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Functional MRI to monitor disease progression in patients with rare kidney disease1Bioengineering Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Ranica (BG), Italy, 2Department of rare diseases, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Ranica (BG), Italy, 3Unit of Radiology, ASST Papa Giovanni XXIII, Bergamo, Italy, 4Unit of Nephrology and Dialysis, ASST Papa Giovanni XXIII, Bergamo, Italy, 5Department of Molecular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy, 6Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy, 7University of Bergamo, Bergamo, Italy
Synopsis
Keywords: Kidney, Quantitative Imaging
This study investigates the correlation between MRI and histologic and clinical findings in 7 patients with C3 glomerulopathy and immune complex–associated membranoproliferative glomerulonephritis, rare diseases denoted by poor prognosis and no specific therapies. Patients underwent repeated kidney MRI, biopsy, and laboratory testing. Kidney diffusivity and perfusion were assessed by diffusion-weighted and phase-contrast MRI. Laboratory and MRI parameters changed very differently from case to case over 1 year. Perfusion biomarkers significantly correlated with histological and clinical findings. Both perfusion and diffusion biomarkers correlated with the clinical evolution of the disease. Current findings highlight MRI potential to monitor kidney disease progression.Introduction
C3 glomerulopathy (C3G) and immune complex–associated membranoproliferative glomerulonephritis (IC-MPGN) are rare diseases with poor prognosis and no specific therapies1-3. Several drugs are currently under investigation for C3G and IC-MPGN, however, clinical trials are challenging and heavily influenced by the heterogeneity of these diseases. Repeated kidney biopsies would be needed to accurately monitor disease progression and response to treatment over time, but they are limited by the risk of complications, hard acceptance by patients, and sampling bias. Recent advances in functional renal MRI techniques have allowed to generate quantitative imaging biomarkers potentially improving the management of kidney diseases4. Diffusion weighted MRI (DWI) has been increasingly used to assess renal microstructural damage even before renal function loss, to predict renal function decline, and to follow microstructure changes occurring in response to treatment in chronic kidney disease (CKD)5. In addition, phase-contrast MRI (PC-MRI) allows to assess renal perfusion, providing complementary information6. This study investigates the correlation between MRI parameters and histologic and clinical markers of disease course in patients with C3G or IC-MPGN, providing evidence of MRI clinical validity in monitoring these rare kidney diseases.Methods
Seven patients (18[17-21] years, 43% females) with C3G or IC-MPGN who underwent repeated non-contrast enhanced kidney MRI in addition to biopsy and clinical and laboratory evaluation, before and after 1 year of treatment with danicopan, in the context of a clinical trial (clinicaltrials.gov ID NCT03723512) were included. DWI and PC-MRI were used to investigate kidney diffusivity and perfusion. DWI signal was interpreted by a segmented fitted biexponential approach allowing to compute pure diffusion - D, pseudo-diffusion - D*, and flowing fraction - F, using in-house Matlab software. The renal artery average velocity profile was computed from PC-MRI and blood flow was averaged over all phases. Total renal artery blood flow (RBF) was computed as sum of left and right RBF. Derivative parameters were computed as follows: renal plasma flow (RPF) = RBF * (1 – hematocrit); filtration fraction (FF) = GFR/RPF*100; and renal vascular resistance (RVR) = mean arterial pressure / RPF. The correlations between MRI and histologic and clinical findings were investigated by Spearman’s correlation.Results
Kidney biopsies showed variable degree of global and segmental glomerular sclerosis ([5-30]% and [10-60]% respectively), mild interstitial fibrosis (<10%), and increased peritubular interstitial volume ([19-40]%). Peritubular interstitial volume, global and segmental glomerular sclerosis, assessed at all available time points, were negatively associated with RBF (rho =-0.81, p=0.022; rho = -0.77, p=0.021; and rho = -0.58, p=0.100, respectively) and RPF (rho=-0.52, p=0.200; rho = -0.73, p=0.031; and rho = -0.47, p=0.200, respectively) and positively associated with RVR (rho=0.65, p=0.083; rho = 0.73, p=0.026; and rho = 0.67, p=0.047) (Figure 1). No significant correlation was found between any MRI parameter and interstitial fibrosis. The albumin to creatinine ratio (A/C) was negatively associated with RBF and FF (rho=-0.86, p<0.001 and rho=-0.6, p=0.043, respectively), while positively correlated with RVR (rho=0.88, p<0.001). No correlation was found between A/C and diffusivity at individual time points (Figure 2A). Measured glomerular filtration rate (GFR) was positively associated with diffusivity in the kidney (rho=0.59, p=0.034), with RBF and FF (rho=0.87, p<0.001 and rho=0.85, p<0.001), while negatively correlated with RVR (rho=-0.89, p<0.001) (Figure 2B). Considering the disease course in individual patients, a decrease in A/C after 1 year follow-up was associated with an increase in kidney diffusivity (rho=-0.5, p=0.27) (Figure 3A). An increase in mGFR was associated with an increase in kidney diffusivity (rho=0.77, p=0.1), RBF and FF (rho=0.7, p=0.23 in both cases), and with a decrease in RVR (rho=-0.7, p=0.23) (Figure 3B).Discussion
Measured GFR and A/C was associated with functional MRI markers, reflecting renal damage and parenchymal changes, in line with a previous study7. Among the histologic parameters, global and segmental glomerular sclerosis were associated with perfusion parameters, indicating a possible detrimental effect of these histologic features on renal function. The significant association found between MRI-based perfusion parameters and peritubular interstitial volume suggests that the latter could represent a possible therapeutic target. Despite several cross-sectional studies5,6, longitudinal evidence of DWI or PC-MRI clinical validity in monitoring kidney disease progression is still limited8-12. Current findings are in line with a recent study showing a good correlation between multiparametric MRI and renal function biomarkers in healthy volunteers and patients with CKD13. Limitations of this study include the small number of patients, still significant due to the rarity of the disease, and the lack of follow-up biopsies, that did not allow to investigate the correlation between changes in MRI biomarkers and changes in histologic parameters.Conclusion
Functional MRI biomarkers significantly correlated with histologic and clinical findings in rare kidney disease patients with very different disease course, suggesting that functional MRI could replace repeated biopsy for monitoring kidney disease progression. Future larger studies are needed to confirm current findings and demonstrate the benefit and cost effectiveness of multiparametric MRI in kidney disease management.Acknowledgements
This study was supported in part by Alexion Pharmaceuticals, Boston, Massachusetts, USA, and by the Italian Ministry of Health, under the frame of ERAPerMed (ERAPERMED2020-326 - RESPECT).References
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