Proteinase-3 and myeloperoxidase serotype in relation to demographic factors and geographic distribution in anti-neutrophil cytoplasmic antibody-associated glomerulonephritis

Proteinase-3 and myeloperoxidase serotype in relation to demographic factors and geographic... Abstract Background In anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, antigen specificity varies between myeloperoxidase (MPO) and proteinase 3 (PR3). This has been reported to vary in relation to age, gender, geography and extrarenal manifestations. However, studies are difficult to compare as criteria for inclusion vary. The aim of this study was to investigate the relationship between ANCA serotype, latitude, ultraviolet (UV) radiation levels, age, gender and renal function at diagnosis in a large study with uniform inclusion criteria. Methods Patients with biopsy-proven ANCA-associated glomerulonephritis were identified from regional or nationwide registries in 14 centres in Norway, Sweden, the UK, the Czech Republic, Croatia, Italy and the USA during the period 2000–13. UV radiation levels for 2000–13 in Europe were obtained from the Swedish Meteorological and Hydrological Institute. Results A total of 1408 patients (45.2% PR3-ANCA) were included in the study. In univariable analysis, PR3-ANCA was significantly associated with male gender {odds ratio [OR] 2.12 [95% confidence interval (CI) 1.71–2.62]}, younger age [OR per year 0.97 (95% CI 0.96–0.98)] and higher glomerular filtration rate [OR per mL/min 1.01 (95% CI 1.01–1.02); P < 0.001] at diagnosis but not with latitude or UV radiation. In multivariable logistic regression analysis, latitude and UV radiation also became significant, with higher odds for PR3-ANCA positivity at northern latitudes/lower UV radiation levels. However, the latitudinal difference in MPO:PR3 ratio is smaller than differences previously reported concerning microscopic polyangiitis and granulomatosis with polyangiitis. Conclusions The ratio between PR3-ANCA and MPO-ANCA varies in glomerulonephritis with respect to age, gender, renal function and geographic latitude/UV radiation levels. ANCA-associated vasculitis, glomerulonephritis, latitude, MPO-ANCA, PR3-ANCA INTRODUCTION Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is often complicated by renal involvement and AAV constitutes one of the most common causes of rapidly progressive glomerulonephritis and nephritic syndrome [1, 2]. Based on extrarenal features, AAV is classified as either microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) or eosinophilic GPA (EGPA) [3]. ANCA-associated nephritis (AAN) is seen in ∼75% of cases, with more frequent occurrence in MPA than in GPA and EGPA [4, 5]. The aetiology of AAV is still unknown but is believed to be dependent on both genetic and environmental factors, with no single factor being sufficient to cause disease [6]. Animal models provide strong evidence for a pathogenic role of ANCA in AAV, but it is less clear why the autoantibodies are formed [7]. In AAN, the autoantibodies are directed against myeloperoxidase (MPO) or proteinase 3 (PR3) [8]. Emerging data on the genetic association and clinical observations are likely to drive more changes in how ANCA-AAV is subgrouped to guide management of these patients. Differences in the epidemiology between myeloperoxidase ANCA (MPO-ANCA) and PR3-ANCA AAN may reveal important clues concerning the aetiology. MPO-ANCA is mainly associated with MPA and PR3-ANCA with GPA [9], and the ratio between MPO-ANCA and PR3-ANCA has also been reported to vary in relation to gender, age and geographic distribution [10, 11]. Furthermore, the histological findings and renal outcome differ between PR3-ANCA and MPO-ANCA-associated glomerulonephritis [12, 13]. The incidence of AAV is similar in the UK, Scandinavia and Japan [11, 14]. However, in Asia there is a great predominance of MPO-ANCA and MPA compared with Europe and North America [15, 16]. In Europe, studies have shown higher incidences of GPA in the north compared with the south [11, 17, 18]. Data from New Zealand suggest a reciprocal gradient in the southern hemisphere [19]. It has also been shown that the incidence of GPA correlates inversely with ambient ultraviolet (UV) radiation [20] and a possible pathogenic explanation for the geographic gradients is the difference in UV radiation exposure at different latitudes. Latitudinal gradients and UV radiation have been studied extensively in other autoimmune diseases, such as multiple sclerosis and type 1 diabetes [21–23], but there are few studies of ANCA-AAV and none focusing on serotype. An alternative explanation for the geographic pattern could be genetic differences between populations. There is evidence of a genetic contribution to AAV, with several genes and polymorphisms predisposing to disease [24, 25]. The genetic composition seems to associate more strongly with ANCA serotype than with the phenotypic disease entities MPA and GPA [26]. Many of the epidemiological studies to date are small single-centre studies and difficult to compare directly due to the heterogeneity of inclusion criteria and patient characteristics. Large, more homogeneous studies with greater geographic distribution are warranted. The objective of the present study was to investigate the relationship between ANCA serotype, latitude, UV radiation levels, age, gender and renal function at diagnosis. This was done using uniform inclusion criteria in a large population of patients with biopsy-proven ANCA-associated glomerulonephritis identified from registries in Europe and North America. MATERIALS AND METHODS Study population Patients with renal biopsy–proven ANCA-associated glomerulonephritis were identified from the Norwegian, Scottish, Croatian and Italian biopsy registries; the Czech vasculitis registry; the regional vasculitis registries in Lund, Linköping and Cambridge; the Glomerular Disease Collaborative Network (GDCN) in North Carolina and Johns Hopkins Vasculitis Centre in Maryland. The Norwegian renal biopsy registry is a national registry run by the Medical Department, Haukeland University Hospital. It started in 1988 and includes all native kidney biopsies except tumor biopsies performed in the country. For the present study, the patients were divided into groups based at four tertiary referral hospitals in the country. The Scottish renal biopsy registry was established in 2005 [27]. For this study, only data from the Greater Glasgow, Clyde and Forth Valley regions were incorporated, as they were known to include all cases of biopsy-proven AAV along with relevant clinical data. The Italian Registry of Renal Biopsies was established in 1987 and has been described in detail previously [28]. For the present study, the patients were divided into two groups according to region of residence. The renal biopsy registry at Dubrava University Hospital in Zagreb is the largest renal biopsy registry in Croatia. Patients from all parts of Croatia referred to the nephrology unit for renal biopsy have been included in this study. In the Czech Republic, a single nationwide vasculitis registry was formed in 2009, in which all patients with AAV diagnosed or followed up in the participating centres were recorded. The regional vasculitis registries in Linköping and Lund, Sweden both contain all patients diagnosed with AAV within defined geographic regions, and they have previously been described in detail [29, 30]. The vasculitis registry in Cambridge is based at a multidisciplinary clinic at Addenbrooke’s Hospital. It contains all patients with vasculitis referred to the hospital. For this study, only patients living in a defined geographic area surrounding the city of Cambridge were included. The GDCN registry enrols patients as they are diagnosed at the University of North Carolina and in private practices throughout the southeastern USA. Patients are primarily identified from renal biopsy diagnoses evaluated through the University of North Carolina Nephropathology Service. The GDCN has been described in detail in previous studies [31, 32]. In this study, only patients residing in North Carolina were included. The Johns Hopkins Vasculitis database enrols subjects who are referred by practices within the state of Maryland and surrounding states in the northeast USA as they are diagnosed at Johns Hopkins Hospital. For this study, only patients residing in Maryland were included. Only registries including consecutive patients from a defined geographic area were used for this study. Tertiary referrals to Cambridge, Linköping and Lund from regions outside the primary catchment area were excluded to reduce referral bias. The inclusion criteria for the study were a clinical diagnosis of AAV verified by renal biopsy during the period 2000–13, ANCA positivity verified by enzyme-linked immunosorbent assay (ELISA) and age ≥18 years. Exclusion criteria were eosinophilic GPA (EGPA) and polyarteritis nodosa (PAN) along with anti-glomerular basement membrane disease, secondary vasculitis and drug-induced vasculitis, in accordance with the exclusion criteria in the European Medicines Agency algorithm [3]. Patients were classified as either PR3-ANCA positive or MPO-ANCA positive depending on the result of the ELISA. Patients who were positive for both PR3-ANCA and MPO-ANCA were classified to the serotype with the highest titre. Double-positive patients were excluded if the ANCA titres were unknown. