Essentials of Nephrology

Published on 05/02/2015 by admin

Last modified 05/02/2015

Print this page

This article have been viewed 3066 times

26 Essentials of Nephrology

Delbert R. Wigfall, John W. Foreman, Allison Kinder Ross

THE ANESTHESIA PRACTITIONER IS OFTEN FACED with a patient who has acute kidney injury (AKI) or renal failure. Renal disease requires the practitioner to be vigilant about fluid homeostasis, acid-base balance, electrolyte management, choice of anesthetics, and potential complications. Maintaining a fine balance, particularly in the neonate and younger child, requires knowledge of the excretory and volume maintenance functions of the kidney. If not managed correctly, perioperative renal dysfunction can lead to multiorgan system compromise and significant morbidity or mortality. The anesthesia provider must understand renal physiology, appropriate preoperative preparation, intraoperative management, and postoperative care of the renal patient.

Renal Physiology

The basic function of the kidney is to maintain fluid and electrolyte homeostasis. The first step in this tightly controlled process is the production of the glomerular filtrate from the renal plasma. The glomerular filtration rate (GFR) depends on renal plasma flow, which depends on blood pressure and circulating volume. The kidneys are the best perfused organs per gram of weight in the body. They receive 20% to 30% of the cardiac output maintained over a wide range of blood pressures through changes in renal vascular resistance. Numerous hormones play a role in this autoregulation, including vasodilators (i.e., prostaglandins E and I₂, dopamine, and nitric oxide) and vasoconstrictors (i.e., angiotensin II, thromboxane, adrenergic stimulation, and endothelin). Congestive heart failure and volume contraction severely limit the ability of the kidney to maintain autoregulation during changes in blood pressure.

When renal blood flow is adjusted for body surface area, it doubles during the first 2 weeks of postnatal life and continues to increase until it reaches adult values by the age of 2 years (see Figs. 6-10 and 6-11).^1,² Increased blood flow results from an increase in cardiac output and a decrease in renal vascular resistance. Paralleling these changes, the GFR, when adjusted for body surface area, also doubles over the first 2 weeks of postnatal life and continues to increase until it reaches adult values by the age of 1 to 2 years. The initial GFR and the rate of increase correlate with gestational age at birth. For example, the GFR of an infant of 28 weeks gestation is half of that of a full-term infant (see Figs. 6-10 and 6-11).³ An estimate of GFR can be made from the serum creatinine concentration and the height of the child according to the following formula^4,⁵:

In the equation, k is 0.45 for infants, 0.55 for children, and 0.7 for adolescent boys. The serum creatinine concentration, especially in the first days of life, reflects the maternal serum creatinine concentration and therefore cannot be used to predict neonatal renal function until at least 2 days after birth.⁶

Fluids and Electrolytes

The kidney regulates total body sodium balance and maintains normal extracellular and circulating volumes.⁷ The adult kidney filters 25,000 mEq of sodium per day, but it excretes less than 1% through extremely efficient resorption mechanisms along the nephron. The proximal tubule resorbs 50% to 70%, the ascending limb of the loop of Henle resorbs about 25%, and the distal nephron accounts for 10% of the filtered load of sodium. Several hormones, including renin, angiotensin II, aldosterone, and atrial natriuretic peptide, and changes in circulating volume play roles in maintaining sodium balance.⁸

Serum osmolality is tightly regulated through changes in arginine vasopressin (AVP) release and the appreciation of thirst.⁹^–¹¹ AVP, also called antidiuretic hormone, is synthesized in the hypothalamus and stored in the posterior pituitary, where it is released in response to an increasing plasma osmolality. AVP is also released in response to a decreased circulating volume or hypotension, including those responses to nausea, vomiting, and possibly opioids. AVP binds to receptors in the collecting duct, increasing the permeability of the tubules to water and leading to increased water resorption and concentrated urine. Neonates are much less able to conserve or excrete water compared with older children, rendering the fluid management and volume issues important tasks of the pediatric anesthesiologist in this young age-group.¹²

The regulation of serum potassium is managed by the kidney and depends on the concentration of plasma aldosterone. Aldosterone binds to receptors on cells in the distal nephron, increasing the secretion of potassium in the urine. Neonates are much less efficient at excreting potassium loads compared with adults, and the normal range of serum potassium concentrations is therefore greater in neonates; Table 26-1 provides the normal values.¹³ Potassium regulation is affected by the acid-base status; excretion of potassium increases in the presence of alkalosis and decreases in the presence of acidosis. Causes of hyperkalemia and hypokalemia are presented in Tables 26-2 and 26-3, respectively.

