The product of duration and amount of proteinuria (proteinuria index) is a possible marker for glomerular and tubulointerstitial damage in IgA nephropathy

BACKGROUND/AIMS: IgA nephropathy (IgAN) is one of the major causes for chronic renal failure (CRF). Presence of massive proteinuria, hypertension, increased serum creatinine level and sclerotic histopathological changes of the glomerulus are known to be determinants for the progression of CRF. However, the relationships between duration of proteinuria/hematuria and histopathological changes, which may be correlated with the renal prognosis, have not been clarified. METHODS: A cross-sectional, univariate analysis of clinical parameters on the four glomerular and three tubulointerstitial histopathological grades in 57 untreated biopsy-proven IgAN patients (M/F = 32/25) was performed. RESULTS: The age at the time of renal biopsy (35.2 +/- 13.0 years; mean +/- SD), average duration of proteinuria (5.3 +/- 5.8 years), mean urinary protein excretion (0.99 +/- 1.22 g/day), serum creatinine (Cr 0.97 +/- 0.28 mg/dl), Cr clearance (Ccr 75.5 +/- 29.4 ml/min), and blood urea nitrogen (BUN 15.4 +/- 3.9 mg/dl) were well correlated with both histopathological grades. The product of duration (years) and urinary protein excretion (g/day) at the time of renal biopsy was more significantly correlated with glomerular and tubulointerstitial histopathological grades and serum Cr. CONCLUSION: The natural course of IgAN is steadily progressive depending on the duration and amount of proteinuria. The product of these two factors (proteinuria index) may be a useful predictor for glomerular and interstitial histopathological changes and the fate of renal function in IgAN.     

IgA肾病治疗的思考

IgA肾病是我国最常见的原发性肾小球疾病。主要以IgA免疫球蛋白沉积于肾小球为病理特征;以血尿、蛋白尿、高血压和肾功能损害为主要临床表现。每次血尿和(或)蛋白尿发作是肾小球损伤的标志,如不有效进行干预,可逐渐出现肾功能损害。控制血尿和(或)蛋白尿,降低尿检异常发生的频率,是治疗原发性IgA肾病及防止肾脏慢性化损伤的关键。ACEI/ARB在减少IgA肾病患者的蛋白尿、保护残存肾功能、延缓其进展为终末期肾病等方面优于其他降压药。IgA肾病如有较多新月体形成、明显血尿和蛋白尿,可考虑使用糖皮质激素和(或)与免疫抑制剂。由于IgA肾病是一个慢性化过程,长期随访对改善该病的预后显得尤为重要。     

150例原发性IgA肾病临床回顾性分析

目的:分析150例原发性IgAN的临床和病理特点,为治疗和预后判断提供依据。方法:对150例原发性IgAN患者的临床和病理特点进行相关性及回归分析。结果:(1)150例患者中有血尿者114例,其中男44例,女70例,女性患者明显多于男性患者(P<0.01);有44例患者发生肉眼血尿,其中24例肉眼血尿与急性扁桃体炎有关。(2)临床特点与病理分级相关性分析结果显示,肾脏病理Lee氏高分级与高血压有相关关系(r=0.557,P=0.000),肾功能损害与肾脏病理Lee氏高分级有相关关系(r=0.678,P=0.000),肾脏病理Lee氏高分级与蛋白尿有相关关系(r=0.588,P=0.001),各病理分级间血尿发生率差异无统计学意义(P>0.05)。(3)回归分析显示肾脏病理Lee分级(P=0.000)和高血压(P=0.001)分别是患者肾功能损害的两个独立危险因素。结论:在本研究中,女性患者血尿发生率高;肉眼血尿发生的诱因以急性扁桃体炎最为常见。蛋白尿的程度、高血压、肾功能损害均与肾脏病理Lee氏分级呈正相关。肾脏病理Lee分级和高血压是本组患者肾功能损害的独立危险因素。     

