DOI: https://doi.org/10.21203/rs.3.rs-2683178/v1
Severe hypoxia would aggravate the acute kidney injure (AKI) in high-altitude areas and continuous renal replacement therapy (CRRT) has been used to treat critically ill patients with AKI. However, the characteristics and outcomes of CRRT of critically ill patients with AKI in high altitude and the optimal timing of CRRT initiation are still unclear. 1,124 patients were diagnosed with AKI and treated with CRRT in ICU, involving high-altitude group (n = 648) and low-altitude group (n = 476). Compared with low-altitude group, patients with AKI in high altitude showed longer CRRT (4.8 vs. 3.7, P = 0.036) and more rapid progression of AKI stages (P < 0.01), but without any significance of minor or major bleeding episode (P > 0.05). Referring to the analysis of survival and kidney recovery curves, a higher mortality but a lower possibility of renal recovery was observed in high-altitude group (P < 0.001). However, in the high-altitude group, the survival rate of early CRRT initiation was significantly higher than that of delayed CRRT initiation (P < 0.001). The findings showed poorer clinical outcomes of patients undergoing CRRT for AKI in high altitude. CRRT at high altitude was unlikely to increase the adverse events. Moreover, early CRRT initiation might reduce the mortality and promote renal recovery in high-altitude patients.
Acute kidney injury (AKI) is characterized as a sudden loss of kidney function and closely associated with the morbidity and mortality in critically ill patients, leading to a massive health resource waste each year [1–3]. A meta-analysis of 3,585,911 participates revealed that 20.0%-31.7% of in-hospital patients suffered from AKI, with an average pooled mortality rate of 23%-49.4% [4, 5]. Kidney is more easily to be injured at high-altitude areas [6]. High-altitude inhabitants who have severe hypoxia and pulmonary hypertension are more likely to develop hyperuricemia, hypertension, and proteinuria, which is defined as “high-altitude renal syndrome” [7, 8]. According to studies, people at high-altitude areas have worse kidney function and a higher prevalence of proteinuria than those at sea level, which is due in part to the effects of hyperuricemia on glomerular hemodynamics and tubular function [6, 9].
Continuous renal replacement therapy (CRRT), an efficient extracorporeal system well recognized for body hemostasis and solute control, is one of the most common used modality for the treatment of AKI in the intensive care unit (ICU) [10, 11]. However, current CRRT prescription in high altitude is largely based on physicians’ experiences because CRRT in high altitude may have different adverse and curative effects on AKI from that in low altitude. On the one hand, previous studies found that long-term environmental hypoxia was an independent factor in coagulation dysfunction, hemostatic disorders and thrombocytopenia at high altitude [12–14]. Sufficient use of anticoagulants in CRRT, which is required to prevent circuit clotting to maintain filter performance, is more likely to increase the bleeding risks and other adverse events in high altitude [1, 7]. On the other hand, emerging data have demonstrated that unwarranted CRRT initiation might result in prolonged CRRT durations and deteriorated kidney injury [15, 16]. The optimal timing of CRRT initiation at high-altitude areas is still remain to resolve.
Although the prevalence of high-altitude renal syndrome has been widely reported in Tibet, data on CRRT of patients with AKI in this region is scarce [9, 17]. Meanwhile, the curative effect, adverse effect and reasonable strategies for CRRT in high altitude need to be detected further. In the current study, we aimed to compare the characteristics, outcomes and adverse events of CRRT of critically ill patients with AKI in both high-altitude group and low-altitude group. Furthermore, the survival rate and kidney related outcomes of early CRRT initiation group and delayed CRRT initiation group were compared to recommend the best timing to start CRRT for high-altitude patients with AKI.
This retrospective, multicenter cohort study included three cohorts of participates from the General Hospital of Tibet Military Command in Lhasa, the People's Hospital of Tibet Autonomous Region in Lhasa, and the Hospital of Chengdu Office of People's Government of Tibetan Autonomous Region in Chengdu. According to the International Statistical Classification of Diseases and Related Health Problems, patients diagnosed with AKI and treated with CRRT in ICU were retrospectively enrolled from January 1, 2011 to December 31, 2021 in the three hospitals listed above [16]. The exclusion criteria were shown in Fig. 1. This retrospective cohort study was approved by the Medical Ethics Committee of the General Hospital of Tibet Military Command of the Chinese People's Liberation Army and the requirement for informed consent was waived by the Ethics Committee owing to its minimal risk nature. All procedures performed in our studies involving human participants with CRRT were in accordance with the ethical standards of the 1964 Helsinki Declaration.
High-altitude patients referred to those who had lived at or above 3,000 meters for at least 10 years and had not visited places below 3,000 meters within 6 months. While low-altitude patients referred to those who had lived below 3,000 meters at least 10 years and had not visited places at or above 3,000 meters within 6 months. The average altitude of each region was obtained from the Center for Disease Control and Prevention (CDC) of Tibet Military Command and verified by Google Earth. Different stages of AKI and acute kidney diseases (AKD) were diagnosed according to the standards of Kidney Disease: Improving Global Outcomes (KDIGO) [18, 19]. CRRT liberation was defined when patient's status was in remission so that CRRT was discontinued for more than 12 h, except that the temporary treatment interruption was required for auxiliary examinations or surgery. For those patients who had more than one CRRT liberation attempts in ICU, only the first was considered in this study. Kidney recovery was defined that the stage 0 of AKD was reached and maintained during the whole hospitalization. Early CRRT initiation referred to that CRRT was started within the 24h after diagnose of AKI, while delayed CRRT initiation referred to that CRRT was started more than 24h after diagnose of AKI[20, 21].
The decisions of CRRT initiation, termination or reinstitution for AKI patients was drawn by the specialized nephrology intensive care groups of the three hospitals. Nurses responsible for dialysis set up and checked the CRRT circuit on a regular basis according to the intensive care physicians’ advice. Continuous veno-venous hemodialysis (CVVHD) or continuous veno-venous hemodiafiltration (CVVHDF), the standard modes of CRRT, were performed in Multifiltrate (Fresenius, Germany) with a 1.4 m2 membrane (AV 600S, Fresenius) or PRISMA (Gambro, Sweden) with a 0.9 m2 membrane (M100, Gambro). As CRRT vascular access, a temporary double-lumen dialysis catheter was implanted in the internal jugular or femoral vein.
