917CHAPTER 74 Glomerulotubular Dysfunction and Acute Kidney Injury activation of T helper lymphocytes, which induce differentia tion of T and B cells that directly injure the interstitium The inabilit[.]
CHAPTER 74 Glomerulotubular Dysfunction and Acute Kidney Injury activation of T-helper lymphocytes, which induce differentiation of T and B cells that directly injure the interstitium The inability of the host to counteract this response with T-suppressor cells permits T- and B-cell activation to go unabated In the effector phase, both humoral and cell-mediated components contribute to tissue injury Antibodies to tissue antigens promote injury by activation of the complement cascade, chemotaxis, and cell-mediated cytotoxicity IgE is also produced, which may recruit eosinophils or mast cells Mononuclear cell infiltration produces tissue injury by release of proteases and lymphokines Eosinophils also damage surrounding tissue by release of proteases, leukotrienes, and toxic oxygen species Pathologically, biopsies are characterized by interstitial inflammatory cell infiltrate Tubules may have mild structural alterations or marked necrosis with loss of brush border Several theories have been proposed to explain the reduced GFR: (1) the “clogged drain,” (2) capillary bed, and (3) vascular tone hypotheses The clogged drain theory proposes that tubular obstruction caused by luminal debris and interstitial edema results in increased pressure in the Bowman space and decreased pressure favoring filtration Interstitial inflammation results in injury to the blood supply of the tubules (capillary bed hypothesis) Because these vessels are postglomerular, the increased resistance and reduced surface area associated with vessel injury result in an increase in efferent arteriolar pressure and a reduction in the pressure gradient across the glomerulus, with a resultant drop in the GFR Decreased sodium reabsorption by injured proximal tubular epithelial cells reduces the medullary interstitial osmolality and impairs the ability to concentrate the urine Thus, an increased volume of filtrate is delivered distally, stimulating the juxtaglomerular apparatus to increase angiotensin II production (vascular tone hypothesis) The net result is vasoconstriction and a diminished GFR ATIN usually resolves with removal of the offending agent, although occasionally chronic kidney insufficiency may result Prednisone and renal replacement therapy also have roles Many patients eventually regain renal function, though some continued to have sequelae of CKD years after ATIN.87 Cardiorenal Syndrome Cardiorenal syndrome (CRS) commonly refers to the primary dysfunction of the heart or kidneys resulting in damage to both organs The physiologic interaction of the heart and kidney is complex, with recognition that disease of one organ system frequently complicates the other The pathophysiology of CRS is not yet fully understood but is thought to involve dysregulation of the neurohormonal systems (renin-angiotensin-aldosterone system and sympathetic nervous system), increased central venous pressure and intraabdominal pressure, oxidative stress, inflammatory mediators, anemia, and heart failure and renal failure.89,90 This can result in elevated systemic vascular resistance, fluid overload, decreased renal perfusion, and other problems Classification of CRS emphasizes the root cause of disease being driven by the heart (cardiorenal) or by the kidneys (renocardiac) and whether it was an acute or chronic process (Fig 74.2).90,91 The relationship between renal function and heart failure in children has not been well studied, and the classification system oversimplifies the complex interrelationship of the two organs It is recognized that acute heart failure and AKI initially start with adaptive mechanisms that become maladaptive with progression in time and chronicity These maladaptive changes are thought to lead to the sequelae of CRS 917 Type or acute cardiorenal syndrome • Rapid worsening of cardiac functions resulting in acute kidney injury Type or chronic cardiorenal syndrome • Chronic abnormalities in cardiac function resulting in progressive chronic kidney disease Type or acute renocardiac syndrome • Rapid worsening of kidney functions leading to acute cardiac dysfunction Type or chronic renocardiac syndrome • Progressive chronic kidney disease resulting in decreased or worsening cardiac functions Type or secondary cardiorenal syndrome • Combined kidney and heart dysfunction due to acute or chronic systemic illness • Fig 74.2 Classification of cardiorenal syndrome CRS remains better characterized in adult medicine There is evidence that right ventricular (RV) dysfunction may