IgA Nephropathy Research Articles

The hemoglobin, albumin, lymphocyte, and platelet (HALP) score is associated with severe renal tubular atrophy/interstitial fibrosis in IgA nephropathy.

This study was performed to investigate the relationship between hemoglobin, albumin, lymphocyte and platelet (HALP) score and Oxford classification severe tubular atrophy/interstitial fibrosis (T2) in IgA nephropathy (IgAN). The clinical data and pathological findings of patients with IgA nephropathy diagnosed through renal biopsy at Hangzhou Hospital of Traditional Chinese Medicine between June 1, 2019 and May 31, 2022 were retrospectively collected and analyzed. The HALP score was calculated as hemoglobin (g/L) × albumin (g/L) × lymphocytes (/L)/ platelets (/L). According to the quartile of HALP scores in the study population, the subjects were divided into four groups: Quartile 1 (< 30.72), Quartile 2 (30.72-39.97), Quartile 3 (39.97-53.25) and Quartile 4(> 53.25). According to the extent of tubular atrophy/interstitial fibrosis, patients were categorized into mild to moderate injury (T0 + T1, ≤ 50%) and severe injury (T2, > 50%). The relationship between HALP score and severe tubular atrophy/interstitial fibrosis was investigated using Spearman's rank correlation coefficient, logistic regression analysis, restricted cubic splines (RCS), and receiver operating characteristic (ROC) curve analysis. A total of 895 patients diagnosed with IgAN were included in this study, with an average age of 40.97 ± 12.261years. Among them, 384 (42.9%) were male and 61 (6.8%) exhibited severe tubular atrophy/interstitial fibrosis. Multifactorial logistic regression analysis revealed that HALP independently influenced T2 (OR = 0.952, 95% CI 0.923-0.982, P = 0.002). Compared to Quartile 1, patients in Quartile 4 exhibited a significantly reduced risk of T2 (OR = 0.205, 95% CI 0.058-0.722, P = 0.014). Restricted cubic splines analysis revealed a linear inverse association between HALP and T2 risk (nonlinear P = 0.896). Furthermore, the receiver operating characteristic curve demonstrated that HALP possessed predictive value for T2 (AUC = 0.693, Jorden index = 0.324), and the cutoff value of HALP score is 36.54. The risk of severe renal tubular atrophy/interstitial fibrosis is higher in IgAN patients with low HALP. HALP greater than 36.54 May reduce the risk of severe tubular atrophy/interstitial fibrosis.

Primary glomerular diseases and long-term adverse health outcomes: A nationwide cohort study.

Although glomerular diseases are the third most frequent cause of end-stage kidney disease worldwide, little is known about their long-term outcomes. In patients with chronic kidney disease (CKD) stage 3-5 enrolled in the Swedish Renal Registry, we compared risks of hospitalization, kidney replacement therapy (KRT), major cardiovascular events (MACE), and death of the four most frequent primary glomerular diseases (IgA nephropathy [IgAN], focal segmental glomerulosclerosis [FSGS], minimal change disease [MCD], and membranous nephropathy [MN]), and patients with CKD due to the most common non-communicable diseases (control-CKD). We identified 2396 patients with glomerular disease (97% biopsy-proven, 69% men, 57 years, eGFR 29mL/min/1.73m2, uACR 88mg/mmol, 1524 with IgAN, 398 FSGS, 94 MCD, and 380 MN) and 37,697 controls (64% men, 74 years, eGFR 25mL/min/1.73m2, uACR 23mg/mmol), mainly with diabetic nephropathy and nephroangiosclerosis. The median follow-up was 6.3 (3.3; 9.9) years. Compared with control-CKD, patients with primary glomerular diseases generally had a lower risk of hospitalization, MACE (adjusted hazard ratios [HRs] ranging from 0.44 to 0.88 depending on the etiology) and death (HRs ranging 0.45-0.76). Patients with IgAN and FSGS had a faster eGFR decline and a higher rate of KRT (HRs 1.26 [95%CI: 1.15-1.37] and 1.34 [1.15-1.57], respectively). Conversely, patients with MN and MCD had a lower KRT rate and slower eGFR decline. Despite having a lower relative risk of hospitalization, cardiovascular events and mortality, patients with IgAN and FSGS are at higher risk of CKD progression than the most common etiologies of CKD, emphasizing the need for more stringent treatment strategies in these patients.

