Usefulness of Oral Ferric Citrate in Patients With Iron-Deficiency Anemia and Chronic Kidney Disease With or Without Heart Failure.

Patients with chronic inflammatory conditions including chronic kidney disease (CKD) and heart failure (HF) are undertreated with iron-deficiency anemia (IDA). Progressive inflammation and reduced iron transport associated with CKD and HF may reduce the efficacy of oral iron therapy. Oral ferric citrate improves anemia markers in CKD, but its effects in patients with CKD and concomitant HF have not been described. Patients with CKD not on dialysis and IDA from a phase 2 and 3 trial were treated with ferric citrate (n = 190) or placebo (n = 188); patients with HF were identified from medical histories. Hemoglobin response was defined as a ≥10.0-g/L increase in hemoglobin. Changes in hemoglobin, transferrin saturation, ferritin, and serum phosphate from baseline to week 12 and the incidence of adverse events potentially related to HF were evaluated. HF was reported in 22% (n = 81) of patients. The proportion of patients with hemoglobin response to ferric citrate treatment did not significantly differ in patients with and without HF (43% vs 49%, respectively; p = 0.47); changes from baseline in hemoglobin, iron parameters, and serum phosphate were similar. Adverse events potentially related to HF were noted more frequently in patients with HF (ferric citrate, 23%; placebo, 17%) versus those without HF (ferric citrate, 12%; placebo, 11%). In conclusion, these results indicate a potential role for ferric citrate in the treatment of IDA in patients with CKD not on dialysis and concomitant HF.

Effects of Ferric Citrate in Patients with Nondialysis-Dependent CKD and Iron Deficiency Anemia.

Iron deficiency anemia is common and consequential in nondialysis-dependent CKD (NDD-CKD). Efficacy and tolerability of conventional oral iron supplements are mixed; intravenous iron administration associates with finite but important risks. We conducted a randomized double-blind clinical trial in adults with NDD-CKD and iron deficiency anemia to compare the safety and efficacy of oral ferric citrate (n=117) and placebo (n=115). The primary end point was the proportion of patients who achieved a ≥1.0 g/dl increase in hemoglobin at any time during a 16-week randomized period. Patients who completed the 16-week period could also participate in an 8-week open-label extension period. Significantly more patients randomized to ferric citrate achieved the primary end point (61 [52.1%] versus 22 [19.1%] with placebo; P<0.001). All secondary end points reached statistical significance in the ferric citrate group, including the mean relative change in hemoglobin (0.84 g/dl; 95% confidence interval, 0.58 to 1.10 g/dl; P<0.001) and the proportion of patients who achieved a sustained increase in hemoglobin (≥0.75 g/dl over any 4-week period during the randomized trial; 57 [48.7%] versus 17 [14.8%] with placebo; P<0.001). Rates of serious adverse events were similar in the ferric citrate (12.0%) and placebo groups (11.2%). Gastrointestinal disorders were the most common adverse events, with diarrhea reported in 24 (20.5%) and 19 (16.4%) and constipation in 22 (18.8%) and 15 (12.9%) patients treated with ferric citrate and placebo, respectively. Overall, in patients with NDD-CKD, we found oral ferric citrate to be a safe and efficacious treatment for iron deficiency anemia.

Mycophenolic acid versus azathioprine as primary immunosuppression for kidney transplant recipients.

