Increasing Obesity Prevalence in the United States End-Stage Renal Disease Population.

Background: Among ESRD patients, obesity may improve dialysis-survival but decreases likelihood of transplantation, and as such, obesity prevalence may directly affect growth of the dialysis population. Objective: The objective of this study was to assess BMI trends in the ESRD population as compared to the general population. Materials and Methods: Incident adult ESRD patients were identified from the United States Renal Data System from 01/01/1995-12/31/2010 (n=1,458,350). Data from the Behavioral Risk Factor Surveillance System (n=4,303,471) represented the US population. Trends in BMI, obesity classes I (BMI of 30-34.9), II (BMI of 35-39.9), and III (BMI ≥ 40), were examined by year of dialysis initiation. Trends in BMI slope were compared between the ESRD and US populations using linear regression. Results: Mean BMI of ESRD patients in 1995 was 25.2 as compared to 29.4 in 2010, a 16.7% increase, while the US population's mean BMI increased from 25.3 to 27.2, a 7.5% increase. BMI increase among the ESRD population was significantly more rapid than among the US population (ß: 0.16, 95% CI: 0.14-0.18, p<0.001). Conclusions and Recommendations: Mean BMI among the ESRD population is increasing more rapidly than the US population. Given decreased access to kidney transplantation among ESRD patients with obesity, future research should be directed at controlling healthcare expenditures by identifying strategies to address the obesity epidemic among the US ESRD population.

Impact of Protease Inhibitor-Based Anti-Retroviral Therapy on Outcomes for HIV+ Kidney Transplant Recipients.

Excellent outcomes have been demonstrated among select HIV-positive kidney transplant (KT) recipients with well-controlled infection, but to date, no national study has explored outcomes among HIV+ KT recipients by antiretroviral therapy (ART) regimen. Intercontinental Marketing Services (IMS) pharmacy fills (1/1/01-10/1/12) were linked with Scientific Registry of Transplant Recipients (SRTR) data. A total of 332 recipients with pre- and posttransplantation fills were characterized by ART at the time of transplantation as protease inhibitor (PI) or non-PI-based ART (88 PI vs. 244 non-PI). Cox proportional hazards models were adjusted for recipient and donor characteristics. Comparing recipients by ART regimen, there were no significant differences in age, race, or HCV status. Recipients on PI-based regimens were significantly more likely to have an Estimated Post Transplant Survival (EPTS) score of >20% (70.9% vs. 56.3%, p = 0.02) than those on non-PI regimens. On adjusted analyses, PI-based regimens were associated with a 1.8-fold increased risk of allograft loss (adjusted hazard ratio [aHR] 1.84, 95% confidence interval [CI] 1.22-2.77, p = 0.003), with the greatest risk observed in the first posttransplantation year (aHR 4.48, 95% CI 1.75-11.48, p = 0.002), and a 1.9-fold increased risk of death as compared to non-PI regimens (aHR 1.91, 95% CI 1.02-3.59, p = 0.05). These results suggest that whenever possible, recipients should be converted to a non-PI regimen prior to kidney transplantation.

Increased Mortality and Graft Loss With Kidney Retransplantation Among Human Immunodeficiency Virus (HIV)-Infected Recipients.

Excellent outcomes have been demonstrated in primary human immunodeficiency virus (HIV)-positive (HIV+) kidney transplant recipients, but a subset will lose their graft and seek retransplantation (re-KT). To date, no study has examined outcomes among HIV+ re-KT recipients. We studied risk for death and graft loss among 4149 (22 HIV+ vs. 4127 HIV-negative [HIV-]) adult re-KT recipients reported to the Scientific Registry of Transplant Recipients (SRTR) (2004-2013). Compared to HIV- re-KT recipients, HIV+ re-KT recipients were more commonly African American (63.6% vs. 26.7%, p < 0.001), infected with hepatitis C (31.8% vs. 5.0%, p < 0.001) and had longer median time on dialysis (4.8 years vs. 2.1 years, p = 0.02). There were no significant differences in length of time between the primary and re-KT events by HIV status (1.5 years vs. 1.4 years, p = 0.52). HIV+ re-KT recipients experienced a 3.11-fold increased risk of death (adjusted hazard ratio [aHR]: 3.11, 95% confidence interval [CI]: 1.82-5.34, p < 0.001) and a 1.96-fold increased risk of graft loss (aHR: 1.96, 95% CI: 1.14-3.36, p = 0.01) compared to HIV- re-KT recipients. Re-KT among HIV+ recipients was associated with increased risk for mortality and graft loss. Future research is needed to determine if a survival benefit is achieved with re-KT in this vulnerable population.

