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PubMed1989

Lactic acidosis.

An understanding of the pathophysiology of lactic acidosis is crucial in facilitating the optimal care of critically ill patients. The relevant biochemistry of lactic acidosis is reviewed, and the more controversial aspects relating to the genesis of the acidosis are highlighted. The current system of classification of lactic acidosis divides etiologies on the basis of the presence or absence of clinical signs of tissue hypoperfusion. Several types of lactic acidosis in which clinical evidence of tissue hypoperfusion is lacking demonstrate hemodynamic evidence of occult hypoperfusion. The diagnostic and therapeutic implications of this observation are discussed. Current diagnostic criteria for lactic acidosis include a pH less than 7.35 and blood lactate concentration greater than 5 to 6 mM/L. An important issue relates to the implications of lactate values that are greater than normal but below this diagnostic range. The use of the oxygen flux test may be valuable in the diagnosis of occult tissue hypoperfusion in patients with low-grade elevations in lactate levels. The current therapy for lactic acidosis involves addressing the primary cause and supportive management. The use of bicarbonate in the therapy for lactic acidosis is controversial due to potential adverse effects on cardiac function. The specifics of this controversy are outlined, and newer therapeutic alternatives are reviewed. The use of blood lactate concentration as a prognostic index may be more useful in patients with shock than without shock.

Acidosis, Lactic↗

PubMed1986

Effect of metabolic acidosis on hindquarter glutamine and alanine release.

The relationship between hindquarter glutamine release and renal glutamine extraction was studied in rats undergoing chronic metabolic acidosis. Metabolic acidosis was induced by maintaining rats on NH4CL for four days; controls were pair-fed NH4HCO3. Metabolic acidosis increased renal glutamine extraction 8-fold and decreased arterial plasma glutamine concentration 40%. Hindquarter glutamine release rose 5-fold in acidosis due to an increased arteriovenous glutamine concentration difference and a significant rise in blood flow through the hindquarters. Both ammonia and glutamate extraction in the hindquarter increased in acidosis and could account for 25% of the glutamine nitrogen released. Alanine release by hindquarters, which exceeded glutamine release in the control animals, was greatly depressed in metabolic acidosis. The reduction in alanine nitrogen release during acidosis could account for 25% of the glutamine nitrogen released. Consequently, metabolic acidosis stimulates hindquarter glutamine release at the expense of alanine and is also supported by greater extraction of ammonia and glutamate. However, other N sources must supply nearly 50% of the glutamine nitrogen released based on balance studies.

Acidosis↗

PubMed1983

PCO2 modulation of ventilation and HCO3- buffer during chronic metabolic acidosis.

Ventilation and acid-base balance were studied in 6 conscious dogs during chronic eucapnic and hypocapnic metabolic acidosis. The dogs had tracheostomas for respiratory studies, exteriorized carotid arteries for obtaining arterial blood and cannulae for sampling cisternal cerebrospinal fluid (CSF). Measurements were obtained on a control diet, and then, during metabolic acidosis induced by adding HCl (7 mmol/kg per day). Initially during metabolic acidosis, PaCO2 was maintained normal by having the dogs breathe 3% CO2 (eucapnia); then the dogs breathed air (hypocapnia). Chronically, arterial and CSF [HCO-3] were related to PCO2. No respiratory compensation occurred during chronic hypocapnic metabolic acidosis since [HCO-3] decreased more than PCO2; consequently, the acidosis worsened. At any [H+], ventilation was related to PCO2. Thus, during hypocapnic metabolic acidosis, ventilation was not increased relative to increase in arterial and CSF [H+]. Modulation of ventilation by PCO2 during severe acidosis may be crucial because stimulation of ventilation by [H+] of arterial blood or CSF would have progressively reduced PCO2 and [HCO-3], resulting in a worsening of the metabolic acidosis.

Acid-Base Equilibrium↗

PubMed2006

[Metformin-associated lactic acidosis].

