Daniël H. van Raalte's research while affiliated with Vrije Universiteit Amsterdam and other places

Background and Aims Cardiac surgery-associated acute kidney injury (CSA-AKI) is a frequent complication of cardiac surgery assisted by cardiopulmonary bypass (CPB). Currently, no effective preventative strategies exist to reduce the incidence of acute kidney injury (AKI). Sodium-glucose transport protein 2 (SGLT2) inhibitors are effective in reducing the incidence of AKI in studies conducted in patients with chronic kidney disease. Therefore, we hypothesized that perioperative SGLT2 inhibition could reduce the incidence of CSA-AKI. Method In this open-label phase IV, randomized, parallel-group, balanced (1:1), pilot study, adult patients undergoing elective cardiac surgery with CPB were randomized to receive 10 mg empagliflozin per os once daily three days before surgery until two days after surgery, or standard care. The primary outcome was AKI incidence according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Other outcomes included hypoxia-inducible factor 1 alpha (HIF1A) and urinary Kidney Injury Molecule (KIM-1), urinary neutrophil gelatinase associated lipocalin (NGAL) and metabolic parameters such as plasma ketone and glucose concentrations. Results Between March 2022 and April 2023, 60 patients were randomized to empagliflozin (n = 29) or control (n = 31). All patients who underwent cardiac surgery with CPB were included in the intention-to-treat analysis (n = 25; empagliflozin group, n = 30; control group). SGLT2 inhibition significantly reduced the incidence of all stages of AKI (20% vs 66.7%; absolute difference 46%, 95% CI .13 to .63, P < .001). This decline in AKI incidence was reflected in the kidney biomarkers. SGLT2 inhibition also significantly reduced the number of patients with postoperative hyperglycemia (28% vs 60%; absolute difference 32%, 95% CI −56.8 to −7.2, P = .029). We observed no differences in the incidence of neither ketoacidosis nor hypoglycemic events. Conclusion Perioperative SGLT2 inhibition, compared with standard of care, demonstrated a significant reduction in AKI incidence rates. These findings merit validation in a larger placebo-controlled trial which is currently ongoing. Supplementary figures:

Aims/hypothesis The prevalence and severity of MASLD in type 1 diabetes remain unclear. Therefore, we investigated the prevalence and severity of MASLD in type 1 diabetes, and assessed which clinical features are most important in predicting MASLD severity. Methods 453 individuals with type 1 diabetes (41.6±15.0 years, 64% female, BMI 25.4±4.2kg/m2, HbA1c 55.6±12mmol/mol) underwent vibration-controlled transient elastography (VCTE), with a controlled attenuation parameter (CAP) score for steatosis (≥ 280.0dB/m) and a liver stiffness measurement (LMS) for fibrosis (≥ 8.0kPa). A machine-learning Extra-Trees classification model was performed to assess the predictive power of the clinical features associated with type 1 diabetes with respect to steatosis and fibrosis. Results The prevalence of hepatic steatosis and fibrosis was 9.5% [95% CI 6.8-12.2] and 3.5% [95% CI 1.8-5.2]. Higher LMS was associated with a longer duration of type 1 diabetes (median 30.5 [IQR 18.0-39.3] years vs. 15.0 [IQR 6.0-27.0] years) and individuals were older and had a higher BMI (mean 27.8 ±5.2 vs. 25.3 ±4.1kg/m2), and a higher CAP score (mean 211.4±51.7 dB/m vs. 241.4±75.6 dB/m). The most important predictive features of fibrosis were duration of type 1 diabetes, age, and systolic blood pressure, with a mean± standard deviation (SD) area under the curve of 0.73±0.03. Conclusion Individuals with type 1 diabetes and high blood pressure, older age, BMI and duration of disease could be considered at high-risk for developing MASLD.

Background Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common postoperative complication. Currently, no effective preventative strategies exist to mitigate CSA-AKI. Sodium-glucose transporter-2 (SGLT2) inhibitors reduced acute kidney injury (AKI) incidence in large, randomized placebo-controlled, cardiovascular and kidney outcome trials conducted in patients with chronic kidney disease. We hypothesized that perioperative SGLT2 inhibition could also reduce CSA-AKI. Methods In this open-label phase IV, randomized, parallel-group, pilot study, adult patients undergoing elective cardiac surgery with cardiopulmonary bypass were randomized to receive the SGLT2 inhibitor, empagliflozin (10 mg; oral), once daily three days prior to surgery and continued to two days after surgery compared with standard-of-care. Biomarkers for acute kidney injury (AKI), including serum and urinary neutrophil gelatinase-associated lipocalin (NGAL), serum and urinary kidney injury molecule-1 (KIM-1), and serum hypoxia-inducible factor-1α (HIF-1α) were measured. Additional outcomes included AKI incidence according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria as well as metabolic parameters, including ketone body concentrations and glycemic control. Results Between March 2022 and April 2023, 55 patients were included (sex: 73% male, age: 66 ± 10 years, BMI: 28 ± 4 kg/m2, empagliflozin n = 25, control n = 30) in the intention-to-treat analysis. Empagliflozin significantly reduced the incidence of AKI (20% vs 66.7%; absolute difference 46.7%, 95% CI, -69.7 – -23.6; P=.001). Following surgery, urinary NGAL, and KIM-1 were found to increase in both arms, whereas a significant increment in serum HIF-1α after surgery was solely observed in the control group. We observed no between-group differences in the incidence of (euglycemic) ketoacidosis or hypoglycemic events. Conclusions Perioperative SGLT2 inhibition, compared with standard of care, significantly reduced the incidence of CSA-AKI. These findings warrant validation in large-scale, double-blind, placebo-controlled, randomized trials.

