2014-18 Acid production in the body Its in the production of approxmately 15,000 mmol of Co2 per day. Acidosis and Alkalosis ganic: lactate, metabolized by the liver and kidney the metabolism of proteins and other substances results in the generation A +H20一>RoH+08HP42-/0.2H2P4+18H The homeostatic response to acid load Chemical buffering Extracellular buffers 1. Chemical buffering by the extracellular and intracellular buffers 2. Changes in alveolar ventilation to control the 3. Alterations in renal H*excretion to regulate ne plasma HCO3- concentration. Henderson-Hasselbalch equation Henderson-Hasselbalch equation Eq.1)H++HCO3-H2C03H20+C02 Eq1)H++HCO3-H2C0O3H20+Co2 PCO2 PC02 X Eq2)[H+]=24 or by the henderson-Hasselbalch equation or by the Henderson-Hasselbalch equation (Eq. 3)pH 6.10+ log 03 PCO2 Acidosis: PCO2=1. X HCO3+8
2014-1-8 1 Acidosis and Alkalosis Hao Chuan-Ming Acid production in the body Carbonic acid: the metabolism of carbohydrates and fats (primarily derived from the diet) results in the production of approximately 15,000 mmol of CO2 per day. Non-carbonic acid: Organic: lactate, metabolized by the liver and kidney Inorganic: the metabolism of proteins and other substances results in the generation of noncarbonic acids (50 – 100 mEq, 1mEq/kg). Methionine —> glucose + urea + SO4(2-) + 2 H+ Arginine+ —> glucose (or CO2) + urea + H+ R-H2PO4 + H2O —> ROH + 0.8 HPO42- / 0.2 H2PO4- + 1.8 H+ The homeostatic response to acid load 1. Chemical buffering by the extracellular and intracellular buffers. 2. Changes in alveolar ventilation to control the PCO2. 3. Alterations in renal H+ excretion to regulate the plasma HCO3- concentration. Chemical buffering • Extracellular buffers • Intracelluar: bone Henderson-Hasselbalch equation (Eq. 1) H+ + HCO3- H2CO3 H2O + CO2 PCO2 (Eq. 2) [H+] = 24 x ———— [HCO3-] or by the Henderson-Hasselbalch equation [HCO3-] (Eq. 3) pH = 6.10 + log ——————— 0.03 PCO2 Henderson-Hasselbalch equation (Eq. 1) H+ + HCO3- H2CO3 H2O + CO2 PCO2 (Eq. 2) [H+] = 24 x ———— [HCO3-] or by the Henderson-Hasselbalch equation [HCO3-] (Eq. 3) pH = 6.10 + log ——————— 0.03 PCO2 Acidosis: PCO2=1.5 X HCO3 + 8
2014-18 Chemical buffering The homeostatic response to acid load Extracellular buffers Intracelluar buffer: bone Ca** release 1. Chemical buffering by the extracellular and intracellular buffers 2. Changes in alveolar ventilation to control the PCO2 3. Alterations in renal H* excretion to regulate the plasma HCO3- concentration The homeostatic response to acid load Acid production and excretion 1. Chemical buffering by the extracellular and intracellular buffers 2. Changes in alveolar ventilation to control the PCO2 3. Alterations in renal H* excretion to regulate e plasma HCo3- concentration add excretion and endogenous RENAL HYDROGEN EXCRETION Excretion of ht in a intercalated cells (1)reabsorption of the filtered HCO3 Tubular Lumen Collecting tubule P (2 )excretion of the 50 to 100 meg of H+ 2. Excretion of nh4+ in the urine oH+co→3Hco3
2014-1-8 2 Chemical buffering • Extracellular buffers • Intracelluar buffer: bone, Ca++ release, osteoclast activation The homeostatic response to acid load 1. Chemical buffering by the extracellular and intracellular buffers. 2. Changes in alveolar ventilation to control the PCO2. 3. Alterations in renal H+ excretion to regulate the plasma HCO3- concentration. The homeostatic response to acid load 1. Chemical buffering by the extracellular and intracellular buffers. 2. Changes in alveolar ventilation to control the PCO2. 3. Alterations in renal H+ excretion to regulate the plasma HCO3- concentration. RENAL HYDROGEN EXCRETION (1) reabsorption of the filtered HCO3- (2) excretion of the 50 to 100 meq of H+ produced per day 1. Formation of titratable acid 2. Excretion of NH4+ in the urine Tubular Lumen Collecting tubule Peritubular capillary H+ H2O2 OH- + CO2 3HCO3 - CA H+ ClATPase ATPase H+ K+ Excretion of H+ in a intercalated cells H+ H+
