Vascular calcification and secondary hyperparathyroidism of severe chronic kidney disease and its relation to serum phosphate and calcium levels

Background and purpose:

Various complications consequent on disordered calcium and phosphate homeostasis occur frequently in chronic kidney disease (CKD) patients. Particularly, vascular calcification has high morbidity and mortality rates. There is a clear need for a better CKD model to examine various aspects of this disordered homeostasis.

Experimental approach:

Oral dosing with adenine induced CKD in rats in only 10 days. Serum calcium, phosphate and parathyroid hormone were measured and calcification in aorta was assessed histologically. The effects of varying phosphorus content of diet or treatment with phosphate binders or active vitamin D₃ on these parameters were examined.

Key results:

After adenine dosing, significant hyperphosphatemia, hypocalcemia and secondary hyperparathyroidism (2HPT) were observed during the experimental period of 15 weeks. Aortic calcification was detected in only some of the animals even at 15 weeks (∼40%). Treatment with vitamin D₃ for 18 days, even at a low dose (100 ng·kg⁻¹, 3–4 times week⁻¹, p.o), caused aortic calcification in all animals and increases in serum calcium levels up to the normal range. The vitamin D₃-induced calcification was significantly inhibited by phosphate binders which lowered serum phosphate levels and the calcium × phosphate product, although serum calcium levels were elevated.

Conclusions:

These data suggest that rats dosed orally with adenine provide a more useful model for analysing calcium/phosphate homeostasis in severe CKD. Controlling serum calcium/phosphate levels with phosphate binders may be better than vitamin D₃ treatment in hyperphosphatemia and 2HPT, to avoid vascular calcification.     

Comparative Efficacy and Safety of Phosphate Binders in Hyperphosphatemia Patients With Chronic Kidney Disease

Background: In this study, we coordinated a network meta‐analysis to establish the efficacy and safety of different agents used in the treatment of hyperphosphatemia patients with chronic kidney disease. Methods: PubMed, CNKI, and Embase were systematically searched to retrieve relevant studies. Outcomes were presented by mean differences, odds ratios, and corresponding 95% credible intervals for continuous outcomes and binary outcomes, respectively. Each therapy was ranked according to the value of surface under the cumulative ranking curve. Consistencies between direct and indirect comparisons were assessed with a node‐splitting plot. Results: In terms of efficacy end points (including levels of serum phosphate, serum calcium, serum intact parathyroid hormone, and serum calcium × phosphorus product), all 7 kinds of agents outperformed or performed at least equally to placebo, with iron‐based phosphate‐binding agents being potentially the most effective. As for safety end points (including mortality, adverse events, and all‐cause discontinuation), almost all agents were equivalent in term of mortality and all‐cause discontinuation except in the comparison between iron‐based phosphate‐binding agents and placebo. Meanwhile, iron‐based phosphate‐binding agents colestilan and nicotinic acid performed poorly compared with placebo in terms of adverse events. Furthermore, iron‐based phosphate‐binding agents were potentially the safest agents followed sequentially by calcium‐based phosphate‐binding agents and placebo. Conclusion: Iron‐based phosphate‐binding agents were the preferable agents when considering efficacy and safety simultaneously.     

Serum phosphate abnormalities in the emergency department

Abnormalities in serum phosphate levels are more prevalent in certain subsets of Emergency Department patients than in the general population. Patients with diabetic ketoacidosis, chronic obstructive pulmonary disease, alcoholism, malignancy, and renal failure are at increased risk. Multiple factors, including nutritional intake, medications, renal or intestinal excretion, and cellular redistribution, are potential etiologies. The clinical manifestations of mild hypophosphatemia or hyperphosphatemia are typically minor and nonspecific (myalgias, weakness, anorexia). When the imbalance is severe, critical complications may occur (tetany, seizures, coma, rhabdomyolysis, respiratory failure, ventricular tachycardia). Mild asymptomatic hypophosphatemia can be treated with oral phosphate supplementation (15 mg/kg daily) on an outpatient basis. Patients with severe or symptomatic hypophosphatemia should be treated with IV phosphate therapy (0.08-0.16 mg/kg over 6 h) and admitted for monitoring and subsequent serum electrolyte testing. Mild asymptomatic hyperphosphatemia is commonly managed in renal failure by limiting dietary intake and reducing absorption with phosphate-binding salts. Hemodialysis may be required for severe hyperphosphatemia with symptomatic hypocalcemia.     

