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REVIEW ARTICLE Table of Contents  
Ahead of print publication
Sepsis-associated acute kidney injury and the need for renal replacement therapy: A physician's perspective


 Department of Nephrology, Command Hospital Air Force, Bengaluru, Karnataka, India

Click here for correspondence address and email

Date of Submission05-Mar-2021
Date of Decision05-May-2021
Date of Acceptance13-Jun-2021
Date of Web Publication02-Mar-2022
 

  Abstract 


Sepsis associated acute kidney injury is a very common complication and carries unacceptable mortality in the setting of critical illness. Physicians should be very prompt to recognise it an an eartly stage, as providing supporting care early will limit further insults to the kidney. By the time patients seek medical attention, acute kidney injury has already happened. Microvascular dysfunction, inflammation, and metabolic reprogramming are three mechanisms that have been proposed to explain the pathophysiology of acute kidney injury associated with sepsis. The role of early renal replacement therapy /blood purification technique is still controversial. We need more studies to better understand the complex pathophysiology of this complication and translate these findings into potential treatment strategies. In this review, new definitions of sepsis and acute kidney injury, risk factors, pathophysiology and management strategies of sepsis- associated acute kidney injury are being discussed.

Keywords: Biomarkers, renal replacement therapy, sepsis-associated acute kidney injury, septic shock


How to cite this URL:
Jha VK, Mahapatra D. Sepsis-associated acute kidney injury and the need for renal replacement therapy: A physician's perspective. APIK J Int Med [Epub ahead of print] [cited 2022 Sep 25]. Available from: https://www.ajim.in/preprintarticle.asp?id=338898





  Introduction Top


Sepsis is a clinical syndrome in which there is a dysregulated host response to infection resulting in physiologic, biologic, and biochemical abnormalities. A 2016 Society of Critical Care Medicine and the European Society of Intensive Care Medicine task force has defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection (Sepsis-3).[1],[2] Organ dysfunction is defined by an increase of two or more points in the sequential organ failure assessment (SOFA) score. Septic shock, a type of vasodilatory or distributive shock, is defined as sepsis that has circulatory, cellular, and metabolic abnormalities that are associated with a greater risk of mortality than sepsis alone (≥40% vs. ≥10%).[3] These patients despite fluid resuscitation require vasopressors to maintain a mean arterial pressure (MAP) ≥65 mmHg and have lactate >2 mmol/L.[1]

The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines define acute kidney injury (AKI) as an increase in serum creatinine by ≥0.3 mg/dl within 48 h, or increase in serum creatinine to 1.5 times baseline, which is known or presumed to have occurred within the prior 7 days, or urine volume <0.5 ml/kg/h for 6 h. The KDIGO criteria allow for correction of volume status and obstructive cause of AKI before classification. AKI is staged using the KDIGO criteria, as given in [Table 1].
Table 1: Kidney disease improving global outcome criteria for staging of acute kidney injury[68]

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  Acute Kidney Injury in Critically Ill Patients Top


A recent multinational study with more than 1800 patients from 97 intensive care units (ICUs) reported that AKI of any stage developed within 1 week of admission in 57% of patients.[4] Stage 2 or 3 AKI occurred in 39% of total patients, and 13.5% required renal replacement therapy (RRT). AKI is an independent risk factor for ICU mortality. Mortality rates of AKI requiring RRT (AKI-RRT) range from 40% to 55%. AKI survivors are also more likely to develop significant morbidities such as chronic kidney disease, end-stage renal disease, and mortality.[5] The mortality of AKI remains high due to multi-organ dysfunction.[6]