2014-18 Excretion of h+ in a intercalated cells Excretion of h* in a intercalated cells Collecting tubule Peritubular capillar Tubular Lumen Collecting tubule Peritubular cap HPO, H oH·CO→3Hco 叶HcO→3Hco3 Can be stimulated by low K Acid-base balance The kidneys must excrete the 50 to 100 meq of noncarbonic acid g The daily acid load is excreted as NH4'and H2(PO)- The daily acid load also cannot be excreted unless virtually all of the Regulation: The extracellular pH Can be independent o serum pH Steps in acid-base diagnosis Henderson-Hasselbalch equation (ABGs)and electrolytes simultaneously Eq1)H++HCO3-H2C0O3H20+Co2 PC02 Eq2)[H+]=24x or by the Henderson-Hasselbalch equation mare change in ( Ci] with change in( Nal Acidosis: PCO2=1. X HCO3+8
2014-1-8 3 Tubular Lumen Collecting tubule Peritubular capillary H+ H2O2 OH- + CO2 3HCO3 - CA HPO + H+ 4 2- H2PO4 ClATPase ATPase H+ K+ Excretion of H+ in a intercalated cells Tubular Lumen Collecting tubule Peritubular capillary H+ H2O2 OH- + CO2 3HCO3 - CA H+ + NH3 NH4 + ClH+ -ATPase NH3 Excretion of H+ in a intercalated cells Can be stimulated by low K Acid-base balance • The kidneys must excrete the 50 to 100 meq of noncarbonic acid generated each day. • The daily acid load is excreted as NH4+ and H2 (PO4 ). • The daily acid load also cannot be excreted unless virtually all of the filtered HCO3- has been reabsorbed, because HCO3- loss in the urine is equivalent to adding H+ ions to the body. • Regulation: – The extracellular pH – the effective circulating volume, – aldosterone, and – the plasma K+ concentration Can be independent of serum pH Steps in acid-base diagnosis • Obtain arterial blood gas (ABGs) and electrolytes simultaneously • Compare [HCO3-]on ABGs and electrolytes to verify accuracy • Calculate anion gap (AG) • Know 4 causes of high AG acidosis – Ketoacidsis – Lactic acid acidosis – Renal failure – Toxins • Know 2 causes of hyperchloremic or nongap acidosis – Bicarbonate loss from GI, – RTA • Estimate compensatory response • Compare ΔAG and ΔHCO3- • Compare change in [Cl] with change in [Na] Henderson-Hasselbalch equation (Eq. 1) H+ + HCO3- H2CO3 H2O + CO2 PCO2 (Eq. 2) [H+] = 24 x ———— [HCO3-] or by the Henderson-Hasselbalch equation [HCO3-] (Eq. 3) pH = 6.10 + log ——————— 0.03 PCO2 Acidosis: PCO2=1.5 X HCO3 + 8
2014-18 Metabolic acidosis Ketoacidosis Lactic acidosis Accumulation of endogenous acids(high anion gap) External losses of bicarbonate(normal anion gap hyperchloremic) Anion Gap Anion Gap ·AG=Na- Cl'-HCO3=12±2 will reduce ag charged. Presence of large amount orOsitive Renal failure Renal failure With mild to moderate reductions in gfR. the acidosis reflects decreased ammoniagenesis and is Despite a daily net positive acid balance it is unusual therefore hyperchloremic for [HCO3-to fall lower than 15 mmol/L. As kidney failure worsens, the calcium and a negative calcium balance ulfate phosphate, and other anions, produces an Chronic acidosis causes protein breakdown, muscle wasting, and a negative nitrogen balance. maintenance of the acid-base balance close to ormal can prevent these consequences
