Louis-Philippe Laurin

Randomized Clinical Trial of Sodium Polystyrene Sulfonate for the Treatment of Mild Hyperkalemia in CKD

BACKGROUND AND OBJECTIVES Hyperkalemia affects up to 10% of patients with CKD. Sodium polystyrene sulfonate has long been prescribed for this condition, although evidence is lacking on its efficacy for the treatment of mild hyperkalemia over several days. This study aimed to evaluate the efficacy of sodium polystyrene sulfonate in the treatment of mild hyperkalemia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In total, 33 outpatients with CKD and mild hyperkalemia (5.0-5.9 mEq/L) in a single teaching hospital were included in this double-blind randomized clinical trial. We randomly assigned these patients to receive either placebo or sodium polystyrene sulfonate of 30 g orally one time per day for 7 days. The primary outcome was the comparison between study groups of the mean difference of serum potassium levels between the day after the last dose of treatment and baseline. RESULTS The mean duration of treatment was 6.9 days. Sodium polystyrene sulfonate was superior to placebo in the reduction of serum potassium levels (mean difference between groups, -1.04 mEq/L; 95% confidence interval, -1.37 to -0.71). A higher proportion of patients in the sodium polystyrene sulfonate group attained normokalemia at the end of their treatment compared with those in the placebo group, but the difference did not reach statistical significance (73% versus 38%; P=0.07). There was a trend toward higher rates of electrolytic disturbances and an increase in gastrointestinal side effects in the group receiving sodium polystyrene sulfonate. CONCLUSIONS Sodium polystyrene sulfonate was superior to placebo in reducing serum potassium over 7 days in patients with mild hyperkalemia and CKD.

MFG-E8 Released by Apoptotic Endothelial Cells Triggers Anti-Inflammatory Macrophage Reprogramming

Apoptotic endothelial cells are an important component of the “response to injury” process. Several atherosclerosis risk factors such as hyperglycemia and oxidized low-density lipoproteins, and immune injuries, such as antibodies and complement, induce endothelial cell apoptosis. While endothelial cell apoptosis is known to affect neighboring vascular wall cell biology, its consequences on macrophage reprogramming are ill defined. In this study, we report that apoptosis of human and mouse endothelial cells triggers the release of milk fat globule-epidermal growth factor 8 (MFG-E8) and reprograms macrophages into an anti-inflammatory cells. We demonstrated that MFG-E8 is released by apoptotic endothelial cells in a caspase-3-dependent manner. When macrophages were exposed to conditioned media from serum-starved apoptotic endothelial cells, they adopt a high anti-inflammatory, low pro-inflammatory cytokine/chemokine secreting phenotype that is lost if MFG-E8 is absent from the media. Macrophage treatment with recombinant MFG-E8 recapitulates the effect of conditioned media. Finally, we showed that MFG-E8-mediated reprogramming of macrophages occurs through increased phosphorylation of signal transducer and activator of transcription-3 (STAT-3). Taken together, our study suggests a key role of MFG-E8 release from apoptotic endothelial cells in macrophage reprogramming and demonstrates the importance of the apoptotic microenvironment in anti-inflammatory macrophage responses.

Association of Dialysis Modality with Risk for Infection-Related Hospitalization: A Propensity Score–Matched Cohort Analysis

BACKGROUND AND OBJECTIVES Peritonitis is a well known complication of peritoneal dialysis (PD), whereas in hemodialysis (HD), bacteremia can be life threatening. Whether patients undergoing PD have higher risk than HD patients for infection-related hospitalizations (IRH) remains unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A propensity score-matched retrospective cohort of patients undergoing long-term dialysis between January 2001 and December 2007 was assembled. Propensity scores were calculated using multivariable (demographic characteristics, smoking, body mass index, comorbid conditions, and laboratory data) logistic regression to estimate probability of receiving PD versus HD. A comparison of IRH risk by dialysis modality was estimated using a counting-process survival model. RESULTS A total of 910 pairs of patients were matched by propensity scores. During a median follow-up of 2.1 years (interquartile range, 1.1-3.5 years), 341 patients were hospitalized once for an infection, 123 twice, and 106 at least three times. PD was associated with an increased risk for IRH compared with HD (propensity-matched hazard ratio [HR], 1.52). PD was associated with a reduced risk for septicemia (HR, 0.31) and pneumonia (HR, 0.58) but also an increased risk for dialysis-related infectious hospitalizations (HR, 3.44), defined as all cases of peritonitis and vascular access-related bacteremia, but not all septicemia cases. CONCLUSIONS PD patients are at higher risk for IRH than are HD patients. This risk is mostly explained by dialysis-related infections. However, further studies are needed to evaluate whether the severity of those hospitalizations is similar and whether this increased risk for IRH is associated with worse outcomes.

