Calcimimetic agents lower serum parathyroid hormone levels in people with chronic kidney disease (CKD), but treatment effects on patient-relevant outcomes are uncertain. We conducted a systematic review and meta-analysis to summarize the benefits and harms of calcimimetic therapy in adults with CKD and used cumulative meta-analysis to identify how evidence for calcimimetic treatment has developed in this clinical setting. Cochrane and Embase databases (through February 7, 2013) were electronically searched to identify randomized trials evaluating effects of calcimimetic therapy on mortality and adverse events in adults with CKD. Two independent reviewers identified trials, extracted data, and assessed risk of bias. Eighteen trials comprising 7,446 participants compared cinacalcet plus conventional therapy with placebo or no treatment plus conventional therapy in adults with CKD. In moderate- to high-quality evidence (based on Grading of Recommendations Assessment, Development, and Evaluation criteria) in adults with CKD stage 5D (dialysis), cinacalcet had little or no effect on all-cause mortality (relative risk, 0.97 [95% confidence interval, 0.89–1.05]), had imprecise effect on cardiovascular mortality (0.67 [0.16–2.87]), and prevented parathyroidectomy (0.49 [0.40–0.59]) and hypercalcemia (0.23 [0.05–0.97]), but increased hypocalcemia (6.98 [5.10–9.53]), nausea (2.02 [1.45–2.81]), and vomiting (1.97 [1.73–2.24]). Data for clinical outcomes were sparse in adults with CKD stages 3–5. On average, treating 1,000 people with CKD stage 5D for 1 y had no effect on survival and prevented about three patients from experiencing parathyroidectomy, whilst 60 experienced hypocalcemia and 150 experienced nausea. Analyses were limited by insufficient data in CKD stages 3–5 and kidney transplant recipients. Cinacalcet reduces the need for parathyroidectomy in patients with CKD stage 5D, but does not appear to improve all-cause or cardiovascular mortality. Additional trials in CKD stage 5D are unlikely to change our confidence in the treatment effects of cinacalcet in this population. Please see later in the article for the Editors' Summary Chronic kidney disease (CKD) refers to a progressive loss in kidney function over time and is caused by several conditions such as diabetes and high blood pressure. CKD is an increasingly common condition, affecting an estimated 26 million adults in the United States alone, with millions more at risk. People with CKD are at increased risk of death compared to the general population, and despite recent improvements in care, people with advanced CKD who are receiving dialysis experience an excess mortality rate of up to 20%. People with CKD also experience several biochemical imbalances—such as increased phosphorus (as a result of retention), low vitamin D and calcium (hypocalcemia), and increased parathyroid hormone—which lead to further health problems (such as a thinning of the bones) and pain. In light of this complication, clinical guidelines for people with CKD currently recommend that the blood levels of phosphorus and parathyroid hormone be maintained in a certain range to prevent the need for surgical removal of the gland (surgical parathyroidectomy). There are several medical therapies that help to keep phosphorus and parathyroid hormone blood levels within the target range, and in 2004, the drug cinacalcet hydrochloride (cinacalcet) was approved in the United States for use in people with end-stage CKD for this purpose. However, despite increasing use and costs of this drug (in the US, cinacalcet has become the largest single drug cost for patients on dialysis, with an annual expenditure of at least US$260 million, and in the UK, prescribing costs increased by up to 33% from 2010 to 2011), the therapeutic value of this drug remains uncertain. So in this study, the researchers systematically reviewed appropriate published studies and analyzed relevant data to investigate whether treatment with cinacalcet improves clinical outcomes in adults with CKD. The researchers identified relevant randomized controlled trials conducted in participants with end-stage CKD by thoroughly searching electronic databases and trial registries, specialist journals, and major conference proceedings. They then extracted data according to specific criteria and assessed the risk of bias. The researchers then graded the quality of evidence into the categories high, moderate, low, and very low quality. Using these techniques, the researchers included 18 trials