Fighting Oxidative Stress with Sulfur:Hydrogen Sulfide in the Renal and Cardiovascular Systems

Hydrogen sulfide (H2S) is an essential gaseous signaling molecule. Research on its role in physiological and pathophysiological processes has greatly expanded. Endogenous enzymatic production through the transsulfuration and cysteine catabolism pathways can occur in the kidneys and blood vessels. Furthermore, non-enzymatic pathways are present throughout the body. In the renal and cardiovascular system, H2S plays an important role in maintaining the redox status at safe levels by promoting scavenging of reactive oxygen species (ROS). H2S also modifies cysteine residues on key signaling molecules such as keap1/Nrf2, NF kappa B, and HIF-1 alpha, thereby promoting anti-oxidant mechanisms. Depletion of H2S is implicated in many age-related and cardiorenal diseases, all having oxidative stress as a major contributor. Current research suggests potential for H2S-based therapies, however, therapeutic interventions have been limited to studies in animal models. Beyond H2S use as direct treatment, it could improve procedures such as transplantation, stem cell therapy, and the safety and efficacy of drugs including NSAIDs and ACE inhibitors. All in all, H2S is a prime subject for further research with potential for clinical use

Reduced nitric oxide bioavailability impairs myocardial oxygen balance during exercise in swine with multiple risk factors

In the present study, we tested the hypothesis that multiple risk factors, including diabetes mellitus (DM), dyslipidaemia and chronic kidney disease (CKD) result in a loss of nitric oxide (NO) signalling, thereby contributing to coronary microvascular dysfunction. Risk factors were induced in 12 female swine by intravenous streptozotocin injections (DM), a high fat diet (HFD) and renal artery embolization (CKD). Female healthy swine (n = 13) on normal diet served as controls (Normal). After 5 months, swine were chronically instrumented and studied at rest and during exercise. DM + HFD + CKD swine demonstrated significant hyperglycaemia, dyslipidaemia and impaired kidney function compared to Normal swine. These risk factors were accompanied by coronary microvascular endothelial dysfunction both in vivo and in isolated small arteries, due to a reduced NO bioavailability, associated with perturbations in myocardial oxygen balance at rest and during exercise. NO synthase inhibition caused coronary microvascular constriction in exercising Normal swine, but had no effect in DM + HFD + CKD animals, while inhibition of phosphodiesterase 5 produced similar vasodilator responses in both groups, indicating that loss of NO bioavailability was principally responsible for the observed coronary microvascular dysfunction. This was associated with an increase in myocardial 8-isoprostane levels and a decrease in antioxidant capacity, while antioxidants restored the vasodilation to bradykinin in isolated coronary small arteries, suggesting that oxidative stress was principally responsible for the reduced NO bioavailability. In conclusion, five months of combined exposure to DM + HFD + CKD produces coronary endothelial dysfunction due to impaired NO bioavailability, resulting in impaired myocardial perfusion at rest and during exercise.</p

Discrepancies between transcutaneous and estimated glomerular filtration rates in rats with chronic kidney disease

Accurate assessment of the glomerular filtration rate (GFR) is crucial for researching kidney disease in rats. Although validation of methods that assess GFR is crucial, large-scale comparisons between different methods are lacking. Both transcutaneous GFR (tGFR) and a newly developed estimated GFR (eGFR) equation by our group provide a low-invasive approach enabling repeated measurements. The tGFR is a single bolus method using FITC-labeled sinistrin to measure GFR based on half-life of the transcutaneous signal, whilst the eGFR is based on urinary sinistrin clearance. Here, we retrospectively compared tGFR, using both 1- and 3- compartment models (tGFR_1c and tGFR_3c, respectively) to the eGFR in a historic cohort of 43 healthy male rats and 84 male rats with various models of chronic kidney disease. The eGFR was on average considerably lower than tGFR-1c and tGFR-3c (mean differences 855 and 216 μL/min, respectively) and only 20 and 47% of measurements were within 30% of each other, respectively. The relative difference between eGFR and tGFR was highest in rats with the lowest GFR. Possible explanations for the divergence are problems inherent to tGFR, such as technical issues with signal measurement, description of the signal kinetics, and translation of half-life to tGFR, which depends on distribution volume. The unknown impact of isoflurane anesthesia used in determining mGFR remains a limiting factor. Thus, our study shows that there is a severe disagreement between GFR measured by tGFR and eGFR, stressing the need for more rigorous validation of the tGFR and possible adjustments to the underlying technique.</p

