Renal disease

Glomerular filtration rate

The GFR is considered the best measure of overall renal function, although it can be normal in some renal disease states (i.e., nephrotic syndrome). The GFR describes the plasma volume filtered per unit time. Conceptually, GFR can be thought of as follows:

where K _f is the surface area for filtration, Δ P is the difference in hydrostatic forces across the membrane, and ΔΠ is the difference in osmotic pressures across the same membrane. Different renal impairments impact the different variables in this equation. For example, diseases of the glomerulus will decrease K _f while prerenal conditions such as hypovolemia will decrease Δ P .

GFR may be calculated from timed urine volumes plus urinary and plasma creatinine concentrations (creatinine clearance), or from the clearance of an exogenous substance such as inulin. A number of formulas exist that estimate the GFR from various serum and urine indices ( Table 21.2 ). Normal values for GFR are 125 to 140 mL/min and vary with gender, body weight, and age. GFR decreases by approximately 8 mL/min per year after the age of 30. A GFR less than 60 mL/min for 3 months or longer is indicative of CKD.

Serum creatinine and creatinine clearance

Creatinine, an endogenous marker of renal filtration, is produced at a relatively constant rate by hepatic conversion of skeletal muscle creatinine. Creatinine is freely filtered by the kidney and is not reabsorbed. As a result, creatinine clearance is the most reliable measure of GFR. Unlike GFR, creatinine clearance does not require corrections based on age or the presence of a steady state.

Normal serum creatinine concentrations range from 0.6 to 1.1 mg/dL in women and 0.8 to 1.3 mg/dL in men, reflecting differences in skeletal muscle mass. A number of factors (i.e., accelerated creatinine production in the setting of a recent meat meal) can increase serum creatinine concentrations in the absence of a concomitant decrease in GFR. Conversely, a small increase in serum creatinine can reflect large decreases in GFR; in this context, knowledge of the baseline creatinine is critical. For example, an increase in creatinine concentration from a baseline 0.7 to 1.2 mg/dL in an elderly adult, while still “normal,” reflects a near 50% decrease in GFR. Creatinine concentrations are normally stable until approximately 40% of renal function is lost. Serum creatinine values are also slow to reflect acute changes in renal function. For example, if AKI occurs and the GFR decreases from 100 to 10 mL/min, serum creatinine values may not plateau for 7 days.

Blood urea nitrogen

Blood urea nitrogen (BUN) concentrations also tend to vary inversely with the GFR. However, the pronounced influences of dietary intake, coexisting disease, and intravascular fluid volume on BUN concentrations make it potentially misleading as a test of renal function. For example, production of urea is increased by high-protein diets or gastrointestinal bleeding, resulting in increased BUN despite a normal GFR. Dehydration and increased catabolism, as occurs during a febrile illness, also causes increased BUN despite a normal GFR. Despite this variability, chronic BUN concentrations higher than 50 mg/dL usually reflect a decreased GFR. An acute rise in BUN/creatinine ratio to 20:1 or higher can be seen in hypovolemia; this condition is often referred to as prerenal azotemia.

Urine concentrating ability

Renal tubular function is most often assessed by measuring urine concentrating ability. Renal tubular dysfunction is established by demonstrating that the kidneys do not produce appropriately concentrated urine in the presence of a physiologic stimulus for the release of ADH. In the absence of diuretic therapy, significant glycosuria, or proteinuria, a urine specific gravity higher than 1.018 suggests adequate urine-concentrating ability.

Proteinuria

The normal daily albumin excretion rate is less than 150 mg/day. Proteinuria is present in 5% to 10% of adults during screening examinations. Transient proteinuria may be associated with fever, congestive heart failure, seizure activity, pancreatitis, and exercise. Orthostatic proteinuria occurs in up to 5% of adolescents while in the upright position and resolves with recumbency; this typically is not associated with any deterioration in renal function. Persistent proteinuria generally connotes significant renal disease. Microalbuminuria is an early sign of diabetic nephropathy. Rates greater than 300 mg/day are considered severely increased and greater than 3500 mg/day are in the nephrotic range. Severe proteinuria may result in hypoalbuminemia, with associated decreases in plasma oncotic pressures and increases in unbound drug concentrations. The severity of albuminuria is used in the staging of CKD.

Fractional excretion of sodium

The fractional excretion of sodium (FENa) is a measure of the percentage of filtered sodium excreted in the urine ( Table 21.3 ). It is most useful in the differentiation between prerenal and renal disease. A FENa less than 1% occurs when normally functioning renal tubules are conserving sodium and is suggestive of prerenal disease. A FENa greater than 2% reflects decreased ability of the renal tubules to conserve sodium and is consistent with tubular dysfunction.

