POSTOPERATIVE RENAL INSUFFICIENCY

POSTOPERATIVE MEDICAL COMPLICATIONS

0025-7125/01 $15.00

+ .OO

POSTOPERATIVE RENAL INSUFFICIENCY Byard F. Edwards, MD

Renal impairment, hospital acquired or chronic, adversely affects patient surgical outcomes. A review of 3954 patients in 14 American Department of Veteran Affairs Medical Centers presenting with chronic renal impairment (serum creatinine >1.5 mg/dL) before surgery revealed higher incidences of stroke, bleeding complications, dialysis initiation, and death, with prolonged mechanical ventilation and increased length of stay? Although the incidence of hospital-acquired renal insufficiency (HARI) in developed countries is low (1.5 patients per 1000 admitted), the impact of HARI on hospital and community resources is significant because it increases the complexity of required care, triples the length of hospital stay, and worsens the patient’s prognosis. Mortality averages 45% with HARI but may exceed 80% if dialysis is r e q ~ i r e d .12,~ 14, , 33, 47, 49 Death usually results from the original disease necessitating the hospitalization or from hospital-acquired complications of shock and infection? 48, but HARI also independently increases patient mortality?, l5 Patients undergoing major surgery have a higher incidence of HARI than the average hospitalized patient population. An 8-year review of 42,773 patients in 43 American Department of Veteran Affairs Medical Centers indicated that 1.1% of patients undergoing coronary artery bypass or valvular surgery required the initiation of dialysis. Mortality was 63% when dialysis was required and only 4.3% when no dialysis was required. In contrast to previous studies that attributed the increased mortality in HARI patients to nonrenal causes, analysis of these data showed an independent association of HARI requiring dialysis with an increased patient mortality (odds ratio, 7.9; confidence interval, 6 to 10).15A similar 2-year review at a tertiary medical center showed that 8.6% of 2800 cardiac surgery patients developed HAW; 0.7% required dialysis. Mortality was 28% with dialysis, 14% without dialysis, and 1%if no HARI was present.2o Despite the advances in diagnostic imaging, surgical techniques, and sup-

From the Department of Medicine, Renal Division, Emory University School of Medicine, Atlanta, Georgia

MEDICAL CLINICS OF NORTH AMERICA VOLUME 85 * NUMBER 5 SEPTEMBER 2001

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port measures, the excessive mortality and morbidity associated with HAM continue. Until improved methods of treatment are developed, preventing HARI through risk reduction and reversing HARI through early detection and intervention are essential components of patient management. CAUSE

The causes of HARI have remained constant since the 1980s, but their relative frequency has changed. Acute tubular necrosis (ATN) remains the primary cause of renal damage (500/, to 65%); hypoperfusion (prerenal) causes 20% to 35%. Contrast-induced nephropathy has increased dramatically from 4% to nearly 20% of all HARI and is the result of the ubiquitous use of contrastdependent diagnostic studies.48,57 The pathology leading to renal damage can be divided into three parts: inflow, outflow, and parenchymal. Inflow reflects the net glomerular perfusion pressure, which is necessary for generating the urinary filtrate. Historically, inflow has been referred to as the prerenal component. Glomerular filtration pressure arises from the net resistance of blood filling the glomeruli from the afferent arterioles, blood emptying the glomeruli from the efferent arterioles, and urine outflow. Consequently, afferent constriction and efferent dilation reduce the glomerular filtration rate (GFR), as does hypotension, beyond the capability for maintaining the autoregulation of renal blood flow. Autoregulation of the renal arterial vessels allows continued effective perfusion of the glomeruli (approximately 40 mm Hg) when a systemic mean arterial pressure (MAP) of 80 mm Hg or greater is present. The presence of renal arteriosclerosis or atherosclerosis requires a higher MAP to maintain an effective renal perfusion.@ Renal MAP can be reduced perioperatively by anesthetics, atherosclerotic emboli, blood loss, decreased vascular resistance, hypotension (absolute or relative), intravascular volume contraction, mechanical ventilation, microangiopathic emboli, sepsis, shock, vasovagal stimulation, and venous pooling. Afferent arteriole autoregulation may be disrupted with nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit vasodilatory prostaglandins.88,89 Angiotensinconverting enzyme inhibitors (ACE-I) and angiotensin receptor blockade (ARB) medications inhibit efferent con~triction.'~ Afferent constriction or efferent dilation decreases the GRF. Diltiazem and verapamil preferentially vasodilate the efferent greater than the afferent arteriole, decreasing the GFR.91Gram-negative sepsis has an exceptional ability to decrease the GFR by simultaneously decreasing peripheral vascular resistance, while increasing renal vasoconstriction through enhanced production of endothelin, thromboxane AP, leukotrienes, and prostaglandin FZ analogues.6,11, 38 These compounds may act directly on the vasculature or by inhibiting the production and release of vasodilatory nitric o~ide.29.31.41. 65 Outflow derangement usually is associated with tubular obstruction resulting from the cellular debris of ATN. After an ischemic or toxic insult, the tubular cells necrose, slough into, and obstruct the tubular lumen. When combined with the secreted Tamm-Horsfall proteins, the necrotic cells form a coarse granular cast (muddy brown cast)." A subsequent intense inflammatory response mediated by infiltrating leukocytes further injures the renal tissue.40,90 Crystals arising from sulfonamides, acyclovir, oxylate, and uric acid may obstruct the tubules, as may the precipitated proteins of myoglobin arising from rhabdomy01yis.l~Tissue sloughing from papillary necrosis may obstruct the calyces or ureter. Postoperative bladder dystonia may induce an outlet obstruc-

