Review

Vasopressin as vasopressor

Kidney function is regulated by a complex interplay between circulating and locally produced chemicals known as vasoactive substances. These substances affect the tone of the renal vasculature, leading to either vasodilation or vasoconstriction; and consequently affect renal blood flow and/or glomerular filtration rate. They belong to a chemically heterogeneous group and include proteins, peptides, lipids, and nucleosides. This chapter summarizes the role of these vasoactive substances in the maintenance of normal renal function and also highlights their role in disease states including acute kidney injury, chronic kidney disease, and hypertension.

Heart failure (HF) is associated with pathological activation of arginine vasopressin, measured in plasma by the pre-hormone fragment copeptin. We hypothesised that copeptin is elevated and associated with worse prognosis in HF, and that left ventricular assist device (LVAD) therapy and heart transplantation (HTx) are associated with lower levels of copeptin.

We measured copeptin in groups of 49 patients with advanced HF, 13 patients one year post-LVAD and 22 patients one year post-HTx and correlated with clinical data and cardiac output. In HF we also assessed the prognostic role of copeptin with Kaplan-Meier analysis and multivariate Cox regression.

In HF, median (interquartile range) copeptin was 28 (18-45) pmol/L, after LVAD 16 (6-27) pmol/L, and after HTx 12 (5-20) pmol/L (p overall <0.001). In HF, copeptin was an independent predictor of death, LVAD or HTx (hazard ratio for log copeptin, 3.28 [95% confidence interval: 1.66-6.50], p=0.001).

Copeptin was elevated in, and independently predicted prognosis in, HF. Copeptin was progressively lower after LVAD and HTx. This suggests that improvement in cardiac output with LVAD and HTx may induce progressively reduced activation of vasopressin, which may be a marker for the beneficial effects of LVAD and HTx.

The level of copeptin, a stable fragment of pro-arginine-vasopressin (AVP), correlates with disease severity. It is an established, short-term prognostic marker for patients with heart failure with reduced ejection fraction (HFREF). We aimed to examine the association between copeptin and long-term mortality. We also studied the clinical usefulness of copeptin as a prognostic biomarker by analysing the improvement of net reclassification.

Copeptin concentrations were measured in a cohort of 195 consecutive patients with HFREF. Disease severity and clinical parameters were determined at baseline, and all-cause mortality was recorded after five-year follow-up.

One hundred and ten patients died during the five-year follow-up (five-year mortality rate: 0.56). Univariate analysis identified copeptin (HR 2.168 [95% CI 1.740-2.700]) as a predictor of mortality. The final, multivariable Cox survival model identified a number of independent predictors of death. These included higher NHYA functional class, previous MI, at least one hospitalisation for worsening HF (within the two years before inclusion into the study), elevated blood urea nitrogen, NT-proBNP-, and copeptin levels, as well as increased red blood cell distribution width, and decreased GFR. The addition of copeptin alone to the baseline predictive model (NT-proBNP only) resulted in a minor (8.21%) improvement, whereas the final, multivariable model showed a significant increase in net reclassification (10.26%, p = 0.015).

These data indicate that copeptin is an independent long-term prognostic marker in HFREF, with possible clinical relevance for multimarker risk prediction algorithms.

Ischemia-reperfusion injury is a complex physiological process responsible for delayed renal function or primary graft non-function, explicitly when kidney allograft are issued from expanded criteria donor. The purpose of this review is to detail the detrimental phenomenons altering kidney allograft's integrity in brain dead donor, therefore suggesting pharmacological interventions aiming to reduce ischemia-reperfusion injuries and improving transplantation outcome. This ischemia-reperfusion phenomenon must therefore be anticipated through the whole procedure starting at the stage of conditioning of the potential donor. Hormonal and haemodynamic consequences of brain death modify perfusion and oxygenation conditions of the organs Thus, after describing the autonomic, metabolic, endocrine and chemokine storm occurring during brain death, the authors focus on strategies to prevent hemodynamic instability in the donor and to limit the consequences of hormonal and immunological changes on organs that will eventually be transplanted.

