© Borgis - Postępy Nauk Medycznych 2/2013, s. 144-153
*Beata Sulikowska, Jacek Manitius
Nefropatia IgA – wybrane zagadnienia z uwzględnieniem chorych w wieku starszym
IgA Nephropathy – selected problems including older patients
Department of Nephrology, Hypertension and Internal Medicine, Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz
Head of Department: prof. Jacek Manitius, MD, PhD
Nefropatia IgA (IgAN) jest to rozplemowa postać kłębuszkowego zapalenia nerek (KZN) z masywnymi złogami IgA w mezangium. W chwili obecnej jest to najczęściej rozpoznawana postać kłębuszkowego zapalenia nerek na świecie. Stanowi od 25 do 50% wszystkich rozpoznań histopatologicznych bioptatów nerek. Ta częstość jest różna w poszczególnych regionach świata, co może zależeć zarówno od rzeczywistych różnic w występowaniu, jak i stosowaniu odmiennych wskazań do biopsji i kryteriów diagnostycznych. IgAN jest chorobą przede wszystkich ludzi młodych, szczyt zachorowań przypada na drugą i trzecią dekadę życia. Spotykana jest również u pacjentów starszych. Uważa się, że zaawansowany wiek może być jednym z czynników doprowadzających do szybszej progresji choroby nerek. W piśmiennictwie niewiele jest doniesień na temat nefropatii IgA u starszych pacjentów. Wynikać to może z faktu, że podstawą rozpoznania kłębuszkowych zapaleń nerki jest biopsja nerki. Natomiast u pacjentów starszych powszechna jest niechęć do wykonywania biopsji nerki, głównie w obawie przed jej powikłaniami. W niniejszej pracy podsumowano dostępne dane na temat epidemiologii IgAN w populacji ogólnej oraz w populacji ludzi starszych. Omówiono również stan wiedzy dotyczący rokowania i strategię postępowania terapeutycznego z uwzględnieniem populacji pacjentów starszych.
IgA nephropathy (IgAN) is a proliferative form of glomerulonephirits with massive residues of IgA in mesangium. Presently it is the most frequently diagnosed form of glomerulonephritis in the world. It constitutes from 25% to 50% of all histopathological identifications of kidney biopsy specimens. This frequency varies according to the world region, which could depend on both real differences in its occurrence and on utilizing different indications in biopsy or diagnostic criteria. IgAN is above all a condition of the young people, and the peak of falling ill is during their twenties and thirties. It does occur in older patients as well. It is believed that the advanced age may be one of the factors causing quicker progression of the kidney disease. In literature not much information can be found concerning IgA nephropathy in older patients. It may result from the fact that the basis for diagnosing glomerulonephrititis is kidney biopsy. However, in older patients reluctance to having a kidney biopsy performed is quite common, mostly due to fear of complications. In this paper available data concerning IgAN epidemiology was summarized, including both general population and the population of seniors. Moreover, the level of knowledge in regard to prognosis and the strategy of therapeutic actions while taking into account older patients’ population was discussed.
IgA nephopathy (IgAN) is a proliferative form of glomerulonephritis with massive residues of IgA in mesangium, which are frequently accompanied by residues of IgG, IgM, complement component C3 and membrane attack complex (MAC) (1).
IgAN was first described by Berger and Hinglais in 1968. Presently, it is the most frequently diagnosed form of glomerulonephritis in the world. It constitutes from 25 to 50% of all hitopathological identifications of kidney biopsy specimens. This frequency varies with regard to the particular world region, which may depend on both real differences on occurrence and utilizing different biopsy indications or diagnostic criteria. In Asian countries (Japan) IgA nephorpathy constitutes 50% of all glomerulonephritis instances, while in Europe it is from 10 to 25%. In the United States it is merely a few percent (2, 3). In Poland the frequency of IgAN occurrence is about 15-20% (4). Such variations in occurrence frequency could suggest genetic basis. In Japan, due to high frequency of the disease in children and young adults between the ages of 6 and 18, urine screening tests are performed, whose aim is to detect symptoms of the disease (5).
IgA nephropathy is the primary glomerulonephritis, but IgA residues may be confirmed by performing a kidney biopsy also during other diseases. Secondary deposits of IgA may occur in kidneys in i.a. coeliac disease, liver diseases, diabetes, chronic rheumatic arthritis, nonspecific inflammatory bowel disease, during progress of HIV, HBV, lymphomas and paraneoplastic syndromes in progress of lung and large intestine cancer (4).
IgAN is considered a disease of immunological complexes. In 50-70% of adult patients and in about 8-16% of children an elevated level of IgA is observed in blood serum (6). In vitro studies provided information that lymphocytes in peripheral blood circulation in patients with IgAN produce more IgA than the lymphocytes of healthy patients (7).
