Publications

Although invasive cytomegalovirus (CMV) disease is uncommon in the era of antiretroviral therapy (ART), asymptomatic CMV coinfection is nearly ubiquitous in HIV infected individuals. While microbial translocation and gut epithelial barrier dysfunction may promote persistent immune activation in treated HIV infection, potentially contributing to morbidity and mortality, it has been unclear whether CMV replication in individuals with no symptoms of CMV disease might play a role in this process. We hypothesized that persistent CMV replication in the intestinal epithelium of HIV/CMV-coinfected individuals impairs gut epithelial barrier function. Using a combination of state-of-the-art in situ hybridization technology (RNAscope) and immunohistochemistry, we detected CMV DNA and proteins and evidence of intestinal damage in rectosigmoid samples from CMV-positive individuals with both untreated and ART-suppressed HIV infection. Two different model systems, primary human intestinal cells differentiated in vitro to form polarized monolayers and a humanized mouse model of human gut, together demonstrated that intestinal epithelial cells are fully permissive to CMV replication. Independent of HIV, CMV disrupted tight junctions of polarized intestinal cells, significantly reducing transepithelial electrical resistance, a measure of monolayer integrity, and enhancing transepithelial permeability. The effect of CMV infection on the intestinal epithelium is mediated, at least in part, by the CMV-induced proinflammatory cytokine IL-6. Furthermore, letermovir, a novel anti-CMV drug, dampened the effects of CMV on the epithelium. Together, our data strongly suggest that CMV can disrupt epithelial junctions, leading to bacterial translocation and chronic inflammation in the gut and that CMV could serve as a target for therapeutic intervention to prevent or treat gut epithelial barrier dysfunction during HIV infection.

Aortic valve stenosis occurs 10-20 years earlier in patients on dialysis compared with the general population. This is likely related to the exposure of the valve to a milieu that predisposes to calcification as well as increased shear stress across the valve. Objective assessment of stenosis severity is largely made using echocardiography though accurate interpretation requires an understanding of the potential pitfalls of the technique and the influence of cardiac output upon the gradient measured across the valve. Timing of valve replacement in severe aortic stenosis is predominantly guided by exercise-induced symptoms (breathlessness, chest pain and [pre] syncope), which are often difficult to assess in the dialysis population who may have limited exercise capacity and symptoms due to renal failure and other comorbidities. Finally, treatment of aortic stenosis remains a constantly evolving area with advances in both conventional surgery and percutaneous techniques.

BACKGROUND

Despite a growing body of literature suggesting that dialysis does not confer morbidity or mortality benefits for all patients with chronic kidney failure, the initiation and continuation of dialysis therapy in patients with poor prognosis is commonplace. Our goal was to elicit nephrologists' perspectives on factors that affect decision making regarding end-stage renal disease.

STUDY DESIGN

Semistructured, individual, qualitative interviews.

METHODOLOGY

Participants were purposively sampled based on age, race, sex, geographic location, and practice type. Each was asked about his or her perspectives and experiences related to foregoing and withdrawing dialysis therapy.

ANALYTICAL APPROACH

Interviews were audiotaped, transcribed, and analyzed using narrative and thematic analysis.

RESULTS

We conducted 59 semistructured interviews with nephrologists from the United States (n=41) and England (n=18). Most participants were 45 years or younger, men, and white. Average time since completing nephrology training was 14.2±11.6 (SD) years. Identified system-level facilitators and barriers for foregoing and withdrawing dialysis therapy stemmed from national and institutional policies and structural factors, how providers practice medicine (the culture of medicine), and beliefs and behaviors of the public (societal culture). In both countries, the predominant barriers described included lack of training in end-of-life conversations and expectations for aggressive care among non-nephrologists and the general public. Primary differences included financial incentives to dialyze in the United States and widespread outpatient conservative management programs in England.

LIMITATIONS

Participants' views may not fully capture those of all American or English nephrologists.

CONCLUSIONS

Nephrologists in the United States and England identified several system-level factors that both facilitated and interfered with decision making around foregoing and withdrawing dialysis therapy. Efforts to expand facilitators while reducing barriers could lead to care practices more in keeping with patient prognosis.