Changes in the clinical presentation of immunoglobulin A nephropathy: data from the Spanish Registry of Glomerulonephritis

Changes in the clinical presentation of immunoglobulin A nephropathy: data from the Spanish... Abstract Background Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis in the world, but there is little epidemiological data about possible changes in its presentation over the years. Available information about the influence of age on the form of clinical presentation is also scarce. Methods The aim of the study was to analyse all renal biopsies performed between 1994 and 2013 and recorded in the Spanish Registry of Glomerulonephritis with a histological diagnosis of IgAN. The study was divided into five 4-year periods (1994–97, 1998–2001, 2002–05, 2006–09 and 2010–13) and patients were divided into four age groups: ≤16, 17–44, 45–64 and ≥65 years. Results From 20.974 renal biopsies recorded, 2961 (14.1%) corresponded to IgAN. The prevalence of IgAN remained stable, but a significant increase in age [from 37.6 (SD 17.7) in 1994–97 to 44.9 (SD 16.8) years in 2010–13; P = 0.001] and worse renal function at presentation [from serum creatinine (SCr) 1.9 (SD 1.9) in 1994–97 to 2.3 (SD 2.1) mg/dL in 2010–13; P = 0.001] were observed over the years. Nephrotic-range proteinuria and acute kidney injury (AKI) as forms of presentation were significantly more common among patients ≥65 years (17.7% and 43.2%, respectively) as compared with the other age groups [≤16 (11.4% and 13.1%, respectively), 17–44 (13.1% and 13%, respectively) and 45–64 (12.1% and 21.3%, respectively)]. Blood pressure, SCr and proteinuria were also significantly higher at presentation among elderly patients. Conclusions Although the prevalence of IgAN in Spain has remained stable over the years, patients are significantly older and present with significantly worse renal function in the last years. The incidence of nephrotic-range proteinuria (17.7%) and AKI (43.2%) as forms of presentation is remarkable among patients ≥65 years of age. AKI, epidemiology, glomerulonephritis, immunoglobulin A nephropathy, renal biopsy INTRODUCTION Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulopathy worldwide [1]. It is particularly common in whites and Asians and rare in blacks [2]. Epidemiological studies suggest that patients of Asian origin have more aggressive presentations and clinical courses than patients of other ethnicities [3–6]. The clinical presentation of IgAN is highly variable. There is a general idea, based on original descriptions of the disease, that IgAN predominantly affects young individuals, in their second or third decade of life, and that most of them have a benign presentation: outbreaks of gross haematuria of short duration with no renal function derangement and/or asymptomatic and persistent urinary disorders (AUDs) (non-nephrotic proteinuria with microhaematuria) [7, 8]. It is also generally accepted that aggressive presentations such as acute kidney injury (AKI), nephrotic syndrome and malignant hypertension are rare. However, most of clinical reports agree on the serious long-term prognosis of IgAN: up to 50% of patients eventually develop end-stage renal disease (ESRD) over 20–30 years of follow-up [9–11]. Treatment of IgAN varies according with clinical presentation. Cases with isolated microhaematuria accompanied or not by outbreaks of gross haematuria do not require treatment, although periodic monitoring is recommended owing to the risk of developing hypertension and increasing proteinuria [12]. In those patients who develop proteinuria >0.5–1 g/24 h, antiproteinuric strategies mainly based on renin–angiotensin–aldosterone system (RAAS) blockade are a proven effective treatment to prevent progression to ESRD [13–16]. Immunosuppression therapy with corticosteroids is recommended for those patients with preserved renal function who maintain proteinuria persistently >1 g/24 h despite RAAS blockade optimization. Nevertheless, information about effective treatments for aggressive forms of presentation (nephrotic syndrome, AKI) is very scarce. Recent prospective studies have seriously questioned the therapeutic value of immunosuppressive therapies in patients who maintain significant proteinuria despite optimized RAAS blockade [17]. In this changing and controversial scenario, registry studies focused on large groups of biopsy-proven IgAN can be very useful, by showing the frequency of the different forms of presentation of the disease and the distribution of clinical syndromes according to age. Importantly, there is no information about possible changes in the presentation of the disease over recent years. The Spanish Registry of Glomerulonephritis was established in 1994 and has included data on unselected renal biopsies of native kidneys by >100 Spanish centres [18, 19]. The aim of this study was to identify the changes in the prevalence of different clinical manifestations of IgAN as well as their distribution according to age over a 20-year period (1994–2013). MATERIALS AND METHODS The database of the Spanish Registry of Glomerulonephritis contains the results of unselected renal biopsies of native kidneys sent by a large number of Spanish centres. A total of 20.974 native kidney biopsies were recorded between 1994 and 2013. As shown in Table 1, the number of biopsies remained relatively stable with the exception of the period 2010–13, in which fewer biopsies were recorded owing to a decrease in the number of collaborating centres. For this study, we retrospectively analysed patients with a histological diagnosis of IgAN. We excluded patients with Schönlein–Henoch purpura, liver disease, diabetes, systemic diseases or any type of secondary IgAN. Patients were divided into four groups according to age at the time of renal biopsy: ≤16, 17–44, 45–64 and ≥65 years. To study changes in the prevalence of IgAN over time, patients were grouped according to the time of renal biopsy into five 4-year periods: 1994–97, 1998–2001, 2002–05, 2006–09 and 2010–13. Table 1 Prevalence of IgAN in glomerulonephritis