Overview
IgA nephropathy, first described by Berger in 1968, is a group of glomerular diseases characterized by thylakoid hyperplasia and significant diffuse IgA deposition in the thylakoid region. IgA nephropathy can be divided into primary and secondary types, the latter often secondary to liver cirrhosis, intestinal diseases, arthritis, herpetic dermatitis and other diseases, and is also characterized by significant IgA deposition in the glomerular thylakoid region. Primary IgA nephropathy is considered to be one of the most common forms of glomerulonephritis in many parts of the world and is a common cause of end-stage renal failure, and this section focuses on primary IgA nephropathy.
Epidemiology
The disease relies on pathologic diagnosis and therefore its prevalence in the general population is not clear. The available epidemiological data are based on the number of kidney biopsies and even kidney disease hospitalizations during the same period. The Nephrology Group of the Chinese Academy of Pediatrics counted 168 cases of IgA nephropathy (7.3%) among a total of 2315 kidney biopsies from 1979 to 1994 in 20 units nationwide. The disease is more common in older children and adults. In primary glomerular disease renal biopsies, IgA nephropathy accounts for about 10% in North America, 10%-30% in Europe, the highest in Asia Pacific, 30% in China, and even up to 50% in Japan.
Etiology
The etiology is not well understood and is related to a variety of factors. Most scholars believe that the disease is caused by the deposition of circulating immune complexes containing IgA in the kidney. The antigens in the complexes may be related to viruses or bacteria infecting the mucosa of the respiratory or gastrointestinal tract, or to certain components of food.
Pathogenesis
1. Pathogenesis. Because of the deposition of IgA, C3 and/or IgA and IgG in the kidney tissue, IgA nephropathy is a kind of immune complex nephritis, and its pathogenesis is closely related to IgA immune abnormalities, and the relevant studies have now penetrated to the level of IgA molecular structure.
(1) Structure and characteristics of immunoglobulin A: IgA is an important immunoglobulin, accounting for about 15.2% of total serum immunoglobulins. 80% of serum IgA is in the form of four chains of monomers, and the connection between monomers is stabilized by disulfide bonds and J-chains. IgA is divided into 2 serotypes, IgA1 and IgA2, depending on the antigenicity of the alpha heavy chain.
IgA1 is the major subtype in serum, accounting for 80% to 90%, while IgA2 accounts for only 10% to 20%. IgA1 stranded chain region is one times longer than IgA2, and IgA2 can be divided into IgA2m(1) and IgA2m(2), although the serum IgA2 concentration is only 1/4 of IgA1, but the 1gA2 concentration in secretory fluid is equal to IgA1. In the structure of IgA2m(1), there is no disulfide bond between the α chain and the light chain, which are connected by non-covalent bonds, but there are disulfide bonds between the light chain and the α chain.
Another form of IgA is called secretory IgA (SIgA), which is found in human exocrine secretions, such as saliva, tears, intestinal secretions and colostrum. Secretory IgA differs from the serotype in that it is a dimeric molecule with a J chain and another exocrine component (SC), forming the (IgA)2-J-SC complex. The serotype, on the other hand, is composed of (IgA)2-J.
The J chain consists of 137 amino acids, has a molecular weight of 1500 and is an acidic glycoprotein containing 8 cystine residues, 6 associated with the formation of disulfide bonds within the chain, while 2 are associated with the attachment of the α chain. The α chain is known to have 18 additional amino acid residues at the C-terminus, and the J chain is linked to the α chain by a second cysteine residue at the C-terminus of the α chain. Both are produced by plasma cells and are joined together at the time of secretion.
SC is synthesized by epithelial cells in mucosal tissue or secretory glands and is linked to one of the 2 monomeric IgA of human SIgA by a disulfide bond. SC is a polypeptide chain of 549 to 558 amino acids with a molecular weight of about 70,000 and a glycosyl content of up to 20%. There are 5 homologous regions on its polypeptide chain, each homologous region consists of 104, 114 amino acids, and these homologous regions are similar to Ig in steric structure. The conformation of SIgA may be: (i) a stacked Y arrangement; (ii) an end-to-end arrangement, where two IgA are connected by the Fcα region to form a double Y structure.
