Hsieh Bs

Bilateral aldosterone-producing adenomas: differentiation from bilateral adrenal hyperplasia

BACKGROUND Primary aldosteronism (PA) is a common curable disease of secondary hypertension. Most such patients have either idiopathic bilateral adrenal hyperplasia (BAH) or unilateral aldosterone-producing adenoma (APA). Bilateral APAs are reportedly extremely rare. AIM To compare the distinctive characteristics, clinical course, and outcomes of bilateral APA vs. BAH. DESIGN Retrospective record review. METHODS From July 1994 to Jan 2007, 190 patients diagnosed with PA underwent surgical intervention at our hospital. Bilateral APA was diagnosed in 7/164 patients with histologically-proven APA. Twenty-one patients diagnosed as BAH, and 21 randomly selected of unilateral APA patients, matched by age and sex served as controls. RESULTS Patients with bilateral APA had similar blood pressure, arterial blood gas analysis, spot urinary potassium to creatinine ratio and clinical symptoms to those with BAH, but lower serum potassium levels (p = 0.027), lower plasma renin activity (p = 0.037), and higher plasma aldosterone concentrations (p = 0.029). Aldosterone-renin ratio (ARR) after administration of 50 mg captopril was higher in bilateral APA than in BAH patients (p = 0.023), but not different between unilateral APA and BAH (p = 0.218). A cut-off of ARR >100 ng/dl per ng/ml/h and plasma aldosterone >20 ng/dl after captopril significantly differentiated bilateral APA from BAH. Bilateral subtotal adrenalectomy normalized blood pressure and biochemistry in all patients with bilateral APA. DISCUSSION Bilateral APA, presenting simultaneously or sequentially, may not be a rare disease, accounting for 4.3% of APA in this sample. The clinical presentations of bilateral functional adenoma are not different from BAH, but patients with low serum potassium and ARR >100 after captopril should be carefully evaluated for bilateral adenoma.

Inhibition by pentoxifylline of TNF‐α‐stimulated fractalkine production in vascular smooth muscle cells: evidence for mediation by NF‐κB down‐regulation

Fractalkine is a CX3C chemokine for mononuclear leukocytes that is expressed mainly by vascular cells, and regulated by pro‐inflammatory cytokines. This study investigated signal transduction mechanisms by which tumor necrosis factor (TNF)‐α stimulated fractalkine expression in cultured rat vascular smooth muscle cells (VSMCs), and the modulatory effect of a haemorrheologic agent, pentoxifylline, on its production. TNF‐α (1–50 ng ml−1) stimulated fractalkine mRNA and protein expression in concentration‐ and time‐dependent manners. Pretreatment with calphostin C (0.4 μM, a selective inhibitor of protein kinase C (PKC), and PD98059 (40 μM), a specific inhibitor of p42/44 mitogen‐activated protein kinase (MAPK) kinase, attenuated TNF‐α‐stimulated fractalkine mRNA and protein expression. In contrast, H‐89 (2 μM), a selective inhibitor of cAMP‐dependent protein kinase, wortmannin (0.5 μM), a selective inhibitor of phosphatidylinositol 3‐kinase, and SB203580 (40 μM), a specific inhibitor of p38 MAPK, had no discernible effect. The ubiquitin/proteosome inhibitors, MG132 (10 μM) and pyrrolidine dithiocarbamate (200 μM), suppressed activation of NF‐κB as well as stimulation of fractalkine mRNA and protein expression by TNF‐α. TNF‐α‐activated phosphorylation of PKC was blocked by calphostin C, whereas TNF‐α‐augmented phospho‐p42/44 MAPK and phospho‐c‐Jun levels were reduced by PD98059. Neither calphostin C nor PD98059 affected TNF‐α‐induced degradation of I‐κBα or p65 nuclear translocation. Pretreatment with pentoxifylline (0.1–1 mg ml−1) decreased TNF‐α‐stimulated fractalkine mRNA and protein expression, which was preceded by a reduction in TNF‐α‐activated phosphorylation of PKC, p42/44 MAPK and c‐Jun as well as degradation of I‐κBα and p65/NF‐κB nuclear translocation. These data indicate that activation of PKC, p42/44 MAPK kinase, and NF‐κB are involved in TNF‐α‐stimulated fractalkine production in VSMCs. Down‐regulation of the PKC, p42/44 MAPK, and p65/NF‐κB signals by PTX may be therapeutically relevant and provide an explanation for the anti‐fractalkine effect of this drug.

Serum soluble transferrin receptor reflects erythropoiesis but not iron availability in erythropoietin-treated chronic hemodialysis patients

