IgA Nephropathy: An Update on Diagnosis and Management
Richard J. Glassock, MD, MACP
IgA nephropathy is very common disease, perhaps affecting several hundred million people around the globe.1,2 Although in many patients it is a rather benign disorder, it can progress to end-stage renal disease (ESRD).1 The clinical features of IgA nephropathy are quite variable but episodes of hematuria, often combined with persistent proteinuria, are common. Nephrotic syndrome at presentation is uncommon.1
Overall, ESRD can be expected to develop in about 1%-2% of patients diagnosed with IgA nephropathy each year, such that a renal survival is about 50% is at about 25-30 years after the initial diagnosis.1 However, long-term outcome depends greatly on the characteristics of the patient at the time of renal biopsy diagnosis and after short-term follow-up.1 The pathogenesis of IgA nephropathy is still incompletely resolved, but it is believed to be an autoimmune disease with an endogenously-derived, under-galactosylated IgA1 as the principal auto-antigen.3
IgA nephropathy exists in three forms: i) lanthanic (covert)—discoverable only by a renal biopsy in an otherwise healthy person (such as a "zero" time biopsy of a donor kidney during transplantation); ii) clinically silent—only found when a routine urinalysis is performed in an asymptomatic individual (such as a pre-employment or pre-insurance physical examination revealing microscopic hematuria and/or or low-grade proteinuria) and a renal biopsy is performed to confirm a diagnosis; iii) clinically overt—diagnosed when a renal biopsy performed in a patient with gross (visible) hematuria and/or proteinuria, with or without hypertension.1
At present, the only way to make a firm diagnosis of IgA nephropathy is to perform a renal biopsy and study the specimen with immunofluorescent or immunoperoxidase probes for detection of the characteristic deposits of IgA1 in the mesangial zones and peripheral capillary loops (often with co-deposition of IgG and complement components C3, C4d).1
Once a renal biopsy diagnosis of IgA nephropathy is made the issue then becomes estimating prognosis (for preservation of renal function) and designing an appropriate short- and long-term treatment strategy. This process must take into account potential risks as well as presumed benefits of potential therapy. The latter is best assessed by comparing the patient's clinical and morpho logical features to the results of randomized controlled trials of treatment that included patients with characteristics similar to those of the patient. This process is known as the practice of evidence-based medicine.4
Unfortunately, such an evidence base suitable for rational therapeutic decision making is available only for a fraction of patients with overt IgA nephropathy, so physicians often must use less reliable data for creating a treatment plan for individual patients. This article analyzes current suggestions for managing IgA nephropathy, including areas of uncertainty.
As stated previously, the first step in developing a treatment plan for a patient with a newly made biopsy diagnosis of IgA nephropathy is to determine, as best as one can, the prognosis for preservation of renal function (i.e., avoidance of the need for treatment of ESRD by dialysis or renal transplantation). This is often expressed as the anticipated rate of decline of glomerular filtration rate (GFR) over time (as estimated by serum creatinine-based formulas or as actual endogenous creatinine clearance values) in mL/min/month or mL/min/year.
Knowing baseline renal function allows one to project (albeit with some lack of precision) when ESRD is likely to supervene, in the absence of any additional interventions or unexpected complications. For example, a 25-year-old woman with IgA nephropathy, a baseline estimated GFR (eGFR) of 55 mL/min/1.73m2, 2 grams of protein excreted in the urine per day, and who is expected to have a GFR loss of about 7 mL/min/year can be expected to require ESRD treatment within about seven years or by age 32. Such a rate of progression might be sufficient to justify a moderately aggressive (and potentially risky) treatment program.
However, a 42-year-old man with a baseline eGFR of 95 mL/min/1.73m2, 600 mg of protein excretion in the urine per day, and who is judged to be at risk for a GFR loss of about 2 mL/min/year would have a projected need for ESRD treatment in 40 years and might be better off with conservative management and careful follow-up rather than exposure to drugs of uncertain efficacy and safety over a prolonged period of time.
Clinicians must recognize that some period of observation is required to estimate progression rates with any semblance of accuracy. Estimates can be quite imprecise when the parameters used to judge the anticipated rate of progression are limited in scope. Intercurrent illnesses and exacerbations of disease can also alter the long-term prognosis.
At present, the best clinical parameters that can be used to judge progression risk are baseline serum creatinine (Scr) or creatinine clearance (Ccr), magnitude of proteinuria (grams/day in a timed urinary collection or the ratio of urinary protein to urinary creatinine concentration [UPCR] in a first or second morning void), and the degree of blood pressure (BP) control (systolic BP).1,5,6
Additional useful information can also be gleaned from the renal biopsy when it is interpreted using the Oxford MEST Classification system,7 but clinical parameters often can outweigh the importance of pathological evidence for progressive disease. Other prognostic tools are in development, usually a urinary biomarker, but they have not been extensively validated in diverse populations.8,9
Many of these biomarkers are not commercially available or well standardized and their utility has not been extensively validated in large cohorts. It is hoped that someday genome wide scanning may yet provide powerful and accessible information on prognosis as well as potential responsiveness to treatment in IgA nephropathy, but we have not yet reached this point.
The objective of the prognostication process, using both clinical and pathological tools, is to segregate patients with IgA nephropathy into good, moderate, or poor prognosis categories. A good prognosis generally means that either no therapy or simple conservative measures, such as BP control, are indicated. A moderate prognosis generally means more intensive therapy or more rigorous monitoring is appropriate. A poor prognosis translates into a justification for aggressive and potentially risky therapy, so long as there is a reasonable prospect for a response and no serious safety risks are present. See Table 1 for a summary of the characteristics of these prognostic groupings.