bluuebunny/crossref_metadata_2025 huggingface dataset:
#1700 Clinical presentation and prognosis in ANCA-associated vasculitis with occupational exposure to silica: a monocentric retrospective study
Authors: Mescia Federica , Ravelli Francesco , Tedesco Martina , Arrighini Marta , Silva Laura , Sestagalli Eva , Gregori Marco , Medici Pierangelo , Albertelli Ivan , Donatoni Claudio , De Palma Giuseppe , Alberici Federico
Published: May 2024

Background and Aims

Exposure to silica is associated with an increased risk of autoimmune diseases, including ANCA-associated vasculitis (AAV) [1–3]. It remains unclear whether silica exposure modifies clinical presentation of AAV, and it is not known whether it affects prognosis. The aim of this work is to address these questions.

Method

This is a retrospective, monocentric observational study comparing clinical and prognostic features between two groups of patients with ANCA-positive AAV: cases with a well-documented history of occupational exposure to silica (confirmed by industrial hygienists) and controls with no exposure. Each case was matched to 2 controls based on time of diagnosis (± 1 year relative to the case). Clinical features were compared across the two groups using Student's t test or chi-squared test, as appropriate. Clinical outcomes were compared across groups with the log-rank test and Cox proportional hazards regression.

Results

We identified 25 patients with AAV and a clear-cut history of occupational exposure to silica and 50 controls with no exposure, diagnosed between 2000 and 2023. Compared to controls, patients exposed to silica were more frequently males and smokers (Table). Average age at presentation was 66 ± 14 years and most patients had microscopic polyangiitis and MPO-ANCAs, with no significant differences according to silica exposure (Table). Patterns of organ involvement were also comparable across the two groups (Table). Renal vasculitis was present in almost all patients, probably reflecting a referral bias. Severity of renal impairment at diagnosis (Table) and evolution to end stage renal disease (Figure) were similar between exposed and unexposed individuals. There was a trend for lower survival in patients with exposure to silica (median survival from AAV diagnosis: 172 months in cases and 111 months in controls, log-rank test p = 0.065, Figure). In multivariate Cox regression, the risk of death was independently associated with age at diagnosis (HR 1.09 per year, 95% CI 1.04-1.14, p < 0.001) and not with silica exposure (HR 0.96, 95% CI 0.39-2.41, p = 0.936) or smoking history (HR 2.06, 95% CI 0.80-5.33, p = 0.135).

Conclusion

Patients with AAV and exposure to silica were more frequently males and smokers, likely reflecting socio-economic factors. We did not identify otherwise distinct clinical features in exposed patients, similarly to other Authors such as Hogan et al [2]. Exposure to silica did not seem to significantly affect renal prognosis or survival either, despite a trend in univariate analysis for higher mortality in individuals with silica exposure. The limited sample size and lack of quantification of silica exposure must be acknowledged and may have reduced statistical power.
#3033 IgA vasculitis: a unexpected diagnosis of pulmonary renal syndrome
Authors: de Bastos José Mário Soares , Medeiros Joana , Marques Sofia Homem Melo
Published: May 2024

Background

IgA vasculitis is an inflammatory condition affecting blood vessels that poses a significant diagnostic and therapeutic challenge in clinical practice. Characterized by the deposition of immunoglobulin A (IgA) on vessel walls, this pathology can manifest in various ways, presenting a broad and sometimes complex clinical spectrum. Ninety percent of cases occur in the pediatric age group. Severe lung involvement, such as pulmonary hemorrhage, is rare in patients with IgAV. We present a case of a 33-year-old patient with pulmonary renal syndrome and without purpura, an atypical presentation of IgA vasculitis.

Case Report

We describe the case of a 33-year-old patient with no relevant medical history or regular medication, who presented to the emergency department in November 2022 with symptoms of hemoptysis, fatigue, myalgias, and pallor. On physical examination, the patient was conscious, cooperative, normotensive, tachycardic, afebrile, with bilateral axillary adenopathies, and scattered crackles on lung auscultation. Laboratory tests revealed anemia with a hemoglobin level of 5.8 g/dL, non-oliguric acute kidney injury with a creatinine level of 2.25 mg/dL, microscopic hematuria (>50/hpf), and proteinuria (UPCR of 2.8 mg/mg and UACR of 1.6 mg/mg). A chest CT scan showed bilateral and scattered ground-glass opacities consistent with alveolar hemorrhage. The patient was admitted to the Nephrology service, underwent 3 sessions of plasma exchange, and started therapy with methylprednisolone 1000 mg for 3 days. A renal biopsy revealed 24 glomeruli, with 3 showing segmental sclerosis and 1 with fibrocellular crescents, mild interstitial nephritis; immunofluorescence showed IgA+++, C3++, IgM, and IgG+- Oxford Classification: M1 E0 S1 T0 C1. Bronchofibroscopy showed a rosy bronchoalveolar lavage and macrophages with hemosiderin pigment deposition. The patient continued with prednisolone at 1 mg/kg. In January 2023 (after two months), there was a >25% reduction in albuminuria with resolution of acute kidney injury. A gradual reduction of prednisolone was initiated, and it was definitively discontinued in October 2023. In the last outpatient visit in January 2024, the patient maintained normal renal function, with no hematuria, UPCR of 100 mg/g, UACR of 70 mg/g, and no further episodes of alveolar hemorrhage.

