Topic Discussion: Gemcitabine induced TMA- what to do?

Thrombotic microangiopathy (TMA) can come in many forms- HUS and TTP might being the two most extreme versions. Gemcitabine induced TMA is a drug induced TMA that can result from dose dependent use of the agent or an immune mediated phenomenon.

In immune-mediated TMA, the drug induces formation of antibodies that react with multiple cells, including platelets, neutrophils, and endothelial cells, but strong binding only occurs in the presence of the drug (or drug metabolite). Therefore, these antibodies are described as drug-dependent antibodies. Toxicity-mediated (ie, non-antibody-mediated) TMA may develop by multiple mechanisms. Many cases are dose related, occurring only after large cumulative exposure over a period of time or exposure to large single doses of a drug. Gemcitabine induced TMA is thought to be due to both the above mechanisms.

Recent review found that of 78 substances to have previously been reported to cause thrombotic microangiopathy (TMA), 22 had definite evidence supporting causal association. However, 9 (clopidogrel, cyclosporine, estrogen/progesterone, gemcitabine, interferon, mitomycin, quinine, tacrolimus, and ticlopidine) accounted for 76% of reports.

Initial management involves immediate discontinuation of suspected drug, or reduction of dose when discontinuation is not a medical option.

What about pheresis or anti complement therapy specifically for Gemcitabine induced TMA?

A twitter pole I did showed these results

Drug induced TMA? Example gemcitabine induced. Would you use Pheresis and or complement inhibitors after holding culprit agent ? #onconephrology

— Kenar Jhaveri (@kdjhaveri) January 27, 2018

Here is the summary from the Pheresis society guidelines https://www.ncbi.nlm.nih.gov/pubmed?term=27322218

In all cases of Gemcitabine induced TMA, ADAMTS13 levels were typically normal. In literature review, among 26 patients not treated with pheresis, 56% recovered from TMA, whereas 30% of 18 patients who received TPE. So based on that data, doubt pheresis will help TMA associated with gemcitabine.

There have been reports of patients with toxicity-mediated DITMA attributed to gemcitabine, case reports have described patients with acute kidney injury attributed to gemcitabine who improved after treatment with anti-complement therapy. However, these case reports do not provide confidence that anti-complement therapy is appropriate. Often the patients have received multiple chemotherapeutic agents, and the selection of gemcitabine as the possible cause-effect cannot be confirmed.

https://www.ncbi.nlm.nih.gov/pubmed?term=24911558

https://www.ncbi.nlm.nih.gov/pubmed?term=27743743

Often a kidney biopsy to document TMA has not been done. Although these preliminary observations do not provide confidence that anticomplement therapy is appropriate, some experts do feel it might be reasonable to consider the use of eculizumab in persistent drug toxicity-mediated TMA that does not improve with supportive care and withdrawal of the offending agent and especially if there is risk for progressive CKD.

So in summary

1. Most important- stop the offending agent
2. Data on use of pheresis- poor and in some instances might be not recommended
3. Data on use of complement inhibitor- poor and unclear at this point- probably would avoid but there might be mixed opinion on this matter in the literature.

Take care of your Nephrologists; a burnout in the making

Burnout is evident in all fields of medicine. Nephrology is no exception.

Check out the rankings of where we fall in that

https://wire.ama-assn.org/life-career/report-reveals-severity-burnout-specialty

Recently, CJASN published 3 articles highlighting this important part of our lives –both attending and fellowship related.  

http://cjasn.asnjournals.org/content/early/2018/01/16/CJN.09870917.full

http://cjasn.asnjournals.org/content/early/2018/01/10/CJN.06800617.full

http://cjasn.asnjournals.org/content/early/2018/01/10/CJN.02310317.full

The issue of physician burnout is important. As the US population grows and ages, the number of physicians needed to care for them increases. When burnout leads physicians to reduce or cease their practice altogether, patient access to medical care is diminished. Moreover, burnt-out physicians are likely to be less productive, make more mistakes, and generally deliver a lower quality of care than their fully engaged colleagues. Finally, physicians are human beings too, and their suffering should summon no less compassion and concern than anyone else's.

