Saturated fatty acids like palmitate contribute to muscle atrophy in a number of conditions (e.g., type II diabetes) by altering insulin signaling. Akt is a key modulator of protein balance that inhibits the FoxO transcription factors (e.g., FoxO3) which selectively induce the expression of atrophy-inducing genes (atrogenes) in the ubiquitin-proteasome and autophagy-lysosome systems. Conversely, omega-3 polyunsaturated fatty acids have beneficial effects on insulin signaling and may preserve muscle mass. In an earlier report, the omega-3 fatty acid docosahexaenoic acid (DHA) protected myotubes from palmitate-induced atrophy; the mechanisms underlying the alterations in protein metabolism were not identified. This study investigated whether DHA prevents a palmitate-induced increase in proteolysis by restoring Akt/FoxO signaling. Palmitate increased the rate of protein degradation, while cotreatment with DHA prevented the response. Palmitate reduced the activation state of Akt and increased nuclear FoxO3 protein while decreasing its cytosolic level. Palmitate also increased the messenger RNAs (mRNAs) of two FoxO3 atrogene targets, the E3 ubiquitin ligase atrogin-1/MAFbx and the autophagy mediator Bnip3. DHA attenuated the effects of palmitate on Akt activation, FoxO3 localization and atrogene mRNAs. DHA, alone or in combination with palmitate and decreased the ratio of LC3B-II:LC3B-I protein as well as the rate of autophagosome formation, as indicated by reduced LC3B-II protein in the presence of 10 mmol/L methylamine, suggesting an independent effect of DHA on the macroautophagy pathway. These data indicate that palmitate induces myotube atrophy, at least in part, by activating multiple proteolytic systems and that DHA counters the catabolic effects of palmitate by restoring Akt/FoxO signaling.
Variability in transplant rates between different dialysis units has been noted, yet little is known about facility-level factors associated with low standardized transplant ratios (STRs) across the United States End-stage Renal Disease (ESRD) Network regions. We analyzed Centers for Medicare & Medicaid Services Dialysis Facility Report data from 2007 to 2010 to examine facility-level factors associated with low STRs using multivariable mixed models. Among 4098 dialysis facilities treating 305 698 patients, there was wide variability in facility-level STRs across the 18 ESRD Networks. Four-year average STRs ranged from 0.69 (95% confidence interval [CI]: 0.64-0.73) in Network 6 (Southeastern Kidney Council) to 1.61 (95% CI: 1.47-1.76) in Network 1 (New England). Factors significantly associated with a lower STR (p-<-0.0001) included for-profit status, facilities with higher percentage black patients, patients with no health insurance and patients with diabetes. A greater number of facility staff, more transplant centers per 10 000 ESRD patients and a higher percentage of patients who were employed or utilized peritoneal dialysis were associated with higher STRs. The lowest performing dialysis facilities were in the Southeastern United States. Understanding the modifiable facility-level factors associated with low transplant rates may inform interventions to improve access to transplantation. Standardized transplant ratios vary widely among the more than 4,000 dialysis facilities in the United States, and facilities with the lowest rates are located in the Southeast. Also see viewpoint by Patzer and Pastan (page 1499) and counterpoint by Srinivas (page 1506).
