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Regional citrate anticoagulation for slow continuous ultrafiltration: risk of severe metabolic alkalosis.

Alsabbagh MM, Ejaz AA, Purich DL, Ross EA - Clin Kidney J (2012)

Bottom Line: We report here the acid-base balance calculations quantifying base accumulation in SCUF compared to continuous venovenous hemofiltration (CVVH).This kinetic approach demonstrates the importance of accounting for the high citrate clearance into CVVH hemofiltrate, which prevents development of the alkalosis seen with the relatively low ultrafiltration rates in SCUF: there was net bicarbonate accumulation of ∼1400 mmol/day with SCUF, compared to 664 to as low as 274 mmol/day during CVVH.We also discuss how citrate's acid-base effects are potentially complicated by metabolism via gluconeogenic and ketone body pathways.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Hypertension and Renal Transplantation, University of Florida, Gainesville, FL, USA.

ABSTRACT

Background: Slow continuous ultrafiltration (SCUF) is a safe and efficient treatment for fluid overload in patients who are hemodynamically unstable, have low urine output, and are not in need of dialysis or hemofiltration for solute clearance. Sustained anticoagulation is required for these long treatments, thus posing clinically challenges for patients having contraindications to systemic anticoagulation with heparin. Regional citrate anticoagulation would be an alternative option; however, we believed that this would be problematic due to citrate kinetics that predicted the development of metabolic alkalosis.

Methods: In that patients' serum bicarbonate reached 45 mEq/L and arterial pH rose to 7.59 after just 3 days of SCUF, we developed equations to study this phenomenon. We report here the acid-base balance calculations quantifying base accumulation in SCUF compared to continuous venovenous hemofiltration (CVVH).

Results: This kinetic approach demonstrates the importance of accounting for the high citrate clearance into CVVH hemofiltrate, which prevents development of the alkalosis seen with the relatively low ultrafiltration rates in SCUF: there was net bicarbonate accumulation of ∼1400 mmol/day with SCUF, compared to 664 to as low as 274 mmol/day during CVVH. The calculations underscore the importance of the relative fluid flow rates as well as the bicarbonate and citrate levels in the various infused solutions. We also discuss how citrate's acid-base effects are potentially complicated by metabolism via gluconeogenic and ketone body pathways.

Conclusions: These acid-base balance findings emphasize why clinicians must be mindful of the risk of metabolic alkalosis when using continuous renal replacement therapy modalities with low rates of ultrafiltration, which thereby presents a contraindication for using citrate anticoagulation for SCUF.

No MeSH data available.


Related in: MedlinePlus

Diagram for citrate metabolism and bicarbonate formation. Shown are key enzymatic reactions catalyzing the formation and degradation of citrate and oxaloacetate, the latter an important metabolite in the TCA (Krebs) cycle, gluconeogenesis as well as the formation of reducing equivalents required for fatty acid biosynthesis. Note that each turn of the TCA cycle generates 2 moles of bicarbonate. The relative flux of oxaloacetate through gluconeogenesis versus the steps catalyzed by MDH and malic enzymes will depend on other metabolic circumstances beyond the scope of this discussion. MDH, malate dehydrogenase; PDH, pyruvate dehydrogenase; acetyl-S-CoA, acetyl-S-coenzyme A.
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fig1: Diagram for citrate metabolism and bicarbonate formation. Shown are key enzymatic reactions catalyzing the formation and degradation of citrate and oxaloacetate, the latter an important metabolite in the TCA (Krebs) cycle, gluconeogenesis as well as the formation of reducing equivalents required for fatty acid biosynthesis. Note that each turn of the TCA cycle generates 2 moles of bicarbonate. The relative flux of oxaloacetate through gluconeogenesis versus the steps catalyzed by MDH and malic enzymes will depend on other metabolic circumstances beyond the scope of this discussion. MDH, malate dehydrogenase; PDH, pyruvate dehydrogenase; acetyl-S-CoA, acetyl-S-coenzyme A.

