In this observational cohort study of HIV-1-infected south Chinese patients who initiated a TDF-containing cART, we quantified the mean loss of eGFR over time and evaluated the determinants of renal dysfunction among patients who initiated TDF-based ART.
The slope of eGFR was negative in most patients, and more than 34% of individuals developed RKFD, but only 2% of patients experienced stage 3 CKD. The effect of TDF on the decrement of eGFR was evident, continuously increased during the 6-years observation period (from − 2.59 mL/min/1.73 m2 before 48 weeks to -17.61 mL/min/1.73 m2 after 288 weeks). The independent factors associated with a greater likelihood of RKFD was higher eGFR and HIV-RNA viral loads at baseline. Patients with anemia had an increased risk of RKFD. Older age and lower baseline eGFR were significantly associated with an increased risk of stage 3 CKD.
Previous studies in Sub-Saharan Africa have shown that renal dysfunction is highly prevalent in HIV-1 infected patients receiving cART. The incidence of stage 3 CKD was estimated to be 5.2–25% [3, 18], which is higher than the incidence of 2% in our results. However, our findings in general decline on renal function related to TDF exposure were based on a population in which the most patients had preserved kidney function, the pre-existing renal impairment (eGFR < 60 mL/min/1.73 m2 at baseline) patients in the two studies were 5.2% and 25.1% respectively, which are both much higher than 0.1% of our research.
Of note, a study carried out by Qing Tan et al. revealed that the overall eGFR improved over 24 months following TDF initiation among 269 patients in Chengdu, South China [11]. But, the median eGFR at baseline in their research was higher than that of our study (124.0 vs. 108.2 mL/min/1.73 m2). Also, Bygrave et al. in South Africa demonstrated that renal function improved in most patients, in which 176 (18.9%) had a baseline creatinine clearance < 50 ml/min [19]. However, their study was highly limited by missing data and lack of key covariates. While, the results of our sensitivity analyses were similar, which were conducted in 5 imputed datasets to reduce bias caused by missing data in our study, making the conclusion of that the overall eGFR decreased throughout the observation period following TDF initiation more robust. Moreover, the decreased trend of eGFR among TDF users was consistent with a previous study conducted among 650 HIV-positive patients with a median eGFR of 108 (IQR: 91–126) mL/min/1.73 m2 at baseline, which is equivalent to our baseline eGFR level [20].
As in other studies, we found a negative association between stage 3 CKD and baseline eGFR, which was consistent with previous data from South Africa [3]. This cohort focused on individuals with TDF exposure for 48-months revealed that patients with mild (eGFR: 60–89 ml/min; HR 4.8, 95%CI: 1.5–15.2) or moderate (eGFR: 30-59ml/min; HR 15.0, 95%CI: 3.4–66.5) renal dysfunction presented a higher risk of nephrotoxicity by 48-months compared to normal renal function. However, the definition of nephrotoxicity in this study was indistinct, which is defined as the occurrence of any decline in kidney function from baseline (acute or chronic) was observed since TDF initiation, which resulted in a lack of precision for the relationship between baseline eGFR and renal dysfunction. Instead, we avoided obscuring associations between the two factors by the clear definition of kidney dysfunction, and the quantification model of the two variables may help clinicians to assess TDF-related CKD risk according to baseline renal function, accurately.
In contrast, the risk of RKFD showed a positive association with baseline eGFR, as also reported by Takeshi and colleagues in Japan [10]. The definition of RKFD in this study was utterly consistent with us. One possible reason for the positive association is that patients with normal renal function show faster responses for TDF exposure compared to patients with renal dysfunction. In our study, the rarely small proportion of patients with kidney impairment conform to this speculation. As in other studies, patients with anemia and higher viral load at baseline were significantly associated with RKFD [21–23]. Such patients deserve particular focus on renal monitoring.
Consistent with previous studies, older age increased the incidence of stage 3 CKD [11, 18, 20]. These findings may reflect the impact of age on TDF circulating levels. Unlike previous studies, we found no evidence that lower body mass index (BMI) was independently associated with a higher risk of renal dysfunction. A study that baseline eGFR is equivalent to ours has shown similar findings to ours [20]. These findings may result from unmeasured confounding, although we enrolled in more covariates than others [10] and adjusted for the cohort to account for some of these differences.
Our primary results provided important clinical and research illumination. Treatment with TDF-containing regimen has been widely used as first-line antiretroviral therapy in developing countries; ours is the first largest and well-powered study, which utilized rigorous methodological approaches, to show the risks of TDF-related CKD on a follow-up duration of 6.5 years in China, to our knowledge. Although the rate of stage 3 CKD was low among individuals with TDF exposure, in a country like China with a high quantity of HIV-1 infected patients (1.25 million), which is increasing year by year, the numbers of TDF-related CKD is expected to be high. Therefore, to assess renal function management and monitoring approaches would definitely provide a relevant benefit either for preventing or salvaging TDF nephrotoxicity in these settings; studies like ours underline an urgent need for this topic. Eventually, we identified age and baseline eGFR as important predictors for CKD among HIV-1 infected South Chinese patients receiving TDF. Future studies should focus on whether or not prediction models combined with the two above factors and other variables, such as weight, can effectively help clinicians identify patients at high risk of TDF-related nephrotoxicity, which may alter and improve the therapeutic program.
Other than the limitations mentioned above, the duration of follow-up in this research was short. Longer follow-up will be necessary to assess the long-term impact of TDF on kidney outcomes [24]. The inherent shortcomings of retrospective observational single-center study limited its generality in other populations, and thus further validations from different races are warranted.
To conclude, the present study suggested that a longer duration of TDF using was associated with faster renal function decline, and compared to the low rate of stage 3 CKD in our study, patients infected with HIV-1 mainly experienced RKFD in South China. With the expanded use of TDF, prior to screening for baseline eGFR and taking account of age are necessary to reduce TDF-related CKD before ART initiation. In addition, anemia patients and those with unsuppressed viral load deserve particular focus on renal monitoring. Our results were consistent across a range of sensitivity analyses, and the large sample size makes the results more powerful for HIV-1 positive patients exposed to TDF in China.