Renal Outcome In Lupus Nephritis Research Articles

Epidemiological, immunological, and treatment response profile of patients with lupus nephritis in Brazil.

Brazil has the largest number of individuals of African descent outside Africa and a very admixed population. Among cases of lupus nephritis (LN) in the country, there are differences in incidence, and even in severity, depending on the location and characteristics of the population studied. The aim of this study was to describe the clinical and epidemiological characteristics of LN in Brazil, as well as to determine which of those characteristics would be risk factors for a poor renal prognosis. This was a retrospective, descriptive observational study of patients diagnosed with LN who underwent kidney biopsy between 1999 and 2015 in the Nephrology Department of the Hospital das Clínicas, in São Paulo, Brazil. Data were collected from electronic medical records. We evaluated 398 patients, among who 94.1% and 77.7% tested positive for antinuclear antibodies and anti-DNA antibodies, respectively, whereas 33.7% showed the full-house pattern. The time from LN symptom onset to biopsy was <6months in 47.5% (early biopsy group) and ≥6months in 52.5% (late biopsy group). In the early biopsy group, the chronicity index was lower and the activity index was higher. Multivariate analysis showed that a higher chronicity index was the only independent risk factor for progression to requiring kidney replacement therapy. Late biopsy seems to be associated with negative renal outcomes in LN. However, it seems that a higher chronicity index is the main predictor of a poor renal outcome among patients with LN in Brazil.

Performance of Clinical and Biochemical Parameters in Identifying Renal Histopathology and Predictors of One-Year Renal Outcome in Lupus Nephritis-A Single Centre Study from India.

Objectives: To assess the performance of clinical and biochemical parameters in identifying renal histopathology. To assess the performance of a combination of demographic, clinical, serological and histopathological parameters in determining renal response at one year. Methods: Data of biopsy-proven (ISN/RPS-2003 criteria) Lupus Nephritis (LN) were extracted from the institute database. Demographic, clinical and biochemical parameters at the time of biopsy were noted, and their associations with histopathological class, activity and chronicity scores were evaluated. Follow-up data at one year were collected. Complete, partial or no response (CR, PR, NR) for renal outcomes at one year and the predictors of NR were assessed. Results: Out of the 333 renal biopsies, 240 (71.8%) were Class III/IV. More patients with Class III/IV LN had hypertension (52.1%) and low eGFR (p &lt; 0.001). Among Class III/IV, AS correlated weakly with UPCR (r = 0.31, p &lt; 0.01), eGFR (r = -0.172; p &lt; 0.01) and CS with eGFR (r = -0.212; p &lt; 0.01). The presence of either hypertension, UPCR &gt; 0.5 g/day, active urinary sediments or serum creatinine &gt;1.3 g/dL had a sensitivity of &gt;96% and specificity of &lt;9% in detecting proliferative LN, crescents, interstitial inflammation and chronicity. NR was higher in males (aOR:3.9, 95% CI:1.4-11.0, p &lt; 0.001), those with abnormal baseline creatinine (aOR: 1.9, 95% CI: 1.1-3.2, p &lt; 0.001), higher renal SLEDAI (p &lt; 0.05), higher AS, CS (p &lt; 0.001) and interstitial inflammation (p &lt; 0.005). In the binary logistic regression, the combination of male sex, baseline creatinine, UPCR and CS performed best in predicting NR (AUC: 0.762; 95% CI: 0.684-0.840, p &lt; 0.001). Conclusions: Clinical and biochemical parameters alone have a poor specificity in identifying renal histopathology. A combination of demographic, clinical and histopathology parameters can better predict renal outcomes at one year.

Response to therapy at 6 months predicts long-term renal outcome in lupus nephritis with poor kidney function

ObjectiveIt is unclear whether aggressive treatment would benefit lupus nephritis (LN) with poor renal function, which has been excluded from most clinical trials. We aimed at demonstrating their clinicopathological features...

