ATTENTION: Workforce shortages as a barrier to optimal dialysis.

Providing optimal end-stage kidney disease (ESKD) management requires an adequately trained and sufficiently staffed workforce, including doctors, nurses, and patient care technicians (PCTs). The growing need for ESKD services for a surging population of dialysis-dependent patients has made obvious a workforce crisis affecting nephrology. For a multitude of reasons, the physician workforce supply available to provide dialysis care has failed to expand commensurate with patients need in recent years. Of most importance, fewer US trainees are choosing to enter nephrology, and fewer international medical graduates are available to fill training program rosters. Equally important but less frequently cited are occupational shortages of trained dialysis nurses and PCTs. This article brings attention to this complex workforce shortage and addresses the limited information available regarding how it might constitute a barrier to optimal dialysis care.

Said the glucose sensor to the insulin pump: can glycemic control be improved in hospitalized ESRD patients with diabetes mellitus?

Although control of chronic glycemia in the population with diabetes and end-stage renal disease (ESRD) has been extensively studied in recent years, the unique problems of short-term glycemic management in acutely ill patients undergoing dialysis have received little attention. Bally et al. evaluated the role of a "closed-loop" (glucose sensor/algorithm tablet device/insulin pump) system in a cohort of hospitalized patients with type 2 diabetes receiving hemodialysis. Compared with usual care, the intervention group had superior glycemic control without increased hypoglycemic events. Additional studies are warranted.

A pair of homoeolog ClpP5 genes underlies a virescent yellow-like mutant and its modifier in maize.

Gene-background interaction is a commonly observed phenomenon in many species, but the molecular mechanisms of such an interaction is less well understood. Here we report the cloning of a maize mutant gene and its modifier. A recessive mutant with a virescent yellow-like (vyl) phenotype was identified in an ethyl methanesulfonate-mutagenized population derived from the maize inbred line B73. Homozygous mutant maize plants exhibited a yellow leaf phenotype after emergence but gradually recovered and became indistinguishable from wild-type plants after approximately 2 weeks. Taking the positional cloning approach, the Chr.9_ClpP5 gene, one of the proteolytic subunits of the chloroplast Clp protease complex, was identified and validated as the candidate gene for vyl. When introgressed by backcross into the maize inbred line PH09B, the mutant phenotype of vyl lasted much longer in the greenhouse and was lethal in the field, implying the presence of a modifier(s) for vyl. A major modifier locus was identified on chromosome 1, and a paralogous ClpP5 gene was isolated and confirmed as the candidate for the vyl-modifier. Expression of Chr.1_ClpP5 is induced significantly in B73 by the vyl mutation, while the expression of Chr.1_ClpP5 in PH09B is not responsive to the vyl mutation. Moreover, expression and sequence analysis suggests that the PH09B Chr.1_ClpP5 allele is functionally weaker than the B73 allele. We propose that functional redundancy between duplicated paralogous genes is the molecular mechanism for the interaction between vyl and its modifier.

Glycemic management in ESRD and earlier stages of CKD.

The management of hyperglycemia in patients with kidney failure is complex, and the goals and methods regarding glycemic control in chronic kidney disease (CKD) are not clearly defined. Although aggressive glycemic control seems to be advantageous in early diabetic nephropathy, outcome data supporting tight glycemic control in patients with advanced CKD (including end-stage renal disease [ESRD]) are lacking. Challenges in the management of such patients include therapeutic inertia, monitoring difficulties, and the complexity of available treatments. In this article, we review the alterations in glucose homeostasis that occur in kidney failure, current views on the value of glycemic control and issues with its determination, and more recent approaches to monitor or measure glycemic control. Hypoglycemia and treatment options for patients with diabetes and ESRD or earlier stages of CKD also are addressed, discussing the insulin and noninsulin agents that currently are available, along with their indications and contraindications. The article provides information to help clinicians in decision making in order to provide individualized glycemic goals and appropriate therapy for patients with ESRD or earlier stages of CKD.

Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue.

