Cases Of IgA Nephropathy Research Articles

Nephrology: what's new in 2022

Severe cases of IGA nephropathy might benefit from corticosteroid therapy. Inflimidase may be a promising treatment of Goodpasture disease. SGLT2 inhibitors and acetazolamide act synergistically with loop diuretics in the treatment of acute cardiac failure. In hemodialysis, use of lung ultrasound to determine the ultrafiltration seems to decrease hospitalizations due to acute heart failure but does not reduce patient-centered outcomes. Icodextrin may mitigate the loss of ultrafiltration in PD patients who are carriers of the Aquaporin I promotor TT genotype. MICA-antibodies have an impact on the risk of graft rejection. Xenotransplantation may become a reality.

IgA-nephropathy in children with alport syndrome

BACKGROUND. The widespread use of genetic methods in clinical practice has shown that pathogenic variants in COL4A3, COL4A4, COL4A5 genes associated with Alport syndrome (AS) are detected in 10 % of sporadic and in 20 % of familial cases of IgA nephropathy (IgAN), which suggested a relationship between the two diseases. THE AIM was to determine the frequency and characteristics of the course of IgAN in children with AS. PATIENTS AND METHODS. A single-centre retrospective pilot study included 102 patients with AS. The inclusion criteria were: age 2-18 years, genetic and/or morphological confirmation of AS, availability of morphological data of pts. The comparison group included children and adolescents 2-18 years with morphologically confirmed primary IgAN; the exclusion criterion was the presence of AS-specific glomerular basement membrane changes. IgAN was classified according to the MESTC scale. Demographic (gender, age), clinical (arterial hypertension, AH) and laboratory data (proteinuria (Pr, mg/m2/day), (Schwartz eGFR, ml/min/1.73m2) at the time of the biopsy and at the last examination of patients were assessed. Arterial pressure ≥95‰ for sex, age, height was defined as AH. Pr >100 mg/m2/day, Pr≥500 mg/m2/day and Pr>1000 mg/m2/day were defined as proteinuria, high-level proteinuria and nephrotic level proteinuria, respectively. The statistic parametric and nonparametric methods were used ("Statistica 10", StatSoft Russia). RESULTS. IgAN was detected in 3 of 102 children with AS (q=0.03): 2 girls had heterozygous variants in COL4A3 and COL4A4, a boy had X-linked AS. Two patients had nephrotic proteinuria, 1 had SRNS at onset of IgAN. The comparison group included 25 children with IgAN (17M). Baseline patients age (9±4.2 vs 13±2.7 years), frequency of AH (q1=0.66 vs q2=0.28), eGFR decrease (q1=0.33 vs q2=0.44), eGFR level (91±24 vs 90.8±24 ml/ min/1.73 m2), morphological characteristics of IgAN did not differ significantly by groups; patients with AS were more likely to have nephrotic proteinuria (q1=1 vs q2=0.32, p=0.023). At follow-up (3.8±1.4 years), the groups were comparable in age (12.3±5.2 vs 15±1.8 years), AH frequency (q1=0.66 vs q2=0.5), eGFR level (87±16 vs 91±13 ml/min/1.73m2); children with AS had higher grade Pr (800[0;1150] vs 30[10;100] mg/m2/day, p=0.048) and more often had high-level Pr (q1=0.66 vs q2=0.06, p=0.006) at follow-up observation. The AS was associated with the development of nephrotic-level Pr at onset (r=0.41, p=0.008) and with high-level Pr (r=0.38, p=0.012) during follow-up. CONCLUSION. IgAN was detected in 3 % of children with AS. The presence of COL4A3, COL4A4, COL4A5 genes variants is associated with more pronounced proteinuria at the onset of IgAN and its preservation in the follow-up, and may be a risk factor for more severe course glomerulonephritis. The main limitations of the study: small sample size and duration of follow-up.

First Diagnosis of Immunoglobulin A Nephropathy Following SARS-CoV-2 mRNA Vaccination in Japan

The SARS-CoV-2 mRNA vaccine has been effective against COVID-19.1,2 However, following mass-scale SARS-CoV-2 mRNA vaccination, several immune-mediated disorders, including newly diagnosed or exacerbated cases of IgA nephropathy (IgAN), have been reported worldwide.3–6 Majority of the reported IgAN cases associated with SARS-CoV-2 mRNA vaccination show gross hematuria; however, the commonality in the kidney histopathological findings remains uncharacterized. In this study, patients first diagnosed with IgAN by kidney biopsy due to gross hematuria following SARS-CoV-2 mRNA vaccination at 6 medical centers were evaluated.