2014-1-8 4 Metabolic acidosis • Influx of organic acid into plasma (high anion gap) – Ketoacidosis – Lactic acidosis – Poisoning • Accumulation of endogenous acids (high anion gap) – Renal failure • External losses of bicarbonate (normal anion gap; hyperchloremic). – GI loss – Renal loss Anion Gap • AG=Na+ -Cl- -HCO3- = 12±2 • albumin: negative charged. Low serum albumin will reduce AG. • Paraprotein (Ig or light chains, MM): positive charged. Presence of large amount of paraprotein reduces AG. Anion Gap Renal failure • With mild to moderate reductions in GFR, the acidosis reflects decreased ammoniagenesis and is therefore hyperchloremic. • As kidney failure worsens, the kidney loses its ability to excrete various anions, and the accumulation of sulfate, phosphate, and other anions, produces an elevated AG. Renal failure • Despite a daily net positive acid balance, it is unusual for [HCO3−]to fall lower than 15 mmol/L. • The buffering of protons by bone results in loss of calcium and a negative calcium balance. • Chronic acidosis causes protein breakdown, muscle wasting, and a negative nitrogen balance. • Maintenance of the acid-base balance close to normal can prevent these consequences
2014-18 Treatment Hyperchloremic Metabolic Acidosis Alkali replacement Causes NaHCO3 Renal loss of alkali-Rta Gl loss of alkali Reciprocal changes in [Cl] and [HCO3 result in normal ag In the absence of such a relationship suggests a mixed disturbance Diarrhea afma NHa cronon Metabolic acidosis renal synthesis and excretion of NH4+, thus rinary pH is around Urinary NH4 levels are high: urine anion gap is Nopat Unne Anion Gap Proximal RTa(type 2) lower(normal: 26-28 mmol/). The distal nephron has a low capacity for Hco3 reabsorption. HCO3 18 mmol/, when all the filtered HCo3 is reabsorbed. espite systemic acidemia development, the urine ph is kaline. However under steady state, the urine can acidified to a ph of less than 5.5
2014-1-8 5 Treatment • Alkali replacement – NaHCO3 – Sodium citrate Hyperchloremic Metabolic Acidosis • Causes: – Renal loss of alkali – RTA – GI loss of alkali • Reciprocal changes in [Cl] and [HCO3] result in normal AG • In the absence of such a relationship suggests a mixed disturbance Diarrhea • Metabolic acidosis • Metabolic acidosis and hypokalemia increase renal synthesis and excretion of NH4+, thus urinary pH is around 6 • Urinary NH4 levels are high: urine anion gap is negative Proximal RTA (type 2) • The threshold for HCO3- reabsorption in the proximal tubule is lower (normal: 26 -28 mmol/l). • The distal nephron has a low capacity for HCO3 reabsorption. • Self-limited bicarbonaturia • In the steady state, the serum HCO3 concentration usually is 16 – 18 mmol/l, when all the filtered HCO3 is reabsorbed. • Despite systemic acidemia development, the urine pH is alkaline. However under steady state, the urine can be acidified to a pH of less than 5.5. HCO3 HCO3 HCO3
2014-18 Proximal RTA: hypokalemia Causes of proximal rta Increased distal Na+ delivery(NaHCO3) Inherited pRTA: NBCe1/SLC4A4)mutation Increased aldosterone levels(dehydration accompanied by ocular abnormalities such as because of loss of Na in the urine) cataracts, glaucoma. Treatment of acidosis with HCO3 improves the Carbonic anhydrase inhibitor: acetazolamide acidosis but worsens the degree of Fanconi syndrome: inherited and acquired Adult with Fanconi: dysproteinemic condition drTa(type 1) Systemic acidosis in drTa tends to be more severe han in patients with a proximal RTA (serum HCO3- can reach as low as 10 mmol/l vs 16 to 18 mmol/l) Hypokelemia can also be severe: musculoskeletal Nephrolithiasis and nephrocalcinosis dRTA: kidney stone dRTA Urinary calcium excretion is high Primary: idiopathic or inherited(SLC4A1 Acidosis induced bone mineral dissolution mutation) Low intraluminal concentration of Hco3- because Urinary citrate levels are low- citrate serve High urine ph decrease the solubility of m phosphate complexes