Effects of Chronic Renal Failure on Brain Drug Transporters in Rats

Studies demonstrated that chronic renal failure (CRF) affects the expression and activity of intestinal, hepatic, and renal drug transporters. Such drug transporters are expressed in brain cells and at the blood-brain barrier (BBB), where they limit the entry and distribution of drugs in the brain. Perturbations in brain drug transporter equilibrium by CRF could lead to central drug toxicity. This study evaluates how CRF affects BBB drug transporters using a 5/6 nephrectomized rat model. Protein and mRNA expression of influx transporters [organic anion-transporting polypeptide (Oatp), organic anion transporter (Oat)] and efflux transporters [P-glycoprotein (P-gp), multidrug resistance-related protein (Mrp), breast cancer resistance protein (Bcrp)] were measured in CRF and control rat brain. Intracerebral accumulation of radiolabeled benzylpenicillin, digoxin, doxorubicin, and verapamil was used to evaluate BBB drug permeability. Protein expression of the transporters was evaluated in rat brain endothelial cells (RBECs) and astrocytes incubated with control and CRF rat serum. We demonstrated significant decreases (30–50%) in protein and mRNA levels of Bcrp, Mrp2 to -4, Oat3, Oatp2 and -3, and P-gp in CRF rat brain biopsies, as well as in astrocytes and RBECs incubated with CRF serum. These decreases did not correlate with in vivo changes because BBB permeability of benzylpenicillin was decreased by 30% in CRF rats, whereas digoxin, doxorubicin, and verapamil permeabilities were unchanged. It thus seems that even with decreased drug transporters, BBB integrity and function is conserved in CRF.

Sternum Length and Rib Cage Dimensions Compared with Bodily Proportions in Adults with Cystic Fibrosis

BACKGROUND A greater structural expansion of the rib cage in females compared with males has been described in cystic fibrosis (CF) patients; however, conflicting data exist as to whether an elongation of the bony ribs and sternum contributes to this expansion. OBJECTIVES To compare height-adjusted anthropometric measures and sternum length between a group of normal subjects and a group of CF patients of both sexes. METHODS Anthropometric measurements including body weight, height, upper and lower limb lengths, biacromial distance and pelvic width were measured in the standing position in 30 CF patients (13 males) and 28 normal subjects (14 males). Body surface measurements of anterior-posterior and lateral diameters of the rib cage at functional residual capacity, and sternum length were also obtained. RESULTS Compared with normal subjects, CF patients had lower body weight, shorter standing height and shorter height-adjusted upper and lower limb lengths. Rib cage diameters were greater in CF patients than in normal subjects of either sex, but height-adjusted sternum length was not different. CONCLUSION Significant differences in bodily proportions were found between normal subjects and CF patients, suggesting a differential growth pattern for the trunk and limbs. However, increased rib cage dimensions with lung hyperinflation and airway obstruction was not associated with an elongation of the sternum.

Regulation of Experimental Peritonitis: A Complex Orchestration

Experimental peritonitis is a frequently used inflammatory model to evaluate leukocyte recruitment. By the intrinsic characteristics of the peritoneal cavity, the various resident cell populations have a role to play in the initiation, the modulation and the resolution of peritoneal inflammation. Through various manipulations of these cell populations, we gained important knowledge on their respective roles in peritoneal inflammation. In this brief review, we will focus on the cellular regulation of leukocyte recruitment in experimental peritonitis.

Hemodialysis effects on phenytoin pharmacokinetics.

Dear editor, Seizure disorders in patients with end-stage renal disease (ESRD) are frequent, and it is not uncommon for patients undergoing maintenance hemodialysis to receive phenytoin as anticonvulsant therapy. The plasma protein binding of phenytoin in these patients is usually reported to be reduced, mainly due to the accumulation of uremic compounds in the serum, which displace phenytoin from protein binding sites [1]. This decreased binding commonly requires frequent monitoring and dosing adjustment in response to the increase in the pharmacologically active, free fraction of phenytoin [1]. Because of the significant variability in the free fraction of phenytoin among patients with ESRD and the increased volume of distribution of the bound drug, dosage adjustment is usually based on free, rather than total phenytoin levels for anticonvulsant efficacy [2]. Accordingly, the accepted concentration range for total phenytoin should be reduced by 50 % in ESRD patients (20–40 μmol/L) in comparison to normal therapeutic range for phenytoin (40–80 μmol/L) to produce a suitable anticonvulsant effect with free phenytoin levels within the reference range (4–8 μmol/L) [3]. Whether hemodialysis may affect phenytoin plasma concentrations by partial removal of uremic compounds (and, therefore, protein binding capacity) remains controversial. A few studies reported in the 1970s that the postdialysis phenytoin serum binding capacity is decreased, and the proportion of unbound drug had a tendency to increase compared to corresponding predialysis measurements [4, 5]. In opposition, recent studies reported a potential reduction in the serum free phenytoin levels in postdialysis serum, suggesting that an additional dose of phenytoin would be required before each hemodialysis treatment [3, 6]. In the light of this controversy, we assessed the effect of hemodialysis on plasma protein binding of phenytoin and its impact on phenytoin plasma concentrations by measuring phenytoin serum concentrations in ten patients on phenytoin maintenance therapy for epilepsy. There were five men and five women, 80 % of whom were on phenytoin monotherapy. Patients were dialysed for 4 h three times a week with highflux polysulfone dialysis membranes. Total and free phenytoin concentrations were measured, with their respective albumin affinity constants, before and after hemodialysis session. Total phenytoin concentration was measured by an in vitro chemiluminescent microparticle immunoassay. The free fraction of phenytoin was determined after ultrafiltration with an Ultracel YM-T membrane. Albumin affinity constant was calculated from theoretical formula using the unbound fraction and serum albumin concentration [1]. The results are summarized in Table 1. In all patients, the unbound phenytoin percentages were significantly higher in predialysis sera compared to postdialysis sera, with a mean value of 24.8±0.04 and 14±0.03 %, respectively (p<0.001). The mean free phenytoin predialysis concentration decreased from 6.86±3.14 μmol/L to 3.90±2.03 μmo/L postdialysis (p<0.001). On the other hand, the mean concentration of total phenytoin did not vary significantly (p=0.75). This could be explained by changes in the volume of distribution or in the intrinsic clearance of phenytoin. The difference in phenytoin concentration between S. Bezzaoucha :A. Merghoub : C. Lamarche :V. Pichette : J.<P. Lafrance : L.<P. Laurin :M. Vallée : R. Robitaille : M. Leblanc : R. Bell Service de Néphrologie, Hôpital Maisonneuve-Rosemont, Département de Médecine, Université de Montréal, Montréal, QC, Canada

