Intradialytic acid-base changes and organic anion production during high versus low bicarbonate hemodialysis

Abstract

The use of high dialysate bicarbonate for hemodialysis in end-stage renal disease is associated with increased mortality, but potential physiological mediators are poorly understood. Alkalinization due to high dialysate bicarbonate may stimulate organic acid generation, which could lead to poor outcomes. Using measurements of β-hydroxybutyrate (BHB) and lactate, we quantified organic anion (OA) balance in two single-arm studies comparing high and low bicarbonate prescriptions. In study 1 ( n = 10), patients became alkalemic using 37 meq/L dialysate bicarbonate; in contrast, with the use of 27 meq/L dialysate, net bicarbonate loss occurred and blood bicarbonate decreased. Total OA losses were not higher with 37 meq/L dialysate bicarbonate (50.9 vs. 49.1 meq using 27 meq/L, P = 0.66); serum BHB increased in both treatments similarly ( P = 0.27); and blood lactate was only slightly higher with the use of 37 meq/L dialysate ( P = 0.048), differing by 0.2 meq/L at the end of hemodialysis. In study 2 ( n = 7), patients achieved steady state on two bicarbonate prescriptions: they were significantly more acidemic when dialyzed against a 30 meq/L bicarbonate dialysate compared with 35 meq/L and, as in study 1, became alkalemic when dialyzed against the higher bicarbonate dialysate. OA losses were similar to those in study 1 and again did not differ between treatments (38.9 vs. 43.5 meq, P = 0.42). Finally, free fatty acid levels increased throughout hemodialysis and correlated with the change in serum BHB ( r = 0.81, P < 0.001), implicating upregulation of lipolysis as the mechanism for increased ketone production. In conclusion, lowering dialysate bicarbonate does not meaningfully reduce organic acid generation during hemodialysis or modify organic anion losses into dialysate.

A New Approach to Bicarbonate Addition During Hemodialysis: Testing Model Predictions in a Patient Cohort

“…Answering these questions is beyond the scope of this contribution and will require large-scale clinical studies with patients observed over long periods. Such studies are very difficult to carry out, as witnessed by the fact that studies similar to ours only involve approximately the same number of patients, see e.g., [6]. We are not aware of experiments with larger numbers of patients but we hope that the insights provided by our mathematical model will encourage researchers to find the financial support needed to carry out larger and longer-term studies to answer the questions raised in our paper.…”

“…Lactate loss into the bath as a measure of H + retention due to lactic acid generation during hemodialysis analyzed from pre-and post-dialysis measured blood lactate concentration. The first column gives the number of patients: 10 from[6] and 20 from the present study.No. bath [HCO −3 ] (a) C (0) C (t end ) After Gibbs-Donnan correction this yields C d .…”

Replenishing Alkali During Hemodialysis: Physiology-Based Approaches

“…Although this hypothesis is compatible with the results of the Sargent model analysis, a recent study indicates that it is likely incorrect. In that study, organic acid production accounts for only a small fraction of H + addition and, more to the point, organic acid production is not notably affected by reducing bath [HCO3 -] 15 . A review of older studies, as well as our most recent patient study, also shows that while organic acid production may be a contributing factor, it is unlikely the primary cause of the excessive buffer response 18,19,21 .…”

“…Even without adjusting bath [HCO3 -] upward, current dialysis prescriptions expose many patients to a bath [HCO3 -] 10-15 mmol/L higher than the blood [HCO3 -] at the onset of treatment 11,12 . This gradient results in rapid initial bicarbonate influx, causing an abrupt rise in blood [HCO3 -] J o u r n a l P r e -p r o o f 5 and pH, followed by a leveling off for the remainder of the treatment (Figure 2, upper curve) 8,11,[13][14][15] . Because fluid removal occurs during most treatments, reducing extracellular fluid (ECF) volume, this pattern means that ECF bicarbonate content actually falls from its peak value during the latter half of treatment (Figure 3, upper curve) 8 .…”

“…Two additional studies have analyzed the acid-base events during hemodialysis 15,20 , and have reported a much lower rate of bicarbonate influx because they isolated the bicarbonate generated from carbon dioxide influx and reaction with hemoglobin and "corrected" for it. Their "correction" assumes that the bicarbonate generated from this reaction remains in the red cell and is stoichiometrically back-titrated as the blood returning from the dialyzer equilibrates with systemic PCO2.…”