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Biomedical subjects

G H Neild

Publications and source records attributed to G H Neild.

At least 91 records · Page 5Linked to original sources
PubMed1991

Haemostatic activation and proteinuria as factors in the progression of chronic renal failure.

Haemostatic activation was measured in patients with either non-diabetic chronic renal failure (CRF) or diabetic nephropathy. We have investigated the relationship between these haemostatic markers and the rate of progression of renal failure. When compared with age- and sex-matched healthy controls, both patient groups showed significantly elevated plasma concentrations of D dimer, von Willebrand factor antigen (vWFAg), and C-reactive protein (CRP) (all P less than 0.001), as well as an increase in spontaneous platelet aggregation (P less than 0.01). Plasma concentration of platelet factor 4 was slightly but not significantly increased. Serum thromboxane was subnormal (P less than 0.01). Multiple regression analysis showed that in non-diabetic CRF proteinuria and serum TxB2 were independently related to the rate of progression of renal failure; in diabetic nephropathy proteinuria and vWFAg were independently related to the rate of progression. In both groups the relationship was stronger with proteinuria (standardised regression coefficients 0.56 and 0.45 respectively) than with serum TxB2 (0.29) or with vWFAg (0.37). We have found haemostatic activation in both non-diabetic and diabetic progressive renal failure. Proteinuria, and also in this study serum TxB2 and vWFAg, appear to be determining factors in the progression of renal failure, and their measurement may have prognostic value.

Adolescent↗
PubMed1991

Effect of enalapril on proteinuria and renal function in patients with healed severe crescentic glomerulonephritis.

Five patients (median age 63 years) with severe crescentic glomerulonephritis had acute renal failure (median plasma creatinine 930, range 690-1390). Following induction of immunosuppressive treatment all patients achieved recovery of adequate renal function (median creatinine 440, range 290-570 mumol/l). After 3-6 months of continuous remission, all patients, despite stable renal function developed increasing proteinuria (median 4.4 g/24 h, range 3.2-6.1), and enalapril (5-20 mg per day) was substituted or introduced as antihypertensive therapy. Immunosuppression was not altered. After 1 year, renal function remained stable in four patients and plasma creatinine increased initially in one patient before becoming stable: proteinuria was reduced substantially in all patients to a median of 0.8 g/24 h, range 0.2-1.3). Patients with severe crescentic glomerulonephritis may develop persistent or increasing proteinuria despite successful treatment of acute disease. We have used enalapril to reduce proteinuria and maintain function in such patients.

Acute Kidney Injury↗
PubMed1991

Insidious loss of renal function in patients with anticardiolipin antibodies and absence of overt nephritis.

Circulating anticardiolipin antibodies are associated with recurrent thrombosis, fetal loss and thrombocytopenia. We have identified four patients with SLE or lupus-like disease who have high circulating levels of ACLA, repeated thrombosis and evidence of renal disease. Their clinical signs and symptoms of lupus activity were minimal, yet all had renal insufficiency with GFR 50 ml/min or less despite no history nor evidence of overt nephritis (proteinuria less than 0.5 g/day and no haematuria). Renal biopsy specimens showed focal ischaemic lesions with no evidence of active lupus nephritis. We describe a new lesion of renal ischaemia secondary to non-inflammatory vascular pathology associated with circulating ACLA.

Adult↗
PubMed1991

Regional heterogeneity of endothelium-dependent vasodilatation in the rabbit kidney.

1. Regional heterogeneity of endothelial function exists but its role in the local regulation of vascular tone is uncertain. This heterogeneity may be very important in the control of the glomerular filtration rate (GFR) in which the differential tone in the afferent and efferent arterioles is crucial. 2. When an endothelium-independent vasodilator, prostacyclin (PGI2) or nitroprusside, was infused into anaesthetized rabbits there were dose-dependent falls in both mean arterial pressure (MAP) and GFR; PGI2 (0.4 nmol kg-1 min-1) altered MAP and GFR by -18.5 +/- 3.6% (mean +/- S.E.M.) and -37.7 +/- 13.3% respectively and nitroprusside (30 nmol kg-1 min-1) by -29.7 +/- 3.1% and -67.0 +/- 2.4%. In contrast infusion of an endothelium-dependent vasodilator, acetylcholine (ACh) or substance P, produced dose-dependent decreases in MAP but dose-dependent increases in GFR; ACh (10 nmol kg-1 min-1) -15.1 +/- 2.0% and +43.8 +/- 16.5% and substance P (30 nmol kg-1 min-1) -18.7 +/- 1.9% and +45.3 +/- 23.1% respectively. The effects of endothelium-dependent and independent vasodilators on GFR was significantly different (p less than 0.005). 3. Simultaneous administration of indomethacin, Methylene Blue or NG-monomethyl-L-arginine (L-NMMA), inhibitors of cyclo-oxygenase and endothelium-derived relaxing factor (EDRF) respectively, attenuated or reversed the effect of ACh (10 nmol kg-1 min-1) on MAP and GFR. 4. These data suggest that endothelium-dependent vasodilatation in the kidney has a heterogeneous effect on the renal microvasculature, exerting a preferential effect on afferent glomerular arterioles and thereby preserving GFR despite the fall in MAP.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1990

Inhibition of prostacyclin formation by cyclosporin is not due to reduced availability of arachidonic acid in membrane phospholipids of cultured human endothelial cells.