The Effect of Cinacalcet on Calcific Uremic Arteriolopathy Events in Patients Receiving Hemodialysis: The EVOLVE Trial

Background and objectives

Uncontrolled secondary hyperparathyroidism (sHPT) in patients with ESRD is a risk factor for calcific uremic arteriolopathy (CUA; calciphylaxis).

Design, setting, participants, & measurements

Adverse event reports collected during the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial were used to determine the frequency of CUA in patients receiving hemodialysis who had moderate to severe sHPT, as well as the effects of cinacalcet versus placebo. CUA events were collected while patients were receiving the study drug.

Results

Among the 3861 trial patients who received at least one dose of the study drug, 18 patients randomly assigned to placebo and six assigned to cinacalcet developed CUA (unadjusted relative hazard, 0.31; 95% confidence interval [95% CI], 0.13 to 0.79; P=0.014). Corresponding cumulative event rates (95% CI) at year 4 were 0.011% (0.006% to 0.018%) and 0.005% (0.002% to 0.010%). By multivariable analysis, other factors associated with CUA included female sex, higher body mass index, higher diastolic BP, and history of dyslipidemia or parathyroidectomy. Median (10%, 90% percentile) plasma parathyroid hormone concentrations proximal to the report of CUA were 796 (225, 2093) pg/ml and 410 (71, 4957) pg/ml in patients randomly assigned to placebo and cinacalcet, respectively. Active use of vitamin K antagonists was recorded in 11 of 24 patients with CUA, nine randomly assigned to placebo, and two to cinacalcet, in contrast to 5%–7% at any one time point in patients in whom CUA was not reported.

Conclusion

Cinacalcet appeared to reduce the incidence of CUA in hemodialysis recipients who have moderate to severe sHPT.     

烟酸治疗维持性血液透析伴高钙高磷血症的有效性及安全性

目的：观察烟酸治疗维持性血液透析同时伴发高钙血症及高磷血症的临床疗效及安全性。方法对经2周洗脱期后血清磷≥1.78 mmol·L-1、血清校正钙≥2.5 mmol·L-1的25例维持性血液透析患者在采用常规治疗基础上给予烟酸口服,观察治疗前及治疗4、8周后血清磷、血清校正钙、钙磷乘积、全段甲状旁腺激素（iPTH）和血碱性磷酸酶、血小板计数、血尿酸、血糖、总胆固醇、三酰甘油、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）的变化。结果与治疗前比较,治疗4周后血清磷及钙磷乘积明显下降（均P〈0.05）,而血清校正钙、血iPTH、血碱性磷酸酶、血小板计数、血尿酸、血糖及总胆固醇、三酰甘油、HDL-C及LDL-C水平无显著变化（均P〉0.05）;与治疗4周后比较,治疗8周后使血清磷及钙磷乘积进一步下降（均P〈0.01）,血iPTH、血碱性磷酸酶、血胆固醇、三酰甘油、LDL-C也显著降低（P〈0.05或P〈0.01）;相反,HDL-C则显著增加（P〈0.05）。血清校正钙、血小板计数、血尿酸及血糖未见显著变化（均P〉0.05）。结论烟酸可有效降低伴有高钙血症血透患者的血磷水平,改善血脂异常,安全性好。     

Cost-Minimization Analysis of Lanthanum Carbonate Versus Sevelamer Hydrochloride in US Patients With End-stage Renal Disease

Purpose

Sevelamer hydrochloride (SH) and lanthanum carbonate (LC) are calcium-free phosphate binders used in the clinical management of hyperphosphatemia in patients with end-stage renal disease (ESRD). The objective of this analysis was to assess the cost-effectiveness of LC monotherapy compared with SH monotherapy in US patients with ESRD in a clinical practice setting.

Methods

This was a post hoc assessment of phosphate binder costs among US patients with ESRD who converted from SH to LC monotherapy in a previously published, 16-week, Phase IV, real-world study. Calculations of drug costs used both average wholesale price (AWP) and wholesale acquisition cost (WAC).

