Research Spotlight

de Albuquerque Rocha, N., I. J. Neeland, P. A. McCullough, R. D. Toto and D. K. McGuire (2018). “Effects of sodium glucose co-transporter 2 inhibitors on the kidney.” Diab Vasc Dis Res 15(5): 375-386.

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Sodium-glucose cotransporter 2 inhibitors are antihyperglycaemic medications with an emerging evidence base for cardiovascular and kidney disease risk reduction. Sodium-glucose cotransporter 2 inhibitors medications lower plasma glucose by inhibiting glucose reabsorption in the proximal tubule of the kidney independent of insulin. Furthermore, they reduce intraglomerular pressure by restoring tubuloglomerular feedback. Large cardiovascular outcome trials of both empagliflozin and canagliflozin have consistently shown beneficial kidney effects that go beyond glycaemic control, such as reducing risk for incident nephropathy and progression of chronic kidney disease. The mechanisms by which sodium-glucose cotransporter 2 inhibitors improve kidney outcomes are not clear. Proposed hypotheses underpinning the kidney benefits include kidney-specific effects such as decreased intraglomerular pressure, activation of angiotensin-(1-7) and the Mas receptor leading to decreased inflammation, decrease in overall kidney oxygen consumption, rise in erythropoietin levels, inhibition of the renal sodium-hydrogen exchanger and secondary kidney effects related to improvements in HbA1c and blood pressure. This review will focus on describing the mechanisms of action of sodium-glucose cotransporter 2 inhibitors in the kidney, clinical efficacy data on their use in patients with chronic kidney disease, postulated physiologic underpinnings of kidney protection observed with sodium-glucose cotransporter 2 inhibitors and the promise and potential pitfalls for their use in patients with chronic kidney disease.

Crews, D. C. and D. E. Wesson (2018). “Persistent Bias: A Threat to Diversity among Health Care Leaders.” Clin J Am Soc Nephrol. Aug 7. [Epub ahead of print].

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Racial/ethnic disparities in primary and nephrology specialty care contribute to marked disparities in CKD in the United States. Eliminating these disparities and thereby improving United States health and its delivery requires ongoing, sustained efforts from leadership of the broad spectrum of health care organizations, including academic centers and those whose primary focus is clinical care delivery. Racial/ethnic diversity among health care leaders galvanizes leadership toward eliminating these disparities, but the current level of diversity in leadership falls short of that necessary critical mass. This lack of diversity persists despite decades of efforts to correct it and obliges the health care community to consider remaining challenges hindering the necessary attainment of this goal. A seldom-acknowledged challenge is the persistence of bias in the United States health care system, including in its organizations. (Introduction from text, p. 1; no abstract available.)

Chiruvolu, A., Y. Daoud and R. W. Inzer (2018). “Effect of delayed cord clamping on very preterm twins.” Early Hum Dev 124: 22-25.

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BACKGROUND: The very preterm infants of twin births may particularly benefit from delayed cord clamping (DCC) as the likelihood of unfavorable outcome is greater compared to singletons. Unfortunately, there is paucity of available information regarding safety and efficacy of DCC in this group. OBJECTIVE: To report the clinical consequences of delayed cord clamping (DCC) in very preterm twins, born between 23(0/7) and 31(6/7) weeks gestation. STUDY DESIGN: In this pre and post intervention retrospective cohort study, we compared 30 very preterm infants born from 15 twin deliveries during historic study period to 32 very preterm infants born from 16 twin deliveries during DCC study period. During historic study period (August 19, 2013 to January 31, 2015), infants included were eligible to receive DCC, but their cords were immediately clamped. DCC study period (February 1, 2015 to January 31, 2017) included infants who had DCC performed for 60s after birth. RESULTS: The Apgar scores and other resuscitation variables were similar between both groups. After adjusting for gestational age and mode of delivery, significantly fewer infants in the DCC cohort needed red blood cell (RBC) transfusions in first week of life compared to the historic cohort (15.6% vs. 43.3%; P=0.03). Death and other major neonatal outcomes were similar between both groups. CONCLUSION: DCC in very preterm twins was safe, feasible and not associated with any adverse neonatal outcomes compared to early cord clamping. DCC was associated with a significant reduction in early RBC transfusions.

