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Adalid-Peralta, L., A. Mathian, et al. (2008). "Leukocytes and the kidney contribute to interstitial inflammation in lupus nephritis." Kidney Int 73(2): 172-80.
Interstitial leucocyte infiltration, a prominent feature of lupus nephritis, predicts deterioration of renal function. We used two models of lupus nephritis in mice, one with chronic spontaneous disease and the other with acute interferon-alpha (IFN alpha)-mediated disease. The latter is characterized by the virtual absence of interstitial infiltration. In vivo migration assays showed that splenic leukocytes from spontaneously nephritic mice tended to migrate into non-inflamed syngeneic kidneys. This was enhanced if the recipient kidneys were already inflamed. Kidneys from both chronical y and acutely nephritic mice showed similar ability to recruit splenic leukocytes from chronical y diseased mice. Leukocytes from acutely diseased mice, however, failed to migrate into chronical y inflamed kidney. Compared with those with chronic nephritis, the kidneys of acute nephritic mice expressed less of the inflammatory chemokine CXCL13/BLC. Moreover, leukocytes from acute nephritic mice displayed impaired migration, in vitro, to T-cel chemokine attractants. This study links leukocyte infiltration to both kidney chemokine expression, and leukocyte chemotaxis to kidney-expressed Ataei, N., M. Haydarpour, et al. (2008). "Outcome of lupus nephritis in Iranian children: prognostic significance of certain features." Pediatr Nephrol 23(5): 749-755.
The objective of this study was to determine the clinical and histopathological features and outcome of children with lupus nephritis (LN). Of 84 children with systemic lupus erythematosus (SLE), we retrospectively studied 58 children (69%) under 15 years of age with biopsy-proven LN who had been fol owed between October 1989 and January 2005. The mean age at diagnosis or initial referral was 10.6 +/- 2.25 years, and the mean fol ow-up was 5.3 +/- 4.1 years. Class IV LN was observed in 34 (58.6%) patients. The 5-year patient and renal survival rates were 82.5 and 78.5%, respectively, in the total group, and 75 and 85.8%, respectively, in patients with Class IV LN. No independent predictor of unfavorable outcome, including renal histology, was detected by multivariate analysis. The mid-term patient and the renal survival rates of Iranian children with biopsy-proven LN are high. Within 5 years of fol ow-up, renal histology was not a predictor for survival.
Bendiksen, S., E. S. Mortensen, et al. (2008). "Glomerular expression of large polyomavirus T antigen in binary tet-off regulated transgenic mice induces apoptosis, release of chromatin and initiates a lupus-like nephritis." Mol Immunol 45(3): 728-39.
Binary tetracycline-regulated polyomavirus large T antigen transgenic mice were generated to study immunological tolerance for nucleosomes. Expression of T antigen resulted in binding of the protein to chromatin, and released T antigen-nucleosome complexes from dying cel s maintained anti-dsDNA and anti-nucleosome antibody-production by activating autoimmune nucleosome-specific B cel s and CD4+ and CD8+ T antigen specific T cel s. Glomerular T antigen expression was observed in these mice. Here, we demonstrate that this expression was linked to glomerular cel apoptosis, release of nucleosomes and association of nucleosomes with glomerulus basement membranes, detected as electron dense structures.
Immune electron microscopy (IEM) revealed that these structures were glomerular targets for induced anti-dsDNA and anti-T antigen antibodies. Co-localization IEM demonstrated that in vivo-bound auto-antibodies co-localized with experimental monoclonal antibodies to dsDNA and to T antigen. A comparative analysis of glomeruli from nephritic (NZWxNZB)F1 and T antigen expressing transgenic mice revealed deposition of nucleosomes in glomerular capil ary and mesangial matrix membranes and binding of anti-nucleosome antibodies in both mice strains. A control ed experimental model that may elucidate the initial events accounting for nucleosome-mediated nephritis has not been available. The transgenic mouse may be important to describe early immunological and cel ular events accounting for the enigmatic Bhat, P. and J. Radhakrishnan (2008). "B lymphocytes and lupus nephritis: new insights into pathogenesis and targeted therapies." Kidney Int 73(3): 261-8.
Lupus nephritis (LN) in systemic lupus erythematosus (SLE) remains a major cause of morbidity and end-stage renal disease. While therapies such as corticosteroids, cyclophosphamide, and mycophenolate mofetil have improved outcomes, a significant proportion of patients have refractory disease or are unable to tolerate these agents.
Limitations in existing therapies, along with advances in our understanding of the immunopathogenesis of SLE, have resulted in the development of new immunosuppressive and immunomodulatory treatments for SLE/LN. Dysfunction of the B lymphocyte-an important component of adaptive immunity-is thought to be important in the pathogenesis of SLE/LN.
The goal of this study is to review our current understanding of the role of B cel s in the pathogenesis of SLE, and to discuss new and emerging therapies that selectively target B cel s in patients with SLE/LN. Novel strategies discussed include B-cel depletion by the monoclonal antibodies to B-cel markers, rituximab and epratuzumab; 'pharmapheresis' of pathogenic antibodies to dsDNA, by abetimus; blockade of T-cel costimulation of B cel s by abatacept, belatacept, BG9588, and IDEC-131; and blockade of B-cel stimulation by belimumab. Preliminary results are promising, but in the absence of large control ed trials, caution must be exercised prior to the widespread use and acceptance of these treatments.
Bigler, C., M. Lopez-Trascasa, et al. (2008). "Antinucleosome antibodies as a marker of active proliferative lupus nephritis." Am J Kidney Dis 51(4): 624-9.
BACKGROUND: Antinucleosome autoantibodies were previously described to be a marker of active lupus nephritis. However, the true prevalence of antinucleosome antibodies at the time of active proliferative lupus nephritis has not been wel established. Therefore, the aim of this study is to define the prevalence and diagnostic value of autoantibodies against nucleosomes as a marker for active proliferative lupus nephritis. STUDY DESIGN: Prospective multicenter diagnostic test study. SETTING & PARTICIPANTS: 35 adult patients with systemic lupus erythematosus (SLE) at the time of the renal biopsy showing active class III or IV lupus nephritis compared with 59 control patients with SLE. INDEX TEST: Levels of antinucleosome antibodies and anti-double-stranded DNA (anti-dsDNA) antibodies.
REFERENCE TEST: Kidney biopsy findings of class III or IV lupus nephritis at the time of sampling in a study population versus clinical y inactive or no nephritis in a control population.
RESULTS: Increased concentrations of antinucleosome antibodies were found in 31 of 35 patients (89%) with active proliferative lupus nephritis compared with 47 of 59 control patients (80%) with SLE. No significant difference between the 2 groups with regard to number of positive patients (P = 0.2) or antibody concentrations (P = 0.2) could be found. The area under the receiver operating characteristic curve as a marker of the accuracy of the test in discriminating between proliferative lupus nephritis and inactive/no nephritis in patients with SLE was 0.581 (95% confidence interval, 0.47 to 0.70; P = 0.2). Increased concentrations of anti-dsDNA antibodies were found in 33 of 35 patients (94.3%) with active proliferative lupus nephritis compared with 49 of 58 control patients (84.5%) with SLE (P = 0.2). In patients with proliferative lupus nephritis, significantly higher titers of anti-dsDNA antibodies were detected compared with control patients with SLE (P < 0.001). The area under the receiver operating characteristic curve in discriminating between proliferative lupus nephritis and inactive/no nephritis in patients with SLE was 0.710 (95% confidence interval, 0.60 to 0.82; P < 0.001).
