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.     

Efficacy of tonsillectomy for patients with recurrence of IgA nephropathy after kidney transplantation

Abstract:  From January 2007, we started to perform the tonsillectomy for every patient with recurrent IgA nephropathy (IgAN) after kidney transplantation. Up to September 2008, four recipients with primary IgAN had biopsy-proven recurrent IgAN. They had also progressive hematuria or proteinuria from on the average 14.3 months after transplantation. Then their specimens diagnosed as recurrent IgAN were collected and they underwent tonsillectomies on the average 52.3 months after transplantation. Abnormal urinary findings of all patients favorably improved after tonsillectomy. All cases but one had mild renal injury, where the severity of glomerular lesions, glomerular hypercellularity, segmental lesions, and sclerosis was mild, and no deteriorated serum creatinine (SCr) before their tonsillectomies. Even the case with exacerbated SCr and severe renal injury, where the severity of glomerular lesions was severe, had her urinary findings ameliorated promptly after tonsillectomy likely as others. At present, they have almost no symptoms after tonsillectomy and no remarkable change of SCr level compared with before and after tonsillectomy and maintain ameliorated urinary findings continuously. Tonsillectomy had possibility to be a favorable treatment of hematuria or proteinuria in recurrent IgAN recipients.     

IgA肾病患者IgA1糖基化异常及其致病机制

IgA肾病(IgAN)是导致终末期肾病最常见的原发性肾小球疾病。其病理特点为IgA1在肾小球系膜区沉积,IgA1分子的异常糖基化是导致IgAN发病的关键因素。多种与IgAN相关的基因位点已经被发现。这些基因编码的细胞因子参与了IgA1糖基化异常的发病机制。此外糖基化酶缺乏、分子伴侣甲基化异常都可能导致IgA1异常糖基化。异常糖基化的IgA1可通过自我聚集或形成免疫复合物沉积于系膜区,进而刺激系膜细胞增殖、分泌系膜基质、细胞因子、趋化因子、生长因子等,导致肾小球损伤。对IgA1异常糖基化的深入研究有助于了解IgA肾病的发病机制并提供新的诊断与治疗措施。     

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.     

IgA肾病治疗的思考

IgA肾病是我国最常见的原发性肾小球疾病。主要以IgA免疫球蛋白沉积于肾小球为病理特征;以血尿、蛋白尿、高血压和肾功能损害为主要临床表现。每次血尿和(或)蛋白尿发作是肾小球损伤的标志,如不有效进行干预,可逐渐出现肾功能损害。控制血尿和(或)蛋白尿,降低尿检异常发生的频率,是治疗原发性IgA肾病及防止肾脏慢性化损伤的关键。ACEI/ARB在减少IgA肾病患者的蛋白尿、保护残存肾功能、延缓其进展为终末期肾病等方面优于其他降压药。IgA肾病如有较多新月体形成、明显血尿和蛋白尿,可考虑使用糖皮质激素和(或)与免疫抑制剂。由于IgA肾病是一个慢性化过程,长期随访对改善该病的预后显得尤为重要。     

Clinicopathological features of paediatric renal biopsies in Shanghai over a 31 year period

Aim: To identify the variations in paediatric renal biopsy pathology and clinicopathological features during the past 31 years. Methods: A retrospective analysis of paediatric renal biopsies performed at a single institution in Shanghai from January 1979 to December 2009 was conducted. Results: The major pathologies included minor glomerular abnormalities (MGA, 26.1%), IgA nephropathy (IgAN, 17%) and mesangial proliferative glomerulonephritis (MsPGN) without IgA deposition (11.3%). The major clinical presentations included nephrotic syndrome (NS, 39.4%), haematuria with proteinuria (24.4%) and persistent microscopic haematuria (15.1%). MGA accounted for 46.9% of the cases in NS. IgAN and HSN accounted for 24% and 28.9% of patients with concomitant haematuria and proteinuria, and thin basement membrane nephropathy accounted for 51.2% of cases with persistent microscopic haematuria. The frequency of IgAN (78.6%) was much higher than that of TBMN (29.0%) in patients with persistent microscopic haematuria with abnormal urinary albumin. Conclusion: Minor glomerular abnormalities and IgAN were the major renal diseases in our study population, and the focus of our paediatric nephrologists. The high proportion of TBMN suggested that there should be limited use of renal biopsy for patients with persistent microscopic haematuria and renal biopsy should be performed in the presence of proteinuria or abnormal levels of urinary albumin.     

