Neuroimmune interplay in kidney health and disease: Role of renal nerves.

Renal nerves and their role in physiology and disease have been a topic of increasing interest in the past few decades. Renal inflammation contributes to many cardiorenal disease conditions, including hypertension, chronic kidney disease, and polycystic kidney disease. Much is known about the role of renal sympathetic nerves in physiology - they contribute to the regulation of sodium reabsorption, renin release, and renal vascular resistance. In contrast, far less is known about afferent, or "sensory," renal nerves, which convey signals from the kidney to the brain. While much remains unknown about these nerves in the context of normal physiology, even less is known about their contribution to disease states. Furthermore, it has become apparent that the crosstalk between renal nerves and the immune system may augment or modulate disease. Research from other fields, especially pain research, has provided critical insight into neuroimmune crosstalk. Sympathetic renal nerve activity may increase immune cell recruitment, but far less work has been done investigating the interplay between afferent renal nerves and the immune system. Evidence from other fields suggests that inflammation may augment afferent renal nerve activity. Furthermore, these nerves may exacerbate renal inflammation through the release of afferent-specific neurotransmitters.

Sequential afferent and sympathetic renal denervation impact on cardiovascular and renal homeostasis in the male Sprague-Dawley rat.

Renal denervation (RDNx) is emerging as a promising treatment for cardiovascular disease, yet the underlying mechanisms and contributions of afferent (sensory) and efferent (sympathetic) renal nerves in healthy conditions remains limited. We hypothesize that sympathetic renal nerves contribute to long-term MAP and renal function, whereas afferent renal nerves do not contribute to the maintenance of cardiovascular and renal function. To test this hypothesis, we performed two experiments. In experiment one, we performed total renal denervation (T-RDNx), ablating afferent and sympathetic renal nerves, in normotensive adult SD rats to determine effects on MAP and renal function. Experiment 2 employed a sequential surgical ablation using: (1) afferent targeted renal denervation (A-RDNx), then (2) sympathetic (T-RDNx) denervation to determine the individual contributions to cardiovascular and renal homeostasis. In experiment 1, MAP decreased following T-RDNx and GFR increased. In experiment 2, A-RDNx led to an increase in MAP but did not change renal function. In contrast, T-RDNx decreased MAP and improved renal filtration. Together, these data partially support our hypothesis that renal sympathetic nerves contribute to the chronic regulation of arterial pressure and renal function. Contrary to the hypothesis, A-RDNx produced an increase in MAP without a detected change in renal function. We concluded that renal sympathetic nerves influence MAP and renal function regulation through a well-defined tonic contribution to renal vascular resistance and sodium reabsorption, whereas afferent renal nerves likely contribute to the maintenance of MAP through a tonic sympatho-inhibitory, negative feedback regulation in the normotensive, healthy rat.

Contributions of afferent and sympathetic renal nerves to cystogenesis and arterial pressure regulation in a preclinical model of autosomal recessive polycystic kidney disease.

