Cholemic Nephrosis: An Autopsy Study of a Forgotten Entity
Valli PRIYAA1, Bheemanathi Hanuman SRINIVAS2, Debasis GOCHHAIT2, Rajesh NACHIAPPA GANESH2, Bhawana A BADHE2, PS PRIYAMVADA3, Deepak AMALNATH4, Siddhartha DAS5, Kusa Kumar SHAHA5
1Department of Pathology, Indira Gandhi Medical College and Research Institute, PUDUCHERRY, INDIA
2Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research, PUDUCHERRY, INDIA
3Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education and Research, PUDUCHERRY, INDIA
4Department of Medicine, Jawaharlal Institute of Postgraduate Medical Education and Research, PUDUCHERRY, INDIA
5Department of Forensic Medicine and Toxicology, Jawaharlal Institute of Postgraduate Medical Education and Research, PUDUCHERRY, INDIA
Keywords: Bile, Toxin, Nephropathy
The aim of the study is to do a clinicopathologic study of post mortem kidney biopsies with significant deposition of bilirubin pigment
within tubular epithelial cells and in the lumen of distal tubules as a bile cast.
Material and Method: All post mortem specimens with acute tubular necrosis, with the presence of bile casts in tubules or bile pigment deposition
in the tubular epithelium during the period 2015-2018 were examined for gross and histopathology along with biochemical parameters and viral
Results: Bile casts with sloughed renal tubular epithelial cells and occasional macrophages were present in the distal convoluted tubule in 78.6%
of biopsies (11/14). The plugging of distal convoluted tubule with casts was similar to that seen in myeloma and myoglobin cast nephropathies.
Bilirubin pigment deposition was present in 35.7% (5/14) of cases. The frequency of bile casts in each biopsy was variable and it did not have
any association with serum bilirubin levels or etiology of liver dysfunction. A striking difference from earlier studies is the high number of
toxin-induced liver damage including six cases of paraquat and 2 cases of yellow phosphorus poisoning.
Conclusion: This study proves importance of the bile cast nephropathy as a reason for kidney injury, especially with varied hepatotoxic etiologies,
especially paraquat and yellow phosphorus.
Acute kidney injury as a result of hepatic failure is a
well-known entity. Hepatorenal syndrome (HRS) (Type
I and Type II), a functional, potentially reversible form
of renal failure resulting from severe vasoconstriction of
the splanchnic vascular bed, is considered as the central
pathophysiologic mechanism behind the kidney failure (1,
2). However, it is reported that only 50% of patients respond
to the standard treatment protocol for HRS. Hence factors
other than a functional disorder might be operational (3-5).
Cholemic (bile) nephrosis or bile cast nephropathy is
an overlooked etiology for kidney injury in liver failure.
Even though this entity was described as early as the
1940s, subsequently, the term had almost disappeared
from medical literature (6). The last decade witnessed a
resurgence in information, mostly as case reports and
case series (7, 8). Cholemic (bile) nephrosis refers to renal
dysfunction as a result of injury to renal tubules due to
bilirubin, along with a spectrum of morphological changes.
Cholephils other than bilirubin, including bile acids, are believed to be nephrotoxic (9,10). Mouse experiments with
bile duct ligation have proved the same (11). Even though
the traditional descriptions came from post mortem studies
in subjects with alcoholic cirrhosis, bile casts have been
described in other conditions like biliary cirrhosis and
acute on chronic liver failure (ACLF) (12,13). These casts
cause tubular obstruction and toxicity in a manner akin
to that of myeloma or myoglobin casts (1). Bilirubin levels
were variably correlated to the presence of bile casts. A firm
counter-argument is that these casts might be an incidental
finding resulting from reduced glomerular filtration and
urinary stasis (14). The current understanding of cholemic
nephrosis is incomplete due to the lack of kidney biopsy
studies in hepatic failure. In this series, we describe the
histopathology of cholemic nephrosis and its correlation
with the etiological and biochemical parameters.
The aim of this study is to do a clinicopathologic study of
post mortem kidney biopsies with significant deposition of
bilirubin pigment within tubular epithelial cells and in the
lumen of distal tubules as a bile cast.
Data was taken from the medical records maintained by
the department of pathology. All post mortem specimens
with acute tubular necrosis, with the presence of bile
casts in tubules or bile pigment deposition in the tubular
epithelium during the period 2015-2018, were included.
The data was collected in a predefined proforma. The
post mortem examinations were conducted either as a
medicolegal requirement or because of a pathological
autopsy requested by the treating clinician. The specimens
were retrieved and analyzed by two pathologists blind to
the clinical data. Gross examination of the liver and both
kidneys was done, followed by microscopic examination.
