Bile cast nephropathy is a common pathologic finding for kid 2013 Kidney Int

Prévia do material em texto

Bile cast nephropathy is a common pathologic
finding for kidney injury associated with severe liver
dysfunction
Charles M. van Slambrouck1, Fadi Salem2, Shane M. Meehan1 and Anthony Chang1
1Department of Pathology, University of Chicago Medical Center, Chicago, Illinois, USA and 2Department of Pathology, Mount Sinai
School of Medicine, New York, New York, USA
Cholemic nephrosis represents a spectrum of renal injury
from proximal tubulopathy to intrarenal bile cast formation
found in patients with severe liver dysfunction. However, the
contribution of this diagnosis has been largely forgotten in
the modern literature. To more precisely define this, we
conducted a clinicopathologic study of 44 subjects (41
autopsies and 3 renal biopsies) from jaundiced patients at
the University of Chicago. Of these, 24 patients had bile casts
with involvement of distal nephron segments in 18 mild
cases and extension to proximal tubules for 6 severe cases.
Eleven of 13 patients with hepatorenal syndrome and all 10
with cirrhosis (due to alcoholism) had tubular bile casts.
These casts significantly correlated with higher serum total
and direct bilirubin levels, and a trend toward higher serum
creatinine, AST, and ALT levels. Bile casts may contribute to
the kidney injury of severely jaundiced patients by direct bile
and bilirubin toxicity, and tubular obstruction. Both
mechanisms are analogous to the injury by myeloma or
myoglobin casts. Accounting for the presence of renal bile
casts provides a more complete representation of the renal
injury that can occur in this unique clinical setting. Thus, bile
cast nephropathy is an appropriate term for the severe form
of injury observed in the spectrum of cholemic nephrosis.
Additional studies are needed to establish the significance of
this parameter for patient management in different clinical
settings.
Kidney International (2013) 84, 192–197; doi:10.1038/ki.2013.78;
published online 13 March 2013
KEYWORDS: cholemic nephrosis; cirrhosis; hepatorenal syndrome
Renal dysfunction is a common and important complication
in patients with liver failure. Hepatorenal syndrome (HRS) is
defined by the presence of acute or chronic liver disease with
advanced liver failure, and renal function impairment.1 Type
1 HRS has a rapid course with doubling of the serum
creatinine to 42.5mg/dl within 2 weeks. Type 2 HRS
develops over months with a moderate decline of the
glomerular filtration rate (serum creatinine between 1.5
and 2.5mg/dl). The incidence of HRS is not well established,
but can occur in up to 40% of cirrhotic patients.2
Our current understanding of the pathophysiology of HRS
centers around the concept that marked intrarenal vasocon-
striction results in a functional impairment of the kidneys,
and there are no structural abnormalities that contribute to
the renal dysfunction.3 In this scenario, pathologic changes of
acute tubular injury (ATI) would be anticipated. However,
several historical papers have described the medical
significance and histologic characteristics of intrarenal bile
casts as a mechanism for renal dysfunction in the setting of
liver failure, which has previously been termed cholemic
nephrosis or bile nephrosis.4–9 Cholemic nephrosis has been
forgotten in the recent medical literature, and ignoring the
contribution of renal bile casts provides an incomplete
representation of the renal injury that may occur in the
setting of liver failure.
We conducted the following clinicopathologic study with
a focus on the prevalence and characteristics of renal bile
casts. Furthermore, we propose that bile cast nephropathy is
an appropriate term for the severe form of injury that can be
observed in the spectrum of cholemic nephrosis.
RESULTS
The clinical data from the 44 patients are summarized in
Table 1. The patients ranged in age from 4 weeks to 89 years
with a mean of 49 years. There were 25 males and 19 females.
Of these, 22 were African American, 15 were Caucasian, 4
were Hispanic, and the ethnicity of 3 patients was unknown.
The laboratory values are summarized in Table 2. Patients
with bile casts had significantly higher levels of serum total
bilirubin (P¼ 0.001) and conjugated bilirubin (P¼ 0.003),
and although the levels of aspartate transaminase and alanine
c l in i ca l inves t iga t ion http://www.kidney-international.org
& 2013 International Society of Nephrology
Correspondence: Anthony Chang, Department of Pathology, University of
Chicago Medical Center, 5841 S. Maryland Avenue (MC 6101), Chicago,
Illinois 60637, USA. E-mail: anthony.chang@uchospitals.edu
Received 1 October 2012; revised 9 November 2012; accepted 3 January
2013; published online 13 March 2013
192 Kidney International (2013) 84, 192–197
transaminase were also higher, these did not reach statistical
significance (P¼ 0.14 and 0.10, respectively).
