Acute Kidney Injury, Schemes and Mind Maps of History

Download Acute Kidney Injury and more Schemes and Mind Maps History in PDF only on Docsity! CCSAP 2017 Book 2 • Renal/Pulmonary Critical Care 7 Acute Kidney Injury Acute Kidney Injury By Linda Awdishu, Pharm.D., MAS; and Sheryl E. Wu, Pharm.D., BCPS INTRODUCTION Acute kidney injury (AKI) results in the abrupt loss of kidney function, leading to the retention of waste products, electrolyte disturbances, and volume status changes. The term AKI has replaced acute renal failure because smaller changes in kidney function without overt fail- ure can result in significant clinical consequences and increased morbidity and mortality. Changes in kidney function are detected by a change in biomark- ers, the most common biomarker being serum creatinine (SCr). Serum creatinine is an imperfect biomarker for recognizing AKI, given that an increase in SCr often lags (48–72 hours) behind the onset of injury. In addition, SCr is not in a steady-state condition in critically ill patients, leading to inaccurate estimates of glomerular filtration rates (eGFRs). Using an imperfect biomarker for AKI definition, rec- ognition, and management may affect patient outcomes. Despite improvements in renal replacement therapy (RRT), AKI outcomes are not optimal (Mehta 2003). This chapter reviews the identification and management of AKI in critically ill patients. DEFINING AKI Prior studies of AKI used different quantitative definitions, leading to challenges for clinicians in interpreting and applying study findings. Some definitions used were complex and difficult to apply because the increase in SCr was different depending on the presence and severity of underlying chronic kidney disease (CKD). Several consen- sus definitions of AKI have been developed over time to improve the recognition and reporting of AKI. RIFLE Classification In 2004, the Acute Dialysis Quality Initiative published the risk, injury, failure, loss, end-stage (RIFLE) criteria. The RIFLE classification is Reviewed by Phillip L. Mohorn, Pharm.D., BCPS, BCCCP; and Wan-Ting Huang, Pharm.D., BCCCP 1. Distinguish among the different types of acute kidney injury (AKI) and identify drug-induced causes. 2. Apply knowledge of organ cross-talk to predict changes in drug pharmacokinetics. 3. Demonstrate knowledge of protein, caloric, electrolyte, and trace element requirements in AKI with and without renal replacement therapy (RRT). 4. Compare and contrast the use of the various RRTs. 5. Estimate renal function, and formulate an appropriate drug-dose regimen for a patient with AKI not receiving RRT. LEARNING OBJECTIVES ABBREVIATIONS IN THIS CHAPTER AIN Acute interstitial nephritis AKI Acute kidney injury AKIN Acute Kidney Injury Network ATN Acute tubular necrosis CKD Chronic kidney disease CRRT Continuous renal replacement therapy eGFR Estimated glomerular filtration rate IHD Intermittent hemodialysis KDIGO Kidney Disease: Improving Global Outcomes KIM-1 Kidney injury molecule-1 NGAL Neutrophil gelatinase-associated lipocalin RIFLE Risk, injury, failure, loss, end-stage RRT Renal replacement therapy Table of other common abbreviations. CCSAP 2017 Book 2 • Renal/Pulmonary Critical Care 8 Acute Kidney Injury based on changes in two markers: SCr and urinary output. The classification includes three graded stages of AKI – risk, injury, and failure – with two outcomes: loss of kidney func- tion greater than 4 weeks and end-stage renal disease greater than 3 months (Lopes 2013). The RIFLE-defined period for change in SCr or urinary output was 7 days. After implementing the RIFLE classification, clinicians and investigators noted two problematic issues. First, AKI outcomes were worse in patients who developed AKI by SCr than by uri- nary output criteria. Second, the defined change in SCr value did not equate to the defined change in GFR (i.e., a 50% increase in SCr corresponds with a 33% decrease in GFR). Subsequently, GFR was not included in the Acute Kidney Injury Network (AKIN) or Kidney Disease: Improving Global Outcomes (KDIGO) definitions. AKIN Criteria In 2007, AKIN updated and modified the RIFLE criteria to define AKI and the staging system. The definition of AKI is an abrupt increase in SCr of 0.3 mg/dL over baseline within 48 hours, a 50% or greater increase in SCr within 7 days, or urinary output of less than 0.5 mL/kg/hour for more than 6 hours. Studies had shown significantly increased mortal- ity with small elevations in SCr (0.3–0.5 mg/dL) over a short period (24–48 hours). The AKIN staging system corresponds with the RIFLE categories. The loss and end-stage renal dis- ease categories are removed from staging and considered outcomes (Table 1-1). KDIGO Guidelines In 2012, the KDIGO clinical practice guidelines defined AKI as an SCr increase of 0.3 mg/dL within 48 hours or a 50% increase in SCr within the previous 7 days (KDIGO 2012). The staging system was maintained the same as AKIN; however, a GFR of less than 35 mL/minute/1.73 m2 was added for pedi- atric patients as a criterion for stage 3 AKI. Biomarkers Serum creatinine is a well-recognized marker of kidney func- tion and not a sensitive kidney injury marker, given that it may lag 48–72 hours from the time of injury. Kidney injury bio- markers are needed to improve AKI detection and will likely replace SCr in the definition and staging of AKI. Kidney dam- age biomarkers, including kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin (IL)-18, liver-type fatty acid binding protein (L-FABP), insu- lin-like growth factor binding protein 7 (IGFBP-7), and tissue BASELINE KNOWLEDGE STATEMENTS Readers of this chapter are presumed to be familiar with the following: • General knowledge of the pathophysiology that leads to acute kidney injury • Kidney Disease Outcome Quality Initiative criteria • CKD stages • Estimate and measure CrCl and GFR • General knowledge of renal replacement therapy Table of common laboratory reference values. ADDITIONAL READINGS The following free resources have additional back- ground information on this topic: • Kidney Disease Improving Global Outcomes (KDIGO). Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl 2012;2:1-138. • Medscape. Acute Kidney Injury. 2017 [homepage on the Internet] Table 1-1. Comparison of RIFLE and AKIN Criteria for AKI Definition RIFLE AKIN RIFLE/AKIN Category SCr or ↓ GFR Stage Increase in SCr Urinary Output Change Risk 1.5-fold ↑ SCr or 25% ↓ GFR 1 1.5- to 1.9-fold ↑ SCr or ↑ SCr ≥ 0.3 mg/dL < 0.5 mL/kg/hr for 6–12 hr Injury 2-fold ↑ SCr or 50% ↓ GFR 2 2- to 2.9-fold ↑ SCr < 0.5 mL/kg/hr for ≥ 12 hr Failure 3-fold ↑ SCr or SCr > 4 mg/dL with acute risk > 0.5 mg/dL or 75% ↓ GFR 3 3-fold SCr or SCr > 4 mg/dL with acute risk > 0.5 mg/dL or RRT < 0.3 mL/kg/hr for ≥ 24 hr or anuria for ≥ 12 hr AKI = acute kidney injury; RRT = renal replacement therapy. Information from: Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl 2012;2:1-138. CCSAP 2017 Book 2 • Renal/Pulmonary Critical Care 11 Acute Kidney Injury conditions may predispose the patient to develop AKI while taking a RAAS agent, specifically volume depletion, hypoten- sion, or concurrent nephrotoxins. In these circumstances, RAAS agents should be held until these conditions have been addressed and may be considered for re-initiation once the AKI has resolved. Nonsteroidal anti-inflammatory drugs inhibit the synthesis of vasodilatory prostaglandins, resulting in vasoconstriction of the afferent arteriole. They also cause sodium and water retention and may increase blood pressure. Calcineurin inhibitors (e.g., cyclosporine and tacrolimus) can cause acute and chronic nephrotoxicity. Acute toxicity results from afferent arteriole vasoconstriction because of the up- regulation of angiotensin II. Toxicity is usually associated with high trough concentrations. This is typically reversible by holding the dose and allowing concentrations to decline to the target range. Over-diuresis with loop diuretics may result in decreased circulating volume and decreased renal perfu- sion, especially in patients with conditions that increase their susceptibility to hemodynamic changes, such as cirrhosis and heart failure. Intrinsic Causes Intrinsic kidney injury includes damage to the glomerulus, tubules, interstitium, and vasculature. These conditions are quite different from a pathophysiologic standpoint and include a wide spectrum of etiologies, disease conditions, or offending drugs. The immune system plays a large role in glomerular disorders, interstitial injury, and vascular injury. Drugs causing intrinsic injury may be direct nephrotoxins, or they may stimulate an immune response. In some cases, drugs can cause injury through more than one mechanism (i.e., tubular injury and interstitial injury). Glomerular Autoimmune disorders play a large role in the etiology of glomerular injury. Glomerular injury may occur from immune- mediated diseases or conditions such as lupus nephritis, immunoglobulin A nephropathy, Wegner syndrome, polyar- teritis nodosa, or post-streptococcal infection. Oncology drugs are the most commonly implicated agents in glomer- ular injury, with increasing recognition of kidney injury from new therapies targeting the immune system. The hallmark biomarker is the presence of proteinuria and increased SCr with a delayed onset of injury (i.e., weeks). Other evidence of glomerular injury includes hematuria and the presence of RBCs, WBCs, and casts on urinalysis. A kidney biopsy is often required to determine the etiology of the glomerular injury and guide management. Medications causing glo- merular injury include interferon, pamidronate, gemcitabine, and vascular endothelial growth factor inhibitors. Interferon can affect podocytes, leading to minimal change disease or focal segmental glomerulosclerosis (FSGS). Pamidronate, a bisphosphonate used to treat hypercalcemia in oncology, has also been associated with FSGS. Gemcitabine has been associated with proteinuria and glomerular injury caused by thrombotic microangiopathy. Vascular endothelial growth factor inhibitors disrupt glomerular endothelial cells and slit diaphragms, leading to changes in glomerular permeabil- ity. Renal injury is accompanied by hypertension caused by decreased endothelial nitric oxide production. Tubular Tubular injury is commonly caused by antimicrobials and nephrotoxic drugs. Acute tubular necrosis is a common eti- ology of AKI in critically ill patients and is the most common type of AKI caused by ischemia or exposure to nephrotoxins. Ischemic ATN occurs when renal hypoperfusion overwhelms autoregulatory mechanisms, initiating cell injury and death. Causes of ischemic ATN include hypovolemic states (i.e., hemorrhage, GI, and insensible losses), low cardiac