Zonal cortical scarring and tubular thyroidization in kidney biopsies of patients with SLE-histologic indicator for antiphospholipid antibodies.

Antiphospholipid antibody syndrome (APS) is an acquired prothrombotic autoimmune disease caused by the presence of antibodies against anionic phospholipids or plasma proteins bound to phospholipids on cell membranes. It can be a primary disease or secondary to other autoimmune diseases, most commonly systemic lupus erythematosus (SLE). Laboratory testing for antiphospholipid antibodies (aPL) may be only transiently positive, so APS could be missed until a catastrophic thrombotic episode or pregnancy morbidity occurs. In the kidneys, this manifests as thrombotic microangiopathy (TMA), and patients present with hypertensive urgency and acute kidney injury. However, APS may not always have a catastrophic presentation but instead a more smoldering course. Kidney biopsy may not show obvious active TMA lesions but rather only chronic injury in the form of zonal cortical scarring and tubular thyroidization. Still, it may warrant anticoagulation therapy. So it is important to recognize this pattern of injury in the biopsy. Herein, we retrospectively study the correlation between presence of this histologic feature in kidney biopsies of SLE patients and positive aPL testing results (anticardiolipin antibodies and/or lupus anticoagulant). Kidney biopsies of SLE patients from 2004 to 2015 ( n = 186) were screened for presence or absence of zonal cortical scarring. Their electronic medical records were reviewed for aPL results. Our study showed low sensitivity (33%) but higher positive predictive value (62%), specificity (89%) and negative predictive value (71%). This histologic finding is therefore not a sensitive screening tool, but if present, greatly increases the likelihood of underlying aPL. We want to emphasize that recognition of this histologic feature in the biopsies of SLE patients is important so as not to miss the opportunity to treat with anticoagulation therapy and possibly slow down the chronic renal damage.

Screening for cognitive impairment in SLE using the Self-Administered Gerocognitive Exam.

Objective Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that can affect the central nervous system in multiple ways, including causing cognitive dysfunction. Cognitive dysfunction is a common complaint of SLE patients yet diagnosis is challenging, time consuming, and costly. This study evaluated the Self-Administered Gerocognitive Exam (SAGE) as a screening test for cognitive impairment in a cohort of SLE patients. Methods A total of 118 SLE patients completed the SAGE. Providers completed the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborative Clinics Damage Index (SLICC-DI). SAGE scores were grouped into normal (>16) and abnormal (≤16) categories. Univariate and multivariate analyses were performed. Results Of the 118 participants, 21(18%) scored ≤16 on the SAGE instrument. In univariate analysis, race, ethnicity, household income, and SLICC-DI scores were associated with the SAGE ( p < 0.05). In multivariable analysis, abnormal SAGE score was independently associated with higher SLICC-DI score (odds ratio (OR) = 1.44, 95% confidence intervals 1.04-1.99, p = 0.03)), Hispanic ethnicity (OR = 43.4, 95% CI 3.1-601, p = 0.005), and lower household income (OR = 11.9 for ≤$15,000 vs >$50,000, 95% CI 2.45-57, p = 0.002). Conclusions In SLE patients, this study demonstrates an independent relationship between neurocognitive impairment (as measured by the SAGE) and higher lupus-related damage, as measured by the SLICC-DI, and lower household income. Abnormal SAGE scores were also associated with Hispanic ethnicity. A language barrier could explain this because the SAGE instrument was conducted in English only. The SAGE was feasible to measure in the clinic setting.

Prospective validation of a novel renal activity index of lupus nephritis.

