Longitudinal patterns of health-related quality of life and dialysis modality: a national cohort study.

BACKGROUND: Health-related quality of life (HrQoL) varies among dialysis patients. However, little is known about the association of dialysis modality with HrQoL over time. We describe longitudinal patterns of HrQoL among chronic dialysis patients by treatment modality. METHODS: National retrospective cohort study of adult patients who initiated in-center dialysis or a home modality (peritoneal or home hemodialysis) between 1/2013 and 6/2015. Patients remained on the same modality for the first 120 days of the first two years. HrQoL was assessed by the Kidney Disease and Quality of Life-36 (KDQOL) survey in the first 120 days of the first two years after dialysis initiation. Home modality patients were matched to in-center patients in a 1:5 fashion. RESULTS: In-center (n=4234) and home modality (n=880) patients had similar demographic and clinical characteristics. In-center dialysis patients had lower mean KDQOL scores across several domains compared to home modality patients. For patients who remained on the same modality, there was no change in HrQoL. However, there were trends towards clinically meaningful changes in several aspects of HrQoL for patients who switched modalities. Specifically, physical functioning decreased for patients who switched from home to in-center dialysis (p< 0.05). CONCLUSIONS: Among a national cohort of chronic dialysis patients, there was a trend towards different patterns of HrQoL life that were only observed among patients who changed modality. Patients who switched from home to in-center modalities had significant lower physical functioning over time. Providers and patients should be mindful of HrQoL changes that may occur with dialysis modality change.

Association of Smoking Status With Mortality and Hospitalization in Hemodialysis Patients.

RATIONALE & OBJECTIVE: The relationship between tobacco smoking and comorbid condition outcomes in hemodialysis (HD) patients is not well understood. This study examined the association of tobacco smoking status with hospitalization and mortality in HD patients. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Adult HD patients at 2,223 US dialysis centers with HD vintage of 30 days or less who completed a tobacco smoking status survey as part of standard care between April 2013 and June 2015. PREDICTOR: Tobacco smoking category: never smoked, currently living with smoker, former smoker, moderate smoker (<1 pack per day), or heavy smoker (≥1 pack per day). OUTCOMES: Death and hospital admissions within 2 years of the tobacco smoking survey. ANALYTICAL APPROACH: Kaplan-Meier analysis and Cox proportional hazards regression for time to death; cumulative incidence function and Cox proportional hazards regression for time to first hospitalization; negative-binomial regression for number of hospitalizations. RESULTS: Of 22,230 patients studied, 13% were active smokers. Mortality probabilities increased with greater exposure to smoking (17%, 22%, 23%, and 27% for never, moderate, former, and heavy smokers, respectively; P<0.001), as did incidence rates for first hospitalization (23%, 27%, 27%, and 30%, respectively; P<0.001). Compared to never smoked, heavy smokers had the highest mortality rate (HR for heavy smokers, 1.41 [95% CI, 1.18-1.69]; HR for moderate smokers, 1.39 [95% CI, 1.24-1.55]; HR for former smokers, 1.19 [95% CI, 1.11-1.28]). Living with a smoker was not associated with mortality (HR, 0.93; 95% CI, 0.72-1.22). HRs for first hospitalization followed similar patterns. The incidence rate of mortality for active smokers with diabetes was 173.7/1,000 patient-years and 103.5/1,000 patient-years for those who never smoked (incidence rate ratio, 1.68; P<0.001). LIMITATIONS: Self-reported survey without detailed history of smoking/cessation. CONCLUSIONS: Risks for death and hospitalization are elevated among HD patients who smoke, being highest among younger individuals and those with diabetes. Second-hand smoke was not associated with poor clinical outcomes.

To cool, or too cool: Is reducing dialysate temperature the optimal approach to preventing intradialytic hypotension?

Abnormal decreases in blood pressure during hemodialysis are frequent in end stage renal disease (ESRD) patients treated with hemodialysis, and thought to be largely due to an inadequate cardiovascular response to the rapid blood volume decline. Intradialytic hypotension (IDH) and cardiac instability during dialysis can increase risks for negative health consequences and is possibly preventable though several types of interventions. One intervention that holds promise for prevention of IDH in hemodialysis patients is to reduce the temperature of the dialysate to or below the patient's core temperature. A considerable number of randomized studies have demonstrated a short term benefit of using a cooler dialysate temperature for the prevention of IDH and improved cardiac stability. Despite this, a key observational study was not able to show long term improvements with lower dialysate temperatures utilized in routine clinical practice, albeit possibly confounded by indication. It appears that cooling the dialysate may be reasonable to consider on an individual basis for patients who suffer from persistent IDH if they can tolerate the adjustment and it is effective. However, careful assessment of the etiology of IDH should be performed when considering treatment options. In this review, we detail the current body of evidence on the effectiveness of using low dialysate temperatures for prevention of IDH in ESRD patients, and suggest areas where further research is needed.