CONCLUSIONS: Antinucleosome antibodies have a high prevalence in patients with severe lupus nephritis. However, our data suggest that determining antinucleosome antibodies is of limited help in the distinction of patients with active proliferative lupus nephritis from patients with SLE without active renal disease.
Chen, Y. E., S. M. Korbet, et al. (2008). "Value of a complete or partial remission in severe lupus nephritis." Clin J Am Soc Nephrol 3(1): 46-53.
BACKGROUND AND OBJECTIVES: The value of a complete remission in severe lupus nephritis is wel known but little is known about the impact of a partial remission in this patient population. The purpose of this study was to evaluate the long-term prognosis of achieving a complete or partial remission in a wel -defined group of patients with severe lupus nephritis.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this study, 86 patients with diffuse lupus glomerulonephritis were reviewed for assessment of the value of a partial remission (50% reduction in baseline proteinuria to < or =1.5 g/d and < or =25% increase in baseline creatinine) and complete remission (proteinuria < or =0.33 g/d and serum creatinine < or =1.4 mg/dl) on outcomes compared with patients who did not attain a remission. These wel -characterized patients were entered into a prospective therapeutic trial conducted by the Col aborative Study Group and were fol owed for more than 10 yr. RESULTS: Al biopsies showed diffuse lupus nephritis. A complete remission was attained in 37 (43%) patients, a partial remission in 21 (24%) patients, and no remission in 28 (32%) patients. Baseline clinical and serologic features were similar among the groups, but patients with a complete remission had a lower serum creatinine and chronicity index compared with patients with partial or no remission. The patient survival at 10 yr was 95% for complete remission, 76% for partial remission, and 46% for no remission. The renal survival at 10 yr was 94% for complete remission, 45% for partial remission, and 19% for no remission, and the patient survival without end-stage renal disease at 10 yr was 92% for complete remission, 43% for partial remission, and 13% for no remission. CONCLUSION: Even a partial remission in lupus nephritis is associated with a significantly better patient and renal survival compared with no Choojitarom, K., O. Verasertniyom, et al. (2008). "Lupus nephritis and Raynaud's phenomenon are significant risk factors for vascular thrombosis in SLE patients with positive antiphospholipid antibodies." Clin Rheumatol 27(3): 345-51.
This study is aimed to determine the predictors of nongravid vascular thrombosis in systemic lupus erythematosus (SLE) patients with positive antiphospholipid antibodies (SLE-aPL). A cohort of 67 SLE-aPL patients who had at least one positive test for lupus anticoagulant (LA), anticardiolipin (aCL), or anti-beta2glycoprotein-1(B2) was examined. Main outcome was the presence of vascular thrombosis. Association between thrombosis and risk factors was examined by contingency table. The odds ratio (OR) of significant predictors was determined by logistic regression. Three percent of patients were LA(+), 6% were aCL(+), 31% were B2(+), 3% were aCL(+)LA(+), 35.8% were aCL(+)B2(+), 7.5% were LA(+)B2(+), and 13.4% were positive for al tests. As for clinical manifestations, 79% had lymphopenia, 76% had lupus nephritis (LN), 41.8% had autoimmune hemolytic anemia, 34.3% had thrombocytopenia, 20.9% had abortion, and 19.4% had Raynaud's phenomenon (RP).
Thrombosis occurred in 26 patients. The prevalence of thrombosis for SLE-aPL was 38.8%.
Thrombosis was observed more frequently in patients with LA(+) (12 of 18) than the others (14 of 49; p = 0.01). Two-by-two table showed that oral contraceptive and LN were significantly associated with increased risk of thrombosis, while lymphopenia and antimalarials were significantly associated with decreased risk of thrombosis. Multivariate analysis confirmed that LN and RP were associated with increased risk of thrombosis (OR = 6.2 and 3.2; p = 0.005 and 0.008), while lymphopenia and antimalarials were associated with decreased risk of thrombosis (OR = 0.86 and 0.18; p = 0.02 and 0.034). LA is the strongest test to determine the risk of thrombosis in SLE-aPL. The presence of LN and RP strongly predicts thrombosis, while lymphopenia and antimalarials are protective. These findings help to identify patients who may benefit from prophylactic therapy.
Chrysochou, C., H. Randhawa, et al. (2008). "Determinants of renal functional outcome in lupus nephritis: a single centre retrospective study." Qjm 101(4): 313-6.
BACKGROUND: Lupus nephritis (LN) is a rare disease but is the strongest predictor of poor outcome in patients with Systemic Lupus Erythematosis (SLE). It is associated with significant morbidity, with 10-20% of patients developing end stage renal failure. As there is a paucity of randomized clinical trial data in LN, and no consistent literature regarding baseline factors that predict renal outcome, we were prompted to analyse our centre's complete experience of managing LN. METHODS: A retrospective analysis was undertaken of al patients presenting to our renal centre with biopsy proven LN from 1979-2003. Patients were divided into two categories, those with stable or deteriorating renal function over time.
Baseline parameters were correlated with renal outcome. RESULTS: Complete clinical records were available for 45 (40 female) patients. Mean (SD) age of onset of SLE was 32 +/- 14 years, and mean age onset of LN was 36 +/- 13 years. Patients were fol owed up for an average of 74 +/- 56 months. Four patients (9%) had WHO Class II LN, 11 (24%) WHO Class III and there were 15 (33%) each in Class IV and V, respectively on renal biopsy. Five (11%) patients presented with acute renal failure and al had proliferative changes on biopsy.
The chief arbiters of renal functional deterioration over fol ow up were longer time to development of LN (P = 0.04), a high platelet count and worse baseline renal function (both P = 0.05). There was a trend relating low haemoglobin or membranous histology to poor renal outcome, and Class IV histology to better outcome. CONCLUSION: The study has identified that longer time to development of LN, high platelet count and poorer renal function at baseline suggest a worse renal outcome in LN. The study was smal but LN is a rare condition. A combination of factors is likely to influence renal outcome in LN and larger prospective trials are required to ascertain consistent baseline prognostic markers.
Du, Y., Y. Fu, et al. (2008). "Experimental anti-GBM nephritis as an analytical tool for studying spontaneous lupus nephritis." Arch Immunol Ther Exp (Warsz) 56(1): 31-40.
Systemic lupus erythematosus (SLE) is an autoimmune disease that results in immune-mediated damage to multiple organs. Among these, kidney involvement is the most common and fatal. Spontaneous lupus nephritis (SLN) in mouse models has provided valuable insights into the underlying mechanisms of human lupus nephritis. However, SLN in mouse models takes 6-12 months to manifest; hence there is clearly the need for a mouse model that can be used to unveil the pathogenic processes that lead to immune nephritis over a shorter time frame. In this article more than 25 different molecules are reviewed that have been studied both in the anti-glomerular basement membrane (anti-GBM) model and in SLN and it was found that these molecules influence both diseases in a paral el fashion, suggesting that the two disease settings share common molecular mechanisms. Based on these observations, the authors believe the experimental anti-GBM disease model might be one of the best tools currently available for uncovering the downstream molecular Ghafari, A., J. Etemadi, et al. (2008). "Renal transplantation in patients with lupus nephritis: a single-center experience." Transplant Proc 40(1): 143-4.
