Therapeutic Options Research Articles

Target engagement of an anti-MT1-MMP antibody for triple-negative breast cancer PET imaging and beta therapy

PurposeTriple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks effective diagnostic and therapeutic options. Membrane type 1 matrix metalloproteinase (MT1-MMP) is an attractive biomarker for improving patient selection. This study aimed to develop a theranostic tool using a highly tumour-selective anti-MT1-MMP antibody (LEM2/15) radiolabelled with 89Zr for PET and 177Lu for therapy in a TNBC murine model. MethodsThe LEM2/15 antibody and IgG isotype control were radiolabelled with 89Zr. PET imaging was performed in a TNBC orthotopic mouse model at 1, 2, 4, and 7 days after administration. Tissue biodistribution and pharmacokinetic parameters were analysed and Patlak linearisation was used to calculate the influx rate of irreversible uptake. The TNBC mice were treated with [177Lu]Lu-DOTA-LEM2/15 (single- or 3-dose regimen) or saline. Efficacy of [177Lu]Lu-DOTA-LEM2/15 was evaluated as tumour growth and DNA damage (γH2AX) in MDA 231-BrM2-831 tumours. ResultsAt 7 days post-injection, PET uptake in tumour xenografts revealed a 1.6-fold and 2.4-fold higher tumour-to-blood ratio for [89Zr]Zr-Df-LEM2/15 in the non-blocked group compared to the blocked and IgG isotype control groups, respectively. Specific uptake of LEM2/15 in TBNC tumours mediated by MT1-MMP-binding was demonstrated by the Patlak linearisation method, providing insights into the potential efficacy of LEM2/15-based treatments. A similar uptake was found for [89Zr]Zr-Df-LEM2/15 and [177Lu]Lu-DOTA-LEM2/15 in tumours 7 days post-injection (6.80 ± 1.31 vs. 5.61 ± 0.66 %ID/g). Tumour doubling time was longer in the [177Lu]Lu-DOTA-LEM2/15 3-dose regimen treated group compared to the control (50 vs. 17 days, respectively). The percentage of cells with γH2AX-foci was higher in tumours treated with [177Lu]Lu-DOTA-LEM2/15 3-dose regimen compared to tumours non-treated or treated with [177Lu]Lu-DOTA-LEM2/15 single-dose (12 % vs. 4–5 %). ConclusionsThe results showed that the 89Zr/177Lu-labelled anti-MT1-MMP mAb (LEM2/15) pair facilitated immune-PET imaging and reduced tumour growth in a preclinical TNBC xenograft model.

#1154 Type I interferon pathway is upregulated in microscopic polyangiitis (vs granulomatosis with polyangiitis)

Abstract Background and Aims The two main types of ANCA-associated vasculitis (AAV), microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), share common characteristics but also differ on many aspects (epidemiological, genetic, clinical, outcomes). These differences did not justify, to date, different patient management. To identify more specific targetable pathways, we characterized the kidney transcriptome of MPA vs. GPA patients with AAV-glomerulonephritis (AAV-GN). Method This retrospective study included adult patients with AAV-GN from the French Maine-Anjou Registry. Immune gene transcript analysis was performed on RNA extracted from 97 kidney biopsies using NanoString technology. Significant transcripts were examined to identify immune pathways of interest. We then used a publicly available dataset to explore these identified pathways (qPCR / ELISA). Results We compared kidney biopsies from GPA (n = 33) and MPA (n = 64) patients. There was no difference in eGFR between both groups at diagnosis. Of the 750 evaluated immune transcripts, 8 genes were found differentially expressed between MPA and GPA patients, all being upregulated in MPA (log2FC > 1, q-value < 0.05) (Fig. 1A). Seven (out of 8) genes belonged to the type I interferon (IFN-I) signaling pathway. A personal analysis of unpublished, publicly available, data1 identified a significantly more pronounced IFN-I signature in the peripheral blood mononuclear cells of patients with MPO-AAV when compared to those with PR3-AAV (Fig. 1B). Serum levels or CXCL10, a cytokine that mediates immune responses through the recruitment and activation of numerous immune cells under the regulation of IFN-I, were found higher in MPO-AAV patients (Fig. 1C). Conclusion We identified a type I interferon signature, both in kidneys and in blood, in patients with MPA (or MPO-AAV) in comparison to GPA (or PR3-AAV). This is in line with previous lines of evidence brough by Kessenbrock et al. and Kessler et al. suggesting a role for IFN-I in AAV and especially in MPO-AAV. This signature may help gain a deeper understanding of the AAV-GN pathogenesis and provide insights for developing new therapeutic options.

