|Year : 2022 | Volume
| Issue : 1 | Page : 1-6
Management of severe acute kidney injury
Sudarsan Krishnasamy, Sriram Krishnamurthy
Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
|Date of Submission||03-Apr-2022|
|Date of Decision||22-May-2022|
|Date of Acceptance||27-May-2022|
|Date of Web Publication||28-Jun-2022|
Department of Pediatrics, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry
Source of Support: None, Conflict of Interest: None
Acute kidney injury (AKI) is encountered in approximately one-fourth of children admitted to the intensive care units (ICUs). As AKI is known to prolong ICU stay as well as increase the overall morbidity and mortality, it is important to identify it timely and take appropriate measures to curtail further injury. Infections continue to be the most common cause in developing countries. While pneumonia, diarrhea, and tropical infections such as dengue, malaria, scrub typhus, and leptospirosis are major causes of AKI in children; glomerular diseases, systemic disorders, envenomations, and drugs also account for a major proportion of AKI in low and low-middle income countries. Fluid overload is associated with adverse outcomes in multiple studies; hence proper assessment of volume status is vital. Novel prognostic markers such as renal angina index and furosemide stress test are increasingly being applied in routine clinical care. The current guidelines recommend against the usage of furosemide for the prevention and management of AKI, except in a situation of fluid overload. Kidney replacement therapy (KRT) should be initiated promptly in AKI when indicated. The timing of initiation of KRT in AKI continues to be debatable and has attracted considerable research. While peritoneal dialysis continues to be the modality most often used in infants and young children, continuous KRT and sustained low-efficiency dialysis are used in hemodynamically unstable patients. Timely identification and management of the various complications reduce mortality. Cutting-edge multinational trials over the past decade have significantly impacted our understanding in managing this complex disorder.
Keywords: Acute kidney injury, biomarkers, children, kidney replacement therapy, management
|How to cite this article:|
Krishnasamy S, Krishnamurthy S. Management of severe acute kidney injury. Asian J Pediatr Nephrol 2022;5:1-6
| Introduction|| |
Acute kidney injury (AKI) is a clinical syndrome characterized by rapid deterioration of kidney function leading to the accumulation of nitrogenous waste products and imbalances in fluid and electrolyte homeostasis. AKI is common in children admitted to the intensive care unit (ICU) and is an important cause of morbidity and mortality in such patients.
There is wide variation in the epidemiology of AKI not only due to the diverse patient population but also due to the different definitions used. Until the last decade, there was no consensus definition for AKI. Subsequently, the Risk, Injury, Failure, Loss, and End-stage (RIFLE), Acute Kidney Injury Network (AKIN) and Kidney Disease Improving Global Outcomes (KDIGO) criteria were developed to standardize the definition of AKI. The KDIGO criteria are now being widely adopted; and the Pediatric Acute Kidney Injury, Risk Factors and Outcomes (AWARE) study reported an AKI incidence of 27% in critically ill children and young adults using these criteria. The quest for newer criteria continues, as is exemplified by the recently published pediatric reference change value optimized for AKI in children (pROCK) criteria.
Conventionally, the etiology of AKI is categorized into prerenal (functional), renal, and postrenal causes. Infections continue to be the most common cause of AKI in children from developing countries, contributing to 55% of included cases. While pneumonia, diarrhea, and tropical infections such as dengue, malaria, scrub typhus, and leptospirosis are the reported major causes of AKI, glomerular diseases, snake envenomation, systemic disorders (such as malignancies and hemolytic anemia), nephrotoxic drugs, plant toxins, industrial chemicals, and renal stones represent other important causes of AKI in the low and low-middle income countries., Sepsis, hypotension, hypoxemia, and multi-organ dysfunction are important risk factors for the development of AKI.
| Evaluation|| |
Evaluation begins with a comprehensive history and physical examination, ably supplemented by volume status assessment and meticulous input–output monitoring. The basic evaluation done in patients with AKI is summarized in [Table 1]. Fluid overload >10% has been shown to have detrimental outcomes, with registry studies showing 3% increased mortality with every 1% increase in fluid overload.,
Renal angina index (RAI) was recently proposed to identify patients at high risk of developing AKI. The index is assessed 12 h after ICU entry and a value ≥8 suggests the presence of renal angina. Of late, studies have attested to the accuracy of this index in critically ill children. In a recent systematic review involving 3701 children, an area under the curve of 0.88 (95% confidence interval [95% CI] 0.85–0.91) for RAI in predicting AKI was documented; with the sensitivity of 85% (95% CI 74–92) and specificity of 79% (95% CI 69–89).
