IgA nephropathy (IgAN) advances from multiple pathogenic "hits" resulting in poorly O-galactosylated IgA1 glycoforms (Gd-IgA1), production of antibodies and glomerular deposition of immune complexes. ...A sequence of immune responses arising from plasma cells, T cells and antigen presenting cells (APCs), causes glomerular injury. This study was designed to phenotype subsets of B cells, monocytes and T cells in the peripheral circulation and their association with inflammatory cytokines and kidney function in patients with IgAN, healthy controls (HC) and disease controls with autosomal dominant polycystic kidney disease (ADPKD).
Patients with IgAN (n = 13), median estimated glomerular filtration rate (eGFR) of 57 ml/min/1.73m2 (IQR 42-84), patients with ADPKD (n = 13) matched for kidney function, gender and age and gender and age-matched HC (n = 13) were recruited. CD3+ and CD3- peripheral blood mononuclear cells were isolated and profiled based on their specific surface markers for different subsets of monocytes, B and T cells and analyzed by flow cytometry. Cytokines were analyzed by ELISA.
We observed a significant decrease in the proportion of pre-switched B cells and plasmablasts, but an increase in long-lived plasma cells in the peripheral circulation of IgAN patients compared to HC. The proportion of non-classical monocytes was significantly higher in IgAN patients compared to both HC and ADPKD. We also report an association between sCD40L levels and the proportion of pre-switched B cells, as well as sCD40L and MCP-1 levels and albuminuria in IgAN patients.
We applied an easy-access method to analyze subsets of immune cells as well as relevant inflammatory mediators in IgAN patients. Our data demonstrate an altered B cell profile that indicates a pathophysiological role of the B cell lineage and an increased proportion of non-classical monocytes that suggests their role in the disease process.
Autoantibodies against a constituent of the glomerular basement membrane (GBM), the α3-chain of type IV collagen, can cause both rapidly progressive glomerulonephritis and alveolar hemorrhage, ...referred to as anti-GBM disease or Goodpasture disease. Anti-GBM antibodies generally are of immunoglobulin G subclass 1 (IgG1) and can in most cases readily be detected in the circulation using enzyme-linked immunosorbent assays (ELISAs). We report 4 cases in which anti-GBM ELISA yielded negative or borderline results despite life-threatening disease. All 4 patients had positive results by IgG4 anti-GBM ELISA and all had undetectable antineutrophil cytoplasmic antibody. All cases were confirmed with kidney biopsy. Two of the patients showed higher signal in anti-GBM ELISA when using a nondenaturing coating buffer. All 4 were young women with severe alveolar hemorrhage and favorable renal outcome, suggesting that patients with predominance of IgG4 autoantibodies may constitute a distinct subgroup of anti-GBM disease. We conclude that patients with idiopathic alveolar hemorrhage can have anti-GBM disease detected by only IgG subclass – specific tests or kidney biopsy.
Fibroblast growth factor-23 (FGF23) regulates mineral metabolism. Circulatory FGF23 levels are increased and predict outcomes in CKD. However, the relation of FGF23 to albuminuria and disease ...progression in patients with CKD and one underlying diagnosis is unknown.
Prospective, observational study in 180 patients with IgA nephropathy (IgAN), CKD stage 1-4, and median 55-month follow-up (range, 12-177 months). Primary outcomes were (1) time-averaged albuminuria, (2A) progression to CKD stage 5 or ≥50% loss of estimated GFR, (2B) progression to CKD stage 5 or ≥25% loss of estimated GFR within 10 years, and (3) annual loss of estimated GFR.
FGF23 was independently associated with baseline and time-averaged albuminuria (change in 1 g/24 hour albuminuria per increase in log FGF23: β = 0.26; P=0.02). Log FGF23 predicted CKD progression in crude models and after adjustment for mineral metabolites (endpoints 2A and 2B). It remained significant after adjustments for age, sex, serum albumin, calcium, phosphate, parathyroid hormone, 25-hydroxyvitamin D, baseline albuminuria, baseline estimated GFR, mean arterial BP, body mass index, and angiotensin-converting enzyme inhibitors/angiotensin-receptor blocker use in endpoint 2B (hazard ratio, 2.53; P=0.02) but not endpoint 2A (hazard ratio, 2.01; P=0.43). Log FGF23 predicted annual loss of estimated GFR in the same model (change in ml/min per 1.73 m(2) per increase in log FGF23, 1.50; P=0.008).
In patients with CKD and IgAN, FGF23 was associated with albuminuria and CKD progression, a finding that suggests its role as a potential biomarker in IgAN.
Chronic kidney disease has been linked to cardiovascular disease and specifically ischemic heart disease (IHD), but large-scale population data in patients with immunoglobulin A nephropathy (IgAN) ...are missing.
