Azzour D. Hazzan

Challenges and opportunities in late-stage chronic kidney disease

There is increasing recognition that chronic diseases are a major challenge for health delivery systems and treasuries. These are highly prevalent and costly diseases and frequency is expected to increase greatly as the population of many countries ages. Chronic kidney disease (CKD) has not received the same attention as other chronic diseases such as congestive heart failure; yet, the prevalence and costs of CKD are substantial. Greater recognition and support for CKD may require that the disease no longer be viewed as one continuous disease state. Early CKD stages require less complex care and generate lower costs. In contrast, late-stage CKD is every bit as complex and costly as other major chronic diseases. Health authorities may not recognize and fund CKD care appropriately until late-stage CKD is defined clearly as separate and distinct from earlier stages of disease. In this review, we describe the burden of chronic diseases, consider the challenges and barriers and propose processes to improve late-stage CKD care. In particular, we recommend the need for improved continuity of care, enhanced use of information technology, multidisciplinary care, timely referral to nephrologists, protocol use and improved patient engagement.

Increasing Hip Fractures in Patients Receiving Hemodialysis and Peritoneal Dialysis

Background/Aims: Dialysis patients are at increased risk for hip fractures. Because changes in treatment of metabolic bone disease in this population may have impacted bone fragility, this study aims to analyze the longitudinal risk for fractures in hemodialysis (HD) and peritoneal dialysis (PD) patients. Methods: Using the United States Renal Data System database from 1992 to 2009, the temporal trend in hip fractures requiring hospitalization was analyzed using an overdispersed Poisson regression model. Generalized Estimating Equations were used to assess the adjusted effect of dialysis modality on hip fractures. Results: 842,028 HD and 87,086 PD patients were included. There was a significant temporal increase in hip fractures in both HD and PD with stabilization of rates after 2005. With stratification, the increase in fractures occurred in patients who were white and over 65 years of age. In adjusted analyses, HD patients had 1.6 times greater odds of hip fracture than PD patients (OR 1.60 95% CI 1.52, 1.68, p < 0.001). Conclusions: In contrast to the declining hip fracture rates in the general population, we identified a temporal rise in incidence of hip fractures in HD and PD patients. HD patients were at a higher risk for hip fractures than PD patients after adjustment for recognized bone fragility risk factors. The increase in fracture rate over time was limited to older white patients in both HD and PD, the demographics being consistent with osteoporosis risk. Further research is indicated to better understand the longitudinal trend in hip fractures and the discordance between HD and PD. i 2014 S. Karger AG, Basel

Bone Parameters and Risk of Hip and Femur Fractures in Patients on Hemodialysis

BACKGROUND AND OBJECTIVES Patients on hemodialysis have a high rate of hip fractures. In this study, we performed a contemporary analysis of mineral and bone parameters and their relationship to hip and femur fracture risk. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Patients on hemodialysis treated between 2000 and 2013 in Fresenius Medical Care North America facilities were included. Predictors were on the basis of data as of December 31 of each baseline year and time-averaged values of selected laboratory parameters and medication doses throughout the year. Four period cohorts were constructed from baseline years: 2000, 2003, 2006, and 2009. Follow-up for each cohort was ≤3 years. RESULTS The incidence of hip and femur fractures remained generally unchanged (P=0.40), except among patients who were white and >65 years of age, in whom the rate decreased significantly over the 14-year period (P<0.01). Results from combined multivariable models indicated that the lowest quartiles of time-averaged intact parathyroid hormone were independently associated with higher hip fracture risk (intact parathyroid hormone =181-272 pg/ml: hazard ratio, 1.20; 95% confidence interval [95% CI], 1.03 to 1.41 and intact parathyroid hormone <181 pg/ml: hazard ratio, 1.20; 95% CI, 1.01 to 1.44; referent third quartile, 273 to <433 pg/ml). The lowest quartile of time-averaged serum calcium was also associated with higher risk (calcium <8.7 mg/dl; hazard ratio, 1.17; 95% CI, 1.00 to 1.37) compared with the referent third quartile of 9.1 to <9.5 mg/dl. CONCLUSIONS We found an association between lower levels of intact parathyroid hormone and serum calcium and greater risk for hip and femur fractures among patients on hemodialysis. These findings support additional research toward elucidating long-term safety of treatment approaches for hyperparathyroidism in patients with ESRD.

