In Translation The Pathogenesis of IgA Nephropathy: What Is New and
In Translation The Pathogenesis of IgA Nephropathy: What Is New and How Does It Change Therapeutic Approaches? Jürgen Floege, MD Immunoglobulin A (IgA) nephropathy is the most common glomerulonephritis worldwide. For example, in Japan, full-blown IgA nephropathy has been detected in ⬃1.5% of all allograft kidneys at the time of transplant. Genetic and environmental modifiers, as well as generic progression factors (eg, hypertension), must have a major role in determining who will become clinically overt and who will experience progression. In patients with clinically overt IgA nephropathy and/or progressive disease, it now is relatively well established that the pathogenesis involves 6 major steps: (1) Increased occurrence of IgA1 with poor galactosylation in the circulation. This might relate to the migration of mucosal B cells to bone marrow, where they produce “correct” poorly galactosylated IgA. Modulation of mucosal immunity may offer new therapeutic options. (2) Generation of IgG antibodies against poorly galactosylated IgA1. This could lay the foundation for immunosuppression, whereas detection of such IgG autoantibodies may accommodate the noninvasive monitoring of IgA nephropathy. (3) Mesangial deposition and/or formation of IgG-IgA1 or IgA1-IgA1 complexes. (4) Activation of mesangial IgA receptors and/or complement; both lend themselves to therapeutic interference. (5) Mesangial cell damage and activation of secondary pathways, such as overproduction of platelet-derived growth factor, which can be targeted specifically. (6) Activation of pathomechanisms that are not specific for IgA nephropathy and that drive glomerulosclerosis and tubulointerstitial fibrosis. Although at present our therapeutic armamentarium is still limited largely to supportive care and immunosuppression in some instances, these new insights can be expected to yield novel, perhaps individualized, therapeutic options in primary and recurrent IgA nephropathy. Am J Kidney Dis. 58(6):992-1004. © 2011 by the National Kidney Foundation, Inc. INDEX WORDS: Immunoglobulin A (IgA) nephropathy; mesangioproliferative glomerulonephritis; recurrence; progression; hypertension; proteinuria. BACKGROUND Immunoglobulin A (IgA) nephropathy is very common. Studies of nonselected autopsy series or zero-hour allograft biopsies have reported that glomerular IgA deposits are detected in up to 20% of all cases.1,2 In a Japanese study, glomerular IgA and C3 deposits plus mesangioproliferative changes, in other words, IgA nephropathy, were noted in 1.6% of presumably healthy donor kidneys.2 Thus, in contrast to the selected patients that we encounter in clinical practice, most patients likely do not come to clinical attention and these patients must run a benign course and/or some IgA nephropathy must resolve spontaneously. In a report of Chinese patients with IgA nephropathy with isolated microhematuria, resolution occurred in 14% and less than one third experienced progression in up to 12 years of follow-up.3 Others also have reported the spontaneous or therapyFrom the Division of Nephrology and Immunology, RWTH University of Aachen, Germany. Received March 25, 2011. Accepted in revised form May 26, 2011. Originally published online August 29, 2011. Address correspondence to Jürgen Floege, MD, Department of Nephrology and Clinical Immunology, RWTH University Hospital Aachen, Pauwelsstr 30, 52074 Aachen, Germany. E-mail: [email protected]. © 2011 by the National Kidney Foundation, Inc. 0272-6386/$36.00 doi:10.1053/j.ajkd.2011.05.033 992 induced disappearance of IgA nephropathy in native4-6 and transplanted kidneys.7 There are 2 important implications of these observations: IgA nephropathy is a dynamic disease and the defect(s) driving the persistence or progression of IgA nephropathy appear to reside largely outside the kidney. CASE VIGNETTE A 42-year-old man presented to the Division of Nephrology of the Aachen Medical School after the discovery of an elevated serum creatinine level (4.3 mg/dL [380.1 mol/L], corresponding to an estimated glomerular filtration rate (eGFR of 30 mL/min/ 1.73 m2 [0.5 mL/s/1.73 m2], calculated by the MDRD [Modification of Diet in Renal Disease] Study equation), and hypertension during a routine checkup. He had been completely asymptomatic and no medical history was present. Both parents had hypertension, but the family history otherwise was unremarkable. His body mass index was 23 kg/m2 and he did not smoke. A routine checkup 7 years earlier was unremarkable, with no hypertension and a serum creatinine level within the reference range. However, a urine dipstick test had not been performed. Working as a teacher, he had assumed intermittent headaches to be job related. On admission, he had already been started on treatment with ramipril, 5 mg/d. Blood pressure was 155/90 mm Hg, urinalysis showed microhematuria, and urine protein-creatinine ratio was 1.5 g/g. A kidney biopsy specimen (Fig 1) showed IgA nephropathy with mesangial hypercellularity, endocapillary hypercellularity, focal glomerulosclerosis of 5 of 8 glomeruli, and tubular atrophy and tubulointerstitial fibrosis involving ⬃80% of the renal interstitium. His angiotensinconverting enzyme–inhibitor dosage was uptitrated and a diuretic, -blocker, and low-dose spironolactone were added, resulting in a Am J Kidney Dis. 2011;58(6):992-1004 Pathogenesis of IgA Nephropathy Figure 1. Renal pathologic characteristics of the patient described in the case vignette. Glomerulus has one small area of a segmental increase in mesangial cell number and mesangial matrix (arrow) in the region of a segmental adhesion. Globally sclerosed glomeruli can be seen in the upper part of the image (arrowhead). Preglomerular vessels (asterisk) are regular. Detached tubular cells can be observed in many damaged tubules (star). Note the division of biopsy tissue into an upper half with a fibrosed interstitium and atrophic tubules, whereas the neighboring tubulointerstitium in the lower half of the image is relatively preserved. (Periodic acid–Schiff stain; original magnification, ⫻40.) Courtesy of H.J. Gröne, DKFZ, Heidelberg, Germany. decrease in blood pressure to 125-130/75-80 mm Hg. Serum creatinine level increased to 4.7 mg/dL (415.5 mol/L; eGFR, 28 mL/min/1.73 m2 [0.47 mL/s/1.73 m2]), and urinary proteincreatinine ratio decreased to 0.6 g/g. Other interventions to retard the progression of kidney disease included native vitamin D, oral bicarbonate, dietary counseling, and low-dose allopurinol, but no immunosuppression. Three years later, in late 2010, his serum creatinine remained at 4.9 mg/dL (433.16 mol/L; eGFR, 25 mL/min/1.73 m2 [0.42 mL/s/1.73 m2]). In early 2011, he acutely presented with progressive weakness, with serum creatinine level of 8.8 mg/dL (777.9 mol/L; eGFR, 14 mL/min/1.73 m2 [0.23 mL/s/1.73 m2]) and worsening of renal anemia. Blood pressure was still well controlled and there was no obvious explanation, such as infection or nephrotoxic drugs, for this abrupt deterioration. His condition did not resolve, peritoneal dialysis therapy finally was started, and the patient was scheduled for a living donor kidney transplant. PATHOGENESIS AND RECENT ADVANCES This patient illustrates a number of problems regularly encountered in patients with IgA nephropathy: (1) patients usually are asymptomatic and IgA nephropathy often is a chance finding; (2) a patient often is first seen when disease has already progressed considerably; (3) despite optimized care, patients still experience progression; and (4) we have no adequate means to assess disease activity. The first issue implies that IgA nephropathy in the worst case may never be identified and that patients, for example, may be mislabeled based on clinical Am J Kidney Dis. 2011;58(6):992-1004 grounds as “hypertensive nephrosclerosis.” Thus, screening programs and adequate follow-up in cases of positive urine findings, including nephrology referral and kidney biopsy, will strongly determine whether such cases become apparent. The remaining issues need to be addressed by the nephrology community: we need better understanding of how IgA nephropathy manifests initially, how it progresses, and how it can be monitored. Better insight into pathophysiologic processes should provide clues to develop therapies, possibly even causative therapy, for the early stages. However, we also need better therapies for advanced stages. Thus, the purpose of this review is to summarize our current understanding of the pathogenesis of IgA nephropathy and discuss potential therapeutic consequences that derive from the various steps involved in IgA nephropathy progression. GENETIC AND/OR GENERIC