Health-related quality of life of patients awaiting kidney and simultaneous pancreas-kidney transplants.

AIM: Patients undergoing kidney and simultaneous pancreas-kidney (SPK) transplants are younger and fitter than the general dialysis population. Intuitively these patients might have better quality of life (QOL) than the general dialysis population, but their QOL scores are not well characterized. The aim of this study was to compare QOL of patients about to undergo kidney or SPK transplants with Australian dialysis outcomes and practice patterns (DOPPS) data and multiple comorbidity and age-adjusted general population data. METHODS: Patients attending Westmead Hospital for transplants from August 2009 to December 2011 were invited to complete the Kidney Disease QOL-SF(™) 1.3 (KDQOL-SF(™) 1.3) questionnaire regarding their immediate pretransplant QOL. This QOL instrument is predictive of hospitalizations and mortality. The questionnaire was completed within 4 weeks of transplantation. RESULTS: Of 180 patients seen within 4 weeks of transplantation 95 (53%) responded, with no differences from non-responders in age, sex, comorbidities or perioperative complications. Compared with DOPPS, these patients had better physical function and less pain, but significantly lower scores for role physical (CI: -19 to -4, P=0.004) and role emotional (CI: -17 to -2, P=0.018). Patients undergoing SPK transplants reported even poorer general health, energy, social support and function. Patients had lower emotional and social function than people with multiple comorbidities, with whom they shared poor general and mental health and vitality. Scores were markedly lower than the general population except for bodily pain (female). CONCLUSION: Younger, fitter patients are more vulnerable to effects of their illness on social, emotional and physical interactions and may benefit from targeted support.

Effects of cholecalciferol on functional, biochemical, vascular, and quality of life outcomes in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Observational studies suggest that calciferol supplementation may improve laboratory and patient-level outcomes of hemodialysis patients with reduced 25-hydroxyvitamin D [25(OH)D] levels. This randomized controlled trial examined effects of cholecalciferol supplementation in patients on hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Sixty patients with 25(OH)D levels ≤24 ng/ml (≤60 nmol/L) were randomized to receive 50,000 IU oral cholecalciferol or placebo, once weekly for 8 weeks and then monthly for 4 months. At baseline (autumn 2011) and 6 months, testing evaluated muscle strength, functional capacity, laboratory parameters, pulse wave velocity (PWV), and health-related quality of life (HRQOL) using the Kidney Disease Quality of Life-36 survey. RESULTS: Patients were well matched by treatment allocation. Median age was 62 years (range, 20-86), 52% were women, 55% had a history of diabetes, and mean serum 25(OH)D was 17±5 ng/ml (43±13 nmol/L). Patients were assessed over 6 months by repeated-measures ANOVA. Patients allocated to cholecalciferol had significantly higher values of 25(OH)D (P<0.001), 1,25-dihydroxyvitamin D (P=0.04), and tartrate-resistant acid phosphatase-5b) (P=0.04) and a greater reduction in phosphorus values (P=0.03) than placebo-treated patients Values of serum calcium, intact parathyroid hormone, and episodes of hypercalcemia and hyperphosphatemia did not differ significantly between the groups. No significant differences were detected in muscle strength, functional capacity, PWV, or HRQOL. CONCLUSIONS: In this randomized controlled trial, patients supplemented with cholecalciferol had higher 25(OH)D, 1,25-dihydroxyvitamin D, and tartrate-resistant acid phosphatase-5b levels, without increased calcium or phosphorus values. However, no effects were detected in muscle strength, functional capacity, PWV, or HRQOL.

Review article: Patient-level outcomes: the missing link.

Treatment of chronic kidney disease (CKD) may be life-saving, but can disrupt every aspect of a patient's life and the lives of family members. Many patients with CKD are elderly with significant comorbidities and sometimes therapies to improve survival may be less important than those that improve or maintain quality of life. In this setting, patient-level benefits become particularly important goals of therapy. Randomized controlled trials (RCT) are also essential to justify expensive therapies, such as medications used in the treatment of CKD mineral and bone disorders. Surprisingly, data to support the efficacy of these drugs for patient-level outcomes remains limited. In fact, fewer RCT are conducted in renal medicine than in any other medical specialty and reliance is often placed on association data and the assessment of intermediate and biochemical end-points. While some of these may prove to be valid surrogates for clinically important outcomes, some may not. Inclusion of patient-level outcomes in clinical research provides a missing link that can inform a more comprehensive approach to clinical practice and patient care. Incorporating measures of health-related quality of life into clinical trials can make outcomes more relevant and may be relatively simple. This paper provides examples of reliable, validated instruments to measure health-related quality of life domains and functional status, together with practical instructions for their use. Most could be incorporated into RCT of CKD mineral and bone disorder treatments. Inclusion of outcomes that are perceived by patients to be significant should become standard practice in renal medicine and in clinical renal research.

