Nephrotic syndrome is an uncommon to rare complication of protein-losing nephropathies. Diagnosis of nephrotic syndrome requires
the concurrent presence of proteinuria, hypoalbuminemia, third-space accumulation of fluid, (such as ascites) and hyperlipidemia;
when present, this diagnosis is pathognomonic for glomerular disease. Patients with hypoalbuminemia, proteinuria, and hyperlipidemia
but no third-spacing of fluid are occasionally referred to as having 'incomplete' or 'incipient' nephrotic syndrome.
The relative prevalence and causes of nephrotic syndrome in dogs or cats with glomerular disease have not yet been published.
Retrospective studies of dogs with glomerular disease have reported 5.8 to 37.5% of patients are diagnosed with nephrotic
syndrome at the time of initial presentation to referral institutions. However, the true prevalence of this complication is
likely less than 10%, considering that patients with nephrotic syndrome are more likely to be referred than those with asymptomatic
proteinuria. In cats nephrotic syndrome is more likely at the time of diagnosis of glomerular disease, perhaps due to the
higher prevalence of massive protein loss due to membranous glomerulopathy in this species.
Nephrotic syndrome in people is more likely with glomerular diseases associated with large amounts of urine albumin loss.
Adults with primary glomerular diseases and nephrotic syndrome are most likely to have membranous glomerulopathy. Nephrotic
syndrome due to secondary glomerular diseases, including amyloidosis and diabetic glomerulosclerosis, increases in prevalence
in geriatric patients. Pediatric patients with nephrotic syndrome are most commonly diagnosed with minimal change disease.
Associations between specific glomerular diseases and development of nephrotic syndrome have not been published in dogs or
cats; however, preliminary results compiled by this author and others from several institutions suggest that the same associations
are not present in dogs or cats.
Patients diagnosed with nephrotic syndrome most commonly present for abdominal distention secondary to ascites. However, it
is not uncommon for patients who are diagnosed with protein-losing nephropathies in the absence of obvious ascites to have
some sub-clinical abdominal fluid accumulation evident upon diagnostic imaging. Patients may also have pitting subcutaneous
edema, particularly in the distal extremities and ventral abdomen, thorax, and neck. Fluid is less commonly found in the pleural
and pericardial spaces, and dyspnea or tamponade are very rare. Extravasated fluid is usually a pure transudate.
A number of complications are noted more frequently in human patients with nephrotic syndrome as opposed to those with asymptomatic
proteinuria, the most common of which is thromboembolism. This increased prevalence may be due to vascular stasis and/or reduced
rate of blood flow due to hypovolemia, and reduced activity levels. Limited retrospective studies in dogs with glomerular
disease suggest that risk of thromboembolism is not linearly associated with severity of proteinuria, but relationship to
nephrotic syndrome in particular has not been examined. Sites of thrombosis in dogs include the splenic, hepatic, intestinal
and other mesenteric veins, pulmonary vasculature, and the renal and adrenal artery and vein. Although people with nephrotic
syndrome are also at increased risk of coronary artery disease, secondary infections, and acute renal failure, these have
not been recognized as occurring more frequently in veterinary patients with nephrotic syndrome versus those with asymptomatic
Nephrotic syndrome may be solely due to massive urinary loss of albumin and other proteins, with third spacing of fluid and
hyperlipidemia being consequences of decreased plasma oncotic pressure. Conversely, other evidence in people and animal models
suggests that these latter components of nephrotic syndrome may only be partially related to hypoalbuminemia, and instead
may result from independent pathologic processes that occur concurrently with glomerular damage:
Proteinuria and hypoalbuminemia: Hypoalbuminemia in patients with nephrotic syndrome is a direct consequence of proteinuria. In people, 'nephrotic range' proteinuria
refers to urine protein loss greater than 3 g/24 hr/1.73 m2 in adults, and identifies patients at increased risk for development of nephrotic syndrome. A similar value has not been
established in dogs and cats, and clinically, the amount of albumin loss that must be present for third-spacing of fluid to
develop in dogs or cats appears to be highly variable. Animals with severe hypoalbuminemia are commonly encountered that have
no or minimal ascites, and conversely occasional patients are evaluated with only modest decreases in serum albumin but nevertheless
obvious third-spacing of fluids. Serum albumin concentration and urine protein excretion in nephrotic versus non-nephrotic
dogs have not been systematically studied in dogs with nephrotic syndrome, but dogs with serum albumin concentrations greater
than 1.5 g/dl or urine protein:creatinine ratios less than 10.0 are not consistently reported to have third-spacing of fluid.
Extravascular fluid accumulation: Hypoalbuminemia is necessary for third-spacing of transudate fluid to occur, but the pathogenesis
of fluid extravasation is more complex than simply due to a drop in plasma oncotic pressure. Under homeostatic conditions
edema is usually prevented by re-uptake of fluid in the distal capillaries and the lymphatics. Hypoalbuminemia results in
a decrease in plasma oncotic pressure and thus initially favors greater net outward flow of fluid. However, albumin usually
rapidly equilibrates between the vascular and interstitial spaces, and a given reduction in plasma albumin concentration should
result in a near-identical decrease in interstitial albumin concentration. Additionally, rodents and dogs with severe, induced
hypoalbuminemia fail to develop edema following fluid challenge despite a significant reduction in plasma oncotic pressure.
The 'underfill' hypothesis argues that the initial decrease in plasma oncotic pressure results in up-regulation of the renin-angiotensin-aldosterone
system due to the initial increase in fluid extravasation and secondary decrease in circulating blood volume. Increased sodium
retention therefore maintains near-normal intravascular hydrostatic pressure which is not matched by an increase in interstitial
hydrostatic pressure, and edema forms. Alternatively, the 'overfill' hypothesis proposes a primary nephron defect, independent
of the glomerular lesion that results in protein loss, which prevents adequate sodium excretion. Sodium avidity secondarily
results in increased intravascular volume, a rise in hydrostatic pressure, and ultimately fluid extravasation. However, hypertension
would be expected in these patients, and this indeed occurs in human adults and many veterinary patients with glomerular disease
with or without nephrotic syndrome. Finally, a third hypothesis, which is supported in some forms of human glomerular disease,
suggests that an unidentified 'permeability factor,' may directly alter vascular and glomerular permeability and be the cause
of edema. These theories are of course complicated by the fact that not all nephrotic syndromes in people likely have the
same pathogenesis; therefore, veterinarians should be cautious in assuming that nephrotic syndrome in veterinary patients
has a similar pathogenesis as in people.
Hyperlipidemia: Although cholesterol is the only lipid routinely measured in most dogs and cats with nephrotic syndrome, human
patients and animal models have both quantitative and qualitative abnormalities in total serum lipoprotein profiles. These
include an increase in serum total, very low-, low-, and intermediate-density lipoprotein cholesterol, serum triglycerides,
and chylomicrons, most of which are proportional to the severity of hypoalbuminemia. A significant correlation between serum
cholesterol and albumin has not been found in dogs with glomerular disease, but patients with nephrotic syndrome have not
been specifically studied. Increases in cholesterol and triglycerides are due to both up-regulated activity of enzymes in
their synthesis pathways as well as reduced catabolism.