Topic Discussion: New Glomerular diseases cases with targeted therapies

Targeted therapies can lead to a glomerular disease. Previously, two reviews didn’t find any glomerular diseases associated with BRAF inhibitors and PD-1 inhibitors.  In the last 6 months, 3 recent papers have highlighted interesting cases of both BRAF-MEK combination and PD-1 inhibitors leading to glomerular diseases.

Encorafenib, a new BRAF inhibitor, and binimetinib, MEK inhibitor—Proliferative GN
Pembrolizumab ( PD-1 inhibitor)- Minimal Change Disease
Dabrafenib, BRAF inhibitor and tramitinib( MEK inhibitor)- Podocytopathy- like MCD

  

While the PD-1 inhibitor case is the first of it’s kind, we must be mindful of GN in these patients as well. In terms of the BRAF+MEK combo, both authors of the above listed papers. Showed that it was the BRAF inhibition that decreased PLCε1 expression in podocytes, accompanied by a reduction in nephrin expression and an increase in permeability to albumin. Additionally, these drugs inhibited the podocyte–vascular endothelial growth factor (VEGF) system leading to perhaps a component of TMA as well.

ASN Robert G Narins Award for 2017 goes to Blogger, educator Joel Topf

The Robert G. Narins Award by ASN honors individuals who have made substantial and meritorious contributions in education and teaching. This award is named for Robert G. Narins, who is also the first recipient of the award.

Dr. Narins' contributions to education and teaching started in 1967 from chairing for eight years the ABIM's Nephrology Board and working on the ACP's Annual Program Committee. His contributions to education in the fields of fluid-electrolyte and acid-base physiology are prodigious and well-recognized.  Dr. Narins was also involved in the creation and planning of many ASN educational programs during Renal Week and throughout the year, including: Board Review Course and Update, one and two day programs at Renal Week, Renal WeekEnds, and NephSAP.

Prior Award winners of this award are( from ASN website)

·    2015 Mark L. Zeidel, MD, FASN
·    2014 Stuart L. Linas, MD, FASN
·    2013 Mark E. Rosenberg, MD, FASN
·    2012 Donald E. Kohan, MD, PhD, FASN
·    2011 Agnes B. Fogo, MD
·    2010 Barry M. Brenner, MD
·    2009 Burton D. Rose, MD
·    2008 Mitchell L. Halperin, MD
·    2007 Richard J. Glassock, MD
·    2006 Robert G. Narins, MD

This year marks a landmark in this award as it’s being presented to Joel Topf, MD.



While all other educators followed a conventional track for teaching and educating, Joel’s contribution to nephrology education has been very unique and different.  Here is what Joel has accomplished in the last 10 years!
1.       Creation and maintaining the Precious Body Fluids Blog with educational material that spans from electrolyte disorders to AKI
2.       The best acid base book written in Nephrology as a “resident”. This is by far the easiest book to understand acid base disorders.
3.       Co creation of the first ever academic journal blog- AJKD blog
4.       Creation of Nephmadness since 2013 ( first ever online game in Nephrology) with educational material that spans all parts of renal medicine
5.       Creation of NephJC( the first and most successful online journal club that meets every 2 weeks)
6.       Co creation of DreamRCT( how to propose and create a dream RCT that we need in nephrology competiton)
7.       Creation of Nephrology Social Media Collective Internship to train trainees, and faculty on become social media experts to improve medical education
8.       Teaching and promoting social media education in nephrology
9.       Showcasing how twitter can be used in nephrology education at it’s best! (https://twitter.com/kidney_boy)
10.   Several teaching awards at his local institution

Most important of all: He has inspired and trained many young and old teachers/and educators due to his passion for nephrology!
Way to go Joel and congrats!

Consult Rounds: Topiramate and the Kidney

Topiramate was first introduced to treat seizures but now is increasingly used to treat migraines and is among the top 6 drugs sold in the United States. In addition, it is used as a weight loss agent as well. Renal toxicity with this agent is not uncommon.

