Mechanism of Yiqi Yangying Heluo Formula in the Treatment of IgA Nephropathy by Affecting Gd-IgA1 Based on BAFF Molecular Level and T Lymphocyte Immunity.

Background: Galactose-deficient IgA1 (Gd-IgA1) is a critical initiating factor in the pathogenesis of IgA nephropathy (IgAN), which plays an important role in the diagnosis and evaluation of this disease. Moreover, the whole pathogenesis process has an intimate association with the immune response of T and B lymphocytes and their inflammatory factors. There is no specific therapy for IgAN at present. Yiqi Yangyin Formula can significantly reduce urinary protein and hematuria in patients with IgAN. Yiqi Yangying Heluo Formula (YYHF) is optimized on the basis of the above prescription, but its specific mechanism remains to be further studied. Methods: The effect of YYHF on urinary protein and urinary red blood cell count in patients with IgAN was observed by a self-controlled clinical study before and after treatment. On this basis, flow cytometry was used to detect the proportion of T lymphocyte subsets in peripheral blood of patients with IgAN before and after treatment and healthy controls. Meanwhile, the levels of Gd-IgA1, B cell activation factor (BAFF), and their cytokines (IL-4, IL-6, and IL-17) in peripheral blood were detected by enzyme-linked immunosorbent assay. The changes in mechanism-related indicators of the two groups were observed and subject to correlation analysis. Results: (1) Compared with the levels before treatment, 24-hour urinary protein content decreased by 47.7% and urinary red blood cell number decreased by 67% in patients with IgAN intervened by YYHF after 48 weeks of follow-up. (2) Compared with the healthy control group, patients with IgAN showed a significantly increased proportion of Th1 cells, Th17 cells, Th1/Th2, Th1/Treg, Th2/Treg, and Th17/Treg, obviously reduced proportion of Th2 cells and Treg cells, and evidently elevated levels of Gd-IgA1, BAFF, and their cytokines (IL-4, IL-6, and IL-17) in the peripheral blood. (3) Following 48 weeks of follow-up after intervention treatment with YYHF, the levels of Gd-IgA1, BAFF, IL-6, and IL-17 were significantly lower, but the level of IL-4 was higher in peripheral blood of patients with IgAN than those before treatment and after 24 weeks of treatment; simultaneously, the proportion of Th1 cells, Th17 cells, Th1/Th2, Th1/Treg, Th2/Treg, and Th17/Treg decreased while that of Th2 cells and Treg cells increased after 48 weeks of follow-up compared with that before treatment in peripheral blood of patients with IgAN. (4) The results of correlation analysis revealed that the level of Gd-IgA1 in peripheral blood of patients with IgAN was positively correlated with the level of BAFF, as well as the proportion of Th1 cells, Th17 cells, Th1/Th2, IL-6, and IL-17 levels, and negatively correlated with the proportion of Treg cells. In addition, the level of Gd-IgA1 in peripheral blood was positively correlated with proteinuria, yet without correlation with hematuria. Conclusion: YYHF can reduce the quantitative level of 24 h urinary protein and urinary red blood cell count in patients with IgAN. Patients with IgAN have obvious T cell immune imbalance. YYHF can significantly reduce the level of Gd-IgA1 in patients with IgAN, and its mechanism may be explained by the reduced level of BAFF in peripheral blood and improved immune balance of T cells.

ANCA vasculitis and IgA nephropathy linked to silica exposure.

There is a recognized association between silica exposure and Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV); however, no clear association between silica exposure and Immunoglobulin A (IgA) nephropathy. We describe the case of a 26-year-old male stonemason who presents with hilar lymphadenopathy, haematuria and acute kidney injury related to silica exposure, AAV and IgA nephropathy. He was asymptomatic on presentation; urinalysis revealed glomerular haematuria (>1000 red blood cells/L) and proteinuria (protein-to-creatinine ratio 84 mg/mmol). ANCA anti-myeloperoxidase serology was strongly positive. Mediastinal lymph node biopsy revealed multiple necrotizing granulomas with silica inclusions, and renal biopsy demonstrated crescentic glomerulonephritis and mesangial IgA staining. The patient was treated with cyclophosphamide and high-dose prednisolone with subsequent improvement in renal function. To our knowledge, this is the first report of both ANCA vasculitis and IgA nephropathy in the setting of silica exposure. This case highlights the relevance of occupational exposures in renal disease, and the immune-stimulatory effect of silica.

