Acute kidney injury in the pregnant patient rosemary Nwoko, Darko Plecas and Vesna D. Garovic abstract



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TITLE

ACUTE KIDNEY INJURY IN THE PREGNANT PATIENT


Rosemary Nwoko, Darko Plecas and Vesna D. Garovic

ABSTRACT
Acute kidney injury (AKI) is costly and associated with increased mortality and morbidity. An understanding of the renal physiologic changes that occur during pregnancy is essential for proper evaluation, diagnosis, and management of AKI. As in the general population, AKI can occur from pre-renal, intrinsic, and post-renal causes. Major causes of pre-renal azotemia include hyperemesis gravidarum and uterine hemorrhage in the setting of placental abruption. Intrinsic etiologies include infections from acute pyelonephritis and septic abortion, bilateral cortical necrosis, and acute tubular necrosis. Particular attention should be paid to specific conditions that lead to AKI during the second and third trimesters, such as preeclampsia, HELLP syndrome, acute fatty liver of pregnancy, and TTP-HUS. For each of these disorders, delivery of the fetus is the recommended therapeutic option, with additional therapies indicated for each specific disease entity. An understanding of the various etiologies of AKI in the pregnant patient is key to the appropriate clinical management, prevention of adverse maternal outcomes, and safe delivery of the fetus. In pregnant women with pre-existing kidney disease, the degree of renal dysfunction is the major determining factor of pregnancy outcomes, which may further be complicated by a prior history of hypertension.

KEY WORDS



Acute kidney injury (AKI) - TTP-HUS (thrombotic thrombocytopenic purpura-Hemolytic uremic syndrome) - HELLP (hemolysis, elevated liver enzymes, low platelets) - TMA (thrombotic microangiopathy) - aHUS (atypical hemolytic uremic syndrome).

INTRODUCTION
Acute kidney injury (AKI) can be defined as the sudden loss of renal function associated with a rise in creatinine levels above a known baseline. In this setting, clearance of nitrogenous wastes, as well as extracellular volume and electrolyte regulation are impaired. AKI in the general population is associated with increased mortality, increased length of hospital stay and financial costs . In the pregnant population the incidence of all AKI cases, including dialysis dependence, is less than 1% in the Western world, with reduced frequency and improved mortality since the 1960s. It is important to note that epidemiologic data on the incidence and prevalence of AKI in pregnancy may vary due to different diagnostic criteria and variable cut-off values for serum creatinine levels that define kidney injury, the lack of creatinine data in this young, healthy population, and the variability in ethnicity and socioeconomic class. New cases of pregnancy-related AKI have declined from approximately 1/3000 to 1/15,000 – 20,000 since the 1960s . Two main factors may be responsible for the overall decline in the incidence of pregnancy-related AKI: improvement in pre-natal care and a decrease in the rate of illegal, septic abortions in developed countries. It is possible that the use of antiprogesterone drugs, such as mifepristone, might have contributed to the declining septic abortion rates, although there is a paucity of data regarding this association.
During pregnancy, AKI can be due to any of the same disorders that affect the general population, such as pre-renal, intrinsic and post-renal causes. In the text that follows, we will review AKI in pregnancy in the context of pre-renal, intrinsic and post-renal etiologies, and will address its presentation and onset with respect to gestational age (i.e., trimester of pregnancy), as this may help to facilitate making a differential diagnosis. Finally, AKI may occur as a new condition, a pre-existing, albeit unrecognized condition, or as a pre-existing condition in patients with normal or impaired renal function. Among conditions that may lead to AKI, and which commonly occur during the second and/or third trimester, special attention will be given to those disease processes that are unique to the pregnancy state.
PHYSIOLOGIC CHANGES IN PREGNANCY

