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Extracellular volume expansion may
Extracellular volume expansion may lead to elevated blood pressure. This long-term adaptation of the vascular bed to extracellular volume overload is considered a multifactorial and not perfectly understood ‘autoregulatory’ event, which is difficult to measure. In this issue, Ebah and colleagues demonstrate a direct relationship between fluid overload and pressure in CKD patients. Surprise, instead of intravascular volume, interstitial fluids and pressures were measured. Finally!
If you ask a nephrologist how and why constancy of extracellular body fluids is rigorously controlled, you probably will be taken on a virtual tour and introduced to a nephrocentric world. You will learn that constancy in amount and concentration of the fluids that bath our body’s cells was a prerequisite for living an independent life once our ancestors left the salty sea and moved forward to the arid land. You will hear that the kidneys filter 180 Liters or water and per day and reabsorb precisely that amount needed to maintain extracellular water content constant. Perhaps you may be told that this process includes filtration of 1500–2000 g of salt, which again will be exactly reabsorbed except of the 9 g of dietary salt that must be excreted to maintain daily steady state sodium balance. Otherwise, edema occurs. And just in case you believe that 21st century research must focus on molecular detail instead of old fashioned electrolyte balance physiology, we can dive deep into the world of renal epithelial transporters and their molecular regulation, understand how any dysbalance between salt intake and renal excretion will inevitably lead to volume overload, and learn that a new steady state between salt intake and renal salt excretion is achieved at the price of arterial hypertension. Even certain selected genes will confirm the concept: the kidneys control blood composition by differential transfer of electrolyte and water into the urine. Such carefully purified blood volume readily equilibrates with interstitial fluids and thereby ensures constancy of body fluid composition and blood pressure. It seems as if differential transfer of salt and water into the urine can explain almost everything there is to know about extracellular fluid composition. The clinical readout to understand salt and water disorders is thus traditionally based on investigation of blood composition, urine composition, acute body weight changes, and their associated changes in pressure.
Living in this nephrocentric world is peaceful; most everything is clear. However, simple questions such as: ‘Where is the extracellular fluid located?’, or ‘Which pressures are important for maintenance of interstitial fluid homeostasis?’ define current basic physiological problems that may have not yet entered the clinical arena. Ebah and colleagues have addressed these questions and conducted an unusual clinical research project. They investigated the relationship between interstitial fluid composition and interstitial fluid pressures in the skin of patients with chronic kidney disease (CKD) and in healthy control subjects.1 The study is remarkable because each individual patient underwent a most careful clinical examination, including the measurement of edema refill time. I am afraid that I have never measured edema refill time in any of my patients; I probably should have. These clinician-scientists also inserted wick needles (not wicked) in their patient’s skin and measured interstitial fluid pressure. The authors then analyzed how interstitial fluid overload, as measured by impedance technology, relates to edema and interstitial fluid pressures. They show that interstitial fluid pressures are negative (−0.9 mm Hg) in healthy controls, and elevated to a positive range (+4.6 mm Hg) in CDK patients with edema. While no correlation between body fluid volumes and blood pressure was found, the amount of sequestered water was directly related to interstitial fluid pressure. This finding suggests that the subcutaneous fluid compartment represents a relatively ‘closed’ compartment in which a tightly coupled pressure-volume relationship exists. The study, which is appealing in its simplicity, may disturb the peaceful nephrocentric world on body fluid composition and suggests that there is more to learn. The kidneys could control extracellular fluid composition everywhere in our body only if extracellular fluids would readily equilibrate. However, this idea implies that there are no real barriers between the intravascular and the interstitial space. Skin and skeletal muscle are the largest organs of the body and contain most of the extracellular volume. If we insist that renal blood purification is the mechanism by which the kidneys control interstitial fluid composition almost exclusively, isn’t it then almost heresy to suggest that this subcutaneous compartment, which is the largest interstitial fluid space, is a relatively ‘closed’ compartment?
Interstitial fluid pressure is determined by a complex interplay between the fluid influx (blood capillary filtration), the fluid outflow (lymph flow), and the compartment’s ability to expand (tissue compliance).2 Interstitial fluid pressure is thus regulated locally at the tissue level. The basic principles of interstitial fluid exchange were developed more than a century ago3 and have been subject of several modifications, resulting in the Starling equation for transmembrane flux, as shown in Figure 1. Hydrostatic and colloid osmotic pressures are referred to as ‘Starling’s forces’. Capillary filtration pressures and interstitial colloid osmotic pressures support transmembrane flux from the capillary into the interstitium, while interstitial fluid pressures and intra-capillary colloid osmotic pressures lead to reabsorption of fluids. The data presented by Ebah are in line with the idea that interstitial pressures in the skin under normal conditions are negative in humans. However, a closer look at Figure 1 suggests that the interstitial fluid pressure increase by 5–6 mm Hg that was found in CKD patients must have been associated with compensatory changes in the local microcirculation. Increasing interstitial fluid pressure may lead to reduced transcapillary filtration into the interstitium (and prevent further fluid influx), or to increased lymph flow (and increase fluid outflow). Comparing this state-of-affairs in CDK patients with acute and with chronic edema, the investigators observed that acute interstitial volume overload was associated with relatively brisk increases in interstitial fluid pressures, while interstitial fluid excess in chronic edema led to only moderate increases in interstitial fluid pressure. This finding suggests that compliance of the interstitial space is a third additional determinant for interstitial fluid pressure homeostasis.4 While it remains unclear which cellular and extracellular matrix components regulate skin tissue compliance in humans, experiments in animals suggest that fibroblasts may control skin tissue compliance and thereby regulate interstitial fluid pressure by β1-integrin mediated contraction of dermal collagen fibers.5
Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author
Starling forces and their relevance for interstitial fluid and pressure homeostasis. Hydrostatic and colloid osmotic pressures are referred to as Starling forces. Capillary filtration pressures (P(c)) and interstitial colloid osmotic pressures (COP(if)) support transmembrane flux from the capillary into the interstitium, while interstitial fluid pressures (P(if)) and intra-capillary colloid osmotic pressures (COP(c)) lead to reabsorption of fluids. The original Starling equation has been modified and updated by capillary reflection coefficients, hydraulic permeability, and local interstitial protein gradients. Besides interstitial fluid content, tissue compliance is an important factor for the generation of interstitial pressure. Additional recent advances in understanding the molecular regulation of lymphangiogenesis provide new insights into outflow of filtrated interstitial fluid via the lymph capillary network. Background is an immunofluorescent view of real lymph vessels (green) and adjacent capillaries (red) courtesy of Agnes Schröder, University of Erlangen.
