Nephritis Flare Research Articles

Infections: The Achilles Heel of Immunosuppression for Renal Transplantation and Immunological Renal Disease Management in the Top End of Northern Australia: Case Reports

Improved immunosuppression regimens have led to better survival for patients with renal transplant grafts and patients with immunological renal diseases worldwide. However, this is not the case in the Northern Territory of Australia. Available limited published data from the Northern Territory of Australia have shown poor outcomes for renal transplantation with survival for both patients and grafts around 50% at 5 years suggesting death with a functioning graft as the commonest cause of graft loss. These studies have shown that the leading cause of death is infections. Achieving the right level of immunosuppression to prevent rejection in renal transplantation and achieve remission in immunological renal diseases can be a major challenge in areas with high prevalence of infections such as the Northern Territory. We present 2 cases of the challenges from infections of immunosuppression in renal transplantation and immunological renal diseases in the Northern Territory of Australia. A 57 year old Aboriginal woman received a deceased donor renal transplant in 2006. She has been plagued by recurrence of several life threatening infections including urinary tract, cytomegalovirus, and severe cryptococcocus infections. This resulted in immunosuppression reduction and failure of the transplant 5 years post transplantation. A 20 year old Aboriginal woman presented with a combination of severe lupus nephritis and severe sepsis. She fully recovered after treatment with antibiotics and careful immunosuppression. However, she has had recurrent hospital admissions with life threatening infections resulting in stopping the immunosuppression. She then had severe lupus nephritis flare leading to dialysis dependence and will need a renal transplant. The cases illustrate the need for tailored and robust immunosuppression and transplant work up protocols. To that effect, prospective studies to analyse outcomes in immunosuppressed individuals, pharmacokinetic studies assessing whether the conventionally recommended drug levels are appropriate for this population and culturally appropriate educational programmes need to be performed.

Lupus and Pregnancy

Systemic lupus erythematosus (SLE) disproportionately affects women in their reproductive age years. Pregnancy in this systemic autoimmune disease has long been associated with poor obstetric outcomes. However, the frequency of pregnancy loss in lupus has dropped to a level commensurate with that of the general US population. The outcomes of lupus pregnancies are better if conception is delayed until the disease has been inactive for at least 6 months, and the medication regimen has been adjusted in advance. Pregnancy in lupus is prone to complications, including flares of disease activity during pregnancy or in the postpartum period, preeclampsia, miscarriage, stillbirth, intrauterine growth retardation, and preterm birth. Active lupus nephritis poses the greatest risk. The recognition of a lupus flare during pregnancy may be difficult because the signs and symptoms may mimic those of normal pregnancy. Monitoring should include baseline and monthly laboratory tests, serial ultrasonography, fetal surveillance tests, and fetal m-mode echocardiography for mothers with SS-A (Ro) or SS-B (La) antibodies. In the absence of any signs or symptoms of active SLE, affected patients require no specific treatment during pregnancy. If hydroxychloroquine was in use before conception, it should be maintained throughout pregnancy. If a woman with SLE has antiphospholipid antibodies, prophylactic treatment with aspirin and/or low-molecular weight heparin is indicated to prevent fetal loss. Lupus flares during pregnancy are generally treated with hydroxychloroquine, low-dose prednisone, pulse intravenous methylprednisolone, and azathioprine. High-dose prednisone and cyclophosphamide are reserved for severe lupus complications but are associated with significant pregnancy-related complications and poor obstetrical outcomes.

