1. ¹Division of Nephrology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
2. ²Division of Nephrology, Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
3. ³Department of Internal Medicine, Meander Medical Center, Amersfoort, The Netherlands
4. ⁴Department of Internal Medicine, Máxima Medical Center, Veldhoven, The Netherlands
5. ⁵Division of Nephrology, Academic Medical Center, Amsterdam, The Netherlands
6. ⁶Division of Clinical Immunology, University Medical Center Groningen, Groningen, The Netherlands
7. ⁷Department of Pathology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
8. ⁸Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
9. ⁹Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
10. ¹⁰Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands
11. ¹¹Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands

Correspondence: C Grootscholten, Radboud University Nijmegen Medical Center, Division of Nephrology (464), PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: m.grootscholten@aig.umcn.nl

Received 27 December 2005; Revised 29 March 2006; Accepted 11 April 2006; Published online 5 July 2006.

Abstract

Until recently, intravenous cyclophosphamide pulses with oral corticosteroids were regarded standard therapy for proliferative lupus nephritis (LN). Azathioprine, a less toxic alternative, was never proven to be inferior. In the first Dutch lupus nephritis study (enrollment between 1995 and 2001), we randomized 87 proliferative LN patients to either cyclophosphamide pulses (750 mg/m², 13 pulses in 2 years) combined with oral prednisone (CY) or to azathioprine (2 mg/kg/day in 2 years) combined with intravenous pulses of methylprednisolone (3 3 pulses of 1000 mg) and oral prednisone (AZA). After a median follow-up of 5.7 years (interquartile range 4.1–7.2 years), doubling of serum creatinine was more frequent in the AZA group, although not statistically significant (relative risk (RR): 4.1, with 95% confidence interval (95% CI): 0.8–20.4). Relapses occurred more often in the AZA group (RR: 8.8, 95% CI: 1.5–31.8). Creatinine and proteinuria at last visit did not differ between the two treatment arms. Moreover, 88.4% of the patients in the AZA arm were still free of cyclophosphamide treatment. During the first 2 years, the frequency of remission was not different, but infections, especially herpes zoster virus infections (HZV) were more frequent in the AZA group. Parameters for ovarian function did not differ between the two groups. In conclusion, in this open-label randomized controlled trial, cyclophosphamide was superior to azathioprine with regard to renal relapses and HZV. At last follow-up, there were no differences in serum creatinine or proteinuria between the two groups. However, since our study lacked sufficient power, longer follow-up is needed to reveal putative differences.