Cinacalcet for secondary hyperparathyroidism in children with end-stage renal disease

The efficacy and acceptability of cinacalcet for treatment of secondary hyperparathyroidism (SHPT) was assessed in seven pediatric patients suffering from end-stage renal disease (ESRD) presenting with inadequately controlled SHPT despite conventional management. Patients received daily treatment with cinacalcet (dosage 0.25 mg/kg body weight) for a total of 4 weeks. Within 4 h after application of the first dose, median levels of serum parathyroid hormone (PTH) had decreased from 932 pg/ml (range 511-1,938 pg/ml) to 584 pg/ml (88-937 pg/ml), and final pre-dose values after 4 weeks were 199 pg/ml (121-940 pg/ml; each P < 0.05 versus baseline). Median concentrations of serum calcium (Ca) decreased within 4 h of the first administration, from 2.56 mmol/l to 2.38 mmol/l, returning to 2.58 mmol/l at 24 h, and they remained slightly decreased compared to baseline values thereafter (each P < 0.05 versus baseline). Both the median levels of serum phosphorus (P) and the Ca x P ion product decreased significantly during the 4-week period. Cinacalcet was well tolerated and without drug-related adverse effects. Thus, even with approximately half of the dose usually given to adult dialysis patients, PTH and the Ca x P ion product were markedly reduced in pediatric ESRD patients presenting with inadequately controlled SHPT. Therefore, our results support the initiation of a randomized, controlled, long-term trial in children.     

The role of bone in phosphate metabolism

Fibroblast growth factor 23 (FGF23) is a humoral factor that is produced by osteocytes and reduces serum phosphate and 1,25-dihydroxyvitamin D levels by acting on kidney through some FGF receptor and Klotho. Excessive action of FGF23 results in several hypophosphatemic diseases characterized by impaired renal tubular phosphate reabsorption. In contrast, deficient action of FGF23 causes familial hyperphosphatemic tumoral calcinosis with enhanced renal tubular phosphate reabsorption. In addition, FGF23 null mice also show hyperphosphatemia. The production and circulatory level of FGF23 seem to be tightly regulated while the detailed mechanism of this regulation remains to be clarified. These results indicate that FGF23 is a physiological factor working as a hormone produced by bone. The discovery of FGF23 has revealed the possibility that bone produces several humoral factors to communicate with other organs.     

Miscellaneous non-inflammatory musculoskeletal conditions. Hyperphosphatemic familial tumoral calcinosis (FGF23, GALNT3 and αKlotho)

Familial tumoral calcinosis (TC) is a rare disorder distinguished by the development of ectopic and vascular calcified masses that occur in settings of hyperphosphatemia (hFTC) and normophosphatemia (nFTC). Serum phosphorus concentrations are relatively tightly controlled by interconnected endocrine activity at the level of the intestine, kidney, and skeleton. Discovering the molecular causes for heritable forms of hFTC has shed new light on the regulation of serum phosphate balance. This review will focus upon the genetic basis and clinical approaches for hFTC, due to genes that are related to the phosphaturic hormone fibroblast growth factor-23 (FGF23). These include FGF23 itself, an FGF23-glycosylating enzyme (GALNT3), and the FGF23 co-receptor α-Klotho (αKL). Our understanding of the molecular basis of hFTC will, in the short term, aid in understanding normal phosphate balance, and in the future, provide potential insight into the design of novel therapeutic strategies for both rare and common disorders of phosphate metabolism.     

Hyperostosis with hyperphosphatemia and tumoral calcinosis: a case report

The combination of hyperostosis and hyperphosphatemia is very rare. In this case report, we present a boy with a combination of diffuse hyperostosis and hyperphosphatemia. We evaluated most possible known causes of hyperphosphatemia and hyperostosis. He had normal renal function and serum parathormone level. Concerning some few similar cases, most of them from Middle Eastern countries, we present this combination (diffuse hyperostosis and hyperphosphatemia) as a new syndrome to be discussed in pediatric textbooks.     

The role of sevelamer in achieving the kidney disease outcomes quality initiative (K/DOQI) guidelines for hyperphosphatemia

SUMMARY

Background: End-stage renal disease (ESRD) is a chronic health care problem associated with multiple co-morbidities and escalating costs. Disregulation of mineral metabolism (principally hyperphosphatemia and hypercalcemia) contributes to substantial morbidity and mortality. Accordingly, new and more-aggressive Kidney Disease Outcomes Quality Initiative (K/DOQI) Guidelines from the National Kidney Foundation promote lower serum phosphorus (3.5–5.5?mg/dL), lower calcium (8.4–9.5?mg/dL), and lower calcium-phosphorus product (< 55?mg²/dL²) targets.

