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 Table of Contents  
Year : 2019  |  Volume : 1  |  Issue : 3  |  Page : 81-88

Fluid Overload and Acute Kidney Injury, Chicken or Eggs?

1 Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
2 Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA

Date of Submission02-May-2019
Date of Acceptance29-Aug-2020
Date of Web Publication28-Oct-2020

Correspondence Address:
Dr. Xuelian Liao
No.37 Guo Xue Xiang, Chengdu, Sichuan 610041
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jtccm.jtccm_9_19

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Fluid overload is one of the main complications associated with intravenous fluid therapy. Weight-based fluid accumulation is often calculated for fluid balance status in most researches. Fluid overload was defined as more than a 10% increase in body weight relative to baseline. There are many evidences that fluid overload is associated with an increased risk of acute kidney injury (AKI) and mortality. This review focuses on the pathophysiological link between fluid overload and AKI. Disruption of endothelial glycocalyx induced by fluid overload plays an important role in AKI. In addition, the compositions of the fluids (some colloids and chloride-rich fluids) may also contribute to kidney injury. On the other side, fluid overload is more obvious and the outcome in patients with AKI or with more critical illness. Therefore, the relationship between fluid overload and AKI should be fully understood and carefully managed.

Keywords: Acute kidney injury, endothelial glycocalyx, fluid overload, renal blood flow

How to cite this article:
Bo H, Harrison AM, Kang Y, Liao X. Fluid Overload and Acute Kidney Injury, Chicken or Eggs?. J Transl Crit Care Med 2019;1:81-8

How to cite this URL:
Bo H, Harrison AM, Kang Y, Liao X. Fluid Overload and Acute Kidney Injury, Chicken or Eggs?. J Transl Crit Care Med [serial online] 2019 [cited 2023 Mar 31];1:81-8. Available from: http://www.tccmjournal.com/text.asp?2019/1/3/81/299481

  Introduction Top

Modern intravenous fluid therapy has been used for almost two centuries. In 1832, Dr. Thomas Latta first used therapeutic intravenous saline in a cholera epidemic.[1] Intravenous fluids are currently used to maintain homeostasis and replace additional fluid losses.

In the clinical setting, patients receive intravenous fluid therapy primarily for fluid resuscitation, fluid maintenance, and fluid replacement.[2] More than 20% of critically ill patients receive fluid resuscitation during the 1st day in the intensive care unit (ICU).[3] Guidelines for fluid resuscitation have been established.[2] However, provider adherence to guidelines is not homogenous.

Acute kidney injury (AKI) is extremely common in ICU.[4] Incidence has been reported as 59% with the first 72 h of an ICU stay. No perfect treatment for AKI exists. The standard of care for the prevention and treatment of AKI is currently intravenous fluid therapy to increase urine output, as well as minimize ischemic and toxic insults to the kidney. Sometimes reversal of hypovolemia and maintenance of organ perfusion for fluid therapy is possible. However, this requires consideration of the dose and type of fluid. Fluid administration after AKI causes increased kidney burden due in part to oliguria. However, there is increasing evidence overdosing of fluid, and inappropriate fluid choice may also damage kidney function and delay recovery after AKI. This review explores the relationship between fluid overload and kidney function. Plausible mechanisms for these relationships will also be reviewed briefly.

  Methods to Assess Fluid Overload Top

Fluid overload is the state of excessive total body water content that requires timely recognition and accurate assessment. Excessive intravenous fluid can result in fluid overload, especially in the presence of coexisting comorbidities, resulting in complications such as pulmonary edema, impaired bowel function and cardiac failure and delayed wound healing. Net fluid balance is usually calculated using the difference between total intake and output. However, standardization is essential to compare and analyze the data in the study. The degree of fluid overload was expressed as the percentage of fluid overload adjusted for body weight. The following formula can be used for calculating fluid overload percentage.[5]

There are many other methods commonly used for fluid status assessment: Daily fluid balance (the daily sum of intakes and outputs), cumulative fluid balance (the sum total of fluid accumulation over a set period time), and peak fluid balance (maximum positive fluid balance over a set period time). Fluid overload is defined as fluid accumulation of 10% of baseline body weight, which is associated with adverse outcomes.[6],[7] A peak of more than 7% of fluid overload has been shown to be associated with adverse clinical outcomes.[8] Fluid Overload Kidney Injury Score using more than 15% of fluid overload combining with other risk factors was developed and validated effectively for predicting the outcome of some pediatric patients.[9] More accurate methods of fluid status assessment and evaluation system in acute or critical illness are needed. Fluid overload is both risk factor for mortality and biomarker for the severity of critical illness.