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tion after the removal of a Foley catheter. Inadvertent unilateral ureteral ligation may go unsuspected because the renal impairment may not be apparent. Prompt reversal of the obstruction limits the development of polyuria, sodium wasting, hyperkalemia, and type I renal tubular acid0sis.3~ Parenchymal damage affects the glomeruli, tubules, vessels, or interstitium. Renovascular obstructive processes, including hemolytic-uremic syndrome, thrombotic thrombocytopenic purpura, and cholesterol emboli, damage the glomeruli. The occlusion of the glomerular capillary loops induces a cornplementmediated inflammatory response.87Diffuse irreversible cortical necrosis occurs within days of developing a microangiopathic glomerulopathy. Renal failure from cholesterol emboli is not apparent for days after the event and is propor74 Initial vessel obstruction is tionate to the percentage of arterioles obstructed.Z1, incomplete because the irregularly shaped emboli do not conform to the shape of the lumen. The subsequent inflammatory reaction completes the obstruction, however, through intimal proliferation and giant cell formation. Recannulation, if it occurs, may be delayed for 8 weeks. Less dramatic glomerular injury occurs in septic shock, in which the inflammatory response injures the basement membrane causing increased proteinuria and h e m a t ~ r i a . ~ ~ Tubular damage commonly results from renal ischemia. If the ischemia is brief, significant tubular damage is avoided.5'j Reversible azotemia, creatinine elevation, and decreased urine output may be the only manifestations of this occurrence. Prolonged ischemia results in tubular cell apoptosis and death.10,36 The sloughing cells obstruct the lumen and increase the luminal pressure until glomerular filtration decreases. The sloughed cells allow the backleak of the glomerular filtrate through the damaged epithelium into the systemic circulation.44,59 Mediators of the intense inflammatory response that are present in the filtrate then enter the systemic circulation and may play a significant role in promoting and propagating the systemic inflammatory response syndrome 51 This factor may explain in part the increased mortality independently (SIRS).41* associated with acute renal failure. In addition to prolonged ischemia, which preferentially damages the outer medullary tubule segments, toxins from antibiotics or iodinated contrast media frequently induce significant ATN.3O Nephrotoxicity occurs in 15% of patients receiving aminoglycosides.64The interval between initial dosing and apparent renal damage usually exceeds 7 days and allows prolonged, continuous tubular injury to occur. Reactive oxygen metabolites resulting from iron-catalyzed reactions, heme pigments, and infiltrating leukocytes induce the tubular injury.8 Iodinated contrast media induce tubular damage within 48 hours of their administration by impairing nitric oxide production and increasing free radical formation.60,73 The tubular injury usually is self-limiting but may require the initiation of dialysis in diabetic patients with creatinine clearance less than 50 mL/min who receive more than 100 mL of contrast medium.58Amphotericin B disrupts distal tubular membrane integrity.53The resulting distal acidification defects impair the normal transepithelial pH gradient, allowing diminished hydrogen secretion through increased backleak and increased potassium and magnesium wasting. Increased polyuria and hypernatremia result from increased antidiuretic hormone resistance in the cortical tubule segments. Tubular ischemia is thought to result from increased tubular glomerular feedback and direct vasoconstriction. Deoxycholate, the solubilizer in amphotericin B, may be responsible for 50% of the antibiotic's toxicity. This compound is absent in the liposomal preparation^.^^ Tubular injury alters the neurohumeral activity feeding back to the glomer~ l iNormal . ~ ~ autoregulation of the glomerular perfusion and filtrate formation is disrupted. Increased macula densa stimulation promotes increased renin re-

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lease and increased in situ angiotensin I1 production. Afferent vasoconstriction occurs, and GFR Interstitial nephritis is an allergic reaction in susceptible patients frequently resulting from exposure to p-lactam antibiotics, sulfonamides, allopurinol, and NSAIDS.'~Eosinophiluria, eosinophilia, and dermatitis may accompany the renal damage. A delayed renal recovery after the discontinuation of the suspected agent may require a renal biopsy to confirm the diagnosis.

PREVENTION The prevention of HARI requires the avoidance of hypovolemia and hypotension as well as the judicious use of potentially nephrotoxic medicat i o n ~ . ~54,y3 ~ , ~Medications ', known to depress renal function must be avoided or used with extreme caution in patients with moderate (estimated creatinine clearance, 50 to 20 mL/min) to severe (estimated creatinine clearance, <20 mL/ min) renal function. Routine use of oral and intravenous NSAIDs, which inhibit prostaglandin I,-mediated and prostaglandin E,-mediated afferent vasodilation, should be avoided in these patients. ACE-I and ARB use may exacerbate the HARI significantly through decreased GFR and promote hyperkalemia. These medications should be withheld perioperatively if the patient has impaired renal function. Intravenous iodinated contrast-induced nephropathy is lessened when the patient's volume is pre-expanded with half-normal saline and less than 100 mL of contrast medium is infused.79Pretreatment with the free radical scavenger n-acetyl cysteine may limit the Alternative radiographic contrast media employing carbon dioxide or gadolinium alleviate the risk for contrast-induced renal injury. When aminoglycosides and amphotericin B are required for lifethreatening infections, nephrotoxicity is limited by pulse dosing the aminoglycosides and dose adjusting for the degree of renal impairment." Amphotericin B-related renal toxicity is reduced if slower infusion rates, intravascular volume expansion, and liposomal preparations are Persistent renal hypoperfusion must be avoided if ATN is to be averted.40, Restoration of adequate MAP may be achieved by withholding blood pressure medications if MAP is less than 80 mm Hg and expanding the vascular space until central venous pressure is greater than 5 mm Hg and pulmonary artery occlusion pressure is greater than 12 mm Hg. The cardiac index should be optimized through vasopressor therapy and inotropic support.86Initial volume expansion usually is accomplished with normal saline until capillary leakage secondary to SIRS develops., Further vascular expansion by continued infusion of crystalloid solutions after developing a capillary leak syndrome results in anasarca. Intracapillary oncotic force is reduced as albumin leaks across the capillaries into the interstitium. Distal capillary resorption of the interstitial fluid is impaired. Skin elasticity prevents equilibration of the interstitial and capillary hydrostatic pressures and allows continued interstitial expansion to occur. Blood does not leave the vascular space with the capillary leak syndrome and should be transfused to expand the vascular space effectively, limit the need for crystalloid volume expansion, and minimize anasarca. Vasopressor therapy should be initiated with dopamine and if associated with an inadequate response be followed by norepinephrine. Epinephrine should be considered in refractory hypotension.86

