Sevelamer hydrochloride prevents ectopic calcification and renal osteodystrophy in chronic renal failure rats

Katsumata, Kyoko; Kusano, Koji; Hirata, Michinori; Tsunemi, Kunihiko; Nagano, Nobuo; Burke, Steven K.; Fukushima, Naoshi

doi:10.1046/j.1523-1755.2003.00126.x

Cited by 149 publications

(177 citation statements)

References 29 publications

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“…It often is an adynamic bone disorder similar to the osteodystrophy in our animal model. Katsumata et al (27) reported that sevelamer prevented development of renal osteodystrophy that was compatible with the increased osteoblast function and bone formation rates reported here in our studies. The mechanism of increased skeletal anabolism that is associated with sevelamer therapy is unknown, but they likely contribute to the effects of sevelamer to decrease VC.…”

Section: Discussionsupporting

confidence: 76%

Reversal of the Adynamic Bone Disorder and Decreased Vascular Calcification in Chronic Kidney Disease by Sevelamer Carbonate Therapy

Mathew

Lund

Strebeck

et al. 2007

Journal of the American Society of Nephrology

103

105

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A model of chronic kidney disease (CKD)-induced vascular calcification (VC) that complicates the metabolic syndrome was produced. In this model, the metabolic syndrome is characterized by severe atherosclerotic plaque formation, hypertension, type 2 diabetes, obesity, and hypercholesterolemia, and CKD stimulates calcification of the neointima and tunica media of the aorta. The CKD in this model is associated the adynamic bone disorder form of renal osteodystrophy. The VC of the model is associated with hyperphosphatemia, and control of the serum phosphorus both in this animal model and in humans has been preventive in the development of VC. This article reports studies that demonstrate reduction of established VC by the addition of sevelamer carbonate to the diets of this murine metabolic syndrome model with CKD. Sevelamer, besides normalizing the serum phosphorus, surprisingly, reversed the CKD-induced trabecular osteopenia. Sevelamer therapy increased osteoblast surfaces in the metaphyseal trabeculae of the tibia and femur. It also increased osteoid surfaces and, importantly, bone formation rates. In addition, sevelamer was found to be effective in decreasing serum cholesterol levels. These results suggest that sevelamer may have important actions in decreasing diabetic and uremic vasculopathy and that sevelamer carbonate may be capable of increasing bone formation rates that are suppressed by diabetic nephropathy. 18: 122-130, 200718: 122-130, . doi: 10.1681 P rogression of diabetic nephropathy (DN) generally is considered in terms of progressive loss of kidney function until end-stage kidney failure occurs and renal replacement therapy begins. However, DN is a systemic disease, and it also is fatal. Indeed, more patients with DN die before reaching the need for dialysis than accrue to modalities of renal replacement therapy (1-3). Cardiovascular mortality in patients with chronic kidney disease (CKD) is extremely high (1,4). Conventional risk factors that are characteristic of the metabolic syndrome (5), such as hypertension, dyslipidemia, insulin resistance, and overt diabetes, are highly prevalent in CKD, but other risk factors with additive affects that are more specific to the uremic milieu also have been identified (6 -8). J Am Soc NephrolOne is the presence of vascular calcification (VC) (9), a form of heterotopic mineralization that is predictive of cardiovascular mortality (10,11) and is both common and severe in CKD (12). The VC of the tunica media that is seen in CKD is similar to that observed in type 2 diabetes without DN, and when CKD is added to diabetes through DN, the cardiovascular risk is at least additive of that of CKD plus diabetes; in other words, extreme. We have developed an animal model of VC that is worsened by CKD (13). The model is partial renal ablation in the LDL receptor-deficient (LDLRϪ/Ϫ) mouse that is fed high-fat/ cholesterol diets. This model resembles the clinical situation of CKD's complicating the metabolic syndrome, because the mice have obesity, hypertension, insulin...

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Section: Discussionsupporting

confidence: 76%

Reversal of the Adynamic Bone Disorder and Decreased Vascular Calcification in Chronic Kidney Disease by Sevelamer Carbonate Therapy

