Translating the efficacy of dapagliflozin in chronic kidney disease to lower healthcare resource utilization and costs: a medical care cost offset analysis.

AIMS: Dapagliflozin was approved for use in patients with chronic kidney disease (CKD) based on results of the DAPA-CKD trial, demonstrating attenuation of CKD progression and reduced risk of cardio-renal outcomes and all-cause mortality (ACM) versus placebo, in addition to standard therapy. The study objective was to assess the potential medical care cost offsets associated with reduced rates of cardio-renal outcomes across 31 countries and regions. MATERIALS AND METHODS: A comparative cost-determination framework estimated outcome-related costs of dapagliflozin plus standard therapy versus standard therapy alone over a 3-year horizon based on the DAPA-CKD trial. Incidence rates of end-stage kidney disease (ESKD), hospitalizations for heart failure (HHF), acute kidney injury (AKI), and ACM were estimated for a treated population of 100,000 patients. Associated medical care costs for non-fatal events were calculated using sources from a review of publicly available data specific to each considered setting. RESULTS: Patients treated with dapagliflozin plus standard therapy experienced fewer incidents of ESKD (7,221 vs 10,767; number needed to treat, NNT: 28), HHF (2,370 vs 4,684; NNT: 43), AKI (4,110 vs. 5,819; NNT: 58), and ACM (6,383 vs 8,874; NNT: 40) per 100,000 treated patients versus those treated with standard therapy alone. Across 31 countries/regions, reductions in clinical events were associated with a 33% reduction in total costs, or a cumulative mean medical care cost offset of $264 million per 100,000 patients over 3 years. LIMITATIONS AND CONCLUSIONS: This analysis is limited by the quality of country/region-specific data available for medical care event costs. Based on the DAPA-CKD trial, we show that treatment with dapagliflozin may prevent cardio-renal event incidence at the population level, which could have positive effects upon healthcare service delivery worldwide. The analysis was restricted to outcome-associated costs and did not consider the cost of drug treatments and disease management.

Chronic kidney disease (CKD) has a high clinical, economic, and societal burden and it affects approximately 8-16% of the global population. The progressive nature of CKD may lead to complications, co-morbidities, and mortality, costing healthcare systems millions and consuming a large proportion of healthcare resources. Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, has been demonstrated to slow CKD progression and reduce cardio-renal complications, as demonstrated in the DAPA-CKD trial. With the emergence of dapagliflozin as a treatment for CKD, it is important for clinicians and healthcare providers to understand how effective treatment can positively affect short-term healthcare service delivery and associated costs. This medical care cost offset modelling analysis considers a scalable population of 100,000 patients in 31 countries/regions worldwide. The analysis estimates treatment with dapagliflozin plus standard therapy to be offset by a 33% reduction in costs associated with key cardio-renal outcomes, translating to an average $264 million in cost offsets per 100,000 treated patients. This modelling analysis of pivotal trial data shows dapagliflozin could have considerable benefits to healthcare systems worldwide that are under strain from the rising burden of CKD.

Control of diabetes mellitus and the risk of neointimal hyperplasia after percutaneous coronary intervention: Post-hoc analysis from the BLADE-PCI trial.

BACKGROUND AND AIMS: Diabetes-mellitus (DM) is associated with increased risk of neointimal hyperplasia (NIH) and restenosis after percutaneous coronary intervention (PCI). We examined a possible association of DM severity at the time of PCI with the development of NIH. METHODS: This post-hoc analysis from the BLADE-PCI randomized, multi-center trial included only patients with DM and baseline data of HbA1c within 14 days prior to the index PCI. All patients were treated with zotarolimus-eluting stents. The primary endpoint was percent of NIH volume at 9 months as evaluated by optical coherence tomography. This endpoint was compared between patients with uncontrolled DM (HbA1c ≥ 7.5%) and controlled DM (HbA1c <7.5%) at the index PCI. RESULTS: The mean percentages of NIH volume were 16.5% ± 9.9 and 12.75% ± 7.9 among patients with baseline HbA1c ≥ 7.5% (n = 74) and <7.5% (n = 102), respectively (p < 0.05). In multivariable analysis, HbA1c ≥ 7.5% was not associated with higher risk of NIH development [95% CI; 2.2 (-0.8, 5.3; p = 0.15)]. Higher HbA1c was not associated with increased risk of NIH at the minimum lumen area site [95% CI; 0.9 (-5.0, 6.7); p = 0.77) or percent stent strut coverage [95% CI; -0.3 (-1.3, 0.6); p = 0.45]. Secondary clinical endpoints including major adverse cardiac and cerebrovascular events, target lesion failure and death were similar between patients with worse and better DM control. CONCLUSIONS: Uncontrolled DM at the time of PCI performed with contemporary drug-eluting stents was not associated with an increased risk of NIH development.