The standard settings for CRRT prescription were listed following: 1) bicarbonate-buffered solution was used for the preparation of dialysis and hemofiltration; 2) blood flow rate was set to 180 ml/min; 3) the dialysis dose was set to 30 ml/kg of body weight/h; 4) 50% of dialysis and 50% of hemofiltration were used when the mode of CVVHDF was performed; 5) the anticoagulant citrate dextrose solution formula A or unfractionated heparin was used for anticoagulation strategies unless the existence of contradictions; 6) for regional citrate anticoagulation, continuous intravenous calcium chloride was infused to maintain homeostasis with dose-adjustments based on the results of ionized calcium measured every 4 hours after CRRT initiation; 7) for unfractionated heparin anticoagulation, the infusion of heparin was increased until the value of activated partial thromboplastin time (APTT) was 2.0 times greater than the normal level; 8) if anticoagulation-related adverse events occurred, the dose of anticoagulant citrate and unfractionated heparin was slightly altered by intensive care physicians.
The demographic, clinical and laboratory data of patients were extracted from electronic medical records by a data collection form including the CRRT application and kidney related outcomes. Laboratory tests consisted of whole blood counts, blood chemistry and electrolyte analysis, coagulation test and kidney function evaluation. Following data collection, two physicians were responsible for data verification, with a third researcher adjudicating any discrepancies in interpretations between them if necessary.
To assess the status and severity of illness at the time of ICU admission, the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Charlson Comorbidity Index, and Sequential Organ Failure Assessment (SOFA) scores were all calculated. Daily data on mechanical ventilation, AKI stages, and patient mortality were collected from electronic medical records.
CRRT associated hemorrhagic events and electrolyte disturbances were investigated within the first 72h after initiation. Hemorrhagic events involved the minor or major bleeding episode, blood transfusion, low platelet count and extended APTT or prothrombin time (PT) values. A major bleeding episode was defined as a drop in hemoglobin of ≥ 1 g/dL in 24 h, while a minor bleeding episode was defined as a drop in hemoglobin of < 1 g/dl in 24 h. Electrolyte disturbances involved hypokalemia (serum potassium < 3.5 mmol/L), hyperkalemia (serum potassium > 5.5 mmol/L), hypophosphatemia (serum phosphorus < 2.5 mg/dL), hyperphosphatemia (serum phosphorus > 6.0 mg/dL), hyponatremia (serum sodium < 130 mmol/L), hypernatremia (serum sodium > 150 mmol/L), hypocalcemia (serum ionized calcium < 2.25 mmol/L), hypercalcemia (serum ionized calcium > 2.75 mmol/L), alkalosis (arterial pH > 7.45), acidosis (arterial pH < 7.35).
All of the eligible patients were retrospectively followed from ICU admission to hospital discharge. The primary outcomes were the mortality. The secondary outcomes included CRRT liberation, persistent renal dysfunction (serum creatinine was 2 times more than the baseline or the value at hospital discharge), the stages of AKI at ICU and hospital discharge, and mechanical ventilation at ICU.
Continuous variables were summarized as median (IQR) and categorical variables as n (%), respectively. The Mann-Whitney U test was used to compare continuous variables between the high-altitude group and the low-altitude group, or between the early CRRT initiation group and the delayed CRRT initiation group, while the χ2 test or Fisher exact test was used to compare categorical variables. Kaplan-Meier curves were used to compare the survival rates of patients in the high-altitude and low-altitude groups, as well as the early CRRT initiation and delayed CRRT initiation groups. At the same time, the corresponding 95% confidence intervals (CIs) and P values were calculated using the log-rank test. The association between altitude or timing of CRRT initiation and the cumulative probability of kidney recovery at hospital discharge was analyzed by Cox proportional hazards regression model and followed with the adjustments of 13 cofounders identified through clinical experiences, literature review and univariate analyses [22]. The 13 cofounders consisted of age, sex, ethnicity, BMI, altitude or timing of CRRT initiation, death, Charlson Comorbidity Index, APACHE Ⅱ scores, SOFA scores, mechanical ventilation duration, CRRT duration, ICU duration and hospitalization duration. The cause-specific “hazard” of recovery was then modeled. Statistical analyses were performed using SPSS Version 22.0. Two-tailed P values less than 0.05 were considered statistically significant unless otherwise specified. R version 4.1.0 was employed for the visualization of Kaplan–Meier curves and Cox model analysis.
After screening, 1124 eligible patients were identified and analyzed in this study. The flowchart of participates enrollment and grouping process was shown in Fig. 1. Of these 1,124 patients, 648 patients (57.7%) from places equal or above 3,000 meters were assigned to high-altitude group and 476 patients (42.3%) from places below 3,000 meters were assigned to low-altitude group, respectively. Although no differences were observed in sex, ethnicity or BMI between high-altitude group and low-altitude group (P > 0.05), patients in high-altitude group were significantly younger (P < 0.001) (Table 1). The average ICU duration was 8.9 (IQR 4.1–18.5) days, and 538 patients (47.9%) died during the study.
