bluuebunny/crossref_metadata_2025 huggingface dataset:
#1558 Mutational spectrum of X-linked hypophosphatemia (XLH) in Hungarian patients
Authors: Balogh Istvan , Szabo Tamas , Reusz Gyorgy , Mikes Balint , Koczok Katalin , Madar Laszlo , Nagy Orsolya , Till Agnes , Meichelbeck Krisztina , Pfliegler Gyorgy , Szabo Andras , Lengyel Anna
Published: May 2024

Background and Aims

X-linked hypophosphatemia (XLH), the most common form of hypophosphatemic rickets, is caused by genetic alterations in the PHEX gene. Prevalence of the X-linked disease is ∼1/20,000. The PHEX gene has 22 exons and encodes a 749 amino acid protein with homology to zinc metallopeptidases. The physiological protein target for PHEX cleavage is unknown. PHEX promotes mineralization by regulating the expression of FGF23. To date, more than 800 disease-causing variants in the PHEX gene have been described in XLH patients. These variants might occur across the entire gene and include missense, nonsense, frameshift, splice site, copy-number variants with a consequence of loss of PHEX protein function. Genetic confirmation of XLH has significant clinical importance from risk prediction to modern treatment options. Here we describe the genetic results of 20 mutation-positive patients from 18 unrelated families, the first such report from Hungary.

Method

The cohort consisted of 8 male and 12 female patients (mean age at genetic diagnosis (range): 8.25 years (3-17 years) and 12 years (2-32 years)). Genomic DNA was isolated from peripheral blood leukocytes and in the mosaic case also from mouthwash sample. PHEX sequencing was performed using next generation sequencing with a custom designed library preparation kit (Twist Biosciences) on an Illumina MiSeq instrument. For the bioinformatic analysis, NextGene software was used. All small-scale mutations were confirmed by Sanger sequencing. For copy number variation (CNV) analysis, a coverage-based pipeline was used. Detected CNVs were confirmed using multiplex ligation-dependent probe amplification (MLPA). Mutation classification was performed according to the ACMG guidelines.

Results

All female patients were heterozygous, while all but one male patients were hemizygous. In case of one male patient, a mosaic deletion of exon 10 was observed. Most common mutation type was nonsense (n = 7) followed by small deletions/insertions (n = 6) and splicing alterations (n = 3). One missense mutation was detected. CNVs were responsible in three cases (two large deletions and one large duplication). From the 11 most common PHEX alleles known from the literature (Hum Mutat 2022;43:143-57), three (c.2104C > T, c.2239C > T, c.871C > T) were detected in our cohort. Nine novel, previously undescribed alterations were found: c.264G > A, c.1073_1074delGA, c.1148dupA, c.1645+1G > C, c.1682G > A, c.1701-1G > C, c.2150T > G, c.2172delT, e6-15dup.

Conclusion

Our data shed more light on the distribution of the PHEX causative variations in the Hungarian XLH patients and opens the possibility of the state-of-the-art treatment in many of them.
#3124 How well do risk assessment guidelines perform for ADPKD?
Authors: Cam Mauricio Alejandro Miranda
Published: May 2024

Background and Aims

The approval of Tolvaptan for treatment of ADPKD heralds a new era when mechanism-based therapy is now possible. However, Tolvaptan is an expensive drug associated with potentially serious side effects and is currently reserved for patients at high-risk for progression to ESKD. Two sets of risk assessment guidelines for ADPKD are now available based on the consensus of two panels of nephrologists from Canada and Europe. However, how well do these guidelines perform in risk assessment has not been formally assessed.

Method

We conducted a prospective study in 474 patients with typical imaging pattern of ADPKD by MRI who also had detailed clinical and laboratory data. We used age- and height-adjusted total kidney volume to derive the Mayo Clinic Imaging Class as a “gold-standard” for risk assessment (i.e. low-risk: 1A-1B; high-risk: 1C-1E). We then applied the revised Canadian guidelines (Can J Kidney Health Dis. 2018) and the updated European guidelines (NDT 2022) to our patient cohort to assess their performance.

Results

The study cohort consisted of 286/474 (60%) high-risk patients with MCIC 1C-1E. Applying the updated Canadian risk assessment algorithm resulted in exclusion of 245/474 (52%) patients including 86/286 (30%) of the high-risk patients. The resultant cohort (229/474) was enriched with 88% high-risk patients but also included 12% of low-risk patients. The updated European guidelines provide a 3-step hierarchal algorithm, when applied resulted in exclusion of 55% (157/286) of high-risk patients. During the last step, 122 patients could not be classified due to a lack of eGFR slope information. The resultant cohort (180/474) was enriched with 72% high-risk patients but also included 28%(51/180) of low-risk patients.

Conclusion

Risk assessment in ADPKD is an evolving process that needs to be redefined by new clinical data and test technologies. Clinical guidelines should be evaluated using real-life data and those that enrich high-risk patients while minimizing low-risk patients have the most clinical utility
#844 Renal manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: an updated systematic review
Authors: Lee Keum Hwa , Hwang Eun Jae , Shin Jae Il , Park Se Jin
Published: May 2024

Background and Aims

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a systemic autoimmune genetic disorder caused by mutation of the forkhead box protein 3 (FOXP3) gene. We performed this study to analyze the clinical and demographic characteristics of renal involvement in IPEX patients, genotype-phenotype correlations and the effect of renal involvement on patient outcome.

Method

We performed a literature search (PubMed and EMBASE) to systematically investigate the case reports of IPEX with renal involvement which were published before Dec 21st, 2023.

