Common Form Of Primary Glomerulonephritis Research Articles

Genome-wide analysis of long noncoding RNAs as cis-acting regulators of transcription factor-encoding genes in IgA nephropathy.

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis in the world, but the disease pathogenesis noncoding is yet to be elucidated. Previous studies have revealed regulatory functions for long noncoding RNA (lncRNA) in various diseases; however, the roles of lncRNA in IgAN and regulation of transcription factors (TFs) have been scarcely investigated. Renal tissue samples (n = 5) from patients with IgAN and control samples (n = 4) were collected and RNA sequencing (RNA-seq) was performed. Four software programs were employed for lncRNA prediction. GO (Gene Ontology)/KEGG (Kyoto Encyclopedia of Genes and Genomes) were employed for analysis of the identified differentially expressed genes (DEGs). A regulatory network model of DE lncRNA-TF-DEG was developed, and the levels of expression of key lncRNAs, TFs, and corresponding target genes were assessed using qRT-PCR and immunofluorescence. The current study identified 674 upregulated and 1,011 downregulated DE mRNAs and 260 upregulated and 232 downregulated DE lncRNAs in IgAN samples compared with control samples. The upregulated DE mRNAs showed enrichment in cell adhesion and collagen glial fiber organization pathways. The DE lncRNAs-DE mRNAs showing co-expression are associated with transmembrane transport. A novel regulatory network model of lncRNA-TF-DEG has been developed. This study identified seven TFs that are cis-regulated by 6 DE lncRNAs, and show co-expression with 132 DEGs (correlation coefficient ≥ 0.8, P ≤ 0.01), generating 158 pairs that showed co-expression. The lncRNAs NQO1-DT and RP5-1057120.6 were found to be highly expressed in IgAN samples. The TFs vitamin D Receptor (VDR) and NFAT5, along with their target genes were also aberrantly expressed. Key lncRNAs and TFs centrally associated with IgAN have been identified in this study. A regulatory network model of lncRNA-TF-mRNA was constructed. Further studies on the genes identified herewith could provide insight into the pathogenesis of IgAN.

Sparsentan, a Dual Endothelin Type A and Angiotensin II Subtype 1 Receptor Antagonist for the Treatment of Immunoglobulin A Nephropathy: Latest Trial Results, Pharmacokinetic Considerations, and Binding Profile

Immunoglobulin A nephropathy (IgAN) is one of the most common forms of primary glomerulonephritis. In some patients, it can progress rapidly, leading to proteinuria, kidney failure, and death. Standard of care is traditionally with an angiotensin converting enzyme inhibitor (ACEi), or an angiotensin II (Ang II) receptor blocker (ARB). More recently, drugs targeting both endothelin 1 (ET-1) and Ang II receptors have been developed, as overactivation of such is implicated in IgAN. Sparsentan is a dual ET Type A (ETAR) and Ang II subtype 1 receptor (AT1R) antagonist. The PROTECT study compared sparsentan with the ARB irbesartan, in patients with IgAN and with proteinuria of ≥1 g/day despite stable dose of ACEi/ARB for ≥90 days. Data presented at the 2023 American Society of Nephrology (ASN) Kidney Week showed that use of sparsentan led to sustained (>110 weeks) decreases in proteinuria, and a significantly greater preservation of kidney function, compared with irbesartan. The ongoing SPARTAN study is investigating the use of sparsentan in recently diagnosed, treatment-naïve patients with IgAN. Preliminary data in 12 patients showed rapid and sustained proteinuria reductions, with little change from baseline in estimated glomerular filtration rate (eGFR), body weight, or total body water mean at Week 36. In both studies, sparsentan was generally well-tolerated with, in PROTECT, a comparable safety profile to irbesartan. Data presented at the congress also showed that sparsentan consistently occupies AT1R at levels exceeding ETAR occupancy. This balance is hypothesised to contribute to sparsentan’s limited risk of fluid retention.

