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IgA nephropathy: Challenges and opportunities

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References

How can IgA nephropathy be diagnosed and treated before the ‘point of no return’?

For patients at risk of developing ESRD, the two most critical goals of treatment are to:

  • Control blood pressure rigorously, preferably with an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist (ARB), or both, and
  • Reduce proteinuria to less than 500 mg/day.

If these two goals can be met without undue side effects and if the patient remains compliant in the long term, many patients can avoid ESRD. Patients who cannot achieve these goals despite vigorous attempts become candidates for adjunctive therapy, such as pulse intravenous methylprednisolone (Solu-Medrol) combined with oral prednisone, or in some cases a cytotoxic drug combined with prednisone. Small randomized controlled trials suggest these adjunctive treatments are effective and safe.

Unfortunately, IgA nephropathy can progress silently, and many patients do not receive the diagnosis until late in its course. In such patients, the disease may relentlessly progress even with optimal therapy. The “point of no return” appears to be an estimated GFR of about 30 mL/min/1.73 m2 (stage 4 chronic kidney disease).14

These observations underscore the need for early diagnosis and treatment based on factors that accurately predict an unfavorable outcome. Finding these factors will not be easy, because it will require detailed observation of homogeneous groups of patients over prolonged periods of time. New findings show great promise for identifying patients earlier in the course of disease who are more or less likely to progress to ESRD. The challenge is to translate these findings into rational, safe, and effective therapies applicable across a broad spectrum of disease.

OPPORTUNITIES: GENETICS, PROTEOMICS, NEW TESTS AND TREATMENTS

Genetic studies may lead to novel treatments for IgA nephropathy

Susceptibility to IgA nephropathy has a genetic component to varying degrees, depending on geography and the existence of “founder effects.” Familial forms of IgA nephropathy are more common in northern Italy and in eastern Kentucky. The familial cases may derive from a mutation of a specific gene occurring in a founder many hundreds of years ago. Several genetic loci are strongly associated with IgA nephropathy (usually as an autosomal-dominant trait with highly variable penetrance).15 Familial IgA nephropathy is most likely genetically heterogeneous, and many cases of IgA nephropathy that are believed to be sporadic may actually have a less apparent genetic basis, with skipped generations, lanthanic (covert) disease, and incomplete penetrance.

At present, genetic testing based on genomic or transcriptosomic analysis does not appear to have much diagnostic value except in clearly familial cases, because many loci are involved. Many asymptomatic people have mesangial IgA deposits that could be detected by renal biopsy but not by genetic analysis, and this inability is a major obstacle for genetic susceptibility studies. Indeed, most current genetic studies actually examine susceptibility to the clinical expression of disease rather than susceptibility to the mesangial IgA deposition that underlies the disease.5

The opportunity that lies ahead in genetic testing of IgA nephropathy (including haplotype analysis) appears to be primarily in the elucidation of potential pathogenetic pathways and in the refinement of prognosis and the definition of treatment responsiveness (pharmacogenomics).

If a gene (or group of genes) can be identified that is strongly and consistently associated with IgA nephropathy across diverse populations, its protein product isolated and characterized, and its role in pathogenesis elucidated, then a new era in targeted therapy of IgA nephropathy will be unleashed, much in the same way as the identification of tyrosine phosphatases played a role in the design of targeted therapy in chronic myelogenous leukemia. Early progress is being made in this area, but many obstacles lie in the way.

Proteomics may prove useful in diagnosis and prognosis of IgA nephropathy

Proteomics—the characterization and analysis of the patient’s entire complement of serum and urinary proteins—is a new, exciting, and largely unexplored area in IgA nephropathy. Preliminary studies have shown that this technique may provide a novel noninvasive means of diagnosing IgA nephropathy, and it may have additional value as a prognostic tool.16

Much work needs to be done to standardize how specimens are collected, stored, and shipped and to verify the precision and accuracy of proteomics in diverse populations of patients with IgA nephropathy, patients with other glomerular diseases, and normal subjects to ascertain this technique’s false-negative and false-positive rates.

IgA1 testing may help detect IgA nephropathy early in its course

Abnormally undergalactosylated and oversialyted epitopes at the hinge region of the IgA1 molecule play a critical role in the pathogenesis of sporadic IgA nephropathy.17 This discovery provides a great opportunity for profiling patients suspected of having IgA nephropathy on the basis of sensitive determination of the serum level of these abnormal IgA1 molecules.7

It may be that pathogenic IgA1 molecules (and autoantibodies to them) arise many months or even years before the onset of clinical manifestations of overt IgA nephropathy, similar to the situation known to occur in systemic lupus erythematosus. It is also possible that an abnormality of the disposal of immune complexes created by the interaction of autoantibodies with the abnormally glycosylated IgA1 creates the opportunity for preferential glomerular mesangial deposition of polymeric IgA.

Clearly, the greatest opportunity lies with understanding the fundamental abnormality leading to defective O-linked galactosylation of the serine/threonine residues at the hinge region of IgA1 in IgA nephropathy. In addition, it would be very useful to know if this is a generalized and acquired abnormality or whether it is focal in distribution (eg, in the tonsils, bone marrow, or lymphoid tissue in the gut).

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