be associated with renal venous congestion Using echocardiographically derived measurements, Testani and colleagues showed that in 151 patients, RV dysfunction remained a significant predictor of change in glomerular filtration rate after controlling for heart rate, hemoglobin, admission serum urea nitrogen, B-type natriuretic peptide level, diuretic dose, length of stay, ejection fraction, cardiac output, tricuspid regurgitation severity, and inferior vena cava inspiratory collapse.92 Renal insufficiency occurs commonly in adult and pediatric patients with heart failure Decreased urine output and resultant fluid retention can aggravate heart failure symptoms and contribute to clinical deterioration Even a modest increase in serum creatinine (.0.2 mg/dL) can predict mortality in adult patients hospitalized for heart failure.93 The relationship between renal function and heart failure in children has not been well examined Retrospective data analysis has shown a high incidence of cardiac disease among children who exhibit renal insufficiency while hospitalized Clinical experience suggests that, as in adults, worsening renal function is associated with worse outcomes among children with heart failure.94 Treatment of CRS remains multifactorial and supportive in nature Rapid removal of volume in patients with venous congestion and endogenous vasodilation in patients with decompensated heart failure is controversial, inotropic support to maintain perfusion pressure to vital organs, neurohormonal axis inhibition with angiotensin-converting-enzyme inhibitors and b-blockade Outcomes in patients with CRS are difficult to measure, as differentiating CRS from sequelae of heart failure, heart surgery, and AKI remains problematic Much of the understanding and research in CRS comes from the pediatric cardiac intensive care setting, where both heart failure and AKI are commonplace.95 Patients with worsening renal function had the worst outcomes of all patients.96,97 Cardiac Surgery–Related Acute Kidney Injury AKI is reported to occur in 40% to 60% of children following cardiac surgery Until recently, the rate of AKI after congenital cardiac surgery was shown to be as low as 11% However, the acceptance and implementation of the KDIGO classification has made this entity easier to track and study.98 The clinical implications of AKI are profound, as development of AKI is associated 918 S E C T I O N V I I Pediatric Critical Care: Renal with increased mechanical ventilator days, requirements for inotropes, longer ICU stays, and increased mortality.99 Risk factors for developing AKI can be categorized as renal and extrarenal In pediatric patients, extrarenal risk factors for AKI include younger age (,90 days), prolonged cardiopulmonary bypass time (,150–180 minutes), prolonged ventilation time, sepsis, hematologic complications, fluid overload, and single-ventricle physiology.100,101 AKI—alongside age, single-ventricle physiology, and fluid overload—is associated with higher mortality and morbidity AKI results from the interactions between the complicated interventions required in the process of congenital cardiac surgery (such as cardiac bypass and the use of blood products), the anatomic variability of the congenital cardiac abnormality (such as single-ventricle physiology), and the surgical correction/palliation of the lesion It likely involves at least six major mechanisms: exogenous toxins and cytokines, metabolic factors, ischemia and reperfusion, neurohormonal activation, inflammation, and oxidative stress.102 These mechanisms of injury are likely to be active at different times with different intensity and probably act synergistically There are also some data suggesting that at least some of the injury may be pigment related, but this is yet to be substantiated.103 Traditional biomarkers for AKI include urine output and serum creatinine (SCr) Studies have shown that a 50% increase in creatinine in the first 48 hours could predict a greater than 50% increase in SCr in the next 48 hours However, nearly 50% of renal function has to be lost before SCr is elevated Borasino et al found that lower urine output after furosemide administration could predict AKI.104 Newer biomarkers of AKI are currently being studied to identify AKI earlier Proximal tubule biomarkers include NGAL, liver fatty acid-binding protein, and cystatin C, reflecting—directly and indirectly—proximal tubule functions Inflammatory biomarkers, such as IL-6 and IL-8, increase in as little as hours after cardiac surgery and have been found to correlate with development of AKI.101 Changes in renal oximetry as measured by near-infrared spectroscopy monitoring were also predictive of AKI