Risk factors for retransplant kidney recipients: relisting and outcomes from patients' primary transplant.

As of November 2013, 14.5% of the waitlist for a donor kidney comprised patients awaiting a retransplant. We performed a retrospective cohort study of 11,698 adult solitary kidney recipients using national Scientific Registry of Transplant Recipients data transplanted between 2002 and 2011. The aim was to investigate whether outcomes from patients' initial transplants are significant risk factors for patients' repeat transplants or for likelihood of relisting after a failed primary transplant. Retransplant recipients were more likely to be treated for acute rejection [adjusted odds ratio (AOR), 95% confidence interval (CI) = 1.26 (1.07-1.48), p = 0.0053] or hospitalized (AOR = 1.19, 95% CI 1.08-1.31, p = 0.0005) within a year of retransplantation if these outcomes were experienced within a year of primary transplant. Delayed graft function following primary transplants was associated with 35% increased likelihood of recurrence (AOR = 1.35, 95% CI = 1.18-1.54, p < 0.0001). An increase in 1-year GFR after primary transplant was associated with GFR 1 year postretransplant (ß = 6.82, p < 0.0001), and retransplant graft failure was inversely associated with 1-year primary transplant GFR (adjusted hazard ratio = 0.74, 95% CI = 0.71-0.76 per 10 mL/min/1.73 m(2) ). A decreased likelihood for relisting was associated with hospitalization and higher GFR following primary transplantation. The increasing numbers of individuals requiring retransplants highlights the importance of incorporating prior transplant outcomes data to better inform relisting decisions and prognosticating retransplant outcomes.

Prominent impact of community risk factors on kidney transplant candidate processes and outcomes.

Numerous factors impact patients' health beyond traditional clinical characteristics. We evaluated the association of risk factors in kidney transplant patients' communities with outcomes prior to transplantation. The primary exposure variable was a community risk score (range 0-40) derived from multiple databases and defined by factors including prevalence of comorbidities, access and quality of healthcare, self-reported physical and mental health and socioeconomic status for each U.S. county. We merged data with the Scientific Registry of Transplant Recipients (SRTR) and utilized risk-adjusted models to evaluate effects of community risk for adult candidates listed 2004-2010 (n = 209 198). Patients in highest risk communities were associated with increased mortality (adjusted hazard ratio [AHR] = 1.22, 1.16-1.28), decreased likelihood of living donor transplantation (adjusted odds ratio [AOR] = 0.90, 0.85-0.94), increased waitlist removal for health deterioration (AHR = 1.36, 1.22-1.51), decreased likelihood of preemptive listing (AOR = 0.85, 0.81-0.88), increased likelihood of inactive listing (AOR = 1.49, 1.43-1.55) and increased likelihood of listing for expanded criteria donor kidneys (AHR = 1.19, 1.15-1.24). Associations persisted with adjustment for rural-urban location; furthermore the independent effects of rural-urban location were largely eliminated with adjustment for community risk. Average community risk varied widely by region and transplant center (median = 21, range 5-37). Community risks are powerful factors associated with processes of care and outcomes for transplant candidates and may be important considerations for developing effective interventions and measuring quality of care of transplant centers.

The prognostic value of kidney transplant center report cards.

SRTR report cards provide the basis for quality measurement of US transplant centers. There is limited data evaluating the prognostic value of report cards, informing whether they are predictive of prospective patient outcomes. Using national SRTR data, we simulated report cards and calculated standardized mortality ratios (SMR) for kidney transplant centers over five distinct eras. We ranked centers based on SMR and evaluated outcomes for patients transplanted the year following reports. Recipients transplanted at the 50th, 100th and 200th ranked centers had 18% (AHR = 1.18, 1.13-1.22), 38% (AHR = 1.38, 1.28-1.49) and 91% (AHR = 1.91, 1.64-2.21) increased hazard for 1-year mortality relative to recipients at the top-ranked center. Risks were attenuated but remained significant for long-term outcomes. Patients transplanted at centers meeting low-performance criteria in the prior period had 40% (AHR = 1.40, 1.22-1.68) elevated hazard for 1-year mortality in the prospective period. Centers' SMR from the report card was highly predictive (c-statistics > 0.77) for prospective center SMRs and there was significant correlation between centers' SMR from the report card period and the year following (ρ = 0.57, p < 0.001). Although results do not mitigate potential biases of report cards for measuring quality, they do indicate strong prognostic value for future outcomes. Findings also highlight that outcomes are associated with center ranking across a continuum rather than solely at performance margins.

