Overlap of membranous nephropathy and IgA nephropathy in a patient with Kimura's disease: a case report and literature review.

Introduction: Kimura's disease (KD) is a rare chronic inflammatory disorder characterized by subcutaneous lymphoid hyperplasia with peripheral eosinophilia. Kidney involvement is reported in 15%-18% of adult patients with KD, in many cases as nephrotic syndrome. We present a case of overlapping membranous nephropathy and IgA nephropathy associated with KD. Case report: A 27-year-old man was admitted with a history of bilateral leg edema for the last 2 months and concomitant progressive increase of cervical mass and fever. Laboratory findings were as follows: peripheral leukocyte count, 10,080/mm³; eosinophils, 3,200/mm³ (31.7%); serum creatinine, 0.83 mg/dL; and eGFR: 140 mL/min per 1.73 m2. Urinalysis revealed the presence of hematuria and proteinuria and the following results: 24-h proteinuria, 12.9 g; serum albumin, 1.3 g/dL; and elevated IgE level, 750 kU/L. Serologies for hepatitis B, hepatitis C, HIV, and VDRL were all negative. Complement C3 and C4 levels were normal. No monoclonal protein was detected in blood and urine. Parasite infestation was discarded. A biopsy of the cervical lymph node revealed eosinophilic lymphoid hyperplasia, suggesting KD. A kidney biopsy revealed findings consistent with the overlapping of membranous nephropathy with IgA nephropathy. The patient was treated for KD with prednisone 1 mg/kg/d with progressive dose tapering and posterior association of methotrexate 15 mg/week. A renin-angiotensin system inhibitor was prescribed for nephrotic syndrome. The cervical mass regressed, and proteinuria achieved partial remission, with an increase in serum albumin level and normalization of eosinophils and IgE levels. Conclusion: Although uncommon, kidney involvement must be considered in patients with KD. Glomerular diseases are the most frequent form of kidney injury.

Effect of tonsillectomy combined with steroid pulse therapy upon IgA nephropathy depending on proteinuria status at diagnosis: a nationwide multicenter cohort study in Japan.

BACKGROUND: The effects of tonsillectomy combined with steroid pulse (TSP) therapy for IgA nephropathy (IgAN) are little known. Therefore, we examined the effects of TSP therapy on the kidney outcomes of IgAN in a large, nationwide cohort study in Japan. METHODS: Between 2002 and 2004, 632 IgAN patients with ≥ 0.5 g/day proteinuria at diagnosis were divided into three groups with mild (0.50-0.99 g/day; n = 264), moderate (1.00-1.99 g/day, n = 216), or severe (≥ 2.00 g/day; n = 153). Decline in kidney function and urinary remission were compared among the three groups after TSP therapy, corticosteroid (ST) therapy, or conservative therapy during a mean follow-up of 6.2 ± 3.3 years. 10.6% and 5.9% of patients in the ST and conservative therapy group underwent tonsillectomy. RESULTS: The rate of urinary remission at the final observation was significantly higher in the TSP therapy group than in the ST or conservative therapy groups (mild proteinuria: 64%, 43%, and 41%; moderate proteinuria: 51%, 45%, and 28%; severe proteinuria: 48%, 30%, and 22%, respectively). In contrast, the rate of a 50% increase in serum creatinine was lower in groups TSP therapy, than ST or conservative therapy (mild proteinuria: 2.1%, 10.1% and 16.7%; moderate proteinuria: 4.8%, 8.8% and 27.7%; severe proteinuria: 12.0%, 28.9% and 43.1%, respectively). In multivariate analysis, TSP therapy significantly prevented a 50% increase in serum creatinine levels compared with conservative therapy in groups with moderate and severe proteinuria (hazard ratio, 0.12 and 0.22, respectively). CONCLUSION: TSP significantly increased the rate of proteinuria disappearance and urinary remission in IgAN patients with mild-to-moderate urinary protein levels. It may also reduce the decline in kidney function in patients with moderate-to-severe urinary protein levels.