out- put in heart failure, and systemic vasodilation with sepsis. Nephrotoxic ATN may be caused by drugs, multiple myeloma, rhabdomyolysis, and contrast media. The kidney is vulnerable to the untoward effects of med- ications. The kidney receives 25% of cardiac output, is rich in blood supply, and is an eliminating organ for medications. Aminoglycoside-associated ATN can occur in 11%–60% of adults and 12% of neonates. Injury includes ATN, distal tubule concentrating defects, and proximal tubular dysfunction with electrolyte abnormalities (e.g., hypomagnesemia, hypocal- cemia, and hypokalemia). The injury is usually reversible if tubular regeneration processes are still intact. Risk factors for aminoglycoside toxicity include advanced age, volume depletion, sepsis, diabetes, liver disease, CKD, electrolyte dis- turbances, concomitant nephrotoxins (e.g., diuretics, NSAIDs, ACEIs/ARBs, and vancomycin), prolonged therapy duration (i.e., greater than 5 days), frequency of dosing (e.g., every 12 hours or every 8 hours), peak and trough concentrations greater than 10 and 2 mcg/mL, respectively (for gentami- cin and tobramycin), an increase in trough concentration by 1 mcg/mL or more for amikacin, and specific agent used (i.e., gentamicin > tobramycin > amikacin). Aminoglycoside- associated nephrotoxicity is often multifactorial, making differentiation from other disease-related etiologies or con- current nephrotoxins difficult. Conventional amphotericin B can cause AKI in around 28% of cases. It causes vasoconstriction of afferent arteri- oles, reducing blood flow and oxygen delivery. It also binds to epithelial cell membranes, creating pores that disrupt perme- ability and lead to tubular injury. Amphotericin B may cause significant potassium and magnesium wasting as well as a distal renal tubular acidosis. Risk factors for amphotericin nephrotoxicity include concurrent nephrotoxins, conventional amphotericin B dose (i.e., greater than 0.5 mg/kg/day), and preexisting CKD. Lipid-based formulations such as liposomal amphotericin B are associated with less nephrotoxicity than conventional amphotericin B. Liposomal amphotericin B has the lowest rate of nephrotoxicity and has largely replaced use CCSAP 2017 Book 2 • Renal/Pulmonary Critical Care 12 Acute Kidney Injury of the conventional formulation. Nephrotoxicity from ampho- tericin B is usually reversible with therapy discontinuation. Vancomycin nephrotoxicity is a topic of much debate. Controversy exists in determining a causal relationship. Many clinicians believe that vancomycin is not nephrotoxic and that high serum concentrations are a result of AKI but not the cause of AKI. Rates of AKI associated with vancomy- cin have increased, with new guidelines that advocate trough concentrations of 15–20 mg/L or higher in some cases for the treatment of complicated infections such as pneumonia (Rybak 2009). Retrospective studies have shown an associ- ation between high trough concentrations, total daily dose, concurrent administration of an aminoglycoside or piper- acillin/tazobactam, and development of AKI (Burgess 2014; Gomes 2014; Meaney 2014; Lodise 2009; Lodise 2008). In a prospective study of vancomycin versus linezolid for noso- comial pneumonia, the rate of nephrotoxicity was higher with vancomycin than with linezolid (18.2% vs. 8.4%) (Wunderink 2012). The mechanism for nephrotoxicity had previously been attributed to the formulation because rates of nephrotoxic- ity decreased after reformulation and has recently increased with new target concentrations. Animal studies have shown that vancomycin induces oxidative stress, mitochondrial damage, and ischemic injury to the kidney. This widely used antibiotic requires careful monitoring of therapeutic drug concentrations and renal function and attention to dosing. Contrast-induced nephrotoxicity occurs in 3%–30% of patients. Contrast agents cause ATN likely by renal vasocon- striction, increasing medullary hypoxia and direct cytotoxicity. In contrast to nephrotoxin-associated ATN, the fractional excretion of sodium (FENa) may be less than 1%, suggest- ing a prerenal contribution as well. The onset of injury is 48 hours with a return to baseline SCr in 3–7 days. Risk factors for contrast-induced nephrotoxicity include age, preexist- ing CKD, diabetes, heart failure, anemia, type of procedure, type of contrast agent, and volume of contrast. Risk-scoring tools have been published. Contrast agents are classified as high (iothalamate), low (iohexol), or iso-osmolar (iodixanol), depending on their osmolality in relation to blood. Iso-osmotic contrast media such as iodixanol (Visipaque) have a lower rate of nephrotoxicity than iohexol but no lower than other low-osmolar agents (Rudnick 2008; Solomon 2007; Aspelin 2003). In high-risk patients, iso-osmolar agents should be used, when possible, to reduce the risk of nephrotoxicity. Interstitial Interstitial damage is commonly a diagnosis of exclusion, given the lack of sensitive or specific biomarkers of intersti- tial injury. Acute interstitial nephritis (AIN) may be caused by infections, medications, or immune disorders. The most common infection includes pyelonephritis, but AIN can also be associated with renal tuberculosis and fungal nephritis. Medications most commonly implicated in AIN include anti- biotics, NSAIDs, and diuretics (see Box 1-1). Additionally, some