"Debra" is a 44-year-old white woman with disseminated intravascular coagulation (DIC) and a history of pulmonary Mycobacterium avium complex (MAC) infection who was transferred to the intensive care unit from an outside hospital for worsening kidney function. She had presented with severe right-sided flank pain, oliguria, hematuria and nausea. She was taking ibuprofen for her flank pain and received ketorolac (Toradol) in the emergency department. As an outpatient, she was being treated for pulmonary MAC with ethambutol (Myambutol), rifampin (Rifadin) and azithromycin (Zithromax) and was nearing the end of her eighth month of treatment.
The physical examination revealed significant lower extremity bruising, right costovertebral tenderness and anuria. Lab studies showed an elevated serum creatinine (SCr) of 7.87, a low platelet count of 40,000, anemia, and peripheral blood smear findings consistent with DIC. A urine sample was not available.
In the ICU, all anti-MAC antibiotics had been stopped. Debra received aggressive fluid therapy and was seen by nephrology, infectious disease and hematology. Her kidney function continued to worsen and she developed fluid overload, as was evidenced by ascites, lower extremity edema, increasing shortness of breath and an 11.7% increase in weight.
Debra's acute kidney injury was thought to be due to atypical hemolytic uremic syndrome (aHUS) from long-term rifampin therapy; NSAID use contributed as well. Dialysis and plasmapharesis were initiated. She was discharged home 3 weeks later, and did not require dialysis. She was advised not to restart her anti-MAC medications because there was no significant change on CT scan to suggest progression of MAC.
Definition and Epidemiology
Acute kidney injury (AKI) is a fairly new term that has been adapted to replace the term acute renal failure.1,2 AKI represents a spectrum of acute renal dysfunction that ranges from minor changes in function to renal failure.1,2 Two staging systems (RIFLE and AKIN) are used to classify the severity of AKI. The RIFLE system is the most common and uses two criteria (GFR/SCr and urine output) to classify the severity of AKI1, 2 (Table 1).
AKI is characterized by rapid loss of kidney function that results in the retention of urea and creatinine, changes in volume status, and electrolyte imbalances.1 It is common in the hospital setting, affecting 1% of patients at the time of admission and 2% to 5% during hospitalization. The incidence increases to 67% in the ICU.2
Clinical Presentation and History
Patients with AKI may be asymptomatic, have few symptoms, or present with nonspecific symptoms. Although some develop flank pain, hematuria and a decrease or cessation in urination, most patients do not present with these renal symptoms. As the urea levels increase in the blood, patients may develop altered mental status, fatigue, nausea and easy bruising secondary to platelet dysfunction from high urea levels.
Patients with a history of heart failure or liver disease can present with symptoms of fluid overload (bloating, lower extremity edema and orthopnea). Patients may develop fluid overload secondary to the kidney's inability to excrete excess fluids and sodium. Patients who take diuretics, who have a history of recent gastrointestinal illness, or who are at risk for malnutrition may have symptoms of hypovolemia.
Patients can also present with cardiac arrest secondary to hyperkalemia. If systemic involvement exists, fever, rash and arthralgias may develop.1,2
Risk Factors and Etiology
Patients are at an increased risk for developing AKI if they have any condition that damages the kidney, decreases renal blood flow or leads to obstruction of the urinary system. Patients who are older than 75 with preexisting kidney disease, diabetes or hypertension should be evaluated for AKI, especially if they present with dehydration or altered mental status. Table 2 lists additional risk factors that should be evaluated in the history.2
The etiology of AKI can be divided into three main categories: prerenal, intrarenal and postrenal (Table 3). Prerenal causes account for the majority of AKI cases and generally result from any conditions that decrease blood flow to the kidneys. Intrarenal causes result in structural injury to the kidney's parenchyma, tubules or glomerulus. Postrenal causes are the least common but often are easier to reverse if detected early. For this reason, any patient with AKI should undergo a renal ultrasound to identify any reversible cause.1,3
Diagnosis and Management
Serum creatinine is the current gold standard used to diagnose AKI. However, AKI is often a late diagnosis because serum creatinine starts rising only after more than 50% of kidney function has been lost. Thus, serum creatinine should be measured serially in patients with suspected AKI.2 A microscopic urinalysis, fractional excretion of sodium and blood urea nitrogen/creatinine ratio are used to differentiate among prerenal, intrarenal and postrenal causes. A basal metabolic panel and complete blood count are recommended as well.