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease equation [33]. All patient data in the present study are anonymous registry data. The project was approved by the Ethical Review Board in Lund, Sweden, the University of North Carolina Institutional Review Board and the institutional review board in Maryland. For the American patients, informed consent was provided by all patients for collection of demographic and medical information, while this was not required for the European patients. Data collection Data were collected from the time of biopsy and included gender, age, ANCA serotype and estimated GFR (eGFR). No follow-up data were collected for the present study. Antigen-specific ELISA was used to detect ANCA. The mean monthly erythemally weighted UV radiation level (International Commission on Illumination) for 2000–13 in the regions in Europe was obtained from the STRÅNG database provided by the Swedish Meteorological and Hydrological Institute [34]. Latitude and longitude coordinates are given in the World Geodetic System 84 coordinate reference system. For Europe the coordinates are given for the centres included in the study and for the USA the coordinates are given for the capital city of every state (Raleigh, NC, USA; Annapolis, MD, USA). Statistical methods Statistical analysis was performed using Statistical Package for the Social Sciences: SPSS Statistics for Windows, version 21.0 (IBM, Armonk, NY, USA). P-values <0.05 were considered significant. Continuous variables were expressed as medians and interquartile ranges. Categorical variables were expressed as percentages. Differences between groups were analyzed using the Mann–Whitney test for non-parametric data and the chi-square test for categorical data. Univariable and multivariable binary logistic regression analysis was used to assess the association between ANCA serotype and the variables gender, age, eGFR, latitude, longitude and UV radiation level. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Spearman’s rank correlation analysis was performed between the input variables to check for strong correlations between the variables entered in the multivariable logistic regression analysis. All analyses exclude missing data. RESULTS Baseline patient characteristics A total of 1408 patients were included in the study. MPO-ANCA positivity was seen in 54.8% of the patients and PR3-ANCA positivity in 45.2% of the patients. The median age at diagnosis was 64 years [interquartile range (IQR) 53–72]. The median estimated glomerular filtration eGFR at the time of biopsy was 19 mL/min/1.73 m2 (IQR 10–36) (Table 1). Male gender was more common in PR3-positive patients compared with MPO-ANCA-positive patients (61.5% versus 43.0%; P < 0.001). The median age was 60 years (IQR 50–69) in PR3-positive patients compared with 67 years (IQR 57–74) in MPO-positive patients (P < 0.001) and the median eGFR was 21 mL/min/1.73 m2 (IQR 11–44) compared with 18 mL/min/1.73 m2 (IQR 10–31) (P < 0.001). The longitude of the participating centres varied between 35.8°S and 69.6°N. UV radiation levels in Europe varied between 5246 mWh/m2 in the northernmost centre and 14 565 mWh/m2 in the southernmost centre (Table 2). Table 1 Clinical and demographic characteristics at the time of biopsy Centre N ANCA PR3/MPO % Gender (male/female), % Age (years), median (IQR) eGFR (mL/min/1.73 m2), median (IQR)a All 1408 45.2/54.8 51.3/48.7 64 (53–72) 19 (10–36) Europe 1167 46.0/54.0 51.2/48.8 64 (54–72) 19 (11–37)  Tromsø 21 57.1/42.9 52.4/47.6 60 (51–69) 17 (7–25)  Trondheim 62 53.2/46.8 45.2/54.8 68 (58–76) 20 (8–38)  Bergen 88 44.3/55.7 52.3/47.7 62 (49–75) 27 (15–54)  Oslo 140 48.6/51.4 54.3/45.7 65 (53–74) 19 (10–40)  Linköping 49 30.6/69.4 61.2/38.8 70 (61–75) 26 (18–37)  Glasgow 238 43.7/56.3 45.8/54.2 67 (59–75) 15 (9–27)  Lund 72 48.6/51.4 51.4/48.6 66 (54–75) 24 (13–44)  Cambridge 54 40.7/59.3 57.4/42.6 64 (58–73) 20 (10–43)  Prague 305 52.5/47.5 53.4/46.6 59 (52–67) 23 (13–47)  Zagreb 42 28.6/71.4 45.2/54.8 64 (47–70) 12 (7–20)  Milan 71 39.4/60.6 46.5/53.5 68 (61–74) 15 (8–25)  Rome 25 36.0/64.0 60.0/40.0 65 (56–70) 8 (6–21) USA 241 41.1/58.9 51.9/48.1 60 (50–72) 18 (10–33)  Maryland 71 42.3/57.7 43.7/56.3 63 (55–72) 18 (10–29)  North Carolina 170 40.6/59.4 55.3/44.7 59 (49–72) 18 (10–36) Centre N ANCA PR3/MPO % Gender (male/female), % Age (years), median (IQR) eGFR (mL/min/1.73 m2), median (IQR)a All 1408 45.2/54.8 51.3/48.7 64 (53–72) 19 (10–36) Europe 1167 46.0/54.0 51.2/48.8 64 (54–72) 19 (11–37)  Tromsø 21 57.1/42.9 52.4/47.6 60 (51–69) 17 (7–25)  Trondheim 62 53.2/46.8 45.2/54.8 68 (58–76) 20 (8–38)  Bergen 88 44.3/55.7 52.3/47.7 62 (49–75) 27 (15–54)  Oslo 140 48.6/51.4 54.3/45.7 65 (53–74) 19 (10–40)  Linköping 49 30.6/69.4 61.2/38.8 70 (61–75) 26 (18–37)  Glasgow 238 43.7/56.3 45.8/54.2 67 (59–75) 15 (9–27)  Lund 72 48.6/51.4 51.4/48.6 66 (54–75) 24 (13–44)  Cambridge 54 40.7/59.3 57.4/42.6 64 (58–73) 20 (10–43)  Prague 305 52.5/47.5 53.4/46.6 59 (52–67) 23 (13–47)  Zagreb 42 28.6/71.4 45.2/54.8 64 (47–70) 12 (7–20)  Milan 71 39.4/60.6 46.5/53.5 68 (61–74) 15 (8–25)  Rome 25 36.0/64.0 60.0/40.0 65 (56–70) 8 (6–21) USA 241 41.1/58.9 51.9/48.1 60 (50–72) 18 (10–33)  Maryland 71 42.3/57.7 43.7/56.3 63 (55–72) 18 (10–29)  North Carolina 170 40.6/59.4 55.3/44.7 59 (49–72) 18 (10–36) a Data missing in 84 patients. Table 1 Clinical and demographic characteristics at the time of biopsy Centre N ANCA PR3/MPO % Gender (male/female), % Age (years), median (IQR) eGFR (mL/min/1.73 m2), median (IQR)a All 1408 45.2/54.8 51.3/48.7 64 (53–72) 19 (10–36) Europe 1167 46.0/54.0 51.2/48.8 64 (54–72) 19 (11–37)  Tromsø 21 57.1/42.9 52.4/47.6 60 (51–69) 17 (7–25)  Trondheim 62 53.2/46.8 45.2/54.8 68 (58–76) 20 (8–38)  Bergen 88 44.3/55.7 52.3/47.7 62 (49–75) 27 (15–54)  Oslo 140 48.6/51.4 54.3/45.7 65 (53–74) 19 (10–40)  Linköping 49 30.6/69.4 61.2/38.8 70 (61–75) 26 (18–37)  Glasgow 238 43.7/56.3 45.8/54.2 67 (59–75) 15 (9–27)  Lund 72 48.6/51.4 51.4/48.6 66 (54–75) 24 (13–44)  Cambridge 54 40.7/59.3 57.4/42.6 64 (58–73) 20 (10–43)  Prague 305 52.5/47.5 53.4/46.6 59 (52–67) 23 (13–47)  Zagreb 42 28.6/71.4 45.2/54.8 64 (47–70) 12 (7–20)  Milan 71 39.4/60.6 46.5/53.5 68 (61–74) 15 (8–25)  Rome 25 36.0/64.0 60.0/40.0 65 (56–70) 8 (6–21) USA 241 41.1/58.9 51.9/48.1 60 (50–72) 18 (10–33)  Maryland 71 42.3/57.7 43.7/56.3 63 (55–72) 18 (10–29)  North Carolina 170 40.6/59.4 55.3/44.7 59 (49–72) 18 (10–36) Centre N ANCA PR3/MPO % Gender (male/female), % Age (years), median (IQR) eGFR (mL/min/1.73 m2), median (IQR)a All 1408 45.2/54.8 51.3/48.7 64 (53–72) 19 (10–36) Europe 1167 46.0/54.0 51.2/48.8 64 (54–72) 19 (11–37)  Tromsø 21 57.1/42.9 52.4/47.6 60 (51–69) 17 (7–25)  Trondheim 62 53.2/46.8 45.2/54.8 68 (58–76) 20 (8–38)  Bergen 88 44.3/55.7 52.3/47.7 62 (49–75) 27 (15–54)  Oslo 140 48.6/51.4 54.3/45.7 65 (53–74) 19 (10–40)  Linköping 49 30.6/69.4 61.2/38.8 70 (61–75) 26 (18–37)  Glasgow 238 43.7/56.3 45.8/54.2 67 (59–75) 15 (9–27)  Lund 72 48.6/51.4 51.4/48.6 66 (54–75) 24 (13–44)  Cambridge 54 40.7/59.3 57.4/42.6 64 (58–73) 20 (10–43)  Prague 305 52.5/47.5 53.4/46.6 59 (52–67) 23 (13–47)  Zagreb 42 28.6/71.4 45.2/54.8 64 (47–70) 12 (7–20)  Milan 71 39.4/60.6 46.5/53.5 68 (61–74) 15 (8–25)  Rome 25 36.0/64.0 60.0/40.0 65 (56–70) 8 (6–21) USA 241 41.1/58.9 51.9/48.1 60 (50–72) 18 (10–33)  Maryland 71 42.3/57.7 43.7/56.3 63 (55–72) 18 (10–29)  North Carolina 170 40.6/59.4 55.3/44.7 59 (49–72) 18 (10–36) a Data missing in 84 patients. Table 2 Latitude, longitude and UV radiation levels of the participating centres Centre Latitude Longitude Mean UV radiation/month (mWh/m2) Mean UV radiation January (mWh/m2) Mean UV radiation June (mWh/m2) Tromsø 69.6°N 18.9°E 5246 31 14 595 Trondheim 63.4°N 10.4°E 6616 141 16 572 Bergen 60.4°N 5.3°E 7082 304 17 724 Oslo 59.9°N 10.7°E 7623 400 18 557 Linköping 58.4°N 15.6°E 9398 523 22 730 Glasgow 55.9°N −4.3°E 8086 736 18 181 Lund 55.7°N 13.2°E 10 087 726 23 243 Cambridge 52.2°N 0.12°E 9851 1119 21 613 Prague 50.1°N 14.4°E 12 262 1588 26 484 Zagreb 45.8°N 16.0°E 14 395 2300 29 484 Milan 45.5°N 9.2°E 13 874 2807 26 890 Rome 41.9°N 12.5°E 14 565 2434 29 562 Maryland 39.0°N −76.5°W North Carolina 35.8°N −78.6°W Centre Latitude Longitude Mean UV radiation/month (mWh/m2) Mean UV radiation January (mWh/m2) Mean UV radiation June (mWh/m2) Tromsø 69.6°N 18.9°E 5246 31 14 595 Trondheim 63.4°N 10.4°E 6616 141 16 572 Bergen 60.4°N 5.3°E 7082 304 17 724 Oslo 59.9°N 10.7°E 7623 400 18 557 Linköping 58.4°N 15.6°E 9398 523 22 730 Glasgow 55.9°N −4.3°E 8086 736 18 181 Lund 55.7°N 13.2°E 10 087 726 23 243 Cambridge 52.2°N 0.12°E 9851 1119 21 613 Prague 50.1°N 14.4°E 12 262 1588 26 484 Zagreb 45.8°N 16.0°E 14 395 2300 29 484 Milan 45.5°N 9.2°E 13 874 2807 26 890 Rome 41.9°N 12.5°E 14 565 2434 29 562 Maryland 39.0°N −76.5°W North Carolina 35.8°N −78.6°W Table 2 Latitude, longitude and UV radiation levels of the participating centres Centre Latitude Longitude Mean UV radiation/month (mWh/m2) Mean UV radiation January (mWh/m2) Mean UV radiation June (mWh/m2) Tromsø 69.6°N 18.9°E 5246 31 14 595 Trondheim 63.4°N 10.4°E 6616 141 16 572 Bergen 60.4°N 5.3°E 7082 304 17 724 Oslo 59.9°N 10.7°E 7623 400 18 557 Linköping 58.4°N 15.6°E 9398 523 22 730 Glasgow 55.9°N −4.3°E 8086 736 18 181 Lund 55.7°N 13.2°E 10 087 726 23 243 Cambridge 52.2°N 0.12°E 9851 1119 21 613 Prague 50.1°N 14.4°E 12 262 1588 26 484 Zagreb 45.8°N 16.0°E 14 395 2300 29 484 Milan 45.5°N 9.2°E 13 874 2807 26 890 Rome 41.9°N 12.5°E 14 565 2434 29 562 Maryland 39.0°N −76.5°W North Carolina 35.8°N −78.6°W Centre Latitude Longitude Mean UV radiation/month (mWh/m2) Mean UV radiation January (mWh/m2) Mean UV radiation June (mWh/m2) Tromsø 69.6°N 18.9°E 5246 31 14 595 Trondheim 63.4°N 10.4°E 6616 141 16 572 Bergen 60.4°N 5.3°E 7082 304 17 724 Oslo 59.9°N 10.7°E 7623 400 18 557 Linköping 58.4°N 15.6°E 9398 523 22 730 Glasgow 55.9°N −4.3°E 8086 736 18 181 Lund 55.7°N 13.2°E 10 087 726 23 243 Cambridge 52.2°N 0.12°E 9851 1119 21 613 Prague 50.1°N 14.4°E 12 262 1588 26 484 Zagreb 45.8°N 16.0°E 14 395 2300 29 484 Milan 45.5°N 9.2°E 13 874 2807 26 890 Rome 41.9°N 12.5°E 14 565 2434 29 562 Maryland 39.0°N −76.5°W North