Our studies have shown that CS inhibits PGI2 production in HUVEC, that this inhibition is not overcome when exogenous AA is supplied, that the inhibitory action of CS is proximal to PGI2 synthetase and finally that there is abundant free AA available in membrane phospholipids of CS treated HUVEC [4,5]. In conclusion, CS does not appear to inhibit PGI2 synthesis by reducing the availability of free AA in the endothelial cell membrane. Although CS appears to inhibit cyclo-oxygenase, we can not exclude an additional effect on acyltransferase.

6-Ketoprostaglandin F1 alpha↗
PubMed1990

Recombinant human erythropoietin shortens the uraemic bleeding time without causing intravascular haemostatic activation.

Blood rheology and haemostasis have been investigated in 8 haemodialysis patients during treatment with recombinant human erythropoietin (rHuEPO). The aim was to elucidate the mechanism by which rHuEPO improves haemostasis, and to determine whether rHuEPO promotes intravascular coagulation. Investigations were performed before, and after 3 months of treatment. Haemoglobin and haematocrit rose significantly after rHuEPO (p less than 0.001) and there was a concurrent shortening of the bleeding time. No significant changes were observed in platelet aggregation, thromboxane generation, or platelet nucleotide content during the treatment period. Whole blood viscosity increased following rHuEPO (p less than 0.01), but plasma viscosity and red cell deformability were unchanged, as were markers of intravascular platelet activation and plasma levels of cross-linked fibrin derivatives. No patient suffered from thrombosis during the study period, and elevation of the haematocrit in uraemic patients up to 0.35 with rHuEPO did not appear to lead to intravascular coagulation. Shortening of the prolonged bleeding time in haemodialyzed patients following rHuEPO appeared to be due to the increase in circulating red cells, rather than to changes in platelet reactivity.

Adult↗
PubMed1990

Blood hyperviscosity and its relationship to progressive renal failure in patients with diabetic nephropathy.

Blood rheology was investigated in patients with diabetic nephropathy and progressive renal insufficiency, and compared with similar non-diabetic patients and healthy control subjects. Plasma viscosity and whole blood viscosity at standardized haematocrit were elevated to a comparable degree in the two patient groups, but erythrocyte deformability was normal. In diabetic patients, the rate of progression of renal failure showed weak, but significant, correlations with plasma viscosity (rs = 0.50, p = 0.005), standardized whole blood viscosity (rs = 0.41, p = 0.021), plasma fibrinogen (rs = 0.46, p = 0.010), C reactive protein (rs = 0.40, p = 0.023), and proteinuria (rs = 0.52, p = 0.003). Both plasma viscosity and plasma fibrinogen correlated significantly with proteinuria (rs = 0.45, p = 0.012 and 0.40, p = 0.027, respectively). Rheological abnormality is probably a manifestation of increased acute phase proteins, but it remains to be determined whether these are the cause or the effect of the renal injury. Abnormal blood rheology may be a risk factor for the progression of renal failure in diabetic nephropathy.

Adult↗
PubMed1990

Infectious complications in the management of systemic vasculitis and rapidly progressive glomerulonephritis.

Patients with microscopic polyarteritis and Wegener's granulomatosis are often elderly. At present 10-20% of these patients will die from infection in the first three months of immunosuppressive treatment. Therapeutic strategies initially must maximize anti-inflammatory and immunosuppressive effects and minimize the later in the longer term. Regimens with pulse MP combined with low dose prednisolone (ie 20 mg/day), together with oral or pulsed cyclophosphamide in the first weeks followed by maintenance treatment with azathioprine and prednisolone are suggested--with PE reserved for those requiring dialysis, lung haemorrhage, or uncontrolled vasculitis.

Communicable Diseases↗
PubMed1990

Cyclosporin nephrotoxicity.

Nephrotoxicity must always be excluded as a cause of renal dysfunction in allograft recipients receiving cyclosporin. Prolonged nephrotoxicity will lead to permanent impairment of renal function. This is a consequence of the renal vasospasm and vascular pathology that leads to ischemia and atrophy of the glomeruli and renal tubules.

