bluuebunny/crossref_metadata_2025 huggingface dataset:
#157 UNI-494 Phase I tolerability and pharmacokinetics: trial in progress
Authors: Reddy Guru , Mourya Sanjay , Hasal Steve , Gupta Shalabh
Published: May 2024

Background and Aims

Acute kidney injury (AKI) is a clinical syndrome defined by the sudden loss of kidney function, resulting in an inability to maintain electrolyte, acid-base and water balance. Currently, there are no effective treatments for AKI approved by the US Food and Drug Administration or the European Medicines Agency (EMA); management of the condition is primarily supportive. The most common cause of AKI was thought to be ischemia. However, more recently the focus has shifted from clinical causes to the underlying cellular processes inherent in these situations, in particular the dysfunction of mitochondria in AKI. UNI-494 is a novel nicotinamide ester derivative and selective mitochondrial ATP-sensitive potassium channel activator that improves mitochondrial function and may be beneficial for several disease states, including AKI. This study aims to evaluate the safety, tolerability, and pharmacokinetics of UNI-494.

Method

This is a single-center, double-blind, placebo-controlled, randomized single ascending dose (SAD) (Part 1) and multiple ascending dose (MAD) (Part 2) study in healthy male subjects and female subjects of non-childbearing potential. Part 1 will enroll up to approximately 40 subjects in 5 cohorts of 8 subjects each (randomized to a ratio of 6 active and 2 placebo per cohort). There will be an interim decision meeting after each cohort/period, to review the safety, tolerability, and PK data up to 48 h post-dose in order to decide the dose level for the subsequent cohort. Part 2 will enroll approximately 20 subjects in 2 cohorts of 10 subjects each, randomized to a ratio of 8 active treatment to 2 placebo who will be dosed for 5 days. The dose level for the Part 2 Cohort 1 will be selected based on the safety, tolerability and PK data from Part 1.

Results

We intend to present results elucidating safety, tolerability, and pharmacokinetics of UNI-494 in healthy subjects.

Conclusion

The safety, tolerability, and pharmacokinetics of UNI-494 in healthy subjects will be evaluated in this study.
#3067 Comparison of the removal of bile acids between hemoperfusion and new extracorporeal albumin detoxification device (Albunique) in critical care
Authors: Stange Jan , Koball Sebastian , Hinz Michael
Published: May 2024

Background and Aims

In subjects with multiorgan failure and in need for CRRT, new onset of jaundice is associated with a significant mortality. Recent research suggests that elevated serum bile acids contribute to severe immune dysfunction, hepatocellular apoptosis, vasodilation, tubular necrosis and thereby are important drivers of multi-organ failure in new onset of liver dysfunction. Extracorporeal Albumin Detoxification and Dialysis (ECAD) and Hemoperfusion have been used to sustain or recover organ function. Recently, Cytosorb, a hemoperfusion device developed for the removal of proinflammatory molecules in cytokine storm showed a reduction of bilirubin and bile acids in vitro. The aim of this study was to compare the reduction of small albumin bound bile acids with the current standard (ECAD), which was developed not to affect the plasma proteome but effectively remove toxins.

Method

After obtaining consent, plasma samples were obtained from the extracorporeal circuit of subjects on CRRT due to acute on chronic liver failure (ACLF) and bile acids above 50 µmol/l before and after a day of treatment from the venous and arterial ports and the total removed bile acids were calculated by Area under the curve calculation. The measurements were done during Cytosorb treatments versus during ECAD using a new Albunique Device based on a new recycling technology.

Results

Despite a high initial reduction rate the capacity of Cytosorb decreased and the total amount of extracorporeal removal was 1720+1189 µmol whereas Albunique removed 7111+2556 µmol, more than 4 times as much and was not saturated after 24 hours.

Conclusion

Although Cytosorb may prove a role in ACLF with hyperinflammation in the future, hemoperfusion appears to loose efficacy for toxic, albumin bound small molecules and therapies based on diffusion appear to be more cost effective and less additional effects with an unclear impact on the course of ACLF.
#2940 Expression and modulation of SGLT2 in human podocytes. Not all in tubule
Authors: Riera Marta , Barrios-Barrera Clara , Galdon Eric , Martyn Claudia , de Bruin Florance , Mosquera Eva Marquez , Crespo Marta
Published: May 2024

Background and Aims

Inhibitors of the sodium-glucose cotransporter type 2 (iSGLT2) modify important non-glycemic pathways that lead to the protection of target organs. Its renoprotective pleiotropic effects in CKD, associated or not with diabetes, justifies further studies to elucidate the mechanisms of action (MoA) of these drugs. Although the co-transporter SGLT2 is mostly expressed in the proximal tubule, its location and function in other cells, that can be potential therapeutic targets for inhibitor drugs, has not been well studied. We explored the presence of SGLT2 in human podocyte cells and whether it is modified in different situations of cellular stress.

Method

Differentiated immortalized human podocytes were cultured under different experimental conditions for 24 or 48 h: Normoxia (Control); Normoxia + High concentration of glucose (HG); Hypoxia(1%)+2 h Reoxygenation(H) and the combination H + HG. Cells were also incubated with 0.1 uM Dihydrotestosterone (DHT). SGLT2 gene expression was determined by quantitative PCR and SGLT2 protein was detected by Western Blot (WB) and immunofluorescence (IF).

Results

Sglt2 gene expression was detected in human podocytes in culture, with an increase of expression after 24 h of exposure to HG. Protein expression by WB showed a trend to increase after 48h of exposure to HG and hypoxia, which was significant with co-incubation with DHT. HG plus DHT also increased the protein expression of SGLT2 under normoxic conditions. The IF measured by intensity of area did not show an increase in the protein expression of the transporter under HG incubation. However, protein expression increased under all hypoxic conditions: Control 50.05 ± 3, Hypoxia 140 ± 16.3 (p < 0.05 vs control) and HG + Hypoxia 253 ± 21.29 (p < 0.001 vs control).

