Characterization of a mouse model of chronic uremia

Gagnon, Raymonde F.; Gallimore, Barbara

doi:10.1007/bf00261969

Cited by 72 publications

(74 citation statements)

References 20 publications

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“…The plasma calcium and phosphate concentrations both were elevated in the CRF mice. The explanation for this remains enigmatic, but a similarly increased plasma calcium concentration has been previously described in mice (38) and dogs (39) with surgically reduced renal mass. Nevertheless, in agreement with a recent study (29), we did not observe calcification of the arterial wall in CRF mice on histologic analysis of the aortic root or on microradiographs of the entire aorta (data not shown).…”

Section: Discussionmentioning

confidence: 88%

Chronic Renal Failure Accelerates Atherogenesis in Apolipoprotein E–Deficient Mice

Bro

Bentzon²,

Falk³

et al. 2003

Journal of the American Society of Nephrology

140

116

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Abstract. Cardiovascular mortality is 10 to 20 times increased in patients with chronic renal failure (CRF). Risk factors for atherosclerosis are abundant in patients with CRF. However, the pathogenesis of cardiovascular disease in CRF remains to be elucidated. The effect of CRF on the development of atherosclerosis in apolipoprotein E-deficient male mice was examined. Seven-week-old mice underwent 5/6 nephrectomy (CRF, n ϭ 28), unilateral nephrectomy (UNX, n ϭ 24), or no surgery (n ϭ 23). Twenty-two weeks later, CRF mice showed increased aortic plaque area fraction (0.266 Ϯ 0.033 versus 0.045 Ϯ 0.006; P Ͻ 0.001), aortic cholesterol content (535 Ϯ 62 versus 100 Ϯ 9 nmol/cm 2 intimal surface area; P Ͻ 0.001), and aortic root plaque area (205,296 Ϯ 22,098 versus 143,662 Ϯ 13,302 m 2 ; P Ͻ 0.05) as compared with no-surgery mice; UNX mice showed intermediate values. The plaques from uremic mice contained CD11b-positive macrophages and showed strong staining for nitrotyrosine. Systolic BP and plasma homocysteine concentrations were similar in uremic and nonuremic mice. Plasma urea and cholesterol concentrations were elevated 2.6-fold (P Ͻ 0.001) and 1.5-fold (P Ͻ 0.001) in CRF compared with no-surgery mice. Both variables correlated with aortic plaque area fraction (r 2 ϭ 0.5, P Ͻ 0.001 and r 2 ϭ 0.3, P Ͻ 0.001, respectively) and with each other (r 2 ϭ 0.5, P Ͻ 0.001). On multiple linear regression analysis, only plasma urea was a significant predictor of aortic plaque area fraction. In conclusion, the present findings suggest that uremia markedly accelerates atherogenesis in apolipoprotein E-deficient mice. This effect could not be fully explained by changes in BP, plasma homocysteine levels, or total plasma cholesterol concentrations. Thus, the CRF apolipoprotein E-deficient mouse is a new model for studying the pathogenesis of accelerated atherosclerosis in uremia.

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Section: Discussionmentioning

confidence: 88%

Chronic Renal Failure Accelerates Atherogenesis in Apolipoprotein E–Deficient Mice

Bro

Bentzon²,

Falk³

et al. 2003

Journal of the American Society of Nephrology

140

116

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“…CKD was induced in 31 animals by the procedure previously described by Gagnon and Gallimore (46). Nineteen animals underwent sham surgery.…”

