© Springer Japan 2016
Yasuhiko Tomino (ed.)Pathogenesis and Treatment in IgA Nephropathy10.1007/978-4-431-55588-9_1313. Differences in Etiology and Treatment in Scandinavian Countries
(1)
School of Medicine, University of Tampere, Tampere, FI-33014, Finland
(2)
Department of Internal Medicine, Tampere University Hospital, 2000, FI-33521 Tampere, Finland
(3)
Department of Nephrology, Helsinki University Hospital, 372, FI-00029 Helsinki, HUS, Finland
Abstract
We here review the studies of IgA nephropathy (IgAN) performed in the Scandinavian countries Denmark, Finland, Iceland, Norway, and Sweden, with emphasis on the etiologic and prognostic factors as well as the treatment of IgAN. During the last decades, most of the published studies about IgAN have come from Sweden and Finland, whereas there are only few reports from the other Scandinavian countries thus far.
Keywords
IgA nephropathyIgA glomerulonephritisScandinavian countries13.1 General Aspects
IgAN was first described almost 50 years ago [1]. The diagnostic hallmark of IgAN is the predominance of glomerular IgA deposits, either alone or with IgG, IgM, or both. Complement C3 deposits are also almost always present [2]. A rare subgroup of primary glomerulonephritis is IgA-IgM nephropathy, in which there are heavy deposits of both IgA and IgM in the glomerular mesangium [3]. Glomerular IgA deposition can be clinically totally silent or “lanthanic” [4, 5]. The ratio of subjects with “lanthanic” glomerular deposits of IgA to those with clinically overt disease can be estimated about 80–1 [4]. In a study from Finland, it was observed that 6.8 % of the necropsy cases from people, who had committed suicide or had encountered violent death, had mesangial IgA deposits [6].
13.2 Epidemiology and Natural Course
The prevalence of nephritis among young Finnish men was examined in a study 30 years ago [7]. During an 8-year period (1975–1982), 174 military conscripts (out of a total of 314,000) were studied in Helsinki University Central Hospital because of hematuria and/or proteinuria. A representative renal biopsy sample was available from 171 cases. Morphological analysis showed that 131 patients had glomerulonephritis, IgAN being the most common type as it was found in 70 patients [7].
A study about the epidemiology and prognosis of glomerulonephritis in Denmark from the years 1985 to 1997 showed that the prognosis of mesangioproliferative glomerulonephritis was unaffected by the presence of IgA deposits in immunofluorescence examination of the renal biopsies [8]. Based on these findings, the annual incidence of IgAN was estimated to be 1.8 cases per million, placing the Danish residents to the lowest end of the spectrum of IgAN incidence in populations [8].
A major finding in a Finnish study, based on the kidney biopsy registry of Tampere University Hospital, was that the annual incidence of a biopsy-proven glomerulonephritis, 17.6 per population of 100,000, was much higher than in any of the European registries [9]. IgAN was the most common glomerulonephritis, representing one third of all glomerulonephritides. Two other studies, one from Australia and one from France, with a corresponding high biopsy rate as in the above study, showed similar figures [10, 11]. There are no significant time trends in the incidence of IgAN during the last decades in Finland. It was also presumed that there is at least a tenfold true incidence of IgAN in the Finnish population when compared with the number of subjects requiring renal replacement therapy, assuming an unrestricted access to replacement therapy [9].
A recent study from Norway analyzed the mortality of 633 IgAN patients during a mean follow-up time of 11.8 years corresponding a total of 7,464 person-years [12]. The major new finding was that the age- and sex-adjusted mortality rate in Norwegian patients was approximately twofold higher when compared with the general population. A surprising finding was also that in IgAN patients, end-stage renal disease (ESRD) occurred 3.2 times more frequently than pre-ESRD deaths [12].
