Renal Remission Research Articles

Intracapillary monoclonal IgM deposits disease with massive pseudothrombi: A clinicopathologic study of 4 cases and literature review.

Intracapillary monoclonal IgM deposits disease (ICMDD) has long been considered a hallmark of Waldenström macroglobulinemia (WM) nephropathy. Intracapillary immunoglobulin thrombi are the characteristic features of cryoglobulinemic glomerulonephritis. Here, we reported 4 cases of ICMDD with massive pseudothrombi but without WM or cryoglobulinemia. We retrospectively analyzed the clinical and pathologic features of patients diagnosed with ICMDD with massive pseudothrombi. A total of 4 patients (2 men and 2 women) aged 62 to 73 years were enrolled in this study. Microscopic hematuria, edema, and renal insufficiency were present in all patients, along with low serum C3 and C4 in 2 patients. Hematologic examination showed abnormal serum free light chain ratios in all patients and high levels of serum IgM in 3 patients. IgM-κ monoclonal band was identified by serum immunofixation electrophoresis in 3 patients. One patient was diagnosed with small B-cell lymphoma by bone marrow aspiration. Renal biopsy specimen showed massive periodic acid-Schiff-positive hyaline thrombi in the glomerular capillary lumens and also less mesangial, subendothelial, and subepithelial deposits on light microscopy. Immunofluorescence indicated positive staining for IgM (++) and κ light chain staining in the glomerular capillary lumens, capillary walls, and mesangium in all patients. By electron microscopy, the glomerular capillary lumens were filled with homogeneous high-electron-dense deposits without substructure. Two patients were treated with prednisone combined with cyclophosphamide, and 2 received plasma cell-targeted chemotherapy. One patient achieved partial renal remission. Intracapillary monoclonal IgM deposits disease is a rare disease and not always related to WM. Most patients have IgM monoclonal immunoglobulinemia; renal biopsy specimens mainly show a large number of pseudothrombi in the glomerular capillary lumens. Cyclophosphamide is effective in some patients.

Successful Treatment of Monoclonal Immunotactoid Glomerulopathy Associated with Chronic Lymphocytic Leukemia Using Ibrutinib.

A 71-year-old woman developed nephrotic syndrome during 10-year follow-up for chronic lymphocytic leukemia. A renal biopsy sample analysis revealed IgG1-lambda-positive monoclonal immunotactoid glomerulopathy (mITG). The patient was treated with ibrutinib, a Bruton tyrosine kinase inhibitor, and complete renal remission was achieved after 24 months. ITG is a rare disease that is characterized by glomerular deposition. In particular, mITG, which presents immune deposits that exhibit light-chain restriction, is often associated with hematologic disorders. Most patients with mITG receive immunosuppressive therapy and/or chemotherapy; however, to our knowledge, there have been no reports of treatment with ibrutinib.

Use of belimumab in treating patients with systemic lupus erythematosus: a single-center, real-world retrospective study

ObjectiveTo investigate the efficacy and safety of belimumab in the treatment of systemic lupus erythematosus (SLE) in a real-world setting and provide a valuable reference for clinical treatment.MethodsIn this retrospective study, 101 patients with SLE who came to our hospital from March 2020 to September 2022, 56 of whom with lupus nephritis (LN), were selected. All patients received belimumab in combination with standard of care(SoC)therapy regimen for more than 52 weeks and their clinical/laboratory data, assessment of disease activity, glucocorticoids dosage and occurrence of adverse events were recorded. Lupus Low Disease Activity State (LLDAS) and DORIS remission as a primary goal in the treatment of SLE. The groups were classified according to the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K): SLEDAI-2 K < 6 was categorized as the mild group (mild activity) and SLEDAI-2 K ≥ 6 was categorized as the active group (moderate-severe activity). The disease of the two groups mentioned above were assessed using the SELENA-SLEDAI Flare Index (SFI) and the SLE Responder Index-4 (SRI-4), respectively. Furthermore, we used complete remission (CR) and partial remission (PR) in the kidney as the standard for efficacy evaluation for LN patients.ResultsAfter 52 weeks of treatment with belimumab, patients’ complement levels increased significantly (p < 0.05); Other indicators such as 24-hour urine protein quantification and daily glucocorticoids dose decreased compared to pretreatment (p < 0.05). At 52 weeks, (i) after evaluation, the whole group of patients showed significant improvement in their condition; (ii) 55.4% of patients achieved LLDAS and 23.8% achieved DORIS remission; (iii) 73.2% of patients with LN achieved CR, 16.1% achieved PR. Adverse reactions were observed in 15 patients (14.9%), all of which normalized after symptomatic treatment.ConclusionsIn general, during treatment with belimumab, immunological and biochemical indices improved in SLE patients, urinary protein levels were reduced in LN patients, and the rate of renal function remission was effectively increased; At the same time, the use of belimumab is associated with a low frequency of side effects, good overall tolerability and a favorable safety profile.

Strongyloides Stercoralis Infection Mimicking Relapse of ANCA Vasculitis

A 48-year-old female with anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis, initially responded well to standard therapy but later presented with diffuse alveolar hemorrhage (DAH), simulating disease relapse. Following renal remission with standard immunosuppressive therapy, the patient exhibited fever, hemoptysis, and declining renal function, suggestive of a relapse. Bronchoscopy revealed DAH, raising concern for vasculitis exacerbation. However, discordant laboratory findings prompted scrutiny, leading to the detection of Strongyloides larvae in bronchoalveolar lavage.

