IgA nephritis in a child with human immunodeficiency virus: a unique form of human immunodeficiency virus-associated nephropathy?

A 9-year-old boy is presented who was antibody positive for human immunodeficiency virus (HIV) and who had recurrent episodes of gross hematuria. Renal biopsy revealed findings typical of IgA nephropathy but also showed electron-microscopic abnormalities seen with HIV-associated nephropathy. In addition, IgA antibodies to multiple HIV proteins were detected in serum by Western blot analysis, and circulating immune complexes of the IgA class were present. Although HIV-associated nephropathy and IgA nephropathy are thought to be distinct conditions, five adults with a similar combination of findings have been reported, and our patient adds to the evidence for a link between these two entities in some patients. We propose that the histological parallels between the conditions may merely represent the limited renal responses available to multiple types of injuries, and we support the attempts underway to probe renal tissue for the HIV genome.     

The nephropathies of HIV infection: pathogenesis and treatment

Several different renal syndromes have been reported in patients with HIV infection. Patient characteristics and a syndrome approach may help the clinician formulate a tentative diagnosis, but a renal biopsy is necessary to make a firm diagnosis in patients with chronic renal disease in the setting of HIV infection. The pathogenesis of the HIV nephropathies can teach us much about the pathophysiology of common renal problems such as IgA nephropathy, immune complex glomerulonephritis, focal segmental glomerulosclerosis, and diabetic renal disease. HIV-associated renal disease may be the result of the interaction of the expression of specific HIV genes in patients with distinct genetic susceptibilities to disease in particular environments. New treatment approaches have provided hope for patients with classic HIV-associated nephropathy.     

Binding of serum immunoglobulins to collagens in IgA nephropathy and HIV infection.

The mechanism of the binding of IgA to the mesangium in IgA nephropathy (IgAN) is unknown. Interactions between IgA and components of the mesangial matrix may contribute. We measured by enzyme-linked immunosorbent assay the binding of serum IgA, IgG, and IgM from patients with IgAN, human immunodeficiency virus type I (HIV) infection, and healthy controls to purified native collagen types I to VI, and to an extract of normal kidney tissue. HIV infection is an appropriate disease control because of the lack of mesangial IgA deposits, despite high serum levels of IgA and IgA1-containing immune complexes. Increased levels of IgA-binding to collagen types I and V and the kidney extract were found only in IgAN. Both IgAN and HIV-infected patients had increased IgA-binding to collagen types II, III, and VI. Preabsorption of the sera with gelatin substantially reduced the IgA-binding to collagen types I to IV, but not to types V and VI. This finding suggests that the binding to collagen type V is not fibronectin-mediated, but may reflect autoantibody formation. Thus, fibronectin-mediated IgA-collagen interactions are not specific for IgAN, and their pathogenetic role is questionable. The role of IgA anti-collagen type V antibodies requires further study.     

Role of macromolecular IgA in IgA nephropathy

Primary IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis, leading to progressive renal failure in almost one third of the patients. The disease is characterized by mesangial deposits of IgA. The pathogenesis of IgAN remains incompletely understood. The basic abnormality of this disorder lies within the IgA immune system rather than in the kidney. Elevated levels of IgA and IgA-containing complexes are found in sera of most patients with IgAN, but increased levels alone are not sufficient to develop IgAN. Therefore abnormal physicochemical properties of circulating IgA, such as size, charge, and glycosylation may play a role. This is supported by the presence of altered glycosylation of serum and mesangial IgA in patients with IgAN. Although the precise origin and nature of the mesangial IgA deposits are still uncertain, they contain at least in part macromolecular IgA, which may be derived from circulating IgA-containing complexes. Recently, novel insights have been obtained in the molecular composition of circulating high-molecular-weight IgA, which might include complexes with underglycosylated IgA1 and IgA-CD89 complexes. In this review various aspects of macromolecular IgA in relation to IgAN will be discussed.     

