I live tweeted this lecture, so the post is my Storify. Got a bit lost during the talk in a string of critical phosphorylations midway through. If you want to know that much about the topic, go read Welling's work!
I live tweeted this lecture, so the post is my Storify. Got a bit lost during the talk in a string of critical phosphorylations midway through. If you want to know that much about the topic, go read Welling's work!
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.
Michael Christensen1, Tomas Schiffer2, Rikke Nørregaard1, Fredrik Palm2. 1Aarhus University, Aarhus N, Denmark, 2Uppsala University, Uppsala, Sweden
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.
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)
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.
Metformin increases PO2 in the outer medulla both in control and diabetic animals, this could in part be mediated by inhibition of UCP2.
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?
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.
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.
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.
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.
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.
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!
I get some test results. They are not yet optimal for whatever the patient has, so I want to make a medication change. We are using a well-established drug with minimal side effects. At the time it was first prescribed, we reviewed alternatives, and the family was in complete agreement with starting this treatment. The drug is also incredibly inexpensive, one of those most pharmacies will provide for $4 per month.
We call to increase the dose, and the family tells us they stopped the drug. Not because it caused side effects or other problems. They have decided to try some supplements for a more natural treatment.
We manage to renegotiate treatment with the original drug. We will now have to test again to assess its effects, at further cost. The insurance covers the cost of the drug, pretty much in full. The supplements the family substituted easily cost five times their out-of-pocket expense for the pharmaceutical agent. So they are more expensive as well as ineffective.
But somehow the family was willing to shoulder those expenses to be "natural," even though there is little "natural" about these supplements. These supplements "support" the systems involved in their child's health issues, so they were worth a try.
Isn't it time to get rid of this costly BS that the supplement industry is allowed to spew?
I feel your pain.
A lot of my patients have to deal with "mail order" pharmacies for chronic medications. Often insurers require that these "services" be used. They often present challenges for healthcare providers. Now I have a perspective from the other side of things.
My husband has been on chemotherapy since April. His regimen involves an oral drug that he takes at home, with few side effects. It is expensive, and our health insurance makes us use a specific national pharmacy. He is to get a round of treatment next week, so I called yesterday to ship the next refill. The pharmacy said they did not have the prescription. OK, I contacted the doctor's office, and they called it in (even though they had faxed back the refill 2 weeks ago - yes, medicine is keeping the fax machine alive).
This morning, I called to arrange the shipment. The prescription , given verbally, is still being "scanned in." They cannot verify the claim and arrange shipment until that happens.
Never mind that we only use this service because our insurer demands it. Never mind that we have filled this prescription monthly for 5 months. None of that is adequate to allow them to schedule the shipment. I have to call back in 2 hours. They cannot make a note to ship when approved. No, I have to call again during my clinic. I can't imagine dealing with this "service" without my medical background.
How this level of red tape saves anyone money is beyond my understanding.
A colleague helpfully pointed me to a website that could put me out of business. The headline promised to repair your kidneys naturally with one ingredient.
I had to know more! Here's the magical advice:
Repairing the kidneys after damage just may lie in a common household item, which you probably already have in your kitchen cabinet. Yes, we are talking about baking soda. In this articled we are going to show you how to cleanse and improve the function of your kidneys with just ½ tsp. of baking soda,every day.
The site goes on to try and explain the magic of sodium bicarbonate, implicating a variety of body systems.
So what's the tiny seed of truth? Acid may be bad for our kidneys.
Being alive generates acid. Metabolizing the food we eat produces acid. Our kidneys produce bicarbonate to neutralize this acid, as well as excreting it in the urine. There is some evidence that higher loads of acid may promote kidney problems, including chronic kidney disease and stones. Eating a lower acid load, by minimizing meat and maximizing fresh fruits and vegetables, may slow the progression of kidney problems.
So could ingesting baking soda help? Yes, but probably not at the level recommended.
1 teaspoon of baking soda can neutralize ~72 mEq of acid. Net acid production for children is 1-2 mEq/kg body weight/day. So a lean, 70 kg adult likely produces at least 70 mEq daily. This dose of baking soda would neutralize about half of that.
The real payoff here is the advice at the bottom of the article, recommending less meat and more fruits and vegetables. A healthy diet seems to be good for everything!
Besides, baking soda is pretty nasty.
We have now completed two months of the new academic year, and times have been a-changing. We had to rearrange the way our patients get covered by residents in the hospital. We attendings have been taking more direct night call on our inpatients as a result. After taking insistent calls from nurses, I have become even more concerned about how we assess and treat pain.
For example, a kid with a kidney disease or transplant comes in with an infection in the urine or a virus. They are not taking fluids well, and they need some intravenous support and/or antibiotics. The kid looks like they feel sick from whatever the underlying problem may be. We start acetaminophen for fever and pain. Later on, when routine vitals get collected, they get asked if they have pain. They then rate the pain on the infamous 1-10 scale. Then, we start getting called about "unrelieved pain."
Patients with kidney problems, including transplants, must avoid non-steroidal anti-inflammatory drugs (NSAIDs; Advil etc). Filtration in the kidney is often dependent on prostaglandins, and these drugs work by inhibiting prostaglandins. In sick infected patients, generous dosing of NSAIDs can lead to kidney failure that might even be permanent. That means pain unrelieved by acetaminophen quickly escalates to pain requiring opioids.
If the kid is sick enough to be admitted, I have no objection to the occasional dose of hydrocodone in the evening (even if I would have told my own kid to put on their big kid underwear and deal with it in a similar situation). It often becomes difficult to scale back the medication during an inpatient stay because we have become so focused on "unrelieved pain" assessment. The number of calls for this while covering a handful of relatively well patients was startling. I cannot imagine the pressure to just hand out "the candy" with more problematic patients and a busier service.
Treating pain is important, but we need to have strategies that do not involve medications. Children often respond well to distraction, relaxation, and other behavioral techniques. Unfortunately, these may be difficult to administer, especially in the middle of the night. And why are we waking them up and asking about pain when they should be sleeping anyway?
I am not a pain doctor. I just wish for a more rational strategy that does not create obvious rewards for overtreatment that may lead to addiction.