Efficacy and safety of Cinacalcet on secondary hyperparathyroidism in Chinese chronic kidney disease patients receiving hemodialysis

Introduction Secondary hyperparathyroidism (SHPT) develops in patients with chronic renal failure. Cinacalcet hydrochloride has been used successfully in U.S., Europe, and Japan in the treatment of SHPT, while maintaining serum levels of calcium and phosphorus. The efficacy and safety profile of Cinacalcet treatment vs. conventional treatments has been of great interest in clinical practice. In this recent phase III study conducted in China, efficacy and safety of a calcimimetic agent, Cinacalcet (Kyowa Hakko Kirin Co., Ltd.), were assessed for SHPT treatment in stable chronic renal disease patients on hemodialysis. Methods In this double‐blind, multicenter, placebo‐controlled, randomized phase III study, 238 subjects were enrolled in 12 centers and randomly divided into a Cinacalcet group and a placebo group. The percentage of patients achieving a serum parathyroid hormone (PTH) level ≤250 pg/mL was the primary efficacy end point. Serum calcium and phosphorus levels were measured. Adverse events and serious adverse events were recorded, and causal analysis performed. Findings In primary analysis, 25.4% of the Cinacalcet group and 3.5% of the placebo group achieved the primary end point (PTH ≤250 pg/mL). Calcium and phosphorus levels and calcium–phosphorus product were lower in the Cinacalcet group compared with the placebo group. Eleven serious adverse events were reported and considered to be not related to study drugs. Mild to moderate hypocalcemia and reduced calcium levels were reported and considered to be Cinacalcet related. Discussion This phase III study demonstrated that Cinacalcet is effective and well tolerated in treating SHPT in Chinese chronic kidney disease patients on hemodialysis, and in a patient population with much higher baseline PTH levels.     

Modifiable variables affecting interdialytic weight gain include dialysis time,frequency, and dialysate sodium

Interdialytic weight gain (IDWG) is associated with hypertension, left ventricular hypertrophy, and all‐cause mortality. Dialysate sodium concentration may cause diffusion gradients with plasma sodium and influence subsequent IDWG. Dialysis time and frequency may also influence the outcomes of this Na⁺ gradient; these have been overlooked. Our objective was to identify modifiable factors influencing IDWG. We performed a retrospective multivariable regression analyses of data from 86 home hemodialysis patients treated by hemodialysis modalities differing in frequency and session duration to determine factors involved that predict IDWG. Age, diabetic status, and residual renal function did not correlate with IDWG in the univariable analysis. However, using a combination of backwards selection and Akaike information criterion to build our model, we created an equation that predicted IDWG on the basis of serum albumin, age, patient sex, dialysis frequency, and the diffusive balance of sodium, represented by the product of the duration of dialysis and the patient plasma to dialysate Na⁺ gradient. This equation was internally validated using bootstrapping, and externally validated in a temporally distinct patient population. We have created an equation to predict IDWG on the basis of independent factors readily available before a dialysis session. The modifiable factors include dialysis time and frequency, and dialysate sodium. Patient sex, age, and serum albumin are also correlated with IDWG. Further work is required to establish how improvements in IDWG influence cardiovascular and other clinical outcomes.     

Hyperprolactinemia in end‐stage renal disease and effects of frequent hemodialysis

Introduction: End‐stage renal disease is associated with elevations in circulating prolactin concentrations, but the association of prolactin concentrations with intermediate health outcomes and the effects of hemodialysis frequency on changes in serum prolactin have not been examined. Methods: The FHN Daily and Nocturnal Dialysis Trials compared the effects of conventional thrice weekly hemodialysis with in‐center daily hemodialysis (6 days/week) and nocturnal home hemodialysis (6 nights/week) over 12 months and obtained measures of health‐related quality of life, self‐reported physical function, mental health and cognition. Serum prolactin concentrations were measured at baseline and 12‐month follow‐up in 70% of the FHN Trial cohort to examine the associations among serum prolactin concentrations and physical, mental and cognitive function and the effects of hemodialysis frequency on serum prolactin. Findings: Among 177 Daily Trial and 60 Nocturnal Trial participants with baseline serum prolactin measurements, the median serum prolactin concentration was 65 ng/mL (25th–75th percentile 48–195 ng/mL) and 81% had serum prolactin concentrations >30 ng/mL. While serum prolactin was associated with sex (higher in women), we observed no association between baseline serum prolactin and age, dialysis vintage, and baseline measures of physical, mental and cognitive function. Furthermore, there was no significant effect of hemodialysis frequency on serum prolactin in either of the two trials. Discussion: Serum prolactin concentrations were elevated in the large majority of patients with ESRD, but were not associated with several measures of health status. Circulating prolactin levels also do not appear to decrease in response to more frequent hemodialysis over a one‐year period.     