Longitudinal Predictors of Uremic Pruritus

OBJECTIVE Pruritus is a common problem among hemodialyzed patients. Its causes are poorly understood, and, as a result, itching is often attributed to elevated serum phosphorus and other disorders of bone and minerals. The primary purpose of this study was to analyze the relationship between pruritus and common tests of bone and mineral disease. METHODS This study was a post hoc analysis of data from a randomized controlled trial of 3 months of ergocalciferol versus placebo treatment in 50 hemodialysis patients with uremic pruritus. A pruritus survey was administered at baseline and then every 2 weeks for 12 weeks. Concurrent serum phosphorus, intact parathyroid hormone (PTH), serum calcium, and calcium-phosphate product were measured. RESULTS Pruritus score was not found to be associated or correlated with serum phosphate, intact PTH, serum calcium, or calcium-phosphate product at each time interval or over time. Likewise, when analyzed by original study group (placebo or ergocalciferol), no association or correlation between the mineral and bone indicators and itching were found. CONCLUSION Neither serum phosphate nor other tests of bone and mineral status were found to be significant predictors of pruritus at any point in time or over time.

Epidemiology and Challenges to the Management of Advanced CKD

Advanced CKD is a period of CKD that differs greatly from earlier stages of CKD in terms of treatment goals. Treatment during this period presents particular challenges as further loss of kidney function heralds the need for renal replacement therapy. Successful management during this period increases the likelihood of improved transitions to ESRD. However, there are substantial barriers to optimal advanced CKD care. In this review, we will discuss advanced CKD definitions and epidemiology and outcomes.

Novel iron-based phosphate binders in patients with chronic kidney disease.

Purpose of reviewManagement of hyperphosphatemia remains an integral component in the care of patients with chronic kidney disease on dialysis. In addition to dietary restriction and dialysis, oral phosphate binders remain a key strategy in the control of serum phosphorus levels in this population. We review two new oral phosphate binders that are currently marketed in the United States. Recent findingsSucroferric oxyhydroxide was approved by the U.S. Food and Drug Administration (FDA) in November 2013. A recent international, multicenter study found the drug to be efficacious and noninferior to sevelamer carbonate in magnitude of serum phosphate control. This was achieved with a significantly reduced daily pill burden for sucroferric oxyhydroxide. A second novel agent, ferric citrate was approved by the FDA in September, 2014. The drug was found to have similar phosphate control efficacy to active comparators and was superior to placebo. In addition, the drug delivers a significant amount of iron, resulting in improved erythropoietic parameters. Both drugs had diarrhea as a fairly frequent side-effect. SummaryThese new phosphate binders offer alternatives to currently available agents. Both have interesting properties that may make them particularly useful in clinical practice.

Ranolazine, Tacrolimus, and Diltiazem Might be a Hazardous Combination in a Transplant Patient

We report a case of a renal transplant patient who was maintained on tacrolimus and diltiazem therapy and developed tacrolimus toxicity leading to reversible acute kidney injury when started on ranolazine. A 62-year-old Caucasian male status post renal transplant in 2009 (on prednisone and tacrolimus) was evaluated for ischemic heart disease and was initiated on ranolazine 500 mg tablets twice daily, which was later increased to 1000 mg twice daily. After 2 weeks, he developed fatigue, loss of appetite, tremors, and decreased urine output and was admitted to our hospital. His other significant medications included enalapril 2.5 mg and diltiazem 240 mg daily. The patient was awake and alert, but lethargic. He was found to be bradycardic with a heart rate of 42/min. The rest of his physical examination was benign. His electrocardiogram revealed sinus bradycardia. Laboratory studies revealed serum creatinine of 2.4 mg/dL from a baseline of 1.5 mg/dL (stable for the past 2 years). The tacrolimus trough was elevated at 14 ng/mL, which decreased after stopping ranolazine, reaching 7 ng/mL after 3 days, while continuing the same dose of tacrolimus. His creatinine trended downward and reached his baseline of 1.5 mg/dL over the next 2 days. His bradycardia and other symptoms resolved after cessation of ranolazine. He was discharged to follow up, to initiate an alternate agent for ischemic heart disease. Specific pharmacokinetic studies are warranted to study these drug interactions, and tacrolimus levels should be closely monitored in transplant patients who initiate ranolazine treatment.

Update on the End-Stage Renal Disease Quality Incentive Program

The End‐Stage Renal Disease Quality Incentive Program continues to evolve and expand. In this article, we will review the programs structure and critically assess the clinical metrics in place. In addition, we will discuss upcoming program changes to help prepare dialysis facilities and nephrologists to meet new proposed metrics.

Should Target Hemoglobin Levels in Dialysis Patients be Lowered to 9–10 g/dl?