BACKGROUND: Modern immunosuppressive regimens after kidney transplantation usually use a combination of two or three agents of different classes to prevent rejection and maintain graft function. Most frequently, calcineurin-inhibitors (CNI) are combined with corticosteroids and a proliferation-inhibitor, either azathioprine (AZA) or mycophenolic acid (MPA). MPA has largely replaced AZA as a first line agent in primary immunosuppression, as MPA is believed to be of stronger immunosuppressive potency than AZA. However, treatment with MPA is more costly, which calls for a comprehensive assessment of the comparative effects of the two drugs. OBJECTIVES: This review of randomised controlled trials (RCTs) aimed to look at the benefits and harms of MPA versus AZA in primary immunosuppressive regimens after kidney transplantation. Both agents were compared regarding their efficacy for maintaining graft and patient survival, prevention of acute rejection, maintaining graft function, and their safety, including infections, malignancies and other adverse events. Furthermore, we investigated potential effect modifiers, such as transplantation era and the concomitant immunosuppressive regimen in detail. SEARCH METHODS: We searched Cochrane Kidney and Transplant's Specialised Register (to 21 September 2015) through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: All RCTs about MPA versus AZA in primary immunosuppression after kidney transplantation were included, without restriction on language or publication type. DATA COLLECTION AND ANALYSIS: Two authors independently determined study eligibility, assessed risk of bias and extracted data from each study. Statistical analyses were performed using the random-effects model and the results were expressed as risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). MAIN RESULTS: We included 23 studies (94 reports) that involved 3301 participants. All studies tested mycophenolate mofetil (MMF), an MPA, and 22 studies reported at least one outcome relevant for this review. Assessment of methodological quality indicated that important information on factors used to judge susceptibility for bias was infrequently and inconsistently reported.MMF treatment reduced the risk for graft loss including death (RR 0.82, 95% CI 0.67 to 1.0) and for death-censored graft loss (RR 0.78, 95% CI 0.62 to 0.99, P < 0.05). No statistically significant difference for MMF versus AZA treatment was found for all-cause mortality (16 studies, 2987 participants: RR 0.95, 95% CI 0.70 to 1.29). The risk for any acute rejection (22 studies, 3301 participants: RR 0.65, 95% CI 0.57 to 0.73, P < 0.01), biopsy-proven acute rejection (12 studies, 2696 participants: RR 0.59, 95% CI 0.52 to 0.68) and antibody-treated acute rejection (15 studies, 2914 participants: RR 0.48, 95% CI 0.36 to 0.65, P < 0.01) were reduced in MMF treated patients. Meta-regression analyses suggested that the magnitude of risk reduction of acute rejection may be dependent on the control rate (relative risk reduction (RRR) 0.34, 95% CI 0.10 to 1.09, P = 0.08), AZA dose (RRR 1.01, 95% CI 1.00 to 1.01, P = 0.10) and the use of cyclosporin A micro-emulsion (RRR 1.27, 95% CI 0.98 to 1.65, P = 0.07). Pooled analyses failed to show a significant and meaningful difference between MMF and AZA in kidney function measures.Data on malignancies and infections were sparse, except for cytomegalovirus (CMV) infections. The risk for CMV viraemia/syndrome (13 studies, 2880 participants: RR 1.06, 95% CI 0.85 to 1.32) was not statistically significantly different between MMF and AZA treated patients, whereas the likelihood of tissue-invasive CMV disease was greater with MMF therapy (7 studies, 1510 participants: RR 1.70, 95% CI 1.10 to 2.61). Adverse event profiles varied: gastrointestinal symptoms were more likely in MMF treated patients and thrombocytopenia and elevated liver enzymes were more common in AZA treatment. AUTHORS' CONCLUSIONS: MMF was superior to AZA for improvement of graft survival and prevention of acute rejection after kidney transplantation. These benefits must be weighed against potential harms such as tissue-invasive CMV disease. However, assessment of the evidence on safety outcomes was limited due to rare events in the observation periods of the studies (e.g. malignancies) and inconsistent reporting and definitions (e.g. infections, adverse events). Thus, balancing benefits and harms of the two drugs remains a major task of the transplant physician to decide which agent the individual patient should be started on.

Fluorescence in situ hybridization testing for the diagnosis of high-grade cervical abnormalities: a systematic review.

OBJECTIVE: We examined the diagnostic performance of fluorescence in situ hybridization (FISH) tests on cervical cytology for precancerous lesions or cancer on cervical histology. MATERIALS AND METHODS: A search was conducted in MEDLINE, the Cochrane Central Register of Controlled Trials, and Scopus through September 3, 2013. Eleven studies examined FISH tests for telomerase RNA component gene (TERC), myelocytomatosis oncogene (MYC), or human papillomavirus (HPV) type 16 or 18 in samples exhibiting atypical squamous cells of unknown significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). None examined HPV-positive, cytologically normal samples. We extracted data on the sensitivity and specificity for high-grade cervical intraepithelial neoplasia (CIN 2+ or CIN 3+). RESULTS: Fluorescence in situ hybridization test probes and thresholds varied across studies. Included populations were convenience samples. Only 1 study testing for TERC specified HPV status. In meta-analysis, FISH for TERC in LSIL (9 studies, 1,082 cases) had a summary sensitivity of 0.76 (95% confidence interval = 0.63-0.85) and a summary specificity of 0.78 (95% confidence interval = 0.57-0.91) for CIN 2+. Fluorescence in situ hybridization for TERC in ASC-US (3 studies, 839 cases) showed sensitivities ranging from 0.75 to 1.00 and specificities from 0.87 to 0.93 for CIN 2+. For CIN 3+, sensitivity and specificity appeared similar, although a small number of studies preclude firm conclusions. For FISH tests for HPV, we found only few studies with small sample sizes. CONCLUSIONS: The evidence on FISH testing is limited given the small number of studies for each cytology subgroup and the lack of studies in well-defined screening contexts stratifying participants by HPV status.

