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BACKGROUND: IgA nephropathy is an important global cause of kidney failure. Dysregulation of IgA production is thought to play a key role in IgA nephropathy pathogenesis, however, little is known about the epigenetic mechanisms such as RNA 5- methylcytosine (5mC) modification in regulating IgA synthesis. METHODS: To decipher the role of RNA 5mC in regulation of IgA class switch, the miR-23b-/- and LCWE induced Kawasaki disease mice were treated with 5-azacytidine. Trdmt1-/- and double Trdmt1-/-/ miR-23b-/- mice, Aid-/- mice or Aid-/-/ miR-23b-/- mice were also employed. RESULTS: We showed that miR-23b down regulated expression of Transfer RNA Aspartic Acid Methyltransferase 1 (Trdmt1) and consequently reduced 5-methylcytosine (m5C) RNA modification and IgA synthesis in B cells. Inhibition of m5C RNA modification normalised serum IgA levels and ameliorated progression of the IgA nephropathy-like kidney disease in miR-23b-/- and Kawasaki disease mice while mesangial IgA and C3 deposition failed to develop in Trdmt1-/-miR-23b-/- mice. By contrast, increased m5C RNA modification resulted in an exaggerated IgA nephropathy phenotype. miR-23b regulation of serum IgA levels and the development of an IgA nephropathy-like kidney disease in miR-23b-/- and Kawasaki disease mice is likely mediated through TRDMT1 driven 5-methylcytosine RNA modification in B cells, resulting in impaired activation-induced cytidine deaminase activity and IgA class switch recombination. CONCLUSIONS: This study revealed TRDMT1 induced RNA 5mC methylation regulate IgA class switch and inhibition of RNA 5mC by 5-Azacytidine could ameliorate progression of IgA nephropathy.
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BACKGROUND: IgA nephropathy is the most common primary glomerulonephritis worldwide, and there is emerging evidence linking galactose-deficient IgA1 (Gd-IgA1) to the pathogenesis of the disease. However, mouse models that can be used to study Gd-IgA1's origin of production, biochemical characteristics, and immune reactivity are lacking. METHODS: We generated a humanized IgA1 mouse model with transgenic expression of the human IGHA1 gene from the mouse chromosomal locus of IgA heavy chain. The IGHA1+/+ mice were crossed with complement factor H heterozygous mutant (FHW/R) to generate IGHA1+/+FHW/R mice. IGHA1+/+ mice were exposed to different levels of environmental pathogens in the first 4 months, as housed in either germ-free, specific pathogen-free, or conventional environments. In addition, wild-type C57BL/6J mice, IGHA1+/+ mice, and IGHA1+/+FHW/R mice were inoculated with Lactobacillus casei cell bacterial wall extract (LCWE) mixed with complete Freund's adjuvant (CFA) at two months of age to develop a mouse model of IgA nephropathy. RESULTS: Elevated levels of human IgA1 in blood circulation and mucosal sites were observed in IGHA1+/+ mice from exposure to pathogens. Compared to buffer-treated control mice, LCWE plus CFA-treated mice had moderately elevated levels of circulating human IgA1 (by one fold) and human IgA1 immune complexes (by two folds). Serum Gd-IgA1 levels increased fourfold following LCWE treatments. Analyses of the O-glycopeptides of the IgA1 hinge region confirmed hypo-galactosylation of IgA1, with the variety of the glycoforms matching those seen in clinical samples. Furthermore, LCWE induced persistent IgA1 and C3 deposition in the glomerular mesangial areas in association with mesangial expansion and hypercellularity, which are frequently observed in IgA nephropathy biopsies. The IGHA1+/+FHW/R mice stimulated with LCWE and CFA developed albuminuria and hematuria. CONCLUSIONS: We observed elevated plasma Gd-IgA1 levels with kidney deposition of IgA1 in the IGHA1+/+ mice following LCWE and CFA. In conjunction with factor H mutation, the mice exhibited severe glomerular alterations, associated with hematuria and albuminuria in resemblance of clinical IgA nephropathy.