In situ hybridization of connective tissue growth factor mRNA in IgA nephropathy

Connective tissue growth factor (CTGF) is a member of the new family of growth regulators. It plays an important role of the pathogenesis of mesangial matrix accumulation and progressive glomerulosclerosis in IgA nephropathy (IgAN).
We investigated the expression and localization of CTGF mRNA in renal tissues of patients with IgAN and normal human kidneys (NHK), using in situ hybridization with digoxigenin-labelled oligonucleotide. Open renal biopsy tissues were obtained from 16 patients with IgAN. The renal pathology was categorized into four grades by light microscopic findings. The expression level of CTGF mRNA was quantified by counting all nuclei, as well as nuclei surrounded by CTGF mRNA-positive cytoplasm in randomly selected non-sclerotic glomeruli and expressing the results as the percentage of total cells.
Connective tissue growth factor mRNA was mainly expressed in glomerular mesangial and epithelial cells in both IgAN and NHK, and cells of Bowman's capsule. In IgAN, CTGF mRNA-positive cells were increased in tubulointerstitial fibrotic areas. The percentage of positive cells for CTGF mRNA was significantly higher in IgAN than in NHK. The percentage of positive cells for CTGF mRNA in each IgAN grade was significantly higher than that in NHK. Furthermore, the percentage of positive cells for CTGF mRNA was significantly greater in IgAN with moderate mesangial proliferative lesions (grade 2, grade 3) than in IgAN with mild mesangial proliferative lesions.
Our study suggests that CTGF may play an important role in the development and progression of glomerulosclerosis and tubulointerstitial fibrosis in IgAN.     

Value of pathological grading in prediction of renal survival in IgA nephropathy

Summary: In order to clarify the most reliable risk factor to predict renal outcome, 206 patients with IgA nephropathy were studied for mean period of 9.2 years. the histopathological changes of this disease using light microscopy were divided into four grades (grade 1–4). These grades included glomerular, interstitial and vascular lesions. the cumulative rate of kidney survival progressing to end stage renal failure (ESRF) in all patients was 94% at 5 years, 87% at 10 years and 80% at 15 years after renal biopsy. None of the patients in grade 1 reached ESRF. the cumulative rate of kidney survival in grade 2 was 99% at 5 years, 98% at 10 years and 89% at 15 years after renal biopsy. In grade 3, it was 94% at 5 years, 79% at 10 years and 75% at 15 years. In grade 4 it was 53% at 5 years, 33% at 10 years and 22% at 15 years after renal biopsy. Forward stepwise multivariate regression analysis revealed that, in addition to the histopathological findings, three more risk factors were found to influence actuarial renal survival rate. These factors were: (i) the levels of serum creatinine; (ii) the level of serum albumin; and (iii) the amount of proteinuria at the time of renal biopsy. In parallel studies, forward stepwise multivariate regression analysis isolated three risk factors that influenced the progression of the reciprocal of serum creatinine. These factors were: (i) the levels of total protein; (ii) the degree of our pathological grading; and (iii) the amount of proteinuria. It was concluded that our pathological grading was useful as a prognostic parameter because of its simplicity and availability in routine clinical activities.     

Recurrent mesangial IgA nephritis following renal transplantation

Recurrence of mesangial IgA deposits in renal allografts ofpatients whose original disease was primary IgA nephropathy(IgAN) has been studied. Forty-six patients with primary IgANreceived 51 renal allografts and have been followed for 3–183months. A prospective study of 11 patients (11 biopsies) anda retrospective analysis of 17 patients (16 biopsies; 2 nephrectomyspecimens) have been combined. Seventeen of the 29 allograftshad recurrent mesangial IgA deposits and of these three patientshave negative urinalysis, normal glomeruli by light microscopy,and stable renal function; six patients have microhaematu-ria,mesangial proliferative nephritis, but at present stable renalfunction; and five have mesangial proliferative glomerulonephritiswith microhaematuria, heavy proteinuria, hypertension, and progressiveallograft failure secondary to IgA disease alone, and one ofthese is now back on dialysis. Three other grafts with recurrentdeposits are failing because of transplant glomerulopathy orrejection. The only predictor identified for recurrence of mesangial IgAdeposits was length of time post-transplantation, with allografttissue being studied at 45.9±10.0 versus 15.3±4.8months (P = 0.008) post-transplantation in patients with andwithout recurrent deposits respectively. Cyclosporin A did notprevent recurrence. By virtue of a longer follow-up of patientspost-transplantation than all other reported series, these resultssuggest that with increasing time post-transplantation recurrenceof mesangial IgA disease will become increasingly importantas a cause of progressive allograft dysfunction and failureunless effective treatment is found for the primary disease.     