by
Stephen Pastan;
Howard Gebel;
Allan Kirk;
Robert Bray;
BI Freedman;
BA Julian;
AK Israni;
D Schladt;
MD Gautreaux;
V Hauptfeld;
RS Gaston;
J Rogers;
AC Farney;
G Orlando;
RJ Stratta;
S Mohan;
L Ma;
CD Langefeld;
PJ Hicks;
ND Palmer;
PL Adams;
A Palanisamy;
AM Reeves-Daniel;
J Divers
Apolipoprotein L1 gene (APOL1) nephropathy variants in African American deceased kidney donors were associated with shorter renal allograft survival in a prior single-center report. APOL1 G1 and G2 variants were genotyped in newly accrued DNA samples from African American deceased donors of kidneys recovered and/or transplanted in Alabama and North Carolina. APOL1 genotypes and allograft outcomes in subsequent transplants from 55 U.S. centers were linked, adjusting for age, sex and race/ethnicity of recipients, HLA match, cold ischemia time, panel reactive antibody levels, and donor type. For 221 transplantations from kidneys recovered in Alabama, there was a statistical trend toward shorter allograft survival in recipients of two-APOL1-nephropathy-variant kidneys (hazard ratio [HR] 2.71; p = 0.06). For all 675 kidneys transplanted from donors at both centers, APOL1 genotype (HR 2.26; p = 0.001) and African American recipient race/ethnicity (HR 1.60; p = 0.03) were associated with allograft failure. Kidneys from African American deceased donors with two APOL1 nephropathy variants reproducibly associate with higher risk for allograft failure after transplantation. These findings warrant consideration of rapidly genotyping deceased African American kidney donors for APOL1 risk variants at organ recovery and incorporation of results into allocation and informed-consent processes.
by
Maria Chavez-Canales;
Juan Pablo Arroyo;
Benjamin Ko;
Norma Vazquez;
Rocio Bautista;
Maria Castaneda-Bueno;
Norma A. Bobadilla;
Robert S. Hoover Jr;
Gerardo Gamba
Objectives: Insulin is recognized to increase renal salt reabsorption in the distal nephron and hyperinsulinemic states have been shown to be associated with increased expression of the renal NaCl cotransporter (NCC). However, the effect of insulin on NCC functional activity has not been reported.
Methods: Using a heterologous expression system of Xenopus laevis oocytes, a mouse distal convoluted cell line, mDCT15 cells, endogenously expressing NCC, and an ex-vivo kidney perfusion technique, we assessed the effect of insulin on the activity and phosphorylation of NCC. The signaling pathway involved was analyzed.
Results: In Xenopus oocytes insulin increases the activity of NCC together with its phosphorylation at threonine residue 58. Activation of NCC by insulin was also observed in mDCT15 cells. Additionally, insulin increased the NCC phosphorylation in kidney under the ex-vivo perfusion technique. In oocytes and mDCT15 cells, insulin effect on NCC was prevented with inhibitors of phosphatidylinositol 3-kinase (PI3K), mTORC2, and AKT1 kinases, but not by inhibitors of MAP or mTORC1 kinases, suggesting that PI3K-mTORC2-AKT1 is the intracellular pathway required. Additionally, activation of NCC by insulin was not affected by wild-type or mutant versions of with no lysine kinase 1, with no lysine kinase 4, or serum glucocorticoid kinase 1, but it was no longer observed in the presence of wild-type or the dominant negative, catalytically inactive with no lysine kinase 3, implicating this kinase in the process.
Conclusion: Insulin induces activation and phosphorylation of NCC. This effect could play an important role in arterial hypertension associated with hyperinsulinemic states, such as obesity, metabolic syndrome, or type 2 diabetes mellitus.
The impact of a new national kidney allocation system (KAS) on access to the national deceased-donor waiting list (waitlisting) and racial/ethnic disparities in waitlisting among US end-stage renal disease (ESRD) patients is unknown. We examined waitlisting pre- and post-KAS among incident (N = 1 253 100) and prevalent (N = 1 556 954) ESRD patients from the United States Renal Data System database (2005-2015) using multivariable time-dependent Cox and interrupted time-series models. The adjusted waitlisting rate among incident patients was 9% lower post-KAS (hazard ratio [HR]: 0.91; 95% confidence interval [CI], 0.90-0.93), although preemptive waitlisting increased from 30.2% to 35.1% (P <.0001). The waitlisting decrease is largely due to a decline in inactively waitlisted patients. Pre-KAS, blacks had a 19% lower waitlisting rate vs whites (HR: 0.81; 95% CI, 0.80-0.82); following KAS, disparity declined to 12% (HR: 0.88; 95% CI, 0.85-0.90). In adjusted time-series analyses of prevalent patients, waitlisting rates declined by 3.45/10 000 per month post-KAS (P <.001), resulting in ≈146 fewer waitlisting events/month. Shorter dialysis vintage was associated with greater decreases in waitlisting post-KAS (P <.001). Racial disparity reduction was due in part to a steeper decline in inactive waitlisting among minorities and a greater proportion of actively waitlisted minority patients. Waitlisting and racial disparity in waitlisting declined post-KAS; however, disparity remains.