As mentioned above, a renal ultrasound should always be done to rule out an obstruction. Depending on the suspected etiology, some cases require more extensive studies (renal biopsy, aortorenal angiography, peripheral blood smear, etc.). A nephrology consult should be ordered as soon as possible.1-3
Management consists of addressing the underlying cause and is mostly supportive in nature. Providers should stop any offending drugs, adequately dose any medications, maintain volume homeostasis, correct any electrolyte abnormalities and acidosis, place a Foley catheter to follow urine output, and then wait for renal function to improve. Dialysis is indicated only in certain situations.2,3
Morbidity and Mortality
Even small increases in serum creatinine are associated with an increased risk for death, independent of the underlying cause or any associated medical conditions. The mortality rate in the hospital is estimated to be 40% to 50% and is higher in the ICU. Despite medical advances, survival rates have not improved significantly.
Patients may develop fluid overload, acidosis, electrolyte abnormalities, GI bleeding, new-onset chronic kidney disease, and higher prevalence of infections. Infections and cardiopulmonary complications are the leading causes of death in AKI. Inadequate antibiotic dosing also contributes to the high mortality and morbidity.2,4 As one author explained, "patients die because of AKI rather than with AKI."4
Case Study Revisited
Debra's AKI had worsened and she developed fluid overload during the course of the hospital stay. This required the initiation of dialysis. Did the fluid overload contribute to her worsening kidney function? Did we administer too much intravenous fluid or was the AKI the cause of the fluid overload? What is the role of fluid overload on kidney function, mortality and morbidity in AKI? Is restrictive fluid therapy a better option?
Rationale for Liberal Fluid Administration
Since it has been established that hypoperfusion and ischemia cause the majority of AKI, current treatment guidelines call for liberal fluid administration. The rationale is to avoid additional kidney injury by increasing blood pressure (important for renal perfusion pressure) and cardiac output, which is necessary for adequate renal perfusion. Fluids are also given to promote urine output (diuresis), dilute any toxins and relieve any obstructions from cast deposits within the kidney.5,6
Studies have shown, however, that renal blood flow does not significantly increase after fluid administration because cardiac output and tissue perfusion do not depend only on blood volume and pressure. Other factors, such as medications and acute or chronic illnesses, can influence heart function and perfusion. The effect of fluid administration is often brief and may only be beneficial during the first few hours; any repeated fluid administration after this initial period could result in fluid overload.5,6
Animal studies have suggested that renal oxygen delivery decreases due to hemodilution that occurs when fluids are administered. Lastly, fluid administration does not promote urine output. During acute illness, such as with AKI, the sympathetic nervous system and the renin-angiotensin system are activated and there is increased secretion of anti-diuretic hormone, both of which promote retention of water and sodium. Administering more fluids could potentially lead to even more fluid accumulation.5,6
Consequences of Fluid Overload
Patients who are critically ill have increased capillary permeability, are not able to excrete exogenous sodium well, and often receive medications in normal saline. Thus, they are at an increased risk for developing fluid overload.5,6
Excessive fluids can result in visceral edema, ascites and eventually intra-abdominal hypertension, which may reduce renal blood flow and GFR. The kidney is an encapsulated organ, so any fluid congestion results in increased intra-capsular pressure and a decrease in renal blood flow. The reduction in GFR leads to uremia and the body responds by retaining salt and water, which results in more fluid overload-a vicious cycle. Thus, fluid overload has a direct effect on the kidney. In addition to directly affecting the kidney, fluid overload can also affect other organs: heart, liver, intestines, brain, lungs and tissues.5,6
Role of Fluid Overload in AKI: Causation vs. Association?
