Characteristics and clinical outcome of nonsteroidal anti-inflammatory drug-induced acute hepato-nephrotoxicity among Chinese patients

Table 1 Clinical manifestations of non-steroidal anti-inflammatory drug-induced kidney and liver injury: Literature summary

No.	Age/Sex	NSAID: Dose and duration of use	Other drugs used concurrently	Peak creatinine	Peak ALT	Peak ALP	Peak bilirubin	Histology	Outcome	Ref.
1	5/F	Acetaminophen: 11 mg/kg per dose, two total doses over 5 h Ibuprofen: 5 mg/kg per dose every 8 h, three total dose	None	6.34 mg/dL	1229 U/L	NK	NK	ND	Recovery	Zaffanello et al[11]
2	25/F	Nimesulide 100 mg b.i.d. for 4 d	Slimming drug containing anthraquinones and ampicillin	431 μmol/L	72 U/L	206 U/L	16 μmol/L	Acute tubular necrosis	Recovery	Li et al[12]
3	70/F	Nimesulide 100 mg b.i.d. for 5 d	None	5.6 mg/dL	1240 U/L	285 U/L	33 mg/dL	Massive necrosis of hepatocytes with more cholestasis	Deceased	Schattner et al[13]
4	56/M	Celecoxib 200 mg one to two tablets per day for 10 mo	Ramipril 10 mg/d	5.2 mg/dL	3 U/L	77 U/L	32.4 mg/dL	Acute interstitial (tubulo)nephritis, acute cholestatic hepatitis	Recovery	Tabibian et al[14]
5	56/M	Diclofenac 100 mg total	Hepatoprotective agents, calcium carbonate, and diuretics	485.3 μmol/L	NK	NK	NK	ND	Recovery	Tomaszewski et al[15]

F: Female; M: Male; ALT: Alanine aminotransferase; ALP: Alanine aminotransferase; NK: Not-known; ND: Not-done; NSAID: Nonsteroidal anti-inflammatory drug.

Table 2 Clinical characteristics of non-steroidal anti-inflammatory drug-induced acute hepato-nephrotoxicity

No.	Sex/Age	Serology of infections	History	NSAID: Dose and duration of use	Other drug concurrent used	Extracellular volume depletion	Peak creatinine	Peak ALT	Peak ALP	Peak bilirubin
1	M/64	HBcAb(+)	Diabetes’s mellitus, alcohol use	Tylenol 0.5 g × 5 pills, Ibuprofen 0.3 g for 2 d	Erythromycin, Telmisartan	Fever (40 °C) watery diarrhea for 2 d	6.7 mg/dL	2565 U/L	141 U/L	131.3 μmol/L
2	M/71	HBsAg(+)	Hypertension, alcohol use	Lysine acetylsalicylate 1.5 g × 2 pills, Nimesulide 0.1 g × 2 pills for 3 d	Cefoxitin, Fosinopril	Fever (39 °C-40 °C) for 3 d	5.3 mg/dL	8960 U/L	598 U/L	265.6 μmol/L
3	M/69	HBcAb(+)	Spondylolisthesis lumbar backaches, alcohol use	Celecoxib 25 mg/d, for 1 yr, Diclofenac Sodium 1/d, for 1 mo	Rhizoma Cibotii, Herba	No evidence	2.2 mg/dL	619 U/L	224 U/L	21.6 μmol/L
					Epimedii, Rhizoma Drynariae,
					Radix Aucklandiae, Caulis Spatholobui, Radix Dipsaci
4	F/53	HBcAb(+) HBeAb(+)	IgA nephropathy, Alcohol use for 20 yr	Indomethacin 75 mg × 2 pills for 2 d	Lotensin, Cefaclor	Fever (39 °C) for 2 d	7.6 mg/dL	1336 U/L	74 U/L	39.1 μmol/L
5	F/68	HBeAb(+)	Arthritis, hypertension, alcohol use	Rofecoxib 25 mg/d, for 1 mo	Irbesartan, Nifedipine, Herb including cinnabar and flower of silktree albizzia	Diarrhea for 3 d	3.9 mg/dL	1186 U/L	209 U/L	336.4 μmol/L
6	F/37	(-)	Polycystic ovary syndrome, dysmenorrhea	Piroxicam 40 mg/d for 10 d, Paracetamol, 0.1 × 35 pills intermittent for 3 mo	Herb for regulating the menstrual cycle, slimming herb	No evidence	2.1 mg/dL	105 U/L	488 U/L	214 μmol/L
7	F/17	HBsAb(+)	Chronic diarrhea for 1 yr, acute pancreatitis for 1 mo	Ibuprofen 0.3 g × 5 pills, Indomethacin 75 mg × 10 pills intermittent for 1 mo	Norfloxacin Baccidal, Rifampicin, Cefoperazone, Meropenem, Hepatoprotective herbs, Diflucan	Diarrhea, intermittent fever for 1 mo	5.6 mg/dL	1548 U/L	600 U/L	350 μmol/L