FC056: Early Reductions in Proteinuria with Voclosporin Treatment Across Lupus Nephritis Biopsy Classes: Pooled Data from the AURA-LV AND AURORA 1 Trials

Abstract BACKGROUND AND AIMS Voclosporin, a novel calcineurin inhibitor, was approved by the FDA for the treatment of adults with active lupus nephritis (LN) in combination with background immunotherapy, and was successfully tested in two pivotal trials, AURA-LV (Phase 2) and AURORA 1 (Phase 3). Pooled data from these trials showed that the addition of voclosporin to mycophenolate mofetil (MMF) and low-dose steroids resulted in significantly higher complete renal response (CRR) rates at 24 weeks and 1 year of treatment in patients with LN. More patients in the voclosporin group achieved urine protein creatinine ratio (UPCR) reductions of ≥ 50% from baseline, and the median time to this endpoint was significantly shorter in the voclosporin group compared with the control group. Reduced proteinuria at 1 year is the best predictor of improved long-term renal outcomes in LN.[1,2] The current report evaluates the impact of voclosporin on the time to proteinuria reduction by biopsy class in pooled data from the AURA-LV and AURORA 1 trials. METHOD Both trials enrolled patients with biopsy-proven LN (Class III, IV or V ± III/IV) within 6 months (or up to 2 years in AURORA 1) and proteinuria ≥ 1.5 mg/mg (≥2 mg/mg for Class V). The pooled analysis included 268 patients in the voclosporin (23.7 mg BID) group and 266 patients in the control group. All patients received MMF (target 1 g BID) and low-dose steroids (target dose 2.5 mg/day by week 16 according to protocol-defined steroid taper). For this post-hoc analysis, hazard ratios (HR) for the times to UPCR ≤ 0.5 mg/mg and UPCR reduction ≥ 50% from baseline were analyzed by biopsy class. RESULTS The addition of voclosporin resulted in faster times to both UPCR ≤ 0.5 mg/mg and UPCR reduction ≥ 50% from baseline in the overall study population and across individual biopsy classes (HR &amp;gt; 1; Table 1). Median times to UPCR of ≤ 0.5 mg/mg and UPCR reduction ≥ 50% from baseline for both pure Class III and pure Class IV were significantly shorter for patients treated with voclosporin than the respective control groups: 142 versus 372 days (Class III) and 142 versus ND (not determinable) days (Class IV) for UPCR ≤ 0.5 mg/mg; 25 versus 84 days (Class III) and 29 versus 57 days (Class IV) for UPCR reduction ≥ 50% from baseline. The differences between the voclosporin and control groups for pure Class III and pure Class IV were apparent within the first month of treatment and sustained at 1 year. Similar results were seen with mixed Class III/V and IV/V. Patients with pure Class V took the longest to achieve both UPCR endpoints; the difference between groups was not statistically significant. CONCLUSION Patients treated with voclosporin in addition to MMF and low-dose steroids achieved earlier reductions in proteinuria across all biopsy classes. As expected, patients with Class V disease took longer to reach both UPCR endpoints than patients with proliferative disease, suggesting this population of patients may require a longer duration of treatment. This analysis further supports the efficacy results observed in the individual AURA-LV and AURORA 1 trials, indicating faster time to response when voclosporin is added to standard of care agents MMF and steroids.

Renal Tubular Cell Ferroptosis: A New Player in Pathogenesis of Lupus Nephritis

Abstract Background New research indicates that the injury to the renal tubular epithelial cells is a better predictor of renal outcomes in lupus nephritis (LN) as compared to glomerular injury. Iron accumulates mostly in the renal tubular cells of LN patients and murine models of LN. Ferroptosis is an incompletely understood form of cell death involving iron mediated lipid peroxidation, but its role in LN is not well established. Experiment LN and control patient biopsies were stained for markers of ferroptosis. Kidneys of female (MRL/lpr) and male (NZW X BXSB) F1, lupus mice were analyzed for markers of ferroptosis. Human proximal tubular cells (PTEC) were treated with LN serum with or without Liporxstatin-2, a novel ferroptosis inhibitor. Results Compared to controls, LN patients expressed higher levels of ACSL4 and 4HNE, the ferroptosis core proteins in the renal tubules. Compared to non-nephritic mice, nephritic mice had significantly higher gene expression of Aifm2, Acsl4, and Gpx1 as well as protein levels of Acsl4. Nephritic mice had an impaired renal glutathione synthesis pathway. Glutathione is an essential positive regulator of glutathione peroxidase 4 (Gpx4: ferroptosis inhibitor) which resulted in lower protein expression of Gpx4. Collectively, LN kidneys displayed a ferroptosis signature and was associated with an increase in Ngal and Kim1, PTEC injury markers. LN patients’ serum induced PTEC ferroptosis and associated pathology were significantly reduced by Liproxstatin-2. Conclusion Our data identify occurrence ferroptosis in renal tubular cell which can contribute to the pathogenesis of LN. Liproxstatin-2 mitigates human LN serum induced PTEC pathology and holds promise as an adjunct therapy to alleviate LN severity. Supported by grants from Vifor Pharma