Current understanding and new insights in the treatment of IgA nephropathy.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, and almost all patients are at risk of progression to end-stage kidney disease within their lifetime. The mechanisms responsible for the presentation and development of IgAN are required for the development of highly targeted therapies for this disease. In this review, we first demonstrate the current treatment strategy of IgAN recommended by the 2021 KDIGO guideline. Then, we update the new insights into disease pathogenesis based on the well acknowledged 'multiple-hit hypothesis' and provide the potential therapeutic targets involved in the upstream production of pathogenic IgA1 and the downstream complement activation. Finally, the recent large randomized controlled trials focusing on these novel targets have been summarized, among which Nefecon and Sparsentan have received approval and Telitacicept have been used off-label for IgAN. In the future, emerging treatment approaches for IgAN is likely to evolve, which will signify a shift in the management of the IgAN from traditional immunosuppressive approaches to an era of targeted treatment based on the understanding of the pathogenic mechanisms.

Complement C3a/C3aR and C5a/C5aR deposits accelerate the progression of advanced IgA nephropathy to end-stage renal disease.

IgA nephropathy (IgAN) is still one of the leading causes of end-stage kidney disease (ESRD), and complement system activation is a key to the pathogenesis of IgAN. The role of complement C3a/C3aR and C5a/C5aR in late stage of IgAN remains unknown. Renal specimens of 75 IgAN patients at the stage 4 CKD were stained using immunofluorescence and immunohistochemistry. The primary outcome was a composite of end-stage renal disease (ESRD) and death. Associations of complement components with baseline clinicopathological characteristics and outcomes were assessed using multivariable Cox regression and Spearman analyses. During a median follow-up of 15.0 months, 27 patients progressed to ESRD and none died. Lower eGFR [hazards ratio (HR), 0.827, 95% confidence interval (CI), 0.732-0.935; P = 0.002] and glomerular C3 deposition (HR, 3.179, 95% CI, 1.079-9.363; P = 0.036) were predictive of time to ESRD in stage 4 CKD IgAN. Higher expression of C3a (P = 0.010), C3aR (P = 0.005), C5a (P = 0.015), and C5aR (P < 0.001) was identified in ESRD group than in non-ESRD group. Glomerular C3a/C3aR and C5a/C5aR deposits were both correlated with a lower baseline eGFR, higher baseline 24 h-urinary protein (24 h-UP) and faster decline of eGFR. Besides, C3a and C5a deposits were found in patients with high S (S1) and T (T1/2) scores, respectively. Complement C3a/C3aR and C5a/C5aR in IgAN patients with stage 4 CKD may portend a faster deterioration of kidney function.

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.

Correlation of Serum Bilirubin with Clinical and Pathological Characteristics of Patients with IgA Nephropathy.

OBJECTIVE: To investigate the correlations of total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL) with various clinical indicators and pathological features of patients with IgA nephropathy (IgAN). METHODS: Patients diagnosed with IgAN were included and divided into low and high TBIL/DBIL/IBIL groups. Correlation analysis was performed to assess the relationships between the bilirubin indices and other clinical and pathological variables. Logistic regression was applied to identify the independent risk factors of mesangial cell proliferation (corresponding to M1 in the Oxford classification of IgAN). RESULTS: Totally 192 patients with IgAN were included, and the patient clinical indicators were compared between the different bilirubin subgroups. Compared to the groups with higher TBIL, DBIL, and IBIL levels, groups with lower values of these bilirubin indices exhibited a higher 24-hour urine protein (24hUP) concentration but a lower proportion of males as well as reduced total protein, albumin, haemoglobin, and glutamic-pyruvic transaminase levels (p < 0.05). Moreover, the low-DBIL group displayed higher total cholesterol, triglyceride, and low-density lipoprotein (LDL) concentrations (p < 0.05) than those in the high DBIL group. Spearman analysis further revealed that TBIL, DBIL, and IBIL were negatively correlated with 24hUP and positively correlated with haemoglobin, total protein, and albumin (p < 0.05). Additionally, DBIL exhibited negative correlations with total cholesterol, triglyceride, and LDL (p < 0.05). From a pathological perspective, M1 incidence was higher in the low TBIL and IBIL groups (both p < 0.05). Furthermore, the high IBIL group showed a lower occurrence of cellular/fibrocellular crescents (C1 (in at least one glomerulus) and C2 (in >25% of glomeruli) in the Oxford classification, p < 0.05). Lastly, the multivariate regression model suggested that IBIL was an independent protective factor for M1 (odds ratio = 0.563, 95% confidence interval = 0.344-0.921, p = 0.022). CONCLUSIONS: Patients with IgAN accompanied by low values of bilirubin indices exhibit worsened disease-related clinical indicators (24hUP, total protein, albumin, and haemoglobin levels). Reduced TBIL and IBIL concentrations are indicative of severe renal pathology, with IBIL being a protective factor against M1.

