Four systematic literature reviews were undertaken to help define best clinical practice in the management of end-stage renal disease (ESRD). Only randomised controlled trials (RCTs) were included. The areas reviewed were (1) Synthetic versus cellulose/modified-cellulose membranes for haemodialysis in ESRD; (2) Bicarbonate versus acetate dialysate for haemodialysis in ESRD; (3) Short versus standard duration dialysis in haemodialysis in ESRD; and (4) Continuous Cyclic Peritoneal Dialysis (CCPD) versus Continuous Ambulatory Peritoneal Dialysis (CAPD) in ESRD. The paucity of trials made it difficult to determine best practice in relation to many outcome measures. The review identified only a modest benefit from synthetic membranes over cellulose membranes in reducing adverse symptoms during dialysis at considerable extra cost. There was good evidence to support the use of bicarbonate in preference to acetate haemodialysis on the basis of greater effectiveness and similar cost. The single study which considered haemodialysis duration did not produce data to support the equal safety of short duration dialysis compared with standard duration. Finally, though the single study identified tended to favour CCPD in preference to CAPD in terms of fewer peritonitis episodes the extra cost involved was considerable. Though approximately 16,000 abstracts were identified by the search strategy only forty-two RCTs met the inclusion criteria for any of the four reviews. Considering the volume of published work and the critical importance of the policy decisions being reviewed, it was disappointing to identify so few. These reviews have highlighted the need for further, large, multi-centre RCTs in nephrology and dialysis. Systematic literature reviews will play a key role in placing the practice of nephrology on a solid foundation of robust scientific evidence. They may also nurture a culture of clinical research in nephrology where the confusion and conflict of many small methodologically week trials is replaced by the scientific clarify of fewer, large, well conducted, methodologically sound RCTs.

My studies have investigated the possible involvement of the plasminogen activator/plasmin system in glomerular physiology and pathology. Urokinase plasminogen activator and its cellular receptor are not found immunocytochemically within the normal or diseased glomerulus in vivo. Plasminogen activator inhibitor-1, an inhibitor of urokinase plasminogen activator was, however, identified in crescents from cases of crescentic glomerulonephritis, but not within the glomerular tuft proper. Culture of human glomerular cells initially revealed urokinase plasminogen activator and plasminogen activator-1 proteins within the supernatant of epithelial cells and mesangial cells, as measured by ELISA. However, immunocytochemical characterisation of each of the cell cultures showed that there was contamination of some of the mesangial cell cultures by epithelial cells. Pure cultures of both types of cell produced plasminogen activator inhibitor-1. However, measurement of urokinase plasminogen activator activity by zymography confirmed that this molecule was not present within supernatants obtained from pure mesangial cell cultures. Furthermore, the use of combined non-isotopic in situ hybridisation and immunocytochemistry allowed identification of urokinase plasminogen activator mRNA only within human cultured glomerular epithelial cells and not within mesangial cells. This finding proved that contaminating epithelial cells were responsible for urokinase plasminogen activator production in cultures thought to be made up of pure mesangial cells. Thus there is excellent evidence for synthesis of this molecule only by epithelial cells. Non-isotopic and radioactive in situ hybridisation were unsuccessful in identifying urokinase plasminogen activator within human kidney sections and the difficulties involved in the methodology of this technique, and the implications of the culture cell work for the role of the plasminogen activator/plasmin system in the glomerulus, are discussed.

<I>Clinical Aim</I>:- To study the safety and efficacy of LDL apheresis in nephrotic patients and to assess the impact of applying a cholesterol "clamp" on the progression of renal disease. <I>Protocol</I>:- 20 patients all with a biopsy proven diagnosis were recruited. Patients were entered into 2 groups using the minimisation technique after scoring for GFR, age, sex, level of proteinuria and presence of concurrent immunosuppression. Group A (n=11) received LDL apheresis in addition to Simvastatin therapy. 12-20 treatments were given to clamp the cholesterol at or below 6.5mmol/l. Group B (n=9) received conventional lipid lowering drug therapy (Simvastatin) only. 1/Cr plots were used to asses progression of disease. Inulin GFR was also measured at entry and at 6 monthly intervals. 24 hour proteinuria, haematology, biochemistry and lipid measurements were made monthly. Patient follow up was for a mean of 17.75 months (SD 7.8). <I>Results</I>:- There was a significant reduction in Total and LDL cholesterol and Triglycerides from baseline values in the apheresis group, for 18 and 15 months respectively. In spite of this sustained lipid "clamp" there was no significant difference in proteinuria or 1/Cr plot. <I>Laboratory Studies </I>1) Lipid peroxidation was measured by diene conjugation. The methodology of this assay was extensively studied and modified to optimise its reproducibility and accuracy. Nephrotic patients did not exhibit LDL with a shortened lag time, but rate and extent of oxidation was affected by treatment. 2) Anti-oxidant status of patients pre and post LDL apheresis and endogenous levels of both groups were assessed. Apheresis did not adversely affect antioxidant profile. 3) The patients were phenotyped and genotyped for apoE polymorphism. There was an excess of the E4 allele compared to the general population.

