IgA Nephropathy Research Articles

Mesangial C1q Deposition in IgA Nephropathy: Does the Classical Complement Pathway Play an Independent Role?

Mesangial C1q Deposition in IgA Nephropathy: Does the Classical Complement Pathway Play an Independent Role?

Combination treatment with telitacicept, mycophenolate mofetil and glucocorticoids for immunoglobulin A nephropathy: A case report

BACKGROUND Telitacicept reduces B cell activation and abnormal immunoglobulin A (IgA) antibody production by inhibiting the activity of B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), thereby decreasing IgA deposition in the glomeruli and local inflammatory response. This ultimately protects the kidneys from damage. This mechanism suggests that Telitacicept has potential efficacy in the treatment of IgA nephropathy. CASE SUMMARY We present the case of a 24-year-old female who was diagnosed with IgA nephropathy due to significant proteinuria and mild renal impairment. Pathologically, she exhibited focal proliferative glomerulonephritis. Treatment with angiotensin II receptor blocker, hormones, and mycophenolate mofetil did not lead to a significant improvement in her condition. However, upon the addition of telitacicept, the patient’s renal function recovered and her proteinuria rapidly reduced. Hormones were swiftly tapered and discontinued, with no occurrence of severe infections or related complications. CONCLUSION Telitacicept combined with hormones and mycophenolate mofetil may be a safe and effective induction therapy for IgA nephropathy.

Significance of intrarenal vascular lesions in Ig A nephropathy prognosis

BackgroundImmunoglobulin A nephropathy (IgAN) is the predominant primary glomerulonephritis globally and remains a subject of active research with a focus on understanding its course and prognosis. Although vascular lesions are associated with IgAN, the current histopathological grading systems do not consider intrarenal vascular lesions when predicting patient prognosis. Therefore, this retrospective study conducted at Kyungpook National University Hospital between October 2016 and December 2021, aimed to elucidate the significance of intrarenal vascular lesions in IgAN by comparing the clinical data of patients with and without such lesions.MethodsData of patients with biopsy-confirmed primary IgAN between October 2016 and June 2021 at Kyungpook National University Hospital (Daegu, South Korea) were collected, and their medical records were reviewed. All slides from these 138 cases were independently pathologically reviewed by two nephropathologists (Y. J. K. and M. S. K.) using light microscope. The vascular lesions included in this study were fibrous intimal thickening, arteriolar wall thickening, and arteriolar hyalinosis. All cases were reviewed according to the Oxford Classification of IgA Nephropathy (2016) and Haas classification.ResultsOf the 138 patients, 88 exhibited at least one intrarenal vascular lesion. Patients with arteriolar wall thickening demonstrated a reduced estimated glomerular filtration rate (eGFR), elevated serum creatinine level and urine protein-to-creatinine ratio, an increased proportion of global glomerulosclerosis, and a higher histologic grade of interstitial fibrosis and tubular atrophy at the time of biopsy.ConclusionArteriolar wall thickening in IgAN are associated with reduced eGFR and global glomerulosclerosis. Moreover, reduced eGFR and global glomerulosclerosis are correlated with the progression to end-stage renal disease. Although the direct correlation between vascular lesions and end-stage renal disease is not entirely clear, a marginally significant association (log-rank test, p = 0.06) was observed with arterial wall thickening. This study suggests the potential importance of vascular lesions in the prognosis of IgAN, encouraging further investigation using larger cohort studies to establish a clearer association.

