Serial Galactose-Deficient IgA1 Levels in Children with IgA Nephropathy and Healthy Controls.

Galactose-deficient IgA1 (Gd-IgA1) is a key pathogenic factor for IgA nephropathy (IgAN) and a potential biomarker for the disease. This study examined serial serum Gd-IgA1 levels over 1 year in 13 children with IgAN and 40 healthy children, to determine whether or not serum Gd-IgA1 levels changed over time. Subjects were younger than 18 years of age. Follow-up measurements were scheduled 6 and/or 12 months later. Analysis of variance and regression models for repeated measures were used to estimate group and time effects. Serum Gd-IgA1 level was higher in initial samples for IgAN patients compared to those of healthy children (P < 0.0001). Serum Gd-IgA1 levels did not change over time for healthy controls but increased for IgAN patients (P = 0.001). Serum Gd-IgA1 level was elevated for 9 children with IgAN at study entry and remained elevated. Two of the 4 IgAN patients with initially normal Gd-IgA1 levels had a subsequent elevated level. The persistent elevation of the serum Gd-IgA1 level in children with IgAN enhances its utility as a potential diagnostic test for IgAN.

Biomarkers in IgA nephropathy: relationship to pathogenetic hits.

INTRODUCTION: IgA nephropathy, the most prevalent glomerular disease in the world, requires a renal biopsy for diagnosis. Reliable biomarkers are needed for the non-invasive diagnosis of this disease and to more fully delineate its natural history and risk for progression. AREAS COVERED: In this review, the authors examine serum levels of galactose-deficient IgA1 (Gd-IgA1) and glycan-specific IgG and IgA autoantibodies that are integral to pathogenesis of IgA nephropathy. They also explore biomarkers related to alternative and lectin pathways of complement activation and serum and urinary peptide biomarkers detected by mass spectrometric methods. The literature search included review of all publications having IgA nephropathy in the title that were cited in PubMed and Scopus over the past 10 years and a non-systematic review of abstracts published for the annual meetings of the American Society of Nephrology and the International Symposia on IgA Nephropathy. EXPERT OPINION: Serum Gd-IgA1 level and glycan-specific autoantibody levels are prime candidates to become diagnostic biomarkers for IgA nephropathy because of their central role in the earliest stages of disease pathogenesis. Assays for serum levels of complement proteins C3 and factor H are readily available in clinical practice and deserve continued study, either alone or in tandem with total serum IgA or serum Gd-IgA1 levels, as prognostic biomarkers for patients with IgA nephropathy. Urinary peptidomic data are also reviewed because this approach can successfully differentiate patients with IgA nephropathy from healthy controls and from patients with other forms of renal disease.

Association of IgG co-deposition with serum levels of galactose-deficient IgA1 in pediatric IgA nephropathy.

OBJECTIVE: To determine whether the absence of mesangial IgG deposits is associated with the absence of elevated blood levels of galactose-deficient IgA1 (Gd-IgA1) in pediatric patients with IgA nephropathy (IgAN). DESIGN AND METHODS: Serum Gd-IgA1 levels were determined by ELISA using an N-acetylgalactosamine-specific lectin from Helix aspersa. Levels of Gd-IgA1 above the 90th percentile for healthy pediatric controls were considered to be elevated. Renal biopsy samples were examined by immunofluorescence for presence and intensity of staining for IgA, IgG, IgM, C3 and C1q and by light microscopy for histological changes. Findings were graded by a single pathologist (L. Gaber) at UTHSC until 2007 and by NephropathTM (Little Rock, AR, USA) thereafter. Staining for the mesangial deposits was considered negative when intensity was trace or less, and positive at greater intensity. Fisher's exact test was used to determine significance of 2 × 2 tables. RESULTS: Serum samples were obtained from 30 patients with IgAN diagnosed before age 18 years. Male:female ratio was 2.3:1. Twenty were Caucasian and 10 were African-American. Blood was obtained within 3 months of biopsy (incident cases) for 12, while 18 provided blood > 3 months after biopsy (prevalent cases). Serum Gd-IgA1 level was elevated in 23 (77%) of cases and 20 (67%) had a biopsy positive for IgG. Of those 20 patients, 18 (90%) had an elevated serum Gd-IgA1 level, whereas 5 (50%) of patients with biopsies without IgG had a normal serum Gd-IgA1 level (p = 0.026). SUMMARY: In this small study we found a weak association between the absence of IgG in the biopsy and normal serum Gd-IgA1 level.

Serum galactose-deficient IgA1 level is not associated with proteinuria in children with IgA nephropathy.

