Reduced cortical oxygenation predicts a progressive decline of renal function in patients with chronic kidney disease

Abstract

Renal tissue hypoxia is a final pathway in the development and progression of chronic kidney disease (CKD), but whether renal oxygenation predicts renal function decline in humans has not been proven. Therefore, we performed a prospective study and measured renal tissue oxygenation by blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) in 112 patients with CKD, 47 with hypertension without CKD, and 24 healthy control individuals. Images were analyzed with the twelve-layer concentric objects method that divided the renal parenchyma in 12 layers of equal thickness and reports the mean R2* value of each layer (a high R2* corresponds to low oxygenation), along with the change in R2* between layers called the R2* slope. Serum creatinine values were collected to calculate the yearly change in estimated glomerular function rate (MDRD eGFR). Follow up was three years. The change in eGFR in CKD, hypertensive and control individuals was -2.0, 0.5 and -0.2 ml/min/1.73m/year, respectively. In multivariable regression analysis adjusted for age, sex, diabetes, RAS-blockers, eGFR, and proteinuria the yearly eGFR change correlated negatively with baseline 24 hour proteinuria and the mean R2* value of the cortical layers, and positively with the R2* slope, but not with the other covariates. Patients with CKD and high outer R2* or a flat R2* slope were three times more likely to develop an adverse renal outcome (renal replacement therapy or over a 30% increase in serum creatinine). Thus, low cortical oxygenation is an independent predictor of renal function decline. This finding should stimulate studies exploring the therapeutic impact of improving renal oxygenation on renal disease progression.

Cortical Perfusion and Tubular Function as Evaluated by Magnetic Resonance Imaging Correlates with Annual Loss in Renal Function in Moderate Chronic Kidney Disease

“…It is not yet clear if such modest change is due to the inherently lower sensitivity of BOLD MRI in evaluating cortical oxygenation [31] or whether the kidney compensates for the lower perfusion and maintains the oxygenation status. Unlike previous studies [26,27] reporting a significant association of cortical R2* with eGFR and eGFR_slope, we did not observe similar associations. We suspect this may be partly related to the moderate CKD in our study, limited range of eGFR values and the smaller number of subjects.…”

“…Only R2*_MC ratio showed significant differences between the CKD and control groups. The modest increase in cortical R2* is consistent with prior studies [26,27]. It is not yet clear if such modest change is due to the inherently lower sensitivity of BOLD MRI in evaluating cortical oxygenation [31] or whether the kidney compensates for the lower perfusion and maintains the oxygenation status.…”

“…We suspect this may be partly related to the moderate CKD in our study, limited range of eGFR values and the smaller number of subjects. It should be noted that the differences between fast progressors and others in the earlier report [26] was small (21.3 ± 2.6 vs. 20.2 ± 1.9 s -1 , p = 0.033), even though reaching statistical significance. Whole kidney and medullary R2* were moderately and negatively associated with eGFR ( Table 3).…”

“…Recent studies have reported that the cortical oxygenation as evaluated by BOLD MRI can predict future loss of renal function [26,27]. Another recent study evaluated BOLD and diffusion MRI in a large multicenter study in subjects with advanced CKD (mean eGFR 33.4 ± 7.2 mL/min/1.73 m 2 ) and demonstrated reduced renal cortical oxygenation and presence of renal fibrosis consistent with the chronic hypoxia hypothesis [28].…”

“…Evaluating responses with BOLD MRI can demonstrate faster responses, typically within 15 min [45]. The recent study that reported increased cortical R2* to be associated with loss of renal function [26], found no association of response to furosemide with eGFR_slope. Even though the exact reason is not yet clear, we suspect this may be related to the use of con- centric rings as ROIs, which combine cortical and medullary tissue, resulting in reduced sensitivity to detect changes in the medulla.…”