| Number (%) | P value | |||
|---|---|---|---|---|
| Total (n = 1,124) | High-altitude group (n = 648) | Low-altitude group (n = 476) | ||
| Age (IQR) | 55.2 (45.6–66.7) | 54.1 (43.6–64.5) | 59.6 (47.1–70.0) | < 0.001 |
| Sex | 0.85 | |||
| Male | 683 (60.8) | 392 (60.5) | 291 (61.1) | |
| Female | 441 (39.2) | 256 (39.5) | 185 (38.9) | |
| Ethnicity | 0.86 | |||
| Han | 498 (44.3) | 289 (44.6) | 209 (43.9) | |
| Tibetan | 626 (55.7) | 359 (55.4) | 267 (56.1) | |
| BMI | 0.41 | |||
| < 18.5 | 65 (5.8) | 39 (6.0) | 26 (5.5) | |
| 18.5–23.9 | 193 (17.2) | 120 (18.5) | 73 (15.3) | |
| 24.0-27.9 | 482 (42.8) | 278 (42.9) | 204 (42.9) | |
| ≥ 28.0 | 384 (34.2) | 211 (32.6) | 173 (36.3) | |
| Laboratory results | ||||
| Serum creatinine (µmol/l) (IQR) | 313.3 (229.6-485.3) | 316.7 (235.2-507.9) | 308.3 (216.7–475.0) | 0.074 |
| Serum BUN (mmol/l) (IQR) | 6.8 (5.4–8.7) | 6.8 (5.5–8.9) | 6.6 (5.3–8.5) | 0.15 |
| Creatinine clearance (ml/min) (IQR) | 38.9 (29.3–49.1) | 34.9 (25.6–45.1) | 47.4 (35.8–56.5) | < 0.001 |
| Total bilirubin (µmol/l) (IQR) | 16.1 (10.6–28.3) | 16.5 (11.8–29.6) | 14.9 (9.0-27.7) | 0.27 |
| Leukocytes, ×109/L (IQR) | 17.2 (12.2–26.1) | 17.3 (12.7–26.6) | 16.9 (11.1–24.9) | 0.097 |
| Platelet count, ×109/L (IQR) | 203.4 (121.7-322.8) | 188.7 (104.3-307.9) | 246.2 (153.7-367.5) | < 0.001 |
| AKI stages | 0.67 | |||
| Stages 1 | 185 (16.5) | 107 (16.5) | 78 (16.4) | |
| Stages 2 | 360 (32.0) | 214 (33.0) | 146 (30.7) | |
| Stages 3 | 579 (51.5) | 327 (50.5) | 252 (52.9) | |
| CRRT modality | 0.11 | |||
| CVVHD | 425 (37.8) | 232 (35.8) | 193 (40.5) | |
| CVVHDF | 699 (62.2) | 416 (64.2) | 283 (59.5) | |
| Anticoagulation strategies | 0.38 | |||
| Regional citrate anticoagulation | 713 (63.4) | 404 (62.3) | 309 (65.0) | |
| Unfractionated heparin | 411 (36.6) | 244 (37.7) | 167 (35.0) | |
| Charlson Comorbidity Index (IQR) | 4 (2–6) | 4 (2–7) | 4 (2–6) | 0.35 |
| APACHE Ⅱ score (IQR) | 27.0 (20.5–40) | 28.5 (21.0-40.8) | 25.0 (19.0-38.8) | 0.098 |
| SOFA score (IQR) | 10 (8–12) | 10 (8–12) | 9 (7–12) | 0.46 |
| PaO2/FiO2 ratio (IQR) | 166.4 (119.9-252.1) | 161.7 (114.0-247.2) | 176.3 (128.5-261.4) | 0.075 |
| Mechanical ventilation | 973 (86.6) | 578 (89.2) | 395 (83.0) | 0.003 |
| Mechanical ventilation duration (days) (IQR) | 6.6 (2.5–14.8) | 7.4 (3.5–15.9) | 5.7 (1.8–13.2) | < 0.001 |
| CRRT duration (days) (IQR) | 4.4 (3.7–6.6) | 4.8 (3.9–6.7) | 3.7 (3.0-5.9) | 0.036 |
| ICU duration (days) (IQR) | 8.9 (4.1–18.5) | 10.5 (4.7–20.1) | 7.2 (3.1–15.8) | 0.007 |
| Hospitalization duration (days) (IQR) | 24.6 (15.6–38.8) | 27.4 (18.8–41.5) | 18.9 (10.3–35.5) | < 0.001 |
| Data are shown by median (IQR) or n (%). P values comparing between the groups are from χ2 test, Fisher's exact test, or Mann-Whitney U test. AKI: Acute kidney injury; APACHE Ⅱ: The Acute Physiology and Chronic Health Evaluation Ⅱ; BMI: Body mass index; BUN: blood urea nitrogen; CRRT: Continuous renal replacement therapy; CVVHD: Continuous venovenous hemodialysis; CVVHDF: Continuous venovenous hemodiafiltration; ICU: Intensive care unit; IQR: Interquartile range; PaO2/FiO2: Arterial oxygen tension/fraction of inspired oxygen; SOFA: Sequential Organ Failure Assessment. | ||||
The laboratory results at the ICU admission indicated that creatinine clearance (CCr) (34.9 ml/min vs. 47.4 ml/min, P < 0.001) and platelet count (PLT) (188.7×109/L vs. 246.2×109/L, P < 0.001) of high-altitude group were significantly lower than that of low-altitude group (Table 1). However, there were no differences of distributions of AKI stages (P = 0.67), CRRT modality application (P = 0.11), or anticoagulation strategies (P = 0.38) between the two groups. During the hospitalization, high-altitude patients received longer treatment of mechanical ventilation or CRRT and had a longer duration in ICU (10.5 days vs. 7.2 days, P = 0.007) or hospital (27.4 days vs. 18.9 days, P < 0.001) compared to the low-altitude patients, in spite of similar severities of illness in Charlson Comorbidity Index (4 vs. 4, P = 0.35), Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score (28.5 vs. 25.0, P = 0.098), and Sequential Organ Failure Assessment (SOFA) score (10 vs. 9, P = 0.46) (Table 1).
