CHAPTER 2 NICHOLAS L. TILNEY, M.D. JULIAN L. SEIFTER, M.D. ROBERT J. RIZZO, M.D.

Renal Dysfunction Perioperative Management of the Patient with Renal Failure

Renal failure is defined as a general loss of kidney function with (1) alterations in volume regulation and ionic composition of body fluids and (2) inadequate excretion of metabolic wastes. Clinical manifestations vary depending on the extent and rate of functional decline: patients with acutely deteriorating kidneys become symptomatic earlier than those who have adapted to progressive chronic renal failure (CRF).1 The three stages of renal dysfunction are diminished renal reserve (creatinine clearance > 30 ml/min), renal failure (creatinine clearance 10 to 30 ml/min), and uremia (creatinine clearance < 10 ml/min).2 Patients with diminished renal reserve are typically asymptomatic. With the onset and progression of renal failure, the following may occur: hypertension, anemia, carbohydrate intolerance, hyperuricemia, hypertriglyceridemia, acidosis, hyperphosphatemia, hypocalcemia, and hyponatremia. (Hyperkalemia occurs infrequently at this stage unless myonecrosis or hemolysis is present or the patient receives a depolarizing muscle relaxant during operation.) Care must be taken in patients with worsening renal failure to prevent or treat acute surgical stressesfor example, hypotension, infection, or use of nephrotoxic agentsthat may further diminish renal function. Finally, as will be described, virtually every major organ system is adversely affected in patients with uremia, who often present with malaise, weakness, nausea, vomiting, weight loss, and edema.3 When evaluating a surgical patient with renal compromise or impending or established renal failure, the surgeon should first obtain answers to the following questions: 1. What are the extent and rate of progression of renal failure? 2. Is renal failure acute or chronic? If acute, to what degree is it reversible? What contributing factors are present, if any, and how can they be corrected? 3. What steps must be taken to prevent further renal injury? 4. What steps must be taken to minimize and manage perioperative complications?

Extent and Rate of Progression of Renal Failure

The seriousness of the patients renal dysfunction may not be apparent from symptoms or physical examination. Acute renal failure (ARF) rarely produces the physical findings of severe chronic uremia, so its extent is best ascertained by laboratory evaluation. Several methods are used to assess glomerular and tubular function. The glomerular filtration rate (GFR) is the most practical measure of renal function. GFR may be estimated clinically by measuring blood urea nitrogen (BUN), the serum creatinine concentration, or creatinine clearance. BUN depends on several variables, including GFR, the rate of urea production, and the rate of tubular reabsorption of urea. Urea production is increased by extrarenal factors, such as blood in the GI tract, a high-protein diet or intravenous nutrition, and administration of glucocorticoid hormones, which stimulate gluconeogenesis and protein catabolism.4 Furthermore, tubular reabsorption of urea is increased by low urine output and volume depletion. An elevated BUN should not be equated with a low GFR. The serum creatinine level is affected by GFR as well as by the rate of production and tubular secretion of creatinine.5 In contrast to BUN levels, the rate of creatinine production is relatively constant in an individual because it depends primarily on products of muscle breakdown and only minimally on increased protein ingestion. Thus, a muscular male with renal dysfunction may have high serum creatinine values, whereas a small female with severe renal failure may have only minor elevations. Creatinine production also decreases with age (by 1 ml/min every year after 35 years of age6) secondary to diminished muscle mass and in proportion to diminished GFR associated with normal aging; therefore, normal creatinine concentrations in elderly individuals do not reflect the same GFR as they would in younger patients. Because the rate of tubular secretion in normal kidneys is also relatively constant, it does not interfere with the inverse correlation between the GFR and serum creatinine concentrations. GFR has been estimated for males by the following formula (for females, the calculated value is decreased by 15 percent7): GFR (ml/min) = (140 - age) weight (kg)/72 serum creatinine This formula assumes a stable creatinine concentration and thus should not be used in the setting of ARF, where the creatinine concentration is rising. On the other hand, estimation of the GFR by measuring creatinine clearance [see II Care in the ICU, 6 Acute Renal Failure] does not require a stable creatinine concentration or correction for age, but it does require accurate collection of urine. (Normal values for men are from 90 to 130 ml/min; for women, normal values are from 80 to 125 ml/min.)8 Because creatinine is secreted preferentially by the renal tubules in renal failure, estimates of the GFR based on creatinine clearance can be too high by as much as 20 percent in normal individuals and by 50 percent when the GFR is reduced to 10 percent of normal.9 In addition, certain conditions increase the serum creatinine concentration and decrease creatinine clearance without altering GFR.10 For example, ketones11 and some cephalosporins12 produce spuriously elevated values for serum creatinine by interfering with its assay, and cimetidine13 and trimethoprim-sulfamethoxazole14 inhibit the tubular secretion of creatinine. Several isotopic methods, including measurement of iodine-125iothalamate clearance, are available for precise measurement of GFR.

