Andrew Z. Fenves

Anaritide in Acute Tubular Necrosis

BACKGROUND: Atrial natriuretic peptide, a hormone synthesized by the cardiac atria, increases the glomerular filtration rate by dilating afferent arterioles while constricting efferent arterioles. It has been shown to improve glomerular filtration, urinary output, and renal histopathology in laboratory animals with acute renal dysfunction. Anaritide is a 25-amino-acid synthetic form of atrial natriuretic peptide. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial of anaritide in 504 critically ill patients with acute tubular necrosis. The patients received a 24-hour intravenous infusion of either anaritide (0.2 microgram per kilogram of body weight per minute) or placebo. The primary end point was dialysis-free survival for 21 days after treatment. Other end points included the need for dialysis, changes in the serum creatinine concentration, and mortality. RESULTS: The rate of dialysis-free survival was 47 percent in the placebo group and 43 percent in the anaritide group (P = 0.35). In the prospectively defined subgroup of 120 patients with oliguria (urinary output, < 400 ml per day), dialysis-free survival was 8 percent in the placebo group (5 of 60 patients) and 27 percent in the anaritide group (16 of 60 patients, P = 0.008). Anaritide-treated patients with oliguria who no longer had oliguria after treatment benefited the most. Conversely, among the 378 patients without oliguria, dialysis-free survival was 59 percent in the placebo group (116 of 195 patients) and 48 percent in the anaritide group (88 of 183 patients, P = 0.03). CONCLUSIONS: The administration of anaritide did not improve the overall rate of dialysis-free survival in critically ill patients with acute tubular necrosis. However, anaritide may improve dialysis-free survival in patients with oliguria and may worsen it in patients without oliguria who have acute tubular necrosis.

Effect of Dipyridamole plus Aspirin on Hemodialysis Graft Patency

BACKGROUND Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity. METHODS We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates. RESULTS At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole-aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P=0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups. CONCLUSIONS Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.)

Deferoxamine Therapy and Mucormycosis in Dialysis Patients: Report of an International Registry

Fifty-nine cases of mucormycosis in dialysis patients have been reported to the registry (25 new cases and 34 previously reported cases). The presenting forms of mucormycosis included disseminated in 44%, rhinocerebral in 31%, and other forms in 25%. The diagnosis was made during life in only 39%, while the diagnosis was discovered at autopsy in 61% of the cases. The fungus, cultured in only 36%, was always Rhizopus. The infection was fatal in 86% of cases. No known risk factors for fungal infections, eg, diabetes mellitus, liver disease, splenectomy, neutropenia, steroid therapy, or other immunosuppressive therapy, were present in 70% of patients, but 78% of patients were being treated with deferoxamine. The role played by this drug and more particularly by its iron chelate, feroxamine, in the pathogenesis of mucormycosis in these patients is underscored. Because of this risk, deferoxamine therapy in dialysis patients should be limited to severe aluminum toxicity, the deferoxamine should be given at the lowest possible dose, and dialytic methods to augment the removal of feroxamine should be studied.

Fatal Rhizopus Infections in Hemodialysis Patients Receiving Deferoxamine

Four hemodialysis patients receiving deferoxamine for metal overload had fatal rhinocerebral rhizopus infections. Serious fungal infections are not commonly seen in patients on dialysis, and none of these patients had the usual risk factors for rhizopus infection. Deferoxamine is being used with increased frequency in dialysis patients for aluminum and iron overload states. We propose that there is a link between the deferoxamine therapy and this unusual infection. Deferoxamine may serve as a specific growth factor for Rhizopus species or may alter host immune function. We suggest searching for fungal organisms in patients with unexplained illnesses receiving deferoxamine.

Increased Anion Gap Metabolic Acidosis as a Result of 5-Oxoproline (Pyroglutamic Acid): A Role for Acetaminophen

The endogenous organic acid metabolic acidoses that occur commonly in adults include lactic acidosis; ketoacidosis; acidosis that results from the ingestion of toxic substances such as methanol, ethylene glycol, or paraldehyde; and a component of the acidosis of kidney failure. Another rare but underdiagnosed cause of severe, high anion gap metabolic acidosis in adults is that due to accumulation of 5-oxoproline (pyroglutamic acid). Reported are four patients with this syndrome, and reviewed are 18 adult patients who were reported previously in the literature. Twenty-one patients had major exposure to acetaminophen (one only acute exposure). Eighteen (82%) of the 22 patients were women. Most of the patients were malnourished as a result of multiple medical comorbidities, and most had some degree of kidney dysfunction or overt failure. The chronic ingestion of acetaminophen, especially by malnourished women, may generate high anion gap metabolic acidosis. This undoubtedly is an underdiagnosed condition because measurements of serum and/or urinary 5-oxoproline levels are not readily available.