#1507 Genetics in suspected cases of hereditary kidney diseases

Abstract Background and Aims Hereditary kidney diseases are the fifth cause of chronic kidney disease (CKD). They are responsible for around 10% of adults with kidney replacement therapy. Genetic testing in suspected cases allows us to make a definitive diagnosis, prognosis, therapeutic options and family counselling. Method We present a descriptive study from Hospital Clínic Barcelona (Spain) of all genetic tests performed in suspected cases of hereditary kidney diseases between 2019 and 2023 by using whole exome sequencing. Diseases are classified into these groups: cyst kidney diseases, Alport syndrome spectrum (ASS), complement-related kidney diseases, tubulointerstitial kidney disease (TID), CKD of unknow etiology (CKDUE), podocytopathies, and miscellaneous. All analyses were made with blood samples. Results As of December 31st, genetic test has been made in 198 patients, of which 172 have definitive results (82/172 women). Genetic tests increase over time with 10 (2019), 15 (2020), 36 (2021), 56 (2022) and 81 (2023). The most frequent suspected genetic kidney diseases were cyst-related (n = 57) followed by CKDUE (n = 43), complement-related kidney disease (n = 27), ASS (n = 20), podocytopathies (n = 16) and TID (n = 6). Globally, 104 genetic alterations were detected; 40,7% (70/172) were pathogenic or likely pathogenic (P/LP) variants; and 19,8% (34/172) were variants of uncertain significance (VUS). The highest test performance was observed in the cyst-related group with 70,2% (40/57) followed by ASS with 45% (9/20) and TID with 33,1% (2/6) while the lowest performance groups were CKDUE and complement-related diseases with 25,6% (11/43) and 11,1% (3/27) respectively. The most frequent P/LP variants identified per group were PKD1 (28/40) and PKD2 (12/40) in cyst-related; COL4A4 (5/9) in ASS; CFH, COQ8B and C3 (1/3 each one) in complement-related; UMOD and MUC (1/2 each one) in TID; COL4A4 (2/11) in CKDUE; and TRPC6:1, LMXB1, COL4A3, COL4A5 and COQB8 (1/5 each one) in podocytopathies. The highest genetic heterogeneity was found in CKDUE with 28 genetic variants detected (11 P/LP and 17 VUS). Conclusion Although the comparison between the different groups of diseases is complex, because of the different genetic study indication in each one, as well as their prevalence and the performance of the test, in our cohort the most suspected hereditary kidney diseases in which a genetic test was performed was cyst-related diseases, with the highest P/LP variants found and the highest test performance. However, it is worth noting that more than half of the patients had non-related cystic disease, thus increasing the knowledge and detection of less common genetic kidney diseases. CKDUE is the second group with more P/LP variants and with the highest heterogeneity. It is essential that national health systems provide access to genetic tests to complete the study of CKD of unknow etiology.

#684 Safety and Tolerability of adipose-derived mesenchymal stem cell “ADR-001” in the treatment of immunoglobulin A nephropathy

Abstract Background and Aims Immunoglobulin A (IgA) nephropathy is one of the most frequent glomerular diseases and is sometimes refractory, requiring kidney replacement therapy. Although corticosteroids are mainly used for treatment, infection is a serious adverse event, and evidence for therapeutic efficacy is insufficient; therefore, new therapeutic options are highly desired. Mesenchymal stem cells (MSCs) contribute to the amelioration of inflammation and recovery of organ function. Due to these properties of MSCs, they have been clinically applied to various inflammatory diseases. Therefore, we decided to conduct the world's first investigator-initiated clinical trial to administer MSCs for refractory IgA nephropathy. Method This trial was a phase 1, open-label, multiple-center, dose-escalation study of adult patients with refractory IgA nephropathy resistant to or difficult to treat with existing therapies. This trial was registered and assigned the number, jRCT2043200002 and NCT04342325. ADR-001 was administered intravenously from three to six patients at a dose of 1 × 108 cells once in the first cohort and to six patients twice at two-week intervals in the second cohort (Fig. 1A). When MSCs were administered, heparin was also administered. The observational period continued until 52 weeks. The primary endpoint was the safety up to 6 weeks after ADR-001 administration. Secondary endpoints will be the respective percentages of patients with adverse events and efficacy, such as clinical remission, partial remission, remission of urine protein, remission of hematuria, time to remission, changes in urine protein, hematuria, and estimated glomerular filtration rate. Results First, regarding the primary endpoint, three patients in the first cohort received single dose of ADR-001, and the data safety monitoring board determined that the safety of the ADR-001 was well controlled because no adverse clinical events occurred. Therefore, the trial shifted the second cohort, and six patients received two doses of ADR-001. In the second cohort, the data safety monitoring board determined that safety was well controlled and that ADR-001 was safe and well tolerated for clinical use. Next, regarding the secondary endpoint, especially regarding to efficacy, kidney damage marker (Fig. 1B) and urinary protein were drastically reduced immediately after administration of ADR-001. Conclusion The safety and tolerability of ADR-001, an adipose-derived MSC, were confirmed. Furthermore, the efficacy of ADR-001 is strongly expected.

#2765 Medium chain fatty acids are potent binding competitors to improve protein-bound uremic toxin clearance in hemodialysis

