Relapse Of Nephritis Research Articles

Abstract 15 — Lupus Low Disease Activity State: An Underutilised Clinical Target that is Attainable and Protective against Lupus Nephritis Relapse

Background Lupus nephritis (LN) is a significant comorbidity affecting approximately 50-60% of patients with systemic lupus erythematosus (SLE). Complete and partial renal response (CRR/PRR) have been recommended as treatment targets in LN. Lupus low disease activity state (LLDAS) is also associated with favourable clinical outcomes. This study aims to investigate the LLDAS attainment rate and outcomes in patients with LN. Methods Patients with biopsy-proven LN during 2010-2020 in Queen Mary Hospital were included. Baseline demographics, blood parameters and urinalysis results were documented. Renal response and LLDAS attainment were assessed at 12 months after LN diagnosis. CRR was defined as proteinuria [Formula: see text]0.5g/day with a normal estimated glomerular filtration rate (eGFR); PRR was defined as a reduction in proteinuria by [Formula: see text]50% with near normal eGFR. A relapse was defined as a biopsy-proven active LN on histology after an initial treatment response of proteinuria reduction of [Formula: see text]50% or to sub-nephrotic range. Time-to-relapse survival analysis was performed to compare the significance of CRR/PRR and LLDAS attainment. Results 143 LN patients were included, with a median follow-up duration of 10.4 years. At 12 months, 57 (40%), 14 (10%) and 69 (48%) patients achieved CRR, PRR and LLDAS, respectively. Although 39 (27%) patients attained both CRR/PRR and LLDAS, a significant number of 30 (21%) patients reached LLDAS without meeting CRR/PRR (Figure 1). Among 136 patients who achieved the pre-defined treatment response, 30 (22%) patients developed LN relapse after a median of 2.98 years. Patients reaching either CRR/PRR or LLDAS had a significantly lower risk of relapse (CRR/PRR: HR = 0.34, p = 0.02; LLDAS: HR = 0.28, p = 0.003). The attainment of both CRR/PRR and LLDAS was associated with the lowest risk of relapse (Figure 2). Conclusion We advocate LLDAS as a target for LN patients as attaining LLDAS reduces future LN relapse risks.

MO038ANTIMYELOPEROXIDASE AND PROTEINASE 3 ANTIBODIES ARE A USEFUL MARKER AS NEPHRITIS FLARE PREDICTOR IN ANCA-ASSOCIATED VASCULITIS

Abstract Background and Aims The diagnostic utility of ANCA antibodies in ANCA associated-vasculitis (AAV), antiproteinase 3 (PR3) and myeloperoxidase (MPO) testing is now undisputed, but the clinical utility of serial MPO/PR3 testing to predict relapses, remain controversial. The aim of this study was to analyze the relevance of serum MPO and PR3 antibody level assessment in the management of AAV. We sought to determine whether MPO and PR3 antibody levels correlated with renal disease activity, and whether an increase could predict a nephritis flare. Method Retrospective multicenter study including AAV-patients with renal involvement from 7 nephrology departments belonging to the Spanish Glomerular Study Group (GLOSEN). The main inclusion criteria were that MPO antibodies were detected by ELISA (Multiplex assay) and PR3 using chemioluminescence immunoassay. For statistical purpose a continuous variable were calculated, called delta MPO/PR3(ΔMPO y ΔPR3) that reflects change in antibodies levels 6 months before renal flare. Clinical data were recorded since complete remission of first nephritis diagnosis flare until second renal relapse. Results 113 AAV-patients with pauci-inmune necrotizing glomerulonephritis were included, 59 (52.2%) women, mean age (64.3±14.8 years), 85 patients (75.2%) MPO-AAV and 28 (24.8%) PR3-AAV, after a mean follow-up of 5±4.8 years, 54 renal relapses occurred in 40 (52,6%) MPO-AAV patients and in 14 (57.1%) PR3-AAVpatients. Serum MPO levels were significant higher in relapser-patients compared with non- relapser patients, 3±1.2 months before nephritis relapse [(n=32) 19.2±12.2 IA vs (n=38) 3.2±5.1 IA, p<0.001)]. Δ MPO levels were significant higher in relapse-patients compared with non-relapser patients [(n=32) 8.3±12 IA vs (n=38) 0.9±3.1.1 IA, p=0.001). The discrimination value of the MPO antibody levels 3 months before renal relapse were established by means of a ROC curve: AUC of 0.82 (95% CI 0.73 to 0.92; p<0.001) and the MPO cut-off value predicting renal relapse were established in 8.3 IA. The discrimination value of the ΔMPO were established by means of ROC curve: AUC of 0.76 (95% CI 0.63 to 0.88; p<0.001), ΔMPO cut-off value were established in an increase of MPO levels of 3.7 IA. Serum PR3 levels were significant higher in relapser-patients 2.8±1.4 months before relapse [(n=14) 58.6±6.6 IA vs (n=7) 2.0±0.6 IA, p<0.001)] and Δ PR3 levels were significant higher in relapse-patients compared with non-relapser patients [(n=14) 57.5±28.5 IA vs (n=7) 0.8±0.2. IA, p<0.001)]. The discrimination value of the PR3 3 months before flare and Δ PR3 antibody levels were established by means of ROC curve: AUC 1. Conclusion Our results show that MPO antibodies, measured by Multiplex assay, could be a useful predictor of glomerulonephritis flare in AAV-patients. MPO levels 3 months before renal flare seems a good marker confirmed by ROC curve results, MPO cut-off value with the best sensitivity and specificity in predicting renal relapse was established in 8.3 IA. Δ MPO levels show that increase in titers ≥ 3.7 IA 6 months before renal flare, predict nephritis relapse However, PR3 antibodies are not a useful predictor marker, rise in antibodies level indicate renal vasculitis activity.

