William J. Stone

Severe allopurinol toxicity: Description and guidelines for prevention in patients with renal insufficiency

A life-threatening toxicity syndrome consisting of an erythematous, desquamative skin rash, fever, hepatitis, eosinophilia, and worsening renal function in 78 patients receiving allopurinol is described. In a majority of cases, the development of this syndrome was associated with the use of standard (200 to 400 mg per day) doses of allopurinol in patients with renal insufficiency. In pharmacologic studies, it was demonstrated that the renal clearance of the major metabolite of allopurinol, oxipurinol, is directly proportional to the renal clearance of creatinine (oxipurinol clearance = 0.22 X creatinine clearance -2.87). An inverse linear relation was noted between the serum oxipurinol half-life and the renal creatinine clearance [( serum oxipurinol half-life in hours]-1 = 0.00034 X creatinine clearance in milliliters per minute + 0.0045). Long-term use of 300 mg per day of allopurinol was found to result in elevated steady-state serum oxipurinol concentrations in patients with renal insufficiency (serum oxipurinol concentration in micromoles per liter = -2.5 X creatinine clearance in milliliters per minute + 326). Avoidance of allopurinol or use of reduced doses in patients with renal insufficiency according to proposed guidelines should be adequate to inhibit uric acid production in most patients and may reduce the incidence of life-threatening allopurinol toxicity.

Overwhelming Strongyloidiasis: An Unappreciated Opportunistic Infection

Strongyloides stercoralis is an intestinal nematode which infects a large portion of the worlds population. Individuals with infection confined to the intestinal tract are often asymptomatic but may have abdominal pain, weight loss, diarrhea, and other nonspecific complaints. Enhanced proliferation of the parasite in compromised hosts causes an augmentation of the normal life-cycle. Resultant massive invasion of the gastrointestinal tract and lungs is termed the hyperinfection syndrome. If the worm burden is excessive, parasitic invasion of other tissues occurs and is termed disseminated strongyloidiasis. A variety of underlying conditions appear to predispose to severe infections. These are primarily diseases characterized by immunodeficiency due to defective T-lymphocyte function (Table 1). Individuals with less severe disorders become compromised hosts because of therapeutic regimens consisting of corticosteroids or other immunosuppressive medication. The debilitation of chronic illness or malnutrition also predisposes to systemic stronglyloidiasis. The diagnosis of strongyloidiasis can be readily made by microscopic examination of concentrates of upper small bowel fluid, stool, or sputum. Important clues suggesting this infection include unexplained gram-negative bacillary bacteremia in a compromised host who may have vague abdominal complaints, an ileus pattern on X-ray, and pulmonary infiltrates. Eosinophilia is helpful, if present, but should not be relied upon to exclude the diagnosis. The treatment of systemic infection due to Strongyloides stercoralis with either thiabensazole 25 mg/kg orally twice daily is satisfactory if the diagnosis is made early. Because of several unusual features of this illness in compromised hosts, the standard recommendation for 2 days of therapy should be abandoned in such patients. Immunodeficiency, corticosteroids, and bowel ileus reduce drug efficacy. Thus a longer treatment period of at leuch as blind loops or diverticula necessitate longer treatment. Stool specimens and upper small bowel aspirates should be monitored regularly and treatment continued several days beyond the last evidence of the parasite. In particularly difficult situations where either worm eradication is impossible or reinfection is probable, short monthly courses of antihelminthic therapy seem to be effective in averting recurrent systemic illness. Finally, prevention of hyperinfection or dissemination due to Strongyloides stercoralis can be accomplished by screening immunocompromised hosts with stool and upper small bowel aspirate examinations. These would be especially important prior to initiating chemotherapy, or before giving immunosuppressive medications or corticosteroids to patients with nonneoplastic conditions such as systemic lupus erythematosus, nephrotic syndrome, or renal allografts.

Beta-2 microglobulin is an amyloidogenic protein in man.

Curvilinear fibrils with the tinctorial properties of amyloid were isolated from a patient with bone and joint involvement complicating chronic dialysis for renal disease. Subunit fractions of 24,000 and 12,000 mol wt were identified after gel filtration under dissociating conditions, the latter containing a significant amount of a dimer of the former. This was confirmed by Edman degradation of each fraction, which yielded the amino terminal sequence of normal human beta-2 microglobulin (B2M) to residues 20 and 30, respectively. The size of the subunit protein (12,000 mol wt) and the amino acid composition make it likely that intact B2M is a major constituent of the fibrils. B2M is thus another example of a low molecular weight serum protein, with a prominent beta-pleated sheet structure, that may adopt the fibrillar configuration of amyloid in certain pathologic states.

