Topic Discussion: Do B regulatory cells exist and do they help in transplant tolerance?

Recently, David Rothstein from Pittsburg gave an amazing grand rounds on B regulatory cells in NYSN in New York. Here are some notes on what I learnt.

B cells can influence T cell differentiation but B cells are effector cells themselves.  B cells also are responsible for antibody production. Do B regulatory cells exist?

Koichi et al showed in an elegant manner that certain subset of B cells in mice produce IL-10 and they might have regulatory function. In addition, IL-10 production was restricted to this CD1d^hiCD5⁺ B cell subset, with IL-10 production diminished in Cd19^−/− mice. Thereby, CD1d^hiCD5⁺ B cells represent a unique subset of potent regulatory B cells per authors in that study.

Ding et al in JCI showed that B cells that had the IL-10 production also had a TIM-1 marker.  What is TIM-1.  T cell Ig domain and mucin domain protein 1 (TIM-1) is a costimulatory molecule that regulates immune responses by modulating CD4⁺ T cell effector differentiation. TIM-1 was expressed by a large majority of IL-10–expressing regulatory B cells in all major B cell subpopulations, including transitional, marginal zone, and follicular B cells, as well as the B cell population characterized as CD1d^hiCD5⁺.  They showed that with a  low-affinity TIM-1–specific antibody that normally promotes tolerance in mice, actually accelerated (T cell–mediated) immune responsiveness in the absence of B cells. TIM-1⁺ B cells that had IL-10 expression  could directly transfer allograft tolerance.  What is possible is that TIM-1 is an inclusive marker for IL-10⁺ Bregs.

Could these be the cells that induce tolerance in transplant patients?

Yeung et al answered this question in mice. B cells that express a mutant form of TIM-1 lacking the mucin domain (TIM-1^Δmucin) are unable to produce IL-10 in response to specific ligation with anti-TIM-1. TIM-1^Δmucin mice also exhibit accelerated allograft rejection, which appears to be due in part to their defect in both  baseline and induced IL-10⁺ Bregs, since a single transfer of WT TIM-1⁺ B cells can restore long-term graft survival.

That’s in mice studies. It is impossible to measure TIM-1 in humans as percentage of these cells might be just <1%.

To make things more exciting, there might even exist a subset of regulatory plasma cells that produce IL-35. So is IL-35 producing cells also a type of B regulatory cells.

No one is aware of a disease entity that exists that is a Breg deficiency. IPEX syndrome is a Treg deficiency syndrome. One study has looked at kidney transplant human samples in JASN and using Breg data. 

Cherukuri etal. examined the cytokine profiles of human samples and found that subsets of CD24(hi)CD38(hi) transitional B cells (TrBs), CD24(hi)CD27(+) memory B cells, and naïve B cells express IL-10 and the proinflammatory cytokine TNF-α simultaneously. TrBs had the highest IL-10/TNF-α ratio and suppressed proinflammatory helper T cell 1 (Th1) cytokine expression by autologous T cells in vitro more potently than memory B cells did, despite similar IL-10 expression. What was important was the  ratio of IL-10/TNF-α expression, a measure of cytokine polarization, as an indicator of regulatory function than IL-10 expression alone. Indeed, compared with TrB cells from patients with stable kidney graft function, TrBs from patients with graft rejection displayed similar IL-10 expression levels but increased TNF-α expression (i.e., reduced IL-10/TNF-α ratio), did not inhibit in vitro expression of Th1 cytokines by T cells, and abnormally suppressed expression of Th2 cytokines. In patients with graft dysfunction, a low IL-10/TNF-α ratio in TrBs associated with poor graft outcomes after 3 years of follow-up. So, B cell-mediated immune regulation is best characterized by the cytokine polarization profile, a finding that was confirmed in renal transplant patients.  This is an amazing start. Hope to see more of this work to help us figure out the holy grail of transplant- tolerance!!