Cheng, L., Q. Wang, G. Li, R. Banga, J. Ma, H. Yu, F. Yasui, Z. Zhang, G. Pantaleo, M. Perreau, S. Zurawski, G. Zurawski, Y. Levy and L. Su (2018). “TLR3 agonist and CD40-targeting vaccination induces immune responses and reduces HIV-1 reservoirs.” J Clin Invest. Aug 27. [Epub ahead of print].

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Activation of HIV-1 reservoirs and induction of anti-HIV-1 T cells are critical to control HIV-1 rebound after combined antiretroviral therapy (cART). Here we evaluated in humanized mice (hu-mice) with persistent HIV-1 infection the therapeutic effect of TLR3 agonist and a CD40-targeting HIV-1 vaccine, which consists of a string of 5 highly conserved CD4+ and CD8+ T cell epitope-rich regions of HIV-1 Gag, Nef, and Pol fused to the C-terminus of a recombinant anti-human CD40 antibody (alphaCD40.HIV5pep). We show that alphaCD40.HIV5pep vaccination coadministered with poly(I:C) adjuvant induced HIV-1-specific human CD8+ and CD4+ T cell responses in hu-mice. Interestingly, poly(I:C) treatment also reactivated HIV-1 reservoirs. When administrated in therapeutic settings in HIV-1-infected hu-mice under effective cART, alphaCD40.HIV5pep with poly(I:C) vaccination induced HIV-1-specific CD8+ T cells and reduced the level of cell-associated HIV-1 DNA (or HIV-1 reservoirs) in lymphoid tissues. Most strikingly, the vaccination significantly delayed HIV-1 rebound after cART cessation. In summary, the alphaCD40.HIV5pep with poly(I:C) vaccination approach both activates replication of HIV-1 reservoirs and enhances the anti-HIV-1 T cell response, leading to a reduced level of cell-associated HIV-1 DNA or reservoirs. Our proof-of-concept study has significant implication for the development of CD40-targeting HIV-1 vaccine to enhance anti-HIV-1 immunity and reduce HIV-1 reservoirs in patients with suppressive cART.

Chang, C. A., K. Murphy, R. R. Kane, M. C. Lawrence and B. Naziruddin (2018). “Early TLR4 Blockade Attenuates Sterile Inflammation-mediated Stress in Islets During Isolation and Promotes Successful Transplant Outcomes.” Transplantation 102(9): 1505-1513.

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BACKGROUND: During the isolation process, pancreatic islets are exposed to an environment of sterile inflammation resulting in an upregulated inflammatory state before transplantation. Toll-like receptor 4 (TLR4) has been identified as a major mediator of sterile inflammation. Therefore, we sought to determine whether early TLR4 blockade would be effective in reducing the inflammatory burden in islets pretransplant. METHODS: Islets from C57BL/6 mice were treated with a TLR4 antagonist during the pancreatic ductal perfusion and digestion steps of the isolation process. Islets were then analyzed for inflammation by RT-PCR and Western blot, and for viability and function in vitro. A syngeneic transplant model using a marginal mass of islets transplanted intraportally into mice with streptozotocin-induced diabetes was used to study transplant outcomes after early TLR4 blockade. RESULTS: Diabetic mice receiving 150 islets treated with early TLR4 blockade achieved euglycemia at a higher rate than mice receiving untreated islets (75% vs 29%; P < 0.05) and had improved long-term function (P < 0.05). Serum markers for islet damage and inflammation were significantly reduced posttransplant (P < 0.05). Both the expression of key inflammatory genes and the activation of mitogen-activated protein kinases were reduced by early TLR4 blockade. Islet viability was improved (P < 0.05) while preserving islet insulin secretory capacity postisolation. CONCLUSIONS: Early TLR4 blockade protects islets from sterile inflammation-mediated stress sustained during isolation and promotes positive transplant outcomes. Our findings support the use of early TLR4 blockade during clinical islet isolation procedures to reduce pretransplant inflammation and improve transplant outcomes.