Discussion
Establishing a clinical diagnosis of drug-induced AIN is exceedingly
difficult given the numerous types of medications associated with AIN.
Although AIN often occurs less than 2 weeks after drug exposure, it has
been shown to vary from days to months depending on the drug [2].
However, a diagnosis of AIN may be established through knowledge of the
patient’s medical history and specific laboratory tests, such as DLST
[2-5]. In fact, DLST has been regarded as a useful diagnostic test
for various types of drug hypersensitivity, including drug-induced AIN,
by measuring drug-induced T cell proliferation in vitro [6,7]. In
the current case, considering that the patient showed a specific high
score for Lexaburo in DLST, the patient’s renal abnormality was
initially considered to have been attributed to drug-induced AIN. We
believe that the subsequent development of TINU syndrome in our patient
may have been caused by the additive, synergistic, or cumulative effects
of the drugs, including Lexaburo. Although DLST results are not
absolute, T cell-mediated mechanisms have been proposed to play a major
pathogenic role in TINU syndrome, which necessitates drug induction
[2,7]. Case information on prior drug use as an estimated risk for
TINU syndrome continues to accumulate [7-10]. However, similar
inducers have been identified in both isolated AIN and TINU syndromes
[2,7,8]. Unfortunately, determining the exact contribution of each
is quite difficult. Whether AIN without TINU syndrome and uveitis is a
different phenotype of the same pathology is particularly important and
crucial issue that needs to be extensively investigated [11]. As
such, we note that recent studies on the pathogenic role of modified CRP
(mCRP) can irreversibly dissociate from native CRP in TINU syndrome
[12,13]. This is because it can be one of the common target
autoantigens in kidney and eye tissue [10,13,14]. Interestingly,
serum levels of anti-mCRP autoantibodies may play a role in
distinguishing patients with TINU syndrome from those with AIN
[13,14]. Unfortunately, such a procedure is inapplicable to the
current patient. Moreover, HLA-type analysis is progressing in TINU
syndrome, with reports showing that HLA-DQA1, HLA-DQB1, and HLA-DRB1 are
associated with the onset [11,15]. The HLA type in the current case
was unknown, with the patient not consenting to genetic testing.
Identifying the patient’s mCRP and HLA types may have helped establish a
diagnosis, and we believe that similar cases will benefit from such
tests in the future. The main treatment for AIN is to discontinue or
reduce the dose of the problematic drug [2,4]. Corticosteroid
therapy has shown no clear benefits after discontinuation of the
problematic drug. One study showed that 72% of patients with TINU
syndrome who did not use systemic steroids were expected to
spontaneously recover from renal dysfunction [16]. In contrast,
another report revealed that two out of four patients who did not
receive steroids progressed to chronic renal failure, with one patient
developing end-stage renal failure [8]. Several reports have
suggested corticosteroid administration may shorten the course of renal
failure [4,5,17]. Considering that no improvement in the renal
function of the current patient was observed following drug
discontinuation, PSL was started at 60 mg/day (1.3 mg/kg/day). The
interval between drug discontinuation and start of steroid treatment was
approximately 3 weeks. Immediately after starting PSL treatment, the
patient’s renal function improved. This finding is consistent with that
reported in previous studies, which showed that patients often respond
to PSL doses of 1–2 mg/kg/day. Many authors agree with corticosteroid
treatment for patients with TINU syndrome who have advanced renal
failure similar to AIN. Simultaneous use of topical ocular steroids and
immunosuppressants may be essential due to the prolonged and/or
recurrent uveitis associated with this syndrome [18-20].