Efficacy and safety of belimumab combined with the standard regimen in treating children with lupus nephritis

The purpose of this study is to evaluate the efficacy and safety of belimumab combined with the standard regimen in treating children with active lupus nephritis. This single-center, retrospective cohort study used clinical data of children with newly active lupus nephritis hospitalized in the Department of Nephrology between December 2004 and February 2023. Patients were divided into a belimumab or traditional treatment group according to whether or not they received belimumab. Renal remission and recurrence rates and glucocorticoid dose were compared between groups. Forty-seven children (median age 11 years) were enrolled, including 30 and 17 children in the traditional treatment and belimumab groups, respectively. The Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2000) score of children in the belimumab group (23.59 ± 7.78) was higher than that in the traditional treatment group (19.13 ± 6.10) (P = 0.035). The two groups showed no significant difference in the frequency of pyuria, gross hematuria, and the levels of 24-h proteinuria and estimated glomerular filtration rate. The complement C3/C4 in the belimumab group recovered faster than that in the traditional treatment group (P < 0.05). There were no between-group differences in the complete renal remission rate at 6 or 12 months (P = 0.442, P = 0.759). There were no between-group differences in 1-year recurrence rate (P = 0.303). Furthermore, 6 and 12 months after treatment, glucocorticoid doses were lower in the belimumab than the traditional treatment group (17.87 ± 6.96 mg/d vs. 27.33 ± 8.40 mg/d, P = 0.000; 10.00 (5.3) mg/d vs. 13.75 (10.0) mg/d, P = 0.007), respectively.ConclusionWith an equivalent renal remission rate, belimumab combined with the standard traditional regimen might promote the tapering of glucocorticoids, and the incidence of adverse events is low.What is known:• Belimumab is documented as an adjunctive treatment with systemic lupus erythematosus (c-SLE) LN with efficacy.• Due to the paucity of studies, its effects and side effects in children with LN remain unclear.What is new:• This single-center, retrospective cohort study evaluated the efficacy and safety of belimumab combined with the standard regimen in treating children with proliferative LN.• Belimumab combined with the standard traditional treatment might promote the tapering of glucocorticoids, while exhibiting a low occurrence of adverse events.

II Brazilian Society of Rheumatology consensus for lupus nephritis diagnosis and treatment

ObjectiveTo develop the second evidence-based Brazilian Society of Rheumatology consensus for diagnosis and treatment of lupus nephritis (LN).MethodsTwo methodologists and 20 rheumatologists from Lupus Comittee of Brazilian Society of Rheumatology participate in the development of this guideline. Fourteen PICO questions were defined and a systematic review was performed. Eligible randomized controlled trials were analyzed regarding complete renal remission, partial renal remission, serum creatinine, proteinuria, serum creatinine doubling, progression to end-stage renal disease, renal relapse, and severe adverse events (infections and mortality). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to develop these recommendations. Recommendations required ≥82% of agreement among the voting members and were classified as strongly in favor, weakly in favor, conditional, weakly against or strongly against a particular intervention. Other aspects of LN management (diagnosis, general principles of treatment, treatment of comorbidities and refractory cases) were evaluated through literature review and expert opinion.ResultsAll SLE patients should undergo creatinine and urinalysis tests to assess renal involvement. Kidney biopsy is considered the gold standard for diagnosing LN but, if it is not available or there is a contraindication to the procedure, therapeutic decisions should be based on clinical and laboratory parameters. Fourteen recommendations were developed. Target Renal response (TRR) was defined as improvement or maintenance of renal function (±10% at baseline of treatment) combined with a decrease in 24-h proteinuria or 24-h UPCR of 25% at 3 months, a decrease of 50% at 6 months, and proteinuria < 0.8 g/24 h at 12 months. Hydroxychloroquine should be prescribed to all SLE patients, except in cases of contraindication. Glucocorticoids should be used at the lowest dose and for the minimal necessary period. In class III or IV (±V), mycophenolate (MMF), cyclophosphamide, MMF plus tacrolimus (TAC), MMF plus belimumab or TAC can be used as induction therapy. For maintenance therapy, MMF or azathioprine (AZA) are the first choice and TAC or cyclosporin or leflunomide can be used in patients who cannot use MMF or AZA. Rituximab can be prescribed in cases of refractory disease. In cases of failure in achieving TRR, it is important to assess adherence, immunosuppressant dosage, adjuvant therapy, comorbidities, and consider biopsy/rebiopsy.ConclusionThis consensus provides evidence-based data to guide LN diagnosis and treatment, supporting the development of public and supplementary health policies in Brazil.