Results

A total of 37 patients were identified. All IPEX patients included had FOXP3 mutations which were most frequently located in the forkhead domain. Among 25 patients in whom detailed information is available, 22 showed single presentation (6 proteinuria, 8 nephrotic syndrome (nephrotic range proteinuria), 3 acute glomerulonephritis, 5 renal insufficiency), 2 showed multiple presentations (1 nephrotic range proteinuria, microscopic hematuria and 1 nephrotic range proteinuria, microscopic hematuria, renal insufficiency). Renal biopsy was documented in 19 patients. Membranous nephropathy (n = 9) was most common, followed by Interstitial nephritis (n = 3), membranoproliferative nephropathy (n = 2), tubulopathy (n = 2), mesangial proliferative glomerulonephritis (n = 2), autoimmune nephritis (n = 1). Nephrotic syndrome was more frequent in patients with intron 6 mutation (p < 0.05). However, renal presentation of IPEX syndrome was not related to patient outcome (death).

Conclusion

We found renal involvement is one of the important manifestations of IPEX syndrome and membranous nephropathy was most common. Close renal monitoring is necessary to detect renal involvement of IPEX syndrome. Further studies are necessary to compare the course of glomerulonephritis between IPEX-related and IPEX-unrelated one. Response to treatment should also be elucidated in patients with IPEX in the future.
#1040 Correlation of genotype to disease onset age and hypertension diagnosis in autosomal dominant polycystic kidney disease
Authors: Evangelou Eirini , Konsta Maria , Gkalitsiou Dimitra , Vasileiou Kyriaki , Poula Angeliki , Markou Niki , Poulli Tsielestina , Palaiologou Danai , Kanellopoulou Konstantina , Tsirpanlis George
Published: May 2024

Background and Aims

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the predominant genetic disease leading to End Stage Kidney Disease (ESKD). Genetic identity could correlate to the disease profile. Correlations between genetic and phenotype characteristics in a cohort of ADPKD patients are investigated.

Method

Genetic analysis was conducted in 85 patients with an ADPKD phenotype, employing targeted Next Generation (tNGS) or Sanger Sequencing and Multiplex ligation-dependent probe amplification (MLPA). Medical history, clinical and laboratory data, including Renal Magnetic Resonance Imaging (MRI) for Total Kidney Volume (TKV) measurement (in 66 patients), were recorded and subsequently correlated to the respective genotypes.

Results

Eighty-five patients (43 females, 42 males, 33 ± 16 years old) were included in the study. The mean age at diagnosis of the disease was at 21.5 ± 13 (0.6-69) years. Fifty-eight out of 85 patients (68%) had a familial history of ADPKD. The mean age at which the affected parent reached ESKD was 53.0 ± 9 years. Hypertension was diagnosed in 60 individuals (71%) within the study cohort. The mean age at hypertension diagnosis was 31 ± 11 years. In the assessment based on height-adjusted TKV and age, the Mayo Clinic Imaging Categories revealed that 9% of patients were classified as 1A, 20% as 1B, 29% as 1C, 29% as 1D, and 13% as 1E. Mutations in PKD1 gene were detected in 70 patients (82%), with 61% exhibiting truncating mutations and 39% non-truncating mutations, while PKD2 mutations were identified in 15 patients (18%). The average age of ADPKD diagnosis differed among genetic subgroups. Patients carrying PKD1-truncating mutations were diagnosed at 17.6 ± 11 years, those with PKD1-non-truncating mutations at 24.5 ± 12 years, and those with PKD2 mutations at 27.3 ± 16 years (p = 0.01). Moreover, the mean age at which the affected parent reached ESKD was 50 ± 8 years, 55 ± 10 and 60 ± 7 years in PKD1-truncating, PKD1-non-truncating and PKD2 patients respectively (p = 0.04). Additionally, the mean age of hypertension diagnosis was 29 ± 12 years in PKD1-truncating, 30 ± 10 years in PKD1-non-truncating and 40 ± 7 years in PKD2 patients (p = 0.05).

Conclusion

Mutation type correlates with the age of ADPKD diagnosis, the renal survival within families and the hypertension onset. Patients with PKD1-truncating mutations manifest an earlier onset of both the disease and hypertension compared to those with PKD2 gene mutations.
#2372 Investigating the effects of low-level and transient DNA damage on kidney health in a novel mouse model of aging
Authors: Takasu Masanobu , Kishi Seiji , Kirita Yuhei , Nagasu Hajime , Kidokoro Kengo , Sasaki Tamaki , Hayano Motoshi , Kashihara Naoki
Published: May 2024

Background and Aims

Increasing life expectancy worldwide underscores the importance of addressing the effects of aging on organ and cell function. Aging is characterized by a gradual decline in organ function that varies among individuals and is influenced by lifestyle choices and various external factors that induce DNA stress. This mismatch between kidney aging and an individual's lifespan contributes to the increase in end-stage renal disease. Among the kidney's constituent cells, the proximal tubules are frequently damaged by external factors such as ischemia and drugs. Our research has focused on DNA damage and its repair mechanisms (DDR) caused by these injuries, and we have previously shown that extensive DNA damage beyond the capacity of DDR or abnormalities in DDR cause cellular senescence in proximal tubules, resulting in incomplete renal repair after injury (Kishi et al. Sci Transl Med 2019, J Clin Invest 2019). In this study, we extend these studies and test whether acquired and mild DNA stress induces renal senescence using a novel mouse model of aging, the Inducible Changes to the Epigenome (ICE) mouse (Hayano et al. Cell. 2023).

Method

ICE mice were generated by mating I-PpoI STOP/+ mice with CreERT2/+ mice. I-PpoI, an endonuclease, cleaves DNA only upon administration of tamoxifen and the resulting DNA damage is subsequently repaired by the DDR. To induce transient DNA damage, 4- to 6-month-old mice were fed a tamoxifen-containing diet for 3 weeks and then housed until they reached 14 months of age. A comprehensive renal analysis was then performed, which included renal tissue evaluation, single-nucleus RNA sequencing, q-PCR, and Western blot analysis for phenotypic analysis of mouse kidneys.