Anti-C1q antibodies have higher correlation with flares of lupus nephritis than other serum markers

Autoantibodies are important in the diagnosis and classification of systemic lupus erythematosus (SLE), but whether they correlate with changes in disease activity within individual patients is controversial. We assessed the association between changes in SLE global and renal activity and changes in several autoantibodies and cell adhesion molecules in patients with SLE. Stored sera collected at two or three clinic visits from each of 49 SLE patients (91% female, 59% African-American, 31% Caucasian, 10% other ethnicity, 38% under 30 years, 41% between 30-44 years, and 21% 45-63 years) were analyzed. The visits were chosen to include one visit with proteinuria, and one or two without, for each patient. Global disease activity was measured by the Physician's Global Assessment (PGA), SELENA-SLEDAI (SLE Disease Activity Index modified to exclude anti-dsDNA and complement) and renal activity assessed by urine protein (by urine dipstick) and Renal Activity Score. Sera were assayed for anti-C1q, anti-chromatin, anti-dsDNA, anti-ribosomal P, monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule (VCAM) intercellular adhesion molecule (ICAM) and complement. The associations between changes in disease activity and changes in biomarker levels were assessed. In terms of global disease activity, anti-C1q had the highest association with the PGA (p = 0.09) and was strongly associated with modified SELENA-SLEDAI (p = 0.009). In terms of renal activity, anti-C1q had the highest association with proteinuria (p = 0.079), and was strongly associated with Renal Activity Score (p = 0.006). Anti-C1q performed the best of the potential biomarkers, being significantly associated with the modified SELENA-SLEDAI and with the Renal Activity Score. This study indicates the potential superior utility of anti-C1q over anti-dsDNA and other measures to track renal activity.

Longterm Followup After Tapering Mycophenolate Mofetil During Maintenance Treatment for Proliferative Lupus Nephritis

To determine the timing for safe reduction of mycophenolate mofetil (MMF) dose during remission-maintenance therapy of proliferative lupus nephritis. The study population consisted of 44 patients evaluated retrospectively; MMF dose was empirically tapered in 18/44 patients until the latest observation. Patients reducing MMF ≤ 18 months after remission/complete remission had a 6.8-fold/6.3-fold higher risk of relapse compared to those taking a stable dose (p = 0.001, p = 0.011, respectively). Reducing MMF later than 18 months was not associated with increased relapse rates. Reducing MMF > 1.5 years after remission/complete remission seems to warrant drug tapering without increased risk of disease flare in proliferative lupus nephritis.

The role of cytokines as biomarkers in systemic lupus erythematosus and lupus nephritis

Cytokines play an important role in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis. This is currently a very active area of research. Of particular interest is the use of cytokines as biomarkers of disease activity in SLE and lupus nephritis. Can cytokine measurements assist in early detection of renal flare in known lupus nephritis? Can such measurements be used to distinguish between flare and chronic damage? Or help to confirm renal remission? Could they be used to help assess the required duration of immunosuppression and reduce the need for invasive renal biopsy? This review discusses limitations of current laboratory methods in monitoring SLE, how measurements of cytokines may contribute in relation to following disease activity and summarizes what is known about cytokines as biomarkers in SLE and lupus nephritis.

Lipoxins as biomarkers of lupus and other inflammatory conditions

Inflammatory events persist in systemic lupus erythematosus (lupus) despite the use of anti-inflammatory (both steroidal and non-steroidal) and immunosuppressive drugs leading to delay in the healing/repair process and so tissue/organ damage continues. The continuation of inflammation in lupus could be attributed to failure of the resolution process due to deficiency of potent endogenous pro-resolution-inducing molecules such as lipoxin A4 (LXA4). It is likely that progression and flares of lupus and lupus nephritis are due to decreased formation and release of LXA4. Hence, administration of LXA4 and its analogues could be of benefit in lupus. Furthermore, plasma and urinary measurement of lipoxins may be used to predict prognosis and response to therapy. It is likely that lipoxins and other bioactive anti-inflammatory lipids such as resolvins, protectins, maresins and nitrolipids play a significant role in other auto-immune diseases such as rheumatoid arthritis, type 1 diabetes mellitus and multiple sclerosis and hence, could be of significant benefit in these diseases.