Conclusion

Our data suggest that podocyte may be one of the therapeutic targets on which the iSGLT2 is acting. The experimental conditions described did not show differences in the expression of the transporter before the single stimulus of glucose, but they did under hypoxia and the combination Hypoxia-high glucose. In addition, co-incubation with testosterone seems to enhance the expression. Studying the MoA of iSGLT2 will open better comprehension of the kidney pathophysiology, particularly in the podocytopathies, regardless of diabetes.
#1792 Phenotypic variability in PAX2-related nephropathies: a monocentric study
Authors: Ciccone Martina , Zacchia Miriam , Perna Alessandra
Published: May 2024

Background and Aims

Pax2 mutations are known to cause kidney disease; both syndromic conditions, as kidney coloboma syndrome, and kidney specific disorders, as FSGS, have been described. Due to the rarity of Pax2-related nephropathies, data on genotype-phenotype correlation are limited.

Method

This observational and mono-centric study describes three families (A, G, P) referring to our Nephrology center, carrying Pax2 mutations. A total of 12 subjects were investigated: 2 individuals in family A, 4 in family G and 6 in the family P. Genetic analysis was carried out by NGS; detected mutations were confirmed by Sanger sequencing.

Results

Family A

It includes 2 affected subjects, a 40 year-old woman and her mother (Fig. 1A). The mother had chorioretinic coloboma and was under hemodialytic therapy since the age of 50. The daughter had chorioretinic coloboma and bilateral renal hypodysplasia, proteinuria and a progressive decline of the eGFR since 34 years; renal biopsy excluded the presence of GN (Table 1).

Both have the heterozygote c.890delC variant (p.Thr297fs) in Pax2.

Family G

It includes 4 affected individuals belonging to 3 different generations (Fig. 1B). The disorder was discovered after the evidence of advanced renal failure in a pregnant 27 y-old lady. The study of her family revealed the presence of kidney disease in her sister (transplanted on young age) and her father; one of her children has the mutation (Table 1).

The PAX2 c.194T>C(p.Val65Ala HET) mutation segregates with the phenotype in the family.

Family P

It includes 6 affected individuals of 3 different generations (Fig. 1C); the index-case presented with heavy proteinuria: kidney biopsy revealed a C3 nephropathy. His son was transplanted when 18 years old for bilateral renal hypoplasia. His mother died after some years of dialysis (Table 1).

PAX2 mutation on exon3: c.361G>A(p.Glu121Lys HET).

Conclusion

This case series demonstrates the phenotypic variability of patients with Pax2 mutations and suggests the utility of new generation genetics (NGS) to get the diagnosis in atypical conditions. The implementation of international registers and basic studies will be indispensable to define the mechanisms involved in the development of the disease and to address the reasons of clinical variability.
#2675 Role of ANXA4 as a modifier in VHL-dependent ccRRC
Authors: Wess Maximilian , Feilen Tobias , Kössinger Anna , Rogg Manuel , Gräwe Katja , Sammarco Alena , Schilling Oliver , Schell Christoph
Published: May 2024

Background and Aims

The von Hippel-Lindau (VHL) syndrome is a rare genetic disease caused by inactivating mutations of the VHL tumor suppressor gene. VHL syndrome patients frequently develop clear cell renal cell carcinomas (ccRCCs). pVHL acts as the substrate recognition subunit of an E3 ligase involved in the ubiquitinylation of HIFs. Consequently, aberrant HIF-signalling results in a pseudo-hypoxic state characterized by pronounced vascularization in respective tumours. Previous studies have indicated VHL-dependent alterations of the extracellular matrix (ECM). However, to date comprehensive description and understanding of VHL-dependent matrisome signatures is missing.

Method

Proteomics were used to reveal VHL-dependent protein expression in ccRCC cell lines (A498, 786-O) and CRISPR/Cas9-modified human proximal tubular epithelial cells (hRPTECs) as well as syndromic and sporadic ccRCC patient cohorts. For candidate proteins analysis of proteomic and histological datasets was performed. Further functional analysis was conducted using overexpression, CRISPR/Cas9-mediated knockout (KO) and shRNA-mediated knockdown (KD) approaches (assessment of proliferation, migration, invasion, ECM, cellular membrane-integrity, protein localisation studies and transcriptomics).

Results

Filtering of proteomic datasets (ccRCC tumors and cell lines) for matrisomal proteins highlighted an enrichment of the ANXA-protein family. Interestingly, functional genetic titration of ANXA4 employing knockdown, overexpression or complete ablation using CRISPR/Cas9 genome editing did not translate into major changes of cellular proliferation or migration in renal cancer or tubular cells. Detailed localization studies revealed that ANXA4 is detectable in distinct cellular compartments, namely the cell membrane and nucleus/nuclear lamina. Various cellular stressors (including cellular densities) initiated shuttling of ANXA4 between these different compartments. Remarkably, similar distribution patterns were detectable in situ in tumours tissue of ccRCC patients. Further transcriptomic analysis of ANXA4 knockout cells demonstrated a major impact on ECM- and cell-adhesion-associated gene sets, reflected by impaired invasive migratory capacity in conditions of reduced ANXA4-expression.