2014-1-8 6 Proximal RTA: hypokalemia • Increased distal Na+ delivery (NaHCO3) • Increased aldosterone levels (dehydration because of loss of Na in the urine). • Treatment of acidosis with HCO3 improves the acidosis but worsens the degree of hypokalemia. Causes of Proximal RTA • Inherited pRTA: NBCe1/SLC4A4) mutation, accompanied by ocular abnormalities such as cataracts, glaucoma. • Carbonic anhydrase inhibitor: acetazolamide • Fanconi syndrome: inherited and acquired • Adult with Fanconi: dysproteinemic condition such as multiple myeloma dRTA (type 1) • Systemic acidosis in dRTA tends to be more severe than in patients with a proximal RTA (serum HCO3- can reach as low as 10 mmol/l vs 16 to 18 mmol/l) • Hypokelemia can also be severe: musculoskeletal weakness • Nephrolithiasis and nephrocalcinosis HCO3 HCO3 HCO3 dRTA: kidney stone • Urinary calcium excretion is high – Acidosis induced bone mineral dissolution – Low intraluminal concentration of HCO3- because of acidosis • Urinary citrate levels are low – citrate serve as the major Ca++ chelator in the urine • High urine pH decrease the solubility of calcium phosphate complexes. dRTA • Primary: idiopathic or inherited (SLC4A1 mutation) • Systemic disease: Sjogren syndrome
2014-18 dRTA-diagnosis drTa NH4CI Irosemide mineralocorticoid Hyperchloremic acidosis (fludrocortisone) Kidney stone Hypokalemia Sjogren syndrome Type 4 RTA Metabolic alkalosis Renal function compromised An elevated arterial pH Hyporeninemic hypoaldosteronism An increase in the serum [HCO3-] and a ncrease in Pco2 Urinary ammonium excretion depressed Often accompanied by hypochloremia and Pathogenesis Differential diagnosis Generative stage: loss of acid Maintenance stage: volume contraction, a low Bartter s or Gitelman s GFR or depletion of Cl or K
2014-1-8 7 dRTA-diagnosis • NH4Cl • Furosemide + mineralocorticoid (fludrocortisone) dRTA • Hyperchloremic acidosis • Kidney stone • Hypokalemia • Sjogren syndrome Type 4 RTA • Renal function compromised • Hyporeninemic hypoaldosteronism • Hyperkalemia • Urinary ammonium excretion depressed Metabolic Alkalosis • An elevated arterial pH • An increase in the serum [HCO3-] and a increase in PCO2 • Often accompanied by hypochloremia and hypokalemia Pathogenesis • Generative stage: loss of acid • Maintenance stage: volume contraction, a low GFR or depletion of Cl or K Differential diagnosis • Mineralocorticoid excess • Bartter’s or Gitelman’s • Diuretics
2014-18 Metabolic alkalosis associated with ECFV contraction Metabolic alkalosis with ECFV expansion K depletion, and secondary hyperreninemia hyperaldosteronism Mineralocorticoid administration or excess Gastrointenstinal production HCO3 retention volume contraction Symptoms Diuretics Nonreaborbable anions and magnesium Related electrolyte abnormalities: hypokalemia Treatment Correcting the underlying stimulus for HCo3 generation After treatment of lactic acidosis or Removing the factors that sustain HCO reabsorption(ECFV ketoacidosis posthypercapnia Respiratory acidosis Clinical features Severe pulmonary disease, respiratory muscle The clinical feature varies according to fatigue or abnormalities in ventilatory control Severity and duration Acute: immediate compensatory