Antibiotic prophylaxis for selected gynecologic surgeries.

BACKGROUND: Antibiotic prophylaxis for surgery is commonly used and is recommended by multiple organizations. OBJECTIVE: To critically review gynecology-specific data regarding surgical antibiotic prophylaxis in selected benign gynecologic surgeries. SEARCH STRATEGY: MEDLINE and Cochrane databases were searched from inception to July 2010. SELECTION CRITERIA: Randomized controlled trials of benign vaginal, cervical, transcervical, abdominal, or laparoscopic procedures other than hysterectomy comparing prophylactic antibiotic use with placebo or with another antibiotic. Outcomes of interest were postoperative infections, additional treatments, and adverse events. DATA COLLECTION AND ANALYSIS: In total, 19 trials met the inclusion criteria. Studies were individually assessed for methodologic quality, then grouped by procedure and evaluated for evidence quality. MAIN RESULTS: There was no difference in infectious outcome for loop electrosurgical excision, hysteroscopic ablation, or laparoscopy, although evidence quality was poor. Fair evidence supports antibiotic prophylaxis for suction curettage or laparotomy. There were insufficient data regarding vaginal surgery prophylaxis. CONCLUSION: Antibiotic prophylaxis may be beneficial in first-trimester suction curettage and laparotomy. No advantage was found for loop electrosurgical excision, hysteroscopy, or laparoscopic gynecologic surgery. Newer procedures and vaginal surgery lack research and merit study.

Clinical practice guideline for abnormal uterine bleeding: hysterectomy versus alternative therapy.

STUDY OBJECTIVE: To develop recommendations in selecting treatments for abnormal uterine bleeding (AUB). DESIGN: Clinical practice guidelines. SETTING: Randomized clinical trials compared bleeding, quality of life, pain, sexual health, satisfaction, the need for subsequent surgery, and adverse events between hysterectomy and less-invasive treatment options. PATIENTS: Women with AUB, predominantly from ovulatory disorders and endometrial causes. INTERVENTIONS: On the basis of findings from a systematic review, clinical practice guidelines were developed. Rating the quality of evidence and the strength of recommendations followed the Grades for Recommendation Assessment, Development, and Evaluation system. MEASUREMENTS AND MAIN RESULTS: This paper identified few high-quality studies that directly compared uterus-preserving treatments (endometrial ablation, levonorgestrel intrauterine system and systemically administered medications) with hysterectomy. The evidence from these randomized clinical trials demonstrated that there are trade-offs between hysterectomy and uterus-preserving treatments in terms of efficacy and adverse events. CONCLUSION: Selecting an appropriate treatment for AUB requires identifying a woman's most burdensome symptoms and incorporating her values and preferences when weighing the relative benefits and harms of hysterectomy versus other treatment options.

Venous thromboembolism prophylaxis in gynecologic surgery: a systematic review.

