Acute Kidney Injury Associated with Pigmenturia or Crystal Deposits

Abolfazl Zarjou

Anupam Agarwal

ACUTE KIDNEY INJURY RESULTING FROM HEME PIGMENTS

Myoglobinuric Acute Kidney Injury

Rhabdomyolysis is a potentially life-threatening syndrome involving damage and the breakdown of skeletal muscle causing myoglobin and other intracellular proteins and electrolytes to be released into the circulation. This syndrome is a relatively common cause of acute kidney injury (AKI)^* and accounts for 7% to 10% of AKI in the United States.¹ Perhaps the first historical suggestion of rhabdomyolysis goes back to biblical times where it is related that the Israelites became ill and died after eating large quantities of quail, which had probably fed on hemlock seeds. In modern times, the initial description of the consequences of traumatic muscle injury on kidney function is attributed to Bywaters and Beall,² who vividly documented the brown-black granular casts, a reduction in urinary output, hyperkalemia, and ultimately, death in the victims of crush injuries at the time of the London bombing during World War II. In addition, Bywaters et al.³,⁴ were the first to establish a definite pathophysiologic relationship between crush injury, myoglobinuria, and acute tubular necrosis.

Causes of Rhabdomyolysis and Myoglobinuria

A variety of conditions and diseases can lead to rhabdomyolysis and AKI, and the list of causes is constantly being expanded with new case reports (Table 36.1). Although the list is long, it can be divided into eight basic categories: (1) direct muscle injury, (2) drugs and toxins, (3) genetic disorders, (4) infections, (5) excessive muscular activity, (6) ischemia, (7) electrolyte and endocrine/metabolic disturbances, and (8) immunologic diseases. The common denominator for all the causes is a disruption of normal skeletal muscle cell structure or metabolism leading to derangements in Ca²⁺ homeostasis. Adenosine triphosphate (ATP) depletion further interferes with Ca²⁺ sequestration, leading to lethal intracellular Ca²⁺ overload that activates a number of autolytic enzymes, causing myofibril and membrane damage.⁵ The subsequent death and lysis of skeletal muscle cells results in the release of intracellular contents into the circulation. In the United States, the three most common causes of rhabdomyolysis are drug abuse (with a substantial percentage related to ethanol use), muscle compression, and seizures.¹

Crush injuries¹,⁶,⁷ and prolonged compression of the limbs can lead to massive rhabdomyolysis and its sequelae, including AKI. Significant volume and electrolyte imbalance may ensue due to a massive influx of extracellular fluid and solutes into and efflux of major intracellular ions such as potassium and phosphate out of the damaged cells.¹,⁷

Drugs and toxins have also been implicated in causing rhabdomyolysis.⁸,⁹ Several mechanisms underlie drug- and toxin-induced rhabdomyolysis, including (1) drug-induced coma leading to compression of a limb; (2) excessive muscular activity (e.g., phencyclidine, LSD, hemlock); (3) druginduced hyperthermia; (4) drug-induced vasoconstriction with muscle ischemia (e.g., cocaine); (5) impaired ATP formation (e.g., cyanide, salicylates); (6) the induction of potassium or phosphorus depletion (e.g., diuretics); (7) a hypersensitivity reaction resulting in myositis; (8) a direct toxic effect on skeletal muscle cells (e.g., ethanol); and (9) drugs whose mechanism of toxicity is still controversial (e.g., statins).¹⁰,¹¹ Although certain drugs, such as heroin¹² or ethanol,¹³ may have a direct toxic effect on skeletal muscle cells, a more important factor in causing rhabdomyolysis is the occurrence of a coma after their use leading to muscle compression and ischemia. In addition, drug use may be associated with other conditions that predispose one to rhabdomyolysis. For example, in the alcoholic patient, concomitant hypokalemia,¹⁴ hypophosphatemia,¹⁵ and starvation¹⁶ may contribute to rhabdomyolysis. The presence of multiple etiologic factors may be a common scenario, as noted in a large clinical series by Gabow et al.,¹⁷ in which more than
one factor capable of injuring muscles was present in 51 of 87 episodes of rhabdomyolysis. One such etiologic factor demonstrating the variable causes of rhabdomyolysis is fire ant bites. In a recent case report, a patient was described who developed AKI because of rhabdomyolysis after extensive red fire ant bites.¹⁸ It was suggested that formic acid, an important constituent of fire ant venom, was the underlying mechanism for rhabdomyolysis. In small doses, formic acid is an antibiotic, but in larger doses it acts as an inhibitor of the mitochondrial cytochrome oxidase complex causing tissue suffocation and, consequently, cell death.¹⁸

