References Capillary Hemodynamics Insights into Salt Handling and Blood Pressure | NEJM Amy mentioned about the 3 phases of the interstitium Are the precapillary sphincters and metarterioles universal components of the microcirculation? An historical review - PMC Safety factor? Renal Function during Recovery from Minimal Lesions Nephrotic Syndrome - Abstract - Nephron 1987, Vol. 47, No. 3 - Karger Publishers Are diuretics effective for idiopathic lymphedema? : Evidence-Based Practice Rapid diuresis in patients with ascites from chronic liver disease: the importance of peripheral edema for fig 16-7 Activation and Inhibition of Sodium-Hydrogen Exchanger Is a Mechanism That Links the Pathophysiology and Treatment of Diabetes Mellitus With That of Heart Failure Additional notes from our chat (might be overlap with Amy’s notes below New insights into the pathophysiology of edema in nephrotic syndrome by Helbert Rondon The hyperlipidemia of the nephrotic syndrome. Relation to plasma albumin concentration, oncotic pressure, and viscosity Plasmin in Nephrotic Urine Activates the Epithelial Sodium Channel Lipoprotein metabolism in experimental nephrosis Viscosity regulates apolipoprotein A-1 gene expression in experimental models of secondary hyperlipidemia and in cultured hepatocytes Amiloride in Nephrotic Syndrome | Clinical Research Trial Listing ( oedema | Edema Hypoalbuminemia and proteinuria contribute separately to reduced lipoprotein catabolism in the nephrotic syndrome Origin of hypercholesterolemia in chronic experimental nephrotic syndrome Extrahepatic lipogenesis contributes to hyperlipidemia in the analbuminemic rat Apolipoprotein gene expression in analbuminemic rats and in rats with Heymann nephritis Amy’s Notes Josh “Blessed are the days” https://link.springer.com/article/10.1007/s00467-013-2435-6 Amy mentions mels’ article Capillary Hemodynamics Insights into Salt Handling and Blood Pressure | NEJM, the 3 phases of the interstitium Josh mentions a re: management of idiopathic edema (from up to date: https://www.uptodate.com/contents/idiopathic-edema) Amy stemmer sign: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635205/, https://pubmed.ncbi.nlm.nih.gov/31281100/ Anna in chat talking about amiloride, ENaC re: edema: https://www.researchgate.net/publication/50989884_New_insights_into_the_pathophysiology_of_edema_in_nephrotic_syndrome Outline Chapter 16 — Edematous States Edema is a palpable swelling produced by expansion of the interstitial fluid volume Conditions associated with this Heart failure Cirrhosis Nephrotic syndrome Pathophysiology of edema formation Two steps Alteration of capillary hemodynamics that favors movement of fluid out of the capillary Dietary sodium and water are retained by the kidney Edema does not become clinically apparent until interstitial volume has increased 2.5 to 3 liters If this fluid came the plasma would have hemoconcentration and shock Instead as fluid moves from vascular space to interstitium you get decreased tissue perfusion leading to kidney Na and water retention Net result is expansion of total extracellular volume with maintenance of plasma volume at close to normal levels This means that the kidney is responding appropriately. Important because therapy with diuretics will break this response and may diminish tissue perfusion. There are other situations where primary abnormality is inappropriate renal fluid retention. Here both the plasma and interstitial volumes are expanded and there is no consequences from diuretic therapy. This is over filling. Seen in cirrhosis, primary renal disease. Certain drugs Capillary hemodynamics Exchange of fluids at teh capillary is determined by the hydraulic and oncotic pressures in each compartment This can be expressed by Starlings law Net filtration = LpS (delta hydraulic pressure - delta oncotic pressure) Lp is the unit permeability or porosity of the capillary wall. S is the surface area. Sigma is the reflection coefficient ranging from zero for completely permeable to 1 for for impermeable Difficult to measure these values in humans and animals 16-1 is a table of starling force values. No reflection coefficient though Figure 16-2 shows values in subcutaneous tissues. PCap 17.3 Oncotic pressure in cap is 28. Says mean net gradient is 0.3 mmHg favoring filtration out of the vascular space. This excess net is returned to the systemic circulation by lymphatics. In the liver the values are different. The hepatic sinusoids are highly permeable to protein so oncotic pressure is neutralized by zero reflection coefficient. SO hydraulic pressure favoring filtration is unopposed. Cap hydraulic pressure is lower since two thirds of hepatic blood flow is from low pressure portal vein. Still large pressure gradient favoring filtration Alveolar capillaries are similar to the liver Low cap hydraulic pressure, more permeable to proteins so no transcapillary oncotic pressure. Edema