Refractory circulatory failure in COVID-19 patients treated with veno-arterial ECMO a retrospective single-center experience.

OBJECTIVE: In this retrospective case series, survival rates in different indications for veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and differential diagnoses of COVID-19 associated refractory circulatory failure are investigated. METHODS: Retrospective analysis of 28 consecutive COVID-19 patients requiring VA-ECMO. All VA-ECMO's were cannulated peripherally, using a femoro-femoral cannulation. RESULTS: At VA-ECMO initiation, median age was 57 years (IQR: 51-62), SOFA score 16 (IQR: 13-17) and norepinephrine dosing 0.53µg/kg/min (IQR: 0.35-0.87). Virus-variants were: 61% wild-type, 14% Alpha, 18% Delta and 7% Omicron. Indications for VA-ECMO support were pulmonary embolism (PE) (n = 5, survival 80%), right heart failure due to secondary pulmonary hypertension (n = 5, survival 20%), cardiac arrest (n = 4, survival 25%), acute heart failure (AHF) (n = 10, survival 40%) and refractory vasoplegia (n = 4, survival 0%). Among the patients with AHF, 4 patients suffered from COVID-19 associated heart failure (CovHF) (survival 100%) and 6 patients from sepsis associated heart failure (SHF) (survival 0%). Main Complications were acute kidney injury (AKI) 93%, renal replacement therapy was needed in 79%, intracranial hemorrhage occurred in 18%. Overall survival to hospital discharge was 39%. CONCLUSION: Survival on VA-ECMO in COVID-19 depends on VA-ECMO indication, which should be considered in further studies and clinical decision making. A subgroup of patients suffers from acute heart failure due to inflammation, which has to be differentiated into septic or COVID-19 associated. Novel biomarkers are required to ensure reliable differentiation between these entities; a candidate might be soluble interleukin 2 receptor.

Interactive exploration of adverse events and multimorbidity in CKD.

BACKGROUND AND HYPOTHESIS: Persons with chronic kidney disease (CKD) are at increased risk of adverse events, early mortality, and multimorbidity. A detailed overview of adverse event types and rates from a large CKD cohort under regular nephrological care is missing. We generated an interactive tool to enable exploration of adverse events and their combinations in the prospective, observational German CKD (GCKD) study. METHODS: The GCKD study enrolled 5217 participants under regular nephrological care with an estimated glomerular filtration rate of 30-60 or >60 mL/min/1.73m2 and an overt proteinuria. Cardio-, cerebro- and peripheral vascular, kidney, infection, and cancer events, as well as deaths were adjudicated following a standard operation procedure. We summarized these time-to-event data points for exploration in interactive graphs within an R shiny app. Multivariable adjusted Cox models for time to first event were fitted. Cumulative incidence functions, Kaplan-Meier curves and intersection plots were used to display main adverse events and their combinations by sex and CKD etiology. RESULTS: Over a median of 6.5 years, 10 271 events occurred in total and 680 participants (13.0%) died while 2947 participants (56.5%) experienced any event. The new publicly available interactive platform enables readers to scrutinize adverse events and their combinations as well as mortality trends as a gateway to better understand multimorbidity in CKD: incident rates per 1000 patient-years varied by event type, CKD etiology, and baseline characteristics. Incidence rates for the most frequent events and their recurrence were 113.6 (cardiovascular), 75.0 (kidney), and 66.0 (infection). Participants with diabetic kidney disease and men were more prone to experiencing events. CONCLUSION: This comprehensive explorative tool to visualize adverse events (https://gckd.diz.uk-erlangen.de/), their combination, mortality, and multimorbidity among persons with CKD may manifest as a valuable resource for patient care, identification of high-risk groups, health services, and public health policy planning.

Prognostic factors for favorable outcomes after veno-venous extracorporeal membrane oxygenation in critical care patients with COVID-19.

