Urinary liver-type fatty acid-binding protein levels as a potential risk factor for renal dysfunction in male HIV-infected Japanese patients receiving antiretroviral therapy: a pilot study

Abstract

Renal dysfunction is recognized with increasing frequency among the non-infectious co-morbidities associated with human immunodeficiency virus (HIV) infection. Recently, urinary liver-type fatty acid-binding protein (L-FABP) was suggested to be a predictor of the progression of renal dysfunction in patients without HIV. However, little is known regarding the utility of urinary L-FABP as a predictor of renal dysfunction in patients with HIV. A retrospective, observational, single-centre study was conducted between July 2014 and December 2016. The primary outcome was renal dysfunction defined as decrease in estimated glomerular filtration rate to less than 60 ml/min/1.73 m². To estimate the effect of urinary L-FABP, proteinuria category, and urinary β2 microglobulin (β2MG) on the time to the first event, a log-rank test was performed. Accuracy, determined by area under the curve and calculated from receiver operating characteristic curves, was also assessed. Thirty Japanese outpatients with HIV receiving antiretroviral therapy (ART) were enrolled. The primary outcome occurred in five patients during the follow-up period. Urinary L-FABP level and proteinuria category were significantly associated with renal dysfunction (p = 0.045 and p = 0.037, respectively). In contrast, urinary β2MG level was not significantly associated with renal dysfunction (p = 0.141). Urinary L-FABP was the most accurate predictor of renal dysfunction among the three urinary parameters. In conclusion, urinary L-FABP levels in HIV patients receiving ART were more accurate for predicting renal dysfunction than proteinuria and urinary β2MG. In addition, urinary L-FABP helped to discriminate those patients with a higher risk for renal dysfunction.

Keywords

Antiretroviral therapy toxicity HIV AIDS

Introduction

Renal dysfunction is recognized with increasing frequency among the non-infectious co-morbidities associated with human immunodeficiency virus (HIV) infection. It is becoming a major cause of morbidity and mortality along with the declining incidence of acquired immune deficiency syndrome observed after the introduction of antiretroviral therapy (ART).^1–3 Chronic kidney disease (CKD) is an important predictive factor for end-stage renal disease (ESRD) and cardiovascular disease, both of which are life-threatening co-morbidities.⁴ Thus, to improve the prognosis of patients with HIV, it is clinically important to identify patients at high risk of CKD as early as possible and to initiate disease management in a timely and appropriate manner.

Proteinuria has been proposed as an early marker of CKD among people with HIV. However, reliance on proteinuria to detect early kidney damage is limited because it typically reflects glomerular injury and may not capture damage to other sites of the nephron. There is a growing body of evidence suggesting that tubulointerstitial damage, as well as glomerular injury, contributes to a decline in renal function.^5–7

Liver-type fatty acid-binding protein (L-FABP) is expressed in the proximal tubules of the human kidney and participates in fatty acid metabolism.^8–10 Urinary L-FABP was previously suggested to be a predictor of the progression of CKD in patients without HIV.^11–13

However, little is known regarding the utility of urinary L-FABP as a predictor of renal dysfunction in patients with HIV. The aim of this study was to gain a better understanding of the clinical significance of urinary L-FABP in patients with HIV.

Methods

Study design and patient population

The pilot study was a retrospective, single-centre cohort design that included a medical chart review done at The Hospital of Hyogo College of Medicine in Hyogo, Japan. The inclusion criteria were as follows: patients with HIV who were ≥20 years old and received ART at baseline, patients with a urinary L-FABP level measured between July 2014 and June 2015, those patients with a baseline estimated glomerular filtration rate (eGFR) ≥60 to <100 ml/min/1.73 m². The following exclusion criteria were applied: patients who were not Japanese, those who were co-infected with hepatitis B virus (HBV) or hepatitis C virus (HCV), those who had initiated ART within 30 days of baseline. Baseline was defined as the nearest date to the eGFR measurement to the first measurement of urinary L-FABP levels between July 2014 and June 2015.

Follow-up evaluation

Patients were followed until December 2016. The primary outcome was renal dysfunction defined as a decrease in eGFR to <60 ml/min/1.73 m².^14–16 Censoring occurred at the date of the last measurement of eGFR within one year of the prior measurement of eGFR or the end of the study period. The time of the outcome was defined as the first date on which either the outcome of renal dysfunction was observed or the patient was censored.