Findings

There were 953 patients with available baseline SH dose data; 950 also had a recorded LC dose >0 mg at baseline, and 691 had dose data available for both SH at baseline and LC at week 16 (post hoc analysis population). Baseline demographic characteristics were similar in excluded patients and the post hoc analysis population. Mean (SD) serum phosphate levels were 5.91 (1.66) mg/dL at baseline and 5.93 (1.85) mg/dL after conversion to LC monotherapy for 16 weeks. Mean AWP costs were US$35.72 (16.89) per day at baseline and US$24.69 (8.28) per day at week 16, yielding an overall mean cost change (defined as LC cost − SH cost) of −US$11.03 (16.37) per day in favor of LC. The overall mean WAC cost change was −US$9.17 (13.64) per day. Within baseline SH dose subgroups 2400 to 4800, >4800 to 7200, >7200 to 9600, and >9600 mg/d, the mean AWP cost change ranged from US$2.78 (9.26) per day in favor of SH for the 2400- to 4800-mg/d subgroup to −US$33.15 (12.58) per day in favor of LC for the >9600-mg/d subgroup. Mean WAC cost changes showed a similar trend, ranging from US$2.33 (7.72) per day to −US$27.59 (10.48) per day. Linear regression analyses revealed that the inflection SH doses corresponding to a mean cost change of zero were 4905 mg/d (AWP) and 4908 mg/d (WAC). For the 455 (66%) patients in the post hoc analysis population who had baseline SH doses at least as high (≥5600 mg/d) as these point estimates, the mean SH:LC tablet ratio was ≥3.7, indicating a mean reduction in the tablet burden after conversion to LC of ≥73%.

Implications

This real-world assessment of comparative phosphate binder drug costs between SH and LC among US patients with ESRD indicates that average cost savings with LC use increased with increasing SH doses. Conversion to LC from SH ≥5600 mg/d reduced drug costs and tablet burden while maintaining serum phosphate levels.     

Real-World Dose-Relativity,Tablet Burden,and Cost Comparison of Conversion Between Sevelamer Hydrochloride/Carbonate and Lanthanum Carbonate Monotherapies

Purpose

Sevelamer hydrochloride/carbonate (SH/C) and lanthanum carbonate (LC) are noncalcium-based phosphate binders used for the management of hyperphosphatemia in patients with end-stage renal disease (ESRD). The objectives of this study were to examine the dose-relativity, tablet burden, and cost difference of bidirectional conversion between SH/C and LC monotherapy in a large cohort of real-world patients with ESRD.

Methods

This retrospective cohort study included three 30-day preconversion periods (days −90 to −61, −60 to −31, and −30 to −1) followed by three 30-day postconversion periods (days 1 to 30, 31 to 60, and 61 to 90); day 0 was the index date of conversion. The full analysis population (FAP) comprised two cohorts: SH/C to LC (S–L) converters and LC to SH/C (L–S) converters. The SH/C:LC dose-relativity ratio was assessed in the dose-relativity subset, defined as patients whose serum phosphate levels fell within a caliper range of ±0.5 mg/dL in the final preconversion (days −30 to −1) and postconversion (days 61 to 90) periods. Tablet burden and phosphate binder costs were assessed in the FAP. Phosphate binder costs were based on average wholesale prices.

Findings

The FAP contained a total of 303 patients, comprising the S–L (128 patients) and L–S (175 patients) converter cohorts. The dose-relativity subset contained 159 patients, 72 from the S–L cohort and 87 from the L–S cohort. The overall mean SH/C:LC dose-relativity ratio was 2.27 (95% CI, 2.04 to 2.52). In SH/C dose strata >800 to 2400, >2400 to 4800, >4800 to 7200, and >7200 mg/d, overall mean dose-relativity ratios were 0.79 (95% CI, 0.57 to 1.10), 1.45 (95% CI, 1.20 to 1.75), 2.05 (95% CI, 1.75 to 2.39), and 3.24 (95% CI, 2.89 to 3.66), respectively. The overall mean tablet burden was 6.6 tablets per day lower with LC monotherapy than with SH/C monotherapy (95% CI, −7.1 to −6.0; P < 0.0001). The overall mean binder cost/patient per month was $1080.40 for SH/C compared with $1006.20 for LC, corresponding to a mean binder cost saving for LC of $74.20/patient per month (95% CI, −141.80 to −6.63; P = 0.032). SH/C >7800 mg/d was the inflection point at which conversion to LC resulted in mean cost savings. Patients requiring SH/C >7800 mg/d comprised 50% of the FAP.

Implications

Converting patients with ESRD and hyperphosphatemia from SH/C to LC monotherapy offers potential drug cost savings and a significant reduction in the daily tablet burden, without compromising the effective management of serum phosphate levels.     

