Causal relationship between Helicobacter pylori infection and IgA nephropathy: a bidirectional two-sample mendelian randomization study.

IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis, and serum Helicobacter pylori (H. pylori) antibody levels are increased in patients with IgA N, but the role of H. pylori infection in the pathogenesis of IgAN is unclear. In this study, we investigated whether there is a causal relationship and reverse causality between IgAN and H. pylori infection by using a bidirectional two-sample Mendelian randomization (MR) analysis. This study was estimated using inverse variance weighted (IVW), MR-Egger and weighted median methods, with the IVW method having the strongest statistical efficacy. Seven common serum H. pylori antibodies were selected as exposure factors for positive MR analysis. The results showed that there was no evidence of a causal relationship between H. pylori infection and IgAN. Reverse MR analysis showed that there was also no evidence that the occurrence of IgAN leads to an increased risk of H. pylori infection.

Warfarin-related nephropathy: unveiling the hidden dangers of anticoagulation.

Warfarin-related nephropathy (WRN) is defined as acute kidney injury subsequent to excessive anticoagulation with warfarin. Patients with mechanical prosthetic valves require long-term anticoagulant therapy. Nonetheless, warfarin remains the sole available option for anticoagulant therapy. Consequently, patients with mechanical prosthetic valves constitute a special group among the entire anticoagulant population. The present study recorded two cases of patients who had undergone mechanical prosthetic valve surgery and were receiving warfarin therapy. They presented to the hospital with gross hematuria and progressive creatinine levels. Notably, their international normalized ratio (INR) did not exceed three. Subsequent renal biopsies confirmed WRN with IgA nephropathy. The two patients continued to receive warfarin as anticoagulation therapy and were prescribed oral corticosteroids and cyclophosphamide, which resulted in improved renal function during the follow-up. Based on a review of all relevant literature and the present study, we proposed a new challenge: must elevated INR levels be one of the criteria for clinical diagnosis of WRN? Perhaps some inspiration can be drawn from the present article.

[Astragaloside IV reduces renal injury in mice with IgA nephropathy by inhibiting TIM-1 signaling pathway and increasing Th1/Th2 cell ratio].

Objective To investigate the effects of astragaloside IV(AS-IV) on the balance of T helper type 1 (Th1) and Th2 cells in mice with IgA nephropathy (IgAN) and its possible mechanism. Methods The IgAN model of BALB/c mice was established. Successfully modeled mice were randomly divided into four groups: model, AS-IV low dose, AS-IV medium dose and AS-IV high dose groups, with 10 mice in each group. Another 10 mice served as the control group. Mice in the low, medium and high dose groups were administered 12.5, 25 and 50 mg/kg AS-IV suspension (prepared in normal saline) by gavage, while the control and model groups were given an equivalent volume of normal saline. The 24-hour urinary protein (24 h UPr) content and urine red blood cell count were measured in each group. The levels of blood urea nitrogen (BUN), serum creatinine (Scr) and albumin (ALB) were determined. Serum interferon γ (IFN-γ), interleukin 4 (IL-4) and IL-10 levels were detected by ELISA. The ratio of Th1/Th2 cells in peripheral blood of mice was detected using flow cytometry. Histopathological changes in the kidney of mice were observed by HE staining. RT-PCR and Western blot were used to detect the mRNA and protein expressions of T cell immunoglobulin and mucin domain gene 1 (TIM-1), Toll-like receptor 4 (TLR4) in mouse kidney tissue. Results Compared with the model group, in weeks 12 and 15, the urine red blood cell count, 24 h UPr, BUN, Scr, levels of IL-4 and IL-10, the proportion of Th2 cells, as well as the mRNA and protein expression levels of TIM-1 and TLR4 were significantly decreased in the low, medium and high dose groups of AS-IV, and the levels of ALB, IFN-γ, the proportion of Th1 cells and Th1/Th2 cell ratio were increased, with the high-dose group showing the best effects. Conclusion AS-IV can inhibit TIM-1 signaling pathway, increase the Th1/Th2 cell ratio, inhibit the inflammatory reaction, and alleviate the renal injury in IgAN mice.

Delayed-Release Budesonide in a Patient With Progressive IgA Nephropathy and Stage 4 Chronic Kidney Disease: A Case Report.