Towards Risk Stratification in Clinical Care for IgA Nephropathy: Genetic Risk Scores

Towards Risk Stratification in Clinical Care for IgA Nephropathy: Genetic Risk Scores

Non-invasive assessment of IgA nephropathy severity with [18F] AlF-NOTA-FAPI-04 PET/CT imaging

Abstract Background Renal biopsy plays a crucial role in diagnosing and assessing the severity of IgA nephropathy (IgAN), despite being an invasive procedure with potential risk of failure. Our study focused on evaluating the capability of [18F] AlF-NOTA-FAPI-04 PET/CT in identifying the extent of pathological alterations in IgAN. Methods Twenty patients (13 males and 7 females; mean age, 44 ± 16 years) with newly diagnosed primary IgAN and 10 patients (7 males and 3 females; mean age, 51 ± 4 years) without known renal disease underwent [18F] AlF-NOTA-FAPI-04 PET/CT imaging. Kidney tissues from biopsies were stained with various techniques and examined using immunofluorescence. The Oxford classification was used to evaluate pathological indicators. Immunohistochemical staining was conducted to assess α-smooth muscle actin (αSMA) and FAP expression. Renal FAPI uptake measured by PET/CT (SUVmax and SUVmean) was correlated with histological findings. Results The renal parenchymal FAPI uptake was significantly higher in IgAN patients compared to control patients (SUVmax = 3.9 ± 1.3 vs 1.9 ± 0.4, SUVmean = 3.6 ± 1.2 vs 1.5 ± 0.4; all P &amp;lt; 0.001). We identified a significant difference in renal parenchymal FAPI uptake among the various categories of the Oxford classification. Correlation analysis revealed a positive association between SUVmax and interstitial fibrosis and tubular atrophy (IF/TA), as well as tubulointerstitial inflammation (TII) scores in scarred cortex and non-scarred cortex (r = 0.637, 0.593, and 0.491, all P &amp;lt; 0.05), Similar associations were observed between SUVmean and these scores (r = 0.641, 0.592, and 0.479, all P &amp;lt; 0.05). Furthermore, significant positive correlations were observed between SUVmax or SUVmean and the staining scores for glomerular αSMA and FAP, as well as for tubulointerstitial αSMA and FAP (all P &amp;lt; 0.01). Conclusion [18F] AlF-NOTA-FAPI-04 PET/CT imaging offers IgAN patients a non-invasive and reproducible auxiliary modality to monitor disease progression.

Investigating potential drug targets for IgA nephropathy and membranous nephropathy through multi-queue plasma protein analysis: a Mendelian randomization study based on SMR and co-localization analysis

