IgA Nephropathy

Immunoglobulin A nephropathy (IgAN) is defined by the predominant deposition of IgA in the glomerular mesangium. Light microscopic appearances and clinical features can vary considerably, reflecting the many patterns of histopathologic injury seen in this glomerulonephritis (GN) Closely associated with IgAN is Henoch-SchoCombining Diaeresisnlein purpura (HSP), a small-vessel systemic vasculitis characterized by small blood vessel deposition of IgA predominantly affecting the skin, joints, gut, and kidney. The nephritis of HSP is also characterized by mesangial IgA deposition and may be histologically indistinguishable from IgAN. Both clinical and laboratory evidence support a close relationship between IgAN and the nephritis of HSP (1). This article focuses on IgAN considering especially new information available since IgAN was last reviewed in the Journal of the American Society of Nephrology (2). In particular, we focus on our growing understanding of the pathogenesis of IgAN, and we discuss the impact of recently published randomized, controlled trials (RCT) on recommended treatment strategies. Epidemiology and Clinical Features The clinical course of IgAN is well established and has recently been reviewed elsewhere (3). There are a number of clinical features for which there is no certain explanation; these include the male preponderance, the apparent peak incidence in the second and third decades of life, the very wide range of presenting clinical features, and the variable tempo of disease after diagnosis. Data from Japan suggest that the prevalence of subclinical “lanthanic” IgAN may be even higher than already suspected, on the basis of renal biopsies in living kidney donors, in which 16% were found to have previously unknown mesangial IgA (4). The geographic differences in apparent prevalence of IgAN—higher in the Pacific Rim, where incidence in older patients is reported to be increasing, and Southern Europe, as opposed to northern Europe and North America—are still the subject of debate. Varying approaches to the use of renal biopsy in patients with mild urinary abnormalities are often cited as one explanation, but worldwide practice is becoming increasingly uniform, and fewer nephrologists now recommend renal biopsy for people with asymptomatic microscopic hematuria in the absence of sustained proteinuria. Most prevalence data are generated from centers in major industrialized cities in which the lifestyle is becoming increasingly uniform, suggesting that the varied incidence more likely represents true differences among racial groups, rather than environmental in origin. However, genetic studies have so far been unrewarding in defining the pathogenesis of IgAN. The diagnosis of IgAN always requires renal biopsy. No clinical presentation is pathognomonic, not even the archetypal young male patient with episodic macroscopic hematuria after an upper respiratory tract infection, which is the presenting feature in 30 to 40% of cases. Most patients have only a few episodes of frank hematuria, and such episodes usually recur for a few years at most. Asymptomatic urine testing identifies 30 to 40% of patients with IgAN in most series. Studies in which renal biopsy has been offered to patients with isolated microscopic hematuria suggest that up to half of such patients in all age groups will have IgAN, with the majority of the remaining patients having either thin-membrane nephropathy or normal biopsies (5,6). It is very rare for proteinuria to occur without microscopic hematuria in IgAN. Nephrotic syndrome is uncommon, occurring in only 5% of all patients with IgAN, but is more common in children and adolescents. Patients may develop nephrotic-range proteinuria at different stages of the disease, both when there is mild glomerular injury and when there is advanced glomerulosclerosis. Acute renal failure is very uncommon (<5% of all cases) and develops by two distinct mechanisms. There may be acute, severe immune and inflammatory injury producing crescent formation: Crescentic IgAN—this may be the first presentation of the disease or can occur superimposed on known milder IgAN. Alternatively, acute renal failure can occasionally occur with mild glomerular injury when heavy glomerular hematuria leads to tubular occlusion and/or damage by red cells. This is a reversible phenomenon, and recovery of renal function occurs with supportive measures. The remainder of patients with IgAN, typically older at presentation, already have proteinuria, renal impairment, and hypertension when they first receive the diagnosis. Rarely, IgAN may present with malignant hypertension. It is usually presumed that they have longstanding IgAN that was not detected earlier because the patient did not have frank hematuria or undergo routine urinalysis. Pathology The range of pathologic features of IgAN is well described (7). Mesangial IgA deposits are the defining hallmark of the disease; they are diffuse and global, even if light microscopic change is focal or segmental. IgA deposits are also occasionally seen in glomerular capillary walls, where their presence has been associated with a worse prognosis. IgA is the sole Ig present in only 15% of biopsies; IgG and IgM accompany IgA in the majority of cases. C3 deposition is usual and has the same distribution as IgA. Light microscopic abnormalities may be minimal, but the most common appearance is mesangial hypercellularity. This most commonly is diffuse and global, but focal segmental hypercellularity is also seen. With progressive disease, there is relentless accumulation of mesangial matrix. Crescentic change may be superimposed on diffuse mesangial proliferative GN with or without associated segmental necrosis. Crescents are a common finding in biopsies that are performed during episodes of macroscopic hematuria with renal impairment. Tubulointerstitial changes do not