Mathew

Lund

Strebeck

et al. 2007

Journal of the American Society of Nephrology

103

105

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“…Sevelamer HCl has been shown to be effective at treating adenine-induced hyperphosphatemia in rats [8,10], and 5/6 nephrectomy-induced hyperphosphatemia in mice [34] and rats [35]. We have recently demonstrated in chicks that sevelamer HCl was effective in preventing the absorption of phosphate liberated from the diet due to the treatment of calcitriol [17].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, concurrent active vitamin D supplementation prescribed due to a reduced ability of the kidney to convert vitamin precursors to active vitamin D further exacerbates phosphate absorption [6,7]. Previously, the rat models including the 5/6 nephrectomy and adenineinduced kidney insufficiency rat model have been extensively used for pre-clinical testing in the development of therapies for chronic kidney disease [8][9][10]. The rat adenine-induced kidney insufficiency model is a less invasive refinement over the 5/6 nephrectomy surgical renal insufficiency model [11,12], and was found useful in the development of sevelamer hydrochloride (Sev HCl) as an oral therapy for treatment of hyperphosphatemia [10].…”

Section: Introductionmentioning

confidence: 99%

“…Previously, the rat models including the 5/6 nephrectomy and adenineinduced kidney insufficiency rat model have been extensively used for pre-clinical testing in the development of therapies for chronic kidney disease [8][9][10]. The rat adenine-induced kidney insufficiency model is a less invasive refinement over the 5/6 nephrectomy surgical renal insufficiency model [11,12], and was found useful in the development of sevelamer hydrochloride (Sev HCl) as an oral therapy for treatment of hyperphosphatemia [10]. Rats fed 0.75% dietary adenine for two weeks developed increased blood phosphate, FGF23, and blood urea nitrogen due to renal insufficiency, appearing sufficient to model human CKD [8,9,11].…”

Section: Introductionmentioning

confidence: 99%

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Adenine-induced hyperphosphatemia in a murine model of renal insufficiency

Bobeck¹,

Piccione²,

Bishop³

et al. 2017

Nephrol Renal Dis

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Hyperphosphatemia in chronic kidney disease (CKD) patients is a risk factor for cardiovascular events, progressive kidney failure, and mortality. Improved therapeutic interventions to control hyperphosphatemia depend greatly on robust animal models that recapitulate the CKD disease process. Murine-based models of CKD as compared to rat models present significant advantages due to available genetic knockout lines that permit mechanistic dissection of CKD etiologies. The rat adenine model of renal failure has been extensively studied, and studies are now emerging describing adenine-induced renal failure in murine models. However, these newly developed murine models have not fully described the responses to calcitriol and phosphate binders, and the reported effects of adenine on serum phosphate is often lacking in murine models. Therefore, the objectives of this study were: 1) To induce hyperphosphatemia in mice using adenine with minimal mortality, and 2) Report the influence of calcitriol and phosphate binders on the disease process through measurement of serum phosphate and histology. In one approach, C57BL/6 male mice gavaged with 4 or 6 mg adenine/day, as compared to 0 mg adenine/day developed hyperphosphatemia, with low mortality. In a second approach, calcitriol exacerbated adenine-induced increases in serum phosphate at day 7 of adenine administration (p<0.05). Notably, adenine treated mice had 4-fold increased stomach weights vs. non-adenine treated mice (p<0.0001). The addition of a phosphate binder (experiment 3, sevelamer hydrochloride) was ineffective at preventing an adenine-induced increase in blood phosphate, a finding that likely resulted from adenine's inhibition of gastric emptying. We report the successful use of adenine to induce hyperphosphatemia, that the hyperphosphatemic status is exacerbated by calcitriol, and a limitation of the model for studying oral therapies for hyperphosphatemia.

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“…Serum calcium, phosphorus, albumin, creatinine, alkaline phosphatase, parathyroid hormone, blood sugar, vitamin D, hemoglobin, ferritin and ESR were measured in each patient [28][29][30][31].…”

Section: Renal Osteodystrophy In End Stage Renal Disease Patients In mentioning

confidence: 99%

Renal Osteodystrophy in End Stage Renal Disease Patients in a Center in South East of Iran: A Cross-Sectional Study

Zohre¹,

Sepehri²,

Afshari³

et al. 2017

Clinical-Skills

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Sevelamer hydrochloride prevents ectopic calcification and renal osteodystrophy in chronic renal failure rats

Abstract: These results suggest that sevelamer treatment might contribute to the suppression of ectopic calcification and ROD.

Cited by 149 publications

References 29 publications

Reversal of the Adynamic Bone Disorder and Decreased Vascular Calcification in Chronic Kidney Disease by Sevelamer Carbonate Therapy

Reversal of the Adynamic Bone Disorder and Decreased Vascular Calcification in Chronic Kidney Disease by Sevelamer Carbonate Therapy

Adenine-induced hyperphosphatemia in a murine model of renal insufficiency

Renal Osteodystrophy in End Stage Renal Disease Patients in a Center in South East of Iran: A Cross-Sectional Study

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