  Epidemiology and Outcomes in Critical Illness Top

As we well-known, critically ill patients are more likely to be administered intravenous fluid and have poor outcomes. Many clinical trials presented the epidemiology of fluid overload and evaluated its association with adverse outcomes and mortality. The dose and type of fluid administrated and the specific context in which they were given should be considered. We focus on the trials relevant for fluid balance in critically illness, which could improve patients' outcomes and change clinical practice.

The implementation of early-goal directed therapy (EGDT) by the Surviving Sepsis Campaign has saved the lives of many critically ill patients.[10] However, after aggressive fluid resuscitation, the patients might be confronted with fluid overload. Fluid overload affects almost 50% of patients with severe sepsis and septic shock treated with EGDT. Fluid overload is correlated with high mortality and more care when adjusting for the severity of illness.[11] If clinicians make interventions to lower fluid balance in critically ill patients, the mortality and intra-abdominal pressure (IAP) might be significantly decreased.[12] Negative cumulative fluid balance during the first 4 days in the ICU decreased mortality in critically ill patients.[13] Daily fluid balance in nonsurvivors of critically illness was higher than that in survivors.[14] Fluid overload is also associated with worse outcomes in other critically ill populations.

Fluid overload is associated with mortality in neurointensive care, surgical, and cardiac patients in many studies. Adequate fluid management can be proved to minimize secondary brain injury (ischemia, cerebral edema, and raised intracranial pressure following the primary injury). Poor-grade patients had higher fluid intake after subarachnoid hemorrhage (SAH) associated with more complications and worse outcomes.[15] Regardless of the severity of SAH, some goal-directed fluid therapy modulates confirmed positive fluid balance was associated with morbidity and adverse neurofunctional outcomes.[16] Optimal perioperative fluid management is also an important component of enhanced recovery after surgery. RELIEF multicenter randomized trial showed that restricted fluid therapy for major abdominal surgery peri- and postoperation didn't deteriorate patients' long survival but reduced 2.4 L fluid per patient for the first 24 h comparing with liberal fluid therapy.[17] However, higher rate of AKI in the restricted group suggested that the fluid regimen seems to be adjusted for patients at high risk and optimal strategy worth further discussion. A present, meta-analysis collecting 65 randomized controlled trials with 9308 patients found that fluid and inotropes-guided hemodynamic-targeted therapy decreased postoperative kidney injury rate in high-risk patients undergoing abdominal or orthopedic surgery.[18] After cardiac surgery, a 10% fluid overload had independently effect on complications (including death) and length of ICU stay.[19] The same finding was also observed in the pediatric study.[20],[21]

In some serious conditions, we also should pay attention to manage fluid balance. Fluid volume in patient undergoing ECMO might be allowed less strictly if hemodynamic stability and oxygenation can be insured by sufficient blood flow.[22] In a retrospective study about VA-ECMO, more than 90% of all the patients were detected by positive fluid balance during VA-ECMO treatment days, but survivors had a lower total fluid balance as compared to nonsurvivors. Prediction of poor outcome of 3 h fluid balance postimplantation had an AUC of 0.726 calculated by ROC.[23] The results did not support liberal fluid therapy in VA-ECMO patients. High prevalence (30%–40%) of intra-abdominal hypertension (IAH) was present in some mixed ICU.[24],[25] Obviously, positive fluid balance is an independent risk factor of IAH and patients with IAH was 3.3 times at risk of mortality as compared to those without IAH. However, standard monitoring parameters and clinical practice in IAH may remain largely data to prove.

