Achieving targets for bone and mineral metabolism: the impact of cinacalcet HCl in clinical practice

Achieving the K/DOQI targets for bone and mineral metabolism has proven difficult with the use of vitamin D analogues and phosphate binders. The introduction of cinacalcet HCl provided a new tool with a novel therapeutic mechanism of action. The purpose of this study was to evaluate the effect of the introduction of combination algorithm for managing secondary hyperparathyroidism (SHPT) on phosphorus, calcium, and biointact parathyroid hormone (PTH). The 61 patients who dialyzed in the facility from January 2004 (baseline) and who remained in the facility as of April 2005 (follow-up) were included in the study. In the baseline period, 37 (61%) of the patients received paricalcitol at some time during the 3-month observation period. In the follow-up period, 19% or 31% of the patients received cinacalcet HCl. Of those not receiving cinacalcet HCl, 67% had PTH at or below target, 17% were felt to be noncompliant with oral meds, 7% had low calcium, and 10% either could not get the medication or were not switched to the combination pathway. Compared with the baseline period, the percent of patients who met the PTH target increased from 19.7% to 37.7%, p<0.05. The percent of patients meeting all 4 targets increased from 14.8% to 24.6%, although this did not reach statistical significance. The introduction of cinacalcet HCl into a treatment algorithm for management of SHPT resulted in a significant increase in the percentage of patients achieving the PTH target while maintaining the other mineral metabolism targets.     

Calcium‐phosphate and parathyroid intradialytic profiles: A potential aid for tailoring the dialysate calcium content of patients on different hemodialysis schedules

Severe hyperparathyroidism is a challenge on hemodialysis. The definition of dialysate calcium (Ca) is a pending issue with renewed importance in cases of individualized dialysis schedules and of portable home dialysis machines with low‐flow dialysate. Direct measurement of calcium mass transfer is complex and is imprecisely reflected by differences in start‐to‐end of dialysis Ca levels. The study was performed in a dialysis unit dedicated to home hemodialysis and to critical patients with wide use of daily and tailored schedules. The Ca‐phosphate (P)‐parathyroid hormone (PTH) profile includes creatinine, urea, total and ionized Ca, albumin, sodium, potassium, P, PTH levels at start, mid, and end of dialysis. “Severe” secondary hyperparathyroidism was defined as PTH > 300 pg/mL for ≥3 months. Four schedules were tested: conventional dialysis (polysulfone dialyzer 1.8–2.1 m²), with dialysate Ca 1.5 or 1.75 mmol/L, NxStage (Ca 1.5 mmol/L), and NxStage plus intradialytic Ca infusion. Dosages of vitamin D, calcium, phosphate binders, and Ca mimetic agents were adjusted monthly. Eighty Ca‐P‐PTH profiles were collected in 12 patients. Serum phosphate was efficiently reduced by all techniques. No differences in start‐to‐end PTH and Ca levels on dialysis were observed in patients with PTH levels < 300 pg/mL. Conversely, Ca levels in “severe” secondary hyperparathyroid patients significantly increased and PTH decreased during dialysis on all schedules except on Nxstage (P < 0.05). Our data support the need for tailored dialysate Ca content, even on “low‐flow” daily home dialysis, in “severe” secondary hyperparathyroid patients in order to increase the therapeutic potentials of the new dialysis techniques.     

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.     

Use of 3‐hour daily hemodialysis and paricalcitol in patients with severe secondary hyperparathyroidism: A case series

Patients with poor metabolic control receiving conventional hemodialysis are at risk for developing severe secondary hyperparathyroidism. We postulated that daily hemodialysis may be effective at controlling parathyroid hormone (PTH) in the setting of severe secondary hyperparathyroidism by improving the control of hyperphosphatemia and allowing increased use of vitamin D analogs. We present 5 patients with severe secondary hyperparathyroidism (median iPTH=1783 pg/mL) who were treated with 3‐hour daily hemodialysis (3 hours × 6 times a week). Daily hemodialysis, at 1 year, was associated with a 70.4% reduction in median PTH (1783 pg/mL [interquartile range: 1321–1983]–472 pg/mL [334, 704], P<0.001). Additionally, there was an increase in paricalcitol dose from 0 mcg/d to 10.8 (2.00, 11.7) mcg/d, a 39% reduction in calcium × phosphorus product (80.3 ± 26.8–48.9 ± 14.0, P<0.01), a 52% reduction in serum phosphorus (9.90 ± 2.34–4.75 ± 0.79 mg/dL, P<0.0001), and a 17.6% increase in serum calcium (8.18 ± 2.04–9.62 ± 0.93 mg/dL, P<0.01). Three‐hour daily hemodialysis with the use of high‐dose paricalcitol is associated with improved control of severe secondary hyperparathyroidism.     

