Lupus Nephritis Flare Research Articles

Systemic Lupus Erythematosus: Clinical Updates in Women's Health Care Primary and Preventive Care Review.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease most commonly involving skin, joints, and kidneys. Usually, it presents in women in puberty or early adulthood. This monograph provides an overview of the role of an obstetrician-gynecologist (ob-gyn) in the treatment of SLE patients. An ob-gyn is uniquely placed in the health care continuum throughout the life cycle of a woman. Notably, an ob-gyn often is the first physician to notice SLE-related rash, swollen joints, cytopenias, or proteinuria in a patient and is the first to provide initial management. Obstetrician-gynecologists must be familiar with SLE effects on reproductive issues, such as SLE effects on the choice of birth control, pregnancy outcomes, and the risks of hormone therapy use, as well as the pregnancy effects on the risk of lupus nephritis flares. Human papillomavirus and associated cancer also are of concern in patients with SLE. Providing care to women with SLE is multifaceted; therefore, ob-gyns often will need to liaise with rheumatologists and other specialists.

Elevated Urinary Neutrophil Gelatinase-Associated Lipocalin Is a Biomarker for Lupus Nephritis: A Systematic Review and Meta-Analysis.

Objective Lupus nephritis (LN) is a major and severe complication of systemic lupus erythematosus (SLE). Neutrophil gelatinase-associated lipocalin (NGAL), as a promising next-generation biomarker in clinical nephrology, has received extensive attention. However, its diagnostic performance in LN has high variability. Therefore, we performed an updated meta-analysis to further evaluate the diagnostic accuracy of urinary NGAL (uNGAL). Materials and Methods PubMed, Embase, and Cochrane Library were searched from inception to October 27, 2019. Meta-analysis was performed with a bivariate random effects model. Additionally, the summary receiver operating characteristic (SROC) curves were established. The sources of heterogeneity were explored by meta-regression, subgroup analysis, and sensitivity analysis. Publication bias was assessed using the Deeks test. Results 19 articles consisting of 21 eligible studies were included. In diagnosing LN, the estimates (95% confidence interval (CI)) were as follows: sensitivity, 0.84 (0.71-0.91); specificity, 0.91 (0.70-0.98); and the SROC-AUC value, 0.92 (0.90-0.94). In identifying active LN, the estimates were as follows: sensitivity, 0.72 (0.56-0.84); specificity, 0.71 (0.51-0.84); and the AUC value, 0.77 (0.74-0.81). With respect to predicting renal flare, the estimates were as follows: sensitivity, 0.80 (0.57-0.92); specificity, 0.67 (0.58-0.75); and the AUC value, 0.74 (0.70-0.78). For the studies to distinguish proliferative LN, the estimates were as follows: sensitivity, 0.87 (0.66-0.97), and specificity, 0.69 (0.39-0.91). Deeks' funnel plot suggested that there was no significant publication bias. Conclusions Our meta-analysis indicates that uNGAL was a useful biomarker for diagnosis, estimation of activity, and prediction of renal flare of LN. In addition, the usefulness of uNGAL to distinguish pathological types of LN needs to be further investigated.

P0492ICAM-1 AND VEGF AS BIOMARKERS FOR PREDICTION LUPUS NEPHRITIS FLARE

Abstract Background and Aims Systemic lupus erythematosus (SLE) is autoimmune systemic disease of the connective tissue and characterized by the development of severe complications associated with damage to vital organs, in particular the kidneys. One of the important issues is an adequate assessment of the current activity and the objective prediction of the lupus nephritis (LN) flare. For this purpose molecular biomarkers are being searched. The work aim is the analyzing role of the intercellular adhesion molecule (ICAM-1) and vascular endothelial growth factor (VEGF) in the serum and urine of patients with SLE as a biomarker for lupus nephritis flare. Method The study group consisted of patients with SLE with LN (n = 23). The control group included patients with SLE without renal pathology (n = 13). The concentration of ICAM-1 and VEGF molecules was determined in blood serum and urine by enzyme-linked immunosorbent assay. Results The median concentration of ICAM-1in serum in patients with LN is 822.41 (580.50; 1300.95) ng/ml. That is two times higher than this indicator in the control group (378.97 (356.47; 439.52) ng/ml). The concentration of the VEGF molecule in serum in the group of LN is 91.99 (74.18; 132.58) ng/ml. That is three times higher than in the control group (31.13 (22.32; 132.58) ng/ml). An increase in the blood serum concentration of patients with SLE ICAM ≥577.7 ng/ml will indicate the presence of LN with a sensitivity of 82.61% and a specificity of 83.33%. ROC analysis showed the AUC coefficient is 0.927 (p = 0.0001). An increase in the blood serum in VEGF concentration of ≥66.43 ng/ml in patients with SLE will indicate the presence of LN with a sensitivity of 80.00% and a specificity of 83.33%. ROC analysis showed that the AUC coefficient is 0.916 (p = 0.006). Conclusion The results allow to conclude that it is possible to use the ICAM and VEGF concentration in serum and urine as early molecular markers of the LN and LN flare in patients with SLE.

