Patients undergoing conventional maintenance hemodialysis typically receive three sessions per week, each lasting 2.5-5.5 hours. Recently, the use of more intensive hemodialysis (.5.5 hours, three to seven times per week) has increased, but the effects of these regimens on survival are uncertain. We conducted a retrospective cohort study to examine whether intensive hemodialysis associates with better survival than conventional hemodialysis. We identified 420 patients in the International Quotidian Dialysis Registry who received intensive home hemodialysis in France, the United States, and Canada between January 2000 and August 2010. We matched 338 of these patients to 1388 patients in the Dialysis Outcomes and Practice Patterns Study who received in-center conventional hemodialysis during the same time period by country, ESRD duration, and propensity score. The intensive hemodialysis group received a mean (SD) 4.8 (1.1) sessions per week with a mean treatment time of 7.4 (0.87) hours per session; the conventional group received three sessions per week with a mean treatment time of 3.9 (0.32) hours per session. During 3008 patient-years of follow-up, 45 (13%) of 338 patients receiving intensive hemodialysis died compared with 293 (21%) of 1388 patients receiving conventional hemodialysis (6.1 versus 10.5 deaths per 100 personyears; hazard ratio, 0.55 [95% confidence interval, 0.34-0.87]). The strength and direction of the observed association between intensive hemodialysis and improved survival were consistent across all prespecified subgroups and sensitivity analyses. In conclusion, there is a strong association between intensive home hemodialysis and improved survival, but whether this relationship is causal remains unknown.

These results indicate that NHD and DTX survival is comparable, and suggest that this intensive dialysis modality may be a bridge to transplantation or even a suitable alternative in the absence of LTX in the current era of growing transplant waiting lists and organ shortage.

The hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-1 act on the pancreas to potentiate glucose-induced insulin secretion (enteroinsular axis). These hormones (incretins) are rapidly hydrolyzed by the circulating enzyme dipeptidyl peptidase IV (DP IV) into biologically inactive NH2-terminally truncated fragments. This study describes the effect of inhibiting endogenous DP IV with a specific DP IV inhibitor, isoleucine thiazolidide (Ile-thiazolidide), on glucose tolerance and insulin secretion in the obese Zucker rat. In initial studies, the specificity of Ile-thiazolidide as an inhibitor of incretin degradation was determined using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. These results showed that inhibiting DP IV activity with Ile-thiazolidide blocked the formation of NH2-terminally truncated GIP and GLP-1. Oral administration of Ile-thiazolidide resulted in rapid inhibition of circulating DP IV levels by 65% in obese and lean Zucker rats. Suppression of DP IV levels enhanced insulin secretion in both phenotypes with the most dramatic effect occurring in obese animals (150% increase in integrated insulin response vs. 27% increase in lean animals). Ile-thiazolidide treatment improved glucose tolerance in both phenotypes and restored glucose tolerance to near-normal levels in obese animals. This was attributed to the glucose-lowering actions of increasing the circulating half-lives of the endogenously released incretins GIP and, particularly, GLP-1. This study suggests that drug manipulation of plasma incretin activity by inhibiting the enzyme DP IV is a valid therapeutic approach for lowering glucose levels in NIDDM and other disorders involving glucose intolerance.