Conclusion

Loss of VHL distinctly alters the ECM composition in ccRCC. We have identified the ECM-associated ANXA4 as a prominently upregulated protein, although canonical hallmarks of cancer were not directly influenced. Based on RNA-sequencing studies and subcellular localization patterns we assume that ANXA4 (co-)regulates matrisome-related transcriptomic signatures in response to various external stressors. These observations highlight the intricate regulation of ECM-associated signalling pathways in the context of VHL-dependent renal cell carcinoma.
#1616 Pregnancy and fetal outcome in women with Alport syndrome
Authors: Aksenova Marina , Konkova Natalya , Lepaeva Tatjana , Nikishina Tatjana , Piruzeeva Oxana , Zaikova Natalya , Dlin Vladimir
Published: May 2024

Background and Aims

Pregnancy in patients with CKD is associated with maternal and fetal risks. The data about pregnancy outcome in Alport syndrome (AS) is limited. The aim was to evaluate the fetal and maternal pregnancy outcome in women with AS.

Method

One center retrospective study included 88 women with AS (86 with COL4A5, 2 with COL4A4 variants). Data at conception (age, arterial hypertension (HP), proteinuria (Pr), GFR), course of pregnancy (HP, Pr, GFR, pre-eclampsia (PE)), delivery (preterm (PD): < 37 weeks; early preterm (EPD): < 34 weeks), fetus characteristics (intrauterine fetal growth restriction (IUGR): L < 2 z-score for gestational age; small for gestational age (SGA): m < 2 z-score (SGA)) were obtained from medical charts and a cross-sectional survey.

Results

Information of 88 women, 133 term pregnancies (2 in 25 pts, 3 in 2 pts) were analyzed. Only 16 (q = 0,18) from 85 (q = 0,96) women with hematuria had diagnosis of AS before pregnancy; one of them had HP, 13 pts had Pr. HP, Pr, decreased GFR were revealed in 11 (q = 0,13), 27 (q = 0,2) and 9 (q = 0,06) pregnant, respectively. PE occurred in 8 cases (q = 0,06); PD was seen in 24 (q = 0,18) and EPD in 1 (q = 0,01) cases; cesarean section was performed in 8 cases (q = 0,07). IUGR and SGA were recorded in 8 (q = 0,06) and 11 (q = 0,08) neonates, respectively; 6 babies (q = 0,05) required a neonatal intensive care unit stay. Pr was the risk factor for PE (CI 14,86 ± 0,85, p < 0,001), PD (CI 6,267 ± 0,49; p < 0,001), IUGR (CI 14,86 ± 0,85, p < 0,001), SGA (CI 8,93 ± 0,67, p < 0,001).

Conclusion

The risk of pre-eclampsia and slowing of fetal growth in women with AS and normal kidney function appears comparable to that in the general population. But AS should be considered as a potential risk factor for preterm delivery. Proteinuria is associated with unfavorable pregnancy and fetal outcome in AS.
#191 An unusual cause of hypocalcemia in a young patient
Authors: Bae Eun Hui , Lim Sang Yup , Choi Hong Sang , MA Seong Kwon , Kim Soo Wan
Published: May 2024

Background and Aims

A 33-year-old man visited the Nephrology Department outpatient clinic with abnormal laboratory findings: his serum calcium level was 5.9 mg/dL in a recent health examination. He denied any underlying disease and was on no medications. He complained of a tingling sensation in his hands and of eyelid twitching. On physical examination, he showed Chvostek's sign. His laboratory findings including serum calcium level are shown in Table 1. He did not have any morphological abnormalities, such as a round face, brachydactyly, or dental anomalies.

Method

Since he showed hypocalcemia, normal 25-hydroxyvitamin D, and elevated parathyroid hormone (PTH) levels, the presence of PTH resistance was presumed. Under strong suspicion of pseudohypoparathyroidism (PHP) in this patient, DNA sequence analysis and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) of GNAS and STX16, genetic regions that are often affected by mutations or imprinting changes in PHP, was performed. No pathogenic mutations in GNAS and STX16 were detected by sequencing.

Results

Results of MS-MLPA of the GNAS locus demonstrated abnormal methylation patterns in the patient after HhaI restriction enzyme treatment. The methylation ratio showed a gain of methylation in the NESP55 region and loss of methylation in the AS, XL, and A/B differentially methylated regions (DMRs) in the patient as compared to a healthy control (Fig. 1). The patient was diagnosed with PHP type 1B (PHP1B) due to the methylation abnormalities in multiple DMRs. His parents both showed normal serum calcium levels; thus, no further genetic testing was conducted. He is on outpatient follow-up with adequate calcium replacement and no specific symptoms.

Conclusion

PHP is a rare disorder of unknown prevalence. It is characterized by hypocalcemia, hyperphosphatemia, and increased PTH levels. PHP1B is a subtype of PHP characterized by isolated renal PTH resistance, usually without physical abnormalities such as Albright hereditary osteodystrophy or other endocrine abnormalities. PHP1B can be sporadic or familial. The genetic characteristics of most sporadic PHP1B remains unclear, but GNAS imprinting abnormalities and hypomethylation at the A/B DMRs have been reported. Symptoms of PHP1B usually begin in childhood due to low calcium levels and may include numbness, seizures, tetany, cataracts, and dental problems. However, as in our case, specific symptoms may not occur until adulthood. Therefore, when evaluating the cause of hypocalcemia, it is necessary to differentiate PHP1B, even in adults, and particularly in cases with hyperphosphatemia and high PTH levels.
#1891 Evaluating the safety and effectiveness of Tolvaptan for management of adult Korean ADPKD patients (ESSENTIAL study): final report
Authors: Kim Yong Chul , Park Hayne Cho , Kim Hyunsuk , Kim Yaerim , Kim Yong-Soo , Jung Yeonsoon , Yoo Tae-Hyun , Na Ki Young , Kim Yeong Hoon , Kim Sung Gyun , Ahn Curie , Oh Yun Kyu
Published: May 2024

Background and Aims

Tolvaptan, a selective vasopressin V2 receptor antagonist, was first approved by Korean FDA in 2015 as a treatment option in autosomal dominant polycystic kidney disease (ADPKD). In order to prescribe Tolvaptan safely and effectively, we designed the phase 4 clinical trial among Korean ADPKD patients with chronic kidney disease (CKD) stage 1-3.