Sequential occurrence of IgA nephropathy and Henoch-Schönlein purpura: support for common pathogenesis

We report a patient who developed Henoch-Schönlein purpura (HSP) 13 years after he presented with IgA nephropathy (IgAN). In both HSP and IgAN renal biopsy most commonly reveals focal proliferative glomerulonephritis on light microscopy and immunofluorescence displays mesangial IgA deposits. In addition, patients with HSP or IgAN have elevated serum IgA levels, circulating IgA immune complexes, IgA-bearing lymphocytes, immunoglobulin-producing cells, and binding of IgG to glomerular components of similar molecular weight. The occurrence of both diseases in the same patient or the same families and the presence of immune abnormalities compatible with HSP or IgAN in relatives of patients with these diseases suggest a common pathogenesis.     

Relationship between tonsils and IgA nephropathy as well as indications of tonsillectomy

Although there are many papers about IgA nephropathy (IgAN) and tonsils, respectively, reviews about the relationship between tonsils, tonsillitis, tonsillectomy, and IgAN are limited. In this review, we introduced the structure, development, and function of tonsils, difference of tonsils with and without IgAN, consistency of both tonsillar IgA and glomerular IgA, the effect of tonsil stimulation, tonsil infection, and tonsillectomy on IgAN showed some evidences in which tonsils were closely related to IgAN and polymeric IgA1 deposited in glomerular mesangium were at least in part of tonsillar origin. Tonsillectomy can improve the urinary findings, keep stable renal function, improve mesangial proliferation and IgA deposit, have a favorable effect on long-tern renal survival in some IgAN patients, and do not cause significant immune deficiency and do not increase incidence of the upper respiratory tract infections, and can be used as a potentially effective treatment. The indications of tonsillectomy in patients with IgAN include mainly the deterioration of urinary findings after tonsillar infection, mild or moderate renal damage. However, tonsillectomy may not be enough and may not change the prognosis in IgAN patients with marked renal damage.     

Virus-related glomerular diseases: histological and clinical aspects

Viral infections can be the causative agent in many glomerular diseases, and diagnostic criteria include clinical and laboratory data and tissue molecular analysis. Hepatitis B virus (HBV) is a well known cause of membranous glomerulonephritis (MGN), membranoproliferative GN (MPGN) and IgA nephropathy (IgAN), frequently in Asian populations. Hepatitis C virus (HCV), besides cryoglobulinemia-mediated glomerulonephritis (GN), is reported to cause other forms of GN. Human immunodeficiency virus (HIV) infection is closely related to a collapsing focal segmental glomerulosclerosis (FSGS), a distinct disease that affects mainly Africans and African-Americans. In the course of HIV infection other immune complex (IC) GN can occur, most frequently in whites. Nephrotic syndrome and progression to renal insufficiency are the main clinical manifestations. HIV-HCV co-infection is related to an IC glomerular disease, sometimes with immunotactoid deposits. Recent reports emphasize the role of parvovirus B19 (PV B19) for "idiopathic" collapsing FSGS and ICGN, and of Coxsackie B virus for IgAN. Renal biopsy is useful for defining virus-related glomerular lesions and a guide for prognostic and therapeutic evaluation.     

Polymeric IgA and immune complex concentrations in IgA-related renal disease

Polymeric IgA (PIgA) and immune complex concentrations in IgA-related renal disease were measured in cross sectional and longitudinal studies to establish the relationship between these parameters and both mucosal infection and renal dysfunction. These studies were performed in 50 patients with IgA nephropathy (IgAN), 17 patients with Henoch Sch?nlein purpura nephritis (HSPN), 11 control patients with IgA negative, diffuse mesangial proliferative glomerulonephritis (DMPGN) and 50 healthy controls. Total PIgA (PIgAT) and PIgA subclass concentrations were measured using a secretory component binding enzyme immunoassay and isotype specific immune complex concentrations were measured using conglutinin (K) binding immunoassays. In cross sectional studies patients with IgAN were found to have increased concentrations of PIgAT, PIgA1, K-IgA1 and K-IgA2 compared to controls. In the longitudinal studies controls and patients had significant increases in PIgAT and PIgA1 concentrations during infection. However, in patients with IgAN, the increases were greater, persisted for longer, and PIgA2 concentrations were also increased. K-IgA1 and K-IgA2 concentrations increased significantly during episodes of infection in IgAN patients in contrast to controls. Patients with HSPN had results similar to those of IgAN patients. No significant correlation was found between PIgA or K-IgA concentrations, and either serum creatinine concentrations or the degree of hematuria. The results indicate that patients with IgA-related renal disease have abnormal regulation of PIgA and immune complexed IgA, and that these abnormalities are exaggerated during mucosal infection.     