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DETECTION The presence of early renal failure frequently goes undetected. In part, this lack of detection results from the lack of a standardized definition for HARI. Multiple parameters, including a rising serum creatinine, a reduction in calculated creatinine clearance, a urine output less than 400 mL/24 hours, and the initiation of dialysis, are used to define HARI. If a patient is considered at risk for increased medical complications at a GFR of 50 mL/min or less, clinical care should be optimized to limit further reductions in renal function below this value.4,93 The determination of the renal function can be problematic, however. Direct glomerular filtration measurement with inulin or radiolabeled iothalamate is neither practical nor readily available outside of the research setting. Estimates of the GFR may be obtained through timed urine collections for creatinine or 51Cr-EDTA, but these methods are cumbersome and impractical for multiple assessments of renal function. Calculated creatinine clearance using the Cockcroft-Gault equation provides a quick, inexpensive, noninvasive method to monitor the renal function repeatedly, if the limitations of the measurement are k110wn.l~ Creatinine, a skeletal muscle waste product derived from the hepatic metabolism of creatine, is released into the circulation at a relatively constant rate if the skeletal muscle mass remains constant. Once filtered by the glomeruli, creatinine is neither reabsorbed nor metabolized; however, in renal failure, the secretion of creatinine in the proximal tubules may account for 35% of creatinine clearance. Multiple agents, including ciprofloxacin, cimetidine, and trimethoprim, block creatinine's secretory pathway, increase serum creatinine levels, and mimic acute renal failure without influencing the GFR. Intravascular volume expansion or pronounced interstitial edema may reduce the serum creatinine concentration by dilution or redistribution and lead to overestimation of the GFR. Undetected reduction of the lean body mass necessarily reduces creatinine production and overestimates the GFR. The lean body mass (LBM) value should be used in the creatinine clearance calculation: Modified Cockcroft-Gault formula: (140 - age) lean body (kg) x 0.85 for women 72 x serum creatinine (mg/dL)

=

creatinine in mL/min clearance

Lean body mass (LBM) estimatea5: Men: 106 lb for first 60 inches, then 6 lb for each additional inch of height Women: 100 lb for first 60 inches, then 5 lb for each additional inch of height Two examples show the problems using the raw serum creatinine and total body weight values to screen for renal failure. 1. A 65-year-old woman (height, 5 feet, 6 inches; weight, 165 lb) has a serum creatinine of 1.1 mg/dL. Although the creatinine level is well within the normal limits (0.5 to 1.4 mg/dL), the estimated creatinine clearance of 47 mL/min indicates moderate renal impairment and places the patient at significant risk for further renal injury. If the total body weight is used to calculate the creatinine clearance, a value of 60 mL/ min is obtained, and the creatinine clearance is overestimated by 13 mL/ min (27%). 2. A 70-year-old man (height, 5 feet, 9 inches; preoperative weight, 170 lb) had a serum creatinine of 1.5 mg/dL. Postoperative complications in-

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cluded the presence of a significant capillary leak syndrome, sepsis, and prolonged ileus limiting nutritional support to weeks of intravenous hyperalimentation. The patient’s weight increased to 195 lb, and serum creatinine was 1.6 mg/dL. Preoperative creatinine clearance estimation of 47 mL/min using an estimated LBM of 160 Ib would be lower postoperatively because the patient now has a reduced lean body mass through catabolism from sepsis and an inability to use the gut for feeding. The increased total body weight indicates a significant fluid expansion (total body water has increased from 44 to >70 L), which increases volume of distribution of creatinine, dilutes concentration of creatinine, and masks the presence of acute renal failure. Reduced lean body mass or increased volume expansion impairs the utility of creatinine in estimating the GRF. Other indices reflecting altered renal function, including increased volume status, decreased urine output, formation of urine sediment, and worsened electrolyte and acid-base status, must be monitored as indicators for HARI.

ASSESSMENT AND INTERVENTION

When HARI has been diagnosed, several interventions may prove useful to determine its cause and guide therapy. The development of a time/event flow chart, including daily body weights, daily trough blood pressures, daily urine output, daily net volume status, dosing of potential nephrotoxins, serum creatinine levels, culture results, and mechanical interventions, frequently indicates the time of renal insult and its potential source. The microscopic examination of spun urine sediment indicates the presence of casts, blood, white blood cells (WBCs), crystals, or micro-organisms. Hyaline casts are concentrated Tamm-Horsfall mucoproteins secreted into the tubular lumens. Their presence may indicate the presence of hypoperfusion. Fine granular casts are nonspecific indices of tubular damage, which may represent progressing renal ischemia. Coarse granular casts consist of necrosed tubular debris compacted within the tubular lumen and represent ATN. Lipoid casts contain cholesterol and are present with the nephrotic syndrome. Lipoid casts may be present with NSAID-induced interstitial nephritis, contrast nephropathy, or glomerulonephritis.WBC and red blood cell (RBC) casts arise from pyelonephritis and nephritis. The presence of viable intact tubular epithelial cells discloses a continuing renal injury and a potential for injury reversal. Blood components may be present in many forms in the urine. If blood is chemically present but conspicuously absent on microscopic examination, either myoglobin or free hemoglobin is present, suggesting the presence of rhabdomyolysis or hemolysis. The morphology of formed RBCs in the sediment may disclose the blood’s source. RBCs with spiculation and crenation suggest the RBCs have undergone an osmotic stress and may be of glomerular origin. Normal RBC morphology most likely represents a bleed originating in the urine collecting system. WBCs may be associated with interstitial nephritis (eosinophils and polymorphonuclear neutrophils, pyelonephritis (WBC casts), or urinary tract infection (WBCs). Fungal and bacterial infections may not be suspected until discovered in the urinalysis.

