David W. Mudge

Randomized, Controlled Trial of Topical Exit-Site Application of Honey (Medihoney) versus Mupirocin for the Prevention of Catheter-Associated Infections in Hemodialysis Patients

The clinical usefulness of hemodialysis catheters is limited by increased infectious morbidity and mortality. Topical antiseptic agents, such as mupirocin, are effective at reducing this risk but have been reported to select for antibiotic-resistant strains. The aim of the present study was to determine the efficacy and the safety of exit-site application of a standardized antibacterial honey versus mupirocin in preventing catheter-associated infections. A randomized, controlled trial was performed comparing the effect of thrice-weekly exit-site application of Medihoney versus mupirocin on infection rates in patients who were receiving hemodialysis via tunneled, cuffed central venous catheters. A total of 101 patients were enrolled. The incidences of catheter-associated bacteremias in honey-treated (n = 51) and mupirocin-treated (n = 50) patients were comparable (0.97 versus 0.85 episodes per 1000 catheter-days, respectively; NS). On Cox proportional hazards model analysis, the use of honey was not significantly associated with bacteremia-free survival (unadjusted hazard ratio, 0.94; 95% confidence interval, 0.27 to 3.24; P = 0.92). No exit-site infections occurred. During the study period, 2% of staphylococcal isolates within the hospital were mupirocin resistant. Thrice-weekly application of standardized antibacterial honey to hemodialysis catheter exit sites was safe, cheap, and effective and resulted in a comparable rate of catheter-associated infection to that obtained with mupirocin (although the study was not adequately powered to assess therapeutic equivalence). The effectiveness of honey against antibiotic-resistant microorganisms and its low likelihood of selecting for further resistant strains suggest that this agent may represent a satisfactory alternative means of chemoprophylaxis in patients with central venous catheters.

Free mycophenolic acid should be monitored in renal transplant recipients with hypoalbuminemia

The current approach for therapeutic drug monitoring in renal transplant recipients receiving mycophenolate mofetil (MMF) is measurement of total mycophenolic acid (MPA) concentration. Because MPA is highly bound, during hypoalbuminemia the total concentration no longer reflects the free (pharmacologically active) concentration. The authors investigated what degree of hypoalbuminemia causes a significant change in protein binding and thus percentage free MPA. Forty-two renal transplant recipients were recruited for the study. Free and total concentrations of MPA (predose, and 1, 3, and 6 hours post-MMF dose samples) and plasma albumin concentrations were determined on day 5 posttransplantation. Six-hour area under the concentration-time curve (AUC0–6) values were calculated for free and total MPA, and percentage free MPA was determined for each patient. The authors found a significant relationship between low albumin concentrations and increased percentage free MPA (Spearman correlation = −0.54, P < 0.0001). Receiver operating characteristic (ROC) curve analysis was performed on the albumin versus percentage free MPA data. The cutoff value of albumin determined from the ROC analysis that differentiated normal from elevated percentage free MPA (defined as ≥3%) in this patient population was 31 g/L. At this cutoff value albumin was found to be a good predictor of altered free MPA percentage, with a sensitivity and specificity of 0.75 and 0.80, respectively, and an area under the ROC curve of 0.79. To rationalize MMF dosing regimens in hypoalbuminemic patients (plasma albumin ≤ 31 g/L), clinicians should consider monitoring the free MPA concentration.

Metabolic syndrome in severe chronic kidney disease: Prevalence, predictors, prognostic significance and effects of risk factor modification

Background:  Metabolic syndrome (MS) is a significant risk factor for cardiovascular disease, mortality and chronic kidney disease (CKD) in the general population. However, the prevalence, predictors, prognostic value and treatment of MS in the CKD population have not been rigorously studied.

The impact of automated eGFR reporting and education on nephrology service referrals

Background. Serum creatinine concentration is an unreliable and insensitive marker of chronic kidney disease (CKD). To improve CKD detection, the Australasian Creatinine Consensus Working Committee recommended reporting of estimated glomerular filtration rate (eGFR) using the four-variable Modification of Diet in Renal Disease (MDRD) formula with every request for serum creatinine concentration. The aim of this study was to evaluate the impact of automated laboratory reporting of eGFR on the quantity and quality of referrals to nephrology services in Southeast Queensland, Australia. Methods. Outpatient referrals to a tertiary and regional renal service, and a single private practice were prospectively audited over 3–12 months prior to and 12 months following the introduction of automated eGFR reporting and concomitant clinician education. The appropriateness of referrals to a nephrologist was assessed according to the Kidney Check Australia Taskforce (KCAT) criteria. Significant changes in the quantity and/or quality of referrals over time were analysed by exponentially weighed moving average (EWMA) charts with control limits based on ±3 standard deviations. Results. A total of 1019 patients were referred to the centres during the study period. Monthly referrals overall increased by 40% following the introduction of eGFR reporting, and this was most marked for the tertiary renal service (52% above baseline). The appropriateness of nephrologist referrals, as adjudicated by the KCAT criteria, fell significantly from 74.3% in the 3 months pre-eGFR reporting to 65.2% in the 12 months thereafter (P < 0.05). Nevertheless, a greater absolute number of CKD patients were appropriately being referred for nephrologist review in the post-eGFR period (24 versus 15 per month). Patients referred following the introduction of eGFR were significantly more likely to be older (median 63.2 versus 59.3 years, P < 0.05), diabetic (25 versus 18%, P = 0.05) and have stage 3 CKD (48% versus 36%, P < 0.01). Conclusion. The introduction of automated eGFR calculation has led to an overall increase in referrals with a small but significant decrease in referral quality. The increase in referrals was seen predominantly in older and diabetic patients with stage 3 CKD and appeared to result in net benefit.

