Saudi Journal of Kidney Diseases and Transplantation

EDITORIAL
Year
: 2008  |  Volume : 19  |  Issue : 5  |  Page : 721--729

Acute Kidney Injury due to Rhabdomyolysis


Rafael Siqueira Athayde Lima, Geraldo Bezerra da Silva Junior, Alexandre Braga Liborio, Elizabeth De Francesco Daher 
 Department of Internal Medicine, School of Medicine, Division of Nephrology, Hospital, Universitario Walter Cantídio, Universidade Federal do Ceara, Fortaleza, Ceara, Brazil

Correspondence Address:
Elizabeth De Francesco Daher
Rua Vicente Linhares, 1198. Fortaleza, CE, Brazil - CEP: 60270-135
Brazil

Abstract

Rhabdomyolysis is a clinical and biochemical syndrome that occurs when skeletal muscle cells disrupt and release creatine phosphokinase (CK), lactate dehydrogenase (LDH), and myoglobin into the interstitial space and plasma. The main causes of rhabdomyolysis include direct muscular injury, strenuous exercise, drugs, toxins, infections, hyperthermia, seizures, meta­bolic and/or electrolyte abnormalities, and endocrinopathies. Acute kidney injury (AKI) occurs in 33-50% of patients with rhabdomyolysis. The main pathophysiological mechanisms of renal injury are renal vasoconstriction, intraluminal cast formation, and direct myoglobin toxicity. Rhabdo­myolysis can be asymptomatic, present with mild symptoms such as elevation of muscular en­zymes, or manifest as a severe syndrome with AKI and high mortality. Serum CK five times higher than the normal value usually confirms rhabdomyolysis. Early diagnosis and saline volume expansion may reduce the risk of AKI. Further studies are necessary to establish the importance of bicarbonate and mannitol in the prevention of AKI due to rhabdomyolysis.



How to cite this article:
Lima RA, da Silva Junior GB, Liborio AB, Daher ED. Acute Kidney Injury due to Rhabdomyolysis.Saudi J Kidney Dis Transpl 2008;19:721-729


How to cite this URL:
Lima RA, da Silva Junior GB, Liborio AB, Daher ED. Acute Kidney Injury due to Rhabdomyolysis. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2019 Sep 16 ];19:721-729
Available from: http://www.sjkdt.org/text.asp?2008/19/5/721/42439


Full Text

 Introduction



Rhabdomyolysis is a syndrome that occurs when skeletal muscle cells disrupt and release creatine phosphokinase (CK), lactate dehydro­genase (LDH), and myoglobin into the inters­titial space and plasma.

Acute kidney injury (AKI) occurs in 33–50% of patients with rhabdomyolysis, and it is the main cause of mortality in them. [1],[2] AKI due to rhabdomyolysis was first described by By­waters and Beall [3] during the 2nd World War, and called it the "crush syndrome". After London bombings, the rubbles survivors suf­fered from hypovolemic shock and dark urine.

The main causes of rhabdomyolysis include direct muscular injury, strenuous exercise, drugs, toxins, infections, hyperthermia, seizures, metabolic, and/or electrolyte abnormalities and endocrinopathies. [4],[5],[6] Risk factors that predis­ poses to rhabdomyolysis include older age, inflammatory muscular diseases, renal failure, and hypothyroidism. [7]

Rhabdomyolysis can be asymptomatic, pre­sent with mild symptoms such as elevation of muscular enzymes, or manifest as a severe syndrome with AKI and high mortality.