AB0412 URINARY SOLUBLE VCAM-1 IS A USEFUL BIOMARKER OF DISEASE ACTIVITY AND TREATMENT RESPONSE IN LUPUS NEPHRITIS

Background:The traditional lupus nephritis (LN) biomarkers are not sensitive nor specific enough for detecting ongoing disease activity and early relapse of nephritis and they do not reflect kidney damage nor have prognostic value1. Urinary biomarkers are directly excreted by the kidney and are easily obtained. They can also differentiate the renal activity of the disease from other organic manifestations more accurately than the serum biomarkers2. Vascular cell adhesion molecule-1 (VCAM-1) is involved in the progression of glomerular and tubulointerstitial injury in LN and its soluble form can be easily assessed in urine (uVCAM-1)3. Several studies correlated the uVCAM-1 levels with urine protein-creatinine ratio (UPC), with general disease activity and with active LN3.Objectives:To assess uVCAM-1 as a biomarker of disease activity and treatment response in LN.Methods:This prospective study enrolled patients with class III, IV or V LN diagnosed within the last three years and divided them in two groups: with and without active nephritis at the inclusion. The patients with active nephritis were included before they started a new immunosuppressive treatment. Active LN was defined as proteinuria (UPC≥0.5) plus active urinary sediment (hematuria, leukocyturia or cellular hematic/granular casts). At each visit, a urine sample was collected for uVCAM-1 evaluation and the nephritis status was accessed.Results:Median uVCAM-1 level was elevated in patients with active compared to inactive LN (p<0.001). The ROC curve of uVCAM-1 demonstrated an AUC of 0.84 and a cutoff of 47.2 ng/mgCr yielded a good sensitivity (74.2%) and specificity (74.2%) for the diagnosis of active LN. A significant correlation was found between uVCAM-1 level and renal activity scores and traditional biomarkers of LN (table 1). The level of uVCAM-1 dropped in patients with active LN who went into remission (p<0.001), increased in patients who went into activity (p=0.002) and did not change in patients who remained inactive (p=0.797) (figure 1). The level of uVCAM-1 peaked during the flare of LN (p<0.05) (figure 2).Table 1.Correlations between urinary soluble VCAM-1 and other LN biomarkers/disease scoresLN biomarkers/disease scoresVCAM-1SLEDAI-2k0.597***Renal SLEDAI0.569***Renal SLAM-R0.470***Renal SLICC0.620***Anti-dsDNA0.342**C3-0.344**C4-0.382**UPC0.654***Spearman’s correlation coefficients*pvalue <0.05; **pvalue <0.01; ***pvalue <0.001C, complement; LN, lupus nephritis; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; renal SLAM-R, The renal Systemic Lupus Activity Measure revised; renal SLICC, The Systemic Lupus International Collaborating Clinics renal activity/response exercise; UPC, urine protein-creatinine ratio.Conclusion:The uVCAM-1 is a reliable biomarker that reflects renal disease activity and is useful for monitoring individual patients with lupus nephritis over time.