The Effect of Mycophenolate Mofetil as First-Line Therapy on the Timing of Urine Protein-to-Creatinine Ratio Reduction in Immunosuppressant-Naive Patients With Lupus Nephritis at a Single Center.

Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis (LN). The purpose of this study was to assess the effect of mycophenolate mofetil (MMF) on the timing of urine protein-to-creatinine ratio reaching 200 mg or less after starting MMF as initial therapy for class III, IV, or V in immunosuppressant-naive patients with LN. Patients who had a diagnosis of biopsy-proven LN were included in this cohort study. The initial dose of MMF was 1000 mg twice daily. If no improvement, it was increased to 1500 mg twice daily after 1 month. For statistical analysis, exact binomial distribution 95% confidence intervals were calculated. Nine patients were identified. There were 3 patients with class III, 3 with class IV, 1 with class III to V, 1 with class II to V, and 1 with class V lupus nephritis. The majority were African Americans (70%). At baseline, proteinuria ranged between 0.41 and 4 g, and 88% had normal estimated glomerular filtration rate. Forty-four percent of patients reached 0.28 g of proteinuria within 8 weeks of starting MMF (95% confidence interval, 14%-79%), all of which maintained the same level of response and normal estimated glomerular filtration rate at 12 months. Thirty-three percent of patients achieved the American College of Rheumatology complete response at 8 weeks. This study demonstrates that only a minority of immunosuppressant-naive LN patients achieved the American College of Rheumatology complete response at 8 weeks after initiation of MMF. A rapid decline in the proteinuria to 0.28 g within the first 8 weeks of the treatment correlated strongly with achieving the same level of response at 12 months.

Interleukin‐17 in urine and serum of patients with nephritis

Recent evidence suggests that interleukin-17 (IL-17) is involved in the pathogenesis of systemic lupus erythematosus (SLE) and it is a promising marker of disease activity in lupus nephritis (LN).1 IL-17 induces the expression of various pro-inflammatory cytokines and chemokines, which increase the influx of various leukocyte subpopulations and thus, causes severe inflammation. These inflammatory mediators enhance the involvement of various leukocyte subpopulations, which ultimately leads to damage.2, 3 Nordin et al published interesting data about IL-17 levels in 120 patients with SLE.4 The authors showed an increase in the levels of IL-17 in the serum and urine of patients and their correlations with British Isles Lupus Assessment Group and SLE Disease Activity Index scores, which is consistent with other studies.5, 6 But IL-17 was not a sensitive or specific marker of SLE activity. In addition, there was no correlations of IL-17 levels in urine or serum with the histological classes of LN. We also studied the levels of IL-17 in the urine and serum of patients with chronic glomerulonephritis (CGN). The levels of IL-17 in serum did not significantly differ from the levels in healthy individuals and did not depend on the activity of nephritis. On the contrary, the levels of IL-17A in the urine of patients with CGN were significantly higher at 3.05 (2.98-3.1) pg/mg creatinine (Cr) than that in healthy individuals 2.93 (2.92-2.94) pg/mg Cr The urinary IL-17A levels were not correlated with proteinuria (R2 = 0.21, P = .29) and serum albumin (R2 = 0.24, P = .21). These results indicate a connection between IL-17 levels in urine and inflammation of renal tissue in CGN patients. Also, IL-17 levels in the urine were significantly higher in the CGN patients with advanced interstitial fibrosis and a renal dysfunction with glomerular filtration rate less than 60 mL/min/1.73 m2 (2.97 [2.96-2.99] pg/mg Cr vs. 2.99 [2.98-3.00] pg/mg Cr in normal renal function, P < .05) regardless of histological forms. Currently, the role of IL-17 in fibrotic accumulation has been discussed. Severe fibrosis in murine radiation-induced lung disease was more pronounced with regard to reduction in Th1 cells in the presence of increased number of Th17 cells and higher levels IL-17.7 IL-6 can induce glomerulosclerosis and interstitial fibrosis in the kidney directly or through activation of IL-17.8 Changes in the Th17/Treg ratio may contribute to the development of advanced tissue fibrosis by transforming growth factor-β signaling through the activation of mitogen-activated protein kinases.9 Therefore, future research is needed to compare IL-17 levels in the urine with activity and sclerosis scores in the renal tissue and renal outcomes in LN.

