Poliquistosis renal autosómica dominante: ¿quiénes se benefician del tratamiento con tolvaptán?. Estado del arte / Autosomal dominant polycystic kidney disease. Who can benefit from tolvaptan therapy? State of the art / Doença renal policística autossômica dominante: quem se beneficia do tratamento com tolvaptano? Estado da arte

Resumen: La poliquistosis renal autosómica dominante es la enfermedad renal hereditaria más frecuente. Se caracteriza por la progresiva aparición de quistes renales que suelen conducir a la enfermedad renal crónica extrema en la edad adulta. La aprobación del uso de tolvaptán (antagonista del receptor V2 de la vasopresina) ha marcado un cambio significativo en el tratamiento de esta enfermedad. En los últimos años apareció evidencia que demuestra el beneficio en iniciar tratamiento con tolvaptán en pacientes que presentan una enfermedad con rápida evolución. Se realiza una revisión descriptiva de los principales estudios clínicos publicados en el periodo 2012-2022 y se sugiere un esquema de utilidad para seleccionar aquellos pacientes que pueden beneficiarse del inicio de tratamiento.

Abstract: Autosomal dominant polycystic kidney disease is the most common hereditary kidney disease. It is characterized by the progressive appearance of renal cysts that usually lead to extreme chronic kidney disease in adulthood. The approval of the use of tolvaptán (V2 vasopressin receptor antagonist) has meant a significant change in the treatment of this disease. In recent years, evidence has proved the benefits of initiating treatment with tolvaptán in patients with a rapidly evolving disease. A descriptive review of the main clinical studies published in 2012-2022 period is carried out and a useful scheme is suggested to select those patients who can benefit from the start of treatment.

Resumo: A doença renal policística autossômica dominante é a doença renal hereditária mais comum. Caracteriza-se pelo aparecimento progressivo de cistos renais que geralmente levam à doença renal crônica extrema na idade adulta. A aprovação do uso do tolvaptano (antagonista do receptor de vasopressina V2) marcou uma mudança significativa no tratamento dessa doença. Nos últimos anos, surgiram evidências que demonstram o benefício de iniciar o tratamento com tolvaptano em pacientes com doença de evolução rápida. Faz-se uma revisão descritiva dos principais estudos clínicos publicados no período 2012-2022 e sugere-se um esquema útil para selecionar aqueles pacientes que podem se beneficiar do início do tratamento.

Experiencia clínica con el uso ambulatorio de tolvaptan. Costes y efectividad en nueve casos / Clinical experience with Tolvaptan outpatient use. Cost and effectiveness in 9 cases

Resumen Introducción: La introducción de tolvaptan ha supuesto la principal novedad en el tratamiento de la hiponatremia en los últimos años. Objetivo: Describir la experiencia con tolvaptan en el Complejo Asistencial Universitario de León, España. Método: Estudio observacional retrospectivo de utilización ambulatoria de tolvaptan en un hospital de tercer nivel, de marzo de 2014 a agosto de 2017. Resultados: Fueron tratados con tolvaptan de forma ambulatoria nueve pacientes, 23.1 % alcanzó eunatremia en 24 horas. Posterior a la administración de tolvaptan se registró reducción en días de hospitalización (361 versus 70, p = 0.007), especialmente por hiponatremia (306 versus 49, p = 0.009). Conclusiones: El uso a largo plazo de tolvaptan parece ser seguro y se relaciona con descenso en los días de hospitalización.

Abstract Introduction: Tolvaptan introduction has constituted the main therapeutic novelty in the management of hyponatremia in recent years. Objective: To describe the experience with this drug at Complejo Asistencial Universitario de León, Spain. Method: Retrospective, observational study of tolvaptan outpatient use in a tertiary care hospital from March 2014 to August 2017. Results: A total of 9 patients were treated with tolvaptan in the outpatient setting. Eunatremia was reached in 24 h by 23.1%. After tolvaptan administration, a reduction in days of hospitalization was recorded (361 vs. 70; p = 0.007), especially in those days of hospitalization that were attributable to hyponatremia (306 vs. 49; p = 0.009). Conclusions: Long-term use of tolvaptan appears to be safe and is associated with a decrease in days of hospitalization.