OBJECTIVE: To comprehensively review and critically assess the available gynecologic surgery venous thromboembolism prophylaxis literature and provide clinical practice guidelines. DATA SOURCES: MEDLINE and Cochrane databases from inception to July 2010. We included randomized controlled trials in gynecologic surgery populations. Interventions and comparators included graduated compression stockings, intermittent pneumatic compression, unfractionated heparin, and low molecular weight heparin; placebo and routine postoperative care were allowed as comparators. METHODS OF STUDY SELECTION: One thousand two hundred sixty-six articles were screened, and 14 randomized controlled trials (five benign gynecologic, nine gynecologic oncology) met eligibility criteria. In addition, nine prospective or retrospective studies with at least 150 women were identified and provided data on venous thromboembolism risk stratification, gynecologic laparoscopy, and urogynecologic populations. TABULATION, INTEGRATION, AND RESULTS: Two reviewers independently screened articles with discrepancies adjudicated by a third. Eligible randomized controlled trials were extracted for these characteristics: study, participant, surgery, intervention, comparator, and outcomes data, including venous thromboembolism incidence and bleeding complications. Studies were individually and collectively assessed for methodologic quality and strength of evidence. Overall incidence of clinical venous thromboembolism was 0-2% in the benign gynecologic population. With use of intermittent pneumatic compression for benign major procedures, venous thromboembolism incidence was less than 1%. No venous thromboembolisms were identified in prospective studies of benign laparoscopic procedures. Overall quality of evidence in the benign gynecologic literature was poor. Gynecologic-oncology randomized controlled trials reported venous thromboembolism incidence (including "silent" venous thromboembolisms) of 0-14.8% with prophylaxis and up to 34.6% without prophylaxis. Fair quality of evidence supports that unfractionated heparin and intermittent pneumatic compression are both superior to placebo or no intervention but insufficient to determine whether heparins are superior to intermittent pneumatic compression for venous thromboembolism prevention. Combining two of three risks (aged 60 years or older, cancer, or personal venous thromboembolism history) substantially elevated the risk of venous thromboembolism. CONCLUSION: Intermittent pneumatic compression provides sufficient prophylaxis for the majority of gynecology patients undergoing benign surgery. Additional risk factors warrant the use of combined mechanical and pharmacologic prophylaxis.

Systematic review highlights difficulty interpreting diverse clinical outcomes in abnormal uterine bleeding trials.

OBJECTIVES: (1) To systematically collect and organize into clinical categories all outcomes reported in trials for abnormal uterine bleeding (AUB); (2) to rank the importance of outcomes for patient decision making; and (3) to improve future comparisons of effects in trials of AUB interventions. STUDY DESIGN AND SETTING: Systematic review of English-language randomized controlled trials of AUB treatments in MEDLINE from 1950 to June 2008. All outcomes and definitions were extracted and organized into major outcome categories by an expert group. Each outcome was ranked "critically important," "important," or "not important" for informing patients' choices. RESULTS: One hundred thirteen articles from 79 trials met the criteria. One hundred fourteen different outcomes were identified, only 15 (13%) of which were ranked as critically important and 29 (25%) as important. Outcomes were grouped into eight categories: (1) bleeding; (2) quality of life; (3) pain; (4) sexual health; (5) patient satisfaction; (6) bulk-related complaints; (7) need for subsequent surgical treatment; and (8) adverse events. CONCLUSION: To improve the quality, consistency, and utility of future AUB trials, we recommend assessing a limited number of clinical outcomes for bleeding, disease-specific quality of life, pain, sexual health, and bulk-related symptoms both before and after treatment and reporting satisfaction and adverse events. Further development of validated patient-based outcome measures and the standardization of outcome reporting are needed.

KDOQI US commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD-Mineral and Bone Disorder (CKD-MBD).

This commentary provides a US perspective on the 2009 KDIGO (Kidney Disease: Improving Global Outcomes) Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). KDIGO is an independent international organization with the primary mission of the promotion, coordination, collaboration, and integration of initiatives to develop and implement clinical practice guidelines for the care of patients with kidney disease. The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI), recognizing that international guidelines need to be adapted for each country, convened a group of experts to comment on the application and implementation of the KDIGO guideline for patients with CKD in the United States. This commentary puts the KDIGO guideline into the context of the supporting evidence and the setting of care delivered in the United States and summarizes important differences between prior KDOQI guidelines and the newer KDIGO guideline. It also considers the potential impact of a new bundled payment system for dialysis clinics. The KDIGO guideline addresses the evaluation and treatment of abnormalities of CKD-MBD in adults and children with CKD stages 3-5 on long-term dialysis therapy or with a kidney transplant. Tests considered are those that relate to laboratory, bone, and cardiovascular abnormality detection and monitoring. Treatments considered are interventions to treat hyperphosphatemia, hyperparathyroidism, and bone disease in patients with CKD stages 3-5D and 1-5T. Limitations of the evidence are discussed. The lack of definitive clinical outcome trials explains why most recommendations are not of level 1 but of level 2 strength, which means weak or discretionary recommendations. Suggestions for future research highlight priority areas.

Graft use in transvaginal pelvic organ prolapse repair: a systematic review.