Conclusion

This case stands out for its atypical presentation: an adult with alveolar hemorrhage and without other more classical manifestations of IgA vasculitis, such as purpura. This is yet another case that emphasizes the importance of the broad spectrum of diagnoses that a nephrologist should consider in the face of acute kidney injury.
#3076 A UK parallel cohort study on renal ANCA associated vasculitis outcomes for avacopan exposed and matched unexposed cohorts
Authors: Francis Lucy , Mcadoo Stephen , Flossman Oliver , Floyd Lauren , King Catherine , Brix Silke , Wessels Julie , Dhaygude Ajay , Chanouzas Dimitrios , Smith Rona , Jayne David R W , Jones Rachel B
Published: May 2024

Background and Aims

Avacopan was approved in the UK for severe ANCA associated vasculitis (AAV) in December 2022. The ADVOCATE trial found the differential effect of avacopan on kidney function was greatest in patients with the lowest estimated glomerular filtration rate (eGFR), at highest risk of progression to end stage kidney disease (ESKD). Patients with an eGFR <15 ml/min/1.73 m2, pulmonary haemorrhage requiring invasive ventilation, under 12 months prognosis, use of plasma exchange and dual therapy with cyclophosphamide (CYC) and rituximab (RTX) were excluded from ADVOCATE; all common scenarios in real life practice. We aim to provide further information on these subgroups and evaluate 6 month renal outcome data in the UK.

Method

Parallel cohort study on renal AAV outcomes for avacopan exposed and matched unexposed cohorts, with severe, active GPA or MPA. 120 patients on avacopan from 7 UK centres have been recruited to date. Controls matched by renal function and age will be presented. Comparisons of ESKD, delta eGFR, eGFR recovery, reduction in proteinuria/haematuria, remission, relapse and mortality will be presented, with subgroup analyses for eGFR<15 ml/min/1.73 m2. Steroid exposure will be presented.

Results

Baseline characteristics of the avacopan cohort are below. Most received oral prednisolone at avacopan initiation (89%, n = 107) and 54% received intravenous methylprednisolone (n = 65). The majority received RTX alone (44%, n = 53) or RTX and CYC combination therapy (43%, n = 52). Fewer received CYC alone (9%, n = 11) and 3% were initiated on alternative immunosuppression (n = 4). 26% (n = 31) underwent plasma exchange and 13% required haemodialysis (n=16). 3% of patients have died.

Excluding dialysis dependent patients at presentation, median eGFR was 22ml/min/1.73 m2 (IQR 10-36). eGFR at the time of avacopan initiation was 21ml/min/1.73 m2 (IQR 11-34).

Conclusion

Avacopan is commonly being used to treat nephritis in patients with a low eGFR, including haemodialysis dependent and elderly patients. Avacopan is frequently used with RTX and CYC combination therapy. 6 month outcome data will provide new data on important patient subgroups excluded from the ADVOCATE trial.
#409 Correlation between ha factor concentration and urinary syndrome in patients with chronic glomerulonephritis when using rivaroxaban
Authors: Abduvakhitova Asalya
Published: May 2024

Background and Aims

Considering the pathogenetic role of factor X of the coagulation system in the formation and progression of chronic glomerulonephritis (CGN), as well as the mechanism of action of rivaroxaban, this study examined the concentration of coagulation factor X in peripheral blood. Aim of our study to reveal the pathogenetic relationship between the concentration of Xa factor and the severity of urinary syndrome in patients with CGN on the background of basic therapy with the inclusion of rivaroxaban.

Method

108 CGN patients, on the background of 3-month baseline therapy with inclusion of rivaroxaban (AC+ group, 55 patients) and without anticoagulant (AC- group, 53 patients). Initially and after 3 months of the study the concentration of coagulation factor Xa in peripheral blood was studied.

Results

In CGN patients the concentration of Xa factor was significantly higher than in CG (122.17 ± 2.23% vs. 104.28 ± 6.54% in CG, p < 0.05). On the background of 3-month therapy including antiaggregant, corticosteroid hormone and cytostatic, the concentration of Xa factor decreased by 18.82 ± 0.64% (p < 0.001 reliability of difference with initial data). The use of rivaroxaban, as expected, was associated with a more significant decrease in Xa factor level—by 38.76 ± 1.40% (p < 0.001 significance of difference with baseline data; significance of difference in relative dynamics of Xa factor concentration between groups depending on anticoagulant use, p < 0.001). Correlation analysis revealed a significant positive strong correlation between the initial concentration of Xa factor in peripheral blood of CGN patients and the severity of hematuria (r = 0.83, p < 0.01) and a positive weak correlation between the concentration of Xa factor and cylindruria as a manifestation of proteinuria (r = 0.30, p < 0.01), as well as a positive weak correlation between the concentration of Xa factor and cylindruria at the end of the 3rd month of observation (r = 0.33, p < 0.01). There was also found a significant negative weak correlation between the initial concentration of Xa factor and the relative dynamics of hematuria (r = −0.48, p < 0.01) and cylindruria (r = −0.33, p < 0.01).

Conclusion

The study confirmed the pathogenetic relationship between the concentration of Xa factor and the severity of urinary syndrome in CGN patients. It was also found that initially high concentration of Xa factor is associated with less positive dynamics of urinary syndrome parameters.
#1577 Rituximab in patients with primary podocytopathies: case series
Authors: Costa Cláudia S , Antunes Amélia , Oliveira João , Pereira Marta Sofia Henriques , Godinho Iolanda , Fernandes Paulo , Jorge Sofia , Lopes José António , Gameiro Joana
Published: May 2024

Background and Aims

Rituximab (RTX) has been reported as an effective treatment alternative in primary forms of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) associated with steroid dependence and frequent relapses. However, the optimal RTX regimen and the outcomes of further doses of RTX remain unclear. This study aimed to evaluate the use of induction and maintenance RTX therapy for adults with primary podocytopathies.