甘露糖结合蛋白基因多态性与维吾尔族IgA肾病免疫病理类型的关系

目的 探讨甘露糖结合蛋白（MBP）基因多态性与维吾尔族IgA肾病（IgAN）患者免疫病理类型之间的关系。 方法 选择68例经肾活检证实的维吾尔族IgAN患者为对象，对照组为200例维吾尔族健康献血员。采用PCR-RFLP的方法对MBP基因第54位密码子基因多态性进行研究。 结果 （1） 维吾尔族IgAN组与健康对照组MBP-54基因多态性之间差异无统计学意义。（2） 维吾尔族IgAN复合沉积组GAC/GGC 基因型频率显著高于单纯沉积组(44.7% 比 20.0%)；IgAN复合沉积组等位基因GAC的发生频率（0.303）显著高于单纯沉积组（0.133），2组之间的差异有统计学意义（χ2 = 5.461, P < 0.05)。 结论 维吾尔族IgAN 免疫病理多样性受基因背景影响，MBP基因54位点突变型等位基因GAC与维吾尔族IgA肾病免疫复合沉积有关     

Immunoglobulin a nephropathy: Pathological markers of renal survival in paediatric patients

IgA nephropathy (IgAN) is one of the leading causes of glomerulonephritis characterized by the findings of IgA and IgG immune deposits in the mesangium of kidney biopsies from patients with persistent microscopic haematuria. IgAN is frequently detected among adolescents and young adults. IgAN presents a highly variable course that includes a spectrum from a very mild disease to end‐stage renal disease (ESRD). There are several clinical and histological factors that strongly determined the final outcome of patients with IgAN. Pathological variables associated with unfavorable outcomes are mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity and interstitial fibrosis/tubular atrophy, according to the Oxford classification. Moreover, some studies also suggest a role for complement activation in the pathogenesis of IgAN. In this regard, staining for C4d may be an independent risk factor for the development of ESRD in IgAN. Despite the growing number of studies assessing IgAN risk factors, this kind of investigation in paediatric patients is still very limited. The aim of this article is to revise pathological markers related to deterioration of renal function in paediatric patients with IgAN, particularly those that can independently affect renal survival.     

Decreased IgA1 response after primary oral immunization with live typhoid vaccine in primary IgA nephropathy.

INTRODUCTION: Patients with primary IgA nephropathy (IgAN) have an increased level of immunological memory to certain parenteral recall antigens. We recently found a deficient IgA1 immune response after intranasal challenge with a neo-antigen: cholera toxin subunit B. In the present study, we assessed the specific IgA1 and IgA2 antibody response in plasma, peripheral blood cells and mucosal secretions after primary enteral immunization. METHODS: Twenty eight IgAN patients, 26 patients with non-immunological renal disease and 32 healthy subjects were immunized orally with three sequential doses of live, attenuated, Salmonella typhi Ty21a. The humoral immune response in body fluids and antibody synthesis by circulating B cells was assessed in specific ELISAs and ELIPSAs respectively. RESULTS: Oral immunization resulted in significantly (P<0.0001) increased IgM, IgG, IgA, IgA1 and IgA2 responses in all groups, both in plasma and in circulating B cells in vitro. The IgA1 response in plasma was significantly (P<0.05) lower in IgAN patients, while no significant differences in IgM (P=0.36), IgG (P= 0.79) or IgA2 (P=0.45) responses were found as compared with matched control groups. The amount of IgA1 synthesized by circulating B cells tended to be lower in IgAN patients. No significant IgA response after oral immunization with S. typhi Ty21a was found in saliva (P=0.11) or tears (P=0.10). CONCLUSIONS: These data suggest an IgA1 hyporesponsiveness in patients with IgAN that is not only apparent after primary challenge of the nasal-associated lymphoid tissue but also after presentation to the gut. Previous results after parenteral recall immunization may be explained by assuming that IgAN patients require more frequent and/or longer exposure to IgA1-inducing antigens on their mucosal surfaces before they reach protective mucosal immunity. As a consequence, overproduction of IgA1 antibodies occurs in the systemic compartment, accompanied by an increased number of IgA1 memory cells.     

