Vanco Pip/Tazo and AKI

On Sunday the story broke that a single center study had found increased AKI with the combination of Vancomycin and  Pipercillin-Tazobactam.

There was an interesting and in depth discussion of the issues on Twitter. I captured the major points this Storify:

Another Candidate for Top Nephrology Story of 2013: HDPAL

Another guest post, this by Christos Argyropoulos of Athens. You know him on Twitter as @ChristosArgyrop.

Lisinopril vs. Atenolol for hypertension in the dialysis unit

Background and Rationale 

A study reporting the relative effectiveness of lisinopril over atenolol for hypertension in the hemodialysis unit was presented in the 2013 Kidney Week meeting. The HDPAL (NCT00582114) was a parallel group, open label randomized control study conducted between 2005-2013 in a single center that was sponsored by IU and supported by NIDDK. The aim of HDPAL (per the clinicialtrials.gov entry) was to “directly test the hypothesis that an initial strategy of lisinopril-based therapy will be more effective than atenolol-based therapy in causing regression of LVH over one year in patients with hemodialysis hypertension despite similar degree of BP reduction”. The justification for the study was provided by the high prevalence (>80%) of hypertension in the dialysis unit and the associated morbidity of stroke and left ventricular hypertrophy, while the choice of interventions tested in  HDPAL  was motivated by prior pilot studies performed by the PI in the late 1990s. These studies showed that atelolol and lisinopril are both able to reduce monitored ambulatory blood pressure (ABPM) to a similar extent i.e. by  ~20/11 when dosed three days a week after dialysis in a supervised fashion.

Study Procedures and Outcomes 

HDPAL randomized HD patients with echocardiographically documented LVH to either atenolol (initial dose: 25mg TIW, titrated to a maximum of 100 mg by doubling the dose q2wks) or lisinopril (initial dose: 10 mg TIW titrated to 40 mg by doubling the dose q2wk). To be eligible to participate, patients with LVH had to either have an ABPM > 135/75 (after a UF trial), or not be receiving any antihypertensives if they did not want to participate in a UF trial. Felodipine (10 mg) could be added once the maximum dose of the study medications had been reached and other anti-hypertensive agents could be added after felodipine if ABPM did not decline below 140/90. 

The primary outcome for the study was regression of LVH by echocardiographic criteria at 12 months, while secondary outcomes to be assessed were regression of LVH by echo at six months and the adjusted (for age, gender, ABPM) index of LV mass/BSA from baseline to month 12.

Patients would have echocardiographic assessments at baseline and again at 6 and 12 months, as well as ABPM at baseline and 3, 6, and 12 months and were also asked to self monitor their BP.

What did the study show?

The study enrolled 200 (mostly African American) patients, but it was stopped prematurely for safety reasons so that only 104 patients completed follow-up (58 in the atenolol and 46 in the lisinopril arm). At the time the study was stopped, patients on atenolol had numerically higher reductions in LVH but this finding did not reach statistical significance. The safety signals were ubiquitous for patients on lisinopril:

• Excess number of serious cardiovascular events(IRR: 2.36, 95% CI 1.36 to 4.23, P=0.001) 
• Excess major cardiovascular events (IRR 2.29 95%CI: 1.07-5.21 p=0.02)
• More frequent hospitalization for all causes (IRR: 1.61 p<0 .01="" li="">
• More frequent hospitalization for congestive heart failure (IRR 3.13 p=0.02)
• More likely to develop hyperkalemia (IRR 3.38 p=0.05)
• More likely to suffer a hypertensive crisis (IRR 3.81 p=0.03)

On the other hand, atenolol was more efficacious in reducing BP, irrespective of the method of assessment (ambulatory v.s. home self-monitoring) by 3.5 and 6.3 mmHg respectively). These patterns of suboptimal BP control by lisinopril were noted despite more aggressive fluid removal and a larger number of additional blood pressure medications.