#5392 THE DIAGNOSTIC JOURNEY OF PATIENTS WITH IMMUNOGLOBULIN A NEPHROPATHY: DATA ANALYSIS OF A REAL-WORLD SURVEY

Abstract Background and Aims Although rare (estimated global annual incidence of 25 cases per million people), immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis. IgAN is associated with a poor prognosis, with 30% or more of patients with >1g/day of proteinuria progressing to kidney failure within 10 years. As poor prognosis is partly due to delayed diagnosis, this analysis aims to describe aspects of the diagnostic pathway for patients with IgAN. Method Data were drawn from the Adelphi IgAN Disease Specific Programme (DSP)™, a point-in-time survey of IgAN-treating nephrologists and their consulting patients, conducted in the United States (US), Europe (EU5: France, Germany, Italy, Spain, United Kingdom [UK]), Japan, and China, between June and October 2021. Nephrologists completed structured online patient record forms for successive patients presenting with IgAN, including demographics, clinical data, time to diagnosis, reasons for delayed diagnosis, and treatment history. A duration of greater than four weeks between first consultation with a physician and diagnosis was considered a delayed diagnosis. Results A total of 295 nephrologists completed records for 1537 patients which had data characterizing the time from first consultation and diagnosis. Mean (standard deviation (SD)) patient age was 43.0 (15.0) years, and 59% were male. At diagnosis, mean (SD) proteinuria (n = 1254) was 2.3 (2.4). Median time from first physician consultation to confirmed IgAN diagnosis varied by physician speciality. When patients initially consulted a nephrologist regarding their IgAN symptoms, median (interquartile range) duration from first consultation to diagnosis was 2.4 (0.7-5.6) weeks (n = 582). For family doctors/ General Practitioners (GPs)/ Primary Care Physicians (PCPs) (n = 656), this was 6.6 (3.0-13.8) weeks, for internal medicine/ internists (n = 120) and urologists (n = 113) the duration was 4.4 (1.3-9.4 and 1.5-12.5) weeks. Most patients were diagnosed by a nephrologist (US 95%, n = 263; EU5 96%, n = 491; Japan 99%, n = 236; China 98%, n = 547). A delayed diagnosis was found in 56% of patients. Across countries, waiting to conduct tests (41%), waiting for referral to a specialist (34%) and waiting for test results (32%) were the top three reasons for delay, except for Japan where 29% of patients were unable to consult sooner. A smaller proportion of patients who experienced a delay initially consulted with a nephrologist (27%) compared to those who did not experience a delay (52%). 78% of patients in China, diagnosed within 4 weeks, were diagnosed by a nephologist. Of the patients who experienced a delay in diagnosis, a higher proportion initially consulted a family doctor/ GP/ PCP (53%) compared to other physician types. In most cases, a kidney biopsy was used for diagnosis (US 89%, n = 263; EU5 81%, n = 491; Japan 98%, n = 236; China 85%, n = 547) and these were typically performed by a nephologist in most countries (US 59%, n = 233; EU5 81%, n = 397; Japan 95%, n = 231; China 97%, n = 464) except in the US, where 40% of cases were done by a radiologist. However, some patients were unable to undergo a biopsy (6%, n = 1531) and in some cases the physician chose to diagnose the patient using non-invasive methods (8%, n = 1531). Conclusion Most of the patients with IgAN in this survey were diagnosed by a nephrologist using a kidney biopsy. These data suggest that initially consulting a family doctor/ GP/ PCP led to a delayed diagnosis for patients. This may be due to the time taken for onward referral to a nephrologist. China had the highest proportion of patients diagnosed within 4 weeks from the first consultation (57%) and the highest proportion of patients who first visited a nephrologist regarding their symptoms. The results from this study suggest that speeding up referral from PCPs to nephrologists may reduce the amount of time taken to confirm IgAN diagnosis.

The Landscape of IgA Nephropathy Treatment Strategy: A Pharmacological Overview

IgA Nephropathy (IgAN) is the most common form of primary glomerulonephritis and is one of the most common causes of end-stage kidney disease (ESKD) worldwide. The immunopathogenic mechanism underlying IgAN is poorly identified. Currently, the mainstay treatment of IgAN is centered on the optimization of blood pressure and a reduction in proteinuria, using an angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs). According to KDIGO, patients who persistently remain at a high risk of progressive ESKD, despite maximal supportive care, are candidates for glucocorticoid therapy. Recent discoveries regarding the pathogenesis of this disease have led to the testing of new therapeutic drugs targeting, in particular, the excessive mucosal immune reaction and the resulting systemic response as well as the complement activation and the following kidney damage and fibrosis. In this review, we examine the various therapeutic approaches to this intriguing disease.

