Dialysate made from dry chemicals using citric acid increases dialysis dose

doi:10.1016/S0272-6386(00)70203-4

American Journal of Kidney Diseases

Volume 35, Issue 3, March 2000, Pages 493-499

https://doi.org/10.1016/S0272-6386(00)70203-4 Get rights and content

Abstract

A new dry dialysate concentrate acidified with citric acid (citrate dialysate) has been used in two separate clinical studies of hemodialysis patients. The first compared a single treatment using this dialysate, with one dialysis using regular standard dialysate acidified with acetic acid (regular dialysate) in a prospective, randomized, crossover study of 74 dialyses. Changes in blood levels of electrolytes and other blood constituents during dialysis were calculated by subtracting postdialysis from predialysis blood concentrations. Compared with acetic acid dialysate, citrate dialysate was associated with significantly greater decreases in total and ionized calcium, magnesium, and chloride levels. Citrate dialysate was also associated with greater increases in serum sodium and citrate concentrations, although their postdialysis concentrations remained within or just outside normal ranges. Changes in other blood constituents were similar with both dialysates. The second study used citrate dialysate exclusively for all dialyses over a 12-week period in 25 patients. Predialysis blood samples were drawn at the start of the study and at 4-week intervals thereafter, and postdialysis blood samples were obtained after the first and last dialysis. Repeated-measure analysis showed that although predialysis blood concentrations of magnesium, potassium, and citrate remained within the normal range, there was a significant declining trend over the course of the study. At the same time, predialysis serum bicarbonate levels increased, and significantly more patients had a predialysis bicarbonate concentration within the normal range at the end of the study than at the start (15 versus 8 patients; P = 0.001, chi-square). In 19 patients (excluding 3 patients for whom the type of dialyzer was changed during the study), the dose of dialysis for the first and last dialysis was calculated by urea reduction ratio and Kt/V. There was a significant increase in both measurements without changes in dialysis time, blood and dialysate flows, or dialyzer used. The urea reduction ratio increased from 68% ± 5.9% to 73% ± 5.3% (P < 0.03), and the Kt/V from 1.23 ± 0.19 to 1.34 ± 0.20 (P = 0.01) from the first to last dialysis, respectively. In conclusion, this citric acid dialysate was well tolerated, and intradialytic changes in blood chemistries were similar to those seen with regular dialysate. Using dialysate containing citric instead of acetic acid increases the delivered dialysis dose.

Section snippets

Patients and methods

An institutional review board approved both studies, and informed consent was obtained from all patients before participation. The citrate A concentrate was prepared from a dry chemical blend (DRYalysate) by mixing it with treated water (Association for the Advancement of Medical Instrumentation [AAMI] quality) to yield a 45-times concentrated solution. The citrate concentrate solution was delivered through the A concentrate input line of Fresenius model D, E, and H (Fresenius USA Inc, Walnut

Crossover study

All the dialyses with citrate dialysate were uneventful, and no unusual events occurred. Results of the blood analyses are listed in Table 2.Changes in the concentration of various constituents were calculated by subtracting the postdialysis concentration from the predialysis concentration. The changes with citrate dialysate were compared with those with acetic acid dialysate. Of 16 serum constituents measured, the intradialytic changes in 7 differed significantly with citric acid compared with

Disussion

The new dialysate containing citric acid was well tolerated, and no untoward effects were seen during either study. No bleeding was noted during or after dialysis with the new citrate dialysate in any patients. The amount of citrate derived from citric acid was 2.4 mEq/L, which is less than the 4 mEq/L of acetate typically derived from acetic acid with current dialysate. The blood citrate level was slightly greater than the upper limit of normal during and immediately after dialysis, decreasing