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.

Urinary Neuropilin-1: A Predictive Biomarker for Renal Outcome in Lupus Nephritis.

At present, Lupus Nephritis (LN) is still awaiting a biomarker to better monitor disease activity, guide clinical treatment, and predict a patient’s long-term outcome. In the last decade, novel biomarkers have been identified to monitor the disease, but none have been incorporated into clinical practice. The transmembrane receptor neuropilin-1 (NRP-1) is highly expressed by mesangial cells and its genetic deletion results in proteinuric disease and glomerulosclerosis. NRP-1 is increased in kidney biopsies of LN. In this work we were interested in determining whether urinary NRP-1 levels could be a biomarker of clinical response in LN. Our results show that patients with active LN have increased levels of urinary NRP-1. When patients were divided according to clinical response, responders displayed higher urinary and tissue NRP-1 levels at the time of renal biopsy. Areas under the receiver operating characteristic curve, comparing baseline creatinine, proteinuria, urinary NRP-1, and VEGFA protein levels, showed NRP-1 to be an independent predictor for clinical response. In addition, in vitro studies suggest that NRP-1could promote renal recovery through endothelial proliferation and migration, mesangial migration and local T cell cytotoxicity. Based on these results, NRP-1 may be used as an early prognostic biomarker in LN.

High plasma mycophenolate acid concentration in the early phase of induction therapy predicts good renal outcome in lupus nephritis

Objectives: To identify the prognostic predictive factor of complete renal response (CR) at week 12 by focusing on the plasma mycophenolic acid (MPA) concentration in induction therapy in lupus nephritis.Methods: We prospectively enrolled patients with biopsy-proven LN class III/IV who were hospitalized between 2016 and 2017. As an induction therapy, mycophenolate mofetil was continuously introduced at 2000 mg/day. We measured the MPA plasma concentration at two time points depending on the induction therapy phase, early (week 4) or middle (week 12). The association between these concentrations and CR rate at week 12 was evaluated.Results: Ten patients were enrolled. A significantly higher AUC0–12 between 0 and 12 h of MPA at the early phase was observed in the patients with CR at week 12 than in those without (p = .03). All the patients with high MPA-AUC0–12 (> 40 mg h/L) at the early phase achieved CR at week 12, but no such association was found at the middle phase. The multivariate analysis revealed that MPA-AUC0–12 was selected as an independent predictive factor of CR at week 12 (odds ratio: 1.12; 95% confidence interval: 1.01–1.45, p = .02).Conclusion: The high AUC0–12 of MPA at the early phase of induction therapy may predict good renal response.

Is serum uric acid a predictor of long-term renal outcome in lupus nephritis?

