Quantitative Evaluation of D-Lactate Pathophysiology: New Insights into the Mechanisms Involved and the Many Areas in Need of Further Investigation

Figures & data

Figure 1 Schematic representations of human and anaerobic bacterial metabolism of L- and D-lactate.

Notes: 1, bacterial D-LDH catalyzes a reversible reaction between pyruvate and D-lactate (allowing for D-lactate production from pyruvate) while in humans this reaction irreversibly converts D-lactate to pyruvate; 2, the anaerobic bacteria cannot dispose of pyruvate via oxidative reactions, hence all pyruvate produced from glycolysis is converted to lactate or other organic acids such as acetate and butyrate.

Table 1 D-Lactate Urinary Excretion (= Clearance) in D-Lactate Acidosis Patients. Renal Clearance Estimated Assuming Either a Urine Output of 1 ml/min or a Normal Plasma Creatinine (88 micromole/L) and Creatinine Clearance (100 ml/min)

Reference	Plasma D-Lactate (mM)	Renal Clearance (mL/min)	Assumptions
Bongaerts^Citation15	0.5	30	[Creat]p = 88 μM; (Creat)clr =100 mL/min
	2	27
Narula^Citation16	11	3.5	Urine output = 1 mL/min
Uribarri^Citation8	3.1	17	Urine output = 1 mL/min
	5.0	10.2
	5.7	35
	6	3.65
	7.6	5.08
	8.5	7.05
	13.2	3.25
	20	7.45
	20	3.65

Table 2 Normal Human D-Lactate Clearance Measurements

Reference	Method	Plasma Conc (mM)	Clearance (mL/min/70 kg)	Vol. Dist (L)
Kuze^Citation54	Const Inf	0.115	710
Kuze^Citation17	Const Inf	0.355	690
Oh^Citation10	Const Inf	2.52	500
		5.24	430
Connor^Citation18	20 min inf	0–2.4	690	23.4

Figure 2 Comparison of the plasma D-lactate experimental data (solid circles) of Connor et al following a 20 minute, 105 millimolar constant IV infusion versus the PBPK model prediction (line) assuming a whole body clearance of 607 mL/min and Km of 5 mM.

Figure 3 Plot of the PBPK model prediction of the plasma D-lactate concentration following 3 consecutive inputs of 500 millimoles of D-lactate with the time course described by eq. 3(3) , each separated by 5 hours. It is assumed that the whole body clearance has the normal value of 607 mL/min. Top panel: input (see eq. 3(3) ): T_T = 30 and T_A = 40 minutes. Bottom panel: input T_T = 30 and T_A = 120 minutes.

Figure 4 Left panel: De Vrese and Barth⁴⁰ experimental plasma D-lactate concentration following ingestion of 74 mmole of D-lactate as yoghurt (solid circles) versus the PBPK model prediction (solid line) for the normal whole body clearance of 607 mL/min. Right panel: The intestinal absorption rate used to generate the PBPK model plasma concentration (total absorption of 38.2 millimoles D-lactate, with absorption rate described by eq. 3(3) : T_T= 21.6 and T_A = 116 minutes).

Figure 5 Schematic representation of the various processes that could influence the plasma D-lactate concentration. The direction of the solid arrows indicates whether an increase in the process potentially increases (up arrow) or decreases (down arrow) plasma D-lactate. For example, an increase in carbohydrate (CHO) ingestion would provide an increased substrate for intestinal bacteria and increase D-lactate production; while an increased CHO intestinal absorption rate would decrease the substrate for the intestinal bacteria and therefore, potentially, decrease plasma D-lactate.

Figure 6 Plot of the PBPK model prediction of the plasma D-lactate concentration following 3 consecutive inputs of 1000 millimoles of D-lactate with the time course described by eq. 3(3) , each separated by 5 hours. It is assumed that the whole body clearance has the normal value of 607 mL/min. Top panel: input (see eq. 3(3) ): T_T = 30 and T_A = 40 minutes. Bottom panel: input T_T = 30 and T_A = 120 minutes.

Figure 7 Plot of the PBPK model prediction of the plasma D-lactate concentration following 3 consecutive inputs of 500 millimoles of D-lactate with the time course shown in Figure 3, each separated by 5 hours. It is assumed that the whole body clearance is 309 mL/min, half the normal value. Top panel: input (see eq. 3(3) ): T_T = 30 and T_A = 40 minutes. Bottom panel: input T_T = 30 and T_A = 120 minutes.

Bongaerts G, Tolboom J, Naber T, Bakkeren J, Severijnen R, Willems H. D-lactic acidemia and aciduria in pediatric and adult patients with short bowel syndrome. Clin Chem. 1995;41(1):107–110. doi:10.1093/clinchem/41.1.107

 PubMed Web of Science ®Google Scholar

Narula RK, El Shafei A, Ramaiah D, Schmitz PG. D-lactic acidosis 23 years after jejuno-ileal bypass. Am J Kidney Dis. 2000;36(2):E9. doi:10.1053/ajkd.2000.9005

 PubMed Web of Science ®Google Scholar

Uribarri J, Oh MS, Carroll HJ. D-lactic acidosis: a review of clinical presentation, biochemical features, and pathophysiologic mechanisms. Medicine. 1998;77(2):73–82. doi:10.1097/00005792-199803000-00001

 PubMed Web of Science ®Google Scholar

Kuze S, Naruse T, Ito Y, Nakamaru K. Comparative study of intravenous administration of Ringer’s lactate, Ringer’s acetate and 5% glucose containing these Ringer’s solutions in human being. J Anesth. 1990;4(2):155–161. doi:10.1007/s0054000040155

 Google Scholar

Kuze S, Naruse T, Yamazaki M, Hirota K, Ito Y, Miyahara T. Effects of sodium L-lactate and sodium racemic lactate on intraoperative acid-base status. Anesth Analg. 1992;75(5):702–707. doi:10.1213/00000539-199211000-00008

 Web of Science ®Google Scholar

Oh MS, Uribarri J, Alveranga D, Lazar I, Bazilinski N, Carroll HJ. Metabolic utilization and renal handling of D-lactate in men. Metabolism. 1985;34(7):621–625. doi:10.1016/0026-0495(85)90088-5

 Web of Science ®Google Scholar

Connor H, Woods HF, Ledingham JG. Comparison of the kinetics and utilisation of D(-)-and L(+)-sodium lactate in normal man. Ann Nutr Metab. 1983;27(6):481–487. doi:10.1159/000176723

 PubMed Web of Science ®Google Scholar

de Vrese M, Barth CA. Postprandial plasma D-lactate concentrations after yogurt ingestion. Z Ernahrungswiss. 1991;30(2):131–137. doi:10.1007/BF01610068

 PubMedGoogle Scholar