Both E. coli and S. aureus were simultaneously injected into the left renal arteries of 55 female dogs. The arteries were occluded for 10 minutes prior to the injection and 10 minutes after. The renal veins were occluded during the injection and for 10 minutes after. Ten animals did not survive longer than 24 hours. Ten of 45 developed neither renal lesions nor bacteriuria; of the remaining 35 which did, five were killed on each of the second, seventh and fourteenth days, and their renal lesions were assessed. Eighteen of the remaining 2 which developed bacteriuria were killed 3 to 12 weeks following surgery when bacteria could no longer be recovered from the urine. Only two dogs had persistent bacteriuria 12 weeks after surgery. All animals which developed bacteriuria had gross lesions in the left kidney but not the right. Naturally occurring renal lesions were found in 17 of 78 random-source dogs at laparotomy. E. coli was cultured from the urine of five of these dogs but not from the kidneys. These lesions were morphologically similar to experimental ones. It is concluded that with this method renal lesions similar to spontaneous ones can be produced, but care must be taken to exclude the relatively large percentage of random-source dogs with naturally occurring lesions from any study. Various forms of infectious nephritis have been reported to be among the commonest diseases of dogs (1, 2). The successful production of chronic pyelonephritis in dogs depends on a variety of factors in addition to injecting bacteria into either the renal artery or ureter. Thus, ureteral obstruction, renal anoxia and reduced pulse pressure increased the susceptibility to renal infection (3, 4, 6, 7, 8). Our laboratory has been concerned with the production of experimental pyelonephritis in dogs so that the efficacy of various treatments could be studied. The present work was undertaken to standardize methods of producing the disease and to compare experimental renal lesions with naturally occurring ones.
The Symplicity HTN-3 recently failed to meet its primary efficacy endpoint in blood pressure reduction. The natural orifice denervation system developed by Verve Medical directs radiofrequency energy to the renal pelvic space where the preponderance of afferent nerves originate. We have previously demonstrated the feasibility of the Verve Medical NephroBlate to ablate these nerves. We developed a protocol to treat a small number of patients (n=3, 4 kidneys) undergoing elective nephrectomy at Muljibhai Patel Urological Hospital on Nadiad, India. We treated three patients with end stage kidney disease prior to explants of the affected diseased kidney. One patient was pre-renal transplant and had both kidneys treated. One week after fluoroscopically aided transurethral treatment with the NephroBlate™ device, the previously planned nephrectomy was performed. Procedure time was between 9 to 15 minutes and no adverse effects were recorded. The histopathological results in all cases showed a significant destruction of the peri-pelvic nerves from the renal pelvic space to the serosa (1.75mm). With a significant elimination of most of the afferent and efferent nerves in the treated area(approximately 1cm), and no change to the adjacent nerves in the control segments in the histopathologic specimens, as well as a safe and painless procedure for the patients, we proceeded with our clinical studies on resistant hypertensive patients. As in the diseased kidney study, the procedures were done under general anesthesia. Within 30 seconds of treatment of the first kidney, a blood pressure response was noted (reduction of mean systolic blood pressure 44mmHg, reduction of mean diastolic blood pressure 13mmHg). Following the procedure, none of the patients had significant pain or bleeding. At one month follow-up, the patients continue to be normotensive with no renal issues. This very small series did not exclude any patients with renal disease and no patients received any anticoagulants. The blood pressure response was immediate and occurred while the patients were under general anesthesia. In this small series of humans treated with limited follow-up, we see a promising nonvascular alternative for renal denervation for treatment for resistant hypertension.
Introduction: Cytokine release syndrome (CRS) and associated cardiovascular (CV) events are common following infusion of chimeric antigen receptor T cell therapy (CAR-T). There are no data characterizing whether CAR-T recipients with a pre-existing cardiac dysfunction (LVEF <53%) are at increased risk for CV events following CAR-T. Hypothesis: We hypothesized that cardiac dysfunction would be associated with a higher rate of CV events following CAR-T infusion. CV events were defined as a composite of cardiogenic shock, clinical heart failure, myocardial infarction, or arrhythmia. Methods: Patients in a multi-center registry of adult CAR-T recipients with a known baseline LVEF were included (n=241). Covariates included standard baseline CV and cancer parameters. Results: In total, 22 (9%) CAR-T patients had a pre-existing cardiac dysfunction. Those with and without [219 (91%)] baseline cardiac dysfunction were similar in age, gender, pre-existing CV risk factors, and ECOG performance status. LVEF among patients with cardiac dysfunction ranged from 25%-52%. There was no difference in prior anthracycline use, cancer type or burden, but cardiac dysfunction patients had higher rates of prior radiation (36% vs 16%, p=0.02). Cardiac dysfunction patients received less investigational CAR-T (9% vs 31%, p=0.03), more tisagenlecleucel (36% vs 18%, p=0.04), and had similar rates of axicabtagene ciloleucel and lisocabtagene maraleucel. There was no difference in mean CRS grade, rate of ≥2 grade CRS, or in tocilizumab or steroids use between those with and without cardiac dysfunction. During a median follow-up of 294 (IQR 123-661) days, 60 (25%) patients experienced CV events with more events in patients with cardiac dysfunction (63% vs 21%, p<0.001). In a Cox model adjusted for covariates identified in univariate analyses, baseline cardiac dysfunction was independently associated with an increased CV events risk (adjusted HR: 4.9, 95% CI 2.54–9.61, p<0.001) Conclusions: CAR-T recipients with pre-existing cardiac dysfunction experience more CV events despite similar rates of CRS.