development and, surprisingly, found that lower baseline average renal oxygen saturation was associated with lower rates of AKI.105 Earlier detection of AKI has the potential for earlier intervention, but current treatment for AKI remains inadequate Potential therapies for AKI include diuretics, dopamine, fenoldopam, and rasburicase, but data are lacking in showing efficacy There have also been attempts at ameliorating the injury with interventions such as N-acetylcysteine However, this has resulted in an increase in bleeding, with any benefit yet to be established.106 Timing and efficacy of continuous arteriovenous hemofiltration, continuous venovenous hemofiltration, and continuous RRT remain controversial Tumor lysis syndrome is detailed in Chapter 92 and summarized on ExpertConsult.com Pigment Nephropathy Rhabdomyolysis is the breakdown of skeletal muscles that produces a nonspecific clinical syndrome that causes extrusion of toxic intracellular contents from myocytes into the circulatory system The possible causes of rhabdomyolysis are myriad—with direct muscle injury remaining the most common cause, additional causes include hereditary enzyme disorders, drugs, toxins, endocrinopathies, malignant hyperthermia, neuroleptic malignant syndrome, heatstroke, hypothermia, electrolyte alterations, diabetic ketoacidosis and nonketotic hyperosmolar coma, severe hypothyroidism or hyperthyroidism, and bacterial or viral infections Most of the data remain adult based In a study of 210 pediatric patients, the most common causes of rhabdomyolysis were viral myositis (38%), trauma (26%), and connective tissue disease (5%) Higher initial creatinine kinase levels (.6000 IU/dL) and higher fluid administration rates were associated with higher maximal creatinine levels.114 Pathophysiology Rhabdomyolysis, which literally means “dissolution of striped [skeletal] muscle,” is the final pathway of many different processes Regardless of the underlying mechanism, myocyte dissolution triggers a cascade of events that leads to the rapid release of calcium ions into muscle cells This results in a pathologic interaction between actin and myosin and activation of cell protease, with subsequent myocyte necrosis of muscle fibers and release of potassium, phosphates, myoglobin, creatinine kinase (CK), and urates into the extracellular space and into the bloodstream As such, myoglobin can precipitate in the glomerular filtrate, particularly in an acidic environment, causing tubular occlusion and severe kidney damage Pigmented myoglobin casts, which characterize the rhabdomyolysis syndrome, are the result of the interaction between myoglobin and Tamm-Horsfall protein in an acid environment.115 Additional mechanisms causing renal damage include (1) a direct cytotoxic effect of myoglobin on renal cells; (2) urate precipitation, leading to intraluminal casts, increased intratubular pressure, and subsequent decreased GFR; (3) renal vasoconstriction and ischemia due to the heme group of myoglobin causing activation of the cytokine cascade; and (4) oxidant injury through heme-induced reactive oxygen species, such as superoxide anion, hydrogen peroxide, or hydroxyl radicals causing direct oxidative damage.116 The classic triad of symptoms of rhabdomyolysis includes myalgia, weakness, and dark urine, although these findings may be inconsistent The definitive diagnosis of rhabdomyolysis requires an elevation of CK levels to greater than five times normal in the absence of significant elevations of brain or cardiac CK fractions The most dangerous sequela of rhabdomyolysis is AKI, the exact mechanisms of which are unclear but may be attributable to vasoconstriction/hypoperfusion, renal tubular dysfunction/cast formation, or myoglobin-induced tubular cytotoxicity The mainstay of treatment for rhabdomyolysis, directed at preventing AKI, is fluid therapy.38 Many clinicians advocate alkalinization of urine with sodium bicarbonate (sometimes with concomitant forced diuresis with mannitol) Once the patient has reached the hospital, fluid infusion should be continued, with the goal of maintaining a brisk urinary flow and a urine pH above 6.5 and plasma pH below 7.50.117 The rate of infusion should be at 150% of maintenance rate, with hemodynamic parameters and urine output monitored closely Some authors also suggest administering mannitol This is done to induce osmotic diuresis and to remove fluid from the damaged muscular interstitium, thus relaxing the compartments involved.118 To force diuresis, some clinicians also recommend the addition of furosemide There is little clinical evidence to support the use of bicarbonate, mannitol, and furosemide It is important to understand that the