Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

CHAPTER 7 – Renal Diseases

Maurizio Cereda, MD,
Jiri Horak, MD,
Patrick Neligan, MD



Renal Physiology



Proximal Tubule



Loop of Henle



Autoregulation of Blood Flow and Medullary Hypoxia



Specific Renal Diseases



Glomerular Diseases



Tubulointerstitial Diseases



Disorders of Tubular Function



Renal Cystic Diseases



Renal Involvement in Systemic Diseases



Vascular Diseases of the kidney



Chronic Renal Failure



Acute Renal Failure



Perioperative Renal Dysfunction



Renal Replacement Therapy



Renal Transplantation



Intraoperative Considerations for the Patient with Renal Disease



Hemodynamic Management



Pharmacologic Choices



Effects of Perioperative Drugs on Renal Function



Risk Modification and Renal Protection Strategies


There are three major anatomic demarcations in the kidney: the cortex, the medulla, and the renal pelvis. The cortex receives most of the blood flow and is mostly concerned with reabsorbing filtered material. The medulla is a highly metabolically active area that serves to concentrate the urine. The pelvis collects urine for excretion.

The functional unit of the kidney is the nephron. There are five parts of the nephron: (1) the glomerulus, which is the blood-kidney interface where plasma is filtered from capillaries into the Bowman's capsule; (2) the proximal convoluted tubule, which reabsorbs most of the filtered load, including nutrients and electrolytes; (3) the loop of Henle, which, depending on its length, concentrates urine by increasing the osmolality of surrounding tissue and filtrate; (4) the distal convoluted tubule, which reabsorbs water and sodium depending on needs; and (5) the collecting system, which collects urine for excretion. There are two types of nephrons, those localized to the cortex and those extending into the medulla. The latter are more metabolically active and are characterized by long loops of Henle.

Renal blood flow is 25% of cardiac output (1200 mL/ min). Of this, renal plasma flow is about 660 mL/min, and 120 mL/min is filtered out of the blood and into the nephron. Ultimately, approximately 1.2 mL of this fluid is excreted as urine (1% of filtered load). The three major determinants of glomerular filtration rate (GFR) are (1) renal blood flow and renal perfusion pressure; (2) the hydrostatic pressure difference between the tubule and the capillaries; and (3) the surface area available for ultrafiltration ( Fig. 7-1 ).


FIGURE 7-1  Filtration and filtration pressure.



Proximal Tubule

In the proximal tubule, two thirds of filtered sodium, water, and chloride are reabsorbed along with most of the filtered glucose, amino acids, bicarbonate, and vitamins. Sodium is actively pumped out of the tubule, and water follows passively.

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Loop of Henle

There are two parts to the loop, a thin descending limb and a thick ascending limb. The loop functions to generate an osmotic gradient in the medulla, so that urine can be concentrated or left dilute, depending on the body's fluid and electrolyte needs. A sodium-potassium-chloride (Na+/K+/2Cl-) pump actively extracts these electrolytes from the tubular fluid in the thick ascending limb, which is impermeable to water ( Fig. 7-2 ). Increased interstitial sodium and chloride leads to a dramatic increase in medullary osmolality. In addition, the loop and distal tubule are impermeable to urea but the collecting duct is not. Consequently, urea is concentrated in the tubules and significantly increases the osmolality of tubular fluid. When this fluid enters the collecting duct, urea diffuses along the concentration gradient into the interstitium, thereby increasing medullary tonicity further. This provides an osmotic gradient for the reabsorption of water from tubular fluid in the distal tubule and collecting duct.


FIGURE 7-2  Sodium chloride is actively pumped from the thick ascending limb of the loop of Henle.



Fluid delivered to the distal convoluted tubule is hypotonic. As this fluid passes down through this tubule and the collecting duct it is exposed to very high osmolar pressures in the surrounding tissues. If the patient is dehydrated, the pituitary gland produces antidiuretic hormone(ADH, vasopressin), making the collecting ducts permeable to water. Water is rapidly reabsorbed along the concentration gradient. In the absence of ADH a dilute urine is excreted.

Extracellular fluid volume depends on the amount of sodium in the body, so one of the essential roles of the kidney is sodium conservation. If the extracellular volume drops, a complex series of neurohormonal interactions lead to the release of aldosterone, which makes the collecting ducts permeable to sodium, which is reabsorbed.

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Fleisher: Anesthesia and Uncommon Diseases, 5th ed.

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Autoregulation of Blood Flow and Medullary Hypoxia

Renal blood flow is directed mostly to the cortex to optimize glomerular filtration and the reabsorption of solute. By contrast, blood flow to the renal medulla is low, to preserve osmotic gradients and enhance urinary concentration. The process of urine production and fluid and electrolyte conservation is intensely energy dependent. The anatomic distribution of medullary vasculature is designed in a hairpin manner to enhance countercurrent exchange; oxygen diffuses from arterial to venous vasa recta, which leaves the outer medulla deficient in oxygen. The medullary Po2 is in the range of 10 to 20 mm Hg, contrasting to the Po2 in the cortex, which is about 50 mm Hg.[1]

Intense demand for oxygen and nutrients and tenuous supply leaves the medulla and its tubules susceptible for ischemic injury. To maintain blood flow, and continuous filtration, a system of autoregulation operates in the kidney. Thus, production of tubular fluid is constant over a wide range of blood pressures.

The kidney neither autoregulates or perfuses at low blood pressures; this appears to be a protective effect because the medulla is relatively hypoxemic. Treatment for oliguria, under these circumstances, is to increase the renal perfusion pressure.

Oliguria, therefore, signals low renal perfusion, and the kidney protects itself from ischemia. The term acute renal success has been used to describe this phenomenon.[2] The coupling of blood flow and urinary concentration is essential for the operation of the nephron, and medullary hypoxia is the inevitable consequence. If excessive, medullary blood flow disrupts the osmolality gradients (built up by countercurrent exchange); if it is too slow, anoxia injures the tubules. Thus diminution of function, manifest as oliguria, has evolved as a protective mechanism for the medulla.[3]

A variety of differing physiologic mechanisms are involved in this regulation of blood flow and tubular transport in the renal medulla ( Table 7-1 ). Loop diuretics increase the partial pressure of oxygen within the medulla, although it is unknown and unclear if this is a beneficial effect. [4] [5]

TABLE 7-1   -- Mechanisms Regulating Blood Flow and Tubular Transport in the Renal Medulla



Medullary Vasodilators



Nitric oxide



Prostaglandin E2












Medullary Vasoconstrictors






Angiotensin II






Inhibitor of Transport in the Medullary Thick Limbs



Prostaglandin E2









Platelet-activating factor



Cytochrome P450–dependent arachidonate metabolites



Tubuloglomerular feedback



Certain agents are known to worsen renal medullary hypoxia and these include amphotericin B, nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin II, calcium, myoglobin, and radiographic contrast agents.[3]

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Based on the structures involved, renal diseases can have glomerular or tubular origin. In the former, the glomerular structures are damaged and deposits of antigen, antibodies, and complement can be detected by microscopy. Typically, patients with glomerular diseases present with various degrees of hematuria, proteinuria, and salt and water retention. In tubular diseases, the tubular cells or the peritubular interstitium are more severely affected than the glomerulus. Abnormal handling of electrolytes characterizes these diseases.

Glomerular Diseases


Glomerulonephritis is an important cause of renal impairment, accounting for 10% to 15% of cases of end-stage renal failure in the United States, following only diabetes and hypertension in importance.[6]It is defined as a disease characterized by intraglomerular inflammation and cellular proliferation associated with hematuria with secondary renal impairment over days to weeks. Hematuria in patients with glomerulonephritis is characterized by the presence of dysmorphic red cells[7] or red cell casts in the urine, findings that differentiate hematuria of glomerular origin from extraglomerular bleeding.

In primary glomerulonephritis, disease is almost entirely restricted to the kidneys, as in IgA nephropathy or post-streptococcal glomerulonephritis, whereas in secondary glomerulonephritis kidney involvement occurs in association with more diffuse inflammation, as in systemic lupus erythematosus or systemic vasculitis.

Both humoral and cell-mediated immune mechanisms play a part in the pathogenesis of glomerular inflammation.[8] A unique initiating stimulus is followed by a common pathway of inflammation with activation of the coagulation and complement cascades and production of proinflammatory cytokines[9] and, subsequently, fibrotic events. Inflammatory, proliferative, and fibrotic changes may affect specific cells of the kidney differently or may result in more global changes with particular patterns resulting in a spectrum of clinical presentations. Thus, many of the underlying diseases can produce a spectrum of clinical pictures.

Patients with glomerulonephritis generally present with one of five clinical syndromes: (1) asymptomatic hema turia, (2) acute glomerulonephritis, (3) rapidly progressive glomerulonephritis, (4) the nephrotic syndrome, or (5) chronic glomerulonephritis.

Asymptomatic hematuria refers to either macroscopically or microscopically detected blood in the urine of patients who have normal GFRs and no evidence of a systemic disease known to affect the kidneys. IgA nephropathy, mesangioproliferative glomerulonephritis, is a common cause of asymptomatic hematuria that is often associated with a simultaneous respiratory or gastrointestinal tract infection. IgA nephropathy occurs in all age groups, with a peak incidence in the second and third decades. [10] [11] Despite a mild clinical presentation with benign hematuria, end-stage renal disease (ESRD) ultimately develops in 20% to 40% of patients 5 to 25 years after diagnosis.[11] There is no cure for IgA nephropathy. In patients at high risk of ESRD, glucocorticoids with or without adjunctive cytotoxic agents have been used in an attempt to retard the progression of this disease.

The renal lesion of Henoch-Schönlein purpura (HSP) is almost identical to that of the more severe variants of IgA nephropathy. However, as a small vessel vasculitis, HSP also has the systemic features of a purpuric rash largely affecting the lower limbs, arthritis or arthralgia, and abdominal pain sometimes in association with rectal bleeding. The disease is most common in subjects who are younger than 20 years of age. Renal involvement can also occur in adults where it is thought to carry a worse prognosis. Although hematuria and proteinuria are the most common renal presentations, up to 29% of patients may present with a combined nephritic and nephrotic picture.

Acute glomerulonephritis is a syndrome characterized by the abrupt onset of macroscopic hematuria, oliguria, and acute renal failure. It manifests with a sudden decrease in the GFR and with fluid retention, resulting in generalized edema and hypertension. Urinary protein excretion varies widely in this syndrome, but the rate is generally less than 3 g of protein per day. Edema probably results from renal sodium retention caused by the sudden decrease in the GFR.

Post-streptococcal glomerulonephritis is the best known example of endocapillary glomerulonephritis, the most common form of acute glomerulonephritis, and is representative of a larger group of postinfectious glomerulonephritis in which acute glomerular injury results from immune events triggered by a variety of bacterial, viral, and protozoal infections. In the United States and Europe this lesion is increasingly seen in infections such as endocarditis after intravenous drug abuse.

Deposits of IgG and C3 are regularly found within glomeruli and suggest that immune-complex formation is involved. However, it remains unclear whether the associated inflammation is mediated by circulating immune complexes, complexes formed in situ, or both.[12]

Poststreptococcal glomerulonephritis is an acute, reversible disease characterized by spontaneous recovery in the vast majority of patients. Typically, gross hematuria and edema develop 7 days to 12 weeks after the streptococcal infection. Spontaneous resolution of the clinical manifestations is generally rapid: diuresis usually ensues within 1 to 2 weeks, and the serum creatinine concentration returns to baseline within 4 weeks.

Poststreptococcal glomerulonephritis predominantly affects children between the ages of 2 and 10 years, but it also occurs in adults. Almost 10% of patients are older then 40. [14] [15] Although most patients eventually have a complete recovery, hypertension, recurrent or persistent proteinuria, and chronic renal insufficiency develop in some.[15] The long-term prognosis of patients with poststreptococcal glomerulonephritis has been controversial. The reported incidence of chronic renal insufficiency can be as high as 20%. [14] [16] [17]

Rapidly progressive glomerulonephritis is a rare clinical syndrome characterized by signs of glomerulonephritis (hematuria, proteinuria, and red cell casts) and a rapid decline in renal function that can lead to end-stage renal failure within days to weeks. It accounts for only 2% to 4% of all cases of glomerulonephritis. Although causes are heterogeneous, the pathologic hallmark of this syndrome is the presence of extensive cellular crescents surrounding most glomeruli. Crescents result from the proliferation of parietal epithelial cells and mononuclear phagocytes within Bowman's capsule.[17] Rapidly progressive glomerulonephritis with glomerular crescent formation can be superimposed on primary glomerular diseases, [18] [19] and it has been associated with infectious and multisystemic diseases as well, including vasculitides, cryoglobulinemia, and systemic lupus erythematosus. It can also occur as a primary disorder.

Rapidly progressive glomerulonephritis is classified pathologically according to the presence or absence of immune deposits and their character on immunofluores cence microscopy. Linear deposition of immunoglobulin along the glomerular basement membrane is detected in approximately 20% of patients. This type of rapidly progressive glomerulonephritis has two peaks of onset age, one in the third decade with a male preponderance and the second in the sixth and seventh decades affecting both sexes equally.[19] Associated lung involvement is more common in young men (Goodpasture's disease), whereas isolated damage to the kidneys is more common in older patients. Lung hemorrhage is the most common cause of death during early disease and should be suspected with hemoptysis or when a chest radiograph shows alveolar shadowing without restriction by anatomic fissures and with sparing of the upper zones.

