Anticoagulation-related complications and their outcomes in hemodialysis patients with acute kidney injury at selected hospitals in Ethiopia

1 Anticoagulation-related complications and their outcomes in 2 hemodialysis patients with acute kidney injury at selected 3 hospitals in Ethiopia. 4 Hanan Muzeyin Kedir ([email protected]) 1*, Abdella Birhan Yabeyu 5 ([email protected])2, Addisu Melkie Ejigu ([email protected])3, Tamrat 6 Assefa Tadesse ([email protected]) 1, Eskinder Ayalew Sisay 7 ([email protected])1 8 1Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, Collage of Health 9 Sciences, Addis Ababa University, Addis Ababa, Ethiopia. 10 2Department of Pharmacy, College of Medicine and Health Sciences, Ambo University, Ambo, 11 Ethiopia. 12 3Department of Internal Medicine, Addis Ababa University, Addis Ababa, Ethiopia 13 *Correspondence Author 14 Hanan Muzeyin Kedir 15 [email protected] 16 Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, Collage of Health 17 Sciences, Addis Ababa University, Addis Ababa, Ethiopia. 18 Telephone: +251912275828 19 These authors contributed equally to this work. 20 . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 2 21 Abstract 22 Introduction: During hemodialysis (HD), the presence of clots in the dialyzer can diminish 23 the effective surface area of the device. In severe cases, clot formation in the circuit can halt 24 treatment and lead to blood loss in the system. Thus, ensuring proper anticoagulation during 25 HD is crucial to prevent clotting in the circuit while safeguarding the patient from bleeding 26 risks. This study aimed to evaluate anticoagulation outcomes and related factors in HD patients 27 with acute kidney injury (AKI) at selected hospitals in Ethiopia. 28 Method: A prospective, multicenter observational study was carried out between October 1, 29 2021, and March 31, 2022. The study encompassed all AKI patients undergoing HD at least 30 once during the study period. Descriptive statistics were utilized to summarize the data, and 31 multinomial logistic regression analysis was employed to identify factors associated to clotting 32 and bleeding. 33 Results: Data were gathered from 1010 HD procedures conducted on 175 patients. 34 Extracorporeal circuit clotting was detected in 34 patients during 39 (3.9%) dialysis sessions, 35 while bleeding incidents occurred in 27 patients across 29 (2.9%) sessions. A statistically 36 significant association was found between both the total number of HD treatments and blood 37 flow rate with incidents of clotting. Factors such as length of hospitalization, serum creatinine 38 levels at admission, signs and symptoms associated with uremia, along with utilization of 39 anticoagulants or antiplatelet medications demonstrated an association with bleeding events. 40 Conclusion: Clotting affected 19.4% of participants, while bleeding occurred in 15.4%, 41 underscoring the importance of close monitoring. The frequency of HD sessions and blood 42 flow rate are correlated with clotting, while hospitalization duration, serum creatinine levels, 43 uremic symptoms, and anticoagulant use are associated with bleeding events. . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 3 44 Keywords: Acute kidney injury, Anticoagulation, Hemodialysis, Ethiopia 45 46 Introduction 47 Hemodialysis (HD) constitutes a medical procedure that facilitates the removal of waste 48 products from the bloodstream externally via a device outfitted with specialized filtration 49 systems. The predominant cause for arteriovenous access failure is attributed to thrombosis, 50 representing 80%-85% of cases (1,2). Within the HD protocol, components such as the dialyzer 51 and other elements of the extracorporeal blood circuit are also vulnerable to thrombotic events. 52 This includes tubing, arterial and venous bubble traps in addition to needles or catheters utilized 53 for vascular access—all factors contributing to coagulation phenomena (3,4). Notably, arterial 54 and venous bubble traps exhibit a heightened susceptibility towards clotting owing to 55 diminished blood flow rates leading potentially to stasis and hence clot formation. Such 56 premature cessation of HD sessions precipitates inadequate dialysis alongside possible 57 hematologic losses. Furthermore clots within this circuitry can herald significant negative 58 repercussions including reduction in solute clearance during therapy amplified costs, and 59 increased operational burden (5-7). 