L’ischémie-reperfusion est un processus aux voies de signalisations complexes et aux conséquences cliniques parfois délétères en transplantation rénale (reprise retardée de fonction ou non fonction primaire), surtout lorsque le transplant est issu d’une donneur à critères élargis. Le but de cette revue est de décrire les phénomènes physiopathologiques survenant chez les donneurs en état de mort encéphalique pour suggérer des stratégies d’intervention pharmacologiques. Ainsi, la compréhension des mécanismes de l’orage dysautonomique, cytokinique et hormonal survenant pendant la mort encéphalique, peut permettre de proposer une prise en charge optimale du risque d’instabilité hémodynamique du donneur et de prévenir les conséquences immunologiques sur l’organe transplanté. L’objectif étant alors de proposer des options thérapeutiques chez le donneur en mort encéphalique visant à limiter les lésions d’ischémie reperfusion du transplant et à améliorer les résultats de la transplantation.

A pesar de que el tratamiento de la insuficiencia cardíaca agudizada se sustenta, fundamentalmente, en la administración de diuréticos de asa de forma intravenosa, la evidencia científica que apoya esta práctica todavía es escasa y hay cierta incertidumbre respecto a las dosis y posología óptimas. La existencia de un porcentaje considerable de pacientes con resistencia al tratamiento diurético y el desarrollo de insuficiencia renal asociada al uso de estos fármacos, con posibles implicaciones sobre la mortalidad a medio plazo, han promovido la búsqueda de alternativas más eficaces y seguras. Técnicas de depuración extracorpórea, como la ultrafiltración, han demostrado eficacia, aunque no una clara superioridad, cuestionada por los posibles efectos adversos asociados a la técnica. El uso de dopamina a dosis bajas no se ha demostrado superior al tratamiento diurético convencional transcurridas las primeras horas de tratamiento. Por otra parte, la combinación con furosemida y suero salino hipertónico podría constituir una alternativa válida para la congestión refractaria en pacientes con fracción de eyección deprimida y creatinina plasmática ≤ 2,5 mg/dl, aunque precisa de más estudios antes de su generalización. El uso de tolvaptán puede ser una alternativa eficaz a corto plazo; sin embargo, su coste puede limitar su utilización. Debe considerarse que todavía hay controversia acerca de si el tratamiento con diuréticos de asa se asocia a mayor mortalidad en todos los grupos de pacientes con insuficiencia cardíaca agudizada. Futuros ensayos clínicos deberán aclarar estas controversias.

Although treatment of acute heart failure is based primarily on the administration of intravenous loop diuretics, evidence supporting this practice is still scarce and there is uncertainty about the optimal dose. The existence of a considerable percentage of patients refractory to diuretic therapy and worsening of renal failure associated with the use of these drugs, with possible implications for medium-term mortality, have prompted the search for more effective and safer alternatives. Extracorporeal purification techniques, such as ultrafiltration, have demonstrated efficacy, although their superiority is unclear, due to the possible adverse effects associated with the procedure. The use of low-dose dopamine is not superior to conventional diuretic therapy after the first few hours of treatment. Moreover, combination with furosemide and hypertonic saline could be a valid alternative for patients with refractory congestion and depressed ejection fraction and serum creatinine ≤ 2.5 mg/dL, but further studies are needed before its widespread use. The use of tolvaptan may be an effective alternative in the short-term but its use may be limited by its price. There is still controversy about whether treatment with loop diuretics is associated with higher mortality in all groups of patients with HF exacerbations. These controversies should be clarified by future clinical trials.

Pulmonary arterial hypertension (PAH) is a rare, deadly condition. Although risk stratification is extremely important for assessment of prognosis and to guide therapy, there is lack of evidence concerning the role of novel biomarkers. In a pivotal study, we sought to comparatively investigate the predictive power of several new biomarkers in PAH.

Patients with prevalent PAH were enrolled in the study protocol, which included clinical, functional and echocardiographic assessment. Blood samples were collected at baseline for determination of NT-proBNP, CT-proET-1, MR-proANP, MR-proADM, copeptin and troponin I. Patients were clinically followed-up up to 12 months for first occurrence of hospital admission due to PAH-related clinical worsening, heart/lung transplantation or all-cause mortality.

Among the 28 included patients the pre-specified end-point occurred in 8 (29% event rate). There were higher baseline levels of CT-proET-1, copeptin, MR-proANP, NT-proBNP and troponin I in patients who reached the composite end-point. They also had larger right atria. In multivariate Cox regression, CT-proET-1 was the only biomarker associated with increased hazard of reaching the primary composite end-point (hazard ratio per tertile increase = 10.1; 95% CI 2.0 to 50.6).

CT-proET-1 provided prognostic information independent of other biomarkers. Importantly, we have provided the first evidence that CT-proET-1 may be superior to commonly used biomarkers.