The outcome of proliferative lupus nephritis with pulse cyclophosphamide therapy

Proliferative lupus nephritis deserves aggressive therapy and cyclophosphamide plays a pivotal role. Thirty nine patients with proliferative lupus nephritis (Class III-7 patients and Class IV- 32 patients) with a median follow up of 38 months were considered for this observational study. All the patients received induction therapy with intravenous methylprednisolone. Cyclophosphamide was given intravenously initially in monthly pulses for six months and later quarterly pulses until remission was achieved or until the target dose (200 mg/kg) was reached. The treatment with intravenous methylprednisolone was repeated in the event of a nephritic flare. Later the corticosteroid was reduced to a minimum effective dose and cyclophosphamide was changed to either azathioprine or mycophenolate mofetil. At the time of the last follow up, 82.05% of the patients were in remission (complete remission 51.28% and partial remission 30.77%). The median interval to achieve remission in responders was 15 months. Early diagnosis (P=0.04), a higher creatinine clearance at presentation (P=0.02), and concurrent use of an ACEI or an ARB (P=007) significantly favored attaining remission. Five patients experienced a doubling of serum creatinine and one of them became dialysis dependent. Risk of doubling of serum creatinine correlated with a low Ccr (P=0.03) at presentation, occurrence of renal flares (P=0.034) and failure to achieve remission (P=0.0001). The parameters like serum creatinine, serum C3, serum C4, activity and chronicity indices on renal biopsy, hypertension were not statistically significant. Therapy with cyclophosphamide, if initiated early, helps in inducing remission and hence can retard the progression to CKD.

Pregnancy outcome in 396 pregnancies in patients with SLE in Saudi Arabia

The aim of this study was to examine the pregnancy outcomes in patients with systemic lupus erythematosus (SLE) and the effect of SLE flare and treatment on pregnancy outcomes. We performed a retrospective evaluation of all pregnancies occurring in patients with SLE during the 27-year period from 1980 to 2006. Of the 319 women with SLE planning pregnancy after SLE onset, 176 (55.2%) conceived resulting in 396 pregnancies. Live births were significantly lower in proportion (70.2% vs. 85.7%) and more likely to end in fetal deaths (29.7% vs. 14.2%) and preterm births (26.7% vs. 5.8 %) in pregnancies occurring after SLE onset than in pregnancies occurring before SLE onset (p < 0.0001). With respect to different disease manifestations, we found that fetal loss was significantly higher in patients with antiphospholipid (aPL) antibodies than without (p < 0.001). Preterm deliveries were significantly more frequent in patients with lupus nephritis, anti-Ro/SSA antibodies, hypertension, history of intravenous cyclophosphamide treatment and aPL than those without these features (p < 0.05). Neonates with intrauterine growth retardation (IUGR) neonates were more common in hypertensive and Raynaud's-positive pregnancies (p < 0.05). SLE flares occurred in 30.8% pregnancies. There was increased risk of fetal loss, preterm births and IUGR in pregnancies with SLE exacerbations than without (p < 0.05). Prednisolone was found to improve the rate of live births, although it was also a predictor of prematurity. The predictors of pregnancy loss were lupus nephritis (odds ratio (OR) 7.3), aPL (OR 3.9), and SLE flares in pregnancy (OR 1.9). There was higher risk of preterm deliveries in patients with lupus nephritis (OR 18.9), anti-Ro antibodies (OR 13.9), hypertension (OR 15.7) and SLE flares (OR 2.5). IUGR was found to be associated with hypertension (OR 37.7), Raynaud's (OR 12.3), and SLE flares (OR 4.2). In conclusion, pregnancies in SLE patients with active lupus nephritis, anti-Ro/SSA antibodies, aPL, hypertension, Raynaud's phenomenon, active disease at conception and SLE exacerbations are at a higher risk of adverse pregnancy outcomes. It is important to carefully plan pregnancy, and experienced rheumatologists and obstetricians should monitor SLE patients in pregnancy and postpartum.