  Sepsis-Associated Acute Kidney Injury Top


Sepsis remains the most important cause of AKI in ICU. Many patients meet consensus criteria for both sepsis and AKI and are deemed to have sepsis-associated AKI (SA-AKI). About 15–20% of patients with SA-AKI were prescribed RRT.[7] In ICUs, abdominal infections are the most common association of SA-AKI.[8] Other risk factors often coexist whenever AKI develops in the context of sepsis which complicates the assessment and management of these patients. Sepsis is associated with 50% of AKI, and up to 60% of patients with sepsis have AKI.[7],[9] Patients with sepsis complicated by AKI have a significantly increased mortality relative to patients without AKI. In the same way, patients with AKI associated with sepsis have a significantly increased mortality relative to those with AKI of another etiology.[8],[10]


  Risk Factors for Sepsis-associated Acute Kidney Injury Top


Identified risk factors for AKI in a general population will confer an equal or even greater risk in patients with sepsis [Table 2]. Observational data suggest that AKI may predispose patients to an increased risk of sepsis. In the Program to Improve Care in Acute Renal Disease study, among the 611 patients with data on sepsis status, 174 (28%) had sepsis before AKI, 194 (32%) remained sepsis free, and 243 (40%) developed sepsis a median of 5 days after AKI.[14] Sepsis developing after AKI portends a poor prognosis with high mortality rates and relatively long length of stay in hospital. Oliguria, higher fluid accumulation and severity of illness scores, nonsurgical procedures after AKI, and provision of dialysis were predictors of sepsis after AKI.[14] In another study,[15] the most important risk factors for the development of AKI in ICU were acute circulatory or respiratory failure, age >65 years, presence of infection, history of heart failure, lymphoma or leukemia, or cirrhosis. Oliguric AKI was an independent risk factor for ICU mortality, and infection increased the contribution to mortality by other factors.[15]
Table 2: Risk factors for sepsis-associated acute kidney injury

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  Pathophysiology of Sepsis-associated Acute Kidney Injury Top


The traditional paradigm that sepsis-related AKI is initiated by renal ischemia as a result of macrovascular dysfunction is under debate, as AKI can develop in the presence of normal or increased renal blood flow (RBF). It was demonstrated in a human study that decreased RBF was not a universal finding in patients with sepsis-induced AKI.[16],[17] New evidence suggests that the inflammatory response causes an adaptive response of the tubular epithelial cells which induces downregulation of the cell function to minimize energy demand and to ensure cell survival. The simultaneous occurrence of renal inflammation and microvascular dysfunction exacerbates the adaptive response of tubular epithelial cells to injurious signals. The endothelial cell injury is also important in the initiation and development of SA-AKI through the nitric oxide pathway, leukocyte adhesion, reactive oxygen species (ROS), and inflammation.[18],[19] Proposed mechanisms leading to SA-AKI are given in [Table 3].
Table 3: Pathophysiology of sepsis-related acute kidney injury

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Disturbances in microcirculatory oxygen delivery may include both decreased flow and diffuse limitation in the setting of organ edema and inflammation.[20] This increases the expression of inflammatory cytokines and leukocyte activity, resulting in capillary plugging and microthrombi. Production of ROS and induction of nitric oxide synthase may further damage the endothelial barrier and the glycocalyx, leading to both structural and functional changes in the setting of sepsis-related AKI.[20],[21]


  Early Detection of Sepsis-associated Acute Kidney Injury and Biomarkers Top


Changes in serum creatinine are often delayed owing to renal reserve and kinetics of AKI. Urine output is often measured inaccurately except in the setting of ICU and is insensitive. Multiple retrospective cohort studies also suggest that the same stage of AKI diagnosed by serum creatinine and urine output may confer differential risk. SA-AKI shows more renal tubule epithelial cells and cast elements compared with nonseptic AKI. A single-center observational study of 423 patients with sepsis showed that new albuminuria was associated with an odds ratio of 1.87 (1.21–2.89) for developing SA-AKI, even after adjustment for baseline GFR, severity of critical illness, and exposure to nephrotoxins.[22] Routine dipstick albuminuria has also been shown to be independently associated with lower rates of recovery from AKI.[23]

