Acute kidney injury associated with acute fatty liver of pregnancy: An update on a rare clinical entity

Abstract

Acute fatty liver of pregnancy (AFLP) is a rare but potentially life-threatening liver disease associated with mitochondrial dysfunction. It is characterized by microvesicular hepatic steatosis and typically occurs in the third trimester, though it may rarely present postpartum. AFLP is considered a non-thrombotic microangiopathy (TMA) but may present with overlapping TMA features. Its incidence ranges from 1 in 7000 to 1 in 20000 pregnancies, although milder cases may go unrecognized. AFLP can rapidly progress to acute liver failure and 20% to 40% of affected women exhibit clinical features of preeclampsia. Acute kidney injury (AKI) is a frequent complication, observed in 55% to 75% of AFLP cases, which is significantly higher than the 7% to 20% occurrence seen in preeclampsia or hemolysis, elevated liver enzymes, and low platelets syndrome. The exact mechanism behind AKI in AFLP remains unclear, but renal histology has shown tubular deposits of free fatty acids, which correlate with current theories regarding liver pathology. While AFLP-associated AKI is often reversible after delivery, some patients may develop persistent AKI that requires dialysis. Therapeutic plasma exchange (TPE) has been explored in these cases, but available evidence is limited. This review summarizes the current understanding of the epidemiology, pathophysiology, clinical features, and management of AKI in the context of AFLP, and discusses the potential role of adjunctive therapies such as TPE.

Key Words: Acute kidney injury; Acute tubular necrosis; Acute fatty liver of pregnancy; Pregnancy complications; Therapeutic plasma exchange

Core Tip: Acute kidney injury (AKI) associated with acute fatty liver of pregnancy (AFLP) occurs more frequently than AKI related to preeclampsia or hemolysis, elevated liver enzymes, and low platelets syndrome; however, it is generally non-oliguric and of relatively low severity. In some cases, kidney function may not fully recover after delivery and could require dialysis. Rarely, AFLP can manifest in the postpartum period, which presents a diagnostic challenge due to lack of prodromal symptoms and occurrence of severe AKI. AKI is key characteristic of AFLP and is included in both its diagnostic and prognostic criteria. Therapeutic plasma exchange may be considered in patients with persistent hepatic or renal dysfunction following delivery. Given that rapid recognition and prompt delivery are crucial for managing AFLP, there is a need for biomarkers, similar to the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio used in preeclampsia, that can facilitate earlier diagnosis and treatment.

INTRODUCTION

Acute fatty liver of pregnancy (AFLP) is a rare but severe complication that typically occurs in late pregnancy, posing significant risks for both maternal and fetal mortality[1-3]. Diagnosis has been made as early as 18 weeks of gestation[4] and even in the immediate postpartum period[1,5]. Sheehan first described it in his landmark pathological study in 1940, where he characterized it as acute hepatic failure in pregnant women[6]. A significant breakthrough came in 1999 when Ibdah et al[7] identified fetal long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency as a critical factor contributing to the onset of AFLP[7]. Awareness of AFLP has increased in recent years, largely due to improved diagnostic protocols.

As AFLP progresses rapidly, the liver's synthetic and metabolic functions become impaired, leading to significant metabolic disturbances and coagulopathy. When complicated by acute kidney injury (AKI), the condition worsens, resulting in severe acid-base and electrolyte imbalances. The causes of AKI in AFLP are thought to be multifactorial[8,9]. Among the systemic complications associated with AFLP, AKI is particularly concerning due to its significant association with maternal mortality. The Swansea criteria developed by Ch'ng et al[10] for the diagnosis of AFLP include various abnormalities, with renal dysfunction being an important criterion.

The pathophysiology of AKI associated with AFLP remains incompletely understood. The underlying mechanisms may include hemodynamic alterations, coagulopathy, hepatorenal syndrome (HRS), acute tubular necrosis (ATN), and endotheliosis associated with coexisting preeclampsia[8,11,12]. An autopsy series reported free fatty acid deposition in renal tubular epithelium in some cases, aligning with current theories regarding liver pathology[13]. While the literature on the severity of AKI in AFLP is limited, it generally suggests that the condition is less severe than initially anticipated, noting that few patients require dialysis for persistent AKI post-delivery[14,15].

