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Biomedical subjects

J Feehally

Publications and source records attributed to J Feehally.

At least 19 recordsLinked to original sources
PubMed2006

Treatment of IgA nephropathy.

IgA nephropathy (IgAN) is an important cause of progressive kidney disease with 25-30% of patients developing end-stage renal disease within 20 years of diagnosis. There is still no treatment to modify mesangial IgA deposition and available treatments are those extrapolated from the management of other patterns of chronic glomerulonephritis. There remains no consensus on the use of immunosuppressive agents for treatment of progressive IgAN and this is compounded by the relative lack in IgAN of randomized controlled trials relevant to current clinical practice. Patients with recurrent macroscopic hematuria or isolated microscopic hematuria and proteinuria <1 g/24 h require no specific treatment. Those with nephrotic syndrome and minimal change on renal biopsy should be managed as for minimal change nephropathy. There is no evidence to support the use of corticosteroids for nephrotic IgAN outside this group of patients. Patients presenting with acute renal failure require evaluation to distinguish acute tubular necrosis, which requires supportive therapy only, from crescentic IgAN, for which treatment with cyclophosphamide and corticosteroids in a regimen similar to that for renal small vessel vasculitis is indicated in the absence of significant chronic histologic injury. Patients at greatest risk of progressive renal impairment are those with hypertension, proteinuria >1 g/24 h, and reduced glomerular filtration rate at diagnosis. All such patients should be treated to a blood pressure of 125/75 mm Hg with dual blockade of the renin-angiotensin system with angiotensin-converting enzyme inhibition and angiotensin receptor blockade. At present, there is insufficient evidence for the additional use of immunosuppressive agents, antiplatelet agents, or anticoagulants.

Disease Progression↗
PubMed2005

Treatment and outcome of adult patients with primary focal segmental glomerulosclerosis in five UK renal units.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is the least studied of the causes of idiopathic nephrotic syndrome, and there are few specific guidelines for treatment. AIM: To review data from five UK renal units to investigate whether adult patients with FSGS were treated uniformly, and to examine the effect of treatment on proteinuria and survival. DESIGN: Retrospective record review. METHODS: We examined electronic records of patients with idiopathic FSGS for information on baseline clinical parameters, treatment regimens and outcomes. RESULTS: Of 136 patients with primary FSGS and nephrotic range proteinuria, 76 (56%) were treated with prednisolone and of this group, 59% were treated with additional immunosuppression. Among the treated patients, the total remission rate (complete and partial) was 67%, and one hospital achieved a remission rate of 80%. Treated patients had a significantly higher remission rate than those who were not treated. Remission was associated with a 5-year survival off dialysis of 94%, compared with 53% if remission was not achieved. Baseline serum creatinine and remission were independently associated with survival off dialysis in a multivariate Cox proportional hazards model. DISCUSSION: Patients with primary FSGS and nephrotic range proteinuria, who are treated with corticosteroids, are more likely to enter remission than those who are not treated. Remission rates of up to 80% can be achieved with prolonged treatment, and remission is an independent predictor of survival off dialysis. Patients who do not achieve remission have a poor prognosis. Further clarification of optimal treatment regimens requires additional, prospective studies.

Adolescent↗
PubMed2002

Expression of T cell receptor variable region families by bone marrow gammadelta T cells in patients with IgA nephropathy.

IgA nephropathy (IgAN) is characterized by mesangial deposition of polymeric IgA (pIgA). Abnormalities of the IgA system include reduced mucosal and increased bone marrow (BM) pIgA production. Gammadelta T cells are regulators of mucosal IgA production and oral tolerance. We have described previously a deficiency of gammadelta T cells expressing Vgamma3 and Vdelta3 from the duodenal mucosa in IgAN. Since pIgA production is displaced to the BM, we have now studied BM gammadelta T cells in IgAN. Peripheral blood and BM aspirates were obtained from 14 patients with IgAN and 15 controls. Expression of TCR gamma and delta V region families was analysed by semiquantitative RT-PCR, and CDR3 spectratyping of Vgamma1-4 and Vdelta3 genes was performed. We found no difference between IgAN and controls in the V region usage of blood gammadelta T cells. However, in the BM of patients with IgAN, there was significantly reduced expression of the V region families Vgamma3 and Vdelta3, with the decrease in Vdelta3 being particularly striking. CDR3 spectratyping showed no abnormalities in blood or BM samples. Vgamma3 and Vdelta3 are underexpressed in the duodenum and the BM in IgAN. The combination of imbalanced mucosal and systemic pIgA production with deficient expression of gammadelta T cells using Vgamma3 and Vdelta3 in both sites may imply a role for these gammadelta T cells in the normal regulation of IgA immune responses, and in the complex immunopathogenesis of IgAN.