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.

Baseline HDAC6 and TFF3 proteins overexpression as prognostic markers of lupus nephritis relapse

Introduction: Lupus nephritis (LN) is a substantial manifestation of systemic lupus erythematosus (SLE). HDAC6 is overexpressed in various kidney diseases, and its inhibition slows kidney injury progression. Urinary TFF3 increases in chronic kidney diseases (CKDs) and may be associated with patient’s outcome. Objectives: This study aimed to examine the relationship between renal HDAC6 and TFF3 proteins expression and with clinicopathologic characteristics and outcome of LN. Patients and Methods: HDAC6 and TFF3 proteins’ expression was immunohistochemically detected in 56 cases of LN. They were correlated to patients’ age, gender, urinary 24 hours protein and serum creatinine levels at baseline and during follow up. Additionally, they were correlated to LN classes, activity index (AI) and chronicity index (CI) and relapse free survival (RFS). Results: HDAC6 overexpression was significantly associated with serum creatinine and 24 hours proteinuria levels at baseline (P = 0.041 and P =0.026 respectively) and during follow up (P < 0.001). It was associated with AI and CI of class III and IV LN (P = 0.047 and 0.003 respectively). TFF3 overexpression was associated with higher serum creatinine and more proteinuria at baseline (P = 0.015 and 0.001 respectively) and during follow up (P < 0.001). It was significantly associated with higher CI (P = 0.001). Both markers were associated with shorter RFS (P < 0.001). Conclusion: HDAC6 and TFF3 proteins are associated with clinicopathologic features of renal damage in LN. They are reliable predictors of patients’ RFS, which makes them good candidates for risk stratification of patients and targeted therapy.

Antibodies targeting circulating protective molecules in lupus nephritis: Interest as serological biomarkers.

Lupus nephritis (LN) is one of the most frequent and severe manifestations of systemic lupus erythematosus (SLE), considered as the major predictor of poor prognosis. An early diagnosis of LN is a real challenge in the management of SLE and has an important implication in guiding treatments. In clinical practice, conventional parameters still lack sensitivity and specificity for detecting ongoing disease activity in lupus kidneys and early relapse of nephritis. LN is characterized by glomerular kidney injury, essentially due to deposition of immune complexes involving autoantibodies against cellular components and circulating proteins. One of the possible mechanisms of induction of autoantibodies in SLE is a defect in apoptotic cells clearance and subsequent release of intracellular autoantigens. Autoantibodies against soluble protective molecules involved in the uptake of dying cells, including complement proteins and pentraxins, have been described. In this review, we present the main autoantibodies found in LN, with a focus on the antibodies against these protective molecules. We also discuss their pathogenic role and conclude with their potential interest as serological biomarkers in LN.