In all, 13 (30%) patients had HRS, of which 11 (85%) had
bile casts, whereas only 13 (42%) patients without HRS had
bile casts. HRS patients with bile casts had higher levels of
total and conjugated bilirubin, aspartate transaminase, and
alanine transaminase, but none were statistically significant.
However, serum alkaline phosphatase was higher in patients
with bile casts in the kidneys (159.5 vs. 79.2 U/l, P¼ 0.049).
With regard to clinical measures of renal function, HRS
patients with bile casts had lower blood urea nitrogen (33.3
vs. 54.8mg/dl, P¼ 0.03), but the higher serum creatinine
values (3.1 vs. 2.7mg/dl, P¼ 0.22) or lower serum albumin
(3.1 vs. 4.7 g/dl, P¼ 0.17) were not statistically significant. It
is worth emphasizing that the presence or absence of HRS
was determined solely on the basis of whether this diagnosis
was mentioned in the medical record. Therefore, it is possible
that a higher percentage of our patients may satisfy the
clinical criteria of HRS.
Macroscopic (gross) evidence of bilirubin staining as seen
by yellowish discoloration of the renal cortex and medulla
was identified in 7 (17%) of the 41 autopsy cases. This
finding did not correlate with a particular racial group or
etiology of liver failure. After formalin fixation, these organs
were green, which is particularly accentuated in the renal
medulla because of the higher concentration of bilirubin in
the distal nephron segments compared with the predomi-
nance of proximal tubules in the renal cortex (Figure 1).
Other nonspecific changes including pallor, petechiae, scars,
cysts, and granular appearance of the cortices, along with
congestion and hemorrhage of the medulla, were present in
29 (71%) autopsy cases. A single case without bile/bilirubin
staining had an incidental renal clear cell carcinoma.
Bile casts identified by light microscopy and confirmed by
the Hall histochemical stain were present in 21 of the 41
autopsy kidney specimens and all 3 renal biopsies. Among
the 41 autopsy specimens, the presence of tubular bile casts
was limited to the distal nephron segments in 15 cases, as 5
cases (12%) showed o5 tubular bile casts (defined as 1þ )
and 10 cases (24%) had bile casts in 45 tubules with a few
strongly bile-stained casts (defined as 2þ ). The cases scored
as either 1þ or 2þ had bile cast formation involving o1%
of the tubules. It should be noted that bile casts were
identified based on the green discoloration as detected by the
Hall histochemical stain. We suspect that this test results in a
severe underestimation of the number of bile casts, but the
minimum concentration that is required to result in the
green color change as observed with the Hall histochemical
stain is unknown. Six cases (15%) showed numerous bile
casts that also involved proximal tubules (defined as 3þ ).
Immunohistochemistry for epithelial membrane antigen,
which is positive in distal portions of the nephron, was
performed in a subset of cases to localizethe bile casts (data
not shown). Of the seven cases with macroscopic evidence of
bile pigmentation upon examination of the organ at autopsy,
one case had 1þ , two cases had 2þ , and four cases showed
3þ bile cast formation. The severity of bile cast formation
did not reveal an apparent relationship with other laboratory
or clinical data. The morphologic spectrum of tubular bile
casts ranged from a greenish yellow acellular material within
tubular lumina to a red to dark red color, which is
particularly characteristic of these casts when visualized by
periodic acid–Schiff stains. Some bile casts contained variable
degrees of sloughed epithelial cells with variable states of
cellular preservation (Figure 2). Green discoloration of
calcium oxalate and/or calcium phosphate crystals was
occasionally noted, but these crystals were not classified as
bile casts.
