Trends in the incidence, demographics, and outcomes of end-stage renal disease due to lupus nephritis in the US from 1995 to 2006. (Arthritis Rheum. 2011;63:1681-1688.)
Objective: This study was undertaken to investigate whether recent advances in lupus nephritis treatment have led to changes in the incidence of end-stage renal disease (ESRD) secondary to lupus nephritis, or in the characteristics, treatments, and outcomes of patients with lupus nephritis ESRD.
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Methods: Patients with incident lupus nephritis ESRD (1995–2006) were identified in the U.S. Renal Data System. Trends in sociodemographic and clinical characteristics were assessed. We tested for temporal changes in standardized incidence rates (SIRs) for sociodemographic groups using Poisson regression. Changes in rates of waitlisting for kidney transplant, kidney transplantation, and all-cause mortality were examined using crude and adjusted time-to-event analyses.
Results: We identified 12,344 incident cases of lupus nephritis ESRD. Mean age at ESRD onset was 41 years; 81.6% of the patients were women and 49.5% were African American. SIRs for lupus nephritis ESRD among those who were ages 5–39 years, African American, or lived in the southeastern U.S. increased significantly from 1995 to 2006. Increases in body mass index and in the prevalence of both diabetes mellitus and hypertension were detected. Mean serum hemoglobin level at ESRD onset increased, while that of serum creatinine decreased over time. More patients received hemodialysis and fewer received peritoneal dialysis. There was a slight increase in the frequency of preemptive kidney transplantation at ESRD onset, but kidney transplantation rates within the first 3 years of ESRD declined. Mortality did not change over the 12 years of study.
Conclusion: Our findings indicate that the characteristics of patients with lupus nephritis ESRD and initial therapies have changed in recent years. While SIRs rose in younger patients, among African Americans, and in the South, outcomes did not improve in over a decade of evaluation.
Activation-induced deaminase–deficient MRL/lpr mice secrete high levels of protective antibodies against lupus nephritis. (Arthritis Rheum. 2011;63:1086-1096.)
Objective: We previously generated MRL/lpr mice deficient in activation-induced deaminase (AID) that lack isotype switching and immunoglobulin hypermutation. These mice have high levels of unmutated (germline) autoreactive IgM, yet they experienced an increase in survival and an improvement in lupus nephritis that exceeded that of MRL/lpr mice lacking IgG. The purpose of the present study was to test the hypothesis that high levels of germline autoreactive IgM in these mice confer protection against lupus nephritis.
Methods: Autoreactive IgM antibodies of various specificities, including antibodies against double-stranded DNA (dsDNA), from AID-deficient MRL/lpr mice were given to asymptomatic MRL/lpr mice, and the levels of cytokines, proteinuria, immune complex deposition in the kidneys, and glomerulonephritis were examined. Novel AID-deficient MRL/lpr mice that lack any antibodies were generated for comparison to AID-deficient MRL/lpr mice that secrete only IgM.
Results: Treatment with IgM anti-dsDNA resulted in a dramatic improvement in lupus nephritis. Other autoreactive IgM antibodies, such as antiphospholipid and anti-Sm, did not alter the pathologic changes. Secretion of proinflammatory cytokines by macrophages and the levels of inflammatory cells and apoptotic debris in the kidneys were lower in mice receiving IgM anti-dsDNA. Protective IgM derived from AID-deficient MRL/lpr mice displayed a distinct B-cell repertoire, with a bias toward members of the VH7183 family.
Conclusion: IgM anti-dsDNA protected MRL/lpr mice from lupus nephritis, likely by stopping the inflammatory cascade leading to kidney damage. A distinct repertoire of VH usage in IgM anti-dsDNA hybridomas from AID-deficient mice suggests that there is enrichment of a dedicated B-cell population that secretes unmutated protective IgM in these mice.
Heparin exerts a dual effect on murine lupus nephritis by enhancing enzymatic chromatin degradation and preventing chromatin binding in glomerular membranes. (Arthritis Rheum. 2011;63:1065-1075.)
Objective: Association of nucleosome–IgG immune complexes with glomerular basement membranes (GBMs) is an important event in the development of lupus nephritis. Preventing this binding and/or increasing nuclease sensitivity of nucleosomes may be viable strategies for the prevention of the disease. Theoretically, heparin may alter nucleosomal structure and increase sensitivity to proteinases and nucleases, and may also inhibit binding of nucleosomes and nucleosome–IgG complexes to basement membrane structures. The aim of this study was to investigate whether and eventually how heparin prevents murine lupus nephritis.