Review findings: Traditional calcium-based and metal-based phosphate binders are effective but are associated with side effects and toxicity that limit their use. Achieving rigorous K/DOQI goals demands higher therapeutic doses of phosphate binders and may require more-aggressive use of calcium-free and metal-free phosphate binders. Sevelamer hydrochloride is a calcium- and metal-free polymer that binds phosphate effectively without contributing to calcium load or metal accumulation. In the Treat-to-Goal trial, sevelamer-treated dialysis patients had less progression of coronary and aortic calcification than patients treated with calcium-based binders. This offers the potential promise of reducing cardiovascular morbidity and mortality. The 800-mg tablet (Renagel*) increases the daily sevelamer dose while reducing the number of tablets required per meal. Nine of the 800-mg tablets per day (3 × 800-mg tablets tid with meals) of sevelamer monotherapy have been shown to achieve K/DOQI serum phosphorus and calcium-phosphorus product targets.

Conclusion: In summary, this review of the current evidence-base concludes that the new, more-aggressive, K/DOQI goals limit the use of metal-based and calcium-based phosphate binders. Sevelamer offers the advantages of lowering serum phosphorus without the risks of calcium or metal accumulation – and offers the promise of slowing the progression of vascular calcification and potentially reducing the morbidity and mortality of hemodialysis patients.     

Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy

The beneficial cardiorenal outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) have been substantiated by multiple clinical trials, resulting in increased interest in the multifarious pathways by which their mechanisms act. The principal effect of SGLT2i (-flozin drugs) can be appreciated in their ability to block the SGLT2 protein within the kidneys, inhibiting glucose reabsorption, and causing an associated osmotic diuresis. This ameliorates plasma glucose elevations and the negative cardiorenal sequelae associated with the latter. These include aberrant mitochondrial metabolism and oxidative stress burden, endothelial cell dysfunction, pernicious neurohormonal activation, and the development of inimical hemodynamics. Positive outcomes within these domains have been validated with SGLT2i administration. However, by modulating the sodium-glucose cotransporter in the proximal tubule (PT), SGLT2i consequently promotes sodium-phosphate cotransporter activity with phosphate retention. Phosphatemia, even at physiologic levels, poses a risk in cardiovascular disease burden, more so in patients with type 2 diabetes mellitus (T2DM). There also exists an association between phosphatemia and renal impairment, the latter hampering cardiovascular function through an array of physiologic roles, such as fluid regulation, hormonal tone, and neuromodulation. Moreover, increased phosphate flux is associated with an associated increase in fibroblast growth factor 23 levels, also detrimental to homeostatic cardiometabolic function. A contemporary commentary concerning this notion unifying cardiovascular outcome trial data with the translational biology of phosphate is scant within the literature. Given the apparent beneficial outcomes associated with SGLT2i administration notwithstanding negative effects of phosphatemia, we discuss in this review the effects of phosphate on the cardiometabolic status in patients with T2DM and cardiorenal disease, as well as the mechanisms by which SGLT2i counteract or overcome them to achieve their net effects. Content drawn to develop this conversation begins with proceedings in the basic sciences and works towards clinical trial data.     

Oral Phosphate Binders: Phosphate Binding Capacity of Iron (III) Hydroxide Complexes Containing Saccharides; and Their Effect on the Urinary Excretion of Calcium and Phosphate in Rats

