Discussion
This is the first prospective study to investigate the risk of AKI in patients receiving anti-TB treatment by regularly monitoring their renal function; we reported three major findings. First, the incidence of AKI during anti-TB treatment was 10.3%, which was higher than that of our previous retrospective study (7.1%). Second, old age, a higher eGFR, and a blood eosinophil count >350 (109/L) were the three independent predictors for AKI. Third, all patients with AKI completed anti-TB treatment with no or one-drug modification in the treatment regimen and exhibited renal recovery within 1 year.
The literature review revealed four retrospective studies and one case series that focused on AKI occurrence during anti-TB treatment; the studies are summarized in Table 5 [8, 13-16]. Three studies enrolled patients receiving anti-TB treatment [13-15], and two have focused on patients receiving RIF [8, 16]. The incidences of AKI in Romania [13] and Taiwan are 0.05% and 7.4%–10.4%, respectively. The lower incidence of AKI in Romania may be due to underestimation because of missing data in the Iasi Hemodialysis Centre registry database [13]. The higher incidence of AKI in Taiwan may be attributed to the aging population (median age between 52 and 68 years) and the application of the KDIGO definition that includes patients with mild (stage 1) AKI also [14]. Moreover, we adopted a prospective study design and performed a regular follow-up of renal function that could precisely capture patients with mild AKI and without clinical symptoms, thereby providing a true estimation of AKI incidence in patients receiving anti-TB treatment.
Among first-line anti-TB drugs, RIF, INH, and EMB are associated with AKI development during treatment [8-12]. EMB-induced acute renal failure is rare, and only three cases of EMB-induced tubulointerstitial nephritis have been reported [11]. Similarly, INH-induced kidney injury has only been reported in a few pediatric cases [12]. Therefore, the most common offending drug for AKI is RIF [8-10]. The definite pathophysiology of RIF-induced AKI is not well documented. However, a study suggested that RIF antigens may induce either a type II or type III hypersensitivity reaction in which anti-RIF antibodies form immune complexes that deposit in the renal vessels, glomerular endothelium, and interstitial area [16]. These reactions cause two different pathologic changes in the kidneys. Immune complex deposition in the vessels causes vascular constriction and tubular ischemia, leading to acute tubular necrosis (ATN), whereas the deposition of immune complexes in the interstitial area leads to acute tubulointerstitial nephritis (ATIN) [16]. The hypothesis is further supported by the current study finding demonstrating that ATIN and ATN are the most common histopathological findings in anti-TB related AKI (Table 5) [8, 13, 15, 16].
In this study, the average time to AKI was 35 days, and the mean AKI duration was 89 days; the results were similar to those of our previous retrospective study [14], where most patients experienced mild AKI (stage 1). Although anti-TB treatment was interrupted in seven (63.6%) patients, RIF was reintroduced successfully. All patients experiencing AKI completed anti-TB treatment with an RIF-containing regimen. On the basis of the FENa value, the etiology of AKI was classified as prerenal (45%) and intrinsic (55%). Prerenal AKI may have been caused by a decrease in food intake due to gastrointestinal side effects. Because few patients undergo renal biopsy, identifying definite causes of intrinsic AKI remains challenging. Renal function recovery was achieved within 9 months, and patients with prerenal or intrinsic AKI exhibited similar recovery rates (Table 3). Compared with the recovery rate of previous studies, our recovery rate of 100% was much higher [8, 13-16]. Because of the prospective setting and nearly all patients adhering to the follow-up protocol, renal function decline could be detected and intervention in the early phase could be performed before patients exhibited AKI symptoms, such as oliguria or generalized edema.
The multivariate Cox regression analysis revealed that older age, a higher baseline eGFR, and a blood eosinophil count >350 (109/L) were the three significant predictors for AKI development during anti-TB treatment. The higher incidence of AKI in older individuals may be attributed to the following: 1) comorbidities that accumulate with age; 2) comorbidities that necessitate interventions (e.g., drugs) that function as kidney stressors or nephrotoxins; and 3) the kidney undergoes age-dependent transcriptomic, hemodynamic, physiologic, and structural alterations over time [20, 21]. Therefore, clinicians should follow renal function regularly during anti-TB treatment, especially in older patients.
A higher eGFR was associated with a higher risk of AKI; however, this finding is contradictory. Previous studies have demonstrated that patients with chronic kidney disease (CKD) or a higher baseline serum creatinine level (the injured kidney) were more vulnerable to AKI [22-24]. Therefore, the finding that a high eGFR is a risk factor for AKI may be because the percentage changes in serum creatinine level after AKI onset are partly confounded by baseline kidney function; therefore, AKI diagnosis in patients with CKD based on the KDIGO guidelines remains challenging [25]. Nevertheless, our results suggested that regular renal monitoring during anti-TB treatment is necessary even in patients with normal renal function.
Eosinophilia is an uncommon presentation in drug-induced AKI, whereas urine eosinophilia is a common finding in drug-induced AKI, especially of ATIN [26]. Although urine eosinophils cannot be used to effectively distinguish ATIN from ATN or other kidney diseases [27], substantial eosinophilia often reflects an allergic drug reaction and may assist in diagnosing patients with hospital-acquired AKI [28, 29]. Higher eosinophil counts may induce a higher immune reaction during anti-TB treatment, thereby inducing kidney injury.
Our study has some limitations. First, a histopathological examination was not performed for a definite AKI diagnosis. Instead, we used FENa values for identifying AKI caused by prerenal or intrinsic factors. Second, the small sample size may not be representative of the population with TB and may not delineate AKI characteristics during anti-TB treatment. Third, because all patients with AKI completed anti-TB treatment with an RIF-containing regimen, whether these episodes of AKI were drug-induced remains uncertain. In our previous retrospective study, RIF was successfully reintroduced in 71% of patients [14]. The high successful reintroduction rate may be attributed to drug desensitization. A study reported that the RIF desensitization protocol led to a high successful drug reintroduction rate (80%–82%) [30, 31].
In conclusion, the incidence of AKI during anti-TB treatment is not rare (10.3%) and occurs frequently in older patients with normal renal function and a blood eosinophil count >350 (109/L). The kidney injury is usually mild, and patients recover without permanent renal damage. Moreover, most patients with AKI complete the standard anti-TB treatment.