Von Willebrand factor short sequence repeat locus 2 (intron 40) consists of three polymorphic subloci.

Currently, identification of alleles within the short sequence repeat locus (SSR locus) of intron 40 of the von Willebrand factor gene (previously known as VNTR II) is based on the size of PCR products that only predicts a certain number of repeats. Through cloning and sequencing, we demonstrated the complexity of nucleotide sequence structure of this region by describing three polymorphic tetranucleotide repeat subloci SSR 'a', SSR 'b' and SSR 'c' within the same originally described locus: the original TCTA (9-14 repeats), a small TCTA repeat locus (2 or 3 repeats) located at the 5' end and 30 nucleotides upstream from the original locus and a TGTA repeat locus (5 or 6 repeats), adjacent to the 2/3 repeat locus. Sequencing of 54 VWF alleles has revealed 14 different sequence combinations in this region while the size variability in the region only amounts to a 7-allele system. While the determination of VNTR alleles by PCR remains a practical methodology in linkage analysis, this may not be applicable in forensic medicine since not all alleles of identical length based on PCR are the same. Our study reveals the important implication of the identification of SSR 2 subloci and concludes that at least in some situations, there may be a necessity to take into consideration these polymorphic subloci.

Identification and functional characterization of a novel 27-bp deletion in the macroglycopeptide-coding region of the GPIBA gene resulting in platelet-type von Willebrand disease.

Interaction between the platelet glycoprotein Ibalpha (GPIbalpha) receptor and its adhesive ligand von Willebrand factor (VWF) has a critical role in the process of hemostasis. Platelet-type von Willebrand disease (PT-VWD) is a rare bleeding disorder that results from gain-of-function mutations in the GPIBA gene. We studied this gene from 5 members of a previously unreported family with a PT-VWD phenotype. We identified a novel in-frame deletion of 27 base pair (bp) in the macroglycopeptide region. This deletion was not found in the unaffected family members or in 50 healthy controls. The patients' platelets expressed normal quantities of GPIb/IX/V complex on their surface and the mutant (Mut) GPIbalpha was expressed at levels indistinguishable from the wild-type (WT) receptor on the surface of transfected Chinese hamster ovary (CHO) beta/IX cells. Analysis of ristocetin-mediated (125)I-VWF binding showed that the Mut receptor binds VWF in the absence of ristocetin and displays an increased sensitivity to lower concentrations of the modulator. This is the first report of a gain-of-function mutation in the GPIbalpha receptor outside the VWF-binding domain in patients with PT-VWD. The mutation provides a molecular basis for the PT-VWD phenotype and supports a role for the macroglycopeptide region in receptor function.

Recombinant FVIIa in the management of uncontrolled hemorrhage.

BACKGROUND: Recombinant FVIIa (rFVIIa/NovoSeven) is a novel hemostatic agent originally developed to treat patients with hemophilia who had developed inhibitors. Several case reports have suggested that rFVIIa may be effective in treating patients without a pre-existing bleeding disorder who have uncontrolled bleeding. STUDY DESIGN AND METHODS: Data on the efficacy and safety of rFVIIa in the treatment of massive hemorrhage were obtained retrospectively from the NovoSeven extended-use data collection system. RESULTS: A total of 40 patients received rFVIIa for uncontrolled bleeding, and in these patients, bleeding stopped or decreased in 32 (80%). Blood product usage was significantly decreased after rFVIIa administration. Thromboembolic events occurred in three patients with additional risk factors for thrombosis. Of 40 patients, 23 (57.5%) died. Bleeding was the direct cause of death in seven cases (all within 24 hr of administration of rFVIIa). The remaining 16 deaths were the result of sepsis, multi-organ failure, or the underlying disease. CONCLUSIONS: In this retrospective study of data voluntarily submitted to a web-based drug surveillance program, we present preliminary results on the use of rFVIIa in nonhemophilia patients with bleeding. Although some efficacy is suggested, there was a high mortality rate from nonhemorrhagic causes. Randomized controlled trials are needed to properly assess the role of rFVIIa in the management of hemorrhage.