Most organ systems in a pregnant female undergo changes in order to accommodate the growing fetoplacental unit. There are considerable changes that occur in the urinary tract system: both kidneys and ureters increase in size by 1 to 1.5 cm , accompanied by dilation of the renal pelvis and calyx. This dilation of the urinary system is due to the hormonal effects of progesterone, external compression by the gravid uterus and morphologic changes in the ureteral wall . Progesterone also reduces ureteral peristalsis, contraction and tone. Decreased bladder tone, bladder hyperemia and edema potentiate asymptomatic bacteruria, while bladder flaccidity may affect the vesicoureteral valve, leading to vesicoureteral reflux . The result of these physiological changes are increased risks for urinary stasis, urinary tract infection, and, ultimately, pyelonephritis. The systemic vasodilatory state, typical of pregnancy, increases renal perfusion and glomerular filtration rate (GFR). Due to the rise in GFR, hypouricemia and increased urine protein excretion occur. Systemic vasodilation leads to the stimulation of anti-diuretic hormone (ADH) release and increased thirst, resulting in a decrease in plasma osmolality and plasma sodium concentration by 4 to 5 mEq/L . Minute ventilation increases due to progesterone-induced stimulation of the central respiratory center in the brain. This results in a decrease in pCO2 and a mild chronic respiratory alkalosis, which is compensated for by renal excretion of bicarbonate.
PRE-RENAL AZOTEMIA
This is defined as a decrease in the effective intravascular volume leading to decreased renal perfusion. Causative factors seen in the non-pregnant population, such as vomiting, diarrhea, congestive heart failure, nephrotic syndrome and diuretic use, are possible etiologies in the pregnant patient .

Pre-renal azotemia during pregnancy may be due to hypovolemia resulting from hyperemesis gravidarum, diuresis, and hemorrhage from trauma, placental previa, placental abruption, a ruptured or atonic uterus or intra-operative bleeding. It may also result from decreased cardiac output in the setting of pre-existing valvular heart disease, ischemia or cardiomyopathy from any cause. Finally, decreased renal perfusion may also occur in the settings of anaphylaxis, sepsis, and the use of non-steroidal anti-inflammatory drugs/ cyclooxygenase-2 inhibitors (NSAIDs/COX-2 inhibitors).

The most common causes of prerenal azotemia in pregnancy include hyperemesis gravidarum and hemorrhage. Hyperemesis gravidarum is defined as severe and persistent nausea and vomiting leading to weight loss, exceeding 5 percent of the pre-pregnancy body weight, and ketonuria . These patients present in the first trimester of pregnancy with acute renal failure associated with a hypokalemic, metabolic alkalosis. Conceivably, metabolic alkalosis may be compensated by a respiratory response, i.e, hypoventilation, but clinical studies supporting this compensatory response are limited. As this occurs in the setting of preexisting respiratory alkalosis, which is a known physiological consequence of the direct progesterone effect on the respiratory center in pregnant women, further evaluation with a blood gas may be necessary in order to evaluate the respiratory and metabolic components and diagnose the underlying acid-base disorder. Other laboratory abnormalities can include an increase in hematocrit (hemoconcentration), mild elevations in aminotransferases , as well as mild hyperthyroidism. The hyperthyroidism is thought to be due to the thyroid stimulating activity of human chorionic gonadotropin . Treatment with antiemetics and intravenous fluids usually corrects the acid-base, electrolyte and renal abnormalities .

The differential diagnoses of hemorrhage during the first trimester of pregnancy differ from the second or third trimesters. Specifically, in the third trimester, placenta previa, abruptio placenta (preeclampsia and prior hypertension are risk factors), uterine rupture and vasa previa may occur.


INTRINSIC KIDNEY INJURY

Damage to the tubulo-interstitium, glomerulus, or cortex can lead to intrinsic kidney damage during pregnancy. Causes of intrinsic AKI include tubular and interstitial damage from acute tubular necrosis (ATN), contrast-induced nephropathy, infections, nephrotoxic drugs and myoglobinuria. The usual causes of glomerulonephritis (GN) in the non-pregnant patient, such as lupus nephritis, post-infectious GN, and focal segmental glomerulosclerosis (FSGS) may occur. The renovascular system can be affected in conditions such as HUS/TTP, anti-phospholipid syndrome, scleroderma renal crisis, HELLP and pre-eclampsia/ eclampsia.


INFECTION

Urinary tract infections are very common in pregnancy, but rarely cause AKI, except when accompanied by septicemia or hypotension. However, acute pyelonephritis, without signs of sepsis or hypotension, may result in abscess formation and kidney injury , although it is unclear why these patients develop significant renal dysfunction.