Section: Induction Of Ckd and Treatment Protocolmentioning

confidence: 99%

Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model

Lund¹,

Davies²,

Brown³

et al. 2004

Journal of the American Society of Nephrology

103

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Abstract. An adynamic bone disorder (ABD) is an important complication of chronic kidney disease (CKD) of unknown etiology for which there is no adequate treatment. Reported is an animal model of ablative CKD complicated by an ABD characterized by the absence of secondary hyperparathyroidism and its successful treatment with a skeletal anabolic factor, bone morphogenetic protein-7 (BMP-7). Adult mice were subjected to electrocautery of the right kidney followed by left nephrectomy. Animals were randomized into groups fed normal chow or fed low-phosphate chow supplemented with calcitriol to maintain normophosphatemia in CKD. All groups were maintained on the regimens for 12 wk. Hyperphosphatemia, secondary hyperparathyroidism, and a mild osteodystrophy developed in the CKD/chow-fed group, as expected. When dietary phosphorus was restricted and calcitriol was administered in the CKD low-phosphate/calcitriol group (ABD), Ca, PO 4 , and parathyroid hormone levels were maintained normal. A significant ABD developed in the ABD group characterized by significant depressions in osteoblast number, perimeters, bone formation rates, and mineral apposition rates when compared with the sham-operated, chow-fed group. The abnormal skeletal histomorphometry was reversed by BMP-7 therapy to normal values and significantly improved from the ABD group (P Ͻ 0.05). The sham-operated low-phosphate/ calcitriol-fed control group and the CKD low-phosphate/calcitriol/BMP-7 groups had reduced phosphate levels compared with the other groups (P Ͻ 0.05). ABD produced in mice with CKD in the absence of hyperparathyroidism was successfully reversed with a bone anabolic, BMP-7, associated with a reduction in plasma phosphorus.Renal osteodystrophy is a term used to describe a heterogeneous spectrum of skeletal abnormalities found in patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). Renal osteodystrophy ranges from states of high bone turnover to states of low bone turnover (1-3). Predominantly hyperparathyroid bone disease results in a high turnover osteodystrophy (osteitis fibrosa), and it is considered the most prevalent bone disorder in chronic kidney disease and ESKD. Low-turnover osteodystrophy reflects the lack of capacity to produce and mineralize bone matrix and has two main histologic forms: osteomalacia and the adynamic bone disorder (ABD). The ABD is an important complication of CKD associated with high rates of bone fractures (4), impaired growth (5,6), and probably vascular calcification (7,8). There has been an increase in the prevalence of ABD in patients with ESKD on dialysis (9).The pathogenesis of the ABD is unknown. It may occur when parathyroid hormone (PTH) levels are aggressively suppressed (10). As a result, practice standards target maintaining elevated intact PTH levels (about three to five times normal) sufficient to prevent the ABD (11,12). Therapy of the ABD besides adjustment of PTH levels is not available. Because secondary hyperparathyroidism in CKD causes a distinct osteodystrophy, in...

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“…The hemopoietic response to recombinant human erythropoietin has been examined in this mutant mouse [15]. Some studies have been carried out on erythropoietin, concerning its plasma concentration, production in the kidney, liver, and bone marrow, and the hemopoietic response in renal anemia [3,6,12,15,29]. The examination of a hemopoietic factor such as erythropoietin in hpk/hpk rats would produce useful information because of the congenital reduction in renal tissue, which is the major source of erythropoietin, that exists in these rats.…”

Section: Discussionmentioning

confidence: 99%

“…In remnant kidney models, a two-step nephrectomy or other treatments are necessary to induce chronic renal failure [6,12,16,22]. In the experimental nephritis induced by the injection of sodium sulfacetylthiazole, the continuous administration of this drug is necessary to induce subchronic renal failure [21].…”

Section: Discussionmentioning

confidence: 99%

“…In general, the considerable loss of nephrons causes progressive chronic renal failure [1,5,14,22] and, secondarily, induces renal anemia [3,6,12,15,29], hyperparathyroidism, and osteodystrophy at the end stage of renal failure [2,6,7,8,10,11,13,16,17,20,21,23]. Although various animal models have been utilized in the study of these conditions [6,12,16,17,20,21,29], genetic animal models that could develop reproducibly chronic renal failure and induce renal secondary disease have been reported only rarely [11,15]. In the report described here, in order to assess the possibility that hpk/ hpk rats are a useful animal model in which we can study the process of progression from renal hypoplasia into renal failure, the process of the development of renal secondary disease, and the pharmacological effects of drugs designed to improve these conditions, we examined the clinical and pathological conditions of progressive renal failure in these rats during the period from adult to advanced age.…”

Section: Animalsmentioning

confidence: 99%

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Rat Hypoplastic Kidney (hpk/hpk) Induces Renal Anemia, Hyperparathyroidism, and Osteodystrophy at the End Stage of Renal Failure.