Of the 44 specimens, 32 (73%) showed variable degrees of
ATI, characterized by tubular epithelium with attenuated
cytoplasm or loss of proximal tubular brush borders or
regenerative changes. Variable degrees of autolysis were
present for all of the autopsy specimens, which somewhat
Table 1 | Clinical and pathologic correlation with renal bile
cast formation
Patients
(% of total)
Bile casts
present
Bile casts
absent
Total 44 24 (55%) 20 (45%)
Males 25 (57%) 15 (60%) 10 (40%)
Females 19 (43%) 9 (47%) 10 (53%)
African American 22 (50%) 12 (55%) 10 (45%)
Caucasian 15 (34%) 8 (53%) 7 (47%)
Hispanic 4 (9%) 1 (25%) 3 (75%)
Unknown ethnicity 3 (7%) 3 (100%) 0
Hepatorenal syndrome, present 13 (30%) 11 (85%) 2 (15%)
Hepatorenal syndrome, absent 31 (70%) 13 (42%) 18 (58%)
Acute tubular injury, present 32 (73%) 21 (66%) 11 (34%)
Acute tubular injury, absent 5 (11%) 1 (20%) 4 (80%)
Acute tubular injury, indeterminate 7 (16%) 2 (29%) 5 (71%)
Gross jaundice, present 7 (17%) 7 (100%) 0
Gross jaundice, absent 34 (83%) 14 (41%) 20 (59%)
Cirrhotic jaundice 23 (52%) 14 (61%) 9 (39%)
Cirrhosis due to HCV 5 (11%) 0 5 (100%)
Cirrhosis due to EtOH 10 (23%) 10 (100%) 0
Cirrhosis due to HCV and EtOH 4 (9%) 2 (50%) 2 (50%)
Cirrhosis due to NASH 1 (2%) 0 1 (100%)
Cirrhosis due to drug (TPN) 1 (2%) 1 (100%) 0
Cirrhosis (cryptogenic) 2 (5%) 1 (50%) 1 (50%)
Cholestatic/obstructive jaundice 14 (32%) 6 (43%) 8 (57%)
Hepatic jaundice 5 (11%) 4 (80%) 1 (20%)
Hemolytic jaundice 2 (5%) 0 2 (100%)
Abbreviations: EtOH, alcohol; HCV, hepatitis C virus; NASH, nonalcoholic
steatohepatitis; TPN, total parenteral nutrition.
Accentuated significant values are shown in bold.
Table 2 | Clinical data for 44 cases
SCr
(mg/dl)
BUN
(mg/dl)
Total
Bili
(mg/dl)
Direct
Bili
(mg/dl)
AST
(U/l)
ALT
(U/l)
ALK
(U/l)
Albumin
(g/dl)
Bile casts present
(n¼ 24)
2.3 35.5 26.2 16.3 302 148 159 3.1
Bile casts absent
(n¼ 20)
1.8 39.2 15.1 9.2 252.8 85 178 3
P-value 0.12 0.11 0.001 0.003 0.14 0.1 0.11 0.2
Abbreviations: ALK, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate
transaminase; Bili, bilirubin; BUN, blood urea nitrogen; SCr, serum creatinine.
Accentuated significant values are shown in bold.
CM van Slambrouck et al.: Bile cast nephropathy c l in i ca l inves t iga t ion
Kidney International (2013) 84, 192–197 193
limited the evaluation, but the presence of mononuclear
inflammatory cells in the vasa recta has been previously
reported in the setting of ATI/necrosis and this was noted in
18 (56%) of the 32 patients. However, 7 (16%) patients could
not be assessed because of the severity of autolysis. In 5
(11%) other cases, definite ATI was not observed. ATI was
present more frequently in kidneys with bile casts (66%)
compared with those without bile casts (34%). In general, the
extent of bile cast formation seemed to correlate with both
the extent of ATI and involvement of the vasa recta by
1 mm 100 µm 70 µm
1 mm 100 µm 70 µm
Figure 2 | Spectrum of histopathologic findings in bile cast nephropathy. (a) There are numerous tubular casts, which are pink, as the
yellowish discoloration cannot be appreciated at this low magnification. There is congestion of vasa recta by red blood cells and these are
distinctly darker red (hematoxylin and eosin (H&E)). (b) A Hall stain highlights many green–yellow tubular casts, which confirms the presence of
bile casts. Some of these casts also contain varying amounts of sloughed epithelial cells. (c) This yellowish green acellular tubular cast in the
distal nephron of the renal medulla is characteristic of a bile cast (H&E). (d) A Hall stain confirms the presence of bilirubin in several tubular
casts. (e) Pigmented sloughed tubular epithelial cells can also be identified (Hall stain). (f) Bile-stained calcium oxalate crystal are occasionally
present and are not considered bile casts (H&E).
Figure 1 | The green discoloration of this kidney at autopsy is because of the conversion of bilirubin to biliverdin after formalin
fixation. The renal pyramids show a darker green color as the concentration of bilirubin is higher in these regions compared with the cortex.
Linear green streaks consistent with bile casts can also be seen throughout the cortex and medulla.