Monoclonal immunoglobulin deposition disease a spectrum? The treatment of an unusual biopsy presentation

Introduction: Monoclonal gammopathy of renal significance (MGRS) is characterized by clonal cell deposition of monoclonal immunoglobulin causing renal manifestations without overt malignancy. MIDD is a subtype of MGRS characterized by deposition of monoclonal light (LCDD), heavy chains (HCDD), or both (LHCDD) along the renal glomerular and tubular basement membranes. Virtually all organs can be involved, and if left untreated, MIDD can progress to MM and end stage renal disease. Although these patients classically did not receive treatment, current MIDD management is primarily focused on controlling the underlying clonal plasma cell disorder. Case description: We present a 56-year-old male with atypical MIDD treated successfully with plasma cell directed therapy consisting of daratumumab, cyclophosphamide, bortezomib, and dexamethasone (DARA-CYBOR-D). Despite a primary diagnosis of diabetic kidney disease, renal biopsy suggested myeloma-related MIDD based on linear immunofluorescent staining for IgG and kappa light chains along the tubular and glomerular basement membranes. Notably there were no electron dense deposits in the mesangium or tubular basement membranes typical to MIDD electron microscopy. Despite the presentation of MIDD on IF only, DARA-CYBOR-D treatment led to hematologic and renal improvement and remission from MIDD, with a GFR increase from 22 to 59 mL/min/BSA and a drop in urine protein from up to 9 to 0.6 g/dL. Conclusions: In conclusion, our case illustrates the efficacy of the DARA-CYBOR-D regimen in a patient with IF-only MIDD. We highlight the importance of obtaining a kidney biopsy when there are other potential causes for real decline and enhance our understanding of pathological and clinical spectrum of MIDD.

#1063 Presentation, treatment, and outcome of IgA nephropathy in children: comprehensive characterization of a Croatian single centre cohort

Abstract Background and Aims IgA nephropathy (IgAN) is a complex disease diagnosed only upon evaluation of a kidney biopsy. Since the threshold to perform this invasive procedure is higher and symptoms usually more indolent in children, the true prevalence might be underestimated, with fewer studies examining the presentation, treatment, and outcome of IgAN in paediatric population. Moreover, there is a substantial heterogeneity of clinical presentation and pathological features between geographical locations, with fewer data available for region of central and southern Europe. We therefore aim to provide a conscientious description of a paediatric IgAN cohort followed for an extended period of time in a centre caring for most of the Croatian paediatric patients. Method Single centre retrospective study of children newly diagnosed as IgAN since 2011 and followed for &amp;gt;2 years in a tertiary referral centre for paediatric nephrology of the Republic of Croatia. Results Total of 15 paediatric (&amp;lt;18 years) patients were included, of which 11 (73%) were male, 14 Caucasians and 1 of Roma origin. All the patients had proteinuria (&amp;gt;150 mg/day) and hematuria (&amp;gt;5 RBC/mm3 in uncentrifuged urine) at the time of the biopsy, with the mean age of 12.2 ± 3.6 years. The median eGFR was 87 (69 – 111) mL/min/1.73m2 and the median value of proteinuria 260 (150 – 370) mg/day. More specifically, 2 patients had mild proteinuria (&amp;lt;20 mg/kg/day), 12 had moderate (20 – 50 mg/kg/day) and 1 had nephrotic range (&amp;gt;50 mg/kg/day). The results of biopsy in terms of MEST-C score showed M1 in 4, E1 in none, S1 in 3, T1 in 4, T2 in 0, C1 in 2 and C2 in none of the patients. The IF was positive for IgA and C3 in all patients, and in 1 for C1q. There was no significant correlation between C3 intensity values (0-4+) and 24 h proteinuria (r = 0.49, p = 0.06) or eGFR (r = −0.22, p = 0.43). Hypertension (≥95 percentile for age) was present in 2 (13%) patients. The median risk of a 30% decline in eGFR or progression to end-stage renal disease 5 years after renal biopsy calculated by International IgAN prediction tool for use in paediatric patents was 8.03% (4.58 – 11.27). Initial presenting episode was treated with ACEi in 7 (47%) and with glucocorticoids in 4 (27%) patients. There was no significant difference in proteinuria (p = 0.19) or risk of decline in eGFR or progression to ESRD (p = 0.16) among treated and untreated patients. In all of the treated patients proteinuria reached a target of &amp;lt;20 mg/kg during the median time of 11 (6 – 21) months. The median follow up was 6.5 (2.8 – 11.1) years. During the follow up 5 patients experienced first relapse of proteinuria, 3 had second and none had third relapse. None of the patients had adverse event related to medications. None were treated with renal replacement therapy or other immunomodulatory drugs. Tonsillectomy was performed in two patients with a substantial improvement of haematuria episodes reported by caregivers. Omega-3 polyunsaturated fatty acid was used in 1 patient. While none of the patients developed CKD during the follow up, none have reached complete renal remission defined as eGFR &amp;gt;90 ml/min/1.73m2, proteinuria &amp;lt;150 mg/day and RBC &amp;lt; 5/mm3 in urinalysis. Conclusion All the patients in our cohort had indolent disease with proteinuria, along with low risk of decline in eGFR or progression to ESRD after biopsy. Almost half of them were treated with ACEi, and a quarter with glucocorticoids, all with beneficial response. Nevertheless, none of the patients in the cohort achieved full renal remission due to the persistent hematuria. While there are few well performed studies on the treatment of IgAN in adult patients, to date, there are no high-quality randomised studies on immunosuppressing and other drugs, as well as nutritional and other interventions in children with IgAN, prompting a case-to-case decision regarding the use of various therapeutic modalities. Therefore, well characterized cohorts from around the globe might provide further reassurance for physicians taking care of children with this intricating disease, support when deciding to commence the intervention and inform while selecting the most appropriate form.

