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This article delves into the intricate challenges of acute kidney injury (AKI) in cirrhosis, a condition fraught with high morbidity and mortality. The complexities arise from distinguishing between various causes of AKI, particularly hemodynamic AKI, in cirrhotic patients, who experience hemodynamic changes due to portal hypertension. The term "hepatocardiorenal syndrome" is introduced to encapsulate the intricate interplay among the liver, heart, and kidneys. The narrative emphasizes the often-overlooked aspect of cardiac function in AKI assessments in cirrhosis, unveiling the prevalence of cirrhotic cardiomyopathy marked by impaired diastolic function. The conventional empiric approach involving volume expansion and vasopressors for hepatorenal syndrome is critically analyzed, highlighting potential risks and variable patient responses. We advocate for a nuanced algorithm for AKI evaluation in cirrhosis, prominently featuring point-of-care ultrasonography (POCUS). POCUS applications encompass assessing fluid tolerance, detecting venous congestion, and evaluating cardiac function.
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AIMS: Renal and liver congestion are associated with adverse outcomes in patients with tricuspid regurgitation (TR). Currently, there are no valid sonographic indicators of fluid status in this population. Intra-renal venous Doppler (IRVD) is a novel method for quantifying renal congestion but its interpretation can be challenging in severe TR due to altered haemodynamics. This study explores the potential of portal vein Doppler (PVD) as an alternative marker for decongestion during volume removal in patients with severe TR. METHODS AND RESULTS: Forty-two patients with severe TR undergoing decongestive therapy were prospectively enrolled. Inferior vena cava diameter, PVD, and IRVD were sequentially assessed during volume removal. Improvement criteria were portal vein pulsatility fraction (PVPF) < 70% and renal venous stasis index (RVSI) < 0.5 for partial improvement, and PVPF < 30% and RVSI < 0.2 for complete improvement. After volume removal, PVPF significantly improved from 130 ± 39% to 47 ± 44% (P < 0.001), while IRVD improved from 0.72 ± 0.08 to 0.54 ± 0.22 (P < 0.001). A higher proportion of patients displayed improvement in PVD compared to IRVD (partial: 38% vs. 29%, complete: 41% vs. 7%) (P < 0.001). Intra-renal venous Doppler only improved in patients with concomitant improvement in severe TR. Portal vein Doppler was the only predictor of achieving ≥5â L of negative fluid balance [area under the ROC curve (AUC) 0.83 P = 0.001]. CONCLUSION: This proof-of-concept study suggests that PVD is the only sonographic marker that can track volume removal in severe TR, offering a potential indicator for decongestion in this population. Further intervention trials are warranted to determine if PVD-guided decongestion improves patient outcomes in severe TR.
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Veia Porta , Estudo de Prova de Conceito , Insuficiência da Valva Tricúspide , Humanos , Veia Porta/diagnóstico por imagem , Masculino , Feminino , Insuficiência da Valva Tricúspide/fisiopatologia , Insuficiência da Valva Tricúspide/diagnóstico , Estudos Prospectivos , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Idoso , Ultrassonografia Doppler/métodos , Hemodinâmica/fisiologia , Veia Cava Inferior/diagnóstico por imagemRESUMO
BACKGROUND: Assessment of dynamic parameters to guide fluid administration is one of the mainstays of current resuscitation strategies. Each test has its own limitations, but passive leg raising (PLR) has emerged as one of the most versatile preload responsiveness tests. However, it requires real-time cardiac output (CO) measurement either through advanced monitoring devices, which are not routinely available, or echocardiography, which is not always feasible. Analysis of the hepatic vein Doppler waveform change, a simpler ultrasound-based assessment, during a dynamic test such as PLR could be useful in predicting preload responsiveness. The objective of this study was to assess the diagnostic accuracy of hepatic vein Doppler S and D-wave velocities during PLR as a predictor of preload responsiveness. METHODS: Prospective observational study conducted in two medical-surgical ICUs in Chile. Patients in circulatory failure and connected to controlled mechanical ventilation were included from August to December 2023. A baseline ultrasound assessment of cardiac function was performed. Then, simultaneously, ultrasound measurements of hepatic vein Doppler S and D waves and cardiac output by continuous pulse contour analysis device were performed during a PLR maneuver. RESULTS: Thirty-seven patients were analyzed. 63% of the patients were preload responsive defined by a 10% increase in CO after passive leg raising. A 20% increase in the maximum S wave velocity after PLR showed the best diagnostic accuracy with a sensitivity of 69.6% (49.1-84.4) and specificity of 92.8 (68.5-99.6) to detect preload responsiveness, with an area under curve of receiving operator characteristic (AUC-ROC) of 0.82 ± 0.07 (p = 0.001 vs. AUC-ROC of 0.5). D-wave velocities showed worse diagnostic accuracy. CONCLUSIONS: Hepatic vein Doppler assessment emerges as a novel complementary technique with adequate predictive capacity to identify preload responsiveness in patients in mechanical ventilation and circulatory failure. This technique could become valuable in scenarios of basic hemodynamic monitoring and when echocardiography is not feasible. Future studies should confirm these results.