Percutaneous coronary intervention with ridaforolimus-eluting stents in long lesions: the BIONICS 38†mm prospective trial.

BACKGROUND: The ridaforolimus-eluting stent (RES) system is a novel cobalt alloy-based coronary stent with a durable elastomeric polymer eluting ridaforolimus. The aim of this trial was to assess the performance of a 38 mm RES in long coronary lesions. METHODS: A prospective, multicenter, single-arm, open-label clinical trial. Clinical follow-up was performed at 30 days, 6 months, and 1 year after the procedure. Target lesions were located in native coronary arteries or bypass graft conduits, with visually estimated diameters of ≥2.75 mm to ≤4.25 mm. The primary endpoint was combined efficacy (final in-stent residual diameter stenosis <30%) without 30-day major adverse cardiovascular events (MACE) (composite of cardiac death, any myocardial infarction), or ischemia-driven target lesion revascularization. RESULTS: A total of 50 patients were enrolled in the study. Fourteen (28%) had acute coronary syndromes; 17 (34%) had diabetes. The mean lesion length was 32.4 mm ±â€…8.3, reference vessel diameter 2.88 mm ±â€…0.45, minimal lumen diameter 0.80 mm ±â€…0.41, and percent diameter stenosis 72.6% ±â€…13.2. The primary endpoint was achieved in 88% (44/50) of the patients (95% confidence interval: 75.7-95.5%). Thirty-day and 1-year MACE rates were 6% and 8%, respectively. Target lesion failure after 1 year occurred in three patients (6%). Forty-seven lesions (94%) were treated successfully, with final in-stent diameter stenosis of < 30% [95% confidence interval: (84-99%). CONCLUSION: Percutaneous coronary intervention (PCI) of long lesions with a 38 mm RES achieved satisfactory results, and support the safety and efficacy of PCI with RES in patients with long lesions. (ClinicalTrials.gov NCT03702608).

Acute Kidney Injury and Hair-Straightening Products: A Case Series.

RATIONALE & OBJECTIVE: Keratin-based hair-straightening treatment is a popular hair-styling method. The majority of keratin-based hair-straightening products in Israel contain glycolic acid derivatives, which are considered safe when used topically. Systemic absorption of these products is possible, and anecdotal reports have described kidney toxicity associated with their use. We report a series of cases of severe acute kidney injury (AKI) following use of hair-straightening treatment in Israel during the past several years. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: We retrospectively identified 26 patients from 14 medical centers in Israel who experienced severe AKI and reported prior treatment with hair-straightening products in 2019-2022. FINDINGS: The 26 patients described had a median age of 28.5 (range, 14-58) years and experienced severe AKI following a hair-straightening procedure. The most common symptoms at presentation were nausea, vomiting, and abdominal pain. Scalp rash was noted in 10 (38%) patients. Two patients experienced a recurrent episode of AKI following a repeat hair-straightening treatment. Seven patients underwent kidney biopsies, which demonstrated intratubular calcium oxalate deposition in 6 and microcalcification in tubular cells in 1. In all biopsies, signs of acute tubular injury were present, and an interstitial infiltrate was noted in 4 cases. Three patients required temporary dialysis. LIMITATIONS: Retrospective uncontrolled study, small number of kidney biopsies. CONCLUSIONS: This series describes cases of AKI with prior exposure to hair-straightening treatments. Acute oxalate nephropathy was the dominant finding on kidney biopsies, which may be related to absorption of glycolic acid derivatives and their metabolism to oxalate. This case series suggests a potential underrecognized cause of AKI in the young healthy population. Further studies are needed to confirm this association and to assess the extent of this phenomenon as well as its pathogenesis.