TABLE 26-1 Normal Values of Serum Potassium

Age	Serum Potassium Range (mEq/L)
0-1 month	4.0-6.0
1 month-2 years	4.0-5.5
2-17 years	3.8-5.0
>18 years	3.2-4.8

TABLE 26-2 Causes of Hyperkalemia

TABLE 26-3 Causes of Hypokalemia

Transcellular Shift

Insulin

β-Adrenergic agonists

Increased Excretion

Renal tubular acidosis

Decreased Intake

Acid-Base Balance

The kidney is involved in the day-to-day regulation of acid-base balance and the response to the stress of illness. The kidney reclaims virtually all of the filtered bicarbonate in the proximal tubule. The kidney also regenerates the bicarbonate () lost in the neutralization of acid generated by the normal combustion of food, especially protein, and the formation of bone. New bicarbonate is generated by the cells of the distal nephron by decomposing the carbonic acid (H₂CO₃) formed from water (H₂O) and carbon dioxide (CO₂) by carbonic anhydrase. The protons (H⁺) that are generated from this process are pumped into the lumen of the collecting duct, where they combine with hydrogen phosphate () or ammonia (NH₃) generated by the catabolism of amino acids, mainly glutamine, in the tubule cells.

Infants, especially neonates, maintain a slightly acidotic pH (7.37) and decreased plasma bicarbonate concentration (22 mEq/L) compared with older children and adults (pH = 7.39; plasma bicarbonate = 24 to 28 mEq/L).¹⁴ Neonates can maintain acid-base homeostasis but are limited in their ability to respond to an acid load.¹⁵ This is especially true for preterm infants. This reduced plasma concentration in infants is the result of a reduced threshold, or the plasma concentration at which is no longer completely resorbed by the kidney.

Disease States

The causes of and differences in renal diseases between children and adults are substantive. Adult renal disease usually results from longstanding diabetes mellitus or hypertension with an associated compromise in cardiovascular function. Children may also have renal failure due to diseases such as sickle cell anemia or systemic lupus erythematosus, but cardiovascular function is far less commonly compromised. Depending on the cause of the renal disease, management may be different.

Acute Renal Failure and Acute Kidney Injury

Acute renal failure (ARF) or acute renal insufficiency can be defined as an abrupt deterioration in the kidney’s ability to clear nitrogenous wastes, such as urea and creatinine. Concomitantly, there is a loss of ability to excrete other solutes and maintain a normal water balance. This leads to the clinical presentation of acute renal insufficiency: edema, hypertension, hyperkalemia, and uremia.

Acute kidney injury (AKI) has almost replaced the traditional term acute renal failure, which was used in reference to the subset of patients with an acute need for dialysis. With the recognition that even modest increases in serum creatinine are associated with a dramatic impact on the risk for mortality, the clinical spectrum of acute decline in GFR is broader. The minor deteriorations in GFR and kidney injury are captured in a working clinical definition of kidney damage that allows early detection and intervention and uses AKI as a replacement for the term ARF. The term ARF is preferably restricted to patients who have AKI and need renal replacement therapy.¹⁶ The prognosis of AKI is assessed in part by the use of the RIFLE criteria, which include three severity categories (i.e., Risk, Injury, and Failure) and two clinical outcome categories (Loss and End-stage renal disease) (Table 26-4).

TABLE 26-4 RIFLE Classification of Renal Failure and Kidney Injury

The term ARF has often been incorrectly used interchangeably with acute tubular necrosis, which usually refers to a rapid deterioration in renal function occurring minutes to days after an ischemic or nephrotoxic event. Although acute tubular necrosis is an important cause of ARF, it is not the sole cause, and the terms are not synonymous. For the purposes of this chapter, AKI refers to the disease formerly called ARF.

Etiology and Pathophysiology

AKI is often multifactorial in origin or the result of several distinct insults. To treat AKI, it is important to understand its causes and pathophysiology. The causes of AKI are varied but in general can be classified as follows (Table 26-5):

Prerenal implies poor renal perfusion.

Renal implies intrinsic renal disease or damage.

Postrenal implies an obstruction to urine excretion.

