While many urologists think of Randall plaques as precursors to stone disease, the events leading up to the formation of Randall plaques appear to be the real source of stones, according to Marshall L. Stoller, MD, professor, Vice Chair of Urology and Medical Director of the Urinary Stone Center at the University of California – San Francisco.
Dr. Stoller reviewed the latest research in stone formation during Monday morning’s Plenary I program. The precise mechanisms are not yet clear, he said, but combining perspectives from urology, chemistry, flow dynamics and other disciplines has created a better picture of the events that precipitate stone formation.
Randall plaques are small, subepithelial calcifications of the renal papilla. These plaques were first described by Alexander Randall in 1940. Dr. Randall examined 1,154 kidney pairs and identified small, calcified lesions in about 20 percent of renal papilla. Some of the plaques were associated with primary renal stones.
“Randall used his eyes 70 years ago and we are not doing much better with our current instrumentation,” Dr. Stoller said. “For the last 30 years, we have had no new therapies for stone disease.”
Stone formation is part biology and part mechanical physics. It’s easy to conceive of renal papilla as a cylindrical, Dr. Stoller said, but they actually take a paraboloid form as they narrow at the tip. This architectural limitation forces the tubules and microvasculature that make up the structure of each papilla to make a sharp turn within the structure. This abrupt change in direction changes the flow dynamics within the papilla. One consequence is lower oxygenation at the tip of the papilla compared to the base.
The change in direction also transforms the smooth, laminar flow of the tubules to a turbulent flow. This abrupt change in flow encourages the formation of precipitates, which deposit in concentric layers as Randall plaques.
“The physical form of the papilla puts us all at risk for stone disease,” Dr. Stoller said. “That’s why it’s so important to understand what happens upstream of Randall plaque formation. That understanding will help us design more effective treatments to interrupt stone formation at an earlier stage.”
Renal calculi are composed of concentric rings of mineralization, a pattern that is also seen in seashells, tree trunks and many other natural structures. Improved imaging techniques have revealed the same concentric formation in Randall plaques. This fractal concept, a physical architecture that is repeated from the nano to micro to macro levels, is one of the keys to understanding the creation and growth of stones, Dr. Stoller explained.
Stone formation is not unique to humans, he added. Fruit flies develop urinary stones, as do cats and other organisms. So do shower heads.
Any disturbance in flow allows for the formation of mineral concretions, the same kind of concretions seen around the edges of shower heads. Over time, the individual tubules within the shower head begin to clog from the edges toward the center. Similar concretions build inside the tubules within the papilla, slowly blocking flow from the edges.
“The lumen remains patent in the center of the papilla, less so at the edges,” Dr. Stoller said. “There is a differential flow at the center versus the edges. As minerals occlude papillary tubules, flow changes and mineralization increases.”
This slow process of mineralization and peripheral blockage begins at an early age, probably in the 20s and 30s, Dr. Stoller said, and increases with age. These interstitial concretions, the Randall plaques, do not cause pain because the duct is not totally occluded. The progression from plaque to stone is what occludes the duct and leads to symptoms.
“We can leverage our better understanding of these Randall plaques to develop better therapies for stone disease,” Dr. Stoller said.