The three forms of renal toxicity are:

Kidney Stones

Renal Tubular Acidosis

Isolated hypokalemia

A study in 2006 published in AJKD showed that topiramate acts through multiple mechanisms, 1 of which is the inhibition of carbonic anhydrase, as in vitro studies have shown. Several case reports described a link between topiramate and the formation of calcium phosphate stones, but the mechanism for this is largely unknown.

The authors conclude that taking topiramate for about 1 year caused systemic metabolic acidosis, significantly increased urine pH, and markedly lowered urine citrate — changes that increase the propensity to form calcium phosphate stones.

With the increasing use of topiramate, reports have emerged that topiramate can cause metabolic acidosis in some patients. It does this by impairing both the normal reabsorption of filtered HCO(3)(-) by the proximal renal tubule and the excretion of H(+) by the distal renal tubule. This combination of defects is termed mixed proximal and distal RTA. Topiramate-induced RTA can make patients prone to kidney stones as stated earlier as well.  The utility of regular monitoring of HCO(3)(-) levels has not been proven and is not routine practice currently.

Finally, isolated refractory renal wasting of potassium has also been reported with this agent.

A large systematic review confirmed the above findings of renal toxicity with this agent. Fourty-seven reports published between 1996 and 2013 were retained for the final analysis. Five case-control studies and six longitudinal studies addressed the effect of topiramate on acid-base and potassium balance. A significant tendency towards mild-to-moderate hyperchloraemic metabolic acidosis (with bicarbonate ≤21.0 mmol l(-1) in approximately every third case) and mild hypokalaemia (with potassium ≤3.5 mmol l(-1) in 10% of the cases) was noted on treatment with topiramate, which was similar in children and adults.

Finally,increasing evidence supports the use of topiramate. Topiramate is generally well tolerated, and serious adverse events are rare. Nonetheless, it is linked with the development of acidosis, hypokalaemia, hyperuricaemia and hypocitraturia and eventually renal stones.

Master teacher: how do you define one?

What makes a “master clinician teacher”—adapted from George Couros, an educator.

This list can be used for teachers in med students, residency and in nephrology fellowship as well.

·         Connects with students and gets to know them individually.

·         Helps students to meet their own individual needs as each might have their own learning styles

·         Makes the curriculum and what is taught relevant.

·         Works with students to develop their love of learning, helping students to find their own spark in learning( concept of intrinsic motivation –often lacking in our trainees)

·         Keeps themselves as a teacher up-to-date. Education and learning will always change ( being a learner for life makes you a better teacher)

·         Focuses on learning goals as opposed to performance goals.

·         Ensures that “character education” is an essential part of learning. Students need to grow emotionally as well as mentally( this is critical in creating the culture for constant life long learning and work life balance)

·         Is passionate about the content they teach( THIS is by far the MOST important quality)

·         Is concerned not just with what is taught in their class but with their overall impact on the school culture( Making a cultural difference is critical on perhaps methods of teaching)

·         Communicates well with all the stakeholders and not just the students( a subtle but needed politician)

·         Behaves as a facilitator of learning- not a “spoon feeder”

All our fellows out there, I am sure you have one mentor who exemplifies these qualities. This is what makes the experience of learning a more meaningful experience. Please take a minute to salute and respect all our teachers and educators in our lives. They teach you medicine but they also may be teaching you a way of life!

In the NEWS: Too much salt intake doesn't lead to increased water drinking

Two published studies in JCI might change how we think the body handles “too much salt”

https://www.jci.org/articles/view/88532/version/3/pdf/render

https://dm5migu4zj3pb.cloudfront.net/manuscripts/88000/88530/JCI88530.v2.pdf

What we learnt in medical school:

If you eat a lot of salt — sodium chloride — you will become thirsty and drink water, diluting your blood enough to maintain the proper concentration of sodium. Ultimately you will excrete much of the excess salt and water in urine.

When salt intake was increased in Russian cosmonauts studied, the urine Na excretion did increase as expected. But, the urine volume was not associated with those changes. When salt intake was high, the folks drank less water in the long run and still excreted increased water amounts. Where was this extra water coming from? The crew members were increasing production of glucocorticoid hormones, which influence both metabolism and immune function and allowed fat breakdown leading to water production.