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.     

Self-reported symptoms in patients on hemodialysis with moderate to severe secondary hyperparathyroidism receiving combined therapy with cinacalcet and low-dose vitamin D sterols

Patients with secondary hyperparathyroidism experience a variety of clinical symptoms which may adversely affect physical and mental function. As part of a multicenter, open-label clinical trial, subjects completed a questionnaire that included the Medical Outcomes Study Short Form-36 and 14 kidney disease-related symptoms at multiple time points during the study. Out of the 567 subjects who received at least one dose of cinacalcet, 528 to 535 (93.8-94.4%) completed all or portions of the questionnaire at baseline. The median bioactive parathyroid hormone (PTH) was 294 pg/mL (10%, 90% range, 172-655 pg/mL). Following treatment with cinacalcet and low-dose vitamin D sterols, subjects reported significant improvement in the frequency of pain in muscles, joints and bones, stiff joints, dry skin, itchy skin, excessive thirst, and trouble with memory. At end of the efficacy assessment phase (Weeks 16 to 22), the magnitude of improvement was the greatest in joint pain, bone pain, dry skin, and excessive thirst (>5 on a 0-100 scale; P < 0.001). There were no clinically or statistically significant changes in any of the Short Form-36 subscales or in the physical or mental health composite scores. Among patients on hemodialysis with moderate to severe secondary hyperparathyroidism, treatment with cinacalcet and low-dose vitamin D sterols results in significant improvement in pain in the muscles, joints and bones, joint stiffness, dry and itchy skin, excessive thirst, and trouble with memory.     

Sternal instability in a hemodialysis patient with secondary hyperparathyroidism

A 77‐year‐old man, 11 years under chronic hemodialysis treatment for chronic renal failure of unknown origin, presented with anterior chest pain, dyspnea with paradoxical breathing, and sternal instability after a simple fall from a standing height. Patient underwent three‐vessel coronary artery bypass grafting 31 months ago. Computed tomography with three‐dimensional volume rendering showed sternal nonunion with a great gap between the two halves of the sternum and at least one fracture in the left half of the sternum. A successful surgical repair followed. Patient suffered from severe secondary hyperparathyroidism for many years. Despite treatment with sevelamer, paricalcitol and cinacalcet, intact parathyroid hormone was 1682 pg/mL. During the last 5 years, serum intact parathyroid hormone remained steadily above 1000 pg/mL. Patient refused parathyroidectomy in the past. We assume that long‐lasting severe hyperparathyroidism contributed to this rare and life‐threatening complication of median sternotomy in our patient, due to the detrimental effect of hyperparathyroidism on bone metabolism and its association with increased incidence of bone fractures and defect in bone fracture healing.     

Severe hypercalcemia caused by Milk‐Alkali syndrome requiring urgent hemodialysis – Tums by the ton