Geddes et al. [13] studied the long-term outcome of IgAN on three continents. They found significant variability in renal survival between centers, with 10-year actual survival rates of 95.7 %, 87.0 %, 63.9 %, and 61.6 % in Helsinki, Sydney, Glasgow, and Toronto, respectively (P < 0.001). This was concluded to be consistent with the hypothesis that geographical variability in the outcome of IgAN is largely explained by lead-time bias and inclusion of milder cases in centers with apparent good outcome. However, these findings do not exclude the possibility that some of the variability is due to other factors such as genetics, diet, or treatment [13].
Several clinical aspects of IgAN in children have been studied by a Swedish group. They reported that childhood IgAN is not a benign disease, as after a median follow-up of 5 years, a number of children had impaired renal function [14]. Moreover, a rising excretion rate of IgG may be a marker of progressive disease [15], while boys with proteinuria showed a significant decrease in renal function [16]. Therefore, children with IgAN should be carefully monitored with adequate glomerular filtration rate (GFR) measurements and urine protein analyses [17]. The value of early diagnosis of IgAN has recently been emphasized by Tomino [18].
The progression of Henoch-Schönlein nephritis was studied in a material of 42 adult patients by a group in Helsinki, Finland. Renal survival 10 years after biopsy was 91 %, and the only factor that was statistically significantly related to progression was proteinuria >1.0 g/24 h [19].
Recently, the value of the Oxford classification was studied in 99 pediatric IgAN patients with a follow-up of more than 5 years in Sweden. Three of the four histology lesions, namely, mesangial hypercellularity score >0.5, presence of endocapillary hypercellularity or tubular atrophy/interstitial fibrosis of >25 %, and also presence of crescents, were valid in predicting poor outcome in the cohort examined [20].
The natural long-term outcome of childhood IgAN was evaluated in a Finnish retrospective study [21]. After a mean follow-up of 19 years, 71 % of patients had abnormal renal findings and 39 % were receiving antihypertensive treatment at their latest follow-up visit. Pregnancy complications were common: 55 % of the pregnancies had been complicated by proteinuria and/or hypertension, and the prematurity rate was 30 % [21].
Swedish authors evaluated if graft survival rates after renal transplantation are better in IgAN patients when compared to those with other original renal diseases. Rejection rates were not reduced in IgAN, and survival of grafts and patients were not better than for the matched controls [22]. In another study by the same group, it was shown that no specific human leukocyte antigen (HLA) is a risk factor for the recurrence of IgAN in renal grafts and that cumulative graft survival was not reduced in living versus cadaveric donor recipients [23].
The aim of a study performed recently in Finland and Spain was to determine the incidence of IgAN recurrence, as assessed by protocol biopsies during the first 2 years after transplantation, and to determine predictive factors for the recurrence [24]. IgA recurrence rate was 32 %. The histological diagnosis was not accompanied by abnormalities in the urinalysis in half of the patients. Full DR match in HLA analyses and the use of cyclosporine were factors associated with non-recurrence [24].
A broad spectrum of clinical presentations and variable prognosis is typical for IgAN. The genetic risk of IgAN, based on replicated genome-wide association studies, is highest in Asians, intermediate in Europeans, and lowest in Africans, and there seems to be increased prevalence of kidney failure in Northern Europe [25]. Country-specific prevalence of IgAN demonstrates a trend for increased risk in the Nordic countries, with the highest prevalence in Northern European countries Sweden, Finland, and Iceland, while the prevalence is lower in Norway and in Denmark [25].
13.3 Pathogenesis
In a Finnish study almost 30 years ago, a single dose of subcutaneously administered inactivated mumps virus vaccine was administered to male patients with IgAN and IgM glomerulonephritis and to healthy controls. It turned out that IgAN patients were high responders for IgA and IgG antibody production, whereas patients with IgM glomerulonephritis were low responders, especially for IgA antibody production [26].
