835 Significant FO represents the most com mon indication for intervention in children with AKI The literature has consistently shown that increasing magnitude of FO is associated with adverse outcome[.]
43 Diagnosis and Treatment of Acute Kidney Injury in Children and Adolescents Significant FO represents the most common indication for intervention in children with AKI. The literature has consistently shown that increasing magnitude of FO is associated with adverse outcomes in a variety of populations, including children treated with continuous renal replacement therapy (CRRT) and other high-risk AKI populations (e.g., ECMO, bone marrow transplant) [30–32] Literature supports that FO >10% should be considered a prognostic marker in ICU patients and a marker of need for intervention In recent years, it has also become clear that the development of FO may predate and delay the 835 diagnosis of AKI. At the heart of this issue is the fact that SCr freely distributes between intracellular and extracellular spaces, resulting in inaccuracies due to fluid status Several studies of ICU children show that failure to account for FO when interpreting AKI severity, as measured by SCr rise, leads to delays in diagnosis and staging of AKI and under-recognition of AKI incidence and association with mortality [33–35] Recent studies have further cemented the concept that FO often occurs before meeting criteria for AKI [36–38] The following formula is commonly utilized in the literature to correct SCr for FO: Corrected creatinine serum creatinine 1 net fluid balance / TBW where total body water TBW 0.6 weight kg iagnostic Laboratory Evaluation D (Table 43.5) The initial laboratory workup of a patient with AKI seeks to identify the underlying etiology and potentially reversible causes of AKI (e.g., hypovolemia, nephrotoxins) The initial evaluation should minimally include electrolyte panel, SCr, urinalysis, urine sodium, urea and creatinine, and renal ultrasound Fractional Excretion of Sodium and Urea With renal hypoperfusion, the kidney expands the intravascular volume by increasing sodium and urea retention, as described above [28] This compensatory mechanism forms the basis of the fractional excretion of sodium (FeNa) and urea (FeUrea) calculations (Table 43.5) Both these calculations compare urine to serum concentrations of solute, corrected for GFR Urinalysis and Urine Microscopy Urinalysis is a critical test to evaluate for hematuria, proteinuria (to rule out glomerular diseases), and/or signs of infection Gross hematuria and severe proteinuria suggest glomerular disease With sterile pyuria, acute interstitial nephritis must always be considered, and urinary eosinophil testing ordered Urine microscopy aids in diagnosing intrinsic renal disease and may reveal muddy brown casts (acute tubular necrosis), red blood cell casts (glomerulonephritis), pyuria or crystals Renal Ultrasound Imaging plays a small role in diagnosing intrinsic renal disease Ultrasound should be considered if there is concern for obstruction or performed with a Doppler to rule out large vessel disease (e.g., vessel thrombosis) Further information about the chronicity of a process may be obtained by evaluating renal size (e.g., small kidneys suggest CKD; larger kidneys may suggest an acute process) Biopsy Renal biopsy is usually done to diagnose intrinsic AKI, findings of which are not reviewed here E H Ulrich et al 836 Table 43.5 A proposed list of investigations for AKI Urine testing Urinalysis and urine culture Dipstick testing for hematuria, proteinuria, signs of infection (leukocytes, nitrites) Urine culture should be collected by catheterization (non-toilet-trained children) or midstream sample (toilet-trained children) Urine microscopy Muddy brown or granular casts are suggestive of acute tubular necrosis Predominant leukocytes are suggestive of acute interstitial nephritis Urinary eosinophils for suspected acute interstitial nephritis Red blood cell casts and/or white blood cell casts are suggestive of acute glomerulonephritis Quantification of proteinuria Total (including glomerular and tubular) protein using protein/creatinine ratio Glomerular protein using albumin/creatinine ratio Tubular protein using ß2-microglobulin Fractional excretion of sodium Fractional excretion of sodium FeNa % urine Na / plasma Na 100 urine creatinine / plasma creatinine FeNa 2.5% for neonatesa) suggests intrinsic AKI Fractional excretion of ureab Fractional excretion of urea FeUrea % b urine urea / plasma urea 100 urine creatinine / plasma creatinine FeUrea 50% suggests intrinsic AKI Blood tests Serum creatinine Indirect measure of GFR Limitations include: Delayed marker of reduction in GFR and tissue damage Delay can be up to 72 h following renal insult Affected by a number of different factors, including age, sex, diet, muscle mass, and medications Serum creatinine varies with fluid status Some investigators suggest correcting serum creatinine for fluid