Carolina 35.8°N −78.6°W There was no difference in the distribution of MPO-ANCA and PR3-ANCA (P = 0.16), gender (P = 0.86) or eGFR (P = 0.32) between the European patients and the American patients. The American patients were younger, with a median age of 60 years (IQR 50–72) compared with 64 years (IQR 54–72) in the European patients (P = 0.008). Comparison between biopsied and non-biopsied patients The Linköping, Lund and Cambridge registries were used to identify all patients with AAV in the uptake area with renal involvement according to Birmingham Vasculitis Activity Score. Patients with ANCA-associated glomerulonephritis verified by renal biopsy (patients included in this study) were compared with patients who did not have a renal biopsy–proven diagnosis (patients excluded from this study). In Linköping, 71.0% of the AAV patients with renal involvement underwent a kidney biopsy, the corresponding figure for Lund was 63.2% and for Cambridge 76.0%. In the Cambridge centre, male gender was significantly more common in biopsied patients when compared with non-biopsied patients. In the Linköping centre, MPO-ANCA was more common in biopsied patients. In the Lund centre, biopsied patients were significantly younger. Overall, MPO-ANCA was more common and age was lower in the biopsied patients (Table 3). Table 3 Biopsy versus no biopsy Clincal parameters All Cambridge Linköping Lund Biopsy (n =175) No biopsy (n = 79) P-value Biopsy (n = 54) No biopsy (n = 17) P-value Biopsy (n = 49) No biopsy (n = 20) P-value Biopsy (n = 72) No biopsy (n = 42) P-value MPO, n (%) 103 (58.9) 34 (43.0) 0.019 32 (59.3) 6 (35.3) 0.084 34 (69.4) 7 (35.0) 0.008 37 (51.4) 21 (50.0) 0.89 PR3, n (%) 72 (41.1) 45 (57.0) 22 (40.7) 11 (64.7) 15 (30.6) 13 (65.0) 35 (48.6) 21 (50.0) Male, n (%) 98 (56.0) 45 (57.0) 0.89 31 (57.4) 5 (29.4) 0.044 30 (61.2) 14 (70.0) 0.49 37 (51.4) 26 (61.9) 0.28 Female, n (%) 77 (44.0) 34 (43.0) 23 (42.6) 12 (70.6) 19 (38.8) 6 (30.0) 35 (48.6) 16 (38.1) Age (years), median (IQR) 67 (58–74) 74 (60–81) 0.002 64 (58–73) 64 (51–72) 0.91 70 (61–75) 72 (60–77) 0.54 66 (54–75) 79 (64–84) 0.001 eGFR (MDRD), median (IQR)a 24 (12–43) 19 (11–56) 0.95 20 (10–43) 16 (8–58) 0.82 26 (18–37) 31 (10–59) 0.92 24 (13–44) 19 (11–47) 0.65 Clincal parameters All Cambridge Linköping Lund Biopsy (n =175) No biopsy (n = 79) P-value Biopsy (n = 54) No biopsy (n = 17) P-value Biopsy (n = 49) No biopsy (n = 20) P-value Biopsy (n = 72) No biopsy (n = 42) P-value MPO, n (%) 103 (58.9) 34 (43.0) 0.019 32 (59.3) 6 (35.3) 0.084 34 (69.4) 7 (35.0) 0.008 37 (51.4) 21 (50.0) 0.89 PR3, n (%) 72 (41.1) 45 (57.0) 22 (40.7) 11 (64.7) 15 (30.6) 13 (65.0) 35 (48.6) 21 (50.0) Male, n (%) 98 (56.0) 45 (57.0) 0.89 31 (57.4) 5 (29.4) 0.044 30 (61.2) 14 (70.0) 0.49 37 (51.4) 26 (61.9) 0.28 Female, n (%) 77 (44.0) 34 (43.0) 23 (42.6) 12 (70.6) 19 (38.8) 6 (30.0) 35 (48.6) 16 (38.1) Age (years), median (IQR) 67 (58–74) 74 (60–81) 0.002 64 (58–73) 64 (51–72) 0.91 70 (61–75) 72 (60–77) 0.54 66 (54–75) 79 (64–84) 0.001 eGFR (MDRD), median (IQR)a 24 (12–43) 19 (11–56) 0.95 20 (10–43) 16 (8–58) 0.82 26 (18–37) 31 (10–59) 0.92 24 (13–44) 19 (11–47) 0.65 MDRD, Modification of Diet in Renal Disease. a Data missing in six patients. Comparison between patients with renal AAV who underwent renal biopsy and patients with renal AAV who did not undergo renal biopsy. Table 3 Biopsy versus no biopsy Clincal parameters All Cambridge Linköping Lund Biopsy (n =175) No biopsy (n = 79) P-value Biopsy (n = 54) No biopsy (n = 17) P-value Biopsy (n = 49) No biopsy (n = 20) P-value Biopsy (n = 72) No biopsy (n = 42) P-value MPO, n (%) 103 (58.9) 34 (43.0) 0.019 32 (59.3) 6 (35.3) 0.084 34 (69.4) 7 (35.0) 0.008 37 (51.4) 21 (50.0) 0.89 PR3, n (%) 72 (41.1) 45 (57.0) 22 (40.7) 11 (64.7) 15 (30.6) 13 (65.0) 35 (48.6) 21 (50.0) Male, n (%) 98 (56.0) 45 (57.0) 0.89 31 (57.4) 5 (29.4) 0.044 30 (61.2) 14 (70.0) 0.49 37 (51.4) 26 (61.9) 0.28 Female, n (%) 77 (44.0) 34 (43.0) 23 (42.6) 12 (70.6) 19 (38.8) 6 (30.0) 35 (48.6) 16 (38.1) Age (years), median (IQR) 67 (58–74) 74 (60–81) 0.002 64 (58–73) 64 (51–72) 0.91 70 (61–75) 72 (60–77) 0.54 66 (54–75) 79 (64–84) 0.001 eGFR (MDRD), median (IQR)a 24 (12–43) 19 (11–56) 0.95 20 (10–43) 16 (8–58) 0.82 26 (18–37) 31 (10–59) 0.92 24 (13–44) 19 (11–47) 0.65 Clincal parameters All Cambridge Linköping Lund Biopsy (n =175) No biopsy (n = 79) P-value Biopsy (n = 54) No biopsy (n = 17) P-value Biopsy (n = 49) No biopsy (n = 20) P-value Biopsy (n = 72) No biopsy (n = 42) P-value MPO, n (%) 103 (58.9) 34 (43.0) 0.019 32 (59.3) 6 (35.3) 0.084 34 (69.4) 7 (35.0) 0.008 37 (51.4) 21 (50.0) 0.89 PR3, n (%) 72 (41.1) 45 (57.0) 22 (40.7) 11 (64.7) 15 (30.6) 13 (65.0) 35 (48.6) 21 (50.0) Male, n (%) 98 (56.0) 45 (57.0) 0.89 31 (57.4) 5 (29.4) 0.044 30 (61.2) 14 (70.0) 0.49 37 (51.4) 26 (61.9) 0.28 Female, n (%) 77 (44.0) 34 (43.0) 23 (42.6) 12 (70.6) 19 (38.8) 6 (30.0) 35 (48.6) 16 (38.1) Age (years), median (IQR) 67 (58–74) 74 (60–81) 0.002 64 (58–73) 64 (51–72) 0.91 70 (61–75) 72 (60–77) 0.54 66 (54–75) 79 (64–84) 0.001 eGFR (MDRD), median (IQR)a 24 (12–43) 19 (11–56) 0.95 20 (10–43) 16 (8–58) 0.82 26 (18–37) 31 (10–59) 0.92 24 (13–44) 19 (11–47) 0.65 MDRD, Modification of Diet in Renal Disease. a Data missing in six patients. Comparison between patients with renal AAV who underwent renal biopsy and patients with renal AAV who did not undergo renal biopsy. Binary logistic regression analysis of ANCA serotype In univariable binary logistic regression analysis, age, gender and eGFR were associated with ANCA serotype. Increasing age was associated with decreasing odds of being PR3-ANCA positive, while increasing eGFR and male gender were associated with higher odds for PR3 positivity. Latitude and longitude were not significantly associated with ANCA serotype in univariable analysis. In multivariable analysis, age, eGFR and gender remained associated with ANCA serotype and the association between latitude and ANCA serotype was significant. Increasing latitude was associated with higher odds for PR3 positivity (Table 4). When analysing the European patients separately, the results remained essentially the same (Table 5). Latitude and UV radiation were strongly correlated (Spearman’s ρ −0.99), so were not entered in the multivariable analysis simultaneously. In multivariable analysis including UV radiation instead of latitude, UV radiation, age, gender and eGFR were significantly associated with ANCA serotype. Increasing UV radiation levels were associated with lower odds for PR3 positivity (Supplementary data, Table S1). In an additional analysis excluding the centres in southern Europe (Zagreb, Milan and Rome) and the USA (North Carolina and Maryland), the association between ANCA serotype and both latitude and UV radiation level was lost, while it remained for age, gender and eGFR (Supplementary data, Table S2). Table 4 Analysis of ANCA serotype Clincial and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.12 (1.71–2.62) <0.001 1.98 (1.58–2.49) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.012 Latitude (per 10 units) 1.12 (0.99–1.27) 0.071 1.29 (1.05–1.58) 0.016 Longitude (per 10 units) 1.03 (0.99–1.06) 0.11 0.98 (0.93–1.03) 0.34 Clincial and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.12 (1.71–2.62) <0.001 1.98 (1.58–2.49) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.012 Latitude (per 10 units) 1.12 (0.99–1.27) 0.071 1.29 (1.05–1.58) 0.016 Longitude (per 10 units) 1.03 (0.99–1.06) 0.11 0.98 (0.93–1.03) 0.34 a The OR refers to the probability of being PR3-ANCA positive. Univariable and multivariable binary logistic regression analysis of ANCA serotype in all patients. Table 4 Analysis of ANCA serotype Clincial and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.12 (1.71–2.62) <0.001 1.98 (1.58–2.49) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.012 Latitude (per 10 units) 1.12 (0.99–1.27) 0.071 1.29 (1.05–1.58) 0.016 Longitude (per 10 units) 1.03 (0.99–1.06) 0.11 0.98 (0.93–1.03) 0.34 Clincial and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.12 (1.71–2.62) <0.001 1.98 (1.58–2.49) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.012 Latitude (per 10 units) 1.12 (0.99–1.27) 0.071 1.29 (1.05–1.58) 0.016 Longitude (per 10 units) 1.03 (0.99–1.06) 0.11 0.98 (0.93–1.03) 0.34 a The OR refers to the probability of being PR3-ANCA positive. Univariable and multivariable binary logistic regression analysis of ANCA serotype in all patients. Table 5 Analysis of ANCA serotype in Europe Clinical and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.25 (1.78–2.85) <0.001 2.08 (1.62–2.68) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.016 Latitude (per 10 units) 1.12 (0.92–1.38) 0.26 1.27 (1.01–1.58) 0.038 Longitude (per 10 units) 1.09 (0.94–1.28) 0.26 0.97 (0.82–1.15) 0.71 UV radiation (per Wh/m2) 0.98 (0.94–1.03) 0.46 Clinical and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.25 (1.78–2.85) <0.001 2.08 (1.62–2.68) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.016 Latitude (per 10 units) 1.12 (0.92–1.38) 0.26 1.27 (1.01–1.58) 0.038 Longitude (per 10 units) 1.09 (0.94–1.28) 0.26 0.97 (0.82–1.15) 0.71 UV radiation (per Wh/m2) 0.98 (0.94–1.03) 0.46 a The OR refers to the probability of being PR3-ANCA positive. Univariable and multivariable binary logistic regression analysis of ANCA serotype in the European patients. Table 5 Analysis of ANCA serotype in Europe Clinical and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.25 (1.78–2.85) <0.001 2.08 (1.62–2.68) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.016 Latitude (per 10 units) 1.12 (0.92–1.38) 0.26 1.27 (1.01–1.58) 0.038 Longitude (per 10 units) 1.09 (0.94–1.28) 0.26 0.97 (0.82–1.15) 0.71 UV radiation (per Wh/m2) 0.98 (0.94–1.03) 0.46 Clinical and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.25 (1.78–2.85) <0.001 2.08 (1.62–2.68) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.016 Latitude (per 10 units) 1.12 (0.92–1.38) 0.26 1.27 (1.01–1.58) 0.038 Longitude (per 10 units) 1.09 (0.94–1.28) 0.26 0.97 (0.82–1.15) 0.71 UV radiation (per Wh/m2) 0.98 (0.94–1.03) 0.46 a The OR refers to the probability of being PR3-ANCA positive. Univariable and multivariable binary logistic regression analysis of ANCA serotype in the European patients. DISCUSSION The aim of this study was to describe geographic, demographic and clinical features in a large population of patients with biopsy-proven ANCA-associated glomerulonephritis using registry data from several countries. We confirmed findings in previous studies showing that PR3-positive patients are younger and have higher eGFR than MPO-positive patients at diagnosis [10, 12, 35]. The OR for PR3 positivity was higher in men, which has also been reported before [35–37]. There was an association between ANCA serotype and both latitude and UV radiation levels in the multivariable analysis. The OR of being PR3 positive increased from south to north and decreased with increasing UV radiation levels. These results are in line with previous studies by Watts et al. [11, 38] showing that GPA is more common in the north of Europe and by Gatenby et al. [20] showing a correlation between GPA and latitude and UV radiation levels. These previous studies of the geographic differences in AAV have been focused on disease phenotype and not on ANCA serotype. To our knowledge, this is the first study to show an association for serotype specifically. The concept of PR3-ANCA AAV and MPO-ANCA AAV in addition to the traditional division in the two disease entities GPA and MPA has been suggested to be preferred due to its superior predictive value in terms of relapses and renal survival [12, 39]. In our study, the two centres in the USA are located furthest south and are the only centres with a westerly longitude. The population in the southeastern USA also has mixed origins, with large contributions from Latin America and Africa along with Europeans who are mainly of British descent. GPA/PR3 positivity has been shown to be less common in patients of non-European origin [40] and in African Americans [41]. It is difficult to exclude an effect of these genetic differences on the association between geographic location and serotype. We therefore conducted an analysis excluding these centres and the results remained essentially the same as in the entire study population. However, when analysing the centres in northern and central Europe separately, the significant association between latitude/UV radiation levels and ANCA serotype was not seen. The latitudinal difference between Tromsø and Prague is 20° and the UV radiation exposure is more than twice as high in Prague compared with Tromsø. If UV radiation levels were of significant importance for ANCA serotype, an association between ANCA serotype and UV radiation levels could be expected in this subanalysis. There are, however, also genetic differences between populations in Europe along a north–south axis [42] and known genetic associations in AAV that affect MPO- and PR3-ANCA differently [26]. One gene variant whose global prevalence varies widely is the Pi*Z variant of alpha-1-antitrypsin, which has been shown to influence the risk of PR3-ANCA but not MPO-ANCA. It is more common in Scandinavia, Western and Central Europe and countries colonized by Europeans [43]. Watts et al. [44] recently showed that GPA incidence is associated with latitude in univariable analysis, but multivariable analysis suggested that this was due to the distribution of HLA-DPB*0401 allele frequency. Hence it is possible that the observed latitudinal difference is caused by genetic differences affecting the distribution of ANCA serotypes rather than an effect of UV radiation levels. One proposed mechanism by which UV radiation could affect the immune system, and thus the occurrence of AAV, is by inducing vitamin D. Kemna et al. [45] demonstrated that among AAV patients who have an ANCA titre increase during fall, those with low vitamin D levels were more likely to experience a relapse compared with those who maintained normal vitamin D levels [45]. However, vitamin D status is not only influenced by UV exposure of the skin, which is dependent on latitude and season, but also by diet, age and skin pigmentation [46]. An effect of differences in dietary intake of vitamin D between the participating countries cannot be ruled out since we did not have data on vitamin D levels. In non-renal AAV, there is a predominance of PR3 positivity and a clinical diagnosis of GPA [10, 35], while in renal AAV the distribution is more equal [10, 32, 35, 47]. In this study, the odds of being PR3 positive was higher at northern latitudes when compared with southern latitudes, but the association was not very strong. Previous studies have shown large differences in the incidence of GPA between northern and southern Europe. It is possible that this difference to a large extent consists of patients with GPA without renal involvement and this patient group is not included in the present study. Whether environment is a major determinant for extrarenal disease manifestations and disease phenotypes such as limited GPA was not within the scope of this study and remains to be determined. There are limitations in this study that need to be taken into account. The use of the latitude and mean UV radiation level for one city in every region do not account for the latitudinal differences and variation in sun exposure within a region or for migration from other regions. We chose to limit the study to renal biopsy–proven glomerulonephritis in order to reduce sampling bias between different regions and different units (nephrology and rheumatology). This makes the study population more homogeneous, but firm conclusions can only be drawn regarding biopsy-proven renal AAV and the results cannot be generalized to non-renal AAV or renal AAV that is not confirmed by renal biopsy. This approach could also introduce a risk of bias based on differences in indications to perform renal biopsy. In an effort to investigate this potential bias, we compared biopsied and non-biopsied patients with renal involvement in three of the participating centres. We found that MPO-ANCA positivity was more common in biopsied patients when compared with non-biopsied patients with renal involvement, which would lead to an underestimation of PR3-positive patients in our study. The reasons for this difference could be that PR3-positive disease more often is confirmed by other organ biopsies (e.g. nasal, skin, muscle or lung) or that MPO-positive patients have more severe renal disease that makes the physician more prone to perform biopsy. We cannot rule out the possibility that there are slight differences in biopsy policies among the centres, and it is important to bear this in mind when interpreting the results. However, it is unlikely that this would have altered the main findings of this study. In conclusion, we found differences in age, gender distribution and renal function at diagnosis between MPO-ANCA-positive and PR3-ANCA-positive glomerulonephritis. There was also a significant association between ANCA serotype and latitude/UV radiation levels, which was not seen in northern and central Europe. The contribution of genetic differences to the observed latitudinal gradient needs to be elucidated in further studies. SUPPLEMENTARY DATA Supplementary data are available at ndt online. ACKNOWLEDGEMENTS The project was launched by the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Immunology Work Group (IWG). STRÅNG data used are from the Swedish Meteorological and Hydrological Institute (SMHI) and were produced with support from the Swedish Radiation Protection Authority and the Swedish Environmental Agency. The authors would like to thank all centres, research nurses and physicians who contributed data to the Czech Registry of ANCA-associated vasculitides; Shunsuke Furuta, Addenbrooke’s Hospital, Vasculitis and Lupus Clinic in Cambridge for his contributions to the vasculitis registry in Cambridge; Emily McQuarrie for her contributions to the Scottish biopsy registry in Glasgow; Ronald J. Falk, J. Charles Jennette and Patrick H. Nachman, University of North Carolina, for their contributions to the GDCN registry and Kresimir Galesic and Ivica Horvatic for their contributions to the renal biopsy registry at Dubrava University Hospital. FUNDING This work was supported by the Ingrid Asp Foundation (to M.S.), the Swedish Renal Foundation (to M.W.), the Swedish Society of Medicine (Svenska Läkaresällskapet) and the Swedish Rheumatism Association (Reumatikerförbundet) (to A.J.M.). The GDCN registry was supported in part by Program Project Grant P01-DK5-30834 from the National Institute for Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, Bethesda, MD, USA. AUTHORS’ CONTRIBUTIONS M.S. initiated the project. M.S. and M.W. were responsible for the final design of the project. M.W. conducted the data analysis and drafted the manuscript. All authors contributed to the acquisition and interpretation of data and revision of the manuscript and approved the final version. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Maixnerova D , Jancova E , Skibova J. Nationwide biopsy survey of renal diseases in the Czech Republic during the years 1994-2011 . 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Proteinase-3 and myeloperoxidase serotype in relation to demographic factors and geographic distribution in anti-neutrophil cytoplasmic antibody-associated glomerulonephritis

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Oxford University Press
