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Renal replacement therapy in children
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Renal Replacement Therapy in Children Felix C. Blanco MD, Gezzer Ortega MD, MPH, Faisal G. Qureshi MD, FACS
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S1055-8586(14)00122-X http://dx.doi.org/10.1053/j.sempedsurg.2014.11.006 YSPSU50526
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Seminars in Pediatric Surgery
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Cite this article as: Felix C. Blanco MD, Gezzer Ortega MD, MPH, Faisal G. Qureshi MD, FACS, Renal Replacement Therapy in Children, Seminars in Pediatric Surgery, http://dx.doi.org/10.1053/j.sempedsurg.2014.11.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
#6 Renal Replacement Therapy in Children Felix C. Blanco, Gezzer Ortega, and Faisal G. Qureshi (corresponding author) Felix C. Blanco, MD Transplant Surgery Fellow University of Minnesota Medical Center 420 Delaware Street SE Minneapolis, MN 55455 [email protected] Gezzer Ortega, MD, MPH Research Associate Howard University College of Medicine Department of Surgery 2041 Georgia Avenue, NW Suite 4B35 Washington, DC 20060 [email protected] Faisal G. Qureshi, MD, FACS Assistant Professor Surgery and Pediatrics George Washington University Children’s National Medical Center 111 Michigan Ave, NW WW 4200 Washington, DC 20010 [email protected]
Corresponding Author
The authors have no disclosures or conflicts of interest.
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Abstract Acute kidney injury (AKI) affects 3.9/1000 at risk children in the United States, a number which has been increasing as critically ill and injured children have access to improved care and the diagnosis of AKI is being made more accurately. Children with AKI have a higher mortality and hospital length of stay as compared to children without AKI. Renal replacement therapy can improve outcomes in these patients. This article reviews the pathophysiology of AKI and the modalities, indications and outcomes of renal replacement for children with AKI.
Key words: Renal Replacement Therapy; Acute Kidney Injury
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Acute Kidney Injury
Renal failure is the inability of the kidneys to maintain fluid, electrolyte and acid-base homeostasis. Sudden deterioration of the renal function, also known as acute renal failure (ARF) is due to a direct insult to the kidney (primary renal disease) or the result of a systemic disease process that affects renal perfusion or injures the renal interstitium (secondary failure). The term ARF was recently changed to acute kidney injury (AKI). AKI describes more exactly the pathophysiology behind ARF, reflecting its potentially reversible course.
Common causes of AKI include hypovolemic states leading to shock, toxins causing interstitial or tubular damage, and acute obstruction of the urinary outflow. These three mechanisms are universally known as prerenal, renal/intrinsic and postrenal AKI.
AKI is manifested clinically by a decline in urine output (UO) and a simultaneous elevation of serum creatinine (Cr). These two clinical parameters, however, are unreliable. A low UO does not necessarily correlate with the severity of renal dysfunction as seen in non-oliguric renal failure or in those patients receiving diuretics. Similarly, minor changes in Cr may not accurately reflect the ongoing kidney injury since nearly a 50% loss in functioning renal mass is needed to affect the serum Cr. Concomitant fluid overload in critically ill children with AKI will dilute and falsely affect the serum Cr.
Chronic kidney disease is defined as the persistence of renal dysfunction beyond the period of resolution of the causative injury and is associated with a progressive decline in the glomerular filtration rate (GFR).
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End-stage kidney disease refers to chronic kidney disease requiring dialysis or kidney transplant.
AKI criteria The Acute Dialysis Quality Initiative (ADQI) Group, (a multidisciplinary group working on developing evidence-based guidelines for the treatment of ARF), identified specific characteristics of AKI to help define and measure outcomes (1).
According to ADQI
guidelines, the acute deterioration of kidney function follows a series of stages to reach permanent cessation of renal function. The RIFLE criteria for acute renal dysfunction are characterized by a progressive decline of UO and GFR, and increasing plasma Cr.
R= Risk of renal dysfunction I= Injury to the kidney F= Failure of kidney function L= Loss of kidney function. Indicates persistent loss requiring RRT for more than 4 weeks E= End stage kidney disease. Indicates need for RRT for more than 3 months.
The initiation of RRT in early stages or “less severe” renal failure (RIFLE-R, RIFLE-I) is associated with improved outcomes and decreased 30 day mortality. In contrast, when RRT was initiated in more severe stages (RIFLE-F, RIFLE-L), the 30 day mortality approached almost 50% (2). A pediatric version of the RIFLE criteria was developed in 2007. The pediatric RIFLE or pRIFLE has a few variations compared to the adult criteria considering only UO and GFR but not serum Cr. Unfortunately, a recent review demonstrated that the pRIFLE criteria were
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inconsistent when used to determine the morbidity and mortality outcomes in children with renal failure (3). Most recently, the Kidney Disease Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group delineated an international guideline to define and stage AKI in adults and children. (4) Stages I, II and III include increase in Cr and decline in UO as follows:
(Insert Table 1)
In children with an established AKI, the estimation of baseline serum Cr may be difficult. The creatinine level and GFR can be estimated using the “modification of diet in renal disease” (MDRD) formula, which normalizes the GFR to the body surface area based on age, sex and race. Unfortunately, this formula can only be used in children over 12 years of age and estimations are inaccurate when the patient is not in a steady state of creatinine balance as in small infants and patients with restricted creatinine secretion due to chemotherapy, cimetidine or AIDS therapy (5). Recently, several plasma and urinary biomarkers released by the kidney under stress or ischemia have been described. These are undergoing intensive research before they are accepted for the prediction and prognosis of AKI. Some of these biomarkers include: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), livertype fatty acid binding protein (L-FABP), and interleukin (IL)-18 (6).
Causes of AKI In developed countries, only 10% of AKI are due to primary kidney disease. The majority are secondary to systemic illnesses, cardiac surgery for congenital heart disease, sepsis and Page 5 of 30
nephrotoxic medications (7-10). Hemolytic uremic syndrome is still the main cause of renal failure in children of developing countries.
Pre-renal AKI In pre-renal AKI, kidney injury occurs from hypoperfusion. The most common cause of hypoperfusion is hypovolemia due to severe dehydration, bleeding, gastrointestinal losses or major burns. Diminished renal perfusion can also occur with normal or elevated extracellular volume in conditions such as congestive heart failure, hepatorenal syndrome or sepsis. Hypoperfusion activates the juxtraglomerular complex (renin-angiotensin-aldosterone axis) promoting avid reabsorption of sodium and water in an attempt to replenish the intravascular volume. Non-steroidal anti-inflammatory medications inhibit cyclooxygenase-1 and cyclooxygenase-2 enzyme activity, diminishing prostaglandin formation that serves as a renal vasodilator. This physiologic response can worsen renal insufficiency in states of hypoperfusion.
Upon activation of the mentioned axis, the release of angiotensin causes vasoconstriction of the glomerular efferent arteriole (closing the exit “valve”), increasing intracapillary pressure and improving transglomerular filtration. The administration of angiotension converting enzyme (ACE) inhibitors to patients with renovascular disease is deleterious since it inhibits this compensatory mechanism by dilating the efferent arteriole (thus decreasing ultrafiltration pressure).
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Mechanical ventilation and conditions that increase the intrathoracic pressure and reduce the pre-load (pneumothorax, cardiac tamponade), may lead to renal hypoperfusion and renal failure. This is particularly true during states of inadequate cardiac filling volumes.
Renal or intrinsic AKI Parenchymal damage prevents the kidney from absorbing water and electrolytes and prevents elimination of byproducts of catabolism (creatinine, urea). Tubular casts precipitate from urinary stasis, low pH, and greater urinary concentration and “plug” the fine tubular system causing acute tubular obstruction, back-leak into the interstitium, loss of epithelial integrity and epithelial damage, a phenomenon known as acute tubular necrosis or ATN. Direct toxicity of myoglobin occurs when the epithelial cells are exposed to free oxygen radicals originating from the oxidation of ferrous oxide to ferric oxide. Acute interstitial nephritis (AIN), an inflammatory infiltration of extraglomerular structures (tubules and interstitium) leads to acute epithelial injury and renal dysfunction due to the activation of proinflammatory cytokines. This process is usually secondary to the use of medications (aminoglycosides, anphotericine). AIN is usually self-limited and rarely progresses to permanent renal injury. Radiocontrast dyes impose a high solute load to the tubular system which in turn imposes high energy demands to the renal medulla (increased tubular activity). Since the renal medulla is an area of limited blood flow, the enormous metabolic demand easily leads to interstitial hypoxia and subsequent renal injury. Kidney injury from contrast dye is known as contrast induced nephropathy or CIN (11).
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Other causes of interstitial nephritis include bacterial and viral infections, systemic lupus and acute transplant rejection Post-renal AKI In post-renal AKI, obstruction of the urinary outflow leads to decreased ultrafiltration pressure and acute tubular injury. The obstruction leads to retrograde or “backflow” of urine causing tubular hypertension. Hydronephrosis or dilatation of the collecting system occurs with prolonged obstruction usually over days. Common causes of post-renal AKI include papillary necrosis, posterior urethral valves, urethral strictures, or acute neurogenic bladder seen in trauma or the presence of a pelvic mass.
AKI and sepsis Sepsis related AKI accounts for one third of cases of renal injury in children (12). Injury mechanisms include systemic hypoperfusion, release of pro-inflammatory mediators, decrease in anti-inflammatory mediators and activation of the coagulation cascade leading to intra-renal microthrombosis (13).
Recent evidence suggests that upregulation of
metalloproteinase-8 and elastase-2e may play a role in sepsis related AKI (14). Whether these biomarkers are causative of AKI or simply a consequence of an increased pro-inflammatory state is unknown.
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Causes of renal failure in young children Common causes of renal failure in young children include interstitial diseases such as renal dysplasia, renal hypoplasia and obstructive uropathy. Glomerular-based disease, typically glomerulonephritis, is more frequent in older children.
Clinical assessment of the child with AKI The clinical evaluation of a child with suspected AKI should include a thorough investigation of previous medical and surgical conditions, presence of hypertension, recent infections and use of medications with potential nephrotoxic side effects. Examination of the child should be focused on the identification of hypovolemia, generalized edema, blood pressure measurement and skin inspection to identify palpable (vasculitis) and non-palpable (hemolytic-uremic syndrome) purpuric lesions. stenosis.