Objectives The renal activity index for lupus (RAIL) score was developed in children with lupus nephritis as a weighted sum of six urine biomarkers (UBMs) (neutrophil gelatinase-associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin and kidney injury molecule 1) measured in a random urine sample. We aimed at prospectively validating the RAIL in adults with lupus nephritis. Methods Urine from 79 adults was collected at the time of kidney biopsy to assay the RAIL UBMs. Using receiver operating characteristic curve analysis, we evaluated the accuracy of the RAIL to discriminate high lupus nephritis activity status (National Institutes of Health activity index (NIH-AI) score >10), from low/moderate lupus nephritis activity status (NIH-AI score ≤10). Results In this mixed racial cohort, high lupus nephritis activity was present in 15 patients (19%), and 71% had proliferative lupus nephritis. Use of the identical RAIL algorithm developed in children resulted in only fair prediction of lupus nephritis activity status of adults (area under the receiver operating characteristic curve (AUC) 0.62). Alternative weightings of the six RAIL UBMs as suggested by logistic regression yielded excellent accuracy to predict lupus nephritis activity status (AUC 0.88). Accuracy of the model did not improve with adjustment of the UBMs for urine creatinine or albumin, and was little influenced by concurrent kidney damage. Conclusions The RAIL UBMs provide excellent prediction of lupus nephritis activity in adults. Age adaption of the RAIL is warranted to optimize its discriminative validity to predict high lupus nephritis activity status non-invasively.

The interleukin-6-hepcidin-hemoglobin circuit in systemic lupus erythematosus flares.

Objective Hepcidin regulates iron availability and may be responsible for the anemia of chronic disease because it is induced by interleukin-6. This study investigated the IL-6-hepcidin-hemoglobin axis in patients with lupus. Methods IL-6 and hepcidin were measured in serial serum samples collected before, during and after lupus flares by specific ELISAs. Results During renal and non-renal SLE flare cycles IL-6 did not predict hepcidin and hepcidin did not predict hemoglobin. When lupus nephritis patients were in remission, IL-6 and hepcidin were correlated, but hepcidin and hemoglobin were not. Conclusion Hepcidin does not contribute significantly to anemia during active lupus.

The impact of tabalumab on the kidney in systemic lupus erythematosus: results from two phase 3 randomized, clinical trials.

INTRODUCTION: Tabalumab is a monoclonal antibody that neutralizes membrane and soluble B-cell activating factor. Two 52-week, randomized, double-blind, placebo controlled phase 3 trials evaluated the safety and efficacy of tabalumab in systemic lupus erythematosus. METHODS: Patients with moderate to severe active systemic lupus erythematosus (without severe active lupus nephritis) were randomly assigned 1:1:1 to receive tabalumab (120 mg subcutaneously every 2 or 4 weeks) or placebo for 52 weeks. Serum creatinine concentration, estimated glomerular filtration rate, urine protein/creatinine ratio, renal flares and renal adverse events were determined monthly. Data were analyzed for the intent-to-treat population and for intent-to-treat patients with baseline urine protein/creatinine ratio >20 mg/mmol (intent-to-treat plus urine protein/creatinine ratio). RESULTS: The trials enrolled 2262 patients. At baseline, demographics, systemic lupus erythematosus disease activity, serum creatinine concentration, estimated glomerular filtration rate and urine protein/creatinine ratio were similar among the treatment arms (with the exception of disease duration). In the intent-to-treat and intent-to-treat plus urine protein/creatinine ratio populations, there were no differences between the arms in the baseline-to-endpoint change in serum creatinine concentration, glomerular filtration rate, urine protein/creatinine ratio, or renal flare rates. Tabalumab resulted in a significant B-cell reduction and decreased immunoglobulin G levels at both doses. CONCLUSIONS: Compared to placebo, tabalumab did not significantly affect the serum creatinine concentration, glomerular filtration rate, urine protein/creatinine ratio, or renal flare rates over 1 year in intent-to-treat or intent-to-treat plus urine protein/creatinine ratio patients. There were no significant renal safety signals.ClinicalTrials.gov identifiers: NCT01205438 and NCT01196091 Lupus (2016) 25, 1597-1601.

Predicting decline of kidney function in lupus nephritis using urine biomarkers.