Abstract Background and Aims Protein-bound uremic toxins (PBUTs) remain a concerning burden in patients with end-stage renal disease (ESRD) since their removal during hemodialysis is limited due to their tight binding to albumin. By increasing their circulating free fraction during HD, “binding competitors” of albumin could be used to increase their dialytic clearance. Medium chain fatty acids (MCFAs, 6 to 12 carbon length) are potent candidates for that purpose. The present study aims to investigate whether MCFAs could serve as potential binding competitors of albumin to enhance the removal of PBUTs, specifically IS and p-CS, during hemodialysis. Method Hexanoate (C6), octanoate (C8), and decanoate (C10) were purchased from Sigma-Aldrich. The binding of MCFAs to albumin was investigated in silico and using fluorescent probes: warfarin (specific of Sudlow's site I) and dansylsarcosine (specific of Sudlow's site II). Indoxyl-sulfate (IS, final concentration 212 µM) and p-cresyl sulfate (p-CS, final concentration 250 µM) were added to a 600 µM bovine serum albumin-phosphate buffered saline solution. The free fractions of IS and p-CS were assayed with or without MCFAs (1-2 mM) using ultrafiltration devices in this solutions and in patients uremic plasma. To mimic the removal of PBUTs during a HD session, batches of 2 liters of fresh bovine blood were loaded with IS and p-CS (final concentration 200 µM). A 2-hours closed-loop HD session was performed using a Fresenius 5008 CorDiax HD generator (Fresenius, Germany). A solution of 224 mM of octanoate was perfused at the rate of 150 µL/min; A solution of saline 0.9% was used as a control. One milliliter of blood was sampled every 15 minutes through the arterial sampling port and concentration of IS and p-CS were assayed by HPLC coupled with fluorescence detection. The hemolytic effect of MCFAs was evaluated in vitro by assaying the free hemoglobin concentration. Results According to the in silico prediction, the binding was predicted to be almost complete for MCFAs ≥ C8 (Fig. 1). The enhanced protein binding appeared to be inversely correlated with water solubility, which became particularly low for MCFAs ≥ C10. Octanoate and decanoate were the more prone to displace dansylsarcosine from Sudlow's site II of albumin (which is the main binding site of IS and p-CS). In vitro, the incubation with 2 mM of octanoate and decanoate increased the free fraction of PBUTs from 12% to 53% for p-CS (4.4 fold, p < 0.05) and from 11% to 45% for IS (4.1 fold, p < 0.05). Octanoate was also able to increase the free fraction of PBUTs in patients uremic plasma (1.6-fold for IS, p < 0.05 and 4.8 fold for p-CS, <0.01). The per-dialytic infusion of octanoate significantly increased the fractional removal of p-CS (from 38% to 88%, p < 0.001) and IS (from 36% to 91%, p < 0.001). No significant hemolysis was observed for concentration of MCFAs lower than 2 mmol/L. Conclusion MCFAs and especially octanoate and decanoate are serious candidates to displace the binding of PBUTs such as p-CS and IS. The per-dialytic administration of octanoate significantly increased the removal of PBUTs and could constitute a new strategy to prevent their accumulation in end-stage kidney disease patients. Due to their good safety profile, MCFAs could be better tolerated than other chemical compounds that has already been tested in a clinical setting such as ibuprofen. Further in vivo studies are however needed to carefully evaluate this potentially new therapeutic option.

Temporomandibular Disorders Management-What's New? A Scoping Review.

Temporomandibular disorders include various conditions that impact the masticatory system, affecting its structure, function, or physiology. Clinicians face a complex array of therapeutic options when treating this group of diseases, emphasizing the importance of evaluating the current evidence to guide decisions in patient care. The main objective of this article is to conduct a scoping review on the available treatment approaches to manage temporomandibular disorders (TMDs). An extensive search of the literature was performed on Scopus, Pubmed, Embase, and Web of Science. Systematic reviews published in the last 5 years were considered. Out of the 2183 publications identified, 109 studies were included in this review. Among them, 39 articles focused on the non-invasive approach, while 120 delved into the minimally invasive approach, and 15 explored the surgical approach. Non-invasive or conservative approaches like cognitive-behavioral therapy, physical therapy, and acupuncture offer effective pain management and functional improvements in TMDs. Emerging treatments offer promising alternatives for treating these disorders. Surgery should be reserved for severe cases, with conservative therapies used in conjunction with invasive procedures for optimal patient outcomes.

#2173 Safety and efficacy of sodium–glucose transporter-2 inhibitors in kidney transplant recipients: preliminary results

Abstract Background and Aims Sodium-glucose transporter-2 (SGLT-2) inhibitors have recently emerged as standard of care for delaying the progression of chronic kidney disease. Data regarding the safety and efficacy of SGLT-2 inhibitors in kidney transplant recipients remain limited. Method We retrospectively analysed the data of all adult kidney transplant recipients who received SGLT-2 inhibitors at our center. We examined the safety and efficacy at 3-, 6- and 12- months post-treatment. Results Thirty-seven kidney transplant recipients (males 70.3%) were treated with SGLT-2 inhibitors at a median time of 8.3 years (IQR 5.2-7.4) post-transplant. Nineteen patients (51.4%) received empagliflozin and 18 (48.6%) dapagliflozin. The median follow-up time post-SGLT-2 inhibitors initiation was 9 months (IQR 5.5-20.8). Type 2 diabetes mellitus was present in 32 kidney transplant recipients (86.5%). The mean estimated glomerular filtration rate (eGFR) pre-SGLT-2 inhibitors therapy was 54.6 ± 17.2 ml/min. During the first 3 months of SGLT-2 inhibitors initiation, the mean eGFR declined by 3.51 ml/min (p:0.024), while at 6 and 12 months no significant changes from the starting value were observed. Urine protein levels decreased from 173 mg (IQR 140-500) to 140 mg (IQR 86-251, p:0.006) in the first 3 months and remained stable at 6 and 12 months. The mean HbA1c declined from 7.06 to 6.80% (p:0.042) at 3 months and the beneficial effect was maintained through the study period. Mean serum magnesium levels exhibited an increasing trend by 0.05 (p:0.080), 0.08 (p:0.074) and 0.09 mg/dl (p: 0.138) at 3, 6 and 12 months, respectively. Urinary tract infections were observed in 7 kidney transplant recipients (18.9%). Stage 1 acute kidney injury occurred in 2 patients, which led to the drug discontinuation in one of them. Conclusion Based on our preliminary data, SGLT-2 inhibitors seem to be a safe therapeutic option for reducing urine protein levels, as well as improving glycemic control and electrolyte disturbances in kidney transplant recipients. Long-term monitoring is required to establish the beneficial effect on renal graft function.

