key: cord-0717107-sft3ndxq authors: Park, Bryan D.; Faubel, Sarah G. title: Acute Kidney Injury and Acute Respiratory Distress Syndrome date: 2021-05-27 journal: Crit Care Clin DOI: 10.1016/j.ccc.2021.05.007 sha: c14539f0d8c96dad3948a1270d2ed79bc0141058 doc_id: 717107 cord_uid: sft3ndxq The most consistent signal for mortality in acute respiratory distress syndrome (ARDS) is multi-organ failure, specifically when it involves the kidneys. Acute kidney injury (AKI) complicates approximately a third of all ARDS cases, and the combination of the two drastically worsens prognosis. Recent advances in ARDS supportive care have led to improved outcomes, however, much less is known on how to prevent and support patients with AKI and ARDS together. Understanding the dynamic relationship between the kidneys and lungs is crucial for the practicing intensivist in order to prevent injury. In this review, we summarize key concepts for the critical care physician managing a patient with ARDS complicated by AKI, including crucial regarding renal replacement therapy. We will finally end on a discussion of AKI in the COVID-19 era. managing a patient with ARDS complicated by AKI, including crucial regarding renal replacement therapy. We will finally end on a discussion of AKI in the COVID-19 era. • AKI in conjunction with ARDS portends a poor prognosis and can help guide the intensivist in goals of care discussion. • AKI can affect the lungs in multiple ways via traditional (e.g., volume overload) and non-traditional (e.g., systemic inflammatory mediators) complications. • Maintaining appropriate fluid balance and ensuring adequate treatment for the underlying cause of ARDS are crucial. • In the event that a patient becomes anuric, renal replacement therapy should be considered. Initiation and management of such treatment should involve a continuous dialogue between the intensivist and nephrologist. survival rate was much lower compared to the entire cohort of patients studied ( Figure 1 ). 26 Severe AKI requiring renal replacement therapy (RRT) was associated with up to 50% mortality, 27 and one retrospective study demonstrated increased ventilator days (10 versus 7 days) and duration of weaning (41 versus 21 hours) in those with ARDS complicated by AKI versus ARDS alone. 28 Traditional complications of AKI such as electrolyte derangements, uremia, and fluid overload have long been considered to contribute to the poor pulmonary outcomes associated with AKI; however, research over the last two decades highlights the importance of non-traditional consequences of AKI (Table 2) . 29 The importance of nontraditional complications to outcomes after AKI is evidenced by the fact that RRT is wellknown to correct the traditional complications of AKI, yet the mortality of AKI requiring RRT in the ICU is 50 to 60%. 30-33 Thus, improving mortality rates in patients with AKI will require therapies targeted beyond modifications and improvements to RRT. AKI and its effects on the lungs has been well studied in animal models. 34 Overall, treatment strategies for patients with both ARDS and AKI is similar to the treatment of either condition alone. Below we discuss the general approach to ARDS and AKI, and how care of one may influence overall treatment and physiology when the two are together. In general, the identification and treatment of underlying causes for ARDS (e.g. sepsis, trauma, and burns) will ensure optimal outcomes. The supportive treatment options for ARDS have been well-studied. 59 The 2012 KDIGO recommendations for the management of AKI has been widely adopted and serve to help the clinician with both prognostication and diagnostic/treatment decisions. 6 Since its publication, several studies have shown that implementation of these guidelines may aid in prompt diagnosis and management of AKI in susceptible populations leading to improved clinical outcomes. 74-76 The first step is to obtain an accurate diagnosis of AKI and identify the cause of kidney injury whenever possible. Next, the prevention of worsening injury revolves around maintaining adequate organ perfusion, avoiding volume overload, avoiding hyperglycemia, discontinuing nephrotoxic agents, and renally dosing medications. Lastly, when such maneuvers are inadequate and the patient develops worsening complications of AKI (e.g. fluid overload, hyperkalemia), RRT is the next appropriate treatment modality to consider. Third, there is no firm consensus on the optimal RRT modality in AKI. Continuous renal replacement therapy (CRRT) is generally preferred over intermittent hemodialysis (iHD) and prolonged intermittent renal replacement therapy (PIRRT) due to perceived J o u r n a l P r e -p r o o f hemodynamic instability in the critically ill. One recent meta-analysis comparing CRRT, iHD, and PIRRT showed no clear advantage of one modality over another on short-term mortality and dialysis dependence. 