Chapter Sixteen, part 1
Channel Your Enthusiasm
Navigating Nephrotic Syndrome Challenges
This chapter explores the intricate management of nephrotic syndrome, focusing on the balance between underfilling and overfilling in patient presentations. The challenges of medication dependence, particularly on diuretics and laxatives, are discussed alongside alternative treatment options, shedding light on ethical concerns and the importance of nephrologist guidance. Additionally, the complexities of medication management and the collaboration required among specialists, especially concerning the transition in heart failure treatments, are critically analyzed.
References
Capillary Hemodynamics Insights into Salt Handling and Blood Pressure | NEJM
Amy mentioned about the 3 phases of the interstitium
Safety factor?
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
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
Plasmin in Nephrotic Urine Activates the Epithelial Sodium Channel
Lipoprotein metabolism in experimental nephrosis
Amiloride in Nephrotic Syndrome | Clinical Research Trial Listing ( oedema | Edema
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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