drugs may crystallize and deposit in the interstitium leading to an immune response. A detailed drug exposure history may help establish a temporal association. Immune- mediated disorders such as glomerulonephritis may cause AIN. Classic findings of fever, rash, and arthralgias as doc- umented in methicillin-associated AIN may be absent in up to two-thirds of patients. Urinary eosinophils may be absent and are not a sensitive marker for AIN. Renal gallium scan- ning may provide some diagnostic evidence for AIN but cannot exclude the diagnosis. Renal biopsy remains the gold standard for diagnosis, but the risk-benefit of biopsy must be considered, especially in mild cases when drug discontinua- tion leads to clinical improvement. Vascular/Thrombotic Renal vascular disorders, which may cause AKI, include vasculitis, malignant hypertension, scleroderma, thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome, thrombotic microangiopathies, disseminated intravascu- lar coagulation, mechanical renal artery occlusion (surgery, emboli, thrombotic occlusion), and renal venous thrombosis. Thrombotic microangiopathy describes a disease of micro- vascular thrombosis, consumptive thrombocytopenia, and microangiopathic hemolytic anemia. Some chemotherapeutic agents have been associated with thrombotic microangiop- athies, including gemcitabine, cisplatin, mitomycin C, and vascular endothelial growth factor inhibitors. Post-renal Causes Post-renal AKI is the result of kidney obstruction. The most common causes of post-renal AKI include nephrolithiasis, benign prostatic hypertrophy, and surgical causes. The four main chemical types of renal calculi are calcium, uric acid, stru- vite, and cysteine, with calcium stones being the most common type. Certain drugs have relatively low solubility in the urine and may crystallize, obstructing the collecting system (see Box 1-1). CLINICAL WORKUP Medical History and Physical Examination Acute kidney injury is a syndrome that results from multiple insults. The etiology of AKI includes many different condi- tions, and often, the injury is worsened by the existence of risk factors. It may be difficult to distinguish the primary cause from contributing factors, and a thorough medical his- tory and physical examination are essential to establish the strength of relationship and temporal association for causal- ity. A complete medical history should include fluid losses; previous SCr and electrolytes; comorbid conditions such as diabetes, hypertension, cancer, transplantation, and heart and liver disease; history of pyelonephritis or UTI; recent sur- gery; radiographic procedures; and known infections (e.g., HIV, hepatitis) and exposures to possible infectious sources (e.g., sewage, waterways, rodents). A complete medication CCSAP 2017 Book 2 • Renal/Pulmonary Critical Care 13 Acute Kidney Injury history should include OTC and prescription therapies as well as herbal medications and recreational drugs. Each drug should be assessed for its potential to cause drug-induced kidney disease (Awdishu 2016). The known onset of injury for the drug together with the laboratory findings can be used to establish causality. Physical examination should include assessment of volume status, signs and symptoms of acute and chronic heart failure, emboli, infection, and sepsis. Laboratory Studies Laboratory tests should include serum chemistry, CBC, uri- nalysis, urinary chemistry, and urine sediment. The urine sediment is often the window to etiology. Gross or microscopic hematuria suggests injury to the glomerulus, vasculature, or interstitium (e.g., stone, tumor, infection, or trauma). Red blood cell casts indicate a glomerular or vascular cause of AKI. Hyaline casts suggest hemodynamic injury. The pres- ence of WBCs or WBC casts may indicate pyelonephritis or autoimmune causes. Crystals may point to drug-induced kidney disease from drugs such as sulfonamides, indinavir, triamterene, or acyclovir. Urine chemistry, including urine sodium and calculation of the FENa, is useful to distinguish between a pre-renal AKI and other etiologies (Table 1-2). A FENa less than 1% indicates pre-renal AKI. When diuretics are administered, a low frac- tional excretion of urea (less than 35%) is a more sensitive marker for pre-renal AKI. Radiographic Studies Renal ultrasonography is necessary to look for reversible causes of AKI, such as obstruction from a kidney stone. Findings of decreased kidney size or echogenicity indi- cate CKD. Renal Doppler ultrasonography may help identify ischemic AKI and reduced renal blood flow. Typically, resis- tive indices are high (i.e., greater than 0.75) in this setting of reduced perfusion. Renal Biopsy Renal biopsy is helpful in patients whose ultrasound findings are normal and who have not recovered after 3–4 weeks when intrinsic kidney disease is suspected. Renal biopsy should be considered if information from the biopsy would change the patient’s treatment. For example, consider a patient with epilepsy who is recently initiated on phenytoin with good response but who has an increase in SCr; the patient’s etiol- ogy of kidney injury is unclear but thought to be phenytoin associated. The decision to change anticonvulsants carries a risk of breakthrough seizures. A biopsy confirming AIN would assist in clinical decision-making because this would warrant a change