Method

Korean patients aged 19 to 50 with rapidly progressing ADPKD were enrolled in the study. The dose titration was performed every one week for a total of 4 weeks. The patient was prescribed Tolvaptan with the maximum tolerable dose up to 120 mg per day. A total duration of Tolvaptan prescription was 24 months. The primary outcome was the incidence of treatment emergent adverse events (TEAE) including drug-induced liver injury (DILI). The secondary outcomes were the annual mean percent change of total kidney volume (TKV) and the annual mean change of estimated glomerular filtration rate (eGFR).

Results

A total of 117 patients were included in the analysis. Mean age was 38.7 ± 8.4 years old and male were predominant (58.1%). The average TKV was 2066 ± 1094 mL and mean eGFR was 79.7 ± 27.7 mL/min/1.73 m2. Mean duration of Tolvaptan exposure was 1.7 ± 0.6 years and the average daily dose of Tolvaptan was 94.4 ± 24.1 mg/day. A total of 489 treatment-emergent adverse events (TEAE) occurred in 106 (90.6%) patients during study duration. The drug-induced liver injury and aquaresis-related adverse events were two most common adverse events. A total of 17 DILI cases (14.5%) occurred during the study period and mostly within 18-month period. However, liver enzymes were normalized after drug discontinuation The patients with previous history of liver disease as well as those who were prescribed higher dose of Tolvaptan demonstrated higher frequency of DILI. Mean growth rate of TKV after Tolvaptan treatment was 4.5 ± 0.5% and mean eGFR decline rate was -3.0 ± 0.39 mL/min/1.73 m2/year. Comparing with the predicted value from calculation, Tolvaptan attenuated both TKV growth and eGFR decline rate.

Conclusion

This study is the first post-marketing survey assessing the safety and efficacy of Tolvaptan in Korean ADPKD patients. The incidence of DILI was higher than the previous studies and especially in those with liver disease and higher Tolvaptan prescription dose. While Tolvaptan can effectively reduce TKV and attenuate eGFR decline, the clinicians should be aware of higher frequency of DILI among Korean population.
#1854 Prevalence of Fabry disease in chronic hemodialysis patients: a multicenter screening approach
Authors: Cafi Erind , Rroji (Molla) Merita , Spahia (Zeneli) Nereida
Published: May 2024

Background and Aims

Fabry disease (FD), an X-linked lysosomal storage disorder caused by alpha-galactosidase A (α-Gal A) deficiency, leads to significant morbidity and early mortality due to progressive organ failure. Given the availability of enzyme replacement therapy, early identification of FD is crucial for improving patient outcomes.

Method

A multicenter screening was conducted among chronic hemodialysis patients across six centers. We utilized a two-tiered diagnostic approach. Initially, α-Gal A activity was measured from dried blood spots on filter paper. Subsequently, those with reduced enzyme levels underwent GLA gene mutation analysis.

Results

Out of 428 patients, 255 (102 females and 153 males) were selected for testing, leading to the analysis of 239 patients. In the male cohort, the average α-Gal A activity was 21.84 ± 11.9 µmol/L/h, with 34 males below the cut-off value (<15.3 µmol/L/h) but with normal lyso-Gb3 levels and no mutations. Among females, α-Gal A levels were typically within the normal range. Notably, one female was found to have a heterozygous variant of uncertain significance in the GLA gene [p.(Asp313Tyr)] in exon 6, with normal α-Gal A and lyso-Gb3 levels. Screening of other family members was not possible, as they resided abroad although we recommended it.

Conclusion

Screening for AFD in high-risk groups, such as hemodialysis patients, is challenging yet essential. Implementing α-Gal A measurement as a standard procedure for newly registered hemodialysis patients could prospectively identify potential Fabry carriers, offering more excellent utility than our cross-sectional study. While identifying index patients at a late disease stage may not benefit the patients themselves, it is crucial for early detection of family members, potentially altering their disease course. This proactive approach, supported by national and international guidelines, could significantly impact the management and outcomes of AFD.
#1601 Cranial vs. caudal direction technique in percutaneous kidney biopsy: an Italian single-center experience
Authors: Gangemi Concetta , Pessolano Giuseppina , Rossi Mattia , Gambaro Giovanni
Published: May 2024

Background and Aims

The percutaneous kidney biopsy (PKB) is the gold standard for diagnosing kidney pathology. For an appropriate diagnosis, an adequate sample size must be obtained. For most light microscopy assessments, 10 glomeruli are needed to assess the severity and the distribution of lesions adequately. However, the PKB procedure has potential risks such as bleeding, hematuria, hematoma, and the formation of an arterio-venous fistula. The PKB is nowadays a well-known technique with a low number of complications. It consists of an automated biopsy needle directed to the cortex of the inferior pole of the kidney. In clinical practices, the needle direction may have a caudal direction (CD) or a cranial direction (CN). Few small studies have compared the two techniques.

Method

We report the results of our experience of 107 percutaneous ultrasound (US)-guided native kidney biopsies with the CN technique performed from January 2021 to December 2023. Two core samples were obtained with a 14-G automated needle. After the biopsy, the patient bed-rested in a supine position for 24 hours. Vital signs and blood count controls were monitored after 2 and 4 hours. The post-biopsy kidney ultrasonogram US was done after 48 hours to detect complications.

Results

We observed 7,5% of complications: one retroperitoneal bleed required blood transfusion and embolization, and 7 perinephric hematoma size ≥ 1 cm. We compared the results of the CN-PKB with a historical cohort of 100 CD-PKB performed from January 2018 to December 2020. These last ones have shown 4% of complications, which resulted in only perinephric hematoma size ≥ 1 cm. The Chi-Square test was performed to compare statistical differences between the groups for categorical variables, showing no statistical significance (p-value >0.05). Samples were always adequate for pathological diagnosis.

