Topic Discussion: Remdesivir in CKD and ESRD patients- what is the data thus far

Acute kidney injury (AKI) occurs at a rate of 30-40% in hospitalized patients with COVID-19.
Chronic kidney disease (CKD) and ESKD are also common comorbidities in patients who develop severe COVID-19. Data on use of these agents in CKD and ESRD is limited. 

The active metabolite of remdesivir is eliminated by the kidneys and can accumulate in patients with reduced estimated glomerular filtration rate (eGFR); moreover, the sulfobutylether-β-cyclodextrin (SBECD)carrier is known to accumulate in these patients. 

The largest clinical trials evaluating the use of this agent in COVID-19 excluded patients with stage 4 CKD or those requiring dialysis.

A multicenter study from Northwell health, BWH, MGH and U of Miami( of 18 patients) and a large study from India (46 patients) recently looked at use of remdesivir in CKD, AKI and ESKD patients. All patients studied had eGFR<30cc/min. 

In the USA study, treatment was well-tolerated, with few other AEs attributed to remdesivir. Five patients discontinued remdesivir early, only 2 of them due to AEs attributed to remdesivir (burning at IV site during the final dose and worsening kidney function); the remainder stopped due to improved clinical status (N=2) or patient preference (N=1). Overall 28-day mortality was 44% (8/18). Among patients requiring intensive care at the time of remdesivir initiation, 8 of 11 died. All 7 patients who were not requiring intensive care at baseline survived to 28 days.

In the India study, most patients tolerated the infusion well. Liver function remained stable in 28 (60.9%) cases. No patient had a severe rise in AST/ALT >5 times the upper limit of normal, therefore therapy was not required to be discontinued for this reason in any of the patients. No kidney function abnormalities attributable to drug were observed. Fourteen (30.4%) patients died, 24 (52.2%) patients were discharged from the hospital after recovery.

 

Publication	USA( Estiverne et al)	India ( Thakare et al)
Total # of AKI on dialysis	3	19
Total # of AKI non on dialysis	5	11( 5 transplant patients)
Total # of CKD patients	8	15
Total # of ESKD patients	2	16
LFT abnormalities attributed to agent	3	3
Remdesivir induced AKI	1	0
Got 5 days course	16	46
Got 10 days course	2	0

Consult Rounds: Hyponatremia from Anti depressants

 As nephrologists we often get called on SIADH from medications. Anti depressants a class of agents that we do consider to cause hyponatremia. Which ones are more likely vs others has always been interesting to know? A study from Denmark has a detailed look into this matter. 

The odds of developing hyponatremia in one large study was the highest in clomipramine, followed by nortriptyline, citalopram, paroxetine, duloxetine, venlafaxine, sertraline and amitriptyline. It had the least odds of association with mirtazapine, mianserin and escitalopram. The development was highest in the first 2 weeks of starting treatment( with the highest incidence of hyponatremia in the first 2 weeks in citalopram and lowest in mianserin. 

So, SSRI had the most association, SNRIs had slightly lower and non adrenergic specific serotogenic antidepressants had the least association. 

Anti Hypertensive Agents and removal by Hemodialysis

Here is a list of common anti hypertensive agents used in ESRD and clearance via HD. In general, ACEI are removed in variable amounts, ARBs and aldo antagonists are not. Beta blockers are variable. CCB are variable but in general not that removed.

Class			%Removal with hemodialysis
Angiotensin converting enzyme inhibitors
Captopril			Yes
Benazepril			20–50%
Enalapril			35%
Fosinopril			<10%
Lisinopril			50%
Quinapril    Ramipril			<10%( limited data) <30%
Angiotensin receptor blockers
Losartan			None
Candesartan			None
Eprosartan			None
Telmisartan			None
Valsartan			None
Irbesartan			None
Aldosterone antagonists
Spironolactonea			None
Eplerenoneb			None
Renin inhibitor
Aliskiren			?
β-Blockers and combined α- and β-blockers
Atenolol			75%
Metoprolol			High
Metoprolol XL			High
Propranolol			<5%
Carvedilol			None
Carvedilol CR			None
Labetalol			<1%
Calcium channel blockers
Amlodipine			None
Diltiazem			<30%
Nifedipine			Low
Nicardipine			?
Felodipine			No
Verapamil			Low
Alpha-adrenergic blockers
Doxazosinc			None
Terazosin			None
Prazosin			?
Other
Clonidine			<5%
Hydralazine			None
Isosorbide dinitrate			Yes
Minoxidil			Partially

Topic Discussion: Phosphorus content of prescription Medications

There is a source of dietary phosphorus that has been noted but is largely unrecognized and unquantified—the phosphorus content of prescription medications. That drugs may contain phosphorus is clear, as it is indicated on the list of inert ingredients reported on their package label. Sherman et al few years back did an amazing study that showcased that medication preservatives might have phosphorus content that we don’t recognize. This might be also causing some phosphorus rises in our patients and need for increased binders.

Medication and dose	Manufacturer	Phosphorus content	Amt of Phos binders required additional
Lisinopril 10mg	Qualitest	40.1mg	2
Lisinopril 10mg	Blue Point labs	32.6mg	1.5
Amlodipine 10mg	Greenstone	27.8mg	1
Amlodipine 10mg	Lupin	8.6mg	-
Paroxetine	Glaxosmith Kline	111.5mg	5
Paroxetine	Cadila	22.7mg	1
Renavite	Cypress	37.7mg	1
Renocaps	Nnodum	1.7mg	-

How do we help our patients with this information? Better would be some way of making prescribers aware that their prescribed medications may be high in phosphorus—they are not ‘dialysis safe’. 