60 Maintaining an optimal balance between insufficient and excessive heparinization is essential 61 for achieving proper anticoagulation during HD in order to avert bleeding and clot formation 62 within the extracorporeal circuit, respectively (6, 8). It is imperative to administer the minimal 63 efficacious dose of anticoagulant to ensure that the dialyzer and venous chamber remain clear 64 of blood cell fragments while also facilitating rapid hemostasis at the vascular access site 65 following treatment (5). Although anticoagulant dosing varies among individuals due to patient- 66 specific factors and HD-related variables, it is generally lower than doses required for full . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 4 67 anticoagulation. Inadequate levels of anticoagulation may reduce dialysis’s effectiveness in 68 eliminating waste products from the bloodstream (4-6). 69 Unfractionated heparin (UFH) is extensively utilized as an anticoagulant during HD owing to 70 its long-standing history in clinical practice and a desirable safety profile characterized by a 71 brief half-life (8,9). The European guidelines for optimal HD practices suggest an initial bolus 72 of 50 IU/kg UFH administered via the arterial access needle, followed by a continuous infusion 73 maintenance dosage ranging from 500 to 1500 IU of UFH per hour. It's recommended that the 74 use of UFH be minimized, especially since patients with acute kidney injury AKI often have 75 compromised health and may require daily dialysis treatments. In instances of clotting or 76 bleeding, modifications in dosage or the implementation of heparin-free dialysis methods might 77 become necessary. Although alternative anticoagulation techniques targeting the extracorporeal 78 circuit exist, their adoption has been limited due to their complex nature and higher requisites 79 for administration time and workforce involvement for monitoring purposes (10-12). 80 Critically ill patients often display impaired coagulation and low platelet counts, which 81 significantly increases their risk of bleeding when systemic anticoagulants are used. As such, it 82 is advised that these individuals avoid any treatments that further heighten this risk, especially 83 those involving systemic anticoagulants (6,13). In situations where the risk of bleeding is a 84 concern, the European Best Practice Guidelines recommend alternatives like regular saline 85 flushing or local citrate anticoagulation during HD, avoiding systemic anticoagents entirely. 86 This approach not only facilitates quick adjustments to treatment but also enables easy 87 monitoring for clotting within the dialyzer and may help in preventing clots from forming 88 initially (2,10). The goal of this study is to explore outcomes related to anticoagulation therapy 89 and factors influencing its outcome among AKI patients receiving HD at Tikur Anbessa . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 5 90 Specialized Hospital (TASH) and St. Paul's Hospital Millennium Medical College (SPHMMC) 91 in Addis Ababa, Ethiopia. 92 Material and Methods 93 Study Setting 94 The study took place in the dialysis departments of TASH and SPHMMC, located in Addis 95 Ababa, Ethiopia. TASH introduced HD services back in 1980 and presently caters to acute 96 dialysis needs. Meanwhile, SPHMMC began its provision of acute dialysis services in August 97 2013 before extending these services to include maintenance dialysis for kidney transplantation 98 starting from early 2015 (14). 99 Despite the lack of a specific written protocol for HD patients, anticoagulation was frequently 100 administered at both hospitals. UFH was used during HD, but the prescribed doses of heparin 101 varied slightly between the two centers. At TASH, UFH was administered in one of three ways: 102 (i) the standard dose, 1 ml (5000 IU) of UFH, was diluted with 4 ml of normal saline (total of 103 5 ml). This was followed by a 2 ml initial bolus and a continuous infusion of 1 ml/hr; (ii) the 104 minimal or half dose of 0.5 ml (2500 IU) of UFH was diluted with 4.5 ml of normal saline 105 (total of 5 ml). This was followed by a 2 ml initial bolus and a continuous infusion of 1 ml/hr; 106 (iii) heparin-free saline flushes of 30 to 50 ml were given every 30 minutes. At SPHMMC, 1 107 ml of UFH was diluted with 3 ml of normal saline (total of 4 ml) and administered as a bolus 108 of 1 ml, followed by a continuous infusion of 1 ml/hr. . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 6 109 Study Design and Period 110 A comprehensive, multicenter observational study was carried out over a duration of six months, 111 starting from October 1st, 2021 and concluding on March 31st, 2022. This study took place at 112 two major hospitals (TASH and SPHMMC) in Addis Ababa, Ethiopia. 113 Sampling and Sample Size Determination 114 On average, the dialysis clinics at TASH and SPHMMC serve approximately 15 and 30 AKI 115 patients per month, respectively. All patients meeting the eligibility criteria were considered 116 for inclusion in the study. Consequently, a total of 175 patients identified during the study 117 period, meeting the established criteria, participated in this research. Specifically, 122 of these 118 patients received treatment at SPHMMC, while the remaining 53 were from TASH. 119 Inclusion and Exclusion Criteria 120 All patients suffering from AKI, aged 12 years and older, who underwent HD at least once 121 during the designated study period were eligible for inclusion in this study. Nonetheless, 122 individuals diagnosed with chronic kidney disease who were undergoing regular maintenance 123 dialysis treatments, as well as those who expressed a refusal to participate in the study, were 124 systematically excluded from consideration. 125 Data Collection Instruments and Techniques 126 The data collection questionnaire, consisting of four sections, was developed through a 127 thorough review of relevant literature related to the study's objectives. The aim was to collect 128 demographic characteristics and clinical variables of patients to assess outcomes related to . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 7 129 anticoagulation. Pre-testing was carried out, and all necessary adjustments to the data collection 130 tool were implemented(4,6,9,15–18). 131 The initial section of the data collection tool was designed to gather information regarding the 132 sociodemographic characteristics of the patients. Subsequently, the second section assessed the 133 clinical features of the patients, including inquiries about the cause of AKI, indications for HD, 134 concomitant medical conditions, co-administered medications, and current use of 135 anticoagulants and/or antiplatelet drugs. The third part of the data collection tool focused on 136 recording essential laboratory results upon admission and discharge. Finally, the fourth section 137 specifically documents the comprehensive details of each HD session. Patients were closely 138 monitored during each session, with data collectors prospectively recording various parameters 139 related to HD, such as venous pressure, ultrafiltration volume, blood flow, dialysate flow, and 140 approach to UFH usage during HD. Additionally, incidents of clotting or bleeding were 141 documented, along with the interventions implemented to manage these occurrences. 142 Data Quality Assurance 143 To ensure data quality, the principal investigator closely monitored each activity to ensure 144 comprehensive data collection. Unclear terms were promptly clarified, and the necessary 145 corrections were made during the pre-test phase before commencing the main study. Data 146 collection was performed using three BSc. nurses and a pharmacist who were recruited as data 147 collectors. They underwent training to establish a consistent understanding and interpretation 148 of the instrument, including a briefing on the study's objectives and commitment to maintaining 149 core ethical principles throughout the data collection period. . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 8 150 Data Analysis 151 Data completeness was verified before entering the statistical package for social science 152 (SPSS) version 26 for a thorough analysis. Descriptive statistics, including the mean, median, 153 percentage, and standard deviation (SD), were then used to succinctly summarize the data. 154 Multinomial logistic regression was used to identify predictive factors for anticoagulation- 155 related outcomes in patients with AKI undergoing HD. A P-value < 0.05 was considered the 156 threshold for declaring statistically significant associations. 157 Ethical Considerations 158 Ethical clearance was secured from Addis Ababa University, School of Pharmacy, the Ethical 159 Review Committee (reference number ERB/SOP/257/13/2021), and the Institutional Review 160 Board of SPHMMC (reference number PM25/386). Study participants provided both written 161 and verbal consent before participating, and their confidentiality was maintained by avoiding 162 the recording of identifying information such as patient names. The collected data remained 163 securely stored throughout the study and was appropriately destroyed upon study completion. 