Plasma binding and disposition of furosemide in the nephrotic syndrome and in uremia

The pharmacokinetic disposition of furosemide has been investigated in six normal subjects, 7 patients with the nephrotic syndrome and 6 patients with uremia. Furosemide levels were measured using a specific HPLC analytical procedure and protein binding was measured by equilibrium dialysis using 3H‐furosemide. The high binding offurosemide in normal subjects (95.9 ± 0.1%) was reduced in both uremia (94.4 ± 0.4%) and the nephrotic syndrome (93.2 ± 0.5%). When alt three study groups were combined, furosemide binding correlated with the serum albumin concentration measured in each subject at the time of the study (r = −0.83, p < 0.001). Approximately 50% of the systemic clearance of total drug in controls (158 ± 11 ml/min) was due to renal clearance. The renal clearance of total furosemide in the nephrotic syndrome was not altered, but renal clearance of unbound drug decreased in proportion to the creatinine clearance. Extrarenal clearance was unaffected in the nephrotic syndrome. In contrast, in uremia, both renal and extrarenal clearances were significantly reduced. The fall in renal clearance was consistent with a reduction in functioning nephrons and the presence of competitive inhibitors for tubular secretion. The volume of distribution offurosemide at steady‐state correlated with both serum albumin (r= +0.73, p < 0.001) and drug binding (r = +0.63, p < 0.005) and was increased in the nephrotic syndrome. Furosemide half‐life was unchanged in nephrotic syndrome but prolonged by threefold in uremia. Chronic hemodialysis for two to four months in 4 of the uremic subjects produced no significant change in any pharmacokinetic parameter. This study indicates that the disposition of furosemide is not only dependent on renal function but also on the serum albumin concentration.

Pathologic Fractures Associated with Idiopathic Amyloidosis of Bone in Chronic Hemodialysis Patients

Amyloid bone lesions were found in 2 chronic hemodialysis patients presenting with pathologic hip fractures. These amyloid deposits were noted as lytic defects on plain skeletal radiographs. No evidence for disseminated amyloidosis was discovered on physical examination, skin biopsy, or bone marrow biopsy. Myeloma, other plasma cell dyscrasia, and preceding chronic inflammatory states were not found in either patient. The amyloid deposits had staining characteristics suggestive of secondary amyloid based on the potassium permanganate reaction. Isolated amyloid bone deposits should be included in the differential diagnosis of lytic bone lesions or pathologic fractures in chronic dialysis patients.

Page Kidney: Case Report and Review of the Literature

Page kidney is caused by the accumulation of blood in the perinephric or subcapsular space, resulting in compression of the involved kidney, renal ischemia, and high renin hypertension. Most patients are young hypertensives with a remote history of blunt trauma to the abdomen or back. We describe a case of acute Page kidney following a renal biopsy in a patient with underlying IgA nephropathy. In addition to the new-onset hypertension, this patient developed a significant decline in renal function due to the inability of the contralateral diseased kidney to compensate. Magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound were valuable in making this diagnosis. Medical and surgical therapeutic options were considered. This report also reviews all previously described cases of Page kidney.

Pharmacology, electrophysiology, and pharmacokinetics of mexiletine☆

Mexiletine is a class I antiarrhythmic agent that is active after both oral and intravenous administration and similar in structure and activity to lidocaine. It decreases phase O maximal rate of depolarization (Vmax) by fast sodium channel blockade. The marked rate dependence of Vmax depression may explain mexiletines lack of effect on normal conduction and its efficacy against ventricular tachyarrhythmias. Mexiletine significantly decreases the relative refractory period in His-Purkinje fibers without changing the sinus rate or atrioventricular and His-Purkinje conduction times. Action potential duration is usually shortened. Mexiletine may aggravate preexisting impairment of impulse generation and conduction. Uptake and distribution of mexiletine are rapid, systemic bioavailability is about 90%, and tissue distribution is extensive. Mexiletine is primarily metabolized in the liver; 10% to 15% is excreted unchanged in the urine. Elimination half-life is 9 to 11 hours after intravenous or oral administration. Microsomal enzyme induction shortens mexiletines elimination half-life, whereas hepatic disease and acute myocardial infarction prolong it. Renal disease has little effect, although hemodialysis increases mexiletine clearance. Plasma concentrations from 0.75 to 2.0 mg/L are usually associated with a desirable therapeutic response.