Treatment of IgA nephropathy

IgA nephropathy (IgAN) is an important cause of progressive kidney disease with 25-30% of patients developing end-stage renal disease within 20 years of diagnosis. There is still no treatment to modify mesangial IgA deposition and available treatments are those extrapolated from the management of other patterns of chronic glomerulonephritis. There remains no consensus on the use of immunosuppressive agents for treatment of progressive IgAN and this is compounded by the relative lack in IgAN of randomized controlled trials relevant to current clinical practice. Patients with recurrent macroscopic hematuria or isolated microscopic hematuria and proteinuria <1 g/24 h require no specific treatment. Those with nephrotic syndrome and minimal change on renal biopsy should be managed as for minimal change nephropathy. There is no evidence to support the use of corticosteroids for nephrotic IgAN outside this group of patients. Patients presenting with acute renal failure require evaluation to distinguish acute tubular necrosis, which requires supportive therapy only, from crescentic IgAN, for which treatment with cyclophosphamide and corticosteroids in a regimen similar to that for renal small vessel vasculitis is indicated in the absence of significant chronic histologic injury. Patients at greatest risk of progressive renal impairment are those with hypertension, proteinuria >1 g/24 h, and reduced glomerular filtration rate at diagnosis. All such patients should be treated to a blood pressure of 125/75 mm Hg with dual blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibition and angiotensin receptor blockade. At present, there is insufficient evidence for the additional use of immunosuppressive agents, antiplatelet agents, or anticoagulants.     

Natural history of immunoglobulin A nephropathy and predictive factors of prognosis: a long-term follow up of 204 cases in China

Aim: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. However, its natural history and risk factors are not well understood. Our aim was to identify the clinical and pathological factors that could predict disease prognosis in Chinese patients. Methods: We studied 204 biopsy‐diagnosed IgAN patients, who were followed for an average of 6.1 years (range, 4–15 years). Chronic kidney disease (CKD) classified according to the Kidney Disease Outcomes Quality Initiative practice guidelines. Renal pathological lesions were graded single‐blindedly according to the Haas classification. The glomerular filtration rate was estimated by the Modification of Diet in Renal Disease equation for Chinese subjects. Results: Patients with CKD were classified as stage 1 (38.10%), stage 2 (35.40%), stage 3 (13.30%), stage 4 (9.90%) and stage 5 (3.30%). During the follow up, 31 patients had progressed to end‐stage renal disease. The renal survival rate following biopsy was 85.1% at the fifth year, and 77.1% at the 10th year. Univariate analysis indicated that patients who were male, had hypertension, proteinuria of more than 1 g/day, renal impairment (estimated glomerular filtration rate, <60 mL/min.1.73 m²), and a high histological grading were associated with poor prognosis. Multivariate analysis indicated that the relative risk of renal failure for patients was 3.9 (P = 0.000) for patients with renal impairment, 2.8 (P = 0.019) for patients with hypertension, and 2.0 (P = 0.003) for patients with high histological grading. Conclusion: We described the natural history of IgAN through follow ups of a relatively large cohort of patients. Most patients were biopsied at an early stage; however, the long‐term prognosis was still poor. Patients with renal impairment, hypertension and advanced histological involvement had the highest risk for disease progression.     

