Grahame J. Elder

Serum Levels of Phosphorus, Parathyroid Hormone, and Calcium and Risks of Death and Cardiovascular Disease in Individuals With Chronic Kidney Disease: A Systematic Review and Meta-analysis

CONTEXT Clinical practice guidelines on the management of mineral and bone disorders due to chronic kidney disease recommend specific treatment target levels for serum phosphorus, parathyroid hormone, and calcium. OBJECTIVE To assess the quality of evidence for the association between levels of serum phosphorus, parathyroid hormone, and calcium and risks of death, cardiovascular mortality, and nonfatal cardiovascular events in individuals with chronic kidney disease. DATA SOURCES The databases of MEDLINE (1948 to December 2010) and EMBASE (1947 to December 2010) were searched without language restriction. Hand searches also were conducted of the reference lists of primary studies, review articles, and clinical guidelines along with full-text review of any citation that appeared relevant. STUDY SELECTION Of 8380 citations identified in the original search, 47 cohort studies (N = 327,644 patients) met the inclusion criteria. DATA EXTRACTION The characteristics of study design, participants, exposures, and covariates together with the outcomes of all-cause mortality, cardiovascular mortality, and nonfatal cardiovascular events at different levels of serum phosphorus, parathyroid hormone, and calcium were analyzed within studies. Data were summarized across studies (when possible) using random-effects meta-regression. DATA SYNTHESIS The risk of death increased 18% for every 1-mg/dL increase in serum phosphorus (relative risk [RR], 1.18 [95% confidence interval {CI}, 1.12-1.25]). There was no significant association between all-cause mortality and serum level of parathyroid hormone (RR per 100-pg/mL increase, 1.01 [95% CI, 1.00-1.02]) or serum level of calcium (RR per 1-mg/dL increase, 1.08 [95% CI, 1.00-1.16]). Data for the association between serum level of phosphorus, parathyroid hormone, and calcium and cardiovascular death were each available in only 1 adequately adjusted cohort study. Lack of adjustment for confounding variables was not a major limitation of the available studies. CONCLUSIONS The evidentiary basis for a strong, consistent, and independent association between serum levels of calcium and parathyroid hormone and the risk of death and cardiovascular events in chronic kidney disease is poor. There appears to be an association between higher serum levels of phosphorus and mortality in this population.

Meta-analysis: vitamin D compounds in chronic kidney disease.