Discussion

As the study was terminated prematurely, the primary and secondary end points could not be fully assessed and the superiority of beta blockers versus ACE inhibitors remains an open question. On the other hand, the reported patterns of blood pressure reduction and the cardiovascular safety signal were surprising given the established track record of ACEis in reversing LVH and the poor relative efficacy of atenolol against other agents in the non-ESRD population (Cochrane Database Systemic Review, though not everyone agrees with this interpretation e.g. Blood Pressure, 2007 and BMJ, 2009). However tempting it may be to attribute these findings to a play of chance, or undifferentiated secular trends (e.g. the study was registered with Clinical Trials.gov in 2005, yet only 104 patients had a year of follow-up by 2013) the possibility that atenolol is indeed a better drug than lisinopril for dialysis patients with LVH should be entertained. Working under this hypothesis, there are at least two possible explanations for the apparent benefit of atenolol on blood pressure control:

1. A ghost of studies past: A number of studies have suggested that African American patients with cardiac disease (either LVH or systolic dysfunction) may respond better to beta blockade compared to RAAS inhibition (a pattern seen in the Losartan Intervention for Endpoint Reduction – LIFE study), or even receive no benefit from ACEs compared to whites (e.g. SOLVD). Considering that the mostly African American participants in HDPAL were on the ultimate “diuretic” (dialysis to dry weight), an intervention that diminishes the relative (in)effectiveness of beta blockers in the non-ESRD African American population, one could hypothesize that the results of this study may reflect a racial benefit of beta-blockers for African American with LVH. It would be interesting to see whether the investigators of the HPDAL broke down the results according to race, as a hypothesis generating analysis.
2. Pharmacokinetics: Atenolol and lisinopril pharmacokinetics on dialysis differ and these differences may explain the inferior blood pressure control in home and ABPM recordings. While both agents are efficiently cleared by hemodialysis, with apparent intradialytic half life between 3.5-5 hrs  (atenolol: BJCP, 1980, Arch Toxicol Suppl, 1980 and Eur J Clin Pharmacol, 1981, Hemodialysis International 2013 and lisinopril BJCP, 1988) there are important differences in the time to the peak (~4hrs with atenolol, 8-44 hrs with lisinopril) and rebound kinetics (larger rebound with atenolol). Based on these considerations one could hypothesize that patients receiving atenolol in the dialysis unit would spend a much shorter period of time under-medicated as a result of the faster absorption of the drug and possibly its higher rebound. This could explain the larger time difference in BP noted in ABPM recordings and home BP measurements. To the extent the investigators obtained blood levels, it might be possible to explore the pharmacokinetic hypothesis by correlating free drug concentrations to ABPM or home BP recordings. To the extent that pharmacokinetics play a role in explaining the HDPAL results, one could consider using alternative RAAS inhibitors (e.g ramipril) that are exhibit more comparable kinetic behavior to atenolol.

Implications for clinical practice

This is an interesting pilot report about therapeutic intervention to control hypertension in dialysis, a common problem for our patients. Current approaches to this problem are unsatisfactory, judging from the frequency with which nephrologists switch agents (BMC Nephrol. 2013) in the unit. Far from definitively proving the superiority of beta blockers over ACE inhibitors due to the limitations of a prematurely stopped and thus underpowered study, HDPAL adds some important information that could help clinicians choose blood pressure medications for their dialysis patients. In particular, HDPAL suggests that the perceived inferiority of beta blockers in the non-ESRD population may not apply to dialysis patients. Though it is customary to say that further studies will be needed (and in fact we do need them!), clinicians managing hypertensive dialysis patients should lead by example and consider applying the HDPAL protocol in the context of “n=1” trials. These studies “consider an individual patient as the sole unit of observation” to investigate the efficacy or side-effect profiles of different interventions (Per Med. 2011). In particular, rather than switching antihypertensives around in no systematic pattern, the nephrologist working with the patient under a shared decision making paradigm carry a structured evaluation of lisinopril (the most commonly prescribed ACEi, used in 20.9% of dialysis patients) vs. atenolol (the least prescribed beta blocker, but still used in 7.2% of patients) correlating home blood pressure (or ABPM if available) in a 4 period crossover fashion. By pooling multiple such studies it may be possible to fill in the knowledge gap that HDPAL tried to fill. 