status: net fluid balance Corrected creatinine serum creatinine 1 total body water Further investigations for severity and etiology of AKI Complete blood count If concern of thrombotic microangiopathy (anemia and thrombocytopenia), send markers of hemolysis, including lactate dehydrogenase, bilirubin, haptoglobin, blood film Further investigations if evidence of hemolysis is observed Sodium, potassium, chloride, bicarbonate, ionized and total calcium, magnesium, phosphate Albumin If concern of rhabdomyolysis, send serum creatine kinase, urine myoglobin Tests, if abnormal, suggest acute on chronic kidney disease Iron studies, including ferritin, iron, transferrin, total iron binding capacity, and calculation of percent transferrin saturation (TSAT) Intact parathyroid hormone 25-[OH]-Vitamin D3 Other tests Diagnostic imaging Includes renal ultrasound with Doppler Other investigations depend on etiology including VCUG, renal MAG3 scan, and DMSA renal scan Renal biopsy Renal biomarkers Neonates have reduced urine concentration and sodium retention due to relative tubular immaturity FeNa and FeUrea will be lowered with high urine flow rates Diuretics reduce sodium reabsorption and thereby increase FeNa FeUrea is less affected by diuretic therapy and may be helpful to distinguish pre-renal AKI from intrinsic AKI in patients treated with diuretics [105] a b 43 Diagnosis and Treatment of Acute Kidney Injury in Children and Adolescents anagement of Acute Kidney M Injury KI Management Prior to Renal A Support Therapy Despite research advances described above, there remain no treatments for AKI. Many interventional trials aimed at treating established AKI have failed Current management strategies are limited to preventing and treating AKI sequelae (FO, electrolyte abnormalities, etc.) There has been a recent paradigm shift from reactive AKI management to risk stratification and early identification Targeted interventions in at-risk populations have shown some promising results for preventing AKI. This section focuses on risk stratification, potential interventions to prevent or treat AKI, and management of established AKI. In addition to close renal function monitoring, AKI management includes optimizing nutrition, avoiding hypotension and excessive FO, and limiting nephrotoxin exposure Often, management decisions require a team-based collaborative approach to weigh AKI risks against benefits of individual interventions I nvestigational Strategies to Risk- Stratify AKI Timely identification of patients at risk for developing severe AKI, before significant SCr rise or AKI sequelae development, is critical to allow early intervention Recent examples of strategies developed to achieve early AKI identification include risk stratification (e.g., renal angina index, below), AKI biomarkers (discussed previously), and a functional assessment of kidney function (e.g., furosemide stress test, below) Renal Angina Index The renal angina index is a scoring system developed and validated to predict AKI risk in ICU children by combining known AKI risk factors and functional evidence of injury (Fig. 43.2) [39] Renal angina index derivation and validation studies showed that a score ≥8 predicted ≥ stage AKI development on ICU day [40, 41] Combining the renal angina index score with AKI biomarker results 837 (neutrophil gelatinase-associated lipocalin) in children at ICU admission led to almost perfect prediction of severe AKI on ICU admission day This work demonstrates that achieving early/ timely AKI and AKI risk identification likely requires both clinical and laboratory evidence of kidney tissue injury [42] Furosemide Stress Test The furosemide stress test is a novel measure that evaluates UO response 6 h after furosemide administration, to predict severe AKI. In adults, patients with 15% RAI index Risk score × injury score (1–40) Renal angina = RAI index ≥8 Fig 43.2 Renal angina index [41] Renal angina index (RAI) is used to prognosticate the risk of developing severe AKI (≥stage 2) 72 h later RAI is calculated 12 h following admission to pediatric intensive care unit (ICU) Patient characteristics are assigned a score for “risk” (0, 1, 3, or 5) Elevation in SCr or fluid overload (%) is assigned a score for “injury.” Baseline SCr is defined as the lowest SCr measured 3 months prior to ICU admission; baseline SCr was back-calculated when not available The highest SCr between admission to ICU and 12 h after admission was used When there was discrepancy between the score for SCr/Baseline or fluid overload, the worse score was used The “risk” and “injury” scores are multiplied to achieve the “RAI Index,” and RAI ≥8 defines renal angina In addition to being an important prognostic marker, the finding of renal angina is strongly associated with worse outcomes considered However, with reduced GFR of AKI, most current diuretics are limited in their ability to reach tubules to exert their effect Diuretics also have adverse