Hypertensive emergency with thrombotic microangiopathy

We admitted a patient with a rip-roaring hypertensive emergency and microangiopathic hemolytic anemia (MAHA). On admission his creatinine was 4. The creatinine kept creeping up despite controlling the blood pressure. Additionally his LDH, platelets and schistocytes either normalized or were heading towards normal, yet the creatinine continued to rise. Early on in his hospitalization we started spironolactone with minimal effect on his blood pressure and no improvement in renal function. As the patient spiraled toward dialysis we decided to attempt to block aldosterone secretion responsible for the thrombotic microangiopathy. We started captopril 50 mg tid. I planned to titrate it up to scleroderma renal crisis-like doses.

Murphy must have been working the night shift because the following morning he was complaining of a swollen lip. We stopped the ACEi due to angioedema. We started aliskiren instead. She tolerated that and for the first time in a week her creatinine leveled off and started to come down.

The biopsy is pending.

Was his renal function about to turn around anyways? Who knows?

The team was conflicted on starting the ACEi. So many times we try to minimize exposure to ACEi in acute kidney injury to maximum glomerular perfusion. He was admitted with severe hypokalemia so aldosterone and renin levels were drawn on admission. Those are send-out labs at our institution and we didn't get results until into the second week. Aldo 60, plasma renin activity 5. That's among the highest aldo I have ever seen.

There is experimental evidence pointing to aldosterone having direct vasculopathic activity driving microangiopathic hemolytic anemia.

Chander et al, took 28 Stroke-prone spontaneously hypertensive rats and then divided them into four groups:

1. Sham surgery
2. Bilateral adrenalectomy
3. Bilateral adrenalectomy + angiotensin 2
4. Bilateral adrenalectomy + aldosterone

Dexamethasone was provided to adrenalectomy rats to prevent Addison's disease.

Blood pressure was elevated in all rats but was less severe in the adrenalectomy group.

Proteinuria was worse in the control group and when aldosterone was restored.

The experimental conditions resulted in malignant hypertension with MAHA as seen in the pathology from the control animals (panel A). Adrenalectomy resulted in sparing of the renal architecture (panel B) and the addition of angiotensin did not induce MAHA (panel C). The addition of aldosterone did induce similar pathology as seen in the control animals implicating aldosterone as the bad actor in this animal model of malignant hypertension and MAHA.

1. MAHA is seen in panel A, control animals
2. Adrenalectomy (panel B) prevents the characteristic lesions of malignant hypertension
3. Likewise with adrenalectomy + AT2 (panel C)
4. The fibrinoid necrosis returns with the aldo infusion in panel D.

From Chander's data it looks like aldosterone is the bad actor, I was unable to find information on using spironolactone to reverse MAHA. There is data showing a protective effect of ramipril to prevent MAHA, again using an animal model of malignant hypertension.

I look forward to see how much renal recovery he gets with aliskiren, though it will be impossible to prove that it was aliskiren, I for one believe.

Another point we debated was the use of aliskiren after ACEi induced angioedema. We decided to use it.  Here is what the package insert has to say:

Angioedema: Two cases of angioedema with respiratory symptoms were reported with Tekturna use in the clinical studies. Two other cases of periorbital edema without respiratory symptoms were reported as possible angioedema and resulted in discontinuation. The rate of these angioedema cases in the completed studies was 0.06%. In addition, 26 other cases of edema involving the face, hands, or whole body were reported with Tekturna use including 4 leading to discontinuation. In the placebo controlled studies, however, the incidence of edema involving the face, hands or whole body was 0.4% with Tekturna compared with 0.5% with placebo. In a long term active control study with Tekturna and HCTZ arms, the incidence of edema involving the face, hand or whole body was 0.4% in both treatment arms [see Warnings and Precautions (5.2)].

++++++++

Below is an annotated biography of additional information, mainly focussing on the poor renal outcomes associated with MAHA in malignant hypertension.

