Sharon J. Nessim

The biocompatibility of neutral pH, low-GDP peritoneal dialysis solutions: benefit at bench, bedside, or both?

For patients on peritoneal dialysis (PD), the development of peritonitis, the decline of residual kidney function, and the loss of peritoneal membrane function are central events that affect both patient and technique survival. The use of glucose as the osmotic agent in conventional PD solutions may increase the susceptibility to each of these events. However, its use may also be associated with systemic metabolic perturbations and, in turn, an increase in cardiovascular morbidity. Both in vitro and in vivo evidence suggest that both the local peritoneal and systemic toxicity induced by the use of glucose may be in part mediated by the presence of glucose degradation products (GDPs) coupled with the hyperosmolarity, reduced pH, and use of lactate as the buffer in conventional PD solutions. Therefore, the use of neutral pH, low-GDP (NpHL(GDP)), bicarbonate-buffered PD solutions may represent a promising strategy to attenuate some of these adverse effects. However, the impact of these novel solutions on clinical outcomes remains largely unknown. In this review, we will highlight evidence regarding the biocompatibility of NpHL(GDP) PD solutions, review the utility of current biomarkers in the evaluation of biocompatibility, and discuss the clinical outcome data with these solutions.

Impact of Age on Peritonitis Risk in Peritoneal Dialysis Patients: An Era Effect

BACKGROUND AND OBJECTIVES Despite reductions in the frequency of peritoneal dialysis (PD)-related infectious complications over time, peritonitis and catheter infection remain important causes of morbidity and mortality. Given the increasing number of elderly patients reaching end-stage renal disease, making informed decisions about PD utilization is contingent on an understanding of the infectious complications of PD in this population. We therefore studied the impact of age on infection rates, organisms and outcomes. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS On the basis of data collected from 1996 to 2005 in the multicenter Baxter Peritonitis Organism Exit sites Tunnel infections database, the study population included 4247 incident Canadian PD patients: 1265 patients aged > or =70 yr and 2982 patients aged <70 yr. We defined two eras of PD initiation: 1996 to 2000 and 2001 to 2005. RESULTS In a negative binomial model, older age was independently associated with a higher peritonitis rate (rate ratio [RR] 1.06 per decade increase; 95% CI 1.01 to 1.10; P = 0.008). However, this association was present only among those who initiated PD at an earlier time (RR 1.13 per decade increase; 95% CI 1.07 to 1.20; P < 0.001 in 1996 to 2000 versus 1.01 per decade increase; 95% CI 0.95 to 1.06; P = 0.81 in 2001 to 2005). Catheter-related infections were less frequent with increasing age regardless of era (RR 0.93 per decade increase; 95% CI 0.89 to 0.97). CONCLUSIONS The higher peritonitis rate observed in elderly patients may represent an era effect, as age was not associated with peritonitis among patients initiating PD between 2001 and 2005. In addition, catheter infection was less frequent with increasing age.

Apixaban Pharmacokinetics at Steady State in Hemodialysis Patients

It is unclear whether warfarin is protective or harmful in patients with ESRD and atrial fibrillation. This state of equipoise raises the question of whether alternative anticoagulants may have a therapeutic role. We aimed to determine apixaban pharmacokinetics at steady state in patients on hemodialysis. Seven patients received apixaban 2.5 mg twice daily for 8 days. Blood samples were collected before and after apixaban administration on days 1 and 8 (nondialysis days). Significant accumulation of the drug was observed between days 1 and 8 with the 2.5-mg dose. The area under the concentration-time curve from 0 to 24 hours increased from 628 to 2054 ng h/ml (P<0.001). Trough levels increased from 45 to 132 ng/ml (P<0.001). On day 9, after a 2.5-mg dose, apixaban levels were monitored hourly during dialysis. Only 4% of the drug was removed. After a 5-day washout period, five patients received 5 mg apixaban twice daily for 8 days. The area under the concentration-time curve further increased to 6045 ng h/ml (P=0.03), and trough levels increased to 218 ng/ml (P=0.03), above the 90th percentile for the 5-mg dose in patients with preserved renal function. Apixaban 2.5 mg twice daily in patients on hemodialysis resulted in drug exposure comparable with that of the standard dose (5 mg twice daily) in patients with preserved renal function and might be a reasonable alternative to warfarin for stroke prevention in patients on dialysis. Apixaban 5 mg twice daily led to supratherapeutic levels in patients on hemodialysis and should be avoided.