OBJECTIVE: To evaluate candidate biomarkers to predict future renal function decline (RFD) in children and adults with lupus nephritis (LN). METHODS: At the time of enrollment into prospective observational LN cohort studies liver-type fatty acid binding protein (LFABP), albumin, monocyte chemoattractant protein-1 (MCP-1), uromodulin, transferrin, and hepcidin were measured in urine samples of two cohorts of patients with LN, one followed at a pediatric (cohort-1; n = 28) and one at an adult institution (cohort-2; n = 69). The primary outcome was RFD, defined in cohort-1 as a decrease in estimated glomerular filtration rate (eGFR) of ≥20% and in cohort-2 as a sustained increase of ≥25% in serum creatinine concentration (SCr), both from baseline. RESULTS: All patients (n = 97) had normal eGFR or SCr at the time of urine collection at baseline. RFD occurred in 29% (8/28) of patients in cohort-1 during a mean follow-up of 6.1 months, and in 30% (21/69) of those in cohort-2 during a mean follow-up of 60 months. Individually, in cohort-1, levels of MCP-1, transferrin, LFABP, and albumin were higher in the RFD group than those who maintained renal function, with statistical significance for LFABP and albumin. In cohort-2 the RFD group also had higher levels of urine MCP-1 and albumin than others. The combination of LFABP, MCP-1, albumin, and transferrin had good predictive accuracy for RFD in both cohorts (area under the ROC curve = 0.77-0.82). CONCLUSION: The combinatorial urine biomarker LFABP, MCP-1, albumin, and transferrin shows promise as a predictor of renal functional decline in LN, and warrants further investigation.

The value of repeat kidney biopsy in quiescent Argentinian lupus nephritis patients.

BACKGROUND: The duration of maintenance therapy after induction therapy for lupus nephritis has not been rigorously established. A common practice is to maintain immunosuppression for 1-2 years after complete remission, and longer for partial remission. The present work addresses whether a repeat kidney biopsy might be informative in deciding who should continue immunosuppression after complete or partial remission. METHODS: The practice in a large Buenos Aires nephrology unit is to repeat a kidney biopsy before finalizing the decision to withdraw or continue immunosuppression. This work reports on a cohort of 25 Hispanic patients that had two or more kidney biopsies, the last occurring after at least 24 months of clinically quiescent disease. RESULTS: Despite normalization of serum creatinine and reduction of proteinuria to <500 mg/d, 30% of patients still had significant activity at the last biopsy. Conversely, 60% of patients with ongoing proteinuria (500-1000 mg/d), or stable but abnormal serum creatinine, had no activity by biopsy. Univariate association analyses demonstrated that improvement in the activity index (AI) of the last biopsy was associated with choice of induction therapy (cyclophosphamide or mycophenolate), improvement in serum creatinine over the first six months of treatment, and improvement in complement component C4. By multivariate regression analyses, two AI prediction models emerged. Cyclophosphamide plus change in serum creatinine or cyclophosphamide plus change in C4 accounted for 50% of the improvement in AI. CONCLUSION: These data suggest that a repeat biopsy may be useful in making the decision to withdraw or continue maintenance immunosuppression.

Advanced diabetic nephropathy with nephrotic range proteinuria: a pilot study of the long-term efficacy of subcutaneous ACTH gel on proteinuria, progression of CKD, and urinary levels of VEGF and MCP-1.

BACKGROUND AND OBJECTIVE: Adrenocorticotropic hormone (ACTH) is able to reduce proteinuria in nondiabetic glomerulopathies through activation of melanocortin receptors (MCR) expressed in the podocyte. To determine the efficacy of ACTH, we conducted a randomized, open-label pilot trial of ACTH gel in patients with advanced diabetic nephropathy. STUDY DESIGN: Twenty-three (23) patients with diabetic nephropathy were randomized to daily subcutaneous (SQ) injections of 16 or 32 units of ACTH gel for six months. Outcome. The primary endpoint was the percentage of patients achieving a complete remission (<300 mg/24 hours) within 6 months. Exploratory endpoints included the percentage of partial (50% reduction) remissions, changes in Cr, and urinary cytokine markers. RESULTS: After 6 months of ACTH gel therapy, 8 of 14 (57%) patients achieved a complete (n = 1) or partial (n = 7) remission. In the low-dose ACTH gel group (16 units), urinary protein fell from 6709 + 953 to 2224 + 489 mg/24 hrs (P < 0.001). In contrast, 2 of 6 patients in the 32-unit group achieved partial remission, but aggregate proteinuria (5324 + 751 to 5154 + 853 mg/24 hours) did not change. Urinary VEGF increased from 388 to 1346 pg/mg urinary creatinine (P < 0.02) in the low-dose group but remained unchanged in the high-dose group. CONCLUSION: ACTH gel stabilizes renal function and reduces urinary protein for up to 6 months after treatment. The ClinTrials.gov identifier is NCT01028287.

