Topic Discussion: CAR-T therapy and the Kidney

A new dawn is breaking in the field of hematologic malignancies, as the first product based on chimeric antigen receptor (CAR) T cells was scrutinized today by a panel of experts and unanimously recommended for approval at the FDA for pediatric and young adult patients (age 3-25 years) with relapsed or refractory acute lymphoblastic leukemia (ALL).

Blood is collected from the patient, and then autologous T cells are separated out and genetically engineered. The process involves inserting a CAR that targets CD19, an antigen expressed on B cells and tumors derived from B cells.  These CAR T cells are then infused back into the patient, who has undergone chemotherapy, and in the body the product homes in on B-cell leukemic cells and destroys them.  The main action happens mostly about 2 weeks after those CAR-T cells have been re-infused.  Some have termed this form of therapy as the “ living drug”

Autologous CAR-T cell therapy first shot into headlines about 4-5 years ago when it was thought about in CLL patients.   Then several other studies were done essentially confirming that the concept is correct but there are serious toxicities.

https://www.ncbi.nlm.nih.gov/pubmed/25317870 (leukemias)

https://www.ncbi.nlm.nih.gov/pubmed/26760100 (myelomas)

https://www.ncbi.nlm.nih.gov/pubmed/28029927 ( gliobastoma)

The technology is complicated and initially when tried in CLL led to multiple toxicities of various organs including CNS, cardiac, renal and mostly requiring ICU admissions from acute cytokine release syndrome. This happens due to high levels of IL-6, a cytokine that is secreted by T cells and macrophages in response to inflammation.  Etanercept and tocilizumab have been used to block the IL-6 activity to treat such side effects.

Acute renal injury following CAR T-cell infusion is multifactorial and almost always reversible. Reduced renal perfusion is often the most important cause of renal injury. Reduced renal perfusion can be caused by cytokine-mediated vasodilation, decreased cardiac output, or intravascular dehydration due to insensible losses from high fevers. Tumor lysis syndrome and drug effect from medications such as antibiotics are other possible causes of renal injury. Electrolyte disturbances, such as hyponatremia, hypokalemia, and hypophosphatemia are not uncommon but have been reported. A recent article in Blood summarizes all toxicities.

Now the therapy has returned and we may see this in many centers. We must be aware of the cytokine release storm that it can cause leading to AKI in that setting.  There might be more in the pipeline of similar products such as the one that just got approved for ALL.

Figure source: http://www.lymphomation.org/programing-t-cells.htm

Consult Rounds: Cholemic nephrosis or Bile cast nephrpathy or should we say Jaundice associated nephropathy

Bile cast nephropathy or also called cholemic nephrosis represents a spectrum of renal injury from proximal tubulopathy to intrarenal bile cast formation found in patients with severe liver dysfunction. Bile can be toxic directly to the tubule or can form casts and have similar damage as myeloma cast nephropathy.

Recently this entity has gained some interest in the literature.

1.      Classically seen with patients with acute or chronic liver disease

2.      Usually, the total bilirubins are over 20 and conjugated over 16 is the cases that had bilirubin casts on kidney biopsies

3.      The LFTS were also higher in these patients

4.      The cause of liver disease doesn’t matter

The mechanisms responsible for tubular dysfunction include uncoupling of mitochondrial phosphorylation (thereby decreasing ATPase activity) by bilirubin  and oxidative damage of tubular cell membranes as well as inhibition of Na-H and Na-K pumps in the tubular cell membranes by bile acids. Cholemic nephrosis is reversible provided bilirubin levels are reduced early. This recovery is however delayed if there is extensive bile cast formation.

Some have suggested jaundice-related nephropathy as a replacement for cholemic nephrosis. Based on their definition, jaundice-related nephropathy would encompass the spectrum of injury that ranges from proximal tubulopathy to extensive tubular injury and tubular pigment. 

As bile passes via tubules, there is pigment nephropathy.

Pathology findings include: extensive acute tubular injury with bile stained tubular casts.
Macroscopic findings will include bile stained yellowish discoloration of the kidneys in jaundiced patients which become dark green after formalin fixation.
The Hall's stain confirms bilirubin presence.

Other interesting articles on this topic

http://www.kidney-international.org/article/S0085-2538(15)56212-1/fulltext

http://onlinelibrary.wiley.com/doi/10.1111/hdi.12169/pdf

http://www.ajkd.org/article/S0272-6386(16)30488-7/abstract

https://www.karger.com/Article/Pdf/371689

Consult Rounds: Acyclovir and dialysis

An often unforgotten drug that we must be aware of in ESRD patients is acyclovir.

Acyclovir can accumulate in ESRD if not dosed appropriately and can lead to neurotoxicities- leading to confusion, tremors and coma.

Initial study of 7 patients with end stage kidney disease receiving hemodialysis looked at levels following hemodialysis with each patient received a single 800-mg tablet of acyclovir. Plasma acyclovir levels were monitored over the next 48 h as well as before and after the next routine dialysis. Peak plasma levels were achieved at 3 h (12.54 +/- 1.76 microM, range 8.5-17.5 microM) with the half-life calculated to be 20.2 +/- 4.6 h. Mean plasma level of 6.29 +/- 0.94 microM were within the quoted range to inhibit herpes zoster virus (4-8 microM) at 18 h. Hemodialysis (4-5 h) eliminated 51 +/- 11.5% of the acyclovir which remained at 48 h. Computer modelling of various dose modifications suggests that a loading dose of 400 mg and a maintenance dose of 200 mg twice daily is sufficient to maintain a mean plasma acyclovir level of 6.4 +/- 0.8 microM. A further loading dose (400 mg) after dialysis would raise the residual acyclovir concentration by 6.1 +/- 1.0 microM.

Acute acyclovir neurotoxicity can be treated in CKD and ESRD patients with dialysis. The drug is water soluble, not albumin bound and small- hence an ideal dialysis candidate for removal.  It is important to keep this toxicity in mind as many might come in to your office with non renal dosing of this agent on ESRD and CKD patients and can lead to neurotoxicity. PD is not an option; HD is preferred mode for removal of acyclovir. 

  Some references

http://www.ajkd.org/article/S0272-6386(12)70234-2/abstract

http://onlinelibrary.wiley.com/doi/10.1111/1346-8138.13196/pdf

http://www.revistanefrologia.com/en-publicacion-nefrologia-articulo-acyclovir-valacyclovir-neurotoxicity-in-patients-with-renal-failure-X2013251412000456

http://www.shmabstracts.com/abstract/the-monster-in-my-room-acyclovir-neurotoxicity-in-a-hemodialysis-patient

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!