Halting Progression of Membranous Nephropathy

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TORONTO—Two-thirds of patients with membranous nephropathy (MN) will present with nephrotic-range proteinuria.

In this group, clinicians must strive to both control patients' symptoms and prevent progression to renal failure, according to Daniel Cattran, MD, Senior Scientist in the Division of Clinical Investigation & Human Physiology at the University Health Network's Toronto General Research Institute.

Of the remaining one third of MN patients who present with lower ranges of proteinuria, 50% of those will develop nephrotic-range proteinuria within one year of their MN diagnosis, said Dr. Cattan, who spoke to nephrologists at the Prevention in Renal Disease 8th Annual Conference.

The natural history remains roughly the same as it did 20 years ago, with a number of studies indicating about a third of patients with this disease will remit spontaneously, another third will experience persistent proteinuria, and the remaining one third will slowly progress to renal failure.

Defining in advance which patients belong to each category remains a challenge. Persistence of high grade proteinuria for at least six months remains the best validated method  for selecting patients with the worse prognosis, but recent studies have suggested using a combination of high levels of urinary immunoglobulin G (above 250 mg/day) plus high urinary levels of β2 microglobulin (above 0.5 mcg/minute), Dr. Cattran said. Male gender and being older than 60 years are among the factors associated with end-stage renal disease and death, but these factors are not modifiable, he said.

For patients who become nephrotic and are considered to be at high risk of progression based on the aforementioned criteria, it is appropriate to attempt induction of either partial or complete remission of their proteinuria, Dr. Cattran said.

Achievement of either type of remission has a significant effect on patients' survival without renal failure. The renal failure-free survival rate is only 50% for patients who remain nephrotic at 10 years compared with 90% for those who achieve partial remission, and 100% for those who have complete remission, according to a study conducted by Dr. Cattran and collaborators (Kidney Int. 2004;66:1199-205).

Therefore, the primary goal of treatment should be complete or partial remission of proteinuria. Other goals include maintenance of a stable glomerular filtration rate and controlling hypertension.

Conservative treatment is the most appropriate first-line approach for patients with MN, Dr. Cattran continued. This involves regular monitoring to ensure the BP remains at or below 125/75 mm Hg and proteinuria remains mild (below 3.5 g /day). Patients whose BP becomes elevated are candidates for an ACE inhibitor or an angiotensin receptor blocker, he said. These drugs might not only reduce BP but also reduce proteinuria.

Individuals with moderate and persistent nephrotic MN for more than six months should receive a combination of cyclophosphamide and steroids, or a calcineurin inhibitor, Dr. Cattran told listeners. To avoid nephrotoxicity with these agents, it is important to monitor patients carefully during immunosuppressive treatment, including calcineurin inhibitor blood levels.

Patients whose proteinuria and other symptoms are not controlled by these treatments are potential candidates for. rituximab treatment, Dr. Cattran said. In an open-label trial of rituximab in 15 refractory severely nephrotic patients, he and others found that proteinuria dropped by approximately 50% within 12 months (Kidney Int. 2008;73:117-25). Furthermore, of the 14 patients who completed follow-up, two achieved full remission and six went into partial remission. Rituximab also can be considered as a replacement for calcineurin inhibitors among patients who have become dependent on this class of agent.

Overall, Dr. Cattran concluded, MN patients have a good prognosis. With careful monitoring and appropriate timing and choice of therapies in patients most likely to progress, a good long-term kidney survival can be obtained in more than 85% of these patients.

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