Nephrocalcinosis and hyperlipidemia in rats fed a cholesterol- and fat-rich diet: association with hyperoxaluria, altered kidney and bone minerals, and renal tissue phospholipid-calcium interaction.
To determine whether an "atherogenic" diet (excess of cholesterol and neutral fat) induces pathological calcification in various organs, including the kidney, and abnormal oxalate metabolism, 24 male Sprague-Dawley rats were fed either normal lab chow (controls, n = 12) or the cholesterol- and fat-rich experimental diet (CH-F, n = 12) for 111 +/- 3 days. CH-F rats developed dyslipidemia [high blood levels of triglycerides, total, low-density lipoprotein (LDL)-, very low-density lipoprotein (VLDL)-, high-density lipoprotein (HDL)-bound cholesterol, total phospholipids], elevated serum total alkaline phosphatase and lactate dehydrogenase (LDH) levels, in the absence of changes in overall renal function, extracellular mineral homeostasis [serum protein-corrected total calcium, magnesium, parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (1,25(OH)2D)], plasma glycolate and oxalate levels. There was a redistribution of bone calcium and enhanced exchange of this within the extraosseous space, which was accompanied by significant bone calcium loss, but normal bone histomorphometry. Liver oxalate levels, if expressed per unit of defatted (DF) dry liver, were three times higher than in the controls. Urinary glycolate, oxalate, calcium and total protein excretion levels were elevated, the latter showing an excess of proteins > 100 kD and a deficit of proteins > 30-50 kD. Urinary calcium oxalate supersaturation was increased, and calcium phosphate supersaturation was unchanged. There were dramatically increased (by number, circumference, and area) renal calcium phosphate calcifications in the cortico-medullary region, but calcium oxalate deposits were not detectable. Electron microscopy (EM) and elemental analysis revealed intratubular calcium phosphate, apparently needle-like hydroxyapatite. Immunohistochemistry of renal tissue calcifications revealed co-localization of phospholipids and calcium phosphate. It is concluded that rats fed the CH-F diet exhibited: (1) a spectrum of metabolic abnormalities, the more prominent being dyslipidemia, hyperoxaluria, hypercalciuria, dysproteinuria, loss of bone calcium, and calcium phosphate nephrocalcinosis (NC); and (2) an interaction between calcium phosphate and phospholipids at the kidney level. The biological significance of these findings for the etiology of idiopathic calcium urolithiasis in humans is uncertain, but the presented animal model may be helpful when designing clinical studies.
Schmiedl
A
A
University Hospital, Department of Surgery, Erlangen, Germany.
Schwille
P O
PO
Bonucci
E
E
Erben
R G
RG
Grayczyk
A
A
Sharma
V
V
D015502:Absorptiometry, Photon; D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D001835:Body Weight; D001842:Bone and Bones / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000097:blood / Q000652:urine; D002129:Calcium Oxalate / Q000652:urine; D002130:Calcium Phosphates / Q000652:urine; D002791:Cholesterol, Dietary / Q000494:pharmacology; D004036:Diet, Atherogenic; D004041:Dietary Fats / Q000494:pharmacology; D006016:Glycolates / Q000652:urine; D006949:Hyperlipidemias / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D006959:Hyperoxaluria / Q000378:metabolism*; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D007669:Kidney Calculi / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008854:Microscopy, Electron; D008903:Minerals / Q000032:analysis / Q000378:metabolism; D009397:Nephrocalcinosis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D010281:Parathyroid Hormone / Q000097:blood; D010743:Phospholipids / Q000032:analysis / Q000097:blood; D011507:Proteinuria / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood
D002130:Calcium Phosphates; D002791:Cholesterol, Dietary; D004041:Dietary Fats; D006016:Glycolates; D008903:Minerals; D010281:Parathyroid Hormone; D010743:Phospholipids; D014807:Vitamin D; D002129:Calcium Oxalate; C097949:1,25-dihydroxyvitamin D; D002118:Calcium