J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

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Review

Volume 7, Number 9, September 2015, pages 667-671

Do Biliary Salts Have Role on Acute Kidney Injury Development?

**Table 1.** Summary of the Main Studies With Evidence of Pro-Toxic Effects of Bilirubin in the Kidneys
Authors/year	Methods	Results	Conclusion
Padillo et al, 2009 [15]	Experimental study. Animals submitted to common bile duct ligation had their renin, aldosterone, endothelin-1 and prostaglandine E2 studied and compared to control group.	Both groups had the same values for diuresis, renin and creatinine clearance at 24 h. Animals with obstructive jaundice had lower sodium concentration and an increase in aldosterone levels (P < 0.03), endothelin-1 (P < 0.001) and prostaglandine E2 (P < 0.001) in urine.	Vasoactive hormones may play a role in renal complications during obstructive jaundice.
Fickert et al, 2013 [13]	Experimental study. Animals submitted to 3-day common bile duct ligation, with a group of receptor knockout (para que?) mice for bile acids and (?) renal histology analyzed.	Bile common duct ligation induced renal tubular epithelial injury predominantly at the level of collecting ducts, followed by progressive interstitial nephritis and tubulointerstitial fibrosis. Knockout mices were completely protected from renal fibrosis.	Urinary excretion of bile acids represents a trigger for renal tubular epithelial injury leading to cholemic nephropathy.
Van Slambrouck et al 2013 [9]	Clinicopathologic study of 44 subjects (41 autopsies and three biopsies) from jaundice patients.	24 patients had bile casts with involvement of distal nephron tubules for?? six severe cases. Eleven of 13 patients with hepatorenal syndrome and all 10 with cirrhosis had tubular bile casts.	Bile cast nephropathy is an appropriate term for severe form of renal injury observed in cirrhotic patients.
Pereira et al, 2008 [23] Esse parece mais table 2	Experimental study. Male Wistar rats were submitted to sham surgery or bile duct ligation. Determination of renal function and histology samples were obtained after 6 weeks.	At 6 weeks the group with bile duct ligation showed features of hepatorenal syndrome including increase in serum creatinine and reduction of creatinine clearance, water excretion and urinary sodium concentration. Histological analysis has shown no alterations.	Bile duct ligation produced progressive renal dysfunction, although without structural changes in the kidneys, characterizing functional HRS.
Bal et al, 2000 [10]	Post-mortem histological analysis from patients died from subacute hepatic failure.	Bile cast nephropathy was observed in three of the patients.	Bile cast nephropathy is an important finding in the kidneys of icteric patients.

Table 1. Summary of the Main Studies With Evidence of Pro-Toxic Effects of Bilirubin in the Kidneys

Authors/year

Methods

Results

Conclusion

Padillo et al, 2009 [15]

Experimental study. Animals submitted to common bile duct ligation had their renin, aldosterone, endothelin-1 and prostaglandine E2 studied and compared to control group.

Both groups had the same values for diuresis, renin and creatinine clearance at 24 h. Animals with obstructive jaundice had lower sodium concentration and an increase in aldosterone levels (P < 0.03), endothelin-1 (P < 0.001) and prostaglandine E2 (P < 0.001) in urine.

Vasoactive hormones may play a role in renal complications during obstructive jaundice.

Fickert et al, 2013 [13]

Experimental study. Animals submitted to 3-day common bile duct ligation, with a group of receptor knockout (para que?) mice for bile acids and (?) renal histology analyzed.

Bile common duct ligation induced renal tubular epithelial injury predominantly at the level of collecting ducts, followed by progressive interstitial nephritis and tubulointerstitial fibrosis. Knockout mices were completely protected from renal fibrosis.

Urinary excretion of bile acids represents a trigger for renal tubular epithelial injury leading to cholemic nephropathy.

Van Slambrouck et al 2013 [9]

Clinicopathologic study of 44 subjects (41 autopsies and three biopsies) from jaundice patients.

24 patients had bile casts with involvement of distal nephron tubules for?? six severe cases. Eleven of 13 patients with hepatorenal syndrome and all 10 with cirrhosis had tubular bile casts.

Bile cast nephropathy is an appropriate term for severe form of renal injury observed in cirrhotic patients.

Pereira et al, 2008 [23]
Esse parece mais table 2

Experimental study. Male Wistar rats were submitted to sham surgery or bile duct ligation. Determination of renal function and histology samples were obtained after 6 weeks.

At 6 weeks the group with bile duct ligation showed features of hepatorenal syndrome including increase in serum creatinine and reduction of creatinine clearance, water excretion and urinary sodium concentration. Histological analysis has shown no alterations.

Bile duct ligation produced progressive renal dysfunction, although without structural changes in the kidneys, characterizing functional HRS.

