Renal Impairment and Renovascular Hypertension

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. 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 developing the syndrome of inappropriate secretion of ADH, isotonic 0.9% normal saline might be a better choice for maintenance fluid therapy.

Approximately 30 mOsm of obligatory renal solute/100 mL of usual maintenance water is taken as the obligatory renal solute load in children 2 months and older. Urinary concentrating capacity increases rapidly during the first year of life and reaches the adult level of 1200–1400 mOsm/L at around year 2. 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.

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 gold 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. As noted previously, 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 by about 0.25 mg/dL in 2 hours and increases the creatinine excretion rate about 75% over the next 3- to 4-hour period. Serum creatinine concentrations are also increased by ingestion of commonly used medications such as salicylate and trimethoprim. ^, These agents compete with creatinine for tubular secretion through a base-secreting pathway. They do not alter GFR, but they 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 Schwartz and is based on the serum creatinine value (as determined by the Jaffe kinetic method) and the child’s height:

where k for infants with low birth weight is 0.33; full-term infants, 0.45; males 2–12 and females 2–21 years, 0.55; and males 13–25 years, 0.70. More recently, the use of enzymatic methods to determine serum creatinine prompted the development of new GFR estimating equations. The Flanders Metadata equation has been used to estimate GFR in healthy children between 2 and 15 years of age. This equation is eGFR (mL/min/1.73 m ² ) = (0.014 × ln(age) + 0.3018) × L/Scr. In contrast and as noted earlier, the updated Schwartz equation, eGFR = 0.413 × L/Scr, was derived from a study of children with CKD. Estimating equations that combine serum creatinine and cystatin C result in more precision, but the complex nature of the equations compromises their clinical usage.

Creatinine is formed by the nonenzymatic dehydration of muscle creatine at a rate of 50 mg creatine/kg muscle. The serum creatine concentration in the neonate reflects the maternal level for the first 3–4 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). 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 2 years of life, GFR increases from 35–45 mL/min/1.73 m ² to the normal adult range of 90–170 mL/min/1.73 m ² . 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. Table 4.2 shows the mean values and ranges for plasma or serum creatinine levels at different ages. Normative data of serum creatinine may differ from one laboratory to another, depending on the methodology used, although efforts are being made for standardization.

Fractional Excretion of Substances

Fractional excretions (FEs) are indices of renal function that are helpful in evaluating specific clinical conditions. Conceptually, an FE is the fraction of the filtered substance that is excreted in the urine. In clinical practice, FE is calculated by obtaining simultaneous blood and urine samples for creatinine and the substance studied. The formula used to express FE as a percentage is:

where Us is urine solute concentration, Ps is plasma solute concentration, Pcr is plasma creatinine concentration, and Ucr is urine creatinine concentration.

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. 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. 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 biomarkers neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1). Biomarkers also have been studied for their ability to distinguish between the various types of AKI and to predict the need for renal replacement therapy. However, at this point, such markers, which seem to have a better negative predictive value in ruling out impending AKI, have not been incorporated into routine clinical practice.

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/kgH ₂ O, and, as discussed earlier, the FE Na is less than 1% in term infants and children and below 2.5% in premature infants. 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 by either repleting the intravascular fluid volume or 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 can impair renal perfusion. In this setting, kidney failure may be alleviated by abdominal decompression.

In an effort to better define AKI and the stages of its severity, in 2004 a group of experts developed the empiric RIFLE (Risk, Injury, Failure, Loss, End-Stage Kidney Disease) criteria. The criteria, later modified to include the pediatric population, are based on the rate of rise in serum creatinine, magnitude of oligoanuria, and severity and length of renal failure. They are currently used primarily for research purposes because the care and prognosis of the individual patient may depend on additional factors such as fluid status, cause of the AKI, and involvement of other systems.

Medical Management

The child with postoperative oliguria and an elevated serum creatinine concentration should be assessed for possible prerenal azotemia. If the child is found to be hypovolemic, an intravenous fluid challenge of 20 mL/kg of isotonic saline or plasma is commonly given. In acidotic patients, it may be physiologically advantageous to provide a solution in which bicarbonate accounts for 25–40 mEq/L of the anions in the fluid bolus (0.5 isotonic NaCl in 5% glucose, to which is added 25–40 mEq/L of 1 M NaHCO ₃ and additional NaCl or NaHCO ₃ to bring the solution to isotonicity). If no response is observed and the child is still dehydrated, the dose can be repeated. When the urine output is satisfactory after fluid replenishment, the child should receive appropriate maintenance and replacement fluids. Body weight, urinary volume, and serum concentrations of urea nitrogen, creatinine, and electrolytes also should be monitored. As discussed later, if a solution containing alkali is used, the serum ionized calcium level should be closely monitored.

If urinary output is inadequate after the fluid challenge, an intravenous dose 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 dose of furosemide, a second, higher dose can be repeated after 1 hour. Some patients may require furosemide every 4–8 hours to maintain satisfactory urinary volume. A protocol with constant furosemide infusion has been successfully used in oliguric children after cardiac surgery. Furosemide is infused at 0.1 mg/kg/h, with the dose increased by 0.1 mg after 2 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. It is very important to maintain adequate blood pressure and effective renal plasma flow. 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 should 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 reevaluated every 4–12 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 serve as a baseline for postoperative evaluation. Ideally, the patient’s hemodynamic status should be assessed continuously by central venous pressure monitoring.

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. 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 2- to 3-hour period, with an increase in the 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 24–48 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.