IgA nephropathy: what’s new?
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Although IgA nephropathy has only been recognized as a definitive entity for fewer than 40 years, its place in the world as a prominent cause for progressive kidney disease is well established. The extent to which we understand the role of genetically derived abnormal forms of the IgA molecule in the disease is evolving, and this will, hopefully, translate into more specific modes of treatment for patients in the future. In the meantime, we have few specific therapeutic options, most of which have not been well studied in large numbers of patients. The extent to which we can define which patients are likely to progress—and hence should be considered candidates for treatment—will be discussed in this Commentary. In addition, the notion that some patients may have reached “the point of no return” will also be addressed. Unfortunately, most of the comments will be based on results obtained in studies conducted in adults—a situation that is very familiar to pediatric nephrologists.
KeywordsIgA nephropathy Children Glycosylation Prognosis
Background and epidemiology
IgA nephropathy (IgAN) is defined as a form of glomerulonephritis in which dominant or co-dominant deposition of IgA in the glomerular mesangium is observed. Since IgAN was first described by Berger in 1968, it has become recognized as the most common form of glomerulonephritis afflicting both children and adults in many parts of the world [1, 2, 3, 4]. This is particularly evident in countries where renal biopsy is widely practiced and in those countries in which annual mass screening of school children is the rule . The degree and level of chronicity of histopathologic injury varies between patients, and this is reflected in the wide spectrum of clinical features observed at the time of clinical presentation [5, 6]. This review will discuss briefly some recent reports that have advanced our knowledge regarding patients with IgAN. More extensive reviews of this subject have been published recently [5, 7].
The diagnosis of IgAN requires a renal biopsy that is processed for immunofluorescence and light microscopy. Although elevated serum IgA levels are often observed in patients with IgAN, there is too much variability for this to be of diagnostic help. There have been no recent non-invasive techniques developed that can establish the diagnosis of IgAN.
Recent studies have documented abnormally low glycosylation of IgA1 molecules in patients with IgAN [8, 9, 10, 11]. This results in the formation of IgA immune complexes that are not taken up and recycled by hepatocytes, as is normally the case. These abnormal IgA complexes have an increased propensity for mesangial deposition, leading to mesangial cell activation . A recent study by Li et al. provides evidence for a genetic predisposition to this anomaly . It is likely that a more complete understanding of the pathogenesis of IgAN will be forthcoming in the next few years as a result of ongoing studies of the glycosylation defect.
The natural history of IgAN varies greatly in patients of all ages [6, 7]. Some children with IgAN experience frequent episodes of gross hematuria, although this finding has been reported less often in Japan and Korea, where IgAN is often diagnosed after a child is noted to have microscopic hematuria +/− proteinuria during a school screening urinalysis program . Up to 30% of adult patients with IgAN have slowly progressive disease, leading eventually to end-stage renal disease (ESRD) . The prognosis for children with the disorder is more favorable—at least during the pediatric years. It is unclear whether the long-term prognosis is different from that observed in adults.
Clinical features which mark a poor prognosis include moderate-to-severe degrees of proteinuria, renal insufficiency and hypertension [6, 7]. In most patients the level of proteinuria appears to correlate with the severity of renal parenchymal damage, although there is a small sub-group in whom the renal biopsy findings are consistent with minimal change disease. These patients are usually steroid sensitive. Recent studies of adults suggest that high serum uric acid levels correlate with renal histopathology and a poor prognosis , but this has not been evaluated in children. Histopathologic features that portend a poor prognosis include glomerulosclerosis, fibrous crescents, tubular atrophy and interstitial fibrosis [6, 7]. Some reports have suggested that peripheral capillary wall IgA deposits (in addition to mesangial deposits) have prognostic significance. Unfortunately, none of these prognostic indicators has sufficient specificity to identify the likely outcome in an individual patient. However, it is likely that all children and adolescents with hypertension and/or moderate-to-severe proteinuria associated with IgAN are at risk for progressive disease and should be regarded as candidates for therapeutic intervention.
Review of treatment options
Although recent literature contains a number of reports on the treatment of IgAN, most of these have involved relatively few patients, making their conclusions suspect. Since the progression of IgAN is usually slow, it is important to study large numbers of patients for prolonged periods of time to define the efficacy of any therapeutic intervention. Although the most relevant outcome indicator for all patients with IgAN is based on deterioration of glomerular filtration rate (GFR), the period from diagnosis to ESRD in most patients, especially children, may be over many decades. Thus, many studies of therapy for IgAN have relied on surrogate markers, such as improvement of renal biopsy findings, and/or decline in the amount of proteinuria or hematuria, in order to reach a conclusion within a reasonable period of time.
