Madhumathi Rao

Ferumoxytol as an Intravenous Iron Replacement Therapy in Hemodialysis Patients

BACKGROUND AND OBJECTIVES Intravenous iron is a key component of anemia management for chronic kidney disease (CKD). Ferumoxytol is a unique intravenous iron product that can be administered as a rapid injection in doses up to 510 mg. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a randomized, open-label, controlled, multicenter Phase 3 trial to evaluate the safety and efficacy of intravenous ferumoxytol compared with oral iron. Anemic patients with CKD stage 5D on hemodialysis and on a stable erythropoiesis-stimulating agent regimen received either two injections of 510 mg of ferumoxytol within 7 d (n = 114) or 200 mg elemental oral iron daily for 21 d (n = 116). The primary efficacy endpoint was the change in hemoglobin from baseline to day 35. Safety was closely monitored. RESULTS Ferumoxytol resulted in a mean increase in hemoglobin of 1.02 +/- 1.13 g/dl at day 35 compared with 0.46 +/- 1.06 g/dl with oral iron (P = 0.0002). Twice as many ferumoxytol-treated patients than oral iron-treated patients achieved a > or =1 g/dl hemoglobin increase at day 35 (P = 0.0002). There was a greater mean increase in transferrin saturation (TSAT) with ferumoxytol compared with oral iron at day 35 (P < 0.0001). The larger hemoglobin increase after ferumoxytol compared with oral iron at day 35 persisted after adjustment for baseline hemoglobin, TSAT, and serum ferritin. Overall adverse event rates were comparable between groups. CONCLUSIONS In patients on hemodialysis, rapid intravenous injection of 510 mg of ferumoxytol led to significantly greater hemoglobin increases compared with oral iron, with comparable tolerability.

Cochlear Implantation in Adults: A Systematic Review and Meta-analysis

IMPORTANCE Sensorineural hearing loss is the third leading cause of years lived with disability worldwide. Cochlear implants may provide a viable alternative to hearing aids for this type of hearing loss. The Coverage and Analysis Group at the Centers for Medicare & Medicaid Services was interested in an evaluation of recently published literature on this topic. In addition, this meta-analysis is to our knowledge the first to evaluate quality-of-life (QOL) outcomes in adults with cochlear implants. OBJECTIVE To evaluate the communication-related outcomes and health-related QOL outcomes after unilateral or bilateral cochlear implantation in adults with sensorineural hearing loss. DATA SOURCES MEDLINE, Cochrane Central Register of Controlled Trials, Scopus, and previous reports from January 1, 2004, through May 31, 2012. STUDY SELECTION Published studies of adult patients undergoing unilateral or bilateral procedures with multichannel cochlear implants and assessments using open-set sentence tests, multisyllable word tests, or QOL measures. DATA EXTRACTION Five researchers extracted information on population characteristics, outcomes of interest, and study design and assessed the studies for risk of bias. Discrepancies were resolved by consensus. RESULTS A total of 42 studies met the inclusion criteria. Most unilateral implant studies showed a statistically significant improvement in mean speech scores as measured by open-set sentence or multisyllable word tests; meta-analysis revealed a significant improvement in QOL after unilateral implantation. Results from studies assessing bilateral implantation showed improvement in communication-related outcomes compared with unilateral implantation and additional improvements in sound localization compared with unilateral device use or implantation only. Based on a few studies, the QOL outcomes varied across tests after bilateral implantation. CONCLUSIONS AND RELEVANCE Unilateral cochlear implants provide improved hearing and significantly improve QOL, and improvements in sound localization are noted for bilateral implantation. Future studies of longer duration, higher-quality reporting, and large databases or registries of patients with long-term follow-up data are needed to yield stronger evidence.

Resistance Training Increases Muscle Mitochondrial Biogenesis in Patients with Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Muscle wasting, a common complication in chronic kidney disease (CKD), contributes to poor outcomes. Mitochondrial biogenesis is critical for the maintenance of skeletal muscle function and structural integrity. The present study--a secondary analysis from a published randomized controlled trial--examined the effect of resistance exercise training on skeletal muscle mitochondrial (mt)DNA copy number and determined its association with skeletal muscle phenotype (muscle mass and strength). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Twenty-three patients with moderate-to-severe CKD were randomized to resistance training (n = 13) or an attention-control (n = 10) group for 12 weeks. After a run-in period of a low-protein diet that continued during the intervention, mtDNA copy number in the vastus lateralis muscle was estimated by quantitative real-time PCR at baseline and 12 weeks. RESULTS Participants mean age was 64 +/- 10 (SD) years and median (interquartile range, IQR) GFR 27.5 (37.0) ml/min. There were no differences between groups at baseline. Median (IQR) mtDNA copy number was 13,713 (10,618). There was a significant increase in muscle mtDNA with exercise compared with controls (1306 [13306] versus -3747 [15467], P = 0.01). The change in muscle mtDNA copy number was positively correlated with previously reported changes in types I and II muscle fiber cross-sectional area. CONCLUSIONS In this pilot study, resistance training was highly effective in enhancing mitochondrial content in patients with moderate-to-severe CKD. This finding suggests that the mitochondrial dysfunction observed with chronic disease could potentially be restored with this exercise modality and should be investigated further.

2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis

To develop recommendations for prevention and treatment of glucocorticoid‐induced osteoporosis (GIOP).