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RATIONALE & OBJECTIVE: Proteinuria is a surrogate end point for predicting long-term kidney outcomes in IgA nephropathy (IgAN) with levels<1g/day identified as a therapeutic target. However, this threshold has not been sufficiently studied. We quantified the associations of progression of IgAN with various levels of proteinuria. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 1,530 patients with IgAN and at least 12 months of follow-up at Peking University First Hospital. EXPOSURE: Proteinuria levels updated over time (time-varying proteinuria, TVP). OUTCOME: A composite kidney outcome of a 50% reduction in the estimated glomerular filtration rate or end-stage kidney disease. ANALYTICAL APPROACH: Marginal structural models. RESULTS: After a median follow-up period of 43.5 (IQR, 27.2-72.8) months, 254 patients (16.6%) developed the composite kidney outcome. A graded association was observed between TVP and composite kidney outcomes with higher risk among those with proteinuria of≥0.5g/day. Compared with TVP<0.3g/day, the HRs for proteinuria levels of 0.3 to<0.5g/day, 0.5 to<1.0g/day, 1.0 to<2.0g/day, and≥2.0g/day were 2.22 (95% CI, 0.88-5.58), 4.04 (95% CI, 1.93-8.46), 8.46 (95% CI, 3.80-18.83), and 38.00 (95% CI, 17.62-81.95), respectively. The trend was more pronounced in patients with baseline proteinuria of≥1.0g/day, among whom a higher risk was observed with TVP of 0.3 to<0.5g/day compared with TVP<0.3g/day (HR, 3.26 [95% CI, 1.07-9.92], P=0.04). However, in patients with baseline proteinuria levels of<1g/day, the risk of composite kidney outcome only began to increase when TVP was≥1.0g/day (HR, 3.25 [95% CI, 1.06-9.90]). LIMITATIONS: Single-center observational study, selection bias, and unmeasured confounders. CONCLUSIONS: This study showed that patients with IgAN and proteinuria levels of>0.5g/day, have an elevated risk of kidney failure especially among patients with proteinuria levels≥1.0g/day before initiating treatment. These data may serve to inform the selection of proteinuria targets in the treatment of IgAN. PLAIN-LANGUAGE SUMMARY: The presence of proteinuria has often been considered a surrogate end point and a possible therapeutic target in clinical trials in IgA nephropathy (IgAN). Some guidelines recommend a reduction in proteinuria to<1g/day as a treatment goal based on the results of previous longitudinal studies. However, these findings may have been biased because they did not properly adjust for time-dependent confounders. Using marginal structural models to appropriately account for these confounding influences, we observed that patients with IgAN and proteinuria levels≥0.5g/day have an elevated risk of kidney failure, especially among patients who had proteinuria levels of≥1.0g/day before initiating treatment. These data may serve to inform the selection of proteinuria targets in the treatment of IgAN.
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Progresión de la Enfermedad , Glomerulonefritis por IGA , Proteinuria , Humanos , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/fisiopatología , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/epidemiología , Proteinuria/etiología , Femenino , Masculino , Adulto , Estudios de Cohortes , Factores de Tiempo , Tasa de Filtración Glomerular , Persona de Mediana Edad , Estudios de SeguimientoRESUMEN
INTRODUCTION: In 2016, the Oxford Classification of IgA nephropathy (IgAN) updated its scoring system for the glomerular crescents. Despite this, the clinical significance of crescentic lesions in the updated Oxford classification is still unexplored through prospective cohort studies. METHODS: 134 patients diagnosed with IgAN accompanied with C2 lesions at Peking University First Hospital were consecutively enrolled and prospectively followed up for analysis. Multivariate Cox regression in combination with LASSO regression was used to analyze risk factors associated with end-stage kidney disease (ESKD). RESULTS: During biopsy, the mean estimated glomerular filtration rate (eGFR) was 39.3 mL/min/1.73 m2, and the mean proteinuria was 4.4 g/day. The proportion of kidney failure at 1 year, 2 years, and 3 years were 24%, 34%, and 47%, respectively. The results of LASSO in combination with Cox regression showed that mean arterial pressure (hazard ratio [HR] = 1.035, 95% confidence interval [95% CI] 1.013-1.056, p = 0.001), eGFR at biopsy (HR = 0.968, 95% CI [0.948-0.990], p < 0.004) and T2 lesions (HR = 2.490, 95% CI [1.179-5.259], p = 0.017) were independent risk factor associated with ESKD in patients with C2 lesions. Furthermore, based on univariate analyses, we found that patients with kidney function declined more than 50% within 3 months prior to biopsy or pathological findings indicated a proportion of crescents exceeding 50% were both associated with a poor kidney prognosis. Lastly, when the proportion of the crescent was less than 50%, patients receiving combined steroid and immunosuppressant treatment did not exhibit a better renal prognosis than those receiving steroid only. CONCLUSION: Patients diagnosed with IgAN and concurrent C2 lesions exhibited a poor clinical prognosis, necessitating more effective treatment strategies.
