Advancing pharmacovigilance through academic-legal collaboration: the case of gadolinium-based contrast agents and nephrogenic systemic fibrosis-a Research on Adverse Drug Events and Reports (RADAR) report.

OBJECTIVE: To compare and contrast three databases, that is, The International Centre for Nephrogenic Systemic Fibrosis Registry (ICNSFR), the Food and Drug Administration Adverse Event Reporting System (FAERS) and a legal data set, through pharmacovigilance and to evaluate international nephrogenic systemic fibrosis (NSF) safety efforts. METHODS: The Research on Adverse Drug events And Reports methodology was used for assessment-the FAERS (through June 2009), ICNSFR and the legal data set (January 2002 to December 2010). Safety information was obtained from the European Medicines Agency, the Danish Medicine Agency and the Food and Drug Administration. RESULTS: The FAERS encompassed the largest number (n = 1395) of NSF reports. The ICNSFR contained the most complete (n = 335, 100%) histopathological data. A total of 382 individual biopsy-proven, product-specific NSF cases were analysed from the legal data set. 76.2% (291/382) identified exposure to gadodiamide, of which 67.7% (197/291) were unconfounded. Additionally, 40.1% (153/382) of cases involved gadopentetate dimeglumine, of which 48.4% (74/153) were unconfounded, while gadoversetamide was identified in 7.3% (28/382) of which 28.6% (8/28) were unconfounded. Some cases involved gadobenate dimeglumine or gadoteridol, 5.8% (22/382), all of which were confounded. The mean number of exposures to gadolinium-based contrast agents (GBCAs) was gadodiamide (3), gadopentetate dimeglumine (5) and gadoversetamide (2). Of the 279 unconfounded cases, all involved a linear-structured GBCA. 205 (73.5%) were a non-ionic GBCA while 74 (26.5%) were an ionic GBCA. CONCLUSION: Clinical and legal databases exhibit unique characteristics that prove complementary in safety evaluations. Use of the legal data set allowed the identification of the most commonly implicated GBCA. ADVANCES IN KNOWLEDGE: This article is the first to demonstrate explicitly the utility of a legal data set to pharmacovigilance research.

Experience with outpatient computed tomographic-guided renal biopsy.

Native kidney biopsy is still performed primarily with hospital inpatient observation period. Experience with outpatient Computed Tomographic (CT)-guided renal biopsy at Yale New Haven Medical Center was studied to assess efficacy and safety. A total of 146 outpatient native kidney biopsies were identified between 1995 and 2001. Records were reviewed for demographics, clinical, and laboratory data and details of the procedure. Time of admission to the outpatient unit, duration of procedure and post-biopsy observation period were recorded. Complications such as bleeding, infection, admission to the hospital, transfusion, or intervention for continued bleeding were noted. Mean age was 43.9 ± 14.9 years and mean serum creatinine was 1.8 ± 1.4 mg/dl. Renal size averaged 11.4 cm. Post-procedure observation time of 4 - 6 h appeared to be adequate. Diagnostic tissue was successfully sampled in 98.6% of cases. Procedure was well tolerated with no hemodynamically significant changes. Hematocrit and hemoglobin concentration changes averaged 3.6 ± 2.5% and 1.0 ± 0.9 mg/dl, respectively (p < 0.001). There were no instances of death or need for intervention. Transfusion was required in 1 patient while 6 patients had detectable bleeding and were hospitalized for observation. Outpatient CT-guided kidney biopsy provides adequate tissue and appears to be safe with very low complication rates.

Treatment of Severe Intradialytic Hypotension With the Addition of High Dialysate Calcium Concentration to Midodrine and/or Cool Dialysate.

Treatment of intradialytic hypotension (IDH) in the end-stage renal disease population has been a difficult task for nephrologists caring for these patients. The presence of multiple pathogenic factors contributes to hemodynamic instability and explains why therapies that modulate only a specific aspect of the problem are only partially effective. Cool dialysate (34.5 degrees C to 35.5 degrees C) and midodrine may provide hemodynamic stability through an increase in peripheral vascular resistance, whereas high dialysate calcium concentration (HDCa; 3.5 mEq/L) improves intradialytic blood pressure through preservation of cardiac output. Theoretically, the combination of these two types of therapies might further reduce the frequency and severity of hypotension during hemodialysis (HD). We undertook a study to evaluate the effect of HDCa added to midodrine and/or cool dialysate in the treatment of patients with severe IDH. Twenty-eight patients met the entry criteria, and 23 patients completed the prospective crossover study. Five patients dropped out of the study secondary to hypercalcemia. The addition of HDCa significantly improved post-HD mean arterial pressure (MAP; 95.6 +/- 12.7 versus 90.8 +/- 12.5 mm Hg; P = 0.002). The decreases in MAP from pre-HD to lowest intradialytic (16.3 +/- 8.2 versus 20.6 +/- 10.0 mm Hg; P = 0.009) and pre-HD to post-HD (2.0 +/- 8.5 versus 8.15 +/- 10.8 mm Hg; P = 0.002) were significantly reduced with HDCa compared with low dialysate calcium. However, there were no significant improvements in symptoms of or interventions for IDH. Thus, it appears that the addition of HDCa to midodrine and/or cool dialysate further improves blood pressure in patients with IDH. However, this therapy did not reduce symptoms or interventions required for IDH. In addition, hypercalcemia complicated this therapy in 22% of the patients.

