902 SECTION VII Pediatric Critical Care Renal volume as measured by renal ultrasound They also used historic reference values to validate their equation Additional research in the field of neonatal re[.]
902 S E C T I O N V I I Pediatric Critical Care: Renal volume as measured by renal ultrasound They also used historic reference values to validate their equation Additional research in the field of neonatal renal function and AKI is clearly needed Biomarkers of Acute Kidney Injury and the Next Generation The currently available tools for assessing AKI are inadequate for detecting the onset of kidney cellular damage and the onset of renal functional impairment Advances in molecular biology have significantly enhanced our understanding of the pathogenesis of AKI, leading to the identification of several potential candidate biomarkers for AKI NGAL is the most extensively studied and one of the most promising.111 NGAL is a ubiquitous 25-kDa protein bound to gelatinase from human neutrophils and constitutively expressed at low levels in the kidneys, lung, liver, and gastrointestinal tract.112 Following ischemia and epithelial cell injury, such as after cardiac bypass, NGAL expression is upregulated, leading to marked increases in serum and urine NGAL levels that precede a rise in serum creatinine.113,114 In a heterogeneous group of critically ill children and adults for whom the onset of kidney injury is unknown, Zappitelli et al.115 found that urine NGAL concentrations increased 48 hours before a serum creatinine increase of 50% or more They also found that sepsisrelated AKI was associated with higher urinary NGAL levels than AKI unrelated to sepsis, a finding also confirmed in adults.116 Thus, urinary NGAL may have variable specificity for predicting AKI on the basis of subtype of AKI Despite this variability, a meta-analysis including adult and pediatric studies concluded that NGAL levels appear to have diagnostic value.117 The emerging data on NGAL indicates utility in the context of AKI prediction, prediction of use of renal replacement therapy, and response to diuretics and fluid balance regulation.118–120 The cell-cycle arrest marker, tissue inhibitor of matrix metalloproteinase-2/ insulin-like growth factor binding protein (TIMP-2/IGFBP7) has demonstrated high predictive efficacy in adult populations for the prediction of AKI and progression of AKI severity.121,122 The expression of kidney injury molecule-1, a transmembrane receptor with unclear function, also appears to be significantly upregulated in proximal tubular cells following ischemic or nephrotoxic injury After undergoing cleavage, the extracellular domain is shed into the urine, where it can be detected approximately 12 to 24 hours following the injury Urinary interleukin-18 (IL-18), a proinflammatory cytokine induced in proximal tubular cells following AKI, appears to be more specific to ischemic AKI and other types of acute tubular necrosis than to other forms of acute kidney disease (e.g., urinary tract infection or prerenal azotemia).123 Livertype fatty acid binding protein (L-FABP)—another promising new biomarker expressed in several organs, including the liver and kidney—is involved with fatty acid metabolism and intracellular signal transduction It may also play a role in both kidney injury and repair Expression within the kidney occurs in both normal and disease states Urine levels of L-FABP have been reported to increase significantly within hours after cardiac surgery in children and adults who subsequently developed AKI by serum creatinine criteria.124 Significant increases have also been noted in patients developing contrast-induced nephropathy.124 The role of biomarkers for AKI detection is emerging and promising Consensus criteria indicate the potential of novel biomarkers to provide contextual information related to AKI (i.e., the “how,” “where,” “when,” and “why”).125–127 Biomarker integration will provide localization of the site of injury within the kidney (glomerular vs tubular) as well as the potential to differentiate subtypes of AKI Indeed, the use of biomarkers in addition to serum creatinine, the traditional marker for AKI, may lead to a new paradigm for AKI: (1) hemodynamic AKI associated with a decrease in GFR but no structural changes within the kidney, (2) subclinical AKI associated with structural injury to the kidney without any apparent loss of function, and (3) AKI in which structural injury to the kidney is associated with a loss of function.128 The idea of integrating biomarkers