Recent studies observed an association between increased serum uric acid (SUA) levels and renal damage in lupus. However, the predictive value of UA for the development of long-term renal dysfunction in lupus nephritis (LN) is still unknown. The aim of this study was to evaluate if SUA may be a predictor of long-term renal outcome in LN. Eighty biopsy-proven LN patients > 7years of follow-up were selected. SUA levels were measured in sera stored at - 70°C. All patients had serum stored from LN baseline, and 32 also had stored serum from 6 and 12months after LN. Renal outcome was addressed after 7years of follow-up to determine if SUA could be a predictor of long-term renal outcome. A good long-term renal outcome in 7years was defined as a creatinine clearance (CrCl) ≥ 90.0mL/min/1.73m2, and poor if CrCl < 90mL/min/1.73m2. Patients were divided in two groups according to the renal outcome to assess whether SUA levels at different time points of follow-up could differentiate such groups. An ROC curve was plotted to assess accuracy. SUA levels at baseline and 6months were not able to differentiate good from poor long-term renal outcomes in LN (respectively p = 0.37, p = 0.28), but at 12months (p = 0.02), they could clearly differentiate the two groups. ROC curve (12months) accuracy was 0.76. SUA cutoff was 6.05mg/dL (sensitivity = 0.67, specificity = 0.89, positive predictive value = 0.85, negative predictive value = 0.73). SUA levels < 6.05mg/dL at 12months of follow-up is a predictor of good long-term renal outcome in lupus nephritis. • Previous studies reported an association between increased serum uric acid level and short-term renal damage in lupus patients. • The predictive value of serum uric acid for the development of long-term renal dysfunction in lupus nephritis was never assessed. • At 12months of follow-up serum uric acid clearly differentiated good from poor long-term renal outcome in lupus nephritis. • SUA level < 6.05mg/dL at 12months of follow-up was a predictor of good long-term renal outcome in lupus nephritis.

Clinical Outcomes and Clinico-pathological Correlations in Lupus Nephritis with Kidney Biopsy Showing Thrombotic Microangiopathy.

Renal thrombotic microangiopathy (TMA) is an uncommon pathological finding in lupus nephritis (LN), and its clinical significance remains to be defined. Twenty-four patients with lupus nephritis (LN) and renal TMA were selected from a retrospective review of 677 biopsy-proven LN patients, and compared with 48 LN controls without TMA (1:2 ratio) matched according to demographics and treatments. Renal TMA was noted in 3.5% of kidney biopsies of LN. TMA was associated with a higher prevalence of anti-Ro (45.8% vs 18.8%; p = 0.016), higher Systemic Lupus Erythematosus Disease Activity Index scores (21.4 ± 8.5 vs 10.8 ± 2.3; p < 0.001), lower estimated glomerular filtration rate (eGFR; 16.8 ± 11.7 ml/min vs 77.8 ± 28.6 ml/min; p < 0.001), and a higher percentage of patients who required dialysis (37.5% vs 2.1%; p < 0.001) at the time of kidney biopsy. Activity and chronicity indices [median (range)] were higher in the TMA group [11 (2-19) and 3 (1-8), respectively, compared with 7 (0-15) and 1 (0-3) in controls; p = 0.004 and p < 0.001; respectively]. Patients with TMA showed inferior 5-year renal survival and higher incidence of chronic kidney disease at last followup (70% and 66.6%, respectively, compared with 95% and 29.2% in controls; p = 0.023 and 0.002, respectively). The TMA group also showed lower median eGFR compared with controls [50.1 (IQR 7-132) ml/min vs 85.0 (IQR 12-147) ml/min; p = 0.003]. Five-year patient survival rate was similar between the 2 groups (87% and 98% in TMA and control group, respectively; p = 0.127). TMA in kidney biopsy was associated with more severe clinical and histological activity, and significantly inferior longterm renal outcome in LN.

Serum Axl predicts histology-based response to induction therapy and long-term renal outcome in lupus nephritis.

Axl is a receptor tyrosine kinase with important functions in immune regulation. We investigated serum levels of soluble (s)Axl in lupus nephritis (LN) in association with renal disease activity, tissue damage and treatment response. We surveyed 52 patients with International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III/IV LN and 20 healthy controls. Renal biopsies were performed at the time of active LN and post-treatment. Patients were classified as clinical responders (CRs) or clinical non-responders based on the American College of Rheumatology (ACR) criteria. Improvement by ≥50% in renal activity index scores defined histological responders (HRs). sAxl levels were elevated in patients compared to controls (median: 18.9 ng/mL), both at baseline (median: 45.7; P<0.001) and post-treatment (median: 41.2 ng/mL; P<0.001). Baseline sAxl levels were higher in patients with class IV (median: 47.7 ng/mL) versus class III (median: 37.5 ng/mL) nephritis (P = 0.008), and showed moderate correlations with albuminuria (r = 0.30, P = 0.030) and creatinine (r = 0.35, P = 0.010). Baseline sAxl levels decreased in CRs (P = 0.002) and HRs (P<0.001), but not in non-responders; levels ≥36.6 ng/mL yielded a >5 times higher probability of histology-based response (odds ratio, OR: 5.5; 95% confidence interval, CI: 1.2–25.1). High post-treatment sAxl levels were associated with worsening in chronicity index scores (P = 0.025); low levels predicted favourable renal outcome (creatinine ≤88.4 μmol/L) 10 years after the baseline renal biopsy (area under the curve: 0.71; 95% CI: 0.54–0.89). In conclusion, sAxl may prove useful as a marker of renal activity, histological response to immunosuppression, and renal damage progression in LN. Persistently high sAxl levels after completion of treatment may be indicative of a need for treatment intensification.

