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Kaohsiung Journal of Medical Sciences (2012) 28, 517e520

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REVIEW ARTICLE

Predictors of prognosis in IgA nephropathy
Yasuhiko Tomino*
Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan
Received 22 November 2011; accepted 22 November 2011 Available online 25 September 2012

KEYWORDS
IgA nephropathy; Predictor; Prognosis

Abstract IgA nephropathy (nephropathy with mesangial IgA and IgG deposits, so-called Berger’s disease) is the most common primary chronic glomerulonephritis worldwide, and was first described in 1968. Histopathologically, IgA nephropathy is characterized by expansion of the glomerular mesangial matrix with mesangial cell proliferation and/or mononuclear cell infiltration. Glomeruli typically contain generalized-diffuse granular mesangial deposits of IgA (mainly IgA1), IgG and C3. This disease, therefore, is considered to be an immune-complexmediated glomerulonephritis although the antigenic agents are still obscure. Clinically, patients with IgA nephropathy show microscopic and macroscopic hematuria and/or proteinuria. Although the clinical course is generally gradual in patients with IgA nephropathy, progression to renal hypertension, renal anemia, and end-stage kidney disease is not as rare as originally thought. Since pathogenesis and radical treatment for IgA nephropathy are still not established, it is necessary to study them using various clinical findings. Copyright ª 2012, Elsevier Taiwan LLC. All rights reserved.

Introduction
IgA nephropathy is the most common primary chronic glomerulonephritis worldwide, and was first described by J. Berger et al. in 1968 [1]. Glomeruli typically contain generalized-diffuse granular mesangial deposits of IgA (mainly IgA1), IgG, and C3 (Fig. 1A). IgA nephropathy is generally considered to be an immune-complex-mediated glomerulonephritis. Clinically, patients with IgA nephropathy show
* Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-Ku, Tokyo 813-8421, Japan. E-mail address: yasu@juntendo.ac.jp.

microscopic and macroscopic hematuria and/or proteinuria. The majority of patients show no symptoms, but occasionally acute nephritic syndrome occurs. The occurrence of nephrotic syndrome is relatively rare, however. Although the clinical course is generally gradual in patients with IgA nephropathy, progression to renal hypertension, renal anemia, and endstage kidney disease (ESKD) is not as rare as originally thought. Early medical intervention may lead to a better renal prognosis, particularly for the those with a relatively poor prognosis according to the Japanese Guidelines, who represent a major portion of the IgA nephropathy population. Thus, it appears that early diagnostic screening and subsequent intervention are important for a good prognosis in IgA nephropathy patients [2].

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and the Japanese Society of Nephrology found in 1995 that it required more than 3 years on average from estimated onset to the first consultation and subsequent diagnosis as IgA nephropathy by renal biopsy [8].15 g/L. (3) serum IgA level of >3. (5) diastolic hypertension. Ministry of Health. the prognostic significance of gene polymorphisms of the renin angiotensin system such as ACE genotype is still controversial in patients with IgA nephropathy. Histology of nephropathy: (A) immunofluorescence (left: IgA. a high ratio might be one of the prognostic markers in this disease (Ohsawa et al. and (7) age below 30 years [3]. Table 1 Clinical nephropathy. (2) mild hematuria.mesangial deposits). right: C3). (B) light microscopy (PAS staining. The objective of this review is to explain the predictors of prognosis in IgA nephropathy based on clinicopathological findings. a T-cell-derived lymphokine. respectively. (D) electron microscopy. Tomino Figure 1.5]: (1) more than five RBCs in urinary sediments. Conversely. various cellular casts. Measurement of urinary IL-6 and MCP-1 is useful for evaluating the degree of glomerular injuries and/ or prognosis in patients with IgA nephropathy [6. unpublished data). In Japan.7]. MCP-1 Serum IgA/C3 ratio: complement activation No essential blood chemistry findings are characteristic of this disease although serum IgA of >3. 1) 2) 3) 4) 5) 6) 7) 8) 9) predictors of prognosis in IgA Heavy proteinuria Mild hematuria Low serum albumin Renal dysfunction at the time of renal biopsy Diastolic hypertension Male sex Age below 30 years Urinary findings: many dysmorphic red blood cells. The total numbers of each type of urinary cast in the urinary sediments should provide highly convincing data for prediction of the prognosis in IgA nephropathy patients prior to renal biopsy [4].5] (Table 1).01. are marked in the advanced stage of IgA nephropathy. arrow. (3) low serum albumin. para. about 70% of IgA nephropathy cases are revealed by abnormalities in urinalysis performed during annual medical check-ups in schools or offices. However. (2) persistent proteinuria (urinary protein of >0. (C) light microscopy (PAS staining. Labor and Welfare of Japan. We have already reported the importance of four clinical markers in the diagnosis of patients with IgA nephropathy or in differential diagnosis from other types of chronic glomerulonephritis as follows [4. levels of urinary IL-6. advanced stage).3 g/day). a chemotactic protein for monocytes and T cells. and (4) serum IgA/complement 3 (C3) ratio of >3. and MCP-1. Many dysmorphic red blood cells (RBCs). and activated platelets in the urinary sediments are frequently observed in the advanced stage of this disease [4. Since the serum IgA/ C3 ratio decreases with improvement of proteinuria and/or hematuria.15 g/L has frequently been observed in adult patients with IgA nephropathy.518 Y. about 60% can avoid ESKD. A Joint Committee of the Special Study Group on Progressive Glomerular Disease. About 30% and 5% to 10% of IgA nephropathy patients develop ESKD within 15% to 20 years and 5 years. IL-6. (6) male sex. Clinical predictors of prognosis in patients with IgA nephropathy Clinical markers for poor prognosis in this disease are as follows: (1) heavy proteinuria. various cellular casts. Furthermore. (4) renal dysfunction at the time of renal biopsy. which is characterized by severe proliferative glomerular changes. .