Two sections each were studied for liver and kidneys,
and they were stained with H&E, PAS, Perls, and Hall’s
stain. Reticulin and Masson’s trichrome stains were also
performed on liver biopsy to assess the architecture and
fibrosis. Liver architecture, type of hepatocyte injury,
portal tract changes, and presence/absence of cirrhosis
were studied. Kidney biopsies were assessed for presence
of bile pigment/casts, glomerular changes, acute tubular
injury, interstitial scarring, and blood vessel changes. The
antemortem clinical details, including the etiology of liver
failure and duration, liver and renal function tests, viral
markers, and urine examination results were collected
A total of 14 cases of bile cast nephropathy/bile nephrosis
were identified during the study period. The median age
was 30(IQR: 23-52). The etiology for hepatic failure was
alcoholic cirrhosis (3), biliary cirrhosis (1), toxins (8), snake
envenoming (1), and fulminant hepatitis (1). Antemortem
investigations were available for twelve patients.
All the patients had hyperbilirubinemia with elevated liver
enzymes. All patients tested negative for Hepatitis A, B, C,
E, and Epstein Barr virus. Serum creatinine median was
2.9(IQR, 1.1-2.4). Proteinuria and hematuria were noted
in three and two patients, respectively. The proteinuria was
subnephrotic, and quantification was not done. Microscopy
of urine sediment showed the presence of bile cast in one
case, and granular casts in two cases. Pyuria was present in
five of seven cases (Table I).
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|Table I: Biochemical investigations in the fourteen cases of bile
Gross Examination and Histopathology
Micronodular cirrhosis was present in 6 cases, while the
remaining cases showed only greenish color with bile staining. No focal lesions were identified in the liver. The
kidneys also showed bile staining (yellowish-green) in 8
cases predominantly in the medulla in contrast to the cortex.
The rest was unremarkable on gross examination. None of
them showed evidence to suggest glomerulonephritis.
On microscopic examination, evidence of cirrhosis was
present in 6 cases (alcoholic cirrhosis in 4, biliary cirrhosis
and cryptogenic cirrhosis one). One of these six cases
also had macrovesicular steatosis, and others had mild
to moderate lymphocytic infiltration in the portal tract.
Six specimens with a history of rodenticide poisoning
showed cholestasis along with central venous congestion
(Figure 1A-D, 2A-D). Two cases (fulminant hepatitis, snake
envenoming) showed submassive necrosis. Two cases of
yellow phosphorus were also studied and showed nodule
formation and cholestasis in one and feathery degeneration
with macrovesicular stetosis in the other (Figure 3A-D).
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|Figure 1: Case 3: A case of paraquat poisoning demonstrating A) Greenish discoloration of liver. B) Liver biopsy demonstrating
cholestasis and central venous congestion (H&E; x100). C) Kidney biopsy demonstrating bile pigment within proximal tubule (H&E;
x200). D) Kidney biopsy with bile casts in distal tubules (H&E; x400).
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|Figure 2: Case 5: A case of paraquat poisoning: A) Bile cast within distal tubules (H&E; x200). B) Bile cast highlighted emerald green in
Hall stain (Hall’s stain; x400). C) Greenish discolouration of kidney due to oxidation of bilirubin to biliverdin. D) Liver biopsy showing
macrovesicular steatosis (H&E; x200).
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|Figure 3: Case 14: Yellow phosphorus poisoning with A) Liver biopsy demonstrating bile ductular proliferation (H&E; x100). B) Liver
biopsy with bile ductular proliferation (CK19 immunostain; x200). C) Urine sediment examination showing bile cast along with sloughed
epithelial cells(Wet mount; x400). D) Kidney biopsy demonstrating acute tubular necrosis with loss of brush border in proximal tubules
The kidneys showed acute tubular injury in all 14 cases,
ranging from loss of brush border to tubular epithelial cell
necrosis. Only bile casts were noted in nine, bile pigments
alone in three, and both bile casts and bile pigments in
two. These were reddish-brown granular to greenishyellow
acellular in nature and located predominantly in
the distal tubules. Hall’s stain highlighted these casts and
helped differentiate from myoglobin and hemoglobin casts,
which may have similar morphology. Additionally, Perl’s
stain was also negative. Some of these casts were associated
with sloughing of the tubular epithelium. However, giant
cell reaction, as seen conspicuously in myeloma cast
nephropathy, was absent. Besides, two cases revealed
sharp ends on these bile casts, with PAS stain. Deposition
of bile pigment along the proximal convoluted tubule was
observed in five instances. Glomeruli were unremarkable in
all. Age-related glomerulosclerosis and blood vessel changes
were noted in five cases. Interstitial scarring in the form of
tubular atrophy and fibrosis was present in four cases. The
individual patient characteristics are given in Table II.
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|Table II: Cases of cholemic nephrosis (bile cast nephropathy) with histopathological, biochemical findings.
