Thiamine and benfotiamine improve renal function …

AGE-Reducing Nutrients
Could Save Your Kidneys

As diabetes goes up, the incidence
of kidney failure increases.
By Will Block

T he renaissance sculptor, painter, architect, engineer, and poet Michelangelo (1475–1564 AD) was also an anatomist. His interest in anatomy began with his participation in public dissections, while merely a teenager, upon joining the court of Lorenzo de’ Medici. Influenced by the court’s physician-philosopher members, by the age of 18 he was performing his own dissections.1 Michelangelo’s intense interest in how the body is put together and how it functions resurfaced later in life when he worked on an anatomy book for artists and a book on medical anatomy illustrations (neither came to fruition). It is ironic that he was treated for kidney stones—a frailty that eventually progressed to kidney disease—because his greatest achievements were created out of stone. Despite surviving plague and malaria and living to nearly 90, at the end Michelangelo succumbed to kidney failure.

Separating Light from Darkness

What isn’t widely known was his penchant for using his fascination with anatomy as a backdrop for his painting, especially the scenes from Genesis on the ceiling of the Sistine Chapel in Rome. Altogether, his paintings, covering 12,000 square feet of the chapel ceiling, represent one of the monumental achievements of Renaissance art. It has previously been reported that Michelangelo concealed an image of the brain in the panel the Creation of Adam.2

And now, a recent report by two American neuroscientists has found that the ventral view of the brainstem is cleverly hidden in the depiction of the “Creator’s” neck and chin in Separation of Light From Darkness, which depicts the first act performed by the biblical God in the creation of the universe.3 Michelangelo was virtually conscripted by Pope Julius II to create the Sistine Chapel masterwork, for which he resented the commission and besmirched the Pope for serving a grandeur complex. As suggested by the American neuroscientists, these clandestine underpinnings may have been coded attacks on the Church’s distain for science.

… and Solids from Liquids

According to another paper published in Kidney International, elsewhere in the Sistine ceiling in his painting of the Separation of Land and Water, Michelangelo used a kidney as the symbolic mantle for the Creator. With creative imagination, along with computer-assisted removal of the figures from the painting, the author reveals that Michelangelo employed the right-hand renal* outline in the scene that represents the separation of solids (Land) from liquid (Water).


* From late Latin, renalis, “of or belonging to the kidneys,” from L. ren (pl. renes) “kidneys.”


With the images of the Creator and the cherubims removed, one can see that the tunic is actually in the shape of a bisected right kidney, with the figure of God emerging from the renal pelvis in a turbulent spiral movement. The cherubims were located in renal pyramids and the color of the mantle is that of the normal renal parenchyma, the functional parts of the kidney. Moreover, the lighter silvery lilac shade of the focal point where the Creator’s tunic is pulled into the rosy robe is close to the real-life coloring of the ureter, renal artery, and renal vein as they leave and enter the renal parenchyma. And so on … Per Giorgio Vasari, one of Michelangelo’s biographers, “Every painter paints himself.”

All of this indicates that Michelangelo was familiar with the view of Galen (129–199 AD), still accepted during the Renaissance, regarding the anatomy and function of the kidney. It was Galen, as anatomist, who first correctly observed that blood is cleared by the kidney. Hippocrates, considered the founder of clinical nephrology (the study of kidneys), noted that bubbles appearing on the surface of the urine indicate diseases of the kidneys. Modern science has confirmed that this is a sign of proteinuria, the presence of excess serum proteins in the urine.

Kidney Malfunctions Increase All-Cause Death Risk

If you don’t die from heart disease, cancer, stroke, chronic lower respiratory disease, accidents, diabetes, Alzheimer’s disease, influenza, or pneumonia, you’re still not out of the Grim Reaper’s reach. That’s because there’s always kidney disease to contend with, and its growth pattern in the last few years has been steep. According to CDC data, since 1999, the age-adjusted death rate for kidney disease has increased by 11.5 percent, compared to downward trends for heart attacks and strokes.4 Some 26 million Americans (13 percent of the U.S. adult population) suffer from kidney disease. And things appear to be getting worse. Along with the obesity epidemic which affects one third of all adults, the increased risk for diabetes and high blood pressure, not to mention aging, lead directly to kidney disease—especially for Baby Boomers. And it would appear that this situation is only going to get worse.


If you don’t die from heart disease,
cancer, stroke, chronic lower
respiratory disease, accidents,
diabetes, Alzheimer’s disease, or
influenza and pneumonia … there’s
always kidney disease.