for an improved precision relating to AKI phenotype was tackled by the 10th Acute Disease Quality Initiative (ADQI) consensus group This group advocated changes to improve the precision of AKI nomenclature, moving away from terms such as prerenal and intrinsic renal to more pathophysiologic terms such functional or tubular damage–associated AKI.126 In addition to the delineation of how time course relates to functional AKI, persistent AKI, and acute kidney disease, the 16th ADQI recommended study (including risk scores, functional markers, and use of biomarkers) to identify, predict, and further characterize patients with persistent AKI (i.e., 48 hours of SCr elevation or oliguria).129 A “combination biomarker” approach facilitates an improved understanding of clinical AKI Combining functional and damage biomarkers identifies patients with creatinine elevation with functional or reversible injury with high predictive specificity compared with creatinine alone.58 Use of biomarkers without context is suboptimal, however In multiple disease processes—most notably, acute coronary syndrome, sepsis, and stroke—the use of confirmatory biomarkers (or diagnostic tests that facilitate an understanding of the active biology of disease) occurs in the context of patient illness Risk stratification models for the identification of kidney injury and progressive renal dysfunction are the pragmatic and most practical method for using any of the estimating equations mentioned earlier in this chapter as well as novel biomarkers Although multiple severity of illness risk stratification systems exist, very few are specific to kidney injury and even fewer actually predict the progression of kidney injury (focused instead on mortality prediction using AKI as a covariate) The renal angina index, a composite of AKI risk factors based on patient demographics and signs of AKI early in the ICU course (after 12 hours of admission) has been validated for the prediction of severe AKI on day of the ICU course, with exceptionally high negative predictive value.130,131 Used for the purpose of targeting patient populations, this prodromal risk score can be used to identify the optimal populations to receive definitive biomarker testing or, ultimately, interventional management.121 Tubular Function Disorders of electrolyte balance, acid-base homeostasis, and volume regulation are also encountered in the ICU and require assessment of kidney tubular function Although the techniques required to assess tubular function may be easier to perform than techniques needed to assess GFRs, the interpretation of test results is not always straightforward Whereas a result may fall within the usual limits reported by the laboratory, this may not represent an appropriate response given the clinical context Urine Urine is the cheapest, most abundantly available, and noninvasive specimen from a patient for analysis of biomarkers or proteomics Thus, urine output is the most pragmatic biomarker Long incorporated into the staging classifications for renal dysfunction and AKI staging, only recently have data demonstrated the importance of incorporating urine output for AKI diagnosis.132,133 CHAPTER 73 Tests of Kidney Function in Children Further, recent data using the standardized quantification of volumetric response to furosemide (the furosemide stress test) indicates the importance of urine output and augmented urine output for the ascertainment of renal reserve.134–136 The assessment of the tubular capacity of the kidney is a new vista of exploration being actively investigated and holds potential for personalized medicine approaches to acute kidney dysfunction.137 Excessive fluid accumulation, termed fluid overload, has been implicated in bidirectional dependency with AKI Repeated data across populations demonstrates poor outcomes in patients with significant fluid accumulation.138 Fluid overload itself is a risk factor for AKI for a number of biological reasons and oliguric AKI is a causal factor for fluid overload The ability of the kidney to regulate net fluid balance is likely a surrogate for overall kidney function and is a reason why fluid overload is incorporated as a risk factor term in the renal angina prodrome Particularly in pediatrics, fluid overload and association with AKI have been explored to determine the isolated effects of each.139 Urine Electrolytes (Sodium and Chloride) As mentioned earlier, although antiquated and no longer recommended by consensus criteria, urine electrolytes can be used to classify the