3.1 Baseline demographic and clinical data
As expressed in Table 2, the average age of the 81 D-ATIN patients was 45.4±12.9 years, with a female predominance (51/81, 63.0%). The interval from the initiation of drug use to the diagnostic biopsy was 30 (14, 63) days. The majority of patients (77/81, 95.1%) were identified as having AKD, and 4 patients (4.9%) were classified with CKD. Eighteen patients (22.2%) required and initiated RRT before the biopsy. Seven patients (8.6%) were oliguric. Twenty patients (24.7%) had an allergic history. Common clinical features included digestive symptoms (61.7%), weakness (48.1%), fever (45.7%) and rash (16.0%). Beta-lactams, herbal medicine and nonsteroidal anti-inflammatory drugs were the most prevalent culprit agents (45.7%, 39.5% and 32.1%, respectively). Thirty-eight patients (46.9%) were identified as using more than one kind of culprit drug.
3.2 Clinical relevance of the SIS in D-ATIN patients
Of the 81 D-ATIN patients, the ESR was elevated in 70 (86.4%), with an average level of 61.0 mm/hr. CRP was elevated in 44 patients (54.3%), with a median value of 9.7 mg/L (Table 2). SISs evaluated by both ESR and CRP levels were positively correlated with sCr values at renal biopsy (r=0.440; P<0.001), leukocyturia (r=0.366; P=0.001) and C3 levels (r=0.533; P<0.001) (Additional Table 1).
Based on the SIS values, there were 23 patients in the low-SIS group, 24 in the medium-SIS group and 34 in the high-SIS group. There was no significant difference in age, sex, allergic manifestations, or causal medications among the three groups of patients. Patients in the low-SIS group had the mildest kidney injuries, with the lowest sCr levels at renal biopsy (median value: 151 μmol/L, P<0.001), lowest RRT rate (4.3%, P=0.023) and highest hemoglobin concentration (114.7±14.0 g/L, P=0.001). It is interesting to note that patients in the medium-SIS group tended to have higher peak sCr levels (median 417 vs 358 μmol/L) and RRT rates (37.5% vs 23.5%) than those in the high-SIS group, yet their disease courses were relatively longer (median 30 vs 17 days) with lower levels of sCr at biopsy (median 274 vs 321 μmol/L). In addition, patients in the high-SIS group had significantly higher C3 levels (1.3±0.2 vs 1.1±0.2 mg/L, P<0.001) with a greater prevalence of leukocyturia (79.4% vs 45.8%, P=0.002) than those in the medium-SIS group (Table 2).
3.3 Pathological relevance of the SIS in D-ATIN patients
Compared to patients in the low-SIS and medium-SIS groups, those in the high-SIS group had the highest degree of interstitial inflammation (P<0.001) and the lowest degree of interstitial fibrosis (P=0.030) (Table 3). The SIS was positively correlated with renal interstitial inflammatory cell infiltration (r= 0.508; P<0.001) and interstitial edema (r = 0.294; P=0.008) and inversely correlated with interstitial fibrosis (r = -0.266; P=0.016) (Additional Table 1). Multiple linear regression analysis demonstrated that only the SIS was significantly correlated with the renal activity index (β coefficient = 0.293, P=0.003).
We next investigated renal interstitial inflammatory cell types through immunofluorescence staining. The number of each kind of interstitial inflammatory cell increased significantly with the increase in SISs (Table 3). When focusing on the constitution of inflammatory cells, the proportions of neutrophils (7.5% vs 2.4% in medium-SIS vs 1.1% in low-SIS; P<0.001) and plasma cells (12.6% vs 9.2% in medium-SIS vs 9.4% in low-SIS; P=0.047) were the highest in patients in the high-SIS group compared with those in the other two groups. There was no significant difference in the proportions of T lymphocytes, B lymphocytes or macrophages among the three groups of patients. Eosinophils, which favor a diagnosis of drug-induced ATIN, were also highest in the high-SIS group (median value: 3.8 vs 0.8 in medium-SIS vs 0.4 in low-SIS; P<0.001).
3.4 Treatment and outcome among three groups with different SISs
As shown in Table 4, prednisone was prescribed at a dosage of 30–40 mg/day in all the patients. Additional immunosuppressive agents, such as mycophenolate, azathioprine and cyclophosphamide, were used in 27.2% (22/81) of patients, with no significant difference among the three groups (P=0.436). Methylprednisolone pulse therapy was performed in 22.2% (18/81) of all patients, and none of the low-SIS patients received methylprednisolone pulse therapy.
Patients were followed for at least 12 months (range: 12-132 months, median 38 months). The high-SIS group tended to have more favorable renal restoration than the other two groups (Figure 2). At 6 months postbiopsy, complete recovery was achieved in 73.5% of high-SIS patients, 50.0% of medium-SIS patients, and 65.2% of low-SIS patients (P=0.195). A decreased eGFR (<60 mL/min/1.73 m2) was observed in 32.4% of high-SIS patients, 66.7% of medium-SIS patients, and 30.4% of low-SIS patients (P=0.014) at 12 months postbiopsy (Table 4). Adding SIS as a continuous variable to age and eGFR measured at biopsy made a small increase for the area under receiver operating characteristic curve by using the logistic regression analysis (from 0.696 to 0.731 for complete recovery at 6 months and from 0.852 to 0.875 for decreased eGFR at 12 months).
Fifty-four patients with severe renal dysfunction at the time of biopsy (eGFR <30 mL/min/1.73 m2) were divided into high-score (N=26) and low-score (N=28) subgroups based on the SIS. The eGFR values at biopsy were similar in the two subgroups (14.3±7.8 mL/min/1.73 m2 in high-score vs 17.7±8.5 in low-score, P=0.131). At 12 months postbiopsy, the eGFR values were significantly higher in the high-score subgroup (65.3±20.2 vs 52.9±20.9 mL/min/1.73 m2 in low-score, P=0.032).