Department of internal medicine and systemic diseases, university of catania, 95100 catania, italy received 29 september 2011 accepted 26 october 2011 academic editor: saulius butenas copyright © 2012 cosimo marcello bruno and maria valenti. This is an open access article distributed under the creative commons attribution license. Which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The authors describe the pathophysiological mechanisms leading to development of acidosis in patients with chronic obstructive pulmonary disease and its deleterious effects on outcome and mortality rate. Renal compensatory adjustments consequent to acidosis are also described in detail with emphasis on differences between acute and chronic respiratory acidosis. Mixed acid base disturbances due to comorbidity and side effects of some drugs in these patients are also examined, and practical considerations for a correct diagnosis are provided.

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On the basis of epidemiologic data, the projection for 2020 indicates that copd will be the third leading cause of death worldwide and the fifth leading cause of disability 1 . About 15% of copd patients need admission to general hospital or intensive respiratory care unit for acute exacerbation, leading to greater use of medical resources and increased costs 2 –5 . Even though the overall prognosis of copd patients is lately improved, the mortality rate remains high, and, among others, acid base disorders occurring in these subjects can affect the outcome.

The aim of this paper is to focus on the main pathogenic mechanisms leading to acid base disorders and their clinical consequences in copd patients. Hypercapnia and respiratory acidosis a major complicance in copd patients is the development of stable hypercapnia 6. In the healthy subject, about 16,0–20,0 mmol/day of carbon dioxide co₂ , derived from oxidation of nutrients containing carbon, are produced.

Under normal conditions, the production of co₂ is removed by pulmonary ventilation. However, an alteration in respiratory exchanges, as occurs in advanced phase of copd, results in retention of co₂. Carbon dioxide is then hydrated with the formation of carbonic acid that subsequently dissociates with release of hydrogen ions h + in the body fluids according to the following equation: c o 2 + h 2 o ⟹ h 2 c o 3 ⟹ − h c o 3 + h +. 1 thus, the consequence of hypercapnia due to alteration of gas exchange in copd patients mainly consists in increase of h + concentration and development of respiratory acidosis, also called hypercapnic acidosis 8 .

According to the traditional method to assess acid base status, the henderson hasselbach equation expresses the relationship between ph logarithm of inverse concentration of h + , bicarbonate ion concentration − hco₃ , and partial pressure of co₂ pco₂ : p h 6. 2 it is evident that the ph and the concentration of hydrogen ions are strictly determined by the bicarbonate/pco₂ ratio, rather than their individual values. A change in ph can thus be determined by a primitive alteration of numerator of this equation, that is, bicarbonate metabolic disorders or of denominator, that is, pco₂ respiratory disorders.

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In either case, compensatory mechanisms are activated to determine a consensual variation of the other factor to keep this ratio as constant as possible and minimize changes in ph. The extent of these compensatory changes are largely dependent on that of the primary alteration and can be to some extent predicted expected compensatory response 9 . Consequently, the compensation to respiratory acidosis consists in a secondary increase in bicarbonate concentration, and the arterial blood gas analysis is characterized by a reduced ph, increased pco₂ initial variation , and increased bicarbonate levels compensatory response. Compensatory mechanisms in acute and chronic respiratory acidosis the response to respiratory acidosis occurs in a different extent either in acute or chronic phase. When hypercapnia occurs acutely, the buffering of h + takes place by proteins, mainly hemoglobin, and other intracellular nonbicarbonate buffers as follows: h 2 c o 3 + − h b ⟹ h h b + − h c o 3. In such condition, for every increase of 10 mmhg pco₂ we expect only 1 meq increase in bicarbonate concentration 10 . Subsequently, renal adaptive changes occur mainly in the proximal tubular cells than in distal tubules leading to increased bicarbonate reabsorption and increased excretion of titratable acid and ammonium 11.

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H + excretion across apical membrane occurs by a na + /h + antiporter nhe3 and to a lesser extent by a proton pump figure 1 . The secreted h + into the tubular fluid combines with filtered bicarbonate ions leading to carbonic acid formation. Co₂ diffuses into the cell where co₂ is rehydrated to carbonic acid. This gives rise to bicarbonate ion that exits from the cell through the basolateral membrane into the interstitium via a 3hco₃ /na nbce1 symporter, while h + is secreted again into the lumen. The basolateral membrane na + /k + atpase antiporter, maintaining a low intracellular sodium concentration, further enhances the nhe3 activity. figure 1: h + secretion and − hco₃ reabsorption in the tubular cells.

In summary, reabsorption of bicarbonate requires carbonic anhydrase and is strictly associated to natrium reabsorption. Experimental studies show that total nhe3 and nbce1 protein abundance are upregulated by chronic respiratory acidosis 13 . However, the main mechanism responsible for the elevation in serum bicarbonate is the increased excretion of titratable acid and ammonium 12 , which are stimulated by persistently elevated pco₂.

Ammonia nh₃ , in the proximal cell, is formed by deamination of glutamine to glutamic acid and then to alpha ketoglutarate. Therefore, for each molecule of glutamine, two molecules of ammonia are formed figure 2 . Ammonia binds h + resulting in ammonium ion nh₄ + which is subsequently secreted into the renal tubular lumen by nhe3, with nh₄ + substituting for h + on the transporter, and excreted into the urine as ammonium chloride nh₄ cl.

For alternative, some nh₄ + can be secreted into the tubular fluid as nh₃. Thus, ammonia replaces bicarbonate ion acting as urinary buffer and binding hydrogen ion. Consequently, for each h + excreted as ammonium ion, a new − hco₃ is returned to the blood.

Nevertheless, a significant reabsorption of nh₄ + occurs in the ascending limb of the loop of henle. In the distal tubule, nh₄ + reabsorbed is subsequently excreted by a nh₄ + transporter belonging to rh glycoproteins family, localized on both apical and basolateral membranes of collecting duct cells 14 . figure 2: cellular mechanism for ammoniagenesis and nh₄ + secretion. Nh₃ can be secreted into the tubular fluid, where it is then protoned, or it can bind h + within the cell, and be secreted as ammonium ion. Thus, collecting duct cells plays a pivotal role in maintaining acid base balance and net acid excretion. If ammonium reabsorbed was not excreted in the urine, it would be metabolized by the liver generating h +. H + derived from the breakdown of carbonic acid are excreted into the tubular lumen where they are buffered by phosphates 2− hpo₄ + h + ⇒ − h₂ po₄ , while − hco₃ crosses the basolateral membrane via an anion exchange ae cl − / − hco₃ antiporter figure 3 .

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Interestingly, acidemia and hypercapnia reduce the threshold for reabsorption of phosphate, thus making available a larger amount of urinary buffer in the distal tubule 15. Pendrin is a bicarbonate/chloride exchanger located in the apical domain of the type b and non a, non b intercalated cell of collecting ducts figure 4 . Hypercapnia determines a reduction of pendrin expression by up to 50%, contributing to the increased plasma bicarbonate and decreased plasma chloride observed in chronic respiratory acidosis 11. figure 4: pendrin, localized in the cellular apical membrane of cortical collecting ducts and connecting tubules, acts as a cl − / − hco₃ exchanger regulating the acid base status and chloride homeostasis.