in the anticonvulsant regimen. ORGAN CROSS-TALK Organ cross-talk describes the effects of one malfunction- ing organ on the function of another. Acute kidney injury has deleterious effects on lung, heart, brain, and liver func- tion. The impact of AKI on other organs goes beyond the effects of uremia alone and is likely related to immune sys- tem up-regulation. Lung dysfunction is an important systemic consequence of AKI, with mortality rates greater than 80% for combined AKI/lung injury in critically ill patients. Acute kidney injury can lead to lung injury and inflammation. Lung injury with its attendant hypoxemia, hypercapnia, and mechanical ventila- tion–associated high positive-end expiratory pressure can also worsen renal hemodynamics and function. Acute kidney injury is associated with development of left ventricular dilatation and cardiorenal syndrome. In addition, ventricular fibrillation is more common in cardiac ischemia with AKI. Azotemia and water retention can result in cardiac failure after renal dysfunction. Up-regulation of IL-1, tumor necrosis factor alpha, and intercellular adhesion molecule-1 messenger RNA expression has been suggested to occur in myocytes post-AKI. These changes result in cell death mediated by myocyte apoptosis and leukocyte infiltration. Neurologic complications of AKI include decreased men- tal awareness, seizures, and encephalopathy. Animal models have shown that AKI leads to inflammation, microvascular permeability, and behavioral dysfunction. Fluid and electro- lyte disturbances as well as drug toxicities are common in patients with kidney failure and can produce CNS depression with encephalopathy (Brouns 2004). Patients with AKI are Table 1-2. Summary of Urinary Indices for Differential Diagnosis Urine Indices Pre-renal/Hemodynamic Acute Tubular Necrosis Postrenal Obstruction Urine sodium (mEq/L) < 20 > 40 > 40 FENa (%) < 1 > 2 > 1 Urine osmolality (mOsm/k) Up to 1200 < 300 < 300 Urine creatinine/ plasma SCr ratio > 40:1 < 20:1 < 20:1 Specific gravity > 1.010 < 1.010 Variable CCSAP 2017 Book 2 • Renal/Pulmonary Critical Care 16 Acute Kidney Injury Expert consensus suggests that ICU patients with AKI be placed on a standard enteral formulation and that standard ICU recommendations for protein (1.2–2 g/kg of actual body weight per day) and energy (25–30 kcal/kg/day) provision be followed. Usual body weight should be used for patients at or near their ideal body weight, and ideal body weight should be used for critically ill patients and patients with obesity. Critically ill patients with AKI receiving hemodialy- sis or CRRT have increased nitrogen losses. Catabolic states such as sepsis and trauma can lead to multi-organ failure and an increase in protein turnover rate, which can lead to a negative nitrogen balance. Hemofiltration and hemodi- afiltration can bind up to 10% of the infused amino acids. These patients have increased protein requirements, up to 2.5 g/kg/day. Energy requirements are 25–30 kcal/kg/day, indicating the need for higher protein feeds or protein-rich supplements to attain an increased nitrogen/calorie ratio. These two guidelines have differing recommendations on protein requirements. The recent American Society for Parenteral and Enteral Nutrition guidelines argue that higher protein prescriptions are needed to achieve a positive nitro- gen balance. RRT FOR AKI Renal replacement therapy is required in 5%–6% of critically ill patients who develop AKI and is associated with increased mortality and health care costs. Despite advances in RRT, ques- tions arise on how to optimize RRT for AKI to improve patient outcomes. Factors to consider in the prescription and deliv- ery of RRT include timing of RRT, modality of RRT, treatment dose or intensity, and type of clearance provided by RRT (e.g., diffusion, convection). We will discuss the impact of these fac- tors on patient outcomes and the implications for practicing pharmacists. Timing Until recently, a fundamental question on the optimal timing of dialysis for AKI was unaddressed in the literature. Debate cen- tered on the risk-benefit ratio of early versus late initiation of dialysis. Clinically, most nephrologists initiate RRT in patients with AKI and volume overload or solute imbalances (i.e., acidosis or hyperkalemia). However, a recent randomized, sin- gle-center, clinical trial showed that early initiation (i.e., within 8 hours of developing stage 2 AKI) of continuous venovenous hemodiafiltration was associated with significantly reduced mortality at 90 days compared with delayed initiation (within 12 hours of stage 3 AKI) (Zarbock 2016). Additional benefits were shown for improved renal recovery and shorter time on RRT, duration of mechanical ventilation, and hospital length of stay. Additional studies are needed to confirm these results because early initiation was associated with a large reduc- tion in mortality not previously shown. Earlier initiation of RRT will affect the assessment of renal function for drug dosing, given that patients with stage 2 AKI may have some residual renal function. Residual renal function should be considered in addition to the clearance provided by dialysis. Modality Supportive therapy for AKI includes intermittent or con- tinuous RRT and hybrid therapies (Table 1-3). Intermittent hemodialysis (IHD) involves renal support for 3–6 hours per