Nephrotic-range proteinuria versus nephrotic syndrome

Adults with  primary FSGS commonly present with nephrotic syndrome. In contrast, patients with secondary FSGS are more likely to present with slowly increasing proteinuria that may be in the nephrotic-range, but the patients do not develop full-blown nephrotic syndrome (with hypoalbuminemia). Thus, it is important to recognize that nephrotic-range proteinuria (>3.5 g/24 h) and nephrotic syndrome (>3.5 g/24 h and serum albumin <3.5 g/dL) are not necessarily synonymous.37

The distinction is crucial, especially in patients who have nephrotic-range proteinuria in which a kidney biopsy shows FSGS or global glomerulosclerosis (FGGS) but who do not have nephrotic  syndrome (e.g., serum albumin is normal), for the lesions in patients without nephrotic syndrome are more likely to arise from secondary processes (e.g., glomerular hyperfiltration, obesity, nephron mass reduction).

However, patients with primary podocytopathy—minimal change disease (MCD) and primary FSGS, which result from a generalized podocyte insult—are more likely to have massive proteinuria and develop nephrotic syndrome.

 
(These patient images are courtesy of Sethi, Sanjeev, MD, PhD)

Top panel shows an FSGS with diffuse foot process effacement, consistent with primary FSGS. Bottom panel shows FSGS (not otherwise specified [NOS]) with only mild focal foot process effacement, consistent with secondary  FSGS. The thin black arrow points at diffuse foot process effacement, while the thick black arrow points at well preserved foot processes. Note diffuse foot process effacement in the top panel, while only mild focal foot process effacement is noted in the bottom panel. Each panel represents a kidney biopsy from a separate patient. (A,  C-periodic acid Schiff stain 40x, B-2500x, D-4730x).

It has been said that nephrotic syndrome occurs in only 50%-60% of patients with FSGS, thus less commonly than MCD, but in our opinion this is due to the inclusion of patients with secondary forms of FSGS, as well as African-Americans as part of the study group.38 In the great majority of hypertensive African-American patients, renal biopsy does not show FSGS but rather FGGS, and EM often shows only segmental foot process effacement.39 The majority of African-Americans included in these studies do not have nephrotic syndrome, but rather subnephrotic-range (<3.5g/24h) proteinuria.40

In the majority of these patients, renal disease is progressive regardless of aggressive blood pressure control and blockade of the angiotensin II (AII) system, which contrasts with the beneficial effect of AII blockade in other forms of proteinuric kidney diseases.41 Thus, we believe that many African-American patients have a disease that is different from the primary/ idiopathic FSGS seen in Caucasians.

Finally, it is important to verify the type of proteinuria. To start, a simple urinary protein/creatinine ratio can be compared to a urinary albumin/creatinine ratio. If <50% of total proteinuria is due to albumin then the possibility of a tubulopathy or presence of light chains should be considered.

Since dip sticks largely detect albumin, a dip stick proteinuria of trace/1+ in a patient with a quantified urinary protein >1 g/24h should serve as a clue that proteins other than albumin (i.e. light chains, tubular proteinuria) account for the proteinuria and further evaluation (urinary protein electrophoresis, retinol binding protein) is necessary to identify the cause of the FSGS lesion.

Can EM examination help?

We believe that the degree of foot process effacement on EM examination is an important factor in helping to differentiate between primary versus secondary FSGS. Since primary FSGS is caused by a circulating “permeability factor” that is toxic to the podocyte, evidence of podocyte damage must be visible as equally distributed among all glomerular capillary loops.

Indeed, tip, cellular, and collapsing FSGS, which are regarded as part of the spectrum of primary FSGS, usually have widespread foot process effacement while in the perihilar FSGS subtype (frequently seen in secondary FSGS), the effacement is relatively mild and focal.42

As discussed above, due to the adaptive origin of the lesion in secondary FSGS, patients are more likely to have mild foot process effacement and present with sub-nephrotic range proteinuria. Patients with primary FSGS, however, are more likely to resemble those with MCD by the presence of widespread foot process effacement (>80%) and nephrotic syndrome. Indeed, the degree of foot process effacement correlates with the amount of proteinuria43,44 and original studies by Velosa, Donadio and Holley showed diffuse foot process in all nephrotic patients with FSGS, involving all glomeruli, whether or not morphologic alterations were noted on light microscopy.11

Some renal pathologists claim that the percentage of foot process effacement represents a continuum rather than a sharp threshold with respect to its value in separating a primary from a secondary form of FSGS.

In this regards, it important to correlate timing with renal biopsy with previous immunosuppressive treatment because low levels of proteinuria in a patient in a partial remission following a course of corticosteroids may show segmental foot process effacement affecting variable portions of the nephron population. This certainly can be seen in patients with MCD undergoing spontaneous remission.45