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Calculating the fractional excretion (FE) of sodium or chloride may help to discern between ATN and hypoperfusion:

FE

=

Urine serum [(electrolyte) x (creatinine)]

+

1

serum urine [(electrolyte) x (creatinine) x 1 0 0 ~ 9

As renal hypoperfusion develops, resorption of water and sodium in the proximal tubules exceeds 90% of the filtered load. Water is resorbed further in cortical segments, with urine osmolarity increasing to its maximum value. A high urinary specific gravity (>1.025) coupled with a low fractional excretion of sodium ( 4 % ) suggests hypoperfusion. If hypoperfusion proceeds to ischemia, the concentration capabilities of the medulla are limited, and urine specific gravity falls to isotonicity (specific gravity, 1.010) and fractional excretion can exceed greater than 4%. The fractional excretion cannot be interpreted after administering diuretics or hyperosmotic agents (mannitol and contrast media), however, because the urine sodium and osmolarity are increased. Obtaining a renal ultrasound may be useful if chronic renal failure or an outlet obstruction is suspected. Atrophic, echo-dense kidneys with a thinned cortex reflect the presence of chronic metabolic disease. The presence of ureteral dilation is more sensitive than calyceal dilation to detect early outlet obstruction. Detection depends, however, on the patient habitus and the technician’s skill. Retrograde ureterograms definitively diagnose an outlet obstruction. Serum chemistries, including sodium, potassium, bicarbonate, creatinine, blood urea nitrogen (BUN), calcium, phosphorus, uric acid, albumin, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), and serum glutamic-oxaloacetic transaminase (SGOT) are useful in the diagnosis and treatment of renal failure. Serum sodium values indicate the need to adjust the free water status. Water deficit is present with hypernatremia.

Estimated - (LBM kg x 0.6) x (1 - [140 mg/dL + serum sodium mg/dL])68 water deficit Hypernatremia occurs from failure to replace insensible water loss, gastric fluids, or water lost during the polyuria phase of renal recovery. The urea concentration gradient washes out in HAM; when coupled with impaired tubule function, this results in copious dilute urine and electrolyte loss during the recovery phase. Water excess results in hyponatremia and requires changing intravenous fluids to normal saline, preparing intravenous medications in normal saline, and restricting water in the patient. If the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is present, however, and the urine osmolarity is unable to fall below the serum osmolarity, infusion of normal saline paradoxically results in more free water resorption by increasing the hypertonic urine output. Volume of free water resorbed (or lost) L

-

([

urine osmolarity

I

.

plasma osmolarity

]

-

urine 1) x output L70

When severe SIADH occurs, hypertonic saline is initiated to raise the serum sodium to 120 mg/L. Further elevation of the serum sodium may be achieved with free water restriction and loop diuretic use. Serum sodium may be altered safely at 0.5 mg/L/h to avoid cerebral edema if lowering the sodium and cerebral myelinolysis if raising the sodium. SIADH results from central nervous system disorders (stroke, hemorrhage, trauma), tumors (usually small cell of lung), medications (serotonin uptake inhibitors, cyclophosphamide, haloperidol, thioridazine, DDAVP), thoracic and

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abdominal surgery, and pneumonitis. Typically the patient shows hyponatremia, hypo-osmolarity, urine sodium greater than 40 mg/L, urine osmolarity greater than 100 mOsm/kg, low serum uric acid levels, normal thyroid function, and normal serum electrolytes. SIADH must be differentiated from hyponatremia secondary to vascular volume contraction (relative and absolute), adrenal insufficiency, hypothyroidism, plasma hyperosmolarity (hyperglycemia, mannitol, urea), hyperlipidemia, and hyperproteinemia. Refractory hyperkalemia occurs in HARI when sustained tissue injury occurs, as with an ischemic limb or bowel. This condition frequently is associated with metabolic lactic acidosis and rhabdomyolysis and necessitates the initiation of dialysis. Less severe hyperkalemia may be managed with sodium/potassium exchange resin, insulin plus glucose, aerosolized P2-adrenergic agonists, and calcium g l u c ~ n a t e .The ~ ~ exchange resin functions only in the bowel lumen; impaired peristaltic motion delays the onset of action if taken orally. Rectal infusions of the resin solution begin to act immediately and gradually lower the serum potassium by 0.5 mEq/L per 15 g instilled but are associated with 1% incidence of bowel necrosis when infused postsurgically with sorbitol. Because of the resin’s slow but prolonged rate of potassium removal, therapy should stop when the serum potassium approaches 5 mEq/L. Insulin and P-agonists rapidly shift the potassium intracellularly through sodium/potassium ATPase stimulation but do not remove the potassium from the body. Insulin may be given as a 10-unit intravenous bolus with 50 mL of 50% dextrose in water followed by a continuous glucose infusion to prevent hypoglycemia. P,-Adrenergic agonists may be given as a nebulizer containing 10 to 20 mg in 4 mL of saline over 10 minutes or as an intravenous infusion containing 0.5 mg. Calcium gluconate inhibits the membrane depolarization changes associated with the hyperkalemia, reducing the incidence of cardiac arrhythmias. Calcium gluconate may be infused as 10 mL of a 10% solution over 5 minutes. Hypokalemia occurs in HARI in the high-output recovery phase when the glomerular filtrate is abnormally processed by the injured tubules and absent urea concentration gradient. Water and electrolytes are lost rapidly and must be repleted rapidly to maintain homeostasis. Potassium when repleted through a functional gut by oral dosing avoids the limitations of dosing and hazards associated with intravenous repletion. Oral potassium chloride can be given as 40 mEq every 4 to 6 hours until the serum potassium is greater than 3.5 mEq/ L. If deficient, magnesium should be replaced as intravenous magnesium sulfate (1 to 4 g during several hours) to prevent further urinary potassium loss. Frequent analysis is required to prevent overdosing of the potassium and magne~ium.’~ Azotemia does not correlate with the degree of renal failure. A BUN-tocreatinine ratio greater than 20:l can be present with a hypercatabolic state (sepsis, steroid administration), a gastrointestinal bleed, intravascular volume contraction, or excessive nitrogen in the feedings. Azotemia is not an absolute indication for dialysis and may represent an acute nonrenal event that should be sought and corrected. Phosphorus derangements can be lethal if uncorrected. Severe hypophosphatemia induces rhabdomyolysis and cardiac and respiratory failure through depletion of intracellular adenosine triphosphate (ATP). Phosphorus can be repleted orally with Fleet Phospho-Soda, which contains 4.25 mmol of inorganic phosphorus per milliliter or milk; rectally with Fleet Phospho-Soda; or intravenously. Hyperphosphatemia associated with a high calcium x phosphorus product (>56) increases the risk for calciphylaxis (soft tissue deposition of calcium), organ failure, and tissue necrosis. Hyperphosphatemia requires the use of phosphorus binders (aluminum hydroxide, calcium acetate, calcium carbonate, or