Only one validated score predicts mortality in patients with SA-AKI who need RR.[24] The performances of critical illness scores and nonspecific AKI risk scores have been disappointing.[25],[26] Several biomarkers such as proenkephalin and cystatin C are both highly associated with AKI and GFR and increase before serum creatinine in critically ill patients with sepsis.[27],[28] One study evaluated the ability of urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein-7 (TIMP2*IGFBP7), markers of cell cycle arrest, to predict the development of Stage 2 or 3 AKI in 232 high-risk critically ill patients with sepsis. The biomarker performed similarly regardless of severity of illness (SOFA score), and a cutoff of 1.0 provided a sensitivity of 77.5% and a specificity of 75% for the development of severe AKI.[29] Neutrophil gelatinase-associated lipocalin (NGAL), which is commercially available in several countries, is upregulated along the renal tubule in the setting of ischemic injury, nephrotoxins, and inflammation. However, NGAL data have been inconsistent in SA-AKI.[30] Biochemical measures such as NGAL or TIMP2*IGFBP7 and real-time data from the electronic health record may be used to identify patients with either sepsis or AKI, and automated alerts for these patients may be combined with biochemical biomarker testing to improve risk stratification and case detection for SA-AKI.

Management strategies of SA AKI are given in [Table 4].
Table 4: Management strategies in a case of sepsis-related acute kidney injury

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  Resuscitation Fluids Top


Sepsis leads to endothelial dysfunction and consequent loss of barrier function and vasomotor tone. This results in hypotension requiring prompt resuscitation of the circulation with intravenous fluids administration. Hyperoncotic starch solutions should be avoided in sepsis and all other patients at risk for AKI, as multiple studies have shown that hydroxyethyl starches are associated with increased risk of AKI and need for RRT compared with a variety of crystalloid solutions.[31] As compared to balanced crystalloid solutions, hyperchloremic crystalloid solutions may be associated with increased AKI and mortality.[32] Subset analysis of patients with sepsis also showed that balanced crystalloids were associated with an even greater reduction in major adverse kidney events, as well as the 30-day mortality component of the composite endpoint.[34] Among the patients who benefitted the most were those who developed some degree of hyperchloremia and kidney injury before enrollment in the study.[33],[34] Although in these trials relatively low volumes of resuscitation fluid were used (approximately 2 L over the first three days), they suggest that balanced crystalloid solutions may improve renal outcomes and survivorship in nonselected and septic critically ill patients.


  Vasoactive Drugs Top


Norepinephrine has been regarded as the mainstay of treatment of septic shock based on many clinical trials suggesting either better outcomes or fewer adverse events than with other vasoactives. Few data suggesting that norepinephrine may exacerbate renal medullary hypoxia as the kidney attempts to preferentially shunt blood flow to the cortex have led to use of other agents.[35] Vasopressin and Septic Shock Trial comparing norepinephrine with vasopressin showed similar outcomes and no increased adverse events across all study patients and a survival benefit in subgroup analysis of patients with less severe shock.[36] The VANISH trial was a prospective, double-blind, randomized clinical trial with a two-by-two (vasopressin or norepinephrine, hydrocortisone or placebo) factorial design in the setting of septic shock.[37] No difference by vasopressor was seen in the development of AKI in patients who survived (vasopressin group 57.0%, norepinephrine group 59.2%), in AKI-free days among patients who died in the hospital (vasopressin group 33.3%, norepinephrine group 29.4%), or in serious adverse events. These data may suggest that vasopressin is a viable first-line alternative to norepinephrine. It has been suggested that phenylephrine and to an even greater extent, dopamine should be avoided as first-line treatment of septic shock.[38],[39] Angiotensin II, a hormone in the renin–angiotensin-aldosterone system, is a novel agent recently investigated in the setting of shock.[40] A small subgroup analysis of patients treated with RRT showed that those receiving angiotensin II needed less RRT, were more likely to survive through day 28 (53% vs. 30%; P = 0.012), and were more likely to be alive and RRT free by day 7 (38% v 15%; P = 0.037) compared with placebo. If these results are validated in larger cohorts, angiotensin II may represent a novel treatment for SA-AKI.[40]