IgA occurs in two subtypes: IgA1 and IgA2. In blood serum 90% of total IgA is IgA1, while IgA2 is present in the tunica mucosa of digestive tract and respiratory system. IgA is secreted in digestive system and respiratory system in response to bacterial and viral antigens, moreover there is a potential correlation between infections in those systems and the development of IgA nephropathy. Identified specific antigens causing mesangial IgA deposits are a heterogenous group including: HSV, EBV, CMV and flu viruses, adenovirus, helicobacter pyroli, β-hemolyzing streptococci, Campylobacter, E. coli and food antigens (eg. gliadin/gluten). In response to those antigens, produced immunoglobulin A stimulates phagocytosis by means of Fc receptor localized on CD89 and it provokes the activation of the complement on the alternative or pectin pathway (8, 9).
IgA can occur as a monomer or a polymer (pIgA) connected with protein chain J. In healthy people most of their pIgA is produced by the immune system of tunica mucosa, however, iin patients with IgA nephropathy an elevated production of pIgA1 is observed in their bone marrow, while a decreased production is observed in tunica mucosa. Studies have shown that pIgA is the main component of the deposits in glomeruli. Such increased pIgA production is also noted in distant observation of patients with IgAN, in whom changes in urine remain, while it decreases during the period of clinical remission (ie. with demission of changes in urine: haematocyturia and/or albuminuria) (10, 11).
In patients with IgA nephropathy, IgA1 has an increased capability to join in larger conglomerates due to abnormal galactosylation in hinge region, so called O-glycosylation. This defect provides IgA1 with a more negative charge, which favors the deposition of IgA aggregates in mesangium and their bonding with fibronectin, laminin and collagen IV. In patients with IgA nephropathy beta 1,3-galactosyltransferase, responsible for attaching galactose to IgA, defect in B lymphocytes is observed. When healthy, IgA1 is catabolized in liver by merging with asialoglycoprotein receptor (ASGPR). In result of O-glycosylation, hepatic clearance of IgA1 is signifiantly lowered. The molecules of IgA1 with lower galactose content create immunological complexes which bond more easily with fibronectin, laminin and collagen IV in mesangium, and that provokes the origin of nonspecific inflammatory response, including the activation of complement C3, leading to the development of nephropathy (10-12).
Mesangial cells express increased activity of ASGPR and they are able to produce pIgA1 nad C3 in IgAN. Proliferation of mesangium cells in IgAN also occurs by means of stimulating transferrin receptor (TfR), which preferentially bonds pIgA1, IgA1 complexes and defectively glicosylated IgA1, it moreover causes secretion of interleukin 6 (Il6) and TGF-β (transforming growth factor-β) (13).
In the pathogenesis of IgAN, participation of immunological complexes IgA-IgG is observed. Their significantly higher level occurs in patients with IgAN when compared to the patients with other types of glomerulus.
Polymeric form of IgA1 induces the expression of genes in the renin-angiotensin system and TGF-β to a significantly greater extent than its monomeric form, which proves its participation in the progress of chronic inflammatory process and kidney fibrosis. TGF-β stimulates proliferations of mesangium cells, however impeding its secretion leads to decrease in accumulation of extracellular matrix proteins (10, 11).
In patients with IgA nephropathy mesangium cells produce platelet-derived growth factor (PDGF) and PDGF B chain, which stimulate mesangium proliferation. In the studies on experimental glomerulonephritis model it was shown that impeding secretion of these factors results in decrease in mesangium proliferation (10, 11).
In IgA nephropathy an elevated presence of macrophages CD68 in the inflammatory infiltration of the interstitium is observed together with an increase in local proliferation in animal experimental subjects, which plays a great role in immunological response, intensification of the inflammatory process in the kidneys and tubulointersitial lesion (10, 11).
In IgAN pathogenesis genetic predisposition is thought to have an important role. It was proven that there was a correlation between histocompatibility antigens HLA Bw12, Bw35 and Bw37, as well as HLA DR1 and DR4, and the progress of IgA nephropathy. German studies have informed that about 10% of subjects with IgAN had one or more relatives with glomerulonephritis (14).