(IgA)2-J produced by local tissue plasma cells is secreted out by: (i) binding to SC on the basolateral surface of epithelial cells and forming IgA-J-SC, which is transferred to the apical surface in a vesicle; (ii) (IgA)2-J enters the circulation via lymphatic vessels, is cleared by binding to SC on the surface of hepatocytes, and is then transferred to the bile duct and finally to the intestine via the vesicle mechanism of hepatocytes.
In addition, IgA has a tendency to form complexes with other proteins, which is due to the easy formation of intermolecular disulfide bonds between the amino acid residues of the alpha chain. These characteristics of IgA molecular structure are important in the development of IgA nephropathy.
(2) IgA deposition in the glomerular thylakoid region: In IgA nephropathy, the mode of IgA deposition is parallel to the pathological changes in the glomerulus. IgA deposition in the thylakoid region is accompanied by thylakoid hyperplasia, and deposition on capillaries is accompanied by changes in the vascular endothelium.
The pathological factors that cause IgA deposition are: (1) entry of antigens from the mucosa and stimulation of the IgA immune system, with a wide range of antigen components including microorganisms, food (ovalbumin, bovine serum albumin, casein), etc. (ii) Abnormal IgA immune response leads to the formation of high molecular weight polymorphic IgA. ③Polymorphic IgA bound to antigen is deposited in the kidney by electrostatic (λ-chain), receptor (FeaR) or binding to fibronectin, and IgA-fibronectin complexes in serum have been found to be characteristic of IgA nephropathy. ④ Impairment or saturation of other IgA clearance mechanisms (e.g., liver).
Available studies have shown that IgA deposited in the glomeruli in IgA nephropathy is mainly multimeric λ-IgA1, and increased levels of serum IgA1, multimeric IgA, and λ-IgA1 are seen in patients with IgA nephropathy. Patients have a defect in β-1,3 galactosyltransferase (β-1,3GT) in B cells, which leads to a decrease in terminal linked galactose upon O-glycosylation of the stranded region of IgA1. This alteration may affect IgA1 binding to the oligosalic acid protein receptor (ASGPR) on hepatocytes and affect IgA clearance, and can increase its binding to kidney tissue while deposited.
Using in situ hybridization, Harpel et al. found that IgA nephropathy intestinal mucosa expressed reduced levels of J-chain mRNA, an essential component for the synthesis of polyIgA, while bone marrow was elevated. In addition, tonsillar PIgA1 production was increased. Since tonsillar PIgA production is much lower than that of mucosa and bone marrow, PIgAl deposited in renal tissues may mainly originate from bone marrow rather than tonsils and mucosa.
(3) Immune abnormalities in IgA nephropathy: Extensive studies of humoral and cellular immunity in IgA nephropathy have demonstrated the presence of immune abnormalities in patients with IgA nephropathy, including.
(1) autoantibodies: Fornesier et al. have identified antibodies against the cytoplasmic macromolecular components of renal thylakoid cells in the sera of patients with nephropathy. There are also antibodies against basement membrane type I, II and III collagen fibrillar mucin, Gliadin and other components. IgA anti-neutrophil cytoplasmic antibodies (IgA-ANCA) were also found in the blood of some patients. 40% to 50% of IgA nephropathy reappeared in the transplanted kidney after receiving a homologous kidney transplant, which indicates that autoantibodies play an important role in the development of IgA nephropathy.
The decrease in IgA-specific inhibitory T-cell activity leads to an increase in IgA synthesis by B-lymphocytes. the number of T-helper cells (Th) is also increased during the active phase of IgA nephropathy, so that Th/Ts are increased during the active phase. T cells with IgA-specific receptors are called Tα cells, and Tα cells have a role in increasing IgA production. It has been found that IgA nephropathy, especially in patients presenting with sarcohematuria, has a marked increase in Tα, and the marked increase in Tα helper cells leads to an increase in IgA synthesis.
