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

General principles of treatment

When must edema be treated

What are the consequences of the removal of fluid

How rapidly should fluid be removed

When

Pulmonary edema is the only form of generalized edema that is life threatening and demands immediate treatment

Important for note: laryngeal edema and angioedema. Cerebral edema

What are the consequences

If the edema fluid is compensatory (heart failure, cirrhosis, capillary leak syndromes) then removal of fluid with diuretics will diminish effective circulating volume.

Despite this drop in effective circulating volume, most patients benefit from the appropriate use of diuretics.

Cardiac output falls 20% with diuresis of pulmonary congestion but exercise tolerance increases

Says to be careful in diuresis leads to increases in Cr

How rapidly should edema fluid be removed

Removing vascular fluid changes starling forces (reduced venous pressure) so fluid rapidly mobilized from interstitium. 2-3 liters per 24 hours can often be removed without difficulty

An exception is cirrhosis and ascites without peripheral edema. Mobilizing ascites is limited to 500-750 ml/day

Heart failure

Edema is due to increase in venous pressure raising capillary hydrostatic pressure

Ischemic and hypertensive CM impairs left ventricular function causing pulmonary but little peripheral edema

In acute pulmonary edema the LV disease results in increased LVEDP and increased left atrial pressure which transmit back to the pulmonary vein

When wedge exceeds 18-20 (normal is 5-12) get pulmonary edema

Cor pulmonale due to pure right heart failure prominent edema in the lower extremities

Cardiomyopathies tend to affect right and left ventricles leading to simultaneous onset of pulmonary and peripheral edema.

Discusses forward hypothesis in which reduction in cardiac output triggers decreased tissue perfusion activation of SNS and RAAS.

Catecholamines increase cardiac output

RAAS increase Sodium retention

Edema is absent and patients can be compensated at the expense of increased LVEDP see Figure 16-6

Figure 16-6 A to B to C with compensation

Eventually the increased sodium retention and increased intracranial pressure are enough to cause edema.

He then brings up multiple important points (in bullets none the less)

Dual effects of fluid retention:

Increased cardiac output

Potential harmful elevation in venous pressure

Benefit is found with increase in LVEDP from 12 to 15, after that it seems mostly deleterious

Vascular congestion (elevated LVEDP) and a low cardiac output do not have to occur together. See points B and C on 16-6.

Frank-Starling relationship varies with exercise.

Patients with moderate heart disease may be okay at rest but fail with mild exertion. This leads to more neurohormonal activation. This can worsen sodium retention and ischemia. Rest here can help augment diuretic effect. Doubling diuretic response. 40% increase in GFR.

Mild to mod heart disease may have no edema with dietary Na restriction. Na intake will initially increase preload and improve cardiac output and allow the Na to be excreted but as the Frank Starling curves flatten then excess sodium cannot be excreted.

Diastolic vs Systolic dysfunction

Decreased compliance in diastolic dysfunction can lead to flash pulmonary edema

More common with hypertension

Look to the ejection fraction

Neurohormonal adaptation

Initial benefit long term adverse effects

Norepi, renin, ADH all are vasoconstrictors

They raise cardiac output

Raise BP which is maladaptive in the long term

Treatment of cardiogenic pulmonary edema

Morphine

Oxygen

Loop diuretic

NTG/nitroprusside

If patient remains in pulmonary edema and has systolic dysfunction consider inotropic agent

Treatment of chronic heart failure

Feels dated

Mentions dig and loop diuretic

But also ACEi/BB and AA

Deep dive

Loop diuretics

ACEi

Cor Polminale

Edema here comes with increased CO2

Associated with increased HCO3 which means increased

HCO3 reabsorption int he proximal tubule which leads to more sodium retention

Hypoxemia can increase Na retention

Cirrhosis and Ascites

Both lymphatic obstruction and increased capillary permeability contribute

Sinusoidal obstruction leads to increased hydraulic pressure in the sinusoids.

Portal hypertension is necessary for ascites

> 12 mmHg

The low albumin is often present but is not contributory to edema

Sinusoids are freely permeable to albumin so no oncotic pressure from albumin here

Mechanism of ascites

Renal sodium conservation is an early finding and some evidence for primary sodium retention but…

Mostly underfill is thought to drive Na retention

Splanchnic vasodilation starts this of

NO drives this

Endotoxin absorption stimulates No

Normally endotoxin is detoxed in liver but portosystemic shunting allows endotoxin to escape the liver.

Hepatorenal syndrome

Progressive hemodynamically mediated fall in GFR

Induced by intense renal vasocontstriction

Where are the PGE and Kinins

Fall in GFR is masked by decreased muscle mass and decreased BUN production

Hyponatremia is a grave prognostic sign, as it is in heart failure, Indicates increased activation of vasopressin

Treatment

Low Na intake

Low water intake

Care with diuretics, can only mobilize 300-500 ml of ascetic fluid a day

Avoid hypokalemia

Stimulates NH3 production

Talks about the mechanism in proximal tubule

Also discusses pKA of NH3->NH4 reaction and if the pH rises, this will shift the Eq to produce NH3

Important aspect in NH3 is lipid soluble and NH is not

Says that Spiro is diuretic of choice

States it is more effective than furosemide in this condition

Effectiveness related to slower rate of drug excretionin urine (compromises furosemide but not spiro) competition with bile salts

Recommends 40 furosemide and 100 of spiro

Resistant ascites

Options

paracentesis

TIPS

Complicated by higher mortality

Peritoneovenous shunt

Largely abandoned,

Primary renal sodium retention

CKD or AKI where low GFR linits excretion of Water and Na

Acute GN or nephrotic syndrome

Broken glom with intact tubules, mean the tubules see less Na so they think “underperfused” and then they increase renal retention of NA

Drugs

Direct vasodilators like minoxidil

Require super high furosemide doses to counter

Other antihypertensives either block sympathetic NS, Na retention directly or block RAAS explains why they don’t cause Na retention

NSAIDS

Fludrocortisone

Pregnancy

Normal pregnancy is associated with retention of 900 to 1000 mEq of Na

And! 6-8 liters of water

Refeeding edema

Insulin stimulate Na retention

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