Biomedical subjects

Bruce A Julian

Publications and source records attributed to Bruce A Julian.

8 recordsLinked to original sources

PubMed2006

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.

Adolescent↗

PubMed2006

Brief communication: Glomerulonephritis in patients with hepatitis C cirrhosis undergoing liver transplantation.

BACKGROUND: Patients infected with hepatitis C virus (HCV) frequently develop renal failure after liver transplantation. OBJECTIVE: To describe renal histologic characteristics and concomitant clinical features in HCV-infected patients with end-stage cirrhosis. DESIGN: Case series. SETTING: Single-center liver transplant program in the United States. PATIENTS: 30 patients who received liver transplants for HCV-induced cirrhosis. INTERVENTION: Kidney biopsy during liver engraftment. MEASUREMENTS: Clinical data and laboratory tests of renal function within 6 months before liver transplantation. RESULTS: Twenty-five patients had immune-complex glomerulonephritis: membranoproliferative glomerulonephritis type 1 (n = 12), IgA nephropathy (n = 7), and mesangial glomerulonephritis (n = 6). Of these patients, 10 had normal serum creatinine levels, normal urinalysis results, and normal quantitative proteinuria. For 5 others, the only renal abnormality was an increased serum creatinine level. No patient had cryoglobulins in the blood or kidney. LIMITATIONS: This small observational study did not include patients with nonviral cirrhosis and did not document post-transplantation outcomes. CONCLUSIONS: Immune-complex glomerulonephritis was common in patients with end-stage HCV-induced cirrhosis and was often clinically silent. Its potential to cause renal failure after liver transplantation may be underappreciated.

Adult↗

PubMed2005

Recurrent IgA nephropathy after renal transplantation despite immunosuppressive regimens with mycophenolate mofetil.

BACKGROUND: Transplantation offers an excellent option for patients with immunoglobulin-A nephropathy (IgAN) with severe renal dysfunction. However, IgAN frequently recurs in allografts treated with azathioprine. We examined the impact of mycophenolate mofetil immunosuppression on recurrence of IgAN. METHODS: We reviewed the charts of patients transplanted for IgAN at our institution in the cyclosporin era. Patients were excluded from further analysis if follow-up was <12 months or if immunosuppression at engraftment did not include azathioprine or mycophenolate mofetil. Laboratory data, medications and allograft biopsy findings were compiled. RESULTS: 152 kidney transplantations met the study criteria. At engraftment, 61 allografts were treated with azathioprine and 91 with mycophenolate mofetil. By 3 years post-transplant, IgAN developed in six of 60 (10.0%) azathioprine-treated allografts and five of 62 (8.1%) mycophenolate mofetil-treated allografts (P = 0.76). Overall, 13 azathioprine-treated and seven mycophenolate mofetil-treated allografts showed recurrence. As expected in this retrospective study, the duration of observation was longer in the azathioprine group. The interval between engraftment and diagnosis of recurrent disease was also longer. Survival of allografts with recurrent IgAN was similar in the two groups. Survival of allografts with recurrent IgAN was worse than for allografts without recurrence or allografts transplanted into patients with non-IgAN renal failure. Neither switching azathioprine to mycophenolate mofetil nor using an angiotensin-converting enzyme inhibitor or angiotensin-II type 1 receptor blocker ameliorated the clinical course after a biopsy documented recurrent IgAN. CONCLUSIONS: Mycophenolate mofetil, compared with azathioprine, did not lessen the recurrence of IgAN or its clinical impact.

Adult↗

PubMed2005

IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells.

BACKGROUND: Sera of patients with IgA nephropathy (IgAN) contain circulating immune complexes (CIC) composed of galactose-deficient IgA1 complexed with antiglycan antibodies. The role of these CIC in the pathogenesis of IgAN is not known. METHODS: We studied how proliferation of cultured mesangial cells (MC) is affected by CIC prepared from sera of IgAN patients and healthy control subjects using size-exclusion chromatography. CIC-containing fractions were added to serum-starved MC in culture, and cell proliferation was measured using (3)H-thymidine incorporation. The results were confirmed by staining MC using an antibody against proliferating cell nuclear antigen. RESULTS: The incubation of starved MC with serum fractions with M(r) 800 to 900 kD, rich with galactose-deficient IgA1, stimulated proliferation, while fractions with smaller complexes were inhibitory. Furthermore, CIC-containing larger molecular mass fractions isolated from serum of an IgAN patient collected during an episode of macroscopic hematuria stimulated MC proliferation more than CIC obtained during a subsequent quiescent phase. To examine the role of IgA, we removed IgA1 from serum before fractionation. The resultant IgA1-depleted fractions were devoid of stimulatory IgA-CIC. Sera of IgAN patients were also fractionated after addition of desialylated galactose-deficient polymeric IgA1 to form additional immune complexes. Supplementation with a small quantity of this IgA1 increased cellular proliferation in assays using serum fractions of M(r)>/=800 to 900 kD; uncomplexed IgA1 did not affect MC proliferation significantly. In contrast, supplementation with a larger quantity of this IgA1 inhibited cellular proliferation in assays using serum fractions of M(r) 700 to 800 kD. CONCLUSION: Overall, these findings suggest that CIC containing aberrantly glycosylated IgA1 affect proliferation of MC in vitro and, thus, likely play a role in the pathogenesis of IgAN.

Adult↗

PubMed2004

Angiotensin II receptor type 1 expression in erythroid progenitors: Implications for the pathogenesis of postrenal transplant erythrocytosis.