JNCVII defines hypertensive emergencies as:

Hypertensive emergencies are characterized by severe elevations in BP (>180/120 mmHg) complicated by evidence of impending or progressive target organ dysfunction... Examples include hypertensive encephalopathy, intracerebral hemorrhage, acute MI, acute left ventricular failure with pulmonary edema, unstable angina pectoris, dissecting aortic aneurysm, or eclampsia.

Strange that acute renal failure is not mentioned as a complication. The recommendation is to reduce the blood pressure by no more than 25% in the first minutes to an hour and subsequently shoot for 160/100 for the next 2-6 hours. The authors point to 2 exceptions: aortic dissection where the SBP should be less than 100 and in acute stroke where the data is less clear. (a moment of clairvoyance for the JNCVII crew as they correctly predicted the lack of benefit from aggressive blood pressure control in the midst of an acute stroke. This was confirmed with 2011's SCAST study)

Meta-analysis showing the lack of benefit from blood pressure treatment in acute stroke

IV blood pressure agents helpful in hypertensive emergency from JNCVII

The first article we looked at was Bert Jan van den Born's retrospective review. These authors looked at patients with malignant hypertension. Cases were identified by looking at every hospital admission with the diagnosis of hypertension and then screening the charts for an ophthmology exam showing:

• bilateral flame-shaped retinal hemorrhages 
• bilateral linear "splinter" retinal hemorrhages 
• or "cotton-wool" exudates.

Wonderful pic of cotton-wool exudates and splinter hemorrhages. Thanks ACP

Flame hemorrhages. Without permission from AAO

If I had to wait for an ophtho consult to make a diagnosis, half my patients would be ready for discharge with the diagnosis still pending.

After patients were deemed to have hypertensive urgency, they were categorized as having MAHA. This was defined as a low platelet count with either an elevated LDH or schistocytes. Additionally the LDH/schistocytes and the platelets had to recover following recovery from the hypertensive crisis.

The endpoints were creatinine and proteinuria at admission and follow-up creatinine.

The study found 110 patients that met the criteria, and 97 were ultimately available for analysis.

• 4 were excluded because the retinal changes were due to intracranial masses rather than hypertension. 
• 5 were excluded because of a lack of platelet count 
• 4 were excluded because they had an alternative explanation for thrombocytopenia

26 of the patients had MAHA. The MAHA cohort was more:

• black (73 vs 35%)
• hypertensive (242/150 vs 225/145
• uremic (Cr 7.8 vs 1.4)
• proteinuric (88% vs 41%)

To convert creatinine from micromol to mg/dl, divide by 88

Dialysis was needed in 15 of the 26 patients with MAHA and 2 of the 71 without MAHA. They had renal recovery in 6 of the dialysis patients: four within 2 months, one at 8 months and the last at two years!

Then the authors drop what might be the worst line of logic ever published in Hypertension:

Improvement of renal function, defined as a reduction of serum creatinine >50% compared with baseline, was noted in 17 patients during follow-up. Cox regression analysis showed that MAHA and systolic blood pressure at admission were the most powerful indicators of renal improvement with an HR of 0.24 (95% CI, 0.08 to 0.75) and 1.02 per mm Hg increase in systolic blood pressure (95% CI, 1.01 to 1.05; Table 4). Improvement of kidney function over time in patients with and without MAHA is shown in Figure 4.

The authors try to make the case that there is more renal healing with MAHA than in the absense of MAHA without specifically addressing that the patients with MAHA had 20x the rate of dialysis of those without it or that the average Cr of MAHA-absent patients was only 1.4, making a 50% reduction in serum creatinine require the growth of a third kidney. Ridiculous.

The second article was Gonzalez's study on the long term renal outcome following hypertensive emergency. The introduction begins with a nice history of hypertensive urgency. They state that patient survival was very poor before the 1970 and the development of effective anti-hypertensive drugs. After 1970 renal and patient survival climber to 50 and 75% respectively at five years. A decade later, with the introduction of calcium channel blockers and ACEi in 1980, survival rose to 81% renal and 90% patient survival at 5 years.

