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When Homocysteine Levels Won’t Come Down

October 2006

By William Faloon

Twenty-five years ago, the Life Extension Foundation warned its members about the dangers of elevated homocysteine. Since then, excess homocysteine has been correlated with common disorders that include Alzheimer’s disease,1-8 osteoporosis,9,10 heart disease,11-18 stroke,3,19,20 depression,21-23 and cognitive impairment.24-38

A simple blood test can measure one’s homocysteine level. If homocysteine blood levels exceed 7-8 µmol/L,39 increasing one’s intake of folic acid,40-49 vitamin B12,50,51 vitamin B6,41-44,49 and/or TMG (trimethylglycine)52-55 usually reduces homocysteine to safe ranges.

Over the past six months, we have received calls from some of our medical advisors and members who report incidences of stubbornly high homocysteine levels, despite aggressive use of homocysteine-lowering nutrients.

While investigating what could be done for these people, I had my own blood tested and was shocked to find my homocysteine had skyrocketed to 15.6 µmol/L, a level that puts me at higher risk for a host of age-related diseases. Serendipitously, I was interacting with our doctors to develop a protocol for members whose homocysteine remains persistently elevated even when high doses of nutrients like folic acid and B6 are ingested.

The encouraging news is that we have been able to identify reversible causes of excess homocysteine occurring in otherwise healthy individuals. Now that these mechanisms are better understood, most members should be able to keep their homocysteine levels in optimal ranges.

Kidney Function, Cardiovascular Risk, and Homocysteine Levels

It has long been known that those with severe kidney disease have startling high homocysteine levels and very high rates of cardiovascular disease. A number of published papers have discussed how excess accumulation of homocysteine in the blood of dialysis patients is one reason for the epidemic of cardiovascular mortality observed in these individuals.56-70 In fact, the risk of cardiovascular disease in chronic kidney disease is up to 30 times that of the general population!71

Recently, scientists have begun to publish papers describing cases of excess homocysteine in people with even mild kidney impairment.72-78 What most doctors don’t know is that the kidneys facilitate the removal of homocysteine from the blood.79,80 The kidneys are also involved in enzymatic reactions that transform homocysteine into safer substances in the body.81 Any impairment in kidney function can result in excess homocysteine accumulation, even when one takes large quantities of classic homocysteine-lowering supplements.

As soon as I saw my homocysteine reading of 15.6 despite my very aggressive homocysteine-lowering strategy (with high-dose B vitamins), I knew I had a kidney problem. At first, even nephrologists (kidney specialists) did not think there was anything wrong with my kidneys. I had to inform these doctors of published scientific studies showing that if one takes high doses of homocysteine-lowering nutrients and homocysteine levels remain elevated, this indicates an underlying kidney problem.82-86

In those with kidney disease, homocysteine levels can remain at dangerously high levels despite supplementation with vitamins B6 and B12, folic acid, and TMG.85,87-91 Some people with end-stage kidney disease may not be able to reduce their homocysteine even with doses of folic acid as high as 60,000 mcg per day!92

I Demanded More Sophisticated Kidney Function Tests

The most widely used screening tool for evaluating kidney function is the creatinine blood test. Most standard CBC/chemistry blood profiles include the creatinine test to evaluate kidney function.

According to standard reference ranges, a creatinine blood level of up to 1.5 mg/dL is considered normal. My creatinine level was 1.3, which made my doctors initially question why I thought my kidneys were impaired. I had to remind them that I was taking massive doses of folic acid and vitamins B12 and B6. That meant my homocysteine reading should have been below 8 µmol/L, whereas in fact it was a startlingly high 15.6. The only reason my homocysteine could be this high, I argued, was a failure of my kidneys to remove and neutralize the excess homocysteine.

Fortunately, one of our scientific advisors enlightened me to a new blood test called Cystatin-C that provides a far more accurate measure of kidney function. Cystatin-C readings of up to 0.91 mg/L are considered normal. When I tested my own Cystatin-C level, it turned out to be 0.95 mg/L. I was thus able to document for my kidney specialist that I indeed had early-stage kidney impairment.

