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Another one bites the dust: TREAT is negative

Darbepoeitin meets a similar fate as epoetin alpha in CKD patients. Here is the press release from the trial onset, a more opportunistic time:

Amgen Inc. (Nasdaq:AMGN), the world’s largest biotechnology company, today announced that the company has initiated a landmark trial to evaluate the impact of treating anemia on cardiovascular outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes. TREAT (Trial to Reduce cardiovascular Events with Aranesp(R) (darbepoetin alfa) Therapy) is one of the largest clinical trials in the company’s 25-year history. The TREAT study design as well as additional Sensipar(R) data was presented at the American Society of Nephrology (ASN) annual meeting in St. Louis.

“Current research suggests that anemia is an augmenter of cardiovascular risk in individuals with CKD and type 2 diabetes,” said TREAT lead investigator Marc Pfeffer, M.D., Ph.D., chief of medicine at Brigham and Women’s Hospital and a professor at Harvard Medical School. “TREAT will be the definitive study to determine if treating anemia with Aranesp does, in fact, lower the risk of death and non-fatal cardiovascular events in individuals with CKD and type 2 diabetes.”

TREAT is an international 4,000 patient, multicenter, randomized, double-blind, placebo-controlled trial. The primary endpoint of TREAT is a composite index of time to mortality or non-fatal cardiovascular event, including myocardial infarction, myocardial ischemia, stroke and heart failure.

The rational for TREAT was published in the American Heart Journal. From the abstract:

BACKGROUND: Patients with chronic kidney disease (CKD) have a high burden of mortality and cardiovascular morbidity. Additional strategies to modulate cardiovascular risk in this population are needed. Data suggest that anemia is a potent and potentially modifiable risk factor for cardiovascular disease in patients with CKD, but these data remain unsubstantiated by any randomized controlled trial (RCT). Furthermore, the clinical practice guidelines for anemia management in patients with CKD are based on limited data. The need for new RCTs to address critical knowledge deficits, particularly with regard to the impact of anemia therapy on cardiovascular disease and survival, is recognized within the guidelines and independent comprehensive reviews of the existing published trial data.

STUDY DESIGN: The Trial to Reduce Cardiovascular Events with Aranesp (darbepoetin alfa) Therapy (TREAT) is a 4000-patient, multicenter, double-blind RCT, designed to determine the impact of anemia therapy with darbepoetin alfa on mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetes mellitus. Subjects will be randomized in a 1:1 manner to either darbepoetin alfa therapy to a target hemoglobin (Hb) of 13 g/dL or control, consisting of placebo for Hb > or =9 g/dL or darbepoetin alfa for Hb <9> or =9 g/dL. TREAT is event-driven and has a composite primary end point comprising time to mortality and nonfatal cardiovascular events, including myocardial infarction, myocardial ischemia, stroke, and heart failure. TREAT will provide data that are critical to evolution of the management of cardiovascular risk in this high-risk population.

This was the last nail in the coffin for use of ESAs to normalize hemoglobin in pre-dialysis CKD. In the years since CHOIR and CREATE one of my partners kept holding out hope for TREAT. He mentioned that TREAT made it through its interim safety monitoring without being stopped so it was unlikely to show the same detrimental findings found in CHOIR.
This data is just preliminary as it was published to satisfy financial requirements. The official results will likely be presented at Renal Week.
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EKGs that will soil your shorts

A long time dialysis patient of ours came to the ED yesterday with the chief complaint of “weakness.”

She had not missed any dialysis in the last week. She had gone to the farmer’s market on Saturday (2 days prior to admission) and had purchased some melon. She ate two melons on Saturday and a third on Monday morning. Additionally, she had potatoes on Saturday night and Sunday morning.
On arrival to the ED this was her initial EKG (click on the image for a larger picture):

The potassium was still pending at this time and no action was taken on those peaked Ts and widened QRS.
Fourteen minutes later the EKG deteriorates to a terrifying sinusoidal pattern:

Potassium was still pending but based on the EKG and history of end-stage renal disease she was given two grams of calcium chloride. The CaCl2 was given via a peripheral line. Calcium chloride should be given only via a central line due to the devastating consequences of extravasation of calcium chloride. However, calcium chloride provides three times the calcium as calcium gluconate and is more effective at squashing hyperkalemic arrhythmias. I aplaud this boldness, as it looks like this patient is about to arrest.
The calcium worked great. A minute later things cool down:
Around this time the potassium came back at 9.4 mmol/L. The patient was then given 4 units of insulin. The low dose is typical of our ED as they tend to be skittish about giving 10 units of insulin to ESRD patients due to concern over symptomatic hypoglycemia. They chased the insulin with an amp of D50 and sixty grams of Kayexalate. The glucose was 84 mg/dL prior to the insulin and D50.
Eighteen minutes later the QRS is down to 128 msec from 168 on the initial EKG:

The patient then went for dialysis for 3.5 hours. Two hours with a zero potassium bath and 90 minutes on a one potassium bath. The potassium the next day was 5.5 mmol/L.

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Delta anion gap. Not as good as we think it is.

One of the concepts that is regularly taught in the evaluation of acid-base status is determining if there are multiple acid base disorders by evaluating the ratio of the delta anion gap/delta bicarbonate.

I teach this concept as determining what the bicarbonae would be in the absence of or prior to the anion gap.

The concept comes from the idea that for every mEq of bicarbonate that is consumed by the strong acid (other anion) the anion gap should rise by one. So if the bicarb is 16, a delta of 8, we would expect an anion gap of 20, a normal anion gap of 12 plus the delta bicarbonate of 8. This is a ∆AG/∆Bicarb of one.

If the patient had a pre-existing metabolic alkalosis with a bicarbonate of 30, then the patient would have a bicarbonate of 22 and an anion gap of 20. This would give ∆AG/∆Bicarb of 8/2 or 4.
If the patient had a pre-existing metabolic acidosis (non-anion gap) with a bicarbonate of 16, then the patient would have a bicarbonate of 8 and an anion gap of 20. This would give ∆AG/∆Bicarb of 8/16 or 0.5.
Concurrent metabolic alkalosis leads to ratios over 1 and preexisting metabolic acidosis (non-anion gap) yield a ratio below 1.
I had always been suspicious of this because the assumption of the one for one change in anion gap and bicarbonate. This didn’t seem to be very biologic. Turns out my suspicion was justified as numerous studies (Androgue, Elisaf) have shown that the ratio does not hold up.
In this paper by Paulson et al they found:
[Some authors] suggested that mixed disturbances should be considered if the ratio is less than 0.8 or greater than 1.2. Paulson, applying this rule to a group of normal control subjects and patients with simple metabolic acidosis, noted that the formula erroneously categorized 56% [specificity of 44%] of this group as mixed disturbances. Use of the 95% confidence interval of ±8 mEq/L increased the specificity to 97% but with a poor sensitivity of only 27%.
That’s terrible. Why torture the brains of medical students with this type of worthlessness.
Good review here.
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High osmolar gap and a low anion gap.

Our fellowship director asked me to do a lecture on osmolar gap. At first I thought that this was an odd topic as toxic alcohols, the standard reason for determining an osmolar gap are relatively rare findings and I was worried I’d be able to find enough to talk about for an hour.

I’m really happy how the lecture turned out. Not my best but pretty strong for a first crack at a new topic.

I structured the topic by looking at patients with low, normal and high anion gaps to go along with the high osmolar gap and started with a case of a high osmolar gap paired with a negative anion gap. I have only seen one negative anion gap and that was a case of hyperkalemia and hypoalbuminemia. This case comes from the Canadian Medical Association Journal. The low anion gap is from the unmeasured cation, lithium. The patient had a lithium level of 14.5 mmol/L.

Lithium is an unmeasured cation which expands the red box and decreases the anion gap.
The differential for a decreased anion gap.
The osmolar gap is driven up because the cation lithium is not part of the calculated osmolality but contributes to the measured osmolality. A unifying theme of osmolar gap is that adulterants that increase the osmolar gap always have relatively low molecular weights. Lithium carbonate does not disappoint with a molecular weight of only 74. Other intoxicants associated with an increased osmolar gap, likewise have a low molecular weight.
The case report then deals with the dialytic removal of lithium and the nature of lithium toxicity.
Here are the causes of an osmolar gap divided by anion gap:
Here it is:
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Alcohol and blood pressure: drink up?