Classification of Renal Failure and Correction of Reversible Factors

ACUTE RENAL FAILURE Potentially reversible acute renal failure may be categorized as prerenal, postrenal, or intrarenal in origin [see Table 1].15 Prerenal factors decrease renal perfusion; they include volume depletion, cardiac failure, systemic vasodilatation, and renovascular obstructive disease. The patient typically presents with oliguria, tachycardia, and hypotension (except for the patient with renovascular disease, who is typically hypertensive). The urinary sediment is unremarkable, and urine osmolality is high. An isolated urine sample with a sodium concentration of less than 10 mEq/L indicates good tubular function and suggests a prerenal mechanism for the renal dysfunction. The fractional excretion of sodium (FENa) provides a good assessment of prerenal states; it is often low (less than one percent) because of sodium and water conservation by the kidneys [see II Care in the ICU, 6 Acute Renal Failure].16 A spot urine sample rather than a timed collection may be employed to determine FENa. Measurements of pulmonary arterial wedge pressure, cardiac output, and systemic vascular resistance also assist in the diagnosis of ARF17 and indicate the direction of subsequent therapy. Correction of prerenal conditions should be aggressive to prevent ischemic renal injury. A special circumstance occurs in the setting of volume depletion or renal arterial stenosis when angiotensin-converting enzyme (ACE) inhibitors or angiotensin II antagonists are used. Reversible oliguria and azotemia develop because of a fall in glomerular pressure that follows dilatation of the efferent arterioles. This development reflects failure of normal autoregulatory function; volume repletion and discontinuance of the drug are required for resolution. Postrenal factors are typically caused by mechanical complications and are usually secondary to urinary tract obstruction or extravasation. Bladder catheterization will relieve or rule out urethral or bladder outlet obstruction. Ultrasonography is most helpful in documenting upper urinary tract obstruction, which may be relieved acutely by retrograde cystoscopy or percutaneous means. Urinary extravasation, as in a patient with a ruptured bladder, is associated with hematuria and may be assessed by means of intravenous or retrograde pyelography or CT scans. It should be noted that the radiopaque dyes used for contrast studies are not without potential hazards. Intravenous urography contrast agents may cause renal failure in patients with multiple myeloma or diabetes mellitus as well as in those with other renal diseases. If ARF persists even after prerenal and postrenal factors have been excluded or corrected, the presence of intrarenal disease must be considered [see Table 1]. Differentiation between acute and chronic causes of intrarenal failure may require a thorough clinical evaluation [see Table 2].3 The causes of acute intrarenal failure may be categorized according to the site of the primary parenchymal abnormalitytubules, glomeruli, vessels, interstitium, papillae, or cortex.15 1. The most common cause of ARF in surgical patients is acute tubular necrosis (ATN) from systemic infection, ischemia, or exposure to nephrotoxins18; patients

with ATN are rarely hypertensive. The urine sediment classically shows pigmented, granular casts; heme pigment may reflect ATN from hemoglobinuria caused by a transfusion reaction or from myoglobinuria caused by a crush injury or muscle ischemia.19 In rhabdomyolysis, serum creatine phosphokinase levels are elevated.20 Nonsteroidal anti-inflammatory agents are a common cause of renal failure, particularly in dehydrated patients. 2. Acute glomerulonephritis often follows systemic infection or collagen vascular disease and is associated with hematuria, proteinuria, hypocomplementemia, and hypertension. 3. Vasculitides involving glomeruli present in much the same way as acute glomerulonephritis, but serum complement levels are normal. Other signs of systemic diseases may be present. A test for antineutrophil cytoplasmic antibodies should be performed. 4. The urine sediment in interstitial nephritis from medication allergy or pyelonephritis may contain eosinophils and mononuclear leukocytes. 5. Acute papillary necrosis may be precipitated by analgesic abuse, diabetes, or urinary tract infection or obstruction; sloughed papillae may lodge in the ureter, creating painful obstruction.21 6. Acute cortical necrosis is particularly likely to occur in an obstetric patient as a consequence of profound shock and disseminated intravascular coagulation after a complicated labor and delivery.22 7. Atheroembolic disease is an important cause of subacute renal failure in patients who have undergone vascular procedures or have received anticoagulants. Most patients with ARF are oliguric, producing urine volumes of less than 400 ml/day, although nonoliguric (high-output) renal failure is not uncommon and is characteristic of aminoglycoside-related ATN.23 Complete anuria suggests bilateral renal artery occlusion, obstructive uropathy, cortical necrosis, or rapidly progressive glomerulonephritis. Severe disease or obstruction of a single kidney and inadvertent ureteral ligation during a difficult retroperitoneal surgical dissection should be ruled out as causes of acute anuria. CHRONIC RENAL FAILURE Irreversible, progressive CRF has many possible causes, including glomerulonephritis, hypertensive nephrosclerosis, diabetic nephropathy, tubulointerstitial disease, obstructive uropathy, chronic pyelonephritis, polycystic kidney disease, and congenital hypoplasia.24 Consequently, the differential diagnosis requires a complete clinical evaluation [see Table 2].3 The history should record symptoms of urinary tract dysfunction, systemic diseases that could affect the kidneys, exposure to nephrotoxins or infectious agents, and family history of renal disease. The physical exam should evaluate blood pressure, the retinas, the cardiovascular system, and the kidneysincluding the presence or absence of renal artery bruits. Urine volume is not usually helpful in evaluating CRF. Many patients continue to excrete urine, at least until dialysis is begun. Broad casts that are granular and waxy are often seen in the urine sediment, reflecting compensatory hypertrophy of surviving nephrons.

