Wednesday, July 27, 2016

Consult Rounds: Hyponatremia and Rhabdomyolysis

A lesser known complication of hyponatremia or its correction is rhabdomyolysis. While recognized causes of rhabdomyolysis (Rb) include injury, seizures, drugs such as statins, hypokalemia and hypophosphatemia are known in the literature, less is known re association of hyponatremia leading to Rb.  

It was first described in 1979. In that patient, the low Na was from psychogenic polydipsia.
Multiple case reports following them( listed below) have been described in the literature. Most recently, this has been described in marathon runners that get both hyponatremic and Rb. In that study, the hyponatremic runners with the lowest post race Na demonstrated the highest CPK values at subsequent checkpoints. This is interesting.

What could be the mechanism?  What does the literature say?
1. Change in osmotic pressures results in failure of regulation of cell volume and cell lysis( so this could occur during hyponatremia or treatment of hyponatremia).
If the Na is corrected too rapidly, the cell has no time to compensate for the osmotic shifts and perhaps leads to Rb.
2. Na/Ca pump in muscle cells might be effected. As extracellular Na drops, Ca leaves the muscle cell and ensuing activation of cellular proteases leading to cell lysis.
3. Seizures leading to the rise in CPK

Situations where this has been described in the literature:
Most commonly: Psychogenic polydipsia
Others: use of thiazides, PPIs, Bactrim, marathon runners, adrenal insufficiency

Hmmm... Should we be checking CPKs in our severe hyponatremia cases? Should we be concerned about Rb in rapid correction ( more than CPM) as Rb is likely more commonly seen then CPM?

Here are some interesting references

Monday, July 25, 2016

In the NEWS: Nephrologists compensations on a rise!!

The recently reported AGMA compensation survey suggests that there is an above average increase in the compensation and salaries of Nephrologists nationally in the USA.  The data even suggested an average of 20% increase in salaries compared to hospitalists.

This is important piece of information as currently there is a major drought in applications in nephrology fellowship. While content being difficult, tough physiology and exposure were considerations why residents never applied for nephrology, compensation might have played a major role in choosing alternative specialty of hospital medicine for their career choice.

Demand and supply working at it's best. Slowly, the tides will turn.

While passion and interest should dictate specialty choice, it doesn't hurt to add appropriate compensation for the work a nephrologist does for the complex patients with tough disease states.

Sunday, July 24, 2016

Clinical Case 88: Answers and Summary

Which one of these immune check point inhibitors leads to loss of transplanted kidney?

The correct answer is nivolumab or PD-1 inhibitors.  Several cases of kidney injury have now been reported when the immune check point inhibitor use in kidney transplant patients. While Lipson et al had initially reported successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma without any rejection, they recently reported a case of tumor regression but allograft rejection after administration of   pembrolizumab.  In addition, three cases of rejection were reported with use of nivolumab  in renal transplant patients with melanoma.
Based on the 6 cases, it appears that PD-1 inhibitors are more prone to causing rejection in the transplanted kidney compared to CTLA-4 antagonists , especially when the  patients  have received anti CTLA-4 agents prior to PD-1 inhibitor treatment.  Graft tolerance might be minimized and hence rejection ensues.

Monday, July 11, 2016

Piperacillin-Tazobactam and Vancomycin and AKI?

Piperacillin-Tazobactam(Zosyn) and vancomycin is the new PPI on the block. It seems that this combination is also nephrotoxic. While I had noticed this observation in practice, I was unsure if this was a vancomycin effect or zosyn effect. A recent prospective study done by Peyko et al  elegantly shows that AKI incidence( as defined by KDIGO) was significantly higher in the Zosyn/vancomycin group compared to cefepime or meropenem and vancomycin group.  This is an important study to help spark more interest in looking into this topic.

Some interesting points regarding the study:
Single center, prospective trial, all sepsis patients were reviewed. Interestingly, there were twice as many patients in the zosyn arm.  18 patients required HD in the zosyn arm compared to 8 in the meropenem or cefepime arm. The vancomycin levels were no different in both arms.  The authors stress that perhaps the study was underpowered but clearly there is a signal of AKI more than the other arm. 
Interestingly, in the last 5 years, several retrospective studies have shown the concern for this combination to be nephrotoxic.  Few of the references are listed below:

Check out tomorrow’s NephJC journal club on this topic for more discussion

Saturday, July 2, 2016

Topic Discussion: Baclofen Neurotoxicity in patients with impaired renal function

  Baclofen is an oral derivative of gamma-aminobutyric acid (GABA) used to treat muscular spasticity from disorders of the central nervous system. It is also used in medical ICU and neurological ICU for alcohol withdrawal, myclonus and other reasons. It is contra indicated in patients with abnormal renal function. Recently, there have been many cases described of this entity where dialysis ultimately was needed to restore normal neuro function of the patient.  Baclofen toxicity presents as altered mental status, somnolence, respiratory depression and even seizures and coma.  