former designations of prerenal and intrinsic renal AKI Urine sodium (UNa) and urine chloride (UCl) are commonly used With prerenal AKI states, UNa is typically less than 20 mEq/L and UCl less than 15 mEq/L as the kidney avidly tries to reclaim sodium, chloride, and water in an effort to restore the extracellular fluid volume, whereas with acute tubular necrosis (ATN), the UNa is typically greater than 40 mEq/L due to structural tubular damage However, overlap can occur as the final concentration of sodium in the urine will depend on not only on the amount of sodium reclaimed by the tubules but also the amount of water reabsorbed in the distal tubule under the influence of antidiuretic hormone Thus, the UNa could exceed 20 mEq/L even in a prerenal state, particularly if oliguria is present The fractional excretion of sodium (FENa) accounts for this differential degree of water reabsorption and therefore provides a more accurate reflection of the kidney’s ability to conserve sodium FENa represents the fraction of filtered sodium that is excreted into the urine: FE Na (U Na /SNa )/(U Cr /SCr ) 100 where UNa and SNa correspond to the urine and serum sodium (mmol/L), respectively, and UCr and SCr (mg/dL) correspond to the urine and serum creatinine, respectively With prerenal azotemia, the FENa is generally less than 1%, whereas with ATN it is greater than 1% In premature infants, due to tubular immaturity, this threshold for FENa is approximately 3%, not 1% It should be noted that FENa is meaningful only in the setting of oliguric AKI In euvolemic patients, the urinary excretion of sodium will be more dependent on dietary sodium intake The accuracy of UNa and FENa is further compromised when urinary salt-wasting conditions are present (e.g., diuretic use, renal dysplasia, chronic renal failure, cerebral salt wasting, as well as mineralocorticoid deficiency such as congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency) These conditions are associated with elevated urinary chloride levels as well.140 Urine Concentration Capacity The urine-specific gravity (USG) and urine osmolality (UOsm) assess the kidney’s ability to concentrate the urine USG and UOsm bear a linear 903 relationship, with USG rising approximately 0.001 for every 30 to 40 mOsm/kg When urine is iso-osmotic to serum, the USG is approximately 1.010 In a healthy kidney, the limits of USG range from 1.003 to 1.035 and UOsm from 50 to 1400 mOsm/kg However, due to renal immaturity, infants have a reduced urinary concentration capacity of about 600 mOsm/kg for preterm and 800 mOsm/kg for full-term infants USG can be easily measured by refractometer; therefore it is clinically used more often than UOsm, which requires an osmometer In general, USG provides a good estimate of the kidney’s concentration ability However, because USG compares the density of urine to that of water, the presence of heavier solutes such as glucose, contrast dye, or protein can increase urine-specific gravity without affecting urine osmolality Therefore, urine osmolality provides a more accurate assessment of the kidney’s response to antidiuretic hormone (ADH) With prerenal azotemia, the appropriate renal response is to retain sodium and water Classically, the USG exceeds 1.020, UOsm exceeds 500, and the urine output decreases, with the patient often becoming oliguric (urine output ,1 mL/kg per hour) With ATN, on the other hand, the conservation of water is impaired secondary to tubular injury, resulting in isosthenuria (USG 1.010, UOsm 300–350 mOsm/kg) However, it is crucial to remember that children with underlying urinary concentration defects and tubular resistance to ADH (e.g., renal dysplasia, nephrogenic diabetes insipidus, chronic kidney failure) may have a low USG, low UOsm, and high urine output despite life-threatening intravascular volume depletion Urine osmolality is also helpful in evaluation of the child with polyuria A low osmolality (,150 mOsm/kg) suggests a urinary concentration defect such as central or nephrogenic diabetes insipidus, whereas a urine osmolality of 300 to 350, associated with a high specific gravity, suggests an osmotic diuresis The urinary concentrating capacity can be assessed by (1) checking the osmolality of a first morning urine after overnight fluid restriction with close monitoring or (2) a water deprivation test Serum Blood Urea Nitrogen/Creatinine Ratio The ratio of serum BUN to creatinine is also frequently used to help differentiate prerenal AKI from ATN Urea, like creatinine, is freely filtered