Nephrocalcinosis in animal models with and without stones

Abstract

Nephrocalcinosis is the deposition of calcium salts in renal parenchyma and can be intratubular or interstitial. Animal model studies indicate that intratubular nephrocalcinosis is a result of increased urinary supersaturation. Urinary supersaturation with respect to calcium oxalate (CaOx) and calcium phosphate (CaP) are generally achieved at different locations in the renal tubules. As a result experimental induction of hyperoxaluria in animals with CaP deposits does not lead to growth of CaOx over CaP. Interstitial nephrocalcinosis has been seen in mice with lack of crystallization modulators Tamm-Horsfall protein and osteopontin. Sodium phosphate co-transporter or sodiumhydrogen exchanger regulator factor-1 null mice also produced interstitial nephrocalcinosis. Crystals plug the tubules by aggregating and attaching to the luminal cell surface. Structural features of the renal tubules also play a role in crystal retention. The crystals plugging the terminal collecting ducts when exposed to the metastable pelvic urine may promote the formation of stone.

Fig. 1

Scanning electron microscopic analysis of the calcium oxalate crystal deposition in rat kidneys. Rats received EG in water and calcium chloride mixed with chow for 8 weeks, a Renal papilla with surface protrusions (solid white arrows). Longitudinal section through similar renal papillae from the hyperoxaluric rats show collecting ducts filled with CaOx crystals (Fig. 2b). Solid black arrows point to the opening of the ducts of Bellini at the papillary tip. b Renal papilla. Aggregates of CaOx crystals plugged the ducts of Bellini and protruded through at the tip. c Higher magnification of the protruding crystal aggregates, d Close-up of some of the dumbbell shaped CaOx monohydrate crystals. Bar 500 µm, a, b; 50 µm c, d

Fig. 2

CaOx crystal deposition in renal tubules of the hyperoxaluria rats. a Transmission electron microscopic image of a renal tubule from kidney of rat made hyperoxaluric by intraperitoneal administration of sodium oxalate [18]. Luminal surface of the epithelial cell is stained dark. Basement membrane of the epithelial cell (dark arrows) continues in the organic matrix of the CaOx crystal (white arrows). Tubular lumen is filled with cellular degradation products and another CaOx crystal close to the luminal epithelial surface, b Light micrograph of longitudinal section through a large intratubular CaOx crystal deposit at papillary tip of a kidney from EG-fed male rat. Birefringent crystals are lined up against the basement membrane (white arrows). c Scanning electron micrograph of proximal tubule from kidney of a rat made hyperoxaluric by feeding EG

Fig. 3

CaP crystal deposition in rat kidneys. Female weanling rats were given AIN 76 diet for 28 days, a Renal CaP deposits (arrows) present in the corticomedullary junction. b Scanning electron micrograph of a CaP crystal deposit. Bar 20 µm. c Transmission electron microscopic illustration of CaP deposit. Arrows point at the junction between the crystals and the tubular epithelium. Concentric laminations are evident. Surface of the large deposit is covered with needle-shaped crystals

Fig. 4

Crystal deposits in Npt2a−/− mice, a 11-month-old mice show renal interstitial CaP deposit (arrows). Original magnification ×40. b 4-month-old male mice were fed glyoxylate to induce hyperoxaluria leading to deposition of CaOx crystals (white arrows) in the kidneys. Black arrows point to CaP deposits. CaOx and CaP crystals are deposited at different locations in the renal kidneys. Original magnification ×20