Predictors of kidney tubular dysfunction induced by adefovir treatment for chronic hepatitis B

Table 1 Patient characteristics n (%)

	Patient without ADV	Patient with ADV	P value
	(n = 49)	(n = 30)
Age (yr)
At the initiation of NA	51.1 ± 10.8	49.9 ± 10.0	NS
At the evaluation of PKTD	55.7 ± 11.1	58.9 ± 9.9	NS
Male/female	30/19	21/9	NS
BMI (kg/m2)	23.0 ± 2.9	22.6 ± 3.0	NS
Current smokers	4 (8.2)	4 (13.3)	NS
Habitual drinkers	5 (10.2)	2 (6.7)	NS
Hypertension	12 (24.5)	12 (40.0)	NS
Diabetes	1 (2.0)	2 (6.7)	NS
Treatment duration of NA (mo)	54.8 ± 38.8	107.5 ± 30.1	< 0.001
SLC22A6 (hOAT1) 4531 G/A,
G/G	37 (75.5)	17 (56.7)	NS
G/A	11 (22.4)	12 (40.0)
A/A	1 (2.0)	1 (3.3)
ABCC2 (MRP2) -24 C/T, rs717620
C/C	28 (57.1)	17 (56.7)	NS
C/T	19 (38.8)	9 (30.0)
T/T	2 (4.1)	4 (13.3)
HBeAg-positive	22.4	16.7	NS
HBV DNA-positive	63.3	30.0	0.004
HBV genotype
B/C/undetected	8/36/5	0/28/2	0.048
Medicated
LAM	19 (38.8)	29 (96.7)	< 0.001
ETV	29 (59.2)	1 (3.3)	< 0.001
TDF	1 (2.0)	0	NS
AST (U/L)	29.4 ± 10.5	31.0 ± 10.8	NS
ALT (U/L)	28.5 ± 16.6	30.5 ± 19.6	NS
ALP (U/L)	242.9 ± 112.0	369.8 ± 293.8	0.03
Serum calcium (mmol/L)	2.3 ± 0.8	2.3 ± 0.1	NS
Serum phosphate (mmol/L)	1.1 ± 0.1	0.9 ± 0.2	< 0.001
Serum uric acid (umol/L)	324.6 ± 71.9	266.1 ± 112.0	0.014
UBCR (mg/gCre)	117.1 (50.5-271.6)	805.2 (61.8-10489.6)	< 0.001
Phosphate diabetes	0	9 (30.0)	< 0.001
Renal hypouricemia	0	10 (33.3)	< 0.001
β2-microglobulinuria	3 (6.1)	15 (50.0)	< 0.001
Nondiabetic glucosuria	0	5 (16.7)	0.003
Metabolic acidosis	0	2 (6.7)	NS
eGFR (mL/min per 1.73 m2)
At the initiation of NA	82.6 ± 15.5	79.9 ± 14.9	NS
At the evaluation of PKTD	76.3 ± 18.2	63.0 ± 16.4	0.002

¹Variant position is relative to accession No. AJ249369. Data are shown as mean ± SD, percentages, or geometric mean ± SD. Overall P values were calculated by unpaired t-test or χ²-test in comparison between patients with and without ADV. ADV: Adefovir dipivoxil; BMI: Body mass index; NA: Nucleos(t)ide analogues; hOAT1: Human organic anion transporter 1; MRP2: Multidrug-resistance protein 2; HBeAg: Hepatitis B e antigen; HBV: Hepatitis B virus; LAM: Lamivudine; ETV: Entecavir; TDF: Tenofovir; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; UBCR: Urine β₂-microglobulin-creatinine ratio; eGFR: Estimated glomerular filtration rate; NS: Not significant; PKTD: Proximal kidney tubular dysfunction.

