Wednesday, April 11, 2018

ATTN Nephrology Fellows: Origins of Renal Physiology fellows course now open for applications

Jeff during a trip to MDIBL
As a senior resident at the Beth Israel Deaconess Medical Center, I was fortunate enough to have had the opportunity to attend the Mount Desert Island Biological Laboratories even before I knew there a course for Renal fellows. It was there that I learned of the importance of comparative physiology in our understanding of the Renal physiology we see every day as nephrologists. For anyone who has attended the Renal Fellows course at MDIBL, the Animal House region of this year's NephMadness undoubtedly made you smile. In fact, choosing a winner was like picking your favorite child. How could you decide between how toads and camels solve their osmolality problems?! They didn't even mention why seagulls "spit" (they excrete salty fluid that drips onto their beaks...and it flies off when they shake their heads!). See what you're missing?

5 years after my first trip to MDIBL, I have been back every year since, teaching in the BIDMC and Hospitalist courses. But I will always have a special place in my heart for the Renal Fellows course, where I learned more in 1 week about basic science, renal physiology, and how lucky I was to be a future nephrologist than I ever thought. We worked hard...and we played hard. When not in the lab, we were exploring Acadia National Park on foot and on bicycle, eating obscene amounts of shellfish in Bar Harbor, and getting to know our fellow fellows and some of the most influential physician-scientists in the field.

In fact, I loved the course so much that I decided to study it! Here is our published paper about just how great the Renal Fellows course is So here's the deal,...if you want to go, you have to APPLY. Your course tuition is on the house! (the NIDDK is footing the bill). This year, it's happening from August 18th through 25th.

Visit the website for all the detail. Application Deadline is July 30th (Seats fill fast)

If you have questions, please don't hesitate to e-mail me -

Jeffrey William, MD
Instructor of Medicine, Harvard Medical School
Beth Israel Deaconess Medical Center  

 Check out all of the posts about this course on RFN

Friday, April 6, 2018

CHANNELing basic science to understand renal electrolyte handling

Let me start with a folktale: an old and very senile king wants to know which of his daughters loves him the most. The elder sister says she cherishes him more than the whole kingdom. The younger one, though, loves him “as dear as meat loves salt”. The king gets upset and orders her execution. As most fairy tales, it has a happy ending:  the king is served dinner without salt, learns his lesson, stops the execution and everyone lives happily ever after. In the modern world this story of a salt-loving family might have another sad “end” – end stage kidney disease, and a broke king spending a lot of gold coins on healthcare. It might have ended differently for him though if we had a better understanding of renal electrolyte handing during a high salt diet. This is a million-dollar question (actually, it’s more like hundreds-of-millions-of-dollars-question – I hope someone at NIH reads this blog); we need to know what happens in the kidney at the molecular and cellular level in a disease state. Knowing all the tiny details would be immensely helpful to discover new pharmacological targets. One of the most studied drug targets for renal diseases are ion channels, and electrophysiology is a sophisticated method for measuring ion channel activity.

In my lab at the Medical University of South Carolina among other things we use electrophysiology to uncover the mechanisms that underlie salt-sensitive hypertension.  Since the Nobel Prize in Physiology and Medicine awarded to Erwin Neher and Bert Sakmann for their “discoveries concerning the function of single ion channels in cells" in 1991, electrophysiology has been an immense help to basic and clinical science. Although this technique is very widespread in brain and cardiovascular research, there is only a handful of labs that use it to answer nephrological questions. I have learnt it during my postdoctoral training in the laboratory of Dr. Alexander Staruschenko (Medical College of Wisconsin) where it has been successfully applied to study kidney function for years.

So what exactly is electrophysiology? Basically, it is a technique that allows direct measurement of how ions (Na+, K+, Cl-, Ca2+ - you name it) move through ion channels in the cell membrane. Using a tiny glass micropipette with an electrode in it, and a micromanipulator, we can press the tip of the pipette to plasma membrane of the cell, and isolate a patch of it that is under the tip (hence the other name of the approach – patch clamp). Since ions have a charge, their movement through the channel to the other side of the membrane generates current that can be sensed by the microelectrode in the pipette. Of course, sensing movement of single ions requires sophisticated amplifiers, filters, digitizers, grounding, knowing Ohm’s law and having a graduate degree in physics (kidding – though I have one, and it does help), and a ton of patience. When performing a patch-clamp experiment we control the environment that the cell is in (we choose the extracellular solution, what we put in the patch micropipette, what voltage we apply to the membrane etc), and this allows us to use different tricks to identify ion channels and then learn how to tweak or test their activity. Using cultured cells, tissues isolated from animal models, or human biopsies, we can directly measure the activity of ion channels and assess what happens in a certain disease condition.

Over the years, scientists have discovered dozens of crucial renal ion channels conducting sodium, calcium, chloride, potassium, magnesium… more are discovered every year. Gain- or loss-of-function mutations that lead to renal diseases have been reported for pretty much each and every one of them. In disease states such as salt-sensitive hypertension a handful of ion channels are known to work improperly, and in order to advance our treatment strategies we need to know how these channels are mediated, what signaling pathways affect them, and what pharmacology can be used to change their activity. As an example, in Dr. Staruschenko’s laboratory it has been shown that epithelial sodium channel (ENaC) in the cortical collecting ducts can be overly active in salt-sensitive hypertension (PMID: 28003189), which meaningfully contributes to an increase in blood pressure. Therefore, specific targeting this ion channel could be a successful means to combat blood pressure in this setting.