Polycystic kidney disease (PKD) is the most common inheritable cause of kidney failure, and the underlying mechanisms remain incompletely uncovered. Renal nerves contribute to hypertension and chronic kidney disease-frequent complications of PKD. There is limited evidence that renal nerves may contribute to cardiorenal dysfunction in PKD and no investigations of the role of sympathetic versus afferent nerves in PKD. Afferent renal nerve activity (ARNA) is elevated in models of renal disease and fibrosis. However, it remains unknown if this is true in PKD. We tested the hypothesis that ARNA is elevated in a preclinical model of autosomal recessive PKD and that targeted renal nerve ablation would attenuate cystogenesis and cardiorenal dysfunction. We tested this by performing total renal denervation (T-RDNx) or afferent renal denervation (A-RDNx) denervation in 4-wk-old male and female PCK rats and then quantified renal and cardiovascular responses 6 wk following treatment. Cystogenesis was attenuated with A-RDNx and T-RDNx versus sham controls, highlighting a crucial role for renal afferent nerves in cystogenesis. In contrast, blood pressure was improved with T-RDNx but not A-RDNx. Importantly, treatments produced similar results in both males and females. Direct renal afferent nerve recordings revealed that ARNA was twofold greater in PCK rats versus noncystic controls and was directly correlated with cystic severity. To our knowledge, we are the first to demonstrate that PCK rats have greater ARNA than noncystic, age-matched controls. The findings of this study support a novel and crucial role for renal afferent innervation in cystogenesis in the PCK rat.NEW & NOTEWORTHY This is the first study to dissect the contributions of renal sympathetic and afferent innervation in the PCK rat, a preclinical model of autosomal recessive polycystic kidney disease. We demonstrated that resting afferent renal nerve activity is greater in the PCK rat than noncystic controls and that basal afferent renal nerve activity is directly correlated with the extent of renal cystogenesis.

Guanylyl cyclase-A phosphorylation decreases cardiac hypertrophy and improves systolic function in male, but not female, mice.

Atrial natriuretic peptide (NP) and BNP increase cGMP, which reduces blood pressure and cardiac hypertrophy by activating guanylyl cyclase (GC)-A, also known as NPR-A or Npr1. Although GC-A is highly phosphorylated, and dephosphorylation inactivates the enzyme, the significance of GC-A phosphorylation to heart structure and function remains unknown. To identify in vivo processes that are regulated by GC-A phosphorylation, we substituted glutamates for known phosphorylation sites to make GC-A8E/8E mice that express an enzyme that cannot be inactivated by dephosphorylation. GC-A activity, but not protein, was increased in heart and kidney membranes from GC-A8E/8E mice. Activities were threefold higher in female compared to male cardiac ventricles. Plasma cGMP and testosterone were elevated in male and female GC-A8E/8E mice, but aldosterone was only increased in mutant male mice. Plasma and urinary creatinine concentrations were decreased and increased, respectively, but blood pressure and heart rate were unchanged in male GC-A8E/8E mice. Heart weight to body weight ratios for GC-A8E/8E male, but not female, mice were 12% lower with a 14% reduction in cardiomyocyte cross-sectional area. Subcutaneous injection of fsANP, a long-lived ANP analog, increased plasma cGMP and decreased aldosterone in male GC-AWT/WT and GC-A8E/8E mice at 15 min, but only GC-A8E/8E mice had elevated levels of plasma cGMP and aldosterone at 60 min. fsANP reduced ventricular ERK1/2 phosphorylation to a greater extent and for a longer time in the male mutant compared to WT mice. Finally, ejection fractions were increased in male but not female hearts from GC-A8E/8E mice. We conclude that increased phosphorylation-dependent GC-A activity decreases cardiac ERK activity, which results in smaller male hearts with improved systolic function.

Impact of angiotensin system inhibitors on esophageal cancer survival.

INTRODUCTION: Angiotensin system inhibitors are associated with improved prognosis in patients with gastrointestinal and hepatobiliary cancers. Data suggest that renin-angiotensin system signaling stimulates the tumor's immune microenvironment to impact overall survival. The goal of this study is to investigate the role of angiotensin system inhibitor use on the overall survival and disease-free survival of esophageal cancer patients. METHODS: Retrospective review of esophagectomy patients with esophageal adenocarcinoma and squamous cell cancer at a single institution tertiary care center from 2007 to 2018 was performed. Outcomes include overall survival and disease-free survival. Patient characteristics were compared with t test and χ2 test. Survival was analyzed with Kaplan-Meier and Cox proportional-hazards regression. RESULTS: One hundred seventy-one patients were identified and 123 underwent esophagectomy for cancer. No significant differences in patient demographics were found between angiotensin system inhibitor users and non-angiotensin system inhibitor users except for the rates of hypertension (40% vs 94%, P < .01) and diabetes (16% vs 47%, P < .01). Distributions of tumor neoadjuvant therapy, adjuvant therapy, pathology, staging, margins, and surgical approach were similar. Postoperatively, there was no difference in major adverse cardiovascular events or infection rates. This study did not find any differences in overall survival and disease-free survival between angiotensin system inhibitor users and non-angiotensin system inhibitor users. CONCLUSION: Angiotensin system inhibitors have been shown to improve survival and decrease relative risk for several types of cancers; however, our data do not support the same effect on esophageal cancer patients undergoing curative intent surgery. Further research is needed to investigate potential nuances in angiotensin system inhibitor dose, chronicity of use, esophageal pathology, and applicability to nonsurgical candidates.

