Tag: uric acid

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OUWB Euvolemic Hyponatremia question

Hello Dr. Topf,

I hope you are enjoying your weekend. I had a question in regards to one of your lectures. I was wondering why there is a low level of Uric acid in euvolemic hyponatremia but not in hypervolemic or hypovolemic hyponatremia. Also, how is it that Na taken in equals Na excreted in euvolemic hyponatremia?

All the best,

 
So why is there a low level of uric acid with euvolemic hyponatremia? Let’s first look at what happens to uric acid in the other causes of hyponatremia, namely hypovolemic and hypervolemic. In both of these situations the kidney is experiencing decreased perfusion, either from absolute volume depletion (diuretics, diarrhea) or perceived volume depletion from pump failure (CHF) or fluid maldistribution (cirrhosis and nephrotic syndrome).
In these volume depleted states there is an increase in the filtration fraction, i.e. more of the plasma that enters the glomerulus is actually filtered. This is how the kidney compensates for a decrease in renal plasma flow while maintaining GFR, it increases the fraction of fluid that is filtered.
A consequence of this, is that the oncotic pressure in the blood leaving the glomerulus is higher because more of the fluid (but none of the protein) has gone down the glomerular drain leaving the plasma in the efferent arterioles with a higher oncotic pressure.
This plasma then enters the vasa recta where it surrounds on the proximal tubule. Here the increased oncotic pressure pulls more fluid back.
This is an ideal situation. The increased filtration fraction maintains GFR in the face of decreased renal plasma flow, and the increased filtration fraction results in enhanced reabsorption of fluid in the proximal tubule limiting fluid loss in situations where patients have decreased perfusion.
Uric acid handling is complex and not fully worked out.
It appears that there is both uric acid secretion and reabsorption in the proximal tubule.
Functionally, uric acid clearance tracks with renal perfusion:
  • Decreased uric acid clearance with decreased renal perfusion
  • Increased uric acid clearance with increased perfusion of the kidney

This is similar to what we see with urea. The following description of urea handling gives a model that will work for uric acid, though the truth of uric handling is much more complex.

The key with urea is that it’s handling in the proximal tubule tracks with total fluid reabsorption in the proximal tubule.
With volume depletion, increased filtration fraction causes increased oncotic pressure in the vasa-recta increasing urea reabsorption in the proximal tubule.
In volume overload, decreased angiotensin 2 decreases sodium reabsorption resulting in less fluid reabsorption and less passive reabsorption of urea  so increased urea loss in the urine and lower serum urea.
Now what happens in euvolemic hyponatremia.
Sodium in equals sodium out. This means that these patients do not have a primary volume abnormality as we see in the hypovolemic and hypervolemic patients. Because of this their sodium regulation volume regulation system is not stressed, they are at homeostasis with regards to body sodium. When you are in homeostasis, in order to stay in homeostasis you need to excrete all the sodium that comes in. In other words sodium in equals sodium out.
However these patients are not in water balance. they have a disease that forces their ADH to 11. They have a fixed ADH secretion and it is set at full blast. This minimizes urinary water excretion, but they are able to stay in sodium balance. So the net of this is they make only a little bit of urine but that small amount of urine carries all of their ingested sodium (sodium in = sodium out) so the sodium is excreted in a small volume at a high concentration.
Now the obvious problem here is that they are holding on to an excess of water. And that will increase their total body volume. This is subtle and doesn’t cause edema, or heart failure, or fluid overload in the lungs, but it is there. This fluid overload suppresses angiotensin 2 and decrease sodium resorption in the proximal tubule and hence decreases urea (and uric acid in our model) reabsorption.
And yes this does mean it is not exactly sodium in = sodium out, there will be a slight excess of sodium excretion.
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#DreamRCT: Prove the uric acid-CKD connection and win Richard Johnson a Nobel

Okay nephrologists, we have suffered the slings and arrows of outrageous trial after trial going

against us. It is time to put down those depressing journals full of non-significant P values and stretch our imagination. It is time to design our own dream randomized controlled trial. The assignment is to target the most important question you see in nephrology today and design a trial to answer it. One question not enough for you? Design a trial to answer two questions ACCORD style, two questions not enough, go all AASK and design a 2×3 factorial design. Money no object, forget about pesky IRBs, let your mind free and create the trial which will meaningfully push back the walls of knowledge.

