Controlled trials of steroid treatments

Corticosteroid therapy for 6 to 24 months or more may be associated with a reduction in proteinuria and perhaps improved renal survival  , although this has not been consistently noted [64] . Benefit in some of these studies was observed only among individuals with preserved kidney function (eg, creatinine clearance above 70 mL/min) [75-78] . However, other studies have found improved outcomes even among individuals with more advanced disease (eg, reduced kidney function and more significant proteinuria)

As an example, a prospective trial from Italy included 86 adults with proteinuria (1 to 3.5 g/day) and at most mild renal insufficiency (median serum creatinine 1 mg/dL [88.4 µmol/L]) [77] . The patients were randomly assigned to supportive therapy alone, or corticosteroids (1.0 gram of intravenous methylprednisolone for three consecutive days at the beginning of months one, three, and five, combined with 0.5 mg/kg of oral prednisolone given on alternate days for six months).

At five and ten years, the steroid treated patients had a markedly lower incidence of the primary end point, which was a doubling in the serum creatinine concentration (2 versus 21 percent at five years and 2 versus 30 percent at ten years) [78] . The effect of ACE inhibitors was not assessed.
In contrast, the trial from the Southwest Pediatric Nephrology Study Group described above found no difference at three years between oral prednisone therapy for two years and placebo in the primary outcome of reduction in GFR to below 60 percent of the baseline value [64] . However, this trial was underpowered for the primary end-point (See "Fish oil" above).
There is a subset of patients with IgA nephropathy in whom prednisone therapy appears to be more clearly beneficial: those with an acute onset of the nephrotic syndrome, little or no hematuria, preserved kidney function, minimal glomerular changes on light microscopy, and diffuse fusion of the foot processes of the glomerular epithelial cells on electron microscopy. These histologic findings are characteristic of minimal change disease, and these patients behave accordingly, frequently developing a remission with corticosteroids and occasionally requiring cyclophosphamide for frequently relapsing proteinuria [83-85] . Mesangial IgA deposits often disappear or are greatly reduced over time [85] . (See "Treatment of minimal change disease in adults").

Nephrotic syndrome can also occur with severe chronic IgA nephropathy and relatively advanced disease on renal biopsy. These patients do not seem to benefit from steroid therapy alone [83,84] .
The role of corticosteroids alone in the treatment of IgA nephropathy is summarized below. (See "Treatment" below).

Combined immunosuppressive therapy — Combined immunosuppressive therapy should only be attempted in patients with more severe active disease as defined by a more rapidly progressive clinical course and/or histologic evidence of severe active inflammation (eg, crescent formation).
Severe or progressive disease — Several trials have suggested a possible benefit from combined immunosuppressive therapy in patients with moderate to severe active disease on biopsy; however, most did not include a comparison group treated with prednisone alone [67,86-90] . In addition, the studies were primarily performed prior to the widespread use of aggressive antihypertensive and antiproteinuric therapy with ACE inhibitors and/or ARBs. (See "Treatment goals" above and see "Antihypertensive therapy and progression of nondiabetic chronic kidney disease").

Two trials in children with moderate to severe histologic findings on renal biopsy, but normal kidney function (initial creatinine clearance >140 mL/min per 1.73 m2), evaluated complicated regimens that included heparin, warfarin and dipyridamole as well as combined immunosuppressive therapy [89,90] . No benefit was observed with these regimens compared with azathioprine and/or prednisone.

There are limited data concerning the effectiveness of cytotoxic agents in adults with progressive IgA nephropathy . Some trials evaluated cyclophosphamide with warfarin and dipyridamole  , a regimen that is not widely used, and one evaluated cyclophosphamide with prednisone [88] . The last trial was a single center study of 38 patients with IgA nephropathy and initially impaired renal function (but no crescents on biopsy) as defined by an initial serum creatinine concentration between 1.5 and 2.8 mg/dL (130 and 250 µmol/L, respectively) that was declining at a relatively moderate rate (by at least 15 percent over the year prior to study entry) [88] . Mean baseline protein excretion was 4.0 to 4.5 g/day.

The patients were given antihypertensive therapy as needed (but not specifically ACE inhibitors and/or ARBs) and randomly assigned to no further therapy or to prednisolone (40 mg per day tapered to 10 mg/day by two years) plus low-dose cyclophosphamide (1.5 mg/kg per day) for the initial three months followed by low-dose azathioprine (1.5 mg/kg per day) for a minimum of two years (some patients were given azathioprine for up to six years). Blood pressure control was similar in both groups, and immunosuppressive therapy was associated with a low incidence of adverse effects.

Compared with the control group, the patients treated with combination therapy had a significant reduction in protein excretion during the first six months of therapy that persisted during follow-up (eg, reached 1.8 g/day in treatment group versus unchanged at 4.4 g/day in controls at one year). Renal survival was significantly higher in the treatment group at years two (82 versus 68 percent) and five (72 versus 6 percent).

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