Portal de Periódicos da CAPES

Acidosis and nutrition

1999; Elsevier BV; Volume: 56; Linguagem: Inglês

10.1046/j.1523-1755.1999.07319.x

1523-1755

Johnathan D. Louden, Russell R. Roberts, Timothy H.J. Goodship,

Metabolism and Genetic Disorders

Acidosis and nutrition. In recent years there has been increasing evidence for the deleterious effect of acidosis on a number of fundamental systems of the body including nutrition1.Adrogue H.J. Madias N.E. Management of life-threatening acid-base disorders. Second of two parts.N Engl J Med. 1998; 338: 107-111Crossref PubMed Scopus (184) Google Scholar,2.Gluck S.L. Acid-base.Lancet. 1998; 352: 474-479Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar. Approximately 70 mmol of hydrogen ions are produced daily by the body, and to maintain acid-base balance there must be an equivalent net acid secretion by the kidney. It is remarkable that extracellular fluid (ECF) pH is maintained within a very narrow range of 7.35–7.45 (35–45 nM), reflecting the fundamental importance of pH on many aspects of basic cellular function particularly proteins. It is important to differentiate between the terms acidosis and acidemia. The former is a pathophysiologic process tending to acidify body fluids, whereas the latter occurs when the ECF hydrogen ion concentration is above the normal range. It is possible to be acidotic (with a reduced serum bicarbonate) but not acidemic because of appropriate buffering of hydrogen ions. The major extracellular buffer is the carbonic acid/hydrogen carbonate system with plasma proteins and hemoglobin contributing significantly less. The major intracellular buffer is protein followed by bone3.Pitts R.F. Buffer mechanisms of tissues and body fluids.Physiology of the Kidney and Body Fluids. Year Book Medical Publishers, Chicago1974: 178Google Scholar. The type of acidosis seen in patients with chronic renal failure changes with decreasing GFR; initially a non-anion gap acidosis is observed secondary to the loss of bicarbonate from the proximal tubule and impaired excretion in the distal tubule. With increasing severity of renal impairment, failure to excrete organic and inorganic acids results in an increased anion gap4.Widmer B. Gerhardt R.E. Harrington J.T. Cohen J.J. Serum electrolyte and acid base composition. The influence of graded degrees of chronic renal failure.Arch Intern Med. 1979; 139: 1099-1102Crossref PubMed Scopus (132) Google Scholar,5.Hakim R.M. Lazarus J.M. Biochemical parameters in chronic renal failure.Am J Kidney Dis. 1988; 11: 238-247Abstract Full Text PDF PubMed Scopus (93) Google Scholar. Acidosis and nutrition. In recent years there has been increasing evidence for the deleterious effect of acidosis on a number of fundamental systems of the body including nutrition1.Adrogue H.J. Madias N.E. Management of life-threatening acid-base disorders. Second of two parts.N Engl J Med. 1998; 338: 107-111Crossref PubMed Scopus (184) Google Scholar,2.Gluck S.L. Acid-base.Lancet. 1998; 352: 474-479Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar. Approximately 70 mmol of hydrogen ions are produced daily by the body, and to maintain acid-base balance there must be an equivalent net acid secretion by the kidney. It is remarkable that extracellular fluid (ECF) pH is maintained within a very narrow range of 7.35–7.45 (35–45 nM), reflecting the fundamental importance of pH on many aspects of basic cellular function particularly proteins. It is important to differentiate between the terms acidosis and acidemia. The former is a pathophysiologic process tending to acidify body fluids, whereas the latter occurs when the ECF hydrogen ion concentration is above the normal range. It is possible to be acidotic (with a reduced serum bicarbonate) but not acidemic because of appropriate buffering of hydrogen ions. The major extracellular buffer is the carbonic acid/hydrogen carbonate system with plasma proteins and hemoglobin contributing significantly less. The major intracellular buffer is protein followed by bone3.Pitts R.F. Buffer mechanisms of tissues and body fluids.Physiology of the Kidney and Body Fluids. Year Book Medical Publishers, Chicago1974: 178Google Scholar. The type of acidosis seen in patients with chronic renal failure changes with decreasing GFR; initially a non-anion gap acidosis is observed secondary to the loss of bicarbonate from the proximal tubule and impaired excretion in the distal tubule. With increasing severity