And the data keeps rolling in...

I am a believer in Richard Johnson's theory regarding fructose uric acid and hypertension/CKD. So I love it when I see another study adding to the foundation. This from Diabetes Care. The investigators looked at 1500 patients with diabetes and normal renal function and no proteinuria. Over 5 years they tracked who developed CKD (either GFR<60 or proteinuria):

During a 5-year follow-up period, 194 (13.4%) patients developed incident CKD. The cumulative incidence of CKD was significantly greater in patients with hyperuricemia than in those without hyperuricemia (29.5 vs. 11.4%, P < 0.001). In univariate logistic regression analysis, the presence of hyperuricemia roughly doubled the risk of developing CKD.

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.

Best lecture ever

On the subject of lectures, if you haven't seen Robert Lustig's lecture on Sugar: the Bitter Truth, stop what you are doing and find 90 minutes to watch it. Fantastic lecture. Amazing how good his lecture is with such pathetic slides. It's not about the deck.



The New York Times is running an excellent profile of the lecture (Really? Sunday New York Times Magazine profile piece on a lecture?)  this Sunday. Gary Taubes wrote the profile, he is the same author who wrote the best article I ever read on the science and politics of the Atkins diet back in 2002.

Take the time to check out the lecture and the profile.

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.

The sugar in soda

From a pretty good article in Fast Company of all places:

But come on, are sodas really so bad? Even coffee drinkers like to use a little sugar. Should we demonize coffee, too? Well, as a thought experiment, imagine that you're in the office kitchen as a colleague adds some sugar to his coffee. As you watch, he adds a teaspoon. And then another. And another. And another. And another. And another. And another.And another. And another. And another. And another. And another. And another. And another. And another. And another. (Dude, want some coffee with your sugar?)

 

Betcha don't know how much sugar is dissolved in your total blood volume

How much sugar is dissolved in your blood?

• assume a blood sugar concentration of 100 mg/dl
• assume 5 liters of blood in a average adult. This is equal to 50 dL
• 50 dL x 100 mg/dl = 5,000 mg of glucose in the total blood volume
• 5,000 mg is 5g which is a teaspoon

How cool is that, the entire blood volume has a single teaspoon of glucose dissolved in it.

A can of Coke has 8 teaspoons of HFCS 55

Hat tip to Michael Eades

More Fructose

I wrote an article for this month's news letter for my practise, SCSP. I wrote it on the work I did for my grand rounds. Enjoy.

in 1964 Walt Disney purchased The "It's a Small World" ride from the New York World's Fair. It became a staple of the American experience and became as beloved a part of Disneyland as mouse ears. In 2007 the ride had to be refurbished, in part due to the increased average size of passengers. The boats had been built for men weighing 175 pounds and women, 135 pounds. The overloaded boats were now routinely running aground in shallow areas, delaying the ride and frustrating patrons.

While this seems to be an innocent anecdote on our expanding waist sizes it serves to remind us that we are different than we used to be. The diseases of today have not always been with us. Obesity is not the only disease of indulgence which newly plagues us. Diabetes and hypertension were both rare diseases at the beginning of the twentieth century: Hypertension used to occur in 6% of adults; it now attacks a third. Diabetes was a one in a thousand diagnosis, now it is found in one fifth of hospital admissions.

These three diseases: obesity, diabetes and hypertension lie near the origin of the major health challenges facing our civilization.

One explanation of why these diseases emerged in the last 100 years is the fundamental change in our diet: a dramatic increase in the amount of sugar we eat. In 1700 Europeans ate one pound of sugar a year. Americans now eat 80 pounds a year.

Table sugar, sucrose, is a disaccharide, which means it is made from binding two simple sugars together: one molecule of glucose and one of fructose. Glucose is the simple sugar our body is tuned to use. The carbohydrates found in breast milk, lactose, is 50% glucose. Every tissue of the body is able to turn glucose into energy, in fact, glucose is the only carbohydrate the brain can use as a fuel supply.