An increased frequency of the Milk‐Alkali syndrome in the last several years has been noticed related to increasing use of calcium carbonate as a phosphate binder in CKD patients, as an antacid or as calcium supplementation. We present a case of severe hypercalcemia secondary to Milk‐Alkali syndrome that precipitated acute renal failure requiring urgent hemodialysis. A 59-year‐old male with history of hypertension, diabetes mellitus, and acid reflux presented to the ER with confusion, lethargy, nausea, vomiting, and diarrhea. His family relayed a history of recent indigestion and relief with Tums. He was taking several tablets at short intervals to self‐treat the indigestion. At the time of presentation, patient was confused and noted to be dehydrated. Lab findings were significant for elevated BUN/Cr‐ 121 mg/dl/11.1 mg/dl (baseline Cr 1.1 mg/dl few months ago), bicarbonate 38 mg/dl, calcium 16.7 mg/dl, ionized Ca of 1.76 mmol/L, iPTH 10 pg/ml, PTHrP 0.7 pg/ml. Medical management with intravenous fluids and furosemide showed no improvement in renal failure, or calcium level. Patient was then started on hemodialysis with 2.0 mmol/L calcium in the dialysate the next day. There was gradual improvement in patient's mental status, calcium values, and renal failure over the ensuing 2 weeks.
Discussion and Conclusions:  The diagnosis of Milk‐Alkali syndrome is made on the basis of history. Metabolic abnormalities involved in this syndrome are hypercalcemia with low to normal PTH and Vit. D levels, renal failure, and metabolic alkalosis. Failed medical management required acute dialysis in this patient. Acute hemodialysis in such a case could be life saving. Due to increasing use of calcium carbonate for dyspepsia and osteoporosis, patients should be made aware of these severe, potentially life-threatening adverse effects.     

Bone‐specific alkaline phosphatase and bone turnover in African American hemodialysis patients

Introduction: Noninvasive measures of bone activity include intact parathyroid hormone (iPTH) and bone‐specific alkaline phosphatase (BSAP). Whether BSAP measurement alone or in combination with other biochemical data provides more reliable information about bone turnover than iPTH alone in African Americans on hemodialysis is unknown. Methods: This cross‐sectional study aimed to determine the optimal predictor and cutoff points for BSAP, iPTH, calcium and phosphorus in classifying bone biopsy findings. Forty‐three African American hemodialysis patients were available for analysis. Biochemical data on the day of biopsy across a spectrum of qualitative histologic bone features were compared. Classification and regression tree analysis was used to determine both the optimal predictor and cutoff points for BSAP, iPTH, calcium and phosphorus in identifying bone turnover status. Findings: Seven subjects had adynamic disease, 31 had mild/moderate hyperparathyroid bone features, and five had severe hyperparathyroid bone disease. BSAP was the optimal predictor of bone biopsy with a cutoff point of 22 ng/mL. Calcium and phosphorus had no predictive value. At BSAP ≤ 22 ng/mL, subjects had either adynamic bone disease or mild/moderate hyperparathyroid bone disease but iPTH was not useful in further classifying biopsy findings. When BSAP was >22 ng/mL, subjects had either mild/moderate or severe hyperparathyroid bone disease, and iPTH was useful in further classifying biopsy findings. With BSAP > 22 ng/mL and iPTH < 726 pg/mL, all subjects had mild/moderate bone turnover features. Discussion: Compared to iPTH, BSAP was shown to be the optimal predictor of biopsy findings with an optimal cutoff at 22 ng/mL.     

Marked improvement in bone metabolism parameters after increasing the dialysate calcium concentration from 2.5 to 3 mEq/L in nonhypercalcemic hemodialysis patients

The optimal dialysate calcium (Ca) concentration for hemodialysis (HD) patients is set at 2.5 mEq/L according to Kidney Disease Outcomes Quality Initiative (K-DOQI) guidelines. This recommendation is opinion-based and could negatively affect secondary hyperparathyroidism. Studies have suggested that a dialysate Ca of 3.0 mEq/L is a compromise between bone protection and cardiovascular risk. The aim of our study was to investigate the effect on bone metabolism parameters after increasing the dialysate Ca concentration from 2.5 to 3.0 mEq/L. The dialysate Ca concentration in our patients was increased from 2.5 to 3.0 mEq/L. Patients with hypercalcemia, normal-high Ca levels with a high Ca-Phosphorus product (Ca x P), excessively suppressed parathyroid hormone (PTH), or a past medical history of calciphylaxis were excluded. Twenty-two patients were studied over 20 weeks. Parathyroid hormone levels decreased significantly (442 +/- 254 vs. 255 +/- 226 pg/mL; p=0.000), without significant changes in serum Ca, P, and Ca x P levels at any sampling point. Better control of secondary hyperparathyroidism allowed us to decrease the paracalcitol dosage in 6 of the 12 patients who had been treated with this drug at the beginning of the study. Other potential factors involved in PTH secretion were not modified. A significant improvement in the rate of patients with 3 or more K-DOQI parameters within the target ranges (8 [36%] vs. 12 [55%]; p=0.026) was observed. In the absence of hypercalcemia or excessively suppressed PTH, an increase from 2.5 mEq to 3.0 mEq/L in dialysate Ca concentration resulted in better control of secondary hyperparathyroidism without affecting Ca, P, and Ca x P levels, thus enabling us to reduce the dosage of vitamin D metabolites.     

