How I Treat Rhabdomyolysis-Induced AKI?

Introduction

Rhabdomyolysis is a condition characterized by the destruction of skeletal muscle fibers and the release of intracellular contents into the bloodstream. In the United States, approximately 26,000 cases of rhabdomyolysis are reported each year, and the number has been increasing over the past 20 years.¹ There are systemic complications associated with rhabdomyolysis, including AKI, which occurs in approximately 50% of cases. Older age and comorbidity are risk factors of rhabdomyolysis-induced AKI, which associates with prolonged hospitalization, high mortality (up to 30%), and increased health care costs.²

Case Presentation

A 40-year-old man without medical history presented with fatigue, nausea/vomiting, decreased urine output, and diarrhea for the past week. He denied recent trauma or surgery. His social history included use of tobacco, drinking alcohol on weekends, and no use of illicit drugs. He was working as a painter and reported recent outdoor work under severe heat conditions. On arrival, his BP was 150/90 mm Hg, heart rate 71 bpm, and oxygen saturation 100% at room air, and he was afebrile. His physical examination was unremarkable. Laboratory data included serum sodium of 126 mmol/L, potassium 4.4 mmol/L, high anion gap metabolic acidosis with bicarbonate of 10 mmol/L, blood urea nitrogen 198 mg/dl, serum creatinine 22.5 mg/dl, hypocalcemia at 5.9 mg/dl (iCa 0.82 mmol/L), and hyperphosphatemia at 10.9 mg/dl. Serum creatine kinase (CK) was 23,138 U/L. Urinalysis revealed pH of 6 and large blood. Urine microscopy showed hyaline casts, pigmented granular casts, renal tubular epithelial cells, and few normomorphic erythrocytes. Urine protein-to-creatinine ratio was 1.2 g/g. Serologic/autoimmune workup was negative or normal. On further evaluation, kidney biopsy revealed severe acute tubular injury with myoglobin casts, confirming the diagnosis of rhabdomyolysis-induced AKI. During the first 24 hours, the patient received 6 L of sodium chloride 0.9%, but his kidney function failed to improve and remained oliguric. Standard calcium replacement was given for hypocalcemia. The patient received three daily sessions of hemodialysis with 2.5 mEq/L calcium baths. Subsequently, his kidney function started to improve, but the patient developed severe hypercalcemia with short QT corrected for heart rate on electrocardiogram and was transferred to the intensive care unit due to altered mental status attributed to hypercalcemia-induced posterior reversible encephalopathy syndrome as per neurologic and head CT findings. Two additional daily hemodialysis sessions (2 mEq/L calcium baths) were provided to treat hypercalcemia concomitantly with isotonic intravenous fluids (IVFs) and calcitonin administration. Once hypercalcemia resolved, his mental status returned to baseline, and his kidney function continued to recover until discharge.

Management of Rhabdomyolysis-Induced AKI

The pathophysiology of rhabdomyolysis-induced AKI is multifactorial and involves various mechanisms starting with hypovolemia from fluid sequestration in the injured muscle (Figure 1). Myoglobin is a heme-containing protein in muscle cells that once released from the muscle due to injury is toxic to the renal tubular epithelium and causes tubular injury. Myoglobin also causes vasoconstriction in the kidney microcirculation, resulting in ischemic injury. Furthermore, myoglobin precipitates with Tamm–Horsfall protein in the setting of aciduria to form intratubular casts, which obstruct and further damage the kidneys. Mitochondrial dysfunction and oxidative stress further contribute to kidney injury. Systemic inflammation and proinflammatory cytokines triggered by muscle injury can also exacerbate kidney injury and contribute to AKI progression.³

Figure 1.

Summary of key pathobiological processes of rhabdomyolysis-induced AKI and management interventions, including areas of uncertainty that need additional research. IVF, intravenous fluid; NaCl, sodium chloride; ROS, reactive oxygen species.

Rhabdomyolysis can occur due to physical causes, such as polytrauma, prolonged immobilization, or strenuous muscular exercise, as well as nontraumatic causes, including alcohol drinking, use of recreational or prescribed drugs (e.g., statins), infections, severe dehydration, electrolyte abnormalities, myopathies, and autoimmune processes. In the presented case, the cause was likely a combination of viral illness, dehydration, and work-related muscular activity under severe heat conditions. Clinical symptoms, such as myalgia, weakness, and dark urine (myoglobinuria), are indicative of rhabdomyolysis. However, the clinical presentation is variable, and some patients, particularly elderly individuals, present with few signs and symptoms. High-risk parameters include CK levels >15,000 U/L, hypoalbuminemia, metabolic acidosis, and coagulopathy suggestive of disseminated intravascular coagulation.⁴ Kidney biopsy is not routinely performed to diagnose rhabdomyolysis-induced AKI.

