Using biopsy to track disease activity
William Check, PhD
Physicians should welcome positive new data, presented in October at this year’s meeting of the American Society of Nephrology, on identifying and treating the most aggressive cases of IgA nephropathy.
Drs. James Tumlin and Randy Hennigar, both of Emory University Hospital and Clinic, designed a study based on histologic similarities between lupus and aggressive cases of IgA nephropathy. Although lupus becomes aggressive far more frequently than IgA nephropathy, Dr. Hennigar says, "Lupus nephritis and the more aggressive cases of IgA nephropathy are similar in many ways. Both are fundamentally mesangial diseases, and IgA nephropathy can become proliferative beyond the mesangium, just like lupus."
Based on this similarity, Dr. Tumlin hypothesized that perhaps the treatment strategies used in lupus nephritis would be useful in more aggressive cases of IgA nephropathy. Dr. Hennigar modified an SLE activity index to measure histologic activity on biopsy, focusing on cellular crescents and endocapillary proliferation. "Biopsy is extremely important in identifying patients with aggressive IgA nephropathy," he says.
Patients were included in the study if 10 to 15 percent of glomeruli exhibited any of the histological activity criteria. Fourteen patients met the criteria. They also had clinical signs of aggressive disease—rapidly increasing proteinuria or rapidly declining creatinine clearance.
Patients were treated with pulse Solumedrol, 1 mg/day for three days, followed by monthly intravenous Cytoxan at 0.5 g/m2 of body surface area for six months. Oral prednisone was also started on day four and given for two months at 1 mg/kg, tapering over four months to 10mg per day. At the end of six months, all patients had an exit biopsy, after which fish oil at 12g per day was added to the ongoing oral prednisone.
"What we found," Dr. Hennigar says, "was that evidence of clinical and histological disease activity was diminished significantly in the vast majority of patients at six months." Serum creatinine stabilized and, in many instances, decreased; proteinuria diminished and often went into remission. For example, Dr. Tumlin reports, mean urine protein at entry was 3.37g per 24 hours; after six months of therapy it was 1.07; currently, after three years of followup, it is 0.74.
An improved clinical course correlated with less histologic activity in the patients’ biopsies. Crescents were decreased or scarred down to fibrous crescents, and residual endocapillary proliferation was diminished. Two other histological markers, fibrinoid necrosis and karyorrhexis, were "markedly diminished or absent from biopsy after six months of therapy," Dr. Hennigar says. Indicators of chronicity related to scarring—glomerulosclerosis, interstitial fibrosis, and tubular atrophy—while not reversible, were minimized on six-month biopsy.
Eleven patients in the Emory database who met the entry criteria for the study were used as historical controls. "We couldn’t do a controlled trial because this is a rare disorder," Dr. Tumlin says. Over three years, one of 14 (seven percent) treated patients came to end-stage renal disease; among the untreated historical controls, 40 percent advanced to ESRD, a rate much higher than previously reported for patients with endocapillary proliferation and crescents.
"Aggressively treating a subset of advanced patients effectively reduced disease activity scores and prevented development of glomerulosclerosis, interstitial fibrosis, and tubule dropout," Dr. Tumlin concludes. A few small studies conducted earlier had shown some benefit with Cytoxan and prednisone, but this study was the first to use biopsy to show decreased activity and chronicity and the first to include historical controls, he says.
The published fraction of IgA nephropathy patients with advanced disease is "highly variable," Dr. Tumlin says, ranging from less than one percent to as much as 30 percent. When he and Dr. Hennigar reviewed biopsy reports of IgA nephropathy patients at Emory from 1980 to 2000, they found almost a 30 percent incidence of crescents or endocapillary proliferation. Dr. Tumlin notes the concordance between this 30 percent incidence and the 30 percent overall rate of progression to ESRD among IgA nephropathy patients. "Do these criteria define the subgroup that goes on to ESRD?" he wonders.