Furosemide stress test (FST) is a novel functional biomarker of AKI. Urine output <200 ml in the 2 h following a bolus of intravenous furosemide at 1 mg/kg (1.5 mg/kg if furosemide exposed in the preceding 7 days) has been shown to predict stage 3 AKI in critically ill adults with a sensitivity of 87.1% and specificity of 84.1%. Similar findings have been replicated in few other studies. A systematic review and meta-analysis of studies reported the diagnostic performance of FST in predicting AKI progression and the need for kidney replacement therapy (KRT) in adults. This review identified 11 studies with a total of 1366 patients. The pooled sensitivity and specificity of FST for predicting AKI progression were 81% (95% CI 74–87) and 88% (95% CI 82–92), respectively. However, FST is not yet validated in children; more studies are warranted before its routine clinical implementation.
Although numerous biomarkers such as cystatin C, NGAL, KIM-1, IL-18, L-FABP, TIMP-2, and IGFBP7 have been identified in the past two decades, most of them have not gained widespread use and are still largely confined to the research settings. Kidney biopsy is not routinely recommended in AKI but is considered in the setting of rapidly progressive kidney failure, presence of active sediments or other markers to suggest glomerular hematuria, kidney manifestations of systemic disease (e.g., systemic lupus erythematosus, vasculitis), allograft dysfunction, and unexplained/persistent kidney impairment.
| Management|| |
The management of AKI is largely supportive, with adequate attention to fluid and electrolyte imbalances, minimizing ongoing and further insult to the kidneys, and allowing adequate time for renal recovery.
AKI may lead to life-threatening electrolyte abnormalities necessitating urgent intervention. The commonly observed complications along with the emergency management are enumerated in [Table 2]. In addition, prompt identification and treatment of the underlying etiology (e.g., methylprednisolone pulses for rapidly proliferative glomerulonephritis, plasma exchange for atypical hemolytic uremic syndrome, bladder catheterization for immediate relief of obstruction in posterior urethral valves, removal of the offending drug in interstitial nephritis) are indispensable.
|Table 2: Complications associated with acute kidney injury and emergency medical management|
Click here to view
When low intravascular volume or dehydration is accompanied by AKI, replenishment of intravascular volume by fluid boluses is paramount. In contrast, in intrinsic renal AKI, fluids have to be prescribed judiciously by appropriate restriction (insensible water losses plus urine output), aiming to avoid fluid overload. Crystalloids are the preferred choice of fluids in AKI. Among the available crystalloids, there is recent literature evidence that persistent hyperchloremia may be associated with delayed recovery of the kidneys as well as mortality hence balanced salt solutions are increasingly being utilized. Diuretics can neither prevent nor treat AKI; their use is justified only for managing fluid overload. Fenoldopam and low-dose dopamine are no longer recommended. Prophylactic theophylline has been shown to reduce the incidence of AKI after radiocontrast administration, and in term neonates with severe birth asphyxia; however, its use in other situations is unclear at present.
Drug doses should be adjusted for dose as well as interval administration based on the modality used and the pharmacokinetic properties of these medications. Antimicrobials such as vancomycin, piperacillin-tazobactam, aminoglycosides, amphotericin, nonsteroidal anti-inflammatory agents such as ibuprofen, and radiocontrast agents such as iohexol are among the commonly used nephrotoxic medications in the ICU which often require dose modification. Quality improvement programs such as Nephrotoxic Injury Negated by Just-in-Time Action have shown promise in reducing drug-induced AKI in centers with well-developed electronic health records. To prevent contrast-associated AKI, prior volume expansion with intravenous isotonic normal saline is recommended in patients with an estimated glomerular filtration rate <60 ml/1.73 m2/min; bicarbonate solutions and N-acetylcysteine are no longer recommended. Enteral nutrition has to be commenced early; with the energy composition being 20%–25% from carbohydrates, 30%–40% from lipids, and the remaining 35%–50% from proteins; targeting caloric intake of 20%–30% above the basal metabolic needs. A protein intake of 2–3 g/kg/day is suggested to overcome the losses during KRT. An algorithmic approach to the evaluation and management of AKI is described in [Figure 1].