Coexistence of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and IgA nephropathy.

Co-occurrence of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and IgA nephropathy (IgAN) is extremely uncommon. To date, only a few case reports have described such patients. Here, we describe the clinical presentation, pathologic features, treatment response, and outcome data of five patients with the rare form of co-existing AAV and IgAN and compared the characteristics of these patients to AAV patients with pauci-immune glomerulonephritis (n = 10) and IgAN patients (n = 10) that were selected as controls by stratified random sampling. In addition, we summarize all the previously reported cases of AAV and IgAN. In total, including the current study, 16 AAV/IgAN overlap cases were reported. Our five patients with the coexistence of AAV and IgAN were younger than the ten AAV patients with pauci-immune glomerulonephritis (22.6 ± 8.2years versus 48.9 ± 15.7years, respectively, P = 0.004). Histologically, they had a significantly lower percentage of glomeruli with fibrous crescents compared with AAV patients (0.0% versus 4.0%, P = 0.038). Compared with ten IgAN patients, our five AAV/IgAN patients had higher levels of ESR (P = 0.032) and CRP (P = 0.031). After accepting treatment with a combination of steroid and immunosuppressants, all patients showed a positive response to therapy, except for one patient in our cohort and another previously reported patient. We described the clinical presentation, pathologic features, treatment response, and outcome data of five patients with overlapping AAV and IgAN. They had mild glomerular pathological lesions and a positive response to aggressive immunosuppressive therapy. They were quite similar to pauci-immune AAV patients in clinical features, except for younger age. They had a lower percentage of glomeruli with fibrous crescents compared with AAV patients. In contrast to IgAN patients, they had higher levels of ESR and CRP. The mechanism of the coexistence of IgAN and AAV needs further study.

Comparison of renal histopathology in three patients with gross hematuria after SARS-CoV-2 vaccination.

We present three cases of IgA nephropathy with gross hematuria following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccination. Case 1 was a 60-year-old woman who has previously experienced transient proteinuria. Case 2 was a 22-year-old woman with no history of urinary abnormality. Finally, case 3 was a 66-year-old woman who has had microscopic hematuria since she was in her 50s. They were all diagnosed as IgA nephropathy with little histological active lesion. Their renal function and proteinuria improved without the use of corticosteroids. There were differences in the findings of vascular endothelial damage based on the time between the appearance of gross hematuria and renal biopsy. Glomerular endocapillary damage could be a part of the mechanism triggered by mRNA vaccination. When a patient presents with gross hematuria following vaccination, a comprehensive approach including renal biopsy should be considered.

Genetic Variants of the COL4A3 , COL4A4 , and COL4A5 Genes Contribute to Thinned Glomerular Basement Membrane Lesions in Sporadic IgA Nephropathy Patients.

Thinned glomerular basement membrane (tGBM) lesions are not uncommon in IgA nephropathy (IgAN). Type IV collagen-built of α 3, α 4, and α 5 chains, encoded by COL4A3 / COL4A4 / COL4A5 genes-is the major component of glomerular basement membrane (GBM). In recent years, mutations in type IV collagen-encoding genes were also reported in patients with a histologic diagnosis of FSGS. Pathogenic COL4A3 / COL4A4 / COL4A5 variants were recently identified in familial cases of IgAN, but the contribution of these variants to sporadic IgAN is still unclear. We compared 161 patients with sporadic IgAN with tGBM lesions (IgAN-tGBM) to matched patients with IgAN without tGBM lesions and matched patients with thin basement membrane nephropathy (TBMN). Variants of COL4A3 / COL4A4 / COL4A5 genes were screened and evaluated after whole-exome sequencing. GBM thickness was measured, and levels of circulating galactose-deficient IgA1 (Gd-IgA1) were assessed by ELISA. The patients with IgAN-tGBM manifested milder disease than did patients with IgAN without tGBM but had more severe features than the patients with TBMN. Exome sequence analysis of the 122 patients with IgAN-tGBM identified 37 diagnostic variants of the COL4A3 / COL4A4 / COL4A5 genes among 38 patients (31.1%). Furthermore, patients with IgAN-tGBM who had diagnostic variants had higher proportions of GBM thickness <250 nm and milder glomerular injury, whereas patients with IgAN-tGBM who did not have diagnostic variants showed more characteristic features of IgAN, including higher intensity of glomerular IgA deposits and elevated Gd-IgA1 levels. These findings suggest different mechanisms in patients with versus without diagnostic variants of these collagen genes. COL4A3 / COL4A4 / COL4A5 variant detection is essential in evaluating patients with sporadic IgAN with tGBM lesions.

