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June 7, 2019

Disease Week: Lupus Nephritis (Summary)

New SLE diagnostic criteria increase sensitivity for lupus nephritis diagnosis, and novel biomarkers could prove helpful to compensate for reduced specificity.

Under the new criteria established by the Systemic Lupus International Collaborating Clinic as a joint effort from the American College of Rheumatology and European League Against Rheumatism, a diagnosis of lupus nephritis can now be made with a positive antinuclear antibody and class III or IV lupus nephritis alone. This increased the sensitivity of diagnosis but reduced specificity, when compared to the 1997 revision of the 1982 American College of Rheumatology SLE diagnostic criteria (Rijnink et al, 2018). With the current classification, lupus-like conditions, such as HIV-associated immune complex disease of the kidney (HIVICK) could be included in a diagnosis of SLE. The development of biomarkers are needed to differentiate lupus nephritis from other lupus-like conditions, such as infections.

The ISN/RPS classification is used to evaluate lupus nephritis on a kidney biopsy. The NIH activity and chronicity indices provide comparisons of disease progression and response to therapy.

The International Society of Nephrology/ Renal Pathology Society classification separates categories of lupus nephritis, but does not provide prognostic value. The NIH Disease Activity and Chronicity indices is used in parallel to do this, but at present, there are no clear cutoffs of activity or chronicity that indicate when to treat lupus nephritis patients (Bajema et al, 2018). Establishing disease activity (and/or chronicity) cutoffs to guide when to start immunosuppressive therapy will be important. There are also likely to be subcategories of proliferative lupus nephritis that may have clinical and prognostic significance. One example are the segmental necrotizing lesions in patients with focal or diffuse lupus nephritis in patients with concurrent positive ANCA serology that predict poorer renal outcomes. The classification of lupus nephritis is also limited by glomerulocentricity, since severe tubulointerstitial injury and vascular involvement have a poor renal prognosis but are not included in the classification scheme.

A lupus classification based on the antigenic drivers of disease may exist in the future.

It is possible that lupus nephritis may be classified according to the inciting autoantigen in the future. Laser capture microdissection studies and elution of immune complexes from tissue combined with proteonomic techniques can be used to identify autoantigens within immune complex-mediated diseases. One recent example is the exostosin 1/2 complex, which was recently identified in membranous lupus nephritis (Sethi et al, 2019). There are likely several other autoantigenic drivers that have yet to be identified and could represent distinct forms of the disease. Development of serological assays could allow for monitoring of disease progression and response to therapy, as is available with the two current antigens for idiopathic membranous glomerulopathy (PLA2R and THSD7A).

Improved serum and urine biomarkers could have predictive value and inform treatment.

Non-invasive serum and urine biomarkers are needed to predict the onset of lupus nephritis in patients with SLE and to predict flares for patients with established disease. Currently, SLE patients are monitored by nephrologists and rheumatologists by non-specific laboratory tests, including serum creatinine, estimated glomerular filtration rate, and urine studies (urine sediment analysis, proteinuria, and hematuria), serum complements, and serologic studies. Anti-dsDNA titers, if present, can be helpful to predict flare, as well as low serum complements. Proteinuria at one year is the best predictor, at present, for long-term kidney outcome. However, resolution of serum creatinine and reduction of proteinuria does not always correlate with the absence of disease activity. Kidney biopsy studies have shown that residual histologic activity is present despite improved serum creatinine and/or proteinuria. Due to this, repeat kidney biopsies may be useful post-treatment to determine when to stop immunosuppressive therapy. An NIH disease activity score >2 on a post-treatment biopsy indicates poor outcomes.

There is a need for development and validation for serum and urine biomarkers to predict disease flare and response to therapy. Prospective studies evaluating novel analytes in clinical trials with long-time follow-up will be helpful to stratify risk, predict flare, monitor response to therapy, and predict disease prognosis. Molecular analyses of kidney biopsies could also be helpful in this process (Parikh et al, 2015)
Enrollment in clinical trials may establish new treatment targets and provide hope to patients at risk of renal failure.

Some factors associated with poor outcomes in lupus nephritis include African or Hispanic ethnicity, male sex, earlier age of onset, frequent disease relapses, incomplete remissions post-immunosuppressive therapy, proteinuria >4 grams at diagnosis, presence of anti-phospholipid antibodies, high titer dsDNA antibodies, anti-C1q antibodies, and crescentic disease or vascular involvement on a kidney biopsy (Rovin et al, 2019). Optimal management for many of these at risk patients has yet to be determined. One example of improved treatment in an at-risk group is mycophenolate mofetil for proliferative lupus nephritis, which has shown improved outcomes in African American patients. Future studies are needed to determine how to optimally treat patients in these risk groups. Increased identification and enrollment in clinical trials will help evaluate the efficacy of new targets and to optimize therapy.

References:

Bajema IM, Wihelmus S, Alpers CE, et al. Revision of the International Society Classification for Lupus Nephritis: Clarification of Definitions, and Modified National Institutes of Health Activity and Chronicity Indices. Kidney International 2018; 93: 789-796.

Parikh SV, Malvar A, Song H, et al. Characterizing the Immune Profile of the Kidney Biopsy at Lupus Nephritis Flare Differentiates Early Treatment Responders from Non-Responders. Lupus Sci Med 2015; 2: e000112.
Rijnink EC, Teng YKO, Kraaji T, et al. Validation of the Systemic Lupus International Collaborating Clinics Classification Criteria in a Cohort of Patients with Full House Glomerular Deposits. Kidney International 2018; 93: 214-220.

Rovin BH, Caster DJ, Cattran DC, Gibson KL, Hogan JJ, Moeller MJ, Roccatello D, Cheung M, Wheeler DC, Winkelmayer WC, Floege J. Management and Treatment of Glomerular Diseases (Part 2): Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney International 2019; 95: 281-295.

Sethi S, Madden BJ, Debiec H, Charlesworth MC, Gross L, Ravidran A, Hummel AM, Specks U, Fervenza FC, Ronco P. Exostosin 1/exostosin 2-associated membranous nephropathy. JASN 2019 Jun 30 (6): 1123-1136