PROGRESSION FACTORS From the few facts mentioned in the introduction, it is clear that powerful genetic, environmental, or other modifiers must determine in whom IgA nephropathy is progressive and who is protected. Hypertension is a potent predictor of outcome in IgA nephropathy.8-10 Whether renoparenchymal or 993 Jürgen Floege primary hypertension is a more potent driver of injury is still unresolved, but it must not be assumed that uncontrolled primary hypertension would not contribute to damage in IgA nephropathy. Apart from hypertension, renal prognosis is worse in obese patients with IgA nephropathy,11 and nonsurgical weight loss can lead to a decrease in proteinuria.12 A large number of studies have investigated individual single-nucleotide polymorphisms (SNPs) and their relation to the manifestation or course of IgA nephropathy. Many of these studies focused on genes related to the renin-angiotensin system13-18 or mesangial cell-specific genes such as megsin.19,20 Others, including hemoxygenase, proinflammatory cytokines, transforming growth factor, and uteroglobin, also have been studied.21-26 Despite the plethora of investigations, no consistent picture has evolved. Most of these studies are too small to provide definitive answers or have studied ethnically heterogeneous populations. Rarely has the role of a particular SNP been confirmed independently in another population or even ethnic group,27 and even then, results have not necessarily been consistent. For example, in our German study, renal survival was extended significantly in patients with the CCR5⌬32 polymorphism compared with those who did not have the deleted version of this chemokine receptor,28 whereas a similar large French study subsequently reported the exact opposite.29 In terms of HLA associations, earlier studies were inconclusive, but some consistently have pointed to an association of the HLA-DQ loci with the course of IgA nephropathy.30 This recently has been confirmed by a genome-wide association study in which a strong association of a DQ locus with susceptibility to IgA nephropathy was noted in British patients.31 Another very large study confirmed a DQ association and identified further loci, in particular in the complement factor H region.32 Genetic associations suggesting autosomal-dominant traits with highly variable penetrance also have been reported in cases of familial IgA nephropathy.33-35 One of these loci was confirmed in a mouse strain prone to develop an IgA nephropathy–like disease.36 However, no strong or consistent signal was seen in the critical interval of chromosome 6q22 in a high-throughput SNP association study involving a large set of patients with IgA nephropathy.37 At present, none of these genetic associations is useful for clinical decision making. The hope is that they will yield new insights into the pathogenesis of IgA nephropathy and thus identify new therapeutic approaches. It also needs to be realized that any genetic study in IgA nephropathy is hampered by the problem of finding true non–IgA nephropathy controls (in view of the high prevalence of “covert” IgA nephropathy) and thus genetic studies 994 may in reality examine factors involved in the clinical manifestation of IgA nephropathy rather than the susceptibility to it. Environmental conditions also must have a strong impact on the manifestation of IgA nephropathy, illustrated best by the inverse relationship between the prevalence of IgA nephropathy and membranoproliferative glomerulonephritis (MPGN). In areas such as Northern Europe, Japan, or Argentina with a relatively high socioeconomic standard, IgA nephropathy prevalence far exceeds that of MPGN, whereas in regions with a lower socioeconomic standard, such as some Balkan countries, Peru, or South Africa, MPGN is the dominant glomerulonephritis type. It has been hypothesized that overcrowding and poor hygiene early in life may predispose to a T helper cell type 1 (TH1)dominant response, as observed in MPGN, whereas dominance of the TH2 subset is related to the increased incidence of allergies, IgA nephropathy, and minimal change disease in industrialized nations.38 When IgA nephropathy has manifested, its course is modulated by inflammatory and infectious complications. For example, we have shown that subclinical induction of the acute-phase response is present in those with progressive IgA nephropathy.39 Macrohematuria is associated with upper respiratory tract infections. In rare cases, spontaneous complete resolution of IgA nephropathy followed the resolution of viral infections, for example, hepatitis A.40 Experimentally, infections and housing conditions, in other words, conventional versus specific pathogen-free conditions, of mouse strains with an IgA nephropathy–like pathologic state, exacerbated renal damage.41 This correlated with higher levels of Toll-like receptor 9 (TLR9).42 Moreover, nasal challenge with CpG oligodeoxynucleotides (ie, synthetic DNA molecules containing cytosine-guanine motifs), which are ligands for TLR9, also has been shown to worsen kidney injury. Staphylococcus aureus cell envelope antigen has been implicated in the induction of IgA nephropathy.43 Although this cannot be excluded, the alternative hypothesis is that microbial superantigens, such as other infectious stimuli, can trigger IgA nephropathy disease activity. In agreement with this hypothesis, peripheral monocytes of patients with IgA nephropathy showed overexpression of TLR4, which, among other ligands, is activated by bacterial lipopolysaccharide.44 Activation of TLR4 by bacterial lipopolysaccharide also has been implicated in methylation of Cosmc, the chaperone of a major enzyme involved in IgA1 glycosylation, and this may contribute to the decreased galactosylation of IgA1 (discussed later).45 Although this latter observation would suggest a specific role of TLRs in IgA nephropathy, it is more likely that TLR activation in patients with IgA nephropathy Am J Kidney Dis. 2011;58(6):992-1004 Modifiers (genetic or environmental generic progression factors) Pathogenesis of IgA Nephropathy Increased occurrence of IgA1 with poor galactosylation in the circulation Manipulation of mucosal immune responses IgG response against poorly galactosylated IgA1, IgA-IgG, or IgA-IgA complex formation Immunosuppression Mesangial deposition of IgA1 and/or immune complexes Removal of glomerular IgA IgA receptors Blockade of Fc-α receptors or complement activation Complement activation Mesangial cell damage & activation of secondary pathways Growth factor antagonists, etc Glomerulosclerosis Tubulointerstitial fibrosis Antifibrotic agents Figure 2. Overview of the major steps in the pathogenesis of immunoglobulin A (IgA) nephropathy, in which each of the key steps (center) likely is affected by potent genetic or environmental modifiers. Potential therapeutic consequences are shown on the right. For further explanations, see text. represents yet another generic progression mechanism given that there is ample evidence that TLR activation represents a universal mode by which glomerular diseases are aggravated.46 Against the background of these potent modifiers, I discuss a 6-step model of the pathogenesis of idiopathic IgA nephropathy (Fig 2), realizing that, as always, some details may be oversimplified. This is particularly true in IgA nephropathy, which may not run in defined phases, rather with many mechanisms operating in parallel, as illustrated by heavily destroyed and normal-appearing nephrons occurring side by side simultaneously (Fig 1). A major problem in investigating the pathogenesis of IgA nephropathy is the absence of a good animal model,47 mainly because of major differences between the rodent and human IgA systems. IgA is mostly monomeric in human serum versus polymeric in mice. Mice lack an IgA hinge region and dominant hepatobiliary IgA clearance, 2 features seen in humans.48 Step 1: Increased Levels of Misglycated IgA1 in the Circulation The major difference between the 2 IgA subclasses, IgA1 and IgA2, is the presence of an 18–amino acid hinge region in IgA1. This difference explains why IgA1, but not IgA2, is a substrate for proteases of Streptococcus, Neisseria, and Haemophilus species.49 More than 85% of serum IgA is monomeric in humans. Di- and polymeric IgA are characterized by the presence of a joining chain (J chain). Secretory IgA on mucosal surfaces contains an additional protein, secretory component (Fig 3). IgA1 is heavily glycosylated, with carbohydrates accounting for ⬃6% of its weight. The IgA1 hinge region contains several sites of Olinked glycan attachments. The tight clustering and variability of sialic acid, galactose, and N-acetylgalac- Figure 3. Schematic illustration of