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BACKGROUND AND HYPOTHESIS: The association between superimposed preeclampsia and an elevated risk of long-term kidney function decline or end-stage kidney disease (ESKD) in patients with chronic kidney disease (CKD) has not been determined. This study aimed to analyze the association between preeclampsia and kidney function deterioration in CKD patients. METHODS: This was a retrospective cohort study that included the clinical information of 103 pregnant CKD patients with preeclampsia and 103 matched CKD patients without preeclampsia who were followed-up for a minimum of 1 year after their first pregnancy from January 1, 2009, to May 31, 2022. Robust Cox regression analysis was also conducted to evaluate the effects of preeclampsia on long-term kidney function decline or ESKD in CKD patients. K-M curves were used to compare renal survival within different subgroups via the log-rank test. RESULTS: During the follow-up period, 44 (42.72%) CKD patients with preeclampsia and 20 (19.42%) without preeclampsia had an estimated glomerular filtration rate (eGFR) decrease >30% or developed ESKD. Compared with CKD patients without preeclampsia, the eGFR decreased more significantly in patients with preeclampsia [98.43 (79.48, 116.47) to 81.32 (41.20, 102.97) mL/min/1.73 m2 vs. 99.43 (79.00, 118.50) to 89.44 (63.69, 105.30) mL/min/1.73 m2; P=0.034]. The rate of eGFR decrease was more pronounced in patients with preeclampsia (17.38% vs. 10.05%, p<0.05). Multivariate analysis revealed that early-onset preeclampsia (preeclampsia that developed before 34 weeks of gestation) (HR=2.61, 95% CI=1.32-5.16, P=0.006) and late-onset preeclampsia (HR=2.54, 95% CI=1.34-4.83, P=0.004) were both risk factors for an eGFR decrease >30% or ESKD. CONCLUSION: Preeclampsia was associated with a greater risk of long-term kidney function decline or ESKD among CKD patients, especially in patients with early-onset preeclampsia.
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BACKGROUND: C4d mesangial deposition, a hallmark of lectin pathway activation in immunoglobulin A nephropathy (IgAN), has been shown to be associated with risk of kidney failure. To date, the relationship between urinary C4d and renal outcome remain unelucidated. METHODS: A total of 508 patients with biopsy-proven IgAN were enrolled in this study, whose baseline urine samples at the time of biopsy were collected and the levels of urinary C4d were quantified by enzyme-linked immunosorbent assay. The time-averaged C4d (TA-C4d) and the change in proteinuria were measured in sequential urine samples obtained from IgAN patients. The kidney progression event was defined as a 50% estimated glomerular filtration rate (eGFR) decline or end-stage kidney disease or death. RESULTS: After a median follow-up of 36 months, 70 (13.8%) of the participants reached the kidney progression event. Higher levels of urinary C4d/Ucr were found to be associated with decreased eGFR, massive proteinuria, lower serum albumin levels, hypertension, and severe Oxford E and T scores. Upon adjusting for traditional risk factors (including demographics, eGFR, proteinuria, hypertension, Oxford pathologic score and immunosuppressive therapy), elevated levels of urinary C4d/Ucr were independently associated with an increased risk of chronic kidney disease progression [adjusted hazard ratio (HR) per standard deviation increment of log-transformed C4d/Ucr: 1.46; 95% CI 1.04-2.06; P = .030]. In reference to the low C4d group, the risk of poor renal outcome increased for the high C4d group (adjusted HR 1.93; 95% CI 1.05-3.54; P = .033). Additionally, a low baseline C4d level was independently associated with a favorable proteinuria response to immunosuppressive therapy at 3 months (adjusted relative risk 2.20; 95% CI 1.04-4.63, P = .038). CONCLUSION: The urinary C4d, serving as a non-invasive biomarker, is associated with the progression of IgAN and holds the potential to predict proteinuria response in this disease.
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Biomarcadores , Complemento C4b , Progresión de la Enfermedad , Tasa de Filtración Glomerular , Glomerulonefritis por IGA , Fragmentos de Péptidos , Humanos , Glomerulonefritis por IGA/orina , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/diagnóstico , Masculino , Femenino , Adulto , Complemento C4b/orina , Estudios de Seguimiento , Biomarcadores/orina , Fragmentos de Péptidos/orina , Pronóstico , Factores de Riesgo , Persona de Mediana Edad , Proteinuria/orina , Proteinuria/etiología , Proteinuria/diagnóstico , Fallo Renal Crónico/orina , Fallo Renal Crónico/etiología , Fallo Renal Crónico/patologíaRESUMEN
BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.