Auscultation may reveal renal artery
The presence of a pelvic mass during the abdominal examination may be
responsible for obstructive renal failure.
Laboratory findings in AKI Urinary osmolality. In pre-renal AKI the avid absorption of sodium and water leads to highlyconcentrated urine. Urine osmolality can reach levels beyond 900 mOsm/L.
In
intrinsic AKI, the inability to concentrate urine leads to diluted urine with osmolality levels of less than 300mOsm/L.
Urinary sodium. The measurement of urinary sodium helps differentiate between pre-renal or intrinsic AKI. In pre-renal AKI the urinary sodium is low, usually less than 20 mEq/L. In
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intrinsic AKI, the kidney has lost its reabsorptive ability and is unable to retain sodium; therefore the urinary sodium is high (greater than 30-40 mEq/L).
Fractional excretion of sodium. FENa refers to the fraction of sodium that is filtrated by the glomerulus but not reabsorbed in the tubules (excreted in urine) and is calculated as: FENa = Urine [Na] / Plasma [Na] Urine [Cr] / Plasma [Cr]
X 100
In pre-renal AKI, FENa is less than 1% as the kidney is trying to conserve as much sodium as possible. In intrinsic AKI, FENa levels are above 2%. Even though FENa provides similar information to that of urinary sodium, it is more accurate as it accounts for variations in water reabsorption. FENa should be carefully interpreted in newborns and preterm infants, in whom the reabsorptive ability is limited by an immature tubular system (15).
Urine microscopy. Microscopic analysis of the urine may reveal the presence of tubular casts, typically seen in intrinsic AKI and absent in normal urine. Epithelial casts are typical of ATN and are due to “shedding” of epithelial cells after tubular injury. White blood cell and eosinophil casts are representative of AIN. Pigmented casts are present in myoglobinuria and red blood cell casts are characteristic of glomerunephritis.
Serum creatinine and BUN. Serum creatinine (Cr) is typically the first biomarker ordered to assess renal function. Cr levels are similar to those of the mother in the immediate neonatal period decreasing by 50% in the first week and reaching normal childhood levels by the second month of life (0.40 mg/dL); normal adult levels are not reached until adolescence (11.5 mg/dL) (16). Preterm infants show an increase, instead of a decrease, in Cr production
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during the first week of life; serum creatinine levels are not comparable to those of term infants until an adjusted conceptional age of 34 weeks (17).
Management of AKI I.
Determine the cause of renal dysfunction. Patients with oliguria and rising plasma creatinine levels should be evaluated with urinary electrolytes and FENa. A microscopic analysis of the urine may give some clues as to whether the renal injury is pre-renal or intrinsic. The physician should carefully review all medications and determine the recent use of intravenous contrast agents. Critically ill patients with severe sepsis often have AKI.
II.
Assess fluid deficit and correct hypovolemia. Hypotension, tachycardia and oliguria are clinical indicators of hypovolemia. Commonly, children with low circulatory volume and oliguria receive an initial fluid bolus challenge of 10-20 mL/kg over 30 min and repeated until there is a response. A central venous catheter (CVC) should be placed to guide fluid management in patients with ARF associated with oliguria. This important measure will prevent the development of pulmonary edema secondary to aggressive fluid resuscitation or commonly generalized edema. CVC allows the measurement of central venous pressure (CVP) and central venous oxyhemoglobin saturation (ScvO2).Crystalloid solutions are preferred over colloid solutions.
III.
Avoid and discontinue nephrotoxic drugs. Drugs with potential nephrotoxic side effects should be immediately discontinued. Radiologic tests should avoid the administration of nephrotoxic contrast agents to prevent CIN. High osmolality agents
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such as diatrizoate sodium (Hypaque) and iothalamete meglumine (Conray) have been associated more commonly with renal dysfunction. Low osmolality agents are preferred in patients with renal dysfunction.
Parenteral hydration to optimize
intravascular volume status may prevent CIN. Normal saline infusion at 1 mL/kg/hr for 12 hours pre-procedure and 12 hours post-procedure is a commonly used protocol. Sodium Bicarbonate [150 mEq] in 850 cc D5W at a rate of 3 mL/kg IV one hour before the procedure and 1 mL/kg IV six hours after the procedure is common practice for some (11) but is controversial and not universally adopted.. Repeat intravenous contrast should be used at least 5 days apart. Acetylcysteine (Mucomyst) has questionable benefits in preventing CIN and there is no consensus on acetylcysteine dosing in children (18). IV.
Adjust medication dosages according to GFR.
Reducing drug doses and
prolonging the dosing intervals are two important strategies in patients with established renal failure. Dosages of medications should be individually adjusted according to the patient’s GFR.
V.
Low-dose Dopamine. Low dose dopamine (<5µg/kg/min) was previously used as an adjuvant therapy due to its renal vasodilator effects but data supporting its use in infants and children is inconsistent (19). A recent meta-analysis including 17 randomized clinical trials indicated that low dose dopamine did not prevent mortality, onset of AKI or need for dialysis (20). Low dose dopamine is no longer a recommended therapy in AKI (21).
Holmes et al demonstrated that low dose
dopamine has deleterious effects in the GI, endocrine, immunologic and respiratory systems and its use is no longer justified in ARF (22).
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VI.
Adequate oxygenation. Adequate oxygen supplementation minimizes the effects of kidney hypoperfusion. High metabolic demands of the renal medulla, a poorly perfused zone, are only met with high oxygen supply (oxygen extraction of renal medulla approaches 90%).
VII.
Correction of hyperkalemia. Hyperkalemia (K >4.7 mEq/L in children) is the result of decreased excretion of potassium in the distal and collecting cortical tubules, normally under the influence of aldosterone and kinases. Elevation of K leads to muscle weakness, respiratory failure, and cardiac conduction abnormalities such as bradycardia, ventricular fibrillation and asystole. Classic electrocardiographic signs include peaked T waves, ST depression, loss of P wave and widening of the QRS. Once identified, parenteral potassium must be stopped and extracellular potassium forced into the intracellular compartment with glucose and insulin infusions. Glucose loading at a rate of 0.5 g/kg/h is sufficient since children have an increased endogenous insulin production in response to glucose. Insulin at a rate 0.05 u/kg/h should be added if blood glucose levels reach 10 mmol/l (23). Cardiac excitability secondary to hyperkalemia with evidence of EKG abnormalities should be treated with IV calcium gluconate at a dose of 0.5 ml/kg over 5–10 minutes (24).
Renal replacement therapy (RRT) Failure of improvement despite supportive therapy requires renal replacement therapy (RRT), which replaces most of the kidney’s metabolic functions. Current evidence supports early institution of RRT (25,26). Long term RRT is called chronic and includes hemodialysis, peritoneal dialysis and renal transplantation. For the purposes of this article we will only focus on acute RRT which include intermittent and continuous hemodialysis.
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Indications for renal replacement therapy 1. Metabolic and electrolyte imbalance 2. Uremia with bleeding and/or encephalopathy 3. Fluid overload with pulmonary edema/respiratory failure 4. Intoxications 5. Inborn errors of metabolism (IEM) 6. Nutritional support (removal of fluid to make space for nutrition)
Hemodialysis Hemodialysis (HD) is a form of RRT that involves the removal of undesired solutes from the blood after it is passed through an “artificial kidney” or dialyzer. Adsorption is the mechanism by which non-desired molecules adhere to the dialyzer membrane. Hemofiltration is the process of clearing blood of metabolic waste by the passage of blood through a semi permeable filter or membrane. Hydrostatic pressure “forces” water and solutes to pass through a filtration membrane (hemofilter), including small and large molecules. The hemofilter is impermeable to proteins and cells due to the small size of its pores. Diffusion is the mechanism by which, solutes are transported across the filtration membrane due to a concentration gradient. Solutes move or “diffuse” to the side of the membrane that has lower concentration of that solute. Diffusion is effective in clearing small molecules such as potassium and urea but ineffective for larger solutes or albumin (LMW proteins).
Most electrolytes, creatinine and urea are small molecules (<500 Daltons).
Medium size molecules are 500-5,000 Daltons. Proteins and cytokines are large molecules, 5,000-50,000 Daltons, and include proteins and cytokines. Sieving coefficient is the ability of a molecule to pass through the membrane. A Sieving coefficient of 1 indicates that 100% of
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the solute will move across the membrane (K, Na, Creatinine, etc). Proteins have a Sieving coefficient of zero as they are unable to pass across the membrane due to their large size.
Continuous vs. intermittent renal replacement therapy Continuous renal replacement therapy (CRRT) clears nitrogenous waste products, corrects electrolytes and acid-base abnormalities and manages fluid overload in a more effective and gentle way than intermittent hemodialysis. Due to the small blood volumes in small children, intermittent HD is difficult. The frequent episodes of hypotension during conventional dialysis could compromise even more the perfusion of end organs in the critically ill child. Continuous RRT uses convection or hemofiltration by which, water and solutes are eliminated without causing volume shifts or hypotension. Hemofiltration is the preferred method of RRT in critically ill and small children due to their small blood volumes.
The most commonly used forms of CRRT are:
1. Continuous Ultrafiltration (CUF) which only removes water and is used in patients with fluid overload or severe electrolyte abnormalities.
2. Continuous Veno-Venous Hemofiltration (CVVH) which uses convection and requires an electrolyte replacement solution. CVVH is indicated in patients with severe kidney injury, uremia or severe pH/electrolyte imbalance with or without fluid overload that require removal of solutes (medium to large molecules) while maintaining a near normal volume.
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CVVH helps remove inflammatory mediators (i.e cytokines, lipopolysaccharide) and is successful for SIRS, ARDS, septic shock or critically ill burn patients (27).
3. Continuous Veno-Venous Hemodialysis (CVVHD) uses diffusion and requires a dialysate solution to create a concentration gradient across the filter (semi permeable membrane). It helps remove small molecules. The dialysate solution uses buffering agents, electrolytes and glucose at normal plasma values with concentrations that can be changed according to the indications for RRT. CVVHD is used in critically ill patients with hemodynamic instability or in children with inborn errors of metabolism (28,29).
4. Continuous Veno-Venous Hemo-Dia-Filtration (CVVHDF) – uses both convection and diffusion providing clearance of a wide range of solutes at very low flow rates. Commonly used in critically ill patients with multiple organ dysfunction syndrome.
CRRT Circuit and Set up A commonly used set up includes the following: 1.
