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The Nephrotic Syndrome and Focal Segmental Glomerular Sclerosis - 8/27/2012

posted Aug 27, 2012, 1:26 PM by Rohit Das   [ updated Dec 27, 2012, 7:00 AM by Purnema Madahar ]

Some interesting topics of discussion today…let’s discuss…

At resident report with Dr. Lief, Lucy Torres presented a case of nephrotic syndrome in a woman with biopsy proven FSGS. Let’s talk about a bit about nephrotic syndrome, then some more nitty gritty stuff about FSGS specifically…

  • Pure nephrotic syndrome is characterized by heavy proteinuria (>3-3.5g/24 hours) in the absence of an active sediment, with associated hypoalbuminemia and peripheral edema. Patients often also have hyperlipidemia, thrombotic issues and an increased susceptibility to infection. Importantly, isolated heavy proteinuria, in the absence of the above clinical issues, is usually associated with SECONDARY causes of nephrotic syndrome, which bring us to…
  • The causes…In adults, 30% of cases are due to underlying systemic diseases, including DM (by far the majority of cases), SLE, and amyloidosis. Of primary disorders causing nephrotic syndrome, recent epidemiologic studies based on biopsy results (one is attached) have suggested that FSGS is the most common (35%...over 50% cases in African-Americans), followed by membranous nephropathy (33%) and minimal change disease (15%).
  • Evaluation should include quantification of proteinuria (in most cases, a morning total protein/creatinine ratio is good enough), appropriate serologies (though usually not diagnostic), and ultimately – renal biopsy.
  • Regarding some general approaches to management:

o   Nephrotic syndrome associated edema is managed with loop diuretics, along with a Na-restricted diet.  There are two factors that necessitate high doses of loop diuretics in patients with nephrotic syndrome; firstly, hypoalbuminemia leads to less drug being delivered to the kidney. Secondly, albuminuria leads to drug being bound to albumin in the tubular lumen, rendering them inactive.

o   Higher degrees of proteinuria have been clearly associated with progression of CKD, regardless of etiology. Therefore, lowering intraglomerular pressures and lowering proteinuria, mainly via ACE inhibition, is the main mode of trying to prevent progression of CKD in patients with nephrotic syndrome. However, there is scarce data whether ACE-I is of benefit specifically in patients with FSGS.

 

Now let’s talk about FSGS, specifically…

  • As mentioned, FSGS is probably the most common cause of nephrotic syndrome, and its incidence has increased over the last few decades (from 15% in the late 70s to 33% more recently). There is also strong evidence that genetics play a significant role in the pathogenesis of FSGS, especially considering its strong association with African-American ethnicity.
  • FSGS is classified as either primary or secondary, and there are a laundry list of secondary causes (Table 1 of the Deegens’ article gives a good overview). Clinically, primary FSGS has a more abrupt presentation, usually with nephrotic syndrome at presentation. Secondary FSGS is much more insidious, and as mentioned above, such patients often don’t classify as having the “syndrome” (i.e., normal albumin, no edema) despite having nephrotic-range proteinuria. Obesity is one of these “secondary causes,” and a nice study regarding this subject is attached.
  • More recently, different histologic subtypes of FSGS have been described (Table 2 of the Deegans’ article gives a nice overview). The clinical value of this classification scheme is not clear. Retrospective data suggest that “tip variant” FSGS (which Lucy’s patient has) has a better prognosis, with up to 50-65% of patients achieving some degree of remission with treatment. The collapsing variant (very often associated with HIV) has the worst outcome
  • Treatment has not been well studied - there are no controlled studies looking at steroids (which are first line) in FSGS, and it is not possible to predict response. Since most patients are treated, it is also difficult to say which proportion of patients have spontaneous remission. Some important prognostic factors include degree of proteinuria (>10g/day is very predictive of ESRD within 5 years), histology (as above) and response to steroids (complete = <200-300mg/day, partial = ≥50% reduction and <3.5g/day).

o   Regarding steroids – prospective data (an abstract one such study is attached) show a response rate (complete and partial remission) of ~50%. Patients were treated for a mean of 5-6 months, and those who responded did so within a mean of 3-4 months. There were no clinical variables predictive of response in multivariate analysis.

o   For “steroid resistant” disease, there are few, small randomized studies showing potential benefits of cyclosporine, and some observational studies looking at mycophenolate. One study (attached) comparing the two found no statistical difference in regard to rate of remission 

I’ll end on an important clinical point – Lucy’s patient came in with a creatinine of 2.9, which has now come down to 0.8 – this with 18 kg of weight loss from diuresis!! Seem paradoxical? Couple of points…

  • Nephrotic syndrome, along with other some other hypervolemic conditions (CHF, Cirrhosis) are SODIUM RETAINING states. That is, even though they have a higher than normal total body volume, they are intravascularly depleted (for complex physiologic reasons, specific for each disorder) and the R-A-A is ramped up…this leads to sodium retention and consequent edema formation.
  • In addition, prolonged renal artery vasoconstriction due to the increased R-A-A activation can lead to pre-renal injury, and if prolonged, ATN.
  • By diuresing and preventing sodium reabsorption (which can also be achieved well with dietary compliance), intravascular hydrostatic pressure goes down, favoring absorption in the capillary bed and mobilization of fluids from the interstitium
  • In a hypervolemic patient with AKI due to pre-renal injury (from effective intravascular volume depletion, as above), gentle diuresis and mobilization of extravascular fluid will increase intravascular volume, turn down the R-A-A system, alleviate renal artery vasoconstriction, and finally, IMPROVE GFR!!

So after all that…my point?? Don’t be afraid to diurese volume overloaded patients with acute kidney injury…it just might be the right treatment!!

A lot to digest today…I’ve attached a few review articles to add to your library. Also, thanks to Dr. Lief for all the added literature, which is also attached. Thanks for reading!!

The Nephrotic Syndrome
Orth et. al., NEJM 1998; Volume 338 (17): 1201-11

Haas et. al., Am J Kid Dis 1997; Volume 30 (5): 621-31

Deegens et. al., Neth Journ of Med 2008; Volume 66 (1): 3-12

Courtesy of Dr. Lief:
Rydell et al., Am J Kid Dis 1995; Volume 25 (4): 534-42

Kambham et. al., Kid Int 2001; Volume 59: 1498-1509

Stokes et. al., Kid Int 2004; Volume 65: 1690-1702

Gipson et. al., Kid Int 2011; Volume 80 (8): 868-872
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