Citrate Anticoagulation for Continuous Kidney Replacement Therapy: An Embarrassment of RICH-es

Commentary on Zarbock A, Kullmar M, Kindgen-Milles D, et al. Effect of regional citrate anticoagulation vs systemic heparin during continuous kidney replacement therapy dialysis filter life span and mortality among critically ill patients with acute injury: A randomized clinical trial. JAMA. 2020;324:1629-1639. The first descriptions (RCA) to maintain circuit patency in (CKRT) were reported 30 years ago.1Mehta R.L. McDonald B.R. Aguilar M.M. Ward D.M. Regional for arteriovenous hemodialysis patients.Kidney Int. 1990; 38: 976-981Abstract Full Text PDF PubMed Scopus (281) Google Scholar More recently, the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) injury (AKI) guideline advocated as first-line CKRT.2Kidney Outcomes (KDIGO) Acute Kidney Injury WorkgroupKDIGO practice injury.Kidney 2012; 2: 1-138Google Despite this, there has been relatively modest uptake anticoagulation, continues be most commonly used anticoagulant CKRT.3Uchino S. Bellomo R. Morimatsu H. al.Continuous renal therapy: a worldwide survey. beginning ending supportive (B.E.S.T. kidney) investigators.Intensive Care Med. 2007; 33: 1563-1570Crossref (427) Potential explanations slow adoption RCA include perceived complexity need monitoring; variability published approaches lack uniform protocol; limited evidence basis. al4Zarbock A. M. D. al.Effect trial.JAMA. 2020; 324: 1629-1639Crossref (86) recently addressed this last limitation by conducting largest controlled trial date comparing CKRT. Citrate Versus Systemic Heparin Anticoagulation CKRT Critically Ill Patients With AKI (RICH) study was randomized, unblinded, that enrolled 596 across 26 medical centers.4Zarbock found one co–primary end points, lifespan, significantly greater compared group (median 47 hours; difference 15 [95% CI, 11-20] P < 0.001). second primary point 90-day all-cause slightly lower (51.2% 53.6%); did not reach statistical significance (adjusted hazard ratio, 0.79 0.63-1.004]; = 0.054), but stopped prematurely thus underpowered outcome. also had fewer major bleeding complications (5.1% 16.9%; 0.001), although transfusion rates similar. RICH therefore both better efficacy safety outcomes Several additional aspects are worth exploring. notable unexpected secondary finding more new infections versus groups (68.0% 55.4%; 0.002). This adverse outcome previous studies, underlying etiology is unclear. investigators postulate it could related an increased risk contamination owing sampling required and/or reduced integrity extended lifespan. It pointing out nearly 40 points evaluated, so potential may chance finding. Nonetheless, clinicians should aware complication future studies measure. Relatively few events groups, exception hypophosphatemia, which occurred frequently (15.4% 6.2%). Essentially, all treated phosphate-free fluids delivered effluent dose 25 mL/kg/h (as achieved study) will become hypophosphatemic within 1-3 days start without phosphate supplementation.5Heung Mueller B.A. Prevention hypophosphatemia therapy-an overlooked problem.Semin Dial. 2018; 31: 213-218Crossref (16) Some predilution phosphate-free, unclear whether use disproportionate between arms, based commercial availability period. As authors discuss, incidence have worsened group, including prolonged respiratory failure even mortality.6Reintam Blaser Gunst J. Ichai C. al.Hypophosphatemia adults children - systematic review.Clin Nutr. 2021; 40: 1744-1754Abstract (21) can easily avoided,5Heung focused efforts at prevention care studies. intervention performed according protocol target postfilter ionized calcium concentration 0.25-0.35 mmol/L, while control activated partial