Arteriovenous hemofiltration as an adjuvant therapy in peritoneal dialysis and hemodialysis in a patient with terminal renal failure]

In the uraemic patient regularly treated with peritoneal dialyses occurring peritonitis caused a decrease of ultrafiltration and transfer abilities of the peritoneum. Other symptoms dangerous for life also appeared: uraemic pericarditis and significant overhydration. Peritoneal dialyses lost its effectiveness. Therefore they were supplemented by arterio-venous haemofiltration. Haemofiltration was also conducted at the beginning of haemodialysis treatment, which was initially unregular. Application of haemofiltration enabled the patient to survive during the time of waiting for regular haemodialyses. It may be useful to consider such a treatment, when the adequacy of proper renal substitutive management of uraemia by other methods is impossible to obtain.     

Impaired muscle glucose metabolism in acute renal failure

Renal failure is associated with peripheral insulin resistance and consequent carbohydrate intolerance. This report investigates carbohydrate metabolism in vitro in epitrochlearis and hemidiaphragm muscles taken from acutely uraemic and sham-operated rats. Muscles from acutely uraemic rats (compared to those from sham-operated rats ) incubated with 5 mM glucose showed increased rates of basal and insulin-stimulated glycolysis and glycogen turnover, but pyruvate dehydro-genase and tricarboxylic acid - cycle flux was not increased in uraemia. Glycolysis (but not glycogen turnover) in muscles from acutely uraemic rats tended to show decreased responsiveness to stimulation by insulin. It is concluded that acute uraemia is associ-ated with a defect(s) in muscle that produces intrinsic insulin resistance and results in diversion of glucose (both in basal and insulin-stimulated states) from glycogen synthesis into glycolysis.     

Effects of glucose-containing peritoneal-dialysis solutions on rates of lipogenesis in vivo in the liver, brown and white adipose tissue of chronic uraemic rats.

Chronic uraemic rats had decreased food intake, and this was accompanied by decreased weight of the epididymal fat-pads and interscapular brown adipose tissue. Normal rats whose food intake was restricted to an amount similar to that of the uraemic rats showed similar decreases in weight of the adipose-tissue depots. In addition, the food-restricted rats had decreased liver weight compared with normal or uraemic rats. The basal rate of lipogenesis was decreased in liver and epididymal fat-pads of food-restricted and uraemic rats and in interscapular brown adipose tissue of uraemic rats. Administration of a low-glucose-containing (1.36%) peritoneal-dialysis solution slightly increased lipogenesis in liver of uraemic rats, but had no significant effect in epididymal fat-pads. For brown fat, the rate of lipogenesis was increased in normal, food-restricted and uraemic groups, but the values for the last group were 4-5-fold lower than for the food-restricted or control groups. A high-glucose-containing (3.86%) peritoneal-dialysis solution gave similar rates of lipogenesis in liver, epididymal fat-pads and brown fat of all three groups, but for brown fat moderately uraemic rats showed a considerably lower rate of lipogenesis than did mildly uraemic rats. The basal plasma insulin concentration was lower in the food-restricted (50%) and uraemic (70%) groups than in the control group. The low-glucose peritoneal-dialysis solution increased plasma insulin to control values in the food-restricted rats, but had no significant effect on plasma insulin in the uraemic rats, despite a significant increase in blood glucose in this group. It is concluded that there is an impairment of the lipogenic response to intraperitoneal glucose loads in interscapular brown adipose tissue of uraemic rats, and that this is not due to the accompanying decrease in food intake. The hypoinsulinaemia may be an important factor. The possible relevance of this finding to the obesity observed in some uraemic patients treated by peritoneal dialysis with glucose-containing solutions is discussed.     

The nature of the collagen cross-links in bone in the chronic uraemic state.

The cross-links from NaB3H4-reduced bone collagen of chronically uraemic rats and pairfed controls were compared. The ratio of the reduced cross-links deltadelta'-dihydroxylysinonorleucine to delta-hydroxylysinonorleucine was significantly increased in the uraemic animals. The observed increment in the dihydroxylysinonorleucine:hydroxylysinonorleucine ratio was accentuated as the uraemic state advanced. The data indicate that osteodystrophy of chronic renal insufficiency is characterized by an alteration of the quantitative relations between cross-links and aldehydic precursors of bone collagen.     