of renal impairment, failure to excrete organic and inorganic acids results in an increased anion gap4.Widmer B. Gerhardt R.E. Harrington J.T. Cohen J.J. Serum electrolyte and acid base composition. The influence of graded degrees of chronic renal failure.Arch Intern Med. 1979; 139: 1099-1102Crossref PubMed Scopus (132) Google Scholar,5.Hakim R.M. Lazarus J.M. Biochemical parameters in chronic renal failure.Am J Kidney Dis. 1988; 11: 238-247Abstract Full Text PDF PubMed Scopus (93) Google Scholar. To understand the relationship between acidosis and nutrition, it is important to understand how malnutrition can develop. Classically, malnutrition is defined as "a condition that arises from deficiencies of specific nutrients or from diets containing the wrong proportion of foods." With regard to chronic renal failure, it is probably more appropriate to revise this to "a state which is characterized by depletion of body protein stores," although it is erroneous to consider that there are stores of body protein. The amount of a protein in the body is normally closely regulated by the functional demand for that protein; an obvious example of this is the muscle wasting seen with immobilization. Body protein can be simply divided into visceral (liver derived such as albumin and transferrin) and somatic (muscle). In conditions associated with a reduction in both caloric and protein intake, such as anorexia nervosa and marasmus, visceral protein levels are maintained until late in the disease. In kwashiorkor, which is characterized by a low protein intake but normal/high carbohydrate intake, hypoalbuminemia is seen early in the disease. This, in part, explains the inappropriate use of albumin as an indicator of nutritional status. While it is possible with appropriate treatment to turn a malnourished individual into one that is well nourished, it is impossible to create a "supernourished" state. Providing nutritional supplements to well-nourished individuals will only result in the development of obesity; likewise, treating a catabolic stimulus such as acidosis in a well-nourished individual is unlikely to improve their nutritional status but may have other benefits. In order to diagnose malnutrition, it is important to assess not only visceral protein status (total protein, albumin and transferrin) and somatic protein status (weight, height, skinfold thickness) but also dietary intake (3 day dietary record). Use of urea kinetic modelling to obtain an index of dietary protein intake assumes that the individual is in a state of neutral nitrogen balance and is not valid in catabolic or anabolic states. The measurement of dietary nitrogen intake and urinary nitrogen output do not reflect the dynamic state of protein turnover that is taking place within the body. For instance, the daily turnover of protein in all body tissues in an adult consuming 60 g of protein per day is of the order of 300 g of protein per day6.Waterlow J.C. Whole-body protein turnover in humans—past, present and future.Annu Rev Nutr. 1995; 15: 57-92Crossref PubMed Scopus (117) Google Scholar. In other words, 300 g of protein is both broken down and synthesized daily. An imbalance between whole body protein synthesis and whole body protein breakdown will result in either gain of body protein (anabolism) or loss of body protein (catabolism). From this it is possible to see that it is not absolute changes in either synthesis or breakdown that result in anabolism/catabolism, but the balance between the two. Most of the studies that have examined the nutritional effects of acidosis have concentrated on protein degradation rather than protein synthesis. There is a variety of methods by which it is possible to measure protein degradation from the level of the cell to the whole body Table 1.Table 1Methods of measuring protein breakdownLevelMethodCellsPulse of tracer amino acidCellsInjection of individually labeled proteinsTissue bedEx vivo incubation following pulse of tracer amino acidTissue bedIn vivo incubation with tracer amino acidWhole bodyConstant infusion or bolus of tracer amino acid Open table in a new tab That acidosis associated with chronic renal failure can have nutritional effects has been known for some time. Lyon7.Lyon D.M. Dunlop D.M. Stewart C.P. The alkaline treatment of chronic nephritis.Lancet. 