Much progress has been made in the 40 years since immunoglobulin A (IgA) nephropathy was first described. We now have a reasonably complete understanding of the pathogenesis and mediation of this disease, but its etiology remains obscure and mysterious. New data on its epidemiology continue to emerge that will undoubtedly have clinical significance. We are beginning to perceive—but only dimly—the genetic predisposition to the disease.
Prognostication remains an imperfect science, but we are clearly making progress. The role of pathology in estimating prognosis in individual patients needs to be thoroughly reexamined, based on a uniformly agreed-upon classification scheme. Such work is currently in progress.
Therapy has certainly advanced, and we now have the rudiments of an evidence-based approach to management. However, much more needs to be done to refine these strategies so that they can be better matched to the characteristics of the patients, and there is a great need for novel therapeutic approaches and more information on multidrug regimens in selected patients. Many opportunities exist for improvement in the control of this common cause of chronic kidney disease, but we should not underestimate the challenges that present themselves in the field of IgA nephropathy in 2008 and beyond.
THE SCOPE OF THE PROBLEM
IgA nephropathy, also called Berger disease, is the most common form of primary glomerular disease in the developed world.1,2 Morphologically, it is characterized by diffuse deposition of IgA in the glomerular mesangium and by various degrees of damage of the glomerular capillary network seen on light microscopy.3,4 By some estimates, as many as 5% to 15% (averaging about 10%) of the general population may have IgA deposits in the glomerular mesangium, but only about 1 in 50 people with IgA deposits will actually have some abnormal clinical manifestation (principally recurring bouts of hematuria, with or without accompanying proteinuria) that brings them to the attention of a physician.5
Although not all patients with IgA nephropathy have progressive renal disease, IgA nephropathy is a significant contributor to the incidence of end-stage renal disease (ESRD) in many countries.1–4
DIAGNOSTIC AND PROGNOSTIC CHALLENGES
Since 1968, when IgA nephropathy was first described,6 great strides have been made in clarifying its epidemiology, its pathogenesis, the prognostic factors involved in its progression to ESRD, and its treatment. However, many gaps in our knowledge remain, particularly regarding its etiology, the genetic factors predisposing to it, its therapy, and the problem of recurrent disease in renal transplant recipients.
Can IgA nephropathy be diagnosed without a renal biopsy?
While renal biopsy and immunochemical analysis of renal tissue remain the gold standard for diagnosing IgA nephropathy, new sensitive and reasonably specific noninvasive tests are emerging and may provide another diagnostic approach. One of the most promising new tests is for abnormal circulating levels of abnormally glycosylated IgA subclass 1 (IgA1), which appears to be involved in the pathogenesis of the disease (see below).7 If noninvasive diagnostic techniques can be simplified and their accuracy validated across diverse populations, they offer great promise for use in epidemiologic and genetic studies, in which routine renal biopsy for diagnosis is impractical.
Signs and symptoms of IgA nephropathy are nonspecific
The most common clinical presentation of IgA nephropathy is recurring bouts of macroscopic hematuria, often but not invariably accompanied by proteinuria.2 Persistent asymptomatic hematuria without any detectable proteinuria (so-called isolated hematuria) affects a minority of patients. The red cells in the urine are typically dysmorphic (altered in size and shape compared with normal red cells), as they are in many other glomerulonephritic diseases.
Because low-grade fever and pain in the loins may accompany these bouts of hematuria, the disorder is often initially mistaken for urinary tract infection or urolithiasis. Careful microscopic examination of the urinary sediment for the characteristic dysmorphic erythrocytes that indicate a glomerular disease often provides the crucial clue that a glomerular disorder is the cause of the hematuria.8
However, a somewhat similar presentation may also be seen in thin basement membrane nephropathy, Alport syndrome (hereditary nephritis), and membranoproliferative glomerulonephritis,2 although these disorders can be readily distinguished from IgA nephropathy on examination of renal biopsy material under light, immunofluorescence, and electron microscopy. In addition, serum complement levels are typically reduced in membranoproliferative glomerulonephritis, and a family history of nephritis (without father-to-son transmission), often with deafness, can be obtained in the X-linked form of Alport syndrome. IgA nephropathy can be reliably distinguished from thin basement membrane nephropathy only by renal biopsy and electron microscopy.