Bile cast nephropathy is suspected in the setting of an acute kidney injury with concomitant direct hyperbilirubinemia. Normally, most bile acids are reabsorbed in the ileum and then transported back to the liver via portal blood circulation to inhibit bile acid synthesis. Small amounts of bile acids are recovered in kidney. Renal-hepatic circulation of bile salts is via organic solute transporters in the proximal tubules. During cholestasis, there is an upregulation of the hepatocytic basolateral bile acid pumps in an attempt to excrete the excess direct bilirubin into the blood. With hyperbilirubinemia, the kidneys will adapt by excreting the excess bile acids, mainly in the proximal convoluted tubules; in fact, it has been reported that in some cases the renal clearance of bilirubin increases from below 5% to almost 90%.

Bilirubin excess has deleterious effects on many fronts when it comes to the kidneys. Bilirubin exerts an oxidative stress on the tubules leading to damage of the tubular cell membranes. This damage could lead, in some patients, to tubular cell hypertrophy. This was observed in 73.5% of autopsies performed on jaundiced individuals. Holmes’ autopsies demonstrated swelling of the tubular epithelium, pigmented casts, hypertrophy, and hyperplasia of the parietal layer of Bowman’s capsule. Similar to the changes seen in diabetic nephropathy, tubuloepithelial hypertrophy is the most likely precursor of later irreversible changes in the tubulointerstitial architecture leading to tubular atrophy and interstitial fibrosis . Bilirubin also inhibits mitochondrial oxidative phosphorylation leading to more damage to the tubular cells with subsequent decrease in adenosine triphosphate activity. Such a decrease leads to mitochondrial defects with increased penetration of cell membranes resulting in modified electrolyte content and cell volume. Particularly, bile acids have been reported to cause inhibition of Na+/H+, Na+/K+, and Na+/Cl− transporters resulting in alterations in the pH in the tubules and contributing to an acidic milieu that favors cast formation. To note, however, bilirubin contains neither heme nor iron; both of which have been associated with kidney injury.

The key finding in this disease entity is the tubular obstruction and injury caused by the bilirubin cast formation within the distal kidney tubules, a mechanism that mimics the damage in myeloma cast nephropathy. Bile salts have low solubility in water, and normally when filtered by the glomerulus, they are transported by the proximal tubules back into the circulation. In the case of extreme hyperbilirubinemia, these transporters will be saturated, thus causing the tubules to be over flooded with bilirubin, a key factor to enhance cast formation and subsequently tubular obstruction, especially with increased acidity in the distal nephron.

Another mechanism by which hyperbilirubinemia has been associated with kidney injury is via its effect on systemic and renal hemodynamics. In fact, studies in mice have shown that excess bilirubin exerts negative ionotropic and chronotropic effects on the heart, leading to a decrease in kidney perfusion. The depressed cardiac performance is occasionally termed “jaundiced heart” by some authors and is expected to improve after resolution of the hyperbilirubinemia. It is also proposed that the lack of enteral bile acids results in systemic endotoxemia and subsequently hypotension and a low perfusion state. Thus, hyperbilirubinemia is related to marked splanchnic and systemic vasodilatation that results in a lower glomerular filtration rate contributing to kidney injury.

In summary, the kidney injury in bile cast nephropathy can be due to the following mechanisms: tubular epithelial injury, basement membrane effects causing tubular leakage and obstruction, and hemodynamic changes affecting both the kidneys and the systemic circulation.

An in vivo model using common bile duct ligation (CBDL) in mice has been proposed to describe the mechanism of kidney injury in cholemic nephropathy. CBDL induced renal tubular epithelial injury occurred predominantly at the level of aquaporin 2–positive collecting ducts with tubular epithelial and basement membrane defects as early as day 3. This was followed by interstitial nephritis and progressive tubulointerstitial renal fibrosis at 3, 6, and 8 weeks.

CONCLUSION

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Journal of Kidney Treatment and Diagnosis