TABLE 36.1 Causes of Rhabdomyolysis

Traumatic muscle injury
	Crush injuries
	Compression/pressure necrosis
	Severe burns
	Contact sports
	Direct muscle trauma
Drugs and toxins (partial list)
	Ethanol
	Heroin
	Barbiturates
	Cocaine
	Amphetamines
	Benzodiazepines
	Phencyclidine
	HMG-CoA reductase inhibitors (statins)
	Fibric acid derivatives (clofibrate, gemfibrozil)
	Hemlock
	Salicylates
	Carbon monoxide
	Ethylene glycol
	Isopropyl alcohol
	Snake and insect venoms
	Succinylcholine
	Colchicine
	Propofol
	Paraphenylenediamine
	Colchicum autumnale (autumn crocus)
	Monensin
Genetic disorders
	Phosphorylase deficiency (McArdle disease)
	Phosphofructokinase deficiency
	α-Glucosidase deficiency
	Carnitine palmityltransferase deficiency
	Amylo-1,6-glucosidase deficiency
	Phosphohexoseisomerase deficiency
Infections (partial list)
	Influenza
	Tetanus
	Gas gangrene
	Legionnaires’ disease
	Shigellosis and salmonellosis
	Coxsackievirus
	Leptospirosis
	Streptococcus
	HIV
Excessive muscular activity
	Vigorous exercise
	Seizures/status epilepticus
	Delirium tremens
	Status asthmaticus
	Psychotic muscle contractions
	Tetany
Ischemia
	Arterial occlusion
	Compression
Electrolyte and endocrine/metabolic disorders
	Hypokalemia
	Hypophosphatemia
	Hypothyroidism
	Diabetic ketoacidosis
	Diabetic hyperosmolar nonketotic coma
	Hypothermia and hyperthermia
Immunologic disease
	Polymyositis
	Dermatomyositis
HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A.

Various hereditary enzyme deficiencies and defects have been associated with rhabdomyolysis and myoglobinuria. These are divided into groups of patients with hereditary deficiency of enzyme(s) in (1) glycolytic/glycogenolytic pathways; (2) the fatty acid oxidation pathway; (3) the Krebs cycle; (4) the pentose phosphate pathway; (5) the purine nucleotide cycle; (6) the mitochondrial respiratory chain; (7) patients prone to malignant hyperthermia; and (8) other miscellaneous causes such as sarcoplasmic Ca²⁺-ATPase deficiency.¹⁹

The myositis occasionally associated with infectious diseases such as influenza, HIV, and leptospirosis can lead to a
disruption of skeletal muscle cells and thus rhabdomyolysis and myoglobinuria.¹⁹,²⁰ In addition, infections like gas gangrene produce a clostridial toxin that is directly myotoxic.²⁰

Excessive muscular activity has been increasingly recognized as a common and preventable cause of rhabdomyolysis.²¹,²² Strenuous and exhaustive exercise, especially in deconditioned men (so-called “white collar” rhabdomyolysis), can result in serious rhabdomyolysis.²³ Contributing factors to this syndrome include exercising in a hot or humid environment, volume depletion, fasting, eccentric muscle contractions (e.g., running downhill), preexistent muscle injury (e.g., alcoholic myopathy), and male sex.²³ Intense muscle contractions deplete energy reserves, thus disrupting normal cellular transport processes and permitting calcium to accumulate in the cell, resulting in the activation of proteolytic enzymes and cell death. Based on a number of studies,²³ physical training raises the threshold and induces a degree of resistance to the development of exertional rhabdomyolysis. Training may induce this adaptation by increasing the number of collateral blood vessels, hence improving oxygen delivery, fuel storage, and use. Other conditions associated with excessive muscle contractions and significant rhabdomyolysis include seizures, tetanus, delirium tremens, electrical shock injury, and extensive burns.

Severe potassium deficiency can lead to rhabdomyolysis, myoglobinuria, and AKI. Hypophosphatemia, especially in the setting of severe alcoholism, has been associated with muscle cell injury and rhabdomyolysis.¹⁵ Other metabolic conditions that have been reported to cause rhabdomyolysis include hyperaldosteronism, ketoacidosis, hypothyroidism, and deranged core body temperature.¹⁹

Myoglobin Metabolism

Myoglobin is composed of a folded polypeptide portion (globin) and a prosthetic group, heme, which contains an atom of iron.²⁴,²⁵ Based on tracer studies, the half-life of myoglobin in the circulation varies from 1 to 3 hours; after 6 hours, it disappears completely.²⁴,²⁵ Small quantities of myoglobin (milligram amounts) released during normal conditions are probably cleared by the reticuloendothelial system. Because of its relatively small molecular weight and size, larger quantities of myoglobin released from the muscle in states of injury or disease are readily filtered at the glomerulus and thus can be cleared by renal mechanisms.

In human circulation, myoglobin appears to be bound to an α₂-globulin that has a binding capacity of 23 mg per deciliter. Because myoglobin is loosely bound to α₂-globulin at concentrations below 23 mg per deciliter, approximately 15% to 50% of the myoglobin is in an unbound state and is filtered (fractional clearance relative to inulin, 0.75) and excreted in the urine. This interesting kinetic relationship between myoglobin and its binding protein probably explains why myoglobin is detected in the urine when plasma levels are less than 23 mg per deciliter.²⁴,²⁵ According to Kagen,²⁶ the effective renal threshold for myoglobin occurs when the plasma concentration exceeds 0.5 to 1.5 mg per deciliter. Based on a distribution volume of myoglobin of 28.5 L and a muscle myoglobin content of 4 mg per gram, Knochel²⁷ has calculated that injury of approximately 102 g of muscle would be required to exceed a renal threshold of 1.5 mg per deciliter. Beyond this threshold, the factors that determine the urinary concentration and the excretion rate of myoglobin include (1) the plasma concentration of myoglobin, (2) the extent of myoglobin binding in plasma, (3) glomerular filtration rate (GFR), and (4) urine flow rate.