Post-traumatic stress disorder (PTSD) is characterized by a heightened emotional and physiological state and an impaired ability to suppress or extinguish traumatic fear memories. Exaggerated physiological responses may contribute to increased cardiovascular disease (CVD) risk in this population, but whether treatment for PTSD can offset CVD risk remains unknown. To further evaluate physiological correlates of fear learning, we used a novel pre-clinical conditioned cardiovascular testing paradigm and examined the effects of Pavlovian fear conditioning and extinction training on mean arterial pressure (MAP) and heart rate (HR) responses. We hypothesized that a fear conditioned cardiovascular response could be detected in a novel context and attenuated by extinction training. In a novel context, fear conditioned mice exhibited marginal increases in MAP (∼3 mmHg) and decreases in HR (∼20 bpm) during CS presentation. In a home cage context, the CS elicited significant increases in both HR (100 bpm) and MAP (20 mmHg). Following extinction training, the MAP response was suppressed while CS-dependent HR responses were variable. These pre-clinical data suggest that extinction learning attenuates the acute MAP responses to conditioned stimuli over time, and that MAP and HR responses may extinguish at different rates. These results suggest that in mouse models of fear learning, conditioned cardiovascular responses are modified by extinction training. Understanding these processes in pre-clinical disease models and in humans with PTSD may be important for identifying interventions that facilitate fear extinction and attenuate hyper-physiological responses, potentially leading to improvements in the efficacy of exposure therapy and PTSD–CVD comorbidity outcomes.
It is unknown whether dialysis facility staff are aware of the new kidney allocation system implemented in December 2014, which changed how deceased donor kidneys are allocated and waiting time is calculated. U.S. dialysis facilities with low annual waitlisting (<15.2%) were surveyed as part of a large randomized study. Among 653 facilities, 57.9% of staff were aware of the policy change, with medical directors (84.4%) being more aware than social workers (73.3%), facility administrators (53.1%), nurse managers (46.4%), and other staff (43.8%). Targeted education among dialysis facilities with low waitlisting may help extend the reach of the new policy.
Background For patients waitlisted for a deceased-donor kidney, hospitalization is associated with a lower likelihood of transplantation and worse posttransplant outcomes. However, individual-, neighborhood-, and regional-level risk factors for hospitalization throughout the waitlist period and specific causes of hospitalization in this population are unknown. Methods We used United States Renal Data System Medicare-linked data on patients waitlisted between 2005 and 2013 with continuous enrollment in Medicare parts A and B (n = 53 810) to examine the association between annual hospitalization rate and a variety of demographic, clinical, and social factors. We used multilevel multivariable ordinal logistic regression to estimate odds ratios. Results Factors associated with significantly increased hospitalization rates among waitlisted individuals included older age, female sex, more years on dialysis before waitlisting, tobacco use, panel-reactive antibody greater than 0, public insurance or no insurance at end-stage renal disease diagnosis, more regional acute care hospital beds, and urban residence (all P < 0.05). Among patients dialysis-dependent when waitlisted, individuals with arteriovenous fistulas were significantly less likely than individuals with indwelling catheters or grafts to be hospitalized (odds ratios, 0.79 and 0.82, respectively, both P < 0.001). The most common causes of hospitalization were complications related to devices, implants, and grafts; hypertension; and sepsis. Conclusions Individual-and regional-level variables were significantly associated with hospitalization while waitlisted, suggesting that personal, health system, and geographic factors may impact patients' risk. Conditions related to dialysis access and comorbidities were common hospitalization causes, underscoring the importance proper access management and care for additional chronic health conditions.
