Bile cast nephropathy: A systematic review of case reports and case series

Table 1 Criteria for assessing reports of bile cast nephropathy and level of evidence for a causal relation between hyperbilirubinemia and the development of acute kidney injury

Criterion	Level of evidence
1 AKI, defined by the KDIGO clinical practice guideline[14]	Definite: 1, 2, 3, and 4 or 5 met
2 Elevated serum total bilirubin level	Probable: 1, 2, and 3, 4, or 5 met
3 Presence of bile casts in the urine sediment or in the tubular lumen (on kidney biopsy/autopsy)	Possible: 1 and 2 met
4 Other causes of AKI excluded (including acute tubular injury and hepato-renal syndrome)	Unlikely: 1 or 2 not met
5 Direct relationship between the degree of hyperbilirubinemia and the AKI

AKI: Acute kidney injury; KDIGO: Kidney Disease: Improving Global Outcomes.

Table 2 Summary of the clinical characteristics, risk factors, treatment modalities, and outcomes of patients with bile cast nephropathy (derived from the 79 case reports)

	Number of evaluable patients	mean ± SD or n (%)	Range
Demographic variables
Age, years	79	48 ± 15	25-87
Male gender	79	66 (83.5)
White race	9	6 (66.7)
Liver-related parameters
Cause of liver disease or cholestasis	79
Drug-induced	79	24 (30.4)
Infection-related	79	15 (18.9)
Benign obstructive cholestasis	79	9 (11.4)
Alcohol-related	79	10 (12.7)
Malignant obstructive cholestasis	79	11 (13.9)
Other	79	10 (12.7)
Total bilirubin, mg/dL
Initial	77	27.1 ± 13.2	4.7-53.0
Peak	49	36.0 ± 15.4	7.3-102.0
Indirect bilirubin, mg/dL
Initial	44	8.5 ± 6.2	1.1-22.7
Albumin, gm/dL	33	2.9 ± 0.7	1.6-4.7
ALT, U/L	61	705 ± 1337	20-5592
AST, U/L	61	619 ± 1184	21-6205
ALP, U/L	52	404 ± 358	40-1419
PT, seconds	18	24 ± 23	10-75
INR	33	1.9 ± 1.1	1.0-6.0
Kidney-related parameters
AKI	79	70 (88.6)
Preexisting CKD	76	9 (11.8)
Acute on CKD	76	9 (11.8)
Serum creatinine, mg/dL
Baseline	26	1.1 ± 0.4	0.6-2.1
Initial	75	3.9 ± 3.2	0.6-14.3
Peak	49	5.9 ± 2.9	1.6-14.5
End-of-follow-up	50	2.1 ± 1.7	0.8-8.0
Dipstick urinalysis findings
Blood	36	15 (41.7)
Protein	39	22 (56.4)
Bilirubin	26	17 (65.4)
Urobilinogen	21	11 (52.4)
Urine sediment findings
Bilirubin/pigmented casts	49	15 (30.6)
Granular casts	49	7 (14.3)
Bilirubin and granular casts	49	4 (8.2)
Other casts	49	7 (14.3)
No casts	49	16 (32.7)
Random urine sodium, mEq/L	12	41 ± 17	15-69
Fractional excretion of sodium, %	4	1.4 ± 1.1	0.1-2.7
Histopathological ascertainment
Kidney biopsy	79	52 (65.8)
Kidney autopsy	79	4 (5.1)
None	79	23 (29.1)
Histopathological findings	56
Bile/bilirubin/green casts or green on autopsy	56	46 (82.1)
Other casts	56	7 (12.5)
Absence of casts	56	3 (5.4)
Sonographic urinary obstruction	31	1 (3.2)
Treatment modalities
Corticosteroids	79	10 (12.7)
Intravenous albumin	27	5 (18.5)
Plasmapheresis	27	11 (40.7)
Dialysis	77	39 (50.6)
Liver dialysis	27	3 (11.1)
Clinical outcomes
Duration of follow-up, months	55	4.0 ± 5.7	0.0-36.0
Liver transplantation	27	5 (18.5)
Liver and kidney transplantation	79	2 (2.5)
Kidney function
Full recovery	73	30 (41.1)
Partial recovery	73	29 (39.7)
Dialysis dependence	73	6 (8.2)
Death	76	11 (14.5)

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; PT: Prothrombin time; INR: International normalized ratio; AKI: Acute kidney injury; CKD: Chronic kidney disease.

Table 3 Characteristics and outcomes of patients with bile cast nephropathy stratified by tertiles of total bilirubin, n (%)