To examine absolute and relative risks for IHD in patients with IgAN.
Population-based register-based cohort study in Sweden. We identified 3945 patients with biopsy-verified IgAN, and 19,272 age- and sex-matched reference individuals from the general population. To reduce residual confounding from genetic factors and early environmental factors we carried out secondary analyses, where we compared 3039 IgAN patients with 6729 siblings, whereas a spousal analysis consisted of 2377 married couples where one of the spouses had IgAN. Data on IHD and end-stage renal disease (ESRD) were retrieved from the nationwide Patient Register. Cox regression estimated hazard ratios (HRs) adjusted for matching variables, education, country of birth, cancer, diabetes mellitus, and other systemic inflammatory diseases.
During a follow-up of 55,527 person-years (py; mean follow-up 14.1 years), 371 patients (9.4%) with IgAN developed IHD (6.7/1000 py), compared with 1070 (5.6%) in 287,677 py in reference individuals (3.7/1000 py). The corresponding adjusted HR was 1.86 (95%CI = 1.63-2.13), equivalent to one extra case of IHD per 34 IgAN patients followed-up for 10 years. HRs were similar in men and women with IgAN, but higher in the first year after diagnosis and in patients born outside the Nordic countries. Patients with IgAN were at increased risk of IHD also compared to siblings (HR = 2.07; 95%CI = 1.62-2-64) and spouses (HR = 1.91; 95%CI = 1.40-2.61).
In this nationwide population-based study, patients with IgAN were at an 86% increased risk of future IHD.
More than 50 years after the description of IgA nephropathy as Berger's disease, 20–40% of affected individuals still progress to end-stage kidney disease within 10–20 years of diagnosis, which ...negatively affects life expectancy.1 Glucocorticoids can halt progression in some patients but rarely prevent the final development of end-stage kidney disease, and side-effects limit the intensity and duration of treatment.2,3 A challenge for the assessment of treatment effects in IgA nephropathy is the usual long time-course to traditional outcomes of doubling of serum creatinine, end-stage kidney disease, or death. The continued double-blind treatment phase up to 110 weeks will allow for analysis of the drug's effect on slowing progression of eGFR decline, required for traditional FDA approval. The combination could also help prevent fluid retention, as shown in a post-hoc analysis of the SONAR trial in diabetic patients with chronic kidney disease.12 We hope that the final publication will also include information concerning previous immunosuppressive treatment in the study population as well as histological findings in the kidney biopsies, classified by MEST-C score.
IgA nephropathy (IgAN) and nephritis in Systemic Lupus Erythematosus (SLE) are two common forms of glomerulonephritis in which genetic findings are of importance for disease development. We have ...recently reported an association of IgAN with variants of TGFB1. In several autoimmune diseases, particularly in SLE, IRF5, STAT4 genes and TRAF1-C5 locus have been shown to be important candidate genes. The aim of this study was to compare genetic variants from the TGFB1, IRF5, STAT4 genes and TRAF1-C5 locus with susceptibility to IgAN and lupus nephritis in two Swedish cohorts.
We genotyped 13 single nucleotide polymorphisms (SNPs) in four genetic loci in 1252 DNA samples from patients with biopsy proven IgAN or with SLE (with and without nephritis) and healthy age- and sex-matched controls from the same population in Sweden.
Genotype and allelic frequencies for SNPs from selected genes did not differ significantly between lupus nephritis patients and SLE patients without nephritis. In addition, haplotype analysis for seven selected SNPs did not reveal a difference for the SLE patient groups with and without nephritis. Moreover, none of these SPNs showed a significant difference between IgAN patients and healthy controls. IRF5 and STAT4 variants remained significantly different between SLE cases and healthy controls. In addition, the data did not show an association of TRAF1-C5 polymorphism with susceptibility to SLE in this Swedish population.
Our data do not support an overlap in genetic susceptibility between patients with IgAN or SLE and reveal no specific importance of SLE associated SNPs for the presence of lupus nephritis.