PETANDA BIOLOGIK TERKINI LUPUS NEFRITIS

Lupus Nephritis (LN) is one of the serious clinical manifestation of Systemic Lupus Erythematosus (SLE). Early detection and treatmentof renal activity may spare patients from renal damage. Conventional biomarkers such as urine sediment, proteinuria, creatinine, antidsDNA antibody and their complement levels are not specific and sensitive enough in detecting the ongoing disease activity in the lupuskidneys and early relapse of nephritis. Renal biopsy is the gold standard in providing information on the histopathology of LN, but isinvasive and it should take a serial of biopsies making it impractical when monitoring LN. Thus, some novel biomarkers are necessary toenhance the diagnostic accuracy and sensitivity of lupus renal disease, prognostic stratification, monitoring of treatment response anddetection of early renal flares as well. Some novel biomarkers have been studied in LN, however, validation on a large scale of patientswith different ethnic backgrounds is still needed.

Comparison Study on the Effect of Treatment Decision Based on Renal Biopsy and Clinical Symptoms in the Outcome of Patients with Recurrent Lupus Nephritis.

Background:Renal involvement in systemic lupus erythematous is one of the most serious complications. The aim of this study was to compare the effects of treatment decisions based on clinical symptoms and renal biopsy on the outcome of patients with recurrent lupus nephritis.Materials and Methods:This descriptive study was conducted in 2012–13 in the Alzahra hospital on patients with lupus nephritis who had referred to the rheumatology clinic of this center due to lupus nephritis relapse. All lupus nephritis patients were diagnosed with renal biopsy and had gone into remission by treatment but due to the discontinuation of treatment and other causes had relapsed. The patients were divided randomly into two groups of 26, the first group was treated without renal biopsy and based on clinical and laboratory symptoms and the second group was re-biopsied through considering the ethical points. Then their relationship with laboratory findings (BUN, Cr, ANA, ds-DNA, C3, C4, CH50, U/A, cast, and proteinuria), treatment and recurrence outcome were compared between the two groups.Results:The mean of SLEDAI-2K index before initial treatment, after the first round of treatment and after the second round of treatment in single biopsy group and twice biopsy group is not significantly different (P = 0.27).Conclusions:Treatment decisions based on clinical and laboratory findings or re-biopsy of the kidney in patients who relapsed after initial treatment had no significant effect on the recovery of patients. Adoption of a treatment plan in patients with lupus nephritis is recommended based on clinical and laboratory finding and the discretion of the physician and if possible, kidney re-biopsy should be avoided.

Lupus nephritis biomarkers

Lupus nephritis (LN), a potentially destructive outcome of SLE, is a real challenge in the management of SLE because of the difficulty in diagnosing its subclinical onset and identifying relapses before serious complications set in. Conventional clinical parameters such as proteinuria, GFR, urine sediments, anti-dsDNA and complement levels are not sensitive or specific enough for detecting ongoing disease activity in lupus kidneys and early relapse of nephritis. There has long been a need for biomarkers of disease activity in LN. Such markers ideally should be capable of predicting early sub-clinical flares and could be used to gauge response to therapy, thus obviating the need for serial renal biopsies with their possible hazardous complications. Since urine can be readily obtained, it lends itself as an obvious biological substrate. In this review, the use of urine and serum as sources of lupus nephritis biomarkers is described, and the results of biomarker discovery studies using candidate and proteomic approaches are summarized.

Serum and Urinary Biomarkers Endothelin-1, Beta-2 Microglobulin, Cystatin C, Galectin-3 and Alpha-1-acid Glycoprotein; Can they Surrogate Clinical and Histological Staging in Lupus Nephritis Patients?