Consider a recent meta-analysis published in The Lancet concluding that two measures of a malfunctioning kidney predict the risk of death from all-causes and from cardiovascular disease.5 These measures are the estimated glomerular filtration rate (GFR)—the rate of filtered fluid flow through the kidney’s glomerular capillaries—and albuminuria, a type of proteinuria, in which the amount of albumin carried out with urination becomes persistent. Albumin (also known as “albumen” when pertaining to egg whites) is a principal protein of plasma, the main function of which is to regulate the colloidal osmotic pressure of blood, thereby ensuring adequate water exchange between plasma and tissue fluid compartments. Consequently, reduced GFR and increased albuminuria collude in all-cause deaths as well as those from heart disease.

Thiamine Reverses Microalbuminuria in Diabetics

High-dose supplements of thiamine (vitamin B1) have been shown to prevent the development of microalbuminuria in experimental diabetes. Microalbuminuria occurs when the kidney leaks small amounts of albumin into the urine, indicating a malfunction in the renal glomerulus. It is a marker of renal damage and a prelude to albuminuria.

In a new study, researchers investigated whether thiamine supplements could hinder microalbuminuria in patients with type 2 diabetes.6 Using 40 type 2 diabetic subjects (21 male, 19 female) with microalbuminuria, the researchers randomized the subjects to two groups of 20, who received either thiamine or placebo. The study was double-blinded and subjects were given 3 100-mg capsules of vitamin B1 or placebo every day for 3 months, with a 2-month follow-up washout period.

Upon measuring urinary albumin excretion (UAE), together with other markers of renal and vascular dysfunction and plasma concentrations of thiamine, it was found that UAE was significantly decreased in those receiving thiamine therapy for 3 months compared to baseline, with no consequential decrease in UAE in those taking placebo. Moreover, UAE continued to decrease in the 2-month washout period, although not significantly. There were no side effects. In summary, high-dose thiamine supplementation was shown to regress UAE in type 2 diabetic patients with microalbuminuria, and thus may prove beneficial for early-stage diabetics and possibly prediabetics.

Thiamine and Benfotiamine Protect Against Protein Damage

A new study reported on the ability of thiamine and benfotiamine to reduce protein damage caused by glycation, oxidation, and nitration. Conducted at the University of Essex in the UK, the study used a rat model of diabetes, and examined the sites of damage and concomitant development of microvascular complications.7 Benfotiamine has been reported to be more bioavailable than thiamine, owing to its lipid-solubility, and while thiamine has antiglycation effects, as a water-soluble form of the vitamin B1 it cannot enter fatty tissues.

Analyzing Glomeruler Filtration and Albuminuria Data

In the meta-analysis of the Lancet study, a number of measurements were examined. Included were urine albumin-to-creatinine ratio (ACR) in 14 studies enrolling a total of 105,872 participants (730,577 person-years), and urine protein measured by dipstick in 7 studies enrolling a total of 1,128,310 participants (4,732,110 person-years). That’s a lot of data.

While the risk for mortality was unrelated to glomerular filtration rates (GFRs) at the higher end (between 75 and 105 mL/minute/1.73 m2), mortality increased at lower GFRs.

Adjusted hazard ratios for all-cause mortality, compared to a GFR of 95 mL/minute/1.73 m2, were 1.18, 1.57 and 3.14 for GFRs of 60, 45, and 15 mL/minute/ 1.73 m2. This means that mortality increased by a factor of 3.14 times when GFRs went from 95 down to 15.

On a logarithmic scale, ACR was linearly associated with the risk for mortality. Adjusted hazard ratios for all-cause mortality vs an ACR of 0.6 mg/mmol were 1.20, 1.63, and 2.22 for ACRs of 1.1, 3.4 and 33.9 mg/mmol. This means that mortality increased by a factor of 2.22 times when ACR went from 0.6 up to 33.9.

Importantly, ACRs and GFRs tended to have multiple effects associated with the risk for all-cause mortality, although there was no evidence for interaction. The results were similar for cardiovascular mortality and in studies with dipstick measurements of urine protein.

In summary, GFRs less than 60 mL/min/1.73 m2 and ACRs equal to or greater than 1.1 mg/mmol (10 mg/g) independently predict mortality risk in the general population. While there were a few limitations owing to differences between the studies corralled, the findings have prompted plans for revisions of global chronic kidney disease guidelines.

