Detective Nephron: the next case

Check out the next venture of Detective Nephron in the August issue of Kidney News 2016

http://www.kidneynews.org/kidney-news/features/detective-nephron-world-renowned-for-expert-analytical-skills-trains-budding-physician-detectives-on

TOPIC DISCUSSION: New anti retrovirals and the kidney

As HIV becomes a chronic illness, novel agents to combat this virus have been out in the last decade. We are familiar with the renal toxicities of tenofivir for many years. Tenofivir is the cisplatin of the ID world.  But what about the new novel agents?
Here is a table that summarizes the new agents and their known or unknown renal toxicities

Drug name( trade)	Mechanism of Action	Renal effect	Excretion	Reference
Rilpivirine(Edurant)	Non nucleoside reverse transcriptase inhibitor	Decreases the secretion of creatinine in the proximal tubule via OCT2 , appear after 1-2 weeks after treatment and can then plateau	Renal	https://www.ncbi.nlm.nih.gov/pubmed/23211772 https://www.ncbi.nlm.nih.gov/pubmed/21763936
Dolutegravir(Tivicay)	Integrase inhibitor	Decreases the secretion of creatinine in the proximal tubule via OCT2, appear 1-2 weeks after treatment and then plateau	Liver	https://www.ncbi.nlm.nih.gov/pubmed/22905856
Cobicistat(Tybost)	Inhibitor liver enzymes so other HIV drugs effect gets enhanced	Decreases in secretion of creatinine  in the apical side of proximal tubule as it inhibits MATE 1 transporter, can be as early as day 7 of start.	Liver	https://www.ncbi.nlm.nih.gov/pubmed/22732469

Tenofivir dispoxil fumarate( TDF) is the classic nephrotoxic agent.  It actively taken up by the proximal tubular cell via OAT1 and 3 and released in urinary space by secretion of MDRP-2 and 4. There is a novel tenofivir formulation called tenofivir alafenamide fumrate( TAF) which is used in lower dosage combinations and lower level of parent drug is noted. In addition, TAF does not bind to these organic transporters and hence less renal tubular trafficking. Once out in clinical use, we might see less tenofivir related renal toxicities. 

A lot of combination agents are being used to combat the virus. The list below from FDA approved AIDS website compiles them with their trade names. The most nephrotoxic ones are the ones that contain TDF as expected or one of the above mentioned agents that block creatinine secretion.

abacavir and lamivudine (abacavir sulfate / lamivudine, ABC / 3TC)	Epzicom	No renal concerns
abacavir, dolutegravir, and lamivudine (abacavir sulfate / dolutegravir sodium / lamivudine, ABC / DTG / 3TC)	Triumeq	Slight increase in creatinine
abacavir, lamivudine, and zidovudine (abacavir sulfate / lamivudine / zidovudine, ABC / 3TC / ZDV)	Trizivir	No renal concerns
atazanavir and cobicistat (atazanavir sulfate / cobicistat, ATV / COBI)	Evotaz	Slight increase in creatinine
darunavir and cobicistat (darunavir ethanolate / cobicistat, DRV / COBI)	Prezcobix	Slight increase in creatinine
efavirenz, emtricitabine, and tenofovir disoproxil fumarate (efavirenz / emtricitabine / tenofovir, efavirenz / emtricitabine / tenofovir DF, EFV / FTC / TDF)	Atripla	Contains tenofivir- renal toxicity can be present
elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide fumarate (elvitegravir / cobicistat / emtricitabine / tenofovir alafenamide, EVG / COBI / FTC / TAF)	Genvoya	Contains tenofivir
elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (QUAD, EVG / COBI / FTC / TDF)	Stribild	Contains tenofivir
emtricitabine, rilpivirine, and tenofovir alafenamide (emtricitabine / rilpivirine / tenofovir AF, emtricitabine / rilpivirine / tenofovir alafenamide fumarate, emtricitabine / rilpivirine hydrochloride / tenofovir AF, emtricitabine / rilpivirine hydrochloride / tenofovir alafenamide, emtricitabine / rilpivirine hydrochloride / tenofovir alafenamide fumarate, FTC / RPV / TAF)	Odefsey	Tenofvir alafenamide does not bind to the proximal tubule transporters and is potentially less nephrotoxic
emtricitabine, rilpivirine, and tenofovir disoproxil fumarate (emtricitabine / rilpivirine hydrochloride / tenofovir disoproxil fumarate, emtricitabine / rilpivirine / tenofovir, FTC / RPV / TDF)	Complera	Contains tenofivir- hence renal failure can occur and rilpivirine can increase crt as well
emtricitabine and tenofovir alafenamide (emtricitabine / tenofovir AF, emtricitabine / tenofovir alafenamide fumarate, FTC / TAF)	Descovy	Novel tenovifir- hence less likely
emtricitabine and tenofovir disoproxil fumarate (emtricitabine / tenofovir, FTC / TDF)	Truvada	Can cause AKI given tenofivir presence
lamivudine and zidovudine (3TC / ZDV)	Combivir	No renal issues
lopinavir and ritonavir (ritonavir-boosted lopinavir, LPV/r, LPV / RTV)	Kaletra	No renal issues

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
http://link.springer.com/article/10.1007%2Fs00421-015-3324-4

https://www.ncbi.nlm.nih.gov/pubmed/25909317

http://www.ncbi.nlm.nih.gov/pubmed/21532723

https://www.ncbi.nlm.nih.gov/pubmed/22975551

http://www.revistanefrologia.com/en-publicacion-nefrologia-articulo-rhabdomyolysis-secondary-hyponatraemia-X2013251411052095

https://www.ncbi.nlm.nih.gov/pubmed/21168782

https://www.ncbi.nlm.nih.gov/pubmed/22778200

https://www.ncbi.nlm.nih.gov/pubmed/11696527

https://www.ncbi.nlm.nih.gov/pubmed/10396001

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1238676/

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.

http://www.kidneynews.org/careers/leading-edge/report-shows-increase-in-compensation-for-nephrologists

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. 

https://www.ncbi.nlm.nih.gov/pubmed/26752406

https://www.ncbi.nlm.nih.gov/pubmed/26951628
https://www.ncbi.nlm.nih.gov/pubmed/26988410
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.

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:

http://www.ncbi.nlm.nih.gov/m/pubmed/24753221/

http://www.ncbi.nlm.nih.gov/m/pubmed/24855041/

http://www.ncbi.nlm.nih.gov/m/pubmed/24118354/

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

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.