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sevelamer), which should be taken with meals or mixed with the gastric tube feedings to decrease phosphate absorption. Phosphorus is removed with dialysis, but dialysis cannot correct hyperphosphatemia. Hyperuricemia-induced uric acid crystallization within the tubules requires the alkalinization of the urine to a pH greater than 6.5 to inhibit crystal formation. This alkalinization may be achieved by acetazolamide, citrate, acetate, or bicarbonate therapy. Hypoalbuminemia falsely lowers serum calcium. Measured calcium levels should be corrected for hypoalbuminemia to avoid errant calcium administration. Corrected serum [Ca] = serum [Ca] + ([4

-

serum (Ca)] X 0.8)

Acute hypocalcemia can cause tetany and hypotension, whereas hypercalcemia may alter the mental status and promote calciphylaxis. Hypercalcemia can be reduced by loop diuretics, volume expansion with normal saline, and bisphosphonates. Hypocalcemia can be corrected with intravenous calcium gluconate. Elevation in CPK, SGOT, and LDH may indicate rhabdomyolysis, ischemic bowel, or myocardium. If rhabdomyolysis is present, the urine should be alkalinized as in hyperuricemia to inhibit protein precipitation within the tubules. Mannitol decreases the tubular damage through free radical scavaging and promotion of increased urine flows, which limits tubular o b s t r ~ c t i o n 92 .~~, Bicarbonate levels are estimated in blood gases; serum bicarbonate measurements are preferred in determining acid-base disturbances and determining if the blood gas result is consistent with the following formula:

Pco,) + HCO, The hydrogen ion concentration equals 40 nmol/L with a pH of 7.4. For each change of 0.1 in the pH, the hydrogen ion alters by a factor of 1.25 (increasing with acidosis, decreasing with alkalosis). If the pH equals 7.2, the hydrogen ion is approximately 62.5 (40 x 1.25 x 1.25); if the pH equals 7.6, the hydrogen ion equals approximately 25.6 (40 + 1.25 + 1.25).Errant blood gases can occur with excessive heparin (an organic acid), unchilled or uncapped specimens, syringes containing air bubbles, leukocytosis, and values not corrected for the patient's body temperature. Concentration of hydrogen ion

=

(24

X

TREATMENT After reversing the hypoperfusion, removing the nephrotoxic agents, and correcting the metabolic and electrolyte derangements, little therapy other than time may be offered to treat The historical therapies (eg., dopamine, furosemide, and mannitol) have not proved effective in clinical trials to prevent or treat HAM' other than the use of mannitol in treating rhabdomyol ~ s i s 22,46, . ~ , 55,78 Although in theory use of these therapies has many advantages, their observed effect is to increase urine output, which in and of itself may simplify patient management, without reversing or improving the renal injury. Other agents have faired no better.3,26 The early success noted with atrial natriuretic peptide was not sustained in a larger randomized trial, when atrial natriuretic peptide failed to improve dialysis-free survival in critically ill patients with ATN.3 Clinical trials continue with new agents, including nitric oxide inhibitors, melanocyte-stimulating hormone analogues, and dopamine ana42, 63

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Until such time that HARI, including ATN, can be treated effectively, dialysis remains an essential tool in patient management. Indications for dialysis include (1)hyperkalemia, metabolic acidosis, or volume expansion that is uncontrollable; (2) symptoms of uremia, including serositis (particularly pericarditis), encephalopathy, or anorexia; and (3) platelet dysfunction inducing a bleeding diathesis. Azotemia is a poor indicator of renal failure because the BUN may be misleadingly low in malnourished states or high with hypercatabolic states, hyperalimentation, and gastrointestinal bleed. Controversies about dialysis membrane selection (degree of biocompatibility), mode of dialysis (continuous or intermittent, peritoneal or hemodialysis), frequency of dialysis (daily or intermittent), and degree of ultrafiltration desired with dialysis persist.18, 24! 35,37,43, 45, 67,82 Of the surviving patients requiring dialysis, 88% eventually recover sufficient renal function to discontinue dialysis.80 SUMMARY