From an editorial that accompanied the paper, “[D]ata from [this] meta-analysis confirm beyond doubt that the current thresholds are indicative of increased all-cause and cardiovascular mortality risk.”1

  1. Leoncini G, Viazzi F, Pontremoli R. Overall health assessment: a renal perspective. Lancet 12 June 2010; 375(9731):2053-4.

Lipoic Acid Inhibits Cardiovascular Upshot in Kidney Disease

Endothelial dysfunction due to reduced nitric oxide (NO) availability precedes the development of atherosclerosis. Asymmetric dimethylarginine (ADMA)—an inhibitor of nitric oxide synthase that is made within the body—also contributes to endothelial dysfunction. Moreover, it is also a predictor of the cardiovascular outcome in end-stage renal disease patients on hemodialysis.

In a study conducted at the University of Ulsan College of Medicine, Seoul, Korea, researchers gave alpha-lipoic acid (ALA) to end-stage renal disease patients on hemodialysis.1 ALA is known to be a strong antioxidant, and has been found to increase NO-mediated vasodilation in diabetic patients. The subject of the investigation was to determine whether ALA could decrease the plasma level of ADMA in diabetic liver disease patients on hemodialysis.

Fifty patients undergoing hemodialysis three times per week were randomly split into a treatment group receiving 600 mg/day of ALA for 12 weeks or a control group receiving placebo. Measurements of cholesterol, albumin, C-reactive protein, oxidized LDL, hemoglobin A1c, and ADMA were taken in both groups at baseline and at 12 weeks. While none of these levels changed in the control group, in the treatment group, ADMA levels decreased significantly by 22%.

Recalling that ADMA is an independent risk factor for cardiovascular outcome in end-stage renal disease patients, ALA may have the potential of a beneficial effect in them, partly by decreasing ADMA levels. It could be valuable for maintaining kidney function in healthy individuals.

  1. Chang JW, Lee EK, Kim TH, Min WK, Chun S, Lee KU, Kim SB, Park JS. Effects of alpha-lipoic acid on the plasma levels of asymmetric dimethylarginine in diabetic end-stage renal disease patients on hemodialysis: a pilot study. Am J Nephrol 2007;27(1):70-4.

Diabetes was induced in male rats, which were then given either thiamine or benfotiamine (7 or 70 mg/kg/day) for 24 weeks. Plasma, urine, and tissues samples were collected and analyzed for protein. At the beginning, there was a two- to four-fold increase in fructosyl-lysine and advanced glycation endproducts (AGEs) content of glomerular, retinal, sciatic nerve and plasma protein in diabetic rats. There was also damage to the content of sciatic nerve protein and plasma glycation free adducts* were increased up to twofold in diabetes.


* An adduct (from the Latin adductus, “drawn toward”) is a product created from the direct addition of two or more separate molecules. The result is a single reaction product containing all atoms of all components, with formation of two chemical bonds and a net reduction in bond multiplicity in at least one of the reactants.



Thiamine supplementation was shown
to regress urinary albumin excretion
in type 2 diabetic patients, and thus
may prove beneficial for early-stage
diabetics and possibly prediabetics.


However, increases in AGEs were reversed by thiamine and benfotiamine therapy, while increases in fructosyl-lysine were not observed. Also, plasma glycation free adducts damage was reversed by thiamine. Urinary excretion of glycation, oxidation and nitration free adducts was increased by seven- to 27-fold in diabetes. These increases were reversed by thiamine and benfotiamine therapy.

AGEs have been found to accumulate at sites of microvascular complication development where they cause markedly increased urinary excretion rates in experimental diabetes. Thiamine and benfotiamine supplementation prevented tissue accumulation and increased urinary excretion of protein glycation, oxidation and nitration adducts. It can be surmised that these nutrients may help reverse early-stage diabetic nephropathy.


Thiamine and benfotiamine
may help reverse early-stage
diabetic nephropathy.


In an earlier study, high-dose thiamine and benfotiamine had been shown to inhibit the development of incipient nephropathy.8 Hyperglycemia is often the trigger for a biochemical dysfunction that leads to the development of diabetic nephropathy—a common complication of diabetes associated with a high risk of cardiovascular disease and mortality. This is because the high glucose concentrations that characterize hyperglycemia cause an increase in triosephosphates, three-carbon phosphorylated sugars that occur as intermediates in several central metabolic pathways. Triosephosphates are involved in the synthesis and breakdown of glucose.


