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Regulación del estado ácido-base

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Presentación del tema: "Regulación del estado ácido-base"— Transcripción de la presentación:

1 Regulación del estado ácido-base
Dr. Guido Ulate Montero Departamento de Fisiología Universidad de Costa Rica

2 La regulación del pH sanguíneo es crucial porque si aumenta o disminuye se alteran funciones como:
La actividad enzimática Los sistemas de transporte La contractilidad muscular, incluida la del corazón La concentración plasmática de calcio ionizado La proliferación celular La resistencia vascular La interacción entre la Hb y el O2

3 Balance diario de hidrogeniones

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6 Manejo tubular del bicarbonato
A.Túbulo proximal; B. Célula intercalada alfa. C. Célula intercalada beta. H+ATPasa puede generar un gradiente de 3 unidades de pH y el NHE de 1. PKA inhibe y PKC estimula al NHE Tipo 2 Tipo 4 En el TP: se reabsorben 2/3 debido al NHE3 y 1/3 a la bomba.

7 Topology of NBCe1-A J Am Soc Nephrol 17: 2368–2382, 2006

8 Dendrograma de los transportadores de bicarbonato de la familia SLC4
En RAGAH Un Na+, 2 bicarbonatos (en misma dirección que el Na+) y un Cl- en dirección opuesta. Regulan pHic. En TCP En RAGAH y TCD En cels intercaladas del TC. También en los GR. J Am Soc Nephrol 17: 2368–2382, 2006

9 Acidez Titulable Excreción de amonio pKa´s: buffer fosfatos: 6.8
α pKa´s: buffer fosfatos: 6.8 buffer creatinina: 5 buffer ac. úrico: 5.75

10 Ammonia transport along the various renal epithelial segments
Ammonia transport along the various renal epithelial segments. Ammonia is primarily produced in the proximal tubule. It is preferentially secreted into the luminal fluid through mechanisms which involve NHE-3-mediated Na+/NH4+ exchange, NH4+ transport through Ba2+-inhibitable K+ channels, and an uncharacterized NH3 transport pathway. Ammonia is reabsorbed by the TAL through a process primarily involving Na+-K+-2Cl− cotransporter (NKCC2)-mediated NH4+ reabsorption. Recycling of ammonia through secretion in the DTL results in ammonia delivery to the turn of the loop of Henle that exceeds total excreted ammonia. NH4+ reabsorption in the TAL, however, results in total ammonia delivery to distal nephron segments that accounts for only a minority of total excreted ammonia. Ammonia secretion in the collecting duct involves parallel H+ and NH3 secretion. Numbers in blue reflect proportion of total urinary ammonia delivered to indicated sites. Specific details of ammonia secretion in each of these nephron segments are provided in the text.

11 Texto de la figura anterior
Ammonia transport along the various renal epithelial segments. Ammonia is primarily produced in the proximal tubule. It is preferentially secreted into the luminal fluid through mechanisms which involve NHE-3-mediated Na+/NH4+ exchange, NH4+ transport through Ba2+-inhibitable K+ channels, and an uncharacterized NH3 transport pathway. Ammonia is reabsorbed by the TAL through a process primarily involving Na+-K+-2Cl− cotransporter (NKCC2)-mediated NH4+ reabsorption. Recycling of ammonia through secretion in the DTL results in ammonia delivery to the turn of the loop of Henle that exceeds total excreted ammonia. NH4+ reabsorption in the TAL, however, results in total ammonia delivery to distal nephron segments that accounts for only a minority of total excreted ammonia. Ammonia secretion in the collecting duct involves parallel H+ and NH3 secretion. Numbers in blue reflect proportion of total urinary ammonia delivered to indicated sites. Specific details of ammonia secretion in each of these nephron segments are provided in the text. Am J Physiol Renal Physiol January; 300(1): F11–F23.

