Biomedical subjects
Publications and source records attributed to A G MacIver.
Thrombotic microangiopathy is an uncommon complication of cyclosporin immunosuppression following renal transplantation. We present a 15-year-old girl who developed clinical features of acute rejection, but in whom an early biopsy revealed thrombotic microangiopathy, allowing a change to FK506 immunosuppression resulting in excellent graft recovery.
Kidneys are innervated by a plexus of nerves around the renal artery, which is disrupted by transplantation. This is a report of a comparison of the nerves in human renal allografts and normal kidneys. There were many sympathetic ganglia around normal renal arteries but none around transplanted vessels, although equal numbers of ganglia were present in hilar tissues of normal and transplanted kidneys. An immunohistological study with an antibody to synaptophysin showed that the number of synapses in transplanted ganglia was severely reduced. Immunohistological studies on allograft kidneys using antibodies to various neurofilament proteins and the Schwann cell marker S100 showed a marked reduction in neurofilament proteins shortly after transplantation with subsequent partial recovery, and a lesser reduction in S100. Renal allografts have structurally abnormal innervation but are not completely denervated.
OBJECTIVES: To confirm the expression of prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) in ductal carcinomas of the prostate, and to analyse p53, Ki67, oestrogen (ER) and androgen (AR) receptors in these tumours. MATERIALS AND METHODS: Paraffin-embedded samples from 12 patients with ductal carcinoma of the prostate were assessed for pattern, mitotic count and the presence of a microacinar carcinoma component. There were six pure ductal and six mixed microacinar and ductal carcinomas. Sections were stained immunohistochemically for the expression of PSA, PAP, Ki67, p53, AR and ER. Clinical data were obtained from case notes. RESULTS: Six of the ductal tumours had a papillary pattern whilst the others had a cribriform appearance. The mitotic rates in the ductal areas were high in the tumours from eight of the 12 patients. PSA and PAP immunohistochemistry were positive in all the cases. No ER immunoreactivity was found in any of the patients. Ten of the ductal tumours showed strong reactivity with AR, the other two were weakly positive; two of the tumours were strongly positive for p53 protein. All the ductal carcinomas expressed Ki67, three having > 25% nuclear marking. One patient who was strongly positive for p53 and had a high Ki67 score survived only one year after diagnosis. Survival ranged from 1 to 13 years after diagnosis. CONCLUSION: This study confirms the expression of PSA and PAP in ductal carcinomas of the prostate. The percentage of tumours expressing p53 was similar to that published for high-grade microacinar carcinomas. The results for Ki67 suggest that ductal tumours have higher scores than microacinar tumours, but further studies are required to ascertain if this is significantly different. As half the patients with ductal tumours had co-existent microacinar tumours, we advise transrectal prostatic biopsies in patients diagnosed with pure ductal carcinomas on transurethral resection specimens, to exclude high-grade microacinar carcinomas. The presence of AR and the lack of ER in all the ductal carcinomas confirms that these tumours are prostatic in origin and should be treated with antiandrogen therapy.
OBJECTIVE: To undertake a follow-up study of 472 men who were screened 3 years previously, in general practice, for prostate cancer, and to investigate the efficacy and patient acceptability of a 3-year screening interval. SUBJECTS AND METHODS: Eligible men (n = 472) were sent postal invitations to attend their Health Centre in North Bristol. Serum prostate-specific antigen (PSA) was the initial screening test. Men with PSA > 4 ng/ml (Hybritech) were referred to the Department of Urology for digital rectal examination and transrectal ultrasound +/- biopsy. RESULTS: A total of 132 (28%) men were excluded because of intercurrent illness, death and migration. Two hundred of 340 (59%) men were re-screened. Thirty-seven men had an elevated PSA and were referred as above. Seventeen men had prostatic biopsies, resulting in the diagnosis of six carcinomas; five were localized to the prostate and one was metastatic. In the latter patient, the PSA had risen from 2 to 120 ng/ml over 3 years. CONCLUSION: Serum PSA alone can be used as an acceptable repeat screening test to detect prostate cancer in general practice, but 3-year repeat screening will not always protect the individual against the interval development of metastatic disease.
Six patients with immune-related potassium-losing interstitial nephritis (IRPLIN) are described, and compared with 34 patients with immune-related distal renal tubular acidosis (IRdRTA) and 24 with familial distal renal tubular acidosis (FdRTA). Close similarities were found between IRPLIN and IRdRTA. In our experience, both syndromes are confined to postpubertal women, and are characterized by systemic features of autoimmune disease and a chronic interstitial nephritis which is probably immune-mediated and responsible for the functional tubular defects of the two syndromes. In IRPLIN, a renal potassium-losing state is the main consequence (probably mediated at least in part by renin and aldosterone hypersecretion secondary to renal sodium-losing), and urinary acidification is normal or minimally disturbed; consequently there is no systemic acidosis, and the syndrome is not complicated by nephrocalcinosis or renal bone disease. In IRdRTA, the renal tubular lesion also usually causes potassium depletion, but the most prominent tubular fault is a defect in urinary acidification, which commonly causes metabolic acidosis and often leads to nephrocalcinosis and bone disease. Familial dRTA, in contrast, is equally prevalent in the two sexes and presents at an earlier age than IRPLIN and IRdRTA. Patients with FdRTA and IRdRTA have a similar urinary acidification defect and propensity to acidosis, nephrocalcinosis and bone disease. FdRTA is frequently complicated by renal potassium-losing, but hypokalaemia is less common and less profound than in IRdRTA and IRPLIN, suggesting that immune-related interstitial nephritis has a particular tendency to cause renal potassium-losing.