TABLE 26-5 Causes of Acute Renal Failure

Prerenal Failure	Renal Failure	Postrenal Failure
Hypovolemia Volume loss Gastrointestinal, renal losses Sequestration (burns, postoperative)	Acute glomerulonephritis Postinfectious Membranoproliferative glomerulonephritis Rapidly progressive glomerulonephritis Glomerulonephritis due to systemic disease (e.g., HUS, DIC, SLE)	Obstruction Intrinsic (papillary necrosis due to diabetes, sickle cell disease, or analgesic nephropathy) Intrarenal abnormalities, ureteral obstruction, obstruction of the bladder or urethra Extrinsic (tumor compression, lymphadenopathy)
Hypotension Shock Vasodilators	Acute interstitial nephritis Drug-induced hypersensitivity (penicillin) Infections
Decreased effective blood flow Low cardiac output Cirrhosis Nephrotic syndrome	Tubular disease ATN (ischemic, nephrotoxic) Intratubular obstruction (uric acid, oxalate)
Renal hypoperfusion Use of ACE inhibitors NSAIDs Hepatorenal syndrome	Cortical necrosis Gram-negative sepsis Hemorrhage Shock
Vascular occlusion Thromboembolic phenomenon Aortic dissection Renal vein thrombosis (dehydration, hypercoagulable state, neoplasm)	Acute renal failure Toxins Organic solvents Heavy metals Insecticides Hemoglobin Myoglobin

	Chronic renal failure Chronic interstitial nephritis Chronic glomerulonephritis Chronic glomerulosclerosis Nephrocalcinosis Obstructive uropathy Hypertension

ACE, Angiotensin-converting enzyme; ATN, acute tubular necrosis; DIC, disseminated intravascular coagulation; HUS, hemolytic uremic syndrome; NSAIDs, nonsteroidal antiinflammatory drugs; SLE, systemic lupus erythematosus.

Prerenal insults are a common cause of AKI, accounting for up to 70% of all cases. Prerenal failure usually results from extracellular fluid loss, such as from gastroenteritis, burns, hemorrhage, or excessive diuresis. It also occurs in the setting of cardiac failure or sepsis. The common feature of this condition is diminished renal perfusion. In response to the reduction in flow, there is a compensatory increase in afferent tone, which decreases the GFR and increases the retention of salt and water. The net effect of these events is a drastic reduction in urine volume, often resulting in oliguria. If the underlying problem is recognized and treated aggressively, progressive renal insufficiency may be averted. Nonsteroidal antiinflammatory drugs, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers can aggravate prerenal azotemia by further reducing glomerular capillary pressure and the GFR.¹⁷

AKI resulting from parenchymal disease or injury accounts for 20% to 30% of cases of abrupt renal insufficiency. Common causes in infants include birth asphyxia, sepsis, and cardiac surgery. Important causes of AKI in older children include trauma, sepsis, and the hemolytic uremic syndrome. Prolonged prerenal azotemia may result in overt renal injury. Similarly, intrarenal obstruction to blood flow from thrombi or vasculitis may cause renal failure. Drugs such as aminoglycosides or amphotericin B or other nephrotoxins, including radiocontrast agents, may induce AKI through tubular injury or cause interstitial injury as a result of allergic reactions, as can be seen with penicillins. Acute glomerulonephritis is another cause of AKI in children. Rarely, pyelonephritis can lead to AKI.

The remaining causes of AKI result from the obstruction to urine flow. In total, these conditions account for less than 10% of all cases of AKI and lead to obstruction of both kidneys. Complete cessation of urine may be a clue to a postrenal cause. The obstruction can occur within the collecting system of the kidney (intrarenal), in the ureter, or in the urethra (extrarenal). Intrarenal obstruction may occur with the tumor lysis syndrome with the deposition of uric acid crystals or from medications such as acyclovir and cidofovir. Extrarenal obstruction can be caused by the presence of stones in the ureters or from external compression due to lymph nodes or tumor. As with other forms of AKI, prompt recognition and appropriate intervention to relieve an obstruction may prevent a permanent reduction in renal function.