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© The Author(s) 2018. 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/gfy106
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Abstract

Abstract Background In anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, antigen specificity varies between myeloperoxidase (MPO) and proteinase 3 (PR3). This has been reported to vary in relation to age, gender, geography and extrarenal manifestations. However, studies are difficult to compare as criteria for inclusion vary. The aim of this study was to investigate the relationship between ANCA serotype, latitude, ultraviolet (UV) radiation levels, age, gender and renal function at diagnosis in a large study with uniform inclusion criteria. Methods Patients with biopsy-proven ANCA-associated glomerulonephritis were identified from regional or nationwide registries in 14 centres in Norway, Sweden, the UK, the Czech Republic, Croatia, Italy and the USA during the period 2000–13. UV radiation levels for 2000–13 in Europe were obtained from the Swedish Meteorological and Hydrological Institute. Results A total of 1408 patients (45.2% PR3-ANCA) were included in the study. In univariable analysis, PR3-ANCA was significantly associated with male gender {odds ratio [OR] 2.12 [95% confidence interval (CI) 1.71–2.62]}, younger age [OR per year 0.97 (95% CI 0.96–0.98)] and higher glomerular filtration rate [OR per mL/min 1.01 (95% CI 1.01–1.02); P < 0.001] at diagnosis but not with latitude or UV radiation. In multivariable logistic regression analysis, latitude and UV radiation also became significant, with higher odds for PR3-ANCA positivity at northern latitudes/lower UV radiation levels. However, the latitudinal difference in MPO:PR3 ratio is smaller than differences previously reported concerning microscopic polyangiitis and granulomatosis with polyangiitis. Conclusions The ratio between PR3-ANCA and MPO-ANCA varies in glomerulonephritis with respect to age, gender, renal function and geographic latitude/UV radiation levels. ANCA-associated vasculitis, glomerulonephritis, latitude, MPO-ANCA, PR3-ANCA INTRODUCTION Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is often complicated by renal involvement and AAV constitutes one of the most common causes of rapidly progressive glomerulonephritis and nephritic syndrome [1, 2]. Based on extrarenal features, AAV is classified as either microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) or eosinophilic GPA (EGPA) [3]. ANCA-associated nephritis (AAN) is seen in ∼75% of cases, with more frequent occurrence in MPA than in GPA and EGPA [4, 5]. The aetiology of AAV is still unknown but is believed to be dependent on both genetic and environmental factors, with no single factor being sufficient to cause disease [6]. Animal models provide strong evidence for a pathogenic role of ANCA in AAV, but it is less clear why the autoantibodies are formed [7]. In AAN, the autoantibodies are directed against myeloperoxidase (MPO) or proteinase 3 (PR3) [8]. Emerging data on the genetic association and clinical observations are likely to drive more changes in how ANCA-AAV is subgrouped to guide management of these patients. Differences in the epidemiology between myeloperoxidase ANCA (MPO-ANCA) and PR3-ANCA AAN may reveal important clues concerning the aetiology. MPO-ANCA is mainly associated with MPA and PR3-ANCA with GPA [9], and the ratio between MPO-ANCA and PR3-ANCA has also been reported to vary in relation to gender, age and geographic distribution [10, 11]. Furthermore, the histological findings and renal outcome differ between PR3-ANCA and MPO-ANCA-associated glomerulonephritis [12, 13]. The incidence of AAV is similar in the UK, Scandinavia and Japan [11, 14]. However, in Asia there is a great predominance of MPO-ANCA and MPA compared with Europe and North America [15, 16]. In Europe, studies have shown higher incidences of GPA in the north compared with the south [11, 17, 18]. Data from New Zealand suggest a reciprocal gradient in the southern hemisphere [19]. It has also been shown that the incidence of GPA correlates inversely with ambient ultraviolet (UV) radiation [20] and a possible pathogenic explanation for the geographic gradients is the difference in UV radiation exposure at different latitudes. Latitudinal gradients and UV radiation have been studied extensively in other autoimmune diseases, such as multiple sclerosis and type 1 diabetes [21–23], but there are few studies of ANCA-AAV and none focusing on serotype. An alternative explanation for the geographic pattern could be genetic differences between populations. There is evidence of a genetic contribution to AAV, with several genes and polymorphisms predisposing to disease [24, 25]. The genetic composition seems to associate more strongly with ANCA serotype than with the phenotypic disease entities MPA and GPA [26]. Many of the epidemiological studies to date are small single-centre studies and difficult to compare directly due to the heterogeneity of inclusion criteria and patient characteristics. Large, more homogeneous studies with greater geographic distribution are warranted. The objective of the present study was to investigate the relationship between ANCA serotype, latitude, UV radiation levels, age, gender and renal function at diagnosis. This was done using uniform inclusion criteria in a large population of patients with biopsy-proven ANCA-associated glomerulonephritis identified from registries in Europe and North America. MATERIALS AND METHODS Study population Patients with renal biopsy–proven ANCA-associated glomerulonephritis were identified from the Norwegian, Scottish, Croatian and Italian biopsy registries; the Czech vasculitis registry; the regional vasculitis registries in Lund, Linköping and Cambridge; the Glomerular Disease Collaborative Network (GDCN) in North Carolina and Johns Hopkins Vasculitis Centre in Maryland. The Norwegian renal biopsy registry is a national registry run by the Medical Department, Haukeland University Hospital. It started in 1988 and includes all native kidney biopsies except tumor biopsies performed in the country. For the present study, the patients were divided into groups based at four tertiary referral hospitals in the country. The Scottish renal biopsy registry was established in 2005 [27]. For this study, only data from the Greater Glasgow, Clyde and Forth Valley regions were incorporated, as they were known to include all cases of biopsy-proven AAV along with relevant clinical data. The Italian Registry of Renal Biopsies was established in 1987 and has been described in detail previously [28]. For the present study, the patients were divided into two groups according to region of residence. The renal biopsy registry at Dubrava University Hospital in Zagreb is the largest renal biopsy registry in Croatia. Patients from all parts of Croatia referred to the nephrology unit for renal biopsy have been included in this study. In the Czech Republic, a single nationwide vasculitis registry was formed in 2009, in which all patients with AAV diagnosed or followed up in the participating centres were recorded. The regional vasculitis registries in Linköping and Lund, Sweden both contain all patients diagnosed with AAV within defined geographic regions, and they have previously been described in detail [29, 30]. The vasculitis registry in Cambridge is based at a multidisciplinary clinic at Addenbrooke’s Hospital. It contains all patients with vasculitis referred to the hospital. For this study, only patients living in a defined geographic area surrounding the city of Cambridge were included. The GDCN registry enrols patients as they are diagnosed at the University of North Carolina and in private practices throughout the southeastern USA. Patients are primarily identified from renal biopsy diagnoses evaluated through the University of North Carolina Nephropathology Service. The GDCN has been described in detail in previous studies [31, 32]. In this study, only patients residing in North Carolina were included. The Johns Hopkins Vasculitis database enrols subjects who are referred by practices within the state of Maryland and surrounding states in the northeast USA as they are diagnosed at Johns Hopkins Hospital. For this study, only patients residing in Maryland were included. Only registries including consecutive patients from a defined geographic area were used for this study. Tertiary referrals to Cambridge, Linköping and Lund from regions outside the primary catchment area were excluded to reduce referral bias. The inclusion criteria for the study were a clinical diagnosis of AAV verified by renal biopsy during the period 2000–13, ANCA positivity verified by enzyme-linked immunosorbent assay (ELISA) and age ≥18 years. Exclusion criteria were eosinophilic GPA (EGPA) and polyarteritis nodosa (PAN) along with anti-glomerular basement membrane disease, secondary vasculitis and drug-induced vasculitis, in accordance with the exclusion criteria in the European Medicines Agency algorithm [3]. Patients were classified as either PR3-ANCA positive or MPO-ANCA positive depending on the result of the ELISA. Patients who were positive for both PR3-ANCA and MPO-ANCA were classified to the serotype with the highest titre. Double-positive patients were excluded if the ANCA titres were unknown. Glomerular filtration rate (GFR) was estimated using the Modification of Diet in Renal Disease equation [33]. All patient data in the present study are anonymous registry data. The project was approved by the Ethical Review Board in Lund, Sweden, the University of North Carolina Institutional Review Board and the institutional review board in Maryland. For the American patients, informed consent was provided by all patients for