Disease Activity In IgA Nephropathy Research Articles

PS-BPR03-10: A CASE OF A WOMAN WITH IGA NEPHROPATHY PRESENTING DURING PREGNANCY

Background: Pregnancy has an influence on autoimmune diseases course and many autoimmune diseases go into remission during pregnancy. The details of the autoimmune mechanism of IgA nephropathy have not been elucidated. The disease activity of IgA nephropathy commonly is stable during pregnancy, however, IgA nephropathy is at high risk of pregnancy complications even if renal function is preserved, and prevention of pregnancy complications are important in pregnant woman with IgA nephropathy. Case: A 29 year-old woman, gravida 2, para 0, no history of abnormal urine analysis before pregnancy, presented preeclampsia at 32 weeks pregnancy, and an emergency cesarean section was performed at 32 weeks and 5 days pregnancy. After delivery, microscopic hematuria persisted. Renal biopsy was performed 1 year and 9 months after delivery, and IgA nephropathy was diagnosed. Tonsillectomy was performed for IgA nephropathy, and the patient's renal function did not deteriorate during the follow-up period. In the second pregnancy, low-dose-aspirin was administered from the first trimester, and full term infants delivered without any pregnancy complications. Conclusion: IgA nephropathy can become apparent in pregnancy. Postpartum evaluation of urinalysis is important for the early detection of the primary renal disease. In pregnant woman with IgA nephropathy, stabilization of the disease state and administration of low-dose aspirin are very important for outcome of pregnancy and maternal renal prognosis.

Galactose-Deficient IgA1-Specific Antibody Recognizes GalNAc-Modified Unique Epitope on Hinge Region of IgA1.

Galactose-deficient IgA1 (Gd-IgA1) that exposes GalNAc or sialylated GalNAc has been shown to be associated with disease activity of IgA nephropathy (IgAN). In a previous report, we established an enzyme-linked immunosorbent assay that measures human Gd-IgA1 using a specific monoclonal antibody KM55 (KM55 mAb), and showed that patients with IgAN contain a higher level of serum Gd-IgA1 than other types of renal diseases. Recently, we also found that the KM55 mAb specifically recognized the glomerular-deposited Gd-IgA1 in renal biopsy. In this study, we aimed to analyze the epitope of KM55 mAb using synthesized peptides corresponding to the hinge region of IgA1 with GalNAc moiety on putative glycosylated Ser/Thr residues, which are Thr225, Thr228, Ser230, Ser232, and Thr236. Binding analysis to single GalNAc-modified hinge region peptide of IgA1 showed that Thr225 with GalNAc is required for recognition of KM55. PST(GalNAC)PP motif was required for KM55 mAb to recognize hinge region peptide of IgA1 which is shown by binding assay with deletion peptide. This result was confirmed by binding of KM55 mAb against peptide with GalNAc at Thr233, which resulted in containing another PST(GalNAC)PP motif. Taken together, we concluded that the epitope of Gd-IgA1-specific KM55 mAb is PST(GalNAc)PP motif.

Circulating complement factor H–related proteins 1 and 5 correlate with disease activity in IgA nephropathy

IgA nephropathy (IgAN) is a common cause of chronic kidney disease and end-stage renal failure, especially in young people. Due to a wide range of clinical outcomes and difficulty in predicting response to immunosuppression, we need to understand why and identify which patients with IgAN will develop progressive renal impairment. A deletion polymorphism affecting the genes encoding the complement factor H-related protein (FHR)-1 and FHR-3 is robustly associated with protection against IgAN. Some FHR proteins, including FHR-1 and FHR-5, antagonize the ability of complement factor H (fH), the major negative regulator of the complement alternative pathway, to inhibit complement activation on surfaces, a process termed fH deregulation. From a large cohort of patients, we demonstrated that plasma FHR-1 and the FHR-1/fH ratio were elevated in IgAN and associated with progressive disease. Plasma FHR-1 negatively correlated with eGFR but remained elevated in patients with IgAN with normal eGFR. Serum FHR5 was slightly elevated in IgAN but did not correlate with eGFR. Neither FHR5 levels nor the FHR-5/fH ratio was associated with progressive disease. However, higher serum FHR-5 levels were associated with a lack of response to immunosuppression, the presence of endocapillary hypercellularity, and histology scores of disease severity (the Oxford Classification MEST score). Thus, FHR-1 and FHR-5 have a role in IgAN disease progression.