Interestingly, in a study done in NEJM where rituximab was used to deplete B cells as induction agent in transplantation, there were more rejection episodes in that arm.  Perhaps there was too much B reg depletion?   

To Match or Not to Match

Nephrology has been facing a very troublesome period for trainees.  In the midst of declining interest in nephrology, there has come a point of conflict amongst the training directors- should we go through the match or stay out of the Match. Almost 10 years ago, nephrology was not part of the Match and candidates were solicited directly from training programs. I remember that my year was the last year that we were a “non-Match” based field. It was fall of 2005 (start of my second year of residency), I had to make a decision about a subspecialty choice and then also a choice of the right program that fit what I wanted in a fellowship program. Why did nephrology go into the Match? It’s simple:- Match-based fellowship ranking is PRO candidate. When there are enough positions and competitive number of candidates, the Match works for the favor of the candidate.  Even when applicant numbers decline, the Match still works in the favor of the candidate allowing them to have access to even more potential program. It also takes away the problem of having an early and late interview based biases that some candidates have to face with certain programs. The simple fact is that without the Match, desirable positions will be taken up early making it difficult for an applicant to find a spot later in one’s residency training. It also allows for candidates an opportunity to look at a variety of programs with no pressure to “sign the letter” on the spot.

Take a look at what happened when GI abandoned the Match in the early 2000’s.

“Over the past 5 years, the application, interview, selection, and notification process has become increasingly chaotic and unfair to applicants. Interviews have been occurring earlier and earlier each cycle, forcing applicants to apply during their internship year before they have time to do electives, conduct research, and obtain letters of recommendation. The timing of interviews is such that not all programs interview during the same time period, eg, “early-interviewing” vs “late-interviewing” programs. Additionally, a short time to accept an offer places the applicant in the awkward position of accepting a premature offer before being able to interview at all programs. We have undoubtedly lost promising applicants because of their reluctance to decide in their internship whether or not to specialize in gastroenterology.”

The advantages of a Match are myriad and include order and fairness to the system, time to allow the applicant to decide to enter a particular, and placement of applicants in the program that is the most appropriate fit for them. In areas where Matches exist, fellows are more mobile, invigorating the field of interest and programs.

When I asked few fellows anonymously about what they would prefer, here are few answers I got

“No Match!!!, Match is a like a lottery, unpredictable!!”

“I prefer the Match. I think it’s hard to know if you want to go somewhere on the spot and making a decision if its offered to you right away maybe impulsive instead of thought out.”

“I think it will be depressing if the Match went away!!”

“Having no Match can make the programs think outside the box and how to make them more marketable.”

“Match only helps large academic programs”

“Match is the best for small community programs and actually will help them the most!”

As one can see that just from a small sampling, the fellows are divided. When there is a competitive specialty such as gastroenterology or cardiology, Match programs can help benefit the applicant and allow them the best possible chance of getting a top fellowship program that fits the candidate. Keep in mind, in early 2000s, GI was not as competitive as it is now. When you have a less competitive field as ours (let’s be real), does the Match process help?  Does it help when there are more open spots then there are candidates?  The answers to these questions are not the reason to have or not have the Match, but are questions that many programs might ask to decide if they need to go with the Match.  But, we have to be fair to the residents and going via the Match is the fairest approach to the process. 

This year, the ASN has responded with a Match task force (similar to what GI did in the early 2000’s) and is mandating that all ACGME programs in nephrology go via the Match process. You are either all in or all out. Why did this group mandate such a strong statement? This is because nephrology is in jeopardy in losing the Match. When programs and applicants feel that the majority of positions are outside of the Match, the process itself will degrade to a point where is not sustainable. It just stops working. This is what was happening in the last few years of the Match. Therefore, the committee made the difficult decision to mandate that all positions join the Match. What drove this decision? This decision hinged on a fear of losing the Match if the current environment continued. Also, the very real downstream consequence, if the Match was abandoned, of having even a lower number of applicants pursue nephrology. If the status quo continued and more and more programs made the decision to offer spots on the fly (as a way to stay competitive) then ERAS was only serving as a means to collect applications. The intended purpose of helping applicants choose a program was lost.