Background: Lupus nephritis (LN) affects up to 50% of patients with Systemic lupus erythematosus (SLE) and is a major cause of morbidity. It is thus essential to identify biomarkers as indices with substantial predictive power to reduce the serious sequelae. However, criteria for disease remission have not been clearly established for these indices, except for the SLE Disease Activity Index (SLEDAI). Objectives: To investigate the relationship of non-invasively renal protein biomarkers and established measures of renal function to histologic findings in LN, and to test whether certain combinations of the above mentioned laboratory measures are diagnostic for specific histologic features of LN and to evaluate their relations to SLEDAI and chronicity. Methods: The study was conducted on 40 SLE female patients, recruited from renal unit of Internal Medicine department and Rheumatology and Rehabilitation department, and Neurology department, Assuit and Aswan University Hospitals, Egypt from May 2011 to January 2014, Renal biopsies were evaluated using the International Society of Nephrology/Renal Pathology Society classification (ISN/RPS), and scored for Activity Index and Chronicity Index; Clinical responders (CR) were required to have ≥50% reduction in proteinuria, normal or improved renal function, and inactive urinary sediment. Histopathological responders (HR) were required to have ≥50% improvement in Activity Index In addition, 40 age and sex matched healthy persons as a control group were enrolled in the study. The GFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Novel serum biomarkers; Endothelin-1 (ET-1), cystatin C, beta-2 microglobulin (B2M), galectin-3 (Gal-3) and alpha-1-acid glycoprotein (AAG) were collected. Urine samples from patients were collected within 2 months of kidney biopsy and assayed for the urinary biomarkers Endothelin-1 (ET-1), α1-acid glycoprotein (AAG), Cystatin C (CysC) and beta-2 microglobulin (B2M). Renal disease activity was estimated using the British Isles Lupus Assessment Group (BILAG) index. Results: The urinary and plasma biomarkers; ET-1, AAG, Cys C and B2M and GAL-3 were statistically significantly higher in patients with LN compared to controls that is reflective of specific histologic features seen in active LN. The combination of ET-1, AAG and CRP levels plus protein: creatinine ratio was excellent in predicting LN activity. The urinary B2M together with ET-1 and AAG plus creatinine clearance was an excellent diagnostic test for LN chronicity. However, plasma and urinary Cys C showed insignificant correlation with chronicity indices with lowest sensitivity and specificity. The statistically significantly high levels of serum and urinary ET-1 and AAG were related to specific histologic findings in LN with significant positive correlations with SLEDAI and chronicity indices in renal biopsy and highest sensitivity and specificity. Notably, these plasma biomarkers were increased linearly as renal function declined whereas urinary ET-1 and AAG rose exponentially. Thus, urinary ET-1 and AAG may be considered as a useful measure of renal inflammatory disease activity while measured renal function is still normal. Nevertheless, urinary and serum B2M exhibit a statistically insignificantly positive correlations and serum GAL-3 show insignificantly statistically negative correlations with SLEDAI and chronicity indices with lowest specificity and sensitivity reflecting the difficulty of being these biomarkers were useful markers for assessing activity and detection of early disease flares in patients with LN. Conventional clinical parameters such as creatinine clearance, proteinuria, urine sediments, anti-dsDNA, and complement levels are not sensitive or specific enough for detecting ongoing disease activity in the LNs and early relapse of nephritis. Conclusions: In this study biomarkers namely; Endothelin -1(ET-1) and α_1-acid glycoprotein (AAG) found to be associated with specific tissue changes observed in conjunction with LN activity and chronicity. The preliminary results suggest that these biomarkers may be part of a panel that in combination may eventually be able to predict histology without the need of an invasive biopsy. Currently, however we try to discover if these promising biomarkers actually alter patient outcomes and improve the lives of the patients with this life-threatening disease complication of SLE

Identification of stage-specific genes associated with lupus nephritis and response to remission induction in (NZB × NZW)F1 and NZM2410 mice.