1931; ii: 1009-1013Abstract Scopus (35) Google Scholar observed in 1931 that "on alkaline treatment clinical improvement was usual, and coincidentally there was also improvement in the blood nonprotein nitrogen, together with an increase in the alkali reserve." In his discussion, he stated that "it is reasonable to conclude therefore that, however the alkali may exert its beneficial effects on the blood chemistry, it is not by altering the amount of protein absorbed, nor by decreasing the amount of protein breakdown in the body." Many would now dispute the latter comment. One of the landmark studies on acidosis and nutrition was undertaken by Papadoyannakis in 1984, who reported that treatment of patients with chronic renal failure with sodium bicarbonate resulted in an improvement in nitrogen balance8.Papadoyannakis N.J. Stefanidis C.J. McGeown M. The effect of the correction of metabolic acidosis on nitrogen and potassium balance of patients with chronic renal failure.Am J Clin Nutr. 1984; 40: 623-627PubMed Google Scholar. The seminal studies of Mitch and colleagues, initially at Harvard and more recently at Emory, that have shown how acidosis exerts its nutritional effects9.Mitch W.E. Influence of metabolic acidosis on nutrition.Am J Kidney Dis. 1997; 29: R46-R48Abstract Full Text PDF Scopus (34) Google Scholar. Working with incubated muscle preparations and the perfused hindquarter model, Mitch's group showed that both acidosis induced with ammonium chloride and the acidosis of chronic renal failure increased muscle protein degradation10.May R.C. Kelly R.A. Mitch W.E. Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism.J Clin Invest. 1986; 77: 614-621Crossref PubMed Scopus (315) Google Scholar,11.May R.C. Kelly R.A. Mitch W.E. Mechanisms for defects in muscle protein metabolism in rats with chronic uremia. Influence of metabolic acidosis.J Clin Invest. 1987; 79: 1099-1103Crossref PubMed Scopus (290) Google Scholar. This increase was dependent upon the action of glucocorticoids. These observations led us as well as other groups to examine the hypothesis that acidosis in humans with chronic renal failure increases protein degradation and amino acid oxidation. This in turn predisposes to malnutrition, leading to increased morbidity and mortality. Using the technique of constant infusions of the stable isotope L-[1–13C]leucine we showed that acidosis induced in normal subjects with ammonium chloride increased protein degradation and amino acid oxidation12.Reaich D. Channon S.M. Scrimgeour C.M. Goodship T.H.J. Ammonium chloride induced acidosis increases protein breakdown and amino acid oxidation in humans.Am J Physiol. 1992; 263: E735-E739PubMed Google Scholar. Subsequently, we found that correction of acidosis in predialysis patients with chronic renal failure with sodium bicarbonate, but not sodium chloride, resulted in a decrease in protein degradation and amino acid oxidation13.Reaich D. Channon S.M. Scrimgeour C.M. Daley S.E. Wilkinson R. Goodship T.H.J. Correction of acidosis in humans with chronic renal failure decreases protein degradation and amino acid oxidation.Am J Physiol. 1993; 265: E230-E235PubMed Google Scholar. When these studies were extended to chronic renal failure (CRF) patients treated with hemodialysis and continuous ambulatory peritoneal dialysis (CAPD), similar effects were seen14.Graham K.A. Reaich D. Channon S.M. Downie S. Gilmour E. Passlick-Deetjen J. Goodship T.H.J. Correction of acidosis in CAPD decreases whole body protein degradation.Kidney Int. 1996; 49: 1396-1400Abstract Full Text PDF PubMed Scopus (134) Google Scholar,15.Graham K.A. Reaich D. Channon S.M. Downie S. Goodship T.H.J. Correction of acidosis in hemodialysis decreases whole body protein degradation.J Am Soc Nephrol. 1997; 8: 632-637PubMed Google Scholar. To date, there has been only one study in humans examining the effect of acidosis on protein synthesis. Using the flooding dose technique, Ballmer et al found that albumin synthesis decreased following the induction of acidosis with ammonium chloride16.Ballmer P.E. McNurlan M.A. Hulter H.N. Anderson S.E. Garlick P.J. Krapf R. Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance.J Clin Invest. 1995; 95: 39-45Crossref PubMed Google Scholar. The evidence that acidosis increases protein degradation is therefore overwhelming. Does this, however, lead to malnutrition, especially in patients with chronic renal failure? A number of studies in hemodialysis patients have examined the relationship between predialysis serum bicarbonate and a variety of indices of nutritional status. Most have found an inverse relationship between bicarbonate and the normalized protein catabolic rate (PCR)17.Movilli E. Bossini N. Viola B.F. Camerini C. Cancarini G.C. Feller P. Strada A. Maiorca R. Evidence for an independent role of metabolic acidosis on nutritional status in haemodialysis patients.Nephrol Dial Transplant. 