OBJECTIVE: The aims of this review are to precise the pathophysiological mechanisms leading to biguanide-associated lactic acidosis, to give elements of diagnosis, and to underline the precautionary conditions for prescribing these drugs by an improvement in physicians and patient's education. DATA SOURCES: A PubMed database research in English and French language reports published until December 2005. The keywords were: lactic acidosis, metformin, biguanide, diabetes mellitus. DATA EXTRACTION: Data in selected articles were reviewed, clinical and basic science research relevant informations were extracted. DATA SYNTHESIS: Metformin, which is an oral antidiabetic agent, is the only one biguanide available in France. It acts by enhancing the sensitivity to insulin by a decrease in the hepatic glucose production and an increase in its peripheral use. In term of glycemic control, it has the same efficiency than the other hypoglycemic agents. It represents the treatment of choice for overweight type 2 diabetic patients because of its beneficial effects on the weight loss and on the cardiovascular complications. The incidence of metformin-associated lactic acidosis is very low when contra-indications and appropriate rules for prescribing this drug are respected. The relationship between metformin and lactic acidosis remains largely controversial. In practical, we can distinguish three situations which have different prognosis. In the first case, metformin seems to be responsible for lactic acidosis because of self-poisoning or accidental overdose, and prognosis is good. In the second case, the association between metformin and lactic acidosis is coincidental rather than causal, and may be induced by an underlying organ failure. In the last case there is a cause of lactic acidosis which is worsened by a precipitating factor leading to metformin accumulation. The 2 latter situations are very severe as mortality rate is about 50%. Symptomatic treatments and renal replacement therapy which allows metformin removal are the curative treatment. Prevention is essential. It requires the respect of metformin contraindications and a better education of physicians and patients for a safe prescription. CONCLUSION: Due to its beneficial effects, metformin is the gold standard treatment for overweight type 2 diabetic patients. The essential precautionary conditions for prescribing metformin as well as the respect of its contra-indications permit largely to prevent lactic acidosis. This complication is serious when it is associated with intercurrent illnesses and metformin accumulation. The curative treatment is based on renal replacement therapy. Prevention only rests on the respect of the contra-indications. Education of physicians and patients concerning the rules of prescription remains essential.

Acidosis, Lactic↗

PubMed2004

Alteration of noncollagenous bone matrix proteins in distal renal tubular acidosis.

Our previous report on bone histomorphometry in patients with distal renal tubular acidosis (dRTA) revealed decreased bone formation rate (BFR) when compared to healthy subjects. The abnormality improved significantly after alkaline therapy. The modest increase in osteoblastic surface, after correction of metabolic acidosis, could not explain the striking improvement in bone formation, suggesting additional influence of metabolic acidosis on osteoblast function and/or bone matrix mineralization. Osteoblasts and, to a lesser extent, osteoclasts synthesize and secrete bone matrix including type I collagen and various noncollagenous proteins (NCPs). Substantial evidence suggested diverse functions of NCPs related to bone formation, resorption, and mineralization. Metabolic acidosis, through its effect on bone cells, may result in an alteration in the production of NCPs. Our study examined bone histomorphometry with detailed analysis on the mineralization parameters and NCPs expression within the bone matrix of patients with dRTA before and after treatment with alkaline. Seven dRTA patients underwent bone biopsy at their initial diagnosis and again 12 months after alkaline therapy. Bone mineral density (BMD) and bone histomorphometry were obtained at baseline and after the treatment. The expression of NCPs was examined by immunohistochemistry, quantitated by digital image analysis, and reported as a percentage of area of positive staining or mineralized trabecular bone area. Alkaline therapy normalized the low serum phosphate and PTH during acidosis. The reduction in BMD at baseline improved significantly by the treatment. Bone histomorphometry demonstrated the increase in osteoid surface and volume without significant alteration after acidosis correction. In comparison to the normal subjects, osteoid thickness was slightly but insignificantly elevated. Osteoblast and osteoclast populations and their activities were suppressed. The reduction in mineral apposition rate and adjusted apposition rate were observed in conjunction with the prolongation of mineralization lag time. Alkaline therapy improved the mineralization parameters considerably. In addition to the increase in BFR relative osteoblast number after acidosis correction, osteocalcin expression in the bone matrix increased significantly from 16.7% to 22.3%. Six of seven patients had decreased osteopontin expression. In conclusion, the abnormal bone remodeling in dRTA is characterized by low turnover bone disease with some degree of defective mineralization. Alteration of NCPs expression suggested the effect of metabolic acidosis on bone cells. Alkaline therapy increased bone mass through the restoration of bone mineral balance and, perhaps, improved osteoblast function.

Acidosis, Renal Tubular↗

PubMed2005

Bone calcium changes during diabetic ketoacidosis: a comparison with lactic acidosis due to volume depletion.