Despite advancements in supportive care and maternal-fetal medicine, management of AFLP associated with systemic complications such as acute liver failure, AKI, and disseminated intravascular coagulation (DIC) remains challenging. Timely diagnosis, urgent delivery, and supportive therapy are crucial for preventing or mitigating the severity of these complications. Recent studies have reported AKI as the most common maternal complication of AFLP[16,17].

There is a recognized need to update clinicians on the management and outcomes of AKI related to AFLP. To our knowledge, no comprehensive review has focused solely on AKI in AFLP. However, recent reviews on AKI in pregnancy and clinical studies have highlighted it as a key complication, analyzing its incidence, pathophysiology, and risk factors[11,18]. This review summarizes current insights into AKI in the context of AFLP, with a focus on epidemiology, pathophysiology, clinical features, patterns of recovery, differential diagnosis, management strategies, and the potential role of emerging adjunctive therapies such as therapeutic plasma exchange (TPE).

EPIDEMIOLOGY OF AKI IN AFLP

AFLP affects approximately 1 in 7000 to 1 in 20000 pregnancies, with variations in incidence influenced by population genetics and access to obstetric care. The true incidence may be lower than reported, as many studies come from large referral centers, which can overestimate the actual rate[12]. AFLP is often recognized only in its most severe cases, while milder cases can be easily overlooked[19]. Additionally, its presentation overlaps with other pregnancy-related disorders, such as hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome and atypical hemolytic uremic syndrome (aHUS). The incidence of AKI in AFLP ranges widely, from 14% to 100%, with a median occurrence of 60%[20]. This variability may be due to differences in diagnostic criteria, populations studied, and the severity of the disease at presentation.

A population-based study by Knight et al[1] analyzed data from the United Kingdom Obstetric Surveillance System and found that over 50% of patients with AFLP developed renal dysfunction, establishing AKI as its core clinical feature, with only 3.5% of patients requiring renal replacement therapy (RRT). Their findings emphasized that early diagnosis and timely delivery can significantly reduce maternal mortality. Nelson et al[2] observed AKI in 96% of AFLP patients and reported characteristic recovery patterns of renal and hepatic dysfunction after delivery. Zhang et al[21] reported AKI in 52% of patients, with 16% experiencing diarrhea, a finding not noted in other studies. A recent study by Vijay et al[22] in India found that 36.84% of patients with AFLP experienced AKI, with most requiring hemodialysis and a higher mortality rate of 21%. Recent studies have reported serum creatinine as an independent risk factor for maternal and perinatal mortality in AFLP[23]. In some studies, AKI was reported as the initial manifestation, preceding other laboratory abnormalities[8,24].

PATHOPHYSIOLOGY OF AKI IN AFLP

Although the exact underlying mechanisms remain unclear, the pathophysiological factors associated with AKI in AFLP are thought to be multifactorial and complex. Recognizing these interconnected mechanisms is vital for early therapeutic intervention, as illustrated in Figure 1.

Figure 1 Pathophysiological mechanisms of acute kidney injury in acute fatty liver of pregnancy. RAAS: Renin-angiotensin-aldosterone system; SNS: Sympathetic nervous system; HELLP: Hemolysis, elevated liver enzymes, and low platelets; DIC: Disseminated intravascular coagulation; AKI: Acute kidney injury; AFLP: Acute fatty liver of pregnancy.

Hypovolemia

Prerenal factors, such as shock or dehydration due to vomiting, are frequently implicated as the causes of azotemia[2,8,11,25]. Complications associated with renal dysfunction, including oliguria and ATN, have been observed primarily in patients who developed hemorrhage. The renal protective mechanisms (e.g., increased prostacyclin production to enhance renal blood flow) are already maximally activated during normal pregnancy and may not be sufficiently augmented in cases of pre-renal AKI; therefore, careful attention to fluid status remains critical even after delivery[8].