Cyclosporins↗
PubMed1990

Haemostatic changes in the loin pain and haematuria syndrome: secondary to renal vasospasm?

Twenty-five patients (seven male, 18 female) were diagnosed as having the loin pain and haematuria syndrome. Presenting symptoms were either loin pain alone or pain associated with macroscopic or microscopic haematuria, and were longstanding, having been present for mean of 9.3 years in males, and 10 years in females. Ten patients described symptoms of passing gravel or renal stones but these were only demonstrated radiologically in two patients. Investigation of all patients showed anatomically normal renal tracts, normal renal function, and no significant proteinuria. Phase-contrast microscopy during episodes of haematuria revealed dysmorphic red cells in all 10 patients studied. Renal biopsies were performed in 20 patients and showed no glomerular pathology, but arteriolar and arterial hyalinosis was seen in 13 of 20 (65 per cent), fibro-elastosis in larger vessels in eight of 20 (40 per cent) and red blood cells in tubules in 13 of 20 (65 per cent) patients. The histological appearance in vessels was similar to that seen in cyclosporin A nephrotoxicity and would be consistent with the hypothesis that regional vasospasm occurs in the cortical circulation. Haematological studies in 22 patients, when compared with age and sex matched controls, showed the presence of circulating platelet aggregates, elevation of plasma beta-thromboglobulin (p less than 0.001), and increased platelet aggregation in response to serotonin and ADP (p less than 0.05 and p less than 0.03, respectively). Plasma concentrations of D dimer (p less than 0.02) and C-reactive protein (p less than 0.03) were also significantly elevated in the patient group. There was no deterioration of renal function during a mean observation period of 3.7 years and no patients developed proteinuria. Treatment was largely supportive; seven patients with intractable loin pain underwent surgical denervation with the relief of pain in four.

Adult↗
PubMed1989

Plasma D dimer: a useful marker of fibrin breakdown in renal failure.

D dimer and other large fragments produced during the breakdown of crosslinked fibrin may be measured by enzyme immunoassay using monoclonal antibodies. In 91 patients with renal disease and varying degrees of renal dysfunction, plasma D dimer showed no correlation with renal function, whereas FgE antigen, a fibrinogen derivative which is known to be cleared in part by the kidney, showed a significant negative correlation with creatinine clearance. Plasma concentrations of D dimer were, however, increased in patients with chronic renal failure (244 +/- 31 ng/ml) (mean +/- SEM) and diabetic nephropathy (308 +/- 74 ng/ml), when compared with healthy controls (96 +/- 13 ng/ml), and grossly elevated in patients with acute renal failure (2,451 +/- 1,007 ng/ml). The results indicate an increase in fibrin formation and lysis, and not simply reduced elimination of D dimer by the kidneys, and are further evidence of activated coagulation in renal disease. D dimer appears to be a useful marker of fibrin breakdown in renal failure.

Biomarkers↗
PubMed1989

HLA-DR display by renal tubular epithelium and phenotype of infiltrate in interstitial nephritis.

Renal tubular display of HLA-DR was estimated semi-quantitatively in 28 biopsies from 27 patients with various forms of tubulointerstitial nephritis (10 following use of non-steroidal anti-inflammatory drugs) using a monoclonal anti-MHC class II non-polymorphic antibody (DK-22). Normal donor kidneys and biopsies from patients with minimal-change nephrotic syndrome were examined as controls. The phenotype of infiltrating cells was also studied quantitatively, using monoclonal antibodies on frozen biopsy tissue; the number of cells infiltrating the interstitium was counted per tubular cross-section. Display of HLA-DR was seen in up to 5% of control tubular cells, but up to 100% expressed HLA-DR in tubulointerstitial nephritis biopsies. There was a correlation between the expression of HLA-DR and the severity of both tubular atrophy and tubulointerstitial fibrosis judged semi-quantitatively by optical microscopy. In controls up to 50 leucocytes per tubular cross-section were evident, but in patients with tubulointerstitial nephritis up to 1500 were observed, approximately 50% being T-lymphocytes, the majority expressing the helper phenotype except in early, active drug-induced tubulointerstitial nephritis; the remainder were mostly monocytes. There were no qualitative differences between the different causes of tubulointerstitial nephritis. Tubular DR expression correlated with the number of DR-positive cells in the interstitium, but not with total leucocytes or T-lymphocytes. HLA-DR tubular expression was greater in the early stages than late stages of NSAID-induced tubulointerstitial nephritis, but this relationship was not present in the group as whole. HLA-DR expression by renal tubular epithelial cells may play a role in localising or amplifying tubular injury in tubulointerstitial nephritis.

Adolescent↗
PubMed1989

Cyclosporin therapy in vivo attenuates the response to vasodilators in the isolated perfused kidney of the rabbit.