Clinical and electrophysiologic findings in dialysis patients

The aim of this study was to quantitatively determine the electrophysiologic changes occurring in the peripheral nerves and muscles in patients with chronic renal failure (CRF) treated with haemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD), and to determine which electrophysiologic parameters are most commonly abnormal in uraemic patients. We investigated the relationship between the parameters of neurography and quantitative electromyography (QEMG) and clinical findings.The study included 42 patients with CRF (30 on HD and 12 on CAPD). Nerve conduction studies (NCSs) of the median, ulnar, tibial, peroneal, and sural nerves, and QEMG of the tibialis anterior and biceps brachii muscles were performed.We found axonal and/or demyelinating polyneuropathies in 97.6% of the patients (100% of HD and 91.7% of CAPD patients), but were not able to verify any significant differences between the HD and CAPD patients using NCS or QEMG. Median, ulnar, sural sensory nerve action potential (SNAP) amplitudes, peroneal CV and F-latency were the most common abnormal parameters in sensory and motor NCSs, respectively. The clinical findings only correlated with the parameters of neurography, and not with the parameters of QEMG. Sural SNAP amplitudes, peroneal and tibial CVs, F-latencies also correlated with the severity of the clinical findings in these patients, suggesting that these parameters can be used in follow up studies in these patients.In this study, most of the uraemic patients were found to have already mild or moderate neuropathies in which the objective clinical signs might be absent, even if they have some clinical symptoms. NCS showed abnormality indicating polyneuropathy in 24 out of 25 patients with clinical neuropathy signs and in 17 out of 17 patients with no clinical signs. Thus, in subclinical conditions NCS is useful to detect the abnormalities in peripheral nerves of the ureamic patients under chronic dialysis.     

BDNF improves axon transportation and rescues visual function in a rodent model of acute elevation of intraocular pressure

Optic neuropathies lead to blindness; the common pathology is the degeneration of axons of the retinal ganglion cells. In this study, we used a rat model of retinal ischemia-reperfusion and a one-time intravitreal brain-derived neurotrophic factor(BDNF)injection; then we examined axon transportation function, continuity, physical presence of axons in different part of the optic nerve, and the expression level of proteins involved in axon transportation. We found that in the disease model, axon transportation was the most severely affected, followed by axon continuity, then the number of axons in the distal and proximal optic nerve. BDNF treatment relieved all reductions and significantly restored function. The molecular changes were more minor,probably due to massive gliosis of the optic nerve, so interpretation of protein expression data should be done with some caution.The process in this acute model resembles a fast-forward of changes in the chronic model of glaucoma. Therefore, impairment in axon transportation appears to be a common early process underlying different optic neuropathies. This research on effective intervention can be used to develop interventions for all optic neuropathies targeting axon transportation.     

THE EFFECT OF ACUTE RENAL FAILURE ON MITOTIC DURATION OF MOUSE ILEAL EPITHELIUM

Previous percentage labelled mitoses studies in acutely uraemic mice have demonstrated a lengthening of the cell cycle and the DNA synthetic phase of ileal epithelium. The mitotic index was unaltered. Further studies have been performed to obtain an estimate of mitotic duration. Acute renal failure was produced by urinary outflow obstruction in male mice. Controls were subjected to sham operation. The mean number of cells per crypt cell column, number of mitoses present per crypt section and differential mitotic stage count were assessed 18 hr after operation for uraemic and control mice. The mean number of metaphases accumulated per crypt section over a 2 hr interval following colchicine injection was obtained in other groups of mice and the mitotic duration calculated. The mean number of mitoses per crypt section was 1.30 ± 0.46 for the controls and 1.48 ± 0.66 for the uraemic group. No evidence for a block in mitosis was indicated by the differential mitotic stage count. After applying Tannock's correction factor the mitotic duration was estimated to be 0.91 ± 0.18 hr for the control group and 2.81 ± 0.89 hr for the uraemic group. The difference in duration between the groups, 1.90 ± 0.91 hr, was significant (P≤0.05). Reduction in cell proliferation may explain the development of uraemic lesions in the gastrointestinal tract.     

Role of Acidosis in Renal Osteomalacia

Of nine patients with uraemic osteomalacia, the underlying renal lesion was pyelonephritis in seven. All of the patients were characterized by impairment of acidifying power and severe metabolic acidosis. It is suggested that metabolic acidosis may be a definite factor in the pathogenesis of uraemic osteomalacia, possibly by reducing the proportion of trivalent phosphate in the plasma and/or by reducing plasma calcium.     

