IgA nephropathy in Greece: data from the registry of the Hellenic Society of Nephrology

IgA nephropathy in Greece: data from the registry of the Hellenic Society of Nephrology Background: Natural history, predisposing factors to an unfavourable outcome and the effect of various therapeutic regimens were evaluated in a cohort of 457 patients with immunoglobulin A nephropathy (IgAN) and follow-up of at least 12 months. Methods: Patients with normal renal function and proteinuria <1 g/24 h as well as those with serum creatinine (SCr) >2.5 mg/dL and/or severe glomerulosclerosis received no treatment. Patients with normal or impaired renal function and proteinuria >1 g/24 h for >6 months received daily oral prednisolone or a 3-day course of intravenous (IV) methylprednisolone followed by oral prednisolone per os every other day or a combination of prednisolone and azathioprine. The clinical outcome was estimated using the primary endpoints of end-stage renal disease and/or doubling of baseline SCr. Results: The overall 10-year renal survival was 90.8%, while end-stage renal disease and doubling of baseline SCr developed in 9.2% and 14.7% of patients, respectively. Risk factors related to the primary endpoints were elevated baseline SCr, arterial hypertension, persistent proteinuria >0.5 g/24 h and severity of tubulointerstial fibrosis. There was no difference in the clinical outcome of patients treated by the two regimens of corticosteroids; nevertheless, remission of proteinuria was more frequent in patients who received IV methylprednisolone (P¼ 0.000). The combination of prednisolone with azathioprine was not superior to IV methylprednisolone followed by oral prednisolone. Side effects related to immunossuppressive drugs were observed in 12.8% of patients. Conclusion: The clinical outcome of patients with IgAN was related to the severity of clinical and histological involvement. The addition of azathioprine to a corticosteroid-based regimen for IgAN does not improve renal outcome. Key words: IgA nephropathy, immunosuppressive drugs, chronic renal failure, prognosis, albuminuria Introduction Materials and methods Immunoglobulin A nephropathy (IgAN) represents the most Patients commonly encountered primary glomerular disease in many Patients [n ¼ 457 (303 males and 154 females), 41.3 6 14.3 years developed countries. Episodes of macroscopic haematuria fol- of age] with biopsy-proven IgAN performed between 1990 and lowing viral infections of the upper respiratory tract and 2010 with follow-up of at least 12 months were included in the asymptomatic microscopic haematuria with proteinuria repre- study. Of the 457 patients, 17 (3.7%) were <18 years old (mean sent commonmanifestationsofIgAN[1, 2]. Nephrotic syn- age 15.2 6 2.4 years). Patients with secondary causes of dis- drome and acute renal failure occur less frequently and ease, such as Henoch–Schonlein purpura, systemic lupus histological involvement ranges from minimal mesangial pro- erythaematosus and hepatic diseases, were excluded. The clin- liferation to advanced glomerular and tubulointerstitial injury ical, biochemical and histological features at diagnosis are [3, 4]. Although the clinical course is typically benign, some pa- summarized in Table 1. The mean follow-up period was tients develop renal failure [5, 6]. An unfavourable clinical out- 63.8 6 37 months. come is related with arterial hypertension, impaired renal function, heavy proteinuria at presentation, severe histolo- gical involvement and persistent proteinuria during follow-up Therapeutic regimens [7, 8]. MEST scores reflecting the severity of mesangial prolifer- ation (M), endocapillary hypercellularity (E), segmental glo- Conservative management merulosclerosis (S) and tubular atrophy/interstitial fibrosis (T) All patients with proteinuria >0.5 g/24 h received angiotensin- are an independent factor predicting outcome [9], whereas the converting enzyme inhibitors (ACEis) or angiotensin receptor combination of MEST scores with clinical data at the time of blockers (ARBs). Patients who received only conservative man- biopsy provides earlier risk prediction [10]. agement (n ¼ 262) had the following characteristics normal Renin–angiotensin system blockers and immunosuppressive renal function and proteinuria <1 g/24 h (n ¼ 225) and baseline drugs have been used in patients with IgAN [11, 12]. Although serum creatinine (SCr) >2.5 mg/dL and/or severe glomeruloscle- patients with deteriorating renal function and severe histolo- rosis (>30% totally sclerosed glomeruli) and tubulointerstitial gical involvement are treated aggressively, a recent randomized fibrosis (T1/T2) (n ¼ 37). controlled trial demonstrated that the addition of immunosup- pressive therapy to intensive supportive care did not signifi- cantly improve the outcome [13]. Immunosuppressive regimens The purpose of this retrospective analysis was to estimate Corticosteroids alone or in combination with azathioprine or the natural history, predisposing factors to an unfavourable mycophenolate mofetil (MMF) were used in patients with nor- outcome and effect of various therapeutic regimens used in a mal or impaired renal function and persistent proteinuria >1g/ large cohort of patients with IgAN from the registry of the 24 h for 6 months after initiation of ACEis or ARBs. The combin- Hellenic Society of Nephrology. ation of corticosteroids with cyclophosphamide was restricted Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/38/4056783 by Ed 'DeepDyve' Gillespie user on 16 March 2018 40 | M. Stangou et al. Table 1. Clinical, biochemical and histological features of all patients to patients with a rapidly progressive course and/or crescents in (N ¼ 457) at presentation the renal biopsy. The immunosuppressive regimens used were the following. Gender (M/F), n (%) 303/154 (66.3/33.7) Age (years) 41.29 6 14.32 Corticosteroids: Baseline SCr (mg/dL) 1.48 6 1.04 Oral prednisolone, 1 mg/kg body weight (BW)/day initially Urine protein (g/24 h) 1.7 6 2.0 followed by gradual tapering for 12 months (n ¼ 76). eGFR (MDRD; mL/min/1.73 m ) 64.09 6 30.7 Intravenous (IV) methylprednisolone, 1 g for 3 consecutive Arterial hypertension (BP> 140/90 mmHg), n (%) 256 (56) days on the first, third and fifth month of treatment followed by Microscopic haematuria, n (%) 403 (88.2) oral prednisolone 0.5 mg/kg BW every other day for 6 months Macroscopic haematuria, n (%) 142 (31.1) (n ¼ 57). Acute kidney injury, n (%) 30 (6.6) Nephrotic range proteinuria, n (%) 56 (12.3) Corticosteroids and azathioprine: Histological features (Oxford classification) Oral prednisolone, 1 mg/kg BW/day initially followed by MEST score, n (%) 198 (43.3) gradual tapering with azathioprine at 2 mg/kg BW/day initially Mesangial hypercellularity (M0/M1) 66/132 reduced to 50 mg/day by the end of the first year and continued Endocapillary hypercellularity (E0/E1) 148/50 for 6 additional months (n ¼ 32). Segmental glomerulosclerosis (S0/S1) 90/108 The clinical, biochemical and histological features of pa- Tubular atrophy/interstitial fibrosis (T0/T1/T2) 140/49/9 tients treated by these regimens are presented in Table 2. Haas classification Mesangial proliferation, n (%) 400 (87.5) Corticosteroids and MMF: Mild 212 Oral prednisolone, 1 mg/kg BW/day initially followed by grad- Moderate 149 ual tapering with MMF, 2 g/day initially, reduced to 1 g/day by the Severe 39 endof the firstyearand continuedfor6additionalmonths(n ¼ 9). Tubular atrophy, n (%) 447 (99.3) Absent 174 Corticosteroids and cyclophosphamide: Present 273 IV methylprednisolone pulse for 3 days followed by prednisol- Interstitial inflammation/fibrosis, n (%) 338 (73.9) 2 one 0.5 mg/kg BW/day and IV cyclophosphamide 0.5 g/m /month Mild 97 for 6 months (n ¼ 21). Cyclophosphamide was then replaced by Moderate 183 azathioprine (50–100 mg/day) for 12 additional months. Severe 58 Vascular hyalinosis, n (%) 338 (73.9) Follow-up and definitions Absent 182 Present 156 BW, blood pressure (BP), biochemical profile and 24-h urinary Severity of mesangial IgA deposits, n (%) 334 (73) protein was recorded regularly during follow-up. All patients Mild (þ) 109 received ACEis or ARBs with a target blood pressure <130/ Moderate (þþ) 181 80 mm Hg. Severe (þþþ)44 The clinical outcome was estimated using the primary endpoints of end-stage renal disease (ESRD) and/or doubling of MDRD, Modification of Diet in Renal Disease. baseline SCr. Remission of proteinuria was defined as a Table 2. Clinical and histological features at presentation of patients treated by oral prednisolone/daily, IV methylprednisolone and then oral prednisolone on alternate days and combination of prednisolone and azathioprine Oral IV methyprednisolone prednisolone and prednisolone Prednisolone plus daily on alternate days azathioprine P-value Clinical features Number of patients 76 57 32 Gender (M/F) 50/26 43/14 25/7 Non significant (NS) Age (years) 39.4 6 15.3 42.36 6 13.25 44.47 6 10.68 NS Baseline SCr (mg/dL) 1.87 6 1.7 1.37 6 0.64 1.69 6 0.78 NS Urine protein (g/24 h) 2.4 6 2.8 2.96 2.3 2.4 6 1.3 NS eGFR (MDRD; mL/min/1.73 m ) 59.2 6 34.4 67.7 6 31.5 50.7 6 28.2 NS Arterial hypertension (BP> 140/90 mmHg), n 10 4 3 NS Microscopic haematuria, n 12 3 3 NS Macrohaematuria, n 21 0 NS Nephrotic range proteinuria, n 31 1 NS Histological characteristics (Oxford classification) MEST score, n 29 30 17 Mesangial proliferation (M0/M1) 7/22 14/16 6/11 NS Endocapillary hypercellularity (E0/E1) 21/8 22/8 9/8 NS Segmental glomerulosclerosis (S0/S1) 10/19 16/14 5/12 NS Tubular atrophy/interstitial fibrosis (T0/T1/T2) 16/8/5 18/10/1 9/8/0 NS MDRD, Modification of Diet in Renal Disease. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/38/4056783 by Ed 'DeepDyve' Gillespie user on 16 March 2018 IgA nephropathy in Greece | 41 reduction of 24-h urinary protein to <0.5 g/24 h, which was con- (88%) and macroscopic haematuria in 142 of 457 patients (31%). sidered as a secondary endpoint. Most patients with macroscopic haematuria had no proteinuria patients (88%). No substantial proteinuria (<0.5 g/24 h) was observed in 114 patients (24.9%), nephrotic range proteinuria in Conventional pathology and grading of 56 (12.3%) and acute renal injury in 30 (6.6%) (Table 1). histopathological lesions The diagnosis of IgAN was made by appropriate biopsy speci- mens (>10 glomeruli) exhibiting mesangial proliferation on Histological findings at diagnosis light microscopy with IgA deposition on immunofluorescence In patients with a MEST score (n ¼ 198), mesangial proliferation [4]. The severity of histological involvement was evaluated from was classified as M0/M1 in 66 and 132 (33.9% versus 66.1%), Masson’s trichrome–stained sections using a semi-quantitative endothelial proliferation as E0/E1 in 148 and 50 (74.7% versus method and graded as mild, moderate and severe. The severity 25.3%), segmental sclerosis as S0/S1 in 90 and 108 (45.5% versus of IgA deposition on immunofluorescence was expressed as 54.5%) and tubulointerstitial fibrosis as T0/T1/T2 in 140, 49 and mild (þ), moderate (þþ) and severe (þþþ). The Oxford classifi- 9 patients (70.7%, 24.7% and 4.5%), respectively (Table 1). cation [mesangial hypercellularity, endocapillary hypercellular- Estimation of the severity of IgA deposition was available in ity, segmental glomerulosclerosis and tubular atrophy/ 334 patients. The severity of IgA deposition was expressed as interstitial fibrosis (MEST) score] was available in 198 of 457 pa- mild in 109 patients (32.7%), moderate in 181 (54.1%) and severe tients (43.3%). According to this classification, the presence of in 44 (13.2%) (Table 1). mild or severe mesangial proliferation is classified as M0 and M1, the absence or presence of endocapillary hypercellularity as E0 and E1 and segmental glomerulosclerosis as S0 and S1. Clinical outcome Tubulointerstitial fibrosis was classified as T0, T1 and T2 ac- cording to its extension to 0–25%, 25–50% or >50% on the kidney The overall 10-year renal survival was 90.8%. The primary endpoints of ESRD and doubling of baseline SCr were noted in biopsy surface, respectively [9]. 42 (9.2%) and 67 (14.7%) patients, respectively (Figure 1A and B). The mean time for doubling of baseline SCr was 109.56 Statistical analysis 1.4 months. SPSS software (SPSS Statistics for Windows, Version 22.0; IBM, Of 42 patients who developed ESRD, 18 received no Armonk, NY, USA) was used for analysis. A P-value of 0.05 was immunosuppressive treatment, 14 received oral prednisolone considered statistically significant. Data are presented as the daily, 4 received IV methylprednisolone initially followed by mean 6 standard deviation (SD) (continuous variables) and as oral prednisolone, 3 received prednisolone and azathioprine, counts, percentages and odds ratios with 95% confidence inter- 2 received prednisolone and cyclophosphamide and 1 received vals (CIs) (categorical variables). The v test was used to deter- prednisolone and MMF. mine significant differences between expected and observed frequencies in categorical variables. Kaplan–Meier and Cox pro- portional hazards models were used to test the association be- Risk factors related to the development of ESRD and tween any factor, covariate and the three endpoints. Survival doubling of baseline SCr analysis (expressed by endpoints) was performed using the log- The risk factors related to the development of both endpoints rank test. A logistic regression model that included two stratifi- were as follows (Table 3) elevated baseline SCr (2.41 6 1.3 mg/dL cation factors (proteinuria remission and time to remission) and 1.96 61.2 mg/dL versus 1.38 60.9 mg/dL in patients with was fitted to the data of endpoints. preserved renal function; P ¼ 0.000); arterial hypertension at diagnosis (P ¼ 0.001); persistent proteinuria >0.5 g/24 h over the Results follow-up period (P ¼ 0.002 and 0.014, respectively); the pres- ence of segmental glomerulosclerosis (S1) (P ¼ 0.009 and 0.003, Clinical presentation respectively) (Figure 2A and B) and the severity of tubular atro- Arterial hypertension (BP > 140/90 mmHg) at presentation was phy/interstitial fibrosis (T1 and T2) (P ¼ 0.000 and 0.001, respect- observed in 256 patients (56.3%), microscopic haematuria in 403 ively) (Figure 2C and D). Fig. 1. (A) Cumulative renal survival free from the endpoints of ESRD) and (B) doubling of baseline SCr in all patients. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/38/4056783 by Ed 'DeepDyve' Gillespie user on 16 March 2018 42 | M. Stangou et al. Table 3. Parameters related to the development of primary endpoints (after 10 years of observation) ESRD Doubling of serum baseline creatinine Mean6 SD or n (%) P-value HR (95% CI) Mean6 SD or n (%) P-value HR (95% CI) Baseline SCr (mg/dL) 2.416 1.3 0.000 0.118 (0.052–0.265) 1.966 1.2 0.000 0.387 (0.238–0.631) Arterial hyperten- 35 (87.5) 0.000 0.173 (0.068–0.440) 50 (72.5) 0.001 0.397 (0.226–0.697) sion at diagnosis, n (%) Persistent urine pro- 37 (92.5) 0.002 0.143 (0.034–0.591) 58 (84.1) 0.014 0.424 (0.210–0.858) tein >0.5 g/24 h over the follow-up period, n (%) Presence of segmen- 19 (47.5) 0.009 0.263 (0.089–0.777) 25 (36.2) 0.003 0.284 (0.116–0.692) tal glomeruloscle- rosis (S1, Oxford classification), n (%) Presence of tubular 15 (37.5) 0.000 0.106 (T1) (0.035–0.339) 17 (24.6) 0.001 0.224 (T1) (0.085–0.589) atrophy/intersti- 0.525 (T2) (0.176–1.564) 0.710 (T2) (0.251–2.002) tial fibrosis (T1/T2, Oxford classifica- tion), n (%) Fig. 2. MEST classification and primary endpoints. (A) Segmental glomerulosclerosis (S0/S1) in the kidney biopsy and survival free from ESRD or (B) doubling of baseline SCr. (C) Tubular atrophy/interstitial fibrosis (T0/T1/T2) in the kidney biopsy and survival free from ESRD or (D) doubling of baseline SCr. Remission of proteinuria proteinuria, 96.3% in those with remission and 75.4% in patients with persistent proteinuria (P < 0.001) (Figure 3). Once remission Of 343 patients with proteinuria >0.5 g/24 h, 217 (63.3%) exhibited of proteinuria was achieved, the rate of survival free from ESRD a reduction of proteinuria to <0.5 g/24 h with either conservative was similar in patients who received immunosuppressive drugs or immunosuppressive treatment. The 10-year renal survival free or conservative management. from ESRD rate was 99% in patients with no substantial Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/38/4056783 by Ed 'DeepDyve' Gillespie user on 16 March 2018 IgA nephropathy in Greece | 43 (n ¼ 32) were comparable to those treated with corticosteroids alone (Table 2). Of these 32 patients, 3 (9.4%) reached ERSD and 5 (15.6%) doubled baseline SCr. Remission of proteinuria to <0.5 g/24 h was observed in 17 patients (53%). No significant difference was observed in the development of primary endpoints between patients treated with prednisol- one and azathioprine and those treated with oral prednisolone daily or IV methylprednisolone. An increased proteinuria remis- sion rate was observed in patients treated with prednisolone and azathioprine compared with those treated with oral pred- nisolone daily (P ¼ 0.037). Corticosteroids and MMF. A combination of prednisolone and MMF was used in nine patients (baseline SCr 1.7460.84 mg/dL, eGFR 51.5 6 26.7 mL/min/1.73 m , urine protein 3.9 6 4.9 g/24 h). Of these patients, one doubled baseline SCr and reached ESRD and six reduced proteinuria to <0.5 g/24 h. Corticosteroids and cyclophosphamide. IV methylprednisolone pulses for 3 days followed by oral prednisolone and IV cyclo- phosphamide every month for 6 months was administered to 21 Fig. 3. Survival free from the endpoint of ESRD in patients with no substantial patients with a rapidly progressive course and/or cellular cres- proteinuria, patients with remission and patients with no remission of cents in >40% of glomeruli in the renal biopsy (baseline SCr proteinuria. 