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Tasa de Filtración Glomerular , Glomerulonefritis por IGA , Proteinuria , Humanos , Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/fisiopatología , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/terapia , Masculino , Femenino , Niño , Adulto , Proteinuria/etiología , Proteinuria/diagnóstico , Adolescente , Estudios Prospectivos , Adulto Joven , Pronóstico , Persona de Mediana Edad , Factores de Edad , Hematuria/etiología , Hematuria/diagnóstico , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Hipertensión/diagnóstico , Riñón/patología , Riñón/fisiopatología , Progresión de la Enfermedad , Glucocorticoides/uso terapéuticoRESUMEN
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.
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BACKGROUND: Thinned glomerular basement membrane (tGBM) lesions are not uncommon in IgA nephropathy (IgAN). Type IV collagen-built of α 3, α 4, and α 5 chains, encoded by COL4A3 / COL4A4 / COL4A5 genes-is the major component of glomerular basement membrane (GBM). In recent years, mutations in type IV collagen-encoding genes were also reported in patients with a histologic diagnosis of FSGS. Pathogenic COL4A3 / COL4A4 / COL4A5 variants were recently identified in familial cases of IgAN, but the contribution of these variants to sporadic IgAN is still unclear. METHODS: We compared 161 patients with sporadic IgAN with tGBM lesions (IgAN-tGBM) to matched patients with IgAN without tGBM lesions and matched patients with thin basement membrane nephropathy (TBMN). Variants of COL4A3 / COL4A4 / COL4A5 genes were screened and evaluated after whole-exome sequencing. GBM thickness was measured, and levels of circulating galactose-deficient IgA1 (Gd-IgA1) were assessed by ELISA. RESULTS: The patients with IgAN-tGBM manifested milder disease than did patients with IgAN without tGBM but had more severe features than the patients with TBMN. Exome sequence analysis of the 122 patients with IgAN-tGBM identified 37 diagnostic variants of the COL4A3 / COL4A4 / COL4A5 genes among 38 patients (31.1%). Furthermore, patients with IgAN-tGBM who had diagnostic variants had higher proportions of GBM thickness <250 nm and milder glomerular injury, whereas patients with IgAN-tGBM who did not have diagnostic variants showed more characteristic features of IgAN, including higher intensity of glomerular IgA deposits and elevated Gd-IgA1 levels. These findings suggest different mechanisms in patients with versus without diagnostic variants of these collagen genes. CONCLUSIONS: COL4A3 / COL4A4 / COL4A5 variant detection is essential in evaluating patients with sporadic IgAN with tGBM lesions.
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Glomerulonefritis por IGA , Nefritis Hereditaria , Humanos , Membrana Basal Glomerular/patología , Colágeno Tipo IV/genética , Nefritis Hereditaria/genética , Glomerulonefritis por IGA/genética , Glomerulonefritis por IGA/patología , Mutación , Membrana BasalRESUMEN
BACKGROUND: Acute kidney injury (AKI) is a severe postoperative complication in patients undergoing major surgery. Proton pump inhibitors (PPIs) are used preoperatively as prophylaxis for postoperative gastrointestinal bleeding. Whether preoperative PPI use is associated with an increased risk of postoperative AKI remains uncertain. METHODS: This retrospective cohort study used electronic medical records from the clinical data warehouse of Peking University First Hospital to screen all adult hospitalizations undergoing major surgery between 1 January 2018 and 31 December 2020. Exposure was preoperative PPI use, defined as PPI use within 7 days before major surgery. The primary outcome was postoperative AKI, defined as AKI occurring within 7 days after major surgery; secondary outcomes included in-hospital AKI and in-hospital mortality. RESULTS: A total of 21,533 patients were included in the study (mean [SD] age, 57.8 [15.0] years; 51.2% male), of which 944 (4.4%) were prescribed PPI within 7 days before major surgery (PPI users). Overall, 72 PPI users (7.6%) and 356 non-users (1.7%) developed postoperative AKI. After adjustment, preoperative PPI use was associated with an increased risk of postoperative AKI (adjusted OR, 1.47; 95% CI, 1.04-2.07) and in-hospital AKI (adjusted OR, 1.41; 95% CI, 1.03-1.94). Moreover, subgroup analyses showed that the risk of PPI on postoperative AKI was amplified by the concomitant use of non-steroidal anti-inflammatory drugs or diuretics. No significant difference was observed between preoperative PPI use and in-hospital mortality in the fully adjusted model (adjusted OR 1.63; 95% CI, 0.55-4.85). CONCLUSIONS: Preoperative PPI use was associated with an increased risk of AKI in patients undergoing major surgery. This risk may be enhanced by the concomitant use of other nephrotoxic drugs. Clinicians should weigh the pros and cons before initiating PPI prophylaxis.