Given the multiorgan involvement of rhabdomyolysis, a multidisciplinary approach should be used for management. The use of isotonic IVF (sodium chloride 0.9% or Ringer lactate) is the cornerstone of treatment to revert hypovolemia, restore renal perfusion, and prevent further kidney damage (Figure 1). Initial IVF rate could range from 200 to 1000 ml/h with a urine output goal of 2–3 ml/kg per hour (i.e., 200 ml/h). IVF should be maintained—albeit not at initial responsive rates—until plasma CK levels are <5000 U/L but promptly stopped if the patient does not exhibit a response in urine output (i.e., remains or becomes oliguric) or develops signs of volume overload. Similar to other conditions that require acute IVF administration, recognition of fluid responsiveness and selection of type of fluid (e.g., balanced solutions) after initial resuscitation are advised. Furthermore, the clinical context of the patient is vital and should be taken into consideration when determining IVF therapy, such as renal perfusion may be further compromised in patients with underlying heart failure that become decompensated with iatrogenic fluid overload.

The use of isotonic IV sodium bicarbonate (i.e., 15 mmol/100 ml) to alkalinize the urine has been suggested when urine pH is <6, CK >30,000 U/L, and if severe metabolic acidosis and hyperkalemia are present. Increasing urine pH may promote the solubility and excretion of myoglobin but could also increase the risk of intratubular calcium-phosphate deposition, and therefore, bicarbonate should be stopped when urine pH is >7.⁵ Furthermore, careful monitoring of hypocalcemia and hypomagnesemia is recommended when bicarbonate is administered. The use of osmotic diuretics, such as mannitol, could reduce the swelling of skeletal muscles and decrease myoglobin–Tamm–Horsfall protein cast formation. However, it can also result in AKI with high doses (daily dose >200 g or cumulative dose >800 g), particularly in patients with hypovolemia. Current data on the protocol-based use of bicarbonate and mannitol to prevent or manage rhabdomyolysis-induced AKI are insufficient, and therefore, their use is not routinely recommended.⁶

KRT should be considered for patients with severe AKI and evolving life-threatening complications (hyperkalemia, dyscalcemia, hyperazotemia, volume overload, etc.). The exclusive use of KRT to remove myoglobin from circulation and prevent or mitigate kidney injury lacks solid evidence and is, therefore, not recommended as the standard of care.⁷ Given that myoglobin has a molecular weight of 17 kDa, its removal from circulation by conventional dialysis is limited. Methods, such as extended hemodialysis using polysulphone high-flux dialyzers, continuous veno-venous hemodialysis using high-cutoff dialyzers, and continous veno-venous hemodiafiltration using high-flux dialyzers, have yielded variable results.^8,9 While clearance of myoglobin could be approximately 20 ml/min with sieving coefficients ranging from 0.1 to 0.3 within the first 24 hours of treatment, its effect on clinical outcomes is unknown.⁷ In the aforementioned case, hemodialysis was provided for solute control, initially due to azotemia, metabolic acidosis, and hyperphosphatemia, and later due to hypercalcemia.

In approximately one third of patients with rhabdomyolysis-induced AKI, a biphasic calcium trajectory pattern occurs. This is characterized by two phases with initial hypocalcemia, followed by hypercalcemia over the course of acute illness.¹⁰ The initial phase of hypocalcemia occurs during the oliguric phase of AKI due to extensive calcium deposition in the necrotic muscle. Hypercalcemia later occurs during the polyuric phase of AKI due to massive calcium release from the muscle (remobilization), typically in the context of frequent and aggressive calcium supplementation during the earlier hypocalcemic phase. This sequential dyscalcemia also results in altered levels of parathyroid hormone and vitamin D metabolites. For management, gentle calcium supplementation is recommended for hypocalcemia, keeping in mind that patients are not calcium deficient but hypocalcemic because of calcium sequestration in the muscle. If hypercalcemia occurs, isotonic IVF, calcitonin, and/or KRT should be considered on the basis of severity and clinical manifestations.

In summary, AKI is a common complication of rhabdomyolysis and is associated with high morbidity and mortality. Early recognition is critical for the management of this condition. Isotonic IVF administration is the cornerstone of treatment. Specific high-risk patients (e.g., CK >30,000 U/L, severe metabolic acidosis, hyperkalemia, and urine pH <6) may benefit from urine alkalinization, but this should be performed with caution. The routine use of mannitol is not recommended. The role of KRT should be supportive and according to solute and volume goals, similar to AKI of other etiologies. Removal of myoglobin by convection or other methods is of limited/variable efficacy and unclear clinical benefits. As highlighted in the case, careful electrolyte monitoring is advised during the course of rhabdomyolysis-induced AKI to recognize and manage complications such as biphasic dyscalcemia.

Disclosures

J.A. Neyra reports consultancy for AcelRx, Baxter, Leadiant Biosciences, Outset Medical, and Vifor Pharma; advisory or leadership roles as a Guest Editor for Critical Care Nephrology in Advances in Chronic Kidney Disease and a Section Editor for Clinical Nephrology; roles on the Editorial Boards of Advances in Chronic Kidney Disease, American Journal of Kidney Diseases, and Kidney360. The remaining author has nothing to disclose.

Funding

J.A. Neyra: NIDDK (R01DK128208, R01DK133539, U01DK12998, and U54DK137307).

Author Contributions

Conceptualization: Yan Lu, Javier A. Neyra.

Writing – original draft: Yan Lu, Javier A. Neyra.

Writing – review & editing: Yan Lu, Javier A. Neyra.