IgA class-switched CD27-CD21+ B cells in IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is characterised by the production of galactose-deficient IgA1 (GdIgA1) antibodies. As the source of pathogenic antibodies, B cells are central to IgAN pathogenesis, but the B cell activation pathways as well as the potential B cell source of dysregulated IgA-secretion remain unknown. METHODS: We carried out flow cytometry analysis of peripheral blood B cells in patients with IgA nephropathy and control subjects with a focus on IgA-expressing B cells to uncover the pathways of B cell activation in IgAN and how these could give rise to pathogenic GdIgA1 antibodies. RESULTS: In addition to global changes in the B cell landscape - expansion of naive and reduction in memory B cells - IgAN patients present with an increased frequency of IgA-expressing B cells that lack the classical memory marker CD27, but are CD21pos. IgAN patients further have an expanded population of IgApos antibody-secreting cells, which correlate with serum IgA levels. Both IgApos plasmabalsts and CD27neg B cells co-express GdIgA1. Implicating dysregulation at mucosal surfaces as the driver of such B cell differentiation, we found a correlation between lipopolysaccharide (LPS) in the serum and IgAposCD27neg B cell frequency. CONCLUSION: We propose that dysregulated immunity in the mucosa may drive de novo B cell activation within germinal centres, giving rise to IgAposCD27neg B cells and subsequently IgA-producing plasmablasts. These data integrate B cells into the paradigm of IgAN pathogenesis and allow to further investigate this pathway to uncover biomarkers and develop therapeutic interventions.

Low dose glucocorticoids, mycophenolate mofetil and hydroxychloroquine in IgA nephropathy, an update of current clinical trials.

This mini-review explores glucocorticoids, mycophenolate mofetil (MMF), and hydroxychloroquine (HCQ) in IgA nephropathy (IgAN). It discusses conflicting findings from pivotal trials like TESTING and STOP-IgAN regarding glucocorticoid efficacy, emphasizing reduced-dose protocols as potentially safer options. MMF's effectiveness varies among populations, demonstrating promise in Chinese cohorts but yielding inconclusive results elsewhere. HCQ shows potential in reducing proteinuria, with ongoing trials investigating its long-term benefits.

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.

Role of serum complement C3 and C4 on kidney outcomes in IgA nephropathy.

IgA Nephropathy (IgAN) is the most prevalent glomerular disease worldwide. Complement system activation is crucial in its pathogenesis. Few studies correlated serum C3 and C4 with disease activity and prognosis. This retrospective study investigated the prognostic value of serum complement at the time of diagnosis in patients with IgAN. Specifically we evaluated whether adding serum C3 and C4 levels to established predictive models-one based on variables related to chronic kidney disease (CKD) progression and another incorporating variables from the International IgA Prediction Tool (IntIgAPT)-enhances the accuracy of outcome prediction. A composite renal outcome was defined as 50% decline in eGFR or onset of kidney failure. 101 patients were stratified according to baseline C3 levels in three groups (Low, Medium and High). During a median follow-up of 54 months, the Low group exhibited higher incidence of primary outcome (16.3 events vs 2.9 and 1.7 events × 100 pts/year, p = 0.0026). Model-1 (M1), consisting of CKD progression variables, and Model-3 (M3), comprising IntIgANPT variables, were implemented with baseline C3 and C4 to create Model-2 (M2) and Model-4 (M4), respectively. M2 demonstrated better predictive performance over M1, showing higher discrimination (lower AIC and BIC, higher C-index and NR2). Similarly, M4 outperformed M3, showing enhanced outcome prediction when C3 and C4 levels were added. Implementation of serum C3 and C4 can enhance prediction accuracy of already-validated prognostic models in IgAN. Lower C3 and higher C4 levels were associated with poorer prognosis, highlighting a more 'Complement-Pathic' subset of patients.