thromboplastin time 45-60 seconds. conducted Germany, predominantly using systems integrated delivery solutions designed (Fresenius Multifiltrate Ci-Ca 22 centers). Of note, system currently unavailable United States except under Expanded Use Authorization (which far included option) COVID-19 pandemic. While impact machine technology unclear, clinician experience protocols highly relevant. how many participating centers pre-existing (nor extent experience). results adjusted center, interaction sites protocol. application findings decision embrace further impacted study’s inclusion exclusion criteria. One common reasons coagulopathy or hemorrhagic diathesis. In real-world settings, however, these exactly who benefit from RCA; their might ability demonstrate reduction. Conversely, 10% screened population excluded persistent severe lactic acidosis, presumably limit toxicity. metabolic observed higher if broadly applied settings. strategies However, other trials anticoagulation. These varied design, protocol, assessed (Table 1). Most contraindications citrate, such liver failure, bleeding, heparin-induced thrombocytopenia. number studied small only 2 200 participants. heterogeneity limits direct comparisons.Table 1Comparison Randomized Clinical TrialsStudyNCKRT ModalityCitrateHeparinOutcomesMonchi al17Monchi Berghmans Ledoux Canivet J.L. Dubois B. Damas P. vs. venovenous hemofiltration: prospective study.Intensive 2004; 30: 260-265Crossref (277) (2004)20 patients; 1 centerPost-CVVH; blood flow 175 mL/minTrisodium iCa 0.3 mmol/LSystemic heparin, bolus 2000-5000 IU, aPTT maintained 60-80 sBetter median (70 h; 0.0007); less RCAKutsogiannis al18Kutsogiannis D.J. Gibney R.T.N. Stollery Gao 2005; 67: 2361-2367Abstract (227) (2005)30 centersPredilution CVVHDF; 125 50 IU/kg, 45-65 (124.5 38.3 0.001); (RR, 0.14 0.02-0.96]; 0.05)Betjes al19Betjes M.G. van Oosterom Agteren de Wetering hemofiltration low bleeding: similar hemofilter survival bleeding.J Nephrol. 20: 602-608PubMed (2007)48 150 mL/minCitrate formulation unspecified, 3000-5000 50-70 sSimilar life; (0 10 events, 0.01); (0.43 0.88 U/d, 0.01)Fealy al20Fealy N. Baldwin I. Johnstone Egi pilot crossover heparinization hemofiltration.Int J Artif Organs. 301-307Crossref (56) (2007)10 (crossover); centerPre-CVVH; mL/minCommercial citrate-buffered fluid (citrate 14 mmol/L) 2000 mL/hRegional (1500 IU/h) protamine post-filter (15 mg/h)Similar (17 13 h, 0.77); (none either group)Oudemans-van Straaten al11Oudemans-van H.M. Bosman R.J. Koopmans al.Citrate hemofiltration.Crit 2009; 37: 545-552Crossref (251) (2009)200 220 mL/minIn-house preparation (500 mL bags 500 mmol/L 1352 sodium, 148 hydrogen); 3 (no titration)Systemic nadoparin, 2850 IU/h 3800 weight > 100 kg; maintenance 380- 456 IU/hLower 90-d (45% 63%, 0.02); (27 0.68); (6 16 patients, 0.08); (0.27 0.36 0.31)Hetzel al21Hetzel G.R. Schmitz Wissing al.Regional haemofiltration: multicentre trial.Nephrol Dial Transplant. 2011; 26: 232-239Crossref (166) (2011)174 9 centersPre-CVVH; 120-200 mL/minCitrate-based CVVH solution, 4 targets specifiedNo 30-d diff (47% 41%, 0.67); longer mean (37.5 26.1 (5.7% 14.5%)Tiranathanagul al22Tiranathanagul K. Jearnsujitwimol O. Susantitaphong reduces polymorphonuclear cell degranulation hemofiltration.Ther Apher 15: 556-564Crossref (47) (2011)20 120 solution 13.6 1300 mL/hSystemic 1000 IU infusion keep value 1.5×No (41% 47%, ± 23 19 0.001)Schilder al23Schilder L. Nurmohamed S.A. Bosch F.H. heparinisation multi-center trial.Crit Care. 2014; 18: 472Crossref (120) (2014)169 4000 mL/h sNo (42% 42%, 1.0); (46 32 episodes (5 10, 0.08)Brain al24Brain M.J. Roodenburg O.S. Adams al.Randomised software algorithm driven Filter Life Renal Replacement Therapy Resusc. 