(iii) Cytokines and inflammatory mediators: Many cytokines are involved in the regulation of the immune system, including lymphokines, interleukin (IL), tumor necrosis factor, and peptide growth factor. These cytokines play an important role in the exercise of normal immune function and can also lead to dysregulation of the cytokine network under abnormal conditions, resulting in immune damage. Cytokines and inflammatory mediators (complement components MAC, IL-1, MCP-1, reactive oxygen species, etc.) play an important role in the process of glomerular tethered cell proliferation.
The HLA antigen loci associated with IgA nephropathy have been reported differently, with Bw35 in Europe and the United States, DR4 in Japan and China, and DRWl2 in the Han Chinese in northern China, in addition to B12, DR1 and IL-RN.2 alleles. ACED/D genotype related reports.
2, pathological changes characteristics. Light microscopy showed glomerular thylakoid hyperplasia, ranging from focal, segmental hyperplasia to diffuse thylakoid hyperplasia. Some of the more severe thylakoid hyperplasia can be seen as thylakoid insertion, forming segmental double tracks. Sometimes segmental glomerulosclerosis, capillary collapse, and balloon adhesions are also seen. Masson’s stain reveals a large number of complex-red deposits in the thylakoid region, and these deposits are of diagnostic value. The expression of type I, III and IV collagen and laminin, fibronectin was significantly increased in the glomerular capillary loops of IgA nephropathy, and the expression of type I and III collagen was also significantly increased in the thylakoid region, and the expression of type IV collagen in the tubular basement membrane was also increased in most patients.
Electron microscopy showed mainly varying degrees of thylakoid cell and stromal hyperplasia, with more electron-dense material deposited in the thylakoid region, and some dense material could also be deposited in the subendothelium. In recent years, ultrastructural changes in the glomerular basement membrane have been reported, and about 10% of IgA nephropathies have basement membrane thinning, whether this is a combination of thin basement membrane disease or a secondary change of IgA nephropathy is unclear.
WHO pathological classification of this disease.
(1)Grade I: Light microscopy most glomeruli are normal, with mild thylakoid hyperplasia with (not with) cellular hyperplasia in a few sites, called microscopic changes, without tubular and interstitial damage.
(2)Grade II: less than 50% of glomeruli had thylakoid hyperplasia, rarely sclerosis, adhesions and small crescent, called minor lesions, without tubular and interstitial damage.
(3) Grade III: Focal segmental or even diffuse glomerular thylakoid widening with cellular hyperplasia, occasional adhesions and small crescents, called focal segmental glomerulonephritis. Occasionally, there is focal interstitial edema and mild inflammatory cell infiltration.
(4) Grade IV: All glomeruli show marked diffuse thylakoid hyperplasia and sclerosis with irregularly distributed, varying degrees of cellular hyperplasia, and often desiccated glomeruli can be seen. Less than 50% of glomeruli have adhesions and crescents, called diffuse thylakoid proliferative glomerulonephritis. There is significant tubular atrophy and interstitial inflammation.
(5) Grade V: similar to but more severe than grade IV, with segmental and/or globular sclerosis, vitelliform changes, glomerular adhesions, and crescent bodies in more than 50% of glomeruli, called diffuse sclerosing glomerulonephritis. The tubular and interstitial damage is more severe than in grade IV.
Clinical presentation
The disease is most commonly seen in older children and young adults, with a male to female ratio of 2:1. The onset of the disease is often preceded by upper respiratory tract infections, and has also been reported to be triggered by diarrhea and urinary tract infections. The clinical manifestations are diverse, ranging from microscopic hematuria only to nephrotic syndrome, all of which can be manifested at the onset of the disease, and the clinical manifestations can also change from one another during the course of the disease.
The incidence is higher in North America and Europe than in Asia, and is often associated with upper respiratory tract infections (Berger’s disease); hematuria occurs at short intervals (24-72 h) with upper respiratory tract infections, or occasionally a few hours later, and there is mostly tonsillar enlargement. Some children also show hematuria and proteinuria, which can be either episodic hematuria or microscopic hematuria. Proteinuria is mostly mild to moderate. IgA nephropathy with nephrotic syndrome accounts for about 15%-30% of the cases, and the “three highs and one low” manifestation is prominent, and there are often few combined respiratory infections before the onset of the disease.
