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 Bergers disease) is the most common primary chronic glomerulonephritis worldwide, and was rst described in 1968. Histopathologically, IgA nephropathy is characterized by expansion of the glomerular mesangial matrix with mesangial cell proliferation and/or mononuclear cell inltration. 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 ndings. Copyright 2012, Elsevier Taiwan LLC. All rights reserved.

Introduction
IgA nephropathy is the most common primary chronic glomerulonephritis worldwide, and was rst 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].

1607-551X/$36 Copyright 2012, Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.kjms.2012.04.012

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Y. Tomino

Figure 1. Histology of nephropathy: (A) immunouorescence (left: IgA, right: C3); (B) light microscopy (PAS staining, arrow; para- mesangial deposits); (C) light microscopy (PAS staining, advanced stage); (D) electron microscopy.

The objective of this review is to explain the predictors of prognosis in IgA nephropathy based on clinicopathological ndings.

Clinical predictors of prognosis in patients with IgA nephropathy

Clinical markers for poor prognosis in this disease are as follows: (1) heavy proteinuria; (2) mild hematuria; (3) low serum albumin; (4) renal dysfunction at the time of renal biopsy; (5) diastolic hypertension; (6) male sex; and (7) age below 30 years [3]. 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]. Many dysmorphic red blood cells (RBCs), various cellular casts, and activated platelets in the urinary sediments are frequently observed in the advanced stage of this disease [4,5] (Table 1).

Table 1 Clinical nephropathy. 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 ndings: many dysmorphic red blood cells, various cellular casts, IL-6, MCP-1 Serum IgA/C3 ratio: complement activation

No essential blood chemistry ndings are characteristic of this disease although serum IgA of >3.15 g/L has frequently been observed in adult patients with IgA nephropathy. Furthermore, levels of urinary IL-6, a T-cell-derived lymphokine, and MCP-1, a chemotactic protein for monocytes and T cells, are marked in the advanced stage of IgA nephropathy, which is characterized by severe proliferative glomerular changes. 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 [6,7]. 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 [4,5]: (1) more than ve RBCs in urinary sediments; (2) persistent proteinuria (urinary protein of >0.3 g/day); (3) serum IgA level of >3.15 g/L; and (4) serum IgA/complement 3 (C3) ratio of >3.01. Since the serum IgA/ C3 ratio decreases with improvement of proteinuria and/or hematuria, a high ratio might be one of the prognostic markers in this disease (Ohsawa et al. unpublished data). However, the prognostic signicance of gene polymorphisms of the renin angiotensin system such as ACE genotype is still controversial in patients with IgA nephropathy. In Japan, about 70% of IgA nephropathy cases are revealed by abnormalities in urinalysis performed during annual medical check-ups in schools or ofces. A Joint Committee of the Special Study Group on Progressive Glomerular Disease, Ministry of Health, Labor and Welfare of Japan, and the Japanese Society of Nephrology found in 1995 that it required more than 3 years on average from estimated onset to the rst consultation and subsequent diagnosis as IgA nephropathy by renal biopsy [8]. About 30% and 5% to 10% of IgA nephropathy patients develop ESKD within 15% to 20 years and 5 years, respectively. Conversely, about 60% can avoid ESKD.

Predictors of IgA nephropathy

519 progression and is useful for predicting long-term renal outcome in patients with IgA nephropathy [10] (Table 2).

Histopathological predictors of prognosis in patients with IgA nephropathy

Histological grading
Histopathologically, IgA nephropathy is characterized by expansion of glomerular mesangial matrix with mesangial cell proliferation and/or mononuclear cell inltration (Fig. 1). Paramesangial deposits and electron dense deposits are also observed in the glomeruli Fig. 1B and 1D). The histological marker for poor prognosis of IgA nephropathy is generally considered to be glomerular and/or tubulointerstitial injury (Fig. 1C). Among numerous histologic grading systems for predicting renal outcome of this disease, the recently published Oxford classication identies prognostic pathologic features, providing substantial evidence that histologic grading systems can be used to predict renal outcome of IgA nephropathy [9]. When developing a histological classication of IgA nephropathy, some issues need to be considered. In Japan, the Special IgA Nephropathy Study Group of the Progressive Renal Diseases Study Committee organized by the Ministry of Health, Labor and Welfare conducted a multicenter retrospective case-control study on IgA nephropathy in 2004 to develop an evidence- and lumped-system-based clinicopathological classication of IgA nephropathy for predicting long-term risk of progression to ESKD [10]. The study enrolled 287 patients with a median follow-up of 9.3 years (range 0.7e34.0 years) after renal biopsy. During follow-up, 49 patients (19%) progressed to ESKD. Multivariate logistic regression analysis showed that the independent pathological variables that predicted progression to ESKD were global sclerosis, segmental sclerosis, and brous crescents for patients who progressed to ESKD within 5 years after biopsy, and global sclerosis and cellular/brocellular crescents for those who progressed to ESKD within 5 to 10 years after biopsy. Four histological grades (HG), i.e., HG 1, HG 2, HG 3, and HG 4, were established corresponding to <25%, 25% to 49%, 50% to 74%, and 75% of glomeruli exhibiting cellular or brocellular crescents, global sclerosis, segmental sclerosis, or brous crescents. Eleven (7%) patients in HG 1, 12 (16%) in HG 2, 13 (31%) in HG 3 and 13 (68%) in HG 4 progressed to ESKD. Multivariate logistic analysis revealed that the risk of progression to ESKD was signicantly higher in HG 2, 3 and 4 than in HG 1 (odds ratios: 2.4, 5.7 and 27.6 vs. 1.0). It appears that this evidence- and lumped-system-based histological classication can identify the magnitude of the risk of disease