We can help improve functionality by
painting our kidneys “pink” with
anti-AGE supplements such as
thiamine, benfotiamine, lipoic acid,
and carnosine.


In this study, thiamine and benfotiamine averted the accumulation of triosephosphates in experimental diabetes, thereby enhancing glomerular filtration function in the kidney and thus strongly inhibiting the development of microalbuminuria. This was associated with decreased protein glycation and oxidative stress, pathways of biochemical dysfunction in hyperglycemia. At the same time, benfotiamine inhibited diabetes-induced hyperfiltration, without change in elevated plasma glucose concentration and glycated hemoglobin. High-dose thiamine and benfotiamine therapy was found helpful for the prevention of clinical diabetic nephropathy.

Carnosine Restrains the Development of Kidney Injury

Metabolic syndrome is a risk factor that increases the risk for development of renal and vascular complications. In a new study, the effects of the administration of carnosine (L-CAR) and of its enantiomer (D-CAR, a mirror-image molecule) on hyperlipidemia, hypertension, advanced glycation end products (AGEs), advanced lipoxidation end products (ALEs) formation, and development of nephropathy were examined. Carnosine is a dipeptide comprised of the amino acids beta-alanine and histidine, which is highly concentrated in muscle and brain tissues. Using non-diabetic, Zucker obese rats, the two test materials, L-CAR or D-CAR, were given in drinking water (30 mg/kg of body weight) for 24 weeks.

At the end of the treatment, plasma levels of triglycerides, total cholesterol, glucose, insulin, creatinine, and urinary levels of total protein, albumin, creatinine were measured in plasma, urine and renal tissue, along with several indices of oxidative/carbonyl stress.

The researchers found that both L- and D-CAR greatly reduced obese-related diseases in obese Zucker rats, by significantly holding back the development of dyslipidemia, hypertension and renal injury, as demonstrated by both urinary parameters and electron microscopy examinations of renal tissue.

The pro-histaminic effect of L-CAR was excluded as an explanation because D-CAR is not a precursor of histidine. Rather, the scientists proposed that some of the biological effects can be mediated by a direct carbonyl quenching mechanism.

  1. Aldini G, Orioli M, et al. The carbonyl scavenger carnosine ameliorates dyslipidemia and renal function in zucker obese rats. J Cell Mol Med 2010 Jun 1. [Epub ahead of print]

Painting One’s Kidneys Healthy

Returning to Michelangelo as an artist who is one who paints himself, it has been said that we are all greater artists than we think.9 Ironically, this may extend to areas less thought of as art, such as the way that we deal with our health. “In the pink” is an expression which refers to the best possible health, but it might just as well apply to kidneys, the state of which, after all, may have far more to do with overall health than has been previously recognized. And how can we help improve kidney functionality? By painting our kidneys “pink” with anti-AGE supplements such as thiamine, benfotiamine, lipoic acid, and carnosine among other nutrients (see “Arginine Keeps Kidneys in the Pink” in the May, 2000, issue of Life Enhancement.)

References

  1. Eknoyan G. Michelangelo: art, anatomy, and the kidney. Kidney Int 2000 Mar;57(3):1190-201.
  2. Meshberger FL. An interpretation of Michelangelo’s Creation of Adam based on neuroanatomy. JAMA 1990 Oct 10;264(14):1837-41.
  3. Suk I, Tamargo RJ. Concealed neuroanatomy in Michelangelo’s Separation of Light From Darkness in the Sistine Chapel. Neurosurgery 2010 May;66(5):851-61; discussion 860-1.
  4. Heron M, Hoyert DL, Murphy SL, Xu J, Kochanek KD, Tejada-Vera B. Deaths: final data for 2006. Natl Vital Stat Rep 2009 Apr 17;57(14):1-134.
  5. Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, Coresh J, Gansevoort RT. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010 Jun 12;375(9731):2073-81.
  6. Rabbani N, Alam SS, Riaz S, Larkin JR, Akhtar MW, Shafi T, Thornalley PJ. High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a randomised, double-blind placebo-controlled pilot study. Diabetologia 2009 Feb;52(2):208-12.
  7. Karachalias N, Babaei-Jadidi R, Rabbani N, Thornalley PJ. Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes. Diabetologia 2010 Jul;53(7):1506-16.
  8. Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes 2003 Aug;52(8):2110-20.
  9. Nietzsche F. Beyond Good and Evil: Prelude to a Philosophy of the Future. Zimmern H, trans. New York, NY: MacMillan, 1907.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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