Last week I turned in a chapter (sub-chapter?) on life-style modification for the control of blood pressure. This is part of a educational initiative for the National Kidney Foundation of Michigan.
I looked at all of the life-style recommendations in JNC-7:
I hope I will get permission to share my section on this blog because I think my conclusions differ in some important ways from the life-style dogma we hear over and over.
For now I want to share one interesting aspect: moderation of alcohol intake to reduce hypertension.
There is compelling data supporting the position that reducing or moderating alcohol intake reduces blood pressure.
One line of data comes from a recent study of two separate prospective observational trials by Sesso HD, Gaziano MJ, Et al: The Women’s Health Study (28,848 women) and the Physicians Health Study (13,455 men). They looked at initially normotensive men and women and followed them to determine the risk of developing hypertension (10.9 years of follow-up for women and 21.8 years for men) based on their exposure to alcohol. In men the risk of hypertension rose linearly with increased alcohol intake. In women, there was a J-curve, with increased risk of hypertension with teetotallers and decreased risk of hypertension until the risk that bottomed out at 5-6 drinks per week. Drinking at least one drink a day was associated with increased risk of hypertension.
Sesso’s data looks at the risk of developing hypertension, so while it provides evidence for the ill-effects of alcohol it does not answer the question of whether decreasing alcohol will ameliorate hypertension.
Xin X, et al. published a meta-analysis of 14 randomized trials of alcohol reduction in which a reduction of blood pressure was one of the end-points. Trial duration had to be at least 1 week:
Alcohol reduction reduced blood pressure to the degree promised in the JNC7 slides 3.3/2 mmHg:
What intrigued me was not the data on the reduction of blood pressure but the data on overall survival. Because the reason we care about blood pressure is because it is an intermediate outcome which is associated with cardiovascular events. If there is data on the actual outcome rather than the intermediate outcome it should by all means trump the intermediate outcome data.
Two large, high profile studies have looked at alcohol intake and survival. The biggest is a study by Thun et al and published in the New England Journal of Medicine in 1997. The data was taken from the 1.2 million American adults enrolled in the Cancer Prevention Study II and looked at 490,000 who provided complete information on smoking and drinking habits. The study showed that drinkers had a lower rate of cardiovascular disease but a higher rate of alcohol related illness. The statistics of this are interesting, a 40% reduction in the common cause of death (cardiovascular disease) ends up having much more influence than the 200-600% increase in the relatively rare deaths from conditions associated with alcohol intake:
Here is the authors description on the cardiovascular benefits of alcohol:

In contrast, the rates of death from all cardiovas-cular diseases combined were 30 to 40 percent lower among men (relative risk, 0.7; 95 percent confidence interval, 0.7 to 0.8) and women (relative risk, 0.6; 95 percent confidence interval, 0.6 to 0.7) reporting at least one drink daily than among nondrinkers. The largest reduction, in both absolute and relative terms, occurred in mortality from coronary heart disease among drinkers who, at enrollment, had reported heart disease, stroke, or some other indication of preexisting risk of cardiovascular disease.

They added a nice figure which illustrated the relative effects of smoking versus alcohol. The protective effects of alcohol are insignificant when compared to the dangers of smoking:
A second study on the mortality benefit of alcohol used the The Physicians Health Study. This is the same data that Sesso used to show the association of alcohol with the risk of hypertension. Malinski et al. looked at a cohort of subjects with pre-existing hypertension and demonstrated a 40% reduction in cardiovascular mortality with daily drinking as compared to rare or non-existent drinking. So even in the cohort that we are specifically advising to reduce alcohol intake, there is a survival benefit from drinking.
Most of my patients do not drink once a day. My feeling is that when they look at recommendations to reduce drinking they interpret that as they should stop drinking and they probably are actually increasing rather than decreasing their risk of death.
Salut
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What is the electrolyte book for me?

I received this e-mail question today:

Hi

I am a second year nephrology fellow. I always find acid base and electrolytes interesting but have always looked for a good book which would help me get a better perspective on this topic. Are there any books that you would recommend.

MD
There is only one answer to this question. If you are nephrology fellow who wants to own electrolytes get Burton Rose’s masterpeice: Clinical Physiology of Acid-Base and Electrolyte Disorders.
You can find this and other recommended nephrology books at PBFluids’ Amazon Store of Knowledge.
Disclosure: I do receive a kickback if anybody every buys a book through these amazon links (still looking to lose my amazon affiliate cherry)
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Things have been coming in pairs: electrolyte free water and hypernatremia

First we had the highest creatinine followed by the lowest creatinine.