Corticosteroids in the treatment of IgA nephropathy: lessons from the TESTING trial.

IgA nephropathy (IgAN), the most common form of primary glomerulonephritis, is mainly observed in young adults and children. Clinical and basic studies indicate the role of immunity in IgAN pathogenesis; however, corticosteroid therapy has been controversial in past decades. The TESTING study, initiated in 2012, is an international, multicenter, double-blinded, randomized, placebo-controlled trial that aimed to evaluate oral methylprednisolone's safety and long-term efficacy under conditions of optimized supportive treatment in patients with IgAN whose risk of progression is high. After a decade of effort, the successful completion of the TESTING study showed that a 6- to 9-month course of oral methylprednisolone is an effective regimen to protect kidney function in high-risk patients with IgAN, but also demonstrated safety concerns. Compared with the full-dose regimen, the reduced-dose regimen was reported to be beneficial, with successfully increased safety. Overall, the TESTING trial provided more data regarding the treatment dosage and safety of corticosteroids, a cost-effective therapy, in IgAN, which have important implications for pediatric patients with IgAN. With a deeper understanding of the disease pathogenesis of IgAN, ongoing studies of novel therapeutic regimens would help further optimize the benefit-risk ratio.

Podocytopathy Associated with IgA Nephropathy in Pregnancy: A Challenging Association

IgA nephropathy is the most common form of primary glomerulonephritis. While associations of IgA and other glomerular diseases have been described, the association of IgA nephropathy with "primary" podocytopathy is rare and has not been reported in pregnancy, due in part to the infrequent use of kidney biopsy during pregnancy, and a frequent overlap with preeclampsia. We report the case of a 33-year-old woman with normal kidney function, referred in the 14th gestational week of her second pregnancy, due to nephrotic proteinuria and macroscopic hematuria. The baby's growth was normal. The patient reported episodes of macrohematuria one year previously. A kidney biopsy performed at 18 gestational weeks confirmed IgA nephropathy, associated with extensive podocyte damage. Treatment with steroids and tacrolimus led to remission of proteinuria and a healthy baby, adequate for gestational age, was delivered at 34 gestational weeks and 6 days (premature rupture of membranes). Six months after delivery, proteinuria was about 500 mg per day, with normal blood pressure and kidney function. This case highlights the importance of timely diagnosis in pregnancy and underlines that good maternal and fetal outcomes can be achieved with appropriate treatment, even in complex or severe cases.

Research progress of IgA nephropathy markers

IgA nephropathy is one of the most common forms of primary glomerulonephritis, and its clinical presentation and prognosis vary greatly among individuals, so early identification of individuals at high risk of poor prognosis is crucial. Currently, the clinical predictors of IgAN include hypertension, proteinuria, glomerular filtration rate and Oxford pathological staging, which are non-specific, invasive and delayed. With further research into the pathogenesis of IgAN, some new, simpler and earlier biomarkers have been identified. In this paper, the role of cytokine, protein and nucleic acid markers in the diagnosis of IgA nephropathy is described in a comprehensive manner based on the pathogenesis of IgA nephropathy. It is expected that based on the pathogenesis of IgA nephropathy, more markers of IgA nephropathy will be discovered by studying the four-fold strike doctrine and other related doctrines to help detect subclinical disease activity, monitor disease progression and assess treatment.

SUMO1 Promotes Mesangial Cell Proliferation Through Inhibiting Autophagy in a Cell Model of IgA Nephropathy.

IgA nephropathy (IgAN) is a common form of primary glomerulonephritis and its main pathological changes are mesangial cell proliferation and matrix expansion. Autophagy inhibition may result in its mesangial cell proliferation and renal lesions. SUMOylation is a eukaryotic-reversible post-translational modification where SUMO is covalently attached to target proteins to regulate their properties. It is largely unclear whether SUMOylation contributes to the pathogenesis of IgAN. This study was designed to investigate the change of protein SUMO1 in mesangial cells of IgAN and its association with autophagy. We found the expression of SUMO1 was upregulated in IgAN, IgA mouse model, and aIgA1-stimulated mesangial cells. In aIgA1-stimulated mesangial cell model, we tested LC3II/I and p62, the autophagy-related proteins suggested the inhibition of autophagy. Inhibited SUMOylation with ginkgolic acid (GA) or silencing SUMO1 could downregulate SUMO1 and SUMO1-p53, promote autophagy, and lessen cell proliferation. In summary, in the mesangial cells stimulated with aIgA1, SUMO1 may contribute to its cell proliferation through inhibited autophagy, and SUMO1-p53 may play a role in this process.