collection of demographic and medical information, while this was not required for the European patients. Data collection Data were collected from the time of biopsy and included gender, age, ANCA serotype and estimated GFR (eGFR). No follow-up data were collected for the present study. Antigen-specific ELISA was used to detect ANCA. The mean monthly erythemally weighted UV radiation level (International Commission on Illumination) for 2000–13 in the regions in Europe was obtained from the STRÅNG database provided by the Swedish Meteorological and Hydrological Institute [34]. Latitude and longitude coordinates are given in the World Geodetic System 84 coordinate reference system. For Europe the coordinates are given for the centres included in the study and for the USA the coordinates are given for the capital city of every state (Raleigh, NC, USA; Annapolis, MD, USA). Statistical methods Statistical analysis was performed using Statistical Package for the Social Sciences: SPSS Statistics for Windows, version 21.0 (IBM, Armonk, NY, USA). P-values <0.05 were considered significant. Continuous variables were expressed as medians and interquartile ranges. Categorical variables were expressed as percentages. Differences between groups were analyzed using the Mann–Whitney test for non-parametric data and the chi-square test for categorical data. Univariable and multivariable binary logistic regression analysis was used to assess the association between ANCA serotype and the variables gender, age, eGFR, latitude, longitude and UV radiation level. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Spearman’s rank correlation analysis was performed between the input variables to check for strong correlations between the variables entered in the multivariable logistic regression analysis. All analyses exclude missing data. RESULTS Baseline patient characteristics A total of 1408 patients were included in the study. MPO-ANCA positivity was seen in 54.8% of the patients and PR3-ANCA positivity in 45.2% of the patients. The median age at diagnosis was 64 years [interquartile range (IQR) 53–72]. The median estimated glomerular filtration eGFR at the time of biopsy was 19 mL/min/1.73 m2 (IQR 10–36) (Table 1). Male gender was more common in PR3-positive patients compared with MPO-ANCA-positive patients (61.5% versus 43.0%; P < 0.001). The median age was 60 years (IQR 50–69) in PR3-positive patients compared with 67 years (IQR 57–74) in MPO-positive patients (P < 0.001) and the median eGFR was 21 mL/min/1.73 m2 (IQR 11–44) compared with 18 mL/min/1.73 m2 (IQR 10–31) (P < 0.001). The longitude of the participating centres varied between 35.8°S and 69.6°N. UV radiation levels in Europe varied between 5246 mWh/m2 in the northernmost centre and 14 565 mWh/m2 in the southernmost centre (Table 2). Table 1 Clinical and demographic characteristics at the time of biopsy Centre N ANCA PR3/MPO % Gender (male/female), % Age (years), median (IQR) eGFR (mL/min/1.73 m2), median (IQR)a All 1408 45.2/54.8 51.3/48.7 64 (53–72) 19 (10–36) Europe 1167 46.0/54.0 51.2/48.8 64 (54–72) 19 (11–37)  Tromsø 21 57.1/42.9 52.4/47.6 60 (51–69) 17 (7–25)  Trondheim 62 53.2/46.8 45.2/54.8 68 (58–76) 20 (8–38)  Bergen 88 44.3/55.7 52.3/47.7 62 (49–75) 27 (15–54)  Oslo 140 48.6/51.4 54.3/45.7 65 (53–74) 19 (10–40)  Linköping 49 30.6/69.4 61.2/38.8 70 (61–75) 26 (18–37)  Glasgow 238 43.7/56.3 45.8/54.2 67 (59–75) 15 (9–27)  Lund 72 48.6/51.4 51.4/48.6 66 (54–75) 24 (13–44)  Cambridge 54 40.7/59.3 57.4/42.6 64 (58–73) 20 (10–43)  Prague 305 52.5/47.5 53.4/46.6 59 (52–67) 23 (13–47)  Zagreb 42 28.6/71.4 45.2/54.8 64 (47–70) 12 (7–20)  Milan 71 39.4/60.6 46.5/53.5 68 (61–74) 15 (8–25)  Rome 25 36.0/64.0 60.0/40.0 65 (56–70) 8 (6–21) USA 241 41.1/58.9 51.9/48.1 60 (50–72) 18 (10–33)  Maryland 71 42.3/57.7 43.7/56.3 63 (55–72) 18 (10–29)  North Carolina 170 40.6/59.4 55.3/44.7 59 (49–72) 18 (10–36) Centre N ANCA PR3/MPO % Gender (male/female), % Age (years), median (IQR) eGFR (mL/min/1.73 m2), median (IQR)a All 1408 45.2/54.8 51.3/48.7 64 (53–72) 19 (10–36) Europe 1167 46.0/54.0 51.2/48.8 64 (54–72) 19 (11–37)  Tromsø 21 57.1/42.9 52.4/47.6 60 (51–69) 17 (7–25)  Trondheim 62 53.2/46.8 45.2/54.8 68 (58–76) 20 (8–38)  Bergen 88 44.3/55.7 52.3/47.7 62 (49–75) 27 (15–54)  Oslo 140 48.6/51.4 54.3/45.7 65 (53–74) 19 (10–40)  Linköping 49 30.6/69.4 61.2/38.8 70 (61–75) 26 (18–37)  Glasgow 238 43.7/56.3 45.8/54.2 67 (59–75) 15 (9–27)  Lund 72 48.6/51.4 51.4/48.6 66 (54–75) 24 (13–44)  Cambridge 54 40.7/59.3 57.4/42.6 64 (58–73) 20 (10–43)  Prague 305 52.5/47.5 53.4/46.6 59 (52–67) 23 (13–47)  Zagreb 42 28.6/71.4 45.2/54.8 64 (47–70) 12 (7–20)  Milan 71 39.4/60.6 46.5/53.5 68 (61–74) 15 (8–25)  Rome 25 36.0/64.0 60.0/40.0 65 (56–70) 8 (6–21) USA 241 41.1/58.9 51.9/48.1 60 (50–72) 18 (10–33)  Maryland 71 42.3/57.7 43.7/56.3 63 (55–72) 18 (10–29)  North Carolina 170 40.6/59.4 55.3/44.7 59 (49–72) 18 (10–36) a Data missing in 84 patients. Table 1 Clinical and demographic characteristics at the time of biopsy Centre N ANCA PR3/MPO % Gender (male/female), % Age (years), median (IQR) eGFR (mL/min/1.73 m2), median (IQR)a All 1408 45.2/54.8 51.3/48.7 64 (53–72) 19 (10–36) Europe 1167 46.0/54.0 51.2/48.8 64 (54–72) 19 (11–37)  Tromsø 21 57.1/42.9 52.4/47.6 60 (51–69) 17 (7–25)  Trondheim 62 53.2/46.8 45.2/54.8 68 (58–76) 20 (8–38)  Bergen 88 44.3/55.7 52.3/47.7 62 (49–75) 27 (15–54)  Oslo 140 48.6/51.4 54.3/45.7 65 (53–74) 19 (10–40)  Linköping 49 30.6/69.4 61.2/38.8 70 (61–75) 26 (18–37)  Glasgow 238 43.7/56.3 45.8/54.2 67 (59–75) 15 (9–27)  Lund 72 48.6/51.4 51.4/48.6 66 (54–75) 24 (13–44)  Cambridge 54 40.7/59.3 57.4/42.6 64 (58–73) 20 (10–43)  Prague 305 52.5/47.5 53.4/46.6 59 (52–67) 23 (13–47)  Zagreb 42 28.6/71.4 45.2/54.8 64 (47–70) 12 (7–20)  Milan 71 39.4/60.6 46.5/53.5 68 (61–74) 15 (8–25)  Rome 25 36.0/64.0 60.0/40.0 65 (56–70) 8 (6–21) USA 241 41.1/58.9 51.9/48.1 60 (50–72) 18 (10–33)  Maryland 71 42.3/57.7 43.7/56.3 63 (55–72) 18 (10–29)  North Carolina 170 40.6/59.4 55.3/44.7 59 (49–72) 18 (10–36) Centre N ANCA PR3/MPO % Gender (male/female), % Age (years), median (IQR) eGFR (mL/min/1.73 m2), median (IQR)a All 1408 45.2/54.8 51.3/48.7 64 (53–72) 19 (10–36) Europe 1167 46.0/54.0 51.2/48.8 64 (54–72) 19 (11–37)  Tromsø 21 57.1/42.9 52.4/47.6 60 (51–69) 17 (7–25)  Trondheim 62 53.2/46.8 45.2/54.8 68 (58–76) 20 (8–38)  Bergen 88 44.3/55.7 52.3/47.7 62 (49–75) 27 (15–54)  Oslo 140 48.6/51.4 54.3/45.7 65 (53–74) 19 (10–40)  Linköping 49 30.6/69.4 61.2/38.8 70 (61–75) 26 (18–37)  Glasgow 238 43.7/56.3 45.8/54.2 67 (59–75) 15 (9–27)  Lund 72 48.6/51.4 51.4/48.6 66 (54–75) 24 (13–44)  Cambridge 54 40.7/59.3 57.4/42.6 64 (58–73) 20 (10–43)  Prague 305 52.5/47.5 53.4/46.6 59 (52–67) 23 (13–47)  Zagreb 42 28.6/71.4 45.2/54.8 64 (47–70) 12 (7–20)  Milan 71 39.4/60.6 46.5/53.5 68 (61–74) 15 (8–25)  Rome 25 36.0/64.0 60.0/40.0 65 (56–70) 8 (6–21) USA 241 41.1/58.9 51.9/48.1 60 (50–72) 18 (10–33)  Maryland 71 42.3/57.7 43.7/56.3 63 (55–72) 18 (10–29)  North Carolina 170 40.6/59.4 55.3/44.7 59 (49–72) 18 (10–36) a Data missing in 84 patients. Table 2 Latitude, longitude and UV radiation levels of the participating centres Centre Latitude Longitude Mean UV radiation/month (mWh/m2) Mean UV radiation January (mWh/m2) Mean UV radiation June (mWh/m2) Tromsø 69.6°N 18.9°E 5246 31 14 595 Trondheim 63.4°N 10.4°E 6616 141 16 572 Bergen 60.4°N 5.3°E 7082 304 17 724 Oslo 59.9°N 10.7°E 7623 400 18 557 Linköping 58.4°N 15.6°E 9398 523 22 730 Glasgow 55.9°N −4.3°E 8086 736 18 181 Lund 55.7°N 13.2°E 10 087 726 23 243 Cambridge 52.2°N 0.12°E 9851 1119 21 613 Prague 50.1°N 14.4°E 12 262 1588 26 484 Zagreb 45.8°N 16.0°E 14 395 2300 29 484 Milan 45.5°N 9.2°E 13 874 2807 26 890 Rome 41.9°N 12.5°E 14 565 2434 29 562 Maryland 39.0°N −76.5°W North Carolina 35.8°N −78.6°W Centre Latitude Longitude Mean UV radiation/month (mWh/m2) Mean UV radiation January (mWh/m2) Mean UV radiation June (mWh/m2) Tromsø 69.6°N 18.9°E 5246 31 14 595 Trondheim 63.4°N 10.4°E 6616 141 16 572 Bergen 60.4°N 5.3°E 7082 304 17 724 Oslo 59.9°N 10.7°E 7623 400 18 557 Linköping 58.4°N 15.6°E 9398 523 22 730 Glasgow 55.9°N −4.3°E 8086 736 18 181 Lund 55.7°N 13.2°E 10 087 726 23 243 Cambridge 52.2°N 0.12°E 9851 1119 21 613 Prague 50.1°N 14.4°E 12 262 1588 26 484 Zagreb 45.8°N 16.0°E 14 395 2300 29 484 Milan 45.5°N 9.2°E 13 874 2807 26 890 Rome 41.9°N 12.5°E 14 565 2434 29 562 Maryland 39.0°N −76.5°W North Carolina 35.8°N −78.6°W Table 2 Latitude, longitude and UV radiation levels of the participating centres Centre Latitude Longitude Mean UV radiation/month (mWh/m2) Mean UV radiation January (mWh/m2) Mean UV radiation June (mWh/m2) Tromsø 69.6°N 18.9°E 5246 31 14 595 Trondheim 63.4°N 10.4°E 6616 141 16 572 Bergen 60.4°N 5.3°E 7082 304 17 724 Oslo 59.9°N 10.7°E 7623 400 18 557 Linköping 58.4°N 15.6°E 9398 523 22 730 Glasgow 55.9°N −4.3°E 8086 736 18 181 Lund 55.7°N 13.2°E 10 087 726 23 243 Cambridge 52.2°N 0.12°E 9851 1119 21 613 Prague 50.1°N 14.4°E 12 262 1588 26 484 Zagreb 45.8°N 16.0°E 14 395 2300 29 484 Milan 45.5°N 9.2°E 13 874 2807 26 890 Rome 41.9°N 12.5°E 14 565 2434 29 562 Maryland 39.0°N −76.5°W North Carolina 35.8°N −78.6°W Centre Latitude Longitude Mean UV radiation/month (mWh/m2) Mean UV radiation January (mWh/m2) Mean UV radiation June (mWh/m2) Tromsø 69.6°N 18.9°E 5246 31 14 595 Trondheim 63.4°N 10.4°E 6616 141 16 572 Bergen 60.4°N 5.3°E 7082 304 17 724 Oslo 59.9°N 10.7°E 7623 400 18 557 Linköping 58.4°N 15.6°E 9398 523 22 730 Glasgow 55.9°N −4.3°E 8086 736 18 181 Lund 55.7°N 13.2°E 10 087 726 23 243 Cambridge 52.2°N 0.12°E 9851 1119 21 613 Prague 50.1°N 14.4°E 12 262 1588 26 484 Zagreb 45.8°N 16.0°E 14 395 2300 29 484 Milan 45.5°N 9.2°E 13 874 2807 26 890 Rome 41.9°N 12.5°E 14 565 2434 29 562 Maryland 39.0°N −76.5°W North Carolina 35.8°N −78.6°W There was no