In this study, we aimed to compare bone calcium system changes from children with diabetic ketoacidosis or acute metabolic acidosis due to dehydration to find out the relative contribution of metabolic acidosis and diabetes-related factors on expected negative calcium balance. We studied a set of non-invasive parameters of bone remodeling in 16 children with diabetic ketoacidosis due to new onset type 1 diabetes and 25 children with acute metabolic acidosis due to dehydration complicating acute gastroenteritis before and after the correction of acidosis. The two groups of subjects were matched for age, sex, pubertal status, and degree of metabolic acidosis and dehydration. A group of 18 age and sex-matched healthy children served as the control group. Plasma ionized calcium levels were increased in both groups, significantly more so in diabetic ketoacidosis. While osteoblastic markers, osteocalcin and alkaline phosphatase, were depressed to a comparable degree in both groups, urinary calcium/creatinine ratio and hydroxyproline excretion were significantly greater in diabetic ketoacidosis. No significant changes in calcitrophic hormone (intact PTH, calcitonin, 25-hydroxy vitamin D3) levels were observed. All study parameters except for serum phosphate levels behaved in parallel in both clinical conditions, and abnormalities disappeared with the correction of acidosis except for IGF-1, which remained low in diabetic subjects. In conclusion, our results suggest that, in diabetic ketoacidosis, the observed severe negative calcium balance occurred through diminished bone formation mediated by metabolic acidosis per se and increased bone mineral dissolution and bone resorption because of severe insulin deficiency and secondarily via metabolic acidosis. Observed changes appear to be independent of calcitrophic hormones.

Acidosis, Lactic↗

PubMed2006

Metformin-associated lactic acidosis treated with continuous renal replacement therapy.

INTRODUCTION: Lactic acidosis is an infrequent complication of metformin therapy for diabetes mellitus. The presence of clinical conditions, such as renal failure, increases the risk of metformin-associated lactic acidosis (MALA). We present a case of lactic acidosis in a patient with diabetes treated with metformin, complicated by acute renal failure in preexisting chronic nephropathy. CASE SUMMARY: A 70-year-old white male, weighing 77 kg, with diabetes mellitus, coronary heart disease, congestive heart failure (New York Heart Association class III), moderate essential hypertension (stage 2), and renal dysfunction (serum urea, 90 mg/dL; serum creatinine, 1.5 mg/dL; creatinine clearance, 49.8 mL/min/1.73 m2) presented to the emergency department of the General Hospital of Rhodes (Rhodes, Greece), complaining of malaise, respiratory distress, myalgias, disorientation, abdominal discomfort, and increasing somnolence of insidious onset. The patient's regimen included isosorbide mononitrate 60 mg QD, furosemide 40 mg QD, quinapril 20 mg QD, and metformin 850 mg TID. Before this hospitalization, he had received a 2-week course of oral diclofenac sodium 25 mg TID for low back pain. Preliminary laboratory evaluation found leukocytosis (27,300/mm3), severe renal failure (serum urea, 215 mg/dL; serum creatinine, 7.4 mg/dL; calculated creatinine clearance, 10.1 mL/min/1.73 m2), and a high anion gap metabolic acidosis (pH, 6.95; anion gap, 33 mEq/L) in arterial blood gas analysis. His medical and drug history, the clinical and laboratory findings, and the determination of lactate in samples of plasma (7.8 mEq/L), aroused the suspicion of MALA. The Naranjo algorithm scores for metformin and diclofenac sodium were 6 and 7, respectively. The patient received a single session of bicarbonate-buffered continuous venovenous hemodiafiltration (CWHDF) that lasted 16 hours. Ultimately, he was stabilized, and progressive restoration of acid-base balance and renal function was observed. DISCUSSION: We suspect that lactic acidosis may have been related to the use of metformin, the presence of heart and renal failure (contributing to metformin toxicity), and previous use of diclofenac sodium. CVVHDF has an advantage over conventional intermittent hemodialysis in that it corrects acidosis and removes lactate and metformin without risk of hypernatremia or fluid overload. CONCLUSIONS: MALA should be strongly suspected in diabetic patients presenting with high anion gap metabolic acidosis and increased serum lactate level. In the case described, prompt recognition of lactic acidosis and early application of bicarbonate-buffered CVVHDF produced successful results.