#1297 Approaches to renal response assessment in rare monoclonal immunoglobulin related glomerulopathies

Abstract Background and Aims AL-amyloidosis (AL) and monoclonal immunoglobulin (MIg) deposition disease are common types of MIg-related glomerulopathies (MIgG) and are well-studied including approaches to treatment and hematological and renal responses (RR) assessment. Other rare MIgG comprise very diverse patterns of glomerular injury e.g. proliferative glomerulonephritis with MIg deposition (PGNMID), C3-glomerulopathy, fibrillary glomerulonephritis etc. Although RR defined as decrease in 24 h proteinuria by 30% without kidney function decline was validated only for renal AL it is widely used for MIg deposition disease and rare MIgG without validation. Nevertheless, the best approach to RR assessment in rare MIgG is still unclear. To shed some light on this problem we performed this study. Method We retrospectively analyzed 31 patients with rare MIgG who were treated with clone-specific treatment and had available follow-up (FUP) ≥6 months (mo). The following morphological patterns were diagnosed: PGNMID (n = 9), C3-glomerulopathy (n = 9), thrombotic microangiopathy (n = 5), cryoglobulinemic glomerulonephritis (n = 3), fibrillary glomerulonephritis (n = 3), immunotactoid glomerulonephritis (n = 1) and membranous nephropathy (n = 1). Patients’ baseline parameters are shown on Fig. 1 as well as treatment modalities. Hematological response defined according to currently accepted criteria is demonstrated on Fig. 1. We evaluated two approaches to the RR assessment: 1) at least partial renal response (PR) defined as 24 h proteinuria decreased by 50% from the baseline and &amp;lt;3.5 g, and 2) according to Palladini's criteria for AL (AL-RR) i.e. 24 h proteinuria decreased by 30% from the baseline or &amp;lt;0.5 g. Both RR were considered as achieved only in the absence of estimated glomerular filtration rate (eGFR) decline &amp;gt;25%. Time points for RR assessment were 6, 12 and 24 mo from the clone-specific treatment initiation. Renal outcome was estimated as initiation of renal replacement therapy or eGFR &amp;lt;15 ml/min/1.73 m2 at the end of follow-up. Death-censored renal survival was analyzed by the Kaplan-Meier method. Cox regression analysis was applied to determine which RR was independently associated with long-term kidney outcome. P-value was assumed at &amp;lt;0.05. Median FUP was 19 (7; 50) mo. FUP ≥12 and ≥24 mo were available in 26 and 17 patients, respectively. Results Total number of patients who achieved AL-RR at any RR assessment time point was 22 (71%). At 6, 12 and 24 mo the achievement of AL-RR was registered in 17, 16 and 10 patients, respectively. PR cumulatively was achieved in 19 (61%) patients: at time points of 6, 12, and 24 mo it was registered in 14, 14 and 9 cases, respectively. The 5-year cumulative renal survival in those who had AL-RR was better than in not responders (Fig. 2A). Patients who ever achieved PR had better cumulative renal survival compared with patients with no renal remission (Fig. 2B). In univariate Cox regression analysis the achievement of AL-RR (Exp(β) 0.158 (95% CI 0.03; 0.819)) was associated with renal outcome as well as the achievement of PR (Exp(β) 0.074 (95% CI 0.09; 0.626)). In multivariate Cox regression model adjusted for eGFR at the time of kidney biopsy AL-RR vs no response was estimated as an independent predictor of renal long-term prognosis (Exp(β) 0.082 (95% CI 0.009; 0.725)) as well as eGFR (Exp(β) 0.89 (95% CI 0.821; 0.985)). The only independent predictor of renal outcome in the model including eGFR at the time of kidney biopsy (Exp(β) 0.85 (95% CI 0.72; 0.99), p = 0.05) was PR (Exp(β) 0.011 (95% CI 0; 0.547), p = 0.021). Conclusion The classical concept of complete and partial renal remission seems to be more appropriate for rare MIgG and requires further validation studies.

#2622 Very late renal recovery in patient with light chain cast nephropathy: the prognostic value of renal biopsy

Abstract Background and Aims Renal biopsy is not necessary to assess LCCN (Light Chain Cast Nephropathy) in patients with laboratory features suggestive of the disease. However, it has been shown that the histological picture often correlates with renal outcome. We present the case of a 55-year-old man with no significant previous medical history that was evaluated in the emergency department for a stage 3 AKI (sCr 17.3 mg/dl, eGFR 3 ml/min/1.73 m2). Laboratory tests showed a Lambda Micromolecular Myeloma (K chains 44.6 mg/l, λ 4160 mg/l and K/ λ 0.01); Bence Jones not evaluable due to anuria. Bone marrow plasmacytosis was 70%. Method The patient started chemotherapy with Bortezomib and Dexamethasone and hemodialysis thrice a week with a PMMA hemofilter in order to improve the FLC (Free Light Chain) removal rate. After three months of treatment the patient achieved a complete hematologic response but he didn't reach any renal response. In order to assess a more precise renal prognosis a kidney biopsy was performed. The histopathological exam showed a Cast Nephropathy (&amp;lt; 5 casts/mm2) associated with low grade interstitial fibrosis and tubular atrophy (IFTA +1). After 5 cycles with Bortezomib and Dexamethasone, one year after onset, the patient underwent ASCT (Autologous Stem Cell Transplantation). Results In the following months, a progressive increase in renal function allowed us to perform a gradual reduction of dialysis rate, until discontinuation occurred 16 months after disease onset. To date, three years after onset, complete hematologic and renal remission persists with an eGFR of 20 ml/min/1.73 m2. Conclusion Renal biopsy, performed even several months after disease onset, could play a pivotal role in cases of LCCN with a discordance between hematologic and renal response. A low cast number and low IFTA grade are known to be positive prognostic factors for renal outcome and they can predict a renal recovery that sometimes could be exceptionally late.