Table 2 Differences between 30 patients treated with adefovir dipivoxil with/without proximal kidney tubular dysfunction n (%)

	PKTD (-)	PKTD (+)	P value
	(n = 21)	(n = 9)
Age (yr)
At the initiation of ADV	52.1 ± 9.3	59.0 ± 9.7	NS
At the evaluation of PKTD	56.0 ± 9.1	65.7 ± 8.6	0.012
Male/female	16/5	5/4	NS
BMI (kg/m2)	23.3 ± 3.0	20.8 ± 2.5	0.038
Current smokers	4 (19.0)	0	NS
Habitual drinkers	2 (9.5)	0	NS
Hypertension	9 (42.9)	3 (33.3)	NS
Diabetes	1 (4.8)	1 (11.1)	NS
Treatment duration of NA (mo)	104.1 ± 32.1	115.1 ± 25.2	NS
Treatment duration of ADV (mo)	56.0 ± 33.5	86.0 ± 21.8	0.021
SLC22A6 (hOAT1) 4531 G/A,
G/G	13 (61.9)	4 (44.4)	NS
G/A	8 (38.1)	4 (44.4)
A/A	0	1 (11.1)
ABCC2 (MRP2) -24 C/T, rs717620
C/C	12 (57.1)	5 (55.6)	NS
C/T	5 (23.8)	4 (44.4)
T/T	4 (19.0)	0
eGFR (mL/min per 1.73 m2)
At the initiation of ADV	81.4 ± 11.6	77.1 ± 17.0	NS
At the evaluation of PKTD	70.0 ± 10.9	46.9 ± 15.8	< 0.001

¹Variant position is relative to accession No. AJ249369. Data are shown as mean ± SD or percentage. Overall P values were calculated by unpaired t-test or χ²-test. PKTD: Proximal kidney tubular dysfunction; ADV: Adefovir dipivoxil; BMI: Body mass index; NA: Nucleos(t)ide analogue; hOAT1: Human organic anion transporter 1; MRP2: Multidrug-resistance protein 2; eGFR: Estimated glomerular filtration rate; NS: Not significant.

Table 3 Logistic regression analysis of the kidney tubular dysfunction of patients treated with adefovir dipivoxil

	OR	95%CI	P value
1Model 1
Age at initiation of ADV (per 5 yr)	2.90	1.16-7.24	0.023
Treatment duration of ADV (per year)	2.31	1.20-4.45	0.013
2Model 2
Age at initiation of ADV (per 5 yr)	5.01	1.07-23.38	0.040
Treatment duration of ADV (per year)	3.21	1.20-8.57	0.020

¹Adjusted for body mass index;

²Adjusted for body mass index, gender, the eGFR level at initiation of ADV, and genotyping of ABCC2 -24 C/T. OR, 95%CI, and P value were calculated by logistic regression analysis. ADV: Adefovir dipivoxil; eGFR: Estimated glomerular filtration rate.

Table 4 Genotype at ABCC2 and parameters of proximal kidney tubular dysfunction and estimated glomerular filtration rate of 30 patients treated with adefovir dipivoxil n (%)

	Genotype CC or CT	Genotype TT	P value
	(n = 26)	(n = 4)
Serum phosphate (mmol/L)	0.86 ± 0.21	1.00 ± 0.25	NS
TmP/GFR (mmol/L)	0.73 ± 0.28	0.95 ± 0.42	NS
Serum uric acid (umol/L)	267.2 ± 120.3	258.7 ± 26.4	NS
FEUA (%)	16.6 ± 14.6	9.5 ± 1.6	0.025
UBCR (mg/gCr)	996.3 (68.2-14555.9)	201.4 (81.5-497.7)	0.038
Phosphate diabetes	8 (30.8)	1 (25.0)	NS
Renal hypouricemia	10 (38.5)	0	NS
β2-microglobulinuria	14 (53.8)	1 (25.0)	NS
Nondiabetic glucosuria	5 (19.2)	0	NS
Metabolic acidosis	2 (7.7)	0	NS
eGFR (mL/min per 1.73 m2)	62.8 ± 17.6	64.4 ± 2.1	NS

Data are shown as mean ± SD, percentage, or geometric mean ± SD. Overall P values were calculated by unpaired t-test or χ²-test in comparison between ABCC2 -24 genotype CC/CT and genotype TT. TmP/GFR: Tubular maximum for phosphate corrected for glomerular filtration rate; FEUA: Fractional excretion of uric acid; UBCR: Urine β₂-microglobulin-creatinine ratio; eGFR: Estimated glomerular filtration rate; NS: Not significant.