Under normal physiological conditions red blood cell production is controlled primarily by erythropoietin, although multiple additional stimulatory factors are likely to be involved. One of these factors, angiotensin II, can modulate erythropoiesis directly via its type 1 receptor, as well as indirectly through multiple secondary mediators. We propose that angiotensin II exerts its stimulatory effect during the early stages of erythropoiesis, and that this effect serves as an important compensatory mechanism if erythropoietin production is chronically inadequate. We speculate that if this compensatory stimulation continues to be abnormally high after restoration of erythropoietin production following renal transplantation, erythrocytosis ensues.

Erythroid Precursor Cells↗

PubMed2004

IgA nephropathy: an update.

PURPOSE OF REVIEW: The elution of nephrectomy specimens from patients with IgA nephropathy yields IgA1 with galactose-deficient glycans in the hinge region. In this review, we summarize recent advances in our understanding of the role of the aberrant immunoglobulin in the pathogenesis of this form of glomerulonephritis. In the absence of a disease-specific therapy, we discuss current therapeutic approaches. RECENT FINDINGS: Galactose-deficient IgA1 forms macromolecular complexes that bind to mesangial cells and stimulate them to proliferate, synthesize various cytokines and chemokines, and secrete extracellular matrix proteins. Whereas progress has been made in understanding the glycosylation pathways of IgA1 O-linked glycans and binding galactose-deficient IgA1-complexes to mesangial cells, there is still no IgA nephropathy-specific therapy. The current approach to suppress the effects of angiotensin II, by angiotensin-converting enzyme inhibitors, angiotensin II receptor type 1 blockers, or both, as a cornerstone of the therapy of IgA nephropathy has been strengthened by recent studies. Treatment with glucocorticoids, cyclophosphamide, or both, may be appropriate for a subset of IgA nephropathy patients. SUMMARY: A better understanding of the mechanisms underlying the synthesis of galactose-deficient IgA1, the formation of circulating immune complexes, and interactions with mesangial cells will provide further insights into the pathogenetic mechanisms that culminate in the glomerular and interstitial damage of IgA nephropathy, and could identify novel therapeutic targets in the prevention and management of this renal disease.

Glomerular Mesangium↗

PubMed2003

Bone mineral density changes within six months of renal transplantation.

BACKGROUND: The effective use of new steroid-sparing immunosuppressive regimens may lower cumulative glucocorticoid use among renal transplant recipients. However, it is unknown what effect this therapeutic trend has had on bone disease. METHODS: Unselected newly transplanted inpatients (n=45) were identified and comprehensively evaluated for metabolic bone disease at a median of 16 days (range 9-33) posttransplant. A follow-up evaluation was conducted a median of 5.7 months (range 4.8-9.3) later. Follow-up values for bone mineral density (BMD) and select laboratories were compared with baseline values using nonparametric statistics. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to describe the associations of baseline characteristics, select laboratory values, and cumulative prednisone and cyclosporine use with spinal BMD loss and were calculated using logistic regression. RESULTS: A significant decrease in intact parathyroid hormone (P<0.001) and a significant increase in calcitriol (P=0.02) were noted postengraftment. At follow-up, subjects had lost a mean of 2.4% BMD at the lumbar spine (P=0.003) but did not experience significant declines at the femoral neck. The highest tertiles of cumulative prednisone (OR=28.4; 95% CI 2.5-329 and OR=15.8; 95% CI 1.4-179, respectively) and past alcohol use (OR=9.3; 95% CI 1.46-58.5) were significantly associated with spinal BMD loss. CONCLUSIONS: Significant loss in lumbar BMD occurred within 6 months of transplantation in more than one third of a prospective cohort of renal transplant recipients. Lumbar bone loss seemed to be mediated primarily by glucocorticoid dose and a history of alcohol use.

Adult↗

PubMed2002

Interactions of human mesangial cells with IgA and IgA-containing immune complexes.

BACKGROUND: IgA nephropathy (IgAN) is characterized by IgA1-containing immune complexes in mesangial deposits and in the circulation. The circulating immune complexes (CIC) are composed of galactose- (Gal) deficient IgA1 and IgG or IgA1 antibodies specific for the Gal-deficient IgA1; interactions of these CIC with mesangial cells (MC) were studied. METHODS: Binding, internalization, and catabolic degradation of myeloma IgA1 protein as a standard control and the isolated CIC were studied using human MC, hepatoma cell line HepG2 expressing the asialoglycoprotein receptor (ASGP-R), and monocyte-like cell line U937 expressing the Fc(alpha)-R (CD89). Biochemical and molecular approaches were used to assess expression of CD89 and ASGP-R by MC. RESULTS: At 4 degrees C, radiolabeled IgA1 bound to MC and HepG2 cells in a dose-dependent and saturable manner. The binding was inhibited by IgA-containing CIC or excess IgA1 or its Fc fragment but not by the Fab fragment of IgA1. At 37 degrees C, the cell-bound IgA1 was internalized and catabolized. In addition to IgA1, HepG2 cells also bound (in a Ca2+-dependent manner), internalized, and catabolized asialoorosomucoid (ASOR), other asialo-(AS)-glycoproteins, and secretory component (SC). The binding by MC appeared to be restricted to IgA1 or AS-IgA1 and was not Ca2+-dependent. Furthermore, MC and HepG2 cells internalized and catabolized IgA1-containing CIC. Using RT-PCR with ASGP-R- or CD89-specific primers, mRNAs of the two respective genes were not detected in MC. CONCLUSIONS: The data showed that the ability of MC to bind IgA1 and IgA1-containing CIC in vitro was mediated by an IgA receptor that was different from CD89 or ASGP-R and had a higher affinity for IgA-CIC than for uncomplexed IgA.

Antibody Affinity↗