The poor clinical outcomes associated with postoperative HAM necessitate increased vigilance for HARI detection and intervention to minimize the progression to dialysis dependency. Patient survival significantly worsens if HARI requires the initiation of dialysis. Postoperative changes, including intravascular volume expansion, SIRS, and reduced lean body mass, frequently confound the detection of HARI. Serum creatinine levels frequently do not reflect the decreased renal function because creatinine production rate is decreased with reduced lean body mass, and the serum creatinine concentration is reduced by increased intravascular volume expansion and increased volume of distribution associated with anasarca. Additional indices of renal function must be used postoperatively, including urine output, net volume status, urinalysis with microscopic examination of the spun pellet, and corrected estimations of creatinine clearance. Few therapeutic interventions currently exist to reverse HARI other than optimization of renal perfusion and limitation of nephrotoxin exposure. Dialysis remains a cornerstone of maintenance therapy for refractory and severe HARI. Selection of dialysis modality continues to be based on modality availability and patient stability. References 1. Agus ZS: Diagnostic approach to hypocalcemia. In Wellsley, MA, UpToDate, Release 8.2 2. Alderson P, Schierhout G, Roberts I, et al: Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev CD000567, 2000 3. Allgren RL, Marbury TC, Rahman SN, et al: Anaritide in acute tubular necrosis. Auriculin Anaritide Acute Renal Failure Study Group. N Engl J Med 336:828-834,1997 4. Anderson RJ, OBrien M, MaWhinney S, et al: Mild renal failure is associated with adverse outcome after cardiac valve surgery. Am J Kidney Dis 35:1127-1134, 2000 5. Anderson RJ, O’Brien M, MaWhinney S, et al: Renal failure predisposes patients to adverse outcome after coronary artery bypass surgery. VA Cooperative Study #5. Kidney Int 55:1057-1062, 1999 6. Badr KF: Sepsis-associated renal vasoconstriction: Potential targets for future therapy. Am J Kidney Dis 20:207-213, 1992 7. Baldwin L, Henderson A, Hickman P: Effect of postoperative low-dose dopamine on renal function after elective major vascular surgery. Ann Intern Med 120744-747, 1994

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8. Baliga R, Ueda N, Walker PD, et al: Oxidant mechanisms in toxic acute renal failure. Drug Metab Rev 31:971-997,1999 9. Barretti P, Soares VA: Acute renal failure: Clinical outcome and causes of death. Ren Fail 19:253-257, 1997 10. Brezis M, Rosen S Hypoxia of the renal medulla-its implications for disease. N Engl J Med 332:647455, 1995 11. Carmines PK, Fleming J T Control of the renal microvasculature by vasoactive peptides. FASEB J 4~3300-3309,1990 12. Chertow GM, Christiansen CL, Cleary PD, et al: Prognostic stratification in critically ill patients with acute renal failure requiring dialysis. Arch Intern Med 155:15051511, 1995 13. Chertow GM, Lazarus JM, Christiansen CL, et al: Preoperative renal risk stratification. Circulation 952378484, 1997 14. Chertow GM, Lazarus JM, Paganini EP, et al: Predictors of mortality and the provision of dialysis in patients with acute tubular necrosis. The Auriculin Anaritide Acute Renal Failure Study Group. J Am SOCNephrol9:692498, 1998 15. Chertow GM, Levy EM, Elliott M, et al: Independent association between acute renal failure and mortality following cardiac surgery. Am J Med 104:343-348, 1998 16. Chiao H, Kohda Y, McLeroy P, et al: Alpha-melanocyte-stimulating hormone inhibits renal injury in the absence of neutrophils. Kidney Int 54:765-774, 1998 17. Choudhury D, Ahmed 2: Drug-induced nephrotoxicity. Med Clin North Am 81:705717, 1997 18. Clark WR, Hamburger RJ, Lysaght MJ: Effect of membrane composition and structure on solute removal and biocompatibility in hemodialysis. Kidney Int 56:2005-2015,1999 19. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:3141, 1976 20. Conlon PJ, Stafford-Smith M, White WD, et al: Acute renal failure following cardiac surgery. Nephrol Dial Transplant 14:1158-1162, 1999 21. Davila-Roman VG, Murphy SF, Nickerson NJ, et al: Atherosclerosis of the ascending aorta is an independent predictor of long-term neurologic events and mortality. J Am Coll Cardiol 33:1308-1316, 1999 22. Dishart MK, Kellum JA: An evaluation of pharmacological strategies for the prevention and treatment of acute renal failure. Drugs 59:79-91, 2000 23. Fortescue EB, Bates DW, Chertow GM: Predicting acute renal failure after coronary bypass surgery: Cross-validation of two risk-stratification algorithms. Kidney Int 572594-2602, 2000 24. Friedman AN, Jaber BL: Dialysis adequacy in patients with acute renal failure. Curr Opin Nephrol Hypertens 8:695-700, 1999 25. Frost L, Pedersen RS, Lund 0, et al: Prognosis and risk factors in acute, dialysisrequiring renal failure after open-heart surgery. Scand J Thorac Cardiovasc Surg 25:161-166, 1991 26. Fuchs S, Yaffe R, Beeri R, et al: Failure of insulin-like growth factor 1 to improve radiocontrast nephropathy. Exp Nephrol 5538-94, 1997 27. Godet G, Fleron MH, Vicaut E, et al: Risk factors for acute postoperative renal failure in thoracic or thoracoabdominal aortic surgery: A prospective study. Anesth Analg 85~1227-1232,1997 28. Guerin C, Girard R, Selli JM, et al: Initial versus delayed acute renal failure in the intensive care unit: A multicenter prospective epidemiological study. Rhone-Alpes Area Study Group on Acute Renal Failure. Am J Respir Crit Care Med 161(3 pt 1):872-879, 2000 29. Heyman SN, Darmon D, Goldfarb M, et al: Endotoxin-induced renal failure: I. A role for altered renal microcirculation. Exp Nephrol 8:26&274, 2000 30. Heyman SN, Reichman J, Brezis M: Pathophysiology of radiocontrast nephropathy: A role for medullary hypoxia. Invest Radio1 34:685-691, 1999 31. Heyman SN, Rosen S, Darmon D, et al: Endotoxin-induced renal failure: 11. A role for tubular hypoxic damage. Exp Nephrol 8:275-282, 2000 32. Holt S, Moore K: Pathogenesis of renal failure in rhabdomyolysis: The role of myoglobin. Exp Nephrol 8:72-76, 2000