Histological predictors of renal outcome in lupus nephritis: the importance of tubulointerstitial lesions and scoring of glomerular lesions.

Introduction Lupus nephritis (LN) affects nearly 60% of patients with systemic lupus erythematosus and up to 30% of them will progress to end-stage renal disease (ESRD), despite receiving aggressive immunosuppressive therapy. The prognostic value of ISN/RPS classification is controversial. Therefore, we aimed to identify clinical and pathological predictors of outcome in LN patients independent of this classification. Material and methods Thirty-seven patients with LN who underwent percutaneous kidney biopsy between 1997 and 2016 were included in this study. Twenty clinical and twenty histological variables were tested for their association with a composite end-point of doubling of serum creatinine, ESRD and death. Univariate and multivariate Cox proportional hazard regression analysis were performed to identify independent predictors of outcome. Results During a median follow-up period of 48 months (IQR: 17.5-120 months), 21.6% of patients reached the composite end-point. The overall survival rate of our cohort was 89% at one year, 86% at five years, 74% at 10 years and 64% at 20 years. Patients with Class IV LN showed the worst prognosis with 44% survival at 10 years, while those who additionally showed crescents and global sclerosis on kidney biopsy had an even lower survival of 21% and 0% at 10 years, respectively. After multivariate adjustment, we identified estimated glomerular filtration rate at baseline (HR, 0.91 per ml/min /1.73 m2; 95% CI, 0.84 to 0.99), 24-hour proteinuria at baseline (HR, 2.04 per g/d; 95% CI, 1.19 to 3.5), crescents (HR, 1.068 per %; 95% CI, 1.003 to 1.091), global sclerosis (HR, 1.036 per %; 95% CI, 0.984 to 1.091), presence of adhesions (HR, 9.2; 95% CI, 1.38 to 61.2) and tubulitis (HR, 13.1; 95% CI; 1.3 to 131) as independent predictors of outcome in our cohort of LN. Conclusions Our study identified glomerular (crescents, global sclerosis, adhesions) and tubulointerstitial (tubulitis) lesions, in addition to clinical variables (renal function, 24-hour proteinuria), as important predictors of renal outcome, independent of the ISN/RPS classification. We suggest that the ISN/RPS classification could be improved by a quantitative assessment of glomeruli with active and chronic lesions and by a greater emphasis given to tubulointerstitial lesions.

Clinical and Histopathologic Characteristics Associated with Renal Outcomes in Lupus Nephritis.

The prognostic significance of histopathologic (sub)classes in the current classification of lupus nephritis (LN) is controversial. We analyzed clinical and histopathologic predictors of renal outcome in LN outside the framework of the classification. Variables (50 histopathologic and ten clinical) were tested in mixed, linear, and Cox regression models for their association with renal flare, ESRD, and eGFR during follow-up (1, 5, and 10 years) in 105 patients with LN who underwent biopsy from 1987 to 2011. The Cockcroft-Gault (normalized to a body surface area of 1.73 m2) and Schwartz formulas were used to calculate eGFR for adults and children, respectively. During median follow-up of 9.9 years (25th-75th percentile, 5.9-13.8), 47 patients experienced a renal flare and 21 progressed to ESRD. Renal flare was predicted by fibrinoid necrosis (hazard ratio [HR], 1.04 per %; 95% confidence interval [95% CI], 1.00 to 1.07) and nonwhite race (HR, 2.23; 95% CI, 1.23 to 4.04). ESRD was predicted by fibrinoid necrosis (HR, 1.08 per %; 95% CI, 1.02 to 1.13), fibrous crescents (HR, 1.09 per %; 95% CI, 1.02 to 1.17), interstitial fibrosis/tubular atrophy (IF/TA) ≥25% (HR, 3.89; 95% CI, 1.25 to 12.14), eGFR at baseline (HR, 0.98 per ml/min per 1.73 m2; 95% CI, 0.97 to 1.00), and nonwhite race (HR, 7.16; 95% CI, 2.34 to 21.91). A higher mean eGFR during follow-up was associated with normal glomeruli (+0.2 ml/min per 1.73 m2 per %; 95% CI, 0.1 to 0.4). Like ESRD, a lower eGFR during follow-up was associated with fibrous crescents, IF/TA≥25%, and nonwhite race, as well as with cellular/fibrocellular crescents (-0.4 ml/min per 1.73 m2 per %; 95% CI, -0.6 to -0.2) and age (-0.8 ml/min per 1.73 m2 per year; 95% CI, -1.2 to -0.4). The LN classification should include an index of evidence-based prognosticators. Awaiting validation of a formal index, we suggest that at least fibrinoid necrosis, fibrous crescents, and IF/TA warrant explicit independent scoring to assess the risk of progressive renal dysfunction in conjunction with clinical findings.