16: 131-137PubMed (2014)30 centerPre- postdilution (prismocitrate 18 predilution); arterial iCaSystemic 5000 difference; life: ITT (34 30.7 0.58); PP (42 24 0.004)Stucker al25Stucker F. Ponte Tataw al.Efficacy citrate-based requiring 2015; 19: 91Crossref (84) (2015)103 100-200 mmol/L); 0.25-0.30 prescribed condition (minimal UI/h required)No diff; (49 28 0.004); (0/54 4/49, no value)Gattas al26Gattas Rajbhandari Bradford Buhr Lo adults.Crit 43: 1622-1629Crossref (115) (2015)212 7 CVVHDF, CVVH; doses 2.5-3.3 flowRegional 1500 IU/h, mg/h)No hospital (29% 31%, 0.7); (39 0.0037); (908 872 RBC, 0.83)Abbreviations: aPTT, time; CKRT, therapy; CVVH, hemofiltration; hemodiafiltration; diff, iCa, calcium; ITT, intention-to-treat; PP, per RCA, anticoagulation; red cell; RR, relative risk. Open table tab Abbreviations: meta-analyses previously All concluded agree improved lifespan heparin. Meta-analyses Zhang Hongying7Zhang Z. Hongying Efficacy undergoing therapy.Intensive 20-28Crossref (119) trials) Bai al8Bai Zhou He updated meta-analysis RCTs.Intensive 41: 2098-2110Crossref (135) (11 prolongs lifespan; conversely, Wu al9Wu M.Y. Hsu Y.H. C.H. Lin Y.F. Tam K.W. trials.Am Dis. 59: 810-818Abstract (147) find life, Liu al10Liu Mao Kang Hu patients: sequential analysis trials.Crit 2016; 144Crossref (14 demonstrated hemofiltration. confirms associated adds conclusion over None showed perhaps surprising any benefit. To date, report Oudemans-van al.11Oudemans-van They nadroparin (48% 0.03), persisted subgroups sepsis, post surgery, Sequential Organ Failure Assessment (SOFA) score 11 age 73 years.11Oudemans-van mechanisms suggested inhibition platelet oxidative stress. replicated convincing largely seen win-win favor CKRT: (filter lifespan) harm (lower complications) meeting confirmatory than novel, rigorously provides strongest date. Centers already employing undoubtedly hail affirmation practices. Furthermore, encourage practices/centers consider adopting appropriate patients. Nephrologists considering implementing CKRT-RCA ask several key questions. First, protocol? volume (eg, <200 patient treatment year), introduction complicated feasible. There must enough exposure allow proper training initial period, well ensure ongoing staff competency. Second, adopted? Table 1, variety formulations choose from, yet comparisons protocols. Further complicating matters US Food Drug Administration approved States. conceptually approach, well-established, extensive RCA.12Swartz Pasko O'Toole Starmann anticoagulation.Clin 61: 134-143Crossref (77) Scholar, 13Tolwani A.J. Prendergast M.B. Speer R.R. Stofan B.S. Wille K.M. practical hemodiafiltration high solute clearance.Clin Am Soc 2006; 1: 79-87Crossref (91) 14Morabito Pistolesi V. Tritapepe Fiaccadori E. RRTs AKI.Clin 9: 2173-2188Crossref (100) our opinion, specific itself important ensuring buy-in Engagement stakeholder (nephrologists, intensivists, nursing, pharmacy, administration) critical successful implementation sustainability. Third, in? (and guideline) recommend against shock, concerns toxicity failed metabolism bicarbonate. recent safely disease close monitoring.15Zhang W. Yu Y. al.Safety review meta-analysis.Crit 2019; 23: 22Crossref (48) At we universally manage increasing clearance shock.16Szamosfalvi Puri Sohaney presumed absent metabolism.Kidney360. 192-204Crossref cirrhosis reasonable try avoid population. conclusion, represents build upon prior suggesting superiority support guideline’s suggestion Balazs Szamosfalvi, MD, Lenar T. Yessayan, Michael Heung, MD. None. declare they relevant financial interests. Received December 7, 2020 response invitation journal. Direct editorial input Associate Editor Deputy Editor. Accepted revised form January 4, 2021.