A review of treatment of relapsing-remitting type of multiple sclerosis (RRMS)

Introduction Multiple sclerosis (SM) is the most common chronic inflammatory-demyelinating disease of the Central Nervous System. In its course, a multifocal damage is done to a nervous tissue - myelin sheaths surrounding axons become disintegrated. This process leads to a dysfunction of the electrical impulses passage along nerve fibers which occurs as various symptoms that hinder the functioning of the patients. Aim of the study This review aims to summarize treatment methods of relapsing-remitting type of multiple sclerosis (RRMS). Following information will be presented: groups of medications, mechanism of its action, its most important side effects and its effectiveness. Material and method This review presents the current state of knowledge about relapsing-remitting type of multiple sclerosis (RRMS) treatment - it is based on Pubmed database and was carried out using keywords concerning the issues of multiple sclerosis. Cited articles were selected in order to base on up-to-date investigation results. Summary A wide range of therapeutic options let neurologists treat their patients accurately, but the basic knowledge about each substance should be assimilated to choose the best individual therapy. Patients suffering from multiple sclerosis differ from each other and a personal approach is needed to implement appropriate treatment as soon as possible. Early start allows patients to not to lose their everyday functioning areas, as the neurodegenerative process is stopped at the initial stage. If some changes in brain tissue structure are permanently done, neurologists should know the options of symptomatic treatment to alleviate a patient's suffering.

Topical 5-Fluorouracil 0.5% as primary treatment for Ocular Surface Squamous Neoplasia.

To evaluate the efficacy of topical treatment with 5-Fluorouracil (5-FU) 0.5% in cases of Ocular Surface Squamous Neoplasia (OSSN), and to assess the tolerance of patients undergoing treatment. Patients with clinical diagnosis of OSSN referred to the Ocular Oncology division from the Federal University of Sao Paulo, Brazil, were recruited for the current study. Patients were treated with topical 5-FU 0.5% using a regimen of 4 times daily for 10 days, followed by a 3-week drug holiday, continued up to 3 cycles before an alternative treatment. Lesions were evaluated at baseline and throughout treatment. Treatment adherence was assessed using the Morisky Medication Adherence scale. Any adverse events along the treatment were noted. A total of 30 eyes of 30 patients adherent to the treatment were included in the study. Among the total cases treated with 5-FU 0.5%, 24 patients achieved therapeutic success after a mean treatment duration of 21.71 ± 7.77 days, representing a success rate of 80.00% (95% CI: 60.75-91.18%). For each 1 mm2 increase in the lesion area, the odds of treatment success decrease by 6% (OR: 0.94; 95%CI: 0.88-0.99; p = 0.033). Only mild adverse events such as ocular discomfort, ocular burning and tearing were observed along the treatment in 8 patients. Topical 5-FU 0.5% is an effective therapeutic option in the treatment of OSSN, with an 80% therapeutic success rate, showing good tolerability. The size of the lesion was identified as a factor influencing treatment success, therefore it should be taken into consideration when defining treatment approaches.

#2932 Our experience in combined and simultaneous liver-kidney transplantation: recipient and kidney graft survival

Abstract Background and Aims Simultaneous combined liver-kidney transplantation is a definitive treatment in patients with terminal failure of both organs, but sometimes, assessing the indication for said combined transplantation can be difficult. The liver from the same donor as the kidney graft protects the kidney immunologically and this provides long-term follow-up with a lower risk of rejection. No such protection is observed when both organs come from different cadaveric donors. There are no differences in graft survival in simultaneous or isolated transplants (liver or kidney), being prolonged in both cases. However, patient survival is lower, due to the complexity of this procedure and the clinical characteristics of the patients. The main aim is to analyze the evolution of patients with combined and simultaneous liver-kidney transplantation in our center in terms of graft survival and overall survival of the recipient. Method It is a retrospective observational study. The computerized clinical history of 50 patients with combined liver-kidney transplantation was reviewed from August 1998 to November 2023. The data were recorded in an Excell-type database. Descriptive and inferential statistics were performed for the analysis. Results 50 combined liver-kidney transplants have been performed, of which 28 (56%) died, and 23 of them (82%) with the kidney graft functioning. The main causes of death were neoplasms (11 patients) and infections (7 patients). The survival of the patients at 5 years was approximately 70%. There were 5 cases of kidney graft loss, excluding death. Chronic rejection was the main cause (70-80%) of kidney graft loss. 60% received a kidney transplant again and died with the graft functioning; 20% died while on hemodialysis; and the remaining 20% are awaiting hemodialysis and are being studied for another kidney transplant. Conclusion Simultaneous liver and kidney transplantation is a good therapeutic option for patients with terminal disease of both organs. However, it is a complex procedure in patients with multiple comorbidities, which affects overall survival. In contrast, kidney graft survival is prolonged and many recipients die with functioning grafts. It seems to be related to the immunological protective function of the liver. Consequently, there are few rejections and, the vast majority are chronic rejection.

Nanoemulsion Carriers for Ocular Fungal Infection: Main Emphasis on Keratomycosis.

