Renal Lymphangiogenesis And Tertiary Lymphoid Organs Formation Were Associated With The Renal Lesion And Prognosis Of IgA Nephropathy

IgA Nephropathy(IgAN), which features IgA deposition in the glomerular mesangium, is the most common form of primary glomerulonephritis worldwide.Previous studies have identified histologic features such as mesangial hypercellularity,segmental glomerulosclerosis, endocapillary hypercellularity and tubular atrophy/interstitial fibrosiswere associated with renal outcome of IgAN according to the Oxford classification.Lymphangiogenesis and tertiary lymphoid organs formation were newly identified in the kidney of patients with chronic kidney disease(CKD). However, there is not much information about the exact role in the progression of IgAN.We performed this prospective study to determine the realtionship between these two" new players" and the renal lesion and prognosis of IgAN.We selected152IgAN paitents who did not receive glucocorticoid or immunosuppressant treatment before renal biopsy.72patients had integrated outcome data after34months follow-up.63patient receive regular glucocorticoids treatment were finally left in the analysis involve prognosis.The density of the density of renal newly formed lymphatic vessels(LVD) and inflammatory cells and the grade of tertiary lymphoid organs(TLO) were evaluated. We found that renal newly formed lymphatic vessels served as "transport channel" of inflammatory cells,the LVD in IgAN renal tissue was correlated with the density of CD68+, DC-SIGN+, CD4+, CD8+, CD20+cells and the interstitial and arterial lesions of kidney and also sensitivity to glucocorticoid treatment.A linear regression analysis revealed the LVD was a significant predictor of an increase of serum creatinine34months after the biopsy. CD68+, DC-SIGN+, CD4+, CD8+, CD20+,CD45RO+,CD138+cells,lymphatic vessels and inflammatory cytokines were found in renal TLO.Patients with more TLO suffered decreased renal function, heavy proteinuria, severe interstitial and arterial lesions.TLO were also associated with progression of IgAN after34months follow up.In conclusion,renal lymphangiogenesis and tertiary lymphoid organs formation reflected the status of the intrarenal inflammatory response,they might also paly an active role in renal lesion by affecting the severity of local immunity. In the future,there will be new strategy to slow the progression of IgAN depending on more detailed mechanism of lymphangiogenesis and TLO. Part I The grade of renal interstitial inflammatory cells were correlated with the renal lesion and prognosis of IgAN patientsObjectives To determine whether the grade of renal inflammatory cells are correlated with the renal lesion of IgAN.Methods The renal lesion of IgAN was scored by Oxford Classification. The relationship between the grade of interstitial inflammatory cells and renal lesion was evaluated. Immunohistochemistrial staining for CD45, IL-1β,TNF α,IFN-γ and IL-17were performed to detect inflammatory cells and inflammatory cytokines in renal biopsy tissues from IgAN patients. Sixty-three patients with IgAN were followed for34months.Results The grade of inflammatory cells in renal interstitium were closely related to the decreased renal function, heavy proteinuria, severe interstitial and arterial lesions in IgAN kidneys. Patients with higher grade of inflammatory cells sufferred higher risk to progress during34months. CD45+cells colocated with inflammatory cytokines suggested inflammatory cells may take part in the progression of IgAN..Conclusion The grade of interstitial inflammatory cells can be used as reliable parameter to evaluate the renal lesion and prognosis of IgAN. Part II Different types of renal interstitial inflammatory cells were correlated with the renal lesion and prognosis of IgAN patientsObjectives To determine the relationship between the density of different types inflammatory cells and the renal lesion of IgAN.Methods Immunohistochemistrial staining for CD68, DC-SIGN, CD4, CD8and CD20 were performed to detect macrophages, dendritic cells, T-helper cells, cytotoxic T cells, B cells respectively in renal biopsy tissues from152adult patients with IgAN. The relationship between inflammatory cells and renal lesion was evaluated. Sixty-three patients with IgAN were followed for34months.Results The density of CD68+, DC-SIGN+, CD4+, CD8+, and CD20+cells in renal interstitium were closely related to the decreased renal function, heavy proteinuria, severe interstitial and arterial lesions in IgAN kidneys.The patients in the severe group contained more CD68+, DC-SIGN+, CD4+, CD8+, and CD20+cells in renal interstitium.The patients who are not sensitive to glucocorticoid treatment had more DC-SIGN+cells in renal interstitium.Conclusions Interstitial infiltrated inflammatory cells reflected the status of the intrarenal inflammatory response, which probably aggravated the renal lesion, and in turn, accelerated the IgAN progression.The sensitivity to glucocorticoid treatment was correlated with density of DC-SIGN+cells Part Ⅲ Renal interstitial newly formed lymphatic vessels were correlated with the renal lesion and prognosis of IgAN patientsObjectives To explore the exact role of newly formed lymphatic vessels in cohort of IgAN patients.Methods152patients with biopsy-proven IgAN were selected. The lymphatic vessels in the renal of examined by IHC. The relationship between the lymphatic vessels density and renal lesion was evaluated.in152IgAN patients.A Follow-up was performed for outpatients by telephone.Results The LVD in IgAN renal tissue was correlated with the density of CD68+, DC-SIGN+, CD4+, CD8+, CD20+cells and the lesions of kidney.A linear regression analysis revealed the density of lymph vessels was a significant predictor of an increase of serum creatinine34months after the biopsy.Conclusions Lymphangiogenesis reflected the status of the intrarenal inflammatory response, their density could be served as a risk factor for IgAN progression.As they served as "transport channel" of inflammatory cells,they might also paly an active role in renal lesion. Part IV Renal interstitial tertiary lymphoid organs were correlated with the renal lesion and prognosis of IgAN patientsObjectives To determine whether interstitial TLO formation are correlated with the renal lesion and progression of IgAN.Methods The relationship between TLO and renal lesion was evaluated.in152IgAN patients.CD68,DC-SIGN,CD4,CD8,CD20,CD45,CD138,D2-40,IL-1β,TNF-α,IFN-γ and IL-17were examined in TLO.Sixty-three IgAN patients were followed for30months.Results CD68+, DC-SIGN+, CD4+, CD8+, CD20+,CD45+,CD138+cells,lymphatic vessels and inflammatory cytokines were found in renal TLO.Patients with more TLO suffered decreased renal function, heavy proteinuria, severe interstitial and arterial lesions.TLO were associated with the progression of IgAN after30months follow up.Conclusions TLO formation reflected the status of the intrarenal inflammatory response, which probably aggravated the renal lesion of IgAN. They could be served as a risk factor for IgAN progression.