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Lesión Renal Aguda , Mortalidad Hospitalaria , Complicaciones Posoperatorias , Inhibidores de la Bomba de Protones , Humanos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , Inhibidores de la Bomba de Protones/efectos adversos , Inhibidores de la Bomba de Protones/administración & dosificación , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Anciano , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Adulto , Factores de Riesgo , Cuidados Preoperatorios/métodos , China/epidemiologíaRESUMEN
Multiple genome-wide association studies (GWASs) have reproducibly identified the MTMR3/HORMAD2/LIF/OSM locus to be associated with IgA nephropathy (IgAN). However, the causal variant(s), implicated gene(s), and altered mechanisms remain poorly understood. Here, we performed fine-mapping analyses based on GWAS datasets encompassing 2762 IgAN cases and 5803 control individuals, and identified rs4823074 as the candidate causal variant that intersects the MTMR3 promoter in B-lymphoblastoid cells. Mendelian randomization studies suggested the risk allele may modulate disease susceptibility by affecting serum IgA levels through increased MTMR3 expression. Consistently, elevated MTMR3 expression in peripheral blood mononuclear cells was observed in patients with IgAN. Further mechanistic studies in vitro demonstrated that MTMR3 increased IgA production dependent upon its phosphatidylinositol 3-phosphate binding domain. Moreover, our study provided the in vivo functional evidence that Mtmr3-/- mice exhibited defective Toll Like Receptor 9-induced IgA production, glomerular IgA deposition, as well as mesangial cell proliferation. RNA-seq and pathway analyses showed that MTMR3 deficiency resulted in an impaired intestinal immune network for IgA production. Thus, our results support the role of MTMR3 in IgAN pathogenesis by enhancing Toll Like Receptor 9-induced IgA immunity.
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Glomerulonefritis por IGA , Animales , Ratones , Alelos , Estudio de Asociación del Genoma Completo , Glomerulonefritis por IGA/patología , Inmunoglobulina A , Leucocitos Mononucleares/metabolismo , Receptor Toll-Like 9 , HumanosRESUMEN
BACKGROUND: Discontinuation of renin-angiotensin system (RAS) inhibitors is common in patients with chronic kidney disease (CKD), and the potential danger has been reported in several studies. However, a comprehensive analysis has not been conducted. OBJECTIVES: This study sought to evaluate the effects of discontinuation of RAS inhibitors in CKD. METHOD: Relevant studies up to November 30, 2022, were identified in the PubMed, Embase, Web of Science, and Cochrane Library databases. Efficacy outcomes included the composite of all-cause mortality, cardiovascular events, and end-stage kidney disease (ESKD). Results were combined using a random-effects or fixed-effects model, and sensitivity analysis used the leave-one-out method. RESULTS: Six observational studies and one randomized clinical trial including 244,979 patients met the inclusion criteria. Pooled data demonstrated that discontinuation of RAS inhibitors was associated with an increased risk of all-cause mortality (HR 1.42, 95% CI 1.23-1.63), cardiovascular event risk (HR 1.25, 95% CI 1.17-1.22), and ESKD (HR 1.23, 95% CI 1.02-1.49). In sensitivity analyses, the risk for ESKD was reduced. Subgroup analysis showed that the risk of mortality was more pronounced in patients with eGFR above 30 mL/min/m2 and in patients with hyperkalemia-related discontinuation. In contrast, patients with eGFR below 30 mL/min/m2 were at great risk of cardiovascular events. CONCLUSIONS: The discontinuation of RAS inhibitors in patients with CKD was associated with a significantly increased risk of all-cause mortality and cardiovascular events. These data suggest that RAS inhibitors should be continued in CKD if the clinical situation allows.
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Enfermedades Cardiovasculares , Fallo Renal Crónico , Insuficiencia Renal Crónica , Humanos , Sistema Renina-Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Antihipertensivos/uso terapéutico , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/inducido químicamente , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/inducido químicamente , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: In chronic kidney disease, current guidelines recommend systolic blood pressure (SBP) below 120 mmHg. However, the renoprotective effect of intensive blood-pressure (BP) lowering on immunoglobulin A nephropathy (IgAN) remains undetermined. We aimed to determine the effect of intensive BP control on the progression of IgAN. METHODS: At Peking University First Hospital, 1530 patients with IgAN were enrolled. An examination of the relationship between baseline and time-updated BP and composite kidney outcomes, defined as development of end-stage kidney disease (ESKD) or a 30% decline in estimated glomerular filtration rate (eGFR), was conducted. Baseline and time-updated BPs were modeled using multivariate causal hazards models and marginal structural models (MSMs). RESULTS: In a median follow-up of 43.5 (interquartile range 27.2, 72.7) months, 367 (24.0%) patients experienced the composite kidney outcomes. No significant associations were found between baseline BP and the composite outcomes. Using MSMs with time-updated SBP for analysis, a U-shaped association was found. In reference to SBP 110-119 mmHg, hazard ratios (95% confidence intervals) for the SBP categories <110, 120-129, 130-139 and ≥140 mmHg were 1.48 (1.02-2.17), 1.13 (0.80-1.60), 2.21 (1.54-3.16) and 2.91 (1.94-4.35), respectively. The trend was more prominent in patients with proteinuria ≥1 g/day and eGFR ≥60 mL/min/1.73 m2. After analyzing time-updated diastolic BP, no similar trend was observed. CONCLUSIONS: In patients with IgAN, intensive BP control during the treatment period may retard the kidney disease progression, but the potential risk of hypotension still needs to be considered.