Seasonal and Secular Trends of Cardiovascular, Nutritional, and Inflammatory Markers in Patients on Hemodialysis.

Background: All life on earth has adapted to the effects of changing seasons. The general and ESKD populations exhibit seasonal rhythms in physiology and outcomes. The ESKD population also shows secular trends over calendar time that can convolute the influences of seasonal variations. We conducted an analysis that simultaneously considered both seasonality and calendar time to isolate these trends for cardiovascular, nutrition, and inflammation markers. Methods: We used data from adult patients on hemodialysis (HD) in the United States from 2010 through 2014. An additive model accounted for variations over both calendar time and time on dialysis. Calendar time trends were decomposed into seasonal and secular trends. Bootstrap procedures and likelihood ratio methods tested if seasonal and secular variations exist. Results: We analyzed data from 354,176 patients on HD at 2436 clinics. Patients were 59±15 years old, 57% were men, and 61% had diabetes. Isolated average secular trends showed decreases in pre-HD systolic BP (pre-SBP) of 2.6 mm Hg (95% CI, 2.4 to 2.8) and interdialytic weight gain (IDWG) of 0.35 kg (95% CI, 0.33 to 0.36) yet increases in post-HD weight of 2.76 kg (95% CI, 2.58 to 2.97). We found independent seasonal variations of 3.3 mm Hg (95% CI, 3.1 to 3.5) for pre-SBP, 0.19 kg (95% CI, 0.17 to 0.20) for IDWG, and 0.62 kg (95% CI, 0.46 to 0.79) for post-HD weight as well as 0.12 L (95% CI, 0.11 to 0.14) for ultrafiltration volume, 0.41 ml/kg per hour (95% CI, 0.37 to 0.45) for ultrafiltration rates, and 3.30 (95% CI, 2.90 to 3.77) hospital days per patient year, which were higher in winter versus summer. Conclusions: Patients on HD show marked seasonal variability of key indicators. Secular trends indicate decreasing BP and IDWG and increasing post-HD weight. These methods will be of importance for independently determining seasonal and secular trends in future assessments of population health.

Remote Treatment Monitoring on Hospitalization and Technique Failure Rates in Peritoneal Dialysis Patients.

Background: An integrated kidney disease healthcare company implemented a peritoneal dialysis (PD) remote treatment monitoring (RTM) application in 2016. We assessed if RTM utilization associates with hospitalization and technique failure rates. Methods: We used data from adult (age ≥18 years) patients on PD treated from October 2016 through May 2019 who registered online for the RTM. Patients were classified by RTM use during a 30-day baseline after registration. Groups were: nonusers (never entered data), moderate users (entered one to 15 treatments), and frequent users (entered >15 treatments). We compared hospital admission/day and sustained technique failure (required >6 consecutive weeks of hemodialysis) rates over 3, 6, 9, and 12 months of follow-up using Poisson and Cox models adjusted for patient/clinical characteristics. Results: Among 6343 patients, 65% were nonusers, 11% were moderate users, and 25% were frequent users. Incidence rate of hospital admission was 22% (incidence rate ratio [IRR]=0.78; P=0.002), 24% (IRR=0.76; P<0.001), 23% (IRR=0.77; P≤0.001), and 26% (IRR=0.74; P≤0.001) lower in frequent users after 3, 6, 9, and 12 months, respectively, versus nonusers. Incidence rate of hospital days was 38% (IRR=0.62; P=0.013), 35% (IRR=0.65; P=0.001), 34% (IRR=0.66; P≤0.001), and 32% (IRR=0.68; P<0.001) lower in frequent users after 3, 6, 9, and 12 months, respectively, versus nonusers. Sustained technique failure risk at 3, 6, 9, and 12 months was 33% (hazard ratio [HR]=0.67; P=0.020), 31% (HR=0.69; P=0.003), 31% (HR=0.69; P=0.001), and 27% (HR=0.73; P=0.001) lower, respectively, in frequent users versus nonusers. Among a subgroup of survivors of the 12-month follow-up, sustained technique failure risk was 26% (HR=0.74; P=0.023) and 21% (HR=0.79; P=0.054) lower after 9 and 12 months, respectively, in frequent users versus nonusers. Conclusions: Our findings suggest frequent use of an RTM application associates with less hospital admissions, shorter hospital length of stay, and lower technique failure rates. Adoption of RTM applications may have the potential to improve timely identification/intervention of complications.