Conclusion

Our results demonstrate that the two PKB techniques performed with the CN and the CD techniques give similar results in terms of adequacy and safety.
#1760 Four cases of ADTKD: AFM analysis of urine sediment
Authors: Iulianiello Pietro , Viggiano Davide , Nappi Felice , Bellizzi Vincenzo , La Verde Antonietta
Published: May 2024

Background and Aims

Autosomal Dominant Tubulointerstitial kidney disease (ADTKD) is a rare disease (16 per million), associated with CV events, hypertension, and gout. ADTKD is characterized by interstitial fibrosis, tubular atrophy, microcysts, and progressive CKD. We describe a case of a family with clinical characteristics of ADTKD and provide for the first time a characterization of their urinary sediment. Given the tendency of a specific type of ADTKD caused by UMOD mutation to form tubular crystals, we have also tested the ability of the urine from ADTKD patients to precipitate and form crystals in vitro.

Method

We examined clinical features and urinary sediment of a family with ADTKD: a 51 years old woman with CKD (eGFR 30 mL/min/1.73 m2, CDK-EPI 2021) and her three sons, a 20 years old male, two daughters of 26 and 24 years old, all with hyperuricemia. Genetic analysis is not yet available. The test of urine precipitation consisted of the analysis of crystals after air-drying a thin layer of urine after enrichment of the organic quota by triple centrifugation for 10 minutes at 1000 rpm. Urinary sediments were also studied by Atomic Force Microscopy (ICSPI nGauge AFM) to achieve a resolution of 20 nm of crystals.

Results

Clinical data for the four patients are reported in the table. None of the patients showed proteinuria.

The urine sediment of all patients showed rare WBC (in greater amounts only in patient 1), rare amorphous granular casts, and rare tubular cells. Three patients showed formations of variably sized crystals in vitro.

The precipitation test did not show crystals in patient 1, whereas patients 2-3 showed several rosette-type crystals often with a wagon-wheel concentric contour which resembled leucine crystals or CaCO3. Adding formalin to the samples resulted in a more clear organization of crystals in wagon-wheel structures. AFM imaging of the crystals showed rod-like structures branching with an angle of 35°.

Conclusion

ADTKD remains a poorly understood genetic condition with no specific treatment options. Our data suggest that patients with this condition may have an enhanced tendency to form crystals in vitro. Speculatively, this might induce tubular injury in vivo. Data from UMOD-ko animal models showed intrarenal crystals (not better specified). Genetic alterations of branched aminoacids metabolism (such as leucine in Maple syrup disease) can also cause tubular diseases, although the systemic manifestations are very different from our patients. Genetic analysis of our family will give further information on the proteins involved in these crystal structures.
#2043 Telitacicept in patients with IgA nephropathy
Authors: Lu Wanhong , Li Huixian
Published: May 2024

Background and Aims

IgA nephropathy (IgAN) is typified by the renal deposition of IgA immune complexes. Advancements in understanding the pathogenesis of this disease have paved the way for innovative therapeutic approaches. Telitacicept is a fusion protein composed of transmembrane activator and calcium-modulating cyclophilin ligand interactor and fragment crystallizable portion of immunoglobulin G (IgG), which neutralizes the B lymphocyte stimulator and a proliferation-inducing ligand. We presented our single-center experience of treating IgAN with Telitacicept.

Method

Six patients with IgAN who received Telitacicept at the First affiliated hospital of Xi'an Jiaotong university between January 2023 and July 2023 were included in this retrospective study. All the patients had proteinuria ≥ 1.0 g/d despite optimal supportive therapy and received subcutaneous telitacicept 160 mg weekly. Clinical and laboratory parameters were evaluated before and after telitacicept treatment.

Results

Of all patients, there were 4 men and mean age was 35.2 ± 7.9 years. Table 1 shows baseline demographic characteristics of these patients. Before telitacicept administration, the mean serum creatinine was 133.2 ± 40.6 umol/L, median protein excretion was 2.23 (IQR, 2.05–3.54) g/d, and MAP was 97.9 ± 17.5 mmHg. After a median follow-up of 151 ± 91 days after telitacicept therapy, the mean proteinuria reduction percentage was 51.1% from baseline. The eGFR remained stable over time. The detailed laboratory parameters were shown in Table 2. No adverse events were observed during the follow-up.

Conclusion

Telitacicept treatment led to a clinically meaningful reduction in proteinuria in patients with IgAN. Larger prospective studies are needed to confirm these findings.
#2659 Clinical characteristics of patients with minimal change disease (MCD) that evolved to focal sclerosing glomerulosclerosis (FSGS)
Authors: Arimuthu Durga Arinandini , Then Ru Fah , Fuah Kar Wah , Lim Christopher Thiam Seong , Ibrahim Fairol Huda , Goh Bak Leong
Published: May 2024

Background and Aims

Minimal change disease (MCD) and focal sclerosing glomerulosclerosis (FSGS) are both podocytopathies and are possibly diseases that lie on a similar spectrum with FSGS being the severe form. We aim to describe the clinical and laboratory parameters along with treatment and outcomes of MCD that were found to be FSGS on repeated biopsy.

Method

All patients who had undergone renal biopsy in Hospital Serdang and had documented diagnosis of FSGS from January 2007 until December 2022 were identified. Data was collected and analysed using SPSS version 17. Results were expressed in mean ± standard deviation (SD) unless stated otherwise.