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Resumen Antecedentes: La enfermedad renal crónica (ERC) representa una elevada carga global de enfermedad debido a la falta de pruebas universales y a la interpretación errónea de biomarcadores. Objetivo: Analizar la epidemiología de la ERC en México y orientar las políticas públicas. Material y métodos: Se utilizaron los datos del estudio Global Burden of Disease (GBD) 2021 para describir la prevalencia y mortalidad de la ERC en México durante el periodo de 1990 a 2021, estratificando por sexo y grupos de edad. Resultados: La prevalencia de la ERC en México en 2021 fue de 9184.9 por 100 000 habitantes. La diabetes constituyó la causa más común de ERC y la mortalidad por ERC fue elevada, se incrementó en 2019 y 2021, posiblemente debido a la pandemia de COVID-19. Conclusiones: La ERC en México presenta una alta carga de mortalidad y años de vida perdidos, pero contribuye poco a la discapacidad. Es esencial mejorar la detección temprana de la ERC, el acceso a tratamientos y la codificación de las causas de la enfermedad. Además, investigar las causas de la ERC de etiología desconocida, incluidos factores genéticos, es crucial para desarrollar tratamientos específicos en el futuro.
Abstract Background: Chronic kidney disease (CKD) represents a substantial global burden of disease due to a lack of universal tests and misinterpretation of biomarkers. Objective: To analyze CKD epidemiology in Mexico and guide public policies. Material and methods: Data from the Global Burden of Disease (GBD) 2021 study were used to describe CKD prevalence and mortality in Mexico for the 1990-2021 period, stratifying by gender and age groups. Results: The prevalence of CKD in Mexico in 2021 was 9,184.9 per 100,000 population. Diabetes was the most common cause of CKD, and CKD-related mortality was high, with an increase in 2019 and 2021, possibly as a consequence of the COVID-19 pandemic. Conclusions: CKD in Mexico entails a high burden of mortality and years of life lost, but it barely contributes to disability. It is essential to improve CKD early detection, access to treatments and coding of the causes of the disease. Moreover, investigating the causes of CKD of unknown etiology, including genetic factors, is crucial in order for specific treatments to be developed in the future.
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BACKGROUND: Chronic kidney disease (CKD) represents a substantial global burden of disease due to a lack of universal tests and misinterpretation of biomarkers. OBJECTIVE: To analyze CKD epidemiology in Mexico and guide public policies. MATERIAL AND METHODS: Data from the Global Burden of Disease (GBD) 2021 study were used to describe CKD prevalence and mortality in Mexico for the 1990-2021 period, stratifying by gender and age groups. RESULTS: The prevalence of CKD in Mexico in 2021 was 9,184.9 per 100,000 population. Diabetes was the most common cause of CKD, and CKD-related mortality was high, with an increase in 2019 and 2021, possibly as a consequence of the COVID-19 pandemic. CONCLUSIONS: CKD in Mexico entails a high burden of mortality and years of life lost, but it barely contributes to disability. It is essential to improve CKD early detection, access to treatments and coding of the causes of the disease. Moreover, investigating the causes of CKD of unknown etiology, including genetic factors, is crucial in order for specific treatments to be developed in the future.