An increased polymeric IgA level is not a prognostic marker for progressive IgA nephropathy.

BACKGROUND: Elution of IgA from renal biopsies of patients with primary IgA nephropathy (IgAN) has suggested that mesangial IgA deposits are mainly multimeric in nature. This macromolecular IgA consists of dimeric and polymeric IgA and may be derived from the circulation. In children with IgAN, circulating macromolecular IgA levels correlate with bouts of macroscopic haematuria, but in adults a correlation with disease activity is less clear. Therefore, we have designed a novel method to assess the levels of polymeric IgA (pIgA) in sera from patients and controls. METHODS: A novel precipitation assay using recombinant CD89 was developed to measure pIgA. Polymeric IgA levels were measured in serum samples obtained from healthy volunteers (n = 21) and patients with IgAN (n = 51). Subsequently, serum pIgA levels were correlated with clinical parameters of disease. RESULTS: Serum pIgA levels were significantly increased in patients with IgAN. However, pIgA concentrations relative to total IgA were significantly lower in sera of patients with IgAN. No correlation was found between serum pIgA levels and clinical parameters of IgAN, such as decline of glomerular filtration rate, haematuria or proteinuria. CONCLUSIONS: Although absolute levels of serum pIgA are increased in patients with IgAN as compared with controls, levels of pIgA relative to total serum IgA are lower. No significant correlation was found between serum concentrations of pIgA and clinical parameters of disease. These data support the notion that it is not the size alone, but the physicochemical composition of the macromolecular IgA that is the key factor leading to mesangial deposition.     

IgA肾病诊疗进展

IgA肾病是全球最常见的原发性肾小球肾炎,亚洲人群中发病率高于其他人种。IgA肾病是目前导致终末期肾病的重要原因之一。临床上以血尿为特点,常伴随蛋白尿、高血压。其病理表现主要为IgA免疫复合物在肾小球系膜区的沉积、系膜细胞增生、毛细血管内皮细胞增生等。其发病机制可能为血液循环中半乳糖缺乏的IgA1增多,在內外界环境刺激下,产生过多的、能沉积于肾小球系膜区的免疫复合物。目前,对IgA肾病的诊断主要依靠病理检查。治疗方面,以肾素-血管紧张素系统阻断剂、控制血压为基础,恰当联合免疫抑制剂、细胞毒性药物、鱼油等或能延缓IgA肾病的进展。本文的目的是对IgA肾病的诊疗现状进行总结和分析,为临床工作及进一步科研提供指导和参考。     

Human immunodeficiency virus and IgA nephropathy

Summary: IgA nephropathy (IgAN) in human immunodeficiency virus (HIV)-infected patients has been described with increasing frequency. In contrast to HIV-associated nephropathy, with collapsing variant of focal and segmental glomerulosclerosis and prominent tubular cell changes, a disorder which is more common in black persons, IgAN is a disease mainly of white patients. Most are asymptomatic carriers of HIV although few have acquired immunodeficiency syndrome (AIDS) or ARC at the time the renal disorder is discovered. The clinical manifestations are generally of haematuria, sometimes with proteinuria. In some patients, the finding of IgA reactive with anti-HIV IgG or IgM in circulating immune complexes and in glomerular eluates strongly suggests this glomerulopathy to be an HIV-associated immune complex disorder. Because of the demographic factors, IgAN may evolve to be an important renal lesion in HIV infection.     

A case report suggesting a common pathogenesis for IgA nephropathy and Henoch-Schönlein purpura

A 7-year-old boy who had been followed for asymptomatic haematuria and elevated serum IgA levels developed Henoch-Schönlein purpura (HSP) after a streptococcal infection of the tonsils. Findings on renal biopsy were compatible with mild IgA nephropathy (IgAN); tonsillectomy was also performed as he had chronic tonsillitis. This case suggests that there is a common pathogenesis for IgAN and HSP, at least in some patients.     

