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.