Antimalarials in Lupus Nephritis: How Strong is the Evidence?

Systemic lupus erythematosus is a chronic multisystem autoimmune disease that affects the kidneys in approximately 50% of patients, with prevalence rising to as high as 70% in certain populations, such as African Americans and Asians. Antimalarials -and particularly hydroxychloroquine- are currently considered a mainstay of therapy, together with immunosuppressants. Over the last decades, several studies have extensively investigated the mechanisms of action of antimalarial agents, and their potential beneficial properties in patients with SLE in general. However, the evidence for the therapeutic benefit of hydroxychloroquine in patients with lupus nephritis (LN) derives mainly from observational studies, conducted in an era prior to the refinement of induction and maintenance protocols for immunosuppressive therapy. Despite the paucity of high-quality evidence on its efficacy in LN, the nephrology community widely supports the universal use of hydroxychloroquine in LN patients, and recommendations for its use are firmly entrenched in various clinical practice guidelines. Nonetheless, the use of antimalarials may also carry inherent risks, underscoring the importance of personalized approaches in these patients. Herein, we comprehensively review the available literature on antimalarials in LN aiming to update the current evidence, limitations, and future perspectives for the use of antimalarials in adults.

Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis With Diffuse Alveolar Hemorrhage With Avacopan.

OBJECTIVE: Avacopan, an activated complement factor 5 receptor antagonist, has been approved as adjunct therapy for severe active antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Current evidence supports the management of AAV presenting with diffuse alveolar hemorrhage (DAH) by administering glucocorticoids combined with either rituximab or cyclophosphamide in addition to supportive care. The role of avacopan in patients with DAH as a primary severe disease manifestation of AAV has not been well established. Furthermore, concerns remain regarding timely access to avacopan, the best glucocorticoid tapering regimen, and long-term efficacy and safety of the drug. We sought to identify clinical features and outcomes of patients presenting with DAH secondary to AAV who received avacopan in addition to glucocorticoids and rituximab or cyclophosphamide. METHODS: We performed a retrospective cohort study of all consecutive patients presenting with DAH as part of active severe granulomatosis with polyangiitis or microscopic polyangiitis. Demographic and clinical characteristics were collected at presentation and follow-up. RESULTS: Fifteen patients met inclusion criteria and were observed for a median time of 17 weeks (interquartile range [IQR] 6-37 weeks) after initiation of avacopan. Patients were predominantly female and White, had never smoked, and were a median age of 66 years (IQR 52-72 years) at diagnosis. The majority had newly diagnosed severe AAV with renal involvement. Three patients progressed to respiratory failure. The timing of avacopan introduction and patterns of glucocorticoid tapers varied widely in this cohort. Two serious adverse events related to infection were observed, including one opportunistic infection leading to the patient's death, although neither was directly attributed to avacopan administration. CONCLUSION: We describe the clinical course of patients who presented with the severe AAV disease manifestation of DAH and received avacopan as adjunct therapy. Most patients achieved remission during follow-up, and adverse events, including infection, were observed.

Predictive Factors of Renal Recovery and Progression to End-Stage Kidney Disease in Patients With Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis With Severe Kidney Disease.

Introduction: A significant number of patients with antineutrophil cytoplasmic antibodies (ANCA)- associated vasculitis (AAV) with glomerulonephritis (AAV-GN) still progress to end-stage kidney disease (ESKD, estimated glomerular filtration rate [eGFR] <15 ml/min per 1.73 m2) despite advances in remission-induction treatment. Methods: This is a retrospective cohort study on myeloperoxidase (MPO)-ANCA or proteinase 3 (PR3)-ANCA positive patients with AAV (microscopic polyangiitis, MPA; or granulomatosis with polyangiitis, GPA) and eGFR <15 ml/min per 1.73 m2 or ESKD at presentation. Renal recovery, dialysis discontinuation, and persistence of ESKD after standard remission-induction, with or without the use of plasma exchange (PLEX) were analyzed. Results: We analyzed 166 patients with biopsy-proven active AAV-GN and eGFR <15 ml/min per 1.73 m2 at the time of diagnosis. Patients received glucocorticoids with cyclophosphamide (CYC) (n = 84) or with rituximab (RTX) (n = 72) for remission-induction, and 49 received PLEX. The predictors of renal recovery were erythrocyte sedimentation rate, serum creatinine (SCr) at diagnosis, and minimal or mild chronicity changes. We further analyzed 71 patients who started dialysis with or without PLEX within 4 weeks of AAV-GN diagnosis. The predictors of dialysis discontinuation were minimal chronicity changes in kidney biopsy at diagnosis (odds ratio = 6.138; 95% confidence interval [CI]: 1.389-27.118; P = 0.017). Predictors of persistence of ESKD within 12 months included higher SCr at diagnosis (incidence rate ratio [IRR] = 1.086; 95% CI: 1.005-1.173; P = 0.037), and moderate (IRR = 3.797; 95% CI: 1.090-13.225; P = 0.036), or severe chronicity changes in kidney biopsy (IRR = 5.883; 95% CI: 1.542-22.439; P =0.009). Conclusion: In our cohort, kidney recovery, dialysis discontinuation, and persistence of ESKD in patients with AAV-GN and eGFR <15 ml/min per 1.73 m2 depended on SCr and histologic findings on kidney biopsies at the time of diagnosis and was not affected by the addition of PLEX.

