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Diabetic kidney disease is the most common cause of end-stage kidney disease and poses a major global health problem. Finding new, safe, and effective strategies to halt this disease has proven to be challenging. In part that is because the underlying mechanisms are complex and not fully understood. However, in recent years, evidence has accumulated suggesting that chronic hypoxia may be the primary pathophysiological pathway driving diabetic kidney disease and chronic kidney disease of other etiologies and was called the chronic hypoxia hypothesis. Hypoxia is the result of a mismatch between oxygen delivery and oxygen demand. The primary determinant of oxygen delivery is renal perfusion (blood flow per tissue mass), whereas the main driver of oxygen demand is active sodium reabsorption. Diabetes mellitus is thought to compromise the oxygen balance by impairing oxygen delivery owing to hyperglycemia-associated microvascular damage and exacerbate oxygen demand owing to increased sodium reabsorption as a result of sodium-glucose cotransporter upregulation and glomerular hyperfiltration. The resultant hypoxic injury creates a vicious cycle of capillary damage, inflammation, deposition of the extracellular matrix, and, ultimately, fibrosis and nephron loss. This review will frame the role of chronic hypoxia in the pathogenesis of diabetic kidney disease and its prospect as a promising therapeutic target. We will outline the cellular mechanisms of hypoxia and evidence for renal hypoxia in animal and human studies. In addition, we will highlight the promise of newer imaging modalities including blood oxygenation level-dependent magnetic resonance imaging and discuss salutary interventions such as sodium-glucose cotransporter 2 inhibition that (may) protect the kidney through amelioration of renal hypoxia., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Mitochondrial dysfunction is thought to be a critical pathway in the development and progression of kidney diseases, but optimal methods to assess kidney mitochondrial dysfunction are not well known. Saeki and colleagues use positron emission tomography imaging with a novel probe, 2-tert-butyl-4-chloro-5-[6-(4- 18 F-fluorobutoxy)-pyridin-3-ylmethoxy]-2H-pyridazin-3-one ( 18 F-BCPP-BF), to visualize and assess kidney mitochondrial status. The authors demonstrate that reduced uptake of 18 F-BCPP-BF, as assessed by positron emission tomography imaging, corresponds to reduced functioning mitochondria in 3 separate animal models of kidney diseases., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Identifying subjects with progressive chronic kidney disease will be important both in clinical practice and in conducting clinical trials. Pruijm et al. (in this issue) demonstrate for the first time that cortical oxygenation as evaluated by blood oxygenation level-dependent magnetic resonance imaging can predict future loss of renal function. These observations provide the necessary stimulus to continue the development of renal blood oxygenation level-dependent magnetic resonance imaging to further improve the sensitivity and specificity to renal oxygenation and hence the predictive power., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Established as a method to study anatomic changes, such as renal tumors or atherosclerotic vascular disease, magnetic resonance imaging (MRI) to interrogate renal function has only recently begun to come of age. In this review, we briefly introduce some of the most important MRI techniques for renal functional imaging, and then review current findings on their use for diagnosis and monitoring of major kidney diseases. Specific applications include renovascular disease, diabetic nephropathy, renal transplants, renal masses, acute kidney injury, and pediatric anomalies. With this review, we hope to encourage more collaboration between nephrologists and radiologists to accelerate the development and application of modern MRI tools in nephrology clinics.

Hypoxia of the renal medulla is a possible precursor to the onset of acute renal failure in humans and therefore an understanding of the factors influencing the oxygenation status within the renal medulla is very important. Blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) has been shown to non-invasively evaluate intra-renal oxygenation levels of the renal medulla in humans. A newly implemented three-dimensional (3-D) multiple gradient-recalled echo sequence, which permits examination of temporal responses to physiological or pharmacological stimuli, was used to monitor changes in intra-renal oxygenation status during water diuresis. Five healthy, young subjects (22+/-1.2 years) took part in the study. BOLD MRI data were acquired before and after water loading. Studies were repeated on a separate day after the subjects were pretreated with naproxen. Water diuresis significantly improved renal medullary oxygenation levels in all subjects (pre-waterload=30.3 1/s vs post-waterload 22.8 1/s); however, the temporal response was found to be subject dependent. In the presence of cyclooxygenase (COX) inhibition by naproxen, the improvement in oxygenation during water diuresis was completely abolished (pre-waterload=27.5 1/s vs post-waterload 28.5 1/s). Monitoring of temporal responses for the first time during water loading allowed for an appreciation of subject dependence. Comparison of the temporal response in terms of slopes demonstrated a significant difference between the waterload studies with and without naproxen (with naproxen=0.056 1/(s min) vs without naproxen=0.25 1/(s min)). The observed effects of naproxen were consistent with previous findings with COX inhibition.

Background: Hypoxia of the renal medulla has been implicated in the development of renal injury, particularly acute renal failure, and its regulation in humans may therefore be relevant to certain renal disorders. Changes in oxygenation of the renal medulla can now be monitored noninvasively with blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI). Using this method, water diuresis has been shown to improve medullary oxygenation in young persons. Urinary excretion of prostaglandin E2 (PGE2) likewise increases during water diuresis in younger but not in older people. We used BOLD MRI to measure the effects of aging and of inhibiting prostaglandin synthetase on the renal response to water diuresis in healthy human subjects., Methods: Nine younger (25 to 31 years) and nine older (59 to 79 years) female volunteers were studied with BOLD MRI during antidiuresis in the postabsorptive state and during water diuresis. Simultaneously, urinary excretion of PGE2 was determined. PG synthetase was inhibited by administering ibuprofen., Results: Renal medullary oxygenation, initially low, greatly improved during diuresis in younger subjects, whereas PGE2 excretion increased. In older women, however, water diuresis elicited no change in oxygenation of renal medulla or PGE2 excretion. Ibuprofen inhibited excretion of PGE2 and blocked the increase in medullary oxygenation normally produced by water diuresis in the young., Conclusions: The increase in oxygenation of the renal medulla accompanying water diuresis depends on PGE2 synthesis. Attenuation of renal PGE2 synthesis in older people is probably responsible, at least in part, for the loss of the ability to improve medullary oxygenation that younger subjects possess. Inability to improve renal medullary oxygenation might predispose to hypoxic renal injury in older patients.