Simultaneous detection of anti-C1q and anti-double stranded DNA autoantibodies in lupus nephritis: predictive value for renal flares

Clinical difficulties in predicting systemic lupus erythematosus (SLE) renal flares are still encountered. Biological markers such as autoantibodies (aAbs) may be of major interest for clinicians in the follow-up of SLE patients. The aim of our study was to investigate the clinical utility of one of these biological markers, anti-C1q aAbs, in predicting renal flares of SLE nephritis in comparison with the 'gold standard' anti-double stranded DNA (anti-dsDNA) aAbs. Anti-C1q aAbs and anti-dsDNA aAbs were analysed through a longitudinal retrospective study of 23 SLE patients presenting with one or more renal flares. Anti-C1q and/or anti-dsDNA aAbs were found in 20 (87%) of 23 patients, of whom 16 (69%) displayed both. Thirty-three renal flares occurred during the course of the study, and anti-C1q aAbs and anti-dsDNA aAbs were positive in 25 (76%) and 24 (73%) of these flares respectively. The sensitivity of anti-C1q and/or anti-dsDNA aAbs in predicting renal flares reached 85%. The specificity of anti-C1q aAbs was 84%, of anti-dsDNA aAbs 77% and of both aAbs 97%. Positive and negative predictive values were as follows: 56% and 70% for anti-C1q aAbs, 53% and 72% for anti-dsDNA aAbs. The combination of both aAbs had the highest positive predictive value (69%), whereas absence of both aAbs was associated with the highest negative predictive value (74%). In conclusion, our results confirm that anti-C1q aAbs are present in a significant percentage of SLE patients with active renal involvement, suggesting that these aAbs could be a useful additional marker. The presence of anti-C1q and anti-dsDNA aAbs was associated with a high risk of renal flare, whereas the absence of both aAbs excluded such an event. These data confirm that systematic detection of anti-C1q and anti-dsDNA aAbs is of interest for the follow-up in SLE patients with renal involvement.

Hepcidin expression by human monocytes in response to adhesion and pro-inflammatory cytokines

Background A previous urine proteomic analysis from our laboratory suggested that hepcidin may be a biomarker for lupus nephritis flare. Immunohistochemical staining of kidney biopsies from lupus patients showed that hepcidin was expressed by infiltrating renal leukocytes. Here we investigated whether inflammatory cytokines relevant to the pathogenesis of lupus nephritis and other glomerular diseases regulate hepcidin expression by human monocytes. Methods Human CD14+ monocytes were incubated with interferon alpha (IFNα), interferon gamma (IFNγ), interleukin-6 (IL6), interleukin-1 beta (IL1β), monocyte chemotactic factor-1 (MCP1), or tumor necrosis factor alpha (TNFα). Hepcidin expression was examined by real-time PCR and enzyme immunoassay. Results Monocyte hepcidin mRNA increased during adherence to the tissue culture wells, reaching a level 150-fold higher than baseline within 12 h of plating. After accounting for the effects of adhesion, monocytes showed time and dose-dependent up-regulation of hepcidin mRNA upon treatment with IFNα or IL6. One hour of incubation with IFNα or IL6 increased hepcidin mRNA 20 and 80-fold, respectively; by 24 h the mRNA remained 5- and 2.4-fold higher than baseline. IL1β, IFNγ, and MCP-1 did not affect monocyte hepcidin expression. TNFα inhibited hepcidin induction by IL6 in monocytes by 44%. After 24 h of treatment with IFNα or IL6, immunoreactive hepcidin production by monocytes increased 3- and 2.6-fold, respectively. Conclusion Human monocytes produce hepcidin in response to adhesion and the pro-inflammatory cytokines IFNα and IL6. General significance The appearance of hepcidin in the kidneys or urine during glomerular diseases may be from infiltrating monocytes induced to express hepcidin by adherence and exposure to pro-inflammatory cytokines found in the renal milieu.