difference in the distribution of MPO-ANCA and PR3-ANCA (P = 0.16), gender (P = 0.86) or eGFR (P = 0.32) between the European patients and the American patients. The American patients were younger, with a median age of 60 years (IQR 50–72) compared with 64 years (IQR 54–72) in the European patients (P = 0.008). Comparison between biopsied and non-biopsied patients The Linköping, Lund and Cambridge registries were used to identify all patients with AAV in the uptake area with renal involvement according to Birmingham Vasculitis Activity Score. Patients with ANCA-associated glomerulonephritis verified by renal biopsy (patients included in this study) were compared with patients who did not have a renal biopsy–proven diagnosis (patients excluded from this study). In Linköping, 71.0% of the AAV patients with renal involvement underwent a kidney biopsy, the corresponding figure for Lund was 63.2% and for Cambridge 76.0%. In the Cambridge centre, male gender was significantly more common in biopsied patients when compared with non-biopsied patients. In the Linköping centre, MPO-ANCA was more common in biopsied patients. In the Lund centre, biopsied patients were significantly younger. Overall, MPO-ANCA was more common and age was lower in the biopsied patients (Table 3). Table 3 Biopsy versus no biopsy Clincal parameters All Cambridge Linköping Lund Biopsy (n =175) No biopsy (n = 79) P-value Biopsy (n = 54) No biopsy (n = 17) P-value Biopsy (n = 49) No biopsy (n = 20) P-value Biopsy (n = 72) No biopsy (n = 42) P-value MPO, n (%) 103 (58.9) 34 (43.0) 0.019 32 (59.3) 6 (35.3) 0.084 34 (69.4) 7 (35.0) 0.008 37 (51.4) 21 (50.0) 0.89 PR3, n (%) 72 (41.1) 45 (57.0) 22 (40.7) 11 (64.7) 15 (30.6) 13 (65.0) 35 (48.6) 21 (50.0) Male, n (%) 98 (56.0) 45 (57.0) 0.89 31 (57.4) 5 (29.4) 0.044 30 (61.2) 14 (70.0) 0.49 37 (51.4) 26 (61.9) 0.28 Female, n (%) 77 (44.0) 34 (43.0) 23 (42.6) 12 (70.6) 19 (38.8) 6 (30.0) 35 (48.6) 16 (38.1) Age (years), median (IQR) 67 (58–74) 74 (60–81) 0.002 64 (58–73) 64 (51–72) 0.91 70 (61–75) 72 (60–77) 0.54 66 (54–75) 79 (64–84) 0.001 eGFR (MDRD), median (IQR)a 24 (12–43) 19 (11–56) 0.95 20 (10–43) 16 (8–58) 0.82 26 (18–37) 31 (10–59) 0.92 24 (13–44) 19 (11–47) 0.65 Clincal parameters All Cambridge Linköping Lund Biopsy (n =175) No biopsy (n = 79) P-value Biopsy (n = 54) No biopsy (n = 17) P-value Biopsy (n = 49) No biopsy (n = 20) P-value Biopsy (n = 72) No biopsy (n = 42) P-value MPO, n (%) 103 (58.9) 34 (43.0) 0.019 32 (59.3) 6 (35.3) 0.084 34 (69.4) 7 (35.0) 0.008 37 (51.4) 21 (50.0) 0.89 PR3, n (%) 72 (41.1) 45 (57.0) 22 (40.7) 11 (64.7) 15 (30.6) 13 (65.0) 35 (48.6) 21 (50.0) Male, n (%) 98 (56.0) 45 (57.0) 0.89 31 (57.4) 5 (29.4) 0.044 30 (61.2) 14 (70.0) 0.49 37 (51.4) 26 (61.9) 0.28 Female, n (%) 77 (44.0) 34 (43.0) 23 (42.6) 12 (70.6) 19 (38.8) 6 (30.0) 35 (48.6) 16 (38.1) Age (years), median (IQR) 67 (58–74) 74 (60–81) 0.002 64 (58–73) 64 (51–72) 0.91 70 (61–75) 72 (60–77) 0.54 66 (54–75) 79 (64–84) 0.001 eGFR (MDRD), median (IQR)a 24 (12–43) 19 (11–56) 0.95 20 (10–43) 16 (8–58) 0.82 26 (18–37) 31 (10–59) 0.92 24 (13–44) 19 (11–47) 0.65 MDRD, Modification of Diet in Renal Disease. a Data missing in six patients. Comparison between patients with renal AAV who underwent renal biopsy and patients with renal AAV who did not undergo renal biopsy. Table 3 Biopsy versus no biopsy Clincal parameters All Cambridge Linköping Lund Biopsy (n =175) No biopsy (n = 79) P-value Biopsy (n = 54) No biopsy (n = 17) P-value Biopsy (n = 49) No biopsy (n = 20) P-value Biopsy (n = 72) No biopsy (n = 42) P-value MPO, n (%) 103 (58.9) 34 (43.0) 0.019 32 (59.3) 6 (35.3) 0.084 34 (69.4) 7 (35.0) 0.008 37 (51.4) 21 (50.0) 0.89 PR3, n (%) 72 (41.1) 45 (57.0) 22 (40.7) 11 (64.7) 15 (30.6) 13 (65.0) 35 (48.6) 21 (50.0) Male, n (%) 98 (56.0) 45 (57.0) 0.89 31 (57.4) 5 (29.4) 0.044 30 (61.2) 14 (70.0) 0.49 37 (51.4) 26 (61.9) 0.28 Female, n (%) 77 (44.0) 34 (43.0) 23 (42.6) 12 (70.6) 19 (38.8) 6 (30.0) 35 (48.6) 16 (38.1) Age (years), median (IQR) 67 (58–74) 74 (60–81) 0.002 64 (58–73) 64 (51–72) 0.91 70 (61–75) 72 (60–77) 0.54 66 (54–75) 79 (64–84) 0.001 eGFR (MDRD), median (IQR)a 24 (12–43) 19 (11–56) 0.95 20 (10–43) 16 (8–58) 0.82 26 (18–37) 31 (10–59) 0.92 24 (13–44) 19 (11–47) 0.65 Clincal parameters All Cambridge Linköping Lund Biopsy (n =175) No biopsy (n = 79) P-value Biopsy (n = 54) No biopsy (n = 17) P-value Biopsy (n = 49) No biopsy (n = 20) P-value Biopsy (n = 72) No biopsy (n = 42) P-value MPO, n (%) 103 (58.9) 34 (43.0) 0.019 32 (59.3) 6 (35.3) 0.084 34 (69.4) 7 (35.0) 0.008 37 (51.4) 21 (50.0) 0.89 PR3, n (%) 72 (41.1) 45 (57.0) 22 (40.7) 11 (64.7) 15 (30.6) 13 (65.0) 35 (48.6) 21 (50.0) Male, n (%) 98 (56.0) 45 (57.0) 0.89 31 (57.4) 5 (29.4) 0.044 30 (61.2) 14 (70.0) 0.49 37 (51.4) 26 (61.9) 0.28 Female, n (%) 77 (44.0) 34 (43.0) 23 (42.6) 12 (70.6) 19 (38.8) 6 (30.0) 35 (48.6) 16 (38.1) Age (years), median (IQR) 67 (58–74) 74 (60–81) 0.002 64 (58–73) 64 (51–72) 0.91 70 (61–75) 72 (60–77) 0.54 66 (54–75) 79 (64–84) 0.001 eGFR (MDRD), median (IQR)a 24 (12–43) 19 (11–56) 0.95 20 (10–43) 16 (8–58) 0.82 26 (18–37) 31 (10–59) 0.92 24 (13–44) 19 (11–47) 0.65 MDRD, Modification of Diet in Renal Disease. a Data missing in six patients. Comparison between patients with renal AAV who underwent renal biopsy and patients with renal AAV who did not undergo renal biopsy. Binary logistic regression analysis of ANCA serotype In univariable binary logistic regression analysis, age, gender and eGFR were associated with ANCA serotype. Increasing age was associated with decreasing odds of being PR3-ANCA positive, while increasing eGFR and male gender were associated with higher odds for PR3 positivity. Latitude and longitude were not significantly associated with ANCA serotype in univariable analysis. In multivariable analysis, age, eGFR and gender remained associated with ANCA serotype and the association between latitude and ANCA serotype was significant. Increasing latitude was associated with higher odds for PR3 positivity (Table 4). When analysing the European patients separately, the results remained essentially the same (Table 5). Latitude and UV radiation were strongly correlated (Spearman’s ρ −0.99), so were not entered in the multivariable analysis simultaneously. In multivariable analysis including UV radiation instead of latitude, UV radiation, age, gender and eGFR were significantly associated with ANCA serotype. Increasing UV radiation levels were associated with lower odds for PR3 positivity (Supplementary data, Table S1). In an additional analysis excluding the centres in southern Europe (Zagreb, Milan and Rome) and the USA (North Carolina and Maryland), the association between ANCA serotype and both latitude and UV radiation level was lost, while it remained for age, gender and eGFR (Supplementary data, Table S2). Table 4 Analysis of ANCA serotype Clincial and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.12 (1.71–2.62) <0.001 1.98 (1.58–2.49) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.012 Latitude (per 10 units) 1.12 (0.99–1.27) 0.071 1.29 (1.05–1.58) 0.016 Longitude (per 10 units) 1.03 (0.99–1.06) 0.11 0.98 (0.93–1.03) 0.34 Clincial and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.12 (1.71–2.62) <0.001 1.98 (1.58–2.49) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.012 Latitude (per 10 units) 1.12 (0.99–1.27) 0.071 1.29 (1.05–1.58) 0.016 Longitude (per 10 units) 1.03 (0.99–1.06) 0.11 0.98 (0.93–1.03) 0.34 a The OR refers to the probability of being PR3-ANCA positive. Univariable and multivariable binary logistic regression analysis of ANCA serotype in all patients. Table 4 Analysis of ANCA serotype Clincial and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.12 (1.71–2.62) <0.001 1.98 (1.58–2.49) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.012 Latitude (per 10 units) 1.12 (0.99–1.27) 0.071 1.29 (1.05–1.58) 0.016 Longitude (per 10 units) 1.03 (0.99–1.06) 0.11 0.98 (0.93–1.03) 0.34 Clincial and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.12 (1.71–2.62) <0.001 1.98 (1.58–2.49) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.012 Latitude (per 10 units) 1.12 (0.99–1.27) 0.071 1.29 (1.05–1.58) 0.016 Longitude (per 10 units) 1.03 (0.99–1.06) 0.11 0.98 (0.93–1.03) 0.34 a The OR refers to the probability of being PR3-ANCA positive. Univariable and multivariable binary logistic regression analysis of ANCA serotype in all patients. Table 5 Analysis of ANCA serotype in Europe Clinical and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.25 (1.78–2.85) <0.001 2.08 (1.62–2.68) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.016 Latitude (per 10 units) 1.12 (0.92–1.38) 0.26 1.27 (1.01–1.58) 0.038 Longitude (per 10 units) 1.09 (0.94–1.28) 0.26 0.97 (0.82–1.15) 0.71 UV radiation (per Wh/m2) 0.98 (0.94–1.03) 0.46 Clinical and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.25 (1.78–2.85) <0.001 2.08 (1.62–2.68) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.016 Latitude (per 10 units) 1.12 (0.92–1.38) 0.26 1.27 (1.01–1.58) 0.038 Longitude (per 10 units) 1.09 (0.94–1.28) 0.26 0.97 (0.82–1.15) 0.71 UV radiation (per Wh/m2) 0.98 (0.94–1.03) 0.46 a The OR refers to the probability of being PR3-ANCA positive. Univariable and multivariable binary logistic regression analysis of ANCA serotype in the European patients. Table 5 Analysis of ANCA serotype in Europe Clinical and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.25 (1.78–2.85) <0.001 2.08 (1.62–2.68) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.016 Latitude (per 10 units) 1.12 (0.92–1.38) 0.26 1.27 (1.01–1.58) 0.038 Longitude (per 10 units) 1.09 (0.94–1.28) 0.26 0.97 (0.82–1.15) 0.71 UV radiation (per Wh/m2) 0.98 (0.94–1.03) 0.46 Clinical and geographical parameters Univariable analysis Multivariable analysis OR (95% CI)a