As mentioned earlier, fluid overload is associated with increased mortality, morbidity and renal non-recovery.5,6 It has been argued by some that fluid overload is only a marker of disease severity rather than the direct cause of mortality, morbidity and renal nonrecovery. Complications of AKI, such as infections, can also affect mortality and kidney function. Finally, patients with AKI often have other comorbid conditions (sepsis, heart failure, critical illness) that can affect mortality and renal recovery.7-9 Four studies, including two randomized controlled trials, were analyzed to determine the role of fluid overload on mortality, morbidity and renal non-recovery:
The PICARD study7 was a multicenter observational study that included 618 patients with AKI. The patients' mortality was measured for 60 days. Fluid overload was associated with higher mortality at 60 days (P = 0.006), 30 days (P = 0.02) and hospital discharge (P = 0.01) for both dialyzed and non-dialyzed patients. When adjusted for severity of illness (with APACHE III score), the difference in mortality was not significant (P = 0.12). Therefore, more studies are needed to determine if fluid overload directly contributes to increased mortality.7
The study also showed that mortality was proportional to the severity and duration of fluid overload present. There was a stepwise increase in mortality as the percentage of fluid accumulation increased. In addition, mortality was higher for patients on dialysis who remained in fluid overload for a longer period of time (P < .0001).7
The FACTT study analyzed data from a study conducted in 2006. This study was a multicenter, randomized, controlled trial that randomized 306 patients with acute lung injury who developed AKI into a liberal or a conservative fluid therapy group. Both groups had similar baseline characteristics (including kidney function). Positive fluid balance was strongly associated with mortality. Survivors had less daily fluid overload (0.3 L/day) than nonsurvivors (3.3 L/day) (P < 0.001).10
The Heung et al study was a single, retrospective observational study that included 170 patients with AKI who were taking renal replacement therapy (RRT). Their renal recovery and mortality were measured after 1 year. Greater degree of fluid overload (P = 0004) was associated with lower incidence of kidney recovery after 1 year. Mortality was significantly higher for patients who did not recover renal function (85.3%) when compared to those who did recover kidney function (29.5%) (P < 0.001).9
The EGDT study was a randomized, controlled trial study with 263 emergency department patients who had sepsis and elevated serum creatinine. Patients were randomized into two groups, early goal-directed therapy (for a period of 6 hours) or conventional fluid therapy (for 7 to 72 hours). The study showed that mortality was higher for the conventional group (46.5% vs. 30.5%; P = 0.009) and conservative fluid therapy was not associated with worsening organ dysfunction (P < 0.001).11,12
AKI is common, increasing in prevalence, and has poor outcomes. Until better detection methods or interventions are identified, proper management is crucial to improving outcomes for patients. Studies have shown that fluid overload is associated with mortality and morbidity, that duration and severity of fluid overload matter, that fluid overload negatively impacts renal recovery, and that conservative fluid therapy is not associated with worsening kidney function. However, more clinical studies are needed to determine if fluid overload is a direct cause of mortality and renal non-recovery in patients with AKI.
Clinical Practice Recommendations
In clinical practice, providers should be aware of AKI risk factors, check medication lists and avoid NSAIDs in suspected cases of AKI. When treating patients with AKI, it is helpful to collect a urine sample right away since this may not be available later due to developing anuria. Providers should watch for fluid overload, periodically reassess fluid status, and be aware of fluid intake, especially in critically ill patients who are already at risk for developing fluid overload. In terms of fluid administration, after initial fluid resuscitation, it may be beneficial to limit fluid administration and strive for neutral or negative fluid balances.
More studies are needed to develop more precise fluid therapy guidelines. Until then, the prognosis of AKI will depend on providers' ability to diagnose AKI early, when outcomes tend to be more favorable.
Olga Trouskova is a physician assistant at West Side Community Services (La Clinica) in St. Paul, MN. Beth Alexander is a pharmacist who is an associate professor of physician assistant studies at Augsburg College in Minneapolis.
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