Effect of metabolic acidosis on branched-chain amino acids in uremia

 Fasting plasma concentrations of branched-chain amino acids (BCAA) valine, leucine, and isoleucine were measured in 20 young patients (aged 18±2 years) with end-stage renal disease just before initiation of dialysis and compared with 7 healthy controls (aged 19±1 years). Plasma valine, leucine, and isoleucine were all lower than control values (P<0.01 in all 3 cases). Plasma valine, but not leucine and isoleucine, correlated with venous pH (P<0.02). Plasma valine, leucine, or isoleucine did not correlate with blood urea nitrogen or serum creatinine. Seven patients (aged 18±1 years) on maintenance hemodialysis with metabolic acidosis were then studied before and after 2 weeks of oral sodium bicarbonate (NaHCO₃) treatment to correct the acidosis. To control for the effect of additional sodium, they were also studied after 2 weeks of an equivalent amount of oral sodium chloride (NaCl). Oral NaHCO₃ treatment led to significant increases in venous pH and serum bicarbonate concentrations, but no significant change in total and ionized calcium, phosphate, sodium, potassium, creatinine, blood urea nitrogen, and intact parathyroid hormone concentrations. Oral NaCl did not change any of the biochemical parameters. Fasting plasma concentrations of BCAA were measured. Before treatment of acidosis, uremic patients had low plasma concentrations of valine, leucine, and isoleucine compared with controls. Following 2 weeks of NaHCO₃ treatment, there were significant increases in the plasma concentrations of valine and leucine (P<0.01), although the values did not normalize. There were no changes in plasma concentrations of valine and leucine following 2 weeks of NaCl. The plasma concentration of isoleucine was not different during baseline (acidotic) and treatment periods with NaHCO₃ and NaCl. Thus treatment of metabolic acidosis ameliorated abnormalities in plasma concentrations of valine and leucine in patients with uremia on hemodialysis. Received: 18 February 1998 / Revised: 22 June 1998 / Accepted: 26 June 1998     

Insulin and growth in chronic renal failure

We studied glucose metabolism using the hyperglycemic technique in a cross-section of 23 children (15 pubertal, 8 prepubertal) with stable chronic renal failure as a possible cause of their poor growth. Linear growth was expressed as growth velocity standard deviation score (GVSDS). GVSDS correlated with glucose disposal rate but not with insulin sensitivity index in the pubertal (r=0.87,P<0.001) and prepubertal (r=0.86,P<0.02) children with chronic renal failure. Thirteen children were followed longitudinally during medical suppression of hyperparathyroidism with dietary phosphate restriction and high-dose phosphate binders. Following significant suppression of serum parathyroid hormone (PTH) levels back to the normal range (932±240 ng/l to 199±50 ng/l), GVSDS, glucose disposal rate and insulin secretion all increased significantly (P<0.01), with no change in insulin sensitivity index and renal function. The changes in GVSDS correlated with the changes in glucose disposal rate (r=0.86,P<0.02) and with the changes in insulin secretion (r=0.80,P<0.01). However, the changes in GVSDS did not correlate with the changes in PTH. The hypothesis that insulin may be more important than PTH in the pathogenesis of growth failure in chronic renal disease deserves further investigation.     

Comparative effects of oral aromatic and branched-chain amino acids on urine calcium excretion in humans

Summary In 30 adults, increasing intake of aromatic amino acids increased calcium excretion and serum IGF-1, but not indices of bone turnover, when compared with similar increases in intake of branched-chain amino acids. The mechanisms involved are not certain but these findings suggest a role for the calcium sensor receptor. Introduction In contrast to branched-chain amino acids (BCAAs), aromatic amino acids (AAAs) bind to the calcium sensing receptor (CaR) and thus have an increased potential to affect calcium homeostasis. In this study we compare the effects of increased intake of AAAs versus BCAAs on calcium excretion, serum IGF-1, markers of bone turnover, and 4-hr calcium excretion after an oral calcium load. Methods After two weeks on low-protein metabolic diets, 30 healthy subjects were randomized to a fivefold increase in intake of AAAs or BCAAs for two weeks. Changes in calcium excretion and other measures were compared in the two groups. Results With the increase in amino acid intake, 24-hr calcium excretion (P = 0.027), IGF-1 (P = 0.022), and 4-hr calcium excretion after an oral load (P = 0.023) increased significantly in the AAA relative to the BCAA group. Group changes in turnover markers did not differ significantly. Conclusion In comparison with BCAAs, AAAs promoted calcium excretion. The calciuria does not appear to result from increases in bone resorption and may occur by increasing calcium absorption. The AAAs also increased circulating levels of IGF-1. Collectively these findings raise the possibility that AAAs may selectively influence calcium homeostasis through their interactions with the CaR. Presented at the American Society of Bone and Mineral Research meeting in Nashville, Tenn., September 2005. This material is based on work supported by a Discovery Grant from Dairy Management, Inc. and by the U.S. Department of Agriculture under agreement No. 59-1950-9001. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors, and do not necessarily reflect the view of the U.S. Department of Agriculture.     