Top Nephrology Stories of 2013 NEPHRON-D: The End of the Combination Treatment Era

This is a guest post. I don't think I have ever done this before but we are trying to get as many voices to weigh in on the Top Nephrology Stories of the Year as possible and I knew that I wanted Ed El Sayed (@iApothecary) to be part of this. If you don't follow him, you should, he is one of the sharpest medical minds on Twitter. When I invited him he said he had no place publish, so I offered a temporary home on PBFluids. Hey Ed, start a Tumblr, they're free!

Here are his words on the top nephrology story of the year:

Diabetic nephropathy is the leading cause of Chronic Kidney Disease (CKD) and End Stage Renal Disease (ESRD) in the US. It has long been postulated that combination pharmacotherapy with

Angiotensin Converting Enzyme Inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs) could slow the progression of nephropathy, and have a positive impact on the prognosis, morbidity, and mortality of patients with diabetic kidney disease. This hypothesis arose from the unfortunate fact that neither ACEi nor ARBs working alone are able to fully block the renin angiotensin aldosterone system (RAAS).

Design of Combination Angiotensin Converting Enzyme Inhibitor Angiotensin Receptor Blocker for Treatment of Diabetic Nephropathy (NEPHRON-D) was a large multi-center, prospective, and parallel trial that was terminated early due to serious side effects. In this study, 1,648 patients (average age of 64 years) with type 2 diabetes, albuminuria, and stage 3 or 4 CKD were recruited. All patients were started on losartan 100 mg and then randomized to receive either Lisinopril 10-40 mg daily or placebo..

As mentioned above, this well designed and well powered trial was terminated early due to a significantly higher rate of adverse events with combination therapy. Investigators reported that the incidence of hyperkalemia was higher with ACEi and ARBs compared to ARBs and placebo (6.3 vs 2.6 events per 100-persons-years with P = 0.001). Acute Kidney Injury (AKI) was also higher with combination therapy (12.2 vs 6.7 events per 100 person-years with P = 0.001).

With 2.2 years of follow up investigators reported no significant difference in the study’s primary end point of progression of renal disease or death (152 vs 132 with P = 0.3).

The ONTARGET and ALTITUDE studies were the two previous attempts to show renal or cardiovascular benefits from combination RAAS blockade (ACEi + ARBs in ONTARGET; ACEi + Renin Inhibitor in ALTITUDE). ONTARGET involved patients with an increased risk for cardiovascular disease but predominantly normal albumin excretion levels, while ALTITUDE involved patients with kidney disease and diabetes who were not necessarily proteinuric. Neither showed any benefit and had increased adverse events with combination therapy.

Experts now have three solid trials that clearly convey one message: Combination pharmacotherapy with ACEi and ARBs in patients with DM induced nephropathy and CKD does not provide any additional benefit and may, in fact, increase the incidence of harm.

It is worthy to note that NEPHRON-D is a perfect example of a “negative” trial that has a huge impact on the strategies used by clinicians in treating their patients; emphasizing the importance of publishing both negative and positive outcome trials.

Update from Twitter:

@kidney_boy IIRC COOPERATE was retracted due to fabricated data, so that only one name should be engraved on that stone
— ChristosArgyropoulos (@ChristosArgyrop) December 11, 2013

Nice discussion about how COOPERATE was retracted via @cardiobrief http://t.co/nEbs4P2cS9
— Matt Sparks (@Nephro_Sparks) December 11, 2013

I set the onset of combo therapy at the publication of COOPERATE because it was a landmark study at the time. It was regularly brought out as justification for the use of dual therapy, because it's end-point was doubling of serum creatinine or ESRD, not just a change in proteinuria. According to the Cardiobrief pos,t that Dr. Sparks referenced, combo therapy was already in wide use at the time of publication but I think COOPERATE was the study that made its use acceptable to EBM purists.

I get some great letters, here is one of the best from a woman with SIADH

An e-mail I received last month:

I love your blog.  I have had SIADH for a zillion years.  I only found out what I had when I went with 5 girlfriends to a fancy spa hotel  in Tucson for a mini-vacation/ 4th of July Weekend in 1997 where the heat increased to an uncomfortable 117 degrees.