Acidosis, Lactic↗

PubMed2004

Stimulation of intestinal glutamine absorption in chronic metabolic acidosis.

BACKGROUND: Amino acid glutamine plays a central role in inter-organ nitrogen transfer in acidosis, a compensatory mechanism that is essential in maintaining acidbase balance. Intestinal glutamine absorption is a key exogenous glutamine source in maintaining glutamine homeostasis. The purpose of this in vivo study was to investigate the regulation of intestinal glutamine absorption during chronic metabolic acidosis. METHODS: Metabolic acidosis in adult male Sprague-Dawley rats was induced by adding 1.5% NH4Cl to drinking water. [3H]-L-glutamine transport activity across brush border membrane vesicles and glutamine transporter ATB0 messenger RNA levels by relative reverse transcriptase-polymerase chain reaction were measured in rat jejunum. Data were analyzed by t test (P < .05). RESULTS: Acidosis occurred as early as 1 day and was partially compensated by 7 days. Glutamine transport in brush border membrane vesicles was increased after 2 days of acidosis. Chronic acidosis (7 days) resulted in an 8-fold increase of glutamine transport activity. The glutamine transport maximal capacity (Vmax) was stimulated 5-fold, while the transport affinity (Km) was not affected by acidosis. Relative reverse transcriptase-polymerase chain reaction showed a 2.5-fold increase of glutamine transporter ATB0 messenger RNA levels. CONCLUSIONS: Chronic metabolic acidosis stimulates intestinal glutamine absorption via a mechanism that involves an increase of functional membrane glutamine transporter units.

Acidosis↗

PubMed2005

Characterisation of metabolic acidosis in Kenyan children admitted to hospital for acute non-surgical conditions.

Metabolic acidosis is associated with most severe malaria deaths in African children, and most deaths occur before maximum antimalarial action is achieved. Thus, specific acidosis treatment may reduce mortality. However, the underlying mechanisms remain poorly understood and no specific interventions have been developed. A detailed characterisation of this acidosis is critical in treatment development. We used the traditional and Stewart's approach to characterise acidosis in consecutive paediatric admissions for malaria and other acute non-surgical conditions to Kilifi District Hospital in Kenya. The overall acidosis prevalence was 21%. Gastroenteritis had the highest prevalence (61%). Both the mean albumin-corrected anion gap and the strong ion gap were high (>13 mmol/l and >0 mmol/l, respectively) in malaria, gastroenteritis, lower respiratory tract infection and malnutrition. Presence of salicylate in plasma was not associated with acidosis but was associated with signs of severe illness (odds ratio 2.11, 95% CI 1.1-4.2). In malaria, mean (95% CI) strong ion gap was 15 (14-7) mmol/l, and lactate, creatinine and inorganic phosphorous explained only approximately 40% of the variability in base excess (adjusted R2 = 0.397). Acidosis may be more common than previously recognised amongst paediatric admissions in Africa and is characterised by the presence of currently unidentified strong anions. In malaria, lactate and ketones, but not salicylate, are associated with acidosis. However, unidentified anions may be more important.

3-Hydroxybutyric Acid↗

PubMed1995

The role of metabolic acidosis in the pathogenesis of renal osteodystrophy.

Renal osteodystrophy is thought to be the result of abnormalities in the serum levels of parathyroid hormone, vitamin D, calcium, and phosphorus, and excess exposure to certain substances such as aluminum and iron. However, a significant amount of data suggest that the metabolic acidosis that develops in the course of chronic renal failure may also play a contributory role. Metabolic acidosis may effect changes in bone by directly inducing dissolution of bone, stimulating osteoclast-mediated bone resorption, inhibiting osteoblast-mediated bone formation, and altering the serum concentrations or the biological actions of parathyroid hormone and vitamin D. As a consequence, in some patients with normal renal function, osteoporosis and osteomalacia have been reported that are linked in part to metabolic acidosis. Also, in patients with chronic renal failure before and after initiation of dialysis, the severity of the metabolic acidosis appears to have a bearing on the presence and degree of hyperparathyroidism, osteitis fibrosa, and osteomalacia. Taken as a whole, these data suggest that correction of the metabolic acidosis of chronic renal failure may have a beneficial effect on the bone disease observed in these patients. This article reviews (1) the data indicating the mechanisms by which metabolic acidosis causes alterations in bone; (2) the types of bone lesions observed in animals and humans with metabolic acidosis in the presence of normal and abnormal renal function; (3) the impact of correction of the acidosis on the bone lesions; and (4) specific recommendations for treatment in patients with chronic renal failure both before and after initiation of maintenance dialysis.