As both authors point out, sick patients, urgent calls, complex cases, midnight phone calls all can add to distress and burnout in nephrology- but for the matter of fact- this is true in many fields in medicine and not specific to nephrology. Toxic learning environments and toxic hospital/institution models can make this problem worse.  Work related stress compounded with family and personal matters can lead to significant burnout in a fellow or attending in practice. While the three articles discuss burnout in details and where and why it might exists, the solutions offered are not very specific to nephrology.

For the attending level burnout, there are multiple hidden causes that are always hard to bring to the forefront:- RVU madness, compensation structure,  disgruntled faculty, inefficient systems in which we work to name a few. If not tackled in a timely fashion, burnout and fatigue can take form of severe depression and lead to high suicide rates.  I just saw this recent post in KevinMd about a young female doctor committing suicide and this post of a survivor.

Pamela Wible, MD nicely states this “The patriarchal reductionist medical model (the basis of Western meded) is dehumanizing by nature. Add more expensive technology & higher throughput with no emotional support and it is a mental health catastrophe for medical students and physicians who sadly are too often valued primarily for their revenue generating capacity per second.”  Check out this film on physician suicide.  One of the commenters nicely put it as  “ is it the strain from the system, sicker patients or retired doctors and the medical business operation”

While organization and structural interventions are needed to reduce burnout in attendings, how do we do that in nephrology?

We need to come up with practical solutions at each institution/division level to help with this.

Some suggestions as I brainstorm but this conversation has to go on – to save our physicians, to save our trainees and to save our patients. A happier physician leads to a safer and happier patient.

1.      Allow for flexibility in work hours to be more productive- as long as the work gets done- why does it have to be 7AM-5Pm?

2.      Use the hospitalists model of division of work- few focus on inpatient rotation and use a buddy system to have someone in the outpatient complete your outpatient dialysis encounters- work better as a team.

3.      Allow for childcare to exists at the premises of the Division or department level to make it possible for some parents to do work and not worry about their kids.

4.      Efficiency goes with loyalty as well- both should be weighed equally and not one over other in terms of promotion.

5.      If you are seeing patients in multiple dialysis units- can that be consolidated to 1-2 units to allow for less driving time- or if many partners in our practice- divide by region and be more efficient about it. This might lead to better patient care as you can spend more time with each patient.

6.      Meanwhile, ASN and NKF and RPA need to step up to discuss our reimbursements as nephrologists. We take care of a sick group of patients. We are thinkers of medicine and come up sometimes with the diagnosis that many physicians have missed. Nephrologists are considered one of the smartest physicians in the hospital- It’s about time American recognizes to pay someone for their THINKING and thoughtful care and not just for Procedures. Lobbying for higher reimbursement is needed for help in this state of physician burnout in nephrology.

Here is a guide I found on line regarding burnout in medicine

https://www.thehappymd.com/blog/bid/290755/physician-burnout-the-three-symptoms-three-phases-and-three-cures

At the end we must remember this important point regarding being a physician:

“At their core, good physicians are not mere moneymakers. Good physicians are professionals. And though today we often forget it, being a professional means more than merely getting paid for what we do. The more we treat physicians as though they were self-interested money grubbers, the more we de-professionalize them. And a de-professionalized physician is inevitably a demoralized and burnt-out one. We must begin early in medical education to help medical students and residents and fellows explore and connect with a sense of calling to the profession. Even late in their careers, physicians need to recall that they are summoned to something older, larger, and nobler than themselves. They must never forget that a career in medicine represents one of life's greatest opportunities to become fully human through service to others.”