differ from those seen in other forms of progressive GN, reflecting the final common pathway of renal parenchymal disease. Mesangial and paramesangial electron dense deposits are the ultrastructural manifestation of mesangial IgA deposition. There is evidence that a proportion of patients with IgAN have diffuse uniform global thinning of the glomerular basement membrane indistinguishable from that seen in thin-membrane nephropathy. It is not yet clear whether this group of patients has any defining clinical or prognostic characteristics compared with typical cases of IgAN (8,9). A number of classifications of IgAN based on light microscopic findings are in use, for example those of Lee and Haas (10–12), but there is little agreement about their relative utility. An international consensus on a pathologic classification for IgAN would be of great value in clinical practice and research in this field; the International IgA Nephropathy Network with the Renal Pathology Society, under the auspices of the International Society of Nephrology, are presently developing such a consensus, which it is expected will be announced in 2006. Do these various clinical presentations and pathologic features of IgAN all arise from the same disease process? It is common to describe IgAN as a single disease, but our present limited understanding of the cause and pathogenesis of IgAN does not yet provide strong support for such a view. Mesangial IgA deposition and subsequent injury may eventually turn out to represent a final common path of glomerular response to a wide range of causative and pathogenic processes, and a very different classification may emerge in due course. Pathogenesis The initiating event in the pathogenesis of IgAN is the mesangial deposition of IgA, which is predominantly polymeric IgA of the IgA1 subclass (pIgA1). Co-deposits of IgG and complement are also commonly seen; however, these are not mandatory for disease activity or progression. The varied glomerular response to IgA deposition is reflected in the renal biopsy findings, clinical presentation, and outcome of patients with IgAN. Three key elements contribute to the development of IgAN, and the extent to which each is operational decides the severity, tempo, and eventual outcome of IgAN in any individual: Synthesis, release, and persistence in the circulation of pIgA1 with characteristics that favor mesangial deposition; The “reactivity” of the glomerular mesangium as judged by: its susceptibility to mesangial deposition its capacity to mount an inflammatory response to that deposition; The tendency of the kidney to respond to injury by mounting a response that favors progressive renal injury rather than resolution of inflammation without ongoing glomerulosclerosis, tubular atrophy, and interstitial fibrosis. The likely interactions of these elements of pathogenesis are shown in Figure 1. Each of these three elements may have a significant genetic component that influences the eventual phenotype of the disease in any individual. Although mesangial IgA deposition and the initiation by IgA of glomerular inflammation are specific to IgAN, mechanisms of the subsequent renal injury followed either by resolution or progressive sclerosis are likely to be generic, not differing substantially from those seen in other forms of chronic GN. In this review, we focus on IgA-specific pathogenic mechanisms. IgA and IgA Production in IgAN A number of abnormalities in circulating IgA and its production are reported in IgAN (13). However, patient cohorts are heterogeneous with respect to these abnormalities, supporting the notion that more than one pathogenic mechanism may result in the production of pathogenic circulating IgA. An increased plasma IgA level is not sufficient per se to produce mesangial IgA deposits; therefore, patients with IgAN must produce a pool of circulating IgA molecules with special characteristics that particularly promote mesangial deposition. Molecular Characteristics of IgA in IgAN. There is no well-supported evidence that IgAN is driven by circulating IgA autoantibodies’ binding to glomerular antigens. Increases in circulating IgA1 antibodies against a variety of antigens have certainly been described, but no single pathogenic antigen has been identified. Studies of serum IgA have by contrast demonstrated a number of unusual physical characteristics in IgAN (Table 1). Although some of these findings have been replicated for IgA eluted from renal biopsy specimens, it is not yet certain which of these features are for the mesangial deposition and mesangial of IgAN. of IgA1 in IgAN has been and there is now evidence for its in the pathogenesis of IgAN The the of of the IgA1 to increased of of the IgA1 in IgAN is more with increased and were to studies of serum IgA, but two studies of IgA1 eluted from isolated have now the same abnormalities in mesangial in the mechanisms of IgA deposition The of IgA1 are under in evidence that IgA1 molecules have an increased tendency both to and to with IgG antibodies against IgA1 the of of pIgA1 and IgA immune which would promote mesangial deposition In IgA1 molecules that and have increased in for the and studies in this have on in of which a more in than the abnormalities in serum and mesangial IgA1 in so there is some about the of these findings to the disease. In studies serum IgA1 isolated from patients with IgAN are now and more likely to produce information A of the specific for the of IgA1 has been as a mechanism for in IgAN is the key the of to and we reported some evidence for a in in blood we have since found no in the activity of this in in IgAN studies have been for some years by of information on the of however, such is now as the and its have now been characterized IgA Production in IgAN. The of production of the pathogenic IgA in IgAN has been an of The of episodic macroscopic hematuria with to the that IgAN