Clinical significance of histological grading and staging for predicting the effectiveness of steroid therapy in IgA nephropathy

Background. A beneficial effect of steroid therapy for IgA nephropathy (IgAN) has been reported. However, precise histological criteria for steroid therapy have not yet been established. The present study was designed to assess the clinical validity of histological grading and staging for predicting the responsiveness to steroid therapy in IgAN. Methods. We performed a retrospective study of 27 patients with IgAN who underwent steroid therapy. The duration of steroid therapy was 42.9 ± 23.1 months, and the mean follow-up period was 7.5 ± 2.4 years, ranging from 4 to 14 years. Responsiveness to the steroid therapy was evaluated by reduction of urinary protein at 1 year after treatment; more than 50% reduction of initial urinary protein and less than 1.0 g/day. Responsiveness to the therapy was also evaluated by preservation of renal function; i.e., maintenance of serum creatinine level under 2.0 mg/dl during follow-up. The histological grading and staging method (G-S system) proposed by Shigematsu was used to evaluate the histological severity of lesions in renal biopsy specimens. Univariate analyses of clinical and histological parameters, using the logistic regression model or Cox proportional hazards model, were performed to find predictive factors for the effectiveness of steroid therapy. Results. No clinical parameters at the start of treatment predicted the effectiveness of the steroid therapy. However, some histological parameters – crescent formation rate (%), grade of glomerular extracapillary lesions (Gex) and grades of acute and chronic interstitial inflammation (Gint and Sint) – were predictive for the effectiveness of steroid therapy. To predict reduction of proteinuria at 1 year after steroid therapy, the crescent formation rate, Gex, Gint, and Sint were significant (odds ratio; P value): crescent formation rate per 10% increment (2.91; P = 0.019), Gex per 0.1 grade increment (1.56; P = 0.021), Gint per one grade increment (0.20; P = 0.022), and Sint per one grade increment (0.33; P = 0.039). These results indicated that a high crescent formation rate and active extracapillary lesions predicted favorable response, and active and chronic interstitial lesions predicted lower efficacy in proteinuria reduction. To predict deterioration of renal function, Gint and Sint were significant (hazard ratio; P value): Gint per one grade increment (3.30; P = 0.015) and Sint per one grade increment (2.99; P = 0.006), indicating that high degrees of acute and chronic interstitial inflammation predicted the deterioration of renal function. Conclusions. The severity of acute glomerular extracapillary lesions predicts the possibility of reduction in proteinuria after steroid therapy, while the severity of interstitial inflammation suggests a lower efficacy for proteinuria reduction and a high risk of renal dysfunction even after steroid therapy in IgAN. Received: August 17, 1999 / Accepted: May 8, 2000     

Clinicopathological study of IgA nephropathy in adults: The influence of onset age on clinical and renal histological findings and on the effect of steroid therapy

Background. The prognosis of IgA nephropathy (IgAN) varies according to the patient's age. It usually affects children or young adults. However, the onset age for IgAN may be at middle-age or older. The influence of onset age on the clinical and renal histological findings of adult IgAN was investigated. Methods. We selected 39 IgAN patients in whom renal biopsy was performed within 2 years from the onset. The patients were divided into two groups according to onset age; early-onset group (under 35 years; group E) and late-onset group (over 35 years; group L). The clinical and histological findings and the response to steroid therapy were compared in the two groups. Results. (1) Clinically, the levels of proteinuria and hematuria in groups E and L were not different, but the creatinine clearance was lower in group L than in group E. Hypertension was frequent in group L (66.7%), but not in group E. (2) Histologically, the rate of glomerular obsolescence and the grades of interstitial fibrosis and arterio- and arteriolosclerosis were more advanced in group L than in group E. However, there were no differences in the grade of mesangial cell proliferation or mesangial matrix increase, nor were the rates of glomerular crescent and tuft adhesion formation different between the two groups. (3) The reduction of proteinuria and hematuria after 1-year steroid therapy was similar in the two groups. Conclusion. Onset age does not affect the severity of glomerular lesions and the effect of steroid therapy in the early phase of adult IgAN. However, advanced interstitial fibrosis and arterio- and arteriolosclerosis, which may be related to hypertension or the aging process, lead to impaired renal function in late-onset IgAN patients. Received: March 18, 1998 / Accepted: October 29, 1998     

Segmental glomerulosclerosis in IgA nephropathy after renal transplantation: relationship with proteinuria and therapeutic response to enalapril