There are also some cases that present with nephritis syndrome, in addition to hematuria, hypertension and renal insufficiency. Hypertension predominates in older people, accounting for 20% of adults and only 5% of children. Hypertension is an important marker of worsening IgA nephropathy, and most cases are accompanied by rapid deterioration of renal function. Less than 5% of patients with IgA nephropathy present with acute progressive nephritis.
Complications
Renal insufficiency, hypertension, and hypoproteinemia occur in some patients. A small number of patients present with acute progressive nephritis.
Laboratory tests
1. Urinalysis
(1) Hematuria: Clinically, about 40% to 45% of the patients show hematuria under the naked eye or microscope, while 35% to 40% of the patients show simple microscopic hematuria or microscopic hematuria with a small amount of proteinuria. Carnal hematuria may last for a few hours to a few days and then turn into persistent microscopic hematuria. In some patients, the hematuria may disappear, but it often occurs in episodes and reappears in carnal hematuria.
(2) Proteinuria: It is mild proteinuria, generally urine protein quantification <1g/24h, a few patients may have large amount of proteinuria or even nephrotic syndrome.
2.Immunological examination
(1) IgA increase: about 1/4 to l/2 patients have increased blood IgA, mainly the increase of multimeric IgA.
(2) Circulating immune complexes: IgA circulating immune complexes and/or IgG circulating immune complexes can be detected in the blood of about 1/5 to 2/3 of the children.
(3) Elevated anti-“O”: A small number of patients have elevated anti-“O” titers.
(4) Complement: C3 and C4 are mostly normal.
(5) Other: IgA rheumatoid factor and IgA ANCA are often positive. It is believed that the elevated IgA-fiber-binding protein complex in blood is a characteristic change of IgA nephropathy and has high diagnostic value.
Other ancillary tests
Ultrasound, electrocardiogram and X-ray if necessary. Immunopathological examination: renal immunopathology is the only key basis for confirming the diagnosis of IgA nephropathy. The specificity and sensitivity of skin biopsy were 88% and 75%, respectively, as reported by Bene et al.
Diagnosis
In older children with recurrent botrythematous hematuria, and most of them have upper respiratory or intestinal infections, this disease should be considered; if the manifestation is simple microscopic hematuria or botrythematuria or moderate proteinuria, IgA nephropathy should also be suspected, and early renal biopsy should be sought. If nephrotic syndrome, acute nephritis syndrome, hypertension with renal insufficiency are the manifestations, this disease should also be considered. It is important to exclude other diseases that can cause thylakoid IgA deposition.
Differential diagnosis
Other causes of hematuria should be excluded, such as urinary tract injury, hypercalciuria, stones, tuberculosis, familial benign hematuria, Alport syndrome, acute attacks of chronic nephritis, etc.
In the case of immunopathological IgA deposition, it should be noted that IgA deposition in the glomerulus can also be present in a variety of other systemic diseases (this is secondary IgA nephropathy). The common causes are as follows.
1. systemic multisystemic diseases allergic purpura, systemic lupus erythematosus, chronic liver disease, Crohn’s disease, herpes-like dermatitis, ankylosing spondylitis, etc.
2.Infectious diseases Mycoplasma infection, toxoplasmosis, hepatitis virus, etc.
3.Other thrombocytopenia, cryoglobulinemia, erythrocytosis, non-Hodgkin’s lymphoma, scleroiditis, certain intestinal or lung cancers, etc.
Most of the above conditions can be differentiated by other manifestations.
Treatment
It was previously believed that there was no specific therapy for this disease and that the prognosis was relatively good, so treatment measures were not very aggressive. The prognosis of IgA nephropathy varies greatly from pathological changes to clinical manifestations, so the treatment must be individualized.