Immunoglobulin A Nephropathy and Immunoglobulin A Vasculitis.

Henoch-Schönlein purpura nephritis and immunoglobulin A nephropathy are common glomerulopathies in the pediatric population that deserve special attention. In some cases the primary care provider can follow the patient but others need more intensive management. Delaying this treatment can lead to worse morbidity. This article provides information on the pathogenesis, outcomes, and follow-up strategies that will aid in the diagnosis and referral of patients at risk for kidney disease.

[IgA nephropathy]. / Glomérulonéphrite à dépôts mésangiaux d'immunoglobulines A.

IgA nephropathy is the most common form of primary glomerulonephritis worldwide and an important cause of chronic kidney disease and end-stage kidney failure. Its pathophysiology remains in part unsolved but it is recognized as an immune complex disease. Recent years have brought progress in the field through the discovery of several genetic susceptibility loci and the formulation of the multi-hit pathogenesis model. Presentation, clinical course and histology can be extremely variable, making any histological classification still difficult. Indeed, most therapeutic studies until now include patients based only on the severity of clinical criteria but the new classification of Oxford should change that. Only the management of patients with nephropathy with minimal change glomerular lesions and nephrotic syndrome, or extra-capillary glomerulonephritis and rapidly progressive renal failure, is consensual: Corticosteroids alone for the first and associated with immunosuppressive drugs for the latter. The recent Kidney Disease Improving Global Outcomes (KDIGO) consensus treatment guideline is still controversial, especially in light of the last clinical studies. Corticosteroid therapy can be discussed in patients with proteinuria greater than 1 g/day without renal failure. All IgA nephropathy patients should benefit from the global management of chronic glomerular disease, including a renin-angiotensin system blocker in the presence of hypertension or proteinuria.

Treatment of IgA nephropathy.

The therapy of IgA nephropathy (IgAN) is cause for debate among nephrologists. Since the early 1980s, many therapeutic attempts have been proposed, but most of them did not prove efficacy. The recent KDIGO Clinical Practice Guideline for Glomerulonephritis recommend long-term ACE-I or ARB treatment when proteinuria is more than 1 g/day, with up-titration of the drug. For patients with GFR >50 ml/min and proteinuria persistently higher than 1 g/day, they suggest a 6-month course of corticosteroid therapy. Based on our experience and the results of the literature, we propose a progressive treatment, which takes into account the time the IgAN is recognized and the clinical conditions present at that time. The treatment can be summarize as follows: (1) in patients with macro-microscopic haematuria, in case with proteinuria less than 0.3 g/day, only annual controls; (2) in patients with proteinuria between 0.3 and 0.9 g/day, ACE-I and/or ARB, with titration of the drugs; (3) in patients with proteinuria higher than 1 g/day, in case with the presence of arterial hypertension and GFR up to 30 ml/min, 6 months course of corticosteroids, in addition to ACE-I and/or ARB; (4) in patients with GFR less than 30 ml/min, ACE-I/ARB, dialysis and kidney transplantation; corticosteroids should be in case considered for patients with persistently high or increasing proteinuria; (5) the immunosuppressants (cyclophosphamide and azathioprine) should be reserved for patients with progressive renal insufficiency or with vasculitic lesions on renal biopsy.

Clinical and pathological analysis on traditional Chinese medicine syndromes in children with immunoglobulin A nephropathy.