IgA glycosylation and IgA immune complexes in the pathogenesis of IgA nephropathy

Circulating immune complexes containing aberrantly glycosylated IgA1 play a pivotal role in the pathogenesis of IgA nephropathy (IgAN). A portion of IgA1 secreted by IgA1-producing cells in patients with IgAN is galactose-deficient and consequently recognized by anti-glycan IgG or IgA1 antibodies. Some of the resultant immune complexes in the circulation escape normal clearance mechanisms, deposit in the renal mesangium, and induce glomerular injury. Recent studies of the origin of these aberrant molecules, their glycosylation profiles, and mechanisms of biosynthesis have provided new insight into the autoimmune nature of the pathogenesis of this common renal disease. An imbalance in the activities of the pertinent glycosyltransferases in the IgA1-producing cells favors production of molecules with galactose-deficient O-linked glycans at specific sites in the hinge region of the alpha heavy chains. By using sophisticated analytic methods, it may be possible to define biomarkers for diagnostic purposes and identify new therapeutic targets for a future disease-specific therapy.     

Immunological aspects of IgA nephropathy

Summary: IgA nephropathy (IgAN) is one of the most common primary renal diseases, and can be readily diagnosed by finding glomerular IgA deposits as either the dominant or codominant immunoglobulin on immunofluorescence microscopy. Despite some contradictory results about the nature and origin of IgA, it is generally accepted that the deposited IgA is polymeric and belongs to the IgA, subclass and systemic compartment is the source of circulating polymeric-IgA in IgAN. Because IgAN presents with asymptomatic microscopic haematuria or with episodic gross haematuria following upper respiratory and gastrointestinal disturbance, various environmental respiratory or gastrointestinal infectious agents and dietary antigens are suggested. Until now, however, it has not been possible to unequivocally identify specific antigens that are responsible for the formation of mesangial IgA deposits in patients with IgAN. Overproduction or delayed clearance of IgA as observed in patients and in animal models and in those processes, polyclonal stimulation of immunoglobulin production, with structural abnormalities of IgA, seems to play an important role. The mechanism responsible for the mesangial deposition of IgA is still unclear. The codeposition of IgA, C3 and properdin without Clq and C4 suggested a possible activation of the alternative pathway by IgA-containing immune complexes. To sum up, in IgAN the predominant antibody appears to be composed of polymeric-IgA₁ originating in the systemic compartment. The deposition of polymeric-IgA₁ in the mesangium and the activation of the alternative pathway of complement are probably crucial in the induction of the inflammatory lesions in the glomeruli and the development of haematuria in IgAN.     

Immunoglobulin A nephropathy complicating ulcerative colitis

Ulcerative colitis is rarely associated with immunoglobulin A nephropathy (IgAN). The development of IgA nephropathy complicates further the clinical course of patients with ulcerative colitis. A 72-year old man with a 30-year history of ulcerative colitis requiring colectomy and modest renal insufficiency secondary to complications of nephrolithiasis and renal artery stenosis developed glomerular hematuria, proteinuria and progressive renal failure. Percutaneous kidney biopsy revealed IgAN with extensive glomerular and interstitial sclerotic changes. After resection of a chronically infected ileo-rectal pouch, renal function improved, while hematuria and proteinuria gradually disappeared without specific treatment of the IgAN. The manifestations of IgAN complicating ulcerative colitis can be improved with effective treatment of the bowel disease even when there are extensive sclerotic changes in the kidneys.     

Haematuria: the forgotten CKD factor?

Haematuria is a frequent manifestation of glomerular disease. However, nephrologists devote more attention to the monitoring and therapeutic targeting of another key manifestation of glomerular injury, proteinuria. Recent reports have propelled haematuria to the forefront of clinical nephrology. Thus, glomerular macroscopic haematuria is associated with the development of acute kidney injury (AKI) with predominant tubular cell damage and there is increasing evidence for the negative impact of glomerular haematuria-associated AKI on long-term renal function outcome both in the context of IgA nephropathy and in anticoagulated patients. In addition, an epidemiological association between isolated microscopic haematuria in young adults and long-term incidence of end-stage renal disease has been described. Finally, a clearer understanding of how haematuria may cause tubular injury is emerging through detailed histological assessment of human biopsies and experimental models of haemoglobin-mediated nephrotoxicity.     

