Wednesday, March 21, 2018

Nephmadness 2018

Neph Madness is back with a new twist in 2018! This time, not only is it the fun game we used to playing for the last 6 years but this year there is CME points awarded.  So you learn and get credit for it!

Thanks to AJKD and NKF on this component of the Neph Madness
and check out the website
I just submitted my picks and all I can say is my top player is related to the heart! Let’s see if the best champion wins. 

Novel things this year
1.       Many visual abstracts
2.       Amazing videos
3.       CME credits this time around
4.       Visually appealing more amazing website design
5.       More varied topics including a Pediatric Neph region, transplant region and an interesting basic science and electrolyte region. 

 Here is the amazing blue ribbon panel
Blue Ribbon Panel
Come play the best online game of the year- Nephmadness 2018! 
Check out this amazing editorial on this years games by Sparks and Topf

Thursday, March 15, 2018

Concept Map: Podocytopathies

In last decade, another way to look at podocyte disorders.
Reference of this form of classification comes from
Click on image for larger size view

Tuesday, February 27, 2018

Consult Rounds: Esclicarbazepine induced hyponatremia

Image result for eslicarbazepine

Carbamazepine and oxcarbazepine are the most common anti epileptic drugs( AEDs) which induce hyponatremia in patients with epilepsy. Recently, other AEDs, such as eslicarbazepine(ESL), sodium valproate, lamotrigine, levetiracetam and gabapentin have also been reported to cause hyponatremia.

In a two year, single center open labeled observational study of ESL in patients with imaging proven stroke with new onset post stroke seizure were included. ESL was titrated between 400 mg and 1200 mg once daily during 1 month observation period. The titrated dose of ESL was continued during 96-week maintenance period. The patients were followed up for seizure control and side effects, including serum sodium on first examination, at the end of 1 month and then at three monthly intervals for 24 months (total eight visits). Hyponatremia developed in four out of 32 (12.5%) patients; it was symptomatic in three and asymptomatic in one patient.
In three controlled epilepsy studies, 1/196 patients (0.5%) treated with 400 mg, 4/415 patients (1.0%) treated with 800 mg, and 6/410 patients (1.5%) treated with 1200 mg of ESL had one or more serum sodium values less than 125 mEq/L during treatment whereas none in placebo group. In contrast hyponatremia is the most frequently reported adverse drug reactions in the post-marketing database for Aptoim (ESL brand approved by the US FDA). In this database there were 140 cases of hyponatremia, in half of them hyponatremia occurred within the recommended range of 400-1200mg of ESL and sodium level as low as 103 mEq/L had been reported. In the above study all four patients who developed hyponatremia were in ESL 800 mg group, and lowest sodium level recorded was 113 mEq/L. As hyponatremia develops across all dose ranges of ESL, thus it appears that ESL induced hyponatremia is probably not dose dependent but most appeared in the 800mg group or higher.

What is the mechanism? Possible mechanism of ESL induced hyponatremia can be understood by the mechanism of hyponatremia in oxcarbazepine. Sachdeo et al. found that oxcarbazepine intake results in significant reductions in serum osmolality and serum sodium concentration after a water–load test, This hypotonic hyponatremia, which is not associated with a significant change in serum ADH, is the result of both a relative inability to dilute the urine and a reduction in the percentage of water excreted after the water–load test. He suggested that oxcarbazepine induced hyponatremia is not attributable to the SIADH. Possible mechanisms include a direct effect of the drug on the renal collecting tubules or an enhancement of their responsiveness to circulating ADH. 

It responds well to fluid restriction, salt supplementation with or without ESL withdrawal.

Thursday, February 8, 2018

MGRS and MGUS- the 1/3-2/3 rule of pathology in the kidney?

When someone has MGUS, what is the true incidence of kidney disease? – this has not been answered. An old study from AJKD in 2003 did help us guide the breakdown of kidney diseases when someone has MGUS.  In other words, if someone has MGUS, and there is some form of renal disease- AKI, proteinuria, hematuria and you biopsy them- what percent of the time you will find renal disease associated with proteinuria, what percent of the time you would find diseases other than paraproteinemic disease?

