By Jon-Emile Kenny, MD
Faculty Peer Reviewed
A 37-year-old man, with no past medical history and taking finasteride for male pattern baldness, is admitted to Medicine with profound lower extremity weakness after a weekend of performing multiple quadriceps exercises. His measured creatine phosphokinase (CPK) is over 35,000 IU/liter. I wonder to myself, what is the risk to his kidneys and can I mitigate the damage?
Rhabdomyolysis means destruction of striated muscle. Physical manifestations range from an asymptomatic illness with an elevation in the CPK level, to a life-threatening condition associated with extreme elevations in CPK, electrolyte imbalances, disseminated intravascular coagulation (DIC), and acute kidney injury (AKI).
CPK elevations are frequently classified as mild, moderate, or severe. These classifications roughly correspond to less than 10 times the upper limit of normal (or 2,000 IU/L), 10 to 50 times the upper limit of normal (or 2,000 IU/L to 10,000 IU/L), and greater than 50 times the upper limit of normal (or greater than 10,000 IU/L), respectively (2). The risk of renal failure increases above 5,000 to 6,000 IU/L . Interestingly, one series found that only patients with a peak CK greater than 20,000 IU/L failed to respond to diuresis and required dialysis .
No studies have found a normal range of CPK levels following exercise. However, the incidence of renal failure does not correlate with CPK levels alone. After triathalons, athletes may have CPK elevations of greater than 20,000 IU/L without any renal compromise . A review of 35 patients with exercise-induced rhabdomyolysis, with an average admission CPK level of 40,000 IU/L, revealed no cases of acute renal failure . The risk of renal failure increases with co-morbid conditions such as sepsis, dehydration, and acidosis .
Hypovolemia and aciduria are felt to be key pathophysiological events leading to acute kidney injury in the setting of muscle breakdown. Damage to the kidneys is mediated by heme-proteins released from myoglobin . There are four converging pathways by which heme-proteins harm the kidneys: 1) renal vasoconstriction; 2) cytokine activation; 3) precipitation of Tamm-Horsfall protein at an acid pH with subsequent cast-nephropathy; and 4) acid-sensitive renal free-radical production . Due to the many liters of fluid sequestered in injured muscle, patients with rhabdomyolysis are profoundly volume depleted. Consequently, homeostatic mechanisms, such as the renin-angiotensin, aldosterone, and vasopressin systems, are activated, leading to renal vasoconstriction. Various cytokines induced in rhabdomyolysis have also been shown to have similar effects on renal perfusion . Because myoglobin becomes concentrated in the presence of aciduria, it precipitates with Tamm-Horsfall protein and also induces free radical production . Given the aforementioned mechanisms of acute kidney injury, evidence of CPK elevation should lead to attempts to protect the kidneys. Treatment should include reversal of fluid deficits with or without urinary alkalinization.
Reversal of hypovolemia with copious amounts of intravenous (IV) normal saline, with individualized urine output goals, is the mainstay of therapy . While no prospective clinical trials have proven the efficacy of volume resuscitation, retrospective analyses support its use . In one study, investigators compared the clinical outcomes of two groups of patients who developed crush syndrome during building collapses. All seven patients in the group that had IV fluids delayed for more than six hours required dialysis, whereas none of the seven patients with similar injuries in the group that received IV fluids at the time of extrication developed acute renal failure .
Despite the protective effects of urinary alkalinization on experimental models of heme-protein nephrotoxicity  and similarly positive reports from various case series , evidence from randomized controlled trials is lacking. A retrospective study of 24 patients demonstrated that augmentation with mannitol and bicarbonate may have no benefit over and above aggressive fluid resuscitation with saline alone . Further, Brown and colleagues retrospectively identified patients with trauma-induced renal failure and CPK levels greater than 5,000 IU. Roughly 40% of these patients received mannitol and bicarbonate with fluid resuscitation, while the remainder received saline alone. No significant differences in the incidence of dialysis or in the mortality rate between the two groups were observed . Nevertheless, large volume saline repletion without alkalinization raises the risk of hyperchloremic acidosis and may perpetuate kidney injury. In a recent NEJM review, Bosch et al. especially recommend both normal saline and sodium bicarbonate in patients with metabolic acidosis . Important to note, studies comparing saline versus saline plus urinary alkalinization are complicated by variable definitions of renal failure (e.g. creatinine > 2.0 mg/dL versus need for dialysis), large variations in study design and patient selection, the number of patients studied, and inconsistent amounts of time between injury and treatment .
In summary, renal injury with high serum CPK values becomes a true concern when levels of CPK reach 5,000 IU/L and the patient has serious co-morbid disease such as volume depletion, sepsis or acidosis. Otherwise, values of up to 20,000 IU/L may be tolerated without untoward event. The key pathophysiological events are volume depletion and aciduria, which should be corrected immediately and primarily with ample IV normal saline and secondarily with urinary alkalinization. As our patient was young and healthy, he was administered IV normal saline only, with a goal of 200 cc per hour of urine output, until his CPK levels trended below 6,000 IU/L. He was counseled on appropriate exercise routines and urged to stop his 5-alpha reductase inhibitor, as this class of drugs has been associated with rhabdomyolysis. He did not experience any renal injury and his weakness improved. He was discharged home 36 hours following his admission.
Studies have suggested that there is a limited time to prevent renal injury, perhaps as little as 6 hours after rhabdomyolysis occurs. Patients should always have their extracellular volume repleted after experiencing third-spacing of plasma volume into injured muscle, in part attributed to the osmotic effects of local proteolysis. However, if kidney injury is already established, continuing to force IV fluids into a patient with renal failure may lead to volume overload and pulmonary edema. This same limitation may explain why alkalinization is of unproven benefit: it’s difficult to get the bicarbonate into the urine if GFR is low. If urine pH fails to rise after volume repletion is achieved, the risk of continued sodium bicarbonate administration far outweighs the little chance of benefit at that late point.
Of note, third-spacing into muscle may lead to compartment syndrome with compression of arteries and nerves; surgical consultation and measurement of compartment hydrostatic pressure is sometimes needed though the risks and benefits of fasciotomy are debated.
Dr. Kenny is a chief resident in internal medicine at NYU Langone Medical Center
Peer reviewed by David Goldfarb, MD, Professor of Medicine, Department of Medicine (Nephrology), NYU Langone Medical Center and Chief of Nephrology at the Department of Veterans Affairs New York Harbor.
Image (model of finasteride) courtesy of Wikimedia Commons.
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