the various forms of immunoglobulin A (IgA). Monomeric IgA consists of 2 heavy chains (with CH1-CH3 domains and the heavy chain V-domain), 2 light chains (with a light chain C- and V-domain), and a flexible heavily Oglycated hinge region. In dimeric IgA, 2 IgA monomers are coupled through 1 J chain. In secretory IgA, an additional molecule (secretory component) is bound to dimeric IgA. In addition, various high-molecular-weight forms of IgA exist. Abbreviation: MBL, mannose-binding lectin. Am J Kidney Dis. 2011;58(6):992-1004 995 Jürgen Floege Figure 4. Immunoglobulin A1 (IgA1) hinge region with its potential glycosylation sites. NAcetylgalactosamine (GalNAc) can be linked to galactose in the 1,3 position by core 1,3 galactosyltransferase. Sialyltransferases can couple sialic acid in the ␣2,3- or ␣2,6-position. In patients with IgA nephropathy (IgAN), the hinge region contains fewer galactose residues due to reduced core 1,3 galactosyltransferase activity and/or “premature” (and excessive) sialylation of GalNAc due to increased N-acetylgalactosamine–specific ␣2,6 sialyltransferase activity. The latter precludes the subsequent addition of a galactose residue to the glycan side chain. tosamine residues may significantly affect the physicochemical properties of IgA1.50 Elevated levels of circulating IgA1 and IgA1containing circulating complexes are observed in primary51 and recurrent IgA nephropathy after kidney transplantation.52 Increased levels of circulating IgAcontaining complexes have even been detected in urine.53 However, given that IgA serum levels can be higher in IgA myeloma, although IgA nephropathy is uncommon in such patients, the mere abundance of IgA may not drive its mesangial deposition. IgA1 overproduction in IgA nephropathy probably locates to the bone marrow rather than mucosal surfaces.54,55 In support of this, IgA nephropathy has been described as developing after allogeneic bone marrow transplant,56 and pre-existing IgA nephropathy has been observed to disappear after bone marrow transplant.57 Similarly, in a murine IgA nephropathy model, renal changes are attenuated by a bone marrow transplant from healthy control mice.58 Tonsillar polymeric IgA1 production in particular poorly galactosylated IgA (discussed later) also is increased,59,60 although IgA nephropathy can occur after tonsillectomy and the tonsils produce a trivial amount of IgA. Data about the effect of tonsillectomy on the further course of IgA nephropathy are inconsistent, with some reporting benefit61,62 and others failing to note an effect.63,64 IgA deposited in glomeruli in IgA nephropathy is mostly polymeric with light chains and more acidic than normal serum IgA.65 The former may contribute to a tendency of the deposited IgA to aggregate.66 However, correlation of levels of circulating polymeric IgA in patients with IgA nephropathy with 996 clinical features of the disease is inconsistent.67,68 Some patients with IgA nephropathy also have elevated circulating levels and mesangial deposits of secretory IgA,69,70 and these patients show more hematuria.71,72 The most noteworthy finding in IgA nephropathy is an elevation in circulating poorly galactosylated IgA1 O-glycoforms (Fig 4).73-76 The amount of poorly galactosylated IgA1 in glomeruli significantly exceeds that occurring in serum,76,77 in particular in patients with active IgA nephropathy78 and proliferative mesangial changes.79 In Henoch-Schönlein purpura, poorly galactysolated IgA is observed only in patients with renal involvement, in other words, IgA nephropathy.80 Experimentally, enzymatically cleaving oligosaccharides from the hinge region of normal IgA significantly enhanced IgA deposition in the mesangium.81 These observations strongly imply that the composition of IgA1 hinge-region glycans is a key contributor to mesangial deposition. The production of poorly galactosylated IgA1 in patients with IgA nephropathy results from a defect in B lymphocytes. Decreased activity of the key enzyme, core -1,3-galactosyltransferase (C13Gal-T), has been shown in both freshly isolated82 and immortalized83 B cells. The poor galactosylation of IgA1 is not shared by the other O-glycated immunoglobulin, IgD, suggesting that it may appear at a later stage in the development of B cells and may be secondary to aberrant immunoregulation.84 The TH2 cytokine interleukin 4 decreases messenger RNA and activity levels of C13Gal-T and its chaperone Cosmc.85 However, others have reported a heritable contribution to poor IgA galactosylation. Thus, patients with IgA nephropAm J Kidney Dis. 2011;58(6):992-1004 Pathogenesis of IgA Nephropathy athy and their first-degree relatives, but not patients’ spouses, show significantly higher IgA1 levels with poorer galactosylation than healthy controls.86-88 These observations in asymptomatic first-degree relatives again support the notion that potent modifiers must exist that determine who develops overt IgA nephropathy. In addition to C13Gal-T, the chaperone Cosmc is specifically required for O-galactosylation of the IgA1 hinge region. Cosmc gene mutations will result in secondary loss of C13Gal-T function with undergalactosylation of glycoproteins and autoimmunity.89 However, no evidence for Cosmc gene mutations has been detected in patients with sporadic or familial IgA nephropathy.45,90 What exactly triggers the overproduction of poorly galactosylated IgA1 in IgA nephropathy is unknown. No evidence for specific viral, bacterial, or alimentary antigens has been found in sera or mesangial deposits91-93; rather, all polymeric IgA responses to systemic immunization with common antigens are increased, possibly related to a switch to an immunoproteasome, whereas the response to mucosal immunization is impaired.94-96 The primary abnormality in IgA nephropathy could be compromised mucosal IgA responses, permitting enhanced antigen challenge to the marrow, in other words, defective oral tolerance.97 A disrupted tolerance model has been produced by transgenic overexpression of lymphotoxin-like inducible protein in mice. These animals develop T-cell–mediated intestinal inflammation and show elevated production of polymeric IgA, as well as some IgA nephropathy–like pathologic characteristics.98 Further evidence for an altered mucosal barrier function is the observation that approximately onethird of Swedish patients with IgA nephropathy had rectal mucosal sensitivity to gluten99 and ovalbumin,100 suggesting there is generalized reactivity with food antigens. A key finding in the context of this discussion is that poor galactosylation is particularly apparent in IgA1 produced against mucosal antigens (Helicobacter pylori) compared with systemic antigens (tetanus toxoid).101 Why levels of mucosal and systemic Oglycosylation of IgA1 are different has yet to be clarified. However, this observation suggests the fascinating possibility that in IgA nephropathy, there is no real defect in IgA1 O-glycosylation, but rather an increase in “mucosal-type” IgA1 in serum, possibly related to migration of mucosal B cells to bone marrow, where they produce their “correct” poorly galactosylated IgA.102 This is consistent with the observation that homing of lymphocytes between mucosal and systemic sites is altered in IgA nephropathy.103,104 Am J Kidney Dis. 2011;58(6):992-1004 Understanding the early events involved in this translocation of B cells may offer new therapeutic options. If there is a mucosal defect and hyperreactivity to antigens, topical rather than systemic immunosuppression may be beneficial in patients with IgA nephropathy. First evidence for this is emerging.105 Step 2: Generation of Antibodies Against Misglycated IgA1 Aberrantly glycated IgA1 may be nephritogenic by self-aggregation and binding to mesangial matrix. Defective glycosylation alone can be sufficient to inflict glomerular damage, as shown in murine studies in which the genetic lack of -1,4-galactosyltransferase I resulted in an IgA nephropathy–like kidney disease.106 Autoimmunity also may contribute to IgA nephropathy. Whereas an autoimmune response to mesangial cells in IgA nephropathy107 has not been confirmed, the misglycated IgA1 hinge region is aberrantly exposed108 and may induce a humoral immune response.109,110 Lymphocytes from patients with IgA nephropathy produce IgG that forms complexes with poorly galactosylated IgA1 in a glycan-dependent manner and triggers the formation of IgA1-IgG immune complexes.111 The presence of glycan-specific IgG antibodies can differentiate patients with IgA nephropathy from healthy and diseased controls with high specificity and sensitivity. This confirms prior data that poorly galactosylated IgA1 O-glycoforms occur mainly in circulating high-molecular-weight IgA complexes in IgA nephropathy.112 Currently, little is known about the kinetics of IgG antiglycan antibodies in IgA nephropathy. It is unclear whether the presence of mesangial IgG deposits in a fraction of patients with IgA nephropathy could reflect fluctuations of IgG autoantibody levels or identifies a particular subgroup of patients. Presently, the value of IgG antiglycan antibodies as a tool to monitor the disease and/or guide therapy in IgA nephropathy remains to be established. The development of IgG antiglycan autoantibodies may relate to prior infections with viruses (eg, EpsteinBarr virus) or Gram-negative bacteria (eg, Streptococcus) that express GalNAc-containing moieties, inducing an IgG response against the glycans. These IgG antibodies subsequently might cross-react with glycans on IgA1.112 This “molecular mimicry” also could explain the association of macroscopic hematuria with upper respiratory tract infections, in which serum levels of microbial-specific IgG increase postinfection and, in error, also bind to poorly galactosylated IgA1, resulting in the formation of IgA1-IgG complexes with mesangial cell activation and hematuria. 