Causal relationship between IgA nephropathy and common neuropsychiatric disorders: A two-sample Mendelian randomization analysis

ObjectiveUtilizing two-sample Mendelian randomization (TSMR), this study seeks to determine the causal relationship between IgA nephropathy and five prevalent neuropsychiatric disorders. By exploring the genetic associations between IgA nephropathy and neuropsychiatric disorders, this research aims to contribute to the prevention of neuropsychiatric disorders in patients with IgA nephropathy. MethodsPublic genome-wide association study databases were searched, with IgA nephropathy as the exposure factor, including 15,587 patients with IgA nephropathy and 462,197 healthy controls. The outcome factors were five common neuropsychiatric disorders (bipolar disorder, depressive disorder, schizophrenia, anorexia nervosa, and Alzheimer's disease), with outcome data drawn from five datasets in the PGC and GWAScatalog databases. Inverse-variance weighting served as the primary method for causal effect estimation, supplemented by MR-Egger, weighted median, weighted mode, and simple mode methods. Heterogeneity was tested using Cochran's Q test, and sensitivity analysis was conducted using MR-Egger and MR-presso. ResultsMR analysis indicated a positive causal relationship between IgA nephropathy and depressive disorder (OR = 1.010, 95%CI: 1.003–1.017, P = 3.27 × 10−3), and a potential positive causal relationship between IgA nephropathy and anorexia nervosa (OR = 1.165, 95%CI: 1.030–1.319, P = 0.015). ConclusionThere is a positive causal relationship between IgA nephropathy and depressive disorder, and a potential positive causal relationship with anorexia nervosa. No causal relationship was found with schizophrenia, bipolar disorder, or Alzheimer's disease.

Is Podocytopathy Associated with Gross Hematuria after COVID-19 Vaccination in Patients with Immunoglobulin A Nephropathy?

We experienced three cases of a fever and subsequent severe, prolonged gross hematuria after COVID-19 vaccination. A kidney biopsy revealed immunoglobulin A (IgA) nephropathy, and electron microscopy showed two types of podocytopathy (podocyte damage): loss of foot processes from the glomerular basement membrane and foot process effacement. Mesangial interposition was also present in cases 1 and 3 but not in case 2. Podocytopathy is known to be a cause of proteinuria; however, the reactions to COVID-19 vaccination described here suggest that it may also be related to hematuria in IgA nephropathy.

Genome-wide studies define new genetic mechanisms of IgA vasculitis.

IgA vasculitis (IgAV) is a pediatric disease with skin and systemic manifestations. Here, we conducted genome, transcriptome, and proteome-wide association studies in 2,170 IgAV cases and 5,928 controls, generated IgAV-specific maps of gene expression and splicing from blood of 255 pediatric cases, and reconstructed myeloid-specific regulatory networks to define disease master regulators modulated by the newly identified disease driver genes. We observed significant association at the HLA - DRB1 (OR=1.55, P=1.1×10 -25 ) and fine-mapped specific amino-acid risk substitutions in DRβ1. We discovered two novel non-HLA loci: FCAR (OR=1.51, P=1.0×10 -20 ) encoding a myeloid IgA receptor FcαR, and INPP5D (OR=1.34, P=2.2×10 -09 ) encoding a known inhibitor of FcαR signaling. The FCAR risk locus co-localized with a cis-eQTL increasing FCAR expression; the risk alleles disrupted a PRDM1 binding motif within a myeloid enhancer of FCAR . Another risk locus was associated with a higher genetically predicted levels of plasma IL6R. The IL6R risk haplotype carried a missense variant contributing to accelerated cleavage of IL6R into a soluble form. Using systems biology approaches, we prioritized IgAV master regulators co-modulated by FCAR , INPP5D and IL6R in myeloid cells. We additionally identified 21 shared loci in a cross-phenotype analysis of IgAV with IgA nephropathy, including novel loci PAID4, WLS , and ANKRD55 .

Clinical and genetic analysis of a child with co-morbid progressive IgA nephropathy and COQ8B-associated glomerulopathy