Results

No significant histological changes were observed in the kidney tissues between the ICE mice and the control group, and the levels of interstitial fibrosis were comparable. To ensure unbiased evaluation, we performed single-nucleus RNA-seq. In ICE mice, there was an increased presence of proximal tubules with incomplete repair expressing KIM-1 and VCAM-1. In addition, ICE mice showed increased gene expression of DNA repair-related enzymes (Mgmt) in proximal tubules and evidence of cellular senescence. No differences in mitochondrial number or biosynthetic capacity were observed.

Conclusion

The consequences of short-term and transient DNA damage were found to have lasting effects on the kidney. In particular, significant changes were observed in the proximal tubules, where DNA instability and accelerated cellular senescence were evident, suggesting an impaired repair phenotype within the proximal tubules. This may be related to increased susceptibility to various external stimuli. For further detailed analysis, studies using proximal tubule-specific ICE mice are currently performed.
#1144 Role of PPAR-alpha in folic acid-induced tubulointerstitial fibrosis
Authors: Estrela Gabriel , Arruda Adriano , Barrera-Chimal Jonatan , Araujo Ronaldo
Published: May 2024

Background and Aims

PPAR-alpha is a nuclear receptor that plays a major role in the regulation of lipid metabolism. Activation of PPAR-alpha has been shown to have beneficial effects in renal diseases. Acute kidney injury (AKI), even if followed by renal recovery, is a risk factor for the future development of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Progressive tubulointerstitial fibrosis is the final common pathway for all kidney diseases leading to chronic renal failure. Our main objective was to determine the importance of PPAR-alpha in tubulointerstitial fibrosis in folic acid induced nephropathy.

Method

Male C57/Bl6 and PPARKO (C57Bl6 background) mice were divided into 4 groups, Control, Folic Acid, Gemfibrozil + Folic Acid and PPARKO + Folic Acid. Animals have been treated with a single dose of Folic Acid (250 mg/kg i.p) and Gemfibrozil (150 mg/kg gavage) euthanized after 28 days for. Renal parameters, histology, real time PCR were performed to investigate renal injury, inflammation, and fibrosis.

Results

After 28 days of folic acid inducing CKD. PPARKO showed the same levels of injury as folic acid alone treated mice, however PPAR-alpha activation with gemfibrozil decreased urinary volume (Folic Acid: 3.870 ± 0.679 Gemfibrozil: 1,242 ± 0,223), creatinine (Folic Acid: 0,7940 ± 0,0357 Gemfibrozil: 0,5820 ± 0,0288), urea levels (Folic Acid: 79,23 ± 3,20 Gemfibrozil: 46,11 ± 3,874), showed less tubulointerstitial fibrosis (Folic Acid: 0,5837 ± 0,0426), Gemfibrozil: 0,2423 ± 0,0293) and lower urine protein/creatinine ratio (Folic Acid: 5,486 ± 0,588 Gemfibrozil: 2,536 ± 0,127).

Conclusion

PPAR-alpha deletion did not show protection in chronic phase, in the other hand PPAR-alpha activation with gemfibrozil showed to be effective against tubulointerstitial fibrosis.
#2983 Correlation of microRNA expression with IgA nephropathy progression: preliminary results
Authors: Konieczniak Karolina , Jesiotr Marzenna , Rymarz Aleksandra , Niemczyk Stanisław
Published: May 2024

Background and Aims

IgA nephropathy (IgAN) is the most common cause of glomerulonephritis worldwide. IgAN is diagnosed based on the result of histopathological examination. The risk factors for disease progression primarily include the level of impairment of renal function at the time of diagnosis (GFR < 60 ml/min/1.73 m2), the presence of hypertension, daily administration of more than 1.0 g, and the occurrence of hematuria. MicroRNAs (miRNAs) are important regulators of gene expression. Their role has a significant impact on the proper functioning of the body, and disorders related to their expression can lead to the development of many pathological processes in the body. The study aimed to assess the dependence of microRNA expression on the stage of the disease in patients with IgA nephropathy.

Method

A study was conducted involving patients newly diagnosed with IgA nephropathy based on histopathological examination results. The expression of microRNA molecules (miR-146a, miR-155, miR-200b, miR-429) was determined in urine sediment and blood. The analysis focused on examining the relationship between microRNA expression and the stage of disease progression (proteinuria, renal parameters). Blood and urine tests were performed before the start of immunosuppressive treatment with glucocorticosteroids according to the Pozzi regimen.

Results

Twenty-seven patients were included in the study group- 14 women (51.9%) and 13 men (48.1%). Nephrotic-range proteinuria (>3000 mg/24 h) was observed in 5 patients (18.5%), while subnephrotic proteinuria was present in 22 patients (77.8%). Reserved kidney function (eGFR > 90) was found in 17 patients (63%). The exact distribution of results according to the stage of renal failure is given in the Table 1.

Statistically significant positive correlation was found between serum creatinine concentration and miR-200b expression in urine (R = 0,398, p = 0,049). Initially, no statistically significant correlation was found between the expression of selected miRNA molecules and the degree of 24-hour proteinuria.

Conclusion

MiRNA molecules may be promising, non-invasive biomarkers widely used in clinical practice. Determining the viability of clinical use of microRNA molecules will require a panel of miRNAs or miRNAs used in combination with other biomarkers and clinical outcomes to improve diagnostic utility.
#2074 Aberrant m6A modification pattern and m6A-related proteins expression in SLE
Authors: Tang Chun , Liu Yu , Wang Xiaohua , Huang Mingcheng , Luo Ailing , Liu Shanshan , Cai Mansi , Li Weinian , Yuan Shiwen , Zheng Zhihua , Liu Xiaoping
Published: May 2024

Background and Aims

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown cause. N6-methyladenosine (m6A) is the most common mRNA modification and is involved in various immune processes leading to immune homeostasis disorders. However, the role of m6A in dysregulated immune response of SLE remains unknown. Here, we aim to explore the m6A pattern and expression of m6A-related proteins in the SLE.