Acid-Base Equilibrium↗

PubMed1975

Effect of acute and chronic metabolic acidosis on serum immunoreactive parathyroid hormone in man.

The effects of acute and chronic metabolic acidosis on serum immunoreactive parathyroid hormone (iPTH) were studied. Acute metabolic acidosis induced by administration of ammonium chloride (NH4Cl) produced a barely detectable increase in serum iPTH. Chronic NH4Cl administration produced a marked elevation of serum iPTH that was well correlated with the magnitude of acid-induced hypercalciuria but not with the degree of acidosis. Acetazolamide administration produced an equivalent degree of acidosis, but hypercalciuria was minimal and iPTH increased only marginally. Methionine administration caused moderate hypercalciuria and a significant but moderate increase in iPTH. Chronic NH4Cl-induced acidosis produced no hypercalciuria when dietary sodium intake was rigidly restricted, and under these conditions serum iPTH remained normal. When sodium intake was suddenly increased while maintaining the acid load, hypercalciuria appeared and was followed by progressive rise in serum iPTH equivalent to that observed during chronic NH4Cl-induced acidosis in subjects consuming salt ad lib. These results indicate that chronic acidosis elevates iPTH mainly by producing hypercalciuria and that acidosis itself is not a primary stimulus to PTH secretion.

Acetazolamide↗

PubMed1982

The kidney of chicken adapts to chronic metabolic acidosis: in vivo and in vitro studies.

Renal adaptation to chronic metabolic acidosis was studies in Arbor Acre hens receiving ammonium chloride by stomach tube 0.75 g/kg/day during 6 days. During a 14-day study, it was shown that the animals could excrete as much as 60% of the acid load during ammonium chloride administration. At the same time urate excretion fell markedly but the renal contribution to urate excretion (14%) did not change. During acidosis, blood glutamine increased twofold and the tissue concentration of glutamine rose in both liver and kidney. Infusion of L-glutamine led to increased ammonia excretion and more so in acidotic animals. Glutaminase I, glutamate dehydrogenase, alanine aminotransferase (GPT), and malic enzyme activities increased in the kidney during acidosis but phosphoenolpyruvate carboxykinase (PEPCK) activity did not change. Glutaminase I was not found in the liver, but hepatic glutamine synthetase rose markedly during acidosis. Glutamine synthetase was not found in the kidney. Renal tubules incubated with glutamine and alanine were ammoniagenic and gluconeogenic to the same degree as rat tubules with the same increments in acidosis. Lactate was gluconeogenic without increment during acidosis. The present study indicates that the avian kidney adapts to chronic metabolic acidosis with similarities and differences when compared to dog and rat. Glutamine originating from the liver appears to be the major ammoniagenic substrate. Our data also support the hypothesis that hepatic urate synthesis is decreased during acidosis.

Acidosis, Renal Tubular↗

PubMed1983

Effect of chronic metabolic acidosis on vitamin D metabolism in humans.

Bone disease may occur in disorders associated with chronic metabolic acidosis. This has been attributed, in part, to reduced production of 1,25(OH)2D3. Although metabolic acidosis in the vitamin D deficient animal has been associated with a reduction in the conversion of radiolabeled 25(OH)D3 to 1,25(OH)2D3, studies in D-replete humans have revealed no effect of acidosis on 1,25(OH)2D3 metabolism. To examine this issue further, we measured serum 25(OH)D, 1,25(OH)2D, and 24,25(OH)2D levels in six healthy subjects before and after 9 days of metabolic acidosis induced by the ingestion of ammonium chloride. In four subjects, we measured the increment in serum levels of 1,25(OH)2D in response to the infusion of parathyroid extract both during control and acidosis. Serum levels of 1,25(OH)2D, 13.6 +/- 1.3 and 14.3 +/- 0.9 pg/ml, in control and acidosis, respectively, were not different. The serum 1,25(OH)2D levels in control and acidosis rose to a similar degree with the infusion of PTE. These data provide strong evidence that metabolic acidosis does not have a substantial impact on the synthesis of 1,25(OH)2D3 metabolism in vitamin D-replete humans.