Histological assessment and DNA flow cytometry have been performed on 15 kidneys containing primary adenocarcinomas which had invaded the renal vein. Comparison of morphological variables showed that samples of the intravenous tumour were more commonly composed of granular cells (53 per cent) than were samples from the main tumour mass (16 per cent), and were also of higher nuclear grade. In 7 of 14 kidneys, DNA studies showed either a higher S-phase fraction (five cases) or DNA aneuploidy (two cases) in tumour cells lying within the renal vein. The mean S-phase fraction was also shown to increase in higher nuclear grades. Thus, both morphological and biological differences exist between invasive tumour cells lying within the renal vein and those in the main tumour. This is a useful model for the investigation of venous invasion and may give a better prediction of the metastatic potential of renal cell carcinoma.
Reports of malignant tumors in enterocystoplasties have recently been accumulating. To date no case of benign tumors has been recorded. We present a case of villous adenoma in a sigmoid colocystoplasty. The possible etiological factors and pathogenesis are discussed, and recommendations are made about followup.
Urinary excretion of tissue kallikrein is reduced in essential hypertension. Although a similar finding has been reported in spontaneously hypertensive rats (SHR), only a few studies have been concerned with the amount of enzyme within the kidney both at the time of onset and during progression of the hypertension. We have performed an ontogenic study on the renal parenchymal values and immunoreactivity of tissue kallikrein in Okamoto SHR aged 4-78 weeks. Additionally, these two parameters were analysed in human biopsies taken from patients with hypertensive nephropathy. The enzymatic activity of renal tissue kallikrein (active and total; specifically antagonized by anti-tissue kallikrein antibodies), increased from 4 to 52 weeks in SHR when compared to normotensive Wistar Kyoto (WKY) rats; this increase was associated with a significant increase in blood pressure. In contrast, 78 weeks SHR and human biopsy tissue showed a substantial reduction in tissue kallikrein values. Also, both renal tissues showed a reduction in immunoreactivity in the cells of the connecting tubules that specifically store the enzyme. In advanced hypertension the observed reduction in tissue kallikrein was probably secondary to a loss of distal tubular mass, as a result of tubular atrophy and fibrosis. The greater values for renal tissue kallikrein in the kidney and reported reduced urinary excretion during the early phases of spontaneous hypertension may be explained by a primary defect in the mechanisms that regulate release of tissue kallikrein from the connecting tubule cells.
The success of a screening programme for cancer depends on the sensitivity of the tests used and on the proportion of the target population that comes forward for screening. To assess the value of digital rectal screening and prostate-specific antigen (PSA) measurement as screening measures, the 814 men in a city general practice aged between 55 and 70 were recruited in one of five different ways. Men with a palpably suspicious prostate or a serum PSA greater than 4 ng/ml were referred for transrectal ultrasonography and, if indicated, biopsy. 472 men (58%) were screened; of these 68 underwent transrectal ultrasonography and 29 biopsy. In 7 the biopsy specimen showed carcinoma. Serum PSA was better than digital examination as a screening test--all men with prostate cancer had raised concentrations of serum PSA, whereas only 1 had a palpably abnormal prostate. All 7 had localised disease, and 5 underwent radical prostatectomy. The best methods of patient recruitment were to send an appointment for screening and to "tag" the patient's notes.
We have localised atrial natriuretic factor (ANF) in the human kidney by immunocytochemistry and radioimmunoassay. ANF is specifically visualised in the distal convoluted tubule cells and the intercalated cells of the connecting tubules and collecting ducts of the human nephron. The number of immunoreactive cells and tissue values for the peptide were compared between samples from normal kidneys and biopsies obtained from hypertensive patients, in whom the tissue ANF immunoreactivity was found to be reduced. Specific experiments are necessary to establish whether renal ANF is synthesised de novo or captured through endocytosis by the renal tubular cells. The possible functional roles of renal ANF are discussed.