Factors Associated with Renal Outcomes in an Inception Cohort of Biopsy-proven Lupus Nephritis Patients

Objective: To identify the clinical factors associated with renal response and flare in lupus nephritis (LN).Methods: All 115 patients with biopsy-proven LN diagnosed between January 2002 and June 2015 in a tertiary centre comprised of an inception cohort that was followed up until February 2017. Baseline demographic, clinical parameters, renal biopsy histology, induction and maintenance immunosuppressive therapies, complete renal response (CRR), creatinine doubling, end-stage renal disease (ESRD), renal flares and infections were retrieved and analyzed with univariate log-rank test and multivariate Cox regression.Results: At the time of the first renal biopsy, the age of patients was 38 ± 12.2 years (mean ± standard deviation), 90% female and systemic lupus erythematosus (SLE) disease duration 46 months (median); 67.0% were LN class IV or class IV + V. Patients were followed up for 104 ±49 months after biopsy. At months 3, 6, 12 and 24, a cumulative 25%, 46%, 66% and 76% of patients had achieved CRR, respectively. However, 49.5% who had CRR experienced [Formula: see text]1 infection of renal flare, with cumulative risk of 5%, 17%, 25% and 43% at year 1, 2, 3 and 5, respectively. Multivariate analysis showed that nephrotic syndrome ([Formula: see text] = 0.03) and delay of renal biopsy [Formula: see text]2 months from the onset of LN ([Formula: see text] ¡ 0.01) were negatively associated with CRR. Hydroxychloroquine use was beneficial in attaining CRR ([Formula: see text] = 0.03, hazard ratio = 1.70, 95% CI: 1.04, 2.80) and preventing renal flare ([Formula: see text] = 0.01, odds ratio = 0.51, 95% CI: 0.29, 0.88). By the end of the study, 80% of patients remained in CRR though 10.4% patients ended up in ESRD (all class IV), 8.7% died and 28.7% had [Formula: see text]1 infection episode requiring hospitalization.Conclusion: Most LN patients could achieve CRR after immunosuppressive therapy but renal flares were common over time. Infective complications were fairly frequent but the incidence of ESRD was low. The use of hydroxychloroquine was associated with better renal response and fewer flares.

Urinary Soluble CD163: a Novel Noninvasive Biomarker of Activity for Lupus Nephritis.

Clinical distinction between patients with lupus nephritis who have active inflammation or chronic kidney damage is challenging. Studies have shown soluble CD163, which derives from cleavage of the CD163 M2c macrophage receptor and can be quantified in urine, correlates with active lupus nephritis. We measured urine CD163 at lupus nephritis flares in patients from a Mexican cohort and cross-sectional and longitudinal United States cohorts. We also performed serial urine CD163 measurements during the treatment of flares in a subset of patients from the Mexican and longitudinal United States cohorts, and assessed response to therapy at 12 months. In addition, we evaluated urinary CD163 agreement with histologic activity in 19 patients from the Mexican cohort who had repeated kidney biopsies on follow-up. Urinary CD163 levels were significantly higher in patients with active lupus nephritis than in patients with active extrarenal SLE, inactive SLE, and other glomerular diseases, and correlated with disease clinical severity, histologic class, and the histologic activity index. Urinary CD163 increased from 6 months preflare to flare, diminishing progressively in complete and partial responders, whereas it remained elevated in nonresponders. Urinary CD163 <370 ng/mmol at 6 months predicted complete renal response at 12 months with >87% sensitivity and >87% specificity. Urinary CD163 <370 ng/mmol or >370 ng/mmol perfectly agreed (κ=1.0) with a histologic activity index ≤1 or >1 in repeated biopsies, respectively. Evaluation of urinary CD163 in patients with persistent proteinuria at 6 months improved the prediction of who would achieve complete renal response at 12 months. Urinary CD163 reflects histologic inflammation in lupus nephritis and is a promising activity biomarker that varies over time with lupus nephritis activity and treatment.

EP34 Assessing the ability of anti-C1q antibody measurement to predict a flare of lupus nephritis