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Regional Citrate Anticoagulation: A Tale of More Than Two Stories
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Calcium is a key clotting factor, and several inorganic molecules that bind to calcium have been found to reduce the clotting propensity of blood. Citrate, a calcium chelator, is used as inhibitor of the coagulation cascade in blood transfusion. Also, it is used as an anaticoagulant during dialysis to maintain patency of the extracorporeal circuit, known as regional citrate anticoagulation (RCA). The amount of citrate should be chosen such that ionized calcium concentrations in the extracorporeal circuit are reduced enough to minimize propagation of the coagulation cascade. The dialytic removal of the calcium–citrate complexes combined with reduced ionized calcium concentrations makes necessary calcium supplementation of the blood returning to the patient. This can be achieved in different ways. In classical RCA, citrate and calcium are infused in the afferent and efferent tubing, respectively, whereas the dialysate does not contain calcium. This setup has been shown to be highly efficacious with a very low clotting propensity. Strict monitoring of blood electrolytes is required. Alternatively, the use of a high-calcium dialysate leads to calcium loading, obviating the need for a separate calcium infusion pump. The main advantages are simplified delivery of RCA and less fluctuation of systemic calcium concentrations. Currently, citric acid is sometimes added to the acid concentrate as a replacement for acetic acid. Differences and similarities between RCA and citrate-containing dialysate are discussed. RCA is an excellent alternative to heparin for patients at high risk of bleeding.
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Advantages of the use of citrate over acetate as a stabilizer in hemodialysis fluid: A randomized ABC-treat study
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La hemodiálisis (HD) con líquido de diálisis (LD) con bicarbonato requiere la presencia de un ácido para prevenir la precipitación del carbonato de calcio y magnesio. El más usado es el ácido acético, y con él se han descrito diversas complicaciones. En un trabajo previo describimos los cambios agudos, durante una sesión, en los pacientes en HD con un LD con citrato en lugar de acetato, y en este referimos los resultados a medio plazo: 16 semanas.
Es un estudio prospectivo, multicéntrico, cruzado y aleatorizado, donde 56 pacientes en HD con bicarbonato 3 veces a la semana se dializaron 16 semanas con 3 mmol/l acetato y 16 semanas con 1 mmol/l de citrato. Se incluyeron pacientes mayores de 18 años con una estancia en HD previa superior a 3 meses y con fístula arteriovenosa normofuncionante. Se recogieron mensualmente datos epidemiológicos, de diálisis, bioimpedancia, bioquímica pre y postHD, así como los episodios de hipotensión.
Después de 16 semanas de tratamiento con citrato el calcio iónico y el magnesio preHD eran significativamente inferiores y la hormona paratiroidea (PTH) más alta que en el periodo con acetato. No se observaron diferencias en la eficacia de la diálisis. Los episodios de hipotensión fueron significativamente más frecuentes con acetato que con citrato: 311 (14,1%) vs. 238 (10,8%) sesiones. El índice de masa magra se incrementó en 0,96 ± 2,33 kg/m² cuando los pacientes pasaron de LD con acetato a citrato.
La HD con citrato modifica varios parámetros del metabolismo óseo-mineral, no solo de forma aguda como se había descrito, sino también a medio plazo. La sustitución del acetato por el citrato mejora la estabilidad hemodinámica, produciendo menos hipotensiones y puede mejorar el estado nutricional.
ClinicalTrials.gov NCT03319680.
Hemodialysis (HD) with bicarbonate dialysis fluid (DF) requires the presence of an acid to prevent the precipitation of calcium and magnesium carbonate. The most used acid is acetic acid, with it several complications have been described. In a previous work, we described the acute changes during an HD session with a DF with citrate instead of acetate. Now, we report the results in the medium term, 16 weeks. It is a prospective, multicenter, crossover and randomized study, where 56 HD patients with bicarbonate three times a week were dialysed for 16 weeks with 3 mmol/L acetate and 16 weeks with 1 mmol/L citrate. Patients older than 18 years with a previous stay on HD of more than 3 months and with a normal functioning arteriovenous fistula were included. Epidemiological data, dialysis, bioimpedance, biochemistry before and after HD, as well as hypotensive episodes, were collected monthly. After 16 weeks of citrate treatment, pre-HD ionic calcium and magnesium were significantly lower and paratiroid hormone (PTH) higher than in the acetate period. No differences were observed in the effectiveness of dialysis. Hypotensive episodes were significantly more frequent with acetate than with citrate: 311 (14.1%) vs 238 (10.8%) sessions. The lean mass index increased by 0.96 ± 2.33 kg/m² when patients switched from DF with acetate to citrate.
