PodCast: Curbsiders #69

I was invited by the Curbsiders to talk about CKD. The discussion went a little long and our discussin got divided into two podcasts, #67 and #69. Here is the second half. I don’t think I made any major mistakes except when discussing combined ACEi and ARB therapy I said ALTITUDE was a study of RAAS inhibtion and endothelin antagonists. Actually ALTITUDE was RAASi and Aliskiren, the direct renin antagonist. And it was stopped not because of hyperkalemia but due to a CV signal (though the combination did have more hyperkalemia). The trial I was thinking about was ASCEND which added the endothelin antagonist avosentin to an ACEi or ARB in patients with diabetic nephropathy. This trial was also stopped early, again for CV issues after only 4 months on the drug!

You can listen to the episode here.

Fructose, hypertension and CKD: an update

Today, I gave grand-rounds at William Beaumont Hospital Royal Oak. I gave the fructose-uric acid lecture I gave in January of 2010.

Over the last 16 months, the science has continued to move forward without any hiccups. Additionally, data supporting direct renal toxicity of fructose and uric acid has matured. This latest version of the lecture adds a section on CKD including a summary of both randomized-controlled-trials examining allopurinol to reduce the progression of chronic kidney disease.

The lecture is available in the under the lecture tab.

NSAIDs and Chronic kidney disease. A great post at the Renal Fellow Network

One of the standard pieces of advice I give patients regarding chronic kidney disease is to avoid NSAIDs. However, not infrequently, patients have co-morbidities that demand NSAIDs. This usually triggers a conversation with my patients where I describe how ibuprofen can cause acute renal failure (I just took care of a new patient who developed RIFLE stage: Failure from a couple of doses of Mobic on top of stepped up ibuprofen use). I then explain that we extrapolate from the acute renal failure that NSAIDs are probably not beneficial in CKD and are likely harmful.

Lisa J Cohen at The Renal Fellow Network has a nice post on the lack of hard data implicating NSAIDs in the progression of CKD:

What about chronic renal dysfunction following long-term NSAID intake? In today’s medical environment, the evidence is weak. Prospective cohort studies in the Physicians’ Health Study (Rexrode et al, JAMA 2001) and the Nurses’ Health Study (Curhan et al, Arch Int Med 2004) failed to show an association between even high levels of cumulative lifetime NSAID intake and decrease in renal function.

My concern about these studies is the effect, we physicians have on the outcomes. Telling kidney patients to avoid ibuprofen and other NSAIDs is standard fare in CKD care. I’m sure these patients tend to use less ibuprofen and more acetaminophen, just as liver patients probably do the opposite. So educated patients with CKD will avoid NSAIDs but regardless of NSAID intake they will have a much higher progression to kidney related endpoints than their peers without a diagnosis of CKD. The epidemiologist sees a large cohort of acetaminophen users (my CKD patients) ending up with renal failure and sees that people with CKD use very little ibuprofen and may infere that acetaminophen causes kidney failure and ibuprofen is protective.

These are the type of questions that CRIC should be able to answer.

Allopurinol a novel way to slow the progression of chronic kidney disease

In my grand rounds on uric acid’s link to renal disease and hypertension I was not able to show any compelling data that allopurinol actually helped adults. There is convincing data on the use of allopurinol for the treatment of adolescent hypertension. The only adult data I could find was a VA study which used a retrospecitve electronic chart review to show that patients prescribed allopurinol had a lower risk of death. Pretty weak sauce.

Now we have more compelling data showing a reduction in the progression of CKD thanks to Goicoechea et al.

This is an interesting, single-center, randomized, controlled trial of allopurinol given to patients with chronic kidney disease. The patients had to have stage 3 CKD or worse (average eGFR was 39.5±12.4 for the control group and 40.6±11.3 for the allopurinol group) that was relatively stable. The patients had hyperuricemia at baseline but nothing too crazy (7.3±1.6 mg/dL for the controls and 7.9±2.1 mg/dL for allopurinol). The patients were not blinded and no placebo was used. Investigators either handled the patients or the laboratory results but no investigator dealt with both.
The primary end point was a little hazy by my read. The authors state:

The primary objective of this study was to analyze the effect of allopurinol in patients with moderate CKD in reduction of inflammatory markers and renal disease progression.

But I couldn’t find a specific case definition of renal progression in Materials and Methods. In the results they showed significant reduction in renal disease progression by two means:

  1. They showed less loss of eGFR over 24 months in patients treated with allopurinol. There was actually a modest increase in renal function in the allopurinol group. P=0.016 for eGFR between groups at 24 months.
  2. They defined renal progression as a loss of more than 0.2 mL/min per month and after using a cox-regression model adjusted for age, gender, diabetes, uric acid, hs-CRP levels, renin-angiotensin system blockers, CKD etiology, and albuminuria they found a hazard ratio of 0.53 (0.28 to 0.99; P=0.048).
As part of the primary end point they also looked at inflammatory markers and those improved remarkably with allopurinol. The investigators saw significant reductions in CRP, C Cystatin. Albuminuria appeared to drop more in the allopurinol group but this was not significant.
One of the secondary end-points was looking at cardiovascular risk and hospitalization. The data looks really exciting. They had a 71% reduction in cardiovascular events and a 62% reduction in hospitalization.