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Glomerulonefritis por IGA , Fallo Renal Crónico , Insuficiencia Renal Crónica , Humanos , Estudios de Cohortes , Glomerulonefritis por IGA/complicaciones , Presión Sanguínea/fisiología , Riñón , Insuficiencia Renal Crónica/complicaciones , Fallo Renal Crónico/etiología , Progresión de la Enfermedad , Tasa de Filtración GlomerularRESUMEN
Mucosal immune regulation is considered a key aspect of immunopathogenesis of IgA nephropathy (IgAN). Direct experimental evidence clarifying the role of intestinal mucosa attributes in IgAN is lacking. In this study, a mouse model was established via multiple low-dose intraperitoneal injections of Lactobacillus casei cell wall extract (LCWE) emulsified with Complete Freund's Adjuvant (CFA). We found continuous and stable deposition of IgA in glomerular mesangial areas, accompanying high circulating levels of IgA and IgA-IgG complexes. Expression of the key extracellular matrix components collagen IV and fibronectin also increased in the mesangial areas of LCWE-induced mice. IgA+ B220+ B-cell proportion increased in the small intestine (SI), Peyer's patches, inguinal lymph nodes, spleen, and bone marrow. The intestinal barrier was dysfunctional in the LCWE-induced mice, and consistent with this, higher levels of serum zonulin (namely prehaptoglobin-2), a regulator of epithelial and endothelial barrier function, were observed in patients with IgAN. Hematoxylin and eosin staining results indicated that immune tissues such as liver, spleen, and lymph nodes showed an inflammatory response and focal lesions. Glucocorticoid methylprednisolone treatment could alleviate serum IgA and IgA-IgG complex levels and mesangial IgA deposition. Taken together, our results indicate that we have successfully constructed a mouse model with IgA deposition in the mesangial areas of the glomeruli and provide evidence for the connection between the intestinal barrier and elevated circulating IgA and IgA-IgG in IgAN. © 2022 The Pathological Society of Great Britain and Ireland.
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Glomerulonefritis por IGA , Lacticaseibacillus casei , Animales , Extractos Celulares/uso terapéutico , Pared Celular/metabolismo , Pared Celular/patología , Preparaciones de Acción Retardada/uso terapéutico , Glomerulonefritis por IGA/patología , Humanos , Inmunoglobulina A/metabolismo , Inmunoglobulina G , Lacticaseibacillus casei/metabolismo , Ratones , Extractos Vegetales/uso terapéuticoRESUMEN
IgA nephropathy (IgAN), the most common form of primary glomerulonephritis, is mainly observed in young adults and children. Clinical and basic studies indicate the role of immunity in IgAN pathogenesis; however, corticosteroid therapy has been controversial in past decades. The TESTING study, initiated in 2012, is an international, multicenter, double-blinded, randomized, placebo-controlled trial that aimed to evaluate oral methylprednisolone's safety and long-term efficacy under conditions of optimized supportive treatment in patients with IgAN whose risk of progression is high. After a decade of effort, the successful completion of the TESTING study showed that a 6- to 9-month course of oral methylprednisolone is an effective regimen to protect kidney function in high-risk patients with IgAN, but also demonstrated safety concerns. Compared with the full-dose regimen, the reduced-dose regimen was reported to be beneficial, with successfully increased safety. Overall, the TESTING trial provided more data regarding the treatment dosage and safety of corticosteroids, a cost-effective therapy, in IgAN, which have important implications for pediatric patients with IgAN. With a deeper understanding of the disease pathogenesis of IgAN, ongoing studies of novel therapeutic regimens would help further optimize the benefit-risk ratio.
