Hemodialysis International 2014; ••:••–••
Case Report
Bile cast nephropathy: An often forgotten diagnosis Adrian SEQUEIRA,1 Xin GU2 1
Division of Nephrology and Hypertension, Department of Medicine, 2Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
Abstract High bilirubin levels are nephrotoxic. Bilirubin can cause a functional proximal tubulopathy or may precipitate into casts associated with acute tubular injury. This condition is known as bile cast nephropathy. The kidney injury is generally reversible if bilirubin levels are decreased early. We present a case wherein an alcoholic patient presented with high bilirubin levels and anuric acute kidney injury. The initial urine analysis suggested intrinsic renal disease. A kidney biopsy, performed a few days after the initiation of dialysis, demonstrated the presence of bile casts along with acute tubular injury. The patient however continued to be dialysis dependent inspite of initiating prednisolone to treat acute alcoholic hepatitis. Key words: Bilirubin, bile, cast, tubulopathy
INTRODUCTION In a jaundiced patient with acute renal failure, the etiology of the renal failure commonly includes hypovolemia, infection, and acute tubular necrosis. Besides these, high levels of bilirubin can cause renal failure. In the past, this was known as bile or cholemic nephrosis. The contribution of this entity to our understanding of the various mechanisms of renal failure in a jaundiced patient has largely been forgotten.1 We present one such case and review its pathophysiology.
CASE HISTORY A 41-year-old woman, with a long-standing history of alcohol and tobacco use, was admitted with a 4-month Correspondence to: A. Sequeira, MD, FACP, FASN, Division of Nephrology and Hypertension, Department of Medicine, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA. E-mail: [email protected] Conflict of Interest: None Financial Disclosure: None
history of progressive abdominal distension and jaundice. For the last 3 weeks prior to her admission, she also suffered from exertional shortness of breath, episodes of black stools, poor oral intake, and decreased urine output. She had been seen 11 months earlier and was diagnosed with alcoholic hepatitis and ascites based on a history of heavy alcohol intake, jaundice and elevated liver enzymes. No liver biopsy was performed. She was advised to stay off alcohol and subsequently placed on aldactone and furosemide. Six months later, her laboratory data revealed a total bilirubin of 2.7 mg/dL and creatinine of 0.8 mg/dL. Since then, she had continued to consume alcohol daily along with ibuprofen for symptomatic ovarian cysts. On exam, she was alert and oriented, afebrile, with a blood pressure of 90/60 mmHg and pulse oximetry of 95% on room air. Scleral icterus was prominent. The abdomen was distended but soft with ascites. No pedal edema or other stigmata of chronic liver disease were noted. Laboratory data were as follows: hemoglobin 8.6 mg/ dL, white blood cell (WBC) count 19 K/uL (no eosinophilia), sodium 131 mmol/L, CO2 19 mmol/L, blood urea nitrogen 30 mg/dL, creatinine 9.2 mg/dL, albumin 1.6 g/ dL, glucose 85 mg/dL, total bilirubin 23.1 mg/dL, direct
© 2014 International Society for Hemodialysis DOI:10.1111/hdi.12169
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Sequeira and Gu
bilirubin 20 mg/dL, aspartate aminotransferase 119 U/L, alanine aminotransferase 55 U/L, alkaline phosphatase 180 U/L and international normalized ratio 2.8. Urine appeared greenish with proteinuria, glycosuria, 10–20 red blood cells (RBCs)/hpf, 5–10 WBCs/hpf along with bilirubin crystals. No RBC casts were found. Spot urine sodium was 47. We were unable to quantify the proteinuria, as she was anuric. Ultrasound revealed a nodular fatty liver with kidneys of normal size and echogenicity. Blood and urine cultures were negative and there was no evidence of peritonitis. Endoscopy revealed candidal esophagitis with gastric ulcers and portal gastropathy. A 55–60% ejection fraction was noted on echocardiogram. She was started on intravenous fluids and albumin initially but with no improvement in creatinine and urine output, midodrine with octreotide was initiated. Over the next 4 days, with no improvement, dialysis was initiated. Since the etiology of her renal failure was unclear, 4 days after dialysis was initiated, a decision to perform a kidney biopsy (after correction of the coagulopathy) was made.
