Steroid and cyclophosphamide in IgA nephropathy

Dario Roccatello1,2,, Michela Ferro4, Giulio Cesano4, Daniela Rossi1, Silvia Berutti4, Mario Salomone3, Giuseppe Piccoli4 and Luigi Massimino Sena5

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
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. IgA nephropathy is associated with a wide spectrum of possible lesions. Therefore, different responses to anti-inflammatory or immunosuppressive therapies should be expected with acute inflammatory changes, which are predominantly reversible, and with prevalently sclerotic lesions.

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 (8–60% in treated and 10–40% in untreated patients) with mild degree of glomerular sclerosis and interstitial changes. Basal creatinine (167 µmol/l, range 79–371 vs132 µmol/l, range 79–256) and proteinuria (3.0 g/24 h, 1.0–4.9 vs 3.3 g/24 h, 1.0–13.7) 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 Kaplan–Meier 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
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Due to its wide variability in clinical presentation and histologic changes, IgA nephropathy has been defined as a ‘microcosmos of glomerular lesions’ [1]. Some histologic lesions are irreversible and progress towards obliteration of glomerular capillaries; others are acute inflammatory processes, potentially susceptible to reversal by means of antiphlogistic and immunosuppressive therapies [1,2]. Therefore, it is difficult to identify truly homogeneous subsets of patients for treatment trials (especially if the entry criteria are based on a single variable such as urinary protein excretion). This possibly explains the conflicting results of reports on corticosteroids and cytotoxic drugs in these patients [3].

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
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 Subjects and methods
 Results
 Discussion
 References
 
Patients and therapeutic schedule
The first group (12 patients, six males and six females, mean age 38.8 years, range 17–77) 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 2 weeks, 0.4 mg/kg for additional 4 weeks and then slowly tapered by 5 mg each month until discontinuation) and 1.5 mg/kg of cyclophosphamide for 8 weeks. A second sample, including eight patients (five males and three females, mean age 46.2 years, range 18–62) with similar clinical and histologic features was not treated due to past history of cancer (one case), low therapeutic compliance (two cases), refusal (two cases) or recruitment from other Nephrology Divisions 3–5 months after renal biopsy (three cases). This served as a control group. Patients were recruited from 1992 to 1994 and were observed over 5 years.

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 79–371) µmol/l vs 132±61 (range 79–256) µmol/l, and proteinuria (3.0±1.5 (1.0–4.9) g/24 h and 3.3±4.2 (1.0–13.7) 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 Kaplan–Meier 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. Mann–Whitney and Wilcoxon tests were used to compare unpaired and paired observations.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The changes in blood pressure did not significantly differ in either the patient groups who were hypertensive or those who were normotensive at baseline. A significant decrease in serum creatinine at the sixth month followed by stabilization of values was observed in treated patients. In the untreated group, a progressive decrease in renal function, that became significant after the third year, was detected. At 60 months, the mean creatinine levels in treated patients was 167±79 (96–299) µmol/l vs 450±348 (96–862) µmol/l in untreated patients (P<0.05).

Proteinuria levels significantly fell at 6 months (1.4±0.6, (0.5–4.9) g/24 h, P<0.05 compared to baseline values) in the treated group, but not in the untreated patients (3.4±2.4 (0.5–8) g/24 h). Similar significant differences were observed over the entire follow-up. At 60 months, mean proteinuria was 0.9±1.0 (0.1–2.8) g/24 h in the treated group and 2.9±3.1 (0.6–6) g/24 h in the untreated patients (P<0.05).

Based on Kaplan–Meier 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 1Go).



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Fig. 1. Estimated cumulative renal survival of treated and untreated patients (Kaplan–Meier analysis).

 
The relative risk of untreated patients to reach the endpoint of a 100% increase of serum creatinine was 3.58 (P=0.034), but as the study had only small sample groups no clinical event was found to significantly influence the renal survival by multivariate Cox regression analysis. Treatment was well tolerated; minor Cushing's-like features occurred in five patients and intercurrent respiratory tract infections in two.



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The main difficulty in interpreting results of therapeutic trials in IgA nephropathy resides in the wide spectrum of the possible histologic lesions, either acute phlogistic and potentially reversible or sclerotic and unresponsive to currently available anti-inflammatory or cytotoxic drugs. Male prevalence, mean age at the time of biopsy (>30 years), moderate to severe intracapillary and extracapillary lesions are generally considered prognostically important in IgAN [4–6]. Crescentic glomerular involvement has been occasionally reported to resolve spontaneously [7] but has been more recently regarded as an indicator of an unfavourable prognosis even if small and focal [8]. Decreased renal function, hypertension and proteinuria over 1.0 g/day were found to be independent risk factors for a poor clinical course of disease in several reports [4–6].

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
 
We gratefully acknowledge Jerilyn Pecotte, PhD, USAC, University of Nevada, for her help in reviewing this manuscript. This work was supported in part by grants from the Ministero dell'Università e della Ricerca Scientifica e Tecnologica, Rome.



   Notes
 
Correspondence and offprint requests to: Dario Roccatello, M.D. Centro Multidisciplinare di Immunopatologia (CMID), Presidi Ospedalieri Asliv Sede Luigi Einaudi, Via Cigna 74, 10152 Torino, Italy. Back



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Emancipator SN. Primary and secondary forms of IgA nephritis, Shönlein–Henoch syndrome. In: Heptinstall RH, ed. Pathology of the Kidney. Little, Brown and Co, Boston: 1992: 389–476
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Received for publication: 1. 3.99
Revision received 21.10.99.