The other half of sucrose, fructose is less useful than glucose. It is only metabolized in the liver. Glucose metabolism is a tightly regimented, stepwise process. Meticulous control is maintained over the breakdown of glucose at three separate steps in its initial metabolism. Fructose, on-the-other-hand, enters the liver and is consumed as fast as possible. The liver goes crazy over fructose and metabolizes it in a haphazard and unregulated process. Since the energy is produced without immediate need, a lot of the metabolic energy is directed into storage, which in the liver takes the form of triglycerides and fat. Fructose consumption leads to non-alcoholic fatty liver disease and has surpassed alcoholism as the number one cause of hepatitis.

The fructose consumption also increases the production of uric acid and raises serum uric acid level. While classically, uric acid is associated with gout, it is increasingly being accepted as a cause of chronic kidney disease and hypertension.

Fructose appears toxic and we are eating more than ever. But there is general confusion about the source of fructose in our diet. High fructose corn syrup was introduced in the 60's and has increased from non-existent in the food supply to an average annual consumption of about 40 lbs a year. HFCS replaced sucrose in both Pepsi and Coke in 1984. HFCS is largely found in two varieties: HFCS-42 and HFCS-55. The number indicates the percent of the which is fructose, 42% in the former and 55% in the latter.

Regardless of which variety of HFCS one encounters, they all have roughly the same amount of fructose as common table sugar. Despite the scary sounding name, HFCS does not contain any more fructose than your sugar bowl. We are eating more fructose than ever but it not because of HFCS, it is because we love sweets.

Happy Valentines Day

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)

Uric Acid, Fructose and Hypertension

View more presentations from Joel Topf.

Great post on the demonization of high fructose corn syrup

High fructose corn syrup is not the enemy; fructose is the enemy and HFCS has about as much fructose as table sugar.

Nice article highlighting this issue as it pertains to diabetes.

For the relationship of fructose to the epidemic of hypertension and chronic kidney disease, come to my Internal Medicine Grand Rounds at Providence Hospital in Southfield Michigan on January 28th.

The Sugar Fix: Chaper Two: Raising Cane

The Sugar Fix: Chapter 2: The birth of dietary sugar comes about 10,000 years ago in New Guinea. Johnson states that this moment is one that alters history as few other discoveries have.

Source Sugar Fix and USDA Economic research service

Sugar is a carbohydrate, one of three macronutrients in our diet (carbohydrate, protein and fat).
Table sugar or sucrose is disaccharide made of the joining of glucose with fructose. Lactose another disaccharide is made from the joining of glucose with galactose.

Sucrose. Note: glucose is on the left and fructose on the right

Fructose is he sweetest monocachide, about twice as sweet as glucose. Most high fructose corn syrup is about 50-60% fructose about he same amount of fructose as found in table sugar. Honey is 70% fructose. Almost all of the fructose we get in our diet comes from sweeteners added to foods.

The drive to eat sweet foods is inherent in our humanness. We don't need to be taught that fruit tastes better than vegetables. Johnson lays out a teleological argument that follows:

• sweet foods offer a survival benefit by promoting weight gain due to their caloric density.
• weight gain is enhanced by the fact that they don't promote satiety, so you can over eat, an advantage when food is in short supply and spoilage prevents storing leftovers
  
• the tendency of fructose to raise blood pressure may have offered a survival advantage to ancestors living on salt poor diets who suffered from chronic hypotension

He suspects that ancient humans ate only 15-20 grams of fructose a day (equivalent to two pieces of fruit) this compares to contemporary humans eating 70-80 g a day.

India was the first country to boil the juice from the New Guinea sugar cane to produce crystalized sugar.

Persian invaders brought home sugar and then the Arab invaders of the 7th century spread sugar from Persia to the rest of the Middle East.

The crusades brought sugar back to England in 1099.

Sugar was thought to have medicinal values and sold at pharmaceutical like prices. In 1319, sugar cost the equivalent of $50 per pound.

Sugar was one of the crops which supported the slave trade between Africa, North America and Europe.

England became a dominant producer of sugar and by 1700, the English were ingesting 4 lbs of sugar a year.