ACE inhibitors do not induce recombinant human erythropoietin resistance in hemodialysis patients.

Angiotensin-converting enzyme (ACE) inhibitors may exacerbate anemia in patients with chronic renal failure, as well as in dialysis patients. To better answer this question, a prospective, crossover study was conducted to evaluate the effect of ACE inhibitors on recombinant human erythropoietin (rHuEPO) requirements in hemodialysis patients. Patients administered an ACE inhibitor when entering the study remained on this drug for the initial 4 months and were then switched to another antihypertensive agent for 4 more months. Patients not initially administered an ACE inhibitor were switched to lisinopril at 4 months. rHuEPO doses were adjusted using a sliding scale based on weekly laboratory hematocrit values. The inclusion criteria were met by 51 patients undergoing dialysis. Demographics were as follows: 61% were women, 64% were black, 46% had diabetes, average age was 53.2 +/- 13.3 years, and time on hemodialysis was 38.0 +/- 44.5 months. Thirty-three patients completed the study. Hematocrit averaged 32.7% +/- 1.9% while on ACE inhibitor therapy and 33.1% +/- 2.1% off ACE inhibitor therapy (P = 0.217). There was no difference in rHuEPO dose per treatment during each period (3,500 +/- 1,549 U on ACE inhibitor therapy versus 3,312 +/- 1,492 U off ACE inhibitor therapy; P = 0.300). No significant differences were found in degree of blood pressure control or various clinical and laboratory parameters that might be associated with rHuEPO resistance between the two periods. Similarly, no differences were found in hospitalization days, duration of infections, or transfusion requirements. These findings suggest that ACE inhibitors do not contribute to rHuEPO resistance in hemodialysis patients.

Immunochemical characterization of Na+/H+ exchanger isoform NHE4.

Mammalian Na+/H+ exchangers (NHEs) are a family of transport proteins (NHE1-NHE5). To date, the cellular and subcellular localization of NHE4 has not been characterized using immunochemical techniques. We purified a fusion protein containing a portion of rat NHE4 (amino acids 565-675) to use as immunogen. A monoclonal antibody (11H11) was selected by ELISA. It reacted specifically with both the fusion protein and to a 60- to 65-kDa polypeptide expressed in NHE4-transfected LAP1 cells. By Western blot analysis, NHE4 was identified as a 65- to 70-kDa protein that was expressed most abundantly in stomach and in multiple additional epithelial and nonepithelial rat tissues including skeletal muscle, heart, kidney, uterus, and liver. Subcellular localization of NHE4 in the kidney was evaluated by Western blot analysis of membrane fractions isolated by Percoll gradient centrifugation. NHE4 was found to cofractionate with the basolateral markers NHE1 and Na+-K+-ATPase rather than the luminal marker gamma-glutamyl transferase. In stomach, NHE4 was detected by immunoperoxidase labeling on the basolateral membrane of cells at the base of the gastric gland. We conclude that NHE4 is a 65- to 70-kDa protein with a broad tissue distribution. In two types of epithelial cells, kidney and stomach, NHE4 is localized to the basolateral membrane.

Reduction in arteriovenous graft impairment: results of a vascular access surveillance protocol.

Impairment of hemodialysis (HD) vascular access, remains a frustrating problem for both the patient who possesses an arteriovenous graft (AVG) and the nephrologist who cares for the patient. We instituted a vascular access surveillance protocol intended to detect and correct evolving stenosis in patients with AVGs. The principal screen was the observation of dynamic venous pressure (VP) at a blood flow rate of 200 mL/min during the first 5 minutes of each HD session. If VP at a blood flow rate of 200 mL/min was 140 mm Hg or greater in three of six consecutive readings, recirculation greater than 15% on two observations, graft-arm swelling observed, or prolonged bleeding postdialysis observed, then the patient was referred for angiography and then angioplasty or surgery if a vascular stenosis of greater than 50% was documented. Sixty-four patients with a synthetic AVG comprised the study group. Seventy-two episodes of AVG impairment (56 with stenosis > or = 50% on angiography, 16 with thrombosis) occurred in these patients during the study period. In 63 of 72 impairment episodes, the preceding vascular access screening test was positive. The calculated sensitivity and specificity of the vascular access protocol was 88% and 81%, respectively. Calculation of the sensitivity and specificity for the VP alone was 81% and 85%, respectively. Comparison of the study group with a similar historical control group (55 patients) showed a significantly lower thrombosis rate (P = 0.03; 95% confidence interval [CI], 0.025 to 0.375) in the study group (0.29 thrombotic episodes/graft-year at risk) versus the historical control group (0.49 thrombotic episodes/graft-year at risk). In summary, a vascular access surveillance protocol is a useful tool to predict patients at risk for AVG venous stenosis and/or thrombosis. A dynamic VP of 140 mm Hg or greater appears to be the optimal threshold pressure. A decrease in synthetic AVG thrombosis rate resulted from the use of this surveillance protocol.