Management of hypophosphatemia in nocturnal hemodialysis with phosphate-containing enema: a technical study

Hypophosphatemia is observed in patients undergoing nocturnal hemodialysis. Phosphate is commonly added to the dialysate acid bath, but systematic evaluation of the safety and reliability of this strategy is lacking. The objectives of this study were 4‐fold. First, we determined whether predictable final dialysate phosphate concentrations could be achieved by adding varying amounts of Fleet^® enema. Second, we assessed the stability of calcium (Ca) and phosphate dialysate levels under simulated nocturnal hemodialysis conditions. Third, we assessed for Ca‐phosphate precipitate. Finally, we evaluated whether dialysate containing Fleet^® enema met the current sterility standards. We added serial aliquots of enema to 4.5 L of dialysate acid concentrate and proportioned the solution on Gambro and Althin/Baxter dialysis machines for up to 8 hours. We measured dialysate phosphate, Ca, pH, and bicarbonate concentrations at baseline, and after simulated dialysis at 4 and 8 hours. We evaluated for precipitation visually and by assessing optical density at 620 nm. We used inoculation of agar to detect bacteria and Pyrotell reaction for endotoxin. For every 30 mL of Fleet^® (1.38 mmol/mL of phosphate) enema added, the dialysate phosphate concentration increased by 0.2 mmol/L. There were no significant changes in dialysate phosphate, Ca, pH, and bicarbonate concentrations over 8 hours. No precipitate was observed in the dialysate by optical density measures at 620 nm for additions of up to 90 mL of enema. Bacterial and endotoxin testing met sterility standards. The addition of Fleet^® enema to dialysate increases phosphate concentration in a predictable manner, and no safety problems were observed in our in vitro studies.     

Calcium phosphate metabolism and bone mineral density with nocturnal hemodialysis

An elevated calcium x phosphate product (Ca x P) is an independent risk factor for vascular calcification and cardiovascular death in dialysis patients. More physiological dialysis in patients undergoing nocturnal hemodialysis (NHD) has been shown to produce biochemical advantages compared with conventional hemodialysis (CHD) including superior phosphate (P) control. Benefits of dialysate with greater calcium (Ca) concentration are also reported in NHD to prevent Ca depletion and subsequent hyperparathyroidism, but there are concerns that a higher dialysate Ca concentration may contribute to raised serum Ca levels and greater Ca x P and vascular disease. The NHD program at our unit has been established for 4 years, and we retrospectively analyzed Ca and P metabolism in patients undergoing NHD (8-9 h/night, 6 nights/week). Our cohort consists of 11 patients, mean age 49.3 years, who had been on NHD for a minimum of 12 months, mean 34.3 months. Commencement was with low-flux (LF) NHD and 1.5 mmol/L Ca dialysate concentration, with conversion to high-flux (HF) dialyzers after a period (mean duration 18.7 months). We compared predialysis serum albumin, intact parathyroid hormone, P, total corrected Ca, and Ca x P at baseline on CHD, after conversion to LF NHD and during HF NHD. We also prospectively measured bone mineral density (BMD) on all patients entering the NHD program. Bone densitometry (DEXA) scans were performed at baseline (on CHD) and yearly after commencement of NHD. With the introduction of HF dialyzers, the Ca dialysate concentration was concurrently raised to 1.75 mmol/L after demonstration on DEXA scans of worsening osteopenia. Analysis of BMD, for all parameters, revealed a decrease over the first 12 to 24 months (N = 11). When the dialysate Ca bath was increased, the median T and Z scores subsequently increased (data at 3 years, N = 6). The mean predialysis P levels were significantly lower on LF NHD vs. CHD (1.51 vs. 1.77 mmol/L, p = 0.014), while on HF NHD P was lower again (1.33 mmol/L, p = 0.001 vs. CHD). Predialysis Ca levels decreased with conversion from CHD to LF NHD (2.58 vs. 2.47 mmol/L, p = 0.018) using a 1.5 mmol/L dialysate Ca concentration. The mean Ca x P on CHD was 4.56 compared with a significant reduction of 3.74 on LF NHD (p = 0.006) and 3.28 on HF NHD (p = 0.001 vs. CHD), despite the higher dialysate Ca in the latter. We conclude that an elevated dialysate Ca concentration is required to prevent osteopenia. With concerns that prolonged higher Ca levels contribute to increased cardiovascular mortality, the optimal Ca dialysate bath is still unknown. Better P control on NHD, however, reduces the overall Ca x P, despite the increased Ca concentration, therefore reducing the risk of vascular calcification.     