Successful management of systemic lupus erythematosus nephritis flare-up during pregnancy with tacrolimus

Systemic lupus erythematosus (SLE) is one of the common autoimmune disorders that affect women during their childbearing years. Disease activity frequently increases during pregnancy and the postpartum period, representing a challenge for both the patient and the treating physician(s). We report a case of successful management of lupus nephritis flare in the first trimester. The patient developed bilateral leg edema and nephrotic-range proteinuria of 5g/day. She was treated with steroids and tacrolimus, which resulted in the induction of remission during pregnancy. The patient reached full-term with no maternal or fetal complications. This case indicates that tacrolimus, which is convenient to use and has limited adverse effects, may represent a potential safe and effective treatment option for SLE nephritis during pregnancy.

Novel therapeutic possibilities in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder involving different organs and organ systems with consequent characteristic clinical and serologic symptoms. Despite of the improvement in lupus survival, approximately 10-20% of patients do not respond to traditional immune suppressive therapies. Relapses are more frequent; e.g. after cyclophosphamide therapy diffuse proliferative nephritis flares in 1/3 of patients. Different immune competent cells and inflammatory mediators participate in the pathogenesis of SLE involving both the adaptive and innate immunity. Several pathogenic elements and mechanisms may serve as therapeutic targets, consequently. Authors summarize novel therapeutic possibilities and their mechanisms regarding the pathogenesis of SLE. Immune modulation of B and T cells, co-stimulatory pathways, cytokine network, soluble mediators and autologous hemopoietic stem cell transplantation are discussed.

Long-Term Outcome of Patients with Lupus Nephritis: A Single Center Experience

Lupus nephritis (LN) is an immune inflammation of kidneys caused by systemic lupus erythematosus (SLE), a chronic inflammatory disease that affects the body's immune system. Aim of this study was to analyze clinical manifestation and treatment results of patients with LN. Forty one patients with clinical signs of LN were included in the study. Mean age of patients was 31.9+/-12.1 years in the moment of first diagnosis of LN, with female-male ratio 8:1. Renal disease was pathohistologically (PTH) verified in 53.7% of patients (4 pts with class III, 17 pts with class IV, one pt with class V of lupus nephrites). Patients with high nephrotic proteinuria were treated with pulse dose of methylprednisolone and pulse doses of cyclophosphamide (CYC) in induction therapy. Corticosteroid and CYC were continued according to treatment protocol. The other group of LN patients with lower nephrotic proteinuria was treated with mycophenolate mofetil (MMF) in induction therapy at a dose of 2x1 g/day for six months, and than in maintenance 2x0.5 g/day. The patients with non-nephrotic proteinuria and normal renal function were treated with oral prednisolone 0.75-1 mg/kg/day in a single morning dose, and then gradually reduced to the dose of maintenance. The mean time of patient's follow-up was 10.9+/-4.1 years. Partial renal remission was accomplished in 29.2% pts, and complete remission in 60.9% pts for period of 17.2+/-13.3 months from the beginning of the treatment. Duration of complete renal remission was 30.1+/-19.1 months. During the period of follow-up, 29.3% pts developed at least one nephritic flare and were treated again. These results confirmed that the aggressive form of lupus nephritis should be treated associating cyclophosphamide with corticosteroids therapeutical regiment. MMF is a new promising immunosuppressive drug for a treatment of this serious disease.

56: Anti-C1Q Antibody Levels Are Not Reliable Forecasters or Markers and Lupus Nephritis Flare

56: Anti-C1Q Antibody Levels Are Not Reliable Forecasters or Markers and Lupus Nephritis Flare

Urinary neutrophil gelatinase-associated lipocalin as a novel biomarker for disease activity in lupus nephritis

