A Case of Complex Pulmonary Hypertension: the Importance of Diagnostic Investigation

Pulmonary hypertension (PH) encompasses several heterogeneous groups of multiple diseases characterized by abnormal pulmonary arterial blood pressure elevation. Unrepaired atrial septal defect (ASD) may be associated with pulmonary arterial hypertension (PAH), indicating pulmonary vascular remodeling. Furthermore, unrepaired ASD could also be associated with other conditions, such as left heart disease or thromboembolism, contributing to the disease progression. We present a case of a 61-years-old woman with complex PH comprising several etiologies, which are PAH due to unrepaired Secundum ASD, mitral regurgitation caused by mitral valve prolapse as a group 2 PH, pulmonary embolism (PE) which progress to chronic thromboembolism PH (CTEPH) and post-acute sequelae of SARS Cov-2. We highlighted the importance of diagnostic investigation in PH, which is crucial to avoid misdiagnosis and inappropriate treatment that could be detrimental for the patient.

Blood Pressure Elevation of Tubular Specific (P)RR Transgenic Mice and Lethal Tubular Degeneration due to Possible Intracellular Interactions between (P)RR and Alternative Renin Products

The prorenin/renin receptor ((P)RR) is a multifunctional protein that is widely distributed in various organs. Despite intensive research for more than 20 years, this receptor has not been fully characterized. In this study, we generated mice overexpressing the tubular epithelial (P)RR gene ((P)RR-TG mice) to test the previously reported functional role of (P)RR by Ramkumar et al. in 2015 using tubular specific (P)RR KO mice. (P)RR-TG mice were maintained and analyzed in individual metabolic cages and were administered angiotensin II blocker (ARB), direct renin inhibitor (DRI), and bafilomycin, that is, vacuolar ATPase (V-ATPase) antagonist. (P)RR-TG mice were hypertensive and had alkalized urine with lower osmolality and Na+ excretion. ARB and DRI, but not bafilomycin, concurrently decreased blood pressure. Bafilomycin acidized urine of (P)RR-TG mice, or equivalently this phenomenon restored the effect of overexpressed transgene, suggesting that (P)RR functioned as a V-ATPase in renal tubules. Afterall, (P)RR-TG mice were mated with alternative renin transgenic mice (ARen2-TG), which we identified as intracellular renin previously, to generate double transgenic mice (DT-TG). Lethal renal tubular damage was observed in DT-TG mice, suggesting that intracellular renin may be a ligand for (P)RR in tubules. In summary, (P)RR did not substantially affect the tissue renin-angiotensin system (RAS) in our model of tubular specific (P)RR gene over-expression, but alternative intracellular renin may be involved in (P)RR signaling in addition to conventional V-ATPase function. Further investigations are warranted.

Dual sEH/COX-2 Inhibition Using PTUPB—A Promising Approach to Antiangiogenesis-Induced Nephrotoxicity

Kidney injury from antiangiogenic chemotherapy is a significant clinical challenge, and we currently lack the ability to effectively treat it with pharmacological agents. Thus, we set out to investigate whether simultaneous soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) inhibition using a dual sEH/COX-2 inhibitor PTUPB could be an effective strategy for treating antiangiogenic therapy-induced kidney damage. We used a multikinase inhibitor, sorafenib, which is known to cause serious renal side effects. The drug was administered to male Sprague–Dawley rats that were on a high-salt diet. Sorafenib was administered over the course of 56 days. The study included three experimental groups; 1) control group (naïve rats), 2) sorafenib group [rats treated with sorafenib only (20 mg/kg/day p.o.)], and 3) sorafenib + PTUPB group (rats treated with sorafenib only for the initial 28 days and subsequently coadministered PTUPB (10 mg/kg/day i.p.) from days 28 through 56). Blood pressure was measured every 2 weeks. After 28 days, sorafenib-treated rats developed hypertension (161 ± 4 mmHg). Over the remainder of the study, sorafenib treatment resulted in a further elevation in blood pressure through day 56 (200 ± 7 mmHg). PTUPB treatment attenuated the sorafenib-induced blood pressure elevation and by day 56, blood pressure was 159 ± 4 mmHg. Urine was collected every 2 weeks for biochemical analysis. After 28 days, sorafenib rats developed pronounced proteinuria (9.7 ± 0.2 P/C), which intensified significantly (35.8 ± 3.5 P/C) by the end of day 56 compared with control (2.6 ± 0.4 P/C). PTUPB mitigated sorafenib-induced proteinuria, and by day 56, it reduced proteinuria by 73%. Plasma and kidney tissues were collected on day 56. Kidney histopathology revealed intratubular cast formation, interstitial fibrosis, glomerular injury, and glomerular nephrin loss at day 56 in sorafenib-treated rats. PTUPB treatment reduced histological features by 30%–70% compared with the sorafenib-treated group and restored glomerular nephrin levels. Furthermore, PTUPB also acted on the glomerular permeability barrier by decreasing angiotensin-II-induced glomerular permeability to albumin. Finally, PTUPB improved in vitro the viability of human mesangial cells. Collectively, our data demonstrate the potential of using PTUPB or dual sEH/COX-2 inhibition as a therapeutic strategy against sorafenib-induced glomerular nephrotoxicity.