Anthropometric and laboratory evaluation

We reviewed the electronic medical charts of all subjects. Non-fasting blood and spot urine samples were collected for analysis as part of routine clinical visits. Creatinine levels were measured via an enzymatic method. Urinary protein was measured using the pyrogallol red assay (lower detection limit, 6 mg/dl). Urinary albumin was measured using an immunoturbidimetric method. The protein-to-creatinine ratio (PCR) or albumin-to-creatinine ratio (ACR) was calculated by dividing the urinary protein or urinary albumin by urinary creatinine. PCR or ACR was classified into three proteinuria categories: PCR < 0.15 g/g creatinine or ACR < 30 mg/g creatinine (A1), 0.15 ≤PCR <0.50 g/g creatinine or 30 ≤ACR < 300 mg/g creatinine (A2), and PCR ≥0.50 g/g creatinine or ACR ≥300 mg/g creatinine (A3). The urinary L-FABP levels were measured using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (CMIC Co., Tokyo, Japan; lower detection limit, 1.5 ng/ml) and were expressed as a ratio to urinary creatinine. In this ELISA kit, urinary sediment did not influence the urinary L-FABP levels. Moreover, urinary L-FABP can be measured from any urine sample: morning urine, fresh urine or 24 h urine. Furthermore, meals do not influence urinary L-FABP levels and there is no daily fluctuation as the L-FABP levels remain stable. With the ELISA kit used, the results of the urinary L-FABP levels can be obtained within 1–3 days after measuring it.¹⁷ The cost of measuring urinary L-FABP was 2100 yen (equivalent to USD 19.2 as of 1 June 2018) from the Healthcare Fee System. Urinary β2 microglobulin (β2MG) was measured with a latex aggregation assay. Serum cystatin C was determined using a colloidal gold immunoassay that was traceable to ERM-DA471/IFCC. eGFR was calculated as eGFR (ml/min/1.73 m²) = 194 × serum creatinine^−1.094 × age^−0.287 in patients receiving ART not including dolutegravir (DTG) or cobicistat (COBI) and eGFR (ml/min/1.73 m²) = 104 × serum cystatin C^−1.019 × 0.996^age − 8 in patients receiving ART including DTG or COBI^18,19 according to the criteria of the Japanese Society of Nephrology.^20,21 The HIV-RNA level was measured using the Cobas TaqMan HIV-1 real-time polymerase chain reaction version 2.0 assay (lower detection limit, 20 copies/ml). Dyslipidaemia was defined as the use of at least one of the following lipid-lowering agents: hydroxymethyl glutaryl coenzyme A reductase inhibitors, fibrates, and Niemann-Pick C1-like 1 inhibitors. Hypertension was defined as any use of antihypertensive agents. Diabetes mellitus was defined as any use of oral antidiabetic agents or insulin. HCV infection was defined as a positive HCV antibody test, while HBV infection was defined as a positive HBV surface antigen test. Urinary L-FABP and urinary protein levels below the lower detection limit were approximated using the mean value between zero and the lower detection limit, 0.75 ng/ml and 3 mg/dl, respectively.

Statistical methods

Categorical variables were compared between the two groups using Fisher’s exact test. The distribution of continuous variables was assessed with the Kolmogorov–Smirnov normality test. As all the continuous variables had a non-normal distribution they were compared using the Mann–Whitney U test. Patients were divided into two groups according to urinary parameters. A Kaplan–Meier analysis and a log-rank test were then performed to estimate the effect of urinary parameters on time to the first event. The sensitivity and specificity were calculated based on cut-off scores. Accuracy was determined by the area under the curve (AUC), calculated from receiver operating characteristic curves. A probability value < 0.05 was considered significant. All analyses were conducted using SPSS Statistics software, version 24.0 (IBM, Tokyo, Japan).

Ethics statement

This study was conducted in accordance with the Declaration of Helsinki and the study protocol was approved by the Ethics Review Board of Hyogo College of Medicine (no. 2778). We obtained consent through an opt-out procedure of our hospital website from all individual participants included in the study.

Results

Patient characteristics

Between July 2014 and June 2015, a total of 259 patients with HIV were treated at The Hospital of Hyogo College of Medicine. Of these, 229 were excluded based on the above-mentioned criteria. Thus, 30 patients were included in the present study (Figure 1). Table 1 summarizes the demographic and clinical characteristics of individuals enrolled in this study at baseline. The primary outcome occurred in five patients (17%) during the follow-up period. Of the five patients, three patients received tenofovir disoproxil fumarate (TDF) and two patients received abacavir. At baseline, four patients (13%) received abacavir. Efavirenz, rilpivirine (RPV), ritonavir-boosted atazanavir (ATV/RTV), ritonavir-boosted darunavir, fosamprenavir (FPV), raltegravir, COBI-boosted elvitegravir, and DTG were used in one (3%), two (7%), three (10%), two (7%), two (7%), three (10%), three (10%), and 14 (46%) of the patients, respectively. Three subjects switched from ATV/RTV to DTG during the follow-up period and one subject each switched from DTG to ritonavir-boosted FPV and from RPV to DTG. During the follow-up period, no patient changed nucleoside/nucleotide reverse transcriptase inhibitors. In six patients (20%), the urinary L-FABP level was below the sensitivity of the assay. Urinary albumin was measured in three patients. Of these, two patients were classified into the A1 proteinuria category. No haemophilia patients were included in the study.