Central double-lumen veno-venous hemodialysis catheter
2.
Extracorporeal circuit and filter (dialyzer)
3.
Blood pump
4.
Dialysate pumps
5.
Replacement fluid pump
(Insert Figure 1)
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Dialyzer The dialyzer is the main component of the circuit allowing blood flow in the opposite direction to the dialysate solution (countercurrent), separated by a dialyzer membrane.
Dialyzer membranes Membranes, made of synthetic and biocompatible materials, are semi permeable as they allow the selective clearance of small, medium or large molecules according to the size of its pores. The AN-69 is a commonly used membrane but is associated with hypotension due to bradykinin
release.
Some
propose
the
use
of
synthetic
membranes
such
as
polyarylethersulfone (PAES) membranes to avoid this reaction. Other biosynthetic membranes are made of polysulfone, polyamida, or polyacrylonitrile.
Dialysate pump The dialysate pump regulates the pressure of the dialysate solution. Although low pressures are preferred on the dialysate side of the system (to promote ultrafiltration), increasing the dialysate pressure could reduce the filtration rate in desired circumstances
Blood priming Blood priming refers to filling the circuit volume with blood prior to its connection to the patient circulation. It is particularly needed when the circuit volume exceeds 10-15% of the estimated blood volume of the child (32).
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Anticoagulant Anticoagulation is needed to keep the circuit patent. a.
Heparin is delivered in the pre-filter area of the circuit and titrated to achieve a post-
filter PTT of 1.5 times normal or an ACT of 180. Heparin is given continuously at a rate of 10-20 units/kg/h after a bolus of 20-30 units/kg. Bleeding complications are more common with heparin (33).
b.
Citrate based anticoagulation is better tolerated in children and has lower
complication rates. Citrate binds free calcium ions thus preventing coagulation. Sodium citrate is delivered to the initial part of the circuit providing a local anticoagulation effect. Calcium chloride is added to the blood before it is returned to the patient. Citrate is converted to bicarbonate in the liver, which could cause metabolic alkalosis. Thus its use has to be carefully regulated patients with hepatic failure. Citrate has also been shown to lead to sodium and calcium imbalance (34).
CRRT Management
Buffering agents Bicarbonate and lactate based dialysate solutions are the two main buffering agents used during CVVHD and CVVHDF. Conversion of lactate to bicarbonate in the liver limits the use of lactate based solutions in patients with associated liver impairment. Furthermore, due to its vasodilator properties and non-physiologic pH, lactate could cause hypotension and worsen acidosis.
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CRRT solutions for dialysate and replacement fluid Dialysates are iso-osmotic solutions with physiologic concentrations of electrolytes and glucose. The lack of urea and other non-desired metabolic byproducts in the dialysate solution creates a concentration gradient by which these solutes are cleared from the blood. High concentrations of urea, potassium and phosphorus in the blood of patients with renal failure are easily eliminated through the membrane both by convection (ultrafiltrate) and diffusion (low or physiologic concentrations in the dialysate solution). Bicarbonate-based fluid is preferred over lactate-based due to the risk of metabolic acidosis leading to cardiac dysfunction, vasodilatation, and hypotension (34). Solutions without calcium are utilized when citrate anticoagulation is used. Albumin can be added to the dialysate fluid to help eliminate protein bound drugs. Dialysate solutions are warmed to a temperature of 35 to 37o to avoid hypothermia.
Circuit flow rate Blood flow (Qb) should be started below the goal rate and advanced to maximum rate over 30 min. Flow rates vary from to 10-12 mL/kg/min in neonates and 2-4 mL/kg/min in older children and adolescents (35). Usually the dialysate flow (Qd) is matched to the Qb to allow maximal exposure time.
Circuit pressure Pressure detectors are placed in both the arterial and venous side of the circuit to regulate transmembrane pressures and allow adequate ultrafiltration. Low arterial pressures may be due to hypotension, kinks in the tubing system, catheter malfunction or stenosis of the arterial inflow. Venous hypertension may be due to clotting of the dialyzer/membrane, kinks in the tubing system or stenosis of the venous outflow.
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Vascular access for RRT Catheter location Hemodialysis catheters should be preferentially placed in the internal jugular (IJ) vein. Femoral vein and SC vein are alternatives to IJ vein but are associated with vein thrombosis and vein stenosis respectively. SC vein stenosis, a common complication of dialysis catheters, is of concern because some patients will eventually require permanent vascular access for chronic hemodialysis.
Catheter size Catheter sizes vary from 7 to 12 F according to the weight of the child. Neonates and children up to 6 kg usually require a 7 Fr catheter; 6 to 15 kg require 8 Fr catheter; 15 to 30 kg require 9 Fr catheter and >30 kg, 10 Fr catheters (36).
Catheter insertion In neonates and small children, venous cut down techniques are used similar to ECMO cannulation. In older children and adolescents, US guided percutaneous catheter insertion is acceptable. Pre-insertion preparation should include evaluation of hematologic parameters, ensuring platelet counts of at least 50,000 and INR of no greater than 1.5 times normal. In children with previous multiple access catheters, US study should be done to evaluate venous patency. Cutdown technique involves the use of general anesthesia in children. Tunneled dialysis catheters can be used in children who will require prolonged HD and in those waiting for renal transplantation (37).
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Complications of RRT Complications include hypotension, circuit clotting and bleeding, catheter complications and electrolyte disturbances. When first connecting to the circuit hypotension has been noted in up to 30% of patients, which often may be prevented by adequate priming of the circuit. The mechanism for this hypotension is usually related to rapid changes in circulating blood volume but may also be due to bradykinin release (38). Bradykinin related hypotension may be avoided by priming with albumin as opposed to blood.
Heparin and citrate both lower the circuit failure rate (42.1±30.8 vs 44.7±35.9 h, respectively), compared to no anticoagulation (27.2±21.5 h, p <0.005). Heparin is however associated with higher bleeding (39) . Soltysiak et al have recently shown improved circuit and overall survival with the use of citrate compared to heparin in children under 10kg, but this has yet to gain widespread acceptance (40). In addition, larger catheters had lower circuit failure rates as did catheters placed in the internal jugular veins (41). Complications of catherization are also well documented in children especially in those less than one year old and 10kg (42).
Although CRRT corrects abnormal electrolytes quite effectively, it can also contribute to significant hyponatremia, hypocalcemia and hypophosphatemia. Practitioners of CRRT in children must monitor these quite closely and change their dialysate solution as needed.
Catheter infection is seen in about 2.2% of adult patients undergoing CRRT.
Routine
changes of central lines have not improved the infectious rates and there is no major
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difference between CRRT and HD in adults.
Further investigation will be required to
understand the infection risks in children undergoing RRT (43).
Outcomes of CRRT in children
The outcomes of children receiving CRRT is dependent on the underlying condition of the child. Patients with fluid overload at initiation of therapy, multi-organ failure, hemodynamic instability and younger age are factors influencing the outcomes of kidney injury and not necessarily CRRT therapy (44-48).
Insert Figure 2
Prior to 2001, most published data on pediatric CRRT was limited to single institution studies with small groups of patients (49). In 2001, Goldstein et al helped develop the Prospective Pediatric CRRT (ppCRRT) Registry group as a multicenter United States collaboration designed to enroll patients undergoing CRRT (50). Overall survival was 58%, with 31% survival in patients with liver failure, 45% in pulmonary failure and 45% in stem cell transplant patients. Patients under 10kg had lower survival (43%) versus those above 10 kg (64%). However, survival of children under 5kg was no different than those between 5 and 10kg. CRRT was feasible even in the smallest of children and extended duration greater than 28 days also had 35% survival rates. Finally, the use of CRRT in children for inborn errors of metabolism, drug intoxication or tumor lysis syndrome also had good survival at 62%, 95% and 82% (51-56).
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Summary Acute kidney injury (AKI) should be assessed using the RIFLE criteria and prognosis is dependent on severity on this scale and the stages developed by the Acute Kidney Injury Work Groups stages of AKI. Management involves the determination of the cause while simultaneously treating with appropriate therapies including: correcting hypovolemia, avoiding nephrotoxic drugs, preventing secondary hypoxemic insults and correcting electrolyte abnormalities.
If these therapies fail, children may need renal replacement
therapy. Acutely ill patients benefit from continuous renal replacement therapy (CRRT). CRRT has been shown to improve outcomes and overall mortality in children with AKI. Complications from CRRT can occur and close management by a pediatric nephrology team is necessary.
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References 1. Rinaldo Bellomo, Claudio Ronco, John A Kellum, Ravindra L Mehta, Paul Palevsky, and the ADQI workgroup. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004; 8(4): R204–R212 2. Kanagasundaram NS. Defining acute kidney injury: further steps in the right direction but can détente be maintained? Crit Care Med. 2011 Dec;39(12):2764-5 3. Slater MB, Anand V, Uleryk EM, Parshuram CS. A systematic review of RIFLE criteria in children, and its application and association with measures of mortality and morbidity. Kidney Int. 2012 Apr;81(8):791‐8. 4. Kellum JA, Lameire N; KDIGO AKI Guideline Work Group Crit Care. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). 2013 Feb 4;17(1):204. doi: 10.1186/cc11454. 5. Pierrat A, Gravier E, Saunders C, Caira MV. Predicting GFR in children and adults: A comparison of the Cockcroft-Gault, Schwartz, and Modification of Diet in Renal Disease formulas Kidney International (2003) 64, 1425–1436; doi:10.1046/j.1523-1755.2003.00208. 6. Davenport A, Will EJ, Davison AM (1991) Hyperlactataemia and metabolic acidosis during haemofiltration using lactate-buffered fluids. Nephron 59:461–465. 7. Williams DM, Sreedhar SS, Mickell JJ, Chan JC. Acute kidney failure: a pediatric experience over 20 years. Arch Pediatr Adolesc Med 2002; 156:893–900. 8. Warady BA, Schaefer F, Alexander SR. Pediatric Dialysis pp 725. 9. Davenport A, Will EJ, Davison AM (1991) Hyperlactataemia and metabolic acidosis during haemofiltration using lactate-buffered fluids. Nephron 59:461–465. 10. Brophy P, Somers MJG, Baum M, et al (2005) Multi-centre evaluation of anticoagulation in patients receiving continuous renal replacement therapy (CRRT). Nephrol Dial Transplant 20:1416–1421. 11. Benko A, Fraser-Hill M, Magner P, et al. Canadian Association of Radiologists: consensus guidelines for the prevention of contrast-induced nephropathy. Can Assoc Radiol J. 2007 Apr;58(2):79-87. 12. Hui-Stickle S, Brewer ED, Goldstein SL. Pediatric ARF epidemiology at a tertiary care center from 1999 to 2001. Am J Kidney Dis 2005;45:96–101. 13. Ronco C, Tetta C, Mariano F, et al. Interpreting the mechanisms of continuous renal replacement therapy in sepsis. The peak concentration hypothesis. Artif Organs 2003;27:792– 801. 14. Basu RK1, Wang Y, Wong HR, Chawla LS, Wheeler DS, Goldstein SL. Incorporation of biomarkers with the renal angina index for prediction of severe AKI in critically ill children.
