#ExpBio - More Medulla Please

(by whizbang) Apr 24 2017

Structure of Metformin

Newly diagnosed patients with type 2 diabetes generally start the drug metformin. Through a number of metabolic effects, this medication improves hyperglycemia. Over time, most drugs prove to have effects other than those initially identified. Metformin seems beneficial to the kidney, but how does that happen?

Once again we will ponder medullary hypoxia. In yesterday's post, the hypoxia occurred acutely, during heart surgery; now, we will address chronic hypoxia due to diabetes.

In this study, rats were made diabetic with streptozotocin. Some were treated with metformin. After approximately 1 month, kidney function and oxygenation in the cortex and medulla were measured under anesthesia. Cortical and medullary tissue were studied for mitochondrial function.

Metformin did not prevent elevation of glomerular filtration rate, a known phenomenon of diabetes. While oxygenation, measured as the partial pressure of O2, was lowered in both the cortex and medulla of control animals, metformin improved oxygenation in the medulla of diabetic animals.

Diabetes also promotes oxidative stress in the kidney. As a defense against this, the mitochondria become less efficient. An uncoupling protein (UCP2) allows respiration to continue but without ATP formation. In the present study, uncoupled respiration doubled in the medulla in diabetic animals, while metformin treatment returned this parameter to normal.

Metformin increases medullary oxygenation in animals, perhaps via inhibiting UCP2. More study is needed to characterize this effect and what it means for diabetic kidney disease. It also points out our ignorance of the medulla on the clinical side of things. When we biopsy a kidney, we examine the cortex. Our attention has been so focused on the glomeruli and the tubules surrounding them that we may be missing the real action.

ABSTRACT

Metformin†Normalises†Medullary†Hypoxia†in†The†Diabetic†Rat†Kidney

Michael Christensen1, Tomas Schiffer2, Rikke Nørregaard1, Fredrik Palm2. 1Aarhus University, Aarhus N, Denmark, 2Uppsala University, Uppsala, Sweden

Background

Metformin is the first choice treatment of type 2 diabetes where it can lower the level of blood glucose by inhibiting hepatic gluconeogenesis and increase cellular glucose uptake. Besides the effect on blood glucose metformin has also shown protective effects in several renal diseases including diabetic nephropathy. The development of hypoxia in the kidney is suggested to be an important driving force for the development of diabetic nephropathy and we therefore wanted to investigate how metformin affects the oxygenation levels and mitochondrial function in the diabetic kidney.

Methods

Sprague Dawley rats were injected with streptozotocin (STZ) (50 mg/kg) and when rats were diabetic, metformin (250 mg/kg) was administrated in the drinking water. Rats were prepared for In†Vivo†measurements 25-30 days after STZ injection. Rats were anesthetized, placed on a heating pad, tracheotomized and a catheter was placed in the left femoral vein for infusion of Ringer solution containing H-inulin and Paraaminohippurate. The left femoral artery was catheterized for blood pressure measurements and blood sampling. The left kidney was exposed by a subcostal flank incision, immobilized in a plastic cup and catheters were placed in the left ureter as well as bladder for collection of urine. Intrarenal pO2 was measured in kidney cortex and medulla by oxygen microsensors. To assess mitochondrial function, mitochondria were isolated from kidney cortex and medulla and analyzed by highresolution respirometry (Oroboros, O2K)

Important findings

Diabetic rats showed increased glomerular filtration rate (GFR), which was not affected by metformin treatment. PO2 was lower both in the outer medulla as well as cortex in the diabetic animals. Metformin treatment elevated PO2 in the outer medulla both in the control animals as well as in the diabetic animals. Isolated mitochondria from the outer medulla of diabetic rats showed a significantly higher GDP dependent respiration which was normalized by metformin treatment indicating inhibition of uncoupling protein 2 (UCP2) activity.

Conclusion

Metformin increases PO2 in the outer medulla both in control and diabetic animals, this could in part be mediated by inhibition of UCP2.

 

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#ExpBio - Urine Oxygen and Acute Kidney Injury

(by whizbang) Apr 24 2017

Original source: ajprenal.physiology.org/content/284/3/F433

All nephrologists know that acute kidney injury (AKI) commonly complicates heart surgery, especially if patients require cardiopulmonary bypass (CPB). AKI increases morbidity and mortality in this setting, so heading it off could improve patient outcomes.

AKI in this setting usually occurs due to acute tubular necrosis, when low oxygen in the outer medulla of the kidney (see image at right) damages proximal tubular cells. Patients often require support with dialysis until these cells can repopulate in a few weeks.

At present, detecting medullary hypoxia is a guessing game. Did the patient get hypoxia? Did the blood pressure drop? How long were they on CPB?