Suzuki

1998

The Journal of Veterinary Medical Science

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ABSTRACT. In rats with genetically hypoplastic kidneys (hpk/hpk) and associated hypogonadism (hgn/hgn), their kidneys contain only onequarter the number of nephrons that are found in those of normal rats [26]. Not surprisingly, therefore, renal excretive function has been shown to be depressed in hpk/hpk rats [26]. In the study presented here, we have examined the process of the progression of renal failure and the development of renal secondary disease in hpk/hpk rats. The plasma concentrations of urea-nitrogen and creatinine were significantly higher in adult hpk/hpk rats than in normal rats. These values elevated gradually and the degree of renal histological damage also progressed with advancing age in the hpk/hpk rats. In addition, renal anemia appeared at 140 days of age or later in these rats, and hyperplasia of the parathyroid glands was visible macroscopically at 280 days of age. In the hpk/hpk rats plasma levels of calcium and phosphorus were significantly lower and higher than in normal rats, respectively, at 280 days of age. Pathologically, the left femora of hpk/hpk rats exhibited fibrous osteodystrophy at 280 days of age and the calcium content of the right femora (as a percentage of the dry weight of bone) was significantly lower than in normal rats at both 210 and 280 days of age. These results indicate that the reduced nephrogenesis of the hpk/hpk rats causes progressive renal failure, secondarily inducing anemia, hyperparathyroidism, and osteodystrophy. -KEY WORDS: disease animal model, hyperparathyroidism, osteodystrophy, renal anemia, renal hypoplasia.J. Vet. Med. Sci. 60(10): 1051-1058, 1998 MATERIALS AND METHODS Animals:The animals used in this study were male hpk/ hpk rats and phenotypically normal litter mates (+/hpk or +/+) from the 24th generation of the HGN line maintained in our department [26]. The hpk/hpk males could be identified externally by their hypogonadism [26]. The rats were bred and fed under the same conditions as described in previous reports [24][25][26][27].Hematological examination: Four groups of 4 hpk/hpk and 4 normal animals were used, one group at each of days 70, 140, 210, and 280 after birth. Blood samples were collected from the jugular vein with a plastic syringe moisturized with a small amount of heparin. Red and white blood cells were counted on a hemacytometer with the aid of a light microscope. The counts of reticulocytes and platelets were performed according to the Rees-Ecker method. The hematocrit was determined using a hematocrit tube and the centrifuging method. The concentration of hemoglobin was determined by the methemoglobin method. Plasma samples were obtained by centrifugation and stored at 40°C until they were used to obtain urea-nitrogen, creatinine, calcium, and phosphorus measurements.Histological examination: After collecting blood samples from the rats they were sacrificed by ether overdose. Their kidneys and parathyroid glands with attached tracheas were removed and fixed in 4% neutral formalin, dehydrated in a graded alcohol series, embed...

show abstract

Characterization of a mouse model of chronic uremia

Cited by 72 publications

References 20 publications

Chronic Renal Failure Accelerates Atherogenesis in Apolipoprotein E–Deficient Mice

Chronic Renal Failure Accelerates Atherogenesis in Apolipoprotein E–Deficient Mice

Successful Treatment of an Adynamic Bone Disorder with Bone Morphogenetic Protein-7 in a Renal Ablation Model

Rat Hypoplastic Kidney (hpk/hpk) Induces Renal Anemia, Hyperparathyroidism, and Osteodystrophy at the End Stage of Renal Failure.

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