The impact of deceased donor kidney risk significantly varies by recipient characteristics.

As of May 2012, over 92 000 patients were awaiting a solitary kidney transplant in the United States and new waitlist registrations have been rising for over a decade. The decreasing availability of donor organs makes it imperative that organ allocation be as efficient and effective as possible. We performed a retrospective cohort study of adult recipients in the United States (n=109 392) using Scientific Registry of Transplant Recipients data. The primary aim was to evaluate the interaction of donor risk with recipient characteristics on posttransplant outcomes. Donor quality (based on kidney donor risk index [KDRI]) had significant interactions by race, primary diagnosis and age. The hazard of KDRI on overall graft loss in non-African Americans was 2.16 (95%CI 2.08-2.25) versus 1.85 (95%CI 1.75-1.95) in African Americans (p<0.0001), 2.16 (95%CI 2.08-2.24) in nondiabetics versus 1.84 (95%CI 1.74-1.94) in diabetics (p<0.0001), and 2.22 (95%CI 2.13-2.32) in recipients<60 years versus 1.83 (95%CI 1.74-1.92) in recipients≥60 (p<0.0001). The relative hazard for diabetics at KDRI=0.5 was 1.49 but at KDRI=2.0 the hazard was significantly attenuated to 1.17; among African Americans the respective risks were 1.50 and 1.17 and among recipients 60 and over, it was between 1.64 and 1.22. These findings are critical considerations for informed decision-making for transplant candidates.

Reduced DNA-dependent protein kinase activity is associated with lung cancer.

Reduced DNA repair capacity of carcinogen-induced DNA damage is now thought to significantly influence inherent susceptibility to lung cancer. DNA-dependent protein kinase (DNA-PK) is a serine-threonine kinase activated by the presence of double-strand breaks in DNA that appears to play a major role in non-homologous recombination and transcriptional control. The purpose of this study was to determine whether DNA-PK activity varies among individuals and how this affects lung cancer risk. DNA-PK activity in peripheral mononuclear cells from individuals with lung cancer (n = 41) was compared with lung cancer-free controls (n = 41). Interindividual variability was seen within each group, however, significant differences (P = 0.03) in DNA-PK activity between cases and controls were seen when comparing the distribution of enzyme activity among these two groups. The percentages of cases and controls with DNA-PK activity in the ranges 2.5-5.0 and 7.6-10.0 units were 39 versus 20% and 7 versus 29%, respectively. The enzyme activity in peripheral mononuclear cells reflected that seen in bronchial epithelial cells, one progenitor cell for lung cancer, supporting the use of peripheral mononuclear cells for larger population-based studies of DNA-PK activity. Its role as a potential modifier for lung cancer risk was supported by the fact that cell growth in bronchial epithelial cells exposed to bleomycin was directly associated with enzyme activity. The results of this study demonstrate that reduced DNA-PK repair activity is associated with risk for lung cancer.

Frequency of trisomy 20 in nonmalignant bronchial epithelium from lung cancer patients and cancer-free former uranium miners and smokers.

Lung cancer is the leading cause of cancer-related deaths. The development of sensitive screening methods to identify at-risk individuals before emergence of clinical disease would permit early intervention that could decrease this mortality. Our previous studies have shown that cells with trisomy 7 can be detected in bronchial epithelium from cancer-free smokers and former uranium miners. However, the use of more than one molecular marker could increase the chance of identifying at-risk individuals. Trisomy 20, which is found in 43-57% of non-small cell lung cancers, is a candidate marker. The purpose of the current investigation was to determine the percentage of cells with trisomy 20 in persons with a high risk for lung cancer. Bronchial epithelial cells that had been assayed for trisomy 7 were assayed for trisomy 20 by fluorescence in situ hybridization. Trisomy 20 was detected in bronchial epithelial cells from lung cancer patients and from smokers and ex-uranium miners without lung cancer. In some cases, patients who were negative for trisomy 7 exhibited trisomy 20. Consequently, more people with field cancerization were identified using both markers. However, the two markers combined did not appear to stratify the risk for lung cancer.