Vitamin D Deficiency Is a Potential Risk for Blood Pressure Elevation and the Development of Hypertension

Background and objectives: Hypertension is a global health problem and a major risk factor for cardiovascular diseases. Vitamin D deficiency is closely related to high blood pressure and the development of hypertension. This study investigated the relationship between the vitamin D and blood pressure status in healthy adults, and their 8-year follow-up was added. Materials and Methods: A total of 491 healthy middle-aged participants without any chronic illness, ages 21 to 67 at baseline, were divided into two groups as non-optimal blood pressure (NOBP) and optimal blood pressure (OBP). NOBP group was divided into two subgroups: normal (NBP) and high normal blood pressure (HNBP). Serum 25-hydroxy vitamin D levels were measured with the immunoassay method. 8-year follow-up of the participants was added. Results: The average vitamin D level was detected 32.53 ± 31.50 nmol/L in the OBP group and 24.41 ± 14.40 nmol/L in the NOBP group, and a statistically significant difference was found (p < 0.001). In the subgroup analysis, the mean vitamin D level was detected as 24.69 ± 13.74 and 24.28 ± 14.74 nmol/L in NBP and HNBP, respectively. Together with parathyroid hormone, other metabolic parameters were found to be significantly higher in the NOBP. During a median follow-up of 8 years, higher hypertension development rates were seen in NOBP group (p < 0.001). Conclusions: The low levels of vitamin D were significantly associated with NBP and HNBP. The low levels of vitamin D were also associated with the development of hypertension in an 8-year follow-up.

Visual deterioration after endonasal endoscopic skull base surgery: causes, treatments, and outcomes

OBJECTIVE Visual deterioration after endoscopic endonasal transsphenoidal surgery (EETS) for sellar and parasellar masses is a rare but serious complication caused by either compressive or ischemic mechanisms. Timely diagnosis and intervention may restore vision if instituted appropriately. The associated risk factors and their relation to the success of intervention are not well understood. METHODS The authors examined a series of 1200 consecutive EETS cases performed by the senior author at Weill Cornell/NewYork-Presbyterian Hospital from 2010 to 2020. Cases with postoperative visual deterioration were identified. Pre- and postoperative clinical data, mechanism of visual decline, latency to intervention, and long-term visual outcome were retrospectively collected and analyzed with appropriate statistical methods. RESULTS Twenty-one patients (1.75%) complained of early postoperative visual deterioration. The most common pathology associated with postoperative visual loss was craniopharyngioma (7.69%), followed by meningioma (5.43%) and then pituitary adenoma (1.94%). Timely intervention restored vision in 81% of patients for a 0.33% rate of permanent visual deterioration. Average time to visual deterioration was 28.8 hours, and over 70% of patients experienced vision loss within the first 13 hours. Compressive etiology (n = 11), consisting of either hematoma (n = 8) or graft displacement (n = 3), occurred 7.3 hours and 70.3 hours after surgery, respectively, and was more common in adenomas. Acute postoperative visual deterioration was more common in firm closures (4.78%) compared with soft closures (1.03%; p = 0.0006). Ischemic etiology (n = 10) occurred 10.3 hours after surgery and was more common with craniopharyngiomas and meningiomas (p = 0.08). Sixteen patients (76.2%) underwent early reoperation to explore and decompress the optic apparatus. Vision was restored to baseline after reoperation in all 11 compressive cases, whereas 6/10 ischemic cases improved with supplemental oxygen and hypervolemic hypertensive therapy (p = 0.02). Fluid expansion from 8 to 16 hours (p = 0.034) and systolic blood pressure elevation from 32 to 48 hours (p = 0.05) after surgery were significantly higher in those ischemic patients who recovered some vision compared with those with persistent visual deficits. CONCLUSIONS Visual deterioration after EETS is a rare event but can be effectively treated if acted upon appropriately and in a timely fashion. Compressive etiology is reversible with early reoperation. Ischemic etiology can be successfully treated in roughly half of cases with supplemental oxygen and hypertensive hypervolemic therapy but may result in permanent visual deterioration if not instituted appropriately or if delayed with unnecessary exploratory surgery.