Context Clinicians often treat patients with kidney disease with vitamin D compounds to prevent secondary hyperparathyroidism. Contribution This meta-analysis of 76 randomized trials found no good evidence that vitamin D compounds reduced risk for death, bone pain, vascular calcification, or need for parathyroidectomy in patients with chronic kidney disease. Compared with placebo, established vitamin D sterols increased risk for hypercalcemia and hyperphosphatemia, whereas newer vitamin D analogues increased hypercalcemia but not hyperphosphatemia. Direct comparisons found no clear benefits of newer analogues over established agents. Implication Though commonly used, vitamin D compounds for chronic kidney disease have unclear benefits and potential harms. The Editors All stages of chronic kidney disease (CKD) are associated with significantly increased rates of all-cause and cardiovascular mortality (1). Several risk factors for death have been identified and targeted by interventions, but registry data have not shown substantial improvements in survival of people with end-stage kidney disease over the past 2 decades (2). Abnormalities of bone metabolism and mineralization, which are risk factors for death in CKD, occur early and become universal as kidney function declines (3). A frequent pattern of biochemical abnormalities includes increased serum phosphorus and parathyroid hormone (PTH) levels, whereas levels of serum calcium may be low, normal, or elevated. These changes are associated with alterations in bone mineral homeostasis, increased bone fragility (4, 5), vascular and soft tissue calcification (6, 7), muscle dysfunction (8), adverse cardiovascular outcomes, and increased mortality (9). Compared with PTH levels of 16.5 to 33.0 pmol/L (150 to 300 pg/mL), levels greater than 66 pmol/L (600 pg/mL) are reported to be associated with a 10% increased risk for death (10). Similar mortality data have been observed for increased serum phosphorus and calcium levels (10). Interventions that are widely used to improve biochemical markers of bone and mineral metabolism include active vitamin D compounds, calcium supplements and noncalcium-containing phosphate binders, and calcimimetics. Vitamin D therapy has historically been based on alfacalcidol (1 -hydroxyvitamin D3) or calcitriol, both of which attenuate secondary hyperparathyroidism (1114). Although these compounds may reduce PTH levels, they increase calcium and phosphorus levels (9, 10, 15, 16). Support for use of the newer vitamin D analogues (22-oxacalcitriol, doxercalciferol, paricalcitol, and falecalcitriol) is based on reports of similar or superior dose-equivalent suppression of PTH, less calcemic and phosphatemic activity, and the possibility of improved survival when compared with established vitamin D sterols (calcitriol or alfacalcidol) (17, 18). Guidelines have suggested that doxercalciferol and paricalcitol may be preferable to calcitriol and alfacalcidol (19). We evaluated available randomized trials to determine the effects of established vitamin D sterols and newer analogues on biochemical, bone, and cardiovascular end points in CKD together with their optimal dose and route of administration. Methods Data Sources and Searches Literature searches for randomized, controlled trials (RCTs) of vitamin D sterols in CKD were performed in MEDLINE (January 1966 to July 2007) and EMBASE (January 1980 to July 2007) using optimally sensitive search strategies (20). The Cochrane Renal Group Renal Health Library and the Cochrane Central Register of Controlled Trials (CENTRAL) were also searched. The complete search strategy is outlined in Appendix Table 1. Authors followed a standardized published protocol for identification of eligible trials (21). Appendix Table 1. Summary of Search Strategy Study Selection We included randomized and quasi-randomized, controlled trials conducted in patients with CKD and that compared vitamin D compounds with placebo, different vitamin D compounds directly, and different vitamin D dose and administration regimens. Studies enrolling patients with any stage of CKD and measuring the effect of these agents on surrogate biochemical end points at the end of treatment (for example, levels of PTH, calcium, phosphorus, and calciumphosphorus product) and hard patient-level end points (for example, all-cause and cardiovascular mortality, fracture, toxicity) were included. We excluded trials enrolling only participants who had parathyroidectomy or kidney transplantation. We also excluded RCTs of vitamin D compounds in osteoporosis because results of these studies were presented without reference to kidney function or CKD was an exclusion criterion. Data Extraction and Quality Assessment Two independent authors assessed each trial. They extracted data on the characteristics of participants, interventions, comparisons, and clinical outcomes, when reported. Hypercalcemia was defined as a serum calcium level of 2.63 mmol/L or greater (10.5 mg/dL), and hyperphosphatemia was defined as a serum phosphorus level greater than 1.62 mmol/L (>5.0 mg/dL). Because trial investigators generally did not report change in values from beginning to end of treatment for continuous variables, we only considered the end-of-treatment values. Where published outcome data were not provided in sufficient detail, an author contacted the trial investigators by electronic or standard mail requesting additional information. Review authors resolved discrepancies in data extraction and quality assessment through discussion. Data Synthesis and Analysis We summarized treatment effects as relative risks (RRs) for categorical variables and weighted mean differences for continuous variables, with 95% CIs. We pooled estimates from individual trials by using the DerSimonian and Laird random-effects model (22). We repeated all analyses by adding 1/n to treatment groups with zero events and using the odds ratio as the measure of effect. Neither method resulted in substantive differences in any clinical outcome. We formally assessed heterogeneity of treatment effects between studies with the Cochran Q and the I 2 statistics (23). We performed subgroup analysis and random-effects metaregression to explore the effect of potential sources of variability on observed treatment effects. We investigated the impacts of the following plausible effect modifiers on treatment outcomes: newer vitamin D analogues versus established vitamin D sterols, baseline PTH concentration (<33 pmol/L, 33 to 66 pmol/L, 66 to 110 pmol/L, and >110 pmol/L), method of PTH assay (amino-terminal, carboxy-terminal, intact, full-length PTH [1-84], or not specified), method of calcium assay (total, corrected, or ionized), baseline serum calcium concentration (<2.63 mmol/L and 2.63 mmol/L [10.5 mg/dL]), baseline serum phosphorus concentration (<1.29 mmol/L and 1.29 mmol/L [4.0 mg/dL]), dialysis modality (peritoneal or hemodialysis) and duration, stage of CKD (CKD stage 3 [estimated glomerular filtration rate, 30 to 59 mL/min per 1.73 m2], 4 [estimated glomerular filtration rate, 15 to 29 mL/min per 1.73 m2], or 5 [estimated glomerular filtration rate <15 mL/min per 1.73 m2]), pediatric versus adult cohorts, use of calcium-based phosphate binders as a co-intervention, prior use of vitamin D sterols, duration of intervention, trial quality, and dose of vitamin D compound (high or low). All analyses were undertaken using RevMan 4.2 (The Cochrane Collaboration, Copenhagen, Denmark) and STATA version 8.0 (STATA, College Station, Texas). Role of the Funding Source The funding source had no role in the study design; collection, analysis, or interpretation of data; or writing of the report. The corresponding author had full access to all study data and had final responsibility for the decision to submit the manuscript for publication. Results The combined search of MEDLINE, EMBASE, the Cochrane Controlled Trial Register, and the Renal Health Library of the Cochrane Renal Group identified a total of 1608 articles (Appendix Figure 1). After full-text analysis, we included 76 eligible RCTs that enrolled a total of 3667 participants with CKD. Two publications each represented combined data from 3 RCTs (24, 25). We identified 3 ongoing studies from trial registries (2628). The number of individuals in each trial ranged from 6 to 266 patients, and 60 out of 76 (79%) studies enrolled fewer than 60 patients. Authors of 18 trials provided additional information, which was included in our analyses (14, 24, 2944). Appendix Figure 1. Study flow diagram. Reasons for exclusions and the number of trials reporting each outcome are provided. RCT = randomized, controlled trial. Trial Characteristics Appendix Tables 2 and 3 list the characteristics of the samples and interventions in the trials of vitamin D included in this meta-analysis. We divided the 76 eligible trials into 3 major groups of studies based on the randomized interventions: vitamin D compounds versus placebo, other vitamin D compounds, or calcium; different routes of administration of vitamin D; and different doses of vitamin D. Appendix Table 2. Characteristics of Populations and Interventions in Trials Comparing Vitamin D Compounds with Placebo, No Treatment, or Other Vitamin D Compounds in People with Chronic Kidney Disease* Appendix Table 3. Characteristics of Populations and Interventions in Trials of Vitamin D and Its Analogues Comparing Different Routes and Schedules of Administration in People with Chronic Kidney Disease* The first group compared established vitamin D compounds with another vitamin D compound, placebo, or calcium alone. This group included 19 trials (981 patients) comparing established vitamin D with placebo, of which 12 trials (669 patients) administered calcitriol (11, 13, 4554), 5 trials (275 patients) administered alfacalcidol (12, 14, 42, 55, 56), and 2 trials (37 patients) administered 24,25-(OH)2 vitamin D3 (31, 44). Fifteen studies (1

