Combination of Functional Magnetic Resonance Imaging and Histopathologic Analysis to Evaluate Interstitial Fibrosis in Kidney Allografts

Abstract

Background and objectives: Recent developments indicated that functional magnetic resonance imaging (MRI) could potentially provide noninvasive assessment of kidney interstitial fibrosis in patients with kidney diseases, but direct evidence from histopathology is scarce. We aimed to explore the diagnostic utilities of functional MRI for the evaluation of kidney allograft interstitial fibrosis.

Design, setting, participants, & measurements: We prospectively examined 103 kidney transplant recipients who underwent for-cause biopsies and 20 biopsy-proven normal subjects with functional MRI. Histomorphometric analyses of interstitial fibrosis and peritubular capillary densities were performed on digitally scanned Masson's trichrome- and CD34-stained slides, respectively. The performances of functional MRI to discriminate interstitial fibrosis were assessed by calculating the area under the curve using receiver-operating characteristic curve.

Results: Main pathologic findings in this single-center cohort were representative of common diagnostic entities in the kidney allografts, with rejection (32%) and glomerulonephritides (31%) accounting for the majority of diagnoses. Apparent diffusion coefficient from diffusion-weighted imaging correlated with interstitial fibrosis (ρ=-0.77; P<0.001). Additionally, decreased arterial spin labelings were accompanied by peritubular capillary density reductions (r=0.77; P<0.001). Blood oxygen level-dependent (BOLD) imaging demonstrated cortical hypoxia with increasing interstitial fibrosis (ρ=0.61; P<0.001). The area under the curve for the discrimination of ≤25% versus >25% interstitial fibrosis and ≤50% versus >50% interstitial fibrosis were 0.87 (95% confidence interval [95% CI], 0.79 to 0.93) and 0.88 (95% CI, 0.80 to 0.93) by apparent diffusion coefficient, 0.92 (95% CI, 0.85 to 0.97) and 0.94 (95% CI, 0.87 to 0.98) by arterial spin labeling, 0.81 (95% CI, 0.72 to 0.88) and 0.86 (95% CI, 0.78 to 0.92) by perfusion fraction, 0.79 (95% CI, 0.69 to 0.87) and 0.85 (95% CI, 0.76 to 0.92) by BOLD imaging, respectively.

Conclusions: Functional MRI measurements were strongly correlated with kidney allograft interstitial fibrosis. The performances of functional MRI for discriminating ≤50% versus >50% interstitial fibrosis were good to excellent.

Keywords: ROC curve; allografts; area under curve; biopsy; cohort studies; confidence intervals; fibrosis; glomerulonephritis; humans; hypoxia; interstitial fibrosis; kidney biopsy; kidney disease; kidney diseases; kidney transplantation; magnetic resonance imaging; oxygen; renal dysfunction; transplantation; transplantation, homologous.

Graphical abstract

Figure 1.

Assessment of kidney allograft interstitial fibrosis with diffusion-weighted imaging. (A) Violin plot demonstrating that apparent diffusion coefficient in the normal control group is significantly higher than in the allograft injury group. The solid line represents the median, and the dotted lines represent the 25% and 75% IQR. (B and C) Representative examples of water molecular movement restriction with increasingly severe interstitial fibrosis. (B) The allograft hue turns from deep red in a normal allograft (Masson) to (C) green in a dysfunctional allograft with severe (>50%) interstitial fibrosis (Masson). (D) Cortical apparent diffusion coefficients were inversely correlated with interstitial fibrosis (rho=−0.77; P<0.001) in patients with allograft injury. Original magnification, ×100 in (B) and (C).

Figure 2.

Assessment of allograft peritubular capillary density with functional MRI-based perfusion quantification. (A and B) Compared with normal allografts (A) with well preserved peritubular capillaries, allografts with severe interstitial fibrosis (B) had peritubular capillary rarefaction and significantly lower allograft perfusion, as suggested by the reduced peritubular capillary density (CD34) and lower arterial spin labeling readings, respectively, in (B) than in (A) (Original magnification, ×40). (C) Allograft arterial spin labeling readings were significantly correlated with peritubular capillary density in the allograft injury group (r=0.77; P<0.001). (D) Arterial spin labeling readings were significantly correlated with cortical perfusion fraction calculated from diffusion-weighted imaging (r=0.59; P<0.001).

Figure 3.

BOLD imaging evaluation of normal allografts and patients with allograft injury. (A) Violin plot demonstrating that the median cortical R2* is significantly higher in the allograft injury group than in the normal control group. The solid line represent the median, whereas the dotted lines represented the 25% and 75% IQR. (B) Cortical R2* was correlated significantly with interstitial fibrosis in patients with allograft injury (rho=0.61; P<0.001). (C) One-way ANOVA with post hoc Tukey test suggested that the mean cortical R2* was significantly higher in allografts with moderate (>25% to ≤50%) and severe (>50%) fibrosis than in normal controls. (D) Representative example of kidney hypoxia (increased R2*) in allografts with severe fibrosis (right) compared with a normal allograft (left). ci, interstitial fibrosis score.