Evolution of Endpoints for Renal Transplant Outcome

Progressive improvement in short-term kidney transplant survival and reduction in acute rejection rates have restricted our ability to assess newer therapy. Past and present conventional endpoints, such as short-term graft survival and acute rejection rates, are no longer practical. This has prompted investigators to search for alternative endpoints. Long-term graft survival is an ideal endpoint. However, this requires a large cohort of patients with longer follow-up. A simpler approach would be to identify short-term markers, which can predict long-term survival. Short-term potential markers that can predict long-term survival are: clinical (renal function), histological (renal pathological markers) and immunological (anti-donor antibody, blood and urine cytokines). Post-transplant renal function estimated by serum creatinine, cystatin C and creatinine clearance within 1 year, and histological indices, as the Banff chronicity score, have the potential to predict long-term graft survival. Serum creatinine is limited as a marker by its variability based on recipient age, body weight, race and sex. Histological indices are limited, due to the invasive nature of evaluation. Post-transplant renal function and histological indices can be used potentially as a composite endpoint, in combination with conventional endpoints, such as graft loss, death and acute rejection. A practical approach for assessing newer therapies in future studies is to use composite endpoints, which combine conventional endpoints (graft loss, death, acute rejection) with newer endpoints (renal function, histological indices).     

Synthesis and effect of affinity-labeled analogs and partial sequences of the bradykinin potentiating nonapeptide BPP9 alpha (teprotide)

Affinity labeled analogues and partial sequences of the bradykinin potentiating nonapeptide BPP9 alpha inhibit the BPP9 alpha induced potentiation of the bradykinin action on the isolated guinea pig ileum. The labeled nonapeptides are more active than the labeled partial sequences. The inhibition of the potentiating action of BPP9 alpha demonstrates, that the influence on bradykinin action is not only a result of the inhibition of peptidyl dipeptide hydrolase.     

The advanced age deceased kidney donor: current outcomes and future opportunities

BaCKGROUND: Due to the aging general population, deceased donors > or =55 years will form an increasingly larger proportion of the deceased kidney donor pool. METHODS: Using data from the United States Renal Data System, we determined the change in graft survival between 1996 and 2000 among 32,557 recipients of donors aged <55 years and > or =55 years in univariate and multivariate survival analyses. We identified donor risk factors for graft loss that might influence the decision to accept or reject donors <55 and > or =55 years. The initial glomerular filtration rate established 6 months after transplantation (initial GFR), and the stability of GFR in the first post-transplant year (GFR at 12 months post-transplantation-GFR at six months post-transplantation) were compared between recipients of donors <55 and > or =55 years and the association of these factors with graft survival was determined. RESULTS: In 2000, one-year graft survival in donors > or =55 years was 86.7%. Between 1996 and 1999 the projected graft half life improved from 11.4 to 14.5 years for recipients of donors <55 years (P < 0.01); however, there was no improvement for recipients of donors > or =55 years (8.2 to 9.2 year, P= 0.46). Among donor factors studied, only cold ischemic time >24 hours identified recipients of donors > or =55 years at risk for graft loss. Compared to recipients of donors <55 years, recipients of donors > or =55 years established a lower initial GFR (42 vs. 56 mL/min/1.73 m(2), P < 0.0001), and had less stable GFR in the first post-transplant year (-1.5 vs. -0.6 mL/min/1.73 m(2), P <.0001). Recipients from donors > or =55 years with initial GFR > or =50 mL/min/1.73 m(2) and no drop GFR during the first post-transplant year had graft survival that was superior to that of donors <55 years with either initial GFR <50 mL/min/1.73 m(2) or a drop in GFR during the first post-transplant year. CONCLUSION: Donors > or =55 years are a valuable resource. Despite improvements in immunosuppression, rejection, and delayed graft function, the projected increase in long-term graft survival among recipients of donors <55 years was not shared among recipients of donors > or =55 years. Recipients of donors > or =55 years had lower initial GFR, and less stable GFR during the first post-transplant year. Limiting cold ischemic time to <24 hours may improve outcomes among recipients of donors > or =55 years. Future studies to maximize initial GFR and minimize early loss of GFR in recipients of donors > or =55 years may lead to improved outcomes from deceased donors > or =55 years.     