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Clin J Am Soc Nephrol. 2014 Apr;9(4):654-62. doi: 10.2215/CJN.09720913. Epub 2014 Mar 27. 15. Carmody, JB (Feb 2011). "Urine electrolytes". Pediatr Rev 32 (2): 68–68. 16. Schwartz GJ, Feld LG, Langford DJ (1984) A simple estimate of glomerular filtration rate in full-term infants during the first year of life. J Pediatr 104:849-854. 17. Stonestreet BS, Oh W (1978) Plasma creatinine levels in low birth weight infants during the first three months of life. Pediatrics 61 : 788-789 18. Hanly L1, Rieder MJ, Huang SH, Vasylyeva TL, Shah RK, Regueira O, Koren G. Nacetylcysteine rescue protocol for nephrotoxicity in children caused by ifosfamide. J Popul Ther Clin Pharmacol. 2013;20(2):e132-45. Epub 2013 Jun 13. 19. Kellum JA, M Decker J. Use of dopamine in acute renal failure: a meta-analysis. Crit Care Med. 2001 Aug;29(8):1526-31. 20. Holmes CL, Walley KR. Bad medicine: low-dose dopamine in the ICU. Chest. 2003 Apr;123(4):1266-75. 21. Prins I, Plotz FB, Uiterwaal CS, et al. Low-dose dopamine in neonatal and pediatric intensive care: a systematic review. Intensive Care Med 2001; 27:206–210 22. Holmes CL, Walley KR. Bad medicine: low-dose dopamine in the ICU. Chest 2003;123:1266-1275. 23. Noyan A, Anarat A, Pirti M, et al. Treatment of hyperkalemia in children with intravenous salbutamol. Acta Paediatr Jpn1995;37:355–7 24. Ahee P, Crowe AV. The management of hyperkalaemia in the emergency department. J Accid Emerg Med 2000;17:188-191 25. Boschee ED1, Cave DA2, Garros D3, Lequier L3, Granoski DA3, Guerra GG3, Ryerson LM4. Indications and outcomes in children receiving renal replacement therapy in pediatric intensive care. J Crit Care. 2014 Feb;29(1):37-42. doi: 10.1016/j.jcrc.2013.09.008. Epub 2013 Nov 15. 26. Payen D, Corne´ lie de Pont A, Sakr Y, et al. A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit Care 2008; 12:R74. 27. Glorieux G1, Vanholder R. New uremic toxins - which solutes should be removed? Contrib Nephrol. 2011;168:117-28. doi: 10.1159/000321750. Epub 2010 Oct 7. 28. Arbeiter AK, Kranz B, Wingen AM, Bonzel KE, Dohna-Schwake C, Hanssler L, Neudorf U, Hoyer PF, Büscher R. Continuous venovenous haemodialysis (CVVHD) and continuous peritoneal dialysis (CPD) in the acute management of 21 children with inborn errors of metabolism. Nephrol Dial Transplant. 2010 Apr;25(4):1257-65. 29. Bunchman TE, Maxvold NJ, Kershaw DB, Sedman AB, Custer JR. Continuous venovenous hemodiafiltration in infants and children. Am J Kidney Dis. 1995 Jan;25(1):1721.
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30. Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, Lo S, McArthur C, McGuinness S,MyburghJ, NortonR,Scheinkestel C,SuS (2009) Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med 361:1627 –1638 31. Sutherland SM, Alexander SR. Continuous renal replacement therapy in children. Pediatr Nephrol. 2012 Nov;27(11):2007-16. 32. Dirkes S, Hodge K. Continuous Renal Replacement Therapy in the Adult Intensive Care Unit: History and Current Trends. Crit Care Nurse 2007, 27:61-80. 33. Brophy P, Somers MJG, Baum M, et al (2005) Multi-center evaluation of anticoagulation in patients receiving continuous renal replacement therapy (CRRT). Nephrol Dial Transplant 20:1416–1421 34. Tolwani A, Wille KM. Advances in continuous renal replacement therapy: citrate anticoagulation update. Blood Purif. 2012; 34(2):88-93. 35. Davenport A, Will EJ, Davison AM (1991) Hyperlactataemia and metabolic acidosis during haemofiltration using lactate-buffered fluids. Nephron 59:461–465. 36. Warady BA, Schaefer F, Alexander SR. Pediatric Dialysis pp 725. 37. Goldstein SL. Advances in pediatric renal replacement therapy for acute kidney injury. 38. Sebestyen JF, Warady BA. Advances in pediatric renal replacement therapy. Adv Chronic Kidney Dis. 2011 Sep;18(5):376-83. 39. Brophy PD, Mottes TA, Kudelka TL, McBryde KD, Gardner JJ, Maxvold NJ, Bunchman TE AN-69 membrane reactions are pH-dependent and preventable. Am J Kidney Dis. 2001 Jul; 38(1):173-8. 40. Soltysiak J1, Warzywoda A, Kociński B, Ostalska-Nowicka D, Benedyk A, SilskaDittmar M, Zachwieja JPediatr Nephrol. Citrate anticoagulation for continuous renal replacement therapy in small children. 2014 Mar;29(3):469-75. 41. Sutherland SM, Goldstein SL, Alexander SR. The Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry: a critical appraisal. Pediatr Nephrol. 2014 Nov;29(11):2069-76. 42. Santiago MJ1, López-Herce J, Urbano J, Solana MJ, del Castillo J, Ballestero Y, Botrán M, Bellón JM. Complications of continuous renal replacement therapy in critically ill children: a prospective observational evaluation study.Crit Care. 2009;13(6):R184. 43. Crit Care. 2009;13(6):R184. doi: 10.1186/cc8172.
44. Wester PJ, de Koning EJ, Geers AB, Vincent HH, de Jongh BM, Tersmette M, Leusink JA. on behalf of the Analysis of Renal Replacement Therapy in the Seriously Ill (ARTIS) Investigators Critical Care Medicine: Catheter replacement in continuous arteriovenous hemodiafiltration: The balance between infectious and mechanical complications. June 2002 - Volume 30 - Issue 6 - pp 1261-1266.
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45. Sutherland S, Zappitelli M, Alexander S, et al (2010) Fluid overload and mortality in children receiving continuous renal replacement therapy: the prospective pediatric continuous renal replacement therapy registry. Am J Kidney Dis 55:316–325. 46. Fernández C, López-Herce J, Flores J, et al (2005) Prognosis in critically ill children requiring continuous renal replacement therapy. Pediatr Nephrol 20:1473–1477. 47. Hui-Stickle S, Brewer ED, Goldstein SL: Pediatric ARF epidemiology at a tertiary care center from1999 to 2001.AmJKidneyDis 45:96–101, 2005. 48. Bunchman TE, McBryde KD, Mottes TE, et al. Pediatric acute renal failure: outcome by modality and disease. PediatrNephrol 16:1067–1071, 2001. 49. Symons JM, Chua AN, Somers MJ, et al. Demographic characteristics of pediatric continuous renal replacement therapy: a report of the prospective pediatric continuous renal replacement therapy registry. Clin J Am Soc Nephrol 2:732–738, 2007. 50. Goldstein SL, Currier H, Graf C. Outcome in children receiving continuous venovenous hemofiltration. Pediatrics 2001; 107:1309 – 1312. 51. Foland JA, Fortenberry JD, Warshaw BL. Fluid overload before con- tinuous hemofiltration and survival in critically ill children: a retrospective analysis. Crit Care Med 2004; 32:1771–1776. 52. Goldstein SL, Somers MJ, Brophy PD, et al. The Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry: design, devel- opment and data assessed. Int J Artif Organs 2004; 27:9 – 14. 53. Sutherland SM, Goldstein SL, Alexander SR. Pediatr Nephrol. 2013 Aug 28. The Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry: a critical appraisal. 54. Goldstein SL Continuous renal replacement therapy: mechanism of clearance, fluid removal, indications and outcomes. Curr Opin Pediatr. 2011 Apr;23(2):181-5 55. Sebestyen JF1, Warady BA. Advances in pediatric renal replacement therapy. Adv Chronic Kidney Dis. 2011 Sep;18(5):376-83. 56. Sohn YB, Paik KH, Cho HY, Kim SJ, Park SW, Kim ES, Chang YS, Park WS, Choi YH, Jin DK. Continuous renal replacement therapy in neonates weighing less than 3 kg.Korean J Pediatr. 2012 August; 55(8): 286–292.
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Figures
Figure 1. System for continuous venovenous hemodiafiltration (31).
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Figure 2. Frequency and survivaal rates of diffferent underrlying diseasses (40).