Figure 1.

Flow chart of the study design. ART: antiretroviral therapy; eGFR: estimated glomerular filtration rate; HBV: hepatitis B virus; HCV: hepatitis C virus; L-FABP: liver-type fatty acid-binding protein.

Table 1.

Patient characteristics and comparison according to urinary biomarker levels.

	All patients	Urinary L-FABP		P value	Proteinuria categories		P value	Urinary β2MG		P value
	All patients	≥4 µg/g creatinine	<4 µg/g creatinine	P value	A2	A1	P value	≥1700 µg/l	<1700 µg/l	P value
Patients, n	30	11	19		3	27		5	25
Follow-up, days	607 (546, 763)	614 (385, 777)	607 (549, 746)	0.832	551 (416, 671)	607 (546, 763)	0.647	490 (140, 791)	607 (551, 763)	0.481
Men, n (%)	30 (100)	11 (100)	19 (100)	–	3 (100)	27 (100)	–	5 (100)	25 (100)	–
Age, years	41 (31, 46)	41 (38, 58)	39 (31, 44)	0.200	62 (54, 63)	39 (31, 44)	0.005	40 (28, 60)	41 (32, 44)	0.829
Duration of receiving ART, days	1133 (364, 2110)	1610 (676, 2372)	731 (361, 1874)	0.268	2237 (2185, 2983)	784 (361, 1874)	0.015	1029 (784, 2132)	1236 (364, 2009)	0.706
CD4 cell count, cells/µl	489 (371, 728)	413 (269, 515)	521 (441, 733)	0.112	352 (307, 579)	496 (418, 699)	0.600	352 (275, 413)	521 (441, 737)	0.027
HIV-RNA level				1.000			1.000			0.538
<20 copies/ml, n (%)	26 (87)	10 (91)	16 (84)		3 (100)	23 (85)		4 (80)	22 (88)
20–200 copies/ml, n (%)	4 (13)	1 (9)	3 (16)		0 (0)	4 (15)		1 (20)	3 (12)
Prior AIDS-defining illness, n (%)	5 (17)	3 (27)	2 (11)	0.327	2 (67)	3 (10)	0.064	1 (20)	4 (16)	1.000
Dyslipidaemia (+), n (%)	3 (10)	1 (9)	2 (11)	1.000	1 (33)	2 (7)	0.280	0 (0)	3 (12)	1.000
Diabetes mellitus (+), n (%)	1 (3)	1 (9)	0 (0)	0.367	1 (33)	0 (0)	0.100	0 (0)	1 (4)	1.000
Hypertension (+), n (%)	2 (7)	2 (18)	0 (0)	0.126	1 (33)	1 (4)	0.193	2 (40)	0 (0)	0.023
Current receiving ART including TDF, n (%)	26 (87)	10 (91)	16 (84)	1.000	2 (67)	24 (89)	0.360	5 (100)	21 ()	1.000
eGFR, ml/min/1.73 m²	84.5 (74.4, 92.6)	84.8 (70.9, 89.7)	84.1 (80.1, 91.8)	0.420	68.1 (66.9, 76.5)	85.0 (77.9, 93.5)	0.086	73.5 (72.5, 85.0)	84.8 (79.4, 92.6)	0.300
Proteinuria categories				0.041			–			0.433
A1, n (%)	27 (90)	8 (73)	19 (100)		0 (0)	27 (100)		4 (80)	23 (92)
A2, n (%)	3 (10)	3 (27)	0 (0)		3 (100)	0 (0)		1 (20)	2 (8)
A3, n (%)	0 (0)	0 (0)	0 (0)		0 (0)	0 (0)		0 (0)	0 (0)
Urinary β2MG level, µg/l	209 (115, 1150)	1150 (420, 3525)	138 (107, 258)	0.016	130 (110, 5048)	240 (117, 1129)	0.948	4751 (2298, 8494)	138 (98, 310)	<0.001
Urinary L-FABP level, µg/g creatinine	2.7 (1.1, 4.6)	5.4 (4.6, 8.1)	1.4 (1.0, 2.7)	<0.001	7.7 (7.3, 31.2)	2.6 (1.1, 4.3)	0.005	8.6 (5.4, 11.4)	2.2 (1.1, 3.0)	<0.001

AIDS: acquired immune deficiency syndrome; ART: antiretroviral therapy; β2MG: beta-2 microglobulin; eGFR: estimated glomerular filtration rate; L-FABP: liver-type fatty acid-binding protein; TDF: tenofovir disoproxil fumarate.