Dosing Eculizumab for Antibody-Mediated Rejection in Kidney Transplantation: A Case Report.

Severe antibody-mediated rejection (AMR) of a blood type-incompatible (ABOi) living donor kidney transplantation (LDKT) can lead to graft failure, and aggressive therapies, such as the anticomplement antibody eculizumab, are often used to rescue the affected graft. Eculizumab therapy can be crippling financially. Current literature suggests a wide variation in the amount and timing of eculizumab given as rescue therapy in the setting of AMR. Herein we describe a limited-eculizumab regimen in the setting of severe AMR that is both clinically and cost effective. Treatment included escalation in plasmapheresis and intravenous immunoglobulin (PP/IVIg) and eculizumab. Eculizumab therapy was discontinued at the first sign of clinical improvement (2-fold decrease in anti-ABO titer and stabilization of serum creatinine). The current standard of care is to redose eculizumab after any PP treatment, and, in some series, continue with maintenance eculizumab doses. In these 2 cases, discontinuing eculizumab therapy upon observed clinical improvement saved 6 unnecessary doses at a cost of $90,000. Both patients have more than 1 year of follow-up and functioning allografts. Although this is a small and limited study, we suggest that a dosing regimen of eculizumab similar to that presented here may be effective in rescuing a graft following AMR while simultaneously limiting cost.

Identification of Optimal Donor-Recipient Combinations Among Human Immunodeficiency Virus (HIV)-Positive Kidney Transplant Recipients.

For some patient subgroups, human immunodeficiency virus (HIV) infection has been associated with worse outcomes after kidney transplantation (KT); potentially modifiable factors may be responsible. The study goal was to identify factors that predict a higher risk of graft loss among HIV-positive KT recipients compared with a similar transplant among HIV-negative recipients. In this study, 82 762 deceased donor KT recipients (HIV positive: 526; HIV negative: 82 236) reported to the Scientific Registry of Transplant Recipients (SRTR) (2001-2013) were studied by interaction term analysis. Compared to HIV-negative recipients, the hepatitis C virus (HCV) amplified risk 2.72-fold among HIV-positive KT recipients (adjusted hazard ratio [aHR]: 2.72, 95% confidence interval [CI]: 1.75-4.22, p < 0.001). Forty-three percent of the excess risk was attributable to the interaction between HIV and HCV (attributable proportion of risk due to the interaction [AP]: 0.43, 95% CI: 0.23-0.63, p = 0.02). Among HIV-positive recipients with more than three HLA mismatches (MMs), risk was amplified 1.80-fold compared to HIV-negative (aHR: 1.80, 95% CI: 1.31-2.47, p < 0.001); 42% of the excess risk was attributable to the interaction between HIV and more than three HLA MMs (AP: 0.42, 95% CI: 0.24-0.60, p = 0.01). High-HIV-risk (HIV-positive/HCV-positive HLAwith more than three MMs) recipients had a 3.86-fold increased risk compared to low-HIV-risk (HIV-positive/HCV-negative HLA with three or fewer MMs)) recipients (aHR: 3.86, 95% CI: 2.37-6.30, p < 0.001). Avoidance of more than three HLA MMs in HIV-positive KT recipients, particularly among coinfected patients, may mitigate the increased risk of graft loss associated with HIV infection.

Center-Level Experience and Kidney Transplant Outcomes in HIV-Infected Recipients.

