Fabio Pellegrini

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.

CARMELA: assessment of cardiovascular risk in seven Latin American cities.

OBJECTIVE This cross-sectional, population-based observational study using stratified multistage sampling assessed the prevalence of cardiovascular risk factors and carotid plaques and measured carotid intima-media thickness in individuals living in major cities in 7 Latin American countries. PATIENTS AND METHODS The study comprised individuals (n=11,550) aged 25 to 64 years, living in Barquisimeto, Bogota, Buenos Aires, Lima, Mexico City, Quito, and Santiago. Data on anthropometric parameters, blood pressure, fasting glucose, total and high-density lipoprotein cholesterol, triglycerides, carotid intima-media thickness, carotid plaque, and smoking status were collected through household interviews and clinical, biochemical, and sonographic measurements. RESULTS The overall prevalence rates (ranges across cities) were as follows: hypertension (> or = 140/90 mm Hg or pharmacologic treatment), 18% (9%-29%); hypercholesterolemia (total cholesterol > or = 240 mg/dL), 14% (6%-20%); diabetes (glycemia > or = 126 mg/dL or self-reported diabetes), 7% (4%-9%); metabolic syndrome, 20% (14%-27%); obesity (body mass index > or = 30 kg/m2), 23% (18%-27%); smoking, 30% (22%-45%); and plaque, 8% (5%-14%). The mean intima-media thickness was 0.65 mm (0.60-0.74 mm). CONCLUSION The prevalence of hypertension mirrored the world average in 3 cities but was lower in the rest. Hypercholesterolemia was highly prevalent even in countries of different socioeconomic levels. The prevalence of diabetes was similar to that in the developed countries. Tobacco use in women living in Santiago and Buenos Aires was among the worlds highest. Intima-media thickness and carotid plaque prevalences varied widely.

Course and prognosis in early-onset MS Comparison with adult-onset forms

Objectives: To establish the prognostic role of clinical and demographic factors in a hospital-based cohort of MS patients categorized by age at clinical onset and clinical course. Methods: Eighty-three patients with MS had a clinical onset of the disease in childhood (age <16 years; early-onset MS [EOMS]) and 710 in adult age (between 16 and 65 years; adult-onset MS [AOMS]). Patients were followed for a mean period of observation of 5 years. Univariate and multivariate analyses of clinical and demographic predictors for rapid progression and disability were performed using a stepwise Cox regression model with time-dependent covariates. Results: In EOMS, the Expanded Disability Status Scale (EDSS) evaluated at last clinical examination was lower than in AOMS, despite a longer disease duration. The probability to reach growth disability and progression was significantly lower in EOMS than in AOMS. Median times to reach EDSS score of 4 and secondary progression were longer in EOMS than in AOMS, but the age at both endpoints was significantly lower in EOMS. In EOMS and AOMS, an irreversible disability was related to a secondary progressive course, a sphincteric system involvement at onset, and an older age at onset (in EOMS only for the group >14 years); in AOMS, other unfavorable factors were a pyramidal involvement at onset and a high relapse frequency in the first 2 years. The risk of entering secondary progression was significantly influenced by a high number of relapses in EOMS and by a higher age at onset and a short interattack interval in AOMS. Conclusion: A slower rate of progression of disease characterized EOMS patients, suggesting more plasticity to recover in developing CNS, but the early clinical manifestation cannot be considered a positive prognostic factor.

New natural history of interferon‐β–treated relapsing multiple sclerosis

To investigate the impact of interferon‐beta (IFNβ) on disease progression in relapsing‐remitting multiple sclerosis patients.

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.

Prevalence of depression in chronic kidney disease: systematic review and meta-analysis of observational studies

Prevalence estimates of depression in chronic kidney disease (CKD) vary widely in existing studies. We conducted a systematic review and meta-analysis of observational studies to summarize the point prevalence of depressive symptoms in adults with CKD. We searched MEDLINE and Embase (through January 2012). Random-effects meta-analysis was used to estimate the prevalence of depressive symptoms. We also limited the analyses to studies using clinical interview and prespecified criteria for diagnosis. We included 249 populations (55,982 participants). Estimated prevalence of depression varied by stage of CKD and the tools used for diagnosis. Prevalence of interview-based depression in CKD stage 5D was 22.8% (confidence interval (CI), 18.6-27.6), but estimates were somewhat less precise for CKD stages 1-5 (21.4% (CI, 11.1-37.2)) and for kidney transplant recipients (25.7% (12.8-44.9)). Using self- or clinician-administered rating scales, the prevalence of depressive symptoms for CKD stage 5D was higher (39.3% (CI, 36.8-42.0)) relative to CKD stages 1-5 (26.5% (CI, 18.5-36.5)) and transplant recipients (26.6% (CI, 20.9-33.1)) and suggested that self-report scales may overestimate the presence of depression, particularly in the dialysis setting. Thus, interview-defined depression affects approximately one-quarter of adults with CKD. Given the potential prevalence of depression in the setting of CKD, randomized trials to evaluate effects of interventions for depression on patient-centered outcomes are needed.