Metabolic Dysfunctions of Intestinal Fatty Acids and Tryptophan Reveal Immuno-Inflammatory Response Activation in IgA Nephropathy.

BackgroundImmunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis. Although an important link between intestinal metabolites and immune activity is widely established, the metabolic profile of IgAN is still poorly understood, which severely limits the mechanistic studies and therapy of IgAN.MethodsThe diversity of intestinal flora and relative abundance of metabolites in IgAN patients and healthy subjects were measured by 16s ribosomal RNA gene sequencing combined with liquid chromatography tandem-mass spectrometry. The levels of serum Gd-IgA1, IL-6, IL-10, IL-22, and TNF-a were tested by ELISA. We employed the tryptophan-targeted UHPLC-MRM-MS approach to assess the content of tryptophan metabolites quantitatively.ResultsIntestinal fatty acid levels, mainly unsaturated fatty acids, were observed to be dramatically decreased in IgAN patients. Disorders in linoleic acid and arachidonic acid metabolism, metabolic imbalances of anti-/pro- inflammatory fatty acid metabolites, and intestinal AhR signaling deficiency might reflect the damage of the intestinal mucosal barrier in IgAN patients. In addition, we found that high levels of Gd-IgA1, IL-22, and TNF-α were associated with the activity of the tryptophan-kynurenine metabolic pathway, as well as lower levels of 3-indolepropionic acid. 3-indolepropionic acid, kynurenine, and indoleacrylic acid had synergistic effects on regulating immuno-inflammatory responses in IgAN patients.ConclusionsThe metabolic characteristic of fatty acids and tryptophan in the intestinal system is disturbed in IgAN patients, leading to active immune-inflammatory reactions.

POS-996 Linkage analysis between the Fcα/μR gene and familial IgA nephropathy

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis around the world. Reports have also indicated that there is an increasing number of families worldwide in which two or more related family members are affected by IgAN; this form of IgAN is known as familial IgAN (FIgAN). Fc alpha/mu receptor (Fcα/μR, CD351) is a receptor with dual specificity for IgA and IgM that may correlate with IgAN.

POS-366 URINARY SOLUBLE CD163 LEVELS TO REFLECT PATHOLOGICAL CHANGE IN PRIMARY IgA NEPHROPATHY

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and the leading cause of CKD. Patients present from asymptomatic microscopic hematuria to macroscopic hematuria and/or proteinuria without specific therapy, leading to an urgent need for developing early diagnostic strategies. Currently, IgAN diagnosis is based on renal biopsy with the major risk of bleeding. Therefore, non-invasive and sensitive biomarkers are necessary for disease evaluation. A recent study revealed that macrophages were the main immune cells in kidneys of IgAN patients.

Efficacy of Modified Huangqi Chifeng decoction in alleviating renal fibrosis in rats with IgA nephropathy by inhibiting the TGF-β1/Smad3 signaling pathway through exosome regulation

IgA nephropathy is the most common form of primary glomerulonephritis and is a major cause of renal failure worldwide. Modified Huangqi Chifeng decoction (MHCD), a traditional Chinese herbal preparation, has clinical efficacy in reducing the 24-h urine protein levels in patients with IgA nephropathy. However, the molecular mechanism of MHCD needs further study. This study aimed to investigate the mechanisms by which MHCD treatment alleviates renal fibrosis. An IgA nephropathy rat model was established using bovine serum albumin, carbon tetrachloride, and lipopolysaccharide. The rats were divided into control, model, telmisartan, low-dose MHCD, medium-dose MHCD, and high-dose MHCD groups. Treatments were administered to these groups for 8 weeks. Subsequently, the 24-h urine protein, serum creatinine, blood urea nitrogen, and blood albumin levels were measured. Pathological changes and degree of fibrosis in renal tissues were observed, and levels of the transforming growth factor-β1 (TGF-β1)/Smad3 signaling pathway components in renal tissues and TGF-β1 in urinary exosomes were measured. Telmisartan and MHCD reduced 24-h urine protein levels, alleviated renal pathological injury, and decreased the renal expression of fibronectin, laminin, and collagen IV in rats with IgA nephropathy. Urinary exosomes were extracted and identified for further investigation of their role in renal fibrosis. MHCD reduced TGF-β1 expression in urinary exosomes and reduced TGF-β1 and p-Smad3 levels in renal tissues. MHCD alleviated renal fibrosis in rats with IgA nephropathy by inhibiting the TGF-β1/Smad3 signaling pathway through the downregulation of TGF-β1 expression in exosomes.