Double-blind, placebo-controlled evaluation of biorest liposomal alendronate in diabetic patients undergoing PCI: The BLADE-PCI trial.

BACKGROUND: Diabetes mellitus (DM) is an important predictor of neointimal hyperplasia (NIH) and adverse clinical outcomes after percutaneous coronary intervention (PCI). LABR-312, a novel intravenous formulation of liposomal alendronate, has been shown in animal models to decrease NIH at vascular injury sites and around stent struts. The aim of the Biorest Liposomal Alendronate Administration for Diabetic Patients Undergoing Drug-Eluting Stent Percutaneous Coronary Intervention trial was to assess the safety, effectiveness, and dose response of LABR-312 administered intravenously at the time of PCI withDES in reducing NIH as measured by optical coherence tomography postprocedure in patients with DM. METHODS: Patients with DM were randomized to a bolus infusion of LABR-312 vs placebo at the time of PCI. Dose escalation of LABR-312 in the study arm was given: 0.01 mg, 0.03 mg, and 0.08 mg. The primary endpoint was the in-stent %NIH volume at 9 months as measured by optical coherence tomography. RESULTS: From September 2016 to December 2017, 271 patients with DM undergoing PCI were enrolled; 136 patients were randomized to LABR-312 infusion and 135 patients were randomized to placebo. At 9-month follow-up, no difference was seen in the primary endpoint of %NIH between LABR-312 and placebo (13.3% ± 9.2 vs 14.6% ± 8.5, P = .35). No differences were present with the varying LABR-312 doses. Clinical outcomes at 9 months were similar between groups. CONCLUSIONS: Among patients with DM undergoing PCI with drug-eluting stents, a bolus of LABR-312 injected systematically at the time of intervention did not result in a lower rate in-stent %NIH volume at 9-month follow-up.

Cardiovascular outcomes following percutaneous coronary intervention with drug-eluting balloons in chronic kidney disease: a retrospective analysis.

BACKGROUND: Chronic kidney disease (CKD) is associated with poorer outcomes following percutaneous coronary intervention (PCI) with drug-eluting stents. Drug-eluting balloons are used for in-stent restenosis and selected cases of de-novo coronary lesions. Little is known regarding the outcomes of individuals with CKD who undergo PCI with drug-eluting balloons. The goal of this study was to assess outcomes of PCI with drug-eluting balloons in individuals with CKD. METHODS: In a retrospective analysis, outcomes of PCI with drug-eluting balloons were compared between 101 patients with CKD and 261 without CKD. CKD was defined as estimated glomerular filtration rate < 60 ml/min/1.73m2. We compared demographics, procedure data and clinical outcomes in the first and second years following the procedure. RESULTS: Rates of major adverse cardiac events (MACE) and myocardial infarction were higher in patients with than without CKD: 23.8% vs. 13.8%, P < 0.005 and 15.9% vs. 3.8%, P < 0.001, respectively. Rates of target lesion revascularization were similar, 14.9 and 11.5%, respectively, P = 0.4. Shorter duration of dual anti-platelet therapy was observed among patients with than without CKD (10.0 + 3.4 vs. 10.9 + 3.7 months, P < 0.05). First-year hemorrhage episodes were similar in the two groups (0.08 ± 0.4 and 0.03 ± 0.2, respectively, P = 0.2). In a multivariate regression analysis, CKD was associated with increased risks of first year MACE (OR 2.1; 95% confidence interval 1.0-4.3, P < 0.001). CONCLUSIONS: PCI with drug-eluting balloons was associated with increased cardiovascular morbidity and mortality in patients with than without CKD. However, rates of target lesion revascularization were similar in the two groups. Shorter duration of dual anti-platelet therapy was observed in the CKD group.

A cat's scratch or a wolf's bite?

Bartonella henselae endocarditis mimicking systemic vasculitis has been reported in patients with valvulopathy. Herein, we describe a patient with B. henselae endocarditis involving a prosthetic pulmonic valve with positive anti-dsDNA antibodies misdiagnosed with systemic lupus erythematosus (SLE) based on the revised classification SLE criteria.

Urea level is an independent predictor of mortality in patients with severe aortic valve stenosis.