INTRODUCTION: Although graft dysfunction has been increasingly reported in post-transplant IgA nephropathy (Tx-IgAN), intragraft morphological changes have been largely overlooked. We evaluated glomerular changes in Tx-IgAN to identify the histological features pertaining to significant proteinuria and therapeutic response to enalapril. MATERIALS AND METHODS: Fifty-four renal allograft biopsies, diagnosed as Tx-IgAN at a median of 46 months after transplantation, were the subject of the study. In 10 patients, glomerular morphometry was performed. In 14 patients who have been treated with enalapril for more than 12 months, we correlated the therapeutic response to enalapril with allograft histology. RESULTS: No uniform pattern was found in the glomeruli of Tx-IgAN. The glomerular mesangium was mostly indistinct. Interstitial fibrosis was negative or mild in 88.9%. By morphometry, the glomerular tuft areas and mesangial areas were significantly larger in Tx-IgAN than those of the normal native kidney (p < 0.05), but were not different from transplant cases without glomerulonephritis. Proteinuria of >/=1 g/24 h was correlated with glomerulosclerosis, interstitial fibrosis and interstitial inflammation at time of biopsy (p < 0.005). The presence of segmental sclerosis (SS) correlated well with the amount of 24-h proteinuria (p < 0.001). After treatment with enalapril, the amount of proteinuria reduced in 64.3%. Therapeutic response to enalapril tended to be less effective in patients having SS (28.6 versus 71.4%), but this finding did not reach a statistical significance. CONCLUSIONS: Significant proteinuria was associated with advanced chronic injury, especially with the presence of SS in Tx-IgAN, but anti-proteinuric effect of enalapril was not affected by graft histology. It remains to be clarified whether glomerular mesangial expansion plays a role in graft dysfunction in a subset of Tx-IgAN showing prominent mesangial changes.     

GMP-17-positive T-lymphocytes in renal tubules predict progression in early stages of IgA nephropathy

Treatment of patients with IgA nephropathy (IgAN) depends on a reliable assessment of disease progression based on measurements of glomerular filtration rate (GFR), proteinuria, hypertension, and tubulointerstitial changes. We sought to determine whether progression could be predicted from analysis of glomerular and tubulointerstitial inflammation in biopsies taken at an early stage of IgAN. We retrospectively analyzed biopsies from 50 patients, relating the subsequent clinical course to infiltration with B- and T-lymphocytes, granule membrane protein of 17 kDa (GMP-17) positive cytotoxic T cells, macrophages, fibroblasts, and tubulointerstitial expression of human leukocyte antigen-D related (HLA-DR). At biopsy, 19 patients had decreased GFR while 13 of 31 patients with normal GFR and progressive IgAN differed significantly from 18 non-progressors in the level of proteinuria and in the severity of scores for mesangial proliferation, tubular atrophy, interstitial fibrosis, and interstitial infiltrates. On multivariate regression analysis these differences disappeared; however, associations with GMP-17-positive cytotoxic T-lymphocytes in intact renal tubules and of B-lymphocytes in the interstitium remained significant. Our study may have identified a marker of disease progression in early stages of IgAN.     

Histological differences in new-onset IgA nephropathy between children and adults.

