The kidney plays a central role in homeostatic control of volume status, blood pressure, plasma electrolyte composition, and acid-base balance, and for excretion of nitrogenous and other waste products. Complications associated with AKI are, therefore, protean, and depend on the severity of AKI and other associated conditions. Mild to moderate AKI may be entirely asymptomatic, particularly early in the course.
Buildup of nitrogenous waste products, manifested as an elevated BUN concentration, is a hallmark of AKI. BUN itself poses little direct toxicity at levels below 100 mg/dL. At higher concentrations, mental status changes and bleeding complications can arise. Other toxins normally cleared by the kidney may be responsible for the symptom complex known as uremia. Few of the many possible uremic toxins have been definitively identified. The correlation of BUN and SCr concentrations with uremic symptoms is extremely variable, due in part to differences in urea and creatinine generation rates across individuals.
Hypervolemia and Hypovolemia
Expansion of extracellular fluid volume is a major complication of oliguric and anuric AKI, due to impaired salt and water excretion. The result can be weight gain, dependent edema, increased jugular venous pressure, and pulmonary edema; the latter can be life threatening. Pulmonary edema can also occur from volume overload and hemorrhage in pulmonary renal syndromes. AKI may also induce or exacerbate acute lung injury characterized by increased vascular permeability and inflammatory cell infiltration in lung parenchyma. Recovery from AKI can sometimes be accompanied by polyuria, which, if untreated, can lead to significant volume depletion. The polyuric phase of recovery may be due to an osmotic diuresis from retained urea and other waste products as well as delayed recovery of tubular reabsorptive functions.
Administration of excessive hypotonic crystalloid or isotonic dextrose solutions can result in hypoosmolality and hyponatremia, which, if severe, can cause neurologic abnormalities, including seizures.
Abnormalities in plasma electrolyte composition can be mild or life threatening. Frequently the most concerning complication of AKI is hyperkalemia. Marked hyperkalemia is particularly common in rhabdomyolysis, hemolysis, and tumor lysis syndrome due to release of intracellular potassium from damaged cells. Potassium affects the cellular membrane potential of cardiac and neuromuscular tissues. Muscle weakness may be a symptom of hyperkalemia. The more serious complication of hyperkalemia is due to effects on cardiac conduction, leading to potentially fatal arrhythmias.
Metabolic acidosis, usually accompanied by an elevation in the anion gap, is common in AKI, and can further complicate acid-base and potassium balance in individuals with other causes of acidosis, including sepsis, diabetic ketoacidosis, or respiratory acidosis.
Hyperphosphatemia and Hypocalcemia
AKI can lead to hyperphosphatemia, particularly in highly catabolic patients or those with AKI from rhabdomyolysis, hemolysis, and tumor lysis syndrome. Metastatic deposition of calcium phosphate can lead to hypocalcemia. AKI-associated hypocalcemia may also arise from derangements in the vitamin D–parathyroid axis. Hypocalcemia is often asymptomatic but can lead to perioral paresthesias, muscle cramps, seizures, carpopedal spasms, and prolongation of the QT interval on electrocardiography. Calcium levels should be corrected for the degree of hypoalbuminemia, if present, or ionized calcium levels should be followed. Mild, asymptomatic hypocalcemia does not require treatment.
Hematologic complications of AKI include anemia and bleeding, both of which are exacerbated by coexisting disease processes such as sepsis, liver disease, and disseminated intravascular coagulation. Direct hematologic effects from AKI-related uremia include decreased erythropoiesis and platelet dysfunction.
Infections are a common precipitant of AKI and also a dreaded complication of AKI. Impaired host immunity has been described in end-stage renal disease and may be operative in severe AKI.
The major cardiac complications of AKI are arrhythmias, pericarditis, and pericardial effusion.
AKI is often a severely hypercatabolic state, and, therefore, malnutrition is a major complication.
Treatment: Acute Kidney Injury
The management of individuals with and at risk for AKI varies according to the underlying cause (Table 279-3). Common to all are several principles. Optimization of hemodynamics, correction of fluid and electrolyte imbalances, discontinuation of nephrotoxic medications, and dose adjustment of administered medications are all critical. Common causes of AKI such as sepsis and ischemic ATN, do not yet have specific therapies once injury is established, but meticulous clinical attention is needed to support the patient until (if) AKI resolves. The kidney possesses remarkable capacity to repair itself after even severe, dialysis-requiring AKI. However, some patients with AKI do not recover fully and may remain dialysis dependent.