Prevention of Further Renal Injury

Prevention of further acute renal injury is a priority in the perioperative care of patients with CRF. Because prerenal and postrenal complications may be superimposed on the already compromised renal function of a previously asymptomatic patient, factors that may precipitate ARF must be eliminated. By reversing these factors, the surgeon may gain time before the patients kidneys fail completely and dialysis becomes necessary. In an acute situation, the patient with renal failure needs close monitoring of daily weight and input/output measurements and hourly urine volume measurements, via an indwelling bladder catheter. An output of at least 0.5 ml/kg/hr should be maintained. Renal perfusion should be optimized by correcting volume deficits and maintaining adequate cardiac output. Unless it is controlled, severe hypertension may worsen preexisting renal failure; overzealous use of antihypertensive medication may also be deleterious, particularly in patients with renal vascular disease.23,25 Autoregulation of renal blood flow, which is an important self-protective mechanism in renal hypoperfusion, is mediated by renal prostaglandins and the renin-angiotensin system.26 Therefore, use of ACE inhibitors, for instance, may lead to further deterioration in renal function.27 As an alternative, low-dose dopamine1 to 3 mg/kg/min, as often used primarily in the cardiac surgical setting to prevent or attenuate ATNaugments renal blood flow with minimal influence on cardiac output.28 Dopamine should be administered with caution, however, because of the potential for arrhythmogenesis. It should be discontinued if the desired effect on urine flow rate is not obtained. If oliguria persists despite correction of prerenal and postrenal factors, an early trial of mannitol29 or a loop diuretic30 may initiate diuresis and convert oliguric to nonoliguric renal failure.23 In a volume-expanded patient who responds to diuretics, constant infusion of furosemide at a rate of 5 to 10 mg/hr may be attempted. Mannitol increases intravascular volume and stimulates an osmotic diuresis; loop diuretics alter tubular reabsorptive mechanisms and may diminish intravascular volume. Thus, mannitol may be used to increase urine flow when intravascular volume can tolerate the osmotic load, and diuretics are appropriate when intravascular volume is high (or when the patient has been receiving diuretics for an extended period and is dependent on them). Mannitol is especially useful in the setting of rhabdomyolysis. When renal blood flow may be compromised intraoperatively (e.g., during cardiac or aortic operation), prophylactic use of mannitol or furosemide has been suggested for inducing diuresis.31 However, in individuals whose intravascular volume is already low, diuretics may precipitate additional renal injury by causing further volume decreases. Several other perioperative precautions may prevent the worsening of compromised renal function.

1. Maintenance of an alkaline urine to diminish free heme pigment, which can be directly toxic to tubular cells (a urine pH > 6 usually discourages dissociation of heme from hemoglobin or myoglobin32). 2. Avoidance of nephrotoxins, with levels of potentially nephrotoxic agents (e.g., aminoglycoside antibiotics) carefully maintained in the nontoxic range. 3. Adequate hydration before33 and during surgical exposure to protect against the nephrotoxicity of contrast agents, aminoglycosides, antineoplastic agents, heme pigment, and hypercalcemia.34 4. Smaller doses of medications for elderly patients, whose GFR is lower given the

same serum creatinine level.35 5. Aggressive treatment of urinary tract infections and other factors that may cause deterioration of kidney function.34 6. Dietary protein restriction, which may slow the progression of renal failure by decreasing glomerular hyperfiltration.36,37 Perioperative Complications of Renal Failure

