System, Renin-Angiotensin

Baseline characteristics were recorded by clinical research associates from medical files or by interview. Data included age, sex, body mass index (BMI), hypertension (patients having an office blood pressure greater than or equal to 140/90 mmHg or an antihypertensive treatment), cardiovascular history (coronary artery disease, arrhythmic disorders, congestive heart failure, stroke, peripheral vascular disease and/or valvulopathy), diabetes (diabetes history or antidiabetic treatment or glycated hemoglobin ≥ 6.5% or fasting glycemia ≥ 7 mmol/l or non-fasting glycemia ≥ 11), gout history, dyslipidemia, primary kidney disease, time since CKD diagnosis (time elapsed from the date of CKD diagnosis found in the medical record and the cohort entry), number of consultation in the previous year with nephrologist and dietician, treatment (urate-lowering therapy (ULT), diuretics, antiplatelet agents, renin-angiotensin system inhibitors (RASi)), laboratory data (serum creatinine, eGFR estimated by the CKD-EPI equation, serum UA, albuminemia, C-reactive protein and, albuminuria—or equivalent—classified according to the KDIGO 2012 guidelines¹⁶ ), salt intake (estimated by 24-h natriuresis) and protein intake (estimated by 24-h urinary urea)^{17 (link)}, medication adherence according to the Girerd score in categories (good, minimal and poor)^{18 (link)}, health literacy according to their need for help reading medical documents (never need vs always or partly need)^{19 (link)} and type of center (university, non-university hospital, private non-profit and private for-profit clinic).

This was a single-center, retrospective cohort study. The subjects comprised 63 patients with advanced heart failure in our Heart Failure Center from Nov 2017 to Dec 2020. Inclusion criteria: Left ventricle ejection fraction (LVEF) of <40% (measured with Simpson of Doppler Echocardiography); the definition of advanced heart failure with reduced ejection fraction (HFrEF, LVEF<40%). Exclusion criteria: (1) Symptomatic hypotension or blood pressure (BP) <85/60 mmHg; (2) Severe arrhythmia; (3) Severe infection and respiratory diseases; (4) Allergy to levosimendan or unable to tolerate long-term intravenous pumping treatment. The Estimated glomerular filtration rate (eGFR) is calculated following formula: male, Ccr = (140-age)*weight (kg)*1.23/Scr (μmol/L) (Ccr, Creatinine Clearance Rate; Scr, Serum creatinine; female); Ccr = (140-age)*weight (kg)*1.03/Scr (μmol/L). AF atrial fibrillation group (n = 29) based on ECG heart rhythm data. Two groups of patients with advanced heart failure received conventional treatment recommended by the guidelines, including diuretics, renin-angiotensin system (RAS) blockers, angiotensin receptor-neprilysin inhibitor (ARNI), aldosterone receptor antagonists, β-receptor blockers, digoxin, etc. Levosimendan was administered in accordance with our center’s approved treatment protocol (7 (link)) (the total dose was 12.5 mg, 0.05 ~ 0.2 μg kg⁻¹ min⁻¹, intravenous 24–48 h, repeated infusion every 2–4 weeks for 3 months). Levosimendan infusion was started at a rate of 0.1 μg kg⁻¹·min⁻¹ during the first hour and increased to 0.2 μg·kg⁻¹·min⁻¹ after that if well tolerated in the case of low systolic blood pressure (SBP) (<90 mmHg). Without applying a beginning bolus, levosimendan was infused via a 24 h lasting infusion (0.1 ug/kg/min) while being monitored for hemodynamic effects in an intermittent care scenario. We measured the levels of B-type natriuretic peptide (BNP) before and 3 days after the infusion. The patients will repeat the blood test with a total observation time of 6 months to assess the blood pressure, resting heart rate, body weight, NYHA classification, Creatinine (Crea), eGFR, LVEF, left ventricular end diastolic diameter (LVEDD) and BNP. Then proceed to investigate the differences between the two groups (as shown in Figure 1).

For our first aim, the outcome was the occurrence of DGF, which was defined as the need for dialysis in the first post-transplant week, failure of serum creatinine to decrease by more than 10% within the first 3 post-operative days or serum creatinine above 250 µmol/L on post-operative day 5 with evidence of acute tubular necrosis on the allograft scintigraphy (1 (link),10 (link)). The exposure, or main independent variable of interest, was high pre-transplant anti-LG3 antibody levels. High anti-LG3 was defined as a value in the highest quartile of the distribution (17 (link)). Anti-LG3 was measured with a locally-developed enzyme-linked immunosorbent assay (17 (link)). As potential interactions between anti-LG3 levels and ischemia/endothelial injury were suggested by our prior animal studies (17 (link)), we defined, a priori, use of hypothermic perfusion machine as an effect modifier to be tested. In the province of Quebec, the only pump available in the field of transplantation is hypothermic perfusion with LifePort® devices, which do not provide oxygenation. There is no protocol in place guiding the use of perfusion devices and the decision to use them is hence left to the discretion of the transplant surgeon recovering and/or transplanting the kidney.
For the second aim, the outcome was kidney allograft survival, which was defined as the time elapsed between transplantation and graft failure, either return to dialysis or retransplantation. Death with a functioning graft was taken into account as a competing risk for kidney graft failure. The exposure was high pre-transplant anti-LG3 antibodies, as defined above. The effect modifier was DGF, as defined above. Covariates for all models were selected on the basis of their previously reported associations with DGF or kidney graft survival (20 (link)–22 (link)). These included both recipient and donor characteristics. Recipient variables included age, sex, race, cause of chronic kidney disease (diabetes, vascular/hypertension, autoimmune and other), time on dialysis before transplantation, height and weight, diabetes, history of cardiovascular disease, smoking status (active, past, never smoker), cytomegalovirus serostatus, pre-transplant and peak panel reactive antibodies, previous transplantations, transfusions, pregnancies, induction (basiliximab as the standard protocol, thymoglobulin with or without intravenous immunoglobulins which are reserved for highly sensitized patients), statin and renin-angiotensin system blockers use on admission. Donor variables included age, sex, height and weight, stroke as cause of death, cytomegalovirus serostatus, history of hypertension, diabetes, vascular disease, terminal creatinine, and number of HLA mismatches with the recipient. Recipient age was the only variable with an a priori association with the exposure, anti-LG3 (17 (link)).