Method

We performed a retrospective case series on adult patients with steroid-dependent podocytopathies who received an induction RTX therapy. Maintenance therapy was performed at physician's discretion. Remission and relapse rates, concomitant corticosteroids and immunosuppressants use, B-cell depletion and adverse events were analyzed.

Results

Fourteen patients (mean age at start of RTX 29.1 ± 21.9 years) with MCD (n = 7) or FSGS (n = 7) were treated with 2 doses of 1000 mg 2 weeks apart (n = 13) or four doses of 375 mg/m2 (n = 1) of RTX. At last follow-up (mean 47.3 ± 101.7 months) ten patients were in complete remission and two remained in partial remission. A reduction in the number of relapses, number of patients under corticosteroids and immunosuppressants, and dose of prednisolone was observed when compared to baseline [14 (100%) vs 5 (35.7%); 8/14 (57.1%) vs 4/12 (33.3%); 13/14 (92.9%) vs 7/12 (58.3%); 20 mg/day vs 5.25 mg/day, respectively]. Maintenance RTX therapy was used in six patients, with sustained complete remission. Infusion reactions were observed in four patients (one required treatment withdrawal).

Conclusion

Our findings support the use of RTX for a steroid-free remission in podocytopathies and suggest that maintenance RTX is well-tolerated and associated with prolonged remission. Further studies are needed to confirm its efficacy and safety and establish the optimal induction and maintenance RTX regimen in steroid-dependent podocytopathies.
#2565 Urine amino acid profiles enlighten new prediction models for renal Fanconi syndrome and its association with eGFR level
Authors: Chen Limeng , Dong Yuan , Shi Xiaoxiao , Hou Zuoxian , Xia Peng , Qiu Ling
Published: May 2024

Background and Aims

Renal Fanconi syndrome (FS) presented dysfunctions of renal proximal tubular (PT) transport with or without excessive urine amino acids (AAs) excretion, which might contribute to the progression of eGFR decline. This study aimed to explore the clinical benefit of 21 urinary AAs excretion patterns in renal FS and eGFR decline.

Method

Liquid chromatography-tandem Mass spectrometry (LC-MS-MS) is currently quantitative and detects over 21 types of amino acids in 157 patients with renal proximal tubular dysfunctions. To evaluate the diagnostic values of urine AAs in renal FS, we established a machine learning algorithm to perform binary classification using Random Forest Regressor in Python (version 3.8.8) with a training set and a testing set (8:2). We used Randomized search to find out the best model hyperparameters, calculated feature importance for contribution evaluation, and Receiver Operating Characteristic (ROC) curves to evaluate the performance of classification algorithms.

Results

A model based on a machine learning algorithm of all urine AAs to diagnose renal FS established with sensitivity = 0.71, specificity = 0.73, and AUC = 0.83 (95% CI 0.648-0.957) (Fig. 1), with similar performance in combined six urine AAs (citrulline, asparagine, threonine, phenylalanine, ornithine, and proline) models. The urine proline level independently correlated with eGFR < 60 ml/min/1.73 m2 (bias regression coefficient 0.84, P = 0.001, OR = 2.31, 95% CI 1.41-3.80) when adjusted by age, etiology, gender, and blood urea nitrogen level. For the primary diseased diagnosis, the most susceptible urine AAs were citrulline (56.7%), proline (56.0%,) threonine (52.2%), and ornithine (45.9%) and the less susceptible ones were histidine (24.8%), aspartate (16.6%), and arginine (13.4%). Accordingly, the most common affected AA transporters were SLC6A19 (B0AT1) and etiology-specific urine AA atlas major in the eight urine AAs (isoleucine, glutamine, methionine, proline, alanine, ornithine, lysine, and arginine). Different from primary Sjӧgren syndrome patients (n = 26) with less susceptible, the patients with plasmacyte diseases (n = 8) showed elevations of almost all the urine AAs except glycine and aspartate. The connection between urine AAs excretion and hypouricemia showed gender differences, with 20 urine AAs significantly negatively correlating with serum uric acid levels in males but only five in females.

Conclusion

We first established a model based on the urine AA atlas detected by (LC-MS-MS) which contributed to differentiating the etiologies of renal tubular dysfunctions and associated well with eGFR. It shed light on the clinical practice in precision evaluation of tubule injury.
#1276 Clinical practice of complement inhibitor use in hemolytic uremic syndrome: findings from the European rare kidney disease registry
Authors: Vujovic Aleksandra
Published: May 2024

Background and Aims

Over the last decade, significant advancements have emerged in the field of rare kidney diseases, notably the introduction of C5 inhibitor therapy. The C5 inhibition has transformed the prognosis for atypical Hemolytic Uremic Syndrome (aHUS), offering improved clinical outcomes. However, despite these advancements, the utilization of C5 inhibitor therapy varies significantly, with disparities in treatment duration, reasons for discontinuation, and consideration of extending treatment to patients with infectious HUS (iHUS). This variability is further compounded by the considerable cost associated with C5 inhibitor treatment.

Method

This retrospective cohort study utilized data from the ERKNet Registry. The study cohort comprised 608 HUS patients enrolled in the ERKNet Registry between November 2018 and September 2023. The dataset encompassed patient demographics, disease and diagnostic records, medication profiles, dialysis or transplantation requirements, kidney function monitoring at the last visit, and clinical outcomes.