Variable  1994–97  1998–2001  2002–05  2006–09  2010–13  Number of renal biopsies  4671  4082  4048  4898  3275  Number of renal biopsies with a diagnosis of glomerulonephritis  2672  2372  2175  2553  1645  Number of renal biopsies with a diagnosis of IgAN  697  632  517  675  440  % of IgAN with respect to the total number of biopsies  14.9  15.5  12.8  13.8  13.4  % of IgAN with respect to renal biopsies with a diagnosis of glomerulonephritis  26.1  26.6  23.8  26.4  26.7  Variable  1994–97  1998–2001  2002–05  2006–09  2010–13  Number of renal biopsies  4671  4082  4048  4898  3275  Number of renal biopsies with a diagnosis of glomerulonephritis  2672  2372  2175  2553  1645  Number of renal biopsies with a diagnosis of IgAN  697  632  517  675  440  % of IgAN with respect to the total number of biopsies  14.9  15.5  12.8  13.8  13.4  % of IgAN with respect to renal biopsies with a diagnosis of glomerulonephritis  26.1  26.6  23.8  26.4  26.7  The diagnosis of IgAN was based on the predominance of IgA deposits detected by immunofluorescence. The following demographic and clinical data were obtained from a questionnaire sent to individual patients at the time of renal biopsy: date of birth, sex, serum creatinine (SCr; mg/dL), estimated glomerular filtration rate (eGFR), proteinuria (g/day) and urinary sediment. Clinical and analytical data at presentation were recorded and grouped into the following types of presentation: AKI: AKI stage was defined according to the Kidney Disease: Improving Global Outcomes guidelines (increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days) [20]. Nephrotic-range proteinuria: proteinuria >3.5 g/day/1.73 m2. AUD: proteinuria <3.5 g/day/1.73 m2 and/or haematuria defined as the presence of >3 red blood cells/field without clinical symptoms. Arterial hypertension: blood pressure ≥140/90 mmHg or the need for hypotensive drugs regardless of blood pressure levels. Gross haematuria. These definitions for the different types of presentation were applied to all the patients, independent of the period in which renal biopsy was performed. The GFR was calculated with the abbreviated four-variable Modification of Diet in Renal Disease (MDRD-4) equation [21]. In the paediatric population, the measurements were adjusted according to body surface area. Statistical analysis The normality of the sample distribution was determined using the Kolmogorov–Smirnov test. Normally distributed quantitative variables are expressed as mean and SD and were compared using the t test. Non-normally distributed variables are expressed as median and interquartile range and were analysed using median tests. The qualitative variables are listed with their frequency distribution and were analysed using the Fisher’s exact and chi-squared tests. Bonferroni corrections were used to adjust for multiple comparisons. A P-value <0.05 was considered statistically significant except when Bonferroni correction was applied and mentioned. The statistical analysis was performed using SPSS version 17.0 Statistical Package for the Social Sciencies (SPSS), Chicago, IL, USA. RESULTS Prevalence of IgAN As shown in Table 1, the prevalence of IgAN remained stable over the years, ranging between 12.8% and 15.5% of all renal biopsies contained in the registry. With regard to the total number of renal biopsies with a diagnosis of glomerulonephritis, IgAN represented 23.8–26.7%, again without significant variations over time. Clinical features according to age at diagnosis As shown in Table 2, IgAN was more frequently diagnosed in patients 17–44 years of age (51.3% of the cases), followed by patients 45–64 years of age (30.9%). Patients who were ≤16 years of age accounted for 8.3% and those ≥65 years of age accounted for 9.5% of the sample. Age distribution along the different periods of time is shown in Figure 1. Table 2 Clinical characteristics according to age at diagnosis Variable  ≤16 years  17–44 years  45–64 years  ≥65 years  P-value  [n = 238  [n = 1473  [n = 888  [n = 274    (8.3%a)]  (51.3%a)]  (30.9%a)]  (9.5%a)]  Age (years), mean (SD)  11.4 (3.7)  31.9 (7.9)  54.2 (5.4)  72.9 (5.2)  0.000  Male (%)  68.4  72  81.6  75.9  0.000  SCr (mg/dL), mean (SD)  1 (1)  1.8 (1.9)  2.4 (2)  3.5 (3.1)  0.000  eGFR (mL/min/1.73 m2)b, mean (SD)  173.9 (87.3)  73.9 (40.5)  47.6 (30)  33.2 (24.8)  0.000   CKD Stage 1 (%)c  79.2  33.2  8.6  3     CKD Stage 2 (%)d  8.4  26.6  18.1  9.4     CKD Stage 3a (%)e  5.3  14.7  21.1  14  0.001*   CKD Stage 3b (%)f  2.6  12.4  21.9  18.1     CKD Stage 4 (%)g  2.6  8.1  19.6  26.8     CKD Stage 5 (%)g  1.9  5  10.7  28.7    Proteinuria (g/24 h), mean (SD)  1.5 (2.9)  2.5 (2.4)  2.7 (2.8)  2.9 (2.9)  0.000   <0.3 g/day (%)h  32.6  8.2  6  5.7     0.3–0.99 g/day (%)h  24.9  16.2  14.9  18.3  0.001*   1–3.5 g/day (%)i  31.1  62.5  67  58.3     Nephrotic-range proteinuria (>3.5 g/day) (%)  11.4  13.1  12.1  17.7    Hypertension (%)  10.2  43.9  71.9  72  0.000  AUD (%)  33.6  42.1  37.2  18.8  0.000  AKI (%)  13.1  13  21.3  43.2  0.000  Gross haematuria (%)  40.6  14.4  4.1  3.4  0.001  Variable  ≤16 years  17–44 years  45–64 years  ≥65 years  P-value  [n = 238  [n = 1473  [n = 888  [n = 274    (8.3%a)]  (51.3%a)]  (30.9%a)]  (9.5%a)]  Age (years), mean (SD)  11.4 (3.7)  31.9 (7.9)  54.2 (5.4)  72.9 (5.2)  0.000  Male (%)  68.4  72  81.6  75.9  0.000  SCr (mg/dL), mean (SD)  1 (1)  1.8 (1.9)  2.4 (2)  3.5 (3.1)  0.000  eGFR (mL/min/1.73 m2)b, mean (SD)  173.9 (87.3)  73.9 (40.5)  47.6 (30)  33.2 (24.8)  0.000   CKD Stage 1 (%)c  79.2  33.2  8.6  3     CKD Stage 2 (%)d  8.4  26.6  18.1  9.4     CKD Stage 3a (%)e  5.3  14.7  21.1  14  0.001*   CKD Stage 3b (%)f  2.6  12.4  21.9  18.1     CKD Stage 4 (%)g  2.6  8.1  19.6  26.8     CKD Stage 5 (%)g  1.9  5  10.7  28.7    Proteinuria (g/24 h), mean (SD)  1.5 (2.9)  2.5 (2.4)  2.7 (2.8)  2.9 (2.9)  0.000   <0.3 g/day (%)h  32.6  8.2  6  5.7     0.3–0.99 g/day (%)h  24.9  16.2  14.9  18.3  0.001*   1–3.5 g/day (%)i  31.1  62.5  67  58.3     Nephrotic-range proteinuria (>3.5 g/day) (%)  11.4  13.1  12.1  17.7    Hypertension (%)  10.2  43.9  