at the glomerulus but, unlike creatinine, has significant tubular reabsorption that further increases with hypovolemia Therefore, in prerenal states, the BUN/creatinine ratio generally exceeds 20:1, while it is lower than this with ATN However, this ratio becomes inaccurate in clinical conditions in which the BUN is elevated for nonrenal reasons, such as a gastrointestinal bleed, catabolic state, or corticosteroid use It is also inaccurate in clinical conditions associated with a low BUN, such as protein calorie malnutrition or liver disease The ratio may also be misleading in conditions associated with a particularly low muscle mass and serum creatinine, such as muscular dystrophy Urine Microscopy Urine microscopy can aid in determining the etiology for AKI The presence of muddy brown or renal cellular casts and renal tubular epithelial cells is consistent with ATN However, the absence of such findings does not rule out less severe ATN In the setting of prerenal azotemia, urine microscopy is bland; hyaline and granular casts may be seen Hematuria with dysmorphic red blood cells (RBCs) and red cell casts is consistent with glomerulonephritis, whereas hematuria with normal RBC morphology suggests lower tract bleeding and hematuria in the absence of RBCs on freshly examined urine suggests hemoglobinuria or myoglobinuria Leukocyturia with white cell casts suggests pyelonephritis or interstitial nephritis Eosinophils in the 904 S E C T I O N V I I Pediatric Critical Care: Renal urine can be detected using special stains and are classically associated with interstitial nephritis but can also be seen with pyelonephritis and urinary tract obstruction.141 Examination of a fresh, concentrated (or first morning) urine specimen optimizes the opportunity for detecting these cellular elements Proteinuria Protein excretion in healthy individuals is minimal (,4 mg/m2 per hour in children) but can increase with renal injury Glomerulopathies are associated with albuminuria and nonspecific proteinuria, while tubulointerstitial disease results in lowmolecular-weight proteinuria (e.g., b2-microglobulin, retinolbinding protein) Urinary protein excretion can be detected qualitatively by reagent strips However, these strips detect albumin only and therefore are helpful for assessing glomerular proteinuria but not tubular or low-molecular-weight proteinuria Low-level proteinuria by dipstick (30–99 mg/dL) can be a false positive in alkaline urine or can signify more significant disease if the patient is polyuric Quantitative assessments of proteinuria can be obtained using a random urine total protein/ creatinine ratio (normal ,0.2 for children older than years) measured by the biuret method142 and are preferred for following glomerular and tubular proteinuria First morning urine specimens are often recommended, as they can distinguish orthostatic proteinuria, which is benign, from fixed proteinuria, which is pathologic Twenty-four-hour urine collections for protein and creatinine can also be performed but are not believed to be advantageous over the random urine protein/ creatinine ratio, particularly in children In diabetics, the development of overt proteinuria detectable by reagent strips is preceded by the presence of microalbuminuria, defined as persistent albumin excretion between 30 and 300 mg/g creatinine.143 Use of the microalbumin/creatinine ratio allows for early detection of glomerular damage in diabetic kidney disease.25 Renal Acidification Metabolic acidosis is also commonly encountered in the PICU When associated with a normal serum anion gap, the major diagnostic consideration is renal tubular acidosis versus gastrointestinal loss of bicarbonate The appropriate renal response to a metabolic acidosis is to increase proton secretion and ammonium production, which will allow increased net acid excretion (also see Chapter 72) The urine pH in this case should fall below 5.3, ideally measured with a pH meter after collecting a fresh specimen in an airtight syringe Whereas a urine pH greater than 5.3 in the setting of systemic acidemia is consistent with renal tubular acidosis (RTA), a urine pH less than 5.3 does not exclude the diagnosis Proximal RTA is characterized by bicarbonaturia secondary to a reduced threshold for bicarbonate reabsorption At low levels of serum bicarbonate (,14 mEq/L), the filtered bicarbonate is able to be reabsorbed, resulting in a low urine pH However, under conditions of bicarbonate loading, the reabsorptive capacity of the proximal tubule is exceeded, leading