Keratomycosis, also termed fungal keratitis (FK), is an invasive eye condition for which there is a lack of available effective treatment due to pharmacological shortages and vital ocular obstacles. This severe corneal infection typically suppurates and eventually ulcerates, ultimately causing blindness or decreased vision. According to epidemiological studies, FK is more common in warm, humid places with an agricultural economy. The use of nanoemulsion carriers for ocular fungal infection has been promoting better treatment and patient compliance. The persistent fungal infection like FK, affecting particularly the stroma heralds complications thereby posing difficulty in diagnosis and treatment. To help treat refractory cases and improve outcomes, recently targeted drug delivery techniques and novel antifungal drugs shall be explored. A delay in diagnosis may cause corneal fungal infections to have irreversible consequences, which cannot be avoided. However, infections can develop into ocular perforation even after receiving intense care. The commonly used chemotherapy for FK is based on topical (natamycin 5% is typically first-line therapy) and systemic administration of azole drugs. To address the problems related to better treatment, various nanoemulsion carriers were discussed. Novel drug delivery systems based on nanoemulsions are a viable therapeutic option for treating keratomycosis and may be a candidate method for overcoming obstacles in the treatment of many other ocular illnesses when combined with different hydrophobic medicines. With a brief explanation of the pathogenesis, this article seeks to give readers a thorough analysis of current trends, various treatment choices, and care strategies for fungal keratitis.

#417 Targeting parietal epithelial cell activation with mineralocorticoid receptor antagonism controls FSGS and crescentic glomerulonephritis

Abstract Background and Aims We have recently demonstrated that targeting specific pathways in parietal epithelial cells (PEC) can markedly alleviate experimental extracapillary glomerular injury [1]. Accumulating evidence has indicated the potential contributions of the mineralocorticoid receptor (MR) to the pathophysiology of chronic kidney disease. MR is expressed in endothelial cells, glomerular mesangial cells, podocytes, and distal tubular cells. Previous studies have shown that administering mineralocorticoid receptor antagonists has beneficial effects in various renal injury animal models, the role of the MR in extracapillary glomerulopathies is still elusive and mechanistically unclear. Methods To investigate the cell-specific role of the MR in PEC in the course of focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (GN), we generated chimeric mice specifically lacking MR (Pec Cre Nr3c2lox/lox) in PECs using an inducible Cre recombinase system. Maladaptive FSGS was induced by combining a high-salt diet and deoxycorticosterone acetate (DOCA) with unilateral nephrectomy (DOCA-UniN). Crescentic glomerulonephritis (GN) was induced using the anti-glomerular basement membrane nephrotoxic serum (NTS) model. Results At baseline, Pec Cre Nr3c2wt/wt and Pec Cre Nr3c2lox/lox mice displayed no kidney morphology and function differences. When challenged by DOCA-UniN, PEC-selective Nr3c2 targeting significantly inhibited the expression of PEC activation markers Ki67, CD44, and FSGS lesions. Importantly, Pec Cre Nr3c2lox/lox mice showed less albuminuria and preserved renal function compared to Pec Cre Nr3c2 wt/wt counterparts. Likewise, Pec Cre Nr3c2lox/lox mice showed less albuminuria and preserved renal function in the NTS-induced CGN model. Crescents were also more numerous and organised in Pec Cre Nr3c2wt/wt mice than in Pec Cre Nr3c2lox/lox animals. Next, we examined whether pharmacological MR inhibition could alleviate the severity of crescentic GN. When Pec Cre Nr3c2wt/wt mice were orally given eplerenone for 14 days after the onset of the crescentic GN, they were significantly protected from renal injury and failure (decreased proteinuria, normal BUN and reduced number of crescent). Such global action was associated with less expression of the CD44 activation marker on PECs. Thus, genetic disruption of MR in PEC and pharmacological inhibition using eplerenone reduced glomerular expression of CD44 and crescent formation. Furthermore, kidney biopsies of individuals diagnosed with crescentic glomerulonephritis displayed increased expression of MR in PEC within FSGS and crescents. We next evaluated PEC migration under various conditions (DMSO, HB-EGF, Eplerenone, or HB-EGF+Eplerenone) for 24 hours. Eplerenone fully abrogated HB-EGF-induced PEC migration and Pcna, Snai1, and Vim mRNA expressions. Conclusion Altogether, these results indicate the critical role of MR in PEC activation during crescentic glomerulonephritis, along with the recently discovered CD9/EGFR/PDGFR [1] and CLDN1 pathways. This further supports the idea that the PEC phenotype switch is not a bystander event but plays a targetable critical active pathogenic role in FGSS and, more surprisingly, in crescentic GN. MR modulation using eplerenone may be a new therapeutic option for the management of such severe disease.

