Rule of Thirds in Membranous Nephropathy

Keeping with our recent theme of "numerical rules in Nephrology", let's briefly discuss the "Rule of Thirds" for Membranous Nephropathy.

The "Rule of Thirds" is frequently taught in medical school and a useful way of thinking about the prognosis of membranous nephropathy. It states that roughly speaking, all patients with the diagnosis of membranous nephropathy can be broken down into 3 equally populated groups with different prognoses:

One third of the patients will experience a spontaneous remission (this particular group, while certainly a desired outcome for all patients, has made interpretation of clinical trials in membranous nephropathy somewhat difficult--you don't know if a particular test subject has gotten better because of a treatment, or would have done so on their own).

One third of the patients will have persistent proteinuria and a reduced but stable renal function.

One third of the patients will have progressive loss of GFR, often leading to ESRD. According to this source, the overall incidence of ESRD is 14% at 5 years, 35% at 10 years, and 41% at 15 years.

While useful for a global understanding of membranous nephropathy, however, the Rule of Thirds is a little too simplistic--we can more accurately predict a patient's prognosis based on risk-stratification. In this 2005 JASN review by Cattan, the author presents a well-utilized strategy for the decision of how aggressively to treat patients with membranous nephropathy. Generally, it advises breaking patients up into low-risk, medium-risk, and high-risk groups based on their response to conservative therapy (e.g., ACE-I/ARBs, edema and lipid management, blood pressure control, etc) over a 6-month period.

Those in the low-risk group (normal renal function and less than 4 grams/day proteinuria over a 6-month period) have less than a 5% risk for progression over a 5-year period and therefore should not be given aggressive immunotherapy.

Those in the medium-risk group (normal renal function and persistent proteinuria between 4 and 8 grams/day proteinuria over a 6-month period). This group has a much higher risk of poor outcomes without treatment than the standard "Rule of Thirds" would suggest, and therefore the data would suggest treatment such as cycling of cytotoxic drugs and steroids.

Those in the high-risk group (worsening renal function and proteinuria greater than 8 grams/day over a 6-month period) represented only about 10% of all patients with idiopathic membranous nephropathy, but make up a very high percentage of those who eventually go on to ESRD. These patients should receive aggressive therapy with the possibility of newer protocols (Rituxan, cyclosporine for failure to achieve remission, enrollment in new trials) and be advised that dialysis is a very real eventual possibility.