Disturbances of cerebral purine and pyrimidine metabolism in young children with chronic renal failure

Chronic renal failure during childhood may be associated with delayed cognitive development. From 10 children with chronic renal failure, aged 2-59 months, plasma and cerebrospinal fluid (CSF) purines and pyrimidines have been determined. A marked increase of pseudouridine and cytidine was demonstrated in CSF of 10 and 8 children, respectively. The plasma concentration of pseudouridine was increased in a varying degree to a maximal value of more than 10 times the upper limit of normal. The plasma concentration of cytidine showed only moderately elevated values. In 3 children the study of CSF and plasma was repeated 6 weeks after the start of continuous ambulatory peritoneal dialysis. The abnormal concentrations of pseudouridine and cytidine were still present in CSF and plasma. Further studies are necessary to elucidate the cause of this unknown biochemical aberration of the central nervous system.     

Carbohydrate metabolism in uremia

Abnormalities of insulin and glucose metabolism, namely glucose intolerance, inhibition of insulin secretion and insulin resistance, are present in children with chronic renal failure. Insulin resistance is universal among children with end-stage renal disease and may be caused by uremic toxins accumulated because of reduced renal function. The normal response of the beta cell is to enhance insulin secretion to overcome the insulin resistance. In patients with secondary hyperparathyroidism, this increase in insulin secretion is inhibited, resulting in glucose intolerance. Presence of glucose intolerance may be responsive for the growth retardation in uremic children. Improvements in glucose tolerance correlate with improvements in linear growth in uremic children. Further research should be directed towards investigation of the mechanisms by which abnormal energy utilization may affect growth in uremia and development of indices of glucose metabolism as predictors of growth in aremia.     

The acute effects of AICAR on purine nucleotide metabolism and postischemic cardiac function

The purine precursor AICAR (5-amino-4-imidazolecarboxamide) has been advocated as a substrate for myocardial adenine nucleotide repletion during postischemic reperfusion. The purpose of this study was to investigate the acute effects of this agent on adenine nucleotides, inosine monophosphate, and postischemic ventricular function in an isolated rat heart preparation. The hearts were perfused at constant flow, either continuously for 90 minutes or for a 30 minute period followed by 10 minutes of global normothermic (37 degrees C) ischemia. The ischemic hearts were then reperfused for 15, 30, and 60 minutes. Both groups were treated with AICAR in a concentration of 100 mumol/L throughout the perfusion protocols. In the nonischemic time control group there was no effect on the levels of adenosine nucleotides or developed pressure over 90 minutes of perfusion. In contrast, AICAR treatment increased tissue inosine monophosphate content four-fold and sevenfold at 60 and 90 minutes, respectively (p less than 0.05), but had no effect on tissue adenosine monophosphate levels. During ischemia, there was a 50% decrease in adenosine triphosphate content in the AICAR-treated hearts and a thirteen-fold increase in adenosine monophosphate levels (p less than 0.05). After 60 minutes of reperfusion, adenosine triphosphate and monophosphate levels in the AICAR-treated hearts recovered to only 52% and 59% of preischemic values, respectively. These findings were similar to those observed in the untreated ischemic hearts. In contrast, tissue inosine monophosphate content in the AICAR-treated hearts during reperfusion remained significantly elevated and was fivefold greater than the reperfusion values in the untreated group. Concurrently, AICAR failed to enhance the recovery of postischemic left ventricular developed pressure. These results suggest that inhibition of the conversion of inosine monophosphate to adenosine monophosphate limits the usefulness of the agent in evaluating the temporal relationships between postischemic adenosine triphosphate repletion and recovery of myocardial function in the acute setting.     

Lactate metabolism in acute uremia.

Lactate is a key metabolite that is produced by every cell and oxidized by most of them, provided that they do contain mitochondria. Its metabolism is connected to energetic homeostasis and the cellular redox state. It is well recognized as an indicator of severe outcome in severely ill patients, however, it is not a detrimental factor per se. Conversely, some recent data tend even to indicate a beneficial effect in several metabolic disorders. Although the liver has long been recognized as a key organ in lactate homeostasis, the kidney also plays a major role as a gluconeogenic organ significantly involved in the glucose-lactate cycle. In acute renal failure, sodium lactate is widely used as a buffer in replacement fluids because the anion (lactate - ) is metabolized and the cation (Na + ) remains, leading to decreased water dissociation and proton concentration. The metabolic disorders related to acute renal failure or associated with it, such as liver failure, may affect lactate metabolism, and therefore they are often regarded as limiting factors for the use of lactate-containing fluids in such patients. By investigating endogenous lactate production in severe septic patients with acute renal failure, we found that an acute exogenous load of lactate did not affect the basal endogenous lactate production and metabolism. This indicates that exogenous lactate is well metabolized even in patients suffering from acute renal failure and severe sepsis with a compromised hemodynamic status.     