BackgroundMembranous nephropathy (MN) and IgA nephropathy (IgAN) pose challenges in clinical treatment with existing therapies primarily focusing on symptom relief and often yielding unsatisfactory outcomes. The search for novel drug targets remains crucial to address the shortcomings in managing both kidney diseases.MethodsUtilizing GWAS data for MN (ncase = 2150, ncontrol = 5829) and IgAN (ncase = 15587, ncontrol = 462197), instrumental variables for plasma proteins were derived from recent GWAS. Sensitivity analysis involved bidirectional Mendelian randomization analysis, MR Steiger, Bayesian co-localization, and Phenotype scanning. The SMR analysis using eQTL data from the eQTLGen Consortium was conducted to assess the availability of selected protein targets. The PPI network was constructed to reveal potential associations with existing drug treatment targets.ResultsThe study, subjected to the stringent Bonferroni correction, revealed significant associations: four proteins with MN and three proteins with IgAN. In plasma protein cis-pQTL data from two cohorts, an increase in one standard deviation in PLA2R1 (OR = 2.01, 95%CI = 1.83–2.21), AIF1 (OR = 9.04, 95%CI = 4.69–17.41), MLN (OR = 3.79, 95%CI = 2.12–6.78), and NFKB1 (OR = 29.43, 95%CI = 7.73–112.0) was associated with an increased risk of MN. Additionally, in plasma protein cis-pQTL data, a standard deviation increase in FCGR3B (OR = 1.15, 95%CI = 1.09–1.22) and BTN3A1 (OR = 4.05, 95%CI = 2.65–6.19) correlated with elevated IgAN risk, while AIF1 (OR = 0.58, 95%CI = 0.46–0.73) exhibited IgAN protection. Bayesian co-localization indicated that PLA2R1 (coloc.abf-PPH4 = 0.695), NFKB1 (coloc.abf-PPH4 = 0.949), FCGR3B (coloc.abf-PPH4 = 0.909), and BTN3A1 (coloc.abf-PPH4 = 0.685) share the same variants associated with MN and IgAN. The SMR analysis indicated a causal link between NFKB1 and BTN3A1 plasma protein eQTL in both conditions, and BTN3A1 was validated externally.ConclusionGenetically influenced plasma levels of PLA2R1 and NFKB1 impact MN risk, while FCGR3B and BTN3A1 levels are causally linked to IgAN risk, suggesting potential drug targets for further clinical exploration, notably BTN3A1 for IgAN.

Urinary sediment mRNA as a potent biomarker of IgA nephropathy

BackgroundThe quantification of mRNA expression in urinary sediments is a reliable biomarker for various diseases. However, few studies have investigated the clinical relevance of urinary mRNA levels in IgA nephropathy (IgAN). Thus, we investigated the expression of urinary mRNAs and their clinical significance in IgAN.MethodsOverall, 200 patients with biopsy-proven IgAN, 48 disease controls, and 76 healthy controls were enrolled. We identified the differential expression of mRNAs in renal tissue between patients with IgAN and normal subjects using the Gene Expression Omnibus dataset and selected candidate mRNAs. mRNA expression in the urinary sediment was measured using quantitative real-time polymerase chain reaction. Associations between urinary mRNA levels and clinicopathological parameters were analyzed and the predictive value of mRNAs for disease progression was evaluated.ResultsThe urinary expression of CCL2, CD14, DNMT1, FKBP5, Nephrin, and IL-6 was significantly upregulated in patients with IgAN compared with healthy controls. C3, FLOT1, and Podocin levels were significantly correlated with renal function, where C3, FLOT1, and TfR levels were significantly correlated with urinary protein excretion. During follow-up, 26 (13.0%) patients with IgAN experienced disease progression, defined as a greater than 50% reduction in the estimated glomerular filtration rate or progression to end-stage renal disease. Urinary mRNA levels of FLOT1 (HR 3.706, 95% CI 1.373–10.005, P = 0.010) were independently associated with an increased risk of disease progression.ConclusionsOur results suggest that urinary sediment mRNAs are a useful biomarker in IgAN patients. Further studies with larger sample sizes and longer follow-up durations are required.

Exploring the mediating role of immune cells in the pathogenesis of IgA nephropathy through the inflammatory axis of gut microbiota from a genomic perspective.