What Causes So Many Kidneys to Fail

Most people over the age of 65 suffer from some degree of kidney dysfunction. Symptoms are usually not present, but blood tests show that a lot of otherwise healthy aging individuals have less-than-optimal kidney function. This fact is not widely recognized by mainstream medical doctors.

Kidney disorders are very common in diabetics.93,94 Those suffering from atherosclerosis,95,96 chronic inflammation,97-100 hypertension,101-103 and certain other disorders also often display diminished kidney function.

In my case, I suffered from none of the underlying medical disorders known to cause kidney impairment. I was, however, taking relatively high doses of the anti-inflammatory drug ibuprofen for its cancer-preventive and sleep-inducing effects. Quite a bit of science supports the anti-cancer effects of drugs like ibuprofen.104-108 Regrettably, however, some people’s kidneys cannot handle the side effects of ibuprofen, and I turned out to be one of them. The good news is that within two months of discontinuing the use of ibuprofen, my creatinine level dropped to 1.0 mg/dL (from 1.3) and my Cystatin-C declined to 0.75 mg/L (from 0.95). It appears that ibuprofen was the culprit, though the FDA does not mandate a kidney warning to be included on the label of these drugs. A quick search of the scientific literature, however, reveals potential risk to the kidneys with long-term ibuprofen use.109-112

Based on our review of the published scientific literature, we are now advising members to pay very close attention to their blood indicators of kidney function. In my case, creatinine levels had risen from 0.8 mg/dL in January 2005 to 1.3 in November 2005—a clear indication that my kidneys were heading downhill. Keeping copies of previous blood tests and comparing the magnitude (or velocity) of change in certain biomarkers can help you identify newly emerging problems.

In addition to the standard blood markers of kidney function (creatinine, BUN, BUN/creatinine ratio), excessive homocysteine in someone taking homocysteine-lowering supplements is also an indication of potential kidney impairment.

Life Extension members already take supplements to protect their kidneys, such as coenzyme Q10,136-138 carnitine,139-143 taurine,144-147 curcumin,148-153 and others. We have published an extensive protocol on the prevention and treatment of kidney disease in our Disease Prevention and Treatment reference book.

How to Suppress Stubbornly High Homocysteine

The aging process often inhibits one’s ability to maintain optimal homocysteine levels. For most people, however, the proper use of folic acid, vitamins B6 and B12, and/or TMG will bring homocysteine down to safe ranges.

Several years ago, I learned that I needed exceptionally high doses of homocysteine-lowering nutrients compared to most people. For instance, while 100 mg of vitamin B6 is all most people need, I required around 1000 mg/day of vitamin B6 to suppress my homocysteine adequately.

Based on what we now know, improving kidney function is another way to reduce homocysteine blood concentrations. In my case, as my blood indicators of kidney function improved (in response to halting the use of ibuprofen), my homocysteine levels steadily declined. I was finally able to lower my homocysteine to the optimal range of below 7-8 µmol/L by taking additional TMG and a new prescription drug that I will describe next.

It is important to remember that I have a genetic predisposition to high homocysteine and have historically had to take large amounts of B vitamins to keep my homocysteine level around 8. Most members respond to homocysteine-lowering supplements much better than I do.

Fortunately, there is a form of folic acid for people like me whose bodies do not properly break down homocysteine. I am going to tell you all kinds of positive data about this form of folic acid, but the best news is that most of you do not even need it.

Ibuprofen and Cancer Prevention

Studies show that people who regularly use pain relievers like ibuprofen have sharply reduced risks of esophageal,113,114 brain,115 colon,114,117 prostate,114 and other cancers.114,117 Ibuprofen’s mechanism of action is thought to be its inhibiting effects on the cyclooxygenase-2 (COX-2) enzyme. Cancer cells use COX-2 as biological fuel to propagate, and studies find that suppressing COX-2 may indeed reduce cancer risk.118 Fortunately, safe nutrients like curcumin also suppress COX-2, but do not inflict damage to the liver or kidneys.

Regular users of drugs like ibuprofen have reduced risks of Alzheimer’s disease.119-124 Fortunately, nutrients such as gamma tocopherol,125-127 curcumin,128-130 fish oil,130-132 and resveratrol133-135 may also protect against Alzheimer’s without inducing the toxic side effects associated with ibuprofen.