BACKGROUND: Few data are available about the long-term outcome of renal transplantation in patients with systemic lupus erythematosus (SLE). METHODS: We retrospectively studied al lupus nephritis patients who received kidney al ografts in our center between June 1989 and 2006. Patient and al ograft outcomes were compared with those of 60 controls.
RESULTS: Mean fol ow-up after renal transplantation was 87 +/- 39 months for patients with lupus and 88 +/- 54 months for controls. Actuarial 10-year patient (83% vs 85%; P = .62) and death-censored graft survival rates (73% vs 69%; P = .36) were not significantly different between lupus patients and controls. Intravascular thrombotic events occurred in 4 patients with SLE (17.4%) and 3 controls (5%; P < .05). Recurrence of lupus nephritis was documented in 1 renal al ograft (4.3%). CONCLUSION: Long-term patient and graft survivals were similar in SLE and non-SLE renal transplant recipients. The risk for thrombotic complications was greater among SLE patients.
Grootscholten, C., I. M. Bajema, et al. (2008). "Interobserver agreement of scoring of histopathological characteristics and classification of lupus nephritis." Nephrol Dial Transplant 23(1):
223-30. BACKGROUND: Assessing renal biopsies from patients with lupus nephritis (LN) is a difficult task and it is subject to interobserver variability. In this study the interobserver agreement amongst five nephropathologists was analysed. METHODS: Five specialized nephropathologists scored 126 biopsies, comprising 87 first and 39 repeat biopsies from 87 patients with biopsy-proven proliferative LN, included in a randomized control ed trial. The interobserver agreement [expressed as intraclass correlation coefficients (ICC)] of the scored histopathological items was calculated. Also, the WHO1995 and ISN/RPS2003 classification systems for LN were compared, with extra attention being given to the comparison between patients with diffuse proliferative LN with either segmental (IV-S) or global (IV-G) lesions.
RESULTS: There was a wide range of agreement. A good interobserver agreement (ICC>0.6) was present in 15%, and a moderate interobserver agreement (ICC 0.4-0.6) in 31% of the scored items. The activity index for LN showed a good (ICC 0.716) and the chronicity index a moderate (ICC 0.494) interobserver agreement. Both classification systems showed low agreement, although consensus was easily reached. Patients classified as IV-S (n=15) had more favorable clinical parameters at study entry than those with class IV-G (n=57). Although suggested by others, we found no differences in outcome between these two subclasses. CONCLUSIONS: This study shows that, although definitions were agreed upon beforehand, even specialized on nephropathologists have difficulties with scoring histopathological characteristics of LN, particularly with SLE the classification systems.
Kal enberg, C. G. and M. Bijl (2008). "Why rheumatologists should be involved in the treatment of lupus nephritis." Nat Clin Pract Nephrol 4(2): 60-1.
Kasitanon, N., M. Petri, et al. (2008). "Mycophenolate mofetil as the primary treatment of membranous lupus nephritis with and without concurrent proliferative disease: a retrospective study of 29 cases." Lupus 17(1): 40-5.
Studies of immunosuppressive therapy, particularly mycophenolate mofetil (MMF), in membranous lupus nephritis (MLN) are limited. We report on our experience with primary (first-line) MMF therapy to induce and sustain renal remission in MLN with and without a concurrent proliferative lesion. Systemic lupus erythematosus (SLE) patients were studied, retrospectively, if treated with MMF for newly diagnosed MLN. Complete remission was defined as proteinuria less than 0.5 g/24 h, inactive urine sediment and normal estimated glomerular filtration rate. Response in pure MLN (Group I, n=10) was compared with mixed MLN and proliferative lupus nephritis (Group II, n=19). By 12 months, 4 (40%) patients in Group I and 7 (36.8%) in Group II achieved complete remission (P=0.87). One (10%) patient in Group I and 2 (10.5%) in Group II had worsening renal disease (P=0.97). Mean time to remission was more than seven months in both groups. The remaining patients had stable disease without improvement or worsening. Only 2 of 11 achieving initial remission had a relapse with an average of 28 months of fol ow-up after remission. Self-limited gastrointestinal symptoms occurred in 12 patients, none requiring withdrawal of the drug.
Mycophenolate mofetil as a primary therapy in MLN was successful in inducing complete remission in about 40% of MLN, particularly in patients with mild proteinuria. However, 12 months of therapy was necessary for best outcomes. Response rate was not different in the presence or absence of a proliferative lesion.
Kazderova, M., E. Jancova, et al. (2008). "Mycophenolate mofetil in low doses stabilizes and improves antineutrophil cytoplasmic antibody-associated vasculitis and lupus nephritis." Arch Med Res 39(1): 115-9.
BACKGROUND: Clinical experience with mycophenolate mofetil (MMF) in glomerulonephritis stil remains limited. METHODS: In order to assess the experience of one center with the efficacy and tolerability of MMF in patients with glomerulonephritis, we performed a retrospective 6-year analysis of 68 patients treated by MMF for glomerular disease, mainly anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV: n=34) and systemic lupus erythematosus and lupus nephritis (SLE: n=24). Indications were maintenance treatment in 40% of patients, induction treatment in patients not tolerating cyclophosphamide in 27%, and disease relapse in 33%. Mean treatment duration was 11.5 months. RESULTS: Efficacy endpoints were serum creatinine, urinary protein excretion, and steroid dose. In AAV patients, MMF was associated with significant improvement in 18%, partial improvement in 26%, stabilization in 29%, and disease progression in 12%; adverse event dropouts total ed 15%.
In SLE, the respective figures were 30, 22, 9, and 22%, with 17% adverse event dropouts.
The most frequent side effects were gastrointestinal events (n=7) and infections (n=3). None was life-threatening and there were no deaths. CONCLUSIONS: MMF, in the relatively low doses used, was safe and effective, stabilizing or improving AAV in 73% of patients and SLE in 61%. Further prospective randomized control ed trials with MMF in renal vasculitis and lupus nephritis are clearly warranted.
Kim, Y. G., H. W. Kim, et al. (2008). "The difference between lupus nephritis class IV-G and IV-S in Koreans: focus on the response to cyclophosphamide induction treatment." Rheumatology (Oxford) 47(3): 311-4.
OBJECTIVES: To evaluate the response to induction therapy with intravenous (i.v.) cyclophosphamide (CYC) in Korean patients with class IV-G (diffuse global proliferative glomerulonephritis) and class IV-S (diffuse segmental proliferative glomerulonephritis) lupus nephritis (LN) according to the classification system of the International Society of Nephrology Renal Pathology Society (ISN/RPS). METHODS: Of the 52 patients with biopsy-proven diffuse proliferative LN, who had been treated with i.v. CYC over a 10-yr period, 42 had been treated with i.v. CYC (equal to or more than 500 mg) for 6 consecutive months and had biopsy specimens containing more than nine glomeruli. The renal pathology of these 42 patients was reclassified according to the International Society of Nephrology and the Renal Pathology Society 2003 classification, and their renal response rates and laboratory indices after induction therapy were analysed. RESULTS: Of the 42 patients assessed, 30 (71%) had IV-G and 12 (29%) had IV-S. Pre-treatment 24 h urinary protein was significantly higher and pre-treatment concentration of anti-dsDNA antibody was significantly lower in IV-G than in IV-S patients. Fol owing induction therapy, complete remission rates were significantly higher in patients with IV-S (67%, 8/12) than in patients with IV-G (33%, 10/30) LN. CONCLUSIONS: Class IV-G LN responded more poorly to induction therapy with i.v. CYC pulse than class Kitiyakara, C., V. Ophascharoensuk, et al. (2008). "Treatment of lupus nephritis and primary glomerulonephritis with enteric-coated mycophenolate sodium." Clin Nephrol 69(2): 90-101.