INTRODUCTION: Severe aortic stenosis (AS) is the most common valvular heart disease in the western world. Various factors are related to severe AS prognosis, including chronic kidney disease. The aim of this study was to evaluate the prognostic value of urea level in patients with severe AS. METHODS: We prospectively enrolled 142 patients (79.1±9.4 years, 88 women) with severe AS (mean valve area 0.67± 0.17 cm2). Clinical assessment, blood tests and echocardiography were performed at enrollment and follow up. The patient population was divided into low and high urea level groups, according to the median urea level at enrollment (72 patients, mean urea 35.5±6.2 mg/dL and 70 patients, mean urea 61.1±17.8 mg/dL, respectively). Hundred and twelve patients (79%) underwent aortic valve intervention. The primary endpoint was all-cause and cardiovascular mortality. OUTCOMES: During follow-up of 37±19.5 months, 56 (37.1%) patients died, 39 due to cardiovascular causes. In univariate analysis, age, urea level, creatinine, New York Heart Association (NYHA) class and aortic valve intervention were associated with all-cause mortality. However, in multivariate analysis only aortic valve intervention and blood urea were independent predictors of all-cause mortality (HR 0.494; 95% CI 0.226-0.918, P = 0.026 and HR 1.015; 95% CI 1.003-1.029, P = 0.046 respectively). Urea level, NYHA class and age were also significant predictors of cardiovascular mortality. Whereas, in multivariate analysis, only urea level predicted cardiovascular mortality in these patients (HR 1.017; CI 1.003-1.031 P = 0.019). CONCLUSIONS: Blood urea, a generally readily available and routinely determined marker of renal function, is an independent prognostic factor in patients with severe AS.

Deletion of the Mir-106b~ 25 MicroRNA cluster attenuates atherosclerosis in Apolipoprotein E knockout mice.

BACKGROUND: MicroRNAs are short non-coding RNAs that regulate gene expression. The aim of this study was to gain an understanding of the possible role of the miR-106b~ 25 microRNA cluster in regulating atherosclerosis in mice. METHODS: MiR-106b~ 25 knockout mice were outcrossed into Apolipoprotein E (ApoE) knockout background to generate double knockout mice. At 36 weeks of age, lesion size was evaluated in the aortic sinus by oil-red-O staining. RESULTS: Lesion size was 2-fold smaller in double KO mice in comparison to ApoE KO mice. In addition, collagen staining showed a trend towards a stable plaque phenotype in the double KO mice. Lipid profiling of plasma samples of double KO and ApoE KO mice using FPLC revealed over 2-fold decrease in Very low density lipoprotein (VLDL) cholesterol content and a 50% decrease in low density lipoprotein (LDL) cholesterol content in double KO mice. By using target prediction software, we have identified several possible targets for the miR-106b~ 25 cluster including the VLDL and LDL receptors. We found that upon feeding miR-106b~ 25 KO mice with high fat diet, the expression of LDL and VLDL receptors was higher than in the wild-type mice, suggesting the miR-106b~ 25 cluster regulates atherosclerosis by influencing clearance of VLDL and LDL from the plasma. CONCLUSIONS: We identified the miR-106b~ 25 cluster as a novel regulator of atherosclerosis in ApoE KO mice, presumably by regulating plasma cholesterol levels.

Percutaneous Coronary Intervention Does Not Lower Cardiovascular Outcomes in Patients with Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) is associated with an increased risk of adverse cardiovascular outcomes, in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). However, most studies used bare-metal stents or first-generation drug-eluting stents, and less guideline-directed therapy to reduce cardiovascular risk was reported in CKD patients. This study investigates the impact of moderate-CKD on patients undergoing PCI in the current era. METHODS: Patient level data were pooled from 2 multicenter randomized trials (BIONICS and NIREUS trials) with a near "all-comers" design, comparing PCI with ridaforolimus-eluting stents vs. zotarolimus-eluting stents in patients with CAD. Patients were classified according to the presence or absence of moderate-CKD, defined as creatinine clearance (CrCl) <60 mL/min. We compared baseline characteristics, angiographic findings, and clinical outcomes 1-year post-PCI. RESULTS: 236/2,201 (10.7%) patients had CKD, mean CrCl of 50.3 + 7.8 mL/min. These patients were generally older and more often with hypertension than non-CKD patients, but the use of guideline-directed therapy was similar between the groups. CKD was associated with an increased risk of cardiovascular death (hazard ratio [HR] 6.08; 95% CI 2.11-17.51; p < 0.001), but with a reduced occurrence of repeated revascularization, including ischemia-driven revascularization (HR 0.47; 95% CI 0.24-0.92; p < 0.05). The rate of repeated angiography per severe cardiovascular adverse event was significantly lower in the CKD than the non-CKD group (23/38 [61%] vs. 253/334 [76%], p < 0.05). CONCLUSIONS: Moderate-CKD in patients with CAD was associated with higher rates of all-cause and cardiovascular mortality, yet with a lower risk of revascularization 1-year following PCI. Lack of guideline-directed medical therapy does not explain the adverse outcome of CKD patients.