Optimal exposure of mycophenolic acid for induction therapy of childhood lupus nephritis patients: an observational cohort study.

Mycophenolic acid (MPA) is recommended for lupus nephritis (LN) treatment, but with large inter-individual variability in pharmacokinetics (PK). The aim of this study is to reveal the relationship between MPA exposure and disease response and adverse drug reactions in pediatric LN patients. This was a population-based observational cohort study. A total of 86 pediatric LN patients treated with mycophenolate mofetil (MMF) for induction therapy were enrolled. The area-under the concentration-time curve (AUC) was calculated using MPA concentrations according to a limited sampling strategy. Receiver operating characteristic analysis was performed to assess the MPA-AUC threshold values. The cumulative incidence of renal remission and inactive systemic lupus erythematosus (SLE) over time was evaluated by Kaplan-Meier's analysis. MPA-AUC was identified as an independent factor associated with renal remission and lupus activity at 6 and 12 months after MMF treatment, and the improved renal remission rates were correlated with higher MPA-AUC, with thresholds of 29.81 and 30.63 μg·h·mL-1 at 6months and 12 months, respectively. Furthermore, the thresholds for maintaining the hypoactive state of LN were 30.96 and 31.19 μg·h·mL-1at 6 months and 12 months, respectively. Patients reaching target thresholds for MPA-AUC achieved renal response or stable disease earlier. In addition, the MPA-AUC threshold for decreasing MMF-related adverse reactions was 50.80 μg·h·mL-1. The initial and long-term treatments of pediatric LN patients with MMF should be individualized according to the MPA-AUC, and the recommended MPA exposure is 31.19-50.80 μg·h·mL-1.

Clinical profile, laboratory parameters and management outcomes in an eight-year-old female with childhood lupus nephritis

Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune disorder characterized by widespread inflammation of connective tissues affecting the skin, joints, kidneys, heart, lungs and nervous system. SLE is most often diagnosed in women during the second to fourth decades of life, but 15-20% cases are found in childhood. Renal involvement occurs in the majority of childhood onset SLE (cSLE) patients and is often fatal and hence constitutes an important determinant of prognosis. Multidisciplinary care is necessary for children with lupus nephritis in terms of immunosuppressive regimes with a common goal of achieving and maintaining renal remission. Despite a low prevalence rate of cSLE, it manifests with fatal complications like lupus nephritis in majority of cases. Renal biopsy is gold standard for staging of lupus nephritis, thus, deciding the modality of management and prognostication of cSLE.

Adolescence-onset atypical hemolytic uremic syndrome: is it different from infant-onset?

Atypical hemolytic uremic syndrome (aHUS) is a rare, mostly complement-mediated thrombotic microangiopathy. The majority of patients are infants. In contrast to infantile-onset aHUS, the clinical and genetic characteristics of adolescence-onset aHUS have not been sufficiently addressed to date. A total of 28 patients (21 girls, 7 boys) who were diagnosed as aHUS between the ages of ≥10years and <18years were included in this study. All available data in the Turkish Pediatric aHUS registry were collected and analyzed. The mean age at diagnosis was 12.8±2.3years. Extra-renal involvement was noted in 13 patients (46.4%); neurological involvement was the most common (32%). A total of 21 patients (75%) required kidney replacement therapy. Five patients (17.8%) received only plasma therapy and 23 (82%) of the patients received eculizumab. Hematologic remission and renal remission were achieved in 25 (89.3%) and 17 (60.7%) of the patients, respectively. Compared with the infantile-onset aHUS patients, adolescent patients had a lower complete remission rate during the first episode (p=0.002). Genetic analyses were performed in all and a genetic variant was detected in 39.3% of the patients. The mean follow-up duration was 4.9±2.6years. At the last visit, adolescent patients had lower eGFR levels (p=0.03) and higher rates of chronic kidney disease stage 5 when compared to infantile-onset aHUS patients (p=0.04). Adolescence-onset aHUS is a rare disease but tends to cause more permanent renal dysfunction than infantile-onset aHUS. These results may modify the management approaches in these patients.

Efficacy and safety of belimumab in patients with lupus nephritis: a real-world retrospective observational study.