Urinalysis

Examination of the urine is useful in the workup of renal and urologic diseases. Substances not ordinarily in a healthy urine can be detected, such as protein, glucose, hemoglobin, leukocytes, and toxins. The urine pH and specific gravity are determined, and sediment microscopy is used to identify the presence of cells, casts, microorganisms, and crystals. Hematuria may be caused by bleeding anywhere between the glomerulus and urethra. Microhematuria may be benign or may reflect glomerulonephritis, renal calculi, or cancer of the genitourinary tract. Sickle cell disease is a consideration in black patients who exhibit hematuria. Red blood cell casts are typical of acute glomerulonephritis. White blood cell (WBC) casts are commonly seen with pyelonephritis. Granular casts are characteristic of acute tubular necrosis (ATN).

Diagnosis of acute kidney injury

Presenting signs and symptoms of AKI range widely depending on the etiology. Patients may be asymptomatic, complain of generalized malaise, or be unresponsive in the setting of severe azotemia and acidosis. A hypovolemic patient with a prerenal injury may have recent weight loss and orthostatic vitals, whereas a cirrhotic patient with prerenal injury may present with dyspnea and appear volume overloaded on exam.

The diagnosis of AKI is usually made based on identification of one of the following: an increase in serum creatinine concentration of more than 0.3 mg/dL within 48 hours, an increase of at least 1.5 times the baseline creatinine within a 7-day period, or an abrupt decrease in urine output to less than 0.5 mL/kg/hr or 500 mL/day. A decrease in urine output does not necessarily accompany all cases of AKI. Depending on urine volume, AKI is divided into oliguric and nonoliguric subtypes. Anuria (i.e., urine output <100 mL/day) rarely occurs in the context of AKI. Azotemia is a condition marked by abnormally high serum concentrations of nitrogen-containing compounds, such as BUN and creatinine, and is a hallmark of AKI regardless of its cause.

Etiology of acute kidney injury

The etiology of AKI is classically divided into prerenal, intrarenal (or intrinsic), and postrenal causes ( Table 21.4 ).

Risk factors for development of acute kidney injury

Risk factors for the development of AKI include preexisting renal disease, advanced age, diabetes, sepsis, trauma, hypovolemia, chronic liver disease, congestive heart failure (CHF), anemia, proteinuria, and burns ( Table 21.6 ). Iatrogenic components that predispose to AKI include emergency surgery, major operative procedures (in particular those requiring cardiopulmonary bypass), inadequate fluid resuscitation, sustained hypotension, delayed treatment of sepsis, and administration of nephrotoxic drugs or dyes.

Complications associated with acute kidney injury

Acute, severe complications of AKI result from impaired fluid balance and electrolyte homeostasis. Retained fluid and solutes, together with inability to maintain pH, lead to volume overload, electrolyte abnormalities, and metabolic acidosis. AKI manifests in organ system dysfunction throughout the body. In addition, infections occur frequently in patients who develop AKI and are a leading cause of morbidity and mortality.

Neurologic complications of AKI include confusion, asterixis, somnolence, seizures, and polyneuropathy. These changes appear to be related to the buildup of protein and amino acids in the blood and fluid overload, and symptoms may be ameliorated by dialysis.

Cardiovascular and pulmonary complications include systemic hypertension, congestive heart failure, and pulmonary edema, reflecting salt and water retention. The presence of congestive heart failure or pulmonary edema suggests the need to decrease the intravascular fluid volume. Cardiac dysrhythmias may develop; peaked T waves and widened QRS complexes are indicative of hyperkalemia. Uremic pericarditis may also occur.

Hematologic complications include anemia, decreased vitamin D activation, and coagulopathy in the setting of uremia-induced platelet dysfunction. Hematocrit values between 20% and 30% are common as a result of hemodilution and decreased erythropoietin (EPO) production.

Metabolic derangements include hyperkalemia, hyperphosphatemia, hypocalcemia, hypermagnesemia, hypoalbuminemia, hyponatremia, and metabolic acidosis.

Gastrointestinal complications include anorexia, nausea, vomiting, and ileus. Gastroparesis may occur due to uremia. Upper gastrointestinal bleeding occurs in as many as one-third of patients who develop AKI and may contribute to anemia.

Infection commonly affects the respiratory and urinary tracts and sites where breaks in normal anatomic barriers have occurred owing to indwelling catheters. Impaired immune responses due to uremia may contribute to the increased likelihood of infections in patients with AKI.