	Number of evaluable patients	Total bilirubin, tertile 1 (n = 26, 4.7-19.3)	Total bilirubin, tertile 2 (n = 26, 19.6-32.8)	Total bilirubin, tertile 3 (n = 25, 33.2-53.0)	P value
Demographic variables
Age, years	77	53 ± 15	47 ± 14	46 ± 17	0.222
Male gender	77	21 (80.8)	18 (69.2)	25 (100)	0.013
White race	9	3 (100.0)	2 (66.7)	1 (33.3)	0.316
Liver-related variables
Cause of liver disease or cholestasis	77				0.062
Drug-induced		8 (30.8)	5 (19.2)	11 (44)
Infection-related		6 (23.1)	1 (3.8)	7 (28)
Obstructive		4 (15.4)	5(19.2)	0 (0)
Alcohol-related		2 (7.7)	6 (23.1)	1 (4.0)
Malignancy		4 (15.4)	4 (15.4)	3 (12.0)
Other		2 (7.7)	5 (19.2)	3(12.0)
Total bilirubin, mg/dL
Initial	77	12.5 ± 4.8	27.0 ± 4.4	42.5 ± 5.7	< 0.001
Peak	47	28.4 ± 11.8	40.0 ± 19.8	46.1 ± 6.7	< 0.001
Initial indirect bilirubin, mg/dL	44	3.6 ± 1.9	8.8 ± 5.3	13.3 ± 6.1	< 0.001
Albumin, gm/dL	33	2.8 ± 0.5	2.8 ± 0.9	3.3 ± 0.7	0.280
ALT, U/L	60	967 ± 1690	169 ± 159	966 ± 1484	0.228
AST, U/L	60	893 ± 1756	251 ± 260	611 ± 913	0.410
ALP, U/L	52	412 ± 357	457 ± 451	323 ± 186	0.892
PT, seconds	18	36 ± 33	16 ± 7	21 ± 24	0.429
INR	33	2.0 ± 1.1	2.1 ± 1.4	1.4 ± 0.5	0.286
Kidney-related variables
AKI	77	23 (88.5)	22 (84.6)	23 (92)	0.714
Preexisting CKD	74	3 (11.5)	4 (15.4)	2 (8)	0.672
Acute on CKD	74	3 (11.5)	4 (15.4)	2 (8)	0.672
Creatinine, mg/dL
Baseline	24	1.2 ± 0.5	1.1 ± 0.4	1.0 ± 0.3	0.732
Initial	73	3.2 ± 3.2	4.4 ± 2.9	3.7 ± 2.7	0.136
Peak	47	6.5 ± 3.0	5.7 ± 2.1	4.9 ± 2.9	0.190
End-of-follow-up	48	2.7 ± 2.1	2.1 ± 1.6	1.6 ± 0.6	0.563
Urinalysis findings
Blood	36	6 (40)	4 (33.3)	5 (55.6)	0.584
Protein	39	5 (38.5)	8 (57.1)	9 (75.0)	0.183
Bilirubin	26	8 (66.7)	7 (70.0)	2 (50.0)	0.771
Urobilinogen	21	6 (60.0)	2 (28.6)	3 (75.0)	0.267
Urine sediment findings	49				0.191
Bilirubin/pigmented casts		4 (26.7)	8 (47.1)	3 (17.6)
Granular casts		1 (6.7)	1 (5.9)	5 (29.4)
Bilirubin and granular casts		1 (6.7)	0 (0.0)	3 (17.6)
Other casts		3 (20.0)	2 (11.8)	2 (11.8)
No casts		6 (40.0)	6 (35.3)	4 (23.5)
Random urine sodium, mEq/L	12	35 ± 26	48 ± 1	42 ± 15	0.603
Fractional excretion of sodium, %	4	0.9 ± 0.0	0.9 ± 1.2	2.7 ± 0.0	0.407
Histopathological ascertainment	77				0.250
Kidney biopsy		13 (50)	18 (69.2)	20 (80)
Kidney autopsy		2 (7.7)	1 (3.8)	1 (4.0)
None		11 (42.3)	7 (26.9)	4 (16)
Histopathological findings	55				0.232
Bile/bilirubin/green casts1		14 (93.3)	13 (68.4)	18 (85.7)
Other casts		0 (0.0)	5 (26.3)	2 (9.5)
Absence of casts		1 (6.7)	1 (5.3)	1 (4.8)
Sonographic urinary obstruction	31	1 (8.3)	0 (0.0)	0 (0.0)	0.442
Treatment modalities
Corticosteroids	77	2 (7.7)	4 (15.4)	4 (16)	0.613
Intravenous albumin	25	1 (20)	3 (23.1)	1 (14.3)	0.465
Plasmapheresis	25	2 (40.0)	3 (23.1)	4 (57.1)	0.465
Dialysis	75	14 (56)	14 (56)	11 (44)	0.618
Liver dialysis	25	1 (20)	1 (7.7)	1 (14.3)	0.465
Clinical outcomes
Duration of follow-up, months	54	3.1 ± 3.4	5.9 ± 8.3	3.2 ± 4.5	0.114
Liver transplantation	25	1 (20)	4 (30.8)	0 (0.0)	0.465
Liver and kidney transplantation	77	1 (3.8)	1 (3.8)	0 (0.0)	0.610
Kidney function	71				0.268
Full recovery		9 (36)	8 (34.8)	12 (52.2)
Partial recovery		8 (32)	10 (43.5)	10 (43.5)
Dialysis dependence		2 (8)	3(13)	1(4.3)
Death	74	5 (20)	2 (8)	4 (16.7)	0.469

¹Including green appearance of kidney on autopsy.

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; PT: Prothrombin time; INR: International normalized ratio; AKI: Acute kidney injury; CKD: Chronic kidney disease.

Table 4 Logistic regression analyses examining factors associated the composite of dialysis requirement or death in patients with bile cast nephropathy

Variable	Odds ratio	95% confidence interval	P value
Univariate analyses
Alcoholic-liver disease, vs other	3.667	0.726-18.526	0.116
Initial serum creatinine, per 1 mg/dL, increase	1.183	0.998-1.401	0.052
Initial serum total bilirubin, per 1 mg/dL, increase	0.986	0.939-1.037	0.589
Multivariable analyses
Alcoholic liver disease, vs other	5.062	0.553-46.310	0.151
Initial serum creatinine, per 1 mg/dL, increase	1.291	1.032-1.615	0.025
Initial serum total bilirubin, per 1 mg/dL, increase	0.968	0.930-1.008	0.112