12 Transporte del NH3/NH4+ en la RAGAH
Ammonia reabsorption in the TAL. The primary mechanism of ammonia reabsorption in the TAL is via substitution of NH4+ for K+ and transport by NKCC2. Electroneutral K+/NH4+ exchange and conductive K+ transport are also present, but are quantitatively less significant components of apical K+ transport. Diffusive NH3 transport across the apical plasma membrane is present, but is not quantitatively significant. Cytosolic NH4+ can exit via basolateral NHE-4. A second mechanism of basolateral NH4+ exit may involve dissociation to NH3 and H+, with NH3 exit via an uncharacterized, presumably diffusive, mechanism and buffering of intracellular H+ released via sodium-bicarbonate cotransporter NBCn1-mediated HCO3− entry Ammonia transport in the proximal tubule. Ammonia is produced in the proximal tubule primarily from metabolism of glutamine and occurs primarily in the mitochondria. The enzymatic details of ammoniagenesis are not shown. Three transport mechanisms appear to mediate preferential apical ammonia secretion. These include Na+/NH4+ exchange via NHE-3, parallel NH3 secretion and NHE-3-mediated Na+/H+ exchange, and a Ba2+-sensitive NH4+ conductance likely mediated by apical K+ channels. HCO3− is produced in equimolar amounts as NH4+ in the process of ammoniagenesis and is primarily transported across the basolateral plasma membrane by NBCe1. Minor components of basolateral NH4+ uptake via Na+-K+-ATPase and by basolateral K+ channels are not shown Transporte del NH3/NH4+ en el TP Transporte del NH3/NH4+ en la RAGAH Ammonia transport in the proximal tubule. Ammonia is produced in the proximal tubule primarily from metabolism of glutamine and occurs primarily in the mitochondria. The enzymatic details of ammoniagenesis are not shown. Three transport mechanisms appear to mediate preferential apical ammonia secretion. These include Na+/NH4+ exchange via NHE-3, parallel NH3 secretion and NHE-3-mediated Na+/H+ exchange, and a Ba2+-sensitive NH4+ conductance likely mediated by apical K+ channels. HCO3− is produced in equimolar amounts as NH4+ in the process of ammoniagenesis and is primarily transported across the basolateral plasma membrane by NBCe1. Minor components of basolateral NH4+ uptake via Na+-K+-ATPase and by basolateral K+ channels are not shown. Ammonia reabsorption in the TAL. The primary mechanism of ammonia reabsorption in the TAL is via substitution of NH4+ for K+ and transport by NKCC2. Electroneutral K+/NH4+ exchange and conductive K+ transport are also present, but are quantitatively less significant components of apical K+ transport. Diffusive NH3 transport across the apical plasma membrane is present, but is not quantitatively significant. Cytosolic NH4+ can exit via basolateral NHE-4. A second mechanism of basolateral NH4+ exit may involve dissociation to NH3 and H+, with NH3 exit via an uncharacterized, presumably diffusive, mechanism and buffering of intracellular H+ released via sodium-bicarbonate cotransporter NBCn1-mediated HCO3− entry.

