ASN Annual Meeting Travel Support Opportunities

It's the time of the year again to start thinking about travel to the ASN annual meeting in Atlanta. Thankfully, in this time of limited travel budgets and sequestration, the ASN offers a number of travel awards that will help pay for the cost of attending the conference. For all attendees, if you are participating in a pre-course, there are travel awards available for each of these courses. For fellows in training, there is a specific award that will pay for conference registration and some of the cost of attending.

To encourage medical students and residents to take part, there is a travel award specifically for this category that also offers complimentary ASN membership and $800 towards travel and accommodation costs. Finally, the Mitch Award offers travel support to 3 US fellows who are from underrepresented minorities and 5 fellows from Mexico and Central and South America. Additionally, recipients of this awards will be invited to attend the President's reception.

Needless to say, prior recipients of these awards cannot reapply and for US fellows, at least one year of training must have been completed prior to applying for travel support.

Renal Grand Rounds - Case of the month

A young woman with h/o polysubstance abuse and seizures was admitted to hospital with status epilepticus. She was treated with a propofol infusion at 5mg/kg/hr which was maintained due to perceived continuing seizure activity. On hospital day 5, she developed an acute metabolic deterioration – rhabdomyolysis : CPK 100,000, AG metabolic acidosis (HCO3 18) and non-oliguric AKI. Her EKG also became abnormal (RBBB). The diagnosis was propofol infusion syndrome.

What is propofol Infusion Syndrome (PRIS)? 

Like many syndromes, PRIS is a conglomeration of clinical and biochemical manifestations.  Based on  83 case reports from 1992-2007, PRIS is characterized by:

1) Metabolic acidosis, (pH less than 7.30 or HCO3 less than 19)

2) Rhabdomyolysis (CPK more than 10K)

3) Renal failure

4) Cardiac dysfunction (Brugada-like EKG pattern, asystole, PEA, sustained VTs, heart failure, or bradycardia) 

5) Hypertriglyceridemia (TG more than 400)

6) Hyperkalemia

7) Hypotension (or use of vasopressor agent)

8) Hepatic transaminitis

9) Hypoxia (PO2 less than 60mmHg). 

The first 5 manifestations are the most common. While there is no requirement for the number of clinical manifestations a patient must exhibit to meet diagnosis for PRIS, a prospective study showed that most patients exhibit at least 3 defining manifestations within 3 days of propofol use.  In the same study, the incidence of PRIS was found to be a low 1% --similar to other estimates.  However, PRIS is associated with high mortality, up to 30% in some studies. Moreover, because many of these manifestations are common, the presence of any of them could be attributed to another etiology, thus delaying diagnosis of PRIS.  For instance, in the case vignette, the initial rise of CK was attributed to seizure rather than PRIS.

Pathophysiology of PRIS

Inhibition of electron flow along the mitochondrial electron transport chain/ impairs oxygen utilization. Propofol or its metabolites inhibits fatty-acid oxidation leading to buildup of toxic fatty acid intermediates. As described in this nice review.

Risks of PRIS?

Critical illness (especially, CNS illness); Use of propofol dosage more than 4 mg/kg/hr —the usual adult maintenance dose is 0.3 to 3mg/kg/hr; duration of Propofol use greater than 24hr; exogenous cathecholamines and corticosteroids; poor intake of carbohydrate, see this reference.

Management of PRIS

Early recognition/diagnosis; Cessation of propofol infusion; Cardiopulmonary support; Hemodialysis (strongly advocated by expert opinion and outcome of case series).  However, there are no known RCT of use of renal replacement therapy in the treatment of PRIS.  Nonetheless, in case series, survivors of PRIS are more likely to have received HD/CVVH.  Therefore, prolonged use of HD/CVVH is worth considering by renal consult service.  Because propofol is lipophilic and has volume of distribution of 20-40L, it is poorly cleared by HD/CVVH, prolonged RRT is likely needed for PRIS management.

The patient in the case was treated with CVVH overnight, and then transitioned to intermittent HD.  At the time of her discharge, she was off HD with her Cr back to baseline.

See this previous post by Nate on PRIS.

Posted by Opeyemi Olabisi

Using the Edelman equation to explain the Pathophysiology of Hyponatremia

The end of Fellowship

Dear Readers,

It's been an honor and a pleasure to have been a contributor and deputy editor here at RFN over the past few years.  I'm writing this on the final day of my fellowship as I get ready to move on to the next stage of my career and as part of this transition I'll be stepping down as deputy editor of RFN.

I remember discovering Nate's posts back when I was a resident and how refreshing it was to read things written from the perspective of a curious and learning trainee.   I've lost count of the number of times posts from the site have answered a real world clinical question, stimulated a conversation or  helped me answer a standardized exam question - of which I have answered far too many.  RFN has made and continues to make learning nephrology more fun.