To evaluate the differences in efficacy and safety between Lupus Nephritis (LN) patients who received belimumab plus standard therapy and those who received only standard therapy in real world practice. Patients diagnosed with LN at the First Affiliated Hospital of Wenzhou Medical University from November 2012 to July 2023 were identified, and eligible cases were divided into two groups according to whether they received additional treatment with belimumab during the course of the disease. A total of 1,169 LN patients were identified from our follow-up database. 112 patients receiving add-on treatment with belimumab (BLM group) and 112 control patients matched for relevant baseline characteristics were enrolled in this study. The median duration of treatment with belimumab was 13.82 [7.24, 20.29] months. Compared with the control group, the BLM group had more significant improvement in disease activity indicators such as serum albumin and complement levels, significantly lower B cell count, immunoglobulin, and earlier first attainment of renal remission, but there was no significant improvement in renal function and kidney-related events or death during the 2-year follow-up period. In the BLM group, the treatment effect of belimumab was more prominent in patients with lower levels of proteinuria. The safety profile of belimumab treatment was favorable, with a lower incidence of respiratory tract infection in the BLM group than in the control group during the follow-up period (p= 0.015). This real-world study revealed that add-on treatment with belimumab provided better disease remission, and the therapeutic effect was more significant in patients with lower proteinuria levels. In addition, it had a favorable safety profile and reduced the risk of respiratory tract infection.

The efficacy of rituximab plus belimumab or telitacicept in refractory lupus nephritis.

Lupus nephritis is a severe and common complication of systemic lupus erythematosus (SLE). The pathogenesis of lupus nephritis is characterized by B-cell activation and autoantibody formation. Rituximab and belimumab, as well as telitacicept, target B cells through different mechanisms, potentially exerting a synergistic effect in the treatment of lupus nephritis. This study aims to investigate the efficacy and safety of treatment with rituximab followed by belimumab or telitacicept in the management of refractory lupus nephritis. We conducted a single-center, open-label, retrospective study, including 25 patients with refractory lupus nephritis. All patients received combination therapy with rituximab in individualized dosages to achieve peripheral B-cell depletion, and then followed by belimumab or telitacicept. The follow-up period was at least 12 months, and the primary end point was renal remission rate at the last follow-up. During a median follow-up of 19 (13, 29) months, 20 of 25 (80%) patients achieved objective remission (OR), including 19 (76%) patients achieved complete renal response (CRR). After rituximab (712 ± 416mg in average), 18 patients received belimumab and seven patients received telitacicept. In the rituximab plus telitacicept group, all patients achieved CRR; while in the rituximab plus belimumab group, 12 (66.7%) patients achieved CRR and 13 (72.2%) patients achieved OR. The mean SLEDAI-2K score decreased from 15 ± 6 to 6 ± 6, representing an average reduction of 60%. At the last follow-up, 18/25 (72%) had prednisone ≤ 5mg/d or even discontinued prednisone use. Adverse effects were mainly immunoglobulin deficiency, respiratory tract infection, urinary tract infections, and rash. No death occurred. Rituximab followed by belimumab or telitacicept may be effective in inducing remission in refractory lupus nephritis, with tolerable adverse effects.

A Prospective Phase II Clinical Study of Low-Frequency Daratumumab for the Treatment of Systemic Light Chain Amyloidosis

Purpose: Systemic light chain (AL) amyloidosis is a disease caused by the misfolding of monoclonal immunoglobulins light chain to form amyloid, which is deposited in tissues and organs, resulting in structural destruction of tissues, organ dysfunction, and progressive progression. Daratumumab is a human CD38-targeting antibody that has been used for the treatment of patients with AL amyloidosis. This is a prospective, single-arm phase II clinical study designed to explore the efficacy and safety of low-frequency Daratumumab in patients with AL amyloidosis. Methods: A total of 47 patients are expected to be enrolled in this study. As of May. 01, 2023, a total of 38 patients with AL amyloidosis meeting the inclusion criteria were included. Low-frequency Daratumumab was administered at 16 mg/kg every two weeks for weeks 1-8 and every four weeks for weeks 9-24, either alone or in combination with bortezomib. The regimen may be discontinued after week 25, or Daratumumab monotherapy every eight weeks for up to two years for maintenance therapy. The efficacy of the previous treatment was assessed before each regimen of Daratumumab. Follow-up was performed every three months after treatment cessation until disease progression or death of the patient from any cause. Results: Of the included patients, 27 (71.1%) were male, with a median age of 64 years (59-71). The median number of involved organs was 2 (1-3), of which 27 (71.1%) had renal involvement, 34 (89.5%) cardiac involvement, and 6 (15.8%) hepatic involvement. 28 (73.7%) were newly diagnosed patients and 10 (26.3%) were recurrent and refractory patients. There were 25 (65.8%) Mayo 2004 stage III patients and 23 (60.6%) Mayo 2012 stage III/IV patients. The median number of treatment cycles was 5 (2-8). All patients (100%) achieved hematologic very good partial response or above (≥VGPR), of which 18 (48.6%) patients achieved hematologic complete response or above (≥CR). The median time to hematologic remission was 15.0 days (14.0-29.0 days) and the median time to hematologic CR was 92.5 days (28.0-119.3 days). 9 (40.9%) patients achieved renal remission, with a median response time of 41.0 days (29.0-87.0 days).11 (33.3%) patients achieved cardiac remission, with a median response time of 145.0 days (30.0-223.0 days). And 1 (16.7%) patient achieved hepatic remission. At a median follow-up of 11.8 months (9.8-13.7 months), median progression-free survival (PFS) and overall survival (OS) were not reached, with a 6-month PFS of 91.0% and a 6-month survival OS of 91.0%. In terms of safety, the most common adverse events were fatigue (22 cases, 57.9%), infection (18 cases, 47.4%), and fever (16 cases, 42.1%). 7 (18.4%) patients had Daratumumab-related infusion reactions. Conclusion: The results of this study showed that the low-frequency daratumumab regimen demonstrated good hematological and organ efficacy in the treatment of patients with AL amyloidosis. Patients had a high early survival rate and better safety profile.

