1 Centro Multidisciplinare di Immunopatologia (CMID), 2 Divisioni di Nefrologia e Dialisi, Ospedali G. Bosco, 3 CTO, 4 Torino, Istituto di Nefrourologia and 5 Dipartimento di Medicina ed Oncologia Sperimentale, Scuola di Specializzazione di Patologia Clinica, Università di Torino, Torino, Italy
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. The effects of a combined schedule of prednisone and cyclophosphamide was analysed in the specific subset of IgA nephropathy patients with acute inflammatory histologic changes associated with haematuria and proteinuria. Two groups of patients, with similar histologic lesions and clinical presentation, were considered. The first group (12 patients) was treated within 1 week after renal biopsy; starting with three pulses of methylprednisolone (1 g) followed by oral prednisone (0.8 mg/kg body weight for 2 weeks, 0.6 mg/kg for another 2 weeks, 0.4 mg/kg for an additional 4 weeks, then slowly tapered by 5 mg each month until discontinuation) and 1.5 mg/kg cyclophosphamide for 2 months. A second sample of eight untreated patients served as a control group. Treated and untreated patients had diffuse mesangial proliferation with florid crescents (860% in treated and 1040% in untreated patients) with mild degree of glomerular sclerosis and interstitial changes. Basal creatinine (167 µmol/l, range 79371 vs132 µmol/l, range 79256) and proteinuria (3.0 g/24 h, 1.04.9 vs 3.3 g/24 h, 1.013.7) were not statistically different between treated and untreated patients respectively. Nine treated and six untreated patients were hypertensive. Blood pressure treatment did not include ACE-inhibitors.
Results. Untreated patients' 5-year renal survival, as assessed by the KaplanMeier method, was found to be significantly lower than treated patients (37.5 vs 91.6%, log-rank P=0.01 and Breslow test P=0.008; relative risk to reach the endpoint of a 100% increase in serum creatinine=3.58, P=0.03).
Conclusion. This short course of therapy with prednisone and cyclophosphamide has been effective in a subset of IgA nephropathy patients with florid glomerular changes and major urinary abnormalities, turning off phlogistic activity and preventing subsequent progression toward renal failure.
Keywords: corticosteroids; cyclophosphamide; IgA nephropathy; renal disease progression
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In order to assess the long-term effects of a combination of prednisone and cyclophosphamide on renal function in a subset of IgA nephropathy patients with acute phlogistic histologic changes associated with haematuria and proteinuria, two samples of patients with similar histologic lesions and clinical presentation were compared.
![]() |
Subjects and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Based on Emancipator's descriptive classification [1], treated patients could be defined as B (one case), C (seven cases), D (four cases); k (eight cases), K (two cases), s (seven cases), S (one case), a (six cases) and A (five cases). They had focal (1 case) or diffuse (11 cases) mesangial proliferation with superimposed focal endocapillary proliferation found in four cases. Florid, i.e. cellular crescents (ranging between 8 and 60%) were present in 10 cases (30% in eight and >30% in two), glomerular sclerosis in eight cases (
30% in seven and >30% in one), and tubular atrophy or interstitial fibrosis in 11 cases (moderate in six and severe in five). Untreated patients were B (two cases), C (six cases), k (four cases), K (two cases), s (two cases), S (one case), a (two cases) and A (four cases). They had focal (two cases) or diffuse (six cases) mesangial proliferation with crescents ranging between 10 and 40% in six cases (
30% in four and >30% in two), glomerular sclerosis in three cases (
30% in two and >30% in one) and tubular atrophy and/or interstitial fibrosis in six cases (moderate in two and severe in four). Fibrinoid necrosis was present in one treated and one untreated patient. There was no difference in the immunofluorescence pattern between the two patients' samples. C3 was detected in all the treated and untreated cases and IgG was found in nine treated and six untreated cases. Capillary deposits of immunoreactants were detected in six treated and six untreated patients. The same pathologist examined each renal specimen including at least 10 glomeruli.
Age, basal serum creatinine (167±96 (SD) (range 79371) µmol/l vs 132±61 (range 79256) µmol/l, and proteinuria (3.0±1.5 (1.04.9) g/24 h and 3.3±4.2 (1.013.7) g/24 h) were not statistically different between treated and untreated patients respectively. At enrolment, five out of 12 treated and two of eight untreated patients had nephrotic range proteinuria (3.5 g/day), and nine treated and six untreated patients were hypertensive. Blood pressure treatment did not include ACE-inhibitors.
Mean blood pressure values were targeted at 90±5 mmHg. Types of anti-hypertensive medication included calcium antagonists, adrenergic antagonists and centrally acting alpha 2-adrenergic agonists.
Statistics
The KaplanMeier method was used to analyse renal survival. Treated and untreated groups were compared by means of the log-rank and Breslow test. Survival analysis was based on the deterioration of the renal function over time, with a 100% increase in baseline serum creatinine value as an endpoint. Despite the small size of patient samples, Cox's regression proportional hazards model was used to estimate the relative risk associated with the baseline covariates of gender, age, serum creatinine, proteinuria, hypertension and haematuria. MannWhitney and Wilcoxon tests were used to compare unpaired and paired observations.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Proteinuria levels significantly fell at 6 months (1.4±0.6, (0.54.9) g/24 h, P<0.05 compared to baseline values) in the treated group, but not in the untreated patients (3.4±2.4 (0.58) g/24 h). Similar significant differences were observed over the entire follow-up. At 60 months, mean proteinuria was 0.9±1.0 (0.12.8) g/24 h in the treated group and 2.9±3.1 (0.66) g/24 h in the untreated patients (P<0.05).
Based on KaplanMeier analysis, the per cent renal survival at 5 years was 37.5% for untreated patients which was significantly lower than for treated patients (91.6%; log-rank P=0.0107; Breslow test P=0.0082) (Figure 1).
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Several risk factors were simultaneously present in most patients of both treated and control groups. The poor clinical course of the untreated patients over a 5-year follow-up period was not surprising. Conversely, a relatively short course of therapy with steroids and cyclophosphamide was effective in this particular subset of patients with florid glomerular changes. In a few studies, treatment with fish oil [9] and ACE-inhibitors [10] appeared to be able to slow disease progression in patients with persistently proteinuric IgA nephropathy. In addition, high dose immunoglobulins [11] and mycophenolate mofetil [12] were shown to stabilize renal function in high risk patients with IgA nephropathy. Compared to other therapeutic approaches, the present schedule has low cost, safety and long-term efficacy.
In a recent controlled study, patients with non-nephrotic proteinuria, normal renal function, limited percentage of crescents and mild degree of tubular atrophy, and intestinal changes, showed a retardation in progression of renal failure and a sustained reduction in urinary protein excretion when treated with steroids [13]. Compared with that study, our patients had a more severe degree of renal disease. Nevertheless, they benefited by our schedule suggesting that an aggressive approach to active and severe phlogistic lesions prevented subsequent sequelae of cytokine-or autoacoid-mediated slow progression toward renal failure.
![]() |
Acknowledgments |
---|
![]() |
Notes |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|