Pathophysiology and Recent Advances in the Management of Renal Osteodystrophy

Bone disease is observed in 75–100% of patients with chronic renal failure as the glomerular filtration rate (GFR) falls below 60 ml/minute. Hyperparathyroid (high turnover) bone disease is found most frequently followed by mixed osteodystrophy, low‐turnover bone disease, and osteomalacia. With advancing renal impairment, “skeletal resistance” to parathyroid hormone (PTH) occurs. To maintain bone turnover, intact PTH (iPTH) targets from two to four times the upper normal range have been suggested, but whole PTH(1–84) assays indicate that amino‐terminally truncated fragments, which accumulate in end‐stage renal disease (ESRD), account for up to one‐half of the measured iPTH. PTH levels and bone‐specific alkaline phosphatase (BSAP) provide some information on bone involvement but bone biopsy and histomorphometry remains the gold standard. Calcitriol and calcium salts can be used to suppress PTH and improve osteomalacia but there is growing concern that these agents predispose to the development of vascular calcification, cardiovascular morbidity, low‐turnover bone disease and fracture. Newer therapeutic options include less calcemic vitamin D analogues, calcimimetics and bisphosphonates for hyperparathyroidism, and sevelamer for phosphate control. Calcitriol and hormone‐replacement therapy (HRT) have been shown to maintain bone mineral density (BMD) in certain patients with end‐stage renal disease (ESRD). After renal transplantation, renal osteodystrophy generally improves but BMD often worsens. Bisphosphonate therapy may be appropriate for some patients at risk of fracture. When renal bone disease is assessed using a combination of biochemical markers, histology and bone densitometry, early intervention and the careful use of an increasing number of effective therapies can reduce the morbidity associated with this common problem.

Benefits and Harms of Phosphate Binders in CKD: A Systematic Review of Randomized Controlled Trials

BACKGROUND Phosphate binders are widely used to control serum phosphorus levels in patients with chronic kidney disease (CKD). We analyzed the effects of phosphate binders on biochemical and patient-level end points in patients with CKD. STUDY DESIGN Systematic review and meta-analysis by searching MEDLINE (1966 to April 2009), EMBASE (1980 to April 2009), and the Cochrane Renal Group Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL). SETTING & POPULATION Patients with CKD. SELECTION CRITERIA FOR STUDIES Randomized controlled trials. INTERVENTION Phosphate binders. OUTCOMES Serum phosphorus, calcium, and parathyroid hormone levels; incidence of hypercalcemia; all-cause mortality; adverse effects. RESULTS 40 trials (6,406 patients) were included. There was no significant decrease in all-cause mortality (10 randomized controlled trials; 3,079 patients; relative risk [RR], 0.73; 95% confidence interval [CI], 0.46 to 1.16), hospitalization, or end-of-treatment serum calcium-phosphorus product levels with sevelamer compared with calcium-based agents. There was a significant decrease in end-of-treatment phosphorus and parathyroid hormone levels with calcium salts compared with sevelamer and a significant decrease in risk of hypercalcemia (RR, 0.47; 95% CI, 0.36 to 0.62) with sevelamer compared with calcium-based agents. There was a significant increase in risk of gastrointestinal adverse events with sevelamer in comparison to calcium salts (RR, 1.39; 95% CI, 1.04 to 1.87). Compared with calcium-based agents, lanthanum significantly decreased end-of-treatment serum calcium and calcium-phosphorus product levels, but with similar end-of-treatment phosphorus levels. Effects of calcium acetate on biochemical end points were similar to those of calcium carbonate. Existing data are insufficient to conclude for a differential impact of any phosphate binder on cardiovascular mortality or other patient-level outcome. LIMITATIONS Few long-term studies of the efficacy of phosphate binders on mortality and musculoskeletal morbidity, significant heterogeneity for many surrogate outcomes, and suboptimal reporting of study methods to determine trial quality. CONCLUSION Currently, there are insufficient data to establish the comparative superiority of non-calcium-binding agents over calcium-containing phosphate binders for such important patient-level outcomes as all-cause mortality and cardiovascular end points. Additional trials are still required to examine the differential effects of phosphate-binding agents on these end points and the mineral homeostasis pathway.