A more common infectious cause of renal failure associated with pregnancy is septic abortion, which has a higher incidence in underdeveloped countries. These patients present with signs and symptoms of septic shock and/or disseminated intravascular coagulation (DIC). Renal failure may be due to volume contraction, acute tubular necrosis or bilateral renal cortical necrosis. Treatment includes supportive care with intravenous fluids and appropriate antibiotics. Dilatation and curettage, as well as hysterectomy may be needed in certain cases.
Thrombotic Microangiopathy (TMA)

Thrombotic microangiopathy is a pathologic diagnosis that may occur with pregnancy, in the setting of severe preeclampsia, with HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome, TTP (thrombotic thrombocytopenic purpura), HUS (hemolytic uremic syndrome), as well as atypical variants of HUS. Although the term TTP-HUS will be used frequently in the following text, it is important to note that both can and do occur as separate disease processes (Table 1). The main feature of platelet thrombi and/or fibrin in the microvasculature, can lead to multi-organ dysfunction. The above differentials should be considered in patients who present in late pregnancy with acute renal failure, microangiopathic hemolytic anemia and thrombocytopenia.

Preeclampsia is characterized by hypertension and proteinuria occurring after 20 weeks gestation. Renal failure is unusual in this setting. Pregnancy termination is the recommended and effective therapy, with abnormalities resolving post-partum, although microalbuminuria may persist for weeks post delivery.

It is widely accepted that preeclampsia occurs in the setting of placental hypoxia and underperfusion. In contrast to normotensive pregnancies, placental spiral arteries in preeclampsia fail to lose their musculoelastic layers, ultimately leading to decreased placental perfusion . Placental hypoxia ensues, which is viewed frequently as an early event that may cause placental production of soluble factors leading to endothelial dysfunction. Recent studies have provided evidence that preeclampsia is associated with elevated levels of the soluble receptor for vascular endothelial growth factor (VEGF) of placental origin. This soluble receptor, commonly referred to as sFlt-1 (from fms-like tyrosine kinase receptor-1), may bind and neutralize VEGF, and thus decrease free VEGF levels that are required for active fetal and placental angiogenesis in pregnancy. Therefore, elevated sFlt-1 may be the missing link between placental ischemia on one side and endothelial dysfunction, mediated by sFlt-1 neutralization of vascular growth factors, on the other.


HELLP syndrome is associated with severe hypertension/preeclampsia during pregnancy. Its overall incidence is 1 to 2 per 1000 pregnancies, and occurs in 10-20 percent of severe preeclamptics/eclamptics. The underlying mechanism of injury is not fully understood, as 15 to 20 percent of affected patients do not have hypertension or proteinuria. In addition to sFlt-1, elevated levels of soluble endoglin may contribute to maternal endothelial dysfunction in HELLP patients . Recent studies are elucidating the role of the dysfunctional complement alternative pathway (CAP) as a risk factor for HELLP. Mutations can occur in the major regulatory proteins of the CAP, factor H, membrane cofactor protein and factor I. In a case series of 11 patients diagnosed with HELLP, 4 patients were found to have missense mutations in 1 of 3 genes encoding for CAP regulatory proteins, which were not found in 100 healthy controls from the same ethnic background . Low C3 and factor B levels may also predispose to HELLP syndrome, even when no specific mutations are found in these genes .

The clinical manifestations of HELLP syndrome include ), abdominal pain (midepigastric, right upper quadrant or below the sternum) nausea, vomiting and malaise. Hypertension (blood pressure > 140/90) and proteinuria may be either present or absent in these patients . Renal failure also may be present, and the frequency of CAP abnormalities may be higher in these patients compared to patients who present without renal involvement . The presence of microangiopathic hemolytic anemia with schistocytes on blood smear, low platelets and elevated liver enzymes are the diagnostic criteria for HELLP. Other indicators of hemolysis include an elevated lactate dehydrogenase (LDH) or indirect bilirubin, and low haptoglobin. However, there is no consensus as to the degree of laboratory abnormalities that are diagnostic of HELLP syndrome. Imaging, such as computed tomography (CT) or magnetic resonance imaging (MRI), may be helpful in cases where complications such as hepatic hematoma, infarction or rupture occur .