AIMS: Mycophenolate mofetil is an effective therapy for lupus nephritis (LN) and other glomerulonephritis (GN). However, gastrointestinal (GI) complications can limit its use.
Enteric-coated mycophenolate sodium (EC-MPS) has been designed to reduce GI adverse events, but it has not been ful y investigated in the treatment of GN. METHODS: Patients with LN and primary GN who had received EC-MPS were studied for effects on renal function.
RESULTS: 30 subjects (17 LN, 13 primary GN) were studied. EC-MPS decreased proteinuria in both LN and GN. In LN, 16 patients had EC-MPS as induction therapy. Of these, 8 patients achieved complete remission (CR), 4 had partial remission (PR) and 1 improved renal function. In primary GN, CR was achieved in 4 out of 5 with minimal change disease, but only 1 did not relapse. PR was achieved in 1 of 4 patients with membranous glomerulopathy, 2 out of 2 patients with focal segmental glomerulosclerosis and 1 out of 2 patients with IgA nephropathy. Infections, anemia and alopecia were observed, but no patient had GI side effects. CONCLUSIONS: EC-MPS is effective in LN, but not as effective in primary GN. The risk of GI side effects appears to be low, but other side effects can stil occur.
Masuda, T., T. Akimoto, et al. (2008). "Changes in the urinary excretion of beta2-microglobulin (beta 2MG) and N-acetyl-beta-D-glucosaminidase (NAG) during treatment for lupus nephritis." Intern Med 47(4): 287-90.
Tubulointerstitial involvement in the kidneys is frequently found but it is a less emphasized feature of lupus nephritis (LN). Recent studies have shown increases in the urinary excretion of beta2-microglobulin (beta 2MG) and N-acetyl-beta-D-glucosaminidase (NAG), which are considered to indicate the presence of tubulointerstitial damage, particularly in cases of LN.
However, the changes in these urinary parameters during the clinical course of LN have not yet been ful y clarified. In this report, we describe the changes in the urinary excretion of beta 2MG and NAG during immunosuppressive treatment combined with double filtration Mok, C. C. (2008). "Who should treat lupus nephritis: rheumatologists or nephrologists?" Nat Clin Pract Nephrol 4(2): E1.
Monrad, S. U., P. D. Kil en, et al. (2008). "The role of aldosterone blockade in murine lupus nephritis." Arthritis Res Ther 10(1): R5.
ABSTRACT: BACKGROUND: The purpose of this study was to examine the effect of aldosterone receptor blockade on the immunopathogenesis and progression of nephritis in the (NZB x NZW) F1 murine lupus model. METHODS: Female NZB/W F1 mice (11 weeks old) were treated daily with 25 or 50 mg/kg oral spironolactone or vehicle. Proteinuria, renal function, and serum autoantibody levels were monitored. Renal histopathology, immune complex deposition, and immunohistochemistry were analyzed at various time points.
Targeted microarray analysis was performed on renal tissue, with subsequent real-time PCR analysis of several differential y expressed genes. RESULTS: Treatment with spironolactone was wel tolerated by the mice throughout the course of their disease progression, with no significant differences in azotemia or serum potassium levels between vehicle-treated and spironolactone-treated animals. By 36 weeks of age, fewer spironolactone-treated mice developed nephrotic range proteinuria as compared with the control mice (control 70.8%, 25 mg/kg spironolactone 51.3%, and 50 mg/kg spironolactone 48.6%). Compared with control mice, mice treated with 25 mg/kg spironolactone had significantly lower serum anti-single-stranded DNA levels (2,042 mug/ml versus 1,036 mug/ml; P = 0.03) and anti-double-stranded DNA levels (3,433 mug/ml versus 614 mug/ml; P = 0.05).
Spironolactone-treated mice exhibited decreased histopathologic evidence of inflammation and tissue damage, as compared with control mice. Additional y, spironolactone treatment resulted in decreased expression in the kidney of several inflammatory and proapoptotic genes, including those encoding interferon-gamma, B lymphocyte stimulator (BlyS), tumor necrosis factor related apoptosis inducing ligand (TRAIL), tumor necrosis factor related weak inducer of apoptosis (TWEAK), and Fas ligand. CONCLUSION: Aldosterone receptor blockade is safe and wel tolerated in progressive murine lupus nephritis, and it results in decreased levels of clinical proteinuria, lower serum levels of autoantibodies, and decreased kidney damage. It appears to modulate inflammatory changes during the progression of glomerulonephritis and may also have a previously undescribed role in attenuating apoptosis.
Mortensen, E. S., K. A. Fenton, et al. (2008). "Lupus nephritis: the central role of nucleosomes revealed." Am J Pathol 172(2): 275-83.
Systemic lupus erythematosus (SLE) is an autoimmune syndrome characterized by autoantibodies to nuclear constituents. Some of these antibodies are diagnostical y important, whereas others act as disease-modifying factors. One clinical y important factor is autoantibodies against dsDNA and nucleosomes, which have overlapping diagnostic and nephritogenic impact in SLE. Although a scientific focus for 5 decades, the molecular and cel ular origin of these antibodies, and why they are associated with lupus nephritis, is stil not ful y understood. A consensus has, however, evolved that antibodies to dsDNA and nucleosomes are central pathogenic factors in the development of lupus nephritis. In contrast, no agreement has been reached as to which glomerular structures are bound by nephritogenic anti-nucleosome antibodies in vivo. Mutual y contradictory paradigms and models have evolved simply because we stil lack precise and conclusive data to provide definitive insight into how autoantibodies induce lupus nephritis and which specificity is critical in the nephritic process(es). In this review, data demonstrating the central role of nucleosomes in inducing and binding potential y nephritogenic antibodies to DNA and nucleosomes are presented and discussed. These autoimmune-inducing processes are discussed in the context of Matzinger's danger model (Matzinger P: Friendly and dangerous signals: is the tissue in control? Nat Immunol 2007, 8:11-13; Matzinger P: The danger model: a renewed sense of self. Science 2002, 296:301-305; Matzinger P: Tolerance, danger, and the extended family. Annu Rev Immunol 1994, 12:991-1045) and Medzhitov's and Janeway's (Medzhitov R, Janeway CA Jr: Decoding the patterns of self and nonself by the innate immune system. Science 2002, 296:298-300; Medzhitov R, Janeway CA Jr: How does the immune system distinguish self from nonself? Semin Immunol 2000, 12:185-188; Janeway CA Jr, Medzhitov R: Innate immune recognition. Annu Rev Immunol 2002, 20:197-216) distinction of noninfectious self (NIS) and infectious nonself (INS). The mechanisms leading to production of potential y nephritogenic anti-nucleosome antibodies and to overt lupus nephritis are interpreted in the context of these paradigms.
Nasr, S. H., V. D. D'Agati, et al. (2008). "Necrotizing and Crescentic Lupus Nephritis with Antineutrophil Cytoplasmic Antibody Seropositivity." Clin J Am Soc Nephrol.
BACKGROUND AND OBJECTIVES: Lupus nephritis is a classic immune complex glomerulonephritis. In contrast, antineutrophil cytoplasmic antibodies are associated with necrotizing and crescentic glomerulonephritis, in the absence of significant immune deposits.
