The safety and efficacy of sodium‐glucose cotransporter 2 inhibitors in posttransplantation diabetes mellitus is unknown. We converted stable kidney transplant patients to 10 mg empagliflozin, aiming at replacing their insulin therapy (<40 IU/d). N = 14 participants (the required sample size) completed the study visits through 4 weeks and N = 8 through 12 months. Oral glucose tolerance test (OGTT)–derived 2‐hour glucose (primary end point) increased from 232 ± 82 mg/dL (baseline) to 273 ± 116 mg/dL (4 weeks, P = .06) and to 251 ± 71 mg/dL (12 months, P = .41). Self‐monitored blood glucose and hemoglobin A1c were also clinically inferior with empagliflozin monotherapy, such that insulin was reinstituted in 3 of 8 remaining participants. Five participants (2 of them dropouts) vs nine of 24 matched reference patients developed bacterial urinary tract infections (P = .81). In empagliflozin‐treated participants, oral glucose insulin sensitivity decreased and beta‐cell glucose sensitivity increased at the 4‐week and 12‐month OGTTs. Estimated glomerular filtration rate and bioimpedance spectroscopy‐derived extracellular and total body fluid volumes decreased by 4 weeks, but recovered. All participants lost body weight. No participant developed ketoacidosis; 1 patient developed balanitis. In conclusion, although limited by sample size and therefore preliminary, these results suggest that empagliflozin can safely be used as add‐on therapy, if posttransplant diabetes patients are monitored closely (NCT03113110).

BackgroundChronic fluid overload is associated with higher mortality in dialysis patients; however, the link with cardiovascular morbidity has not formally been established and may be influenced by subclinical inflammation. We hypothesized that a relationship exists between fluid overload and [i] cardiovascular laboratory parameter as well as between fluid overload and [ii] inflammatory laboratory parameters. In addition, we aimed to confirm whether volume status correlates with nutritional status.MethodsWe recorded baseline characteristics of 244 hemodialysis patients at three hemodialysis facilities in Vienna (Austria) and determined associations with volume measurements using the body composition monitor (Fresenius/Germany). In one facility comprising 126 patients, we further analyzed cardiovascular, inflammatory and nutritional parameters.ResultsWe detected predialysis fluid overload (FO) in 39% of all patients (n = 95) with FO defined as ≥15% of extracellular water (ECW). In this subgroup, the absolute FO was 4.4 +/-1.5 L or 22.9 ± 4.8% of ECW. A sub-analysis of patients from one center showed that FO was negatively associated with body mass index (r = -0.371; p = <0.001), while serum albumin was significantly lower in fluid overloaded patients (p = 0.001). FO was positively associated with D-Dimer (r = 0.316; p = 0.001), troponin T (r = 0.325; p < 0.001), and N-terminal pro-B-type natriuretic peptide (r = 0.436; p < 0.001), but not with investigated inflammatory parameters.ConclusionsFluid overload in HD patients was found to be lower in patients with high body mass index, indicating that dry weight was inadequately prescribed and/or difficult to achieve in overweight patients. The association with parameters of cardiovascular compromise and/or damage suggests that fluid overload is a biomarker for cardiovascular risk. Future studies should determine if this applies to patients prior to end-stage renal disease.

Predialysis volume overload is the sum of interdialytic weight gain (IDWG) and residual postdialysis volume overload. It results mostly from failure to achieve an adequate volume status at the end of the dialysis session. Recent developments in bioimpedance spectroscopy and possibly relative plasma volume monitoring permit noninvasive volume status assessment in hemodialysis patients. A large proportion of patients have previously been shown to be chronically volume overloaded predialysis (defined as >15% above ‘normal' extracellular fluid volume, equivalent to >2.5 liters on average), and to exhibit a more than twofold increased mortality risk. By contrast, the magnitude of the mortality risk associated with IDWG is much smaller and only evident with very large weight gains. Here we review the available evidence on volume overload and IDWG, and question the use of IDWG as an indicator of ‘nonadherence' by describing its association with postdialysis volume depletion. We also demonstrate the relationship between IDWG, volume overload and predialysis serum sodium concentration, and comment on salt intake. Discriminating between volume overload and IDWG will likely lead to a more appropriate management of fluid withdrawal during dialysis. Consensually, the present authors agree that this discrimination should be among the primary goals for dialysis caretakers today. In consequence, we recommend objective measures of volume status beyond mere evaluations of IDWG.

Cardiovascular and renal pathologies are frequently associated with an activated renin-angiotensin-system (RAS) and increased levels of its main effector and vasoconstrictor hormone angiotensin II (Ang II). Angiotensin-converting-enzyme-2 (ACE2) has been described as a crucial enzymatic player in shifting the RAS towards its so-called alternative vasodilative and reno-protective axis by enzymatically converting Ang II to angiotensin-(1-7) (Ang-(1-7)). Yet, the relative contribution of ACE2 to Ang-(1-7) formation in vivo has not been elucidated. Mass spectrometry based quantification of angiotensin metabolites in the kidney and plasma of ACE2 KO mice surprisingly revealed an increase in Ang-(1-7), suggesting additional pathways to be responsible for alternative RAS activation in vivo. Following assessment of angiotensin metabolism in kidney homogenates, we identified neprilysin (NEP) to be a major source of renal Ang-(1-7) in mice and humans. These findings were supported by MALDI imaging, showing NEP mediated Ang-(1-7) formation in whole kidney cryo-sections in mice. Finally, pharmacologic inhibition of NEP resulted in strongly decreased Ang-(1-7) levels in murine kidneys. This unexpected new role of NEP may have implications for the combination therapy with NEP-inhibitors and angiotensin-receptor-blockade, which has been shown being a promising therapeutic approach for heart failure therapy.