A preliminary probabilistic nomogram model for predicting renal arteriolar damage in IgA nephropathy from clinical parameters.

Background: IgA nephropathy (IgAN) is a significant contributor to chronic kidney disease (CKD). Renal arteriolar damage is associated with IgAN prognosis. However, simple tools for predicting arteriolar damage of IgAN remain limited. We aim to develop and validate a nomogram model for predicting renal arteriolar damage in IgAN patients. Methods: We retrospectively analyzed 547 cases of biopsy-proven IgAN patients. Least absolute shrinkage and selection operator (LASSO) regression and logistic regression were applied to screen for factors associated with renal arteriolar damage in patients with IgAN. A nomogram was developed to evaluate the renal arteriolar damage in patients with IgAN. The performance of the proposed nomogram was evaluated based on a calibration plot, ROC curve (AUC) and Harrell's concordance index (C-index). Results: In this study, patients in the arteriolar damage group had higher levels of age, mean arterial pressure (MAP), serum creatinine, serum urea nitrogen, serum uric acid, triglycerides, proteinuria, tubular atrophy/interstitial fibrosis (T1-2) and decreased eGFR than those without arteriolar damage. Predictors contained in the prediction nomogram included age, MAP, eGFR and serum uric acid. Then, a nomogram model for predicting renal arteriolar damage was established combining the above indicators. Our model achieved well-fitted calibration curves and the C-indices of this model were 0.722 (95%CI 0.670-0.774) and 0.784 (95%CI 0.716-0.852) in the development and validation groups, respectively. Conclusion: With excellent predictive abilities, the nomogram may be a simple and reliable tool to predict the risk of renal arteriolar damage in patients with IgAN.

Hydroxychloroquine blood concentrations and effects in Chinese patients with IgA nephropathy.

BACKGROUND: Hydroxychloroquine (HCQ) is recommended for Chinese patients with immunoglobulin A nephropathy (IgAN). However, the relationship between HCQ blood concentration and the therapeutic effect for IgAN has not yet been defined. This study investigates the optimal and efficacious range of HCQ blood concentrations in Chinese patients with IgAN. METHODS: Seventy-three patients with biopsy-proven IgAN who were at risk of progression were included in this study. Thirty-eight patients with IgAN were treated with HCQ plus an optimized renin-angiotensin-aldosterone system inhibitor (RAASi), and thirty-five patients received only RAASi. Blood HCQ concentration and 24-h proteinuria were examined at three and six months after treatment. RESULTS: The baseline proteinuria levels were comparable between the RAASi and HCQ groups. The HCQ group had lower 24-h proteinuria than the RAASi group three months after treatment, though the difference was not significant (p = 0.38). After six months, the median proteinuria level was significantly lower in the HCQ group than in the RAASi group (p < 0.05). The percentage reduction in 24-h proteinuria in the HCQ group was greater than that in the RAASi group at three (p < 0.05) and six months (p < 0.05). Hydroxychlorquine blood concentration and efficacy were positively correlated at three months (r = 0.428, p < 0.05) and six months (r = 0.48, p < 0.05). Moreover, the optimal blood concentration of HCQ for three-month efficacy was 418.96 ng/mL and that for six-month efficacy was 582.48 ng/mL. No serious adverse events were reported during HCQ treatment. CONCLUSIONS: Hydroxyhloroquine safely reduces proteinuria in Chinese patients with IgAN. The efficacy of HCQ is positively correlated with its blood concentration.

Causal role of immune cells in IgA nephropathy: a mendelian randomization study.