71.9  72  0.000  AUD (%)  33.6  42.1  37.2  18.8  0.000  AKI (%)  13.1  13  21.3  43.2  0.000  Gross haematuria (%)  40.6  14.4  4.1  3.4  0.001  a With respect to the total number of IgAN biopsies with available data (n = 2873). b The eGFR was calculated with the abbreviated MDRD-4 equation. CKD Stage 1: eGFR ≥90; Stage 2: 60–89; Stage 3a: 45–59; Stage 3b: 30–44; Stage 4: 15–29; Stage 5: <15. c P < 0.008 between all groups. d P < 0.008 between all groups except ≤16 years versus ≥65 years. e P < 0.008 between all groups except 17–44 years versus ≥65 years. f P < 0.008 between all groups except 45–64 years versus ≥65 years. g P < 0.008 between all groups. h P < 0.008 between all groups except 17–44 years versus ≥65 years and 45–64 years versus ≥65 years. i P < 0.008 between ≤16 years versus all groups. *Global P. FIGURE 1 View largeDownload slide Age distribution in the different periods of time. FIGURE 1 View largeDownload slide Age distribution in the different periods of time. Clinical features at diagnosis varied according to the age of the patients. As shown in Table 2, renal function worsened in parallel with ageing—the older the patient, the worse the renal function. Proteinuria and the number of hypertensive patients also showed a significant increase in parallel with ageing. The proportion of patients presenting with hypertension, AKI and nephrotic-range proteinuria significantly increased with ageing, whereas that of patients with AUD decreased (Table 2). Changes in clinical presentation over time The mean age at diagnosis showed a significant progressive increase from 37.6 ± 17.8 years in the period 1994–97 to 44.9 ± 16.8 in the period 2010–13 (Figure 1 and Table 3). Paralleling this trend, a significant change towards a worse clinical profile at diagnosis was found: worse renal function (Figure 2A), increasing proteinuria, increasing proportion of hypertensive patients and cases presenting with AKI and nephrotic-range proteinuria and decreasing number of patients with AUD (Table 3 and Figure 2B). Table 3 Changes in clinical and laboratory parameters over time (all the patients) Variable  1994–97  1998–01  2002–05  2006–09  2010–13  P-value  (n = 655)  (n = 616)  (n = 514)  (n = 675)  (n = 440)  Age (years), mean (SD)  37.6 (17.8)  40.4 (17.7)  40.1 (17.4)  42.9 (17.6)  44.9 (16.8)  0.000  Male (%)  74.2  76.9  75.1  75.1  72.3  0.46  SCr (mg/dL), mean (SD)  1.9 (1.9)  1.9 (1.6)  2.4 (3.2)  2.2 (2.2)  2.3 (2.1)  0.000  eGFR (mL/min/1.73 m2)a, mean (SD)  78.4 (58.5)  73.2 (53.6)  72.1 (61.2)  64.1 (48.8)  60.6 (47.2)  0.000   CKD Stage 1 (%)b  29.4  25.2  24.9  22.3  20  0.003*   CKD Stage 2 (%)c  21.3  25.4  21.3  18.6  17.9   CKD Stage 3a (%)  15.8  13.2  16.8  18  17.6   CKD Stage 3b (%)  13.4  16.7  15.1  16  17   CKD Stage 4 (%)  12.8  12.1  11.9  15.7  15   CKD Stage 5 (%)d  7.3  7.4  10  9.4  12.5  Proteinuria (g/24 h), mean (SD)  2.3 (2.4)  2.8 (3.1)  2.5 (3.1)  2.5 (2.4)  2.5 (2.4)  0.02   <0.3 g/day (%)e  13.4  8  7  7.4  10     0.3–0.99 g/day (%)f  17.1  12.7  18  18.3  17.3     1–3.5 g/day (%)  59.7  65.5  62.3  59.8  56.8  0.001*   Nephrotic-range proteinuria (>3.5 g/day) (%)g  9.8  13.8  12.7  14.5  15.9    Hypertension (%)  44.1  50.1  51.4  59.2  57.5  0.000  AUD (%)  44.4  43  37.2  33.3  28.4  0.000  AKI (%)  13.2  11.4  19.8  23.9  25.2  0.000  Gross haematuria (%)  20  14.3  12.3  6.6  5.9  0.000  Variable  1994–97  1998–01  2002–05  2006–09  2010–13  P-value  (n = 655)  (n = 616)  (n = 514)  (n = 675)  (n = 440)  Age (years), mean (SD)  37.6 (17.8)  40.4 (17.7)  40.1 (17.4)  42.9 (17.6)  44.9 (16.8)  0.000  Male (%)  74.2  76.9  75.1  75.1  72.3  0.46  SCr (mg/dL), mean (SD)  1.9 (1.9)  1.9 (1.6)  2.4 (3.2)  2.2 (2.2)  2.3 (2.1)  0.000  eGFR (mL/min/1.73 m2)a, mean (SD)  78.4 (58.5)  73.2 (53.6)  72.1 (61.2)  64.1 (48.8)  60.6 (47.2)  0.000   CKD Stage 1 (%)b  29.4  25.2  24.9  22.3  20  0.003*   CKD Stage 2 (%)c  21.3  25.4  21.3  18.6  17.9   CKD Stage 3a (%)  15.8  13.2  16.8  18  17.6   CKD Stage 3b (%)  13.4  16.7  15.1  16  17   CKD Stage 4 (%)  12.8  12.1  11.9  15.7  15   CKD Stage 5 (%)d  7.3  7.4  10  9.4  12.5  Proteinuria (g/24 h), mean (SD)  2.3 (2.4)  2.8 (3.1)  2.5 (3.1)  2.5 (2.4)  2.5 (2.4)  0.02   <0.3 g/day (%)e  13.4  8  7  7.4  10     0.3–0.99 g/day (%)f  17.1  12.7  18  18.3  17.3     1–3.5 g/day (%)  59.7  65.5  62.3  59.8  56.8  0.001*   Nephrotic-range proteinuria (>3.5 g/day) (%)g  9.8  13.8  12.7  14.5  15.9    Hypertension (%)  44.1  50.1  51.4  59.2  57.5  0.000  AUD (%)  44.4  43  37.2  33.3  28.4  0.000  AKI (%)  13.2  11.4  19.8  23.9  25.2  0.000  Gross haematuria (%)  20  14.3  12.3  6.6  5.9  0.000  a The eGFR was calculated with the abbreviated MDRD-4 equation. CKD Stage 1: eGFR ≥ 90; Stage 2: 60–89; Stage 3a: 45–59; Stage 3b: 30–44; Stage 4: 15–29; Stage 5: < 15. b P < 0.005 between 1994 and 1997 with 2006–09 and 2010–13 period. c P < 0.005 between 1998 and 2001 with 2006–09 and 2010–13 period. d P < 0.005 between 1994 and 1997 versus 2010–13 period and 1998–2001 versus 2010–13 period. e P < 0.005 between 1994 and 1997 with 1998–2001, 2002–05 and 2006–09 period. f P < 0.005 between 1998 and 2001 versus 2006–09 period. g P < 0.005 between 1994 and 1997 with 2006–09 and 2010–13 period. * Global P. FIGURE 2 View largeDownload slide (A) Changes in eGFR over time according to age group. (*P < 0.05, intragroup; **P < 0.05, intergroup). (B) Changes in major clinical forms of presentation over time (all patients). FIGURE 2 View largeDownload slide (A) Changes in eGFR over time according to age group. (*P < 0.05, intragroup; **P < 0.05, intergroup). (B) Changes in major clinical forms of presentation over time (all patients). IgAN in patients ≥65 years of age Clinical manifestations at diagnosis were particularly aggressive among patients ≥65 years of age. As shown in Table 2, AKI was the most common clinical presentation (43.2%), and 17.7% presented with nephrotic-range proteinuria. Hypertension was found in a majority of patients (72%). In contrast, AUD was the type of presentation in only 18.8% of elderly patients. DISCUSSION Initial