Clinical and laboratory markers in current use have limited specificity and sensitivity for predicting the development of renal disease in lupus patients. In this longitudinal study, we investigated whether urinary neutrophil gelatinase-associated lipocalin (uNGAL) predicts active nephritis and renal flares in lupus patients with and without a history of biopsy-proven lupus nephritis. Renal disease activity and flare status was determined by SLEDAI and BILAG scores. Random effects models were used to determine whether uNGAL was a significant predictor for renal disease activity in SLE patients, and for renal flares in patients with established nephritis. To assess the predictive performance of uNGAL, receiver operating characteristic (ROC) curves were constructed using the previous visit's uNGAL level. These curves were then compared with curves constructed with currently used biomarkers. Cut-offs determined by ROC curves were tested in an independent validation cohort. uNGAL was found to be a significant predictor of renal disease activity in all SLE patients, and a significant predictor for flare in patients with a history of biopsy-proven nephritis, in multivariate models adjusting for age, race, sex and anti-double-stranded (ds)DNA antibody titres. As a predictor of renal flare in patients with biopsy-proven nephritis, uNGAL outperformed anti-dsDNA antibody titres. These results were confirmed in an independent validation cohort. uNGAL predicts renal flare in patients with a history of biopsy-proven nephritis with high sensitivity and specificity. Furthermore, uNGAL is a more sensitive and specific forecaster of renal flare in patients with a history of lupus nephritis than anti-dsDNA antibody titres.

Posterior Reversible Encephalopathy Syndrome in a Patient with Lupus Nephritis

Posterior reversible encephalopathy syndrome (PRES) has been described in various clinical settings, including severe hypertension, eclampsia, lupus and immunosuppressive therapy. We report a 27 year-old female systemic lupus erythematosus patient who developed severe headache, seizure and hemiparesis during her lupus nephritis flare. Magnetic resonance image (MRI) showed multi-focal high signal intensity lesions in the parieto-occipital cortex bilaterally and in the subcortical white matter. Her condition improved with immunosuppressive treatments, antihypertensives and hemodialysis. The extent of her lesions decreased on follow-up MRI 2 months later. This case suggests that PRES can be treated with immunosuppressive drugs that do not increase blood pressure.

The clinical relevance of a repeat biopsy in lupus nephritis flares

The clinical utility of performing repeat biopsies during lupus nephritis flares is questionable and data pointing towards frequent class switches are based on the old WHO classification. This retrospective study investigates the hypothesis that clinically relevant switches from proliferative to non-proliferative lesions and vice versa as determined by the new ISN/RPS classification are a rare event and that repeat biopsies are unnecessary in many cases. Thirty-five patients with lupus nephritis and one or more repeat renal biopsies were included. Eighty-four biopsies were blindly reassessed according to the ISN/RPS classification. Twenty-five patients had one repeat biopsy, 6 patients had two and 4 patients had three repeat biopsies. Forty-nine comparisons between reference and repeat biopsies could be made. In 25 cases (54.3%), there was no shift in ISN/RPS class on repeat biopsies. In 41 instances, paired biopsies showed proliferative lesions both on reference and repeat biopsies, whereas five of six cases with non-proliferative lesions on a reference biopsy switched to proliferative lesions on a repeat biopsy. Clinically significant class switches during lupus nephritis flares were more frequent in patients with non-proliferative lesions in their reference biopsy (P < 0.001). The results show that patients with proliferative lesions in the original biopsy rarely switch to a pure non-proliferative nephritis during a flare. Therefore, a repeat biopsy during a lupus nephritis flare is frequently not necessary if proliferative lesions were found in the reference biopsy. However, in the case of a non-proliferative lesion in the reference biopsy, class switches are frequently found and repeat biopsies are advisable.