One of my good colleagues once compared ion channel electrophysiology to fishing. I have never fished in my life, but since I’ve done a lot of patch-clamp I feel I could easily have an alternative career as a fisherwoman. Nevertheless, although patch clamp electrophysiology is a “long wait – high reward” approach, this unique technique is crucial for our understanding of renal electrolyte handling, and – in skilled and patient hands - it has tremendous potential to push the medical field forward.

Daria Ilatovskaya, MS, PhD, 
Past Ben J. Lipps Research Fellow of the ASN  
Medical University of South Carolina 
Department of Medicine, Division of Nephrology 
Charleston, SC

Monday, March 26, 2018

#NephMadness Living Kidney Donor Case Challenge #LKDCC #7 (Wrap-up)

Link to all of the #LKDCC cases here:

Case 1: Rajiv

Case 2: Hayley

Case 3: Barry

Case 4: Beatriz

Case 5: Ari

Case 6: Helen

Read more about the #NephMadness Transplantation Region at the AJKD Blog and submit your #NephMadness brackets here by Friday March 30!

Created by Kate Robson (Nephrologist, Melbourne, Australia and NSMC Intern 2018)

Saturday, March 24, 2018

#NephMadness Living Kidney Donor Case Challenge #LKDCC #6

Helen, 37, is single and works full-time as a teacher. She is very keen to be a kidney donor to her loved one. You measure her BP at 140/85. Her BMI is 28kg/m2. Her physical examination and urinalysis are unremarkable. Talking to Helen, you establish a family history of hypertension and type 2 diabetes in her older relatives, and learn that she does not plan on becoming pregnant in the future.

Pending completion of investigations, you believe:
A) Helen is an acceptable candidate to donate to her 4 year-old son Ryan.
B) Helen is an acceptable candidate to donate to her 68 year-old father, Bert, who has diabetes and is on dialysis.
C) Helen must not be permitted to donate while she is of childbearing age.
D) Helen should be refused as a donor because she is overweight and has a family history of both diabetes and hypertension.
E) I've read all the blog posts this week and I'm still unsure which answer to choose.

Here's how you responded:
Now, before you make a formal complaint, you’re absolutely right: this question would not hold water as a standardized board-level MCQ! There’s more than one correct answer. It’s controversial. And it’s perhaps not a direct test of the knowledge you’ve worked to acquire over the course of Living Kidney Donor Case Challenge.

However, every response from A through D is a real-life comment from a real-life nephrologist in an equivalent clinical scenario. So the range of responses from our #LKDCC community is not at all surprising. And if you chose E, don’t worry!

By following the whole week of #LKDCC, you’ve gained an insight into the available evidence regarding risks to kidney donor candidates. You’ve learnt about the risks of ESKD, proteinuria and pre-eclampsia. You’ve pondered the potential contribution of body composition, ethnic background, family history, dysglycaemia and age to these risks. You can confidently explain the ‘known knowns’ to would-be kidney donors. And hopefully you recognise the ‘known unknowns’ as well: the current gaps in evidence that are equally important to discuss with donors, but partly explain why there is such diversity between nephrologist attitudes in this field.  We all - doctors and patients - weigh unquantifiable risk differently: some are more conservative, others more adventurous.

So what does this mean for Helen? Helen is a motivated donor candidate with some risk factors for future metabolic and cardiovascular disease, including elevated BMI and family history. It’s essential that these are addressed in the informed consent process as we counsel Helen. We should explain to Helen how lifestyle choices could reduce her future risk of diabetes, discussing the benefits of weight loss and physical activity. She is of childbearing age, and therefore our consultation should also take into account her reproductive history and the potential impact of donation on any future pregnancy.

Is it important to us, as Helen’s medical advocate, who the intended recipient is? Arguably, it is not, except perhaps to establish that Helen’s relationship with the recipient is not complicated by coercion or exploitation. Our role is to assess Helen’s medical suitability as a donor, and to ensure she understands the implications of donation. As a mother who performs peritoneal dialysis for her son every day, and wishes for a long healthy life for him, Helen brings an understandably strong motivation for donation. As a donor to her father, Helen may be aware of the potentially shorter lifespan of the donated organ, but remain motivated to relieve her father of the burden of haemodialysis, thereby improving his survival and quality of life, and, by extension, her quality of life as a daughter and carer. Given the choice, as resource allocators, we would prefer to see Helen's kidney give benefit to a younger recipient - perhaps that explains why 43.5% of the #LKDCC team chose Option A. Similarly, if there were an alternative choice of donor, such as Helen's mother, whose lifetime risk may be lower than 37 year-old Helen, that risk differential should be clearly outlined in counselling Helen and her family.  Ultimately, when it comes to risk-benefit analysis in living kidney donation, there are no measurable medical benefits. The potential benefits are all psychosocial, and therefore only truly definable by each individual donor, after thorough counselling.

Living kidney donors don’t need paternalistic protection from unquantifiable long-term risks. They need our guidance, in providing them with all the available information to make a reasoned decision, while continuing the research required to expand the evidence base. They need our advocacy, firmly representing their individual needs in the multi-pronged transplant process. And they need our support to undertake a risk-benefit analysis that is truly unique across all of medicine.
Thank you for participating in #LKDCC: please give us your feedback here
Now you'll have a whole new perspective on Living Kidney Donor Risk
and the #NephMadness #TransplantRegion
Don't forget to submit your #NephMadness brackets here

Please note these are fictional cases with open access stock images. They do not represent real cases.
Created by Kate Robson (Nephrologist, Melbourne, Australia and NSMC Intern 2018)