Results

Total minimal change disease were 70 patients. A total of 14 were identified as FSGS on repeated biopsy. At time of biopsy, all patients presented as relapse in nephrotic syndrome (NS). Mean age of diagnosis was 18 years for MCD while mean age of FSGS diagnosis was 23.8 years. 11 were males and two patients had positive family history of kidney disease while 10 had some form of haematuria. All patients were on steroids with 4 of them developing steroid resistance. 11 patients were on second line agents either due to steroid resistance or toxicity. Majority of patients were on azathioprine followed by cyclosporine and mycophenolate mofetil. Mean follow up was 5.7 years. Those with MCD had higher platelet (mean 462) and total cholesterol (mean 14.2) values at diagnosis of FSGS. Mean relapse after diagnosis of FSGS was 2.2 episodes. (Patients remain in remission for 31 months before relapsing) As of December 2022, 9(65%) patients had normal kidney function, 2 end stage renal disease on dialysis while 3 CKD V had passed away due to acute coronary syndrome.

Conclusion

Minimal change disease is part of a spectrum podocytopathies along with FSGS. Those with frequent relapses in MCD, older children with nephrotic syndrome and those with presence of haematuria may be warranted for a repeated biopsy to rule out evolution to FSGS.
#401 Cardiovascular risk evaluation in lupus nephritis and ANCA-associated vasculitis
Authors: Lee Tung Lin , Chew Wen Xuan , Loo Felicia , Lim Lydia , Tan Hui Zhuan , Mok Irene , Choo Jason , Lim Cynthia
Published: May 2024

Background and Aims

Individuals with lupus nephritis (LN) and renal ANCA-associated vasculitis (AAV) have amplified cardiovascular risks. Early recognition and intervention for metabolic disease may mitigate cardiovascular risk. We aimed to evaluate the prevalence of cardiovascular metabolic risk evaluation among adults with kidney disease due to LN and AAV treated with immunosuppressants.

Method

Retrospective cohort study of 219 patients with kidney LN (n = 175) and AAV (n = 44) diagnosed between November 2015 and December 2022. The outcomes were the prevalence of cardiovascular metabolic risk evaluation (HbA1c, fasting glucose and lipid) during the first two years of treatment.

Results

The median age was 48.6 (33.3, 60.9) years. Table 1 showed that the AAV group had lower eGFR and higher prevalence of diabetes mellitus, hypertension, and hyperlipidemia.

Glycemic evaluation was more frequent during the first year than the second year (81.0% versus 61.2%, p < 0.001) for the cohort, as well as the LN (79.2% versus 61.7%, p < 0.001) and AAV groups (88.4% versus 58.8%, p = 0.003). Lipid evaluation was more frequent during the first year than the second year for the cohort (60.5% versus 50.3%, p = 0.04) and for AAV (81.4% versus 47.1%, p = 0004), but not the LN group (55.1% versus 51.0%, p = 0.52).

Conclusion

Cardiovascular metabolic risk evaluation during lupus nephritis (LN) and ANCA-associated vasculitis (AAV) long-term follow-up should be optimized.
#823 Effect of dapsone on the treatment of refractory IgA vasculitis
Authors: Lee Keum Hwa , Hwang Eun Jae , Park Se Jin , Kim Ji Hong , Shin Jae Il
Published: May 2024

Background and Aims

IgA vasculitis (IgAV), previously known as Henoch-Schönlein purpura, is a systemic IgA-mediated vasculitis of the small vessels commonly seen in children. The natural history of IgAV is generally self-limiting. However, one-third of patients experience symptom recurrence and a refractory course. We performed this study to examine the use of dapsone (4,4'-sulfonyldianiline or diaminodiphenyl sulfone) in refractory IgAV cases.

Method

A literature search of PubMed databases retrieved 16 articles published until May 31, 2023. A total of 38 patients with IgAV were recruited.

Results

A palpable purpura persisted in nearly all the patients with refractory course, followed by joint pain (25 of 38 patients; 69.2%). Hematuria and proteinuria were noted in 11 (28.9%) and 7 (18.4%) of the patients, respectively. Treatment response within 1-2 days was obtained in 12 of 38 patients (31.6%), compared to within ≥3 days in 22 patients (57.9%). Relapse after treatment discontinuation was reported in 21 patients (55.3%) but not in 11 patients (28.9 %). Twelve of the 38 patients (31.6%) reported adverse effects of dapsone, including arthralgia (5.3%), rash (5.3%), dapsone hypersensitivity syndrome (2.6%), methemoglobinemia (21%), and hemolysis (15.8%). These findings indicate that dapsone may have a beneficial effect on refractory IgAV.

Conclusion

It is observed that in spite of several adverse effects, dapsone treatment exerts a beneficial effect in IgAV patients with prolonged cutaneous manifestation refractory to corticosteroid. Close renal monitoring may be needed to discover renal involvement of IgAV. Multicenter randomized placebo-controlled trials are necessary to determine the standard dosage of dapsone at initial or tapering of treatment in IgAV patients.
#933 Serum and kidney complement and severity of ANCA associated vasculitis in the kidney
Authors: Lee Tung Lin , Tan Hui Zhuan , Mok Irene , Lim Cynthia , Choo Jason
Published: May 2024

Background and Aims

Kidney involvement in ANCA associated vasculitis (AAV) is commonly described as pauci-immune based on histological characteristics. However, we now know that the complement system is activated and contributes to the pathogenesis of AAV – with Avacopan (C5a inhibitor) demonstrating superior efficacy in maintenance of remission over Prednisolone in the ADVOCATE trial. Our aim was to evaluate if there is an association between kidney disease severity and the presence of serum and histological complement activation markers.