Intrinsic Kidney Pathology in Children and Adolescents Following COVID-19 Vaccination: A Systematic Review.

Global COVID-19 vaccination programs for children and adolescents have been developed with international clinical trial data confirming COVID-19 mRNA vaccine safety and efficacy for the pediatric population. The impact of COVID-19 vaccination in the kidneys is thought to be explained by a complex immune-mediated relationship between the two, although the pathophysiological mechanisms of how COVID-19 vaccination potentially induces kidney pathology are not presently well known. Whilst intrinsic kidney pathologies following COVID-19 vaccination have been reported in adults, such cases are only being recently reported with greater frequency in children and adolescents. Conforming to the PRISMA checklist, we conducted a systematic review of the current literature to provide an overview on the range of intrinsic kidney pathologies that have been reported following COVID-19 vaccination in children and adolescents. All English language research articles published on or before 30 June 2022 reporting new-onset or relapsed intrinsic kidney pathology in children or adolescents (≤18 years) following COVID-19 vaccination were selected for qualitative analysis. Out of 18 cases from the 13 published articles selected, there were 10 cases of IgA nephropathy (1 case of rapidly progressive glomerulonephritis requiring acute hemodialysis), 5 cases of minimal change disease (MCD), 1 case of concurrent MCD/tubulointerstitial nephritis (TIN) and 2 cases of TIN. There is no indication currently to avoid vaccination, unless specific circumstances exist, as the benefits of COVID-19 vaccination far outweigh its risks. Concluding the findings from our systematic review based on preliminary evidence, potential adverse effects to the kidney from COVID-19 vaccination affects a small number of children and adolescents among the many who have been vaccinated. There remains good reason at present to support vaccination of children and adolescents with a greater morbidity status, such as those living with preexisting chronic kidney disease. Close observation of all children and adolescents receiving COVID-19 vaccination is recommended, particularly in those with preceding intrinsic kidney pathology to identify risks of relapsed disease.

CRESCENTS – CHARMING CATASTROPHES

Background and Objectives: Crescentic Glomerulonephritis is a medical emergency because patients will progress to Rapidly Progressive Glomerulonephritis, a fatal condition. Crescentic Glomerulonephritis can be pauci immune, immune complex mediated or anti glomerular basement membrane disease.The presence of crescents indicates a poor prognosis for the patient. This paper highlights the various presentations of Crescentic Glomerulonephritis. Prospective study. Tertiary care centre in South India. 34 Study Design: Setting: Materials and Method: renal biopsies were received over a period of 18 months (January 2021 to June 2022). 6 cases of Crescentic glomerulonephritis have been reported. Histopathological examination, ANCA and Immunouorescence were done for these cases.Results:Out of the 6 cases, 1 was a case of anti-GBM disease, 1 was a case of pauci immune glomerulonephritis, 2 were cases of lupus nephritis and 2 were cases of IgA Nephropathy. Crescentic Glomerulonephritis is a medical emergency.It Conclusion: is the duty of the Pathologist to inform the Nephrologist as soon as possible to look for the etiology and instigate appropriate therapy

IgA nephropathy with acute kidney disease: Characteristics, prognosis, and causes