Traumatic brain injury associated with hyponatremia

Background: Traumatic brain injury (TBI) is a one of the commonest injuries treated at the Neurosurgery Department. The incidence rate is approximately 3% in the general population and the mortality rate is about 30% of all injury deaths. Hyponatremia leads to high morbidity and/or mortality in TBI patients. Our study discusses the epidemiology of TBI associated with hyponatremia. Methods: Retrospective analysis of 80 patients with TBI between February 2017 and November 2018 was performed. The relationship between the incidence of hyponatremia in TBI patients and age, sex, GCS, type, severity of injury and whether the patient was submitted to surgery or not. Results: Out of 80 TBI patients recruited for the study, 25 of them suffered from hyponatremia. Hyponatremia following TBI wasn't related to age, sex but it was related to the type of injury, the Glasgow Coma Scale (GCS) score ≤ 8, surgical history. TBI with hyponatremia usually had longer stay in the hospital and bad outcome. Conclusions: Sever TBI patients (GCS score ≤ 8), intracranial hemorrhage and/or skull base fracture are susceptible to developing hyponatremia and require additional treatment aiming to normalization of serum sodium levels to prevent deterioration of their condition. Abbreviations: ANP, Atrial natriuretic peptide; CSWS, Cerebral salt wasting syndrome; SIADH, Syndrome of inappropriate secretion of antidiuretic hormone; TBI, Traumatic brain injury

Tolvaptán en un caso de síndrome cardiorrenal pediátrico: ¿Cuál es su papel? / Tolvaptan in a pediatric cardiorenal syndrome: What is its role?

El síndrome cardiorrenal se define como la asociación de insuficiencia renal y cardíaca de forma aguda o crónica. Se establece una resistencia a los diuréticos convencionales que hace difícil el manejo de estos niños. El tolvaptán, un antagonista de los receptores de vasopresina, ha sido empleado con éxito en adultos, aunque la experiencia en niños es muy limitada. Se presenta el caso de una paciente de 5 años en lista de trasplante cardíaco que padecía síndrome cardiorrenal. Había tenido una hospitalización prolongada con buena respuesta a dosis mínimas de tolvaptán (0,1 mg/kg/día). Se analizaron las curvas de urea, creatinina, sodio y volumen urinario, y se evidenció una mejoría llamativa en la función renal. Al cuarto día de haber iniciado el tratamiento, se le pudo dar el alta con seguimiento ambulatorio y buena evolución hasta el trasplante. El tolvaptán podría considerarse una opción de tratamiento en niños con resistencia a diuréticos convencionales e insuficiencia cardíaca, especialmente, cuando presentan insuficiencia renal.

The cardiorenal syndrome has been defined as a situation in which therapy to relieve congestive symptoms of heart failure is limited by a decreased renal function. The resistance to conventional diuretic treatment makes difficult managing these patients. Tolvaptan, a selective vasopressin-2 receptor antagonist, has been used successfully in adults with this pathology but the experience with children is very limited. A five-year-old girl with renal failure waiting for a heart transplant is presented. Tolvaptan (0.1 mg/kg/day) was started at very low dosage, resulting in an excellent response. We analyzed the creatinine, urea, urine volume and sodium evolution. Renal function also improved. She could be discharged after four days of treatment (156 days of hospitalization) with ambulatory favourable follow-up until heart transplant. Tolvaptan should be considered in pediatric cases of conventional diuretic-resistant congestive heart failure, especially when complicated by kidney disease.

