Tracking renal injury using multiparametric MRI

Acute kidney injury (AKI) is an abrupt decrease in renal function with or without structural kidney damage. AKI may result in complete recovery of renal function in a few weeks. However, patients who had an episode of AKI have an eightfold increase in risk for chronic kidney disease (CKD) and a threefold increase in risk for end-stage renal disease (ESRD) (2). The mechanisms for the progression from AKI to CKD and ESRD are not fully understood, and the diagnostic markers and strategies for predicting AKI progression to CKD and ESRD are lacking. While impaired renal function such as elevated serum creatinine levels is completely recovered and within normal ranges, ongoing kidney damage may still be gradually progressing. Yet there are limited tools available for in vivo evaluation of structural kidney damage during CKD progression.

In a recent issue of American Journal of Physiology-Renal Physiology, Jiang et al. (6) detected longitudinal evolution of renal structural and functional changes in folic acid-induced AKI in mice using multiparametric magnetic resonance imaging (MRI). The study demonstrated that the impairments of renal perfusion and glomerular filtration rate (GFR) were partially recovered by 4 weeks post-AKI, but kidney atrophy, renal tissue hypoxia, and interstitial fibrosis were progressively deteriorated following AKI (6). Renal tissue hypoxia and fibrosis play a critical role in the AKI-to-CKD transition in different disease models, including ischemic, toxic, and sepsis-induced AKI (9). Decreased renal oxygenation enhances tissue fibrosis through a variety of cellular processes, such as epithelial-mesenchymal transdifferentiation (3). Interstitial fibrosis in turn worsens renal tissue oxygenation by compromising renal capillaries and limiting oxygen supply (3). Hypoxia and fibrosis, the two main contributors for CKD and ESRD, form a vicious cycle and promote the AKI-to-CKD transition (7). While quantification of renal oxygenation and fibrosis may help in tracking continuous kidney damage following AKI, it is challenging to perform in vivo.

Renal MRI, as a noninvasive medical diagnostic tool, has been used to measure renal function such as renal perfusion and GFR. Furthermore, sensitivity-enhanced MRI detector enables observation of glomerular blood flow in individual nephrons (8). Along with the advances in MRI techniques, renal MRI is also able to detect additional functional and structural kidney changes in vivo. For instance, blood oxygen level-dependent MRI (BOLD-MRI) has been developed for assessing renal tissue hypoxia, and magnetization transfer imaging (MTI) and magnetization transfer ratio (MTR) have been established for evaluating renal tissue fibrosis (5). Also, renal MRI has been used to monitor the progression of renal fibrotic responses in various animal models (4). Jiang et al.’s study found that renal fibrosis detected by MTR in vivo was consistent with the results from Trichrome staining of kidney sections, suggesting that MTR is a reliable method for quantifying renal fibrotic changes (6). This study provides a noninvasive and longitudinal monitoring of the major structural kidney damage during the AKI-to-CKD transition. Between renal tissue hypoxia and fibrosis, it is still unclear which is the cause or consequence. Increasing the MRI measurement time points may help to reveal that either hypoxia or fibrosis occurs earlier than the other. Unfortunately, Jiang et al.’s study had only two time points. Further studies focusing on the colocalization or time sequence of hypoxia and fibrosis may help our understanding of the causative relationship between renal tissue hypoxia and fibrosis. Potential toxicities associated with contrast agents used to measure GFR may limit frequent and multiple measurements. Therefore, it is necessary to design and develop safer MRI contrast agents. Nevertheless, multiparametric MRI may benefit the mechanistic study underlying the development of CKD and ESRD following an episode of AKI, leading to the discovery of reliable predictive markers for the AKI-to-CKD progression. Early prediction and identification of patients who are at risk of CKD could provide a potential opportunity for early therapeutic interventions.

Recent studies show that a number of subcellular and molecular events may contribute to the AKI-to-CKD transition. Several alterations of signaling pathways such as transforming growth factor-β and hypoxia-inducible factor promote renal fibrosis following AKI, resulting in accelerated progression of CKD (3). Our recent study found that downregulation of transient receptor potential vanilloid type 1 (TRPV1) channels predisposes to renal tissue damage and salt-induced hypertension after AKI and that activation of TRPV1 with its agonist capsaicin prevents post-AKI renal fibrotic changes (10). These specific changes at the molecular level in post-AKI renal tissues may be detected by MRI molecular imaging. For example, microparticles of iron oxide targeting vascular cell adhesion molecule-1 (VCAM-1) were used to assess VCAM-1 protein expression in mouse kidney tissues after ischemia-reperfusion injury (1), which would help us to understand the molecular events involved in the AKI-to-CKD transition.

Taken together, multiparametric renal MRI techniques may be potentially used to longitudinally monitor the pathologic processes of the AKI-to-CKD transition, which would improve our understanding of molecular mechanisms, identification of high-risk populations, and evaluation of therapeutic effects in patients with previous AKI.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

S.M. drafted manuscript; C.Q. and D.W. edited and revised manuscript; S.M., C.Q., and D.W. approved final version of manuscript.