5/6 nephrectomy as a validated rat model mimicking human warfarin-related nephropathy.

BACKGROUND/AIMS: We previously reported that patients with chronic kidney disease (CKD) receiving warfarin therapy and whose international normalized ratio increases to >3.0 may develop acute kidney injury (AKI) as a result of glomerular hemorrhage and formation of obstructive red blood cell (RBC) casts. We named this condition warfarin-related nephropathy (WRN). We also previously reported that acute excessive anticoagulation with brodifacoum (superwarfarin) induces AKI in 5/6 nephrectomy (5/6NE) rats. Limitations of the brodifacoum model precluded a careful assessment of dose-response relationships. METHODS: Warfarin treatment was used in 5/6NE. RESULTS: Herein we report that warfarin treatment of 5/6NE rats resulted in a dose-dependent increase in serum creatinine (SC). The increase in SC following warfarin treatment was greater at 3 and 19 weeks after the ablative surgery, than that observed 8 weeks after the ablative surgery. The SC increase was correlated with the prothrombin time increase. Morphologically, 5/6NE, but not control rats, had acute tubular injury with RBC and RBC casts in the tubules. Treatment with vitamin K prevented SC increase and morphologic changes in the kidney associated with warfarin treatment. A single episode of WRN did not affect the progression of CKD in 5/6NE. CONCLUSION: (1) The 5/6NE model of CKD is an appropriate animal model to study the pathogenesis of WRN. (2) The pharmacokinetics of warfarin is better suited to the study of WRN than that of brodifacoum. (3) The more advanced stages of 5/6NE are more susceptible to WRN than the earlier stages. (4) Vitamin K treatment prevents WRN.

Evidence that abnormally large seasonal declines in vitamin D status may trigger SLE flare in non-African Americans.

Cross-sectional studies have shown that low vitamin D (25-hydroxyvitamin D (25(OH)D)) is associated with increased systemic lupus erythematosus (SLE) activity. This study is the first to assess the temporal relationship between 25(OH)D levels and onset of SLE flare. This assessment was made possible because of the specimen bank and database of the Ohio SLE Study (OSS), a longitudinal study of frequently relapsing SLE that involved regular bimonthly patient follow-up. We identified for this study 82 flares from 46 patients that were separated by at least 8 months from previous flares. Serum 25(OH)D levels were measured at 4 and 2 months before flare, and at the time of flare (a flare interval). We found that for flares occurring during low daylight months (LDM, Oct-Mar), 25(OH)D levels were decreased at the time of flare, but only in non-African American (non-AA) patients (32% decrease at flare, compared to 4 months prior, p < 0.001). To control for seasonal effects, we also measured 25(OH)D levels in the LDM "no-flare" intervals, which were intervals that matched to the same calendar months of the patients' LDM flare intervals, but that didn't end in flare (n = 24). For these matches, a significant decrease occurred in 25(OH)D levels during the flare intervals (18.1% decrease, p < 0.001), but not during the matching no-flare intervals (6.2% decrease, p = 0.411). For flares occurring during high daylight months (HDM), 25(OH)D levels changed only in non-AA patients, increasing slightly (5.6%, p = 0.010). Analysis of flare rates for the entire OSS cohort (n = 201 flares) revealed a tendency for higher flare rates during LDM compared to HDM, but again only in non-AA patients (p = 0.060). Flare rates were lower during HDM for non-AA patients compared to AA patients (p = 0.028). In conclusion, in non-AA SLE patients, unusually large declines in 25(OH)D during LDM may be mechanistically related to SLE flare, whereas relatively high 25(OH)D levels during HDM may protect against flare.

Vitamin D deficiency as marker for disease activity and damage in systemic lupus erythematosus: a comparison with anti-dsDNA and anti-C1q.