The incretins glucose-dependent insulinotropic polypeptide (GIP 1-42 ) and glucagon-like peptide-1-(7-36)-amide (GLP-1 7-36 ), hormones that potentiate glucose-induced insulin secretion from the endocrine pancreas, are substrates of the circulating exopeptidase dipeptidyl peptidase IV and are rendered biologically inactive upon cleavage of their N-terminal dipeptides. This study was designed to determine if matrix-assisted laser desorption/ionization-time of flight mass spectrometry is a useful analytical tool to study the hydrolysis of these hormones by dipeptidyl peptidase IV, including kinetic analysis. Spectra indicated that serumincubated peptides were cleaved by this enzyme with only minor secondary degradation due to other serum protease activity. Quantification of the mass spectrometric signals allowed kinetic constants for both porcine kidney-and human serum dipeptidyl peptidase IVcatalyzed incretin hydrolysis to be calculated. The binding constants (K m ) of these incretins to purified porcine kidney-derived enzyme were 1.8 ؎ 0.3 and 3.8 ؎ 0.3 M, whereas the binding constants observed in human serum were 39 ؎ 29 and 13 ؎ 9 M for glucose-dependent-insulinotropic polypeptide and glucagon-like peptide-1-(7-36)-amide respectively. The large range of K m values found in human serum suggests a heterogeneous pool of enzyme. The close correlation between the reported kinetic constants and those previously described validates this novel approach to kinetic analysis.Incretins are hormones of the enteroinsular axis, which potentiate the actions of glucose on the endocrine pancreas (1). The most potent known incretins are glucose-dependent insulinotropic polypeptide (GIP 1 and truncated forms of glucagon-like peptide-1 (GLP-1 7-36 -amide and GLP-1 7-37 ); both are members of the glucagon family of hormones sharing considerable N-terminal sequence homology (2, 3). Both hormones are released from the gut in response to ingested nutrients and were recently shown to be substrates of the circulating exopeptidase dipeptidyl peptidase IV (DP IV, EC 3.4.14.5) (4, 5). This enzyme is a highly specific protease, preferentially hydrolyzing peptides with N-terminal Xaa-Pro and Xaa-Ala motifs (6). Hydrolysis of GIP 1-42 and GLP-1 7-36 by DP IV yields GIP 3-42 and GLP-1 9 -36 and the dipeptides Tyr-Ala and His-Ala, respectively. Activation or inactivation of biologically active peptides is frequently associated with DP IV catalysis. Work by ourselves and others (7,8) has demonstrated that GIP 3-42 and GLP-1 9 -36 are biologically inactive, and it has been hypothesized that serum degradation of GIP 1-42 and GLP-1 7-36 by DP IV is the primary step in the metabolism of these hormones in the circulation (4, 5, 9). In 1993 Mentlein and co-workers (4) reported on the kinetics of enzymatic degradation of GIP 1-42 and GLP-1 7-36 by purified human placental DP IV, as determined by high performance liquid chromatography (HPLC), and suggested that this may be a physiologically important pathway for the degradation of these hormones. This ...

Background and objectives: As a result of improved clinical and quality-of-life outcomes compared with conventional hemodialysis, interest in nocturnal home hemodialysis (NHD) has steadily increased in the past decade; however, little is known about the flow of patients through NHD programs or about patient-specific predictors of mortality or technique failure associated with this modality. This study addressed this gap in knowledge. Design, setting, participants, & measurements: This study included 247 NHD patients of the Canadian Slow Long nightly ExtEnded dialysis Programs (CAN-SLEEP) cohort from 1994 through 2006 inclusive. The association between program-and patient-specific variables and risk for adverse outcomes was determined using uni-and multivariable Cox regression.Results: A total of 14.6% of the cohort experienced death or technique failure. Unadjusted 1-and 5-year adverse event-free survival was 95.2 and 80.1%, respectively. Significant predictors of a composite of mortality and technique failure included advanced age (P < 0.001), diabetes (P < 0.001), central venous catheter use (P ‫؍‬ 0.01), and inability to perform NHD independently (P ‫؍‬ 0.009) and were adjusted for center effect. Weekly frequency of NHD was not predictive. Age and diabetes remained significant with multivariable analysis (hazard ratio 1.07 and 2.64, respectively). Unadjusted 1-and 5-year technique survival was 97.9 and 95.2%, respectively. Only age was a significant predictor of technique failure.Conclusions: NHD is associated with excellent adverse event-free survival. This study underscores the importance of modality-specific predictors in the success of home hemodialysis, as well as favorable baseline characteristics such as younger age and the absence of diabetes.