Then we had a case of hyponatremia/SIADH that we evaluated with the concept electrolyte free water and now we have a case of hypernatremia that we also evaluated with electrolyte free water.

I have a special fondness for dysnatremia formulas that work with either hyper- or hyponatremia because there is an elegance in using a model that works at both extremes.
Both the change of sodium formula and electrolyte free water calculation work as well with hypernatremia as they do with hyponatremia.
The case: 56 year old African American nursing home resident with a history of bipolar disease. She presents with altered mental status and initial labs reveal acute kidney injury and hypernatremia.
Body weight 70 kg
Na 177
Cr 4.18
On exam the patient had obvious hypovolemia and the elevated sodium reveals dehydration. The primary team appropriately uses half normal saline to correct both of these deficiencies.
The sodium came down to 167 the following day and after that they have been unable to further correct it. The patient remained in the ICU for 4 days prior to us being consulted for persistant hypernatremia. The creatinine rapidly corrected over four days to 1.6.
Additional data:
Admission urine sp grav 1.011
Admission urine Na 10
Admission urine osmolality 330
On the fourth day of the admission the urine output was 1,500 over the prior 8 hours
The primary team had been using the water deficit formula to estimate the amount of fluid to give the patient to correct the sodium over 2 days:
The water deficit equation asks how much water will be needed to dilute all the solutes to some ideal. In many books and programs the ideal sodium is fixed at 140 mmol/L. I usually use 145 mmol/L, which is the least amount of change in sodium to get a normal sodium. I do this because the downside of correcting sodium is all on the side over correction and inducing cerebral edema.
The equations often wont let you determine the % body water and fill in 60%. This is a large source of error because in the United States we’re all fat and fat people are relatively anhydrous. Also, since typical internal medicine patient is about 100, and old people are likewise anhydrous 60% is a over estimation of total body water. My fellow estimated the total body water to be 35 liters.
The calculated free water water deficit is 7.7 liters. I usually administer half of that in the first 24 hours unless the sodium is very high, as in this case, and then I would have given about a third of the volume in the first day and correct the sodium over three days. I shoot for a change of about 12 mmol/l per day.
The equation worked well initially with the sodium going from 177 to the mid 160’s but after that they stalled. The reason the sodium stopped improving was that they cured the patient of her renal failure and the urine output increased. Neither the team nor the water deficit formula accounted for this.
We can account for the urine output by replacing the electrolyte free water clearance:
So one would have to add 2.8 liters of electrolyte free water to the free water deficit calculation to account for urinary loss of electrolyte free water. If one were to recalculate the water formula using the partially corrected sodium of 167 you get:
If you plan to give half that in the first day that is 2.65 liters. Compare that to the electrolyte free water loss of 2.8 liters and it immediately becomes obvious why the sodium remained stable for days.
Teaser: An elevated electrolyte free water clearance in the presence of hypernatremia is presumptive evidence of diabetes insipidis. I will save that discussion for my next post.
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Crazy numbers: lowest creatinine

The consult team is now taking care of a patient with what I think is the lowest creatinine I have ever seen: 0.29 mg/dL. I’m not a bench nephrologist but I think that is a pretty typical mouse creatinine.

Update: some commenters asked about the BUN: 6 mg/dL. FYI today the Cr is down to 0.28 and the BUN fell to 3!

The patient has SIADH and low creatinines are a usual finding. She also has a crazy low uric acid of 1.4. Not quite Uricase low but getting close. Her admission sodium was 108, her urine sodium today was a whopping 156 with a urine potassium of 34. So if you calculate her electrolyte free water clearance (the amount of her urine which is electrolyte free water):

You get a negative 826 mL. A negative electrolyte free water is not unusual in SIADH and distinguishes it from the hyponatremia seen with heart failure (or other conditions of decreased effective circulating volume).
In this case the negative clearance means that for every liter of urine this patient makes it is as if she drank 826 mL of fluid. The very act of urinating lowers the sodium further by diluting the plasma sodium.
This throws a wrench in the standard plan of adding the urinary output to the insensible losses and setting the fluid restriction to be 200-500 mL below that. This works in conditions like heart failure where the electrolyte free water is positive but with a negative free water clearance you need to account for the negative free water clearance by adding it to the water intake, not the renal losses.
See this presentation on electrolyte free water clearance for further details.