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      Bile Cast Nephropathy in a Patient With Obstructive Jaundice

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          Introduction 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. 1 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. 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. Case Presentation 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. Figure 1 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). Figure 2 Serum creatinine and bilirubin throughout patient admission. Discussion 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. 2 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. 3 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. 6 Fajers 7 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 8 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. 9 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. 9 Conclusion 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. Consent 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. Disclosure All the authors declared no competing interests.

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          Most cited references 9

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          Renal failure in cirrhosis.

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            Bile acids trigger cholemic nephropathy in common bile-duct-ligated mice.

            Tubular epithelial injury represents an underestimated but important cause of renal dysfunction in patients with cholestasis and advanced liver disease, but the underlying mechanisms are unclear. To address the hypothesis that accumulation and excessive alternative urinary elimination of potentially toxic bile acids (BAs) may contribute to kidney injury in cholestasis, we established a mouse model for detailed in vivo time course as well as treatment studies. Three-day common bile duct ligation (CBDL) induced renal tubular epithelial injury predominantly at the level of aquaporin 2-positive collecting ducts with tubular epithelial and basement membrane defects. This was followed by progressive interstitial nephritis and tubulointerstitial renal fibrosis in 3-, 6-, and 8-week CBDL mice. Farnesoid X receptor knockout mice (with a hydrophilic BA pool) were completely protected from CBDL-induced renal fibrosis. Prefeeding of hydrophilic norursodeoxycholic acid inhibited renal tubular epithelial injury in CBDL mice. In addition, we provide evidence for renal tubular injury in cholestatic patients with cholemic nephropathy.
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              Bile acid solubility and precipitation in vitro and in vivo: the role of conjugation, pH, and Ca2+ ions.

              The principles governing the in vitro solubility of the common natural conjugated and unconjugated bile acids and salts in relation to pH, micelle formation, and Ca2+ concentration are considered from a theoretical standpoint and then correlated first with experimental observations on model systems and second with the formation of precipitates containing bile acids in health and disease. In vitro, taurine-conjugated bile acids are soluble at strongly acidic pH; glycine-conjugated bile acids are poorly soluble at moderately acidic pH; and many of the common, natural unconjugated bile acids are insoluble at neutral pH. For both glycine-conjugated and unconjugated bile acids, solubility rises exponentially, with increasing pH, until the concentration of the anion reaches the critical micellization concentration (CMC) when micelle formation occurs and solubility becomes practically unlimited. In vivo, in health, conjugated bile acids are present in micellar form in the biliary and intestinal tract. Unconjugated bile acids formed in the large intestine remain at low monomeric concentrations because of the acidic pH of the proximal colon, binding to bacteria, and absorption across the intestinal mucosa. In diseases in which proximal small intestinal content is abnormally acidic, precipitation of glycine-conjugated bile acids (in protonated form) occurs. Increased bacterial formation of unconjugated bile acids occurs with stasis in the biliary tract and small intestine; in the intestine, unconjugated bile acids precipitate in the protonated form. If the precipitates aggregate, an enterolith may be formed. In vitro, the calcium salts of taurine conjugates are highly water soluble, whereas the calcium salts of glycine conjugates and unconjugated bile acids possess limited aqueous solubility that is strongly influenced by bile acid structure. Precipitation occurs extremely slowly from supersaturated solutions of glycine-conjugated bile acids because of metastability, whereas super-saturated solutions of unconjugated bile acids rapidly form precipitates of the calcium salt. In systems containing Ca2+ ions and unconjugated bile acids, pH is important, since it is the key determinant of the anion concentration. For bile acids with relatively soluble calcium salts (or with a low CMC), the concentration of the anion will reach the CMC and micelles will form, thus precluding formation of the insoluble calcium salt. For bile acids, with relatively insoluble calcium salts (or with a high CMC), the effect of increasing pH is to cause the anion to reach the solubility product of the calcium salt before reaching the CMC so that precipitation of the calcium salt occurs instead of micelle formation.(ABSTRACT TRUNCATED AT 400 WORDS)

                Author and article information

                Kidney Int Rep
                Kidney Int Rep
                Kidney International Reports
                18 September 2018
                February 2019
                18 September 2018
                : 4
                : 2
                : 338-340
                [1 ]Kidney Health Service, Metro North Hospital and Health Service, Herston, Queensland, Australia
                [2 ]Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
                [3 ]Pathology Queensland, Metro North Hospital and Health Service, Herston, Queensland, Australia
                Author notes
                [] Correspondence: Samuel Chan, Faculty of Medicine, The University of Queensland, Herston, Queensland 4029, Australia. samuel.chan@
                © 2018 International Society of Nephrology. Published by Elsevier Inc.

                This is an open access article under the CC BY-NC-ND license (

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