Discrepancies between transcutaneous and estimated glomerular filtration rates in rats with chronic kidney disease

Accurate assessment of the glomerular filtration rate (GFR) is crucial for researching kidney disease in rats. Although validation of methods that assess GFR is crucial, large-scale comparisons between different methods are lacking. Both transcutaneous GFR (tGFR) and a newly developed estimated GFR (eGFR) equation by our group provide a low-invasive approach enabling repeated measurements. The tGFR is a single bolus method using FITC-labeled sinistrin to measure GFR based on half-life of the transcutaneous signal, whilst the eGFR is based on urinary sinistrin clearance. Here, we retrospectively compared tGFR, using both 1- and 3- compartment models (tGFR_1c and tGFR_3c, respectively) to the eGFR in a historic cohort of 43 healthy male rats and 84 male rats with various models of chronic kidney disease. The eGFR was on average considerably lower than tGFR-1c and tGFR-3c (mean differences 855 and 216 μL/min, respectively) and only 20 and 47% of measurements were within 30% of each other, respectively. The relative difference between eGFR and tGFR was highest in rats with the lowest GFR. Possible explanations for the divergence are problems inherent to tGFR, such as technical issues with signal measurement, description of the signal kinetics, and translation of half-life to tGFR, which depends on distribution volume. The unknown impact of isoflurane anesthesia used in determining mGFR remains a limiting factor. Thus, our study shows that there is a severe disagreement between GFR measured by tGFR and eGFR, stressing the need for more rigorous validation of the tGFR and possible adjustments to the underlying technique.</p

Перспективи розвитку світової енергетики й забезпечення енергетичної безпеки України

Проблеми забезпечення енергетичної безпеки (ЕнБ) безпеки були та залишаються головними складовими забезпечення національної безпеки та загального сталого розвитку

Whole-body insulin clearance in people with type 2 diabetes and normal kidney function:Relationship with glomerular filtration rate, renal plasma flow, and insulin sensitivity

OBJECTIVE: Kidney insulin clearance, proposed to be the main route of extra-hepatic insulin clearance, occurs in tubular cells following glomerular filtration and peritubular uptake, a process that may be impaired in people with type 2 diabetes (T2D) and/or impaired kidney function. Human studies that investigated kidney insulin clearance are limited by the invasive nature of the measurement. Instead, we evaluated relationships between whole-body insulin clearance, and gold-standard measured kidney function and insulin sensitivity in adults with T2D and normal kidney function. RESEARCH DESIGN AND METHODS: We determined insulin, inulin/iohexol and para-aminohippuric acid (PAH) clearances during a hyperinsulinemic-euglycemic clamp to measure whole-body insulin clearance and kidney function. Insulin sensitivity was expressed by glucose infusion rate (M value). Associations between whole-body insulin clearance, kidney function and insulin sensitivity were examined using univariable and multivariable linear regressions models. RESULTS: We investigated 44 predominantly male (77%) T2D adults aged 63 ± 7, with fat mass 34.5 ± 9 kg, lean body mass 63.0 ± 11.8 kg, and HbA1c 7.4 ± 0.6%. Average whole-body insulin clearance was 1188 ± 358 mL/min. Mean GFR was 110 ± 22 mL/min, mean ERPF 565 ± 141 mL/min, and M value averaged 3.9 ± 2.3 mg/min. Whole-body insulin clearance was positively correlated with lean body mass, ERPF and insulin sensitivity, but not with GFR. ERPF explained 6% of the variance when entered in a nested multivariable linear regression model op top of lean body mass (25%) and insulin sensitivity (15%). CONCLUSIONS: In adults with T2D and normal kidney function, whole-body insulin clearance was predicted best by lean body mass and insulin sensitivity, and to a lesser extent by ERPF. GFR was not associated with whole-body insulin clearance. In contrast to prior understanding, this suggests that in this population kidney insulin clearance may not play such a dominant role in whole-body insulin clearance