Gonzalez retrospectively looked at patients with a diagnosis of malignant hypertension. They also required retinal changes (hypertensive retinopathy grade 3 or 4). Strangely, they excluded a third of patients who had secondary hypertension behind the malignant hypertension. This, along with a few other exclusions due to lack of follow-up for various reasons, left 197 in the cohort. The cohort was divided by ultimate renal outcome. Group 1 had stable or improved renal function while group 2 had worsening renal function.

They found that patients who developed worsenning kidney function had at baseline: 

• pre-existing CKD
• higher creatinine on presentation
• more proteinuria 
• more microscopic hematuria.

125 (85%) had acute kidney injury on admission and 15 required dialysis. 8 of these had no prior CKD. Only 2 patients recovered sufficient renal function to stop dialysis.

On multivariate analysis only proteinuria in follow-up was associate with a lack of renal stabilization or improvement. 

83% of the patients with worsening kidney function (group 2) ultimately were started on dialysis. Remember, they had over 30 years of follow-up for some of these patients and there is some selection bias as group 2 was defined by a lack creatinine stabilization/improvement.

Since the cohort was collected over 30 years (1974-2007) the authors made some observations regarding the change in malignant hypertension over time. There was no change in the incidence, however there were fewer people needing dialysis. Treatment evolved from diuretics to calcium-channel blockers and RAS blocked.

The third article was a case report and lit review by Shavit et al. The article defines malignant nephrosclerosis as renal failure due to malignant hypertension. They describe three cases with varying outcomes:

1. 55 year old admitted with a blood pressure of 220/130, Cr 11, normal platelet count, LDH 1,100. A renal biopsy showed concentric intimal hyperplasia, fibrinoid necrosis of arteriolar wall, shrinkage of the glomerular tufts. The patient remained dialysis dependent 2 years after presentation.
2. 55 year old admitted with 240/125, Cr 13, LDH 1,430, normal platelet count. Kidney biopsy revealed intimal thickening, luminal narrowing, fibrinoid necrosis. His creatinine improved over 2 months and he remained dialysis free with significant CKD 2 years after presentation.
3. 28 year old admitted with a blood pressure of 210/135, Cr 4.5, K 2.9, normal platelet count. Kidney biopsy showed severe intimal thickening, and fibrinoid necrosis. Creatinine improved over 2 weeks to 1.8 and remains stable at 3 years of follow-up.

The authors then review the literature with an interesting discussion that renin and aldo levels are commonly elevated in malignant nephrosclerosis and that there is a strong correlation between renin activity and the presence of MAHA, suggestive of renin mediated vascular damage.

They mention research finding low levels of ADAMTS13 in malignant hypertension. ADAMTS13 level fall as LDH levels rise and platelet count fall. A follow-up study of 21 patients failed to confirm these findings.

The next article we pulled was by Akimoto et al, Clinical Features of Malignant Hypertension with Thrombotic Microangiopathy. This was retrospective review of 16 cases of malignant hypertension. MH was defined as an elevated blood pressure with retinal changes. MAHA was defined by an increase in LDH, low hemoglobin and low haptoglobin. Additionally to meet the definition of MAHA patients needed to normalize these indices after correction of the blood pressure. Of note 7 patients had biopsies. Five of those biopsies showed evidence of malignant nephrosclerosis (fibrinoid necrosis) but only 3 of them met the authors' clinical definition of MAHA. Interesting that those reasonable clues could be missing 40% of cases.

They found higher aldosterone levels in patients with MAHA than in patients without. They found a tight correlation between aldosterone levels and LDH, R² of 0.4 (p=0.0096).

