Stay in the loop: new insights about Randall’s plaques and stone disease

The prevalence of kidney stone formation is expected to rise and cause an extensive economic burden worldwide (4, 8). Unfortunately, there are no treatments available to cure or prevent stone recurrence. Individuals with stones have a high recurrence rate and increased risk for secondary metabolic diseases (6). Genetics and lifestyle factors, such as diet and low water intake, have all been associated with the development of stones within the urinary space. The etiology of kidney stone disease is complex and not fully characterized. Thus, understanding how stones form, where they form, and how they recur is critical to treat and manage patients suffering from kidney stone disease.

It has been established that supersaturation of urine with insoluble salts such as calcium, oxalate, and phosphate can promote crystallization and stone growth (6). In particular, accumulation of calcium phosphate (CaP) crystals can form deposits in the interstitial tissue to form Randall’s plaque, which serves as a nidus for calcium oxalate (CaOx) kidney stones, the most prevalent form of stones (5). Randall’s plaques were initially described as hard cream-colored deposits composed of calcium carbonate and phosphate in renal papillae by Dr. Alexander Randall (1). Since his discovery, modern techniques have been used to determine that Randall’s plaques are found commonly in idiopathic CaOx stone formers and associate with the basement membrane of the loop of Henle (3). The loop of Henle is composed of both ascending and descending limbs and functions to recover water and solutes from urine using counter current mechanisms. Urine is highly concentrated in the ascending limb as this region is water impermeable, whereas the descending limb is extremely water permeable. Two key factors identified to contribute to Randall’s plaque formation are urinary volume and urinary composition. Elevated urinary calcium stimulates CaP crystal formation which can aggregate to form plugs and plaques within the renal space or be excreted in the urine (6). Plaques that remain in the renal space can infiltrate the interstitium and penetrate the papillary epithelium before being exposed to urinary proteins, macromolecules, and CaOx crystals. Over time, continuous exposure to this chemical milieu supports crystal attachment and promotes stone growth and retention.

The article in this issue of American Journal of Physiology-Renal Physiology, entitled “Randall's plaque in stone formers originates in ascending thin limbs” by Evan and colleagues (2) specifically identifies where Randall’s plaques originate in the nephron and enhances our understanding about stone formation in humans. The authors examined renal papillae biopsies from five idiopathic CaOx stone formers to investigate the precise location of Randall’s plaque using clever approaches. Based on the “vas washdown” theory, they hypothesized that plaque formation begins in the ascending thin limb of the loop of Henle since calcium super-saturation occurs near the thin limbs. They tested whether plaques formed primarily on the basolateral or apical side of the ascending versus descending thin loop of Henle using immunohistochemistry. They evaluated the presence of plaques using Yasue staining and assessed loop of Henle segment-specific proteins, Aquaporin 1 (AQP-1) and chloride voltage-gated channel Ka (ClC-Ka). Both AQP-1 and ClC-Ka have been identified to play significant physiological roles in the descending and ascending thin limbs, respectively (7). Specifically, AQP-1 reabsorbs water and CLC-Ka reabsorbs sodium chloride from the renal tubular fluid. Thus, the selection of these two proteins to assess where plaque formation occurs precisely within the loop of Henle was fitting. The authors found that plaque remarkably colocalized with ClC-Ka and not AQP-1 in several serial sections from patients’ kidneys. They also determined Randall’s plaque originated in the basement membrane of the thin segment where osmotic water permeability is nonexistent. This was not surprising as fluids in this region of the nephron are highly concentrated and conducive for plaque pathogenesis.

It is important to dissect the physiological mechanisms and exact locations where kidney stones originate, grow, and form within the nephron in order to identify sound strategies to minimize crystal and stone growth in patients. The current work by Evan and colleagues, for the first time, shows Randall’s plaques originating in the ascending thin limb of Henle in idiopathic CaOx stone formers. This work is exciting because it validates previous research reports and extends our current knowledge about where Randall’s plaques form in humans. A few important questions arise from this research that remain to be examined: What is the chemical composition of this region of the nephron that promotes Randall’s plaques? Is this chemical makeup different from patients who do not form Randall’s plaques? What proteins are associated with plaques? Do Randall’s plaques develop in the ascending thin limbs in other types of stone formers? Can targeted drugs to the ascending thin limb minimize crystallization to prevent plaque formation? Can this information be used to manage treatment modalities for patients? Taken together, the findings from Evan and colleagues have the potential to guide therapeutic treatment options (i.e., medications, dietary recommendations, etc.) in patients and offer new insight about the development of Randall’s plaques. We look forward to staying in the loop about future studies that will determine the significance of these observations in patients with Randall’s plaques and stone disease.

GRANTS

This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK106284. This content is solely the responsibility of the author and does not represent views of the NIH.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the author.

AUTHOR CONTRIBUTIONS

T.M. drafted manuscript; edited and revised manuscript; approved final version of manuscript.