33. Hou SH, Bushinsky DA, Wish JB, et a1 Hospital-acquired renal insufficiency: A prospective study. Am J Med 74:243-248, 1983 34. Ikenaga H, Fallet RW, Carmines PK: Contribution of tubuloglomerular feedback to renal arteriolar angiotensin I1 responsiveness. Kidney Int 49:34-39, 1996 35. Jaber BL, Cendoroglo M, Balakrishnan VS, et al: Impact of dialyzer membrane selection on cellular responses in acute renal failure: A crossover study. Kidney Int 5721072116, 2000 36. Jaffe R, Ariel I, Beeri R, et al: Frequent apoptosis in human kidneys after acute renal hypoperfusion. Exp Nephrol 5:399403, 1997 37. Karsou SA, Jaber BL, Pereira BJ: Impact of intermittent hemodialysis variables on clinical outcomes in acute renal failure. Am J Kidney Dis 35:980-991, 2000 38. Khan RZ, Badr KF: Endotoxin and renal function: Perspectives to the understanding of septic acute renal failure and toxic shock. Nephrol Dial Transplant 14:814-818, 1999 39. Klahr 5: Obstructive nephropathy. Intern Med 39:355-361, 2000 40. Klausner JM, Paterson IS, Goldman G, et al: Postischemic renal injury is mediated by neutrophils and leukotrienes. Am J Physiol256(5 pt 2):F794-802, 1989 41. Koch T Origin and mediators involved in sepsis and the systemic inflammatory response syndrome. Kidney Int Suppl 64:S6&69, 1998 42. Kohda Y, Chiao H, Star RA: Alpha-melanocyte-stimulating hormone and acute renal failure. Curr Opin Nephrol Hypertens 7413-417, 1998 43. Kresse 5, Schlee H, Deuber HJ, et al: Influence of renal replacement therapy on outcome of patients with acute renal failure. Kidney Int 56(suppl 72):575-78, 1999 44. Kribben A, Edelstein CL, Schrier RW Pathophysiology of acute renal failure. J Nephrol 12(Suppl 2):S142-151, 1999 45. Kumar VA, Craig M, Depner TA, et al: Extended daily dialysis: A new approach to renal replacement for acute renal failure in the intensive care unit. Am J Kidney Dis 36994-300, 2000 46. Lassnigg A, Dormer E, Grubhofer G, et al: Lack of renoprotective effects of dopamine and furosemide during cardiac surgery. J Am SOCNephrol 11:97-104, 2000 47. Levy EM, Viscoli CM, Horwitz RI: The effect of acute renal failure on mortality: A cohort analysis. JAMA 275:1489-1494, 1996 48. Liano F, Pascual J: Epidemiology of acute renal failure: A prospective, multicenter, community-based study. Madrid Acute Renal Failure Study Group. Kidney Int 50:811818, 1996 49. Liano F, Pascual J: Outcomes in acute renal failure. Semin Nephrol 18:541-550, 1998 50. Linas SL, Whittenburg D, Parsons PE, et al: Ischemia increases neutrophil retention and worsens acute renal failure: Role of oxygen metabolites and ICAM 1. Kidney Int 48:1584-1591, 1995 51. Linas SL, Whittenburg D, Parsons PE, et al: Mild renal ischemia activates primed neutrophils to cause acute renal failure. Kidney Int 42:610-616, 1992 52. Llanos A, Cieza J, Bernard0 J, et al: Effect of salt supplementation on amphotericin B nephrotoxicity. Kidney Int 40:302-308, 1991 53. Luke RG, Boyle JA: Renal effects of amphotericin B lipid complex. Am J Kidney Dis 31:780-785, 1998 54. Mangano CM, Diamondstone LS, Ramsay JG, et al: Renal dysfunction after myocardial revascularization: Risk factors, adverse outcomes, and hospital resource utilization. The Multicenter Study of Perioperative Ischemia Research Group. Ann Intern Med 128:194-203, 1998 55. Marik PE, Iglesias J: Low-dose dopamine does not prevent acute renal failure in patients with septic shock and oliguria. NORASEPT I1 Study Investigators. Am J Med 107:387-390, 1999 56. Mattson DL, Lu S, Roman RJ, et al: Relationship between renal perfusion pressure and blood flow in different regions of the kidney. Am J Physiol264(3 pt 2):R578-583, 1993 57. McCarthy J T Prognosis of patients with acute renal failure in the intensive-care unit: A tale of two eras. Mayo Clin Proc 71:117-126, 1996 58. McCullough PA, Wolyn R, Rocher LL, et al: Acute renal failure after coronary intervention: Incidence, risk factors, and relationship to mortality. Am J Med 103:368-375, 1997