Data are expressed as number (percentage) or median (25, 75% interquartile range).

A1: protein-to-creatinine ratio (PCR) < 0.15 g/g creatinine or albumin-to-creatinine ratio (ACR) < 30 mg/g creatinine; A2: 0.15 ≤ PCR < 0.50 g/g creatinine or 30 ≤ ACR < 300 mg/g creatinine; A3: PCR ≥ 0.50 g/g creatinine or ACR ≥ 300 mg/g creatinine.

Survival curve of primary endpoint

In the Kaplan–Meier survival probabilities for renal dysfunction based on the urinary parameters, the cumulative risk of renal dysfunction was higher in patients with higher urinary L-FABP levels and in the A2 proteinuria category than in those with a lower urinary L-FABP level and in the A1 proteinuria category (p = 0.045 and p = 0.037, respectively) (Figure 2(a) and (b)). In contrast, the cumulative risk of renal dysfunction was not significantly different between patients with a higher urinary β2MG level and a lower urinary β2MG level at baseline (p = 0.141) (Figure 2(c)).

Figure 2.

Kaplan–Meier curves for event-free survival of three urinary biomarkers. Patients were divided into two groups based on (a) urinary L-FABP, (b) proteinuria categories, and (c) urinary β2MG. The group with a higher level of urinary biomarkers is represented by the black line and the group with lower levels is represented by the grey line. Differences between the higher and lower group are compared using a log-rank test. β2MG: beta-2 microglobulin; L-FABP: liver-type fatty acid-binding protein.

Values of urinary parameters for predicting renal dysfunction

The cut-off values, sensitivity, specificity, positive predictive value, negative predictive value, and AUC of renal dysfunction for urinary L-FABP, proteinuria category, and urinary β2MG are shown in Table 2. Urinary L-FABP had the highest sensitivity, and the proteinuria category had the highest specificity among the three urinary parameters (Table 2). The AUC of the urinary L-FABP for predicting renal dysfunction (0.784, 95% confidence interval: 0.574–0.994, p = 0.048) was the greatest among the three urinary parameters (Table 2).

Table 2.

Predictive validity of urinary markers for renal dysfunction.

Factors	Cut-off value	Sensitivity	Specificity	PPV	NPV	AUC	95% CI	P value
Urinary L-FABP	4 µg/g creatinine	0.800	0.720	0.364	0.947	0.784	0.574–0.994	0.048
Proteinuria categories	A2	0.400	0.960	0.667	0.889	0.680	0.380–0.980	0.211
Urinary β2MG	1700 µg/l	0.400	0.880	0.400	0.880	0.700	0.467–0.933	0.164

AUC: area under the curve from receiver operating characteristic curves; β2MG: beta-2 microglobulin; L-FABP: liver-type fatty acid-binding protein; NPV: negative predictive value; PPV: positive predictive value.

A2: 0.15 ≤ protein-to-creatinine ratio < 0.50 g/g creatinine or 30 ≤ albumin-to-creatinine ratio < 300 mg/g creatinine.

Sensitivity is the percentage of factors greater than or equal to the cut-off value among occurrence of renal dysfunction.

Specificity is the percentage of factors less than the cut-off value among no occurrence of renal dysfunction.

PPV is the percentage of occurrence of renal dysfunction among individuals with factors greater than or equal to the cut-off value.

NPV is the percentage of no occurrence of renal dysfunction among individuals with factors less than the cut-off value.

Discussion

The purpose of this study was to identify urinary parameters as a potential risk factor for renal dysfunction in people with HIV who have already received ART. This study demonstrated two findings. First, the urinary L-FABP level was potentially a risk factor for renal dysfunction. Second, urinary L-FABP had the most accuracy for predicting renal dysfunction compared with the proteinuria category and urinary β2MG.