人类免疫缺陷病毒感染伴肾病患者的临床病理分析

目的对行肾组织活检的人类免疫缺陷病毒(HIV)感染合并肾病患者进行病理分析。方法纳入2011年1月至2018年12月四川大学华西医院肾内科接受肾组织活检的HIV合并肾病患者,分析其病理特征、干预措施和预后等。结果共纳入9例患者,其中肾病综合征患者6例,急性肾功能损伤患者1例,慢性肾炎综合征患者2例。组织学诊断:肾小球微小病变患者3例,膜性肾病患者1例,塌陷型局灶节段性肾小球肾炎(FSGS)伴膜性肾病患者1例,FSGS非特异型(NOS)患者1例,急性间质性肾炎患者1例,Ig A肾病患者1例,糖尿病肾病患者1例。5例患者在肾组织活检时首诊HIV感染(其中塌陷型FSGS伴膜性肾病、糖尿病肾病、急性间质性肾炎各1例,2例为肾小球微小病变),其余4例在HIV感染确诊后的不同时期(均行抗逆转录病毒治疗)发病。并发症:糖尿病1例,梅毒感染1例,甲状腺功能减退2例,乙型肝炎病毒感染3例。随访情况:3例患者失访,6例患者随访期间未发生严重感染,其中2例仍有大量蛋白尿,其余4例患者血尿消失,肾功能恢复正常水平,复查尿蛋白定量显著减少至可疑阳性或24 h定量<300 mg/d。结论HIV感染者出现肾脏损伤的临床表现多样,可出现不同程度蛋白尿和(或)血尿,伴或不伴肾功能不全,病理类型不仅限于人类免疫缺陷病毒相关性肾病(HIVAN),可出现糖尿病肾病、肾小球轻微病变、膜性肾病、非塌陷型FSGS、急性间质性肾炎、Ig A肾病。肾组织活检有助于明确诊断。抗逆转录病毒治疗有效情况下,依据患者的病理诊断,有针对性地给予糖皮质激素及细胞毒药物,并加强随访,有助于改善患者预后。肾病患者应加强HIV筛查。     

IgA-containing immune complexes in the urine of IgA nephropathy patients.

BACKGROUND: Sera of IgA nephropathy (IgAN) patients contain high levels of circulating immune complexes composed of IgA1 molecules with aberrantly glycosylated hinge-region O-linked oligosaccharides and IgG or IgA1 antibodies with anti-glycan or anti-hinge-region peptide specificities. Due to damaged sieving properties of the glomerular capillary wall in IgAN, these immune complexes may appear in the urine. METHODS: We collected urine samples from 29 patients with biopsy-proven IgAN (Group I), 27 proteinuric patients with non-IgA nephropathies (Group II) and 28 healthy volunteers (Group III). The levels of urinary IgA and IgG and IgA-IgG-containing immune complexes were measured by ELISA and standardized for urinary creatinine concentrations. RESULTS: The urinary IgA and IgG levels were significantly higher in Groups I and II than in Group III. Although the excretion of IgA as a fraction of total urinary protein was not significantly greater in IgAN patients than in patients with other renal diseases, the excretion of aberrantly glycosylated IgA1 was observed by western blot in 68% of the IgAN patients but in none of the healthy controls. The urinary levels of IgA-IgG immune complexes were significantly higher in Group I than in Groups II (P < 0.01) and III (P < 0.05). There was no significant difference in the levels between Groups II and III. These immune complexes had a molecular mass between 650-850 kDa, as shown by size-exclusion chromatography. CONCLUSION: The amounts of urinary IgA-IgG-containing immune complexes were significantly higher in patients with IgAN than in patients with non-IgA nephropathies or healthy controls.     