Tumoral amyloidosis of bone of beta2-microglobulin origin in association with long-term hemodialysis: A new type of amyloid disease

Amyloid lesions of bone are rare and limited almost exclusively to patients with amyloidosis secondary to plasma cell dyscrasias. The present report describes the cases of two patients receiving long-term hemodialysis (nine and 12 years) who had multiple lytic lesions of bone proved by biopsy to contain an unusual type of amyloid. Results of serum protein electrophoreses and immunoelectrophoreses, as well as bone marrow examinations, were normal. In both cases the amyloid displayed characteristic Congo red affinity and birefringence on polarized light microscopy that was inhibited by potassium permanganate treatment of sections prior to staining. Although this staining reaction was described previously exclusively in AA amyloid (i.e., the material associated with classic secondary amyloidosis), immunoperoxidase staining for AA protein in these cases was negative. Transmission electron microscopy revealed the amyloid fibrils to have unusual curvilinear configurations. Immunoperoxidase staining for beta 2-microglobulin (beta 2m) was positive in the amyloid lesions of both patients at the light microscopic level. Ultrastructural immunohistochemical studies for beta 2m, performed in one case, were positive. Both patients had markedly elevated serum beta 2m levels. By Ouchterlony immunodiffusion, purified beta 2m demonstrated partial identity with purified amyloid protein fractions and a serum constituent. Bone lesions composed of amyloid related to beta 2M probably represent a new subgroup of amyloid disease that may be linked to renal failure and long-term hemodialysis.

Evaluation of the effect of intravenous L-carnitine therapy on function, structure and fatty acid metabolism of skeletal muscle in patients receiving chronic hemodialysis.

Chronic hemodialysis (HD) leads to significant losses of carnitine from plasma and muscle. Because L-carnitine is important in the production of energy from fatty acid oxidation (FAO) in muscle, we examined the role of carnitine replacement by administering therapeutic doses of intravenous carnitine to 14 male patients receiving HD. Placebo or carnitine was given 2 g i.v. 3 times weekly for 6 months in a double-blind manner. To evaluate long-term toxicity of carnitine, all patients subsequently received 1 g i.v. carnitine for 10 months. Patients were rated for muscle strength each week. After 6 months, definite improvement in strength occurred in 4 of 7 carnitine-treated patients and in none of 7 controls. During the subsequent 10 months of carnitine administration, no adverse effects were noted and muscle strength improved in 9 of 14 patients. Muscle biopsy was performed in 13 patients before and after the first 6 months of treatment and in 6 healthy controls. FAO and carnitine were measured in each muscle biopsy. FAO was significantly lower in both carnitine- and placebo-treated HD patients compared to healthy controls. Although carnitine therapy increased the muscle concentration of carnitine 3-fold in muscle of HD patients, muscle FAO did not increase significantly and never reached the level of healthy controls. Muscle histopathology and ultrastructure were not specific for HD myopathy. Carnitine may be useful in treating some patients with muscle weakness related to HD.

Opportunistic strongyloidiasis in renal transplant recipients.

Eight patients with severe strongyloidiasis complicating renal transplantation are reported. Twenty-one additional cases from the English-language literature are reviewed. In this setting, systemic strongyloidiasis is an often baffling illness involving multiple organ systems that is frequently complicated by serious bacterial infection. Bacteremia, meningitis, urinary tract infection, and pneumonia resulting from enteric organisms are common. In order to make the diagnosis, larvae must be sought by direct microscopy of stool, upper intestinal fluid, sputum, urine, or biopsy specimens. Treatment with oral thiabendazole in prolonged or repeated courses is recommended. Effective parenteral therapy is not available. Following treatment, previously parasitized patients must be tested at regular intervals to detect therapeutic failure or reinfection. Screening of patients awaiting renal transplantation for chronic intestinal strongyloidiasis is suggested. Improvement of the observed 52% mortality will depend upon heightened awareness by physicians caring for renal transplant candidates, and upon improved therapeutic regimens.