R (39) Ref
Tables
Table1. Kidney Disease Improving Global Outcomes Acute Kidney Injury Work Group International Stages of Acute Kidney Injury in adults and children. (4) Stage I
Stage II
SCr increase ≥0.3 mg/dL in 48 h SCr or
increase
times
1.5–1.9 times
Stage III 2.0–2.9 SCr = 3x baseline or SCr > 4.0 mg/dL Or RRT initiation or If <18 y of age then eGFR <35 mL/min/1.73
UO<0.5 mL/kg/h for 6–12 h
UO <0.5 mL/kg/h for 12 UO <0.5 mL/kg/h for 24 h h
or UO <0.3 mL/kg/h for 12 h
SCr = Serum Creatinine UO = Urine Output RRT = Renal Replacement Therapy eGFR = estimated glomerular filtration rate
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Renal Replacement Therapy in Children Felix C. Blanco MD, Gezzer Ortega MD, MPH, Faisal G. Qureshi MD, FACS
www.elsevier.com/locate/semped-
PII: DOI: Reference:
S1055-8586(14)00122-X http://dx.doi.org/10.1053/j.sempedsurg.2014.11.006 YSPSU50526
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Seminars in Pediatric Surgery
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Cite this article as: Felix C. Blanco MD, Gezzer Ortega MD, MPH, Faisal G. Qureshi MD, FACS, Renal Replacement Therapy in Children, Seminars in Pediatric Surgery, http://dx.doi.org/10.1053/j.sempedsurg.2014.11.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
#6 Renal Replacement Therapy in Children Felix C. Blanco, Gezzer Ortega, and Faisal G. Qureshi (corresponding author) Felix C. Blanco, MD Transplant Surgery Fellow University of Minnesota Medical Center 420 Delaware Street SE Minneapolis, MN 55455 [email protected] Gezzer Ortega, MD, MPH Research Associate Howard University College of Medicine Department of Surgery 2041 Georgia Avenue, NW Suite 4B35 Washington, DC 20060 [email protected] Faisal G. Qureshi, MD, FACS Assistant Professor Surgery and Pediatrics George Washington University Children’s National Medical Center 111 Michigan Ave, NW WW 4200 Washington, DC 20010 [email protected]
Corresponding Author
The authors have no disclosures or conflicts of interest.
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Abstract Acute kidney injury (AKI) affects 3.9/1000 at risk children in the United States, a number which has been increasing as critically ill and injured children have access to improved care and the diagnosis of AKI is being made more accurately. Children with AKI have a higher mortality and hospital length of stay as compared to children without AKI. Renal replacement therapy can improve outcomes in these patients. This article reviews the pathophysiology of AKI and the modalities, indications and outcomes of renal replacement for children with AKI.
Key words: Renal Replacement Therapy; Acute Kidney Injury
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Acute Kidney Injury
Renal failure is the inability of the kidneys to maintain fluid, electrolyte and acid-base homeostasis. Sudden deterioration of the renal function, also known as acute renal failure (ARF) is due to a direct insult to the kidney (primary renal disease) or the result of a systemic disease process that affects renal perfusion or injures the renal interstitium (secondary failure). The term ARF was recently changed to acute kidney injury (AKI). AKI describes more exactly the pathophysiology behind ARF, reflecting its potentially reversible course.
Common causes of AKI include hypovolemic states leading to shock, toxins causing interstitial or tubular damage, and acute obstruction of the urinary outflow. These three mechanisms are universally known as prerenal, renal/intrinsic and postrenal AKI.
AKI is manifested clinically by a decline in urine output (UO) and a simultaneous elevation of serum creatinine (Cr). These two clinical parameters, however, are unreliable. A low UO does not necessarily correlate with the severity of renal dysfunction as seen in non-oliguric renal failure or in those patients receiving diuretics. Similarly, minor changes in Cr may not accurately reflect the ongoing kidney injury since nearly a 50% loss in functioning renal mass is needed to affect the serum Cr. Concomitant fluid overload in critically ill children with AKI will dilute and falsely affect the serum Cr.
Chronic kidney disease is defined as the persistence of renal dysfunction beyond the period of resolution of the causative injury and is associated with a progressive decline in the glomerular filtration rate (GFR).
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End-stage kidney disease refers to chronic kidney disease requiring dialysis or kidney transplant.
AKI criteria The Acute Dialysis Quality Initiative (ADQI) Group, (a multidisciplinary group working on developing evidence-based guidelines for the treatment of ARF), identified specific characteristics of AKI to help define and measure outcomes (1).
According to ADQI
guidelines, the acute deterioration of kidney function follows a series of stages to reach permanent cessation of renal function. The RIFLE criteria for acute renal dysfunction are characterized by a progressive decline of UO and GFR, and increasing plasma Cr.
R= Risk of renal dysfunction I= Injury to the kidney F= Failure of kidney function L= Loss of kidney function. Indicates persistent loss requiring RRT for more than 4 weeks E= End stage kidney disease. Indicates need for RRT for more than 3 months.
The initiation of RRT in early stages or “less severe” renal failure (RIFLE-R, RIFLE-I) is associated with improved outcomes and decreased 30 day mortality. In contrast, when RRT was initiated in more severe stages (RIFLE-F, RIFLE-L), the 30 day mortality approached almost 50% (2). A pediatric version of the RIFLE criteria was developed in 2007. The pediatric RIFLE or pRIFLE has a few variations compared to the adult criteria considering only UO and GFR but not serum Cr. Unfortunately, a recent review demonstrated that the pRIFLE criteria were
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inconsistent when used to determine the morbidity and mortality outcomes in children with renal failure (3). Most recently, the Kidney Disease Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group delineated an international guideline to define and stage AKI in adults and children. (4) Stages I, II and III include increase in Cr and decline in UO as follows:
(Insert Table 1)
In children with an established AKI, the estimation of baseline serum Cr may be difficult. The creatinine level and GFR can be estimated using the “modification of diet in renal disease” (MDRD) formula, which normalizes the GFR to the body surface area based on age, sex and race. Unfortunately, this formula can only be used in children over 12 years of age and estimations are inaccurate when the patient is not in a steady state of creatinine balance as in small infants and patients with restricted creatinine secretion due to chemotherapy, cimetidine or AIDS therapy (5). Recently, several plasma and urinary biomarkers released by the kidney under stress or ischemia have been described. These are undergoing intensive research before they are accepted for the prediction and prognosis of AKI. Some of these biomarkers include: neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), livertype fatty acid binding protein (L-FABP), and interleukin (IL)-18 (6).
Causes of AKI In developed countries, only 10% of AKI are due to primary kidney disease. The majority are secondary to systemic illnesses, cardiac surgery for congenital heart disease, sepsis and Page 5 of 30
nephrotoxic medications (7-10). Hemolytic uremic syndrome is still the main cause of renal failure in children of developing countries.
Pre-renal AKI In pre-renal AKI, kidney injury occurs from hypoperfusion. The most common cause of hypoperfusion is hypovolemia due to severe dehydration, bleeding, gastrointestinal losses or major burns. Diminished renal perfusion can also occur with normal or elevated extracellular volume in conditions such as congestive heart failure, hepatorenal syndrome or sepsis. Hypoperfusion activates the juxtraglomerular complex (renin-angiotensin-aldosterone axis) promoting avid reabsorption of sodium and water in an attempt to replenish the intravascular volume. Non-steroidal anti-inflammatory medications inhibit cyclooxygenase-1 and cyclooxygenase-2 enzyme activity, diminishing prostaglandin formation that serves as a renal vasodilator. This physiologic response can worsen renal insufficiency in states of hypoperfusion.
Upon activation of the mentioned axis, the release of angiotensin causes vasoconstriction of the glomerular efferent arteriole (closing the exit “valve”), increasing intracapillary pressure and improving transglomerular filtration. The administration of angiotension converting enzyme (ACE) inhibitors to patients with renovascular disease is deleterious since it inhibits this compensatory mechanism by dilating the efferent arteriole (thus decreasing ultrafiltration pressure).
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Mechanical ventilation and conditions that increase the intrathoracic pressure and reduce the pre-load (pneumothorax, cardiac tamponade), may lead to renal hypoperfusion and renal failure. This is particularly true during states of inadequate cardiac filling volumes.
Renal or intrinsic AKI Parenchymal damage prevents the kidney from absorbing water and electrolytes and prevents elimination of byproducts of catabolism (creatinine, urea). Tubular casts precipitate from urinary stasis, low pH, and greater urinary concentration and “plug” the fine tubular system causing acute tubular obstruction, back-leak into the interstitium, loss of epithelial integrity and epithelial damage, a phenomenon known as acute tubular necrosis or ATN. Direct toxicity of myoglobin occurs when the epithelial cells are exposed to free oxygen radicals originating from the oxidation of ferrous oxide to ferric oxide. Acute interstitial nephritis (AIN), an inflammatory infiltration of extraglomerular structures (tubules and interstitium) leads to acute epithelial injury and renal dysfunction due to the activation of proinflammatory cytokines. This process is usually secondary to the use of medications (aminoglycosides, anphotericine). AIN is usually self-limited and rarely progresses to permanent renal injury. Radiocontrast dyes impose a high solute load to the tubular system which in turn imposes high energy demands to the renal medulla (increased tubular activity). Since the renal medulla is an area of limited blood flow, the enormous metabolic demand easily leads to interstitial hypoxia and subsequent renal injury. Kidney injury from contrast dye is known as contrast induced nephropathy or CIN (11).
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Other causes of interstitial nephritis include bacterial and viral infections, systemic lupus and acute transplant rejection Post-renal AKI In post-renal AKI, obstruction of the urinary outflow leads to decreased ultrafiltration pressure and acute tubular injury. The obstruction leads to retrograde or “backflow” of urine causing tubular hypertension. Hydronephrosis or dilatation of the collecting system occurs with prolonged obstruction usually over days. Common causes of post-renal AKI include papillary necrosis, posterior urethral valves, urethral strictures, or acute neurogenic bladder seen in trauma or the presence of a pelvic mass.
AKI and sepsis Sepsis related AKI accounts for one third of cases of renal injury in children (12). Injury mechanisms include systemic hypoperfusion, release of pro-inflammatory mediators, decrease in anti-inflammatory mediators and activation of the coagulation cascade leading to intra-renal microthrombosis (13).
Recent evidence suggests that upregulation of
metalloproteinase-8 and elastase-2e may play a role in sepsis related AKI (14). Whether these biomarkers are causative of AKI or simply a consequence of an increased pro-inflammatory state is unknown.
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Causes of renal failure in young children Common causes of renal failure in young children include interstitial diseases such as renal dysplasia, renal hypoplasia and obstructive uropathy. Glomerular-based disease, typically glomerulonephritis, is more frequent in older children.
Clinical assessment of the child with AKI The clinical evaluation of a child with suspected AKI should include a thorough investigation of previous medical and surgical conditions, presence of hypertension, recent infections and use of medications with potential nephrotoxic side effects. Examination of the child should be focused on the identification of hypovolemia, generalized edema, blood pressure measurement and skin inspection to identify palpable (vasculitis) and non-palpable (hemolytic-uremic syndrome) purpuric lesions. stenosis.
Auscultation may reveal renal artery
The presence of a pelvic mass during the abdominal examination may be
responsible for obstructive renal failure.