#1572 Recurrent parvovirus B19 infection-associated pure red cell aplasia in kidney transplantation

Abstract Background and Aims Anemia is frequent in kidney transplant (KT) recipients, with multiple potential causes. Parvovirus B19 (PVB19) infection-associated pure red cell aplasia (PRCA) becomes an important diagnosis in KT recipients experiencing persistent anemia, in whom other etiologies have been excluded. PVB19-associated PRCA is described in up to 27% of KT recipients with anemia and recurrent disease in up to 33% of cases. The authors describe a case of a recurrent PVB19-associated PRCA in a KT recipient. Method - Results A 42-year-old male with chronic kidney disease of unknown etiology underwent KT from a deceased donor after circulatory death in January 2021. He received induction immunosuppression (IS) with thymoglobulin and maintenance IS with prednisolone, tacrolimus, and mycophenolate mofetil (MMF). Three months after KT, the patient complained of progressive asthenia, and normocytic normochromic (NN) anemia was detected. A thorough investigation revealed normal leucocyte and platelet counts, low reticulocyte count, and no signs of bacterial infection, iron deficiency, or hemolysis; thyroid function, erythropoietin, folate, and vitamin B12 levels were normal, direct Coombs test was negative and no monoclonal spike was detected on protein electrophoresis. Endoscopic studies and cervico-thoraco-abdomino-pelvic computer tomography were unremarkable. Serum PCR of PVB19 was positive and confirmed the diagnosis of PVB19-associated PRCA. MMF was discontinued but anemia continued aggravating (nadir hemoglobin [Hg] level of 6.6 g/dL) with a sustained PVB19 load. He was admitted to the hospital, received blood transfusions, and was started on intravenous immunoglobulin (IVIG) 2 g/kg. A bone marrow aspirate was performed and was compatible with recovery after erythroid aplasia. The patient was discharged with Hg 8 g/dL and reduced PVB19 load. Although MMF remained suspended, and close monitoring of Hg and PVB19 load was performed, four months later he developed recurrent PVB19-associated PRCA, which motivated another hospital admission for IVIG with excellent response. In addition, he presented kidney dysfunction, and a kidney biopsy revealed borderline acute T-cell mediated rejection. In this setting, IS was altered to TRANSFORM SCHEEME. Four months later, he presented a second recurrence of PVB19-associated PRCA, requiring new hospitalization and treatment with IVIG. Considering the recurrent PVB19-associated PRCA, in a patient with chronic allograft dysfunction, high immunologic risk, and the foscarnet's probable nephrotoxicity, preventive therapy with IVIG (0.4 mg/kg) every 4 weeks was started. After 7 months of preventive IVIG infusion, no relapse was identified, the Hg is 11.5 g/dL (and increasing, without erythropoiesis stimulants) and the PVB19 load remains low. Conclusion PVB19-associated PRCA is characterized by persistent NN anemia with low reticulocyte counts, which is unresponsive to erythropoietin. One significant risk factor is induction IS, particularly thymoglobulin. In the setting of solid organ transplants, the absence of PVB19 antibodies does not exclude this diagnosis and viral detection should be performed. The initial therapeutic approach involves reducing IS. However, the risk of allograft rejection must be acknowledged. If this approach proves insufficient, IVIG treatment is usually successful. In our patient, considering the facts that allograft rejection limits the reduction of IS, the need for blood transfusions, and the inherent immunization, in a young patient that will possibly require a second KT, the undesirable nephrotoxicity of foscarnet, the successful response to IVIG, and patient's quality of life, chronic IVIG therapy was thought to be the best choice and proved efficacious in preventing relapses. Despite the absence of precise guidelines for chronic PVB19 infection management, maintenance therapy with prolonged IVIG infusions may be a therapeutic option for recurrent PRCA, but more studies are necessary to define the appropriate duration of treatment.

Targeted Therapeutic Options in R/R Follicular Lymphoma

Targeted Therapeutic Options in R/R Follicular Lymphoma

Exosomes derived from mesenchymal stem cells containing berberine for ulcerative colitis therapy

Berberine (Ber), an isoquinoline alkaloid, is a potential drug therapy for ulcerative colitis (UC) because of its anti-inflammatory activity, high biological safety, and few side effects. Nevertheless, its clinical application is hindered by its limited water solubility and low bioavailability. Currently, compared to synthetic nanocarriers, exosomes as carriers possess advantages such as low toxicity, high stability, and high specificity. Human placental mesenchymal stem cell-derived exosomes (HplMSC-Exos) have emerged as a promising drug delivery system, offering intrinsic anti-inflammatory and antioxidant activities. Therefore, we engineered MSC-Exos loaded with Ber (Exos-Ber) to enhance the solubility and bioavailability of Ber and for colon targeting, revealing a novel approach for treating UC with natural compounds. Structurally and functionally, Exos-Ber closely resembled unmodified Exos. Both in vitro and in vivo investigations confirmed the antioxidant and anti-inflammatory properties of Exos-Ber. Notably, Exos-Ber exhibited reparative effects on injured epithelial cells and reduced cellular apoptosis. Furthermore, Exos-Ber concurrently demonstrated anti-inflammatory and antioxidant activities, contributing to the mitigation of UC, possibly through its modulation of the MAPK signaling pathway. Overall, our findings demonstrate the potential of Exos-Ber as a promising therapeutic option for alleviating UC, highlighting its capacity to enhance the clinical applicability of Ber.