Intradermal versus intramuscular hepatitis B vaccination in hemodialysis patients: a prospective open-label randomized controlled trial in nonresponders to primary vaccination.

BACKGROUND Primary hepatitis B virus (HBV) vaccination through the intramuscular (IM) route is less efficacious in dialysis patients than in the general population. Previous studies suggest improved seroconversion with intradermal (ID) vaccination. STUDY DESIGN Prospective open-label randomized controlled trial. SETTING & PARTICIPANTS Hemodialysis patients nonresponsive to primary HBV vaccination. INTERVENTION Revaccination with either ID (10 microg of vaccine every week for 8 weeks) [DOSAGE ERROR CORRECTED] or IM (40 microg of vaccine at weeks 1 and 8) HBV vaccine . OUTCOMES PRIMARY OUTCOME proportion of patients achieving HBV surface antibody (anti-HBs) titer of 10 IU/L or greater within 2 months of vaccination course. SECONDARY OUTCOMES time to seroconversion, predictors of seroconversion, peak antibody titer, duration of seroprotection, and safety and tolerability of vaccine. MEASUREMENTS Anti-HBs titer to 24 months. RESULTS 59 patients were analyzed. Seroconversion rates were 79% ID versus 40% IM (P = 0.002). The unadjusted odds ratio for seroconversion for ID versus IM was 5.5 (95% confidence interval [CI], 1.6 to 18.4) and increased with adjustment for baseline differences. The only factor predictive of seroconversion was the ID vaccination route. The geometric mean peak antibody titer was significantly greater in the ID versus IM group: 239 IU/L (95% CI, 131 to 434) versus 78 IU/L (95% CI, 36 to 168; P < 0.001). There was a trend toward longer duration of seroprotection with ID vaccination. ID vaccine was safe and well tolerated. LIMITATIONS Inability to distinguish whether the mechanism of the greater efficacy of ID vaccination was the cumulative effect of multiple injections or route of administration; use of anti-HBs as a surrogate marker of protection; lack of evidence of long-term protection. CONCLUSIONS Significantly greater seroconversion rates and peak antibody titers can be achieved with ID compared with IM vaccination in hemodialysis patients nonresponsive to primary vaccination. ID vaccination should become the standard of care in this setting.

The impact of extended-hours home hemodialysis and buttonhole cannulation technique on hospitalization rates for septic events related to dialysis access

Few studies adequately document adverse events in patients receiving long, slow, and overnight hemodialysis (NHD). Concerns about high rates of dialysis access complications have been raised. This is an observational cohort study comparing hospital admission rates for vascular access complications between alternate nightly NHD (n=63) and conventional hemodialysis (n=172) patients established on chronic hemodialysis for at least 3 months. Overall, hospital admission rates and hospital admission rates for cardiac and all infective events are also reported. The NHD cohort was younger and less likely to be female, diabetic, or have ischemic heart disease than the conventional hemodialysis cohort. When NHD and buttonhole cannulation technique were used simultaneously, there was a demonstrated increased risk of septic dialysis access events: incidence rate ratio 3.0 (95% confidence interval 1.04–8.66) (P=0.04). The majority of blood culture isolates in NHD patients were gram‐positive organisms, particularly Staphylococcus aureus. Alternate nightly NHD did not significantly change total hospital admissions or hospital admissions for indications other than dialysis access complications, compared with conventional hemodialysis. Our data suggest that buttonhole cannulation technique should be used with caution in patients performing extended‐hours hemodialysis as this combination appears to increase the risk of septic access complications. Randomized‐controlled trials are needed to confirm these findings.

Peritoneal dialysis practice in Australia and New Zealand: A call to action

Peritoneal dialysis technique survival in Australia and New Zealand is lower than in other parts of the world. More than two‐thirds of technique failures are related to infective complications (predominantly peritonitis) and ‘social reasons’. Practice patterns vary widely and more than one‐third of peritoneal dialysis units do not meet the International Society of Peritoneal Dialysis minimum accepted peritonitis rate. In many cases, poor peritonitis outcomes reflect significant deviations from international guidelines. In this paper we propose a series of practical recommendations to improve outcomes in peritoneal dialysis patients through appropriate patient selection, prophylaxis and treatment of infectious complications, investigation of social causes of technique failure and a greater focus on patient education and clinical governance.