descriptions of IgAN were of an entity typically affecting young people and in which aggressive presentations were rare. Bouts of gross haematuria, according to these initial descriptions, constituted the most striking clinical feature, generally occurring in the early phases of the disease. Persistent AUD (non-nephrotic proteinuria, microhaematuria) could go unnoticed for many years in patients without gross haematuria episodes [22, 23]. Subsequent studies identified the amount of proteinuria, particularly in patients with proteinuria >0.5–1 g/day, as the most important risk factor for a slowly progressive deterioration of renal function occurring in a substantial number of patients after several decades of follow-up [12, 13, 24]. Our data show a clinical scenario quite different from this traditional view of IgAN. Although AUD is altogether the most frequent form of presentation, the proportion of patients with aggressive clinical presentations (nephrotic-range proteinuria, AKI) was remarkable, as shown in Table 2. Particularly striking was the frequency of aggressive types among patients >65 years of age, in whom AKI was the most frequent form of presentation. By dividing the 20-year period of patient’s inclusion into five 4-year consecutive periods (Table 3), it was found that the clinical presentation of IgAN has tended to be more aggressive in recent years, with a progressively higher number of patients presenting with AKI and nephrotic-range proteinuria and a lower number presenting with subclinical AUD. Importantly, the same definitions for the different types of presentation (AUD, nephrotic-range proteinuria, AKI) were applied to all the patients, independent of the period in which the renal biopsy was performed. Notably, this change in clinical profile parallels an increasingly older age at diagnosis that has changed from 37.6 years in the period 1994–97 to 44.9 years in the period 2010–13. The reasons for this change in the presentation of the disease are not clear. Although systematic studies have not been performed, there are no data suggesting changes in the policy of routine analytical controls. Changes in renal biopsy policy, for example, by a tendency to restrict their performance to older patients with more aggressive presentations, might be one of the reasons. However, there are several arguments against this possibility. First, the registry data are obtained by the collaboration of a large number of centres in Spain (>100), making it difficult to conceive such a similar and simultaneous tendency in all of them. Second, as shown in Table 1, the prevalence of IgAN has remained stable in our country over the 20-year period studied, which does not support a change in the policy of renal biopsy performance in patients suspected to have IgAN. Although our study confirms that the most common age at diagnosis is between 17 and 45 years (second to fourth decade of life), it should be stressed that 8.3% and 9.5% of the cases corresponded to children/adolescents and patients >65 years of age, respectively. In addition, 30.9% of cases were diagnosed in patients 45–65 years old. Particularly worrying was the profile of clinical presentation in the group of patients >65 years of age. Only 18.8% of them presented with AUD and AKI was the most common clinical presentation, occurring in 43.2% of the patients. Reasons for these changes in the clinical profile of elderly IgAN patients are not apparent. Gross haematuria-induced tubular damage is a leading cause of AKI in IgAN patients [25, 26] and anticoagulant therapy can induce haematuria and AKI in elderly patients [27]. Therefore, anticoagulation therapy could be a precipitating factor for haematuria-induced AKI in elderly IgAN patients. However, information on gross haematuria associated with anticoagulation was not collected in the registry, so its possible influence on more aggressive presentations of elderly IgAN patients should be explored in future studies. Our study confirms that gross haematuria is more frequent in younger patients (Table 2). The decrease in the frequency of gross haematuria at presentation in the more recent periods, as shown in Table 3 and Figure 2B, could be related with the increasing age of the patients. Our study has important limitations. The collected clinical data were rather limited and histological features were not collected. Information about treatments and outcomes of registered patients was not included in the information provided by centres. In contrast, the main strength of the study is the large number of biopsy-proven IgAN patients collected (>2900) and the extended period of time (20 years), which has allowed us to analyse changes in the clinical profile at diagnosis. There is general agreement about the indication of RAAS blockade in IgAN with proteinuria targeted to reduce it to <0.5–1 g/day. In contrast, controversy persists about the indication of immunosuppressive therapy with corticosteroids or other agents in IgAN. This controversy is partly due to the disparate results of several randomized controlled trials (RCTs). It should be stressed that RCT designed to analyse the influence of immunosuppressive therapies in IgAN are generally focused on patients with AUD in whom proteinuria is >1 g/day despite RAAS blockade. According to our data, RCTs designed to evaluate therapeutic alternatives for patients with aggressive forms of the disease are urgently needed. In conclusion, IgAN patients are significantly older and have presented with significantly worse renal function in recent years. Further studies are needed to analyse the reasons for this change and to evaluate therapies for these aggressive forms of presentation. ACKNOWLEDGEMENTS We would like to thank all participating hospitals for sending us the results of their renal biopsies. 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Changes in the clinical presentation of immunoglobulin A nephropathy: data from the Spanish Registry of Glomerulonephritis

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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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0931-0509