The American Society for Apheresis (ASFA) JCA Special Issue Writing Committee is charged with reviewing, updating and categorizating indications for therapeutic apheresis. Beginning with the 2007 ASFA Special Issue (Fourth Edition), the committee has incorporated systematic review and evidence-based approach in the grading and categorization of indications. This Sixth Edition of the ASFA Special Issue has further improved the process of using evidence-based medicine in the recommendations by consistently applying the category and GRADE system definitions, but eliminating the "level of evidence" criteria (from the University HealthCare Consortium) utilized in prior editions given redundancy between GRADE and University HealthCare Consortium systems. The general layout and concept of a fact sheet that was utilized in the Fourth and Fifth Editions, has been largely maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of therapeutic apheresis in a specific disease entity. This article consists of 78 fact sheets (increased from 2010) for therapeutic indications in ASFA categories I through IV, with many diseases categorized having multiple clinical presentations/situations which are individually graded and categorized.

Tough choices: dialysis, palliative care, or a third option for elderly ESRD.

Dialysis should not be presumed to be the treatment of choice for all elderly chronic kidney disease stage 5 patients. Nondialysis active medical management, as an alternative to dialysis or palliative care, is a reasonable alternative in select cases. Early referral of CKD 5 elderly patients may lead to early initiation of dialysis, which may not be advantageous; it also provides an opportunity to institute active management as a treatment alternative. The informed decision to proceed with dialysis must involve both an assessment of evidence-based outcomes applicable to the patient, and allowance of patient preference. Prognostic tools are increasingly sought to aid in decision-making for elderly CKD 5 patients. Chronological age alone is not a sufficient predictor of benefit from dialysis treatments, according to observational studies and limited clinical trial data. The survival advantage of dialysis appears to be lost in patients with high levels of comorbidity. Establishing patient preference is an imperfect process, and many patients appear to regret their decision to undergo dialysis. With active medical management, efforts shift from prolonging life to emphasis on symptom control, dietary and medical treatment, and quality of life. Patient survival time can be remarkably long.

Aging and ESRD demographics: consequences for the practice of dialysis.

The disproportionate increase in the prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in the elderly is now recognized as a national and global reality. Among the major contributing factors are the aging of the population, a growing prevalence of CKD, greater access to care, and increased comorbidities. The utilization of renal replacement therapy in the geriatric population has concomitantly increased. It is imposing enormous challenges to the practice of ESRD care, the largest of which may be to determine the best application of clinical performance targets to a population with limitations in life expectancy. Concurrently, increased focus on quality of life will be required. The effective dialysis practitioner will need to adapt to the aging ESRD demographics with an increased focus on physical and mental well-being of the geriatric patient.

Making sense of glucose sensors in end-stage kidney disease: A review.

Diabetes mellitus remains the leading cause of end-stage kidney disease worldwide. Inadequate glucose monitoring has been identified as one of the gaps in care for hemodialysis patients with diabetes, and lack of reliable methods to assess glycemia has contributed to uncertainty regarding the benefit of glycemic control in these individuals. Hemoglobin A1c, the standard metric to evaluate glycemic control, is inaccurate in patients with kidney failure, and does not capture the full range of glucose values for patients with diabetes. Recent advances in continuous glucose monitoring have established this technology as the new gold standard for glucose management in diabetes. Glucose fluctuations are uniquely challenging in patients dependent on intermittent hemodialysis, and lead to clinically significant glycemic variability. This review evaluates continuous glucose monitoring technology, its validity in the setting of kidney failure, and interpretation of glucose monitoring results for the nephrologist. Continuous glucose monitoring targets for patients on dialysis have yet to be established. While continuous glucose monitoring provides a more complete picture of the glycemic profile than hemoglobin A1c and can mitigate high-risk hypoglycemia and hyperglycemia in the context of the hemodialysis procedure itself, whether the technology can improve clinical outcomes merits further investigation.

A Dynamic Mass Redistribution Assay for the Human Sweet Taste Receptor Uncovers G-Protein Dependent Biased Ligands.