Abstract Background Systemic lupus erythematous (SLE) is a multi-system autoimmune disease which has a relapsing and remitting course. Patients with lupus nephritis (LN) are at risk of relapse and hence long term follow up and disease monitoring are of particular importance. Anti-C1q antibodies (C1Q Ab) are observed in 30-60% of patients with SLE. It has been postulated that the presence of C1Q Ab can predict a flare of LN. Here we undertook a prospective follow up of patients after having a C1Q Ab measurement to determine whether the result predicted a flare of LN. Methods SLE patients attending an Inner-City Lupus Center, were involved in the study. All fulfilled the 2012 SLICC criteria for SLE. A point-in-time measurement of C1Q Ab was made using an ELISA kit (Orgentec Diagnostika GmbH). A positive test defined by the manufacturer is a level above 10 U/ml. Medical records of patients were reviewed over the following 1 year to identify LN flares. A renal flare was defined as a doubling of the protein creatinine ratio with a subsequent decision to escalate immunosuppressive therapy. Chi Squared tests were used to assess statistical significance. 9 patients who were being treated for a flare of LN at the time of C1Q Ab were excluded from the analysis. Results 116 lupus patients were included in the study. Of those, 52 had biopsy proven LN (45%). Positive C1Q ab was more common in patients with a history of biopsy proven LN (n = 17, 32.7%) compared to those with non-renal SLE (n = 10, 15.6%),(p = 0.03). Renal flares tended to be more common in C1q ab positive LN patients (n = 4, 26.7%) compared to those without C1q ab (n = 2, 7.14%). (p = 0.782). Of the 64 patients with non-renal SLE, 1 (10%) C1Q Ab positive patient subsequently developed LN compared with 1 (1.85%) C1Q Ab negative patient (p = 0.173).There was no correlation between the level of C1Q Ab and the rate of LN flares. Having a positive dsDNA antibody level at the time of sampling also did not appear to predict a flare. Conclusion C1Q Ab has a known correlation with LN, however its ability to predict flares has been less well characterised. Our prospective analysis shows that although the C1Q Ab positive patients were more likely to have a flare of LN in the following year, there was not a statistically significant difference between the C1Q Ab positive and negative groups. In addition, only a relatively small proportion of C1Q Ab positive patients went on to have a flare (20%). Our data therefore does not support the use of C1Q Ab as a predicting factor for a subsequent flare of LN. Disclosures S. Bahal None. D. Pyne None. R. Rajakariar None. M. Lewis None. A. Pakozdi None. A. Cove-Smith None.

Contribution of Clinically Indicated Repeat Renal Biopsy in Indian Patients with Lupus Nephritis.

Background:Repeat renal biopsy is usually done for lupus nephritis (LN) flare or resistant disease. We analyzed the changes between first and repeat biopsy and the contribution of repeat biopsy on renal outcome in LN patients.Methods:This was a retrospective study carried out at a tertiary care center in India. Sixty-two LN patients who underwent repeat biopsy for clinical indications, between January 2012 to December 2016, were included. Clinical and histological parameters at first and second biopsies were compared. Logistic regression analysis was done to determine parameters on repeat biopsy predicting response at last visit.Results:Repeat biopsy was done for relapse in 56% and for resistant disease in 44% patients. Seven (13.7%) out of 51 patients with baseline proliferative histology converted to non-proliferative lesion on second biopsy, while 2 (18.2%) out of 11 with baseline non-proliferative lesion converted to proliferative lesion on second biopsy. On repeat biopsy, the presence of endocapillary proliferation decreased, whereas glomerulosclerosis, interstitial fibrosis/tubular atrophy (IFTA), and glomerular basement membrane thickening increased. At the last visit (median follow-up of 38.6 months after first biopsy and 13.8 months after second biopsy), 79% of patients were in remission and 6.5% needed renal replacement therapy. The presence of IFTA >30% and thrombotic microangiopathy (TMA) on second biopsy independently predicted response at last visit.Conclusion:In Indian patients with LN, chronicity markers and superimposed membranous pattern increased on repeat biopsy done for clinical indications. The presence of IFTA and TMA on second biopsy predicted response at last visit.

High frequency of nocturnal hypertension in lupus nephritis: should ABPM be implemented in usual practice?