The clinical characteristics and kidney-related outcomes of patients in both high-altitude group and low-altitude group were shown in Table 2. Throughout the study, progressively higher mortality were observed in high-altitude group (P < 0.05). Compared with the low-altitude group, patients of high-altitude group experienced a higher level of AKD staging at CRRT liberation (P = 0.033), ICU (P < 0.001) and hospital discharge (P < 0.001), but no changes at 24h after CRRT initiation (P = 0.96). Meanwhile, more frequent mechanical ventilation was required in high-altitude group at 24h after CRRT initiation (64.4% vs. 51.7%, P < 0.001) and CRRT liberation (424.4% vs. 25.0%, P < 0.001). At 24h after CRRT initiation, the PaO2/FiO2 ratio (193.6 vs. 229.3, P = 0.024), serum creatinine (126.3 µmol/l vs. 87.3 µmol/l, P = 0.007), CCr (33.2 ml/min vs. 41.8 ml/min, P < 0.001), serum blood urea nitrogen (BUN) (4.4 mmol/l vs. 3.1 mmol/l, P = 0.025) and total bilirubin (32.6 µmol/l vs. 26.5 µmol/l, P = 0.039) were significantly worse in high-altitude patients. However, the changes of serum creatinine (81.6 µmol/l vs. 77.2 µmol/l, P = 0.16) and BUN (2.9 mmol/l vs. 2.6 mmol/l, P = 0.42) were weakened at CRRT liberation.
| Number (%) | P value | |||
|---|---|---|---|---|
| Total (n = 1,124) | High-altitude group (n = 648) | Low-altitude group (n = 476) | ||
| 24h after CRRT initiation | ||||
| AKD stages | 0.96 | |||
| Stages 0 | 12 (1.1) | 6 (1.0) | 6 (1.3) | |
| Stages 1 | 89 (7.9) | 51 (7.9) | 38 (8.0) | |
| Stages 2 | 135 (12.0) | 75 (11.5) | 60 (12.6) | |
| Stages 3 | 605 (53.8) | 337 (52.0) | 268 (56.3) | |
| Mechanical ventilation | 663 (59.0) | 417 (64.4) | 246 (51.7) | < 0.001 |
| PaO2/FiO2 ratio (IQR) | 204.8 (146.9–298.0) | 193.6 (137.1-289.6) | 229.3 (166.2-315.4) | 0.024 |
| Serum creatinine (µmol/l) (IQR) | 107.7 (57.3-184.2) | 126.3 (61.8-217.9) | 87.3 (41.9-169.5) | 0.007 |
| Creatinine clearance (ml/min) (IQR) | 35.9 (26.4–48.7) | 33.2 (24.7–45.8) | 41.8 (30.6–53.0) | < 0.001 |
| Serum BUN (mmol/l) (IQR) | 4.0 (2.8–6.1) | 4.4 (3.1–6.8) | 3.1 (1.6–5.3) | 0.025 |
| Total bilirubin (µmol/l) (IQR) | 30.1 (23.0-43.6) | 32.6 (24.7–45.2) | 26.5 (19.6–41.3) | 0.039 |
| Mortality | 283 (25.2) | 179 (27.6) | 104 (21.8) | 0.031 |
| CRRT liberation | ||||
| AKD stages | 0.033 | |||
| Stages 0 | 23 (2.0) | 12 (1.9) | 11 (2.3) | |
| Stages 1 | 86 (7.7) | 47 (7.3) | 39 (8.2) | |
| Stages 2 | 172 (15.3) | 76 (11.7) | 96 (20.2) | |
| Stages 3 | 448 (39.9) | 257 (39.6) | 191 (40.1) | |
| Mechanical ventilation | 394 (35.1) | 275 (42.4) | 119 (25.0) | < 0.001 |
| PaO2/FiO2 ratio (IQR) | 281.5 (200.4-399.7) | 276.1 (187.8-394.5) | 297.4 (221.0-401.2) | 0.047 |
| Serum creatinine (µmol/l) (IQR) | 80.1 (35.4-166.3) | 81.6 (37.9-184.1) | 77.2 (32.8-142.6) | 0.16 |
| Serum BUN (mmol/l) (IQR) | 2.9 (1.2–5.2) | 2.9 (1.3–5.2) | 2.6 (1.0–5.0) | 0.42 |
| Creatinine clearance (ml/min) (IQR) | 42.1 (32.6–55.8) | 40.7 (31.0-52.4) | 47.9 (35.4–61.3) | 0.017 |
| Total bilirubin (µmol/l) (IQR) | 39.2 (26.1–52.4) | 41.6 (28.7–55.3) | 32.9 (21.7–46.2) | 0.016 |
| CRRT reinstitution | 181 (16.1) | 117 (18.1) | 64 (13.4) | < 0.001 |
| Mortality | 395 (35.1) | 256 (39.5) | 139 (29.2) | < 0.001 |
| ICU discharge | ||||
| AKD stages | < 0.001 | |||
| Stages 0 | 104 (9.3) | 58 (9.0) | 46 (9.7) | |
| Stages 1 | 97 (8.6) | 25 (3.6) | 72 (15.1) | |
| Stages 2 | 110 (9.8) | 52 (8.2) | 58 (12.2) | |
| Stages 3 | 327 (29.1) | 206 (31.8) | 121 (25.4) | |
| Mortality | 486 (43.2) | 307 (47.4) | 179 (37.6) | < 0.001 |
| Hospital discharge | ||||
| AKD stages | < 0.001 | |||
| Stages 0 | 350 (31.1) | 168 (25.9) | 182 (38.2) | |
| Stages 1 | 87 (7.6) | 31 (4.8) | 56 (11.8) | |
| Stages 2 | 86 (7.6) | 47 (7.3) | 39 (8.2) | |
| Stages 3 | 63 (5.8) | 53 (8.1) | 10 (2.1) | |
| Mortality | 538 (47.9) | 349 (53.9) | 189 (39.7) | < 0.001 |
| Data are shown by median (IQR) or n (%). P values comparing between the groups are from χ2 test, Fisher's exact test, or Mann-Whitney U test. AKD: Acute kidney diseases; BUN: blood urea nitrogen; CRRT: Continuous renal replacement therapy; ICU: Intensive care unit; IQR: Interquartile range; PaO2/FiO2: Arterial oxygen tension/fraction of inspired oxygen | ||||
Based on the data of Table 1 and Table 2, compared to low-altitude group, high-altitude patients undergoing CRRT showed worse kidney-related outcomes, including more mechanical ventilation usage at ICU admission (89.2% vs. 83.0%, P = 0.003), 24h after CRRT initiation (64.4% vs. 51.7%, P < 0.001) and CRRT liberation (424.4% vs. 25.0%, P < 0.001); longer durations of mechanical ventilation (7.4 days vs. 5.7 days, P < 0.001), CRRT (4.8 days vs. 3.7 days, P = 0.036), ICU (10.5 days vs. 7.2 days, P = 0.007) and hospitalization (27.4 days vs. 18.9 days, P < 0.001); lower incidence of AKD stage 0 at CRRT liberation (1.9% vs. 2.3%, P = 0.033), ICU (9.0% vs. 9.7%, P < 0.001) and hospital discharge (25.9% vs. 38.2%, P < 0.001); higher possibility of CRRT reinstitution after first liberation attempt (18.1% vs. 13.4%, P < 0.001); as well as higher mortality at 24h after CRRT initiation (27.6% vs. 21.8%, P = 0.031), CRRT liberation (39.5% vs. 29.2%, P < 0.001), ICU (47.4% vs. 37.6%, P < 0.001) and hospital discharge (53.9% vs. 39.7%, P < 0.001).