Abstract Background and Aims KDIGO recommends proteinuria <1 g/d as a treatment target in patients with immunoglobulin A nephropathy (IgAN) because of high-risk of progression to kidney failure. ...However, long-term kidney outcomes in patients with low-grade proteinuria remain poorly studied. Method We enrolled patients with biopsy-proven primary IgAN from the Swedish Renal Registry and analyzed associations between first-recorded urinary albumin-to-creatinine ratio (uACR, in categories <0.3, 0.3-0.5, 0.5-1.0, 1.0-1.5, 1.5-2.0 and >2.0 g/g) and the occurrence of major adverse kidney events (MAKE, a composite of kidney replacement therapy KRT and >30% decline in eGFR). We also explored the risk of MAKE associated with the fold-change in uACR within a year. Results We enrolled 1269 patients with primary IgAN (74% men, median 53 years, mean eGFR 33 mL/min/1.73 m², median uACR 0.7 g/g). Compared to patients with uACR <0.3 g/g, those with higher uACR levels were younger, more often men, had a higher prevalence of hypertension, diabetes, acute kidney injury, lower eGFR and serum albumin level, and were less often prescribed RASi. Over median follow-up of 5.5 2.8;9.2 years, 667 MAKE and 517 KRT events occurred, and 528 patients experienced > 30% eGFR decline. In multivariable analyses, and compared with uACR <0.3 g/g, any higher uACR category strongly and incrementally associated with the risk of MAKE (Figure), with Hazard Ratios (HR) ranging from 1.56 95% CI 1.14-2.14 in patients with uACR 0.3-0.5 g/g to 4.53 3.36-6.11 in patients with uACR>2g/g. Similar graded relationships were observed for KRT (HR ranging from 1.39 to 4.65), and for >30% decline in eGFR (HR ranging from 1.76 to 3.47). In the 785 patients who had repeated uACR measurements within a year, and compared with stable uACR, the risk of kidney events was lower if uACR decreased by 2-fold (HR ranging from 0.47 to 0.49), and higher if uACR increased by 2-fold (HR from 1.18 to 2.56), irrespective of baseline uACR. Conclusion Our findings show substantial risk of adverse kidney outcomes among patients with IgAN and uACR between 0.3 and 1.0 g/g, a population currently considered at low-risk of CKD progression. Reduction in uACR is associated with better kidney outcomes, irrespective of baseline uACR.
Abstract Background and Aims IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. Dysregulation of the complement system is considered a part of the pathogenesis and can occur both ...in the circulation and locally in the kidney. Despite this, most studies have focused on complement biomarkers in the blood, rather than in urine. Our aim was to evaluate a wide range of complement-related proteins in blood and urine at diagnosis and their association with disease activity in biopsy findings, proteinuria, and outcome. We added PTX-3, a protein expressed in activated endothelial cells, which can be both produced by and activate mesangial cells in IgAN and has a function in all three complement pathways. Adult-onset IgA vasculitis with renal involvement (IgAVN) shares many similarities with IgAN and cannot currently be distinguished by kidney biopsy or any established biomarker. We therefore also aimed to compare the same biomarkers between these two disorders. Method In a Swedish cohort of 96 patients with IgAN (n = 65) and IgAVN (n = 31), who had been followed prospectively for a median of 10.8 years, we performed the following analysis in plasma and urine in samples stored at the time of kidney biopsy. Analyses in plasma (p-) included C3bc, C4c, C5b-9, MASP2, MASP3, MAP1, FCN 1-3, MBL, CL11 and PTX-3 and in urine (u-) C3bc, C4c, C5b-9, MASP3, FCN2, FCN3, MBL and PTX-3. An in-house developed sandwich ELISA was used for all analyses. Kidney biopsies were classified according to the Oxford MEST-C score, describing (simplified for this small cohort) the presence vs absence (1 vs 0) of mesangial proliferation (M), endocapillary proliferation (E), segmental sclerosis (S), tubular atrophy/interstitial fibrosis (T) and crescents (C). Severe outcome was defined by a combination of an eGFR slope > 2.5 ml/min/1.73 m2 per year or end stage kidney disease. For statistical analysis, Mann-Whitney U test was performed for comparison between independent groups, Chi squared test and Fisher's test for categorical variables and Spearman's ranks test for correlation analysis. Median values are presented without IQR for this abstract. Results Urine samples were available in 59 patients (IgAN n = 39, IgAVN n = 20). Patients with detectable u-MBL (28.9%) and u-C5b-9 (27.1%) had higher levels of proteinuria than those with undetectable levels (1.5 g/d vs 0.71g/d; p = 0.009 and 2.3 g/d vs 0.7 g/d respectively; p < 0.001). Lower eGFR (71 ml/min/1.73 m2 vs 88 ml/min/1.73 m2; p = 0.034) were observed if u-C5b-9 was measurable. Detectable levels of u-PTX-3 and u-MBL were more often found in the presence of M1 vs M0 (53% vs 20%; p = 0.022 and 47% vs 12.5%; p = 0.011), E1 vs E0 (55% vs 14%; p = 0.001 and 40% vs 11%; p = 0.020) and C1 vs C0 (56% vs 11%; p = 0.003 and 44% vs 11%; p = 0.012). No