Results

Among 230 aHUS patients, 23 underwent kidney transplantation. 11 received C5 inhibitor therapy before kidney failure. The majority of these patients had genetic aHUS with various mutations (3 CFH, 2 CFI, and 1 CD46). The only death in the study was from this group of patients, unresponsive to C5 Inhibition. Out of 175 aHUS patients treated with Eculizumab, 23 (13%) transitioned to Ravulizumab. Among 104 patients who discontinued C5 inhibitors, 14 (14%) had to resume treatment, half of them with genetic aHUS, with 3 cases of CD46 mutations, 2 cases CFHR5 mutations, and one each involving mutations in CFI and C3. Only two patients required dialysis.. Among 371 iHUS patients, 82 (22%) received C5 Inhibitor treatment.

Conclusion

In the context of aHUS, we found that discontinuing C5 inhibitors is generally safe, with a slightly higher relapse rate in patients with complement gene variants, though most relapses were mild, requiring dialysis in only a few cases. Long-term follow-up revealed a return to normal kidney function following TMA relapses. Transitioning from Eculizumab to Ravulizumab exhibited promising outcomes, with no relapses or kidney failures in 23 patients. Our analysis of C5 inhibitor use in iHUS emphasized its association with more severe disease progression. While some studies question C5 inhibitors' acute-phase efficacy, others report remarkable improvements in patients unresponsive to other treatments. Overall, our findings underscore the safety of discontinuation practices, the potential benefits of Ravulizumab, and the ongoing need for further research on C5 inhibitor treatment in iHUS.
#689 Obinutuzumab in patients with previously untreated primary membranous nephropathy
Authors: Du Xuanyi , Lin Xiaojing , Fu Rao
Published: May 2024

Background and Aims

Primary membranous nephropathy (PMN) is the most common cause of nephrotic syndrome (NS) in adults and is currently considered an autoimmune-related disease. B cell depleting treatments, currently the most commonly used is rituximab, are usually effective in treating membranous nephropathy (MN). However, about 35% of patients treated with rituximab fail to respond, and relapses after RTX-induced remission are frequent. Among the new anti-B cell therapeutics, obinutuzumab has shown significant efficacy in treating refractory MN, including those that have failed treatment with RTX. The literature on the clinical efficacy of obinutuzumab as an initial treatment for MN is very limited. This study aimed to evaluate the efficacy and safety of obinutuzumab as an initial treatment for PMN.

Method

We reviewed all patients (n = 6) with PMN diagnosed by renal biopsy who were followed up for ≥3 months and received obinutuzumab as initial therapy at our center. We analyzed the trend of changes in related indicators such as urine protein, serum albumin, serum creatinine, serum PLA2R antibody, B lymphocyte count, and the response time and remission rate.

Results

After obinutuzumab therapy, all patients achieved remission at a median follow-up of 3 months (IQR, 2.5–3.25 months). The remission rate at three months was 83.3%. Two patients experienced adverse reactions in our study: one had interstitial pneumonia and eczema, and one had transient leukopenia.

Conclusion

As the initial treatment for primary membranous nephropathy, obinutuzumab induces a safe and rapid response. Large prospective studies are needed to provide more evidence.
#2988 Use of rivaroxaban for prevention of thrombotic events in patients with nephrotic syndrome
Authors: Rapetskaya Nadzeya , Komissarov Kirill , Kalachyk Aleh
Published: May 2024

Background and Aims

Patients with nephrotic syndrome are at increased risk of thrombotic events. The risk of thromboembolism is particularly high in patients with primary membranous nephropathy, elderly patients and patients with severe hypoalbuminemia. Although increased incidence of thrombosis is a well reported complication associated with nephrotic syndrome, management strategies are not well established. Use of aspirin seems to be insufficient to prevent venous thromboembolism. Use of warfarin and low-molecular-weight heparins is inconvenient for outpatients.

The aim of the trial was to evaluate effectiveness and safety of rivaroxaban in venous thromboembolism prophylaxis in patients with nephrotic syndrome.

Method

The randomized single-center trial was performed from October 2020 to November 2023. 30 adult patients with nephrotic syndrome due to primary glomerular diseases and glomerular filtration rate more than 60 ml/min were divided into two groups. The treatment group (n = 15) received 10-20 mg of rivaroxaban daily. The control group (n = 15) had no anticoagulation therapy. Thrombotic events and bleedings were recorded.

Results

Patients in both groups received immunosuppressive treatment of nephrotic syndrome according to primary disease. Rivaroxaban was prescribed for the entire treatment period until the onset of remission. Patients with membranous nephropathy were equally represented in both study groups (4 per group). No thromboembolic events were recorded in both groups. As well as there were no bleeding complications in patients who received rivaroxaban.

Conclusion

Rivaroxaban might be a possible alternative to warfarin and low-molecular-weight heparins in prevention of thrombosis in nephrotic syndrome. However, indications for anticoagulant prophylaxis, its duration and discontinuation are still not clear. Future studies should address the question regarding the utility of primary thromboprophylaxis.
#1609 Effect of dapagliflozin in proteinuria reduction and glomerular filtration rate in a group of Alport syndrome patients
Authors: Gomes Ana Marta , Malheiro Jorge , Lemos Carolina , Dias Joana Pereira , Lopes Daniela , Almeida Clara , Beirão Idalina
Published: May 2024

Background and Aims

Alport syndrome (AS) is the most common cause of inherited chronic kidney disease. This disorder is caused by deleterious variants on COL4A3, COL4A4 or COL4A5 genes. These genes codify the proteins that constitute collagen type IV of the glomerular basement membrane (GBM). Alterations in any of collagen type IV constituents cause disruption of the GMB structure, allowing the leakage of red blood cells and proteins, mainly albumin, into the urine resulting in kidney damage and loss of renal function.