Full figure and legend (138K)
Collagen and glycosaminoglycans (GAG) are polyanionic macromolecules, resulting in a microenvironment, which attracts cations and repel anions. Tissue components with high GAG density therefore could have lower albumin concentrations, lower interstitial oncotic pressures, and lower water flux than predicted. Updated versions of the original Starling model suggest that the Starling forces driving fluid exchange at the capillary level may only occur immediately distal to the blood capillary filtration barrier.6 Also not incorporated into the traditional Starling equation are recent data claiming that skin Na+ content is significantly increased in the skin interstitium and is not paralleled by commensurate water retention in rats and mice fed a high-salt diet.7 This water-free Na+ storage is paralleled by infiltration of regulatory macrophages, which increase the density of cutaneous lymph capillaries. Most recent data suggest that these macrophages exert their regulatory activity in an effort to locally control interstitial electrolyte composition in the skin via lymph capillary electrolyte clearance in response to interstitial hypertonicity. Similar to renal electrolyte and fluid elimination, this clearance process is coupled with systemic blood pressure control (in press).
For maintenance of interstitial fluid homeostasis, the net flux of filtered plasma is balanced by lymph fluid formation into the initial lymphatic vessels. Three mechanisms for the uptake
If you ask a nephrologist how and why constancy of extracellular body fluids is rigorously controlled, you probably will be taken on a virtual tour and introduced to a nephrocentric world. You will learn that constancy in amount and concentration of the fluids that bath our body’s cells was a prerequisite for living an independent life once our ancestors left the salty sea and moved forward to the arid land. You will hear that the kidneys filter 180 Liters or water and per day and reabsorb precisely that amount needed to maintain extracellular water content constant. Perhaps you may be told that this process includes filtration of 1500–2000 g of salt, which again will be exactly reabsorbed except of the 9 g of dietary salt that must be excreted to maintain daily steady state sodium balance. Otherwise, edema occurs. And just in case you believe that 21st century research must focus on molecular detail instead of old fashioned electrolyte balance physiology, we can dive deep into the world of renal epithelial transporters and their molecular regulation, understand how any dysbalance between salt intake and renal excretion will inevitably lead to volume overload, and learn that a new steady state between salt intake and renal salt excretion is achieved at the price of arterial hypertension. Even certain selected genes will confirm the concept: the kidneys control blood composition by differential transfer of electrolyte and water into the urine. Such carefully purified blood volume readily equilibrates with interstitial fluids and thereby ensures constancy of body fluid composition and blood pressure. It seems as if differential transfer of salt and water into the urine can explain almost everything there is to know about extracellular fluid composition. The clinical readout to understand salt and water disorders is thus traditionally based on investigation of blood composition, urine composition, acute body weight changes, and their associated changes in pressure.
Living in this nephrocentric world is peaceful; most everything is clear. However, simple questions such as: ‘Where is the extracellular fluid located?’, or ‘Which pressures are important for maintenance of interstitial fluid homeostasis?’ define current basic physiological problems that may have not yet entered the clinical arena. Ebah and colleagues have addressed these questions and conducted an unusual clinical research project. They investigated the relationship between interstitial fluid composition and interstitial fluid pressures in the skin of patients with chronic kidney disease (CKD) and in healthy control subjects.1 The study is remarkable because each individual patient underwent a most careful clinical examination, including the measurement of edema refill time. I am afraid that I have never measured edema refill time in any of my patients; I probably should have. These clinician-scientists also inserted wick needles (not wicked) in their patient’s skin and measured interstitial fluid pressure. The authors then analyzed how interstitial fluid overload, as measured by impedance technology, relates to edema and interstitial fluid pressures. They show that interstitial fluid pressures are negative (−0.9 mm Hg) in healthy controls, and elevated to a positive range (+4.6 mm Hg) in CDK patients with edema. While no correlation between body fluid volumes and blood pressure was found, the amount of sequestered water was directly related to interstitial fluid pressure. This finding suggests that the subcutaneous fluid compartment represents a relatively ‘closed’ compartment in which a tightly coupled pressure-volume relationship exists. The study, which is appealing in its simplicity, may disturb the peaceful nephrocentric world on body fluid composition and suggests that there is more to learn. The kidneys could control extracellular fluid composition everywhere in our body only if extracellular fluids would readily equilibrate. However, this idea implies that there are no real barriers between the intravascular and the interstitial space. Skin and skeletal muscle are the largest organs of the body and contain most of the extracellular volume. If we insist that renal blood purification is the mechanism by which the kidneys control interstitial fluid composition almost exclusively, isn’t it then almost heresy to suggest that this subcutaneous compartment, which is the largest interstitial fluid space, is a relatively ‘closed’ compartment?
