Overview Of Nephrotic Syndrome
The nephrotic syndrome encompasses a constellation of clinical and laboratory ﬁndings related to the loss of large quantities of protein in urine. The major symptom is edema, and the laboratory ﬁndings include (1) “nephrotic-range” proteinuria, deﬁned in adults as more than 3.5 g of protein excretion per 24 hours, (2) hypoalbuminemia, and (3) hyperlipidemia. The thresh old for nephrotic proteinuria in children is lower and depends on body weight.
“Nephrotic syndrome” is a nonspeciﬁc diagnosis that suggests underlying glomerular disease. The normal, noninﬂamed glomerulus forms a tight barrier to proteins, such as albumin, largely because of the slit diaphragms that connect podocyte (visceral epithelial cell) foot processes on the outside surface of the glomerular basement membrane.
In nephrotic syndrome, inﬂammation disrupts the normal structure of the slit diaphragms, permitting the passage of potentially large amounts of protein into the urine. In most cases, the foot processes appear “fused” or “effaced,” meaning that a continuous layer of podocyte cytoplasm is seen over the glomerular capillaries, rather than the discrete, individual processes seen in the normal state. Such effacement reﬂects widening, shortening, and retraction of the foot processes. Although the glomerular inﬂammation is typically not severe enough to cause an acute decline in overall ﬁltration, scarring and loss of renal function may occur over time.
The ongoing loss of albumin into urine causes hypoalbuminemia. The decline in serum albumin concentration, however, is often out of proportion to the degree of proteinuria. One possible explanation is that the proximal tubular catabolism of albumin is accelerated because of the increased ﬁltered load.
In response to the low serum albumin concentrations, the liver increases its production of numerous proteins, including lipoproteins, leading to hyperlipidemia.
Edema occurs for at least two possible reasons. The ﬁrst, known as the “underﬁlling hypothesis,” argues that low serum albumin concentrations lead to a reduction in intravascular oncotic pressure. As a result, plasma moves from the capillary lumen to the interstitium, which leads to edema. The resulting intravascular depletion activates the renin-angiotensin-aldosterone system, which promotes retention of sodium and water and thus further worsens the edema. The second hypothesis, known as the “overﬁlling hypothesis,” argues that there is primary retention of sodium at the level of the collecting duct, perhaps triggered by the ﬁltered proteins themselves, that leads to edema. It appears probable that both hypotheses are correct, and that the primary mechanism for edema may vary across patients and across time.
Patients with nephrotic syndrome are at increased risk for lower extremity, pulmonary, and renal vein thromboses (see Plate 4-35) because of urinary losses of anticoagulant proteins, such as antithrombin and plasminogen, as well as increased hepatic production of procoagulant proteins, such as ﬁbrinogen and other clotting factors. Among the nephrotic syndromes, thromboses are most often seen in patients with membranous nephropathy, but any patient with proteinuria above 10 g/day and albumin levels below 2 g/dL should be considered at risk.
Three primary glomerular diseases minimal change disease (MCD, see Plate 4-8), focal segmental glomerulosclerosis (FSGS, see Plate 4-10), and membranous nephropathy (MN, see Plate 4-12)—all cause signiﬁcant proteinuria, which is often sufﬁcient to result in nephrotic syndrome.
Other primary glomerular diseases, such as the various glomerulonephritides (see Plate 4-14), typically cause proteinuria, hematuria, and a variable degree of renal dysfunction. In a subset of cases, the proteinuria is sufﬁcient to result in nephrotic syndrome.
Finally, many systemic conditions or environmental agents can cause nephrotic syndrome, either by causing a distinct pattern of glomerular inﬂammation (i.e., amyloidosis see Plate 4-47], diabetes mellitus [see Plate 4-45]) or by causing one of the renal diseases listed previously. Examples of the latter include secondary MCD in the setting of lymphoma, infection (e.g., tuberculosis), allergies, and lithium or NSAID use; secondary FSGS in the setting of HIV infection, heroin abuse, and sickle cell disease; and secondary MN in the setting of systemic lupus erythematosus, rheumatoid arthritis, viral hepatitis infection, syphilis, penicillamine use, gold poisoning, and solid tumors in general.
In both children and adults, the annual incidence of nephrotic syndrome is approximately ﬁve cases per 100,000 individuals. This incidence, however, likely underestimates the true disease burden because many cases, especially those secondary to diabetes, do not undergo biopsy-proven diagnosis.