Table 279-3 Management of Ischemia- and Nephrotoxin-Associated AKI |Favorite Table|Download (.pdf)
Table 279-3 Management of Ischemia- and Nephrotoxin-Associated AKI
1. Optimization of systemic and renal hemodynamics through volume resuscitation and judicious use of vasopressors
2. Elimination of nephrotoxic agents (e.g., ACE inhibitors, ARBs, NSAIDs, aminoglycosides) if possible
3. Initiation of renal replacement therapy when indicated
a. Rhabdomyolysis: consider forced alkaline diuresis
b. Tumor lysis syndrome: allopurinol or rasburicase
2. Volume overload
a. Salt and water restriction
a. Restriction of enteral free water intake, minimization of hypotonic intravenous solutions including those containing dextrose
a. Restriction of dietary potassium intake
b. Discontinuation of potassium-sparing diuretics, ACE inhibitors, ARBs, NSAIDs
c. Loop diuretics to promote urinary potassium loss
d. Potassium binding ion-exchange resin (sodium polystyrene sulfonate)
e. Insulin (10 units regular) and glucose (50 mL of 50% dextrose) to promote entry of potassium intracellularly
f. Inhaled beta-agonist therapy to promote entry of potassium intracellularly
g. Calcium gluconate or calcium chloride (1 g) to stabilize the myocardium
5. Metabolic acidosis
a. Sodium bicarbonate (if pH <7.2 to keep serum bicarbonate >15 mmol/L)
b. Administration of other bases e.g., THAM
c. Renal replacement therapy
a. Restriction of dietary phosphate intake
b. Phosphate binding agents (calcium acetate, sevelamer hydrochloride, aluminum hydroxide—taken with meals)
a. Calcium carbonate or calcium gluconate if symptomatic
a. Discontinue Mg2+ containing antacids
a. Acute treatment is usually not required except in the setting of tumor lysis syndrome (see above)
a. Sufficient protein and calorie intake to avoid negative nitrogen balance
11. Drug dosing
a. Careful attention to dosages and frequency of administration of drugs, adjustment for degree of renal failure
Prevention and treatment of prerenal azotemia requires optimization of renal perfusion. The composition of replacement fluids should be targeted to the type of fluid lost. Severe acute blood loss should be treated with packed red blood cells. Isotonic crystalloid and/or colloid should be used for less severe acute hemorrhage or plasma loss in the case of burns and pancreatitis. Crystalloid solutions are less expensive and probably equally efficacious as colloid solutions. Crystalloid has been reported to be preferable to albumin in the setting of traumatic brain injury. Isotonic crystalloid (e.g., 0.9% saline) or colloid should be used for volume resuscitation in severe hypovolemia, whereas hypotonic crystalloids (e.g., 0.45% saline) suffice for less severe hypovolemia. Excessive chloride administration from 0.9% saline may lead to hyperchloremic metabolic acidosis. Use of bicarbonate-containing solutions (e.g., dextrose water with 150 mEq sodium bicarbonate) should be used if metabolic acidosis is a concern.
Optimization of cardiac function in the cardiorenal syndrome (i.e., renal hypoperfusion from poor cardiac output) may require use of inotropic agents, preload- and afterload-reducing agents, antiarrhythmic drugs, and mechanical aids such as an intraaortic balloon pump. Invasive hemodynamic monitoring to guide therapy may be necessary.
Cirrhosis and Hepatorenal Syndrome
Fluid management in individuals with cirrhosis, ascites, and AKI is challenging because of the frequent difficulty in ascertaining intravascular volume status. Administration of intravenous fluids as a volume challenge may be required diagnostically as well as therapeutically. Excessive volume administration may, however, result in worsening ascites and pulmonary compromise in the setting of hepatorenal syndrome or AKI due to superimposed spontaneous bacterial peritonitis. Peritonitis should be ruled out by culture of ascitic fluid. Albumin may prevent AKI in those treated with antibiotics for spontaneous bacterial peritonitis. The definitive treatment of the hepatorenal syndrome is orthotopic liver transplantation. Bridge therapies that have shown promise include terlipressin (a vasopressin analog), combination therapy with octreotide (a somatostatin analog) and midodrine (an α1-adrenergic agonist), and norepinephrine, all in combination with intravenous albumin (25–50 mg per day, maximum 100 g/d).
