Kidney News May 2016 8#5 : Page 1

May 2016 | Vol. 8, Number 5 Basic Science Research Yields Possible New Treatment Targets for AKI ischemia-reperfusion injury (IRI)—each of which identifies a potentially useful new therapeutic target. “There is increasing awareness that acute kidney injury is both a major source of immediate morbidity and mortality and has a long-term impact on the development of chronic kid-ney disease,” said Raymond Harris, MD, FASN, President of the Ameri-can Society of Nephrology. “Unfor-tunately, we still lack effective thera-pies to prevent or treat AKI. Therefore, it is encouraging that these three studies provide important new insights into the pathogenesis and offer potential avenues for prevention and treatment of AKI.” pathway (CAP) as the central mechanism of protection. In a new study, Tsuyoshi Inoue, MD, PhD, Chikara Abe, MD, and colleagues at the University of Virginia School of Medicine in Charlottesville sought to build on that knowledge by testing whether similar protective effects could be induced by ultrasound stimulation of the vagus nerve. In their mouse model, vagal nerve stimulation (VNS) amelio-rated renal IRI via the same CAP activat-ed by ultrasound. The findings included evidence that vagal efferents were the common pathway activating the CAP. The results highlight the importance of neuroimmunomodulatory mecha-nisms of AKI—for example, the “inter-organ crosstalk” by which injury to one kidney affects the response of the other kidney. “In the setting of multiorgan failure, such neural mechanisms are likely to be even more important,” writes Simon J. Atkinson, PhD, Vice Chancellor of Research at Indiana University–Purdue University, Indianapolis, in an accompa-Continued on page 2 Inside Policy Update CMS’s new pay models: Could MACRA’s shift from fee-for-service open up ways for nephrologists to create better care models? Transforming Medical Education Look to kidney care as a model Distinguished Conversations Sharon Moe, MD, interviews Sharon Anderson, MD, about career-life balance, what it was like to be the first woman president of ASN, and much more B asic science research into the un-derlying mechanisms of acute kidney injury (AKI) poses unique challenges, making it difficult to iden-tify promising new targets for prevention and treatment. This month, The Journal of Clinical Investigation presents three new and unique basic science studies ex-ploring differing mechanisms of AKI and Possible protective effect of vagal nerve stimulation Previous research has suggested that ul-trasound preconditioning of adrenergic neurons innervating the spleen has an anti-inflammatory effect—including pro-tection against severe sepsis-induced AKI in a mouse model. Those studies identi-fied the cholinergic anti-inflammatory Cancer and the Kidney ASN Onco-Nephrology Forum releases new curriculum Climate Change May Contribute to Rising Rates of Chronic Kidney Disease of Unknown Origin By Tracy Hampton Glomerular Diseases What should nephrologists know about complement? C Findings called heat stress nephropathy may represent a disease of neglected popu-lations, but one that may emerge as a major cause of poor kidney health as the climate continues to change (Gla-ser J, et al. Clin J Am Soc Nephrol . doi: 10.2215/CJN.13841215 [published online May 5, 2016]). Over the next century, climate change and resulting water shortages are likely to affect a wide variety of health issues related to dehydration and heat stress—with risks increasing for cogni-tive dysfunction, malnutrition, water-borne infectious diseases, CKD, and other conditions. Some health situa-tions, such as a great geographic spread of tropical and infectious diseases, may be more noticeable than gradual chang-es such as incremental increases in pol-len counts that could lead to longer al-lergy seasons and worse asthma cases. In Continued on page 3 hronic, severe dehydration linked to working in hot, hu-mid climates for long hours may be accelerating rates of chron-ic kidney disease (CKD). Research published in the Clinical Journal of the American Society of Nephrol-ogy (CJASN) suggests that a condition Incompatible live-donor kidney transplant improves survival compared with waiting

Basic Science Research Yields Possible New Treatment Targets For AKI

Basic science research into the underlying mechanisms of acute kidney injury (AKI) poses unique challenges, making it difficult to identify promising new targets for prevention and treatment. This month, The Journal of Clinical Investigation presents three new and unique basic science studies exploring differing mechanisms of AKI and ischemia-reperfusion injury (IRI)—each of which identifies a potentially useful new therapeutic target.

“There is increasing awareness that acute kidney injury is both a major source of immediate morbidity and mortality and has a long-term impact on the development of chronic kidney disease,” said Raymond Harris, MD, FASN, President of the American Society of Nephrology. “Unfortunately, we still lack effective therapies to prevent or treat AKI. Therefore, it is encouraging that these three studies provide important new insights into the pathogenesis and offer potential avenues for prevention and treatment of AKI.”