Excellent outcomes among HIV+ kidney transplant (KT) recipients have been reported by the NIH consortium, but it is unclear if experience with HIV+ KT is required to achieve these outcomes. We studied associations between experience measures and outcomes in 499 HIV+ recipients (SRTR data 2004-2011). Experience measures examined included: (1) center-level participation in the NIH consortium; (2) KT experiential learning curve; and (3) transplant era (2004-2007 vs. 2008-2011). There was no difference in outcomes among centers early in their experience (first 5 HIV+ KT) compared to centers having performed >6 HIV+ KT (GS adjusted hazard ratio [aHR]: 1.05, 95% CI: 0.68-1.61, p = 0.82; PS aHR: 0.93; 95% CI: 0.56-1.53, p = 0.76), and participation in the NIH-study was not associated with any better outcomes (GS aHR: 1.08, 95% CI: 0.71-1.65, p = 0.71; PS aHR: 1.13; 95% CI: 0.68-1.89, p = 0.63). Transplant era was strongly associated with outcomes; HIV+ KTs performed in 2008-2011 had 38% lower risk of graft loss (aHR: 0.62; 95% CI: 0.42-0.92, p = 0.02) and 41% lower risk of death (aHR: 0.59; 95% CI: 0.39-0.90, p = 0.01) than that in 2004-2007. Outcomes after HIV+ KT have improved over time, but center-level experience or consortium participation is not necessary to achieve excellent outcomes, supporting continued expansion of HIV+ KT in the US.

The impact of proposed changes in liver allocation policy on cold ischemia times and organ transportation costs.

Changes to the liver allocation system have been proposed to decrease regional variation in access to liver transplant. It is unclear what impact these changes will have on cold ischemia times (CITs) and donor transportation costs. Therefore, we performed a retrospective single center study (2008-2012) measuring liver procurement CIT and transportation costs. Four groups were defined: Local-within driving distance (Local-D, n = 262), Local-flight (Local-F, n = 105), Regional-flight <3 h (Regional <3 h, n = 61) and Regional-Flight >3 h (Regional >3 h, n = 53). The median travel distance increased in each group, varying from zero miles (Local-D), 196 miles (Local-F), 384 miles (Regional <3 h), to 1647 miles (Regional >3 h). Increasing travel distances did not significantly increase CIT until the flight time was >3 h. The average CIT ranged from 5.0 to 6.0 h for Local-D, Local-F and Regional <3 h, but increased to 10 h for Regional >3 h (p < 0.0001). Transportation costs increased with greater distance traveled: Local-D $101, Local-F $1993, Regional <3 h $8324 and Regional >3 h $27 810 (p < 0.0001). With proposed redistricting, local financial modeling suggests that the average liver donor procurement transportation variable direct costs will increase from $2415 to $7547/liver donor, an increase of 313%. These findings suggest that further discussion among transplant centers and insurance providers is needed prior to policy implementation.

Vehicle rollover risk and electronic stability control systems.

BACKGROUND: Electronic stability control (ESC) systems were developed to reduce motor vehicle collisions (MVCs) caused by loss of control. Introduced in Europe in 1995 and in the USA in 1996, ESC is designed to improve vehicle lateral stability by electronically detecting and automatically assisting drivers in unfavorable situations. AIM: To examine the relationship between vehicle rollover risk and presence of ESC using a large national database of MVCs. METHODS: A retrospective cohort study for the period 1995 through 2006 was carried out using data obtained from the National Automotive Sampling System General Estimates System. All passenger cars and sport utility vehicles (SUVs)/vans of model year 1996 and later were eligible. Vehicle ESC (unavailable, optional, standard) was determined on the basis of make, model, and model year. Risk ratios (RRs) and 95% CIs were calculated to compare rollover risk by vehicle ESC group. RESULTS: For all crashes, vehicles equipped with standard ESC had decreased risk of rollover (RR = 0.62, 95% CI 0.50 to 0.77) compared with vehicles with ESC unavailable. The association was consistent for single-vehicle MVCs (RR = 0.61, 95% CI 0.46 to 0.82); passenger cars had decreased rollover risk (RR = 0.77, 95% CI 0.52 to 1.12), but SUVs/vans had a more dramatically decreased risk (RR = 0.40, 95% CI 0.26 to 0.61). CONCLUSIONS: This study supports previous results showing ESC to be effective in reducing the risk of rollover. ESC is more effective in SUVs/vans for rollovers related to single-vehicle MVCs.

Risk of injury for occupants of motor vehicle collisions from unbelted occupants.