to fractional excretion of bicarbonate greater than 15% to 20%: FE bicarb (U HCO3 /SHCO3 )/(U Cr /S Cr ) 100 where UHCO3 and SHCO3 are the urine and serum bicarbonate concentrations in mmol/ L and UCr and SCr are the urine and serum creatinine concentrations in mg/dL Assessment of distal acidification includes calculation of the urine net charge and osmolal gap, both of which provide an indirect assessment of ammonium production, which cannot be routinely measured The former is simpler to calculate: Urine net charge (U Na U K U Cl ) where UNa is the urine sodium concentration (mEq/L), UK is the urine potassium concentration (mEq/L), and UCl is the urine chloride concentration (mEq/L) Assuming that chloride is the major anion excreted, an appropriate urine net charge in the setting of acidosis should be negative (230 to 250), indicating the presence of ammonium, an unmeasured cation Therefore, a positive net charge would suggest impaired ammonium production or proton secretion The urine net charge, however, has limited utility when the urine sodium concentration is low (,25 mEq/L), as occurs with hypovolemia In this setting, the kidney avidly conserves sodium and chloride (urine chloride ,15 mEq/L), leaving less anion available for excretion with ammonium and resulting in a reversible impairment of urinary acidification The urine net charge is also misleading in the presence of unmeasured anions (e.g., b-hydroxybutyrate and acetoacetate in diabetic ketoacidosis, hippurate from toluene ingestion/ glue sniffing, or penicillins) In this setting, the urine net charge is positive and underestimates ammonium excretion because the cations—ammonium, sodium, and potassium—are excreted with the unmeasured anion instead of chloride In infants, the validity of the urine net charge is also compromised owing to considerable variability in the unmeasured ionic composition of the urine.144 The urinary osmolal gap is more informative because it accounts for the excretion of the unmeasured anions.145 It represents the difference between the measured and calculated urine osmolalities, in which the calculated osmolality is U Osm {2 [U Na (mmol/L) U K (mmol/L)]} [U urea (mg/dL)/2.8] [U glucose (mg/dL)/18] Assuming that urinary ammonium is the predominant unmeasured cation, the concentration of excreted ammonium is approximately half of the urine osmolal gap During periods of systemic acidosis, urinary ammonium excretion increases to concentrations greater than 75 mEq/L; a level less than 25 mEq/L in this setting suggests impaired ammoniagenesis.146 More sophisticated tests are available to assess distal tubular acidification (proton secretion) Traditional tests include (1) measuring the difference in partial pressure of carbon dioxide between the urine and blood during bicarbonate loading and (2) an NH4Cl loading test However, these can be difficult to perform and may not be well tolerated More recently, simultaneous administration of furosemide to enhance distal sodium delivery and fludrocortisone to enhance distal sodium reabsorption, as well as stimulate proton secretion, has been used as an alternative test for distal acidification In the presence of intact distal acidification, the urine pH should decrease to less than 5.3 This test has the advantages of being easy to perform and well tolerated.147 Potassium Regulation Unlike urine sodium, which can be extremely efficiently reclaimed by the tubules, there is an obligate potassium (K) excretion of at least to 10 mmol/day due to potassium secretion that occurs in the distal tubule Potassium excretion is primarily dependent on the aldosterone activity and serum potassium concentration but also requires an adequate urine flow rate and delivery of sodium to the distal nephron The transtubular potassium gradient (TTKG) provides an assessment of potassium excretion CHAPTER 73 Tests of Kidney Function in Children secondary to mineralocorticoid activity and is calculated as follows: TTKG [U K SOsm ]/SK U Osm ] where UK and SK represent urine and serum concentrations of potassium (mEq/L), respectively, and SOsm and UOsm represent serum and urine osmolalities (mOsm/kg) In the setting of hyperkalemia, the TTKG should be elevated; therefore, a low TTKG (,4.1 in children; ,7 in adults) suggests hypoaldosteronism In the setting of hypokalemia, on the other hand, the TTKG would be expected to be quite low; levels greater than suggest that aldosterone activity is not appropriately suppressed.140,148 Generalized Proximal Tubulopathy Generalized proximal