Method

Peripheral blood mononuclear cells (PBMCs) from healthy controls and SLE patients were collected to compare the m6A modification profile by methylated RNA immunoprecipitation sequencing (MeRIP-seq). Expression of 3 m6A-related proteins, including methyltransferase 3 (METTL3), Alkb homologue 5 (ALKBH5), and Fat mass and obesity-associated protein (FTO) and in PBMCs of SLE patients were detected using western blotting (WB). Renal METTL3 expression was further examined in MRL/lpr mice using WB and immunofluorescence.

Results

SLE patients contained only 28.74% of the same m6A peaks as healthy controls, and 7.881% of the peaks were specific in SLE group (Fig. 1A). The m6A differential peaks were enriched in exon, intron and near 3’ UTR region (Fig. 1B). In addition, compared with healthy controls, m6A modified motifs were obviously aberrant in SLE patients (Fig. 1C). GO and KEGG enrichment analysis showed that some of the m6A peak differential genes were associated with regulation of cellular process, and cytokine-cytokine receptor interaction signaling pathway (Fig. 1D and 1E). Expression of METTL3 and ALKBH5 in SLE patients were significantly increased (METTL3, SLE-AP vs HC, p < 0.001; SLE-SP vs HC, p = 0.0042; ALKBH5, SLE-AP vs HC, p < 0.001; SLE-SP vs HC, p < 0.001; Fig. 1F). There were no significant differences in FTO expressions between the two groups (SLE-AP vs HC, p = 0.167; SLE-SP vs HC, p = 0.477; Fig. 1F). Compared with C57BL/6 mice, renal METTL3 in the MRL/lpr mice was distinctly elevated (p < 0.001; Fig. 1G), which co-localized with CD138 + plasma cells (Fig. 1H).

Conclusion

These results suggested a distinctly abnormal m6A modification features and m6A-related proteins in SLE patients, indicating the potential significant role of m6A in the pathogenesis of SLE.
#2555 C4d—a novel predictor of the disease progression and treatment failure in primary focal segmental glomerulosclerosis?
Authors: Zagorec Nikola , Horvatic Ivica , Kasumović Dino , Šenjug Petar , Sovic Slavica , Ljubanović Danica Galešić , Galesic Kresimir
Published: May 2024

Background and Aims

Complement system seems to play a role in the pathogenesis of primary focal segmental glomerulosclerosis (pFSGS) where, due to unpredictable clinical course and outcome, novel prognostic factors are sought. The split product of C4 and tissue marker of complement activation, C4d, is a potential candidate whose prognostic significance was determined in this study.

Method

Patients >18 years with features consistent with pFSGS (full blown nephrotic syndrome, diffuse podocyte foot processes effacement and exclusion of known causes of FSGS), were recruited from our Hospital registry of kidney biopsies, from 2003 to 2021. Patients with end-stage renal disease (ESRD) defined as eGFR <15 ml/min/1.73 m2 were not included. Every renal biopsy specimen was analyzed by light, immunofluorescence and electron microscopy with additional immunochemistry for C4d performed on paraffin-embedded tissue using monoclonal rabbit antibody (detection system Ventana BenchMark Ultra). Samples with at least one non-globally sclerosed glomerulus (GSG) were examined by two renal pathologists who classified every non-GSG into C4d positive and negative. Based on ratio of C4d+ non-GGS/total N of non-GSG and C4d+ nonsclerotic glomeruli (NSG)/total N of NSG, patients were stratified into two groups: <50% and ≥50%. Primary outcome was defined as composite of ESRD and initial eGFR declining >50%. Failure to meet criteria for at least partial remission at the last follow-up visit according to KDIGO 2021 Guidelines was defined as treatment failure. Numeric variables are shown as median with interquartile range (IQR) and P value <0.05 was considered as significant.

Results

Relevant data of 58 included patients with renal outcomes are shown in Table. Median follow up was 90.7 (IQR 48-167) months. Patients with ≥50% of C4d+ non-GSG had higher proportion of treatment failure (Table) and worse renal survival (log-rank test, p = 0.006). In multivariate Cox regression analysis, after inclusion of age, sex, initial eGFR and 24-h proteinuria, IFTA, serum albumin and C4d category, only C4d ≥50% (HR = 4.077, 95% CI 1.101-15.09, p = 0.035) and IFTA (HR = 1.052, 95% CI 1.019-1.085, p = 0.002) remained independent predictors of progression to defined endpoint. Likewise, patients with ≥50% of C4d+ NSG/total N of NSG had higher proportion of treatment failure (chi-square, p = 0.03) and worse renal survival (log-rank, p = 0.037).

Conclusion

C4d deposition is an independent predictor of disease progression, treatment failure and renal survival in pFSGS. Significant influence of NSG-C4d deposition on disease progression may indicate pathophysiological role of the complement system activation in pFSGS independently of the presence of glomerular sclerosis.
#1386 Hypertension is associated with deterioration of kidney function among patients with systemic lupus erythematosus, with or without lupus nephritis
Authors: Benchetrit Sydney , Bar-Ziv Dorin , Kabaha Mohamad , Kenis Irina , Tayer-Shifman Oshrat E , Cohen-Hagai Keren
Published: May 2024

Background and Aims

Systemic lupus erythematosus (SLE) frequently involves the kidneys, contributing to morbidity and mortality among this population. While hypertension often coexists with kidney involvement, it is not represented in the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index. Its effect on the morbidity and mortality of the SLE population in the Middle East should be evaluated. Our aims is to characterize the role of hypertension in Israeli SLE patients and identify variables associated with decreased eGFR over time.

