NaHCO3 loading causes increased arterial pressure and kidney damage in rats with chronic kidney disease.

Sodium bicarbonate (NaHCO3) is commonly utilized as a therapeutic to treat metabolic acidosis in people with chronic kidney disease (CKD). While increased dietary sodium chloride (NaCl) is known to promote volume retention and increase blood pressure, the effects of NaHCO3 loading on blood pressure and volume retention in CKD remain unclear. In the present study, we compared the effects of NaCl and NaHCO3 loading on volume retention, blood pressure, and kidney injury in both 2/3 and 5/6 nephrectomy remnant kidney rats, a well-established rodent model of CKD. We tested the hypothesis that NaCl loading promotes greater volume retention and increases in blood pressure than equimolar NaHCO3. Blood pressure was measured 24 h daily using radio telemetry. NaCl and NaHCO3 were administered in drinking water ad libitum or infused via indwelling catheters. Rats were housed in metabolic cages to determine volume retention. Our data indicate that both NaHCO3 and NaCl promote hypertension and volume retention in remnant kidney rats, with salt-sensitivity increasing with greater renal mass reduction. Importantly, while NaHCO3 intake was less pro-hypertensive than equimolar NaCl intake, NaHCO3 was not benign. NaHCO3 loading significantly elevated blood pressure and promoted volume retention in rats with CKD when compared with control rats receiving tap water. Our findings provide important insight into the effects of sodium loading with NaHCO3 in CKD and indicate that NaHCO3 loading in patients with CKD is unlikely to be benign.

Galectin-3 Mediates Vascular Dysfunction in Obesity by Regulating NADPH Oxidase 1.

BACKGROUND: Obesity is associated with increased risk of cardiovascular disease, but underlying mechanisms remain elusive. Metabolic dysfunction, especially hyperglycemia, is thought to be a major contributor, but how glucose impacts vascular function is unclear. GAL3 (galectin-3) is a sugar-binding lectin upregulated by hyperglycemia, but its role as a causative mechanism of cardiovascular disease remains poorly understood. Therefore, the objective of this study was to determine the role of GAL3 in regulating microvascular endothelial vasodilation in obesity. METHODS: GAL3 was measured and found to be markedly increased in the plasma of overweight and obese patients, as well as in the microvascular endothelium of diabetic patients. To investigate causative mechanisms in cardiovascular disease, mice deficient in GAL3 were bred with obese db/db mice to generate lean, lean GAL3 knockout, obese, and obese GAL3 knockout genotypes. Endothelial cell-specific GAL3 knockout mice with novel AAV-induced obesity recapitulated whole-body knockout studies to confirm cell specificity. RESULTS: Deletion of GAL3 did not alter body mass, adiposity, or plasma indices of glycemia and lipidemia, but levels of plasma reactive oxygen species as assessed by plasma thiobarbituric acid reactive substances were normalized in obese GAL3 knockout mice. Obese mice exhibited profound endothelial dysfunction and hypertension, both of which were rescued by GAL3 deletion. Isolated microvascular endothelial cells from obese mice had increased expression of NOX1 (nicotinamide adenine dinucleotide phosphate oxidase 1), which we have previously shown to contribute to increased oxidative stress and endothelial dysfunction, which was normalized in microvascular endothelium from mice lacking GAL3. Cell-specific deletion confirmed that endothelial GAL3 regulates obesity-induced NOX1 overexpression and subsequent microvascular function. Furthermore, improvement of metabolic syndrome by increasing muscle mass, improving insulin signaling, or treating with metformin decreased microvascular GAL3, and thereby NOX1, expression levels. CONCLUSIONS: Deletion of GAL3 normalizes microvascular endothelial function in obese db/db mice, likely through a NOX1-mediated mechanism. Pathological levels of GAL3, and in turn NOX1, are amenable to improvements in metabolic status, presenting a potential therapeutic target to ameliorate pathological cardiovascular consequences of obesity.

A Non-Systemic Phosphodiesterase-5 Inhibitor Suppresses Colon Proliferation in Mice.