ANTECEDENTES: La enfermedad renal crónica (ERC) representa una elevada carga global de enfermedad debido a la falta de pruebas universales y a la interpretación errónea de biomarcadores. OBJETIVO: Analizar la epidemiología de la ERC en México y orientar las políticas públicas. MATERIAL Y MÉTODOS: Se utilizaron los datos del estudio Global Burden of Disease (GBD) 2021 para describir la prevalencia y mortalidad de la ERC en México durante el periodo de 1990 a 2021, estratificando por sexo y grupos de edad. RESULTADOS: La prevalencia de la ERC en México en 2021 fue de 9184.9 por 100 000 habitantes. La diabetes constituyó la causa más común de ERC y la mortalidad por ERC fue elevada, se incrementó en 2019 y 2021, posiblemente debido a la pandemia de COVID-19. CONCLUSIONES: La ERC en México presenta una alta carga de mortalidad y años de vida perdidos, pero contribuye poco a la discapacidad. Es esencial mejorar la detección temprana de la ERC, el acceso a tratamientos y la codificación de las causas de la enfermedad. Además, investigar las causas de la ERC de etiología desconocida, incluidos factores genéticos, es crucial para desarrollar tratamientos específicos en el futuro.
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Carga Global da Doença , Insuficiência Renal Crônica , Humanos , México/epidemiologia , Pandemias , Análise de Dados , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologiaRESUMO
Despite the widespread use of intravenous fluids in acute kidney injury (AKI), solid evidence is lacking. Intravenous fluids mainly improve AKI due to true hypovolaemia, which is difficult to discern at the bedside unless it is very pronounced. Empiric fluid resuscitation triggered only by elevated serum creatinine levels or oliguria is frequently misguided, especially in the presence of fluid intolerance syndromes such as increased extravascular lung water, capillary leak, intra-abdominal hypertension, and systemic venous congestion. While fluid responsiveness tests clearly identify patients who will not benefit from fluid administration (i.e. those without an increase in cardiac output), the presence of fluid responsiveness does not guarantee that fluid therapy is indicated or even safe. This review calls for more attention to the concept of fluid tolerance, incorporating it into a practical algorithm with systematic venous Doppler ultrasonography assessment to use at the bedside, thereby lowering the risk of detrimental kidney congestion in AKI.
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Injúria Renal Aguda , Oligúria , Humanos , Oligúria/terapia , Injúria Renal Aguda/terapia , Hidratação , RimRESUMO
Accurate assessment of the hemodynamic status is vital for appropriate management of patients with critical illness. As such, there has been a constant quest for reliable and non-invasive bedside tools to assess and monitor circulatory status in order to ensure end-organ perfusion. In the recent past, point of care ultrasonography (POCUS) has emerged as a valuable adjunct to physical examination in various specialties, which basically is a clinician-performed bedside ultrasound to answer focused questions. POCUS allows visualization of the internal anatomy and flow dynamics in real time, guiding apt interventions. While both arterial (forward flow) and venous (organ outflow or afterload) limbs of hemodynamic circuit are important for tissue perfusion, the venous side remains relatively under-explored. With recent data underscoring the deleterious consequences of iatrogenic volume overload, objective evaluation of venous congestion is gaining attention. Bedside Doppler ultrasound serves this purpose and aids in diagnosing and monitoring the congestion/venous blood flow pattern. In this article, we summarize the rationale for integrating this technology into routine care of patients with volume-related disorders, discuss the normal and abnormal waveforms, limitations, and future directions.