Interstitial fluid pressure is determined by a complex interplay between the fluid influx (blood capillary filtration), the fluid outflow (lymph flow), and the compartment’s ability to expand (tissue compliance).2 Interstitial fluid pressure is thus regulated locally at the tissue level. The basic principles of interstitial fluid exchange were developed more than a century ago3 and have been subject of several modifications, resulting in the Starling equation for transmembrane flux, as shown in Figure 1. Hydrostatic and colloid osmotic pressures are referred to as ‘Starling’s forces’. Capillary filtration pressures and interstitial colloid osmotic pressures support transmembrane flux from the capillary into the interstitium, while interstitial fluid pressures and intra-capillary colloid osmotic pressures lead to reabsorption of fluids. The data presented by Ebah are in line with the idea that interstitial pressures in the skin under normal conditions are negative in humans. However, a closer look at Figure 1 suggests that the interstitial fluid pressure increase by 5–6 mm Hg that was found in CKD patients must have been associated with compensatory changes in the local microcirculation. Increasing interstitial fluid pressure may lead to reduced transcapillary filtration into the interstitium (and prevent further fluid influx), or to increased lymph flow (and increase fluid outflow). Comparing this state-of-affairs in CDK patients with acute and with chronic edema, the investigators observed that acute interstitial volume overload was associated with relatively brisk increases in interstitial fluid pressures, while interstitial fluid excess in chronic edema led to only moderate increases in interstitial fluid pressure. This finding suggests that compliance of the interstitial space is a third additional determinant for interstitial fluid pressure homeostasis.4 While it remains unclear which cellular and extracellular matrix components regulate skin tissue compliance in humans, experiments in animals suggest that fibroblasts may control skin tissue compliance and thereby regulate interstitial fluid pressure by β1-integrin mediated contraction of dermal collagen fibers.5
Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author
Starling forces and their relevance for interstitial fluid and pressure homeostasis. Hydrostatic and colloid osmotic pressures are referred to as Starling forces. Capillary filtration pressures (P(c)) and interstitial colloid osmotic pressures (COP(if)) support transmembrane flux from the capillary into the interstitium, while interstitial fluid pressures (P(if)) and intra-capillary colloid osmotic pressures (COP(c)) lead to reabsorption of fluids. The original Starling equation has been modified and updated by capillary reflection coefficients, hydraulic permeability, and local interstitial protein gradients. Besides interstitial fluid content, tissue compliance is an important factor for the generation of interstitial pressure. Additional recent advances in understanding the molecular regulation of lymphangiogenesis provide new insights into outflow of filtrated interstitial fluid via the lymph capillary network. Background is an immunofluorescent view of real lymph vessels (green) and adjacent capillaries (red) courtesy of Agnes Schröder, University of Erlangen.
Full figure and legend (138K)
Collagen and glycosaminoglycans (GAG) are polyanionic macromolecules, resulting in a microenvironment, which attracts cations and repel anions. Tissue components with high GAG density therefore could have lower albumin concentrations, lower interstitial oncotic pressures, and lower water flux than predicted. Updated versions of the original Starling model suggest that the Starling forces driving fluid exchange at the capillary level may only occur immediately distal to the blood capillary filtration barrier.6 Also not incorporated into the traditional Starling equation are recent data claiming that skin Na+ content is significantly increased in the skin interstitium and is not paralleled by commensurate water retention in rats and mice fed a high-salt diet.7 This water-free Na+ storage is paralleled by infiltration of regulatory macrophages, which increase the density of cutaneous lymph capillaries. Most recent data suggest that these macrophages exert their regulatory activity in an effort to locally control interstitial electrolyte composition in the skin via lymph capillary electrolyte clearance in response to interstitial hypertonicity. Similar to renal electrolyte and fluid elimination, this clearance process is coupled with systemic blood pressure control (in press).