BACKGROUND: Patients with COVID-19 and severe acute respiratory failure may require veno-venous extracorporeal membrane oxygenation (VV ECMO). Yet, this procedure is resource-intensive and high mortality rates have been reported. Thus, predictors for identifying patients who will benefit from VV ECMO would be helpful. METHODS: This retrospective study included 129 patients with COVID-19 and severe acute respiratory failure, who had received VV ECMO at the University Medical Center Regensburg, Germany, between 1 March 2020 and 31 December 2021. Patient-specific factors and relevant intensive-care parameters at the time of the decision to start VV ECMO were investigated regarding their value as predictors of patient survival. In addition, the intensive-care course of the first 10 days of VV ECMO was compared between survivors and patients who had died in the intensive care unit. RESULTS: The most important parameters for predicting outcome were patient age and platelet count, which differed significantly between survivors and non-survivors (age: 52.6±8.1 vs. 57.4±10.1 years, p<0.001; platelet count before VV ECMO: 321.3±132.2 vs. 262.0±121.0 /nL, p = 0.006; average on day 10: 199.2±88.0 vs. 147.1±57.9 /nL, p = 0.002). A linear regression model derived from parameters collected before the start of VV ECMO only included age and platelet count. Patients were divided into two groups by using receiver operating characteristics (ROC) analysis: group 1: 78% of patients, mortality 26%; group 2: 22% of patients, mortality 75%. A second linear regression model included average blood pH, minimum paO2, and average pump flow on day 10 of VV ECMO in addition to age and platelet count. The ROC curve resulted in two cut-off values and thus in three groups: group 1: 25% of patients, mortality 93%; group 2: 45% of patients, mortality 31%; group 3: 30% of patients, mortality 0%.

Evaluation of models for prognosing mortality in critical care patients with COVID-19: First- and second-wave data from a German university hospital.

BACKGROUND: In a previous study, we had investigated the intensive care course of patients with coronavirus disease 2019 (COVID-19) in the first wave in Germany by calculating models for prognosticating in-hospital death with univariable and multivariable regression analysis. This study analyzed if these models were also applicable to patients with COVID-19 in the second wave. METHODS: This retrospective cohort study included 98 critical care patients with COVID-19, who had been treated at the University Medical Center Regensburg, Germany, between October 2020 and February 2021. Data collected for each patient included vital signs, dosage of catecholamines, analgosedation, anticoagulation, and antithrombotic medication, diagnostic blood tests, treatment with extracorporeal membrane oxygenation (ECMO), intensive care scores, ventilator therapy, and pulmonary gas exchange. Using these data, expected mortality was calculated by means of the originally developed mathematical models, thereby testing the models for their applicability to patients in the second wave. RESULTS: Mortality in the second-wave cohort did not significantly differ from that in the first-wave cohort (41.8% vs. 32.2%, p = 0.151). As in our previous study, individual parameters such as pH of blood or mean arterial pressure (MAP) differed significantly between survivors and non-survivors. In contrast to our previous study, however, survivors and non-survivors in this study showed significant or even highly significant differences in pulmonary gas exchange and ventilator therapy (e.g. mean and minimum values for oxygen saturation and partial pressure of oxygen, mean values for the fraction of inspired oxygen, positive expiratory pressure, tidal volume, and oxygenation ratio). ECMO therapy was more frequently administered than in the first-wave cohort. Calculations of expected mortality by means of the originally developed univariable and multivariable models showed that the use of simple cut-off values for pH, MAP, troponin, or combinations of these parameters resulted in correctly estimated outcome in approximately 75% of patients without ECMO therapy.

Severe acidosis due to 5-oxoprolinase inhibition by flucloxacillin in a patient with shoulder prosthesis joint infection.

We report a case of a 64-year-old female patient with severe metabolic acidosis. Inhibition of 5-oxoprolinase by flucloxacillin was found to be the cause of the metabolic derailment.

Collateral effects of the SARS-CoV-2 pandemic on oncologic surgery in Bavaria.

