Iatrogenic Fistula in Hemodialysis Patients: An Alternative Approach to Thrombectomy of Arteriovenous Graft (AVG) Thrombosis.

Arterial venous (AV) fistula is the first choice of vascular access to perform hemodialysis in the vast majority of suitable patients followed by arteriovenous grafts (AVG). An iatrogenic fistula can occur when a second vein adjacent to the graft is punctured and the needle traverses the vein. In normal circumstances, this has no clinical repercussions and does not need correction, and in prior reports, it has helped to maintain the patency of partially occluded grafts but rarely can lead to thrombosis of the graft due to reduced flow and pressure in the graft lumen. We report here what we believe is a unique approach to perform thrombectomy of an occluded graft in a 71-year-old patient on hemodialysis to avoid placement of tunneled hemodialysis catheters and complications associated with catheters. When the outflow of basilic vein in this patient was thrombosed and could not be traversed, we successfully used an iatrogenic fistula as main outflow vein for the graft and created an alternative vein for drainage thus avoiding placement of a tunneled catheter for hemodialysis.

Combination Treatment with Sodium Nitrite and Isoquercetin on Endothelial Dysfunction among Patients with CKD: A Randomized Phase 2 Pilot Trial.

BACKGROUND AND OBJECTIVES: Endothelial dysfunction is common among patients with CKD. We tested the efficacy and safety of combination treatment with sodium nitrite and isoquercetin on biomarkers of endothelial dysfunction in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This randomized, double-blind, placebo-controlled phase 2 pilot trial enrolled 70 patients with predialysis CKD. Thirty-five were randomly assigned to combination treatment with sodium nitrite (40 mg twice daily) and isoquercetin (225 mg once daily) for 12 weeks, and 35 were randomly assigned to placebo. The primary outcome was mean change in flow-mediated vasodilation over the 12-week intervention. Secondary and safety outcomes included biomarkers of endothelial dysfunction, inflammation, and oxidative stress as well as kidney function, methemoglobin, and adverse events. Intention-to-treat analysis was conducted. RESULTS: Baseline characteristics, including age, sex, race, cigarette smoking, history of hypertension and diabetes, use of renin-angiotensin system blockers, BP, fasting glucose, lipid profile, kidney function, urine albumin-creatinine ratio, and endothelial biomarkers, were comparable between groups. Over the 12-week intervention, flow-mediated vasodilation increased 1.1% (95% confidence interval, -0.1 to 2.3) in the treatment group and 0.3% (95% confidence interval, -0.9 to 1.5) in the placebo group, and net change was 0.8% (95% confidence interval, -0.9 to 2.5). In addition, changes in biomarkers of endothelial dysfunction (vascular adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, vWf, endostatin, and asymmetric dimethylarginine), inflammation (TNF-α, IL-6, C-reactive protein, IL-1 receptor antagonist, and monocyte chemoattractant protein-1), and oxidative stress (oxidized LDL and nitrotyrosines) were not significantly different between the two groups. Furthermore, changes in eGFR, urine albumin-creatinine ratio, methemoglobin, and adverse events were not significantly different between groups. CONCLUSIONS: This randomized phase 2 pilot trial suggests that combination treatment with sodium nitrite and isoquercetin did not significantly improve flow-mediated vasodilation or other endothelial function biomarkers but also did not increase adverse events compared with placebo among patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Nitrite, Isoquercetin, and Endothelial Dysfunction (NICE), NCT02552888.

Acute Kidney Injury Associated with Coronavirus Disease 2019 in Urban New Orleans.

