| Abstract|| |
Immunoglobulin A (IgA) nephropathy (IgAN) represents a common glomerular disease treated by various therapeutic regimens. We studied 50 IgAN patients to determine the effect of different regimens selected according to severity of the disease on the clinical outcome of patients over a follow-up period of five years. Patients with normal renal function and proteinuria <1 g/24-h received no treatment (Group A, n = 6). Thοse with normal renal function, proteinuria >1 g/24-h and mild to moderate histological lesions received angiotensin-converting enzyme inhibitors (ACEi) and corticosteroids (Group B, n = 23). Patients with baseline serum creatinine (Scr) <2.5 mg/dL, proteinuria >3.5 g/24-h and severe histological lesions received ACEi, corticosteroids and other immunosuppressive drugs (Group C, n = 18). Finally, patients with Scr >2.5 mg/dL, glomerulosclerosis and tubulointerstitial fibrosis received ACEi and fish oil (Group D, n = 3). Doubling of baseline Scr was observed in nine (18%) patients; two (8.7%) patients from Group B, five (27.7%) patients from Group C and two (66.7%) patients from Group D. Of the seven (14%) patients who reached end-stage renal disease, one (4.3%) patient was from Group B, four (21.0%) patients were from Group C and two (66.7%) patients were from Group D. Reduction of proteinuria was observed in all (100%) patients from Group B and in 15 (83.3%) patients from Group C. Adverse reactions occurred in three of 18 (16%) patients treated with immunosuppressive drugs. The choice of therapeutic regimen used in the treatment of patients with IgAN could be based on the severity of clinical and histological involvement in order to achieve the maximum effect with the least of adverse reactions.
|How to cite this article:|
Kalliakmani P, Komninakis D, Gerolymos M, Papasotiriou M, Savvidaki E, Goumenos DS. Treatment of IgA nephropathy based on the severity of clinical and histological features. Saudi J Kidney Dis Transpl 2015;26:516-25
|How to cite this URL:|
Kalliakmani P, Komninakis D, Gerolymos M, Papasotiriou M, Savvidaki E, Goumenos DS. Treatment of IgA nephropathy based on the severity of clinical and histological features. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2021 Jan 16];26:516-25. Available from: https://www.sjkdt.org/text.asp?2015/26/3/516/157356
| Introduction|| |
Immunoglobulin A (IgA) nephropathy (IgAN) represents the most commonly encountered primary glomerular disease in the developed countries. , Although the clinical course is usually benign, some patients develop progressive renal disease. , Presence of renal insufficiency and heavy proteinuria at presentation, persistence of proteinuria >1 g/24-h after the first year of follow-up, arterial hypertension and severe histological involvement have been related to an unfavorable outcome. ,,
Various regimens are used in the treatment of patients with IgAN.  Patients with normal renal function and lack of proteinuria are not usually treated, whereas patients with deteriorating renal function and severe histological involvement are treated aggressively.
The aim of our study was to evaluate the effect of therapeutic regimens selected according to the severity of the disease in the clinical course of the patients with IgAN over a follow-up period of five years (69.5 ± 34.9 months).
| Patients and Methods|| |
We studied all patients (n = 50, 39 male and 11 female, aged 47.9 ± 14 years) with biopsyproven IgAN performed in the Department of Nephrology of the University Hospital of Patras-Greece over a decade (from 1998 to 2008). The therapeutic regimen used was selected according to the severity of clinical and histological involvement.
Four groups of patients were created in this prospective observational study:
Patients with normal renal function, proteinuria <1 g/24-h and mild mesangial proliferation were classified as Group A (n = 6) and received no specific treatment; patients with normal renal function, proteinuria between 1 and 3.5 g/24-h and mild to moderate mesangial proliferation and tubulointerstitial involvement were classified as Group B (n = 23) and treated with a combination of angiotensin-converting enzyme inhibitors (ACEis) and corticosteroids; patients with normal or impaired renal function [baseline serum creatinine (Scr) <2.5 mg/dL], proteinuria >3.5 g/24-h and/or moderate to severe histological lesions were classified as Group C (n = 18) and treated with a combination of ACEi and corticosteroids with other immunosuppressive drugs (patients of Group C were subdivided into those with normal renal function, heavy proteinuria and lack of glomerulosclerosis and tubulointerstitial fibrosis, who received cyclosporine and corticosteroids (n = 10), and those with impaired renal function (Scr between 1.4 and 2.5 mg/dL) and moderate to severe mesangial proliferation and tubulointerstitial involvement, who received azathioprine and corticosteroids (n = 5), and those with crescents in >20% of the glomeruli who received cyclophosphamide and corticosteroids (n = 3). Finally, patients with baseline Scr >2.5 mg/dL, severe glomerulosclerosis and tubulointerstitial fibrosis were classified as Group D (n = 3) and treated with only ACEi and fish oil.