Molecular genetics in IgA nephropathy

Evidence from both genotypic and phenotypic perspectives is considered that patients may be genetically predisposed to IgA nephropathy (IgAN) or Henoch-Sch?nlein purpura (HSP) or that a factor(s) might exclusively contribute to their progression to chronic renal failure. In contrast to most other renal diseases, both IgAN and HSP are uncommon in blacks; this is unexplained but is not due to their low frequency of the A2m(1) allotype. The association of these diseases or their progression with a variety of abnormalities of IgA immunobiology in patients and their families has not been linked to any genotype; similarly, no HLA antigen has been positively or negatively associated in any consistent way. Although complement factor 3 universally accompanies IgA glomerular deposition, complement pathway abnormalities are only sporadically reported with either IgA deposition or disease progression. Whether angiotensin-related polymorphism including the converting enzyme alleles have a specific predictable role, particularly in the progression of renal failure in IgAN, remains problematic. The promising possibility that a structural defect in IgA1 due to an as yet unidentified genetic defect accounts for the deposition of IgA is considered in some detail. Nevertheless, the genetic mechanism(s) of progressive renal failure, whether exclusive to IgAN or to glomerular diseases generally, is of paramount importance.     

Selective elevation of monomeric IgA1 in IgA nephropathy patients with normal renal function

The molecular form of the pathognomonic IgA in IgA nephropathy (IgAN) remains controversial. Because characterization of the molecular form of IgA molecules can lend insight into their origin (systemic v mucosal), we developed immunoassays to measure both total and J chain-containing (polymeric) IgA1 and IgA2. These assays were used to measure IgA in sera from two groups of IgAN patients (with normal or decreased renal function), as well as from a group of normal individuals. IgA1 levels were higher in both groups of patients with IgAN when compared with the controls. The elevation appeared to be restricted to non-J chain-containing (monomeric) IgA1 in patients with normal renal function, whereas polymeric IgA1 was also slightly elevated in patients whose renal function was diminished. While there were no significant differences between the groups in terms of the levels of total IgA2, the patient group with normal kidney function appeared to have lower levels of polymeric IgA2. The observation that the elevation in serum IgA appears to be restricted to the monomeric form of IgA1, at least when renal function is normal, implies a systemic origin of the pathognomonic IgA in IgAN and further suggests an abnormality in the regulation of IgA secretion by immunoglobulin-producing cells in bone marrow, the site of systemic IgA synthesis.     

Henoch-Schönlein purpura in Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome (WAS) is a rare immune deficiency disease. Sialophorin glycosylation is defective in WAS. Although it is not very common, renal involvement including IgA nephropathy (IgAN) was reported. Abnormal glycosylation plays a key role in the pathogenesis of IgAN. We present an 8-year-old boy with WAS who had recurrent episodes of Henoch-Schönlein purpura with renal involvement following upper respiratory tract infections. His renal function did not deteriorate. Both IgAN and WAS have glycosylation defects, but there must be some other factors (genetic and environmental) to explain their rare association.     

Is Henoch-Sch?nlein purpura the systemic form of IgA nephropathy?

Despite different clinical features, IgA nephropathy (IgAN) and Henoch-Sch?nlein purpura (HSP) are indistinguishable by histopathology, leading to the suggestion that HSP is a systemic form of IgAN. This review compares and contrasts the clinical, pathologic, and experimental similarities and differences of these two disorders. Many patients with HSP have minimal extrarenal disease, while up to 30% of patients with IgAN will subsequently have systemic symptoms. Although patients with HSP are usually much younger than those with IgAN, the age distributions often overlap. Both may have recurrent macroscopic hematuria associated with pharyngitis, a similar risk of developing renal insufficiency, and recurrent disease after kidney transplantation. Although the pattern of IgA subclass and complement deposition are similar, monocytic and T lymphocytic infiltrates have been observed only in HSP. Dermal blood vessels of many patients with IgAN have IgA immunofluorescence similar to that in HSP, supporting a systemic process in IgAN. Although the pathogenesis is not clearly understood for either disease, investigations of potential disease mechanisms have revealed striking similarities. These include an up-regulated in vitro IgA immune response, circulating IgA-containing immune complexes and autoantibodies, and decreased Fc receptor-mediated immune clearance. Finally, immunogenetic studies suggest that patients with both conditions inherit a predisposition for disease.     