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.     

Branched chain amino acids in heptatic encephalopathy

BACKGROUND: Early theories or hepatic encephalopathy focused on ammonia-driven disruption of the Krebs cycle and cellular energy production. The "false-neurotransmitter" theory directed attention toward the interactions of amino acids, metabolism, the blood-brain barrier and neurotransmission. As they evolved, these studies revealed surprising and subtle effects of ammonia on brain amino acid uptake. DATA SOURCES: Research over a 15-year period in Josef E. Fischer's laboratory explored many aspects of these interactions. Subsequent studies by others have confirmed and extended them into other areas. Insights from this work continue to stimulate attempts to confirm or disprove the clinical utility of branched chain amino acids. CONCLUSIONS: Increased understanding of the factors affecting ammonia, amino acid and neurotransmitter disturbances in chronic liver failure have made a significant and ongoing contribution to the study of metabolism in health and disease.     

血液透析对尿毒症胰岛素拮抗和糖代谢的影响

目的研究血液透析对尿毒症胰岛素拮抗和糖代谢的影响。方法采用口服葡萄糖耐量试验（ＯＧＴＴ）和胰岛素释放试验（ＩＲＴ）方法，检测２２例血透（ＨＤ），２２例非透析（ＮＤ）尿毒症者和１２例正常者胰岛素敏感指数（ＩＳＩ）、机体糖利用率（Ｍ）、糖和胰岛素反应曲线下面积（ＡＵＣＧ和ＡＵＣＩＮＳ）。结果（１）ＨＤ组糖负荷后血糖、胰岛素水平及其ＡＵＣＧ、ＡＵＣＩＮＳ均显著低于ＮＤ组，但仍明显高于正常对照组；（２）ＨＤ组ＩＳＩ、Ｍ值显著高于ＮＤ组，但明显低于正常对照组，其胰岛素拮抗（ＩＲ）和糖耐量异常（ＩＧＴ）发生率均显著低于ＮＤ组：（３）胰岛素拮抗组血透时间显著短于非胰岛素拮抗组，透析时间与ＩＳＩ有正相关趋势；（４）ＨＤ组较ＮＤ组血ｐＨ值、血ＨＣＯ－３水平显著增高，但Ｎ－ＰＴＨ水平显著低下。结论ＨＤ可部分改善尿毒症胰岛素拮抗，高胰岛素血症和糖耐量异常。     

Essential branched-chain amino acids and alpha-ketoanalogues in haemodialysis patients.

Homeostasis of essential amino acids and their transamination derivatives (ketoacids) is disturbed in haemodialysis (HD) patients. In long-term HD patients a hypercatabolic state is often paired with severe anaemia. To understand metabolic regulation mechanisms we measured with an improved fluorescence-HPLC method plasma concentrations of valine (Val), isoleucine (Ile), and leucine (Leu) and their corresponding ketoacids ketoisovaleric acid (KIV), ketomethylvaleric acid (KMV), and ketoisocaproic acid (KIC). The values of 18 modestly anaemic HD patients (group A: Hb greater than 11 g/dl) and of 16 severely anaemic HD patients (group B: Hb less than 8 g/dl) were compared with 19 healthy control persons (100%; significance of patient values vs controls P less than 0.05) and with each other (significantly different at P less than 0.05). Both branched chain amino acids and ketoacids are diminished in HD patients. This disturbance of protein metabolism is intensified with severe anaemia. The decrease of transamination products KIV and KMV parallels that of their corresponding Val and Ile, whereas KIC is reduced out of proportion to Leu. Leu has anabolic function and KIC antiproteolytic effects. Decreased Leu and KIC indicate catabolism. Reduced transamination of Leu and KIC suggests an endogenous protective mechanism against catabolism independent of anaemia. These differences should be considered with supplementation therapy of branched-chain compounds in HD patients.     