In summary, the AJKD paper looked at a single center experience of their paraprotein related kidney diseases biopsy bank.  Patients who underwent renal biopsy and had monoclonal gammopathy on serum and/or urine electrophoresis and/or had a renal biopsy diagnosis related to paraprotein (cryoglobulinemic glomerulonephritis(cryo) monoclonal immunoglobulin deposition disease [MIDD], light chain cast nephropathy [CN], or light chain amyloidosis [AL]) were identified.  One hundred twenty-one patients met the inclusion criteria and were classified as having renal disease related or unrelated to monoclonal gammopathy. Among 66 cases of renal disease related to monoclonal gammopathy, diagnoses were cryo (30.3%), MIDD (28.8%), CN (19.7%), AL (19.7%), and CN plus MIDD (1.5%).

Among 55 patients with monoclonal gammopathy and unrelated renal disease (63.2% of all patients with monoclonal gammopathy), various lesions were found, including diabetic nephropathy (18.1%), focal segmental glomerulosclerosis (18.1%), arterionephrosclerosis (12.7%), membranous glomerulonephritis (9.0%), minimal change disease (7.3%), various immune complex diseases, interstitial nephritis, or nonspecific changes. MPGN was also included in this group. We know now that MPGN is likely related to MGUS and not a non paraprotein disease.

But what about patient’s with MGUS and true MGRS- what I calculated from the paper was around 22( either had cyro, CN, AL or MIDD) patients and if we remove MPGN from the current 55 patients stated above, would be 52 patients.  This makes it a 1/3-2/3 rule.  So if there is MGUS or smoldering MM and some form of renal disease on clinical presentation , there is 1/3 chance that their disease would be paraprotein related in the kidney if you did a kidney biopsy. But majority of the time, it would be a non paraprotein mediated disease.

While this paper looks at it at a single center, it gives some insight into the incidence of true MGRS when there are renal clinical presentations. 

Sunday, February 4, 2018

#Nephrocards2018 CME on March 10th 2018

Northwell health in Long Island New York will host a one-day symposium aimed at providing updates on the Nephro-Cardiology on Saturday March 10th( #nephrocards2018)

Go to this link for more information and to register. Fellow, Students and Residents registration is free

ASN, ISN, NKF and Cardio-renal society of America endorsed

Below is the itinerary

7:30am Registration, Breakfast and Exhibits

8am Contrast Nephropathy? Does it Exist-The Latest Update and Prevention
Paul M. Palevsky, MD

9am Cardio-Renal Syndrome
Jai Radhakrishnan, MD, MS, MRCP

9:30am TAVR and the Kidney
a. Basics of Transcatheter Aortic Valve Replacement: A Primer
Bruce Rutkin, MD

b. The Renal Effects of Transcatheter Aortic Valve Replacemen
Kenar D. Jhaveri, MD

10:30am Break

10:45am Left Ventricular Assist Devices
a. Basics of Left Ventricular Assist Devices
David Majure, MD

b. Left Ventricular Assist Devices and the Kidney
Daniel W. Ross, MD

11:30am Novel Agents Used in Hyperkalemia - What Cardiologists and Nephrologists Need to Know
Steven Fishbane, MD

12:15pm Interventional Therapies for Refractive Hypertension
Avneet Singh, MD

12:40pm Lunch 1:30pm Novel Anticoagulants and the Kidney
Nupur N. Uppal, MD

2pm Cardiac Workup of the Kidney Transplant Patient
Alexander Lee, MD

2:30pm Cardiac Surgery and the Kidney
Mitchell H. Rosner, MD

3:30pm Panel Discussion

4pm Program Conclusion

Sunday, January 28, 2018

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

Here is the summary from the Pheresis society guidelines

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.

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.

Tuesday, January 23, 2018

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

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

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

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.”

Sunday, January 21, 2018

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

Thursday, January 11, 2018

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.

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

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!!

Tuesday, January 2, 2018

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
Graft loss(yes/no
Ipilimumab +pembrolizumab
5 weeks
Cellular and antibody rejection
8 weeks
Cellular rejection
Ipilimumab +  nivolumab
5 weeks
Cellular rejection
6 weeks
Cellular rejection
6 weeks
Cellular rejection
3 weeks
Cellular rejection
Ipilimumab + nivolumab
1 week
Cellular rejection
Pembrolizumab + chemo

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.

What are your thoughts?

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