Method

Retrospective cohort study of 59 patients with AAV diagnosed between November 2015 and May 2019. Complement activation markers were serum complements (C3 and C4) levels and presence of complement (C3, C1q and C4) in glomerular capillary walls in immunofluorescence with intensity of 2+ and 3+. Kidney disease severity markers were peak serum creatinine value at presentation, anti-MPO or anti-PR3 levels, and number and proportion of glomeruli with crescents on kidney biopsy. Associations were evaluated using Spearman correlation or Mann Whitney U test as appropriate

Results

Among 59 patients with biopsy-proven AAV in the kidney, the median (25th percentile, 75th percentile) age was 68.8 (60.7, 73.4) years, serum creatinine was 263 (156, 560) µmol/L, and anti-MPO and anti-PR3 levels were 100.0 (81.5, 199.2) and 128.8 (22.9, 200) in 41 and 7 patients, respectively. respectively. The number and proportion of glomeruli with crescents were 6 (3, 12) and 33.3% (12.0%, 42.6%), respectively.

Serum C3 and C4 were performed in 41 patients and the median levels were 1.00 (0.83, 1.14) and 0.24 (0.18, 0.31), respectively. Serum C3 level did not correlate with serum creatinine, anti-MPO or anti-PR3 titers, and number and proportion of glomeruli with crescents. Serum C4 level was negatively correlated with anti-MPO titer (34 patients; r = −0.393, p = 0.02) but did not correlate with serum creatinine or number or proportion of crescents.

Complement in the glomerular capillary wall was present in 8 patients (13.6%): C3, C1q and C4 were present in 8, 3 and 1 patients, respectively. Serum creatinine [median 299 (IQR 133, 998) µmol/L versus 261 (156, 359) µmol/L, p = 0.39], anti-MPO titer [100 (88.3, 200) IU/ml versus 100 (79.4, 198) IU/ml, p = 0.74], number of crescents [14 (4, 21) versus 5 (3, 12), p = 0.90] and proportion of crescents [38.9% (12.5%, 42.3%) versus 31.3% (11.1%, 44.3%), p = 0.59] were not different in those with and without complement in the kidney biopsy.

Conclusion

The presence of complement activation markers was not associated with kidney disease severity in AAV. However, the detection of clinically significant associations may have been limited by our cohort size.
#1337 Evolution of ANCA-associated vasculitis in a population with confirmed renal involvement. Myeloperoxidase and proteinase 3 antibodies, which is worse?
Authors: Subiela José Enrique Ruiz-Cabello , Talavera Andrea Cifuentes , Wang Yali Chen , González Javier García , Galindo-Izquierdo María , Ruiz Enrique Morales
Published: May 2024

Background and Aims

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of rare but potentially serious diseases with high mortality. Renal involvement is frequent in AAV with patients developing end-stage renal disease (ESRD) or becoming dependent on dialysis in up to 23% of patients. Several studies suggest the presence of clinical factors as predictors of survival in these diseases.

The objective of this study was to analyze clinical evolution of AAV and to identify potential risk factors for developing renal events (ESRD or dialysis) and death in patients with AAV, with special attention to the implications that the presence of myeloperoxidase (MPO) or proteinase 3 (PR3) antibodies at diagnosis may have on the disease progression.

Method

We conducted a retrospective observational study of patients under follow-up for AAV. We considered only those with a confirmed diagnosis of AAV through renal biopsy for the present study. We collected clinical and laboratory variables at the time of disease presentation. We divided the patients based on the presence of MPO or PR3. Subsequently, we analyzed the patients' progression towards the occurrence of renal events (ESRD or dialysis) and mortality.

Results

Out of the 42 studied patients, 29 were MPO-positive and 13 were PR3-positive. We observed statistically significant differences in age and the frequency of hypertension, with the MPO group being older and more hypertensive than the PR3 group. On the contrary, PR3-positive patients exhibited a higher percentage of diabetes and increased severity of vasculitis at diagnosis as measured by the Birmingham Vasculitis Activity Score (BVAS). While most MPO-positive patients met criteria for microscopic polyangiitis (MPA), all PR3-positive patients met criteria for granulomatosis with polyangiitis (GPA) according to the ACR/EULAR 2022 guidelines. There were no statistically significant differences regarding clinical or laboratory variables analyzed, neither with induction nor maintenance treatment. We did not observe differences in the progression towards renal events or mortality between groups. However, we did observe a higher percentage of disease recurrence among PR3-positive patients (Table 1).

Conclusion

There were no statistically significant differences observed in the progression towards renal events (ESRD and dialysis) or mortality regardless of MPO or PR3 antibodies.
#2724 Renal amyloidosis cohort registry in our health area
Authors: Moreno Fernando Bertomeu , de la Torre Molina Águeda López , Garcia Fabiola Alonso , De la Prada Francisco José , Lazo Mercedes Salguiera
Published: May 2024

Background and Aims

Renal amyloidosis is the pathological phenomenon of amyloid deposition in the kidney with marked differences in renal function impairment, proteinuria, need for renal replacement therapy (RRT) and exitus, depending on the protein involved.

Light chain amyloidosis (AL) and serum protein A (AA) amyloidosis are the most common.

Typical symptoms are severe proteinuria, nephrotic syndrome, and end-stage chronic kidney disease (ESRD).

Method

Retrospective study of a cohort of patients with renal amyloidosis. Data extracted from the biopsy registry of the HUVM Nephrology Service (2013-2022).

We collected demographic, clinical, analytical, histological and clinical outcome variables (RTT, Exitus). Results are analyzed using Mayo Clinic staging criteria.

Results

19 patients with a mean age of 63.4a; 57.9% male.

Mean laboratory values at diagnosis: creatinine (Cr) 1.56 mg/dl and proteinuria 3.9 g/24 h.

Abdominal fat biopsy in 13 cases; 3 (23%) tested positive.

Comparative analysis of AL vs non-AL forms, Cr values (1.14 vs 2.27 mg/dl respectively) (p=0.57) differed.

Proteinuria according to the histological location of the amyloid: 4.6 g/24 h in glomerular involvement vs. 0.3 g/24 h in those who did not present it (p<0.05).

31.6% required RTT with a mean onset time of 250.6 d from biopsy. Exitus of 21.1%: average time of 426.5 d. (See analysis in attached table).