In AS progressive kidney impairment can be delayed or possibly prevented by timely initiation of renin angiotensin aldosterone inhibitors (RAAi): in males with X-linked AS and in autosomal recessive AS ARAS at diagnosis and in females with XLAS and autosomal dominant AS at the onset of microalbuminuria. Recently, it was showed that sodium-cotransporter-2 inhibitors (SGLT2i) reduce proteinuria and slow the progression of kidney disease in many glomerular diseases. Thus, also in AS, SGLT2i could be promising in renal disease progression control.

The aim of this study was to determine the proteinuria reduction and the effect on the glomerular filtration rate (GFR) in a group of AS patients with persistent proteinuria besides the use of RAAi in maximum tolerated doses after adding SGLT2i to the treatment.

Method

This study was single-center, observational and prospective study evolving 8 AS adult patients, without a diagnosis of diabetes, with persistent proteinuria besides the use of RAAi in maximum tolerated doses. All patients were prescribed wit dapagliflozin 10 mg daily. We determine the changes from baseline of urinary protein/creatine (Up/cr) and glomerular filtration rate (based on epiGFR formula).

Results

Eight AS patients were included in this study. All were male patients. One patient has XLAS and the other 7 patients have ADAS. No patient was diabetic, and all were under RAAi in maximum tolerated doses. We determine de Up/cr and epiGFR at baseline and median time of 213.5 days (IQR 208.3-259) after SGLT2i initiation. At baseline, the median of Up/cr was 1.4 (IQR 0.8-2.1) and after SGLT2i Up/cr was 1.5 (0.8-2.6), p = 0.727. Up/cr, after SGLT2i treatment, reduced in 3 patients and worsened in 5. Median epiGFR at baseline was 80.3 ml/min (IQR 40.9-109.5) and after SGLT2i initiation was 74.7 ml/min (40.4-112.0), p = 0.727.

Conclusion

In this study, we did not observe an improvement in Up/cr of AS patients with SGLT2i treatment. A slight decrease in GFR was observed that may be due to the well know hemodynamic effects of SGLT2i. The small cohort and short time of the study are factors that can interfere in these results and should not discourage the treatment of AS patients with SGLT2i.
#2187 Rare disease, novel approach: C3GN and Iptacopan case report
Authors: Groome Ciaran , Padmanabhan Neal , Wong Edwin , Yule Ailson , Fairweather Jack
Published: May 2024

Background and Aims

C3 glomerulonephritis (C3GN) is a rare disease characterised on biopsy by proliferative lesions of predominant C3 deposition on immunofluorescence, particularly deposits within the mesangium and capillary walls. Dysregulation of the alternative complement pathway is thought to be the underlying mechanism [1]. There are no approved treatments for C3G and prognosis is poor, with 50% progression to kidney failure over 10 years and similar rates of transplant loss due to disease recurrence. Iptacopan (a selective Factor B complement inhibitor) is proposed to suppress key enzymes involved in the alternative pathway cascade [2]. It is being studied in clinical trials of C3G [3].

We sought to describe our experience in diagnosing and managing a 25-year-old with C3GN who presents with nephrotic syndrome, hypertension, and a reduction in his estimated glomerular filtration rate (eGFR) with a novel small molecule therapeutic.

Method

This report charts the clinical course of one male patient over 11 months from presentation with C3GN, to the introduction of immunosuppression and of Iptacopan, and the assessment of his response to the foregoing. The patient consented to the publication of his case.

Results

A 25-year-old male with a background of autism spectrum disorder was referred to his regional nephrology service due to reduction in his eGFR and proteinuria. His creatinine was 158 µmol/L with an eGFR was 51.8 ml/ml/1.73 m2 (CKD-EPI equation); urinary protein creatinine ratio (uPCR) 500 mg/mmol; urinary albumin creatinine ratio (uACR) 400.2 mg/mmol. Serum album 32g/L. His C3 0.22 (normal range 0.82–1.85 g/L); C4 0.27 (normal 0.15–0.53 g/L). A renal biopsy was performed which demonstrated diffuse MPGN dominant C3 staining; cholesterol crystals; and moderate to severe chronic tubulointerstitial damage.

1 mg/kg oral prednisolone with mycophenolate mofetil (MMF) titrated up to a dose of 1g twice a day was initiated. As he was established on the therapy his eGFR rose back to 57.9 ml/min over approximately 8 weeks from a nadir of 33.8 ml/min. Following initial weaning of his prednisolone dose, his eGFR dropped back down to 29.7 ml/min with a creatinine of 250 µmol/L.

With involvement and clinical support from the National Renal Complement Therapeutics Centre an application was made to Novartis for the compassionate use of Iptacopan which was commenced early August 2023 (he would not have been eligible for recruitment into any current clinical trials). His latest eGFR is 47.5 ml/ml/1.73 m2 with a uACR of 9.1 mg/mmol and normal C3 and C5b-9 levels after 5 months of Iptacopan.

His prednisolone dose is 10 mg. MMF continues at 2g total dose.

Conclusion

Iptacopan has so far resulted in the normalisation of serum C3 levels, reduction of uACR and stabilisation of serum creatinine as we have reduced the prednisolone dose.
#2349 Lysyl oxidase-like 2 inhibitor ameliorates tubulointerstitial fibrosis and albuminuria in cyclosporine induced nephropathy
Authors: Park Hyeong Cheon , Kim Hyo Jeong , Choi Hoon Young , Lee Jung Eun
Published: May 2024

Background and Aims

Lysyl oxidase-like 2 (LOXL2), an amine oxidase, contributes to fibrotic scarring in the tissue by facilitating collagen cross-linking. Recent data demonstrated upregulation of lysyl oxidase and LOXL2 in the fibrotic kidneys after administration of cylosporine A (CsA). Thus, inhibition of LOXL2 may render therapeutic effects against CsA-induced nephropathy by ameliorating tubulointerstitial fibrosis.

