Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors

Ogata, Hiroaki; Ritz, Eberhard; Odoni, Giulio; Amann, Kerstin; Orth, Stephan R.

doi:10.1097/01.asn.0000056188.23717.e5

Cited by 139 publications

(109 citation statements)

References 59 publications

(67 reference statements)

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“…A delayed and less intense rise of albumin excretion was achieved with R-568 and calcitriol, consistent with previous findings in experimental studies (17,19) and clinical observations (2).…”

Section: Discussionsupporting

confidence: 91%

“…Furthermore, in this model, Ogata et al (17) showed that the effects of the calcimimetic agent and parathyroidectomy are comparable.…”

Section: Discussionmentioning

confidence: 75%

“…In addition, however, Ogata et al (17) showed that short-term treatment with R-568 reduces albuminuria and attenuates glomerular and tubulointerstitial lesions in subtotally nephrectomized (SNX) rats.…”

mentioning

confidence: 99%

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Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats

Piecha¹,

Kökény²,

Nakagawa³

et al. 2008

American Journal of Physiology-Renal Physiology

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Patients with renal insufficiency develop secondary hyperparathyroidism. Monotherapy with active vitamin D or calcimimetics ameliorates secondary hyperparathyroidism. We compared kidney damage in subtotally nephrectomized (SNX) rats treated with active vitamin D (calcitriol) or the calcimimetic R-568. Male Sprague-Dawley SNX and sham-operated (sham-op) rats were randomized into the following treatment groups: SNX ϩ R-568, SNX ϩ calcitriol, SNX ϩ vehicle, sham-op ϩ R-568, sham-op ϩ calcitriol, and sham-op ϩ vehicle. Albuminuria and blood pressure were monitored and kidneys were examined using morphometry, immunohistochemistry, quantitative RT-PCR, and in situ hybridization. Parathyroid hormone concentrations were lowered to the same extent by the two interventions, although phosphorus and the calcium-phosphorus product were reduced only by R-568 treatment. SNX rats developed marked albuminuria, which was significantly reduced in ad libitum-and pair-fed animals treated with R-568 and animals treated with calcitriol. Mean glomerular volume (6.05 Ϯ 1.46 vs. 2.70 Ϯ 0.91 mm 3 ), podocyte volume (831 Ϯ 127 vs. 397 Ϯ 67 m 3 ), the degree of foot process fusion (mean width of foot processes ϭ 958 Ϯ 364 vs. 272 Ϯ 35 nm), and glomerular basement membrane thickness (244 Ϯ 6 vs. 267 Ϯ 23 nm), as well as desmin staining, were significantly higher in vehicletreated SNX than sham-operated animals. These changes were ameliorated with R-568 and calcitriol. In SNX, as well as sham-operated, animals, expression of the calcium-sensing receptor (protein and mRNA) was upregulated by treatment with the calcimimetic, but not calcitriol. Calcitriol and R-568 were similarly effective in ameliorating kidney damage. secondary hyperparathyroidism; chronic renal failure; nephroprotection; calcimimetics; calcitriol SECONDARY HYPERPARATHYROIDISM (sHPT) is a common feature of chronic kidney disease. Parathyroid hormone (PTH) concentrations increase progressively with diminishing glomerular filtration rate, but it is unclear whether PTH per se modifies progression.Active metabolites of vitamin D are widely used to control sHPT. Moreover, beneficial effects of active vitamin D on progression of chronic kidney disease have been documented (13,19).A therapeutic alternative is the use of calcimimetics (R-568 and, in humans, cinacalcet HCl), allosteric activators of the calcium-sensing receptor (CaSR), which reduce PTH secretion and interfere with parathyroid hyperplasia (4,20,22). In addition, however, Ogata et al. (17) showed that short-term treatment with R-568 reduces albuminuria and attenuates glomerular and tubulointerstitial lesions in subtotally nephrectomized (SNX) rats.The present study was designed to compare the effect of the two interventions on albuminuria and morphological lesions of the kidney in the SNX rat. The readouts were morphology and ultrastructure of podocytes, glomerulosclerosis index (GSI), and tubulointerstitial damage index, as well as expression profile of TGF-␤1, endothelin-1 (ET-1), and VEGF using immunohistochemistry a...