Perhaps creating a database of all drugs and their phosphorus content might be useful.  Or is this not consequential to our patients as diet is the biggest factors… the above is just the sample of drugs the author had inquired.. imagine the rest of the medications and other chemotherapy and other anitbiotics we give our patients.

Immunosuppresion Medications in Nephrology

Since the 1970s, the transplant literature has been soaring with anti rejection medications. In the last decade, we as nephrologists are starting to learn from Rheumatology and Oncology on novel targets to treat GNs and Rejections in grafts. A recent review in CJASN highlights the different categories of agents in immunosuppression that we have to our disposal.

T cell directed therapy that target signal 1 from TCR and antigen presenting cell such as OKT3 and  and CNIs
T cell directed therapy that target signal 2 that is costimulatory such as Abatecept and belatacept. In addition, there are newer agents being developed for co situmatory blockade by CD154;CD40 targeting.

B cell directed therapy such as Anti CD20 agents such as rituximab, ocrelizumab and veltuzumab
B cell directed therapy such as Anti CD22 agents such as epratuzumab being tried in SLE
B cell targeting agents for B cell differentiation such as belimumab and atacicept.
Plasma cell targeting agents such as bortezomib( carfilzomib hasn't entered the renal world yet)

Complement inhibitors such as eculizumab
Cytokine targeting agents such as steroids
Specific cytokine agents such as anti IL-2 antagonist( basiliximab) and anti TNF alpha
IL-1 antagonists such as anikinra and canakinumab
IL-6 inhibition by tocilizumab being studied in transplant patients
IL-17 inhibition by secukinumab not currently being utilized in renal patients

mTOR inhibitor such as sirolimus and everolimus
Anti CD52 such as campath and alemtuzumab
Inhibition of DNA synthesis by azathioprine, mycophenolate, and leflunomide
Cytotoxic agents such as cyclophosphamide used for many GNs
Finally, pooled polyclonal abs such as IVIG have been used and polyclonal antithymocyte globulins for induction.

Tyrosine Kinase Inhibitors vs Anti VEGF therapy: What does the podocyte see?

Anti VEGF therapy has been known to cause proteinuric renal disease. A recent study published in Medicine has the largest single center series looking at biopsy proven findings of Anti VEGF and tyrosine kinase inhibitor therapies.

Some interesting points:

Most patients were biopsied for proteinuria

TMA was the most common biopsy finding if the drug used was an anti VEGF or TRAP agent, 50% of which were only renal limited.

Minimal Change disease/FSGS was the most common finding associated with tyrosine kinase inhibitors along with interstitial or tubular disease.  

This is an interesting observation that was not reported before. It appears that the VEGF inhibitors are strictly likely to behave like pre eclampsia like syndromes but the TKIs are more likely to cause a pure nephrotic syndrome like GN.  None had gotten steroids. It might be interesting to see if these drug induced MCD respond to steroids and hence we can then continue the agent for good cancer treatment.

Hypertension and proteinuria resolved following drug discontinuation and antihypertensive agents.

No patient developed severe renal failure requiring dialysis. 

SiteGPR: A website for renal dosing of medications

Dosing of drugs in renal disease is a common topic of discussion. A nice website tool that helps manage that better is here.
http://sitegpr.com/index.php

SiteGPR presents evidence-based recommendations on drugs dosage adjustments in patients with renal insufficiency.

In addition, it has a long list of medications that are linked with renal toxicity.
A great tool to be used.

Acetaminophen and hypertension?

We know about NSAIDS and hypertension. Is there anything about acetaminophen(AT) and hypertension?

One group of researchers looked at this question.

They compared effect of 1gm three times a day of AT to placebo on well controlled HTN with CAD.
2 week follow up was done.  Ambulatory monitoring of BP was done for 24 hours to see changes and endothelial function tests were also done. N =33.  The average BP was higher in AT group with statistical significance b 3/2mmHg.  Heart rate also increased by 2 beats/min.  The biomarkers of endothelial damage, renin and aldosterone levels were unchanged in both groups.

Interesting but so far - only one study, small group of patients, only in one center.  A change of BP doesn't seem that significant. We will have to see what else comes out in the future.

Ref:

http://circ.ahajournals.org/content/122/18/1789.long 

TOPIC DISCUSSION: FUROSEMIDE in HYPERCALCEMIA

Treatment of symptomatic hypercalcemia is treating the underlying cause but also some symptomatic management.  Usually aggressive IV hydration is warranted sometimes even at 150-200-250 CC/HR.
Once volume depletion is addressed, a loop diuretic MAY be used for augmentation of calcium excretion.
A recent review and analysis published in Annals of Internal Medicine sheds some light about use of loop diuretic in this setting.
The review suggests the following points:

1. Aggressive hydration is necessary
2. Use of diuretics without aggressive hydration might be harmful
3. Found only 9 articles documenting the use of furosemide in hypercalcemia and latest one published in 1983 and total was only 37 patients.
4. Average dose was 1120mg over 24 hours ( really??)
5. Normalization of Ca occurred in only 14 of 39 cases
6. Study with lower doses didn't achieve normalization ( and what do we use????)
7. complications of other electrolyte disorders ensued
8. Finally, recommended against the use of this agent routinely except for cases of volume overloaded with hypercalcemia.
I think the tile of the paper listed below nicely puts it:- Furosemide in hypercalcemia is an unproven but common practice ( really not evidence based)

Ref: http://www.ncbi.nlm.nih.gov/pubmed/18711156