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1460-2385
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10.1093/ndt/gfx058
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Abstract

Abstract Background Immunoglobulin A nephropathy (IgAN) is the most common glomerulonephritis in the world, but there is little epidemiological data about possible changes in its presentation over the years. Available information about the influence of age on the form of clinical presentation is also scarce. Methods The aim of the study was to analyse all renal biopsies performed between 1994 and 2013 and recorded in the Spanish Registry of Glomerulonephritis with a histological diagnosis of IgAN. The study was divided into five 4-year periods (1994–97, 1998–2001, 2002–05, 2006–09 and 2010–13) and patients were divided into four age groups: ≤16, 17–44, 45–64 and ≥65 years. Results From 20.974 renal biopsies recorded, 2961 (14.1%) corresponded to IgAN. The prevalence of IgAN remained stable, but a significant increase in age [from 37.6 (SD 17.7) in 1994–97 to 44.9 (SD 16.8) years in 2010–13; P = 0.001] and worse renal function at presentation [from serum creatinine (SCr) 1.9 (SD 1.9) in 1994–97 to 2.3 (SD 2.1) mg/dL in 2010–13; P = 0.001] were observed over the years. Nephrotic-range proteinuria and acute kidney injury (AKI) as forms of presentation were significantly more common among patients ≥65 years (17.7% and 43.2%, respectively) as compared with the other age groups [≤16 (11.4% and 13.1%, respectively), 17–44 (13.1% and 13%, respectively) and 45–64 (12.1% and 21.3%, respectively)]. Blood pressure, SCr and proteinuria were also significantly higher at presentation among elderly patients. Conclusions Although the prevalence of IgAN in Spain has remained stable over the years, patients are significantly older and present with significantly worse renal function in the last years. The incidence of nephrotic-range proteinuria (17.7%) and AKI (43.2%) as forms of presentation is remarkable among patients ≥65 years of age. AKI, epidemiology, glomerulonephritis, immunoglobulin A nephropathy, renal biopsy INTRODUCTION Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulopathy worldwide [1]. It is particularly common in whites and Asians and rare in blacks [2]. Epidemiological studies suggest that patients of Asian origin have more aggressive presentations and clinical courses than patients of other ethnicities [3–6]. The clinical presentation of IgAN is highly variable. There is a general idea, based on original descriptions of the disease, that IgAN predominantly affects young individuals, in their second or third decade of life, and that most of them have a benign presentation: outbreaks of gross haematuria of short duration with no renal function derangement and/or asymptomatic and persistent urinary disorders (AUDs) (non-nephrotic proteinuria with microhaematuria) [7, 8]. It is also generally accepted that aggressive presentations such as acute kidney injury (AKI), nephrotic syndrome and malignant hypertension are rare. However, most of clinical reports agree on the serious long-term prognosis of IgAN: up to 50% of patients eventually develop end-stage renal disease (ESRD) over 20–30 years of follow-up [9–11]. Treatment of IgAN varies according with clinical presentation. Cases with isolated microhaematuria accompanied or not by outbreaks of gross haematuria do not require treatment, although periodic monitoring is recommended owing to the risk of developing hypertension and increasing proteinuria [12]. In those patients who develop proteinuria >0.5–1 g/24 h, antiproteinuric strategies mainly based on renin–angiotensin–aldosterone system (RAAS) blockade are a proven effective treatment to prevent progression to ESRD [13–16]. Immunosuppression therapy with corticosteroids is recommended for those patients with preserved renal function who maintain proteinuria persistently >1 g/24 h despite RAAS blockade optimization. Nevertheless, information about effective treatments for aggressive forms of presentation (nephrotic syndrome, AKI) is very scarce. Recent prospective studies have seriously questioned the therapeutic value of immunosuppressive therapies in patients who maintain significant proteinuria despite optimized RAAS blockade [17]. In this changing and controversial scenario, registry studies focused on large groups of biopsy-proven IgAN can be very useful, by showing the frequency of the different forms of presentation of the disease and the distribution of clinical syndromes according to age. Importantly, there is no information about possible changes in the presentation of the disease over recent years. The Spanish Registry of Glomerulonephritis was established in 1994 and has included data on unselected renal biopsies of native kidneys by >100 Spanish centres [18, 19]. The aim of this study was to identify the changes in the prevalence of different clinical manifestations of IgAN as well as their distribution according to age over a 20-year period (1994–2013). MATERIALS AND METHODS The database of the Spanish Registry of Glomerulonephritis contains the results of unselected renal biopsies of native kidneys sent by a large number of Spanish centres. A total of 20.974 native kidney biopsies were recorded between 1994 and 2013. As shown in Table 1, the number of biopsies remained relatively stable with the exception of the period 2010–13, in which fewer biopsies were recorded owing to a decrease in the number of collaborating centres. For this study, we retrospectively analysed patients with a histological diagnosis of IgAN. We excluded patients with Schönlein–Henoch purpura, liver disease, diabetes, systemic diseases or any type of secondary IgAN. Patients were divided into four groups according to age at the time of renal biopsy: ≤16, 17–44, 45–64 and ≥65 years. To study changes in the prevalence of IgAN over time, patients were grouped according to the time of renal biopsy into five 4-year periods: 1994–97, 1998–2001, 