Antiglomerular basement membrane (anti-GBM) disease is characteristically described with linear deposition of IgG along the GBM. We report two unusual cases of IgA and IgM anti-GBM disease associated with diffuse thinning of the GMB, and review the literature on atypical immunoglobulin species in this disorder. Both patients were male, aged 55 and 49 years, and presented with isolated microscopic haematuria, neither having shown evidence of impaired renal or pulmonary function on follow-up for 4 and 6 years respectively. Renal histology revealed minor focal mesangial changes only, but immunoperoxidase preparations demonstrated intense linear staining of the GBM with IgA in one case, and IgM with C3 in the other. On electron-microscopy there was diffuse thinning of the GBM in both cases, mean thickness 220 and 295 nm respectively (normal range 350-450 nm). Antinuclear antibodies were not detected and their glucose tolerance tests were normal. Assays for circulating IgG anti-GBM antibodies using indirect immunofluorescence (IF) and radioimmunoassay (RIA) were negative in both patients, although IgA anti-GBM antibodies with specificity confirmed by inhibition studies were identified in the first case. Thin GBMs in these patients may expose the Goodpasture antigen to toxic or infectious insults, thus altering its antigenic profile and promoting this unusual immune response.
Three patients with inverted papilloma of the ureter are described. A range of histological features was seen, including one showing malignant change. This condition, which is probably more common than previously thought, can be successfully treated by conservative surgery and close follow-up.
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The presence of tissue kallikrein in polymorphonuclear (PMN) leucocytes from normal human blood and from patients with rheumatoid arthritis and pyelonephritis was investigated. Immunoreactive tissue kallikrein was specifically detected in neutrophil leucocytes. PMN leucocytes displayed a granular staining. In the synovial membrane and kidney, the cells were aggregated into pockets as part of an inflammatory infiltrate. The presence of immunoreactive tissue kallikrein in human PMN leucocytes may provide a new insight into the importance of this enzyme in inflammation.
We have identified a tissue kallikrein in polymorphonuclear (PMN) leucocytes of normal human blood and bone marrow by immunocytochemistry, radioimmunoassay and enzymology. Immunoreactive tissue kallikrein was visualized in the mature neutrophil leucocytes and in immature forms such as metamyelocytes and myelocytes. No tissue kallikrein was detected in eosinophil leucocytes, lymphocytes, macrophages, megakaryocytes and platelets. So far, we have failed to observe immunoreactivity to tissue kallikrein in basophils. The presence of tissue kallikrein in extracts prepared from PMN leucocytes isolated from peripheral blood was demonstrated by immunodiffusion, dot-blotting and by radioimmunoassay. The kininogenase and amidase activity of the extracts resembled that of tissue kallikrein in being resistant to soya bean trypsin inhibitor and sensitive to trasylol. The amidase activity attributable to tissue kallikrein was completely inhibited by specific antisera.
Interstitial cystitis (IC) is characterised by recurrent inflammation and destruction of bladder tissue without obvious cause. To determine whether this self-perpetuating disease is the result of an autoimmune disorder, we studied 26 patients with IC of mean duration 5 years and compared the results with those of a control group of similar age and sex with other urological complaints. We performed a standard autoimmune profile and looked for specific antibodies to normal human bladder in the serum, using an indirect immunofluorescence technique. Deep bladder biopsies were examined by conventional histology and cryostat sections were studied with peroxidase-conjugated anti-human antibodies in a search for immunoglobulin deposition within the bladder. Seventeen of 26 patients with IC (65%) and 5 of 14 controls (36%) demonstrated non-organ-specific antibodies; 40% of those with IC had anti-nuclear antibodies; 18 IC patients (75%) and 4 of 10 controls (40%) had anti-bladder antibodies present in the serum, but 5 healthy volunteers showed no such antibody activity. There was no statistically significant difference between the two groups for either type of antibody (Fisher's exact test). Only 5 of 17 patients with IC (29%) showed immunoglobulin deposition in the bladder epithelium, a similar proportion to controls (38%); 4 of these 5 had circulating anti-bladder antibodies present in the serum. Although IC patients demonstrated a non-specific increase in antibody formation, this was not significantly different from a similar group of other urological patients. The lack of specificity makes this immunological response more likely to be a secondary phenomenon associated with inflammatory damage to the bladder rather than the primary cause of the disease.
To elucidate the natural course of the nephropathy associated with penicillamine and thereby facilitate its clinical management 33 patients with rheumatoid arthritis who developed proteinuria during treatment with oral penicillamine were studied in detail throughout their renal illness. Renal biopsies were performed, and creatinine clearance and proteinuria were measured serially for 74 months (range 16-148 months). Fourteen patients developed proteinuria within six months after the start of treatment and 27 within 12 months. When treatment was stopped the proteinuria reached a median peak of 4.2 g/24 h (range 0.3-15.0 g/24 h) at one month (range 0-7 months) before resolving spontaneously by six months (12 patients), 12 months (21), or 18 months (29). In all patients but one, who developed carcinoma of the renal pelvis, proteinuria resolved by 21 months and its median duration was eight months. The median first and last measurements of creatinine clearance showed no appreciable change (80 ml/min and 78 ml/min), and no patient died from or needed treatment for renal failure. The HLA-B8 or HLA-DR3 alloantigen, or both, were identified in 10 patients. Renal biopsy specimens showed membranous glomerulonephritis in 29 patients, minimal change nephropathy in two, and electron dense deposits in the mesangial regions in two. In all the patients whose nephropathy was due solely to treatment with penicillamine the proteinuria resolved completely when the drug was withdrawn; renal function did not deteriorate, and corticosteroids were unnecessary.
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