tubulopathies (Fanconi syndrome) can be congenital (e.g., cystinosis, tyrosinemia) or acquired (e.g., aminoglycoside toxicity, ifosfamide, severe ATN) and may be partial or complete Biochemical abnormalities associated with a complete Fanconi syndrome include hypokalemia, metabolic acidosis, hypophosphatemia, hypouricemia, and low serum carnitine associated with urinary wasting of sodium, potassium, bicarbonate, phosphorus, uric acid, carnitine, glucose, amino acids, and low-molecular-weight proteins A generalized proximal tubulopathy should be suspected when electrolyte wasting is profound and/or involves several electrolytes Integration of Kidney Function Assessment in Critical Care Missing from the decades of work enhancing precision to GFR estimating equations, identification of AKI, and outcomes research is a practical demonstration of use in the pediatric critical care environment As discussed earlier, an integrated and riskstratified approach will be required (Fig 73.3) As the field moves past the monocular reliance on creatinine for diagnosis, prediction, risk stratification, proof of therapy, and long-term assessment, more data emerge on the importance of AKI phenotype derivation Combination biomarkers are vital to this work A refined approach that integrates novel functional and tubular injury markers will undoubtedly lead to opportunities for further targeting and innovation with regard to assessment of kidney function Key References Hoste L, Dubourg L, Selistre L, et al A new equation to estimate the glomerular filtration rate in children, adolescents and young adults Nephrol Dial Transplant 2014;29:1082-1091 Kaddourah A, Basu RK, Bagshaw SM, et al Epidemiology of acute kidney injury in critically ill children and young adults N Engl J Med 2017;376(1):11-20 Supportive care Host Recovery Creatinine change Insult CRRT Low Host CKD, ESRD, Death No AKI AKI/FO phenotype Insult Risk stratification High Supportive care prevention bundle Functional AKI (SCr or oliguria) Functional AKI (SCr + oliguria) KINETIC GFR Fluid overload % Fluid corrected SCr Biomarker profiling Renal oximetry Furosemide stress test Real-time GFR 905 Functional AKI with fluid overload Outcome Damage AKI without oliguria Damage AKI and oliguria Damage AKI and high fluid overload • Fig 73.3 Existing static and limited diagnostic strategy with the existing management options and associated epidemiology is juxtaposed with the potential paradigm change offered via a multimodal and longitudinal approach to acute kidney injury (AKI) assessment, management, and therapeutics Adjudication of AKI by different modalities, incorporating creatinine change (SCr) and urine output changes (UOP), may identify specific phenotypes of AKI amenable to targeted therapy CKD, Chronic kidney disease; CRRT, continuous renal replacement therapy; ESRD, end-stage renal disease; FO, fluid overload; GFR, glomerular filtration rate Targeted therapies 906 S E C T I O N V I I Pediatric Critical Care: Renal Kellum JA, Lameire N, KDIGO AKI Guideline Work Group Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1) Crit Care 2013;17:204 Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group KDIGO 2012 Clinical practice guideline for the evaluation and management of chronic kidney disease Kidney Int Suppl 2013;3:1-150 Rink N, Zappitelli M Estimation of glomerular filtration rate with and without height: effect of age and renal function level Pediatr Nephrol 2015;30:1327-1336 Schwartz GJ, Munoz A, Schneider MF, et al New equations to estimate GFR in children with CKD J Am Soc Nephrol 2009;20:629-637 Soveri I, Berg UB, Bjork J, et al Measuring GFR: a systematic review Am J Kidney Dis 2014;64:411-424 Srivastava T, Alon US, Althahabi R, Garg U Impact of standardization of creatinine methodology on the assessment of glomerular filtration rate in children Pediatr Res 2009;65:113-116 The full reference list for this chapter is available at ExpertConsult.com ... prerenal states, the BUN/creatinine ratio generally exceeds 20:1, while it is lower than this with ATN However, this ratio becomes inaccurate in clinical conditions in which the BUN is elevated for... than 1%, whereas with ATN it is greater than 1% In premature infants, due to tubular immaturity, this threshold for FENa is approximately 3%, not 1% It should be noted that FENa is meaningful only... state, particularly if oliguria is present The fractional excretion of sodium (FENa) accounts for this differential degree of water reabsorption and therefore provides a more accurate reflection