Approach to the treatment of a patient with IgAN
It is important to maintain all children and adolescents with IgAN in a normotensive range, utilizing norms for blood pressure that are appropriate for age, gender and height . It is most appropriate to prescribe angiotensin antagonists for patients with hypertension and/or proteinuria [15, 16, 17, 18]. Whether such patients should be treated with maximal tolerated doses of an ACE inhibitor alone or with an ACEi combined with angiotensin receptor blockers (ARBs) has not been fully defined. In a recent placebo-controlled clinical trial, investigators in 23 European centers evaluated the effect of benazepril (0.2 mg/kg per day) on proteinuria and renal function in 57 children and young adults <35 years of age . The patient cohort included 29 patients ≤18 years of age, and 74% of the patients had their initial renal abnormalities when they were ≤18 years of age. A significant benefit was observed with benazepril in preventing progression of renal disease in those patients (defined as reduction in GFR by 30% versus baseline, or worsening of proteinuria to ≥3.5 g/1.73 m2 body surface area per day). Such progression was seen in 9/34 (26%) of the placebo group but only 1/23 (4%) of the benazepril group. The percentage of patients with proteinuria <0.5 g/1.73 m2 per day in the benazepril group at the end of the trial was significantly higher than in the placebo group [13/23 (56%) vs 3/34 (9%), P = 0.0002].
Although there are no prospective clinical trials evaluating the role of tonsillectomy in patients with IgAN, a series of reports over the past 20 years has advocated this procedure for children and adult patients with IgAN. Many of those reports indicated that such patients have fewer episodes of gross hematuria following tonsillectomy. However, there has been little information regarding the impact of the procedure on the long-term outcome of the patients . Most of the “studies” are retrospective in nature, and many of them evaluated the benefit of tonsillectomy in patients who received multiple other concomitant medications. At the present time, there is no convincing evidence that tonsillectomy interferes with progressive IgAN in children or adults.
Patients with rapidly declining GFR
Crescentic IgAN associated with active glomerular inflammation and deteriorating renal function in the absence of significant chronic damage should be treated very aggressively. The prognosis for children and adults with crescentic IgAN has been dismal in most reports, although some uncontrolled studies have indicated that pulse steroids given intravenously may be efficacious. A recent report on adults provided a thorough overview of the options available when a patient is found to have crescentic IgAN 
Patients with nephrotic range proteinuria and/or other risk factors for progressive disease
As stated previously in this commentary, children who present with the nephrotic syndrome, normal renal function and light microscopy showing minimal glomerular changes often respond well to a regimen appropriate for minimal-change nephrotic syndrome (NS). However, most patients with high grades of proteinuria have more severe renal histology, and these patients are the most challenging from the standpoint of developing a treatment strategy that is appropriate for their needs [5, 6, 7]. The next few sections will discuss treatment options that have been studied recently in such patients. Most of those studies have included corticosteroids in the therapeutic approaches.
Two recent studies have shown very dissimilar effects of corticosteroid therapy in adult patients with IgAN. This most likely resulted from the very different levels of the intensity of therapy employed by the two groups of investigators [21, 22]. Pozzi et al. used an aggressive regimen that included nine 1 g intravenous (i.v.) pulses of methylprednisolone , whereas Katafuchi et al. evaluated the efficacy of low-dose prednisone—with inferior results . A recent multicenter, placebo-controlled trial was conducted by the Southwest Pediatric Nephrology Study Group (SPNSG), to compare the efficacy of a 24-month course of a tapering dose of alternate-day prednisone (60 mg/m2 q.o.d. for 3 months; 40 mg/m2 q.o.d. for 9 months; then 30 mg/m2 q.o.d. for 12 months) versus placebo in both children and adults with IgAN . The results showed no benefit from prednisone therapy when the outcome was based on a decrease of GFR to less than 60% of baseline . However, significant improvement was detected in patients receiving prednisone compared to placebo throughout the period of therapy when the efficacy was determined on the basis of changes in the level of proteinuria compared to baseline .
The efficacy of prednisone combined with azathioprine was recently evaluated by two studies in children by Yoshikawa et al. [25, 26]. In one prospective randomized clinical trial (PRCT), the effect of combination therapy using prednisone (P), azathioprine (A), heparin (H), warfarin (W) and dipyridamole (D) in 40 children was compared with that of prednisone alone in 40 children . Both regimens were given for 24 months. All patients were required to have IgA nephropathy associated with diffuse mesangial hypercellularity on initial renal biopsy. Patients in each of the treatment arms showed considerable improvement in proteinuria. This was observed in 92% of the combination therapy group and in 74% of the prednisone group (P difference = 0.007). The authors also noted that the combination therapy was not associated with any increase in glomerulosclerosis, whereas this progressed significantly in the group on prednisone (P = 0.0003). It should be noted, however, that patients in this trial were not allowed to receive ACEi or ARB therapy.
In earlier PRCT, Yoshikawa et al. compared the efficacy of the same combination therapy versus H/W/D . The combination group had a significant reduction of proteinuria following therapy (1.35 g per day to 0.22 g per day), while the H/W/D group patients did not (0.98 g per day to 0.88 g per day). There was also a significant decrease in glomerular IgA staining in follow-up biopsies in the first group of patients but not in the second group. Repeat biopsies again showed progression of glomerular sclerosis in control patients but not in those receiving P/A/H/W/D.