Myoglobin is visible in plasma or urine to the unaided eye when the concentration exceeds 100 mg per deciliter. Because of the relatively rapid renal clearance of myoglobin, visible plasma levels of myoglobin have never been reported. Knochel²⁷ has estimated that a visible plasma level of myoglobin would require the destruction of 7.1 kg of muscle in an anephric patient. In contrast, because myoglobin is cleared rapidly in patients with a normal renal function, visible myoglobinuria is achieved with far less muscle necrosis. For example, necrosis of only 178 g of muscle, achieving a plasma myoglobin level of only 2.5 mg per deciliter, is sufficient to produce visible myoglobinuria in a patient with normal renal function excreting concentrated urine.²⁷ However, reduced renal function or a high urine flow rate decreases the concentration of myoglobin in urine, thus diminishing the use of a visual inspection of the urine to detect myoglobinuria for a given amount of muscle necrosis. In these situations, benzidine, guaiac, or orthotoluidine (dipstick) tests detect levels as low as 0.5 mg per 100 mL. These tests, however, do not distinguish between myoglobin and hemoglobin. This can be accomplished by immunodiffusion.²⁸ Multiple alternative methods of detection are now available, including hemagglutination inhibition, radioimmunoassay, and complement fixation.¹⁹

Given the rapid renal clearance of myoglobin (1 to 6 hours), its presence in the blood or urine may not be the most sensitive method to detect rhabdomyolysis. In contrast, creatine kinase, an intracellular muscle enzyme, appears to be a more sensitive plasma marker for rhabdomyolysis because of its slower clearance (serum half-life, 1.5 days), and therefore is the preferred diagnostic modality.²⁹

Pathophysiology of Myoglobinuric and Hemoglobinuric Acute Kidney Injury

Given the biochemical similarity between myoglobin and hemoglobin, the general consensus that they share a common pathogenetic pathway, and the fact that the classical animal models used to study pigment-induced oliguric AKI share intravascular hemolysis (hemoglobinuria) and rhabdomyolysis (myoglobinuria), the pathogenesis of these two pigments are presented together in this discussion.

The proposed mechanisms by which myoglobinuria or hemoglobinuria cause AKI include (1) hypovolemia and renal ischemia, (2) direct tubular toxicity of myoglobin/hemoglobin, (3) tubular obstruction from heme pigment casts, and (4) glomerular fibrin deposition. As in many clinical syndromes, it is probably the interplay of these proposed
mechanisms that results in AKI rather than any one single factor. These interactions are schematized in Figure 36.1.

FIGURE 36.1 The pathophysiologic processes involved in myoglobinuric and hemoglobinuric acute kidney injury. (Modified from Zager RA. Rhabdomyolysis and myohemoglobinuric acute renal failure. Kidney Int. 1996;49:317, with permission.)

Hypovolemia and Renal Ischemia

During the initial phase of glycerol-induced AKI (an animal model for rhabdomyolysis), there is a marked reduction in cardiac output (36%), renal blood flow (RBF) (20%), and an increase in renal vascular resistance.³⁰ Subcutaneous or intramuscular (but not intravenous) glycerol not only produces muscle injury but also causes sequestration of fluid into the injection site.³¹ Thus, the hemodynamic changes are due, in part, to the migration of plasma water into the site of injury with consequent severe intravascular volume contraction occurring in this model of myohemoglobinuric AKI. Comparable hemodynamic changes occur in clinical settings that damage and cause necrosis of the skeletal muscle such as crush syndrome.⁷ Moreover, the conditions that predispose one to rhabdomyolysis, such as drug-induced coma with accompanying poor oral intake, or excessive insensible fluid losses from exhaustive exercise or burns, contribute to intravascular volume depletion and compromise of renal function.

In the initial phases of glycerol-induced AKI, the reduction in RBF is associated with a redistribution of regional blood flow from the outer to the inner cortex³² and vasoconstriction of the afferent and efferent arteriole. The proposed mediators of this initial renal vasoconstriction include (1) increased sympathetic nerve activity, (2) augmented activity of the renin-angiotensin system, (3) reduced nitric oxide production and availability, (4) suppressed renal prostaglandin production, (5) increased plasma vasopressin concentration, and (6) glomerular microthrombi.³³ The reduction in nitric oxide may be due to the fact that heme proteins can scavenge this important endogenous vasodilator. Nitric oxide synthase inhibition worsens and nitric oxide supplementation protects against glycerol-induced AKI. This lends support to the protective effects of nitric oxide in the pathogenesis of myoglobin-induced AKI.³⁴

The critical role that intravascular volume depletion plays in the pathogenesis of myohemoglobinuric AKI is demonstrated by studies in which volume status is manipulated in the glycerol-treated rat. In initial studies, Oken et al.³⁵,³⁶ noted that renal damage was ameliorated if the rats ingested adequate quantities of water before the administration of glycerol. Similarly, Hsu et al.³⁰ found that the reduction in RBF and function in response to the administration of glycerol was attenuated in rats chronically drinking saline compared with rats drinking water. Reineck et al.³⁷ provided a better understanding of the important temporal relationship
between volume expansion and improvement of renal function in the glycerol-treated rat. Like other investigators, they noted a significant reduction in RBF and GFR after the administration of glycerol. These variables could be restored to normal levels by volume expansion with Ringer’s solution at 3 and 6 hours, but not at 18 hours after the administration of glycerol. They concluded that the initial decrease in GFR and the low fractional excretion of sodium was due to a decrease in RBF (renal hypoperfusion), whereas other events (e.g., tubular necrosis) accounted for decreased GFR at later time points. These preclinical studies support the clinical observation that, initially, patients with myoglobinuric AKI have features of prerenal azotemia, including a low urinary fractional excretion of sodium.³⁸ In addition, they provide the rationale for early use of volume expansion in patients with rhabdomyolysis and hemoglobinuria.

