Renal Crystal Growth

September 8, 2016

The growth of novel crystals was my main research occupation for many years. I was involved in the growth of magnetic garnets for bubble memory and magneto-optical devices, cerium-doped oxides for use as xray detectors, and β-barium borate for optical frequency doubling. As these crystals were being grown in the laboratory, I was simultaneously growing a crystal inside my body - a kidney stone.

Synthetic Berlinite (AlPO4) crystals grown using a hydrothermal process by some of my colleagues in the 1980s. This is a centimeter ruler with millimeter divisions. (My own photo, via Wikimedia Commons.)

According to the US National Institutes of Health, 8.8% of the population of the United States has had a kidney stone.[1] Mine was a side-effect of a medication I had been taking, and it was sonically pulverized in situ (or, would that be in renibus?) by a process called lithotripsy. I stopped taking that medication, and I've been fine for decades since.

Although it was not analyzed, my kidney stone was likely composed of either calcium oxalate, or calcium phosphate. Calcium oxalate, which grows when the urine is too acidic, is found 80% of the time. Calcium phosphate, which grows when the urine is too basic, is found 10% of the time. Astronauts are prone to kidney stones, since bone loss from inactivity provides the calcium for kidney stone growth.

Calcium balance for Skylab astronauts, indicating calcium loss over time. (Drawn using Inkscape from NASA data in ref. 2.)[2]

When growing crystals from solution, the degree of supersaturation is important. Supersaturation is the condition when there is more material dissolved in a solvent than the solvent can hold; that is, more than it can solvate. Supersaturation is easily obtained in nearly all cases by dissolving the material at high temperature, and then cooling. Most liquids can solvate greater quantities at high temperature than low.

As an example of table salt in water, you can dissolve about 39 grams of NaCl in a 100 grams of water at 100°C, but only 35.7 at 20°C. The growth of rock candy is a good introductory experiment for children, and it works well, since 476 grams of sucrose (C₁₂H₂₂O₁₁) will dissolve in 100 grams of water at 100°C, but only about 200 gram will dissolve at room temperature, so you can grow quite a lot of crystal when cooling between those extremes. As usual, Wikipedia has a convenient table of solubilities.

Rock candy, crystallized on a stick. In this case, a small amount of yellow food coloring was added to the solution to produce the colored crystals. string or yarn can be used in place of a stick. There are several YouTube videos about the process, including this video. (Photo by Douglas Whitaker (cropped), via Wikimedia Commons.)

As in the kidney stone case, inhibiting crystal formation is often as important as promoting crystal growth. Unwanted crystals can clog filters in various industrial processes, and one technique for inhibiting crystal growth is by adding another chemical to the pot. In one series ofexperiments, I found that adding germanium dioxide inhibited the growth rate of YAG (yttrium aluminum garnet).[3] In that case, my solution wasn't water, but molten lead oxide.

For kidney stones, physicians prescribe potassium citrate. Potassium citrate is an alkaline chemical that acts as a growth inhibitor for calcium oxalate formation. Such treatment should prevent calcium oxalate kidney stone formation, but what about dissolution of existing stones? That's the problem that was addressed in research by scientists at the University of Houston (Houston, Texas), the University of Pittsburgh (Pittsburgh, Pennsylvania), and Litholink Corporation (Chicago, Illinois).[4-6]

A kidney stone. One glance at this explains why kidney stones are painful. The structure also indicates why lithotripsy can easily break these apart. (University of Houston image.)

As in my YAG experiment and many others, crystal growth inhibitors are merely that - they inhibit crystal growth, but they don't enhance crystal dissolution. The material studied by the researchers, hydroxycitrate (HCA), actually causes dissolution of calcium oxalate when it's adsorbed onto its crystal surface, and this dissolution occurs even in supersaturated solutions where the hydroxycitrate inhibitor exists in just a tenth percent of the concentration of the calcium oxalate.[4]

Hydroxycitrate is found in tropical fruits, including the Malabar tamarind (garcinia cambogia).[6] It's safe for human consumption, and it's used as a weight-loss supplement, although such use is not clinically proven.[7] It's also chemically similar to citric acid, another chemical shown to be effective as a kidney stone inhibitor.[5]

To uncover the mechanism for this unusual phenomenon, the research team used atomic force microscopy (AFM) to record, in real time, crystal growth and dissolution at near-molecular resolution.[5] AFM showed the facets at the crystal surface shrinking in response to the hydroxycitrate.[5] Their working hypothesis is that the inhibitor molecules impart a local strain to the crystal lattice, and the crystal reacts to relieve this strain by shedding oxalate and calcium ions.[4-5]

Calcium oxalate monohydrate crystal dissolution, as revealed through atomic force microscopy. (University of Houston image.)

In a clinical study, seven people took a hydroxycitrate supplement for three days. It was found that the hydroxycitrate is excreted through urine, which is a requirement if hydroxycitrate is used as a kidney stone treatment.[5] It appears that hydroxycitrate can be used as an alternative treatment to citrate for kidney stones, but a larger clinical study is needed to pinpoint the dosage and long-term safety.[4-5]

Says Jeffrey Rimer, associate professor of Chemical Engineering at the University of Houston and an author of the study, "If it works in vivo, similar to our trials in the laboratory, HCA has the potential to reduce the incidence rate of people with chronic kidney stone disease."[5]

computer modeling indicates that adsorption of hydroxycitrate causes lattice strain that's resolved by crystall dissolution. (University of Houston image.)

References:

1. Kidney Stones in Adults, National Institutes of Health Web Site.
2. Risk of Renal Stone Formation, Report HRP-47060, National Aeronautics and Space Administration, March 2008.
3. D.M. Gualtieri, Liquid Phase Epitaxy of Yttrium Aluminum Garnet: Reduction of Growth Rate by Germanium Oxide, Appl. Phys. Lett., vol. 59, no. 6 (August 5, 1991), pp. 650-652.
4. Jihae Chung, Ignacio Granja, Michael G. Taylor, Giannis Mpourmpakis, John R. Asplin, and Jeffrey D. Rimer, "Molecular modifiers reveal a mechanism of pathological crystal growth inhibition," Nature, Advanced Online Publication, August 8, 2016, doi:10.1038/nature19062.
5. Researchers propose new treatment to prevent kidney stones, University of Houston Press Release, August 8, 2016.
6. Jill Daly, "Crystal research finds possible kidney stone treatment," Pittsburgh Post-Gazette, August 16, 2016.
7. Steven B. Heymsfield, MD; David B. Allison, PhD; Joseph R. Vasselli, PhD; Angelo Pietrobelli, MD; Debra Greenfield, MS, RD; and Christopher Nunez, MEd, "Garcinia cambogia (Hydroxycitric Acid) as a Potential Antiobesity AgentA Randomized Controlled Trial," JAMA, vol. 280, no. 18 (1998), pp. 1596-1600, doi:10.1001/jama.280.18.1596.