OBJECTIVES: To study the sensitivity and specificity of vitamin D deficiency for predicting disease activity and damage of systemic lupus erythematosus (SLE) in comparison with anti-dsDNA and anti-C1q. METHODS: Consecutive patients who fulfilled four or more ACR criteria for SLE were studied. Levels of 25-hydroxyvitamin D3, anti-C1q, anti-dsDNA and complement levels were measured. Relationship among these markers, concurrent disease activity and damage scores of SLE was studied by Spearman's rank correlation method. RESULTS: In total, 290 SLE patients were studied (95% women; mean age 38.9 ± 13.1 years; SLE duration 7.7 ± 6.7 years). Clinical or serological lupus activity (SLEDAI ≥ 1) was present in 225 (78%) patients. Vitamin D deficiency (< 15 ng/ml) was detected in 78 (27%) patients. Levels of 25-hydroxyvitamin D3 correlated inversely with the clinical SLE disease activity score (Rho = -0.26; p < 0.001). A negative correlation was also observed between 25-hydroxyvitamin D3 and anti-dsDNA levels (Rho = -0.13; p = 0.02), or anti-C1q (Rho = -0.14; p = 0.02). However, there was no significant relationship between levels of 25-hydroxyvitamin D3 and complement C3 (Rho = 0.09; p = 0.12) or C4 (Rho = 0.09; p = 0.13). Both 25-hydroxyvitamin D3 deficiency and anti-C1q were more specific but less sensitive than anti-dsDNA for concurrent clinical renal and non-renal SLE activity. Levels of 25-hydroxyvitamin D3, anti-dsDNA or anti-C1q did not correlate significantly with the SLE damage scores. CONCLUSIONS: 25-hydroxyvitamin D3 correlated inversely and significantly with clinical SLE activity, anti-C1q and anti-dsDNA titers, but not with complement levels or damage scores. Deficiency of 25-hydroxyvitamin D3 was as specific as anti-C1q, but less sensitive than anti-dsDNA, for detecting concurrent renal and non-renal clinical activity of SLE.

Cytochrome P450 polymorphisms and the response of lupus nephritis to cyclophosphamide therapy.

BACKGROUND AND AIMS: The addition of cyclophosphamide to corticosteroids significantly improves the prognosis of severe kidney involvement in systemic lupus erythematosus (SLE). However, not all patients respond to cyclophosphamide. It has been suggested that genetic variations that reduce the metabolism of cyclophosphamide reduce its effectiveness. Cyclophosphamide is metabolized and activated by the cytochrome P450 (CYP) system and in particular CYP enzymes 2B6 and 2C19. Both CYP2B6 and CYP2C19 have variant alleles (CYP2B6*5 and CYP2C19*2) that attenuate or eliminate enzymatic activity. This investigation was done to determine the impact of CYP2B6*5 and CYP2C19*2 on the renal response in cyclophosphamide-treated lupus nephritis (LN) patients. METHODS: Patients with SLE (n = 237), unclassified autoimmune disease (n = 51), and healthy controls (n = 294) were genotyped for CYP2B6*5 and CYP2C19*2. Associations between these alleles and achievement of complete or partial response, development of end-stage renal disease, and time to remission were determined. RESULTS: The frequencies of the variant alleles CYP2B6*5 and CYP2C19*2 were 6.3 % and 15.9%, respectively. CYP2C19*2 genotypes were more frequent among African Americans than European Americans, and CYP2B6*5 genotypes were more frequent among European Americans than African Americans. Among LN patients treated with cyclophosphamide (n = 36), there were no differences between those with or without these genotypes relative to the frequency of complete or partial remissions or time to remission. CONCLUSION: This retrospective analysis failed to show an association between CYP2B6*5 and CYP2C19*2 and treatment outcomes in LN. This suggests that genotyping for these CYP450 variants may not be useful in individualizing treatment for severe LN.

The complex nature of serum C3 and C4 as biomarkers of lupus renal flare.

To assess the relationship between serum C3 or C4 levels and lupus renal flare, C3 and C4 levels were measured bimonthly in 71 lupus nephritis patients for a mean of 35 months, during which time 70 renal flares were identified. Comparing baseline, pre-flare, and at-flare values indicated that neither C3 nor C4 levels decreased pre-flare, but both decreased on average significantly at flare. However, sensitivity/specificity for C3 (75%/71%) and C4 (48%/71%) were low. To account for other influencing factors, multiple regression was performed that included bimonthly values of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and genotype data on C3 (S/F), CRP (1846G > A), and the complement regulator factor H (Y402H). This analysis revealed that reduced levels of C4, but not C3, were independently associated with the two-month pre-flare period. Conversely, reduced levels of C3, but not C4, were independently associated with the flare visit. Significant pro-flare interactions included low C3 levels with the factor H 402HH-encoding genotype, and low CRP levels with the C3 F allele. Together these data suggest that C4 activation is critical for initiating renal flare while C3 activation is involved in the actual tissue damage, and that these effects are influenced by genetic variability in complement activation and regulation.

