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.”

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