BackgroundThe clinical manifestations and prognosis of IgA nephropathy (IgAN) are diverse. Some patients may present with kidney dysfunction lasting shorter than 3 months and meet the acute kidney disease (AKD) criteria. This study aimed to investigate the clinicopathological features, causes and prognosis of newly diagnosed cases of IgAN with AKD. Methods1320 IgAN patients diagnosed via kidney biopsy between January 2012 and June 2018 were included in this retrospective study, with a median follow-up period of 35 months. We analyzed the clinicopathological, etiological variables, as well as short-term and long-term prognosis. The main outcome was a composite event of 40% decline in eGFR, kidney failure or death. ResultsIncidence of AKD was 8.8% in the newly diagnosed IgAN patients, and was found to be an independent risk factor affecting the short-term (HR, 7.1; 95% CI, 2.3–22.2; P = 0.001) and long-term (HR, 1.8; 95% CI, 1.2–2.6; P = 0.006) prognosis, respectively. The most common cause of AKD was malignant hypertension-related AKD (MHT-AKD; 24.1%), followed by hematuria-related AKD (H-AKD; 12.9%), nephrotoxic–drug–exposure-related AKD (NTDE-AKD; 12.1%) and crescents-related AKD (C-AKD; 11.2%). The patients in AKD group had more severe clinicopathological characteristics and poor short-term and long-term prognosis than non-AKD group. In subgroup analysis, the MHT-AKD had the worst 5 years survival rate, followed by NTDE-AKD and C-AKD, whereas H-AKD had the best survival rate. ConclusionsAKD is not rare among IgAN patients, and is an independent risk factor for short-term and long-term prognosis. IgAN patients with AKD resulting from different causes have different prognosis.

POS-020 ARTIFICIAL INTELLIGENCE ASSISTED QUANTIFICATION OF COMPLEMENT CONVERTASES IN GLOMERULONEPHRITIS

POS-020 ARTIFICIAL INTELLIGENCE ASSISTED QUANTIFICATION OF COMPLEMENT CONVERTASES IN GLOMERULONEPHRITIS

FC073: An Epigenetically Driven Mechanism Triggered by Viral and Bacterial RNA Regulates the IL-6 Levels in IGA Nephropathy

BACKGROUND AND AIMSSeveral models have been proposed to describe the pathogenesis of Immunoglobulin A nephropathy (IgAN) and, among them, the multihit model where the gut-microbiota may play an important role. These models explain the pathogenesis of IgAN caused by the production of aberrant IgA, but it is believed that further predisposing factors are present, including immunological, genetic, environmental or nutritional factors.Recently, the role of IL-6 in IgAN pathogenesis is becoming increasingly important. It is essential for the deposition of glomerular immunoglobulin A and the development of renal disease in Cd37-deficient mice, although the pathogenetic mechanisms that determine its increase are not well known.A possible hypothesis emerges from our recent work on genome-wide DNA methylation screening in patients with IgAN, which identified, among other findings, a hypermethylated region comprising Vault 2–1 RNA (VTRNA2-1), a non-RNA coding also known as a precursor of miR-886 (pre-mi-RNA). Consistently, VTRNA2-1 expression was found downregulated in IgAN patients.Here we studied the involvement of the VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN.METHODTotal RNA were isolated from PBMCs of IgAN patients, transplanted IgAN patients (TP-IgAN), non-IgAN transplanted patients (TP) and healthy subjects (HS). VTRNA2-1, CREB and PKR transcripts were evaluated by RT-PCR. Total and phosphorylated PKR, CREB and Il-6 proteins were evaluated by ELISA. Poly (I: C), a synthetic analogue of dsRNA and Pfizer-BioNTech COVID-19 COMIRNATY vaccine were used to transfect patient PBMCs. PKR inhibitor imoxin (C16) 1 µM was used to stimulate patient PBMCs.RESULTSHere we confirm that VTRNA2-1 transcript was down-regulated in native and transplanted IgAN subjects compared to HS and non IgAN transplanted patients, with a decrease of 30- and 100-folds, respectively (P < 0.05, and P < 0.0001). IgAN patients with downregulated VTRNA2-1 showed a PKR overactivation (fold increase of phosphorilation of 2.6- in IgAN and 2-folds in TP-IgAN patients; P < 0.05), coherently with the role played by VTRNA2-1 that binds to PKR and inhibits its phosphorylation. Then, we found that PKR causes the activation of CREB, a classical cAMP-inducible CRE-binding factor (fold increase of phosphorilation of 3- in IgAN and 2.67-folds in TP-IgAN patients; P < 0.01). CREB, interacting with a region of the IL-6 promoter, led to IL-6 production. Indeed, in IgAN patients we showed a IL-6 mean increase to 120 pg/mL compared to the respective controls (P < 0.05). Moreover, the IL-6 levels correlated with CREB and PKR phosphorylation (r = 0.97; P = 0.0006 and r = 0.89; P = 0.0064, respectively, for IgAN and TP-IgAN patients).Since PKR is normally activated by bacterial and viral RNA, we hypothesized that these microorganisms can further activate the PKR/CREB/IL-6 pathway leading to an excess of IL-6 production. This may explain both the high levels of IL-6, and infection involvement in the disease, and cases of IgAN associated with COVID-19 infection or with COVID-19 RNA-vaccination, and recent data showing microbiota involvement in IgAN. Effectively, we found that IgAN PMBCs stimulated with RNA poly(I: C) or the COVID-19 RNA-vaccine showed a significant increase in IL-6 levels compared to not-stimulated PBMCs (P < 0.05), supporting the pathogentic role played by viral RNA in IgAN pathogenesis and explaining the cases of IgAN patients developing episodes of macrohematuria after a COVID-19 infection or vaccination.Finally, we showed that the IL-6 secretion can be reduced by the PKR inhibitor imoxin (fold decrease of 5-folds in IgAN and TP-IgAN patients; P < 0.05).CONCLUSIONIn conclusion, the discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide a new pathogenic mechanism in IgAN and may be useful for the development of novel therapeutic approaches, likely by modulating the VTRNA2-1 methylation level in IgAN patients.