effects, and many studies in adults have shown no benefit of diuretic use in AKI on time to AKI recovery or mortality Thus, when using diuretics in AKI, frequent reassessment of benefit (negative balance, nutrition) vs risk should be performed managed by restricting fluid Hyperkalemia is managed by reducing intake, correcting acidosis, and increasing elimination or intracellular shifts using diuretics, cation exchange resins (e.g., polystyrenes), beta-2 adrenergic receptor agonists (e.g., albuterol, salbutamol), or insulin with dextrose When electrocardiogram changes are present or with severe hyperkalemia, cardioprotection with calcium gluconate is critical to preventing life-threatening arrhythmias In refractory cases or those with a high potassium load (i.e., rhabdomyolysis), RST may be needed (see Timing and Modality of Renal Support Therapy) Hypocalcemia and hyperphosphatemia are treated with dietary adjustments and/or phosphate binders It is important to appreciate that in severe hyperphosphatemia, together with severe hypocalcemia, RST may be the best treat- Electrolyte Management Electrolyte management involves managing acute disturbances and anticipating potential problems In oligoanuric AKI, the most common electrolyte disturbances are hyponatremia, hyperkalemia, hypocalcemia, and hyperphosphatemia Hyponatremia occurs due to sodium and water retention, and this is most commonly 43 Diagnosis and Treatment of Acute Kidney Injury in Children and Adolescents ment option as infusing large amounts of IV calcium in patients with severe hyperphosphatemia may cause unwanted diffuse calcium-phosphate crystal formation Also, when administering sodium bicarbonate therapy to correct acidosis or hyperkalemia, it is important to know the patient’s calcium concentration, which will drop with bicarbonate infusions Overall, it is crucial to be aware of all electrolyte abnormalities and anticipate the effects from treating one electrolyte abnormality on homeostasis of other electrolytes 839 iming and Modality of Renal T Support Therapy Treating a patient with AKI with RST, even temporarily, is a decision carrying tremendous weight for the child, family, and healthcare team There remains significant equipoise about the optimal timing of initiation of RST and the best modality to use in AKI Traditional indications for RST in AKI are well entrenched in the minds of nephrologists and intensivists, including severe electrolyte or Pharmacological Therapy metabolic disturbances (especially hyperkalemia, Historically, vasodilators were felt to be reno- severe metabolic acidosis, or severe hyperphosprotective Low-dose dopamine causes vaso- phatemia with hypocalcemia), uremia (with uredilation of the renal vasculature and temporary mic pericarditis or encephalopathy, more typically increased natriuresis and GFR. However, many seen with severe CKD), symptomatic FO, and randomized controlled trials (RCTs) have shown removal of a dialyzable toxin that is contributing that dopamine does not prevent or treat AKI, to AKI. However, as our understanding of AKI and some studies have shown that it can cause moves beyond a binary model of “failure” or “not tachyarrhythmias and ischemia Other vasodila- failure” to a graded level of injury and dysfunction, tors, including fenoldopam (dopamine receptor the optimal timing of initiation of RST becomes agonist) and natriuretic peptides, are not cur- less clear Several large RCTs have compared rently recommended for AKI prevention or treat- early vs delayed RST initiation in ICU adults and ment Vasopressors, however, are recommended produced conflicting results In a single-center trial for patients with fluid-responsive hemodynamic (Zarbock et al.) comparing RST initiation within compromise, to maintain renal perfusion 8 h of stage AKI (“early”) vs within 12 h of There is emerging, tenuous evidence that ade- stage AKI (“late”), “early” RST was associated nosine receptor antagonists (e.g., theophylline, with higher 90-day survival (difference in hazard caffeine, aminophylline) may prevent or reduce ratio of 15%, p = 0.03) [53] The second trial was severity of AKI in some children These drugs a multicenter study (Gaudry et al.) including only have been studied mostly in neonates or children patients with stage AKI; patients with “delayed” having cardiac surgery in RCTs and observa- RST (requiring additional criteria, such as severe tional studies, with conflicting results [48–50] hyperkalemia, for >72 h to initiate RST) had no The latest KDIGO guideline suggests that the- significantly different 60-day mortality vs the earophylline may reduce AKI or AKI severity in lier RST group [54] Most recently, a multicenter neonates with hypoxic-ischemic encephalopathy RCT (Barbar et al.) including patients with septic However, there is no strong evidence supporting shock and severe AKI compared “early” (within routine use of adenosine receptor antagonists in 12 h) vs “late” RST initiation (>48 