Three extrarenal manifestations drive much of the morbidity and mortality that results from nephrotic syndrome (NS). Edema reduces the self-reported quality of life and may lead to infectious complications. Dyslipidemia, although often clinically silent, is a key driver of long-term cardiovascular complications that may become even more relevant in those patients who progress to chronic or end-stage kidney disease. Many patients with NS acquire a profound and complex hypercoagulopathic state that is also clinically silent but is thought to be a key driver of both arterial and venous thromboembolic disease. This chapter briefly covers the pathogenesis, evaluation, and clinical management considerations for these systemic consequences of NS.
The extrarenal manifestations of NS arise from proteinuria-induced dysregulation of albumin, sodium, lipid, and coagulation enzyme metabolism.1
Edema is often attributed to the development of hypoalbuminemia owing to urinary protein losses in NS. This explanation has come to be described as the “underfill
The low intravascular oncotic pressure resulting from hypoalbuminemia leads to increased movement of fluid into the interstitial space, resulting in edema. As a result, the effective arterial blood volume is low driving activation of the renin-angiotensin-aldosterone system (RAAS) and subsequent sodium retention that compounds the edema. However, data from both animal and human studies suggest that this explanation is incomplete, if not incorrect. Hypoalbuminemic animal models demonstrated that the oncotic pressure of the interstitial compartment parallels that of the serum.8
Movement of fluid from the vasculature to the interstitium is thought to both dilute albumin concentration and increase delivery of albumin to the lymphatic system, leading to relative maintenance of the osmotic gradient between the vasculature and the interstitium.8
Similar findings have also been described in patients with NS, suggesting additional mechanisms must contribute to edema (Figure 4.1
” edema hypothesis suggests that the primary driver of edema is sodium retention and subsequent volume overload. A variety of factors seem to drive sodium retention, including increased sympathetic nervous system activity leading to resorption of sodium, relative resistance to atrial natriuretic peptide, and increased collecting duct Na+
-ATPase pump expression and
Increases in vasopressin (antidiuretic hormone [ADH]) may also occur and lead to additional free water retention (although this may be more likely in those with true intravascular volume depletion). Perhaps the contributor that seems most specific to NS is that of an increase in the activity of the epithelial sodium channel (ENaC).8
Evidence has suggested that the excretion of plasminogen and its subsequent activation (to plasmin) in the urine of patients with nephrosis leads to the removal of an ENaC γ-subunit inhibitory domain, activating its open state to enhance sodium retention.11
Interestingly, activation of the RAAS does not appear to have a major role in sodium retention in patients with nephrosis.8
Most of these observations are from animal models or humans at single time points during NS. Thus, it is likely that many of these pathophysiologic factors that play a role in edema formation are dynamic over the course of the disease.
FIGURE 4.1: Mechanisms that contribute to edema in patients with nephrotic syndrome. RAAS, renin-angiotensin-aldosterone system. ENaC, epithelial sodium channel.
The mechanisms underlying dyslipidemia have been comprehensively studied.1
These derangements arise as a consequence of decreased lipoprotein lipase and hepatic lipase activity in the face of increased levels of proprotein convertase subtilisin/kexin type 9 (PCSK9). These abnormalities, along with derangements of many other enzymes and receptors involved in lipid metabolism, result in decreased fatty acid delivery to fat and muscle tissues where they are normally stored and/or consumed. Increased PCSK9 levels lead to accelerated degradation of hepatic low-density lipoprotein (LDL) receptors and thus reduce LDL clearance from circulation.12
Meanwhile, there is impaired clearance of very low-density lipoprotein (VLDL) and chylomicrons, leading to hypertriglyceridemia, increased cholesterol and LDL production, and impaired reverse cholesterol transport, the latter leading to increased high-density lipoprotein (HDL) concentrations and increased cholesterol to LDL ratios.1
Both venous and arterial thromboembolism risks are enhanced by a complex hypercoagulopathy that is acquired during NS (Table 4.1
Many of the coagulation system proteins have a molecular weight similar to or less than that of albumin and are thus lost at an excessive rate into the urine. Meanwhile, other components of the system are too large to be lost via proteinuria. These latter, mostly prothrombotic, components accumulate in the plasma compartment due to increased compensatory protein synthesis across the entire system as it attempts to compensate for massive NS-mediated protein losses. One published study also suggests that clot structure may be altered in nephrotic syndrome resulting in impaired fibrinolysis.13
Recent studies have demonstrated that hypercoagulopathy severity is proportional to NS disease activity and resolves with NS remission.14
TABLE 4.1 Possible Factors Contributing to Thrombotic Risk in Patients With Nephrotic Syndrome
Reduction in antithrombina
Reduction in protein C, protein Sa
Elevation in fibrinogena
Changes leading to impaired fibrinolysis
Reduction in plasminogena
Reduction in tissue plasminogen activator (tPA)a
Elevation in lipoprotein(a)
Increased red blood cell aggregation
Altered clot structure
Genetic predisposition for thrombophiliab
a Not consistent across studies.
b Reported in case series.