2.64 6 1.43 mg/dL, eGFR 37.7 6 27.8 mL/min/1.73 m , urine pro- tein 2.9 6 2.8 g/24 h). Of 21 patients, 2 doubled baseline SCr and Persistent proteinuria (>0.5 g/24 h) was related to endocapil- reached ESRD and 14 reduced proteinuria to <0.5 g/24 h. lary hypercellularity (E1), tubular atrophy/interstitial fibrosis (T1/T2) (P ¼ 0.020 and 0.006) and the severity of mesangial IgA deposition (P ¼ 0.001). Side effects of treatment Side effects related to immunosuppressive drugs were observed Therapeutic regimens and clinical course in 25 of 195 treated patients (12.8%). Adverse events related to corticosteroids included osteonecrosis and/or osteopenia in Conservative management three patients, myopathy in four, glaucoma in two, cushingoid Of 262 patients who received conservative management, 18 symptoms in six and deterioration of bipolar disease in one. (6.9%) progressed to ESRD and 35 (13.4%) doubled their baseline Among patients who received azathioprine, gastrointestinal SCr. The main differences between patients who reached the symptoms were observed in two, elevated liver enzymes in two primary endpoints or preserved renal function were the degree and leucopenia in one. Among patients who received MMF, of renal function and severity of proteinuria. SCr, estimated gastrointestinal symptoms were observed in one, leucopenia in glomerular filtration rate (eGFR) and 24-h urine protein at one and osteomyelitis in one. diagnosis in patients who reached ESRD, doubled baseline SCr or preserved their renal function were 1.76 6 0.63 mg/dL, 47.08 6 24.8 mL/min/1.73 m and 1.8 6 0.9 g/24 h; 1.48 6 0.62 mg/ Discussion dL, 59.5 6 28.6 mL/min/1.73 m and 1.4 6 0.6 g/24 h and 1.23 6 0.69 mg/dL, 68.9 6 28.3 mL/min/1.73 m and 1.1 6 1.1 g/ The natural history of IgAN, the parameters related to an un- 24 h, respectively. Of 37 patients with baseline SCr >2.5 mg/dL favourable outcome and the effects of treatment with various and/or severe glomerulosclerosis, 13 reached ESRD (35%). Of 225 immunosuppressive drugs were estimated in a retrospective patients with normal renal function and proteinuria <1 g/24 h, 5 analysis of a large cohort from the registry of the Hellenic developed ESRD (2.2%). Society of Nephrology. Macroscopic haematuria, a common manifestation of the Corticosteroids disease, was frequently observed, whereas nephrotic range pro- Oral corticosteroids daily versus IV pulse followed by oral corticoster- teinuria and acute kidney injury were confirmed as rare mani- oids every other day. The clinical and histological features of festations. The 10-year renal survival was 90.8%, which is patients treated with oral prednisolone daily (n ¼ 76) or by IV similar to that reported in the literature [5, 6]. methylprednisolone for 3 consecutive days on the first, third Recent data from the European Validation Study of the and fifth month of treatment followed by oral prednisolone Oxford Classification of IgA Nephropathy (VALIGA) study dem- every other day (n ¼ 57) were comparable (Table 2). onstrated that time averaged proteinuria <0.5 g/day was a sig- Of 76 patients treated with oral prednisolone, 14 (18.4%) nificant marker of better outcome [14]. Elevated baseline SCr, reached ESRD and 15 (19.7%) doubled baseline SCr. Of 57 pa- arterial hypertension, persistent proteinuria >0.5 g/24 h, pres- tients treated with IV methylprednisolone, 4 (7%) reached ESRD ence of segmental glomerulosclerosis and severity of and 9 (15.8%) doubled baseline SCr. No significant differences tubulointerstitial fibrosis were related to the development of were found in reaching ESRD or doubling of SCr between pa- ESRD and doubling of baseline SCr in our cohort. The presence tients in these two different treatment groups. Reduction of pro- of crescents in the biopsy was not related to a more rapid de- teinuria to <0.5 g/24 h was achieved in 35 patients (46%) in the cline of renal function in some studies [15], a finding that was former group and in 41 patients (72%) in the latter group also confirmed in this study in patients with cellular crescents (P ¼ 0.000). in >40% of the total number of glomeruli in the kidney biopsy, Corticosteroids and azathioprine. The clinical and histological probably due to the aggressive treatment administered to these features of patients treated with prednisolone and azathioprine patients. Of note, the rate of survival free from ESRD was not Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/38/4056783 by Ed 'DeepDyve' Gillespie user on 16 March 2018 44 | M. Stangou et al. related to conservative or immunosuppressive treatment, but given the limited number of patients treated with MMF. only to proteinuria remission. The degree of proteinuria at diag- Cytotoxic drugs have been used in patients with rapidly pro- nosis, presence of endocapillary hypercellularity, tubulointersti- gressive IgAN with good results [35, 36]. In a randomized pro- tial fibrosis and severity of IgA deposition correlated with spective trial, patients with progressive disease and proteinuria persistent proteinuria. The correlation of mesangial prolifer- were allocated to either prednisolone (40 mg/day) and cyclo- ation and endocapillary hypercellularity with proteinuria has phosphamide (1.5 mg/kg BW/day for 3 months) followed by aza- been recognized in VALIGA [14]. thioprine for 2 years or conservative management [37]. A better Patients with normal renal function and a lack of proteinuria renal survival rate after 5 years of follow-up was observed in pa- have a favourable outcome, whereas patients with baseline SCr tients treated with immunosuppressive drugs. The beneficial >2.5 mg/dL and severe glomerulosclerosis are not good candi- effects of corticosteroids and cyclophosphamide have also been dates for immunosuppressive treatment because they have reported in patients with aggressive disease and proteinuria [38, reached the ‘point of no return’ [16]. Of 42 patients who reached 39]. In this study, a combination of corticosteroids and IV cyclo- ESRD, 18 received no immunosuppressive drugs, including 13 phosphamide every month for 6 months was effective in pa- patients from the subgroup of 37 patients with baseline SCr tients with a rapidly progressive course. However, this >2.5 mg/dL and/or severe glomerulosclerosis. The remaining 5 combination should be used with great caution given the long- patients were from the subgroup of 225 patients with normal term risk of the development of malignancies [40]. In a recent renal function and proteinuria <1 g/24 h. These patients had in- randomized controlled trial, the addition of immunosuppres- adequate control of their BP over a long period of time. sive therapy to intensive supportive care in patients with high- Administration of a 6-month course of corticosteroids (1 g IV risk IgAN was estimated over a 3-year follow-up period [13]. methylprednisolone for 3 consecutive days every other month During a 6-month run-in phase, all patients received compre- and 0.5 mg/kg BW oral prednisolone every other day) in patients hensive supportive care with blockers of the renin–angiotensin with proteinuria (1–3.5 g/24 h) and well-preserved renal function system to reduce proteinuria to <0.75 g/day. High-risk patients (SCr < 1.5 mg/dL) was more effective than supportive treatment who had persistent proteinuria entered a 3-year study phase in a randomized trial over a 10-year follow-up [17]. A beneficial and were randomly assigned to supportive care or supportive effect with low-dose prednisolone was also observed in a con- care plus immunosuppressive therapy with corticosteroids or a trolled prospective trial in patients with moderate histological combination of corticosteroids with cyclophosphamide as pre- changes [18]. These results were confirmed in a meta-analysis viously reported [17, 39]. According to the results, the addition of all randomized prospective trials [19]. Recent studies demon- of immunosuppressive therapy to intensive supportive care did strate that treatment with corticosteroids in combination with not significantly improve outcome and was followed by more ACEis is more effective than ACEis alone in patients with pro- adverse effects. teinuria [20, 21]. The beneficial effect of corticosteroids in add- The main limitation of our study is that this is a retrospect- ition to renin–angiotensin system blockade was also confirmed ive analysis including patients from many centres with possible in VALIGA and other studies [22, 23]. Although a considerable different therapeutic principles. However, as was confirmed at amount of data on the use of two regimens of corticosteroids in the end, the general recommendations have been adopted by patients with IgAN has been reported, no comparison between all centres. these regimens has been reported to date. In this study, both In conclusion, the choice of the therapeutic regimen should regimens were used in patients with similar clinical and histo- be based on the severity of clinical and histological