Acidosis↗

PubMed1992

Chronic metabolic acidosis accelerates whole body proteolysis and oxidation in awake rats.

Previous work has documented an acceleration of proteolysis and branched-chain amino acid oxidation when muscles from rats with chronic metabolic acidosis were incubated in vitro. The present study examines the impact of chronic metabolic acidosis on whole body amino acid turnover and oxidation in chronically catheterized awake male Sprague-Dawley rats using stochastic modeling and a primed continuous infusion of L-[1-14C] leucine. Whole body protein turnover was accelerated by acidosis as reflected in a 70% increase in proteolysis and a 55% increase in protein synthesis. Amino acid oxidation was increased 145% in rats with chronic metabolic acidosis relative to control rats receiving diets identical in protein and calories based on a reciprocal pool model and plasma alpha-ketoisocaproate specific radioactivity. These changes were accompanied by a 104% increase in liver branched-chain ketoacid dehydrogenase (BCKAD) activity in rats with acidosis, similar to previously documented increases in skeletal muscle BCKAD activity caused by acidosis. In contrast, kidney BCKAD activity was decreased 38% by acidosis, illustrating the tissue-specificity of the changes that were present. We conclude that chronic metabolic acidosis accelerates whole body protein turnover and affects the reincorporation of amino acid into body proteins by accelerating amino acid oxidation.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗

PubMed1997

Effect of chronic metabolic acidosis on the growth hormone/IGF-1 endocrine axis: new cause of growth hormone insensitivity in humans.

The effects of metabolic acidosis on growth hormone and IGF-1 are poorly understood. We investigated the effects of chronic metabolic acidosis (induced by administration on NH4Cl, 4.2 mmol/kg body wt/day) on the growth hormone/IGF-1 endocrine axis in 6 normal male volunteers during metabolic balance conditions. NH4Cl administration resulted in hyperchloremic metabolic acidosis with plasma bicarbonate decreasing from 25 +/- 0.4 to 15.5 +/- 0.9 mmol/liter (P < 0.001). Metabolic acidosis significantly decreased serum IGF-1 concentration from 45 +/- 6 to 33 +/- 6 nmol/liter (P = 0.002), while serum IGF binding protein 3 concentration was not affected significantly. The growth hormone response to growth hormone releasing factor administration (1 microgram per kg body wt, intravenous bolus) was enhanced significantly during acidosis. The IGF-1 response to growth hormone administration (0.1 U kg body wt subcutaneously, every 12 hr for 48 hr) was blunted significantly during acidosis. Apparent endogenous serum half-life and metabolic clearance rates of growth hormone were not altered significantly by acidosis. Metabolic acidosis in humans results in a significant decrease in serum IGF-1 concentration without a demonstrable effect on IGF binding protein 3, and is related to a resistance to the hepatocellular action of growth hormone. The primary defect in the growth hormone/IGF-1 axis occurs via an impaired IGF-1 response to circulating growth hormone with consequent diminution of normal negative feedback inhibition of IGF-1 on growth hormone, as evidenced by the exaggerated growth hormone response to growth hormone releasing factor administration.

Acidosis↗

PubMed1977

Effects of metabolic alkalosis, metabolic acidosis and uraemia on whole-body intracellular pH in man.

1. Whole-body intracellular pH (pHi) was measured by the 14C-labelled DMO method in twenty-four control subjects, eighteen normal subjects with induced acute metabolic alkalosis, ten normal subjects with induced acute metabolic acidosis, twelve normal subjects with chronic acidosis and in fifteen patients with chronic renal insufficiency and acidosis. 2. The change in pHi per unit change in extracellular pH is significantly larger in acute metabolic alkalosis than in acute metabolic acidosis. In chronic metabolic acidosis, pHi decreased in proportion to the total amount of ammonium chloride administered; pHi was normal in patients with uraemic acidosis. 3. These observations confirm the role that tissue buffers play in the protection of the cellular environment in some forms of acidosis. When the acid load overwhelms tissue buffer capacity, pHi becomes a function of extracellular pH. 4. Cells seem more protected from acute acidosis than from acute alkalosis.

Acid-Base Equilibrium↗

PubMed1995

Metabolic acidosis does not contribute to chronic renal injury in the rat.