Background: Non-adherence to dialysis recommendations is common and associated with poor outcomes. We used data from a cohort of in-center hemodialysis patients to determine whether patients’ reported difficulties with adherence were associated with achievement of clinical targets for treatment recommendations. Patients and Methods: We included 799 in-center patients receiving hemodialysis from February 2010 to October 2016 at Emory Dialysis (Atlanta, GA, USA). Patient-reported difficulty with adherence (yes vs no) across multiple domains (coming to dialysis, completing dialysis sessions, fluid restrictions, diet restrictions, taking medications) was obtained from baseline social worker assessments. Achievement of clinical targets for coming to dialysis (missing ≥3 expected sessions), completing dialysis sessions (shortening >3 sessions by ≥15 min), fluid restrictions (mean interdialytic weight gain ≥3 kg), diet restrictions (mean potassium ≥5.0 mEq/L, mean phosphate >5.5 mg/dL), and taking medications (mean phosphate >5.5 mg/dL) was estimated over the following 12 weeks, using electronic medical record data. Crude agreement was assessed, and multivariable logistic regression was used to estimate the associations between these measures. Results: Agreement between reported difficulty in adherence and failure to achieve clinical targets was generally poor across all domains (percent agreement: 52.9–65.3%). After adjustment, patients reporting difficulty with fluid restrictions were 62% more likely to have mean interdialytic weight gain ≥3 kg than those not reporting difficulty (OR: 1.62, 95% CI: 1.08, 2.43). Patients reporting difficulty with coming to dialysis were 41% more likely to miss ≥3 expected dialysis sessions over 12 weeks (OR: 1.41, 95% CI: 0.96, 2.07); however, this association was not statistically significant. There were no significant associations between reported difficulty and failure to achieve clinical targets in other categories. Conclusion: While reported difficulty with only fluid restrictions and coming to dialysis were associated with failure to achieve clinical targets in our study, the general lack of agreement between reported difficulty with adherence and failure to achieve clinical targets highlights a gap that could be explored to develop and target educational interventions aimed at increasing adherence among dialysis patients.
by
Timo P. Hiltunen;
Kati M. Donner;
Antti‐Pekka Sarin;
Janna Saarela;
Samuli Ripatti;
Arlene Chapman;
John G. Gums;
Yan Gong;
Rhonda M. Cooper-DeHoff;
Francesca Frau;
Valeria Glorioso;
Roberta Zaninello;
Erika Salvi;
Nicola Glorioso;
Eric Boerwinkle;
Stephen T. Turner;
Julie A. Johnson;
Kimmo K. Kontula
Background: Identification of genetic markers of antihypertensive drug responses could assist in individualization of hypertension treatment. Methods and Results: We conducted a genome‐wide association study to identify gene loci influencing the responsiveness of 228 male patients to 4 classes of antihypertensive drugs. The Genetics of Drug Responsiveness in Essential Hypertension (GENRES) study is a double‐blind, placebo‐controlled cross‐over study where each subject received amlodipine, bisoprolol, hydrochlorothiazide, and losartan, each as a monotherapy, in a randomized order. Replication analyses were performed in 4 studies with patients of European ancestry (PEAR Study, N=386; GERA I and II Studies, N=196 and N=198; SOPHIA Study, N=372). We identified 3 single‐nucleotide polymorphisms within the ACY3 gene that showed associations with bisoprolol response reaching genome‐wide significance (P<5×10−8); however, this could not be replicated in the PEAR Study using atenolol. In addition, 39 single‐nucleotide polymorphisms showed P values of 10−5 to 10−7. The 20 top‐associated single‐nucleotide polymorphisms were different for each antihypertensive drug. None of these top single‐nucleotide polymorphisms co‐localized with the panel of >40 genes identified in genome‐wide association studies of hypertension. Replication analyses of GENRES results provided suggestive evidence for a missense variant (rs3814995) in the NPHS1 (nephrin) gene influencing losartan response, and for 2 variants influencing hydrochlorothiazide response, located within or close to the ALDH1A3 (rs3825926) and CLIC5 (rs321329) genes. Conclusions: These data provide some evidence for a link between biology of the glomerular protein nephrin and antihypertensive action of angiotensin receptor antagonists and encourage additional studies on aldehyde dehydrogenase–mediated reactions in antihypertensive drug action.