Possible protective effect of vagal nerve stimulation

Previous research has suggested that ultrasound preconditioning of adrenergic neurons innervating the spleen has an anti-inflammatory effect—including protection against severe sepsis-induced AKI in a mouse model. Those studies identified the cholinergic anti-inflammatory pathway (CAP) as the central mechanism of protection.

In a new study, Tsuyoshi Inoue, MD, PhD, Chikara Abe, MD, and colleagues at the University of Virginia School of Medicine in Charlottesville sought to build on that knowledge by testing whether similar protective effects could be induced by ultrasound stimulation of the vagus nerve. In their mouse model, vagal nerve stimulation (VNS) ameliorated renal IRI via the same CAP activated by ultrasound. The findings included evidence that vagal efferents were the common pathway activating the CAP.

The results highlight the importance of neuroimmunomodulatory mechanisms of AKI—for example, the “interorgan crosstalk” by which injury to one kidney affects the response of the other kidney.

“In the setting of multiorgan failure, such neural mechanisms are likely to be even more important,” writes Simon J.Atkinson, PhD, Vice Chancellor of Research at Indiana University–Purdue University, Indianapolis, in an accompaNying commentary. “This is a relatively neglected aspect of AKI and one that, as this new work clearly demonstrates, deserves much more attention.”

Dr. Atkinson said the findings of VNS and ultrasound show promise as a “practical preventative clinical strategy” for AKI—although, unfortunately, likely not for treatment of AKI that has already started to progress. “Given the risk and benefit profile of this strategy, one could imagine this approach being employed widely in critical care settings to reduce the risk of the serious consequences of AKI,” he said.

Drs. Inoue and Abe and colleagues note that VNS is already clinically used for treatment of drug-resistant epilepsy and depression, and is being studied for use in inflammatory disorders such as rheumatoid arthritis and inflammatory bowel disease. They predict that future studies will inform the use of therapeutic ultrasound, as a less-invasive alternative to VNS, to prevent acute injury to the kidneys as well as other organs.

Estrogen and sugar blockade as potential AKI targets

Two additional papers provide evidence of other novel mechanisms and possible therapeutic targets for AKI and IRI. Wuding Zhou, MD, PhD, and Steven H. Sacks, MD, PhD, of King’s College London led research on the contribution of C-type lectin collectin-11 (CL-11), a recently described innate immune factor, in the development of AKI. In a mouse model of ischemic injury, they found that CL-11 interacts with the stress-induced ligand L-fucose, triggering renal epithelial cell injury.

The findings clearly showed that the proximal tubule cell was the source of CL-11 responsible for mediating postischemic renal injury. The researchers also found that CL-11 binding to targeted epithelial cells was easily blocked by soluble monosaccharide inhibitors—suggesting a “physiological control mechanism that merits further exploration and exploitation” of CL-11 as a therapeutic target for hypoxic renal injury. Drs. Zhou and Sacks and colleagues add, “The broad expression of CL-11 and its putative ligands makes it possible that CL-11 operates on a wider scale, promoting inflammation and immunity in other organs and conditions.”

David D. Aufhauser, Jr., MD, and Zhonglin Wang, MD, of the University of Pennsylvania performed a study to explore the previous finding of improved recovery from IRI in females compared to males. In a mouse model of renal ischemia, the researchers found that tolerance of IRI was “profoundly increased” in females versus males. They also noted an “intermediate phenotype” of IRI tolerance after neutering of either sex.

Further experiments found that renal IRI was greater in female estrogen receptor-a knockout mice, as well as a protective effect of supplemental estrogen administration to female mice before induction of ischemia.

Are the findings relevant to human transplant recipients? Analysis of United Network for Organ Sharing data on deceased-donor kidney recipients found a stronger association with delayed graft function in male versus female recipients. “We demonstrated that both donor and recipient hormonal milieus contribute to renal IRI tolerance,” the researchers write. “Recipient effects are dominant in human transplant outcomes, while donor effects appear somewhat stronger in mice.”

Obviously, more research will be needed to explore the clinical ramifications of the findings. But for now, Drs. Aufhauser and Wang and coauthors conclude, “[O] ur results demonstrate that sex affects renal IRI tolerance in mice and humans and indicate that estrogen administration has potential as a therapeutic intervention to clinically improve ischemia tolerance.”

If the protective effects of estrogen are supported by further studies, there may be important implications for protecting against AKI as well, according to an accompanying editorial by Dr. Sanjeev Noel and colleagues of Johns Hopkins University. Coronary artery bypass graft surgery and other scenarios associated with a high risk of AKI “are excellent opportunities to examine the role of sex-specific differences in IRI and determine whether estrogen therapy can be beneficial toward protecting the kidney,” they write.