Aims Gut microbiota have been linked to blood lipid levels and cardiovascular diseases (CVDs). The composition and abundance of gut microbiota trophic networks differ between ethnicities. We aim to evaluate the relationship between gut microbiotal trophic networks and CVD phenotypes. Methods and results We included cross-sectional data from 3860 individuals without CVD history from 6 ethnicities living in the Amsterdam region participating in the prospective Healthy Life in Urban Setting (HELIUS) study. Genetic variants were genotyped, faecal gut microbiota were profiled, and blood and anthropometric parameters were measured. A machine learning approach was used to assess the relationship between CVD risk (Framingham score) and gut microbiota stratified by ethnicity. Potential causal relationships between gut microbiota composition and CVD were inferred by performing two-sample Mendelian randomization with hard CVD events from the Pan-UK Biobank and microbiome genome-wide association studies summary data from a subset of the HELIUS cohort (n = 4117). Microbial taxa identified to be associated with CVD by machine learning and Mendelian randomization were often ethnic-specific, but some concordance across ethnicities was found. The microbes Akkermansia muciniphila and Ruminococcaceae UCG-002 were protective against ischaemic heart disease in African-Surinamese and Moroccans, respectively. We identified a strong inverse association between blood lipids, CVD risk, and the combined abundance of the correlated microbes Christensenellaceae–Methanobrevibacter–Ruminococcaceae (CMR). The CMR cluster was also identified in two independent cohorts and the association with triglycerides was replicated. Conclusion Certain gut microbes can have a potentially causal relationship with CVD events, with possible ethnic-specific effects. We identified a trophic network centred around Christensenellaceae, Methanobrevibacter, and various Ruminococcaceae, frequently lacking in South-Asian Surinamese, to be protective against CVD risk and associated with low triglyceride levels.

OBJECTIVE β-cell dysfunction and insulin resistance magnify the risk of kidney injury in type 2 diabetes. The relationship between these factors and intraglomerular hemodynamics and kidney oxygen availability in youth with type 2 diabetes remains incompletely explored. RESEARCH DESIGN AND METHODS Fifty youth with type 2 diabetes (mean age ± SD 16 ± 2 years; diabetes duration 2.3 ± 1.8 years; 60% female; median HbA1c 6.4% [25th, 75th percentiles 5.9, 7.6%]; BMI 36.4 ± 7.4 kg/m2; urine albumin-to-creatinine ratio [UACR] 10.3 [5.9, 58.0] mg/g) 21 control participants with obesity (OCs; age 16 ± 2 years; 29% female; BMI 37.6 ± 7.4 kg/m2), and 20 control participants in the normal weight category (NWCs; age 17 ± 3 years; 70% female; BMI 22.5 ± 3.6 kg/m2) underwent iohexol and p-aminohippurate clearance to assess glomerular filtration rate (GFR) and renal plasma flow, kidney MRI for oxygenation, hyperglycemic clamp for insulin secretion (acute C-peptide response to glucose [ACPRg]) and disposition index (DI; ×103 mg/kg lean/min), and DXA for body composition. RESULTS Youth with type 2 diabetes exhibited lower DI (0.6 [0.0, 1.6] vs. 3.8 [2.4, 4.5] × 103 mg/kg lean/min; P < 0.0001) and ACPRg (0.6 [0.3, 1.4] vs. 5.3 [4.3, 6.9] nmol/L; P < 0.001) and higher UACR (10.3 [5.9, 58.0] vs. 5.3 [3.4, 14.3] mg/g; P = 0.003) and intraglomerular pressure (77.8 ± 11.5 vs. 64.8 ± 5.0 mmHg; P < 0.001) compared with OCs. Youth with type 2 diabetes and OCs had higher GFR and kidney oxygen availability (relative hyperoxia) than NWCs. DI was associated inversely with intraglomerular pressure and kidney hyperoxia. CONCLUSIONS Youth with type 2 diabetes demonstrated severe β-cell dysfunction that was associated with intraglomerular hypertension and kidney hyperoxia. Similar but attenuated findings were found in OCs.

Recent studies indicate that accumulation of adipose tissue in various organs such as liver and kidney may contribute to the pathophysiology of metabolic syndrome. We aim to investigate the association between kidney and liver adipose tissue accumulation, assessed by the magnetic resonance imaging (MRI) proton density fat fraction technique, along with its relation to clinical and biochemical parameters. We included 51 volunteers with phenotypical features of metabolic syndrome (mean age = 34 years, mean body-mass index = 26.4 kg/m2) in our study in which liver and kidney adipose tissue accumulation was assessed via MRI-proton density fat fraction along with multiple other clinical and biochemical parameters such as estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio, serum lipid profile, liver function tests and body-mass index (BMI). Our results from the univariate linear regression analysis indicate that both the kidney and liver scores were positively correlated with markers such as BMI, urine albumin-to-creatinine ratio, triglycerides (p < 0.001) and negatively correlated with eGFR (p < 0.05). In multivariate analysis, urine albumin-to-creatinine ratio (p < 0.05), triglycerides (p < 0.01), eGFR (p < 0.05) and BMI (p < 0.001) were found to be independently associated with kidney and liver fat accumulation, respectively (R2 = 0.64; R2 = 0.89). There was also a positive correlation between kidney and liver fat accumulation. We have found a significant association between adipose tissue accumulation in liver and kidney and the parameters of metabolic syndrome. Moreover, the presence of a strong association between kidney and liver fat accumulation and kidney function parameters such as urine albumin-to-creatinine ratio and eGFR may be an indicator of the clinical significance of parenchymal fat accumulation.