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.