Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Dec 1;305(11):F1574-84.
doi: 10.1152/ajprenal.00382.2013. Epub 2013 Oct 2.

A Test of the Hypothesis That Oxalate Secretion Produces Proximal Tubule Crystallization in Primary Hyperoxaluria Type I

Affiliations
Free PMC article

A Test of the Hypothesis That Oxalate Secretion Produces Proximal Tubule Crystallization in Primary Hyperoxaluria Type I

Elaine M Worcester et al. Am J Physiol Renal Physiol. .
Free PMC article

Abstract

The sequence of events by which primary hyperoxaluria type 1 (PH1) causes renal failure is unclear. We hypothesize that proximal tubule (PT) is vulnerable because oxalate secretion raises calcium oxalate (CaOx) supersaturation (SS) there, leading to crystal formation and cellular injury. We studied cortical and papillary biopsies from two PH1 patients with preserved renal function, and seven native kidneys removed from four patients at the time of transplant, after short-term (2) or longer term (2) dialysis. In these patients, and another five PH1 patients without renal failure, we calculated oxalate secretion, and estimated PT CaOx SS. Plasma oxalate was elevated in all PH1 patients and inverse to creatinine clearance. Renal secretion of oxalate was present in all PH1 but rare in controls. PT CaOx SS was >1 in all nonpyridoxine-responsive PH1 before transplant and most marked in patients who developed end stage renal disease (ESRD). PT from PH1 with preserved renal function had birefringent crystals, confirming the presence of CaOx SS, but had no evidence of cortical inflammation or scarring by histopathology or hyaluronan staining. PH1 with short ESRD showed CaOx deposition and hyaluronan staining particularly at the corticomedullary junction in distal PT while cortical collecting ducts were spared. Longer ESRD showed widespread cortical CaOx, and in both groups papillary tissue had marked intratubular CaOx deposits and fibrosis. CaOx SS in PT causes CaOx crystal formation, and CaOx deposition in distal PT appears to be associated with ESRD. Minimizing PT CaOx SS may be important for preserving renal function in PH1.

Keywords: calcium oxalate; primary hyperoxaluria; proximal tubule; renal histopathology.