OBJECTIVE: To estimate the anatomic and symptomatic efficacy of graft use in transvaginal prolapse repair and to estimate the rates and describe the spectrum of adverse events associated with graft use. DATA SOURCES: Eligible studies, published between 1950 and November 27, 2007, were retrieved through Medline and bibliography searches. METHODS OF STUDY SELECTION: To assess anatomic and symptomatic efficacy of graft use, we used transvaginal prolapse repair studies that compared graft use with either native tissue repair or repair with a different graft. To estimate rates of adverse events from graft use, all comparative studies and case series with at least 30 participants were included. For spectrum of adverse events, all study designs were included. TABULATION, INTEGRATION AND RESULTS: Eligible studies were extracted onto standardized forms by one reviewer and confirmed by a second reviewer. Comparative studies were classified by vaginal compartment (anterior, posterior, apical, or multiple), graft type (biologic, synthetic-absorbable, synthetic nonabsorbable) and outcome (anatomic, symptomatic). We found 16 comparative studies, including six randomized trials, 37 noncomparative studies with at least 30 women, 11 case series with fewer than 30 women, and 10 case reports of adverse events. One randomized trial and one prospective comparative study evaluating synthetic, nonabsorbable graft use in the anterior compartment reported favorable anatomic and symptomatic outcomes with graft use. Data regarding graft use for posterior and apical compartments or for biologic or synthetic absorbable graft use in the anterior compartment were insufficient to determine efficacy. Rates and spectrum of adverse events associated with graft use included bleeding (0-3%), visceral injury (1-4%), urinary infection (0-19%), graft erosion (0-30%), and fistula (1%). There were insufficient data regarding dyspareunia, sexual, voiding, or defecatory dysfunction. CONCLUSION: Overall, the existing evidence is limited to guide decisions regarding whether to use graft materials in transvaginal prolapse surgery. Adequately powered randomized trials evaluating anatomic and symptomatic efficacy as well as adverse events are needed.

Low rates of testing and diagnostic codes usage in a commercial clinical laboratory: evidence for lack of physician awareness of chronic kidney disease.

Improving outcomes for chronic kidney disease (CKD) requires early identification and recognition by physicians. There are few data on rates of testing or use of diagnostic codes for CKD. A cross-sectional analysis was performed of patients who were older than 40 yr and had one or more laboratory tests between April 1, 2002, and March 31, 2003, at a Laboratory Corporation of America regional laboratory. Objectives were to determine the frequency of testing for serum creatinine; prevalence of CKD, defined as estimated GFR <60 ml/min per 1.73 m2; and sensitivity of diagnostic codes for CKD for patients with and without risk factors for CKD and with or without cardiovascular disease (CVD). Of the 277,111 patients, 19% had serum creatinine measured, compared with 33 and 71% who had measurements of serum glucose and lipids, respectively. Patients with hypertension, diabetes, and age >60 yr were more likely to be tested for serum creatinine with odds ratio (OR; 95% confidence interval) of 2.09 (2.05 to 2.14), 1.22 (1.19 to 1.25), and 1.24 (1.22 to 1.27) respectively. Among patients tested, 30% had CKD. Sensitivity and specificity of kidney disease diagnostic codes compared with CKD defined by estimated GFR <60 ml/min per 1.73 m2 were 11 and 96%, respectively. In patients with hypertension, diabetes, age >60 years, and CVD, rates of testing and sensitivity of diagnostic codes were 53 and 14%, respectively. Low rates of testing for serum creatinine and insensitivity of diagnostic codes for CKD, even in high-risk patients, suggests inadequate physician awareness of CKD and limited utility of administrative databases for identification of patients with CKD.

Traditional cardiac risk factors in individuals with chronic kidney disease.

Individuals with chronic kidney disease (CKD) are at increased risk for the development and progression of cardiovascular disease (CVD). The increased risk is due to a higher prevalence of both traditional risk factors as well as nontraditional risk factors. In this review we focus on individuals at all stages of CKD and discuss modifiable traditional risk factors, namely hypertension, dyslipidemia, diabetes mellitus and poor glycemic control, smoking, and physical inactivity. The prevalence of each risk factor and its relationship with CVD is described. Treatment recommendations are provided using evidence available from populations with CKD or evidence extrapolated from the general population when there are insufficient data on individuals with CKD.