Antineutrophil cytoplasmic antibodies are detected by indirect immunofluorescence in 20% of patients with systemic lupus erythematosus. We report 10 cases of necrotizing and crescentic lupus nephritis with antineutrophil cytoplasmic antibody seropositivity. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Ten patients with systemic lupus erythematosus, antineutrophil cytoplasmic antibody positivity, and renal biopsy findings of lupus nephritis and antineutrophil cytoplasmic antibody-associated glomerulonephritis were identified. The clinical features, pathologic findings, and outcomes are described. RESULTS: The cohort consisted of eight women and two men with a mean age of 48.4 yr. Perinuclear antineutrophil cytoplasmic antibody was detected by indirect immunofluorescence in nine patients. Four of the nine patients and the single remaining patient were found to have myeloperoxidase-antineutrophil cytoplasmic antibodies by enzyme-linked immunosorbent assay. Clinical presentation included proteinuria, hematuria, and acute renal insufficiency, with mean creatinine of 7.1 mg/dl. Al biopsies exhibited prominent necrosis and crescents with absent or rare subendothelial deposits and were interpreted as lupus nephritis and antineutrophil cytoplasmic antibody-associated glomerulonephritis. Al patients received cyclophosphamide and prednisone. Three patients died of infectious complications. Among the remaining seven patients, five achieved a complete or near-complete remission, one had a remission with subsequent relapse, and one had no response to therapy. CONCLUSION: Antineutrophil cytoplasmic antibody-associated necrotizing and crescentic glomerulonephritis may occur superimposed on lupus nephritis. In patients with lupus nephritis and biopsy findings of prominent necrosis and crescent formation in the absence of significant endocapil ary proliferation or subendothelial deposits, antineutrophil cytoplasmic antibody testing by enzyme-linked immunosorbent assay is recommended.
Nezhad, S. T. and R. Sepaskhah (2008). "Correlation of clinical and pathological findings in patients with lupus nephritis: a five-year experience in iran." Saudi J Kidney Dis Transpl 19(1): 32-40.
Lupus nephritis (LN) is the most common and serious manifestation of systemic lupus erythematousus (SLE). The World Health Organization (WHO) and International Society of Nephrology/Renal Pathology Society (ISN/RPS 2003) classifications tend to correlate with the clinical syndrome and provide valuable information regarding prognosis and guideline for treatment. We retrospectively studied patients with biopsy proven lupus nephritis at our center from 1999 - 2003 to find whether clinical and laboratory parameters used to evaluate how close the diagnosis correlated with WHO and/ or ISN/RPS 2003 classification. There were 144 patients of whom 84.7 % were females with a mean age of 25.6 +/- 10.3 years at the time of renal biopsy. The most frequent SLE presenting features were arthralgia, edema and hypertension. WHO class IV and ISN/RPS class IV were compatible with these most frequent SLE presenting features in 56% and 54.9% of the cases, respectively. Edema, hypertension, increased BUN and Creatinine, increased 24 hours urine protein excretion and decreased serum albumin level were related with a worse class of lupus nephritis. We conclude that there is a correlation between some clinical and laboratory findings, and histopathological lupus classification on renal biopsy ,which remains indispensable in the Oates, J. C., S. R. Shaftman, et al. (2008). "Association of serum nitrate and nitrite levels with longitudinal assessments of disease activity and damage in systemic lupus erythematosus and lupus nephritis." Arthritis Rheum 58(1): 263-72.
OBJECTIVE: Reactive intermediate production is an essential component of the innate immune response that is induced during disease activity in murine lupus. This study was undertaken to determine whether a marker of systemic nitric oxide (NO) production correlates with prospectively studied disease activity in human systemic lupus erythematosus (SLE) and lupus nephritis patients. METHODS: Eighty-three SLE patients and 40 control subjects were studied longitudinal y. The SLE group included 23 patients with lupus nephritis documented by renal biopsy and 26 with a history of lupus nephritis. During each visit, fol owing a 24-hour low-nitrate diet, traditional markers of disease activity and damage were determined. Serum nitrate plus nitrite (NOx) levels were determined by chemiluminescence detection. RESULTS: NOx levels were higher in SLE patients than in controls during the first visit. In univariate longitudinal analyses, NOx levels were associated with SLE Disease Activity Index scores. In multivariate analyses, NOx levels were associated with serum levels of C3 and creatinine and the urinary protein:creatinine ratio. Among patients with lupus nephritis, those with proliferative lesions had higher NOx levels, and higher NOx levels were associated with accumulation of renal damage and lack of response to therapy. CONCLUSION: This is the first study to prospectively demonstrate longitudinal associations between serum NOx levels and markers of SLE and lupus nephritis disease activity. The more pronounced association with proliferative lupus nephritis and with longitudinal response to lupus nephritis therapy provides a rationale for the study of reactive intermediates as biomarkers of disease activity and therapeutic targets in proliferative lupus nephritis.
Rovin, B. H. (2008). "The chemokine network in systemic lupus erythematous nephritis." Front Biosci 13: 904-22.
In response to renal immune complex accumulation in systemic lupus erythematosus (SLE), monocytes, T lymphocytes, and neutrophils infiltrate the kidney and mediate tissue injury and renal dysfunction. Chemotactic factors induced by immune complexes are responsible for recruiting these inflammatory cel s to the kidney. Considerable attention has focused on the role of the chemokine network in regulating renal leukocyte recruitment in autoimmune glomerular diseases. In animal models of SLE nephritis, intervention studies directed at chemokines or chemokine receptors have provided definitive proof that specific chemokines are involved in the pathogenesis of renal inflammation. These same chemokines and chemokine receptors are expressed in the kidney during human SLE nephritis, and correlate with markers of renal injury and inflammation. This review wil describe and integrate the animal and human data to build a case for targeting the chemokine network as a novel approach to the treatment of SLE nephritis. Anti-chemokine therapies hold the promise of efficacy with fewer adverse side-effects than the non-specific immunosuppression regimens Rubinstein, T., M. Pitashny, et al. (2008). "The novel role of neutrophil gelatinase-B associated lipocalin (NGAL)/Lipocalin-2 as a biomarker for lupus nephritis." Autoimmun Rev 7(3): 229-34.
Lupus nephritis, a potential y devastating outcome of systemic lupus erythematosus (SLE), poses a real chal enge in the management of SLE patients because of the difficulty in diagnosing its onset and identifying relapses before serious renal damage has ensued.
Neutrophil gelatinase-B associated lipocalin (NGAL)/Lipocalin-2 has been implicated in the pathogenesis of several disease states in different organ systems, and especial y in kidney diseases. Lipocalin-2 may play a protective role in the context of renal insults through the induction or prevention of apoptosis by an iron-transport dependent mechanism. Clinical y, urinary Lipocalin-2 significantly correlates with measures of lupus nephritis disease activity, and may be an important and convenient marker for relapses.
Sabry, A., H. Abo-Zenah, et al. (2008). "A comparative study of two intensified pulse cyclophosphamide remission-inducing regimens for diffuse proliferative lupus nephritis: an Egyptian INTRODUCTION: Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that is usual y treated with an extended course of intravenous (IV) cyclophosphamide (CYC). Given the side effects of this regimen, we evaluated the short-term efficacy and toxicity of a course of low-dose remission-inducing IV CYC fol owed by azathioprine (AZA) in a prospective control ed study among Egyptian patients with severe LN.