While many programs might like this idea, there might be program directors that might not be in complete agreement with this process. There are a few programs that have never participated in the Match, and now are obliged to participate in the Match. There are many reasons why they should join.

1. Continuing the Match will help ensure a healthy applicant pool for the entire field.

2. The potential for more applicants will interview at your program

3. Applicants will not feel pressured to sign up and thus will make a more informed decision.

How does one help the program directors and programs where their medicine department or health system put pressure on them to go out of the Match? It is shocking that this even happens. If the medicine department or administrator puts that much pressure on a program that they feel compelled to offer positions outside the Match just to fill: it is an environment that values the work and service and not the applicant and education.

We don’t know the answers to these questions or thoughts but as a community that trains nephrologists, we need to have unity and fairness in the process. The “all in” approach is a good first step in the right direction. It is PRO candidate, PRO trainee and PRO unity in nephrology.  The Match task force was left with the decision to mandate an “all in” approach. The current system in place is not working and if it was left up to the program (as it currently is).  Then the current degradation of the system would only continue and thus we would be in jeopardy of losing the Match.

We would like to hear other thoughts on this as it’s an important component in this year’s Match process.

Kenar D. Jhaveri and Matthew A. Sparks

Venous thrombosis and CKD : IS there a connection?

Cancer can lead to increased risk of clots and DVTs. Many cancer patients also have decreased GFR. Does GFR alone increase the risk of DVTS or blood clots?

Ocak et al answered this question in a recent publication in Circulation in 2014.

Pro-coagulant factors were reviewed in patients with varied degree of GFR compared to a cohort of normal GFR patients with venous thrombosis.

Factor VIII and VWF levels were increased with each percentile category drop in GFR.  The odds of having a venous clot also increased independent of other risk factors( DM, Factor V leiden, malignancy, arterial thrombosis, BMI, immobilization, surgery, steroids use) with drop in GFR.

Adjustment of those factor levels did attenuate the odds ratio related to GFR.  The authors did conclude that impaired kidney function affects venous thrombosis risk via concurrently raised factor VIII and von Willebrand factor levels. 

In both the Longitudinal Investigation of Thromboembolism Etiology (LITE) and Prevention of Renal and Vascular End-Stage Disease (PREVEND) study, chronic kidney disease was associated with an increased risk of venous thrombosis. This study showed the pathophysiologic mechanism perhaps why this happens. 

New York Society of Nephrology Fellows Night Event: Please submit abstracts

         NYSN Fellows Night

                                 Date: May 20th 2015

                                       Location:

                   The New York Academy of Medicine

                     1216 Fifth Avenue (103rd Street)

                              New York, NY 10029

Abstract Submission: April 28th, 2015

Abstract Acceptance Notice: May 6th, 2015

Abstract Guidelines:

1)      Page Length –Please describe their project in NO MORE than 300 words

2)      Fellow must present their own work in which they made a significant contribution.

3)      Research Mentor should be a member of the NYSN with paid dues. Dues are $100.00 and should be send to Dr. Enver Akalin, Montefiore Medical center, 111 East 210th street, Kidney Transplant Program, Bronx, NY 10467.

4)      Please identify the research into one of two categories: Clinical Or Basic

5)      Mentor/advisor name has to be part of the abstract.

6)      Please submit your abstracts to kjhaveri@nshs.edu when ready.

7)      Top Clinical and Basic research abstracts will be selected for ORAL presentation on May 20th evening

a.      Presentation: Power Point

b.      Presentation Length: 8 minutes

c.      Questions / Answers: 4 minutes

d.      Abstract presentations will be judged based on the following:

i.      Research Question / Knowledge about the topic

ii.     Study Design / Data Presentation

iii.    Interpretation of Data / Responses to Questions

e.      Prizes - First place and Second places will be awarded in BOTH categories.