997 Jürgen Floege IgA-containing immune complexes in the circulation increase during clinical relapses of IgA nephropathy.68 An autoimmune component in the pathogenesis of IgA nephropathy currently provides the best rationale for immunosuppressive therapy. As reviewed elsewhere,113 there is now compelling evidence that corticosteroids are beneficial in proteinuric patients with IgA nephropathy at risk of progression. At least in Asian patients, there also is evidence for a benefit from mycophenolate mofetil, but to date, no benefit has been observed in white patients. However, 2 caveats have to be kept in mind. First, there is no evidence that immunosuppressive combination therapy is more beneficial than corticosteroids alone.113 This contrasts with most other autoimmune glomerular diseases, such as membranous nephropathy, in which corticosteroid monotherapy generally is less effective than immunosuppressive combinations. Second, the efficacy of any immunosuppressive regimen used after kidney transplant to prevent recurrence of IgA nephropathy has not yet been shown.7 Step 3: Mesangial Deposition of Misglycated IgA1 and/or Immune Complexes Mesangial IgA consists at least in part of di- and polymeric IgA.65,114 However, glomerular deposition of polymeric IgA alone cannot explain the pathogenesis of IgA nephropathy: glomerular amounts of polymeric IgA are not associated with disease severity and glomerular eluates of patients with IgA nephropathy do not differ from disease controls.115 Thus, in addition to size, molecular alterations also likely contribute to the IgA1 localization in glomeruli in IgA nephropathy. Binding of IgA1 to mesangial cells depends on anionic charge.116 Poorly galactosylated IgA1 may be sequestered in the mesangium in IgA nephropathy by self-aggregation, which seems to be related to insufficient conformational stiffness of the hinge peptide.74,117,118 In addition, galactose-depleted IgA1 has been reported to have the highest affinity for a number of extracellular matrix proteins.119 Whether poor galactosylation also may impair IgA1 clearance by impeding IgA1 interactions with hepatic IgA receptors120 is uncertain because IgA1 in general shows little hepatic clearance.121 In addition to aggregated IgA1, mesangial deposition likely derives from circulating IgA1-containing immune complexes. Poorly galactosylated IgA1 has been detected in complexes with IgG.122 Both mesangial deposition of circulating immune complexes and their in situ formation are compatible with observations that mesangial IgA deposits are cleared when an IgA nephropathy kidney is inadvertently transplanted 998 Box 1. Characteristics of IgA Receptors ● ● ● ● ● Fc␣R1 (CD89) 〫 Binds IgA1 and IgA2 〫 Association with FcR␥ chain determines inhibitory or activating signals Fc␣/R 〫 Binds IgA and IgM Polymeric immunoglobulin receptor 〫 Mediates immunoglobulin transport across epithelial barriers Asialoglycoprotein receptor 〫 Alternative receptor for IgA Transferrin receptor (CD71) 〫 Alternative receptor for IgA Abbreviation: IgA, immunoglobulin A. into a patient without IgA nephropathy.123 When formed, IgA-containing immune complexes, like poorly galactosylated IgA1 alone, show a high affinity for mesangial matrix proteins.124 Finally, formation of IgA1-IgG complexes may alter serum IgA1 levels by decreasing the rate at which it is eliminated and catabolized by the liver.122 An interesting approach at the stage of mesangial IgA deposition might be its therapeutic removal. As mentioned, IgA1 is susceptible to degradation by bacterial proteases. In a passive mouse model of IgA nephropathy, treatment with Haemophilus influenzae– derived protease removes both the antigen and antibody components of glomerular IgA immune complexes.125 Although this approach works in an acute passively induced model, its relevance to the slow and chronic human IgA nephropathy and its potential antigenicity render predictions on the clinical usefulness difficult.126 Step 4: Binding of Mesangial IgA Receptors and/or Activation of Complement Two key events after the mesangial deposition of IgA1 and/or IgA1-containing immune complexes include binding of IgA to mesangial receptors and complement activation. Five types of IgA receptors exist in humans (Box 1): Fc␣R1 (CD89), polymeric immunoglobulin receptor, Fc␣/R, asialoglycoprotein receptor, and transferrin receptor (CD71).127 Patients with IgA nephropathy show overexpression of CD71 in the mesangium, which colocalizes with IgA deposits, and polymeric and misglycated IgA1 were identified as a major inducers of CD71 in mesangial cells.128-131 Early data for human mesangial cells also suggested that polymeric IgA and/or IgA immune complexes activate the cells through Fc␣R132 or the asialoglycoprotein receptor.133 Several other studies subsequently failed to detect Fc␣R1, asialoglycoprotein receptor, or polymeric immunoglobulin receptor on human mesangial Am J Kidney Dis. 2011;58(6):992-1004 Pathogenesis of IgA Nephropathy cells.134-138 However, on monocytes of patients with IgA nephropathy, CD89 is downregulated, in particular by polymeric IgA1,139 and there is reduced binding of monomeric IgA.140 Both may contribute to impaired degradation of IgA1, in particular polymeric IgA1, and IgA1 immune complexes. Transgenic mice expressing human CD89 on macrophage/monocytes shed soluble CD89 into the circulation and develop an IgA nephropathy–like renal pathologic state.141 However, the relevance of this pathway for human IgA nephropathy has been questioned.142,143 Patients with IgA nephropathy with progressive kidney disease show lower soluble CD89 levels than stable patients.144 Although to date, these insights have not yet been translated into clinical therapy, first approaches are emerging. For example, monovalent targeting of CD89 by anti-Fc␣RI Fab stimulates potent inhibitory signaling through the associated FcR␥ chain and can experimentally decrease renal inflammation.145,146 Polymeric IgA and IgA-containing immune complexes activate complement through the alternative and lectin-binding pathways,72,147 and using very sensitive methods, systemic complement activation can be detected in patients with IgA nephropathy.148 Mesangial IgA deposits frequently are associated with complement C3, C5, and properdin.149 Mesangial secretory IgA deposits are associated with the detection of mannose-binding lectin (MBL) and C4d.69 Glomerular expression of the components of the MBL pathway is particularly notable in younger patients and those with more severe disease.150-152 Activation of C4 with mesangial C4d deposits also identifies patients with IgA nephropathy with a worse prognosis.153 Activation of the MBL pathway also can be detected in Henoch-Schönlein–related nephritis.154 These data suggest that inhibitors of complement activation may have a role in the treatment of highrisk patients with IgA nephropathy. Step 5: Mesangial Cell Damage and Activation of Secondary Pathways Binding of polymeric IgA1 or IgA1-containing immune complexes to mesangial cells has many biological consequences, for example, increased production of cytokines,72,130 macrophage migration-inhibitory factor,155 growth factors,130,156 inducible nitric oxide synthase,156 and renin,157 as well as changes in proliferation and apoptosis.158,159 In kidney biopsy specimens, the extent of IgA deposition in glomeruli correlates with that of neutrophil infiltration and mesangial hypercellularity. Consistent with this, injection of misglycated IgA1 into rats leads to glomerular deposits and neutrophil