Martin Wilkie

The OPTIMA Study: Assessing a New Cinacalcet (Sensipar/Mimpara) Treatment Algorithm for Secondary Hyperparathyroidism

BACKGROUND AND OBJECTIVES Cinacalcet, a novel calcimimetic, targets the calcium-sensing receptor to lower parathyroid hormone (PTH), calcium, and phosphorus levels in dialysis patients with secondary hyperparathyroidism (SHPT). This study compared the efficacy of a cinacalcet-based regimen with unrestricted conventional care (vitamin D and phosphate binders) for achieving the stringent National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) targets for dialysis patients. STUDY DESIGN In this multicenter, open-label study, hemodialysis patients with poorly controlled SHPT were randomized to receive conventional care (n = 184) or a cinacalcet-based regimen (n = 368). Doses of cinacalcet, vitamin D sterols, and phosphate binders were adjusted during a 16-wk dose-optimization phase with the use of algorithms that allowed cinacalcet to be used with adjusted doses of vitamin D. The primary end point was the proportion of patients with mean intact PTH < or =300 pg/ml during a 7-wk efficacy assessment phase. RESULTS A higher proportion of patients receiving the cinacalcet-based regimen versus conventional care achieved the targets for PTH (71% versus 22%, respectively; P < 0.001), Ca x P (77% versus 58%, respectively; P < 0.001), calcium (76% versus 33%, respectively; P < 0.001), phosphorus (63% versus 50%, respectively; P = 0.002), and PTH and Ca x P (59% versus 16%, respectively, P < 0.001), and allowed a 22% reduction in vitamin D dosage in patients receiving vitamin D at baseline. Achievement of targets was greatest in patients with less severe disease (intact PTH range, 300 to 500 pg/ml) and the cinacalcet dose required was lower in these patients (median = 30 mg/d). CONCLUSIONS Compared with conventional therapy, a cinacalcet-based treatment algorithm increased achievement of KDOQI treatment targets in dialysis patients in whom conventional therapy was no longer effective in controlling this disease.

Clinical practice guidelines for peritoneal access.

Faculdade de Enfermagem, Nutricao e Fisioterapia,1 Pontificia Universidade Catolica do Rio Grande do Sul, Brazil; Department of Nephrology,2 Serdang Hospital, Jalan Puchong, Kajang, Selangor, Malaysia; Sheffield Kidney Institute,3 Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom; Nephrology,4 Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia; Renal Services,5 Glasgow Royal Infirmary, Glasgow, Scotland, United Kingdom; Nephrology,6 Sri Ramachandra University, Chennai, India; Dialysis Unit,7 Dianet Dialysis Centers and Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Encapsulating peritoneal sclerosis:: clinical significance and implications

Encapsulating peritoneal sclerosis (EPS) is a rare but serious complication of peritoneal dialysis (PD). This review discusses the current understanding of the aetiology and pathogenesis of EPS, highlighting histological features which differentiate it from simple sclerosis of the peritoneal membrane which develops with time on PD. Diagnostic criteria are presented, including the role of imaging techniques. To date there are no randomised controlled trials to guide therapy; however, surgical techniques are an important treatment option. Collaborative research will be essential if this serious problem facing PD is to be solved.

Iron-magnesium hydroxycarbonate (fermagate): a novel non-calcium-containing phosphate binder for the treatment of hyperphosphatemia in chronic hemodialysis patients.

BACKGROUND AND OBJECTIVES This phase II study tested the safety and efficacy of fermagate, a calcium-free iron and magnesium hydroxycarbonate binder, for treating hyperphosphatemia in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A randomized, double-blind, three-arm, parallel-group study compared two doses of fermagate (1 g three times daily or 2 g three times daily with placebo). Sixty-three patients who had been on a stable hemodialysis regimen for > or =3 mo were randomized to the treatment phase. Study medication was administered three times daily just before meals for 21 d. The primary endpoint was reduction in serum phosphate over this period. RESULTS In the intention-to-treat analysis, mean baseline serum phosphate was 2.16 mmol/L. The fermagate 1- and 2-g three-times-daily treatment arms were associated with statistical reductions in mean serum phosphate to 1.71 and 1.47 mmol/L, respectively. Adverse event (AE) incidence in the 1-g fermagate arm was statistically comparable to the placebo group. The 2-g arm was associated with a statistically higher number of patients reporting AEs than the 1-g arm, particularly gastrointestinal AEs, as well as a higher number of discontinuations, complicating interpretation of this doses efficacy. Both doses were associated with elevations of prehemodialysis serum magnesium levels. CONCLUSIONS The efficacy and tolerability of fermagate were dose dependent. Fermagate showed promising efficacy in the treatment of hyperphosphatemia in chronic hemodialysis patients as compared with placebo in this initial phase II study. The optimal balance between efficacy and tolerability needs to be determined from future dose-titration studies, or fixed-dose comparisons of more doses.