Both elective and emergency operations can be performed in patients with renal failure, provided that physiologic homeostasis is reestablished by judicious and aggressive perioperative dialysis.38,39 Dialysis particularly improves abnormalities of hemostasis that are caused largely by platelet dysfunction40; however, anticoagulants and antiplatelet medications that are used to maintain patency of arteriovenous fistulae may also contribute to excessive bleeding [see Discussion, Hematologic System, below]. In addition, heparin may still be active in patients undergoing operation soon after hemodialysis, and heparin rebound may occur because of the shorter action of protamine in relation to heparin.41 Abnormal prothrombin times are correctable by means of fresh frozen plasma or vitamin K, although such measures are usually unnecessary; in fact, angioaccess devices commonly thrombose after operation. Attention to intraoperative hemostasis and technique is also important for a successful outcome. For the uremic patient, whose host defense mechanisms are often altered or depressed,42 broad-spectrum antibiotics should be administered perioperatively to prevent infection.43 In patients receiving long-term steroid therapy, coverage with stress steroids may be required [see 9 Adrenal Insufficiency]. PREOPERATIVE CONSIDERATIONS IN ELECTIVE SURGERY Preoperative preparation of the stable renal failure patient for elective surgery is routine. For the unstable patient, however, preoperative dialysis should be performed to correct volume overload; requirements depend on the severity of renal failure and the potential extent of the operative procedure.1 Patients on long-term maintenance dialysis are usually dialyzed the day before and the day after operation, most often

against a low-potassium bath in anticipation of the increased intraoperative release of potassium that occurs secondary to muscle relaxant administration,44 tissue manipulation and breakdown, and blood transfusions.1 Patients in whom acute renal failure develops require earlier and more aggressive dialysis, particularly if they are hypercatabolic.3 Indications for dialysis before elective surgery are less clear in patients with compromised renal function who do not yet require maintenance dialysis.1 Conservative correction of fluid, electrolyte, and metabolic abnormalities usually suffices unless the condition necessitating operation could possibly increase catabolism and the potential for uremic complications. Asymptomatic patients who have a normal physical examination and reasonable blood chemistries usually do not require preoperative dialysis, but this prophylactic treatment should be employed at the first sign of need.

PREOPERATIVE CONSIDERATIONS IN EMERGENCY SURGERY If dialysis cannot be performed preoperatively, evidence of hyperkalemia should prompt aggressive treatment by other methods.1 Aggressive measures are especially necessary in hypercatabolic patients who have suffered trauma or severe burns, because these patients may experience a rapid elevation of serum potassium levels. In these patients, prompt initiation of aggressive dialysis may be lifesaving. In addition, administration of calcium may be necessary. Calcium (5 to 10 ml of 10 percent calcium chloride solution I.V. over a two-minute period) directly antagonizes the cardioplegic effects of hyperkalemia and allows time for instituting less dramatic measures: 1. Sodium bicarbonate (44 mEq I.V. over a five-minute period), glucose (250 ml of 20 percent dextrose), and insulin (10 to 25 U I.V. over a 30-minute period) all drive extracellular potassium into cells. 2. Sodium polystyrene sulfonate (Kayexalate), a potassium-binding ion exchange resin, can be given orally every three to four hours in doses of 25 to 50 g administered with 100 ml of 20 percent sorbitol to decrease constipation. (Given alone, Kayexalate can cause extensive colonic concretions that may be difficult to remove. For this reason, Kayexalate and aluminum-containing phosphate binders should not be given simultaneously.) Alternatively, 50 g of Kayexalate with 50 g of sorbitol in 200 ml of water can be given every one to two hours as a retention enema; however, this treatment should be avoided in the immediate postoperative period because of the potential hazard of colonic necrosis.45 Preoperative correction of other renal failure abnormalities can be done more leisurely. Excess intravascular fluid can be removed by plasmapheresis, packed red blood cells can be used to correct anemia and to establish some hematologic reserve, and sodium bicarbonate can be given to correct acidosis as well as to reduce hyperkalemia1provided that volume status will allow the sodium load. ANESTHETIC CONSIDERATIONS

Some neuromuscular blockers (particularly pancuronium and tubocurarine) can potentiate both acidosis and hyperkalemia, so their use is contraindicated in anesthetic management of the patient with renal failure. Gallamine is also contraindicated because it is excreted by the kidneys and is not dialyzable. Halothane has been used frequently and without complications as a general anesthetic in patients with compromised kidney function. Methoxyflurane is nephrotoxic and is no longer used.46 Because extracellular fluid volume may be decreased immediately after dialysis, hypotension that occurs after the induction of general anesthesia should be treated judiciously with colloid infusions.47 In addition, the hemodialysis access site must be protected; the involved upper arm should never be used for blood pressure measurement or I.V. infusion. Finally, patients on dialysis tend to be very anxious

and typically have undergone several operative procedures, so they may require general or regional anesthesia in situations in which local anesthesia is usually used. POSTOPERATIVE CONSIDERATIONS