Adult↗
PubMed2001

Turnover of human tubular cells exposed to proteins in vivo and in vitro.

BACKGROUND: The cause of tubulointerstitial pathology in glomerular disease is uncertain. Proteinuria may be a causative factor and has been shown to increase the turnover of tubular cells in a rat model of proteinuria. We investigated whether increased tubular cell proliferation occurs in human proteinuric renal disease. A human cell culture model was used to investigate the effects of proteins on tubular cell turnover further. METHODS: Tubular proliferation in renal biopsies from patients with membranous nephropathy (MN) and minimal change nephropathy (MCN) was assessed by in situ hybridization for histone mRNA. Proliferation was measured in polarized human tubular cell cultures using tritiated thymidine, following addition of proteins to the apical medium. Toxicity was assessed by lactate dehydrogenase (LDH) release and monolayer permeability to inulin. RESULTS: Increased tubular cell histone mRNA expression occurred in biopsies in MN (3.0-fold increase, P < 0.002) and MCN (3.6-fold increase, P < 0.02). Serum proteins added to the medium on human tubular cell cultures increased thymidine uptake (1.3-fold, P < 0.005), LDH release (1.5-fold, P < 0.001), and monolayer permeability (1.7-fold, P < 0.005). The effects were reproduced by a fraction of molecular weight 40 to 100 kD, but not by pure albumin or transferrin. CONCLUSIONS: Proliferation of tubular cells is associated with proteinuria in vivo and is caused by proteins in cell culture. Toxicity of proteins to tubular cells and increased cell turnover may contribute to tubulointerstitial pathology in glomerular disease.

Adult↗
PubMed2001

Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: observations in three patients.

BACKGROUND: In IgA nephropathy (IgAN), circulating IgA1 molecules display an abnormal pattern of O-glycosylation. This abnormality may potentially contribute to mesangial IgA1 deposition, but this is unproven because the O-glycosylation of mesangial IgA1 has not been analyzed. METHODS: IgA1 was eluted from glomeruli isolated from the kidneys of three IgAN patients obtained after nephrectomy or at postmortem. Serum from these patients, other patients with IgAN, and controls was subjected to the same treatment as the glomerular eluates. The O-glycosylation of eluted and serum IgA1 was measured by lectin binding using an enzyme-linked immunosorbent assay-based system. RESULTS: In all three cases, the lectin binding of IgA1 eluted from the glomeruli of IgAN patients was markedly higher than that of the serum IgA1 of the same individual, and also all but one of a series of serum IgA1 samples from other patients and controls. CONCLUSIONS: The higher lectin binding of glomerular compared with serum IgA1 suggests that O-glycosylated IgA1 molecules abnormally and selectively deposit in the kidney. These results provide the first evidence that mesangial IgA1 is abnormally O-glycosylated, and support a direct role for abnormal IgA1 O-glycosylation in the mechanism of mesangial IgA deposition in IgAN.

Adult↗
PubMed2000

Identification of a novel Fcalpha receptor expressed by human mesangial cells.

BACKGROUND: IgA nephropathy (IgAN) is characterized by mesangial deposits of polymeric IgA (pIgA). The pathological consequences of IgA deposition are believed to center on direct interaction between IgA and the glomerular mesangial cell (MC). We have characterized a novel mesangial receptor that recognizes the Fc portion of IgA. METHODS: Five primary MC cultures were evaluated for IgA binding by flow cytometry, and specificity of binding was determined by competitive inhibition. Relative affinities of the receptor for all IgA isoforms were also determined, and binding of pIgA1 was compared to monomer. The identified Fc receptor was then compared with CD89, hitherto the only other Fcalpha receptor reported. CD89 protein and mRNA expression were detected by conventional and intracellular flow cytometry, sequencing of reverse transcription-polymerase chain reaction (RT-PCR) products, and Northern blotting. RESULTS: All MCs constitutively expressed a receptor that bound IgA in an Fcalpha-dependent fashion. The receptor recognized secretory and serum IgA1 and IgA2 equally, but pIgA bound with much greater affinity than monomer. At no time were we able to detect CD89 synthesis, although three novel CD89-related mRNA transcripts were identified by RT-PCR. CONCLUSIONS: We have clearly demonstrated that MCs consistently express an FcalphaR distinct from the myeloid FcalphaR CD89. This novel receptor binds pIgA with high affinity and may therefore mediate the mesangial injury that follows IgA deposition in IgAN. While immunogenically distinct, the mesangial Fcalpha receptor may share some molecular homology with CD89, as mRNA transcripts with partial identity to CD89 were found in all five MC cultures.