Delayed-release (DR) budesonide received expedited approval from the US Food and Drug Administration (FDA) as a treatment for reducing proteinuria in individuals with primary IgA nephropathy (IgAN) who are at significant risk of disease progression. The approval was based on clinical trials primarily involving patients with an estimated glomerular filtration rate (eGFR) greater than 30 mL/min/1.73 m2. However, the efficacy of DR budesonide in reducing kidney function decline, especially in patients with an eGFR less than 30 mL/min/1.73 m2 and proteinuria less than 1 g/d, remains unclear. We report the case of a 43-year-old man with a long-term history of hypertension and biopsy-proven IgAN who experienced a progressive increase in proteinuria and serum creatinine, along with a decline in eGFR to 28 mL/min/1.73 m2 despite maximal supportive management. Following therapy with DR budesonide, a decreasing trend in proteinuria and a stabilization of eGFR were observed in the recent measurements. While initial data suggested the effectiveness of DR budesonide primarily in patients with an eGFR over 30 mL/min/1.73 m2, our case demonstrates the potential of DR budesonide for use in scenarios beyond its currently approved indications. This underscores the need for additional research on patients with advanced stages of chronic kidney disease.

An Unusual Case of Alcoholic Liver Disease Associated with Secondary IgA Vasculitic Nephritis presenting as Rapidly Progressive Glomerulonephritis.

IgA nephropathy (IgAN) is a fairly common association with alcoholic liver disease. However, IgA vasculitis (IgAV) is quite an uncommon association with alcoholic liver cirrhosis and only a handful of cases have been reported in literature. Secondary IgAN usually presents in a docile manner, progressing slowly in about 5-25 years. It is usually responsive to steroid therapy, very rarely progressing to End-Stage Renal Disease. Here, we present a man in his late 50s, a known hypertensive and alcohol related liver-cirrhotic, who presented to our hospital with rash and rapidly progressive renal failure (RPRF). He was diagnosed with IgA nephritis with IgA vasculitis (IgAVN). His diagnosis was confirmed with skin and renal biopsy. He was started on renal replacement therapy for his renal failure and began oral steroid therapy. After administration of steroid therapy for 6 months, the patient recovered and was dialysis independent with stable renal parameters.

Immunoglobulin A Nephropathy Presenting in Young Adults as Advanced Chronic Kidney Disease and Posttransplant Early Recurrence: A Case Series.

Immunoglobulin A nephropathy (IgAN) is the most common glomerular disease, leading to chronic kidney disease. The disease is characterized by microscopic hematuria, gross episodic hematuria, hypertension, and subnephrotic proteinuria with or without renal function impairment. It affects individuals of all age groups, commonly seen in 10-40 years of age. It is progressive in nature and leads to chronic kidney disease, necessitating renal replacement therapy. This case series of in a tertiary care hospital in Western India highlights the presentation of this disease in young adults, its aggressive course, its rapid progression, and its early recurrence in the posttransplant period. It also summarizes the treatment recommendations for IgA recurrence in kidney recipients. The disease is known to have a high chance of posttransplant recurrence. Optimizing renin-angiotensin-aldosterone system (RAAS) blockade, blood pressure control, and increasing immunosuppression in rapidly deteriorating cases are the strategies recommended to treat IgA recurrence in kidney transplant recipients.

Immunosuppressive therapy for IgA nephropathy in children.

BACKGROUND: IgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis. It is a heterogeneous disease with different presentations and high morbidity. Thirty per cent of adults and 20% of children (followed into adulthood) will have a 50% decline in kidney function or develop kidney failure after 10 years. OBJECTIVES: To determine the benefits and harms of immunosuppressive therapy for the treatment of IgAN in children. SEARCH METHODS: We contacted the Information Specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 03 October 2023 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs) investigating the treatment of IgAN in children with immunosuppressive therapies compared to placebo, no treatment, supportive care, standard therapy (Japanese protocol), other immunosuppressive therapies or non-immunosuppressive therapies. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the risk of bias. Random effects meta-analyses were used to summarise estimates of treatment effects. Treatment effects were expressed as risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes, and the mean difference (MD) and 95% CI for continuous outcomes. The risk of bias was assessed using the Cochrane risk of bias tool for RCTs and the ROBIN-I tool for NRSIs. The certainty of the evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). MAIN RESULTS: This review included 13 studies with 686 participants. Ten RCTs included 334 children and 191 adults, and three NRSIs included 151 participants, all children. Most participants had mild kidney disease. The risk of bias was unclear for most of the domains relating to allocation concealment, blinding of participants, personnel, and outcome assessment. In children with IgAN, it is uncertain if corticosteroid (steroid) therapy, compared to placebo reduces proteinuria (1 study, 64 children and young adults: RR 0.47, 95% CI 0.13 to 1.72; low certainty evidence) or the decline in estimated glomerular filtration rate (eGFR) (1 study, 64 children and young adults: RR 0.47, 95% CI 0.09 to 2.39; low certainty evidence). It is uncertain if steroids reduce proteinuria compared to supportive care (2 studies, 61 children: RR 0.04, 95% CI -0.83 to 0.72; low certainty evidence). Adverse events associated with steroid therapy were not assessed due to heterogeneity in steroid protocols, including dose and duration, and lack of systematic assessment for adverse events in the included studies. Azathioprine, mycophenolate mofetil, mizoribine, or cyclophosphamide alone or in combination with steroid therapy had uncertain effects on improving proteinuria or preventing eGFR decline in children with IgAN. Fish oil, vitamin E and tonsillectomy had uncertain effects on improving proteinuria or preventing eGFR decline. Effects of other immunosuppressive therapies, secondary outcomes and adverse events were not assessed due to insufficient data. AUTHORS' CONCLUSIONS: There is a lack of high-quality evidence to guide the management of IgAN in children. There is no evidence to indicate that steroids, other immunosuppressive therapies, or tonsillectomy, when added to optimal supportive care, prevent a decline in eGFR or proteinuria in children with IgAN. Available studies were few, with small numbers, low-quality evidence, high or uncertain risk of bias, did not systematically assess harms associated with treatment, or report net benefits or harms. Severe cases and atypical presentations of IgAN were not included in the reviewed studies, and our findings cannot be generalised to these situations.