Topic Discussion: Pre-Renal Success

Pre renal success is an interesting way to think about increases in serum creatinine when overall the patient is improving due to a therapy. Classically, this has been utilized when one uses ACEI/ARBs. Too often the internists ( and even nephrologists) diagnose initial decline in GFR following ACEI/ARB as “pre renal” AKI and reverse the beneficial effects of these amazing therapies.  Many times I have seen such meds taken off due to an increase in creatinine. Long term effects on mortality and CKD are more important than short term hardships of elevated creatinine.  In an article many years ago in Kidney International, a term pre renal success was suggested rather than renal failure for such cases to allow for non nephrologists to feel that it’s a success from a patient stand point even though the serum creatinine increased mild to moderately.  We see this a lot in HTN control as well.  A patient bp runs in 170/100 range and after few months of good therapy, you have got it good control to 130-140 SBP range but serum creatinine increased from 1 to 1.3mg/dl—big deal! – This is PRE RENAL SUCCESS as long term- this bp control is benefiting the patient from cardio vascular benefits.

A recent article in AJN, this term is being re introduced.

Similarly, in CHF patients, aggressive diuresis also leads to the rise in creatining that scares the cardiologists and nephrologist to further diuresis the patients. A recent  publication in Circulation confirms the assertion with use of tubular markers such as NGAL and KIM-1 that aggressive diuresis associated increases in creatinine are not bad. This is also pre renal success as overall, the patient benefits from being “less short of breath” and decreased hospitalizations.  Levels of NAG and KIM-1 did not change with aggressive diuresis. Worsening renal function occurred in 21.2% of the population and was not associated with an increase in any marker of renal tubular injury: Interesting, these increases in NGAL, NAG, and KIM-1 were paradoxically associated with improved survival (adjusted HR: 0.80 per 10 percentile increase, 95% CI: 0.69-0.91; P=0.001)—again suggesting this concept of Pre renal success

These findings reinforce the notion that the small to moderate deteriorations in renal function commonly encountered with aggressive diuresis are dissimilar from traditional causes of acute kidney injury.

It’s about time we called the following situations Pre Renal Success( this is personal opinion and there is room for debate)

1.    Increases in creatinine 25-30% after initiation of ACEI/ARB and perhaps we can add SGLT-2 inhibitors here as well

2.    Increase in creatinine 25-30% after aggressive 2-4 months of blood pressure control in a patient with severe HTN

3.    Increases in creatinine 25-30% after aggressive diuresis and a patient with severe CHF

Topic Discussion: SGLT-2 Inhibitors: An update

The glucoretics SGLT-2 inhibitors have really come with a wave to improve the outcomes in diabetic patients, especially cardio-vascular and renal outcomes. I had the pleasure to listen to Inzucchi SE recently on this topic and the science has really taken off.

Here is a summary of what is happening in the world of SGLT-2 inhibitors and what we need to know as nephrologists.

SLGT-2 inhibitors overall(  all of them) only have a minor to modest effect on A1C reduction. For anything, it might even stay the same after 12 weeks on the drug. This doesn’t translate into the benefits we see in trials. Regardless of the A1C being only modestly decreased, the cardiac benefits are amazing.

Even though they have a weight loss effect( usually just 2kg total no matter what), they are not approved for weight loss

Even though they have a significant bp effect, not approved for BP management

Obviously, they are not going to work if you have no URINE, so unclear benefit in ESRD patients

All trials, from CANVAS to EMPA-REG(empagliflozin), the cardiovascular benefits have been astounding- decreased number of MACE events( MI, stroke, cardiac event).

What the cardiologist world is excited about is also the decreased CHF admissions and readmissions ( perhaps due to the naturetic effect of the agent acting as a proximal tubule diuretic without really increasing renin-aldo axis)—making it an amazing drug for volume management. Recent studies have also shown increase in HCT with the drug use showing it’s effect on plasma volume.  Ongoing trials might shed light on CHF management in diabetics and non-diabetics with this agent. A recent review summarizes this.

Renal outcomes in EMPA-REG, initial decrease in GFR was reversible – related to the hyperfiltration decrease( similar to ACEI/ARB). But hard renal outcomes, 46% decrease in  doubling of crt, RRT or renal death. In addition, decrease in macro and micro-albuminuria as well.