ХАРАКТЕРИСТИКА γδТ-ЛИМФОЦИТОВ У ПАЦИЕНТОВ С IgA-НЕФРОПАТИЕЙ

Currently, IgA-nephropathy is the most common form of primary glomerulonephritis resulted in the development of end-stage renal failure, the causes of which are not only genetic, but also environmental factors that contribute to epigenetic changes in the both cellular and humoral immunity. The main triggers of chronic autoimmune inflammation in IgA-ne- phropathy are environmental factors such as industrial pollutants, infectious agents, allergens and nephrotoxic xenobiotics resulted in not only the disruption of immunoglobulin A production in mucosae but also changes in the composition of microbiota and mucosal lymphoid cells, including the minor population of γδT-lymphocytes. In this study, the composition of γδT-cells subsets, their activation potential and cytotoxic activity were determined as well as the correlation of γδT-cells immunophenotype with biochemical and histological parameters of disease progression were established in patients with IgA-nephropathy. The redistribution of γδT-lymphocytes subsets in peripheral blood of patients with IgA-nephropathy was found characterizing by a predominance of tissue-resident cells (Vδ1+ and Vδ3+T-lymphocytes) and a statistically significant decrease of Vδ2+T-cells subpopulation as compared to the control group. It was shown that γδT-lym- phocytes did not demonstrate the cytotoxic activity, however, the detected increase of activated marker HLA-DR expression on Vδ1+ and Vδ3+T-lymphocytes indicated their possible antigen-presenting role in disease pathogenesis. The obtained results can be used as potential biomarkers in the early diagnosis of autoimmune kidney pathology.

Deletion of the miR-25/93/106b cluster induces glomerular deposition of immune complexes and renal fibrosis in mice.

IgA nephropathy (IgAN), the most common form of primary glomerulonephritis, is caused by immune system dysfunction and affects only the kidneys. miRNA was involved in IgAN, in which their roles are still unknown. Herein, we found increased glomerular medulla size, proteinuria, kidney artery resistance, kidney fibrosis and immune complex deposition in 5‐month miR‐25/93/106b cluster knockout (miR‐TKO) mice. In vitro, the inhibition of miR‐25 cluster could promote cell proliferation and increase fibrosis‐related protein and transferrin receptor (TFRC) expression in human renal glomerular mesangial cell (HRMC). Luciferase assay revealed that inhibition of miR‐93/106b cluster could upregulate Ccnd1 expression through direct binding with the 3’UTR of Ccnd1. Conversely, inhibition of Ccnd1 expression prevented miR‐93/106b‐induced effect in HRMC. These findings suggested that miR‐25 cluster played an important role in the progression of IgAN, which provided new insights into the pathogenesis and treatment of IgAN.

