Noninvasive evaluation of renal pH homeostasis after ischemia reperfusion injury by CEST‐MRI

Abstract

Acute kidney injury (AKI) in mice caused by sustained ischemia followed by reperfusion is associated with acute tubular necrosis and renal dysfunctional blood flow. Although the principal role of the kidney is the maintenance of acid-base balance, current imaging approaches are unable to assess this important parameter, and clinical biomarkers are not robust enough in evaluating the severity of kidney damage. Therefore, novel noninvasive imaging approaches are needed to assess the acid-base homeostasis in vivo. This study investigates the usefulness of MRI-chemical exchange saturation transfer (CEST) pH imaging (through iopamidol injection) in characterizing moderate and severe AKI in mice following unilateral ischemia reperfusion injury. Moderate (20 min) and severe (40 min) ischemia were induced in Balb/C mice, which were imaged at several time points thereafter (Days 0, 1, 2, 7). A significant increase of renal pH values was observed as early as one day after the ischemia reperfusion damage for both moderate and severe ischemia. MRI-CEST pH imaging distinguished the evolution of moderate from severe AKI. A recovery of normal renal pH values was observed for moderate AKI, whereas a persisting renal pH increase was observed for severe AKI on Day 7. Renal filtration fraction was significantly lower for clamped kidneys (0.54-0.57) in comparison to contralateral kidneys (0.84-0.86) following impairment of glomerular filtration. The severe AKI group showed a reduced filtration fraction even after 7 days (0.38 for the clamped kidneys). Notably, renal pH values were significantly correlated with the histopathological score. In conclusion, MRI-CEST pH mapping is a valid tool for the noninvasive evaluation of both acid-base balance and renal filtration in patients with ischemia reperfusion injury.

Non-invasive Investigation of Tumor Metabolism and Acidosis by MRI-CEST Imaging

“…Their first application as pH CEST-MRI agents involved the use of iopamidol (Isovue R , Bracco Diagnostic), possessing two amide proton pools that can be saturated at 4.2 and 5.5 ppm (91,92). The set-up of a ratiometric procedure allows to accurately measure extracellular tissue pH (pHe) in the pH range of 5.5-7.9, independently of the contrast agent concentration, with an accuracy of 0.1 units at several magnetic fields (93)(94)(95). CEST-MRI tumor pH imaging was combined to FDG-PET to elucidate the deregulation of tumor metabolism in a breast cancer model (96).…”

When to stop renal replacement therapy in anticipation of renal recovery in AKI: The need for consensus guidelines

“…MRI‐chemical exchange saturation transfer (CEST) pH imaging can be used to evaluate renal ischemia reperfusion injury. In mouse models, it distinguishes the evolution from moderate to severe AKI, with subsequent restoration of normal pH values serving as an indicator for renal recovery . Arterial spin labeling perfusion MRI also accurately assesses cortical and medullary malperfusion in the setting of AKI, but the relationship between arterial spin labeling measurements and renal recovery could not be quantified .…”

pH Imaging Using Chemical Exchange Saturation Transfer (CEST) MRI

“…In particular, the average pH increased from 6.7 to 7.3 at 3 days after injury, but returned back to 6.7 at 21 days of glycerol administration. This same group showed that pH changes associated with AKI caused by sustained ischemia followed by reperfusion can be detected in a unilateral injury model (one kidney injured) . In this second study, both moderate (20 min) and severe (40 min) injuries were induced through clamp occlusion, which were imaged at several time points thereafter (Days 0, 1, 2, 7).…”

“…(d), (f), representative MRI‐CEST pH maps over imposed onto anatomical images before and after moderate (d), and severe (f), AKI at different time points (day 1, day 2, and day 7) showing pronounced alkalinazation and reduced filtration (non‐colored pixels within the renal region) of the pH‐responsive contrast agent in clamped kidney in comparison to contralateral kidney. Reproduced from:…”