Conclusion

We did not observe significant deterioration of renal function, which is greater in non-AL forms of amyloidosis.

Fat biopsy was less cost-effective than reported in the literature.

Significantly lower levels of proteinuria were found in the amyloidosis group without glomerular involvement.

In our series, the prognostic capacity associated with the MAYO staging was confirmed.
#3019 Hepcidin and erythropoietin along with iron indices to asses anemia in lupus nephritis population
Authors: Badawi Mohamed Hosney , Mohamed Nourelsabah , Refaie Ayman F , Zayed Karem N , Mortada Wael I , Nabieh Kareem A , Sobh Mohamed A
Published: May 2024

Background and Aims

There is a broad spectrum of hematologic manifestations in SLE including lymphopenia, anemia, thrombocytopenia, or pancytopenia. lymphadenopathy and splenomegaly are also identified especially with high disease activity. Anemia of chronic disease, representing approximately one third of the cases in patients with SLE. Santacruz et al, also reported that iron deficiency anemia is also a common cause, usually caused by blood loss. serum hepcidin levels are high in patients with CKD, and are associated with erythropoiesis stimulating agent resistant anemia due to the inability of stored iron to be accessed for erythropoiesis, they are also high in autoimmune diseases as SLE. we evaluated anaemia in lupus nephrites population by assessing the level of hepcidin, erythropoietin along with iron study

Method

in this observational study We identified 100 patients with SLE and diagnosed as lupus nephritis by means of renal biopsy ISN/RPS classification 2004 with some missed data about biopsy details, the patients assessed for anaemia by haemoglobin level, iron study (TSAT, ferritin), hepcidin (10-120 μg/L) and erythropoietin level (3-36 IU/L). Demographics, disease characteristics and comorbidities were ascertained and adjusted for.

Results

52 % of patients with SLE, LN (mean age 37.85 (9.40) years, 94 % female,) had Hgb<12 g/dl. The two groups of patient were comparable in disease duration but anemia had higher disease activity than patients with normal Hgb (p. value 0.9, 0.001 ). Furthermore, incidence of DM and HTN wasn't have statical significant, laboratory investigation showed anemia is microcytic hypochromic with low TSAT, hepcidin is almost high in 72% of all patients but wasn't significantly different between the two groups but erythropoietin level was normal in 100% of patients in both groups.

Conclusion

Patients with SLE and LN have an increased prevalence of anemia due to different factors. Our data suggest that iron deficiency anaemia was prevalent in the study group which may be due to high hepcidin level in those group of patient or blood loses especially the majority were females, erythropoietin level as marker of anaemia in lupus nephritis patient had been found to be not an indicator, its receptor resistance or antibodies found in SLE patients.
#388 IONIS-FB-LRx, an antisense oligonucleotide to complement factor B for treatment of IgA nephropathy
Authors: Hladunewich Michelle , Barbour Sean , Makris Angela , Tan Sven Jean , Choo Jason , Yang Qingqing , Lin Lixuan , Barrett Terry , Schneider Eugene , Geary Richard , Mccaleb Michael , Brice Gary
Published: May 2024

Background and Aims

Pathogenesis of IgA nephropathy (IgAN) is known to be dependent upon multiple factors, one being the complement system. Since overactivity of the complement Alternative Pathway (AP) has been proposed to contribute to pathogenesis of IgAN, it has been hypothesized that a reduction of AP activity would improve proteinuria. IONIS-FB-LRx, (ISIS696844, RO7434656), is an investigational antisense oligonucleotide targeting complement factor B (CFB) mRNA and reduces CFB production in the liver. We have previously demonstrated that administration of IONIS-FB-LRx lowered the production of CFB, a required component of the AP, and led to reduction of AP and reduction in proteinuria in IgAN patients (2023 ASN Abstract#SA-PO926, N = 13 patients). Current abstract provides an update to our previous report extending results to 19 patients treated with IONIS-FB-LRx.

Method

An exploratory, single-arm, multi-national open-label Ph2 study (NCT04014335) recruited patients with biopsy-confirmed IgAN, proteinuria >1.5 g/d, eGFR >40 mL/min/1.73 m2, and hematuria despite maximum tolerated RAAS blockade and/or stable dose of SGLT-2 inhibitor for a minimum of 6 months. Study drug was administered at Weeks 1, 3, and 5, and then every 4 weeks through

Week 25 (Cohort A) and at Week 1 and then every 4 weeks through Week 25 (Cohort B). Primary outcome was change in 24-hr proteinuria at Week 29 (4 weeks after last dose) compared to baseline (BL).

Results

19 patients have completed study to date (13Nov2023), 25-62 yr, 42% Female, 11 Asian, and 8 White. Median 24-hr UPCR at BL was 1.56 g/g (IQR 1.23, 2.33 g/g). At Week 29, a 45% geometric mean ratio reduction was observed. There was little change in eGFR at Week 29 compared to BL (mean ± SD; BL 72 ± 22; Week 29 74.6 ± 20 mL/min/1.73 m2). The drug demonstrated an acceptable safety profile with no Treatment Emergent SAEs; the only clinically meaningful laboratory finding was reversible and transient ALT elevation without a change in bilirubin. All patients completed the study and one patient discontinued study drug after 4 months to initiate SGLT-2 inhibitors. That patient experienced a 38% reduction in 24-hr UPCR collected 3 weeks (Week 27) after the last dose of IONIS-FB-LRx, but prior to use of SGLT-2 inhibitors.

Conclusion

This Ph2 open-label study provides continuing clinical evidence that IONIS-FB-LRx reduces complement levels and proteinuria in patients with IgAN, supporting Ph3 development (NCT05797610) to determine the potential of IONIS-FB-LRx to reduce the progression of IgAN.