PATIENTS AND METHODS: In this single center, prospective clinical trial, we assigned 46 SLE patients with diffuse proliferative glomerulonephritis to either a high-dose (a maximum of 1 g/dose) of IV CYC (HD-CYC) for six monthly pulses fol owed by two quarterly pulses or a fixed low-dose (500 mg/dose) of IV CYC (LD-CYC) for six fortnightly pulses with a cumulative dose of 3 g. Each regimen was fol owed by AZA. THE OBJECTIVE: To compare between efficacy, potential toxicity and outcome of parenteral LD-CYC versus HD-CYC therapy for severe LN. RESULTS: Twenty patients (2 male and 18 female) received fortnightly fixed LD-CYC while 26 (5 male and 21 female) received monthly HD-CYC therapy. At the end of the study (1 year after starting therapy), there was no difference either in patients' or in renal survival in both groups. Significant improvement of disease activity (SLE disease activity index) as wel as rise of serum albumin was noticed with both regimens. Renal relapse was observed in 11.5% of HD-CYC patients and in none of the LD-CYC therapy patients.
Treatment failure was seen in 5% and 3.4% (P = NS) of LD-CYC and HD-CYC patients, respectively. Infection (pneumonia and cel ulitis) occurred in five patients in the LD-CYC group and four patients of HD-CYC; again this difference was not statistical y significant.
CONCLUSION: A remission-inducing regimen of LD-CYC (cumulative dose 3 g) fol owed by AZA for SLE patients with proliferative LN achieves clinical results comparable to those obtained with HD-CYC without serious infection in both regimens.
Schieppati, A. and G. Remuzzi (2008). "Novel therapies of lupus nephritis." Curr Opin Nephrol Hypertens 17(2): 156-61.
PURPOSE OF REVIEW: To review the results of the current therapy of lupus nephritis, highlighting successes and pitfal s, and summarizing the evidence available on the new agents RECENT FINDINGS: The established treatment of lupus nephritis with aggressive immunosuppression, based on cyclophosphamide and steroids, has improved the outcome of lupus nephritis, but is burdened with significant adverse effects. The search for alternative, less toxic, therapeutic strategies has prompted a number of clinical studies, mycophenolate mofetil being the agent most studied. Results of trials showed that this drug is equal y effective with fewer toxic complications than standard therapy, but its long-term efficacy is not yet known. During the last few years experimental studies in the pathogenesis of lupus nephritis have provided an enormous improvement in our knowledge and have offered the possibility to attempt targeting the disease with a more selective approach. The evidence for the role of these new therapies is reviewed. SUMMARY: While the current alternative to standard therapy, i.e. mycophenolate mofetil, stil needs to be confirmed with wel designed, properly powered studies, new therapeutic agents, targeted to the pathogenetic mechanism of the disease, are promising improved efficacy with less toxicity.
Schiffer, L., R. Bethunaickan, et al. (2008). "Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis." J Immunol 180(3): 1938-47.
Costimulatory blockade with CTLA4Ig and anti-CD40L along with a single dose of cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F(1) mice. To understand the mechanisms for remission and for impending relapse, we examined the expression profiles of 61 inflammatory molecules in the perfused kidneys of treated mice and untreated mice at different stages of disease. Further studies using flow cytometry and immunohistochemistry al owed us to determine the cel ular origins of several key markers. We show that only a limited set of inflammatory mediators is expressed in the kidney fol owing glomerular immune complex deposition but before the onset of proteinuria.
Formation of a lymphoid aggregate in the renal pelvis precedes the invasion of the kidney by inflammatory cel s. Regulatory molecules are expressed early in the disease process and during remission but do not prevent the inevitable progression of active inflammation. Onset of proliferative glomerulonephritis and proteinuria is associated with activation of the renal endothelium, expression of chemokines that mediate glomerular cel infiltration, and infiltration by activated dendritic cel s and macrophages that migrate to different topographical areas of the kidney but express a similar profile of inflammatory cytokines. Increasing interstitial infiltration by macrophages and progressive tubular damage, manifested by production of lipocalin-2, occur later in the disease process. Studies of treated mice identify a type II (M2b)-activated macrophage as a marker of remission induction and impending relapse and suggest that therapy for systemic lupus erythematosus nephritis should include strategies that prevent both activation of monocytes and their migration to the kidney.
Seong, S. S., C. B. Choi, et al. (2008). "Effect of lower dose intravenous cyclophosphamide on remission induction in Korean patients with lupus nephritis." Rheumatol Int 28(5): 453-8.
This study retrospectively investigated the efficacy and adverse events of applying a lower dose (0.5 g/m(2)) of monthly intravenous (IV) cyclophosphamide (CYC) for lupus nephritis in Korean patients. Adverse events occurred in 64 patients (61.5%) of 104 lupus nephritis patients who were treated with IV CYC, with the most common being those related to the gastrointestinal system, fol owed by infection, symptoms related to the hematopoietic system, skin and its appendages, reproductive system, and urinary system. Lower-dose IV CYC therapy resulted in renal remission or response in 76 patients (73.1%), which was as effective as the reported outcomes of higher-dose (0.75-1.0 g/m(2)) IV CYC regimens. Adverse events were more likely (with borderline statistical significance, p = 0.055) in those who achieved renal remission or response than in nonresponders.
Siedner, M. J., A. C. Gelber, et al. (2008). "Diagnostic accuracy study of urine dipstick in relation to 24-hour measurement as a screening tool for proteinuria in lupus nephritis." J Rheumatol 35(1): 84-90.
OBJECTIVE: Early detection of renal involvement in lupus prevents poor outcomes. Although published guidelines recommend urine dipstick as an appropriate screening test and evidence suggests a majority of American rheumatologists use dipstick to screen for proteinuria, the performance of this diagnostic approach in lupus has not been reported. We examined the validity of qualitative urine dipstick versus quantitative 24-hour measurement to accurately detect proteinuria, including low-level proteinuria. METHODS: We performed a diagnostic accuracy study using paired samples from the Johns Hopkins University School of Medicine and the Ohio State University School of Medicine lupus cohorts. Al qualitative urine dipstick values were obtained within 1 day of a 24-hour urine col ection. RESULTS: We analyzed the performance of 3 urine dipstick assays to detect proteinuria compared to 24-hour protein/creatinine ratios, using 2224 dipstick measures from 296 patients. The sensitivity of a > or = 1+ dipstick result to detect quantitative proteinuria (> or = 0.50 g protein g creatinine) was 82.7% for the Clinitek, 97.7% for the Atlas, and 85.5% for the Bayer assay.
The corresponding sensitivity to detect low-level proteinuria, (0.50-0.99 g protein/g creatinine) was 63.1%, 96.4%, and 80.7%, respectively. The specificity to correctly exclude proteinuria (< 0.50 g protein/g creatinine) with negative/trace results was 86.1%, 62.2%, and 59.4%. There was considerable variability in the range of protein/creatinine ratios detected at each dipstick level of proteinuria. CONCLUSION: Urine dipsticks demonstrate substantial variability and often poor validity to accurately detect proteinuria at quantitative levels; this warrants further diagnostic evaluation. Clinicians should consider quantified proteinuria assays as a more accurate screening tool in the diagnostic evaluation of lupus nephritis.
Silva-Fernandez, L., J. L. Andreu-Sanchez, et al. (2008). "Current therapy of lupus nephritis. Which is the best option?" Rev Clin Esp 208(3): 138-41.