Epoetin Beta and C-Terminal Fibroblast Growth Factor 23 in Patients With Chronic Heart Failure and Chronic Kidney Disease

Background In patients with chronic heart failure and chronic kidney disease, correction of anemia with erythropoietin-stimulating agents targeting normal hemoglobin levels is associated with an increased risk of cardiovascular morbidity and mortality. Emerging data suggest a direct effect of erythropoietin on fibroblast growth factor 23 (FGF23), elevated levels of which have been associated with adverse outcomes. We investigate effects of erythropoietin-stimulating agents in patients with both chronic heart failure and chronic kidney disease focusing on FGF23. Methods and Results In the EPOCARES (Erythropoietin in CardioRenal Syndrome) study, we randomized 56 anemic patients (median age 74 [interquartile range 69-80] years, 66% male) with both chronic heart failure and chronic kidney disease into 3 groups, of which 2 received epoetin beta 50 IU/kg per week for 50 weeks, and the third group served as control. Measurements were performed at baseline and after 2, 26, and 50 weeks. Data were analyzed using linear mixed-model analysis. After 50 weeks of erythropoietin-stimulating agent treatment, hematocrit and hemoglobin levels increased. Similarly, C-terminal FGF23 levels, in contrast to intact FGF23 levels, rose significantly due to erythropoietin-stimulating agents as compared with the controls. During median follow-up for 5.7 (2.0-5.7) years, baseline C-terminal FGF23 levels were independently associated with increased risk of mortality (hazard ratio 2.20; 95% CI, 1.35-3.59; P=0.002). Conclusions Exogenous erythropoietin increases C-terminal FGF23 levels markedly over a period of 50 weeks, elevated levels of which, even at baseline, are significantly associated with an increased risk of mortality. The current results, in a randomized trial setting, underline the strong relationship between erythropoietin and FGF23 physiology in patients with chronic heart failure and chronic kidney disease. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00356733

SGLT2 inhibition versus sulfonylurea treatment effects on electrolyte and acid-base balance:secondary analysis of a clinical trial reaching glycemic equipoise: Tubular effects of SGLT2 inhibition in Type 2 diabetes

Sodium-glucose transporter (SGLT)2 inhibitors increase plasma magnesium and plasma phosphate and may cause ketoacidosis, but the contribution of improved glycemic control to these observations as well as effects on other electrolytes and acid-base parameters remain unknown. Therefore, our objective was to compare the effects of SGLT2 inhibitors dapagliflozin and sulfonylurea gliclazide on plasma electrolytes, urinary electrolyte excretion, and acid-base balance in people with Type 2 diabetes (T2D). We assessed the effects of dapagliflozin and gliclazide treatment on plasma electrolytes and bicarbonate, 24-hour urinary pH and excretions of electrolytes, ammonium, citrate, and sulfate in 44 metformin-treated people with T2D and preserved kidney function. Compared with gliclazide, dapagliflozin increased plasma chloride by 1.4 mmol/l (95% CI 0.4-2.4), plasma magnesium by 0.03 mmol/l (95% CI 0.01-0.06), and plasma sulfate by 0.02 mmol/l (95% CI 0.01-0.04). Compared with baseline, dapagliflozin also significantly increased plasma phosphate, but the same trend was observed with gliclazide. From baseline to week 12, dapagliflozin increased the urinary excretion of citrate by 0.93 ± 1.72 mmol/day, acetoacetate by 48 μmol/day (IQR 17-138), and β-hydroxybutyrate by 59 μmol/day (IQR 0-336), without disturbing acid-base balance. In conclusion, dapagliflozin increases plasma magnesium, chloride, and sulfate compared with gliclazide, while reaching similar glucose-lowering in people with T2D. Dapagliflozin also increases urinary ketone excretion without changing acid-base balance. Therefore, the increase in urinary citrate excretion by dapagliflozin may reflect an effect on cellular metabolism including the tricarboxylic acid cycle. This potentially contributes to kidney protection