Probe sits just above catheter tip

Experimental evidence from animals showed that the pressure of oxygen in the urine (UO2) correlates with medullary hypoxia. A surgical group wondered if UO2 during operations might predict AKI in heart surgery patients requiring CPB. UO2 can be measured with a fiber-optic probe inside the urinary catheter all of these patients have placed before the cutting begins (see diagram).

Their study included 35 adult patients, with 14 developing AKI (defined as rise in creatinine). The lowest intra-operative UO2 was 50% lower in patients who developed AKI than those who did not (p=0.02). Worse levels of UO2 had even greater predictive value for AKI. However, no level of UO2 completely eliminated AKI risk.

Continuous monitoring of UO2 can be done and may provide additional information about renal risk during heart surgery with CPB. As a pediatric nephrologist, I wonder about it's use in other conditions with high risk for AKI.

ABSTRACT

IntraOperative Urinary Hypoxia During Cardiac Surgery on Cardiopulmonary Bypass Predicts Later Development of Acute Kidney Injury

Roger G. Evans1, Michael Z. Zhu1,2, Julian A. Smith2, Gerard K. Harrop1, Amanda G. Thrift3, Andrew D. Cochrane2. 1Cardiovascular Disease Program, Biosciences Discovery Institute and Department of Physiology, Monash University, Melbourne, Australia, 2Department of Surgery (School of Clinical Sciences), Monash University and Department of Cardiothoracic Surgery, Monash Health, Clayton, Australia, 3Department of Medicine (School of Clinical Sciences) at Monash Health, Monash University, Clayton, Australia

Renal medullary hypoxia may be a common pathway in the development of acute kidney injury (AKI). There are no validated methods to detect medullary hypoxia in patients. However, experimental findings indicate that changes in urinary oxygen tension (UPO2) reflect changes in medullary PO2. Therefore, we evaluated the relationship between intraoperative UPO2 and the development of AKI after cardiac surgery requiring cardiopulmonary bypass (CPB). From January 2015 to July 2016, thirty-five adult patients undergoing onpump cardiac surgery were prospectively enrolled. UPO2 was continuously recorded intraoperatively via a fiberoptic probe deployed through the lumen of the urinary catheter, with the end of the probe at the catheter tip, where it was in contact with bladder urine. UPO2 fell during surgery, particularly during CPB. The lowest (nadir) UPO2 was most frequently observed during the rewarming phase of CPB, or shortly after weaning from CPB (n=25, 71%). Fourteen patients (40%) developed AKI as defined by an increase in serum creatinine from baseline of either > 26.5 μmol/L (0.3 mg/dL) within 48 hours or > 50% within 5 days. Nadir intraoperative UPO2 was lower in patients who later developed AKI (8.5 ± 1.6 mmHg, mean ± SE) than in those who did not (16.5 ± 4.2 mmHg, P†= 0.02). UPO2 below 10 mmHg at any time during surgery was associated with a 4.5fold [95% confidence limits 1.6 19.1] greater risk of AKI (P†= 0.03). Furthermore, urinary PO2 below 15 mmHg for longer than the median time for all patients (5.6 min per hour of surgery) was associated with a 7.3fold [1.8 35.1] greater risk of AKI (P†= 0.01) and an area under the receiver operator curve of 0.73 [0.56 0.90] (P†= 0.03). We conclude that low UPO2 during cardiac surgery requiring CPB is strongly associated with later development of AKI. Continuous intraoperative monitoring of UPO2 is simple and relatively noninvasive. It may provide a realtime biomarker of risk of AKI. Early detection of risk of AKI may in turn provide a window of opportunity to intervene and thus avoid development of AKI in patients undergoing cardiac surgery.

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#ExpBio - Safer Is Not Safe; Just Don't Vape

(by whizbang) Apr 23 2017

Electronic cigarettes, or vaping, has been advertised as a safer alternative to smoking tobacco. It provides the addictive ingredient in tobacco (nicotine) in a liquid base that gets heated and delivers it in an inhaled form. Nicotine patches and gum may provide levels of the chemical, but they do not satisfy the ritual of smoking. Vape liquid can contain high amounts of nicotine, often in a flavored liquid base. Heating elements in the devices can release other chemicals into the mix as well.

Tobacco has systemic effects well beyond the lungs. These include cardiovascular disease and kidney dysfunction.

In this study, mice were exposed to vapor generated by a commercial vaping device and then collected and piped into mice. Mice breathed the vapor for 1 hr each day, 5 days each week. In the first experiment, the default laboratory mice (C57Bl6) vaped for 3 months. Findings included a 20% reduction in glomerular filtration rate and an 87% increase in kidney scarring. Changes in heart rate and blood pressure suggested cardiovascular damage as well.

