Steroids and Azathioprine in Early and Advanced IgA Nephropathy: Amendments to a Prospective Randomised Multicenter Trial

It is know well established that IgAN outcome is often unfavourable, with end-stage renal disease (ESRD) occurring in 5-25% of cases within ten years and in 25-50% of cases within 20 years. The degree of impairment in renal function at presentation is certainly an important predictor of this poor outcome. However, although high serum creatinine at the time of diagnosis may allow the detection of patients who are more likely to progress (and perhaps may get some benefit from therapy), no established treatment exists in advanced IgAN. This is likely explained by the fact that renal impairment is often associated with renal biopsy indexes of chronicity such as glomerular sclerosis, tubulointerstitial atrophy or fibrosis. It has also been suggested that in this disease, as in other chronic nephropathy, there is "a point of no return" after which non-immunological mechanisms have been considered to play a central role in a relentless progression.

Most patients with IgAN develop ESRD in middle age and this represents not only a significant problem for the patient itself but also a social and economic burden for society as a whole. For this reason, while waiting for more specific therapies able to complete prevent progression in IgAN, the possibility of delaying the beginning of renal replacement therapy of some years could be considered an important goal in these patients.

In this regard, the investigators were impressed from the results of an uncontrolled retrospective study of combined treatment with corticosteroids for 18 months and azathioprine for 24 months. Although the treatment seemed to be ineffective in the patients with normal renal function (because of the very low number of events in this very-slowly progressive group) and the lack of randomisation led to a severe bias concerning the choice of the patients to be treated (higher risk patients), in those with impaired renal function, a smaller percentage of treated subjects had a progressive course (20.5% vs 63.4%, p < 0.001). Similarly, Tsuruya et al. retrospectively found that combination therapy with prednisolone and cyclophosphamide was effective in reducing urinary protein excretion and in slowing the rate of progression in histologically advanced IgAN.

Given all these consideration, the investigators decided to test the efficacy of the combination of steroids with azathioprine at various degree of renal function deterioration by extending the trial to patients with more advanced disease (serum creatinine > 2 mg/dl). Considering the high likelihood of these patients to have a certain degree of sclerosis and that in focal segmental glomerulosclerosis longer treatments seem to lead to slightly better results in term of achievement and maintenance of partial and complete remissions, in the patients of amendment II the investigators decided to continue the treatment with steroids and azathioprine at a very low dose for other six months, with an overall one-year treatment duration.

Study design The patients are randomly allocated to treatment with steroids (methylprednisolone 1 g i.v. for three consecutive days at the beginning of months 1, 3 and 5, plus oral prednisone 0.5 mg/kg every other day for six months, then 0.2 mg/kg every other day for other six months) plus azathioprine 1.5 mg/kg/day for six months and 50 mg/day for other six months (experimental group) or steroids alone (methylprednisolone 1 g i.v. for three consecutive days at the beginning of months 1, 3 and 5, plus oral prednisone 0.5 mg/kg every other day for six months, then 0.2 mg/kg every other day for other six months) (control group).