Renal Denervation and Celiac Ganglionectomy Decrease Mean Arterial Pressure Similarly in Genetically Hypertensive Schlager (BPH/2J) Mice.

Renal denervation (RDNX) lowers mean arterial pressure (MAP) in patients with resistant hypertension. Less well studied is the effect of celiac ganglionectomy (CGX), a procedure which involves the removal of the nerves innervating the splanchnic vascular bed. We hypothesized that RDNX and CGX would both lower MAP in genetically hypertensive Schlager (BPH/2J) mice through a reduction in sympathetic tone. Telemeters were implanted into the femoral artery in mice to monitor MAP before and after RDNX (n=5), CGX (n=6), or SHAM (n=6). MAP, systolic blood pressure, diastolic blood pressure, and heart rate were recorded for 14 days postoperatively. The MAP response to hexamethonium (10 mg/kg, IP) was measured on control day 3 and postoperative day 10 as a measure of global neurogenic pressor activity. The efficacy of denervation was assessed by measurement of tissue norepinephrine. Control MAP was similar among the 3 groups before surgical treatments (≈130 mm Hg). On postoperative day 14, MAP was significantly lower in RDNX (-11±2 mm Hg) and CGX (-11±1 mm Hg) groups compared with their predenervation values. This was not the case in SHAM mice (-5±3 mm Hg). The depressor response to hexamethonium in the RDNX group was significantly smaller on postoperative day 10 (-10±5 mm Hg) compared with baseline control (-25±10 mm Hg). This was not the case in mice in the SHAM (day 10; -28±5 mm Hg) or CGX (day 10; -34±7 mm Hg) group. In conclusion, both renal and splanchnic nerves contribute to hypertension in BPH/2J mice, but likely through different mechanisms.

Antimicrobial susceptibility of biliary stents do not predict infectious complications after whipple.

BACKGROUND: Postoperative infectious complications after a pancreaticoduodenectomy remain a significant cause of morbidity. Studies have demonstrated that a preoperative biliary stent increases the risk of postoperative infectious complications. Few studies have investigated the specific preoperative biliary stent bacterial sensitivities to preoperative antibiotics and the effect on infectious complications. The goal of this study was to investigate if the presence of a preoperative biliary stent increases the risk of postoperative infectious complications in patients undergoing a pancreaticoduodenectomy. Additionally, we aimed to investigate biliary stent culture sensitivities to preoperative antibiotics and determine if those sensitivities impacted postoperative infectious complications after a pancreaticoduodenectomy. METHODS: A retrospective chart review of patients who had undergone a pancreaticoduodenectomy at a single institution tertiary care center from 2007 to 2018 was performed. Perioperative variables including microbiology cultures from biliary stents were collected and analyzed. RESULTS: A total of 244 patients underwent a pancreaticoduodenectomy. A preoperative biliary stent was present in 45 (18%) patients. Infectious complications occurred in 25% of those patients with a preoperative biliary stent, and 19% of those without (P = .37). Of those patients with a stent that was cultured intraoperatively, 92% grew bacteria and 61% of those were resistant to the preoperative antibiotics administered. Of the patients with a preoperative biliary stent and bacteria resistant to the preoperative antibiotics, 17% developed a postoperative infectious complication, compared with 20% if the bacteria cultured was susceptible to the preoperative antibiotics (P = .64). CONCLUSION: Infectious complications after pancreaticoduodenectomy are a significant cause of morbidity. Stent bacterial sensitivities to preoperative antibiotics did not reduce the postoperative infectious complications in the preoperative biliary stent group suggesting a multifactorial cause of infections.