session three or four times weekly. Continuous therapies are Table 1-3. RRT Modalities for AKI Therapy Advantage Disadvantage IHD Short duration allows patient “off time” for procedures More rapid removal of small solutes (treatment of hyperkalemia) Less resource intensivea Hypotension CRRT Hemodynamic stability Better control of volume and solute removal Need for continuous anticoagulation and bleeding risks Downtime for procedures or tests may be reduced Resource intensivea Will not rapidly correct electrolyte disturbances Electrolyte wasting with continued therapy SLED or EDD Less resource intensivea Allows for “off time” for procedures Less anticoagulation than CRRT Fewer studies on drug dosing Lower efficiency than CRRT Staff training/expertise aResources include nursing staff, nursing time, and equipment. CRRT = continuous renal replacement therapy; EDD = extended daily dialysis; IHD = intermittent hemodialysis; SLED = sustained low-efficiency dialysis. CCSAP 2017 Book 2 • Renal/Pulmonary Critical Care 17 Acute Kidney Injury delivered theoretically 24 hours a day, 7 days a week. Hybrid therapies combine the advantages of both intermittent and continuous therapies, delivering a prolonged, gentler IHD treatment to improve patient tolerability and increase treat- ment efficiency compared with traditional IHD. Studies to date have not shown improved mortality between intermit- tent and continuous modalities (Liang 2016; Rabindranath 2007). The KDIGO guidelines suggest CRRT in patients with hemodynamic instability, excessive volume overload, or significant acid-base imbalances. Continuous renal replace- ment therapies are advantageous over intermittent RRT in achieving euvolemia, which is a critical factor in the ICU population. Dose The RRT dose is the prescribed clearance provided by the treatment and a measure of the quantity of blood purified from waste products and toxins. Clearance is defined as the volume of blood purified of urea per unit of time and is typi- cally expressed in milliliters per minute. For IHD, the therapy is provided at least three times weekly with a goal of achiev- ing a Kt/V (clearance of urea/unit time/volume of blood) of around 1.3. For CRRT, most centers use a dose of 25–35 mL/ kg/hour. Historically, much attention was focused on whether higher clearance would remove inflammatory mediators in sepsis and improve patient outcomes. Several studies have investigated whether higher CRRT doses improve mortality or renal recovery. In a study of critically ill patients with AKI and non-renal organ failure or sepsis, increasing the intensity of IHD (six vs. three times weekly) or CRRT (35 vs. 20 mL/ kg/hour) did not change mortality, renal recovery, or non-re- nal organ failure (VA/NIH Acute Renal Failure Trial Network 2008). Subsequently, additional trials of adult and pediatric patients from other countries similarly found no survival ben- efit with increasing the CRRT intensity to a dose of 35–40 mL/kg/hour. An important consideration for pharmacists is that the pre- scribed clearance is not equivalent to the delivered clearance, given that the therapies may often be interrupted because of procedures, tests, or filter clotting. To determine the actual clearance provided by the treatment, the pharmacist should review the treatment flow sheet to calculate the net efflu- ent delivered in the previous 24 hours and convert this value to milliliters per minute. For example, if a patient is initiated on continuous venovenous hemodiafiltration at a flow rate of 1 L/hour of dialysate and 1 L/hour of ultrafiltration, the prescribed clearance is 2 L/hour, or 33 mL/minute. However, if the patient is off treatment for a CT scan and is taken to the operating room for surgery, the prescribed clearance is not the same as the delivered clearance. After reviewing the treatment flow sheet, the effluent volume is determined to be 36 L. The delivered clearance is actually 25 mL/minute (i.e., 36 L/24 hours/60 minutes). This discrepancy in clear- ance often leads to unexpected drug concentrations during the therapeutic drug monitoring of antibiotics. Pharmacists are encouraged to be aware of this issue and to verify deliv- ered clearances. DRUG DOSING IN AKI Pharmacokinetic Alterations Acute kidney injury is associated not only with reduced renal clearance and renal metabolism of drugs but also with other impairments, such as changes in absorption, hepatic metabolism, plasma protein binding, and drug distribution. These changes may be particularly prominent in patients with severely impaired renal function and may occur even when the renal route is not the primary route of drug elimi- nation. However, the FDA does not require pharmacokinetic studies of drugs in patients with AKI for drug applications/ submissions. Information on pharmacokinetic alterations in AKI is largely extrapolated from studies of patients with CKD. However, such extrapolations may be inappropriate, given dif- ferences in the inflammatory milieu and organ cross-talk in AKI. Rapidly evolving changes in kidney function can lead to variable pharmacokinetic parameters during a patient’s hos- pital stay. In critically ill patients, drug absorption may be impaired because of decreased GI motility. Patients with sepsis may be receiving vasopressors, which may reduce gut perfusion, altering the bioavailability of orally administered