MO276TOTAL AND SPECIFIC IGE IN PATIENTS WITH IGA NEPHROPATHY

Abstract Background and Aims IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis characterized by impaired immunological tolerance. One of possible trigger factors for IgAN initiation and development are allergens which have been described to form IgA complexes deposited in the mesangium. Previous studies reported that serum immunoglobulin class E (IgE) levels are elevated and suggested as a prognostic indicator in glomerular diseases. However, mechanisms of IgE/IgG4-mediated allergic reactions involvement in IgAN as well as specific allergens and their clinical significance have poorly been investigated. The aim of the study was to assess the total serum IgE and IgG4 level and to determine the allergoprofile in IgAN patients. Method The peripheral blood was obtained from 21 IgAN patients (aged of 32.0 (27.0 ÷ 36.0) y.o., male/female ratio as 14/7) and 18 donors (aged of 38.0 (30.0 ÷ 46.0) y.o., male/female ratio as 10/8). IgAN diagnosis was confirmed in patients’ biopsy materials according to the Oxford classification (MEST-C score). The concentrations of total IgE and IgG4 were determined using «IgE total-ELISA-BEST» kit («Vector-Best», RF) and «Human IgG4 Platinum ELISA» kit («eBioscience», Austria)». Allergen-specific IgE to 55 inhalation (domestic, epidermal, fungal, plant) or food allergens were measured using «EUROLINE Atopy Screen IgE» immunoblot kit («Euroimmun», Germany). Statistical analysis was done in Statistica 8.0. Results The increased level of total IgE (in 47,4% of cases) but not IgG4 was established in sera of IgAN patients as compared to donors (p=0.004). Moreover, proteinuria was lower in IgAN patients with a high IgE level as compared to normal one (610 (220 ÷ 910) mg/day vs 1545 (600 ÷ 2200) mg/day, p=0.01) as well as there were no any crescent formation. The investigation of allergen-specific IgE in IgAN patients revealed a strong positive reaction to dust mite allergens of Dermatophagoides pter. (22,75 (16,72 ÷ 35,69) IU/ml – in 29% of cases) and Dermatophagoides farinae (38,24 (12,19 ÷ 65,88) IU/ml – in 43% of cases) correlated with the total IgE (R=0,57, p=0,03) and IgM (R=0,54, p=0,04). The more concentration of specific IgE to dust mite allergens was the lower the severity of segmental glomerulosclerosis (R= -0.55, p=0.04), crescent formation (R= -0.56, p=0.03), proteinuria (R= -0.65, p=0.01) and haematuria (R = -0.55, p = 0.04) were reported. A weak positive reaction was established to other domestic (house dust, honey bee venom, common wasp venom, cockroach), epidermal (cat), plant (sweet vernal grass, orchard grass, timothy grass, cultivated rye, alder, birch, hazel, oak, common ragweed, mugwort, plantain) and food (carrot, sesame, hazelnut, apple) allergens in 9–18% of IgAN patients. Conclusion The prevailing of specific IgE to dust mite allergens of Dermatophagoides pter. and Dermatophagoides farinae but not to food or plant allergens was determined in IgAN patients. The obtained data demonstrated that IgAN pathogenesis in patients with latent sensibilization to dust mite allergens is characterized by a milder disease course what allows to identify this cohort as possible secondary form of IgAN.

POS-762 IgA NEPHROPATHY IN KIDNEY TRANSPLANT RECIPIENTS: ONE CENTER EXPERIENCE

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis leading to end-stage kidney disease. Every year more and more patients with IgAN undergo kidney transplantation and each of these patients has the risk of recurrence in their renal transplant. As overall kidney graft survival rate has been improved the prevalence of recurrent glomerulonephritis, in particular IgA nephropathy, is expected to increase. Data from 612 kidney transplant biopsies performed in Minsk, Belarus from 2015 to 2020 were retrospectively evaluated. Cases of pre- and/or posttransplant IgA nephropathy were analyzed. 42 cases (6,86%) of posttransplant IgA nephropathy were identified. Only 8 of them (19%) had biopsy-proven IgA disease in native kidneys, so could be regarded as recurrent IgAN patients. Male to female ratio was 2:1. Mean age was 41,71 ± 11,78 years. Clinical indications for renal graft biopsy were: proteinuria more than 1.0 g per 24 hours with and without hematuria – 45,24%; proteinuria less than 1.0 g per 24 hours with and without hematuria – 42,86%; isolated hematuria – 9,52%; elevation in serum creatinine – 2,38%. The term from transplantation to IgAN revealing was from 1 to 122 month, with an average of 49,59 ± 30,34 month. 13 patients (30,95%) have lost their graft function and 11 of them (84,6%) had proteinuria greater than 1.0 g per day. The prevalence of IgA nephropathy in kidney transplant recipients was 6,68% and only 19% of posttransplant IgAN cases were considered as recurrent. The main clinical manifestation of IgAN in renal graft was proteinuria associated with hematuria. Graft survival rate was 69,05%. Such well-known risk factor of IgAN poor outcome in native kidneys as proteinuria more than 1.0 g per day potentially hold true to recurrent disease, as 84,6% of posttransplant IgAN patients with non-functional transplant had severe proteinuria. Histological verification of native kidney primary disease is definitely required for risk stratification and early recurrence predicting.