Both the high-altitude and low-altitude groups had a low incidence of CRRT-related adverse events (Supplementary table 1). Notably, the differences were not significant in terms of minor (9.1% vs. 6.5%, P = 0.12) or major (16.8% vs. 14.3%, P = 0.28) bleeding episodes between these two groups. Although the high-altitude group had lower PLT (188.7×109/L vs. 246.2×109/L, P < 0.001) at the ICU admission (Table 1), the percentages of patients with PLT < 100×109/L of the two groups (33.5% vs. 28.4%, P = 0.069) were similar within the first 72h after CRRT initiation. Owing to the high efficiency of body hemostasis of CVVHDF and CVVHD, the differences of major electrolyte disturbances were not noticed between these two groups (P > 0.05).
Early after randomization, the survival curves diverged in favor of the high-altitude group and remained separated afterwards (log Rank-Chi-square test, P < 0.001) (Supplementary Fig. 1). Moreover, patients in low-altitude group spent more time outside of the ICU (10.5 days vs. 7.2 days, P = 0.007) (Table 1).
The Cox model was used to assess the relevant factors affecting the cumulative probability of renal recovery across the entire cohort. After adjustments for confounders, an independent relationship between altitude and renal recovery was discovered (hazard ratio, 0.36; 95% CI, 0.24 to 0.56; P < 0.001) (Supplementary table 4). Simultaneously, we noticed that death was also correlated to renal recovery (hazard ratio, 1.18; 95% CI, 1.03 to 1.27; P = 0.003) (Supplementary table 4). Even after accounting for death as a competing risk of kidney recovery, the cumulative probability of kidney recovery in the low-altitude group was still higher than that in the high-altitude group (P < 0.001) (Supplementary Fig. 2).
Subsequently, high-altitude patients (n = 648) were divided into early CRRT initiation group (n = 406) and delayed CRRT initiation group (n = 242) based on the time of CRRT initiation to investigate the optimal timing of CRRT initiation. While 476 low-altitude patients were divided into early CRRT initiation group (n = 291) and delayed CRRT initiation group (n = 185) (Fig. 1). For high-altitude patients, the median time from diagnosis of AKI to CRRT initiation in the early group was significantly shorter compared with the delayed group (16.5 h vs. 34.5 h, P = 0.004). Early CRRT initiation group had better kidney-related outcomes than delayed CRRT initiation group, including more rapid recovery of laboratory results of PaO2/FiO2 ratio (189.2 vs. 254.5, P = 0.007), serum creatinine (54.2 µmol/l vs. 109.5 µmol/l, P < 0.001), CCr (45.1 min vs. 37.6 ml/min, P < 0.001), BUN (2.0 mmol/l vs. 4.1 mmol/l, P = 0.002) and total bilirubin (34.2 µmol/l vs. 46.3 µmol/l, P = 0.003) at CRRT liberation; shorter durations of mechanical ventilation (5.8 days vs. 9.9 days, P = 0.028), CRRT (3.5 days vs. 6.3 days, P = 0.014), ICU (7.6 days vs. 14.3 days, P = 0.006) and hospitalization (20.7 days vs. 31.2 days, P < 0.001); higher incidence of AKD stage 0 at CRRT liberation (2.2% vs. 1.2%, P = 0.026), ICU (9.6% vs. 7.9%, P < 0.001) and hospital discharge (33.7% vs. 12.8%, P < 0.001); lower possibility of CRRT reinstitution after first liberation attempt (12.8% vs. 26.9%, P < 0.001) (Table 3 and supplementary table 2). However, no differences were observed between early and delayed CRRT initiation groups for low-altitude patients.
