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Biomedical subjects

P N Furness

Publications and source records attributed to P N Furness.

At least 19 recordsLinked to original sources
PubMed2001

Research using human tissues--a crisis of supply?

It is a paradox that the pursuit of ethical practice can sometimes produce distinctly unethical results. Pathologists seek to study diseased human tissues for the benefit of mankind, but in the UK there has been a sudden restriction in the availability of this basic resource, supposedly on ethical grounds. This was triggered by adverse publicity about the inappropriate retention of whole organs at paediatric post-mortem, but the reaction has spread to influence the use of 'surgical waste' left over after routine analysis of therapeutic resections, diagnostic biopsies, and even blood samples. The use of such material for research is being restricted, and its use in teaching and laboratory quality control is being questioned. This has occurred despite the facts that public opinion favours using such 'waste' material for research; that the tissues would otherwise be incinerated; and that until very recently, such tissues were regarded as having been 'abandoned' by the patient. This review attempts to chart how this dramatic change has occurred. It then considers some of the ethical problems in using such 'surplus' tissues and proposes mechanisms by which this valuable resource can remain available for most biomedical research, while maintaining or enhancing the autonomy of individual patients. This crisis has shown a tendency for regulatory authorities to apply very restrictive, oversimplified rules, without due consideration of the character of each project. The motivation is to avoid the possibility of media criticism, even though such rules block ethically sound work which is of value to all, including the individuals whose protection is supposedly being sought. The moral need for logical ethical arguments instead of such 'one size fits all' regulations is emphasized.

Clinical Trials as Topic↗
PubMed2001

International variation in the interpretation of renal transplant biopsies: report of the CERTPAP Project.

BACKGROUND: The Banff working formulation of renal transplant pathology is intended to have international application. There remains a need to develop methods to harmonize the application of such grading systems between laboratories. Banff grades do not always permit precise management decisions to be made. Alternative schemes have been devised for the diagnosis of acute rejection, but there have been no independent tests of the different approaches. METHODS: Sections from 55 renal transplant biopsies were circulated around the laboratories of 22 major transplant units for the Convergence of European Renal Transplant Pathology Assessment Procedures (CERTPAP) Project. Participating pathologists were asked to grade 32 different histological features, without any clinical information. After each circulation of five cases, feedback was provided to participants. Statistical evidence of improvement in interobserver variation was sought. At the end of the study, correlations with the original clinicopathological diagnosis were sought. RESULTS: Interobserver variation was greater than has previously been reported. For every feature studied, some pathologists consistently under-grade or over-grade. There was relatively little evidence of improvement in interobserver variation as a result of the feedback system. No single feature permitted a reliable diagnosis of acute rejection. Applying the Banff and CCTT schemas to the histological grades showed no clear diagnostic advantage for either system, but a simple computer-based inference network, which combined data from 12 histological features, out performed either approach. Within the "protocol" biopsies studied, long-term survival correlated better with "acute" than with "chronic" histological features. CONCLUSIONS: These results do not undermine the value of the Banff classification, but they demonstrate a need for caution when translating biopsy results between institutions. It is obvious that evaluation of biopsies in multicenter trials must be done in one center. In the management of individual patients, the need to interpret Banff grades in the light of local experience and clinical information is stressed.

Biopsy↗
PubMed2000

Inactive matrix metalloproteinase 2 is a normal constituent of human glomerular basement membrane. An immuno-electron microscopic study.

Remodelling of the extracellular matrix requires tight control not only of matrix synthesis, but also of matrix degradation. Control of matrix degradation is achieved mainly through the matrix metalloproteinase (MMP) enzymes. In the glomerulus, MMP-2 and MMP-9 are believed to be particularly important, as they have activity against type IV collagen. This study has demonstrated by immuno-electron microscopy that most of the immunoreactivity for MMP-2 in the normal glomerulus is located within the glomerular basement membranes and mesangial matrix. mRNA for MMP-2 is also detectable in normal glomeruli, but the other main gelatinase, MMP-9, could not be localized by immuno-electron microscopy. In the normal glomerulus, it seemed likely that MMP-2 is present in an inactive form. To confirm this, in situ zymography was carried out using frozen sections of normal kidney. Baseline activity of normal kidney was relatively weak, but this was dramatically increased by chemical activation of metalloproteinases. The results imply that MMP-2, in an inactive form, is a normal constituent of the extracellular matrix and glomerular basement membranes. Activation would presumably render the matrix 'self-degrading'; membrane-bound MMPs (MT-MMPs) seem particularly likely to be involved in leukocyte penetration of basement membranes in inflammation.

Basement Membrane↗
PubMed2000

Sub-clinical acute rejection detected using protocol biopsies in patients with delayed graft function.

Acute rejection in renal transplants is difficult to diagnose when patients have delayed graft function (DGF) in the early post-transplant period. In this study protocol, renal transplant biopsies were performed in an attempt to detect sub-clinical acute rejection episodes. Eighty-three patients were eligible for the study, of whom 33 had DGE All had protocol renal transplant biopsies performed under ultrasound control at 7 days post-transplant, and those with DGF had further biopsies weekly until the graft functioned. All histologically confirmed acute rejection episodes were treated. Sub-clinical acute rejection was detected in 6/33 (18%) patients with DGF compared to 2/50 (4%) in the other patients (P < 0.05). Borderline rejection was present in 4/33 (12%) and 4/50 (8%) patients, respectively. Because of the high detection rate of sub-clinical acute rejection and the low morbidity of renal transplant biopsies, their use is recommended in patients with DGF.

Acute Disease↗
PubMed2000

Differential effects of cyclosporin and tacrolimus on the expression of fibrosis-associated genes in isolated glomeruli from renal transplants.