Mitochondrial dysfunction in renal tubular cells

In AFLP, mitochondrial dysfunction is not confined to the liver. Early kidney involvement may result from impaired β-oxidation of fatty acids within renal mitochondria[26]. Renal histopathological studies show tubular lipid droplet accumulation and vacuolar degeneration, suggesting that lipotoxicity, likely due to accumulated long-chain fatty acids, directly damages renal tubular cells[8,13,24]. Together, these findings suggest that renal complications in AFLP may develop, at least in part, independently of hepatic dysfunction.

Preeclampsia-associated endothelial injury

Preeclampsia can lead to glomerular endotheliosis, proteinuria, and AKI. Studies reported a frequent overlap between AFLP and preeclampsia[2,8]. Differentiating AFLP from preeclampsia/HELLP syndrome can be challenging, as 20% to 40% of AFLP patients are diagnosed with concurrent preeclampsia or HELLP syndrome[2].

Coagulopathy/DIC

AFLP is often complicated by DIC, which can contribute to renal dysfunction[16].

Other factors

Complications such as acute pancreatitis and sepsis may contribute to persistent renal dysfunction after delivery. The incidence of acute pancreatitis has been reported in up to 16% of AFLP cases[2]. One study observed a higher incidence of severe AKI (33%) among patients with AFLP who also developed acute pancreatitis; of these, three were diagnosed with ATN, and one required renal transplantation due to acute cortical necrosis[27].

CLINICAL FEATURES OF AKI IN AFLP

AFLP typically manifests during the third trimester (from the 30^th to 38^th weeks of gestation), though it has been rarely reported as early as the 18^th week or in immediate postpartum[1,4]. Initial symptoms often include gastrointestinal symptoms, nausea, malaise, and anorexia, which can progress to vomiting and abdominal discomfort. Some patients may also experience polydipsia and polyuria due to decreased metabolism of vasopressinase because of reduced hepatic metabolism. AKI is often part of a multiorgan dysfunction syndrome (MODS) that includes hepatic failure and coagulopathy.

Most of the patients with AFLP present with AKI early in the disease course, which can help to differentiate it from other related syndromes[28]. In some cases, AKI may be the initial abnormality, prompting further investigations leading to the diagnosis of AFLP[2,8,24]. This highlights the importance of considering AFLP in pregnant patients who develop unexplained AKI during the third trimester. Table 1 summarizes the clinical characteristics of AKI in AFLP.

Table 1 Characteristic features of acute kidney injury in acute fatty liver of pregnancy.

Feature	Description
Incidence	Occurs in 60%-70% of AFLP cases (vs < 15% in HELLP)
Clinical severity	Often moderate to severe; RRT required in < 5%
Initial presentation	AKI may be an early or presenting feature
Liver function tests	AST/ALT: Moderately elevated (< 300 IU/L)- Bilirubin: Markedly elevated. GGT: Usually normal (↑ in viral hepatitis)
Differentiation	AFLP: Microvesicular steatosis → cholestasis → ↑ bilirubin > transaminases. HELLP/Hepatitis: Hepatocellular necrosis → ↑. AST/ALT > bilirubin- 20% of AFLP cases may overlap with HELLP- May show features of TMA
Metabolic disturbances	Hyperuricemia: Markedly raised (hepatic + renal causes). Acidosis: Mixed lactic and anion gap acidosis
Urinalysis	Mild-moderate proteinuria in about 70%; hematuria uncommon
AKI type/urine output	Non-oliguric AKI: Common in mild/prerenal cases- Oliguric AKI (about 20%): Often from ATN or hepatorenal-like physiology. Rare postpartum cases present abruptly with oliguria and MODS
Recovery pattern	Typically rapid after delivery with supportive care. Most recover in 1-3 weeks. Delayed in MODS
Liver vs kidney recovery	Liver: Transaminases drop rapidly post-delivery; bilirubin and synthesis markers recover slowly. Kidney: Gradual, linear recovery
Post-recovery issues	Rare delayed/biphasic recovery. Risk of second hits (sepsis, DIC, volume depletion). Temporary RRT may be needed. Usually reversible (renal cortical necrosis very rare)
Renal histopathology	Commonly ATN without glomerular/immune complex involvement; tubular fatty acid deposition reported