 Pathophysiology



Causes of rhabdomyolysis usually result in destruction of muscle cells and consequent release of intracellular contents into extra­cellular fluid or circulation. When cells are subjected to mechanical stress, there is influx of sodium and calcium into the cell, which causes several pathologic processes due to the excess of calcium. Excessive intracellular cal­cium results in persistent contraction of the myofibers, depletion of adenosine triphosphate (ATP), production of free radicals, activation of vasoactive molecules, release of proteases, and ultimately cell death. Afterwards, neutro­phils invade and amplify the damage with release of proteases and augmented production of free radicals, and a self-sustaining, inflam­matory myolytic reaction develops. [8]

The main mechanism of muscular injury is associated with a reperfusion process. [9] After a period of ischemia and reestablishment of tissue perfusion, migration of leukocytes and production of free radicals occurs. Compart­mental syndrome also contributes to the pa­thophysiology of rhabdomyolysis, since most muscle groups are contained within rigid fas­cial compartments, and swelling by the 3 rd spa­cing of fluids associated with a traumatized muscular tissue can result in increased intra­compartmental pressure that can cause addi­tional damage by compromising both venous and arterial blood flow. [9]

Different mechanisms are associated with AKI due to rhabdomyolysis such as hypovo­lemia, intraluminal obstruction by myoglobin, uric acid casts, direct myoglobin toxicity, renal ischemia secondary to muscular vasoconstric­tors, and production of free radicals. [4],[10],[11]

Myoglobin released from lysis of muscular cells does not have a specific binding protein, and it is freely filtered by the glomeruli. Myo­globin levels return to normal values in 1–6 hours after injury due to hepatic metabolism and renal excretion. [12] Casts are produced after filtration of myoglobin through the glomerular basement membrane. Water reabsorption cau­ses rise of myoglobin concentration, and in the presence of acid urine, myoglobin precipitates and forms obstructive casts. [4] Moreover, myo­globin can, through the heme fraction, induce the release of free iron, which catalyses free radical production and further enhances ische­mic tubule damage. In the absence of hypo­volemia and acid urine, myoglobin has a less nephrotoxic effect. [13],[14]

Another factor that can exacerbate tubular obstruction is the disseminated intravascular coagulopathy associated with rhabdomyolysis due to activation of the coagulation cascade by the substances released from damaged muscle cells. [4],[15],[16]

The factors associated with AKI due to rhab­domyolysis are presented in [Figure 1].

 Etiology



There are numerous causes of rhabdomyo­lysis. Sulowicz et al [6] found the following cau­ses among 81 patients: trauma (49%), hypo­thermia (18%), seizures (17%), and strenous exercise (1%).

Strenous exercise

Extreme physical activity can result in mus­cular disintegration and release of muscular constituents into the extracellular fluid and cir­culation. Strenuous muscular exercise seems to play a decisive role in the pathogenesis of rhabdomyolysis, especially in untrained people or in individuals experiencing it in extremely hot or humid conditions. [15],[17],[18] Similar process is found in the "raver´s hematuria", which occurs in people who dance for hours, usually with concomitant ingestion of amphetamines, and develop rhabdomyolysis and hematuria. [19]

Compartmental syndrome

Compartment syndrome can result in hypo­ volemic shock and AKI. [4],[10],[20] Compartmental syndrome should be suspected in patients presenting with swollen legs, as illustrated in [Figure 2]. In non-traumatic obese patients may suffer from muscle compression during elec­tive surgery because of unsuitable positioning or tourniquet use. [21],[22] Mognol et al [23] found an incidence of 22.7% for rhabdomyolysis in obese patients undergoing laparoscopic gastric banding or gastric bypass, and they identified the duration of the operation as an important risk factor for rhabdomyolysis in such patients. Bostanjian et al [24] suggest routine measurement of CK levels immediately postoperatively and then daily, until the values reveal clear trend to normality.