The pathogenetic potential of environmental antigens in IgA nephropathy

Patients with IgA nephropathy (IgAN) can be considered high responders for IgA production; data which indicate a generalized hyperreactivity of the immune system include autoantibody production, increased response to viral vaccination, and high titers of antibodies to various common respiratory and gastrointestinal microbes. From clinical and experimental observations, two types of antigen seem to be most involved in the pathogenesis of IgAN, ie, environmental respiratory or gastrointestinal infectious agents and dietary antigens. A role played by microbes has been suggested because macroscopic hematuria shortly follows a pharyngitis or a gastrointestinal disturbance. Antibodies to a wide spectrum of viral and bacterial infectious agents have been detected in sera from patients with IgAN. The possible role of dietary antigens has been demonstrated experimentally in animal models. In human IgAN, antibodies to various dietary antigens have been detected in sera; antibodies have also been found in IgA immune complexes and renal eluates. In human IgAN, a significant decrease in serum levels of IgA-containing circulating immune complexes after a gluten-free diet has been observed. The present experience accounts for 27 IgAN patients followed for 6 months to 3 years on a gluten-free diet. A decrease in serum levels of IgA-containing circulating immune complexes was observed in 64% of the patients whose initial levels were high during a period of unrestricted diet. Patients with basal high levels also had significantly high levels of IgA antibodies to dietary antigens, including bovine serum albumin, ovalbumin, and various gluten fractions. After 1 year of gluten-free diet the levels significantly decreased. A disappearance of antigliadin IgA, observed in 80% of the cases, was paralleled by a decrease in titers of the other antibodies to dietary components. These data support the hypothesis that in patients with IgAN, gluten may act as a toxic lectin, increasing the permeability of the intestinal mucosa to various dietary antigens.     

Pathogenic role of the IgA molecule in IgA nephropathy

SUMMARY: Deposits of IgA together with complement in different body tissues support the hypothesis that IgA can trigger inflammatory mechanisms. IgA nephropathy (IgAN) is characterized by predominant mesangial IgA₁ deposits of a polymeric nature. So far, the mechanism of polymeric IgA₁ deposition in the kidney mesangium is poorly understood in IgAN. the exact pathophysiological sequel preceding renal fibrosis following the mesangial deposition of IgA immune complexes remains speculative. Recent in vitro studies revealed that binding of IgA to mesangial cells led to increased expression of growth factors, cytokines, and integrins. the release of these proinflammatory factors is likely to enhance inflammatory injury. In addition, the local renin-angiotensin system present in renal tissues also contributes to renal fibrosis through the activation of transforming growth factor-β. the question of whether polymeric IgA isolated from patients with IgAN exerted any upregulatory effect on the synthesis of macrophage migration inhibitory factor (MIF) and components of the renin-angiotensin system in human mesangial cells was explored. the in vitro studies revealed that polymeric IgA from IgAN patients upregulated the gene expression of renin and MIF in human mesangial cells in a dose-dependent manner. These findings further support the notion that glomerular deposition of IgA is not only a pathological epiphenomenon of IgAN, but that polymeric IgA exerts a pathophysiologic effect on the mesangial cells leading to renal fibrosis.     

Immunoglobulin-antiimmunoglobulin interactions and immune complexes in IgA nephropathy

IgA nephropathy (IgAN) is characterized by mesangial co-deposition of IgA and C3. Elevated levels of circulating immune complexes containing these components in significant numbers of patients have been found in several studies; IgAN is therefore assumed by many investigators to be an immune complex-mediated disease. Our studies have shown that IgG is often co-complexed with IgA within circulating immune complexes, and we have begun to examine the potential mechanisms for these observations. In this regard, elevated levels of IgA rheumatoid factor and of IgG anti-IgA antibodies were found in some patients. Nevertheless, we were unable to correlate levels of circulating immune complexes with any clinical index of disease. Furthermore, many individuals with the acquired immune deficiency syndrome (AIDS) also have elevated levels of circulating immune complexes containing IgG and IgA, IgA rheumatoid factor, and IgG anti-IgA antibodies, although these patients apparently do not have mesangial IgA deposits. Therefore, the role of circulating IgA-containing immune complexes in the pathogenesis of IgAN requires further evaluation.