AKI: Acute kidney injury; RRT: Renal replacement therapy; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: Gamma glutamyl transferase; HELLP: Hemolysis, elevated liver enzymes, and low platelets; DIC: Disseminated intravascular coagulation; MODS: Multiple organ dysfunction syndrome; ATN: Acute tubular necrosis; TMA: Thrombotic microangiopathy; AFLP: Acute fatty liver of pregnancy.

Hyperbilirubinemia is typically more pronounced in AFLP than the elevation of liver enzymes. This distinction helps in differentiating AFLP from other pregnancy-related liver disorders, such as HELLP syndrome or acute viral hepatitis. In AFLP, the primary liver injury is caused by microvesicular steatosis of hepatocytes, which impairs hepatocellular function rather than causing cell lysis[3]. Liver enzymes are usually mildly elevated (typically below 300 IU/L); however, in the presence of shock, superimposed ischemic necrosis may lead to marked increases resembling those found in viral hepatitis[29]. Furthermore, in critically ill patients, bilirubin levels may be elevated while liver enzyme levels may be reduced, a phenomenon known as “biliary enzyme separation”[30]. In contrast, HELLP syndrome and acute viral hepatitis involve hepatocellular necrosis, leading to markedly elevated liver enzymes with less pronounced bilirubin elevation. Coagulation findings reveal low fibrinogen, prolonged prothrombin time (PT), and low levels of antithrombin. These abnormalities stem from the liver's reduced production of these factors. In contrast, the DIC seen in severe pre-eclampsia and placental abruption is due to abnormal consumption of clotting factors[12].

Interestingly, despite the accumulation of fat in the liver, patients often exhibit normal or even low serum lipid levels (e.g., cholesterol and triglycerides)—a phenomenon referred to as the “lipid paradox”. This occurs because impaired mitochondrial function hinders the proper metabolism and export of lipids from hepatocytes, leading to intracellular fat accumulation[2,21,31]. In addition, patients with AFLP frequently present with leukocytosis and hypoglycemia, which are considered supportive diagnostic features and are included in the Swansea criteria[1,10].

Hyperuricemia is commonly observed and can serve as an early indicator and may develop before hyperbilirubinemia[32]. In cases of AFLP with AKI, hyperuricemia, and metabolic acidosis may be especially severe due to the combined effects of hepatic and renal dysfunction. Hepatic mitochondrial injury disrupts fatty acid oxidation and increases purine catabolism, resulting in elevated uric acid production. Concurrent AKI decreases the renal clearance of uric acid. Additionally, metabolic acidosis results from lactic acid accumulation due to hepatic failure[3], impaired excretion of hydrogen ions in AKI, and elevated fatty acid intermediates contributing to anion gap acidosis. This dual-organ failure exacerbates biochemical derangements, even when renal impairment appears modest.

Urinalysis can provide valuable insights into the pathophysiology of AKI, which often arises from a combination of prerenal injury and ATN. While proteinuria may be present in 70% of cases[24], it is typically mild to moderate and not as pronounced as in conditions like preeclampsia or HELLP syndrome. Hematuria is usually not observed in AFLP cases, though it is noted in 28% of HELLP syndrome cases[24].