Four of the seven patients with MAHA required dialysis, however 2 were able to come off. Three of the nine patients without MAHA required dialysis and none recovered renal function.

cyberNephrology, what a piece of cyberCrap--updated

I was browsing the Renal Fellow Network and saw a link to a website I hadn't previously heard of, cyberNephrology. It had a prominent position on the list of Other Nephrology-Related Blogs, so I went to check it out. The prefix cyberis very 1990's and cyberNephrology does not disappoint it. It has that a few years after the zombie apocalypse  feel.

Starting at the top the What's New page links to a pair of talks from 2009.

The three large banners are role overs that open to text based pages. The communication page is essentially a link to an E-mail discussion group. In today's world of Twitter and Facebook are e-mail discussion groups relevant? Hint: No.

According to cyberNephrology, e-mail discussion groups are not only a relevant form of communication, they are the only forms of communication.

The additional resources includes a link to the Highlights of the Nephrol e-mail discussion list, last updated in 2000. A link to a Nephrology Internet Bibliography, last updated in 2002.

The nephrology related websites is a page of links to a couple of dozen large institutions and a handful of defunct links to smaller sites, The Catalan Transplant Foundation (now a squatters site) KidneyWeb (a site that brings back memories of the worst of GeoCities), e-dialysis.org (now behind a paywall). Amazingly this page claims it was updated in January 2011, though they don't show any link-love back to the Renal Fellow Network.

The Education link on the home page leads to a page that is similarly outdated with links to NKF's spring meetings up through 2008. The funniest part is that 2008 is considered next years meeting, as there is a separate link to Past meetings.

The other trip down memory lane is the link to "New Technology--Palm OS, PDA." Unfortunately, for nostalgia's sake, the link is broken.

The last target on the home page is a new vision. This leads to more gobbley gook but does place the responsibility for this load of crap at the feet of none other than PBFluids hero, Dr. Robert Schrier. Shame on you Dr. Schrier.

The new vision page includes a contact form. I sent a comment and after pressing send I was redirected to this page of crap.

What's the chance I ever hear word one from them?

There was a time when having a "homepage" counted for something, but now these are just embarrassing relics. NKF should just euthanize cyberNephrology. 

It also calls into question what type of editorial control RFN has after getting endorsed by NKF. Do the editors really feel that cyberNephrology is a worthy site that belongs on the same list as Clinical Cases-Nephrology and Dialysis from the Sharp End of the Needle? Or was cybernephrology added in deference to their new overlords?

Update 9/1/11:

About 16 hours after posting Dr. Kim Solez commented here. You can read his plans for cyberNephrology below, but part of his plans included shuttering cyberNephrology and starting a new google+ charged version of the Nephrol e-mail list serve. Additionally a number of readers have chimed in, through the comments and other communications, regarding the value of the Nephrol list serves. This maybe a case where this author judged a book by its cover.

That said Dr. Solez has not made good on his promise and cyberNephrology is still up, though I occasionally get pointed to the new NephrolPlus project (not sure what's up with that). When cyberNephrology ultimately disappears you maybe able to dig up the bones at the NKF's kidney.org site, which currently carries a partial copy of cybernephrology. 

Lastly, the Renal Fellow Network has removed cyberNephrology from their website and have, to my satisfaction, established that there is no editorial control from the NKF. I feel a little foolish for pointing that finger. Sorry guys.

Should Registered Organ Donors Get Priority as Recipients?

Pay to Play: Should Registered Organ Donors Get Priority as Recipients?

Could fixing (or more realistically improving) organ allocation be this easy?

Good luck Steve and thanks for your dent in the Universe

We're here to make a dent in the universe. Otherwise, why even be here? We're creating a completely new consciousness, like an artist or a poet. That’s how you have to think of this. We're rewriting the history of human thought with what we're doing. --Steve Jobs

I was sad to hear the news of Job's resignation from Apple. My wife and I watched Pirates of Silicon Valley as a toast to the man who I view as a modern Leonardo De Vinci. A genius who revolutionized our world.

I said hi to Steve once. On the day the Fifth Avenue Store opened in New York I was walking around the plaza and saw Steve walking up to the store with another person. I was about ten feet away and I said, "Steve!"