OBJECTIVE: To evaluate the common Traditional Chinese Medicine (TCM) syndromes and analyze their relationship to clinical and pathological manifestations in children with IgA nephropathy. METHODS: Forty five children diagnosed as having primary IgA nephropathy by renal biopsy for the first time were enrolled in this trial, and their TCM syndromes were evaluated and the distribution of TCM syndromes was observed. All the sick children were growed? according to clinical manifestations and pathological damages, and the differences in TCM syndromes were compared between the groups. RESULTS: The first 5 TCM symptoms were common cold, hyperhidrosis, red dry throat, dark yellow urine and lassitude. In the acute nephritis group, edema and aching pain in loin and knees were significant (P=0.021 and P=0.000). In the severe pathological damage group, edema was obvious (P= 0.004), and 24 h urinary protein was positively correlated with edema (P=0.015) while negatively with common cold (P=0,007). The score of mesangial cell proliferation was correlated with edema, red dry throat and common cold (P=0.006, 0.013 and 0.029 respectively). The score of segmental pathological change was positively correlated with edema (P=0.039). CONCLUSION: Common cold, hyperhidrosis, red dry throat, dark yellow urine, lassitude and other symptoms of qi deficiency of the spleen and lung mainly seen in children with IgA nephropathy may bear a close relationship to clinical manifestations and pathological damages.

[Distribution features of Chinese medicine syndrome types in IgA nephropathy patients complicated with hypertension and analysis of its correlated factors].

OBJECTIVE: To explore the distribution features of Chinese medicine syndrome types in immunoglobin A (IgA) nephropathy patients complicated with hypertension and its correlation with main prognostic indicators of hypertension classification and chronic kidney disease (CKD) staging, thus providing the diagnostic standards of Chinese medicine syndrome types and reliance for accurate syndrome differentiated medication. METHODS: By on-the-spot survey, the Chinese medicine syndrome and laboratory testing data of 154 IgA nephropathy patients complicated with hypertension confirmed by the pathology of kidneys were collected to analyze the distribution of Chinese medicine syndrome types, its correlation with hypertension classification and CKD staging. RESULTS: Asthenia was the most common syndrome in the 154 patients (146 cases, 94.81%), covering Pi-Shen deficiency syndrome (58, 37.66%), Shen qi-yin deficiency syndrome (48, 31.17%), and Gan-Shen yin deficiency syndrome (40, 25.97%). Of them, asthenia accompanied by asthenia was seen in 80 cases (54.79%) and pure asthenia in 8 cases (5.2%). Shen qi-yin deficiency syndrome and Gan-Shen yin deficiency syndrome were mostly seen in hypertension III, while Pi-Shen deficiency syndrome was mostly seen in hypertension I. Pi-Shen deficiency syndrome was mostly seen in CKD stage 4, Shen qi-yin deficiency syndrome mostly seen in CKD stage 1-2, and Gan-Shen yin deficiency syndrome mainly distributed in CKD stage 1-3. No obvious correlation was seen between Chinese medicine syndrome types and 24-h urine protein quantitation. CONCLUSIONS: Pi-Shen deficiency syndrome, Shen qi-yin deficiency syndrome, and Gan-Shen yin deficiency syndrome were main Chinese medicine syndrome types in IgA nephropathy patients complicated with hypertension. Asthenia accompanied by asthenia was mostly seen. Pi-Shen deficiency syndrome was mostly seen in hypertension I. Shen qi-yin deficiency syndrome and Gan-Shen yin deficiency syndrome were mostly seen in hypertension III, Shen qi-yin deficiency syndrome mostly seen in CKD stage 1-2, and Gan-Shen yin deficiency syndrome mainly distributed in CKD stage 1-3. Pi-Shen deficiency syndrome was mostly seen in CKD stage 4 patients.

[Study on the quantization diagnostic method for immunoglobulin A nephropathy of qi-yin deficiency syndrome].