Healthcare workers in the hotel kept handing out bottles of water at each hotel exercise location with orders to “hydrate, hydrate, hydrate” and I stupidly followed their directions.  I drank myself into a 6 day coma.

The only time that sentence has been used for water, not alcohol.

Very non-traumatic for me. Very traumatic for my family. I woke up on day 6 saying, “I am STARVING!  Will someone go get me a taco?” which was very anxiety-relieving for all of them; they’d been sure I’d wake up cognitively impaired.  I wasn’t.  This “taco” sentence sounded JUST like me.  And I have continued to be not cognitively impaired despite interesting lab numbers.

My dad (who is a physician too) has SIADH as well, though his was diagnosed after mine.  I was mis-diagnosed for 9 years prior to my coma as having a “seizure disorder.”  The excellent care I received when my mental status went to heck in a handbasket was truly life-saving.  I remain a very grateful nephrology patient.  And I really do love your blog.

Thought you should know this.

She wrote back a few days later giving me permission to post her letter:

I am dying (well not literally dying) to start an SIADH group on Facebook.  We are so not connected to one another, and each of our nephrologists only have a handful of patients and of course the doctors can't introduce us to eachother because of HIPAA. 

• For those of us that have the Syndrome without lung cancer and so on and have to live our lives thirsty
• and our summers avoiding the sun through our sunroofs (Demeclocycline)
• and have to, if we're female, find inventive ways to paint our nails to avoid Demeclocycline making our nailbeds ugly colors
• and have to fear that Otsuka Pharmaceutical will convince the ONE manufacturer who makes Demeclocycline to stop making it and force us into buying Tolvaptan even though they never tested it in 3rd stage human trials on people that weren't already cognitively impaired (I know because I volunteered for every single US trial), 

Well, we NEED each other.  We need tips on nail polish, tips on drinking our fluids out of 1 ounce shot glasses, tips on rolling ice cubes around our mouths during the days our sodium is tanking, and your website is a GREAT place for us to meet up!  

You have my non-dying thanks and permission to reprint/repost any or all of my statements!

The best story that wasn't nominated.

Its oscar season in nephrology. The RFN is winnowing down the top stories in nephrology of 2013 but maybe the most important isn't even nominated. It came out too late. On November 27, Kidney International released this study in advance of print:

The bullet point I learned in fellowship was that the rate of renal failure in kidney donors was no higher than the general public, of course the kidney donors are screened to be much healthier than the general public, so the fact that the rate of renal failure is not significantly lower than the general public is an important signal.

Have I mentioned how
much I love MedCalc?

Donors don't have obesity, diabetes, hypertension. Of course most of them also have family history of kidney disease, so when they do develop kidney failure attributing the cause cause can be tricky, certainly some of these people would progress to renal failure even if they didn't donate.

Into this statistical Gordian knot wades the Norwegians.

• 15 years of follow up for donors that were 46 years old at the time of donation. That is adequate follow-up in my mind.
• Their center had no preoperative mortality. They did 2,269 living donations with out losing a donor. Great work by the surgical team.
• They found an increased risk of death by any cause, HR 2.49 (CI 2.13-2.91). 
• Adjusted HR for all-cause mortality fell to 1.48 (CI 1.17-1.88). 
• I used their raw mortality data to calculate the Number Needed to Harm. It was a frightening 23 (4.3% absolute risk increase). I do not think this is a valid use of NNH, see below.
• The CV Mortality HR was 1.4 (CI 1.03-1.91).
• ESRD was increased from 0.01% per year to 0.03% a relative risk of 3 but a number needed to harm of 5000. (i.e. you would have to do 5,000 living transplants a year to see one additional cases of dialysis in a donor)

The lines only begin to separate after 10 years. This indicates that we should probably ignore studies with less than a decade of follow-up

The data is eye opening, but I would really be interested in seeing what the difference between first degree relatives and people not related. I think much of the increased danger comes from being related to the patient who needed the transplant in the first place.

