C. Matthew Stewart, MD, PhDResident
Johns Hopkins Hospital
Mark T. Fahlen, MD
Modesto Kidney Medical Group
Patricia C. Aristimuno, MD
Department of Internal Medicine
University of Texas Medical Branch
A 41-year-old black man was found in status epilepticus. More than 40 minutes of grand mal seizures were documented, and he developed cardiac arrest requiring 14 minutes of cardiopulmonary resuscitation. His medical history included HIV infection, with a recent CD4+ count of 39 cells/?L, and type 2 diabetes. His daily medications were zidovudine (Retrovir), lamivudine (Epivir), abacavir sulfate (Ziagen), insulin, glyburide (DiaBeta, Glynase, Micronase), trimethoprim/sulfamethoxazole (Bactrim, Cotrim, Septra), and azithromycin (Zithromax). On initial presentation to an outside hospital he was noted to have hypoglycemia and a severe anion gap metabolic acidosis (pH, 6.9). Serum and urine toxicology screens and computed tomography (CT) scanning of the head were negative. His seizures were presumed to be secondary to hypoglycemia. He was mechanically ventilated, and intravenous (IV) vasopressors were given for hypotension. He developed nonoliguric acute renal failure: serum creatinine concentration, 10.7 mg/dL; total serum calcium concentration, 4.1 mg/dL. He had 3 conventional hemodialysis sessions. His renal failure was attributed to prolonged hypotension, and serum creatine kinase levels were not checked at that time.
The patient was transferred to our intensive care unit (ICU) 12 days later. His vital signs were: temperature, 38.1?C; blood pressure, 203/86 mm Hg; pulse, 117 beats/min. He was thin, able to follow simple commands, and was nasally intubated. He had no jugular venous distention. Auscultation of the lungs revealed coarse upper-airway sounds. Cardiovascular and abdominal examinations were normal, and no lower-extremity edema was present. Urine output was 4 L in the first 24 hours. Significant laboratory results included: blood urea nitrogen, 118 mg/dL; serum creatinine concentration, 9.7 mg/dL; potassium, 4.6 mEq/L; creatine kinase, 7490 U/L; phosphate, 5.7 mg/dL; calcium, 8.2 mg/dL; albumin, 2.3 g/dL. Urine myoglobin was 2+, and urine microscopy revealed muddy brown casts consistent with acute tubular necrosis.
The patient was extubated and underwent 2 more sessions of conventional hemodialysis for progressive azotemia. His serum creatinine level declined to 1.7 mg/dL, without further dialysis therapy, and he was transferred to a medical ward, where he was noted to have profound weakness in the psoas and quadriceps muscles but normal strength in the dorsiflexors and plantar flexors. Magnetic resonance imaging scans of the brain and spine were unremarkable.
On hospital day 25, the patient was hyperkalemic, with a serum potassium concentration of 6.2 mEq/L. He was given 2 g of IV calcium gluconate twice. His serum creatinine level remained in the 1.7 to 1.9 mg/dL range. Three days later, his serum calcium level was 13.2 mg/dL. IV saline and IV furosemide were started, along with 90 mg of IV pamidronate disodium. The next day, his serum calcium concentration was 17.9 mg/dL, and the patient developed confusion. He was transferred back to the ICU, where he underwent 3 consecutive conventional hemodialysis sessions using a 2.5 mEq/L calcium dialysis solution. The hypercalcemia did not improve, and the patient became stuporous.
Because of his worsening condition, it was deemed necessary to convert from intermittent to continuous venovenous hemodialysis using a calcium-free dialysis solution, which improved the serum calcium concentration (Figure 1). However, the patient developed hypercarbia and hypoxemia and required reintubation and mechanical ventilation. Significant laboratory values from blood drawn during the period of peak hypercalcemia included: intact serum parathyroid hormone (PTH) level, 7.9 pg/mL; 1,25-dihydroxyvitamin D level, less than 4.0 ng/mL; normal thyroid function tests; and normal serum electrophoresis, with no evidence of monoclonal gammopathy. CT scanning of the thorax, abdomen, and pelvis demonstrated densities suggestive of calcium deposits within the pectoralis major, erector spinae, psoas minor, and iliopsoas muscles (Figure 2). Atechnetium Tc 99m (99mTc) pyrophosphate scan showed increased isotope uptake in the lung or soft tissues of the chest wall, as well as in the thighs and proximal legs, confirming ectopic calcification (Figure 3). These findings correlated with the CT densities and indicated calcifications within muscular tissue.
The patient required a total of 9 days of continuous venovenous hemodialysis before his calcium levels normalized. He was subsequently extubated and recovered. At the time of discharge 6 weeks after his initial presentation, his lower-extremity weakness was improving, but he required the aid of a walker to ambulate short distances.