Drugs

Rhabdomyolysis can be caused by diverse drugs such as statins with incidence in 1ndash;5% of patients who ingest this drugs. [25] The mechanism of rhabomyolysis associated with the use of statins is not completely understood, and it involves depletion of the intermediary meta­bolites of cholesterol synthesis, cellular apop­tosis induction, and alterations in conductance of chloride channels in the myocytes. [7]

Atorvastatine, lovastatine and simvastatine induce apoptosis of muscular cells in a dose­dependent mechanism, [26] and the association of the statins with other drugs such as fibrates, nicotinic acid, cyclosporine, antifungal, macro­lides, amoxicillin, protease inhibitors, nefazo­done, verapamil, amiodarone, and chlopidogrel increases the risk of rhabdomyolysis due to a synergistic myotoxic effect or by increasing the serum levels of statines. [27],[28],[29],[30],[31],[32],[33],[34] The proposed risk factors for statin-induced rhabdomyolysis are shown in [Table 2]. [35]

Muscular symptoms can start at any time during treatment with statins, but usually one to four weeks after the start of these drugs. [36] After 3–30 days of withdrawal of statins the muscular symptoms usually decrease, and the CK normalizes. [36] Although this risk of myo­pathy during the use of statins is established, the routine monitorization of CK and transami­nases is not recommended. However, patients must be alerted about the possibility of mus­cular weakness and myalgia. [37],[38]

Moreover, cases of AKI and rhabdomyolysis have been described in patients using halope­ridol and other neuroleptics, presenting as neuroleptic malignant syndrome. [39] Tuccori et al [40] described an 85-year-old diabetic woman with gabapentin-induced severe myopathy (CK: 3095 U/L, myoglobin: 17000 mg/dL, and creatinine: 4.77 mg/dL).

Metabolic Disorders

The McArdle´s disease, an autossomal rece­ssive metabolic disorder, was first described in 1951. [41] There is myophosphorylase deficiency in type II muscular fibers leading to ATP dep­letion and myonecrosis during physical exer­cise. [42] The disease was described in patients who developed rhabdomyolysis after heavy muscular exercise and an asthmatic attack. [43],[44]

Electrolyte abnormalities such as hypophos­phatemia may contribute for muscular cellular lysis in the presence of previous muscular injury. Chronic hypophosphatemia can cause myopathy, but the isolated association with rhabdomyolysis is rare. Furthermore, hypo­phosphatemia and hypocalemia are risk factors for alcohol myotoxicity. [45]

Infections

Although only 5% of cases of rhabdomyo­lysis may be due to infections, [46] there are many agents involved. Infections by Influenza A and B virus are known causes of rhabdo­myolysis. [47],[48] The most frequent bacteria that can cause rhabdomyolysis include Legionellae, Streptococcus, Salmonella and Francisella tularensis. [49]

Toxins

The venom of wasps, hornets and yellow jackets contains a wide spectrum of peptides, amines, and enzymes that are responsible for the local and systemic effects. Allergic mani­festations to honeybee and wasp stings are well recognized, however, more serious com­plications like anaphylaxis, intravascular hemo­lytic, rhabdomyolysis, thrombocytopenia, acute renal failure, liver impairment, and myocardial infarction are less common. [50],[51]

Daher et al [52] described two patients with al­most 600 and 1500 honeybee (Apis Mellifera) stings, respectively. The most frequent clinical findings were generalized edema, arterial hypo­tension, hemolysis, rhabdomyolysis and acute renal failure. Moreover, Koya et al [53] reported a 59–year-old patient who developed rhabdo­myolysis and AKI after extensive red fire ant bites. AKI is usually due to a toxic-ischemic mechanism that includes hypovolemia, myo­globinuria, hemoglobinuria, renal ischemia, and direct venom toxicity. [54],[55]

Intoxication

Non-traumatic rhabdomyolysis is usually caused by a toxic reaction to drugs. Talaie et al [56] found that among 143 patients with rhabdo­myolysis due to poisoning the most common cause was opium, and in 7% of the cases with multiple drug poisoning AKI was predominant.

Electrolyte abnormalities caused by alcohol ingestion are also important in causing muscle damage. Ethanol intoxication, for instance, can cause water-electrolyte and acid-base distur­bances such as metabolic acidosis, hypomag­nesemia, hypocalcemia, and hypophosphatemia, which can result in muscular cytolysis. [6]

Moreover, rhabdomyolysis is very common after cocaine use, because of prolonged vasoconstriction that causes muscle ischemia. [57] Blood pressure frequently rises after using cocaine and it appears to contribute towards the development of rhabdomyolysis.