Clinicopathologic and Prognostic Study of Primary IgA Nephropathy With Light Chain λ Restriction in the Mesangial Deposits

IntroductionPrimary IgA nephropathy (IgAN) with light chain λ restriction in the mesangial deposits (IgAN-λ) has unique immunofluorescence (IF) features. Nevertheless, its clinicopathology and prognosis are still ambiguous.MethodsFrom January 2002 to December 2020, the clinical and pathologic data of 3872 patients who were diagnosed with having primary IgAN by renal biopsy in our hospital were reviewed. A total of 187 patients who met the selection criteria for IgAN-λ were enrolled to conduct a retrospective single-center study. The selection criteria were that IF features conform to light chain λ restriction in the mesangial deposits. According to age, sex, renal function (estimated glomerular filtration rate [eGFR]), and follow-up time, the control group was constructed with 1:3 matched cases of IgAN. The clinicopathologic and prognostic differences between the 2 groups were analyzed.ResultsCompared with that in the IgAN group, the serum fibrinogen level in the IgAN-λ group was significantly higher (P < 0.001). Furthermore, cluster analysis indicated the different clusters involved in fibrinogen between the IgAN-λ and IgAN groups and that fibrinogen is associated with factors reflecting renal function in IgAN-λ but proteinuria levels in IgAN. The light chain λ deposit in the mesangium is associated with the formation of crescents in those with IgAN-λ, but complement C3 deposition in those with IgAN. Our Kaplan-Meier analysis revealed that the prognosis of the IgAN-λ group was significantly worse than that of the IgAN group within >6 years of follow-up (P = 0.02). The multi-Cox analysis revealed that the light chain λ restriction in the mesangial deposits was an independent risk factor for poor outcomes (eGFR decreased from the baseline ≥ 30% continuously or reached end-stage renal disease [ESRD] or died).ConclusionThe prognosis of those with IgAN-λ was worse than that of those with IgAN, which may be attributed to the light chain λ restriction in the mesangial deposits inducing a significant systemic inflammation manifested as severe clinical features and frequent crescent.