Predictors of Good Long-Term Renal Outcomes in Lupus Nephritis: Results from a Single Lupus Cohort.

This study aims to elucidate the predictive capabilities of proteinuria, serum creatinine (Cr), and urine RBCs (uRBCs) with respect to long-term renal outcomes in lupus nephritis (LN) in patients followed in clinic. Methods. A retrospective analysis was performed on patients with LN. We evaluated the ability of proteinuria, serum Cr, and uRBCs at 12 months to predict good long-term renal outcomes defined as serum Cr ≤ 100 mmol/L and kidney transplant/dialysis-free at the 7th year. Receiver operator characteristic curves were generated for proteinuria, serum Cr, and uRBCs to study their ability to predict good long-term outcomes and to identify their best cut-off. Descriptive statistics studied the pattern of change of proteinuria and serum Cr. Results. Proteinuria of 0.6 g/d and Cr of 83 mmol/L performed independently moderately well in predicting good long-term renal outcomes while uRBC was less accurate. Combining serum Cr to proteinuria gave a small increase in positive predictive value with a trade-off in sensitivity. Proteinuria changed within the first year whereas serum Cr changed until the 7th year. Conclusions. Both proteinuria and Cr predict good long-term renal outcomes in LN. Proteinuria's ability to change faster at 12 months makes it a favorable endpoint for clinical trials and research studies.

Serum soluble tumour necrosis factor receptor-2 (sTNFR2) as a biomarker of kidney tissue damage and long-term renal outcome in lupus nephritis

Objectives: We investigated the performance of soluble tumour necrosis factor receptor-2 (sTNFR2) as a biomarker of renal activity, damage, treatment response, and long-term outcome in lupus nephritis (LN).Method: Serum sTNFR2 levels were assessed in 64 LN patients (52 proliferative, 12 membranous) before and after induction treatment, and in 314 non-lupus controls. In LN patients, renal biopsies were performed at baseline and post-treatment. Patients with ≥ 50% reduced proteinuria, normal or improved estimated glomerular filtration rate (eGFR) by ≥ 25%, and inactive urinary sediment were considered clinical responders (CRs). Patients with ≥ 50% improved renal activity index were considered histopathological responders (HRs). Long-term renal outcome was determined using the chronic kidney disease (CKD) stage after a median follow-up of 11.3 years.Results: sTNFR2 levels were elevated in LN patients versus controls both at baseline (p < 0.001) and post-treatment (p < 0.001), and decreased following treatment (p < 0.001). Baseline sTNFR2 correlated with Chronicity Index scores in both baseline (r = 0.34, p = 0.006) and post-treatment (r = 0.43, p < 0.001) biopsies. In membranous LN, baseline sTNFR2 levels were higher in CRs (p = 0.048) and HRs (p = 0.03) than in non-responders, and decreased only in CRs (p = 0.03). Both baseline (p = 0.02) and post-treatment (p = 0.03) sTNFR2 levels were associated with decreasing eGFR throughout long-term follow-up, and post-treatment levels were higher in patients with long-term follow-up CKD stage ≥ 3 versus 1–2 (p = 0.008).Conclusions: Our data suggest serum sTNFR2 as a marker of kidney tissue damage and a predictor of long-term prognosis in LN, and merit further evaluation of sTNFR2 as a predictor of clinical and histopathological treatment outcomes in membranous LN.