Phenotypes, genotypes and disease susceptibility associated with gene copy number variations: complement C4 CNVs in European American healthy subjects and those with systemic lupus erythematosus.

A new paradigm in human genetics is high frequencies of inter-individual variations in copy numbers of specific genomic DNA segments. Such common copy number variation (CNV) loci often contain genes engaged in host-environment interaction including those involved in immune effector functions. DNA sequences within a CNV locus often share a high degree of identity but beneficial or deleterious polymorphic variants are present among different individuals. Thus, common gene CNVs can contribute, both qualitatively and quantitatively, to a spectrum of phenotypic variants. In this review we describe the phenotypic and genotypic diversities of complement C4 created by copy number variations of RCCX modules (RP-C4-CYP21-TNX) and size dichotomy of C4 genes. A direct outcome of C4 CNV is the generation of two classes of polymorphic proteins, C4A and C4B, with differential chemical reactivities towards peptide or carbohydrate antigens, and a range of C4 plasma protein concentrations (from 15 to 70 mg/dl) among healthy subjects. Deliberate molecular genetic studies enabled development of definitive techniques to determine exact patterns of RCCX modular variations, copy numbers of long and short C4A and C4B genes by Southern blot analyses or by real-time quantitative PCR. It is found that in healthy European Americans, the total C4 gene copy number per diploid genome ranges from 2 to 6: 60.8% of people with four copies of C4 genes, 27.2% with less than four copies, and 12% with more than four copies. Such a distribution is skewed towards the low copy number side in patients with systemic lupus erythematosus (SLE), a prototypic autoimmune disease with complex etiology. In SLE, the frequency of individuals with less than four copies of C4 is significantly increased (42.2%), while the frequency of those with more than four copies is decreased (6%). This decrease in total C4 gene copy number in SLE is due to increases in homozygous and heterozygous deficiencies of C4A but not C4B. Therefore, it is concluded that lower copy number of C4 is a risk factor for and higher gene copy number of C4 is a protective factor against SLE disease susceptibility.

Thiazide diuretic monotherapy for hypertension: diuretic's dark side just got darker.

Diuretic monotherapy is the current recommendation of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure for initial antihypertensive therapy. There is mounting concern, however, that the benefits of diuretic's superior blood pressure control may be offset by its multiple metabolic disturbances that increase cardiovascular risk. Reungjui et al. document a new concern, nephrotoxicity by thiazide monotherapy. This and other recently published evidence of diuretic's 'dark side' is discussed.

Spot urine protein/creatinine ratios are unreliable estimates of 24 h proteinuria in most systemic lupus erythematosus nephritis flares.

The diagnosis of glomerulonephritis flares in systemic lupus erythematosus (SLE) is usually based on whether the magnitude of proteinuria has changed. Our study tests two methods to assess proteinuric change: protein/creatinine (P/C) ratios of intended 24-h urine collections or that of spot urine samples. Sixty-four patients with glomerulonephritis due to SLE followed in the Ohio SLE Study provided bimonthly paired spot and intended 24-h urine collections. Completeness of each collection was estimated as the ratio of the measured creatinine to the expected creatinine based upon Cockroft-Gault. Intended 24-h urine collections with measured/expected creatinine ratios between 0.5 and 0.9 (237 samples overall) showed ratios that were not significantly different from ratios of complete 24-h urine collections with ratios of 0.9-1.1 (159 samples). To compare spot and 24 h P/C ratios, we randomly selected pairs of samples with measured/expected ratios above 0.75. Consistent with previous studies, spot and 24-h urine P/C ratios showed good correlation over the range of values as well as reasonably strong concordance. Over the range of most SLE glomerulonephritis flares, however, correlation was present but concordance was poor. Our work suggests that the use of spot urine P/C ratios will yield more false-positive and -negative diagnoses of glomerulonephritis flares in patients with SLE than the ratio in 24-h urines.