Ultrapure Filter does not Confer Short-Term Benefits over Two Reverse Osmosis Systems in Chronic Hemodialysis Patients.

BACKGROUND: Dialysate purity contributes to the inflammatory response that afflicts hemodialysis patients. OBJECTIVES: To compare the clinical and laboratory effects of using ultrapure water produced by a water treatment system including two reverse osmosis (RO) units in series, with a system that also includes an ultrapure filter (UPF). METHODS: We performed a retrospective study in 193 hemodialysis patients during two periods: period A (no UPF, 6 months) and period B (same patients, with addition of UPF, 18 months), and a historical cohort of patients treated in the same dialysis unit 2 years earlier, which served as a control group. RESULTS: Mean C-reactive protein, serum albumin and systolic blood pressure worsened in period B compared to period A and in the controls. CONCLUSIONS: A double RO system to produce ultrapure water is not inferior to the use of ultrapure filters.

First-in-Man Experience with a Novel Catheter-Based Renal Denervation System of Ultrasonic Ablation in Patients with Resistant Hypertension.

PURPOSE: To report results of renal denervation (RDN) with the first catheter-based, non-balloon occlusion ultrasonic system in patients with resistant hypertension. MATERIALS AND METHODS: In a multicenter, single-arm trial, 39 patients with resistant hypertension (defined as uncontrolled hypertension while taking ≥ 3 antihypertensive medications) were treated. The cohort consisted of 4 groups: severe resistant hypertension (office systolic blood pressure [OSBP] ≥ 160 mm Hg) treated with a unidirectional catheter (group 1; n = 14); severe resistant hypertension treated with a multidirectional catheter (group 2; n = 18); moderate resistant hypertension (OSBP 140-159 mm Hg) treated with a multidirectional catheter (group 3; n = 5); and recurrent severe resistant hypertension, after an initial response to RF RDN (group 4; n = 2). Blood pressure monitoring was performed for 6 months. RESULTS: Severe adverse events were not noted immediately after the procedure or during follow-up. Treatment time was longer with unidirectional than with multidirectional catheters (36.7 min ± 9.6 vs 11.9 min ± 5.8; P < .001). Mean reductions in office blood pressure (systolic/diastolic) at 1, 3, and 6 months were -26.1/-9.6 mm Hg, -28.0/-9.9 mm Hg, and -30.6/-14.1 mm Hg (P < .01 for all). Per-group analysis showed significant OSBP reduction for groups 1 and 2. Patients with isolated systolic hypertension had a significantly smaller reduction in OSBP after 6 months compared with patients with combined systolic/diastolic hypertension (-16.2 mm Hg ± 18.5 vs -9.9 mm Hg ± 33.4; P < .005). CONCLUSIONS: Use of the RDN system was feasible and safe in this phase I study. Significant blood pressure reductions were observed over 6 months, although less in patients with isolated systolic hypertension.

Ambulatory blood-pressure monitoring, antihypertensive therapy and the risk of fall injuries in elderly hypertensive patients.