A retrospective study found patients with greater severity of illness tended to have higher fluid balance, and longer ICU stays. Moreover, patients with high-risk factors such as AKI and chronic heart or renal failure had more risk of death because of positive fluid balance.[27] The higher the creatinine increased during ICU stay, the more the effect of fluid overload on mortality. Fluid monitoring and management are especially important in critically ill patients. For some patients with high-risk factors, strict fluid therapy may improve prognosis.

  Potential Mechanism of Fluid Overloads Leading to Acute Kidney Injury Top

Fluid overload directly and indirectly damages kidney tissue and affects renal blood flow (RBF) by activation of the neurohumoral system [Figure 1]. Fluid overload causes enhanced shedding of endothelial glycocalyx (EGL) and impairs the vascular barrier. The focus of intravenous fluid therapy needs to maintain the integrity of the EGL. When the integrity of EGL is broken, the body homeostatic balance will be disrupted.
Figure 1: Primary pathophysiology of AKI caused by fluid overload. EGL: endothelial glycocalyx, ANP: atrial natriuretic peptide, RAAS: renin-angiotensin-aldosterone system, Ang II: Angiotensin II, GFR: glomerular filtration rate, AKI: acute kidney injury

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EGL is considered to play an important role of vascular barrier in the revised Starling model. EGL is a lumen between flowing blood and the endothelial cell layer, which is produced by endothelium.[28] The main compositions of EGL are proteoglycan, glycoproteins, and glycosaminoglycans (GAGs). Syndecan and glypicans, two types of proteoglycans that firmly adhere to the cell membrane form the backbone of the EGL to which the negatively charged sulfated GAGs attach. Glycocalyx forms a meshwork in which proteins and soluble GAGs attach. Some soluble proteins molecular weight <70 kDa, such as albumin, hormones, enzymes, and adhesion molecules, are present in dynamic portions of the EGL layer. The average EGL thickness is about 2 um, which is thinner in the microcirculation (<0.2um) and thicker in larger vessels (almost 8 um).[29] The negative charged GAGs in EGL repel the negatively charged molecules like red blood cell and white blood cell as a barrier and anionic proteins. EGL separates plasma from the sub-EGL space. This potential space between EGL and the vascular endothelium has little to no protein.

The revised starling principle suggests opposing oncotic gradient between plasma oncotic pressure and sub-EGL space oncotic pressure prevents net filtration. The osmotic pressure of fluid does not directly determine transendothelial fluid exchange. The revised starling-EGL model explains why there is little difference in hemodynamic and volume infused between colloid and crystalloid in previous trials. In hypovolemia infusion, colloid solution increases plasma volume, and crystalloid increases the intravascular volume, but both do not affect transvascular fluid flow. Thus, the use of crystalloids is recommended in preference to the use of colloids in the resuscitation phase considering cost-effect and side effects.[30]

Disruption of EGL may increase capillary permeability, which can result in the extravascular leakage of protein and fluid, leading to tissue edema and interstitial fluid accumulation. At the organ level, the kidney is an encapsulated vital organ, noncompliant to increased interstitial renal pressure. Disruption of EGL may increase capillary barrier permeability in the glomerular and peritubular microcirculations. Interstitial renal pressure increases the pressure gradient across the glomerular capillary resulting in microcirculatory flow impairment and capillary collapse. EGL shedding of the peritubular capillaries may lead to tubular dysfunction that accompanies AKI. At system effect, fluid overload also causes edema in the abdomen. High IAP affected abdominal organs dysfunction. High IAP causes a reduction in venous return leading to venous congestion.[31] Venous congestion and elevation of renal parenchymal pressure significantly impair glomerular filtration rate (GFR) at IAP of 15 mmHg and increase vascular resistance at IAP of 20 mmHg.[31],[32]

EGL is very fragile in some pathophysiological conditions.[33] Release of atrial natriuretic peptide (ANP) from the heart in response to sodium and fluid overload increases EGL shedding leading to vascular permeability. In an artificially infused, isolated heart model, ANP increased capillary permeability, a histologically detectable degradation of EGL, and significant tissue edema.[34] Fluid overload in patients undergoing elective general surgery induced a release of ANP and increased the serum concentration of glycocalyx constituents.[35] The rapid intravenous infusion can transiently raise atrial pressure, resulting in ANP release, then damage the EGL. The release of ANP can activate matrix metalloproteases to induce EGL shedding.[36] In critical illness, there are many other factors contributing to EGL destruction, such as inflammation and ischemia,[37] hypoxia, and hyperglycemia.[38] Ischemia can degrade the EGL in guinea pig coronary arteries.[39] Sepsis-induced damage of EGL has been proved in animal models and at least one clinical study.[40],[41],[42] These results suggest fluid resuscitation during critical illness, such as sepsis, must be guided carefully to avoid fluid overload.

