IgA Nephropathy

Abstract

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-Scho[Combining Diaeresis]nlein 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 lig