Method

This retrospective study, conducted between 2014–2023 included adult patients with a diagnosis of SLE for at least 12 months. Kidney involvement was assessed based on a diagnosis of lupus nephritis (LN) on kidney biopsy. Hypertension was diagnosed based on documented diagnosis. Systolic and diastolic blood pressures were collected as continuous variables at multiple time-points. Associated variables, including socio-demographics, disease-related characteristics, kidney-related factors, comorbidities and all-cause mortality were assessed.

Results

A total of 182 patients were followed for a mean duration of 16.2 ± 13.8 years. Fifty-nine patients (32.4%) had chronic hypertension. Hypertension was more prevalent among SLE patients with LN [odds ratio (OR) 1.5, 95% CI 0.8-2.9, p = 0.23] as well as patients with chronic kidney disease (OR 7.2, 95% CI 1.9-27.7, p = 0.001). Patients with chronic hypertension had significantly relatively high rate of proteinuria at last follow-up (54.7%). On univariate analysis, patients with hypertension had higher rates of end-stage kidney disease (ESKD) (11.9% vs 1.6%, p = 0.003), heart failure (20.3% vs. 0.8%, p < 0.001), and all-cause mortality (16.9% vs. 0%, p < 0.001). All deaths (n = 10) occurred among hypertensive patients. LN and age were the most important predictors of hypertension on multivariate analysis (OR 6.2, 95% CI 2.4-16, p < 0.001; OR 1.1, 95% CI 1.1-1.2 p < 0.001, respectively). Repeated measures analysis showed that hypertension was significantly associated with decreased eGFR among SLE patients with or without LN (Fig. 1). Systolic and diastolic blood pressure were significantly correlated with age and inversely correlated with eGFR at last follow-up (Spearman's correlation coefficient 0.4, p < 0.01; 0.1, p = 0.07; −0.4, p < 0.01; −0.2, p = 0.04, respectively).

Conclusion

Hypertension is prevalent among Israeli patients with SLE, constituting a substantial comorbidity associated with ESKD, heart failure and mortality, irrespective of LN presence. Routine assessment and vigorous treatment of hypertension should be part of the management of patients with SLE.
#1093 Remission rates and long-term outcomes of relapsed idiopathic nephrotic syndrome children treated with cyclophosphamide vs. cyclosporin A
Authors: Vachvanichsanong Prayong , Sophark Praewa , Limratchapong Chompoonut , Dissaneewate Pornsak
Published: May 2024

Background and Aims

Approximately seventy percent of nephrotic syndrome (NS) children experience relapse episodes which are classified as frequently-relapsing nephrotic syndrome (FRNS), steroid-dependent nephrotic syndrome (SDNS), or steroid-resistant nephrotic syndrome (SRNS). In such cases, immunosuppressive drugs are combined to reduce the steroid side effects and prolong the remission period. However, the benefit of immunosuppressants and their side effects should be balanced.

Objectives

This study aimed to determine the remission rates and long-term outcomes of FRNS, SDNS, and SRNS children treated with cyclophosphamide vs. cyclosporin A (Cy A).

Methods

A retrospective review of medical records of children (aged < 15 years) with relapsed idiopathic nephrotic syndrome at Prince of Songkla University Hospital, southern Thailand during 2010-2021 was conducted. Demographic data, treatment responses, and adverse events were recorded. The remission rates, incidences of infection and acute kidney injury (AKI) in FRNS/SDNS and SRNS were compared between oral cyclophosphamide and Cy A treatments.

Results

There were 148 relapsed NS children, 102 (68.9%) boys, with a median age of 4.6 (IQR 2.5-8.4) years. FRNS, SDNS, and SRNS accounted for 37 (25.0%), 50 (33.8%), and 61 (41.2%) children, respectively.

The cyclophosphamide treatment group (N = 135) had significantly higher remission rates in FRNS/SDNS than SRNS (63/85 (74.1%) vs. 11/50 (22.0%), P < 0.001), while the difference in remission rates in the Cy A treatment group (N = 53) was not statistically significant between FRNS/SDNS and SRNS (14/20 (70.0%) vs. 18/33 (54.5%), P = 0.265).

Patients who had the Cy A treatment had significantly higher proportions of infections and AKI than children in the cyclophosphamide treatment group (20/53 (37.7%) vs 10/95 (10.5%), P < 0.001 and 21/53 (39.6%) vs 9/95 (9.5%), P < 0.001, respectively).

Of the 148 children, at a median follow-up time of 8.7 (IQR 5.2–12.2) years, 21 (14.2%) and 9 (6.1%) children had developed chronic kidney disease (CKD) stage III or end-stage kidney disease (ESKD), respectively. The mean duration from CKD stage III to ESKD was 5.0+5.5 months.

Conclusions

Seventy percent of FRNS/SDNS children achieved remission with either Cy A or cyclophosphamide, but the SRNS children achieved remission proportionately better with Cy A than cyclophosphamide. However, the Cy A-treated children had higher proportions of infections and AKI than the cyclophosphamide treatment group. Overall, one-fifth of the relapsed childhood NS children developed CKD.
#1442 Retrospective evaluation of etiology, clinical and laboratory findings in patients diagnosed with secondary and genetic FSGS
Authors: Yilmaz Aysenur , Suleymanova Vafa , Dirim Ahmet Burak , Kalayci Tugba , Artan Ayse Serra , Oto Ozgur Akin , Ozturk Sukru , Palanduz Sukru , Ozturk Savas , Turkmen Aydin , Yazici Halil
Published: May 2024

Background and Aims

Focal segmental glomerulosclerosis (FSGS) is a glomerulonephritis characterized by segmental sclerosis in at least one of the glomeruli and may develop due to primary, secondary, genetic etiology. We compared clinical, histopathological, and laboratory findings, treatment options, and response to treatment in patients with secondary and genetic FSGS.