Granular immune-complex deposition is detected in an additional 30% of patients.[17] In the remaining patients, no immune deposits are detectable in glomeruli (“pauci-immune” disease). Serologically, however, these diseases are linked in about 90% of cases by the finding of antineutrophil cytoplasmic antibodies. This category is represented by microscopic polyangiitis, Wegener's granulomatosis, and idiopathic crescentic glomerulonephritis. Microscopic polyangiitis is associated with cutaneous (purpura), neurologic (mononeuritis multiplex), or gastrointestinal vasculitis together with renal failure. Pulmonary symptoms, due to nongranulomatous arteriolar vasculitis and capillaritis, are present in only 50% of cases. By contrast, Wegener's granulomatosis is dominated by pulmonary manifestations with upper and lower pulmonary hemorrhage due to granulomatous vasculitis, respiratory tract involvement, and cavitating lung lesions, which are seen by radiography.

Unless complicated by systemic disease, rapidly progressive glomerulonephritis typically has an insidious onset, with nonspecific symptoms such malaise and lethargy. Urinalysis invariably demonstrates hematuria (usually dysmorphic red cells) and moderate proteinuria; nephrotic-range proteinuria occurs in less than 30% of patients.[17]

Rapidly progressive glomerulonephritis should be treated aggressively. A delay in the diagnosis and initiation of therapy increases the risk of ESRD, and the likelihood of renal recovery is poor without therapy. [21] [22] [23] Glucocorticoids and cyclophosphamide are the main therapeutic agents.[23] Plasma exchange is commonly used to remove circulating pathogenic autoantibodies in patients with glomerular basement membrane disease.[24]

Chronic glomerulonephritis is a syndrome manifested by progressive renal insufficiency in patients with glomerular inflammation, hematuria, and, often, hypertension. The kidney is the organ most commonly affected by systemic lupus erythematosus, and lupus nephritis is one of the most serious manifestations of this autoimmune disease. The clinical spectrum of lupus nephritis ranges from mild urinary abnormalities to acute and chronic renal failure. Patients, most commonly women in their 20s and 30s with a black preponderance, frequently suffer from lethargy, arthralgia or arthritis, rashes, and the symptoms of pleurisy and pericarditis in the months before presentation.[25] Clinically significant nephritis develops most commonly within 3 years after diagnosis and rarely develops after 5 years.[26]Asymptomatic hematuria or non-nephrotic proteinuria may be the only clues to renal involvement and should prompt further tests for other evidence of glomerular disease. Although tubulointerstitial nephritis can be a prominent component of lupus nephritis, immune-complex glomerulonephritis is the primary histopathologic finding.

Nephrotic syndrome presents as “heavy” proteinuria (protein excretion >3 g/day), hypoalbuminemia, edema, and varying degrees of hyperlipidemia and lipiduria.

The most common histologic lesions associated with primary nephrotic syndrome are focal segmental glomerulosclerosis, membranous glomerulopathy, minimal change disease, and membranoproliferative glomerulonephritis. [28] [29] Diabetes is the most common cause of nephrosis ( Table 7-2 ). Among the nondiabethic glomerulopathies, minimal change disease accounts for the majority of the cases of nephrosis in children whereas membranous glomerulopathy causes most of the adult cases.[29] Idiopathic membranoproliferative glomerulonephritis generally affects persons between the ages of 5 and 30 years and has a slight female predominance. The recent recognition of a causal relation between hepatitis C infection and membranoproliferative glomerulonephritis has led to the suggestion that this virus may be responsible for as many as 60% of cases previously deemed to be idiopathic.[30] Patients present 10 to 15 years after infection in middle age and have subclinical liver disease with mild biochemical abnormalities. Renal disease is often seen in the context of cryoglobulinemia. Patients suffer malaise, anemia, peripheral neuropathy, polyarthralgia, and a purpuric rash, together with lower limb ulceration and Raynaud's disease.

TABLE 7-2   -- Differential Diagnosis of Nephrotic Syndrome






Minimal change disease



Membranous glomerulopathy



Human immunodeficiency virus infection









Approximately half of patients with membranoproliferative glomerulonephritis present with the nephrotic syndrome, whereas the remainder present with either acute glomerulonephritis or asymptomatic urinary abnormalities.Some degree of renal functional impairment is evident in half of patients at presentation. Spontaneous remissions are rare, and the disease generally has a chronic, progressive course.

The use of cytotoxic drugs and glucocorticoids has not proved to be consistently beneficial. Nephrotic syndrome also occurs as a complication of a wide variety of systemic diseases, cancer, infections, and drug therapy.

Depending on the disease that causes it, nephrotic syndrome may be reversible or eventually result in renal failure, whereas in other cases it may respond to corticosteroid and immunosuppressant therapy. Angiotensin-converting enzyme (ACE) inhibitors are often used in both hypertensive and nonhypertensive patients, because they are known to limit urinary protein loss. Fluid management can be particularly complex in patients with nephrotic syndrome, and assessment of their volume status may require invasive monitoring. Low plasma oncotic pressure causes diffuse interstitial edema owing to leakage of fluid from the intravascular space and may result in low intravascular volume,[31] particularly in patients who are undergoing aggressive diuretic treatment. These subjects may benefit from intravenous albumin administration rather than from large volume crystalloid administration. It has been suggested that plasma volume can be increased in some nephrotic patients, owing to enhanced sodium and water reabsorption at the tubular level.[32] In these cases, diuretic therapy may be necessary. Patients with nephrotic syndrome tend to respond poorly to diuretics because of the binding of these drugs with intratubular albumin. Therefore, higher and more frequent diuretic doses or the combined use of loop diuretics and thiazides may be needed.[33] The low proteinemia associated with nephrotic syndrome significantly affects the pharmacokinetics of drugs with a high protein binding, and therefore the dosing of most anesthetic drugs should be reduced accordingly.[32]

Patients with nephrotic syndrome have a particularly high frequency of cardiovascular disease and should undergo a thorough cardiac evaluation before higher risk surgeries. In fact, altered apolipoprotein metabolism causes hyperlipidemia while loss of anticoagulant plasma proteins leads to a hypercoagulable state. The risk of thromboembolic events is near 50%,[34] and these patients require diligent prophylactic anticoagulation with heparin and compressive devices ( Table 7-3 ).

TABLE 7-3   -- Preparation and Intraoperative Management in Patients with Nephrotic Syndrome



Perform cardiac risk stratification.



Measure albumin concentration.



Assess volume status; consider invasive monitoring.



Reduce doses of drugs with high protein binding.



Provide venous thromboembolism prophylaxis.



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Tubulointerstitial Diseases


Acute interstitial nephritis is characterized by a peritubular inflammation causing renal insufficiency, sterile pyuria, and leukocyte casts ( Table 7-4 ). Hematuria and proteinuria are also observed but are of lower degree than in glomerular diseases. Altered sodium reabsorption and reduced urine-concentrating ability are more frequent than edema and hypertension.[29] Systemic manifestations such as rash, fever, and peripheral eosinophilia are often observed. Acute interstitial nephritis is caused by drugs, particularly antibiotics and NSAIDS, but can be caused also by infectious and autoimmune diseases. Discontinuation of the offending agent usually results in renal recovery, but corticosteroids can be necessary in some cases.

TABLE 7-4   -- Signs of Nephritis

Acute interstitial nephritis

Sterile pyuria, leukocyte casts, eosinophiluria, eosinophilia

Chronic tubulointerstitial nephropathy

Polyuria, acidosis, hyperkalemia


Pyuria, bacteriuria, signs of infection, flank pain



Pyelonephritis is an acute interstitial inflammation caused by a bacterial infection. Fever and signs of acute infection are usually observed, although the inflammatory response can be blunted in elderly and immunosuppressed patients. Pyelonephritis can be a cause of septic shock, particularly in hospitalized patients.

Chronic tubulointerstitial nephropathy is a slowly evolving interstitial inflammation and is a relatively common cause of chronic renal failure. Patients usually have pyuria, mild proteinuria, and minimal or no hematuria. Tubular dysfunction characterizes this disease, with hyperkalemia, non-gap metabolic acidosis, and polyuria. Chronic tubulointerstitial nephropathy can be caused by chronic ingestion of NSAIDS and acetaminophen.[35] Other drugs, such as cyclosporine and tacrolimus, toxins, autoimmune and neoplastic disorders can cause chronic tubulointerstitial nephropathy.

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Disorders of Tubular Function

Bartter's syndrome is characterized by sodium, chloride, and potassium wasting. It is caused by a defect of the Na+/K+/2Cl- transporter in the thick ascending limb of the loop of Henle and is inherited with an autosomal recessive pattern.[36] Two forms of this syndrome exist: a neonatal one, characterized by polyhydramnios, and a classic form with onset at 2 or 3 years of life, characterized by polyuria, failure to thrive, and vomiting. Bartter's syndrome is diagnosed based on hypokalemia, hypochloremic metabolic alkalosis, and increased urinary concentrations of sodium, potassium, and chloride. Patients with Bartter's syndrome are not hypertensive, although renin, angiotensin, and aldosterone levels are elevated. Renal prostaglandin production is typically increased. Bartter's syndrome is treated acutely with saline infusion and potassium supplementation. The syndrome responds to chronic inhibition of prostaglandin synthesis, probably owing to a reduction of cortical blood flow.[29]

Gitelman's syndrome is an autosomal recessive disorder of the Na+/Cl- transporter in the distal convoluted tubule, it has similar features to Bartter's syndrome, but it has a later onset and is characterized by hypocalciuria and hypomagnesemia.[36]

Liddle's syndrome is an autosomal dominant disorder characterized by constant activation of the epithelial sodium channel in the collecting tubule in spite of low aldosterone levels. Patients present in their teenage years with hypertension, polyuria, failure to thrive, and hypokalemia. Treatment includes salt restriction, potassium supplementation, and lifelong administration of triamterene or amiloride.[29]

Pseudohypaldosteronism type I is an autosomal dominant resistance to the action of aldosterone, characterized by renal sodium loss and decreased sodium concentrations in sweat and saliva. The levels of aldosterone and its metabolites are typically increased. The onset is in early life, with failure to thrive, vomiting, and hyponatremia. Respiratory tract infections are common and resemble cystic fibrosis. Treatment mainly consists of sodium supplementation and is particularly important during periods of stress, such as illness or surgery.

Fanconi's syndrome is a global dysfunction of the proximal tubules, resulting in urinary loss of amino acids, glucose, bicarbonate, sodium, potassium, and phosphate. The main clinical manifestations are growth retardation, rickets, hyperchloremic acidosis, polyuria, dehydration, and symptomatic hypokalemia. Fanconi's syndrome has multiple causes that may lead to dysfunction of different tubular channels. Among the inherited causes, cystinosis is the most important one and is an autosomal recessive disorder that leads to generalized lysosomal cystine accumulation with renal and extrarenal manifestations. Other inherited causes of Fanconi's syndrome are Wilson's disease, galactosemia, and glycogenosis. Acquired causes of Fanconi's syndrome include heavy metal poisoning and exposure to multiple drugs such as tetracycline and chemotherapeutics. Treatment involves sodium and fluid replacement, correction of acidosis and hypokalemia, vitamin D and phosphate supplementation, and correction of the underlying causes when possible. Cystinosis usually evolves to ESRD within 10 years from diagnosis. The early use of cysteamine decreases lysosomal cystine and delays the evolution of renal failure, avoiding renal transplant in some cases.[37]

Renal tubular acidosis (RTA) is a group of differing renal tubular defects that have in common abnormalities of handling sodium and chloride. Normal renal function, and indeed control of acid-base balance, requires the kidney to excrete a net load of chloride over sodium, because dietary intake of these ions is roughly similar. In RTA the nephron excretes insufficient chloride, reducing the strong ion difference and resulting in metabolic acidosis. [39] [40] [41] Similarly, pseudohypoaldosteronism appears to result from high chloride reabsorption.[41] Bartter's syndrome is caused by a mutation in the gene encoding the chloride channel, CLCNKB, that regulates the Na+/K+/2Cl- cotransporter NKCC2.[42]

Proximal renal tubular acidosis (type II) is a problem of sodium and chloride handling in the proximal tubule leading to hypokalemic non-gap metabolic acidosis. It may occur alone, presumably secondary to a genetic defect, or as part of Fanconi's syndrome. Proximal RTA is defined by the inability to acidify the urine below a pH of 5.5. In some cases there is excess urinary elimination of sodium and its companion anion bicarbonate owing to mutations in the gene SLC4A4, encoding the Na+/HCO-3 cotransporter NBC-1.[43] Treatment is by administration of sodium either as sodium acetate or as sodium bicarbonate. Hypokalemia is due to activation of aldosterone secretion due to hypovolemia. This type of acidosis is most commonly caused by Fanconi's syndrome, but it can be also isolated. The diagnosis of proximal tubular acidosis can be confirmed by urine alkalinization to more than 7.5 after an intravenous sodium bicarbonate load.[29]

Hypokalemic distal tubular acidosis (type I) is due to an abnormality of chloride excretion in the distal tubule. There is a parallel reduction in the excretion of NH+4. In its autosomal dominant form, distal RTA is associated with mutations in the gene encoding the Cl-/HCO-3 exchanger AE1 or band 3 protein.[44]

Patients have severe metabolic acidosis with serum bicarbonate levels close to 10 mmol/L and are unable to acidify urine to less than a pH of 5.5. Hypovolemia and hyperaldosteronism cause hypokalemia. The patients frequently present with kidney stones due to hypercalciuria, which is caused by increased calcium mobilization from bone buffers. The most common cause of this type of acidosis is Sjögren's syndrome.