BACKGROUND: The ongoing SARS-COV-2 pandemic has severe implications for people and healthcare systems everywhere. In Germany, worry about the consequences of the pandemic led to the deferral of non-emergency surgeries. Tumor surgery accounts for a large volume in the field of visceral surgery and cannot be considered purely elective. It is not known how the SARS-COV-2 pandemic has changed the surgical volume in tumor patients. METHODS: Retrospective analysis of the amount of oncological surgeries in three academic visceral surgery departments in Bavaria, Germany, in 2020. Procedures were split into subgroups: Upper Gastrointestinal (Upper GI), Colorectal, Hepato-Pancreato-Biliary (HPB), Peritoneal and Endocrine. Procedures in 2020 were compared to a reference period from January 1st, 2017 to December 31st 2019. Surgical volume was graphically merged with SARS-COV-2 incidence and the number of occupied ICU beds. RESULTS: Surgical volume decreased by 7.6% from an average of 924 oncologic surgeries from 2017 to 2019 to 854 in 2020. The decline was temporally associated with the incidence of infections and ICU capacity. Surgical volume did not uniformly increase to pre-pandemic levels in the months following the first pandemic wave with lower SARS-COV-2 incidence and varied according to local incidence levels. The decline was most pronounced in colorectal surgery where procedures declined on average by 26% following the beginning of the pandemic situation. CONCLUSION: The comparison with pre-pandemic years showed a decline in oncologic surgeries in 2020, which could have an impact on lost life years in non-COVID-19 patients. This decline was very different in subgroups which could not be solely explained by the pandemic.

Reduction of Tissue Na+ Accumulation After Renal Transplantation.

INTRODUCTION: Chronic kidney disease (CKD) engenders salt-sensitive hypertension. Whether or not tissue Na+ accumulation is increased in CKD patients remains uncertain. How tissue Na+ is affected after renal transplantation has not been assessed. METHODS: We measured tissue Na+ amount in 31 CKD patients (stage 5) and prospectively evaluated tissue Na+ content at 3 and 6 months, following living-donor kidney transplantation. Additionally, pre- and post-transplantation data were compared to 31 age- and sex-matched control subjects. 23Na-magnetic resonance imaging (23Na-MRI) was used to quantify muscle and skin Na+ of the lower leg and water distribution was assessed by bioimpedance spectroscopy. RESULTS: Compared to control subjects, CKD patients showed increased muscle (20.7 ± 5.0 vs. 15.5 ± 1.8 arbitrary units [a.u.], P < 0.001) and skin Na+ content (21.4 ± 7.7 vs. 15.0 ± 2.3 a.u., P < 0.001), whereas plasma Na+ concentration did not differ between groups. Restoration of kidney function by successful renal transplantation was accompanied by mobilization of tissue Na+ from muscle (20.7 ± 5.0 vs. 16.8 ± 2.8 a.u., P < 0.001) and skin tissue (21.4 ± 7.7 vs. 16.8 ± 5.2 a.u., P < 0.001). The reduction of tissue Na+ after transplantation was associated with improved renal function, normalization of blood pressure as well as an increase in lymphatic growth-factor concentration (vascular endothelial growth factor C [VEGF-C] 4.5 ± 1.8 vs. 6.7 ± 2.7 ng/ml, P < 0.01). CONCLUSIONS: Tissue Na+ accumulation in predialysis patients with CKD was almost completely reversed to the level of healthy controls after successful kidney transplantation.

Lower blood pH as a strong prognostic factor for fatal outcomes in critically ill COVID-19 patients at an intensive care unit: A multivariable analysis.

BACKGROUND: Data of critically ill COVID-19 patients are being evaluated worldwide, not only to understand the various aspects of the disease and to refine treatment strategies but also to improve clinical decision-making. For clinical decision-making in particular, prognostic factors of a lethal course of the disease would be highly relevant. METHODS: In this retrospective cohort study, we analyzed the first 59 adult critically ill Covid-19 patients treated in one of the intensive care units of the University Medical Center Regensburg, Germany. Using uni- and multivariable regression models, we extracted a set of parameters that allowed for prognosing in-hospital mortality. RESULTS: Within the cohort, 19 patients died (mortality 32.2%). Blood pH value, mean arterial pressure, base excess, troponin, and procalcitonin were identified as highly significant prognostic factors of in-hospital mortality. However, no significant differences were found for other parameters expected to be relevant prognostic factors, like low arterial partial pressure of oxygen or high lactate levels. In the multivariable logistic regression analysis, the pH value and the mean arterial pressure turned out to be the most influential prognostic factors for a lethal course.