IgA nephropathy (IgAN) is a chronic glomerular disease characterized by the deposition of IgA antibodies in the kidney's mesangium. Its pathogenesis involves genetic, immune, and environmental factors, particularly within the mucosal immune system and gut microbiota. Immune cells play a central role in mediating these processes, which this study investigates using Mendelian Randomization (MR) to explore causal relationships among gut microbiota, inflammatory markers, blood cells, and immune cells in IgAN pathogenesis. We conducted a two-sample MR analysis using Genome-Wide Association Study (GWAS) summary data to assess the causal effects of gut microbiota, inflammatory markers, and blood cell traits on IgAN. Data sources included the FinnGen dataset for IgAN and relevant GWAS datasets for immune traits, blood cells, and inflammatory markers. Inverse variance weighting (IVW) was the primary MR method, supported by sensitivity analyses. We particularly examined the mediation effect of immune cells on these exposures' influence on IgAN. Significant associations were found between several factors and IgAN. Gut microbiota traits, such as Firmicutes E and Sporomusales, increased IgAN risk, while Citrobacter A and Herbinix reduced it. Inflammatory markers, including Interleukin-10 and Fibroblast Growth Factor 23, promoted IgAN onset. Blood cell traits like red blood cell perturbation response increased risk, while monocyte perturbation response was protective. Immune traits played a key mediating role, with Transitional %B cells reducing IgAN risk and CD28- CD25 + + CD8br %T cells increasing it. This study highlights the pivotal mediating role of immune cells in the interactions between gut microbiota, inflammatory markers, and IgAN risk. These findings identify potential biomarkers and therapeutic targets, providing new insights into the immune mechanisms underlying IgAN and opportunities for intervention.

Proteinuria and Progression of Renal Damage: The Main Pathogenetic Mechanisms and Pharmacological Approach

The integrity of the glomerular filtration barrier maintains protein excretion below 150 mg/day. When urinary proteins increase, this indicates damage to the filtration barrier. However, proteinuria is not only a marker of kidney damage but also exacerbates it through various mechanisms involving the glomerular and tubulointerstitial compartments. Therefore, it is essential to intervene with renoprotective action that reduces the proteinuria. In this context, Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are cornerstone treatments. Recent advancements include sodium–glucose cotransporter 2 inhibitors, initially used for glycemic control, now recognized for their renoprotective properties in both diabetic and non-diabetic populations. Another drug, Finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, has emerged as a promising agent, offering anti-inflammatory and antifibrotic benefits with fewer side effects than traditional steroidal options. Finally, dual inhibition of angiotensin II and endothelin-1 receptors through agents like Sparsentan presents a novel approach with significant antiproteinuric effects in IgA nephropathy and focal segmental glomerulosclerosis. This brief review summarizes the mechanisms by which proteinuria promotes kidney damage and the renoprotective therapeutic approaches available, which can be combined with lifestyle modifications and specific treatments for underlying diseases to mitigate the progression of chronic kidney disease.

Association between different proportions of crescents and the progression of IgA nephropathy (IgAN): a systematic review and meta-analysis.

Immunoglobulin A nephropathy (IgAN) is a complex renal disease with a highly variable clinical course. Identifying reliable prognostic markers is crucial for risk stratification and treatment decisions. This study aimed to understand the influence of different proportions of crescents (Cs) on the progression of IgAN. Four databases (PubMed, Web of Science, Embase, and Cochrane Library) were searched until September 25, 2023. The study encompassed IgAN patients, focusing on kidney outcomes and end-stage kidney disease (ESKD). Statistical analysis included calculating hazard ratios (HR) for binary outcomes and examining publication bias. The meta-analysis involved thirteen studies comprising 11,849 patients. For kidney outcomes, crescent formation may be linked to an elevated risk (HR = 2.01, 95%CI 1.40-2.87, P < 0.001). Furthermore, significantly increased risks of kidney outcomes were observed with a crescent proportion > 10 (HR = 1.8, 95%CI 1.32-2.45, P < 0.001) and > 25%(HR = 2.11, 95% CI 1.47-3.02, P < 0.001). Regarding ESKD, a proportion > 25% also displayed an elevated risk (HR = 1.70, 95% CI 1.18-2.44, P = 0.004). However, a proportion > 10% (including > 25%) did not show a significant association with ESKD (HR = 1.12, 95% CI 0.36-3.47, P = 0.842) versus less. This systematic review and meta-analysis established a strong association between crescent proportions and the progression of IgAN. Higher proportions, notably exceeding 25%, were reliable prognostic markers, indicating a greater risk of adverse kidney outcomes and ESKD. These findings have significant clinical implications, offering the potential for more precise risk stratification in IgAN patients.

