Challenges and Opportunities in Lupus Nephritis
Anokhi Saklecha, BS
Division of Rheumatology, Allergy and Immunology University of California, San Diego, USA
Chelsey J. F. Smith, MD
Division of Rheumatology, Allergy and Immunology University of California, San Diego, USA
Abstract
Active lupus nephritis poses severe maternal and fetal risks in pregnant patients. Management in pregnancy is challenging and limited by lack of pregnancy-safe medication options. Preeclampsia is an associated maternal risk that shares many clinical features with lupus nephritis, often making it difficult to identify the primary disease process. In this report, we present a case of severe preeclampsia superimposed on active lupus nephritis in a 25-year-old pregnant female. We highlight the risks and management options for lupus nephritis in pregnancy, the overlaps in presentation between lupus nephritis and preeclampsia, and techniques to clinically distinguish between the two.
Dr. Manjuri Sharma
Prof & Head, Dept. of Nephrology, Gauhati Medical College & Hospital.
Dr. Benjamin S Sangma
Senior Resident, Dept. of Nephrology, Gauhati Medical College & Hospital.
Abstract
Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease with varied manifestations, significantly impacting women and potentially leading to Lupus Nephritis (LN), a major cause of morbidity and mortality. The review article explores the unique challenges and opportunities in managing lupus nephritis (LN) in North Eastern India, a region characterised by diverse ethnicities, cultures, and socioeconomic challenges. With a higher than average prevalence of systemic lupus erythematosus (SLE) and lupus nephritis (LN), the region presents distinct epidemiological patterns, likely influenced by genetic, environmental, and lifestyle factors. The management and prognosis of LN are further complicated by the region’s geographical and infrastructural limitations, including access to specialised healthcare and socioeconomic barriers, which impacts the patient’s outcome. Despite the challenges, there are emerging opportunities for improvement through innovations in healthcare delivery, governmental and non-governmental initiatives aimed at enhancing healthcare access, and the adaptation of treatment guidelines to the local context. This review article underscores the importance of region-specific research and healthcare strategies to improve care and outcome for lupus nephritis (LN) patients in North Eastern India, thus contributing to the broader understanding of the disease in diverse populations and settings.
Teresa V. Gouveia
Department of Internal Medicine, Centro Hospitalar Lisboa-Norte, Lisboa, Portugal.
Lucía B. Molinero
Department of Internal Medicine, Hospital Provincial del Centenario, Rosario, Argentina.
David A. Isenberg
Centre for Rheumatology, Department of Medicine, University College London, London, United Kingdom
Abstract
Systemic lupus erythematosus (SLE) is a life-threatening autoimmune disease, which involves the production of class-switched autoantibodies against intracellular antigens, particularly nuclear antigens, leading to tissue damage and immune complex deposition in multiple organs. Strategies for B cell modulation include direct depletion using monoclonal antibodies, such as rituximab, or indirect impairment of survival via targeting B cell activating factors, notably belimumab. While the pursuit of autoreactive B cell modulation has yielded progress, challenges persist, including modest therapeutic responses, allergic reactions and infections. Thus, to overcome these challenges and focus on achieving a more effective B cell depletion, new strategies may involve fully humanized monoclonal antibodies, such as obinutuzumab, which demonstrated promising results in the NOBILITY study, involving patients with lupus nephritis, Another approach is the use of chimeric antigen receptor T cells therapy, a strategy that has been approved for the treatment of patients with relapsed or refractory B-cell malignancies and has been shown in lupus patients to lead to a rapid and sustained breakdown of the B cell-mediated autoimmune response, reported to lead to drug-free remission of refractory SLE. In addition, combinations of existing therapies and innovative cellular approaches, such rituximab plus belimumab, have been studied. There have now been four studies describing the use of a rituximab plus belimumab in lupus nephritis and non-renal lupus. In the BEAT-LUPUS, the primary endpoint (reduction in anti-double strand DNA) was achieved, however, in BLISS-BELIEVE study the primary endpoint (Systemic Lupus Erythematosus Disease Activity Index 2000) was not met. The CALIBRATE trial was a safety study. The SynBioSe 1 study demonstrated clinical improvement, as indicated by the Systemic Lupus Erythematosus Disease Activity Index and Lupus Low Disease Activity State indices.
This review will provide a brief review of the established conventional approaches to B cell depletion and then discuss the trends towards innovative concepts aimed at achieving this goal.