In the second vaccination study by the same group, oral polio vaccine was examined in 51 IgAN patients and 44 healthy controls [27]. Again, IgAN patients showed an enhanced antibody response compared with controls, and they presented with higher frequency of strong increases in neutralizing antibody titers as well as higher levels of virus-specific IgA-class antibodies. The responses in IgG-class antibodies showed similar activity in both groups. The IgA antibodies synthesized by the patients seemed to be functionally competent antibodies. It was concluded that in IgAN patients, augmentation of antigen-specific IgA response occurs and is induced by different antigens and via different routes of inoculation [27].
In a Swedish study, stimulation of peripheral blood monocyte cells with a polyclonal activator resulted in a threefold increase in synthesis of both IgA subclasses with a preference for IgA1 ribonucleic acid (RNA). It was concluded that increased cytokine production and hyperresponsiveness to polyclonal stimulation may play an important role in the increased synthesis of IgA in IgAN [28].
Swedish authors have demonstrated that patients with IgAN have circulating IgA antibodies against collagen IV alpha chains [29]. In another study from Sweden, the occurrence of anti-C1q antibodies was demonstrated in both IgAN and systemic lupus erythematosus (SLE) nephritis, which was considered to suggest a similar pathogenic mechanism involved in these renal disorders [30]. In one study, the degree of monocyte activation as measured by monocyte respiratory burst was studied in IgAN. The study demonstrated a higher monocyte respiratory burst in patients with IgAN when compared to the cells obtained from healthy controls, as well as a significant reduction in this parameter after a relatively short time (1 month) of treatment with 20 mg of atorvastatin daily [31].
A recent study from Iceland was set up to determine if defective glycosylation might promote IgA antibody deposition and subsequently influence the clinical prognosis in IgAN [32]. The subjects included 44 patients and 46 controls, and it turned out that increased IgA glycosylation in IgAN was associated with low levels of IgA, concomitant glomerular IgA1 and IgA2 deposits, and poor clinical outcome. Altogether, about 20 % of the patients had detectable glomerular IgA2 deposits [32]. One Japanese group has also reported IgA2 in the glomerular deposits of some IgAN patients [33].
The role of streptococcal infection in IgAN has been studied by Swedish authors. They have shown that mesangial IgA deposits co-localize with streptococcal IgA-binding regions of M proteins [34], and that children with IgAN have high antibody levels to IgA-binding streptococcal M proteins [35]. In a recent report, they demonstrated that IgA-binding M4 protein binds preferentially to galactose-deficient polymeric IgA1 and that these proteins together induce excessive pro-inflammatory responses and proliferation of human mesangial cells. Thus, tissue deposition of streptococcal IgA-binding M proteins may contribute to the pathogenesis of IgAN [36]. These findings are interesting as B cells in the tonsil may be linked to the production of nephritogenic galactose-deficient IgA, which subsequently induces polymeric IgA1 and IgA/IgG immune complex formation [37].
In another Swedish study, the gene and protein expression of proteoglycans were investigated in biopsies from 19 IgAN patients and 14 healthy kidney donors [38]. Distinct patterns of gene expression were seen in glomerular and tubulointerstitial cells. Three of the proteoglycans investigated were found to be upregulated in glomeruli: perlecan, decorin, and biglycan. Perlecan gene expression negatively correlated with albumin excretion and progress of the disease. Abundant decorin protein expression was found in sclerotic glomeruli, but not in unaffected glomeruli from IgAN patients or in controls. Transforming growth factor beta (TGF-ß) was upregulated both on gene and protein level in the glomeruli. Upregulation of biglycan and decorin, as well as TGF-ß itself, indicated that the regulation of TGF-ß, and other profibrotic markers could play a role in IgAN pathology [38].
13.4 Genetics
Immunoglobulin heavy chain switch region gene polymorphism was studied in three European populations. Patients and controls from the UK, Italy, and Finland were included. It was concluded that these genes are not important in conferring disease susceptibility to IgAN in any of the countries studied [39].