was with antigen particularly because both mesangial IgA and the increased IgA in serum IgA are which is at rather than in systemic immune However, studies that were published years that the presence of in the circulation be to and the studies that plasma are normal or even in IgAN, in are not and are than However, increased pIgA1 plasma are found in the in IgAN, and systemic antigen in increased of circulating pIgA1 with normal in the of pIgA1 is likely to be based systemic immune such as the with both systemic and antigen in systemic immune (13). The of the plasma that this pIgA1 a for debate. is that they are plasma that have up in systemic rather than to their of this requires are a that a in and promote IgA patterns of by have been reported in both the and the in patients with IgAN the of these findings have not yet been yet is known of specific mechanisms that may IgA in the different immune There is evidence that in the of IgA can vary between immune differences in than a the for of serum it may be that pIgA1 is a normal of IgA in some immune such as the the of this IgA in the serum in IgAN a of plasma IgA the the for the serum IgA1 the is that the mesangium is to IgA that would not by mesangial of such IgA as a result of its unusual may the IgA accumulation and mesangial of IgAN. IgA in IgAN. of normal IgA and IgA immune mechanisms will their persistence in the In studies that have the of IgA from the circulation a key for the with in IgAN An for IgA is the for IgA, which IgA and In IgAN, is on which may to of IgA from the circulation and contribute to increased serum IgA It has also been shown that IgA well to in IgAN, and this may to the of systemic IgA in IgAN IgA and the all mesangial IgA deposition is associated with the development of glomerular is IgA deposition Mesangial IgA deposits when with subclinical IgAN are did not have IgAN, biopsy studies suggest that clinical is by of IgA deposits In IgAN, mesangial IgA accumulation occurs because the of IgA deposition this capacity and/or the IgA is in some to mesangial Mesangial IgA In are particularly to mesangial deposition. It that the increased of serum IgA in IgAN promote mesangial deposition mesangial by the There is also evidence from that that are generated after binding of IgA to are associated with mesangial IgA deposition This has to the that may of the circulating pool of IgA in IgAN, other data suggest that may not be specific to IgAN well as there is evidence that IgA deposition may be by interactions between IgA and specific mesangial IgA1 to the of mesangial IgA may also promote interactions with mesangial Mesangial IgA and IgA The pathway for IgA is and of IgA The of the IgA The is by in it IgA, and pIgA1 may to it There is one of increased mesangial in IgAN, this is not by There is also evidence that may in a an and an of which is there is in evidence that are of and of IgA It is that binding to mesangial IgA and contribute to IgA accumulation and the development of GN, as yet there is no evidence for this in of IgAN is not associated with a suggesting that most of the glomerular injury is by an in glomerular cells. Although IgG and complement are often IgA to be sufficient to glomerular injury in the individual. This occurs predominantly of and complement There is strong in evidence that of IgA with IgA a and in (13). with the mesangial hypercellularity seen in renal biopsy specimens, in response to IgA. to IgA has been shown to of both the and of the IgA is also of interactions by and this may have an in of the mesangium after glomerular of to IgA is also of initiating a of and the of the and development of an of IgA There is also evidence that by IgG may contribute to the development of a phenotype and the of glomerular It is not yet clear which specific of mesangial IgA however, there is some in evidence that IgA from patients with IgAN can both and and the of and in This with the of IgA in mesangial IgA suggest that IgA1 a in both the deposition of IgA and the subsequent Although of the complement is not for the development of IgAN, there is evidence that complement can the extent of glomerular Mesangial IgA of C3 occurs the and this leads to the of of which can to produce inflammatory as well as C3 and not only are in the kidney in IgAN but also can be by the in the of by as It is therefore, that having IgA, are of complement generated C3 and of any systemic complement The of this in complement and to progressive glomerular injury is not also complement which may in IgAN does not usually result in of IgAN There is little that there are genetic to the pathogenesis and clinical of IgAN. This has been from the of forms of IgAN, the presence of serum IgA and of IgA by in and the failure of to mesangial IgA deposits to to IgAN in all Most studies in IgAN to have been small genetic studies that have in single The of many of these studies both small and the of such a in a disease. This is by as to whether IgAN is a single and the that IgAN may as a subclinical in normal many of the published studies have reported on genetic that of renal failure in IgAN to many chronic kidney rather than on disease pathogenesis in 30 has demonstrated of IgAN to There are no the and no was found in the same for a number of other that all have been in the pathogenesis of IgAN. of the the is still It is not certain that genetic findings from these unusual will have on more typical cases of IgAN. and than of all patients with IgAN have resolution of urinary IgAN has the for progressive chronic renal impairment, eventually to to of any published will renal to years of first of patients with IgAN have been to per The of course will be by the because centers with a for renal biopsy for patients with mild urine will likely IgAN in a number of patients with mild disease and the outcome of the studies have features at presentation that a (Table Although these prognostic