Antigens, CD↗
PubMed2000

A comparison of the results of renal transplantation from non-heart-beating, conventional cadaveric, and living donors.

BACKGROUND: In an attempt to address the shortage of conventional kidney donors, a non-heart-beating donor (NHBD) organ retrieval program has been established. We compared the results of kidney transplants from NHBDs (N = 77) with those from heart-beating cadaveric (HBD; N = 224) and living donors (LD; N = 49), performed in the same eight-year period. METHODS: Patients dying after failed attempts at resuscitation in the accident department or after intracerebral hemorrhage/anoxia were considered as potential NHBDs. After death, in situ kidney perfusion and cooling were achieved using an intra-aortic catheter inserted via a femoral artery cut down. Kidney retrieval and transplant operations were performed using standard techniques. RESULTS: The median (range) warm ischemic time for NHBD kidneys was 25 minutes (5 to 53 min). The initial function rates for NHBD, HBD, and LD transplants were 6.5, 76.3, and 93%, respectively. Primary nonfunction occurred in 5 of 75 evaluable NHBD transplants (7%) compared with only 6 out of 224 (2.7%) HBD and 1 out of 49 (2%) LD transplants (P = NS). Eighty-four percent of NHBD kidney recipients required postoperative dialysis for a median of 19 days. The mean (SD) serum creatinine at 12 months was 179 (73) micromol/L in NHBD kidneys compared with 152 (57) micromol/L for HBD kidneys and 138 (44) micromol/L for LD kidneys. The actuarial five-year graft survival rates for NHBD, HBD, and LD transplants were 79, 75, and 78%, respectively. During the period under study, NHBD organs accounted for 22% of the total renal transplant program. CONCLUSIONS: Despite being associated with poor initial graft function, the long-term allograft survival of NHBD kidneys does not differ significantly from the results of HBD and LD transplants.

Adult↗
PubMed2000

IgA myeloma presenting as Henoch-Schönlein purpura with nephritis.

IgA nephropathy (IgAN) and Henoch-Schönlein purpura (HSP) are both characterized by IgA-mediated tissue injury, including mesangial proliferative glomerulonephritis. Abnormalities of IgA1 glycosylation are described in IgA nephropathy and HSP nephritis. IgA-antineutrophil cytoplasmic antibodies (ANCA) have been inconsistently described in the serum of patients with HSP. In IgA myeloma, the paraprotein-mediated renal lesion is typically cast nephropathy; IgAN or HSP have only rarely been reported in myeloma even when an IgA paraprotein is circulating in large concentrations. We report the case of a 50-year-old man with IgA myeloma who presented with HSP including nephritis and rapidly progressive renal failure. His IgA1 had altered O-glycosylation in the pattern seen in IgAN and also contained an IgA-ANCA. This case adds further weight to the evidence that IgA1 O-glycosylation abnormalities predispose to mesangial IgA deposition and also that IgA-ANCA may have a pathogenic role in the development of HSP.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed2000

Outcome of acute renal failure following surgical repair of ruptured abdominal aortic aneurysms.

