Introduction

Bile cast nephropathy is a form of acute kidney injury (AKI) manifesting in patients with severe direct hyperbilirubinemia [1]. It is a rare entity that is often thought of last when it comes to explaining an AKI. It is also known as cholemic nephropathy, bile acid nephropathy, biliary nephrosis, and jaundice related nephropathy [1,2,3].

It was initially described by Qunicke in 1899 in autopsy studies of patients with acute jaundice and renal insufficiency [2, 4]. Later in 1922, Haessler et al. showed that biliary salt sediments were found in the urine of dogs and humans with jaundice, and that the amount of sediments decreased as jaundice resolved [1, 3,4,5]. The gold standard for diagnosing this entity is renal biopsy.

The prevalence of bile cast nephropathy is probably underestimated as pathological diagnosis is often missing considering the increased bleeding risk of renal biopsy in coagulopathic patients with liver disease; however, it has been recognized more frequently lately with the utilization of transjugular renal biopsy [1, 2, 5, 6]. Nonetheless, Nayak et al. conducted a study on postmortem kidney biopsy [7]. Their aim was to investigate the frequency of bile cast nephropathy detected on postmortem renal biopsy among patients with decompensated cirrhosis who had been admitted with AKI due to hepatorenal syndrome. They were able to detect bile cast nephropathy in 44.8% of all the postmortem renal biopsy specimens and in 72.1% of the patients with acute on top of chronic liver failure. So, it is imperative to recognize this entity early, as directed treatment and management may lead to a better prognosis [2].

Pathophysiology of bile cast nephropathy

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 [8]. Small amounts of bile acids are recovered in kidney [8]. Renal-hepatic circulation of bile salts is via organic solute transporters in the proximal tubules [9]. 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 [2]. 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% [2, 10].

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 [1,2,3, 11]. This damage could lead, in some patients, to tubular cell hypertrophy [3, 11, 12]. This was observed in 73.5% of autopsies performed on jaundiced individuals [13]. Holmes’ autopsies demonstrated swelling of the tubular epithelium, pigmented casts, hypertrophy, and hyperplasia of the parietal layer of Bowman’s capsule [13]. 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 [14]. Bilirubin also inhibits mitochondrial oxidative phosphorylation leading to more damage to the tubular cells with subsequent decrease in adenosine triphosphate activity [2, 15,16,17]. Such a decrease leads to mitochondrial defects with increased penetration of cell membranes resulting in modified electrolyte content and cell volume [17]. 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 [2, 6, 15, 18]. To note, however, bilirubin contains neither heme nor iron; both of which have been associated with kidney injury [15].

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 [11, 19]. 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 [3, 20]. 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 [2, 3, 10, 21].

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 [2, 15, 18, 22]. The depressed cardiac performance is occasionally termed “jaundiced heart” by some authors and is expected to improve after resolution of the hyperbilirubinemia [23, 24]. It is also proposed that the lack of enteral bile acids results in systemic endotoxemia and subsequently hypotension and a low perfusion state [1, 2, 22]. Thus, hyperbilirubinemia is related to marked splanchnic and systemic vasodilatation that results in a lower glomerular filtration rate contributing to kidney injury [3, 25].

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 [16]. 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 [16]. This was followed by interstitial nephritis and progressive tubulointerstitial renal fibrosis at 3, 6, and 8 weeks [16].

Pathology

Macroscopically, the kidney’s cortex and medulla of patients with hyperbilirubinemia appear yellow due to the presence of bilirubin and bilirubin casts. After treatment of these kidneys with formalin fixation, the bilirubin will be converted to biliverdin and the color changes from yellow to green [1, 3]. The green color is more prominent in the medulla due to the presence of higher cast concentration in the distal nephrons [1, 3].