Norepinephrine and vasopressin remain consensus first-line agents for the treatment of septic shock, although treatment should be individualized. Although previous studies have shown that MAP targets higher than the 65 mmHg recommended in sepsis guidelines decreased the rate of RRT in patients with hypertension, this did not translate to improved survival.[41]


  Mechanical Ventilation Top


Mechanical ventilation with positive pressure (PPV) has long been known to have potentially deleterious effects on kidney perfusion and function.[42] PPV increases intrathoracic pressure and reduces venous return, cardiac output, and renal perfusion.[43] In a randomized controlled trial (RCT) of low tidal volume ventilation in ARDS, renal failure was seen less often in patients in the lower tidal volume intervention arm.[44] Mechanical ventilation probably also induces both neurohormonal and inflammatory changes that potentially increase the risk for AKI. Both mechanical ventilation and the ventilator strategy of permissive hypercapnia are known to induce sympathetic tone and the renin–angiotensin system, decreasing RBF, redistributing renal flow to the medulla, and decreasing GFR.[43] In addition, mechanical ventilation at any volume or pressure has consistently been shown to create a cascade of inflammation including multiple interleukins, tumor necrosis factor-α, and Fas ligand that may contribute to AKI.[43]


  Drugs Used in Sepsis-associated Acute Kidney Injury Top


The prophylactic use of diuretics to prevent AKI is unsuccessful and potentially harmful in critically ill patients.[45],[46] Diuretics have not been shown to ameliorate or attenuate AKI once it is established.[47] However, their utility in regulating and maintaining fluid balance advocates their continued use in the setting of critical illness. In secondary analysis of a single-center randomized, double-blind, placebo-controlled trial of 70 patients with septic shock, those randomized to receive intravenous thiamine (200 mg twice a day for 7 days) had less severe AKI and fewer patients receiving RRT.[48] The role of steroids remains controversial in setting of sepsis, but two recent studies showed limited effects on SA-AKI. APROCCHSS trial, which looked at hydrocortisone and fludrocortisone, showed no difference in the need for RRT between patients who did and did not receive steroids (27% vs. 28.1%).[49] ADRENAL trial showed no difference in the use of RRT (30.6% in hydrocortisone group; 32.7% in placebo group; P = 0.18), and no difference in number of days spent alive and RRT free (P = 0.29).[50] Most investigation of erythropoietin and AKI has occurred in cardiac surgery patients, but two large trials investigating its use in mixed ICU populations failed to show improvement in AKI outcomes.[51],[52] Large-scale prospective RCT of surgical ICU patients showed 41% reduction in AKI requiring RRT with blood sugar between 80 and 110 mg/dL,[53] but this effect was not validated in several follow-up studies including investigation specifically in patients with sepsis. Follow-up studies in ICU patients showed no renal effects and perhaps signal for increased mortality with blood sugar 81–108 mg/dl.[54] Meta-analysis of seven RCTs showed no effect on mortality across statin agents and several dosing ranges.[55]


  Renal Replacement Therapy Top


Several trials have focused on patients specifically with SA-AKI, and these are summarized in [Table 5]. The sepsis and SA-AKI-specific data around the timing of RRT point to potential harm with earlier initiation. In a recent post hoc analysis of the Artificial Kidney Initiation in Kidney Injury trial in 174 patients in each arm with septic shock, no difference in 60-day mortality was seen between the early and delayed arms. A significant increase was seen in renal recovery, as measured by urine output, in patients in the delayed arm.[63] These findings, suggesting the benefits of delayed RRT, were not replicated by a recent trial investigating the timing of RRT in ICU patients (32% with severe sepsis).[64]
Table 5: Timing and dose of renal replacement therapy in various trials in sepsis-associated acute kidney injury