Histologic and Clinical Factors Associated with Kidney Outcomes in IgA Vasculitis Nephritis.

BACKGROUND: Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. METHODS: Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2-5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. RESULTS: M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. CONCLUSIONS: Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.

Membranous nephropathy treatment standard.

Membranous nephropathy (MN) is characterized by deposition of immune complexes leading to thickening of glomerular basement membranes. Over time, the understanding of MN has evolved, with the identification of specific autoantibodies against novel podocyte antigens and the unraveling of intricate pathogenic pathways. Although the anti-CD20 monoclonal antibody rituximab is favored as part of the initial therapy in MN, a subgroup of MN patients may be resistant to rituximab necessitating the use of alternative agents such as cytotoxic therapies. In addition, newer agents such as novel anti-CD20 monoclonal antibodies, therapies targeting the CD38-positive plasma cells and anti-complement therapy are being studied in patients who are resistant to traditional treatment strategies. This manuscript furnishes a review of the novel developments in the pathophysiology of MN including the identification of target antigens and current treatment standards for MN, concentrating on evidenced-based interventions designed to attain remission and to prevent disease progression.

Monoclonal Gammopathy and Its Association with Progression to Kidney Failure and Mortality in Patients with CKD.

BACKGROUND: Little is known about the prognostic significance of monoclonal gammopathy of undetermined and renal significance (MGUS and MGRS) in patients with CKD. The objective of this study was to determine the clinical and kidney outcomes of patients with CKD with either MGUS or MGRS compared with those with CKD without MGUS or MGRS. METHODS: We conducted a retrospective cohort study from 2013 to 2018. Patients who had both CKD diagnosis and monoclonal testing were identified. Patients were divided into MGRS, MGUS, and no monoclonal gammopathy groups. Cumulative incidence functions and Cox proportional hazards regression were used to model time to event data and to evaluate the association between monoclonal gammopathy status and risk of kidney failure, with death treated as a competing risk. RESULTS: Among 1535 patients, 59 (4%) had MGRS, 648 (42%) had MGUS, and 828 (54%) had no monoclonal gammopathy. Unadjusted analysis showed that compared with no monoclonal gammopathy patients, patients with MGRS were at higher risk of kidney failure (hazard ratio [HR] [95% confidence interval]: 2.5 [1.5 to 4.2] but not patients with MGUS (HR [95% confidence interval]: 1.3 [0.97 to 1.6]), after taking death into account as a competing risk. However, in the multivariable analysis, after adjusting for age, sex, eGFR, proteinuria, and Charlson Comorbidity Index, the risk of progression to kidney failure (with death as competing risk) in the MGRS group was no longer statistically significant (HR: 0.9 [0.5 to 1.8]). The same was also true for the MGUS group compared with the group with no monoclonal gammopathy (HR: 1.3 [0.95 to 1.6]). When evaluating the association between MGUS/MGRS status and overall survival, MGRS was significantly associated with mortality in fully adjusted models compared with the group with no monoclonal gammopathy, while MGUS was not. CONCLUSIONS: After adjusting for traditional risk factors, MGUS/MGRS status was not associated with a greater risk of kidney failure, but MGRS was associated with a higher risk of mortality compared with patients with no monoclonal gammopathy.

Microscopic hematuria as a risk factor for IgAN progression: considering this biomarker in selecting and monitoring patients.