Method

Low salt fed CD-1 mice were administered saline or CsA (15 mg/kg/day, intraperitoneally) for 8 weeks. At 4 weeks, CsA-treated animals were divided into 2 groups respectively and treated with: (1) vehicle, (2) LOXL2 inhibitor (10 mg/kg/day, gavage feeding) for another 4 weeks up to 8 weeks. We explored the reduction of tubulointerstitial fibrosis as well as albuminuria with administration of LOXL2 inhibitor in CsA nephropathy mouse model.

Results

CsA administration significantly increased the levels of serum creatinine (10.0 ± 1.2 vs. 28.4 ± 4.3, p = 0.02), tubular injury scores (0.1 ± 0.2 vs. 3.6 ± 1.3, p = 0.03), tubulointerstitial fibrosis (Sirius red positive area, 14 ± 6% vs. 204 ± 43%, p = 0.01), F4/80 positive inflammatory cell infiltration in mouse kidney (2 ± 1 vs. 21 ± 4, p = 0.001). These changes were associated with upregulated mRNA expression of LOXL2, TGF-β1, and monocyte chemoattractant protein-1 (MCP-1). Administration of LOXL2 inhibitor significantly suppressed the expression of alpha-SMA and collagen 1A, intrarenal F4/80 positive inflammatory cell infiltrations (21 ± 4 vs. 14 ± 2, p = 0.001) and improved tubular injury scores (3.6 ± 1.3 vs. 1.6 ± 1.1, p = 0.02). Moreover, LOXL2 inhibitor effectively reduced albuminuria excretion (46 ± 4 vs. 22 ± 6, p = 0.02).

Conclusion

Our results suggest that LOXL2 inhibitor treatment can attenuate CsA nephropathy progression and LOXL2 may be a potential therapeutic target in CsA nephropathy.
#2651 Microwave tissue digestion and flame atomic absorption spectroscopy for measuring tissue sodium content in CKD patients
Authors: van Duin Robert , Oppelaar Marjet , Heisel Annalena , Annor Ataa Akua Kromo , Wouda Rosa , van Zuilen Kirsten , Naessens Daphne , De Vos Judith , Bakker Erik , Hagner Matthias , Engberink Rik Olde , Vogt Liffert
Published: May 2024

Background and Aims

Skin and muscle sodium accumulation has been demonstrated in CKD patients and may contribute to progression of the disease. Various methods are available for measuring tissue sodium content. However, the accuracy and reproducibility of these methods remain unknown. Dry ashing is the most used digestion method, but is expensive, time consuming and has a risk of incomplete digestion. This study compared microwave digestion, dry ashing, and two electrolyte quantification methods for quantifying tissue sodium and potassium.

Method

We compared microwave digestion (Ethos LEAN Compact Microwave Digestion System, Milestone SRL) and dry ashing (Nabertherm S27) as sample preparation methods, and flame atomic absorption spectroscopy (FAAS, Model 425 Flame Photometer, Sherwood Scientific) and inductively coupled plasma optical emission spectrometry (ICP-OES, Varian 720-ES, Varian Inc.) as electrolyte quantification methods. Skin and muscle samples were obtained from rats and mice, and human skin samples were used. Tissues biopsies were cut in three pieces and digested separately. The methods were compared using interclass correlation coefficient (ICC) and Bland-Altman analysis. The third piece of tissue was microwave-digested by another operator to test inter-operator reproducibility by calculating the ICC and absolute overall mean difference.

Results

With microwave digestion and FAAS median (IQR) human skin concentration was 114.8 (99.2-157.0, n = 12) mmol/L, confirming tissue sodium storage. When including all tissues, FAAS and ICP-OES showed high agreement for sodium (ICC 0.98, bias –0.00008 mmol/g, n = 141 and potassium (ICC 0.98, bias –0.005 mmol/g, n = 141). Microwave digestion and ashing showed agreement for sodium (ICC 0.93, bias –0.002 mmol/g, n = 61) and potassium (ICC 0.93, bias –0.02 mmol/g, n = 61). The inter-operator agreement was good for sodium (ICC 0.95, absolute mean difference (SD) 0.044 mmol/g (0.073), n = 70) and potassium (ICC 0.96, absolute mean difference (SD) 0.031 mmol/g (0.032), n = 70).

Conclusion

Microwave digestion with FAAS is a reliable and consistent method for sodium and potassium trace analysis in animal and human tissues compared to ashing and ICP-OES, respectively. This method showed more quantification of cations than the most frequently reported method, representing an easier, and less time-consuming way to quantify tissue sodium in CKD research.
#1825 Treating hyperphosphatemia in CKD via targeting Npt2a in the kidney
Authors: Rieg Timo
Published: May 2024

Background and Aims

Targeting the renal sodium phosphate cotransporter 2a (Npt2a) offers a novel strategy for treating hyperphosphatemia in chronic kidney disease (CKD). In patients with and without reduced kidney function, hyperphosphatemia is associated with cardiovascular complications and currently treatment options are limited.

Method

To study the role of a novel Npt2a inhibitor (PF-06869206) we used in vitro (Opossum kidney [OK] cells) and in vivo approaches (C57Bl/6 and Npt2a knockout [Npt2a−/−] mice). As models of CKD, 5/6 nephrectomy (5/6 Nx) as well as novel Alport/Npt2a knockout mice (Alport/Npt2a−/−) were studied.