features may be for of they as yet do not have the to an with An that information on and proteinuria can the of this still will only for of In milder disease, one that proteinuria may in be a than expected Although prognostic that use clinical and laboratory data have been there is not yet sufficient consensus to recommend that they be in clinical practice for the of It whether pathologic classification in the in defining the has been limited by the of international consensus on pathologic classification of IgAN. after Renal of IgAN after renal has been for 30 It is as a cause of failure as of It typically is patients will have a progressive course. evidence at a 5% for failure as a result of a for significant and at for IgA deposition. The for to when a first was to There is no evidence that these differ between living and There is no evidence that any the incidence of IgAN after or of the of in the most IgAN is only very it is not yet to whether may have a of IgAN of the treatment of IgAN the prevalence of IgAN, published are few in and even are not always to provide information on no treatment is known to mesangial deposition of IgA, and available treatment are at immune and inflammatory that may on to renal of macroscopic hematuria are and by a range of most commonly In a of episodes are by and may be Although this will to episodic hematuria in the the of that it also studies from Japan support its of is and the use of other treatment these data to An of in IgAN would be and such a is now in and or No The consensus that there is no specific treatment for patients with isolated microscopic hematuria and little or no proteinuria, is A for proteinuria of is usually recommended to those are at higher this is an and the to proteinuria is certainly a IgAN The of treatment is for patients with IgAN are at for progressive renal those with proteinuria or at the of diagnosis. is usually studies with are to the of any with and many recently published studies are to these such trials in IgAN use clinical the presence of proteinuria to with variable in This is in for to studies in in which usually and the of consensus on a histopathologic classification of IgAN. In the few new data have been reported on a number of that are to immune and inflammatory that are in progressive IgAN, and of the to with the of it is that a number of these studies or at a when the to progressive glomerular disease was well The to such patients to a of and to proteinuria has been recommended in years for IgAN, predominantly by from other studies of progressive renal disease, one small in IgAN the of an on progressive renal disease to in proteinuria the evidence for when an is in with an in renal disease, in proteinuria with no of patients in this IgAN A of available trials of sufficient that may be in proteinuria and for the impact on renal function is clear The of now has of with from treatment in proteinuria and However, this is by many as likely to even is reported by the was in only a of patients in this among the and was not in with (Table of only a in proteinuria with no of a by the to the of but was even was not (Table This a and in our be only when proteinuria and Most trials of in progressive IgAN patients with nephrotic-range proteinuria, because many this as an for However, the only that this a response to only in patients with or on light The use of when syndrome IgAN with features other than change is and we do not this There is evidence in one for the of followed by in with that is to patients are at very for in all cases However, these are only a small of patients in clinical and use of (Table and in our there is evidence to the use of in IgAN in IgAN with progressive renal failure published studies no of the of and it is that the that no blood with use of an (Table a of on proteinuria no of in more advanced disease serum at The small of the studies so far available and other studies are in this we do not recommend the use of Although the of that there are still no studies to support its and a that other published studies did not suggest The of a more no of of treatment with compared with and do not recommend the use of and The in the was than is reported in most of these (Table The and suggest that with and be the against which any be well as a of in all patients with IgAN, we recommend when proteinuria is with a single In our with or other be only when there is still sustained proteinuria a of with In our few patients these and it be that and have not been in the of such a Data on or were not available in the published that for and so the that these were was not It is becoming increasingly to the of any new The of the that of any will increasingly and to of outcome are to studies to be without of Crescentic IgAN Crescentic IgAN is an uncommon clinical There are no of in IgAN associated with progressive renal studies are increasingly about the value of treatment with usually in with renal in IgAN is to that in other forms of GN, systemic vasculitis and disease. in IgAN is a and in IgAN is recommended only when there is injury without major chronic In such we use and in a to that in renal in our there is evidence to the of plasma of major elements of pathogenesis of IgA nephropathy circulating serum IgA is the of mesangial IgA deposits in IgAN. The of serum IgA that has a for mesangial however, is and the that is of initiating glomerulonephritis (GN) is The response of the mesangium in particular, the mesangial to the IgA is to the development of IgAN. an genetic to develop IgAN, IgA deposition can be a with little or no for GN. However, an genetic serum IgA will favor mesangial IgA and the mesangial response will on a in significant IgAN of if this will the of progressive renal and may the of in renal of IgA in normal and in The common features of serum and mesangial IgA in at presentation in of and use of in randomized, controlled