Hematuria-either macroscopic hematuria or asymptomatic microscopic hematuria-is a clinical feature typical but not specific for immunoglobulin A nephropathy (IgAN). The only biomarker supported by the Kidney Disease: Improving Global Outcomes group as a predictor of progression, identifying patients needing treatment, is proteinuria >1 g/day persistent despite maximized supportive care. However, proteinuria can occur in the setting of active glomerulonephritis or secondary to sclerotic renal lesions. Microscopic hematuria is observed in experimental models of IgAN after IgA-IgG immunocomplex deposition, activation of inflammation and complement pathways. Oxidative damage, triggered by hemoglobin release, is thought to contribute to the development of proteinuria and progression. Despite being a clinical hallmark of IgAN and having a rational relationship with its pathophysiology, the value of microscopic hematuria in assessing activity and predicting outcomes in patients with IgAN is still debated. This was partly due to a lack of standardization and day-to-day variability of microhematuria, which discouraged the inclusion of microhematuria in large multicenter studies. More recently, several studies from Asia, Europe and the USA have highlighted the importance of microhematuria assessment over longitudinal follow-up, using a systematic approach with either experienced personnel or automated techniques. We report lights and shadows of microhematuria evaluation in IgAN, looking for evidence for a more consistent consensus on its value as a marker of clinical and histological activity, risk assessment and prediction of treatment response. We propose that hematuria should be included as part of the clinical decision-making process when considering when to use immunosuppressive therapy and as part of criteria for enrollment into clinical trials to test drugs targeting the inflammatory reaction elicited by immune pathway activation in IgAN.

Mayo Clinic Consensus Report on Membranous Nephropathy: Proposal for a Novel Classification.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Mayo Clinic consensus report on membranous nephropathy: proposal for a novel classification.

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment.

Anti-CD20 should be the first-line treatment in high-risk membranous nephropathy.

Membranous nephropathy (MN) is a common cause of nephrotic syndrome (NS) in adults and if untreated can progress to endstage kidney disease. Factors considered to place a patient at high or very high risk for progression include elevated serum creatinine at baseline, declining kidney function, persistent heavy proteinuria (>8 g/24 h), or persistent NS, presence of life-threatening complications related to NS (such as venous thromboembolic events), or very high anti-PLA2R antibody titers (>150 RU/ml). Patients who are at high or very high risk of progression should be treated with immunosuppression therapy to induce remission of proteinuria and to avoid progressive loss of kidney function. Traditional forms of immunosuppression for patients with MN have included the use of cyclic courses of corticosteroids with cyclophosphamide or calcineurin inhibitors. These forms of therapy are associated with significant toxicity, e.g. corticosteroids (infections, diabetes, weight gain), cyclophosphamide (infertility, severe leukopenia, malignancy), and calcineurin inhibitors (hypertension, nephrotoxicity). The introduction of anti-CD20+ B-cell therapies in the late 1990s has changed the landscape. In this article we will argue that anti-CD20+ B therapy should be the treatment of choice for patients at high/very high risk of progression when considering its efficacy and side-effect profile.

Anti-PLA2R Antibody Levels and Clinical Risk Factors for Treatment Nonresponse in Membranous Nephropathy.

BACKGROUND: The 2021 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend following anti-phospholipase A2 receptor (PLA2R) antibody levels as a marker of treatment response in membranous nephropathy; however, the optimal timing to evaluate antibody levels and how to combine them with other clinical variables are currently unknown. METHODS: We used a cohort of 85 patients from the Membranous Nephropathy Trial Of Rituximab (MENTOR) with anti-PLA2R antibodies ≥14 RU/ml to identify risk factors for not experiencing proteinuria remission after 12 months of treatment with cyclosporine or rituximab. Three landmark times were considered: at baseline and after 3 and 6 months of treatment. Logistic regression model performance was evaluated using C-statistics and model fit (Akaike information criterion [AIC], R 2 ). RESULTS: The model at baseline that best predicted no remission included anti-PLA2R antibodies >323 RU/ml and creatinine clearance; the best model after 3 months included the change from baseline in both antibody and albumin levels; and the best model after 6 months included antibody levels >14 RU/ml, creatinine clearance, and the change from baseline in albumin. Compared with the model at baseline, the model at 3 months had better model fit (AIC 70.9 versus 96.4, R 2 51.8% versus 30.1%) and higher C-statistic (0.93 versus 0.83, P = 0.008). The model at 6 months had no difference in performance compared with the model at 3 months (AIC 68.6, R 2 53.0%, C-statistic 0.94, P = 0.67). CONCLUSIONS: In patients with membranous nephropathy treated with cyclosporine or rituximab in the MENTOR trial, we found that the optimal method to evaluate risk factors for the probability of treatment response was to use anti-PLA2R antibody levels combined with albumin levels after 3 months of treatment, which was significantly better than using antibody levels alone or risk factor evaluation at baseline, with no added benefit of waiting until 6 months of treatment. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_10_09_CJN0000000000000237.mp3.