To explore the genetic etiology and clinical outcome of a child with co-morbid progressive IgA nephropathy and COQ8B-associated glomerulopathy. A child who was admitted to Peking University First Hospital on March 2, 2021 was selected as the study subject. Genomic DNA was extracted from peripheral blood samples from the child and his parents and sister. Whole exome sequencing was carried out, and candidate variant was verified by Sanger sequencing. This study was approved by the Peking University First Hospital (Ethics No. 2016[1029]). The child, a 7-year-old boy who had developed proteinuria 8 months before, was diagnosed with IgA nephropathy (M1E1S1T1C1). With steroid, cyclophosphamide, cyclosporine and angiotensin-converting enzyme inhibitor therapy, partial remission of proteinuria was achieved. However, his serum creatinine level had increased from 53.8 mol/L at the onset of disease to 86.7 mol/L after 3.9 years, along with massive proteinuria. Kidney biopsy still indicated IgA nephropathy (M0E0S1T0C0). The child was found to harbor a homozygous c.737G>A (p.Ser246Asn) missense variant of the COQ8B gene, for which his parents and sister were heterozygous carriers. The variant was predicted to be pathogenic (PS1+PM2_Supporting+PM3+PP3+PP4) based on the guidelines from the American College of Medical Genetics and Genomics. The child was treated with high-dose coenzyme Q10 in combination with steroid and/or mycophenolate mofetil, though his serum creatinine level still increased to 286 mol/L after 7.3 years, which conformed to a chronic kidney disorder with glomerular filtration rate category of G3b. The homozygous c.737G>A missense variants of the COQ8B gene probably underlay the progressive kidney dysfunction in this child. For children with IgA nephropathy presenting with atypical clinical manifestations, unsatisfactory therapeutic effect, and/or early onset of kidney function decline, coexistence of other diseases should be suspected.

Doppler ultrasound imaging and shear wave elastography for evaluation of interstitial fibrosis/tubular atrophy in IgA nephropathy.

The purpose of this study was to explore the value of Doppler ultrasound imaging and shear wave elastography (SWE) in evaluating renal interstitial fibrosis/tubular atrophy (IFTA). During April 2019 and November 2023, biopsy-proven IgA nephropathy (IgAN) patients were enrolled in our study. Conventional ultrasound, Doppler ultrasound imaging and SWE measurements were performed, and related parameters were collected. According to the Oxford classification of IgAN, interstitial fibrosis/tubular atrophy (T) lesions were grouped into T0, T1 and T2 group. Receiver operating characteristic (ROC) curves were constructed to evaluate the diagnostic accuracy of SWE in identifying IFTA. A total of 100 IgAN patients were enrolled in the final cohort. 67 patients were in the T0 group, and 33 patients were in the T1/T2 group. The average SWE values were 42.17 ± 9.11kPa in the T0 group and 36.83 ± 10.32kPa in the T1/T2 group (p = 0.01). Multivariate logistic regression revealed that the SWE value and end diastolic velocity (EDV) of the interlobar artery were found to be independent risk factors for IFTA. For the diagnosis of IFTA, the area under the ROC curve (AUC) of SWE alone was 0.652, whereas the AUC of SWE in combination with the EDV was 0.807 (p = 0.008). The combination of Doppler ultrasound imaging and SWE measurements could improve the diagnostic performance of quantitative assessment of IFTA in IgAN patients.

Immunoglobulin A nephropathy is not what it used to be!

Immunoglobulin A (IgA) nephropathy is the most common primary glomerulonephritis worldwide and thought to be a benign disease. Recent literature review would suggest otherwise, with outcomes remaining generally poor. Few patients do not progress to kidney failure in their lifetime even in population groups previously thought to be low risk. The previously established treatment approach predominantly focuses on supportive care through renin-angiotensin-aldosterone system inhibition and steroid-based immunosuppression in selected cases. However, recent advances in the understanding of the pathogenic mechanisms underlying this disease process have allowed for the development of new target therapies. This brief review provides an overview of improved understanding of IgA nephropathy and novel therapeutic strategies.

Efficacy and Safety of Nefecon in Patients with Immunoglobulin A Nephropathy from Mainland China: 2-Year NefIgArd Trial Results.