Fluid accumulation within the tissue can alter the diffusion of oxygen, compromising intra-renal oxygenation. Renal microvascular oxygenation was impaired, and renal function decreased by almost 45% from the baseline because of renal interstitial edema after short-term intravenous crystalloid therapy (36 ml/kg) in pigs.[43] Regional renal hypoxia drives many signal pathway cascades resulting in tissue damage and dysfunction.[44]

Fluid overload increases the cardiac load, which alters the RBF and damage tissue by activation of the renin-angiotensin-aldosterone system (RAAS). Almost 50% of patients with congestive heart failure develop renal dysfunction.[45] Fluid overload may be both a result and a precipitating factor of AKI in heart failure. Reduced cardiac output both increases renal venous pressure (RVP) and constricts arterioles. Some studies have demonstrated an increase in RVP can reduce RBF,[46] causing injury of podocytes and expansion of the extracellular matrix.[47] An association with lower RBF, the renal interstitial hydrostatic pressure gradually increased then compressed the renal tubules, which cause GFR reduction.[47] Activated RAAS system may further cause injury of renal tissue.[48] Angiotensin II (AII), which is the key effector peptide of RAAS, might induce vasoconstriction to elevate glomerular hypertension and decrease RBF through AII type 1 receptor, and increase expression of inflammatory factor and induce oxidative stress, apoptosis through AT2 receptor.[49] Although meta-analysis found blocking RAAS is not as effective as the mechanism for the prevention of AKI after cardiac surgery.[50] AII, as an AKI biomarker was associated with the severity of AKI and its outcomes.[51] For patients with heart failure, avoiding fluid overload not only protects the heart but also protects the kidney.

  Overload Has a Dual Meaning Top

Volume overload and composite overload, which relates to chloride and colloid overload. Excessive chloride decreases the RBF and thereby compromises renal function.[52] Although intravenous saline was first used for the treatment of diseases and is very effective for a wide range of conditions, normal saline (0.9% NaCl) contains supra-physiological chloride concentration at 154 mEq/L, which is 40%–50% higher than plasma (96–106 mEq/L). However, this fact has been not given enough attention by clinicians for many years. In recent years, hypochloremia has been shown to have a negative impact on clinical outcomes.[53],[54],[55] This conclusion was derived from the SPLIT, SMART, and SALT-ED trial via a detailed analysis on the association and effect of the composition of various intravenous fluids in prospective randomized control studies.

The SPLIT trial concluded there was no difference in the rate of development of AKI within 90 days in ICU.[53] SMART study showed among critically ill adults death in hospital, new renal-replacement therapy, and persistent renal dysfunction (a final serum creatinine >200% of baseline value or ≥Stage 2 AKI by KDIGO criteria) occurred significantly higher in the saline group than in the balanced crystalloid group.[54] SALT-ED trial also showed that in the emergency department, there was a lower incidence of major adverse kidney events (showed in above) at 30 days in the balanced crystalloid group.[55] Although SMART and SALT-ED were not blinded, these three studies combined caution excessive chlorine may be harmful.