#2748 Combined rituximab and daratumumab treatment in difficult to treat nephrotic syndrome cases

Abstract Background and Aims Common treatments for multidrug-resistant and multidrug-dependent nephrotic syndrome (NS) are inconsistently effective and burdened by long-term toxicities. Moreover, affected patients are at high risk of progression to end-stage kidney failure. Objective To test the safety/efficacy profile of combined single infusion of rituximab and daratumumab in inducing proteinuria remission in multidrug resistant nephrotic syndrome and maintaining drug free disease remission in patients with multidrug-dependent nephrotic syndrome after removal of oral immunosuppression. Method We here present a Phase 2 Proof-of-Concept single-arm clinical trial, that enrolled consecutive participants at the Nephrology Unit of the IRCCS Giannina Gaslini Children's Hospital in Genoa, Italy, between September 2021 and March 2023. Enrolled patients, aged between 3 and 24 years, were multidrug-dependent or multidrug-resistant nephrotic syndrome for at least 12 months before enrolment. Multidrug-dependency was defined by the need of at least 2 oral immunosuppressive drugs (prednisone and/or calcineurin inhibitors and/or mycophenolate mofetil) and by the occurrence of at least two consecutive relapses on two immunosuppressive drugs. Multidrug-resistance nephrotic syndrome was defined by the lack of antiproteinuric effect of a double immunosuppressive therapy. Exclusion criteria included genetic forms of NS and administration of monoclonal therapies in the last 9 months before enrolment. Interventions: Rituximab and daratumumab were administered as single doses at 375 mg/m2 and 16 mg/kg, respectively, 15 days apart. Main Outcomes and Measures:Proteinuria, serum albumin, Immunoglobulin M and G, B and T lymphocyte subsets, safety, Quality of Life. Results A total of 7 consecutive multidrug-resistant and 16 multidrug-dependent NS, respectively, were enrolled. In multidrug-resistant NS, combined rituximab and daratumumab promoted complete or partial remission in 6 patients (Fig. 1A). Five subjects experienced proteinuria relapse, that was effectively treated with a second course of combined treatment. Decreased of I'm, but not IgG, correlated with improvement of proteinuria (Fig. 1B).These treatment allowed to reduce the chronic immunosuppressive treatment daily administered (Fig. 1C). In multidrug-dependent NS, combined rituximab and daratumumab extended the relapse-free time, allowing us to remove oral immunosuppressant (Fig. 1D). Disease relapse was invariably anticipated by a recovery of circulating IgM:patients with IgM levels below median values measured at 3 mo post-treatment had a significantly lower rate of relapse at 9 mo than patients with higher IgM levels at 3 mo (Fig. 1E). Combined treatment induced significative reduction of CD38+ plasma cells (Fig. 1F) and IgM, but not IgG. Treatment was well tolerated and significantly increased quality of life. Conclusion Combined rituximab and daratumumab was safe and effective in the treatment of complicated forms of NS, offering a new therapeutic option for this severe condition.

#1790 Metformin versus standard of care in slowing progression of autosomal dominant polycystic kidney disease and correlation with total kidney volume

Abstract Background and Aims Autosomal dominant kidney disease (ADPKD) is the most common monogenic disorder leading to renal failure with very limited therapeutic options. Apart from lifestyle modifications and control of hypertension, tolvaptan is the only Food and Drug Administration (FDA) approved disease modifying drug. Although, it has proven therapeutic benefit in slowing disease progression in high risk Mayo Class (Mayo Class 1C-E), the aquaretic potential, potential hepatotoxicity and the cost limits its widespread use especially in resource constrained country. Metformin has been shown to be effective in ADPKD in preclinical studies and is also well tolerated by the general population. We planned this study to assess the efficacy and safety of metformin in non diabetic ADPKD patients. Method Our study is a prospective, randomized controlled, open labelled clinical trial of 52 non diabetic adults 18 to 60 years of age with typical ADPKD, estimated glomerular filtration rate (eGFR) > 45 ml/min/m2 and no risk factors of rapid progression. Participants were randomized in a 1:1 ratio by a computer-generated random number table into Metformin + standard of care group (Metformin arm) and standard of care group (Placebo arm). Primary outcome of the study was to evaluate the effects of metformin versus placebo arm on the percentage and absolute change in eGFR over 6-month period. Secondary outcomes were to study the effect of metformin versus placebo arm on the percentage and absolute change in height adjusted total kidney volume (htTKV ml/m) at 6 months, to evaluate the effect of baseline plasma copeptin levels with percentage change in htTKV and eGFR over 6 months, to evaluate metformin tolerability, to evaluate the effects of metformin versus placebo on the changes in body weight, BMI, blood pressure and urine protein excretion at 6 months period. Results Mean (SD) age of the cohort was 37.15 (10.16) years with half of them being females. The mean (SD) baseline htTKV and eGFR was 335.67 (153.3) ml/m and 100.23 (25.95) ml/min/m2. Clinical exome sequencing was available in 9 (17.3%) patients of which two third had PKD1 mutation. Baseline characteristics were distributed equally across randomized groups. Baseline proteinuria was significantly higher in the Metformin arm (p = 0.014). The eGFR difference and percentage change in eGFR was not different between the groups at 6 months (p = 0.535, 0.483). There was no statistically significant difference in htTKV difference and percentage change in htTKV at 6 months between the groups although increase in htTKV was numerically smaller in the metformin group (p = 0.769, 0.805). Blood pressure, weight, body mass index (BMI) and proteinuria also did not differ between two groups. Half of the cohort tolerated the maximum dose of metformin. Around 2/3rd patients reported adverse effects most commonly asthenia. There was no lactic acidosis or significant gastrointestinal side effects as assessed by gastrointestinal rating scale (GSRS) scale. Baseline copeptin levels did not correlate with eGFR or htTKV difference at 6 months. Conclusion Metformin appears to be safe and tolerable in non diabetic ADPKD patients over 6 months. However larger clinical trials are needed to conclude regarding the efficacy in terms of eGFR decline or htTKV progression.