All general principles of postoperative care apply to renal failure patients, with some exceptions1 and additional considerations. Fluids, electrolytes, and acid-base balance should be monitored closely. Because levels of toxins are increased and their clearance is decreased, uremic manifestations may worsen rapidly. The development of a pericardial rub or asterixis are two clues that uremia may be worsening. Prophylactic dialysis should be instituted early, before complications of advanced uremia develop.1 It is usually initiated the day after operation because heparinization is thought to be less dangerous than the bleeding disorders that result from a buildup of uremic toxins. To prevent hemorrhage at the operative dissection site (a potential but uncommon complication), fractional or regional heparinization is used during dialysis. Cardiac failure may occur secondary to ischemic coronary artery disease, a common problem in elderly patients on dialysis.48 Hypotension may result from abnormal receptor function49 or from volume depletion, sepsis, tamponade, or myocardial ischemia. Another cause of hypotension is the removal of vasopressive agents after bilateral nephrectomy.50 Wound healing, particularly healing of serosal surfaces,51 may be delayed in renal failure patients. An exteriorized bowel may not seal to the abdominal wall, intestinal anastomoses may leak, and intraperitoneal infection or perforation may occur in the absence of fever or in the presence of a diminished leukocyte response. The common bile duct may be very slow to heal; T tubes should be left in for several weeks. Thus, the surgeon should be slow to remove nasogastric tubes, some wound

drains, and skin or retention sutures but aggressive in treating suspected surgical complications.1 Protein malnutrition impairs both wound healing and immunity. Nutritional support with a diet high in carbohydrates and essential amino acids (or their alpha ketoanalogues) has been shown to limit protein catabolism without eliciting uremic symptoms.37 Endogenous urea may be used as a source of nonessential amino acids for protein synthesis.52 In undernourished patients, protein-containing nutrition should not be withheld to maintain a low BUN. It is better to provide nitrogen via amino acids and then to dialyze if necessary. Techniques for continuous renal replacement therapy are now available. These procedures (e.g., continuous arteriovenous and venovenous hemodialysis) are particularly useful in hypercatabolic patients in the ICU, who require large volumes of replacement fluid and intravenous nutrients. Drug dosages should be modified in renal failure patients. Consideration should be given to the absence of renal excretion and the possible dialytic removal of medications.53 Consideration should also be given to the potential systemic toxicity of medications. For example, meperidine should not be given to patients with renal failure because of the possibility of serious neurologic sequelae.

Discussion Pathophysiological Mechanisms in Renal Failure The pathophysiological mechanisms in renal failure include the progression of kidney disease and the effects of the uremic syndrome on metabolism and the major body systems. The general pathophysiology of renal failure has been thoroughly reviewed elsewhere [see II Care in the ICU, 6 Acute Renal Failure]. PROGRESSION OF KIDNEY DISEASE The progression of kidney disease is related to underlying aggravating factors, which may include dehydration, infection, obstruction, poorly controlled hypertension, and intrarenal deposition of crystals.54 In addition, the processes of adaptation may actually induce further damage. Progressive glomerulosclerosis may develop in the normal nephrons that remain after surgical removal of large amounts of kidney tissue.55 Both the rate of progression of injury and the magnitude of the glomerular hemodynamic changes in the remaining nephrons correlate directly with the proportion of tissue removed. Moderate dietary protein restriction may blunt adaptive hyperperfusion and hyperfiltration of the kidney remnants, thus limiting further glomerular injury.56 Treatment with ACE inhibitors, which decrease arteriolar and glomerular capillary pressures, also limits glomerular injury in patients with diabetic and nondiabetic renal disease.57 THE UREMIC SYNDROME The uremic syndrome is a clinical state resulting from loss of renal function;

regulation of body fluid volume and ionic composition, excretion of endogenous and exogenous metabolic wastes, and participation in endocrine metabolic processes are subsequently impaired. The resulting adverse effects hamper a range of intracellular and systemic body processes. The Effects of Uremia on Major Organ Systems Although severe uremia can impair the function of most major body systems, the most obvious and profound effects seldom occur today because of prompt and aggressive treatment. These effects must be considered, however, when patients with CRF are evaluated for surgery. Cardiovascular system Cardiovascular complications are responsible for more than half of the deaths in patients with chronic renal disease,58 primarily because of the frequency of severe atherosclerosis in this population.59,60 Cardiac hypertrophy is common, often occurring secondary to hypertension. Deposition of calcium and oxalate crystals may cause decreased myocardial function, leading to congestive