Hyperkalemic distal renal tubular acidosis (type IV) is caused by impaired excretion of both chloride and potassium ions in the distal tubule, leading to non-gap acidosis and hyperkalemia. There is an abnormality in the genes encoding the WNK1 and WNK4 kinases, which are responsible for transcellular conductance of chloride.[45] There is an association with diminished secretion of aldosterone. Urine pH is usually lower than 5.5, unlike type I acidosis. The acquired version of type IV RTA is usually mild and is often associated with chronic renal insufficiency. Its most common cause is diabetes mellitus, but exposure to NSAIDs and cyclosporine is a possible cause. Patients need treatment when the hyperkalemia is significant. Use of fludrocortisone, thiazides, and sodium bicarbonate can be considered.[29]

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Renal Cystic Diseases

Renal cysts can be observed in a significant percentage of the population and are usually asymptomatic. Polycystic kidney is a severe inherited disease that can be transmitted in an autosomal recessive or dominant manner. The recessive form has an incidence of 1 in 20,000 live births and usually results in perinatal death due to extreme renal enlargement causing pulmonary compression and hypoplasia. The dominant form occurs in 1 of 800 live births and results in significant disease by adult age. The pathogenesis involves alteration in the synthesis of the tubuloepithelial membrane receptor polycistin.[46] At the age of presentation, the kidneys are massively enlarged and patients complain of flank pain, hypertension, hematuria, and recurrent pyelonephritis. This disease leads to ESRD in 50% of the cases.[29]Ten percent of cases also have cerebral arterial aneurysms. Therapy includes management of hypertension, prevention of kidney infections, and renal transplantation. Some cases may require nephrectomy due to recurrent severe pyelonephritis or to discomfort from the massive kidney enlargement.

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Renal Involvement in Systemic Diseases

Hypertension and Diabetes

Long-standing, poorly controlled hypertension frequently causes renal dysfunction and causes approximately 20% of the cases of ESRD.[47] African-American ethnicity is a particular risk factor for this complication. Hypertension initially causes functional alterations in the renal circulation, with rightward displacement of the autoregulatory curve ( Fig. 7-3 ), followed by permanent histologic changes at the arteriolar level.[48]


FIGURE 7-3  The relationship between intraglomerular pressure and mean arterial pressure follows a typically sigmoid curve due to autoregulation of afferent and efferent vessel tone with the effect of maintaining a constant glomerular blood flow in spite of significant changes in blood pressure. In hypertensive patients, this relationship is shifted to the right but maintained. When renal disease superimposes, the curve becomes more linear and changes in blood pressure directly affect glomerular blood pressure and flow.  (From Palmer BF: Renal dysfunction complicating the treatment of hypertension. N Engl J Med 2002;347:1256-1261.)




When autoregulation is completely lost, both systemic hypotension and hypertension may result in worsening renal function. High glomerular intravascular pressures cause increased capillary permeability and proteinuria[49] whereas low blood pressure results in renal cell ischemia.

Accelerated hypertension is a particular condition in which an extremely elevated blood pressure causes a significant acute renal injury characterized by marked proteinuria. The goal in the management of patients with this condition should be to obtain an acute reduction in diastolic blood pressure to less than 120 mm Hg followed by further reductions over a time frame of weeks. In patients who present with accelerated hypertension, excessively rapid correction of blood pressure can lead to renal ischemic injury.

Diabetes mellitus is the most important cause of ESRD. Although type 1 diabetes is more frequently associated with renal involvement, the prevalence of patients with type 2 diabetes and renal disease has increased, probably owing to longer survival of these patients. Diabetic nephropathy is characterized by proteinuria, the extent of which predicts the onset and the outcome of renal insufficiency.[50]Proteinuria is not only a marker of renal disease, but it also contributes to causing further renal damage.[51] In fact, it has been shown in animal models that excessive tubular reabsorption of protein may cause interstitial inflammation, scarring, and fibrosis.[49] Poorly controlled blood pressure, hyperglycemia, and hypercholesterolemia are risk factors for the development of diabetic nephropathy,[52] and, therefore, control of these factors is important in the prevention or the limitation of diabetic kidney disease. Improved glycemic control has been shown to reduce the incidence of diabetic nephropathy.[53]Strict blood pressure control has beneficial effects on the kidney in diabetic patients,[54] and its benefit is probably higher for those patients with significant proteinuria.[55] Although the blood pressure goal can be reached with any agent, ACE inhibitors are more effective in slowing nephropathy than other classes of antihypertensive drugs both in diabetic and in nondiabetic patients.[56] This effect of ACE inhibitors is probably related to their ability in reducing or preventing proteinuria.[57] Similar renoprotective effects have been shown also with angiotensin receptor blockers.[58] The use of ACE inhibitors in patients with compromised renal function is often associated with a moderate increase in serum creatinine and potassium levels. This effect should be seen as a normal response to decreased blood pressure and a marker of drug effectiveness rather than a sign of deterioration of renal function and an indication to discontinuation of ACE inhibitor therapy.[48] Calcium channel blockers also have beneficial effects on renal function, although the use of amlodipine was associated with adverse outcomes in African-American patients with hypertensive nephropathy. Additional measures proposed to slow the progression of chronic diabetic and nondiabetic nephropathy are dietary protein intake restriction, smoking cessation, and lipid-lowering medications.

Sickle Cell Disease

Sickle cell disease is the cause of a significant nephropathy with manifestations that can include hematuria, papillary necrosis due to occlusion of vasa recta, acute renal failure due to renal hypoperfusion or rhabdomyolysis, and chronic renal failure due to glomerulosclerosis. Proteinuria is detected in a high percentage of patients. An inability to concentrate urine is the hallmark of sickle cell nephropathy and is due to loss of the countercurrent exchange mechanism from loss of perfusion to the vasa recta. The intraoperative management of patients with sickle cell nephropathy should follow the general recommendations on sickle cell management, with additional care to avoid renal hypoperfusion.[59]

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Copyright © 2005 Saunders, An Imprint of Elsevier

Vascular Diseases of the Kidney

Chronic atherosclerotic stenosis of the renal arteries is a relatively common condition in the population with advanced age and with extrarenal atherosclerosis, as shown by angiographic studies.[60] Renal artery stenosis can cause progressive ischemic nephropathy and, when bilateral, it results in significant renal dysfunction. However, this condition is often underdiagnosed, mainly owing to the lack of specific chemical markers of renal ischemic disease. Most often, the diagnosis is made by radiologic investigations such as duplex ultrasonography, angiography, computed tomography, or magnetic resonance imaging angiography. Although renal artery atherosclerosis is often associated with systemic hypertension, correction of the stenosis does not always result in blood pressure normalization, because hypertension is more likely to be essential in the majority of cases.[61] Thrombosis of the renal artery may complicate preexisting stenosis or may be caused by hypercoagulability, trauma, or aortic dissection; and it can precipitate acute renal failure. Fibromuscular dysplasia of the renal artery occurs mainly in young women and still has no known causes. Unlike atherosclerotic stenosis, this condition is associated with renovascular hypertension and rarely causes renal failure.[62]

Medical management of renal artery stenosis is centered on control of hypertension, and ACE inhibitors are the drugs of choice for this purpose, although inhibition of angiotensin-mediated efferent tone may precipitate renal failure in patients with bilateral renal artery stenosis. Surgical correction of renal artery stenosis is aggravated by a significant rate of complications, particularly in patients with coexisting aortic disease, and is probably not indicated in patients with advanced nephropathy.[61] The use of percutaneous angioplasty and stenting has emerged as an attractive alternative to the surgical corrective approach.[63]

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Copyright © 2005 Saunders, An Imprint of Elsevier

Chronic Renal Failure

Chronic renal failure (CRF) has become increasingly frequent in the western world,[64] reaching a prevalence of 0.1% in the United States. Data from the U.S. Renal Data System showed a 104% increase in the prevalence of CRF between 1990 and 2001.[65] The prevalence is higher in advanced ages and in certain ethnic groups such as the African American and Native American.[66] Recent studies have detected an impressively high rate of mild to moderate renal dysfunction in the U.S. population, particularly in the elderly ( Fig. 7-4 ).[67] These patients are at risk for progression to renal failure if further kidney damage is superimposed.


FIGURE 7-4  Distribution of glomerular filtration rate (expressed as mL/min/1.73 m2 BSA) by age for nondiabetic subjects.  (From Clase CM, Garg AX: Classifying kidney problems: Can we avoid framing risks as diseases? BMJ 2004;329:912-915.)




An elevated number of patients with CRF undergo surgeries for reasons that may or may not be related to kidney disease; therefore, understanding the pathophysiology and the clinical management of these patients is highly important for the anesthesiologist. In fact, CRF significantly complicates perioperative management and has a relevant impact on surgical outcomes. In patients with CRF necessitating dialysis, mortality rates of 4% after general surgery and of 10% after cardiac surgery have been reported, with morbidity rates approaching 50%.[68] This increased rate of complications is probably due to the low renal reserve of patients with CRF and to their reduced ability to respond to the stress, fluid load, and tissue trauma caused by surgery. However, additional morbidity is created by the organ dysfunctions and the coexisting diseases frequently met in these patients.


Many different renal and extrarenal pathologic conditions result in the loss of glomerular function as their “final common pathway.” Renal dysfunction is progressive and is usually divided in stages according to the GFR ( Table 7-5 ).[69]

TABLE 7-5   -- Stages of Renal Dysfunction



Creatinine Clearance (GFR)(mL/min/1.73 m2)

Metabolic Consequences


Normal or increased GFR; people at increased risk or with early renal damage




Early renal insufficiency


Concentration of parathyroid hormone starts to rise (GFR∼60–80)


Moderate renal failure (chronic renal failure)


Decrease in calcium absorption (GFR < 50)




Lipoprotein activity falls








Onset of left ventricular hypertrophy




Onset of anemia (erythropoietin deficiency)


Severe renal failure (pre–end-stage renal disease)


Triglyceride concentrations start to rise








Metabolic acidosis




Tendency to hyperkalemia


End-stage renal disease (uremia)


Azotemia develops

Adapted from Parmar MS: Chronic renal disease. BMJ 2002;325:85–90.

GFR, glomerular filtration rate.



May be normal for age.



Proteinuria is also used as an index of the severity of kidney disease and can be used to predict renal survival.[70] The loss of GFR can be accelerated by events such as intercurrent diseases, nephrotoxins, and surgery. Eventually, ESRD is reached when the GFR decreases below a critical point and the kidney is unable to maintain homeostasis unless renal replacement therapy is initiated.

When renal tissue is lost, surviving nephrons undergo adaptive changes, with tubular hypertrophy, afferent vessel vasodilation, and increased glomerular blood flow.[71] By increasing tubular excretion or reabsorption of water and solutes, these changes allow the remaining nephrons to compensate for lost tissue and to maintain near-normal handling of the glomerular ultrafiltrate. On the other side, these same changes seem to accelerate the progression of kidney disease. Glomerular capillary hypertension due to afferent vasodilation causes glomerulosclerosis, increased endothelial permeability, and proteinuria. The latter probably promotes further renal damage, [71] [73] because excessive tubular reabsorption of urinary protein may cause peritubular inflammation, scarring, and fibrosis.[71]

A progressive inability to maintain tight control of body fluid composition follows the exhaustion of renal compensatory mechanisms. Patients with very low GFR are prone to sodium accumulation and to hypervolemia, because they may not be able to excrete the equivalent of their sodium intake. When the regulation of urine osmolality and of free water excretion is impaired, changes in water intake may cause sodium concentration abnormalities. Inability to excrete potassium by the distal tubule results in accumulation of this electrolyte. Patients with CRF usually tolerate significant hyperkalemia, partly due to increased intestinal excretion. However, acute processes such as acidosis, surgery, and tissue necrosis can trigger rapid increases in serum potassium and cause life-threatening arrhythmias. Decreased phosphate excretion causes accumulation of this electrolyte and its precipitation in tissues together with calcium. Hypocalcemia is also caused by deficient renal production of vitamin D and by lower intestinal absorption of calcium, and it results in secondary hyperparathyroidism, bone reabsorption, and renal osteodystrophy.

Patients with renal failure develop a metabolic acidosis that is initially associated with hyperchloremia and normal anion gap. When renal failure becomes severe, inability to excrete titratable acids causes an increased anion gap.