194 Kidney International (2013) 84, 192–197
c l in i ca l inves t iga t ion CM van Slambrouck et al.: Bile cast nephropathy
mononuclear inflammatory cells. The extent of interstitial
fibrosis and tubular atrophy was typically absent, minimal, or
mild, with only three cases showing severe to diffuse
tubulointerstitial scarring. Of the 44 cases, 33 (75%) had
no significant interstitial inflammation. However, 7 (64%) of
the 11 cases with interstitial inflammation also had
intratubular bile casts. In these cases the extent of
inflammation roughly correlated with the extent of bile cast
formation and was often prominent around ruptured
tubules. Immunohistochemistry in a subset of cases showed
more CD3-positive T cells than CD20-positive B cells
without any other specific patterns of involvement.
Aside from bile casts, ATI, or interstitial inflammation,
additional renal pathologic findings included arterionephro-
sclerosis (n¼ 22, 50%) or nephrocalcinosis (n¼ 6, 13.6%),
and other findings were found in p2 cases including
diabetic nephropathy, acute pyelonephritis, thrombotic
microangiopathy, renal hemorrhage, membranoproliferative
glomerulonephritis, ischemic glomerulopathy, collapsing
glomerulopathy, obstructive nephropathy, tubulointerstitial
nephritis, or Randall plaques. We did not identify any renal
disorders that were predisposing factors to the formation of
intrarenal bile casts.
The etiology of jaundice could be assigned to one of the
following four categories: (1) cirrhotic jaundice with cirrhosis
secondary to alcohol abuse, hepatitis C virus, nonalcoholic
steatohepatitis, or cryptogenic causes (n¼ 23); (2) chole-
static/obstructive jaundice with markedly elevated alkaline
phosphatase and cholestasis or biliary obstruction because of
primary sclerosing cholangitis, obstructive masses in the liver
or pancreas, cholangitis lenta, or sinusoidal obstructive
syndrome (n¼ 14); (3) hepatic jaundice with severe acute
liver damage including shock liver, giant cell hepatitis, or
fulminant autoimmune hepatitis (n¼ 5); or (4) hemolytic
jaundice with an elevation of primarily indirect bilirubin and
a clinical history of hemolytic anemia (n¼ 2).
Intrarenal bile casts were observed in all categories of
jaundice except for the hemolytic group, which is character-
ized by accumulation of indirect or unconjugated bilirubin,
but there were only two patients. It is noteworthy that all 10
(100%) patients with cirrhosis secondary to alcoholism had
bile casts, and this consisted of an equal number of African-
American and Caucasian patients. None of the 5 patients
with cirrhosis secondary to hepatitis C virus had bile casts,
and 2 (50%) of 4 patients with cirrhosis secondary to
hepatitisC virus and alcoholism had bile casts.
Limited clinical follow-up information is available for
two of the three patients with medical renal biopsies
demonstrating intrarenal bile casts. A 28-year-old Caucasian
male developed cholestatic jaundice secondary to usage
of a dietary supplement (methyl 1-P) for 2 months, which
is considered an anabolic steroid. The patient ceased
using methyl 1-P, and was managed with ursodiol, diphen-
hydramine, amlodipine, and prednisone. After 8 weeks,
his liver and kidney function normalized and jaundice
resolved without additional information. A 50-year-old
African-American female with alcoholic cirrhosis received a
simultaneous orthotopic liver and kidney transplant. The
patient’s posttransplant course has been complicated by
multiple alcohol relapses, and one episode of acute T
cell–mediated rejection in the renal allograft at 3 years after
transplantation. A liver transplant biopsy at 4 years after
transplantation showed mild acute rejection and steatohepa-
titis, and this patient is currently alive and well 5 years after
her dual-organ transplantation.
DISCUSSION
It is unclear why cholemic nephrosis has been largely
forgotten in the modern medical literature. In the past
decade, there are only three reports of four patients with
cholemic nephrosis.10–12 However, tubular bile cast formation
is not a new concept, as most studies of cholemic nephrosis
occurred between 1920 and 1970.4–9 In 1922, Haessler et al.13
studied the renal elimination of bilirubin and recounted the
detailed description of cholemic nephrosis by Quincke in
1899, who believed that the observed changes ‘cannot but
result in a lessened renal activity and thus may have serious
consequences for the organism as a whole.’ Haessler et al.13
analyzed the urine from both dogs and humans with jaundice
and concluded that bile-stained urinary sediment could
occur in the kidney and not only during the passage through
bile-stained urine. As the liver injury resolves and renal
function recovers, the bile-stained casts in the urine decrease
in frequency until they disappear altogether.14,15
Depending on the study population, bile cast formation
ranges from 2.6 to 73.5% of examined kidneys. Holmes6
studied 68 autopsies of jaundiced individuals mostly due to
obstructive causes and observed swelling of the tubular
epithelium, pigmented casts, hypertrophy, and hyperplasia of
the parietal layer of Bowman’s capsule in 50 (73.5%) cases.