Hyponatremia in Liver Cirrhosis / 대한소화기학회지

Hyponatremia is a commonly observed complication that is related to hypoalbuminemia and portal hypertension in patients with advanced liver cirrhosis. Hyponatremia in patients with liver cirrhosis is mostly dilutional hyponatremia and is defined when the serum sodium concentration is below 130 meq/L. The risk of complications increases significantly in cirrhotic patients with hyponatremia, which includes spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy. In addition, hyponatremia is associated with increased morbidity and mortality in patients with cirrhosis, and is an important prognostic factor before and after liver transplantation. The conventional therapies of hyponatremia are albumin infusion, fluid restriction and loop diuretics, but these are frequently ineffective. This review investigates the pathophysiology and various therapeutic modalities, including selective vasopressin receptor antagonists, for the management of hyponatremia in patients with liver cirrhosis.

Utility and Safety of Tolvaptan in Cirrhotic Patients with Hyponatremia: a Prospective Cohort Study

Abstract: Introduction and aim. Hyponatremia is common in patients with decompensated cirrhosis and is associated with increased mortality. Tolvaptan, a vasopressor V2 receptor antagonist, can increase free wáter excretion, but its efficacy and safety in cirrhotic patients remain unclear. Material and methods. We studied the usage and safety of tolvaptan in cirrhotic patients in a real-life, non-randomized, multicenter prospective cohort study. Forty-nine cirrhotic patients with hyponatremia were treated with tolvaptan 15 mg daily, and 48 patients not treated with tolvaptan in the same period served as controls. Improvement in serum sodium level was defined as an increase in serum sodium from < 125 to ≥ 125 mmol/L or from 125-134 to ≥ 135 mmol/L on day 7. Results. Twenty-three (47%) patients in the tolvaptan group and 17 (35%) in the control group had normal serum sodium on day 7 (p = 0.25). Serum sodium improved in 30 (61%) patients in the tolvaptan group and 17 (35%) patients in the control group (p = 0.011). Adverse events occurred in 46-47% of patients in both groups, and tolvaptan was not associated with worsened liver function. No patient with normal serum sodium on day 7 died within 30 days of treatment, whereas 16% of those with persistent hyponatremia died (p = 0.0019). Conclusion. In conclusion, short-term tolvaptan treatment is safe and can improve serum sodium level in cirrhotic patients with hyponatremia. Normalization of serum sodium level is associated with better survival.

SIADH secundario a adenocarcinoma seroso de ovario tratado con tolvaptán / SIADH secondary to serous ovarian adenocarcinoma treated with tolvaptan

La hiponatremia es la alteración electrolítica más frecuente en el medio hospitalario, y en un 30% de los casos se debe a un síndrome de secreción inapropiada de vasopresina (SIADH). El SIADH está descrito como cuadro paraneoplásico endocrinológico en múltiples tumores, entre los que excepcionalmente se encuentra el de ovario y las neoplasias ginecológicas en general. Presentamos un caso de SIADH paraneoplásico por un citoadenocarcinoma seroso de ovario de alto grado, estadio IV. Se trata del primer caso de SIADH crónico por cáncer de ovario tratado con Tolvaptán. En el presente caso el objetivo de eunatremia se alcanzó con una dosis baja de acuarético, lo que apoya la elevada sensibilidad, ya previamente documentada, de los SIADH tumorales al tratamiento con Tolvaptán.

Hyponatremia is the most common electrolyte disturbance in hospitals, and 30% of cases are due to syndrome of inappropriate secretion of antidiuretic hormone (SIADH). SIADH is described as an endocrine paraneoplastic syndrome in multiple tumors including, ovary and gynecological malignancies in general, although these are exceptional. We report a case of paraneoplastic SIADH for high-grade serous ovarian cystoadenocarcinoma stage IV. This is the first case of chronic SIADH for ovarian cancer treated with Tolvaptan. In this case the target of eunatremia was reached with a low dose of aquaretic, which supports the high sensitivity, as previously documented, of paraneoplasic SIADH to Tolvaptan.