treatment benchmark is aggressive forced hydration with saline and glucose solutions Studies in humans show that alkalinization and osmotic and diuretic treatment add little to the beneficial effect of hydration Forced hydration should be continued until the disappearance of myoglobinuria, which typically occurs after the third day Hyperkalemia must be managed with the usual techniques, considering that treatment with 918.e1 Tumor Lysis Syndrome Despite advances in diagnosis and treatment of cancer patients, large population-based studies have cited a 1-year risk of AKI of 17.5% and a 5-year risk of 27%.107 One major contributor to this statistic is tumor lysis syndrome (TLS) TLS is an oncologic emergency that is usually seen when tumor cells undergo rapid decomposition spontaneously or, more often, in response to cytoreductive therapy with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation (see also Chapter 92) Catabolism of the nucleic acids to uric acid leads to hyperuricemia A marked increase in uric acid excretion can result in the precipitation of uric acid in the renal tubules, causing obstruction and resulting in acute renal failure With stronger chemotherapy agents, the prevalence of TLS and AKI has increased, occurring with oncologic diagnoses previously thought to be low risk Even mild AKI that does not require RRT has been associated with increased long-term risk for renal failure and mortality The levels of phosphorus in malignant cells can be up to four times the levels found in normal cells Rapid release of these stores can result in hyperphosphatemia, with an increase in serum levels by as much as 2.1 mmol/L in children Initially, the kidneys respond by increasing urinary excretion and decreasing tubular resorption However, tubular transport mechanisms eventually become saturated, leading to increasing serum phosphorus levels Acute renal insufficiency caused by uric acid or other complications may further exacerbate the development of hyperphosphatemia In 2008, a group of researchers published evidence-based guidelines for the prevention and treatment of TLS Management Vigorous IV hydration with diuresis has long been the cornerstone to prevention and treatment of TLS (to achieve urine output of 80–100 mL/m2 per hour) Increasing intravascular volume and urine output increases the renal excretion of uric acid and phosphate Alkalinization of the urine is no longer recommended owing to the lack of supporting evidence and potential for enhancing the precipitation of xanthine in the urine.33 Allopurinol works to lower serum uric acid levels by reducing the production of uric acid from purine precursors by inhibiting xanthine oxidase Because it does not alter the uric acid already formed, it works best when initiated at least 48 hours prior to chemotherapy.33 It is generally well tolerated and can be given orally or intravenously; the dose needs adjustment for preexisting renal impairment Rasburicase Recombinant urate oxidase exerts its pharmacologic activity by enzymatic oxidation of uric acid into allantoin It works rapidly, often dropping the uric acid level to less than normal within hours The traditional recommended dosage is 0.15 to 0.20 mg/kg per dose IV daily for up to days Investigators recommend the use of rasburicase as the first-line intervention for high-risk patients and as backup therapy for moderate-risk therapy for those patients who go on to develop hyperuricemia despite allopurinol and hydration (eTable 74.3).108,109 Work by Hobbs and associates showed partial reversal of infant AKI associated with elevated uric acid when treated with rasburicase.110 Rasburicase is remarkably well tolerated The rare, but serious, adverse events that require prompt and permanent discontinuation of rasburicase are methemoglobinemia and hemolysis Glucose-6-phosphate dehydrogenase (G6PD) deficiency is regarded as the main predisposing factor for hemolysis and remains a contraindication to its use (the mechanism is related to oxidative stress from the hydrogen peroxide produced as uric acid is converted to allantoin), justifying, when possible, the screening for patients at high risk for G6PD deficiency (e.g., African or Mediterranean ancestry) More recent British guidelines support the use of prophylactic rasburicase in prevention of TLS in highrisk pediatric oncology patients, effective at a single dose of 0.2 mg/kg with proper laboratory monitoring.111 Role of Renal Replacement Therapy The understanding of the optimal start time, method, and dosage of RRTs has evolved (see also Chapter 75) Early intervention is favored, because most AKI survivors leave the hospital with independent kidney function.112 Once the process