Background/Aims: Heart failure (HF) is a main cause of mortality of hemodialysis (HD) patients. While HF with reduced ejection fraction (HFrEF) is known to only affect a minority of patients, little is known about the prevalence, associations with clinical characteristics and prognosis of HF with preserved ejection fraction (HFpEF). Methods: We included 105 maintenance HD patients from the Medical University of Vienna into this prospective single-center cohort study and determined the prevalence of HFpEF (per the 2013 criteria of the European Society of Cardiology) and HFrEF (EF <45%), using standardized post-HD transthoracic echocardiography. We also assessed clinical, laboratory and volume status parameters (by bioimpedance spectroscopy). These parameters served to calculate prediction models for both disease entities, while clinical outcomes (frequency of cardiovascular hospitalizations and/or cardiac death) were assessed prospectively over 27±4 months of follow-up. Results: All but 4 patients (96%) had evidence of diastolic dysfunction. 70% of the entire cohort fulfilled HF criteria (81% HFpEF, 19% HFrEF). Age, female sex, body mass index, blood pressure and dialysis vintage were predictive of HFpEF (sensitivity 86%, specificity 63%; AUC 0.87), while age, female sex, NT pro-BNP, history of coronary artery disease and atrial fibrillation were predictive of HFrEF (sensitivity 85%, specificity 90%; AUC 0.95). Compared to patients without HF, those with HFpEF and HFrEF had a higher risk of hospitalization for cardiovascular reason and/or cardiac death (adjusted HR 4.31, 95% CI 0.46-40.03; adjusted HR 3.24, 95% CI 1.08-9.75, respectively). Conclusion: Diastolic dysfunction and HFpEF are highly prevalent in HD patients while HFrEF only affects a minority. Distinct patient-specific characteristics predict diagnosis of either entity with good accuracy.

New-onset diabetes after transplantation (NODAT) is a serious complication after kidney transplantation, but therapeutic strategies remain underexplored. Dipeptidyl peptidase-4 (DPP-4) inhibitors selectively foster insulin secretion without inducing hypoglycemia, which might be advantageous in kidney transplant recipients (KTRs) with NODAT. We conducted a randomized, double-blind, placebo-controlled, phase II trial to assess safety and efficacy of the DPP-4 inhibitor vildagliptin. Intraindividual differences in oral glucose tolerance test (OGTT)-derived 2-h plasma glucose (2HPG) from baseline to 3 months after treatment served as primary endpoint. Among secondary outcomes, we evaluated HbA1c, metabolic and safety parameters, as well as OGTTs at 1 month after drug discontinuation. Of 509 stable KTRs who were screened in our outpatient clinic, 63 (12.4%) had 2HPG !200 mg/dL, 33 of them were randomized and 32 completed the study. In the vildagliptin group 2HPG and HbA1c were profoundly reduced in comparison to placebo (vildagliptin: 2HPG ¼ 182.7 mg/dL, HbA1c ¼ 6.1%; placebo: 2HPG ¼ 231.2 mg/dL, HbA1c ¼ 6.5%; both p 0.05), and statistical significance was achieved for the primary endpoint (vildagliptin: 2HPG-difference À73.7 AE 51.3 mg/dL; placebo: À5.7 AE 41.4 mg/dL; p < 0.01). Adverse events were generally mild and occurred at similar rates in both groups. In conclusion, DPP-4 inhibition in KTRs with overt NODAT was safe and efficient, providing a novel treatment alternative for this specific form of diabetes.

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Background In recent months numerous health care professional acquired COVID-19 at the workplace resulting in significant shortages in medical and nursing staff. We investigated how prior COVID-19 affects SARS-CoV-2 vaccination and how such knowledge could facilitate frugal vaccination strategies. Methods In a cohort of 41 healthcare professionals with (n=14) and without (n=27) previous SARS-CoV-2 infection, we assessed the immune status before, during and after vaccination with BNT162b2. The humoral immune response was assessed by receptor binding domain ELISA and different SARS-CoV-2 neutralisation assays using wildtype and pseudo-typed viruses. T cell immunity against SARS-CoV-2 surface and nucleocapsid peptides were studied using interferon-γ release assays and intracellular flow cytometry. Vaccine-related side effects were captured. Findings Prior COVID-19 resulted in improved vaccine responses both in the B and T cell compartment. In vaccine recipients with prior COVID-19, the first vaccine dose induced high antibody concentrations comparable to seronegative vaccine recipients after two injections. This translated into more efficient neutralisation of virus particles, even more pronounced than expected from the RBD ELISA results. Furthermore, T cell responses were stronger in convalescents and particularly strong against the SARS-CoV-2 nucleocapsid protein. Interpretation Herein, we corroborate recent findings suggesting that in convalescents a single vaccine dose is sufficient to boost adequate in vitro neutralisation of SARS-CoV-2 and therefore may be sufficient to induce adequate protection against severe COVID-19. New spike mutated virus variants render the highly conserved nucleocapsid protein – eliciting strong SARS-CoV-2 specific T cell immunity – an interesting additional vaccine target. Funding Christian Doppler Research Association, Johannes Kepler University Linz