Method

This study analyzed 172 patients with secondary and genetic FSGS at our Glomerular Diseases Clinic (1987-2022). Criteria included at least 16 weeks of follow-up, absence of other primary glomerular diseases, and age over 18. Retrospective data were collected on demographics, diagnosis, renal biopsies, genetic tests, imaging, treatments, treatment responses, end-stage renal disease (ESRD) development, and transplantation. The focus was on predicting genetic FSGS and ESRD.

Results

103 of our patients were female (59.8%), and the mean age at diagnosis was 38.46 ± 13.75 years. Of these patients, 29 were diagnosed with genetic FSGS and 141 with non-genetic secondary FSGS. Forty-one patients with non-genetic secondary FSGS were obese, and 21 had a single kidney. The patients had a median follow-up of 78 (38-134) months. 28 patients developed ESRD during follow-up, 16 of whom underwent renal transplantation. Familial renal disease (p < 0.001), familial ESRD (p < 0.001), and hematuria at diagnosis (p = 0.005) were more common in patients with genetic FSGS. Comparison of genetic FSGS and non-genetic secondary FSGS patients shown in Figure 1. The number of glomeruli with global sclerosis (p = 0.006) and C3 accumulation (p = 0.048) on renal biopsy was more frequent in patients with ESRD. Comparison of ESRD and non-ESRD patients are shown in Figure 2.

Conclusion

Differentiating genetic and non-genetic secondary FSGS is vital in clinical practice. For those with a family history of renal disease, hematuria, or unresponsive to immunosuppressive therapy, consider genetic FSGS and request genetic testing. Patients with secondary FSGS, diagnosed with high creatinine, a substantial presence of sclerosing glomeruli on biopsy, and C3 accumulation, should be closely monitored for ESRD.
#1782 Clinicopathological study of renal limited pauci-immune vasculitis and its short-term outcome: a single centre observational study
Authors: Sangma Benjamin , Sharma Manjuri , Doley Prodip
Published: May 2024

Background and Aims

Pauci immune crescentic glomerulonephritis, is a leading cause of RPGN. The majority of patients with PICGN have glomerular diseases as a part of a systemic small vessel vasculitis, a minority may present as renal-limited vasculitis. In north-east India, there are still no major studies in this group of patients. Therefore, our study involving north-east Indian population constitutes an effort to prospectively study the clinico-pathological feature of patients with PICGN and assess the short-term outcome.

Method

This single-centre, prospective, observational, study was conducted over 12 months at the Department of Nephrology, Gauhati Medical College. All renal biopsy-proven patients with pauci-immune renal vasculitis were included, excluding those with secondary vasculitis. Baseline characteristics and laboratory data were recorded, and disease activity was assessed using the Birmingham Vasculitis Activity Score. The ANCA tests were performed using a standardised essay for both indirect immunofluorescence assay and antigen-specific ELISA. The renal biopsy specimen obtained was evaluated by light microscopy and direct immunofluorescence. The sample size was calculated based on the prevalence of pauci-immune glomerulonephritis, and data were analysed using SPSS.

Results

The study involved 24 patients, predominantly females (70.83%), aged 14-65 years, presenting predominantly with pedal oedema and oliguria. Laboratory findings showed varying levels of haemoglobin, total count, platelet count, creatinine, and 24-hour urine protein. 50% of the patients were (MPO) positive, 33.3% were (PR3) positive while 16% were ANCA negative. Renal biopsy analysis showed a majority with mixed class according to the Berden classification. Treatment involved induction with Methylprednisolone and Cyclophosphamide, with dialysis administered to 58.3% of patients. At six months, 36.3% had a stable GFR, and 50% were on maintenance hemodialysis. Factors predicting renal loss included oliguria, dialysis at presentation, and fibrous/fibrocellular crescents. The best predictor of renal outcome was serum creatinine at presentation.

Conclusion

Pauci-immune CrGN is a severe disease affecting a wide age range. Early diagnosis and treatment initiation are crucial for better outcomes, including lower ESRD risk and relapse rates. Prognostic factors include baseline serum creatinine levels and fibrous crescents. Optimising treatment regimens may improves outcomes.
#1165 Targeted-release budesonide can preserve the glomerular filtration rate in patients diagnosed with IgA nephropathy after 3 months of administration.
Authors: Keskinis Christodoulos , Moysidou Eleni , Pateinakis Panagiotis , Christodoulou Michalis , Stai Stamatia , Zoidakis Jerome , Stangou Maria
Published: May 2024

Background and Aims

The four-hit hypothesis constitutes the main immunological sequence of the IgA nephropathy (IgAN) pathogenesis. However, the activation of intestinal-renal axis is considered the initial step during IgA nephropathy (IgAN) pathogenesis. Aim of this prospective pilot study is to evaluate parameters which influence early response to targeted release budesonide.

Method

Adult IgAN patients, diagnosed the last 10 years, maintaining eGFR >30 ml/min/1.73m2 and Uprotein >750 mg/24 hr, despite standard supportive treatment, commenced on budesonide 16 mg/d, and followed for 3 months. Renal biopsies were re-evaluated and scored according to Oxford classification, parameters of renal function recorded at time of diagnosis (T-d),at the beginning of treatment (T0), and 3 months later (T3).

Results

Fifteen IgAN patients, M/F:12/3, Mean age: 52 (34-74) years from two different departments fulfilled the criteria and they have already started on budesonide treatment, 51.6 ± 45 months following diagnosis. eGFR had declined from T-d to T0, 57.43 ± 10.58 to 49.23 ± 13.63 ml/min/1.73 m2, p = 0.03, and Uprot was stable 3.33 ± 1.16 to Uprot = 2.98 ± 1.19 gr/24 hrs, p = NS. During the 3 first months of budesonide (T3), eGFR showed slight improvement, eGFR = 54.38 ± 13.67 while Uprot remained stable 3.17 ± 1,04 gr/24 hrs. Improvement in renal function was not associated with any of histologic findings, but was remarkably more evident within patients with <4 years of diagnosis, eGFR from 62 ± 5.2 to 73 ± 2.4, compared to change in the eGFR from 23 ± 5.6 ml/min/1.73 m2 to 25 ± 3.6 ml/min/1.73 m2.