Bal et al, 2000 [10]

Post-mortem histological analysis from patients died from subacute hepatic failure.

Bile cast nephropathy was observed in three of the patients.

Bile cast nephropathy is an important finding in the kidneys of icteric patients.

**Table 2.** Summary of the Main Studies With Evidence Against Toxic Effects of Bilirubin in the Kidneys
Authors/year	Methods	Results	Conclusion
Leung et al, 2001 [24]	Experimental study. Animals were submitted to common bile duct ligation and hypertonic glycerol was used to induce acute tubular necrosis (ATN). Renal injury was assessed by plasma creatinine concentration and histology.	Ligation of the common bile duct markedly reduced acute renal injury evidenced by less severe ATN and lower plasma creatinine. Ligation of the bile duct induced heme oxygenase-1 expression in the kidneys.	Ligation of bile common duct confers resistance to glycerol-induced acute renal injury which may be related to the expression of heme oxygenase-1 in the kidneys.
Guo et al, 2011 [30]	Experimental study. Animals divided into groups with biliary cirrhosis induced by bile duct ligation and sham. Expression of heme oxygenase-1 in kidneys was analyzed as serum creatinine and renal blood flow.	Heme oxygenase-1 expression, serum creatinine levels and renal blood flow were lower in the cirrhotic group (P < 0.05).	Intervention to increase the expression of heme oxygenase-1 in kidneys played a role in bilirubin protective effect in renal failure.
Deetman et al, 2012 [21]	Prospective data collected from August 2001 and July 2003 from non-icteric renal transplant recipients patients with a functioning graft for > 1 year.	Median data follow up to 7.1 years. Circulating levels of bilirubin were inversely associated with late graft failure, independently of urinary protein excretion, calcineurin inhibitors and gender.	Findings consistent with a protective effect of increased endogenous bilirubin against development of late graft failure in renal transplant recipients.
Oh et al, 2013 [22]	Experimental study. Male rats were submitted to intraperitoneal injection of bilirubin three times daily for 1 week before the administration of ciclosporine and a control group only with ciclosporine administration.	Ciclosporine induced increase in urine kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Bilirubin reduced KIM-1 (P < 0.05) while NGAL exhibited a downregulation trend. The protein expression of NOX4 and p22phox was reduced by bilirubin and also apoptosis evaluated by TUNEL assay was ameliorated by bilirubin injection (P < 0.01).	The direct administration of bilirubin protected against ciclosporine induced tubular injury via inhibition of oxidative stress and apoptosis.

Table 2. Summary of the Main Studies With Evidence Against Toxic Effects of Bilirubin in the Kidneys

Authors/year

Methods

Results

Conclusion

Leung et al, 2001 [24]

Experimental study. Animals were submitted to common bile duct ligation and hypertonic glycerol was used to induce acute tubular necrosis (ATN). Renal injury was assessed by plasma creatinine concentration and histology.

Ligation of the common bile duct markedly reduced acute renal injury evidenced by less severe ATN and lower plasma creatinine. Ligation of the bile duct induced heme oxygenase-1 expression in the kidneys.

Ligation of bile common duct confers resistance to glycerol-induced acute renal injury which may be related to the expression of heme oxygenase-1 in the kidneys.

Guo et al, 2011 [30]

Experimental study. Animals divided into groups with biliary cirrhosis induced by bile duct ligation and sham. Expression of heme oxygenase-1 in kidneys was analyzed as serum creatinine and renal blood flow.

Heme oxygenase-1 expression, serum creatinine levels and renal blood flow were lower in the cirrhotic group (P < 0.05).

Intervention to increase the expression of heme oxygenase-1 in kidneys played a role in bilirubin protective effect in renal failure.

Deetman et al, 2012 [21]

Prospective data collected from August 2001 and July 2003 from non-icteric renal transplant recipients patients with a functioning graft for > 1 year.

Median data follow up to 7.1 years. Circulating levels of bilirubin were inversely associated with late graft failure, independently of urinary protein excretion, calcineurin inhibitors and gender.

Findings consistent with a protective effect of increased endogenous bilirubin against development of late graft failure in renal transplant recipients.

Oh et al, 2013 [22]

Experimental study. Male rats were submitted to intraperitoneal injection of bilirubin three times daily for 1 week before the administration of ciclosporine and a control group only with ciclosporine administration.

Ciclosporine induced increase in urine kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Bilirubin reduced KIM-1 (P < 0.05) while NGAL exhibited a downregulation trend. The protein expression of NOX4 and p22phox was reduced by bilirubin and also apoptosis evaluated by TUNEL assay was ameliorated by bilirubin injection (P < 0.01).

The direct administration of bilirubin protected against ciclosporine induced tubular injury via inhibition of oxidative stress and apoptosis.