The renin-angiotensin-aldosterone system in peritoneal dialysis: is what is good for the kidney also good for the peritoneum?

Morphological changes of the peritoneal membrane that occur over time among patients on peritoneal dialysis include fibrosis and neoangiogenesis. While the pathophysiologic mechanisms underlying these changes are not fully understood, the activation of the renin-angiotensin-aldosterone system (RAAS) may have an important role. Components of the RAAS are constitutively expressed within peritoneal mesothelial cells, and are upregulated in the presence of acute inflammation and chronic exposure to peritoneal dialysate. The high glucose concentration, low pH, and the presence of glucose degradation products in peritoneal dialysis solutions have all been implicated in modulation of peritoneal RAAS. Furthermore, activation of the RAAS, as well as the downstream production of transforming growth factor-beta, contributes to epithelial-to-mesenchymal transformation of mesothelial cells, resulting in progressive fibrosis of the peritoneal membrane. This process also leads to increased vascular endothelial growth factor production, which promotes peritoneal neoangiogenesis. Functionally, these changes translate into reduced ultrafiltration capacity of the peritoneal membrane, which is an important cause of technique failure among patients on long-term peritoneal dialysis. This brief review will describe our current state of knowledge about the role of peritoneal RAAS in peritoneal membrane damage and potential strategies to protect the membrane.

A Randomized Controlled Trial Comparing Mupirocin and Polysporin Triple Ointments in Peritoneal Dialysis Patients: The MP3 Study

BACKGROUND AND OBJECTIVES Infectious complications remain a significant cause of peritoneal dialysis (PD) technique failure. Topical ointments seem to reduce peritonitis; however, concerns over resistance have led to a quest for alternative agents. This study examined the effectiveness of applying topical Polysporin Triple ointment (P(3)) against mupirocin in a multi-centered, double-blind, randomized controlled trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS PD patients routinely applied either P(3) or mupirocin ointment to their exit site. Patients were followed for 18 months or until death or catheter removal. The primary study outcome was a composite endpoint of exit-site infection (ESI), tunnel infection, or peritonitis. RESULTS Seventy-five of 201 randomized patients experienced a primary outcome event (51 peritonitis episodes, 24 ESIs). No difference was seen in the time to first event for P(3) (13.2 months; 95% confidence interval, 11.9-14.5) and mupirocin (14.0 months; 95% confidence interval, 12.7-15.4) (P=0.41). Twice as many patients reported redness at the exit site in the P(3) group (14 versus 6, P=0.10). Over the complete study period, a higher rate per year of fungal ESIs was seen in patients using P(3) (0.07 versus 0.01; P=0.02) with a corresponding increase in fungal peritonitis (0.04 versus 0.00, respectively; P<0.05). CONCLUSIONS This study shows that P(3) is not superior to mupirocin in the prophylaxis of PD-related infections. Colonization of the exit site with fungal organisms is of concern and warrants further study. As such, the use of P(3) over mupirocin is not advocated in the prophylaxis of PD-related infections.

Variation in the Level of eGFR at Dialysis Initiation across Dialysis Facilities and Geographic Regions