Severe toxicity associated with a markedly elevated mycophenolic acid free fraction in a renal transplant recipient.

A 58-year-old man with end-stage renal failure secondary to polycystic kidney disease developed a profoundly elevated mycophenolic acid (MPA) free fraction and associated severe toxicity after cadaveric renal transplantation. Initial immunosuppressive therapy was 4 mg/kg body weight bid cyclosporin (Neoral; Novartis Pharmaceutical Co Ltd, Sydney, Australia) given orally with 1 g bid mycophenolate mofetil (MMF) (CellCept; Roche Products Pty Ltd, Sydney, Australia). In the first 5 days posttransplantation, the serum creatinine concentration fell, and the patient developed profound hypoalbuminemia (serum albumin <20 g/L) and hyperbilirubinemia (serum bilirubin >150 micromol/L) that resulted from progressing biliary obstruction. On day 5 posttransplantation, the 2-hour whole-blood cyclosporin concentration and total MPA area under the curve (AUC(0-6)) were low (837 microg/L and 12.6 mg x h/L, respectively), while the total mycophenolic acid glucuronide (MPAG) AUC(0-6) was elevated (1317 mg x h/L). MMF was continued at the same dose, but tacrolimus substituted for cyclosporin. The patient subsequently experienced severe nausea, vomiting, hematemesis, and pancytopenia (nadir white cell count 1.6 x 10(9)/L, platelet count 32 x 10(9)/L, and hemoglobin 73 g/L) that were normalized after cessation of MMF. Retrospective measurement of the free MPA concentration on day 5 showed that free MPA AUC(0-6) was markedly elevated at 2.3 mg x h/L, as was the free fraction, at 18.3%. This case illustrates how altered protein binding can be associated with severe MMF toxicity caused by an increased free MPA concentration despite relatively low total MPA. These data support the monitoring of free MPA concentrations in those patients considered at risk for MMF-related toxicity.

The effect of oral iron admiinistration on mycophenolate mofetil absorption in renal transplant recipients: a randomized, controlled trial.

Background. Oral iron supplements are frequently prescribed to renal transplant recipients in the early posttransplant period. A recent trial in seven healthy volunteers demonstrated a significant 91% reduction in mycophenolate mofetil (MMF) absorption when coadministered with oral iron. However, the effect of iron on MMF absorption in renal transplant patients has not been studied. Methods. An open-label, randomized, controlled trial was undertaken in which new renal transplant recipients were randomly allocated to receive iron supplements with a morning dose of MMF, iron supplements given 4 hr after MMF at midday, or no iron supplements. Blood samples were taken for estimation of mycophenolic acid (MPA) area under the curve (AUC) at day 5 posttransplant. The primary endpoint was the day 5 MPA AUC, with secondary endpoints including acute rejection and MMF toxicity in the first 4 weeks posttransplant. Prospective power calculations indicated that a minimum of 13 patients in each group would be required to have a 90% probability of detecting a clinically significant reduction (10 mg/hr/L) in MPA AUC for iron-treated patients. Results. Forty patients completed the study. There were no differences in baseline demographic data between the groups. The mean±standard deviation MPA AUC measurements for the groups receiving no iron (n=13), iron and MMF together (n=14), and iron and MMF spaced apart (n=13) were 34.5±8.7, 33.7±11.4, and 32.1±8.1 &mgr;g/hr/mL, respectively (P =0.82). Rates of acute rejection, cytopenia, infection, and gastrointestinal intolerance were comparable between the groups. Conclusions. There is no significant effect of oral iron supplements on MMF absorption as determined by measured blood concentrations. The practice of routinely giving oral iron in such patients seems safe from an immunosuppression drug-interaction standpoint.

Achieving Salt Restriction in Chronic Kidney Disease

There is consistent evidence linking excessive dietary sodium intake to risk factors for cardiovascular disease and chronic kidney disease (CKD) progression in CKD patients; however, additional research is needed. In research trials and clinical practice, implementing and monitoring sodium intake present significant challenges. Epidemiological studies have shown that sodium intake remains high, and intervention studies have reported varied success with participant adherence to a sodium-restricted diet. Examining barriers to sodium restriction, as well as factors that predict adherence to a low sodium diet, can aid researchers and clinicians in implementing a sodium-restricted diet. In this paper, we critically review methods for measuring sodium intake with a specific focus on CKD patients, appraise dietary adherence, and factors that have optimized sodium restriction in key research trials and discuss barriers to sodium restriction and factors that must be considered when recommending a sodium-restricted diet.