Giovanni F.M. Strippoli

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.

Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials

Objective To analyse the benefits and harms of statins in patients with chronic kidney disease (pre-dialysis, dialysis, and transplant populations). Design Meta-analysis. Data sources Cochrane Central Register of Controlled Trials, Medline, Embase, and Renal Health Library (July 2006). Study selection Randomised and quasi-randomised controlled trials of statins compared with placebo or other statins in chronic kidney disease. Data extraction and analysis Two reviewers independently assessed trials for inclusion, extracted data, and assessed trial quality. Differences were resolved by consensus. Treatment effects were summarised as relative risks or weighted mean differences with 95% confidence intervals by using a random effects model. Results Fifty trials (30 144 patients) were included. Compared with placebo, statins significantly reduced total cholesterol (42 studies, 6390 patients; weighted mean difference −42.28 mg/dl (1.10 mmol/l), 95% confidence interval −47.25 to −37.32), low density lipoprotein cholesterol (39 studies, 6216 patients; −43.12 mg/dl (1.12 mmol/l), −47.85 to −38.40), and proteinuria (g/24 hours) (6 trials, 311 patients; −0.73 g/24 hour, −0.95 to −0.52) but did not improve glomerular filtration rate (11 studies, 548 patients; 1.48 ml/min (0.02 ml/s), −2.32 to 5.28). Fatal cardiovascular events (43 studies, 23 266 patients; relative risk 0.81, 0.73 to 0.90) and non-fatal cardiovascular events (8 studies, 22 863 patients; 0.78, 0.73 to 0.84) were reduced with statins, but statins had no significant effect on all cause mortality (44 studies, 23 665 patients; 0.92, 0.82 to 1.03). Meta-regression analysis showed that treatment effects did not vary significantly with stage of chronic kidney disease. The side effect profile of statins was similar to that of placebo. Most of the available studies were small and of suboptimal quality; mortality data were provided by a few large trials only. Conclusion Statins significantly reduce lipid concentrations and cardiovascular end points in patients with chronic kidney disease, irrespective of stage of disease, but no benefit on all cause mortality or the role of statins in primary prevention has been established. Reno-protective effects of statins are uncertain because of relatively sparse data and possible outcomes reporting bias.

Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials

Objective To evaluate the benefits and harms of low dose aspirin in people with diabetes and no cardiovascular disease. Design Meta-analysis of randomised controlled trials. Data sources Medline (1966-November 2008), the Cochrane central register of controlled trials (Cochrane Library 2008;issue 4), and reference lists of retrieved articles. Review methods Randomised trials of aspirin compared with placebo or no aspirin in people with diabetes and no pre-existing cardiovascular disease were eligible for inclusion. Data on major cardiovascular events (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, and all cause mortality) were extracted and pooled with a random effect model. Results are reported as relative risks with 95% confidence intervals. Results Of 157 studies in the literature searches, six were eligible (10 117 participants). When aspirin was compared with placebo there was no statistically significant reduction in the risk of major cardiovascular events (five studies, 9584 participants; relative risk 0.90, 95% confidence interval 0.81 to 1.00), cardiovascular mortality (four studies, n=8557, 0.94; 0.72 to 1.23), or all cause mortality (four studies, n=8557; 0.93, 0.82 to 1.05). Significant heterogeneity was found in the analysis for myocardial infarction (I2=62.2%; P=0.02) and stroke (I2=52.5%; P=0.08). Aspirin significantly reduced the risk of myocardial infarction in men (0.57, 0.34 to 0.94) but not in women (1.08, 0.71 to 1.65; P for interaction=0.056). Evidence relating to harms was inconsistent. Conclusions A clear benefit of aspirin in the primary prevention of major cardiovascular events in people with diabetes remains unproved. Sex may be an important effect modifier. Toxicity is to be explored further.

Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review

Abstract Objective To evaluate the effects of angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (AIIRAs) on renal outcomes and all cause mortality in patients with diabetic nephropathy. Data sources Medline, Embase, the Cochrane controlled trials register, conference proceedings, and contact with investigators. Study selection Trials comparing ACE inhibitors or AIIRAs with placebo or with each other in patients with diabetic nephropathy. Data extraction Mortality, renal outcomes (end stage renal disease, doubling of serum creatinine concentration, prevention of progression of microalbuminuria to macroalbuminuria, remission of microalbuminuria), and quality of trials. Data synthesis 36 of 43 identified trials compared ACE inhibitors with placebo (4008 patients), four compared AIIRAs with placebo (3331 patients), and three compared ACE inhibitors with AIIRAs (206 patients). We obtained unpublished data for 11 trials. ACE inhibitors significantly reduced all cause mortality (relative risk 0.79, 95% confidence interval 0.63 to 0.99) compared with placebo but AIIRAs did not (0.99, 0.85 to 1.17), although baseline mortality was similar in the trials. Both agents had similar effects on renal outcomes. Reliable estimates of the unconfounded relative effects of ACE inhibitors compared with AIIRAs could not be obtained owing to small sample sizes. Conclusion Although the survival benefits of ACE inhibitors for patients with diabetic nephropathy are known, the relative effects of ACE inhibitors and AIIRAs on survival are unknown owing to the lack of adequate head to head trials.

Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials

BACKGROUND Antiviral prophylaxis is commonly used in recipients of solid-organ transplants with the aim of preventing the clinical syndrome associated with cytomegalovirus infection. We undertook a systematic review to investigate whether this approach affects risks of cytomegalovirus disease and death. METHODS Randomised controlled trials of prophylaxis with antiviral medications for cytomegalovirus disease in solid-organ-transplant recipients were identified. Data were combined in meta-analyses by a random-effects model. FINDINGS Compared with placebo or no treatment, prophylaxis with aciclovir, ganciclovir, or valaciclovir significantly reduced the risks of cytomegalovirus disease (19 trials, 1981 patients; relative risk 0.42 [95% CI 0.34-0.52]), cytomegalovirus infection (17 trials, 1786 patients; 0.61 [0.48-0.77]), and all-cause mortality (17 trials, 1838 patients; 0.63 [0.43-0.92]), mainly owing to lower mortality from cytomegalovirus disease (seven trials, 1300 patients; 0.26 [0.08-0.78]). Prophylaxis also lowered the risks of disease caused by herpes simplex or zoster virus, bacterial infections, and protozoal infections, but not fungal infection, acute rejection, or graft loss. Meta-regression showed no significant difference in the risk of cytomegalovirus disease or all-cause mortality by organ transplanted or cytomegalovirus serostatus; no conclusions were possible for cytomegalovirus-negative recipients of negative organs. In trials of direct comparisons, ganciclovir was more effective than aciclovir in preventing cytomegalovirus disease. Valganciclovir and intravenous ganciclovir were as effective as oral ganciclovir. INTERPRETATION Prophylaxis with antiviral medications reduces the risk of cytomegalovirus disease and associated mortality in recipients of solid-organ transplants. This approach should be used routinely in cytomegalovirus-positive recipients and in cytomegalovirus-negative recipients of organs positive for the virus.

Associations between Hemodialysis Access Type and Clinical Outcomes: A Systematic Review

Clinical practice guidelines recommend an arteriovenous fistula as the preferred vascular access for hemodialysis, but quantitative associations between vascular access type and various clinical outcomes remain controversial. We performed a systematic review of cohort studies to evaluate the associations between type of vascular access (arteriovenous fistula, arteriovenous graft, and central venous catheter) and risk for death, infection, and major cardiovascular events. We searched MEDLINE, EMBASE, and article reference lists and extracted data describing study design, participants, vascular access type, clinical outcomes, and risk for bias. We identified 3965 citations, of which 67 (62 cohort studies comprising 586,337 participants) met our inclusion criteria. In a random effects meta-analysis, compared with persons with fistulas, those individuals using catheters had higher risks for all-cause mortality (risk ratio=1.53, 95% CI=1.41-1.67), fatal infections (2.12, 1.79-2.52), and cardiovascular events (1.38, 1.24-1.54). Similarly, compared with persons with grafts, those individuals using catheters had higher risks for mortality (1.38, 1.25-1.52), fatal infections (1.49, 1.15-1.93), and cardiovascular events (1.26, 1.11-1.43). Compared with persons with fistulas, those individuals with grafts had increased all-cause mortality (1.18, 1.09-1.27) and fatal infection (1.36, 1.17-1.58), but we did not detect a difference in the risk for cardiovascular events (1.07, 0.95-1.21). The risk for bias, especially selection bias, was high. In conclusion, persons using catheters for hemodialysis seem to have the highest risks for death, infections, and cardiovascular events compared with other vascular access types, and patients with usable fistulas have the lowest risk.

Benefits and Harms of Statin Therapy for Persons With Chronic Kidney Disease: A Systematic Review and Meta-analysis

BACKGROUND Statins have uncertain benefits in persons with chronic kidney disease (CKD) because individual trials may have insufficient power to determine whether treatment effects differ with severity of CKD. PURPOSE To summarize the benefits and harms of statin therapy for adults with CKD and examine whether effects of statins vary by stage of kidney disease. DATA SOURCES Cochrane and EMBASE databases (inception to February 2012). STUDY SELECTION Randomized trials comparing the effects of statins with placebo, no treatment, or another statin on mortality and cardiovascular outcomes. DATA EXTRACTION Two independent reviewers extracted data and assessed risk of bias. DATA SYNTHESIS Eighty trials comprising 51099 participants compared statin with placebo or no treatment. Treatment effects varied with stage of CKD. Moderate- to high-quality evidence indicated that statins reduced all-cause mortality (relative risk [RR], 0.81 [95% CI, 0.74 to 0.88]), cardiovascular mortality (RR, 0.78 [CI, 0.68 to 0.89]), and cardiovascular events (RR, 0.76 [CI, 0.73 to 0.80]) in persons not receiving dialysis. Moderate- to high-quality evidence indicated that statins had little or no effect on all-cause mortality (RR, 0.96 [CI, 0.88 to 1.04]), cardiovascular mortality (RR, 0.94 [CI, 0.82 to 1.07]), or cardiovascular events (RR, 0.95 [CI, 0.87 to 1.03]) in persons receiving dialysis. Effects of statins in kidney transplant recipients were uncertain. Statins had little or no effect on cancer, myalgia, liver function, or withdrawal from treatment, although adverse events were evaluated systematically in fewer than half of the trials. LIMITATION There was a reliance on post hoc subgroup data for earlier stages of CKD. CONCLUSION Statins decrease mortality and cardiovascular events in persons with early stages of CKD, have little or no effect in persons receiving dialysis, and have uncertain effects in kidney transplant recipients.

Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review.

Aims/Hypothesis Diabetes treatments were related with either an increased or reduced risk of cancer. There is ongoing debate about a potential protective action of metformin. To summarize evidence on the association between metformin and risk of cancer and cancer mortality in patients with diabetes. Methods Data source: MEDLINE and EMBASE (January 1966-April 2012). We selected randomized studies comparing metformin and other hypoglycaemic agents and observational studies exploring the association between exposure to metformin and cancer. Outcomes were cancer mortality, all malignancies and site-specific cancers. Results Of 25307 citations identified, 12 randomized controlled trials (21,595 patients) and 41 observational studies (1,029,389 patients) met the inclusion criteria. In observational studies there was a significant association of exposure to metformin with the risk of cancer death [6 studies, 24,410 patients, OR:0.65, 95%CI: 0.53-0.80], all malignancies [18 studies, 561,836 patients, OR:0.73, 95%CI: 0.61-0.88], liver [8 studies, 312,742 patients, OR:0.34; 95%CI: 0.19-0.60] colorectal [12 studies, 871,365 patients, OR:0.83, 95%CI: 0.74–0.92], pancreas [9 studies, 847,248 patients, OR:0.56, 95%CI: 0.36–0.86], stomach [2 studies, 100701 patients, OR:0.83, 95%CI: 0.76–0.91], and esophagus cancer [2 studies, 100694 patients, OR:0.90, 95%CI: 0.83–0.98]. No significant difference of risk was observed in randomized trials. Metformin was not associated with the risk of: breast cancer, lung cancer, ovarian cancer, uterus cancer, prostate cancer, bladder cancer, kidney cancer, and melanoma. Conclusions/Interpretation Results suggest that Metformin might be associated with a significant reduction in the risk of cancer and cancer-related mortality. Randomized trials specifically designed to evaluate the efficacy of metformin as an anticancer agent are warranted.

Meta-analysis: Erythropoiesis-stimulating agents in patients with chronic kidney disease

BACKGROUND Previous meta-analyses suggest that treatment with erythropoiesis-stimulating agents (ESAs) in chronic kidney disease (CKD) increases the risk for death. Additional randomized trials have been recently completed. PURPOSE To summarize the effects of ESA treatment on clinical outcomes in patients with anemia and CKD. DATA SOURCES MEDLINE (January 1966 to November 2009), EMBASE (January 1980 to November 2009), and the Cochrane database (to March 2010) were searched without language restriction. STUDY SELECTION Two authors independently screened reports to identify randomized trials evaluating ESA treatment in people with CKD. Hemoglobin target trials or trials of ESA versus no treatment or placebo were included. DATA EXTRACTION Two authors independently extracted data on patient characteristics, study risks for bias, and the effects of ESA therapy. DATA SYNTHESIS 27 trials (10 452 patients) were identified. A higher hemoglobin target was associated with increased risks for stroke (relative risk [RR], 1.51 [95% CI, 1.03 to 2.21]), hypertension (RR, 1.67 [CI, 1.31 to 2.12]), and vascular access thrombosis (RR, 1.33 [CI, 1.16 to 1.53]) compared with a lower hemoglobin target. No statistically significant differences in the risks for mortality (RR, 1.09 [CI, 0.99 to 1.20]), serious cardiovascular events (RR, 1.15 [CI, 0.98 to 1.33]), or end-stage kidney disease (RR, 1.08 [CI, 0.97 to 1.20]) were observed, although point estimates favored a lower hemoglobin target. Treatment effects were consistent across subgroups, including all stages of CKD. LIMITATIONS The evidence for effects on quality of life was limited by selective reporting. Trials also reported insufficient information to allow analysis of the independent effects of ESA dose on clinical outcomes. CONCLUSION Targeting higher hemoglobin levels in CKD increases risks for stroke, hypertension, and vascular access thrombosis and probably increases risks for death, serious cardiovascular events, and end-stage renal disease. The mechanisms for harm remain unclear, and meta-analysis of individual-patient data and trials on fixed ESA doses are recommended to elucidate these mechanisms. PRIMARY FUNDING SOURCE None.

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