differences in proteinuria or eGFR were seen in patients with or without detectable u-PTX-3. The degree of proteinuria was positively correlated to the levels of u-C3bc (r = 0.33; p = 0.011) and u-C4c (r = 0.39; p < 0.001). U-C4c levels were higher in patients with M1 vs M0 (54.4 Au/mL vs 23.8 Au/mL; p = 0.037) and T1 vs T0 (53.2 Au/mL vs 23.8 Au/mL; p = 0.034). Concerning the analyses in plasma (n = 95), lower p-MASP3 and p-CL11 levels were correlated with lower eGFR (r = 0.29; p = 0.004 and r = 0.31, p = 0.002). Moreover, lower p-MASP3 levels were detected in patients with E1 vs E0 (2918 ng/mL vs 3404 ng/mL; p = 0.002) and C1 vs C0 (3053 ng/mL vs 3427 ng/mL; p = 0.015). Both p-C5b-9 (13.3 Au/mL vs 8.2 Au/mL; p = 0.001) and p-FCN 1 (395 ng/mL vs 289 ng/mL; p = 0.001) were higher in patients with C1 vs C0. No single complement-related protein was associated with severe outcome, and no statistically significant differences in plasma or urine levels between patients with IgAN and IgAVN were observed. Conclusion Increased urinary levels of MBL and PTX-3 could be potential biomarkers of disease activity in both IgAN and IgAVN, whereas excretion of C5b-9 might be more unspecific and associated with chronic damage. However, these results need to be confirmed in larger and more ethnically diverse cohorts. The impact of treatment on these potential biomarkers for disease activity need to be evaluated in longitudinal studies.
The clinical course of IgA nephropathy (IgAN) varies from asymptomatic nonprogressive to aggressive disease, with up to one in four patients manifesting ESRD within 20 years of diagnosis. Although ...some studies have suggested that mortality appears to be increased in IgAN, such studies lacked matched controls and did not report absolute risk.
We conducted a population-based cohort study in Sweden, involving patients with biopsy-verified IgAN diagnosed in 1974-2011; main outcome measures were death and ESRD. Using data from three national registers, we linked 3622 patients with IgAN with 18,041 matched controls; we also conducted a sibling analysis using 2773 patients with IgAN with 6210 siblings and a spousal analysis that included 2234 pairs.
During a median follow-up of 13.6 years, 577 (1.1%) patients with IgAN died (10.67 per 1000 person-years) compared with 2066 deaths (0.7%) in the reference population during a median follow-up of 14.1 years (7.45 per 1000 person-years). This corresponded to a 1.53-fold increased risk and an absolute excess mortality of 3.23 per 1000 person-years (equaling one extra death per 310 person-years) and a 6-year reduction in median life expectancy. Similar increases in risk were seen in comparisons with siblings and spouses. IgAN was associated with one extra case of ESRD per 54 person-years. Mortality preceding ESRD was not significantly increased compared with controls, spouses, or siblings. Overall mortality did not differ significantly between patients with IgAN-associated ESRD and patients with ESRD from other causes.
Patients with IgAN have an increased mortality compared with matched controls, with one extra death per 310 person-years and a 6-year reduction in life expectancy.
Introduction: Within 30 years, 20–50% of IgA nephropathy (IgAN) patients progress to end-stage kidney disease (ESKD). Identifying these patients can be difficult since renal function may deteriorate ...after being stable for years. The International IgAN Risk Prediction tool (IgAN-RPT) combines histologic lesions and clinical risk factors to predict renal outcome up to 5 or 7 years of follow-up. The clinical value beyond 7 years is unknown and microhematuria data has not been assessed. Methods: We studied the long-term renal outcome of 95 Swedish IgAN patients from the derivation cohort for the IgAN-RPT. The median follow-up was 11.2 years. Microhematuria at baseline was defined as high-degree by microscopy measurement of >10 red blood cell/high-power field of view or urine dipstick grading of 2–3. Primary outcome was defined as a 50% decrease in estimated glomerular filtration rate or ESKD. Results: The mean predicted 5-year risk for increasing quartiles was 0.95%, 2.57%, 5.88%, and 23.31% and the observed 5-year-outcome was 0%, 0%, 0%, and 33.33%. During continued follow-up, 0%, 4.2%, 21.7%, and 75.0% of patients reached the primary outcome. ROC curve analysis identified the 5-year risk thresholds of under 4% and over 11% for very low and very high-risk patients, respectively. High-degree microhematuria was not significantly associated with renal outcome (p = 0.14). Conclusions: The IgAN-RPT identifies long-term high- and low-risk patients, which can guide decisions on the frequency of clinical control visits and the selection of patients for clinical trials. Patients with intermediate risk remain a clinical challenge with an urgent need for novel biomarkers and treatments. Microhematuria could be a valuable marker of inflammatory activity, but measurement needs to be standardized for implementation in risk prediction tools.
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