Correlation of E1 lesions and CD68 count with proteinuria and clinical outcome in IgA nephropathy

Background: IgA nephropathy (IgAN) has variable course; few patients have a benign presentation and other patients present with late stage disease. Endocapillary hypercellularity has a prognostic significance in IgAN. It is important to identify E1 lesions accurately. The use of CD68 immunohistochemistry marker to identify glomerular macrophages will standardize the reporting and help the clinicians prognosticate the patients. Subjects and Methods: The material is from a referral laboratory for renal biopsies in a tertiary care hospital. Renal biopsies are processed as per protocol including light microscopy, immunofluorescence and electron microscopy where ever required. CD68 was used in this study to identify macrophages in E1 lesions. A total of 1220 primary glomerular diseases were diagnosed from January 2019 till date. Out of these, IgA constituted 11.9% of primary glomerular diseases. Renal biopsies received were from the department of nephrology and various other nephrology centers. Biopsies were received in 10% buffered formalin. Immunofluorescence is done on all biopsies, and electron microscopy was done in few cases to differentiate from other lesions with dominant IgA deposits. CD68 was done in 50 cases of IgAN. Apart from hematoxylin and eosin stains, periodic acid-Schiff, Masson trichrome, Jones silver stain were also done. Results: IgAN constituted 11.9% of cases. Twenty-five cases of E0 and twenty-five cases of E1 lesions were correlated with clinical and morphological features. There was correlation with proteinuria and hypertension in E1 lesions. There was no significant correlation with the morphological variants like crescents, focal segmental glomerulosclerosis. Conclusions: Inter observer correlation of E lesions is poor in classifying IgAN. Use of CD68 is a useful adjunct to identify macrophages. E1 lesions have more proteinuria requiring treatment for delaying the progression to end stage disease. Despite significant association of E1 lesions with progression, there may be many unmeasured factors which would influence the outcome.

Genetic Variants in MIR3142HG Contribute to the Predisposition of IgA Nephropathy in a Chinese Han Population

Background: The study aimed to evaluate the association of genetic variants in MIR3142HG with the predisposition of IgA nephropathy (IgAN) in a Chinese Han population. Methods: Six single-nucleotide polymorphisms (SNPs) in MIR3142HG were chosen for genotyping among 417 IgAN cases and 424 healthy controls using Agena MassARRAY technique. Logistic regression models adjusted for age and gender were used to calculate odds ratios (ORs) and 95% confidence intervals (CI). Haploview and multifactor dimensionality reduction analysis were used to analyze the role of combined SNPs in IgAN risk. Results: Rs17057846-AA genotype (OR = 2.11, 95% CI: 1.04–4.27, p = 0.039) and rs58747524-CC genotype (OR = 1.89, 95% CI: 1.06–3.38, p = 0.032) had the higher risk for IgAN developing in the overall. Interestingly, rs7727115 had a reduced risk for IgAN in females, while rs17057846, rs2961920, and rs58747524 were related to the increased susceptibility to IgAN in females and the subjects with age ≤35 years; moreover, rs17057846 and rs58747524 conferred to the higher risk for Lee’s grade ≥III IgAN (p < 0.05 for all). Besides, the combination of rs1582417, rs7727115, and rs2961920 was the best model (testing accuracy = 0.5468, CVC = 10/10, p < 0.001) to predict IgAN predisposition compared to the single SNP alone. Conclusions: Our study firstly indicated that rs17057846 and rs58747524 in MIR3142HG contributed to the elevated risk for IgAN in a Chinese Han population. These results might provide a new insight for the molecular mechanism in the progression of IgAN.

The Influence of ACE Insertion/Deletion Gene Polymorphism on the Risk of IgA Nephropathy: A Debatable Topic.

Background The connection between angiotensin-converting enzyme insertion/deletion (ACE I/D) gene polymorphisms and IgA nephropathy (IgAN) was conflicting. This pooled analysis was performed to explore this issue. Methods All eligible investigations were identified from various electronic databases, and the pooled analysis was evaluated using Stata software. Results 27 studies with 2538 IgAN cases and 3592 controls were included. In overall subjects, ACE D allele, DD, and II genotype were associated with IgAN susceptibility (D vs. I: OR = 1.21, 95% CI: 1.10–1.32, P < 0.001; DD vs. ID + II: OR = 1.38, 95% CI: 1.20–1.60, P < 0.001; and II vs. DD + ID: OR = 0.83, 95% CI: 0.73–0.95, P=0.007). In Asian and Chinese patients, ACE I/D gene polymorphism was also correlated with IgAN vulnerability. Moreover, ACE D allele, DD, and II genotype were correlated with the progression of IgAN (D vs. I: OR = 1.37, 95% CI: 1.09–1.73, P=0.008; DD vs. ID + II: OR = 1.57, 95% CI: 1.06–2.31, P=0.024; and II vs. DD + ID: OR = 0.69, 95% CI: 0.49–0.99, P=0.045). Conversely, in Caucasian subjects, there was no link between ACE I/D gene polymorphism and the risk of IgAN. Conclusion ACE I/D gene polymorphism was correlated with the vulnerability and progression of IgAN in Asian and Chinese patients, and ACE D allele and DD homozygote genotype could be adverse factors for IgAN, while the II homozygote genotype could be an advantage factor. But, no significant association was found between ACE I/D gene polymorphism and IgAN in Caucasians.