Glomerular cytokine expression

Several cytokines and/or growth factors, such as interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor-a (TNFa), plateletderived growth factor and transforming growth factor-b, have been shown to be involved in glomerular mesangial cell proliferation and hyperproduction of extracellular matrices, i.e. bronectin, type IV collagen, and laminin. Intercellular adhesion molecule-1 (ICAM-1), a glycoprotein of 90 kD to 110 kD, which belongs to the immunoglobulin superfamily, is a lymphokine, i.e. IL-1-, TNFa and/or interferon-a-inducible cell-surface molecule. Using immunouorescence, the authors examined patients with IgA nephropathy to determine whether the expression of ICAM-1 in glomeruli might reect disease activity. Glomeruli that showed increases of ICAM-1 expression had marked inltration of lymphocytes and monocytes. 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. It appears that the expression of ICAM-1 is closely linked to glomerular cell inltration of lymphocytes and monocytes in patients with IgA nephropathy [11].

Podocyte injury
The number of podocytes per glomerulus should serve as a podocyte injury parameter and provide prognostic information in patients with IgA nephropathy. Development of glomerulosclerosis in IgA nephropathy patients is associated with podocyte injury, which may be caused by apoptosis, necrosis, detachment from the glomerular basement membrane (GBM) or autophagy of these cells. Podocytes in adults do not undergo mitosis, and normally the only way to respond to injury is by cell hypertrophy. Thus, increased podocyte surface area reects the extent of podocyte hypertrophy. In severe patients, segments of the GBM become denuded. Direct contact of the naked portion of the GBM with the parietal epithelium of Bowmans capsule might lead to adhesion to Bowmans capsule and potentially to segmental sclerosis [12]. Lemley et al. [13] reported that podocyte loss, i.e. podocytopenia, is concurrent with increasing disease severity in patients with IgA nephropathy. They observed no corresponding correlations between the clinical indices of injury and the number of mesangial and endothelial cells in this disease. Endothelial and mesangial cell damage is followed by regeneration, but this is not the case with podocytes. Hishiki et al. [14] also reported that podocyte injuries e i.e. 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. Thus, podocyte injury might provide additional prognostic information about for such patients. Dendrin, which is a novel component of the glomerular slit diaphragm, accumulates in the nucleus of injured podocytes in experimental nephritis. Recently, Kodama et al. 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. 1) Glomerular and tubulointerstitial injuries 2) Expressions of glomerular cytokines and/or extracellular matrices 3) Podocyte injury (podocytopenia) 4) Mast cell inltration in the interstitium 5) Others

520 nucleus and disease progression in patients with IgA nephropathy. A positive correlation was observed between acute extracapillary changes and the number of dendrin positive nuclei per glomerulus. It appears that the number of dendrin positive nuclei in renal biopsy specimens is useful in evaluation of disease activity in patients with IgA nephropathy (unpublished data).