Hypertension management in lupus nephritis (LN) is guided by in-office blood pressure (BP); however, recent studies demonstrate that lupus patients frequently have nocturnal hypertension and reduced BP dipping. The aim of the study was to evaluate 24-h blood pressure in patients with active LN and after response to treatment. Seventy active LN patients were evaluated during a LN flare by ambulatory blood pressure monitoring (ABPM). Later, 10 patients with complete response were re-evaluated after 12 months along with 20 matched controls. Overall, daytime and nightime BP, day-to-night dipping, BP load and variability, and the incidence of abnormal BP patterns were assessed. Blood pressure levels were correlated with clinical and histologic parameters and independent associations evaluated by linear regression. Overall systolic hypertension occurred in 25 (36%) patients and diastolic hypertension in 28 (40%). Nighttime systolic and diastolic hypertension occurred in 35 (50%) and 44 (63%) of patients, respectively. Nocturnal systolic day-to-night BP decrease was abnormal in 59 (84%) patients. Only 18 (26%) were diagnosed with HT by in-office evaluation while 29 (41%) had masked hypertension (MH)/masked uncontrolled hypertension (MUCH), and 3 (4%) had white coat hypertension. Patients with MH had lower eGFR, complement C3, hemoglobin, and higher systolic variability compared with patients with normal BP. Systolic and diastolic BP levels were associated with the years under corticosteroid treatment, activity biomarkers (proteinuria, complement C3), and the degree of interstitial inflammation in the kidney biopsy. A re-evaluation at 12 months showed that although 9 out of 10 patients had normal in-office BP and BP loads improved, still 5 patients remained with MH due to nocturnal hypertension, and 7 remained with abnormal day-to-night dipping. These numbers were higher than those of matched controls. Due to the high frequency of nocturnal hypertension and abnormal day-to-night dipping, office BP measurements alone may not be sufficient to guide hypertension management in patients with LN.Key Points• Nocturnal hypertension and abnormal BP patterns are frequent and not detectable by the standard in-office BP evaluation in LN patients.• BP abnormalities may not be fully corrected after a complete clinical response to treatment in lupus nephritis and are only detectable by ABPM.• The degree of interstitial inflammation in the kidney biopsy in LN patients is associated to BP levels. This supports the hypotheses underlining the role of interstitial inflammation in salt sensitivity and hypertension.

Contraception and CKD.

In general, nephrologists give little thought to contraception, leaving this task to other practitioners, but the significant risks associated with drugs routinely prescribed to treat kidney disease; the potential for pregnancy-associated adverse outcomes in women with CKD; and the effect that

Kidney biopsy–based management of maintenance immunosuppression is safe and may ameliorate flare rate in lupus nephritis

The optimal duration of maintenance immunosuppressive therapy for patients with lupus nephritis who have achieved clinical remission has not been established. Furthermore, clinical and histologic remissions are often discordant. We postulated that continuing therapy for patients with persistent histologic activity on kidney biopsies done during maintenance and discontinuing therapy only for patients without histologic activity would minimize subsequent lupus nephritis flares. To test this, a cohort of 75 prospectively-followed patients with proliferative lupus nephritis was managed using kidney biopsies performed during maintenance therapy. These patients had been on immunosuppression for at least 42 months, had responded, and had maintained their clinical response for at least 12 months before the kidney biopsy was repeated. Maintenance therapy was withdrawn if the biopsy showed an activity index of zero, but was continued if the biopsy showed an activity index of one or more. A lupus nephritis flare developed in seven patients during the average 50 months from the third biopsy and the final clinic visit for a flare rate of 1.5/year; significantly less than reported flare rates. Baseline clinical parameters (serum creatinine, proteinuria) and serologic parameters (complement C3, C4 and anti-dsDNA) did not predict an activity index of zero on the third biopsy or who would have a lupus nephritis flare. No patients developed end-stage kidney disease. Four patients developed de novo chronic kidney disease. There were no serious adverse events related to biopsy. Thus, at an experienced center, biopsy-informed management of maintenance immunosuppression is safe and may improve the lupus nephritis flare rate compared to conventional clinical management.

Correlation Between Serological Makers and Immunofluorescence Deposits i n Kidney Tissue of Patients with Lupus Nephritis

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease. Few biomarkers for SLE have been validated and widely accepted for the laboratory follow-up of inflammatory activity. In SLE patients, with lupus nephritis (LN), complement activation leads to fluctuation of serum C3 and C4 that are frequently used as clinicalm biomarker of disease activity in SLE. Patients and Methods: In this study the number of patients were 37, seven patients were excluded for incomplete data collection, 28 were females ,2 were males. The duration of the study is two years from 2015 to 2017. Patients were considered to have SLE and LN according to American College of Rheumatology (ACR) criteria, and International Society of Nephrology/ Renal Pathology Society (ISN/RPS). All patients were evaluated withm clinical presentation, laboratory investigations. Our patients underwent kidney biopsy according to standard procedure by Kerstin Amann, and their tissue specimens were studied in the laboratory with light microscope (LM) and immunofluorescence microscope reagents. The relationship between the serological markers and immunofluorescence deposits in kidney biopsy of all patients were studied using the statistical analysis of Pearson correlation and single table student's T test. A P value 0.05 was considered statistically significant. Results: The granular pattern of IF deposits was present in all LN patients, and in more than two third of patients these IF deposits presented in glomerular, tubular, and mesangium sites. While less than one third of patients had IF deposits in the mesangium only. There was no statistically significant correlation between serum ANA, anti-dsDNA, and IF deposits of different types. There was significant correlation between serum C3 and C4 hypocomplementemia and IgG immune deposits in kidney biopsy, and there was significant relationship between serum C3 hypocomplementemia and full house immunofluorescence (FHIF) deposits inm kidney biopsy.Conclusions:Immunofluorescence deposits is mainly granular pattern in LN patients. There was no significant association between serum ANA, anti-dsDNA, and immune deposits in kidney tissue. Immunofluorescence deposits of IgG type correlates significantly with serum C3 and C4 hypocomplemetemia, and these immune deposits in association with low complement levels correlates with LN flare. There was significant correlation between C3 hypocomplementemia and FHIF.

