The accumulation of clinically significant systemic edema generally requires that the kidneys retain salt and water (the acute capillary leak syndromes are exceptions). Renal salt retention certainly develops in patients with nephrotic syndrome. The most proximal signal, or signals, responsible for the renal salt retention of these patients remain uncertain. The classic pathophysiologic explanation for the salt retention of nephrotic syndrome is the underfill hypothesis and follows the sequence shown in Fig. 1. The initial abnormality is the increase in glomerular permeability to albumin which produces albuminuria and accelerates albumin catabolism. The resulting fall in blood albumin concentration increases the hepatic albumin synthetic rate, but the increase is initially inadequate to restore balance so that plasma albumin concentrations continue to fall. As the filtered albumin load decreases both albumin excretion and catabolism also decrease. The plasma albumin concentration eventually stabilizes at a level which permits hepatic synthesis to match the renal excretion and total catabolic rates.
In the systemic vascular beds, hypoalbuminemia shifts the balance of Starling forces to favor filtration of fluid out of capillaries and reduces capillary reabsorption of fluid (see Chapter VA1). The net translocation of fluid from the vascular to the interstitial space simultaneously produces edema and contracts intravascular volume. The reduction in vascular volume increases renal salt and water retention which partially reexpands this space. Otherwise, severe hypovolemia and hypotension would result. This is the underfill hypothesis. It requires contraction of intravascular volume (and effective arterial blood volume (EAVB), see Chapter VA1) to trigger a series of vascular and neurohormonal mediators which stimulate renal sodium reabsorption. They include the sympathetic nervous and the renin-angiotensin systems, aldosterone, and vasopressin. A number of other less well characterized hormone, paracrine, and autocrine factors also participate. The kidney becomes relatively resistant to natriuretic peptides ,
Renal vascular resistance increases but selective constriction contracts the
efferent postglomerular arterioles more strongly than the afferent preglomeru-lar arterioles. This selective constriction will increase the glomerular filtration fraction (filtration fraction = glomerular filtration rate/renal plasma flow rate; FF = GFR/RPF). This hemodynamic profile also stimulates renal salt retention and interacts synergistically with the high levels of salt-retaining hormones. The salt and water retained by the kidneys of nephrotic patients preferentially accumulates in their interstitial spaces, as a result of the Starling force alterations created by the hypoalbuminemia .
The accumulation of edema within the interstitial spaces activates local mechanisms which oppose additional edema formation. They include increased hydrostatic pressure within the interstitial space, increased lymphatic drainage out of the interstitial space, and lower interstitial fluid albumin concentrations (oncotic pressure). These mechanisms must be overcome before significant quantities of edema can accumulate (see Chapter VA1).
The basic principles of the underfill pathophysiologic hypothesis, as described above, was proposed over 80 years ago and became widely accepted by 1948 , It requires physiologically and anatomically normal kidneys except for increased glomerular protein permeability. The renal retention of salt and water in this model is a response to systemic hypovolemia and low vascular and EAB volumes. The signals which drive the kidneys to retain salt originate within the systemic circulation. They result from the fluid shifts produced by the altered Starling forces. However, in many clinical and experimental studies of nephrotic syndrome, the underfill hypothesis could not be proven. In those cases it is possible that subtle intrinsic intrarenal alterations also participate in the salt retaining process.
Some disorders which cause the nephrotic syndrome also produce overt structural renal derangements which reduce renal perfusion and glomerular filtration. In such cases, these renal abnormalities may be the principal cause of salt and water retention. This is the obvious explanation for the salt retention which occurs when a proliferative glomerulonephritis produces both the nephrotic syndrome and renal insufficiency. However, in many patients no other apparent functional or structural renal derangements exist. For example, when nephrotic syndrome is due to minimal change disease, this can be considered a "pure" form of nephrosis. In this group underfill pathophysiology is most likely. However, even in many of these pure nephrotic patients, some studies suggest that the salt-retaining signals originate within the kidney itself. If this is correct, an alternative hypothesis to explain the salt retention of nephrosis becomes necessary.
The major alternate pathophysiologic sequence, called the overflow hypothesis, is shown in Fig. 2. The central tenet of the overflow hypothesis is an intrarenal stimulus which causes salt and water retention. This model does not require initial hypovolemia to trigger renal salt retention. Instead, renal salt and water retention develop first and expand the extracellular fluid (ECF), vascular volume, and the EABV. The Starling force derangements secondary to hypoal-buminemia cause the retained salt and water to preferentially accumulate in the interstitial space. The major distinction between the underfill and overflow theories of nephrotic edema formation is the status of the vascular and/or EABV: reduced in the underfill sequence and normal or increased with overfill physiology.
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