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Section: Discussionsupporting

confidence: 91%

“…Furthermore, in this model, Ogata et al (17) showed that the effects of the calcimimetic agent and parathyroidectomy are comparable.…”

Section: Discussionmentioning

confidence: 75%

See 1 more Smart Citation

Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats

Piecha¹,

Kökény²,

Nakagawa³

et al. 2008

American Journal of Physiology-Renal Physiology

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“…When these effects are reversed, renal function may deteriorate acutely. In the long term, however, these hemodynamic changes may attenuate progression of renal failure as was shown in an animal model [50]. Overall, there appears to be no difference in the overall graft survival between patients who underwent PTX between 1966 and 1997 [51] and those who did so later [47,52].…”

Section: Surgical Concepts In Renal Hyperparathyroidismmentioning

confidence: 81%

Surgical management of secondary hyperparathyroidism in chronic kidney disease—a consensus report of the European Society of Endocrine Surgeons

Lorenz

Bartsch

Sancho

et al. 2015

Langenbecks Arch Surg

104

130

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Background Despite advances in the medical management of secondary hyperparathyroidism due to chronic renal failure and dialysis (renal hyperparathyroidism), parathyroid surgery remains an important treatment option in the spectrum of the disease. Patients with severe and complicated renal hyperparathyroidism (HPT), refractory or intolerant to medical therapy and patients with specific requirements in prospect of or excluded from renal transplantation may require parathyroidectomy for renal hyperparathyroidism. Methods Present standard and actual controversial issues regarding surgical treatment of patients with hyperparathyroidism due to chronic renal failure were identified, and pertinent literature was searched and reviewed. Whenever applicable, evaluation of the level of evidence concerning diagnosis and management of renal hyperparathyroidism according to standard criteria and recommendation grading were employed. Results were discussed at the 6th Workshop of the European Society of Endocrine Surgeons entitled Hyperparathyroidism due to multiple gland disease: An evidence-based perspective.Results Presently, literature reveals scant data, especially, no prospective randomized studies to provide sufficient levels of evidence to substantiate recommendations for surgery in renal hyperparathyroidism. Appropriate surgical management of renal hyperparathyroidism involves standard bilateral exploration with bilateral cervical thymectomy and a spectrum of four standardized types of parathyroid resection that reveal comparable outcome results with regard to levels of evidence and recommendation. Specific patient requirements may favour one over the other procedure according to individualized demands. Conclusions Surgery for patients with renal hyperparathyroidism in the era of calcimimetics continues to play an important role in selected patients and achieves efficient control of hyperparathyroidism. The overall success rate and longterm control of renal hyperparathyroidism and optimal handling of postoperative metabolic effects also depend on the timely indication, individually suitable type of parathyroid resection and specialized endocrine surgery.

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“…13 These small compounds allosterically modulate the CaSR, making it more responsive to Ca 2 þ . The beneficial effects of calcimimetics on heart morphology, comparable with that of parathyroidectomy, were earlier suggested by a study in experimental uremia, 14 but no information is available on cardiac function and signaling pathways. We have shown earlier that the calcimimetic R-568 decreases albuminuria in subtotally nephrectomized rats.…”

mentioning

confidence: 95%

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

Koleganova

Piecha

Ritz

et al. 2009

Laboratory Investigation

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In patients with chronic renal failure, the heart undergoes remodeling, characterized by hypertrophy, fibrosis, and capillary/myocyte mismatch. In this study, we observed the effects of the calcimimetic agent R-568 on microvascular disease and interstitial fibrosis of the heart. Three-month-old male Sprague-Dawley rats were randomized to subtotal nephrectomy (SNX) or sham operation and subsequently received vehicle or R-568 under two experimental protocols, one for 1 month and the other for 3 months. Echocardiography, capillary length density, volume density of interstitial tissue, and immunohistochemistry and western blots (calcium-sensing receptor, collagen I and III, transforming growth factor (TGF)-b, mitogen-activated protein kinases, and nitrotyrosine) were assessed. After SNX, weight and wall thickness of the left and the right ventricle were elevated. The ratio of heart to body weight and interventricular septum thickness were not changed by R-568 treatment. The left ventricle fractional shortening (by echocardiography) was lower in SNX; this was ameliorated by R-568. Reduced capillary length density and increased interstitial fibrosis in SNX were improved by R-568, which also reduced the expression of TGF-b, and collagen I and III. The calcimimetic increased the activation of ERK-1/2, normalized p38 and JNK signaling, and prevented oxidative stress. We conclude that lowering parathyroid hormone with a calcimimetic significantly improves cardiac histology and function but not the left ventricular mass in SNX.

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Beneficial Effects of Calcimimetics on Progression of Renal Failure and Cardiovascular Risk Factors

Cited by 139 publications

References 59 publications

Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats

Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats

Surgical management of secondary hyperparathyroidism in chronic kidney disease—a consensus report of the European Society of Endocrine Surgeons

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

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