Renal involvement in systemic lupus erythematosus (SLE) is an important cause of morbidity and mortality, reaching a prevalence of 39% during the course of the disease. Currently, the therapy for severe lupus nephritis is based on the use of high-dose corticosteroids and immunosuppressive drugs, being traditional y cyclophosphamide the most frequently used agent. Recent studies have demonstrated the efficacy of mycophenolate mofetil as induction therapy for lupus nephritis. Azathioprine, a safe drug during pregnancy, has not been demonstrated to be as effective as mycophenolate or cyclophosphamide as induction therapy, although it is an effective drug for maintenance of remission.
Suzuki, M., K. M. Wiers, et al. (2008). "Neutrophil gelatinase-associated lipocalin as a biomarker of disease activity in pediatric lupus nephritis." Pediatr Nephrol 23(3): 403-412.
We hypothesized that neutrophil gelatinase-associated lipocalin (NGAL) is an early predictive biomarker of disease activity in lupus nephritis. NGAL in serial plasma (PNGAL) and urine (UNGAL) samples was measured by enzyme-linked immunosorbent assay (ELISA) in 85 participants with pediatric systemic lupus erythematosus (pSLE), healthy children (n = 50), and children with juvenile idiopathic arthritis (JIA) (n = 30). Disease activity was measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Plasma and urinary NGAL were significantly increased in subjects with pSLE compared with those with JIA or with healthy controls (al p < 0.03), and unrelated to subjects' age, weight, or height. Plasma and urinary NGAL were stable in pSLE subjects with unchanged disease activity. The pSLE subjects with worsening global or renal disease activity had a mean +/- standard error (SE) increase of UNGAL (in ng/ml) of 11.5 +/- 6.4 or 36.6 +/- 12.1 (p < 0.01), corresponding to a 156% or 380% increase, respectively. PNGAL increased with worsening disease but to a much lesser degree than UNGAL [global disease activity (mean +/- SE): 7.3 +/- 6.2 or 21%; renal disease activity: 20.2 +/- 6.0 or 51%; both p = not significant]. In conclusion, NGAL in urine but not in plasma represents a novel biomarker for renal disease activity in pSLE.
Sverzut, A. T., M. Al ais, et al. (2008). "Oral manifestation of systemic lupus erythematosus: lupus nephritis--report of a case." Gen Dent 56(1): 35-41.
Systemic lupus erythematosus (SLE) is a disease of unknown origin that can affect organs and cause severe damage. Lupus is diagnosed through biopsies and laboratory examinations; however, certain clinical characteristics and the presence of lesions can help with early diagnosis and improve the disease prognosis. SLE patients general y receive immunosuppressants that may cause systemic implications---such as suture dehiscence, increased risk of infection, and delayed healing--that deserve specific attention during dental treatment. This article presents a case of a SLE patient with oral manifestations: ulcerative lesions in the mouth and development of lupus nephritis. This article seeks to emphasize the importance of recognizing the lesions related to SLE, which may help the dentist to establish Tam, L. S. and C. C. Szeto (2008). "Are spot urine samples adequate for assessment of proteinuria in patients with lupus nephritis?" Nat Clin Pract Nephrol 4(2): 72-3.
Teramoto, K., N. Negoro, et al. (2008). "Microarray analysis of glomerular gene expression in murine lupus nephritis." J Pharmacol Sci 106(1): 56-67.
To elucidate the molecular mechanism of glomerular events in lupus nephritis, we performed genome-wide mRNA expression analysis of glomeruli microdissected from lupus mice. MRL lpr mice (12-week-old) were oral y given vehicle or prednisolone (10 mg/kg per day) for 4 weeks. Renal histology of MRL/lpr mice revealed mesangial proliferative glomerulonephritis with cel ular infiltration of macrophages, T cel s, and neutrophils. We identified 567 up-regulated genes in MRL/lpr glomeruli compared to control congenic mice. Those included complement components, adhesion molecules, chemokines and their receptors, and molecules related to antigen presentation. Over 130 genes were considered preferential y or exclusively expressed in hematopoietic cel lineages possibly reflecting leukocytes accumulation. Of note is the finding that chemokines and chemokine receptors (CCL3, CCL4, CCL5, CXCL9, CXCL10, CXCL11, CXCL16, CCR5, CXCR3, and CXCR6) that are related to T helper 1 (Th1) cel s accumulation were up-regulated concomitantly with increased expression of Ebi3, a subunit of IL-27 that plays a role in Th1 predominance. These changes were accompanied by increased mRNA expression of many genes that were inducible by Th1 cytokine interferon-gamma. Prednisolone markedly attenuated glomerular lesion and leukocyte influx paral el with the reduction of enhanced gene expression. The present study shows additional evidence supporting glomerular Th1 cel s accumulation and their role. Our data also provide an important resource in seeking new therapeutic targets to lupus nephritis.
Supplemental table: available only at
Tsubouchi, Y., W. Fukuda, et al. (2008). "A case of lupus nephritis improved after appropriately adjusting the dosage of mizoribine." Mod Rheumatol 18(1): 91-5.
A 29-year-old male presenting nephrotic syndrome and facial skin erythema was admitted to our hospital in September of 2000. We diagnosed him as having systemic lupus erythematosus (SLE) accompanied by lupus nephritis (WHO class V). The disease activity had decreased after treatment with methylprednisolone (m-PSL) pulse therapy, which was fol owed by oral PSL. Thereafter, when tapering the dosage from 60 to 30 mg/day, the lupus nephritis flared up and he was re-hospitalized in February of 2001. After successful retreatment with m-PSL pulse therapy fol owed by the tapering of the dosage from 60 to 30 mg/day, we used mizoribine (MZR) as a combination therapy. The lupus nephritis flared up again after tapering down to 17.5 mg/day of PSL. Then, we changed the MZR dosage from 150 mg/day in three divided daily doses to 200 mg/day in two divided daily doses. This modification increased the peak blood concentration (Cmax) of MZR from 0.63 to 1.55 mug ml. At present, we have been able to successful y taper the dosage to 7.5 mg/day of oral PSL and the patient has achieved a state of remission without any side effects. Monitoring of the serum concentration of MZR is thus considered to be important for achieving effective therapy of SLE, especial y for steroid-resistant lupus nephritis. If the serum concentration of MZR does not reach an effective level, then the dosage of MZR should be adjusted appropriately in order to maintain an adequate serum concentration of MZR.
Tucci, M., C. Quatraro, et al. (2008). "Glomerular accumulation of plasmacytoid dendritic cel s in active lupus nephritis: role of interleukin-18." Arthritis Rheum 58(1): 251-62.
OBJECTIVE: Defective circulating dendritic cel s (DCs) have been described in systemic lupus erythematosus (SLE) and correlated with high levels of interferon-alpha (IFNalpha).
DCs are differentiated as being either myeloid or plasmacytoid, according to chemokine expression and the tendency to migrate toward inflamed tissue. We investigated the potential role of interleukin-18 (IL-18) in driving the glomerular migration of DCs in lupus nephritis (LN) and in affecting the ability of DCs to induce an imbalance in the Th1:Th2 ratio. METHODS: DC subsets were characterized by flow cytometry and defined as either myeloid or plasmacytoid according to the expression of CD11c/blood dendritic cel antigen 1 (BDCA-1) and CD123/BDCA-2, respectively. The serum Th1:Th2 profile was studied by enzyme-linked immunosorbent assay. IL-18 receptor (IL-18R) and other chemokine receptors were analyzed by flow cytometry. Glomerular levels of IL-18/IL-18R and the presence of plasmacytoid DCs and myeloid DCs were investigated by immunohistochemical analysis. RESULTS: The number of peripheral plasmacytoid DCs was decreased in patients with SLE compared with control subjects, and this defect in the number of DCs was correlated with LN. Patients with LN showed a prevalent Th1 response, with high production of IL-18, IL-12 and IFNgamma.