For maintenance of interstitial fluid homeostasis, the net flux of filtered plasma is balanced by lymph fluid formation into the initial lymphatic vessels. Three mechanisms for the uptake
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Ngoại bào khối lượng mở rộng có thể dẫn tới huyết áp cao. Này thích ứng dài hạn của đáy mạch máu để tình trạng quá tải ngoại bào khối lượng được coi là một sự kiện multifactorial và không hoàn toàn hiểu 'autoregulatory', mà là khó khăn để đo lường. Trong vấn đề này, Ebah và các đồng nghiệp chứng minh một mối quan hệ trực tiếp giữa chất lỏng quá tải và áp lực ở những bệnh nhân CKD. Bất ngờ, thay vì mạch khối lượng, chất lỏng kẽ và áp lực được đo. Cuối cùng!Nếu bạn yêu cầu một nephrologist như thế nào và tại sao tánh kiên nhẩn của chất lỏng ngoại bào của cơ thể một cach nghiêm tuc được kiểm soát, bạn có thể sẽ được thực hiện trên một tour du lịch ảo và giới thiệu đến một thế giới nephrocentric. Bạn sẽ tìm hiểu tánh kiên nhẩn đó trong số lượng và sự tập trung của các chất lỏng đó tắm các tế bào của cơ thể của chúng tôi là một điều kiện tiên quyết để sống một cuộc sống độc lập khi tổ tiên của chúng tôi rời biển mặn và di chuyển về phía trước đến vùng đất khô cằn. Bạn sẽ nghe thấy rằng thận lọc 180 lít hoặc nước và mỗi ngày và reabsorb chính xác số tiền đó cần thiết để duy trì liên tục nội dung ngoại bào nước. Có lẽ bạn có thể được cho biết rằng quá trình này bao gồm lọc của 1500-2000 g muối, một lần nữa sẽ được chính xác reabsorbed ngoại trừ của 9 g muối chế độ ăn uống phải được bài tiết để duy trì sự cân bằng natri trạng thái ổn định hàng ngày. Nếu không, phù nề xảy ra. Và chỉ trong trường hợp bạn tin rằng thế kỷ 21 nghiên cứu phải tập trung vào các chi tiết phân tử thay vì cũ thời điện cân bằng sinh lý học, chúng tôi có thể lặn sâu vào thế giới của vận chuyển biểu mô thận và quy định phân tử của họ, hiểu như thế nào bất kỳ dysbalance giữa lượng muối và thận bài tiết chắc chắn sẽ dẫn đến khối lượng quá tải, và tìm hiểu rằng một trạng thái ổn định mới giữa lượng muối và thận bài tiết muối là đạt được mức tăng huyết áp động mạch. Thậm chí một số gen đã chọn sẽ xác nhận khái niệm: thận kiểm soát thành phần máu bằng chuyển vi phân của chất điện phân và nước vào nước tiểu. Khối lượng máu tinh khiết một cách cẩn thận như vậy dễ dàng equilibrates với chất lỏng kẽ và do đó đảm bảo tánh kiên nhẩn của thành phần cơ thể và huyết áp. Nó có vẻ như nếu chuyển vi phân của muối và nước vào nước tiểu có thể giải thích hầu như tất cả mọi thứ có là biết về thành phần chất lỏng ngoại bào. Readout lâm sàng để hiểu rối loạn muối và nước do đó theo truyền thống dựa trên các điều tra của thành phần máu, nước tiểu thành phần, cơ thể cấp tính trọng lượng thay đổi, và của họ thay đổi liên kết áp lực.Sống trong thế giới nephrocentric này là hòa bình; Hầu hết mọi thứ đều rõ ràng. Tuy nhiên, đơn giản câu hỏi như: 'Nơi là các chất lỏng ngoại bào nằm?', hoặc 'áp lực đó là quan trọng để duy trì chất lỏng kẽ homeostasis?' xác định hiện tại vấn đề sinh lý cơ bản có thể đã không được nhập trên trường lâm sàng. Ebah và các đồng nghiệp đã giải quyết những câu hỏi này và tiến hành một dự án nghiên cứu lâm sàng không bình thường. Họ điều tra mối quan hệ giữa các thành phần chất lỏng kẽ và áp lực chất lỏng kẽ trong da của bệnh nhân mắc bệnh thận mãn tính (CKD) và trong khỏe mạnh subjects.1 nghiên cứu là đáng chú ý vì mỗi từng bệnh nhân trải qua một cuộc kiểm tra lâm sàng đặt cẩn thận, bao gồm các phép đo phù nề nạp tiền thời gian. Tôi sợ rằng tôi đã không bao giờ đo phù nề nạp tiền thời gian trong bất kỳ của bệnh nhân của tôi; Tôi có lẽ cần phải có. Các bác sĩ, nhà khoa học cũng đưa vào wick kim (không độc ác) trong da của bệnh nhân và đo áp lực chất lỏng kẽ. Các tác giả sau đó phân tích cách kẽ chất lỏng tình trạng quá tải, được đo bằng công nghệ trở kháng, liên quan đến phù nề và áp lực chất lỏng kẽ. Họ thấy rằng áp lực chất lỏng kẽ là tiêu cực (−0.9 mm Hg) ở khỏe mạnh điều khiển, và cao cho một phạm vi tích cực (+4.6 mm Hg) ở bệnh nhân CDK phù nề. Trong khi không có sự tương quan giữa khối lượng cơ thể và huyết áp được tìm thấy, lượng nước sequestered trực tiếp liên quan đến áp lực chất lỏng kẽ. Tìm kiếm này cho thấy rằng chất lỏng khoang dưới da đại diện cho một tương đối 'đóng' khoang trong đó mối quan hệ chặt chẽ cùng áp suất, khối lượng tồn tại. Nghiên cứu này, là hấp dẫn trong đơn giản của nó, có thể làm phiền thế giới hòa bình nephrocentric trên thành phần cơ thể và cho thấy rằng có nhiều hơn để tìm hiểu. Thận có thể kiểm soát các thành phần chất lỏng ngoại bào ở khắp mọi nơi trong cơ thể của chúng tôi chỉ nếu chất lỏng ngoại bào sẽ dễ dàng equilibrate. Tuy nhiên, ý tưởng này ngụ ý rằng không có không có rào cản thực giữa các mạch và không gian kẽ. Da và cơ xương là cơ quan lớn nhất của cơ thể và có chứa hầu hết khối lượng ngoại bào. Nếu chúng ta nhấn mạnh rằng thận máu thanh lọc là cơ chế do đó thận kiểm soát thành phần chất lỏng kẽ gần như độc quyền, không phải là nó sau đó gần như tà giáo để đề nghị này khoang dưới da, đó là không gian chất lỏng kẽ lớn nhất, là một khoang tương đối 'đóng'?