Desflurane enhances reactivity during the use of the laryngeal mask airway

BACKGROUND: Desflurane and sevoflurane have markedly different pungencies. The tested hypothesis was that patients breathing equivalent concentrations of desflurane or sevoflurane through a laryngeal mask airway (LMA) would have similar responses. METHODS: After institutional review board approval and informed consent were obtained, 60 patients were enrolled and given intravenous midazolam (14 microg/kg) and fentanyl (1 microg/kg) 5 min before induction of anesthesia. The LMA was inserted at loss of consciousness after 2 mg/kg propofol. When spontaneous breathing returned, a randomly assigned volatile anesthetic was started at an inspired concentration of either 1.8% sevoflurane or 6% desflurane at a fresh gas flow of 6 l/min in air:oxygen (50:50). After 5 min, a controlled movement of the LMA took place. Three minutes later, the inspiratory anesthetic concentration was changed to either 3.6% sevoflurane or 12% desflurane for 3 min. A blinded observer recorded movements and airway events during the start of anesthetic, LMA movement, deepening of the anesthetic, and emergence before LMA removal. RESULTS: There were no differences at anesthetic start and LMA movement. Desflurane titration to 12% increased heart rate, increased mean arterial blood pressure, and initiated frequent coughing (53% vs. 0% sevoflurane) and body movements (47% vs. 0% sevoflurane). During emergence, there was a twofold greater incidence of coughing and a fivefold increase in breath holding in the desflurane group. CONCLUSIONS: When airway responses to sevoflurane and desflurane were compared in elective surgical patients breathing through an LMA, there were significantly more adverse responses with desflurane at 12% concentrations and during emergence.     

A new tool for measurement of process-based performance of multispecialty tertiary care hospitals

There is an increasing need of a model for the process-based performance measurement of multispecialty tertiary care hospitals for quality improvement. Analytic hierarchy process (AHP) is utilized in this study to evolve such a model. Each step in the model was derived by group-discussions and brainstorming sessions among experienced clinicians and managers. This tool was applied to two tertiary care teaching hospitals in Barbados and India. The model enabled identification of specific areas where neither hospital performed very well, and helped to suggest recommendations to improve those areas. AHP is recommended as a valuable tool to measure the process-based performance of multispecialty tertiary care hospitals.     

Incarceration and risk for HIV infection among injection drug users in Bangkok.

OBJECTIVE: To assess potential multiple relationships between incarceration and HIV infection among injecting drug users (IDUs) in Bangkok. Previous cross-sectional studies have shown strong relationships between incarceration and HIV infection but have not been able to assess potential causal pathways. METHODS: Injection drug users seen at methadone treatment programs in Bangkok were screened during 1995 to 1996 for enrollment into the study. With informed consent, 1,209 seronegative IDUs were enrolled in a cohort study to determine HIV incidence and identify factors associated with incident infections. Follow-up visits were conducted every 4 months, with HIV testing and assessment of risk behaviors. RESULTS: Overall incidence rate was 5.8 per 100 person-years (95% confidence interval [CI], 4.8-6.8) of follow-up. A four-step "injection risk" scale was constructed that included less frequent than daily injection, daily injection, daily injection with reported sharing of injection equipment, and injection while incarcerated. This scale was strongly related to HIV incidence, with incidence approximately doubling for each step in the scale. Incidence rate for follow-up periods that contained drug injection while incarcerated was 35/100 person-years at risk. In multivariate analyses, incarceration was related to incident HIV infection in multiple ways: previous incarceration and recent incarceration without drug injection, and the injection risk scale were all independently predictors of incident HIV infection. CONCLUSIONS: Incarceration is related to incident HIV infection through multiple pathways. Previous incarcerations are likely to serve as markers for unmeasured high-risk behaviors, and it is also highly likely that HIV is transmitted during periods of incarceration. Programs to reduce HIV transmission in jails and prisons, including drug abuse treatment of inmates and programs to reduce the likelihood of incarceration of IDUs, are needed urgently. Given the current diffusion of injecting drug use, of HIV infection among drug injectors, and of the common policy of incarcerating drug users, it is very likely that the problem of HIV transmission in jails and prisons is increasing in many countries throughout the world.     

The analysis of microarray data

This article describes issues, techniques and algorithms for analyzing data from microarray experiments. Each such experiment generates a large amount of data, only a fraction of which comprises significant differentially expressed genes. The precise identification of these interesting genes is heavily dependent not only on the statistical data analysis techniques used but also on the accuracy of the previous oligonucleotide probe design and image analysis steps as well. Indeed, wrong decisions in these steps can multiply the number of false positives by many-fold, thus necessitating a careful choice of algorithms in all three steps. These steps are described here and placed in the context of commercial and public tools available for the analysis of microarray data.     

Differential requirements for CTL generation by novel immunostimulants: APC tropism,use of the TAP-independent processing pathway,and dependency on CD80/CD86 costimulation

A major drawback of subunit vaccines is their inability to generate cytolytic T lymphocytes (CTL), a deficit attributed to segregation of the class I and class II antigen-processing pathways. We sought to understand processes involved in CTL induction by three proprietary adjuvants: Tomatine, PROVAX, and a synthesized glycolipid (Glc-N-(8/16), Glycolipid). We used in vivo models to investigate antigen uptake, macrophage involvement, TAP-independent processing, and costimulatory molecule dependencies. Glycolipid required splenic and lymph node macrophages, whereas Tomatine generated CTL independently of either macrophage population. In contrast, PROVAX showed partial macrophage requirements. Immunized TAP knockout mice revealed that ovalbumin (OVA)-Tomatine and OVA-PROVAX, but not OVA-Glycolipid, generate class I-peptide complexes. All three immunostimulants also elicited CD86-dependent TH1 cytokine responses.