The Effectiveness of Atezolizumab in Metastatic Large Cell Neuroendocrine Carcinoma of the Lungs: Insights from the LANCE Pilot Study.

Large cell neuroendocrine carcinoma (LCNEC) presents significant treatment challenges due to its rarity and limited therapeutic options. The LANCE study was designed to explore the survival benefits of incorporating atezolizumab in chemotherapy for metastatic LCNEC. In this non-randomized study, patients with metastatic LCNEC were prospectively enrolled and assigned to receive either standard chemotherapy plus atezolizumab followed by maintenance with atezolizumab or standard chemotherapy alone. The primary outcomes measured were 12- and 24-month survival rates, progression-free survival (PFS), and overall survival (OS) between the two groups. Of the 22 patients screened, 17 met the inclusion criteria and received either atezolizumab plus platinum-based chemotherapy (n = 10) or chemotherapy alone (n = 7). After a median follow-up of 23.3 months, the 12-month survival rate was 57.1% (95% CI: 32.6-100%) and 14.3% (95% CI: 2.33-87.7%) for the atezolizumab and the chemotherapy-only groups, respectively. The survival benefit for the atezolizumab group was sustained at 24 months (45.7% vs. 14.3%). Overall survival was significantly higher for the atezolizumab group, and PFS was non-significantly associated with the addition of atezolizumab (log-rank p = 0.04 and 0.05, respectively). This pilot study suggests that the addition of atezolizumab to standard platinum-based chemotherapy may provide a substantial survival benefit compared with chemotherapy alone in the first-line treatment of metastatic LCNEC.

Treatment of vascular leg ulcers with leukocyte- and platelet-rich fibrin (L-PRF): A systematic review.

Objectives: This systematic review aimed to assess the efficacy of Leukocyte- and Platelet-Rich Fibrin (L-PRF) for the treatment of vascular leg ulcers. Method: Following PRISMA guidelines, a literature search was done for studies where L-PRF was used to treat vascular leg ulcers. Results: Among six included articles, a total of 76 venous leg ulcers were treated with L-PRF. None of the studies included ulcers of arterial or lymphatic origin. Fifty-seven (75.0%) of the venous ulcers completely healed at end of follow-up. Mean time to complete healing was 6.7weeks (SD = 5.0). All non-healed ulcers showed an important reduction in wound area. No adverse effects related to L-PRF therapy were reported. Conclusions: The results suggest that L-PRF could be a safe, simple to use and effective therapeutic option for the treatment of venous leg ulcers, however, caution is advised as the results are based on small sample sizes.

#2153 Difelikefalin: a new solution against itching in CKD-aP patients

Abstract Background and Aims Chronic kidney disease-associated pruritus (CKD-aP) is one of the most common and burdensome symptom affecting patients with advanced chronic kidney disease, with an estimated prevalence of 53.3%. The clinical presentation is extremely variable, from minor lesions to true scratch injuries, and significantly affects the patient's quality of life (QoL), sleep quality and mood, as well as being associated with increased mortality. At present, high-quality evidence on which to base treatment is limited. Currently proposed first-line therapeutic options include optimization of dialysis treatment, emollient agents, UVB light, antihistamines, gabapentin and pregabalin. Recently difelikefalin, a k-opioid receptor agonist, has been the first Food and Drug Administration (FDA) approved drug for moderate-severe CKD-aP treatment. The aim of our study is to demonstrate the efficacy of this drug in relieving symptoms in CKD-aP patients. Method For this preliminary retrospective observational study, 19 patients (9 females, 10 males) with CKD-aP performing dialysis at our Dialysis Center were recruited. All of them had appropriate Kt/V values and had previously been treated with first-line medications. The other main demographic and clinical characteristics of our population, such as calcium-phosphate metabolism and inflammation's indexes, can be seen in Table 1. Our population underwent the Worst Itch Numeric Rating Scale (WI-NRS) by which the presence, intensity, and impact on sleep of this symptom were investigated. They also were subjected to questions that investigate their quality of life (SF-PCS12, SF-MCS12). All patients completed those questionnaires before starting Difelikefalin treatment (t0) and after one month of treatment (t1), 15 of them were evaluated also after three months (t3) and 10 patients, those who first started therapy, reached the assessment at six months (t6). Results Statistical analysis of our preliminary study shows very encouraging data regarding the efficacy of difelikefalin on CKD-aP and sleep quality. As shown in Table 2, we recorded a significant decrease (p value <.001, ƞ2 0.552) in the intensity of itching, most noticeable in the first month, confirming that the effect of this drug is evident and considerable already after four weeks. Our data also demonstrate a significant and lasting positive effect of difelikefalin on sleep quality (p value 0.006, ƞ2 0.592), as shown in Table 3. We found no significant data on the improvement in the QoL of the patients in the study, probably due to the difficulty in standardising this complex feature and due to the limited size of the statistical sample. Furthermore, it should be considered that 3 of the patients enrolled in the study had to discontinue the medication due to the onset of side effects such as diarrhea and headache. Conclusion The most influential limitation of this retrospective observational study is the small number of recruited patients, in addition to the fact that not all of them reached a 6-months treatment evaluation. Our aim is to complete the study by enrolling a larger number of patients from our Dialysis Centre and to monitor the effect of difelikefalin during a longer treatment period, in order to achieve a more accurate analysis and significative results applicable on a larger scale. As far as we can currently evaluate, this drug is significantly effective in reducing CKD-aP and thus in improving the quality of sleep.