A systematic review and meta-analysis of COVID-19 in kidney transplant recipients:Lessons to be learned

Kidney transplant recipients (KTR) may be at increased risk of adverse COVID-19 outcomes, due to prevalent comorbidities and immunosuppressed status. Given the global differences in COVID-19 policies and treatments, a robust assessment of all evidence is necessary to evaluate the clinical course of COVID-19 in KTR. Studies on mortality and acute kidney injury (AKI) in KTR in the World Health Organization COVID-19 database were systematically reviewed. We selected studies published between March 2020 and January 18th 2021, including at least five KTR with COVID-19. Random-effects meta-analyses were performed to calculate overall proportions, including 95% confidence intervals (95% CI). Subgroup analyses were performed on time of submission, geographical region, sex, age, time after transplantation, comorbidities, and treatments. We included 74 studies with 5559 KTR with COVID-19 (64.0% males, mean age 58.2 years, mean 73 months after transplantation) in total. The risk of mortality, 23% (95% CI: 21%-27%), and AKI, 50% (95% CI: 44%-56%), is high among KTR with COVID-19, regardless of sex, age and comorbidities, underlining the call to accelerate vaccination programs for KTR. Given the suboptimal reporting across the identified studies, we urge researchers to consistently report anthropometrics, kidney function at baseline and discharge, (changes in) immunosuppressive therapy, AKI, and renal outcome among KTR

Decreased native renal T1 up to one week after gadobutrol administration in healthy volunteers

Background: Gadolinium-based contrast agents (GBCAs) are widely used in MRI, despite safety concerns regarding deposition in brain and other organs. In animal studies gadolinium was detected for weeks after administration in the kidneys, but this has not yet been demonstrated in humans. Purpose: To find evidence for the prolonged presence of gadobutrol in the kidneys in healthy volunteers. Study Type: Combined retrospective and prospective analysis of a repeatability study. Population: Twenty-three healthy volunteers with normal renal function (12 women, age range 40–76 years), of whom 21 were used for analysis. Field Strength/Sequence: Inversion recovery-based T 1 map at 3T. Assessment: T 1 maps were obtained twice with a median interval of 7 (range: 4–16) days. The T 1 difference (ΔT 1) between both scans was compared between the gadolinium group (n = 16, 0.05 mmol/kg gadobutrol administered after T 1 mapping during both scan sessions) and the control group (n = 5, no gadobutrol). T 1 maps were analyzed separately for cortex and medulla. Statistical Tests: Mann–Whitney U-tests to detect differences in ΔT 1 between groups and linear regression to relate time between scans and estimated glomerular filtration rate (eGFR) to ΔT 1. Results: ΔT 1 differed significantly between the gadolinium and control group: median ΔT 1 cortex –98 vs. 7 msec (P < 0.001) and medulla –68 msec vs. 19 msec (P = 0.001), respectively. The bias corresponds to renal gadobutrol concentrations of 8 nmol/g tissue (cortex) and 4 nmol/g tissue (medulla), ie, ~2.4 μmol for both kidneys (0.05% of original dose). ΔT 1 correlated in the gadolinium group with duration between acquisitions for both cortex (regression coefficient (β) 16.5 msec/day, R 2 0.50, P < 0.001) and medulla (β 11.5 msec/day, R 2 0.32, P < 0.001). Medullary ΔT 1 correlated with eGFR (β 1.13 msec/(ml/min) R 2 0.25, P = 0.008). Data Conclusion: We found evidence of delayed renal gadobutrol excretion after a single contrast agent administration in subjects with normal renal function. Even within this healthy population, elimination delay increased with decreasing kidney function. Level of Evidence: 3. Technical Efficacy: Stage 3. J. Magn. Reson. Imaging 2020;52:622–631