Analysis and results of the recombinant factor VIIa extended-use registry.

This paper describes the analysis of recombinant factor VIIa (rFVIIa; NovoSeven; Novo Nordisk, Bagsvaerd, Denmark) use in 40 patients with intractable bleeding in the UK. All cases were reported on the 'rFVIIa extended use database' (Traumanet) between its launch in February 1999 and 12 March 2002. Twenty-one other cases reporting rFVIIa use in different circumstances were excluded from the analysis. Recombinant FVIIa was effective in stopping or markedly reducing blood loss in 80% of patients; 20% of patients did not respond to treatment. Non-responders tended to have more deranged coagulation and lower platelet counts compared with responders. Despite a wide range of underlying illnesses, including malignancy and sepsis, few patients suffered adverse events. Thrombotic events occurred in three of 40 (7.5%) patients and these patients were considered as already at risk of thrombosis from other causes. The data suggest that rFVIIa is safe and effective therapy in patients with uncontrollable haemorrhage.

Mechanical methods of reducing blood transfusion in cardiac surgery: randomised controlled trial.

OBJECTIVE: To assess the effectiveness of two mechanical methods of blood conservation in reducing the need for allogeneic red blood cells or coagulation products during cardiac surgery. DESIGN: Randomised controlled trial. SETTING: Regional cardiac centre in a teaching hospital in Southampton. PARTICIPANTS: 263 adults aged 18-80 years undergoing elective coronary artery bypass surgery entered the study, of whom 252 completed the trial. All patients received routine perioperative care. Patients were allocated to one of three treatment groups: intraoperative cell salvage, intraoperative cell salvage with acute perioperative normovolaemic haemodilution, or no mechanical blood conservation. There were 84 patients in each group. MAIN OUTCOME MEASURES: Numbers of patients who received allogeneic blood or coagulation products, and the mean number of units of blood transfused per patient. RESULTS: Of the patients in the intraoperative cell salvage group, 26 were given a transfusion of allogeneic blood, compared with 43 in the control group (odds ratio 0.43 (95% confidence interval 0.23 to 0.80)). The mean number of units of allogeneic blood transfused per patient in the intraoperative cell salvage group was 0.68 units (SD=1.55), compared with 1.07 (1.56) units in the control group. 32 of the patients in the intraoperative cell salvage group were given any blood product, compared with 47 in the control group (odds ratio 0.47 (0.25 to 0.89); P=0.019). Combining acute perioperative normovolaemic haemodilution with intraoperative cell salvage conferred no additional benefits. CONCLUSIONS: An intraoperative cell salvage device should be used in elective coronary artery bypass grafting. Pharmacological strategies may achieve further reductions in blood transfusions. Yet further reductions in blood transfusions could be achieved if the lower safe limit of haemoglobin concentration in patients undergoing cardiac surgery were known.

Haemostasis and Thrombosis: Current Clinical Practice: Low-Molecular-Weight Heparins in The Prophylaxis and Treatment of Thrombo-Embolic Disease.

Low-Molecular-Weight Heparin (LMWH) fractions are prepared from standard unfractionated heparin (UFH) and are thus similar to it in many aspects. The major advantages of LMWH are improved efficacy and safety, longer half-life and reduced need for laboratory monitoring. In addition, the dangers of UFH administered by continuous infusion in the hospital setting are often not fully appreciated and the necessary monitoring and dosage adjustment poorly carried out resulting in inadequate doses being given. LMWHs are the drug of choice in many clinical situations. Four LMWHs are now licensed in the UK for prophylaxis of venous thrombo-embolism during or after surgery (Certoparin, Dalteparin [Fragmin], Enoxaparin [Lovenox/Clexane] and Tinzaparin [Innohep]; a fifth is licensed but not currently available in the UK. Dalteparin, Enoxaparin and Tinzaparin are licensed for the treatment of Deep Vein Thrombosis (DVT), and Tinzaparin additionally for the treatment of Pulmonary Embolism (PE), but so far none is licensed for use in pregnancy or paediatrics.