I'm hopeful that medical students, interns, residents and fellows who are currently reading the site are as stimulated by it as I was.  If you like the site, think about writing for it!  It's been a highlight of my fellowship years and has introduced me to a whole group of great and entertaining people who have been an immense pleasure to work with.

Remember, spin the urine, when in doubt ask the patient, and always call nephrology early.

Graham Abra, MD
Nephrology Fellow
.

Lonely Glomeruli

One of the difficulties in doing molecular research on the kidney is the diversity highly specialized cells that exist in the glomerulus. As a result, it is important to be able to isolate glomerular tissue from the surrounding kidney. A recent paper in KI detailing a method for isolated podocytes reminded me of a relatively simple technique that I was taught a few years ago for glomerular isolation in mice.

The technique was first described in this paper from 2002 but in brief, it involves injecting the mouse heart with deactivated magnetic beads (after euthanizing them of course). Some of these beads (which are just 5µm in diameter) get trapped in the glomerular capillaries. The kidneys are then removed, minced, digested and passed through a 100µm strainer to remove any larger particulate matter. Finally, the remaining tissue is suspended and exposed to a magnet to pull the glomeruli (with the beads inside) out of the mixture. The glomeruli are then left stuck to the wall of the tube next to the magnet and they can be easily removed.

The picture below is a low-power view of the glomeruli following isolation. You can see that there is very little non-glomerular tissue present, which is remarkable given that the glomeruli make up such a small proportion of renal tissue.

Below is a higher power view of 3 more glomeruli following isolation. You can clearly see the microbeads trapped in the glomerular capillaries. Cool science. (Click on any image to enlarge)

Electrolyte Channels and Aldosteronism

Over the past few years, it has become apparent that hyperaldosteronism is far commoner than was once suspected and screening of unselected patients with hypertension reveals that about 5-10% of patients have primary hyperaldosteronism. In patients with resistant hypertension, that percentage increases to 15-20%. About 30% of hyperaldosteronism is caused by aldosterone producing adrenal adenomas (APA). Most of the rest is related to bilateral adrenal hyperplasia with less than 5% of cases being familial. The secretion of aldosterone in adrenal cells is dependent on the intracellular calcium concentration and increases in response to higher plasma calcium. Entry of calcium into the cells is in turn dependent on voltage-gated membrane calcium channels (which allow calcium influx when the cells are depolarized) and a calcium ATPase which removes calcium from the cells. Under normal circumstances, adrenal cells are hyperpolarized thus keeping these calcium channels closed. Cell polarization is maintained by a combination of the action of the Na-K-ATPase (which exchanges 3 intracellular Na for 2 extracellular K) and membrane K channels lead to K loss from the cells.

Angiotensin II inhibits the Na-K-ATPase leading to cell depolarization, calcium influx into cells and aldosterone secretion. Similar effects are seen when cells are treated with oubain, a specific Na-K-ATPase inhibitor that also leads to hyperaldosteronism.

In 2011 in a seminal paper in Science, Choi et al reported finding somatic mutations in KCNJ5, a membrane potassium channel in patients with APA. These were identified by sequencing tissue from the tumors and comparing with the surrounding tissue. Subsequently, it has been found that about 30-40% of patients with APA have somatic mutations in KCNJ5. These mutations are believed to reduce the ion selectivity of the channels, allowing Na to move into the cell and reduce the resting membrane potential. A number of families have been identified with KCNJ5 mutations resulting in bilateral hyperplasia - now called Familial Hyperaldosteronism type III.

Recently, a paper was published in Nature Genetics which attempted to determine if there were other somatic mutations in patients with APA. In this study, they took KCNJ5-normal patients and sequenced the exons of the tumors and the surrounding tissue. There were very few mutations identified but 5/9 patients had mutations in ATP1A1, a component of the Na-K-ATPase or ATP2B3, a component of the calcium ATPase that removes calcium from adrenal cells. Follow-up targeted sequencing of 300 patients with APA revealed that about 7% had mutations in one of these two genes. Patients with these mutations had higher aldosterone levels, lower minimum potassium levels and higher systolic BP, all indicators of more severe disease. Notably, no families have been identified with these mutations. In vitro studies revealed that cells with these mutations have very low membrane potentials and it is speculated that if this was a germline mutation, it would likely not be compatible with life. This is a fascinating insight into how very small changes in electrolyte channels can have far-reaching consequences and shows a great progression from exome sequencing to the bench and to clinical investigation.

The images in this post are taken from the recent paper in Nature Genetics. One would wonder if somatic mutations explain some of the missing heritability that were are seeing in genetic studies of common diseases. See this previous post by Lisa on the genetic causes of hypertension.