drugs. Use of histamine receptor blockers and proton pump inhibitors to prevent stress ulcers increases gastric pH and may reduce the absorption of azole antifungals such as itraconazole or ketoconazole. Acute kidney injury may significantly affect the volume of distribution (Vd) of drugs because of changes in total body water and distribution of body water. Sepsis causes endo- thelial damage and capillary leak, resulting in fluid shifts from the vasculature to the interstitium. Patients with sep- sis may have effective volume depletion with increased total body stores of water. This may affect the Vd of hydrophilic drugs such as aminoglycosides, β-lactams, and glycopep- tides. For example, the Vd of aminoglycosides was 0.35 L/ kg in patients with AKI compared with 0.25 L/kg in patients with normal renal function. To determine changes in Vd, peak drug concentrations should be obtained for drugs with ther- apeutic drug monitoring. In CRRT, more rapid attainment of euvolemia and continuous re-equilibration between the dif- ferent compartments minimize fluctuations in Vd. Protein binding of drugs is altered in AKI for several rea- sons. Decreased synthesis of proteins, such as albumin in critical illness, can elevate the free fraction of drugs, leading to toxicity. In addition, albumin-binding capacity is decreased, likely because of the binding of endogenous inhibitors and pH changes. In CKD, uremia alters the conformational binding of substrates to albumin, leading to decreases in the protein binding of drugs such as phenytoin. Uremia likely has the CCSAP 2017 Book 2 • Renal/Pulmonary Critical Care 18 Acute Kidney Injury same effects in AKI, but the extent of protein binding changes is unknown, given the acuteness of the injury. Acute kidney injury generally reduces total clearance for drugs with significant clearance by the kidneys (i.e., renal clearance less than 30% of total clearance). Reduced GFR and CrCl correspond well with reduced clearance of drugs such as antimicrobials. Sepsis may also alter renal tubular function, but this has not been fully elucidated. For example, renal elimination of fluconazole is primarily by fil- tration, but fluconazole also undergoes significant tubular reabsorption. In anuric patients, the drug is not filtered or reabsorbed and requires significant dose reduction. When CRRT is applied, fluconazole is filtered into the effluent; however, tubular reabsorption is not restored, resulting Patient Care Scenario A 53-year-old woman (weight 71 kg, height 62 in) is trans- ferred from a community hospital to an academic medical center for sepsis secondary to a recurrent LLE cellulitis. Her medical history includes open-reduction, internal fixation of the left ankle; recurrent LLE cellulitis; HTN; and hypothyroidism. At the community hospital she was treated with intravenous clindamycin. She has worsen- ing pain, erythema, swelling to LLE with new open wound to left lateral ankle. Her home drugs include carvedilol 12.5 mg orally twice daily, lisinopril 20 mg orally daily, clindamycin 300 mg orally three times daily, and levothy- roxine 137 mcg orally daily. Her vital signs include BP 90/65 mm Hg, heart rate 98 beats/minute, respiratory rate 16 breaths/minute, O2 saturation 98%, and pain score 8/10. She is started on intravenous fluids, vancomycin (goal trough 15-20 mg/L), and piperacillin/tazobactam. Her oral anti-hypertensives are discontinued. On day 2 of her admission she develops AKI, which continues to worsen over the next few days. Laboratory parameters Admission Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 SCR (mg/dL) 0.89 1.68 2.29 2.35 2.31 2.34 2.45 GFR (mL/min/1.73 m2) >60 32 22 22 22 22 21 Vancomycin concentration (mg/dL) 18.8 20.8 WBC (x 103 cells/mm3) 22.4 21.9 13.1 12.8 14.7 12.6 12.3 What is the etiology of her AKI and what is best to recommend for this patient? ANSWER The most likely etiology would be hemodynamic or pre-re- nal AKI secondary to sepsis. The patient presented with low blood pressure secondary to her infection as well as anti-hypertensive therapy. Lisinopril would be considered a risk factor for her development of AKI. Angiotensin con- verting enzyme inhibitors dilate the efferent arteriole and reduce intraglomerular pressure, which can be problem- atic in the setting of hypoperfusion and volume depletion. Vancomycin and piperacillin/tazobactam therapies have been associated with an increased risk of AKI in several retrospective studies. However, in this case, the rise in SCr by day 2 suggests that injury occurred prior to the administration of vancomycin and piperacillin/tazobac- tam. Vancomycin and piperacillin/tazobactam may have contributed to the severity of injury as the SCr continued to increase. This case is difficult to manage because the patient requires adequate antibiotic therapy to treat sepsis but also mitigation of AKI risk factors to reduce severity of AKI, mortality and improve recovery of renal function. Fluids represent the initial therapy of choice for hemo- dynamic AKI to restore volume and improve perfusion. Normal saline remains the solution of choice for the treat- ment of AKI. If hemodynamics do not improve with fluid replacement, then vasopressors would be considered. By day 2 of the admission, the SCr is 1.68 mg/dL almost dou- ble her baseline. Estimates of kidney function include her GFR of 32, CLcr 