BACKGROUND: It is suggested that IgA nephropathy (IgAN) manifests differently in children vs adults on the basis of biopsy findings. However, this has been difficult to establish owing to the uncertainty of the timing of disease onset in adult IgAN. We addressed this question by comparing both histology and leucocyte accumulation in biopsies of recently diagnosed childhood and adult IgAN. METHODS: Biopsies taken within 2 years from the onset of renal abnormalities in 33 childhood (10 +/- 3 years of age) and 38 adult (35 +/- 6 years) cases of IgAN were examined for histological changes (cellularity in mesangial, endocapillary and extracapillary areas, matrix expansion, adhesions/crescents and interstitial damage), glomerular deposition of immunoglobulin and complement, and the presence of macrophages, activated macrophages and T cells by immunohistochemistry. RESULTS: Glomerular hypercellularity owing to increased cells in mesangial area was prominent in paediatric IgAN and significantly greater than in adult IgAN. In contrast, glomerular matrix expansion, crescent formation and interstitial damage were more severe in adults compared to paediatric IgAN. Indeed, glomerular hypercellularity correlated with proteinuria in paediatric but not in adult IgAN, whereas glomerular matrix correlated with proteinuria and renal function in adult but not in paediatric IgAN. The degree of C3c deposition was significantly greater in paediatric IgAN, while deposition of fibrinogen was greater in adult IgAN. Glomerular and interstitial CD68+ macrophages and a subset of sialoadhesin (Sn)+ activated macrophages were identified in both paediatric and adult IgAN, being significantly greater in number in adult IgAN. Glomerular leucocyte infiltration correlated with proteinuria while interstitial leucocyte infiltration correlated with interstitial damage in both groups. However, only the subset of Sn+ macrophages gave a significant correlation with renal function, glomerular hypercellularity and glomerular matrix. CONCLUSIONS: This study has demonstrated significant differences in the early glomerular lesions of IgAN in children vs adults. Furthermore, Sn+ activated macrophages are implicated in the pathogenesis of IgAN in both patient groups. The prognostic significance of these findings warrants further study.     

Evaluation of Renal Clinicopathological Changes in IgA Nephropathy by Urinary Podocytes Excretion and Podocalyxin Expression

Objective: To explore the association of urinary podocyte excretion and renal expression of podocyte-specific marker podocalyxin (PCX) with clinicopathological changes in immunoglobulin A nephropathy (IgAN). Methods: Morning urine samples from IgAN patients and healthy controls were collected. The expression of glomerular PCX was quantified in 50 IgAN patients diagnosed by renal biopsy. IgAN was classified based on the Lee’s Grading system and scored according to the Katafuchi semiquantitative criteria. Morphological evaluation of podocyte was determined by electron microscopy. Results: The amount of urinary podocytes in the IgAN patients was significantly higher than that in the healthy controls (p < 0.01). Pairwise comparison among Lee’s grades of IgAN showed that the median of urinary podocytes in Lee’s I–II group was lower than that in Lee’s III, IV, and V groups (p < 0.05); group III lower than group V (p < 0.05). The positive rate of urinary podocytes was the highest in Lee’s IV and V groups (100%), and lowest in Lee’s I–II group (55%). Multiple comparison among groups of Lee’s grades of IgAN showed that the glomerular PCX expression in Lee’s I–II group was higher than that in Lee’s III, IV, and V groups (p < 0.05); groups III and IV higher than group V (p < 0.05). The amount of urinary podocytes in IgAN patients was negatively correlated with PCX expression (r = ?0.702, p < 0.01), but positively correlated with 24-h urinary protein (r = 0.465, p < 0.01) and glomerular (r = 0.233, p < 0.01) and renal tubular pathological scores (r = 0.307, p < 0.05). The glomerular PCX expression was negatively correlated with 24-h urinary protein (r = ?0.367, p < 0.05) and glomerular (r = ?0.560, p < 0.05) and tubular pathological scores (r = ?0.377, p < 0.05). Electron microscopy showed significant changes in podocytes of IgAN, especially in the foot process. Conclusion: The amount of urinary podocyte can reflect the loss of podocytes in renal tissue, which may be a marker of IgAN progression.     

移植肾IgA肾病临床病理及预后分析

目的探讨移植肾IgA肾病(IgAN)复发或新发的诱因及移植肾生存的危险因素。方法选取2012年11月至2018年12月浙江大学医学院附属第一医院经肾活检确诊为移植肾IgAN的患者,按照血肌酐(Scr)增高水平、估算肾小球滤过率(eGFR)下降率分为稳定组(Scr升高值<20μmol/L,eGFR下降率<10%)和进展组(Scr增高但未达翻倍值,30%相似文献   

Clinical remission and pathological progression after tonsillectomy in a renal transplant patient with recurrent IgA nephropathy