OBJECTIVE: To study the method for establishing a quantization diagnostic standard for immunoglobulin A (IgA) nephropathy of qi-yin deficiency syndrome (QYDS). METHODS: 1,016 patients with primary IgA nephropathy were recruited in this study. They were randomly assigned to the training sample group (344 cases of QYDS and 456 cases of non-QYDS) and the testing sample group (77 cases of QYDS and 139 cases of non-QYDS) using SPSS software. On the basis of epidemiological survey, the typing standards for QYDS and common clinical symptoms were taken as candidate correlated factors. The correlated factors were selected using binary Logistic stepwise regression. The correlated factors were scored using conditional probability conversion method. The threshold value of the quantization diagnostics was determined using maximum likelihood method. The receiver operating characteristic (ROC) curve was drawn to calculate the area under curve (AUC), sensitivity, specificity, and accuracy rating. The retrospective and prospective tests were performed on the established quantization diagnostic standard for QYDS. RESULTS: The quantization diagnosis threshold value of IgA nephropathy of QYDS was 12 points. The sensitivity, specificity, and accuracy rating of the quantization diagnostic standard were 75.3%, 68.0%, and 71.1% in the retrospective test, as well as 60.4%, 84.4%, and 69.0% in the prospective tests. The AUC was 0.80 and 0.78 respectively. CONCLUSIONS: It was a feasible method to set up a quantization diagnostic standard for IgA nephropathy of QYDS by taking the occurrence frequency of symptoms. But this method failed to cover the strength information of symptoms.

[Correlation analysis on blood stasis syndrome, clinical features and renal pathology in 174 patients with primary glomerular diseases].

OBJECTIVE: To investigate the relationship between degree of TCM blood-stasis syndrome (BSS) with clinic features and renal pathological type of primary glomerular disease (PGD). METHODS: On-site investigation was adopted, 174 patients with PGD conforming to the inclusive/exclusive criteria were enrolled, and their degree of BSS and deficiency syndrome were scored in 3 days before renal biopsies. The relation of clinical indexes, including age, course of disease, symptoms of deficiency syndrome, 24-h urinary protein excretion (Upro), condition of hypertension and its controlling, glomerular filtrating rate (GFR) based on the predigesting equation of MDRD, and blood levels of uric acid (UA), triglyceride (TG), cholesterol (CHO), hemoglobin (Hb), and albumin (ALB), with the renal pathological type and the BSS score were analyzed. RESULTS: (1) Among the 174 patients, 159 cases (91.38%) were differentiated as BSS, with the degree of moderate in 111 cases and severe in 48 cases; (2) The BSS score was significantly correlated with the level of Upro, CHO, TG, ALB and deficiency syndrome (P < 0.01), but showed insignificant correlation with age, course of disease, grade of the hypertension, and GFR, UA and Hb levels. Multivariate stepwise regression analysis showed that the level of Upro and TG and score of deficiency syndrome had significance for regression equation establishment (P<0.01). (3) Further analysis on renal pathological type in 119 patients of non-nephrotic syndrome showed that the BSS score was insignificantly different among patients with different renal pathological types as the minor/minimal type (3 cases), the focal/segmental glomerular type (72 cases), and the diffuse glomerulonephritis (44 cases, P > 0.05). Further stratified analysis on the 72 cases with focal/segmental lesion showed that BSS score in patients of focal proliferative sclerosing glomerulonephritis were significantly higher than that in those of focal proliferative glomerulonephritis (P < 0.01). CONCLUSION: BSS is a TCM syndrome most commonly seen in patients with primary glomerular disease, BSS score is significantly correlated with the level of Upro, TG and deficiency syndrome score, and exhibits a higher level in patients with focal proliferative glomerulonephritis accompanying glomerulus sclerosis, indicating that the BSS could give certain clues of the renal chronic changes of primary glomerular disease, being one of risk factors in TCM syndrome in the development of renal diseases.

Urinary neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy.

Renal tubulointerstitial injury plays an important role in the development of IgA nephropathy (IgAN), the most common form of glomerulonephritis. Few currently in use biomarkers can sensitively detect the earliest signs of renal tubular injury, hindering our efforts to launch preventive and therapeutic measures for this disorder in a timely manner. Neutrophil gelatinase-associated lipocalin (NGAL) is an acute phase protein that is rapidly released from not only neutrophils but also a variety of cell types upon inflammation and tissue injury. Its small molecular size and protease resistance could render it an excellent biomarker of renal injury in IgAN. In this study, we tested this hypothesis by measuring urinary levels of NGAL, creatinine and N-acetyl-beta-D-glucosaminidase (NAG) in 40 healthy individuals and 70 IgAN patients with various disease severities. The urinary NGAL levels and NGAL/creatinine values were significantly upregulated in Lee grade III IgAN patients, in correlation with progressive glomerular mesangial proliferation and tubulointerstitial injury. Compared with urinary NAG levels, the urinary NGAL levels elevated much more drastically and can be readily detected even in Lee grade II IgAN patients when their NAG levels showed almost no change. Our findings suggest the promising use of urinary NGAL as an early biomarker for tubulointerstitial injury of IgA nephropathy and perhaps other types of renal disease in general.