of cell turnover is uncoupled, the rapid release of intracellular contents into the bloodstream occurs—including anions, cations, proteins, and nucleic acids In this clinical paradigm, the early institution of renal replacement interrupts the cascade before the occurrence of tumor lysis–related AKI with life-threatening complications Therefore, the group recommended that for pediatric patients at high risk of TLS, cytotoxic chemotherapy should only be administered in a facility with ready access to dialysis Although dialysis usage has been reduced since the introduction of rasburicase, as many as 3% of patients (1.5% of pediatric patients and 5% of adult patients) still require RRT.37 In line with this observation, the panel recommended that renal consultation be obtained immediately if urine output is low, if there are persistently elevated phosphate levels, or in the case of hypocalcemia.113 918.e2 eTABLE 74.3 Patient Stratification by Risk RISK Type of Cancer High Intermediate Low NHL Burkitt lymphoblastic, B-ALL DLBCL Indolent NHL ALL WBC 100,000 WBC 50,000–100,000 WBC #50,000 AML WBC 50,000, monoblastic WBC 10,000–50,000 WBC #10,000 CLL WBC 10,000–100,000 Tx w/fludarabine WBC #10,000 Other hematologic malignancies (including CML and multiple myeloma) and solid tumors Rapid proliferation with expected rapid response to therapy Remainder of patients ALL, Acute lymphoblastic leukemia; AML, acute myeloid leukemia; B-ALL, Burkitt acute lymphoblastic leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; DLBCL, diffuse large B-cell lymphoma; NHL, non-Hodgkin lymphoma; Tx, treatment; WBC, white blood cell count Data from Coiffier BJ Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review Clin Oncol 2008;26:2767–2778; and Zaffanello M, Antonucci R, Cuzzolin L, et al Early diagnosis of acute kidney injury with urinary biomarkers in the newborn J Matern Fetal Neonatal Med 2009;3(suppl 22):62–66 CHAPTER 74 Glomerulotubular Dysfunction and Acute Kidney Injury glucose and insulin may prove to be ineffective in this context due to the damaged muscle’s inability to capture potassium from the extracellular space It is often necessary to treat severe hyperkalemia with RRT Hypocalcemia Secondary sequestration of calcium into damaged muscle cells must be viewed critically Administration of IV calcium (either chloride or gluconate) should be used only to treat life-threatening electrocardiographic alterations secondary to hyperkalemia or extreme hypocalcemia Drug-Induced Nephrotoxicity Many different drugs and agents may cause AKI in children In the ICU, factors such as age, pharmacogenetics, underlying disease, the dosage of the toxin, and concomitant medication all interact and influence the severity of nephrotoxic insults Pediatric retrospective studies have reported incidences of AKI in PICUs of between 8% and 30%.119 It is widely recognized that neonates have higher rates of AKI, especially following cardiac surgery, severe asphyxia, or premature birth Although in most cases the etiology of AKI in the ICU is multifactorial (e.g., sepsis, ischemia/hypoperfusion), several large epidemiologic studies have shown that nephrotoxic drugs were contributing factors in 19% to 25% of cases of severe acute renal failure in critically ill adult patients.120 NSAIDs, antibiotics, amphotericin B, antiviral agents, angiotensin-converting enzyme (ACE) inhibitors, CNIs, radiocontrast media, and cytostatics are the most important drugs implicated in the etiology of AKI in children The mechanisms of nephrotoxicity include constriction of intrarenal vessels, acute tubular necrosis, acute interstitial nephritis, and, more infrequently, tubular obstruction Aminoglycoside Nephrotoxicity Aminoglycosides (AGs) are non–protein-bound drugs that are primarily excreted unmetabolized by glomerular filtration Their nephrotoxicity is due to selective endocytosis and accumulation of the multiligand receptor megalin, particularly at the proximal tubule epithelial cells.121 Intracellular accumulation of AG within lysosomes eventually saturates, leading to leakage of AG from lysosomal structures Cytoplasmic AG has direct and indirect effects on mitochondria, is thought to interfere with normal cellular function, and stimulates calciumsensing receptor on the apical membrane, which can all to lead to apoptosis.122,123 Risk factors for AG nephrotoxicity include the type of AG, high peak serum levels, cumulative dose, the duration and frequency of administration, and patient-related factors, such as age, preexisting renal dysfunction, hypoalbuminemia, liver dysfunction, decreased renal perfusion, and the concomitant use of nephrotoxic drugs.124 Rank order of nephrotoxicity is as