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Glomerulonefritis por IGA , Adulto Joven , Humanos , Niño , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/tratamiento farmacológico , Corticoesteroides/efectos adversos , Metilprednisolona/efectos adversos , Protocolos Clínicos , Estudios Multicéntricos como AsuntoRESUMEN
BACKGROUND: Hydroxychloroquine (HCQ) is recommended as a treatment for IgA nephropathy (IgAN) to control proteinuria. The long-term effects of HCQ compared to systemic corticosteroid therapy remain unclear. METHODS: We conducted a retrospective caseâcontrol study at Peking University First Hospital. Thirty-nine patients with IgAN who received HCQ for at least 24 months without corticosteroids (CSs) or other immunosuppressive agents were included. Thirty-nine matched patients who received systemic CS therapy were selected using propensity score matching. Clinical data over a 24-month period were compared. RESULTS: In the HCQ group, the level of proteinuria decreased from 1.72 [1.44, 2.35] to 0.97 [0.51, 1.37] g/d (-50.5 [-74.0, -3.4] %, P < 0.001) at 24 months. A significant decline in proteinuria was also found in the CS group, but no significant differences were found between the HCQ group and CS group in the levels of proteinuria (0.97 [0.51, 1.37] vs. 0.53 [0.25, 1.81] g/d, P = 0.707) and change rates (-50.5% [-74.0%, -3.4%] vs. -63.7% [-78.5%, -24.2%], P = 0.385) at 24 months. In addition, the decline rates of eGFR between the HCQ and CS groups were comparable (-7.9% [-16.1%, 5.8%] vs. -6.6% [-14.9%, 5.3%], P = 0.758). More adverse events were observed in the CS group. CONCLUSIONS: Long-term use of HCQ can maintain stable renal function with minimal side effects. In patients who cannot tolerate corticosteroids, HCQ might be an effective and safe supportive therapy for IgAN.
Asunto(s)
Glomerulonefritis por IGA , Hidroxicloroquina , Humanos , Corticoesteroides/uso terapéutico , Estudios de Casos y Controles , Estudios de Seguimiento , Tasa de Filtración Glomerular , Hidroxicloroquina/uso terapéutico , Proteinuria/tratamiento farmacológico , Proteinuria/inducido químicamente , Estudios RetrospectivosRESUMEN
BACKGROUND: IgA nephropathy is a common primary glomerulonephritis caused by mesangial deposition of poly-IgA complexes. The disease follows a variable course of clinical progression, with a high risk of kidney failure. Although no specific therapy is available, enzymatic strategies to clear IgA deposits are being considered for the treatment of rapidly progressive IgA nephropathy. METHODS: We chose an IgA protease of commensal bacterium Clostridium ramosum, termed AK183, as the template for constructing a recombinant biologic. To extend the t1/2 in blood, we fused AK183 to the Fc segment of human IgG1. Activities of this Fc-AK183 fusion protein toward the cleavage and subsequent clearance of IgA were tested in mouse models. RESULTS: First, we discovered an autocleavage activity of AK183 that separates the N-terminal protease from its C-terminal autotransporter ß domain. Therefore, we grafted Fc to the N terminus of AK183 and demonstrated its week-long enzymatic activity in mice. In addition, the proteolytic fragments of IgA generated in the reaction with Fc-AK183 were effectively removed from circulation via kidney filtration. The combined actions of Fc-AK183-mediated cleavage and subsequent renal clearance of IgA resulted in a lasting obliteration of blood IgA, as demonstrated in a human IgA-injection model and in a humanized α1KI transgenic model. Fc-AK183 was also able to remove chronic IgA and associated complement C3 deposits in the glomerulus. CONCLUSION: We constructed a chimeric fusion of IgA protease with Fc and demonstrated its long-lasting efficacy as a promising targeted therapy for IgA nephropathy in mouse models.
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Glomerulonefritis por IGA , Animales , Modelos Animales de Enfermedad , Femenino , Firmicutes , Glomerulonefritis por IGA/terapia , Humanos , Inmunoglobulina A/metabolismo , Inmunoglobulina G , Masculino , Ratones , Receptores Fc , Serina EndopeptidasasRESUMEN
BACKGROUND: Positive glomerular C4d staining, representative of lectin pathway activation, has been proven to be associated with unfavorable outcomes in immunoglobulin A nephropathy (IgAN). Our previous study suggested that urinary C4d correlated positively with an increase in crescents while the relationship between urinary C4d and disease severity and progression remains unelucidated. METHODS: In this study we enrolled 168 patients diagnosed with IgAN with varying proportions of crescent formation at the time of biopsy. An independent cohort of 107 IgAN patients was enrolled for validation. Kidney biopsy specimens were stained using immunohistochemistry. Urinary C4d levels at renal biopsy were measured by enzyme-linked immunosorbent assay. The primary endpoint was end-stage kidney disease (ESKD). RESULTS: Higher urinary C4d/creatinine levels were associated with a lower estimated glomerular filtration rate (eGFR); massive proteinuria; hypertension and severe Oxford M, E, T and C scores. After a median follow-up of 19 months (interquartile range 9-27), 53 (31.5%) participants reached ESKD. High urinary C4d/creatinine levels were independently and significantly associated with a risk of developing ESKD [hazard ratio per standard deviation increment of log-transformed C4d/creatinine 7.623 (95% confidence interval 4.117-14.113)]. CONCLUSIONS: The urinary C4d/creatinine level is a potential useful biomarker that was associated with disease severity and progression in patients with IgAN and crescents.