COVID-19 and Glomerular Diseases.

COVID-19 is a systemic disease, and the kidney is one of the target organs of infection. Kidney injury is common and can occur in up to 40% of patients. Several glomerular diseases have been reported in association with COVID-19. Some are likely related to COVID-19 whereas many are likely coincidental. Glomerular diseases that are frequently reported in COVID-19 and have a plausible mechanistic explanation are likely to be related to COVID-19. In contrast, glomerular diseases that are seldom reported and have no known plausible mechanism, are likely to be unrelated. Collapsing glomerulopathy (CG) is by far the most prevalent. Its association with COVID-19, resembling HIV and CG, led to the newly proposed term "COVID-19 associated nephropathy" or "COVAN." High-risk APOL1 genotypes are the major risk factor in COVAN patients. Podocytopathy, membranous nephropathy (MN), pauci-immune crescentic glomerulonephritis (GN), and thrombotic microangiopathy (TMA) are also reported. In kidney allografts, CG remains the most common glomerular pathology. Patients typically present with acute kidney injury (AKI) or abnormal urinary findings at the time of or shortly after COVID-19 diagnosis. Treatment of glomerular disease in patients with COVID-19 is challenging. Providers should cautiously consider balancing risks and benefit of immunosuppression, particularly in patients with active diseases. Short-term outcomes vary but generally remain poor with high morbidity and mortality. Future study of long-term outcomes is needed to improve our understanding of glomerular disease associated with COVID-19.

PLEX in AAV-GN: insights from the meta-analysis results and impact on remission induction treatment recommendations.

The risk of progression to end-stage kidney disease (ESKD) in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and glomerulonephritis (AAV-GN) remains high. At 5 years of follow-up, 14-25% of patients will evolve to ESKD, suggesting that kidney survival is not optimized in patients with AAV. The addition of plasma exchange (PLEX) to standard remission induction has been the standard of care, particularly in patients with severe renal disease. However, there is still some debate regarding which patients benefit from PLEX. A recently published meta-analysis concluded that the addition of PLEX to standard remission induction in AAV probably reduced the risk of ESKD at 12 months and that PLEX was associated with an estimated absolute risk reduction for ESKD at 12 months of 16.0% for those at high risk or with a serum creatinine >5.7 mg/dl (high certainty of important effects). These findings were interpreted as supportive of offering PLEX to patients with AAV and a high risk of progression to ESKD or requiring dialysis and are making their way into societies recommendations. However, the results of the analysis can be debated. We provide an overview on the meta-analysis as an attempt to guide the audience through how the data were generated, to comment on our interpretation of the results and to explain why we feel uncertainty remains. In addition, we would like to provide insights in two questions that we believe are very relevant to consider when addressing the role of PLEX: the role of kidney biopsy findings in the decision making of whom might benefit from PLEX and the impact of novel treatments (i.e. complement factor 5a inhibitors) in avoiding progression to ESKD at 12 months. The treatment of patients with severe AAV-GN is complex and further studies that include only patients at high risk of progression to ESKD are needed.

Relapsing and Remitting Proliferative Glomerulonephritis With Monoclonal Immunoglobulin Deposits in Association With Infection and Vaccination: A Case Report.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is the second most common monoclonal gammopathy of renal significance. Rates of progression to kidney failure as well as rates of recurrence after kidney transplantation are high, especially in the absence of treatment. Treatment is usually targeted toward the abnormal clone, but even in the absence of an identifiable clone, empiric treatment is still recommended to avoid worsening prognosis. In this report, we present an unusual course of a PGNMID case with a relapsing and remitting pattern of illness, likely triggered by infection and vaccination. The patient in this case showed subsequent improvement after each episode, with stable kidney function over the years. This case report highlights the importance of investigating possible recent infectious exposures or vaccinations as potential triggers for this disease. This association should be considered for future patients with PGNMID, especially when there is no identifiable clone to help guide therapy.