The democratization of sucrose accelerated following the discovery of the by which sugar could be extracted from beets.

In 1866 scientists in Buffalo invented a way to convert corn starch into sweet tasting corn syrup. Corn syrup is made of glucose chains of varying lengths. There is no fructose in corn syrup, so it is not as sweet as sucrose.

In the 1960s, glucose isomerase was discovered. THIS enzyme could convert some of the glucose in corn syrup to fructose ushering in high fructose corn syrup (HFCS).

HFCS is cheaper than sugar mainly because of the phenomenal overproduction of corn in this country. See the Omnivore's Dilemma. By the end of the 70's Americans were eating 10 pounds of HFCS every year.

In 1982 the US Government began to limit the amount of sugar which could be imported every year and by 1984 both Coke and Pepsi converted from sucrose to HFCS as the primary sweetener in their respective colas. The sweetwener in most colas is HFCS-55 which has 55% fructose only slightly more than sucrose, 50%.

Johnson states that another common variety of HFCS found in non-carbonated fruit juices is HFCS-42 (42% fructose).

He then claims that much of the harm from HFCS is not because it is anymore toxic than equal amounts of sucrose but rather that, its low-cost has resulted in more consumption.
This explains the expansion in the sizes an portions over the last 20 years. He points out the change in the size of a single serving of Coke. In the fifties it was 6.5 oz and now I am seeing 1 liter bottles (33 ozs) for sale.
The conclusion of the chapter has this wonderful sentence:

More to the point, the composition of basic nutrients that most people eat today is vastly different from what early humans consumed, or even what the typical American ate a century ago.

The Sugar Fix: Chapter One: The Fructose Factor

Johnson starts The Sugar Fix with the assertion that a century ago heart disease, diabetes and obesity were rare conditions.

In 1890 a survey of 5,000 US citizens revealed that only 3.4% of Americans were obese and they were typically isolated to the upper class. This compares to a contemporary rate of 32%. Two thirds of Americans are either overweight or obese. This includes one third of school children. This obesity rate has doubled since 1976 (CDC Source). The rapid increase in girth cannot be explained by genetics. Johnson feels that the rapid change in the frequency of obesity exonerates genetics as the cause, he states that the human genome has been relatively stable going back a few thousand years.



This leaves an environmental change. He then considers and discards changes in physical activity as the etiology. This is supported by the most recent analysis revealed at the 2009 European Congress on Obesity.

Johnson goes on to implicate fructuse. He states that fructose intake has increased 30% since the 1970's. Fructose is the main source of sugar in fruit. It is half of the molecule sucrose, table sugar. In 1970 the average American consumed half a pound of High Fructose Corn Syrup. By 2000 that had increased to 42 pounds a year. Though HFCS consumption has risen by two orders of magnitude, fructose exposure has only gone up by 30%. This likely means that HFCS has largely replaced the prior source of fructose in the diet, table sugar. The authors don't address that inconsistancy in this chapter.

Fructose causes obesity through multiple mechanisms:

• fructose causes more and faster weight gain than seen with other sugars
• fructose does not satisfy your appetite resulting in more calorie intake
  
• increased fructose dulls the brains responce to the normal satiety signals so that following chronic fructose exposure subjects eat more as they don't sence "fullness"
• fructose upregulates enzymes which promote obesity

Johnson believes that other conditions have increased in prevalence in lockstep with the increased exposure to fructose including:

• hypertension: 73 million Americans
  
• diabetes: 20 million Americans (CDC Source)
• kidney disease: 20 million Americans
• liver disease: emergence of NASH, now effect 2-5% of Americans (NIDDK Source)
  
• metabolic syndrome 55 million Americans

The mechanism linking fructose and these problems comes from multiple metabolic consequences of fructose:

• fructose is the only sugar which increases the production of uric acid which leads to hypertension
• fructose increases the production of triglyceridesand lowers HDL
• fructose causes insulin resistance
• fructose causes kidney disease

This last section is not supported by any references or data but Johnson promises to reveal the details later in the book.

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.