Course of symptoms and health-related quality of life during specialized pre-dialysis care.

BACKGROUND: Concerns are present on the limited value of renal function alone in defining the optimal moment to start dialysis. Disease-related symptoms and health-related quality of life (HRQOL) may have additional clinical value in defining this moment, but little is known about how these parameters change during pre-dialysis care. The aims of our study were to describe the course of symptoms and HRQOL during pre-dialysis care and to investigate their association with poor health outcomes. METHODS: In the prospective PREPARE-2 cohort, incident patients starting specialized pre-dialysis care were included when referred to one of the 25 participating Dutch outpatient clinics (2004-2011). In the present analysis, 436 patients with data available on symptoms and HRQOL were included. Clinical data, symptoms (revised illness perception questionnaire), and HRQOL (short form-36 questionnaire; physical and mental summary score) were collected every 6-month interval. A time-dependent Cox proportional hazard model was used to associate symptoms and HRQOL with the combined poor health outcome (i.e. starting dialysis, receiving a kidney transplant, and death). RESULTS: All symptoms increased, especially fatigue and loss of strength, and both the physical and mental summary score decreased over time, with the most pronounced change during the last 6-12 months of follow-up. Furthermore, each additional symptom (adjusted HR 1.04 (95% CI, 1.00-1.09)) and each 3-point lower physical and mental summary score (adjusted HR 1.04 (1.02-1.06) and 1.04 (1.02-1.06) respectively) were associated with a higher risk of reaching the combined poor health outcome within the subsequent 6 months. CONCLUSIONS: The number of symptoms increased and both the physical and mental HRQOL score decreased during pre-dialysis care and these changes were associated with starting dialysis, receiving a kidney transplant, and death. These results may indicate that symptoms and HRQOL are good markers for the medical condition and disease stage of pre-dialysis patients.

The role of secretory IgA and complement in IgA nephropathy.

IgA nephropathy (IgAN) is characterized by glomerular deposition of IgA, often together with complement components. This deposited IgA is mainly polymeric in nature. Although early studies suggested a role for local complement activation in the development of glomerular injury in IgAN, recent attention has focused on the involvement of the lectin pathway of complement activation in the progression of renal disease in IgAN. In addition, we have found that glomerular secretory IgA deposition may be one of the initiators of local complement activation in the kidney. In the present review we discuss recent developments in this area and provide a model of how mucosal immunity and renal inflammation may be interconnected.

Immuno-histological analysis of dendritic cells in nasal biopsies of IgA nephropathy patients.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Intranasal vaccination of patients with IgAN has shown mucosal and systemic IgA hyporesponsiveness. Here, we investigated whether this IgA hyporesponse in IgAN patients can be explained by reduced numbers or altered subset distribution of dendritic cells (DCs) in nasal mucosa. METHODS: Eighteen IgAN patients and 18 healthy volunteers were recruited for this study. Nasal biopsies were taken, after local anaesthesia, from the lower edge of the inferior turbinate. Staining for different subsets of DCs was performed using specific monoclonal antibodies. To detect myeloid DCs, we used CD1a, DC-SIGN and blood dendritic cell antigen-1 (BDCA-1) as a marker and for plasmacytoid DCs we used BDCA-2. DC-cell numbers in the epithelium and in lamina propria were counted separately and expressed as positively stained cells per mm(2). RESULTS: Both myeloid and plasmacytoid DC could be demonstrated in nasal biopsies. Quantification showed that IgAN patients contained significantly more DC-SIGN-positive cells in the lamina propria compared to controls. In addition, in IgAN patients, we observed more CD1a-positive cells in the epithelium. No differences in BDCA-1 and BDCA-2-positive cells were found between patients and controls. The number of positively stained cells in the epithelial layer correlated strongly with the number of positively stained cells in the lamina propria. CONCLUSIONS: Patients with IgAN have higher numbers of CD1a-positive cells in the epithelial layer and more DC-SIGN-positive cells in the lamina propria. Therefore, the earlier observed IgA hyporesponsiveness in IgAN patients after mucosal vaccination cannot be explained by lower numbers of nasal DCs.

Differential glycosylation of polymeric and monomeric IgA: a possible role in glomerular inflammation in IgA nephropathy.

IgA nephropathy (IgAN) is characterized by mesangial deposition of polymeric IgA1 (pIgA1) and complement. Complement activation via mannose-binding lectin and the lectin pathway is associated with disease progression. Furthermore, recent studies have indicated a possible role for secretory IgA. IgAN is associated with abnormalities in circulating IgA, including aberrant O-linked glycosylation. This study characterized and compared functional properties and N-linked glycosylation of highly purified monomeric IgA (mIgA) and pIgA from patients with IgAN and control subjects. Total serum IgA was affinity-purified from patients (n = 11) and control subjects (n = 11) followed by size separation. pIgA but not mIgA contained secretory IgA, and its concentration was significantly higher in patients with IgAN than in control subjects. Both in patients with IgAN and in control subjects, IgA binding to the GalNAc-specific lectin Helix Aspersa and to mannose-binding lectin was much stronger for pIgA than for mIgA. Furthermore, binding of IgA to mesangial cells largely was restricted to polymeric IgA. Binding of pIgA to mesangial cells resulted in increased production of IL-8, predominantly with IgA from patients with IgAN. Quantitative analysis of N-linked glycosylation of IgA heavy chains showed significant differences in glycan composition between mIgA and pIgA, including the presence of oligomannose exclusively on pIgA. In conclusion, binding and activation of mesangial cells, as well as lectin pathway activation, is a predominant characteristic of pIgA as opposed to mIgA. Furthermore, pIgA has different N-glycans, which may recruit lectins of the inflammatory pathway. These results underscore the role of pIgA in glomerular inflammation in IgAN.

Dendritic cells of IgA nephropathy patients have an impaired capacity to induce IgA production in naïve B cells.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, characterized by mesangial IgA1 deposits. We have previously demonstrated that IgAN patients have a hampered IgA immune response after mucosal challenge with a neoantigen. Dendritic cells are critically involved in the initiation of humoral immune responses, not only via activation of T-helper cells, but also via direct effect on naïve B cells. The aim of this study was to investigate the capacity of dendritic cells from IgAN patients to regulate IgA production. METHODS: Dendritic cells were generated by culturing monocytes for 7 days in the presence of interleukin (IL)-4 and granulocyte macrophage-colony-stimulating factor (GM-CSF). Dendritic cells from either IgAN patients (N= 12) or controls (N= 12) were cultured for 14 days with naïve B cells in the presence of CD40L-transfected mouse fibroblasts (L-CD40L cells) and medium with or without IL-2 or IL-10. Supernatants were tested for the presence of immunoglobulins by specific enzyme-linked immunosorbent assay (ELISA). RESULTS: In the presence of CD40L and IL-10, dendritic cells were able to increase immunoglobulin production by naïve B cells. Dendritic cells of IgAN patients induced significantly (P= 0.026) less IgA production than dendritic cells of control persons (2.30 microg/mL vs. 5.24 microg/mL), whereas no differences were found in the IgG and IgM production. When dendritic cells were replaced by supernatant of CD40L-stimulated dendritic cells of patients and controls, IgA production was increased, but no difference was seen between the two groups. CONCLUSION: In the present study we show that dendritic cells of IgAN patients have an impaired capacity to induce IgA production in naïve B cells, which might explain the observed IgA hyporesponse upon mucosal challenge with a neoantigen.