Phosphodiesterase-5 inhibitors (PDE5i) are under investigation for repurposing for colon cancer prevention. A drawback to conventional PDE5i are their side-effects and drug-drug interactions. We designed an analog of the prototypical PDE5i sildenafil by replacing the methyl group on the piperazine ring with malonic acid to reduce lipophilicity, and measured its entry into the circulation and effects on colon epithelium. This modification did not affect pharmacology as malonyl-sildenafil had a similar IC50 to sildenafil but exhibited an almost 20-fold reduced EC50 for increasing cellular cGMP. Using an LC-MS/MS approach, malonyl-sildenafil was negligible in mouse plasma after oral administration but was detected at high levels in the feces. No bioactive metabolites of malonyl-sildenafil were detected in the circulation by measuring interactions with isosorbide mononitrate. The treatment of mice with malonyl-sildenafil in the drinking water resulted in a suppression of proliferation in the colon epithelium that is consistent with results previously published for mice treated with PDE5i. A carboxylic-acid-containing analog of sildenafil prohibits the systemic delivery of the compound but maintains sufficient penetration into the colon epithelium to suppress proliferation. This highlights a novel approach to generating a first-in-class drug for colon cancer chemoprevention.

Pleural Effusion and Malnutrition Are Associated With Worse Early Outcomes After Liver Transplant.

INTRODUCTION: Pulmonary complications after liver transplantation (LT) have previously been associated with longer hospital stays and ventilator time, and higher mortality. This study reports the outcomes for a specific pulmonary complication, pleural effusion, in LT recipients. METHODS: Records from a single transplant center were analyzed retrospectively for all adult LT patients. Patients with documented pleural effusion by radiographic imaging within 30 days pre- or post-transplant were considered as cases. Outcomes included length of hospital stay, discharge disposition, hospital readmission, discharge with home oxygen, and 1-year survival. RESULTS: During the 4-year study period, 512 LTs were performed, with 107 patients (21%) developing a peri-transplant pleural effusion. In total, 49 patients (10%) had a pre-transplant effusion, 91 (18%) had a post-transplant effusion, and 32 (6%) had both. Characteristics associated with the presence of any pleural effusion included an increasing model for end-stage liver disease score, re-transplantation, diagnosis of alcoholic liver disease, low protein levels, and sarcopenia. Effusion patients had longer hospital stays (17 vs 9 days, P < .001) and higher likelihood of discharge to a care facility (48% vs 21%, P < .001). Ninety-day readmission occurred in 69% of effusion patients (vs 44%, P < .001). One-year patient survival with any effusion was 86% (vs 94%, P < .01). CONCLUSIONS: Overall, 21% of recipients developed a clinically significant peri-transplant pleural effusion. Pleural effusion was associated with worse outcomes for all clinical measures. Risk factors for the development of pleural effusion included higher MELD score (>20), re-transplantation, alcoholic liver disease, and poor nutrition status, including poor muscle mass.

Galectin-3 Mediates Vascular Dysfunction in Obesity by Regulating NADPH Oxidase 1.

Rationale: Obesity increases the risk of cardiovascular disease (CVD) through mechanisms that remain incompletely defined. Metabolic dysfunction, especially hyperglycemia, is thought to be a major contributor but how glucose impacts vascular function is unclear. Galectin-3 (GAL3) is a sugar binding lectin upregulated by hyperglycemia but its role as a causative mechanism of CVD remains poorly understood. Objective: To determine the role of GAL3 in regulating microvascular endothelial vasodilation in obesity. Methods and Results: GAL3 was markedly increased in the plasma of overweight and obese patients, as well as in the microvascular endothelium of diabetic patients. To investigate a role for GAL3 in CVD, mice deficient in GAL3 were bred with obese db/db mice to generate lean, lean GAL3 knockout (KO), obese, and obese GAL3 KO genotypes. GAL3 KO did not alter body mass, adiposity, glycemia or lipidemia, but normalized elevated markers of reactive oxygen species (TBARS) in plasma. Obese mice exhibited profound endothelial dysfunction and hypertension, both of which were rescued by GAL3 deletion. Isolated microvascular endothelial cells (EC) from obese mice had increased NOX1 expression, which we have previously shown to contribute to increased oxidative stress and endothelial dysfunction, and NOX1 levels were normalized in EC from obese mice lacking GAL3. EC-specific GAL3 knockout mice made obese using a novel AAV-approach recapitulated whole-body knockout studies, confirming that endothelial GAL3 drives obesity-induced NOX1 overexpression and endothelial dysfunction. Improved metabolism through increased muscle mass, enhanced insulin signaling, or metformin treatment, decreased microvascular GAL3 and NOX1. GAL3 increased NOX1 promoter activity and this was dependent on GAL3 oligomerization. Conclusions: Deletion of GAL3 normalizes microvascular endothelial function in obese db/db mice, likely through a NOX1-mediated mechanism. Pathological levels of GAL3 and in turn, NOX1, are amenable to improvements in metabolic status, presenting a potential therapeutic target to ameliorate pathological cardiovascular consequences of obesity.