Non-oliguric AKI is more common in AFLP, usually occurring in milder cases or early in disease progression, particularly when only prerenal azotemia is present, without overt tubular damage. Rolfes et al[29] reported oliguric AKI in 20% of patients. Oliguric AKI in AFLP reflects ATN or HRS-like physiology, often occurring along with hepatic failure and systemic complications[8]. Oliguric presentation is also reported in cases manifesting AFLP in the early postpartum period[33-35], and these cases need to be differentiated from aHUS. Metabolic encephalopathy frequently results from hepatic dysfunction. Notably, hypertension is present in 30%-50% of AFLP cases, but it is much more common in HELLP syndrome and severe eclampsia[36]. ATN is the most common finding in renal biopsy; a study demonstrated ATN in five autopsied cases, while one case exhibited the glomerular lesion associated with endotheliosis[29].

PATTERN OF RECOVERY

AKI in patients with AFLP is generally reversible, and acute cortical necrosis has been rarely reported in association with AFLP[27]. Typically, the need for RRT in AKI patients is less than 5%[1,2]. However, one follow-up study reported a higher RRT requirement of 44%; notably, all patients eventually recovered[37].

In cases of AFLP complicated by AKI, recovery of liver and kidney function often occurs on different timelines. Renal function recovery is relatively rapid after delivery. The prerenal component and ongoing organ injury can progress in some women to ATN[38]. Importantly, the prerenal component is usually reversible, with most patients showing a steady decline in serum creatinine to approximately 1 mg/dL within the first week postpartum[39].

Most women recover clinically within 3 to 4 days after delivery, but laboratory parameters often take longer to normalize. The recovery of hepatic dysfunction is not always concordant with the severity of accompanying renal and hemostatic dysfunction. Ongoing hepatocellular damage began to decrease shortly after delivery, evidenced by rapidly declining serum aspartate aminotransferase levels during the first 2 to 3 days, reaching a plateau around 5 to 7 days post-delivery. Jaundice often worsens after delivery, but this may be due to ongoing hemolysis[2].

Although initial improvement in renal function is often observed following delivery with supportive care, a secondary deterioration or plateau may occur due to a "second hit", such as superimposed sepsis or volume depletion. Moreover, persistent liver dysfunction and systemic inflammation can exacerbate renal ischemia or contribute to microvascular injury.

DIAGNOSIS

The development of the Swansea criteria by Ch'ng et al[10] has been pivotal in standardizing the diagnosis of AFLP. It incorporates various abnormalities, including hepatic, renal, hematologic, and metabolic components. Although these criteria are not pathognomonic, they have been validated through prospective studies and are widely utilized. Additionally, they have proven to be effective screening tools with positive and negative predictive values of 85% and 100%, respectively, for detecting hepatic microvesicular steatosis as confirmed by liver biopsy[40]. However, a recent study reported low accuracy of the Swansea criteria in diagnosing AFLP. It revealed that conditions such as HELLP syndrome and acute viral hepatitis can also meet many of the diagnostic criteria for AFLP[41].

Additional diagnostic criteria for AFLP have been developed, but they are not widely used. In 2011, Vigil-de Gracia et al[42] proposed the "AFLP-triad", which consists of a combination of symptoms, laboratory findings, and complications. Other diagnostic criteria include the acronym "FACT", specifically, in the context of elevated liver enzymes, AFLP is associated with hypofibrinogenemia (F), defined as less than 150 mg/dL; acute renal insufficiency (A), indicated by serum creatinine levels greater than 1 mg/dL; hypocholesterolemia (C); and hyperbilirubinemia, with associated increased numbers of nucleated red blood cells (T)[43].

Although the diagnosis of AFLP is primarily clinical and biochemical, imaging can support the diagnosis, but it is not definitive. Ultrasound (USG) of the liver may show increased echogenicity or brightness of the liver consistent with hepatic steatosis, but this is not diagnostic[44]. For example, USG findings are one element of the Swansea criteria, but only one-fourth of women with AFLP have the classic USG findings-ascites or a bright liver[1]. Castro et al[45] used the following criteria for diagnosis: (1) USG showing increased echogenicity; (2) Computed tomography (CT) showing a subjectively decreased attenuation; and (3) Magnetic resonance imaging (MRI) showing increased signal in the T1-weighted images. The highest detection rate they reported was 50% using CT[45].