Introduction. Percentage of galactose-deficient IgA1 (Gd-IgA1) relative to total IgA in serum was recently reported to correlate with proteinuria at time of sampling and during follow-up for pediatric and adult patients with IgA nephropathy. We sought to determine whether this association exists in another cohort of pediatric patients with IgA nephropathy. Methods. Subjects were younger than 18 years at entry. Blood samples were collected on one or more occasions for determination of serum total IgA and Gd-IgA1. Gd-IgA1 was expressed as serum level and percent of total IgA. Urinary protein/creatinine ratio was calculated for random specimens. Spearman's correlation coefficients assessed the relationship between study variables. Results. The cohort had 29 Caucasians and 11 African-Americans with a male : female ratio of 1.9 : 1. Mean age at diagnosis was 11.7 ± 3.7 years. No statistically significant correlation was identified between serum total IgA, Gd-IgA1, or percent Gd-IgA1 versus urinary protein/creatinine ratio determined contemporaneously with biopsy or between average serum Gd-IgA1 or average percent Gd-IgA1 and time-average urinary protein/creatinine ratio. Conclusion. The magnitude of proteinuria in this cohort of pediatric patients with IgA nephropathy was influenced by factors other than Gd-IgA1 level, consistent with the proposed multi-hit pathogenetic pathways for this renal disease.

IgA1 immune complexes from pediatric patients with IgA nephropathy activate cultured human mesangial cells.

BACKGROUND: Circulating immune complexes (CIC) containing galactose (Gal)-deficient IgA1 from adults with IgA nephropathy (IgAN) induce proliferation of cultured mesangial cells, but activities of CIC from pediatric patients with the disease have not been studied. METHODS: CIC of different sizes were isolated from sera of pediatric and adult IgAN patients and their effects on cultured human mesangial cells (MC) were assessed by measuring cellular proliferation, expression of IL-6 and IL-8 and laminin and phosphotyrosine signaling. RESULTS: Large CIC from pediatric IgAN patients (>800 kDa) containing Gal-deficient IgA1 stimulated cellular proliferation, whereas in some patients, smaller CIC were inhibitory. Addition of stimulatory and inhibitory CIC to MC differentially altered phosphorylation patterns of three major tyrosine-phosphorylated proteins of molecular mass 37, 60 and 115 kDa. The stimulatory CIC transiently increased tyrosine-phosphorylation of the 37-kDa protein and decreased phosphorylation of the other two proteins, whereas the inhibitory CIC increased phosphorylation of all three proteins. Furthermore, we investigated the influence of IgA1-containing CIC from sera of children with IgAN with clinically active disease (i.e., abnormal urinalysis and/or serum creatinine concentration) or inactive disease (i.e., normal urinalysis and serum creatinine concentration) on the expression of IL-6 and IL-8 genes by mesangial cells. Real-time reverse transcription-polymerase chain reaction results showed that the CIC from a patient with active disease stimulated MC to express the two cytokine genes at higher levels than did the CIC from a patient with inactive disease. Moreover, stimulatory CIC increased production of the extracellular matrix protein laminin. CONCLUSION: These data indicate that sera of pediatric IgAN patients contain biologically active CIC with Gal-deficient IgA1.

Aberrant glycosylation of IgA1 is inherited in both pediatric IgA nephropathy and Henoch-Schönlein purpura nephritis.

Serum galactose-deficient immunoglobulin A1 (Gd-IgA1) is an inherited risk factor for adult IgA nephropathy (IgAN). In this paper, we determined the heritability of serum Gd-IgA1 levels in children with IgAN and Henoch-Schönlein purpura nephritis (HSPN), two disorders with clinical phenotypes sharing common pathogenic mechanisms. Serum Gd-IgA1 concentrations were quantified using a Helix aspersa-lectin-based enzyme-linked immunosorbent assay. As a group, 34 children with either disorder (20 with HSPN and 14 with IgAN) had significantly higher Gd-IgA1 levels compared with 51 age- and ethnicity-matched pediatric controls. Serum levels of Gd-IgA1 were also elevated in a large fraction of 54 first-degree relatives of pediatric IgAN and HSPN patients compared with 141 unrelated healthy adult controls. A unilineal transmission of the trait was found in 17, bilineal transmission in 1, and sporadic occurrence in 5 of 23 families when both parents and the patient were analyzed. There was a significant age-, gender-, and household-adjusted heritability of serum galactose-deficient IgA1 estimated at 76% in pediatric IgAN and at 64% in HSPN patients. Thus, serum galactose-deficient IgA1 levels are highly inherited in pediatric patients with IgAN and HSPN, providing support for another shared pathogenic link between these disorders.

Galactose-deficient IgA1 in African Americans with IgA nephropathy: serum levels and heritability.

