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Glomerulonephritis 2010: Comparing New Therapeutics to Old

Lynda A. Szczech, MD, MSCE

Dec 15, 2010

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The treatment of glomerulonephritis is difficult to study. Glomerulonephridities often have heterogeneous progression ratesand are relatively infrequent in any given nephrologist practice, and complete remission is often not durable (ie, relapse is common). These factors necessitate the coordination of large numbers of centers to conduct protocols with relatively few patients to produce power calculations. With that logistical hurdle in mind, 2010 saw a number of well-conducted studies in the treatment of glomerulonephritis. The trials themselves have a single common theme: They attempt to incorporate newer immunosuppressives into evidence that was derived prior to 2000 using agents such as cyclophosphamide and azathioprine.

ANCA-Associated Vasculitis: Two Trials

With respect to antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, 2 trials were conducted look ing at the effects of the newer agents rituximab and mycophenolate mofetil on induction and maintenance care, respectively.[1,2] Jones and colleagues [1] randomly assigned 44 patients with a new diagnosis of ANCAassociated vasculitis to receive either rituximab with cyclophosphamide every other month or cyclophosphamide monthly in a 3:1 manner. Both groups received standard doses of glucocorticoids. Participants had a median age of 68 years and advanced k idney disease with a glomerular filtration rate (GFR) of 18 mL/minute. Similar proportions of participants achieved complete remissions between arms (76% vs 82% in the rituximab and cyclophosphamide arms, respectively [P = .77]). The rates of serious adverse events and deaths, as well as the increase in median GFR, were also similar between groups. Hiemstra and colleagues [2] examined the effect of mycophenolate mofetil on the lik elihood of maintaining a remission in subjects with ANCA-associated vasculitis with renal involvement. They randomly assigned 156 patients to either azathioprine or mycophenolate mofetil and followed them for a median of 39 months. However, unlik e the rituximab trial in which no statistical difference was seen, relapses in renal disease were seen more frequently in the mycophenolate mofetil group (HR = 1.69; 95% CI, 1.06-2.70; P = .03). The conclusion of these 2 trials is that rituximab may be as effective as cyclophosphamide in inducing a remission when supplemented with cyclophosphamide. However, the use of mycophenolate mofetil as an alternative therapy to the current azathioprine standard was less effective in maintaining remission.

Two Trials on Lupus Nephritis

The effectiveness of mycophenolate mofetil in achieving and maintaining remission was also studied in lupus nephritis. Touma and colleagues [3] performed a meta-analysis of trials examining the effect of mycophenolate mofetil in achieving complete remission. Four trials [4-7] were combined for a total of 618 patients, with no demonstrated
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difference in the lik elihood of partial or complete remission among patients receiving mycophenolate mofetil as compared to cyclophosphamide (RR = 0.89; 95% CI, 0.711.10). Although there were also no differences between arms with respect to many safety parameters, there was a lower incidence of alopecia and amenorrhea among those receiving mycophenolate mofetil. Houssiau and colleagues [8] randomly assigned 105 patients with lupus nephritis who had achieved remission to either azathioprine or mycophenolate mofetil. All patients received 6 pulses of cyclophosphamide and glucocorticoids. Over a 3-year period, renal function and proteinuria was similar between the 2 groups. Renal flairs were seen in 25% of the azathioprine group and 19% of the mycophenolate mofetil group. Adverse events were similar between groups, but hematologic complications were slightly more frequent in the group receiving azathioprine (P = .03).

Summary
In 2010, trials in glomerulonephritis continued to try to define how newer immunosuppressives might complement more standard therapies for ANCA-associated glomerulonephritis and lupus nephritis. Although these newer agents provided similar outcomes in all except 1 trial,[2] notably their safety profiles were similar or, in some cases, better. Limitations included low power due to small sample size. However, this problem is found across most trials in glomerulonephritis given the uncommon incidence. Regardless, these trials clearly show a place for newer, easier-to-use agents in our armamentarium to treat inflammatory glomerular disease.
References

1. Jones RB, Tervaert JW, Hauser T et al; Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. European Vasculitis Study Group. N Engl J Med. 2010 15;363:211-220. Abstract 2. Hiemstra TF, Walsh M, Mahr A, et al; European Vasculitis Study Group (EUVAS).Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA. 2010;304:2381-2388. Epub 2010 Nov 8. 3. Touma Z, Gladman DD, Urowitz MB, Beyene J, Uleryk EM, Shah PS. Mycophenolate mofetil for induction treatment of lupus nephritis: A systematic review and metaanalysis. J Rheumatol. 2010 Oct 15. [Epub ahead of print] 4. Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005; 353:2219-2228. Abstract 5. Chan TM, Tse KC, Tang CS, Mok MY, Li FK; Hong Kong Nephrology Study Group. Long-term study of mycophenolate mofetil as continuous induction and maintenance treatment for diffuse proliferative lupus nephritis. J Am Soc Nephrol. 2005;16:1076-1084. Epub 2005 Feb 23. 6. Appel GB, Contreras G, Dooley MA, et al. Aspreva Lupus Management Study Group. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009;20:1103-1112. Epub 2009 Apr 15 7. Ong LM, Hooi LS, Lim TO, Goh BL, et al. Randomized controlled trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis. Nephrology (Carlton). 2005;10:504-510.
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Abstract 8. Houssiau FA, D'Cruz D, Sangle S et al; MAINTAIN Nephritis Trial Group Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis. 2010;69:2083-2089. Epub 2010 Sep 10. Medscape Nephrology 2010 WebMD, LLC

Cite this article: Lynda A. Szczech. Glomerulonephritis 2010: Comparing New Therapeutics to Old. Medscape. Dec 15, 2010.

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