It is thought that high chloride concentration at the Maculadensa increases tubuloglomerular feedback causing preglomerular vasoconstriction, resulting in the reduction of renal perfusion.[56] Chloride load higher than 500 mEq was independently associated with postoperative AKI development.[57] Restricted chloride administration might decrease the incidence of AKI-induced injury and the use of renal replacement treatment in critically ill patients.[58]

Colloids, especially hydroxyethyl starches (HES), has the potential to induce renal toxicity. HES was found to increase renal failure (risk ratios (RR) = 1.27, 95% confidence interval [CI] 1.02–1.17) and use of renal replacement (RR = 1.32, 95%CI 1.15–1.50).[59] One of the mechanisms of colloid-induced AKI is osmotic nephrosis. Based on the histopathological examination, the characteristics of osmotic nephrosis are vacuolization and swelling of the renal proximal tubular cells.[60] HES infusion in potential renal donors was found to be associated with osmotic-nephrosis-like lesions of renal[61] and impair immediate renal function in kidney recipients.[61],[62] HES molecules are taken up by the proximal tubule cell through pinocytosis. The accumulation of molecules in lysosomes results in classic osmotic nephrosis. HES as a foreign substance, may be identified by circulating macrophages, histiocytes, and mesenchymal cells and lead to inflammation. After infusion of 10% HES (200/0.5) for haemodilution interstitial cell proliferation, macrophage influx and the tubular injury was significantly higher than the crystalloid solution.[63] Osmotic nephrosis has been reported with other compounds, including mannitol,[64] and dextran.[65] In 2013 both the European medicines agency (EMA) and US Food and Drug Administration issued a safety warning about HES solutions. In 2018 EMA indicates that HES solutions must not be used in patients with sepsis or kidney impairment or critically ill patients.

  Fluid Overload: Clinical Manifestation of Acute Kidney Injury Top

A common complication and symptom of AKI is fluid overload, particularly in patients with oliguria and anuria. Fluid overload is a significant risk factor for mortality in patients with AKI.[66]

The adverse effect of fluid overload on survival was more evident in patients with AKI accompanying sepsis or more severe illness.[5] Fluid overload was the primary indication of initiation of continuous renal replacement therapy (RRT) in 65% patients in a pediatric ICU, which was significantly associated with high mortality.[67] Retrospectively analyzed data on more than 15,000 patients in the ICU revealed patients with AKI received lower cumulative fluid balance which could improve 30-day survival.[68] The peak fluid overload was a significant risk factor for mortality, which every 1% increasing had an odds ratio for death of 1.075 (CI 1.055–1.095). Moreover, the level of peak fluid overload was more harmful for patients with AKI than non-AKI cohort.[69] Patient with >10% fluid overload at the initiation of RRT was associated with mortality comparing with who without fluid overload. After RRT initiation, the more positive mean daily fluid balance increased the risk of hospital mortality. It supports the safety of less positive fluid management strategy during RRT and decreasing fluid accumulation may improve renal recovery in patient with AKI.[70],[71] However, rapid fluid removal during RRT is also harm for survival. RENAL trial found that during CVVHDF net ultrafiltration rate >1.75 ml/kg/h was associated with 90-day mortality.[72] Fluid overload increases the risk of renal damage and shorten the survival time of patients with AKI.

The mechanism of fluid overload caused by AKI is a rapid decline in GFR and RBF resulting in water and sodium retention. Sepsis, hypotension, and nephrotoxic drugs may cause acute tubular necrosis resulting in AKI. Except for tubular injury, the impairment in hemodynamic regulation decreases RBF. Inflammatory signals participate in the progressive process following AKI. The mechanisms involved in AKI are complex. Then when AKI occurs, fluid imbalance or overload should be taken seriously.

Does the relationship between fluid overload and AKI fall into a causality dilemma like “who came first, chicken or eggs?” To some extent, it is a false dilemma and the circular causality does make sense. Sometimes the relationship between fluid overload and AKI is completely intertwined. Patients with AKI are at risk for fluid overload. Conversely, fluid overload can cause kidney injury, especially in critically ill patients.

  Conclusion Top

A previous study concluded that fluid overload can contribute directly to poor outcomes, especially in critically ill patients. Kidneys should be particularly prone to damage from fluid overload and tissue edema. The dose and composition of fluid should be both considered before treatment in critically ill patients or with AKI. If patients with cardiac dysfunction fluid overload may aggravate existing disease and damage the kidney. In future, protecting and remedy EGL may be an effective treatment for kidney injury. Most studies support for a more conservative fluid balance strategy in critically ill patients beyond the initial resuscitative period.

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