The uremic syndrome characterizes renal decompensation and is due to accumulation of catabolic byproducts. Although the severity of uremia is usually quantified from the serum urea nitrogen levels, this syndrome is caused by accumulation of different substances and by several hormonal and metabolic dysfunctions. Central nervous system manifestations may range from personality changes to coma and seizures, and their onset is more related to the rapidity of the onset of azotemia than to its absolute level. Peripheral and autonomic neuropathies are relatively common and cause sensory loss, gastroparesis, and sympathetic dysregulation. Uremia causes gastric mucosal irritation and gastric ulcers in a significant fraction of patients who have uncompensated renal failure. Uremic patients have a bleeding diathesis even when coagulation times are normal. This bleeding tendency is caused by a platelet dysfunction resulting from inadequate release of von Willebrand factor and factor VIII by the endothelial cells.[73] Renal failure may also cause a predisposition to thrombosis due to hyperfibrinogenemia, antiphospholipid antibodies, hyperhomocysteinemia, and anticoagulatory protein C deficiency. Patients with CRF typically have a significant anemia that is mainly due to deficient production of erythropoietin, although gastrointestinal bleeding and iron deficiency may contribute to its genesis.

Multiple cardiovascular derangements are associated with CRF. Hypertension is usually due to fluid overload but also to neuroendocrine imbalances. Patients with CRF often have significant left ventricular hypertrophy and enlargement, associated with systolic and diastolic dysfunction, and are prone to heart failure.[74] Anemia significantly contributes to the adverse effects of CRF on the cardiovascular system, by increasing cardiac output and myocardial oxygen demand and by causing left ventricular hypertrophy and enlargement.[73] Uremic pericarditis is not frequent in patients on dialysis, but it should be considered because, if present, it can be complicated by pericardial hemorrhage and tamponade.

Clinical Presentations

Patients with CRF often present with a history of a known kidney disease that has been medically managed along its evolution and that has relatively controlled manifestations. Therefore, many patients with CRF present in a compensated state and with relatively mild symptoms. Vague malaise or nocturia may be the only complaints. However, some patients may present with the signs and the symptoms of acute renal decompensation and uremic emergency ( Table 7-6 ), a condition that should be rapidly addressed by a nephrologist and that often requires emergent initiation of hemodyalis.[73] This is more likely to happen in patients with rapidly progressing or unrecognized renal disease. In other patients, an acute event or illness may overcome the residual renal reserve or cause further kidney damage, precipitating acute on chronic renal failure ( Table 7-7 ).

TABLE 7-6   -- Signs of Uremic Emergency

Fluid overload

Hypertension, pulmonary edema, peripheral edema

Electrolyte imbalance

Hyperkalemia, hyponatremia, hypocalcemia

Acid-base abnormalities

Increased anion gap, hyperchloremia, low plasma CO2, hyperventilation


Seizures, coma, decreased airway reflexes, obtundation

Systemic hypoperfusion

Congestive heart failure, cardiac tamponade

Bleeding diathesis

Normal platelet counts and coagulation times, increased bleeding times



TABLE 7-7   -- Causes of Acute on Chronic Renal Failure









Uncontrolled hypertension



Renal disease exacerbation



Heart failure






Urinary obstruction



Major surgery



Patients who have been receiving chronic dialysis usually present in a relatively compensated state, but they may have signs of hypovolemia if fluid removal has beenoverzealous. When either the dose or the timing of dialysis is inadequate ( Table 7-8 ), some of the clinical manifestations of uremia resurface.[75] Pericardial effusions due to uremic pericarditis are slow to evolve and rarely result in tamponade, but they should be suspected in the presence of hypotension, pulsus paradoxus, and jugular vein enlargement.

TABLE 7-8   -- Signs of Inadequate Dialysis



Anorexia, nausea, vomiting, diarrhea



Peripheral neuropathy



Weakness, poor functional status



Decreased alertness



Ascites, pericarditis



Hypertension, fluid overload



Persistent anemia despite erythropoietin



Small urea reduction with dialysis



Anemia accounts for many of the symptoms and signs observed in CRF patients, such as malaise, low exercise ability, decreased mental acuity, left ventricular dilatation, and hypertrophy. Most of these manifestations improve if anemia is corrected by erythropoietin administration.[73] Patients who are not receiving dialysis are typically undernourished due to anorexia and hypercatabolism associated to CRF. Additionally, some patients may be receiving a low protein diet as an attempt to delay the need for dialysis and to limit the progression of renal disease.[64] The protein weight loss is often masked by the increase in body water content. Patients who do receive dialysis should be fed an adequate amount of protein, because currently available dialysis systems afford efficient solute-clearing capabilities and protein intake limitation is unnecessary.[75] The clinical manifestations of renal osteodystrophy are usually evident only when bone and renal disease are advanced and include bone and joint pain, lytic lesions on radiographs, and, occasionally, spontaneous bone fractures.[73] Growth retardation and bone deformities are common in children. Pruritus is common in patients with severe renal failure, particularly in those on dialysis, and is probably caused by calcium precipitation in the skin.

Patients receiving hemodialysis have a surgically created access that can consist of a native arteriovenous fistula or a synthetic graft. Some patients may present with a hemodialysis catheter placed in a central or femoral vein. Dialysis access sites are at high risk of clotting and infection and should be inspected for patency and local irritation. Long-term dialysis patients have a long history of peripheral and central cannulation and may present a challenge for central access.

Differential Diagnosis

Any diseases that damage the kidney at the glomerular or tubular level may progress to CRF. Diabetes and hypertension are by large the most important causes of ESRD, accounting together for more than 60% of cases in the United States.[65] Glomerular diseases and tubulointerstitial diseases cause 18% and 7% of cases of ESRD, followed by cystic kidney disease (5%).[64]

The differential diagnosis is usually straightforward and based on history, imaging, and laboratory analysis ( Table 7-9 ). Renal biopsy is indicated in patients with unexplained CRF who do not have atrophic kidneys on ultrasound and in patients with nondiabetic nephrotic syndrome.[73] Establishing a differential diagnosis is important, especially when the condition causing renal failure can be controlled and further renal damage can be prevented, such as with vasculitis, drug-induced nephropathy, autoimmune disease, renal ischemia, and infectious diseases.

TABLE 7-9   -- Differential Diagnosis of Chronic Renal Failure












Cystic kidney disease



Ischemic renal disease






Analgesic nephropathy



Hereditary diseases



Autoimmune diseases






Given the high prevalence of diabetes and hypertension in patients with CRF it is not surprising that the most important comorbidities associated with CRF involve the cardiovascular system ( Table 7-10 ). Cardiac disease is the most important cause of death in patients with ESRD. [67] [75] Congestive heart failure is present in 40% of patients receiving dialysis and is an important predictor of death. Seventy-five percent of CRF patients have left ventricular hypertrophy and diastolic dysfunction at the time of initiation of dialysis.[74] Left ventricular dysfunction improves with dialysis, correction of anemia, and renal transplant.[75] Coronary arterydisease is common in patients with CRF, with a reported prevalence of 40%,[76] and it is an important cause of ventricular dysfunction and mortality. The “classic” risk factors contribute to the prevalence of coronary artery disease, but renal failure itself might be an independent risk factor for this condition. This hypothesis has been suggested by the fact that significant coronary artery disease is observed also in CRF patients who are neither hypertensive nor diabetic.[76]

TABLE 7-10   -- Comorbidities of Chronic Renal Failure









Coronary artery disease



Congestive heart failure






Peripheral vascular disease



Immune depression



Hypertension is almost universal in renal failure and is both an important causative factor for renal disease, as discussed earlier, and as a manifestation of fluid overload and endocrine dysregulation. Hyperlipidemia has a high prevalence in CRF patients, and it manifests with increases in triglycerides and in very low density lipoproteins, and with decreases in high-density lipoproteins.[73] Patients with nephrotic syndrome have a 90% prevalence of hypercholesterolemia. Control of hyperlipidemia is important not only to decrease the risk of coronary artery disease but also because it might reduce proteinuria and help to preserve glomerular function.

Patients with advanced renal disease are particularly prone to infections and to delayed wound healing and may not respond to certain immunizations, such as hepatitis B. This is partly due to malnutrition but also to specific deficiencies in humoral and cell-mediated immunity, such as impaired phagocytosis, defective lymphocyte function, and impaired antibody response.[73] Hemodialysis does not completely correct this immunodeficiency and causes additional risk of infection. Patients on dialysis have impaired febrile response even with severe infections and are at particularly high risk for staphylococcal infections and tuberculosis.[75]

When CRF is associated with vasculitis and autoimmune diseases, the systemic manifestations of these diseases should be remembered, particularly when they affect the cardiovascular and respiratory system as seen, for example, with Goodpasture's disease, lupus, and rheumatoid arthritis.

Preoperative Evaluation and Preparation

The preoperative evaluation of the patient with CRF should start with a thorough history and physical examination and should focus on the comorbidities associated with kidney diseases and on the signs and symptoms of uremia, fluid overload, and inadequate dialysis. Laboratory studies should be aimed at assessing electrolyte concentrations, acid-base status, urea and creatinine levels, hematocrit, platelet count, and coagulation. Electrolytes should not be measured immediately after dialysis, owing to incomplete equilibration between plasma and intracellular fluids. Platelet dysfunction is not related to a low platelet count, and it can be detected only using the bleeding time, measured as the time to cessation of hemorrhage after a standardized skin incision.[77] However, this test seems to have a limited predictive value for clinical bleeding and is uncommonly used. Patients who are receiving adequate dialysis are less likely to have significant platelet dysfunction and their risk of bleeding should not be excessive. A chest radiograph is usually ordered to rule out fluid overload, although it may probably be avoided in younger patients who are adequately dialyzed, have good exercise tolerance, and are undergoing lower risk surgeries. An electrocardiogram is obtained to screen for changes caused by myocardial ischemia and by electrolyte abnormalities.

The cardiac risk stratification of patients with CRF is not straightforward. In fact, the sensitivity and specificity of symptoms such as chest pain and reduced exercise tolerance is reduced, compared with the population without renal disease. Silent myocardial ischemia is relatively common owing to the frequency of diabetes and of autonomic neuropathy whereas dyspnea on exertion may be caused also by fluid overload. At the same time, the classic signs of congestive heart failure may be absent in patients who have ventricular dysfunction but are receiving adequate dialysis. The cardiac evaluation of CRF patients is further complicated by the fact that noninvasive evaluation has a decreased accuracy in this population. In renal transplantation candidates, myocardial scintigraphy and dobutamine stress echocardiography had less than 75% sensitivity for significant coronary artery disease as detected by angiography and had poor predictive power for myocardial events.[78] Therefore, in CRF patients undergoing higher risk surgeries the threshold for requesting a cardiac evaluation and for obtaining a coronary angiogram should be probably lower than in the nonrenal population.[76] An evaluation algorithm proposes that renal transplantation candidates who are asymptomatic for myocardial ischemia but have diabetes or are older than age 50 years should undergo noninvasive cardiac evaluation, followed by coronary arteriography and revascularization if indicated.[79] According to this same algorithm, patients who are symptomatic for ischemia or heart failure should all receive an invasive evaluation. Although no evidence is available in patients undergoing nontransplant surgeries, it is reasonable to follow a similar approach for procedures with similar and higher risk. The outcomes of revascularization in patients with CRF are worse compared with the remaining population. Percutaneous balloon angioplasty has a higher rate of restenosis in renal than in nonrenal patients, although better results have been obtained with stent placement.[80] Coronary artery bypass graft in renal failure patients has a higher perioperative morbidity and mortality, but it may have a lower rate of restenosis and higher long-term survival compared with angioplasty.[76]

In preparation for elective surgery, patients with ESRD should receive dialysis the day before the operation. This is essential to achieve a volume status as close to normovolemic as possible, to allow the patient to tolerate fluid loads associated with surgery, and to obtain normal electrolyte concentrations. On the other hand, excessive fluid removal may cause hypovolemia and make the patient prone to intraoperative hemodynamic instability. The dialysis records, when available, can help to assess the adequacy of dialysis. Urea should decrease more than 65% during a dialysis session. Dry weight, defined as the lowest weight tolerated in absence of hypovolemic symptoms, is recorded to monitor the efficacy of fluid removal and ideally should be relatively stable over time, with 3% to 4% weight gain between sessions.[81] Dialysis should not be given immediately before the surgery because of the possibility of causing rapid fluid shifts and hypokalemia. In the case of emergent surgery, it may be possible to proceed without dialysis if a minimal weight gain between treatments is documented; however, patients with signs of fluid overload or with life-threatening hyperkalemia may need emergent dialysis before the operation if time allows. Otherwise, patients have to be managed medically and receive dialysis after the operation. Significant hyperkalemia, when present, can be temporarily controlled with pharmacologic means. Intraoperative use of ultrafiltration is relatively common during on-pump cardiac surgery,[82] and it also has been reported during noncardiac surgery. [84] [85] Potassium levels above 5.5 mEq/L are usually considered a contraindication to elective surgery because tissue trauma and cell death can cause potassium to increase to life-threatening levels. Hypokalemia should not be treated unless at life-threatening levels.

Blood pressure should be optimized before elective surgery. Current recommendations for long-term CRF management set a blood pressure goal of lower than 130/80 mm Hg in patients with CRF.[76]Hypertension in CRF patients is usually volume dependent and responds to adequate dialysis, but most patients will also require pharmacologic therapy.[75] Perioperative β blockers should be considered for patients at increased cardiac risk. Hypertension management is important not only for myocardial protection but also because the use of certain antihypertensive drugs such as ACE inhibitors and angiotensin receptor blockers has been shown to limit the evolution of renal disease.