The sweet taste receptor is rather unique, recognizing a diverse repertoire of natural or synthetic ligands, with a surprisingly large structural diversity, and with potencies stretching over more than six orders of magnitude. Yet, it is not clear if different cell-based assays can faithfully report the relative potencies and efficacies of these molecules. Indeed, up to now, sweet taste receptor agonists have been almost exclusively characterized using cell-based assays developed with overexpressed and promiscuous G proteins. This non-physiological coupling has allowed the quantification of receptor activity via phospholipase C activation and calcium mobilization measurements in heterologous cells on a FLIPR system, for example. Here, we developed a novel assay for the human sweet taste receptor where endogenous G proteins and signaling pathways are recruited by the activated receptor. The effects of several sweet taste receptor agonists and other types of modulators were recorded by measuring changes in dynamic mass redistribution (DMR) using an Epic® reader. Potency and efficacy values obtained in the DMR assay were compared to those results obtained with the classical FLIPR assay. Results demonstrate that for some ligands, the two assay systems provide similar information. However, a clear bias for the FLIPR assay was observed for one third of the agonists evaluated, suggesting that the use of non-physiological coupling may influence the potency and efficacy of sweet taste receptor ligands. Replacing the promiscuous G protein with a chimeric G protein containing the C-terminal tail 25 residues of the physiologically relevant G protein subunit Gαgustducin reduced or abrogated bias.

The goal of blood pressure control for prevention of early diabetic microvascular complications.

Lowering blood pressure may confer a benefit to diabetic microvascular complications comparable with glycemic control. Hypertension is causally related to kidney outcomes and is a risk factor for the development of diabetic retinopathy. The prevalence of hypertension increases as kidney disease progresses, so that it coexists with diabetes in up to 80% of those with overt nephropathy. A significant number of patients have hypertension or rising blood pressures in earlier stages, or even before microvascular complications appear. Because microalbuminuria markedly increases the risk of overt nephropathy as well as of cardiovascular complications, primary prevention (i.e., preventing or delaying the onset of microalbuminuria) continues to be explored, predominantly through use of renin-angiotensin blockade. Available data reviewed suggest that primary prevention through blood pressure reduction is more likely to benefit select groups (those with hypertension, cardiovascular risks, or old age). This review discusses the relationship between hypertension, diabetes, and kidney disease, the rationale for primary prevention, and the data that led to that conclusion.

Social Adaptability Index: application and outcomes in a dialysis population.

BACKGROUND: Patient groups associated with disparities in health care are usually defined on the basis of race, gender or geographic location. Social Adaptability Index (SAI), calculated based on education, marital status, income, employment and substance abuse, has been strongly associated with clinical outcome in other patient populations and may be used to identify individuals at risk. We used data from the United States Renal Data System to evaluate the role of SAI in survival of patients on dialysis. METHODS: We used Cox model analyses to study the association between SAI and patient survival in patients with ESRD on dialysis, as well as in the subgroups based on age, race, sex, comorbidites and diabetic status. RESULTS: We analyzed 3396 patients (age of ESRD onset 56.9 ± 16.1 years, 54.2% males, 64.2% white, 30.3% African-American). Mean SAI of the entire population was 7.1 ± 2.5 (range 0-12 points). SAI was higher in whites (7.4 ± 2.4) than in African-Americans (6.5 ± 2.5) (analysis of variance, P <0.001) and greater in men (7.4 ± 2.4) than in women (6.7 ± 2.5) (t-test, P <0.001). In a Cox model adjusted for potential confounders, SAI was associated with decreased mortality [hazards ratio of 0.97 (95% confidence interval 0.95-0.99), P = 0.006]. Subgroup analysis demonstrated an association of SAI with survival in most of the subgroups. Potential limitations of the study include reverse causality, possible misclassification and retrospective design. CONCLUSION: We demonstrated that SAI is significantly associated with mortality in dialysis patients. SAI could be used to identify individuals at risk for inferior clinical outcomes.

Genetic factors associated with favourable pollinator traits in the wheat cultivar Piko.