|Figure 1: Algorithmic approach to the evaluation and management of AKI. AKI: Acute kidney injury, eGFR: Estimated glomerular filtration rate (calculated from modified Schwartz equation); FO: Fluid overload; FST: Furosemide stress test; ICU: Intensive care unit; KRT: Kidney replacement therapy; NGAL: Neutrophil gelatinase associated lipocalin|
Click here to view
Kidney replacement therapy
The timing of initiation of KRT, apart from the standard urgent indications of refractory hyperkalemia and metabolic acidosis, uremia, pulmonary edema, and fluid overload, has for long been a matter of debate. Over the past few years, five well-conducted, high-quality, randomized controlled trials in adults have tried to address this important question. The multicentric artificial kidney initiation in kidney injury (AKIKI) trial enrolled 620 patients from 31 ICUs in France and demonstrated that initiating KRT within 6 h of KDIGO stage 3 AKI did not provide mortality benefit when compared to initiating it beyond 72 h of oliguria or for standard emergency indications. The ELAIN trial from Germany reported a mortality benefit if KRT was initiated within 8 h of severe AKI. However, this trial was criticized for small sample size from a single center consisting predominantly of surgical patients, thereby limiting its external validity. Furthermore, this study had a fragility index of 3. In view of these diametrically opposite findings, the Initiation of Dialysis Early Versus Delayed in the Intensive Care Unit (IDEAL-ICU) trial was conducted by researchers from France, who compared KRT initiation within 12 h of severe AKI, to that initiated 48 h later. The trial was stopped midway as it was deemed futile by the data safety monitoring board. No mortality benefit was noted in the patients who were randomized to the early group. Subsequently, Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI), the largest trial in AKI, involving 3000 patients from 15 countries, was reported. After affirming clinical equipoise from the attending physicians, patients were randomized to receive KRT either within 12 h of severe AKI or upon the development of an emergency indication. Accelerated KRT initiation did not result in a lower mortality at 90 days in this study. As an extension to their previous trial, the AKIKI-2 trial collaborators demonstrated that postponing KRT initiation beyond 72 h of KDIGO stage 3 AKI did not confer additional benefit and was associated with potential harm. Summing up these and other similar randomized trials, an individual patient data meta-analysis failed to show mortality benefit from earlier initiation of KRT.
Modalities of kidney replacement therapy
It is the simplest and often the only KRT modality available in many developing countries. The peritoneal membrane acts as a natural semipermeable membrane for exchange of fluid and solutes with the blood compartment. Peritoneal dialysis (PD) has numerous advantages. First, it is a simple and safe technique which can be applied even in critically ill children on vasoactive support as the fluid removal is gradual and continuous and does not cause hemodynamic instability. Second, it can be easily performed in neonates and young infants in whom establishing vascular access may be challenging. Third, it is more physiological and less pro-inflammatory than hemodialysis. Finally, it can be performed with minimal infrastructure and workforce at a much lower cost compared to the other extracorporeal modalities such as continuous KRT or sustained low-efficiency daily dialysis. However, there are several limitations. PD cannot be performed effectively in children with recent abdominal surgeries, cellulitis, peritonitis, or inguinal hernia. Slow clearance of small solutes makes it less preferred in certain conditions such as hyperammonemia and inborn errors of metabolism. PD may not be appropriate in patients with massive fluid overload and pulmonary edema in whom quick fluid removal is desirable. As a result, the use of PD has declined considerably in many developed nations where continuous KRT (CKRT) or sustained low-efficiency dialysis (SLED) is preferred.