Áp lực chất lỏng kẽ được xác định bởi một hổ tương tác dụng phức tạp giữa dòng chất lỏng (máu mao mạch lọc), dòng chảy chất lỏng (bạch huyết lưu lượng) và khả năng của khoang mở rộng (mô tuân thủ).2 áp lực chất lỏng kẽ do đó quy định tại địa phương ở cấp độ mô. Các nguyên tắc cơ bản của trao đổi chất lỏng kẽ đã phát triển nhiều hơn một ago3 thế kỷ và đã là đối tượng của một số sửa đổi, dẫn đến phương trình Starling cho màng tuôn ra, như minh hoạ trong hình 1. Áp lực thẩm thấu thủy tĩnh và keo được gọi là 'Sáo của lực lượng'. Mao mạch lọc áp lực và áp lực thẩm thấu keo kẽ hỗ trợ xuyên tuôn ra từ mao mạch vào interstitium, trong khi áp lực chất lỏng kẽ và mao mạch nội keo áp lực thẩm thấu dẫn đến huyệt của chất lỏng. Các dữ liệu trình bày bởi Ebah là phù hợp với ý tưởng rằng các áp lực kẽ trong da dưới điều kiện bình thường là tiêu cực trong con người. Tuy nhiên, một cái nhìn sâu hơn về hình 1 cho thấy rằng sự gia tăng áp lực chất lỏng kẽ bởi 5-6 mm Hg đã được tìm thấy ở những bệnh nhân CKD phải có được liên kết với các thay đổi đền bù trong microcirculation địa phương. Tăng áp lực chất lỏng kẽ có thể dẫn đến giảm transcapillary lọc vào interstitium (và ngăn ngừa thêm dòng chất lỏng), hoặc để tăng bạch huyết lưu lượng (và tăng dòng chảy chất lỏng). So sánh này nhà nước-của-giao ở những bệnh nhân CDK với cấp tính và mãn tính phù nề, các điều tra viên quan sát thấy rằng tình trạng quá tải cấp tính khối lượng kẽ được liên kết với tăng tương đối nhanh trong áp lực chất lỏng kẽ, trong khi kẽ chất lỏng dư thừa trong mãn tính phù nề đã dẫn đến chỉ trung bình tăng áp lực chất lỏng kẽ. Tìm kiếm này cho thấy rằng việc tuân thủ của không gian kẽ là một yếu tố quyết định bổ sung thứ ba cho áp lực chất lỏng kẽ homeostasis.4 trong khi nó vẫn chưa rõ ràng mà di động và thành phần ngoại bào ma trận điều chỉnh da mô tuân thủ trong con người, các thí nghiệm ở động vật cho thấy rằng fibroblasts có thể kiểm soát sự tuân thủ mô da và do đó điều chỉnh áp lực chất lỏng kẽ bởi β1-integrin trung gian co lại của da collagen fibers.5Hình 1.Hình 1 - tiếc là chúng tôi là không thể cung cấp truy cập văn bản thay thế cho việc này. Nếu bạn cần trợ giúp để truy cập vào hình ảnh này, xin vui lòng liên hệ với help@nature.com hoặc tác giảSáo lực lượng và sự liên quan của họ cho homeostasis kẽ chất lỏng và áp lực. Áp lực thẩm thấu thủy tĩnh và keo được gọi là sáo lực lượng. Mao mạch lọc áp lực (P(c)) và kẽ keo áp suất thẩm thấu (COP(if)) hỗ trợ xuyên tuôn ra từ mao mạch vào interstitium, trong khi áp lực chất lỏng kẽ (P(if)) và mao mạch nội keo áp suất thẩm thấu (COP(c)) dẫn đến huyệt của chất lỏng. Phương trình Starling ban đầu đã được sửa đổi và Cập Nhật bởi hệ số phản ánh mao mạch, thấm thủy lực, và địa phương kẽ protein gradient. Bên cạnh nội dung chất lỏng kẽ, mô tuân thủ là một yếu tố quan trọng cho các thế hệ của áp lực kẽ. Bổ sung các tiến bộ gần đây trong việc tìm hiểu các quy định phân tử của lymphangiogenesis cung cấp những hiểu biết mới vào dòng chảy của chất lỏng kẽ filtrated thông qua mạng lưới mao mạch bạch huyết. Nền là một lần xem immunofluorescent của mạch bạch huyết thực (xanh) và liền kề các mao mạch (màu đỏ) đúng trách nhiệm của Agnes Schröder, đại học Erlangen.Con số đầy đủ và huyền thoại (138K)Collagen và glycosaminoglycans (GAG) là đại phân tử polyanionic, dẫn đến một microenvironment, thu hút các cation và đẩy lùi các anion. Mô thành phần với mật độ cao GAG do đó có thể có nồng độ thấp hơn Albumin tạo, thấp kẽ oncotic áp lực và thông lượng nước thấp hơn dự đoán. Các phiên bản Cập Nhật của các mô hình Starling ban đầu đề nghị rằng các lực lượng Starling lái xe chất lỏng trao đổi ở mức độ mao mạch có thể chỉ xảy ra ngay lập tức xa để máu mao mạch lọc barrier.6 cũng không đưa vào phương trình Starling truyền thống là dữ liệu gần đây tuyên bố rằng da Na + nội dung tăng đáng kể trong da interstitium và không song song bởi khả năng giữ nước xứng trong chuột và chuột ăn một diet.7 cao-muối này miễn phí nước Na + lí song song bởi xâm nhập của các đại thực bào quy định, mà tăng mật độ của Mao mạch bạch huyết da. Đặt dữ liệu cho thấy rằng các đại thực bào phát huy hoạt động pháp lý của họ trong một nỗ lực để kiểm soát tại địa phương kẽ điện thành phần trong da thông qua giải phóng mặt bằng điện mao mạch bạch huyết để đáp ứng với hypertonicity kẽ. Tương tự như thận điện và loại bỏ chất lỏng, quá trình giải phóng mặt bằng này được kết hợp với hệ thống huyết áp kiểm soát (trong báo chí).Để bảo trì homeostasis chất lỏng kẽ, thông lượng lưới lọc plasma được cân bằng bởi sự hình thành chất lỏng bạch huyết vào các mạch bạch huyết ban đầu. Ba cơ chế cho sự hấp thu
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Extracellular volume expansion may lead to elevated blood pressure. This long-term adaptation of the vascular bed to extracellular volume overload is considered a multifactorial and not perfectly understood ‘autoregulatory’ event, which is difficult to measure. In this issue, Ebah and colleagues demonstrate a direct relationship between fluid overload and pressure in CKD patients. Surprise, instead of intravascular volume, interstitial fluids and pressures were measured. Finally!