Read the full article at http://onlinedigeditions.com/article/Basic+Science+Research+Yields+Possible+New+Treatment+Targets+For+AKI/2479905/301771/article.html.

Climate Change May Contribute To Rising Rates Of Chronic Kidney Disease Of Unknown Origin

Tracy Hampton

Chronic, severe dehydration linked to working in hot, humid climates for long hours may be accelerating rates of chronic kidney disease (CKD). Research published in the Clinical Journal of the American Society of Nephrology (CJASN) suggests that a condition called heat stress nephropathy may represent a disease of neglected populations, but one that may emerge as a major cause of poor kidney health as the climate continues to change (Glaser J, et al. Clin J Am Soc Nephrol. Doi: 10.2215/CJN.13841215 [published online May 5, 2016]).

Over the next century, climate change and resulting water shortages are likely to affect a wide variety of health issues related to dehydration and heat stress—with risks increasing for cognitive dysfunction, malnutrition, waterborne infectious diseases, CKD, and other conditions. Some health situations, such as a great geographic spread of tropical and infectious diseases, may be more noticeable than gradual changes such as incremental increases in pollen counts that could lead to longer allergy seasons and worse asthma cases. In This latest CJASN research, investigators found that CKD that is not associated with traditional risk factors (CKDu) also appears to be increasing in rural hot communities as worldwide temperature progressively rises.

The researchers believe the risk for heat stress nephropathy—or CKD consistent with heat stress—has increased owing to global warming and an increase in heat waves, and it is having a disproportionate impact on vulnerable populations, such as agricultural workers.

“So far, the profile for impacted communities seems to be extreme heat and heavy labor. As you leave these extremely hot areas, there are far fewer cases recorded to date even though some of the other proposed risk factors remain relatively unchanged,” said lead author Jason Glaser, of La Isla Foundation, in Nicaragua and the US. Decreasing precipitation exacerbates this epidemic by reducing the water supply and water quality as temperatures climb.

“We were able to connect increased rates of chronic kidney disease in different areas to an underlying mechanism—heat stress and dehydration—and to climate,” said senior author Richard Johnson, MD, of the University of Colorado School of Medicine. “A new type of kidney disease, occurring throughout the world in hot areas, is linked with temperature and climate and may be one of the first epidemics due to global warming.”

Mechanistically, dehydration may inhibit an individual’s ability to excrete toxins as effectively as those who are well hydrated, leading to higher concentrations in the blood and kidney. Dehydration also results in the kidney concentrating the urine. While this is a healthy process that is normally protective in the acute setting, repeated dehydration appears to carry a cost to the kidney, according to Johnson. “Specifically, recurrent dehydration can lead to chronic elevations in vasopressin that may induce kidney damage,” he said. “It can also activate processes that lead to fructose generation in the kidney that can cause local oxidative stress. High concentrations of uric acid can also precipitate in the concentrated urine and may exacerbate injury. These processes may be amplified by rehydrating with drinks high in sugar or high fructose corn syrup.”

Earlier studies by the investigators in Nicaragua and El Salvador revealed a remarkable decrease of kidney function in male sugarcane cutters after highintensity harvesting in hot conditions (García-Trabanino R, et al. Environ Res 2015; 142:746–755; Wesseling C, et al. Environ Res 2016; 147:125–132). Other studies have uncovered similar hotspots in other parts of Central America, as well as in South Asia, North and South America, Africa, and the Middle East.

“I don’t think this disease is new—I think it has been with us for some time, and is more recognized due to increasing surveillance but also because the factors that put people at risk are exacerbated by extreme demands at the workplace to meet production needs,” said Glaser. “The result is over 40,000 dead in the last 10 years in Mesoamerica and Sri Lanka alone. Of course, we think that due to surveillance being so inadequate for these at-risk populations, the disease is much more widespread.”

To address the problem, interventions— such as those proposed in La Isla’s and Solidaridad’s Worker Health and Efficiency (WE) Program (www.Weprogram.org)—are needed to improve worksite conditions and ensure adequate hydration. In addition, governments and scientists should work together to conduct epidemiological and clinical studies to document the presence of these epidemics and their magnitude. To this end, the World Health Organization, in collaboration with the Sri Lankan government, called together approximately 45 global experts from various organizations, institutions, and disciplines in late April. Also, Johnson is working with Glaser and others on a simple and practical protocol to estimate distributions of kidney function in rural communities globally. The Disadvantaged populations estimated glomerular filtration rate (eGFR) epidemiology study (DEGREE) will provide key information to inform hypotheses and to guide further research into the sources of CKDu.

Read the full article at http://onlinedigeditions.com/article/Climate+Change+May+Contribute+To+Rising+Rates+Of+Chronic+Kidney+Disease+Of+Unknown+Origin/2479907/301771/article.html.

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