Laboratory findings in AKI Urinary osmolality. In pre-renal AKI the avid absorption of sodium and water leads to highlyconcentrated urine. Urine osmolality can reach levels beyond 900 mOsm/L.
In
intrinsic AKI, the inability to concentrate urine leads to diluted urine with osmolality levels of less than 300mOsm/L.
Urinary sodium. The measurement of urinary sodium helps differentiate between pre-renal or intrinsic AKI. In pre-renal AKI the urinary sodium is low, usually less than 20 mEq/L. In
Page 9 of 30
intrinsic AKI, the kidney has lost its reabsorptive ability and is unable to retain sodium; therefore the urinary sodium is high (greater than 30-40 mEq/L).
Fractional excretion of sodium. FENa refers to the fraction of sodium that is filtrated by the glomerulus but not reabsorbed in the tubules (excreted in urine) and is calculated as: FENa = Urine [Na] / Plasma [Na] Urine [Cr] / Plasma [Cr]
X 100
In pre-renal AKI, FENa is less than 1% as the kidney is trying to conserve as much sodium as possible. In intrinsic AKI, FENa levels are above 2%. Even though FENa provides similar information to that of urinary sodium, it is more accurate as it accounts for variations in water reabsorption. FENa should be carefully interpreted in newborns and preterm infants, in whom the reabsorptive ability is limited by an immature tubular system (15).
Urine microscopy. Microscopic analysis of the urine may reveal the presence of tubular casts, typically seen in intrinsic AKI and absent in normal urine. Epithelial casts are typical of ATN and are due to “shedding” of epithelial cells after tubular injury. White blood cell and eosinophil casts are representative of AIN. Pigmented casts are present in myoglobinuria and red blood cell casts are characteristic of glomerunephritis.
Serum creatinine and BUN. Serum creatinine (Cr) is typically the first biomarker ordered to assess renal function. Cr levels are similar to those of the mother in the immediate neonatal period decreasing by 50% in the first week and reaching normal childhood levels by the second month of life (0.40 mg/dL); normal adult levels are not reached until adolescence (11.5 mg/dL) (16). Preterm infants show an increase, instead of a decrease, in Cr production
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during the first week of life; serum creatinine levels are not comparable to those of term infants until an adjusted conceptional age of 34 weeks (17).
Management of AKI I.
Determine the cause of renal dysfunction. Patients with oliguria and rising plasma creatinine levels should be evaluated with urinary electrolytes and FENa. A microscopic analysis of the urine may give some clues as to whether the renal injury is pre-renal or intrinsic. The physician should carefully review all medications and determine the recent use of intravenous contrast agents. Critically ill patients with severe sepsis often have AKI.
II.
Assess fluid deficit and correct hypovolemia. Hypotension, tachycardia and oliguria are clinical indicators of hypovolemia. Commonly, children with low circulatory volume and oliguria receive an initial fluid bolus challenge of 10-20 mL/kg over 30 min and repeated until there is a response. A central venous catheter (CVC) should be placed to guide fluid management in patients with ARF associated with oliguria. This important measure will prevent the development of pulmonary edema secondary to aggressive fluid resuscitation or commonly generalized edema. CVC allows the measurement of central venous pressure (CVP) and central venous oxyhemoglobin saturation (ScvO2).Crystalloid solutions are preferred over colloid solutions.
III.
Avoid and discontinue nephrotoxic drugs. Drugs with potential nephrotoxic side effects should be immediately discontinued. Radiologic tests should avoid the administration of nephrotoxic contrast agents to prevent CIN. High osmolality agents
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such as diatrizoate sodium (Hypaque) and iothalamete meglumine (Conray) have been associated more commonly with renal dysfunction. Low osmolality agents are preferred in patients with renal dysfunction.
Parenteral hydration to optimize
intravascular volume status may prevent CIN. Normal saline infusion at 1 mL/kg/hr for 12 hours pre-procedure and 12 hours post-procedure is a commonly used protocol. Sodium Bicarbonate [150 mEq] in 850 cc D5W at a rate of 3 mL/kg IV one hour before the procedure and 1 mL/kg IV six hours after the procedure is common practice for some (11) but is controversial and not universally adopted.. Repeat intravenous contrast should be used at least 5 days apart. Acetylcysteine (Mucomyst) has questionable benefits in preventing CIN and there is no consensus on acetylcysteine dosing in children (18). IV.
Adjust medication dosages according to GFR.
Reducing drug doses and
prolonging the dosing intervals are two important strategies in patients with established renal failure. Dosages of medications should be individually adjusted according to the patient’s GFR.
V.
Low-dose Dopamine. Low dose dopamine (<5µg/kg/min) was previously used as an adjuvant therapy due to its renal vasodilator effects but data supporting its use in infants and children is inconsistent (19). A recent meta-analysis including 17 randomized clinical trials indicated that low dose dopamine did not prevent mortality, onset of AKI or need for dialysis (20). Low dose dopamine is no longer a recommended therapy in AKI (21).
Holmes et al demonstrated that low dose
dopamine has deleterious effects in the GI, endocrine, immunologic and respiratory systems and its use is no longer justified in ARF (22).
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VI.
Adequate oxygenation. Adequate oxygen supplementation minimizes the effects of kidney hypoperfusion. High metabolic demands of the renal medulla, a poorly perfused zone, are only met with high oxygen supply (oxygen extraction of renal medulla approaches 90%).
VII.
Correction of hyperkalemia. Hyperkalemia (K >4.7 mEq/L in children) is the result of decreased excretion of potassium in the distal and collecting cortical tubules, normally under the influence of aldosterone and kinases. Elevation of K leads to muscle weakness, respiratory failure, and cardiac conduction abnormalities such as bradycardia, ventricular fibrillation and asystole. Classic electrocardiographic signs include peaked T waves, ST depression, loss of P wave and widening of the QRS. Once identified, parenteral potassium must be stopped and extracellular potassium forced into the intracellular compartment with glucose and insulin infusions. Glucose loading at a rate of 0.5 g/kg/h is sufficient since children have an increased endogenous insulin production in response to glucose. Insulin at a rate 0.05 u/kg/h should be added if blood glucose levels reach 10 mmol/l (23). Cardiac excitability secondary to hyperkalemia with evidence of EKG abnormalities should be treated with IV calcium gluconate at a dose of 0.5 ml/kg over 5–10 minutes (24).
Renal replacement therapy (RRT) Failure of improvement despite supportive therapy requires renal replacement therapy (RRT), which replaces most of the kidney’s metabolic functions. Current evidence supports early institution of RRT (25,26). Long term RRT is called chronic and includes hemodialysis, peritoneal dialysis and renal transplantation. For the purposes of this article we will only focus on acute RRT which include intermittent and continuous hemodialysis.
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Indications for renal replacement therapy 1. Metabolic and electrolyte imbalance 2. Uremia with bleeding and/or encephalopathy 3. Fluid overload with pulmonary edema/respiratory failure 4. Intoxications 5. Inborn errors of metabolism (IEM) 6. Nutritional support (removal of fluid to make space for nutrition)
Hemodialysis Hemodialysis (HD) is a form of RRT that involves the removal of undesired solutes from the blood after it is passed through an “artificial kidney” or dialyzer. Adsorption is the mechanism by which non-desired molecules adhere to the dialyzer membrane. Hemofiltration is the process of clearing blood of metabolic waste by the passage of blood through a semi permeable filter or membrane. Hydrostatic pressure “forces” water and solutes to pass through a filtration membrane (hemofilter), including small and large molecules. The hemofilter is impermeable to proteins and cells due to the small size of its pores. Diffusion is the mechanism by which, solutes are transported across the filtration membrane due to a concentration gradient. Solutes move or “diffuse” to the side of the membrane that has lower concentration of that solute. Diffusion is effective in clearing small molecules such as potassium and urea but ineffective for larger solutes or albumin (LMW proteins).
Most electrolytes, creatinine and urea are small molecules (<500 Daltons).
Medium size molecules are 500-5,000 Daltons. Proteins and cytokines are large molecules, 5,000-50,000 Daltons, and include proteins and cytokines. Sieving coefficient is the ability of a molecule to pass through the membrane. A Sieving coefficient of 1 indicates that 100% of
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the solute will move across the membrane (K, Na, Creatinine, etc). Proteins have a Sieving coefficient of zero as they are unable to pass across the membrane due to their large size.
Continuous vs. intermittent renal replacement therapy Continuous renal replacement therapy (CRRT) clears nitrogenous waste products, corrects electrolytes and acid-base abnormalities and manages fluid overload in a more effective and gentle way than intermittent hemodialysis. Due to the small blood volumes in small children, intermittent HD is difficult. The frequent episodes of hypotension during conventional dialysis could compromise even more the perfusion of end organs in the critically ill child. Continuous RRT uses convection or hemofiltration by which, water and solutes are eliminated without causing volume shifts or hypotension. Hemofiltration is the preferred method of RRT in critically ill and small children due to their small blood volumes.
The most commonly used forms of CRRT are:
1. Continuous Ultrafiltration (CUF) which only removes water and is used in patients with fluid overload or severe electrolyte abnormalities.
2. Continuous Veno-Venous Hemofiltration (CVVH) which uses convection and requires an electrolyte replacement solution. CVVH is indicated in patients with severe kidney injury, uremia or severe pH/electrolyte imbalance with or without fluid overload that require removal of solutes (medium to large molecules) while maintaining a near normal volume.
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CVVH helps remove inflammatory mediators (i.e cytokines, lipopolysaccharide) and is successful for SIRS, ARDS, septic shock or critically ill burn patients (27).
3. Continuous Veno-Venous Hemodialysis (CVVHD) uses diffusion and requires a dialysate solution to create a concentration gradient across the filter (semi permeable membrane). It helps remove small molecules. The dialysate solution uses buffering agents, electrolytes and glucose at normal plasma values with concentrations that can be changed according to the indications for RRT. CVVHD is used in critically ill patients with hemodynamic instability or in children with inborn errors of metabolism (28,29).
4. Continuous Veno-Venous Hemo-Dia-Filtration (CVVHDF) – uses both convection and diffusion providing clearance of a wide range of solutes at very low flow rates. Commonly used in critically ill patients with multiple organ dysfunction syndrome.
CRRT Circuit and Set up A commonly used set up includes the following: 1.
Central double-lumen veno-venous hemodialysis catheter
2.