heart failure, arrhythmias, and, sometimes, sudden death.61 Potential myocardial toxins include phenol,62 parathyroid hormone, and cobalt.63 Large arteriovenous fistulas used for dialysis access may also contribute to high-output myocardial failure.64 Improvement of myocardial function with dialysis has been correlated specifically with increased plasma levels of calcium.65 Pericarditis may present as chest pain, fever, pericardial friction rub, or acute cardiovascular collapse; hypotension, jugular venous distention, and pulsus paradoxus may appear during dialysis secondary to hemopericardium and pericardial tamponade. Constrictive pericarditis also may result in circulatory instability.66 The etiology of uremic pericarditis is unknown, but it may be a response to uremic toxins, fluid overload, or infection.67 Pericardial effusion can be diagnosed by ultrasonography, tamponade by equalization of atrial pressures, and constrictive pericarditis by angiography and catheterization.68 Aggressive dialysis is indicated for uremic patients with pericarditis, and fluid balance must be carefully managed. Acute tamponade or enlarging effusions call for drainage, and constrictive pericarditis may necessitate pericardiectomy.69 Pulmonary system Abnormal pulmonary function in renal failure patients is associated with anemia, fluid overload, and the direct effects of toxins on pulmonary tissue.70 In the uremic lung, increased densities in the perihilar and inner lung zones form a butterfly appearance on x-ray.71 As pulmonary vascular permeability increases,72 pulmonary edema may occur with relatively low pulmonary arterial pressures.73,74 In uremic pneumonitis, membranes formed within alveoli and fibrin deposited in the interstitium eventually give rise to interstitial fibrosis.75 Restrictive pulmonary insufficiency may occur secondary to diffuse pulmonary calcification.76 Fibrinous pleuritis, which may also cause a restrictive defect, responds to dialysis and thoracentesis; only rarely is surgical decortication required.77 Gastrointestinal system Severe uremia may alter the entire GI tract from nasopharynx to rectum because urea diffuses into the lumen and is converted to

ammonia by bacterial urease. The result may be edema, hemorrhage, ulceration, or necrosis.78 Constipation is a common problem in dialysis patients, who are also being given phosphate binders; fecal impactions may become massive, and they occasionally cause serious problems. Patients on dialysis also have an increased propensity for the development of adynamic ileus and diverticulosis; perforation of diverticula is very common and is a possibility in any renal failure patient with abdominal discomfort.79,80 Prompt Gastrografin enema and removal of the involved segment with formation of an end colostomy have been very effective in reducing mortality from this condition81; CT scan of the colon has been helpful in diagnosing diverticulitis.82 Phosphate enemas should be avoided in patients with renal failure because of the risk of severe, acute hyperphosphoremia. The regenerative capacity of the liver is diminished in renal failure,83 and albumin and protein synthesis is decreased.84 The incidence of hepatitis C has been reported to be nearly 60 percent in hemodialysis patients, and hepatitis B incidence is increased as well.85 Peptic ulcer disease is not uncommon in patients with renal failure.

Magnesium-containing antacids may cause severe hypermagnesemia and should therefore be avoided. Cimetidine carries a significant risk of neurotoxicity in renal failure patients. In addition, such patients may experience gastroparesis, particularly if they are diabetic. Amyloidosis, which may develop in long-term dialysis patients, may involve the stomach and lead to GI bleeding. Endocrine system Metabolism of vitamin D is markedly altered by diminished renal conversion of 25-hydroxyvitamin D3 to its most active metabolite, 1,25-dihydroxyvitamin D3.86 The resulting decrease in intestinal calcium absorption contributes to the development of secondary hyperparathyroidism, as does hyperphosphatemia caused by decreased excretion of phosphate by the kidneys.87 Renal failure patients require calcium carbonate, both as a source of calcium and as a phosphate binder when given at mealtime. 1,25-dihydroxyvitamin D3 should be administered to hypocalcemic patients after the serum phosphate level has been normalized. This step will lower the parathyroid hormone level; an appropriate parathyroid hormone level is approximately two to three times the normal one. Severe metabolic acidosis should be corrected by giving bicarbonate to diminish bone loss. Hematologic system Anemia is common among renal failure patients, many of whom have hematocrits in the range of 20 to 25 percent. Decreased production of red blood cells is almost always a feature of the anemia of renal failure. The rate of red cell production by the marrow is determined by erythropoietin elaboration in the kidneys [see Figure 1]. Whereas individuals with normal kidney function generally employ compensatory mechanisms in the presence of mild hemolysis, those with renal failure cannot compensate for hemolysis, because decreased production of erythropoietin by the diseased kidneys impairs erythropoiesis in the marrow.88 (In normal kidneys, endothelial cells in the proximal tubules or peritubular capillaries in the cortex and the outer medulla are thought to produce most of the renal erythropoietin.89 Synthesis is stimulated by renal hypoxia.) In renal disease, the normal physiologic response to anemiathat is, a homeostatic increase in marrow erythropoiesiscannot occur. Patients with end-stage renal disease have serum erythropoietin levels that are within normal ranges for healthy, nonanemic