OBJECTIVE: Unbelted occupants may increase the risk of injury for other occupants in a motor vehicle collision (MVC). This study evaluated the association between occupant restraint use and the risk of injury (including death) to other vehicle occupants. DESIGN: A population based cohort study. SETTING: United States. SUBJECTS: MVC occupants (n = 152 191 unweighted, n = 18 426 684 weighted) seated between a belted or unbelted occupant and the line of the principal direction of force in frontal, lateral, and rear MVCs were sampled from the 1991-2002 National Automotive Sampling System General Estimates System. Offset MVCs were not included in the study. MAIN OUTCOME MEASURE: Risk ratios and 95% confidence intervals for injury (including death) for occupants seated contiguous to unbelted occupants compared to occupants seated contiguous to belted occupants. Risk ratios were adjusted for at risk occupant's sex, age, seating position, vehicle type, collision type, travel speed, crash severity, and at risk occupants' own seat belt use. RESULTS: Exposure to unbelted occupants was associated with a 40% increased risk of any injury. Belted at risk occupants were at a 90% increased risk of injury but unbelted occupants were not at increased risk. Risks were similar for non-incapacitating and capacitating injuries. There was a 4.8-fold increased risk of death for exposed belted occupants but no increased risk of death for unbelted occupants. CONCLUSIONS: Belted occupants are at an increased risk of injury and death in the event of a MVC from unbelted occupants.

A cross-sectional study of triallate exposure and neurological health among workers at a pesticide manufacturing and formulating facility.

AIMS: To evaluate the relation between an indicator of cumulative exposure to triallate and selected measures of neurological function, including nerve conduction, the prevalence of certain neurological deficits as determined by a medical examination, and vibration perception threshold testing in workers at a pesticide manufacturing plant. METHODS: Subjects were 50 workers with high estimated triallate exposure ("high triallate" group) and 50 workers with no or low triallate exposure ("no/low triallate" group). Industrial hygienists used existing work histories and personal knowledge of plant operations to develop a triallate score. In-person interviews elicited information on past medical history and on occupational and non-occupational exposures. A neurologist carried out nerve conduction tests of the sural and the peroneal nerves, a standardised neurological examination, and vibration sensation testing. RESULTS: Differences between the high and the no/low triallate groups were minimal for all but one of the six nerve conduction tests, for the prevalence of neurological abnormalities, and for vibration sensation perception. The high triallate group had lower mean sural nerve peak amplitude than the no/low triallate group (11.7 v 15.2 microV, p = 0.03). This difference was reduced when adjusted for other potential risk factors (12.5 v 14.5 microV, p = 0.25) and was not associated with cumulative triallate score. We also noted several associations between factors other than triallate and nerve conduction measures. CONCLUSION: The results were consistent with the absence of an association between triallate and measures of neurological function.

Fasting increases the extent of muscle necrosis in the mdx mouse.

1. The effects of fasting for 48 h were investigated in C57BL/10 (wild type) and age-matched C57BL/10 dystrophin-deficient (mdx) mice. 2. Fasting resulted in an increased percentage of necrotic fibres in muscles from the hindlimb and lumbar regions of mdx mice. The percentage of necrotic fibres of forelimb and chest muscles of mdx mice was unaltered by fasting. In wild-type mice, very few necrotic fibres were observed after fasting. 3. The necrotic changes in fasted mdx muscle were not accompanied by altered energy status as evaluated by muscle ATP and phosphocreatine concentrations. 4. A significantly decreased rectal temperature was observed in mdx but not in wild-type mice after fasting. 5. Fasting would normally be expected to cause a reduction in muscle fibre size. The high prevalence of necrosis in fasted mdx mice is therefore an unusual response that may be related to disturbance of the mechanisms which, in the fed state, compensate for the dystrophin deficiency in these animals.

Effect of passive stretching on the wasting of muscle in the critically ill.

This study examine whether muscle wasting in critically ill patients can be prevented by passive stretching alone in the absence of contractile activity. Five critically ill patients who required a complete neuromuscular blockade for 7 days of ventilator support were studied. One leg of each patient was treated with continuous passive motion (CPM) for three 3-h periods daily while the other leg received only routine nursing care. Fiber atrophy was prevented in the more severely ill patients and there was a slight gain in fiber area (mean increase, +11%) in the CPM limb compared with the control leg, which decreased (mean decrease, -35%) over 7 days. Fiber area was preserved in both fiber types but was more pronounced in type I muscle fibers. Protein loss was significantly less in the CPM limb. There was a significantly greater increase in wet weight per mg DNA in the control limb. However, as an index of wasting, the ratio of protein to DNA decreased similarly in both limbs. Passive stretching can preserve the architecture of muscle fibers. Whether it can prevent muscle wasting remains uncertain.