Monoclonal antibodies for high-resolution localization of NHE3 in adult and neonatal rat kidney.

Previous immunochemical studies have shown that NHE3 is an apical Na+/H+ exchanger in some renal epithelia. The purpose of the present study was to develop high-affinity, isoform-specific monoclonal antibodies (MAbs) that would be useful for carrying out high-resolution immunocytochemical studies of NHE3 in the adult and neonatal mammalian kidney. Three MAbs were developed to a fusion protein containing amino acids 702-832 of rabbit NHE3. Specificity was established by immunoblotting membranes from NHE-deficient LAP cells that had been transfected with either NHE1,-2, -3, or -4. With the use of high-resolution immunocytochemical techniques, NHE3 was found in vesicles in the apical cytoplasm of proximal tubule cells, as well as in the apical plasma membrane of the proximal tubule, and in both the thin and thick limbs of the loop of Henle. When localized in the 1-day-old rat kidney, NHE3 was first detected in the late stages of the S-shaped body. In later stages of nephron development, the pattern of NHE3 staining was similar to that seen in the adult. This study demonstrates 1) the specificity of three MAbs for Na+/H+ exchanger isoform NHE3; 2) NHE3 is present in an intracellular vesicular compartment in cells of the proximal tubule, consistent with possible regulation by membrane recycling; and 3) NHE3 is expressed on the apical membrane in early stages of the developing nephron.

Cathepsin D in intestinal ganglion cells. A potential aid to diagnosis in suspected Hirschsprung's disease.

There is still a need for a better method of detecting immature ganglion cells in paraffin sections of colorectal luminal biopsies in cases suspected of Hirschsprung's disease. The lysosomal aspartic proteinase cathepsin D has been immunolocalized to various cell types, including ganglion cells. We investigated its expression in intestinal ganglion cells to determine whether it could be used as an aid in the detection of immature ganglion cells in rectal biopsies from children suspected of having Hirschsprung's disease. Routinely processed tissues of eight adult intestines resected for gunshot wounds and six ganglioneuromas (for mature ganglion cells), of six colons resected for neonatal necrotizing enterocolitis (for immature ganglion cells), and of 11 cases of suspected and three cases of known Hirschsprung's disease were immunostained with a polyclonal antibody to cathepsin D using the avidin-biotin-peroxidase method. In all cases, all ganglion cell bodies present showed intense granular cytoplasmic reactivity for cathepsin D. The granules crowded the cytoplasm and formed a collarette around the nucleus. In the submucosa, the only other immunoreactive cells were histiocytes, but they could be distinguished from ganglion cells by their characteristic nuclear features and their occurrence singly and unassociated with nerves. The three resection specimens with Hirschsprung's disease showed a clear transition between the ganglionic and the aganglionic segments. We conclude that cathepsin D is a promising marker of immature ganglion cells in cases suspected of Hirschsprung's disease.

Mucosal biopsy findings and venous abnormalities in idiopathic myointimal hyperplasia of the mesenteric veins.

Idiopathic myointimal hyperplasia of the mesenteric veins (IMHMV) is a rare cause of intestinal ischemia secondary to venous compromise. A patient with this condition who presented with crampy abdominal pain, diarrhea, and rectal bleeding initially attributed to inflammatory bowel disease had several colonoscopies and ultimately a sigmoid colectomy. The colonic mucosa in biopsies performed at initial presentation and subsequently and in the resection specimen contained numerous hyperplastic, thick-walled, hyalinized vessels in the lamina propria, which have not been described in this entity previously. Examination of the mucosa in 27 resection specimens of ischemic enterocolitis of various etiologies, in five resections of prolapsed rectum, and in seven colostomy specimens revealed no instance in which there were similar histologic abnormalities. When seen on biopsy, therefore, these features should lead to inclusion of IMHMV in the differential diagnosis. Furthermore, the characteristic lesions of the submucosal and extramural veins in IMHMV were compared with those of 14 examples, from several organs, of veins subjected to arterial pressure and 21 cases of venous hypertension. The marked similarity of the arterialized veins to the mural veins of IMHMV suggests a role for arteriovenous fistulization in the pathogenesis of IMHMV, and a mechanism by which this might occur is proposed.