h) [55] This AKI. Dexmedetomidine, an alpha-2 adrener- trial was halted due to findings of futility of early gic receptor agonist, may reduce post-cardiac RST. It thus remains unclear if earlier RST inisurgery AKI rates, but more research is needed tiation improves patient outcomes Notably, early Rasburicase, a urate oxidase commonly used to RST was not found to be significantly associated reduce urate levels in tumor lysis syndrome, may with adverse events in these studies A larger mulalso benefit patients with severe hyperuricemia ticenter study is currently underway to compare in specific AKI settings (e.g., rhabdomyolysis; accelerated vs standard CRRT initiation in adults hemolytic uremic syndrome) [51, 52] (ClinicalTrials.gov NCT02568722) 840 E H Ulrich et al using PD to treat AKI. Recent data suggest a preferential shift toward use of CRRT. Today, PD is often preferred in small infants, where vascular access remains challenging [58] PD is commonly used in children undergoing cardiac surgery for the additional benefit of abdominal decompression (to reduce venous pressure and improve renal perfusion) [5, 59] Finally, for patients with some primary renal diseases (e.g., glomerular diseases, hemolytic uremic syndrome) that not require a critical care setting, PD is preferred because it is well tolerated and allows vessel preservation [57] A number of studies have evaluated PD in Modality of RST infants and small children undergoing cardiac There are several RST modalities for AKI treat- surgery Some centers place “prophylactic” PD ment commonly used in children, including peri- catheters in high-risk patients at the time of cartoneal dialysis (PD), intermittent hemodialysis diac surgery, and some observational studies have (IHD), continuous renal replacement therapy shown benefit with this approach [60], including (CRRT), and also sustained low-efficiency daily earlier negative fluid balance and improved clinidialysis (SLEDD) Many factors contribute to cal outcomes A single-center RCT showed supeRST modality choice, including patient size, ease rior fluid removal with PD compared to standard of access, comorbidities, and center experience dose diuretics [61] Several observational studies and resources Decisions regarding modality, par- have shown benefit of earlier PD initiation folticularly pertaining to FO, will be discussed here lowing high-risk cardiac surgery Prophylactic SLEDD, which uses conventional HD machines PD is generally defined as PD initiation in to administer IHD over prolonged periods (e.g., patients without FO or reduced UO; a single6–12 h), will not be discussed The technical center RCT did not show improved outcomes aspects of each modality in AKI will be discussed [62], while another study showed >40% reduced later in this section 30- and 90-day mortality in the prophylactic arm [63] At this time, there is consensus that PD is Peritoneal Dialysis Historically, PD was the the preferred modality for infants and small chilpreferred RST modality for AKI in children due dren following cardiac surgery However, it is not to ease of use and availability (see Chap 1) A known which patients should have prophylactic major advantage of PD is the lack of need for vas- PD catheter insertion at the time of surgery As cular access, which can be very challenging in well, there is equipoise regarding early PD initiachildren PD is well suited in children compared tion compared to standard use In North America, to adults because the peritoneal membrane sur- other pediatric populations are predominantly face area is larger relative to patient weight, treated with CRRT, unless limited by vascular enabling more efficient clearance PD is less pro- access inflammatory and promotes hemodynamic stability because it provides physiologic continuous Intermittent Hemodialysis Although there has RST [57] Disadvantages of PD include inconsis- been significant shift away from PD toward tency of fluid removal and solute clearance, CRRT, the use of intermittent hemodialysis slower solute clearance (vs IHD or CRRT), and (IHD) in AKI has remained relatively constant PD catheter site post-insertion leaks, especially for the treatment of life-threatening hyperkalein very edematous patients Frequency of these mia or acute poisoning (with or without AKI) complications is likely lower in centers primarily However, several studies have shown that with In children, there are no such trials However, many observational studies have identified that higher FO at CRRT initiation is associated with poorer outcomes In one multicenter study, the highest mortality (>65%) was seen with patients with ≥20% FO at CRRT initiation; this mortality is 8.5 times higher vs patients with 48 h) [55] This AKI. Dexmedetomidine, an alpha-2 adrener-... discussed [62], while another study showed >40% reduced later in this section 30- and 90-day mortality in the prophylactic arm [63] At this time, there is consensus that PD is Peritoneal Dialysis