13 Transporte del NH3/NH4+ en el TC
Model of collecting duct ammonia secretion. In the interstitium, NH4+ is in equilibrium with NH3 and H+. NH3 is transported across the basolateral membrane through both Rhesus glycoproteins Rhbg and Rhcg. In the IMCD, basolateral Na+-K+-ATPase is a major mechanism of basolateral NH4+ uptake, followed by dissociation of NH4+ to NH3 and H+ (grey lines). Intracellular NH3 is secreted across the apical membrane by apical Rhcg. H+ secreted by H+-ATPase and H+-K+-ATPase combine with luminal NH3 to form NH4+, which is “trapped” in the lumen. In addition, there may also be minor components of diffusive NH3 movement across both the basolateral and apical plasma membranes (dotted lines). The intracellular H+ that is secreted by H+-ATPase and H+-K+-ATPase is generated by carbonic anhydrase (CA) II-accelerated CO2 hydration that forms carbonic acid, which dissociates to H+ and HCO3−. Basolateral Cl−/HCO3− exchange transports HCO3− across the basolateral membrane; HCO3− combines with H+ released from NH4+, to form carbonic acid, which dissociates to CO2 and water. This CO2 can recycle into the cell, supplying the CO2 used for cytosolic H+ production. The net result is NH4+ transport from the peritubular space into the luminal fluid. In the non-A, non-B cell, which lacks substantial basolateral Rhcg expression, Rhbg is likely the primary basolateral NH3 transport mechanism. The B-type intercalated cell, which lacks detectable Rhbg and Rhcg expression, likely mediates transcellular ammonia secretion through mechanisms only involving lipid-phase NH3 diffusion and thus transports ammonia at significantly slower rates. Expression of Rhbg and Rhcg in different intercalated cell populations. The expression and localization of Rhbg and Rhcg differ in the type A, type B, and non-A, non-B intercalated cells. The type A intercalated cell, characterized by apical H+-ATPase and basolateral AE1, expresses apical and basolateral Rhcg and basolateral Rhbg. The type B intercalated cell, characterized by apical pendrin and basolateral H+-ATPase, does not express either Rhbg or Rhcg detectable by immunohistochemistry. The non-A, non-B intercalated cell, characterized by apical pendrin and apical H+-ATPase, expresses apical, but not basolateral, Rhcg and expresses basolateral Rhbg. This figure is based on a drawing originally prepared by Dr. Ki-Hwan Han. Expression of Rhbg and Rhcg in different intercalated cell populations. The expression and localization of Rhbg and Rhcg differ in the type A, type B, and non-A, non-B intercalated cells. The type A intercalated cell, characterized by apical H+-ATPase and basolateral AE1, expresses apical and basolateral Rhcg and basolateral Rhbg. The type B intercalated cell, characterized by apical pendrin and basolateral H+-ATPase, does not express either Rhbg or Rhcg detectable by immunohistochemistry. The non-A, non-B intercalated cell, characterized by apical pendrin and apical H+-ATPase, expresses apical, but not basolateral, Rhcg and expresses basolateral Rhbg. This figure is based on a drawing originally prepared by Dr. Ki-Hwan Han. Transporte del NH3/NH4+ en el TC Model of collecting duct ammonia secretion. In the interstitium, NH4+ is in equilibrium with NH3 and H+. NH3 is transported across the basolateral membrane through both Rhesus glycoproteins Rhbg and Rhcg. In the IMCD, basolateral Na+-K+-ATPase is a major mechanism of basolateral NH4+ uptake, followed by dissociation of NH4+ to NH3 and H+ (grey lines). Intracellular NH3 is secreted across the apical membrane by apical Rhcg. H+ secreted by H+-ATPase and H+-K+-ATPase combine with luminal NH3 to form NH4+, which is “trapped” in the lumen. In addition, there may also be minor components of diffusive NH3 movement across both the basolateral and apical plasma membranes (dotted lines). The intracellular H+ that is secreted by H+-ATPase and H+-K+-ATPase is generated by carbonic anhydrase (CA) II-accelerated CO2 hydration that forms carbonic acid, which dissociates to H+ and HCO3−. Basolateral Cl−/HCO3− exchange transports HCO3− across the basolateral membrane; HCO3− combines with H+ released from NH4+, to form carbonic acid, which dissociates to CO2 and water. This CO2 can recycle into the cell, supplying the CO2 used for cytosolic H+ production. The net result is NH4+ transport from the peritubular space into the luminal fluid. In the non-A, non-B cell, which lacks substantial basolateral Rhcg expression, Rhbg is likely the primary basolateral NH3 transport mechanism. The B-type intercalated cell, which lacks detectable Rhbg and Rhcg expression, likely mediates transcellular ammonia secretion through mechanisms only involving lipid-phase NH3 diffusion and thus transports ammonia at significantly slower rates. Expression of Rhbg and Rhcg in different intercalated cell populations. The expression and localization of Rhbg and Rhcg differ in the type A, type B, and non-A, non-B intercalated cells. The type A intercalated cell, characterized by apical H+-ATPase and basolateral AE1, expresses apical and basolateral Rhcg and basolateral Rhbg. The type B intercalated cell, characterized by apical pendrin and basolateral H+-ATPase, does not express either Rhbg or Rhcg detectable by immunohistochemistry. The non-A, non-B intercalated cell, characterized by apical pendrin and apical H+-ATPase, expresses apical, but not basolateral, Rhcg and expresses basolateral Rhbg. This figure is based on a drawing originally prepared by Dr. Ki-Hwan Han.

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15 La excreción neta de ácido renal (ENAR)
ENAR = Vo ([NH4+] + AT - [HCO3-])

16 Regulación de la reabsorción tubular de bicarbonato y de la excreción de ácido fijo
Esta regulación ocurre sobre todo en el TP y TC. En el TP: 1. Factores que estimulan al NHE también favorecen la reabsorción de HCO3-: contracción del LEC, ANGII, pHic, SS. Factores que inhiben NHE disminuyen reabsorción de HCO3-:pHic. 2.  MF de HCO3- =  reabsorción 3. Actividad de AC 4. Producción de amonio  cuando pHic y por los GCs 5.  PaCO2  secreción de H+ y  la reabsorción de HCO3- 6. [K+]p: activa NHE y el NBCe1 por efecto en pHic. Estimula síntesis de amonio 7. ET-1 y GCs (ambos liberados ante acidosis ic): estimulan al NHE3 y al NBCe1. 8. PTH:  la reabsorción de fosfatos en el TP

17 Regulación de la reabsorción tubular de bicarbonato y de la excreción de ácido fijo
En TC: 1. Aldosterona favorece la acidificación urinaria 2. [K+]p en c. intercaladas alfa: activa H+/K+ATPasa 3. En acidosis se estimulan los Rhbg y Rhcg. En alcalosis: c. intercaladas alfa  beta.

