Clinical and pathological characteristics
There were altogether 20 individuals recruited for this study, including 5 ATIN patients, 15 CTIN patients, and 5 healthy control. Four patients were excluded from the study because the quality of their fMR images was poor to be used(Fig 1. flow chart). Four patients with ATIN, thirteen patients with CTIN, and four healthy control were finally enrolled. The demographic and clinical data of the subjects are summarized in table 1. The ATIN patients were 43.8±19.4 years old, with an averaged 52.0±13.3 years old of CTIN patients. All the ATIN patients experienced acute kidney injury (AKI) defined using the Kidney Disease: Improving Global Outcomes (KDIGO)[26-27] criteria and consensus report of the Acute Disease Quality Initiative 16 Work group. There were two patients in AKI stage 1, two in AKI stage 2 and one in AKI stage 3. Renal pathology revealed that in ATIN kidneys, the glomeruli were relatively intact. Focal or diffuse tubular injuries, and diffuse interstitial edema and mononuclear cells infiltration were predominant pathological findings[Fig 4]. The activity index was averaged 12.8±3.3, with the chronicity index 3.5±0.6. Urinary albumin was increased to an average of 102.0 ± 65.9 mg/L. The Scr level was 112~401μmol/l (217.4±126.4 μmol/l, eGFR 37.4±31.5 ml/min/1.73m2) at the time of renal biopsy, and gradually declined to normal level after short-term steroids administration during the following three months, the eGFR was averaged 65.5±29.0 ml/min, 74.4±41.1 ml/min at the third (T3) and sixth month (T6). The hemoglobulin of ATIN patients was 99.0±13.4 g/L initially, and corrected to 129.0±13.2 g/L.
Thirteen patients with CTIN were from our out-patient specialty for tubulointerstitial nephritis under integrative supportive therapy for CKD. The renal function was stable the recent three months before MR imaging. Patients were in CKD stage 2~5 non-dialysis, whose eGFRs were averaged 34.7±21.9 ml/min (Scr 102~526 μmol/l). Urinary albumin was 30.0 ± 17.5 mg/L. Renal anemia of CTIN patients had already been corrected to 126.8±16.8 g/L, which was matchable with healthy control.
Functional MR imaging features
In control kidneys[Fig 5], the outline was smooth and there was clear differentiation between renal cortex and medulla on T1-weighted SE and IR sequence. The averaged volume of kidneys was (144.6±16.8)×103 mm3. Global ADC values of DW imaging was 3.39±0.11 and 2.16 ±0.08 respectively when b value was 0, 200 or 0, 800 s/mm2. Cortical R2* value calculated from BOLD MR imaging was 19.7±2.1 Hz, that was obviously lower than medulla [(33.1±4.1) vs. (19.4±1.9) Hz, p<0.05] .
In ATIN patients, swollen kidneys were observed [Fig 6]. The volume was (176.8±82.8)×103 mm3. ADC values obtained in DW imaging both when b value 0, 200 s/mm2 and 0, 800 s/mm2 were used, were all found to have significant decreases as 18.5%, 15.6% respectively than control group (Table 1). And obvious rising of decreased ADC values were observed following improvement of renal function to achieve a 93.5%, 100% recovery at the third month (see Table 1). Both cortical and medullary R2* values of ATIN kidneys were also lower than controls at the time of renal biopsy, the differences was significant in MR2* values as 26.6% (difference in CR2* values was 10.7%). The medullary R2* values firstly went back to a level similar as control, while the cortical R2* values remained low (92.9% of control). For CTIN patients [Fig 7], extremely shrink kidneys with irregular outlines were found (fig 2). The volume was 89.0±23.0×103 mm3. Both ADC values when b value 0, 200 s/mm2 and b value 0,800 s/mm2 were similar as healthy control. In R2* map, medullary R2* value of CTIN kidneys was averaged 28.0±5.0 Hz, which was lower than control but the difference was not statistically significant.
Further analysis disclosed that neither ADC values nor R2* values, was correlated to histopathological indexes including tubular injuries (tubular epithelial cells atrophy, vacuolar degeneration, brush border shedding, necrosis and tubulitis) and interstitial changes (edema, inflammation and fibrosis) when compared separately. We also found no relationship within ADC values, R2* values, AI and CI. It seems that ADC and R2* values changed along with that of renal function (Table 1) in ATIN kidneys, while close relationship was only identified in MR2* values with eGFR (R=0.8, P=0.017) and Scr (R=-0.502,P=0.012). The situation was similar whether for CTIN patients (R=0.615, P=0.025) or all TIN patients (R=0.682, P=0.001). ADC when b was 0, 800 s/mm2 in ATIN kidneys was negatively correlated with albuminuria (R=-0.951, P=0.001), while there was no such relationship with CTIN. ATIN Patients having a lower ADC when b value was 0,200 s/mm2, showed more significant changes of ADC (ΔADC, the change of ADC value over the following three months, R=-0.956, P=0.044) and MR2* (ΔMR2* , R=-0.949, P=0.05) after therapy. ΔADC b value 0,200 s/mm2, was also correlated to the change of medullary R2* values (ΔMR2*, the change of MR2* value over the following three months, R=0.995, P=0.005), which was regarded as a marker mainly affected by blood perfusion. Renal long-term prognosis analysis among candidate predictive markers showed that no relationship was found with time-point ADC or R2* values, but as MR2* having a significant correlation to eGFR and Scr levels as above mentioned, it was speculated that more lower the ADC value (b was 0, 200 s/mm2) was, the greater increase of ADC and MR2* after therapy, more decrease of Scr level would be. In ATIN kidneys, a significant reduction of medullary R2* value and ratio of MR2* to CR2* were detected. The rapid and reversible change of the medullary R2* value suggested that the tubular injury was mainly caused by ischemic factors.
Although both CR2* and MR2* were decreased than those of healthy control at ATIN, their changes after treatment were varied, with further decline of CR2* in two patients; in the CTIN group, only a low level of MR2* was observed while CR2* could remain at the normal level. These suggest that there might be a delayed recovery of AKD injury, and the "pseudo normalization" of CR2* is caused by oxygen adaptation changes during CKD.