Clinical characteristics and risk factors for kidney involvement in children with immunoglobulin A vasculitis.

BACKGROUND: Immumoglobulin A (IgA) vasculitis (IgAV), formerly known as Henoch-Schönlein purpura (HSP), is a self-limiting systemic vasculitis in children. Kidney involvement is associated with a long-term unfavorable outcome and can lead to significant morbidity. This study was conducted to describe the clinical and laboratory characteristics of childhood IgAV with kidney involvement and to identify risk factors associated with IgAV nephritis (IgAVN). METHODS: This was an ambidirectional descriptive study of 77 children with IgAV. All demographic data, clinical features, and laboratory tests were collected from electronic medical records from January 2010 to December 2022. Risk factors for kidney involvement in IgAV were assessed using multivariate logistic regression. Kaplan-Meier survival analysis was used to calculate the time to commencement of kidney involvement. RESULTS: Twenty-five children (32.4% of the IgAV patients) developed IgAVN. The common findings in IgAV with kidney involvement were microscopic hematuria (100%), nephrotic range proteinuria (44%), and non-nephrotic range proteinuria (40%). Multivariate logistic regression showed that age greater than 10 years (adjusted hazard ratio, AHR 4.66; 95% confidence interval, CI, 1.91-11.41; p = 0.001), obesity (body mass index, BMI, z-score ≥ +2 standard deviations, SDs) (AHR 3.59; 95% CI 1.41-9.17; p = 0.007), and hypertension at onset (AHR 4.78; 95% CI 1.76-12.95; p = 0.002) were associated significantly with kidney involvement. During follow up, most IgAV patients developed nephritis within the first 9 months. CONCLUSION: Age greater than 10 years, obesity, and hypertension at presentation were predictive factors for IgAVN. Our study emphasized that IgAV patients with risk factors should be closely monitored for at least 1 year after the onset of the disease.

Advancements in understanding the role of intestinal dysbacteriosis mediated mucosal immunity in IgA nephropathy.

IgA nephropathy, presently recognized as the foremost primary glomerular disorder, emerges as a principal contributor to renal failure globally, with its pathogenesis yet to be fully elucidated. Extensive research has highlighted the critical role of gut microbiome in the onset and progression of IgA nephropathy, underscoring its importance in accurately delineating the disease's etiology. For example, gut microbiome dysbacteriosis can lead to the production of nephritogenic IgA1 antibodies, which form immune complexes that deposit in the kidneys, causing inflammation and damage. The gut microbiome, a source of numerous bioactive compounds, interacts with the host and plays a regulatory role in gut-immune axis modulation, earning it the moniker of the "second brain." Recent investigations have particularly emphasized a significant correlation between IgA nephropathy and gut microbiome dysbacteriosis. This article offers a detailed overview of the pathogenic mechanisms of IgA nephropathy, specifically focusing on elucidating how alterations in the gut microbiome are associated with anomalies in the intestinal mucosal system in IgA nephropathy. Additionally, it describes the possible influence of gut microbiome on recurrent IgA nephropathy following kidney transplantation. Furthermore, it compiles potential therapeutic interventions, offering both theoretical and practical foundations for the management of IgA nephropathy. Lastly, the challenges currently faced in the therapeutic approaches to IgA nephropathy are discussed.