| High-altitude group (n = 648) | P value | Low-altitude group (n = 476) | P value | |||
|---|---|---|---|---|---|---|
| Early CRRT initiation group (n = 406) | Delayed CRRT initiation group (n = 242) | Early CRRT initiation group (n = 291) | Delayed CRRT initiation group (n = 185) | |||
| 24h after CRRT initiation | ||||||
| AKD stages | 0.48 | 0.38 | ||||
| Stages 0 | 4 (1.0) | 2 (0.8) | 3 (1.0) | 3 (1.6) | ||
| Stages 1 | 38 (9.4) | 13 (5.4) | 33 (11.3) | 15 (8.1) | ||
| Stages 2 | 49 ( 12.1) | 26 (10.8) | 32 (11.0) | 28 (15.1) | ||
| Stages 3 | 213 (52.4) | 124 (51.2) | 160 (55.1) | 98 (53.0) | ||
| Mechanical ventilation | 259 (63.8) | 158 (65.3) | 0.74 | 154 (52.9) | 92 (49.7) | 0.50 |
| PaO2/FiO2 ratio (IQR) | 206.2 (157.3-314.5) | 181.8 (114.0-252.9) | 0.085 | 234.1 (182.5-327.6) | 218.7 (158.8-298.4) | 0.098 |
| Serum creatinine (µmol/l) (IQR) | 104.5 (39.8-187.6) | 159.7 (101.1-243.9) | < 0.001 | 81.3 (35.9-152.4) | 95.0 (52.7-181.2) | 0.17 |
| Creatinine clearance (ml/min) (IQR) | 40.6 (28.5–50.1) | 29.3 (20.7–41.4) | < 0.001 | 42.4 (32.5–58.0) | 39.5 (28.3–46.8) | 0.23 |
| Serum BUN (mmol/l) (IQR) | 3.5 (2.3–5.9) | 5.2 (3.9–7.7) | 0.004 | 3.0 (1.4-5.0) | 3.5 (1.9–5.8) | 0.11 |
| Total bilirubin (µmol/l) (IQR) | 31.8 (22.9–43.5) | 33.2 (26.1–48.4) | 0.17 | 25.7 (17.8–38.1) | 27.4 (21.3–43.9) | 0.13 |
| Mortality | 102 (25.1) | 77 (31.8) | 0.070 | 63 (21.6) | 41 (22.2) | 0.91 |
| CRRT liberation | ||||||
| AKD stages | 0.026 | 0.46 | ||||
| Stages 0 | 9 (2.2) | 3 (1.2) | 7 (2.4) | 5 (2.7) | ||
| Stages 1 | 33 (8.1) | 14 (5.8) | 24 (8.2) | 15 (8.1) | ||
| Stages 2 | 60 (14.7) | 16 (6.6) | 46 (15.8) | 40 (21.6) | ||
| Stages 3 | 157 (38.8) | 100 (41.4) | 127 (43.7) | 73 (39.5) | ||
| Mechanical ventilation | 153 (37.7) | 122 (50.4) | < 0.001 | 68 (23.4) | 51 (27.6) | 0.35 |
| PaO2/FiO2 ratio (IQR) | 289.2 (196.7-401.3) | 254.5 (168.3-377.6) | 0.007 | 305.2 (233.8-415.5) | 289.7 (210.6-391.4) | 0.089 |
| Serum creatinine (µmol/l) (IQR) | 54.2 (21.7-168.3) | 109.5 (50.2-224.8) | < 0.001 | 75.9 (31.7-138.6) | 81.1 (33.5-151.9) | 0.095 |
| Serum BUN (mmol/l) (IQR) | 2.0 (1.0-3.9) | 4.1 (2.0-6.8) | 0.002 | 2.5 (1.0-4.6) | 2.8 (1.0-5.5) | 0.10 |
| Creatinine clearance (ml/min) (IQR) | 45.1 (36.3–62.7) | 37.6 (26.8–48.4) | < 0.001 | 48.1 (36.9–62.5) | 46.8 (35.1–59.7) | 0.14 |
| Total bilirubin (µmol/l) (IQR) | 34.2 (22.8–46.5) | 46.3 (32.7–60.8) | 0.003 | 31.8 (20.4–44.9) | 33.5 (23.2–48.0) | 0.093 |
| CRRT reinstitution | 52 (12.8) | 65 (26.9) | < 0.001 | 35 (12.0) | 29 (15.7) | 0.32 |
| Mortality | 147 (36.2) | 109 (45.0) | 0.031 | 87 (29.9) | 52 (28.1) | 0.76 |
| ICU discharge | ||||||
| AKD stages | < 0.001 | 0.75 | ||||
| Stages 0 | 39 (9.6) | 19 (7.9) | 27 (9.3) | 19 (10.3) | ||
| Stages 1 | 18 (4.4) | 7 (2.9) | 41 (14.1) | 31 (16.8) | ||
| Stages 2 | 48 (11.8) | 4 (1.7) | 35 (12.0) | 23 (12.4) | ||
| Stages 3 | 123 (30.4) | 83 (34.2) | 78 (26.8) | 43 (23.2) | ||
| Mortality | 178 (43.8) | 129 (53.3) | 0.023 | 110 (37.8) | 69 (37.3) | 0.92 |
| Hospital discharge | ||||||
| AKD stages | < 0.001 | 0.69 | ||||
| Stages 0 | 137 (33.7) | 31 (12.8) | 111 (38.1) | 71 (38.4) | ||
| Stages 1 | 22 (5.4) | 9 (3.7) | 34 (11.7) | 22 (11.9) | ||
| Stages 2 | 34 (8.4) | 13 (5.4) | 24 (8.2) | 15 (8.1) | ||
| Stages 3 | 11 (2.7) | 42 (17.4) | 8 (2.8) | 2 (1.1) | ||
| Mortality | 202 (49.8) | 147 (60.7) | 0.007 | 114 (39.2) | 75 (40.5) | 0.78 |
| Data are shown by median (IQR) or n (%). P values comparing between the groups are from χ2 test, Fisher's exact test, or Mann-Whitney U test. AKD: Acute kidney diseases; BUN: blood urea nitrogen; CRRT: Continuous renal replacement therapy; ICU: Intensive care unit; IQR: Interquartile range; PaO2/FiO2: Arterial oxygen tension/fraction of inspired oxygen. | ||||||
Supplementary table 3 summarizes the incidence of CRRT-related adverse events in the early CRRT initiation group and the delayed CRRT initiation group. For high-altitude patients, both minor (8.4% vs. 10.3%, P = 0.40) or major (15.0% vs. 19.3%, P = 0.13) bleeding episodes and coagulation functions of PLT (32.2% vs. 35.5%, P = 0.44), APTT (40.8s vs. 45.4s, P = 0.074) or PT (21.8s vs. 27.4s, P = 0.098) were comparable. However, the lower incidence rates of hypokalemia (6.9% vs. 14.0%, P = 0.004), hyperkalemia (9.1% vs. 17.4%, P = 0.003), hyperphosphatemia (10.8% vs. 19.0%, P = 0.005), hyponatremia (5.2% vs. 10.7%, P = 0.012), hypocalcemia (28.8% vs. 42.1%, P = 0.001), acidosis (11.8% vs. 19.0%, P = 0.015) were observed in early CRRT initiation group.
