Safety and in vivo expression of a GNE-transgene: a novel treatment approach for hereditary inclusion body myopathy-2.

Hereditary inclusion body myopathy-2 (HIBM2) is an adult-onset, muscular disease caused by mutations in the GNE gene. HIBM2-associated GNE mutations causing hyposialyation have been proposed to contribute to reduced muscle function in patients with HIBM2, though the exact cause of this disease is unknown. In the current studies we examined pre-clinical in vivo toxicity, and expression of the plasmid-based, CMV driven wild-type GNE plasmid vector. The plasmid vector was injected intramuscularly (IM) or systemically (IV) into BALB/c mice, following encapsulation in a cationic liposome (DOTAP:Cholesterol). Single IM injections of the GNE-lipoplex at 40 microg did not produce overt toxicity or deaths, indicating that the no observable adverse effect level (NOAEL) dose for IM injection was >or=40 microg. Single intravenous (IV) infusion of GNE-lipoplex was lethal in 33% of animals at 100 microg dose, with a small proportion of animals in the 40 microg cohort demonstrating transient toxicity. Thus the NOAEL dose by the IV route was greater than 10 microg and less than or equal to 40 microg. Real-time RT-qPCR analysis demonstrated recombinant human GNE mRNA expression in 100% of muscle tissues that received IM injection of 40 microg GNE-lipoplex, at 2 weeks. These results indicate that GNE-lipoplex gene transfer is safe and can produce durable transgene expression in treated muscles. Our findings support future exploration of the clinical efficacy of GNE-lipoplex for experimental gene therapy of HIBM2.

Optimal timing of initiation of chronic hemodialysis?

Despite the availability of clinical guidelines for the timing of dialysis initiation in both the United States and Canada, patients continue to start dialysis at very low levels of predicted glomerular filtration rate (GFR). A cross-sectional study was performed to determine the demographic and clinical characteristics of patients who started hemodialysis, their level of GFR, and mortality at 1 and 2 years following the initiation of dialysis. Retrospective data were collected on all eligible patients who commenced chronic hemodialysis in 1 tertiary care center in Canada from March 2001 to February 2005. Only those patients who had been followed by a nephrologist in the chronic kidney disease clinic before dialysis initiation were included (n=271). Seventeen percent of patients started hemodialysis late (GFR<5 mL/min/1.73 m(2)). Compared with the group of patients who started dialysis earlier, the late start group were significantly younger (p=0.008), had more females (p=0.013), more employed (p=0.051), less cardiac (p<0.001), and peripheral vascular disease (p=0.031), and were taking medication for hypertension (p=0.041). Serum albumin was lower in the late start group (p=0.023). At year 1, there was no difference in mortality rate while at year 2, the earlier the dialysis, the greater the mortality rate (p=0.022). After adjustment for demographic variables and comorbidities, only antihypertensive use had an independent but weak association with the 2 year mortality. Adjustment for all these variables eliminated the significant association noted for the 2 year mortality in the early versus late dialysis start. The survival benefit for late versus early dialysis start appears to be multifactorial and relates to a preponderance of clinical and demographic factors favoring a lengthened survival occurring in the late dialysis group. Our survival benefit findings suggest the premorbid health condition is a more important determinant of 2 year survival than the timing of dialysis initiation.

Evaluation of GFR estimating equations in the general community: implications for screening.

The Kidney Disease Outcomes Quality Initiative has recommended the use of GFR estimating equations to detect silent chronic kidney disease (CKD) in the community. The benefit of general reporting of CKD must be balanced with the harm of mislabeling people who do not have CKD. The popular Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) GFR estimating equations were compared with the recently devised Rule equation in a representative community population sample (2166) divided into subsamples with (385) and without (1781) previous renal impairment. The prevalence of CKD was CG > MDRD >> Rule estimates. The magnitude of difference in prevalence of CKD as detected by the MDRD and CG versus the Rule equation increases markedly when the subsamples with (30.8 and 29.7 versus 17.5%) and without (12 and 11.3 versus 3.0%) previous kidney impairment are compared. General demographic and potential or known risk factors were used in a logistic regression model to assess the association with CKD. The MDRD estimates note female gender (odds ratio 2.19; 95% confidence interval 1.63 to 2.95) and both MDRD and the Rule equations identify hypertension and diabetes as significant CKD risk factors. All estimating equations identify age to be associated with CKD. The annualized serial decline in GFR was CG > MDRD > Rule estimates. Only the Rule GFR estimates detected a greater decline in renal impaired versus unimpaired populations. The calibrated Rule equation seems to perform better than CG and MDRD (CKD 3 versus 11.3 to 12%) but lacks validation against gold standards for community-based screening.