involve- logical features. Although there was no significant difference in ment. A combination of conservative management with im- the development of primary endpoints, a significantly higher munosuppressive drugs seems to be a reasonable approach in remission rate of proteinuria to <0.5 g/24 h was noted with IV patients with persistent proteinuria and severe histological in- methylprednisolone followed by oral prednisolone every other volvement to delay progression of IgAN. day (remission rate 72% versus 46%: P ¼ 0.000). Corticosteroids in combination with azathioprine offers a Conflict of interest statement beneficial effect in patients with heavy proteinuria (>3 g/24 h) and impaired renal function in a retrospective study with 10- None declared. year follow-up [24]. Others report that IgAN patients who do not respond to steroids might respond to a combination of steroids References and azathioprine [25]. However, in a randomized prospective trial, the effect of a 6-month course of corticosteroids and aza- 1. D’Amico G. The commonest glomerulonephritis in the thioprine was not superior to a 6-month course of corticoster- world: IgA nephropathy. Q J Med 1987; 64: 709–727 oids alone [26]. The same authors reported that the addition of 2. Donadio JV, Grande JP. IgA nephropathy. N Engl J Med 2002; azathioprine may be slightly more effective than corticosteroids 347: 738–748 alone in patients with chronic renal insufficiency and protein- 3. Barratt J, Feehaly J. IgA nephropathy. J Am Soc Nephrol 2005; uria [27], but it can increase the risk of side effects [28]. In this 16: 2088–2097 study, no significant difference in the development of primary 4. Haas MJ. Histology and immunohistology of IgA nephrop- endpoints was observed between patients treated with prednis- athy. J Nephrol 2005; 18: 676–680 olone and azathioprine and those treated with corticosteroids 5. D’Amico G. Influence of clinical and histological features onac- alone. However, an increased remission rate of proteinuria was tuarial renal survival in adult patients with idiopathic IgA nephr- noted among patients treated with prednisolone and azathio- opathy, membranous nephropathy and membranoproliferative prine and patients treated with IV methylprednisolone com- glomerulonephritis: survey of the recent literature. Am J Kidney pared with patients treated with oral prednisolone daily Dis 1992; 20: 315–323 (P ¼ 0.037). 6. Nicholls KM, Fairley KF, Dowling JP et al. The clinical course MMF has also been used in patients with IgAN, with conflict- of mesangial IgA associated nephropathy in adults. Q J Med ing results [29–34]. No conclusions can be drawn from our study 1984; 53: 227–250 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/38/4056783 by Ed 'DeepDyve' Gillespie user on 16 March 2018 IgA nephropathy in Greece | 45 24. Goumenos D, Davlouros P, El Nahas AM et al. Prednisolone 7. D’Amico G. Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome. Semin Nephrol and azathioprine in IgA nephropathy: a ten-year follow up 2004; 24: 179–196 study. Nephron Clin Pract 2003; 93: 58–68 8. Coppo R, D’Amico G. Factors predicting progression of IgA 25. Stangou M, Ekonomidou D, Giamalis P et al. Steroids and aza- nephropathies. J Nephrol 2005; 18: 503–512 thioprine in the treatment of IgA nephropathy. Clin Exp 9. Cattran DC, Coppo R, Cook HT et al. The Oxford classification Nephrol 2011; 15: 373–380 of IgA nephropathy: rationale, clinicopathological correl- 26. Pozzi C, Andrulli S, Pani A et al. Addition of azathioprine to ations and classification. Kidney Int 2009; 76: 534–545 corticosteroids does not benefit patients with IgA nephrop- 10. Barbour SJ, Espino-Hernandez G, Reich HN et al. The MEST athy. J Am Soc Nephrol 2010; 21: 1783–1790 score provides earlier risk prediction in IgA nephropathy. 27. Pozzi C, Andrulli S, Pani A et al. IgA nephropathy with severe Kidney Int 2016; 89: 167–175 chronic renal failure: a randomized controlled trial of cor- 11. Floege J, Eitner F. Current therapy for IgA nephropathy. JAm ticosteroids and azathioprine. J Nephrol 2013; 26: 86–93 Soc Nephrol 2011; 22: 1785–1794 28. Sarcina C, Tinelli C, Ferrario F et al. Changes in proteinuria 12. Kidney Disease: Improving Global Outcomes Glomerulonephritis and side effects of corticosteroids alone or in combination Work Group. KDIGO clinical practice guideline for glomerulo- with azathioprine at different stages of IgA nephropathy. nephritis. Immunoglobulin A nephropathy. Kidney Int Suppl 2012; Clin J Am Soc Nephrol 2016; 11: 973–981 2: 209–217 29. Chen X, Chen P, Cai G et al. A randomized control trial of 13. Rauen T, Eitner F, Fitzer C et al. Intensive supportive care mycophenolate mofetil treatment in severe IgA nephrop- plus immunosuppression in IgAN nephropathy. N Engl J Med athy. Zhonghua Yi Xue Za Zhi 2002; 82: 796–801 2015; 373: 2225–2236 30. Tang SC, Tang AW, Wong SS et al. Long-term study of myco- 14. Coppo R, Troyanov S, Bellur S et al. Validation of phenolate mofetil treatment in IgA nephropathy. Kidney Int the Oxford classification of IgA nephropathy in cohorts with 2010; 77: 543–549 different presentations and treatments. Kidney Int 2014; 86: 31. Mayes BD, Oyen R, Claes K et al. Mycophenolate mofetil in 828–836 IgA nephropathy: results of a 3-year prospective placebo- 15. Lee MJ, Kim SJ, Oh HJ et al. Clinical implication of crescentic contolled randomized study. Kidney Int 2004; 65: 1842–1849 lesions in immunoglobulin A nephropathy. Nephrol Dial 32. Frisch G, Lin J, Rosenstock J et al. Mycophenolate mofetil Transplant 2014; 29: 356–364 (MMF) vs placebo in patients with moderately advanced IgA 16. Scho ¨ ll U, Wastl U, Risler T et al. The “point of no return” and nephropathy: a double-blind randomized controlled trial. the rate of progression in the natural history of IgA neph- Nephrol Dial Transplant 2005; 20: 2139–2145 ritis. Clin Nephrol 1999; 52: 285–292 33. Navaneetham SD, Viswanathan G, Strippoli GF. Meta- 17. Pozzi C, Andrulli S, Del Vecchio L et al. Corticosteroid effect- analysis of mycophenolate mofetil in IgA nephropathy. iveness in IgA nephropathy: long-term results of a random- Nephrology 2008; 13: 90 ized controlled trial. J Am Soc Nephrol 2004; 15: 157–163 34. Chen Y, Li Y, Yang S et al. Efficacy and safety of mycopheno- 18. Katafuchi R, Ikeda K, Mizumasa T et al. Controlled, prospect- late mofetil treatment in IgA nephropathy:a systematic re- ive trial of steroid treatment in IgA nephropathy: a limita- view. BMC Nephrol 2014; 15: 193 tion of low-dose prednisolone therapy. Am J Kidney Dis 2003; 35. Roccatello D, Ferro M, Coppo R et al. Report on intensive 41: 972–983 treatment of extracapillary glomerulonephritis with focus 19. Samuels JA, Strippoli GF, Craig JC et al. Immunosuppressive treat- on crescentic IgA nephropathy. Nephrol Dial Transplant 1995; ments for immunoglobulin A nephropathy: a meta-analysis of 10: 2054–2059 randomized controlled trials. Nephrology 2004; 9: 177–185 36. Tumlin JA, Lohavichan V, Hennigar R. Crescentic, prolifera- 20. Lv J, Zhang H, Chen Y et al. Combination therapy of prednis- tive IgA nephropathy. Clinical and histological response to one and ACE inhibitor versus ACE-inhibitor therapy alone in methylprednisolone and intravenous cyclophosphamide. patients with IgA nephropathy: a randomized controlled Nephrol Dial Transplant 2003; 18: 1321–1329 trial. Am J Kidney Dis 2009; 53: 26–32 37. Ballardie FW, Roberts IS. Controlled prospective trial of pred- 21. Manno C, Torres DD, Rossini M et al. Randomized controlled nisolone and cytotoxics in progressive IgA nephropathy. clinical trial of corticosteroid plus ACE-inhibitors with long- J Am Soc Nephrol 2002; 13: 142–148 term follow-up in proteinuric IgA nephropathy. Nephrol Dial 38. Rasche FM, Klotz CH, Czock D et al. Cyclophosphamide pulse Transplant 2009; 24: 3694–3701 therapy in advanced progressive IgA nephropathy. Nephron 22. Tesar V, Troyanov S, Bellur S et al. Corticosteroids in IgA Clin Pract 2003; 93: 131–136 nephropathy: a retrospective analysis from the VALIGA 39. Peters HP, van den Brand JA, Berger SP et al. Immunosup- study. J Am Soc Nephrol 2015; 26: 2248–2258 pressive therapy in patients with IgA nephropathy. Neth J 23. Kalliakmani P, Komninakis D, Gerolymos M et al. Treatment Med 2015; 73: 284–289 of IgA nephropathy based on the severity of clinical and 40. Oshima S, Kawamura O. Long-term follow-up of patients histological features. Saudi J Kidney Dis Transpl 2015; 16: with IgA nephropathy treated with prednisolone and cyclo- 516–525 phosphamide therapy. Clin Exp Nephrol 2008; 12: 264–269 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/38/4056783 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Loading next page...
 
/lp/ou_press/iga-nephropathy-in-greece-data-from-the-registry-of-the-hellenic-Kn8kokXWC2
Publisher
European Renal Association - European Dialysis and Transplant Association
Copyright
© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.