Spectrum of peripheral neuropathies associated with surgical interventions; A neurophysiological assessment

Background

We hypothesized that a wide range of surgical procedures may be complicated by neuropathies, not just in close proximity but also remote from procedural sites. The aim of this study was to classify post-operative neuropathies and the procedures associated with them.

Methods

We retrospectively identified 66 patients diagnosed with post-procedure neuropathies between January 2005 and June 2008. We reviewed their referral cards and medical records for patient demographics, information on procedures, symptoms, as well as clinical and neurophysiological findings.

Results

Thirty patients (45.4%) had neuropathies remote from procedural sites and 36 patients (54.5%) had neuropathies in close proximity to procedural sites. Half of the remote neuropathies (15/30) developed following relatively short procedures. In 27% of cases (8/30) remote neuropathies were bilateral. Seven patients developed neuropathies remote from operative sites following hip arthroplasties (7/30: 23.3%), making hip arthroplasty the most common procedure associated with remote neuropathies. Sciatic neuropathies due to hip arthroplasty (12/36, 33.3%) accounted for the majority of neuropathies occurring in close proximity to operative sites. Five medial cutaneous nerve of forearm neuropathies occurred following arterio-venous fistula (AVF) formation.

Conclusions

An array of surgical procedures may be complicated by neuropathy. Almost half of post-procedure neuropathies occur remote from the site of procedure, emphasizing the need to try to prevent not just local, but also remote neuropathies. Mechanical factors and patient positioning should be considered in the prevention of post-operative neuropathies. There is a possible association between AVF formation and medial cutaneous nerve of forearm neuropathy, which requires further study for validation.     

Defective antigen presentation by monocytes in ESRD patients not responding to hepatitis B vaccination: impaired HBsAg internalization and expression of ICAM-1 and HLA-DR/Ia molecules

This study was undertaken to evaluate the monocyte function of uraemic non-responders to hepatitis B vaccination. Therefore, some parameters concerning antigen processing by monocytes (Mo) as antigen presenting cells (APC) were analysed. It was found that in uraemic non-responders, (1) the internalization of HBsAg by monocytes was significantly decreasjed-HBsAg complexed with specific IgG or as immune complex isolated from patients is better internalized compared with free HBsAg; (2) during antigen presentation the expression of adhesion (ICAM-1) and accessory (HLA-DR/Ia) molecules was significantly decreased in uraemic patients, especially in non-responders; and (3) impaired internalization of HBsAg as well as a decrease in ICAM-1 and HLA-DR/Ia expression, correlated well with the blunted proliferation of CD4(+) T cells stimulated by autologous monocytes induced by HBsAg.     

Studies on platelet surface carbohydrates in normal and uraemic platelets using 125I-labelled lectins

Binding studies with six different purified 125I-labelled lectins, concanavalin A (con A), wheat germ agglutinin (WGA), Ricinus communis agglutinin II (RCA II), Dolichos biflorus (DB), Tetranolobus purpureus (TP) and P-phyto-hemagglutinin (P-PHA), were used to investigate the surface topography of carbohydrates in platelets from uraemic and normal subjects. Compared with normal the uraemic platelets, bear significantly decreased (more than 2.5-fold) numbers of receptors for P-PHA (N-acetyl D-galactosamine specificity) and Con A (specificity glucose, mannose). The number of WGA, RCA, II, DB and TP receptors in uraemic platelets did not differ from the number in normal platelets. Binding studies with 125I-labelled lectins provide further evidence of molecular defects in uraemic platelets. Moreover, this method might provide a fast and reliable technique for identifying abnormalities in the surface topography of carbohydrates on platelets in several pathological states.     

Nerve growth factor‐mediated regulation of pain signalling and proposed new intervention strategies in clinical pain management

Nerve growth factor (NGF) is the founding member of the neurotrophins family of proteins. It was discovered more than half a century ago through its ability to promote sensory and sympathetic neuronal survival and axonal growth during the development of the peripheral nervous system, and is the paradigmatic target‐derived neurotrophic factor on which the neurotrophic hypothesis is based. Since that time, NGF has also been shown to play a key role in the generation of acute and chronic pain and in hyperalgesia in diverse pain states. NGF is expressed at high levels in damaged or inflamed tissues and facilitates pain transmission by nociceptive neurons through a variety of mechanisms. Genetic mutations in NGF or its tyrosine kinase receptor TrkA, lead to a congenital insensitivity or a decreased ability of humans to perceive pain. The hereditary sensory autonomic neuropathies (HSANs) encompass a spectrum of neuropathies that affect one's ability to perceive sensation. HSAN type IV and HSAN type V are caused by mutations in TrkA and NGF respectively. This review will focus firstly on the biology of NGF and its role in pain modulation. We will review neuropathies and clinical presentations that result from the disruption of NGF signalling in HSAN type IV and HSAN type V and review current advances in developing anti‐NGF therapy for the clinical management of pain.     