follows: neomycin gentamicin tobramycin amikacin netilmicin streptomycin.124 This is compounded by AG’s narrow therapeutic window and resultant misuse in the pediatric setting.125 Multiple definitions of pediatric AKI have led to variable incidence of AKI following AG use Neonates being discharged from neonatal ICUs have reported rates of AG use of 58% to 86%, with roughly 25% developing AKI Children have rates of AKI following more than days of AG use of 20% and 33% as defined by the Acute Kidney Injury Network (AKIN) and pRIFLE, 919 respectively Cystic fibrosis (CF) patients receive both IV and inhaled AGs for CF exacerbations, and AKI was associated 88% of the time with concurrent AG use.126 Several approaches have been evaluated in both animals and humans as potential treatments to attenuate the nephrotoxicity of AGs Investigators have demonstrated that calcium supplementation reduces the nephrotoxic effect, likely through competitive inhibition of calcium channels in the proximal tubule.127 Similarly, calcium channel blockers have been shown to attenuate AG nephrotoxicity.128 Also, the protective effect of concomitant use of b-lactam antibiotics has been recognized for several years, although the mechanism by which this may occur is somewhat unclear.129,130 More recent investigations have evaluated a possible role for antioxidants in renoprotection.131 Once-daily dosing of aminoglycosides is the only clinical approach that is commonly used to reduce nephrotoxicity and is especially prevalent in treatment of CF.132–134 The rationale for the efficacy of consolidated AG dosing against gram-negative bacteria is based on two pharmacodynamic properties of aminoglycosides: (1) the bacteriocidal mechanism of action is concentration dependent and (2) there is a prolonged postantibiotic effect Clinical evidence of AG-induced acute tubular necrosis is seen within week of initiation of AG treatment AG-induced acute renal failure is generally nonoliguric and may be associated with decreased urine concentrating ability and urinary magnesium wasting Fractional excretion of magnesium is a marker of AG-induced nephrotoxicity in neonates.135 It is generally reversible after discontinuation of the drug; however, supportive RRT may be required Alternative antimicrobials may be considered when possible in patients at high risk for AG nephrotoxicity If required and consolidated AG dosing is used, renal function should be assessed daily to monitor for changes in renal function; trough levels should be followed to guide dosage Amphotericin B The use of antifungals has become more commonplace in ICUs, as the prevalence of fungemia (specifically, candidemia) has increased in critically ill patients For decades, amphotericin B was the drug of choice because of its broad spectrum of activity and its wide availability However, its use has been sharply curtailed because of its considerable side effects (specifically, nephrotoxicity) and the availability of newer, less toxic agents Approximately 80% of patients who receive treatment with amphotericin B will experience some renal dysfunction.136 There are several mechanisms by which amphotericin B is thought to induce renal dysfunction Amphotericin B directly binds to and damages tubular epithelial cells in the cortical collecting duct, resulting in altered cell permeability The same mechanism by which amphotericin B is able to destroy membranes of fungal cells by binding to ergosterol causes cell death by leakage of K1, Na1, H1, and Cl Amphotericin B also directly causes afferent arteriolar (preglomerular) vasoconstriction, leading to decreased RBF and GFR and ischemic injury.137–139 Risk factors for amphotericin B nephrotoxicity include preexisting renal insufficiency, hypokalemia, volume depletion, the use of concomitant nephrotoxins, and large individual and cumulative dosages.140,141 A number of strategies have been studied to minimize the associated nephrotoxicity, including sodium loading and longer infusion rates.142 Lipid-based formulations of amphotericin B also are available, which may produce less nephrotoxicity However, ... precipitation of xanthine in the urine.33 Allopurinol works to lower serum uric acid levels by reducing the production of uric acid from purine precursors by inhibiting xanthine oxidase Because... also been attempts at ameliorating the injury with interventions such as N-acetylcysteine However, this has resulted in an increase in bleeding, with any benefit yet to be established.106 Timing... common cause, additional causes include hereditary enzyme disorders, drugs, toxins, endocrinopathies, malignant hyperthermia, neuroleptic malignant syndrome, heatstroke, hypothermia, electrolyte