Renal Survival in Patients with Collapsing Compared with Not Otherwise Specified FSGS

BACKGROUND AND OBJECTIVES Idiopathic collapsing FSGS has historically been associated with poor renal outcomes. Minimal clinical data exist on the efficacy of immunosuppressive therapy. Our study sought to provide a comprehensive description of renal survival in patients with collapsing and not otherwise specified FSGS after controlling for factors affecting renal prognosis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We performed a retrospective analysis of an inception cohort study of patients diagnosed between 1989 and 2012. All potential patients with collapsing FSGS fulfilling the inclusion criteria were identified and compared with patients with not otherwise specified FSGS (approximately 1:2 ratio) on the basis of biopsy report and record availability. Time to ESRD was analyzed using Cox proportional hazards models. RESULTS In total, 187 patients were studied (61 collapsing and 126 not otherwise specified), with a mean follow-up of 96 months. At baseline, patients with collapsing FSGS had higher median proteinuria (12.2 [5.6-14.8] versus 4.4 [2.3-8.1] g/d, respectively; P<0.001), lower median albuminemia (2.4 [1.9-3.0] versus 2.9 [1.8-3.7] g/dl, respectively; P=0.12), and lower median eGFR (48 [26-73] versus 60 [42-92] ml/min per 1.73 m2, respectively; P=0.01) than patients with not otherwise specified FSGS. The proportion of patients with remission of proteinuria was similar in patients with collapsing FSGS and patients with not otherwise specified FSGS (65.7% [23 of 35] versus 63.2% [72 of 114], respectively; P=0.84). The overall renal outcome (ESRD defined as eGFR<15 ml/min per 1.73 m2, dialysis, or transplantation) of patients with collapsing FSGS was not poorer than that of patients with not otherwise specified FSGS in multivariate analyses after adjusting for baseline characteristics and immunotherapy (hazard ratio, 1.78; 95% confidence interval, 0.92 to 3.45). CONCLUSIONS Compared with not otherwise specified FSGS, idiopathic collapsing FSGS presented with more severe nephrotic syndrome and lower eGFR but had a similar renal survival after controlling for exposure to immunosuppressive treatment. These results highlight the importance of early diagnosis and institution of immunosuppressive therapy in patients with collapsing FSGS.

Association between vitamin D receptor activator and the risk of infection-related hospitalizations among incident hemodialysis patients: a nested case–control study†

Patients suffering from chronic kidney disease are at greater risk of developing infection than the normal population, and infections are the second cause of mortality after cardiovascular complications in this population. Some reports suggest that the intake of active vitamin D might be beneficial to prevent infections. Therefore, we aimed to determine if the oral intake of vitamin D receptor activator (VDRA) is associated with a lower risk of infection‐related hospitalization (IRH) among incident chronic hemodialysis patients.

Changes in Urinary and Serum Levels of Novel Biomarkers after Administration of Gadolinium-based Contrast Agents

Objective The aim of our study is to describe the changes in urinary and serum levels of novel biomarkers after gadolinium contrast administration in patients with normal renal function. Methods We measured four biomarkers in 28 volunteers: interleukin-18 (IL-18), N-acetyl-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin, and cystatin C. Urinary and serum samples were collected at 0, 3, and 24 hours following gadolinium administration. Results Baseline serum creatinine was 57.8 ± 34.5 μmol/L and remained stable. Urinary IL-18 levels increased significantly at three hours (10.7 vs. 7.3 ng/mg creatinine; P < 0.05). Similarly, urinary NAG levels increased significantly at three hours (3.9 vs. 2.2 IU/mg creatinine; P < 0.001). For both these markers, the difference was no longer significant at 24 hours. No statistically significant differences were observed for urinary and serum neutrophil gelatinase-associated lipocalin levels and for serum cystatin C levels. Conclusions Urinary IL-18 and NAG levels increased transiently after administration of gadolinium-based contrast agents in patients with normal renal function.