Maintenance of Remission and Risk of Relapse in Myeloperoxidase-Positive ANCA-Associated Vasculitis with Kidney Involvement.

BACKGROUND: The optimal strategy for remission-maintenance therapy in patients with myeloperoxidase-ANCA (MPO-ANCA)-associated vasculitis is not established. Defining parameters to guide maintenance therapy is required. METHODS: This was a retrospective cohort study of all patients with MPO-ANCA-associated vasculitis (microscopic with polyangiitis and granulomatosis with polyangiitis) and GN followed at the Mayo Clinic between 1996 and 2015. Relapse rate, MPO-ANCA status, and remission-maintenance therapies were reviewed. Logistic regression models, Kaplan-Meier method, and Cox proportional hazards regression models were applied. RESULTS: We analyzed 159 patients with active MPO-ANCA-associated vasculitis with GN. Sixty-six (42%) patients had at least one relapse, and 52 (33%) relapsed before 60 months. Patients with MPO-ANCA who became persistently negative did not relapse (hazard ratio [HR], 0.03; 95% confidence interval [95% CI], 0.002 to 0.431; P =0.01). The reappearance of MPO-ANCA was associated with a higher risk of relapse (HR, 1.91; 95% CI, 1.109 to 3.293; P =0.02). Immunosuppression was withdrawn in 80 (50%) patients, and this was less likely in those who received cyclophosphamide for remission induction or in patients with persistently positive MPO-ANCA (odds ratio [OR], 0.44; 95% CI, 0.228 to 0.861; P =0.02 and OR, 0.42; 95% CI, 0.213 to 0.820; P =0.01, respectively). Relapse frequency was not different between patients with persistently positive MPO-ANCA and patients with MPO-ANCA reappearance (44% versus 39%, P =0.49), irrespective of remission-maintenance treatment. Ear, nose, and throat involvement (OR, 6.10; 95% CI, 1.280 to 29.010; P =0.02) and MPO-ANCA reappearance (OR, 9.25; 95% CI, 3.126 to 27.361; P <0.001) were independently associated with relapse after treatment withdrawal. CONCLUSIONS: Patients persistently MPO-ANCA negative are at low risk for relapse even without remission-maintenance therapy. Persistence or subsequent reappearance of MPO-ANCA is associated with a higher risk of relapse. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast.aspx?p=CJASN&e=2023_01_10_CJN06460622.mp3.

Incidence, Prevalence, and Mortality of Lupus Nephritis: A Population-Based Study Over Four Decades Using the Lupus Midwest Network.

OBJECTIVE: There is a paucity of population-based studies investigating the epidemiology of lupus nephritis (LN) in the US and long-term secular trends of the disease and its outcomes. We aimed to examine the epidemiology of LN in a well-defined 8-county region in the US. METHODS: Patients with incident LN between 1976 and 2018 in Olmsted County, Minnesota (1976-2009) and an 8-county region in southeast Minnesota (2010-2018) were identified. Age- and sex-specific incidence rates and point prevalence over 4 decades, adjusted to the projected 2000 US population, were determined. Standardized mortality ratios (SMRs), survival rates, and time to end-stage renal disease (ESRD) were estimated. RESULTS: There were 72 patients with incident LN between 1976 and 2018, of whom 76% were female and 69% were non-Hispanic White. Mean ± SD age at diagnosis was 38.4 ± 16.24 years. Average annual LN incidence per 100,000 population between 1976 and 2018 was 1.0 (95% CI 0.8-1.3) and was highest in patients ages 30-39 years. Between the 1976-1989 and 2000-2018 time periods, overall incidence of LN increased from 0.7 to 1.3 per 100,000, but this was not statistically significant. Estimated LN prevalence increased from 16.8 per 100,000 in 1985 to 21.2 per 100,000 in 2015. Patients with LN had an SMR of 6.33 (95% CI 3.81-9.89), with no improvement in the mortality gap in the last 4 decades. At 10 years, survival was 70%, and 13% of LN patients had ESRD. CONCLUSION: The incidence and prevalence of LN in this area increased in the last 4 decades. LN patients have poor outcomes, with high rates of ESRD and mortality rates 6 times that of the general population.