Consistent with the lower mortality in early CRRT initiation group at CRRT liberation (36.2% vs. 45.0%, P = 0.031), ICU (43.8% vs. 53.3%, P = 0.023) and hospital discharge (49.8% vs. 60.7%, P = 0.007) (Table 3) of high altitude patients, the Kaplan–Meier curves analysis also indicated significant survival differences between the two groups (log Rank-Chi-square test, P < 0.001) (Fig. 2). Nevertheless, early CRRT did not seem to influence the survival rates of low altitude patients (P = 0.12). Meanwhile, a positive association of CRRT initiation and renal recovery was calculated in high-altitude group after adjustments for confounders (hazard ratio, 0.25; 95% CI, 0.15 to 0.43; P < 0.001) (Supplementary table 5). Likewise, the cumulative probability of kidney recovery was also statistically higher in the early CRRT initiation group (P = 0.002) (Fig. 3). But the relationship was not likely to be applicable to low-altitude group (Fig. 3 and supplementary table 6).
In this retrospective, multi-center cohort study, our findings indicated that the worse clinical outcomes of patients treated with CRRT for AKI in high altitude. Compared with low-altitude patients, high-altitude patients had a higher mortality rate but a lower rate of kidney recovery. At the same time, altitude was found to be independently correlated to the cumulative probability of kidney recovery. Despite the fact that critically ill patients at high altitude had fewer platelets and more coagulation dysfunction, CRRT for AKI was not likely to increase bleeding risks or other adverse events. In contrast, Kaplan-Meier curves and Cox model analysis revealed that early CRRT initiation may reduce mortality and promote renal recovery in high altitude.
Numerous studies [2, 22–25] have reported on the poor kidney-related outcomes of critically ill patients with AKI in the ICU [2, 23–26]. A meta-analysis of twenty-four observational studies of trauma patients in ICU found that the incidence of post-traumatic AKI was 24%, and their risk of death was 3.4 times higher than those without AKI [26]. Meanwhile, a recent multinational study with over 1800 patients from 97 ICUs in America demonstrated that 57% of patients developed AKI within one week after admission, with the mortality rates ranging from 40–55%, revealing that AKI was the independent risk factor for death in ICU [24, 25]. Our study's findings were consistent with previous researches. During the observation, the overall mortality rate was 47.9%. High-altitude patients died at a significantly higher rate than low-altitude patients (53.9% vs. 39.7%, P < 0.001). However, merely 31.1% of the patients reached stage 0 of AKD and acquired kidney recovery at the end of the study, which differed slightly from previous studies [2, 25]. In addition, high-altitude patients also experienced lower incidence of kidney recovery compare to low-altitude patients (25.9% vs 38.2%, P < 0.001).
The increased risk of AKI mortality in high altitude might be partly contributed to the severe hypoxemia. Our study was conducted in Tibet of China, one of the highest places in the world, with approximately 64% oxygen concentration at the sea level [27]. The native highlanders here suffered from hypoxia all years around. Accumulating studies had demonstrated that hypoxia was directly related to the development of kidney injury symptoms, such as the elevation of blood creatinine and urea, hematuria, proteinuria as well as cytokines and cytokine storms [28–30]. Respiratory syndrome coronavirus 2 (SARS-CoV-2) caused body oxygen deficiency due to lung damages, leading to 5–23% of patients diagnosed with AKI in hospital and 68% in ICU [31, 32]. Although the precise mechanisms were unclear, hypoxia-inducible factor (HIF) signaling pathway and reactive oxygen species (ROS) resulting in regulated cell death of renal tubular cells might play an important role in AKI [33]. In our study, differences of oxygenation function between the high-altitude and low-altitude groups were in accordance with that of mortality. Although no changes of PaO2/FiO2 ratio were found at ICU admission between the two groups (P = 0.075), high-altitude patients had a slower recovery of PaO2/FiO2 ratio at 24h after CRRT initiation (P = 0.024) and CRRT liberation (P = 0.047). Two possible reasons were speculated for the PaO2/FiO2 ratio consistency at ICU admission: on the one hand, chronic high-altitude exposure resulted in many positive adaptations involving the stability of the PaO2/FiO2 ratio in native highlanders [27]; on the other hand, the majority of critically ill patients in ICU developed expiratory muscle weakness and oxygenation disorders, which might have narrowed the gaps of PaO2/FiO2 ratio at ICU admission [34]. However, the changes in PaO2/FiO2 ratio were not entirely consistent with the mechanical ventilation results. In our study, high-altitude patients were likely to require more frequent and longer mechanical ventilation, indicating that these patients had persistent hypoxia. Further research into the pathogenesis and mechanisms of hypoxemia and AKI mortality at high altitude will be critical in understanding this phenomenon.
The polycythemia of highlanders was another possible pathogenetic mechanism underlying the higher mortality of AKI in high altitude. Excess erythrocytosis, characterized as hemoglobin (Hb) > 190 g/L, was found to be more common in native highlanders living at altitudes above 2500m [6]. Long-term exposure to hypoxic environment of high altitude would upregulate the expression of HIF-2α, resulting in polycythemia with high blood viscosity and a remarkable decrease in renal plasma flow [6, 35]. When the increased filtration fraction failed to compensate for the reduction in chronic hypoxia, mechanical stress-induced kidney injury occurred [6, 33]. As a result, persistent kidney injury and death from AKI were more likely to be presented in high altitude areas.
CRRT had been widely used for the management of critically ill patients in ICU. However, the incidences of CRRT related adverse effects were highly scrutinized and needed to be reduced in order to promote CRRT quality and patients’ safety [36]. The main concerns about CRRT were bleeding risks and electrolyte losses. Anticoagulation therapy, including heparin and citrate anticoagulation, was applied to prevent filter overclotting, but at the expense of increased bleeding risks [36]. Notably, bleeding risks in high altitude might be more dangerous because various reports had described the detrimental coagulation disorders there [37]. Our findings, however, revealed no differences in bleeding risks or blood transfusion requirements between the high-altitude and low-altitude groups. At least two reasons contributed to the safety of CRRT in our study. On the one hand, citrate anticoagulation, the most common applied in our study, had little influence on coagulation as previous reported [38]. On the other hand, heparin dosage adjustments should strictly adhere to the laboratory results of APTT. Accurate calculation of heparin dose in our study avoided the accidental occurrence of bleeding risks and other adverse events. However, despite the comparable anticoagulation strategies between high altitude group and low altitude group (Table 1), we must admit that the comparison of bleeding risks for those who only applied heparin between the two groups seemed more persuasive, because the differences might be underestimated when the comparison was conducted in the whole cohort. Further study was needed to confirm the adverse effects of heparin for CRRT in high altitude. Besides, the molecular losses need to be emphasized for hemostasis owing to the nonselective dialysis of CRRT membranes [38]. Because of the standardized CRRT prescription, the results of electrolyte levels of the two groups were comparable. According to the findings of our study, CRRT for critically ill patients of AKI was relatively safe in high altitude on the premise of a standard dynamic evaluation approach and specialized group.
