Renal Impairment
Body Fluid and Electrolyte Regulation
Effective kidney function maintains the normal volume and composition of body fluids. Although there is a wide variation in dietary intake and nonrenal expenditures of water and solute, water and electrolyte balance is maintained by the excretion of urine, with the volume and composition defined by physiologic needs. Fluid balance is accomplished by glomerular ultrafiltration of plasma coupled with modification of the ultrafiltrate by tubular reabsorption and secretion.1,2 The excreted urine, the modified glomerular filtrate, is the small residuum of the large volume of nonselective ultrafiltrate modified by transport processes operating along the nephron. The glomerular capillaries permit free passage of water and solutes of low molecular weight while restraining formed elements and macromolecules. The glomerular capillary wall functions as a barrier to the filtration of macromolecules based on their size, shape, and charge characteristics. The glomerular filtrate is modified during passage through the tubules by the active and passive transport of certain solutes into and out of the lumenal fluid and the permeability characteristics of specific nephron segments. The transport systems in renal epithelial cells serve to maintain global water, salt, and acid–base homeostasis.
The rate of ultrafiltration across the glomerular capillaries is determined by the same forces that allow the transmural movement of fluid in other capillary networks.3 These forces are the transcapillary hydraulic and osmotic pressure gradients and the characteristics of capillary wall permeability. A renal autoregulatory mechanism enables the kidney to maintain relative constancy of blood flow in the presence of changing systemic arterial and renal perfusion pressures.1 This intrinsic renal autoregulatory mechanism appears to be mediated in individual nephrons by tubuloglomerular feedback involving the macula densa (a region in the early distal tubule that juxtaposes the glomerulus) and the magnitude of resistance in the afferent and efferent arterioles,
Renal Function Evaluation
The evaluation of kidney function begins with the history, physical examination, and laboratory studies. Persistent oliguria or significant impairment in renal concentrating capacity should be evident from the history. Examination of the urinary sediment may provide evidence of renal disease if proteinuria and/or cellular casts are present. Normal serum concentrations of sodium, potassium, chloride, total CO2, calcium, and phosphorus indicate appropriate renal regulation of the concentration of electrolytes in body fluids. The serum creatinine concentration is the usual parameter for GFR. Important limitations and caveats must be observed when using creatinine to estimate GFR. Urinary creatinine excretion reflects both filtered and secreted creatinine because creatinine is not only filtered by the glomerular capillaries, but is also secreted by renal tubular cells. As a consequence, creatinine clearance, which is calculated by using serum creatinine concentration and the urinary excretion of creatinine, overestimates true GFR measured by using inulin clearance by 10–40%.4 Serum creatinine concentration and the rate of urinary creatinine excretion are affected by diet. The ingestion of meat, fish, or fowl, which are substances containing preformed creatinine and creatinine precursors, causes an increase in serum creatinine concentration and in urinary creatinine excretion.5 The overestimation of GFR by creatinine clearance increases as kidney function deteriorates owing to the relative increase in the tubular component of urine creatinine. Another caveat should be applied in the case of the patient with an abnormal muscle mass. The smaller the muscle mass, the lower is the release of creatinine into the circulation resulting in lower blood levels and urine excretion rates. The opposite picture will be seen in a patient with a very large muscle mass.
During the past 15 years, the serum concentration of cystatin C, a nonglycosylated 13.3 kDa basic protein, has been shown to correlate with GFR as well as or better than serum creatinine.6–9 From about age 12 months and up until age 50 years, normal serum cystatin C concentrations are similar in children and adults (0.70–1.38 mg/L). Currently, the measurement of cystatin C has not been incorporated into routine clinical practice. However, in the near future it may become a new tool in the assessment of GFR. In contrast, a ‘bedside’ equation is used to estimate GFR:
has recently been developed in children with chronic kidney disease based on data generated from the measurement of GFR using the plasma disappearance of iohexol.10 The bedside formula is most applicable to those children whose GFR is in the range of 15–75 mL/min/1.73m2.