The exact pathophysiology of AKI remains unclear, but several factors have been identified.¹⁸ There is a profound vasoconstriction in the initial phase of AKI that contributes to the reduced GFR (Fig. 26-1). Factors implicated in increased vasoconstriction include increased activity of the renin-angiotensin and the adrenergic systems and endothelial dysfunction with increased endothelin release and decreased nitric oxide synthesis. However, therapeutic interventions to increase vasodilatation, such as prostaglandin and dopamine infusions, ACE inhibitors, calcium channel blockers, and endothelin receptor antagonists, have not significantly improved established AKI.¹⁹

FIGURE 26-1 Hemodynamic factors in the pathogenesis of acute renal failure.

Another factor in the pathogenesis of AKI is renal tubule cell injury that is a direct result of a nephrotoxic agent or from an ischemic insult (Fig. 26-2). Cellular injury leads to sloughing of the brush border, swelling, mitochondrial condensation, disruption of cellular architecture, and loss of adhesion to the basement membrane with shedding of cells into the tubular lumen.²⁰ These changes, which occur within minutes of an ischemic event, contribute to the decreased GFR by obstructing the lumen of the tubule.²¹ These cellular changes allow the filtrate to leak back into the peritubular blood, reducing the excretion of solutes and the effective GFR.

FIGURE 26-2 Influences of specific injuries on the nephron in the pathogenesis of acute renal failure. ATP, Adenosine triphosphate.

Some of these cell derangements in AKI, such as a decrease in ATP concentrations,²¹ cell membrane injury by reactive oxygen molecules,²² and increased intracellular calcium levels from changes in membrane phospholipid metabolism, lead to cell death. Reactive oxygen molecules also stimulate the production of cytokines and chemokines that play a role in cell injury and vasoconstriction.

Infiltrating neutrophils, recruited during reperfusion injury after renal ischemia, mediate parenchymal damage.²³ Reperfusion injury increases intracellular adhesion molecule 1 (ICAM-1) on endothelial cells promoting the adhesion of circulating neutrophils and their eventual infiltration into the parenchyma. Neutrophils then release reactive oxygen molecules, elastases, proteases, and other enzymes that lead to further tissue injury.

Diagnostic Procedures

A thorough history and physical examination can yield important clues to the possible cause of renal failure. The initial laboratory assessment of a child with AKI should include the measurement of serum urea, creatinine, and electrolytes and a urinalysis. Prerenal azotemia is typically associated with a ratio of blood urea nitrogen (BUN) to creatinine that is usually greater than 20. In cases of renal parenchymal dysfunction, this ratio is approximately 10. Hematuria and proteinuria are seen in all causes of AKI, but the presence of cellular casts, especially red blood cell casts, in the urinary sediment suggests glomerulonephritis. Granular casts may be seen in prerenal azotemia.

One test to distinguish prerenal azotemia from established renal failure from ischemia or nephrotoxins is the fractional excretion of sodium (FE_Na). The FE_Na is calculated using the following equation:

U_Na and S_Na are urine and serum sodium concentrations, and U_Cr and S_Cr are the urine and serum creatinine concentrations, respectively. In prerenal azotemia, the FE_Na is usually less than 1% for adults and children and less than 2.5% for infants. In established AKI from ischemia and nephrotoxins, but not acute glomerulonephritis, the FE_Na is usually increased above 1%. Diuretics confound the interpretation of this test.

The initial radiologic assessment of children with AKI is ultrasonography. Renal ultrasound does not depend on renal function and can define renal anatomy, changes in parenchymal density, and possible obstruction by demonstrating dilation of the urinary tract. Doppler interrogation of the renal vessels provides information on vascular flow. Further radiographic studies, such as voiding cystourethrography, nuclear renal flow scanning, and abdominal computed tomography (CT) may be indicated in selected children.

Therapeutic Interventions

Therapeutic interventions in children with AKI should be aimed at the underlying cause and at improving renal function and urine flow. Children with AKI due to hypovolemia should be fluid resuscitated with at least 20 mL/kg over 30 to 60 minutes of normal saline or a balanced salt solution. For children with significant hypotension, an alternative choice is a colloid-containing solution. Children with oliguria due to hypovolemia usually respond within 4 to 6 hours with increased urine output. Although there are anecdotal reports supporting low-dose dopamine in AKI, clinical trials have not shown a benefit from dopamine in preventing or improving AKI.²⁴

Diuretics have been commonly used to treat oliguric AKI. There are several theoretical reasons why mannitol, furosemide, or other loop diuretics may ameliorate AKI. Diuretics may convert oliguric AKI to nonoliguric AKI. Loop diuretics decrease energy-driven transport in the loop of Henle, and this may protect cells in regions of hypoperfusion. However, neither mannitol nor loop diuretics can predictably convert an oliguric patient with AKI to a polyuric patient. Diuretics have not been shown in clinical studies to influence renal recovery, need for dialysis, or survival in patients with AKI.^25,²⁶ Diuretics should be used only after the circulating volume has been adequately restored and should be stopped if there is no early response.