BACKGROUND AND OBJECTIVES: Serum levels of galactose-deficient IgA1 (Gd-IgA1) are elevated and heritable in Caucasian and Asian patients with IgA nephropathy (IgAN), but have not been characterized in African Americans (AA). Our objective was to determine whether serum Gd-IgA1 levels are increased in AA patients with IgAN and whether this is a heritable trait in this group. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Blood and urine samples were obtained from 18 adult and 11 pediatric AA patients with biopsy-proven IgAN and from 34 of their first-degree relatives. Healthy controls included 150 Caucasian adults, 65 AA adults, 45 Caucasian children, and 49 AA children. Serum total IgA and Gd-IgA1 levels were measured in patients and controls. Significant differences between patient and control groups for serum total IgA, Gd-IgA1, and ratio of Gd-IgA1/total IgA were determined by the Mann-Whitney U test. Heritability was calculated using SOLAR. RESULTS: After stratifying by age, 7 of 11 pediatric and 9 of 18 adult AA patients with IgAN had serum Gd-IgA1 levels above the 95th percentile for age-appropriate AA controls. For first-degree relatives, the serum Gd-IgA1 level was >95th percentile for 1 of 8 when the patient's level was <95th percentile and 12 of 26 when the patient's level was >95th percentile (P = 0.116, Fisher exact test). Heritability was 0.74 (P = 0.007). CONCLUSIONS: Serum levels of Gd-IgA1 are often elevated in AA patients with IgAN and their first-degree relatives. Thus, aberrant IgA1 glycosylation is a heritable risk factor for IgAN in African Americans.

Work up of the child with hypertension.

This paper outlines the work up of children with hypertension. In those with confirmed hypertension, the initial work up should be focused on the evaluation for renal parenchymal and renovascular disease. Secondary evaluation should be focused on history and clinical findings. Consideration of angiography should be made in children with severe hypertension and no evidence of renal parenchymal disease, with hypertension requiring more than a single antihypertensive agent to achieve adequate BP control, or with confirmed BP > 99th percentile for sex/age/height percentile. Screening for endocrinopathies should be directed by compatible history and findings on physical examination and should not be a part of a routine initial work up. In any child diagnosed with hypertension, attempts should be made to evaluate for end-organ disease and co-morbid conditions, particularly left ventricular hypertrophy. Pediatricians should establish a degree of comfort in the evaluation and management of hypertension; however, children with severe and complicated hypertension should be referred to a specialist well versed and practiced in the evaluation and management of this disease.

Two cases of hematuria with hemoglobin C trait.

Patients with sickle cell disease commonly experience painless hematuria. Hematuria may be found in patients with sickle cell trait, sickle cell anemia, and sickle cell hemoglobin C disease, but it is believed to be uncommon in patients with other hemoglobinopathies, such as hemoglobin C disease and hemoglobin C trait. We report two cases of children with hemoglobin C trait who presented with persistent painless hematuria. Because it is possible that hematuria in a patient with hemoglobin C trait is purely coincidental, all patients with a hemoglobinopathy and hematuria should undergo a complete evaluation so as not to overlook other causes of hematuria.

IgA nephropathy and Henoch-Schönlein purpura nephritis.

PURPOSE OF REVIEW: IgA nephropathy and Henoch-Schönlein purpura nephritis are common glomerular disorders in pediatrics that can potentially progress to end-stage renal disease in some patients. This review summarizes our current understanding of the pathogenesis of these closely related conditions and discusses the rationale for development of diagnostic tests and prognostic markers. The review also presents the best data for long-term outcome, clinical markers of prognosis, and the results of randomized controlled trials. RECENT FINDINGS: Our understanding of the defective galactosylation of O-linked glycans in the hinge region of human IgA1 and its role in the pathogenesis of IgA nephropathy and Henoch-Schönlein purpura nephritis has evolved over the past decade. This review discusses studies that suggest that demonstration of galactose-deficient IgA1 in the serum may become an important diagnostic tool for these conditions. Proteomic techniques for development of biomarkers for diagnosis and prognosis show promise. Although data from randomized controlled trials have failed to support the use of immunosuppressive agents in pediatric IgA nephropathy and Henoch-Schönlein purpura nephritis, recent data indicate that angiotensin converting enzyme inhibitor therapy is indicated for reduction of proteinuria. SUMMARY: Childhood IgA nephropathy and Henoch-Schönlein purpura nephritis have the potential for serious morbidity, either during childhood or later in adulthood. In the future clinical tests will be used for noninvasive diagnosis and as markers for judging response to treatment, particularly in those individuals at highest risk for eventual progression to end-stage renal disease.