HD with citrate modifies several parameters of bone mineral metabolism, not only acutely as previously described, but also in the long-term. The substitution of acetate for citrate improves hemodynamic stability, producing less hypotension and can improve nutritional status.
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L’ajout d’acide acétique à faible concentration (3–7 mmol/L) permet d’acidifier le dialysat et prévient ainsi la précipitation du bicarbonate avec les cations divalents. L’acide acétique n’est néanmoins pas dénué d’effets indésirables. D’autres acides, l’acide chlorhydrique et plus récemment l’acide citrique, ont été proposés pour s’en affranchir totalement. L’acide chlorhydrique permet théoriquement de s’affranchir des complications métaboliques engendrées par l’acétate. Cependant, sa forte acidité engendre des contraintes de fabrication, de conditionnements et d’utilisation. Le surcoût engendré par ces contraintes techniques et l’arrivée sur le marché des dialysats au bicarbonate acidifiés à l’acide citrique ont probablement freiné la généralisation des dialysats à l’acide chlorhydrique. Les intérêts potentiels de l’acide citrique sont multiples : la dialyse sans héparine, l’amélioration de la perméabilité de la membrane grâce à l’action anticoagulante de l’acide citrique, l’amélioration de la biocompatibilité, une meilleure stabilité hémodynamique en séance, le contrôle de l’acidose. Les résultats des études sont néanmoins contradictoires et de nombreuses questions, notamment quant à son impact sur le métabolisme phosphocalcique et acidobasique, restent ouvertes. À la lumière des données actuelles, il ne semble pas raisonnable de proposer le remplacement systématique de l’acide acétique par l’acide citrique.
The mix of bicarbonate and divalent cations requires a small amount of acid to avoid insoluble precipitation in the dialysate buffer. Small doses of acetic acid (3–7 mmol/L) are commonly used. Acetic acid may be replaced by hydrochloric acid or citric acid to achieve acetate-free haemodialysis. Hydrochloric acid theoretically avoids metabolic side effects of acetate. However, additional cost generated by technical constraints probably slowed its generalization. Citric acid has been proposed as a more biocompatible acidifier than acetic acid. By binding calcium, citric acid inhibits both coagulation and complement activation and may reduce the treatment-induced inflammatory response. However, results of the study are conflicting, especially regarding impact on calcium and phosphate metabolism and acid-base metabolism. On the basis of current findings, systematic replacement of acetic acid by citric acid cannot be proposed for all the patients.
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Citation Excerpt :
Because citric acid is a naturally-occurring biochemical and generally regarded as safe, it is subject to fewer restrictions than synthetic additives in commercial products. In biological systems, citric acid facilitates calcium transport [6], which is important for calcium bioavailability [7], bone metabolism [8] and dialysis [9]. Fick equations give a concise and convenient description of mutual diffusion in terms of the fluxes of the total citric acid(1) and total calcium citrate(2) solution components.
Taylor dispersion is used to measure ternary mutual diffusion in aqueous citric acid(1) + calcium citrate(2) solutions at 25 °C. Main diffusion coefficients D₁₁ and D₂₂ reach values 25% to 60% larger than the respective binary diffusion coefficients of aqueous citric acid and calcium citrate. Of additional interest, cross-coefficient D₁₂ is large and negative, indicating that each mole of diffusing calcium citrate counter-transports up to two moles of citric acid. Nernst-Planck (NP) equations are used to relate the fluxes of the citric acid and calcium citrate components to the fluxes of the solution species: molecular citric acid (H₃Cit) and its dissociation products (H⁺, H₂Cit⁻, HCit²⁻ and Cit³⁻ ions), Ca²⁺ ions, and calcium complexes produced by ion association (CaCit⁻, CaHCit, CaH₂Cit⁺). The NP analysis identifies key roles in the coupled diffusion of citric acid and calcium citrate played by ion association and by ion migration in the electric field generated by hydrogen-ion concentration gradients.
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: Address reprint requests to Suhail Ahmad, MD, Scribner Kidney Center, 2150 N 107th St, Suite 160, Seattle, WA 98133. E-mail: [email protected]

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Original InvestigationsDialysate made from dry chemicals using citric acid increases dialysis dose

Abstract

Section snippets

Patients and methods

Crossover study

Disussion

Am J Kidney Dis

Second-generation logarithmic estimates of single-pool variable-volume Kt/V: An analysis of error

J Am Soc Nephrol

Citrate anticoagulation and divalent cations in hemodialysis

Blood Purif

Correction of acidosis in humans with CRF decreases protein degradation and amino acid oxidation

Am J Physiol

Potential effect of metabolic acidosis on beta2-microglobulin generation: In vivo and in vitro studies

J Am Soc Nephrol

Original Investigations
Dialysate made from dry chemicals using citric acid increases dialysis dose