ISSN
2048-8505
eISSN
2048-8513
D.O.I.
10.1093/ckj/sfx076
Publisher site
See Article on Publisher Site

Abstract

Background: Natural history, predisposing factors to an unfavourable outcome and the effect of various therapeutic regimens were evaluated in a cohort of 457 patients with immunoglobulin A nephropathy (IgAN) and follow-up of at least 12 months. Methods: Patients with normal renal function and proteinuria <1 g/24 h as well as those with serum creatinine (SCr) >2.5 mg/dL and/or severe glomerulosclerosis received no treatment. Patients with normal or impaired renal function and proteinuria >1 g/24 h for >6 months received daily oral prednisolone or a 3-day course of intravenous (IV) methylprednisolone followed by oral prednisolone per os every other day or a combination of prednisolone and azathioprine. The clinical outcome was estimated using the primary endpoints of end-stage renal disease and/or doubling of baseline SCr. Results: The overall 10-year renal survival was 90.8%, while end-stage renal disease and doubling of baseline SCr developed in 9.2% and 14.7% of patients, respectively. Risk factors related to the primary endpoints were elevated baseline SCr, arterial hypertension, persistent proteinuria >0.5 g/24 h and severity of tubulointerstial fibrosis. There was no difference in the clinical outcome of patients treated by the two regimens of corticosteroids; nevertheless, remission of proteinuria was more frequent in patients who received IV methylprednisolone (P¼ 0.000). The combination of prednisolone with azathioprine was not superior to IV methylprednisolone followed by oral prednisolone. Side effects related to immunossuppressive drugs were observed in 12.8% of patients. Conclusion: The clinical outcome of patients with IgAN was related to the severity of clinical and histological involvement. The addition of azathioprine to a corticosteroid-based regimen for IgAN does not improve renal outcome. Key words: IgA nephropathy, immunosuppressive drugs, chronic renal failure, prognosis, albuminuria Introduction Materials and methods Immunoglobulin A nephropathy (IgAN) represents the most Patients commonly encountered primary glomerular disease in many Patients [n ¼ 457 (303 males and 154 females), 41.3 6 14.3 years developed countries. Episodes of macroscopic haematuria fol- of age] with biopsy-proven IgAN performed between 1990 and lowing viral infections of the upper respiratory tract and 2010 with follow-up of at least 12 months were included in the asymptomatic microscopic haematuria with proteinuria repre- study. Of the 457 patients, 17 (3.7%) were <18 years old (mean sent commonmanifestationsofIgAN[1, 2]. Nephrotic syn- age 15.2 6 2.4 years). Patients with secondary causes of dis- drome and acute renal failure occur less frequently and ease, such as Henoch–Schonlein purpura, systemic lupus histological involvement ranges from minimal mesangial pro- erythaematosus and hepatic diseases, were excluded. The clin- liferation to advanced glomerular and tubulointerstitial injury ical, biochemical and histological features at diagnosis are [3, 4]. Although the clinical course is typically benign, some pa- summarized in Table 1. The mean follow-up period was tients develop renal failure [5, 6]. An unfavourable clinical out- 63.8 6 37 months. come is related with arterial hypertension, impaired renal function, heavy proteinuria at presentation, severe histolo- gical involvement and persistent proteinuria during follow-up Therapeutic regimens [7, 8]. MEST scores reflecting the severity of mesangial prolifer- ation (M), endocapillary hypercellularity (E), segmental glo- Conservative management merulosclerosis (S) and tubular atrophy/interstitial fibrosis (T) All patients with proteinuria >0.5 g/24 h received angiotensin- are an independent factor predicting outcome [9], whereas the converting enzyme inhibitors (ACEis) or angiotensin receptor combination of MEST scores with clinical data at the time of blockers (ARBs). Patients who received only conservative man- biopsy provides earlier risk prediction [10]. agement (n ¼ 262) had the following characteristics normal Renin–angiotensin system blockers and immunosuppressive renal function and proteinuria <1 g/24 h (n ¼ 225) and baseline drugs have been used in patients with IgAN [11, 12]. Although serum creatinine (SCr) >2.5 mg/dL and/or severe glomeruloscle- patients with deteriorating renal function and severe histolo- rosis (>30% totally sclerosed glomeruli) and tubulointerstitial gical involvement are treated aggressively, a recent randomized fibrosis (T1/T2) (n ¼ 37). controlled trial demonstrated that the addition of immunosup- pressive therapy to intensive supportive care did not signifi- cantly improve the outcome [13]. Immunosuppressive regimens The purpose of this retrospective analysis was to estimate Corticosteroids alone or in combination with azathioprine or the natural history, predisposing factors to an unfavourable mycophenolate mofetil (MMF) were used in patients with nor- outcome and effect of various therapeutic regimens used in a mal or impaired renal function and persistent proteinuria >1g/ large cohort of patients with IgAN from the registry of the 24 h for 6 months after initiation of ACEis or ARBs. The combin- Hellenic Society of Nephrology. ation of corticosteroids with cyclophosphamide was restricted Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/38/4056783 by Ed 'DeepDyve' Gillespie user on 16 March 2018 40 | M. Stangou et al. Table 1. Clinical, biochemical and histological features of all patients to patients with a rapidly progressive course and/or crescents in (N ¼ 457) at presentation the renal biopsy. The immunosuppressive regimens used were the following. Gender (M/F), n (%) 303/154 (66.3/33.7) Age (years) 41.29 6 14.32 Corticosteroids: Baseline SCr (mg/dL) 1.48 6 1.04 Oral prednisolone, 1 mg/kg body weight (BW)/day initially Urine protein (g/24 h) 1.7 6 2.0 followed by gradual tapering for 12 months (n ¼ 76). eGFR (MDRD; mL/min/1.73 m ) 64.09 6 30.7 Intravenous (IV) methylprednisolone, 1 g for 3 consecutive Arterial hypertension (BP> 140/90 mmHg), n (%) 256 (56) days on the first, third and fifth month of treatment followed by Microscopic haematuria, n (%) 403 (88.2) oral prednisolone 0.5 mg/kg BW every other day for 6 months Macroscopic haematuria, n (%) 142 (31.1) (n ¼ 57). Acute kidney injury, n (%) 30 (6.6) Nephrotic range proteinuria, n (%) 56 (12.3) Corticosteroids and azathioprine: Histological features (Oxford classification) Oral prednisolone, 1 mg/kg BW/day initially followed by MEST score, n (%) 198 (43.3) gradual tapering with azathioprine at 2 mg/kg BW/day initially Mesangial hypercellularity (M0/M1) 66/132 reduced to 50 mg/day by the end of the first year and continued Endocapillary hypercellularity (E0/E1) 148/50 for 6 additional months (n ¼ 32). Segmental glomerulosclerosis (S0/S1) 90/108 The clinical, biochemical and histological features of pa- Tubular atrophy/interstitial fibrosis (T0/T1/T2) 140/49/9 tients treated by these regimens are presented in Table 2. Haas classification Mesangial proliferation, n (%) 400 (87.5) Corticosteroids and MMF: Mild 212 Oral prednisolone, 1 mg/kg BW/day initially followed by grad- Moderate 149 ual tapering with MMF, 2 g/day initially, reduced to 1 g/day by the Severe 39 endof the firstyearand continuedfor6additionalmonths(n ¼ 9). Tubular atrophy, n (%) 447 (99.3) Absent 174 Corticosteroids and cyclophosphamide: Present 273 IV methylprednisolone pulse for 3 days followed by prednisol- Interstitial inflammation/fibrosis, n (%) 338 (73.9) 2 one 0.5 mg/kg BW/day and IV cyclophosphamide 0.5 g/m /month Mild 97 for 6 months (n ¼ 21). Cyclophosphamide was then replaced by Moderate 183 azathioprine (50–100 mg/day) for 12 additional months. Severe 58 Vascular hyalinosis, n (%) 338 (73.9) Follow-up and definitions Absent 182 Present 156 BW, blood pressure (BP), biochemical profile and 24-h urinary Severity of mesangial IgA deposits, n (%) 334 (73) protein was recorded regularly during follow-up. All patients Mild (þ) 109 received ACEis or ARBs with a target blood pressure <130/ Moderate (þþ) 181 80 mm Hg. Severe (þþþ)44 The clinical outcome was estimated using the primary endpoints of end-stage renal disease (ESRD) and/or doubling of MDRD, Modification of Diet in Renal Disease. baseline SCr. Remission of proteinuria was defined as a Table 2. Clinical and histological features at presentation of patients treated by oral prednisolone/daily, IV methylprednisolone and then oral prednisolone on alternate days and combination of prednisolone and azathioprine Oral IV methyprednisolone prednisolone and prednisolone Prednisolone plus daily on alternate days azathioprine P-value Clinical features Number of patients 76 57 32 Gender (M/F) 50/26 43/14 25/7 Non significant (NS) Age (years) 39.4 6 15.3 42.36 6 13.25 44.47 6 10.68 NS Baseline SCr (mg/dL) 1.87 6 1.7 1.37 6 0.64 1.69 6 0.78 NS Urine protein (g/24 h) 2.4 6 2.8 2.96 2.3 2.4 6 1.3 NS eGFR (MDRD; mL/min/1.73 m ) 59.2 6 34.4 67.7 6 31.5 50.7 6 28.2 NS Arterial hypertension (BP> 140/90 mmHg), n 10 4 3 NS Microscopic haematuria, n 12 3 3 NS Macrohaematuria, n 21 0 NS Nephrotic range proteinuria, n 31 1 NS Histological characteristics (Oxford classification) MEST score, n 29 30 17 Mesangial proliferation (M0/M1) 7/22 14/16 6/11 NS Endocapillary hypercellularity (E0/E1) 21/8 22/8 9/8 NS Segmental glomerulosclerosis (S0/S1) 10/19 16/14 5/12 NS Tubular atrophy/interstitial fibrosis (T0/T1/T2) 16/8/5 18/10/1 9/8/0 NS MDRD, Modification of Diet in Renal Disease. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/38/4056783 by Ed 'DeepDyve' Gillespie user on 16 March 2018 IgA nephropathy in Greece | 41 reduction of 24-h urinary protein to <0.5 g/24 h, which was con- (88%) and macroscopic haematuria in 142 of 457 patients (31%). sidered as a secondary endpoint. Most patients with macroscopic haematuria had no proteinuria patients (88%). No substantial proteinuria (<0.5 g/24 h) was observed in 114 patients (24.9%), nephrotic range proteinuria in Conventional pathology and grading of 56 (12.3%) and acute renal injury in 30 (6.6%) (Table 1). histopathological lesions The diagnosis of IgAN was made by appropriate biopsy speci- mens (>10 glomeruli) exhibiting mesangial proliferation on Histological findings at diagnosis light microscopy with IgA deposition on immunofluorescence In patients with a MEST score (n ¼ 198), mesangial proliferation [4]. The severity of histological involvement was evaluated from was classified as M0/M1 in 66 and 132 (33.9% versus 66.1%), Masson’s trichrome–stained sections using a semi-quantitative endothelial proliferation as E0/E1 in 148 and 50 (74.7% versus method and graded as mild, moderate and severe. The severity 25.3%), segmental sclerosis as S0/S1 in 90 and 108 (45.5% versus of IgA deposition on immunofluorescence was expressed as 54.5%) and tubulointerstitial fibrosis as T0/T1/T2 in 140, 49 and mild (þ), moderate (þþ) and severe (þþþ). The Oxford classifi- 9 patients (70.7%, 24.7% and 4.5%), respectively (Table 1). cation [mesangial hypercellularity, endocapillary hypercellular- Estimation of the severity of IgA deposition was available in ity, segmental glomerulosclerosis and tubular atrophy/ 334 patients. The severity of IgA deposition was expressed as interstitial fibrosis (MEST) score] was available in 198 of 457 pa- mild in 109 patients (32.7%), moderate in 181 (54.1%) and severe tients (43.3%). According to this classification, the presence of in 44 (13.2%) (Table 1). mild or severe mesangial proliferation is classified as M0 and M1, the absence or presence of endocapillary hypercellularity as E0 and E1 and segmental glomerulosclerosis as S0 and S1. Clinical outcome Tubulointerstitial fibrosis was classified as T0, T1 and T2 ac- cording to its extension to 0–25%, 25–50% or >50% on the kidney The overall 10-year renal survival was 90.8%. The primary endpoints of ESRD and doubling of baseline SCr were noted in biopsy surface, respectively [9]. 42 (9.2%) and 67 (14.7%) patients, respectively (Figure 1A and B). The mean time for doubling of baseline SCr was 109.56 Statistical analysis 1.4 months. SPSS software (SPSS Statistics for Windows, Version 22.0; IBM, Of 42 patients who developed ESRD, 18 received no Armonk, NY, USA) was used for analysis. A P-value of 0.05 was immunosuppressive treatment, 14 received oral prednisolone considered statistically significant. Data are presented as the daily, 4 received IV methylprednisolone initially followed by mean 6 standard deviation (SD) (continuous variables) and as oral prednisolone, 3 received prednisolone and azathioprine, counts, percentages and odds ratios with 95% confidence inter- 2 received prednisolone and cyclophosphamide and 1 received vals (CIs) (categorical variables). The v test was used to deter- prednisolone and MMF. mine significant differences between expected and observed frequencies in categorical variables. Kaplan–Meier and Cox pro- portional hazards models were used to test the association be- Risk factors related to the development of ESRD and tween any factor, covariate and the three endpoints. Survival doubling of baseline SCr analysis (expressed by endpoints) was performed using the log- The risk factors related to the development of both endpoints rank test. A logistic regression model that included two stratifi- were as follows (Table 3) elevated baseline SCr (2.41 6 1.3 mg/dL cation factors (proteinuria remission and time to remission) and 1.96 61.2 mg/dL versus 1.38 60.9 mg/dL in patients with was fitted to the data of endpoints. preserved renal function; P ¼ 0.000); arterial hypertension at diagnosis (P ¼ 0.001); persistent proteinuria >0.5 g/24 h over the Results follow-up period (P ¼ 0.002 and 0.014, respectively); the pres- ence of segmental glomerulosclerosis (S1) (P ¼ 0.009 and 0.003, Clinical presentation respectively) (Figure 2A and B) and the severity of tubular atro- Arterial hypertension (BP > 140/90 mmHg) at presentation was phy/interstitial fibrosis (T1 and T2) (P ¼ 0.000 and 0.001, respect- observed in 256 patients (56.3%), microscopic haematuria in 403 ively) (Figure 2C and D). Fig. 1. (A) Cumulative renal survival free from the endpoints of ESRD) and (B) doubling of baseline SCr in all patients. Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/38/4056783 by Ed 'DeepDyve' Gillespie user on 16 March 2018 42 | M. Stangou et al. Table 3. Parameters related to the development of primary endpoints (after 10 years of observation) ESRD Doubling of serum baseline creatinine Mean6 SD or n (%) P-value HR (95% CI) Mean6 SD or n (%) P-value HR (95% CI) Baseline SCr (mg/dL) 2.416 1.3 0.000 0.118 (0.052–0.265) 1.966 1.2 0.000 0.387 (0.238–0.631) Arterial hyperten- 35 (87.5) 0.000 0.173 (0.068–0.440) 50 (72.5) 0.001 0.397 (0.226–0.697) sion at diagnosis, n (%) Persistent urine pro- 37 (92.5) 0.002 0.143 (0.034–0.591) 58 (84.1) 0.014 0.424 (0.210–0.858) tein >0.5 g/24 h over the follow-up period, n (%) Presence of segmen- 19 (47.5) 0.009 0.263 (0.089–0.777) 25 (36.2) 0.003 0.284 (0.116–0.692) tal glomeruloscle- rosis (S1, Oxford classification), n (%) Presence of tubular 15 (37.5) 0.000 0.106 (T1) (0.035–0.339) 17 (24.6) 0.001 0.224 (T1) (0.085–0.589) atrophy/intersti- 0.525 (T2) (0.176–1.564) 0.710 (T2) (0.251–2.002) tial fibrosis (T1/T2, Oxford classifica- tion), n (%) Fig. 2. MEST classification and primary endpoints. (A) Segmental glomerulosclerosis (S0/S1) in the kidney biopsy and survival free from ESRD or (B) doubling of baseline SCr. (C) Tubular atrophy/interstitial fibrosis (T0/T1/T2) in the kidney biopsy and survival free from ESRD or (D) doubling of baseline SCr. Remission of proteinuria proteinuria, 96.3% in those with remission and 75.4% in patients with persistent proteinuria (P < 0.001) (Figure 3). Once remission Of 343 patients with proteinuria >0.5 g/24 h, 217 (63.3%) exhibited of proteinuria was achieved, the rate of survival free from ESRD a reduction of proteinuria to <0.5 g/24 h with either conservative was similar in patients who received immunosuppressive drugs or immunosuppressive treatment. The 10-year renal survival free or conservative management. from ESRD rate was 99% in patients with no substantial Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/38/4056783 by Ed 'DeepDyve' Gillespie user on 16 March 2018 IgA nephropathy in Greece | 43 (n ¼ 32) were comparable to those treated with corticosteroids alone (Table 2). Of these 32 patients, 3 (9.4%) reached ERSD and 5 (15.6%) doubled baseline SCr. Remission of proteinuria to <0.5 g/24 h was observed in 17 patients (53%). No significant difference was observed in the development of primary endpoints between patients treated with prednisol- one and azathioprine and those treated with oral prednisolone daily or IV methylprednisolone. An increased proteinuria remis- sion rate was observed in patients treated with prednisolone and azathioprine compared with those treated with oral pred- nisolone daily (P ¼ 0.037). Corticosteroids and MMF. A combination of prednisolone and MMF was used in nine patients (baseline SCr 1.7460.84 mg/dL, eGFR 51.5 6 26.7 mL/min/1.73 m , urine protein 3.9 6 4.9 g/24 h). Of these patients, one doubled baseline SCr and reached ESRD and six reduced proteinuria to <0.5 g/24 h. Corticosteroids and cyclophosphamide. IV methylprednisolone pulses for 3 days followed by oral prednisolone and IV cyclo- phosphamide every month for 6 months was administered to 21 Fig. 3. Survival free from the endpoint of ESRD in patients with no substantial patients with a rapidly progressive course and/or cellular cres- proteinuria, patients with remission and patients with no remission of cents in >40% of glomeruli in the renal biopsy (baseline SCr proteinuria. 