involving 7,446 adults with CKD in their analysis. All included trials evaluated cinacalcet (at a dose of 30 mg to 180 mg/day) and how this drug compared to conventional therapy or conventional therapy plus placebo. The researchers found that, compared to placebo or no treatment, in high-quality evidence, cinacalcet had little or no effect on all-cause mortality (relative risk [RR], 0.97) for people in the final stage of CKD (stage 5D) and unclear effects on all-cause mortality in low-quality evidence for people in the less severe stages (stages 3–5) of CKD (RR, 0.29). Cinacalcet also had uncertain effects on cardiovascular mortality for participants with CKD stage 5D (RR, 0.67) and CKD stages 3–5 (RR, 0.29), and also its role in fracture prevention was unclear in people with CKD stage 5D. Furthermore, cinacalcet had significant side effects, such as increased risk of hypocalcemia (RR, 7.38), nausea (RR, 2.05), vomiting (RR, 1.95), and diarrhea (RR, 1.15), but reduced the risk of hypercalcemia (RR, 0.23). The researchers found that in high-quality evidence, cinacalcet prevented surgical parathyroidectomy in people with CKD stage 5D (RR, 0.49). However, overall, they also found that, on average, routinely treating 1,000 people with cinacalcet for one year has no effect on mortality, prevents about three people from experiencing surgical parathyroidectomy, and leads to approximately 60 and 150 people experiencing hypocalcemia and nausea, respectively. These findings suggest that routine cinacalcet (30 to 180 mg/day) therapy in people with end-stage CKD (stage 5D) reduces parathyroid concentrations and hypercalcemia, and may prevent surgical parathyroidectomy, but has little or no effect on all-cause mortality, has an unclear effect on cardiovascular death, and is frequently associated with adverse effects such as hypocalcemia, nausea, vomiting, and diarrhea—adverse gastrointestinal effects that may affect nutrition and quality of life. Although the evidence in people with CKD stages 3–5 is limited and generally of low quality, this analysis shows that despite the widespread use of cinacalcet and the associated high costs, this drug provides little clinical benefit. Therefore, routine use of cinacalcet therapy in people with CKD does not appear warranted; benefits may be limited to preventing parathyroidectomy in the small number of patients for whom surgery is contraindicated. Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001436.

Although measurement of haemoglobin A1c has become the cornerstone for diagnosing diabetes mellitus in routine clinical practice, the role of this biomarker in reflecting long-term glycaemic control in patients with chronic kidney disease has been questioned. Consensus review paper based on narrative literature review. As a different association between glycaemic control and morbidity/mortality might be observed in patients with and without renal insufficiency, the European Renal Best Practice, the official guideline body of the European Renal Association-European Dialysis and Transplant Association, presents the current knowledge and evidence of the use of alternative glycaemic markers (glycated albumin, fructosamine, 1,5-anhydroglucitol and continuous glucose monitoring). Although reference values of HbA1C might be different in patients with chronic kidney disease, it still remains the cornerstone as follow-up of longer term glycaemic control, as most clinical trials have used it as reference.

Type 2 diabetes mellitus (T2DM) is associated with increased risk of cardiovascular disease and nephropathy—now the leading cause of end-stage renal disease and dialysis in Europe and the United States. Inflammation and oxidative stress play a pivotal role in the development of diabetic complications. Silymarin, an herbal drug with antioxidant and anti-inflammatory properties, may improve glycemic control and prevent the progression of the complications. In a systematic review and meta-analysis including five randomized controlled trials and 270 patients, routine silymarin administration determines a significant reduction in fasting blood glucose levels (−26.86 mg/dL; 95% CI −35.42–18.30) and HbA1c levels (−1.07; 95% CI −1.73–0.40) and has no effect on lipid profile. Benefits for silymarin on proteinuria and CKD progressions are reported in only one small study and are uncertain. However, being aware of the low quality of the available evidence and elevated heterogeneity of these studies, no recommendation can be made and further studies are needed.