Rhabdomyolysis, or myocyte necrosis, is a leading cause of acute renal failure.1 Causes of rhabdomyolysis include trauma, seizures, physical exercise, vascular occlusion, drugs, toxins, electrolyte disturbances, and temperature extremes.1 Abnormal calcium homeostasis is a common feature of rhabdomyolysis.2
Hypocalcemia often occurs in the early stages of acute renal failure and is thought to be due to hyperphosphatemia and skeletal resistance to PTH. In contrast, hypercalcemia occurs during the recovery phase of acute renal failure in up to 30% of patients.3 The pathogenesis of the hypercalcemia is undefined, but release of calcium from ectopic soft-tissue calcification is one potential explanation. Previously reported cases of delayed hypercalcemia after rhabdomyolysis-induced acute renal failure have responded to conservative measures with no major complications.
Our patient was a 41-year-old man who developed severe hypercalcemia with respiratory failure 28 days after nonoliguric renal failure from seizure-induced rhabdomyolysis. His hypercalcemia was refractory to IV fluids, furosemide, pamidronate, and conventional hemodialysis. However, continuous venovenous hemodialysis with a calcium-free dialysis solution successfully controlled his hypercalcemia.
Changes in calcium metabolism
Alterations in calcium metabolism are common complications of rhabdomyolysis-induced acute renal failure, and hypercalcemia is common during the diuretic phase. The etiology of the disorder is controversial. Proposed mechanisms include hyperparathyroidism, increased 1,25-dihydroxyvitamin D levels, and mobilization of calcium from soft-tissue deposits. The first report of hypercalcemia in the diuretic phase of rhabdomyolysis-induced acute renal failure, published in 1964, suggested that the cause was transient secondary hyperparathyroidism.4 But levels of PTH have also been shown to be depressed during maximal hypercalcemia.5 Some investigators have suggested that an underlying mechanism for hypercalcemia could be mobilization of the vitamin D stored in muscles and uncontrolled production of 1,25-dihydroxyvitamin D by the recovering kidney.5,6 A direct relationship has been found between serum levels of 1,25-dihydroxyvitamin D and hypercalcemia.7
Subsequent reports suggested that calcium mobilization from ectopic sites was the primary factor in the pathogenesis of this syndrome. Some experts contend that hyperparathyroidism and elevated serum calcitriol levels are not involved, and that the etiology is mobilization of calcium from necrotic muscle.8,9 Indeed, mobilization of calcium from damaged muscle has been demonstrated on serial 99mTc pyrophosphate scans during prolonged resolution of rhabdomyolysis-induced hypercalcemia.10 Muscle-biopsy proven active removal of calcium deposits associated with suppression of PTH secretion and decreased bone turnover have also been demonstrated in the hypercalcemic phase after rhabdomyolysis.9
There is considerable circumstantial evidence in support of this hypothesis.3 A 1996 case report,5 as well as our case, provide further evidence that PTH and 1,25-dihydroxyvitamin D levels are appropriately suppressed during maximal hypercalcemia, which points to calcium mobilization from soft tissue deposits as being central to the pathogenesis of this syndrome.
A remarkable feature of our case was the life-threatening severity of the patient's hypercalcemia. It had been previously reported that hypercalcemia in the context of rhabdomyolysis-induced acute renal failure is generally self-limited in nature, and therapy should be conservative.3 Our patient did not respond to conservative measures and required a prolonged period of continuous venovenous hemodialysis with a calcium-free dialysis solution?a treatment that may not be available in many hospitals.
To our knowledge, this is the first reported case of rhabdomyolysis-associated delayed hypercalcemia that was successfully treated with continuous venovenous hemodialysis. We believe that the initial severity of the man's muscle injury probably led to massive deposition of calcium into the soft tissues. This, as well as IV infusions of calcium, resulted in severe hypercalcemia with life-threatening complications that required aggressive therapy.
Alterations in calcium metabolism are a common complication of rhabdomyolysis-induced acute renal failure. Although hypocalcemia is common during the initial phase, hypercalcemia can develop in the recovery phase. Hypercalcemia associated with rhabdomyolysis-induced acute renal failure has previously been considered self-limited. As this case illustrates, however, it can be a potentially life-threatening condition requiring rapid and aggressive intervention.
This case, therefore, highlights the need for close surveillance for the development of hypercalcemia in the recovery phase of rhabdomyolysis-induced acute renal failure. The use of IV calcium in such patients should be avoided, except in cardiovascular or neurologic emergencies.
All care for this patient was provided at the University of Texas Medical Branch, Galveston, Tex, when Drs Stewart and Fahlen were with that institution. The authors thank Dr Tejinder Ahuja for his thoughtful review of the manuscript.
J Am Soc
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