2002–05, 2006–09 and 2010–13. Table 1 Prevalence of IgAN in glomerulonephritis Variable  1994–97  1998–2001  2002–05  2006–09  2010–13  Number of renal biopsies  4671  4082  4048  4898  3275  Number of renal biopsies with a diagnosis of glomerulonephritis  2672  2372  2175  2553  1645  Number of renal biopsies with a diagnosis of IgAN  697  632  517  675  440  % of IgAN with respect to the total number of biopsies  14.9  15.5  12.8  13.8  13.4  % of IgAN with respect to renal biopsies with a diagnosis of glomerulonephritis  26.1  26.6  23.8  26.4  26.7  Variable  1994–97  1998–2001  2002–05  2006–09  2010–13  Number of renal biopsies  4671  4082  4048  4898  3275  Number of renal biopsies with a diagnosis of glomerulonephritis  2672  2372  2175  2553  1645  Number of renal biopsies with a diagnosis of IgAN  697  632  517  675  440  % of IgAN with respect to the total number of biopsies  14.9  15.5  12.8  13.8  13.4  % of IgAN with respect to renal biopsies with a diagnosis of glomerulonephritis  26.1  26.6  23.8  26.4  26.7  The diagnosis of IgAN was based on the predominance of IgA deposits detected by immunofluorescence. The following demographic and clinical data were obtained from a questionnaire sent to individual patients at the time of renal biopsy: date of birth, sex, serum creatinine (SCr; mg/dL), estimated glomerular filtration rate (eGFR), proteinuria (g/day) and urinary sediment. Clinical and analytical data at presentation were recorded and grouped into the following types of presentation: AKI: AKI stage was defined according to the Kidney Disease: Improving Global Outcomes guidelines (increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days) [20]. Nephrotic-range proteinuria: proteinuria >3.5 g/day/1.73 m2. AUD: proteinuria <3.5 g/day/1.73 m2 and/or haematuria defined as the presence of >3 red blood cells/field without clinical symptoms. Arterial hypertension: blood pressure ≥140/90 mmHg or the need for hypotensive drugs regardless of blood pressure levels. Gross haematuria. These definitions for the different types of presentation were applied to all the patients, independent of the period in which renal biopsy was performed. The GFR was calculated with the abbreviated four-variable Modification of Diet in Renal Disease (MDRD-4) equation [21]. In the paediatric population, the measurements were adjusted according to body surface area. Statistical analysis The normality of the sample distribution was determined using the Kolmogorov–Smirnov test. Normally distributed quantitative variables are expressed as mean and SD and were compared using the t test. Non-normally distributed variables are expressed as median and interquartile range and were analysed using median tests. The qualitative variables are listed with their frequency distribution and were analysed using the Fisher’s exact and chi-squared tests. Bonferroni corrections were used to adjust for multiple comparisons. A P-value <0.05 was considered statistically significant except when Bonferroni correction was applied and mentioned. The statistical analysis was performed using SPSS version 17.0 Statistical Package for the Social Sciencies (SPSS), Chicago, IL, USA. RESULTS Prevalence of IgAN As shown in Table 1, the prevalence of IgAN remained stable over the years, ranging between 12.8% and 15.5% of all renal biopsies contained in the registry. With regard to the total number of renal biopsies with a diagnosis of glomerulonephritis, IgAN represented 23.8–26.7%, again without significant variations over time. Clinical features according to age at diagnosis As shown in Table 2, IgAN was more frequently diagnosed in patients 17–44 years of age (51.3% of the cases), followed by patients 45–64 years of age (30.9%). Patients who were ≤16 years of age accounted for 8.3% and those ≥65 years of age accounted for 9.5% of the sample. Age distribution along the different periods of time is shown in Figure 1. Table 2 Clinical characteristics according to age at diagnosis Variable  ≤16 years  17–44 years  45–64 years  ≥65 years  P-value  [n = 238  [n = 1473  [n = 888  [n = 274    (8.3%a)]  (51.3%a)]  (30.9%a)]  (9.5%a)]  Age (years), mean (SD)  11.4 (3.7)  31.9 (7.9)  54.2 (5.4)  72.9 (5.2)  0.000  Male (%)  68.4  72  81.6  75.9  0.000  SCr (mg/dL), mean (SD)  1 (1)  1.8 (1.9)  2.4 (2)  3.5 (3.1)  0.000  eGFR (mL/min/1.73 m2)b, mean (SD)  173.9 (87.3)  73.9 (40.5)  47.6 (30)  33.2 (24.8)  0.000   CKD Stage 1 (%)c  79.2  33.2  8.6  3     CKD Stage 2 (%)d  8.4  26.6  18.1  9.4     CKD Stage 3a (%)e  5.3  14.7  21.1  14  0.001*   CKD Stage 3b (%)f  2.6  12.4  21.9  18.1     CKD Stage 4 (%)g  2.6  8.1  19.6  26.8     CKD Stage 5 (%)g  1.9  5  10.7  28.7    Proteinuria (g/24 h), mean (SD)  1.5 (2.9)  2.5 (2.4)  2.7 (2.8)  2.9 (2.9)  0.000   <0.3 g/day (%)h  32.6  8.2  6  5.7     0.3–0.99 g/day (%)h  24.9  16.2  14.9  18.3  0.001*   1–3.5 g/day (%)i  31.1  62.5  67  58.3     Nephrotic-range proteinuria (>3.5 g/day) (%)  11.4  13.1  12.1  17.7    Hypertension (%)  10.2  43.9  71.9  72  0.000  AUD (%)  33.6  42.1  37.2  18.8  0.000  AKI (%)  13.1  13  21.3  43.2  0.000  Gross haematuria (%)  40.6  14.4  4.1  3.4  0.001  Variable  ≤16 years  17–44 years  45–64 years  ≥65 years  P-value  [n = 238  [n = 1473  [n = 888  [n = 274    (8.3%a)]  (51.3%a)]  (30.9%a)]  (9.5%a)]  Age (years), mean (SD)  11.4 (3.7)  31.9 (7.9)  54.2 (5.4)  72.9 (5.2)  0.000  Male (%)  68.4  72  81.6  75.9  0.000  SCr (mg/dL), mean (SD)  1 (1)  1.8 (1.9)  2.4 (2)  3.5 (3.1)  0.000  eGFR (mL/min/1.73 m2)b, mean (SD)  173.9 (87.3)  73.9 (40.5)  47.6 (30)  33.2 (24.8)  0.000   CKD Stage 1 (%)c  79.2  33.2  8.6  3     CKD Stage 2 (%)d  8.4  26.6  18.1  9.4     CKD Stage 3a (%)e  5.3  14.7  21.1  14  0.001*   CKD Stage 3b (%)f  2.6  12.4  21.9  18.1     CKD Stage 4 (%)g  2.6  8.1  19.6  26.8     CKD Stage 5 (%)g  1.9  5  10.7  28.7    Proteinuria (g/24 h), mean (SD)  1.5 (2.9)  2.5 (2.4)  2.7 (2.8)  2.9 (2.9)  0.000   <0.3 g/day (%)h  32.6  8.2  6  5.7     0.3–0.99 g/day (%)h  24.9  16.2  14.9  18.3  0.001*   1–3.5 g/day (%)i  31.1  62.5  67  58.3     Nephrotic-range proteinuria (>3.5 g/day) (%)  11.4  13.1  12.1  17.7    Hypertension (%)  10.2  43.9  71.9  72  0.000  AUD (%)  33.6  42.1  37.2  18.8  0.000  AKI (%)  13.1  13  21.3  43.2  0.000  Gross haematuria (%)  40.6  14.4  4.1  3.4  0.001  a With respect to the total number of IgAN biopsies with available data (n = 2873). b The eGFR was calculated with the abbreviated MDRD-4 equation. CKD Stage 1: eGFR ≥90; Stage 2: 60–89; Stage 3a: 45–59; Stage 3b: 30–44; Stage 4: 15–29; Stage 5: <15. c P < 0.008 between all groups. d P < 0.008 between all groups except ≤16 years versus ≥65 years. e P < 0.008 between all groups except 17–44 years versus ≥65 years. f P < 0.008 between all groups except 45–64 years versus ≥65 years. g P < 0.008 between all groups. h P < 0.008 between all groups except 17–44 years versus ≥65 years and 45–64 years versus ≥65 years. i P < 0.008 between ≤16 years versus all groups. *Global P. FIGURE 1 View largeDownload slide Age distribution in the different periods of time. FIGURE 1 View largeDownload slide Age distribution in the different periods of time. Clinical features at diagnosis varied according to the age of the patients. As shown in Table 2, renal function worsened in parallel with ageing—the older the patient, the worse the renal function. Proteinuria and the number of hypertensive patients also showed a significant increase in parallel with ageing. The proportion of patients presenting with hypertension, AKI and nephrotic-range proteinuria significantly increased with ageing, whereas that of patients with AUD decreased (Table 2). Changes in clinical presentation over time The mean age at diagnosis showed a significant progressive increase from 37.6 ± 17.8 years in the period 1994–97 to 44.9 ± 16.8 in the period 2010–13 (Figure 1 and Table 3). Paralleling this trend, a significant change towards a worse clinical profile at diagnosis was found: worse renal function (Figure 2A), increasing proteinuria, increasing proportion of hypertensive patients and cases presenting with AKI and nephrotic-range proteinuria and decreasing number of patients with AUD (Table 3 and Figure 2B). Table 3 Changes in clinical and laboratory parameters over time (all the patients) Variable  1994–97  1998–01  2002–05  2006–09  2010–13  P-value  (n = 655)  (n = 616)  (n = 514)  (n = 675)  (n = 440)  Age (years), mean (SD)  37.6 (17.8)  40.4 (17.7)  40.1 (17.4)  42.9 (17.6)  44.9 (16.8)  0.000  Male (%)  74.2  76.9  75.1  75.1  72.3  0.46  SCr (mg/dL), mean (SD)  1.9 (1.9)  1.9 (1.6)  2.4 (3.2)  2.2 (2.2)  2.3 (2.1)  0.000  eGFR (mL/min/1.73 m2)a, mean (SD)  78.4 (58.5)  73.2 (53.6)  72.1 (61.2)  64.1 (48.8)  60.6 (47.2)  0.000   CKD Stage 1 (%)b  29.4  25.2  24.9  22.3  20  0.003*   CKD Stage 2 (%)c  21.3  25.4  21.3  18.6  17.9   CKD Stage 3a (%)  15.8  13.2  16.8  18  17.6   CKD Stage 3b (%)  13.4  16.7  15.1  16  17   CKD Stage 4 (%)  12.8  12.1  11.9  15.7  15   CKD Stage 5 (%)d  7.3  7.4  10  9.4  12.5  Proteinuria (g/24 h), mean (SD)  2.3 (2.4)  2.8 (3.1)  2.5 (3.1)  2.5 (2.4)  2.5 (2.4)  0.02   <0.3 g/day (%)e  13.4  8  7  7.4  10     0.3–0.99 g/day (%)f  17.1  12.7  18  18.3  17.3     1–3.5 g/day (%)  59.7  65.5  62.3  59.8  56.8  0.001*   Nephrotic-range proteinuria (>3.5 g/day) (%)g  9.8  13.8  12.7  14.5  15.9    Hypertension (%)  44.1  50.1  51.4  59.2  57.5  0.000  AUD (%)  44.4  43  37.2  33.3  28.4  0.000  AKI (%)  13.2  11.4  19.8  23.9  25.2  0.000  Gross haematuria (%)  20  14.3  12.3  6.6  5.9  0.000  Variable  1994–97  1998–01  2002–05  2006–09  2010–13  P-value  (n = 655)  (n = 616)  (n = 514)  (n = 675)  (n = 440)  Age (years), mean (SD)  37.6 (17.8)  40.4 (17.7)  40.1 (17.4)  42.9 (17.6)  44.9 (16.8)  0.000  Male (%)  74.2  76.9  75.1  75.1  72.3  0.46  SCr (mg/dL), mean (SD)  1.9 (1.9)  1.9 (1.6)  2.4 (3.2)  2.2 (2.2)  2.3 (2.1)  0.000  eGFR (mL/min/1.73 m2)a, mean (SD)  78.4 (58.5)  73.2 (53.6)  72.1 (61.2)  64.1 (48.8)  60.6 (47.2)  0.000   CKD Stage 1 (%)b  29.4  25.2  24.9  22.3  20  0.003*   CKD Stage 2 (%)c  21.3  25.4  21.3  18.6  17.9   CKD Stage 3a (%)  15.8  13.2  16.8  18  17.6   CKD Stage 3b (%)  13.4  16.7  15.1  16  17   CKD Stage 4 (%)  12.8  12.1  11.9  15.7  15   CKD Stage 5 (%)d  7.3  7.4  10  9.4  12.5  Proteinuria (g/24 h), mean (SD)  2.3 (2.4)  2.8 (3.1)  2.5 (3.1)  2.5 (2.4)  2.5 (2.4)  0.02   <0.3 g/day (%)e  13.4  8  7  7.4  10     0.3–0.99 g/day (%)f  17.1  12.7  18  18.3  17.3     1–3.5 g/day (%)  59.7  65.5  62.3  59.8  56.8  0.001*   Nephrotic-range proteinuria (>3.5 g/day) (%)g  9.8  13.8  12.7  14.5  15.9    Hypertension (%)  44.1  50.1  51.4  59.2  57.5  0.000  AUD (%)  44.4  43  37.2  33.3  28.4  0.000  AKI (%)  13.2  11.4  19.8  23.9  25.2  0.000  Gross haematuria (%)  20  14.3  12.3  6.6  5.9  0.000  a The eGFR was calculated with the abbreviated MDRD-4 equation. CKD Stage 1: eGFR ≥ 90; Stage 2: 60–89; Stage 3a: 45–59; Stage 3b: 30–44; Stage 4: 15–29; Stage 5: < 15. b P < 0.005 between 1994 and 1997 with 2006–09 and 2010–13 period. c P < 0.005 between 1998 and 2001 with 2006–09 and 2010–13 period. d P < 0.005 between 1994 and 1997 versus 2010–13 period and 1998–2001 versus 2010–13 period. e P < 0.005 between 1994 and 1997 with 1998–2001, 2002–05 and 2006–09 period. f P < 0.005 between 1998 and 2001 versus 2006–09 period. g P < 0.005 between 1994 and 1997 with 2006–09 and 2010–13 period. * Global P. FIGURE 2 View largeDownload slide (A) Changes in eGFR over time according to age group. (*P < 0.05, intragroup; **P < 0.05, intergroup). (B) Changes in major clinical forms of presentation over time (all patients). FIGURE 2 View largeDownload slide (A) Changes in eGFR over time according to age group. (*P < 0.05, intragroup; **P < 0.05, intergroup). (B) Changes in major clinical forms of presentation over time (all patients). IgAN in patients ≥65 years of age Clinical manifestations at diagnosis were particularly aggressive among patients ≥65 years of age. As shown in Table 2, AKI was the most common clinical presentation (43.2%), and 17.7% presented with nephrotic-range proteinuria. Hypertension was found in a majority of patients (72%). In contrast, AUD was the