Page 712 - Small Animal Internal Medicine, 6th Edition

684 PART V Urinary Tract Disorders

associated with serosal inflammation. FMF is caused by volume expansion and edema formation. Recent studies
mutations in the pyrin gene, which is expressed in neutro- have suggested that upregulation of the electrogenic sodium
VetBooks.ir phils and normally inhibits inflammation provoked by minor channel (ENaC) in collecting duct epithelial cells may
mediate this sodium retention.
insults. If untreated, most people with FMF develop reactive
The underfill and overfill hypotheses of sodium retention
amyloidosis, nephrotic syndrome, and renal failure in middle
age. Colchicine prevents most febrile attacks and prevents and edema formation in the nephrotic syndrome can be
development of amyloidosis in this population. Colchicine reconciled by considering the stage of disease. Earlier in the
(0.03 mg/kg/day) may be beneficial in Shar Pei dogs with disease process, when the serum albumin concentration and
recurrent fever and joint swelling (so-called Shar Pei fever) intravascular oncotic pressure are adequate, intrarenal
that may be at risk for the development of systemic amyloi- sodium retention may result in expansion of circulating
dosis, but no prospective placebo-controlled study is avail- volume and suppression the RAAS (overfill). Later in the
able to support this treatment. Adverse effects of colchicine disease process, when severe hypoalbuminemia and low cir-
include gastrointestinal upset and rare development of culating volume caused by decreased intravascular oncotic
neutropenia. pressure develop, the RAS would be activated, despite the
presence of an intrarenal mechanism for sodium retention
(underfill).
COMPLICATIONS
THROMBOEMBOLISM
HYPOALBUMINEMIA The nephrotic syndrome results in a hypercoagulable state.
The hypoalbuminemia of nephrotic syndrome is only par- Occasionally, thromboembolic phenomena are responsible
tially explained by the urinary loss of albumin. Hepatic for the major presenting signs and overshadow the under-
albumin synthesis is increased in nephrotic syndrome but lying renal disease, thus complicating the clinical course
this increase is insufficient for the degree of hypoalbumin- and delaying the primary diagnosis. Hypercoagulability and
emia. Low plasma oncotic pressure is thought to be the thromboembolism associated with the nephrotic syndrome
primary stimulus for increased hepatic synthesis of albumin occur secondary to several abnormalities in the coagulation
in this syndrome. Renal catabolism of albumin is increased system. Mild thrombocytosis and platelet hypersensitivity
in nephrotic syndrome because of increased reabsorption of occur in association with hypoalbuminemia and result in
filtered protein. Although an increase in dietary protein increased platelet adhesion and aggregation. Plasma arachi-
stimulates hepatic albumin synthesis, it does not correct donic acid normally is protein-bound, and more arachidonic
hypoalbuminemia in patients with nephrotic syndrome and acid is free to bind to platelets in the presence of hypoalbumin-
only worsens the urinary loss of protein. emia. This may result in increased thromboxane production
by platelets and platelet hyperaggregability. Hypercholester-
SODIUM RETENTION olemia also may contribute to platelet hyperaggregability by
The underfill hypothesis of edema and ascites formation in altering platelet membrane composition or affecting platelet
the nephrotic syndrome involves activation of the RAAS. adenylate cyclase response to prostaglandins.
Progressive loss of albumin through the glomeruli and inad- Loss of antithrombin (AT; molecular weight [MW],
equate hepatic synthesis of albumin lead to hypoalbumin- 65,000) in urine also contributes to hypercoagulability. AT
emia, which in turn leads to decreased oncotic pressure with acts in concert with heparin to inhibit serine proteases (clot-
loss of water and electrolytes from the vascular compart- ting factors II, IX, X, XI, and XII) and normally plays a vital
ment. Decreased circulating volume leads to decreased renal role in modulating thrombin and fibrin production.
blood flow and activation of the RAAS with aldosterone Decreased plasma concentrations of factors IX, XI, and XII
release and consequent renal conservation of sodium and occur because of urinary loss of these proteins. Hyperfi-
water. Attempted restoration of circulating volume is unsuc- brinogenemia and decreased fibrinolysis contribute to
cessful because hypoalbuminemia and decreased oncotic hypercoagulability. Decreased fibrinolysis occurs as a result
pressure prevent retention of water in the vascular compart- of decreased concentration of plasminogen and increased
ment. In addition to the RAAS, nonosmotic stimulation of concentration of α 2 -macroglobulin (a plasmin inhibitor).
antidiuretic hormone (ADH) release and increased sympa- Increased concentration of large-MW coagulation factors
thetic nervous system activity could be invoked by decreased (factors II, V, VII, VIII, and X) may lead to a relative increase
circulating volume and also would promote renal water and in coagulation factors as compared with regulatory proteins.
sodium retention. This increase may result from increased protein synthesis by
The overfill hypothesis is based on evidence for a primary the liver as it attempts to correct hypoalbuminemia.
intrarenal mechanism of sodium retention in nephrotic syn- Thromboembolism has been reported to occur in 15% to
drome. Aldosterone concentrations frequently are normal or 25% of dogs with nephrotic syndrome. It is rare but has been
even low in affected human patients, and treatment with reported in cats with glomerular disease. Animals with
ACEi does not always prevent sodium retention. Primary fibrinogen concentrations more than 300 mg/dL and AT
intrarenal sodium retention in nephrotic syndrome occurs concentrations less than 70% of normal are considered at
in the distal nephron and contributes to extracellular fluid risk for thromboembolism, and anticoagulant therapy (e.g.,