1. General treatment. The most common clinical type in children is recurrent sarcoid hematuria, and most of them have causative factors, such as acute upper respiratory tract infection, so it is important to actively control the infection, remove the lesion and pay attention to rest. Short-term antibiotic therapy is also useful for controlling symptoms in the acute phase. For children with combined edema and hypertension, diuretic and anti-swelling drugs should be given accordingly, and low salt and low protein diet should be adopted.
2. Adrenocorticosteroids and immunosuppressants. For children with nephrotic syndrome or acute nephritis syndrome, they should be treated with corticosteroids and immunosuppressants. In a nationwide multicenter controlled study conducted in Japan, children with IgA nephropathy treated with prednisone and immunosuppression had a significantly lower rate of long-term renal insufficiency than children treated with general therapy.
Kabayashi has retrospectively studied two groups of patients, one with 29 cases with proteinuria >2g/d, treated with prednisone for 1 to 3 years and followed up for 2 to 4 years, and the results showed that early hormone therapy (when Ccr was above 70ml/min) was beneficial in stabilizing renal function and delaying disease progression. In another group of 18 cases of IgA nephropathy with proteinuria of 1 to 2 g/d also treated with corticosteroids, along with 42 IgA patients on dipyridamole (Pansentin) and indomethacin (anti-inflammatory pain) as controls, the treatment group was significantly better than the control group in stabilizing renal function and lowering blood pressure and reducing proteinuria.
Lai et al. reported the results of a prospective randomized controlled trial in which 17 patients were given prednisone daily for 4 months. There was no significant difference in endogenous creatinine clearance between the two groups compared with 17 controls observed for a mean of 38 months. Prednisone therapy significantly improved remission rates in patients with nephrotic syndrome with mild lesions, but with some adverse effects. This study suggests that prednisone therapy is beneficial in IgA nephropathy. A controlled study in adults with IgA nephropathy was reported to examine the efficacy of azathioprine and prednisone. 66 patients treated with azathioprine and prednisone showed a beneficial effect in slowing the progression of IgA nephropathy compared with 48 controls who did not receive this treatment.
Recently, Nagaoka et al. reported a new immunosuppressive agent, mizoribine, for the treatment of IgA nephropathy in children, which is safe, easily tolerated, and can be taken for a long time, and significantly reduced the degree of proteinuria and hematuria, with reduced renal tissue lesions confirmed by repeat renal biopsies. A randomized, single-blind controlled trial of cyclosporine was conducted by Lai et al. 12 patients in the treatment and control groups each with proteinuria greater than 1.5 g/d and reduced creatinine clearance Ccr (77±6) ml/min were treated with cyclosporine for 12 weeks to control plasma concentration levels at 50-100 ng/ml. The results showed that protein excretion was significantly reduced, accompanied by an increase in plasma creatinine clearance, but these changes disappeared after termination of treatment.
In conclusion, the efficacy of immunosuppressants in the treatment of IgA nephropathy remains to be evaluated. woo and wallker observed the effect of combined treatment with cyclophosphamide, warfarin, dipyridamole (pansentin) and hormones, respectively, and the results showed a reduction in proteinuria and stabilization of renal function during treatment compared to the control group, but there was no significant difference in renal function protection compared to the control group after 2 to 5 years of follow-up.
3. Immunoglobulins. In a group of open prospective studies, Postoker et al. used high-dose human blood gammaglobulin intravenously at 2 g/kg once/d for 3 months, then changed to 16.5% human blood gammaglobulin intramuscularly at 0.35 ml/kg once every half month for 6 months, and found that urinary protein excretion decreased from 5.2 g/d to 2.2 g after treatment It was found that after treatment, urinary protein excretion decreased from 5.2g/d to 2.2g/d, hematuria and leukocyturia disappeared, and the monthly decreasing rate of glomerular filtration rate slowed down from 3.78ml/min to 0.