The pathology induced by the excess bilirubin is mainly limited to the tubules [1, 3, 16]. Light microscopy and immunofluorescence would show no glomerular abnormalities [4, 10, 26]. Many case reports of kidney biopsies have demonstrated bilirubin cast deposition mainly in the distal renal tubules and minimally in the proximal tubules [12, 15, 27]. A clinico-pathologic study done by van Slambrouck et al. on 3 renal biopsies and 41 autopsy studies of patients with jaundice showed distal deposition of bile casts in more than 50% of them, while only 6 biopsies had proximal tubular involvement [1, 3, 5]. The degree of bile cast formation correlated significantly with the severity of jaundice [1, 3].

Bile casts are formed of sloughed epithelial cells and acellular material. Thus, they can be identified the by Hall stain which detects bilirubin [17]. This stain utilizes Fouchet reagent, which converts bilirubin to biliverdin thus yielding a green color (Fig. 1) [1, 10, 28, 29]. Iron stain in these cases is negative indicating the absence of heme.

Fig. 1
figure 1

Bile casts visualized by Hall stain (Courtesy of Dr. Samih Nasr)

Full size image

Acute tubular necrosis (ATN) is a prominent feature of biopsies of patients with bile cast nephropathy. Several case studies have reported ATN as a feature in the biopsy [10, 19] (Table 1). Pathological features include loss of tubular brush borders, attenuated cytoplasm of tubular cells, dilatation of the tubular lumen, cytoplasmic vacuolization, apical blebbing, and tubular necrosis and desquamation [2, 4, 19, 28]. In the study done by van Slambrouck, ATN was noted in 76% of the biopsies [3, 5, 15, 26].

Table 1 Summary of the clinical and pathological characteristics of all biopsy proven bile cast nephropathy reported in literature since 2000
Full size table

Another key finding on kidney biopsy in patients with bile cast nephropathy is hypertrophy of the tubules [2, 3, 12]. Immunofluorescence and electron microscopy studies show no abnormalities [4].

Approach and diagnosis

The diagnosis of bile cast nephropathy can be made clinically when other causes of AKI have been ruled out. The definitive diagnosis is via a kidney biopsy; however, a transcutaneous kidney biopsy carries higher risk of bleeding in those coagulopathic patients, and so it is seldom performed. Moreover, since the pathology of bile cast nephropathy is mainly evident in the distal nephron, we may argue that a conventional kidney biopsy (which reaches the cortex) might not reach these segments. A trans-jugular renal biopsy (TJRB) approach might be a reasonable alternative. Four hundred patients underwent TJRB and were compared to four hundred patients who underwent percutaneous renal biopsy [42]. They reported a diagnostic tissue adequacy of 95.8%, with a major complication rate of 1% [42]. Sam et al. described their experience with TJRB in 29 patients with coexisting kidney and liver diseases [43]. They concluded that TJRB appears to be a safe and effective procedure for establishing a histological diagnosis in patients with advanced liver disease and contraindications to conventional percutaneous renal biopsy.

The diagnosis of bile cast nephropathy can be strongly suspected when urinalysis shows bile crystals [12]; although their role in the pathophysiology of the disease remains unclear [2, 10,11,12]. In some cases, granular casts have been reported due to the role of ATN in the pathophysiology of bile cast nephropathy [11]. Hyperuricosuria also develops because bilirubin is said to inhibit the absorption of uric acid in the proximal tubules [12]. Potassium wasting also occurs and is consistent with the tubular injury caused by the bilirubin casts.

Treatment and outcome

Treatment of bile cast nephropathy depends on prompt management of hyperbilirubinemia to avoid kidney damage. Several case studies reported reversal of kidney injury with reduction of bile acid and bilirubin levels, though at different recovery rates [10,11,12, 28]. We compiled a summary of the clinical and pathological characteristics of all biopsy proven bile cast nephropathy reported in literature since 2000 along with the management modalities used (Table 1). We also included the different outcomes with each treatment used in that table.