Methods: Surface plasmon resonance was used to analyze if heparin inhibits binding of nucleosomes to laminin and collagen. The effect of heparin on nuclease- and proteinase-mediated degradation of nucleosomes was analyzed by sodium dodecyl sulfate–polyacrylamide gel electrophoresis and agarose gel electrophoresis. In vitro results were compared with analyses in vivo in heparin-treated (NZB × NZW)F1 mice. Anti–double-stranded DNA antibody production, deposition of nucleosome–IgG complexes in GBMs, and development of proteinuria were monitored, and circulating chromatin fragments were quantified using quantitative polymerase chain reaction.
Results: In vitro studies demonstrated that heparin increased enzymatic degradation of nucleosomes and almost completely inhibited binding of nucleosomes to laminin and collagen. (NZB × NZW)F1 mice treated with heparin demonstrated delayed or no antibody production and higher variation of circulating chromatin levels compared with untreated control mice. This effect was accompanied by highly reduced nucleosome–IgG complexes in GBMs and delayed development of nephritis.
Conclusion: Increasing the degradation of nucleosomes, reducing their immunogenicity, and preventing binding of nucleosome–IgG complexes in glomeruli together provide an alternative basis for the treatment of lupus nephritis.
Alterations in Wnt pathway activity in mouse serum and kidneys during lupus development. (Arthritis Rheum. 2011;63:513-522.)
Objective: The canonical Wnt/β-catenin pathway was recently identified as a factor in the pathogenesis of several renal diseases. The aim of this study was to evaluate Wnt signaling activity during disease development in a murine model of lupus nephritis.
Methods: Wnt activity and Dkk-1 expression were serially assayed in the serum and kidneys of (NZB × NZW)F1 mice during progression of lupus nephritis. The effects of serum obtained from mice with lupus and serum-equivalent concentrations of Dkk-1 on mesangial cells were assessed in vitro.
Results: Gene expression analyses revealed increased canonical Wnt pathway activity in kidneys during development of lupus nephritis, paralleled by an increase in renal and serum levels of the Wnt inhibitor Dkk-1. Sera obtained from proteinuric-stage (NZB × NZW)F1 mice showed strong Wnt-inhibitory effects in vitro. Dkk-1 concentrations comparable to those observed in lupus-prone mice induced apoptosis in tubular and mesangial cells in vitro, whereas no such effect was seen for the range of concentrations observed in young prediseased mice and control BALB/c mice.
Conclusion: These data demonstrate that renal Wnt signaling activity is increased in lupus and is accompanied by an increase in renal and serum levels of Dkk-1. The Wnt pathway is involved in the turnover of extracellular matrix constituents and represents a potential mediator of the morphologic changes that occur within the glomerulus during the development of nephritis. Furthermore, increased levels of Dkk-1 serve as a potential proapoptotic stimulus in vitro and possibly in vivo and could be an important element in the initiation and progression of systemic and end-organ disease manifestations in systemic lupus erythematosus.
The NZM2410-derived lupus susceptibility locus Sle2c1 increases Th17 polarization and induces nephritis in fas-deficient mice. (Arthritis Rheum. 2011;63:764-774.)
Objective: Sle2 is a lupus susceptibility locus that has been linked to glomerulonephritis in the NZM2410 mouse. By itself, Sle2 does not induce any autoimmune pathology but results in the accumulation of B-1a cells. This study was designed to assess the contribution of Sle2 to the pathogenesis of autoimmunity.
Methods: Sle2 or its subcongenic intervals (Sle2a, Sle2b, and Sle2c1) were bred to Fas-deficient B6.lpr mice. Lymphoid phenotypes, which were focused on T cells, were assessed by flow cytometry, and histopathologic changes were compared between cohorts of B6.Sle2.lpr congenic mice and B6.lpr mice of ages up to 6 months.
Results: Sle2 synergized with lpr, resulting in a greatly accelerated lymphadenopathy that largely targeted T cells and mapped to the Sle2c1 locus. This locus has been identified as the main contributor to B-1a cell expansion. Further analyses showed that Sle2c1 expression skewed the differentiation and polarization of Fas-deficient T cells, with a reduction of the CD4+CD25+FoxP3+ regulatory T-cell subset and an expansion of the Th17 cells. This was associated with a high number of T-cell infiltrates that promoted severe nephritis and dermatitis in the B6.Sle2c1.lpr mice.