Intermittent hemodialysis (IHD) provides the fastest and most efficient small molecule clearance and ultrafiltration compared to the other KRT modalities. This makes it suitable for certain conditions such as hyperammonemia, inborn errors of metabolism, poisoning, and tumor lysis syndrome where rapid removal is desirable. The short duration of IHD allows time for other diagnostic and therapeutic maneuvers in critically ill patients. However, as the HD machines are not specifically suited for neonates and small infants, it is technically difficult to perform IHD in such young infants. Establishing vascular access in them may be challenging too. Furthermore, heparin anticoagulation might increase the risk of bleeding.
The HD prescription typically includes blood flow rate, dialysis flow rate, ultrafiltration rate, extracorporeal circuit, and anticoagulation. While the blood flow rate is set at 5–8 mL/kg/min, the dialysis flow rate is usually kept between 300 and 500 mL/min. The composition of the dialysate can be adjusted to suit the patients' needs (e.g., decreasing or increasing the potassium, bicarbonate, and calcium concentrations). The ultrafiltration rate is decided based on the assessment of dry weight from interdialytic weight gain and the presence of edema and hypertension; fluid removal up to 1.5%–2% per hour of estimated dry weight is well tolerated. Blood tubing, needle, and dialyzer contribute to the extracorporeal circuit; and it should not exceed 10% of blood volume (7–8 ml/kg) to prevent hypotension. In those with low blood pressures at the time of initiation of hemodialysis, priming the circuit with packed red cells or 5% albumin is beneficial. Unfractionated heparin is the commonly used anticoagulant, given at a bolus dose of 20–60 U/kg followed by 10–30 U/kg/h; targeting an activated clotting time ~ 50% over the baseline value but not exceeding 200 s. In patients with thrombocytopenia or bleeding diathesis and short dialysis sessions with intermittent saline flushes without any anticoagulation are routinely practiced. With improvements in dialysis technology, numerous monitoring systems including noninvasive blood volume monitors are now available.
Continuous kidney replacement therapy
It is the preferred modality in hemodynamically unstable patients with AKI as the gradual solute and fluid removal allows for better hemodynamic stability and decreased transcellular shifts. As fluid removal is predictable, titrating inputs to allow for adequate nutrition is feasible. While it is generally preferred in older children, the recent introduction of Cardiorenal Pediatric Emergency Dialysis Machine (CARPEDIEM®), Newcastle Infant Dialysis and Ultrafiltration System (NIDUS®), and Aquadex® system for ultrafiltration make CKRT a promising modality even in small neonates. However, it is very expensive, requires dedicated nursing personnel, and continuous anticoagulation to prevent circuit clot. While continuous veno-venous hemofiltration, continuous veno-venous hemodialysis, and continuous veno-venous hemodiafiltration modes are described, there is no significant benefit of one over the other. The recommended intensity for CKRT is a dialysis flow rate of 2000 mL/1.73 m2/h and an effluent flow of 20–25 mL/kg/h; doses higher than this are associated with complications. Although heparin is the most common anticoagulant used in these extracorporeal modalities, recent data suggest that regional citrate anticoagulation may be preferred due to significantly improved filter and circuit life.
Sustained low-efficiency dialysis
It is a hybrid modality which combines the advantages of both IHD and CKRT. The low blood flow rate of 3–5 mL/kg/min combined with low dialysis flow rate set at 1.5–2 times the blood flow rate continued for 8-12 h (at least 6 h) makes it an interesting modality. The low blood flow rate avoids hemodynamic instability in patients on inotropic support, thus making it suitable for them. Furthermore, it is less expensive and simpler to perform than CKRT, and allows time for other diagnostic procedures, making it an attractive alternative in critically ill patients with AKI.
