Dietary zinc is a key environmental modifier in the progression of IgA nephropathy.

IgA nephropathy (IgAN) shows diverse epidemiological characteristics, resulting from both genetic and acquired (e.g., environmental) causes. Environmental factors, such as diet or exposure to exogenous antigens, may prescribe the progression or prognosis of IgAN. It remains unclear as to how diet and infection influence susceptibility to IgAN. A relationship, such as Toll-like receptors (TLRs), especially TLR9 and TLR4, was demonstrated between IgAN and pathogen-recognition molecules. Recently, zinc (Zn) was discovered to be involved in various immune-related diseases, affecting B, T, and dendritic cells (DCs). This study investigates the relationship between dietary Zn and IgAN development in IgAN-prone mice. Seven-week-old IgAN-prone mice were divided into low, normal, and high Zn diet groups. To assess exogenous pathogen-mediated immune responses, lipopolysaccharide (LPS) was nasally administered. The activity of IgAN was biochemically and pathologically evaluated during the disease course. We also examined in vitro IgA production in spleen cells or in combinations of cocultured B, T, and DCs under various Zn conditions with or without LPS. Dietary conditioning with Zn affected serum immunoglobulins and urinary albumin levels, and mesangial deposition of IgA and IgG. Zn deficiency is associated with IgAN progression through the activation of the TLR4/TIR-domain-containing adapter-inducing interferon-β (TRIF), but not the TLR9, in DCs. Zn supplementation prevented disease aggravation. Our findings indicate that immune conditioning with dietary Zn alters nephritogenic IgA production after mucosal infection

Serum concentration of immunoglobulins for each dietary zinc condition.

<p>Dietary zinc intervention altered the serum concentrations of IgA and IgA–IgG immune complexes but not of IgG and IgM. *p<0.05.</p

Intensity of mesangial IgA and IgG deposition.

<p>The intensity of IgA and IgG deposition was scored on a 1–5 scale based on an average of more than 10 glomeruli. IgA deposition was significantly attenuated in the high zinc (Zn) diet group. IgG deposition in the low Zn diet group was significantly higher than that in the normal and high Zn diet groups. *p<0.05; **p<0.01.</p

IgA production by various spleen cells.

<p>(A) IgA production by B cells increased when cocultured with T cells and/or dendritic cells (DCs). (B) Under low zinc (Zn) conditions, IgA production was significantly increased in the presence of DCs. Under high Zn conditions, IgA production by all cell combinations was suppressed. (C) Coculture of untreated B cells with low Zn-treated T cells and/or DCs. IgA production increased in the presence of DCs. (D) Coculture of B cells and DCs with or without lipopolysaccharide (LPS). LPS significantly enhanced IgA production despite the absence of T cells. (E) Coculture of B cells and DCs from gddY or BALB/c mice. A combination of both B cells and DCs from gddY mice yielded the highest production of IgA. **p<0.01; ***p<0.001.</p

Urinary albumin levels for each dietary zinc condition.

<p>Urinary levels of albumin were significantly higher in the low zinc (Zn) diet group and lower in the high Zn diet group on the sixth week. *p<0.05; **p<0.01.</p

Expression of Toll-like receptor 4, MyD88, TRIF, and interferon-β in each zinc condition.

<p>(A) Expression of Toll-like receptor 4 (TLR4) for each zinc (Zn) condition with/without lipopolysaccharide (LPS). Expression of TLR4 was significantly increased when stimulated by LPS under low and normal Zn conditions. However, TLR4 expression under high Zn conditions was low despite LPS stimulation. (B) Expression of MyD88 at each Zn condition. Expression of MyD88 remained constant at each Zn condition. (C) Expression of TRIF for each Zn condition. Expression of TRIF under low Zn conditions was significantly higher than that in other groups. (D) Expression of interferon-β in each Zn condition. Expression of interferon-β was higher in low Zn condition and lower in high Zn condition. *p<0.05; **p<0.01.</p

Reactivity against lipopolysaccharide.

<p>Lipopolysaccharide (LPS) was nasally administered to some mice in each dietary group, while others received saline as a vehicle control; samples were collected during the sixth week. We calculated the ratio (sixth:fourth week) of each parameter. Although ACR in all groups increased after LPS stimulation, the elevation in the low zinc (Zn) diet group was very high. Serum concentrations of IgA and IgA–IgG immune complexes (ICs) in the low and normal Zn diet groups tended to be higher after LPS stimulation. However, the high Zn diet group maintained low concentrations of serum IgA and IgA–IgG ICs despite LPS stimulation. *p<0.05.</p

Effects of Acetate-Free Citrate Dialysate on Glycoxidation and Lipid Peroxidation Products in Hemodialysis Patients

Background/Aims: Previous studies have shown the presence of high levels of glycoxidation and lipid peroxidation products in association with atherosclerosis in patients with end-stage kidney disease. Acetates are commonly used buffer for correcting metabolic acidosis in hemodialysis (HD) patients. Since the toxic effects of acetates are well established, acetate-free citrate dialysate (AFD) has become available in Japan. The objective of the present study was to evaluate the suppressive effects of AFD on oxidative stress in maintenance HD patients by measuring plasma pentosidine and malondialdehyde-modified low-density lipoprotein (MDA-LDL) levels as markers for glycoxidation and lipid peroxidation products. Methods: Plasma pentosidine, MDA-LDL and other laboratory parameters were examined on maintenance HD at the Juntendo University Hospital before and after switching to AFD. Results: MDA-LDL levels divided by LDL cholesterol were significantly lower than those before switching to AFD. Furthermore, levels of plasma pentosidine were lower than those before switching to AFD. Stepwise multiple regression analysis revealed that the percent change of the calcium-phosphorus product in the nondiabetic group and that of phosphorus in the diabetic group were predictive variables for the percent change of MDA-LDL/LDL, whereas the percent change of log high-sensitive C-reactive protein and that of systolic blood pressure in the nondiabetic group and that of diastolic blood pressure in the diabetic group were predictive variables for the percent change of plasma pentosidine. Conclusions: It appears that AFD decreases glycoxidation and lipid peroxidation products when compared with acid citrate dextrose in HD patients. The reduction of oxidative stress by AFD during HD may have possible beneficial effects on atherosclerosis through calcium-phosphorus metabolism and blood pressure