Detection of trisomy 7 in nonmalignant bronchial epithelium from lung cancer patients and individuals at risk for lung cancer.

Early identification and subsequent intervention are needed to decrease the high mortality rate associated with lung cancer. The examination of bronchial epithelium for genetic changes could be a valuable approach to identify individuals at greatest risk. The purpose of this investigation was to assay cells recovered from nonmalignant bronchial epithelium by fluorescence in situ hybridization for trisomy of chromosome 7, an alteration common in non-small cell lung cancer. Bronchial epithelium was collected during bronchoscopy from 16 cigarette smokers undergoing clinical evaluation for possible lung cancer and from seven individuals with a prior history of underground uranium mining. Normal bronchial epithelium was obtained from individuals without a prior history of smoking (never smokers). Bronchial cells were collected from a segmental bronchus in up to four different lung lobes for cytology and tissue culture. Twelve of 16 smokers were diagnosed with lung cancer. Cytological changes found in bronchial epithelium included squamous metaplasia, hyperplasia, and atypical glandular cells. These changes were present in 33, 12, and 47% of sites from lung cancer patients, smokers, and former uranium miners, respectively. Less than 10% of cells recovered from the diagnostic brush had cytological changes, and in several cases, these changes were present within different lobes from the same patient. Background frequencies for trisomy 7 were 1.4 +/- 0.3% in bronchial epithelial cells from never smokers. Eighteen of 42 bronchial sites from lung cancer patients showed significantly elevated frequencies of trisomy 7 compared to never smoker controls. Six of the sites positive for trisomy 7 also contained cytological abnormalities. Trisomy 7 was found in six of seven patients diagnosed with squamous cell carcinoma, one of one patient with adenosquamous cell carcinoma, but in only one of four patients with adenocarcinoma. A significant increase in trisomy 7 frequency was detected in cytologically normal bronchial epithelium collected from four sites in one cancer-free smoker, whereas epithelium from the other smokers did not contain this chromosome abnormality. Finally, trisomy 7 was observed in almost half of the former uranium miners; three of seven sites positive for trisomy 7 also exhibited hyperplasia. Two of the former uranium miners who were positive for trisomy 7 developed squamous cell carcinoma 2 years after collection of bronchial cells. To determine whether the increased frequency of trisomy 7 reflects generalized aneuploidy or specific chromosomal duplication, a subgroup of samples was evaluated for trisomy of chromosome 2; the frequency was not elevated in any of the cases as compared with controls. The studies described in this report are the first to detect and quantify the presence of trisomy 7 in subjects at risk for lung cancer. These results also demonstrate the ability to detect genetic changes in cytologically normal cells, suggesting that molecular analyses may enhance the power for detecting premalignant changes in bronchial epithelium in high-risk individuals.

Hyperoxic suppression of Fc-gamma receptor-mediated phagocytosis by isolated murine pulmonary macrophages.

Lower respiratory tract exposure to high oxygen (O2) concentrations is known to induce changes in pulmonary function through effects on several cell types located within the lung parenchyma, including pulmonary macrophages (PM). We studied the effects of hyperoxic exposure on phagocytosis via Fc-gamma receptors (FcR) on isolated murine PM. PM cultured in hyperoxic conditions exhibited little change in ingestion via FcR for up to 96 h, compared with significant increases in ingestion by PM cultured in 21% O2 over the same time period. This suppression was reversible and occurred whether 50 or 100% O2 concentrations were used for hyperoxic exposure. Addition of the potent macrophage-activating agent interferon-gamma (IFN-gamma) to cultured PM further increased FcR-mediated phagocytosis in normoxic PM but had no effect on PM cultured in 100% O2. Analysis of FcR expression by flow cytometry using monoclonal antibodies specific for two different FcR classes revealed that culture in normoxic conditions increased surface expression of both FcR classes. Hyperoxic culture inhibited up-regulation of the high-affinity FcR but did not affect low-affinity FcR up-regulation, suggesting that hyperoxic effects were not due solely to effects on regulation of FcR expression. However, hyperoxic exposure completely suppressed FcR-mediated actin polymerization. These findings suggest that hyperoxic exposure impairs PM ability to increase FcR-mediated phagocytic activity after appropriate stimulation, which could impair the lung's defenses against infection.