There is no solid evidence to suggest that one KRT modality is better than the other; the choice is often based on availability and local expertise. In hemodynamically stable older children, IHD is the preferred modality while PD through a soft Tenckhoff catheter placed bedside is often used in infants and young children. While CKRT is the first choice in hemodynamically unstable patients, SLED is increasingly being applied with close monitoring in carefully selected patients on stable low-dose inotropic support, especially in resource-limited settings. Once kidney functions recover, KRT is discontinued and patients are closely monitored. There is emerging evidence that both early initiation (within 12 h of severe AKI) and high-dose intensive KRT (>35 mL/kg/h) are associated with delayed recovery of kidney function.,
While the prognosis of AKI depends on the underlying etiology, AKI is associated with longer ICU and hospital stay, duration of mechanical ventilation, and mortality. AKI survivors have been shown to have a higher risk of rehospitalization and also develop hypertension, proteinuria, and chronic kidney disease in the long term hence regular monitoring for these complications is recommended in all of these patients during follow-up.,,
In conclusion, AKI is common in children admitted to the pediatric ICUs and is associated with increased morbidity and mortality. Regular assessment of volume status and prevention of fluid overload is vital. Novel methods for risk stratification and severity prediction are likely to improve our prognostic abilities. No significant difference in mortality has been identified among the various modalities of KRT; hence, the choice should be guided by availability and local expertise. High-quality research in the past decade has revolutionized our understanding of the management of AKI, with expectant management combined with good supportive care becoming the new standard.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Kaddourah A, Basu RK, Bagshaw SM, Goldstein SL, AWARE Investigators. Epidemiology of acute kidney injury in critically ill children and young adults. N Engl J Med 2017;376:11-20.
Xu X, Nie S, Zhang A, Jianhua M, Liu HP, Xia H, et al.
A new criterion for pediatric AKI based on the reference change value of serum creatinine. J Am Soc Nephrol 2018;29:2432-42.
Krishnamurthy S, Mondal N, Narayanan P, Biswal N, Srinivasan S, Soundravally R. Incidence and etiology of acute kidney injury in southern India. Indian J Pediatr 2013;80:183-9.
Mehta P, Sinha A, Sami A, Hari P, Kalaivani M, Gulati A, et al.
Incidence of acute kidney injury in hospitalized children. Indian Pediatr 2012;49:537-42.
Macedo E, Cerdá J, Hingorani S, Hou J, Bagga A, Burdmann EA, et al.
Recognition and management of acute kidney injury in children: The ISN 0by25 Global Snapshot study. PLoS One 2018;13:e0196586.
Sutherland SM, Zappitelli M, Alexander SR, Chua AN, Brophy PD, Bunchman TE, et al.
Fluid overload and mortality in children receiving continuous renal replacement therapy: The prospective pediatric continuous renal replacement therapy registry. Am J Kidney Dis 2010;55:316-25.
Gist KM, Selewski DT, Brinton J, Menon S, Goldstein SL, Basu RK. Assessment of the independent and synergistic effects of fluid overload and acute kidney injury on outcomes of critically ill children. Pediatr Crit Care Med 2020;21:170-7.
Basu RK, Kaddourah A, Goldstein SL, AWARE Study Investigators. Assessment of a renal angina index for prediction of severe acute kidney injury in critically ill children: A multicentre, multinational, prospective observational study. Lancet Child Adolesc Health 2018;2:112-20.
Abbasi A, Mehdipour Rabori P, Farajollahi R, Mohammed Ali K, Ataei N, Yousefifard M, et al.
Discriminatory precision of renal angina index in predicting acute kidney injury in children; a systematic review and meta-analysis. Arch Acad Emerg Med 2020;8:e39.
Chawla LS, Davison DL, Brasha-Mitchell E, Koyner JL, Arthur JM, Shaw AD, et al.
Development and standardization of a furosemide stress test to predict the severity of acute kidney injury. Crit Care 2013;17:R207.
Chen JJ, Chang CH, Huang YT, Kuo G. Furosemide stress test as a predictive marker of acute kidney injury progression or renal replacement therapy: A systemic review and meta-analysis. Crit Care 2020;24:202.
Barhight MF, Brinton JT, Soranno DE, Faubel S, Mourani PM, Gist KM. Effects of hyperchloremia on renal recovery in critically ill children with acute kidney injury. Pediatr Nephrol 2020;35:1331-9.
Bhatt GC, Gogia P, Bitzan M, Das RR. Theophylline and aminophylline for prevention of acute kidney injury in neonates and children: A systematic review. Arch Dis Child 2019;104:670-9.
Goldstein SL, Dahale D, Kirkendall ES, Mottes T, Kaplan H, Muething S, et al.
A prospective multi-center quality improvement initiative (NINJA) indicates a reduction in nephrotoxic acute kidney injury in hospitalized children. Kidney Int 2020;97:580-8.
Davenport MS, Perazella MA, Yee J, Dillman JR, Fine D, McDonald RJ, et al.