Relation of peritubular capillary features to class of lupus nephritis.

BackgroundExperimental studies have linked peritubular capillary (PTC) loss with progression of chronic kidney disease. Minimal information on PTC in lupus nephritis (LN) has been reported. We therefore evaluated the PTC area in different classes of LN and determined if specific clinical characteristics correlated with PTC changes.MethodsRenal biopsies of 253 subjects with LN (categorized using the ISN/RPS 2003 classification) and 13 normal renal donors (the controls) were retrospectively evaluated for PTC morphology by staining for CD31 with immunohistochemistry method. The percent positive area of PTC (% PTC) was correlated with serum and urinary measures of renal function and renal pathology.ResultsSignificant PTC loss was observed in all classes of LN compared to controls. The % PTC area was highest in controls (7.64±1.48 %) with levels of 1.95±1.50, 4.16±3.85, 4.19±4.45, 5.02±1.79, and 4.45±3.75 in classes II, III, IV, IV combined with V and V, respectively (all p values < 0.05). The lowest PTC density was observed in class II LN, but this may be because some cases with worse classes of LN showed increased PTC density due to abnormally dilated capillaries associated with acute inflammation and angiogenesis. %PTC was increased in those with hematuria (5.8±5.2 vs. 3.6±3.4 %, red blood cells 3-10 vs. < 3 cells/high power field, p < 0.05) and was reduced in those with a moderately declined renal function (3.29±3.40 vs. 4.42±4.12, eGFR 15-59 vs. ≥ 60 ml/min/1.73 m2, p < 0.05). Nephrotic-range proteinuria also trended to be associated with lower PTC density although it did not reach statistical significance (3.1±2.6 vs. 4.9±4.5, p= 0.067).ConclusionsLN is associated with PTC loss and the severity correlates with reduced renal function. Further studies are needed to investigate whether a loss of PTC can predict long term renal outcomes in LN.Electronic supplementary materialThe online version of this article (doi:10.1186/s12882-016-0388-2) contains supplementary material, which is available to authorized users.

A proteinuria cut-off level of 0.7 g/day after 12 months of treatment best predicts long-term renal outcome in lupus nephritis: data from the MAINTAIN Nephritis Trial

BackgroundAlthough an early decrease in proteinuria has been correlated with good long-term renal outcome in lupus nephritis (LN), studies aimed at defining a cut-off proteinuria value are missing, except a...

Plasma-soluble urokinase-type plasminogen activator receptor levels are associated with clinical and pathological activities in lupus nephritis: a large cohort study from China.

In this study, we detected plasma urokinase plasminogen activator (uPA) and soluble urokinase-type plasminogen activator receptor (uPAR) levels in Chinese lupus nephritis patients from a large cohort. The associations between plasma uPA and soluble uPAR and clinico-pathological characteristics were further analyzed. The levels of plasma uPA and soluble uPAR were detected by ELISA in 202 patients with active lupus nephritis, 17 systemic lupus erythematosus (SLE) patients without renal involvement and 21 normal controls. There were no significant differences in the levels of the average plasma uPA among the lupus nephritis group, non-renal SLE group and normal control group (p = 0.129). The plasma-soluble uPAR level in the lupus nephritis group was significantly higher than that in the non-renal involvement SLE group (p = 0.004) and that in normal controls (p < 0.001). The plasma uPAR levels were positively associated with SLEDAI scores (r = 0.215, p = 0.007). In renal pathological data, there was significant difference of plasma-soluble uPAR levels among various pathological classes, which was the highest in the class IV group (p = 0.012). The level of plasma-soluble uPAR was found to be a risk factor for long-term renal outcomes in lupus nephritis by univariate survival analysis (p = 0.013, HR = 6.326, 95% CI: 1.466-27.298). Our study showed that the significantly increased plasma levels of soluble uPAR could be found in active lupus nephritis, and they were associated with some clinico-pathological features. Its involvement in the pathogenesis of lupus nephritis warrants further study.