There are strong age and race predilections for the various causes of nephrotic syndrome. In children, the most common cause by far is MCD. In adults, the most common cause of secondary nephrotic syndrome is diabetes mellitus, whereas the two most common causes of idiopathic nephrotic syndrome are MN and FSGS. Until recently, MN was the most common cause in white adults, whereas FSGS was the most common cause in black adults. More recent data, however, shows a steadily rising incidence of FSGS, in part because of the large number of cases occurring secondary to obesity. As a result, FSGS may soon emerge as the most common cause of idiopathic nephrotic syndrome in all adults.
Presentation And Diagnosis
Edema is the most common presenting symptom. Gravity increases intracapillary hydrostatic pressure and is thus the major determinant of the extravascular ﬂuid distribution. Thus edema is typically most severe in the lower extremities; however, after sleeping in a prone position, the patient may experience swelling of the face, especially in the periorbital region. Severe ﬂuid retention can also lead to pulmonary edema (with associated shortness of breath), effusions, or frank anasarca. Hypertension may occur in a minority of patients. Finally, patients may also describe weakness, malaise, and a “foamy” or “bubbly” appearance to their urine.
Patients with edema do not necessarily have nephrotic syndrome, since other diseases—notably congestive heart failure and cirrhosis can present in this fashion. The diagnosis of nephrotic syndrome is suggested, however, when urine dipstick reveals marked proteinuria. Urine microscopy may reveal oval fat bodies, lipid droplets, and fatty casts (which resemble “Maltese crosses” under polarized light), which reﬂect the presence of lipoproteins in the urine. The presence of dysmorphic red blood cells and red cell casts suggests the proteinuria is the result of an underlying glomerulonephritis.
Once proteinuria is established, urine should be sent for protein quantiﬁcation using a 24-hour urine collection or, for the sake of convenience, a spot urine protein: creatinine ratio. The latter offers a reasonable approximation of 24-hour proteinuria, especially if it is based on the ﬁrst morning void.
Blood should be sent for measurement of albumin, cholesterol, electrolyte, and creatinine concentrations. Once laboratory tests reveal the triad of heavy proteinuria, hypoalbuminemia, and hypercholesterolemia, the patient clearly has nephrotic syndrome. The differential diagnosis at this point, therefore, is centered on determining the cause.
In children, MCD accounts for such an overwhelming majority of cases that treatment for this condition is offered on an empiric basis. Further workup, including renal biopsy, is not performed unless such treatment fails.
In adults, the differential diagnosis of nephrotic syndrome is broad enough to warrant a renal biopsy in cases where an apparent cause, such as long-standing diabetes mellitus, is not present. The histologic ﬁndings associated with each particular disease are described later in this section. In addition, adults should undergo screening for the most common causes of secondary nephrotic syndrome. For example, serologic testing should be performed for hepatitis B/C, HIV, lupus, and syphilis, and serum and urine protein electrophoresis should be performed to rule out amyloidosis and plasma cell disorders. Testing levels of serum complements (C3 and C4) can also be helpful because some causes of nephrotic syndrome are associated with depressed levels (e.g., membranoproliferative glomerulonephritis).
The optimal treatment strategies depend on the underlying cause of nephrotic syndrome and are discussed later in this book. Some treatments, however, are useful in almost all patients.
Renin-angiotensin system blockers (e.g., ACE inhibitors), for example, should be provided to all patients to lower blood pressure and reduce the degree of proteinuria. A cholesterol-lowering medication, such as a statin, should also be provided to minimize cardiovascular complications. Diuretics should be used as needed to treat edema; combinations of loop diuretics (e.g., furosemide), thiazides (e.g., chlorthalidone), and potassium-sparing diuretics (e.g., spironolactone) may be required. Anticoagulation may be necessary in patients who are at high risk for thrombosis or have already experienced a clotting event.
Many patients receive at least a short course of oral corticosteroids, although other immune-suppressing agents (such as calcineurin inhibitors, alkylating chemotherapy agents, and monoclonal antibodies) may also be used in certain circumstances.
Lifestyle changes are also important. Patients should adopt a low-salt diet to reduce edema and improve blood pressure control. Exercise may help mobilize edema and allow natural diuresis, as well as lower blood pressure and improve cholesterol levels.
Treatment success is deﬁned as reduction or resolution of proteinuria, ideally to less than 300 mg/day, with preserved kidney function. Patients who achieve this endpoint generally have a very favorable prognosis. In contrast, those patients with nephrotic-range proteinuria that do not respond to treatment have a poor overall renal prognosis because ongoing glomerular inﬂammation will eventually lead to scarring and a permanent loss of renal function.