Background Chronic kidney disease is characterised by low estimated glomerular filtration rate (eGFR) and high albuminuria, and is associated with adverse outcomes. Whether these risks are modified by diabetes is unknown. Methods We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and end-stage renal disease (ESRD) associated with eGFR and albuminuria in individuals with and without diabetes. Findings We analysed data for 1 024 977 participants (128 505 with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 chronic kidney disease cohorts. In the combined general population and high-risk cohorts with data for all-cause mortality, 75 306 deaths occurred during a mean follow-up of 8·5 years (SD 5·0). In the 23 studies with data for cardiovascular mortality, 21 237 deaths occurred from cardiovascular disease during a mean follow-up of 9·2 years (SD 4·9). In the general and high-risk cohorts, mortality risks were 1·2–1·9 times higher for participants with diabetes than for those without diabetes across the ranges of eGFR and albumin-to-creatinine ratio (ACR). With fixed eGFR and ACR reference points in the diabetes and no diabetes groups, HR of mortality outcomes according to lower eGFR and higher ACR were much the same in participants with and without diabetes (eg, for all-cause mortality at eGFR 45 mL/min per 1·73 m2 [νs 95 mL/min per 1·73 m2], HR 1·35; 95% CI 1·18–1·55; νs 1·33; 1·19–1·48 and at ACR 30 mg/g [νs 5 mg/g], 1·50; 1·35–1·65 νs 1·52; 1·38–1·67). The overall interactions were not significant. We identified much the same findings for ESRD in the chronic kidney disease cohorts. Interpretation Despite higher risks for mortality and ESRD in diabetes, the relative risks of these outcomes by eGFR and ACR are much the same irrespective of the presence or absence of diabetes, emphasising the importance of kidney disease as a predictor of clinical outcomes.

Acute kidney injury increases mortality risk among those with established chronic kidney disease. In this study we used a propensity score-matched cohort method to retrospectively evaluate the risks of death and de novo chronic kidney disease after reversible, hospital-associated acute kidney injury among patients with normal pre-hospitalization kidney function. Of 30,207 discharged patients alive at 90 days, 1610 with reversible acute kidney injury that resolved within the 90 days were successfully matched across multiple parameters with 3652 control patients who had not experienced acute kidney injury. Median follow-up was 3.3 and 3.4 years (injured and control groups, respectively). In Cox proportional hazard models, the risk of death associated with reversible acute kidney injury was significant (hazard ratio 1.50); however, adjustment for the development of chronic kidney injury during follow-up attenuated this risk (hazard ratio 1.18). Reversible acute kidney injury was associated with a significant risk of de novo chronic kidney disease (hazard ratio 1.91). Thus, a resolved episode of hospital-associated acute kidney injury has important implications for the longitudinal surveillance of patients without preexisting, clinically evident kidney disease.

SummaryBackground and objectives Estimates of the effect of estimated GFR (eGFR) decline on mortality have focused on populations with normal kidney function, or have included limited information on factors previously shown to influence the risk of death among patients with CKD.Design, setting, participants, & measurements We retrospectively assessed the effect of rate of eGFR decline on survival of patients with CKD receiving primary care through a large integrated health care system in central Pennsylvania between January 1, 2004, and December 31, 2009.Results A total of 15,465 patients were followed for a median of 3.4 years. Median rates of eGFR change by those in the lower, middle, and upper tertiles of eGFR slope were Ϫ4.8, Ϫ0.6, and 3.5 ml/min per 1.73 m 2 /yr, respectively. In Cox proportional hazard modeling for time to death, adjusted for baseline proteinuria, changes in nutritional parameters, and episodes of acute kidney injury during follow-up (among other covariates), the hazard ratio for those in the lower (declining) and upper (increasing) eGFR tertiles (relative to the middle, or stable, tertile) was 1.84 and 1.42, respectively. Longitudinal changes in nutritional status as well as episodes of acute kidney injury attenuated the risk only modestly. These findings were consistent across subgroups.Conclusions eGFR change over time adds prognostic information to traditional mortality risk predictors among patients with CKD. The utility of incorporating eGFR trends into patient-risk assessment should be further investigated.

The metabolism and mode of action of penciclovir [9-(4-hydroxy-3-hydroxymethylbut-1-yl) Penciclovir, through its triphosphate ester (Fig. 1), is a potent and selective antiherpesvirus agent, particularly against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2, respectively) and varicella-zoster virus (VZV) (9, 3, 4). Previous studies (3,4,9) showed that penciclovir has a spectrum of antiviral activity similar to that of acyclovir, but that penciclovir has an antiviral effect that is longer lasting than that of acyclovir. This may relate to the efficient trapping of the active metabolite, the triphosphate ester of penciclovir, within virus-infected cells (22). Penciclovir and its well-absorbed oral form, famciclovir (23), are undergoing clinical trials for their efficacies not only against HSV-1 infections but also against HSV-2 and VZV infections. There may be appreciable quantitative differences between the rates of metabolism of penciclovir in HSV-and VZVinfected cells. The uptake and phosphorylation in VZVinfected cells has been reported for a pyrimidine analog, 1-3-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (25), and for acyclovir at 250 ,uM (1), but we are unaware of any reports of similar work with acycloguanosine analogs at clinically relevant concentrations. Only recently (2) have we been able to provide a clear indication that penciclovir has prolonged antiviral activity in VZV-infected cells. Therefore, it was of particular interest to determine whether penciclovir-triphosphate (PCV-TP) is formed and then remains at high concentrations within VZV-infected cells following treatment of the cell culture for a short period.In this report, we describe the continuation of our studies * Corresponding author.of the mode of action of penciclovir in comparison with that of acyclovir. We investigated the phosphorylation of the acyclonucleosides in HSV-2-and VZV-infected human cells and the stability of PCV-TP in these cells. Also, we report results of our initial studies in which we investigated the effect of PCV-TP on HSV and VZV DNA polymerases. The phosphate esters of penciclovir, unlike those of acyclovir, are chiral with the possibility that the (R) and (S) enantiomers of the triphosphate ester are formed, although the (S) enantiomer is the predominant form in HSV-1-infected cells