Urine Volume
The appropriate urine volume depends on the status of body fluids, fluid intake, extrarenal losses, obligatory renal solute load, and renal concentrating and diluting capacity. Patients with impaired renal concentrating capacity require a larger urinary volume for excretion of the obligatory renal solute load. On the other hand, patients with elevated levels of antidiuretic hormone (ADH) retain water out of proportion to solute and are prone to hyponatremia. Increased levels of ADH may occur because of physiologic factors such as hypertonic body fluids or a decrease in the effective circulatory volume (as encountered with low levels of serum albumin or with generalized vasodilatation as with sepsis). Some researchers have expressed concern that ‘usual maintenance fluids’ (Table 4-1) providing 2–3 mEq/L of sodium, potassium, and chloride per 100 calories metabolized may contribute to the development of hyponatremia in children hospitalized with conditions likely to be associated with ADH excess.11 The children at risk are those with nonosmotic stimuli for ADH release, such as central nervous system disorders, the postoperative patient, pain, stress, nausea, and emesis. It has been proposed that in patients prone to develop the syndrome of inappropriate secretion of ADH, isotonic 0.9% normal saline might be a better choice for maintenance fluid therapy.12
TABLE 4-1
Usual Maintenance Water Requirements
| Weight Range (kg) | Maintenance Water |
| 2.5–10 | 100 mL/kg |
| 10–20 | 1000 mL + 50 mL/kg >10 kg |
| >20 | 1500 mL + 20 mL/kg >20 kg |
Approximately 30 mOsm of obligatory renal solute/100 mL of usual maintenance water is taken as the obligatory renal solute load in children aged 2 months and older.13 Urinary concentrating capacity increases rapidly during the first year of life and reaches the adult level of 1200–1400 mOsm/L at around year two.14 The maximum urinary concentrating capacity of the term infant from 1 week to 2 months of age is about 800 mOsm/L; from 2 months to 3 years, about 1000 mOsm/L; and beyond that age, about 1200 mOsm/L.
Noteworthy is the recent re-characterization of acute renal failure as acute kidney injury (AKI) to better describe renal dysfunction.l5,16 Nonoliguric AKI occurs about as frequently as oliguric AKI. It is diagnosed when the patient with normal urine output has elevated serum creatinine and urea nitrogen concentrations.
Glomerular Filtration Rate
GFR is the most useful index of renal function because it reflects the volume of plasma ultrafiltrate presented to the renal tubules. Decline in GFR is the principal functional abnormality in both acute and chronic renal failure. Assessment of GFR is important not only for evaluating the patient with respect to kidney function, but also for guiding the administration of antibiotics and other drugs. Inulin clearance, which is the accepted standard for measurement of GFR, is too time consuming and inconvenient for use in the clinical evaluation of most patients. Serum urea nitrogen concentration shows so much variation with dietary intake of nitrogen-containing foods that it is not a satisfactory index of GFR. Serum creatinine concentration and creatinine clearance have become the usual clinical measures for determining the GFR. However, precautions should be taken when creatinine alone is used for estimation of GFR because of the effect of diet as well as common medications on serum creatinine concentration and excretion rate. Ingestion of a meal containing a large quantity of animal protein increases serum creatinine levels about 0.25 mg/dL in two hours and increases the creatinine excretion rate about 75% over the next three- to four-hour period.5 Serum creatinine concentrations are also increased by ingestion of commonly used medications such as salicylate and trimethoprim.l7,18 These agents compete with creatinine for tubular secretion through a base-secreting pathway. They do not alter GFR but do elevate the serum creatinine concentration.
Because of the difficulties in timed urine collection, several equations have been developed to estimate GFR. Historically the most commonly used equation has been the one developed by Schwartz19–21 and is based on the serum creatinine value (as determined by the Jaffe kinetic method) and the child’s height:
where k for low birth weight infants is 0.33, full-term infants, 0.45; males 2–12 and females 2–21 years old, 0.55: and males 13–25 years old, 0.70.
Creatinine is formed by the nonenzymatic dehydration of muscle creatinine at a rate of 50 mg creatinine/kg muscle.4 The serum creatinine concentration in the neonate reflects the maternal level for the first three to four days of life and somewhat longer in the premature infant due to delayed maturation of kidney function. After this time, the serum creatinine concentration should decrease. From age 2 weeks to 2 years, the value averages about 0.4 ± 0.04 mg/dL (35 ± 3.5 µM).22 The serum creatinine concentration is relatively constant during this period of growth because the increase in endogenous creatinine production, which is directly correlated with muscle mass, is matched by the increase in GFR. During the first two years of life, GFR increases from 35–45 mL/min/1.73 m2 to the normal adult range of 90–170 mL/min/1.73 m2. The normal range for serum creatinine concentration increases from 2 years through puberty, although the GFR remains essentially constant when expressed per unit of surface area. This occurs because growth during childhood is associated with increased muscle mass and, therefore, increased creatinine production, which is greater than the increased GFR per unit of body weight.22 Table 4-2 shows the mean values and ranges for plasma or serum creatinine levels at different ages.23 Normative data of serum creatinine may differ from one laboratory to another, depending on the methodology used, although efforts are being made for standardization.20,24
TABLE 4-2
Plasma Creatinine Levels at Different Ages
aConversion factor: mmol/L = mg/dL × 88.4
Adapted from Changler C, Barratt TM. Laboratory evaluation. In: Holiday MA, editor. Pediatric Nephrology. 2nd ed. Baltimore: Williams & Wilkins; 1987. p. 282–99.
