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Nephrolithiasis: site of the initial solid phase
David A. Bushinsky
University of Rochester School of Medicine and Dentistry and the Nephrology Unit, Strong Memorial Hospital, Rochester, New York, USA
Address correspondence to: David A. Bushinsky, University of Rochester School of Medicine and Dentistry, Nephrology Unit, Strong Memorial Hospital, 601 Elmwood Avenue, Box 675, Rochester, New York 14642, USA. Phone: (585) 275-3660; Fax: (585) 442-9201; E-mail: David_Bushinsky@urmc.rochester.edu.
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Published March 1, 2003 - More info
J Clin Invest. 2003;111(5):602–605. https://doi.org/10.1172/JCI18016.
© 2003 The American Society for Clinical Investigation
Most cases of nephrolithiasis are associated with the relatively common metabolic abnormality of idiopathic hypercalciuria (1). These patients generally absorb an excess amount of dietary calcium leading to increased urine calcium excretion and supersaturation with respect to calcium oxalate and calcium phosphate; they subsequently form stones. Other patients with nephrolithiasis, who have had an intestinal bypass procedure, absorb oxalate in excess leading to increased urine oxalate excretion and supersaturation with respect to calcium oxalate; they also subsequently form stones. In these and other causes of nephrolithiasis, the site of the initial solid phase has long been the subject of debate. Over 65 years ago, A. Randall demonstrated that interstitial crystals located at, or adjacent to, the papillary tip, Randall’s plaques, were common in stone formers (2). He found that these crystals were composed not of calcium oxalate, the most common solid phase found in patients with nephrolithiasis, but of calcium phosphate (3). He believed that the calcium phosphate crystals formed in the papillary interstitium and then eroded into the urinary space, serving as a heterogeneous nucleation surface for calcium oxalate. B. Finlayson later argued that, due to rapid flow of the renal ultrafiltrate through the tubule, there was insufficient time for formation of a lumen-obstructing solid phase (4), which also suggested that an intratubular site of stone formation was unlikely. However, other investigators found that calcium oxalate crystals adhered to cultured tubular cells (5), where they could either be endocytosed or remain on the cell surface, serving as a nidus for growth into larger, clinically significant, calculi.
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Site of the initial solid phase
Where is the site of initial crystallization — the interstitium, the tubular lumen, or perhaps the renal calyx, where supersaturated fluid awaits excretion into the ureter? Knowing the site of initial crystallization would improve understanding of the pathogenesis of stone formation and allow investigators to propose and test more focused hypotheses. This would help them to devise effective therapy aimed at preventing recurrent nephrolithiasis, which afflicts approximately 50% of stone formers within five years of the initial stone (6). Yet until the elegant study by A.P. Evan et al. reported in this issue of the JCI (7), we did not have an answer to this rather elementary question. These investigators performed kidney biopsies on stone-forming patients to determine the anatomical site and composition of the initial solid phase. They sampled areas adjacent to Randall’s plaques in patients undergoing percutaneous nephrolithotomy. In hypercalciuric calcium oxalate stone formers, they found initial calcium phosphate (apatite) crystallization in the basement membrane of the thin limbs of the loop of Henle (Figure 1) with subsequent extension to the vasa recta, then to the interstitial tissue surrounding the terminal collecting ducts, and finally, in the most severe cases, to the papillae. Erosion of this solid phase into the urinary space, which is supersaturated with respect to calcium oxalate, may have promoted heterogeneous nucleation and formation of kidney stones. In patients with hyperoxaluria resulting from intestinal bypass, the initial crystals were again a calcium phosphate complex, but these arose within the tubule lumens of terminal collecting ducts (Figure 2). Contact of these crystals with urine, supersaturated with respect to calcium oxalate, may have promoted heterogeneous nucleation and formation of kidney stones. Nonstone formers, subjected to nephrectomy, had neither plaque nor crystals. Thus there are different sites of initial crystallization depending upon the metabolic abnormality leading to stone formation.
Figure 1Stone formation in patients with idiopathic hypercalciuria. Initial calcium phosphate (apatite) crystallization was found in the basement membrane of the thin limbs of the loop of Henle (A) with subsequent extension to the vasa recta (B), then to the interstitial tissue surrounding the terminal (inner medullary) collecting ducts (C), and finally, in the most severe cases, extension to the papillae (D). Erosion of this solid phase into the urinary space (E), which is supersaturated with respect to calcium oxalate (CaOx), may have promoted heterogeneous nucleation and formation of calcium oxalate kidney stones (F).
Figure 2Stone formation in patients following intestinal bypass. Initial calcium phosphate (apatite) crystallization was found within the tubule lumens of the terminal collecting ducts (A and B). Contact with the urine, supersaturated with respect to calcium oxalate, may have promoted heterogeneous nucleation and formation of calcium oxalate kidney stones (C).
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