Mentions: The impact of a net positive citrate balance can be appreciated on the basis of the metabolic fate for this buffer/chelator. While clinical concern has centered on bicarbonate generation from citrate degradation, the citrate pathway is neither straightforward nor the only possible fate of the buffer. Surprisingly, little is known about how humans handle high loads of citrate, such as those described in this report. As shown in Figure 1, each ‘turn’ of the tricarboxylic acid (TCA or Krebs cycle) cycle forms 2 moles of bicarbonate and 1 mole of oxaloacetate. Citrate is also converted to oxaloacetate and acetyl-CoA by ATP-citrate lyase. Fatty acid biosynthesis is another metabolic fate of acetyl-CoA produced in the lyase reaction. Oxaloacetate may undergo NADH-dependent reduction to malate by malate dehydrogenase, followed by the formation of NADPH (a fuel for fatty acid formation) by the malic enzyme, the latter producing bicarbonate. Oxaloacetate is also a substrate for gluconeogenesis, which, along with glycolysis, determines pyruvate availability for fueling the TCA cycle. Although not indicated in Figure 1, intracellular transport of citrate between cytosolic and mitochondrial compartments is mediated by the citrate transport protein [19], an electroneutral co-transporter of oxaloacetate (and other dicarboxylic acids) and protonated citrate (reaction: ). Evaluation of the relative contributions of these pathways to citrate utilization during SCUF lies beyond the scope of this report. It is sufficient to say that citrate can lead to bicarbonate formation, directly via the TCA cycle or indirectly through the formation of oxaloacetate. The latter leads back to the TCA cycle or indirectly through gluconeogenesis and glycolysis to generate pyruvate, which is a substrate for pyruvate dehydrogenase (decarboxylating) and pyruvate carboxylase. The portion of the large citrate load that instead serves as a substrate for gluconeogenesis or fatty acid production (Figure 1) remains to be determined in these patients.


Regional citrate anticoagulation for slow continuous ultrafiltration: risk of severe metabolic alkalosis.

Alsabbagh MM, Ejaz AA, Purich DL, Ross EA - Clin Kidney J (2012)

Diagram for citrate metabolism and bicarbonate formation. Shown are key enzymatic reactions catalyzing the formation and degradation of citrate and oxaloacetate, the latter an important metabolite in the TCA (Krebs) cycle, gluconeogenesis as well as the formation of reducing equivalents required for fatty acid biosynthesis. Note that each turn of the TCA cycle generates 2 moles of bicarbonate. The relative flux of oxaloacetate through gluconeogenesis versus the steps catalyzed by MDH and malic enzymes will depend on other metabolic circumstances beyond the scope of this discussion. MDH, malate dehydrogenase; PDH, pyruvate dehydrogenase; acetyl-S-CoA, acetyl-S-coenzyme A.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400517&req=5