Myoglobin and Hemoglobin Nephrotoxicity. Bywaters and coworkers²,³ expanded on their original description of the clinical syndrome of rhabdomyolysis-induced AKI to examine the role of myoglobin as a direct nephrotoxin. They noted that rabbits ingesting an acid diet with a urine pH below 6.0 had AKI after the infusion of human myoglobin, whereas rabbits ingesting a normal diet were spared from renal injury.³ Other investigators³⁹,⁴⁰ have confirmed this observation that intravenous infusions of myoglobin are relatively benign but can become highly nephrotoxic in the setting of acidemia/aciduria and volume depletion. Vetterlein et al.⁴¹ demonstrated that infusions of myoglobin had no effect on RBF in normal rats, but worsened RBF in hypotensive animals. Thus, it appears that heme proteins can intensify the degree of vasoconstriction in the setting of hypovolemia. This may explain the clinical observation that the mere presence of myoglobinuria or a markedly elevated creatine kinase at the time of hospital admission had little predictive value in determining who experiences AKI.¹⁷ These observations suggest that other conditions (i.e., volume depletion, acidemia) are required for renal injury to occur.

To address the question of why heme pigments are nephrotoxic only in certain metabolic conditions, Braun et al.³¹ investigated the effect of breakdown products of heme pigments on renal tubular transport. First, they noted that 4 hours after a subcutaneous glycerol administration to rats there was both swelling and pallor of the proximal tubule and depression of normal tubular uptake of hippurate and tetraethylammonium. The investigators measured the uptake of hippurate in renal cortical slices incubated with various specific heme proteins or their derivatives and found that incubation with hemoglobin did not depress uptake if the pH of the medium was kept at 7.4. However, uptake was depressed when the pH was lowered to 5.4 or during hypoxic conditions. In an acidic medium (pH <5.6), both myoglobin and hemoglobin dissociate into ferrihemate (hematin; molecular weight, 670 Da) and their respective globin moieties.⁴² Incubation with ferrihemate, regardless of the pH of the medium, depressed the uptake of hippurate in the renal cortical slices, whereas incubation with either globin or albumin alone had no significant effect on transport. The inhibitory action of ferrihemate on hippurate transport could be mitigated if the incubation medium also contained albumin, which presumably bound the ferrihemate. Intravenous injection of ferrihemate has been shown to cause glomerular and tubular damage in the dog.⁴³ Therefore, it has been proposed that after filtration by the glomerulus, myoglobin or hemoglobin is converted to ferrihemate in the presence of an acid tubular fluid, or after exposure to the acid pH of cellular lysosomes, and it is this metabolite that is directly nephrotoxic.

These and other studies implicate the heme moiety as a potent pro-oxidant molecule.⁴⁴,⁴⁵ It is well established that free heme can facilitate the production of reactive oxygen species via Fenton/Haber-Weiss reactions. Under physiologic conditions, free heme is sequestered by heme binding proteins, and oxidative stress can cause the release of heme, thereby increasing free heme levels. In addition, evidence suggests that the iron component of heme is the culprit of heme-induced oxidative damage.⁴⁴,⁴⁵ The central role of iron has been substantiated by a number of studies demonstrating amelioration of both myoglobinuric and hemoglobinuric AKI and lipid peroxidation by the iron chelator, deferoxamine.⁴⁶ On the other hand, Zager⁴⁷ has also shown that deferoxamine attenuates renal damage in the glycerol-induced model of AKI, but concluded that iron toxicity is mediated by factors other than free radical generation. For example, it has been suggested that heme protein endocytosis in the proximal tubule sensitizes the tubular cell membranes to the damaging effects of phospholipase A₂.⁴⁸ In addition, heme proteins appear to deplete cellular ATP stores and, thus, have an adverse effect on cellular energetics.⁵ Iron toxicity may be due to redox cycling of the heme moiety from ferrous to ferric and to ferryl oxidation states.⁴⁹

In order to contend with the pro-oxidant heme moiety, the kidney induces antioxidant defensive machinery, including heme oxygenase-1 (HO-1).⁴⁴,⁴⁵ HO-1 catalyzes the ratelimiting step in the oxidative degradation of heme liberating equimolar amounts of iron, carbon monoxide, and biliverdin. Iron in turn induces the expression of ferritin. HO-1 is known to have important antioxidant, anti-inflammatory, and antiapoptotic functions that have been attributed to one or more of its byproducts.⁴⁴,⁴⁵ Nath et al.⁵⁰ have demonstrated that the renal induction of both HO-1 and ferritin is increased in the glycerol-induced model of myohemoglobinuric AKI. Prior induction of HO-1 coupled with increased ferritin synthesis attenuated renal damage, whereas pharmacologic inhibition of the enzyme or its gene deletion worsened renal function.⁵⁰,⁵¹ This increased activity of HO-1, or possibly a broad-based proximal tubular cytoresistance in the kidney, may explain the experimental observation that after induction of myohemoglobinuric AKI rechallenging the animals with a second dose of glycerol does not result in AKI.⁵² One speculation is that in the setting of clinical myoglobin-induced AKI, there may be factors contributing to the inhibition of HO-1 and ferritin synthesis, or a
diminution in proximal tubular resistance, resulting in both an accumulation of nephrotoxic iron and in tubular necrosis.