BACKGROUND: Fall injuries are common among the elderly. The aim of this study was to investigate whether blood-pressure patterns, as measured by 24-h ambulatory blood pressure monitoring (ABPM), or intensification of antihypertensive therapy following the 24-h ABPM, may be associated with fall injuries in hypertensive elderly patients. METHODS: In a retrospective study, community-based elderly patients (age ≥ 70 years) who were referred to 24-h ABPM were evaluated for fall injuries within one-year post-ABPM. We compared the clinical characteristics, 24-h ABPM patterns and the intensification of hypertensive therapy following 24-h ABPM, between patients with and without a fall injury. RESULTS: Overall 1032 hypertensive elderly patients were evaluated. Fifty-five (5.3%) had a fall injury episode in the year following ABPM. Patients with a fall injury were significantly older, and with higher rates of previous falls. Lower 24-h diastolic blood-pressure (67.3 ± 7.6 vs. 70.7 ± 8.8 mmHg; P < 0.005) and increased pulse-pressure (74.7 ± 14.3 vs. 68.3 ± 13.7 mmHg; P < 0.005), were found in the patients with a fall injury, compared to those without a fall injury. After adjustment for age, gender, diabetes mellitus and previous falls, lower diastolic blood-pressure and increased pulse-pressure were independent predictors of fall injury. Intensification of antihypertensive treatment following the 24-h ABPM was not associated with an increased rate of fall injury. CONCLUSIONS: Low diastolic blood-pressure and increased pulse-pressure in 24-h ABPM were associated with an increased risk of fall injury in elderly hypertensive patients. Intensification of antihypertensive treatment following 24-h ABPM was not associated with an increased risk of fall injury.

Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome.

BACKGROUND AND OBJECTIVES: Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes. RESULTS: In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome. CONCLUSIONS: Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.

Renal Sympathetic Denervation System via Intraluminal Ultrasonic Ablation: Therapeutic Intravascular Ultrasound Design and Preclinical Evaluation.

PURPOSE: To assess the safety and performance of a nonfocused and nonballooned ultrasonic (US) catheter-based renal sympathetic denervation (RDN) system in normotensive swine. MATERIALS AND METHODS: RDN with the therapeutic intravascular US catheter was evaluated in 3 experiments: (i) therapeutic intravascular US RDN vs a control group of untreated animals with follow-up of 30, 45, and 90 days (n = 6; n = 12 renal arteries for each group); (ii) therapeutic intravascular US RDN vs radiofrequency (RF) RDN in the contralateral artery in the same animal (n = 2; n = 4 renal arteries); and (iii) therapeutic intravascular US RDN in a recently stent-implanted renal artery (n = 2; n = 4 renal arteries). RESULTS: In the first experiment, therapeutic intravascular US RDN was safe, without angiographic evidence of dissection or renal artery stenosis. Neuronal tissue vacuolization, nuclei pyknosis, and perineuronal inflammation were evident after RDN, without renal artery wall damage. Norepinephrine levels were significantly lower after therapeutic intravascular US RDN after 30, 45, and 90 days compared with the control group (200.17 pg/mg ± 63.35, 184.75 pg/mg ± 44.51, and 203.43 pg/mg ± 58.54, respectively, vs 342.42 pg/mg ± 79.97). In the second experiment, deeper neuronal ablation penetrance was found with therapeutic intravascular US RDN vs RF RDN (maximal penetrance from endothelium of 7.0 mm vs 3.5 mm, respectively). There was less damage to the artery wall after therapeutic intravascular US RDN than with RF RDN, after which edema and injured endothelium were seen. In the third experiment, denervation inside the stent-implanted segments was feasible without damage to the renal artery wall or stent. CONCLUSIONS: The therapeutic intravascular US system performed safely and reduced norepinephrine levels. Deeper penetrance and better preservation of vessel wall were observed with therapeutic intravascular US RDN vs RF RDN. Neuronal ablations were observed in stent-implanted renal arteries.

High prevalence of elevated blood pressure among children with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis type 1 (NF1) is a common neurocutaneous disease characterized by café-au-lait spots, axillary and inguinal freckling, neurofibromas, and optic gliomas. Increased rates of hypertension (HTN) were reported among NF1 patients, however, the prevalence of HTN and pre-HTN in pediatric NF1 patients has not been clarified. METHODS: Blood pressure (BP) measurements, weight, and renal ultrasound were assessed in 224 NF1 pediatric patients followed in a specialized NF1 clinic. RESULTS: The cohort's mean age was 9.1 ± 4.1 years. Overweight and obesity were found in 12.9 and 10.3 % of them, respectively. BP was measured averagely 2.9 times per patient on different occasions. Blood pressure was in the pre-HTN and HTN ranges in 14.9 and 16.9 % of measurements, respectively. BP >95th was detected in 20.5 % at the first measurement. Of 114 children with at least three BP measurements, 18.4 % had two values in the HTN range and 6.14 % had at least three. Overweight was not associated with HTN among children with NF1. Urinary tract ultrasonographic abnormalities were detected in 6.8 % (11/161) of cases. CONCLUSIONS: The prevalence of increased BP in pediatric NF1 is much higher than in the general pediatric population. BP has to be regularly assessed and managed in this high-risk population.