80 CRRT is associated with a high incidence of severe hypophosphatemia occurring in up to 70% of patients. [81] [82] [83] Phosphate is essential for all cells and is important for cell membrane integrity, bone structure, cell signaling, acid-base buffering, and energy storage in the form of adenosine triphosphate. 84 As such, severe hypophosphatemia has been implicated in respiratory muscle failure and prolonged duration of mechanical ventilation. [85] [86] [87] Additionally, reduced levels of phosphate can impair myocardial contractility and lead to arrhythmias which may be improved once hypophosphatemia is corrected. 84 Hypophosphatemia has been associated with prolonged MV, 88 longer vasopressor duration, 88 longer duration of CRRT use, 83 longer ICU stays, 83 and higher doses of CRRT. 89 Therefore, it is important to monitor and treat the common complication of hypophosphatemia in RRT patients. SARS-CoV-2 is a novel coronavirus that was first reported in December 2019, 90 and has since become the most significant pandemic in the modern era. Initial reports suggested that the rates of AKI were low, 91,92 however, more recent data suggests AKI to be a common complication with values reported as high as 37%. [92] [93] [94] [95] The ICU J o u r n a l P r e -p r o o f incidence of AKI is more significantly elevated at over 50% in multiple studies, and has been associated with significant mortality. 94, 96, 97 Notably, a large registry from the European Renal Association-European Dialysis and Transplant Association has shown a high short term mortality rate of 20% for both dialysis and renal transplant patients. 98 Independent risk factors for AKI included elderly, black ace, diabetes, cardiovascular disease, hypertension, MV, and vasopressor use. 94, 99 The pathophysiologic mechanism underlying AKI in COVID-19 is still incompletely understood. The best evidence to date indicates that the underlying mechanism is similar to severe sepsis with one case series reporting acute tubular necrosis in approximately 66% of cases. 97 Another important consideration is the cytokine storm phenomenon experienced in severe COVID-19 ARDS patients, which may lead to hypotension and sepsis further compromising renal perfusion. Focal kidney fibrin thrombi have been identified in histologic specimens, but are not currently thought to directly contribute to AKI and are instead considered a sequelae of deranged coagulopathy. 100 AKI in COVID-19 patients may also be as a result of prerenal azotemia and tubular injury as a result of toxic insults, such as rhabdomyolysis. 101 Collapsing glomerulopathy is an uncommon, but well-established cause of AKI that is associated with nephrotic syndrome and has been described particularly in the setting of high-risk APOL1 alleles. 102 immune pathway activation, and angiotensin dysregulation. 104 However, these studies also report on patient samples that did not demonstrate significant viral particle staining. At time of submission, there are two therapies approved for use in severe COVID-19 illness (remdesivir and dexamethasone), 105 . Of note, remdesivir is currently contraindicated in those with a reduced GFR, but recent evidence suggests that it may be suitable in those receiving RRT. 106 The initial concern for remdesivir use in patients with AKI revolved around the nephrotoxic accumulation of sulfobutylether-β-cyclodextrin (SBECD), but evidence suggests there is adequate removal of SBECD with dialysis. 106,107 The risk of venous thromboembolism seems to be higher in this syndrome, however, recent critical care guidelines recommend against full anticoagulation without evidence of venous thromboembolisms, and recommend typical thromboprophylaxis and monitoring as key. 108 The indications for RRT in the management of severe AKI in the setting of COVID-19 disease are the same as for other critically ill patients. 95, 109 One important distinction is the use of anticoagulation since higher incidence of filter clotting during CRRT in COVID-19 disease has been reported. [110] [111] [112] Several studies have reported distinct perturbations in the clotting cascade in COVID-19 patients including J o u r n a l P r e -p r o o f thrombocytopenia and prolonged prothrombin/partial thromboplastic time, which may contribute to the high incidence of filter clotting. 