type of presentation in only 18.8% of elderly patients. DISCUSSION Initial descriptions of IgAN were of an entity typically affecting young people and in which aggressive presentations were rare. Bouts of gross haematuria, according to these initial descriptions, constituted the most striking clinical feature, generally occurring in the early phases of the disease. Persistent AUD (non-nephrotic proteinuria, microhaematuria) could go unnoticed for many years in patients without gross haematuria episodes [22, 23]. Subsequent studies identified the amount of proteinuria, particularly in patients with proteinuria >0.5–1 g/day, as the most important risk factor for a slowly progressive deterioration of renal function occurring in a substantial number of patients after several decades of follow-up [12, 13, 24]. Our data show a clinical scenario quite different from this traditional view of IgAN. Although AUD is altogether the most frequent form of presentation, the proportion of patients with aggressive clinical presentations (nephrotic-range proteinuria, AKI) was remarkable, as shown in Table 2. Particularly striking was the frequency of aggressive types among patients >65 years of age, in whom AKI was the most frequent form of presentation. By dividing the 20-year period of patient’s inclusion into five 4-year consecutive periods (Table 3), it was found that the clinical presentation of IgAN has tended to be more aggressive in recent years, with a progressively higher number of patients presenting with AKI and nephrotic-range proteinuria and a lower number presenting with subclinical AUD. Importantly, the same definitions for the different types of presentation (AUD, nephrotic-range proteinuria, AKI) were applied to all the patients, independent of the period in which the renal biopsy was performed. Notably, this change in clinical profile parallels an increasingly older age at diagnosis that has changed from 37.6 years in the period 1994–97 to 44.9 years in the period 2010–13. The reasons for this change in the presentation of the disease are not clear. Although systematic studies have not been performed, there are no data suggesting changes in the policy of routine analytical controls. Changes in renal biopsy policy, for example, by a tendency to restrict their performance to older patients with more aggressive presentations, might be one of the reasons. However, there are several arguments against this possibility. First, the registry data are obtained by the collaboration of a large number of centres in Spain (>100), making it difficult to conceive such a similar and simultaneous tendency in all of them. Second, as shown in Table 1, the prevalence of IgAN has remained stable in our country over the 20-year period studied, which does not support a change in the policy of renal biopsy performance in patients suspected to have IgAN. Although our study confirms that the most common age at diagnosis is between 17 and 45 years (second to fourth decade of life), it should be stressed that 8.3% and 9.5% of the cases corresponded to children/adolescents and patients >65 years of age, respectively. In addition, 30.9% of cases were diagnosed in patients 45–65 years old. Particularly worrying was the profile of clinical presentation in the group of patients >65 years of age. Only 18.8% of them presented with AUD and AKI was the most common clinical presentation, occurring in 43.2% of the patients. Reasons for these changes in the clinical profile of elderly IgAN patients are not apparent. Gross haematuria-induced tubular damage is a leading cause of AKI in IgAN patients [25, 26] and anticoagulant therapy can induce haematuria and AKI in elderly patients [27]. Therefore, anticoagulation therapy could be a precipitating factor for haematuria-induced AKI in elderly IgAN patients. However, information on gross haematuria associated with anticoagulation was not collected in the registry, so its possible influence on more aggressive presentations of elderly IgAN patients should be explored in future studies. Our study confirms that gross haematuria is more frequent in younger patients (Table 2). The decrease in the frequency of gross haematuria at presentation in the more recent periods, as shown in Table 3 and Figure 2B, could be related with the increasing age of the patients. Our study has important limitations. The collected clinical data were rather limited and histological features were not collected. Information about treatments and outcomes of registered patients was not included in the information provided by centres. In contrast, the main strength of the study is the large number of biopsy-proven IgAN patients collected (>2900) and the extended period of time (20 years), which has allowed us to analyse changes in the clinical profile at diagnosis. There is general agreement about the indication of RAAS blockade in IgAN with proteinuria targeted to reduce it to <0.5–1 g/day. In contrast, controversy persists about the indication of immunosuppressive therapy with corticosteroids or other agents in IgAN. This controversy is partly due to the disparate results of several randomized controlled trials (RCTs). It should be stressed that RCT designed to analyse the influence of immunosuppressive therapies in IgAN are generally focused on patients with AUD in whom proteinuria is >1 g/day despite RAAS blockade. According to our data, RCTs designed to evaluate therapeutic alternatives for patients with aggressive forms of the disease are urgently needed. In conclusion, IgAN patients are significantly older and have presented with significantly worse renal function in recent years. Further studies are needed to analyse the reasons for this change and to evaluate therapies for these aggressive forms of presentation. ACKNOWLEDGEMENTS We would like to thank all participating hospitals for sending us the results of their renal biopsies. 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Nephrology Dialysis TransplantationOxford University Press

Published: Mar 1, 2018

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