OBJECTIVES: to establish the mortality of ARF following surgical repair of ruptured abdominal aortic aneurysms (AAAs) and to identify clinical variables which might assist in predicting outcome. DESIGN, MATERIALS AND METHODS: all cases of ARF complicating repair of ruptured AAAs treated at Leicester General Hospital between 1984 and 1996 were identified in a retrospective study based on review of clinical records. The main outcome measures were overall mortality, duration of hospital treatment and renal function in survivors. RESULTS: in 65 cases identified, overall hospital mortality was 75%. Six patients did not receive RRT, since their clinical state was judged irreversible; all died. Of the 16 survivors, 11 were left with irreversible renal impairment and one patient required maintenance dialysis. Over half of the survivors had died at 5 years>> follow-up. Non-survivors had more vascular disease (p=0.048), required more surgery during AAA repair (p=0.042) and were more likely to have developed multiple organ failure (p=0.01). A clinical severity score based on these three variables allowed stratification into prognostic groups. CONCLUSIONS: ARF following surgical repair of ruptured AAA has an overall hospital mortality of 75%. A clinical severity score, calculated at the time dialysis was considered, may assist in prediction of outcome.

APACHE↗
PubMed1999

Exaggerated systemic antibody response to mucosal Helicobacter pylori infection in IgA nephropathy.

Numerous studies in the literature report aberrant immune responsiveness in immunoglobulin A (IgA) nephropathy. However, all these studies investigate immune responses invoked by an artificially engineered antigen challenge. For the first time in IgA nephropathy, we report the systemic humoral responses generated as part of an active mucosal immune response against a common environmental pathogen, Helicobacter pylori (Hp). We studied 22 patients with IgA nephropathy and 9 controls without renal disease who were shown to be infected with Hp, using a 13C-urea breath test. Hp antigen-specific enzyme-linked immunosorbent assays were established to measure the anti-Hp IgA, IgG, and IgA and IgG subclass antibody levels. In addition, anti-Hp responses in the monomeric and polymeric (pIgA) fractions of serum IgA were measured after separation by gel filtration high-performance liquid chromatography. IgA nephropathy was associated with both a greater rate of IgA anti-Hp seropositivity (P < 0.05) and a more pronounced IgA anti-Hp antibody response (P < 0.01). In almost all cases, IgA anti-Hp was IgA1, and more than 90% was polymeric. There was no difference in the frequency of IgG anti-Hp seropositivity, but patients produced a much greater IgG anti-Hp response (P < 0.01). In addition, the IgG subclass responses were markedly different, with IgG1 predominant in controls and IgG2 and IgG3 the major subclasses produced in IgA nephropathy. We have shown an exaggerated systemic antibody response to mucosal infection caused by Hp in patients with IgA nephropathy, predominantly consisting of pIgA1, IgG2, and IgG3. This suggests that in IgA nephropathy, not only is pIgA1 production poorly controlled, but regulation of IgG isotype switching in response to mucosal pathogens is also deranged.

Adolescent↗
PubMed1999

Renal effects of amlodipine in normotensive renal transplant recipients.

Renal effects of amlodipine in normotensive renal transplant recipients. The use of cyclosporin A (CsA) has improved the success of renal transplantation, but is associated with hypertension and significant renal toxicity. Previous reports suggest that calcium channel blockers may be useful in opposing the adverse effects of CsA. We have evaluated the effects of amlodipine (5 mg, once daily for 8 weeks) on renal function in 27 normotensive renal transplant recipients with stable renal function, in a double-blind, placebo-controlled, multicentre, cross over study. Amlodipine significantly reduced serum creatinine concentration relative to placebo (mean+/-SD: 168+/-65 vs 177+/-66 micromol/l; P=0.002) and there was a strong trend towards an increase in effective renal plasma flow on amlodipine relative to placebo (238+/-92 vs 217+/-87 ml/min; P=0.055). Glomerular filtration rate and lithium clearance were unaffected. Trough CsA blood concentration was unaffected. Amlodipine was well tolerated, with a low incidence of adverse events, and did not affect blood pressure or heart rate. In conclusion, amlodipine reduced serum creatinine in normotensive renal transplant recipients after only 8 weeks treatment, and was well tolerated in concomitant administration with CsA.

Adolescent↗
PubMed1999

Vascular endothelial growth factor mRNA expression in minimal change, membranous, and diabetic nephropathy demonstrated by non-isotopic in situ hybridisation.