Prednisolone was prescribed at an initial dose of 1 mg/kg body weight/day, followed by gradual tapering over a period of 12 months. Cyclosporine was prescribed at a starting dose of 3 mg/kg body weight/day, adjusted to trough blood levels of 100 ng/mL for 12-18 months and then gradually reduced. Repeat of renal biopsies in order to estimate potential cyclosporine nephrotoxicity was not contemplated because the drug was not used for a period longer than two years. Azathioprine was commenced at a dose of 2 mg/kg body weight/day, reduced to 50 mg/day by the end of the first year and continued for six more months. Cyclophosphamide was administered intravenously at a dose of 0.7 g/m 2 once every month for six months and then replaced by azathioprine (50-100 mg/day) for 12 more months.
Body weight, blood pressure, biochemical profile and 24-h urinary protein of each patient were recorded every month during the followup period. All patients received ACEi, with a blood pressure target of <130/80 mm Hg.
Remission of proteinuria was considered if proteinuria was reduced to below 1 g/24-h. Relapse was considered if the amount of protein excreted in the urine increased again to the same or higher levels to those observed before the administration of treatment. The clinical outcome was estimated using the endpoints of doubling of baseline Scr and/or development of end-stage renal disease (ESRD) during the follow-up period of five years.
The diagnosis of IgAN was made by appropriate biopsy specimens (>10 glomeruli) showing mesangial proliferation on light microscopy with IgA deposits on immunofluorescence.  The degree of glomerular sclerosis, mesangial proliferation, interstitial fibrosis and inflammation as well as tubular atrophy were evaluated from the Masson's trichrome-stained sections of each biopsy using a semiquantitative method. The severity of glomerular sclerosis was expressed as a percent of the totally sclerosed glomeruli, whereas that of other histological parameters was graded as mild (10- 20%), moderate (20-30%) and severe (>30% of the tissue surface involved).
| Statistical Analysis|| |
In the present study, averages and standard deviations described continuous variables. Bivariate non-parametric statistical tests explore the type of relationship between two variables. When the two variables were discrete nominal, the Pearson's chi-square test was used and when they were ordinal, the Kendal's tau-b and tau-c tests for square and rectangular tables were employed, respectively. When the one variable was continuous and the other variable was discrete with two categories, the Mann-Whitney U test was used. Odds and odds ratios, risks and relative risks and their statistical significance were calculated. Survival distributions were estimated, plotted and tested using the Kaplan Meier algorithms. All aforementioned tests and distribution estimations were performed using the IBM SPSS for windows v.20 software.
| Results|| |
The clinical, biochemical and histological features of all patients at diagnosis are summarized in [Table 1].
|Table 1: Clinical, biochemical and histological features of patients at presentation.|
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Of 50 patients, nine (18%) patients reached the endpoint of doubling of baseline Scr (odds: 0.219, risk: 0.18), whereas seven out of nine developed ESRD (odds: 0.162, risk: 0.14).
No patient from group A (n = 6) showed either doubling of baseline Scr or ESRD [Figure 1]A and [Figure 2]A. Scr at diagnosis and at the end of the follow-up period (81.6 ± 57.1 months) was 1.0 ± 0.23 and 1.0 ± 0.25 mg/dL, respectively, P = NS.
|Figure 1: Cumulative survival free from doubling of baseline serum creatinine (Scr) in patients in Group A (1A), Group B (1B), Group C (1C) and Group D (1D).|
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Of 23 patients from Group B, two (8.7%) patients showed doubling of baseline Scr (odds: 0.095, risk: 0.086) and one of these two reached ESRD (odds: 0.045, risk: 0.043) [Figure 1]B and [Figure 2]B. Scr at diagnosis and at the end of the follow-up period (69.7 ± 26.9 months) was 1.2 ± 0.42 and 1.3 ± 0.85 mg/dL, respectively, P = NS.
|Figure 2: Cumulative survival free from end-stage renal disease (ESRD) in patients in Group A (2A), Group B (2B), Group C (2C) and Group D (2D).|
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Of 18 patients from Group C, five (27.7%) patients developed doubling of baseline Scr (odds: 0.384, risk: 0.277) and four of these five patients reached ESRD (odds: 0.285, risk: 0.222) [Figure 1]C and [Figure 2]C.
Scr at diagnosis and at the end of the follow-up period (70.9 ± 38.6 months) was 1.5 ± 0.96 and 2.4 ± 2.26 mg/dL, respectively, P = NS. Of five patients with doubling of baseline Scr, three received cyclosporine, one received azathioprine and one received cyclophosphamide.