1. The endothelium releases a number of vasoactive compounds, including the vasodilator prostaglandins, prostacyclin (PGI2) and prostaglandin E2 (PGE2) and endothelium-derived relaxing factor (EDRF), which play an important role in the regulation of vascular tone in the microcirculation. Nephrotoxicity is the major complication of cyclosporin (CS) therapy and is related to an increase in intrarenal vascular tone. Endothelial cell generation of PGI2 is inhibited by CS although this cannot fully explain the changes in vascular tone observed. We have investigated the possibility that EDRF-dependent vasodilatation is also affected by CS therapy in vivo. 2. CS nephrotoxicity was induced in rabbits with CS (15 mg kg-1 per day s.c. for 20 days (n = 6]; 6 rabbits were given CS vehicle (Veh) and 9 animals were studied without any treatment. Creatinine clearance fell significantly during treatment in the CS-treated rabbits (11.78 +/- 1.5 ml min-1, mean +/- s.e. mean, to 7.79 +/- 1.2 after 20 days treatment) but did not change in the vehicle-treated animals. 3. The responses to the endothelium-dependent (acetylcholine (ACh] and endothelium-independent (nitroprusside (NP) and PGI2) vasodilators were assessed in indomethacin-treated isolated perfused kidneys (IPKs) from untreated, CS- and Veh-treated animals. Vascular tone was induced with a constant infusion of noradrenaline 150 nM and the perfusion rate adjusted to produce a perfusion pressure of 90 mmHg. Perfusate flow rate (22.3 +/- 4.6 vs 20.4 +/- 3.1 ml min-1) and glomerular filtration rate (2.04 +/- 0.37 vs 1.88 +/- 0.16 nl min-1) did not differ between IPKs from CS- and Veh-treated animals. 4. The vasodilator response to ACh was reduced in the kidneys from CS-treated animals compared with those from untreated and Veh-treated animals (mean reduction 35.3 + 2.3% compared with Veh) as were the responses to both NP (42.8 + 3.6%) and PGI2 (27.7 + 7.4%). 5. This suggests that CS nephrotoxicity is not mediated via an effect on endothelium-dependent responses and that it is more likely that CS has a direct effect on vascular smooth muscle.

Animals↗
PubMed1989

Endothelin induces an increase in renal vascular resistance and a fall in glomerular filtration rate in the rabbit isolated perfused kidney.

1. The effects of endothelin infusion on renal vascular resistance (RVR), glomerular filtration rate (GFR) and the interaction with locally generated endothelium-derived relaxant factor (EDRF) were studied in the rabbit isolated perfused kidney (IPK). For comparison the effects of infusions of angiotensin II (AII) and noradrenaline (NA) were also assessed. 2. Each kidney was perfused at a constant rate of 10 ml min-1 and alterations in RVR determined by measuring changes in perfusion pressure. GFR was determined by the clearance of [51Cr]-EDTA, using timed urine collections. 3. Endothelin (10(-11)-10(-9) M) produced a dose-related increase in RVR. Endothelin was approximately 30 times more potent in molar terms than AII and 500 times more than NA at inducing a 50 mmHg increase in perfusion pressure. 4. Endothelin appeared to be a weak inducer of EDRF release in the IPK as EDRF inhibitors methylene blue (10 microM) or haemoglobin (10 microM) only slightly augmented the increase in RVR at a given concentration of endothelin. In contrast the effect of NA on RVR was significantly increased by methylene blue (10 microM) whereas that induced by AII was not affected. 5. Endothelin infusion produced a significant, dose-dependent decrease in GFR of the IPK, contrasting with an increase in GFR during AII infusion and a minimal effect of NA on GFR. This supports evidence that AII is predominantly a constrictor of effernt glomerular arterioles and that NA constricts both afferent and efferent glomerular vessels. We suggest that the vasoconstrictive effect of endothelin in the kidney is predominantly preglomerular, which explains its effect on GFR.

Angiotensin II↗
PubMed1989

Increased incidence of renal transplant arterial stenosis in children.

We have found an increase from 10% to 16.4% in the incidence of clinically significant transplant arterial stenosis since the introduction of cyclosporin immunosuppression. During the same period there has been a coincidental increase in the use of donor kidneys harvested from children less than 6 years of age. In patients treated with cyclosporin these stenoses of the donor artery are not related to the surgical anastomosis, and have only rarely been associated with clinical or histological evidence of rejection, whereas those patients who have developed transplant arterial stenosis whilst receiving azathioprine have had a higher incidence of rejection. Regardless of immunosuppressive regimes, the use of small donor kidneys appears to be the most significant association with transplant arterial stenosis in our experience, and this finding has major implications for cadaveric renal transplantation in children.

Adolescent↗