164 Operational Definition 165 Anticoagulation-related complication: were defined as the occurrence of any circuit clotting or 166 bleeding during HD, whether with the use of UFH as an anticoagulant for dialysis or in a 167 heparin-free approach. . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 9 168 Results 169 Socio-demographic Characteristics of Study Participants 170 Of the 175 patients included in the study, an almost equal number were males (50.9%) and 171 females (49.1%), with a mean age of 40 ± 17.8 years involved and four female were pregnant. 172 Among the 175 patients, 66.9% were paid out-of-pocket for dialysis and 2.3% were involved 173 in smoking, drinking alcohol, and chewing khat (Table 1). 174 Table 1: Socio-demographic characteristics of AKI patients who undergo HD (n=175) Variable Category n (%) Age (years),mean ± SD 40±17.8 Male 89 (50.9)Sex Female 86 (49.1) Single 55 (31.4) Married 103 (58.9) Widowed 10 (5.7) Marital status Divorced 7 (4) Pregnancy Pregnant 4 (4.7) Not pregnant 71 (82.5) Postpartum 11 (12.8) Unable to read and write 23 (13.1) Primary education 42 (24) Education Secondary education 63 (36) . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 10 Diploma and above 47 (26.9) Weight (Kg) 61±13.9 Insurance 58 (33.1)Method of payment Out of pocket 117 (66.9) Substance use Smoking 7 (4) Chewing Khat 9 (5.1) Alcohol 26 (14.9) Smoking + Khat + Alcohol 4 (2.3) 175 176 Clinical Characteristics 177 The average length of hospital stay was 14.2 days, range, 2–40 days. The three most common 178 causes of AKI were acute tubular necrosis (29%), nephrotic syndrome (24%), and sepsis 179 (22.9%). Pregnancy-related causes also included preeclampsia/eclampsia (5.1%) and HELLP 180 syndrome (4.6%). The major indications for dialysis were uremic signs and symptoms (70.3%), 181 followed by fluid overload (50.3%). Common underlying comorbidities identified were 182 hypertension (55.4%) and anaemia (49.7%), and 13.1% of AKI cases were superimposed on 183 chronic kidney disease. UFH 7500 IU twice per day (48%) was the most widely used 184 anticoagulant regimen in the study population, followed by 5000 IU twice a day (14.3%) to 185 prevent deep venous thrombosis (Table 2). 186 Table 2: Clinical characteristics of AKI patients who undergo HD (n=175) n (%)Variables Category Yes . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 11 Length of hospitalization (days), mean ± SD 14.2 ± 9.9 Cause of AKI Acute tubular necrosis 49 (28) Nephritic syndrome 42 (24) Sepsis 40 (22.9) Severe dehydration 17 (9.7) Interstitial nephritis 25 (14.3) Shock 19 (10.9) Poison 17 (9.7) Urinary tract obstruction 11 (6.3) Nephrotoxic drugs 8 (4.6) Rhabdomyolysis 3 (1.7) HELLP syndrome 8 (4.6) Post-kidney transplant rejection 6 (3.4) Lupus nephritis 9 (5.1) Preeclampsia/Eclampsia 9 (5.1) Acute Glomerulonephritis 7 (4) Hemorrhage 5 (2.9) Others* 4 (2.3) Dialysis indication Uremic signs and symptoms 123 (70.3) Fluid overload 88 (50.3) Hyperkalemia 79 (45.1) Metabolic Acidosis 66 (37.7) . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 12 Comorbidity Atrial fibrillation 1 (0.6) Coronary arterial disease 1 (0.6) Stroke 6 (3.4) Hypertension 97 (55.4) Congestive heart disease 22 (12.6) Gastrointestinal ulceration 29 (16.6) Chronic Kidney Disease 23 (13.1) Anemia 87 (49.7) Deep vein thrombosis 5 (2.9) Pulmonary embolism 3 (1.7) Type 2 Diabetes 22 (12.6) HIV 11 (6.3) Pulmonary tuberculosis 9 (5.1) Hepatitis B virus 5 (2.9) Others** 41 (23.4) Concurrent anticoagulant and/or antiplatelet 124 (70.9) UFH 2500 IU SC BID 1 (0.6) UFH 5000IU SC Bid 25 (14.3) UFH 7500IU SC Bid 84 (48) UFH 17500IU SC Bid 5 (2.9) Warfarin 5mg PO Daily 8 (4.6) ASA 81mg PO Daily 20 (11.4) Enoxaparin 40mg SC Bid 3 (1.7) Clopidogrel 75mg PO Daily 2 (1.1) . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 13 Concomitant drugs use 166 (94.9) 187 * (malaria, kidney trauma, cardio-renal syndrome, acute fatty liver of pregnancy) 188 ** (prostate cancer, BPH, epilepsy, leukemia, gout arthritis, cerebral malaria) 189 Laboratory Findings 190 Upon admission and upon discharge, it was noted that there were low hemoglobin levels present. 191 Furthermore, the mean serum creatinine level recorded at the time of admission stood at 8.3 ± 192 3.4 mg/dl, which experienced a significant decrease by 3 mg/dl by the time of discharge. Table 193 3 in our document provides a summarized outline showing these changes among other selected 194 laboratory parameter values observed during this period. 