Publications

The alveolar epithelium serves as a barrier to the entry of potential respiratory pathogens. Alveolar Type II (TII) cells have immunomodulatory functions, but whether Type I (TI) cells, which comprise approximately 95% of the alveolar epithelium, also play a role in immunity is unknown. Because the renin-angiotensin system (RAS) is emerging as an important mediator of inflammation, and angiotensin-converting enzyme 2 (ACE2), an element of the RAS, has been implicated in lung injury, we hypothesize that TI cells can produce cytokines in response to LPS stimulation, and that this inflammation can be modulated by the RAS. Alveolar TI cells were isolated from adult Sprague-Dawley rat lungs that had been injured with an intratracheal instillation of LPS. PCR was performed to determine whether TI cells expressed transcripts for TNF-α, IL-6, or IL-1β at baseline and after lung injury. Immunocytochemical and protein analysis detected angiotensin II (Ang II) and ACE2, as well as angiotensin Type 1 receptor (AT1R) and Type 2 receptor (AT2R), in TI cells. To separate cell-specific responses, primary TI cells were isolated, cultured, and exposed to LPS, Ang II, or specific inhibitors of AT1R or AT2R. Cytokine production was assayed by ELISA. LPS stimulated the production of all cytokines, whereas ACE2 and losartan, an AT1R inhibitor, blocked elements of the LPS-induced cytokine response. Primary TI cells produce cytokines when treated with LPS, contain important components of the RAS, and can modulate LPS-induced cytokine production via the RAS, suggesting a role for TI cells in the innate immune response of the lung.

BACKGROUND

Despite improvements in survival with human immunodeficiency virus (HIV) infection, kidney disease remains an important complication. Few studies have evaluated risk factors associated with the development of end-stage renal disease (ESRD) in HIV-infected individuals. We sought to identify traditional and HIV-related risk factors for ESRD in HIV-infected individuals and compare ESRD risk by estimated glomerular filtration rate (eGFR) and proteinuria levels.

STUDY DESIGN

Retrospective cohort study.

SETTING & PARTICIPANTS

22,156 HIV-infected veterans without pre-existing ESRD receiving health care in the Veterans' Affairs medical system between 1996 and 2004.

PREDICTORS

Hypertension, diabetes, cardiovascular disease, hypoalbuminemia (serum albumin <3.5 mg/dL), CD4 lymphocyte count, HIV viral load, hepatitis C virus coinfection, proteinuria, and eGFR were identified using the Veterans' Affairs electronic record system.

OUTCOMES

ESRD was ascertained by the US Renal Data System.

RESULTS

366 cases of ESRD occurred, corresponding to 3 cases/1,000 person-years. Hypertension (HR, 1.9; 95% CI, 1.5-2.4), diabetes (HR, 1.7; 95% CI, 1.3-2.2), and cardiovascular disease (HR, 2.2; 95% CI, 1.7-2.7) were associated independently with ESRD risk in multivariate-adjusted models, as were CD4 lymphocyte count <200 cells/μL (HR, 1.5; 95% CI, 1.2-2.0), HIV viral load ≥30,000 copies/mL (HR, 2.0; 95% CI, 1.5-2.8), hepatitis C virus coinfection (HR, 1.9; 95% CI, 1.5-2.4), and hypoalbuminemia (HR, 2.1; 95% CI, 1.8-2.5). Compared with persons without chronic kidney disease, defined as eGFR >60 mL/min/1.73 m(2) and no proteinuria, lower eGFR and higher proteinuria categories were associated jointly with exponentially higher ESRD rates, ranging from 6.6 events/1,000 person-years for persons with urine protein excretion of 30-100 mg/dL and eGFR >60 mL/min/1.73 m(2) to 193 events/1,000 person-years for persons with urine protein excretion ≥300 mg/dL and eGFR <30 mL/min/1.73 m(2).

LIMITATIONS

Results may not be generalizable to female and nonveteran populations.

CONCLUSIONS

In HIV-infected persons, ESRD risk appears attributable to a combination of traditional and HIV-related risk factors for kidney disease. Combining eGFR and proteinuria for chronic kidney disease staging is most effective for stratifying the risk of ESRD.

OBJECTIVE

Colonoscopy may fail to prevent colorectal cancer, especially in the proximal colon and in women. Nonpolypoid colorectal neoplasms may potentially explain some of these post-colonoscopy cancers. In the present study, we aimed to examine the prevalence and malignant potential of nonpolypoid colorectal neoplasms in a large population, with special attention to gender and location.

METHODS

We performed a cross-sectional study of all consecutive patients undergoing elective colonoscopy at a single academic medical center. The endoscopists were familiarized on the detection and treatment of nonpolypoid lesions. Advanced histology was defined by the presence of high-grade dysplasia or early cancer.

RESULTS

We included 2310 patients (53.9% women, mean age 58.4 years) with 2143 colorectal polyps. Prevalences of colorectal neoplasms and nonpolypoid colorectal neoplasms were lower in women than in men (20.9% vs. 33.7%, p < 0.001 and 3.0% vs. 5.5%, p = 0.002). In women, nonpolypoid colorectal neoplasms were significantly more likely to contain advanced histology than polypoid ones (OR 2.89, 95% CI 1.24-6.74, p = 0.01), while this was not the case in men (OR 0.91, 95% CI 0.40-2.06, p = 0.83). Proximal neoplasms with advanced histology were more likely to be nonpolypoid than distal ones (OR 4.68, 95% CI 1.54-14.2, p = 0.006).

CONCLUSION

Nonpolypoid mechanisms may play an important role in colorectal carcinogenesis, in both women and men. Although women have fewer colorectal neoplasms than men, they have nonpolypoid colorectal neoplasms, which frequently contain advanced histology.