Of three patients from Group D, two (66.7%) patients developed doubling of baseline Scr (odds: 2, risk: 0.666) and reached ESRD (odds: 2, risk: 0.666) [Figure 1]D and [Figure 2]D. Scr at diagnosis and at the end of the follow-up period (48.0 ± 31.7 months) was 2.5 ± 0.64 and 4.30 ± 0.91 mg/dL, respectively, P = 0.05. Odds ratios and relative risks for both doubling of baseline Scr and development of ESRD were estimated only among Groups B, C and D because, for Group A, no odds or risk could be estimated. These results are shown in [Table 2], [Table 3], [Table 4] and [Table 5].
Remission of proteinuri
Proteinuria was below 1 g/24-h in all the patients at diagnosis and at the end of follow-up (0.598 ± 0.408 vs. 0.211 ± 0.120 g/24-h) [Figure 3]A.
|Figure 3: Proteinuria at diagnosis and at the end of the follow-up period in patients in Group A (3A), Group B (3B), Group C (3C) and Group D (3D).|
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Remission of proteinuria to <1 g/24-h was observed in 23/23 (100%) patients from Group B. Proteinuria at diagnosis and at the end of follow-up was 2.05 ± 3.54 and 0.770 ± 1.1g/24-h, P = 0.009 [Figure 3]B.
Remission of proteinuria to <1 g/24-h was observed in 15 of 18 (83.3%) patients from Group C. Of these 15 patients, ten patients received cyclosporine, three patients received azathioprine and two patients received cyclophosphamide. Proteinuria at diagnosis and at the end of follow-up was 5.77 ± 6.08 and 2.95 ± 4.69 g/24-h, respectively, P = 0.037 [Figure 3]C.
Proteinuria at diagnosis and at the end of follow-up was 1.60 ± 1.31 and 2.07 ± 1.94 g/24-h, respectively, P = NS [Figure 3]D.
Relapses of proteinuria
Relapses of proteinuria were observed in three of 23 (13%) patients of Group B and in three of ten (30%) patients of Group C, treated with cyclosporine. Of the three patients from Group B who relapsed, one received only ACEi because of intolerance of corticosteroids at the first cycle of treatment; the second patient, a young female planning pregnancy, remained without treatment; and the third patient was treated with a combination of corticosteroids with azathioprine because he showed rapid deterioration of renal function. The first patient showed stable renal function, the second showed doubling of baseline Scr and the third patient developed ESRD during the follow-up period. Of the three patients from Group C who received corticosteroids and cyclosporine as the initial treatment and relapsed, one patient received a second cycle of the same treatment and the other two patients received a combination of corticosteroids with azathioprine. The first patient maintained stable renal function, the second patient developed ESRD and the third patient progressed to doubling of baseline Scr during the follow-up period.
Parameters related to clinical outcome
Parameters related to the development of endpoints of doubling of baseline Scr and ESRD were (a) baseline Scr (P = 0.000 and P = 0.000, respectively), (b) persistence of proteinuria >1 g/24-h during the follow-up or relapses of proteinuria (P = 0.000 and P = 0.001, respectively), (c) severity of mesangial proliferation (P = 0.005 and P = 0.004, respectively), (d) presence of crescents (P = 0.044 and P = 0.007, respectively), (e) interstitial fibrosis (P = 0.012 and P = 0.01, respectively) and (f) tubular atrophy (P = 0.006 and P = 0.002, respectively).
Side-effects of treatment
Side-effects were observed in three of 41 (7.3%) patients treated with corticosteroids and other immunosuppressive regimens. One patient developed diabetes mellitus and required oral hypoglycemic agents, one patient developed Cushing's syndrome and one patient developed leukopenia. None of the aforementioned side-effects resulted in discontinuation of treatment.
| Discussion|| |
The recent clinical practice guidelines for IgAN treatment suggest that patients with normal renal function and lack of proteinuria need only observation, whereas patients with heavy proteinuria, impaired renal function and moderate to severe histological involvement need specific treatment. 
The results of our study found close effects therapeutic regimens on the clinical outcome of patients with IgAN over a five-year followup period. Patients with normal renal function, proteinuria below 1 g/24-h, mild mesangial proliferation and lack of tubulointerstitial lesions (Group A) received no specific treatment and showed an excellent outcome over the five-year follow-up period, a finding confirming the favorable profile of these patients. The patients with normal or slightly impaired renal function, proteinuria between 1 g/24-h and 3.5 g/24-h and mild to moderate mesangial proliferation and tubulointerstitial injury were treated by a combination of ACEi and corticosteroids (Group B). All these patients achieved remission of proteinuria to <1 g/24-h, but 13% of them developed relapses. Doubling of baseline Scr was observed in two (8.7%) patients and ESRD was observed in one of these two patients during follow-up. The administration of a six-month course of corticosteroids (1 g methylprednisolone intravenously for three consecutive days every other month and oral prednisolone 0.5 mg/kg body weight every other day) in patients with proteinuria (1 - 3.5 g/24-h) and well-preserved renal function  was found to be more effective than supportive treatment in a randomized controlled trial over a 10-year follow-up period.  Similar effects were observed by Katafuchi et al with a low prednisolone dose (20 mg/day) in a controlled prospective trial.  Recent studies showed that a combination of corticosteroids with ACEi was more effective than ACEi alone in patients with significant proteinuria (1 - 5 g/day). , After eight years of follow-up, 4.2% of patients from the combination treatment group and 26.5% patients from the monotherapy group developed the combined outcome of doubling baseline Scr or ESRD. Furthermore, decrease of proteinuria to <1 g/day was observed in 75% of patients treated by this combination.  Similar results were found in our study with the combination of the ACEi and the corticosteroids, as 8.7% of patients had doubling of baseline Scr and 4.3% developed ESRD, whereas all the patients showed proteinuria remission to <1 g/24-h.