Successful pregnancy in a patient with IgA nephropathy treated with telitacicept: a case report.

BACKGROUND: IgA nephropathy (IgAN) is the most common cause of primary glomerulonephritis, with complex pathogenic mechanisms involving abnormal B-cell activation. As a novel biologic agent, telitacicept inhibits both B-lymphocyte stimulating factor and a proliferation-inducing ligand. It also inhibits both B cells and plasma cells and the production of galactose-deficient IgA1 (Gd-IgA1) and its autoantibodies, thus exerting an immunosuppressive effect. Women with IgAN are at a higher risk of adverse pregnancy outcomes such as preeclampsia and miscarriage, especially those with uncontrolled massive proteinuria and advanced chronic kidney disease. Therefore, IgAN disease control before and during pregnancy is essential. Here, we report the case of a woman with IgAN who had a successful pregnancy with significant improvement and long-term remission after treatment with telitacicept. This is the first report of a pregnancy following exposure to telitacicept. CONCLUSION: This report describes the efficacy of telitacicept in patients with IgAN and explores its value in women of childbearing age, suggesting effective and safe treatment options for women who wish to conceive.

Drugs in Development to Treat IgA Nephropathy.

IgA nephropathy is a common glomerulonephritis consequent to the autoimmune response to aberrant glycosylated immunoglobulin (Ig) A antibodies. Although it has historically been considered a benign disease, it has since become clear that a substantial percentage of patients reach end-stage kidney failure over the years. Several therapeutic attempts have been proposed, with systemic steroids being the most prevalent, albeit burdened by possible serious adverse events. Thanks to the more in-depth knowledge of the pathogenesis of IgA nephropathy, new treatment targets have been identified and new drugs developed. In this narrative review, we summarise the molecules under clinical development for the treatment of IgA nephropathy. As a search strategy, we used PubMed, Google, ClinicalTrials.gov and abstracts from recent international congresses. TRF budesonide and sparsentan are the two molecules at a more advanced stage, just entering the market. Other promising agents are undergoing phase III clinical development. These include anti-APRIL and anti-BLyS/BAFF antibodies and some complement inhibitors. Other new possible strategies include spleen tyrosine kinase inhibitors, anti-CD40 ligands and anti-CD38 antibodies. In an era increasingly characterised by 'personalised medicine' and 'precision therapy' approaches and considering that the potential therapeutic armamentarium for IgA nephropathy will be very broad in the near future, the identification of biomarkers capable of helping the nephrologist to select the right drug for the right patient should be the focus of future studies.

Immune checkpoint activity exacerbate renal interstitial fibrosis progression by enhancing PD-L1 expression in renal tubular epithelial cells.

Renal interstitial fibrosis (RIF) is often associated with inflammatory cell infiltration and no effective therapy. Programmed death cell-1 (PD-1) and its ligand PD-L1 were playing critical roles in T cell coinhibition and exhaustion, but the role in RIF is unclear. Here the data analyses of serum from 122 IgA nephrology (IgAN) patients showed that high level of soluble PD-1(sPD-1) was an independent risk factor for RIF and renal function progression. PD-L1 was also overexpressed in renal interstitial tissues from both IgAN patients with high level of sPD-1 and the unilateral ureteral obstruction (UUO) mouse. PD-L1 was significantly overexpressed in HK-2 cells with upregulated collagen and α-SMA when stimulated by inflammation or hypoxia in vitro. Additionally, matrix metalloproteinases (MMP-2) could increase the level of sPD-1 in culture supernatant when added in co-culture system of HK-2 and jurkat cells, which implied serum sPD-1 of IgAN might be cleaved by MMP-2 from T cells infiltrated into the tubulointerstitial inflammatory microenvironment. Crucially, injection of PD-L1 fusion protein, the blocker of sPD-1, could ameliorate kidney fibrosis in UUO mice by increasing T cell coinhibition and exhaustion, suggesting the therapeutic potential of PD-L1 fusion targeting for renal fibrosis. Take together, it reveals a novel causal role of sPD-1 in serum and PD-L1 of renal interstitial tissues in the development of renal fibrosis of IgAN, and targeting sPD-1 in serum by PD-L1 fusion protein is a potential therapeutic approach to prevent renal fibrosis of IgAN.

[Anti-Proteinuric Effect of GLP1-RA as Add-On to SGLT2-i and ACE-i in a Diabetic Patient with IgA Nephropathy].