1998; 13: 674-678Crossref PubMed Scopus (41) Google Scholar. The increased PCR in the acidotic patients could equally reflect a higher dietary protein intake or catabolism. Most of the studies have found no evidence of malnutrition; if anything, the acidotic subjects are better nourished. It is probable that in cross sectional studies, acidosis is a marker of a high dietary protein intake18.Gotch F.A. Sargent J.A. Keen M.L. Hydrogen ion balance in dialysis therapy.Artif Organs. 1982; 6: 388-395Crossref PubMed Scopus (47) Google Scholar. In many patients, the anabolic effects of this may outweigh the catabolic effects induced by the acidosis. Cross sectional studies are not, however, the ideal way to examine the hypothesis that acidosis-induced changes in protein degradation and amino acid oxidation result in malnutrition; this needs randomized, controlled, longitudinal studies. The largest to date was undertaken by Stein and his colleagues in Leicester, who randomly assigned 200 new patients starting CAPD to either a high alkali (HA) regimen, using a dialysate lactate buffer concentration of 40 mM plus supplemental sodium bicarbonate and calcium carbonate, or a low alkali regimen (LA) using a dialysate lactate concentration of 35 mM19.Stein A. Moorhouse J. Ilessmith H. Baker F. Johnstone J. James G. Troughton J. Bircher G. Walls J. Role of an improvement in acid-base status and nutrition in CAPD patients.Kidney Int. 1997; 52: 1089-1095Abstract Full Text PDF PubMed Scopus (176) Google Scholar. When evaluated one year after entry into the study, bicarbonate and pH were significantly higher in the HA group. There was evidence on anthropometric measurements (weight gain and mid arm circumference) of an improvement in nutritional status in the HA group whilst morbidity as measured by hospital admission was significantly lower in the HA group. This study to date provides the strongest evidence for the beneficial effect of bicarbonate therapy. Of the two randomized studies examining the effect of increasing dialysate bicarbonate concentration in hemodialysis patients20.Brady J.P. Hasbargen J.A. Correction of metabolic acidosis and its effect on albumin in chronic hemodialysis patients.Am J Kidney Dis. 1998; 31: 35-40Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar,21.Williams A.J. Dittmer I.D. McArley A. Clarke J. High bicarbonate dialysate in haemodialysis patients: effects on acidosis and nutritional status.Nephrol Dial Transplant. 1997; 12: 2633-2637Crossref PubMed Scopus (80) Google Scholar, in only one was there evidence of an improvement in nutritional status with a significantly greater triceps skinfold thickness in the group receiving the higher dialysate bicarbonate concentration. There are other nutritional benefits to be gained from correction of acidosis. Insulin resistance is a well recognized feature of chronic renal failure22.Defronzo R.A. Alvestrand A. Smith D. Hendler R. Hendler E. Wahren J. Insulin resistance in uremia.J Clin Invest. 1981; 67: 563-568Crossref PubMed Scopus (465) Google Scholar, and it is also well established that acidosis induces insulin resistance in normal subjects23.Defronzo R.A. Beckles A.D. Glucose intolerance following chronic metabolic acidosis in man.Am J Physiol. 1979; 236: E328-E334PubMed Google Scholar. Using the euglycaemic clamp technique we showed that correction of acidosis in predialysis CRF patients was associated with an improvement in insulin sensitivity24.Reaich D. Graham K.A. Channon S.M. Hetherington C. Scrimgeour C.M. Wilkinson R. Goodship T.H.J. Insulin-mediated changes in PD and glucose uptake after correction of acidosis in humans with CRF.Am J Physiol. 