Identification of a novel interplay between intestinal bacteria and metabolites in Chinese patients with IgA nephropathy via integrated microbiome and metabolome approaches.

BackgroundImmunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis. The intestinal microbial ecosystem and metabolic network of IgAN have not been systematically analyzed. The present study aims to improve understanding of the gut microbiota and its metabolic capabilities to facilitate the development of diagnostic, therapeutic, and prognostic methods for IgAN.MethodsWe characterized the gut microbiota and metabolic patterns of fecal and serum samples of IgAN patients and healthy controls from the south of China using 16s ribosomal RNA gene sequencing and liquid chromatography-tandem mass spectrometry, respectively, and bioinformatics approaches.ResultsWe found that the relative abundances of Streptococcus and Enterococcus were higher in IgAN patients, whereas Bacteroidetes and Bacteroides were lower. Changes in the gut microbiota of IgAN affected the metabolism and absorbance of microbiota-associated metabolites, in particular polyunsaturated fatty acids, free amino acid, and oligopeptides, and activated the phenylalanine metabolism pathway, thereby constructing a unique metabolic system of IgAN. We identified six pivotal metabolites, including bilirubin, trimethoprim, stearamide, phenylalanine, cis-9,10-epoxystearic acid, and phosphatidylethanolamine 17:0, that connected the metabolic networks of the gut and blood. Additionally, 5-hydroxyeicosatetraenoic acid and 5-hydroxy-6E,8Z,11Z-eicosatrienoic acid were shown to be associated with the classification of glomerular sclerosis.ConclusionsWe establish a relational network between microbiota, fecal metabolites, and serum metabolites in IgAN. The core microbiota and metabolites identified have promising value in therapeutic applications.

Differential expression of transfer RNA-derived small RNAs in IgA nephropathy.

Background:IgA nephropathy (IgAN) is one of the most common forms of primary glomerulonephritis. Recent studies have indicated that small noncoding RNAs, such as tRNA-derived small RNAs (tsRNAs), might be novel biomarkers for glomerulonephritis. We therefore investigated the potential roles and possible functions of the tsRNAs in IgAN.Method:Peripheral blood mononuclear cells (PBMCs) were extracted from blood samples of the patients with IgAN and healthy control groups. The expression profiles of tsRNAs were assessed by small RNA sequencing (RNA-Seq) in PBMCs of the IgAN and control groups. Dysregulated tsRNAs were selected for validation by quantitative real-time polymerase chain reaction (qRT-PCR). Target gene prediction and enrichment were performed by bioinformatics analysis.Results:The results revealed that 143 significantly upregulated and 202 significantly downregulated tsRNAs were differentially altered in the IgAN group compared with the control group. Five upregulated tsRNAs (tRF-Val-AAC-007, tRF-Ala-AGC-063, tRF-Gln-CTG-010, tRF-Tyr-GTA-011 and tRF-Thr-AGT-007) and 3 downregulated tsRNAs (tiRNA-Val-TAC-004, tRF-Gly-CCC-005 and tRF-His-GTG-006) were selected for validation by qRT-PCR; the results were consistent with the sequencing data. Gene Ontology (GO) analysis revealed that the target genes predicted by upregulated tsRNAs were mostly enriched in “nucleic acid metabolic process," “intracellular part," and “ion binding," whereas the target genes predicted by downregulated tsRNAs were mostly enriched in “regulation of cellular component organization," “membrane-bound organelle," and “ion binding." Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the target genes predicted by upregulated tsRNAs were mostly enriched in “herpes simplex virus 1 infection," whereas the target genes predicted by downregulated tsRNAs were mostly enriched in “circadian rhythmConclusions:The present study confirmed the differential expression of tsRNAs in patients with IgAN, and these dysregulated tsRNAs might be novel potential targets for the diagnosis and treatment of IgAN.

