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40 Year Old Woman with Hepatitis C and History of Drug Use

William F. Glass II, M.D., Ph.D., M.B.A.

Specimen Type:

Renal Cortex

History:

The patient was a female in her early 40’s who presented with a swollen arm, microscopic hematuria, acute kidney injury with eGFR =2 ml/min, and approximately 500 mg/dL urinary protein. Recent medications included Advil, Tylenol, Naproxen and Aleve. She was hepatitis C positive and had a history of cocaine use. Serum creatine kinase (CK) was approximately 560 units.

Pathologic Features:

Light microscopy:

The specimen consisted of two cores of renal cortex. Approximately 20 glomeruli were examined and appeared normal. There was diffuse tubulointerstitial edema with early, mild fibrosis, no tubular atrophy, and focal mild to moderate inflammation with lymphocytes and occasional plasma cells. Tubules contained frequent casts composed of, round, course granules that were brightly eosinophilic. Proximal tubules were focally ectatic with absent brush borders and there were focal tubules containing detached cells. Some cells had hyperchromatic nuclei. Arteries and arterioles were normal. H&E-stained section frozen section also showed brightly eosinophilic casts. Unstained frozen section showed that the casts were light brown.

Immunofluorescence:

Immunofluorescence was negative for immunoglobulins, IgG, IgA, kappa light chain, and lambda light chains as well as C1q. There was minor (1+) diffuse, mesangial, granular IgM and C3 and diffuse, weak tubulointerstitial fibrinogen.

Electron microscopy:

The glomerular basement membranes were normal thickness. The mesangial matrix was not expanded. Subendothelial, subepithelial, and mesangial/paramesangial electron-dense, immune complex-type deposits and paraprotein deposits were not present. Podocyte foot processes appeared generally to be intact. However, there were focal, intratubular, round, often-aggregated, electron-dense granules which focally had a target-like variation in electron density.

Differential Diagnosis:

The major differential diagnosis for acute tubular injury with pigment casts is rhabdomyolysis and intravascular hemolysis, both of which can be associated with coarsely granular brownish casts in urine or unstained sections and brightly eosinophilic granular casts in histological section. These must be distinguished from similar or identical-appearing casts that can result from intratubular degradation of red blood cells. However, these degenerate casts are usually accompanied by some casts with residual identifiable red blood cells of fragments. Furthermore, acute glomerulonephritis can usually be identified associated with degenerate RBC casts. Usually, the clinical history or additional laboratory testing will provide sufficient information to determine whether the underlying disease process is rhabdomyolysis or hemolysis. In particular, creatine kinase (CK) is typically elevated. While the value is frequently greater than 16,000 units/L when acute renal failure is present (1), in this case it was only 560 units, but when rhabdomyolysis is accompanied by typical high levels of CK, biopsy is unlikely to be necessary to make the diagnosis clinically. Additionally, urine dipstick may be positive in rhabdomyolysis in the absence of RBCs microscopically. Specific urine tests can be done for myoglobin, but these usually take several days to get results back and a negative test result does not rule out rhabdomyolysis (2). Pathologically, immunohistochemistry for myoglobin can be used to make this distinction from hemoglobin casts if necessary.

Diagnosis:

Acute tubuloepithelial injury with pigment casts consistent with rhabdomyolysis (Pigment Cast Nephropathy)

Rhabdomyolysis is a common potentially lethal clinical syndrome with approximately 26,000 cases annually in the United States, with acute renal failure occurring in approximately 15 – 33% of cases (1). Rhabdomyolysis is a term that refers to injury to skeletal muscle that is sufficiently severe as to cause dissolution or disruption of the muscle cells releasing the contents in the extracellular fluid and circulation. Particularly relevant to the causation of acute renal failure is the release of myoglobin an 18,000 Dalton protein which is freely filtered by the glomerulus. In most cases, myoglobin passes through the kidney into the urine without significant renal injury, however dehydration and acidic pH can facilitate the aggregation and precipitation of myoglobin in the tubules. The mechanisms of renal injury involve both obstructive and toxic effects (3). An evaluation of 475 patients presenting at Johns Hopkins Hospital between 1993 and 2001 revealed that the most common etiologic factor identified in these cases was illicit drugs/alcohol (34%) followed by prescription medications (11%) (2). While this paper did not provide a breakdown of the specific illicit drugs, one review lists cocaine, amphetamine, ecstasy (MDMA), and LSD (1). The mechanism thought responsible for cocaine-induced rhabdomyolysis include vasospasm with muscular ischemia, seizures, hyperpyrexia, coma with muscle compression, and direct myofibrillar damage (4). The most common prescription medications associated with rhabdomyolysis included antipsychotics (7.6%) and statins (4.2%), SSRIs (3.2%) while other medications included zidovudine, colchicine, lithium, antihistamines, valproic acid, leuprolide, amiodarone, and omeprazole (2). The list of other causes is long and includes muscle diseases, trauma, NMS, idiopathic, seizures, immobility, metabolic, HIV/AIDS, ICU myopathy, malignant hyperthermia, exercise, heat dehydration, multiple myeloma, and hypothermia (2). In many cases, more than one factor may be contributory. When treated early and aggressively, rhabdomyolysis has an excellent prognosis for full recovery with restoration of full renal function (4).

References:

  1. Sauret, J. M., G. Marinides, et al. (2002). "Rhabdomyolysis." Am Fam Physician 65(5): 907-12.
  2. Melli, G., V. Chaudhry, et al. (2005). "Rhabdomyolysis: an evaluation of 475 hospitalized patients." Medicine (Baltimore) 84(6): 377-85.
  3. Vanholder, R., M. S. Sever, et al. (2000). "Rhabdomyolysis." J Am Soc Nephrol 11(8): 1553-61.
  4. Khan, F. Y. (2009). "Rhabdomyolysis: a review of the literature." Neth J Med 67(9): 272-83.