Treatment of acute kidney injury

Management of AKI is aimed at limiting further renal injury and correcting fluid, electrolyte, and acid-base derangements. Triage should be performed to assess the need for emergent renal replacement therapy (RRT). Underlying causes should be identified and terminated or reversed where possible. Specifically, hypovolemia, hypotension, and low cardiac output should be corrected, sepsis treated, and ongoing insults such as nephrotoxic drugs removed. A mean arterial pressure (MAP) of 65 mm Hg should be attained, but there is no evidence of better outcomes when supraphysiologic values of either systemic pressure or cardiac output are targeted.

Fluid resuscitation and vasopressor therapy are universally emphasized in the prevention and treatment of AKI. While there is significant practice variation on choice of crystalloid, balanced salt solutions such as lactated Ringer are increasingly used, particularly if a significant amount of fluid administration is anticipated. Traditionally, 0.9% normal saline was the preferred crystalloid for use in patients with renal dysfunction because it lacks potassium. However, significant resuscitation with normal saline increases the risk of hyperchloremic metabolic acidosis with resultant hyperkalemia and may predispose to AKI. Hydroxyethyl starch should be avoided, as it has been implicated as a possible cause of AKI.

In the treatment of AKI associated with sepsis, most recommendations favor the use of norepinephrine, titrating to maintain a MAP of 65 to 70 mm Hg or baseline blood pressure if known. Vasopressin is an alternative to traditional vasopressors in the treatment of septic shock and may be effective when other agents have failed. It may be of particular use in managing vasoplegia after cardiopulmonary bypass.

The use of dopamine to either treat or prevent AKI is not supported by the literature and in fact may have undesirable side effects, including tachycardia. Fenoldopam is a dopamine analogue with exclusively dopamine-1 agonist activity. Fenoldopam causes renal vasodilation at low doses and peripheral vasodilation at higher doses. Despite the theoretical renal benefit, the results of clinical trials using fenoldopam have been mixed, and it is not recommended in the setting of AKI.

Loop diuretics can be used in the hypervolemic, nonanuric patient with AKI; they can be continued if the patient is diuretic responsive. There is some evidence to suggest that the risk of posttransplantation ATN may be reduced in patients treated with mannitol plus hydration compared with hydration alone. The mechanism of action presumably relates to mannitol’s ability to cause renal vasodilation through the production of renal prostaglandins. Mannitol is also commonly used in the treatment of pigment-induced nephropathies; however, clinical evidence of its benefit in this context is weak.

Prophylactic administration of N-acetylcysteine, an antioxidant that acts as a free radical scavenger, has been evaluated to protect against contrast-induced AKI. However, it is not recommended owing to conflicting data and the risk of serious complications such as anaphylactoid reactions. The same is true of the prophylactic administration of mannitol, statins, and sodium bicarbonate. However, alkalinization of urine with sodium bicarbonate is helpful in the treatment of pigment-induced nephropathies such as rhabdomyolysis, as it increases the solubility of myoglobin and prevents the formation of tubular precipitates.

Patients with AKI should receive adequate nutrition, ideally enterally. Protein and energy requirements increase in the context of sepsis and worsening underlying disease, and malnutrition can contribute to impaired immune system function. In diabetics, glucose should be kept under reasonable control to avoid exacerbation of the renal injury. Maintaining blood glucose below 180 mg/dL is a reasonable strategy. Restrictions on potassium, phosphorous, and sodium intake are usually necessary.

Renal replacement therapy remains the mainstay of treatment for severe AKI. The acronym AEIOU calls to mind indications for emergent RRT: severe metabolic a cidosis, severe e lectrolyte abnormalities (in particular hyperkalemia), i ngestion of dialyzable toxin (i.e., lithium, ethylene glycol), fluid o verload (i.e., pulmonary edema), and signs or symptoms of severe u remia (i.e., seizures, hemodynamically significant pericardial effusion). RRT modalities include continuous RRT, intermittent hemodialysis, and peritoneal dialysis. The purpose of all of them is to remove excess fluid and solutes from the blood and optimize pH and electrolyte balance. The choice of RRT modality depends on the availability of resources and patient characteristics; there are no data supporting one method over another.

Prognosis for patients with acute kidney injury

AKI is a significant risk factor for both short- and long-term mortality. AKI in hospitalized patients confers an approximately 30% increased risk of death. For AKI in the setting of multiorgan failure, the mortality rate exceeds 50%. The most common causes of death are sepsis, cardiovascular dysfunction, and pulmonary complications. Patients who survive AKI have an increased risk of developing CKD.