BACKGROUND AND OBJECTIVES The relative influence of facilities and regions on the timing of dialysis initiation remains unknown. The purpose of the study is to determine the variation in eGFR at dialysis initiation across dialysis facilities and geographic regions in Canada after accounting for patient-level factors (case mix). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In total, 33,263 dialysis patients with an eGFR measure at dialysis initiation between January of 2001 and December of 2010 representing 63 dialysis facilities and 14 geographic regions were included in the study. Multilevel models and intraclass correlation coefficients were used to evaluate the variation in timing of dialysis initiation by eGFR at the patient, facility, and geographic levels. RESULTS The proportion initiating dialysis with an eGFR≥10.5 ml/min per 1.73 m(2) was 35.3%, varying from 20.1% to 57.2% across geographic regions and from 10% to 67% across facilities. In an unadjusted, intercept-only linear model, 90.7%, 6.6%, and 2.7% of the explained variability were attributable to patient, facility, and geography, respectively. After adjustment for patient and facility factors, 96.9% of the explained variability was attributable to patient case mix, 3.1% was attributable to the facility, and 0.0% was attributable to the geographic region. These findings were consistent when the eGFR was categorized as a binary variable (≥10.5 ml/min per 1.73 m(2)) or in an analysis limited to patients with >3 months of predialysis care. CONCLUSIONS Patient characteristics accounted for the majority of the explained variation regarding the eGFR at the initiation of dialysis. There was a small amount of variation at the facility level and no variation among geographic regions that was independent of patient- and facility-level factors.

MICROBIOLOGY OF PERITONITIS IN PERITONEAL DIALYSIS PATIENTS WITH MULTIPLE EPISODES

♦ Background: Peritoneal dialysis (PD)–associated peritonitis clusters within patients. Patient factors contribute to peritonitis risk, but there is also entrapment of organisms within the biofilm that forms on PD catheters. It is hypothesized that this biofilm may prevent complete eradication of organisms, predisposing to multiple infections with the same organism. ♦ Methods: Using data collected in the Canadian multicenter Baxter POET (Peritonitis, Organism, Exit sites, Tunnel infections) database from 1996 to 2005, we studied incident PD patients with 2 or more peritonitis episodes. We determined the proportion of patients with 2 or more episodes caused by the same organism. In addition, using a multivariate logistic regression model, we tested whether prior peritonitis with a given organism predicted the occurrence of a subsequent episode with the same organism. ♦ Results: During their time on PD, 558 patients experienced 2 or more peritonitis episodes. Of those 558 patients, 181 (32%) had at least 2 episodes with the same organism. The organism most commonly causing repeat infection was coagulase-negative Staphylococcus (CNS), accounting for 65.7% of cases. Compared with peritonitis caused by other organisms, a first CNS peritonitis episode was associated with an increased risk of subsequent CNS peritonitis within 1 year (odds ratio: 2.1; 95% confidence interval: 1.5 to 2.8; p < 0.001). Among patients with repeat CNS peritonitis, 48% of repeat episodes occurred within 6 months of the earlier episode. ♦ Conclusions: In contrast to previous data, we did not find a high proportion of patients with multiple peritonitis episodes caused by the same organism. Coagulase-negative Staphylococcus was the organism most likely to cause peritonitis more than once in a given patient, and a prior CNS peritonitis was associated with an increased risk of CNS peritonitis within the subsequent year.

Vascular Access Type and Patient and Technique Survival in Home Hemodialysis Patients: The Canadian Organ Replacement Register.

BACKGROUND While central venous catheter (CVC) use has expanded home hemodialysis (HHD) eligibility to many patients who may be unable to self-cannulate an arteriovenous (AV) access, the association between CVC use and mortality has not been directly examined among HHD patients. STUDY DESIGN Registry-based retrospective observational cohort study. SETTING & PARTICIPANTS Incident HHD patients in The Canadian Organ Replacement Register who had information for vascular access type (CVC vs AV access) within the first year of HHD therapy initiation. PREDICTOR Use of a CVC versus an AV access (AV fistula or graft) within the first year of HHD therapy initiation. OUTCOME The composite of all-cause mortality and technique failure (long-term transfer to an alternate dialysis modality). A Cox proportional hazards model was used to evaluate the adjusted composite outcome and each outcome separately. RESULTS 1,869 patients initiated HHD therapy in Canada in 1996 to 2012, of whom 1,217 had an access type recorded within the first year of HHD therapy initiation. Compared to CVC use (n=523) and during a median follow-up of 513 and 427 days for AV access and CVC patients, respectively, AV access use (n=694) was associated with lower risk for the composite event of death and technique failure (490 events; adjusted HR, 0.78; 95% CI, 0.64-0.94) and lower adjusted all-cause mortality (129 deaths; adjusted HR, 0.63; 95% CI, 0.43-0.91); the risk for technique failure was nominally lower, but this result was not statistically significant (361 events; adjusted HR, 0.84; 95% CI, 0.67-1.05). Results were robust to sensitivity analyses and after missing data imputation. LIMITATIONS Missing information for vascular access type (n=659[35% of patients]) and lack of information for longitudinal changes in vascular access type. CONCLUSIONS Compared to CVC use, AV access use was associated with superior survival. Minimizing CVC use and maximizing AV access use while addressing barriers to their placement and self-cannulation may improve HHD outcomes.