Urine podocyte mRNAs mark disease activity in IgA nephropathy.

Podocyte depletion is a major mechanism driving glomerulosclerosis. We and others have previously projected from model systems that podocyte-specific mRNAs in the urine pellet might serve as glomerular disease markers. We evaluated IgA nephropathy (IgAN) to test this concept. From 2009 to 2013, early morning voided urine samples and kidney biopsies from IgAN patients (n = 67) were evaluated in comparison with urine samples from healthy age-matched volunteers (n = 28). Urine podocyte (podocin) mRNA expressed in relation to either urine creatinine concentration or a kidney tubular marker (aquaporin 2) was tested as markers. Urine podocyte mRNAs were correlated with the severity of active glomerular lesions (segmental glomerulosclerosis and acute extracapillary proliferation), but not with non-glomerular lesions (tubular atrophy/interstitial fibrosis) or with clinical parameters of kidney injury (serum creatinine and estimated glomerular filtration rate), or with degree of accumulated podocyte loss at the time of biopsy. In contrast, proteinuria correlated with all histological and clinical markers. Glomerular tuft podocyte nuclear density (a measure of cumulative podocyte loss) correlated with tubular atrophy/interstitial fibrosis, estimated-glomerular filtration rate and proteinuria, but not with urine podocyte markers. In a subset of the IgA cohort (n = 19, median follow-up period = 37 months), urine podocyte mRNAs were significantly decreased after treatment, in contrast to proteinuria which was not significantly changed. Urine podocyte mRNAs reflect active glomerular injury at a given point in time, and therefore provide both different and additional clinical information that can complement proteinuria in the IgAN decision-making paradigm.

Serum levels of galactose-deficient immunoglobulin (Ig) A1 and related immune complex are associated with disease activity of IgA nephropathy

BackgroundThe primary abnormal manifestation in immunoglobulin A nephropathy (IgAN) is recurring bouts of hematuria with or without proteinuria. Although immunohistochemical analysis of renal biopsy tissue remains the gold standard not only for diagnosis but also for evaluating the activity of IgAN, new sensitive and reasonably specific noninvasive tests are emerging to guide therapeutic strategy applicable to all stages of IgAN. The present study examined serum levels of galactose-deficient IgA1 (Gd-IgA1) and its immune complex (IgA/IgG-IC) as noninvasive markers for the disease activity.MethodsWe enrolled 50 IgAN patients (male 40 %, median age 37 years) showing complete or partial clinical remission after steroid pulse therapy with tonsillectomy (TSP) whose clinical data and serum could be followed up for 3–5 years.ResultsCross-sectional analysis revealed that the degree of hematuria and proteinuria were significantly associated with levels of Gd-IgA1 and levels of IgA/IgG-IC. Longitudinal analysis further showed that from the group of 44 patients with heavy hematuria before TSP, 31 patients showed complete disappearance of hematuria (group A), but the remaining patients did not (group B). Although the levels of Gd-IgA1 and IgA/IgG-IC in the two groups before TSP were similar, percentage decrease of Gd-IgA1 and IgA/IgG-IC levels in group A was significantly higher than in group B.ConclusionDisease activity of IgAN assessed by hematuria and proteinuria correlated with serum levels and changes of Gd-IgA1 and IgA/IgG-IC. These new noninvasive disease activity markers can be useful for future activity scoring system and guiding therapeutic approaches.