Control of anemia is important because anemia is an important cause of left ventricular hypertrophy, heart failure, and angina. Hematocrit should be optimized before surgery. For ambulatory ESRD patients, hemoglobin of 11 to 12 g/dL is considered optimal,[75] and this value is also used as a target before surgery, although this practice is not supported by clinical evidence. The target hemoglobin level can be achieved by increasing erythropoietin administration if time allows or by transfusion for urgent surgery. Correction of anemia also helps to improve the platelet dysfunction of renal failure.[85] If platelet dysfunction is suspected or documented, it can be treated by administration of desmopressin or cryoprecipitate, both of which increase the level of von Willebrand factor and improve the interaction between platelets and endothelial cells.[73] Their onset of action is rapid, which renders both drugs useful intraoperatively. However, the prolonged use of desmopressin is limited by induction of tachyphylaxis. Estradiol is also effective in the treatment of platelet dysfunction, but its peak effect is delayed for several days. Most commonly encountered chronic medications in patients with CRF are listed in Table 7-11 .

TABLE 7-11   -- List of Chronic Medications That Are Common in Chronic Renal Failure


β Blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin antagonists

Fluid overload

Thiazides, furosemide

Osteodystrophy and hypocalcemia

Calcium supplements, phosphate binders, calcitriol


Insulin, oral hypoglycemics


Erythropoietin, iron



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Acute Renal Failure

Acute renal failure (ARF) refers to a variety of syndromes leading to abrupt reduction in GFR. ARF refers to a reduction in renal function, not necessarily renal damage, and it may occur de novo or in a patient with preexisting chronic renal disease.

Renal failure manifests as acute reduction in urinary output (oliguria) or an increase in the circulating concentration of nitrogenous waste products, which ultimately lead to the syndrome of uremia. In clinical practice, serum urea and creatinine are used as measurable markers of uremia but are not responsible for it. Oliguria is defined as a urine volume of less than 400 to 500 mL/24 hr. Oliguria is not necessary for the diagnosis of ARF, although it is often the presenting sign. Unfortunately, there is no consensus on an operational definition of ARF. Indeed, the term “failure” is problematic, because it does not separate extrarenal and renal components.[86]

The ARF syndromes have traditionally been classified into three major categories on the basis of their pathophysiology: prerenal, renal, and postrenal ARF. Prerenal ARF is associated with a reduction in renal blood flow and glomerular perfusion, secondary to hypotension or hypovolemia. In the initial stages there is no damage to the tubules; however, if it is sustained, ischemic injury results. Postrenal ARF is characterized by acute obstruction to the urinary tract. The obstruction can be at any level in the urinary tract from the renal pelvis to the urethra; however, for obstruction proximal to the urinary bladder to result in ARF it must be bilateral or occur in the setting of a single functional kidney. Abdominal compartment syndrome (see later) appears to combine prerenal and postrenal components. Intrinsic ARF is associated with renal parenchymal injury. This results from ischemic or toxic injury to renal tubular epithelial cells (acute tubular necrosis) and from glomerular, vascular, and interstitial inflammatory disease processes ( Table 7-12 ).

TABLE 7-12   -- Causes of Intrinsic Acute Renal Failure



Acute Tubular Necrosis









Hypovolemic shock






Cardiac arrest



Cardiopulmonary bypass



Drug-Induced Nephropathy






Radiocontrast agents









Pigment Nephropathy



Intravascular hemolysis









Acute Interstitial Nephritis
























Nonsteroidal anti-inflammatory drugs (NSAIDs)






Bacterial infection



Viral infections



Rickettsial disease









Systemic Diseases



Systemic lupus erythematosus



Multiple myeloma



Diabetes mellitus






Acute glomerulonephritis



Poststreptococcal glomerulonephritis



Rapidly progressive glomerulonephritis



Vascular Syndromes



Hemolytic-uremic syndrome



Thrombotic thrombocytopenic purpura



Systemic vasculitis



Renal artery thromboembolism



Renal vein thrombosis



Acute Tubular Necrosis

Acute tubular necrosis (ATN) results in ARF due to a number of processes. Medullary ischemia results from hypoxic injury to the thick limb of the loop of Henle. This leads to sloughing of cells (casts), which block tubular flow. The tubular pressure builds up and glomerular filtration is inhibited. Ischemic ATN is common in perioperative medicine, resulting from hypovolemia, hypotension, deliberate ischemia, such as application of suprarenal cross clamps (in cardiac and aortic surgery). ATN also results from a variety of toxic insults. These include aminoglycoside and glycopeptide (vancomycin) antibiotics, NSAIDs, radiographic contrast, pigment (rhabdomyolysis), heavy metals, and solvents.

The clinical course of ATN can be divided into three phases: initiation, maintenance, and recovery. The initiation phase refers to the period in which the kidney is injured and progression is potentially preventable. When renal failure becomes established there may be a dramatic reduction in GFR, manifest as oliguria, with accumulation of nitrogenous waste products of metabolism and the development of uremia, confusion and cognitive decline, pericarditis, platelet dysfunction, and so on. This phase lasts days to weeks. The recovery phase lasts 4 to 6 weeks and is characterized by poor renal concentrating capacity and polyuria. Cellular repair takes place, and GRF gradually returns to normal.

Renal Function Tests

A normally functioning kidney is able to conserve salt and water. A sensitive indicator of tubular function is sodium handling because the ability of an injured tubule to reabsorb sodium is impaired, whereas an intact tubule can maintain this reabsorptive capacity in the face of a hemodynamic stress. With a prerenal insult, the urine sodium concentration should be less than 20 mEq, and the calculated fractional excretion of sodium (FENa) should be less than 1% [FENa = (UNa/PNa) ÷ (UCreatinine/ PCreatinine)]. Urinary osmolality is high in prerenal syndrome. If the patient has tubular damage for any reason the urinary sodium concentration will be greater than expected (>80 mEq) and the urinary osmolality low.

There is very little consensus as to what exactly constitutes ARF. In clinical practice, urea, a breakdown product of protein that is partially reabsorbed, and creatinine, a metabolic byproduct of muscle metabolism that is partially secreted, are used as markers for renal failure. Serum urea underestimates GFR. Serum creatinine is a better marker, assuming that muscle turnover is constant. Hence, in a trauma victim, when there may be significant muscle injury, creatinine may underestimate renal function. Serum creatinine is very insensitive to even substantial declines in GFR. The GFR may be reduced by up to 50% before the serum creatinine level becomes elevated. Creatinine overestimates the GFR, so it is difficult to assess true renal function using the serum creatinine value. Conventional wisdom relates that a doubling of the serum creatinine level is indicative of renal failure. However, this may be misleading in patients with reduced muscle turnover (i.e., critically ill or elderly patients). The creatinine clearance has been used as a method of overcoming these problems. The most commonly used method of calculation is:[*]

There are many reasons why this calculation may be inaccurate, including variations in creatinine production from person to person and from time to time. Furthermore, the weight as an index of muscle mass may be inaccurate in obese or edematous (particularly in critical care) patients. A more effective method would be to compare what is in the urine to what is in the serum as a measure of clearance.

The serum creatinine level is usually falsely raised by error inherent in measurement. The urinary creatinine level is falsely raised by tubular secretion. These errors tend to cancel each other out, so the following equation gives a reasonably accurate estimate of GFR:

Finally, the differences in the way the kidneys handle urea and creatinine is of diagnostic value ( Table 7-13 ). It is known that urea is reabsorbed and creatinine is not. In dehydration (prerenal syndrome) the ratio of urea to creatinine is elevated (from a factor of 10 to a factor of 20).

TABLE 7-13   -- Evaluation of Oliguria



Acute Tubular Necrosis

U:P osmolality



U:P creatinine



Urine sodium (mEq/L)



Fractional excretion of sodium (%)






Creatinine clearance (mL/min)



Blood urea nitrogen/creatinine



U: P, urine : plasma; RFI, renal failure index, calculated as urinary sodium/(urinary creatinine/serum creatinine).




In conclusion, if renal dysfunction is suspected, concentrating capacity (urinary sodium and osmolality) and GFR (creatinine clearance) should be measured. Renal failure index (RFI) is a consolidated figure that may be used as a single score. It is calculated as follows:

Urinary microscopy is a useful diagnostic technique for ARF, particularly in the early stages. The presence of different cells or casts indicate the etiology of the disease process ( Table 7-14 ).

TABLE 7-14   -- Urinalysis Findings in Acute Renal Failure

Type of Renal Injury



Benign or hyaline casts

Acute tubular necrosis

Heme granular or epithelial cell casts

Acute interstitial nephropathy

WBCs, WBC casts, eosinophils, proteinuria

Acute glomerulonephritis

RBCs, dysmorphic RBCs, RBC casts, proteinuria


Benign ± hematuria

WBC, white blood cell; RBC, red blood cell.




*  Multiply by 0.85 if female.

Trauma-Associated Renal Failure

ARF is a frequent complication of major trauma, often associated with severe hypovolemia and ATN. This is prevented with early, aggressive volume resuscitation and control of the source of bleeding.


Rhabdomyolysis refers to the release of large quantities of muscle cell contents as the result of traumatic or nontraumatic injury of skeletal muscle. There is a linear relationship between the degree of trauma and the likelihood of developing pigment nephropathy, as quantified by the serum creatine phosphokinase level. In addition to myoglobin, the protein primarily responsible for renal injury, there is a dramatic increase in the serum concentration of intracellular ions: phosphate, potassium, and magnesium. The serum calcium concentration subsequently falls dramatically.

Four mechanisms are believed to contribute to the development of ARF in myoglobinuria: hypovolemia,renal vasoconstriction, heme-mediated proximal tubular cell toxicity, and intratubular cast formation. Renal perfusion rapidly decreases after muscle cell injury as a result of massive fluid sequestration into the injured tissue. There is a dramatic increase in the circulating concentration of renal vasoconstrictors: epinephrine, norepinephrine, endothelin and angiotensin II. Usually myoglobin is reabsorbed by the proximal tubule and metabolized by releasing free iron, which is soaked up by glutathione, but in rhabdomyolysis this mechanism is overwhelmed. Free heme proteins scavenge nitrous oxide, contributing to vasoconstriction, and generate free radicals, which are nephrotoxic. In addition, in the presence of an acidic urine, myoglobin binds with a renal excretory protein (Tamm-Horsfall) to form a cast that obstructs the tubules and causes ATN.

Although rhabdomyolysis was first described in trauma, it also occurs in other circumstances ( Table 7-15 ). Presenting symptoms in rhabdomyolysis usually reflect the primary disease process with superimposed symptoms of muscle injury or renal failure. Occasionally the patient may present with acute limb compartment syndrome. This may result from a closed fracture of crush injury or inappropriate surgical closure. The patient complains of pain, swelling, tenderness, and bruising. Where there is neurovascular impairment the pain is severe. Urgent fasciotomy is required. Rhabdomyolysis is suspected by the presence of tea-colored urine and a rising creatine phosphokinase level. If the diagnosis cannot be separated from hemoglobinuria, microscopic examination of the urine is necessary. The patient may develop severe hyperkalemia, hyperphosphatemia, hyperuricemia, and lactic acidosis. Profound hypocalcemia may develop as the result of deposition of calcium salts in injured muscle.

TABLE 7-15   -- Causes of Rhabdomyolysis



Traumatic Causes



Crush injury



Lightning strike/electrocution






Extensive burns



Heat-Related Causes






Overexertion (marathon running)



Malignant hyperthermia



Neuroleptic malignant syndrome



Inflammatory Causes












Snake bites



Toxic Causes/Associations












Ecstasy (MDMA)






HMG-CoA reductase inhibitors



Several strategies have been proposed to prevent the development of ARF in rhabdomyolysis. The only approach supported by evidence is aggressive volume replacement. The nature of the fluid (isotonic, hypotonic) is less important than the absolute volume. Urinary alkalization with sodium bicarbonate or sodium acetate is unproven, as is the use of mannitol to promote diuresis. [88] [89]

Abdominal Compartment Syndrome

The abdominal compartment syndrome refers to an abrupt increase in intra-abdominal pressure leading to organ dysfunction. This results in hypotension, respiratory compromise, liver and mesenteric ischemia and renal failure. Abdominal compartment syndrome most commonly is seen in trauma patients who require massive volume resuscitation. Extravasation of large quantities of resuscitation fluid into the bowel wall leads to massive edema and abdominal hypertension. It may also occur in settings associated with mechanical limitations of the abdominal wall, such as tight surgical closures or scarring after burn injuries, that reduce abdominal compliance. Renal insufficiency results from decreased renal perfusion and correlates with the severity of the increased intra-abdominal pressure. Oliguria usually develops when the intra-abdominal pressure exceeds 15 mm Hg; anuria usually develops at pressures greater than 30 mm Hg. The specific cause of renal abdominal compartment syndrome is unclear. There is no correlation between intra-abdominal pressure and urinary output. Venous compression and obstruction undoubtedly plays a part, along with direct cortical compression and aortic and renal artery compression.

The diagnosis of abdominal compartment syndrome is based on clinical suspicion and measurement of bladder pressures. This is achieved by injecting 50 mL of saline into the empty bladder through the Foley catheter. The tubing of the drainage bag is cross clamped and a 16-gauge needle is inserted through the aspiration port and connected to a pressure transducer.