2.64 6 1.43 mg/dL, eGFR 37.7 6 27.8 mL/min/1.73 m , urine pro- tein 2.9 6 2.8 g/24 h). Of 21 patients, 2 doubled baseline SCr and Persistent proteinuria (>0.5 g/24 h) was related to endocapil- reached ESRD and 14 reduced proteinuria to <0.5 g/24 h. lary hypercellularity (E1), tubular atrophy/interstitial fibrosis (T1/T2) (P ¼ 0.020 and 0.006) and the severity of mesangial IgA deposition (P ¼ 0.001). Side effects of treatment Side effects related to immunosuppressive drugs were observed Therapeutic regimens and clinical course in 25 of 195 treated patients (12.8%). Adverse events related to corticosteroids included osteonecrosis and/or osteopenia in Conservative management three patients, myopathy in four, glaucoma in two, cushingoid Of 262 patients who received conservative management, 18 symptoms in six and deterioration of bipolar disease in one. (6.9%) progressed to ESRD and 35 (13.4%) doubled their baseline Among patients who received azathioprine, gastrointestinal SCr. The main differences between patients who reached the symptoms were observed in two, elevated liver enzymes in two primary endpoints or preserved renal function were the degree and leucopenia in one. Among patients who received MMF, of renal function and severity of proteinuria. SCr, estimated gastrointestinal symptoms were observed in one, leucopenia in glomerular filtration rate (eGFR) and 24-h urine protein at one and osteomyelitis in one. diagnosis in patients who reached ESRD, doubled baseline SCr or preserved their renal function were 1.76 6 0.63 mg/dL, 47.08 6 24.8 mL/min/1.73 m and 1.8 6 0.9 g/24 h; 1.48 6 0.62 mg/ Discussion dL, 59.5 6 28.6 mL/min/1.73 m and 1.4 6 0.6 g/24 h and 1.23 6 0.69 mg/dL, 68.9 6 28.3 mL/min/1.73 m and 1.1 6 1.1 g/ The natural history of IgAN, the parameters related to an un- 24 h, respectively. Of 37 patients with baseline SCr >2.5 mg/dL favourable outcome and the effects of treatment with various and/or severe glomerulosclerosis, 13 reached ESRD (35%). Of 225 immunosuppressive drugs were estimated in a retrospective patients with normal renal function and proteinuria <1 g/24 h, 5 analysis of a large cohort from the registry of the Hellenic developed ESRD (2.2%). Society of Nephrology. Macroscopic haematuria, a common manifestation of the Corticosteroids disease, was frequently observed, whereas nephrotic range pro- Oral corticosteroids daily versus IV pulse followed by oral corticoster- teinuria and acute kidney injury were confirmed as rare mani- oids every other day. The clinical and histological features of festations. The 10-year renal survival was 90.8%, which is patients treated with oral prednisolone daily (n ¼ 76) or by IV similar to that reported in the literature [5, 6]. methylprednisolone for 3 consecutive days on the first, third Recent data from the European Validation Study of the and fifth month of treatment followed by oral prednisolone Oxford Classification of IgA Nephropathy (VALIGA) study dem- every other day (n ¼ 57) were comparable (Table 2). onstrated that time averaged proteinuria <0.5 g/day was a sig- Of 76 patients treated with oral prednisolone, 14 (18.4%) nificant marker of better outcome [14]. Elevated baseline SCr, reached ESRD and 15 (19.7%) doubled baseline SCr. Of 57 pa- arterial hypertension, persistent proteinuria >0.5 g/24 h, pres- tients treated with IV methylprednisolone, 4 (7%) reached ESRD ence of segmental glomerulosclerosis and severity of and 9 (15.8%) doubled baseline SCr. No significant differences tubulointerstitial fibrosis were related to the development of were found in reaching ESRD or doubling of SCr between pa- ESRD and doubling of baseline SCr in our cohort. The presence tients in these two different treatment groups. Reduction of pro- of crescents in the biopsy was not related to a more rapid de- teinuria to <0.5 g/24 h was achieved in 35 patients (46%) in the cline of renal function in some studies [15], a finding that was former group and in 41 patients (72%) in the latter group also confirmed in this study in patients with cellular crescents (P ¼ 0.000). in >40% of the total number of glomeruli in the kidney biopsy, Corticosteroids and azathioprine. The clinical and histological probably due to the aggressive treatment administered to these features of patients treated with prednisolone and azathioprine patients. Of note, the rate of survival free from ESRD was not Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/38/4056783 by Ed 'DeepDyve' Gillespie user on 16 March 2018 44 | M. Stangou et al. related to conservative or immunosuppressive treatment, but given the limited number of patients treated with MMF. only to proteinuria remission. The degree of proteinuria at diag- Cytotoxic drugs have been used in patients with rapidly pro- nosis, presence of endocapillary hypercellularity, tubulointersti- gressive IgAN with good results [35, 36]. In a randomized pro- tial fibrosis and severity of IgA deposition correlated with spective trial, patients with progressive disease and proteinuria persistent proteinuria. The correlation of mesangial prolifer- were allocated to either prednisolone (40 mg/day) and cyclo- ation and endocapillary hypercellularity with proteinuria has phosphamide (1.5 mg/kg BW/day for 3 months) followed by aza- been recognized in VALIGA [14]. thioprine for 2 years or conservative management [37]. A better Patients with normal renal function and a lack of proteinuria renal survival rate after 5 years of follow-up was observed in pa- have a favourable outcome, whereas patients with baseline SCr tients treated with immunosuppressive drugs. The beneficial >2.5 mg/dL and severe glomerulosclerosis are not good candi- effects of corticosteroids and cyclophosphamide have also been dates for immunosuppressive treatment because they have reported in patients with aggressive disease and proteinuria [38, reached the ‘point of no return’ [16]. Of 42 patients who reached 39]. In this study, a combination of corticosteroids and IV cyclo- ESRD, 18 received no immunosuppressive drugs, including 13 phosphamide every month for 6 months was effective in pa- patients from the subgroup of 37 patients with baseline SCr tients with a rapidly progressive course. However, this >2.5 mg/dL and/or severe glomerulosclerosis. The remaining 5 combination should be used with great caution given the long- patients were from the subgroup of 225 patients with normal term risk of the development of malignancies [40]. In a recent renal function and proteinuria <1 g/24 h. These patients had in- randomized controlled trial, the addition of immunosuppres- adequate control of their BP over a long period of time. sive therapy to intensive supportive care in patients with high- Administration of a 6-month course of corticosteroids (1 g IV risk IgAN was estimated over a 3-year follow-up period [13]. methylprednisolone for 3 consecutive days every other month During a 6-month run-in phase, all patients received compre- and 0.5 mg/kg BW oral prednisolone every other day) in patients hensive supportive care with blockers of the renin–angiotensin with proteinuria (1–3.5 g/24 h) and well-preserved renal function system to reduce proteinuria to <0.75 g/day. High-risk patients (SCr < 1.5 mg/dL) was more effective than supportive treatment who had persistent proteinuria entered a 3-year study phase in a randomized trial over a 10-year follow-up [17]. A beneficial and were randomly assigned to supportive care or supportive effect with low-dose prednisolone was also observed in a con- care plus immunosuppressive therapy with corticosteroids or a trolled prospective trial in patients with moderate histological combination of corticosteroids with cyclophosphamide as pre- changes [18]. These results were confirmed in a meta-analysis viously reported [17, 39]. According to the results, the addition of all randomized prospective trials [19]. Recent studies demon- of immunosuppressive therapy to intensive supportive care did strate that treatment with corticosteroids in combination with not significantly improve outcome and was followed by more ACEis is more effective than ACEis alone in patients with pro- adverse effects. teinuria [20, 21]. The beneficial effect of corticosteroids in add- The main limitation of our study is that this is a retrospect- ition to renin–angiotensin system blockade was also confirmed ive analysis including patients from many centres with possible in VALIGA and other studies [22, 23]. Although a considerable different therapeutic principles. However, as was confirmed at amount of data on the use of two regimens of corticosteroids in the end, the general recommendations have been adopted by patients with IgAN has been reported, no comparison between all centres. these regimens has been reported to date. In this study, both In conclusion, the choice of the therapeutic regimen should regimens were used in patients with