Background: AKI is a manifestation of COVID-19 (CoV-AKI). However, there is paucity of data from the United States, particularly from a predominantly black population. We report the phenotype and outcomes of AKI at an academic hospital in New Orleans. Methods: We conducted an observational study in patients hospitalized at Ochsner Medical Center over a 1-month period with COVID-19 and diagnosis of AKI (KDIGO). We examined the rates of RRT and in-hospital mortality as outcome measures. Results: Among 575 admissions (70% black) with COVID-19 [173 (30%) to an intensive care unit (ICU)], we found 161 (28%) cases of AKI (61% ICU and 14% general ward admissions). Patients were predominantly men (62%) and hypertensive (83%). Median body mass index (BMI) was higher among those with AKI (34 versus 31 kg/m2, P<0.0001). AKI over preexisting CKD occurred in 35%. Median follow-up was 25 (1-45) days. The in-hospital mortality rate for the AKI cohort was 50%. Vasopressors and/or mechanical ventilation were required in 105 (65%) of those with AKI. RRT was required in 89 (55%) patients. Those with AKI requiring RRT (AKI-RRT) had higher median BMI (35 versus 33 kg/m2, P=0.05) and younger age (61 versus 68, P=0.0003). Initial values of ferritin, C-reactive protein, procalcitonin, and lactate dehydrogenase were higher among those with AKI; and among them, values were higher for those with AKI-RRT. Ischemic acute tubular injury (ATI) and rhabdomyolysis accounted for 66% and 7% of causes, respectively. In 13%, no obvious cause of AKI was identified aside from COVID-19 diagnosis. Conclusions: CoV-AKI is associated with high rates of RRT and death. Higher BMI and inflammatory marker levels are associated with AKI as well as with AKI-RRT. Hemodynamic instability leading to ischemic ATI is the predominant cause of AKI in this setting.

Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis.

RATIONALE: Systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) portends worse outcome than other forms of PAH. Vasoconstrictive and vascular remodeling actions of endothelin (ET) 1 and angiotensin (Ang) II via endothelin receptor type A (ETAR) and Ang receptor type-1 (AT1R) activation are implicated in PAH pathogenesis. OBJECTIVES: We hypothesized that stimulating autoantibodies (Abs) targeting and activating AT1R and ETAR may contribute to SSc-PAH pathogenesis, and tested their functional and biomarker relevance. METHODS: Anti-AT1R and -ETAR Abs were detected by ELISA in different cohorts of patients and tested in vitro and in an animal model for their pathophysiological effects. MEASUREMENTS AND MAIN RESULTS: The Abs were significantly higher and more prevalent in patients with SSc-PAH (n = 81) and connective tissue disease-associated PAH (n = 110) compared with other forms of PAH/pulmonary hypertension (n = 106). High anti-AT1R and anti-ETAR Abs predicted development of SSc-PAH and SSc-PAH-related mortality in a prospective analysis. Both Abs increased endothelial cytosolic Ca(2+) concentrations in isolated perfused rat lungs, which could be blocked by respective specific receptor antagonists. Ab-mediated stimulation of intralobar pulmonary rat artery ring segments increased vasoconstrictive responses to Ang II and ET-1, and implicated cross-talk between both pathways demonstrated by reciprocal blockade with respective antagonists. Transfer of SSc-IgG containing both autoantibodies into healthy C57BL/6J mice led to more abundant vascular and airway α-smooth muscle actin expression and inflammatory pulmonary vasculopathy. CONCLUSIONS: Anti-AT1R and -ETAR Abs are more frequent in SSc-PAH/connective tissue disease-PAH compared with other forms of pulmonary hypertension, and serve as predictive and prognostic biomarkers in SSc-PAH. Both antibodies may contribute to SSc-PAH via increased vascular endothelial reactivity and induction of pulmonary vasculopathy.

Successful transplantation of HIV patients: the Louisiana experience.

Human immunodeficiency virus (HIV) seropositivity has historically been an absolute contraindication for solid organ transplantation. However, the successful application of HAART (highly active anti-retroviral therapy) drug regimens has greatly prolonged the life expectancy of HIV-positive patients. Therefore, it has become appropriate to consider this patient population for transplantation. HIV positive transplants are being performed around the country in controlled settings, usually as part of a research protocol. The aim of our study is to describe the Louisiana experience with organ transplantation into HIV-positive patients. We identified seven HIV-positive patients who underwent kidney or kidney/pancreas transplantation at our center between 2007 and 2010. We performed a retrospective chart review to ascertain graft function, as well as virologic and immunologic status post-transplant. Renal function (glomerular filtration rate and serum creatinine concentrations) improved in all subjects post-transplant, and six of seven (85.8%) subjects remained virologically suppressed with no progression to Acquired Immunodeficiency Syndrome (AIDS). Overall, two-year graft and patient survival rates were 85.5%. HIV seropositive End Stage Renal Disease (ESRD) patients represent a new population of patients that can be successfully transplanted. This offers a new dimension in care for successful HAART therapy to prolong the life of HIV-infected patients.

Renal ischemia and transplantation predispose to vascular constriction mediated by angiotensin II type 1 receptor-activating antibodies.

