Wednesday, August 10, 2016

Hydroxycitrate is Reported to Prevent Kidney Stones Formation in Humans

Hydroxycitric acid (also HCA; 1,2-dihydroxypropane-1,2,3-tricarboxylic acid) is a derivative of citric acid that is found in a variety of tropical plants including Garcinia cambogia and Hibiscus subdariffa. The tropical plants Garcinia cambogia and Hibiscus subdariffa produce hydroxycitric acid, of which the absolute configurations are (2S,3S) and (2S,3R), respectively. (2S,3S)-HCA is an inhibitor of ATP-citrate lyase, which is involved in fatty acid synthesis. (2S,3R)- HCA inhibits pancreatic α-amylase and intestinal α-glucosidase, leading to a reduction in carbohydrate metabolism.
Garcinia species, including G. cambogia, G. indica, and G. atroviridis, grow prolifically on the Indian subcontinent and in western Sri Lanka. HCA is also enriched in the calyxes of Hibiscus subdariffa and H. rosa-sinensis, which are cultivated in several tropical and semitropical countries.

Natural Source of Hydroxycitric Acid

A kidney stone (also renal calculus or nephrolith) is a solid piece of material which is formed in the kidneys from minerals in urine. Kidney stones typically leave the body in the urine stream, and a small stone (less than 3 millimeters) may pass without causing symptoms.
If stones grow to sufficient size (usually at least 3 millimeters) they can cause blockage of the ureter. This leads to pain, most commonly beginning in the flank or lower back and often radiating to the groin.
Though the exact reason for stone formation is not very clear but researchers point to a combination of genetics and environmental factors. Drinking less amount of fluids (hydrating ones) is pointed as one the main cause, followed by overweight, certain foods (usually protein rich ones), some medications (actually calcium supplements).
Urinary stones are typically classified by their location in the kidney (nephrolithiasis), ureter (ureterolithiasis), or bladder (cystolithiasis), or by their chemical composition (calcium-containing, struvite, uric acid, or other compounds).
Pain due to stones is often known as renal colic and typically comes in waves lasting 20 to 60 minutes. Other associated symptoms include: nausea, vomiting, fever, blood in the urine, pus in the urine, and painful urination. Blockage of the ureter can cause decreased kidney function and dilation of the kidney.

The treatment of kidney stones is one of the unmet problem of medical history and nothing substantial has come out in last 30 years. The most common treatment includes intake of lots of water, so that stone passes out in urine. Pain is managed by using medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids. NSAIDs are best studied as opioids induce constipation; which is equally problematic. More severe cases such as big stones may require procedures. For example, some stones can be shattered into smaller fragments using extracorporeal shock wave lithotripsy. Others require cystoscopic procedures. Well, drinking beer too is found to be effective in removing stones from human body (ask any Indian and this is the favourite treatment regime).

Citric Acid and Hydroxy-Citric Acid

Present Day:
The scientific literature suggests that the most common type of kidney stones worldwide contains calcium. For example, calcium-containing stones represent about 80% of all cases; these typically contain calcium oxalate either alone or in combination with calcium phosphate in the form of apatite or brushite.
The research work from University of Houston offers the first evidence that the compound hydroxycitrate (HCA) is an effective inhibitor of calcium oxalate crystal growth that, under certain conditions, is actually able to dissolve these crystals. The findings are the result of a combination of experimental studies, computational studies and human studies.

Concept: Patients who are at risk of developing stones to drink lots of water and avoid foods rich in oxalate, such as ladyfinger, spinach and almonds, etc. They often recommend taking citrate (CA), in the form of potassium citrate, a supplement that can slow crystal growth, but some people are unable to tolerate the side effects. This situation has been the same for last 30 years.
As HCA is chemically similar to CA, it was decided to study the effects of both these compounds on the kidney stones. Moreover, as HCA is available as a dietary supplement, it was considered safe for human consumption.
Experiments: The team of researchers then used atomic force microscopy, (AFM), to study interactions between the crystals, CA and HCA under realistic growth conditions. The technique allows recording of crystal growth in real time with near-molecular resolution.
Observations: AFM images recorded the crystal actually shrinking when exposed to specific concentrations of HCA. As inhibitors are reported to stop the crystal growth but never shrink it, this initial observation was seen an anomaly. But, subsequent batches produced the same “shrinking” results, aroused the curiosity.
Using density functional theory (DFT) method, researchers discovered HCA formed a stronger bond with crystal surfaces, inducing a strain that is seemingly relieved by the release of calcium and oxalate, leading to crystal dissolution.
This explanation is new in line of thinking, different form the classical theory of dissolution and crystallization. This phenomenon of dissolving crystal occurs even in supersaturated solutions where inhibitor concentration is three orders of magnitude less than that of the solute. The results of bulk crystallization, in situ atomic force microscopy, and density functional theory studies are qualitatively consistent with a hypothesis that inhibitor–crystal interactions impart localized strain to the crystal lattice and that oxalate and calcium ions are released into solution to alleviate this strain.
HCA was also tested in human subjects, as seven people took the supplement for three days, allowing researchers to determine that HCA is excreted through urine, a requirement for the supplement to work as a treatment. In vitro assays using human urine reveal that the molecular modifier hydroxycitrate is as effective an inhibitor of nucleation of calcium oxalate monohydrate nucleation as is citrate.

Results: The head-to-head studies of CA and HCA determined that while both compounds inhibit the growth of calcium oxalate crystals. HCA was more potent and displayed unique qualities that are advantageous for the development of new therapies.

Article Citation: Rimer, J. D.; et. al. Molecular modifiers reveal a mechanism of pathological crystal growth inhibition. Nature 2016, 1-5: doi:10.1038/nature19062