HELLP may be difficult to differentiate from TTP-HUS, as thrombocytopenia and microangiopathic hemolysis occur with both conditions. However, the presence of elevated liver enzymes strongly suggests HELLP syndrome (Table 1).
TTP-HUS is a form of TMA that can be due to a deficiency in ADAMTS13 (TTP), a von Willebrand factor (vWF) processing enzyme, or due to mutations in genes that encode proteins responsible for regulating the CAP system (atypical HUS). Deficiency in ADAMTS13 can be acquired or genetic, and patients have severe thrombocytopenia and mild renal involvement. These patients commonly develop neurological manifestations, and typically present in the second or third trimesters of their pregnancies, when ADAMTS13 levels tend to fall . Atypical HUS (non-Shiga toxin) is associated with mutations in genes coding for proteins in the alternative complement pathway. This results in spontaneous and excessive activation of CAP leading to endothelial cell damage. Complement abnormalities occur due to acquired anti-Factor H antibodies, inactivating mutations in factors H and I, or membrane co-factor protein, and activating mutations in factor B or C3 coding genes. Patients predominantly have renal involvement, and thrombocytopenia may not be as severe as seen in TTP-HUS. The pregnancy state may trigger abnormal complement activation leading to atypical HUS. In a recent series of 100 patients with atypical HUS, 21 percent developed during pregnancy, with 79% occurring post-partum . Complement abnormalities were detected in 18 of the 21 patients, and this patient group had poor outcomes with respect to time to end stage renal disease (ESRD), as well as risks of fetal loss and preeclampsia . The interactions among complement components, angiogenic factors, and the clinical features of preeclampsia were documented further using pregnant mouse models. Results of this study demonstrated that complement activation targets the placenta, leading to endothelial dysfunction through the release of anti-angiogenic factors that have been associated previously with hypertension and proteinuria
Renal biopsy is rarely needed for the diagnosis of these conditions, as clinical and laboratory data are usually sufficient to distinguish and establish a diagnosis. In addition, renal biopsy findings may be characteristic of TMA, but may not differentiate among disease entities (e.g. HELLP versus atypical HUS). Light microscopy typically shows double-contouring of the glomerular basement membrane and mesangiolysis, with vascular changes such as arteriolar and capillary thrombi

TTP-HUS may occur de novo with pregnancy, may relapse during pregnancy and/or recur with subsequent pregnancies. The distinction among severe forms of preeclampsia (and HELLP in particular), TTP, and HUS may be facilitated by certain clinical and laboratory features, but it is not always possible (Table 1). Renal biopsy should be considered if the laboratory evaluation is non-diagnostic and/or in the presence of co-morbidities, such as systemic lupus erythematosus, where the renal biopsy findings may have a major impact on a patient’s treatment. For example, biopsy-proven lupus nephritis optimally is managed with immunosuppression, whereas delivery, even remote from term, is indicated for HELLP syndrome. In pregnant patients with adequate blood pressure control and normal coagulation parameters, renal biopsy can be safely performed . However, renal biopsy is typically not advisable after 32 weeks of gestation.

Finally, a thrombotic microangiopathy, similar to TTP, can occur in patients with anti-phospholipid antibodies presenting with renal disease, thrombocytopenia, and hemolytic anemia during pregnancy . In these patients, it is possible that a hypercoagulable state, which is characteristic of pregnancy, may contribute to the pre-existing subclinical thrombotic state due to the presence of anti-phospholipid antibodies, resulting in a clinically apparent syndrome of thrombotic microangiopathy during pregnancy (Figure 2). The role of anticoagulation in the prevention/treatment of renal involvement in these patients is unclear.


ACUTE FATTY LIVER OF PREGNANCY

Fatty infiltration of hepatocytes may occur during pregnancy, and can be associated with renal failure in 60% of cases . It should be suspected in women with preeclampsia. This is a disease of the third trimester of pregnancy, and patients present with elevated liver function tests, thrombocytopenia, hypofibrinogenemia, hypoglycemia and coagulation abnormalities . In severe cases, patients may present with encephalopathy. Renal failure may be due to acute tubular necrosis and decreased renal perfusion.