Abstract:  We discuss a renal transplant patient with recurrent IgA nephropathy (IgAN) before and after tonsillectomy. A 36-year-old man started on hemodialysis support in 1996 due to biopsy-proven IgAN, living related renal transplantation was then performed in 1997. Six years after transplantation, the patient presented with microhematuria and proteinuria. Graft biopsy for these urinary abnormalities showed recurrent IgAN. Tonsillectomy was subsequently performed in December 2003, proteinuria remitted 6 months after the tonsillectomy and microhematuria disappeared three years later. Protocol graft biopsy was subsequently performed twice, at 2 yr after the tonsillectomy (2005) and 4 yr after (2008). Comparing the findings of the pre-tonsillectomy biopsy and the two post-tonsillectomy biopsies, an increase in mesangial cells and matrix in 2005, and an expansion of the mesangial matrix and proliferation of mesangial interposition in 2008. In addition, global sclerosis of glomeruli increased over time, the area of tubulointerstitial damage has extended as well. While the tonsillectomy led to clinical remission of recurrent IgAN, the chronicity progressed on these protocol biopsies. This is the first report of the efficacy and the limitations of tonsillectomy in a case of recurrent IgAN in a transplant patient.     

Benign nephrosclerosis: incidence, morphology and prognosis

AIMS: Study of benign nephrosclerosis (BNS) is often mixed up with IgA nephritis (IgAN) associated with hypertension or thin basement membrane disease (TBMD). Here we examined the clinicopathological features, incidences and prognosis of decompensated BNS. MATERIALS AND METHODS: BNS was identified in 590 (8.3%) adult cases among 7,108 renal biopsies of a mean age of 56.5 years (male: female ratio = 2.5:1). The post-biopsy follow-up period ranged from 3 to 22 years (10.1 +/- 4.6 years). RESULTS: Patients with progressive BNS were more likely to develop end-stage renal disease within 5 years of biopsy. Poor prognostic factors included poor or no control of arterial blood pressure by anti-hypertensive drugs, global glomerulosclerosis (GS) (> or = 41%) at biopsy, presence of collapsed glomeruli and/or segmented or semi-global GS. Tubulointerstitial damage, glomerular hypertrophy and loop dilatation were secondary to GS. Gender, duration of HT and onset of HT to biopsy were not significant factors. CONCLUSION: GS in BNS is due to ischemia induced by luminal narrowing or obstruction of preglomerular vessels, and glomerular HT due to loss of autoregulation in preglomerular vessels (irregularly shaped atrophic or segmented medial smooth muscle cells, with expansion of extracellular matrix with or without fibrous intimal thickening). GS resulted in luminal dilatation. Both pathological changes affecting the glomerulus may occur in the same kidney and different nephron units.     

Anti-macrophage migration inhibitory factor reduces transforming growth factor-beta 1 expression in experimental IgA nephropathy.

BACKGROUND: In human glomerulonephritis, including immunoglobulin-A nephropathy (IgAN), glomerular expression of macrophage migration inhibitory factor (MIF) is found to correlate with progressive renal injury. We have shown previously that polymeric IgA is capable of inducing MIF production in cultured human mesangial cells, suggesting a role in inducing inflammatory injury in IgAN. Herein, we examined whether IgA deposition and the subsequent renal injury can be ameliorated with anti-MIF treatment in an experimental murine model of IgAN. METHODS: Glomerular IgA deposition was induced in 4-week-old BALB/c mice by intravenous injection of immune complexes consisting of dinitrophenyl-conjugated bovine serum albumin (DNP-BSA) and IgA MOPC-315 myeloma anti-DNP antibodies. To determine the therapeutic effect of anti-MIF, mice were given anti-MIF (5 mg/kg) or isotypic control antibody intravenously 2 h before the immune complexes administration. The mice were sacrificed 48 h after injection of DNP-IgA. Proteinuria and haematuria were determined and the kidneys were removed for histopathology, immunostaining and immunoblotting. The effect of exogenous MIF on production of TGF-beta 1 by cultured mesangial cells was also examined. RESULTS: IgA deposits were detected in glomeruli of all mice receiving the immune complexes while no glomerular deposit was detected in the control mice. Microscopic haematuria and mesangial hypercellularity were present in mice of the three experimental groups and were absent in the control group. Proteinuria was absent in all groups. Anti-MIF treatment also resulted in decreased renal expression of TGF-beta 1. Moreover, the reduction in TGF-beta 1 expression was confined mainly to glomerular mesangium. An in vitro culture experiment demonstrated that MIF increased TGF-beta 1 production in a time- and dose-dependent fashion. MIF-induced TGF-beta 1 synthesis was abolished by incubating cells with neutralizing antibody against MIF. CONCLUSIONS: Our finding shows that anti-MIF treatment can ameliorate kidney injury and reduce glomerular TGF-beta 1 expression in an experimental model of IgAN.     