infiltration.81 Finally, inducAm J Kidney Dis. 2011;58(6):992-1004 tion of oxidative stress in IgA nephropathy predicts the prognosis.160 Glomerular IgA also can induce a number of paracrine effector mechanisms. For example, mesangial cells activated by IgA release tumor necrosis factor ␣, transforming growth factor , and platelet-activating factor, all of which can damage podocytes and/or tubular cells.161-163 Consistent with this, podocyte loss correlates with disease severity and outcome in IgA nephropathy164,165 and both focal segmental glomerulosclerosis and tubulointerstitial damage predict outcome in IgA nephropathy.166-169 Whereas most of these factors lend themselves to therapeutic intervention, few intervention studies in models of IgA nephropathy or mesangioproliferative glomerulonephritis models are available. The single best-established factor responsible for driving proliferation of mesangial cells is platelet-derived growth factor (PDGF). Mice lacking PDGF-B fail to develop a mesangium, and antagonism of PDGF-B or -D is a highly effective approach to inhibit pathologic mesangial cell proliferation matrix accumulation in vivo as well as secondary focal segmental glomerulosclerosis and tubulointerstitial damage.170 Elevated serum PDGF-DD levels also may serve as a biomarker of IgA nephropathy.171 As reviewed elsewhere,171 the rationale to test anti-PDGF therapy in IgA nephropathy is now extensive. Step 6: Activation of Nonspecific Profibrotic Pathomechanisms Space limitations prevent a detailed discussion of potential therapeutic targets in glomerular and tubulointerstitial fibrosis. We and others recently have reviewed this topic in general172-175 and with particular focus on PDGF.176 In particular, factors such as PDGF, which operate in both the active mesangioproliferative processes and secondary tubulointerstitial damage, lend themselves to therapeutic trials because as mentioned, in IgA nephropathy, both active glomerular inflammation and more degenerative tubulointerstitial damage may coexist. SUMMARY Although our therapeutic armamentarium at present is still largely limited to optimal supportive care and immunosuppression in some instances, these new insights into the pathogenesis can be expected to yield novel, perhaps individualized, therapeutic options in patients with primary or recurrent IgA nephropathy. ACKNOWLEDGEMENTS Prof H.J. Gröne, DKFZ Heidelberg, Germany, kindly provided Figure 1. 999 Jürgen Floege I apologize to all authors whose important work I could not cite due to space restrictions. Support: This work was funded by grants from the Deutsche Forschungsgemeinschaft (DFG; SFB 542/C7 and SFB TRR57). Financial Disclosure: The author declares that he has no relevant financial interests. REFERENCES 1. Waldherr R, Rambausek M, Duncker WD, Ritz E. Frequency of mesangial IgA deposits in a non-selected autopsy series. Nephrol Dial Transplant. 1989;4(11):943-946. 2. Suzuki K, Honda K, Tanabe K, Toma H, Nihei H, Yamaguchi Y. Incidence of latent mesangial IgA deposition in renal allograft donors in Japan. Kidney Int. 2003;63(6):2286-2294. 3. Szeto CC, Lai FM, To KF, et al. The natural history of immunoglobulin A nephropathy among patients with hematuria and minimal proteinuria. Am J Med. 2001;110(6):434-437. 4. Shima Y, Nakanishi K, Kamei K, et al. Disappearance of glomerular IgA deposits in childhood IgA nephropathy showing diffuse mesangial proliferation after 2 years of combination/prednisolone therapy. Nephrol Dial Transplant. 2011;26(1):163-169. 5. Nieuwhof C, Doorenbos C, Grave W, et al. A prospective study of the natural history of idiopathic non-proteinuric hematuria. Kidney Int. 1996;49(1):222-225. 6. Hotta O, Furuta T, Chiba S, Tomioka S, Taguma Y. Regression of IgA nephropathy: a repeat biopsy study. Am J Kidney Dis. 2002;39(3):493-502. 7. Floege J. Recurrent IgA nephropathy after renal transplantation. Semin Nephrol. 2004;24(3):287-291. 8. Berthoux F, Mohey H, Laurent B, Mariat C, Afiani A, Thibaudin L. Predicting the risk of dialysis or death in IgA nephropathy. J Am Soc Nephrol. 2011;22(4):752-761. 9. Reich HN, Troyanov S, Scholey JW, Cattran DC. Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol. 2007;18(12):3177-3183. 10. Nagy J, Kovacs T, Wittmann I. Renal protection in IgA nephropathy requires strict blood pressure control. Nephrol Dial Transplant. 2005;20(8):1533-1539. 11. Bonnet F, Deprele C, Sassolas A, et al. Excessive body weight as a new independent risk factor for clinical and pathological progression in primary IgA nephritis. Am J Kidney Dis. 2001;37(4):720-727. 12. Navaneethan SD, Yehnert H, Moustarah F, Schreiber MJ, Schauer PR, Beddhu S. Weight loss interventions in chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2009;4(10):1565-1574. 13. Hunley TE, Julian BA, Phillips JA III, et al. Angiotensin converting enzyme gene polymorphism: potential silencer motif and impact on progression in IgA nephropathy. Kidney Int. 1996; 49(2):571-577. 14. Yoshida H, Mitarai T, Kawamura T, et al. Role of the deletion of polymorphism of the angiotensin converting enzyme gene in the progression and therapeutic responsiveness of IgA nephropathy. J Clin Invest. 1995;96(5):2162-2169. 15. Bjorck S, Blohme G, Sylven C, Mulec H. Deletion insertion polymorphism of the angiotensin converting enzyme gene and progression of diabetic nephropathy. Nephrol Dial Transplant. 1997;12(suppl 2):67-70. 16. Amoroso A, Danek G, Vatta S, et al. Polymorphisms in angiotensin-converting enzyme gene and severity of renal disease in Henoch-Schoenlein patients. Italian Group of Renal Immunopathology. Nephrol Dial Transplant. 1998;13(12):3184-3188. 17. Beige J, Offermann G, Distler A, Sharma AM. Angiotensinconverting-enzyme insertion/deletion genotype and long-term renal allograft survival. Nephrol Dial Transplant. 1998;13(3):735738. 1000 18. Schmidt S, Stier E, Hartung R, et al. No association of converting enzyme insertion/deletion polymorphism with immunoglobulin A glomerulonephritis. Am J Kidney Dis. 1995;26(5):727731. 19. Li YJ, Du Y, Li CX, et al. Family-based association study showing that immunoglobulin A nephropathy is associated with the polymorphisms 2093C and 2180T in the 3= untranslated region of the megsin gene. J Am Soc Nephrol. 2004;15(7):1739-1743. 20. Xia Y, Li Y, Du Y, et al. Association of MEGSIN 2093C2180T haplotype at the 3= untranslated region with disease severity and progression of IgA nephropathy. Nephrol Dial Transplant. 2006;21(6):1570-1574. 21. Courtney AE, McNamee PT, Heggarty S, Middleton D, Maxwell AP. Association of functional haem oxygenase-1 gene promoter polymorphism with polycystic kidney disease and IgA nephropathy. Nephrol Dial Transplant. 2008;23(2):608-611. 22. Tuglular S, Berthoux P, Berthoux F. Polymorphisms of the tumour necrosis factor alpha gene at position ⫺308 and TNFd microsatellite in primary IgA nephropathy. Nephrol Dial Transplant. 2003;18(4):724-731. 23. Vuong MT, Lundberg S, Gunnarsson I, et al. Genetic variation in the transforming growth factor-beta1 gene is associated with susceptibility to IgA nephropathy. Nephrol Dial Transplant. 2009;24(10):3061-3067. 24. Aupetit C, Drouet M, Pinaud E, et al. Alleles of the alpha1 immunoglobulin gene 3= enhancer control evolution of IgA nephropathy toward renal failure. Kidney Int. 2000;58(3):966-971. 25. Masutani K, Miyake K, Nakashima H, et al. Impact of interferon-gamma and interleukin-4 gene polymorphisms on development and progression of IgA nephropathy in Japanese patients. Am J Kidney Dis. 2003;41(2):371-379. 26. Matsunaga A, Numakura C, Kawakami T, et al. Association of the uteroglobin gene polymorphism with IgA nephropathy. Am J Kidney Dis. 2002;39(1):36-41. 27. Frimat L, Kessler M. Controversies concerning the importance of genetic polymorphism in IgA nephropathy. Nephrol Dial Transplant. 2002;17(4):542-545. 28. Panzer U, Schneider A, Steinmetz OM, et al. The chemokine receptor 5 delta32 mutation is associated with increased renal survival in patients with IgA nephropathy. Kidney Int. 2005;67(1): 75-81. 29. Berthoux FC, Berthoux P, Mariat C, Thibaudin L, Afiani A, Linossier MT. CC-chemokine receptor five gene polymorphism in primary IgA nephropathy: the 32 bp deletion allele is associated with late progression to end-stage renal failure with dialysis. Kidney Int. 2006;69(3):565-572. 30. Fennessy M, Hitman GA, Moore RH, et al. HLA-DQ gene polymorphism in primary IgA nephropathy in three European populations. Kidney Int. 1996;49(2):477-480. 31. Feehally J, Farrall M, Boland A, et al. HLA has strongest association with IgA nephropathy in genome-wide analysis. J Am Soc Nephrol. 2010;21(10):1791-1797. 32. Gharavi A, Kiryluk K, Choi M, et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet. 2011;43(4):321-327. 