Abetimus sodium: a medication for the prevention of lupus nephritis flares

Background: Lupus nephritis, one of the most severe and therapeutically challenging manifestations of systemic lupus erythematosus (SLE), has been the target of drug development by La Jolla Pharmaceutical Company. Abetimus sodium, an example of the La Jolla Pharmaceutical Company's Tolerance Technology® is an intravenously administered tetrameric oligonucleotide conjugate that safely reduces antidouble-stranded DNA (anti-dsDNA) antibodies. Given the importance of anti-dsDNA antibodies in the pathogenesis of lupus nephritis, the Phase II and III trials were designed to evaluate whether treatment with abetimus sodium could prolong the time to renal flare in cohorts of patients at high risk of nephritic flares. Objective and methods: The available data regarding abetimus were reviewed and the current status of the drug's development program is reported. Conclusions: Animal studies have demonstrated the ability of abetimus to reduce the titers of anti-dsDNA antibodies as well as of antidsDNA antibody-secreting cells. Administration of abetimus to patients with SLE has uniformly been associated with reductions in circulating anti-dsDNA antibodies. However, two pivotal trials with large numbers of lupus nephritis patients failed to demonstrate statistically signi ficant prolongations in time to renal flare. An event-driven randomized placebo-controlled trial was abruptly terminated in February 2009 after an interim data safety monitoring board determined that achievement of a successful study outcome was futile.

CXCR3+CD4+ T cells are enriched in inflamed kidneys and urine and provide a new biomarker for acute nephritis flares in systemic lupus erythematosus patients

The high frequency of CD4+ T cells in interstitial infiltrates of patients with lupus nephritis suggests a contribution of these cells to local pathogenesis. The aim of this study was to examine the role of CXCR3 and the chemokine CXCL10 in recruiting these cells into the kidney and to determine whether the infiltrating T cells could be monitored in the urine to provide a reliable biomarker for acute lupus nephritis. The frequencies of CD3+ T cells, CXCR3+ cells, and CXCL10+ cells were determined by immunohistochemical and immunofluorescence analyses of kidney sections from 18 patients with lupus nephritis. The frequency of CXCR3+CD4+ T cells was determined by flow cytometry of peripheral blood and urine from 38 patients with systemic lupus erythematosus (SLE), and the values were compared with disease activity as determined by the Systemic Lupus Erythematosus Disease Activity Index. In renal biopsy tissues from patients with lupus nephritis, a mean of 63% of the infiltrating cells expressed CXCR3, approximately 60% of them were T cells, and the CXCR3+ cells colocalized with CXCL10-producing cells. In biopsy tissues from SLE patients with acute nephritis, approximately 50% of the urinary CD4+ T cells were CXCR3+, as compared with 22% in the peripheral blood, and the frequency of urinary CXCR3+CD4+ T cells correlated with disease activity. Moreover, the number of urinary CD4+ T cells reflected nephritis activity, and elevation above 800 CD4+ T cells per 100 ml of urine sharply delineated active from inactive nephritis. CXCR3+ T cells are recruited into the inflamed kidneys, are enriched in the urine, and are a valuable marker of nephritis activity in SLE. They also present a potential target for future therapies.

Biomarkers of lupus nephritis determined by serial urine proteomics

Lupus nephritis is a frequent and serious complication of systemic lupus erythematosus (SLE), the treatment of which often requires the use of immunosuppressives that can have severe side effects. Here we determined the low-molecular weight proteome of serial lupus urine samples to uncover novel and predictive biomarkers of SLE renal flare. Urine from 25 flare cycles of 19 patients with WHO Class III, IV, and V SLE nephritis were obtained at baseline, pre-flare, flare and post-flare. Each sample was first fractionated to remove proteins larger than 30 kDa, then applied onto weak cation exchanger protein chips for analysis by SELDI-TOF mass spectrometry. We found 176 protein ions of which 27 were differentially expressed between specific flare intervals. On-chip peptide sequencing by integrated tandem mass spectrometry positively identified the 20 and 25 amino-acid isoforms of hepcidin, as well as fragments of alpha1-antitrypsin and albumin among the selected differentially expressed protein ions. Hepcidin 20 increased 4 months before renal flare and returned to baseline at renal flare, whereas hepcidin 25 decreased at renal flare and returned to baseline 4 months after the flare. These studies provide a beginning proteomic analysis aimed at predicting impending renal relapse, relapse severity, and the potential for recovery after SLE nephritis flare.