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Glomerulonefritis por IGA , Fallo Renal Crónico , Humanos , Biomarcadores/metabolismo , Estudios de Cohortes , Creatinina , Progresión de la Enfermedad , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/patología , Fallo Renal Crónico/complicaciones , Lectinas , Estudios RetrospectivosRESUMEN
BACKGROUND: Rapidly progressive immunoglobulin A nephropathy (RPIgAN) is a severe clinical phenotype of IgAN associated with a poor outcome. The recently published Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Guideline for the Management of Glomerular Diseases has proposed a new definition for RPIgAN that is based simply on a ≥50% decline in the estimated glomerular filtration rate (eGFR) over ≤3 months. METHODS: In 1677 IgAN patients followed at a single centre in China, we evaluated the utility of this new definition to identify the highest-risk IgAN patients who might be suitable for combination immunosuppressive therapy. RESULTS: The proportion of a ≥50% decline in eGFR over ≤3 months was 5.2%. The majority of these patients had reversible causes, with only 2.3% (39/1677) meeting the KDIGO 2021 criteria for RPIgAN. These patients had a significantly higher risk for end-stage kidney disease (ESKD) than non-RPIgAN patients (logrank P < 0.001). RPIgAN was an independent risk factor for ESKD [hazard ratio 3.99 (95% confidence interval 2.25-7.09); P <0.001]. A minority of the RPIgAN patients (25.6%) had ≥50% crescents. There was no significant difference in the risk for ESKD between patients in the RPIgAN group with ≥50% crescents and Ë50% crescents (logrank P = 0.27). Patients with RPIgAN and ≥50% crescents had a higher risk for ESKD than patients with non-RPIgAN and ≥50% crescents (logrank P = 0.04). CONCLUSIONS: These data support the validity of the KDIGO 2021 definition but require independent validation in other non-Chinese cohorts.
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Glomerulonefritis por IGA , Fallo Renal Crónico , Humanos , Glomerulonefritis por IGA/patología , Pronóstico , Riñón/patología , Fallo Renal Crónico/terapia , Fallo Renal Crónico/complicaciones , Tasa de Filtración GlomerularRESUMEN
IgA nephropathy (IgAN) is the most common type of glomerulonephritis worldwide, which follows a chronic but nonetheless highly variable course of progression. IgA immune complexes are the primary source of renal deposits in IgAN. Apart from the presence of granular IgA1 deposits in the glomerular mesangium and mesangial hypercellularity as common features, the detailed process of IgA1 deposition and clearance in the kidney remains unclear. We sought to examine the dynamics of IgA deposition and tissue plasticity in response to deposits including their intrarenal clearance. We followed a synthetic approach to produce a recombinant fusion between IgA Fc (rIgA) and a biotin tag, which was subsequently induced with streptavidin (SA) to form an oligomeric poly-IgA mimic. Both uninduced rIgA (mono-rIgA) and polymeric SA-rIgA (poly-rIgA) were injected intravenously into Wistar rats. Plasma IgA levels and renal and liver histology were examined in a time series. In contrast to mono-rIgA, this synthetic poly-rIgA analog formed renal deposits exclusively in the glomerulus and were mostly cleared in 3 h. However, repeated daily injections for 12 days caused long-lasting and stronger glomerular IgA deposition together with IgG and complement C3, in association with mesangial cell proliferation, matrix expansion, and variable degrees of albuminuria and hematuria that phenocopied IgAN. Ex vivo, poly-rIgA bound cultured mesangial cells and elicited cytokine production, in addition to activating plasma C3 that was consistent with the actions of IgA immune complexes in IgAN pathogenesis. Remarkably, the kidneys were able to reverse all pathologic manifestations and restore normal glomerular histology 2 weeks after injections were halted. The synthetic model showed the kinetics between the intricate balance of renal deposition and clearance, as well as glomerular plasticity towards healing. Together, the results revealed a priming effect of existing deposits in promoting stronger and longer-lasting IgA deposition to cause renal damage. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.