33. Gharavi AG, Yan Y, Scolari F, et al. IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22-23. Nat Genet. 2000;26(3):354-357. 34. Bisceglia L, Cerullo G, Forabosco P, et al. Genetic heterogeneity in Italian families with IgA nephropathy: suggestive linkage for two novel IgA nephropathy loci. Am J Hum Genet. 2006;79(6):1130-1134. 35. Paterson AD, Liu XQ, Wang K, et al. Genome-wide linkage scan of a large family with IgA nephropathy localizes a novel susceptibility locus to chromosome 2q36. J Am Soc Nephrol. 2007;18(8):2408-2415. Am J Kidney Dis. 2011;58(6):992-1004 Pathogenesis of IgA Nephropathy 36. Suzuki H, Suzuki Y, Yamanaka T, et al. Genome-wide scan in a novel IgA nephropathy model identifies a susceptibility locus on murine chromosome 10, in a region syntenic to human IGAN1 on chromosome 6q22-23. J Am Soc Nephrol. 2005;16(5):12891299. 37. Liu XQ, Paterson AD, He N, et al. IL5RA and TNFRSF6B gene variants are associated with sporadic IgA nephropathy. J Am Soc Nephrol. 2008;19(5):1025-1033. 38. Johnson RJ, Hurtado A, Merszei J, Rodriguez-Iturbe B, Feng L. Hypothesis: dysregulation of immunologic balance resulting from hygiene and socioeconomic factors may influence the epidemiology and cause of glomerulonephritis worldwide. Am J Kidney Dis. 2003;42(3):575-581. 39. Janssen U, Bahlmann F, Kohl J, Zwirner J, Haubitz M, Floege J. Activation of the acute phase response and complement C3 in patients with IgA nephropathy. Am J Kidney Dis. 2000;35(1): 21-28. 40. Han SH, Kang EW, Kie JH, et al. Spontaneous remission of IgA nephropathy associated with resolution of hepatitis A. Am J Kidney Dis. 2010;56(6):1163-1167. 41. Kawasaki Y, Mitsuaki H, Isome M, Nozawa R, Suzuki H. Renal effects of Coxsackie B4 virus in hyper-IgA mice. J Am Soc Nephrol. 2006;17(10):2760-2769. 42. Suzuki H, Suzuki Y, Narita I, et al. Toll-like receptor 9 affects severity of IgA nephropathy. J Am Soc Nephrol. 2008;19(12): 2384-2395. 43. Koyama A, Sharmin S, Sakurai H, et al. Staphylococcus aureus cell envelope antigen is a new candidate for the induction of IgA nephropathy. Kidney Int. 2004;66(1):121-132. 44. Coppo R, Camilla R, Amore A, et al. Toll-like receptor 4 expression is increased in circulating mononuclear cells of patients with immunoglobulin A nephropathy. Clin Exp Immunol. 2010; 159(1):73-81. 45. Qin W, Zhong X, Fan JM, Zhang YJ, Liu XR, Ma XY. External suppression causes the low expression of the Cosmc gene in IgA nephropathy. Nephrol Dial Transplant. 2008;23(5):16081614. 46. Anders HJ, Schlondorff DO. Innate immune receptors and autophagy: implications for autoimmune kidney injury. Kidney Int. 2010;78(1):29-37. 47. Eitner F, Boor P, Floege J. Models of IgA nephropathy. Drug Disc Today. 2010;7:21-26. 48. Kerr MA. The structure and function of human IgA. Biochem J. 1990;271(2):285-296. 49. Woof JM, Kerr MA. The function of immunoglobulin A in immunity. J Pathol. 2006;208(2):270-282. 50. Barratt J, Smith AC, Molyneux K, Feehally J. Immunopathogenesis of IgAN. Semin Immunopathol. 2007;29(4):427-443. 51. Montenegro V, Monteiro RC. Elevation of serum IgA in spondyloarthropathies and IgA nephropathy and its pathogenic role. Curr Opin Rheumatol. 1999;11(4):265-272. 52. Coppo R, Amore A, Cirina P, et al. IgA serology in recurrent and non-recurrent IgA nephropathy after renal transplantation. Nephrol Dial Transplant. 1995;10(12):2310-2315. 53. Matousovic K, Novak J, Yanagihara T, et al. IgA-containing immune complexes in the urine of IgA nephropathy patients. Nephrol Dial Transplant. 2006;21(9):2478-2484. 54. Harper SJ, Allen AC, Pringle JH, Feehally J. Increased dimeric IgA producing B cells in the bone marrow in IgA nephropathy determined by in situ hybridisation for J chain mRNA. J Clin Pathol. 1996;49(1):38-42. 55. Buck KS, Smith AC, Molyneux K, El-Barbary H, Feehally J, Barratt J. B-cell O-galactosyltransferase activity, and expression of O-glycosylation genes in bone marrow in IgA nephropathy. Kidney Int. 2008;73(10):1128-1136. Am J Kidney Dis. 2011;58(6):992-1004 56. Hu SL, Colvin GA, Rifai A, et al. Glomerulonephritis after hematopoietic cell transplantation: IgA nephropathy with increased excretion of galactose-deficient IgA1. Nephrol Dial Transplant. 2010;25(5):1708-1713. 57. Iwata Y, Wada T, Uchiyama A, et al. Remission of IgA nephropathy after allogeneic peripheral blood stem cell transplantation followed by immunosuppression for acute lymphocytic leukemia. Intern Med. 2006;45(22):1291-1295. 58. Imasawa T, Nagasawa R, Utsunomiya Y, et al. Bone marrow transplantation attenuates murine IgA nephropathy: role of a stem cell disorder. Kidney Int. 1999;56(5):1809-1817. 59. Itoh A, Iwase H, Takatani T, et al. Tonsillar IgA1 as a possible source of hypoglycosylated IgA1 in the serum of IgA nephropathy patients. Nephrol Dial Transplant. 2003;18(6):11081114. 60. Horie A, Hiki Y, Odani H, et al. IgA1 molecules produced by tonsillar lymphocytes are under-O-glycosylated in IgA nephropathy. Am J Kidney Dis. 2003;42(3):486-496. 61. Xie Y, Nishi S, Ueno M, et al. The efficacy of tonsillectomy on long-term renal survival in patients with IgA nephropathy. Kidney Int. 2003;63(5):1861-1867. 62. Chen Y, Tang Z, Wang Q, et al. Long-term efficacy of tonsillectomy in Chinese patients with IgA nephropathy. Am J Nephrol. 2007;27(2):170-175. 63. Piccoli A, Codognotto M, Tabbi MG, Favaro E, Rossi B. Influence of tonsillectomy on the progression of mesangioproliferative glomerulonephritis. Nephrol Dial Transplant. 2010;25(8):25832589. 64. Rasche FM, Schwarz A, Keller F. Tonsillectomy does not prevent a progressive course in IgA nephropathy. Clin Nephrol. 1999;51(3):147-152. 65. Monteiro RC, Halbwachs-Mecarelli L, Roque-Barreira MC, Noel LH, Berger J, Lesavre P. Charge and size of mesangial IgA in IgA nephropathy. Kidney Int. 1985;28(4):666-671. 66. Almogren A, Kerr MA. Irreversible aggregation of the Fc fragment derived from polymeric but not monomeric serum IgA1— implications in IgA-mediated disease. Mol Immunol. 2008;45(1): 87-94. 67. van der Boog PJ, van Kooten C, van Seggelen A, et al. An increased polymeric IgA level is not a prognostic marker for progressive IgA nephropathy. Nephrol Dial Transplant. 2004; 19(10):2487-2493. 68. Feehally J, Beattie TJ, Brenchley PE, Coupes BM, Mallick NP, Postlethwaite RJ. Sequential study of the IgA system in relapsing IgA nephropathy. Kidney Int. 1986;30(6):924-931. 69. Oortwijn BD, Rastaldi MP, Roos A, Mattinzoli D, Daha MR, van Kooten C. Demonstration of secretory IgA in kidneys of patients with IgA nephropathy. Nephrol Dial Transplant. 2007; 22(11):3191-3195. 70. Zhang JJ, Xu LX, Liu G, Zhao MH, Wang HY. The level of serum secretory IgA of patients with IgA nephropathy is elevated and associated with pathological phenotypes. Nephrol Dial Transplant. 2008;23(1):207-212. 71. Oortwijn BD, van der Boog PJ, Roos A, et al. A pathogenic role for secretory IgA in IgA nephropathy. Kidney Int. 2006;69(7): 1131-1138. 72. Oortwijn BD, Roos A, Royle L, et al. Differential glycosylation of polymeric and monomeric IgA: a possible role in glomerular inflammation in IgA nephropathy. J Am Soc Nephrol. 2006; 17(12):3529-3539. 73. Allen AC, Harper SJ, Feehally J. Galactosylation of N- and O-linked carbohydrate moieties of IgA1 and IgG in IgA nephropathy. Clin Exp Immunol. 1995;100(3):470-474. 74. Hiki Y, Kokubo T, Iwase H, et al. Underglycosylation of IgA1 hinge plays a certain role for its glomerular deposition in IgA nephropathy. J Am Soc Nephrol. 1999;10(4):760-769. 1001 Jürgen Floege 75. Renfrow MB, Cooper HJ, Tomana M, et al. Determination of aberrant O-glycosylation in the IgA1 hinge region by electron capture dissociation fourier transform-ion cyclotron resonance mass spectrometry. J Biol Chem. 2005;280(19):19136-19145. 76. Hiki Y, Odani H, Takahashi M, et al. Mass spectrometry proves under-O-glycosylation of glomerular IgA1 in IgA nephropathy. Kidney Int. 2001;59(3):1077-1085. 77. Allen AC, Bailey EM, Brenchley PE, Buck KS, Barratt J, Feehally J. Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: observations in three patients. Kidney Int. 2001; 60(3):969-973. 78. Xu LX, Yan Y, Zhang JJ, Zhang Y, Zhao MH. The glycans deficiencies of macromolecular IgA1 is a contributory factor of variable pathological phenotypes of IgA nephropathy. Clin Exp Immunol. 2005;142(3):569-575. 79. Xu LX, Zhao MH. Aberrantly glycosylated serum IgA1 are closely associated with pathologic phenotypes of IgA nephropathy. Kidney Int. 2005;68(1):167-172. 80. Allen AC, Willis FR, Beattie TJ, Feehally J. Abnormal IgA glycosylation in Henoch-Schonlein purpura restricted to patients with clinical nephritis. Nephrol Dial Transplant. 1998;13(4):930934. 