Several agents have been tested and have failed to show benefit in the treatment of ischemic acute tubular injury. These include atrial natriuretic peptide, low-dose dopamine, endothelin antagonists, loop diuretics, calcium channel blockers, α-adrenergic receptor blockers, prostaglandin analogs, antioxidants, antibodies against leukocyte adhesion molecules, and insulin-like growth factor and many others. Most studies have enrolled patients with severe and well-established AKI, and treatment may have been initiated too late. Novel kidney injury biomarkers may provide an opportunity to test agents earlier in the course of AKI.
AKI due to acute glomerulonephritis or vasculitis may respond to immunosuppressive agents and/or plasmapheresis (Chap. 277). Allergic interstitial nephritis due to medications requires discontinuation of the offending agent. Glucocorticoids have been used, but not tested in randomized trials, in cases where AKI persists or worsens despite discontinuation of the suspected medication. AKI due to scleroderma (scleroderma renal crisis) should be treated with ACE inhibitors.
Early and aggressive volume repletion is mandatory in patients with rhabdomyolysis, who may require 10 L of fluid per day. Alkaline fluids (e.g., 75 mmol sodium bicarbonate added to 0.45% saline) may be beneficial in preventing tubular injury and cast formation, but carry the risk of worsening hypocalcemia. Diuretics may be used if fluid repletion is adequate but unsuccessful in achieving urinary flow rates of 200–300 mL/h. There is no specific therapy for established AKI in rhabdomyolysis, other than dialysis in severe cases or general supportive care to maintain fluid and electrolyte balance and tissue perfusion. Careful attention must be focused on calcium and phosphate status because of precipitation in damaged tissue and released when the tissue heals.
Prompt recognition and relief of urinary tract obstruction can forestall the development of permanent structural damage induced by urinary stasis. The site of obstruction defines the treatment approach. Transurethral or suprapubic bladder catheterization may be all that is needed initially for urethral strictures or functional bladder impairment. Ureteric obstruction may be treated by percutaneous nephrostomy tube placement or ureteral stent placement. Relief of obstruction is usually followed by an appropriate diuresis for several days. In rare cases, severe polyuria persists due to tubular dysfunction and may require continued administration of intravenous fluids and electrolytes for a period of time.
Hypervolemia in oliguric or anuric AKI may be life threatening due to acute pulmonary edema, especially since many patients have coexisting pulmonary disease, and AKI likely increases pulmonary vascular permeability. Fluid and sodium should be restricted, and diuretics may be used to increase the urinary flow rate. There is no evidence that increasing urine output itself improves the natural history of AKI, but diuretics may help to avoid the need for dialysis in some cases. In severe cases of volume overload, furosemide may be given as a bolus (200 mg) followed by an intravenous drip (10–40 mg/h), with or without a thiazide diuretic. Diuretic therapy should be stopped if there is no response. Dopamine in low doses may transiently increase salt and water excretion by the kidney in prerenal states, but clinical trials have failed to show any benefit in patients with intrinsic AKI. Because of the risk of arrhythmias and potential bowel ischemia, it has been argued that the risks of dopamine may outweigh the benefits in the treatment or prevention of AKI.
Electrolyte and Acid-Base Abnormalities
The treatment of dysnatremias and hyperkalemia is described in Chap. 45.Metabolic acidosis is not treated unless severe (pH <7.20 and serum bicarbonate <15 mmol/L). Acidosis can be treated with oral or intravenous sodium bicarbonate (Chap. 47), but overcorrection should be avoided because of the possibility of metabolic alkalosis, hypocalcemia, hypokalemia, and volume overload. Hyperphosphatemia is common in AKI and can usually be treated by limiting intestinal absorption of phosphate using phosphate binders (calcium carbonate, calcium acetate, sevelamer, or aluminum hydroxide). Hypocalcemia does not usually require therapy unless symptoms are present.
Protein energy wasting is common in AKI, particularly in the setting of multisystem organ failure. Inadequate nutrition may lead to starvation ketoacidosis and protein catabolism. Excessive nutrition may increase the generation of nitrogenous waste and lead to worsening azotemia. Total parenteral nutrition requires large volumes of fluid administration and may complicate efforts at volume control.