Machine Learning Analysis of Time-Dependent Features for Predicting Adverse Events During Hemodialysis Therapy: Model Development and Validation Study

Background Hemodialysis (HD) therapy is an indispensable tool used in critical care management. Patients undergoing HD are at risk for intradialytic adverse events, ranging from muscle cramps to cardiac arrest. So far, there is no effective HD device–integrated algorithm to assist medical staff in response to these adverse events a step earlier during HD. Objective We aimed to develop machine learning algorithms to predict intradialytic adverse events in an unbiased manner. Methods Three-month dialysis and physiological time-series data were collected from all patients who underwent maintenance HD therapy at a tertiary care referral center. Dialysis data were collected automatically by HD devices, and physiological data were recorded by medical staff. Intradialytic adverse events were documented by medical staff according to patient complaints. Features extracted from the time series data sets by linear and differential analyses were used for machine learning to predict adverse events during HD. Results Time series dialysis data were collected during the 4-hour HD session in 108 patients who underwent maintenance HD therapy. There were a total of 4221 HD sessions, 406 of which involved at least one intradialytic adverse event. Models were built by classification algorithms and evaluated by four-fold cross-validation. The developed algorithm predicted overall intradialytic adverse events, with an area under the curve (AUC) of 0.83, sensitivity of 0.53, and specificity of 0.96. The algorithm also predicted muscle cramps, with an AUC of 0.85, and blood pressure elevation, with an AUC of 0.93. In addition, the model built based on ultrafiltration-unrelated features predicted all types of adverse events, with an AUC of 0.81, indicating that ultrafiltration-unrelated factors also contribute to the onset of adverse events. Conclusions Our results demonstrated that algorithms combining linear and differential analyses with two-class classification machine learning can predict intradialytic adverse events in quasi-real time with high AUCs. Such a methodology implemented with local cloud computation and real-time optimization by personalized HD data could warn clinicians to take timely actions in advance.

Abstract P242: The Role Of Kappa Opioid Receptors In The Development Of Hypertension And Kidney Injury In Sprague-Dawley Rats

The extensive use of opioid-based pain management strongly correlates with poor cardiovascular and cardiorenal outcomes. Our recent studies suggest that treatment with kappa opioid receptor (KOR) agonist BRL 52537 leads to the progression of chronic kidney disease (CKD) and aggravation of salt-sensitive hypertension. We hypothesize that stimulation of KORs leads to blood pressure elevation, albuminuria, and kidney damage in healthy Sprague-Dawley (SD) rats. To characterize the effect of the KOR agonist BRL 52537 on the development of blood pressure and kidney function in vivo , SD rats were treated with a daily i.v. bolus infusion of BRL 52537 or a corresponding vehicle. To test the contribution of KOR stimulation on calcium homeostasis in podocytes, BRL 52537 was used on freshly isolated glomeruli from SD rats. Single-channel analysis was applied to assess the effect of KORs stimulation on TRPC6 channel activity in the human immortalized podocytes. Chronic treatment with BRL 52537 leads to increased mean arterial pressure (88±1 vs 101±4 mmHg, vehicle vs treated, p<0.05), podocyte basal calcium (90±12 vs 216±16 a.u., vehicle vs treated, p<0.05), and GFB impairment in SD rats which is reflected by a transient increase in albumin excretion (Alb/cre ratio 0.35±0.1 vs 0.72±0.2, vehicle vs treated, p<0.05). Cumulative probability distribution analysis of the glomerular injury score revealed a rightward shift toward a high glomerular injury score in the group treated with BRL 52537 (p<0.05). Angiotensin II level was higher in a BRL-treated group (156±17 vs 232±59 pmol, vehicle vs treated, p=0.065); however, it did not reach a statistical difference. Acute application of BRL 52537 resulted in sustained calcium response (0.23±0.01 a.u., Fluo4/FuraRed, maximum calcium response) in freshly isolated glomeruli from SD rats. Furthermore, patch-clamp experiments in human immortalized podocytes (cell-attached configuration) revealed that BRL 52537 activated TRPC6 channels. Taken together, these data support the hypothesis that administration of opioids in SD rats leads to activation of the KOR/TRPC6 pathway, which in turn led to glomerular filtration barrier impairment, increased glomerular damage, and blood pressure elevation.