BACKGROUND: Previous observational studies have shown that immune cells play an important role in IgA nephropathy. However, the specific causal relationship between the two is inconsistent. METHODS: We used a two-sample mendelian randomization(MR) analysis to investigate the causal association between 731 immune cell signatures and IgA nephropathy in this study. Based on published GWAS data, immune cells were characterized by four immune types absolute cell (AC) counts, median fluorescence intensity (MFI), morphological parameters (MP), relative cell (RC) counts. Meanwhile, heterogeneity test, horizontal pleiotropy and sensitivity test were used to evaluate the robustness and reliability of the results. RESULTS: An important causal association was achieved for 14 RC traits/IgA nephropathy, 3 AC traits/IgA nephropathy, 10 MFI traits/IgA nephropathy, and 1 MP trait/IgA nephropathy. However, after false discovery rate (FDR) correction, only one immunophenotype was found to be protective against IgA nephropathy. The OR of herpesvirus entry mediator (HVEM) on terminally differentiated CD4+ T cell (maturation stages of T-cell panel) on IgA nephropathy risk was estimated to be 0.727 (95%CI: 0.624-0.847, p = 4.20e - 05, PFDR = 0.023) according to inverse variance weighting (IVW) method, and the weighted-median method yielded similar results (OR = 0.743, 95% CI: 0.596-0.927, p = 0.008). Although not statistically significant, the association was consistent with MR-Egger, simple mode and weighted mode. CONCLUSIONS: Our study further confirmed that immune cells play a complex and important role in the pathogenesis of IgA nephropathy, providing evidence for clinical research.

The prognostic value of the systemic immune inflammation index in patients with IgA nephropathy.

BACKGROUND: Immune and inflammatory factors are considered the basic underlying mechanisms of IgA nephropathy (IgAN). The systemic immune inflammation index (SII) is a new inflammatory biomarker and has been identified as a prognostic indicator for various diseases. However, limited studies have been conducted on the prognostic value of the SII in patients with IgAN, and we aimed to address this gap. METHODS: A total of 374 patients with IgAN confirmed by renal biopsy performed from 1 January 2015 to 1 April 2019, were retrospectively included. The follow-up period of all patients was at least 12 months after diagnosis, and the endpoint was defined as end-stage kidney disease (ESKD). Patients were further divided into a high-risk group (SII ≥ 456.21) and a low-risk group (SII < 456.21) based on the optimal cutoff value of the SII determined by receiver operating characteristic (ROC) curve analysis. Baseline clinicopathological parameters were compared between the groups, and Cox proportional hazards analyses and Kaplan-Meier analysis were performed to assess renal survival in IgAN patients. RESULTS: After a median follow-up period of 32.5 months, a total of 53 patients eventually reached ESKD. Patients in the high-SII group tended to have a lower hemoglobin level (p = 0.032) and eGFR (p < 0.001), a higher serum creatinine level (p = 0.023) and 24-hour total protein level (p = 0.004), more severe tubular atrophy and interstitial fibrosis (p = 0.002) and more crescents (p = 0.030) than did those in the low-SII group. Univariate and multivariate Cox regression analyses demonstrated that an SII ≥456.21 was an independent risk factor for poor renal survival in IgAN patients (HR 3.028; 95% CI 1.486-6.170; p = 0.002). Kaplan-Meier analysis revealed that a high SII was significantly associated with poor renal prognosis (p < 0.001) and consistently exhibited remarkable discriminatory ability across different subgroups in terms of renal survival. CONCLUSION: A high SII was associated with more severe baseline clinical and pathological features, and an SII ≥456.21 was an independent risk factor for progression to ESKD in IgAN patients.

High systemic inflammatory response index (SIRI) is an independent risk factor for poor outcome in IgA nephropathy patients.

BACKGROUND: The systemic inflammatory response index (SIRI), a straightforward and easily accessible measure of inflammation and prognosis, has drawn more attention lately. It is unknown, however, if SIRI is important for IgA nephropathy (IgAN) patients' outcomes. To better clarify these concerns, we conducted this investigation. METHOD: This retrospective study involved 981 patients with biopsy-confirmed IgAN from West China Hospital of Sichuan University between 2008 and 2019. The patients were divided into two groups based on the SIRI's optimal cut-off value calculated by the X-tile: the low SIRI group (SIRI ≤ 0.63, n = 312) and the high SIRI group (SIRI > 0.63, n = 669). Basic clinical characteristics at the time of renal biopsy were evaluated, and the relationship between SIRI and the combined endpoint was analyzed. We also used the Cox proportional hazard model and Kaplan‒Meier curve to evaluate the renal prognosis of IgAN. RESULTS: A total of 981 IgAN patients were included. During a median follow-up period of 56.7 months (36.8-80.4 months), 122 patients progressed to the combined endpoint (12.4%). Patients were divided into a low SIRI group (SIRI ≤ 0.63, n = 312) and a high SIRI group (SIRI > 0.63, n = 669) according to the optimal cut-off value of the systemic inflammatory response index (SIRI). Further analysis showed that a higher SIRI value was significantly associated with the risk of IgAN patients reaching the composite endpoint (HR 1.62, 95% CI 1.02-2.56, p = 0.041). CONCLUSION: High SIRI is a significant and independent risk factor for renal disease progression in IgAN patients.