Progression of CKD in people with HIV is accelerated by co-morbidities including hypertension,^22,23 hyperlipidaemia,²⁴ hyperglycaemia,^24,25 as well as ageing,^26,27 and HIV-related factors, including low CD4 cell count, high viral load, intravenous drug use, and HCV co-infection.²⁸ Progression of CKD can also be accelerated by ART, mainly TDF, indinavir, lopinavir/ritonavir, ATV/RTV, and abacavir.²⁹ These disorders either cause glomerular injury that leads to tubulointerstitial damage or directly provoke tubulointerstitial damage because of haemodynamic dysfunction. Tubulointerstitial damage is widely known to be the final common pathway in ESRD and it is strongly associated with renal prognosis.^5,6 In this context, urinary L-FABP reflected tubular proximal cell injury that is associated with tubulointerstitial damage. In other studies on people without HIV, a higher urinary L-FABP was a risk factor for progression of CKD.^11–13,30 In people with HIV, it has been shown that the levels of the urinary L-FABP were associated with a HCV co-infection, a lower weight in patients receiving TDF³¹ and associated with mortality in HIV-infected women.³² Moreover, classification of CKD by combining albuminuria with eGFR generally reflected kidney outcomes.³³ Our previous cross-sectional study demonstrated that urinary L-FABP levels were independently associated with the CKD classification in patients with HIV.³⁴ These studies support our results. Therefore, urinary L-FABP may be a potential predictor of renal dysfunction in people with HIV receiving ART.

The present study demonstrated that urinary L-FABP was more accurate at predicting renal dysfunction than the proteinuria category and urinary β2MG. Our results showed that proteinuria was also a risk factor for renal dysfunction, which is also supported by several studies demonstrating that proteinuria and albuminuria are risk factors for CKD.³⁵ Regarding urinary β2MG, it has been reported that urinary β2MG was associated with TDF-related renal dysfunction.³⁶ Urinary β2MG was not a significant predictor of renal dysfunction and had poor sensitivity and accuracy because patients receiving ART without TDF were included in the present study. Urinary protein or albumin levels increase after the occurrence of glomerular structural injury and urinary β2MG levels increase after the occurrence of proximal tubular structural injury. However, urinary excretion of L-FABP from the proximal tubules due to ischaemia and oxidative stress on the renal tubule may increase before progression of glomerular and proximal tubular damage.³⁷ It has been shown that urinary L-FABP is important for identifying CKD and AKI in their early stages and several studies showed that L-FABP was excellent biomarker for early prediction of kidney disease. Furthermore, L-FABP can help to determine a patient’s diagnosis and prognosis, compared with other urinary biomarkers, including urinary N-acetyl-β-d-glucosaminidase and β2MG.^38–42 Moreover, it has been reported that urinary L-FABP is more sensitive than urinary protein for predicting the progression of CKD.⁴³ In ESRD, it is possible that chronic ischaemia could have induced an increase in urinary excretion of L-FABP, even in the absence of albuminuria. A recent study also demonstrated that renal function can rapidly decline without an increase in urinary albumin excretion.⁴⁴ Our previous cross-sectional study in people with HIV has also demonstrated that the urinary L-FABP level was independently associated with CKD classification, although the urinary β2MG level was not associated with CKD classification.³⁴ Therefore, measurement of urinary L-FABP may be particularly useful for patients without overt proteinuria.

Our study has several limitations. First, the findings should be considered preliminary because this was a pilot study with too small a sample size to perform a multivariate analysis. Additional studies are needed to confirm these findings using a larger sample size. A longer follow-up period will give more predictable results and would confirm the study’s validity. Second, our study was designed as an observational study, not an interventional trial. The treatment protocol for patients in this cohort was not controlled, and the time-dependent changes in urinary L-FABP levels during the follow-up period were not assessed. Urinary L-FABP may be modified by any intervention.^45,46 Thus, further studies are required to answer the important question of whether changes in urinary L-FABP levels are associated with prognosis. Third, eGFR was assessed using the formula of the Japanese Society of Nephrology^20,21 because the Chronic Kidney Disease Epidemiology Collaboration equation is limited by the differences in creatinine among ethnicities.²¹ Therefore, these results may not be generalizable to non-Japanese populations.

In conclusion, the present study demonstrates that urinary L-FABP levels are a potential risk factor for renal dysfunction in Japanese men with HIV receiving ART. In addition, urinary L-FABP was the most accurate predictor of renal dysfunction compared with urinary β2MG and proteinuria categories. Measurement of urinary L-FABP may be useful for the detection of patients at greater risk of progression to renal dysfunction. L-FABP may also be used to help direct the management of patients with HIV during ART.

Footnotes

Acknowledgements

We would like to thank Editage () for English language editing.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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