Abstract MP31: A20 In Renal Tubular Cells Protects Against Hypertension

The ubiquitin-editing protein A20 suppresses NF-κB signaling, which contributes to hypertension and kidney inflammation. However, whether A20 generated directly in the kidney tubule regulates blood pressure requires elucidation. To examine the role of tubular A20 in hypertension, we bred A20 flox/flox mice with the Pax8-rtTA and Tet-On lines to generate inducible renal epithelial cell A20 knockout mice (A20 iKKO). Mice with all 3 transgenes were used as the A20 iKKO group, while mice lacking the Pax8-rtTA or Tet-On transgene acted as wild-type (WT) controls. Prior to experiments, all mice were given 2mg/ml of doxycycline in the drinking water for 2 weeks to ablate A20 in renal tubular cells. By qPCR, mRNA levels for A20 were selectively reduced by 63% in A20 iKKO kidneys vs WT controls. Baseline blood pressures were similar in the groups. During 3 weeks of chronic angiotensin (Ang) II infusion (500ng/kg/min), A20 iKKO mice exhibited higher mean arterial pressures measured by telemetry compared to WTs (155±2 vs. 143±4 mmHg; p =0.024). As a result, the A20 iKKOs had worse cardiac hypertrophy than the WTs after AngII (7.10±0.17 vs. 6.27±0.16 mg heart/g body weight; p <0.005.). In addition, mRNA levels for TNF-α were markedly increased (1.54±0.21 vs. 1.0±0.1 arbitrary units; p <0.05) in A20 iKKO kidneys compared to WTs, whereas the genes encoding IL-1β and IFNγ were similarly expressed in the groups. In the 3 rd week of AngII, levels of sodium-hydrogen exchanger 3 (NHE3) protein (1.50±0.10 vs. 1.0±0.1; p <0.0005) and NF-κB p50 subunit mRNA (1.30±0.14 vs. 1.0±0.06; p <0.05) were increased in A20 iKKO kidneys compared to WTs. Treating both WTs and A20 iKKOs with the TNF-α inhibitor (R7050, 12mg/body weight) every other day during the 1 st week of AngII infusion yielded similar levels of blood pressure elevation (141.57±4.54 vs. 140.35±5.60 mmHg; p =0.87). These data suggest that tubular A20 limits sodium reabsorption and blood pressure elevation by inhibiting NF-κB/ TNF-dependent NHE3 induction in the kidney.

Abstract 18: Excess Dietary Salt-induced Blood Pressure Elevation Is Associated With Impaired Bile Acid Signaling And Human Monocyte Activation

Excess dietary sodium (Na + ) is a major risk for hypertension and cardiovascular disease. We previously found that excess dietary salt induces gut microbial dysbiosis and leads to activation of antigen presenting cells and hypertension, but the mechanisms are not known. The gut microbiome metabolizes bile acids, and these have been implicated in activation of antigen presenting cells. We hypothesized that high dietary Na + -induced inflammation leading to hypertension is associated with impaired bile acids signaling. We measured plasma bile acids via a metabolomics analysis in 75 volunteers. Blood pressure was also monitored. Based on the recommendations by the American Heart Association, we classified daily Na + intake <2.3g as normal salt (NS, n=23), and high salt (HS, n=52) for subjects consuming ≥ 2.3g Na + . Spearman correlation was used to assess the relationship between Na + intake and blood pressure. We found that elevated diastolic (r=0.331, p=0.003), systolic (r=0.383, p<0.001) and mean arterial pressure (r=0.278, p=0.014) were associated with increased Na + intake. Five taurine and glycine-conjugated secondary bile acids including taurodeoxycholate (1.320 ± 0.238 vs. 2.820 ± 0.669; p=0.010); glycodeoxycholate (1.197± 0.154 vs. 1.998± 0.432; p= 0.033); glycodeoxycholate sulfate (1.037± 0.132 vs. 1.521± 0.192; p= 0.044); glycolithocholate (0.829± 0.094 vs. 1.622± 0.363; p= 0.006) and glycolithocholate sulfate (1.083± 0.127 vs. 1.598± 0.205; p= 0.030) were lower in the HS when compared to the NS group. Interestingly, using RNA sequencing in human monocytes, we found that the NR1H4 gene which encodes the farnesoid X receptor, a nuclear receptor activated by bile acids, was significantly downregulated by high salt treatment, and this was associated with a pro-inflammatory phenotype (9.80± 1.65 vs. 11.82± 1.64; adjusted p-value=0.043). Our findings suggest that high salt impairs bile acids signaling leading to inflammation and salt-induced hypertension.