Abstract
Background: In the majority of lupus patients, lupus nephritis (LN) develops within the first five years of diagnosis. Here we evaluated patients treated in our department during the past 40 years distinguishing those with very early onset [within one year of diagnosis]; early onset [ two to five years post diagnosis]; medium-term onset [between six to ten years after diagnosis]; late onset [presenting six to 15 years after diagnosis] and very late onset LN [presenting 16 years or later after diagnosis]. Early onset [ two to five years post diagnosis]; medium-term onset [between six to ten years after diagnosis]; late onset [presenting six to 15 years after diagnosis] and very late onset LN [presenting 16 years or later after diagnosis].early onset [within two years of diagnosis]; medium-term onset [between two and five years after diagnosis]; late onset [presenting five to ten years after diagnosis] and very late onset LN [presenting ten years after diagnosis].
Aim: To compare the differences in demography, clinical data, serological profile and follow up of patients with LN of early, medium, late and very late onset.
Methods: This was a retrospective study of 226 systemic lupus erythematosus (SLE) patients with biopsy proven nephritis. We focused on a comparison of their epidemiology, serology, clinical and follow-up data.
Results: We identified 97 (43%) very early-onset patients; 69 (31%) early-onset; 28 (12%) medium onset; 22 (10%) late-onset and 10 (4%) very late-onset LN patients. Comparing those patients whose LN was delayed by> 10 years post their lupus diagnosis compared to those with LN onset <10 years we found that these patients were statistically significantly more likely to be Caucasian [p=0.04]; to have arthritis [p=0.001] and to be leucopaenic [p=0.004]. There were no other difference between the groups. Among the 10 patients with very late onset LN there was an increase trend towards them having higher ANA titer (>1:640) [p=0,044] and having biopsy-proven combined type of LN (III+V, IV+V) [p=0.034].
Conclusion: Although the majority of SLE patients who get LN do so within 10 years of diagnosis in our experience 14% [approximately 1:7] developed renal involvement 10 years or more after SLE diagnosis. The observation emphasis the need to be vigilant when caring for SLE patients long term.
Niclas Stefan Rasmussen
Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Copenhagen Research Center for Autoimmune Connective Tissue Diseases – COPEACT, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Søren Jacobsen
Copenhagen Research Center for Autoimmune Connective Tissue Diseases – COPEACT, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Claus Henrik Nielsen
Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Christoffer Tandrup Nielsen
Copenhagen Research Center for Autoimmune Connective Tissue Diseases – COPEACT, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Abstract
Background: Generation of galectin-3 binding protein (G3BP)-expressing microvesicles can be induced in-vitro by Toll-like receptor 9 ligation in mononuclear cells. Microvesicles co-expressing G3BP and double-stranded DNA are associated with active lupus nephritis. However, whether the microvesicular G3BP mainly deposits from circulation or is endogenously derived is unknown. In this study, we aim to delineate the origin of G3BP on in-vitro generated microvesicles by using serum as a source of native G3BP.
Methods: G3BP-expressing microvesicles, generated by stimulation of systemic lupus erythematosus patient-derived mononuclear cells with the Toll-like receptor 9-agonist ODN2395, were incubated with normal human serum, heat-inactivated human serum, recombinant human C1q or human albumin. The expression of G3BP by microvesicles was examined by flow cytometry, and the binding of soluble recombinant human C1q to recombinant human G3BP was investigated by ELISA.
Results: Approximately half of the microvesicles released from mononuclear cells expressed G3BP. Surprisingly, the staining was abrogated by incubation of the microvesicles with normal human serum, while incubation with heat-inactivated human serum did not have a similar effect. Reasoning that C1q might be the heat-labile factor blocking access of our G3BP antibody detection system, we incubated microvesicles with recombinant human C1q, which on average inhibited the detectable proportion of G3BP-bearing microvesicles by 87%. Soluble recombinant human C1q bound to immobilized recombinant human G3BP in a dose-dependent manner.
Conclusion: Our data suggest that soluble C1q binds to G3BP on Toll-like receptor 9-induced microvesicles released from systemic lupus erythematosus patient-derived mononuclear cells. This interaction may exarcerbate inflammation in systemic lupus erythematosus but may also serve as a general mechanism for the appropriate clearance of these potentially pathogenic factors.