Carpal Tunnel Syndrome With Cystic Bone Lesions Secondary to Amyloidosis in Chronic Hemodialysis Patients

Carpal tunnel syndrome (CTS) is increasingly recognized in patients undergoing chronic hemodialysis. Although the etiology remains obscure, angioaccess-related vascular engorgement and edema, and ischemic neuropathy are two likely possibilities. Amyloidosis is a relatively rare cause of CTS and had previously been thought to occur almost exclusively in patients with multiple myeloma. We report seven patients on chronic hemodialysis who developed CTS and were shown to have amyloid deposition within the synovium. Amyloid was demonstrated by characteristic staining with Congo red on polarizing microscopy and confirmed by electron microscopy. Six patients also exhibited radiolucent carpal bone cysts which were histologically shown to be due to bone replacement by an amyloid-positive synovitis. The average age of the patient and time on dialysis were 59.1 and 7.9 years, respectively. Serum and urine immunoelectrophoresis and bone marrow aspirates showed no evidence for plasma cell dyscrasia in six patients, while one patient did manifest a monoclonal IgA spike. Autopsies in three patients and liver biopsy in another showed no other evidence for disseminated amyloid. These hemodialysis patients exhibited a unique syndrome of CTS, lytic lesions of the carpal bones, and amyloid deposition in the synovium and within the bone cysts.

Assessment and Management of Hypertension in Transplant Patients

Hypertension in renal transplant recipients is common and ranges from 50% to 80% in adult recipients and from 47% to 82% in pediatric recipients. Cardiovascular morbidity and mortality and shortened allograft survival are important consequences of inadequate control of hypertension. In this review, we examine the epidemiology, pathophysiology, and management considerations of post-transplant hypertension. Donor and recipient factors, acute and chronic allograft injury, and immunosuppressive medications may each explain some of the pathophysiology of post-transplant hypertension. As observed in other patient cohorts, renal artery stenosis and adrenal causes of hypertension may be important contributing factors. Notably, BP treatment goals for renal transplant recipients remain an enigma because there are no adequate randomized controlled trials to support a benefit from targeting lower BP levels on graft and patient survival. The potential for drug-drug interactions and altered pharmacokinetics and pharmacodynamics of the different antihypertensive medications need to be carefully considered. To date, no specific antihypertensive medications have been shown to be more effective than others at improving either patient or graft survival. Identifying the underlying pathophysiology and subsequent individualization of treatment goals are important for improving long-term patient and graft outcomes in these patients.

Membranous glomerulonephritis associated with Graves' disease.

Renal involvement in thyroid diseases is an unusual event. Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis has been reported in propylthiouracil-treated patients. Membranous glomerulonephritis has been reported in association with both antithyroglobulin and thyroid antimicrosomal antibodies. The development of membranous glomerulonephritis may be associated with administration of 131I. We present a patient who developed membranous glomerulonephritis after administration of 131I. The clinical and pathological features of renal involvement in thyroid diseases are reviewed.

Disseminated adenovirus infection in renal transplant recipients: the role of cidofovir and intravenous immunoglobulin

R. Saquib, L.B. Melton, A. Chandrakantan, K.M. Rice, C.W. Spak, R.D. Saad, A.Z. Fenves, Y.M. Barri. Disseminated adenovirus infection in renal transplant recipients: the role of cidofovir and intravenous immunoglobulin.
Transpl Infect Dis 2010: 12: 77–83. All rights reserved

5-oxoproline (pyroglutamic) acidosis associated with chronic acetaminophen use

Metabolic acidosis is a common acid-base disturbance in hospitalized patients. Distinguishing anion gap from non–anion gap metabolic acidosis is a very helpful exercise and enables the clinician to narrow the etiology of the particular acidosis. The use of the anion gap was popularized in an article by Emmett and Narins (1). Over the past few years, the list of conditions that can cause an anion gap metabolic acidosis has expanded. Mehta et al recently developed a “new mnemonic for the 21st century” to add three forms of anion gap metabolic acidosis not included in several popular mnemonics and to delete several obsolete causes (2). The new mnemonic is GOLD MARK, an acronym for glycols (ethylene and propylene), oxoproline (5-oxoproline also called pyroglutamic acid), L-lactate, D-lactate, methanol, aspirin, renal failure, and ketoacidosis. The new additions are D-lactic acidosis, typically seen in patients with short gut syndromes; the accumulation of propylene glycol, a common diluent for intravenous medications; and 5-oxoproline, an increasingly recognized disorder most commonly associated with chronic acetaminophen ingestion. We report a case of 5-oxoproline acidosis in a woman with a history of chronic acetaminophen use.