COVID-19 Vaccination and Glomerulonephritis

IntroductionmRNA COVID-19 vaccine is more effective than traditional vaccines owing to superior immune activation. Nevertheless, the impact of mRNA COVID-19 vaccine on triggering de novo/relapsing glomerulonephritis (GN) is limited. We report a case series of patients who developed new or relapsing GN postvaccination.MethodsWe evaluated baseline characteristics, vaccine type, and clinical outcomes of 13 patients from our institution who had a new diagnosis or relapse of their GN post–mRNA COVID-19 vaccination.ResultsOf 13 patients, 8 patients were newly diagnosed with having GN and 5 patients had relapse. Median age was 62 years (range 19–83 years). Autoimmune disease (38%) was the most prevalent underlying disease followed by cancer (23%). Most patients were White males. IgA nephropathy (IgAN) was the most common GN in our series (5 patients, 38%) followed by membranous nephropathy (MN) (3 patients, 23%). There was 1 patient with IgAN who had evidence of IgA deposits before vaccination suggesting the immune activation after vaccination triggered a flare of the disease. Our case series also included the first case report of tip-variant focal segmental glomerulosclerosis (FSGS), NELL-1–associated MN, and atypical anti–glomerular basement membrane (GBM) nephritis. A total of 77% developed acute kidney injury (AKI) with most being Kidney Disease: Improving Global Outcomes stage 1 (67%). Outcomes are favorable with 80% responding to therapy.ConclusionNew cases and relapse of GN can present shortly after mRNA COVID-19 vaccination. New cases of IgAN may result from unmasking of undiagnosed IgAN owing to robust immune activation rather than development of new deposits.

Activation of fibroblast growth factor-inducible 14 in the early phase of childhood IgA nephropathy.

IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. Pediatric patients in Japan are diagnosed with IgAN at an early stage of the disease through annual urinary examinations. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) have various roles, including proinflammatory effects, and modulation of several kidney diseases; however, no reports have described their roles in pediatric IgAN. In this study, we performed pathological and immunohistochemical analyses of samples from 14 pediatric IgAN patients. Additionally, gene expression arrays of glomeruli by laser-captured microdissection were performed in hemi-nephrectomized high serum IgA (HIGA) mice, a model of IgA nephropathy, to determine the role of Fn14. Glomeruli with intense Fn14 deposition were observed in 80% of mild IgAN cases; however, most severe cases showed glomeruli with little or no Fn14 deposition. Fn14 deposition was not observed in obvious mesangial proliferation or the crescent region of glomeruli, but was detected strongly in the glomerular tuft, with an intact appearance. In HIGA mice, Fn14 deposition was observed mildly beginning at 11 weeks of age, and stronger Fn14 deposition was detected at 14 weeks of age. Expression array analysis indicated that Fn14 expression was higher in HIGA mice at 6 weeks of age, increased slightly at 11 weeks, and then decreased at 26 weeks when compared with controls at equivalent ages. These findings suggest that Fn14 signaling affects early lesions but not advanced lesions in patients with IgAN. Further study of the TWEAK/Fn14 pathway will contribute to our understanding of the progression of IgAN.

Immunohistological score of transcription factor 21 had a positive correlation with its urinary excretion and proteinuria in immunoglobulin A nephropathy.