8)      Alison Norris Nephrology Fellow Award: Third year in a row, this award will be given the paper that is focused on some psychosocial/ethical aspect of the care of kidney patients.

Kenar Jhaveri, MD

Program Chair

NYSN

Tyrosine Kinase Inhibitors vs Anti VEGF therapy: What does the podocyte see?

Anti VEGF therapy has been known to cause proteinuric renal disease. A recent study published in Medicine has the largest single center series looking at biopsy proven findings of Anti VEGF and tyrosine kinase inhibitor therapies.

Some interesting points:

Most patients were biopsied for proteinuria

TMA was the most common biopsy finding if the drug used was an anti VEGF or TRAP agent, 50% of which were only renal limited.

Minimal Change disease/FSGS was the most common finding associated with tyrosine kinase inhibitors along with interstitial or tubular disease.  

This is an interesting observation that was not reported before. It appears that the VEGF inhibitors are strictly likely to behave like pre eclampsia like syndromes but the TKIs are more likely to cause a pure nephrotic syndrome like GN.  None had gotten steroids. It might be interesting to see if these drug induced MCD respond to steroids and hence we can then continue the agent for good cancer treatment.

Hypertension and proteinuria resolved following drug discontinuation and antihypertensive agents.

No patient developed severe renal failure requiring dialysis. 

SiteGPR: A website for renal dosing of medications

Dosing of drugs in renal disease is a common topic of discussion. A nice website tool that helps manage that better is here.
http://sitegpr.com/index.php

SiteGPR presents evidence-based recommendations on drugs dosage adjustments in patients with renal insufficiency.

In addition, it has a long list of medications that are linked with renal toxicity.
A great tool to be used.

Nephtangles: The nephrology interface with ABIM MOC

As we are all aware of the increased requirements from ABIM in the last few years for board certification.  What are we to do? Sit tight and wait for a final decision? Is MOC here to stay or to go? What is our role as a practicing physician.

I urge all to read Nephtangles blog
http://nephtangles.blogspot.com/

The blog has multiple posts highlight some important developments in the last few months on this very important topic.

Blood Transfusions and AKI following CABG: Does age of PRBCs matter?

Blood transfusions have been linked with risk of AKI following cardiac surgery. Anemia and number of PRBCs transfusion are independent risk factors for development of AKI post CABG, Catalytic iron can produce oxidative stress, surrogate for hypotension and a “sick patient” and age of PRBCs maybe the culprit? In addition, PRBCs have been linked with non renal adverse outcomes such as 16% increase risk of mortality post CABG, risk of sepsis and pneumonia and risk of increased length of intubation.

A recent study called RECESS trial just published in NEJM looked at the age of PRBCS and risk of outcomes following CABG. RECESS was a randomized trial at multiple sites from 2010 to 2014 looking at patients 12 years of age or older who had complex cardiac surgery and were likely to undergo transfusion of red cells were randomly assigned to receive leukocyte-reduced red cells stored for 10 days or less (shorter-term storage group) or for 21 days or more (longer-term storage group) for all intraoperative and postoperative transfusions.

The primary outcome was the change in Multiple Organ Dysfunction Score (MODS; range, 0 to 24, with higher scores indicating more severe organ dysfunction) from the preoperative score to the highest composite score through day 7 or the time of death or discharge.Overall results showed that the duration of PRBCS storage was not associated with MODS events. In addition, adverse events did not differ significantly between groups except that hyperbilirubinemia was more common in the longer-term storage group.

What about renal outcomes? In the supplementary sections, the renal outcomes are mentioned and there was no difference in both arms. Serious renal adverse events in both arms were also similar. So AKI risk might still exist due to PRBCs transfusion risk but it’s not due to the age of the PRBCS. 

Acute Kidney Injury Associated with Cardiac Surgery

Here is a slide share of a talk I gave on AKI in the cardiac surgery unit.