I also recommend ignoring all the unadjusted data (including the number needed to harm) because the control group was nearly a decade younger than the donors. A ten year difference in age when the total follow-up is only 16 years makes the unadjusted data deceptive, IMHO.

I would love to see a study where the control group was made up of other people who were evaluated and cleared to donate a kidney but ended up deferring, due to the recipient getting another organ or dying or going off the list for some other reason. That would be the ideal control population.

The reality is that people want to donate a kidney to their loved ones. Telling them there maybe a small increase risk of death when you are in your late 50's or early sixty's. Will probably not eliminate many close relatives, but altruistic donors and family members should be aware of the risks as understood today. It is probably time to bury the old line about "No increased risk of renal failure than the general public."

Another study on this from 2010 can be read here.

Add to the list of top stories of 2013

In my manifesto on Tolvaptan, I mentioned there was another breakthrough that should be on the list of top stories of 2013, and it is...The gathering momentum of renal denervation for hypertension. This feels like it is rapidly maturing and will be a viable option in the near future.

The latest data presented at American Heart Association looks promising.

Go to Renal Fellow Network. Vote for your favorite!

Go #TeamTolvaptan

This is just a picture of the ballot
go to RFN to cast you ballot.

One of my favorite end-of-the-year traditions is Renal Fellow Network's top nephrology stories of the year. Make sure you vote. The authors did a great job selecting 2013's top stories of nephrology somehow they forgot the Omontys allergic reaction, voluntary recall and abandonment of peginesatide.

(I thought of one more but it escapes me, I'll update this post when I remember it.)

Looking over the list, I think the story of the year is Tolvaptan's failure to FDA gain approval for ADPKD. If Tolvaptan gains FDA approval in the next year or two following re-submission this story will quickly be forgotten. But if the future goes the other way, if Otsuka abandons tolvaptan for ADPKD and decides to remain in the limited ghetto of inpatient management of hyponatremia that would be a tragedy.

Part of what gets my blood boiling is the raging hypocrisy that the very same organization that approved:

• Zemplar (paricalcitol)
• Hecterol (doxercalciferol)
• Renagel (sevelamer)
• Renvela (sevelamer again)
• Fosrenal (lanthium carbonate)
• Sensipar (cinacalcet)

(all drugs that have never been shown to help a patient but merely to improve some biochemical target. Hell, even sevelamer and cinacalcet tried and failed to show reduced mortality and they remain on the market) had the gall to deny tolvaptan for ADPKD.

ADPKD slowed cyst growth and slowed the progression of kidney disease. Not just for one year but for three years! It joins ACEi/ARBs and insulin in the pantheon of drugs that can slow the progression of CKD (though bicarbonate and allopurionol are walking toward the door). Denying it was preposterous.

The other part of my rage comes from possibilities of having tolvaptan available as an outpatient option for patients. I certainly want this drug available for ADPKD but turning it from a limited duration in-patient drug to a chronic outpatient therapy will completely remake the cost structure.

The price will remain high but it will no longer be $300/pill. Let us say $1000 per month. The TEMPO trial used 120 mg per day, so a month worth would be 120 pills. That would go a long way if you were interested in using tolvaptan for aquaresis. This drug is effective at increasing urine output by a mechanism totally novel to us. We are being given control over one of the fundamental control levers of the kidney. There are only limited number of these levers:

Look it how useful the drugs are that affect these hormones. The list is full of all-stars. Tolvaptan has already been proven a winner in ADPKD and maybe useful in CHF. Tolvaptan failed a pivotal trial called EVEREST, but the drug did increase diuresis, fluid loss, and the effects were long lasting. Tolvaptan failed one trial on heart failure, but alternative patient selection or dosing regimens could turn this turkey into another critical tool for heart failure. We need to have this drug available to see where it can be useful because today we are primitives.

If the FDA approves it, the fact that it failed its first application will be quickly forgotten, but if Otsuka decides to retreat from this breakthrough and live happily ever after correcting mild asymptomatic hyponatremia nephrology will be a poorer place.