Phosphate binders that contain aluminum or calcium are frequently prescribed to treat hyperphosphatemia in patients with end-stage renal disease (ESRD), but an accumulation of aluminum can lead to encephalopathy, aluminum related bone disease (ARBD) such as osteomalacia, anaemia, and resistance to erythropoietin, and calcium accumulation can lead to hyperculcaemia. High phosphate concentrations are reducd in vitro and in vivo by a phosphate adsorption pill, which is synthesized by hydrolyzing ferrous sulfate in the presence of saccharides, to form an iron (III)-saccharide complex that is acid resistant anti binds phosphate greater than iron (III) hydroxide alone. Under in vitro conditions, containing 3.26 mg P/dL, the iron (III)-sucrose complex showed the highest phosphate adsorption capacity at pH 2 with artificial gastric juice, 58.9 mg P/g binder. For the 7 day in vivo study, 0% (Group 1), 1% (Group 2), 4% (Group 3), and 8% (Group 4) iron (III)-sucrose complex was admixed into the rodent chow by weight and fed to 15 male Wistar rats. The weight and volume of the feces and urine, and the calcium, iron, and phosphorus excretions in the feces and urine samples were monitored for any signs of irregularity. Total urine outfrow was collected during a 24-h period to determine the amount of phosphate recovered, which indicates the ability of the phosphate binder to reduce gastrointestinal phosphate absorption. The fecal iron excretion was significantly effected by the amount of binder ingested throughout the study for Group 2 (p < 0.001), Group 3 (p < 0.01), and Group 4 (p < 0.001). The urinary calcium excretion (mg/rat/24-h) significantly increased by the 7th day for Group 2 (p < 0.05) and Group 4 (p < 0.01) in comparison to the control. Finally, after 7 days, there was a significant drop in the urinary phosphorus levels (mg P/rat/24-h) in a dose dependant manner for Group 2: from 7.82 ± 1.46 to 1.98 ± 0.10 mg P/rat/24-h (102 mg P/dL/24-h; p < 0.05); Group 3: from 6.70 ± 1.14 to 0.16 ± 0.09 mg P/rat/24-h (6.0 mg P/dL/24-h; p < 0.01); and Group 4: fiom 8.25 ± 0.67 to 0.04 ± 0.01 mg P/rat/24-h (0.9 mg P/dL/24-h; p < 0.01). The results show that this new adsorbent might provide an alternative to conventional aluminum and calcium containing phosphate-binding agents for combating hyperphosphataemia.     

Changes in Basic Metabolic Elements Associated With the Degeneration and Ossification of Ligamenta Flava

Abstract

Objective: To determine the association between levels of basic metabolic elements and degeneration and ossification of the ligamentum flavum (LF).

Subjects: Fourteen consecutive patients with degenerative lumbar stenosis, 11 with ossification of the thoracic ligamenta flava, and 11 control subjects.

Methods: The basic elements of calcium (Ca), phosphorus (P), magnesium (Mg), zinc (Zn), copper (Cu), manganese (Mn), molybdenum (Mo), and fluoride (F) in the specimens were measured using atomic absorption spectrometry, the phosphomolybdic blue method, and a fluoride-selected electrode.

Results: Ca content and the ratio of Ca/Mg in the LF specimens increased significantly in the sequence of control, degeneration, and ossification groups. Compared with values for the control group, the Zn, Mn, and Mo contents in the ossification and degeneration groups were significantly lower (P < 0.01 ); in contrast, Cu content was significantly higher (P < 0.01 ). As to F, its content in the specimens of the ossification group was much higher than those in the degeneration and control groups (P < 0.01); the F content in the ligamenta flava and sera from patients with fluorosis was also significantly higher than in those from patients without fluorosis (P < 0.01). Compared with the control group, there were no differences in the F content in serum from patients without fluorosis; however, the F content in ligamenta flava specimens from patients without fluorosis was significantly higher (P < 0.01).

Conclusions: There are trends in the contents of basic metabolic elements in the degeneration and ossification of ligamenta flava. These basic metabolic elements may play an important role in this process.     

慢性肾脏病继发性甲状旁腺功能亢进的治疗进展

继发性甲状旁腺功能亢进症(SHPT)是慢性肾脏病（CKD）患者最常见的并发症之一,是肾性骨病的重要原因,也是加速CKD病程进展和增加病死率的重要合并症。严重的SHPT是临床医生面临的难题,也是近年来研究的热点。本文综述了CKD导致SHPT的治疗新进展。     

碳酸镧治疗维持性透析患者并发高磷血症疗效观察

目的评价碳酸镧治疗维持性透析患者高磷血症的有效性。方法根据是否服用碳酸镧将患者分为观察组和对照组。碳酸镧观察组16例,均服用碳酸镧,每次500 mg,2³次/d;对照组23例,口服碳酸钙,0.75g/次,每天2次。结果与治疗前比较,治疗1、2、6个月后,观察组血磷水平均下降(P<0.01),对照组下降不明显(P>0.05),且观察组较对照组各时点血磷下降明显[(1.80±0.25)mmol/L vs.(2.21±0.33)mmol-/L、(1.56±0.19)mmol儿vs.(2.28±0.26)mmol/L、(1.51±0.17)mmo;/L vs.(2.29±0.25)mmol/L](P<0.01)。2组血钙下降均不明显(P>0.05);治疗6个月后,观察组PTH较对照组下降更明显[(614.8±178.38)pg/ml vs.(982.63±716.34)pg/ml](P<0.05)。结论碳酸镧治疗维持性透析患者高磷血症较传统降磷方法治疗有效。