Hybrid breeding in wheat has the potential to boost yields. An efficient hybrid seed production system requires elite pollinators; however, such germplasm is limited among modern cultivars. Piko, a winter wheat (Triticum aestivum L.) cultivar, has been identified as a superior pollinator and has been used in Europe. Piko has favourable pollinator traits for anther extrusion, anther length, pollen mass and hybrid seed set. However, the genetic factors responsible for Piko's favourable traits are largely unknown. Here, we report on the genetic analysis of a Piko-derived F2 mapping population. We confirmed that Piko's Rht-D1a allele for tall stature is associated with large anthers and high anther extrusion. However, Rht-D1 was not found to be associated with anther filament length, confirmed by near isogenic lines. Piko's photoperiod sensitive Ppd-B1b allele shows an association with increased spike length, more spikelets and spike architecture traits, while the insensitive Ppd-B1a allele is linked with high anther extrusion and larger anthers. We identified an anther extrusion quantitative trait locus (QTL) on chromosome 6A that showed significantly biased transmission of the favourable Piko allele amongst F2 progenies. The Piko allele is completely absent in the distal 6AS region and the central 6A region revealed a significantly lower ratio (<8%) of F2 with homozygous Piko alleles. Our study provided further evidence for the effects of Rht-D1 and Ppd-B1 loci on multiple pollinator traits and a novel anther extrusion QTL that exhibits segregation distortion.

Diabetic CKD/ESRD 2010: a progress report?

Both in the United States and many regions of the world, chronic kidney disease and end-stage renal disease (ESRD) in patients with diabetes mellitus have reached epidemic proportions in recent years. The large prevalent diabetic ESRD population in the US involves remarkable risk in African Americans and an increasing population of elderly diabetic patients, including many octogenarians. In the US and globally, over 90% of diabetic ESRD patients have type 2 diabetes. The multinational epidemic of diabetic ESRD has been linked to increases in the prevalence of diabetes in many populations, related to obesity, ageing, and physical inactivity. It is anticipated that the worldwide prevalence of diabetes over the next 20 years will reach a level twice that of the year 2000. The excessive morbidity and mortality of the diabetic ESRD population are well documented. However, the growth in incidence and prevalence rates for diabetic ESRD has remained somewhat stable in the US in recent years, and new data suggest that the incidence of ESRD expressed per diabetic population may finally be declining, suggesting that proven therapies are making "progress on progression."

A quality improvement model for optimizing care of the diabetic end-stage renal disease patient.

Persons with diabetes mellitus whose kidney disease progresses to end-stage requiring dialysis have poorer outcomes compared to nondiabetic patients who commence maintenance dialysis. In the diabetic patient without renal failure, sustained strict glycemic, lipid, and blood pressure (BP) control can retard or thwart diabetic complications such as retinopathy, neuropathy, coronary disease, and peripheral vascular disease. Achieving these outcomes requires multidisciplinary collaborative care. Best care of the diabetic person requires a dedicated clinician who knows the patient well, who closely follows the course of clinical problems, who provides frequent assessments and interventions, and who also directs care to other agencies, clinics, and specialized clinicians who provide expert focused evaluations and interventions aimed at specific clinical concerns. Diabetic patients who reach end-stage renal disease (ESRD) have even greater clinical need of a dedicated principal care clinician than the diabetic patient who has minimal or moderate kidney disease. The diabetic patient with ESRD exhibits greater fluctuations in glucose and BP due to dialysis-related diet patterns and fluid balances and has more active cardiovascular problems due to the combined influences of calcium, phosphorus, and lipid imbalances. These problems warrant exceptional care that includes frequent surveillance and monitoring with timely interventions if patient outcomes are to be improved. We present here a quality improvement model for optimizing care of the diabetic dialysis patient that relies on a dedicated practitioner who can evaluate and intervene on the multiple variables within and beyond the dialysis clinic that impact the patient's health. We present three detailed clinical care pathways that the dedicated clinician can follow. We believe that patient outcomes can be improved with this approach that provides customized problem-focused care, collaborates with the dialysis-provider team, and extends and directs diabetic self-care, home-care, and specialized clinical care in the challenging areas of cardiac and peripheral vascular disease, glycemic control, lipid control, infection prevention, and BP management.