Conclusion

Our preliminary findings suggest that, independent of renal histology, budesonide treatment showed a trend in improving renal function, mainly in patients with relatively short time from diagnosis. So, budesonide can
#1347 Development and validation of a nomogram for predicting complete kidney function recovery after drug-induced acute interstitial nephritis
Authors: Caravaca-Fontán Fernando , Praga Manuel , Fernández-Juárez Gema
Published: May 2024

Background and Aims

Drug-induced acute interstitial nephritis (DI-AIN) represents a common cause of acute kidney injury. Early withdrawal of the culprit drug along with corticosteroid therapy (CS) remains the mainstay of treatment. Despite this, up to 50% of patients may not fully recover kidney function after DI-AIN.

The aims of this study were to develop and externally validate a predictive nomogram to assess the probability of complete recovery (CR) of kidney function at 6 months after treatment.

Method

Multicenter, retrospective, observational study in 13 nephrology departments belonging to the GLOSEN group. Patients with biopsy proven DI-AIN treated with CS between 1996-2023 were included. Other potential causes of AIN such as infections or systemic diseases were carefully ruled out. Dataset was randomly divided into training group (n = 164) and validation group (n = 60). The least absolute shrinkage and selection operator (LASSO) regression was used to screen the main predictors of CR (serum creatinine value <25% of the last value before DI-AIN), and used to build the nomogram. Accuracy of the nomogram was assessed by discrimination and risk calibration, in the training and validation sets.

Results

The study group comprised 224 patients with DI-AIN, of whom: 51 (31%) in the training group and 19 (32%) in the validation set, achieved CR at 6 months after treatment with CS. Median age was 70 (IQR 57–76), and 115 (51%) were males. The clinical characteristics were well balanced between the training and validation data sets. The selected variables by LASSO were age (under/above 65 years), gender, degree of interstitial fibrosis and time to CS initiation (under/above 7 days). Based on multivariable logistic regression model, a nomogram was developed for assessing the probability of CR (Fig. 1). The area under the curve (AUC) of the nomogram was 0.809 (95% CI 0.721–0.880) indicating a good discriminative power. Bootstrap self- sampling was performed 1000 times for validation of the nomogram model. The AUC was 0.837 (95 % CI: 0.705–0.931), indicating good predictive stability. Calibration plot revealed that the predicted outcomes aligned well with the observations. Decision curve analysis (DCA), and clinical impact curve analysis (CICA) suggested that the model had clinical benefit.

Conclusion

We constructed and validated a practical nomogram with good discrimination and calibration, to predict the probability of CR of kidney function at 6 months in DI-AIN treated with corticosteroids. This clinical tool can provide clinicians with an estimate of kidney prognosis and can potentially assist them in titrating the intensity and duration of corticosteroid therapy.
#1495 5 and 10 year kidney outcomes in acute interstitial nephritis: a retrospective single-centre cohort study
Authors: Sebastian Kuruvilla , Cowhig Cliona , Coughlan Conor , Mayer Nick , Burke Louise , Gleeson James , Eustace Joseph , Moran Sarah , Clarkson Michael
Published: May 2024

Background and Aims

Acute interstitial nephritis (AIN) is a common cause of acute kidney injury (AKI), histologically characterized by an interstitial inflammatory cell infiltrate. Data regarding long term kidney outcomes is lacking. We performed a retrospective cohort study to evaluate the long-term kidney and mortality outcomes in patients with biopsy-proven AIN between 2011-2018.

Method

We serve as a tertiary referral centre and sole nephrology provider for a population of over 650,000 people. We identified biopsy-proven AIN cases from the years 2011-2018 from our pathology database. Demographic data, creatinine, eGFR (calculated using CKD-EPI 2021 formula), dialysis and mortality data were collected from our electronic medical record. Ethical approval was obtained.

Results

Between 2011 – 2018, 576 native kidney biopsies were performed in our centre. 66 (11.5%) cases had pathologically confirmed AIN as the primary kidney diagnosis. Long-term outcome data was available for 90.9% (60).

The median age at time of biopsy was 52.5 years (IQR 41.5 - 68.3). 68% of patients were male. The aetiology of AIN was medication in 42%, autoimmune in 15% and infection-associated in 3%. Of the cases of drug-induced AIN the predominant culprits agents were non-steroidal anti-inflammatories 28%, proton pump inhibitors in 24%, antibiotics 20%, with other medications in 8%.

The median eGFR at the time of biopsy was 13.6 (IQR 7.9 -25.4) mls/min/1.73 m2. The median eGFR at year 1 was 47.8 (IQR 30.7 - 72.7) mls/min/1.73 m2, 54.4 (IQR 31.2 -79.6) mls/min/1.73 m2 at year 5 and 69.4 (IQR 19.9 - 86.1) mls/min/1.73 m2 at year 10. See Table 1 for results.

At one year 64.3% of cases had eGFR < 60 mls/min/1.73 m2 (CKD III or higher). Interestingly the rate of CKD was lower at years 5 and 10 (54.7% and 50% respectively). GFR <30 mls/min (CKD IV or higher) were present in 25% at year 1, 26% at year 5 and 37% at year 10.

23% (14/60) people had dialysis-requiring AKI at the time of biopsy. Of these 21.4% (3) remained dialysis dependent at one year. In this group, no additional cases of ESKD were seen between years 1 through 5, one additional case of ESKD occurred by year 10.

A composite outcome of kidney failure (GFR <15, dialysis or kidney transplantation) occurred in 48.2% at year 1, 54.7% at year 5 and 56.2% at year 10.

Mortality data was available on 58 patients. 18.9% (11) people had died at 10 years follow-up. 8 out of the 11 deaths were within 5 years, 2 of which were within 1 year of diagnosis.