Combined glomerular deposition of polymeric rat IgA and IgG aggravates renal inflammation

BACKGROUND: IgA nephropathy (IgAN) is characterized by deposition in the glomerular mesangium of IgA together with C3, C5b-9, and properdin. IgG deposition as a risk factor in IgAN was recently confirmed by a long-term follow-up of patients with IgAN. We previously reported on an acute model of IgA-mediated glomerular inflammation in Wistar rats. METHODS: To investigate the effect of the combination of IgA and IgG on glomerular injury, Wistar rats were injected with a minimum dose of rat IgG in the presence or absence of a subnephritogenic dose of polymeric rat IgA. Subsequently, glomerular complement activation, influx of inflammatory cells, proteinuria, and hematuria were assessed. RESULTS: Administration of IgG to the rats resulted in maximal proteinuria of 20.3 +/- 12.1 mg/24 h on day 2 and an absence of overt glomerular inflammation. Administration of polymeric rat IgA antibodies to rats resulted in hematuria with a moderate mesangial complement deposition. In the combination group, however, glomerular deposition of C5b-9 was dramatically increased. This was accompanied by increased proteinuria as compared with rats receiving IgA or IgG antibody injections alone on day 7. Microhematuria occurred in rats receiving either polymeric rat IgA or IgG alone or the combination. While both rat IgG and polymeric IgA induced minor mesangial cell (MC) proliferation and MC lysis, the combination resulted in a pronounced, significant increased percentage of aneurysm formation on day 7 after injection. CONCLUSIONS: We conclude that in this model of IgA-induced glomerulopathy, a selective, complement-dependent glomerular inflammation is induced in Wistar rats by glomerular codeposition of rat isotypic monoclonal antibodies.     

Repeat renal biopsy in children with IgA nephropathy

Serial renal biopsy findings in 61 children with IgA nephropathy were correlated with their clinical course. At the time of the second biopsy, 23 patients showed clinical remission defined as complete disappearance of proteinuria and hematuria with normal renal function while 38 had persistent urinary abnormalities with normal renal function at the second biopsy. There were no differences between the two groups with regard to initial clinical findings and pathologic findings of the initial renal biopsy. The second biopsy of patients with clinical remission showed improvement of the glomerular changes on light microscopy, disappearance or diminution of IgA deposits in the mesangium and decrease of electron-dense deposits, whereas the second biopsy of patients with persistent urinary abnormalities showed progression of glomerular changes on light microscopy, persistence of mesangial IgA deposits and persistence of electron-dense deposits. Our study results show the importance of repeat renal biopsy in children with IgA nephropathy with persistent urinary abnormalities, as a progression of glomerular changes is common in these patients. These observations suggest that the deposition of IgA in the mesangium may be responsible for the glomerular damage in children with IgA nephropathy.     

Methodological approaches to the analysis of IgA1 O-glycosylation in IgA nephropathy.

IgA nephropathy (IgAN) is a common form of glomerulonephritis in which IgA1 molecules deposit in the renal mesangium, leading to progressive glomerular inflammatory injury in a significant proportion of patients. The mechanisms underlying the pathogenesis of IgAN remain poorly understood, but altered O-glycosylation, a physicochemical abnormality of IgA1 observed in these patients, may be a contributory factor. Although many studies have reported aberrant IgA1 O-glycosylation in IgAN, the precise structural nature of the defect remains to be fully characterised, and analysis of IgA1 O-glycans has proved technically challenging. Three main strategies have been employed: lectin binding to the O-glycans in situ on the whole IgA1 molecule; mass spectroscopy of isolated O-glycosylated glycopeptides; and size/charge separation of free O-glycans released from IgA1. In this review, the basic principles, strengths and weaknesses of each of these methodological approaches are considered, together with a summary of the data obtained from their use. One of the common criticisms of many studies of IgA1 O-glycosylation is the method of IgA1 purification employed, and therefore, this issue is also critically discussed.     

Persistent dipstick haematuria following renal transplantation

Despite widespread testing for dipstick haematuria following renal transplantation, there are no published series describing the prevalence and possible causes of this complication in an adult population. A cross-sectional study of 640 renal transplant recipients under review at our follow-up clinic was performed. Persistent haematuria was defined as a minimum of 1+ of blood on urinalysis stick testing detected at not fewer than 75% of clinic visits since its onset, or since the start of routine testing, present over a period of at least 4 weeks. The prevalence of persistent dipstick haematuria was 13.3%. Median serum creatinine was higher in patients with persistent haematuria but age, gender and length of time since transplantation were not significantly different. Potential explanations for persistent haematuria in 21 of 85 affected patients were chronic infection, ureteric stent without chronic infection, regular or intermittent self-catheterization, persistent menstrual bleeding, anticoagulant therapy, graft calculus, and allograft renal cell carcinoma. Recurrent or de novo glomerular disease was confirmed by graft biopsy in 10 of 85 patients. Among the 41 recipients whose original cause of renal failure was IgA nephropathy (IgAN), the prevalence of persistent haematuria was 31.7% compared with 12% in the remaining patients (relative risk 2.6, 95% CI: 1.6-4.3). Persistent haematuria in IgAN patients was not associated with gender, age or time since transplantation. After 29 months of follow-up, 20% of patients with haematuria had progressed to graft failure or death compared with 11.6% of the unaffected group (p = 0.029). However, despite the association with earlier graft failure, haematuria did not predict this endpoint independently of renal function.     