Y. Tomino
[2] Okazaki K, Suzuki Y, Kobayashi T, Kodama F, Horikoshi S, Tomino Y. Inuence of the period between onset of IgA nepjropathy and medical intervention on renal prognosis. Health 2011;3:518e23. [3] Goto M, Wakai K, Kawamura T, Ando M, Endoh M, Tomino Y. A scoring system to predict renal outcome in IgA nephropathy: a nationwide 10-year prospective cohort study. Nephrol Dial Transplant 2009;24:3068e74. [4] Maeda A, Gohda T, Funabiki K, Horikoshi S, Shirato I, Tomino Y. Signicance of serum IgA levels and serum IgA/C3 ratio in diagnostic analysis of patients with IgA nephropathy. J Clin Lab Anal 2003;17:73e6. [5] Nakayama K, Ohsawa I, Maeda-Ohtani A, Murakoshi M, Satoshi Horikoshi S, Tomino Y. Prediction of diagnosis of immunoglobulin A nephropathy prior to renal biopsy and correlation with urinary sediment ndings and prognostic grading. J Clin Lab Anal 2008;22:114e8. [6] Saitoh A, Suzuki Y, Takeda M, Kubota K, Tomino Y. Urinary levels of chemoattractant protein (MCP)-1 and disease activity in patients with IgA nephropathy. J Clin Lab Anal 1998;12:1e5. [7] Tomino Y, Funabiki K, Ohmuro H, Shimizu M, Yokoyama K, Shirato I, et al. Urinary levels of interleukin-6 and disease activity in patients with IgA nephropathy. Am J Nephrol 1991; 11:459e64. [8] Koyama A, Igarashi M, Kobayashi M. Natural history and risk factors for immunoglobulin A nephropathy in Japan. Research Group on Progressive Renal Diseases. Am J Kidney Dis 1997;29: 526e32. [9] Working Group of the International IgA Nephropathy Network and the Renal Pathology Society, Cattran DC, Coppo R, Cook HT, Feehall J, Roberts IS, et al. The Oxford classication of IgA nephropathy: rationale, clinicopathological correlations, and classication. Kidney Int 2009;76:534e45. [10] Kawamura T, Joh K, Okonogi H, Koike K, Utsunomiya Y, Miyazaki Y, et al. A histologic classication of IgA nephropathy for predicting long-term prognosis: emphasis on end-stage renal disease. J Nephrol 2012 Jun 7:0. http: //dx.doi.org/10.5301/jn.5000151. [Epub ahead of print]. [11] Tomino Y, Ohmuro H, Kuramoto T, Shirato I, Eguchi K, Sakai H, et al. Expression of intercellular adhesion molecule-1 and inltration of lymphocytes in glomeruli of patients with IgA nephropathy. Nephron 1994;67:302e7. [12] Kriz W, Kretzler M, Nagata M, Provoost AP, Shirato I, Uiker S, et al. A frequent pathway to glomerulosclerosis: detection of tuft architecture-podocyte damage-segmental sclerosis. Kidney Blood Press Res. 1996;18:245e53. [13] Lemley KV, Lafayette RA, Safai M, Derby G, Blouch K, Squarer A, et al. Podocytopenia and disease severity in IgA nephropathy. Kidney Int 2002;61:1475e85. [14] Hishiki T, Shirato I, Takahashi Y, Funabiki K, Horikoshi S, Tomino Y. Podocyte injury predicts prognosis in patients with IgA nephropathy using a small amount of renal biopsy tissue. Kidney Blood Press Res. 2001;24:99e104. [15] Kurusu A, Suzuki Y, Horikoshi S, Shirato I, Tomino Y. Relationship between mast cells in the tubulointerstitium and prognosis of patients with IgA nephropathy. Nephron 2001;89: 391e7. [16] Sakamoto-Ihara T, Suzuki Y, Kurusu M, Yamashita M, Horikoshi S, Tomino Y. Possible involvement of mast cells in renal brosis in patients with IgA nephropathy. Inamm Res 2007;56:421e7.

Mast cell inltration in the interstitium

Mast cells are derived from hematopoietic progenitors and migrate into inammatory lesions. Human mast cells can be classied into two types according to their protease composition: those containing only tryptase (MCT) and those containing both tryptase and chymase (MCTC). MCT are involved in immunological responses, whereas MCTC seem instead to play a role in angiogenesis and tissue remodeling. Some reports have suggested that mast cells play an important role in the development of brosis and the degradation of extracellular matrices. Kurusu et al. [15] reported that the number of MCT in the brotic and nonbrotic areas may be one of the predictive factors for the prognosis of patients with IgA nephropathy. Sakamoto-Ihara et al. [16] also reported that IgA nephropathy patients had more MCTC than MCT in the interstitial lesions. Mast cells were observed around but not in the conglomerate of angiotensin II (Ang-II)-positive cells. The number of Ang-IIpositive cells was correlated with MCTC and MCT in patients with IgA nephropathy with the most severe pathological changes. It appears that chymase-dependent Ang-II synthesis due to human mast cells may be involved in the inammatory and brotic processes of IgA nephropathy [16].

Conclusion and future perspectives

Although the clinical course is generally gradual in patients with IgA nephropathy, progression to renal hypertension, renal anemia and ESKD is not as rare as was originally thought. There are several clinical and pathological predictors of the prognosis of this disease. Thus, it is suggested that early diagnostic screening of prognosis predictors and subsequent intervention are important for good prognosis in patients with IgA nephropathy.

Acknowledgments
I sincerely thank my colleagues in the Division of Nephrology, Department of Internal Medicine at Juntendo University Faculty of Medicine, Tokyo, Japan.

References
[1] Berger J, Hinglais N. Les depots intercapillaries dIgA-IgG. J Urol Nephrol 1968;74:694e5.