Effect of Correction of Metabolic Acidosis on Bone Mineralisation Rates in Patients with Renal Osteomalacia

Cochran, M.; Wilkinson, Robert H.

doi:10.1159/000180501

Cited by 57 publications

(27 citation statements)

References 21 publications

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“…Chronic metabolic acidosis is common in advanced stages of CKD, and it is associated with adverse consequences, including increased mortality, acceleration of kidney disease progression, increased muscle breakdown and insulin resistance, and the development or exacerbation of bone disease (5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Clinical evidence shows that treatment of low serum bicarbonate can improve kidney, muscle, bone, and nutritional sequelae of chronic metabolic acidosis (17)(18)(19)(20)(21)(22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD

Bushinsky

Hostetter

Klaerner³

et al. 2017

CJASN

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Background and objectives Metabolic acidosis is common in patients with CKD and has significant adverse effects on kidney, muscle, and bone. We tested the efficacy and safety of TRC101, a novel, sodium-free, nonabsorbed hydrochloric acid binder, to increase serum bicarbonate in patients with CKD and metabolic acidosis.Design, setting, participants, & measurements One hundred thirty-five patients were enrolled in this randomized, double-blind, placebo-controlled, multicenter, in-unit study (designated the TRCA-101 Study). Patients had a mean baseline eGFR of 35 ml/min per 1.73 m 2 , a mean baseline serum bicarbonate of 17.7 mEq/L, and comorbidities, including hypertension (93%), diabetes (70%), and heart failure (21%). Patients ate a controlled diet and were treated for 14 days with placebo or one of four TRC101 dosing regimens (1.5, 3, or 4.5 g twice daily or 6 g once daily). After treatment, patients were discharged and followed for 7-14 days.Results All TRC101 treatment groups had a mean within-group increase in serum bicarbonate of $1.3 mEq/L (P,0.001) within 72 hours of the first dose and a mean increase in serum bicarbonate of 3.2-3.9 mEq/L (P,0.001) at the end of treatment compared with placebo, in which serum bicarbonate did not change. In the combined TRC101 treatment group, serum bicarbonate was normalized (22-29 mEq/L) at the end of treatment in 35% of patients and increased by $4 mEq/L in 39% of patients. After discontinuation of TRC101, serum bicarbonate decreased nearly to baseline levels within 2 weeks. All adverse events were mild or moderate, with gastrointestinal events most common. All patients completed the study.Conclusions TRC101 safely and significantly increased the level of serum bicarbonate in patients with metabolic acidosis and CKD.

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Section: Introductionmentioning

confidence: 99%

Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD

Bushinsky

Hostetter

Klaerner³

et al. 2017

CJASN

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“…In-vivo rat studies have also shown the stimulation of cell-mediated bone resorption during prolonged acidosis [34,48]. Further support for bone buffering the acid load comes from studies of acidosis patients in which the bone mineral loss could be corrected by bicarbonate ion administration [49][50][51].…”