31 by Cockcroft Gault equation, CLcr 25 mL/min by Jelliffe equation. The MDRD and Cockcroft Gault equations lead to overestimates of her kidney func- tion since SCr is not in steady state. Re-evaluation of her antibiotic dosing is imperative with frequent therapeutic drug monitoring. Reassessment of the goal vancomycin trough is needed to minimize further injury since stud- ies have demonstrated increased risks with troughs > 20 mg/L. In the case of cellulitis, a lower trough goal of 15 mg/L would provide adequate exposure while reducing her ongoing AKI risk. Exposures to other nephrotoxins should be minimized if possible (e.g., NSAIDs, contrast agents). Initiation of dialysis in this case would depend on addi- tional factors including acid-base balance, volume status and electrolyte disturbances. Close monitoring of kidney function should be continued with follow-up at hospital discharge if the injury has not fully resolved. 1. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012;2:1-138. 2. van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother 2013;57:734-44. 3. Hanrahan TP, Harlow G, Hutchinson J, et al. Vancomycin-associated nephrotoxicity in the critically ill: A retrospective multivariate regression analysis. Crit Care Med 2014;42:2527-36. CCSAP 2017 Book 2 • Renal/Pulmonary Critical Care 21 Acute Kidney Injury the patient may have acute kidney disease, and exposure to nephrotoxins in this period may result in a secondary injury. Recurrent AKI episodes have been documented as a risk factor for CKD progression. In addition, patients require education on their AKI episode, avoidance of nephrotoxins, kidney function estimates, and modifiable risk factors to prevent progression to CKD. CONCLUSION Acute kidney injury can be caused by several conditions and should be considered a syndrome rather than an injury alone because of the many complications and effects on other organs. Pharmacists are uniquely positioned because of their knowledge base to improve AKI outcomes by identifying and avoiding nephrotoxins, optimizing medication therapy during an AKI episode, and accurately estimating kidney function in patients receiving or not receiving dialysis. Pharmacists can play a special role in educating patients on appropriate follow-up and avoiding nephrotoxins to minimize the risk of recurrent AKI and progression to CKD. REFERENCES Aspelin P, Aubry P, Fransson SG, et al; Nephrotoxicity in High-Risk Patients Study of Iso-Osmolar and Low- Osmolar Non-Ionic Contrast Media Study Investigators. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med 2003;348:491-9. Awdishu L, Coates CR, Lyddane A, et al. 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Comparison of dopamine and norepi- nephrine in the treatment of shock. N Engl J Med 2010;362:779-89. Fiaccadori E, Parenti E, Maggiore U. Nutritional support in acute kidney injury. J Nephrol 2008;21:645-56. Finfer S, Bellomo R, Boyce N, et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247-56. Gomes DM, Smotherman C, Birch A, et al. Comparison of acute kidney injury during treatment with vancomycin in combination with piperacillin-tazobactam or cefepime. Pharmacotherapy 2014;34:662-9. Gordon AC, Mason AJ, Thirunavukkarasu N, et al. Effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock: the VANISH randomized clinical trial. JAMA 2016;316:509-18. Haase M, Kellum JA, Ronco C. Subclinical AKI – an emerging syndrome with important consequences. Nat Rev Nephrol 2012;8:735-9. Han WK, Bailly V, Abichandani R, et al. Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int 2002;62:237-44. Practice Points AKI is a syndrome caused by a spectrum of different etiol- ogies and has many significant consequences on patient outcomes. Early recognition of AKI provides opportu- nity to improve patient outcomes through the following interventions: • Treatment of the underlying etiology of AKI. Determin- ing the etiology is paramount to implementing therapy to reverse AKI. • In pre-renal or hemodynamic AKI, fluid replacement and hemodynamic monitoring is key to reversing the injury. Normal saline is the preferred fluid for replacement since sodium chloride loading reduces tubuloglomerular feed- back and pre-renal injury. There is no vasopressor of choice for pre-renal AKI. The selection of a vasopressor should be based on the etiology of AKI. • Drugs are a common cause of intrinsic AKI, often neces- sitating the discontinuation of the offending drug. Novel chemotherapeutic agents are being recognized as an in- creasing cause of intrinsic AKI. Data regarding the benefit of steroids for acute interstitial nephritis is controversial and steroids are used more commonly in refractory cases that do not improve after drug discontinuation. • During an AKI episode, clinicians should be cautious to avoid or minimize concurrent nephrotoxin exposures. • Loop diuretics should be reserved for the management of volume overload or hyperkalemia. • Assessment of renal function should be done using a mea- sured creatinine clearance or the Jelliffe equation. Concur- rent medications should be evaluated on a daily basis for dosage adjustment. Therapeutic drug monitoring should be employed when possible to guide drug dosing. • Early initiation of dialysis (i.e., within 8 hours of Stage 2 AKI) may improve outcomes. 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