If you ask a nephrologist how and why constancy of extracellular body fluids is rigorously controlled, you probably will be taken on a virtual tour and introduced to a nephrocentric world. You will learn that constancy in amount and concentration of the fluids that bath our body’s cells was a prerequisite for living an independent life once our ancestors left the salty sea and moved forward to the arid land. You will hear that the kidneys filter 180 Liters or water and per day and reabsorb precisely that amount needed to maintain extracellular water content constant. Perhaps you may be told that this process includes filtration of 1500–2000 g of salt, which again will be exactly reabsorbed except of the 9 g of dietary salt that must be excreted to maintain daily steady state sodium balance. Otherwise, edema occurs. And just in case you believe that 21st century research must focus on molecular detail instead of old fashioned electrolyte balance physiology, we can dive deep into the world of renal epithelial transporters and their molecular regulation, understand how any dysbalance between salt intake and renal excretion will inevitably lead to volume overload, and learn that a new steady state between salt intake and renal salt excretion is achieved at the price of arterial hypertension. Even certain selected genes will confirm the concept: the kidneys control blood composition by differential transfer of electrolyte and water into the urine. Such carefully purified blood volume readily equilibrates with interstitial fluids and thereby ensures constancy of body fluid composition and blood pressure. It seems as if differential transfer of salt and water into the urine can explain almost everything there is to know about extracellular fluid composition. The clinical readout to understand salt and water disorders is thus traditionally based on investigation of blood composition, urine composition, acute body weight changes, and their associated changes in pressure.
Living in this nephrocentric world is peaceful; most everything is clear. However, simple questions such as: ‘Where is the extracellular fluid located?’, or ‘Which pressures are important for maintenance of interstitial fluid homeostasis?’ define current basic physiological problems that may have not yet entered the clinical arena. Ebah and colleagues have addressed these questions and conducted an unusual clinical research project. They investigated the relationship between interstitial fluid composition and interstitial fluid pressures in the skin of patients with chronic kidney disease (CKD) and in healthy control subjects.1 The study is remarkable because each individual patient underwent a most careful clinical examination, including the measurement of edema refill time. I am afraid that I have never measured edema refill time in any of my patients; I probably should have. These clinician-scientists also inserted wick needles (not wicked) in their patient’s skin and measured interstitial fluid pressure. The authors then analyzed how interstitial fluid overload, as measured by impedance technology, relates to edema and interstitial fluid pressures. They show that interstitial fluid pressures are negative (−0.9 mm Hg) in healthy controls, and elevated to a positive range (+4.6 mm Hg) in CDK patients with edema. While no correlation between body fluid volumes and blood pressure was found, the amount of sequestered water was directly related to interstitial fluid pressure. This finding suggests that the subcutaneous fluid compartment represents a relatively ‘closed’ compartment in which a tightly coupled pressure-volume relationship exists. The study, which is appealing in its simplicity, may disturb the peaceful nephrocentric world on body fluid composition and suggests that there is more to learn. The kidneys could control extracellular fluid composition everywhere in our body only if extracellular fluids would readily equilibrate. However, this idea implies that there are no real barriers between the intravascular and the interstitial space. Skin and skeletal muscle are the largest organs of the body and contain most of the extracellular volume. If we insist that renal blood purification is the mechanism by which the kidneys control interstitial fluid composition almost exclusively, isn’t it then almost heresy to suggest that this subcutaneous compartment, which is the largest interstitial fluid space, is a relatively ‘closed’ compartment?