Immunoglobulin A nephropathy (IgAN), an immune-mediated kidney disease, is particularly prevalent among individuals of East Asian ancestry. Nefecon is a novel, oral, targeted-release budesonide formulation designed to inhibit galactose-deficient-IgA1 formation underlying IgAN pathophysiology. We present findings in patients with IgAN from mainland China participating in the 2-year, multicenter, randomized, double-blind, phase 3 NefIgArd trial of Nefecon. Patients (aged ≥18 years) with primary IgAN (estimated glomerular filtration rate [eGFR] 35-90 ml/min per 1.73 m2, persistent proteinuria [urine protein-creatinine ratio ≥0.8 g/g or proteinuria ≥1 g/24 h] despite optimized renin-angiotensin system blockade) received Nefecon or placebo over 9 months, followed by a 15-month follow-up phase on supportive care alone. The primary efficacy end point was time-weighted average of eGFR over 2 years. Sixty-two patients from mainland China were included in this prespecified analysis. The primary efficacy end point was 9.6 ml/min per 1.73 m2 (95% confidence interval [CI], 2.0 to 19.8) in favor of Nefecon versus placebo. This was consistent with (and numerically greater than) that of the global study population. Time to confirmed 30% eGFR reduction or kidney failure from baseline was substantially delayed with Nefecon (patients with an event: 9%) versus placebo (30%; hazard ratio, 0.21; 95% CI, 0.04 to 0.73]). No deaths were reported in the China cohort. In the Nefecon group, treatment-emergent serious adverse events were reported by one patient during treatment and two patients during follow-up (versus no patients and seven patients, respectively, in the placebo group). No severe infections requiring hospitalization were reported. Nefecon treatment for 9 months showed greater preservation of eGFR over 2 years compared with placebo. The efficacy outcomes were consistent with global study results, with a numerically greater treatment benefit observed in patients from China. Nefecon was well tolerated, with no unexpected safety signals.

The contribution of the sphingosine 1-phosphate signaling pathway to chronic kidney diseases: recent findings and new perspectives.

Chronic kidney disease (CKD) is a multifactorial condition with diverse etiologies, such as diabetes mellitus, hypertension, and genetic disorders, often culminating in end-stage renal disease (ESRD). A hallmark of CKD progression is kidney fibrosis, characterized by the excessive accumulation of extracellular matrix components, for which there is currently no effective anti-fibrotic therapy. Recent literature highlights the critical role of sphingosine 1-phosphate (S1P) signaling in CKD pathogenesis and renal fibrosis. This review provides an in-depth analysis of the latest findings on S1P metabolism and signaling in renal fibrosis and in specific CKDs, including diabetic nephropathy (DN), lupus nephritis (LN), focal segmental glomerulosclerosis (FSGS), Fabry disease (FD), and IgA nephropathy (IgAN). Emerging studies underscore the therapeutic potential of modulating S1P signaling with receptor modulators and inhibitors, such as fingolimod (FTY720) and more selective agents like ozanimod and cenerimod. Additionally, the current knowledge about the effects of established kidney protective therapies such as glucocorticoids and SGLT2 and ACE inhibitors on S1P signaling will be summarized. Furthermore, the review highlights the potential role of S1P as a biomarker for disease progression in CKD models, particularly in Fabry disease and diabetic nephropathy. Advanced technologies, including spatial transcriptomics, are further refining our understanding of S1P's role within specific kidney compartments. Collectively, these insights emphasize the need for continued research into S1P signaling pathways as promising targets for CKD treatment strategies.

Clinical correlates and pathology of non-diabetic renal disease in diabetes mellitus

Objectives: Early identification and differentiation of patients with non-diabetic renal disease (NDRD) from diabetic nephropathy (DN) or those with NDRD superimposed on DN improves the prognosis and reduces associated morbidity. The objectives of the study were to compare the clinical profile, nature of renal involvement, and etiopathogenesis (renal biopsy) of patients with isolated NDRD and NDRD superimposed on DN. Materials and Methods: It is a descriptive study in patients with T2D and renal involvement suggestive of non-diabetic etiology further evaluated with renal biopsy and grouped as NDRD alone or NDRD with DN. Results: Of the total 50, 66% were male, the mean age was 55.57 ± 12.28 years, and all were proteinuric. Overall, isolated NDRD and NDRD superimposed on DN were observed in 64% and 36% of patients, respectively. Diabetic retinopathy was absent in 82% of cases. The most common finding in isolated NDRD was membranous nephropathy, followed by immunoglobulin A (IgA) nephropathy and rapid progression of glomerular nephritis (RPGN). At the same time, in the NDRD and DN group, maximum patients displayed IgA nephropathy followed by acute tubular necrosis and RPGN. The incidence of atypical features of renal disease was almost twice as high in the isolated NDRD group than in the group with both NDRD + DN. Conclusion: NDRDs are highly prevalent, and DN may superimpose these. Recognizing NDRD solely on the basis of clinical indicators is challenging. Therefore, histopathological analysis seems essential to accurately diagnose NDRD in diabetic patients to reduce the probability of missed NDRD diagnosis and initiate prompt treatment.