Acidosis prevents growth hormone-induced growth in experimental uremia

The effects of 2 weeks of a daily injection (2 IU/day) of recombinant human growth hormone (GH) were studied in young (60-g) growing rats in two experiments. Experiment 1 was performed in uremic animals (mean plasma creatinine 65–71 mol/l) who were either acidotic (mean bicarbonate 11.5 mmol/l) or had acidosis corrected (mean bicarbonate 26 mmol/l) by addition of sodium bicarbonate to the diet. Experiment 2 used rats with normal renal function (plasma creatinine 25 mol/l) who were either non-acidotic but restricted to the dietary intake of uremic rats or rendered acidotic by ammonium chloride. GH induced an increase in body weight and length in nonacidotic uremic (+33% and +41%) and in non-acidotic food-restricted (+13% and +42%) rats, associated with an increased rate of protein synthesis and little change in plasma insulin-like growth factor 1 (IGF 1). In both acidotic rat groups, GH altered none of the parameters studied. Thus: (1) the presence of severe metabolic acidosis blunts the response to GH in uremic and non-uremic rats and (2) the increment of growth rate does not depend on a rise in plasma IGF 1.     

高支链氨基酸在肝功能损害外科患者肠外营养中的作用

目的 探讨高支链氨基酸对肝功能受损外科患者的安全性和营养治疗作用.方法 前瞻性随机对照研究.复旦大学附属中山医院普外科2008年6月至2009年6月收治的82例梗阻性黄疸、肝硬化门静脉高压等肝功能损害手术患者.82例患者随机分为两组.两组给予为期1周的等热卡(25 kcal·kg-1·day-1)等氮(0.2 g·kg-1·day-1),肠外营养研究组42例使用高支链氨基酸注射液,对照组40例使用复方氨基酸注射液(15AA).研究期间检测两组的肝、肾功能、总胆固醇、三酸甘油酯、血糖、氮平衡和尿三甲基组氨酸浓度等.结果 两组病例不良事件发生率、人体测量值、生命体征、内脏蛋白浓度、血液学检查、肝肾功能、电解质、氮平衡、蛋白质分解代谢等方面无显著差异,研究组患者外周血免疫球蛋白、血淋巴细胞数回升较快,与照组比较差异有统计学意义(P＜0.05).结论 高支链氨基酸注射液是一种安全、有效的营养型氨基酸,对肝功能损害的外科患者术后肝功能和免疫系统的恢复切实有效.

Abstract：

Objective To confirm the safety and nutritional efficacy of high branched-chain amino acids through a pragmatic study allowing its use as an alternative to 15AA in patients with liver dysfunction. Methods The study was performed as a randomized, prospective trial. Eighty two patients with liver dysfunction undergoing operation were randomly assigned to receive high branchedchain amino acids or 15AA as part of their TPN regimens for 7 days. Daily parenteral intakes of energy nitrogen and lipid were equal in the two groups. Results Efficacy analysis showed that high branched-chain amino acids were as efficient as 15AA in avoiding protein catablosim. No serious adverse event was reported in the two groups. For hematology, renal, hepatic safety criteria and for the vital signs,no significant difference was observed between the 2 groups. No significant difference was observed concerning nitrogen balance and protein catablosim. For peripheral immunoglobulin and lymphocytes, a statistically significant difference was observed between the high branched-chain amino acids and the 15AA groups. Conclusion High branched-chain amino acids is new, safe and efficient amino acids for parenteral nutrition.     

Insulin and its role in chronic kidney disease

The body’s resistance to the actions of insulin (type II diabetes defect) results in compensatory increased production and secretion by the pancreas and leads to hyperinsulinemia in order to maintain euglycemia. When insulin secretion cannot be increased adequately (type I diabetes defect) to overcome insulin resistance in maintaining glucose homeostasis, hyperglycemia and glucose intolerance ensues. Insulin resistance and glucose intolerance has been well recognized in patients with advanced chronic kidney diseases (CKD). The etiology may involve uremic toxins from protein catabolism, vitamin D deficiency, metabolic acidosis, anemia, poor physical fitness, inflammation, and cachexia. Glucose and insulin abnormalities in nondiabetic CKD patients are implicated in the pathogenesis of hyperlipidemia and may represent important risk factors for accelerated atherosclerosis in these patients. Insulin secretion inadequacy has been associated with growth retardation in adolescents with CKD. Normal adolescents demonstrate an increase in insulin secretion as they go into puberty. It seems that the puberty growth spurt in adolescents both with normal health and renal failure may require increased insulin secretion as one of its hormonal requirements. Finally, insulin resistance has been associated with CKD. Whether insulin resistance is an antecedent of CKD or a consequence of impaired kidney function has been a subject of debate. The goal of this review was to provide an update of the literature on insulin pathophysiology in CKD, current understanding of its mechanisms, and epidemiological association of insulin resistance and CKD. Supported by a Mid-Career Research Development Award K24 DK59574 and U01 DK-03–012 from the National Institute of Health to RHM.     