Immunoglobulin A (IgA) nephropathy is a common glomerulonephritis, but its treatment remains matter of debate. Recommendation for corticosteroids has been supported, but renin-angiotensin inhibitors, RAAS, and sodium-glucose co-transporter 2 inhibitors (SGLT2i) are increasingly used because of a better benefit/safety balance in comparison with systemic steroids and immunosuppressive treatments. In this case report, a patient with type 2 diabetes (T2DM) and biopsy-proven nephrotic IgA-related nephropathy documented a rapid meaningful reduction of proteinuria and the effect was persistent for 2 years, after receiving the treatment with a GLP1-RA on top of the previous treatment with ACE-inhibitors and SGLT2-i. Considering the beneficial effects of GLP1-RA in diabetes related chronic kidney disease, the present case report supports the notion that these drugs could also represent a beneficial treatment option in IgA nephropathy.

Complement system is overactivated in patients with IgA nephropathy after COVID-19.

IgA nephropathy (IgAN), which has been confirmed as a complement mediated autoimmune disease, is also one form of glomerulonephritis associated with COVID-19. Here, we aim to investigate the clinical and immunological characteristics of patients with IgAN after COVID-19. The level of plasma level of C5a (p < 0.001), soluble C5b-9 (p = 0.018), FHR5 (p < 0.001) were all significantly higher in Group CoV (33 patients with renal biopsy-proven IgAN experienced COVID-19) compared with Group non-CoV (44 patients with IgAN without COVID-19), respectively. Compared with Group non-CoV, the intensity of glomerular C4d (p = 0.017) and MAC deposition (p < 0.001) and Gd-IgA1 deposition (p = 0.005) were much stronger in Group CoV. Our finding revealed that for IgAN after COVID-19, mucosal immune responses to SARS-CoV-2 infection may result in the overactivation of systemic and renal local complement system, and increased glomerular deposition of Gd-IgA1, which may lead to renal dysfunction and promote renal progression in IgAN patients.

The predictive value of free thyroxine combined with tubular atrophy/interstitial fibrosis for poor prognosis in patients with IgA nephropathy.

Background: IgA nephropathy (IgAN), the most common type of glomerulonephritis, has great individual differences in prognosis. Many studies showed the relationship between thyroid hormones and chronic kidney disease. However, the relationship between free thyroxine (FT4), as a thyroid hormone, and IgAN is still unclear. This study aimed to evaluate the impact of FT4 on IgAN prognosis. Methods: This retrospective study involved 223 patients with biopsy-proven IgAN. The renal composite outcomes were defined as: (1) ESRD, defined as eGFR < 15 ml/(min·1.73 m2) or initiation of renal replacement therapy (hemodialysis, peritoneal dialysis, renal transplantation); (2) serum creatinine doubled from baseline; (3) eGFR decreased by more than 50% from baseline. The predictive value was determined by the area under the curve (AUC). Kaplan-Meier and Cox proportional hazards analyses assessed renal progression and prognosis. Results: After 38 (26-54) months of follow-up, 23 patients (10.3%) experienced renal composite outcomes. Kaplan-Meier survival curve analysis showed that the renal survival rate of the IgAN patients with FT4<15.18pmol/L was lower than that with FT4≥15.18pmol/L (P < 0. 001). Multivariate Cox regression model analysis showed that FT4 was a protective factor for poor prognosis of IgAN patients, whether as a continuous variable or a categorical variable (HR 0.68, 95%CI 0.51-0.90, P =0.007; HR 0.04, 95%CI 0.01-0.20, P <0.001). ROC curve analysis showed that FT4 combined with t score had a high predictive value for poor prognosis of IgAN patients (AUC=0.881, P<0.001). Conclusion: FT4 was a protective factor for IgAN. In addition, FT4 combined with tubular atrophy/interstitial fibrosis had a high predictive value for poor prognosis of IgAN.

Immune checkpoint inhibitor therapy associated with IgA nephropathy: a case report and literature review.

Immune checkpoint inhibitors (ICIs) dramatically improve the prognosis of many malignancies but at the cost of numerous side effects, which may limit their benefits. Acute kidney injury associated with immune checkpoint inhibitors most frequently are acute tubulointerstitial nephritis (ATIN), but various cases of glomerulonephritis have also been reported. Herein, we report a case of severe IgA nephropathy (IgAN) associated with ICIs and carry out a literature review. IgAN was diagnosed in a median time of 5 months (range 1-12 months) after the initiation of ICIs, with heterogeneous severity, and usually treated by corticosteroid and discontinuation of ICIs. In contrast to our case, renal outcomes in literature were often favorable, with recovery of renal function and a reduction in proteinuria on treatment. Although IgAN related to ICIs is a much rarer complication than ATIN, it may still be underdiagnosed. Careful questioning and screening for asymptomatic hematuria should be performed before using ICIs.