Tubular Obstruction. Filling of the tubular lumen by pigmented casts that become inspissated and obstruct urinary flow with subsequent injury to tubular epithelium is one of the earliest mechanisms proposed to explain the nephrotoxicity of the heme pigments.⁵³ In their original clinical description of rhabdomyolysis-induced AKI, Bywaters and Beall² described the prominent histologic features, including the appearance of tubular obstruction by cellular debris and pigmented casts. It has been suggested that hypovolemia and academia, and the concomitant acidic concentrated urine, facilitate the precipitation of filtered myoglobin or hemoglobin leading to obstructive cast formation.⁵⁴ The presence of the Tamm-Horsfall protein in the tubular lumen is critical for heme protein cast formation in the distal nephron. Moreover, an obstructing cast induces urinary stasis, providing for an extended time for proximal tubular heme reabsorption and its attendant tubular toxicity, as noted previously.⁵⁵

Tubular obstruction can decrease GFR either by increasing the tubular pressure and thus decreasing the glomerular transcapillary hydraulic pressure, or by inducing the release of factors (e.g., thromboxane) that cause renal vasoconstriction, thereby reducing glomerular blood flow. The importance of tubular obstruction as a possible mechanism of heme pigment-induced AKI is suggested by the studies of Zager⁴⁷ that explored the reasons why mannitol exerts a protective effect against this syndrome. The major beneficial effect of mannitol was attributed to its diuretic effect, which presumably decreased cast formation and proximal tubular uptake of heme proteins. Similarly, alkalinization of the urine may mitigate against myoglobinuric AKI by increasing the solubility of myoglobin (reduced cast formation) and inducing a solute diuresis.⁵⁴

Although there is evidence that tubular obstruction may be a factor in the pathogenesis of the AKI, it probably is not the primary cause of the initial decrease in GFR in myohemoglobinuric AKI. Rather than high intratubular pressures from obstructing casts, intratubular pressures were found to be low in the glycerol-induced model of AKI.³⁵ This observation was interpreted to indicate that the presence of casts is the result, rather than the cause, of the decrease in GFR and urine flow. Instead of causing the initial decrease in renal function, cast formation may play a role in the maintenance of the renal failure once it develops.⁵⁶

Glomerular Fibrin Deposition. Because of the liberation of tissue factors, both rhabdomyolysis and intravascular hemolysis can initiate disseminated intravascular coagulation (DIC).¹⁹ Fibrin strands have been demonstrated in glomeruli from patients⁵⁷ and experimental animals⁵⁸ with rhabdomyolysis-induced AKI. Intravenous infusion of a muscle extract in rabbits resulted in DIC, renal dysfunction, and glomerular microthrombi, whereas an intravenous infusion of pure myoglobin had no untoward effect.⁵⁹ This led to the conclusion that myoglobin, per se, is not the primary cause of the coagulation cascade activation in the crush syndrome, but rather it is the release of other muscle constituents that induces DIC and the subsequent deposition of glomerular microthrombi that are responsible for rhabdomyolysis-induced AKI.

Clinical and Laboratory Features of Rhabdomyolysis and AKI

The diagnosis of myoglobinuria can be suspected from a history and physical examination. However, the clinical features of rhabdomyolysis are nonspecific and the course of the syndrome is quite variable depending on the underlying cause and the general condition of the patient. The syndrome has local as well as systemic features and early or late complications may occur. Because the prompt recognition of rhabdomyolysis is critical to preventing late complications, all suspected cases must undergo a complete clinical inquiry, observation, and laboratory follow-up.

Risk Factors for Acute Kidney Injury. The frequency of AKI in the setting of rhabdomyolysis is unknown, and reports of frequency have ranged from 13% to 50%.¹ Gabow and colleagues¹⁷ emphasized that no single laboratory value could predict which patients are at high risk for the development of AKI. However, using discriminant analysis, patients could be separated into high- and low-risk groups, with the high-risk group (elevated serum potassium and creatinine and reduced serum albumin concentrations) having a 41% prevalence of AKI.

Based on a large historical cohort (157 patients), Ward⁶⁰ identified clinical and laboratory differences between those patients in whom renal failure did or did not develop, and factors predictive of progression to renal failure. As shown in Table 36.2, patients with rhabdomyolysis and renal failure were older, had a higher incidence of hypertension, and were more hypotensive and volume depleted. A significantly greater proportion of them had a creatine kinase level greater than 16,000 IU per liter, although elevations to this degree were seen in 10.7% of patients in whom renal failure did not develop (Table 36.3). The renal failure group also had significantly higher serum potassium and phosphorus levels and lower serum calcium and albumin concentrations, and was more acidemic with a concomitant lower urinary pH. Sepsis, burns, and drug ingestion were the causes of rhabdomyolysis more closely associated with the development of renal failure. Using multiple logistic regression analysis, a scoring system was developed predicting the risk of renal failure in patients with rhabdomyolysis based on the variables of serum phosphorus, potassium, albumin, and creatine kinase concentrations, and the presence of volume depletion and sepsis. A point score of 7 or higher predicted a greater than 50% likelihood for the development of renal failure. In a multivariate analysis of 72 consecutive patients with rhabdomyolysis due to illicit
drug use, patients with a creatine kinase level greater than 25,000 IU per liter, hypotension, and leukocytosis were at a greater risk of developing AKI, whereas hyperthermia (temperature >38.5°C) was associated with a reduced risk.⁶¹ This association does not indicate that hyperthermia is protective against rhabdomyolysis, rather it is most likely due to earlier presentation to, or evaluation or fluid resuscitation in the emergency department.