Denosumab treatment for refractory hypercalcemia in a hemodialysis patient with tertiary hyperparathyroidism

The most appropriate surgical procedure for tertiary hyperparathyroidism is still controversial. Medical management may be considered in those patients with failed previous surgical intervention. There are limited medical options for tertiary hyperparathyroidism with renal dysfunction. The monoclonal antibody denosumab has been used in patients with osteoporosis and hypercalcemia of malignancy. We report a case of medically refractory hypercalcemia caused by tertiary hyperparathyroidism treated with denosumab. A 46-year-old female was on hemodialysis for 10 years. She was diagnosed with tertiary hyperparathyroidism due to hypercalcemia with a high level of intact parathyroid hormone (iPTH, 1411 pg/ml). After right parathyroidectomy 6 weeks, her serum calcium remained persistently elevated (Ca, 3.17 mmoL/L). Denosumab (60 mg) was administered subcutaneously, and her serum calcium quickly decreased (from 3.43 to 2.04 mmoL/L within 8 days) and was slightly elevated (Ca, 2.8 mmoL/L) 3 months later. We conclude that denosumab has a significant effect on the reduction of serum calcium for tertiary hyperparathyroidism patients. The long-term treatment effect and safety warrant more studies in the future.     

Intensive In-Center Hemodialysis for Children: A Case for Longer Dialysis Duration

Background:  Children with renal failure need their dialysis time optimized. Although traditional surrogate markers of outcome in pediatric patients have been growth and development, increasing attention is being focused on cardiovascular risk factors, such as hypertension, volume overload, malnutrition, and elevated calcium (Ca) and phosphorus (P) levels. We have previously shown catch-up growth without growth hormone, in children undergoing long intermittent hemodialysis. Recently we analyzed retrospectively cardiovascular risk factors in patients treated with this regimen.
Methods:  Patients starting dialysis between 1997 and 2001 and on dialysis at least 6 months were evaluated. Charts were reviewed for Ca, P, parathyroid hormone (PTH), albumin, hemoglobin and blood pressure levels, Ca intake, blood pressure medications, dialysis time, and clearance and ultrafiltration rates. Means were calculated for 6- month intervals, up to 36 months.
Results:  Mean equilibrated dialyzer Kt/V _urea ranged from 1.9 to 2.1, and mean weekly dialysis time for oliguric patients varied from 14.8 to 16.3 hr, with average hourly ultrafiltration rates from 0.3 to 0.4 L. Mean values for P and Ca × P were below 1.8 mM and 4.4 mmol   ² /L ² , respectively. Mean hemoglobin levels were 115 to 126 g/L, albumin 39 to 41 g/L, and PTH 156 to 231 pg/mL. Most patients had normal predialysis blood pressures.
Conclusions:  In this pediatric cohort, intensive center hemodialysis was associated with excellent growth, nutrition, Ca, P, and anemia control and reasonable blood pressure values. Large multicenter studies are needed to better determine optimal dialysis therapy for children.     

The opposing actions of the two parathyroid hormones, 1-84 PTH and 7-84 PTH: Improvement in renal bone and calcium metabolism management