Intestinal epithelium dysfunctions cause IgA deposition in the kidney glomeruli of intestine-specific Ap1m2-deficient mice.

BACKGROUND: Intestinal epithelial cells (IECs) serve as robust barriers against potentially hostile luminal antigens and commensal microbiota. Epithelial barrier dysfunction enhances intestinal permeability, leading to leaky gut syndrome (LGS) associated with autoimmune and chronic inflammatory disorders. However, a causal relationship between LGS and systemic disorders remains unclear. Ap1m2 encodes clathrin adaptor protein complex 1 subunit mu 2, which facilitates polarized protein trafficking toward the basolateral membrane and contributes to the establishment of epithelial barrier functions. METHODS: We generated IEC-specific Ap1m2-deficient (Ap1m2ΔIEC) mice with low intestinal barrier integrity as an LSG model and examined the systemic impact. FINDINGS: Ap1m2ΔIEC mice spontaneously developed IgA nephropathy (IgAN)-like features characterized by the deposition of IgA-IgG immune complexes and complement factors in the kidney glomeruli. Ap1m2 deficiency markedly enhanced aberrantly glycosylated IgA in the serum owing to downregulation and mis-sorting of polymeric immunoglobulin receptors in IECs. Furthermore, Ap1m2 deficiency caused intestinal dysbiosis by attenuating IL-22-STAT3 signaling. Intestinal dysbiosis contributed to the pathogenesis of IgAN because antibiotic treatment reduced aberrantly glycosylated IgA production and renal IgA deposition in Ap1m2ΔIEC mice. INTERPRETATION: IEC barrier dysfunction and subsequent dysbiosis by AP-1B deficiency provoke IgA deposition in the mouse kidney. Our findings provide experimental evidence of a pathological link between LGS and IgAN. FUNDING: AMED, AMED-CREST, JSPS Grants-in-Aid for Scientific Research, JST CREST, Fuji Foundation for Protein Research, and Keio University Program for the Advancement of Next Generation Research Projects.

Immunoglobulin A Nephropathy in a Patient With Bilateral Metal-on-Metal Hip Arthroplasty.

Immunoglobulin A (IgA) nephropathy in the presence of a metal-on-metal (MoM) hip arthroplasty is a rare condition that requires close monitoring. A 61-year-old male with bilateral hip osteoarthritis underwent resurfacing hip arthroplasty with MoM articulating surfaces. Prior to his four-year postoperative visit, the patient was diagnosed with IgA nephropathy. During this visit, the patient reported clicking in the left resurfacing hip arthroplasty, and serum metal ions were significantly elevated. Consequently, the patient underwent conversion to bilateral ceramic-on-cross-linked polyethylene total hip arthroplasty, which resulted in the restoration of metal ion levels to normal. This case highlights that IgA nephropathy played a critical role in impeding the clearance of metal ions. Routine metal ion counts are warranted in patients with MoM articulating interfaces and a newly diagnosed nephropathy.

The impact of mild and moderate COVID-19 infection on the progression of kidney dysfunction in patients with IgA nephropathy.