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The dose of RRT has also been extensively studied in the setting of SA-AKI, with several studies showing no benefit to the increased dosing of RRT [Table 5]. Much of the dosing guidelines stem from two large-scale multicenter RCTs; however, these two trials were not exclusively done in the setting of SA-AKI. The Veterans Administration-NIH Acute Renal Failure Trial Network enrolled 1055 patients, 579 (54.9%) of whom had sepsis; the Randomized Evaluation of Normal versus Augmented Level (RENAL) Replacement Therapy Trial studied 1465 patients, 723 (49.3%) of whom had severe sepsis. Their combined results have shown that if continuous RRT is needed, the recommended delivered dose should be 20–25 mL/kg/h, with close attention being paid to all drug dosing.[65],[66] As the delivered dose is often lower than the prescribed dose, so in the setting of SA-AKI, the dosing of continuous RRT should be at least at the 30–35 mL/kg/h range to ensure adequate delivery.[65] Finally, these two large -scale studies and smaller ones specific to SA-AKI have shown that higher doses (for example, 70 ml/kg/h) of continuous RRT do not improve patient's survival.[60],[65],[66]

Limited data suggest a benefit with any specific RRT modality over another one. An RCT randomized 77 patients with AKI needing continuous RRT to receive either 35 mL/kg/h of continuous venovenous hemofiltration or continuous venovenous hemodialysis (63 [82%] of whom had sepsis).[67] The results showed no difference in renal recovery or 60-day mortality (56% vs. 55%).[67] Finally, no data support the use of intermittent hemodialysis over continuous RRT (or vice versa) in the setting of SA-AKI.


  Blood Purification Techniques for Septic Acute Kidney Injury Top


During the past decades, several extracorporeal blood purification techniques have been developed for sepsis and sepsis-induced AKI management. These therapies could act on both the infectious agent itself and the host immune response. These therapies and relevant human RCTs are summarized in [Table 6].[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85]
Table 6: Blood purification techniques, human randomized controlled trials, and outcomes

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  Renal Recovery and Long-Term Outcomes Top


Data specific for SA-AKI recovery are lacking. In a prospective observational cohort of 1753 critically ill patients with AKI, SA-AKI (n = 833) was associated with increased risk of inpatient mortality but was also associated with a trend toward lower serum creatinine and dependence on RRT (9% vs. 14%; P = 0.052) at hospital discharge (n = 920).[8] This is in contrast to a recent study defining patterns of recovery in 16,968 critically ill patients with Stage 2 or 3 AKI.[86] Sepsis was associated with an increased risk of relapse compared with patients with early sustained reversal (odds ratio 1.34 [1.18–1.52]; P < 0.001).[86] A retrospective study also showed that diabetes makes recovery from SA-AKI less likely (41.1% in nondiabetic SA-AKI versus 60% in diabetic SA-AKI; P < 0.001).[87] Given the size and observational nature of these datasets, further investigation of SA-AKI-associated renal recovery is required.


  Conclusion Top


Sepsis-related AKI portends a worse prognosis and remains a common and highly morbid complication of common critical illness. Patients at risk for SA–AKI must be screened aggressively to allow its early identification and timely implementation of management strategies. Even with the current best medical practices, it is very unlikely that the burden of SA-AKI will be significantly ameliorated. Assessment of coexisting risk factors complicating management is also very important. Physicians should emphasize the prompt and effective treatment of underlying infection, avoidance of secondary kidney injury, and optimization of systemic hemodynamics.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Vijoy Kumar Jha,
Command Hospital Air Force, PO-Agram, Bengaluru - 560 007, Karnataka
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajim.ajim_30_21




 
 
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Abstract
Introduction
Acute Kidney Inj...
Sepsis-Associate...
Risk Factors for...
Pathophysiology ...
Early Detection ...
Resuscitation Fluids
Vasoactive Drugs
Mechanical Venti...
Drugs Used in Se...
Renal Replacemen...
Blood Purificati...
Renal Recovery a...
Conclusion
References
Article Tables

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