MRI-based liver fat quantification, performed in the peripartum period, and then repeated several days after delivery when liver function tests showed improvement, appears to be an effective tool for diagnosing AFLP without the need for a liver biopsy[46]. Although liver biopsy is considered gold standard for diagnosis, it is rarely performed due to the risks associated with coagulopathy and the invasive nature of the procedure.

DIFFERENTIAL DIAGNOSIS TO CONSIDER

When evaluating women who appear to have AFLP, it's important to consider other potential diagnoses:

HELLP syndrome

Patients with AFLP typically present with elevated levels of bilirubin, creatinine, uric acid, and neutrophils, along with prolonged PT, acidosis, and hypoglycemia[45]. Prodromal vomiting is more common in cases of AFLP, whereas epigastric pain is typically associated with HELLP syndrome[24].

Sepsis or drug-induced AKI

This is particularly relevant if there is evidence of infection or exposure to nephrotoxic drugs during or after delivery.

Thrombotic microangiopathy

This category includes atypical HUS and thrombotic thrombocytopenic purpura (TTP), which may present similarly to AFLP. Patients with thrombotic microangiopathy (TMA) often experience anuria and exhibit specific laboratory or histological features indicative of TMA[47]. AFLP that occurs in the early postpartum period presents a diagnostic challenge due to abrupt onset, severe AKI and other organ dysfunctions[33-35].

Viral hepatitis and biliary obstruction

It is essential to rule out these conditions before confirming a diagnosis of AFLP.

MANAGEMENT OF AKI IN AFLP

Expert guidelines recommend that patients diagnosed with AFLP should undergo delivery within 24 hours[48]. Therefore, it may be reasonable for patients with suspected AFLP to have a re-examination within that same time frame to confirm the diagnosis. The management of AFLP primarily focuses on rapid recognition and supportive care, such as reversing coagulopathy and preparing for delivery as soon as feasible. It requires collaboration with a multidisciplinary team, including obstetricians, hepatologists, nephrologists, and intensivists.

Wang et al[49] conducted a meta-analysis that found cesarean sections are associated with improved pregnancy outcomes in AFLP patients[49]. Specifically, their analysis showed that maternal mortality risk was 44% lower among women who had cesarean sections compared to those who underwent vaginal deliveries. However, no significant differences were observed between two groups regarding other organ injuries, such as AKI, acute pancreatitis, and MODS. It is important not to rush into cesarean delivery without adequate preparations for potential excessive bleeding. It is advisable to aim for a plasma fibrinogen level of at least 150 mg/dL. Additionally, women with significant thrombocytopenia (platelet count less than 50000/mL) may require platelet replacement before cesarean delivery.

The primary approach to manage AKI in AFLP focuses on supportive therapies. Key components include initial stabilization, proper fluid management, and correction of hypovolemia. Additionally, electrolyte corrections and continuous monitoring of vital signs are important. It's crucial to avoid nephrotoxic drugs; medications that are cleared through the kidneys should either be avoided or administered at lower doses, such as magnesium sulfate.

Until the fetus is delivered, ongoing liver failure continues with its associated complications. After delivery, although there will be a gradual improvement in laboratory abnormalities, some pathophysiological changes associated with AFLP may persist for up to 10 days. Postpartum care needs to be provided in a dedicated unit due to the high incidence of postpartum hemorrhage, DIC, and AKI[50] in these women. Some cases require RRT. Compared with hemodialysis, continuous venovenous hemofiltration (CVVH) not only stabilizes the internal environment but also continuously removes small- and medium-sized toxins (including inflammatory mediators, blood ammonia, endotoxin fragments, nitrogenous metabolic wastes, etc.). Consequently, inflammation is suppressed, and multiple organ failure may be prevented[51,52]. CVVH may also assist in the recovery from hepatic encephalopathy by maintaining acid-base balance and electrolyte levels[37,38].