Patients especially on dialysis, the half life of the drug is significantly increased and recommended dose or even low doses of baclofen as little as 5mg or cumulative dose of 15mg can cause rapid accumulation and severe toxicity. 
One of the first cases were reported in 2000 in NDT. Roberts et al describe three cases where aggressive dialysis made full recovery in patients who were ESRD. Although mechanism of baclofen elimination during HD is not well understood but up to 79% of the serum baclofen can be eliminated by one HD session.

The largest study that looked at all literature review was of 41 patients.  Most were elderly males, and 62% on dialysis. The manifestations of the drug toxicity happened 2-3 days later. The recovery time was 2 hours in patients who received HD to 8 days with conservative management.  

Friday, June 24, 2016

UKidney Toxicology Series

Check out the Nephrology Social Media interns discuss an up to date information on Toxico-Nephrology.

Wednesday, June 1, 2016

Topic Discussion: Novel ways to combat Intradialytic hypotension

Intradialytic hypotension(IDH) during hemodialysis(HD) is a challenging clinical concern and often hard to treat.  After one has ruled out cardiac disorder ( especially diastolic dysfunction), common medications and ideas attempted are: midodrine pre dialysis, low temperature during dialysis, daily short dialysis sessions, florinef use, steroids in the right clinical setting, and sodium and or calcium profiling.  Switching to peritoneal dialysis can be an option as well.  The KDOQI guidelines recommends most of these above mentioned changes.
What are some other novel mechanisms that can be used?

1.Carnitine:  Carnitine deficiency has been associated with IDH and trial of L-carnitine at 20mg/kg with dialysis might help reduce IDH

2.Sertraline: This anti- depressant has shown improvement in orthostatic hypotension. Both retrospective and prospective studies in small number of patients demonstrated that treatment with sertraline hydrochloride was associated with an improvement in the hemodynamic parameters in patients with IDH. A recent randomized control trial from Iran also showed good benefit with this agent in IDH. The dose one can usually start is 50mg once a day and then max at 100mg daily per most trials when used for IDH.

Some good references:

Rho et al nicely demonstrated in a CJASN paper in 2008 that IDH patients experienced greater decreases in both systolic and diastolic blood pressure during the dialysis session despite equivalent ultrafiltration in both groups. AVP concentration did not increase in the IDH patients compared with controls despite hypotensive episodes. As a result, many have tried to use DDAVP as a treatment option for IDH.
As early as 1990s, vasopressin was tried in 6 patients to help IDH in one single center study with success.  The largest study(17 patients) using this was from Iran. In that study, the treatment arm received intranasal DDAVP (two puffs) 30 minutes before all HD.  Hypotensive episode occurred 18 times (8.82%) in vasopressin group compared with 125 times (61.27%) in placebo group and there was a significant association between them (p=0.0001). In addition mean arterial blood pressure in vasopressin group was 80.77 and in placebo group was 73.92 and also there was a significant association (p=0.0001). The mean Kt/v in group 1 and 2 were 1.29 and 1.28 without any differences between them (p=0.896). This might be another interesting option to consider in IDH.  Risk of  thrombotic events might be something to think about.


This agent has been approved by FDA for autonomic neuropathy.. The trade name is Northera. Droxidopa is a synthetic amino acid precursor which acts as a prodrug to the neurotransmitter norepinephrine. Unlike norepinephrine, droxidopa is capable of crossing the protective blood–brain barrier. Why in IDH? Well recently published trial that was a placebo controlled, phase 2 study looked at efficacy and safety of this agent in IDH.  The investigators looked at placebo vs 400mg vs 600mg dose.  Increase in droxidopa intra-HD MAP were not significantly different from placebo, although droxidopa groups showed significant improvements in mean SBP after HD of +4.8 ± 11.6 mm Hg (600-mg) and +3.4 ± 13.1 (400-mg) compared with -4.4 ± 17.9 mm Hg in placebo, and the drop seen in mean nadir SBP pre- to intra-HD was also reduced. HD terminations decreased 5-fold in the 600-mg group and 2-fold in the 400-mg group, whereas the number of discontinuations stayed unchanged in the placebo group. Treatment of both dosages were well tolerated. This might be an interesting option as well. The most common side effects noted were GI related. 

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