similar clinical and histo- be based on the severity of clinical and histological involve- logical features. Although there was no significant difference in ment. A combination of conservative management with im- the development of primary endpoints, a significantly higher munosuppressive drugs seems to be a reasonable approach in remission rate of proteinuria to <0.5 g/24 h was noted with IV patients with persistent proteinuria and severe histological in- methylprednisolone followed by oral prednisolone every other volvement to delay progression of IgAN. day (remission rate 72% versus 46%: P ¼ 0.000). Corticosteroids in combination with azathioprine offers a Conflict of interest statement beneficial effect in patients with heavy proteinuria (>3 g/24 h) and impaired renal function in a retrospective study with 10- None declared. year follow-up [24]. Others report that IgAN patients who do not respond to steroids might respond to a combination of steroids References and azathioprine [25]. However, in a randomized prospective trial, the effect of a 6-month course of corticosteroids and aza- 1. D’Amico G. The commonest glomerulonephritis in the thioprine was not superior to a 6-month course of corticoster- world: IgA nephropathy. Q J Med 1987; 64: 709–727 oids alone [26]. The same authors reported that the addition of 2. Donadio JV, Grande JP. IgA nephropathy. N Engl J Med 2002; azathioprine may be slightly more effective than corticosteroids 347: 738–748 alone in patients with chronic renal insufficiency and protein- 3. Barratt J, Feehaly J. IgA nephropathy. J Am Soc Nephrol 2005; uria [27], but it can increase the risk of side effects [28]. In this 16: 2088–2097 study, no significant difference in the development of primary 4. Haas MJ. Histology and immunohistology of IgA nephrop- endpoints was observed between patients treated with prednis- athy. J Nephrol 2005; 18: 676–680 olone and azathioprine and those treated with corticosteroids 5. D’Amico G. Influence of clinical and histological features onac- alone. However, an increased remission rate of proteinuria was tuarial renal survival in adult patients with idiopathic IgA nephr- noted among patients treated with prednisolone and azathio- opathy, membranous nephropathy and membranoproliferative prine and patients treated with IV methylprednisolone com- glomerulonephritis: survey of the recent literature. Am J Kidney pared with patients treated with oral prednisolone daily Dis 1992; 20: 315–323 (P ¼ 0.037). 6. Nicholls KM, Fairley KF, Dowling JP et al. The clinical course MMF has also been used in patients with IgAN, with conflict- of mesangial IgA associated nephropathy in adults. Q J Med ing results [29–34]. No conclusions can be drawn from our study 1984; 53: 227–250 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/38/4056783 by Ed 'DeepDyve' Gillespie user on 16 March 2018 IgA nephropathy in Greece | 45 24. Goumenos D, Davlouros P, El Nahas AM et al. Prednisolone 7. D’Amico G. Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome. Semin Nephrol and azathioprine in IgA nephropathy: a ten-year follow up 2004; 24: 179–196 study. Nephron Clin Pract 2003; 93: 58–68 8. Coppo R, D’Amico G. Factors predicting progression of IgA 25. Stangou M, Ekonomidou D, Giamalis P et al. Steroids and aza- nephropathies. J Nephrol 2005; 18: 503–512 thioprine in the treatment of IgA nephropathy. Clin Exp 9. Cattran DC, Coppo R, Cook HT et al. The Oxford classification Nephrol 2011; 15: 373–380 of IgA nephropathy: rationale, clinicopathological correl- 26. Pozzi C, Andrulli S, Pani A et al. Addition of azathioprine to ations and classification. Kidney Int 2009; 76: 534–545 corticosteroids does not benefit patients with IgA nephrop- 10. Barbour SJ, Espino-Hernandez G, Reich HN et al. The MEST athy. J Am Soc Nephrol 2010; 21: 1783–1790 score provides earlier risk prediction in IgA nephropathy. 27. Pozzi C, Andrulli S, Pani A et al. IgA nephropathy with severe Kidney Int 2016; 89: 167–175 chronic renal failure: a randomized controlled trial of cor- 11. Floege J, Eitner F. Current therapy for IgA nephropathy. JAm ticosteroids and azathioprine. J Nephrol 2013; 26: 86–93 Soc Nephrol 2011; 22: 1785–1794 28. Sarcina C, Tinelli C, Ferrario F et al. Changes in proteinuria 12. Kidney Disease: Improving Global Outcomes Glomerulonephritis and side effects of corticosteroids alone or in combination Work Group. KDIGO clinical practice guideline for glomerulo- with azathioprine at different stages of IgA nephropathy. nephritis. Immunoglobulin A nephropathy. Kidney Int Suppl 2012; Clin J Am Soc Nephrol 2016; 11: 973–981 2: 209–217 29. Chen X, Chen P, Cai G et al. A randomized control trial of 13. Rauen T, Eitner F, Fitzer C et al. Intensive supportive care mycophenolate mofetil treatment in severe IgA nephrop- plus immunosuppression in IgAN nephropathy. N Engl J Med athy. Zhonghua Yi Xue Za Zhi 2002; 82: 796–801 2015; 373: 2225–2236 30. Tang SC, Tang AW, Wong SS et al. Long-term study of myco- 14. Coppo R, Troyanov S, Bellur S et al. Validation of phenolate mofetil treatment in IgA nephropathy. Kidney Int the Oxford classification of IgA nephropathy in cohorts with 2010; 77: 543–549 different presentations and treatments. Kidney Int 2014; 86: 31. Mayes BD, Oyen R, Claes K et al. Mycophenolate mofetil in 828–836 IgA nephropathy: results of a 3-year prospective placebo- 15. Lee MJ, Kim SJ, Oh HJ et al. Clinical implication of crescentic contolled randomized study. Kidney Int 2004; 65: 1842–1849 lesions in immunoglobulin A nephropathy. Nephrol Dial 32. Frisch G, Lin J, Rosenstock J et al. Mycophenolate mofetil Transplant 2014; 29: 356–364 (MMF) vs placebo in patients with moderately advanced IgA 16. Scho ¨ ll U, Wastl U, Risler T et al. The “point of no return” and nephropathy: a double-blind randomized controlled trial. the rate of progression in the natural history of IgA neph- Nephrol Dial Transplant 2005; 20: 2139–2145 ritis. Clin Nephrol 1999; 52: 285–292 33. Navaneetham SD, Viswanathan G, Strippoli GF. Meta- 17. Pozzi C, Andrulli S, Del Vecchio L et al. Corticosteroid effect- analysis of mycophenolate mofetil in IgA nephropathy. iveness in IgA nephropathy: long-term results of a random- Nephrology 2008; 13: 90 ized controlled trial. J Am Soc Nephrol 2004; 15: 157–163 34. Chen Y, Li Y, Yang S et al. Efficacy and safety of mycopheno- 18. Katafuchi R, Ikeda K, Mizumasa T et al. Controlled, prospect- late mofetil treatment in IgA nephropathy:a systematic re- ive trial of steroid treatment in IgA nephropathy: a limita- view. BMC Nephrol 2014; 15: 193 tion of low-dose prednisolone therapy. Am J Kidney Dis 2003; 35. Roccatello D, Ferro M, Coppo R et al. Report on intensive 41: 972–983 treatment of extracapillary glomerulonephritis with focus 19. Samuels JA, Strippoli GF, Craig JC et al. Immunosuppressive treat- on crescentic IgA nephropathy. Nephrol Dial Transplant 1995; ments for immunoglobulin A nephropathy: a meta-analysis of 10: 2054–2059 randomized controlled trials. Nephrology 2004; 9: 177–185 36. Tumlin JA, Lohavichan V, Hennigar R. Crescentic, prolifera- 20. Lv J, Zhang H, Chen Y et al. Combination therapy of prednis- tive IgA nephropathy. Clinical and histological response to one and ACE inhibitor versus ACE-inhibitor therapy alone in methylprednisolone and intravenous cyclophosphamide. patients with IgA nephropathy: a randomized controlled Nephrol Dial Transplant 2003; 18: 1321–1329 trial. Am J Kidney Dis 2009; 53: 26–32 37. Ballardie FW, Roberts IS. Controlled prospective trial of pred- 21. Manno C, Torres DD, Rossini M et al. Randomized controlled nisolone and cytotoxics in progressive IgA nephropathy. clinical trial of corticosteroid plus ACE-inhibitors with long- J Am Soc Nephrol 2002; 13: 142–148 term follow-up in proteinuric IgA nephropathy. Nephrol Dial 38. Rasche FM, Klotz CH, Czock D et al. Cyclophosphamide pulse Transplant 2009; 24: 3694–3701 therapy in advanced progressive IgA nephropathy. Nephron 22. Tesar V, Troyanov S, Bellur S et al. Corticosteroids in IgA Clin Pract 2003; 93: 131–136 nephropathy: a retrospective analysis from the VALIGA 39. Peters HP, van den Brand JA, Berger SP et al. Immunosup- study. J Am Soc Nephrol 2015; 26: 2248–2258 pressive therapy in patients with IgA nephropathy. Neth J 23. Kalliakmani P, Komninakis D, Gerolymos M et al. Treatment Med 2015; 73: 284–289 of IgA nephropathy based on the severity of clinical and 40. Oshima S, Kawamura O. Long-term follow-up of patients histological features. Saudi J Kidney Dis Transpl 2015; 16: with IgA nephropathy treated with prednisolone and cyclo- 516–525 phosphamide therapy. Clin Exp Nephrol 2008; 12: 264–269 Downloaded from https://academic.oup.com/ckj/article-abstract/11/1/38/4056783 by Ed 'DeepDyve' Gillespie user on 16 March 2018

Journal

Clinical Kidney JournalOxford University Press

Published: Feb 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off