81. Sano T, Hiki Y, Kokubo T, Iwase H, Shigematsu H, Kobayashi Y. Enzymatically deglycosylated human IgA1 molecules accumulate and induce inflammatory cell reaction in rat glomeruli. Nephrol Dial Transplant. 2002;17(1):50-56. 82. Allen AC, Topham PS, Harper SJ, Feehally J. Leucocyte beta 1,3 galactosyltransferase activity in IgA nephropathy. Nephrol Dial Transplant. 1997;12(4):701-706. 83. Suzuki H, Moldoveanu Z, Hall S, et al. IgA1-secreting cell lines from patients with IgA nephropathy produce aberrantly glycosylated IgA1. J Clin Invest. 2008;118(2):629-639. 84. Smith AC, de Wolff JF, Molyneux K, Feehally J, Barratt J. O-Glycosylation of serum IgD in IgA nephropathy. J Am Soc Nephrol. 2006;17(4):1192-1199. 85. Yamada K, Kobayashi N, Ikeda T, et al. Down-regulation of core 1 beta1,3-galactosyltransferase and Cosmc by Th2 cytokine alters O-glycosylation of IgA1. Nephrol Dial Transplant. 2010; 25(12):3890-3897. 86. Lin X, Ding J, Zhu L, et al. Aberrant galactosylation of IgA1 is involved in the genetic susceptibility of Chinese patients with IgA nephropathy. Nephrol Dial Transplant. 2009;24(11):33723375. 87. Gharavi AG, Moldoveanu Z, Wyatt RJ, et al. Aberrant IgA1 glycosylation is inherited in familial and sporadic IgA nephropathy. J Am Soc Nephrol. 2008;19(5):1008-1014. 88. Hastings MC, Moldoveanu Z, Julian BA, et al. Galactosedeficient IgA1 in African Americans with IgA nephropathy: serum levels and heritability. Clin J Am Soc Nephrol. 2010;5(11):20692074. 89. Ju T, Cummings RD. Protein glycosylation: chaperone mutation in Tn syndrome. Nature. 2005;437(7063):1252. 90. Malycha F, Eggermann T, Hristov M, et al. No evidence for a role of cosmc-chaperone mutations in European IgA nephropathy patients. Nephrol Dial Transplant. 2009;24(1):321-324. 91. Floege J, Feehally J. IgA nephropathy: recent developments. J Am Soc Nephrol. 2000;11(12):2395-2403. 92. Floege J, Burg M, Al Masri AN, Grone HJ, von Wussow P. Expression of interferon-inducible Mx-proteins in patients with IgA nephropathy or Henoch-Schonlein purpura. Am J Kidney Dis. 1999;33(3):434-440. 93. van den Wall Bake AW, Bruijn JA, Accavitti MA, et al. Shared idiotypes in mesangial deposits in IgA nephropathy are not disease-specific. Kidney Int. 1993;44(1):65-74. 94. Roodnat JI, de Fijter JW, van Kooten C, Daha MR, van Es LA. Decreased IgA1 response after primary oral immunization 1002 with live typhoid vaccine in primary IgA nephropathy. Nephrol Dial Transplant. 1999;14(2):353-359. 95. de Fijter JW, Eijgenraam JW, Braam CA, et al. Deficient IgA1 immune response to nasal cholera toxin subunit B in primary IgA nephropathy. Kidney Int. 1996;50(3):952-961. 96. Coppo R, Camilla R, Alfarano A, et al. Upregulation of the immunoproteasome in peripheral blood mononuclear cells of patients with IgA nephropathy. Kidney Int. 2009;75(5):536-541. 97. Gesualdo L, Lamm ME, Emancipator SN. Defective oral tolerance promotes nephritogenesis in experimental IgA nephropathy induced by oral immunization. J Immunol. 1990;145(11):36843691. 98. Wang J, Anders RA, Wu Q, et al. Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy. J Clin Invest. 2004;113(6):826-835. 99. Smerud HK, Fellstrom B, Hallgren R, Osagie S, Venge P, Kristjansson G. Gluten sensitivity in patients with IgA nephropathy. Nephrol Dial Transplant. 2009;24(8):2476-2481. 100. Kloster Smerud H, Fellstrom B, Hallgren R, Osagie S, Venge P, Kristjansson G. Gastrointestinal sensitivity to soy and milk proteins in patients with IgA nephropathy. Clin Nephrol. 2010;74(5):364-371. 101. Smith AC, Molyneux K, Feehally J, Barratt J. OGlycosylation of serum IgA1 antibodies against mucosal and systemic antigens in IgA nephropathy. J Am Soc Nephrol. 2006; 17(12):3520-3528. 102. Barratt J, Eitner F, Feehally J, Floege J. Immune complex formation in IgA nephropathy: a case of the ‘right’ antibodies in the ’wrong’ place at the ‘wrong’ time? Nephrol Dial Transplant. 2009;24(12):3620-3623. 103. Batra A, Smith AC, Feehally J, Barratt J. T-Cell homing receptor expression in IgA nephropathy. Nephrol Dial Transplant. 2007;22(9):2540-2548. 104. Buren M, Yamashita M, Suzuki Y, Tomino Y, Emancipator SN. Altered expression of lymphocyte homing chemokines in the pathogenesis of IgA nephropathy. Contrib Nephrol. 2007;157:50-55. 105. Smerud HK, Barany P, Lindstrom K, et al. New treatment of IgA nephropathy: enteric budesonide targeted to the ileocecal region ameliorates proteinuria [published online ahead of print March 4, 2011]. Nephrol Dial Transplant. doi:10.1093/ndt/gfr052. 106. Alexander WS, Viney EM, Zhang JG, et al. Thrombocytopenia and kidney disease in mice with a mutation in the C1galt1 gene. Proc Natl Acad Sci U S A. 2006;103(44):16442-16447. 107. O’Donoghue DJ, Darvill A, Ballardie FW. Mesangial cell autoantigens in immunoglobulin A nephropathy and HenochSchonlein purpura. J Clin Invest. 1991;88(5):1522-1530. 108. Kokubo T, Hiki Y, Iwase H, et al. Exposed peptide core of IgA1 hinge region in IgA nephropathy. Nephrol Dial Transplant. 1999;14(1):81-85. 109. Kokubo T, Hashizume K, Iwase H, et al. Humoral immunity against the proline-rich peptide epitope of the IgA1 hinge region in IgA nephropathy. Nephrol Dial Transplant. 2000;15(1): 28-33. 110. Tomana M, Novak J, Julian BA, Matousovic K, Konecny K, Mestecky J. Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies. J Clin Invest. 1999;104(1):73-81. 111. Suzuki H, Fan R, Zhang Z, et al. Aberrantly glycosylated IgA1 in IgA nephropathy patients is recognized by IgG antibodies with restricted heterogeneity. J Clin Invest. 2009;119(6):16681677. 112. Novak J, Julian BA, Tomana M, Mestecky J. IgA glycosylation and IgA immune complexes in the pathogenesis of IgA nephropathy. Semin Nephrol. 2008;28(1):78-87. Am J Kidney Dis. 2011;58(6):992-1004 Pathogenesis of IgA Nephropathy 113. Floege J, Eitner F. Current therapy for IgA nephropathy J Am Soc Nephrol. 2011. In press. 114. Tomino Y, Sakai H, Miura M, Endoh M, Nomoto Y. Detection of polymeric IgA in glomeruli from patients with IgA nephropathy. Clin Exp Immunol. 1982;49(2):419-425. 115. van der Boog PJ, van Kooten C, de Fijter JW, Daha MR. Role of macromolecular IgA in IgA nephropathy. Kidney Int. 2005;67(3):813-821. 116. Leung JC, Tang SC, Lam MF, Chan TM, Lai KN. Chargedependent binding of polymeric IgA1 to human mesangial cells in IgA nephropathy. Kidney Int. 2001;59(1):277-285. 117. Hiki Y, Iwase H, Kokubo T, et al. Association of asialogalactosyl beta 1-3N-acetylgalactosamine on the hinge with a conformational instability of Jacalin-reactive immunoglobulin A1 in immunoglobulin A nephropathy. J Am Soc Nephrol. 1996;7(6): 955-960. 118. Kokubo T, Hiki Y, Iwase H, et al. Evidence for involvement of IgA1 hinge glycopeptide in the IgA1-IgA1 interaction in IgA nephropathy. J Am Soc Nephrol. 1997;8(6):915-919. 119. Kokubo T, Hiki Y, Iwase H, et al. Protective role of IgA1 glycans against IgA1 self-aggregation and adhesion to extracellular matrix proteins. J Am Soc Nephrol. 1998;9(11):2048-2054. 120. Leung JC, Tang SC, Chan DT, Lui SL, Lai KN. Increased sialylation of polymeric lambda-IgA1 in patients with IgA nephropathy. J Clin Lab Anal. 2002;16(1):11-19. 121. Rifai A, Fadden K, Morrison SL, Chintalacharuvu KR. The N-glycans determine the differential blood clearance and hepatic uptake of human immunoglobulin (Ig)A1 and IgA2 isotypes. J Exp Med. 2000;191(12):2171-2182. 122. Tomana M, Matousovic K, Julian BA, Radl J, Konecny K, Mestecky J. Galactose-deficient IgA1 in sera of IgA nephropathy patients is present in complexes with IgG. Kidney Int. 1997;52(2): 509-516. 123. Silva FG, Chander P, Pirani CL, Hardy MA. Disappearance of glomerular mesangial IgA deposits after renal allograft transplantation. Transplantation. 1982;33(2):241-246. 124. Emancipator SN, Rao CS, Amore A, Coppo R, Nedrud JG. Macromolecular properties that promote mesangial binding and mesangiopathic nephritis. J Am Soc Nephrol. 1992;2(10)(suppl 2): S149-S158. 125. Lamm ME, Emancipator SN, Robinson JK, et al. Microbial IgA protease removes IgA immune complexes from mouse glomeruli in vivo: potential therapy for IgA nephropathy. Am J Pathol. 2008;172(1):31-36. 126. Eitner F, Floege J. Bacterial protease for the treatment of IgA nephropathy. Nephrol Dial Transplant. 2008;23(7):21732175. 127. Monteiro RC, Van De Winkel JG. IgA Fc receptors. Annu Rev Immunol. 2003;21:177-204. 128. Moura IC, Centelles MN, Arcos-Fajardo M, et al. Identification of the transferrin receptor as a novel immunoglobulin (Ig)A1 receptor and its enhanced expression on mesangial cells in IgA nephropathy. J Exp Med. 2001;194(4):417-425. 129. Haddad E, Moura IC, Arcos-Fajardo M, et al. Enhanced expression of the CD71 mesangial IgA1 receptor in Berger disease and Henoch-Schonlein nephritis: association between CD71 expression and IgA deposits. J Am Soc Nephrol. 2003;14(2):327-337. 