Currently, there are no consensus guidelines regarding who should be considered for liver transplantation in cases of AFLP, as this condition is still regarded as potentially reversible[37,53]. A retrospective analysis conducted by Kushner et al[53] examined liver transplantation outcomes for AFLP using data from the United Network for Organ Sharing registry. Although liver transplantation is rarely necessary, maternal survival rates after transplantation are generally favorable. However, fetal mortality remains high, which underscores the importance of early delivery in the management of AFLP. Additionally, existing liver transplantation guidelines may not apply to patients with AFLP, as they are primarily based on the King’s College Criteria, which have not been validated for pregnancy-related liver injuries[54].

TPE IN AFLP

AFLP develops rapidly and results in metabolic disorders, coagulation disorders, and the accumulation of toxic substances such as bilirubin and fatty acids. The condition can become more serious if complicated by AKI, leading to more pronounced acid-base and electrolyte imbalance, as well as retention of metabolic waste. In such cases, standard supportive therapy proves inadequate. It is crucial to focus on toxin removal and maintaining body homeostasis. To address these needs, several blood purification technologies have been developed. TPE and extracorporeal liver support (ECLS) have been explored as interventions for AFLP. These therapies have shown potential benefits, such as shorter hospital stay and reduced time in intensive care unit, but they have not significantly impacted maternal mortality rate[55,56].

In AFLP, the origin of the disease is liver dysfunction, necessitating the clearance of certain macromolecule and fat-soluble toxins that cannot be removed by RRT[57]. TPE has additional benefits, including the removal of circulating endotoxins, replacement of normal coagulation factors and proteins, interruption of coagulopathy, correction of hepatic encephalopathy, and the improvement of renal function[54].

A study involving combined blood purification treatment, which included TPE and CVVH, demonstrated lower maternal mortality rates with this combined therapy, making it a consideration in cases with persistent organ dysfunction despite the termination of pregnancy[58]. A recent study by Peng et al[59] also reported improved prognosis for patients with AFLP receiving ECLS. As per a recent meta-analysis, TPE can serve as a therapeutic approach for AFLP particularly in severe or refractory cases[60]. Large RCTs and propensity-matched studies are needed to better understand the safety and efficacy of TPE. TPE in hemodynamically unstable patients may pose risks, including hemodynamic worsening, thereby potentially affecting overall outcomes negatively. Active sepsis is considered a contraindication for TPE. To prevent infection flare-ups after apheresis, intravenous immunoglobulin (100-400 mg/kg) may be administered following TPE[60]. Although the molecular adsorbent recirculating system has been reported to be effective against AFLP in some cases, its clinical application is limited due to high costs and operational challenges[58].

MATERNAL AND RENAL OUTCOMES

AFLP is associated with an increased risk of maternal mortality and various complications. Historically, maternal mortality was as high as 70%, but recent data shows that it has decreased to less than 10% due to rapid recognition, improved care, and timely delivery. Despite this progress, maternal complications remain significant[61]. In contrast, HELLP syndrome has a much lower maternal mortality rate, typically between 1% and 2%, particularly when it is recognized and treated promptly[28].

Timely termination of pregnancy and preventive plasma transfusion can improve clinical outcomes for most patients but multicenter comparative studies were needed to verify the value of preventive plasma transfusion[62]. Studies have shown serum creatinine levels as independent risk factor for maternal outcomes along with increased total bilirubin, international normalized ratio, decreased platelet count, and severe hepatic encephalopathy[23,59,63]. Renal outcomes are generally favorable with timely diagnosis and management, although concurrent multiorgan failure can increase morbidity and mortality. Short-term renal outcomes are favorable, with laboratory findings returning to normal after delivery, although the long-term effects of AFLP are not well understood[50,64,65]. Table 2 summarizes studies that highlight AKI in AFLP.

Table 2 Summary of relevant studies on acute kidney injury in acute fatty liver of pregnancy.