The safety of corticosteroid therapy in IGA nephropathy: analysis of a real-life Italian cohort.

Systemic steroids are recommended for patients with IgA nephropathy (IgAN) and proteinuria. However, there are concerns about their safety due to an excess of serious adverse events (SAEs) in previous randomised trials. This study evaluates the incidence of SAEs in IgAN patients receiving different treatment regimens in clinical practice. Multicentre, retrospective, observational cohort study of 1209 patients (M/F: 864/345, mean age: 41.73 ± 14.92years) with biopsy-proven IgAN treated with renin angiotensin system (RAS) inhibitors (RASI) (n = 285), intravenous + oral steroids (n = 633), oral steroids (n = 99), steroids + immunosuppressants (n = 192). A total of 119 (9.8%) adverse events were reported, of which 67 (5.5%) were considered treatment-emergent, and 36 (2.9%) were SAEs (n = 23, 63.8% were infections). One patient died due to sepsis. A significant association was observed between AEs and immunosuppression [8 (2.8%) in RASI, 60 (9.4%) in steroids + immunosuppressants, 14 in oral steroids (14.1%) and 37 pts (19.2%) in steroids + immunosuppressants (p < 0.01)], age and estimated glomerular filtration rate (eGFR), but not with proteinuria and sex. On multivariate analysis, only older age was associated with the occurrence of SAEs. According to our findings, the incidence of SAEs during therapy with steroids alone or associated with immunosuppressors is lower in everyday clinical practice than in randomised clinical trials.

6424 From Hyperparathyroidism To Neurologic Crisis: A Tale Of Brown Tumor And Spinal Cord Compression

Abstract Disclosure: A. Kormanis: None. M. Anderson: None. M. McKnight: None. H. Darapu: None. Background/Objective: In this case, we present a rare and severe consequence of secondary hyperparathyroidism, a Brown tumor leading to spinal cord compression, in a young adult with end-stage renal disease. Case Report: A 26-year-old male with a medical history of polycystic kidney disease and IgA Nephropathy complicated by ESRD, history of brown cell tumors (s/p surgery) was admitted for hospitalization due to hypocalcemia after presenting to the Emergency Department with right lower extremity weakness. Examination revealed right hip flexor weakness and right foot clonus. Lab results showed serum calcium of 10.4 mg/dL . MRI displayed a 2.5cm X 3.7 cm soft tissue mass with circumferential encroachment of the epidural space leading to severe spinal canal stenosis of T4-T5 at the site of prior Brown tumor resection. Ultimately, the patient underwent subtotal parathyroidectomy with left cervical thymectomy, leading to an intra-operative PTH drop from &amp;gt;3500 to 247 pg/mL. Discussion: In the context of treating vertebral brown tumors, the consensus suggests that parathyroidectomy plays a crucial role in achieving both clinical and radiographical amelioration of the tumor. However, in cases like ours where paresis is present, surgical decompression of the tumor becomes imperative. Conclusion: The development of Brown tumors is a severe and rare long-term complication for hyperparathyroidism, and the location of a Brown tumor in the thoracic spine causing symptomatic cord compression is even more rare. Presentation: 6/2/2024

Immunoglobulin A-dominant membranoproliferative glomerulonephritis-like pattern of injury as a possible paraneoplastic nephropathy in a breast cancer patient.