Gene expression profiles of circulating leukocytes correlate with renal disease activity in IgA nephropathy

The goal of these studies was to explore the possibility of using gene expression profiles of circulating leukocytes as a functional fingerprint of nephritic disease activity. This feasibility study utilized IgA nephropathy (IgAN) as a model system. Genes differentially expressed in IgAN patients were identified by Affymetrix GeneChip microarrays, and compared with gene expression of focal segmental glomerulosclerosis (FSGS), minimal change disease, antineutrophil cytoplasmic antibody (ANCA) glomerulonephritis, and with healthy volunteers. Of the genes identified, 15 transcriptionally up-regulated were validated in a larger cohort of patients using TaqMan polymerase chain reaction (PCR). To test whether increased expression of these genes correlated with disease activity, cluster analyses were performed utilizing the TaqMan PCR values. Taking a mathematical approach, we tested whether gene expression values were correlative with kidney function, as reflected by serum creatinine and creatinine clearance values. We identified 15 genes significantly correlative with disease activity in IgAN. This gene signature of IgAN patients' leukocytes reflected kidney function. This was demonstrated in that mathematically generated theoretical values of serum creatinine and creatinine clearance correlated significantly with actual IgAN patient values of serum creatinine and creatinine clearance. There was no apparent correlation with hematuria and proteinuria. The expression levels of this same gene set in ANCA glomerulonephritis or Lupus nephritis patients were not correlative with serum creatinine or creatinine clearance values. These data indicate that leukocytes carry informative disease-specific markers of pathogenic changes in renal tissue.

Gene expression profiles of circulating leukocytes correlate with renal disease activity in IgA nephropathy

Gene expression profiles of circulating leukocytes correlate with renal disease activity in IgA nephropathy

Glomerular expression of alpha-smooth muscle actin reflects disease activity of IgA nephropathy.

To elucidate the relationship between histological disease states and clinicopathological features in immunoglobulin A nephropathy (IgAN), 90 needle-biopsy specimens diagnosed as IgAN were analyzed. The specimens were divided into four groups according to histological grade and stage index. Immunohistochemical features of alpha-smooth muscle actin (alpha-SMA), macrophages positive for myeloid/histiocyte antigen (MAC387), and expression of type I, III and IV collagens were all examined. Glomerular expression scores of alpha-SMA and the degree of intraglomerular macrophage infiltration were highest in the active and non-sclerotic groups. Type I and IV collagens were significantly more abundant in the sclerotic groups than in the active groups. Type III collagen was strongly expressed in both the active and sclerotic groups. Double immunolabeling of alpha-SMA and intercellular adhesion molecule (ICAM)-1 revealed that ICAM-1 was expressed around the alpha-SMA-positive mesangial area. In multivariate analysis, the glomerular expression score of alpha-SMA was mostly correlated with histological grading in the 10 clinicopathological parameters. Type IV collagen score was mostly correlated with histological staging. These results suggest that glomerular alpha-SMA expression reflects the histological activity of IgAN. Immunohistological staining of alpha-SMA is valuable to estimate the degree of disease activity in IgAN.

Increased Interleukin 6 mRNA Expression by Peripheral Blood T Cells From Patients With IgA Nephropathy

We investigated interleukin 6 (IL-6) mRNA expression in peripheral blood T-cells obtained from 36 patients with IgA nephropathy (IgAN), 36 patients with other glomerulonephritides and 24 healthy age-matched controls. The majority of patients with IgAN had increased IL-6 mRNA expression by their T cells; no IL-6 mRNA was detected in T cells obtained from patients with other glomerulonephritides or normal controls. A positive correlation was noted between the IL-6 mRNA level and quantity of protein excretion in the urine, histopathological findings, and renal function. However, there was no significant correlation between IL-6 mRNA expression and the IgA-immune complex titer, serum IgA level or blood pressure. mRNA levels in T cells obtained from patients with grade III or IV renal histopathological findings were significantly higher than in those with grade I or II histopathology. In addition, mRNA levels in T cells obtained from patients with more than 1.0 g/day proteinuria were markedly higher than those with less than 1.0 g/day proteinuria. We also studied the clinical course of 11 patients with IgAN during hospitalization. The IL-6 mRNA levels in these patients decreased gradually, as did proteinuria, after treatment. These studies suggest that abnormally regulated IL-6 mRNA expression in peripheral blood T cells may be associated with disease activity in IgAN.