He turned to me and I said, "You changed my life."

He smiled, said thank-you and then kept walking.

I felt like such a dork. "you changed my life." Ughh. I wish I had said something better.

It was 2006 and all I had with me was a Palm Treo

Later that night, my wife and I saw a show (I think it was Avenue Q) and then went to check out the scene at the Cube. We waited in line and went down into the store on opening night. It's the only Apple event I've witnessed.

Still smiling after saying hi to Steve hours
earlier, and my extremely understanding wife

The resignation letter states that he will continue to have a role at Apple, and it's likely we will see little different from Apple but as I wrote when he took his most recent leave of absence, "I want to live in a world where the man who launched the PC revolution is still leading it." As of today, that's no longer the case.

So long Steve, and thanks for your dent in the universe.

Crazy idea or genius? Nephrology Merit Badges

I want to create a series of buttons to give to residents and students to mark achievements in nephrology.

My birthday is coming up, looking at the 1 inch beginner button system

One of the common resident complaints regarding nephrology is that it's too hard. The nephrologist response to this complaint  is usually to deny the difficulty, because its not hard for the nephrologist. Perhaps that denial is counterproductive, first it's hard to disrupt a widely held belief that is continually reinforced by the community of medicine, secondly when you deny the difficulty you insult the intelligence of the student struggling with new concepts. Its essentially saying, "Hard? differentiating among the pulmonary renal syndromes is easy, what are you stupid?"

Instead of denying the difficulty we should re-frame the meme. Yes, nephrology is hard and look how cool it is that you mastered these concepts.

Merit badges, or pieces of flare as my fellow interjected, would add levity and encourage residents to tackle deeper concepts.

Potential nephrology merit badges:

• It's the heart, no it's the kidney, no it's the heart, no it's the kidney...: diagnose and successfully treat a case of cardiorenal syndrome
• ABG guru: interpret ABGs showing all four primary acid-base disturbances
• Quinton: insert a temporary dialysis access to provide emergency dialysis access
• Tissue is the Issue: perform a renal biopsy
• Look Closely: correctly interpret a urine microscopy specimen
• K/DOQI Genius  : use the K/DOQI guidelines to craft a plan of care for a CKD patient
• RIFLEry: use the rifle criteria to correctly stage a case of AKI
• RTA (pronounced like Fonzie would RTAAAAAA!): use urinary anion gap and other clues to correctly diagnose and classify an RTA
• Bud Rose: use free water clearance to draw meaningful conclusions about hypo- or hypernatremia
• Put on your Helmut (Rennke): be a star in the pathology room
• Gerry Appel: exceptional management of nephrotic syndrome
• Ron Falk: diagnose and manage a patient with ANCA-associated vasculitis
• The Town Schrier: Use FENa, FEUrea and BUN:Cr ratio in a meaningful way to diagnose a subtle case of pre-renal azotemia
• Mark Halperin: Master of the Cortical Collecting Duct: use the TTKG equation intelligently to help in the management of a patient
• Wisdom of Solomon: prevent a case of contrast nephropathy
• Cry me a river: for expertise in the use of high dose diuretics
• EPA Super Fund Site: use dialysis to correct uremia in AKI

Suggested merit badges from other creative nephrologists:

• Way to Go KDIGO: use the KDIGO guidelines to do what ever you want to your dialysis patient 
• Golden Pocket: Forgetting to tighten the cap on the urine that you are bringing back to the lab to spin

Thanks to Steve Rankin and Edgar Lerma

The "are you a medical nerd?" quiz

Another great post from Cartoon Guide to Becoming a Doctor

Follow the link to interpret your score

As I finished up this post I noticed that I had previously created the tag "Nerd Humor." Having a nephrology blog with that tag should be worth 5 points, minimum.