Impact of Overweight on Renal Prognosis in Malignant Hypertension Patients With Thrombotic Microangiopathy.

Overweight and obesity is a risk factor for hypertension. Malignant hypertension (MHT) is the most severe form of hypertension, and thrombotic microangiopathy (TMA), one of its complications, has been linked to significant renal outcomes. However, the impact of overweight and obesity on renal prognosis in MHT patients with TMA is not well understood. This was a prospective cohort enrolled 288 MHT patients with renal TMA from 2008 to 2023. The clinical and histopathological characteristics were recorded based on body mass index (BMI, < 25 and ≥ 25 kg/m2). The outcome was the incidence of kidney failure. The associations of BMI with kidney failure were examined in logistic regression models. Among 288 patients, 180 (62.5%) progressed to kidney failure, including 113 (68.5%) patients with BMI < 25 kg/m2. Participants with obesity had higher levels of hemoglobin, estimated glomerular filtration rate and C3, but lower levels of serum creatinine and IgA nephropathy. BMI ≥ 25 kg/m2 was associated with a better outcome of kidney failure in MHT patients with TMA (odd ratios [ORs]: 0.49 [95% confidence interval (CI): 0.27-0.91], p = 0.025). Male, uric acid, onion skin lesions, and global sclerosis ratio were correlated with higher risk of kidney failure; serum albumin and treatment with renin-angiotensin system blockers were related to lower risk of kidney failure. In MHT patients with renal TMA, normal-weight rather than overweight was found to associate with a worse renal prognosis. Management efforts for MHT may be directed toward controlling body weight within a reasonable range for patients.

The proteinuria selectivity index value predicts the remission of IgA nephropathy: a retrospective cohort study

IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide and leads to end-stage kidney disease. The proteinuria selectivity index (PSI) has been used to assess the prognosis in nephrotic syndrome, but its predictive value in patients with IgAN remains unclear. This single-center retrospective cohort study included patients who diagnosed with IgAN between March 2012 and March 2020. The PSI was calculated at the time of kidney biopsy. Patients were followed up from the time of kidney biopsy to kidney replacement therapy, death, transfer to another facility, or study completion. Ninety-four patients with a median age of 51 years were enrolled and divided according to the cutoff value of PSI determined by the receiver operating characteristic curve analysis into low-PSI (PSI <0.243, n = 39) and high-PSI groups (PSI ≥0.243, n = 55). The median follow-up duration was 70 months. Rates of remission of proteinuria and survival without a two-fold increase in serum creatinine were significantly better in the low-PSI group (both p < 0.01, log-rank test). Cox regression analysis showed that a low PSI was significantly associated with an increased likelihood of remission of proteinuria and hematuria (hazard ratio [HR] 1.96; 95% confidence interval [CI] 1.02–3.85 and HR 1.75; 95% CI 1.01–3.13, respectively), and a decreased risk of a two-fold increase in serum creatinine (HR 0.10; 95% CI 0.01–0.81). In conclusion, The PSI could have the potential to support the assessment of the prognosis of IgAN, in addition to established prognostic markers, by reflecting the overall glomerular permeability.

An inflammatory cytokine signature predicts IgA nephropathy severity and progression.

IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis, resulting in end-stage renal disease and increased mortality rates. Prognostic biomarkers reflecting molecular mechanisms for effective IgAN management are urgently needed. Analysis of kidney single-cell transcriptomic sequencing data demonstrated that IgAN expressed high-expression levels of inflammatory cytokines TNFSF10, TNFSF12, CCL2, CXCL1, and CXCL12 than healthy controls (HCs). We also measured the urine proteins in 120 IgAN (57 stable and 63 progressive) and 32 HCs using the proximity extension assay (PEA), and the multivariable and least absolute shrinkage and selection operator (LASSO) logistic regression analysis both revealed that CXCL12, MCP1 were the prognostic significant variables to predict IgAN progression severity. These two proteins exhibited negative correlation with the estimated glomerular filtration rate (eGFR) and patients with higher expression levels of these two proteins had a higher probability to have poorer renal outcome. We further developed a risk index model utilizing CXCL12, MCP1, and baseline clinical indicators, which achieved an impressive area under the curve (AUC) of 0.896 for prediction of IgAN progression severity. Our study highlights the significance of the inflammatory protein biomarkers for noninvasive prediction of IgAN severity and progression, offering valuable insights for clinical management.

Rutin reduces inflammation and fibrosis via TGF-β/SMAD pathways in IgA nephropathy induced rats.

Rutin is a flavonoid glycoside obtained from the plant Ruta graveolens. It was known to have immunosuppressant activities. This study was focused on effect of rutin against immunoglobulin A (IgA) nephropathy. IgA nephropathy was induced in Sprague-Dawley rats with various inducing agents described in text. During the later part of the induction phase, rutin was administered. Control group rats did not receive any treatment or inducing agent, induced group rats received only the inducing agents, whereas treatment group received the inducing agents as well as rutin. During the study, various biochemical parameters pertaining to kidney function were evaluated and also, the expression of proteins and cytokines responsible for inflammation and fibrosis were assessed. The effect of rutin in IgA nephropathy was promising as treatment with rutin reduced the deposition of IgA in the glomeruli of rats. Along with this we also tried to establish the probable mechanism of action of rutin and based on the summary of the results it was concluded that rutin reduced the inflammation and fibrosis related to IgA nephropathy by inhibiting the TGF-β/SMAD pathways and ultimately reducing the expression of α-smooth muscle actin (α-SMA). Comprehending all the above consideration, it may be safely said that that rutin alleviated inflammation and also fibrosis mediated by IgA, by suppressing the transforming growth factor-β (TGF-β) activities through suppressor of mothers against decapentaplegic pathways and reduced the epithelial-to-mesenchymal transition by downregulating the α-SMA which is a marker for fibrosis.

Patients with IgA Nephropathy Show Abnormal Frequencies of B cell Subsets and Unconventional T Cells and High Levels of Gd-IgA1 Coated Gut Bacteria

BackgroundMucosal inflammation is involved in the pathophysiology of Immunoglobulin-A nephropathy (IgAN), but peripheral immune phenotype analyses of IgAN patients often do not include unconventional T cells, the major subset in mucosal immunity. MethodsWe measured serum total IgA, gd-IgA1, secretory IgA, B cell activating factor (BAFF), and A proliferation-inducing ligand (APRIL) in 66 IgAN patients and 30 healthy controls (HC). We also quantified total IgA and gd-IgA1 in stool supernatant and coated on bacteria. In 35 patients and 14 controls, we performed extensive phenotyping (CyTOF) of circulating immune cells, including unconventional T cells [mucosal associated invariant T (MAIT) cells, γδ T, and NK T cells]. The results were validated using RNAseq data from a larger cohort of 179 patients with IgAN, 140 patients with minimal change disease (MCD), and 91 HC. ResultsIgAN patients had higher circulating levels of total IgA, gd-IgA1, and APRIL and higher IgA- and gd-IgA1-coated gut bacteria than controls, while serum levels of secretory IgA and BAFF did not differ between groups. IgAN patients showed more class switched memory and double negative B cells than controls. MAIT cells and γδ T cells were significantly lower, and CD4- CD8- NK T cells significantly higher in IgAN patients than in HC. We validated the significant decrease in MAIT cells in an independent cohort of patients with IgAN. ConclusionThe data indicate that patients with IgAN have increased circulating class switched memory and double negative B cells associated with abnormal T cell immunity, involving defects in unconventional T cell frequency. This may suggest putative alterations at mucosal sites due to cell migration leading to altered IgA production.