[A multi-centeric epidemiological survey on TCM syndrome in 1016 patients with IgA nephropathy and analysis of its relevant factors].

OBJECTIVE: To investigate the distribution pattern of TCM syndrome in patients with IgA nephropathy and its relationship with the main clinical prognostic indexes to provide a basis for the standardization of integrative medicine in diagnosis and treatment of IgA nephropathy. METHODS: Multi-centeric epidemiological field survey was adopted to collect the materials of 1016 IgA nephropathic patients, including demography, TCM syndrome and laboratory findings, for exploring the distribution pattern of TCM syndrome of IgA nephropathy patients. RESULTS: Probability of over 10% could be found in the TCM syndromes as yin deficiency, qi deficiency, yang deficiency, damp-heat and blood stasis syndrome, the highest (41.5%) was found in qi-yin deficiency syndrome and the lowest (8.1%) in yang deficiency of Pi and Shen. Along with the increasing of age, the percentage of patients with Pi-Fei qi asthenia syndrome descended while those with Pi-Shen yang asthenia ascended. In the accompanying syndromes, damp-heat syndrome and blood stasis syndrome, with the proportion of 32.6% and 28.9% respectively, were the most frequently encountered. The levels of 24 h urinary protein, serum creatinine and urea nitrogen in patients with Pi-Fei qi asthenia syndrome, qi-yin deficiency syndrome and Gan-Shen yin asthenia syndrome were significantly lower than those in patients with Pi-Shen yang asthenia syndrome, respectively (P < 0.05), while the blood pressure in patients with Pi-Fei qi asthenia syndrome, and qi-yin deficiency syndrome were significantly lower than that in patients with Gan-Shen yin asthenia syndrome and Pi-Shen yang asthenia syndrome (P<0.01). CONCLUSION: Qi-asthenia and yin deficiency is the principal clinical manifestation of IgA nephropathy. TCM syndrome types are closely related with the prognostic indexes as urine protein, hypertension, renal lesion, etc.

[Study on the relationship between blood stasis syndrome and clinical pathology in patients with IgA nephropathy].

OBJECTIVE: To explore the relationship between blood stasis Syndrome and clinical pathological parameters in patients with IgA nephropathy (IgAN). METHODS: The clinicopathological data were analyzed of 94 IgAN patients of traditional Chinese medicine blood stasis syndrome. RESULTS: Of the 94 IgAN patients, 61.70% had blood stasis syndrome (BS) and 38.30% had non- blood stasis syndrome (non-BS). In patients with BS, dark purple tongue proper was the symptom most commonly seen; the clinical manifestations were mostly proteinuria with hematuria, often accompanied with hypertension and renal dysfunction. Compared with those in patients without BS, plasma levels of serum creatinine (SCr), triglyceride (TG) and plasma fibrinogen (FIB) were obviously higher, activated partial thromboplastin time (APTT), and urokinase-type plasminogen activators (u-PA) significantly lower; and scores of glomerular sclerosis, tubular interstitial lesions, interstitial inflammatory cell infiltration, interstitial fibrosis, tubular atrophy and vascular sclerosis significantly higher. Besides, the Lee's grades in them of III - V were mostly seen. CONCLUSION: Blood stasis syndrome of IgAN are correlated with certain clinical parameters and severity of renal pathological changes. The combination of TCM holistic syndrome differentiation and modern medicinal micro-differentiation is more favorable for making clear the nature of blood stasis Syndrome of IgAN.