Changes in Body Composition, Muscle Strength, and Fat Distribution Following Kidney Transplantation.

RATIONALE & OBJECTIVE: Low muscle mass relative to fat mass (relative sarcopenia) has been associated with mortality and disability but has not been examined after kidney transplantation. We studied how measures of body composition change after receipt of a kidney allograft. STUDY DESIGN: Prospective longitudinal cohort study. SETTING & PARTICIPANTS: 60 kidney transplant recipients, aged 20-60 years, at the University of Pennsylvania. EXPOSURE: Kidney transplantation. OUTCOME: Dual-energy x-ray absorptiometry measures of fat mass index (FMI) and appendicular lean mass index (ALMI, representing muscle mass), computed tomography measures of muscle density (low density represents increased intramuscular adipose tissue), dynamometer measures of leg muscle strength, and physical activity. ALMI relative to FMI (ALMFMI) is an established index of relative sarcopenia. ANALYTICAL APPROACH: Measures expressed as age, sex, and race-specific z scores for transplant recipients were compared with 327 healthy controls. Regression models were used to identify correlates of change in outcome z scores and compare transplant recipients with controls. RESULTS: At transplantation, ALMI, ALMIFMI, muscle strength, and muscle density z scores were lower versus controls (all P≤0.001). Transplant recipients received glucocorticoids throughout. The prevalence of obesity increased from 18% to 45%. Although ALMI increased after transplantation (P<0.001) and was comparable with the controls from 6 months onward, gains were outpaced by increases in FMI, resulting in persistent ALMIFMI deficits (mean z score of-0.31 at 24 months; P=0.02 vs controls). Muscle density improved after transplantation despite gains in FMI (P=0.02). Muscle strength relative to ALMI also improved (P=0.04) but remained low compared with controls (P=0.01). Exercise increased in the early months after transplantation (P<0.05) but remained lower than controls (P = 0.02). LIMITATIONS: Lack of muscle biopsies precluded assessment of muscle histology and metabolism. CONCLUSIONS: The 2-year interval after kidney transplantation was characterized by gains in muscle mass and strength that were outpaced by gains in fat mass, resulting in persistent relative sarcopenia.

Viral infiltration of pancreatic islets in patients with COVID-19.

Metabolic diseases are associated with an increased risk of severe COVID-19 and conversely, new-onset hyperglycemia and complications of preexisting diabetes have been observed in COVID-19 patients. Here, we performed a comprehensive analysis of pancreatic autopsy tissue from COVID-19 patients using immunofluorescence, immunohistochemistry, RNA scope and electron microscopy and detected SARS-CoV-2 viral infiltration of beta-cells in all patients. Using SARS-CoV-2 pseudoviruses, we confirmed that isolated human islet cells are permissive to infection. In eleven COVID-19 patients, we examined the expression of ACE2, TMPRSS and other receptors and factors, such as DPP4, HMBG1 and NRP1, that might facilitate virus entry. Whereas 70% of the COVID-19 patients expressed ACE2 in the vasculature, only 30% displayed ACE2-expression in beta-cells. Even in the absence of manifest new-onset diabetes, necroptotic cell death, immune cell infiltration and SARS-CoV-2 viral infection of pancreatic beta-cells may contribute to varying degrees of metabolic dysregulation in patients with COVID-19.

ECMO in COVID-19-prolonged therapy needed? A retrospective analysis of outcome and prognostic factors.