Clinical effectiveness of steroid pulse therapy combined with tonsillectomy in patients with immunoglobulin A nephropathy presenting glomerular haematuria and minimal proteinuria

Aim: The effectiveness of steroid pulse therapy combined with tonsillectomy (ST) has been shown in immunoglobulin A nephropathy (IgAN) patients with moderate or severe urinary abnormalities. The present study aimed to clarify whether the effectiveness may be extrapolated to IgAN with minor urinary abnormalities, and whether the effectiveness may depend on the histological severity with minor urinary abnormalities. Methods: Data on 388 IgAN patients diagnosed by renal biopsies between 1987 and 2000 in Sendai Shakaihoken Hospital, who presented glomerular haematuria and minimal proteinuria (≤0.5 g/day) at baseline, were analyzed. Cox regression was used to examine associations between baseline use of ST and subsequent clinical remission (CR), defined as negative proteinuria by dipstick and urinary erythrocytes of less than 1/high‐power field. The instrumental variable method was also used to overcome confounding by treatment indication. Results: During a median follow up of 24 months, we observed 170 CR cases. Patients receiving ST were younger and showed a better case‐mix profile. Patients with ST had a significantly higher rate of CR than patients without tonsillectomy or steroid pulse in an unadjusted (hazard ratio (HR) = 5.51, 95% confidence interval (CI) = 3.33–9.12, P < 0.001) or adjusted Cox model (HR = 4.65, 95% CI = 2.43–8.88, P < 0.001). Less severe histological findings were substantially associated with higher CR rate in ST group. Adjusting for confounding by treatment indication showed an attenuated but still significant effect of ST (HR = 3.10, 95% CI = 2.02–4.77, P < 0.001). Conclusion: ST significantly increased the probability of CR in IgAN patients with glomerular haematuria and minimal proteinuria, and it was more effective in those with less severe histological findings.     

In situ hybridization studies of stromelysin and tissue inhibitor of metalloproteinase 1 in IgA nephropathy

Summary: Accumulation of the extracellular matrix (ECM) in IgA nephropathy (IgAN) is thought to cause deterioration of glomerular function. Stromelysin and tissue inhibitor of matrix proteinase 1 (TIMP1) may play an important role in the turnover of the glomerular ECM. However, the expression of these enzymes in human renal tissues remains undefined. In the present study, non-radioactive in situ mRNA hybridization, which permitted the analysis at a cellular level, was performed to localize stromelysin and TIMP1 in renal tissue of IgAN. We also determined the percentage of cells positive for stromelysin or TIMP1 mRNA among intraglomerular cells. A total of 16 patients with IgAN were examined, including eight patients with severe histopathological changes and eight with mild changes. Three patients without glomerular disease were also studied. Stromelysin and TIMP1 mRNA were weakly expressed in the mesangium of normal kidneys and IgAN renal tissues with mild damage. However, the expression of both mRNA was significantly increased in the area of mesangial proliferation, in glomerular epithelial cells and in Bowman's capsule of advanced lesions. Several cells in the area of mesangial proliferation were double positive for stromelysin and TIMP1 mRNA, while certain cells positive for stromelysin mRNA did not express TIMP1 mRNA. In the interstitium, epithelial cells of certain tubules and some mononuclear cells were positively stained for these mRNA, especially in advanced lesions. Our results indicated that stromelysin and TIMP1 genes were expressed in glomerular resident cells, tubular epithelial cells and infiltrated mononuclear cells in IgAN, and their expression was enhanced in advanced tissue damage. the demonstration of a co-expression and discordant expression of the genes indicates that each gene expression may be regulated in a cell type-specific manner and that it could also be altered by cellular environmental factors.