TABLE 36.2 Univariate Analysis of Clinical Variables in Patients with Rhabdomyolysis Developing and Not Developing Renal Failure

	Group
Variables	Renal Failure (N = 26)	Nonrenal Failure (N= 131)	P^a
Age, year (SD)	53.7 ± 20.6	41.4 ± 18.1	0.002
Male (%)	69.2	61.1	0.418
Hypertension (%)	46.2	22.9	0.026
Diabetes mellitus (%)	11.5	7.6	0.562
Previous renal disease (%)	19.2	3.8	0.051
Dehydration (%)	38.5	4.6	0.001
Hypotension (%)	34.6	14.5	0.040
Nephrotoxin exposure (%)	19.2	39.7	0.020
Diuretic use (%)	30.8	16.8	0.147
Nonsteroid drug use (%)	19.2	6.1	0.101
IV hydration (%)^b	80.7	54.2	0.289
Osmotic treatment (%)	26.9	22.9	0.674
Bicarbonate treatment (%)	50.0	12.2	0.001
^aThe P value for difference in means or proportions between renal failure and nonrenal failure groups. ^bGreater than 150 mL per hour averaged over the first 24 hours after admission. SD, standard deviation; IV, intravenous.

Urinalysis. Examination of the urine provides the first laboratory clue to the presence of myoglobinuria. Classically, the initial urine is dark (Table 36.4) and usually with an acid pH; the benzidine or orthotoluidine reagent gives a positive reaction for blood (3+ to 4 +), but microscopic examination of the urinary sediment fails to reveal any red blood cells (RBCs). Specific tests for urine myoglobin determination are available in some clinical laboratories but, as noted earlier, urine myoglobin levels are not the most sensitive clinical markers for rhabdomyolysis. Although the strongest clinical clue for myoglobinuria is the presence of strongly heme-positive urine and the absence of RBCs, in one major series¹⁷ hematuria was present in 32% and the dipstick was heme negative in 18% of the patients with rhabdomyolysis. In addition, proteinuria was detected by dipstick in 45% of patients,¹⁷ which may be attributed to altered glomerular permeability or tubular transport of small proteins.⁶² The urinary sediment demonstrates brown “debris” and, with the evolution of renal injury, pigmented brown granular casts and renal tubular epithelial cells are seen.

Serum Potassium Concentration. The most life-threatening consequence of rhabdomyolysis is the release of large amounts of intracellular potassium into the circulation. Given the crucial role that potassium plays in maintaining the homeostasis of resting membrane potential, it is evident that vital organs such as the heart are at greatest risk to sustain arrhythmogenic activity. This implies that an electrocardiographic follow-up is mandatory to monitor for potentially grave arrhythmias. Because more than 98% of total body potassium resides in cells, and skeletal muscle represents 60% to 70% of the total cellular mass, breakdown of even a small area of skeletal muscle releases a considerable potassium load. The presence of
acidosis may shift more potassium extracellularly and worsen the hyperkalemia. As noted in the previous section on Risk Factors for AKI, admission serum potassium levels tend to be higher in patients who go on to experience AKI.⁶⁰ Approximately half of an acute potassium load is handled by renal excretion⁶³; therefore, in AKI, serious hyperkalemia can result and is usually the major indication for dialysis.

TABLE 36.3 Univariate Analysis of Laboratory Variables in Patients with Rhabdomyolysis Developing and Not Developing Renal Failure

	Group
Variables	Renal Failure (N = 20)	Nonrenal Failure (N= 131)	p
Peak creatine kinase >16,000 IU/L, %	57.7	10.7	<0.001
Serum bicarbonate (mmol/L)	21.4 ± 7.2	23.7 ± 4.0	0.1306
Serum potassium (mmol/L)	4.73 ± 1.2	3.92 ± 0.6	0.0018
Serum phosphorus (mmol/L)	1.85 ± 1.08	0.06 ± 0.35	0.0006
Serum calcium (mmol/L)	2.02 ± 0.4	2.14 ± 0.2	0.1452
Serum albumin (g/L)	30.8 ± 10.0	35.9 ± 8.0	0.0107
Arterial pH	7.33 ± 0.10	7.38 ±0.11	0.0495
Urinary pH	5.19 ± 0.06	5.75 ± 1.0	0.0009
All values are mean standard deviation except peak creatine kinase.