Taking these observations to the lab, the investigators began a study of mice in the laboratory. The more salt the investigators added to the animals’ diet, the less water the mice drank(counter to what we think science teaches us when we eat a high salt diet). The animals were getting water by not drinking it but via  increased levels of glucocorticoid hormones breaking  down fat and muscle in their own bodies. This freed up water for the body to use.

Now published, the authors report the unexpected observation that long-term high salt intake did not increase water consumption in humans but instead increased water retention. Moreover, salt and water balance was influenced by glucocorticoid and mineralocorticoid fluctuations. 

This leads to a even bigger question? – does high salt intake= potential weight loss as fat breakdown is happening? So in other words, a high salt intake body is behaving similar to a starving body.

 I am sure that there is more to it!  In the long run, this is probably not a good adaption of the body and high glucocorticoid state is likely a risk of diabetes.  But these studies show us that we really don’t understand salt homeostasis in humans as we thought we did.

Bravo to the scientists on publishing this alternate view on salt intake and water production.

In the NEWS: AKI and marathon runners

An interesting study in AJKD published revealed a possible risk of AKI with marathon runners. This is the first study to evaluate urine microscopy in parallel with conventional and novel biomarkers of injury and repair in marathon runners. The authors prospectively showed that the AKI in runners is secondary to structural injury, mainly acute tubular injury, as evidenced by serum creatinine levels, urine microscopy analysis, and levels of novel biomarkers of injury and repair.

One would expect these changes likely were related to elevated CPK levels and rhabdomyolysis.  Interesting, while the subjects had high CPK levels, they did not correlate with AKI episodes. The authors hypothesize that heat stress and increase in core body temperature along with systemic inflammation are likely associated with AKI in marathon runners. They said that this might be similar to the CKD that is prevalent in Central American in sugarcane workers. Agricultural workers have been shown to have acute decreases in kidney function and progression to CKD associated with dehydration, systemic inflammation, and oxidative stress.  It is also possible that compared with agricultural workers, marathon runners have controlled ischemic preconditioning throughout their training, which may improve the kidney’s ability to better tolerate repeated injury.  That is an interesting analogy.

82% developed AKIN defined stage 1 and 2 AKI. A total of 16 (73%) runners were scored as having positive microscopy findings on day 1 or day 2. Some ( minor amount ) were taking NSAIDS but 50% were on some form of herbal medications.  Regardless, this is an interesting study and perhaps should be repeated in a larger marathon population such as the NYC marathon. In addition, curious what the hyponatremia incidence was? 

Topic Discussion: Capillary Leak Syndrome

A recent review in KI summarizes the pathophysiology of capillary leak syndrome and numerous etiologies that can cause it along with an interesting management strategy.

Besides sepsis, capillary leak syndrome(CLS) can be seen in:

1.       Drug induced CLS—classically interleukin 2, gemcitabine and certain monoclonal antibodies such as OKT3, anti CD-28 antibody TGN1412  ( steroids can help treat)

2.       Engraftment syndrome- seen post HSCT ( usually 4-7 days post) with increased inflammatory markers and AKI( 12-25% in most HSCT patients)( steroids can help treat)

3.       Differentiation syndrome( retinoic acid) – steroids help in this situation as well

4.       Ovarian hyperstimulation syndrome(OHSS)—two variants( early time course, vs late following HCG treatment)—supportive care

5.       Hemophagocytic lymphohistiocytosis

6.       Hemorrhagic fever( viruses such as Ebola, Marburg, Puumala)

7.       Clarkson’s disease( idiopathic CLS)—supportive therapy, IVIG, theophylline

8.       Others:- snake bites, Ricin overdose, APLAS, Kawasaki disease

In addition to hypotension, cytokines are likely to be important in the pathophysiology of acute kidney injury in capillary leak syndrome. Fluid management is a critical part of the treatment of capillary leak syndrome; hypovolemia and hypotension can cause organ injury, whereas capillary leakage of administered fluid can worsen organ edema leading to progressive organ injury.

The first phase of treatment is volume resuscitation including fluids, pressors and or IV albumin. The second phase includes loop diuretics, diuretics with albumin and finally renal replacement therapy.

Full article here

https://www.ncbi.nlm.nih.gov/pubmed/28318633