Conclusion: These results show that Sle2c1 contributes to lupus pathogenesis by affecting T-cell differentiation in combination with other susceptibility loci, such as lpr. The significance of the cosegregation of this phenotype and B-1a cell expansion in Sle2c1-expressing mice in relation to the pathogenesis of lupus is discussed.
The benefit of targeted and selective inhibition of the alternative complement pathway for modulating autoimmunity and renal disease in MRL/lpr mice. (Arthritis Rheum. 2011;63:1076-1085.)
Objective: Complement has both protective and pathogenic functions in lupus due to a balance between its role in the clearance of immune complexes (ICs) and apoptotic cells and its role in inflammation. The classical pathway contributes to IC and apoptotic cell clearance, whereas the alternative pathway is a key mediator of renal inflammation. The aim of this study was to investigate the effect of a new targeted inhibitor of the alternative pathway, CR2-fH, on lupus-like renal disease in MRL/lpr mice.
Methods: Mice were treated with either saline, CR2-fH, CR2-Crry (which inhibits all complement pathways), or soluble CR2 (sCR2; C3d-binding targeting vehicle). Sera were analyzed every 2 weeks for autoantibodies, circulating ICs, and C3. Urinary excretion of albumin was also determined, and kidneys were collected at 23 weeks for histologic evaluation.
Results: Treatment with CR2-fH or CR2-Crry improved survival and significantly reduced proteinuria, glomerular C3 deposition, and the level of circulating ICs. CR2-fH, but not CR2-Crry, also significantly reduced glomerulonephritis, expression of serum anti–double-stranded DNA (anti-dsDNA) antibodies, and glomerular IgG and C1q deposition. Interestingly, sCR2 also significantly reduced the levels of anti-dsDNA antibodies and circulating ICs and reduced glomerular deposition of IgG, C1q, and C3, although there was no significant reduction in glomerulonephritis, proteinuria, or mortality.
Conclusion: Targeted and selective inhibition of the alternative complement pathway is an effective treatment of murine lupus and is more effective than blockade of all pathways. The data demonstrate benefits to leaving the classical/lectin pathways intact and indicate distinct roles for the classical and alternative pathways of complement in disease progression. The sCR2-targeting vehicle contributes to therapeutic activity, possibly via modulation of autoimmunity.
Premature cardiovascular disease in patients with systemic lupus erythematosus influences survival after renal transplantation. (Arthritis Rheum. 2011;63:733-737.)
Objective: To assess graft and patient survival as well as causes for graft loss and patient death after renal transplantation in patients with systemic lupus erythematosus (SLE).
Methods: Eighty-seven renal transplantations were performed in 77 patients with SLE from 1972 to 2005. Each recipient with SLE was matched (for date of transplant, age, donor source [living versus deceased], and sex) with 2 renal graft recipients who had non-SLE glomerulonephritis, and the SLE and non-SLE groups were compared with regard to graft survival and patient survival.
Results: The mean ± SD age of SLE patients at the time of transplantation was 37.4 ± 12.8 years, and the majority of SLE patients were female (80.5%). SLE patients were well matched to control transplant patients for date of transplant, age, and donor source (living versus deceased donor). The death-censored graft survival rate for SLE patients receiving transplants corresponded closely to that for the control groups; the 1-, 5-, and 10-year graft survival rates were 88%, 81%, and 71%, respectively, for SLE patients, and 91%, 83%, and 74%, respectively, for patients with non-SLE glomerulonephritis (P=0.31). Patient survival differed significantly; the rates of survival for recipients with SLE were 94%, 83%, and 71% at 1, 5, and 10 years, respectively. The corresponding rates of patient survival in the non-SLE glomerulonephritis cohort were 96%, 92%, and 85% (P=0.018). Cardiovascular events were the most prominent cause of death in SLE patients (66.7%, versus 39.5% in the control group; P=0.03).
Conclusion: Transplant patients with SLE have a graft survival rate that matches that of recipients with non-SLE glomerulonephritis. SLE patients who receive transplants have a lower survival rate than control patients. The excessive mortality in SLE is attributed to a greater number of cardiovascular deaths.