Consumption of erythrocyte CR1 (CD35) is associated with protection against systemic lupus erythematosus renal flare.

Erythrocyte complement receptor type one (E-CR1) is thought to protect against immune complex (IC) disease through interactions that lead to E-CR1 consumption, and low E-CR1 levels are characteristic of systemic lupus erythematosus (SLE). The purpose of this study was to test the hypothesis that E-CR1 consumption can predict or mark SLE flare. Recurrently active SLE patients [n = 43; 28 with past or present major renal manifestations (SLER) and 15 without (SLENR)], were evaluated every 2 months by detailed protocol testing (mean follow-up 22 months), including direct measurements of E-CR1 levels using a radioimmunoassay. In all patients, detectable E-CR1 levels fluctuated widely through acute periods of consumption and regeneration, preventing the use of any single value as a baseline. However, when individual chronic baseline values were used, determined as the mean of all E-CR1 values 4 months or more from a flare, a clear trend was observed. In 16 of 16 instances of non-renal flare in SLER patients, E-CR1 levels decreased at flare (mean decrease 34%, P < 0.0001). In contrast, no consistent difference was observed for flare in SLENR patients or for renal flare in SLER patients. Changes in E-CR1 levels did not correlate with plasma CR1 levels. In conclusion, single occurrences of E-CR1 consumption did not generally predict or mark SLE flare. However, compared to the average E-CR1 levels measured during no-flare intervals, E-CR1 consumption in SLER patients at flare was strongly associated with freedom from signs of renal involvement. We postulate that E-CR1 consumption reflects E-CR1 function that includes protecting against SLE nephritis.

Differentiation-dependent regulation of the cyclooxygenase cascade during adipogenesis suggests a complex role for prostaglandins.

AIM: A thorough understanding of the mechanisms of adipocyte differentiation and metabolism is important for the prevention and/or treatment of obesity and its complications, including type 2 diabetes mellitus. A complex role for prostaglandins (PGs) in adipogenesis is suggested. We examined the expression and cellular localization of enzymes in the cyclooxygenase (COX) cascade that synthesize PGs as well as the PG profile as a function of differentiation status in 3T3-L1 cells. METHODS: Murine 3T3-L1 preadipocytes were used as a model for studies of adipocyte differentiation induced by a hormone cocktail and compared with the parental fibroblastic line NIH 3T3. Both cell lines were incubated in maintenance medium or differentiation medium. Nine days after differentiation, the expression of enzymes in the COX cascade was evaluated by immunoblot analysis, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunocytochemistry, and PG formation was examined using enzyme immunoassay. RESULTS: A differentiation-dependent diminution of COX-1 and COX-2 mRNA and cognate proteins in 3T3-L1 cells was observed. PG release, including PGE(2), 6-keto PGF(1alpha), PGD(2) and 15d-PGJ(2), significantly decreased following differentiation in 3T3-L1 cells (anova/Tukey, p < 0.05). However, microsomal PGE synthase (mPGES) and lipocalin-type PGD synthase (L-PGDS) were selectively upregulated. Immunocytochemistry revealed that COX-1 and COX-2 became intracellularly more diffuse upon differentiation, whereas mPGES was redistributed to the nuclear compartment. CONCLUSIONS: Regulation of PG formation and COX-2 expression in 3T3-L1 cells is differentiation-dependent and involves changes in the levels of gene expression of the individual isoforms as well as redistribution of the enzymes within cellular compartments.

Of mice and men: the relevance of the mouse to the study of human SLE.

A number of mouse models have been utilized to study the pathophysiology of immune complex (IC) disease, and the hallmark IC disease systemic lupus erythematosus (SLE). Many of these studies have provided exciting new insights into IC-mediated inflammation and autoimmunity. However, numerous differences exist between mice and humans that suggest that mouse studies are not always applicable to human disease. These differences can be found in the biological systems that interact with circulating IC, in the specifics of disease presentation, and in the general physiology of the two species. Furthermore, although the mechanisms of SLE-like autoimmune disease in the mouse are being defined through analyses of the murine models of SLE, it remains to be proven that these mechanisms are relevant to human SLE. Thus, generalizing the results of the mouse studies to human SLE and other human IC diseases must be done with caution.