Fractional Excretion of Substances
where Us is urine solute concentration, Ps is plasma solute concentration, Pcr is plasma creatinine concentration, and Ucr is urine creatinine concentration.
Fractional Excretion of Sodium
The fractional excretion of sodium (FE Na) is 2–3% in normal newborns and may be higher in premature infants. In older children it is usually less than 1%, but may be elevated with high salt intake, adaptation to chronic renal failure, and diuretic administration.25 When a decrease in renal perfusion occurs, which is common in intravascular volume depletion or congestive heart failure, the normal renal response results in a marked increase in the tubular reabsorption of sodium leading to a decrease in sodium excretion and consequently a FE Na of less than 1%. The FE Na, is usually greater than 2% in ischemic AKI (also known as acute tubular necrosis), reflecting the impaired ability of the tubules to reabsorb sodium.
Renal Tubular Acidosis
Renal tubular acidosis (RTA) describes a group of disorders in which metabolic acidosis occurs as a result of an impairment in the reclamation of filtered HCO3 in the proximal tubule or from a defect in the renal hydrogen ion excretion in the distal tubule, assuming an absence of a significant reduction in GFR.26 RTA is considered in the differential diagnosis of the patient with metabolic acidosis; a normal serum anion gap (hyperchloremic metabolic acidosis), and, other than a few exceptions, a urinary pH above 6.0. It is important to remember that an identical biochemical profile is seen in the child with diarrhea, which needs to be excluded before considering the diagnosis of RTA.
In addition to several genetic disorders such as cystinosis, proximal tubular damage is often seen in children receiving chemotherapy. The diagnosis of a defect in proximal tubular reabsorption of HCO3 is made by showing that the fraction excretion of bicarbonate (FE HCO3) is greater than 15% when the plasma HCO3 concentration is normalized with alkalization. Classic distal RTA is caused by a defect in the secretion of H+ by the cells of the distal nephron. It is characterized by hyperchloremic metabolic acidosis, urine pH greater than 6.0 at normal as well as at low serum HCO3 concentrations, and a FE HCO3 less than 5% when the serum HCO3 is normal.26,27
Type IV RTA, a form of distal RTA associated with low urinary pH (<6.0) and hyperkalemia, is a result of decreased H+ and K+ secretion in the distal tubule and is related to a failure to reabsorb sodium.26,27 Type IV RTA is probably the most commonly recognized type of RTA in both adults and children. The hyperkalemia inhibits ammonia synthesis, resulting in decreased available ammonia to serve as a urinary buffer. Therefore, a low urinary pH occurs despite decreased H+ secretion (NH3 + H+ = NH4+). Type IV RTA is physiologically equivalent to aldosterone deficiency, which is one cause of the disorder. In children, it may reflect true hypoaldosteronism but it is much more common as a consequence of renal parenchymal damage, especially that due to obstructive uropathy. In children, the physiologic impairment of type IV RTA resolves in a few weeks to months after relief of an obstructive disorder.28
Acute Kidney Injury
Pathophysiology
AKI is characterized by an abrupt decrease in kidney function. Because AKI is caused by a decrease in the GFR, the initial clinical manifestations are elevations in serum urea nitrogen and creatinine concentrations, and frequently a reduction in urine output. Among pediatric surgical patients, an impairment in kidney function is most common to those who are undergoing cardiopulmonary procedures.29,30 In recent years, research has focused on the identification of biomarkers that indicate imminent kidney failure, even before a rise in serum creatinine is noted.31 The idea is to identify urine and possibly blood proteins and enzymes released from the tubules very early in the development of AKI. A substantial amount of data has been collected in children undergoing elective heart surgery, using the biomarker neutrophil gelatinase-associated lipocalin (NGAL).31 However, at this point, such markers have not been incorporated into routine clinical practice.32
The most important factor in the pathogenesis of postoperative kidney failure is decreased renal perfusion. In the early phase, the reduction in renal blood flow results in a decline in GFR. Intact tubular function results in enhanced reabsorption of sodium and water. This clinical condition is recognized as prerenal azotemia. Analysis of the patient’s urine reveals a high urinary osmolality of greater than 350 mOsm/kg H2O and a urine sodium concentration less than 10 mEq/L (20 mEq/L in the neonate).33 The most useful index for the tubular response to renal hypoperfusion with intact tubular function is FE Na. The FE Na test is invalid if the patient received diuretics before giving the urine sample. With renal hypoperfusion and intact renal function, FE Na is less than 1% in term infants and children, and below 2.5% in premature infants.34 In most patients with prerenal azotemia, intravascular volume depletion is clinically evident. However, in patients with diminished cardiac output (pump failure), clinical appreciation of reduced renal perfusion can be obscured because body weight and central venous pressure may suggest fluid overload. Similarly, assessment of volume status is difficult in patients with burns, edema, ascites, anasarca, or hypoalbuminemia. The reduced effective intra-arterial volume might be evident from the reduced systemic blood pressure, tachycardia, and prolonged capillary refill time.
