IgA nephropathy (IgAN), an important cause of kidney failure, is characterized by glomerular IgA deposition and is associated with changes in O-glycosylation of the IgA1 molecule. Here, we sought to identify genetic factors contributing to levels of galactose-deficient IgA1 (Gd-IgA1) in Caucasian and Chinese populations.Gd-IgA1 levels were elevated in IgAN patients compared with ethnically matched healthy subjects and correlated with evidence of disease progression. Caucasian IgAN patients exhibited significantly higher Gd-IgA1 levels than Chinese patients. Among individuals without IgAN, Gd-IgA1 levels were not correlated with kidney function. Gd-IgA1 level heritability (h ). This association was replicated in GWAS of separate cohorts comprising: 308 UK patients with membranous glomerulonephritis (p<10

Background: Muscle wasting is a common complication of Chronic Kidney Disease (CKD) and is clinically important given its strong association with morbidity and mortality in many other chronic conditions. Exercise provides physiological benefits for CKD patients, however the molecular response to exercise remains to be fully determined. We investigated the inflammatory and molecular response to resistance exercise before and after training in these patients.Methods: This is a secondary analysis of a randomized trial that investigated the effect of 8 week progressive resistance training on muscle mass and strength compared to non-exercising controls. A sub-set of the cohort consented to vastus lateralis skeletal muscle biopsies (n = 10 exercise, n = 7 control) in which the inflammatory response (IL-6, IL-15, MCP-1 TNF-α), myogenic (MyoD, myogenin, myostatin), anabolic (P-Akt, P-eEf2) and catabolic events (MuRF-1, MAFbx, 14 kDa, ubiquitin conjugates) and overall levels of oxidative stress have been studied.Results: A large inflammatory response to unaccustomed exercise was seen with IL-6, MCP-1, and TNF-α all significantly elevated from baseline by 53-fold (P < 0.001), 25-fold (P < 0.001), and 4-fold (P < 0.001), respectively. This response was reduced following training with IL-6, MCP-1, and TNF-α elevated non-significantly by 2-fold (P = 0.46), 2.4-fold (P = 0.19), and 2.5-fold (P = 0.06), respectively. In the untrained condition, an acute bout of resistance exercise did not result in increased phosphorylation of Akt (P = 0.84), but this was restored following training (P = 0.01). Neither unaccustomed nor accustomed exercise resulted in a change in myogenin or MyoD mRNA expression (P = 0.88, P = 0.90, respectively). There was no evidence that resistance exercise training created a prolonged oxidative stress response within the muscle, or increased catabolism.Conclusions: Unaccustomed exercise creates a large inflammatory response within the muscle, which is no longer present following a period of training. This indicates that resistance exercise does not provoke a detrimental on-going inflammatory response within the muscle.

IgA nephropathy is characterized by mesangial deposition of IgA, mesangial cell proliferation, and extracellular matrix production. Mesangial cells bind IgA, but the identity of all potential receptors involved remains incomplete. The transferrin receptor (CD71) acts as a mesangial cell IgA receptor and its expression is upregulated in many forms of glomerulonephritis, including IgA nephropathy. CD71 is not expressed in healthy glomeruli and blocking CD71 does not completely abrogate mesangial cell IgA binding. Previously we showed that mesangial cells express a receptor that binds the Fc portion of IgA and now report that this receptor is an isoform of β-1,4-galactosyltransferase. A human mesangial cell cDNA library was screened for IgA binding proteins and β-1,4-galactosyltransferase identified. Cell surface expression of the long isoform of β-1,4-galactosyltransferase was shown by flow cytometry and confocal microscopy and confirmed by immunoblotting. Glomerular β-1,4-galactosyltransferase expression was increased in IgA nephropathy. IgA binding and IgA-induced mesangial cell phosphorylation of spleen tyrosine kinase and IL-6 synthesis were inhibited by a panel of β-1,4-galactosyltransferase-specific antibodies, suggesting IgA binds to the catalytic domain of β-1,4-galactosyltransferase. Thus, β-1,4-galactosyltransferase is a constitutively expressed mesangial cell IgA receptor with an important role in both mesangial IgA clearance and the initial response to IgA deposition.

IgA vasculitis can present as a glomerulonephritis histologically indistinguishable from IgA nephropathy (IgAN). In IgAN, the alternative and lectin pathways mediate glomerular injury and contribute to kidney function decline. Narsoplimab is a monoclonal antibody against mannan-binding lectin serine peptidase 2 (MASP-2), a key component of the lectin pathway. It is being evaluated in a phase III trial in IgAN (NCT03608033). Histopathological similarities with IgAN suggest lectin pathway activation also occurs in IgAV-associated nephritis (IgAVN). Here, we report the first ever case of narsoplimab use for the treatment of IgAVN.

Background and objectives The reason why mesangial C4d deposits are detected in only certain biopsies of IgA nephropathy remains unclear. We analyse the association between IgA glycosylation patterns, mesangial C4 deposition and clinical phenotypes in IgA nephropathy. Design, setting, participants and measurements: This cross-sectional study included 145 patients with idiopathic IgA nephropathy. We measured the serum levels of three different IgA1 lectin-binding specificities, using enzyme-linked-immunosorbent assays with and without treatment with neuraminidase, and we analysed the relationship between these glycoforms, C4d mesangial deposits and clinical phenotypes. Results C4d-positive vs Cd4-negative patients had higher proteinuria (median: 3.1 g/g [0.9-4.2] vs. 1.8 g/g [1-2.2]; p = 0.000), hematuria (223 cel/µL [32-278] vs 99 cel/µL [25-186], p = 0.000), and higher levels of IgA binding to neuraminidase untreated Helix Aspersa (HA IgA1 neu-) (150.6 ± 52 U vs 96.2 ± 64.1 U, p = 0.000), neuraminidase untreated Helix Pomatia (HPA IgA1 neu-) (0.34 ± 0.15 vs 0.27 ± 0.13p = 0.04), Triticum vulgaris (TV IgA1) (85.1 ± 31.7 vs42.2 ± 26.9p = 0.000), and Canavalia ensiformis (ConA IgA1) (32.5 ± 18 U vs 16.7 ± 9.38 U, p = 0.000). The levels of HA IgA1 neu-, HPA IgA1 neu-, TV IgA1 and ConA IgA1 were all associated with the mesangial deposition of C4d, extracapillary proliferation and acute kidney injury. In ROC curves, HA IgA1 neu-, HPA IgA1 neu-, TV IgA1 and ConA IgA1 significantly discriminated between C4d positive ad C4d-negative biopsies. In logistic models, TVIgA1 and ConAIgA1 were the only independent predictors of mesangial C4d deposits. Conclusions In IgA nephropathy, the severity of the disease is associated with the level of IgA exposing N-Acetyl-D-Galactosamine, N-Acetyl-D-Glucosamine or mannose whereas C4d deposits are only associated with elevated levels of IgA1 glycoforms exhibiting glycan residues with specificity for mannose and N-Acetyl-D-Glucosamine binding lectins.