Rosanna Coppo, Licia Peruzzi, Alessandro Amore, Antonio Piccoli, Pierre Cochat, Rosario Stone, Martin Kirschstein, Tommy Linné
IgACE: a placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria.
J Am Soc Nephrol. 2007 Jun;18(6):1880-8. doi: 10.1681/ASN.2006040347. Epub 2007 May 18.
Abstract/Text
This European Community Biomedicine and Health Research-supported, multicenter, randomized, placebo-controlled, double-blind trial investigated the effect of an angiotensin-converting enzyme inhibitor (ACE-I) in children and young people with IgA nephropathy (IgAN), moderate proteinuria (>1 and <3.5 g/d per 1.73 m(2)) and creatinine clearance (CrCl) >50 ml/min per 1.73 m(2). Sixty-six patients who were 20.5 yr of age (range 9 to 35 yr), were randomly assigned to Benazepril 0.2 mg/kg per d (ACE-I) or placebo and were followed for a median of 38 mo. The primary outcome was the progression of kidney disease, defined as >30% decrease of CrCl; secondary outcomes were (1) a composite end point of >30% decrease of CrCl or worsening of proteinuria until > or =3.5 g/d per 1.73 m(2) and (2) proteinuria partial remission (<0.5 g/d per 1.73 m(2)) or total remission (<160 mg/d per 1.73 m(2)) for >6 mo. Analysis was by intention to treat. A single patient (3.1%) in the ACE-I group and five (14.7%) in the placebo group showed a worsening of CrCl >30%. The composite end point of >30% decrease of CrCl or worsening of proteinuria until nephrotic range was reached by one (3.1%) of 32 patients in the ACE-I group, and nine (26.5%) of 34 in the placebo group; the difference was significant (log-rank P = 0.035). A stable, partial remission of proteinuria was observed in 13 (40.6%) of 32 patients in the ACE-I group versus three (8.8%) of 34 in the placebo group (log-rank P = 0.033), with total remission in 12.5% of ACE-I-treated patients and in none in the placebo group (log-rank P = 0.029). The multivariate Cox analysis showed that treatment with ACE-I was the independent predictor of prognosis; no influence on the composite end point was found for gender, age, baseline CrCl, systolic or diastolic BP, mean arterial pressure, or proteinuria.
N Yoshikawa, H Ito, T Sakai, Y Takekoshi, M Honda, M Awazu, K Ito, K Iitaka, Y Koitabashi, K Yamaoka, K Nakagawa, H Nakamura, S Matsuyama, Y Seino, N Takeda, S Hattori, M Ninomiya
A controlled trial of combined therapy for newly diagnosed severe childhood IgA nephropathy. The Japanese Pediatric IgA Nephropathy Treatment Study Group.
J Am Soc Nephrol. 1999 Jan;10(1):101-9.
Abstract/Text
The most appropriate treatment for patients with IgA nephropathy is controversial. Treatment with prednisolone, azathioprine, heparin-warfarin, and dipyridamole early in the course of disease may prevent immunologic renal injury in children with severe IgA nephropathy. To determine whether similar results can be obtained with a combination of just heparin-warfarin and dipyridamole, the effects of such treatment were compared to those of treatment with prednisolone, azathioprine, heparin-warfarin, and dipyridamole in 78 children with newly diagnosed IgA nephropathy showing diffuse mesangial proliferation. The patients were randomly assigned to receive either prednisolone, azathioprine, heparin-warfarin, and dipyridamole for 2 yr (group 1) or heparin-warfarin and dipyridamole for 2 yr (group 2). All of the 40 patients in group 1 and 34 of the 38 patients in group 2 completed the trial. The mean urinary protein excretion fell in group 1 patients (P < 0.0001), but remained unchanged in group 2 patients. The mean serum IgA concentration was reduced in group 1 patients (P = 0.0002), but was unchanged in group 2 patients. BP and creatinine clearance were normal at the end of the trial in all but one group 2 patient, who developed chronic renal insufficiency. The percentage of glomeruli showing sclerosis was unchanged in group 1 patients, but increased in group 2 patients (P = 0.006). The intensity of mesangial IgA deposits decreased in group 1 patients (P = 0.02), but remained unchanged in group 2 patients. In conclusion, the present study shows that treatment of children with severe IgA nephropathy with prednisolone, azathioprine, heparin-warfarin, and dipyridamole for 2 yr early in the course of disease reduces immunologic renal injury and prevents increase of sclerosed glomeruli.
