Multiparametric magnetic resonance imaging: A robust tool to test pathogenesis and pathophysiology behind nephropathy in humans

Chronic kidney disease (CKD) is a major population disease. In diabetes as well as hypertension, kidney disease is one of the most serious complications. Recent research has demonstrated that chronic hypoxia is a key actor in the pathogenesis of CKD. In this review, we focus on how functional magnetic resonance imaging (fMRI) techniques can shed light on pathogenetic mechanisms and monitor new treatments aimed at preventing or ameliorating the disease. Multiparametric MRI techniques can measure changes in renal artery flow, tissue perfusion, and oxygenation repetitively over short time periods, enabling high time resolution. Furthermore, renal fibrosis can be quantified noninvasively by MRI diffusion tensor imaging, and techniques are upcoming to measure renal oxygen consumption. These techniques are all radiation and contrast‐free.

renal fibrosis can be quantified noninvasively by MRI diffusion tensor imaging, and techniques are upcoming to measure renal oxygen consumption. These techniques are all radiation and contrast-free.
We briefly present data, demonstrating that fMRI techniques can play a major role in future research in CKD, and possibly also in daily clinical practice.

K E Y W O R D S
ASL, BOLD, chronic kidney disease, DTI, kidney, MRI, perfusion, RBF The kidney is prone to hypoxia due to very high metabolic demands and a complex arrangement of vessels and tubules needed for urinary concentration. Hypoxia has now been established as a central factor in the pathogenesis of human chronic kidney disease (CKD) (Heyman et al., 2008;Inoue et al., 2011).
In diabetic kidney disease, the risk of hypoxia is further aggravated by an increased reabsorptive load of sodium and glucose due to hyperfiltration, by defects in the renoprotective vasodilating mechanisms and also by decreased energy efficiency (Hansell et al., 2013).
Recently, increasing focus has been on the role hypoxia plays in diabetic kidney disease, as demonstrated experimentally and reviewed by Packer (Packer, 2021). Here, it is described how diabetes leads to kidney hypoxia and oxidative stress, which changes the balance between the hypoxia inducible factors, HIF1α and HIF2α, causing inflammation and impaired erythropoiesis.
Given that chronic hypoxia is a final common pathway to endstage kidney disease, we will briefly review how modern functional MRI (fMRI)-techniques can help us demonstrate and quantitate these disease mechanisms.
Renal blood oxygenation can be estimated, using the paramagnetic property of deoxyhemoglobin as a surrogate measure, so called blood oxygenation level-dependent contrast (BOLD). The BOLD imaging signal is expressed by the transverse relaxation time (T 2 *) or rate (R 2 * = 1/T 2 *). BOLD measurements established that hypoxia is present in CKD in humans (Li et al., 2020;Packer, 2021).
The parameter T 2 * has been validated to have a linear relationship to renal cortical and medullary tissue PO 2 levels (Pedersen et al., 2005;Zhang et al., 2014). Changes in R 2 * (or BOLD signal) have been validated as an indirect measure of changes in renal blood oxygenation (Liss et al., 2013;Milani et al., 2017;Pruijm et al., 2018), and acute changes in R 2 * are considered a better surrogate measure of changes in blood oxygenation than baseline R 2 * as a measure of resting blood oxygenation Khatir et al., 2014). For example, CKD patients having similar R 2 * values as healthy controls but have significantly larger changes in R 2 * when inhaling 100% oxygen (Cox et al., 2017;Khatir et al., 2014).
Tissue oxygenation, importantly, is a function of oxygen consumption and oxygen delivery by tissue perfusion, which means that changes in oxygenation cannot be interpreted without monitoring the perfusion.
Renal tissue perfusion can be measured simultaneously in the cortex and medulla with arterial spin labeling (ASL) with intermittent magnetic labeling of protons and measuring in the same area after a postlabeling delay (Roberts et al., 1995).
Renal artery flow in mL/min can be measured by phase contrast imaging, which is a well-documented technique (Debatin et al., 1994).
It is possible to do interleaved measurements of these parameters in the same study (multiparametric MRI).
Studies using such multiparametric MRI techniques are increasing in number and becoming more clinically viable Boer et al., 2021;Cox et al., 2017). Quantification of renal hemodynamics with these techniques has been successfully employed to measure fluctuations in healthy subjects during various challenges and identify deficits in patient groups encompassing different forms of nephropathy (Milani et al., 2017;Niendorf et al., 2015;Pruijm et al., 2013;Yin et al., 2012). Furthermore, the repeatability of these multiparametric measures has been thoroughly evaluated Boer et al., 2021), and an expert consensus has emerged regarding technical aspects for an optimized application of ASL (Nery et al., 2020), phase contrast (Boer et al., 2022), and R 2 * imaging Dekkers et al., 2020) in a clinical setting.
By using interleaved measurements with the above-mentioned techniques, we could demonstrate that hand grip exercise bouts of only 5 min duration caused a decrease of renal artery flow and cortical and medullary perfusion, but an increase in medullary oxygenation due to reduced reabsorptive workload (Haddock et al., 2018). Thus, a complete set of measurements (renal artery flow, cortical and medullary oxygenation and perfusion) can be repeated with 7 min intervals, making this technique ideal for evaluating acute responses to a pharmacological intervention ( Figure 1). Using this technique, we have shown that the wellknown increase of medullary oxygenation after furosemide does not involve a change of perfusion (Haddock et al., 2019).
The technique was also applied in human studies to investigate mechanisms behind the renal effects of sodium/glucose cotransporter 2 inhibitors (SGLT 2i) and glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), both antidiabetic classes of drugs known for their proven efficacy and safety profile. Of note, in cardiovascular outcome trials, both drugs have demonstrated beneficial cardiovascular actions in patients with type II diabetes, partly attributable to renoprotection (Marso, Bain, et al., 2016, Marso, Daniels et al., 2016Muskiet et al., 2017).
In patients with diabetic nephropathy, a single dose of Dapagliflozin, an SGLT2-inhibitor, improved renal cortical oxygenation without changing renal artery flow or cortical perfusion (Laursen et al., 2021).
In healthy subjects, GLP-1 increases mainly renal medullary perfusion, but also cortical perfusion and renal oxygenation during sodium loading (Haddock et al., 2023) (Figure 2). By preserving tissue oxygenation, improved perfusion may contribute to the beneficial long-term renal and cardiovascular effects of GLP-1 RAs.
Measurements of renal oxygen consumption with fMRI is also possible, using the technique called TRUST (T2 relaxation under spin tagging) to monitor the oxygen concentration in the renal vein (Liss et al., 2013), and is now under validation.
Furthermore, renal fibrosis can be quantified by fMRI, using a technique called diffusion tensor imaging. It has been shown that water diffusion is limited in a characteristic way by renal fibrosis, and the diffusion parameter apparent diffusion coefficient has shown a close correlation to biopsy-verified renal fibrosis in subjects with diabetic nephropathy (Inoue et al., 2011). In summary: in CKD, modern fMRI-techniques offer insight into pathophysiological mechanisms, short-and long-term hemodynamic and metabolic effects of drugs and quantitation of chronic changes such as fibrosis. Of note, all the methods are noninvasive, contrastand radiation-free. In due course, these methods will likely find applications in daily clinical practice as well.

CONFLICT OF INTEREST STATEMENT
Dr Asmar consulted for Novo Nordisk. No conflicts of interest, financial or otherwise, are declared by the remaining authors.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.