Mitochondrial DNA Injury and Mortality in Hemodialysis Patients

The role of mitochondrial injury in the pathogenesis of complications of uremia is incompletely defined, although diminished bioenergetic capacity and the accumulation of mitochondrial DNA (mtDNA) mutations have been reported. This study was undertaken to evaluate the prevalence of mtDNA injury in 180 patients who had ESRD and were enrolled into the baseline phase of the HEMO study and to relate these markers to all-cause mortality. The mitochondrial injury markers studied in peripheral blood mononuclear cells were the mtDNA copy number per cell, measured by quantitative PCR, and the presence of the mtDNA(4977) mutation. After frequency-matching healthy control subjects for age, mtDNA copy number was lower among older dialysis patients compared with older healthy subjects (P = 0.01). A one-log increase in mtDNA copy number was independently associated with a decreased hazard for mortality (adjusted hazard ratio 0.64; 95% confidence interval 0.46 to 0.89). The mtDNA(4977) deletion was present in 48 (31%) patients and was independently associated with a decreased hazard for mortality (adjusted hazard ratio 0.33; 95% confidence interval 0.19 to 0.56). In summary, the mtDNA(4977) seems to predict survival in ESRD, but a reduced mitochondrial copy number seems to predict a poor outcome. Although further exploration of these associations is needed, evaluation of mitochondrial DNA copy number and somatic mtDNA mutations may provide simple genomic biomarkers to predict clinical outcomes among patients with ESRD.

Inflammatory biomarkers and cardiovascular risk: association or cause and effect?

With the current understanding that atherosclerosis is an inflammatory disorder, markers of the associated systemic inflammatory response have been extensively studied as predictors of cardiovascular disease. Recently the use of high‐sensitivity C‐reactive protein (hsCRP) has been proposed for risk assessment in individuals at intermediate risk of coronary heart disease. The traditional view of inflammatory biomarkers, including CRP, regards them as risk markers rather than risk factors. Either category of marker would serve a diagnostic role, monitor disease activity, and indicate the efficacy of therapy or changing prognosis. However a risk factor with a causal role would be a potential target for therapy. This review discusses the available evidence that argues for and against a causal role for inflammatory biomarkers, with specific reference to CRP, in the atherosclerotic process.

Two-stage arthroplasty for prosthetic joint infection: a systematic review of acute kidney injury, systemic toxicity and infection control.

Periprosthetic infections of hip and knee joints are now treated by two-stage revision arthroplasty with an infection control rate of 91%. The present systematic review studied the reported incidence of acute kidney injury (AKI) and infection recurrence from January 1989 to June 2012 to assess the risk-benefit ratio of antibiotic spacer use. Ten observational studies (n=544 patients) with clinical outcomes showed an average incidence of AKI of 4.8%. The average reported persistence or recurrence rate of infection was 11% during a follow-up period that ranged from 13 to 108 months. The risk-benefit ratio presently favors treatment although there appears to be higher complication rates and incidence of AKI than previously reported. Marked heterogeneity in practice and lack of detail in reporting precluded more robust quantitative synthesis. Clinicians need to be aware of the potential risk of AKI, particularly in high-risk patients; practice patterns for the use of antibiotic spacers need to be standardized.

Mitochondrial cytopathies and cardiovascular disease

The global epidemic of cardiovascular disease remains the leading cause of death in the USA and across the world. Functional and structural integrity of mitochondria are essential for the physiological function of the cardiovascular system. The metabolic adaptation observed in normal heart is lost in the failing myocardium, which becomes progressively energy depleted leading to impaired myocardial contraction and relaxation. Uncoupling of electron transfer from ATP synthesis leads to excess generation of reactive species, leading to widespread cellular injury and cardiovascular disease. Accumulation of mitochondrial DNA mutation has been linked to ischaemic heart disease, cardiomyopathy and atherosclerotic vascular disease. Mitochondria are known to regulate apoptotic and autophagic pathways that have been shown to play an important role in the development of cardiomyopathy and atherosclerosis. A number of pharmacological and non-pharmacological treatment options have been explored in the management of mitochondrial diseases with variable success.

UNRESOLVED ISSUES IN DIALYSIS: Inflammatory Biomarkers and Cardiovascular Risk: Association or Cause and Effect?

With the current understanding that atherosclerosis is an inflammatory disorder, markers of the associated systemic inflammatory response have been extensively studied as predictors of cardiovascular disease. Recently the use of high‐sensitivity C‐reactive protein (hsCRP) has been proposed for risk assessment in individuals at intermediate risk of coronary heart disease. The traditional view of inflammatory biomarkers, including CRP, regards them as risk markers rather than risk factors. Either category of marker would serve a diagnostic role, monitor disease activity, and indicate the efficacy of therapy or changing prognosis. However a risk factor with a causal role would be a potential target for therapy. This review discusses the available evidence that argues for and against a causal role for inflammatory biomarkers, with specific reference to CRP, in the atherosclerotic process.

The Study of Treatment for Renal Insufficiency: Data and Evaluation (STRIDE), a National Registry of Chronic Kidney Disease

Optimization of care in patients with chronic kidney disease (CKD) could be the key to improved clinical and economic outcomes, both during the phase of CKD as well as in patients with end‐stage renal disease (ESRD). CKD is a major public health problem that has been insufficiently studied. There is little published information on outcomes among CKD patients, specifically, data on mortality, morbidity, and quality of life. Indeed, recent efforts by the National Kidney Foundation (NKF) have served to define the classification, evaluation, and approach to management of CKD in practice. The Study of Treatment for Renal Insufficiency: Data and Evaluation (STRIDE) registry is an initiative to study CKD patients in nephrology practices across the country. It is a prospective observational study whose objective is to profile demographic and clinical variables, practice patterns, comorbid conditions, quality of life, and outcomes in a nationally based sample of CKD patients. This article details the design, methodology, and process of enrollment into the registry.