Immunohistochemical and biochemical indicators of muscle damage in vitro: the stability of control muscle and the effects of dinitrophenol and calcium ionophore.

The biochemical, histological and ultrastructural effects of 2,4-dinitrophenol and the calcium ionophore, A23187, on rat soleus muscle incubated in vitro have been examined to test the hypothesis that immunohistochemical techniques can be used to recognize early structural features of fibre damage. In control muscles, despite mild glycogen depletion and a mild reduction in protein synthetic rate in the central portion of the muscle, fibres throughout the muscle appear to be viable with normal cytoskeletal and contractile protein architecture, normal concentrations of high energy phosphates and no creatine kinase efflux. Dinitrophenol causes rapid creatine kinase efflux, extensive loss of immunolabelling for desmin and dystrophin, and abnormal myosin immunolabelling. Creatine kinase efflux and the changes in desmin and dystrophin are reduced by the exclusion of calcium. A23187 causes more gradual creatine kinase efflux associated with changes in myosin immunolabelling, but loss of desmin and dystrophin immunolabelling is restricted to a few of the most peripheral fibres. The results suggest that immunohistochemical methods can be used to reveal differences in the intracellular mechanisms of muscle damage. Although both dinitrophenol and A23187 may act, in part, through calcium-mediated processes, their effects on cytoskeletal proteins differ. Creatine kinase efflux after A23187 may not be due to gross sarcolemmal damage.

Effects of calcium on protein turnover of incubated muscles from mdx mice.

Mdx mice have a genetic defect similar to that which causes Duchenne muscular dystrophy in humans. The influence of calcium on muscle protein metabolism of mdx and wild type (C57BL/10) mice was examined in vitro. Incubation of mdx muscles in a medium containing calcium at a concentration of 2.0 mM (but not 0.2 mM) resulted in proteolytic rates that were greater than those of C57BL/10 muscles. At 2.0 mM extracellular calcium, mdx muscle proteolysis was attenuated by thiol protease inhibitors but not by the weak base methylamine. Protein synthetic rates were higher in incubated mdx muscles than in incubated C57BL/10 muscles, but no effect of extracellular calcium concentration was observed in either strain. These data suggest that mdx mice have an abnormality of muscle calcium handling, which results in activation of nonlysosomal proteolytic processes but does not exert acute effects on protein synthetic rate.

Acute effects of phorbol esters on the protein-synthetic rate and carbohydrate metabolism of normal and mdx mouse muscles.

1. mdx mice do not express dystrophin, the product of the gene which is defective in Duchenne and Becker muscular dystrophy. We have previously shown that protein-synthetic rates (ks) are increased in mdx mouse muscles [MacLennan & Edwards (1990) Biochem. J. 268, 795-797]. 2. The tumour-promoting stereoisomer of phorbol 12,13-didecanoate (4 beta-PDD) acutely increased the ks of muscles from mdx and wild-type (C57BL/10) mice incubated in vitro in the absence of insulin. The effects of 4 beta-PDD are presumably mediated by activation of protein kinase C (PKC). 3. The muscle glycogen concentrations of mdx mice were higher than those of C57BL/10 mice. Studies performed in vivo and in vitro suggested that the effect might be at least partially due to increased rate of glycogen synthesis in mdx muscle. 4. 4 beta-PDD increased the glycogen-synthetic rates rates of C57BL/10, but not mdx, muscles incubated in vitro in the absence of insulin. 5. In muscles from both species incubated in the absence of insulin, treatment with 4 beta-PDD also induced increased rates of glucose uptake and lactate production. Kinetic studies of C57BL/10 and mdx muscles suggested that 4 beta-PDD raised the Vmax. of glucose uptake, but did not alter the Km for the process. 6. The possible role of PKC in controlling the protein and carbohydrate metabolism of normal and mdx mouse muscles is discussed.