Extensive initial injury has been associated with delayed recovery [3, 12, 28]. Currently, there are no accepted treatment guidelines; rather, there is a focus on decreasing bilirubin levels and reversing the cause of the liver injury. In case of biliary stones or tumors for instance, endoscopic retrograde cholangiopancreatography with or without stenting is used to relieve the obstruction. Removal of excess bilirubin and bile acids has been carried out by extracorporeal therapies.

Extracorporeal therapies for bile cast nephropathy are divided into two major groups: biologic and non-biologic (Fig. 2) [44]. Biological devices use living liver cells (human or porcine) to support the failing liver through detoxification and synthetic function [45]. Non-biologic devices use artificial membranes and adsorbents for detoxification [44]. These include plasmapheresis and albumin dialysis.

Fig. 2
figure 2

Extracorporeal therapies

Full size image

Plasmapheresis can be utilized to remove the excess toxins and bilirubin in persistent cholestasis to improve the symptoms and the outcomes [26]. Not only that, it replenishes albumin, coagulation factors, and hepatic regenerative stimulating substances [46]. Plasmapheresis is mostly mentioned in the literature for the management of liver failure [46,47,48,49]. Keklik et al. published their experience with plasma exchange as a treatment for patients with severe hyperbilirubinemia [48]. They observed a statistically significant decline in total and direct bilirubin levels after plasma exchange [48]. A case of steroid induced bile cast nephropathy that was treated with plasma exchange was also reported by El Khoury et al. [50].

Albumin dialysis is based on the removal of unwanted albumin-bound and water-soluble substances such as bilirubin, bile acids, and other hepatotoxins which are mostly albumin bound [44]. It can take place in two forms: molecular absorbent recirculating system (MARS) and single pass albumin dialysis (SPAD).

MARS consists of two separate dialysis circuits; the first consists of exogenous human albumin in contact with the patient’s blood via a semi-permeable polysulfone membrane while maintaining a constant flow of albumin as dialysate in the extracapillary compartment [44, 45]. A counter-current bicarbonate based dialysate removes water soluble toxins from the toxin enriched albumin solution. Albumin in the dialysate is regenerated by adsorber columns containing activated charcoal and anion exchange resin [51]. This regenerated albumin dialysate is then recirculated for new uptake of toxins in the blood.

SPAD is a form of venovenous hemodialysis incorporating albumin into the conventional hemodialysis solution [52, 53]. Unlike MARS, the albumin dialysate is not regenerated (single pass) [54]. Sens et al. reported drastic improvement of kidney function in their patient with cholemic nephropathy after one MARS and eight SPAD sessions were performed [26].

MARS was compared to single-pass albumin dialysis (SPAD) in terms of reduction of bilirubin levels and influence on other parameters such as creatinine [55]. Although both systems reduced plasma bilirubin similarly [55], MARS reduced creatinine and bile acids more significantly [55]. This might support the role of MARS in bile cast nephropathy.

In spite of suggested improvement with albumin dialysis, these studies were small and hence large scale studies should be conducted to gather more outcome data on this therapeutic technique. Medical therapy using steroids, ursodeoxycholic acid, cholestyramine, or lactulose have little to no benefit in bile cast nephropathy [2].

Conclusion

Bile cast nephropathy should be kept in mind when approaching a patient with acute renal failure in the setting of hyperbilirubinemia. Several mechanisms such as tubular damage, tubular obstruction, and hemodynamic changes have been proposed to explain kidney injury in patients with bile cast nephropathy. Definitive diagnosis of this entity remains a challenge; nonetheless, there seems to be a promising role for trans-jugular renal biopsy. In the absence of a clear cause of renal injury, one should consider initiating prompt treatment if bile cast nephropathy is suspected. Suggested treatment options include reversal of the cause of liver injury and initiation of albumin dialysis. Studies are lacking whether pre-emptive treatment with bilirubin lowering therapy can help prevent kidney injury.