fig1: Diagram for citrate metabolism and bicarbonate formation. Shown are key enzymatic reactions catalyzing the formation and degradation of citrate and oxaloacetate, the latter an important metabolite in the TCA (Krebs) cycle, gluconeogenesis as well as the formation of reducing equivalents required for fatty acid biosynthesis. Note that each turn of the TCA cycle generates 2 moles of bicarbonate. The relative flux of oxaloacetate through gluconeogenesis versus the steps catalyzed by MDH and malic enzymes will depend on other metabolic circumstances beyond the scope of this discussion. MDH, malate dehydrogenase; PDH, pyruvate dehydrogenase; acetyl-S-CoA, acetyl-S-coenzyme A.
Mentions: The impact of a net positive citrate balance can be appreciated on the basis of the metabolic fate for this buffer/chelator. While clinical concern has centered on bicarbonate generation from citrate degradation, the citrate pathway is neither straightforward nor the only possible fate of the buffer. Surprisingly, little is known about how humans handle high loads of citrate, such as those described in this report. As shown in Figure 1, each ‘turn’ of the tricarboxylic acid (TCA or Krebs cycle) cycle forms 2 moles of bicarbonate and 1 mole of oxaloacetate. Citrate is also converted to oxaloacetate and acetyl-CoA by ATP-citrate lyase. Fatty acid biosynthesis is another metabolic fate of acetyl-CoA produced in the lyase reaction. Oxaloacetate may undergo NADH-dependent reduction to malate by malate dehydrogenase, followed by the formation of NADPH (a fuel for fatty acid formation) by the malic enzyme, the latter producing bicarbonate. Oxaloacetate is also a substrate for gluconeogenesis, which, along with glycolysis, determines pyruvate availability for fueling the TCA cycle. Although not indicated in Figure 1, intracellular transport of citrate between cytosolic and mitochondrial compartments is mediated by the citrate transport protein [19], an electroneutral co-transporter of oxaloacetate (and other dicarboxylic acids) and protonated citrate (reaction: ). Evaluation of the relative contributions of these pathways to citrate utilization during SCUF lies beyond the scope of this report. It is sufficient to say that citrate can lead to bicarbonate formation, directly via the TCA cycle or indirectly through the formation of oxaloacetate. The latter leads back to the TCA cycle or indirectly through gluconeogenesis and glycolysis to generate pyruvate, which is a substrate for pyruvate dehydrogenase (decarboxylating) and pyruvate carboxylase. The portion of the large citrate load that instead serves as a substrate for gluconeogenesis or fatty acid production (Figure 1) remains to be determined in these patients.

Bottom Line: We report here the acid-base balance calculations quantifying base accumulation in SCUF compared to continuous venovenous hemofiltration (CVVH).This kinetic approach demonstrates the importance of accounting for the high citrate clearance into CVVH hemofiltrate, which prevents development of the alkalosis seen with the relatively low ultrafiltration rates in SCUF: there was net bicarbonate accumulation of ∼1400 mmol/day with SCUF, compared to 664 to as low as 274 mmol/day during CVVH.We also discuss how citrate's acid-base effects are potentially complicated by metabolism via gluconeogenic and ketone body pathways.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Hypertension and Renal Transplantation, University of Florida, Gainesville, FL, USA.

ABSTRACT

Background: Slow continuous ultrafiltration (SCUF) is a safe and efficient treatment for fluid overload in patients who are hemodynamically unstable, have low urine output, and are not in need of dialysis or hemofiltration for solute clearance. Sustained anticoagulation is required for these long treatments, thus posing clinically challenges for patients having contraindications to systemic anticoagulation with heparin. Regional citrate anticoagulation would be an alternative option; however, we believed that this would be problematic due to citrate kinetics that predicted the development of metabolic alkalosis.

Methods: In that patients' serum bicarbonate reached 45 mEq/L and arterial pH rose to 7.59 after just 3 days of SCUF, we developed equations to study this phenomenon. We report here the acid-base balance calculations quantifying base accumulation in SCUF compared to continuous venovenous hemofiltration (CVVH).

Results: This kinetic approach demonstrates the importance of accounting for the high citrate clearance into CVVH hemofiltrate, which prevents development of the alkalosis seen with the relatively low ultrafiltration rates in SCUF: there was net bicarbonate accumulation of ∼1400 mmol/day with SCUF, compared to 664 to as low as 274 mmol/day during CVVH. The calculations underscore the importance of the relative fluid flow rates as well as the bicarbonate and citrate levels in the various infused solutions. We also discuss how citrate's acid-base effects are potentially complicated by metabolism via gluconeogenic and ketone body pathways.

Conclusions: These acid-base balance findings emphasize why clinicians must be mindful of the risk of metabolic alkalosis when using continuous renal replacement therapy modalities with low rates of ultrafiltration, which thereby presents a contraindication for using citrate anticoagulation for SCUF.

No MeSH data available.


Related in: MedlinePlus