Kidney histopathology in predicting flares following drug withdrawal in proliferative lupus nephritis in clinical remission.

Residual renal histopathological activity at clinical remission in Proliferative Lupus Nephritis (PLN) can predict renal flare upon immunosuppression withdrawal. Data on the role of histological renal remission in predicting extra-renal flares is lacking. We assessed renal histopathology prior to drug withdrawal and the occurrence of renal and extra-renal flares over 52weeks after drug withdrawal in PLN patients in long-term clinical remission. This is a subgroup analysis of a non-inferiority, open-label randomized (1:1) controlled trial. Patients with biopsy-proven Class III/IV LN in the past (biopsy 1), on immunosuppressants (IS) ≥ 3years, in clinical remission for ≥ 1year, on stable prednisolone dose (≤ 7.5mg/day) plus a maintenance IS and hydroxychloroquine (HCQ) were subjected to a repeat renal biopsy (biopsy 2). Individuals with biopsy 2 having activity index (AI) < 4/24 were randomised to either prednisolone or IS withdrawal. Primary end-point was the proportion experiencing a flare [SELENA-SLEDAI flare index (SFI)] at week 52. Twenty-eight eligible patients underwent biopsy 2 and randomized to prednisolone (n = 15) and IS (n = 13) withdrawal. At biopsy 1, 12 (43%) had class III, 15 (53.5%) had class IV, and 1 (3.5%) had class III + V. At biopsy 2, PLN persisted in 4 (14.2%) while 18 (64.2%) were in histological remission (AI = 0) with 6(21.4%) in class II. Following drug withdrawal, 9/28 (32%) had flares especially musculoskeletal (55.5%), mucocutaneous (44.4%), and renal (33.3%). Among the four persistent PLN patients, one of the two (50%) with AI = 1 had extra-renal flare while both the two with AI = 2 (100%) had renal and extra-renal flares. In those with histological remission (biopsy 2), 6/18 (66.6%) experienced extra-renal flare of whom one also had renal flare. Upon drug withdrawal, renal histopathology findings with any activity index can predict renal flare while histological remission is not enough to predict extra-renal flare, thus making it an unsuitable marker for deep SLE remission.

Efficacy and Safety of Daratumumab in Combination with Bortezomib, Thalidomide, and Dexamethasone Regimens in Newly Diagnosed Multiple Myeloma with Renal Insufficiency in Real-World: A Non-Interventional Prospective Multicenter Observational Study

Background: Renal impairment (RI) is one of the common serious complications of MM. The DARE Phase 2 clinical study is daratumumab-based regimen for the treatment of MM patients with renal insufficiency, which is designed to use daratumumab in combination with dexamethasone for the treatment of RRMM with severe renal insufficiency. According to the updated data, after 8.3 months of follow-up, the 6-month PFS rate was 48.6%, ORR was 41.4%, renal response rate (RRR) was 20.7%. CASSIOPEIA phase III clinical study showed that with the extension of treatment time, the sCR rate and minimal residual disease (MRD) negative rate in D-VTd group were significantly improved compared with those in VTd group. According to the evidence from previous large phase III clinical trials of daratumumab in NDMM as well as its DARE phase II study and clinical case reports, daratumumab based treatment has a rapid onset of action in the treatment of MM patients with severe renal insufficiency, effectively response to the disease and improve the renal function of patients. An observational, multi-center, non-interventional study was designed to evaluate the safety and efficacy of daratumumab in combination with VTD in NDMM patients with renal dysfunction in real-world clinical practice. (NCT 05561049) Methods:NDMM patients older than 18 years and with a glomerular filtration rate(eGFR) of less than 40 ml/min were enrolled. Patients received VTD for C1, then go to DaraVTD for C2-4. The dose of Daratumumab was 16 mg/kg I.V. every week for 2cycles(cycles 2-3) , 16 mg/kg I.V. every 2 weeks for one more cycles;“Thalidomide”: 100 mg, P.O., Days 1-28/1-4 cycles;“Bortezomib”: 1.3 mg/m2, SC, Days 1, 4, 8, 11/1-4 cycles; Dexamethasone: 20-40mg, PO/I.V., qw/1-4 cycles. After induction therapy, patients entered consolidation therapy. Transplant eligable patients undergo stem cell collection and autologous stem cell transplantation followed by consolidation with DVTd regimen for 2 more cycles. Four more cycles of consolidation with DVTd were performed in transplant ineligible patients. The primary endpoint of this study is to evaluate VGPR+ rate after consolidation. The secondary endpoint is ORR, renal response rate (RRR), CR rate, MRD negativity after consolidation, and DOR, PFS, OS. NCI CTCAE V5.0 criteria were used to evaluate adverse events. Result: From Jan 1th to June 30 th 2023, 23 patients were enrolled. The median age of these 23 patients was 64 (34-78), 69.6%(16/23) was male.(Table 1) Among the 18 patients who have had response evaluation, the ORR was 94.4%. median onset time of response was 2 months. After induction therapy, the ORR was 100%, 50% patients had gotten CR. After consolidation, All patients were above VGPR and CR and were NGS MRD negative.55.5% patients(10/18) achieved renal remission after one cycle, while 86.7% after 2 cycles, 91.7% after 3 cycles and 100% after 4cycles. Among the 20 patients who have had adverse events evaluation. The main treatment-related adverse events were hematological toxicity, including neutropenia (n=10/20, grade 1-2 for 6 pts and grade 3-4 for 4 pts), lymphopenia (n=5/20, grade 1-2 for 5 pts) and thrombocytopenia (n=8/20, grade 1-2 for 6 pts and grade 3-4 for 2 pts). One patient with acute pancreatitis had to stop treatment. Other toxicities to date included pneumonia (n=5/20, grade 1 for 4 pts and grade 2 for 1 pts), peripheral neuropathy (n=10/20, grade 1 for 7 pts and grade 2 for 3 pts), and rash(n=5). The infusion related reactions were 37.5%(n=6/18, grade 1 for 4 pts and grade 2 for 2 pts). Conclusion: In Chinese NDMM patients with RI, quad-drug induction of DVTD with/without ASCT consolidation showed nice tolerability and high overall response of disease even with a high percentage of high-risk patients. This preliminary study also suggested excellent efficacy with rapid improvement in renal function. The most common adverse events were hematological toxicity. Updated results will be presented at the following phase.