Newer aspects of carnitine metabolism in uremia

New knowledge on the physiologic role of L-carnitine and on the rationale of its use in patients on maintenance hemodialysis is provided. In particular, carnitine normalizes plasma and muscle carnitine levels and modifies both enzymatic pattern of muscle and morphology of single fibers, improving exercise tolerance. In addition, carnitine reduces erythropoietin requirements, the number of hypotensive episodes, improves ejection fraction, and decreases hospitalization.     

Impaired metabolism of guanidinoacetic acid in uremia

In order to investigate the guanidinoacetic acid (GAA) metabolism in uremia, we have measured serum guanidino compounds in patients with chronic renal failure (CRF) in comparison with normal subjects, and the renal content of GAA and glycine amidinotransferase (GAT) activity in the kidney of experimental CRF rabbits. Serum concentrations of guanidinosuccinic acid (GSA) and methylguanidine (MG) in the patients with CRF were higher than those in the normal subjects, as well as serum urea nitrogen (BUN) and creatinine (Cr) levels. The serum GAA levels were however, significantly lower and showed a tendency to decrease inversely with the elevation of BUN in the patients with CRF under conservative therapy. On the contrary, in the patients under maintenance hemodialysis (MHD) therapy, the serum GAA level did not decrease in spite of the elevation of BUN. Four anephric patients under MHD therapy showed a level of serum GAA similar to the other MHD patients. In the CRF rabbits, the renal GAA content was significantly lower than in the sham-operated rabbits and showed an inverse correlation with BUN. Renal GAT activity was also significantly lower in the CRF rabbits, showing a positive correlation with serum GAA concentration and an inverse correlation with BUN. These results indicate that renal GAT activity decreases as the BUN level rises in the course of renal damage, resulting in lower concentration of serum GAA in the uremic state; in a more advanced stage of renal failure, the inability of the kidney to synthesize GAA may be compensated by other organ(s). Some dialyzable substances which might inhibit renal GAT activity may also be present.     

Activities of enzymes involved in purine metabolism and some related adenine nucleotide concentrations of leucocytes in renal failure

We have studied purine metabolism in mononuclear and polymorphonuclear cells from uraemic patients using microradiochemical enzyme assays and high-pressure liquid chromatography. In mononuclear cell lysates the mean activities of adenosine deaminase (EC 3.5.4.4) and 5'-nucleotidase (EC 3.1.3.5) were significantly diminished. The activities of adenylate kinase (EC 2.7.4.3), purine nucleoside phosphorylase (EC 2.4.2.1), adenine phosphoribosyltransferase (EC 2.4.2.7), and hypoxanthine phosphoribosyltransferase (EC 2.4.2.8) were not significantly different in the two groups. The activities of adenosine deaminase and adenine phosphoribosyltransferase were reduced in the polymorphonuclear cell lysates. No clear differences emerged in the concentration of adenine nucleotides in the mononuclear cells. The significance of these changes, which are less marked than those in erythrocytes, is discussed with reference to the immunodeficiency associated with uraemia.     