P0364A NOVEL INTERPLAY BETWEEN INTESTINAL BACTERIA AND METABOLITES IN IGA NEPHROPATHY IDENTIFIED VIA INTEGRATED MICROBIOME AND METABOLOME APPROACHES

Abstract Background and Aims Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis. Intestinal bacteria and their metabolites have been implicated in various diseases. Improved understanding of the gut microbiota and its metabolic capabilities will facilitate development of diagnostic, therapeutic, and prognostic methods for IgAN Method We identified gut microbiota and metabolite biomarkers of IgAN by analyzing microbiomes and metabolomes of fecal and serum samples of IgAN patients and healthy controls using 16s ribosomal RNA gene sequencing and liquid chromatography-tandem mass spectrometry, respectively, and bioinformatics approaches Results We found that relative abundances of Streptococcus and Enterococcus were higher in IgAN patients, whereas Bacteroidetes and Bacteroides were lower. The changes in gut microbiota affected metabolism and absorbance of microbiota-associated metabolites of IgAN patients, in particular polyunsaturated fatty acids, free amino acids and oligopeptides, and activated the phenylalanine metabolism pathway. Also, 5-hydroxyeicosatetraenoic acid and 5-hydroxy-6E,8Z,11Z-eicosatrienoic acid were proved to be associated with the classification of segmental glomerular sclerosis but not 24h urine protein and estimated glomerular filtration rate. Conclusion Our findings demonstrate an interplay between intestinal bacteria and metabolites in IgAN. The identified metabolites may have diagnostic and therapeutic applications.

Homocysteine and IgA nephropathy: observational and Mendelian randomization analyses.

Background:High levels of plasma homocysteine occur almost uniformly in patients with end-stage renal disease (ESRD). IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis and a common cause of ESRD in young adults. Here, we aimed to detect whether homocysteine was elevated and associated with clinical-pathologic manifestations of IgAN patients and tested its causal effects using a two-sample Mendelian randomization (MR) approach.Methods:For observational analysis, 108 IgAN patients, 30 lupus nephritis (LN) patients, 50 minimal change disease (MCD) patients, and 206 healthy controls were recruited from April 2014 to April 2015. Their plasma homocysteine was measured and clinical-pathologic manifestations were collected from medical records. For MR analysis, we further included 1686 IgAN patients. The missense variant methylenetetrahydrofolate reductase C677T (rs1801133) was selected as an instrument, which was genotyped by TaqMan allele discrimination assays.Results:Majority of IgAN patients (93.52%, 101/108) showed elevated levels of plasma homocysteine (>10 μmol/L). Plasma homocysteine in IgAN patients was significantly higher than that in MCD patients (median: 18.32 vs. 11.15 μmol/L, Z = −5.29, P < 0.01) and in healthy controls (median: 18.32 vs. 10.00 μmol/L, Z = −8.76, P < 0.01), but comparable with those in LN patients (median: 18.32 L vs. 14.50 μmol/L, Z = −1.32, P = 0.19). Significant differences were observed in sub-groups of IgAN patients according to quartiles of plasma homocysteine for male ratio (22.22% vs. 51.85% vs. 70.37% vs. 70.37%, χ2 = 14.29, P < 0.01), serum creatinine (median: 77.00 vs. 100.00 vs. 129.00 vs. 150.00 μmol/L, χ2 = 34.06, P < 0.01), estimated glomerular filtration rate (median: 100.52 vs. 74.23 vs. 52.68 vs. 42.67 mL·min−1·1.73 m−2, χ2 = 21.75, P < 0.01), systolic blood pressure (median: 120.00 vs. 120.00 vs. 125.00 vs. 130.00 mmHg, χ2 = 2.97, P = 0.05), diastolic blood pressure (median 80.00 vs. 75.00 vs. 80.00 vs. 81.00 mmHg, χ2 = 11.47, P < 0.01), and pathologic tubular atrophy and interstitial fibrosis (T) (T0/T1/T2: 62.96%/33.33%/3.70% vs. 29.63%/40.74%/29.63% vs. 24.00%/48.00%/28.00% vs. 14.81%/37.04%/48.15%, χ2 = 17.66, P < 0.01). The coefficient of each rs1801133-T allele on homocysteine levels after controlling age and sex was 7.12 (P < 0.01). MR estimates showed causal positive effects of homocysteine on serum creatine (β = 0.76, P = 0.02), systolic blood pressure (β = 0.26, P = 0.02), diastolic blood pressure (β = 0.20, P = 0.01), and pathologic T lesion (β = 0.01, P = 0.01) in IgAN.Conclusions:By observational and MR analyses, consistent results were observed for associations of plasma homocysteine with serum creatinine, blood pressures, and pathologic T lesion in IgAN patients.