Glomerular epithelial cell injury accelerates the progression of antibody-induced mesangial proliferative nephritis

BACKGROUND: Anti-Thy-1.1 antibody induces mesangioproliferative glomerulonephritis; however, the mesangial lesion is spontaneously recovered to the normal feature. Glomerular epithelial cells (GECs) play a crucial role in the glomerular function. Very little is known about the involvement of GECs in this disease model. This study is designed to investigate whether GEC injury prolongs the mesangial lesion. METHODS: The effects of GEC damage on mesangioproliferative nephritis were studied with combined treatment using puromycin aminonucleoside (PAN) and monoclonal antibody (MAb) against rat mesangial Thy-1.1. Urinary protein, BUN, Pcr and Ccr were measured. To clarify the underlying mechanisms, morphological study and immunohistochemistry for alpha-SMA, FGF-2 and PCNA were carried out. RESULTS: Simultaneous administration of PAN plus MAb induced progressive mesangioproliferative nephritis compared to PAN or MAb alone. Rats with combined treatment displayed renal dysfunction with massive proteinuria. Morphological studies showed that the glomeruli in combined group had features resembling those of progressive mesangial proliferative glomerulonephritis in humans. Morphologic lesions of GECs in acute nephritic phase were severer than those in other groups. Immunohistochemistry revealed that glomeruli of combined treatment exhibited persistent overexpression of alpha-SMA and FGF-2. CONCLUSIONS: Simultaneous dysfunction of GECs and mesangial cells can lead to persistent glomerular perturbations with prolonged phenotypic change of mesangial cells, resulting in end-stage renal deficiency. GEC damage during the acute nephritic phase contributes to the progression of irreversible renal disease.     

Significance of mononuclear phagocytes in IgA nephropathy

To clarify the significance of mononuclear phagocytes in IgA nephropathy, renal biopsied materials from 45 patients with the disease were examined by the indirect immunoperoxidase method using anti-human monoclonal antibodies and by ultrastructural peroxidase (PO) cytochemistry. The monoclonal antibodies were FMC32, S-100 (alpha), My4, and LeuM5 for detection of mononuclear phagocytes and HLA-DR for Ia antigens. Mesangial hypercellularity in IgA nephropathy was divided into three grades. The number of monocyte/macrophages per glomerulus differed significantly among the grade of mesangial hypercellularity. In the capillary lumen, monocytes were more numerous in the group with slight mesangial hypercellularity. By contrast, macrophages were often found in the Bowman's space and mesangial area of the glomeruli in the advanced group. In the renal interstitium, the number of monocyte/macrophages per 100 interstitial cells differed significantly among the degree of interstitial damage, and they were observed mainly around sclerotic glomeruli. Ultrastructural PO cytochemistry revealed infiltration of monocytes, exudate macrophages, and/or PO-negative macrophages. Clinicopathological study showed a relationship between the number of monocyte/macrophages per glomerulus and the number of glomerular crescents and the degree of proteinuria. The constancy of the percentage of exudate macrophages and polymorphonuclear leukocytes were observed irrespective of the grade of mesangial hypercellularity. On the other hand, the increasing percentage of PO-negative macrophages and decreasing percentage of monocytes were observed over the grade. These results suggest that mononuclear phagocytes might play an important role in the pathogenesis of mesangial hypercellularity, and irreversible glomerular damage and interstitial tissue injury in IgA nephropathy.