A middle-aged woman was found to have proteinuria during a health check-up. About sixteen months later, she was diagnosed with stage IIA invasive ductal carcinoma of the right breast. Her proteinuria progressed to nephrotic syndrome with significant hematuria. Hormone therapy was initiated for her estrogen and progesterone receptor-positive breast cancer. A kidney biopsy performed 47days after starting the therapy revealed an IgA-dominant membranoproliferative glomerulonephritis-like pattern of injury. Electron microscopy showed subendothelial-dominant electron-dense deposits (EDD), with small amounts of mesangial EDD and a single occurrence of subepithelial hump-like EDD, along with occasional mesangial interpositions. Similar pathology can be caused by IgA vasculitis with nephritis, IgA-dominant infection-associated glomerulonephritis, and liver disease-associated glomerulopathy, but all of these were ruled out. The deposited IgA was found to be galactose-deficient IgA1. Thus, IgA nephropathy with glomerular capillary IgA deposition was considered. She underwent a right partial mastectomy and sentinel lymph node biopsy in the right axilla 75days after starting hormone therapy, followed by adjuvant radiation. Proteinuria and hematuria tended to decrease after the treatment, and this trend continued even after corticosteroid therapy for glomerulonephritis, which was administered 156days after starting hormone therapy. Approximately 15months after starting hormone therapy, her proteinuria had reduced to around 1.0g/g of creatinine, and her hematuria was negative. IgA nephropathy with glomerular capillary IgA deposition is known to be resistant to corticosteroid therapy. The favorable clinical course of the rare glomerulopathy following breast cancer treatment suggested a diagnosis of paraneoplastic glomerulopathy secondary to breast cancer in our patient.

An Updated Comprehensive Review on Diseases Associated with Nephrotic Syndromes.

There have been exciting advances in our knowledge of primary glomerular diseases and nephrotic syndromes in recent years. Beyond the histological pattern from renal biopsy, more precise phenotyping of the diseases and the use of modern nephrogenetics helps to improve treatment decisions and sometimes also avoid unnecessary exposure to potentially toxic immunosuppression. New biomarkers have led to easier and more accurate diagnoses and more targeted therapeutic decisions. The treatment landscape is becoming wider with a pipeline of promising new therapeutic agents with more sophisticated approaches. This review focuses on all aspects of entities that are associated with nephrotic syndromes with updated information on recent advances in each field. This includes podocytopathies (focal segmental glomerulosclerosis and minimal-change disease), membranous nephropathy, membranoproliferative glomerulonephritis, IgA nephropathy, fibrillary glomerulonephritis, amyloidosis, and monoclonal gammopathy of renal significance in the context of the nephrotic syndrome, but also renal involvement in systemic diseases, diabetic nephropathy, and drugs that are associated with nephrotic syndromes.

Safety and efficacy assessment of fecal microbiota transplantation as an adjunctive treatment for IgA nephropathy: an exploratory clinical trial

To assess the safety and efficacy of fecal microbiota transplantation (FMT) as an adjunctive therapeutic intervention for IgA nephropathy (IgAN). Fifteen patients with IgA nephropathy were recruited based on inclusion and exclusion criteria and underwent FMT using enteric microbial capsules. Clinical indicators, intestinal microbiota and metabolomic profiles, as well as changes in serum immune cells and cytokines, were monitored before and after FMT. No severe adverse reactions were observed in the subjects. After FMT, there was a reduction in the 24-h urinary protein quantification in subjects. The relative abundances of Phocaeicola_vulgatus, Bacteroides_uniformis, Prevotella_copri, Phocaeicola_dorei, Bacteroides_ovatus, Bacteroides_xylanisolvens, Parabacteroides _distasonis, Bifidobacterium_pseudocatenulatum, Bacteroides_sp._HF-162, and Bifidobacterium_longum changed after FMT. In terms of intestinal metabolites, the levels of acylcarnitine18:0 (ACar.18:0), cotinine, N-arachidonoyl-L-serine, phosphatidylcholine (PC. (18:3e/22:6)), serotonin, and fumagillin showed significant changes. Flow cytometry analysis showed the absolute count of plasma B cells decreased in subjects, and this change correlated with alterations in the intestinal microbiota and metabolites. This study preliminarily evaluates the safety and efficacy of FMT in patients with IgAN. No significant adverse reactions were observed, and the administration of FMT alongside ACEI/ARB therapy was effective in reducing urinary protein levels in patients with IgAN, a process that may be associated with B-cell immunity.