An outbred mouse strain (CD1) received the same exposure for 6 months. This genetically heterogeneous strain might have more resistance to adverse exposures. However, it showed a 64% increase in kidney scarring over control animals. Cardiac scarring increased 2.75-fold over controls. Multiple pro-fibrotic factors studied in each tissue were elevated with exposure to vaping. These patterns of damage were similar to those seen with tobacco smoke exposure in animals from a separate but parallel study (data not included; noted during discussion at poster).

Vaping may not carry the cancer risk of tobacco use, but this animal study strongly suggests it still promotes cardiovascular and kidney disease.

ABSTRACT

Chronic Electronic Cigarette Vapor Inhalation Induces Renal Injury and Functional Decline in Female Mice

Christopher Drummond1, Laura E Crotty Alexander2,3, Jiang Tian1. 1Medicine, University of Toledo, Toledo, OH, 2Pulmonary, Critical Care and Sleep Medicine, University of California San Diego, La Jolla, CA, 3Pulmonary Critical Care, Veterans Affairs San Diego Health System, La Jolla, CA

Clinical studies indicate that combustible cigarette smoke increases renal and cardiac tissue injury progression and functional decline in the setting of chronic kidney disease (CKD). Novel nicotine delivery devices like electronic (e)cigarettes are used by over 10% of the population and produce vapor which may also induce renal injury. To establish whether ecigarette vapor inhalation induced renal injury in the form of fibrosis and decreased renal injury our current study utilized a noseonly

inhalation exposure system to induce 8 weekold female mice to inhale ecigarette vapor containing 24mg/mL of nicotine suspended in a solution of 50% propylene glycol and 50% vegetable glycerin using the following parameters: 12 seconds of vapor exposure every 60 seconds for 60 minutes five days per week for 1, 3 and 6months. Following ecigarette exposure, assessment of renal fibrosis, glomerular filtration rate, and expression of the antifibrotic microRNA miR29b3p were evaluated. Mice exposed to ecigarette vapor suffered a 31% decline in renal tissue expression of miR29b3p vs airexposed

controls (p<0.05). Additionally, mRNA targets of miR29b3p that regulate fibrosis formation or are part of fibrosis were also significantly increased in the kidneys of ecigarette exposed mice versus air controls, i.e., Collagen 1A1 (increased 98%; p<0.05); Collagen 3A1 (129% increase; p<0.05); Collagen 4a1 (72%

increase; p<0.05); Integrin beta 1 (58% increase; p<0.05); and Fibrillin 1 (100% increase; p<0.05). Additionally, we observed a significant increase in renal fibrosis at the 3and 6month

time points as assessed by Trichrome staining in these animals. Lastly, following 3months of

exposure to ecigarette vapor renal function was significantly reduced by 21% versus air exposed controls (p=0.017). These data are the first to indicate that ecigarettes induce renal fibrosis and functional decline. In addition, these data suggest a novel miR29b3p mediated mechanism linking ecigarette vapor exposure and renal injury and functional decline.

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#ExpBio - Cannon Lecture

(by whizbang) Apr 23 2017

The most prestigious award of the American Physiological Society is named for Walter Cannon, who developed the concept of homeostasis. This year’s award goes to Michael Welsh, a professor of medicine and physiology at the University of Iowa. He presented his life’s research into the pathogenesis of the lung disease of CF.

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Facebook Bummer

(by whizbang) Apr 22 2017

The badge on my Facebook app called this morning. Someone had tagged me! But then, the top of my feed provided a Facebook memory from 1 year ago - Jim ringing the bell after completing his initial course of radiation for the glioblastoma multiforme.

That radiation and chemo produced great effects. He was pretty normal over the summer and fall, and we had some great times. Now, of course, that bastard tumor has returned. Chemo and radiation have returned as well.

A year ago, that radiation gave us hope. Today, we must acknowledge that this tumor generally wins the war. Therapy buys us time, and not as much as we would like.

My spouse has insisted that I take my current trip to blog at Experimental Biology. You will see a lot more activity at WhizBang for the next 5 days, and it will be real science blogging.

What a pleasant break from the realities of our life.

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The Problem with Podcasts

(by whizbang) Apr 04 2017

Yesterday I received notice of a podcast. The topic sounded interesting, and they gave a teaser summary that had me considering listening. They even gave a table of contents for it, with the time point where various topics within the recording would be addressed.

The stuff I really wanted to know started 45 minutes into the piece, but I likely needed to listen to the earlier stuff to get the gist. Did I really want to spend an hour of my life taking notes on a podcast?

I don’t think podcasts should be forbidden. I listen to NPR discussions and interviews most of my day, and many podcasts present similar audio adventures. However, I really learn best when I read something, not when I hear it. Listening to Serial as entertainment is fine; if I really want to retain something, I need to read it.