The diagnosis is made clinically based upon presentation, laboratory and imaging data. A liver biopsy is not necessary, but may be useful in atypical presentations . Characteristic liver biopsy findings consist of microvesicular fatty infiltration of hepatocytes in the central and mid-zonal lobular regions, with sparing of the portal tracts .

Primary treatment includes maternal stabilization, with correction of coagulation abnormalities (with fresh frozen plasma, platelets, cryoprecipitate and red blood cells) as needed and prompt delivery. Acute fatty liver of pregnancy may recur in subsequent pregnancies, although the risk of recurrence is unknown.


RENAL CORTICAL NECROSIS

Renal cortical necrosis is a rare, but catastrophic process secondary to ischemic necrosis of the renal cortex .It occurs as the end result of various severe pregnancy complications, including abruptio placentae, placenta previa, prolonged intrauterine fetal death or amniotic fluid embolism . Obstetric etiologies account for approximately 50-70% of cases of renal cortical necrosis . Patients present with the abrupt onset of oliguria or anuria, gross hematuria, flank pain and hypotension . The diagnosis can be made by ultrasonography or CT scan. There is no specific treatment available and many patients will require dialysis, with 20-40 % of patients having partial renal recovery . In one series, 42 of 45 patients (87.5%) with biopsy-confirmed renal cortical necrosis were dialysis dependent upon hospital discharge . In patients who recover partial renal function, creatinine clearance stabilizes between 15 and 50 ml/min .
POST-RENAL KIDNEY INJURY
A common finding during the later stages of pregnancy is mild to moderate dilatation of the collecting system from the gravid uterus, and relaxation of the ureteral smooth muscle . While the majority of patients are asymptomatic and have normal renal function , this functional hydronephrosis, in rare cases, may cause renal failure. Placing the patient in a lateral recumbent position, thereby relieving uterine pressure on the ureter, may improve urine output and creatinine. In contrast, patients with obstruction due to either extrinsic (e.g. uterine fibroid), or intrinsic (e.g. renal stone) causes, are commonly symptomatic and present with varying degrees of renal insufficiency. Post-renal kidney injury occurs from obstruction of part or all of the genitourinary system. Kidney stones, papillary necrosis, surgical ligation, cervical cancer, and urethral obstruction by catheter malfunction, or blood clots may be inciting factors. In the above cases, treatment involves relief of the obstruction.
PREEXISTING RENAL DISEASE

Approximately 4% of childbearing-age women have chronic kidney disease, with diabetic nephropathy being the most common cause found in pregnant women . A variety of primary and/or systemic kidney diseases can occur in the pregnant population and lead to an increased incidence of fetal prematurity, low birth weight and fetal loss . Due to major obstetric and neonatologic advancements, fetal outcomes in women with impaired renal function have improved in recent years . However, the risk for fetal loss remained higher in pregnant patients with preexisting renal insufficiency compared to a control group of women with medical problems other than renal disease Factors predicting fetal loss included severity of proteinuria and degree of renal dysfunction . Other risk factors for complications include decreased GFR, nephrotic range proteinuria, advanced maternal age and the presence of underlying diseases, such as diabetes mellitus, hypertension, and active systemic lupus nephritis.

Pregnancy likely does not contribute to the progression of renal insufficiency when the maternal creatinine is less than 1.4 mg/dl and the blood pressure is normal. There are increased risks of renal decline and pregnancy loss with a creatinine ≥1.4 mg/dl,; women with creatinine values of 3 mg/dl or greater should be strongly discouraged against pregnancy, due to the high risks for adverse fetal outcomes and maternal events, including further renal decline . Other data have shown an increased risk of deterioration of maternal renal function when the creatinine clearance at conception is less than 25-30 ml/min .