Norishige Yoshikawa, Masataka Honda, Kazumoto Iijima, Midori Awazu, Shinzaburou Hattori, Koichi Nakanishi, Hiroshi Ito, Japanese Pediatric IgA Nephropathy Treatment Study Group
Steroid treatment for severe childhood IgA nephropathy: a randomized, controlled trial.
Clin J Am Soc Nephrol. 2006 May;1(3):511-7. doi: 10.2215/CJN.01120905. Epub 2006 Apr 5.
Abstract/Text
A previous trial showed that treatment of children with severe IgA nephropathy (IgAN) using prednisolone, azathioprine, heparin-warfarin, and dipyridamole for 2 yr early in the course of disease reduced the severity of immunologic renal injury and prevented any increase in the percentage of sclerosed glomeruli. This study compared the effects of prednisolone, azathioprine, warfarin, and dipyridamole (combination) with those of prednisolone alone in 80 children with newly diagnosed IgAN that showed diffuse mesangial proliferation. Patients were randomly assigned to receive either the combination or prednisolone alone for 2 yr. The primary end point was the disappearance of proteinuria, defined as urinary protein excretion <0.1 g/m2 per d, and the secondary end points were urinary protein excretion at the end of treatment, the change in the percentage of sclerosed glomeruli during the trial, and adverse effects. The two study groups were similar in terms of baseline characteristics. Thirty-nine of the 40 patients who received the combination and 39 of the 40 who received prednisolone completed the trial. Thirty-six (92.3%) of the 39 patients who received the combination and 29 (74.4%) of the 39 who received prednisolone reached the primary end point by the 2-yr follow-up point (P = 0.007 log-rank). The percentage of sclerosed glomeruli was unchanged in the patients who received the combination but increased from 3.1 +/- 4.8 to 14.6 +/- 15.2% in the prednisolone group (P = 0.0003). The frequency of adverse effects was similar in the two groups. It is concluded that combination treatment may be better for severe IgAN than treatment with prednisolone alone.
Norishige Yoshikawa, Koichi Nakanishi, Kenji Ishikura, Hiroshi Hataya, Kazumoto Iijima, Masataka Honda, Japanese Pediatric IgA Nephropathy Treatment Study Group
Combination therapy with mizoribine for severe childhood IgA nephropathy: a pilot study.
Pediatr Nephrol. 2008 May;23(5):757-63. doi: 10.1007/s00467-007-0731-8. Epub 2008 Jan 26.
Abstract/Text
In two previous randomized controlled trials we showed that treatment of severe childhood immunoglobulin A nephropathy (IgA-N) using prednisolone, azathioprine, heparin-warfarin, and dipyridamole prevented any increase of sclerosed glomeruli and that prednisolone alone did not prevent a further increase of sclerosed glomeruli. Accordingly, the immunosuppressant is considered to be important. Often, however, we were unable to complete azathioprine regimen due to toxicity. Therefore, a different but effective immunosuppressant may be worth trying. Mizoribine, like azathioprine, is an antimetabolite that exerts its immunosuppressant effect by inhibiting lymphocyte proliferation. In this pilot study, we administered mizoribine instead of azathioprine as part of the combination therapy for treating 23 children with severe IgA-N and evaluated the efficacy and safety. Eighteen patients reached the primary endpoint (urine protein/creatinine ratio <0.2) during the 2-year treatment period. The cumulative disappearance rate of proteinuria determined by Kaplan-Meier was 80.4%. Median protein excretion was reduced from 1.19 g/m(2)/day to 0.05 g/m(2)/day (p < 0.0001). After treatment, the median percentage of glomeruli showing sclerosis was unchanged in comparison with that before treatment. No patients required a change of treatment. In conclusion, the efficacy and safety of the mizoribine combination seems to be acceptable for treating children with severe IgA-N.