Our findings also indicated the difficulty of kidney recovery in high altitude after AKI. Based on the results of Cox model analysis, patients in high altitude experienced a lower cumulative probability of kidney recovery compared with those in low altitude (P < 0.001). The kidney of AKI, unlike chronic kidney disease (CKD), may be resolved to some extent, though the course may range from several days to years [1, 39]. A prospective cohort study proved that early recovery of kidney function was closely linked to better long-term outcomes of AKI-D [40]. Our results were in accordance with the previous study. The high-altitude group's early recovery of kidney function was also lower at 24h after CRRT initiation (P < 0.05). The Randomised Evaluation of Normal versus Augmented Level of Renal Replacement Trial (RENAL) study previously demonstrated that CRRT could aid renal recovery [41]. However, the application of CRRT did not seem to completely offset the effects of altitude on the outcomes of AKI patients. There were two possible reasons that contributed to the failed kidney recovery in high altitude. The first one was the persistent existence of uncorrectable hypoxia. In spite of mechanical ventilation, long-term high-altitude exposure kept the body in a condition of hypoxia, resulting in continuous kidney damage [29, 30, 42]. The second one was the poorer condition of kidney in high altitude. High-altitude renal syndrome impeded the kidney function recovery of these patients [6, 16].
The optimal timing of CRRT initiation in critically ill patients with AKI had long been debated. Considering economic benefits and possibility of renal function recovery in absence of CRRT, a watchful waiting strategy for those patients of AKI without the life-threatening hyperkalemia or hemodynamics dysfunction was confirmed safe and effective [2, 43]. A study focusing on AKI patients with septic pointed out no significant differences of mortality at 90 days between the early and delayed CRRT strategy [21]. However, many nephrologists advocated the early initiation of CRRT in ICU for its potential superiorities in fluid control, inflammatory cytokines removal, body homeostasis and severe complications prevention [23, 44, 45]. Another single-center clinical trial involving 231 critically ill patients with AKI showed early CRRT application was more likely to reduce mortality over the first 90 days [20]. However, according to our findings, early CRRT initiation might rather contribute to a higher rate of survival and kidney recovery in high altitude than that in low altitude. Moreover, the early CRRT initiation in high altitude also had a lower incidence of CRRT-related adverse events. The heterogeneity of the studied populations was one of the possible reasons for the advantages of early CRRT initiation in our study. In contrast to previous studies, we paid attention to the high altitude population here. Just as aforementioned, high-altitude patients with AKI had worse outcomes and faster progressions, which appeared to make early CRRT initiation more beneficial to them [2, 23, 24]. Besides, electrolyte disorders and cytokine imbalances resulted from hypoxia tended to occur in high-altitude patients, leading to severe damages to kidney coupled with AKI [6, 8, 9]. Thus, elimination of redundant products by early CRRT might provide an opportunity for kidney rest and repair for those patients. However, additional researches were required to validate the hypothesis. Our results at least offered one of the efficient ways to solve the increase mortality of critical patients with AKI in high altitude.
Our study still has several limitations. First of all, although a large amount of cases and time points had been designed to predict outcomes of AKI, 60 days’ follow-up might not be long enough to detect the differences in long-term survival or cumulative probability of renal recovery between groups. Actually, follow-up after hospital discharge might be more meaningful in determining the kidney-related outcomes. But the data for this retrospective study was difficult to obtain. Secondly, the majority of baseline serum creatinine values in our study were unavailable. As a result, we tried best to estimate the baseline values with the serum creatinine at hospital discharge as an alternative for AKI-D diagnosis and staging. But we must admit the possibility of bias in our study. Thirdly, due to the inherent flaws of retrospective study, there were no completely predefined standard criteria of CRRT practices before the study. We could not exclude the possibility of physicians making empirical decisions about CRRT initiation, termination or reinstitution. A larger, prospective study was warranted to confirm our findings. Fourthly, other criteria have been used to define the timing of the initiation of CRRT, such as BUN, urine output, AKI staging, and others. Here, only the time from diagnosis to CRRT initiation focused in this study might affect the results.
In this retrospective, multicenter cohort study, we suggested the worse clinical outcomes of patients undergoing CRRT for AKI in high altitude. Compared with low-altitude patients, high-altitude patients experienced higher mortality and worse kidney related outcomes. At the same time, altitude was independently correlated to the cumulative probability of kidney recovery. In spite of fewer platelets and coagulation dysfunction in critically ill patients in high altitude, CRRT for AKI was not likely to increase the bleeding risks and other adverse events. Conversely, the results of Kaplan–Meier curves and Cox model analysis showed that early CRRT initiation might decrease the mortality and promote renal recovery of high-altitude patients.
Data Availability Statement
The original contributions presented in the study are included in the article or supplementary information. Further inquiries can be directed to the corresponding authors
Author Contributions
BW and YD were responsible for the study concept, designed the study, and took responsibility for the integrity of the data and the accuracy of the data analysis. BW, MJ, HH, and CL collected the data. BW, MJ, JW, JH, and FF drafted the paper and did the statistics analysis. YD and YL revised the manuscript and gave final approval for the version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors contributed to the article and approved the submitted version.
Conflict of Interest
All authors declare no competing interests.
Acknowledgements
Environmental data were kindly provided by CDC of Tibet Military Command. We are grateful to Dr. Kaige Peng for his help for statistics analysis. We are also appreciate to our specialized intensive care groups for their dedication to the management of CRRT.