Assessing blood flow and oxygen bioavailability reproducibly is important in both native and transplanted kidneys, because trends in these functional parameters can be followed longitudinally and related to kidney function non-invasively in humans [1
]. Furthermore, fMRI allows us to study kidney physiology as a dynamic interaction between renal blood flow and oxygenation, thus advancing our knowledge in basic human kidney function and the roles blood flow and oxygen balance play in disease states. Currently, fMRI is an active area of research to determine the most clinically useful methods for assessing renal function.
The results of this study demonstrate BOLD and perfusion MR imaging can non-invasively assess changes in blood flow and oxygen bioavailability in the cortex and medulla of transplanted kidneys during a single exam. Compared to allografts with normal function and those with ATN, allografts with biopsy-proven acute rejection have significantly decreased medullary R2* values on BOLD MR imaging and decreased medullary blood flow by perfusion MR imaging. The decrease in R2* values in the medulla of rejecting allografts indicates decreased deoxyhemoglobin levels and increased oxyhemoglobin levels, despite decreases in medullary blood flow.
The findings of decreased blood flow and increased oxygen bioavailability in the medulla of acutely rejecting transplanted kidneys is suggestive of a greater decrease in oxygen utilization compared to the decline in medullary perfusion. This apparent increase in oxygen bioavailability may be due to a decrease in glomerular filtration in this group. In animal studies, other investigators have noted increases in oxygen partial pressure in the medulla of kidneys with decreases in glomerular filtration rates [4
]. However, there was a decrease in glomerular filtration as measured by serum creatinine levels in the ATN group as well, yet the R2* measurements in the medulla were not significantly different from normal functioning allografts. Although the number of subjects with ATN in our study is small, our initial results suggest that the changes seen in the acutely rejecting allografts could represent an accumulation of medullary oxyhemoglobin due to impaired oxygen delivery to the cells as a result of parenchymal and microvascular inflammatory injury or decreased metabolic rate of the tubular cells, rather than being due to a decrease in the glomerular filtration rate.
Other investigators have noted decreases in medullary R2* in transplanted kidneys compared to normal native kidneys, as well as allografts undergoing acute rejection compared to normal functioning allografts [19
]. In separate studies, changes in cortical and medullary perfusion have been noted using a qualitative MR perfusion imaging technique, which analyzed the magnitude of the peak signal intensity of the first pass during contrast enhanced MR imaging [15
]. The current study supports the findings of other investigators and is the first study to date to correlate cortical and medullary perfusion and oxygen bioavailability in transplanted kidneys within the same exam.
BOLD and perfusion MR parameters were not significantly decreased in patients with ATN compared to normal functioning allografts. Post-transplant ATN or delayed graft function is primarily due to kidney allograft injury secondary to prolonged cold-ischemia time. In surgically successful transplants, with no septic or hypotensive episode following the procedure, the allograft blood flow is not compromised. Therefore, regional perfusion and oxygenation levels may not be significantly impaired in the absence of ongoing hemodynamic or immunological injury [8
There was a correlation between cortical and medullary MR measured blood flows. This is not surprising knowing the medulla receives its blood flow via the vasa recta that emanate from cortical arterioles [35
]. There was also an inverse relationship between serum creatinine and both cortical and medullary blood flows. This was an expected finding as the renal blood flow decreases during many varied pathologic and pharmacologic stresses that cause decreased renal function as measured by creatinine [4
There was a significant correlation between medullary blood flow and medullary R2* but not between cortical blood flow and cortical R2*. We interpret this in the context of using deoxyhemoglobin as an endogenous contrast agent [22
]. The oxyhemoglobin saturation dissociation curve suggests that at PaO2 values above 40 mmHg, as in the renal cortex, the curve is relatively flat and changes in the PaO2 result in small changes in oxyhemoglobin saturation. However between PaO2 of 10 and 40 mmHg, as in the renal medulla, changes in PaO2 result in large changes in oxyhemoglobin saturation [38
]. Therefore small alterations in PaO2 in the medulla cause changes in oxyhemoglobin concentrations detectable by BOLD MR imaging. Conversely, the changes in PaO2 in the cortex may result in minimal changes in oxyhemoglobin concentration; these differences may not be detectable by BOLD MR imaging at 1.5 Tesla.
There are limitations to consider when interpreting the results of our study. First is the small number of subjects that were studied. Despite the large differences we report between the group of allografts with acute rejection and those with normal function and ATN, our results need to be validated with a large cohort of subjects. This study is a point-in-time analysis and both blood flow and oxygen bioavailability are dynamic physiologic processes. Further studies are needed to determine if a single time point or a series of time points will be more sensitive and specific in the diagnosis of renal transplant dysfunction. Also, we only included patients who were less than four months post-transplantation and therefore our findings may not be applicable to patients with allograft dysfunction beyond the early postoperative period. Lastly, while our perfusion MR measurements in the cortex and medulla of transplanted kidneys are consistent with accepted values published in the literature [10
], the model used to estimate perfusion (Appendix A
) assumes contrast agent does not leave the vascular space during the first pass. However, filtration of gadolinium is known to occur instantaneously, and during the first pass up to 20 percent is filtered in a normally functioning kidney [38
]. This is a constant that can potentially be related to the subject’s serum creatinine. Therefore our perfusion measures are estimates of absolute perfusion and are in part dependent on the glomerular filtration rate.
In light of recent concerns about gadolinium-containing contrast agent and nephrogenic systemic fibrosis (NSF), our group had performed all of these experiments well before this association was suspected [39
]. Currently, contrast perfusion MR imaging needs to be approached cautiously, particularly in those with elevated serum creatinine values or diminished glomerular filtration rates. As data on the subject of gadolinium containing contrast agents and NSF emerges, the hope is to find a more stable agent that can be used safely in patients with renal insufficiency [40
]. Furthermore, non-contrast arterial spin labeling techniques are being developed to study renal perfusion and may take the place of contrast MR perfusion techniques in those with decreased renal function.
In conclusion, this study demonstrated the feasibility of using BOLD and perfusion MR imaging methods to assess changes in transplanted kidney function during a single exam. Compared to normal functioning allografts and those with ATN, MR-measured blood flow was decreased and oxygen bioavailability was increased in the medulla of acutely rejecting kidneys. Further studies verifying these changes in transplanted kidney physiology are warranted as fMRI may provide a sensitive and specific method for the diagnosis of disease in transplanted kidneys and a means by which to follow patients non-invasively during treatment.