Background: Previous research indicates that coronavirus disease 2019 (COVID-19) infection may have a role in triggering immunoglobulin A (IgA) nephropathy. However, limited research has explored the clinical implications of COVID-19 infection in individuals already diagnosed with IgA nephropathy. This study aimed to determine whether COVID-19 infection independently affects the subsequent trajectory of kidney function in IgA nephropathy patients. Methods: This was a single-center cohort study. The study included 199 patients diagnosed with IgA nephropathy. The COVID-19 infection status was determined using a combined method: a questionnaire and the Health Code application, both administered at the end of 2022 in northern China. Kidney function trajectory was assessed by the estimated glomerular filtration rate (eGFR), calculated based on serum creatinine levels measured during follow-up outpatient visits. The primary endpoint of interest was the eGFR trajectory. Results: Out of the 199 participants, 75% (n = 181) reported a confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, determined through antigen or polymerase chain reaction tests, accounting for 79% (n = 143) of the infected patients. A significant majority (98%) experienced mild to moderate symptoms. Over a median follow-up period of 10.7 months post-COVID-19 infection, notable clinical events included gross hematuria in 30 patients (16.6%), which normalized within an average of 3 days. Additionally, a 2-fold increase in proteinuria or progression to the nephrotic range was observed in 10 individuals (5.5%). No cases of acute kidney injury were noted. COVID-19 exposure was associated with an absolute change in eGFR of 2.98 mL/min/1.73 m2 per month (95% confidence interval 0.46 to 5.50). However, in a fully adjusted model, the estimated changes in eGFR slope post-COVID-19 were -0.39 mL/min/1.73 m2 per month (95% confidence interval -0.83 to 0.06, P = .088) which included the possibility of no significant effect. Notably, a higher rate of kidney function decline was primarily observed in patients with a baseline eGFR <45 mL/min/1.73 m2 [-0.56 mL/min/1.73 m2 (-1.11 to -0.01), P = .048]. In the cohort, there were few instances of severe COVID-19 cases. The absence of long-term follow-up outcomes was observed. Conclusions: Overall, mild to moderate COVID-19 infection does not appear to significantly exacerbate the subsequent decline in kidney function among IgA nephropathy patients, particularly in those with preserved baseline kidney function.

Cathepsin S (CTSS) in IgA nephropathy: an exploratory study on its role as a potential diagnostic biomarker and therapeutic target.

Introduction: IgA nephropathy (IgAN), a prevalent form of glomerulonephritis globally, exhibits complex pathogenesis. Cathepsins, cysteine proteases within lysosomes, are implicated in various physiological and pathological processes, including renal conditions. Prior observational studies have suggested a potential link between cathepsins and IgAN, yet the precise causal relationship remains unclear. Methods: We conducted a comprehensive bidirectional and multivariable Mendelian randomization (MR) study using publicly available genetic data to explore the causal association between cathepsins and IgAN systematically. Additionally, immunohistochemical (IHC) staining and enzyme-linked immunosorbent assay (ELISA) were employed to evaluate cathepsin expression levels in renal tissues and serum of IgAN patients. We investigated the underlying mechanisms via gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and immune cell infiltration analysis. Molecular docking and virtual screening were also performed to identify potential drug candidates through drug repositioning. Results: Univariate MR analyses demonstrated a significant link between increased cathepsin S (CTSS) levels and a heightened risk of IgAN. This was evidenced by an odds ratio (OR) of 1.041 (95% CI=1.009-1.073, P=0.012) as estimated using the inverse variance weighting (IVW) method. In multivariable MR analysis, even after adjusting for other cathepsins, elevated CTSS levels continued to show a strong correlation with an increased risk of IgAN (IVW P=0.020, OR=1.037, 95% CI=1.006-1.069). However, reverse MR analyses did not establish a causal relationship between IgAN and various cathepsins. IHC and ELISA findings revealed significant overexpression of CTSS in both renal tissues and serum of IgAN patients compared to controls, and this high expression was unique to IgAN compared with several other primary kidney diseases such as membranous nephropathy, minimal change disease and focal segmental glomerulosclerosis. Investigations into immune cell infiltration, GSEA, and GSVA highlighted the role of CTSS expression in the immune dysregulation observed in IgAN. Molecular docking and virtual screening pinpointed Camostat mesylate, c-Kit-IN-1, and Mocetinostat as the top drug candidates for targeting CTSS. Conclusion: Elevated CTSS levels are associated with an increased risk of IgAN, and this enzyme is notably overexpressed in IgAN patients' serum and renal tissues. CTSS could potentially act as a diagnostic biomarker, providing new avenues for diagnosing and treating IgAN.