Functional roles of Phe of deacetyl-thymosin beta4 in the impaired blastogenic response of uraemic T-lymphocytes

Phe(12) of deacetyl-thymosin beta(4) is one of the structural essentials for restorative effect on the impaired blastogenic response of uraemic T-lymphocytes. In order to evaluate the functional roles of this phenyl group in the restorative effect on impaired T-lymphocytes, two analogues, [1- Nal(12)]deacetyl-thymosin beta(4) and [Cha(12)]deacetyl4 thymosin beta(4), were synthesized by a solid-phase method and evaluated for restorative effect on the impaired blastogenic response of uraemic T-lymphocytes. The results indicated that [1-Nal(12)]deacetyl-thymosin beta(4) which had a bulky naphthyl ring showed a stronger restorative effect than that of deacetyl-thymosin beta(4), but it was slightly weaker than that of [Phe(4F)(12)]deacetyl-thymosin beta(4). However, [Cha(12)]deacetyl-thymosin beta(4) showed no restorative effect on the impaired blastogenic response of uraemic T-lymphocytes.     

Cholestyramine in uraemic pruritus.

In a patient with longstanding severe uraemic pruritus who was undergoing chronic haemodialysis cholestyramine caused the pruritus to disappear completely within a few days. A four-week randomised controlled double-blind study was therefore performed in 10 other patients with uraemic pruritus who were on chronic haemodialysis. The pruritus improved considerably in four of the five treated patients, whereas only one of those treated with placebo experienced relief. The patient who had no relief while on cholestyramine showed a considerable improvement when the dose subsequently doubled. One of the five patients receiving cholestyramine experienced mild and easily reversible constipation, and another suffered nausea. Neither of these complications prevented the patients from continuing treatment. Cholestyramine seems to be useful in treating uraemic pruritus, although it is not known how it acts.     

Regulation of intracellular creatine in erythrocytes and myoblasts: Influence of uraemia and inhibition of Na,K-ATPase

The regulation of intracellular creatine concentration in mammalian cells is poorly understood, but is thought to depend upon active sodium-linked uptake of creatine from extracellular fluid. In normal human erythrocytes, creatine influx into washed cells was inhibited by 40 per cent in the absence of extracellular sodium. In washed cells from uraemic patients, sodium-independent creatine influx was normal, whereas the sodium-dependent component of creatine influx was 3·3 times higher than normal, possibly relecting the reduced mean age of uraemic erythrocytes. In spite of this, the intracellular creatine concentration was no higher than normal in uraemic erythrocytes, implying that some factor in uraemic plasma in vivo inhibits sodium-dependent creatine influx. Both in normal and uraemic erythrocytes, the creatine concentration was 10 times that in plasma, and the concentration in the cells showed no detectable dependence on that in plasma, suggesting that the intracellular creatine concentration is controlled by an active saturable process. Active sodium-dependent accumulation of creatine was also demonstrated in L6 rat myoblasts and was inhibited when transport was measured in the presence of 10^?4M ouabain or digoxin, implying that uptake was driven by the transmembrane sodium gradient. However, when creatine influx was measured immediately after ouabain or digoxin had been washed away, it was higher than in control cells, suggesting that Na,K-ATPase and/or sodium-linked creatine transport are up-regulated when treated with inhibitors of Na,K-ATPase.     

Beta2-microglobulin causes abnormal phosphatidylserine exposure in human red blood cells