Interstitial fluid pressure is determined by a complex interplay between the fluid influx (blood capillary filtration), the fluid outflow (lymph flow), and the compartment’s ability to expand (tissue compliance).2 Interstitial fluid pressure is thus regulated locally at the tissue level. The basic principles of interstitial fluid exchange were developed more than a century ago3 and have been subject of several modifications, resulting in the Starling equation for transmembrane flux, as shown in Figure 1. Hydrostatic and colloid osmotic pressures are referred to as ‘Starling’s forces’. Capillary filtration pressures and interstitial colloid osmotic pressures support transmembrane flux from the capillary into the interstitium, while interstitial fluid pressures and intra-capillary colloid osmotic pressures lead to reabsorption of fluids. The data presented by Ebah are in line with the idea that interstitial pressures in the skin under normal conditions are negative in humans. However, a closer look at Figure 1 suggests that the interstitial fluid pressure increase by 5–6 mm Hg that was found in CKD patients must have been associated with compensatory changes in the local microcirculation. Increasing interstitial fluid pressure may lead to reduced transcapillary filtration into the interstitium (and prevent further fluid influx), or to increased lymph flow (and increase fluid outflow). Comparing this state-of-affairs in CDK patients with acute and with chronic edema, the investigators observed that acute interstitial volume overload was associated with relatively brisk increases in interstitial fluid pressures, while interstitial fluid excess in chronic edema led to only moderate increases in interstitial fluid pressure. This finding suggests that compliance of the interstitial space is a third additional determinant for interstitial fluid pressure homeostasis.4 While it remains unclear which cellular and extracellular matrix components regulate skin tissue compliance in humans, experiments in animals suggest that fibroblasts may control skin tissue compliance and thereby regulate interstitial fluid pressure by β1-integrin mediated contraction of dermal collagen fibers.5
Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author
Starling forces and their relevance for interstitial fluid and pressure homeostasis. Hydrostatic and colloid osmotic pressures are referred to as Starling forces. Capillary filtration pressures (P(c)) and interstitial colloid osmotic pressures (COP(if)) support transmembrane flux from the capillary into the interstitium, while interstitial fluid pressures (P(if)) and intra-capillary colloid osmotic pressures (COP(c)) lead to reabsorption of fluids. The original Starling equation has been modified and updated by capillary reflection coefficients, hydraulic permeability, and local interstitial protein gradients. Besides interstitial fluid content, tissue compliance is an important factor for the generation of interstitial pressure. Additional recent advances in understanding the molecular regulation of lymphangiogenesis provide new insights into outflow of filtrated interstitial fluid via the lymph capillary network. Background is an immunofluorescent view of real lymph vessels (green) and adjacent capillaries (red) courtesy of Agnes Schröder, University of Erlangen.
Full figure and legend (138K)
Collagen and glycosaminoglycans (GAG) are polyanionic macromolecules, resulting in a microenvironment, which attracts cations and repel anions. Tissue components with high GAG density therefore could have lower albumin concentrations, lower interstitial oncotic pressures, and lower water flux than predicted. Updated versions of the original Starling model suggest that the Starling forces driving fluid exchange at the capillary level may only occur immediately distal to the blood capillary filtration barrier.6 Also not incorporated into the traditional Starling equation are recent data claiming that skin Na+ content is significantly increased in the skin interstitium and is not paralleled by commensurate water retention in rats and mice fed a high-salt diet.7 This water-free Na+ storage is paralleled by infiltration of regulatory macrophages, which increase the density of cutaneous lymph capillaries. Most recent data suggest that these macrophages exert their regulatory activity in an effort to locally control interstitial electrolyte composition in the skin via lymph capillary electrolyte clearance in response to interstitial hypertonicity. Similar to renal electrolyte and fluid elimination, this clearance process is coupled with systemic blood pressure control (in press).
For maintenance of interstitial fluid homeostasis, the net flux of filtered plasma is balanced by lymph fluid formation into the initial lymphatic vessels. Three mechanisms for the uptake
If you ask a nephrologist how and why constancy of extracellular body fluids is rigorously controlled, you probably will be taken on a virtual tour and introduced to a nephrocentric world. You will learn that constancy in amount and concentration of the fluids that bath our body’s cells was a prerequisite for living an independent life once our ancestors left the salty sea and moved forward to the arid land. You will hear that the kidneys filter 180 Liters or water and per day and reabsorb precisely that amount needed to maintain extracellular water content constant. Perhaps you may be told that this process includes filtration of 1500–2000 g of salt, which again will be exactly reabsorbed except of the 9 g of dietary salt that must be excreted to maintain daily steady state sodium balance. Otherwise, edema occurs. And just in case you believe that 21st century research must focus on molecular detail instead of old fashioned electrolyte balance physiology, we can dive deep into the world of renal epithelial transporters and their molecular regulation, understand how any dysbalance between salt intake and renal excretion will inevitably lead to volume overload, and learn that a new steady state between salt intake and renal salt excretion is achieved at the price of arterial hypertension. Even certain selected genes will confirm the concept: the kidneys control blood composition by differential transfer of electrolyte and water into the urine. Such carefully purified blood volume readily equilibrates with interstitial fluids and thereby ensures constancy of body fluid composition and blood pressure. It seems as if differential transfer of salt and water into the urine can explain almost everything there is to know about extracellular fluid composition. The clinical readout to understand salt and water disorders is thus traditionally based on investigation of blood composition, urine composition, acute body weight changes, and their associated changes in pressure.