Results

OK cell experiments showed that the Npt2a inhibitor caused dose-dependent reductions of Na+-dependent Pi uptake (IC50: ∼1.4 μmol/L) and Michaelis-Menten kinetics identified a ∼2.4-fold higher Km for Pi in response to Npt2a inhibition with no significant change in apparent Vmax, indicating a competitive mode of action. In vivo, Npt2a inhibition enhanced urinary excretions of Pi, Ca2+, and Na+ dose-dependently, which is recapitulated in animal models with reduced kidney function (5/6 Nx and Alport mice). Reductions in plasma Pi occur within 30 minutes and reach a maximum (40-50%) after 2 hours, this coincided with ∼50% reductions in PTH levels. No effects on FGF23 were observed in this time frame. In C57Bl/6 mice qualitative immunohistochemistry after 24 hours showed reductions in Npt2a labelling in apical microvilli compared to vehicle treatment. Providing proof of concept, Npt2a−/− and Alport/Npt2a−/− mice confirmed specificity of the drug, effects on urinary and plasma Pi were absent. Further electrophysiological studies in acutely isolated connecting tubule/cortical collecting duct showed that open probability of the epithelial Na+ channel (ENaC) was reduced in response to Npt2a inhibition, suggesting that the natriuretic effect is mediated, at least in part, by inhibition of ENaC.

Conclusion

Npt2a inhibition offers a promising therapeutic approach for treating hyperphosphatemia and possibly offers the opportunity of reducing cardiovascular complications in CKD.
#1496 High levels of sclerostin promote bone resorption and changes and mineral metabolism
Authors: Muñoz-Castañeda Juan R , Ortiz Maria Encarnacion Rodriguez , Diaz-Tocados Juan Miguel , Romero Ana Torralbo , Lopez-Baltanas Rodrigo , Jurado Daniel , Garcia-Saez Raquel , Naves-Díaz Manuel , Alonso-Montes Cristina , Victoria Pendon-Ruiz de Mier M , Rodelo-Haad Cristian , Rodriguez Mariano
Published: May 2024

Background and Aims

The physiological function of sclerostin (SOST) remains unknown. It is known that SOST is produced in osteocytes and functions as an inhibitor of the Wnt/β-catenin pathway. Similarly, it is well-established that low levels of SOST lead to bone alterations affecting cortical bone, resulting in osteopetrosis and reduced calciuria. High levels of SOST are associated with osteoporosis.

In this study, we aimed to investigate the impact of three elevated doses of SOST on cortical, trabecular, and subchondral bone, as well as its relationship with other parameters of mineral metabolism.

Method

Bone histomorphometry, mCT, immunohistochemistry, and analysis of mineral metabolism parameters revealed that high doses of SOST over a 14-day period led to a reduction in trabecular bone volume due to a significant increase in bone resorption through the direct activation of osteoclastogenesis.

Results

Bone resorption, as measured by TRAP activity, was higher in trabecular, cortical, and subchondral bone. Similarly, high doses of SOST increased the number of hypertrophic chondrocytes, consequently expanding the growth plate area. Cortically, positive TRAP staining was observed, suggesting osteocytic osteolysis and trabecularization of cortical bone. The increased bone resorption resulted in a substantial rise in urinary excretion of phosphorus and calcium, accompanied by elevated levels of FGF23 and a significant decrease in PTH.

Conclusion

The findings suggest that elevated levels of SOST promote bone resorption through the activation of osteoclasts and the generation of osteocytic osteolysis. The increase in calcium and phosphorus levels led to changes in mineral metabolism, indicating a close relationship between SOST and other mineral metabolism parameters.
#2215 Early molecular and cellular features of aortic remodeling in a mild CKD-MBD model with low bone turnover
Authors: Bogdanova Evdokia , Beresneva Olga , Zubina Irina , Kutikhin Anton , Dobronravov Vladimir
Published: May 2024

Background and Aims

Vascular calcification associated with a maladaptive bone response is common in CKD and is a major cause of mortality (up to 60% depending on CKD stage). Alterations in several intracellular signaling pathways have been reported during the cellular phenotype transition and vascular calcification, however the initial phases of vascular remodeling in early CKD-MBD remain poorly understood. The aim of this study was to investigate the early molecular and cellular features of aortic remodeling prior to calcification in a model of mild CKD-MBD with low bone turnover.

Method

We induced CKD-MBD by 3/4 nephrectomy (Nx, n = 8) in adult male spontaneously hypertensive rats (SHR) with normal phosphate (Pi) intake (0.6%). Controls were sham-operated Wistar rats (n = 8) and SHR (n = 8). Chronic kidney injury and Pi exchange parameters, serum levels of calciprotein particles (CPPs), intact PTH, intact FGF23, dickkopf-1 and sclerostin, static bone histomorphometry, aortic morphology (H&E, Masson's trichrome, calcein, von Kossa stain), CD31, aSMA, nestin, Col1a1, PDGFR-beta, PiT1, LGR4 and intracellular signaling molecules—phospho-ERK1/2, active (non-phospho) beta-catenin, Hes1, Gli1 were analyzed by IHC with quantitative morphometry and IF after 4 months. Confocal microscopy was performed at the Centre for Collective Use of the Pavlov Institute of Physiology, Russian Academy of Sciences (Zeiss LSM 710).

