Knowledge of secondary mediators may also lead to new treatments for IgA nephropathy
Detailed knowledge of the participation of specific cell types and the “cytokine milieu” (eg, interleukin 4, interferon) in directing the abnormality toward defective glycosylation would also be very important in designing new approaches to diagnosis and therapy.
A better understanding is slowly emerging of the pathways by which pathogenic immune complexes containing IgA are deposited and cleared, and of the secondary mediator systems evoked by their formation and tissue localization. Interference with these secondary mediator processes, such as alternative or mannose-dependent complement activation, platelet-derived growth factor or transforming growth factor stimulation, also offers a new approach to therapy.
We lack a suitable animal model of IgA nephropathy that mimics all aspects of the human condition, which has impeded progress in this area. A fully humanized mouse model of disease would be a welcome addition to the investigative toolkit.
Prognostic biopsy analysis may be improved in IgA nephropathy
As discussed above, the science of prognostication and stratification of patients with IgA nephropathy into those at high or low risk of ESRD has clearly advanced but is still quite incomplete, especially with respect to individual patients.
Great opportunities lie in refining the value of renal biopsy in prognostication. Although the “snapshot” nature and potential sampling errors intrinsic to diagnostic renal biopsy cannot easily be overcome, at least not without performing multiple and repeated renal biopsies (a very impractical approach to prognostication), refinements in the laboratory seem to offer numerous opportunities for advancement. Much better clinicopathological correlations, especially with respect to outcomes, among well-characterized patients with IgA nephropathy are greatly needed. New nonconventional markers of progression, such as “tubulitis,” deposition of fibroblast-specific proteins, and the proteome of the deposited immunoglobulins and complement show much promise.18
Immunosuppressive therapy could be added to ACE inhibitors or ARBs in IgA nephropathy
The management of IgA nephropathy has clearly advanced over the last several decades, largely as the result of randomized clinical trials.3,19 However, these trials had serious limitations: the numbers of patients were relatively small, follow-up was relatively short, and the findings may not apply to the IgA nephropathy population at large or to specific patients having features that diverge from those in the patients enrolled in the studies.
The value of initial therapy with an ACE inhibitor, an ARB, or both in combination appears well established. However, details of dosage, duration of therapy, and the relative values of monotherapy and combined therapy remain uncertain.
Many opportunities for combining angiotensin II inhibition and immunosuppressive therapy are being explored. By and large, all current therapies are empiric and their long-term effects relatively uncertain, owing to small study size and short duration.
Oral and parenteral glucocorticoids,20 combined regimens of cyclophosphamide (Cytoxan) and azathioprine (Imuran),21 omega-3 fatty acids,22 and anticoagulants and anti-thrombotics3 each have their advocates and their specified target populations.
Tonsillectomy as a treatment has been particularly controversial. While no controlled studies have been performed yet, observational studies (most of them conducted in some prefectures in Japan) have suggested a higher rate of clinical remission with tonsillectomy than with steroid treatment alone.5 However, long-term observations have not shown any consistent effect of tonsillectomy on progression to ESRD.
We hope that a better understanding of the fundamental mechanisms of disease and its mediation will provide an impetus for development of more rational targeted therapy. Evaluating potentially promising targeted therapies will be very difficult. Evaluation of safety and efficacy with long-term use will be a key requirement for a successful novel therapeutic agent.
FOR NOW, AN EMPIRIC APPROACH TO IGA NEPHROPATHY
Start with an angiotensin II inhibitor
The current body of evidence for choosing a particular therapeutic approach for a given patient with IgA nephropathy cannot be regarded as definitive, owing to limitations in the quality and strength of the trials serving as the basis of the evidence. Nonetheless, patients with IgA nephropathy and abnormal protein excretion (> 500 mg/day) should probably always be given angiotensin II inhibitor therapy (an ACE inhibitor, an ARB, or both) if they have no contraindications to it such as a hypersensitivity reaction or pregnancy, as a base for future monitoring and adjuvant therapy.
A response, tentatively defined as a 30% to 50% decline in proteinuria from baseline levels or a decrease to less than 500 mg/day, would be a reason to continue this conservative approach. Lack of a response after several months of observation at maximal tolerated dosage (plus salt restriction or a diuretic) would be a reason for considering adjuvant therapy.
If the patient does not respond to an ACE inhibitor or ARB and his or her estimated GFR is over 70 mL/min/1.73 m2, a trial of oral and parenteral glucocorticoids might be undertaken, as suggested by Pozzi and coworkers.20
On the other hand, if the estimated GFR is in the range of 30 to 70 mL/min/1.73 m2 and declining at a rate that predicts that ESRD will develop in less than 5 to 7 years, this would be a possible indication for low-dose oral cyclo-phosphamide and then azathioprine, as suggested by Ballardie and Roberts.21 Omega-3 fatty acids (Omacor) could also be considered as add-on therapy, particularly for patients with very heavy proteinuria (> 3.0 g/d) and reduced estimated GFR.22
Patients with an estimated GFR of less than 30 mL/min/1.73 m2 and chronic (irreversible) changes on renal biopsy—the point of no return—probably will not respond to any therapy other than an ACE inhibitor, an ARB, or both.