BACKGROUND: The role of venovenous extracorporeal membrane oxygenation (VV ECMO) in patients with COVID-19-induced acute respiratory distress syndrome (ARDS) still remains unclear. Our aim was to investigate the clinical course and outcome of those patients and to identify factors associated with the need for prolonged ECMO therapy. METHODS: A retrospective single-center study on patients with VV ECMO for COVID-19-associated ARDS was performed. Baseline characteristics, ventilatory and ECMO parameters, and laboratory and virological results were evaluated over time. Six months follow-up was assessed. RESULTS: Eleven of 16 patients (68.8%) survived to 6 months follow-up with four patients requiring short-term (<28 days) and seven requiring prolonged (⩾28 days) ECMO support. Lung compliance before ECMO was higher in the prolonged than in the short-term group (28.1 (28.8-32.1) ml/cmH2O vs 18.7 (17.7-25.0) ml/cmH2O, p = 0.030). Mechanical ventilation before ECMO was longer (19 (16-23) days vs 5 (5-9) days, p = 0.002) and SOFA score was higher (12.0 (10.5-17.0) vs 10.0 (9.0-10.0), p = 0.002) in non-survivors compared to survivors. Low viral load during the first days on ECMO tended to indicate worse outcomes. Seroconversion against SARS-CoV-2 occurred in all patients, but did not affect outcome. CONCLUSIONS: VV ECMO support for COVID-19-induced ARDS is justified if initiated early and at an experienced ECMO center. Prolonged ECMO therapy might be required in those patients. Although no relevant predictive factors for the duration of ECMO support were found, the decision to stop therapy should not be made dependent of the length of ECMO treatment.

Autopsy findings after long-term treatment of COVID-19 patients with microbiological correlation.

Between April and June 2020, i.e., during the first wave of pandemic coronavirus disease 2019 (COVID-19), 55 patients underwent long-term treatment in the intensive care unit at the University Hospital of Regensburg. Most of them were transferred from smaller hospitals, often due to the need for an extracorporeal membrane oxygenation system. Autopsy was performed in 8/17 COVID-19-proven patients after long-term treatment (mean: 33.6 days). Autopsy revealed that the typical pathological changes occurring during the early stages of the disease (e.g., thrombosis, endothelitis, capillaritis) are less prevalent at this stage, while severe diffuse alveolar damage and especially coinfection with different fungal species were the most conspicuous finding. In addition, signs of macrophage activation syndrome was detected in 7 of 8 patients. Thus, fungal infections were a leading cause of death in our cohort of severely ill patients and may alter clinical management of patients, particularly in long-term periods of treatment.

Relationship Between Ubiquitin-Specific Peptidase 18 and Hypertension in Polish Adult Male Subjects: A Cross-Sectional Pilot Study.

BACKGROUND Arterial hypertension (HT) is a leading cause of cardiac hypertrophy and heart failure. Ubiquitin-specific peptidase 18 (USP18) has been recently described as a factor that prevents myocardial dysfunction. The present study measured serum USP18 levels in normotensive (n=29), isolated diastolic hypertensive (n=20), and systolic-diastolic hypertensive (n=30) male participants and correlated these results with biochemical parameters that are included in routine assessments of patients with hypertension. MATERIAL AND METHODS Seventy-nine men, aged 24 to 82 years (mean=50.8±11.4 years), were included in the study. None of the participants had ever been treated for HT. Blood and urine parameters were assessed using routine techniques. Serum USP18 levels were measured by enzyme-linked immunosorbent assay. RESULTS The means and 95% confidence intervals (CIs) of USP18 levels in the HT(-), iDHT(+), and HT(+) groups were 69.3 (22.1-116.5) pg/ml, 90.1 (29.0-151.3) pg/ml, and 426.7 (163.1-690.3) pg/ml, respectively. In the HT(+) group, the mean serum USP18 level was 6.2-times higher than in the HT(-) group (p=0.014) and 4.7-times higher than in the iDHT(+) group (p=0.19). The partial correlation analysis that was adjusted for risk factors of arteriosclerosis indicated that USP18 levels were correlated with systolic blood pressure, pulse pressure, and heart rate. CONCLUSIONS This preliminary study found that serum USP18 levels were significantly higher in drug-naive male participants with arterial hypertension compared with normotensive controls. USP18 exerts cardiovascular-protective effects. Elevations of USP18 levels may indicate a counterregulatory process that is engaged during increases in pressure in the left ventricle.

Retinal neurodegeneration in patients with end-stage renal disease assessed by spectral-domain optical coherence tomography.