Amorn Sankhaanuruk, M.D.
Division of Rheumatology, Department of Internal Medicine 1 , Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Nuntana Kasitanon, M.D.
Division of Rheumatology, Department of Internal Medicine 1 , Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Worawit Louthrenoo, M.D.
Division of Rheumatology, Department of Internal Medicine 1 , Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
Abstract
Background: Nowadays, we have standard treatment guidelines for lupus nephritis (LN), a substantial proportion of patients have LN flare. The aims here to determine the incidence of LN flare in patients who had renal complete remission (CR) after receiving induction therapy (IT) and to identify factors associated with renal flare after CR in clinical practice.
Methods: Retrospective analysis in a tertiary-level center for the clinical outcomes of patients who had first LN episode, achieved CR (24hr urine protein <0.5 gm/day with normal renal function) within 12 months after received IT and received the maintenance therapy (MT).
Results: Eighty-seven out of 548 patients (96.6% female with mean age 29.5±10.8 years) met the inclusion criteria. During 6.1±3.4 years of observation after CR, 42 (48.3%) patients had LN flare. The incidence ratio of LN flare was 10.9/100 patient-years. The mean time from CR to flare was 3.1 years. Using Cox-regression analysis, induction to remission therapy ≥6 months (OR=0.33, p=0.006), and using statins ≥9 months after reached CR (OR=0.44, p=0.032) had a lower incidence of LN flare, while age at onset of disease ≤20 years had a higher incidence of LN flare.
Conclusion: Despite achieving CR with standard treatment, almost half of the patients had an LN flare within a few years. Young SLE patients had an increased incidence of LN flare, the long period of induction therapy and using statins may retard a flare of the disease.
Guilherme Guilherme Trindade Martins Moreira Da Silva
Álvaro Luís Steiner Fernandes de Souza
Anna Carolina Alves Guimarães Aragão
Vitor Guedes Bonisson
Valério Fuks
Álvaro Luís Steiner Fernandes de Souza
Ludmilla da Rocha Freitas Vieitas
Thiago Sant’Anna Coutinho
Abstract
Herein we present the case of a 27-year-old male patient who was recently diagnosed with Systemic Lupus Erythematosus (SLE) associated with nephritis with atypical findings on kidney biopsy and premature cardiovascular disease despite scarce traditional risk factors and negative laboratory findings for antiphospholipid syndrome. A literature review on the epidemiology and pathogenesis of coronary disease in SLE was conducted. The patient was admitted for pulse therapy after refractory disease on outpatient care but evolved with ventricular fibrillation secondary to acute thrombosis in the proximal segment of the anterior left descending artery, with no evidence of atherosclerotic disease. Laboratory findings were also negative for antiphospholipid syndrome both upon diagnosis and after the coronary event. He underwent manual thrombus aspiration and angioplasty with a drug-eluting stent, successfully weaning off mechanical ventilation and vasopressors at the intensive care unit and showing no neurological deficits or left ventricular function impairment. Kidney biopsy later resulted positive for immunoglobulin A nephropathy. The patient was discharged asymptomatic on guideline-directed therapy for coronary disease, warfarin associated with clopidogrel, anti-hypertensive drugs and a combination of immunosuppressants, remaining well on three-month follow-up. SLE is a chronic inflammatory disease that has increasingly been recognized as a major cardiovascular risk factor due to a variety of mechanisms involving accelerated atherosclerosis and thrombosis. As patients survive the first years of disease onset from infection and disease-specific complications, cardiovascular outcomes become a great concern. However, early events such as in this case are possible, especially in the context of flaring disease. We emphasize the importance of an interdisciplinary approach to such patients for better outcomes.
John Robertson
Department of Biomedical Engineering and Mechanics, College of Engineering, Virginia Tech, Blacksburg, VA, United States of America (USA); Section of Nephrology, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Rametrix Technologies, Inc., Blacksburg, VA, USA.
Amr Sayed Issa
Department of Biomedical Engineering and Mechanics, College of Engineering, Virginia Tech, Blacksburg, VA, United States of America (USA).
Mariana Gomez
Internal Medicine/Infectious Disease, Carilion Clinic, Roanoke, VA, USA.
