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ACUTE KIDNEY INJURY IN THE PREGNANT PATIENT
Rosemary Nwoko, Darko Plecas and Vesna D. Garovic
1
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.
2
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
3
– 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
4
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
5
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
6
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
7
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.
8
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 .
9
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).
10
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
11
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.
12
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 .
13
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
14
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
15
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.
16
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
17
develop specific preventive and treatment options. Future research may be
crucial in identifying the underlying pathogenetic mechanisms and related
therapeutic targets.
TABLE 1
18
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
19
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
20
process of double-contouring. She has remained on chronic hemodialysis and is
currently being evaluated for a renal transplant.
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