Bone biopsy, while invasive, is the gold standard for assessing bone status. According to published bone biopsy studies, half of the end‐stage renal disease patients have adynamic bone disease. Compared to high‐bone‐turnover disease, adynamic bone disease has the higher mortality and is associated with arterial calcification. The treatment for high‐bone‐turnover disease is divergent from the treatment for adynamic bone disease. The parathyroid hormone (PTH) assay has been relied on as the routine, noninvasive diagnostic method to assess bone status. According to bone biopsy studies, the intact PTH assay has been demonstrated as ineffective at differentiating adynamic bone disease from normal and high‐bone‐turnover disease. For example, bone biopsy studies found the normal range for iPTH to be 451 to 1339 pg/mL and the range for adynamic bone disease to be 400 to 919 pg/mL. Intact PTH measures the sum of the two PTH hormones 1‐84 PTH and 7‐84 PTH. Specific 1‐84 PTH assays neglect the role of the 7‐84 PTH hormone, which is to lower bone turnover. According to independent bone biopsy studies, the 1‐84 PTH/7‐84 PTH ratio is 94% accurate in identifying adynamic bone disease and 94% accurate in assessing bone‐turnover status.     

Intensive weight loss combining flexible dialysis with a personalized,ad libitum,coach‐assisted diet program. A “pilot” case series

Obesity is a growing problem on dialysis. The best approach to weight loss has not been established. The risks of malnutrition may offset the advantages of weight loss. Personalized hemodialysis schedules, with an incremental approach, are gaining interest; to date, no studies have explored its potential in allowing weight loss. This case series reports on combining flexible, incremental hemodialysis, and intensive weight loss. Setting: a small Dialysis Unit, following incremental personalized schedules (2–6 sessions/week, depending on residual function), tailored to an equivalent renal clearance >12 mL/min. Four obese and two overweigh patients (5 male, 1 female; age: 40–63 years; body mass index [BMI] 31.1 kg/m²) were enrolled in a coach‐assisted weight loss program, with an “ad libitum” approach (3–6 foods/day chosen on the basis of their glycemic index and glycemic load). The diet consists of 8 weeks of rapid weight loss followed by 8–12 weeks of maintenance; both phases can be repeated. This study measures weight loss, side effects, and patients' opinions. Over 12–30 months, all patients lost weight (median ?10.3 kg [5.7–20], median ΔBMI–3.2). Serum albumin (pre‐diet 3.78; post‐diet 3.83 g/dL), hemoglobin (pre‐diet 11; post‐diet 11.2 g/dL), and acid–base balance (HCO₃ pre‐diet: 23.3; post‐diet: 23.4 mmol/L) remained stable, with decreasing needs for erythropoietin and citrate or bicarbonate supplements. Calcium‐phosphate‐parathyroid hormone (PTH) balance improved (PTH‐pre 576; post 286 pg/mL). Three out of 4 hypertensive patients discontinued, 1 decreased antihypertensives. None experienced severe side effects. Patient satisfaction was high (9 on a 0–10 analog scale). Personalized, incremental hemodialysis schedules allow patient enrollment in intensive personalized weight loss programs, with promising results.     

Treating mineral metabolism disorders in patients undergoing long hemodialysis: A search for an optimal strategy

In hemodialysis (HD) patients, mineral metabolism (MM) disorders have been associated with an increased mortality rate. We report the evolution of MM parameters in a stable HD population undergoing long hemodialysis by performing an annual cross-sectional analysis for every year from 1994 to 2008. The therapeutic strategy has changed: the dialysate calcium concentration has decreased from a mean of 1.7 ± 0.1 to 1.5 ± 0.07 mmol/L and has been adapted to parathyroid hormone serum levels (from 1 to 1.75 mmol/L). The use of calcium-based and aluminum-based phosphate binders has decreased and they have been replaced by sevelamer; alfacalcidol has partly been replaced by native vitamin D. The percentage of patients with a parathyroid hormone serum level between 150 and 300 pg/mL has increased from 9% to 67% (P<0.001); the percentage of patients with phosphataemia between 1.15 and 1.78 mmol/L has increased from 39% to 84% (P<0.001). The percentage of those with albumin-corrected calcemia between 2.1 and 2.37 mmol/L has increased from 29% to 61% (P<0.001), and that of patients with a calcium-phosphorous product (Ca × P) level >4.4 mmol/L decreased from 8.8% to 2% (P=0.02). Although patients undergo long and intensive HD treatment, MM disorders are common. However, an appropriate strategy, mostly consisting of native vitamin D supplementation, progressive replacement of calcium-based phosphate binders with non–calcium-based ones, and individualization of dialysis session duration and dialysate calcium concentration, would result in a drastic improvement.