TABLE 36.4 Differential Diagnosis of Pigmenturia

Factors	Myoglobinuria	Hemoglobinuria	Porphyria
Urine color	Brown	Reddish brown	Dark red
Serum color	Clear	Pink	Clear
Orthotoluidine reaction	Positive	Positive	Negative
Watson-Schwartz porphobilinogen	Negative	Negative	Positive
Muscle pain/tenderness	Present	Absent	Absent
Serum creatine kinase level	Elevated	Normal	Normal
Serum haptoglobin	Normal	Decreased	Normal
Reprinted from Schultze VE. Rhabdomyolysis as a cause of acute renal failure. Postgrad Med. 1982;72:145, with permission.

Creatine Kinase. The classic laboratory finding of rhabdomyolysis is an elevated serum creatine kinase of at least five
times the normal value, where the striated muscle isoenzyme (CK-MM) is predominately found. The serum half-life of creatine kinase (˜36 hours) is much longer than myoglobin, which makes it a more reliable tool for diagnosis. Normal creatine kinase levels are 45 to 260 IU per liter. Following muscle injury, the level rises within 12 hours, peaks in 1 to 3 days, and declines 3 to 5 days after the cessation of muscle injury.²⁹ Although no correlation has been established between the absolute level of the creatine kinase and the risk for development of AKI, creatine kinase levels are significantly higher in patients in whom renal failure develops.¹⁹,²⁹ Following admission, changes in creatine kinase concentrations provide some insight into whether the rhabdomyolysis is worsening or resolving, and following levels is essential to observe for the “second wave” phenomenon (described later in this chapter).

Acid-Base Balance. The conditions that cause rhabdomyolysis involve tissue trauma or ischemia and predispose one to an augmented acid load. In a study by Ward,⁶⁰ patients with rhabdomyolysis who progressed to renal failure tended to be more acidemic. An elevated serum anion gap is usual in patients with rhabdomyolysis and due to the impaired renal excretion of intracellular organic acids released from damaged muscles, as well as a retention of inorganic anions such as phosphate.⁶⁴

Uric Acid. Due to the release of intracellular purines from damaged myocytes, hyperuricemia is expected in patients with rhabdomyolysis, especially when the muscle injury is due to strenuous exercise or exertion.

Blood Urea Nitrogen: Creatinine Ratio. Both AKI and the increased release of creatine from damaged myocytes increase the serum concentrations of blood urea nitrogen (BUN) and creatinine. However, the rise in creatinine is more pronounced and, in turn, alters the normal 10:1 ratio of BUN to creatinine to a ratio of 6:1 or less. Based on creatine:creatinine kinetics and their respective concentrations in skeletal muscle, Oh⁶⁵ challenged this conventional view. He pointed out that the patient population in which rhabdomyolysis develops tends to have a larger percentage of younger men with a greater muscle mass, whereas other forms of AKI are more often associated with older and more cachectic patients who have less muscle mass and thus reduced creatinine production rates.

Calcium-Phosphorus Metabolism. The perturbations of calcium and phosphorus metabolism usually seen in most types of AKI appear to be exaggerated in rhabdomyolysisinduced AKI.¹⁹,⁶⁶ Following the destruction of muscle cells, the release of inorganic phosphorus into the plasma causes hyperphosphatemia¹⁹,⁶⁴ and subsequent hypocalcemia through the deposition of calcium phosphate in the destroyed muscle cells (dystrophic calcification) and other tissues. Hypocalcemia may be accentuated by the inhibition of renal vitamin D 1α-hydroxylase, which results in the downregulation of the production of the active form of vitamin D (1,25[OH]₂D₃). This observation may be explained by hyperphosphatemia, which is known to decrease synthesis of 1,25(OH)₂D₃ and to stimulate the production of the parathyroid hormone.⁶⁴,⁶⁷ A recent case report described elevated FGF23 levels in rhabdomyolysis-induced AKI and may provide a mechanism for the inhibition of renal 1α-hydroxylase.⁶⁸ Regardless of the mechanism, in the absence of frank tetany, hypocalcemia usually does not require treatment. In fact, correction of the hypocalcemia with vigorous intravenous calcium replacement may increase both dystrophic (calcium deposition in damaged muscle) and metastatic calcification due to the high serum PO₄ and the Ca × PO₄ product.

Approximately 20% to 30% of patients with myoglobinuric AKI experience transient hypercalcemia during the recovery (diuretic) phase.¹⁹,⁶⁴ Early studies⁶⁹,⁷⁰ suggested that hypercalcemia was due to the normal remobilization of calcium deposits in the injured muscle that occurs during the recovery phase of AKI. Alternatively, it has been proposed that as renal function improves, the combination of a decreasing serum phosphorus concentration and the ambient secondary hyperparathyroidism, secondary to hypocalcemia, stimulates the synthesis of 1,25(OH)₂D₃ resulting in an “overshoot” hypercalcemia.⁶⁴ This augmented 1,25(OH)₂D₃ production may be due, in part, to the release of vitamin D from damaged muscle tissue.⁶⁴,⁷¹

Urinary Sodium Excretion. Impaired renal tubular reabsorption of sodium is typically seen in most types of oliguric AKI as manifested by a high fractional excretion of sodium. However, in both myoglobinuric and hemoglobinuric AKI, a low fractional excretion of sodium (<1%) has been observed³⁸ that resembles a prerenal azotemia during the early course. As noted earlier in this chapter, this phenomenon is most likely due to hypovolemia and vasoconstriction, which lead to renal hypoperfusion.