MAIT cells altered phenotype and cytotoxicity in lupus patients are linked to renal disease severity and outcome.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which circulating immune complexes can cause different types of glomerulonephritis, according to immune deposits and to the type of glomerular cell injury. Proliferative lesions represent the most severe form of lupus nephritis (LN) and often lead to kidney failure and death. Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells that recognize microbial-derived ligands from the riboflavin synthesis pathway. Although abundant in peripheral blood, MAIT cells are enriched in mucosal and inflamed tissues. While previous studies have reported concordant results concerning lower MAIT cell frequencies in the blood of SLE patients, no information is known about MAIT cell function and LN severity and outcome. In the current study, we analyzed the baseline phenotype and function of peripheral blood MAIT cells by flow cytometry in 26 patients with LN and in a control group of 16 healthy individuals. We observe that MAIT cell frequencies are markedly reduced in blood of LN patients. MAIT cells from patients have an altered phenotype in terms of migration, proliferation and differentiation markers, notably in most severe forms of LN. Frequencies of PMA/ionomycin stimulated MAIT cells secreting effector molecules, such as proinflammatory IL-17 and cytotoxic protein granzyme B, are higher in LN patients. Patients undergoing a complete renal remission after immunosuppressive therapy had higher MAIT cell frequency, lower expression of proliferation marker Ki-67 and granzyme B (GzB) at inclusion. Remarkably, GzB production defines a predictive model for complete remission. We report here that blood MAIT cells display proinflammatory and cytotoxic function in severe lupus nephritis which may play a pathogenesis role, but without association with systemic lupus activity. Finally, low cytotoxic profile of MAIT cells may represent a promising prognostic factor of lupus nephritis remission one year after induction therapy.

Safety and efficacy of biological agents in the treatment of Systemic Lupus Erythematosus (SLE)

BackgroundTo determine the safety and efficacy of biological agents used in the treatment of systemic lupus erythematosus (SLE) in adults.MethodsSystematic review and meta-analysis following PRISMA guidelines.Data sourcesMEDLINE (through Pubmed), EMBASE, Cochrane library, Clinicaltrials.gov, Australianclinicaltrials.gov.au, ANZCTR.org.au and WHO International Clinical Trials Registry Platform for studies published from 20 May 2021 and 15 years prior. A grey literature search was performed and completed on 31 May 2021.Study criteriaPhase II, III or quasi randomised controlled trials, studies with only cerebral or cutaneous lupus were excluded. Data extraction: Two authors independently screened studies for eligibility, extracted, reviewed data for accuracy, and used the Cochrane tool to assess risk of bias.ResultsForty-four studies were identified, consisting of 15 groups of drugs and 25 different biological agents, totalling 16,889 patients. The main outcomes assessed included Systemic Lupus Erythematosus Responder Index (SRI), BILAG-Based Composite Lupus Assessment (BICLA) and combined combined/partial renal remission (CRR/PRR).Four groups of biologics were found to improve outcomes. Anti-interferons: Anifrolumab increased BICLA response and SRI 5 to 8, decreased prednisone dosages, with increased herpes zoster infections, but fewer serious adverse events. Sifalimumab improved SRI but also increased herpes zoster infections. Anti BAFF/BLyS and/or APRIL: Belimumab consistently improved SRI 4, decreased prednisone dosages, increased combined CRR/PRR, and had no adverse safety outcomes. Tabalumab increased SRI 5 at 52 weeks with no steroid sparing effect but was associated with increased infusion related adverse events. Telitacicept improved SRI 4 at 52 weeks, with no increased adverse events, though data was rather sparse. Anti CD-20 monoclonal antibody, Obinutuzumab increased combined CRR/PRR at 1 and 2 years. Anti IL12/23 monoclonal antibody, Ustekinumab, increased SRI 4 to 6, but not BICLA at 24 weeks, with no concerning safety outcomes.ConclusionMultiple biologic agents are shown in high quality studies to have a significant therapeutic impact on outcomes in SLE.