Revisiting KDIGO clinical practice guideline on chronic kidney disease—mineral and bone disorder: a commentary from a Kidney Disease: Improving Global Outcomes controversies conference

A new definition and classification of chronic kidney disease-mineral and bone disorder (CKD-MBD) was proposed in 2005 and it was later followed by a guideline publication on this topic from Kidney Disease: Improving Global Outcomes (KDIGO) in 2009. This work recognized that CKD-MBD is a syndrome of bone abnormalities, laboratory abnormalities, and vascular calcification linked to fractures, cardiovascular disease, and mortality. Because of limited data at the time of the original guideline systematic review, many of the recommendations were cautiously vague. KDIGO convened a Controversies Conference in October 2013 to review the CKD-MBD literature published since the 2009 guideline. Specifically, the objective of this conference was to determine whether sufficient new data had emerged to support a reassessment of the CKD-MBD guideline and if so to determine the scope of these potential revisions. This report summarizes the results of these proceedings, highlighting important new studies conducted in the interval since the original KDIGO CKD-MBD guideline.

Bisphosphonates in Chronic Kidney Disease; Balancing Potential Benefits and Adverse Effects on Bone and Soft Tissue

Cardiovascular disease is highly prevalent in chronic kidney disease (CKD) and is often associated with increased vascular stiffness and calcification. Recent studies have suggested a complex interaction between vascular calcification and abnormalities of bone and mineral metabolism, with an inverse relationship between arterial calcification and bone mineral density (BMD). Although osteoporosis is recognized and treated in CKD 1 to 3, the interpretation of BMD levels in the osteoporotic range is controversial in CKD 4, 5, and 5D when renal osteodystrophy is generally present. In addition, there is a paucity of data for patients with CKD mineral and bone disorder (MBD), because studies using bisphosphonates in postmenopausal and glucocorticoid-induced osteoporosis have generally excluded patients with significant CKD. For these patients, treatment of low BMD using standard therapies for osteoporosis is not without potential for harm due to the possibility of worsening low bone turnover, osteomalacia, mixed uraemic osteodystrophy, and of exacerbated hyperparathyroidism; and bisphosphonates should only be used selectively and with caution. Some experimental and clinical studies have also suggested that bisphosphonates may reduce progression of extra-osseous calcification and inhibit the development of atherosclerosis. The authors review the potential benefits and risks associated with bisphosphonate use for bone protection in CKD, and assess their effect on vascular calcification and atherosclerosis.

25-Hydroxyvitamin D Deficiency and Diabetes Predict Reduced BMD in Patients With Chronic Kidney Disease†

In this study of 242 patients with renal failure, women, patients with diabetes, and patients on peritoneal dialysis had the highest risk of 25‐hydroxyvitamin D deficiency. Levels correlated positively to BMD Z scores, and hip BMD was inversely related to prevalent fracture. Increasing 25‐hydroxyvitamin D levels may benefit these patients.

Sevelamer Versus Calcium-Based Binders for Treatment of Hyperphosphatemia in CKD: A Meta-Analysis of Randomized Controlled Trials