Disseminated Intravascular Coagulation. DIC is commonly present in patients with rhabdomyolysis and may be due to the release of intracellular thromboplastins that activate the clotting cascade.⁶³,⁶⁴ Moreover, DIC may be an important factor in the pathogenesis of the AKI (see section on Glomerular Fibrin Deposition, previously).

Differential Diagnosis

Myoglobin-induced AKI should be suspected in patients with trauma presenting with the classic triad of heme-positive urine, an elevated serum creatine kinase level, and dark (pigmented) urine containing dirty-brown granular casts without RBCs. More subtle cases, usually associated with diffuse nontraumatic rhabdomyolysis, may be more difficult to detect. The differential diagnosis of pigmenturia is limited (Table 36.4). Although certain drugs may impart an orange, red, or brown hue to the urine such as rifampin and nitrofurantoin, they do not react with the benzidine or orthotoluidine reagent on the urine dipstick. Porphyrins also color the urine brown
but do not react to give a positive test for occult blood. The most difficult challenge is to discriminate myoglobin from hemoglobin in the urine. Because these are heme proteins, they both react with the benzidine or orthotoluidine reagent and both are associated with the absence of RBCs in the urine sediment. One helpful clue may be the color of the serum in these two conditions. Because myoglobin is relatively rapidly cleared by the kidney, serum levels of myoglobin are not sufficiently elevated to alter the color of the serum in patients with rhabdomyolysis. In contrast, because of its much larger size and its avid binding to haptoglobin, hemoglobin is not as rapidly cleared by the kidney and serum levels may be high enough to result in a pink discoloration of the serum in patients with hemoglobinuria.

Clinical Course and Complications of Myoglobinuric Acute Kidney Injury

Myoglobinuric AKI can run a course ranging from mild renal dysfunction with only transient oliguria and rapid recovery to a much more catastrophic disease requiring frequent dialysis for periods of 2 or 3 weeks. Typically, the duration of oliguria is 7 to 10 days; during this interval a period of anuria may exist for up to 3 days. Resumption of more normal urine formation heralds the recovery of renal function as patients enter the diuretic phase with a subsequent clearing of azotemia and the cessation of the requirement for hemodialysis.

In addition to muscle injury and AKI, patients with rhabdomyolysis may have peripheral neuropathies. These can result from compartment syndromes in which involved muscles become edematous in confined tissue spaces with compromise of blood supply to both muscle and nerves in the area.⁶⁹ Measurement of tissue pressure has been advocated as a tool in identifying those areas of damaged muscle at risk, and a surgical fasciotomy may be required to avoid this complication.⁶⁴ Swelling of the muscles can lead to impairment in the blood supply of the muscles, resulting in a recurrence or “second wave” of muscle necrosis, as reflected by a second rise in the serum creatine kinase concentration. Neuropathy also can result from traction if rhabdomyolysis is caused by prolonged coma, as from drug overdose.⁶⁴

Prevention and Treatment of Myoglobinuric Acute Kidney Injury

Understanding the possible mechanisms by which rhabdomyolysis causes AKI can provide the basis for the various therapies advocated for this disorder. If possible, treatment of the underlying condition is a priority. Given the pathogenic nature of hypovolemia, renal hypoperfusion and, based on experimental and clinical data, early intravascular volume expansion by intravenous administration of NaCl 0.9% is essential to restore RBF, maintain GFR, and ultimately prevent AKI.⁶⁴,⁷² Because myoglobin is more nephrotoxic at an acid pH, most groups advocate alkalinization of the urine with sodium bicarbonate.⁶⁴,⁷²,⁷³ By correcting cellular acidosis, bicarbonate therapy may reduce renal tubular epithelial swelling and attenuate renal tubular and vascular collapse.⁷⁴ There is a theoretical concern that inducing a metabolic alkalosis with such treatment may enhance metastatic calcification, but the salutary benefit of bicarbonate therapy probably outweighs any untoward effect.

Following the repletion of volume and the production of urine within an acceptable range, the patient could undergo forced diuresis. Mannitol has long been recognized to be an effective agent in the prophylaxis against the development of experimental and clinical AKI, in particular when there is suspicion of compartment syndrome. However, recent studies have shown that the administration of NaCl 0.9% in combination with mannitol is not more effective in the prevention of AKI than the administration of NaCl 0.9% alone. Furthermore, mannitol can cause AKI and should be used with caution.⁷⁵

Furosemide, a loop diuretic, has the theoretic advantage of inhibiting sodium transport in the thick ascending limb of the Henle loop. Oxygen consumption is dictated primarily by the rate of sodium transport, and a precarious balance exists in this segment between the rate of oxygen delivery and its consumption.⁷⁶ By inhibiting sodium transport, furosemide may reduce oxygen consumption in the face of limited delivery and thereby preserve cell viability. In addition, the augmented urinary flow induced by the diuretic may reduce the risk of tubular obstruction. However, loop diuretics can cause increasing acidification of the urine, worsening intravascular volume depletion, and can induce ototoxicity, and thus the use of these agents has not been generally recommended.⁷⁷

Although there are no controlled trials to show a direct benefit of a “mannitol-bicarbonate cocktail” in the prevention of AKI in rhabdomyolysis, there are case reports suggesting such therapy was instrumental in averting renal injury.⁷⁸,⁷⁹

Only gold members can continue reading. Log In or Register to continue