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The physiological role of the shorter isoform of with no lysine kinase (WNK)1 that is exclusively expressed in the kidney (KS-WNK1), with particular abundance in the distal convoluted tubule, remains elusive. KS-WNK1, despite lacking the kinase domain, is nevertheless capable of stimulating the NaCl cotransporter, apparently through activation of WNK4. It has recently been shown that a less severe form of familial hyperkalemic hypertension featuring only hyperkalemia is caused by missense mutations in the WNK1 acidic domain that preferentially affect cullin 3 (CUL3)-Kelch-like protein 3 (KLHL3) E3-induced degradation of KS-WNK1 rather than that of full-length WNK1. Here, we show that full-length WNK1 is indeed less impacted by the CUL3-KLHL3 E3 ligase complex compared with KS-WNK1. We demonstrated that the unique 30-amino acid NH2-terminal fragment of KS-WNK1 is essential for its activating effect on the NaCl cotransporter and recognition by KLHL3. We identified specific amino acid residues in this region critical for the functional effect of KS-WNK1 and KLHL3 sensitivity. To further explore this, we generated KLHL3-R528H knockin mice that mimic human mutations causing familial hyperkalemic hypertension. These mice revealed that the KLHL3 mutation specifically increased expression of KS-WNK1 in the kidney. We also observed that in wild-type mice, the expression of KS-WNK1 was only detectable after exposure to a low-K+ diet. These findings provide new insights into the regulation and function of KS-WNK1 by the CUL3-KLHL3 complex in the distal convoluted tubule and indicate that this pathway is regulated by dietary K+ levels.NEW & NOTEWORTHY In this work, we demonstrated that the kidney-specific isoform of with no lysine kinase 1 (KS-WNK1) in the kidney is modulated by dietary K+ and activity of the ubiquitin ligase protein Kelch-like protein 3. We analyzed the role of different amino acid residues of KS-WNK1 in its activity against the NaCl cotransporter and sensitivity to Kelch-like protein 3.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Rim/enzimologia , Proteínas dos Microfilamentos/metabolismo , Potássio na Dieta/metabolismo , Pseudo-Hipoaldosteronismo/enzimologia , Proteína Quinase 1 Deficiente de Lisina WNK/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas Culina/metabolismo , Estabilidade Enzimática , Feminino , Rim/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Mutação , Domínios e Motivos de Interação entre Proteínas , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteólise , Pseudo-Hipoaldosteronismo/genética , Pseudo-Hipoaldosteronismo/fisiopatologia , Membro 3 da Família 12 de Carreador de Soluto/genética , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Proteína Quinase 1 Deficiente de Lisina WNK/deficiência , Proteína Quinase 1 Deficiente de Lisina WNK/genética , Xenopus laevisRESUMO
The management of complex fluid and electrolyte disorders is central to the practice of nephrologists. The sensitivity of physical examination alone to determine fluid status is limited, precluding accurate clinical decision making. Point-of-care ultrasonography (POCUS) is emerging as a valuable, noninvasive, bedside diagnostic tool for objective evaluation of physiologic and hemodynamic parameters related to fluid status, tolerance, and responsiveness. Rapid bedside sonographic evaluation can obtain qualitative data on cardiac function and quantitative data on pulmonary congestion. Advanced POCUS, including goal-directed Doppler echocardiography, provides additional quantitative information, including flow velocities and pressures across the cardiac structures. Recently, abnormal Doppler flow patterns in abdominal organs secondary to increased right atrial pressure have been linked to congestive organ damage, adding another component to the hemodynamic assessment. Integrating POCUS findings with clinical and laboratory data can further elucidate a patient's hemodynamic status. This drives decisions regarding crystalloid administration or, conversely, diuresis or ultrafiltration and allows tailored therapy for individual patients. In this article, we provide an overview of the focused assessment of cardiovascular function and pulmonary and venous congestion using POCUS and review relevant literature.
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Sistemas Automatizados de Assistência Junto ao Leito , Desequilíbrio Hidroeletrolítico , Humanos , Nefrologistas , Ultrassonografia , Ultrassonografia Doppler , Desequilíbrio Hidroeletrolítico/diagnósticoRESUMO
Familial hyperkalemic hypertension (FHHt) can be mainly attributed to increased activity of the renal Na+:Cl- cotransporter (NCC), which is caused by altered expression and regulation of the with-no-lysine (K) 1 (WNK1) or WNK4 kinases. The WNK1 gene gives rise to a kidney-specific isoform that lacks the kinase domain (KS-WNK1), the expression of which occurs primarily in the distal convoluted tubule. The role played by KS-WNK1 in the modulation of the WNK/STE20-proline-alanine rich kinase (SPAK)/NCC pathway remains elusive. In the present study, we assessed the effect of human KS-WNK1 on NCC activity and on the WNK4-SPAK pathway. Microinjection of oocytes with human KS-WNK1 cRNA induces remarkable activation and phosphorylation of SPAK and NCC. The effect of KS-WNK1 was abrogated by eliminating a WNK-WNK-interacting domain and by a specific WNK inhibitor, WNK463, indicating that the activation of SPAK/NCC by KS-WNK1 is due to interaction with another WNK kinase. Under control conditions in oocytes, the activating serine 335 of the WNK4 T loop is not phosphorylated. In contrast, this serine becomes phosphorylated when the intracellular chloride concentration ([Cl-]i) is reduced or when KS-WNK1 is coexpressed with WNK4. KS-WNK1-mediated activation of WNK4 is not due to a decrease of the [Cl-]i. Coimmunoprecipitation analysis revealed that KS-WNK1 and WNK4 interact with each other and that WNK4 becomes autophosphorylated at serine 335 when it is associated with KS-WNK1. Together, these observations suggest that WNK4 becomes active in the presence of KS-WNK1, despite a constant [Cl-]i.