I beg those of you who aim to provide information and skills to the public to remember that not all of us can benefit fully from listening. Please provide a transcript of each and every podcast for those of us who want or need it. That includes those of us who learn better with the written word, as well as the hearing impaired.

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My Mantra

(by whizbang) Mar 24 2017

Today I will be repeating the following:

  1. I am a bitch
  2. Bitches get stuff done
  3. I can handle this because I have resources, I can find help, and I am a bitch.

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What I'm Watching: Heptapods on Earth

(by whizbang) Feb 27 2017

Over the weekend, we watched Arrival, an Oscar-nominated film. The movie was beautiful and made me think, but perhaps not in the way intended.

WARNING - SPOILERS

These aliens show up in 12 locations on earth. Ultimately we find out that they have arrived to teach us their language. As humans learn their articulation, our brains change so that we can appreciate time in a non-linear fashion, the way these heptapods do. Turns out, the aliens have arrived to give us their language because they will need humanity's help in 3000 years. We need to be prepared.

As the linguistics professor, Louise Banks, learns to speak with the aliens, she begins to experience things from her future life, including the birth and death of a child. Her relationship with the child's father deteriorates when she reveals that their daughter will die of cancer, and he leaves. Even knowing that all of this is ahead, she chooses to live this life.

But why?

Clearly non-linear time perception allows the heptapods to go to a timepoint and give us humans the tools to make us useful 3000 years from now. So nonlinear time perception allows at least some interference in outcomes, otherwise they wouldn't bother. Are there rules for such things? Or are all the outcomes written and it doesn't matter what we do?

So why doesn't Dr. Banks try to change some outcomes? Not the big stuff - having the child - but telling the father that his daughter will get cancer and die in a few years when she knows what that will trigger? Perhaps she could visit a time in the future when her daughter's disease could be cured? They make clear in the movie that at least a couple of people are running about through time, telling each other critical things.

Of course, I then had to ask myself if I would change my life, even the bad stuff. There are many things that I could have lived without, but what would I have done differently? I don't have to know, because, for me, time is strictly linear.

At the end of the movie, that's the biggest problem: it's very difficult to imagine time as anything but a linear construct of past - now - future. And that's OK, until the heptapods land for real.

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Medical Stress

(by whizbang) Feb 24 2017

Yesterday I received a medical bill for my husband, hardly an unusual occurrence given his brain tumor. Unlike the usual bills, this one included almost $4,000 in charges when his out-of-pocket expenses were satisfied last March.

Going through line-by-line, I discovered that no one filed claims for three procedures in November and December, including a surgical procedure that resulted in most of the amount due.

All of this should be covered.

I called the billing office, and they told me to tear up the bill and await a corrected one.

Yesterday was a stressful day anyway. We found out that the tumor was progressing again, and we are now waiting to hear what other trials my spouse can try.

Getting that bill was unnecessary stress. Part of me wanted to curl up and pretend it didn't exist. Part of me thought about just paying the damn thing so it went away. Luckily, the part that won said, "WTF? How can that be?" and went through the charges to find the problem.

Brain tumors suck.

 

 

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Review: @IconUndies the Pee-Proof Underwear

(by whizbang) Jan 18 2017

I'm a woman "of a certain age" to put it delicately. I have birthed some babies, including my 9 1/2 lb son.

Even with lots of Kegel exercises, a full bladder and a sneeze can leave me with wet panties. And not in a good way.

Pantiliners for such events are fine, but not ideal. They get pretty pricey over time. When I saw an ad for Icon Pee-Proof Underwear, I decided to give them a go (pun not intended, but it works).  The crotch of each pair has a special interior lining that can hold several teaspoons of urine without odor or leakage. They can be machine washed and dried without any problems.

After several wearings, I can report that these undies work as promised. I wear the bikini cut (see photo at right), and I tried one thong. They also come in a hip hugger and high-waist version. Colors are limited to black and beige in my size and styles, but what else do we really need? They do seem to stretch out a bit as washed, so you may need to go down a size.

This company also makes Thinx, the period-proof underwear. I don't need those (the certain age thing again), but I bet they work. The site is full of urine puns and "whizdom." And all their products help support the Fistula Foundation, providing surgical repair of obstetrical fistulas. A fistula is a connection between stuctures, in this case the things that empty out down there. Women in countries without modern obstetrical care often suffer genitourinary damage leading to urinary or fecal incontinence afterwards. Fistulas make my teensy bit of urinary leakage seem like such a first world problem...

I still have some other undies at this point, but they will be replaced by IconUndies as they age and go to panty-heaven. It's fun to be pad-free!

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