Angiotensin-converting enzyme inhibitor therapy in chronic hemodialysis patients: any evidence of erythropoietin resistance?

Exacerbation of anemia associated with angiotensin-converting enzyme (ACE) inhibitor therapy has been noted to occur in patients with chronic renal failure, end-stage renal disease, and renal transplantation. Angiotensin-converting enzyme inhibitors appear to cause anemia through induction of decreased red blood cell production. There are data suggesting that ACE inhibitors may impair erythropoiesis via either suppression of angiotensin-mediated erythropoietin (EPO) production or bone marrow response to EPO. Patients on chronic hemodialysis receive recombinant human EPO (rHuEPO) for therapy of anemia and may also receive an ACE inhibitor for hypertension or congestive heart failure. We undertook a retrospective study to evaluate whether patients treated with ACE inhibitors developed a more severe anemia or required a higher dose of rHuEPO to maintain a similar hematocrit. Ninety-five of 108 chronic hemodialysis patients met study criteria (hemodialysis for 4 months and no treatment with an ACE inhibitor for at least 4 months = group 1; therapy with an ACE inhibitor for at least 4 months = group 2). Forty-eight patients (group 1, n = 24; group 2, n = 24) were available for analysis after exclusion for a variety of factors. There was no difference between the two groups in terms of baseline characteristics, number of blood transfusions or hospital days, or other laboratory parameters. There was no statistically significant difference in average hematocrit between group 1 (33.5% +/- 3.9%) and group 2 (32.6% +/- 1.6%). Similarly, no significant difference was observed for the average rHuEPO dose/treatment between group 1 (3,272 +/- 1,532 IU/treatment; 50.69 +/- 26.94 IU/kg/treatment) and group 2 (3,401 +/- 1,009 IU/treatment; 52.87 +/- 19.38 IU/kg/treatment). These results suggest that ACE inhibitors do not significantly induce more severe anemia or alter rHuEPO response in chronic hemodialysis patients.

An immunohistochemical study of thyroid Hurthle cells and their neoplasms: the roles of S-100 and HMB-45 proteins.

The histological and cytological features of follicular thyroid neoplasms with oxyphilic change (Hurthle cell tumors) may lead to the differential diagnosis of metastatic malignant melanoma. S-100 and HMB-45 staining was studied in 18 Hurthle cell tumors, 6 Hurthle cell carcinomas, and 5 cases of Hashimoto's thyroiditis using a rabbit polyclonal antibody to S-100 protein, a mouse monoclonal antibody to HMB-45 protein, and the avidin alkaline phosphatase method. All 6 carcinomas and 17 of 18 Hurthle cell tumors exhibited strong cytoplasmic and nuclear staining for S-100. One Hurthle cell carcinoma also contained a spindle cell anaplastic area that was negative for S-100. All cases of Hashimoto's thyroiditis displayed intense staining in Hurthle cells for S-100, with weak to negative staining in nonoxyphilic follicular epithelium. In the three studied lesions, all cases were negative for HMB-45 protein. Three nonthyroid oncocytic tumors (renal oncocytoma, oncocytic carcinoma of the parotid, and parathyroid oxyphilic adenoma) were found to be negative for both S-100 and HMB-45 staining. Hurthle cell lesions should be included in the differential diagnosis of S-100-positive tumors. HMB-45 remains a marker more restricted to melanocytic lesions.

Functional and structural changes in the jejunum of the rat following cysteamine and stress-induced duodenal ulcer.

The effects of cysteamine and stress-induced duodenal ulcer on the functional and structural properties of the rat jejunum were investigated. The absorptive capacity of the jejunum was determined using alanine as the permeant solute and the single-pass perfusion technique. A statistically significant decrease (p < 0.01) in alanine absorption was observed after 8 h and 3 days of duodenal ulcer induction by stress and cysteamine respectively. However, alanine transport measured 7 days after cysteamine or stress ulcer induction showed no significant change from control values. Cysteamine and stress-induced duodenal ulcer did not show any significant change in water absorption across the jejunum when measured after 8 h, 3 and 7 days of ulcer induction. Microscopically, the jejunum of rats with 3-day cysteamine-induced ulcer exhibited diffuse type of apical derangements with excessive swelling of the villi and progressive degenerative changes. No such changes were noticed on the 7th day nor in the jejunum of the rats with stress-induced duodenal ulcer. The results suggest that cysteamine-induced duodenal ulcer produces an inhibition in the absorptive capacity of the jejunum which is time-dependent and reversible.