Figures

Fig. 1.
Fig. 1.
Oxalate physiology and tubule calcium oxalate supersaturation. Plasma oxalate rises progressively with falling creatinine clearance (top left). Urine oxalate excretion rises with oxalate filtered load; a majority of points from primary hyperoxaluria type 1 (PH1) cases lie above the diagonal line of identity indicating that oxalate secretion is present (top right). Absolute oxalate secretion (bottom left) is minimal in ordinary stone formers (grey circles), but present to a varying extent in the PH1 patients. Estimated maximal proximal tubule CAOx supersaturation (see methods) rises with urine oxalate excretion (bottom right) and exceeds 1, the solubility limit, in a majority of PH1 patients. Symbols: black circles, patients 1, 2, 4, and 5 before transplant; black triangles, patients 3, 6, 7, and 11; grey triangles, patients 8, 9, and 10; grey diamonds, PH1 patients 1, 2, 4, and 5 posttransplant; grey circles, idiopathic calcium stone formers and normals.
Fig. 2.
Fig. 2.
Histopathologic images of cortical biopsies from percutaneous nephrolithotomy (PNL) and end stage renal disease (ESRD) PH1 patients. Yasue-stained cortical biopsy sections from PNL patients 7 (creatinine clearance 123 ± 16; A) and 6 (creatinine clearance 74 ± 6) (not shown) revealed normal glomerular (arrowhead) and proximal tubule (arrows) morphology and no mineral deposits. Only minimal interstitial fibrosis was detected by Masson trichrome stain (A, inset) in the cortical biopsies. However, occasional small birefringent crystals (B, white arrows) were noted at the brush border of otherwise normal appearing proximal tubular cells of both PNL patients. No hyaluronan stained proximal tubular cells (arrows) or glomeruli (arrowheads) were seen in the cortical biopsies of patients 6 (C) and 7 (not shown). Low magnification, light microscopy (D) shows widely scattered mineral deposition concentrated within the lumens of proximal tubular segments and the interstitium at the corticomedullary junction (between arrowheads, dark black-brown material) of ESRD patient 1. This crystalline pattern of the ESRD patient is in stark contrast to the lack of large cortical deposits in the PNL PH1 patients (A). E: Yasue-positive deposits in the lumen of the S3 segment of the proximal tubule shown here within the outer stripe of the outer medulla. A nearby outer medullary collecting duct is marked by a white arrowhead. Hyaluronan staining of cortical tissue from patient 1 (F) shows intraluminal deposits (arrow) along with the apical cell surface of the adjacent proximal tubular cells positive for hyaluronan as well as positive staining of numerous nearby tubular segments (arrowheads), primarily proximal tubules, that do not possess intraluminal deposits. Original magnification: ×100 (A and E); ×200 (B); ×50 (C); ×75 (D); ×125 (F).
Fig. 3.
Fig. 3.
Histopathologic changes of papillary biopsies from PNL PH1 patients. Yasue (A and C, arrows) and microcomputed tomography (μCT) images (A, bottom right inset) of papillary biopsies of both patients 6 (creatinine clearance 74 ± 6) and 7 (creatinine clearance 123 ± 16) detected varying sized intraluminal deposits in a few inner medullary collecting ducts (IMCD). All deposits are birefringent (A, top left inset) when viewed by polarizing optics. Tissue sections stained with Masson trichrome to mark sites of fibrosis a greenish-blue revealed extensive interstitial fibrosis at sites adjacent to and away from (B, arrowheads) intraluminal deposits. Extensive interstitial fibrosis is also seen the Yasue-stained sections (A and C) at (arrows) and away from sites of deposits (arrowheads). Prominent hyaluronan staining was noted in biopsies from the papillary tip from both patients 6 and 7 (D, patient 6). Two large intraluminal deposits (marked by arrows) show hyaluronan staining of the crystalline material as well as adjacent lining cells. A number of nearby IMCD segments with no intraluminal deposits also show hyaluronan staining of their apical cell surface (arrowheads). This staining pattern is in stark contrast to the lack of hyaluronan staining in the outer cortex of patients 6 and 7. Original magnification: ×75 (A); ×100 (B and D); ×200 (C).
Fig. 4.
Fig. 4.
Histopathologic changes in cortical and papillary biopsies from ESRD PH1 patients. A: μCT image of a kidney from patient 1 that shows the pattern of crystalline deposits from the renal capsule to the papillary tip. While a few mineral deposits are present in the outer cortex (also see Fig. 2D), the majority of crystals are concentrated at the corticomedullary junction (between arrowheads) with extensive mineral deposition in the papillary tips (double white arrows) and stones in minor calyces (single white arrows). Light microscopy (B) shows large dilated IMCD filled with mineral (double arrows) and when examined by polarizing optics (top left inset) contains only birefringent material. Stone material (single arrow) was noted in the minor calyx. This pattern of mineral deposition is identical to that seen by μCT (Fig. 4A). The same pattern of hyaluronan staining seen in the cortex of patient 1 (Fig. 2F) is noted in the inner medulla (C), hyaluronan positive intraluminal deposits (arrow) as well as staining of nearby nephron segments, in this case IMCDs (arrowheads) that do not possess intraluminal deposits. High magnification light microscopic images of the cortex shows crystalline deposits in the lumens (arrows) and cells (arrowheads) of primarily proximal tubules (D) as well as the interstitium (double arrows). Sites of exotubulosis (arrowheads) are noted in some proximal tubules. Extensive interstitial fibrosis encapsulates many cortical nephron segments (D). Original magnification: ×5 (A); ×50 (B); ×100 (C); ×125 (D).
Fig. 5.
Fig. 5.
Intraoperative and ex vivo endoscopic images of papillae from PNL (cases 3, 6, and 7) and ESRD (cases 1 and 2) PH1 patients. AD: intraoperative endoscopic images collected at the time of mapping and stone removal from patients 3 (A), 6 (B), and 7 (C and D). Papillary morphology varied from normal (B and C) to flattened (A and D). A few dilated ducts of Bellini (A and C, *) with (C, double arrows) and without (A, *) protruding plugs were seen scattered between sites of yellow plaque (arrowheads). The same kidney of patient 7 seen in C was studied a second time 2 yr later and one papilla now showed an eroded tip and a protruding plug with a stone overgrowth not seen previously (D, arrow). With the use of ex vivo ureteroscopy, nonadherent stones (E, arrow) were noted lying on a papillary tip in patient 1, an adult with PH1 and ESRD. Removal of one of these stones revealed a dilated opening to a duct of Bellini (E, *). Small sites of yellow plaque (arrowheads) are noted nearby. F: ex vivo ureteroscopy image from patient 2, an infant with PH1 and ESRD. A dilated opening to a duct of Bellini (*) and sites of yellow plaque (arrowheads) appear similar to that seen in patient 1 in E, however, no stones are found.

Similar articles

See all similar articles

Cited by 16 articles

See all "Cited by" articles

Publication types

Supplementary concepts

LinkOut - more resources

Feedback