BACKGROUND AND OBJECTIVES People with CKD stages 3-5 and on dialysis (5D) have dramatically increased mortality, which has been associated with hyperphosphatemia in many studies. Oral phosphate binders are commonly prescribed to lower serum phosphate. We conducted an updated meta-analysis of the noncalcium-based binder (non-CBB) sevelamer versus CBBs in CKD stages 3-5D. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Randomized, controlled trials comparing sevelamer with CBBs were identified through MEDLINE and the Cochrane Central Register of Controlled Trials. Patient-level outcomes included all-cause mortality, cardiovascular events and mortality, hospitalization, and adverse effects. Intermediate outcomes included vascular calcification and bone changes. Biochemical outcomes included serum phosphate, calcium, parathyroid hormone, lipids, and hypercalcemia. We conducted and reported this review according to Cochrane guidelines. RESULTS We included 25 studies to March 31, 2015 with 4770 participants (88% on hemodialysis). Patients receiving sevelamer had lower all-cause mortality (risk ratio [RR], 0.54; 95% confidence interval [95% CI], 0.32 to 0.93), no statistically significant difference in cardiovascular mortality (n=2712; RR, 0.33; 95% CI, 0.07 to 1.64), and an increase in combined gastrointestinal events of borderline statistical significance (n=384; RR, 1.42; 95% CI, 0.97 to 2.08). For biochemical outcomes, patients receiving sevelamer had lower total serum cholesterol (mean difference [MD], -20.2 mg/dl; 95% CI, -25.9 to -14.5 mg/dl), LDL-cholesterol (MD, -21.6 mg/dl; 95% CI, -27.9 to -15.4 mg/dl), and calcium (MD, -0.4 mg/dl; 95% CI, -0.6 to -0.2 mg/dl) and a reduced risk of hypercalcemia (RR, 0.30; 95% CI, 0.19 to 0.48). End of treatment intact parathyroid hormone was significantly higher for sevelamer (MD, 32.9 pg/ml; 95% CI, 0.1 to 65.7 pg/ml). Serum phosphate values showed no significant differences. CONCLUSIONS Patients with CKD stages 3-5D using sevelamer have lower all-cause mortality compared with those using CBBs. Because of a lack of placebo-controlled studies, questions remain regarding phosphate binder benefits for patients with CKD stages 3-5 and not on dialysis.

Effects of Cholecalciferol on Functional, Biochemical, Vascular, and Quality of Life Outcomes in Hemodialysis Patients

BACKGROUND AND OBJECTIVES Observational studies suggest that calciferol supplementation may improve laboratory and patient-level outcomes of hemodialysis patients with reduced 25-hydroxyvitamin D [25(OH)D] levels. This randomized controlled trial examined effects of cholecalciferol supplementation in patients on hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Sixty patients with 25(OH)D levels ≤24 ng/ml (≤60 nmol/L) were randomized to receive 50,000 IU oral cholecalciferol or placebo, once weekly for 8 weeks and then monthly for 4 months. At baseline (autumn 2011) and 6 months, testing evaluated muscle strength, functional capacity, laboratory parameters, pulse wave velocity (PWV), and health-related quality of life (HRQOL) using the Kidney Disease Quality of Life-36 survey. RESULTS Patients were well matched by treatment allocation. Median age was 62 years (range, 20-86), 52% were women, 55% had a history of diabetes, and mean serum 25(OH)D was 17±5 ng/ml (43±13 nmol/L). Patients were assessed over 6 months by repeated-measures ANOVA. Patients allocated to cholecalciferol had significantly higher values of 25(OH)D (P<0.001), 1,25-dihydroxyvitamin D (P=0.04), and tartrate-resistant acid phosphatase-5b) (P=0.04) and a greater reduction in phosphorus values (P=0.03) than placebo-treated patients Values of serum calcium, intact parathyroid hormone, and episodes of hypercalcemia and hyperphosphatemia did not differ significantly between the groups. No significant differences were detected in muscle strength, functional capacity, PWV, or HRQOL. CONCLUSIONS In this randomized controlled trial, patients supplemented with cholecalciferol had higher 25(OH)D, 1,25-dihydroxyvitamin D, and tartrate-resistant acid phosphatase-5b levels, without increased calcium or phosphorus values. However, no effects were detected in muscle strength, functional capacity, PWV, or HRQOL.

Association between 25-hydroxyvitamin D, somatic muscle weakness and falls risk in end-stage renal failure

Objective  Suboptimal levels of 25‐hydroxyvitamin D (25OHD) are common in haemodialysis patients (Chronic Kidney disease‐5D: CKD‐5D) and may be associated with reduced muscle strength and increased falls risk. We tested the hypothesis that 25OHD levels may be independently associated with falls risk in CKD‐5D.