Commentary on the Current Guidelines for the Diagnosis of Lupus Nephritis Flare.

Lupus nephritis flare is a frequent complication in patients with systemic lupus erythematosus. Recognizing disease activity is crucial in lupus nephritis management. Proteinuria magnitude and urine sediment change are major clinical indicators of lupus nephritis activity. This work updates these insights in light of recent findings regarding proteinuria quantification and urine sediment analyses. Currently, BILAG and SLEDAI estimate proteinuria magnitude based on the protein/creatinine ratio of "spot" (single void collections) or "intended" 24-h urine collections without specifying the extent to which the collection approaches a 24-h collection. As discussed here, and based on our recently published work, these approaches often incur serious errors that can adversely affect SLE patient management. Also incorporated into this work is a new analysis of the clinical significance of urine sediment hematuria and pyuria changes with regard to recent-onset SLE glomerulonephritis (GN) flare. This analysis is based on a prospective study of urine sediment changes in the Ohio SLE Study, which was an NIH-sponsored prospective observational study of SLE GN patients with SLE flare of recent onset. We propose that BILAG and SLEDAI renal flare criteria can be made more rigorous by incorporating recently published insights into proteinuria quantification using the protein/creatinine ratio of an intended 24-h urine collection that is at least 50% complete based on its creatinine content. Also proposed are new insights into the interpretation of urine sediment hematuria and pyuria based on findings from the Ohio SLE Study.

Multiple vasculitic ulcers with lupus nephritis flare in pregnancy

Vasculitic ulcer in a case of systemic lupus erythematosus is considered as nonspecific cutaneous manifestations and those presenting with multiorgan involvement in pregnancy carry a higher maternal and fetal risk with disease flares. Presentation of a pregnant patient with severe lupus nephritis (LN) along with multiple cutaneous vasculitic ulcers is very uncommon. Aggressive treatment with immunosuppressants along with supportive treatment of cutaneous ulcerations will not only control the disease flares including LN but also result in complete healing of ulcerations.

A Markov Multi-State model of lupus nephritis urine biomarker panel dynamics in children: Predicting changes in disease activity

BackgroundA urine ‘biomarker panel’ comprising alpha-1-acid-glycoprotein, ceruloplasmin, transferrin and lipocalin-like-prostaglandin-D synthase performs to an ‘excellent’ level for lupus nephritis identification in children cross-sectionally. The aim of this study was to assess if this biomarker panel predicts lupus nephritis flare/remission longitudinally. MethodsThe novel urinary biomarker panel was quantified by enzyme linked immunoabsorbant assay in participants of the United Kingdom Juvenile Systemic Lupus Erythematosus (UK JSLE) Cohort Study, the Einstein Lupus Cohort, and the South African Paediatric Lupus Cohort. Monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 were also quantified in view of evidence from other longitudinal studies. Serial urine samples were collected during routine care with detailed clinical and demographic data. A Markov Multi-State model of state transitions was fitted, with predictive clinical/biomarker factors assessed by a corrected Akaike Information Criterion (AICc) score (the better the model, the lower the AICc score). ResultsThe study included 184 longitudinal observations from 80 patients. The homogeneous multi-state Markov model of lupus nephritis activity AICc score was 147.85. Alpha-1-acid-glycoprotein and ceruloplasmin were identified to be the best predictive factors, reducing the AICc score to 139.81 and 141.40 respectively. Ceruloplasmin was associated with the active-to-inactive transition (hazard ratio 0.60 (95% confidence interval [0.39, 0.93])), and alpha-1-acid-glycoprotein with the inactive-to-active transition (hazard ratio 1.49 (95% confidence interval [1.10, 2.02])). Inputting individual alpha-1-acid-glycoprotein/ceruloplasmin values provides 3, 6 and 12 months probabilities of state transition. ConclusionsAlpha-1-acid-glycoprotein was predictive of active lupus nephritis flare, whereas ceruloplasmin was predictive of remission. The Markov state-space model warrants testing in a prospective clinical trial of lupus nephritis biomarker led monitoring.