Target Hemoglobin May Be Achieved with Intravenous Iron Alone in Anemic Patients with Cardiorenal Syndrome: An Observational Study.

BACKGROUND: The treatment of anemia in patients with cardiorenal syndrome (CRS) is based mainly on intravenous (IV) iron therapy and/or erythropoiesis-stimulating agents (ESAs). There are concerns about the safety of ESAs due to a potentially higher risk for stroke and malignancy. OBJECTIVE: We aimed to explore whether IV iron alone is sufficient to improve anemia in CRS patients and to define the predictors of treatment response. METHODS: We retrospectively analyzed data of 81 CRS patient treated for anemia at our clinic. All patients received IV iron for 6 weeks. A subset of patients was additionally given subcutaneous ESAs. The end point was the improvement from baseline in hemoglobin (Hb) and ferritin levels at week 7. RESULTS: We retrieved the files of 81 patients; 34 received IV iron alone and 47 were given IV iron and ESAs (the combination group). The Hb levels significantly increased in both groups (in the IV iron alone group: 10.6 ± 1.1 to 11.9 ±1.1 g/dl, p < 0.001; in the combination group: 10.2 ± 0.9 to 12.4 ± 1.3 g/dl, p < 0.001), but more pronouncedly in the combination group (2.17 vs. 1.24 g/dl; p = 0.001). The platelet count decreased significantly in the IV iron alone group but was unchanged in the combination group. Eighty percent of patients attained a Hb target of 11 g/dl, with no significant difference between the two groups (73.5 vs. 85.1%; p = 0.197). Low baseline Hb was the only predictor of a favorable outcome to treatment. CONCLUSION: Our observational study suggests that IV iron treatment without ESAs may substantially raise the Hb level to ≥11 g/dl in CRS patients. This treatment strategy may reduce the use of ESAs and hence its potential adverse effects.

Preclinical and Preliminary Clinical Evaluation of Genetically Transduced Dermal Tissue Implants for the Sustained Secretion of Erythropoietin and Interferon α.

Protein drugs are currently delivered by bolus injection and although treatment frequently is successful, these methods also have major drawbacks, which call for the development of alternative technologies allowing prolonged delivery of these drugs. We developed a new ex vivo gene therapy platform called Transduced Autologous Restorative Gene Therapy (TARGT) for sustained long term production and secretion of autologous therapeutic proteins. A biopsy of dermal tissue taken from the patient is transduced ex vivo with a viral vector encoding the required gene under a constitutive promoter. Following measurement of protein secretion ex vivo, the transduced dermal tissue is implanted back into the patient, where it secretes the therapeutic protein into the circulation for several months or longer. A major hurdle to this approach is potential immunogenicity of the transduced tissue following implantation. In this paper we describe the preclinical and early clinical development of this technology, which allowed for overcoming these hurdles. To that end, we have used the helper dependent (HD) adenoviral vector with newly designed expression cassette containing genetic elements to optimize transgene expression. Moreover, we have developed procedures for TARGT tissue implantation, with measures to improve engraftment and reduce inflammation and rejection. Implantation of human TARGT to severe combined immune deficient (SCID) mice indicated long-term production of active proteins in the blood. Preliminary results of a clinical trial from two anemic end-stage renal disease patients, implanted with TARGTs expressing the human erythropoietin (EPO) gene, demonstrated prolonged secretion with physiologic blood level of the hormone and hemoglobin maintenance in the desired range, for a period of at least 5 months without exogenous EPO administration. We believe that the TARGT technology has the potential to become a platform for the sustained delivery of therapeutic proteins in various clinical indications.