1. Metabolic acidosis invariably accompanies chronic renal failure, and short periods of metabolic acidosis cause renal growth and proteinuria in normal rats. Rates of ammoniagenesis are increased in chronic renal failure, and it has been suggested that this contributes to disease progression. This study assessed (i) whether prolonged acidosis causes chronic renal injury in the normal kidney and (ii) whether abrogation of acidosis slows disease progression in the remnant kidney. 2. Metabolic acidosis was induced in normal rats by dietary hydrochloric acid. Urinary excretion of total protein, lysozyme and albumin increased, peaking at week 8 but returning to baseline by week 14. At killing after 14 weeks, kidney weights, glomerular filtration rates and serum creatinine were the same in both groups, but kidney/body weight and kidney/heart weight ratios were greater in the acidotic group. All kidneys were normal by light microscopy. 3. Rats subjected to five-sixths nephrectomy were given sufficient dietary bicarbonate to abolish uraemic acidosis, and their outcome was compared with that of non-alkalinized remnants (controls). Proteinuria, glomerular filtration rates, blood pressure, histological injury and time to the development of terminal uraemia were no better in bicarbonate-supplemented animals than in controls. 4. These data demonstrate that metabolic acidosis neither causes nor exacerbates chronic renal injury. We conclude that the treatment of uraemic acidosis is unlikely to influence disease progression in patients with chronic renal failure.

Acidosis, Renal Tubular↗

PubMed2000

Chronic metabolic acidosis in azotemic rats on a high-phosphate diet halts the progression of renal disease.

BACKGROUND: Hyperphosphatemia and metabolic acidosis are general features of advanced chronic renal failure (RF), and each may affect mineral metabolism. The goal of the present study was to evaluate the effect of chronic metabolic acidosis on the development of hyperparathyroidism and bone disease in normal and azotemic rats on a high-phosphate diet. Our assumption that the two groups of azotemic rats (acid-loaded vs. non-acid-loaded) would have the same degree of renal failure at the end of the study proved to be incorrect. METHODS: Four groups of rats receiving a high-phosphate (1.2%), normal-calcium (0.6%) diet for 30 days were studied: (1) normal (N); (2) normal + acid (N + Ac) in which 1.5% ammonium chloride (NH4Cl) was added to the drinking water to induce acidosis; (3) RF, 5/6 nephrectomized rats; and (4) RF + acid (RF + Ac) in which 0.75% NH4Cl was added to the drinking water of 5/6 nephrectomized rats to induce acidosis. RESULTS: At sacrifice, the arterial pH and serum bicarbonate were lowest in the RF + Ac group and were intermediate in the N + Ac group. Serum creatinine (0.76 +/- 0.08 vs. 1.15 +/- 0.08 mg/dL), blood urea nitrogen (52 +/- 8 vs. 86 +/- 13 mg/dL), parathyroid hormone (PTH; 180 +/- 50 vs. 484 +/- 51 pg/mL), and serum phosphate (7.46 +/- 0.60 vs. 12.87 +/- 1.4 mg/dL) values were less (P < 0.05), and serum calcium (9.00 +/- 0.28 vs. 7.75 +/- 0.28 mg/dL) values were greater (P < 0.05) in the RF + Ac group than in the RF group. The fractional excretion of phosphate (FEP) was greater (P < 0.05) in the two azotemic groups than in the two nonazotemic groups. In the azotemic groups, the FEP was similar even though PTH and serum phosphate values were less in the RF + Ac than in the RF group. NH4Cl-induced acidosis produced hypercalciuria in the N + Ac and RF + Ac groups. When acid-loaded (N + Ac and RF + Ac) and non-acid-loaded (N and RF) rats were combined as separate groups, serum phosphate and PTH values were less for a similarly elevated serum creatinine value in acid-loaded than in non-acid-loaded rats. Finally, the osteoblast surface was less in the N + Ac group than in the other groups. However, in the acid-loaded azotemic group (RF + Ac), the osteoblast surface was not reduced. CONCLUSIONS: The presence of chronic metabolic acidosis in 5/6 nephrectomized rats on a high-phosphate diet (1) protected against the progression of RF, (2) enhanced the renal clearance of phosphate, (3) resulted in a lesser degree of hyperparathyroidism, and (4) did not reduce the osteoblast surface. The combination of metabolic acidosis and phosphate loading may protect against the progression of RF and possibly bone disease because the harmful effects of acidosis and phosphate loading may be counterbalanced.

Acidosis↗