The patients with more severe disease received ACEi and a combination of corticosteroids with cyclosporine, azathioprine or cyclophosphamide (Group C, n = 18). Of these, five (27.7%) patients showed doubling of baseline Scr, whereas four of five patients reached ESRD. Proteinuria remission to <1 g/24-h was observed in 15 of 18 (83.3%) patients. We used cyclosporine in patients with heavy proteinuria without fibrosis and observed remission of proteinuria in all the patients, and only three (30%) patients relapsed and reached the endpoints.
The combination of corticosteroids with azathioprine has been reported to have a beneficial effect in patients with heavy proteinuria (>3 g/24-h) and impaired renal function. , Furthermore, this regimen is followed by stabilization of the histological lesions in about two-thirds of patients, as it was confirmed on repeated biopsies.  In a recent randomized prospective trial, the effect of treatment with corticosteroids and azathioprine for six months was similar to a six-month course of corticosteroids alone, and was followed by more frequent side-effects.  However, the same authors reported that the addition of azathioprine might be slightly more effective than corticosteroids alone in patients with chronic renal insufficiency and proteinuria.  In this study, of five patients treated with corticosteroids and azathioprine, only one (20%) showed doubling of baseline Scr.
The combination of corticosteroids and cyclophosphamide is effective in rapidly progressive IgAN and in patients with progressive disease (Scr between 1.4 and 2.8 mg/dL) and proteinuria. ,, In a randomized controlled trial, cyclophosphamide was replaced by azathioprine after three months of treatment, and the renal survival rate after five years of follow-up was significantly higher in treated than in untreated patients (72% vs. 0%).  Similar results were observed in our study, because, of three patients treated with corticosteroids and cyclophosphamide, two patients maintained stable renal function and remission of proteinuria.
The patients with established renal insufficiency, severe glomerulosclerosis and tubulointerstitial fibrosis were treated with ACEi and fish oil (Group D, n = 3). Of these three patients, two (66.7%) patients progressed to ESRD. Conflicting results have been reported with fish oil in patients with advanced IgAN, whereas a combination of ACEi with polyunsaturated fatty acids has been reported to reduce proteinuria. ,,, Our experience with this small number of patients was not positive for the combination of ACEi with fish oil.
The need for individualized treatment according to the severity of clinical and histological involvement is further supported by the fact that the development of endpoints of doubling of baseline Scr and ESRD is related to baseline Scr, persistence of proteinuria, relapses during follow-up and severity of the histological involvement.
The main limitation of our study was the small number of patients in each study subgroup and the absence of a control group. Furthermore, the follow-up period might be another limitation of the study. Although five years seem to be an adequate time period of follow-up for patients of Groups C and D who had more severe disease, a longer follow-up period would be more appropriate for the patients of Groups A and B who had milder disease. In our study, the mean follow-up period for the patients of Group A was about seven years and that of patients of Group B was six years. Especially for patients of Group C who received combinations of different immunosuppressive drugs, a sub-analysis of these regimens might be the best method to estimate their efficacy, but the small numbers of patients in each subgroup rendered the analysis meaningless. However, it should be noted that the results of our study represent an application of the general suggestions-recommendations in the everyday clinical practice in a single center.
In conclusion, the results of this study demonstrate that the choice of the therapeutic regimen for patients with IgAN could be based on the severity of the clinical and histological involvement in order to attain the maximum beneficial effect with the least of adverse reactions. Ongoing large randomized controlled trials are expected to clarify the indication of the different regimens in patients with IgAN. 
Conflicts of Interest
All authors did not receive any sponsorship or funding arrangements related to this research.
All subjects have given their informed consent and the study protocol is in accordance with the Helsinki Declaration as revised in 2000 and has been approved by the Patras University Hospital Human Research Committee.
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Prof. Dimitrios Komninakis
Department of Nephrology and Renal Transplantation, University Hospital of Patras, 26500 Patras
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]