CANVAS study- with a different drug- also similar MACE outcomes as EMPA-REG, but component of MACE individual were less pronounced. Comparable CHF benefits. Canaglifozin related CANVAS had more amputations and fractures as a major side effect that EMPA-REG(empagliflozin) data didn’t show that when re done to look for it; unclear why one drug does it and other doesn’t.  Visual abstract from NephJC

CANVAS Renal outcomes…40% reduction with agent with change in EGFR, dialysis and death-almost similar.

Should we start using this drug in diabetic patients with CKD? Or even CKD patients without DMII given significant cardio-vascular and renal benefit. When cost analysis was done, empagliflozin use resulted in higher total lifetime treatment costs ($371,450 versus $272,966) but yielded greater QALYs (10.712 vs. 9.419) compared to standard treatment. This corresponded to an ICER of $76,167 per QALY gained. This suggested that empagliflozin would be cost-effective in 96% of 10,000 iterations assuming a willingness-to-pay threshold of $100,000 per QALY gained.

Here is a nice review on both drugs and effects.

If we start prescribing as nephrologists, likely will be empagliflozin and dose of 10mg given similar effect and monitor for what effects? As might not change A1C anyway—more long term benefits such as cardio-vascular and renal effects.

We truly have entered a new era!!

Immune check point inhibitors and renal transplant: the saga continues with more twists and turns

Immune check point inhibitors have been used sparingly in the organ transplant world.
A review last time we did on this topic in Journal of Onconephrology listed a list of cases that led to rejection in majority of the cases when PD-1 inhibitors( nivolumab or pembrolizumab) was used alone or in combination with CTLA-4 inhibitors. 

Last year, a case from our institution(Barnett et al.) showed that if pre emptive steroids and mTOR inhibitors were used, rejection could be potentially prevented in a single case report. To date, to my knowledge, this has not been repeated. Nevertheless, new cases have come to light showing more rejection but a few showing no rejection despite PD-1 inhibitor use.

The table below is an updated list since our last publication in JON and NEJM(appendix)

Transplant type	ICI therapy	Time	Rejection(yes/no)	Graft loss(yes/no	Reference
DDRT	Ipilimumab	None	No	No	Lipson et al
DDRT	Ipilimumab	None	No	No	Lipson et al
DDRT	Ipilimumab +pembrolizumab	5 weeks	Cellular and antibody rejection	Yes	Alhamad et al
DDRT	Pembrolizumab	8 weeks	Cellular rejection	Yes	Lipson et al
DDRT	Ipilimumab +  nivolumab	5 weeks	Cellular rejection	Yes	Spain et al
DDRT	Nivolumab	6 weeks	Cellular rejection	Yes	Bolis et al
DDRT	Pembrolizumab	6 weeks	Cellular rejection	Yes	Kwatra et al
DDRT	Nivolumab	3 weeks	Cellular rejection	Yes	Deltombe et al
DDRT	Ipilimumab + nivolumab	1 week	Cellular rejection	Yes	Miller et al
LRRT	Pembrolizumab	None	No	No	Saadat et al
DDRT	Pembrolizumab + chemo	None	No	No	Wu et al

The last four cases shed some new light. Miller et al and Deltombe et al showed two cases that had converted to everolimus but still had rejection. No pre treatment of steroids were used. Saadat et al and Wu et al, no immunosuppressive treatments were made and PD-1 inhibitors were used and no rejection happened but cancers did progress. Saadat et al did use high levels of sirolimus during the treatment of the PD-1 inhibitor. The last case is fascinating as no pre- treatment was used and the patient had a DDRT and despite getting cisplatin, bevacizumab and PD-1 inhibitor, the creatinine remained stable. Could VEGF inhibition be protective here? Why did this patient not reject? Perhaps The Barnett et al case and Saadat et al didn’t reject due to being LRRT and having accommodation and tolerance but Wu case is intriguing.

A twitter poll I did on what folks are doing around showed the following when using PD-1 inhibitors in the renal transplant world.

Are you using Pd-1 inhibitors in renal Transplant patients ?

— Kenar Jhaveri (@kdjhaveri) January 1, 2018

What are your thoughts?