1995; 268: E121-E126PubMed Google Scholar. That acidosis is associated with osteomalacia in adults and rickets in children has been known for many years. In chronic renal failure the degree of acidosis in the predialysis period correlates with the severity of osteomalacia on bone biopsy25.Mora Palma F.J. Ellis H.A. Cook D.B. Dewar J.H. Ward M.K. Wilkinson R. Kerr D.N.S. Osteomalacia in patients with chronic renal failure before dialysis or transplantation.Q J Med. 1983; 52: 332-348PubMed Google Scholar. Acidosis induces osteomalacia because bone directly buffers hydrogen ions and acidosis inhibits the activity of the 1-hydroxylase responsible for activating 25-hydroxycholecalciferol26.Bushinsky D.A. Bone disease in moderate renal failure: Cause, nature, and prevention.Annu Rev Med. 1997; 48: 167-176Crossref PubMed Scopus (30) Google Scholar. That acidosis might also play a role in the development of hyperparathyroidism was suggested by the study of Lefebvre et al who showed that high bicarbonate dialysis slowed the progression of hyperparathyroidism in hemodialysis patients27.Lefebvre A. De Vernejoul M.C. Gueris J. Goldfarb B. Graulet A.M. Morieux C. Optimal correction of acidosis changes progression of dialysis osteodystrophy.Kidney Int. 1989; 36: 1112-1118Abstract Full Text PDF PubMed Scopus (165) Google Scholar. We have subsequently examined the hypothesis that correction of acidosis will improve the sensitivity of the parathyroid glands to calcium in hemodialysis patients before and after the correction of acidosis. We did this by acutely lowering and raising serum calcium during hemodialysis with zero and high calcium dialysate. Simultaneous samples were analyzed for iPTH and Ca2+; the relationship between the two showed a significant improvement in the sensitivity of the parathyroid gland to calcium28.Graham K.A. Hoenich N.A. Tarbit M. Ward M.K. Goodship T.H.J. Correction of acidosis in hemodialysis patients increases the sensitivity of the parathyroid glands to calcium.J Am Soc Nephrol. 1997; 8: 627-631PubMed Google Scholar. What therefore should the serum bicarbonate be in CRF patients? Data from a very large cohort of hemodialysis patients reported by Lowrie and Lew showed that predialysis bicarbonate associated with the lowest mortality was between 20 and 22.5 mM29.Lowrie E.G. Lew N.L. Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities.Am J Kidney Dis. 1990; 15: 458-482Abstract Full Text PDF PubMed Scopus (1757) Google Scholar. The Renal Association "Recommended Standards and Audit Measures" document makes the recommendation that in HD patients the predialysis bicarbonate should be in the normal range quoted by the local pathology laboratory in all patients after 3 months treatment30.The Renal Association Treatment of Adult Patients with Renal Failure Recommended Standards and Audit Measures. Royal College of Physicians of London, London1997Google Scholar. Because serum bicarbonate declines linearly in the interdialytic period this means that there will inevitably be a period of alkalosis after the end of dialysis. There are potential adverse consequences associated with hyperkalemia including cardiovascular (arteriolar constriction, reduction in coronary blood flow, reduction in angina threshold and predisposition to arrhythmias), respiratory, cerebral and metabolic31.Adrogue H.J. Madias N.E. Management of life-threatening acid-base disorders. First of two parts.N Engl J Med. 1998; 338: 26-34Crossref PubMed Scopus (249) Google Scholar. It is also of concern that post dialysis alkalosis might represent a form of milk alkali syndrome, especially in the presence of hypercalcemia, which would predispose to ectopic calcification. The first report of the Renal Association's Renal Registry showed a wide range (between 10 and 83%) in the number of patients in various renal units achieving the Association's target, although the range was narrower in peritoneal dialysis patients (82–95%)32.The Renal Registry Annual Report. The Renal Registry, 1998Google Scholar. Concerns have been expressed that the variability in sample handling and measurement of bicarbonate might be contributing to this variability. It is certainly well established that underfilling sample tubes and delay in measurement will result in a falsely low measurement33.Herr R.D. Swanson T. Serum bicarbonate declines with sample-size in vacutainer tubes.Am J Clin Pathol. 1992; 97: 213-216Crossref PubMed Scopus (15) Google Scholar. Moreover, the measurement itself can be associated with a coefficient of variation of up to 10%. In conclusion, there is overwhelming evidence that acidosis is a catabolic stimulus. Whether this results on a routine clinical basis in depletion of body protein remains to be established. However, the benefits to be gained with regard to osteomalacia, insulin resistance, hyperparathyroidism and cell signaling indicate that acidosis in chronic renal failure is associated with substantial morbidity.