A prospective observational cohort study highlights kidney biopsy findings of lupus nephritis patients in remission who flare following withdrawal of maintenance therapy

One of the most difficult management issues in lupus nephritis (LN) is the optimal duration of maintenance immunosuppression after patients are in clinical remission. Most patients receive immunosuppression for years, based mainly on expert opinion. Prospective data are unavailable. Complicating this issue are data that patients in clinical remission can still have histologically active LN; however, the implications of this are unknown. To study this, the Lupus Flares and Histological Renal Activity at the end of Treatment study (ClinicalTrial.gov, NCT02313974) was designed to examine whether residual histologic activity predisposes to LN flares in class III and IV LN. Patients in complete clinical remission for at least 12 months who had received at least 36 months of immunosuppression were eligible. Patients consented to a second kidney biopsy, were tapered off maintenance immunosuppression and were then followed prospectively for LN flares over 24 months. Forty-four patients were enrolled, and 36 completed the study. LN flares occurred in 11 patients, and ten of these had residual histologic activity on the second biopsy. All patients with an NIH activity index over two flared. The activity index and duration of systemic lupus erythematosus at the second biopsy were independent predictors of flare. A predictive equation based on these variables discriminated between flare and no flare with a sensitivity of 100%, specificity of 88%, and a misclassification rate of 8.3%. Thus, a repeat kidney biopsy may be useful in managing maintenance immunosuppression in LN, and patients in histologic remission may be candidates for withdrawal of therapy.

Immune gene expression in kidney biopsies of lupus nephritis patients at diagnosis and at renal flare.

Up to 50% of lupus nephritis (LN) patients experience renal flares after their initial episode of LN. These flares contribute to poor renal outcomes. We postulated that intrarenal immune gene expression is different in flares compared with de novo LN, and conducted these studies to test this hypothesis. Glomerular and tubulointerstitial immune gene expression was evaluated in 14 patients who had a kidney biopsy to diagnose LN and another biopsy at their first LN flare. Ten healthy living kidney donors were included as controls. RNA was extracted from laser microdissected formalin-fixed paraffin-embedded kidney biopsies. Gene expression was analyzed using the Nanostring nCounter® platform and validated by quantitative real-time polymerase chain reaction. Differentially expressed genes were analyzed by the Ingenuity Pathway Analysis and Panther Gene Ontology tools. Over 110 genes were differentially expressed between LN and healthy control kidney biopsies. Although there was considerable molecular heterogeneity between LN biopsies at diagnosis and flare, for about half the LN patients gene expression from the first LN biopsy clustered with the repeated LN biopsy. However, in all patients, a set of eight interferon alpha-controlled genes had a significantly higher expression in the diagnostic biopsy compared with the flare biopsy. In contrast, nine tumor necrosis factor alpha-controlled genes had higher expression in flare biopsies. There is significant heterogeneity in immune-gene expression of kidney tissue from LN patients. There are limited but important differences in gene expression between LN flares, which may influence treatment decisions.

Urinary levels of sirtuin-1 associated with disease activity in lupus nephritis.

Identifying new markers of disease flares in lupus nephritis (LN) that facilitate patient stratification and prognosis is important. Therefore, the aim of the present study was to analyze whether urinary SIRT1 expression was altered in LN and whether SIRT1 values in urine could be valuable biomarker of disease activity. In a cohort study, urinary pellets from 40 patients diagnosed with systemic lupus erythematosus (SLE) were analyzed. Clinical measures of lupus activity were assessed. The expression of SIRT1 was quantified by quantitative PCR (qRT-PCR) and immunoblot, then compared between patients with active lupus nephritis, in remission and healthy controls. Association with lupus activity and renal histological features was also analyzed. A significant increase in SIRT1 mRNA levels in patients with active LN was observed compared with those in remission (P=0.02) or healthy controls (P=0.009). In addition, SIRT-1 protein levels were also augmented in LN group than remission (P=0.029) and controls (P=0.001). A strong association was found between SIRT1 expression with anti-dsDNA in SLE and in patients with LN. In addition, histological features in LN biopsies were related with SIRT1, increasing its expression in proliferative forms. Finally, SIRT1 expression values showed a strong discriminatory power of renal injury in SLE. Our study demonstrated an altered urinary expression of SIRT1 and a strong association with disease activity in LN patients, being a valuable marker of renal injury. These results showed the role of the SIRT1 pathway in the SLE pathogenesis.