formation requires alteration of one or more starling forces to favor net filtration Increased capillary hydraulic pressure would do it Increased interstitial oncotic pressure too Reduction in plasma oncotic pressure Lymphatic obstruction too Increased capillary hydraulic pressure Capillary hydraulic pressure is insensitive to alteration in arterial pressure due to autoregulation in the pre-capillary sphincter Constricts in response to increases in arterial pressure No sphincter at venous end, so changes in venous pressure are transmitted to capillary bed. Blood volume expanded increases pressure in enough system Heart failure Renal disease Venous obstruction Cirrhosis DVT Decreased plasma oncotic pressure Hypo albuminuria May be less common than previously suspected Increased capillary permeability Promotes edema directly and by permitting albumin to move into interstitium, decreasing the oncotic pressure gradient Burns both histamine and oxygen free radicals cause microvascular injury Therapy with IL-2 increases capillary permeability Episodic idiopathic capillary leak syndromes by IL-2 receptors on mononuclear cells or increased generations of kinins. Patients often with monoclonal gammopathy and during episodes have a massive leak of proteins and fluids, hematocrit rises 70-80%. Aminophylline and terbutaline may prevent. episodes ARDS Ischemia or sepsis induced release of cytokines such as IL-1, IL-8 or TNF may have role in creasing pulmonary capillary permeability DM also increases capillary permeability and may have a role in the edema which is primarily generated by other factors, heart failure or NS Lymphatic obstruction Most often with nodal enlargement due to malignancy Called lymphedema Hypothyroidism marked increase in interstitial accumulation of albumin and other proteins. Low lymphatic flow in hypothyroidema, myxedema. Resistant to diuretics which will put patient at risk of hypovolemia. Safety factors Needs to be 15 mmHg increase in the gradient favoring filtration before edema is seen Three factors explain this protective response Increased lymphatic flow can remove excess filtrate Fluid entry into interstitium lowers the oncotic pressure by dilution and lymphatic mediated removal of proteins Increased fluid entry to interstitium increases interstitial hydraulic pressure Talks about hypoalbuminemia and edema This is a lot of underfill vs overfill theory. Nice bullet points at bottom of 487 how heterogeneity of etiology of edema with MCD. Talks about pulmonary edema and how high interstitial protein provides large safety factor, interstitial albumin has a long way to fall to prevent pulmonary edema. Mentions kwashiorkor and how it may not be low albumin that causes this. Renal sodium retention Can be due to primary renal disease causing sodium retention NS, GN More commonly is renal salt retention is an appropriate compensatory response to decreased effective circulating volume States that decreased effective circulating volume can become compensated and renin falls back to normal. Had interesting figure 16-5 “The Compensated State” Symptoms and diagnosis Three factors important in the mechanism of edema The pattern of distribution of edema which reflects those capillaries with altered hemodynamic forces The central venous pressure Presence or absence of pulmonary edema Pulmonary edema Shortness of breath and orthopnea Tachypnic, diaphoretic, wet rales, gallops, murmurs Check a chest x-ray Cardiac disease is most common But differential includes primary renal Na retention and ARDS Wedge pressure will exceed 18-20 mmHg with heart or primary Na retention, but is relatively normal with ARDS Uncomplicated cirrhosis does not cause pulmonary edema Increased capillary pressure in this disorder is only seen below the hepatic vein Normal or reduced blood volume in the cardiopulmonary circulation Peripheral edema and ascites Peripheral edema is cosmetically undesireable but produces less serious symptoms Symptoms: swollen legs, difficulty walking, increased abdominal girth, shortness of breath due to pressure on the diaphragm. Pitting edema found in dependent areas Ascites found in abdomen Nephrotic syndrome low tissue pressure areas like eye orbits Heart Failure (right sided) peripheral edema, abdominal wall, SOB is due to concomitant pulmonary disease. Right sided heart failure increases venous pressure Cirrhosis develop cirrhosis and lower extremity edema, pressure above the hepatic vein is normal or low. Tense ascites can increase the pressure above the diaphragm but is relieved with a tap Portal pressure > 12 mmHg required for fluid retention Love the case history 16-1 Primary renal sodium retention Pulmonary and peripheral edema Jugular venous pressure is elevated Nephrotic Syndrome Periorbital and peripheral edema, rarely ascites CVP normal to high Idiopathic edema Behaves as volume depleted (especially with diuretics) Etiology and treatment Gener