Identification and characterization of mefloquine efficacy against JC virus in vitro.

Progressive multifocal leukoencephalopathy (PML) is a rare but frequently fatal disease caused by the uncontrolled replication of JC virus (JCV), a polyomavirus, in the brains of some immunocompromised individuals. Currently, no effective antiviral treatment for this disease has been identified. As a first step in the identification of such therapy, we screened the Spectrum collection of 2,000 approved drugs and biologically active molecules for their anti-JCV activities in an in vitro infection assay. We identified a number of different drugs and compounds that had significant anti-JCV activities at micromolar concentrations and lacked cellular toxicity. Of the compounds with anti-JCV activities, only mefloquine, an antimalarial agent, has been reported to show sufficiently high penetration into the central nervous system such that it would be predicted to achieve efficacious concentrations in the brain. Additional in vitro experiments demonstrated that mefloquine inhibits the viral infection rates of three different JCV isolates, JCV(Mad1), JCV(Mad4), and JCV(M1/SVEDelta), and does so in three different cell types, transformed human glial (SVG-A) cells, primary human fetal glial cells, and primary human astrocytes. Using quantitative PCR to quantify the number of viral copies in cultured cells, we have also shown that mefloquine inhibits viral DNA replication. Finally, we demonstrated that mefloquine does not block viral cell entry; rather, it inhibits viral replication in cells after viral entry. Although no suitable animal model of PML or JCV infection is available for the testing of mefloquine in vivo, our in vitro results, combined with biodistribution data published in the literature, suggest that mefloquine could be an effective therapy for PML.

Tract dilation to salvage failing buttonholes in arteriovenous dialysis fistulae.

INTRODUCTION: Hemodialysis patients with an arteriovenous fistula can use buttonhole techniques for cannulation. Although buttonholes generally work well, patients may report difficult and painful cannulation, and buttonholes may fail over time. We aimed to assess the effectiveness of tract dilation in treatment of failing buttonholes. METHODS: We retrospectively analyzed data from patients treated with buttonhole tract dilation at an outpatient vascular access center between January 2013 and August 2015. RESULTS: Data from 23 patients were analyzed. There were 51 tract dilation procedures during 36 encounters for failing arteriovenous fistula buttonhole tract(s). The technical success rate for established tract dilation with "blunt-recanalization" was 90% (n = 46). The five remaining buttonholes had "sharp-recanalization" to create and dilate new tract through the buttonhole. For 46 buttonholes treated with "blunt-recanalization," there was an 85% clinical success rate at one week (39 buttonholes), and one was lost to follow-up; there was a 70% clinical success rate after one month (32 buttonholes). In the five buttonholes with "sharp-recanalization," there was only one clinical success with p < 0.05 for difference in success rate compared to "blunt-recanalization" at both one week and one month. There was one complication from "sharp-recanalization" requiring abandonment of the buttonhole tract. DISCUSSION: Buttonhole tract dilation is a useful method to treat difficult cannulation and painful cannulation and has the potential to extend the life of failing buttonholes.

The cytohesin guanosine exchange factors (GEFs) are required to promote HGF-mediated renal recovery after acute kidney injury (AKI) in mice.

The lack of current treatment and preventable measures for acute kidney injury (AKI) in hospitalized patients results in an increased mortality rate of up to 80% and elevated health costs. Additionally, if not properly repaired, those who survive AKI may develop fibrosis and long-term kidney damage. The molecular aspects of kidney injury and repair are still uncertain. Hepatocyte growth factor (HGF) promotes recovery of the injured kidney by inducing survival and migration of tubular epithelial cells to repopulate bare tubule areas. HGF-stimulated kidney epithelial cell migration requires the activation of ADP-ribosylation factor 6 (Arf6) and Rac1 via the cytohesin family of Arf-guanine-nucleotide exchange factors (GEFs), in vitro. We used an ischemia and reperfusion injury (IRI) mouse model to analyze the effects of modulating this signaling pathway on kidney recovery. We treated IRI mice with either HGF, the cytohesin inhibitor SecinH3, or a combination of both. As previously reported, HGF treatment promoted rapid improvement of kidney function as evidenced by creatinine (Cre) and blood urea nitrogen (BUN) levels. In contrast, simultaneous treatment with SecinH3 and HGF blocks the ability of HGF to promote kidney recovery. Immunohistochemistry showed that HGF treatment promoted recovery of tubule structure, and had enhanced levels of active, GTP-bound Arf6 and GTP-Rac1. SecinH3 treatment, however, caused a dramatic decrease in GTP-Arf6 and GTP-Rac1 levels when compared to kidney sections from HGF-treated IRI mice. Additionally, SecinH3 counteracted the renal reparative effects of HGF. Our results support the conclusion that cytohesin function is required for HGF-stimulated renal IRI repair.