PATHOLOGY The biopsy revealed renal cortex containing six to seven glomeruli in multiple levels of hematoxylin and eosin, periodic acid Schiff, Jones’ silver and Masson’s trichrome stained sections. No renal medulla was present. All glomeruli were essentially normal with open capillary loops and regular, smooth capillary membranes. There was no evidence of interstitial fibrosis or inflammatory infiltration. Several proximal tubules contained brownish-ridged bile casts, associated with tubular epithelial injury (Figure 1). Some tubules were filled with granular pigmented bile material. Similar pigmented materials were also present in the reabsorption droplets within tubular epithelial cytoplasm (Figure 2). The bile casts were highlighted by Hall’s bile stain (grey-green color) that showed clusters of casts with rigid and fractured appearance (Figure 3). As shown in Figure 1, features of tubular epithelial injury were present in association with accumulation of intratubular bile casts. The injured epithelial cells were detached from the tubular basement membrane. Obliteration of tubular lumina by cellular debris, detached cells and bile casts were noted in some tubules. Nevertheless, there was no rupture of tubular basement membranes. No casts were identified in the sections containing distal tubules. Once the biopsy result was obtained, she was started on prednisolone for the treatment of acute alcoholic hepatitis while midodrine and octreotide were discontinued. Her bilirubin gradually decreased to 16 mg/dL with
2
Figure 1 Bile casts (white arrows) within tubular lumina along with features of tubular epithelial injury. In addition to casts, the tubules also contain cellular debris and detached epithelial cells.
an improvement in urine output (up to 500 cc/day), although she still needed dialysis for poor clearance.
DISCUSSION The term cholemic or bile nephrosis signifies renal injury secondary to the constituents of bile. Urinary sediment consisting of leucocytes and renal epithelial cells containing granular or crystalline bilirubin or with yellowish bile stained cytoplasm along with bile stained casts (granular, waxy or epithelial) is noted.2–4 Hematuria and proteinuria
Figure 2 Brownish granular bile material obliterating the lumen of the tubule (black arrow). Bile material is also present within the epithelial cytoplasm (white arrow).
Hemodialysis International 2014; ••:••–••
Bile cast nephropathy
Figure 3 Hall’s stain demonstrating grayish-green color intratubular bile casts (white arrow).
are minimal.3 The histologic picture is characterized by tubules filled with degenerated epithelial cells and bile pigment casts. Some tubules may be dilated and obstructed by these elements. Features of acute tubular injury may also be seen.3 The risk of acute tubular injury increases when bilirubin levels are greater than 20 mg/dL especially in the presence of hypoalbuminemia and acidosis.5,6 This leads to decreased binding of bile acids and bilirubin to albumin, thereby allowing them to be filtered by the glomerulus with subsequent increased tubular exposure.7,8 Proximal tubular dysfunction may occur prior to structural changes manifesting as glucosuria, phosphaturia, uricosuria, α-1, and β-2 microglobulinuria.9,10 In patients with high bilirubin levels, a two-phase response is noted depending on the absence or presence of hypoalbuminemia—natriuresis in the former and sodium retention in the latter.5 The mechanisms responsible for tubular dysfunction include uncoupling of mitochondrial phosphorylation (thereby decreasing ATPase activity) by bilirubin11 and oxidative damage of tubular cell membranes as well as inhibition of Na-H and Na-K pumps in the tubular cell membranes by bile acids.10,12 Cholemic nephrosis is reversible provided bilirubin levels are reduced early. This recovery is however delayed if there is extensive bile cast formation.1 In 2006, Betjes and Bajema suggested the term “jaundice related nephropathy” to describe the spectrum of functional and structural injury associated with this condition.12 Later, van Slambrouck et al. suggested the term “bile cast nephropathy” to specifically describe the presence of bile casts causing tubular toxicity and obstruction.1 Interestingly, some patients with hepatorenal syndrome (HRS) also demonstrate bile stain-
Hemodialysis International 2014; ••:••–••
ing of tubular cells and bile casts on biopsy.1 While HRS is generally considered a functional abnormality in the presence of a normal kidney biopsy, the co-existence of bile casts in such a situation may delay renal recovery. Our patient was admitted with acute renal failure in the setting of acute alcoholic hepatitis. The lack of improvement with hydration raised the possibility of acute tubular necrosis and HRS as well. She, however, failed to respond to midodrine and octreotide. In the face of persistent hypotension, HRS can evolve into acute tubular necrosis that will not respond to vasoconstrictors.9 The urine analysis suggested the possibility of intrinsic renal disease. A kidney biopsy was therefore needed to ascertain the diagnosis and prognosis. With the diagnosis established, prednisolone was initiated for the treatment of acute alcoholic hepatitis with the hope of reducing bilirubin levels. Although the bilirubin levels decreased and her urine output improved, she still needed dialysis for clearance. This may be secondary to the co-existent acute tubular necrosis. In summary, bile cast nephropathy should be considered in a patient with acute renal failure, high bilirubin levels and features of proximal tubulopathy. The diagnosis is confirmed by biopsy.
