Stone Morphology Distinguishes Two Pathways of Idiopathic Calcium Oxalate Stone Pathogenesis

Abstract

Introduction: About 1 in 11 Americans will experience a kidney stone, but underlying causes remain obscure. The objective of the present study was to separate idiopathic calcium oxalate stone formers by whether or not they showed positive evidence of forming a stone on Randall's plaque (RP). Materials and Methods: In patients undergoing either percutaneous or ureteroscopic procedures for kidney stone removal, all stone material was extracted and analyzed using micro-CT imaging to identify those attached to RP. Twenty-four-hour urine samples were collected weeks after the stone removal procedure and patients were off of medications that would affect urine composition. The endoscopic video was analyzed for papillary pathology (RP, pitting, plugging, dilated ducts, and loss of papillary shape) by an observer blinded to the data on stone type. The percent papillary area occupied by RP and ductal plugging was quantified using image analysis software. Results: Patients having even one stone on RP (N = 36) did not differ from non-RP patients (N = 37) in age, sex, BMI, or other clinical characteristics. Compared with the non-RP group, RP stone formers had more numerous, but smaller, stones, more abundant papillary RP formation, and fewer ductal plugs, both by quantitative measurement of surface area (on average, three times more plaque area, but only 41% as much plug area as in non-RP patients) and by semiquantitative visual grading. Serum and blood values did not differ between RP and non-RP stone formers by any measure. Conclusions: Growth of many small stones on plaque seems the pathogenetic scheme for the RP stone-forming phenotype, whereas the non-RP phenotype stone pathogenesis pathway is less obvious. Higher papillary plugging in non-RP patients suggests that plugs play a role in stone formation and that these patients have a greater degree of papillary damage. Underlying mechanisms that create these distinctive phenotypes are presently unknown.

Keywords: calcium oxalate; infrared spectroscopy; kidney stones; micro CT; nephrolithiasis.

FIG. 1.

Example of stone work-up prepared for each patient. The report for Patient 1, who had 12 stones, none on RP, but one on a ductal plug. The stone report shows photomicrographs of each stone on mm paper, along with a micro-CT image slice, and sometimes a 3D surface rendering of the micro-CT image stack. Verification of mineral composition by infrared spectroscopy was routinely done on at least one stone in each kidney. This report, along with those for each of the 73 patients, is part of the Supplementary Data, StoneReports.pdf. RP = Randall's plaque.

FIG. 2.

Examples of stone classification. (A) Small stone growing on RP. Note overgrowth of calcium oxalate (in this case, the monohydrate, COM). The apatite of RP is typically less dense (here, darker gray) farther into the tissue. Luminal spaces (arrowheads) here are 20 to 30 μm in diameter, consistent with the sizes of thin limbs and capillaries, confirming identification of calcified papillary tissue that is the definition of RP. This stone was from patient 13, whose 17 stones were all classified as being on RP. (B) Thick plate of RP with a tiny region of COM overgrowth. The large spaces within RP here have diameters consistent with collecting ducts (CD). From patient 37, whose 13 stones included 7 as naked RP or with COM on RP. (C) Stone classified as RP but meeting only the minimal criteria. Apparent RP is not within a concavity of the stone and shows no luminal spaces but does show diminution of apatite content (darker gray) away from the stone surface. From patient 28, whose 32 stones included 2 on RP. (D) COM stone with concavity, but no sign of RP. From patient 1, whose 12 stones included none on RP, but one on a plug (F). (E) Stone completely covered with COD crystals and no apparent attachment site. From patient 8, none of whose five stones were on RP. (F) Stone from patient 1 that grew on a ductal plug. This stone was noted by the surgeon as coming out of a dilated collecting duct. The plug is composed of apatite, with COM overgrowth. COD = calcium oxalate dihydrate.

FIG. 3.

Quantitative measures of surface area of RP and ductal plugging as percent of papillary area. Points show average values for individual patients. Median values for RP were 3.2% [2.3%, 4.6%] for RP and 1.0% [0.2%, 2.2%] for non-RP and for mineral plugging were 0.0% [0.0%, 0.2%] for RP and 0.4% [0.1%, 1.2%] for non-RP. RP = calcium oxalate stone formers with at least one stone found on RP; non-RP = calcium oxalate stone formers with no stones on RP.

FIG. 4.

Visual scoring of papillae using the semiquantitative papillary grading scale. Median scores for RP were 1.3 [1.0, 1.7] for RP and 0.5 [0.1, 0.9] for non-RP; plugging/dilated ducts, 0.1 [0, 0.4] for RP and 0.9 [0.3, 1.5] for non-RP; pitting, 1.0 [0.7, 1.6] for RP and 0.3 [0.1, 0.6] for non-RP; and loss of contour, 0 [0, 0.2] for RP and 0.3 [0, 0.7] for non-RP. Symbols as in Figure 3, with gray fill indicating RP patients with <50% of their stones on RP.

FIG. 5.

Counts of papillae with at least one dilated duct normalized to total number of papillae graded for each patient. Median values were 0% [0%, 0%] papillae with dilated ducts for RP and 25% [1.6%, 50%] for non-RP patients. Symbols as in Figures 3 and 4, with gray fill indicating RP patients with <50% of their stones on RP.

FIG. 6.

Coverage of papilla with RP shows more of a correlation with urine calcium in RP stone formers than in non-RP patients. Symbols as in Figures 3 and 4, with gray fill indicating RP patients with <50% of their stones on RP.