The efficacy and safety of tolvaptan on treating heart failure patients with hyponatremia / 中华心血管病杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of tolvaptan on treating congestive heart failure patients with hyponatremia.</p><p><b>METHODS</b>This randomized double-blind placebo-controlled multicenter trial enrolled 65 patients with congestive heart failure and hyponatremia. On top of standard therapy, patients were randomized to receive either tolvaptan 15 - 60 mg daily or placebo according to the serum sodium concentration. The primary end points were the change of average daily serum sodium concentration from baseline to day 4 and to day 7 respectively. Patients' weight, urine volume, sign of heart failure, heart function, blood pressure, heart rate, and all adverse events were observed.</p><p><b>RESULTS</b>The daily serum sodium concentration increase was significantly higher in tolvaptan group than in placebo group during the first 4 days [(5.6 ± 3.5) mmol/L vs. (2.5 ± 3.4) mmol/L, P < 0.05] and 7 days [(5.9 ± 3.5) mmol/L vs. (2.8 ± 3.3) mmol/L, P < 0.05]. Moreover, urine volume increase and body weight decrease were more significant in tolvaptan group than in placebo group (all P < 0.05). The change of sign of heart failure, heart function, blood pressure and heart rate was similar between two groups (P > 0.05). There were more drug related adverse events of thirst (11.4%) and hypernatremia (5.7%) in Tolvaptan group. One patient in tolvaptan group developed agranulocytosis during therapy period and recovered post therapy.</p><p><b>CONCLUSIONS</b>Tolvaptan could effectively increase serum sodium concentration, urine volume, and improve liquid balance in heart failure patients with hyponatremia. Tolvaptan related serious adverse event was low and could be well tolerated by patients tested in this cohort.</p>

Arginine vasopressin stimulates proliferation of adult rat cardiac fibroblasts via protein kinase C-extracellular signal-regulated kinase 1/2 pathway / 生理学报

Arginine vasopressin (AVP), a neurohormone and hemodynamic factor implicated in the pathophysiology of hypertension and congestive heart failure, can also act as a growth-stimulating factor. Our previous work demonstrated that AVP is a mitogen for neonatal rat cardiac fibroblasts (CFs). In the present study, we extended our investigations to adult rat CFs to explore whether AVP could induce adult rat CF proliferation and, if so, to identify the mechanism involved. Adult rat CFs were isolated, cultured and subjected to AVP treatment. DNA synthesis and cell cycle distribution were analyzed by [(3)H]-thymidine incorporation and flow cytometry. Cellular extracellular signal-regulated kinase 1/2 (ERK1/2) activity was measured by in vitro kinase assay using myelin basic protein (MBP) as a substrate. Protein expressions of total- and phospho-ERK1/2, p27(Kip1), cyclins D1, A, E were assessed by Western blot. The results showed that AVP stimulated DNA synthesis in adult rat CFs, and the effect was abolished by a V1 receptor antagonist, d(CH(2))(5)[Tyr(2)(Me), Arg(8)]-vasopressin (0.1 μmol/L), but not by a V2 receptor antagonist, desglycinamide-[d(CH(2))(5), D-Ile(2), Ile(4), Arg8]-vasopressin (0.1 μmol/L). AVP induced an activation of ERK1/2, which could be mimicked by the protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA, 30 nmol/L, 5 min), but abolished by depletion of PKC via chronic PMA incubation (2.5 μmol/L, 24 h). In addition, AVP down-regulated protein expression of p27(Kip1), increased protein expressions of cyclins D1, A and E, and induced cell cycle progression from G(0)/G(1) into S stage. Inhibition of ERK1/2 activation by PD98059 (30 μmol/L) abolished the effect of AVP on DNA synthesis, protein expressions of p27(Kip1), cyclins D1, A and E as well as cell cycle progression. These results suggest that AVP is also a growth factor for adult rat CFs. The mitogenic effect of AVP is mediated via V1 receptors and PKC-ERK1/2 pathway. Moreover, AVP modulates the expressions of cell cycle regulatory proteins p27(Kip1) and cyclins D1, A and E, which lie downstream of ERK1/2 activation, and induces cell cycle progression in adult rat CFs.