We have been asked to consider whether the hemoglobin (Hgb) target during ESA treatment for hemodialysis patients should be lowered to 9–10 g/ dl. We will consider this question as a debate proposition and will work through key logical considerations. While there is no broad consensus on a Hgb target range, the proposed range is certainly lower than typical practice. When erythropoietin analogs (the current preferred term is erythropoiesis-stimulating agents [ESA]) were first FDA approved in 1989, clinicians generally sought to raise Hgb levels of hemodialysis patients to approximately 9–10 g/dl. By 1994, the mean Hgb level of patients had increased to above 10 g/dl, in 1999 to above 11 g/dl, and in 2005 to a peak of 12 g/dl (1). At that time, the Kidney Disease Outcomes Quality Initiative (KDOQI) anemia guideline recommended a Hgb target of 11–12 g/dl while FDA product labeling had a Hgb target of 10–12 g/dl. It might, therefore, be surprising that the mean Hgb in 2005 in hemodialysis patients was at the upper end of recommended target ranges. But a general belief in the benefits of therapy and misaligned economic incentives led to an aggressive treatment approach.

Quality of reporting of randomization methodology in nephrology trials

Steven Fishbane1, Azzour D. Hazzan1, Shayan Shirazian2, Ezra Israel1 and Giovanni F. Strippoli3–6 1Hofstra North Shore-LIJ School of Medicine, Great Neck, New York, USA; 2Winthrop-University Hospital, Mineola, New York, USA; 3Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy; 4University of Sydney School of Public Health, Sydney, Australia; 5Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy; and 6Diaverum Medical Scientific Office, Lund, Sweden. Correspondence: Steven Fishbane, Hofstra North ShoreLIJ School of Medicine, 100 Community Drive, 2nd Floor, Great Neck, New York 11021, USA. E-mail: sfishbane@nshs.edu T he randomized controlled trial (RCT) is the ideal study design to address intervention questions.1 In an RCT, patients are allocated to an intervention or control group on the basis of chance. The strengths of this methodology include that it minimizes confounding by producing groups that are comparable in terms of baseline characteristics. In theory, this provides comparable prognoses of the groups prior to intervention. The reliability of an individual RCT, however, is affected by the methodological aspects of randomization procedures, which are reflected by the completeness and quality of reporting. When reporting is inadequate or superficial, confidence in the credibility of study procedures and results is diminished. There are certain attributes that define the quality of the procedures and reporting of RCTs. The Consolidated Standards of Reporting Trials (CONSORT) Statement, a widely accepted set of standards for reporting of clinical trials, lists four minimum requirements for reporting of randomization methodology.2 The first is a clear explanation of the method by which the random sequence is generated. Second is an explanation of the type of randomization as simple ran domization, permuted block (to avoid imbalances in allocation), stratification (to balance the distribution of certain baseline risk factors), or a combination of these techniques. Third is allocation concealment, the method of preventing study personnel from having awareness of treatment assignment before enrolling patients. Finally, there needs to be full reporting on the methods of implementation of randomization procedures.2 It is well worth noting that the CONSORT Statement goes well beyond reporting on randomization, and other aspects are highly valuable.2 Clinicians, guideline groups, and policy makers rely on the results of RCTs. It is clear, therefore, that the quality of design, conduct, and reporting of RCTs is a fundamental step in determining valid and applicable results. Studies with suboptimal quality may be misleading as to the true effects of interventions. The ability to advance clinical care may hence be hindered, while both resources and the volunteerism of study subjects may be squandered. High-quality reporting of methodology increases the credibility, applicability, and generalizability of methods and results. It should be noted that nephrology publishes the fewest RCTs of any medical specialty.3 When the number of RCTs in a field is less, then the contribution of each individual study to the accumulated literature and knowledge base is proportionately greater. As a result there is an even heightened burden of responsibility for high-quality reporting. The purpose of this Editorial is to discuss quality of randomization reporting in clinical trials in nephrology. We reviewed nephrology RCTs published in 13 nephrology and four general medical journals between 1 July 2010 and 30 June 2011 (see Supplementary Methods and Supplementary Figure S1 online) to explore these domains. A total of 74 articles met the inclusion criteria, and their characteristics are reported in Table 1. Sixty of 74 (82%) were published in nephrology journals, and 52 of 74 (70%) had sample sizes of fewer than 200 patients. The four CONSORT indicators of the quality of randomization could be ascertained from all articles. The method of sequence generation was not reported in 44 of 74 studies (59.5%) (Table 2). Randomization type was not reported in 29 of 74 publications (39.2%). When the type was reported, some form of stratification, permuted block, or a combination was used in 48.6% of studies (permuted block alone in 12.2%, stratification alone in 20.3%). Most studies that did not report randomization type used simple randomization, on the basis of responses provided by the authors of 16 studies. The method of allocation concealment was not reported in 43 of 74 studies (58.1%); when it was reported, central allocation was the most common procedure. Finally, in the vast majority of cases, information was not provided on how and by whom randomization was implemented. Quality of reporting of randomization methodology in nephrology trials