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IgA nephropathy: Challenges and opportunities

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Can we better predict which patients with IgA nephropathy will develop renal failure?

Although the rate of progression is very slow, and in only about 50% (or less) of patients does IgA nephropathy progress to ESRD within 25 years of diagnosis, the risk varies considerably among populations.9 Spontaneous clinical remissions are relatively uncommon in adults but much more common among children.

Several factors, if present at the time of discovery or developing within a relatively short time thereafter (usually within 6 months to 1 year), appear to predict a progressive course and, eventually, ESRD.9,10 We need to characterize and validate these risk factors in detail to be able to design and carry out appropriately powered, randomized, controlled clinical trials of treatment.

Unfortunately, cumulatively, the risk factors identified so far explain less than 50% of the variation in observed outcome of IgA nephropathy. Many of the risk factors identified so far are primarily indicators of the extent of disease at a particular time, and it is therefore not surprising that they would have some ability to predict the later behavior of the disease.

Clinical and pathologic risk factors in IgA nephropathy

Although imperfect, the major risk factors auguring a poor prognosis are:

  • Proteinuria (> 500 mg/day) that persists for more than 6 months
  • Elevated serum creatinine at diagnosis
  • Microscopic hematuria that persists for more than 6 months
  • Poorly controlled hypertension
  • Extensive glomerulosclerosis or interstitial fibrosis or both on renal biopsy.7,10

Extensive crescentic disease also confers a worse short-term prognosis, often accompanied by a rapidly progressive loss of renal function.

Are clinical risk factors more useful than pathologic risk factors in IgA nephropathy?

Of importance, clinical factors, such as persistent proteinuria or declining renal function on follow-up appear to have greater predictive power than pathologic factors for long-term outcome.9–12 Clinical factors, such as decreasing estimated glomerular filtration rate (GFR) after short-term follow-up, persistent moderate to marked proteinuria (500–1,000 mg/day, or more), hyperuricemia, hyperlipidemia, concomitant obesity, poorly controlled hypertension, absence of treatment with angiotensin II inhibitors, and, possibly, persistent micro-hematuria are the most consistent factors independently associated with a poor prognosis in multivariate analysis. Pathologic changes noted in the original diagnostic renal biopsy do not consistently add greatly to the precision of prognosis beyond the analysis of these clinical and laboratory factors.11

A detailed and uniform immunologic and morphologic approach to classifying the pathology of IgA nephropathy may yet uncover some new and very useful prognostic factors, independent of those generated by simple clinical assessment. Efforts are under way, and such a development would greatly improve the accuracy and precision of outcome prediction and reduce the amount of unexplained variation in prognosis observed in groups of patients with IgA nephropathy.

At present, the heterogeneity of participants in clinical trials of therapy, the tendency for the disease to progress slowly, and the variation in prognosis due to unexplained factors pose major challenges in designing and carrying out randomized controlled trials of therapy in IgA nephropathy. If we can find new risk factors that can predict progressive disease earlier, the knowledge will help us in designing future clinical trials, which will be vital if progress is to be made towards controlling IgA nephropathy.

Prognosis in individual patients vs populations with IgA nephropathy

At present, we need a way to determine the prognosis more precisely in individual patients rather than in groups of patients. After all, physicians are called upon to determine the likely outcome in single patients, not in a population. Several prediction formulas have been devised, most of them based on relatively simple clinical factors present at discovery or short-term follow-up.12,13

Conventional pathologic observations have limited utility in such individualized prognostic formulations.12 This is not to say that renal biopsy only offers diagnostic utility and has little if any value as a prognostic tool. However, the challenge is to enhance the prognostic usefulness of renal biopsy by refining the examination of the tissue specimens using modern approaches and to conduct the appropriate correlative studies to confirm the value of new pathologic criteria in prognostication, independent of clinical features alone.

For example, the risk of ESRD is greater if the patient has very extensive (> 50%) crescentic glomerular involvement with a rapidly progressive glomerulonephritic evolution. The risk is less if there are minimal glomerular changes with nephrotic-range proteinuria. Extensive interstitial fibrosis and glomerulosclerosis in the original “diagnostic” renal biopsy merely highlight the existence of prior progressive disease that is likely to continue. The significance of persistent focal necrotizing glomerular lesions (capillaritis) in IgA nephropathy, often associated with persistent microhematuria, is not entirely clear and needs to be specifically explored, especially as it pertains to the need for immunosuppressive therapy added to treatment for hypertension, proteinuria, or both with inhibitors of the renin-angiotensin system (see below).

At present, the most powerful prognostic factor in IgA nephropathy is moderate to severe proteinuria that persists for 6 months or longer.9,10,12 The relationship between the level of proteinuria and the outcome is continuous, ie, the greater the proteinuria, the worse the prognosis. Compared with some other primary glomerular diseases (such as membranous nephropathy or focal and segmental glomerulosclerosis), progressive disease in IgA nephropathy is associated with lower levels of persistent proteinuria (usually 500 mg to 3 g/day).

The estimated GFR at the time IgA nephropathy is discovered is a rather weak independent predictor of outcome (up to a point; see below). Many patients have stable (but reduced) renal function in the long term, especially if they receive angiotensin II inhibitor therapy and can keep their systolic blood pressure between 110 and 120 mm Hg.

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