Drug dosing in patients with acute kidney injury

Renal impairment affects most organ systems and consequently the pharmacology of many drugs. The selection of drugs that do not rely on the kidneys for excretion is ideal but not always possible. Consultation with a pharmacist is recommended.

The first step in tailoring drug dosing for patients with renal impairment is to estimate the GFR. Doses rarely require modification until the GFR is less than 30 mL/min. If creatinine is stable, then the calculated estimate of GFR is a reasonable estimate of renal function. If creatinine is rapidly rising, however, calculated GFR is likely an overestimate. Conversely, if creatinine is falling quickly, the estimated GFR (eGFR) is probably less than the actual GFR.

Loading doses often require no adjustment, unless the estimated volume of distribution is increased, as in cases of fluid overload. Maintenance doses are usually decreased in proportion to the decrease in GFR, taking into account the percentage of drug that is renally cleared. In general, maintenance doses may be reduced by one of two methods: the interval method or the dose method. With the interval method, the patient receives the usual drug dose at longer dosing intervals. With the dose method, the patient receives a smaller drug dose at the usual dosing interval.

For medications with wide therapeutic ranges or long plasma half-lives, the interval between doses is generally increased. For medications with narrow therapeutic ranges or short plasma half-lives, reduced doses at normal intervals are advised. In reality, a combination of the two methods of dose adjustment is frequently used ( Table 21.7 ).

Drugs with active or toxic metabolites are best avoided, as these metabolites can accumulate in patients with renal disease. Predictable nephrotoxins are also to be avoided. These include drugs that reduce renal perfusion (e.g., ACE inhibitors, angiotensin receptor blockers [ARBs], NSAIDs, diuretics) and those that are may act as renal tubular toxins (aminoglycosides, vancomycin, and contrast media).

Gastrointestinal absorption can be reduced in AKI due to gut edema, nausea and vomiting, and coadministration with phosphate binding drugs; however, this would rarely be of concern perioperatively because the vast majority of medications are given intravenously.

Anesthetic management of patients with acute kidney injury

A thorough preoperative evaluation of the patient with AKI should include an electrocardiogram (ECG), serum chemistries, complete blood count, coagulation parameters, and urinary indices. Chest imaging is reasonable if there is respiratory insufficiency. Owing to the high morbidity and mortality, only lifesaving surgery should be undertaken in patients with AKI. The principles guiding the management of anesthesia are the same as those that guide supportive treatment of AKI, namely maintenance of an adequate systemic blood pressure and cardiac output and avoidance of further renal insults, including hypovolemia, hypoxia, and exposure to nephrotoxins.

Adequate peripheral venous access must be obtained, which often requires a second and large-bore IV. Invasive hemodynamic monitoring is advised to facilitate careful control of blood pressure and to accommodate frequent blood gas analyses and electrolyte measurements. Hyperkalemia in particular should be monitored for closely and treated aggressively, if identified.

Preoperative dialysis may be indicated in high-risk patients. If there is a suspicion of platelet dysfunction, desmopressin (DDAVP) can be administered preoperatively to temporarily increase concentrations of von Willebrand factor (vWF) and factor VIII and improve coagulation. Correction of anemia, targeting a hemoglobin of 10 g/dL, is also likely to reduce bleeding. This can be done with administration of iron, EPO, or transfusion depending on the etiology of the anemia and the urgency of the surgery. Estrogens and cryoprecipitate may also be of use in suspected uremic bleeding.

Maintenance (and restoration, if necessary) of intravascular fluid volume is essential to maintain renal perfusion. It is also important to maintain adequate systemic blood pressure and cardiac output and to avoid excessive peripheral vasoconstriction. Potentially nephrotoxic substances (i.e., NSAIDs, aminoglycosides, radiocontrast, proton pump inhibitors) and those that may contribute to prerenal injury (i.e., diuretics, ACE inhibitors, ARBs) should be prescribed cautiously, particularly during acute illness. For the particular case of anticipated contrast exposure, preventative measures include use of low-osmolar agents, reduced doses, and periprocedural volume expansion with isotonic fluids.

If a large volume resuscitation is required during a procedure, or if there are signs of hypervolemia, diuretics can be considered in the nonoliguric patient to reduce the risk of complications of volume overload. For patients who meet criteria, postoperative dialysis should be initiated as soon as the patient is hemodynamically stable.