In another study, HLA-DP gene polymorphism was studied in the same above three European populations to determine whether ethnic variation exists in the genetic susceptibility for IgAN [40]. The frequency distribution of the DPA1 and DPB1 fragments was found to be similar between these Caucasoid IgAN patient groups when compared with their respective controls. These results suggested that HLA-DP region genes were not important in conferring disease susceptibility to IgAN and did not influence clinical disease expression [40].
The third study with the same three IgAN populations did not demonstrate a consistent association between HLA-DQ region and IgAN [41]. It was concluded that there is no single DQ allele which predisposes to IgAN in these populations. The proportion of patients presenting with macroscopic hematuria and renal impairment varied between the three groups, and this might have influenced the results [41].
Complement component C4 phenotyping and C4 isotope quantification were performed in 93 IgAN patients from Southern Sweden. Phenotype frequencies did not deviate from those of healthy controls. However, the findings suggested that homozygous C4A deficiency predisposes to the development of end-stage renal failure in IgAN [42].
In a material of 168 IgAN patients from Finland, it was shown that patients with angiotensin-converting enzyme (ACE) genotype II (insertion-insertion) have a more favorable prognosis than those with genotypes ID/DD (deletion-deletion). In patients with the ACE genotype II, renal function deteriorated very seldom, and the degree of proteinuria decreased during the follow-up when compared with proteinuria observed at time of diagnosis [43].
Another study from Finland evaluated the polymorphism of the important cytokine genes of inflammation interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1RA) in 167 patients with IgAN and 400 healthy controls. The carriage of ILß2 and IL1RN*2 together with non-carriage of TNF2 increase the risk of IgAN fivefold. However, no association was found between IgAN progression and cytokine gene polymorphism during the follow-up time of 6–17 (median 11) years from renal biopsy [44].
Genetic factors that predispose to sporadic IgAN were investigated in a high-throughput single nucleotide polymorphism (SNP) association study in 732 patients with biopsy-proven IgAN and 503 control subjects from Canada, France, and Finland. Two significant association signals were found at IL5RA and TNFRSF6B, the latter being a gene that encodes a decoy receptor for a TNF family ligand that causes IgA in mice when overexpressed [45]. As discussed by the authors, they were unable to confirm a previous report that found a genetic association at the selectin gene cluster with IgAN in Japanese patients [46].
A group from Sweden has studied many genetic factors in a clinical material of about 200 biopsy-proven IgAN patients. They have found that TGF-ß1 gene is an important contributor to the susceptibility to IgAN, but no differences in genotype frequencies between the non-progression and the progression groups of the patients could be found [47]. In another study by the group, interferon regulatory factor 5 (IRF5), signal transducer and activator of transcription (STAT4), and TNF receptor-associated factor 1-complement component 5 (TRAF1-C5) polymorphisms did not show an association with susceptibility and/or severity of IgAN. Further, the results did not support an overlap in genetic susceptibility between patients with lupus nephritis and IgAN [48]. There was no association between CD89 gene polymorphism and susceptibility to IgA, but there was an association between the levels of soluble CD89-IgA complexes in serum and the severity of IgAN [49]. In the cohort of Swedish Caucasian IgAN patients, it was found that the variants of HLA-DRB1 were associated with IgAN, of which the HLA-DRB1*03 revealed a strong protective effect of IgAN. The conclusion was that involvement of adaptive immunity may be of importance in the development of IgAN [50].
13.5 Etiology
IgAN was originally described as a primary glomerulonephritis [1] and was also found in patients with the Henoch-Schönlein syndrome (HSS) [51]. Soon thereafter, it was found that glomerular IgA deposits are often present in patients with alcoholic liver cirrhosis [52]. Primary IgAN and HSS are considered to be parts of the spectrum of IgA-related diseases [53]. A clinical spectrum was also visible in a previous Finnish material, as some patients had a fully developed HSS and some only had a purpuric rash in addition to IgAN [54].