This study is study suffers from the weaknesses often seen in the first studies of an exciting hypothesis. It is a single center study, it is too short and it is too small; that said, the investigators were able to show reductions in both patient oriented outcomes (cardiovascular events and hospitalizations) and important biochemical factors (CRP, loss of renal function). I’m also excited to see that this didn’t come from Richard Johnson’s lab. Too much of the data on fructose and uric acid comes from his group. Nice to see some fresh faces in this field. 
I am looking forward to a larger study with harder end-points than a change in the slope of eGFR. Show me a decrease in the doubling of serum creatinine and/or decrease in the initiation of dialysis.
I, personally, am already a believer in the fructose/uric acid model of hypertension and progression of chronic kidney disease. Goicoechea, et al. is an important brick in the wall but it is still not enough to warrant the blanket treatment of asymptomatic hyperuricemia.

Hyperkalemia as an indication for dialysis

A few weeks ago we admitted a patient who has been approaching ESRD for a number of years. Most of her medical care had been provided in the hospital as she bounced from admission to admission. Though we tried to get her into our CKD clinic she always failed to show up. You can track the progression of her CKD from hospitalization to hospitalization with a gradually increasing baseline creatinine.

On this most recent admission, she came in with the triple 8s:

  • Hemoglobin 8.8
  • Creatinine 8.1
  • Potassium 8.6

Here is her initial EKG with that potassium:

The most remarkable part of the EKG was the profound bradycardia, heart rate of 30. Also she has beautifully peaked T waves. I’m surprised by the lack of a prolonged QRS. She had a great response to medical management with her K falling to the 5s. The repeat EKG was rather unremarkable.
The patient received dialysis on the day of admission and the following day I set her up for chronic dialysis. Whenever a patient progresses to chronic dialysis from CKD I always try to remind myself of how rare this event is. As nephrologists it is too common and seeing that unfortunate outcome alters our perception so that we may overestimate its frequency. End-stage renal disease is an exceptional, not a routine outcome of CKD. The vast majority of patients with CKD ultimatly expire of something other than renal failure. Let’s review three important studies to emphasize this:
Keith et al looked at the five-year outcome of 28,000 patients with chronic kidney disease. He divided them by CKD stage and found that of the 11,278 patients with CKD stage 3, only 1.1% of then received dialysis and 0.2% received a transplant. A quarter of them died (24.3%). The authors summarized the results:

The likelihood of renal replacement therapy, either transplant or dialysis, was near zero (≤1.3%) for patients in all stages except stage 4, where 2.3% ± 1.1% of patients received a transplant and 17.6% ± 2.7% had dialysis initiated.

Eriksen et al found similar results in a 10-year study, with a 4% risk of renal failure for patients with CKD stage three compared to a 51% risk of death.
And lastly, O’Hare, et al’s VA study that looked explicitly at renal failure and the competing outcome of death. They asked, “At what age and GFR is renal failure more likely than death?”. Obviously, at a younger age, when death is a more remote possibility, a higher GFR will have the time to deteriorate to the point of requiring renal replacement therapy. The results showed surprisingly low GFRs:
To read the graph, find your patients age and then line it up with their GFR. If the intersection is in the black, they are more likely to die, if it is in the grey then hello Mr. Fresenius, nice to meet you Ms. Tacrolimus. Note, that in a 75 year old with a GFRas low as 16 mL/min, death is still more likely than ESRD.
So, the next time you see a patient initiating dialysis after a long run of chronic kidney disease don’t be frustrated by the fact that they didn’t do enough to prevent this, be amazed that they survived to this outcome. 

Highest creatinine in chronic renal failure

Mr. S., a 38 y.o. African American male, came to the hospital with nausea, vomiting and fatigue. Initial creatinine was 36.2 mg/dl. After hydration overnight it came back at 38 mg/dl.

Update: one of the comments asked about the patients body habitus, rhabdo and BUN.

  • Mr S. is muscular but no body builder
  • He was not in rhabdo. I would not include an elevated creatinine due to muscle breakdown under the crazy numbers tag as it essentially represents a lab error, in that the creatinine is no longer a measure of severity of the renal failure or the chronicity but rather a measure of the aggregate muscle damage.
  • His BUN was 139 mg/dL

This patient had a remote diagnosis of hypertension but had been out of any medications for months. The computer showed a 2 year old creatinine of 2 but the patient denied any memory of being told he had CKD.

One of my co-fellows, Rajiv Poduval, used to call this acute ESRD. Chronic kidney disease that goes unrecognized until the patient rolls into the ED in need of dialysis.