Lupus nephritis: redefining the treatment goals

The course of proliferative lupus nephritis is characterized by flares of activity alternating with periods of quiescence against a background of chronic immune dysregulation. An accurate assessment of disease activity is of unassailable importance to tailor therapy. In the present communication, we discuss the available clinical, serologic, and histologic tools to evaluate disease activity and how they may be applied to redefine the treatment goals in lupus nephritis. Traditionally, treatment response is judged by the degree of proteinuria reduction and improvement of kidney function, but this fails to differentiate ongoing inflammatory disease from chronic damage. Despite intensive research, no novel biomarker has proved useful for clinical practice, and we continue to rely on anti–double-stranded DNA antibody levels to assess serologic activity. Repeat kidney biopsies sometimes reveal persistent inflammation despite apparent clinical remission, giving credibility to the conviction that histologic remission should be a treatment goal and protocol biopsies be part of the decision-making process. However, the discrepancies between clinical and histologic responses to therapy can be explained by persistent systemic autoimmunity with low-grade immune complex deposition or, alternatively, by delayed clearance of intrarenal inflammation once immunologic remission has been achieved. Because persistent immune dysregulation is the motor of disease activity in lupus nephritis, it should be the principal focus of therapy and monitoring. We propose to replace the traditional induction-remission maintenance protocol by a more dynamic and individualized approach and aim for 3 treatment goals, concomitantly rather than sequentially: (i) clinical remission, by attenuating renal inflammation, using microscopic hematuria, proteinuria, estimated glomerular filtration rate, and complement levels as biomarkers; (ii) immunologic remission, by decreasing immune complex generation, using anti–double-stranded DNA antibody as a biomarker; and (iii) preservation of kidney function, by curtailing chronic kidney damage, using estimated glomerular filtration rate slope as a biomarker.