Dialysate calcium and calcium/phosphate balance in hemodialysis

The changing pattern of pharmaceutical use in dialysis patients has resulted in several alterations to dialysate calcium concentration over the past 40 years. Non‐calcium–containing phosphate binders and calcimimetics are the most recent examples of drugs that influence the overall calcium balance in dialysis patients. Renal osteodystrophy, vascular disease, and mortality are believed to be linked in patients with chronic kidney disease (CKD), although to date most of the evidence is based only on statistical associations. The precise pathophysiology of vascular calcification in end‐stage renal disease is unknown, but risk factors include age, hypertension, time on dialysis, and, most significantly, abnormalities in calcium and phosphate balance. Prospective studies are required before “cause and effect” can be established with certainty, but it is an active metabolic process with inhibitors and promoters. Serum calcium levels are clearly influenced by dialysate calcium and may therefore play an important role in influencing vascular calcification. Clinical management of hyperphosphatemia is being made easier by the introduction of potent non‐calcium–based oral phosphate binders such as lanthanum carbonate. Short‐term and long‐term studies have demonstrated its efficacy and safety. Vitamin D analogs have been a disappointment in the control of serum parathyroid hormone (PTH) levels, but evidence is emerging that vitamin D has other important metabolic effects apart from this, and may confer survival advantages to patients with CKD. Calcimimetics such as cinacalcet enable much more effective and precise control of PTH levels, but at the cost of a major financial burden. While it is unreasonable to expect that any one of these recent pharmacological developments will be a panacea, they provide researchers with the tools to begin to examine the complex interplay between calcium, phosphate, vitamin D, and PTH, such that further progress is fortunately inevitable.     

Looking at calcimimetics impact on hypercalcemia of immobilization: hypotheses and a case study

For the treatment of secondary hyperparathyroidism (HPTH-II) in dialysis patients and hypercalcemia in patients with parathyroid carcinoma. Calcimimetics are a new class of drugs approved in the European Community and the United States by the Food and Drug Administration that were designed to suppress parathyroid hormone (PTH) levels with a simultaneous reduction in serum calcium and phosphorus levels, and calcium phosphorus product (Ca x P). Hypocalcemia is a frequent finding during the correction phase of the HPTH-II with calcimimetics. By contrast, the appearance of a hypercalcemia has yet to be described. In this paper, we report a case of severe hypercalcemia of immobilization in a 40-year-old hemodialyzed woman treated by cinacalcet HCl for a severe HPTH-II (PTH>1,000 pg/mL). A kidney transplantation recipient 1983 to 1995, she was diagnosed with Charcot-Marie Tooth disease in 1991. She had multiple orthopedic interventions for kidney-related osteoarticular problems probably favored by the kidney graft and the immunosuppressive treatment. While she was receiving the maximum dose of 180 mg/day of cinacalcet HCl and PTH at 443 pg/mL, she needed to be hospitalized for a right hip prothesis. Two weeks after the intervention she developed a symptomatic hypercalcemia of 3.57 mmol/L which was resistant to several measures including lowering the calcium concentration in the dialysate, withdrawing all vitamin D and calcium supplementation and the administration of calcitonin. Her serum calcium level was finally stabilized in the 2.37-2.95 mmol/L by administration of a single intravenous dose of pamidronate. This observation illustrates that the pharmacological activation of the parathyroid CaR and other putative CaR on bone cells by calcimimetics did not protect against the occurrence of hypercalcemia of immobilization favored by a severe HPTH-II in a hemodialysis patient.     