Renal Inflammation in DOCA-Salt Hypertension.

Recent reports indicate that, in addition to treating hypertension, renal denervation (RDN) also mitigates renal inflammation. However, because RDN decreases renal perfusion pressure, it is unclear whether these effects are because of the direct effects of RDN on inflammatory signaling or secondary to decreased arterial pressure (AP). Therefore, this study was conducted to elucidate the contribution of renal nerves to renal inflammation in the deoxycorticosterone (DOCA)-salt rat, a model in which RDN decreases AP and abolishes renal inflammation. In Experiment 1, we assessed the temporal changes in renal inflammation by measuring renal cytokines and AP in DOCA-salt rats. Uninephrectomized (1K) adult male Sprague Dawley rats that received surgical RDN or sham (Sham) were administered DOCA (100 mg, SC) and 0.9% saline for 21 days. AP was measured by radiotelemetry, and urinary cytokine excretion was measured repeatedly. In Experiment 2, the contribution of renal nerves in renal inflammation was assessed in a 2-kidney DOCA-salt rat to control for renal perfusion pressure. DOCA-salt treatment was administered after unilateral (U-)RDN. In Experiment 1, DOCA-salt-induced increases in AP and renal inflammation (assessed by urinary cytokines) were attenuated by RDN versus Sham. In Experiment 2, GRO/KC (growth-related oncogene/keratinocyte chemoattractant), MCP (monocyte chemoattractant protein)-1, and macrophage infiltration were lower in the denervated kidney versus the contralateral Sham kidney. No differences in T-cell infiltration were observed. Together, these data support the hypothesis that renal nerves mediate, in part, the development of renal inflammation in the DOCA-salt rat independent of hypertension. The mechanisms and cell-specificity mediating these effects require further investigation.

Targeted afferent renal denervation reduces arterial pressure but not renal inflammation in established DOCA-salt hypertension in the rat.

Recent preclinical studies show renal denervation (RDNx) may be an effective treatment for hypertension; however, the mechanism remains unknown. We have recently reported total RDNx (TRDNx) and afferent-selective RDNx (ARDNx) similarly attenuated the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Whereas TRDNx abolished renal inflammation, ARDNx had a minimal effect despite an identical antihypertensive effect. Although this study established that ARDNx attenuates the development of DOCA-salt hypertension, it is unknown whether this mechanism remains operative once hypertension is established. The current study tested the hypothesis that TRDNx and ARDNx would similarly decrease mean arterial pressure (MAP) in the DOCA-salt hypertensive rat, and only TRDNx would mitigate renal inflammation. After 21 days of DOCA-salt treatment, male Sprague-Dawley rats underwent TRDNx ( n = 16), ARDNx ( n = 16), or Sham ( n = 14) treatment and were monitored for 14 days. Compared with baseline, TRDNx and ARDNx decreased MAP similarly (TRDNx -14 ± 4 and ARDNx -15 ± 6 mmHg). After analysis of diurnal rhythm, rhythm-adjusted mean and amplitude of night/day cycle were also reduced in TRDNx and ARDNx groups compared with Sham. Notably, no change in renal inflammation, injury, or function was detected with either treatment. We conclude from these findings that: 1) RDNx mitigates established DOCA-salt hypertension; 2) the MAP responses to RDNx are primarily mediated by ablation of afferent renal nerves; and 3) renal nerves do not contribute to the maintenance of renal inflammation in DOCA-salt hypertension.