Acute kidney injury (AKI) is common in patients with severe hepatic failure and is
associated with significant morbidity and mortality. Ischemia and inflammation are
the hallmarks of the pathophysiology of kidney injury in cirrhosis.
Additionally, an important nonvasomotor mechanism of AKI in cirrhosis is the toxicity
of cholephiles, often known as bile cast nephropathy, with histological evidence of
tubular bile cast formation and tubular epithelial injury. Recently, an increasing
number of cases have been described from kidney biopsies, although most cases included
other causes of AKI, such as hepatorenal syndrome. Here, we report a case of bile
cast nephropathy in a patient with obstructive cholestasis caused by choledocholithiasis,
without evidence of hepatorenal syndrome. This is an excellent teaching case, particularly
to the nephrology trainee, and the teaching points are highlighted in Table 1.
Distinct teaching points for kidney trainee audience
• Bile cast nephropathy has been a largely forgotten diagnosis as a cause of acute
kidney injury and is diagnosed via a kidney biopsy.
• Bile cast nephropathy is promoted by associated kidney ischemia, but severe isolated
cholestasis is sufficient to induce its occurrence.
• Bile cast nephropathy represents a spectrum of renal injury from proximal tubulopathy
to intrarenal bile cast formation found in patients with severe liver dysfunction.
• The management of bile cast nephropathy is through normalization of bilirubinemia,
which may require time on renal replacement therapy.
A 61-year-old man was admitted to the Royal Brisbane and Women’s Hospital in April
2018, with fatigue, anorexia, and severe jaundice. He had a background of T3N0 transitional
cell bladder carcinoma, bilateral retinoblastoma, and multiple malignant melanomas.
Before his admission, his baseline kidney function was normal with a serum creatinine
of 86 μmol/l (normal 60 μmol/l to 120 μmol/l) (corresponding to estimated glomerular
filtration rate of greater than 90 ml/min per 1.73 m2 as calculated by the Chronic
Kidney Disease Epidemiology Collaboration creatinine equation, which is the normal
reference range). Blood pressure on admission was 110/70 mm Hg and heart rate was
68 beats per minute regularly regular. He had no fever but was oliguric. His skin
was markedly jaundiced and scleral icterus was present, but he demonstrated no peripheral
stigmata of chronic liver disease. His abdomen was not tender or peritonitic and there
was no evidence of ascites. Laboratory tests revealed a cholestatic picture with increased
total bilirubin (260 mg/dl) (normal <20 mg/dl), alkaline phosphatase (1070 IU/l) (normal
30–110 IU/l), and γ-glutamyltranspeptidase (450 IU/l) (normal <38 IU/l) levels. Serum
creatinine level was elevated at 463 μmol/l (estimated glomerular filtration rate
11 ml/min per 1.73 m2 as calculated by the Chronic Kidney Disease Epidemiology Collaboration
creatinine equation). C-reactive protein level was 4.5 mg/l (normal <5 mg/l). Autoimmune
and infectious causes were excluded. Proteinuria was measured at protein excretion
of 1.1 g per 24 hours (normal <15 mg per 24 hours). There was no microhematuria. Computed
tomography of the abdomen and pelvis without injection of iodine contrast did not
reveal an etiology. A magnetic resonance cholangiopancreatography showed obstructive
cholestasis with intrahepatic and extrahepatic dilated bile ducts caused by common
bile duct stones. In the absence of signs of portal hypertension and with preserved
natriuresis (sodium urinary excretion, 95 mmol/l), hepatorenal syndrome was excluded.
The patient’s kidney dysfunction progressed, and he became acidemic and oliguric,
requiring commencement of hemodialysis via a central catheter.
A kidney biopsy was subsequently performed. The renal cortical tissue sample measured
0.7 cm and included 23 glomeruli of which 3 were globally sclerosed (Figure 1). The
remaining glomeruli were normal by light microscopy. They did not show mesangial or
endocapillary hypercellularity. There were no crescents or necrotizing lesions, and
no lesions of segmental sclerosis were identified. Arterial vessels showed mild fibro-intima
thickening. There was no vasculitis. There was no discernible tubular atrophy or interstitial
fibrosis. Many of the tubules contained yellow to green casts, some of which were
birefringent when viewed under polarized light. There were additional features of
tubular injury with epithelial flattening, detachment of cells into the lumen, and
occasional mitotic figures. The interstitium was edematous and contained a relatively
mild but diffuse infiltrate of chronic inflammatory cells, including eosinophils.
In addition, there appeared to be a few small non-necrotizing granulomata. There was
no immunofluorescence directed against IgG, IgA, IgM, complement components C3 and
C1q, or κ and λ light chains. The diagnosis of bile cast nephropathy in the setting
of obstructive cholestasis, most likely caused by common bile duct stones, was made.
Three tubules contain brown granular casts with obstruction of their lumen. Several
adjacent tubules also contain golden brown cytoplasmic pigment. Hematoxylin and eosin
stain (original magnification ×200).
Endoscopic retrograde cholangiopancreatography with sphincterotomy and stent insertion
was performed with extensive sludge noted but no stones were found at the time of
the procedure. A significant decrease in serum bilirubin levels occurred after the
stent insertion, accompanied by a reduction in serum creatinine (Figure 2). Three
months after the occurrence of the AKI, kidney function had recovered to close to
baseline, with a serum creatinine level of 115 μmol/l (corresponding estimated glomerular
filtration rate 67 ml/min per 1.73 m2, as calculated by Chronic Kidney Disease Epidemiology
Collaboration creatinine equation).
Serum creatinine and bilirubin throughout patient admission.
This case is a histologic description of bile cast nephropathy in the setting of cholestasis
without underlying hepatopathy. The mechanism by which bile cast nephropathy occurs
is controversial, but has been reported in the literature. Kidney injury combined
with marked cholestasis may result from the precipitation of cholephiles in renal
tubules with toxicity on the epithelial cells.
The formation of casts may be secondary to the poor water solubility of cholephiles
and/or the limits of absorption in the proximal tubules, above which casts may form
and cause tubular obstruction.
Bile casts are conventionally found in the distal tubule, classically at the level
of the aquaporin 2−positive collecting duct,4, 5 which may be the result of a higher
urinary concentration caused by water reabsorption or lower urinary pH, subsequently
decreasing bile cast solubility.
studied the effects of cholemia with or without renal ischemia and showed that 2 days
of isolated cholemia induced only slight and insignificant morphologic changes in
the kidneys and that lesions were more severe with concomitant ischemia.
Hyperbilirubinemia has additionally been shown to attenuate the development of angiotensin
II−induced arterial hypertension by reducing the production of superoxide
and sodium reabsorption in the thick ascending loop of Henle.8, 9 Bilirubin may also
cause deleterious effects on kidney cells. Using cortical slices of kidney, another
study showed that bilirubin was taken up by renal epithelial cells via the organic
anion transport system and, within the cell, inhibit adenosine triphosphate production.
Lower adenosine triphosphate levels were in turn associated with mitochondrial structural
defects, which led to increased permeability of cell membranes, resulting in modified
electrolyte content and cell volume.
In summary, bile cast nephropathy appears to be promoted by associated kidney ischemia,
but severe isolated cholestasis may be sufficient to induce its occurrence. AKI in
these cases is most likely due to epithelial cell damage and tubular obstruction caused
by bile casts. Normalization of bilirubinemia in the aforementioned patient may have
led to complete kidney function recovery.
Written informed consent was obtained from the patient for publication of this case
report and any accompanying images. A copy of the written consent is available for
review by the Editor-in-Chief of this journal.
All the authors declared no competing interests.