However, the actual percentage of cases with pigmented casts
is unclear and the other parameters are well-described
features of ATI. Holmes6 noted that in his study of
jaundiced rats, only one with intense jaundice had bile
casts. De Tezanos et al.4 found renal bile casts in 13 (12%) of
105 patients with liver disease and renal dysfunction, which is
similar to the percentage of cases in our study with severe
bile cast formation. Bal et al.16 identified bile casts in all
three post-mortem kidney biopsies from patients who died
of subacute hepatic failure. Shet et al.17 found that renal
bile casts were more prominent and extensive in biliary
cirrhosis and involved four of seven pediatric patients with
extrahepatic biliary atresia at autopsy.
A recent murine model of liver ischemia/reperfusion
injury demonstrates acute kidney injury that can develop
24 h after the hepatic injury, and tubular casts with possibly
bile or heme were identified.18 However, another model of
acute liver damage in cirrhotic rats did not reveal renal bile
casts, but the investigators may not have specifically searched
for this finding.19
If the literature was clear on the significance of intrarenal
bile casts, this pathologic finding might not have disappeared.
Kidney International (2013) 84, 192–197 195
CM van Slambrouck et al.: Bile cast nephropathy c l in i ca l inves t iga t ion
Fajers20 studied the effects of cholemia with or without renal
ischemia in a total of 9 rabbits divided into four experimental
groups and found only slight and insignificant morphologic
changes in the kidneys that could be accounted by the
ischemic injury alone, but the duration of cholemia was only
2 days, which likely does not reflect the severity of injury that
results in tubular bile casts. Sant and Purandare21 found only
2 (2.6%) jaundiced patients at autopsy with renal bile casts,
but their only inclusion criterion was acute diffuse liver
necrosis that included 10 pregnant females that died within
24 h of delivery and other diverse etiologies. They did find
albumin, bile pigment, and bile salts in the urine of 27
patients. They further studied 42 rabbits after ligating the
common bile ducts and identified rare pigmented casts in one
animal and concluded that injury from cholemic nephrosis
was primarily due to ischemia rather than toxicity.
Bile is a well-established carcinogen and has been
implicated in the carcinogenesis of cholangiocarcinoma,
and esophageal, gastric, and colon carcinomas.22,23 Serum
bile and bilirubin levels increase in the setting of liver
failure. Increased serum levels of bile acids or bilirubin can
impair proximal tubular function (proximal tubulopathy),
which resolves as the serum levels normalize.24–26 The low
water solubility of bile acids may also contribute to cast
formation within the low pH microenvironment of the
distal nephron. The current paradigm of renal dysfunction in
HRS is primarily attributed to marked splanchnic/systemic
vasodilation that results in a reduction of the glomerular
filtration rate.3 However, this schema is incomplete without
incorporating the impact of renal bile casts. It is not
known when bile cast formation occurs throughout this
injury process, which is beyond the scope of our study,
but the likelihood of bile cast formation increases with
prolonged exposure to high levels of bilirubin, which are
typically 420mg/dl. If the liver injury is reversed, recovery
of renal function could be delayed depending on the extent
of proximal tubulopathy and bile cast formation. For
instance, in the evaluation of cirrhotic patients for liver
transplantation, the presence and severity of bile cast
formation may be an important factor in determining
whether a simultaneous liver and kidney transplant should
be performed. Currently, clinicians may not want to subject
patients with liver and renal dysfunction to the small risk of a
renal biopsy if they only expect a diagnosis of ATI. However,
knowing if renal bile casts are present may affect patient
management in this and possibly other clinical scenarios.