Spectral-domain optical coherence tomography (SD-OCT) represents a reliable tool for retinal layer volume and thickness measurement. The aim of this study was to evaluate retinal changes indicating neurodegenerative processes in patients with end-stage renal disease (ESRD) compared to healthy controls. This was a cross-sectional, single-center study comprising 32 ESRD patients and 38 controls. Sectoral retinal nerve fiber layer (RNFL) thickness and retinal layer volumes were obtained by SD-OCT. Age- and gender-adjusted retinal layer volumes such as total retinal volume (p = 0.037), ganglion cell layer volume (GCL, p = 0.003), ganglion cell layer - inner plexiform layer volume (GCL-IPL, p = 0.005) and inner retinal layer volume (IRL, p = 0.042) of the right eye were lower in ESRD patients. Inner plexiform layer volume of both eyes (IPL, right eye: p = 0.017; left eye: 0.044) was reduced, as was RNFL thickness in the temporal superior sector (right eye: p = 0.016). A subgroup analysis excluding patients with diabetes revealed that GCL (p = 0.014) and GCL-IPL volume of the right eye (p = 0.024) and temporal superior sector of the RNFL scan (p = 0.021) in ESRD patients were still significantly thinner. We observed a decrease in several retinal layer volumes and temporal RNFL thickness indicative of retinal neurodegenerative processes in patients with ESRD.

Patterns of medication use and the burden of polypharmacy in patients with chronic kidney disease: the German Chronic Kidney Disease study.

BACKGROUND: Patients with chronic kidney disease (CKD) bear a substantial burden of comorbidities leading to the prescription of multiple drugs and a risk of polypharmacy. However, data on medication use in this population are scarce. METHODS: A total of 5217 adults with an estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m2 or an eGFR ≥60 mL/min/1.73m2 and overt proteinuria (>500 mg/day) were studied. Self-reported data on current medication use were assessed at baseline (2010-12) and after 4 years of follow-up (FU). Prevalence and risk factors associated with polypharmacy (defined as the regular use of five or more drugs per day) as well as initiation or termination of polypharmacy were evaluated using multivariable logistic regression. RESULTS: The prevalence of polypharmacy at baseline and FU was almost 80%, ranging from 62% in patients with CKD Stage G1 to 86% in those with CKD Stage G3b. The median number of different medications taken per day was eight (range 0-27). ß-blockers, angiotensin-converting enzyme inhibitors and statins were most frequently used. Increasing CKD G stage, age and body mass index, diabetes mellitus, cardiovascular disease and a history of smoking were significantly associated with both the prevalence of polypharmacy and its maintenance during FU. Diabetes mellitus was also significantly associated with the initiation of polypharmacy [odds ratio (OR) 2.46, (95% confidence interval 1.36-4.45); P = 0.003]. CONCLUSION: Medication burden in CKD patients is high. Further research appears warranted to address the implications of polypharmacy, risks of drug interactions and strategies for risk reduction in this vulnerable patient population.

Association of donor hypertension and recipient renal function in living donor kidney transplantation: A single-center retrospective study.

Transplant centers now accept living donors with well-controlled hypertension. Little is known whether hypertension in living donors affects recipient's kidney function. We aimed to examine potential differences in kidneys from hypertensive donors compared to normotensive donors with respect to renal function over 36 months and histologic findings at transplantation (T0) and 12 months after transplantation (T1). Retrospective single-center analysis of 174 living donor-recipient pairs (age > 18; transplantation date 1/2008-3/2016). Hypertension in donors was defined as being on antihypertensive medication. All biopsies were assessed by the same blinded, experienced renal pathologist. Biopsies were scored for glomerulosclerosis, IFTA, and arteriosclerosis. Regression models were used to examine the relationship of donor hypertension with renal function and histologic changes. Hypertensive donors were significantly older than normotensive donors. Chronic changes such as tubular atrophy and atherosclerosis were more evident in kidneys from hypertensive donors at T0 as well as T1. Donor hypertension was independently associated with histologic changes at T0 and T1 but not with renal function over the follow period. Despite more pronounced histologic changes in kidneys from hypertensive living donors, these grafts exhibited a similar functional outcome. However, they subsequently might be at a greater risk and warrant thorough follow-up care.

Evidence of neurodegeneration in individuals with only mildly elevated blood pressure.