F: Female; M: Male; NSAID: Nonsteroidal anti-inflammatory drug; ALT: Alanine aminotransferase; ALP: Alanine aminotransferase; HBcAb: Hepatitis B core antibody; HBsAg: Hepatitis B surface antigen; HBeAb: Hepatitis B e antibody; HBsAb: Hepatitis B surface antibody.

Table 3 Comparison between patients with combined acute hepato-nephrotoxicity and patients with mere acute kidney injury

	Combined acute hepato-nephrotoxicity (n = 7)	AKI (n = 124)	P value
Age (≥ 60 yr)	4	23	0.030
Hypertension	3	56	0.910
Diabetes mellitus	1	19	0.940
Alcohol use	5	24	0.006
Positive hepatitis B virus markers	6	29	0.001
Extracellular volume depletion	5	85	0.870
RAAS inhibitor combined used	4	68	0.910

AKI: Acute kidney injury; RAAS: Renin-angiotensin-aldosterone system.

Table 4 Comparison between patients with combined acute hepato-nephrotoxicity and patients with mere acute liver injury

	Combined acute hepato-nephrotoxicity (n = 7)	ALI (n = 96)	P value
Age (≥ 60 yr)	4	17	0.030
Hypertension	3	21	0.350
Diabetes mellitus	1	10	0.560
Alcohol use	5	69	0.910
Positive hepatitis B virus markers	6	75	0.640
Extracellular volume depletion	5	14	0.002
RAAS inhibitor combined used	4	11	0.008

ALI: Acute liver injury; RAAS: Renin-angiotensin-aldosterone system.

Table 5 Histology and outcome of non-steroidal anti-inflammatory drug-induced acute hepato-nephrotoxicity

No.	Sex/Age	Immunofluorescent staining	Renal lesion	Liver lesion	Treatment and outcome
1	M/64	IgM++, IgA±, C3±	Acute tubulointerstitial disease	Acute hepatitis	Steroid 0.5 mg/kg, tappered to zero in 3 mo, ALT normalized in day 33, Scr normalized in day 182
2	M/71	Negative	Acute interstitial nephritis	Acute hepatitis	Anti-hepatitis B virus, steroid 0.5 mg/kg, tappered to zero in 3 mo, ALT normalized in day 50, Scr normalized in day 60
3	M/69	IgM±, IgA±, C3±	Acute tubulointerstitial disease	Acute hepatitis	Steroid 1 mg/kg, tappered to zero in 6 mo, cyclophosphamide accumulated to 6 g, potassium supplement, correction of acidosis, ALT normalized in day 40, Renal tubular acidosis normalized in day 15, Scr 140 μmol/L (10/8/2013)
4	F/53	IgA2+, C3+	Focal proliferative IgA nephropathy associated with acute tubulointerstitial nephropathy	Acute hepatitis	Steroid 1 mg/kg, tappered to 10 mg/d in 1 yr, cyclophosphamide accumulated to 6 g, ALT normalized in day 46, Scr 154 μmol/L (11/16/2013)
5	F/68	IgM+, C3±	Acute interstitial nephritis	ND	Steroid 0.5 mg/kg, tappered to zero in 3 mo, ALT normalized in day 145, Scr normalized in day 12.
6	F/37	Negative	Acute interstitial nephritis	Acute cholestasis	symptomatic treatment, Scr normalized in day 35, ALT normalized in day 86
7	F/17	ND	ND	Chronic cholestatic hepatitis (during transplantation)	Symptomatic treatment, Scr normalized in day 205, liver transplantation

F: Female; M: Male; ND: Not-done; ALI: Acute liver injury.