Prerenal azotemia can be alleviated by improving renal perfusion either by repleting the intravascular fluid volume or by improving the cardiac output. The improved kidney function is recognized by increased urine output and normalization of serum urea nitrogen and creatinine concentrations. However, if renal hypoperfusion persists for a significant period or if other nephrotoxic factors are present, parenchymal kidney failure can result. Factors that may predispose the patient to AKI include preexisting congenital urinary anomalies or impaired kidney function, septicemia, hypoxemia, hemolysis, rhabdomyolysis, hyperuricemia, drug toxicity, and the use of radiocontrast agents. Also, abdominal compartmental syndrome resulting from tense ascites may impair renal perfusion. In this setting, kidney failure may be alleviated by abdominal decompression.35
Medical Management
If urinary output is inadequate after the fluid challenge, an intravenous infusion of furosemide, 1 mg/kg, may be given. Patients with renal failure may require higher doses, up to 5 mg/kg. If no response occurs after the initial infusion of furosemide, a second, higher dose can be repeated after one hour. Some patients may require furosemide every four to eight hours to maintain satisfactory urinary volume. A protocol with constant furosemide infusion has been successfully used in oliguric children after cardiac surgery.36 Furosemide is infused at 0.1 mg/kg/h, with the dose increased by 0.1 mg after two hours if the urinary volume remains less than 1 mL/kg/h. The maximum dose is 0.4 mg/kg/h. At times, urine output can be increased by the use of vasoactive agents such as dopamine, However, their efficacy in otherwise altering the course of AKI is not well established.37,38 It is very important to maintain adequate blood pressure and effective renal plasma flow.
Careful monitoring of the patient’s fluid and electrolyte status is essential. Those children who fail to respond to furosemide are at risk for fluid overload. Overzealous fluid administration during anesthesia and surgery and for the management of persistent hypoperfusion, along with decreased urinary output, can result in hypervolemia, hypertension, heart failure, and pulmonary edema. In extreme cases, fluid administration must be decreased to the minimum necessary to deliver essential medications. In less severe instances, and in euvolemic patients with impaired kidney function, total fluid intake should equal insensible water loss, urine volume, and any significant extrarenal fluid losses. Urine output must be monitored hourly and fluid management should be re-evaluated every four to 12 hours, as clinically indicated. Valuable information about the patient’s overall fluid status can be obtained by carefully monitoring blood pressure, pulse, and body weight. The preoperative values of these parameters help serve as a baseline for postoperative evaluation. Ideally, the patient’s hemodynamic status should be assessed continuously by using central venous pressure monitoring. In patients with complicated cardiac problems, a Swan–Ganz catheter that monitors pulmonary wedge pressure should be used.
Fluid overload can lead to hyponatremia. In most cases, because total body sodium remains normal or high, the best way to normalize serum sodium concentration is by restriction of fluid intake and enhancement of urinary volume.39 In patients with acute symptomatic hyponatremia, careful infusion of NaCl 3% solution (512 mEq Na/L or 0.5 mEq/mL) may be given to correct hyponatremia. Rapid correction at a rate of 1–2 mEq/h over a two to three-hour period, with an increase of serum sodium level by 4–6 mEq/L, is usually well tolerated and adequate. Infusion of 6 mL/kg of 3% NaCl increases serum sodium concentration by about 5 mEq/L. Hyponatremia present for more than 24 to 48 hours should not be corrected at a rate more rapid than 0.5 mEq/L/h.
In children with AKI, hyperkalemia often develops. The early sign of potassium cardiotoxicity is peaked T waves on the electrocardiogram. Higher levels of serum potassium can cause ventricular fibrillation and cardiac asystole. The treatment of hyperkalemia is shown in Box 4-1. Emergency treatment of hyperkalemia is indicated when the serum potassium concentration reaches 7.0 mEq/L or when electrocardiographic changes are noted.