To elucidate the molecular mechanisms involved in renal inflammation during the progression, remission, and relapse of nephritis in murine lupus models using transcriptome analysis. Kidneys from (NZB × NZW)F1 (NZB/NZW) and NZM2410 mice were harvested at intervals during the disease course or after remission induction. Genome-wide expression profiles were obtained from microarray analysis of perfused kidneys. Real-time polymerase chain reaction (PCR) analysis for selected genes was used to validate the microarray data. Comparisons between groups using SAM, and unbiased analysis of the entire data set using singular value decomposition and self-organizing maps were performed. Few changes in the renal molecular profile were detected in prenephritic kidneys, but a significant shift in gene expression, reflecting inflammatory cell infiltration and complement activation, occurred at proteinuria onset. Subsequent changes in gene expression predominantly affected mitochondrial dysfunction and metabolic stress pathways. Endothelial cell activation, tissue remodeling, and tubular damage were the major pathways associated with loss of renal function. Remission induction reversed most, but not all, of the inflammatory changes, and progression toward relapse was associated with recurrence of inflammation, mitochondrial dysfunction, and metabolic stress signatures. Immune cell infiltration and activation is associated with proteinuria onset and is reversed by immunosuppressive therapy, but disease progression is associated with renal hypoxia and metabolic stress. Optimal therapy for lupus nephritis may therefore need to target both immune and nonimmune disease mechanisms. In addition, the overlap of a substantial subset of molecular markers with those expressed in the kidneys of lupus patients suggests potential new biomarkers and therapeutic targets.

Relapsing tubulointerstitial nephritis in an adolescent with inflammatory bowel disease without aminosalicylate exposure

A 14-year-old boy presented with ongoing constipation as a manifestation of newly diagnosed Crohn's disease (CD) and a concomitant decline in renal function with biopsy-proven interstitial nephritis. Initiation of steroid therapy and mesalazine was associated with an improvement in symptoms and renal function. We describe a rare case of a 5-aminosalicylic acid (5-ASA)-naïve patient who developed interstitial nephritis in association with CD with no evidence of other primary glomerulopathy. A unique feature of the case being a profound systemic inflammatory response at the time of diagnosis and a relapse in nephritis 2 months after cessation of mesalazine in the absence of any macroscopic colitis.

Biomarkers for Lupus Nephritis: A Critical Appraisal

Kidney disease is one of the most serious manifestations of systemic lupus erythematosus (SLE). Despite the improvement in the medical care of SLE in the past two decades, the prognosis of lupus nephritis remains unsatisfactory. Besides exploring more effective but less toxic treatment modalities that will further improve the remission rate, early detection and treatment of renal activity may spare patients from intensive immunosuppressive therapies and reduce renal damage. Conventional clinical parameters such as creatinine clearance, proteinuria, urine sediments, anti-dsDNA, and complement levels are not sensitive or specific enough for detecting ongoing disease activity in the lupus kidneys and early relapse of nephritis. Thus, novel biomarkers are necessary to enhance the diagnostic accuracy and sensitivity of lupus renal disease, prognostic stratification, monitoring of treatment response, and detection of early renal flares. This paper reviews promising biomarkers that have recently been evaluated in longitudinal studies of lupus nephritis.

Predictors of Relapse and End Stage Kidney Disease in Proliferative Lupus Nephritis

The prevalence and significance of remission and relapse in children, adolescents, and young adults with lupus nephritis in the United States are poorly understood. Patterns and predictors of disease progression in a southeastern U.S. pediatric cohort with severe lupus nephritis are presented. Individuals age 21 or less with kidney biopsy-proven lupus nephritis followed in the Glomerular Disease Collaborative Network were included. Cox regression models were used to evaluate predictors of relapse and end stage kidney disease (ESKD). Seventy-three subjects with a mean age of 15.6 +/- 3.4 yr were included. Five-year kidney survival was 77%. Complete and partial remission rates within 1 yr of induction therapy were 25 and 64%, respectively. Relapse and ESKD rates were similar between complete and partial responders. Relapse occurred in 35% of responders (complete or partial) in 45 +/- 32 mo. Disease relapse was a predictor of ESKD (HR = 10.12, P < 0.0001). Treatment resistance was documented in African Americans more often than non-African Americans (eight versus 0; P = 0.03). ESKD HR associated with treatment resistance was 6.25, P < 0.002. Remission whether complete or partial is associated with improved kidney survival in children with lupus nephritis. Nephritis relapse is a strong predictor of progression to ESKD. Treatment resistance portends a high risk of ESKD and disproportionately affects African American children with lupus nephritis.