Dopamine has been widely used to prevent and manage AKI. In low doses (0.5 to 2.0 µg/kg/min), dopamine increases renal plasma flow, GFR, and renal sodium excretion by activating dopaminergic receptors. Infusion rates in excess of 3 µg/kg/min stimulate α-adrenergic receptors on systemic arterial resistance vasculature causing vasoconstriction; cardiac β₁-adrenergic receptors increasing cardiac contractility, heart rate, and cardiac index; and β₂-adrenergic receptors on systemic arterial resistance vasculature causing vasodilatation. In a meta-analysis of 24 studies and 854 patients, dopamine did not prevent renal failure, alter the need for dialysis, or change the mortality rate.²⁷ In a randomized clinical trial of low-dose dopamine in 328 critically ill patients, dopamine did not change the duration or severity of the renal failure, need for dialysis, or mortality.²⁸ From these data, the routine use of low-dose dopamine in patients with AKI cannot be supported.

Several other agents that were useful in experimental models of AKI have been investigated but not shown clinical success. Atrial natriuretic peptide increases GFR in animal models of AKI by increasing renal perfusion pressure and sodium excretion. Initial studies demonstrated some benefit in patients with AKI,²⁹ especially oliguric AKI,³⁰ but a subsequent study of 222 patients with oliguric AKI revealed no statistical difference between patients treated with atrial natriuretic peptide and placebo in terms of the need for dialysis or mortality.³¹ Insulin-like growth factor 1 has been beneficial in animal models of AKI, presumably by potentiating cell regeneration. However, in a multicenter, placebo-controlled trial enrolling 72 patients with AKI, insulin-like growth factor 1 did not speed recovery, decrease the need for dialysis, or alter the mortality rate.³² Thyroxine abbreviates the course of experimental acute renal failure but had no effect on the duration of renal failure in patients and increased mortality threefold (by suppression of thyroid-stimulating hormone).³³

In patients with severe AKI, renal replacement therapy through dialysis is life sustaining. The indications for initiation of dialytic therapy are persistent hyperkalemia, volume overload refractory to diuretics, severe metabolic acidosis, and overt signs and symptoms of uremia such as pericarditis and encephalopathy. Many nephrologists advocate for initiation of dialysis if the BUN value approaches 100 mg/dL or even earlier, especially in the oliguric patient, although this has not proved to alter outcome. A retrospective study that compared early (BUN <60 mg/dL) versus late (BUN >60 mg/dL) initiation of dialysis in 100 adult patients suggested that early initiation improved survival.³⁴ However, the timing of the initiation of dialysis remains an unresolved question.

The three modalities of renal replacement for the support of critically ill children and adults are hemodialysis, peritoneal dialysis, and a variation of continuous replacement therapies, such as venovenous hemofiltration (CVVH), hemodialysis (CVVHD), and hemodiafiltration (CVVHDF). No form of replacement therapy has been clearly superior to the others. However, in the individual child, one form may be more practical than the others. Hemodialysis is technically more difficult than peritoneal dialysis in the infant and hemodynamically unstable child. Continuous replacement therapies appear to cause less hemodynamic instability compared with hemodialysis but offer more predictable solute and fluid removal than peritoneal dialysis. Hemodialysis and continuous replacement therapies require large-bore vascular access to achieve the high blood flow rates necessary for these modalities.

Although the modalities are technically different, they are based on the same principles (Fig. 26-3). The aim of all renal replacement therapies is to promote the removal of nitrogenous wastes (i.e., urea), excess fluid, and excess solute, especially potassium. This is achieved by exposing blood to a salt solution (i.e., dialysate), with the two separated by a semipermeable membrane. The movement of solute occurs by diffusion (i.e., solute moves across the membrane in response to a concentration gradient) and ultrafiltration (i.e., osmotic or hydrostatic pressures). The rate of removal of water and solute waste depends on membrane characteristics (i.e., pore size and selectivity), diffusion, and ultrafiltration.³⁵