AIM: To investigate vascular endothelial growth factor (VEGF) mRNA expression in glomerular disease in the context of heavy proteinuria. METHODS: Non-radioisotopic in situ hybridisation was performed using a cocktail of 12 deoxyoligonucleotides complementary to VEGF mRNA labelled during solid phase synthesis with 2,4-dinitrophenyl. Archival renal biopsies were studied from cases of minimal change nephropathy, membranous nephropathy, diabetic nephropathy, and controls, matched for age, sex, race, and storage time. Hybrid detection used NBT/BCIP colorimetric development. RESULTS: More VEGF mRNA positive glomerular cells per unit cross sectional diameter were seen in minimal change nephropathy (mean (SEM), 19.35 (1.5)) compared with controls (12.6 (1.73)), p < 0.01. In contrast, fewer were seen in diabetic nephropathy (5.93 (0.97)) compared with controls (9.97 (1.25)), p < 0.03. Analysis of membranous nephropathy (10 (1.62)) showed no difference from controls (10.98 (1.51)), NS. In addition, in minimal change nephropathy there was a significant correlation between 24 hour protein excretion at the time of biopsy and the number of VEGF mRNA cells per glomerulus (r = 0.08, p = 0.01). CONCLUSIONS: Using non-radioisotopic in situ hybridisation, VEGF mRNA is almost exclusively expressed by visceral glomerular epithelial cells. Abnormal numbers of cells are seen in both minimal change and diabetic nephropathy. As VEGF exists in a number of functionally distinct isoforms, further study of qualitative VEGF isoform expression in diagnostic groups is indicated.

Diabetic Nephropathies↗
PubMed1999

Analysis of IgA1 O-glycans in IgA nephropathy by fluorophore-assisted carbohydrate electrophoresis.

Abnormal O-glycosylation of IgA1 may contribute to pathogenic mechanisms in IgA nephropathy (IgAN). Observations of altered lectin binding to IgA1 in IgAN suggest that the O-glycan chains may be undergalactosylated, but precise structural definition of the defect has proved technically difficult, and it remains unconfirmed. This is the first study using fluorophore-assisted carbohydrate electrophoresis (FACE) to analyze IgA1 O-glycans in IgAN and controls. IgA1 was purified from serum, and the intact O-glycans were released by hydrazinolysis at 60 degrees C. After re-N-acetylation, the glycans were fluorophore-labeled and separated by polyacrylamide gel electrophoresis. Sequential exoglycosidase digestions of IgA1 allowed identification of the different O-glycan bands on FACE gels, and their relative frequencies in IgA1 samples were measured by ultraviolet densitometry. Lectin binding of the IgA1 samples was also measured. In some patients with IgAN, FACE analysis demonstrated a significant increase in the percentage of IgA1 O-glycan chains consisting of single N-acetyl galactosamine (GalNAc) units rather than the more usual galactosylated and sialylated forms. This finding was confirmed using both desialylated IgA1 and enzymatically released O-glycans. Good correlation was also found between O-glycan agalactosylation on FACE analysis and IgA1 lectin binding in IgAN, supporting the value of lectins as tools for detection of this abnormality. This is the first study in which all of the predicted O-glycan forms of IgA1 have been analyzed simultaneously, and demonstrates that in IgAN, the IgA1 Oglycan chains are truncated, with increased terminal GalNAc. This abnormality has the potential to significantly affect IgA1 behavior and handling with pathogenic consequences in IgAN.

Adult↗
PubMed1999

Pathogenesis of IgA nephropathy.

IgA nephropathy (IgAN) is initiated by glomerular deposition of polymeric IgA1(pIgA1). In IgAN pIgA production is reduced in the mucosal immune system, perhaps mediated by a mucosal gamma delta T cell defect, and mucosal IgA responses to immunisation are impaired. But pIgA1 production by the marrow is increased. Human pIgA1 has an O-glycosylated hinge region unique to circulating immunoglobulins and there is reduction of galactosyl residues in the hinge of serum IgA1 in IgAN and Henoch-Schönlein nephritis. This reduced galactosylation may be due to a functional defect in plasma cell beta 1,3-galactosyltransferase. Altered hinge region glycosylation may alter IgA1 structure, modifying interactions with matrix proteins, IgA receptors and complement, and therefore influence mesangial deposition and subsequent injury through mechanisms other than classical antigen-antibody reactions. IgA clearance through the hepatic asialoglycoprotein receptor or Fc alpha receptors on circulating white cells may also be impaired. The unique features of human IgA1 have prevented development of satisfactory animal models for the early stages of IgAN. It is likely that events after pIgA1 deposition which result in glomerular inflammation and scarring are not specific to IgAN but generic to many forms of glomerulonephritis.

Animals↗