Manuscript received January 2014; revised March 2014.
REFERENCES 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; 84:192–197. 2 Haessler H, Rous P, Broun GO. The renal elimination of bilirubin. J Exp Med. 1922; 35:533–552. 3 Elsom KA. Renal function in obstructive jaundice. Arch Intern Med. 1937; 60:1028–1033. 4 Eknoyan G. Letter: Renal disorders in hepatic failure. Br Med J. 1974; 2:670. 5 Sitprija V, Kashemsant U, Sriratanaban A, Arthachinta S, Poshyachinda V. Renal function in obstructive jaundice in man: Cholangiocarcinoma model. Kidney Int. 1990; 38:948–955. 6 Wardle EN. Renal failure in obstructive jaundice— Pathogenic factors. Postgrad Med J. 1975; 51:512– 514. 7 Odell GB. Influence of pH on distribution of bilirubin between albumin and mitochondria. Exp Biol Med. 1965; 120:352–354. 8 Odell GB. The distribution of bilirubin between albumin and mitochondria. J Pediatr. 1966; 68:164–180.
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9 Rector WG Jr, Kanel GC, Rakela J, Reynolds TB. Tubular dysfunction in the deeply jaundiced patient with hepatorenal syndrome. Hepatology. 1985; 5:321–326. 10 Bairaktari E, Liamis G, Tsolas O, Elisaf M. Partially reversible renal tubular damage in patients with obstructive jaundice. Hepatology. 2001; 33:1365–1369.
4
11 Fogarty BJ, Parks RW, Rowlands BJ, Diamond T. Renal dysfunction in obstructive jaundice. Br J Surg. 1995; 82:877–884. 12 Betjes MG, Bajema I. The pathology of jaundice-related renal insufficiency: Cholemic nephrosis revisited. J Nephrol. 2006; 19:229–233.
Hemodialysis International 2014; ••:••–••
Case Report
Bile cast nephropathy: An often forgotten diagnosis Adrian SEQUEIRA,1 Xin GU2 1
Division of Nephrology and Hypertension, Department of Medicine, 2Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA
Abstract High bilirubin levels are nephrotoxic. Bilirubin can cause a functional proximal tubulopathy or may precipitate into casts associated with acute tubular injury. This condition is known as bile cast nephropathy. The kidney injury is generally reversible if bilirubin levels are decreased early. We present a case wherein an alcoholic patient presented with high bilirubin levels and anuric acute kidney injury. The initial urine analysis suggested intrinsic renal disease. A kidney biopsy, performed a few days after the initiation of dialysis, demonstrated the presence of bile casts along with acute tubular injury. The patient however continued to be dialysis dependent inspite of initiating prednisolone to treat acute alcoholic hepatitis. Key words: Bilirubin, bile, cast, tubulopathy
INTRODUCTION In a jaundiced patient with acute renal failure, the etiology of the renal failure commonly includes hypovolemia, infection, and acute tubular necrosis. Besides these, high levels of bilirubin can cause renal failure. In the past, this was known as bile or cholemic nephrosis. The contribution of this entity to our understanding of the various mechanisms of renal failure in a jaundiced patient has largely been forgotten.1 We present one such case and review its pathophysiology.