腹部手术后中枢单胺类神经递质和外周血游离氨基酸的变化与术后疲劳的关系

目的研究腹部大手术后大鼠中枢单胺类神经递质含量的变化,探讨术后疲劳综合征中枢水平发生机制。方法将84只雄性成年SD大鼠随机分为疲劳评估组（包括模型组和假手术组）和实验组（分为术后1、3、5、7和14d恢复组及各组对应的对照组）。术后对大鼠进行疲劳评估,并在相应时间点取出大脑海马、中脑、下丘脑,检测脑组织5。羟色胺（5-HT）、去甲肾上腺素（NE）、多巴胺（DA）的含量及外周血游离色氨酸和支链氨基酸浓度。结果3个脑区5-HT变化趋势类似,在术后3d内明显升高,术后第5天降至最低,至术后第14天逐渐恢复至平稳状态,实验组间比较及实验组与相应对照组比较．差异均有统计学意义（P〈0．05）。海马和下丘脑NE和DA水平总体变化不明显,中脑NE和DA均在术后1d明显升高（P〈0．05）。外周血中游离色氨酸和游离色氨酸／支链氨基酸比值在术后早期升高后．至第5天降至最低．后期游离色氨酸仍低于对照组水平,而游离色氨酸／支链氨基酸比值和支链氨基酸恢复至对照组水平．实验组间比较及实验组与相应对照组比较．差异均有统计学意义（P〈0．05）。结论外周血中游离色氨酸和游离色氨酸／支链氨基酸比值及中枢5-HT水平的波动可能与腹部大手术后疲劳综合征的发生发展有着重要的联系。     

氨基酸对抗顺铂所致急性肾功能衰竭的研究

目的探讨８种Ｌ氨基酸合剂的肾功能保护作用及机理。方法雄性ＳＤ鼠静脉注射２ｍｌ氨基酸合剂后接受１０ｍｇ／ｋｇ顺铂,随后氨基酸以２ｍｌ／ｈ维持３小时,测定尿钠、钾浓度、肾小球滤过率（ＧＦＲ）及肾小管细胞线粒体呼吸功能。结果顺铂注射后３０分钟,尿钠、钾浓度分别增加５６％及２６倍。３小时后状态４呼吸升高１倍,状态３呼吸、呼吸控制率及氰化物解偶联呼吸分别减少４６％、７４％及４７％。该氨基酸合剂能增加ＧＦＲ８５％,改善肾小管钠、钾排泄异常,肾小管细胞线粒体呼吸障碍显著改善。结论该氨基酸合剂有明显的对抗顺铂肾毒性作用,增加ＧＦＲ,其机理可能通过改善受损细胞线粒体呼吸功能。     

The effect of amino acids,carbohydrate and fat emulsion on the metabolism in gastrectomized patients

Nitrogen balance and other metabolic activity can be maintained by adequate calorie and protein supply during immediate post-gastrectomy period. Despite high intake of protein, great loss of nitrogen seems to occur in urine during infusion with polyalcohol sugars as compared with natural sugars, e.g., glucose, fructose and maltose. The best utilization of amino acids resulting in positive nitrogen balance and energy utilization were shown to be achieved by combined use of Intralipid, glucose, maltose and essential as well as non-essential amino acids in the clinical and laboratory studies.     

兴奋性氨基酸及其受体与阿片耐受

运用阿片类药物治疗疼痛时常产生耐受,而致阿片类药效降低。大量研究表明兴奋性氨基酸及其受体参与影响了阿片类药物的抗伤害性作用及其耐受机制。近年来众多学者通过对兴奋性氨基酸受体进行干预,在增强阿片类药物抗伤害作用的同时抑制其耐受的发展,证明其在阿片耐受的机制中产生了重要影响,并为临床阿片治疗急慢性疼痛提供了新的治疗方案。     