The anemia seen in AKI is usually multifactorial and is not improved by erythropoiesis stimulating agents, due to their delayed onset of action and the presence of bone marrow resistance in critically ill patients. Uremic bleeding may respond to desmopressin or estrogens, but may require dialysis in the case of longstanding or severe uremia. Gastrointestinal prophylaxis with proton pump inhibitors or histamine (H2) receptor blockers is required. Venous thromboembolism prophylaxis is important and should be tailored to the clinical setting; low-molecular-weight heparins and factor Xa inhibitors have unpredictable pharmacokinetics in severe AKI and should be avoided.
Dialysis Indications and Modalities
(See also Chap. 281) Dialysis is indicated when medical management fails to control volume overload, hyperkalemia, acidosis, in some toxic ingestions, and when there are severe complications of uremia (asterixis, pericardial rub or effusion, encephalopathy, uremic bleeding). The timing of dialysis is still a matter of debate. Late initiation of dialysis carries the risk of avoidable volume, electrolyte, and metabolic complications of AKI. On the other hand, initiating dialysis too early may unnecessarily expose individuals to intravenous lines and invasive procedures, with the attendant risks of infection, bleeding, procedural complications, and hypotension. The initiation of dialysis should not await the development of a life-threatening complication of renal failure. Many nephrologists initiate dialysis for AKI empirically when the BUN exceeds 100 mg/dL in patients without clinical signs of recovery of kidney function.
The available modes for renal replacement therapy in AKI require either access to the peritoneal cavity (for peritoneal dialysis) or the large blood vessels (for hemodialysis, hemofiltration, and other hybrid procedures). Small solutes are removed across a semipermeable membrane down their concentration gradient ("diffusive" clearance) and/or along with the movement of plasma water ("convective" clearance). The choice of modality is often dictated by the immediate availability of technology and the expertise of medical staff. Peritoneal dialysis is performed through a temporary intraperitoneal catheter. It is rarely used in the United States for AKI in adults but has enjoyed widespread use internationally, particularly when hemodialysis technology is not available. Dialysate solution is instilled into and removed from the peritoneal cavity at regular intervals in order to achieve diffusive and convective clearance of solutes across the peritoneal membrane; ultrafiltration of water is achieved by the presence of an osmotic gradient across the peritoneal membrane, typically due to high concentrations of dextrose in the dialysate. Being a continuous procedure, it is often better tolerated than intermittent procedures like hemodialysis in hypotensive patients. Peritoneal dialysis may not be sufficient for hypercatabolic patients due to inherent limitations in dialysis efficacy.
Hemodialysis can be employed intermittently or continuously, and can be done through convective clearance, diffusive clearance, or a combination of the two. Vascular access is through the femoral, internal jugular, or subclavian veins. Hemodialysis is an intermittent procedure that removes solutes through diffusive and convective clearance. Hemodialysis is performed 3–4 h per d, three to four times per week, and is the most common form of renal replacement therapy for AKI. One of the major complications of hemodialysis is hypotension, particularly in the critically ill.
Continuous intravascular procedures were developed in the early 1980s to treat hemodynamically unstable patients without inducing the rapid shifts of volume, osmolarity, and electrolytes characteristic of intermittent hemodialysis. Continuous renal replacement therapy (CRRT) can be performed by convective clearance [continuous venovenous hemofiltration (CVVH)], in which large volumes of plasma water (and accompanying solutes) are forced across the semipermeable membrane by means of hydrostatic pressure; the plasma water is then replaced by a physiologic crystalloid solution. CRRT can also be performed by diffusive clearance [continuous venovenous hemodialysis (CVVHD)], a technology similar to hemodialysis except at lower blood flow and dialysate flow rates. A hybrid therapy combines both diffusive and convective clearance [continuous venovenous hemodiafiltration (CVVHDF)]. To achieve some of the advantages of CRRT without the need for 24-h staffing of the procedure, a newer form of therapy has been introduced, termed slow low-efficiency dialysis (SLED) or extended daily dialysis (EDD). In this therapy, blood flow and dialysate flow are higher than in CVVHD, but the treatment time is reduced to 12 h.
The optimal dose of dialysis for AKI is not clear. Daily intermittent hemodialysis and high-dose CRRT do not confer a demonstrable survival or renal recovery advantage, but care should be taken to avoid undertreatment. Studies have failed to show that continuous therapies are superior to intermittent therapies. If available, CRRT is often preferred in patients with severe hemodynamic instability, cerebral edema, or significant volume overload.