Kathleen Sullivan
Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Ryan Senger
Department of Biological Systems Engineering, College of Life Sciences and Agriculture, Virginia Tech, Blacksburg, VA, USA; Department of Chemical Engineering, College of Engineering, Virginia Tech, Blacksburg, VA, USA; Department of Biomedical Engineering and Mechanics, College of Engineering, Virginia Tech, Blacksburg, VA, United States of America (USA).
Abstract
Background: Many systemic and urinary tract diseases alter renal structure and function, including changing the composition of urine. While routine urinalysis (physical properties, sediment evaluation, urine chemistry analytes) is useful in screening, it has limitations on separating disease processes, structural changes, and functional abnormalities. Likewise, while many individual ‘biomarkers’ have been used to screen for disease, they have not met with widespread clinical adoption. The recent COVID19 Pandemic and the recognition of post-acute sequelae SARS-CoV-2 infection (PASC) have highlighted the need for rapid, scalable, economical, and accurate screening tools for managing disease.
Aims: Validate a Raman spectroscopy-based screening technology for urine analysis that could be used for recognition and quantification of systemic and renal effects of acute and PASC COVID19 disease.
Methods: One hundred ten (110) urine specimens were obtained from consented adults diagnosed with COVID19 disease by RT-PCR and/or proximate (household) contact With RT-PCR-confirmed COVID19 disease. Samples were analyzed using Raman chemometric urinalysis, a technology that detects hundreds of discrete chemicals in urine and applies computational comparison-machine learning to detect COVID19-associated molecular patterns (‘fingerprints’).
Results: When compared with the urine multimolecular ‘fingerprints’ of healthy individuals and patients with known systemic diseases (diabetes mellitus, lupus) that alter renal structure and function, patients with acute and PASC COVID19 had unique ‘fingerprints’ indicative of alterations in renal function (i.e. – infection altered urine composition). Differences in disease severity (mild to severe) were reflected by different ‘fingerprints’ in urine. Roughly 20% of hospitalized patients developed a degree of renal dysfunction (decrements in eGFR) that were correlated with distinct changes in urine fingerprints.
Conclusion: Raman chemometric urinalysis may be a useful tool in management of patients with COVID19 disease, particularly in detecting patients with evolving renal dysfunction for whom there should be attention to medication use and renal health restoration/preservation.
Kartik Ganesh
Consultant Nephrologist and Renal Transplant Physician, VPS Lakeshore Hospital, Kochi, Kerala, India
Aneesh Kumar GS
Senior Resident, Nephrology, VPS Lakeshore Hospital, Kochi, Kerala, India
Jithin S Kumar
Consultant Nephrologist and Renal Transplant Physician, VPS Lakeshore Hospital, Kochi, Kerala, India
Abi Abraham M
Director of Renal Transplant Services, VPS Lakeshore Hospital, Kochi, Kerala, India
Abstract
Aims and Objectives: To identify the prevalence of posterior reversible encephalopathy syndrome in patients with renal disease at a single center over a two year duration and to analyse their clinical profile.
Materials and methods: A retrospective analysis of all patients admitted in the ICU under the department of Nephrology in the past 2 years at VPS Lakeshore Hospital and Research Centre, Kochi was done to look for patients with posterior reversible encephalopathy syndrome (PRES). Their presenting symptoms, degree of hypertension, immunosuppression status, recurrence rates, findings on imaging and prognosis after treatment was evaluated.
Results: In 636 intensive care unit (ICU) admissions under Nephrology, there were 6 cases of PRES. 4 were females and 2 were males. The median age was 27.6 years. 4 patients were cases of chronic kidney disease stage V on maintenance hemodialysis, one case was a case of CKD on conservative management and one patient had just undergone living donor kidney transplantation. 1 patient was on calcineurin inhibitors. Three patients (50%) had IgA Nephropathy, one (16.6%) had lupus nephritis, one (16.6%) had membranous nephropathy and one (16.6%) had chronic glomerulonephritis. Clinical features were seizures (50%) and confusion with depressed consciousness (50%). One patient had recurrence of PRES. Three patients (50%) had typical locations of radiological findings whereas three patients (50%) had findings in unusual areas. 5 patients (83.3%) had severe hypertension (BP>180/ 100mm Hg). All patients recovered completely and there was no mortality
Conclusions: posterior reversible encephalopathy syndrome can be seen in association with kidney disease in various scenarios with many atypical features such as atypical radiological distribution and absence of hypertension. It is an under-represented entity and merits further studies.