Only plasmacytoid DCs expressed IL-18R. Patients with severe LN showed a high accumulation of IL-18 within glomeruli in association with the presence of plasmacytoid DCs, whereas myeloid DCs were almost absent. CONCLUSION: A deficient number of peripheral plasmacytoid DCs correlated with high levels of Th1 cytokines and was associated with LN.
Both serum and glomerular IL-18 were increased in LN. It is suggested that the high level of expression of IL-18R by peripheral plasmacytoid DCs al ows the DCs to relocate within glomeruli under IL-18 stimulation and triggers the resident T cel s, thus promoting renal Yao, G., Z. H. Liu, et al. (2008). "Evaluation of renal vascular lesions using circulating endothelial cel s in patients with lupus nephritis." Rheumatology (Oxford) 47(4): 432-6.
OBJECTIVE: Currently the detection of renal vascular lesions (VLS) mainly depends on biopsy examination, and lacks surrogate biomarkers for clinical dynamic evaluation. The aim of this study is to find the correlation between numbers of circulating endothelial cel s (CECs) and renal VLS in lupus nephritis (LN). METHODS: Thirty LN patients with VLS and 30 LN patients without VLS were recruited. Thirty age- and sex-matched healthy volunteers served as controls. CECs were isolated from peripheral blood with anti-CD-146-coated immunomagnetic Dynabeads and were counted under microscopy. Parameters of renal involvement, including blood urea nitrogen, serum creatinine, 24 h urine protein excretion and quantitative urine sedimentation were also measured. RESULTS: The number of CECs showed no difference between LN patients without VLS and controls. In patients with VLS, the number of CECs was significantly higher than those without VLS (P < 0.01). A strong positive correlation was found between CECs and serum creatinine (r = 0.503, P < 0.01) and mean blood pressure (r = 0.423, P < 0.05). In al LN patients with VLS, CEC number of the patients with thrombotic microangiopathy (TMA) significantly increased compared with those without TMA (P < 0.01). CONCLUSION: Numeration of CECs may serve as a potential and useful marker for vasculopathy in LN. Dynamic observations of CEC number can be used not only to provide evidence for monitoring disease severity and disease activity, but also to determine therapy efficacy in LN patients.
Yung, S. and T. M. Chan (2008). "Anti-DNA antibodies in the pathogenesis of lupus nephritis - The emerging mechanisms." Autoimmun Rev 7(4): 317-21.
Lupus nephritis is a major organ manifestation of systemic lupus erythematosus (SLE) that could lead to acute or chronic renal failure. Active lupus is characterized serological y by high titres of anti-DNA antibodies. Compel ing evidence suggests that anti-DNA antibodies, in addition to being an important diagnostic marker, are also actively involved in the pathogenesis of lupus nephritis through their ability to bind to cel surface antigens or components of the glomerular basement membrane either directly (cross-reactivity) or indirectly (via chromatin material). Accumulating data indicate that fol owing cel ular binding anti-DNA antibodies can be internalized, and the process is associated with induction of inflammatory cascades and alteration of cel ular functions such as proliferation, viability, or morphological changes. Circulating anti-DNA antibodies represent a heterogeneous population. The nephritogenic property of sub-sets of anti-DNA antibodies stems in part from their ability to recognize intrinsic glomerular or tubular structures. However, recent data have shown that lupus nephritis could develop in some animal models in the absence of anti-DNA antibodies, suggesting that nephritogenicity is not an exclusive or unique property of these antibodies. This review wil discuss the mechanisms through which anti-DNA antibodies mediate tissue injury and initiate inflammatory processes in the kidney.
Zappitel i, M., C. M. Duffy, et al. (2008). "Evaluation of activity, chronicity and tubulointerstitial indices for childhood lupus nephritis." Pediatr Nephrol 23(1): 83-91.
Few data exist on use of the National Institutes of Health (NIH) activity index (AI) and chronicity index (CI) in childhood lupus nephritis (LN). A tubulointerstitial activity index (TIAI) has been derived but not validated. We evaluated clinicopathologic correlations of the AI, CI and TIAI in children with LN who had undergone initial renal biopsy (n = 25, age 12.4 +/- 2.7 years, biopsy 1) and 1 year after treatment (n = 15, biopsy 2). The TIAI correlated with the AI at biopsy 1 (r = 0.76, P = 0.001) and biopsy 2 (r = 0.52, P = 0.05), but not with CI scores.
Mean AI and CI scores changed substantial y from biopsy 1 to biopsy 2 (P < 0.05), but TIAI scores did not. Higher AI and TIAI scores correlated with proteinuria at both biopsies (r = 0.51-0.76, P < 0.05); CI scores correlated with estimated creatinine clearance (r = 0.46-0.58, P < 0.05). Improved AI score from biopsy 1 to biopsy 2 was associated with decrease in proteinuria. These results suggest that the AI and CI are useful in childhood LN. The TIAI may be a valid measure to evaluate the tubulointerstitium, but research is needed to define its responsiveness to change with therapy.
Zheng, L., R. Sinniah, et al. (2008). "Pathogenic Role of NF-{kappa}B Activation in Tubulointerstitial Inflammatory Lesions in Human Lupus Nephritis." J Histochem Cytochem.
In vitro and in vivo experimental studies suggest that the transcription factor NF-kappaB plays a role in tubulointerstitial injury. We investigated possible cel ular and molecular mechanisms involving NF-kappaB activation in the progression of tubulointerstitial lesions in human lupus nephritis (LN). Paraffin-embedded renal biopsies from 50 patients with LN and 6 control patients with minimal change disease (MCD) were examined by Southwestern histochemistry for in situ detection of active NF-kappaB and AP-1. Immunohistochemistry was performed to examine the expression of NF-kappaB, AP-1, NF-kappaB regulatory proteins (IkappaB-alpha, p-IkappaB-alpha and IKK-alpha proteins), as wel as NF-kappaB and AP-1 downstream target proinflammatory molecules (ICAM-1, TNF-alpha , IL-1beta, IL-6 and GM-CSF) and NF-kappaB upstream signaling molecules (CD40 and CD40L). We observed extensive upregulation of activated NF-kappaB in renal tubular cel s and interstitial cel s, in paral el with overactivation of transcription factor AP-1 in LN, as compared to normal controls and MCD.
Tubular expression of activated NF-kappaB correlated wel with the degree of tubulointerstitial histopathologic indices and/or renal function. Tubulointerstitial IKK-alpha expression was specifical y upregulated in LN. IkappaB-alpha and p-IkappaB-alpha were only detected in interstitial cel s in LN. Tubulointerstitial expression levels of NF-kappaB and AP-1 downstream inflammatory molecules and NF-kappaB upstream signaling molecules CD40 and CD40L were markedly enhanced in LN as compared to MCD or normal controls, and were associated with tubulointerstitial histopathologic indices and/or renal function. The results suggest that altered IKK-alpha expression and NF-kappaB activation, along with AP-1 overexpression, may play a pathogenic role in tubulointerstitial injury in human LN, mediated through a network of downstream proinflammatory molecules.


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