Left ventricular mass index and aortic arch calcification score are independent mortality predictors of maintenance hemodialysis patients

To analyze predictive factors for all‐cause mortality, cardiovascular (CV) mortality, nonfatal CV events (CVE) in maintenance hemodialysis (MHD) patients, and to compare the effects of standard hemodialysis (HD) and online hemodiafiltration (HDF) on these factors and outcomes. A total of 333 MHD patients were prospectively followed up for 50 ± 15 months and all‐cause death, CV death and CVE were registered. At the baseline, demographic, clinical, and laboratory data of the whole population were recorded. Then, patients were stratified into two groups according to the dialysis modalities, HD (n = 268) and HDF (n = 65). At the end of 6th month, clinical and laboratory data were recorded again. The predictive factors at baseline for all‐cause mortality, CV mortality, and CVE were analyzed by Cox regression. The effects of HD and HDF on these factors at the 6th month and long‐term outcomes were compared by t‐test and Kaplan–Meier method, respectively. Age, gender, left ventricular mass index (LVMI), aortic arch calcification score (AoACS), hemoglobin (Hb) <10 g/dL, and ferritin >500 ng/mL maintained independent associations with all‐cause mortality. C‐reactive protein (CRP), LVMI, AoACS, and Hb <10 g/dL were associated with CV mortality. Prior cardiovascular disease (CVD), AoACS and LVMI were independent predictors of nonfatal CVE. Higher body mass index (BMI), body weight, total serum cholesterol, Hb concentration, and lower CRP level, LVMI, and AoACS were found in patients on HDF at the end of the 6th month. Improved outcomes with longer survival time for all‐cause mortality, CV mortality, and CVE were found in HDF group. Age, gender, LVMI, AoACS, Hb, and ferritin were predictors of all‐cause mortality in MHD patients. CRP, LVMI, AoACS, and Hb were associated with CV mortality. Prior CVD, AoACS, and LVMI were independent predictors of nonfatal CVE. HDF could improve BMI, body weight, total serum cholesterol, Hb, CRP, LVMI, AoACS, and long‐term outcomes, including all‐cause mortality, CV mortality, and CVE.     

Effects of l‐carnitine supplement on serum inflammatory cytokines,C‐reactive protein,lipoprotein (a), and oxidative stress in hemodialysis patients with Lp (a) hyperlipoproteinemia

Inflammation, oxidative stress, and high concentration of serum lipoprotein (a) [Lp (a)] are common complications in hemodialysis patients. The present study was designed to investigate the effects of l ‐carnitine supplement on serum inflammatory cytokines, C‐reactive protein (CRP), Lp (a), and oxidative stress in hemodialysis patients with Lp (a) hyperlipoproteinemia [hyper Lp (a)]. This was an unblinded, randomized clinical trial. Thirty‐six hyper Lp (a) hemodialysis patients (23 men and 13 women) were randomly assigned to either a carnitine or control group. Patients in the carnitine group received 1000 mg/d oral l ‐carnitine for 12 weeks, whereas patients in the control group did not receive any l ‐carnitine supplement. At baseline and the end of week 12, 5 mL of blood were collected after a 12‐ to 14‐hours fast and serum free carnitine, CRP, interleukin‐1β, interleukin‐6 (IL‐6), tumor necrosis factor‐α, Lp (a), and oxidized low‐density lipoprotein were measured. Serum free carnitine concentration increased significantly by 86% in the carnitine group at the end of week 12 compared with baseline (P<0.001), while serum CRP and IL‐6 showed a significant decrease of 29% (P<0.05) and 61% (P<0.001), respectively. No significant changes were observed in serum free carnitine, CRP, and IL‐6 in the control group. There were no significant differences between the two groups in mean changes of serum interleukin‐1β, tumor necrosis factor‐α, Lp (a), and oxidized low‐density lipoprotein concentrations. l ‐carnitine supplement reduces inflammation in hemodialysis patients, but has no effect on hyper Lp (a) and oxidative stress.     

Predictors of cardiovascular events in hemodialysis patients after stress myocardial perfusion imaging

Cardiovascular prognosis in patients under normal stress myocardial perfusion images (MPI) is generally excellent. However, this is not true for patients with chronic kidney disease (CKD) treated by hemodialysis. This study evaluated prognostic factors of adverse cardiovascular events in hemodialysis patients in whom stress MPI was performed. Pharmacological stress MPI was performed in 88 hemodialysis patients, and we retrospectively followed‐up for 26 months. Cardiovascular events included cardiac death, nonfatal myocardial infarction, and unstable angina. Cardiovascular events occurred in 16 patients (18%). Univariate Cox regression analysis revealed that peripheral artery disease (PAD) and parameters of stress MPI were significant predictors of cardiovascular events. Multivariate Cox regression analysis revealed that only PAD (hazard ratio = 6.54; P = 0.002), and abnormal stress MPI (hazard ratio = 8.26; P = 0.008) were independent and significant predictors of cardiovascular events. Kaplan–Meier analysis showed better prognosis in patients with normal stress MPI than in patients with abnormal stress MPI (P < 0.001, log–rank test). However, in patients with normal stress MPI, cardiovascular events occurred in 10 of the 76 patients (13%). Among patients with normal stress MPI, Kaplan–Meier analysis showed that patients with no PAD had better prognosis than patients with PAD (P = 0.001, log–rank test). In hemodialysis patients, both PAD and stress MPI were powerful cardiovascular predictors. Normal stress MPI alone cannot guarantee good prognosis in terms of cardiovascular events. Consideration of PAD may improve the predictive value of stress MPI in some patients.     