Mycophenolate mofetil (MMF) is an immunosuppressive drug that inhibits purine synthesis. There have been no controlled trials evaluating the efficacy and safety of MMF in children with IgAN. In trials of this agent in adults with IgAN, the results have been mixed. Two studies conducted in the western hemisphere have shown no benefit from MMF in this condition [27, 28], whereas two other studies—from the Orient—have demonstrated significant improvement in proteinuria [29, 30]. It is not clear why these trials produced discordant results. Possible explanations include the small numbers of patients in each trial; the different therapeutic combinations and study designs that were employed, and varying degrees of severity and chronicity of the renal lesions when patients were enrolled into the trials. We are hoping to clarify the role of MMF in a multicenter trial that is ongoing in the USA . In this trial, which involves both children and adults, patients are only randomized to receive MMF or placebo if they continue to show significant proteinuria after a 3-month course of high-dose omega-3 fatty acids and ACE inhibitors (lisinopril)—or ARB (losartan) if patients are unable to tolerate the ACEi.
A recent retrospective study in Japan showed that mizoribine, which blocks purine synthesis in a manner similar to that of MMF, resulted in a significant reduction in proteinuria when given to 20 patients in combination with prednisolone (P), warfarin (W) and dipyridamole (D) . This was significantly better than the reduction in proteinuria seen in 21 historic control patients who were given only P, W, and D, or in 20 historic control patients who received i.v. pulses of methylprednisolone in addition to P, W, and D. Follow-up renal biopsies in the mizoribine-treated patients showed no progression of chronic lesions, whereas the other two sets of patients had a significant increase in the chronicity index .
Fish oil/omega 3 fatty acids
The use of omega-3 fatty acid supplements, in various doses and formulations, for patients with IgA nephropathy has been a controversial issue for over 15 years. Most of the studies have excluded pediatric patients and, hence, we must extrapolate our conclusions from results obtained in adults. The largest study—and the one reporting the most positive results—was published by Donadio et al. in 1994 . In this trial, the members of the Mayo Nephrology Collaborative Group provided evidence that patients who received omega-3 fatty acids for 2 years had better preservation of GFR than did a control group. Of interest, the authors did not observe any benefit of their treatment on the level of proteinuria. In studies that we have conducted we have been unable to confirm the observations of Donadio et al. on GFR , but we observed a rather striking dose per kilogram dependent effect of omega-3 fatty acids on plasma phospholipid fatty profiles and on the level of proteinuria after both 3 months and 24 months of therapy . Donadio et al. have subsequently confirmed our observation on the fatty acid profiles, but not on the level of proteinuria . It is, therefore, unclear whether the discordant results in the previous studies relate to the various doses of omega-3 fatty acids given to patients in the different trials. Based upon the limited evidence available now, we are unable to make a firm recommendation regarding the use of fish oil supplements for treatment of IgAN in pediatric patients. However, the lack of any significant side-effects, and the potential for benefit, makes omega-3 fatty acid preparations an attractive initial option for patients with IgAN and proteinuria.
Summary and conclusions
- 23.Hogg R, Lee J, Nardelli N, Julian B, Cattran, Waldo B, Wyatt R, Jennette J, Sibley R, Hyland K, Fitzgibbons L, Hirschman G, Donadio J, Holub B (2006) Clinical trial to evaluate omega-3 fatty acids and alternate day prednisone in patients with IgA nephropathy: report from the Southwest Pediatric Nephrology Study Group. Clin J Am Soc Nephrol 1:467–474CrossRefGoogle Scholar
- 26.Yoshikawa N, Ito H, Sakai T, Takekoshi Y, Honda M, Awazu M, Ito K, Iitaka K, Koitabashi Y, Yamaoka K, Nagagawa K, Nakamura N, Matsuyama S, Seino Y, Takeda N, Hattori S, Ninomiya M, Japanese Pediatric IgA Nephropathy Treatment Group (1999) A controlled trial of combined therapy for newly diagnosed severe childhood IgA nephropathy. J Am Soc Nephrol 10:101–109PubMedGoogle Scholar
- 28.Frisch G, Lin J, Rosenstock J, Markowitz G, D’Agati V, Radhakrishnan J, Preddie D, Crew J, Valeri A, Appel G (2005) Mycophenolate mofetil (MMF) vs placebo in patients with moderately advanced IgA nephropathy: a double-blind randomized controlled trial. Nephrol Dial Transplant 20:2139–2145CrossRefGoogle Scholar
- 30.Chen X, Chen P, Cai G, Wu J, Cui Y, Zhang Y, Liu S, Tang L (2002) A randomized control trial of mycophenolate mofetil treatment in severe IgA nephropathy. Zhonghua Yi Xue Za Zhi 25:796–801Google Scholar
- 32.Kawasaki Y, Hosoya M, Suzuki J, Onishi N, Takahashi A, Isome M, Nozawa R, Suzuki H (2004) Efficacy of multidrug therapy combined with mizoribine in children with diffuse IgA nephropathy in comparison with multidrug therapy without mizoribine and with methylprednisolone pulse therapy. Am J Nephrol 24:576–581CrossRefGoogle Scholar
- 35.Barratt J, Feehally J, Hogg R (2007) Management of IgA nephropathy: evidence-based recommendations for adults and children. BMJ Publications (in press)Google Scholar