After you post your entry at your site of choice, UKidney will host a summary with a link for each entry and gather votes for the best. You can take a look at Jordan Weinstein’s Dream RCT here.

And may the IRB be ever in your favor.

My Dream RCT: Background

Humans have higher uric acid levels than almost other animals. This is primarily due to the lack of uricase, but also due to our efficient renal reabsorption of filtered uric acid by URAT1 and GLUT9. Traditionally, it has been believed that hyperuricemia causes renal disease by precipitating intraluminal crystals, analogous to gout crystals in the joints. More recent data however, implicates lower levels of uric acid in hypertension and chronic kidney disease through suppression of nitric oxide formation, stimulation of inflammation through NF-kappa beta and other mechanisms. Supporting these theories are animal studies that show febuxostat and allopurinol reduce renal damage in multiple models of kidney disease (here and here).

Epidemiologic studies linking uric acid to chronic kidney disease show a definite association but whether the uric acid causes the kidney disease is difficult to tease out. Attempts to show that have shown mixed results.

Four interventional studies have attempted to answer this question in humans:

  • Siu et al. randomized 54 hyperuricemic patients to placebo or enough allopurinol to normalize the hyperuricemia. After a year there was less creatinine progression with the allopurinol.
  • Goicoechea et al. randomized 113 hyperuricemic patients to no therapy or 100 mg of allopurinol for two years. They found improved renal function with drug compared to modest loss of function without allopurinol. And intriguingly they also found a significant reduction in cardiovascular events.
  • Shi et al. evaluated 40 patients with IgA nephropathy for 6 months. This was a negative study with no effect on GFR (but that is hardly surprising given the very short follow-up time), but it did have a beneficial effect on hypertension
  • Momeni et al. performed a 4 month double blind, placebo controlled trial of type 2 diabetics and found a reduction in proteinuria.

From Goicoechea’s study of 100 patients

More information can be found on uric acid in my grand-rounds or in an excellent Narrative Review from AJKD.

Despite multiple randomized trials showing allopurinol to be effective in CKD, don’t be fooled, both trials were tiny with limited follow-up.

Diameter of the circle is proportional to the trial size

Given that background, it seems well past time to commit to finding a definitive answer to the question of whether we should be using xanthine oxidase inhibitors to slow the progression of chronic kidneys disease.

Scouring ClincalTrials.gov I could find only one study that is addressing this hole in our knowledge. The Joslen Center is planning, but has not yet started enrolling, a double-blind, placebo controlled multi-center trial of allopurinol in type 1 diabetics. The study design looks pretty sharp with iothalamate GFRs after 3 yrs of therapy being the primary outcome. However I am dreaming bigger and want my study to apply to all patients, not just type 1 diabetics with nephropathy.

My Dream RCT: methods

My dream study is a placebo controlled, double-blind, multi-center, randomized controlled trial. The study population is CKD stage 3 patients with hyperuricemia (uric acid over 7 mg/dL). This represents a lot of the population with kidney disease which means that the results, if positive, would literally influence the treatment of millions of people. The study will use block randomization and quotas to assure a varied distribution of renal disease. At least a third of the population will have proteinuria and half will have diabetes.

All patients with proteinuria would need to be on RAAS inhibition unless they could not tolerate it. Blood pressure would be treated by the treating physician using JNC8 guidelines. Patients would be randomized to one of three arms:

  • placebo
  • allopurinol 100 mg daily
  • fubuxostat 40 mg daily

If the uric acid remained above 7 after one month of treatment the study drug would be doubled. Patients intolerant to the assigned drug could cross over to the other study drug. Study coordinators would signal a central dispensary that patients were intolerant and the dispensary would change patients on placebo to another placebo (essentially no change at all) and patients on one of the xanthine oxidase inhibitors would cross over to the other xanthine oxidase inhibitor. By employing this three arm approach we will be able to assess if any affects is due to a specific xanthine oxidase inhibitor or a more general effect of lowering the uric acid. It will also allow us to get detailed data on the tolerability and safety of the drugs in CKD.

The primary end-point is a composite of doubling of serum creatinine, death or dialysis.

Secondary endpoints are achieved ambulatory blood pressures, hospitalizations, new cardiovascular events, and gout.