Betjes and Bajema10 recently suggested jaundice-related
nephropathy as a replacement for cholemic nephrosis, which
is similar to the replacement of lipoid nephrosis by minimal
change disease. Based on their definition, jaundice-related
nephropathy would encompass the spectrum of injury that
ranges from proximal tubulopathy to extensive tubular injury
and tubular pigment. We propose that bile cast nephropathy
is an appropriate pathologic term, which emphasizes the
severe end of the spectrum of the renal injury in this unique
clinical setting. We acknowledge that this term excludes
patients without bile casts, who may have a significant
proximal tubulopathy, which we agree is also an important
component of the renal injury. However, bile cast
nephropathy has the advantage of being self-explanatory
and bile casts are somewhat analogous to ‘myeloma’ or
myoglobin casts as both of these also have direct toxic effects
on tubular epithelial cells and an obstructive capacity.
Bile casts appear to be a poor prognostic finding even
when present in a small minority of nephrons, but this is due
in part to the preponderance of autopsy studies in which this
finding is more commonly observed. Of the five reported
renal biopsy cases of bile cast nephropathy, including two
patients from our current study, with follow-up information,four patients recovered and one died.10,11 However, more
kidney biopsies and additional studies need to be performed
to determine whether this finding can be further refined for
clinical management.
In summary, bile cast nephropathy is an important
pathologic entity that may account for the renal function
impairment of many patients with severe liver dysfunction. It
can occur in a wide spectrum of liver disorders and in both
pediatric and adult population as well as in patients with or
without cirrhosis. Of interest, all 10 patients in our study
with cirrhosis due to alcohol abuse had bile casts, whereas
none of the 5 patients with cirrhosis secondary to hepatitis C
virus had bile casts, but further studies need to be performed
to validate this observation. Kidney biopsy is necessary to
diagnose bile cast nephropathy, which may otherwise be
overlooked in this patient population.
MATERIALS AND METHODS
The autopsy archives at the University of Chicago Department of
Pathology were searched and consecutive patients with clinically and
pathologically confirmed jaundice were identified from 2004 to
2011. Patients included in the study met all of the following criteria:
(1) clinical history of jaundice, (2) skin jaundice and/or scleral
icterus noted at autopsy, and (3) premortem bilirubin levels42mg/
dl. In addition, three percutaneous renal biopsies obtained over the
same time period with a diagnosis of intratubular bile casts were
included in the study. Demographic, clinical, and laboratory data
were obtained with particular attention to each patient’s liver and
renal function test results. These data were reviewed and correlated
with the pathologic findings at autopsy. The presence of HRS was
established if this clinical consideration was mentioned in the
available medical records. We did not distinguish between type I or
type II HRS nor did we attempt to determine whether patients
satisfied the criteria of HRS as established by Salerno et al.1 This
study was approved by the institutional review board of the
University of Chicago.
Each case was evaluated by light microscopy using hematoxylin
and eosin stains. A Hall (or Fouchet) histochemical stain was
performed on paraffin-embedded tissue sections on all cases to
assess the presence of bilirubin. Standard immunohistochemistry for
myoglobin was performed in a subset of cases to exclude the
presence of intratubular myoglobin casts. Immunohistochemistry
for epithelial membrane antigen (Clone MC5, Ventana Medical
Systems, Tucson, AZ), which identifies distal nephron segments, was
used in a subset of cases to localize the presence of the intratubular
196 Kidney International (2013) 84, 192–197
c l in i ca l inves t iga t ion CM van Slambrouck et al.: Bile cast nephropathy
bile casts. Immunohistochemistry for CD3 (Labvision, Fremont,
CA) and CD20 (DAKO, Carpinteria, CA) was performed on a subset
of cases with interstitial inflammation. Histochemistry for Prussian
blue iron was performed to exclude the presence of hemosiderin.
The diagnosis of intratubular bile casts was made when at least
one cast was identified within the renal tubules, which stained
positively on the Hall stain. On a scale of 0 to 3þ , the extent of bile
cast formation was semiquantitatively graded for the 41 autopsy
cases as follows: 1þ ,p5 tubules contain bile casts; 2þ ,45 tubules
contain bile casts along with rare strongly bile-stained acellular casts
limited to the distal nephron; 3þ , numerous bile casts that could be
found in both distal nephron segments and proximal tubules.
Statistical analysis of the data using Mann–Whitney test was
performed when appropriate. A P-value of o0.05 was considered
statistically significant.
DISCLOSURE
All the authors declared no competing interests.
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CM van Slambrouck et al.: Bile cast nephropathy c l in i ca l inves t iga t ion
	Bile Cast Nephropathy Is A Common Pathologic Finding For Kidney Injury Associated With Severe Liver DysfunctionnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullResultsnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnullnull
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