The current study examined the renal and liver pathologies
in patients who succumbed to chronic liver disease and
hepatic failure. The study showed the presence of bile
casts and bile pigments in cirrhosis of various etiologies,
cholestasis as well as hepatic necrosis. Renal pathologies,
other than the hepatorenal syndrome, are often overlooked
in patients with liver dysfunction (13). Performing a kidney
biopsy might not be feasible in these patients considering
the presence of coagulopathy. Post mortem biopsy data
points towards the existence of other pathologies that
would coexist in these patients. The current understanding
of the role of bile as a nephrotoxin has significant lacunae
owing to the limited published literature.
The resurgence of literature on the potential nephrotoxicity
of bile casts started with van Slambrouck et al. reporting the presence of bile casts in around 54% of kidney biopsy
specimens (1). The samples were mostly post mortem, and
all subjects with alcoholic liver disease and kidney failure
had bile casts in the kidney. The prevalence of bile casts
was lesser among subjects with other etiologies. They also
noticed that a higher proportion of subjects with a diagnosis
of HRS had bile casts compared to those without HRS. They
also reported considerably higher bilirubin levels in those
with bile casts; however, there were no differences in the
severity of renal failure or transaminitis (1).
Another post mortem series reported a prevalence of 55%
in cirrhotic patients. Unlike the reports of van Slambrouck
et al., they found a higher incidence of bile casts among
patients with chronic liver disease secondary to HCV
infection. The absolute values of bilirubin were much lower
(Mean value:10 mg/dL) compared to those reported by van Slambrouck et al. (1, 15). Another series by Nayak et
al. reported a prevalence of 44.8%, with 2.5-fold higher
frequency in subjects with acute on chronic liver failure
compared to cirrhosis (13).
Again bilirubin and severity of liver failure assessed by MELS
score were the only predictors of the presence of bile casts.
From the above studies, it appears that the most important
determinant for the presence of bile casts is the degree of
hepatic dysfunction. However, it should be recalled that
serum creatinine is often unreliable in subjects with liver
failure, due to the lower muscle mass as well as reduced
hepatic production. None of the studies have reported any
correlation with urinary findings. One of the cases in the present study showed bile-stained casts along with renal
tubular epithelial cells. Krones et al. also noted similar
findings, and they correlated with renal biopsy findings of
bile cast nephropathy (12). There are multiple case reports
describing the presence of bile casts in obstructive jaundice,
anabolic steroid use, etc. (12).
Renal Gross and Biopsy Findings
Most of the studies report the greenish staining of renal
parenchyma with accentuation in the medulla, which is
due to the higher concentration of bilirubin in DCT. van
Slambrouk et al. noted it in 17 % of cases and it did not
correlate with any particular etiology of liver failure (1).
This finding is seen in 57.1% (8/14) of our cases.
Renal biopsy showed presence of bile casts with sloughed
renal tubular epithelial cells and occasional macrophages
in the distal convoluted tubule in 78.6% of the biopsies
(11/14). The plugging of DCT with casts was similar to that
seen in myeloma and myoglobin cast nephropathies. The
frequency of bile casts in each biopsy was variable and it
did not have any association with serum bilirubin levels or
etiology of liver dysfunction. van Slambrouk et al. noted
bile casts in 51.2% (21/41) of which 15/21 were confined to
the distal nephrons whereas 6 cases involved both proximal
and distal nephron segments. None of the fourteen cases
in the present study showed bile casts in the proximal
Nayak et al. studied cases of decompensated cirrhosis, acute
on chronic liver failure (ACLF), in which 57/127 (44.8%) demonstrated bile casts (13). The other changes noted
were interstitial edema (19.3%), fibrosis (10.5), and tubular
atrophy (1.7%) Additionally, bilirubin deposition was seen
in 35.7% (5/14) of the cases.
Initial suspicion of bile casts was made on H/E, PAS section
which showed reddish brown granular casts. They were
confirmed with halls histochemical stain that showed
emerald green staining in bile casts. It is observed in some
studies that Hall’s stain underestimated the number of bile
casts and a certain concentration of bilirubin was needed
for it to be interpreted as positive (15). In present study
also we observed that Hall’s stain showed variable positivity
within the same renal biopsy and between different cases,
possibly as a result of different concentrations of serum
bilirubin as well as different GFR values and urinary stasis.
Various studies have been done on renal pathological
changes in hepatic failure either due to acute or chronic
causes. Hepatorenal syndrome is thought to be the most
important cause of renal dysfunction in hepatic failure.
However, studies by van Slambrouk and Nayak et al. have
suggested other findings including bile cast nephropathy (1,
13). An important difference from the present studies is the
striking number of toxin-induced liver damage. Six cases of paraquat and 2 cases of yellow phosphorus poisoning
which resulted in bile cast nephropathy have been studied.