CASE HISTORY A 41-year-old woman, with a long-standing history of alcohol and tobacco use, was admitted with a 4-month Correspondence to: A. Sequeira, MD, FACP, FASN, Division of Nephrology and Hypertension, Department of Medicine, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA. E-mail: [email protected] Conflict of Interest: None Financial Disclosure: None
history of progressive abdominal distension and jaundice. For the last 3 weeks prior to her admission, she also suffered from exertional shortness of breath, episodes of black stools, poor oral intake, and decreased urine output. She had been seen 11 months earlier and was diagnosed with alcoholic hepatitis and ascites based on a history of heavy alcohol intake, jaundice and elevated liver enzymes. No liver biopsy was performed. She was advised to stay off alcohol and subsequently placed on aldactone and furosemide. Six months later, her laboratory data revealed a total bilirubin of 2.7 mg/dL and creatinine of 0.8 mg/dL. Since then, she had continued to consume alcohol daily along with ibuprofen for symptomatic ovarian cysts. On exam, she was alert and oriented, afebrile, with a blood pressure of 90/60 mmHg and pulse oximetry of 95% on room air. Scleral icterus was prominent. The abdomen was distended but soft with ascites. No pedal edema or other stigmata of chronic liver disease were noted. Laboratory data were as follows: hemoglobin 8.6 mg/ dL, white blood cell (WBC) count 19 K/uL (no eosinophilia), sodium 131 mmol/L, CO2 19 mmol/L, blood urea nitrogen 30 mg/dL, creatinine 9.2 mg/dL, albumin 1.6 g/ dL, glucose 85 mg/dL, total bilirubin 23.1 mg/dL, direct
© 2014 International Society for Hemodialysis DOI:10.1111/hdi.12169
1
Sequeira and Gu
bilirubin 20 mg/dL, aspartate aminotransferase 119 U/L, alanine aminotransferase 55 U/L, alkaline phosphatase 180 U/L and international normalized ratio 2.8. Urine appeared greenish with proteinuria, glycosuria, 10–20 red blood cells (RBCs)/hpf, 5–10 WBCs/hpf along with bilirubin crystals. No RBC casts were found. Spot urine sodium was 47. We were unable to quantify the proteinuria, as she was anuric. Ultrasound revealed a nodular fatty liver with kidneys of normal size and echogenicity. Blood and urine cultures were negative and there was no evidence of peritonitis. Endoscopy revealed candidal esophagitis with gastric ulcers and portal gastropathy. A 55–60% ejection fraction was noted on echocardiogram. She was started on intravenous fluids and albumin initially but with no improvement in creatinine and urine output, midodrine with octreotide was initiated. Over the next 4 days, with no improvement, dialysis was initiated. Since the etiology of her renal failure was unclear, 4 days after dialysis was initiated, a decision to perform a kidney biopsy (after correction of the coagulopathy) was made.
PATHOLOGY The biopsy revealed renal cortex containing six to seven glomeruli in multiple levels of hematoxylin and eosin, periodic acid Schiff, Jones’ silver and Masson’s trichrome stained sections. No renal medulla was present. All glomeruli were essentially normal with open capillary loops and regular, smooth capillary membranes. There was no evidence of interstitial fibrosis or inflammatory infiltration. Several proximal tubules contained brownish-ridged bile casts, associated with tubular epithelial injury (Figure 1). Some tubules were filled with granular pigmented bile material. Similar pigmented materials were also present in the reabsorption droplets within tubular epithelial cytoplasm (Figure 2). The bile casts were highlighted by Hall’s bile stain (grey-green color) that showed clusters of casts with rigid and fractured appearance (Figure 3). As shown in Figure 1, features of tubular epithelial injury were present in association with accumulation of intratubular bile casts. The injured epithelial cells were detached from the tubular basement membrane. Obliteration of tubular lumina by cellular debris, detached cells and bile casts were noted in some tubules. Nevertheless, there was no rupture of tubular basement membranes. No casts were identified in the sections containing distal tubules. Once the biopsy result was obtained, she was started on prednisolone for the treatment of acute alcoholic hepatitis while midodrine and octreotide were discontinued. Her bilirubin gradually decreased to 16 mg/dL with
2
Figure 1 Bile casts (white arrows) within tubular lumina along with features of tubular epithelial injury. In addition to casts, the tubules also contain cellular debris and detached epithelial cells.
an improvement in urine output (up to 500 cc/day), although she still needed dialysis for poor clearance.
DISCUSSION The term cholemic or bile nephrosis signifies renal injury secondary to the constituents of bile. Urinary sediment consisting of leucocytes and renal epithelial cells containing granular or crystalline bilirubin or with yellowish bile stained cytoplasm along with bile stained casts (granular, waxy or epithelial) is noted.2–4 Hematuria and proteinuria
Figure 2 Brownish granular bile material obliterating the lumen of the tubule (black arrow). Bile material is also present within the epithelial cytoplasm (white arrow).