Effect of Pamidronate on Bone Loss After Kidney Transplantation: A Randomized Trial

BACKGROUND Kidney transplantation is associated with an increased risk of bone fracture and rapid loss of bone mineral density after kidney transplantation. STUDY DESIGN Randomized controlled trial. SETTING & PARTICIPANTS Patients were randomly assigned to treatment (n = 46) or control (no treatment; n = 47) groups. Patients were stratified according to parathyroid hormone level and sex. Those with parathyroid hormone level less than 150 pg/mL were excluded. INTERVENTION The treatment and control groups received pamidronate, 1 mg/kg, perioperatively and then at 1, 4, 8, and 12 months or no treatment, respectively. All received calcium (500 mg) and vitamin D (400 units) daily. Immunosuppression was cyclosporine and prednisolone, with no difference in dosing between the 2 groups. OUTCOMES & MEASUREMENTS Bone mineral density was evaluated by means of dual-energy x-ray absorptiometry of the lumbar spine and hip at baseline and 3, 6, 12, and 24 months, with the primary end point at 1 year of percentage of change in bone mineral density from baseline. Clinical fractures were recorded and also evaluated by means of spinal radiographs at baseline and 1 and 2 years. RESULTS Pamidronate protected bone mineral density at the lumbar spine; bone mineral density increased by 2.1% in the treatment group and decreased by 5.7% in the control group at 12 months (P = 0.001). Protection was also seen in Wards area of the hip (P = 0.002) and the total hip (P = 0.004). There was no difference in femoral neck bone mineral density loss between the 2 groups. Fracture rates in the treatment and control groups were 3.3% and 6.4% per annum, respectively. LIMITATIONS This study was not powered to detect differences in fracture rates. CONCLUSION Pamidronate protects against posttransplantation bone loss at the lumbar spine and Wards area of the hip.

Cyclosporine and cremaphor modulate von Willebrand factor release from cultured human endothelial cells.

Cyclosporine has been associated with microangiopathic hemolysis (MAHA) and other thrombotic complications of bone marrow and renal transplantation. MAHA is characterized by intravascular platelet aggregation, which, in some situations, is thought to be mediated by hyperactive high molecular weight von Willebrand factor (vWF). We have hypothesized that transplant-related MAHA may be caused by CsA-mediated release of von Willebrand factor from endothelial cells. This hypothesis was tested by studying vWF release from human umbilical vein endothelial cells primed with either CsA or cremophor EL. CsA and cremophor alone did not increase vWF release until toxic concentrations were reached (50-100 micrograms/ml). However, at therapeutic concentrations (0.1-5 micrograms/ml) vWF release by cells stimulated with thrombin, histamine, PMA, and the calcium ionophore A23187 was enhanced by both CsA and cremophor in a concentration-dependent manner. In single isolated endothelial cells, the thrombin-induced increase in cytosolic free calcium was enhanced by both CsA and cremophor. Preincubation for 24 hr with CsA but not cremophor suppressed vWF release after thrombin stimulation. These observations were mirrored by a concentration-dependent suppression of [3H]thymidine uptake by CsA. We conclude that CsA vehicle, cremophor, enhances stimulated vWF release in vitro, probably by processes dependent upon increased cytosolic free calcium. This suggests a possible mechanism for thrombotic transplant complications.

Dietary Phosphate Modulates Atherogenesis and Insulin Resistance in Apolipoprotein E Knockout Mice—Brief Report

Objective— Epidemiological studies link higher serum phosphate and the phosphatonin fibroblast growth factor 23 with cardiovascular events and atheroma, and they link lower serum phosphate with insulin resistance and the metabolic syndrome. We investigated whether manipulating dietary phosphate influences atherogenesis or insulin sensitivity in mice. Methods and Results— Apolipoprotein E knockout mice were fed an atherogenic diet with low (0.2%), standard (0.6%), or high (1.6%) phosphate content. Serum phosphate and fibroblast growth factor 23 significantly increased with increasing dietary phosphate intake, but lipid profile and blood pressure were unaffected. After 20 weeks, mice on the higher phosphate diet had significantly more atheroma at the aortic sinus (42±1.9% versus 30±1.5% for high versus low phosphate, P<0.01). Compared with standard and high-phosphate diet groups, mice on a low-phosphate diet had more adipose tissue and a 4-fold increase in insulin resistance measured by homeostatic model assessment (43.7±9.3 versus 8.9±0.7 for low versus high phosphate, P<0.005). Conclusion— A high-phosphate diet accelerates atherogenesis in apolipoprotein E−/− mice, whereas low phosphate intake induces insulin resistance. These data indicate for the first time that controlling dietary phosphate intake may influence development of both atherosclerosis and the metabolic syndrome.