What is also described is the influence of polymorphism of angiotensin converting enzyme (ACE) gene and renin-angiotensin gene system on IgAN progress. The issue of most value for genetic studies of IgA nephropathy is so called ACE I/D polymorphism. “I” indicates insertion – the presence of intron 16, which in the final effect decreases ACE activity, while “D” stands for deletion, which is the lack of said intron leading to the increase in ACE activity. Genotype’s property is that of forming ACE activity in tissues and plasma, and the highest activity was observed for homozygote DD. Angiotensin II, which originated due to ACE involvement, intensifies fibrosis and hypertrophy in target cells, including kidney. There, it stimulates collagen production, causes an increase in TGFβ and PDGF concentration in mesangium and epithelium of proximal convoluted tubules. It was proven that the frequency of genotype DD is significantly higher in patients whose clinical progress is characterized by quicker development of chronic kidney disease and can be a marker for unfavorable prognosis for the progress of IgA nephropathy. It was stated that patients with genotype DD and ID exhibit significantly higher albuminuria, sclerosis and adhesion with Bowman’s capsule in the glomeruli, as well as tubulointersitial lesion when compared to patients with genotype II. It is thought that I/D polymorphism is related to the process of chronic kidney damage, however it does not influence the acute phase of this process (15).
In light microscope a diffuse or segmented proliferation of mesangium is observed, and in more advanced stages – hardening of glomeruli and fibrosis of stroma. The condition of diagnosis is exhibiting mesangial residue of IgA.
Those residues may be accompanied by residues of IgM, IgG and C3. A third of studies under electron microscope state dense immunological residue and thinning of glomerular basement membrane (GBM). Histopathological changes are presented in table 1 (1).
Table 1. Histopathological changes in IgA nephropathy according to Hass.
| ||Classification||Histopathological features||10-year life span of kidney function (%)|
|I.||Minimum changes||Minimum proliferation in mesangium.||90|
|II.||Focal segmental hardening||Resembles primary FSGS without the crescents.||90|
|III.||Focal profilerative glomerulonephritis||< 50% of glomeruli with proliferation, a possibility of crescents, majority of lesions is segmental.||55|
|IV.||Diffuse proliferative glomerulonephritis||> 50% of glomeruli with proliferation, a possibility of crescents.||20|
|V.||Advanced chronic glomerulonephritis||> 40% of fibrated glomeruli and > 40% of tubules atrophy.||20|
IgA nephropathy is more frequent in men (3:1). Macroscopic haematuria is the most frequent manifestation of the disease, reported by 40-50% of patients. Haematuria may occur for the first timeduring or a few days after an infection of the upper respiratory tract, less frequently one of digestive tract, and it can recur during other infections. Urine usually is brown (not red) and it does not contain blood clots. First symptoms in adults occur in their twenties and thirties. Haematuria, on occasion together with pain in the loins area, can last from a few hours up to a few days. During an intense haematuria a decrease of glomeruli filtration is noted in about 40% of patients and usually it is irreversible.
In 30-40% of patients asymptomatic haematuria and albuminuria are sole symptoms of of IgA nephropathy and frequently isolated haematuria occurs without albuminaria. It extremely rare for albuminaria and nephrotic syndrome to express without haematuria. Nephrotic syndrome is observed in about 10% of patients. Arterial hypertension occurs in about 20-40% of patients. In clinical image an acute kidney failure can be observed. It is a result of great intensification of inflammatory changes, with extracapillary proliferation and crescents or a result of renal tubules obturation by erythrocytes during major haematuria. Both situations are relatively rare.
In previously undiagnosed cases first symptoms of the disease can be the symptoms of advanced chronic kidney failure, which is frequently accompanied by severe arterial hypertension (16).
IgAN is first of all a disease of young people, peak of acquiring it is when they are in their twenties or thirties. It can also be observed in older patients. It is thought that advanced age can be one of the factors leading to fast progression of kidney disease.
There is not much information in literature concerning IgA nephropathy in older patients. It may result from the fact that the basis for diagnosing glomerulonephritis is kidney biopsy. However, in older patients reluctance towards kidney biopsy is quite common, mostly due to their fear of complications. It is contradicted by the results of analysis of complications which occurred after an Indian study (17). 210 patients underwent a biopsy, including 26 in advanced age (61 to 78). One of the most frequent complication in older patients was haematuria (4 in 26 patients when compared to 7 in 186 among younger patients). Three patients had haematuria for one – two days and one patient for a week. Among older patients haematuria of such intensification was not observed that it would require blood transfusion or cause hemodynamic disorders. This group did not exhibit such complications as haematoma or the need of surgical intevention. In literature it is emphasized that prior to kidney biopsy in older patients one cannot suddenly lower blood pressure with calcium blockers because it can cause bleeding as a result of vasodilation of the intrarenal vessels changed with age and inhibiting platelet functions (18).
An interestin epidemiological study analyzing the frequency of occurrence of glomerulonephritis in one region in France inhabited by nearly 400 thousand caucasian people is a study published by Simon et al. (19). During 14 years 942 kidney biopsies were performed there, and primary glomerulonephritis was diagnosed in 480 patients (51%). IgAN was the most frequently observed type of nephropathy (33,4%) in those patients. Diffusion of this glomerulonephritis was 1.9 in 1,000 citizens, 3.3 in 1,000 men and 1 in 1,000 women. The difference in the frequency of occurrence depending on sex was strongly marked in the population between the ages of 10 and 19, while the weakest differences were observed between the ages of 60 and 79. IgAN is the most frequent type of glomerulonephritis up to the age of 59, however, at the ages 60 to 79 the most frequent type of glomerulonephritis is membranous nephropathy, rapidly progressive glomerulonephritis and IgAN. In the mentioned study IgAN and rapidly progressive glomerulonephritis are the most frequent causes of irreversible chronic kidney failure.