This study would have results applicable to the millions of people with chronic kidney disease and would open up the first novel front in the war on CKD since the wide use of RAAS inhibition.

UPDATE
Apparently this RCT is not a dream but a trial that is going to be done, from Swapnil Hiremath:

.1/2 @kidney_boy Joel, I thought you knew about the ongoing CKD FIX trial down under: https://t.co/DnG4BHu5vp Allopurinol 100-300 mg …
— swapnil hiremath (@hswapnil) January 29, 2014

2/2 @kidney_boy gr8 It’s in CKD patients, n 620, with change in GFR as 1 outcome.
— swapnil hiremath (@hswapnil) January 29, 2014

Looking through the registry data the CKD-FIX trial sounds like a pretty close match to my Dream RCT, my one concern is they were supposed to begin enrolling patients in March of 2012 but have yet to enroll they”re first patient (according to the registry). Anyone know if this study is still going to happen?

UPDATE 2
It is on. CKD-FIX to start enrolling next month.

. @kidney_boy confirmed : CKD – FIX recruitment set to begin in Feb 2014, starting in Brisbane
— swapnil hiremath (@hswapnil) January 31, 2014

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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.

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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.
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My Grand Rounds

For the last 6 weeks I have been pounding the computer finishing and perfecting my lecture which I gave at Grand Rounds at both Providence Hospital and St John’s Hospital.

I delivered the second one yesterday.

Here is the lecture with an audio track. My presentations are not self-contained most of the important data comes from me presenting. I hope you like it. (.zip file of native Keynote file)

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The Sugar Fix: The Introduction

In the introduction of The Sugar Fix, Johnson uses a broad brush to establish the scope and purpose of what he intends to prove in the subsequent 300 pages.

  • He gives a brief anecdote about the increasing prevalence of obesity. His uric acid hypothesis is going to explain this huge health problem.
  • He outlines how he was initially looking for the cause of hypertension when he realized the weight-loss potential of a low fructose diet.
  • He then speeds through a handful of clinical studies, both epidemiologic and interventional, which implicate uric acid as a powerful risk factor for cardiovascular disease, i.e. uric acid as the new cholesterol. He admits that the scientific establishment has not accepted his theory as facts and that uric acid today is where smoking was in the 50s and cholesterol was in the 60s.

He concludes the chapter by disclosing two potential sources of bias. He is the Dr. Cade Professor of Medicine at the University of Florida and that his salary and research is supported by sales of Gatorade by the PepsiCo corporation. This is an interesting disclosure because the cola companies are the principle villains in this morality tale. I wonder if part of the reason for the release of Pepsi Throwback (sucrose rather than high-fructose corn syrup (HFCS) as the principle sweetener) is the pushback against HFCS partially lead by Dr. Johnson.

He also explains that he has applied for multiple patents that could financially benefit him if the relationship of uric acid and cardiovascular disease bears fruit.

(pdf)
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I am doing Grand-Rounds on the relationship of uric acid and hypertension

About three years ago I had the privledge to attend a day long seminar on gout put together by Jerry Yee from Henry Ford Hospital. The highlight of the day was a lecture by Richard Johnson from the University of Florida. I had learned about Johnson at my fellowship as the principle discoverer of the link between hepatitis C and membranoproliferative glomerulonephritis (review), in my mind, among the most significant discoveries in nephrology in the last twenty years. Before seeing him I had not made the connection between Richard Johnson and the author of the deservedly popular nephrology text Comprehensive Clinical Nephrology, but it is one and the same.

At that seminar Dr. Johnson gave the greatest lecture I have ever heard. The lecture was on uric acid and its etiologic role in hypertension, obesity and diabetes.

When I heard that he was writing a book on the subject I purchased it and have been reading it on and off for the last 8 months or so. Unfortunately, the book doesn’t have nearly the punch as his 90 minute lecture. My sense is that he writes to the level of the typical purchaser of diet books and comes across more as a carnival barker than one of the most respected researchers in nephrology today.

As I get ready for my grand rounds I am going to blog about uric acid, fructose and the epidemics of diabetes, obesity and hypertension as presented by Dr. Johnson in his book: The Sugar Fix. Should be an interesting ride as the subject is blessed with lots of data, industry influence, huge health implications and a likely Nobel prize if Johnson has really discovered the cause of the bulk of essential hypertension.