Network Pharmacological Analysis of Hydroxychloroquine Intervention in the Treatment of Iga Nephropathy.

IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis globally and has a high propensity to develop into end-stage renal disease (ESRD). Hydroxychloroquine has been proven to reduce proteinuria in IgAN patients, but the precise mechanism remains unclear. Therefore, network pharmacology was used to investigate the mechanism. PubChem and SwissADME databases were utilized to acquire the structure of hydroxychloroquine. The SwissTargetPrediction, PharmMapper, DrugBank, TargetNet, and BATMAN-TCM databases were then utilized to obtain the targets. The target genes related to IgAN were then gathered from the databases, which included GeneCards, PHARMGKB, DrugBank, OMIM, and DisGeNET. Common targets were obtained by UniProt. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to define the main molecular mechanisms and pathways. Furthermore, a protein-protein interaction (PPI) network was constructed using the STRING tool, and the core targets were obtained by Cytoscape. Finally, molecular docking between the core targets and hydroxychloroquine was performed. 167 common target genes were acquired by overlapping. The core targets were TNF, ALB, IL1B, JUN, FOS, SRC, and MMP9. The GO and KEGG results showed the targets to be related to the production of inflammatory cytokines and chemokines and were engaged in the toll-like receptor (TLR) signaling pathway. At the same time, the molecular docking results showed that the core targets all combined with hydroxychloroquine closely. This study proved that hydroxychloroquine may treat IgAN through the TLR signaling pathway, and the restraint of TNF, TLR, IL1B, and JUN may be essential for the treatment.

Coexisting nutcracker phenomenon and refractory hypertension in a patient with IgA nephropathy: A case report and literature review.

The entrapment of the left renal vein (LRV) may contribute to changes in hemodynamics within kidney and could also be associated with IgA nephropathy (IgAN). Although the relationship between the nutcracker phenomenon and IgAN has not yet been elucidated, it is speculated that this patient's refractory hypertension is a combined effect of nutcracker syndrome (NCS) and IgAN.

A first-in-human, randomized study of the safety, pharmacokinetics and pharmacodynamics of povetacicept, an enhanced dual BAFF/APRIL antagonist, in healthy adults.

Therapeutic agents targeting the tumor necrosis factor (TNF) superfamily cytokines B-cell activating factor (BAFF, BLyS) and/or A PRoliferation Inducing Ligand (APRIL) have demonstrated clinical effectiveness in multiple autoimmune diseases, such as systemic lupus erythematosus, lupus nephritis, and immunoglobulin A nephropathy (IgAN). However, their clinical utility can often be limited by incomplete and/or prolonged times to clinical response and inconvenient dosing regimens, which may be improved by more potent dual inhibition of both cytokines. Povetacicept (ALPN-303; TACI vTD-Fc) is a crystallizable fragment (Fc) fusion protein of an engineered transmembrane activator and CAML interactor (TACI) domain which mediates more potent inhibitory activity than wild-type TACI-Fc or BAFF- or APRIL-specific antibodies and demonstrates superior pharmacokinetic and pharmacodynamic activity in multiple preclinical disease models. In this first-in-human study in healthy adults, povetacicept was well-tolerated as single ascending doses of up to 960 mg administered intravenously or subcutaneously. Dose-dependent pharmacokinetics were observed. Coverage of BAFF and APRIL was observed for 2-3 weeks and ≥4 weeks after doses of 80 mg and ≥240 mg, respectively. Maximal pharmacodynamic effects were observed at dose levels ≥80 mg for a single dose, associated with on-target reductions in antibody-secreting cells as well as in all circulating immunoglobulin isotypes, including the IgAN disease-related biomarker galactose-deficient-immunoglobulin A1 (Gd-IgA1), and were superior to results reported for wild-type TACI-Fc. These data strongly support further development of povetacicept for the treatment of B-cell-mediated automimmune diseases.