Treatment consists of abdominal decompression usually surgical. The abdominal wall is opened, and the fascia is left open. This is covered by a wound device or the skin. Once edema has subsided, the abdominal wound is closed, although definitive surgery may be delayed for a year or more. If abdominal hypertension is suspected, the anesthesiologist must weigh the cost and benefit of further fluid resuscitation. There is a direct relationship between the volume of crystalloid administered and the incidence of abdominal compartment syndrome. In this situation, colloid resuscitation is probably preferable. [90] [91] [92]

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Perioperative Renal Dysfunction

Renal dysfunction is relatively common in the postoperative period. Its frequency is higher in certain types of surgery such as aortic reconstruction, where a 25% rate has been reported.[92] Postoperative renal dysfunction manifests with a spectrum of severity that can range from mild defects to renal failure requiring dialysis. When acute renal failure superimposes to other underlying diseases, a significant increase in morbidity and mortality is observed [94] [95] but even a moderate renal dysfunction can worsen surgical outcomes. In fact, long-term survival after cardiac surgery is decreased in patients who have moderate renal impairment postoperatively[95] and longer postoperative hospital stays have been observed in patients with mild renal dysfunction after vascular surgery.[96] Thus, the importance of perioperative renal morbidity cannot be underestimated and its prevention assumes a particular importance. Unfortunately, none of the strategies that have been so far proposed to protect from this complication is supported by strong clinical evidence. The study of risk reduction of renal complications is therefore continuing.


The kidney is subject to multiple harmful events in the perioperative period. Among these, renal hypoperfusion is one of the most important factors that contribute to renal dysfunction.[97] The most common causes of decreased renal blood flow are hypovolemia, heart failure, and vascular clamping. Renal hypoperfusion results in hypoxic damage to the outer portion of the renal medulla, an area that is exquisitely sensitive to hypoxia. In fact, this region receives a poor blood supply relative to its high oxygen consumption owing to intense solute reabsorption by the thick segment of the loop of Henle. Alterations in ionic pumps, loss of intracellular adenosine triphosphate, increased intracellular calcium, tubular epithelial cell swelling and sloughing are characteristically observed during renal hypoxic damage. Additionally, hypoxic injury might render the kidney more sensitive to subsequent ischemic events, as suggested by the loss of renovascular autoregulation observed in animals after renal ischemia.[97]

Nephrotoxic substances are also important contributors to renal injury, and it is recognized that their effect is synergistically increased by concomitant renal ischemia and hypoperfusion.[98] One of the mechanisms of contrast dye nephropathy, a common cause of perioperative renal dysfunction, is probably the ultrafiltration of a high osmotic load that, by stimulating an increased tubular solute reabsorption, may increase tubular oxygen consumption and favor cell hypoxia. Anti-inflammatory drugs acutely injure renal cells by inhibiting formation of prostaglandins and their effect is enhanced when the kidney is hypoperfused. In fact, prostaglandins are generated during renal hypoperfusion with the effect of maintaining blood flow to the peritubular vessels and to decrease tubular reabsorption. Suppression of their formation may lead to tubular cell ischemia. Finally, preexisting renal disease, diabetes, hypertension, and chronic ischemia increase the susceptibility of the kidney to superimposed ischemic or chemical insults.[99] This is related to lower renal functional reserve, to impaired renovascular autoregulation as seen in hypertensive patients, and to the fact that the effects of renal insults are often permanent and probably add to each other in a cumulative manner in the course of a life span.

Risk Factors

The risk of perioperative renal dysfunction is significantly affected by patient-related factors such as advanced age,[92] left ventricular dysfunction,[93] and preexisting renal insufficiency.[93] A significant part of the population has mild to moderate renal dysfunction, particularly in the elderly (see Fig. 7-4 ),[67] and is at increased risk for progression to renal failure if further renal damage is superimposed in the perioperative period. The presence of diabetes and systemic hypertension is associated with increased risk for postoperative renal dysfunction, although it is not clear whether this is an independent risk factor or it is rather a consequence of preexisting renal insufficiency. Cholestasis is associated with an increased risk of renal morbidity, probably owing to increased endotoxemia.[100] Recently, evidence of a genetic predisposition to postoperative renal impairment has been reported. In a prospective study on patients undergoing cardiac surgery, certain alleles of the apolipoprotein E genotype have been associated with higher postoperative elevation of creatinine,[101] suggesting that risk stratification might be accomplished by gene testing in the future. Table 7-16 lists the risk factors for perioperative renal dysfunction.

TABLE 7-16   -- Risk Factors for Perioperative Renal Dysfunction and Anesthetic Management

Patient Factors

Preexisting renal disease

Optimize volume status and cardiac output, intravenous fluids and/or inotropes; consider invasive hemodynamic monitoring and/or transesophageal echography.

Heart failure

Optimize blood pressure management before surgery; maintain near-basal blood pressure introperatively.

Advanced age












Surgical Factors

Vascular surgery

Optimize volume status and cardiac output.

Heart surgery

Consider mannitol for vascular clamping, although there is little supporting evidence.

Major abdominal surgery






Pharmacologic Factors

Avoid hypovolemia.


Avoid nephrotoxic antimicrobials, or optimize schedule and formulation.


Avoid NSAIDs in patients at risk.

Contrast dye

Avoid contrast studies or give N-acetylcysteine, bicarbonate; consider ultrafiltration.



Among surgery-related factors, extensive surgery, high intraoperative blood loss, and transfusion requirement significantly increase the risk for renal dysfunction,[92] but vascular and cardiac surgery are associated with the highest risk of renal morbidity. In particular, the incidence of postoperative renal morbidity after aortic surgery is high and has not decreased in recent times, in spite of improvements of surgical and anesthetic management. In patients undergoing aortic thoracoabdominal aneurism repair, Rectenwald and colleagues detected a 28% incidence of renal dysfunction that was associated with worsened outcomes.[102] Patients undergoing vascular surgery have a high incidence of preoperative kidney disease[92] owing to their comorbidities, a fact that partly explains the high frequency of perioperative renal morbidity in this population. Both proximal location and prolonged duration of aortic cross-clamping[103] are associated with worsened renal function after aortic surgery. Renal injury after aortic clamping is related not only to parenchymal ischemia but also to inflammatory activation and ischemic reperfusion injury of the bowel. Avoidance of aortic cross-clamping with endovascular repair should prevent these complications. The most recent randomized controlled study comparing endovascular and open infrarenal aortic aneurism repair showed a similarly low incidence of renal complications in both study arms, a finding that was probably due to the low rate of renal complications in patients with only infrarenal aneurisms.[104] Newer devices allowing repair of more proximal aneurysms that would otherwise require suprarenal clamping have the potential of decreasing the incidence of renal complications in the future.

Patients undergoing cardiac surgery have a high risk of renal complications, and the risk is further increased with valve replacement.[105] In a prospective cohort study in patients undergoing cardiac surgery, Chertow and coworkers identified 10 risk factors for renal morbidity and stratified patients in three groups with increasing risk ( Table 7-17 ).[106] This model has been validated in a broader population of patients and may provide a guide for the risk stratification of patients undergoing this type of surgery.[107] Renal impairment after cardiac surgery is related to renal hypoperfusion, inflammatory activation by the cardiopulmonary bypass, and endotoxemia resulting from bowel ischemia. However, it is not clear whether the avoidance of cardiopulmonary bypass decreases the incidence of postoperative renal failure. The finding of a significant decrease in renal impairment with off-pump surgery [109] [110] has not been confirmed in all studies. [111] [112] The largest randomized controlled study comparing off-pump with on-pump coronary bypass did not specifically address renal morbidity but showed comparable outcomes and better cost-effectiveness with off-pump technique.[112]

TABLE 7-17   -- Independent Risk Factors for Acute Renal Failure After Cardiac Surgery



Valvular surgery



Decreased creatinine clearance



Intra-aortic balloon pump



Prior heart surgery



New York Heart Association class IV



Peripheral vascular disease



Ejection fraction < 35%



Pulmonary rales



Chronic obstructive pulmonary disease



Systolic hypertension or hypotension

Modified from Chertow GM, Lazarus JM: Preoperative renal risk stratification. Circulation 1997;95:878-884.




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Renal Replacement Therapy

Renal replacement therapy involves the use of semipermeable biocompatible membranes to remove nitrogenous waste products, ion products of metabolism and fluid from the body. Indications for renal replacement therapy are listed in Table 7-18 . There are three types: intermittent hemodialysis, peritoneal dialysis, and continuous renal replacement therapy. Two processes underlie renal replacement therapy: diffusion and convection.

TABLE 7-18   -- Indications for Renal Replacement Therapy



Oliguria (urine output < 200 mL/12 hr)



Anuria (urine output < 50 mL/12 hr)



Hyperkalemia (K+ > 6.5 mEq/L)



Severe acidemia (pH < 7.1)



Azotemia (urea > 180 mg/dL)



Pulmonary edema



Uremic encephalopathy



Uremic pericarditis



Uremic neuropathy/myopathy



Severe dysnatremia (Na+ > 160 or < 115 mEq/L)






Drug overdose with dialyzable toxin



Diffusion is a process in which the movement of solutes along an electrochemical gradient from a compartment in which they are in high concentration to one in which they are in lower concentration ( Fig. 7-5 ). An electrolyte solution runs countercurrent to blood flowing on the other side of a semipermeable (small-pore) filter. Small molecules such as urea move along the concentration gradient into the dialysate fluid. Larger molecules are poorly removed by this process. Solute removal is directly proportional to the dialysate flow rate.


FIGURE 7-5  Schematic representation of diffusion.



Convection/ultrafiltration is a process in which solute is carried across a semipermeable membrane in response to a transmembrane pressure gradient (a process known as solvent drag). This mimics the actual situation in the normal human kidney ( Fig. 7-6 ). The rate of ultrafiltration depends on the porosity of the membrane and on the hydrostatic pressure of the blood, which depends on blood flow. This is very effective in removal of fluid and middle-sized molecules, which are thought to cause uremia.


FIGURE 7-6  Schematic representation of convection.



Intermittent hemodialysis is the most widely used and effective modality. Large amounts of fluid can be removed, and electrolyte abnormalities can be rapidly corrected. The system includes a double-lumen intravenous catheter or arteriovenous fistula, a pump that forces blood into a filter (semipermeable membrane), dialysate fluid (usually deionized water) that flows in and out, and a return line to the patient. The blood flow rate is 200 to 400 mL/min, the dialysate flow is approximately 500 mL/min, the filtration rate is between 300 and 2000 mL/hr, and urea clearance is 150 to 250 mL/min. With this high flow and clearance rate patients, depending on the extent of their catabolism, only require 3 to 4 hours of dialysis, two or three times a week. There are dramatic fluid and osmotic shifts between the intravascular and extravascular compartments, causing transient hypotension and disequilibrium. Many critically ill patients cannot tolerate this. With hemodialysis, preferential solute and water removal from blood occurs as blood courses through the dialyzer and comes in “contact” with dialysate across a closed network of semipermeable membranes. These membranes allow diffusive movement of non-protein-bound solutes according to their molecular size and chemical gradients between the dialysate and blood. Water and sodium removal depends on a hydrostatic transmembranepressure gradient between the dialysate and blood that is set up by the head of pressure of blood moving into the dialyzer, resistance to blood return to the patient, and negative pressure in the dialysate compartment created by rapid countercurrent flow of dialysate through it. Anticoagulation with heparin is the standard method for preventing thrombosis of the extracorporeal circuit during acute intermittent dialysis.

Dialysis disequilibrium syndrome is a self-limited condition characterized by nausea, vomiting, headache, altered consciousness, and rarely seizures or coma. It typically occurs after a first dialysis in very uremic patients. The syndrome is triggered by rapid movement of water into brain cells following the development of transient plasma hypo-osmolality as solutes are rapidly cleared from the bloodstream during dialysis. The incidence of this complication has fallen in recent years with the more gradual institution of dialysis and the precise prescription of dialysis to include such variables as membrane size, blood flow rate, and sodium profile.

Peritoneal dialysis has the advantage of being simple and cost effective. A small tube is surgically inserted into the peritoneal cavity. Dextrose is infused into the peritoneum and left in situ for 4 to 6 hours. Waste products diffuse along the concentration gradient into the fluid, which is drained over 30 to 40 minutes. The major disadvantages of peritoneal dialysis are poor solute clearance, poor uremic control, risk of peritoneal infection, and mechanical obstruction of pulmonary and cardiovascular performance.