Extracorporeal circuit and filter (dialyzer)
3.
Blood pump
4.
Dialysate pumps
5.
Replacement fluid pump
(Insert Figure 1)
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Dialyzer The dialyzer is the main component of the circuit allowing blood flow in the opposite direction to the dialysate solution (countercurrent), separated by a dialyzer membrane.
Dialyzer membranes Membranes, made of synthetic and biocompatible materials, are semi permeable as they allow the selective clearance of small, medium or large molecules according to the size of its pores. The AN-69 is a commonly used membrane but is associated with hypotension due to bradykinin
release.
Some
propose
the
use
of
synthetic
membranes
such
as
polyarylethersulfone (PAES) membranes to avoid this reaction. Other biosynthetic membranes are made of polysulfone, polyamida, or polyacrylonitrile.
Dialysate pump The dialysate pump regulates the pressure of the dialysate solution. Although low pressures are preferred on the dialysate side of the system (to promote ultrafiltration), increasing the dialysate pressure could reduce the filtration rate in desired circumstances
Blood priming Blood priming refers to filling the circuit volume with blood prior to its connection to the patient circulation. It is particularly needed when the circuit volume exceeds 10-15% of the estimated blood volume of the child (32).
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Anticoagulant Anticoagulation is needed to keep the circuit patent. a.
Heparin is delivered in the pre-filter area of the circuit and titrated to achieve a post-
filter PTT of 1.5 times normal or an ACT of 180. Heparin is given continuously at a rate of 10-20 units/kg/h after a bolus of 20-30 units/kg. Bleeding complications are more common with heparin (33).
b.
Citrate based anticoagulation is better tolerated in children and has lower
complication rates. Citrate binds free calcium ions thus preventing coagulation. Sodium citrate is delivered to the initial part of the circuit providing a local anticoagulation effect. Calcium chloride is added to the blood before it is returned to the patient. Citrate is converted to bicarbonate in the liver, which could cause metabolic alkalosis. Thus its use has to be carefully regulated patients with hepatic failure. Citrate has also been shown to lead to sodium and calcium imbalance (34).
CRRT Management
Buffering agents Bicarbonate and lactate based dialysate solutions are the two main buffering agents used during CVVHD and CVVHDF. Conversion of lactate to bicarbonate in the liver limits the use of lactate based solutions in patients with associated liver impairment. Furthermore, due to its vasodilator properties and non-physiologic pH, lactate could cause hypotension and worsen acidosis.
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CRRT solutions for dialysate and replacement fluid Dialysates are iso-osmotic solutions with physiologic concentrations of electrolytes and glucose. The lack of urea and other non-desired metabolic byproducts in the dialysate solution creates a concentration gradient by which these solutes are cleared from the blood. High concentrations of urea, potassium and phosphorus in the blood of patients with renal failure are easily eliminated through the membrane both by convection (ultrafiltrate) and diffusion (low or physiologic concentrations in the dialysate solution). Bicarbonate-based fluid is preferred over lactate-based due to the risk of metabolic acidosis leading to cardiac dysfunction, vasodilatation, and hypotension (34). Solutions without calcium are utilized when citrate anticoagulation is used. Albumin can be added to the dialysate fluid to help eliminate protein bound drugs. Dialysate solutions are warmed to a temperature of 35 to 37o to avoid hypothermia.
Circuit flow rate Blood flow (Qb) should be started below the goal rate and advanced to maximum rate over 30 min. Flow rates vary from to 10-12 mL/kg/min in neonates and 2-4 mL/kg/min in older children and adolescents (35). Usually the dialysate flow (Qd) is matched to the Qb to allow maximal exposure time.
Circuit pressure Pressure detectors are placed in both the arterial and venous side of the circuit to regulate transmembrane pressures and allow adequate ultrafiltration. Low arterial pressures may be due to hypotension, kinks in the tubing system, catheter malfunction or stenosis of the arterial inflow. Venous hypertension may be due to clotting of the dialyzer/membrane, kinks in the tubing system or stenosis of the venous outflow.
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Vascular access for RRT Catheter location Hemodialysis catheters should be preferentially placed in the internal jugular (IJ) vein. Femoral vein and SC vein are alternatives to IJ vein but are associated with vein thrombosis and vein stenosis respectively. SC vein stenosis, a common complication of dialysis catheters, is of concern because some patients will eventually require permanent vascular access for chronic hemodialysis.
Catheter size Catheter sizes vary from 7 to 12 F according to the weight of the child. Neonates and children up to 6 kg usually require a 7 Fr catheter; 6 to 15 kg require 8 Fr catheter; 15 to 30 kg require 9 Fr catheter and >30 kg, 10 Fr catheters (36).
Catheter insertion In neonates and small children, venous cut down techniques are used similar to ECMO cannulation. In older children and adolescents, US guided percutaneous catheter insertion is acceptable. Pre-insertion preparation should include evaluation of hematologic parameters, ensuring platelet counts of at least 50,000 and INR of no greater than 1.5 times normal. In children with previous multiple access catheters, US study should be done to evaluate venous patency. Cutdown technique involves the use of general anesthesia in children. Tunneled dialysis catheters can be used in children who will require prolonged HD and in those waiting for renal transplantation (37).
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Complications of RRT Complications include hypotension, circuit clotting and bleeding, catheter complications and electrolyte disturbances. When first connecting to the circuit hypotension has been noted in up to 30% of patients, which often may be prevented by adequate priming of the circuit. The mechanism for this hypotension is usually related to rapid changes in circulating blood volume but may also be due to bradykinin release (38). Bradykinin related hypotension may be avoided by priming with albumin as opposed to blood.
Heparin and citrate both lower the circuit failure rate (42.1±30.8 vs 44.7±35.9 h, respectively), compared to no anticoagulation (27.2±21.5 h, p <0.005). Heparin is however associated with higher bleeding (39) . Soltysiak et al have recently shown improved circuit and overall survival with the use of citrate compared to heparin in children under 10kg, but this has yet to gain widespread acceptance (40). In addition, larger catheters had lower circuit failure rates as did catheters placed in the internal jugular veins (41). Complications of catherization are also well documented in children especially in those less than one year old and 10kg (42).
Although CRRT corrects abnormal electrolytes quite effectively, it can also contribute to significant hyponatremia, hypocalcemia and hypophosphatemia. Practitioners of CRRT in children must monitor these quite closely and change their dialysate solution as needed.
Catheter infection is seen in about 2.2% of adult patients undergoing CRRT.
Routine
changes of central lines have not improved the infectious rates and there is no major
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difference between CRRT and HD in adults.
Further investigation will be required to
understand the infection risks in children undergoing RRT (43).
Outcomes of CRRT in children
The outcomes of children receiving CRRT is dependent on the underlying condition of the child. Patients with fluid overload at initiation of therapy, multi-organ failure, hemodynamic instability and younger age are factors influencing the outcomes of kidney injury and not necessarily CRRT therapy (44-48).
Insert Figure 2
Prior to 2001, most published data on pediatric CRRT was limited to single institution studies with small groups of patients (49). In 2001, Goldstein et al helped develop the Prospective Pediatric CRRT (ppCRRT) Registry group as a multicenter United States collaboration designed to enroll patients undergoing CRRT (50). Overall survival was 58%, with 31% survival in patients with liver failure, 45% in pulmonary failure and 45% in stem cell transplant patients. Patients under 10kg had lower survival (43%) versus those above 10 kg (64%). However, survival of children under 5kg was no different than those between 5 and 10kg. CRRT was feasible even in the smallest of children and extended duration greater than 28 days also had 35% survival rates. Finally, the use of CRRT in children for inborn errors of metabolism, drug intoxication or tumor lysis syndrome also had good survival at 62%, 95% and 82% (51-56).
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Summary Acute kidney injury (AKI) should be assessed using the RIFLE criteria and prognosis is dependent on severity on this scale and the stages developed by the Acute Kidney Injury Work Groups stages of AKI. Management involves the determination of the cause while simultaneously treating with appropriate therapies including: correcting hypovolemia, avoiding nephrotoxic drugs, preventing secondary hypoxemic insults and correcting electrolyte abnormalities.
If these therapies fail, children may need renal replacement
therapy. Acutely ill patients benefit from continuous renal replacement therapy (CRRT). CRRT has been shown to improve outcomes and overall mortality in children with AKI. Complications from CRRT can occur and close management by a pediatric nephrology team is necessary.
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References 1. Rinaldo Bellomo, Claudio Ronco, John A Kellum, Ravindra L Mehta, Paul Palevsky, and the ADQI workgroup. Acute renal failure – definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004; 8(4): R204–R212 2. Kanagasundaram NS. Defining acute kidney injury: further steps in the right direction but can détente be maintained? Crit Care Med. 2011 Dec;39(12):2764-5 3. Slater MB, Anand V, Uleryk EM, Parshuram CS. A systematic review of RIFLE criteria in children, and its application and association with measures of mortality and morbidity. Kidney Int. 2012 Apr;81(8):791‐8. 4. Kellum JA, Lameire N; KDIGO AKI Guideline Work Group Crit Care. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). 2013 Feb 4;17(1):204. doi: 10.1186/cc11454. 5. Pierrat A, Gravier E, Saunders C, Caira MV. Predicting GFR in children and adults: A comparison of the Cockcroft-Gault, Schwartz, and Modification of Diet in Renal Disease formulas Kidney International (2003) 64, 1425–1436; doi:10.1046/j.1523-1755.2003.00208. 6. Davenport A, Will EJ, Davison AM (1991) Hyperlactataemia and metabolic acidosis during haemofiltration using lactate-buffered fluids. Nephron 59:461–465. 7. Williams DM, Sreedhar SS, Mickell JJ, Chan JC. Acute kidney failure: a pediatric experience over 20 years. Arch Pediatr Adolesc Med 2002; 156:893–900. 8. Warady BA, Schaefer F, Alexander SR. Pediatric Dialysis pp 725. 9. Davenport A, Will EJ, Davison AM (1991) Hyperlactataemia and metabolic acidosis during haemofiltration using lactate-buffered fluids. Nephron 59:461–465. 10. Brophy P, Somers MJG, Baum M, et al (2005) Multi-centre evaluation of anticoagulation in patients receiving continuous renal replacement therapy (CRRT). Nephrol Dial Transplant 20:1416–1421. 11. Benko A, Fraser-Hill M, Magner P, et al. Canadian Association of Radiologists: consensus guidelines for the prevention of contrast-induced nephropathy. Can Assoc Radiol J. 2007 Apr;58(2):79-87. 12. Hui-Stickle S, Brewer ED, Goldstein SL. Pediatric ARF epidemiology at a tertiary care center from 1999 to 2001. Am J Kidney Dis 2005;45:96–101. 13. Ronco C, Tetta C, Mariano F, et al. Interpreting the mechanisms of continuous renal replacement therapy in sepsis. The peak concentration hypothesis. Artif Organs 2003;27:792– 801. 14. Basu RK1, Wang Y, Wong HR, Chawla LS, Wheeler DS, Goldstein SL. Incorporation of biomarkers with the renal angina index for prediction of severe AKI in critically ill children.