Section: In-vivo Observationsmentioning

confidence: 99%

Mechanism of acid-induced bone resorption

Krieger

Frick

Bushinsky

2004

Current Opinion in Nephrology and Hypertension

215

134

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Purpose of reviewThis review presents our current understanding of the way metabolic acidosis induces calcium efflux from bone, and in the process, buffers additional systemic hydrogen ions associated with acidosis. Recent findingsAcid-induced changes in bone mineral are consistent with a role for bone as a proton buffer. In response to metabolic acidosis in an in-vitro bone organ culture system, we observed a fall in mineral sodium, potassium, carbonate and phosphate, which each buffer protons and in vivo should increase systemic pH towards the physiologic normal. Initially, metabolic acidosis stimulates physicochemical mineral dissolution and subsequently cell-mediated bone resorption. Acidosis suppresses the activity of bone-resorbing cells, osteoblasts, decreasing gene expression of specific matrix proteins and alkaline phosphatase activity. There is concomitant acid stimulation of prostaglandin production by osteoblasts, which acting in a paracrine manner increases synthesis of the osteoblastic receptor activator of nuclear factor kappa B ligand (RANKL). The acid induction of RANKL then stimulates osteoclastic activity and recruitment of new osteoclasts to promote bone resorption and buffering of the proton load. Both the regulation of RANKL and acid-induced calcium efflux from bone are mediated by prostaglandins. Summary Metabolic acidosis, which occurs during renal failure, renal insufficiency or renal tubular acidosis, results in decreased systemic pH and is associated with an increase in urine calcium excretion. The apparent protective function of bone to help maintain systemic pH, which has a clear survival advantage for mammals, will come partly at the expense of its mineral stores. Abbreviations GAPDH glyceraldehyde-3-phosphate dehydrogenase HCO 3 7 bicarbonate ion MGP matrix gla protein PGHS prostaglandin G/H synthase PTH parathyroid hormone RANK receptor activator of nuclear factor kappa B RANKL receptor activator of nuclear factor kappa B ligand TGF-b transforming growth factor beta

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“…The current standard is the result of a compromise between the advantages of normalizing pre-dialysis acidosis and the side effects of the transient peri-and post-dialysis alkalosis resulting from bicarbonate transfer. The adverse consequences on the one hand of persistent metabolic acidosis on bone metabolism [3][4][5] and nitrogen balance [6,7] and on the other of transient metabolic alkalosis on neuromuscular excitability and on cerebral blood fl ow (inducing paresthesias, twitching and cramping) [8][9][10] are well established. Furthermore, the positive inotropic effect induced by alkalemia in experimental models [11,12] seems to be at least in part counterbalanced by the resultant reduction in ionized calcium in serum [13] .…”

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confidence: 99%

Does Bicarbonate Transfer Have Relevant Hemodynamic Consequences in Standard Hemodialysis?

et al. 2005

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Background: In a previous study we demonstrated that mild metabolic alkalosis resulting from standard bicarbonate hemodialysis induces hypotension. This study aimed to compare hemodynamic consequences of either a decrease in the dialysate bicarbonate from 32 to 26 mmol/l or an increase in the dialysate calcium of 0.25 mmol/l and to verify whether the calcium shift secondary to alkalemia explains the consequences on blood pressure. Methods: In this randomized controlled trial with a single-blind, cross-over design, we used dialysis liquids with two different bicarbonate (32 mmol/l in modalities A and C, and 26 mmol/l in modality B) and calcium (1.25 mmol/l in modalities A and B, and 1.50 mmol/l in modality C) concentrations, and in 27 patients, 243 dialysis sessions, compared blood pressure, heart rate and the incidence of hypotension. Results: No significant differences were seen between A and B while an increase in systolic and diastolic blood pressures and a decrease in the incidence of hypotension (10.5 vs. 1.2%, p < 0.05) were documented in C. The subgroup of patients who with A showed a lower mean systolic blood pressure received more angiotensin-converting enzyme inhibitors or angiotensin II type-1 receptor blockers (36 vs. 0%, p <0.05) and in C showed a less important increase in systolic and diastolic pressures, but the incidence of hypotensive episodes between A and B was not significantly different (9.1 vs. 15.1%). Conclusions: In the present study it was not possible to demonstrate hemo dynamic instability associated with mild metabolic alkalosis. Even in the subgroup showing a lower blood pressure with a higher dialysate bicarbonate, significant hemodynamic or clinical consequences were not noticed. The calcium shift (0.05 mmol/l) related to alkalemia would justify a mean decrease in systolic blood pressure of only about 1 mm Hg.

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Effect of Correction of Metabolic Acidosis on Bone Mineralisation Rates in Patients with Renal Osteomalacia

Cited by 57 publications

References 21 publications

Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD

Randomized, Controlled Trial of TRC101 to Increase Serum Bicarbonate in Patients with CKD

Mechanism of acid-induced bone resorption

Does Bicarbonate Transfer Have Relevant Hemodynamic Consequences in Standard Hemodialysis?

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