Continuous renal replacement therapy is used in intensive care units to treat hemodynamically unstable patients. In critical illness the phenomenon of capillary leak increases the interstitial volume and makes patients edematous. This makes the clearance of solute difficult to calculate and indeed implement. Continuous techniques lead to more effective urea and water clearance. Continuous renal replacement therapy combines dialysis and ultrafiltration, and has been used to manage patients with acute renal failure, shock, sepsis, and massive fluid overload. Typical blood flow rates are 120 to 150 mL/min and dialysate rates of 1 to 4 L/hr. A more aggressive version high-volume ultrafiltration is in widespread use, in particular, in patients with sepsis-induced renal failure. In high-volume ultrafiltration up to 35 mL/kg/hr is ultrafiltered from the patient.[113] Cole and colleagues have suggested that this may be an effective method of reducing pressor requirements in sepsis.[114]

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Renal Transplantation

Renal transplantation provides better survival and quality of life than dialysis for patients with ESRD. There is a long-term survival advantage associated with cadaveric (“deceased donor kidney” is preferred by the Association of Organ Procurement Organizations) renal transplantation over dialysis. This difference is most pronounced in patients with diabetes and glomerulonephritis as causes of ESRD. [116] [117] [118]

Ideally, renal transplantation should precede the need for dialysis. The unfavorable relationship between time spent on dialysis therapy and outcome has been shown to be progressive. Four years of dialysis therapy confers approximately 70% of additional mortality and graft loss compared with transplantation before the dialysis therapy. [119] [120] Renal transplantation may lead to complete resolution of cardiovascular complications, systolic dysfunction, left ventricular hypertrophy, left ventricular dilatation, or uremia,[120] as well as other comorbidities related to ESRD.[121]

The rate of cadaveric kidney donation remains at approximately 9,000 per year despite persistent public education and legislative adjustments to facilitate the organ donation process. Thus, the wait for a cadaveric kidney can be as long as several years. Meanwhile, the mean annual mortality of dialysis patients waiting for a transplant is between 6% and 10%.[115] Fortunately, major progress has been made in increasing the numbers of living kidney donors. In 2001, for the first time in the United States, the number of living donors exceeded the number of cadaveric donors.[122]

The introduction of cyclosporine in 1983 and a series of effective new immunosuppressive agents corticosteroids, tacrolimus, mycophenolate, azathioprine, and sirolimus and protocols in following years led to low mortality rates and a 1-year graft survival rate close to 90% by the mid 1990s. [124] [125] [126] Antilymphocyte antibodies are now used in addition to immunosuppressants. [127] [128]

In 1987, the United Network for Organ Sharing (UNOS) began to administer the Organ Procurement and Transplantation Network under contract with the U.S. Department of Health and Human Services. An allocation algorithm was developed that ranked patients according to their waiting time and provided points for varying degrees of human leukocyte antigen matching in an effort to use organs in an equitable fashion.

The algorithm for cadaveric donor kidney allocation between 1995 and October 2002 is listed in Table 7-19 , together with subsequent changes. The algorithm requires constant re-evaluation as the reality of the expanding waiting list changes with time and new information regarding the implications of previous policy decisions becomes available.

TABLE 7-19   -- UNOS Point System for Cadaver Kidney Allocation Before October 2002 with Subsequently Implemented, Adopted, and Proposed Changes


Points Assigned Before October 2002


Time of waiting

1 point assigned to the patient waiting the longest, fractions proportionately assigned to the remainder, 1 additional point for each full year waiting

No change

Estimation of wait

From time of UNOS registration after GFR < 20 mL/min

From time of dialysis or GFR < 20 mL/min[*]


Time lost during inactivity

No loss for inactivity[†]

Antigen mismatch

7 points for 0 B and DR mismatch

2 points for 0 DR mismatch


5 points for 1 B or DR mismatch

1 point for 1 DR mismatch[‡]


2 points for 2 B or DR mismatch


Panel-reactive antibody

4 points, if panel-reactive antibody > 80%

No change


4 points for age < 11 y; 3 points for age of 11 y but < 18 y

No change

ECD kidneys

Waiting time-based allocation[‡]

No category

From Danovitch GM, Cecka JM: Allocation of deceased donor kidneys: Past, present, and future. Am J Kidney Dis 2003;42:882-890.

GFR, glomerular filtration rate; B, blood; DR, donor-related; ECDs; all donors > 60 years or donors > 50 years with a history of hypertension, renal

dysfunction, or nontraumatic cause of death.



Proposed changes.


Subsequently implemented.



Anesthetic Considerations

Because of the presence of coexisting disease in the population with chronic renal failure, a more extensive preoperative evaluation is required. One proposed management strategy for patients with ESRD who are candidates for transplantation is shown in Figure 7-7 .


FIGURE 7-7  Management strategy for ESRD patients who are candidates for transplantation. CABG, coronary artery bypass grafting; CAD, coronary artery disease; CHF, congestive heart failure; ECG, electrocardiogram; echo, echocardiogram; LVSF, left ventricular systolic function; MI, myocardial infarction.  (From De Lemos JA, Hillis LD: Diagnosis and management of coronary artery disease in patients with end-stage renal disease on hemodialysis. J Am Soc Nephrol 1996;7:2044-2054.)




Anesthesia monitoring should be selected based on specific cardiac comorbidities. A pulmonary artery pressure catheter is rarely required, but it should be considered in patients with severe coronary artery disease and left ventricle dysfunction, moderate to severe valvular abnormalities, or significant pulmonary artery hypertension.

Volume status can vary with the time since the last dialysis. Intraoperative volume expansion increases renal blood flow and is associated with improved graft function. [129] [130] [131] [132] [133] Only administration of mannitol combined with volume expansion has been shown to decrease the incidence of acute tubular necrosis after transplantation. [134] [135] Hydroxyethyl starch solutions should be used with caution because of their potential worsening effect on renal function.[135]


Multiple hemostatic abnormalities have been associated with ESRD.[136] Abnormal platelet function and decreased levels of both factor VIII and von Willebrand factor are common. Preoperative dialysis improves platelet function and is the mainstay of the prevention of uremic bleeding, although it is not always immediately effective. Desmopressin, 0.3 μg/kg, given intravenously 1 hour before surgery, and cryoprecipitate, 10 units over 30 minutes, effective in 1 hour, offer an alternative and effective treatment for the temporary reversal of uremic bleeding in patients who require urgent invasive procedures.[138] [139]


Mild to moderate hyperkalemia leading to direct, aldosterone-independent, renal potassium secretion is now considered to be an adaptive response.[139] Stable serum potassium levels of 5.0 to 5.5 mmol/L before surgery should be tolerated.

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Hemodynamic Management

Intraoperative hemodynamic management of the renal patient is challenging. In patients who are anuric or oliguric, intravenous fluid administration should be limited to the correction of losses, given their reduced tolerance to fluid overload. In patients who have residual renal function, hypotension, hypovolemia, and renal hypoperfusion may accelerate the progression to ESRD and should be avoided. However, the frequent coexistence of systolic and diastolic left ventricular dysfunction renders these patients prone to having low cardiac output. Additionally, many patients present to surgery with poorly controlled hypertension while their kidneys cannot tolerate large swings in blood pressure due to compromised autoregulation. Therefore, patients with renal disease undergoing higher-risk procedures often need invasive hemodynamic monitoring with arterial, central venous, and pulmonary artery catheters. There are no definite recommendations guiding the choice of monitoring techniques. In fact, the accuracy of filling pressures to estimate patient volume status is questionable,[140] while no benefit of the routine intraoperative use of pulmonary artery catheters has been documented.[141] The choice of hemodynamic monitoring should be based on the history and characteristics of the individual patient and should be directed to specific hemodynamic goals such as optimization of cardiac output. The use of intraoperative transesophageal echocardiography for hemodynamic and volume status monitoring may have a role in patients with renal disease.

The available evidence guiding the choice of intravenous fluids is still scanty but the use of balanced solutions rather than normal saline offers advantages such as avoidance of hyperchloremic acidosis. Potassium-containing solutions are usually avoided in anuric patients with higher potassium levels, although the potassium intake associated with administration of moderate amounts of these fluids is minimal. It is still unclear whether the use of colloids benefits renal patients. Renal toxicity of dextran is known, but alterations in renal function have been reported also with hetastarch, and the safety of its use in patients with renal insufficiency is unclear.[142] However, in one study hetastarch given in a 15-mL/kg dose did not cause renal damage in patients with no preexisting renal disease[143] and more recent hetastarch formulations with added balanced solutions and with lower molecular weight have improved the safety profile of this drug. [145] [146] Albumin administration should probably be reserved for patients with nephrotic syndrome with very low serum albumin levels.

Intravenous access is usually difficult in patients with ESRD, and central venous access is often needed. The veins and arteries of the nondominant upper extremity should be spared from vascular cannulation, because they may be needed for dialysis access in the future. Subclavian vein cannulation should also be avoided because this procedure is frequently complicated by thrombosis, which compromises dialysis access.

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Pharmacologic Choices

The anesthetic management of patients with renal failure is complicated by the fact that the pharmacokinetics of several anesthetic drugs are significantly altered. Drugs that are lipid insoluble, are ionized, and that undergo significant renal excretion are more heavily affected by kidney dysfunction. Although renal failure does not always increase the duration of a single dose of these drugs, repeat administration or infusion should be at reduced dosage and the effect should be monitored if possible. Renal failure may also affect the response to more liposoluble drugs that are not mainly excreted by the kidney. In fact, some drugs are biotransformed by the liver to active metabolites that do undergo significant renal excretion and, therefore, can be accumulated in patients with renal failure. Additionally, all drugs that are highly protein bound have an increased free fraction in the presence of hypoproteinemia, such as with nephrotic syndrome. Finally, the response to hypnotic drugs is often increased in uremic patients, an effect that has been ascribed to higher permeability of the hematoencephalic barrier. Table 7-20 lists various anesthetic choices in patients with chronic renal failure.

TABLE 7-20   -- Choices of Anesthetic Agents for Renal Patients

Agent Type


Used with Caution


Inhaled agents








Induction agents
























Neuromuscular blockers















Doses of induction agents should be decreased significantly owing to increased free fraction of these drugs, particularly when barbiturates are used. The same consideration applies to benzodiazepines when used for induction or as premedicants. Propofol is not significantly excreted by the kidney; and, although patients with ESRD have slightly increased volume of distribution for this drug, the half-life of propofol is not significantly prolonged in these patients.[146] A higher induction dose requirement for propofol has been reported in one study comparing patients with ESRD with normal patients, a result that has been ascribed to concomitant anemia and a hyperdynamic circulatory state.[147] The choice of anesthetic induction dose should also consider the possible presence of autonomic dysfunction, hypovolemia, pericardial tamponade, and the preoperative use of ACE inhibitors,[148] all factors that can cause hypotension after induction of anesthesia. A safe induction strategy is a slow titration of anesthetic and sedative agents, unless rapid-sequence induction is indicated.

Ketamine is hepatically metabolized, has a short redistribution half life, is well tolerated hemodynamically, and is indicated in patients at risk for hypotension. However, the active metabolites norketamine and dehydronorketamine are renally excreted and have the theoretical potential for accumulation after prolonged use.[149] Etomidate can be used in hemodynamically unstable patients, given the good hemodynamic profile of this drug. The use of prolonged infusions of etomidate is contraindicated owing to adrenal suppression and to the possible accumulation of the solvent propylene glycol in patients with renal failure.

Muscle Relaxants

Rapid-sequence induction is often indicated in patients with renal failure, owing to the high incidence of gastroparesis. Succinylcholine is not contraindicated as long as there is no preexisting hyperkalemia. In fact, this drug causes a transient increase in serum potassium levels but this effect in renal patients is similar to normal subjects.[150] The use of succinylcholine in absence of significant adverse effects has been reported also in moderately hyperkalemic patients.[151] Rocuronium is an acceptable alternative to succinylcholine for rapid-sequence induction if a longer paralysis can be accepted. Renal failure does not affect the response to a single dose of rocuronium. The elimination of rocuronium is mainly biliary, although a 26% renal excretion has been measured in humans.[152] Its duration of action is only slightly prolonged after repeat doses.[153] In fact, the plasma clearance of this drug is not affected by renal dysfunction, although the volume of distribution is increased, resulting in a longer half-life.

Pancuronium has an increased half-life when creatinine clearance is lower than 50 mL/min,[154] and, therefore, its prolonged or repeat administration should be avoided. Owing to the presence of alternative muscle relaxants that are less affected by renal dysfunction, pancuronium is usually avoided in these patients. Vecuronium is mainly biotransformed and excreted by the liver, with only a 15% renal excretion. However, its duration of action is prolonged in patients with ESRD. This effect is due to a decreased clearance, to an increased response to blood concentrations of the drug, and to accumulation of the active metabolite 3-desacetyl-vecuronium.[155] Although the prolonged infusion of vecuronium for muscle relaxation in the intensive care unit should be avoided, the intraoperative use of this drug in patients with chronic renal failure is safe, provided that the appropriate dose adjustments and neuromuscular monitoring are implemented.

Doxacurium, another nondepolarizing muscle relaxant, is mainly excreted by the kidney, and the time to recovery from muscle relaxation is significantly increased in patients with creatinine clearance lower than 40 mL/min.[156] Atracurium and its isomer cisatracurium are the most attractive options for patients with renal failure. In particular, cisatracurium is more potent and leads to less histamine liberation than atracurium, and for these reasons it has become popular. Both drugs undergo non-organ-dependent elimination by the Hoffman reaction, with a non-dose-dependent clearance, and with production of laudanosine.[157] Although accumulation of laudanosine caused cerebral irritation in experimental models, there are no reports of seizures caused by cisatracurium in humans.[158]

Even when the elimination of muscle relaxant is prolonged owing to renal failure, the use of reversal agents is still safe, because these drugs undergo significant renal excretion (50% in the case of neostigmine) and their duration of action is prolonged by renal dysfunction.[159] Additionally, reversal of muscle relaxation with neostigmine is not delayed after a single dose of vecuronium.[160]

Maintenance and Postoperative Period

The effects of inhaled anesthetics in patients with and without renal dysfunction have been discussed previously. Although most of the intravenous agents used during anesthesia and postoperatively undergo hepatic metabolism, some of them undergo transformation to active metabolites that are renally excreted and may accumulate during renal failure. This effect is more significant after prolonged use, such as in the postoperative period. Morphine undergoes 10% conjugation to morphine-6-glucuronide, a molecule with very high potency that rapidly accumulates in the cerebrospinal fluid of patients in renal failure[161] and that may lead to significant sedation. Morphine-6-glucuronide has significant interindividual variability, probably owing to genetic polymorphism at the opioid receptor,[162] and has a delayed onset, probably from a slow transfer through the hematoencephalic barrier.[163]

Morphine-6-glucuronide can be cleared by hemodialysis. Similar to morphine, meperidine and hydromorphone are transformed to neurotoxic metabolites and should be used with care or avoided. Remifentanil, fentanyl, and alfentanil do not have active metabolites and are well tolerated in patients with renal failure.