Conclusion

In this single centre study, kidney failure occurred in 48% of people at 10 years of follow up. 78% of dialysis-requiring cases recover independent renal function.
#163 Multiome-seq and spatial transcriptomics of refractory PLA2RAb(+) membranous nephropathy reveals importance of immunomodulatory function of B cells
Authors: Park Sehoon , Joo Kwon Wook , Kim Dong Ki
Published: May 2024

Background and Aims

PLA2RAb-associated membranous nephropathy (MN) is a glomerulonephritis that may require immunosuppression to achieve proteinuria remission. However, the disease course is heterogeneous, and some patients exhibit refractory or relapsing nephrotic-range proteinuria. Additional biomarker studies are necessary to dissect the molecular profiles that reflect substantial differences in treatment response and clinical courses. Multiome-seq includes the investigation of gene expression profiles and ATAC-sequencing for open-chromatin regions, which may reveal pathophysiologic gene expression biomarkers and pathways.

Method

We performed multiome-sequencing of peripheral blood mononuclear cells (PBMCs) from 6 refractory or relapsing primary PLA2RAb-associated MN cases, 7 PLA2RAb-associated MN cases that reached complete remission, and disease controls including 6 minimal change disease and 6 diabetic kidney disease cases. We also collected PBMCs from 7 healthy controls. Cell type clustering, comparison of cell type proportions, and differential gene expression analysis were performed. Additionally, we conducted ATAC-sequencing analysis and identified open-chromatin profiles specific to the refractory or relapsing MN group. Lastly, we investigated the glomerular spatial transcriptome using GeoMx digital spatial profiling to determine whether transcriptomic profiles differ based on the disease courses of MN in the initial kidney tissue.

Results

We successfully identified diverse PBMCs in the multiome-seq data. In the DEG analysis, we identified a number of cell-type-specific DEGs in the refractory or relapsing MN cases. Of these, CD83 was the top gene that was lowly expressed in the B cells of refractory/relapsing MN compared to the remission cases. In the ATAC data, among the number of differentially expressed peaks, NFKB2 was the region that consistently showed a low open chromatin profile in the B cells of CD83. When comparing the cell subtype proportions, refractory or relapsing MN cases showed low regulatory T cells in the peripheral blood. Lastly, in the kidney tissue spatial transcriptomic profiling, there were no significant DEGs between the refractory/relapsing MN and MN with remission in the glomerulus.

Conclusion

The clinical course or risk of remission of PLA2RAb-associated MN was more likely a result of differences in systemic immunity rather than differences in the glomerular transcriptome at the initial diagnosis. Both CD83 and NFκB2 are well-known biomarkers of activated B cells that may have immunomodulatory roles leading to the enrichment of regulatory T cells. Such a deficient immunomodulatory status in refractory/relapsing PLA2RAb-associated MN may explain the disease course.
#2095 Genetic kidney disease in pregnancy – experience of tertiary referral hospital
Authors: Marchão Natália , Da Costa José Oliveira , Peres Nadiesda , Godinho Iolanda , Jorge Sofia , Rodrigues Márcia , Gonçalves Sara , Fonseca José Agapito , Centeno Mónica , Lopes José António , Pinto Luisa , Nogueira Estela
Published: May 2024

Background and Aims

Genetic kidney diseases (GKD) are rarely seen in pregnancy and some diagnosis will only be made during gestation, due to a high proportion of chronic kidney diseases (CKD) of unknown etiology and recent advances in genetic testing. Genetic counseling and, when possible, preimplantation genetic testing (PGT) should be offered pre-pregnancy to this specific CKD population.

Method

Retrospective analysis of maternal, obstetric and perinatal outcomes of pregnant women with GKD surveilled at Hospital Santa Maria, at the nephro-obstetric clinic from 2011 to 2023.

Results

We evaluated 34 pregnancies in 28 women, mean maternal age 30±6 years-old [21-37], 89% Caucasian. Molecular genetic testing was performed pre-pregnancy, during and post-pregnancy in 12/19, 2/19 and 5/19 patients, respectively. At baseline, mean serum creatinine (SCr) and proteinuria (Pr) was 1.0±0.9 mg/dL and 222±516 mg/g, with CKD stage 1/2/3/4/5 in 27/2/2/1/2 gestations and chronic hypertension (HTN) in 11/34 pregnancies. Only 1/28 patients performed PGT, while 1/28 patient declined it.

De novo or increased Pr occurred in 10/34 gestations and de novo or worsening HTN in 5/34 gestations. Deterioration of renal function occurred in one patient (CKD3) without recovery and one patient (CKD5) induced dialysis 4 months post-pregnancy. Nephrotic Pr developed in 4/34 gestations. One patient (FSGS APOL1) was treated with tacrolimus and low dose steroids. The patient with TSC re-started sirolimus on week 22 to treat severe fetal ventricular rhabdomyoma. Miscarriage occurred in 2 pregnancies. The C section rate was 21,8%. There were 7 preterm deliveries of which 3 before 32 weeks of pregnancy, mainly due to severe preeclampsia. Mean gestational age at delivery was 37,6 ± 4 weeks (26-41), mean birth weight 2756 ± 831 g (560-3835). Eight newborns were admitted to neonatal ICU due prematurity, fetal TSC, and feeding difficulties. Pulmonary hemorrhage and sepsis caused the death of 2 newborns. We found 1 maternal death, due to rupture of a cerebral aneurism 1 month postpartum (PKD patient).

Conclusion

Our cohort was very heterogenous regarding CKD etiologies, but generally with good kidney function, which allowed overall good obstetric outcomes. Still, maternal, obstetric and fetal complications, namely HTN, Pr, PE and prematurity had an increased incidence compared to pregnancy in healthy patients. This particular population should be approached by an experienced multidisciplinary team in CKD pregnancy care to optimize outcome.