Rituximab and mycophenolate mofetil for relapsing proliferative lupus nephritis: a long-term prospective study

Subsequent to cyclophosphamide-based induction therapy of lupus nephritis, and despite maintenance chronic immunosuppressive treatment, many patients experience relapses. This prospective, observational study included 10 women with biopsy-proven relapse of proliferative lupus nephritis occurring during maintenance with mycophenolate mofetil (MMF) or azathioprine. The long-term outcome after a single course of the B-cell depleting anti-CD20 antibody rituximab (4 weekly infusions of 375 mg/m(2)), combined with daily MMF (2 g) and prednisolone (0.5 mg/ kg/day for 4 weeks, tapered thereafter) is presented. While renal function was not severely impaired at baseline, partial remission (>50% improvement in all abnormal renal parameters) was achieved in eight patients at a median of 3.5 months. In seven patients, with 24-h urinary protein of 2.5 +/- 1.1 g (mean +/- SD), complete remission, associated with increases in serum complement levels and decreases in anti-dsDNA titres, was subsequently established (normal serum creatinine/albumin levels, inactive urine sediment and 24-h urinary protein <0.5 g). Complete nephritis remission was sustained at the follow-up end (median of 38 months) in six patients. Combination treatment was well tolerated. The efficacy of this low-toxicity combination was particularly evident in patients with subnephrotic proteinuria due to proliferative lupus nephritis relapse. Controlled trials to define the role of rituximab/MMF in this condition are warranted.

Effects of long-term treatment with mizoribine in patients with proliferative lupus nephritis

Mizoribine (MZR) is a purine antimetabolic immunosuppressant agent that has few little severe adverse events. We studied whether maintenance therapy with MZR and prednisolone (PSL) in severe proliferative lupus nephritis patients could improve immunity, reduce proteinuria, prevent renal relapse, and reduce steroid dose. Long-term maintenance therapy with MZR and PSL was evaluated in ten patients with biopsy-proven proliferative lupus nephritis. Patients with severe lupus nephritis, who had proteinuria of 0.5 g or more even after treatments with plasma exchange and/or pulse methyl prednisolone, were recruited. MZR at an average dose of 140 +/- 10 (100 - 200) mg was administered two to three times/day in combination with PSL. The average period for the MZR maintenance therapy was 89.7 +/- 5.5 (70 - 126) months. Urine protein excretion, serum hemolytic complement activity (CH50), C3, serum creatinine, general and biochemical blood examinations, anti-ds-DNA antibody were collected at each monthly medical examination. All patients were females, mean age 43.0 +/- 3.3 years. A significant decrease in proteinuria was noted two years after the combination therapy (p = 0.0016). Five patients experienced lupus nephritis relapse. Patients who did not experience relapses had their MZR combination therapy initiated earlier (p = 0.037) when compared with the patients who experienced relapses. Serum creatinine levels remained unchanged in all patients throughout treatment and follow-up, even during renal relapses. Levels of C3 and CH50 normalized as proteinuria decreased. None of the patients developed serious side effects during MZR treatment. A significant steroid-sparing effect was observed three years after initiating MZR (p = 0.0025). From our long-term observation, maintenance therapy with low-dose PSL combined with MZR can eliminate proteinuria and have steroid-sparing effect. Early initiation of the therapy can protect against renal relapses among severe proliferative lupus nephritis patients without serious side effects.

Treatment of pure membranous lupus nephropathy with prednisone and azathioprine: an open-label trial

Background: The aim of this study was to report the outcome of pure membranous lupus nephropathy treated with prednisone and azathioprine (AZA). Methods: Consecutive patients with pure membranous lupus glomerulonephritis (World Health Organization [WHO] Va and Vb) from 4 regional hospitals were recruited for an open-label treatment trial consisting of prednisone and AZA. Remission status was evaluated at 12 months. Maintenance treatment with low-dose prednisone and AZA was continued indefinitely for those who achieved remission. Factors predictive of initial renal remission and subsequent relapse were studied by statistical analyses. Results: Thirty-eight patients (31 women and 7 men) were studied. The mean age was 35.0 ± 9.2 years, and the duration of systemic lupus erythematosus was 48.5 ± 59 months. Seventeen (45%) patients had WHO class Va lupus nephritis, whereas 21 (55%) had class Vb disease. Two patients withdrew from the protocol because of idiosyncratic reactions to AZA. At 12 months, 24 (67%) patients achieved complete remission (CR), 8 (22%) achieved partial remission (PR), and 4 (11%) were treatment resistant. Patients who achieved CR or PR were maintained on low-dose prednisone and AZA. Over a mean follow-up period of 90.4 ± 59 months, 6 (19%) patients had relapse of nephritis (proteinuric flare in 4 and nephritic flare in 2). The cumulative risk of renal relapse was 12% at 36 months and 16% at 60 months. No particular clinical variables were found to predict renal remission or relapses. Over a mean follow-up of 90 months, 13% of patients had decline of creatinine clearance by 20%, but none had doubling of serum creatinine. Renal outcome was not significantly worse in patients presenting with nephrotic syndrome. Treatment generally was well tolerated. Conclusion: A combination of prednisone and AZA is reasonably effective for the initial treatment of pure membranous lupus nephritis. Severe adverse effects are uncommon. The additional efficacy of AZA in comparison with prednisone alone has to be confirmed with randomized, controlled trials.