111, 113, 114 CRRT filter clotting is an important concern as it can lead to blood loss and lost time on RRT. ADQI guidelines for the management of AKI in COVID-19 patients recommend the use of anticoagulation if not otherwise contraindicated, monitoring for impending signs of circuit failure, and establishing center-specific stepwise escalation options for CRRT anticoagulation. 95 Finally, as the pandemic continues, there is concern about dialysis and CRRT availability, including consumables, machines, and staff. 115 Critical shortages were seen during the initial surge in New York City and similarly experienced abroad; therefore preparation of resources in the coming months will be key. 115, 116 Summary AKI is a common complication during hospital and ICU stays, and is particularly problematic when coexisting with ARDS. Previous studies have highlighted that AKI is an independent predictor for death in patients who are critically ill with acute lung injury. Clinical and experimental data indicate that there is significant cross talk between injured kidneys and the lung, and that AKI exerts a multitude of deleterious effects on the lung via fluid overload leading to cardiogenic pulmonary edema, cytokine excess leading to non-cardiogenic pulmonary edema, and others. The organ-organ effects of kidney and lung injury have been especially poignant in the era of the novel SARS-CoV- Advances in critical care for the nephrologist: acute lung injury/ARDS Acute kidney injury in patients with acute lung injury: impact of fluid accumulation on classification of acute kidney injury and associated outcomes Refining predictive models in critically ill patients with acute renal failure Acute Kidney Injury Network: report of an initiative to 79 Strategies for the optimal timing to start renal replacement therapy in critically ill patients with acute kidney injury Systematic review and meta-analysis of renal replacement therapy modalities for acute kidney injury in the intensive care unit Hypophosphatemia during continuous veno-venous hemofiltration is associated with mortality in critically ill patients with acute kidney injury Phosphate supplementation for hypophosphatemia during continuous renal replacement therapy in adults Predictors of Hypophosphatemia and Outcomes during Continuous Renal Replacement Therapy Treatment of hypophosphatemia in the intensive care unit: a review Hypophosphatemia as a cause of failed weaning: the importance of metabolic factors Effect of hypophosphatemia on diaphragmatic contractility in patients with acute respiratory failure Hypophosphatemia-associated respiratory The relationship between hypophosphataemia and outcomes during low-intensity and high-intensity continuous renal replacement therapy A Novel Coronavirus from Patients with Pneumonia in China Coronavirus Disease 19 Infection Does Not Result in Acute Kidney Injury: An Analysis of 116 Hospitalized Patients from Wuhan, China Clinical Characteristics of Coronavirus Disease 2019 in China Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Acute kidney injury in patients hospitalized with COVID-19 COVID-19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup Acute Kidney Injury in Hospitalized Patients with COVID-19 Results from the ERA-EDTA Registry indicate a high mortality due to COVID-19 in dialysis patients and kidney transplant recipients across Europe Clinicopathological Features and Outcomes of Acute Kidney Injury in Critically Ill COVID-19 with Prolonged Disease Course: A Retrospective Cohort Postmortem Kidney Pathology Findings in Patients with COVID-19 COVID-19-Associated Kidney Injury: A Case Series of Kidney Biopsy Findings AKI and Collapsing Glomerulopathy Associated with COVID-19 and APOL 1 High-Risk Genotype Kidney Biopsy Findings in Patients with COVID-19 Acute Kidney Injury in COVID-19: Emerging Evidence of a Distinct Pathophysiology COVID-19) Treatment Guidelines. National Institutes of Health Prevention, Diagnosis, and Treatment of VTE in Patients With Coronavirus Disease COVID-19) Treatment Guidelines. National Institutes of Health High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study Filter clotting with continuous renal replacement therapy in COVID-19 Anticoagulation Strategies and Filter Life in COVID-19 Patients Receiving Continuous Renal Replacement Therapy: A Single-Center Experience Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia Incidence of thrombotic complications in critically ill ICU patients with COVID-19 COVID-19 in dialysis patients: outlasting and outsmarting a pandemic