Another epidemilogical study analyzing frequency of glomerulonephritis occurrence in one of the regions of China is a study published by Wu et al. (20). In the period of 5 years 1550 kidney biopsies were performed, based on which primary glomerulonephritis was diagnosed. IgAN was second most frequent type of nephropathy diagnosed (24.5%) in all biopsied patients. However in the group of senior patients older than 60 (N = 42 subjects) it was diagnosed in only 9.5%. Authors of this study do not provide the information concerning criteria for biopsy in older patients. However, in the whole biopsied group nephrotic syndrome occurred in 60% of patients.
Next epidemiological study analyzing frequency of glomerulonephritis in older patients in Irish population is a study published by Brown et al. (21). In the period of 5 years 1372 kidney biopsies were performed there, including 234 (17%) on patients older than 65. The oldest patient was 90 years old. The most frequent biopsy indications were: acute kidney failure (32%), nephrotic syndrome (25%), albuminuria (8%). Other, more rare causes were elevated creatinine concentration, exacerbation of chronic kidney failure, diabetes, arterial hypertension. In studied population of older patients IgA nephropathy was diagnosed in 7.6% of patients (as fourth most frequent) and was significantly more rare diagnosis than rapidly progressive glomerulonephritis (17.4%), tubulointerstitium diseases (11%), membranous glomerulonephritis (9%). Authors of this study do not analyze treatment in those patients. However, they summarize that a group of 102 patients who under observation having a biopsy had a creatinine concentration of 427 umol/L, and after three years a mean of 192 umol/L. Authors in their final conclusions emphasize a very crucial role of kidney biopsy also in the group of older patients, which according to them is important not only in diagnosis but it significantly influences prognosis and treatment.
Presently, we do not have such detailed study at our disposal concerning Polish population. Great hopes of obtaining epidemiological data are connected with efforts put into founding Polish Register of Nephropathy.
Observations concerning differences in clinical and pathomorphological image of younger and older patients with IgAN are published in literature.
One of such studies concerning Polish population analyzed a group of 64 patients with IgA nephropathy, where 14 patients was older than 45 (22%). In all patients haematuria and haematocyturia were observed. A detailed analysis revealed that in younger patients intense haematocyturia was more frequent. Albuminuria of various intensity occurred in almost every patient. However, proteinuria of medium and high level predominated in the group of older patients. Creatinine concentration above 1.5 mg/dl was comparable in both groups. Arterial hypertension occurred in statistically significant manner in the group of older patients. In microscopic study of renal biopsy specimens in all patients extensive, proliferative, mesangial glomerulonephritis of various degree of intensity of changes in glomeruli and interstitium was diagnosed. Intensification of mesangial proliferative changes in glomeruli was more frequent in younger patients, however, in older patients adhesion and agglutination in the glomeruli area was observed. Segmental or complete hardening of glomeruli was more frequent in the group of older patients. Similarly, in the group of older subjects a considerable atrophy of tubules and focal proliferation of connective tissue in intertisium as well as features of arterioles hardening were observed statistically significantly more frequently. Authors of this study in their summary state conclusions consilient with data available in literature, that differences shown in both groups of subjects concerning intensification of clinical changes (higher albuminuria and higher proportion of hypertension in the group of older patients) and differences in the degree of kidney lesions (particularly greater intensification of interstitium changes in the group of older patients) support a worse prognosis in this group of patients.
In prospective study of Frimat et al. (23) concerning French population in the vicinity of Nancy, clinical image and disease progress of patients with IgA nephropathy over 50 (mean age about 62) – a group of 96 patients, and under 50 (mean age about 30) – a group of 33 patients – were compared. Older patients originally (at the time of the kidney biopsy) had higher contractile arterial pressure readings, higher albuminuria and lower creatinine clearance than younger patients. In this study no significant, statistically important differences were stated in kidney biopsy specimens between both groups, older patients had more intense changes in arteries. During a 40 month observation there were significantly more deaths in the group of older patients than younger ones (respectively 5 vs. 1 death) for reasons other than nephrological. There were no differences in the progress of chronic kidney disease in both groups, and the final point ie. the necessity of renal replacement therapy (dialysis or kidney transplant) reached a comparably identical proportion of subjects in the group of younger and older patients (15% vs 18% – differences not statistically significant).
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