Results

The study found that Nx rats with chronic kidney injury comparable to human CKD S2 exhibited lower bone turnover (Fig. 1). The Nx group had higher serum levels of Pi and CPPs vs. control group, but there were no differences in Pi-regulatory factors (Figs 1, 2b). Additionally, the Nx group showed aorta remodeling, which was characterized by an increase in intima thickness, cellularity, and collagen accumulation in the medial layer (Figs 1, 2a). The histological parameters of intimal remodeling and perivascular fibrosis were found to be directly correlated with serum levels of Pi and CPPs. In Nx, there was a decrease in medial αSMA expression accompanied by an increase in phospho-ERK1/2, PiT1, nestin, Gli1, beta-catenin, dickkopf-1, and an decrease in Hes1 immunomorphological staining (Figs 1, 2a, c). αSMA-negative cells demonstrated the expression of osteogenesis-related molecules, such as phospho-ERK1/2 (Fig. 2a, c), and occasionally, RunX2 (Fig. 2a). Phospho-ERK1/2 and PiT1 were found to co-localize in Nx (Fig. 2c). Intimal remodeling was observed, characterized by increased beta-catenin and nestin expression (Fig. 2c).

Conclusion

In mild CKD-MBD with low bone turnover, early intimal and medial aortic remodeling was associated with higher serum Pi and CPPs levels, and upregulation of PiT1, ERK1/2. In addition, other signals likely related to osteogenesis (RunX2, LGR4) and regulation of vascular progenitor cells (Nestin, Wnt, Notch, Hedgehog) may be implicated.
#1756 Development and internal validation of machine learning algorithms for mortality prediction model of people with DM and CKD
Authors: Zou Yutong , Liu Fang
Published: May 2024

Background and Aims

Diabetes Mellitus (DM) and Chronic Kidney Disease (CKD) are leading causes of morbidity and mortality, presenting challenges in patient management. The aim of this study is to develop a machine learning-based predictive model for mortality in DM and CKD patients, improving early intervention and treatment personalization.

Method

3,637 participants with DM and CKD from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 were included. All-cause mortality was ascertained by linkage to National Death Index records through 31 December 2019 in NHANES. The dataset included clinical profiles, demographic details, and laboratory results of patients with DM and CKD. We performed 100 random groupings, dividing the data into a 75% training set and a 25% validation set each time. We then visualized the results of 100 AUC measurements using a boxplot. The objective was to forecast patient survival over 1, 3, 5, and 10-year horizons using a variety of machine learning algorithms. The algorithms tested included Logistic Regression (LR), Decision Tree (DT), Random Forest (RF), K-Nearest Neighbors (KNN), Gaussian Naive Bayes (GNB), Multinomial Naive Bayes (MNB), Bayesian Network Classifier (BNC), AdaBoost (Ada), Gradient Boosting (Gradient), and Extreme Gradient Boosting (XG). The performance of each algorithm was evaluated based on the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC), with the results visualized in boxplot format.

Results

Upon result shown as the boxplots, it becomes evident that the Random Forest (RF) algorithm consistently exhibits one of the highest AUCs on average across all prediction intervals, suggesting a strong and stable predictive capacity. In the 1-year survival prediction, the RF algorithm demonstrates a highest AUC, implying consistent performance. The 3 and 5-year predictions reveal a slight dip in AUC for most models, including RF, but it still remains one of the top-performing algorithms with fewer outliers than XG and Gradient Boosting. The mean AUC of RF is particularly noteworthy at the 10-year mark, where most algorithms struggle with prediction accuracy, as indicated by lower median AUCs and greater variability. Notably, the RF algorithm identified six major factors for 1-year survival prediction: systolic blood pressure, uric acid, blood urea nitrogen, lactate dehydrogenase, lymphocyte count and total cholesterol, as well as three major factors for 10-year survival prediction: age, lymphocyte and gamma-glutamyl transferase.

Conclusion

Overall, the study indicates that while machine learning can be a powerful tool for survival prediction in patients with DM and CKD, the choice of algorithm is crucial, with RF standing out for its consistent and reliable performance.
#963 Discrepancy between actual and estimated urine creatinine excretion predicts mortality in chronic kidney disease: from the KNOW-CKD study
Authors: Kim Yujung , Lee Ju Young , Huh Daseul , Kim Keonhwa , Yang Jihyun , Lee Kyu-Beck , Kim Hyang , Oh Kook-Hwan , Hyun Young Youl
Published: May 2024

Background and Aims

Urine creatinine excretion is a surrogate marker of muscle mass and low urine creatinine excretion is a predictor of poor clinical outcome. There are several methods to estimate urine creatinine excretion. However, little is known about the clinical implication of discrepancy between actual and estimated urine creatinine excretion in chronic kidney disease (CKD). The aim of this study is to investigate the association between actual and estimated urine creatinine excretion discrepancy and mortality in CKD.

Method

This study analysed 1805 participants from the KNOW-CKD cohort. They underwent 24-hr urine collection and measured urine creatinine excretion at baseline. Their estimated urine creatinine excretion was calculated by Joachim's method. Discrepancy between actual and estimated urine creatinine excretion (dUCr) was defined as actual urine creatinine excretion minus estimated urine creatinine excretion. Patients were divided into 3 groups according to their tertile of dUCr. The study endpoint was all-cause death.

Results

During a follow-up of 13 062 person-years (median 8.0 years), 151 patients (8.4%) died, with a corresponding death rate of 11.6 (95% CI 9.9-13.6) per 1000 patients-years. 86 (14.4%), 41 (6.8%) and 24 (3.4%) patients from each 1st to 3rd tertile of dUCr died (P < 0.001). In multivariate Cox proportional hazard analysis, there was a graded association of dUCr with all-cause mortality. The adjusted hazard ratios (95% CI) of 2nd and 3rd tertile were 0.58 (0.39-0.86) and 0.36 (0.22-0.58) compared with the 1st tertile.

Conclusion

Higher discrepancy between actual and estimated urine creatinine excretion is associated with lower risk of mortality in predialysis CKD patients. This association was independent of various conventional and CKD-related risk factors.