Use of Intravenous iodinated contrast media in patients with kidney disease: Consensus statements from the American College of Radiology and the National Kidney Foundation. Radiology 2020;294:660-8.
Sethi SK, Maxvold N, Bunchman T, Jha P, Kher V, Raina R. Nutritional management in the critically ill child with acute kidney injury: A review. Pediatr Nephrol 2017;32:589-601.
Gaudry S, Hajage D, Schortgen F, Martin-Lefevre L, Pons B, Boulet E, et al.
Initiation strategies for renal-replacement therapy in the Intensive Care Unit. N Engl J Med 2016;375:122-33.
Zarbock A, Kellum JA, Schmidt C, Van Aken H, Wempe C, Pavenstädt H, et al.
Effect of early vs. delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: The ELAIN Randomized Clinical Trial. JAMA 2016;315:2190-9.
Barbar SD, Clere-Jehl R, Bourredjem A, Hernu R, Montini F, Bruyère R, et al.
Timing of renal-replacement therapy in patients with acute kidney injury and sepsis. N Engl J Med 2018;379:1431-42.
STARRT-AKI Investigators, Canadian Critical Care Trials Group, Australian and New Zealand Intensive Care Society Clinical Trials Group, United Kingdom Critical Care Research Group, Canadian Nephrology Trials Network, Irish Critical Care Trials Group, et al.
Timing of initiation of renal-replacement therapy in acute kidney injury. N Engl J Med 2020;383:240-51.
Gaudry S, Hajage D, Martin-Lefevre L, Lebbah S, Louis G, Moschietto S, et al.
Comparison of two delayed strategies for renal replacement therapy initiation for severe acute kidney injury (AKIKI 2): A multicentre, open-label, randomised, controlled trial. Lancet 2021;397:1293-300.
Gaudry S, Hajage D, Benichou N, Chaïbi K, Barbar S, Zarbock A, et al.
Delayed versus early initiation of renal replacement therapy for severe acute kidney injury: A systematic review and individual patient data meta-analysis of randomised clinical trials. Lancet 2020;395:1506-15.
Vasudevan A, Phadke K, Yap HK. Peritoneal dialysis for the management of pediatric patients with acute kidney injury. Pediatr Nephrol 2017;32:1145-56.
Sanderson KR, Harshman LA. Renal replacement therapies for infants and children in the ICU. Curr Opin Pediatr 2020;32:360-6.
Wang Y, Gallagher M, Li Q, Lo S, Cass A, Finfer S, et al.
Renal replacement therapy intensity for acute kidney injury and recovery to dialysis independence: A systematic review and individual patient data meta-analysis. Nephrol Dial Transplant 2018;33:1017-24.
Raina R, Agrawal N, Kusumi K, Pandey A, Tibrewal A, Botsch A. A meta-analysis of extracorporeal anticoagulants in pediatric continuous kidney replacement therapy. J Intensive Care Med 2022;37:577-94.
Ye Z, Wang Y, Ge L, Guyatt GH, Collister D, Alhazzani W, et al.
Comparing renal replacement therapy modalities in critically ill patients with acute kidney injury: A systematic review and network meta-analysis. Crit Care Explor 2021;3:e0399.
Sutherland SM, Ji J, Sheikhi FH, Widen E, Tian L, Alexander SR, et al.
AKI in hospitalized children: Epidemiology and clinical associations in a national cohort. Clin J Am Soc Nephrol 2013;8:1661-9.
Greenberg JH, Coca S, Parikh CR. Long-term risk of chronic kidney disease and mortality in children after acute kidney injury: A systematic review. BMC Nephrol 2014;15:184.
Hessey E, Morissette G, Lacroix J, Perreault S, Samuel S, Dorais M, et al.
Healthcare utilization after acute kidney injury in the pediatric Intensive Care Unit. Clin J Am Soc Nephrol 2018;13:685-92.
Robinson CH, Jeyakumar N, Luo B, Wald R, Garg AX, Nash DM, et al.
Long-term kidney outcomes following dialysis-treated childhood acute kidney injury: A population-based cohort study. J Am Soc Nephrol 2021;32:2005-19.
[Table 1], [Table 2]