P-value OR (95% CI)a P-value Age (per year) 0.97 (0.96–0.98) <0.001 0.97 (0.97–0.98) <0.001 Gender (male) 2.25 (1.78–2.85) <0.001 2.08 (1.62–2.68) <0.001 eGFR (per mL/min/1.73 m2) 1.01 (1.01–1.02) <0.001 1.01 (1.00–1.01) 0.016 Latitude (per 10 units) 1.12 (0.92–1.38) 0.26 1.27 (1.01–1.58) 0.038 Longitude (per 10 units) 1.09 (0.94–1.28) 0.26 0.97 (0.82–1.15) 0.71 UV radiation (per Wh/m2) 0.98 (0.94–1.03) 0.46 a The OR refers to the probability of being PR3-ANCA positive. Univariable and multivariable binary logistic regression analysis of ANCA serotype in the European patients. DISCUSSION The aim of this study was to describe geographic, demographic and clinical features in a large population of patients with biopsy-proven ANCA-associated glomerulonephritis using registry data from several countries. We confirmed findings in previous studies showing that PR3-positive patients are younger and have higher eGFR than MPO-positive patients at diagnosis [10, 12, 35]. The OR for PR3 positivity was higher in men, which has also been reported before [35–37]. There was an association between ANCA serotype and both latitude and UV radiation levels in the multivariable analysis. The OR of being PR3 positive increased from south to north and decreased with increasing UV radiation levels. These results are in line with previous studies by Watts et al. [11, 38] showing that GPA is more common in the north of Europe and by Gatenby et al. [20] showing a correlation between GPA and latitude and UV radiation levels. These previous studies of the geographic differences in AAV have been focused on disease phenotype and not on ANCA serotype. To our knowledge, this is the first study to show an association for serotype specifically. The concept of PR3-ANCA AAV and MPO-ANCA AAV in addition to the traditional division in the two disease entities GPA and MPA has been suggested to be preferred due to its superior predictive value in terms of relapses and renal survival [12, 39]. In our study, the two centres in the USA are located furthest south and are the only centres with a westerly longitude. The population in the southeastern USA also has mixed origins, with large contributions from Latin America and Africa along with Europeans who are mainly of British descent. GPA/PR3 positivity has been shown to be less common in patients of non-European origin [40] and in African Americans [41]. It is difficult to exclude an effect of these genetic differences on the association between geographic location and serotype. We therefore conducted an analysis excluding these centres and the results remained essentially the same as in the entire study population. However, when analysing the centres in northern and central Europe separately, the significant association between latitude/UV radiation levels and ANCA serotype was not seen. The latitudinal difference between Tromsø and Prague is 20° and the UV radiation exposure is more than twice as high in Prague compared with Tromsø. If UV radiation levels were of significant importance for ANCA serotype, an association between ANCA serotype and UV radiation levels could be expected in this subanalysis. There are, however, also genetic differences between populations in Europe along a north–south axis [42] and known genetic associations in AAV that affect MPO- and PR3-ANCA differently [26]. One gene variant whose global prevalence varies widely is the Pi*Z variant of alpha-1-antitrypsin, which has been shown to influence the risk of PR3-ANCA but not MPO-ANCA. It is more common in Scandinavia, Western and Central Europe and countries colonized by Europeans [43]. Watts et al. [44] recently showed that GPA incidence is associated with latitude in univariable analysis, but multivariable analysis suggested that this was due to the distribution of HLA-DPB*0401 allele frequency. Hence it is possible that the observed latitudinal difference is caused by genetic differences affecting the distribution of ANCA serotypes rather than an effect of UV radiation levels. One proposed mechanism by which UV radiation could affect the immune system, and thus the occurrence of AAV, is by inducing vitamin D. Kemna et al. [45] demonstrated that among AAV patients who have an ANCA titre increase during fall, those with low vitamin D levels were more likely to experience a relapse compared with those who maintained normal vitamin D levels [45]. However, vitamin D status is not only influenced by UV exposure of the skin, which is dependent on latitude and season, but also by diet, age and skin pigmentation [46]. An effect of differences in dietary intake of vitamin D between the participating countries cannot be ruled out since we did not have data on vitamin D levels. In non-renal AAV, there is a predominance of PR3 positivity and a clinical diagnosis of GPA [10, 35], while in renal AAV the distribution is more equal [10, 32, 35, 47]. In this study, the odds of being PR3 positive was higher at northern latitudes when compared with southern latitudes, but the association was not very strong. Previous studies have shown large differences in the incidence of GPA between northern and southern Europe. It is possible that this difference to a large extent consists of patients with GPA without renal involvement and this patient group is not included in the present study. Whether environment is a major determinant for extrarenal disease manifestations and disease phenotypes such as limited GPA was not within the scope of this study and remains to be determined. There are limitations in this study that need to be taken into account. The use of the latitude and mean UV radiation level for one city in every region do not account for the latitudinal differences and variation in sun exposure within a region or for migration from other regions. We chose to limit the study to renal biopsy–proven glomerulonephritis in order to reduce sampling bias between different regions and different units (nephrology and rheumatology). This makes the study population more homogeneous, but firm conclusions can only be drawn regarding biopsy-proven renal AAV and the results cannot be generalized to non-renal AAV or renal AAV that is not confirmed by renal biopsy. This approach could also introduce a risk of bias based on differences in indications to perform renal biopsy. In an effort to investigate this potential bias, we compared biopsied and non-biopsied patients with renal involvement in three of the participating centres. We found that MPO-ANCA positivity was more common in biopsied patients when compared with non-biopsied patients with renal involvement, which would lead to an underestimation of PR3-positive patients in our study. The reasons for this difference could be that PR3-positive disease more often is confirmed by other organ biopsies (e.g. nasal, skin, muscle or lung) or that MPO-positive patients have more severe renal disease that makes the physician more prone to perform biopsy. We cannot rule out the possibility that there are slight differences in biopsy policies among the centres, and it is important to bear this in mind when interpreting the results. However, it is unlikely that this would have altered the main findings of this study. In conclusion, we found differences in age, gender distribution and renal function at diagnosis between MPO-ANCA-positive and PR3-ANCA-positive glomerulonephritis. There was also a significant association between ANCA serotype and latitude/UV radiation levels, which was not seen in northern and central Europe. The contribution of genetic differences to the observed latitudinal gradient needs to be elucidated in further studies. SUPPLEMENTARY DATA Supplementary data are available at ndt online. ACKNOWLEDGEMENTS The project was launched by the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Immunology Work Group (IWG). STRÅNG data used are from the Swedish Meteorological and Hydrological Institute (SMHI) and were produced with support from the Swedish Radiation Protection Authority and the Swedish Environmental Agency. The authors would like to thank all centres, research nurses and physicians who contributed data to the Czech Registry of ANCA-associated vasculitides; Shunsuke Furuta, Addenbrooke’s Hospital, Vasculitis and Lupus Clinic in Cambridge for his contributions to the vasculitis registry in Cambridge; Emily McQuarrie for her contributions to the Scottish biopsy registry in Glasgow; Ronald J. Falk, J. Charles Jennette and Patrick H. Nachman, University of North Carolina, for their contributions to the GDCN registry and Kresimir Galesic and Ivica Horvatic for their contributions to the renal biopsy registry at Dubrava University Hospital. FUNDING This work was supported by the Ingrid Asp Foundation (to M.S.), the Swedish Renal Foundation (to M.W.), the Swedish Society of Medicine (Svenska Läkaresällskapet) and the Swedish Rheumatism Association (Reumatikerförbundet) (to A.J.M.). The GDCN registry was supported in part by Program Project Grant P01-DK5-30834 from the National Institute for Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, Bethesda, MD, USA. AUTHORS’ CONTRIBUTIONS M.S. initiated the project. M.S. and M.W. were responsible for the final design of the project. M.W. conducted the data analysis and drafted the manuscript. All authors contributed to the acquisition and interpretation of data and revision of the manuscript and approved the final version. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Maixnerova D , Jancova E , Skibova J. Nationwide biopsy survey of renal diseases in the Czech Republic during the years 1994-2011 . 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Nephrology Dialysis TransplantationOxford University Press

Published: Apr 30, 2018

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