Transcription factor 21 (TCF21) contributes to mammalian nephrogenesis, and especially to glomerular maturation. Our previous study suggested its influence on glomerular injury, showing that TCF21 expression in podocytes had a positive correlation with the urinary protein value and also with the urinary TCF21 concentration. We now focus on its influence on the clinical course of immunoglobulin A nephropathy (IgAN), as patients with IgAN constitute the largest population of individuals with primary chronic glomerulonephritis in the world. Twenty cases of IgAN were divided into two groups according to the immunohistological score (IHS) of glomerular TCF21 expression: group IHS1 (n=7) and group IHS2+3 (n=13). Sixteen of the 20 cases were followed up for 2 years. Group IHS2+3 had heavier urinary protein (p=0.03) and a greater urinary TCF21 level (p<0.001) compared to group IHS1 at baseline. None of the other factors including hematuria, estimated glomerular filtration rate (eGFR), or the Oxford classification showed a statistically significant difference between these two groups. At the 2-year follow-up, even though the rate of remission in urinary protein, hematuria and the eGFR decline were not statistically correlated to IHS, the IHS2+3 group had a slight tendency toward a steeper eGFR decline compared to IHS1 (p=0.31). The present study suggested that the higher IHS of TCF21 corresponded to heavier proteinuria and a higher urinary TCF21 level in IgAN. This could be the first step in determining the TCF21 value for predicting the prognosis for IgAN.

Immunohistochemical Expression of FOXP3+ Regulatory T Cells in Proteinuric Primary Glomerulopathies.

FOXP3+ regulatory T-cell (Tregs) detection in renal allograft biopsies has been associated with a less intense immune response. Data about FOXP3+ Tregs' presence and role in primary glomerulopathies of native kidneys are minimal. We comparatively studied the immunohistochemical expression of FOXP3+ Tregs, CD4+ and CD3+ T cells in IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), and membranous glomerulopathy (MGN). We retrospectively reviewed 71 renal biopsies (28 from patients with IgAN, 22 from patients with FSGS and 21 from patients with MGN) performed with proteinuria as the main indication. FOXP3+ Tregs and CD4+ and CD3+ T cells in inflammatory cell infiltrates of the interstitial tissue and periglomerular space were automatically counted using image analysis software. Univariable and multivariable logistic regressions were applied for statistical analysis. Nuclear FOXP3+ immunohistochemical expression was observed in T cells in 64% of IgAN cases, 77% of FSGS cases, and 76% of MGN cases (p > 0.05). Absolute FOXP3+ Tregs count in the interstitial tissue was higher in patients without arteriolar hyalinosis than in those with arteriolar hyalinosis (1.814 ± 2.160 vs. 831 ± 696; p = 0.029). In patients with a high FOXP3+/CD4+ ratio in the interstitial tissue, the odds ratio for CKD-EPI eGFR ≥60 ml/min/1.73 m2 at biopsy was 4.80 (95% CI: 1.29–17.91; p = 0.019). FOXP3+ Tregs intrarenal infiltration in primary glomerulopathies is common. FOXP3+ Tregs' increased expression may be associated with milder histological lesions. High FOXP3+/CD4+ ratio in the interstitial tissue may have prognostic significance for renal function preservation.

Association of Co-dominant Immunoglobulin G Deposit in Immunoglobulin A Nephropathy With Poor Clinicopathological and Laboratory Parameters.

Introduction: Immunoglobulin A (IgA) nephropathy is the commonest primary glomerulonephritis with a wide range of clinical presentations and laboratory findings. There is a paucity of studies regarding the significance of co-dominant immunoglobulin G (IgG) deposition in IgA nephropathy.Methods: The study included retrospective and prospective biopsy-proven cases of IgA nephropathy from 2013-2020 with a minimum of eight glomeruli. Clinical and laboratory parameters were analysed for the IgA and IgG co-dominant cases as compared to those of the non-IgG group.Results: A total of 58 cases of IgA nephropathy were included in the study out of which 25 biopsies (43.1%) were categorized as IgA plus IgG, and the rest 33 biopsies (56.8%) as the non-IgG group. A significant correlation was noted amongst the IgA plus IgG group with respect to the elevated mean arterial pressure (MAP) (p=0.038) and proteinuria (p=0.002) as compared to the non-IgG group. Amongst the MEST-C (mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, tubular atrophy/interstitial fibrosis, crescents) variables, endocapillary hypercellularity correlated with elevated MAP (p=0.04), raised serum creatinine (p=0.005), and decreased estimated glomerular filtration rate (eGFR) (p=0.002).Conclusion: Co-dominant IgG deposit serves as an adverse marker pointing towards a deranged renal function in IgA nephropathy.