BACKGROUND: Chronic allograft nephropathy is characterized by an excessive accumulation of extracellular matrix proteins leading to glomerular and interstitial fibrosis. The aim of this study was to determine the effects of two different immunosuppressive agents (cyclosporin and tacrolimus) on the expression of the genes controlling extracellular matrix deposition in renal transplant glomeruli. METHODS: Fifty-one renal transplant recipients were randomized to receive immunosuppression with either microemulsion cyclosporin or tacrolimus. Isolated glomeruli were plucked from protocol transplant biopsies performed 1 week, 3 months and 6 months after transplantation. Expression of the genes for collagen IValpha2, collagen III, matrix metalloproteinase 2, tissue inhibitor of metalloproteinases (TIMP) 1 and TIMP-2, tenascin and transforming growth factor (TGF) beta1 was studied by quantitative reverse transcriptase-polymerase chain reaction. RESULTS: The expression of messenger RNA (mRNA) for collagen III and TIMP-1 was significantly higher in patients receiving cyclosporin therapy than in those having tacrolimus (P < 0.01); this finding was accounted for by differences in the biopsy material at 1 week. A significant difference in collagen III, TIMP-1 and TIMP-2 mRNA expression was also detected between patients depending on the source of renal donor (cadaveric or living). There were no significant differences in the level of glomerular TGF-beta1. CONCLUSION: The data provide new in vivo evidence that tacrolimus may exert a less fibrogenic influence on transplant glomeruli than cyclosporin.

Adult↗
PubMed2000

A prospective randomized trial of three different sizes of core-cutting needle for renal transplant biopsy.

BACKGROUND: Needle-core biopsy remains one of the most important investigations in cases of renal allograft dysfunction. The size and quality of the biopsy material are likely to be important factors in achieving an accurate diagnosis. The aim of this study was to compare the success and complication rates of renal transplant biopsy procedures using three differently sized needles. METHODS: One hundred renal allograft recipients undergoing transplant biopsy using an automated needle core method were randomized to a 14, 16, or 18 gauge (G) needle. The size of each biopsy core was measured, and the presence or absence of renal cortical and medullary tissue and the number of glomeruli were recorded. Assessments of the ease with which the procedure was performed, the diagnostic usefulness of the biopsy material, and the discomfort associated with the procedure were made using verbal response and linear analog scales. RESULTS: Fourteen G biopsy cores (N = 33) were larger than both 16G (N = 33) and 18G (N = 34) cores and contained more gomeruli (mean number for 14G, 16G, and 18G = 15, 11 and 9, respectively). There were no differences in the ease of use of the three needle types, but scores for diagnostic usefulness were higher for 14G versus 18G and 16G versus 18G. The 14G needle was associated with significantly more pain than the two smaller needles when this was assessed using a linear analog score. Macroscopic hematuria occurred in eight patients, but there were no differences in complications rates between the three groups. CONCLUSIONS: All three needle sizes are safe for use in renal allograft biopsy using a semiautomated biopsy gun. The larger needles provide more tissue and glomeruli and, thus, are more diagnostically useful. Use of a 14G needle may be associated with more pain, and the 16G needle appears to offer the best compromise between diagnostic usefulness and patient acceptability.

Acute Kidney Injury↗
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

Acp. Best practice no 160. Renal biopsy specimens.

Taking a kidney biopsy is not a trivial procedure. The sample is almost invariably smaller than the pathologist would like. Investigation usually requires division into even smaller samples to permit the application of specialist techniques. In some cases the biopsy is taken not for diagnosis, but to assess the extent of tissue damage. The clinical need is sometimes extremely urgent. These features all underline the crucial importance of collaboration between pathologist and nephrologist if maximum benefit is to be obtained from such very small samples. Consequently, in deciding what to do with a renal biopsy, flexibility and thought are required rather than a single prescribed list of procedures. This article, written after extensive international consultation, represents an attempt to define current best practice in the laboratory handling of renal biopsy specimens, while not neglecting the need to tailor processing to the individual needs of each case.

Benchmarking↗
PubMed1999

Computerized histomorphometric assessment of protocol renal transplant biopsy specimens for surrogate markers of chronic rejection.

BACKGROUND: Chronic transplant rejection has emerged as the commonest cause of long-term renal allograft failure, and early identification of those grafts at risk could allow the targeting of specific therapies aimed at delaying this process. This study explores the usefulness of quantitative immunohistochemistry in defining biopsy-based surrogate markers of allograft damage. METHODS: A consecutive series of 52 renal transplant recipients immunosuppressed with cyclosporine were studied. Needle core transplant biopsies were performed at 1, 3, and 6 months postoperatively. Immunostaining for collagen III, and smooth muscle actin, tenascin, and infiltrating leukocytes was performed using an indirect immunoperoxidase technique. The interstitial area stained (%) was measured using a semiautomatic image analysis system. The results were related to glomerular filtration rates (GFR) measured at 6, 12, and 24 months after transplantation using rank correlation coefficients. RESULTS: The area fraction of immunostained collagen III correlated with 6-month GFR (r=-0.42, P=0.005) and was predictive of 12-month GFR (r=-0.32, P=0.03). An area fraction of immunostained collagen III of >40% at 6 months was associated with a significantly lower GFR at 24 months, compared with a percentage area of < or =40% (31+/-4 versus 45+/-4 ml/min/1.73 m2, P=0.01). Furthermore, a collagen III of >40% at 6 months identified patients who were at risk of progressive deterioration in graft function. CONCLUSIONS: Grafts with poorer long-term function can be predicted using 6-month protocol biopsy specimens immunostained for collagen III. This should prove to be a useful ad interim surrogate marker of allograft damage in studies addressing the effects of new immunosuppressive agents on the development of chronic rejection.

Adolescent↗