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Cloretos/metabolismo , Rim/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Sódio/metabolismo , Proteína Quinase 1 Deficiente de Lisina WNK/metabolismo , Animais , Ativação Enzimática , Feminino , Humanos , Oócitos , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Ratos , Membro 3 da Família 12 de Carreador de Soluto/genética , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Proteína Quinase 1 Deficiente de Lisina WNK/genética , Proteínas de Xenopus/metabolismo , Xenopus laevisRESUMO
The thiazide-sensitive Na-Cl cotransporter (NCC) is the major pathway for salt reabsorption in the mammalian distal convoluted tubule. NCC plays a key role in the regulation of blood pressure. Its inhibition with thiazides constitutes the primary baseline therapy for arterial hypertension. However, the thiazide-binding site in NCC is unknown. Mammals have only one gene encoding for NCC. The eel, however, contains a duplicate gene. NCCα is an ortholog of mammalian NCC and is expressed in the kidney. NCCß is present in the apical membrane of the rectum. Here we cloned and functionally characterized NCCß from the European eel. The cRNA encodes a 1043-amino acid membrane protein that, when expressed in Xenopus oocytes, functions as an Na-Cl cotransporter with two major characteristics, making it different from other known NCCs. First, eel NCCß is resistant to thiazides. Single-point mutagenesis supports that the absence of thiazide inhibition is, at least in part, due to the substitution of a conserved serine for a cysteine at position 379. Second, NCCß is not activated by low-chloride hypotonic stress, although the unique Ste20-related proline alanine-rich kinase (SPAK) binding site in the amino-terminal domain is conserved. Thus, NCCß exhibits significant functional differences from NCCs that could be helpful in defining several aspects of the structure-function relationship of this important cotransporter.
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Resistência a Medicamentos/efeitos dos fármacos , Enguias/metabolismo , Proteínas de Peixes/metabolismo , Inibidores de Simportadores de Cloreto de Sódio/farmacologia , Simportadores de Cloreto de Sódio/metabolismo , Animais , Enguias/genética , Proteínas de Peixes/genética , Humanos , Oócitos , Ratos , Simportadores de Cloreto de Sódio/genética , Xenopus laevisRESUMO
PURPOSE OF REVIEW: Abundant evidence supports that the NaCl cotransporter (NCC) activity is tightly regulated by the with-no-lysine (WNK) kinases. Here, we summarize the data regarding NCC regulation by WNKs, with a particular emphasis on WNK4. RECENT FINDINGS: Several studies involving in-vivo and in-vitro models have provided paradoxical data regarding WNK4 regulation of the NCC. Although some studies show that WNK4 can activate the NCC, other equally compelling studies show that WNK4 inhibits the NCC. Recent studies have shown that WNK4 is regulated by the intracellular chloride concentration ([Cl]i), which could account for these paradoxical results. In conditions of high [Cl]i, WNK4 could act as an inhibitor via heterodimer formation with other WNKs. In contrast, when [Cl]i is low, WNK4 can activate Ste20-related, proline-alanine-rich kinase (SPAK)/oxidative stress responsive kinase 1 (OSR1) and thus the NCC. Modulation of WNK4 by [Cl]i has been shown to account for the potassium-sensing properties of the distal convoluted tubule. Other regulators of WNK4 include hormones and ubiquitination. SUMMARY: Modulation of WNK4 activity by [Cl]i can account for its dual role on the NCC, and this has important physiological implications regarding the regulation of extracellular potassium concentration. Defective regulation of WNKs by ubiquitination explains most cases of familial hyperkalemic hypertension.