13.5.1 Associated Diseases
In two Finnish studies, associated diseases were found in 54–62 % among IgAN patients [54, 55]. These diseases did not include various acute infectious illnesses that are known to provoke the clinical manifestations of IgAN. Interestingly, in many of these diseases, a high serum IgA concentration has been documented: ankylosing spondylitis, psoriatic arthritis, systemic lupus erythematosus, rheumatoid arthritis (RA), idiopathic pulmonary siderosis, chronic bronchitis, pulmonary fibrosis, sarcoidosis, alcoholic liver cirrhosis, celiac disease (CD), HSS, scleroderma, and certain neoplastic diseases as discussed below [54, 55].
Case reports of IgAN associated with chronic viral infections such as hepatitis C and B and human immunodeficiency virus (HIV) have been reported in the literature. However, the prevalence of these infections is quite low in the Scandinavian countries as compared to many other parts of the world. This may explain why no such reports have emerged from Scandinavia.
In many reports during the 1970s and 1980s, IgAN was reported to coexist with several types of diseases including rheumatic, gastrointestinal, hepatic, dermatologic, ophthalmologic, hematologic, neoplastic, and unclassified diseases, as reviewed by Mustonen and Pasternack [55]. In 1984, Australian authors suggested that IgAN should be regarded as a syndrome, and they divided IgAN into primary and secondary forms [56].
One study examined whether there were any differences in the clinical, histopathologic, or immunologic features in IgAN between the patient groups with associated diseases and those without any extrarenal diseases [57]. The only discovered differences were higher prevalence of renal interstitial cell infiltrates and IgA deposited along glomerular capillary walls in patients with associated diseases. No differences were observed in the severity or prognosis between these two groups of patients [57].
Without an understanding of the pathogenesis of primary IgAN, it remains difficult to dissect out those diseases in which there is only an association with primary IgAN by chance versus those diseases in which there might be shared pathophysiology [58].
13.5.2 Malignancies
In 1978, two IgAN patients with bronchial carcinoma and Henoch-Schönlein purpura were described [59]. Later, we reported two cases of patients with a bronchial small cell carcinoma coexisting with IgAN [60]. One of the patients had also a purpuric rash suggestive of HSS. It was calculated that a causal relationship between bronchial carcinoma and IgAN was very likely [60]. Some years later, we reported four more IgAN patients with a malignancy: carcinoma of the tongue, nasopharyngeal papilloma, retroperitoneal liposarcoma, and pancreatic carcinoma [61]. Interestingly, many of these malignancies affect mucosal membranes and have been shown to associate with high serum IgA levels. As we concluded then, the relationship between neoplastic diseases and IgAN still remains unresolved [61].
13.5.3 Rheumatic Diseases
The prevalence of IgAN in the Finnish population has been estimated to be 1.3 % [6]. The corresponding prevalence in a Finnish renal biopsy material of patients with RA was 8 %, which suggests that IgAN is more common than expected in patients with RA [62]. Among 37 RA patients with mesangial glomerulonephritis (MesGN), there were two main patterns of the nephropathy. Immunofluorescence study showed mesangial IgM deposits as the sole or main finding in 25 patients [62]. This finding closely resembles morphologically the so-called IgM nephropathy [63]. IgAN was found in 9 out of 37 patients. The biopsy indications were quite liberal, since five of these patients had microscopic hematuria and proteinuria, while four subjects had only hematuria as the clinical manifestation of IgAN. The intensity of mesangial IgA deposition, graded from – to +++, correlated significantly with the age of the patients, duration of RA, class of functional capacity, erythrocyte sedimentation rate, and especially with the serum IgA level in the whole group of 37 patients. The prevalence and the concentrations of IgA-rheumatoid factor (RF) were especially high in patients with IgAN [62]. It was suggested that RFs may be involved in the renal injury in these patients and that MesGN represents an extra-articular manifestation of the basic rheumatic disease [62]. Mesangial proliferative glomerulonephritis with IgA deposits has also been reported to be the most common type of nephropathy in Japanese patients with RA [64]. The authors suggested that IgA-RF may play little pathogenetic part in the development of IgAN in RA [64].