Specific defects in insulin-mediated muscle metabolism in acute uremia

The mechanisms underlying the abnormal insulin-mediated muscle glucose metabolism occurring in acute uremia (ARF) have not been identified. To characterize the defects, insulin dose-response curves for glucose uptake, glycogen synthesis, glucose oxidation, glycolysis, and lactate release were measured in incubated rat epitrochlearis muscles. ARF did not affect insulin sensitivity, but decreased the responsiveness to insulin of glucose uptake, glycogen synthesis, and glucose oxidation. Glycogen synthesis was subnormal at all levels of insulin and at the maximal insulin concentration; it was 54% lower in muscles of ARF compared to control rats. This inhibition of glycogen synthesis in ARF could be caused by a 23% decrease in the total activity of muscle glycogen synthase and the percentage of enzyme in the activated form. Glycogen phosphorylase activity was unchanged by ARF. ARF also increased the ratio of muscle lactate release to glucose uptake at concentrations of insulin from 10 to 10(4) microU/ml. In the absence and presence of insulin, muscle protein degradation was increased by ARF. In individual muscles incubated with insulin, the rate of proteolysis was correlated with the ratio of lactate release to glucose uptake (r = + 0.82; P less than 0.01). From the insulin dose-response relationships and changes in enzyme activities, we conclude that ARF increases protein degradation in muscle and causes abnormal insulin-mediated glucose metabolism. The abnormalities in glucose metabolism are caused by changes in post-receptor events.     

The purine nucleotide cycle activity in renal cortex and medulla

Formation of adenine nucleotides, IMP, malate + fumarate, ammonia, adenosine, and inosine + hypoxanthine + uric acid were measured in cytosolic extracts from renal cortex and medulla. The order of substrate addition was IMP, then 2-deoxyglucose, then P-creatine. Compared with cortex, medulla showed greater rates of formation of adenosine triphosphate (ATP) from P-creatine, of adenosine monophosphate (AMP) from 2-deoxyglucose, and of total adenine nucleotides from IMP. These results suggest that the purine nucleotide cycle is more active in medulla than in cortex. This cycle may provide a mechanism in medulla for storing purine nucleotides which can be used to restore ATP pools in the relatively hypoxic conditions of this part of the kidney.     

Disturbances of mineral metabolism in a French hemodialysis unit

Recent data from DOPPS in the field of the mineral metabolism showed that there is a relative homogeneity between most of the countries and continents studied. In reference to the American recommendations (NKF-K/DOQI 2003) the majority of the patients are apart from the desired targets. Approximately 70% of the patients have a relative biological hypoparathyroidism (PTHi<150 pg/ml) or a hyperparathyroidism (PTHi > 300 pg/ml). Only 4.7-5.5% of the patients are in the standard targets, for the four criteria which are: the calcemia, the phosphatemia, serum calcium-phosphorus product and PTH. Many open questions remained to explain why such an overall homogeneity, and why there is such an important inadequacy with the recommendations. In the present work we compared the data of our hemodialysis patients with data from DOPPS I and DOPPS II.     

Disturbances of lipid metabolism in children with chronic renal failure

This review discusses the pathogenesis, clinical significance and current therapy of hyperlipoproteinaemia (HLP) in children with chronic renal failure. Uraemic dyslipidaemia, characterized by hypertriglyceridaemia and low high-density lipoprotein-cholesterol levels, is present in the majority patients with chronic renal failure. In addition, serum levels of total cholesterol, very lowdensity lipoprotein-cholesterol, low-density lipoproteincholesterol and apolipoprotein B are frequently elevated. The pathophysiological mechanisms causing these disturbances are complex and mainly involve a diminished catabolism of triglyceride-rich lipoproteins. For unknown reasons and independent of other lipoproteins, serum levels of the highly atherogenic and thrombogenic lipoprotein(a) are also often elevated. HLP is an important factor in cardiovascular morbidity and mortality. In addition, dyslipidaemia may enhance progression of renal disease in patients with residual renal function. Therefore, treatment of HLP seems indicated in overtly hyperlipidaemic patients, but until there is more experience with lipid-lowering drugs in children, no safe recommendations for pharmacological treatment of HLP can be given. Dietary modifications can be recommended only to a limited extent.     

Vitamin K1 and C metabolism in uremia during hemodialysis

Plasma concentrations of vitamin K1, ascorbic acid and its derivatives were investigated in uremic patients during a session of systemic hemodialysis at the dialyzers input, output and in dialyzing solution. The data showed practically unchanged clearances of vitamin C and diketogulonic acid during the session of hemodialysis. In the course of its passage through the dialyzer, plasma ascorbic acid was partially oxidized to dehydroascorbic acid, partially it converted to a dialysate, partially it returned to the human body. Plasma level of vitamin K1 in uremic patients was 1.8 times lower than that in the healthy; 24-hour its excretion in uremic patients and in the healthy was similar. It is supposed that the vitamin K1 decrease correlates with lipoid changes in uremia. During a session of hemodialysis no significant vitamin K1 losses were revealed.