18 Regulación extrarrenal del pH y trastornos ácido-base

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20 pKas de principales buffers
HCO3-/CO2 6.1 Lact-/Ac láctico 3.9 NH3/NH4+ 9.2 Acet-/Ac acet 3.6 HPO42-/H2PO4- Para otros 2: 6.8 (2.1 y 12.4) Hb oxigenada Hb desoxigenada 6.7 7.9 Citr3-/Citr2- 5.5 OH but-/OH butírico 4.8 Urato-/Ac úrico 5.75 Creat-/Creat 5.0

21 Capacidad buffer total de la sangre (): aproximadamente 80 sl (mEq/L/unidad pH): 55 sl del buffer de bicarbonato abierto (si fuera cerrado sería solo 2.6 sl) y 25 de los “no bicarbonato”. Del plasma, no bicarbonato: 5 sl. Estos  dependen del rango de titulación. Recordar que buffer del bicarbonato (abierto) : 2.3 sl/mmol y el de HPO42- (cerrado) 0.58 sl/mmol.

22 [H+] = Ka1[H2CO3]/[HCO3-] = Ka2[H2PO4-]/[HPO42-] = Ka3[ProtH+]/[Prot-]
Distribución de la capacidad buffer según tipo y ubicación de los buffers LIC LEC Bicarbonato 36% 86% No bicarbonato 64% 14% En el organismo el estado de los buffers se determina según el principio isohídrico: [H+] = Ka1[H2CO3]/[HCO3-] = Ka2[H2PO4-]/[HPO42-] = Ka3[ProtH+]/[Prot-]

23 Valores normales de los gases sanguíneos
Promedio Rango Sangre arterial pH 7.40 PCO2 (mmHg) 40 [HCO3-] 24 22-26 Sangre venosa 7.38 46 26

24 Valores normales de los gases sanguíneos se ven modificados ante ciertas situaciones como: posición acostada PaCO2 tiende a estar de 3 a 4 mmHg más alta que en posición de pie o sentada. Las mujeres durante la fase luteínica del ciclo ovárico presentan PaCO2 de 2 a 4 mmHg más baja que durante la fase proliferativa. Durante el embarazo se desarrolla una hipocapnia marcada, especialmente en el último trimestre del embarazo: PaCO mmHg. Con la edad: niños PaCO mmHg (hasta los 3 años de edad), idénticas a la del adulto después de los 17 años. Dieta: carnívora: descenso en concentración de bicarbonato. Altura a la que se habita: hipocapnia por hiperventilación.

25 4 Chronic

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30 Nomograma de Davemport
(instrumento gráfico de cálculo)

31 Brecha Aniónica o Anion Gap
AG = [Na+]p - ([Cl-]p + [HCO3-]p) valor normal: 9-13 mEq/L Se utiliza en AcM: Con AG nl con  [Cl-]: acidosis tubulares renales, AcM secundarias a diarrea Con AG  y normocloremia: ac. láctica, cetoacidosis, intoxicación por salicilato.

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33 Estos factores aumentan la ENAR cuando existe una acidosis
ET-B R= NHE3 y NBCe1 ARNm de NHE3 y NBCe1 Tanto la ET-1 como los GCs se liberan ante la pHic. Probablemente ET-1 y GCs estimulan transportadores involucrados en reabsorción de bicarbonato  Fosfatos en orina = AT

34 Tiempo necesario para alcanzar la compensación y límite de esta según el tipo de trastorno ácido-base Trastorno Tiempo para alcanzar la compensación Límite de la compensación Ac Metab 12-24 h Paco2 de 10 mmHg Alk Metab 24-36 h Paco2 de 55 mmHg Ac R Ag 5-10 min [HCO3-] de 30 mEq/L Ac R Cr 72-96 h [HCO3-] de 45 mEq/L Alk R Ag [HCO3-] de mEq/L Alk R Cr 48-72 h [HCO3-] de mEq/L Kraut JA, Madias NE. Approach to patients with acid-base disorders. Respiratory Care (4)

35 Algoritmo para el estudio de pacientes con acidosis metabólica
[Lactato]p = 1-2 mEq/L [C. cetónicos]p = mg/dL Osmolal gap: diferencia entre la osmolalidad medida y la calculada d-lactic acid: producido por bacterias Gram (+) Ethylene glycol

36 xq [H+]ic = reabs HCO3-, NH4+, H+/K+ ATPasa

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