195 Table 3: Selected Laboratory Values of AKI patients who undergo HD (n=175) Mean ± SDVariables Admission Discharge Hemoglobin (g/dl) 10.3 ± 7.6 10.3 ± 6.4 WBC count (103/ml) 11.1 ± 5.6 9.8 ± 4.9 Platelet count (103/ml) 235.9 ± 140.1 268.3 ± 131 Serum creatinine (mg/dl) 8.3 ± 3.4 5.3 ± 3.1 Urea (mg/dl) 137.5 ± 80.3 82.1 ± 63.4 Serum potassium (mEq/L) 5.3 ± 1.1 4.4 ± 0.8 196 . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 14 197 Characteristics of HD Sessions 198 From October 2021 to March 2022, a total of 1010 HD sessions were conducted on 175 patients. 199 The average frequency of dialysis sessions was calculated at 5.8 ± 3.8 per patient, ranging from 200 one single session to a maximum of fifteen sessions with each session lasting an average 201 duration of approximately 3.1 ± 0.6 hours. Patients underwent HD therapy thrice weekly using 202 catheters as the primary means for vascular access across all cases in this study. During these 203 treatments, blood products were administered in approximately 9.8% or essentially, during 204 almost ten out all hundred HD procedures. UFH was administered for circuit anticoagulation 205 in 626 sessions, accounting for 62% of the total. The average dose given was 1 mL (5000 IU). 206 Of these UFH sessions, infusion was stopped 60 minutes before discontinuation in 546 cases, 207 making up 87.2% of the total. The average pressure in the venous chamber was recorded as 208 125 ± 39.3 mmHg, with the dialysis blood flow rate averaging 227.2 ± 22.8 ml/min. 209 Table 4: Characteristics of HD sessions included in the study (N=1010) Variables mean ± SD Total number of HD sessions (N=1010) 5.8 ± 3.8 HD duration (in hour) 3.1 ± 0.6 Venous chamber pressure (mmHg) 125 ± 39.3 Ultrafiltration volume (ml) 885 ± 650.9 Blood flow rate (ml/min) 227.2 ± 22.8 Dialysate flow rate (ml/min) 481 ± 46.6 Total UFH dose (ml)* 1 ± 0.2 Category n (%) UFH infusion stopped . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 15 Before 30 minutes 70 (11.3) Before 60 minutes 546 (87.2) Before 120 minutes 8 (1.3) At the end of dialysis 1 (0.2) 210 211 Anticoagulation-related complication and HD Outcome 212 Of the 175 patients, extracorporeal circuit clotting occurred in 34 patients in 39 (3.9%) sessions 213 and 27 patients in 29 (2.9%) experienced bleeding. HD circuit clotting resulted in the 214 discarding of the bloodline and early termination of dialysis in 17 sessions. Additionally, 215 nursing interventions, that is, the use of UFH and a normal saline flush, were required in 10 216 and 5 sessions, respectively, to prevent abrupt HD treatment interruptions due to circuit 217 clotting. Some of the measures taken when bleeding occurred included holding UFH at the 218 time, and for the next session/s (n = 14 sessions), blood transfusion (n = 2 sessions), and 219 applying pressure at catheter insertion site in 6 sessions (Table 5). On the other hand, the 220 majority of AKI patients (44.6%) were discharged with improvement, while more than one- 221 fourth (26.9%) of them died after undergoing HD (Figure 1). 222 Table 5: Anticoagulation related complication and HD outcome among AKI patients in 223 the study. Variables mean ± SD Circuit clotting (34 patients, 19.4%) 39 (3.9) Measures taken when circuit clotting occurs Discard the blood line and HD terminated early 17 (1.7) . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 16 Blood transfusion during HD 99 (9.8) Using UFH during HD 626 (62) Additional UFH given 10 (1) Continued HD by using normal saline flush 5 (0.5) Return the blood and HD terminated early 2 (0.2) Manipulate the access and continued HD 3 (0.3) Use UFH intermittently for the next sessions 2 (0.2) Bleeding (27 patients, 15.4%) 29 (2.9) Bleeding from nose 15 (1.5) Catheter site bleeding 6 (0.6) Vaginal bleeding 4 (0.4) Others** 4 (0.4) Measures taken when bleeding occurs Hold UFH at the time, and for the next session/s 14 (1.4) Blood transfused 2 (0.2) Applied pressure at catheter insertion site 6 (0.6) Use UFH intermittently for the next sessions 2 (0.2) Return the blood and HD terminated early 1 (0.1) . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 17 No measure taken 4 (0.4) 224 *1ml=5000 IU 225 ** bleeding form rectum, bloody vomiting, subcutaneous hematoma, bleeding form bullet 226 penetrating injury site 227 Factors associated with anticoagulation related outcomes 228 To determine the predictors of anticoagulation-related outcomes during HD (clotting and 229 bleeding risks), multinomial regression analysis was used. Based on the model comparing 230 participants who had HD circuit clotting with those who did not have any clotting/bleeding, 231 as the total number of HD sessions increased, the probability of circuit clotting increased 232 (AOR=1.932, 95% CI, 1.227-3.043, p= 0.004). In contrast, a higher blood flow rate was 233 associated with a lower HD circuit clotting risk (AOR=0.868, 95% CI, 0.812-0.928, p= 234 0.001). 235 On the other hand, bleeding was more likely to occur in participants who had longer 236 hospitalization and elevated serum creatinine at admission (AOR=1.247, 95% CI, 1.053-1.478, 237 p= 0.010; AOR=1.886, 95% CI, 1.285-2.769, p= 0.001) respectively. While, the rate of 238 bleeding in patients who had no uremic signs and symptoms was lower (AOR=0.092, 95% CI, 239 0.009-0.955, p= 0.004) than those having it. Likewise, patients who did not receive 240 prophylactic or therapeutic anticoagulant and/or antiplatelet drug were less likely to develop 241 bleeding (AOR=0.017, 95% CI, 0.001-0.446, p= 0.014) compared to those taking these drugs 242 (Table 6). . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 18 243 Table 5: Multinomial regression of predictive factors associated with anticoagulation 244 related outcomes during HD OutcomesVariables Clotting AOR (95% CI) Bleeding AOR (95% CI) P-value Total no of HD sessions 1.932 (1.227-3.043)a 1.068 (0.713-1.601) 0.004* Blood flow rate (ml/min) 0.868 (0.812-0.928)a 1.026 (0.974-1.081) <0.001* Length of hospitalization (days) 0.946 (0.843-1.06) 1.247 (1.053-1.478)a 0.010* Serum creatinine (mg/dl) at admission 0.911 (0.699-1.189) 1.886 (1.285-2.769)a 0.001* Uremic signs and symptoms Yes 1 1 No 0.532 (0.079-3.57) 0.092 (0.009-0.955)a 0.04* Using of anticoagulant and/or antiplatelet drug Yes 1 1 No 1.156 (0.168-7.936) 0.017 (0.001-0.446)a 0.014* 245 Reference Variable: No clotting/bleeding 246 *Variables that showed a significant association, P < 0.05 247 aVariable category with P <0.05 . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 19 248 Discussion 249 As the first prospective study in the Ethiopian context on anticoagulation among patients with 250 AKI on HD, this study provides insight into extracorporeal circuit clotting or bleeding 251 occurrences and the predictive factors associated with these complications. In this study, 1010 252 HD sessions performed on 175 patients were prospectively followed. Clotting and bleeding 253 data are expressed as percentages of both participants and sessions. Circuit clotting occurred 254 in 3.9% of HD sessions (19.4% patients), and bleeding in 2.9% sessions (15.4% patients). 255 A similar result was reported in the United States of America, that evaluated clotting of the HD 256 circuit in general care patients and critically ill patients. The overall rate of extracorporeal 257 circuit clotting was 5.2% in all sessions (12). Circuit clotting occurred in 2.4% of HD sessions 258 with heparin, according to a retrospective study comparing two intra-dialytic heparin protocols: 259 "routine heparin-use" during HD (routine heparin prime/bolus dose) and heparin-free HD 260 (saline prime, heparin avoidance). However, heparin-free HD is associated with a higher rate 261 of HD circuit clotting (9.1%) (13). In contrast, other studies reported a higher rate of circuit 262 clotting during HD. A study conducted in Brazil showed that filter clotting occurred in 19 263 patients (25.3%) and 29 sessions (14.9%) (19). This study evaluated and compared intra- and 264 post-dialysis complications in critically ill AKI patients undergoing extended daily dialysis 265 sessions of different durations (6 versus 10 hours), which could explain the higher rate of HD 266 filter clotting events, and the fact that many critically ill patients develop hemostatic 267 abnormalities in addition to the longer dialysis duration. 268 Additionally, a retrospective cohort study conducted in Belgium found that circuit coagulation 269 was reported in 17.5% of the sessions. This higher rate of clotting events could be attributed to 270 the absence of systemic anticoagulation (20). Moreover, this study conducted a retrospective . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 20 271 analysis of HD sessions in intensive care unit patients, which could be an additional factor 272 contributing to clotting occurrences. Patients admitted to the intensive care unit and requiring 273 dialysis for AKI often present with a systemic inflammatory state (21), which is known to be 274 associated with the activation of coagulation pathways (22). 275 Lower clotting of the HD circuit incidence was reported in a retrospective study conducted in 276 the USA (1% of 400 HD treatments) (23). This may be attributed to the operational definition 277 of clotting used in this study. The researchers defined clotting as complete clotting that required 278 replacement of the blood tubing and dialyzer to complete treatment. The higher blood flow rate 279 (378 ± 46 mL/min) and more aggressive normal saline flushing of the circuit employed in this 280 protocol could also explain the lower rate of clotting. Moreover, there might be underreporting 281 of clots due to the retrospective study design, in which existing data were extracted from chart 282 reviews. Another study from Spain found that 1.9% of patients developed clotting, which is 283 lower than our finding (19.4% of patients) with a higher mean blood pump flow (346 ± 47 284 ml/min), given a higher risk of coagulation from a lower pump flow (17). 285 In the current study, 15.4 % of patients developed bleeding, and this finding was higher than a 286 study conducted in Spain (4.4%) (17). This variation might be due to the difference in the study 287 design and setting, even though the study reported that oral anticoagulants were administered 288 to 18.4% of patients, which by itself is thought to increase the risk of bleeding. However, in a 289 Spanish study, each patient was asked to report any bleeding or thrombotic complications that 290 arose in the week prior to data collection. 291 In the present study, it was observed that anticoagulation was achieved with UFH or saline 292 flushes of 30 to 50 ml administered every 30 min if UFH was contraindicated. There were three 293 strategies regarding UFH order for HD in current study settings, and each patient was dialyzed 294 using any of these anticoagulation methods. The first is the standard dosing regimen of UFH, . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 21 295 consisting of a bolus of 1250–2000 U, followed by a continuous infusion of 1000–1250 U/h. 296 The second was the minimal/half-dose method with a 625–1000 bolus dose and 500–625 297 infusion rate. Heparin-free dialysis was also the third method used in patients who were 298 actively bleeding or were at an increased risk of bleeding. 299 Due to its brief half-life and extensive medical usage over time, UFH has emerged as the 300 predominant anticoagulant for HD (9). Nonetheless, the dosage administered shows significant 301 divergence. This study reveals that the average total UFH dose throughout HD sessions was 302 5000 ± 1000 units, with heparin infusion being discontinued one hour before dialysis 303 completion in the majority (87.2%) of cases to reduce the potential for bleeding from the access 304 site post needle withdrawal. 305 In the present study, extracorporeal circuit clotting was assessed by visual inspection and noted 306 by nurses. It is characterized by extremely dark blood or black striations in the tube and a 307 sudden rise in pressure readings. They only recorded clotting as being present or absent without 308 grading it in line with several studies done elsewhere (13,17,19,24). In contrast, other studies 309 have reported the degree of clotting by classifying it as mild/slight, moderate, and severe. 310 HD is often performed three times a week for three–four hours each session; however, the 311 length of these sessions varies from patient to patient. One consequence of intradialysis, circuit 312 clotting, includes treatment interruption and patient blood loss, which may exacerbate 313 haemodynamic instability (19). In 1.7% of all sessions with clotting, dialysis was stopped early 314 without the possibility of retransfusing blood from the extracorporeal circuit; hence, the 315 bloodline was discarded. However, in 0.2% of the sessions, dialysis was terminated early by 316 the return of blood. . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 22 317 According to a study from Belgium, clotting reduced the length of time spent receiving dialysis 318 in 15.2% of sessions, completely blocking the circuit, and preventing retransfusion in 4.2% of 319 sessions, which is greater than our findings (20). These variations may be due to differences in 320 dialysis protocols. In contrast to our study, the study combined a citrate-enriched dialysate with 321 a heparin-coated dialyzer with no systemic UFH. Similarly, a study conducted in the USA 322 comparing two intradialytic heparin protocols reported that in a heparin-free HD protocol, 323 circuit clotting resulted in a change of the extracorporeal circuit in 7.3% of sessions. However, 324 this was required in only 0.8% of HD sessions with heparin, and early termination of HD 325 (1.6%) was similar to that in this study (13). Bleeding is another important intradialysis 326 complication that might require adjusting the dose of UFH (1.6% of all sessions with bleeding) 327 or blood transfusion (0.2%). Another study revealed that patient weight, circuit clotting, and 328 bleeding of the vascular access after disconnection were the most frequently employed 329 techniques for changing the dosage (17). 330 Identifying predictors of anticoagulation-related outcomes during HD in patients with AKI is 331 important. Identifying and preventing patients at risk of such complications can increase 332 practitioner awareness of HD-related complications. Similar to other studies (12,13,20,23), the 333 blood flow rate showed a statistically significant association with the occurrence of circuit 334 clotting. In this study, lower delivered blood flow rates were associated with higher circuit- 335 clotting rates. Additionally, as the total number of HD sessions increased, the probability of 336 circuit clotting increased, unlike in a study conducted in Belgium (20). This difference could 337 be due to variations in their research methodology and the inclusion of study participants with 338 varying levels of clotting risk. Patients who did not receive prophylactic or therapeutic 339 anticoagulants and/or antiplatelet drugs were less likely to develop bleeding compared to those 340 taking these drugs. Similarly, a study from Spain found that bleeding complications were more . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 23 341 frequent in patients receiving oral anticoagulants (17). Consistent with previous studies, age 342 and sex were not associated with bleeding events (13,17). 343 However, there were some limitations to our study. Bleeding was reported only at the time of 344 the dialysis session. Therefore, this may not provide a comprehensive picture of the bleeding 345 risk associated with dialysis. Additionally, the study did not exclude patients with 346 comorbidities (such as deep vein thrombosis, active malignancy, severe heart failure, or severe 347 liver disease). These conditions can impact anticoagulation outcomes and may confound the 348 interpretation of results. 349 Conclusions 350 In conclusion, clotting was observed in 19.4% of the participants in the study, while bleeding 351 was reported in 15.4% of them. These findings highlight the importance of thorough 352 monitoring due to the complications resulting in treatment interruptions and blood loss. The 353 study identified a significant association between circuit clotting and variables such as blood 354 flow rate and the frequency of HD sessions. Furthermore, it revealed a notable occurrence of 355 bleeding during HD, mainly manifesting as minor cases. Individuals who received prophylactic 356 or therapeutic anticoagulants and/or antiplatelet medications were more susceptible to bleeding 357 compared to those who did not undergo these treatments. 358 359 Abbreviations 360 AKI: Acute Kidney Injury; HD: Hemodialysis; SPHMMC: St. Paul's Hospital Millennium 361 Medical College; TASH: Tikur Anbessa Specialized Hospital; UFH: Unfractionated heparin. . CC-BY 4.0 International licenseIt is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint The copyright holder for thisthis version posted February 29, 2024. ; https://doi.org/10.1101/2024.02.28.24303493doi: medRxiv preprint 24 362 Acknowledgement 363 The authors thank the School of Pharmacy, College of Health Sciences, Addis Ababa 364 University, and the nursing staff at TASH and SPHMMC dialysis clinics, who were very 365 cooperative and helpful in providing constant assistance. 366 Availability of Data and Materials 367 All the data and materials used in this paper are available from the corresponding author upon 368 reasonable request. 369 Disclosure interest 370 The authors declare that they have no conflicts of interest. 371 Funding details 372 The authors received no specific funding for this study. 373 374 375 376 377 378 379 380 381 382 383 . 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