Paraquat poisoning has variable effects at different doses
and its toxicity to the liver is well known. In present study
also most of the cases (5/6) showed cholestasis and one
case showed sub massive necrosis. However, the effect of
paraquat in renal biopsy has not been widely reported. Few
papers demonstrate acute tubular injury alone as a cause for renal dysfunction (16, 17). We have found a large number
of such patients to demonstrate bile cast nephropathy. This
could prove an important factor in the management of such
In conclusion, current understanding of cholemic nephrosis
is incomplete due to the lack of kidney biopsy studies in
hepatic failure. This study proves the importance of acute
kidney injury along with bile cast nephropathy as a reason
for the same with varied hepatotoxic etiologies, especially
paraquat and yellow phosphorus. A larger volume of
antemortem and post mortem studies are essential to avoid
ignorance of this old forgotten entity.
CONFLICT of INTEREST
The authors declare no conflict of interest.
Concept: VP, BHS, RNG, PSP, Design: VP, BHS, RNG,
PSP, Data collection or processing: VP, BHS, DG, RNG,
BAB, PSP, DA, SDAS, KKS, Analysis or Interpretation:
VP, BHS, RNG, Literature search: VP, BHS, DG, RNG,
Writing: VP, BHS, Approval: VP, BHS, DG, RNG, BAB,
DA, Das S, KKS, PSP.
1) van Slambrouck CM, Salem F, Meehan SM, Chang A. Bile cast
nephropathy is a common pathologic finding for kidney injury
associated with severe liver dysfunction. Kidney Int. 2013;84:192-7.
2) Wadei HM, Mai ML, Ahsan N Gonwa TA. Hepatorenal syndrome:
Pathophysiology and management. Clin J Am Soc Nephrol 2006;
3) Salerno F, Gerbes A, Ginčs P, Wong F, Arroyo V. Diagnosis,
prevention and treatment of hepatorenal syndrome in cirrhosis.
4) McCormick PA, Donnelly C. Management of hepatorenal
syndrome. Pharmacol Ther. 2008;119:1-6.
5) Nazar A, Pereira GH, Guevara M, Martín-Llahi M, Pepin MN,
Marinelli M, Solá E, Baccaro ME, Terra C, Arroyo V, Ginčs P.
Predictors of response to therapy with terlipressin and albumin
in patients with cirrhosis and type 1 hepatorenal syndrome.
6) Thompson LL, Frazier WD, Ravdin IS. The renal lesion in
obstructive jaundice. Am J Med Sci. 1940;199:305–12.
7) Sequeira A, Gu X. Bile cast nephropathy: An often forgotten
diagnosis. Hemodial Int. 2015;19:132-5.
8) Pitlick M, Rastogi P. All that glitters yellow is not gold: Presentation
and pathophysiology of bile cast nephropathy. Int J Surg Pathol.
9) Topuzlu C, Stahl WM. Effect of bile infusion on the dog kidney. N
Engl J Med. 1966;274:760-3.
10) Gollan JL, Billing BH, Huang SN. Ultrastructural changes in the
isolated rat kidney induced by conjugated bilirubin and bile acids.
Br J Exp Pathol. 1976;57:571-81.
11) Fickert P, Krones E, Pollheimer MJ, Thueringer A, Moustafa T,
Silbert D, Halilbasic E, Yang M, Jaeschke H, Stokman G, Wells
RG, Eller K, Rosenkranz AR, Eggertsen G, Wagner CA, Langner
C, Denk H, Trauner M. Bile acids trigger cholemic nephropathy
in common bile-duct-ligated mice. Hepatology. 2013;58:2056-69.
12) Krones E, Wagner M, Eller K, Rosenkranz AR, Trauner M, Fickert
P. Bile acid-induced cholemic nephropathy. Dig Dis. 2015;33:367-75.
13) Nayak SL, Kumar M, Bihari C, Rastogi A. Bile cast nephropathy in
patients with acute kidney injury due to hepatorenal syndrome:
A postmortem kidney biopsy study. J Clin Transl Hepatol.
14) Heyman SN, Darmon D, Ackerman Z, Rosenberger C, Rosen S.
Bile cast nephropathy. Kidney Int. 2014;85:479.
15) Foshat M, Ruff HM, Fischer WG, Beach RE, Fowler MR, Ju H,
Aronson JF, Afrouzian M. Bile cast nephropathy in cirrhotic
patients: Effects of chronic hyperbilirubinemia. Am J Clin Pathol.
16) Soontornniyomkij V, Bunyaratvej S. Fatal paraquat poisoning: A
light microscopic study in eight autopsy cases. J Med Assoc Thai.
1992;75 Suppl 1:98-105.
17) Ravichandran R, Amalnath D, Shaha KK, Srinivas BH. Paraquat
poisoning: A retrospective study of 55 patients from a tertiary care
center in Southern India. Indian J Crit Care Med. 2020;24:155-9.