Cervical tumoral calcinosis with secondary hyperparathyroidism in a chronic hemodialysis patient

Tumoral calcinosis is an uncommon and severe complication of chronic renal failure. It is generally associated with the presence of a high‐serum calcium‐and‐phosphorus product. We report here a case of a patient on maintenance hemodialysis who presented with progressively increasing, solitary, tumor‐like swelling over the nape of the neck. A 50‐year‐old female on thrice weekly maintenance hemodialysis for the last 3 years presented with a small swelling over the nape of the neck that had been progressively increasing over the last 1 year to cricket ball size. The patient was investigated and diagnosed as having tumoral calcinosis. The metastatic calcification occurring in the patient was most likely related to high calcium × phosphate product with coexistent secondary hyperparathyroidism possibly aggravated by vitamin D therapy. The patient was treated with withdrawal of vitamin D therapy, strict control of serum phosphate levels with noncalcemic phosphate binders, and subtotal parathyroidectomy. The neck swelling started decreasing in size after 2 months of parathyroidectomy and there was marked clinical improvement with drop in serum parathormone levels, over a period of 6 months. After 2 years of parathyroidectomy, the neck swelling again started increasing in size with increase in serum parathormone levels. The patient was treated with cinacalcet and the neck swelling gradually decreased in size along with control of serum parathormone and phosphate levels.     

Severe carbamazepine intoxication unresponsive to albumin‐enhanced continuous venovenous hemodiafiltration with low dialysate flow

Carbamazepine (CBZ) intoxication can be associated with severe toxicity, including neurological and cardio‐respiratory abnormalities. Highly protein‐bound, CBZ is not removed efficiently through conventional hemodialysis. Charcoal hemoperfusion is the most effective extracorporeal elimination therapy for CBZ intoxication. Recent reports have indicated that continuous venovenous hemodiafiltration (CVVHDF), albumin‐enhanced continuous venovenous hemodialysis, high‐flux hemodialysis and plasma exchange can be as effective as charcoal hemoperfusion. In contrast to recent reports, which demonstrated the effectiveness of CVVHDF with high dialysate flow in CBZ intoxication, we observed that serum CBZ level was decreased minimally by albumin‐enhanced CVVHDF with low dialysate flow. Therefore, albumin‐enhanced CVVHDF with high dialysate flow should be considered in severe CBZ intoxication, if hemoperfusion is unavailable because of the lack of facilities or if it cannot be performed.     

Endotoxemia after high cutoff hemodialysis for treatment of patient with multiple myeloma can be prevented by using ultrapure dialysate: A case report

To report endotoxemia presented in a case with multiple myeloma (MM) treated by high cutoff hemodialysis (HCO‐HD) being prevented by using ultrapure dialysate. A female inpatient with MM received six times HCO‐HD (HCO 2100 dialyzer) within 3 weeks after initiation of a chemotherapy based on vincristine + epirubicin + dexamethasone protocol. Conventional dialysate was used in the first three times and then changed to ultrapure dialysate due to elevation of body temperature after HCO‐HD. Free light chains (FLC) and endotoxin levels in blood and dialysate were monitored. After six times HCO‐HD, her serum FLC λ decreased from 4689 mg/L to 492.7 mg/L, with a trend of decline of serum creatinine. The clearance, reduction ratio, and removal amount of FLC λ was 38.4 mL/min, 71.0–85.2%, and 9.06–18.02 g, respectively, in the setting of dialysate flow rate 500 mL/min, while in the setting of dialysate flow rate 200 mL/min, the removal efficacy of FLC λ was lower than the former. A rise of body temperature up to 38.5°C after treatment and endotoxemia (endotoxin levels 0.122 EU/mL) was found when using conventional dialysate (endotoxin levels 0.112–0.145 EU/mL), but not seen after changing to ultrapure dialysate. Combined with appropriate chemotherapy, HCO‐HD can effectively remove and reduce blood FLC. Attention should be paid to the endotoxemia and the rise of temperature after treatment when conventional dialysate is used, which can be prevented by using ultrapure dialysate.