Preemptive immunosuppressive treatment for asymptomatic serological reactivation may reduce renal flares in patients with lupus nephritis: a cohort study.

Serological activity may precede clinical flares of lupus nephritis (LN) but the management of asymptomatic serological reactivation (ASR) remains undefined. We conducted a retrospective analysis of 138 episodes of ASR, which included 53 episodes in which immunosuppression was increased preemptively and 85 episodes in which treatment was unaltered. Preemptive immunosuppressive treatment comprised increasing the dose of prednisolone to ∼0.5 mg/kg/day, and in patients already on mycophenolate mofetil (MMF) or azathioprine (AZA), increasing the dose to 1.5 g/day and 100 mg/day, respectively. Thirty-four episodes of renal flare occurred during follow-up (88.8 ± 77.3 and 82.8 ± 89.7 months in the preemptive group and controls, respectively), following 5 (9.4%) of preemptively treated ASR and 27 (31.8%) of untreated ASR [hazard ratio 0.3 (confidence interval 0.1-0.7), P = 0.012]. Preemptive treatment was associated with superior survival free of renal relapse (99, 92 and 90% at 6, 12 and 24 month, respectively, compared with 94, 69 and 64% in controls; P = 0.011), whereas survival rate free of extrarenal relapse was similar in the two groups. Preemptively treated patients who did not develop renal flares showed better renal function preservation (estimated glomerular filtration rate slope +0.54 ± 0.43 mL/min/1.73 m2/year, compared with -2.11 ± 0.50 and -1.00 ± 0.33 mL/min/1.73 m2/year, respectively, in controls who did and did not develop subsequent renal flares; P = 0.001 and 0.012, respectively). Preemptive treatment was associated with an increased incidence of gastrointestinal side effects attributed to MMF (P = 0.031), whereas infection rate did not differ between the two groups. A preemptive moderate increase of immunosuppression for ASR in LN patients may reduce renal flares and confer benefit to long-term renal function.

Clinical predictors of proteinuric remission following an LN flare - evidence from the UK JSLE cohort study

BackgroundProteinuria is a well-known risk factor for progression of renal dysfunction in a variety of chronic kidney diseases. In adult-onset Systemic Lupus Erytematosus (SLE) patients with lupus nephritis (LN), proteinuria takes a significant period of time to normalise, with proteinuric remission being associated with improved renal survival and reductions in mortality. The length of time required to attain proteinuric remission has not previously been investigated in Juvenile-onset SLE (JSLE). The aim of this study was to elucidate when proteinuric remission occurs, and whether clinical/demographic factors at LN onset bear influence on the time to proteinuric remission.MethodsParticipants of the UK JSLE Cohort Study and Repository were included if they had active LN (renal biopsy and/or renal British Isles Lupus Assessment Grade (BILAG) score defined active LN) and proteinuria. Univariate Cox proportional hazard regression modelling was used to explore factors associated with time to proteinuric recovery. Covariates with p-value < 0.2 were included in a multivariable Cox regression model, and backward stepwise variable selection applied.Result64/350 (18%) of UK JSLE Cohort Study patients fulfilled the study inclusion criteria. 25 (39%) achieved proteinuric remission within a median of 17 months (min 2.4, max 78). Within a multivariate Cox proportional hazard regression model, age at time of LN flare (p = 0.007, HR 1.384, CI 1.095–1.750), eGFR (p = 0.035, HR 1.016, CI 1.001–1.030) and haematological involvement (p = 0.016, HR 0.324, CI 0.129–0.812) at the time of LN onset were found to be significantly associated with time to proteinuric recovery.ConclusionsA significant proportion of children with LN have on-going proteinuria approximately two years after their initial flare. Poor prognostic factors all at time of LN onset include younger age, low eGFR, and concomitant haematological involvement.