Living in this nephrocentric world is peaceful; most everything is clear. However, simple questions such as: ‘Where is the extracellular fluid located?’, or ‘Which pressures are important for maintenance of interstitial fluid homeostasis?’ define current basic physiological problems that may have not yet entered the clinical arena. Ebah and colleagues have addressed these questions and conducted an unusual clinical research project. They investigated the relationship between interstitial fluid composition and interstitial fluid pressures in the skin of patients with chronic kidney disease (CKD) and in healthy control subjects.1 The study is remarkable because each individual patient underwent a most careful clinical examination, including the measurement of edema refill time. I am afraid that I have never measured edema refill time in any of my patients; I probably should have. These clinician-scientists also inserted wick needles (not wicked) in their patient’s skin and measured interstitial fluid pressure. The authors then analyzed how interstitial fluid overload, as measured by impedance technology, relates to edema and interstitial fluid pressures. They show that interstitial fluid pressures are negative (−0.9 mm Hg) in healthy controls, and elevated to a positive range (+4.6 mm Hg) in CDK patients with edema. While no correlation between body fluid volumes and blood pressure was found, the amount of sequestered water was directly related to interstitial fluid pressure. This finding suggests that the subcutaneous fluid compartment represents a relatively ‘closed’ compartment in which a tightly coupled pressure-volume relationship exists. The study, which is appealing in its simplicity, may disturb the peaceful nephrocentric world on body fluid composition and suggests that there is more to learn. The kidneys could control extracellular fluid composition everywhere in our body only if extracellular fluids would readily equilibrate. However, this idea implies that there are no real barriers between the intravascular and the interstitial space. Skin and skeletal muscle are the largest organs of the body and contain most of the extracellular volume. If we insist that renal blood purification is the mechanism by which the kidneys control interstitial fluid composition almost exclusively, isn’t it then almost heresy to suggest that this subcutaneous compartment, which is the largest interstitial fluid space, is a relatively ‘closed’ compartment?
Interstitial fluid pressure is determined by a complex interplay between the fluid influx (blood capillary filtration), the fluid outflow (lymph flow), and the compartment’s ability to expand (tissue compliance).2 Interstitial fluid pressure is thus regulated locally at the tissue level. The basic principles of interstitial fluid exchange were developed more than a century ago3 and have been subject of several modifications, resulting in the Starling equation for transmembrane flux, as shown in Figure 1. Hydrostatic and colloid osmotic pressures are referred to as ‘Starling’s forces’. Capillary filtration pressures and interstitial colloid osmotic pressures support transmembrane flux from the capillary into the interstitium, while interstitial fluid pressures and intra-capillary colloid osmotic pressures lead to reabsorption of fluids. The data presented by Ebah are in line with the idea that interstitial pressures in the skin under normal conditions are negative in humans. However, a closer look at Figure 1 suggests that the interstitial fluid pressure increase by 5–6 mm Hg that was found in CKD patients must have been associated with compensatory changes in the local microcirculation. Increasing interstitial fluid pressure may lead to reduced transcapillary filtration into the interstitium (and prevent further fluid influx), or to increased lymph flow (and increase fluid outflow). Comparing this state-of-affairs in CDK patients with acute and with chronic edema, the investigators observed that acute interstitial volume overload was associated with relatively brisk increases in interstitial fluid pressures, while interstitial fluid excess in chronic edema led to only moderate increases in interstitial fluid pressure. This finding suggests that compliance of the interstitial space is a third additional determinant for interstitial fluid pressure homeostasis.4 While it remains unclear which cellular and extracellular matrix components regulate skin tissue compliance in humans, experiments in animals suggest that fibroblasts may control skin tissue compliance and thereby regulate interstitial fluid pressure by β1-integrin mediated contraction of dermal collagen fibers.5
Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author
Starling forces and their relevance for interstitial fluid and pressure homeostasis. Hydrostatic and colloid osmotic pressures are referred to as Starling forces. Capillary filtration pressures (P(c)) and interstitial colloid osmotic pressures (COP(if)) support transmembrane flux from the capillary into the interstitium, while interstitial fluid pressures (P(if)) and intra-capillary colloid osmotic pressures (COP(c)) lead to reabsorption of fluids. The original Starling equation has been modified and updated by capillary reflection coefficients, hydraulic permeability, and local interstitial protein gradients. Besides interstitial fluid content, tissue compliance is an important factor for the generation of interstitial pressure. Additional recent advances in understanding the molecular regulation of lymphangiogenesis provide new insights into outflow of filtrated interstitial fluid via the lymph capillary network. Background is an immunofluorescent view of real lymph vessels (green) and adjacent capillaries (red) courtesy of Agnes Schröder, University of Erlangen.
Full figure and legend (138K)
Collagen and glycosaminoglycans (GAG) are polyanionic macromolecules, resulting in a microenvironment, which attracts cations and repel anions. Tissue components with high GAG density therefore could have lower albumin concentrations, lower interstitial oncotic pressures, and lower water flux than predicted. Updated versions of the original Starling model suggest that the Starling forces driving fluid exchange at the capillary level may only occur immediately distal to the blood capillary filtration barrier.6 Also not incorporated into the traditional Starling equation are recent data claiming that skin Na+ content is significantly increased in the skin interstitium and is not paralleled by commensurate water retention in rats and mice fed a high-salt diet.7 This water-free Na+ storage is paralleled by infiltration of regulatory macrophages, which increase the density of cutaneous lymph capillaries. Most recent data suggest that these macrophages exert their regulatory activity in an effort to locally control interstitial electrolyte composition in the skin via lymph capillary electrolyte clearance in response to interstitial hypertonicity. Similar to renal electrolyte and fluid elimination, this clearance process is coupled with systemic blood pressure control (in press).
For maintenance of interstitial fluid homeostasis, the net flux of filtered plasma is balanced by lymph fluid formation into the initial lymphatic vessels. Three mechanisms for the uptake
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