130. Moura IC, Arcos-Fajardo M, Gdoura A, et al. Engagement of transferrin receptor by polymeric IgA1: evidence for a positive feedback loop involving increased receptor expression and mesangial cell proliferation in IgA nephropathy. J Am Soc Nephrol. 2005;16(9):2667-2676. 131. Moura IC, Arcos-Fajardo M, Sadaka C, et al. Glycosylation and size of IgA1 are essential for interaction with mesangial transferrin receptor in IgA nephropathy. J Am Soc Nephrol. 2004; 15(3):622-634. Am J Kidney Dis. 2011;58(6):992-1004 132. Suzuki Y, Ra C, Saito K, et al. Expression and physical association of Fc alpha receptor and Fc receptor gamma chain in human mesangial cells. Nephrol Dial Transplant. 1999;14(5):11171123. 133. Gomez-Guerrero C, Duque N, Egido J. Mesangial cells possess an asialoglycoprotein receptor with affinity for human immunoglobulin A. J Am Soc Nephrol. 1998;9(4):568-576. 134. Diven SC, Caflisch CR, Hammond DK, Weigel PH, Oka JA, Goldblum RM. IgA induced activation of human mesangial cells: independent of FcalphaR1 (CD 89). Kidney Int. 1998;54(3): 837-847. 135. Leung JC, Tsang AW, Chan DT, Lai KN. Absence of CD89, polymeric immunoglobulin receptor, and asialoglycoprotein receptor on human mesangial cells. J Am Soc Nephrol. 2000;11(2):241-249. 136. Novak J, Vu HL, Novak L, Julian BA, Mestecky J, Tomana M. Interactions of human mesangial cells with IgA and IgA-containing immune complexes. Kidney Int. 2002;62(2):465475. 137. Westerhuis R, Van Zandbergen G, Verhagen NA, KlarMohamad N, Daha MR, van Kooten C. Human mesangial cells in culture and in kidney sections fail to express Fc alpha receptor (CD89). J Am Soc Nephrol. 1999;10(4):770-778. 138. Barratt J, Greer MR, Pawluczyk IZ, et al. Identification of a novel Fcalpha receptor expressed by human mesangial cells. Kidney Int. 2000;57(5):1936-1948. 139. Grossetete B, Launay P, Lehuen A, Jungers P, Bach JF, Monteiro RC. Down-regulation of Fc alpha receptors on blood cells of IgA nephropathy patients: evidence for a negative regulatory role of serum IgA. Kidney Int. 1998;53(5):1321-1335. 140. van Zandbergen G, van Kooten C, Mohamad NK, et al. Reduced binding of immunoglobulin A (IgA) from patients with primary IgA nephropathy to the myeloid IgA Fc-receptor, CD89. Nephrol Dial Transplant. 1998;13(12):3058-3064. 141. Launay P, Grossetete B, Arcos-Fajardo M, et al. Fcalpha receptor (CD89) mediates the development of immunoglobulin A (IgA) nephropathy (Berger’s disease). Evidence for pathogenic soluble receptor-Iga complexes in patients and CD89 transgenic mice. J Exp Med. 2000;191(11):1999-2009. 142. van der Boog PJ, van Kooten C, van Zandbergen G, et al. Injection of recombinant FcalphaRI/CD89 in mice does not induce mesangial IgA deposition. Nephrol Dial Transplant. 2004;19(11): 2729-2736. 143. van der Boog PJ, De Fijter JW, Van Kooten C, et al. Complexes of IgA with FcalphaRI/CD89 are not specific for primary IgA nephropathy. Kidney Int. 2003;63(2):514-521. 144. Vuong MT, Hahn-Zoric M, Lundberg S, et al. Association of soluble CD89 levels with disease progression but not susceptibility in IgA nephropathy. Kidney Int. 2010;78(12):1281-1287. 145. Kanamaru Y, Pfirsch S, Aloulou M, et al. Inhibitory ITAM signaling by Fc alpha RI-FcR gamma chain controls multiple activating responses and prevents renal inflammation. J Immunol. 2008;180(4):2669-2678. 146. Kanamaru Y, Arcos-Fajardo M, Moura IC, et al. Fc alpha receptor I activation induces leukocyte recruitment and promotes aggravation of glomerulonephritis through the FcR gamma adaptor. Eur J Immunol. 2007;37(4):1116-1128. 147. Roos A, Bouwman LH, van Gijlswijk-Janssen DJ, FaberKrol MC, Stahl GL, Daha MR. Human IgA activates the complement system via the mannan-binding lectin pathway. J Immunol. 2001;167(5):2861-2868. 148. Zwirner J, Burg M, Schulze M, et al. Activated complement C3: a potentially novel predictor of progressive IgA nephropathy. Kidney Int. 1997;51(4):1257-1264. 149. Wyatt RJ, Julian BA. Activation of complement in IgA nephropathy. Am J Kidney Dis. 1988;12(5):437-442. 1003 Jürgen Floege 150. Endo M, Ohi H, Ohsawa I, Fujita T, Matsushita M, Fujita T. Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy. Nephrol Dial Transplant. 1998;13(8):1984-1990. 151. Lhotta K, Wurzner R, Konig P. Glomerular deposition of mannose-binding lectin in human glomerulonephritis. Nephrol Dial Transplant. 1999;14(4):881-886. 152. Roos A, Rastaldi MP, Calvaresi N, et al. Glomerular activation of the lectin pathway of complement in IgA nephropathy is associated with more severe renal disease. J Am Soc Nephrol. 2006;17(6):1724-1734. 153. Espinosa M, Ortega R, Gomez-Carrasco JM, et al. Mesangial C4d deposition: a new prognostic factor in IgA nephropathy. Nephrol Dial Transplant. 2009;24(3):886-891. 154. Hisano S, Matsushita M, Fujita T, Iwasaki H. Activation of the lectin complement pathway in Henoch-Schonlein purpura nephritis. Am J Kidney Dis. 2005;45(2):295-302. 155. Leung JC, Tang SC, Chan LY, Tsang AW, Lan HY, Lai KN. Polymeric IgA increases the synthesis of macrophage migration inhibitory factor by human mesangial cells in IgA nephropathy. Nephrol Dial Transplant. 2003;18(1):36-45. 156. Amore A, Conti G, Cirina P, et al. Aberrantly glycosylated IgA molecules downregulate the synthesis and secretion of vascular endothelial growth factor in human mesangial cells. Am J Kidney Dis. 2000;36(6):1242-1252. 157. Lai KN, Tang SC, Guh JY, et al. Polymeric IgA1 from patients with IgA nephropathy upregulates transforming growth factor-beta synthesis and signal transduction in human mesangial cells via the renin-angiotensin system. J Am Soc Nephrol. 2003; 14(12):3127-3137. 158. Novak J, Tomana M, Matousovic K, et al. IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells. Kidney Int. 2005;67(2):504-513. 159. Amore A, Cirina P, Conti G, Brusa P, Peruzzi L, Coppo R. Glycosylation of circulating IgA in patients with IgA nephropathy modulates proliferation and apoptosis of mesangial cells. J Am Soc Nephrol. 2001;12(9):1862-1871. 160. Descamps-Latscha B, Witko-Sarsat V, Nguyen-Khoa T, et al. Early prediction of IgA nephropathy progression: proteinuria and AOPP are strong prognostic markers. Kidney Int. 2004;66(4): 1606-1612. 161. Lai KN, Leung JC, Chan LY, et al. Podocyte injury induced by mesangial-derived cytokines in IgA nephropathy. Nephrol Dial Transplant. 2009;24(1):62-72. 162. Coppo R, Fonsato V, Balegno S, et al. Aberrantly glycosylated IgA1 induces mesangial cells to produce platelet-activating 1004 factor that mediates nephrin loss in cultured podocytes. Kidney Int. 2010;77(5):417-427. 163. Chan LY, Leung JC, Tsang AW, Tang SC, Lai KN. Activation of tubular epithelial cells by mesangial-derived TNF-alpha: glomerulotubular communication in IgA nephropathy. Kidney Int. 2005;67(2):602-612. 164. Lemley KV, Lafayette RA, Safai M, et al. Podocytopenia and disease severity in IgA nephropathy. Kidney Int. 2002;61(4):1475-1485. 165. El Karoui K, Hill GS, Karras A, et al. Focal segmental glomerulosclerosis plays a major role in the progression of IgA nephropathy. II. Light microscopic and clinical studies. Kidney Int. 2011;79(6):643-654. 166. Cattran DC, Coppo R, Cook HT, et al. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int. 2009;76(5):534-545. 167. Roberts IS, Cook HT, Troyanov S, et al. The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility. Kidney Int. 2009;76(5):546-556. 168. Hill GS, Karoui KE, Karras A, et al. Focal segmental glomerulosclerosis plays a major role in the progression of IgA nephropathy. I. Immunohistochemical studies. Kidney Int. 2011; 79(6):635-642. 169. Myllymaki JM, Honkanen TT, Syrjanen JT, et al. Severity of tubulointerstitial inflammation and prognosis in immunoglobulin A nephropathy. Kidney Int. 2007;71(4):343-348. 170. Floege J, Eitner F, Alpers CE. A new look at plateletderived growth factor in renal disease. J Am Soc Nephrol. 2008; 19(1):12-23. 171. Boor P, Eitner F, Cohen CD, et al. Patients with IgA nephropathy exhibit high systemic PDGF-DD levels. Nephrol Dial Transplant. 2009;24(9):2755-2762. 172. Boor P, Ostendorf T, Floege J. Renal fibrosis: novel insights into mechanisms and therapeutic targets. Nat Rev. 2010; 6(11):643-656. 173. Boor P, Sebekova K, Ostendorf T, Floege J. Treatment targets in renal fibrosis. Nephrol Dial Transplant. 2007;22(12): 3391-3407. 174. Zeisberg M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol. 2010;21(11):1819-1834. 175. Lee SB, Kalluri R. Mechanistic connection between inflammation and fibrosis. Kidney Int Suppl. 2010;119:S22-S26. 176. Boor P, Floege J. Special series: chronic kidney disease growth factors in renal fibrosis. Clin Exp Pharmacol Physiol. 2011;38(7):391-400. Am J Kidney Dis. 2011;58(6):992-1004
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