Antibiotic Locks

I'm finding my self using antiniotic locks more and more. Michael Allon, one of the key investigators who drove the adoption of albuterol for hyperkalemia is a player in this space. Here is one of his convincing studies:

Treatment of catheter-related bacteraemia with an antibiotic lock protocol: effect of bacterial pathogen

Calling all nephrologists! If you care about anemia, you have until August 30th

The Centers for Medicare and Medicaid Services has proposed changes in the Quality Incentive Program (QIP) for 2013. The changes specifically involve anemia. The QIP was created to assure that even though the costs of providing dialysis care are born exclusively by the dialysis provider, there are specific quality goals that if not met result in financial penalties. The quality goals currently place are:

• Percentage of Medicare patients with an average Hemoglobin < 10.0g/dL (Hemoglobin Less Than 10g/dL Measure)
• Percentage of Medicare patients with an average Hemoglobin > 12.0g/dL (Hemoglobin Greater Than 12g/dL Measure)
• Percentage of Medicare patients with an average Urea Reduction Ratio (URR) ≥ 65 percent (URR Hemodialysis Adequacy Measure).

Dialysis units that fail to hit the goals perscribed by the quality score receive a reduction in the Medicare payment by 0.5-2%. It should be apparent that the required hemoglobin targets ares problematic, especially given the recent action by the FDA (see my recent post Between a rock and a hard place). CMS is proposing the elimination of the floor on hemoglobin targets:

...Therefore, for the PY 2013 ESRD QIP, we propose to continue to use the following two measures previously adopted for the PY 2012 ESRD QIP:

• Hemoglobin Greater Than 12g/dL Measure.
• URR Hemodialysis Adequacy Measure.

This feels wrong to me. Creating an economic incentive that puts the cost of treating anemia on the provider but doesn't provide any minimal goals may result in a race to the lowest hemoglobin. What's to stop a rogue dialysis unit from removing ESAs from their formulary. We can all freely admit that ESAs have some previously under appreciated risks and that our enthusiasm for treating anemia was not entirely evidence-based, but our response to should not be to turn back the calendar to 1988.

After the release of Epo, the transfusion rate plummets. It falls by two thirds in a year and continues to fall so that the current rate of 0.3% per quarter represents a 98% reduction in transfusions. Revolutionary. And this doesn't even begin to address the quality of life brought to dialysis patients by higher hemoglobins.

CMS states that they cannot add another unique quality indicator for 2013 and are looking toward 2014 to do this. In the absence of new quality guidelines they should keep the goal to maintain a hemoglobin over 10 g/dl but lower the target to 9 g/dL for 2013.

Patients deserve an incentive that keeps providers conscious of anemia. In study after study, low hemoglobins walk hand in hand with poor outcomes. The concern regarding anemia has been driven by attempts to normalize hemoglobin. It is clear that normalization is hazardous and without scientific support; however a failure of the experimental group does not mean we should abandon the therapy given to the control group. In every study the control group received ESA to maintain hemoglobins at least 9 g/dL.  Removing the hemoglobin floor from the quality measures would be giving a de facto license to withhold an important medication from dialysis patients.

The TREAT trial is the best study every done on outcomes in CKD with an ESA.

These dosing groups resulted in an effective separation in hgb with little profound anemia

I have copied this post to Regulations.gov as my comment on the latest guidelines.

The deadline for comments is August 30th.

A science liaison at Amgen told me that Amgen was advocating for a hemoglobin floor of 10 g/dl. The Renal Physician Association is also supporting a hemoglobin of 10 g/dL. [This paragraph was updated 8/22/11, after a complaint that I mis-interpreted Amgen's position. My apologies.]

I have heard that CMS has received few comments from physicians. Embarrassing. Anemia is important and nephrologists should care how the governments crafts incentives that will change how our patients are treated. Go now and comment. Tell CMS what you think.

If you are still looking for a reason to read Presentation Zen...

Presentation Zen has an excellent post on the use of faces in slides. Great stuff.

Medical Education in One Panel

Not sure where the original came from but I found it here, via @FutureDocs