuresis and dehydration. In the anticipation and management of these problems, specialized neonatologists and a tertiary care neonatal intensive care unit are important components of the multidisciplinary team. 8. 9. 10. 11. 12. 13. CONCLUSION The uniqueness of medical care in pregnancy lies in two areas: the body’s dramatic alterations caused by gestation and the need to treat two patients simultaneously, only one directly accessible. 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