Evaluating the risk of cardiovascular events associated with different immunosuppression treatments for glomerular diseases.

Patients with glomerular disease are at high risk of cardiovascular disease but the contribution of immunosuppression to this risk is unclear. In this retrospective cohort study of 1912 patients (comprised of 759 with IgA nephropathy, 540 with focal segmental glomerulosclerosis, 387 with membranous nephropathy and 226 with minimal change disease) from British Columbia, Canada, we evaluated the association between exposure to specific immunosuppressive medications and a composite outcome including coronary artery, cerebrovascular and peripheral arterial events. Survival models were adjusted for baseline cardiovascular risk factors, type of glomerular disease, estimated glomerular filtration rate (eGFR) and proteinuria over time. During a median follow-up of 6.8 years, 212 patients (11.1%) experienced the primary outcome. Corticosteroid exposure was not significantly associated with the primary outcome after adjusting for cardiovascular risk factors. In fully adjusted models, cumulative calcineurin inhibitor exposure at modest (150-300 defined daily doses [DDD]) and higher (300 or more DDD) doses were associated with a 2-fold higher risk of cardiovascular events (hazard ratio 2.98, 95% confidence interval 1.27-6.95) and (2.78, 1.32-5.84), respectively. A peak daily dose of antimetabolite (azathioprine, mycophenolate mofetil and mycophenolate sodium) of 0.5 or more DDD was associated with higher risk of cardiovascular events after adjustment for baseline risk factors and type of glomerular disease, but not after adjusting for time-varying eGFR and proteinuria (1.70, 0.91-3.20). Each 10 grams of cumulative cyclophosphamide exposure was associated with a 1.5-fold higher risk of cardiovascular events in a fully adjusted model (1.46, 1.22-1.75) Thus, our findings suggest that immunosuppressive therapies used in the treatment of glomerular disease may have different cardiovascular risk profiles, which should be considered when deciding on immunosuppression for individual patients and as a safety endpoint in future clinical trials.

Using prediction models to improve care and communicate risk: updated modeling for children with IgA nephropathy

Clinical risk prediction models are being generated at an increasing rate. One important component is the identification of groups for whom such models might require recalibration to retain their desired performance. To this end, an update of the postbiopsy International IgA Nephropathy Prediction Tool for children has been published in this issue of Kidney International. We review the methods used and generalizability in practice, along with broader concepts in model development and application.

Kikuchi–Fujimoto Disease: A Case Series and Review of the Literature

Kikuchi–Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is a rare, self-limiting disorder characterized by fever typically lasting for 1 week up to 1 month and painful necrotizing lymphadenopathy, primarily affecting young adults of Asian ancestry. Although the exact cause remains unclear, infectious and autoimmune mechanisms have been implicated in the pathogenesis of the disease. In this case series, we aim to describe the histopathological features of KFD over a ten-year period at Mount Sinai Medical Center of Florida, and review the current understanding of its pathogenesis, clinical presentation, diagnosis, and management. A retrospective review of our pathology database between January 2013 and May 2024 was performed to identify patients diagnosed with KFD at our institution. Eight cases of KFD were identified, with a mean age of 35 years (range 24–49) and slight male predilection (5:3). Three patients exhibited leukopenia, and two had concurrent HIV infection. One patient developed systemic lupus erythematosus (SLE), and another developed IgA nephropathy during follow-up. Histopathological examination revealed the characteristic features of KFD, including lymph node architectural effacement, histiocytic infiltration, and necrosis. In conclusion, KFD remains a diagnostic challenge due to its overlapping clinical features with other infectious and autoimmune diseases, particularly SLE. While most cases resolve spontaneously, long-term follow-up is warranted due to the potential for recurrence and autoimmune associations.