Among the benzodiazepines, midazolam, lorazepam, and diazepam are transformed to renally excreted metabolites and should be used with care, particularly during postoperative sedation. Additionally, current lorazepam formulations contain propylene glycol, a renally excreted toxic substance that accumulates after prolonged high-dose administration in patients with renal failure.[164]

The use of total intravenous anesthesia with propofol, remifentanil, and cisatracurium has been proposed for renal patients and is probably safe.[165] However, the advantage of such complex and costly strategy is unclear given the safety of current inhalation anesthetics.

Regional anesthesia is commonly chosen in renal patients, particularly for peripheral procedures such as creation of arteriovenous fistulas, for which brachial plexus blocks are a popular choice. Central neuraxial blockade can be used safely, provided that it is remembered that renal patients are prone to hemodynamic instability and hypotension when sympathetic blockade is superimposed to preexisting autonomic dysfunction. The occurrence of epidural hematoma after neuraxial block has been reported in a patient with chronic renal failure,[166] and a high index of suspicion should be maintained. However, this is probably a very rare event in patients who are adequately dialyzed.

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Effects of Perioperative Drugs on Renal Function


Anesthetic agents affect kidney function mainly through their systemic effects. In fact, most anesthetics depress cardiac output and blood pressure, causing a decrease in renal perfusion that can be corrected by adequate volume and hemodynamic support. Surgical stress may alter glomerular blood flow by promoting local vasoconstriction through sympathetic activation, whereas hypovolemia may trigger inappropriate secretion of ADH, which, independently from serum osmolality, causes decreased excretion of free water and of urine. These alterations are usually transient unless hypovolemia and renal hypoperfusion are not corrected.

The evidence that some inhalational anesthetics can lead to altered renal function has raised the concern that renal morbidity may be caused by these agents. Both methoxyflu rane and enflurane have been shown to cause impairment in urine concentrating ability and ADH-resistant polyuria. [168] [169] [170] This effect has been ascribed to the fact that both these gases are highly biotransformed, because the minimally metabolized isoflurane and desflurane are not associated with renal effects, [171] [172] even when they are administered for an extended time.[172] Renal injury from anesthetic gases is related to liberation of inorganic fluoride.[173] In experimental studies, fluoride has been shown to cause damage of the collector duct cell and crystal deposition at the mitochondrial level, probably resulting in impairment of Na+, K+ ATPase and of water reabsorption.[174] Based on animal dose-response curves, a critical fluoride level of 50 μM is considered toxic to the kidney.[175] Sevoflurane has been associated with liberation of fluoride near the toxic range. [177] [178] Alterations in sensitive biochemical markers of altered renal functions have been observed when sevoflurane was administered to healthy volunteers, as compared with desflurane.[178] However, no alterations in blood urea nitrogen or creatinine were observed with sevoflurane in these volunteers. Multiple clinical studies have failed to show clinically significant renal function alterations after administration of sevoflurane. [180] [181] [182] This discrepancy between sevoflurane and methoxyflurane, in spite of comparable serum fluoride levels, may be explained by the faster clearance of the former agent, which results in shorter exposure of renal cells to increased fluoride. However, the recent finding that methoxyflurane, and not sevoflurane, undergoes significant microsomal biotransformation in the kidney, with resulting higher intraparenchymal fluoride concentrations, may explain why actual renal injury does not seem related to serum fluoride concentrations.[182]

Sevoflurane is degraded to the vinyl ether named compound A when administered at low fresh gas flow (<1 L/min) and particularly when baralyme absorbers of smaller size are used. Compound A induces dose-related nephrotoxicity in animal models,[183] and the concern that toxic blood levels of this substance are possible in humans undergoing low flow sevoflurane anesthesia has resulted in considerable concern and in a warning by the U.S. Food and Drug Administration against the use of sevoflurane at fresh gas flows less than 2 L/min. However, there is little evidence that sevoflurane leads to clinically significant renal alterations compared with other inhaled anesthetic agents, as observed by Mazze and colleagues in a retrospective analysis of 1941 patients undergoing sevoflurane anesthesia.[184] This can be explained by the fact that compound A levels in humans are well below the levels observed in animal studies and that human kidney is probably less sensitive to this substance than rat kidney, owing to different biotransformation. The concern that sevoflurane might exacerbate preexisting renal disease has been also raised. However, renal toxicity has not been detected when sevoflurane was administered in patients with renal insufficiency with a relatively high flow of 4 L/min.[185]

Antibiotics and Contrast Dyes

Several antimicrobial agents that are commonly used in the perioperative period are known to be nephrotoxic. Aminoglycosides are associated with a significant incidence of renal failure. The common practice of monitoring the blood levels of these drugs has not been shown to prevent injury, whereas once-daily administration seems to be protective, compared with the traditional three times per day schedule.[186] The common antifungal amphotericin-B is associated with a nephropathy that can be attenuated by fluid administration and by the use of the lipid-complexed forms of the drug.[187] Newer drugs, such as voriconazole, may have less nephrotoxicity with similar antifungal effectiveness, compared with amphotericin.[188]

Administration of radiographic contrast dye is relatively common in the perioperative period and is an important cause of renal dysfunction or failure in hospitalized patients. Risk factors for contrast dye nephropathy include previous renal disease, older age, hypovolemia, heart failure, and diabetes.[189] Noniodinated dyes with low osmolarity have been shown to be somewhat less harmful to the kidney. Excessive osmolar load, renovascular vasoconstriction, and oxidant damage are thought to be involved in the pathogenesis of contrast dye nephropathy. Until recently, intravenous hydration was the only strategy proven to have some effectiveness in preventing this nephropathy in high-risk patients, whereas furosemide and mannitol had no positive effect.[190] More recently, the use of N-acetylcysteine combined with intravenous hydration and administered before and after the contrast dye has been shown to protect against worsened renal injury in patients with chronic renal failure.[191] However, these encouraging results have not been confirmed in another study.[192]

More recently, intravenous hydration using a sodium bicarbonate solution had a lower incidence of contrast medium-related nephropathy compared with normal saline, in patients with creatinine values greater than 1.1 mg/dL.[193] Finally, the use of continuous hemofiltration during percutaneous coronary intervention in patients with chronic renal failure reduced the incidence of nephropathy, compared with intravenous saline infusion alone.[194] Hemofiltration was associated also with a reduction of in-hospital and 1-year mortality, a result that underlines the clinical relevance of contrast medium-induced nephropathy and the importance of its prevention.

Nonsteroidal Anti-inflammatory Drugs

Several NSAIDs have been associated with acute and chronic nephropathy. This condition can be diagnosed by specific computed tomographic findings, and its classic presentation is papillary necrosis.[195]The pathophysiologic mechanisms are multiple and include an allergic-mediated nephritis, a direct toxicity due to chronic high dosage exposure, and medullary ischemia from inhibition of prostaglandin formation.[196] Although there is a clear association between nephropathy and the use of excessive analgesic doses, the incidence of this condition in patients taking usual doses of these drugs is unknown. The incidence of nephropathy due to NSAIDs in surgical patients with no preexisting renal disease is probably very limited, although case reports of adverse renal events exist in the literature, particularly with the use of ketorolac.[197] Renal dysfunction is more likely if NSAIDs are administered to patients who have preexisting renal disease, who are hypovolemic, and who are receiving other nephrotoxic drugs.[198] Perioperative administration of ketorolac did not cause renal dysfunction in patients receiving high-flow sevoflurane anesthesia.[199] Diclofenac did not cause a decrease in glomerular function in elderly patients who had a baseline creatinine clearance of higher than 40 mL/min/1.73 m2.[200] It is still not clear whether the use of selective cyclooxygenase inhibitors lowers the incidence of renal side effects.[201]

Antihypertensive Agents

ACE inhibitors are commonly used by hypertensive patients and have proven benefits in patients with congestive heart failure, coronary artery disease, and renal insufficiency. In the last group ACE inhibitors decrease urinary protein excretion and seem to delay the progression of renal insufficiency. Angiotensin receptor antagonists are a new class of drugs that have been recently introduced in the therapy for patients with ACE inhibitor intolerance and seem to share the same benefits of these drugs. Although the acute preoperative administration of ACE inhibitors seems to have favorable effects on renal perfusion,[202] investigators have reported that patients who are chronically managed with these drugs have pronounced hypotension after induction of anesthesia if the drug is not stopped before the day of the surgery.[203] Similar results have been observed in patients taking angiotensin receptor antagonists.[204] These results have been ascribed to an impairment of angiotensin-mediated hemodynamic regulation, as suggested by a bigger hypotensive response to hypovolemia in animals pretreated with these drugs.[205] Additionally, Cittanova and coworkers have shown in a prospective observational study that chronic use of ACE inhibitors predicts postoperative renal dysfunction, expressed as a 20% reduction in creatinine clearance.[206] However, the results of this study are limited by its retrospective design, although confounding factors such as the presence of heart failure were accounted for. Besides, increases in creatinine concentration are commonly observed during ACE inhibition and are not due to permanent kidney damage. The clinical relevance of the renal dysfunction reported by Cittanova and coworkers is unclear; therefore, routine discontinuation of these drugs before surgery cannot be recommended.

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Copyright © 2005 Saunders, An Imprint of Elsevier

Risk Modification and Renal Protection Strategies

A considerable amount of research has been invested in trying to identify effective strategies that could alter the course of perioperative renal dysfunction, and several agents have been shown to afford renal protection from toxic or ischemic insults in animal models. Unfortunately, none of these agents has been demonstrated to be effective in well-conducted clinical trials. Among these agents dopamine has been known for a long time to cause a selective renal vasodilation when infused with a low rate owing to a specific action on dopaminergic receptors. This effect has been shown to result in increased sodium and water excretion in animals,[207] and it has been hypothesized that the use of dopamine at low dosages may result in protection from renal injury. The use of dopamine in patients with high risk for renal damage or with established renal failure has widely spread. However, recent evidence from well-conducted studies does not support this practice. In a blinded, randomized study by Lassnigg and colleagues comparing low-dose dopamine to placebo or furosemide in cardiac surgery patients, dopamine did not improve creatinine clearance, urine output, or sodium excretion in the postoperative period.[208] Additional evidence that dopamine does not improve renal outcomes is provided by a randomized study by Bellomo and associates on patients with systemic inflammatory response syndrome and acute renal dysfunction. In this study, dopamine decreased neither creatinine concentrations nor the number of patients requiring renal replacement therapy.[209]

Mannitol is also considered to be a renoprotective agent, owing to its ability to increase urine output, decrease tubular cell swelling, and scavenge oxygen radicals. This drug is often used during cardiac and vascular surgery, although the evidence supporting this use is very poor.[210] Loop diuretics block ion pumps and may reduce tubular cell oxygen consumption, theoretically providing protection from ischemia.[97] However, in the study by Lassnigg and coworkers on cardiac surgery patients, the group treated with furosemide had significantly worsened creatinine clearance and a higher number of patients with renal injury, compared with the dopamine and placebo groups.[208] It is worth noticing that the furosemide group had the highest urine output, compared with the other two groups. Evidence in patients with acute renal failure[211] suggests that the use of diuretics to increase urine output may be associated with worsened outcomes, although the results have not been confirmed in one study.[212]These results combined suggest that using pharmacologic agents to increase urine output may not necessarily lead to improved outcomes in patients with renal dysfunction or who are at high risk for it.

Other agents have been suggested to be renoprotective. Among these, calcium channel blockers might protect from tubular cell hypoxia by decreasing intracellular calcium and have been shown to limit tubular damage during cardiac surgery.[213] ADH analogues and other dopamine receptor agonists such as fenoldopam might also have a renoprotective action. However, evaluation in larger clinical trials is awaited before reverting to their routine use with the intent to limit or improve renal injuries in high-risk patients. In the meanwhile, the only recommendations that can be made, in the perioperative management of the patients at high-risk for renal dysfunction, are to try to limit exposure to known insults by avoiding or carefully using nephrotoxic drugs, choose noncontrast imaging studies when possible[214] or use one of the available protection techniques, and select lower risk surgical procedures. Given the importance of ischemic injury in the determination of renal dysfunction in the perioperative period, restoration and maintenance of normovolemia can be considered as the most effective renal protection strategy. This can be a challenging task, given the limitations of the available monitoring techniques and the uncertainties on the quantity and the quality of the optimal intraoperative fluid management.

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Copyright © 2005 Saunders, An Imprint of Elsevier


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