Some experts have suggested that patients with anti-phospholipid antibody syndrome and a history of arterial thrombotic events (strokes, in particular), should be advised against becoming pregnant . These women, despite adequate anticoagulation, appear to be at risk for recurrent strokes. Poorly controlled diabetes mellitus and active lupus nephritis are also relative contraindications to pregnancy. Patients with preexisting renal disease should undergo preconception counseling prior to attempting to conceive. Diabetic patients should be closely monitored by an endocrinologist, with goals for tight diabetic control before conception. A minimum of 6 consecutive months without a flare, as well as stable renal function with a creatinine <1.4 mg/dL, is required prior to conception in lupus patients In patients with lupus nephritis, in remission, teratogenic anti-hypertensives and immunosuppressives must be changed to safe alternatives prior to conception.


MANAGEMENT

An understanding of the physiologic changes occurring during pregnancy, as well as early identification of women with pre-existing renal dysfunction, will enable proper management of AKI that may occur during pregnancy. Therapy should be directed at the underlying cause, and delivery of the fetus may be required in certain instances, as discussed above. Severe renal failure may require dialysis, and both hemodialysis and peritoneal dialysis can be safely used . Similar to non-pregnant patients, plasma exchange should be considered for those with peri-partum TTP-HUS. For patients with ESRD undergoing dialysis, it is crucial to prevent intrauterine azotemia, manage anemia, provide adequate nutritional support and avoid dialysis-associated hypotension.

Volume contraction from dehydration and hemorrhage from any cause can be readily managed by resuscitation with intravenous fluids and blood products. Urinary tract infections should be treated with appropriate antibiotic therapy that is safe for both mother and fetus. Antibiotics should always be adjusted for the level of GFR. Renal obstruction can be treated conservatively or with surgical interventions.
CONCLUSION

In this review, we have discussed the different etiologies of AKI, in general, and those unique to pregnancy. The management of AKI during pregnancy presents a challenge that requires knowledge of potential causative factors, proper evaluation and treatment, and consideration of both maternal and fetal well-being. With respect to pregnancy-specific disorders, such as preeclampsia and HELLP, their etiologies and pathogeneses remain elusive, resulting in a failure to develop specific preventive and treatment options. Future research may be crucial in identifying the underlying pathogenetic mechanisms and related therapeutic targets.

TABLE 1





Preeclampsia

HUS

TTP

Time of onset


Late 3rd trimester

Post-partum

2nd and 3rd trimesters

Renal failure

Unusual

Common

Minimal or absent

Renal prognosis

Recovery

76% ESRD

Fair

Neurological findings

Present

Minimal or absent

Dominant

Low platelet count

Present (HELLP)

Present

Present

DIC

Present

Absent

Absent

Abnormal liver enzymes

Present (HELLP)

Absent

Absent

Complement alternative pathway

Present (HELLP)

Present

Absent

Low ADAMTS13

Mild to moderate

Absent

Severe

FIGURE LEGENDS


Table1. Differential diagnosis of TMA in pregnancy: the role of clinical and laboratory findings
Figure 1. Flow diagram showing the differential diagnosis of thrombotic microangiopathy.
Figure 2 Light (A) and electron microscopy (B) from a renal biopsy consistent with TMA. A 43-year old admitted at 33 weeks gestation for increasing edema and decreased urinary output. This was the patient’s first pregnancy (twins) through in vitro fertilization. She presented in hemorrhagic shock, with elevated liver enzymes, and LDH, thrombocytopenia and a creatinine of 2.7 mg/dl. A diagnosis of HELLP was made and the patient underwent urgent Cesarean section. Her kidney function further deteriorated post-partum and she required hemodialysis. As her clinical course was not consistent with HELLP syndrome (Table 1), additional work up was initiated. ADAMTS 13 levels ranged within 45-68% of normal, with normal C3, C4, CH50, factor H and factor I levels. Factor H antibody was negative. Lupus anticoagulant was positive. Her renal biopsy was consistent with TMA.

2A: Light microscopy showing fibrin (yellow thin arrow) and a thrombus (green thick arrow) within a vessel that propagates to the vascular pole of the glomerulus. There is also evidence of endothelial cell swelling (dashed black arrow) resulting from inflammation and injury.

2B: Electron microscopy showing foot process effacement (multiple short arrows) and the formation of new glomerular basement membrane (thin long arrow), the process of double-contouring. She has remained on chronic hemodialysis and is currently being evaluated for a renal transplant.

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