Hemodialysis International 2014; ••:••–••
Bile cast nephropathy
Figure 3 Hall’s stain demonstrating grayish-green color intratubular bile casts (white arrow).
are minimal.3 The histologic picture is characterized by tubules filled with degenerated epithelial cells and bile pigment casts. Some tubules may be dilated and obstructed by these elements. Features of acute tubular injury may also be seen.3 The risk of acute tubular injury increases when bilirubin levels are greater than 20 mg/dL especially in the presence of hypoalbuminemia and acidosis.5,6 This leads to decreased binding of bile acids and bilirubin to albumin, thereby allowing them to be filtered by the glomerulus with subsequent increased tubular exposure.7,8 Proximal tubular dysfunction may occur prior to structural changes manifesting as glucosuria, phosphaturia, uricosuria, α-1, and β-2 microglobulinuria.9,10 In patients with high bilirubin levels, a two-phase response is noted depending on the absence or presence of hypoalbuminemia—natriuresis in the former and sodium retention in the latter.5 The mechanisms responsible for tubular dysfunction include uncoupling of mitochondrial phosphorylation (thereby decreasing ATPase activity) by bilirubin11 and oxidative damage of tubular cell membranes as well as inhibition of Na-H and Na-K pumps in the tubular cell membranes by bile acids.10,12 Cholemic nephrosis is reversible provided bilirubin levels are reduced early. This recovery is however delayed if there is extensive bile cast formation.1 In 2006, Betjes and Bajema suggested the term “jaundice related nephropathy” to describe the spectrum of functional and structural injury associated with this condition.12 Later, van Slambrouck et al. suggested the term “bile cast nephropathy” to specifically describe the presence of bile casts causing tubular toxicity and obstruction.1 Interestingly, some patients with hepatorenal syndrome (HRS) also demonstrate bile stain-
Hemodialysis International 2014; ••:••–••
ing of tubular cells and bile casts on biopsy.1 While HRS is generally considered a functional abnormality in the presence of a normal kidney biopsy, the co-existence of bile casts in such a situation may delay renal recovery. Our patient was admitted with acute renal failure in the setting of acute alcoholic hepatitis. The lack of improvement with hydration raised the possibility of acute tubular necrosis and HRS as well. She, however, failed to respond to midodrine and octreotide. In the face of persistent hypotension, HRS can evolve into acute tubular necrosis that will not respond to vasoconstrictors.9 The urine analysis suggested the possibility of intrinsic renal disease. A kidney biopsy was therefore needed to ascertain the diagnosis and prognosis. With the diagnosis established, prednisolone was initiated for the treatment of acute alcoholic hepatitis with the hope of reducing bilirubin levels. Although the bilirubin levels decreased and her urine output improved, she still needed dialysis for clearance. This may be secondary to the co-existent acute tubular necrosis. In summary, bile cast nephropathy should be considered in a patient with acute renal failure, high bilirubin levels and features of proximal tubulopathy. The diagnosis is confirmed by biopsy.
Manuscript received January 2014; revised March 2014.
REFERENCES 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; 84:192–197. 2 Haessler H, Rous P, Broun GO. The renal elimination of bilirubin. J Exp Med. 1922; 35:533–552. 3 Elsom KA. Renal function in obstructive jaundice. Arch Intern Med. 1937; 60:1028–1033. 4 Eknoyan G. Letter: Renal disorders in hepatic failure. Br Med J. 1974; 2:670. 5 Sitprija V, Kashemsant U, Sriratanaban A, Arthachinta S, Poshyachinda V. Renal function in obstructive jaundice in man: Cholangiocarcinoma model. Kidney Int. 1990; 38:948–955. 6 Wardle EN. Renal failure in obstructive jaundice— Pathogenic factors. Postgrad Med J. 1975; 51:512– 514. 7 Odell GB. Influence of pH on distribution of bilirubin between albumin and mitochondria. Exp Biol Med. 1965; 120:352–354. 8 Odell GB. The distribution of bilirubin between albumin and mitochondria. J Pediatr. 1966; 68:164–180.
3
Sequeira and Gu
9 Rector WG Jr, Kanel GC, Rakela J, Reynolds TB. Tubular dysfunction in the deeply jaundiced patient with hepatorenal syndrome. Hepatology. 1985; 5:321–326. 10 Bairaktari E, Liamis G, Tsolas O, Elisaf M. Partially reversible renal tubular damage in patients with obstructive jaundice. Hepatology. 2001; 33:1365–1369.
4
11 Fogarty BJ, Parks RW, Rowlands BJ, Diamond T. Renal dysfunction in obstructive jaundice. Br J Surg. 1995; 82:877–884. 12 Betjes MG, Bajema I. The pathology of jaundice-related renal insufficiency: Cholemic nephrosis revisited. J Nephrol. 2006; 19:229–233.
Hemodialysis International 2014; ••:••–••