individuals; in anemic patients with normal renal function, however, serum erythropoietin levels may be markedly increased and therefore are not useful for predicting the response to exogenous erythropoietin. Blood losses from the GI tract, menstruation, multiple laboratory determinations, or even dialysis itself can also contribute to anemia. It has been estimated that the average dialysis patient loses about 2.5 L of blood a year, and this figure does not include occasional large losses caused by rupture of the dialysis coil, bleeding from access devices, or surgical procedures.90 Patients with uremia also have increased bleeding tendencies, even though their prothrombin times, partial thromboplastin times, and platelet counts are usually normal.91 Heparin anticoagulation during dialysis, combined with abnormal platelet function, may predispose the patient to epistaxis, hemopericardium, intracranial hemorrhage, retroperitoneal bleeding, and other complications.92-94 Subdural hematoma may mimic dialysis dysequilibrium syndrome. The most important clotting defect in uremiaone that correlates directly with the severity of renal failureinvolves platelet dysfunction, which is measured as decreased release of platelet factor 3 and diminished platelet aggregation and

adhesiveness and which is believed to be related to the presence of guanidinosuccinic acid, a dialyzable toxin in uremic plasma.95 Phenolic acid, cyclic adenosine triphosphate (cATP), hypermagnesemia, and elevated prostacyclin levels may be toxic to platelets; peritoneal dialysis markedly inhibits these adverse effects. On the other hand, the nephrotic syndrome (usually associated with membranous glomerulonephritis in patients who are not yet in end-stage renal failure) has been associated with a hypercoagulable state that may produce renal vein thrombosis; antithrombin III deficiency may become significant when the serum albumin level has fallen to less than 2 mg/dl.96,97 Anticoagulation may be necessary to prevent thrombosis, but the condition may be resistant to heparin. Hemodialysis may induce a transient thrombocytopenia through contact activation on dialyzer membranes, but antiplatelet agents such as short-acting prostacyclins can block this effect. Operative blood loss secondary to platelet dysfunction is rare if the patient is well dialyzed.98 However, the use of heparin during dialysis and the extended use of coumadin or antiplatelet drugs to maintain the patency of dialysis accesses may potentiate intraoperative blood loss. In addition, even if heparinization is regional during the preoperative dialysis, heparin rebound may occur during operation.99 Therefore, the surgeon must be aware of the type and the degree of preoperative anticoagulation. The effects of heparin can generally be reversed intraoperatively by the intravenous infusion of protamine; the prothrombin times of patients on long-term coumadin regimens can be normalized by the administration of vitamin K. More urgent reversal can be accomplished with fresh frozen plasma. Occasionally, blood loss is excessive even when such coagulation defects have been reversed, particularly with retroperitoneal dissection for procedures on the abdominal aorta or the iliac arteries. The surgeon must also be aware of the increased likelihood of clotting of the arteriovenous fistula postoperatively. Treatment of anemia in patients with end-stage renal disease should include iron

replacement if iron stores are depleted, as determined by measuring transferrin iron saturation (a value of < 20 percent signals depletion). Until the 1990s, blood transfusions were the mainstay of therapy. Since then, however, recombinant erythropoietin has come to play a prominent role. The availability of recombinant human erythropoietin constitutes a tremendous advance in the care of patients with end-stage renal disease. The drug largely eliminates the need for transfusions, thereby not only improving the anemia but also avoiding the acute and chronic hazards of transfusion (viral infection and iron overload).100,101 Recombinant human erythropoietin also corrects clotting changes.100,101 Indeed, most patients who are now receiving erythropoietin have normal bleeding times. The drug has other benefits as well, including increased energy level, greater exercise tolerance, and improved overall well-being. The most effective approach to uremic bleeding is prevention by means of adequate dialysis. Regional heparinization may be used with good results; patients come to surgery after dialysis with their clotting ability reasonably intact. Cryoprecipitate, conjugated estrogens, and 1-desamino-8-D-arginine vasopressin (DDAVP) may be administered postoperatively as needed to correct bleeding disorders; conjugated estrogens may take several days to influence bleeding times.102 In most cases, however, none of these measures are necessary if dialysis is adequate. Immune system Alteration of leukocyte and immunologic function in renal failure patients is thought to contribute to their increased susceptibility to infection.43 Neutrophil counts are usually normal but may decrease transiently after hemodialysis because of leukocyte sequestration in pulmonary capillaries, possibly