Gentamicin-Resistant Infections in Peritoneal Dialysis Patients Using Topical Gentamicin Exit-Site Prophylaxis: A Report of Two Cases

Exit-site infections and peritonitis occurring because of periluminal entry of organisms along the peritoneal dialysis (PD) catheter tunnel are not infrequent and can be associated with adverse outcomes (1). The most studied antibacterial ointment is mupirocin, a topical agent with excellent activity against gram-positive organisms, which account for approximately 75% of exit-site infections (2). The application of mupirocin to the nares or the catheter exit site has been shown not only to reduce the risk of exit-site infection (3–6), but also peritonitis (4–6). More recent studies have focused on gentamicin applied to the PD catheter exit site based on the hypothesis that topical gentamicin would be as effective as mupirocin for the prevention of gram-positive infections and more effective for the prevention of gram-negative infections, particularly those caused by Pseudomonas. In 2005, Bernardini et al. published the results of a randomized controlled trial comparing topical mupirocin with gentamicin for exit-site prophylaxis. Their study demonstrated that, compared with patients using mupirocin, those who used gentamicin cream for prophylaxis experienced fewer peritonitis episodes overall and a reduction in gram-negative peritonitis and exit-site infection (7). Two subsequent observational studies showed equivalent results with mupirocin and gentamicin (8,9). Despite the favorable results with exit-site gentamicin, some practitioners have raised concerns about the potential for the development of gentamicin resistance, which would limit antibiotic options for the treatment of any subsequent gram-negative infections. To date, no gentamicin resistance has been reported. Here, we report the cases of 2 patients using prophylactic topical gentamicin who developed exitsite infections with an organism that was found to be gentamicin-resistant. CASE 1

The Case | Hypercalcemia in a renal transplant recipient

A 71-year-old man presented to the emergency department with a 2-week history of worsening cough and shortness of breath. The patient had a history of end-stage renal disease secondary to diabetic nephropathy, and he had received a deceased donor renal transplant 3 years before presentation. His baseline estimated glomerular filtration rate was approximately 50 ml/min. He was also known to have hypertension, type 2 diabetes mellitus, hyperlipidemia, coronary artery disease, and active hepatitis B. His medications included extended-release tacrolimus 16 mg daily, mycophenolic acid 720 mg twice daily, prednisone 5 mg daily, lamivudine, valsartan, metoprolol, doxazocin, atorvastatin, pantoprazole, and insulin. On examination, the patient was hemodynamically stable but tachypneic, with an oxygen saturation of 87% while breathing ambient air. His jugular venous pressure was not elevated, and there was no peripheral edema. His cardiac and respiratory examination was otherwise unremarkable. On laboratory investigations, the patient was noted to have hypercalcemia (total corrected calcium 3.09 mmol/l) which was not present during routine lab testing 2 weeks earlier. His parathyroid hormone level was suppressed. Renal function was unchanged from his previous values. Pertinent laboratory data are presented in Table 1. Chest radiograph on presentation showed diffuse increased markings over the left lung field with relative oligemia of the right lung. Further investigations included a negative ventilation perfusion scan and a normal transthoracic echocardiogram. Computed tomography (CT) of the chest revealed diffuse ground-glass opacities, involving the posterior portions of both lungs and the apices bilaterally. In the context of the hypercalcemia, CT scan of the abdomen and pelvis was performed, and there was no evidence of an underlying malignancy.