Eleven-Year Experience with Selective Adrenal Vein Sampling in Management of Primary Adrenal Hormonal Hypersecretion.

Introduction: Nearly half of the adult population in the United States has been diagnosed with hypertension. Adrenal hormonal hypersecretion is a leading cause of secondary hypertension. Adrenal vein sampling (AVS) may assist in differentiating between unilateral and bilateral adrenal hormonal hypersecretion to identify patients who are candidates for adrenalectomy. We reviewed the use of AVS at our institution along with associated outcomes after adrenalectomy. Materials and Methods: A retrospective chart review was conducted of patients with a diagnosis of primary hyperaldosteronism (PA) or adrenocorticotropic hormone-independent Cushing syndrome (AICS) and who underwent adrenalectomy between January 1, 2010, and December 1, 2021. Patient data of baseline characteristics, preoperative workup, including AVS, and postoperative outcomes were collected and analyzed. Results: Seventy-one patients were identified in the study period (48 PA and 23 AICS). Computed tomography scan identified unilateral adrenal nodules in 52 patients (29 left; and 23 right), bilateral nodules in 13 patients, and no nodules in 6 patients. AVS was performed in 45 patients with PA (93%) and 5 patients with AICS (21%). After surgery, the number of PA patients with hypokalemia or requiring potassium supplementation significantly decreased after adrenalectomy (before surgery: 33 [68.7%]; and after surgery: 5 [10.4%], P < .01). The number of medications required for hypertension in AICS patients also significantly decreased. No major adverse events were noted. Conclusions: Our long-term experience demonstrates the ongoing use of AVS during workup of patients with primary hyperaldosteronism and for select patients with adrenocorticotropic hormone-independent Cushing syndrome. However, a low level of discordance between imaging and AVS findings in PA patients suggests that there may be a subset of patients in whom preoperative AVS is not necessary.

Radiologic Assessment of Muscle and Fat Stores in Long-Term Type I Diabetics Referred for Pancreas Transplant Compared to Healthy Controls.

Type 1 diabetes (DM1) is associated with loss of skeletal muscle and bone mass and may affect body fat stores. This study employs computed tomography (CT) scans to assess the body composition of DM1 patients referred for pancreas transplant compared to healthy controls. A 1:1 case-control design matched study patients with otherwise healthy patients from the trauma database. Matching criteria included age ± 5 years, gender, and body mass index (BMI) ± 2kg/m2. Nutrition variables included serum albumin and protein levels, BMI, and CT measures of muscle mass and fat stores. There were 22 subjects and 22 controls (median DM1 duration 24 years). DM1 patients had less muscle mass and less subcutaneous fat but no difference in visceral fat. Patients with the greatest muscle deficit were those with DM1 greater than 20 years and those younger than age 40. DM1 patients maintain similar BMI and protein levels compared to healthy controls but have marked deficits of muscle and subcutaneous fat. These results inform the nutritional management of DM1 patients and quantify the muscle and fat deficits present in these patients. At highest risk are young patients and those with duration of DM1 over 20 years.

Tracheostomy Post Liver Transplant: Predictors, Complications, and Outcomes.