Voltage-gated sodium channels in taste bud cells.

BACKGROUND: Taste bud cells transmit information regarding the contents of food from taste receptors embedded in apical microvilli to gustatory nerve fibers innervating basolateral membranes. In particular, taste cells depolarize, activate voltage-gated sodium channels, and fire action potentials in response to tastants. Initial cell depolarization is attributable to sodium influx through TRPM5 in sweet, bitter, and umami cells and an undetermined cation influx through an ion channel in sour cells expressing PKD2L1, a candidate sour taste receptor. The molecular identity of the voltage-gated sodium channels that sense depolarizing signals and subsequently initiate action potentials coding taste information to gustatory nerve fibers is unknown. RESULTS: We describe the molecular and histological expression profiles of cation channels involved in electrical signal transmission from apical to basolateral membrane domains. TRPM5 was positioned immediately beneath tight junctions to receive calcium signals originating from sweet, bitter, and umami receptor activation, while PKD2L1 was positioned at the taste pore. Using mouse taste bud and lingual epithelial cells collected by laser capture microdissection, SCN2A, SCN3A, and SCN9A voltage-gated sodium channel transcripts were expressed in taste tissue. SCN2A, SCN3A, and SCN9A were expressed beneath tight junctions in subsets of taste cells. SCN3A and SCN9A were expressed in TRPM5 cells, while SCN2A was expressed in TRPM5 and PKD2L1 cells. HCN4, a gene previously implicated in sour taste, was expressed in PKD2L1 cells and localized to cell processes beneath the taste pore. CONCLUSION: SCN2A, SCN3A and SCN9A voltage-gated sodium channels are positioned to sense initial depolarizing signals stemming from taste receptor activation and initiate taste cell action potentials. SCN2A, SCN3A and SCN9A gene products likely account for the tetrodotoxin-sensitive sodium currents in taste receptor cells.

Chronic kidney disease/bone and mineral metabolism: the imperfect storm.

As kidney function declines, chronic kidney disease (CKD) becomes an increasingly systemic disorder. Most patients with CKD eventually develop subclinical or clinical abnormalities in bone and mineral metabolism. Recent observational and basic scientific studies have led to a new emphasis on the changes in phosphorus and calcium metabolism, parathyroid hormone, and vitamin D that lead to this complex systemic bone/mineral disorder (CKD/BMD). At the center of the disorder are relationships among all 4 factors that conspire to create a perfect storm, leading to secondary hyperparathyroidism (SHPT). Some key current issues that are reviewed here are as follows: (1) factors promoting SHPT, (2) the role of fibroblast growth factor-23 in CKD/BMD, (3) molecular mechanisms of SHPT, (4) mechanisms of vascular calcification, and (5) medical management of the disorder, including calcimimetics. Current therapies directed at correcting the primary abnormalities (ie, improve conditions to an imperfect storm) and minimizing the consequences of CKD/BMD are discussed.

Management of diabetes in dialysis patients.

Diabetes mellitus is the most common cause of kidney disease worldwide, and of end-stage renal disease (ESRD) in the United States and elsewhere. Mortality rates of patients with diabetes mellitus (DM) on chronic dialysis exceed those of non-DM patients. ESRD and dialysis add to the complexity of glycemic management in this population. Abnormal glucoregulation includes reduced insulin sensitivity and renal clearance of the hormone. Implementation of dialysis affects glucose and insulin levels, while increasing insulin sensitivity. Tight glycemic control carries an increased risk of hypoglycemia in ESRD. Monitoring glycemic control with hemoglobin A(1c) (HbA(1c)) levels may be suboptimal because of analytical and clinical variability of the test. Recent studies on HbA(1c) and clinical outcomes in this population present complementary results on the role of glycemic control in patients with DM with ESRD.