Soluble Epoxide Hydrolase Inhibition Attenuates Proteinuria by Alleviating Renal Inflammation and Podocyte Injuries in Adriamycin-Induced Nephropathy.

Soluble epoxide hydrolase (sEH) has previously been demonstrated to play an important part in kidney diseases by hydrolyzing renoprotective epoxyeicosatrienoic acids to their less active diols. However, little is known about the role of sEH in primary glomerular diseases. Here, we investigated the effects of sEH inhibition on proteinuria in primary glomerular diseases and the underlying mechanism. The expression of sEH in the renal tubules of patients with minimal change disease, IgA nephropathy, and membranous nephropathy was significantly increased. Renal sEH expression level was positively correlated with the 24 h urine protein excretion and negatively correlated with serum albumin. In the animal model of Adriamycin (ADR)-induced nephropathy, renal sEH mRNA and protein expression increased significantly. Pharmacological inhibition of sEH with AUDA effectively reduced urine protein excretion and attenuated renal pathological damage. Furthermore, sEH inhibition markedly abrogated the abnormal expressions of nephrin and desmin in glomerular podocytes induced by ADR. More importantly, AUDA treatment inhibited renal NF-κB activation and reduced TNF-α levels in rats with ADR-induced nephropathy. Overall, our findings suggest that sEH inhibition ameliorates renal inflammation and podocyte injury, thus reducing proteinuria and exerting renoprotective effects. Targeting sEH might be a potential strategy for the treatment of proteinuria in primary glomerular diseases.

Study Design and Baseline Characteristics of ALIGN, a Randomized Controlled Study of Atrasentan in Patients With IgA Nephropathy

IntroductionEndothelin A (ETA) receptor activation is a driver of proteinuria, kidney inflammation and fibrosis in IgA nephropathy (IgAN). Atrasentan, a selective ETA receptor antagonist, has potential to reduce proteinuria and preserve kidney function in IgAN. ALIGN (NCT04573478) is a phase 3, randomized, double-blind, placebo-controlled clinical trial of atrasentan in patients with IgAN at high risk of kidney function loss. MethodsEligibility criteria for the ALIGN main stratum included patients with biopsy-proven IgAN, total protein excretion ≥1g/d, eGFR ≥30 mL/min/1.73m2, receiving a maximally-tolerated stable dose of a renin-angiotensin system inhibitor (RASi). An exploratory stratum enrolled participants also receiving a stable dose of sodium glucose cotransporter-2 inhibitors (SGLT2i). Participants were randomized to 0.75 mg atrasentan or placebo orally daily for 132 weeks followed by a 4-week wash-out period. The primary outcome is proteinuria change from baseline (24h urine protein–creatinine ratio UPCR) to Week 36 in the main stratum. Key secondary endpoints include eGFR change from baseline to Week 136, safety and tolerability. ResultsEnrolment occurred across 20 countries; 404 patients are randomized: 340 in the main stratum and 64 in the SGLT2i stratum. At baseline in the main stratum, mean age was 44.7 years, 42.4% were female, mean eGFR and median UPCR were 58.9 mL/min/1.73 m2 and 1.4 g/g, respectively. ConclusionThe ongoing ALIGN trial evaluates the efficacy and safety of atrasentan in a representative global IgAN population at risk for disease progression despite optimized RASi therapy and includes an exploratory stratum evaluating atrasentan use in combination with an SGLT2i.

IgA Nephropathy: A Timeline from Hematuria/Proteinuria to Nephrology Referral and Kidney Biopsy

IgA Nephropathy: A Timeline from Hematuria/Proteinuria to Nephrology Referral and Kidney Biopsy