Ref.	Year	Key AKI findings	Study population	AKI incidence	Key outcomes
Slater et al[13]	1984	Renal histology showed lipid accumulation in 50% of cases	Case series	All cases had severe AKI	Renal changes may be early features of AFLP
Rolfes et al[29]	1985	Histology showed acute tubular necrosis and one case of endotheliosis	35 autopsied cases	Most had AKI; 20% oliguric AKI; 1 required RRT	Highlights renal pathology in AFLP
Castro et al[8]	1999	AKI was an early sign even with normal LFT; 21.4% had preeclampsia	28 cases	All had AKI	Full renal and hepatic recovery; AFLP was termed as “reversible peripartum liver failure”
Vigil-De Gracia et al[24]	2001	AKI occurred early in AFLP, later in HELLP; serum lipids levels lower in AFLP	Retrospective study	90% in AFLP vs 20% in HELLP	Renal function normalized at discharge
Ch'ng et al[10]	2002	Renal dysfunction-a key finding in Swansea criteria	Prospective analysis		60% had prolonged hospitalization due to multiorgan involvement
Knight et al[1]	2008	Observed Improved maternal outcome	Prospective cohort study	58% had AKI; 3.5% required RRT	60% ICU admission; 1 maternal death
Tang et al[58]	2012	CBPT improved renal and hepatic recovery	17 AFLP cases with AKI		Maternal mortality 5.9%
Nelson et al[2]	2013	Hepatorenal dysfunction was nearly universal	Retrospective study (n = 51)	96% had AKI; 2% required RRT	Recovery in 7-10 days postpartum. Renal recovery patterns described
Xiong et al[37]	2015	High RRT requirement (32%)	Single-center series	72%	Full renal recovery at discharge
Zhang et al[21]	2016	Higher ICU admission and multiorgan dysfunction; 16% had diarrhea	Retrospective study (n = 56)	52%	Maternal mortality 7%
Gao et al[23]	2018	Serum creatinine identified as mortality risk factor	Retrospective study (n = 133)	55.6%; RRT 241%	Maternal mortality 16.5%
Chen et al[17]	2019	AKI was most common complication	Retrospective (n = 44)	79.5%	AKI usually moderate; prognosis favorable
Meng et al[16]	2021	Developed a mortality prediction model using serum creatinine and other variables	Retrospective (n = 106)	67%	Maternal mortality 9.4%
Vijay et al[22]	2023	5% had preeclampsia; many required RRT	Retrospective	36.8%	Maternal mortality 21%
Peng et al[59]	2024	Serum creatinine predicted poor outcomes	Retrospective (n = 78)		Outcomes improved with artificial liver support

AKI: Acute kidney injury; AFLP: Acute fatty liver of pregnancy; LFT: Liver function test; HELLP: Hemolysis elevated liver enzymes, and low platelets; RRT: Renal replacement therapy; ICU: Intensive care unit; CBPT: Combined blood purification treatment; LFT: Liver function test.

CONCLUSION

AKI in AFLP is typically non-oliguric and reversible, with recovery often coinciding with the resolution of other systemic complications associated with AFLP. While recovery generally occurs after delivery, some cases may require dialysis, and a few patients may develop postpartum deterioration. Disproportionate hyperbilirubinemia, rather than elevated liver enzyme levels, helps to differentiate AFLP from HELLP syndrome and acute viral hepatitis. TPE may be considered for those with persistent renal dysfunction, although current evidence supporting this treatment is not sufficiently strong. Despite the high maternal morbidity associated with AKI in AFLP, the overall prognosis is favorable with early diagnosis and supportive care. Residual renal impairment is uncommon, and the majority of women recover fully, although postpartum monitoring is crucial. However, further research is needed to clarify the pathogenesis of AKI, long-term outcomes, and role of emerging therapeutic options such as TPE. Given that rapid recognition and prompt delivery are crucial for managing AFLP, there is a need for biomarkers similar to the sFlt-1/PlGF ratio used in preeclampsia to facilitate an earlier diagnosis.

ACKNOWLEDGEMENTS

The authors gratefully acknowledge Professor Himansu S. Mahapatra for his valuable guidance and contributions during the preparation of this manuscript.