13.5.4 Celiac Disease and Intestinal Tract
In 1983, we documented the occurrence of IgAN in three patients with CD, two of whom had also dermatitis herpetiformis (DH) [5]. Both CD and DH are characterized by gluten-sensitive enteropathy. All patients presented with elevated serum IgA levels as well as dermal IgA deposits either in the papillary pattern typical of DH or within the dermal vessel walls.
Glomerular immunopathology was studied in 25 patients with newly diagnosed CD [65]. None of the subjects had any clinical signs of renal disease. Glomeruli were obtained by atraumatic fine-needle aspiration biopsy [66], and the specimens were studied by indirect immunofluorescence for immunoglobulin and complement [67]. Mesangial IgA deposits were found in eight (32 %) of the patients, but C3 was not present in any of them. IgA-class circulating immune complexes, antireticulin and antigliadin antibodies, as well as IgA-RF occurred more often in patients with IgA deposits than in those without mesangial IgA. These results suggested that glomerular IgA deposits are frequently present in untreated CD without inducing overt clinical glomerulonephritis [65].
To clarify possible intestinal mucosal involvement in IgAN, 17 patients with IgAN underwent gastroscopic examination and small bowel mucosal findings were studied [68]. In all specimens, the mucosal architecture was normal. The amount of gamma-delta T cells and the total amount of T cells, as indicated by cluster of differentiation 3+ (CD3+) positivity, were both significantly increased in IgAN patients when compared to patients who had undergone gastroscopy because of dyspepsia and who served as controls. The number of alpha-beta T cells was also higher in IgAN patients. Villous epithelium of the patients disclosed a significant increase in the expression of HLA-DR antigen and GroEL stress protein. A conclusion was made that ongoing small bowel inflammation and stress are present in IgAN. Despite normal morphology that excludes CD, there is reason to believe that intestinal mucosa is involved in the pathogenesis of IgAN [68].
Intestinal inflammation in IgAN was further studied by using duodenal biopsy specimens of the same 17 IgAN patients as above [69]. The amount of CD3+ cells and cyclooxygenase-2 (COX-2)-positive cells was significantly increased, and J-chain-producing plasma cells were decreased in IgAN patients compared to controls. CD3+ cells were coexpressed with COX-2 protein and COX-2-positive cells also expressed CD45RO antigen. The number of lymphocytes and COX-2 expression correlated with serum IgA level. COX-2-positive subepithelial fibroblasts were a conspicuous finding in IgAN. Also, in CD68+ and CD15+ cells, a significant increase was seen. These results clearly indicate that small bowel inflammation in IgAN is presented as an increased number of mucosal inflammatory cells. However, polymeric IgA production is decreased. Active intestinal inflammation in IgAN was strongly related with serum IgA, proteinuria, and hematuria. Subepithelial bowel fibroblasts seemed also to be involved in the process [69].
CD is strongly associated with the HLA-DQ2 and DQ8 haplotypes [70]. In one study, we sought to establish how common CD is in patients with IgAN and whether the possible association can be explained by similar HLA-DQ status [71]. A total of 223 adult patients with IgAN were studied. Eight patients (3.6 %) with IgAN were found to have also CD. All CD cases had the HLA-DQ2 or HLA-DQ8 haplotype, but these haplotypes were not more common in 168 IgAN patients eligible for haplotyping than in their controls. As many as 14 % of HLA-DQ2-positive patients with IgAN had CD. It was concluded that patients with IgAN carry a risk of contracting CD. This association cannot be explained by a similar accumulation of HLA-DQ haplotypes. A hypothesis was presented that increased intestinal permeability in IgAN may predispose genetically susceptible patients to CD [71].