Effect of acute changes of serum phosphate on fibroblast growth factor (FGF)23 levels in humans

Fibroblast growth factor (FGF)23 was identified as a humoral factor involved in the development of several hypophosphatemic diseases. Subsequent studies indicated that FGF23 is a hormone regulating serum phosphate level. However, it is still unknown how the production and serum level of FGF23 are regulated. This study was designed to determine whether acute changes of serum phosphate modulate FGF23 levels in human. Four healthy volunteers participated in the study. In the phosphate infusion study, dibasic potassium phosphate was infused at a rate of 10 mEq/h for 4 h, and serum FGF23 levels were measured for up to 6 h after the start of the infusion. In the carbohydrate study, partially hydrolyzed starch corresponding to 150 g glucose was ingested and FGF23 levels were measured similarly for 6 h. Phosphate infusion significantly increased and carbohydrate ingestion decreased serum phosphate levels, respectively. However, FGF23 did not change by these maneuvers. It is concluded that acute changes of serum phosphate do not modify FGF23 levels in the healthy human.     

肾衰宁胶囊对慢性肾脏病合并高磷血症大鼠的药效学研究

目的 研究肾衰宁胶囊对慢性肾脏病合并高磷血症大鼠模型的改善作用。方法 选择90只雄性SD大鼠,腺嘌呤联合高磷饮食诱导慢性肾脏病合并高磷血症大鼠模型,依据血磷水平及肾损伤程度分为模型组（16只）、司维拉姆组（阳性药,掺食法给予3%碳酸司维拉姆片,14只）和肾衰宁低、中、高剂量组（ig给予肾衰宁胶囊400、600、800 mg·kg^-1,低剂量组15只,高、中剂量组分别有16只）,另设对照组（正常饲料喂养）,连续给药5周。将各组大鼠置于代谢笼中24 h,记录饮水及饮食量,收集各组大鼠24 h尿液及粪便,记录大鼠的尿量、粪便排泄量;试剂盒法测定动物血清磷、钙、肌酐、尿素氮、成纤维细胞生长因子23（FGF-23）、1,25-二羟基维生素D[1,25（OH）₂D]、甲状旁腺激素（PTH）、碱性磷酸酶活力（ALP）水平,计算钙磷乘积;取肾脏称质量、计算肾脏指数,肾脏组织HE、Masson病理染色评价损伤程度;体外磷结合实验检测在pH 3、5、7、8条件下肾衰宁（2.75、5.50、13.75 mg·mL^-1）是否与磷结合。结果 与模型组比较,肾衰宁低、高剂量组日饮食量、24 h排便量、24 h排便颗粒显著升高（P<0.05、0.001）,低、中、高剂量组日饮水量显著降低（P<0.05、0.01）,高剂量组24 h排尿量显著降低（P<0.05）;低、高剂量组血清磷水平、钙磷乘积显著降低（P<0.01、0.001）;高剂量组血清肌酐水平显著降低（P<0.05）,低、高剂量组血清尿素氮水平显著降低（P<0.05、0.01）;各剂量组肾脏外观明显改善,高剂量显著改善肾脏病理损伤程度（P<0.01）;高剂量组FGF-23、PTH、ALP水平显著降低（P<0.05、0.01、0.001）,1,25（OH）₂D水平均显著升高（P<0.001）;体外磷结合实验未出现肾衰宁结合磷的现象。结论 肾衰宁胶囊可以改善模型动物的钙磷代谢紊乱,改善肾损伤,调节钙磷代谢相关激素水平。     

Phosphate binders for the treatment of hyperphosphatemia in chronic kidney disease patients on dialysis: a comparison of safety profiles

Introduction: Hyperphosphatemia is common in the late stages of chronic kidney disease (CKD) and is associated with elevated parathormone levels, abnormal bone mineralization, extraosseous calcification and increased risk of cardiovascular events and death. Several classes of oral phosphate binders are available to help control phosphorus levels. Although effective at lowering serum phosphorus, they all have safety issues that need to be considered when selecting which one to use.

Areas covered: This paper reviews the use of phosphate binders in patients with CKD on dialysis, with a focus on safety and tolerability. In addition to the more established agents, a new resin-based phosphate binder, colestilan, is discussed.

Expert opinion: Optimal phosphate control is still an unmet need in CKD. Nonetheless, we now have an extending range of phosphate binders available. Aluminium has potentially serious toxic risks. Calcium-based binders are still very useful but can lead to hypercalcemia and/or positive calcium balance and cardiovascular calcification. No long-term data are available for the new calcium acetate/magnesium combination product. Lanthanum is an effective phosphate binder, but there is insufficient evidence about possible long-term effects of tissue deposition. The resin-based binders, colestilan and sevelamer, appear to have profiles that would lead to less vascular calcification, and the main adverse events seen with these agents are gastrointestinal effects.