plateletderived growth factor and transforming growth factor-b. i. segmental sclerosis. Multivariate logistic regression analysis showed that the independent pathological variables that predicted progression to ESKD were global sclerosis. Among numerous histologic grading systems for predicting renal outcome of this disease. detachment from the glomerular basement membrane (GBM) or autophagy of these cells. In severe patients. Podocyte injury The number of podocytes per glomerulus should serve as a podocyte injury parameter and provide prognostic information in patients with IgA nephropathy. or fibrous crescents. which is a novel component of the glomerular slit diaphragm. 1) Glomerular and tubulointerstitial injuries 2) Expressions of glomerular cytokines and/or extracellular matrices 3) Podocyte injury (podocytopenia) 4) Mast cell infiltration in the interstitium 5) Others . Endothelial and mesangial cell damage is followed by regeneration. i. 1B and 1D).7 and 27. Glomeruli that showed increases of ICAM-1 expression had marked infiltration of lymphocytes and monocytes. 5. They observed no corresponding correlations between the clinical indices of injury and the number of mesangial and endothelial cells in this disease. segmental sclerosis. i.. Histopathological predictors of prognosis in patients with IgA nephropathy Histological grading Histopathologically. Development of glomerulosclerosis in IgA nephropathy patients is associated with podocyte injury. [14] also reported that podocyte injuries e i. Dendrin. the Special IgA Nephropathy Study Group of the Progressive Renal Diseases Study Committee organized by the Ministry of Health. 1). Thus. podocytopenia. 25% to 49%. podocyte injury might provide additional prognostic information about for such patients. and HG 4.e.e. During follow-up.4.0). global sclerosis. the recently published Oxford classification identifies prognostic pathologic features. 1.Predictors of IgA nephropathy 519 progression and is useful for predicting long-term renal outcome in patients with IgA nephropathy [10] (Table 2). Four histological grades (HG). 3 and 4 than in HG 1 (odds ratios: 2. In Japan. some issues need to be considered. 50% to 74%. IL-6.7e34. The average number of these cells in glomeruli was increased in advanced-stage patients who showed an increase of ICAM-1 expression in the glomeruli. Eleven (7%) patients in HG 1. reduction of absolute number per glomerulus and increase of glomerular surface area covered by one podocyte e were related to the progression of disease in patients with IgA nephropathy. and 75% of glomeruli exhibiting cellular or fibrocellular crescents. Podocytes in adults do not undergo mitosis.e. a glycoprotein of 90 kD to 110 kD. [13] reported that podocyte loss. necrosis. TNFa and/or interferon-a-inducible cell-surface molecule.e. fibronectin. tumor necrosis factor-a (TNFa). such as interleukin (IL)-1.6 vs. Recently. Lemley et al. and normally the only way to respond to injury is by cell hypertrophy. accumulates in the nucleus of injured podocytes in experimental nephritis. Hishiki et al. which belongs to the immunoglobulin superfamily. and global sclerosis and cellular/fibrocellular crescents for those who progressed to ESKD within 5 to 10 years after biopsy. Kodama et al. The histological marker for poor prognosis of IgA nephropathy is generally considered to be glomerular and/or tubulointerstitial injury (Fig. When developing a histological classification of IgA nephropathy. but this is not the case with podocytes. It appears that the expression of ICAM-1 is closely linked to glomerular cell infiltration of lymphocytes and monocytes in patients with IgA nephropathy [11]. IL-2. segments of the GBM become denuded. 49 patients (19%) progressed to ESKD. increased podocyte surface area reflects the extent of podocyte hypertrophy. which may be caused by apoptosis. type IV collagen. and laminin. HG 3. 13 (31%) in HG 3 and 13 (68%) in HG 4 progressed to ESKD. is concurrent with increasing disease severity in patients with IgA nephropathy. the authors examined patients with IgA nephropathy to determine whether the expression of ICAM-1 in glomeruli might reflect disease activity. IL-1-. is a lymphokine. Direct contact of the naked portion of the GBM with the parietal epithelium of Bowman’s capsule might lead to adhesion to Bowman’s capsule and potentially to segmental sclerosis [12]. have been shown to be involved in glomerular mesangial cell proliferation and hyperproduction of extracellular matrices. Using immunofluorescence. providing substantial evidence that histologic grading systems can be used to predict renal outcome of IgA nephropathy [9]. investigated the presence of nuclear dendrin and the relationship between relocation of dendrin to the podocyte Table 2 Histopathological predictors of prognosis in IgA nephropathy. i. The study enrolled 287 patients with a median follow-up of 9. 12 (16%) in HG 2. Intercellular adhesion molecule-1 (ICAM-1). Multivariate logistic analysis revealed that the risk of progression to ESKD was significantly higher in HG 2. It appears that this evidence. Thus. HG 2. and fibrous crescents for patients who progressed to ESKD within 5 years after biopsy.0 years) after renal biopsy.3 years (range 0. HG 1.and lumped-system-based clinicopathological classification of IgA nephropathy for predicting long-term risk of progression to ESKD [10].and lumped-system-based histological classification can identify the magnitude of the risk of disease Glomerular cytokine expression Several cytokines and/or growth factors. IgA nephropathy is characterized by expansion of glomerular mesangial matrix with mesangial cell proliferation and/or mononuclear cell infiltration (Fig. Paramesangial deposits and electron dense deposits are also observed in the glomeruli Fig. were established corresponding to <25%. Labor and Welfare conducted a multicenter retrospective case-control study on IgA nephropathy in 2004 to develop an evidence. 1C).e.

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