Immunosuppressive therapy of lupus nephritis.

Aggressive immunosuppressive therapy should be considered for patients with proliferative lupus nephritis as the risk for progression to end stage renal disease is high. Intermittent intravenous cyclophosphamide therapy improves renal survival; longer duration of therapy is associated with fewer relapse of nephritis and decreased risk of diminished renal function. While azathioprine therapy does not differ statistically from steroids alone in prolonging renal survival, this therapy may be considered in patients with few risk factors for progression to renal insufficiency. Methylprednisolone as a single therapy does not prolong renal survival compared with regimens including cyclophosphamide. Plasmapheresis remains under study but has not shown additional benefit in treatment of severe lupus nephritis. The potential roles for cyclosporin A and mycophenylate mofetil in the therapy of proliferative lupus nephritis remain to be defined. Supportive care including rigorous control of hypertension, consideration of angiotensin receptor inhibition or blockade to reduce proteinuria and prolong renal function, control of hyperlipidemia, prevention of osteoporosis, and prevention of pregnancy remain important clinical goals. Current research efforts focus on genetic and socioeconomic factors involved in racial differences in expression of lupus nephritis, hormonal manipulation to preserve gonadal function during cyclophosphamide therapy, and the potential impact on lupus activity of estrogen-containing oral contraceptives or postmenopausal hormone replacement therapy.

Cumulative rate of relapse of lupus nephritis after successful treatment with cyclophosphamide.

To determine the cumulative rate of relapse of lupus nephritis that has been treated successfully with cyclophosphamide (CYC), and to estimate the association between time to relapse and demographic, clinical, laboratory, and treatment variables. This was an observational study of 48 systemic lupus erythematosus (SLE) patients who were treated successfully with CYC between 1979 and 1993 and followed up thereafter at 3 university hospitals. Demographic and clinical variables, laboratory data during the first month of nephritis, and therapy-related variables were recorded from charts. Renal biopsy specimens were retrieved and analyzed by a pathologist. Relapse of nephritis was the outcome of interest. Descriptive analysis of patients who did and those who did not have a relapse was performed by chi-square test, Fisher's exact test, and Wilcoxon 2-sample test. The cumulative rate of relapse was computed using the actuarial method. Univariate comparisons of time to relapse were computed by log-rank test. Proportional hazards modeling was used to assess the combined effect of patient characteristics that have been hypothesized to be prognostic factors. Nephritis relapsed in 11 patients. Previous hematologic disorder, arthritis or arthralgia, and the use of CYC in oral form were more frequent in patients who had a relapse. The cumulative rate of relapse was 25% and 46% at 5 years and 10 years, respectively. A significant univariate difference in time to relapse was found when patients were stratified by time from diagnosis to initiation of CYC treatment (< or = 5 months versus > 5 months; P = 0.02). By multivariate analysis, age < 29 years at nephritis onset (relative risk [RR] 6.29, 95% confidence interval [95% CI] 1.13-34.94, P = 0.03) and delay of > 5 months from onset of nephritis to initiation of CYC therapy (RR 3.66, 95% CI 1.06-12.63, P = 0.04) were independently associated with time to relapse. A selected population of SLE patients may have long-term remission of renal disease following successful CYC therapy. Patients in whom CYC treatment is delayed or who are young at the time of nephritis onset are at increased risk of relapse.