elevation Underlying disease HCO3, which increases 1 mmol/L for every 10 whether there is hypoxemia ty, dyspnea mmHg increase in pCo2 confusion. coma Chronic(>24h): renal adaptation increases the Chronic hypercapnea: sleep disturbances, loss o [HCO3] by 4 mmol/L Treatment Respiratory alkalosis Acute respiratory acidosis HCO3/PCO2 When PaCO2 is 40-15 mmHg, the relationship between measures to reverse the underlying cause should arterial [H+]and Paco2 is about 0.7 mmol/L per mmHg, and be undertaken simultaneously with restoration of of plasma [HCo3]is O adequate alveolar ventilation Hypocapnia sustained longer than 2 to 6 h is further Chronic respiratory acidosis Improving lung function Full renal adaptation may take several days and require normal volume status and renal function 8
2014-1-8 8 Metabolic alkalosis associated with ECFV contraction, K depletion, and secondary hyperreninemic hyperaldosteronism • Gastrointenstinal – HCO3 retention + volume contraction • Renal origin – Diuretics – Nonreaborbable anions and magnesium deficiency – Potassium depletion – After treatment of lactic acidosis or ketoacidosis – posthypercapnia Metabolic alkalosis with ECFV expansion, hypertension and hyperaldosteronism • Mineralocorticoid administration or excess production • Symptoms: – changes in central and peripheral nervous system function: confusion, obtundation, a predispositin to seizures … • Related electrolyte abnormalities: hypokalemia • Treatment – Correcting the underlying stimulus for HCO3 generation – Removing the factors that sustain HCO reabsorption (ECFV contraction) Respiratory acidosis • Severe pulmonary disease, respiratory muscle fatigue or abnormalities in ventilatory control • Acute: immediate compensatory elevation in HCO3, which increases 1 mmol/L for every 10 mmHg increase in pCO2 • Chronic (>24h): renal adaptation increases the [HCO3] by 4 mmol/L Clinical features • The clinical feature varies according to – Severity and duration – Underlying disease – Whether there is hypoxemia • A rapid increase in pCO2: anxiety, dyspnea, confusion… coma • Chronic hypercapnea: sleep disturbances, loss of memory, .. Treatment • Acute respiratory acidosis – can be life-threatening, – measures to reverse the underlying cause should be undertaken simultaneously with restoration of adequate alveolar ventilation • Chronic respiratory acidosis – Improving lung function Respiratory alkalosis • Alveolar hyperventilation decreases PaCO2 and increases the HCO3/PCO2 • When PaCO2 is 40 – 15 mmHg, the relationship between arterial [H+] and PaCO2 is about 0.7 mmol/L per mmHg, and that of plasma [HCO3] is 0.2 mmol/ per mmHg • Hypocapnia sustained longer than 2 to 6 h is further compensated by a decrease in renal ammonium and titratable acid excretion. • Full renal adaptation may take several days and require normal volume status and renal function
2014-18 duration and severity but are primarily those of the Paresthesia, circumoral numbness, chest wall tightness yates are the most common cause of drug induced respiratory alkalosis Progesterone increases ventilation Respiratory alkalosis is often an early finding of G 9
2014-1-8 9 • The effect of respiratory alkalosis vary according to duration and severity but are primarily those of the underlying disease • Hyperventilation syndrome – Paresthesia, circumoral numbness, chest wall tightness, dizziness… • Salicylates are the most common cause of drug induced respiratory alkalosis • Progesterone increases ventilation • Respiratory alkalosis is often an early finding of Gsepticemia