Alveolar and interstitial macrophage populations in the murine lung.

Pulmonary macrophages (PM) exist in two general anatomical compartments in the lower respiratory tract: the alveolar space (alveolar macrophages, AM) and the interstitium (interstitial macrophages, IM). We determined the relative contribution that macrophages in each of these compartments make to the size of the total PM population found in the lungs of C3H/OUJ mice, while also evaluating how efficiently bronchoalveolar lavage (BAL) removes AM from the murine lung. These objectives were accomplished by combining extensive BAL with subsequent mechanical and enzymatic dissociation of the lungs in conjunction with in situ and in vitro phagocytic assays involving opsonized erythrocytes (EA) to identify mononuclear phagocytes. On average, 2.5 x 10(6) cells were recovered by extensive BAL, and approximately 78% of these cells ingested EA in vitro. To determine the efficiency of BAL in removing PM from the alveolar space, EA were instilled intratracheally into intact lungs, which had been removed from the chest cavity, and allowed to incubate for 60 min; this was followed by exhaustive BAL and subsequent lung digestion. After these procedures, approximately 4% of the dissociated lung cells contained EA, indicating that these cells were alveolar in origin but had not been removed despite extensive BAL. Subtraction of these AM from the total EA+ cells in lung cell suspensions following a second in vitro incubation with EA indicated that approximately 37% of all PM were within the interstitium. These results suggest that, while AM comprise the majority of lung macrophages, IM constitute a larger component of the total PM population in murine lungs than previously reported. In addition, this study, like several previous investigations using other species, indicates that a significant proportion of AM remain in the lung despite attempts to remove them with BAL. Accordingly, residual AM significantly contaminate the IM population present in murine lung cell suspensions even after extensive lavage.

C-reactive protein receptors on the human monocytic cell line U-937. Evidence for additional binding to Fc gamma RI.

C-reactive protein (CRP) is an acute-phase protein that binds to components of damage tissue, activates C, and stimulates phagocytic cells. CRP binding to receptors on monocytic and polymorphonuclear phagocytes has been shown. Recently, CRP-binding proteins of 38 to 40 kDa and 57 to 60 kDa have been identified on the human promonocyte cell line U-937 and the mouse macrophage cell line PU5 1.8, respectively. However, analysis of CRP binding to these cells and to peripheral blood leukocytes suggests that additional CRP receptor sites may be present. Because many studies have shown interactions between CRP binding and IgG binding to leukocytes, we have examined further the CRP binding sites on U-937 cells and determined their relationship to the FcR for IgG (Fc gamma R) expressed on these cells. Our results demonstrate specific saturable binding of CRP to peripheral blood monocytes and U-937 cells, which is readily inhibited by aggregated IgG. Monomeric IgG, which binds specifically to Fc gamma RI, inhibited a maximum of 20% of CRP binding to these cells. mAb 197 and mAb IV.3, which block IgG binding to Fc gamma RI and Fc gamma RII, respectively, failed to inhibit CRP binding to U-937 cells. Two CRP-binding molecules were identified by precipitation of lysates from surface-labeled U-937 cells and cross-linking experiments. One of these had a molecular mass of 43 to 45 kDa, similar to the molecule previously described as the CRPR on U-937 cells. The other had the same mobility by SDS-PAGE as Fc gamma RI. The identity of this protein with Fc gamma RI was confirmed by the ability of both IgG-Sepharose and CRP-Sepharose to preclear the protein from cell lysates and by inhibition of binding to both IgG-Sepharose and CRP-Sepharose by anti-Fc gamma RI mAb 197.