BACKGROUND Liver transplant (LT) patients have an increased risk of postoperative respiratory failure requiring tracheostomy. This study sought to characterize objective clinical predictors of tracheostomy. MATERIAL AND METHODS The records for 2017 LT patients at a single institution were reviewed. Patients requiring tracheostomy were first compared with all other patients. A case-control subgroup analysis was conducted in which 98 tracheostomy patients were matched with 98 non-tracheostomy LT patients. For the case-control study, muscle mass was assessed using preoperative computed tomography scans. RESULTS Among 2017 LT patients, 98 required tracheostomy (5%), with a 19% complication rate. Tracheostomy patients were older and had a higher model for end-stage liver disease score, a lower body mass index (BMI), and a greater smoking history. Tracheostomy patients had a longer hospital stay (45 vs. 10 days, P<0.001) and worse 1-year survival (65% vs. 91%, P<0.001). Ten-year Cox regression patient survival for tracheostomy patients was significantly worse (32% vs. 68%, P<0.001). In the case-control analysis, respiratory failure patients were older (P<0.01) and had a lower BMI (P=0.05). They also had a muscle mass deficit of -39% compared with matched LT controls (P<0.001). No significant differences were seen with pre-LT total protein or albumin or with forced expiratory volume in 1 s divided by forced vital capacity (FEV1/FVC) values. CONCLUSIONS Predictors for respiratory failure requiring post-LT tracheostomy include higher model for end-stage liver disease score, older age, lower BMI, greater smoking history, and worse sarcopenia. Patients requiring tracheostomy have dramatically longer hospital stays and worse survival.

Severe Sarcopenia and Increased Fat Stores in Pediatric Patients With Liver, Kidney, or Intestine Failure.

OBJECTIVES: Malnutrition and wasting predict clinical outcomes in children with severe chronic illness. Objectively calculated malnutrition in children with end-stage organ failure has not been well studied. This analysis compares children with kidney, liver or intestine failure to healthy controls to quantitate the disparity in muscle and fat stores. METHODS: Children younger than 19 years with end-stage liver, kidney, or intestine failure and with pretransplant computed tomography (CT) imaging were selected from the transplant database. Age- and sex-matched healthy controls were selected from the trauma database. Measures of nutrition status included a scaled scoring of core muscle mass, and visceral and subcutaneous fat stores. Analysis was conducted using the pooled and individually matched subject-control differences. RESULTS: There were 81 subjects included in the final analysis (liver [n = 35], kidney [n = 20], and intestine [n = 26]). Children with end-stage liver disease had a 23% reduction in muscle mass, a 69% increase in visceral fat, and a 29% increase in subcutaneous fat. End-stage renal disease patients had a 19% reduction in muscle mass and a 258% increase in subcutaneous fat. Intestine failure patients had a 24% reduction in muscle mass, a 30% increase in visceral fat, and a 46% increase in subcutaneous fat. CONCLUSIONS: These results demonstrate significant sarcopenia and increased fat stores in end-stage organ failure patients, which supports the idea of an active physiologic mechanism to store fat while losing muscle mass. Sarcopenia may be related to total protein loss from a catabolic state, or from decreased synthesis (liver), wasting (kidney), or malabsorption (intestine).

Minimal Improvement in Glomerular Filtration Rate in the First Year After Liver Transplantation.

BACKGROUND: Renal function is an important predictor of liver transplantation (LT) outcome. This study examines the change in glomerular filtration rate (GFR, mL/min per m) in the first year after LT, with subgroup analysis by baseline GFR, model for end-stage liver disease (MELD), age, sex, race, and diabetes/hypertension. METHODS: The records of 1275 consecutive deceased donor, liver, and liver/kidney transplants were reviewed retrospectively, with the liver/kidney data analyzed separately. Glomerular filtration rate was calculated using the modification of diet in renal disease equation. RESULTS: Among liver only patients, 25% had GFR less than 60 (mL/min per 1.73 m) at LT, and this increased to 39% at 1 year. There were 42% of patients with normal renal function (GFR > 90) at baseline, and this decreased to 18% at 1 year. Only patient subgroups with MELD > 25 experienced any 1-year improvement in GFR, whereas all lower MELD groups experienced a significant decline in GFR. At 1 year after transplantation, there were 42% of recipients that had an absolute GFR decrease greater than 20 mL/min per 1.73 m, and 39% that decreased greater than 25% from their transplant baseline. Only 22% had an absolute improvement in GFR greater than 5 mL/min per 1.73 m. CONCLUSIONS: Sixty-four percent of liver transplant recipients overall experience a decrease in GFR 1 year after transplantation. Recipients with severe kidney disease at transplant (GFR < 30) are the group most likely to experience improvement in GFR after transplantation. However, at 1 year, as a group, they remain at GFR less than 60 (stage III chronic kidney disease). These results suggest that severe renal dysfunction may be marginally reversible after LT, but only 22% of the recipients in this cohort experienced any post-LT improvement in renal function.