In a Swedish population-based prospective cohort study comprising 27,160 individuals with CD and no previous renal disease, seven (0.026 %) individuals with CD developed IgAN. An increased risk of biopsy-verified IgAN among individuals with CD was threefold, even after adjustment for prior liver disease and country of birth [72].
Rectal mucosal inflammatory reaction to gluten was examined in 27 patients with IgAN and 18 controls in a study performed by authors from Sweden and Norway [73]. The rectal mucosal production of nitric oxide and release of myeloperoxidase and eosinophil cationic protein were measured. Gluten reactivity was observed in 8 of 27 IgAN patients but in none of the controls. A hypothesis was presented that subclinical inflammation to gluten might be involved in the pathogenesis of IgAN in a subgroup of patients [73].
A study made by the authors from Sweden, Norway, and Iceland evaluated rectal mucosal sensitivity to soy and cow’s milk protein in 28 IgAN patients by using a recently developed mucosal patch technique. Approximately half of the patients had a rectal mucosal sensitivity to these proteins, suggesting immune reactivity against these antigens in IgAN [74].
The aim of a recent study from the USA was to evaluate a large series of kidney biopsy specimens to define the spectrum and relative frequencies of inflammatory bowel disease (IBD)-associated kidney abnormalities [75]. Eighty-three of 33,713 renal biopsy specimens were from patients with IBD, so 54 cases were suffering from Crohn’s disease and 38 from ulcerative colitis. IgAN was the most common diagnosis in these patients, which suggested a shared pathophysiology between intestinal and kidney disease [75]. A previous Finnish material of 230 IgAN patients included only two cases with ulcerative colitis and none with Crohn’s disease as an associated disease [55].
In a recent comprehensive review by Coppo [76], a tempting new hypothesis for a strong intestine-kidney connection in IgAN was presented. This may include abnormal response to microbiota with alterations of the intestinal barrier, including increased absorption of alimentary antigens and bacterial toxins, triggering mucosal-associated lymphoid tissue (MALT) activation, and subclinical intestinal inflammation [76].
In a genome-wide association study (GWAS) of IgAN, six new significant associations were identified [77]. Interestingly, most of the loci found were either directly associated with the risk of IBD or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. Moreover, the study demonstrated significant overlap of these loci with the loci for other autoimmune and inflammatory disorders, such as RA, systemic sclerosis, alopecia areata, Graves’ disease, follicular lymphoma, and type 1 diabetes [77].
13.5.5 Vascular Diseases
In a material of 221 adult IgAN patients, we demonstrated that vascular diseases are notably common in them [78]. The patients had significantly more frequent coronary heart disease and cerebrovascular disease than the general population in Finland. Especially, patients with progressive IgAN had elevated risk of developing vascular disease. Vascular changes seen in renal biopsy specimens of the patients signify an elevated risk of vascular diseases [78]. This is interesting, as it is possible that IgA-mediated inflammation may modify the vascular injury associated with hypertension and atherosclerosis in IgAN [79]. To our knowledge, there are no studies published in which the incidence or prevalence of vascular diseases has been compared between IgAN patients from different countries.
13.6 Progression
In our own study, body mass index (BMI) was higher at the time of renal biopsy among those IgAN patients who showed progression of renal disease during follow-up when compared with those who did not progress [80]. In a French study, excessive body weight at the time of diagnosis has also been shown to be an independent risk factor for chronic renal failure in IgAN [81]. Moreover, it was recently reported in Japanese IgAN patients that even slightly elevated BMI is a risk factor for the progression of the disease [82]. Our group has observed in prospective studies that in addition to the well-known risk factors age, hypertension, and proteinuria, several metabolic factors such as hypertriglyceridemia, hyperuricemia, and hyperinsulinemia are also risk factors for the progression of IgAN [80, 83]. In another study, we evaluated the impact of inflammatory markers and observed that also sensitive C-reactive protein, serum albumin, and white blood cell count were associated with the progression of IgAN [84].
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