OBJECTIVE: Initiation of antihypertensive drug treatment in low-risk individuals with grade 1 hypertension is under debate. The aim of this study was to examine the impact of mildly elevated blood pressure (BP) on early neurodegenerative processes independent of ageing. METHODS: Sixty-two individuals were included in this study: 25 young (aged <40 years) and 37 older (aged ≥40 years) individuals at low cardiovascular risk and grade 1 hypertension at most. Macular retinal layer volumes of both eyes were determined by SD-OCT. Total retinal volume but also each inner retinal layer volume separately including retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), and GCL-IPL were measured in each individual. RESULTS: Retinal layer volumes were lower among older individuals compared with young individuals (RNFL right eye: P = 0.037/left eye: P = 0.021; GCL and GCL-IPL: both eyes P < 0.001; IPL right eye: P = 0.005/left eye: P = 0.002; total retinal volume: both eyes P = 0.002) and there was an inverse correlation between retinal layer volumes and age. Partial correlation analysis, excluding age as a cofactor, revealed an inverse association between retinal layer volumes and DBP. In multiple regression analysis, DBP was identified as a determinant of retinal neurodegenerative processes. CONCLUSION: In the current study, we observed an inverse association between retinal neurodegenerative processes and DBP, suggesting that BP-lowering therapy by early antihypertensive drug-treatment might be beneficial to avoid early neurodegeneration.

How does empagliflozin improve arterial stiffness in patients with type 2 diabetes mellitus? Sub analysis of a clinical trial.

BACKGROUND: Empagliflozin has been shown to reduce cardiovascular mortality, but the underlying pathogenetic mechanisms are poorly understood. It was previously demonstrated that empagliflozin improved arterial stiffness. METHODS: Our analysis comprising 58 patients with type 2 diabetes mellitus identifies factors triggering the improvement of arterial stiffness. All patients participated in an investigator-initiated, prospective, double-blind, randomized, placebo-controlled, interventional clinical trial ( http://www.ClinicalTrials.gov : NCT02471963, registered 15th June 2015, retrospectively registered) and received either 6-weeks treatment with 25 mg empagliflozin orally once daily or placebo (crossover). Central systolic pressure and central pulse pressure were recorded by the SphygmoCor System (AtCor Medical). Now, we investigated the impact of parameters of glucose metabolism, volume status, sympathetic activation, lipids, uric acid, blood pressure and inflammation on vascular parameters of arterial stiffness using multivariate regression analysis. RESULTS: As previously reported, therapy with empagliflozin improved arterial stiffness as indicated by reduced central systolic blood pressure (113.6 ± 12.1 vs 118.6 ± 12.9 mmHg, p < 0.001), central pulse pressure (39.1 ± 10.2 vs 41.9 ± 10.7 mmHg, p = 0.027) forward (27.1 ± 5.69 vs 28.7 ± 6.23 mmHg, p = 0.031) as well as reflected wave amplitude (18.9 ± 5.98 vs 20.3 ± 5.97 mmHg, p = 0.045) compared to placebo. The multivariate regression analysis included age, sex and change between empagliflozin and placebo therapy of the following parameters: HbA1c, copeptin, hematocrit, heart rate, LDL-cholesterol, uric acid, systolic 24-h ambulatory blood pressure and high sensitive CRP (hsCRP). Besides the influence of age (beta = - 0.259, p = 0.054), sex (beta = 0.292, p = 0.040) and change in systolic 24-h ambulatory blood pressure (beta = 0.364, p = 0.019), the change of hsCRP (beta = 0.305, p = 0.033) emerged as a significant determinant of the empagliflozin induced reduction in arterial stiffness (placebo corrected). When replacing HbA1c with fasting plasma glucose in the multivariate regression analysis, a similar effect of the change in hsCRP (beta = 0.347, p = 0.017) on arterial stiffness parameters was found. CONCLUSION: Besides age and sex, change in systolic 24-h ambulatory blood pressure and change in hsCRP were determinants of the empagliflozin induced improvement of vascular parameters of arterial stiffness, whereas parameters of change in glucose metabolism and volume status had no significant influence. Our analysis suggests that empagliflozin exerts, at least to some extent, its beneficial vascular effects via anti-inflammatory mechanisms. Trial registration http://www.ClinicalTrials.gov : NCT02471963, registered 15th June 2015, retrospectively registered.