4.Fish oil: Patients with IgA nephropathy lack essential fatty acids, and fish oil can supplement essential fatty acids, thus preventing early glomerular damage. Fish oil is rich in long-chain ω-3-polyunsaturated fatty acids, EPA, DHA, which can replace arachidonic acid and function as a substrate for lipoxygenase and cyclooxygenase to change membrane fluidity and reduce platelet aggregation. As early as 1984 Hamazaki collected 20 patients with IgA nephropathy and did a preliminary study. The treatment group received fish oil for 1 year and maintained stable renal function, while the control group, which did not receive fish oil, showed a decrease in plasma creatinine clearance.
A multicenter, double-blind randomized controlled trial was conducted by Donadio in 1994. A total of 55 patients were collected, taking 12 g of fish oil orally daily as the treatment group and 51 patients taking olive oil as the control group. 68% of the selected cases had increased basal blood creatinine values, with an initial observed endpoint of a >50% rise in blood creatinine, resulting in only 6% of patients in the fish oil group progressing to the observed endpoint during the treatment period (2 years), compared to 33% in the control group, with an annual rate of increase in blood creatinine of 0.03 The incidence of end-stage renal disease after 4 years was 40% in the control group and 10% in the treatment group, with statistically significant results, and no patient discontinued treatment due to adverse effects. This indicates that fish oil slows the rate of decline in GFR. This author also reported in 1999 the results of the long-term follow-up of the above cases, showing that early and continued use of fish oil significantly delayed the onset of renal failure in patients with high-risk IgA nephropathy.
5. Other Copp recently organized a 6-year prospective multicenter double-blind randomized controlled study to investigate the efficacy of long-acting benazepril [benazepril, 0.2 mg/(kg・d)] in pediatric and young adult patients with moderate proteinuria and good renal function with IgA nephropathy, which was completed in 2004. Previously, phenytoin sodium 5mg/(kg・d) was used for the treatment of IgA nephropathy, and it was found that it could reduce the serum levels of IgA and poly-IgA, and the number of hematuric episodes was reduced, but the circulating immune complexes were not reduced, and the long-term efficacy was not certain, so it has been rarely used in recent years. For moderate proteinuria, the use of Regulus polyglucoside tablets lmg/(kg・d) for 3 months can achieve significant results.
6.Dialysis and kidney transplantation Dialysis and transplantation are feasible for patients with end-stage renal failure.
Prognosis
About 15% of adults with IgA nephropathy progress to end-stage renal failure after 10 years, rising to 25%-30% after 20 years. In children, the prognosis of IgA nephropathy is better than that of adults, and Yoshikawa reported that 10% progressed to end-stage renal failure after 20 years. Many factors affect the prognosis; heavy proteinuria, hypertension, glomerulosclerosis and severe interstitial tubulopathy are indicators of poor prognosis; men are also prone to progression; the relationship between sarcoid hematuria and prognosis is controversial. The rate of GFR reduction in patients with IgA nephropathy is reported to be 1 to 3 ml/min per year from normal renal function, while the rate of GFR reduction in patients with IgA nephropathy manifesting as nephrotic syndrome is 9 ml/min. In combination with hypertension, the rate of GFR reduction is as high as 12 ml/min per year, therefore, controlling blood pressure and proteinuria is crucial in the treatment of IgA nephropathy.
Prevention
IgA nephropathy is an immune-responsive disease, so for preventing the occurrence and recurrence of this disease, the invasion of antigenic substances should be avoided in the first place. Therefore, we should actively prevent and treat respiratory tract infections, avoid gastrointestinal mucosal damage, and reduce the intake of food that may become antigenic substances as much as possible. When a patient’s morbidity is found to be associated with recurrent inflammation of his tonsils, tonsil removal can be considered after the inflammation is controlled. Spicy foods should be consumed as little as possible, and smoking and alcohol should be avoided. While adolescents absorb nutrients, they should pay attention to a balanced and light diet and not eat too much high-protein and high-fat food. In addition, when studying and working, they should pay attention to rest and avoid overexertion. Moderate sports can enhance physical fitness and reduce various types of infections or tonsillitis caused by colds and weaknesses, but it is also necessary to pay attention to the amount of sports, not to carry out too strenuous exercise, resulting in overexertion.