BACKGROUND: We previously described angiotensin II type 1 receptor-activating antibodies (AT1R-Abs) in renal transplant recipients with vascular rejection and malignant hypertension. In this study, we tested the hypothesis that AT1R-Abs can cause renal artery contraction by AT1R activation with renal ischemia representing a key permissive factor and therefore contribute to renal pathologic condition. METHODS: Isolated renal and mesenteric arteries from Lewis rats were incubated with purified AT1R-Abs from patients with human leukocyte antigen antibody-negative vascular rejection. Vascular contraction was measured using small vessel myography. The measurements were repeated with renal arteries derived from native kidneys subjected to ischemia-reperfusion or after transplantation in a low-responder Fischer 344-to-Lewis rat kidney-transplantation model. RESULTS: AT1R-Abs acted in a vascular bed-specific manner and caused small contractions only in native rat renal arteries but not in mesenteric arteries. AT1R-Abs did not alter the vascular reactivity to phenylephrine, angiotensin II, or acetylcholine in native renal arteries. In contrast, AT1R-Abs caused a pronounced (>10-fold) contraction of renal arteries after ischemia and after allogeneic transplantation. Pretreatment with pharmacologic AT1R blocker only partially inhibited the AT1R-Abs-induced contraction, which was almost completely abolished by neutralizing peptides targeting epitopes of AT1R-Abs on the second loop of AT1R. CONCLUSIONS: These data demonstrate that AT1R-Abs can induce renal vascular contraction under predisposing conditions such as in ischemic or transplanted kidneys. Neutralizing antibodies against specific epitopes in the AT1R can ameliorate this contraction.

Involvement of functional autoantibodies against vascular receptors in systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) features autoimmunity, vasculopathy and tissue fibrosis. The renin-angiotensin and endothelin systems have been implicated in vasculopathy and fibrosis. A role for autoantibody-mediated receptor stimulation is hypothesised, linking three major pathophysiological features consistent with SSc. METHODS: Serum samples from 478 patients with SSc (298 in the study cohort and 180 from two further independent cohorts), 372 healthy subjects and 311 control-disease subjects were tested for antibodies against angiotensin II type 1 receptor (AT(1)R) and endothelin-1 type A receptor (ET(A)R) by solid phase assay. Binding specificities were tested by immunoprecipitation. The biological effects of autoantibodies in microvascular endothelial cells in vitro were also determined, as well as the quantitative differences in autoantibody levels on specific organ involvements and their predictive value for SSc-related mortality. RESULTS: Anti-AT(1)R and anti-ET(A)R autoantibodies were detected in most patients with SSc. Autoantibodies specifically bound to respective receptors on endothelial cells. Higher levels of both autoantibodies were associated with more severe disease manifestations and predicted SSc-related mortality. Both autoantibodies exert biological effects as they induced extracellular signal-regulated kinase 1/2 phosphorylation and increased transforming growth factor ß gene expression in endothelial cells which could be blocked with specific receptor antagonists. CONCLUSIONS: Functional autoimmunity directed at AT(1)R and ET(A)R is common in patients with SSc. AT(1)R and ET(A)R autoantibodies could contribute to disease pathogenesis and may serve as biomarkers for risk assessment of disease progression.

Inhibition of 20-HETE synthesis and action protects the kidney from ischemia/reperfusion injury.

20-Hydroxyeicosatetraenoic acid (20-HETE) production is increased in ischemic kidney tissue and may contribute to ischemia/reperfusion (I/R) injury by mediating vasoconstriction and inflammation. To test this hypothesis, uninephrectomized male Lewis rats were exposed to warm ischemia following pretreatment with either an inhibitor of 20-HETE synthesis (HET0016), an antagonist (20-hydroxyeicosa-6(Z),15(Z)-dienoic acid), an agonist (20-hydroxyeicosa-5(Z),14(Z)-dienoic acid), or vehicle via the renal artery and the kidneys were examined 2 days after reperfusion. Pretreatment with either the inhibitor or the antagonist attenuated I/R-induced renal dysfunction as shown by improved creatinine clearance and decreased plasma urea levels, compared to controls. The inhibitor and antagonist also markedly reduced tubular lesion scores, inflammatory cell infiltration, and tubular epithelial cell apoptosis. Administering the antagonist accelerated the recovery of medullary perfusion, as well as renal medullary and cortical re-oxygenation, during the early reperfusion phase. In contrast, the agonist did not improve renal injury and reversed the beneficial effect of the inhibitor. Thus, 20-HETE generation and its action mediated kidney injury due to I/R. Whether or not these effects are clinically important will need to be tested in appropriate human studies.