related to complement activation.103 Chemotaxis of granulocytes and phagocytes is also depressed, both by inhibitors in uremic serum104 and by an intrinsic cell defect,105 and it is worsened by hemodialysis (although less so by peritoneal dialysis). Transplantation restores depressed chemotaxis.105,106 In some patients, lymphocytopenia with impaired cellular immunity develops.107 T cell function is depressed by uremic serum but improved by dialysis.108 B cellmediated antibody response to some stimuli may also be attenuated,109 although serum immunoglobulin levels are not always decreased110 and response to vaccines is usually normal.111 Musculoskeletal system Myopathy in renal failure may be secondary to malnutrition,112 hyperparathyroidism,113 abnormal vitamin D metabolism,114 or aluminum accumulation115; correction requires 1,25-dihydroxyvitamin D3 administration,116 aluminum chelation,115 or renal transplantation. Uremic bursitis may be a result of generalized serositis.117 The olecranon bursa of the access arm has an increased predilection for bursitis from prolonged pressure on the bed or chair during hemodialysis.118 The incidence of tendon ruptures increases in association with hyperparathyroidism,119 in which crystal deposition120 and septic arthritis are common.121 Dialysis amyloidosis is a debilitating condition that includes arthropathy and is attributable to retention of b2-macroglobulin in tissues. Bone demineralization may result from altered vitamin D metabolism and secondary hyperparathyroidism,122,123 aluminum intoxication from dialysate or aluminum-containing phosphate binders,124 or metabolic acidosis requiring buffering of hydrogen ion with bone salts.125 Renal osteodystrophy may result, with osteitis

fibrosis, osteomalacia, osteosclerosis, osteoporosis, and growth retardation. Physical manifestations of renal osteodystrophy include bone pain, proximal muscle weakness, pruritus, calciphylaxis (ischemic lesions of soft tissues and skin, with vascular calcifications), and skeletal deformities.123 Treatment consists of administration of aluminum and calcium carbonate phosphate binders126 and calcium supplements,127 an increased dialysate calcium level,128 1,25-dihydroxyvitamin D3 administration,129 and aluminum chelation with deferoxamine.130 A few patients require parathyroidectomy,131 although bone biopsies should be performed first to rule out aluminum-related osteomalacia that is unresponsive to parathyroidectomy.132 Nervous system The neurologic effects of uremia include encephalopathy and neuropathy.133 Manifestations of uremic encephalopathy include confusion, tremor and asterixis, myoclonic seizures, delirium, and coma. Severity varies directly with the degree and rate of development of renal failure and its response to dialysis. Uremic neuropathy is typically a mixed motor and sensory distal polyneuropathy that affects the lower extremities preferentially and symmetrically; the etiology of axonal degeneration with demyelination is unclear. An early manifestation is restless legs syndrome: pulling sensations and pruritus relieved by movement. Autonomic and cranial nerve dysfunction, particularly affecting the eighth cranial nerve, is also associated with uremia. Uremic polyneuropathy may mimic diabetic neuropathy. Dialysis itself is associated with several central nervous system disorders. Dialysis dysequilibrium syndrome, associated with rapid hemodialysis (particularly when it is initiated in a patient with an extremely elevated BUN), causes headache, nausea, vomiting, cramps, restlessness, tremors, blurred vision, hypertension, confusion, syncope, seizures, and arrhythmias. Short, frequent dialyses or continuous ambulatory peritoneal dialysis134 can prevent dialysis dysequilibrium syndrome. Dialysis dementia is a chronic, progressive, and often fatal disorder associated with long-term hemodialysis135; dialysis dementia may be part of a syndrome that includes

osteomalacia, proximal myopathy, and anemia. Because of this disorders frequent association with aluminum intoxication from dialysate contamination, administration of aluminum chelators such as deferoxamine may be beneficial. The incidence of aluminum toxicity has in fact decreased as a result of improved management of dialysis. Intracranial hemorrhage is associated with anticoagulation during dialysis,93 hypertension, and abnormal hemostasis. Nonketotic hyperosmolar coma may occur because of high glucose concentrations in the dialysate.136 Dermal system Pruritus commonly complicates uremia137 and may be related to skin gland atrophy or to altered calcium and phosphate metabolism and hyperparathyroidism.138 Cutaneous calcification also causes pruritus.139 Hyperpigmentation is common and is the result of retained urochromes140 and increased melanin deposition.141

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hyperparathyroidism in uremia. N Engl J Med 279:697, 1968 139. Androgue HJ, Frazier MR, Zeluff B, et al: Systemic calciphylaxis revisited. Am J Nephrol 1:177, 1981 140. Scoggins RB, Haran WR: Cutaneous manifestations of hyperlipidemia and uremia. Postgrad Med 41:537, 1967 141. Aronin N, Liotta AS, Schickmanter B, et al: Impaired clearance of beta-lipotropin in uremia. J Clin Endocrinol Med 53:797, 1981 Acknowledgment Figure 1 Dana Burns-Pizer. Adapted from Reversing the Anemia of Renal Failure, by Fred E. Hatch, in Hospital Practice 25(2A):25, 1990. Winter 1997

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