Kidney ailments affect millions of people in the US and worldwide. These include, but not limited to chronic kidney disease (CKD), kidney stones, renal cancers, and acute kidney injury. The current gold standard to globally detect renal dysfunction is through the reduction in glomerular filtration rate (GFR) coupled with the analysis of the urine (proteinuria, chemistry, microscopic examination). Imaging (MRI, CT and US) is also used, but is restricted mainly to assessing anatomy and not function. The tests used today to assess kidneys health either provide global output information (GFR, chemistry and urinalysis) or address anatomy (imaging). Functional and metabolic changes may precede anatomical or global markers. Moreover, the functional changes can be heterogenous; affecting only certain areas of the kidney, or only one kidney, while GFR, urinalysis and gross anatomy appear normal. One of the main functions in the kidney is excretion of urea. In a normal kidney, there is a well-maintained radial gradient for pH and urea (higher in the deep medulla). Failure to maintain these gradients reflects defects in renal function. Thus non-invasive mapping of pH and urea spatial distribution will provide sensitive functional information about kidney function. Here, we intent to develop such detection method. Chemical Exchange Saturation Transfer is an Magnetic Resonance Imaging contrast mechanism that relies on the selective pre-saturation of the chemically exchanging protons and observation of the subsequent water signal decrease due to exchange of the saturated protons with water. The CEST effect is inherently sensitive to pH, since the rate of chemical exchange is often pH dependent. At the same time the CEST effect is also dependent on the concentration of the exchanging group. Endogenous urea is a natural CEST agent: it possesses two amine groups with protons in chemical exchange with water. Thus, the CEST using these endogenous groups (urCEST) can provide a read-out of urea concentration as well as extracellular pH. Our hypothesis: quantitative urCEST provides spatial maps of pH distribution and the urea concentration in kidneys. We employ technological advances such as: high (3T) field strength, time-interleaved parallel RF transmit, state-of-the-art post-processing. We expand the so-called Omega-plot CEST quantification method to urea, allowing independent determination of the urea concentration and exchange rate (which has one-to-one correspondence to pH). The hypothesis will be validated in phantoms containing aqueous urea in water solutions and agarose gels as well as in the urine samples containing various urea concentrations and pH. These will be followed by in-vivo experiments in normal volunteers undergoing different controlled physiological challenges. Comparison of the pH and concentration determined in bladder using MRI vs urine analysis will serve as the gold standard to validate and characterize the methods developed.
Many kidney diseases alter normal cortico-medullary concentration gradient for solutes, including pH and urea. These disturbances often precede detectable reduction in glomerular filtration rate (GFR), the current clinical 'gold standard' to detect and quantify renal dysfunction. Moreover, current tests cannot provide any focal information about the physiologic read-outs: pH and urea concentration in kidneys. In this proposal we develop a new MRI method, urCEST, aimed at quantitative mapping of renal pH and urea concentration, potentially providing a tool for a real-time, non-invasive, spatially specific assessment of kidney physiology and function.
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