Glomerular disease: Sugars and immune complex formation in IgA nephropathy

Mesangial deposition of IgA is the principal trigger for the development of glomerulonephritis in IgA nephropathy (IgAN). Recurrence of IgA deposition in the majority of recipients of renal allografts suggests that this IgA is derived from a circulating pool of pathogenic IgA molecules

Immune complex formation in IgA nephropathy: a case of the ‘right’ antibodies in the ‘wrong’ place at the ‘wrong’ time?

One of the most striking findings in IgAN is an increase in the circulating levels of poorly galactosylated IgA1 O-glycoforms (Figure 1B). This has been observed in patient populations from North America, Europe and Asia, using a variety of techniques [1–3]. Importantly, two studies of IgA1 eluted from isolated glomeruli have shown that mesangial IgA is enriched with poorly galactosylated IgA1 O-glycoforms, strongly implicating the composition of IgA1 hinge region glycans in the mechanism of IgA1 deposition [4,5]. Novak and colleagues have also reported that these poorly galactosylated IgA1 O-glycoforms are predominantly found in circulating high molecular weight IgA-IC in IgAN [6]

ROC curves for the cognitive screening tests Montreal Cognitive Assessment and Mini-Mental State Examination.

<p>The receiver operating characteristics curves for the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) illustrate the discriminative capacity of each of the screening tests, displaying their individual sensitivity, specificity and area under the curve (AUC). The MoCA shows good levels of sensitivity and specificity, as well as an overall greater AUC than the MMSE, while the MMSE presents a high specificity and relatively low sensitivity. Notes. MoCA = Montreal Cognitive Assessment; MMSE = Mini-Mental State Examination; AUC = Area under the curve.</p

Demographic and health characteristics.

<p>Demographic and health characteristics.</p

Demographic and clinical characteristics of the hemodialysis patients and healthy control groups.

<p>All data shown as mean (SD), except where noted. Charlson Comorbidity Index (CCI) corrected for dialysis patients and corrected for age in the control group. CV = Cerebrovascular; py = pack years; CKD = Chronic kidney disease. Other causes include progression of CKD due to post-operative infections, reflux diseases, analgesic medication.</p><p>Demographic and clinical characteristics of the hemodialysis patients and healthy control groups.</p

Histogram.

<p>Distributions of the brain water content (X-axis) and T1 (Y-axis) from HD patients (red thin histogram lines before dialysis, thin green histograms lines after dialysis) and healthy controls (blue thin histogram lines for first time point, black for second time point) are shown. Left: Individual data and mean value histograms (bold) for T1 (Y-axis, left) reveal no significant differences in HD patients compared to healthy controls. Lower panel: Individual data as well as mean value histograms (bold) for water content (X-axis) reveal increased white matter water content (~2%) as shown by the observed shift, but only mild changes in gray matter in HD patients compared to controls.</p

Quantitative brain water content maps.

<p>Axial slices of water content maps obtained from a representative HD patient (a) and from an age-matched healthy control (b). Differences between HD patients and healthy controls groups were assessed using non-parametric Wilcoxon rank-sum test and are shown as an overlaid p-value map on a MNI template. Analyses of water content revealed increase of water content in predominantly white matter in HD patients compared to controls. Hereby, enhanced brain hydration was found in particular in the parietal cortex, followed by occipital and fronto-temporal regions (c). The color bar in a) and b) represents the water content in percent ranging from zero to hundred percent, the color bar in c) displays the p-values.</p

Association between brain water content and clinical parameters.

<p>Boxplots illustrating the association between water content in different focal subregions and clinical parameters. Fig 3A suggests that increased water content in several white and gray matter regions is associated with longer dialysis vintage. In Fig 3B the association between smaller intradialytic weight changes and increased water content in white and grey matter structures is shown.</p

Combined results for new significant and suggestive GWAS signals: serum Gd-IgA1 levels were determined using HAA lectin-based ELISA, normalized and adjusted for age, case-control status and serum total IgA levels.

<p>Combined results for new significant and suggestive GWAS signals: serum Gd-IgA1 levels were determined using HAA lectin-based ELISA, normalized and adjusted for age, case-control status and serum total IgA levels.</p

siRNA knock-down of C1GALT1, COSMC and COSMC+C1GALT1 in IgA1-secreting cell lines increases Gd-IgA1 production.

<p><b>(a)</b> knock-down in IgA1-secreting cell lines from healthy controls; mock-control (n = 5), non-targeting siRNA (n = 7), C1GALT1 siRNA (n = 5), COSMC siRNA (n = 7), and COSMC+C1GALT1 siRNA (n = 2); <b>(b)</b> knock-down in IgA1-secreting cell lines from IgAN patients; mock-control (n = 5), non-targeting siRNA (n = 7), C1GALT1 (n = 5), COSMC siRNA (n = 7), and COSMC+C1GALT1 siRNA (n = 2); <b>(c)</b> relative change in mRNA in IgA1-secreting cell lines after siRNA knock-down of C1GALT1 (n = 5), COSMC (n = 7), and COSMC+C1GALT1 (n = 2) compared to non-targeting siRNA control.</p