Morphine (and codeine, which is metabolized to morphine), meperidine, and tramadol are best avoided in patients with reduced GFR due to the possible accumulation of the toxic metabolites morphine-6-glucuronide (neurotoxicity), normeperidine (seizures), and O-desmethyltramadol (seizures), respectively. Succinylcholine is typically avoided if potassium concentrations are greater than 5.5 mEq/L. If neuromuscular blockade is required, cisatracurium is a good choice due to its degradation by Hofmann elimination in the plasma. Antibiotics known to be nephrotoxic should be avoided or administered in reduced dose.

Diagnosis

Signs and symptoms of CKD are often undetectable ( Table 21.8 ). When they do appear, complaints are nonspecific, such as fatigue, malaise, and anorexia. Most patients will have the diagnosis made during routine testing. The workup is similar to that described for AKI. A careful history and laboratory evaluation, including serum creatinine and urinary sediment analysis, is helpful in establishing the diagnosis and etiology of renal dysfunction. Renal ultrasound is useful to rule out obstructive disease and screen for polycystic kidney disease. It is also helpful for assessing the renal vasculature and estimating the extent of parenchymal disease through evaluation of renal echogenicity and kidney size. Computed tomography (CT) scanning remains the gold standard for the diagnosis of nephrolithiasis. Renal biopsy may be required to establish the diagnosis.

Progression of chronic kidney disease

Staging of CKD has been established by the international guideline group Kidney Disease: Improving Global Outcomes (KDIGO). Staging is based on eGFR (G-stage) and severity of albuminuria (A-stage) ( Table 21.9 ). The cause of CKD is used in some staging paradigms. The degree of albuminuria may be evaluated by measuring daily albuminuria or using the albumin -to-creatinine ratio (ACR) in a spot urine sample. An ACR greater than 30 mg/g (3.4 mg/mmol) is considered abnormal. Established risk factors for rapid progression of CKD are hypertension, hyperglycemia, severe proteinuria, and black race.

Adaptation to chronic kidney disease

The normally functioning kidneys precisely regulate the concentrations of solutes and water in the extracellular fluid despite large variations in daily dietary intake. Owing to substantial renal reserve function, patients with CKD often remain relatively asymptomatic until renal function is less than 10% of normal.

The kidneys exhibit various compensatory mechanisms to the loss of nephron volume that accompanies CKD. While effective in the short term, these mechanisms can contribute to long-term exacerbation of kidney injury. For example, there is accelerated filtration in the normally functioning nephrons—a process known as hyperfiltration. This occurs as a result of glomerular hypertension and increased glomerular permeability. Filtered macromolecules may result in inflammation and further injury, including glomerulosclerosis. Activation of the renin-angiotensin-aldosterone axis can contribute to chronic tubulointerstitial ischemia and resulting injury. Treatments seek to intervene in this harmful chain of events.

Adaptation to progressive functional impairment can be divided into several stages. The first adaptation involves an increase in substances such as creatinine and urea, which are largely dependent on glomerular filtration for urinary excretion. As the GFR decreases, the plasma concentrations of these substances increase, but the increase is not directly proportional to the degree of GFR impairment. For example, serum creatinine concentrations frequently remain within normal limits despite a 50% decrease in GFR. Beyond a certain point, however, when the renal reserve has been exhausted, even minimal further decreases in the GFR can result in significant increases in the serum creatinine and urea concentrations.

The second stage of adaptation is seen with solutes such as potassium. Serum potassium concentrations are maintained within normal limits until GFR approaches 10% of normal, at which point hyperkalemia manifests. As nephrons are lost, the remaining nephrons increase their secretion of potassium through increased blood flow and increased sodium delivery to the collecting tubules. In addition, because aldosterone secretion increases in patients with renal failure, there is a greater loss of potassium through the gastrointestinal tract. This system of enhanced gastrointestinal secretion is an effective compensatory mechanism in the presence of normal dietary intake of potassium but can be easily overwhelmed by an acute exogenous potassium load (i.e., packed RBC administration during the perioperative period) or acute endogenous potassium load (i.e., hemolysis or tissue trauma such as that associated with surgery).

The third stage of adaptation is seen in sodium homeostasis and regulation of the extracellular fluid compartment volume. In contrast to the levels of other solutes, sodium balance remains intact despite progressive deterioration in renal function and variations in dietary intake. Nevertheless, the system can be overwhelmed by abruptly increased sodium intake (resulting in volume overload) or decreased sodium intake (resulting in volume depletion).

Complications of chronic kidney disease affect multiple organ system