The exposure of the aminophospholipid phosphatidylserine on the external leaflet of red blood cell plasma membrane can have several pathophysiological consequences with particular regard to the processes of cell phagocytosis, haemostasis and cell-cell interaction. A significant increase in phosphatidylserine-exposing erythrocytes has been reported in chronic haemodialysis patients and found to be strongly influenced by the uraemic milieu. To identify uraemic compound(s) enhancing phosphatidylserine externalization in erythrocytes, we fractionated by chromatographic methods the ultrafiltrate obtained during dialysis, and examined by flow cytometry the effect of the resulting fractions on phosphatidylserine exposure in human red cells. Chromatographic procedures disclosed a homogeneous fraction able to increase erythrocyte phosphatidylserine exposure. The inducer of such externalization was identified by monodimensional gel electrophoresis and mass spectrometry investigations as beta2-microglobulin. To confirm the beta2-microglobulin effect and to examine the influence of protein glycation (as it occurs in uraemia) on phosphatidylserine erythrocyte exposure, erythrocytes from normal subjects were incubated with recombinant beta2-microglobulin (showing no glycation sites at mass analysis), commercial beta2-microglobulin (8 glycation sites), or with in vitro glycated recombinant beta2-microglobulin (showing multiple glycation sites). Elevated concentrations of beta2-microglobulin (corresponding to plasma levels reached in dialysis patients) increased slightly but significantly the protein's ability to externalize phosphatidylserine on human erythrocytes. Such an effect was markedly enhanced by glycated forms of the protein. Beta2-microglobulin is recognized as a surrogate marker of middle-molecule uraemic toxins and represents a key component of dialysis-associated amyloidosis. Our study adds further evidence to the potential pathophysiologic consequences of beta2-microglobulin accumulation in chronic uraemic patients.     

Evaluation of monocyte chemotactic responsiveness in uraemic patients undergoing haemodialysis with different dialytic membranes

Recent data show that monocyte chemotactic peptide-1 (MCP-1), a chemotactic factor specific for monocytes, may play a central role in regulating the activation of these cells. For this reason, the production of MCP-1 in peripheral blood mononuclear cell (PBMC) cultures of eight healthy subjects, six chronic uraemic subjects under conservative treatment and six chronic uraemic patients undergoing haemodialysis (HD), was assessed. In the latter group of individuals, complement-activating membranes such as cuprophan (CU) were used for 1 month followed by biocompatible non-complement-activating membranes, like polymethylmetacrylate (PMMA) for the next 30 days. The chemotactic index (CI) elicited by PBMC supernatants from patients undergoing dialysis was found to be significantly higher than that obtained by supernatants recovered from normal subjects or uraemic patients on conservative therapy. Furthermore, the CI from PBMC supernatants having had contact with CU membranes was higher than that obtained from PBMC activated by PMMA. Finally, the increased chemotactic ability in the supernatants was closely correlated with the augmented MCP-1 gene expression and production, as assessed by in vitro hybridization studies.     

Quinpramine ameliorates rat experimental autoimmune neuritis and redistributes MHC class II molecules

Activation of inflammatory cells is central to the pathogenesis of autoimmune demyelinating diseases of the peripheral nervous system. The novel chimeric compound quinpramine--generated from imipramine and quinacrine--redistributes cholesterol rich membrane domains to intracellular compartments. We studied the immunological and clinical effects of quinpramine in myelin homogenate induced Lewis rat experimental autoimmune neuritis (EAN), a model system for acute human inflammatory neuropathies, such as the Guillain-Barré syndrome. EAN animals develop paresis of all limbs due to autoimmune inflammation of peripheral nerves. Quinpramine treatment ameliorated clinical disease severity of EAN and infiltration of macrophages into peripheral nerves. It reduced expression of MHC class II molecules on antigen presenting cells and antigen specific T cell proliferation both in vitro and in vivo. Quinpramine exerted its anti-proliferatory effect on antigen presenting cells, but not on responder T cells. Our data suggest that quinpramine represents a candidate pharmaceutical for inflammatory neuropathies.     

The effect of hypovolemia on the renal and cardiovascular responses to atrial natriuretic factor (ANF) infusion.

The renal and cardiovascular effects of ANF infusion have been examined in separate series of experiments; in conscious instrumented sheep following either hemorrhage (10 mL/kg body weight) or removal of 500 mL of plasma by ultrafiltration. Renal arterial infusion of hANF (99-126) at 50 micrograms/h increased sodium excretion from 99 +/- 30 to 334 +/- 102 (p less than 0.05) in normal animals, and from 77 +/- 31 to 354 +/- 118 mumol/min in hemorrhaged animals. Similarly in sheep following ultrafiltration, cardiac output and stroke volume were reduced by intravenous infusion of ANF (100 micrograms/h), although these effects were less marked than those observed in normal animals. The rapid modulation of natriuretic responses to ANF observed in volume expanded animals is not seen in this model of acute volume depletion suggesting that the mechanism through which the renal response to ANF is modulated in low sodium or volume states is not simply the reverse of that which produces rapid enhancement of response following blood volume expansion.