Folate, vitamin B12, and sulfur amino acid levels in patients with renal failure

We examined the plasma profile of sulfur amino acids (SAA) in patients with chronic renal failure (CRF) and looked for any correlation with serum folate (FA) and/or vitamin B₁₂. Group 1 comprised 9 patients with CRF and glomerular filtration rate (GFR) >20 ml/min per 1.73 m², 9 patients with GFR<20 ml/min per 1.73 m² comprised group 2, and 14 patients on hemodialysis group 3. The control group comprised 16 healthy children. Homocysteine (Hcy), methionine (Met), cysteine (Cys), and serine (Ser) were measured with gas chromatography. FA and vitamin B₁₂ were measured using enzymatic immunoassay. Median SAA concentrations were significantly lower in controls than in the three groups of patients. Hcy concentrations were 0.8 μmol/l in controls versus 5 μmol/ (group 1), 9 μmol/l (group 2), and 20 μmol/l (group 3). Met concentrations were 26 μmol/l in controls versus 26 μmol/l (group 1), 66 μmol/l (group 2), and 281 μmol/l (group 3). Cys concentrations were 10 μmol/ in controls versus 98 μmol/l (group 1), 54 μmol/l (group 2), and 122 μmol/l (group 3). Ser concentrations were 88 μmol/ in controls versus 153 μmol/l (group 1), 239 μmol/l (group 2), and 240 μmol/l (group 3). The median concentrations of FA were lower in controls than in groups 2 and 3: 5.5 ng/ml versus 8 ng/ml and 15 ng/ml, respectively. Vitamin B₁₂ concentrations did not differ between groups. Vitamin levels did not correlate with SAA. The only difference between patients with Hcy levels in the lower and upper quartile was in Met concentration (38 vs. 263 μmol/l, P<0.02) and GFR (P<0.01). In conclusion, patients with CRF had higher SAA concentrations than healthy children. FA concentrations are higher in CRF patients than in healthy children but did not correlate with concentrations of SAA. Received: 3 January 2000 / Revised: 21 September 2000 / Accepted: 11 October 2000     

Alterations of the growth plate in chronic renal failure

Chronic renal failure modifies the morphology and dynamics of the growth plate (GP) of long bones. In young uremic rats, the height of cartilage columns of GP may vary markedly. The reasons for this variation are unknown, although the severity and duration of renal failure and the type of renal osteodystrophy have been shown to influence the height of GP cartilage. Expansion of GP cartilage is associated with that of the hypertrophic stratum. The interference of uremia with the process of chondrocyte differentiation is suggested by some morphological features. However, analysis by immunohistochemistry and/or in situ hybridization of markers of chondrocyte maturation in the GP of uremic rats has yielded conflicting results. Thus, there have been reported normal and reduced mRNA levels for collagen X, parathyroid hormone/parathyroid hormone-related peptide receptor, and matrix metalloproteinase 9, as well as normal mRNA and protein expression for vascular endothelial growth factor and chondromodulin I, peptides related to the control of angiogenesis. In addition, a decreased immunohistochemical signal for growth hormone receptor and low insulin-like growth factor I mRNA in the proliferative zone of uremic GP are supportive of reduced chondrocyte proliferation. Growth hormone treatment improves chondrocyte maturation and activates bone metabolism in the primary spongiosa.This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany     

Alterations in stress-induced responses in the rat produced by amino acids

The effects of repetitive exposure of rats to immobilization stress were examined in terms of alterations in body weight gain, adrenal size and plasma levels of corticosterone, fatty acids and glucose. Prestress administrations of small doses of L-alanine, L-tryptophan and L-tyrosine were tested for ability to modulate the stress-induced effects. In general, L-alanine had no characteristic actions, L-tryptophan exacerbated and L-tyrosine modulated the stress effects.     

Growth hormone binding protein and free growth hormone in chronic renal failure

Chronic renal failure in children is associated with growth failure. While the pathogenesis of uremic growth failure is multifactorial, an abnormal growth hormone/insulin-like growth factor (GH-IGF) axis is an important contributory element. Patients with uremia exhibit insensivivity to the action of GH, as exemplified by high plasma GH levels, low IGF-I activity, and poor somatic growth. This insensitivity can be overcome by supraphysiological doses of exogenous GH. Plasma GH binding protein (GHBP, the circulating ectodomain of the GH receptor) levels are decreased in patients with renal failure, as are hepatic GH receptor levels in animal models. Since GHBP levels are thought to reflect GH receptor levels in tissues, it is likely that the uremic GH insensitivity in humans is mediated by a decreased number of GH receptors. Another implication of the low plasma GHBP is a disproportionate elevation of free plasma GH (the biologically active moiety) relative to total GH, lending additional support to the concept of GH insensitivity in uremia. GH kinetics are altered in renal failure because of: (1) inability to excrete GH and (2) changes in the bound fraction of GH in the circulation.