ARF-GEF cytohesin-2/ARNO regulates R-Ras and α5-integrin recycling through an EHD1-positive compartment.

When expressed in epithelial cells, cytohesin-2/ARNO, a guanine nucleotide exchange factor (GEF) for ARF small GTPases, causes a robust migration response. Recent evidence suggests that cytohesin-2/ARNO acts downstream of small the GTPase R-Ras to promote spreading and migration. We hypothesized that cytohesin-2/ARNO could transmit R-Ras signals by regulating the recycling of R-Ras through ARF activation. We found that Eps15-homology domain 1 (EHD1), a protein that associates with the endocytic recycling compartment (ERC), colocalizes with active R-Ras in transiently expressed HeLa cells. In addition, we show that EHD1-positive recycling endosomes are a novel compartment for cytohesin-2/ARNO. Knockdown or expression of GEF-inactive (E156K) cytohesin-2/ARNO causes R-Ras to accumulate on recycling endosomes containing EHD1 and inhibits cell spreading. E156K-ARNO also causes a reduction in focal adhesion size and number. Finally, we demonstrate that R-Ras/ARNO signaling is required for recycling of α5-integrin and R-Ras to the plasma membrane. These data establish a role for cytohesin-2/ARNO as a regulator of R-Ras and integrin recycling and suggest that ARF-regulated trafficking of R-Ras is required for R-Ras-dependent effects on spreading and adhesion formation.

Interaction and co-localization of JC virus large T antigen and the F-box protein ß-transducin-repeat containing protein.

Lytic infection and transformation of cultured cells by JC virus (JCV) require five tumor proteins, which interact with factors regulating critical cellular processes. We demonstrate that JCV large T antigen (TAg) binds the F-box proteins ß-transducin-repeat containing protein-1 and 2 (ßTrCP1/2). These interactions involve a phosphodegron (DpSGX(2-4)pS) found in ßTrCP substrates. TAg stability is unaltered, suggesting TAg is a pseudo-substrate. ßTrCP and TAg co-localize in the cytoplasm, and a functional SCF complex is required. We examined whether TAg influences the levels of ß-catenin, a ßTrCP substrate. We were unable to demonstrate that TAg elevates ß-catenin as previously reported, and a mutant TAg unable to bind ßTrCP also had no detectable effect on ß-catenin stability. Results presented in this study link JCV TAg to the cellular degradation complex, SCF(ßTrCP1/2). Proteasomal degradation is essential for proper regulation of cellular functions, and interference with proteasomal pathways highlights possible JCV pathogenic and oncogenic mechanisms.

JC virus small T antigen binds phosphatase PP2A and Rb family proteins and is required for efficient viral DNA replication activity.

BACKGROUND: The human polyomavirus, JC virus (JCV) produces five tumor proteins encoded by transcripts alternatively spliced from one precursor messenger RNA. Significant attention has been given to replication and transforming activities of JCV's large tumor antigen (TAg) and three T' proteins, but little is known about small tumor antigen (tAg) functions. Amino-terminal sequences of tAg overlap with those of the other tumor proteins, but the carboxy half of tAg is unique. These latter sequences are the least conserved among the early coding regions of primate polyomaviruses. METHODOLOGY AND FINDINGS: We investigated the ability of wild type and mutant forms of JCV tAg to interact with cellular proteins involved in regulating cell proliferation and survival. The JCV P99A tAg is mutated at a conserved proline, which in the SV40 tAg is required for efficient interaction with protein phosphatase 2A (PP2A), and the C157A mutant tAg is altered at one of two newly recognized LxCxE motifs. Relative to wild type and C157A tAgs, P99A tAg interacts inefficiently with PP2A in vivo. Unlike SV40 tAg, JCV tAg binds to the Rb family of tumor suppressor proteins. Viral DNAs expressing mutant t proteins replicated less efficiently than did the intact JCV genome. A JCV construct incapable of expressing tAg was replication-incompetent, a defect not complemented in trans using a tAg-expressing vector. CONCLUSIONS: JCV tAg possesses unique properties among the polyomavirus small t proteins. It contributes significantly to viral DNA replication in vivo; a tAg null mutant failed to display detectable DNA replication activity, and a tAg substitution mutant, reduced in PP2A binding, was replication-defective. Our observation that JCV tAg binds Rb proteins, indicates all five JCV tumor proteins have the potential to influence cell cycle progression in infected and transformed cells. It remains unclear how these proteins coordinate their unique and overlapping functions.