 Clinical and Laboratory Evaluation



Patients with rhabdomyolysis can present with increased body temperature, muscular weak­ness, generalized or localized myalgia, edema and dark brown urine. [58],[59] The spectrum of muscle toxicity is described in [Table 3].

Laboratory findings include urine dipstick positive for blood in the absence of urinary erythrocytes, myoglobinuria, granular casts, epithelial cells in the sediment, and elevated muscle enzymes levels in the serum such as CK, LDH, and aspartate and alanine aminotrans­ferases (AST, ALT), besides elevated serum phosphate and potassium serum levels and ini­tially low serum calcium concentration. [15],[60] Se­rum CK, AST, ALT, and LDH levels correlate with the extent of muscular damage. However, these findings have no prognostic value. [12]

Rhabdomyolysis can easily be confused with the diagnosis of deep vein thrombosis when the patient presents with acutely swollen and painful legs and an absence of pulse in the foot. [60]

Myoglobin is quickly filtered and excreted until renal failure limits its excretion, and con­tributes to the brownish urine color. [12],[61]

Elevated serum CK levels are enough to establish the diagnosis of rhabdomyolysis. A five times higher than the normal value CK increase confirm the diagnosis of rhabdomyo­lysis. [1],[10] Maximum CK concentration is usua­lly reached during the first 24 hours in 70% of the cases. [11] Serum myoglobin higher than 30 µg/mL also confirms rhabdomyolysis. [10]

Magnetic resonance image (MRI) is the method of choice to evaluate the distribution and extension of the affected muscles, espe­cially when fasciotomy is considered for treat­ment. Even though MRI findings are non­specific, the sensitivity in the detection of muscle involvement is higher than that of computed tomography or ultrasound. [62]

Rhabdomyolysis can also be diagnosed with a muscle biopsy. The histopathologic findings usually include loss of cell nucleus and muscular stria with absence of inflammatory cells. [63]

 Treatment



Treatment should be instituted immediately in order to modify the factors that cause AKI, such as volume depletion, tubular obstruction, aciduria, and release of free radicals. [4] The prognosis is usually excellent if the underlying mechanism of rhabdomyolysis can be identi­fied and reversed, whenever it is possible. [15]

There is a consensus for intravascular volume expansion by using saline solution and manni­tol to maintain urine output at more than 200­300 ml/hour. [15] Alkalization of urine can be attempted to reduce the formation of myo­globin casts in renal tubules. [15] In an experi­mental study, [64] the association of saline solu­tion, sodium bicarbonate, and mannitol was more effective than hypertonic saline-dextran in decreasing oxidant injury in rhabdomyo­lysis. Accordingly, if CK exceeds 5,000 IU/L it is advisable to institute aggressive venous hydration, prophylactic bicarbonate and man­nitol. Better et al [65] advocate the administration of saline solution (1.5 L/h) as soon as possible in traumatic cases of rhabdomyolysis. Further­more, Altintepe et al [66] concluded that the rapid fluid therapy accompanied by the prophylactic administration of mannitol-bicarbonate are largely effective in preventing the develop­ment of AKI in cases of crush syndrome.

On the other hand, Brown et al [67] performed a study with 2,083 patients with post-traumatic rhabdomyolysis in intensive care unit and concluded that the administration of bicarbo­nate and mannitol should be reevaluated since they did not prevent renal failure (creatinine > 2.0 mg/dL), dialysis, or mortality in patients with CK levels greater than 5,000 U/L.

In summary, rhabdomyolysis is an important medical problem that can be found in different clinical settings and should be rapidly recog­nized in order to provide an adequate treat­ment. Early diagnosis and volume expansion usually reduce the risk of AKI. Further studies are necessary to establish the importance of bicarbonate and mannitol in the prevention of AKI and reduction of mortality due to rhab­domyolysis.[Table 1]

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