Chronic renal failure (CRF) is associated with loss of lean body mass, a high incidence of malnutrition, and with insulin resistance. CRF is often complicated by metabolic acidosis. Metabolic acidosis is known to alter both protein and carbohydrate metabolism. A series of studies have been undertaken to investigate the effect of metabolic acidosis on protein metabolism in both normal and CRF human subjects, and to study whether metabolic acidosis in CRF affects insulin sensitivity. Protein turnover was studied using the technique of primed constant infusions of L-[1-¹³C]leucine. Normal subjects were studied before and after ammonium chloride induced metabolic acidosis. Acidosis was associated with increased protein turnover and amino acid oxidation. In CRF subjects, correction of acidosis with sodium bicarbonate decreased protein turnover and amino acid oxidation. The effect of acidosis in CRF on insulin mediated carbohydrate metabolism was studied using the technique of the hyperinsulinaemic euglycaemic clamp. Insulin sensitivity increased with correction of acidosis. By combining L-[1-¹³C]leucine infusions with hyperinsulinaemic euglycaemic clamps, the response of protein metabolism to hyperinsulinaemia was measured before and after correction of acidosis. The presence of acidosis did not impair the ability of insulin to modulate protein metabolism. There is therefore, dissociation between the effects of acidosis in CRF on insulin mediated carbohydrate metabolism and insulin mediated protein metabolism. In summary, metabolic acidosis increases protein catabolism in both normal and CRF man and may contribute to the loss of lean body mass characteristic of CRF. Insulin resistance in CRF improves with correction of acidosis. However the effects of acidosis on protein metabolism are not mediated via alterations in insulin sensitivity.

No description available.

Obesity-related glomerulopathy (ORG) is an emerging epidemic for which an established model, diagnostic guidelines, and dietary treatments are absent. Oxylipins influence inflammation and hemodynamics, yet the renal oxylipin profile or the influence of dietary linoleic acid (LA) and alpha-linolenic acid (ALA) on their formation has yet to be examined. Therefore, obese-prone rats were provided high fat lard/soy diets to induce obesity and subsequently divided among 7 diets with varying LA and ALA levels. The diet-induced obese experimental model developed characteristics of ORG; morphology and histology revealed glomerulomegaly as an early diagnostic marker as it was the first pathological change and indicated further renal damage. Liquid chromatography-tandem mass spectrometry detected 30 oxylipins. Higher dietary ALA resulted in greater n-3 oxylipin levels and resulted in reduced progression of glomerulomegaly and glomerular damage. To conclude, ORG may be diagnosed earlier with glomerulomegaly and treated with dietary oils rich in ALA which alter the oxylipin profile.

No description available.

No description available.

No description available.

Persistent elevation of portal venous pressure (portal hypertension- PH), is linked to chronic liver disease and invariably leads to multi-organ circulatory complications. Hallmarks of PH are renal dysfunction and a characteristic hemodynamic profile (hyperdynamic circulation), which synergistically cause the development of the fatal sequelae of PH. Despite extensive research, PH remains a serious clinical problem, with no effective treatment. In large part, this is due to lack of comprehensive knowledge regarding the initiation and early progression of renal dysfunction and the hyperdynamic circulation. The spleen, which is actively engaged in cardiovascular regulation, is intimately connected with the portal venous system such that splenic venous pressure (SVP) is also elevated in PH. We therefore investigated the contribution of the spleen to PH-related cardiovascular dysregulation. Specifically, we employed an acute rat model to elucidate the existence of neurohormonal pathways activated in early PH. It was known that PH-related renal dysfunction is functional and neurally mediated (via the hepato-renal reflex). We hypothesized that, in addition, selective elevation of splenic venous pressure (SVP) also increases renal vascular resistance and modulates renal vascular function, through reflex activation of splenic afferent and renal sympathetic nerves. Indeed, acutely elevated SVP by partial splenic vein occlusion (SVO) did increase splenic afferent nerve activity and reflexly increased renal sympathetic nerve activity (RSNA). Simultaneously, renal blood flow (RBF) and renal arterial conductance fell; this was α1 adrenergic receptor-mediated and dependent on intact splenic and renal nerves. Moreover, our data showed that, in the absence of increased SVP, PH did not affect RSNA or renal vascular function. Although splanchnic vasodilation is characteristic of the hyperdynamic circulation in PH, its development is thought to be contingent upon an initial transient mesenteric vasoconstriction. Our data revealed that increased SVP reflexly activates mesenteric efferent nerves, and reduces mesenteric arterial blood flow, vascular conductance and resistance artery diameter; this was primarily mediated through angiotensin II release (spleno-renal reflex-, renal baroreceptor-, and mesenteric angiotensinergic nerve-mediated). In conclusion, the spleen neurohormonally modulates renal and mesenteric circulations, thus contributing to the initiation of renal dysfunction and hyperdynamic circulation of PH.