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Clin J Am Soc Nephrol. 2014 Apr;9(4):654-62. doi: 10.2215/CJN.09720913. Epub 2014 Mar 27. 15. Carmody, JB (Feb 2011). "Urine electrolytes". Pediatr Rev 32 (2): 68–68. 16. Schwartz GJ, Feld LG, Langford DJ (1984) A simple estimate of glomerular filtration rate in full-term infants during the first year of life. J Pediatr 104:849-854. 17. Stonestreet BS, Oh W (1978) Plasma creatinine levels in low birth weight infants during the first three months of life. Pediatrics 61 : 788-789 18. Hanly L1, Rieder MJ, Huang SH, Vasylyeva TL, Shah RK, Regueira O, Koren G. Nacetylcysteine rescue protocol for nephrotoxicity in children caused by ifosfamide. J Popul Ther Clin Pharmacol. 2013;20(2):e132-45. Epub 2013 Jun 13. 19. Kellum JA, M Decker J. Use of dopamine in acute renal failure: a meta-analysis. Crit Care Med. 2001 Aug;29(8):1526-31. 20. Holmes CL, Walley KR. Bad medicine: low-dose dopamine in the ICU. Chest. 2003 Apr;123(4):1266-75. 21. Prins I, Plotz FB, Uiterwaal CS, et al. Low-dose dopamine in neonatal and pediatric intensive care: a systematic review. Intensive Care Med 2001; 27:206–210 22. Holmes CL, Walley KR. Bad medicine: low-dose dopamine in the ICU. Chest 2003;123:1266-1275. 23. Noyan A, Anarat A, Pirti M, et al. Treatment of hyperkalemia in children with intravenous salbutamol. Acta Paediatr Jpn1995;37:355–7 24. Ahee P, Crowe AV. The management of hyperkalaemia in the emergency department. J Accid Emerg Med 2000;17:188-191 25. Boschee ED1, Cave DA2, Garros D3, Lequier L3, Granoski DA3, Guerra GG3, Ryerson LM4. Indications and outcomes in children receiving renal replacement therapy in pediatric intensive care. J Crit Care. 2014 Feb;29(1):37-42. doi: 10.1016/j.jcrc.2013.09.008. Epub 2013 Nov 15. 26. Payen D, Corne´ lie de Pont A, Sakr Y, et al. A positive fluid balance is associated with a worse outcome in patients with acute renal failure. Crit Care 2008; 12:R74. 27. Glorieux G1, Vanholder R. New uremic toxins - which solutes should be removed? Contrib Nephrol. 2011;168:117-28. doi: 10.1159/000321750. Epub 2010 Oct 7. 28. Arbeiter AK, Kranz B, Wingen AM, Bonzel KE, Dohna-Schwake C, Hanssler L, Neudorf U, Hoyer PF, Büscher R. Continuous venovenous haemodialysis (CVVHD) and continuous peritoneal dialysis (CPD) in the acute management of 21 children with inborn errors of metabolism. Nephrol Dial Transplant. 2010 Apr;25(4):1257-65. 29. Bunchman TE, Maxvold NJ, Kershaw DB, Sedman AB, Custer JR. Continuous venovenous hemodiafiltration in infants and children. Am J Kidney Dis. 1995 Jan;25(1):1721.
Page 25 of 30
30. Bellomo R, Cass A, Cole L, Finfer S, Gallagher M, Lo S, McArthur C, McGuinness S,MyburghJ, NortonR,Scheinkestel C,SuS (2009) Intensity of continuous renal-replacement therapy in critically ill patients. N Engl J Med 361:1627 –1638 31. Sutherland SM, Alexander SR. Continuous renal replacement therapy in children. Pediatr Nephrol. 2012 Nov;27(11):2007-16. 32. Dirkes S, Hodge K. Continuous Renal Replacement Therapy in the Adult Intensive Care Unit: History and Current Trends. Crit Care Nurse 2007, 27:61-80. 33. Brophy P, Somers MJG, Baum M, et al (2005) Multi-center evaluation of anticoagulation in patients receiving continuous renal replacement therapy (CRRT). Nephrol Dial Transplant 20:1416–1421 34. Tolwani A, Wille KM. Advances in continuous renal replacement therapy: citrate anticoagulation update. Blood Purif. 2012; 34(2):88-93. 35. Davenport A, Will EJ, Davison AM (1991) Hyperlactataemia and metabolic acidosis during haemofiltration using lactate-buffered fluids. Nephron 59:461–465. 36. Warady BA, Schaefer F, Alexander SR. Pediatric Dialysis pp 725. 37. Goldstein SL. Advances in pediatric renal replacement therapy for acute kidney injury. 38. Sebestyen JF, Warady BA. Advances in pediatric renal replacement therapy. Adv Chronic Kidney Dis. 2011 Sep;18(5):376-83. 39. Brophy PD, Mottes TA, Kudelka TL, McBryde KD, Gardner JJ, Maxvold NJ, Bunchman TE AN-69 membrane reactions are pH-dependent and preventable. Am J Kidney Dis. 2001 Jul; 38(1):173-8. 40. Soltysiak J1, Warzywoda A, Kociński B, Ostalska-Nowicka D, Benedyk A, SilskaDittmar M, Zachwieja JPediatr Nephrol. Citrate anticoagulation for continuous renal replacement therapy in small children. 2014 Mar;29(3):469-75. 41. Sutherland SM, Goldstein SL, Alexander SR. The Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry: a critical appraisal. Pediatr Nephrol. 2014 Nov;29(11):2069-76. 42. Santiago MJ1, López-Herce J, Urbano J, Solana MJ, del Castillo J, Ballestero Y, Botrán M, Bellón JM. Complications of continuous renal replacement therapy in critically ill children: a prospective observational evaluation study.Crit Care. 2009;13(6):R184. 43. Crit Care. 2009;13(6):R184. doi: 10.1186/cc8172.
44. Wester PJ, de Koning EJ, Geers AB, Vincent HH, de Jongh BM, Tersmette M, Leusink JA. on behalf of the Analysis of Renal Replacement Therapy in the Seriously Ill (ARTIS) Investigators Critical Care Medicine: Catheter replacement in continuous arteriovenous hemodiafiltration: The balance between infectious and mechanical complications. June 2002 - Volume 30 - Issue 6 - pp 1261-1266.
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45. Sutherland S, Zappitelli M, Alexander S, et al (2010) Fluid overload and mortality in children receiving continuous renal replacement therapy: the prospective pediatric continuous renal replacement therapy registry. Am J Kidney Dis 55:316–325. 46. Fernández C, López-Herce J, Flores J, et al (2005) Prognosis in critically ill children requiring continuous renal replacement therapy. Pediatr Nephrol 20:1473–1477. 47. Hui-Stickle S, Brewer ED, Goldstein SL: Pediatric ARF epidemiology at a tertiary care center from1999 to 2001.AmJKidneyDis 45:96–101, 2005. 48. Bunchman TE, McBryde KD, Mottes TE, et al. Pediatric acute renal failure: outcome by modality and disease. PediatrNephrol 16:1067–1071, 2001. 49. Symons JM, Chua AN, Somers MJ, et al. Demographic characteristics of pediatric continuous renal replacement therapy: a report of the prospective pediatric continuous renal replacement therapy registry. Clin J Am Soc Nephrol 2:732–738, 2007. 50. Goldstein SL, Currier H, Graf C. Outcome in children receiving continuous venovenous hemofiltration. Pediatrics 2001; 107:1309 – 1312. 51. Foland JA, Fortenberry JD, Warshaw BL. Fluid overload before con- tinuous hemofiltration and survival in critically ill children: a retrospective analysis. Crit Care Med 2004; 32:1771–1776. 52. Goldstein SL, Somers MJ, Brophy PD, et al. The Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry: design, devel- opment and data assessed. Int J Artif Organs 2004; 27:9 – 14. 53. Sutherland SM, Goldstein SL, Alexander SR. Pediatr Nephrol. 2013 Aug 28. The Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry: a critical appraisal. 54. Goldstein SL Continuous renal replacement therapy: mechanism of clearance, fluid removal, indications and outcomes. Curr Opin Pediatr. 2011 Apr;23(2):181-5 55. Sebestyen JF1, Warady BA. Advances in pediatric renal replacement therapy. Adv Chronic Kidney Dis. 2011 Sep;18(5):376-83. 56. Sohn YB, Paik KH, Cho HY, Kim SJ, Park SW, Kim ES, Chang YS, Park WS, Choi YH, Jin DK. Continuous renal replacement therapy in neonates weighing less than 3 kg.Korean J Pediatr. 2012 August; 55(8): 286–292.
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Figures
Figure 1. System for continuous venovenous hemodiafiltration (31).
Page 28 of 30
Figure 2. Frequency and survivaal rates of diffferent underrlying diseasses (40).
R (39) Ref
Tables
Table1. Kidney Disease Improving Global Outcomes Acute Kidney Injury Work Group International Stages of Acute Kidney Injury in adults and children. (4) Stage I
Stage II
SCr increase ≥0.3 mg/dL in 48 h SCr or
increase
times
1.5–1.9 times
Stage III 2.0–2.9 SCr = 3x baseline or SCr > 4.0 mg/dL Or RRT initiation or If <18 y of age then eGFR <35 mL/min/1.73
UO<0.5 mL/kg/h for 6–12 h
UO <0.5 mL/kg/h for 12 UO <0.5 mL/kg/h for 24 h h
or UO <0.3 mL/kg/h for 12 h
SCr = Serum Creatinine UO = Urine Output RRT = Renal Replacement Therapy eGFR = estimated glomerular filtration rate
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