Summary of the 5th Edition of the Renal Association Clinical Practice Guidelines (2009-2012)

Robert Mactier, Simon Davies, Chris Dudley, Paul Harden, Colin Jones, Suren Kanagasundaram, Andrew Lewington, Donald Richardson, Maarten Taal, Peter Andrews Richard Baker, Cormac Breen, Neill Duncan, Ken Farrington, Richard Fluck, Colin Geddes, David Goldsmith, Nic Hoenich, Stephen Holt, Alan Jardine, Sarah Jenkins, Mick Kumwenda, Elizabeth Lindley, Mark MacGregor, Ashraf Mikhail, Edward Sharples, Badi Shrestha, Rajesh Shrivastava, Simon Steddon, Graham Warwick, Martin Wilkie, Graham Woodrow, Mark Wright

Vitamin D Deficiency and Exogenous Vitamin D Excess Similarly Increase Diffuse Atherosclerotic Calcification in Apolipoprotein E Knockout Mice

Background Observational data associate lower levels of serum vitamin D with coronary artery calcification, cardiovascular events and mortality. However, there is little interventional evidence demonstrating that moderate vitamin D deficiency plays a causative role in cardiovascular disease. This study examined the cardiovascular effects of dietary vitamin D deficiency and of vitamin D receptor agonist (paricalcitol) administration in apolipoprotein E knockout mice. Methods Mice were fed atherogenic diets with normal vitamin D content (1.5IU/kg) or without vitamin D. Paricalcitol, or matched vehicle, was administered 3× weekly by intraperitoneal injection. Following 20 weeks of these interventions cardiovascular phenotype was characterized by histological assessment of aortic sinus atheroma, soluble markers, blood pressure and echocardiography. To place the cardiovascular assessments in the context of intervention effects on bone, structural changes at the tibia were assessed by microtomography. Results Vitamin D deficient diet induced significant reductions in plasma vitamin D (p<0.001), trabecular bone volume (p<0.01) and bone mineral density (p<0.005). These changes were accompanied by an increase in calcification density (number of calcifications per mm2) of von Kossa-stained aortic sinus atheroma (461 versus 200, p<0.01). Paricalcitol administration suppressed parathyroid hormone (p<0.001), elevated plasma calcium phosphate product (p<0.005) and induced an increase in calcification density (472 versus 200, p<0.005) similar to that seen with vitamin D deficiency. Atheroma burden, blood pressure, metabolic profile and measures of left ventricular hypertrophy were unaffected by the interventions. Conclusion Vitamin D deficiency, as well as excess, increases atherosclerotic calcification. This phenotype is induced before other measures of cardiovascular pathology associated clinically with vitamin D deficiency. Thus, maintenance of an optimal range of vitamin D signalling may be important for prevention of atherosclerotic calcification.

Using behavioural theories to optimise shared haemodialysis care: a qualitative intervention development study of patient and professional experience

BackgroundPatients in control of their own haemodialysis report better outcomes than those receiving professional controlled care in a hospital setting, even though home and hospital haemodialysis are largely equivalent from mechanical and physiological perspectives. Shared Haemodialysis Care (SHC) describes an initiative in which hospital haemodialysis patients are supported by dialysis staff to become as involved as they wish in their own care; and can improve patient safety, satisfaction and may reduce costs. We do not understand why interventions to support self-management in other conditions have variable effects or how to optimise the delivery of SHC. The purpose of this study was to identify perceived patient and professional (nurses and healthcare assistants) barriers to the uptake of SHC, and to use these data to identify intervention components to optimise care.MethodsIndividual semi-structured interviews with patients and professionals were conducted to identify barriers and facilitators. Data were coded to behavioural theory to identify solutions. A national UK learning event with multiple stakeholders (patients, carers, commissioners and professionals) explored the salience of these barriers and the acceptability of solutions.ResultsA complex intervention strategy was designed to optimise SHC for patients and professionals. Interviews were conducted with patients (n = 15) and professionals (n = 7) in two hospitals and three satellite units piloting SHC. Data from patient and professional interviews could be coded to behavioural theory. Analyses identified key barriers (knowledge, beliefs about capabilities, skills and environmental context and resources). An intervention strategy that focuses on providing, first, patients with information about the shared nature of care, how to read prescriptions and use machines, and second, providing professionals with skills and protected time to teach both professionals/patients, as well as providing continual review, may improve the implementation of SHC and be acceptable to stakeholders.ConclusionsWe have developed an intervention strategy to improve the implementation of SHC for patients and professionals. While this intervention strategy has been systematically developed using behavioural theory, it should be rigorously tested in a subsequent effectiveness evaluation study prior to implementation to ensure that shared haemodialysis care can be delivered equitably, efficiently and safely for all patients.