POSTOPERATIVE RENAL INSUFFICIENCY

1253

59. Moran SM, Myers BD: Pathophysiology of protracted acute renal failure in man. J Clin Invest 76:1440-1448, 1985 60. Murphy SW, Barrett BJ, Parfrey P S Contrast nephropathy. J Am SOCNephrol 11:177182, 2000 61. Navar LG, Inscho EW, Harrison-Bernard LM, et al: Paracrine interactions regulating renal microcirculatory function. Clin Invest 72:682484, 1994 62. Obialo CI, Okonofua EC, Tayade AS, et al: Epidemiology of de novo acute renal failure in hospitalized African Americans: Comparing community-acquired vs hospital-acquired disease. Arch Intem Med 160:1309-1313, 2000 63. Pararajasingam R, Weight SC, Bell PR, et al: Prevention of renal impairment following aortic cross-clamping by manipulation of the endogenous renal nitric oxide response. Eur J Vasc Endovasc Surg 19:396-399, 2000 64. Prins JM, Buller HR, Kuijper EJ, et al: Once versus thrice daily gentamicin in patients with serious infections. Lancet 341:335339, 1993 65. Raij L: Nitric oxide and the kidney. Circulation 87(suppl 2):V26-29, 1993 66. Raij L, Baylis C: Glomerular actions of nitric oxide. Kidney Int 4820-32, 1995 67. Ronco C, Bellomo R, Home1 P, et a1 Effects of different doses in continuous venovenous haemofiltration on outcomes of acute renal failure: A prospective randomised trial. Lancet 356:26-30, 2000 68. Rose B D Clinical Physiology of Acid-Base and Electrolyte Disorders, ed 4. New York, McGraw-Hill, pp 720-723, 1994 69. Rose BD: Pathophysiology of Renal Disease, ed 2. New York, McGraw-Hill, 1987, PP 68-69 70. Rose B D Renal water excretion and reabsorption. In Wellsley, MA UpToDate, Release 8.2, 2000 71. Rose BD Treatment of hyperkalemia. In Wellsley, MA UpToDate,.Release 8.2 72. Rose BD: Treatment of hypokalemia. In Wellsley, MA UpToDate, Release 8.2 73. Rudnick MR, Bems JS, Cohen RM, et al: Contrast media-associated nephrotoxicity. Semin Nephrol 17:15-26, 1997 74. Rudnick MR, Bems JS, Cohen Rh4, et al: Nephrotoxic risks of renal angiography: Contrast media-associated nephrotoxicity and atheroembolism-a critical review. Am J Kidney Dis 24:713-727, 1994 75. Safirstein R, Andrade L, Vieira JM, et ak Acetylcysteine and nephrotoxic effects of radiographic contrast agents-a new use for an old drug. N Engl J Med 343:21&212,2000 76. Sawaya BP, Briggs JP, Schnermann J: Amphotericin B nephrotoxicity: The adverse consequences of altered membrane properties. J Am SOCNephrol 6:154-164, 1995 77. Sheridan AM, Bonventre J V Cell biology and molecular mechanisms of injury in ischemic acute renal failure. Curr Opin Nephrol Hypertens 9:427-434, 2000 78. Sirivella S, Gielchinsky I, Parsonnet V Mannitol, furosemide, and dopamine infusion in postoperative renal failure complicating cardiac surgery. Ann Thorac Surg 69:501506, 2000 79. Solomon R, Werner C, Mann D, et al: Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med 331:1416-1420, 1994 80. Spumey RF, Fulkerson WJ, Schwab SJ: Acute renal failure in critically ill patients: Prognosis for recovery of kidney function after prolonged dialysis support. Crit Care Med 19:8-11, 1991 81. Star RA: Treatment of acute renal failure. Kidney Int 54:1817-1831, 1998 82. Star RA, Kimmel P L Biocompatibility and acute renal failure. Lancet 355:314, 2000 83. Steele T H Hyperuricemic nephropathies. Nephron 8l(suppl 1):4549, 1991 84. Steinhausen M, Endlich K, Wiegman DL: Glomerular blood flow. Kidney Int 38:769784, 1990 85. Steinkamp RC, Cohen NL, Gaffey WR, et al: Measures of body fat and related factors in normal adults: 11. A simple clinical method to estimate body fat and lean body mass. J Chronic Dis 18:1291-1307, 1965 86. Task Force of the American College of Critical Care Medicine, Society of Critical Care Medicine: Practice parameters for hemodynamic support of sepsis in adult patients in sepsis. Crit Care Med 27:639-660, 1999

1254

EDWARDS

87. Thadhani RI, Camargo CA Jr, Xavier RJ, et al: Atheroembolic renal failure after invasive procedures: Natural history based on 52 histologically proven cases. Medicine (Baltimore)74:350-358, 1995 88. Toto RD, Anderson SA, Brown-Cartwright D, et al: Effects of acute and chronic dosing of NSAIDs in patients with renal insufficiency. Kidney Int 30:760-768, 1986 89. Whelton A, Stout RL, Spilman PS, et a1 Renal effects of ibuprofen, piroxicam, and sulindac in patients with asymptomatic renal failure: A prospective, randomized, crossover comparison. Ann Intern Med 112:568-576, 1990 90. Willinger CC, Schramek H, Pfaller K, et al: Tissue distribution of neutrophils in postischemic acute renal failure. Virchows Arch B Cell Pathol Incl Mol Pathol 62937243, 1992 91. Young EW, Diab A, Kirsh MM: Intravenous diltiazem and acute renal failure after cardiac operations. Ann Thorac Surg 65:1316-1319, 1998 92. Zager RA: Rhabdomyolysis and myohemoglobinuric acute renal failure. Kidney Int 49:314-326, 1996 93. Zanardo G, Michielon P, Paccagnella A, et a1 Acute renal failure in the patient undergoing cardiac operation: Prevalence, mortality rate, and main risk factors. J Thorac Cardiovasc Surg 1071489-1495, 1994

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