BACKGROUND The diagnosis of iron deficiency using the current commonly used tests is usually difficult in hemodialysis patients. Soluble transferrin receptor (sTfR) has caught the attention of physicians recently as regards its use as a parameter for the evaluation of iron status. This study was conducted in order to evaluate the correlation of serum soluble transferrin receptor (sTfR) concentration with hematological parameters and iron profiles, in the role of identifying iron deficiency among dialysis patients. METHODS Seventy-three patients having received chronic hemodialysis and stable maintenance recombinant human erythropoietin (rHuEPO) therapy were included. Iron, total iron-binding capacity, ferritin and sTfR were measured in the first week. Following this, these patients began to receive intravenous iron dextran (2 mg/kg/week) for 4 weeks. The hematocrit (Hct), hemoglobin (Hb) levels and reticulocyte counts were evaluated weekly. At the beginning of fifth week, the sTfR level was measured again. Patients were classified as belonging to one of the following groups: serum ferritin < 100 microg/L - absolute iron-deficient group; initial ferritin level > or = 100 microg/L with an increase in hemoglobin of greater than 1 g/dL at the end of the study occult iron deficiency group; others - non iron-deficient group. RESULTS Seventy-one patients completed the study. The concentration of sTfR was positively correlated with Hct, Hb and reticulocyte index at the beginning (r = 0.236, p = 0.047; r = 0.257, p = 0.04; r = 0.401, p < 0.01, respectively) and at the end of the study (r = 0.384, p < 0.01; r = 0.338, p < 0.01; r = 0.427, p < 0.001, respectively). After 4 weeks of iron and rHuEPO therapy, the sTfR concentration increased, rather than declined, from 21.85 +/- 8.06 nM to 23.76 +/- 7.42 nM (p = 0.04) and the change was positively correlated with the changes in Hct, Hb and reticulocyte index. The administered rHuEPO doses did not differbetween the iron deficiency group (absolute deficiency, n = 3; occult deficiency, n = 10) and non-iron deficiency group (n = 58). The sTfR levels failed to identify the occult iron deficiency group because there was no difference between occult iron-deficient and non-iron-deficient patients (24.73 +/- 9.09 nM versus 21.60 +/- 7.89 nM, p = 0.34). Instead, transferrin saturation (TS) could be a differential marker between the 2 groups (19.0 +/- 10.9% versus 30.1 +/- 12.7%, p = 0.012). CONCLUSION The serum sTfR concentration is indeed an appropriate marker for erythropoiesis. The erythropoitic effect of administered rHuEPO could mask the effect of iron status on the sTfR concentration. This might make the sTfR concentration no longer an appropriate index to identify the presence of occult iron deficiency. Thus, TS and ferritin currently remain better methods for the evaluation of iron status in rHuEPO-treated chronic hemodialysis patients.

Pentoxifylline Inhibits Platelet-Derived Growth Factor-Stimulated Cyclin D1 Expression in Mesangial Cells by Blocking Akt Membrane Translocation

Pentoxifylline (PTX) is a potent inhibitor of mesangial cell proliferation, but its underlying mechanism is poorly understood. Here, we demonstrate that in platelet-derived growth factor (PDGF)-stimulated mesangial cells, PTX causes G1 arrest by down-regulation of cyclin D1 expression, which subsequently attenuates Cdk4 activity. In vivo, PTX similarly reduces cyclin D1 expression in mesangial cells of rats with acute Thy1 glomerulonephritis. The mechanism by which PTX reduces cyclin D1 is also investigated. PTX blocks Akt but not phosphatidylinositol 3-kinase (PI3K) activation in response to PDGF and abrogates cyclin D1 induction by PI3K, suggesting an effect of PTX on Akt itself. Indeed, PTX is capable of blocking the membrane translocation of Akt, and enforced targeting of Akt to cell membrane prevents the inhibition of Akt and cyclin D1 by PTX. Because PTX is known to increase intracellular cAMP levels by inhibiting phosphodiesterase, the role of protein kinase A (PKA) in these events is investigated. The PKA antagonist N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89) abolishes cell proliferation effects of PTX and restores cyclin D1 expression as well as Akt membrane translocation and activation by PDGF, whereas dibutyryl cAMP and forskolin recapitulate the functions of PTX in mesangial cells. In conclusion, our results indicate that PTX, acting through PKA, interferes with PDGF signaling to Akt activation by blocking Akt membrane translocation, thereby inhibiting cyclin D1 expression and mesangial cell proliferation.

The Renoprotective Potential of Pentoxifylline in Chronic Kidney Disease

&NA; Current interventions with proven efficacy, such as glycemic and blood pressure control, dietary protein restriction, and angiotensin II blockade, slow the progression of chronic kidney disease (CKD); however, whether long‐term cessation of CKD progression is possible remains unclear. Because of the pathogenetic complexity of this condition, multidrug interventions with the least adverse effects should be investigated as the next step in attempts to stop CKD progression. Pentoxifylline, a non‐selective phosphodiesterase inhibitor with indiscernible toxicity, exerts potent inhibitory effects against cell proliferation, inflammation, and extracellular matrix accumulation, all of which play important roles in CKD progression. Pentoxifylline monotherapy markedly reduces proteinuria in patients with membranous nephropathy. Moreover, limited human studies have proven pentoxifylline efficacy in reducing proteinuria in patients with diabetes receiving angiotensin‐converting enzyme inhibitors, and in patients with nephrotic syndrome secondary to lupus nephritis despite immunosuppressive therapy. Further clinical trials are necessary to examine whether pentoxifylline can improve renal outcomes in patients receiving interventions of proven efficacy.

Plasma interleukin-18 levels in chronic renal failure and continuous ambulatory peritoneal dialysis.

Background/Aims: Based on associations of interleukin (IL)-18 with chronic inflammation, we investigated IL-18, IL-6, and tumor necrosis factor-α (TNF-α) in patients with chronic renal failure (CRF) and patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Methods: Plasma was evaluated by ELISA methodology in 15 healthy controls, 27 CRF and 15 CAPD patients. Results: Plasma IL-18 levels in CRF (572.5 ± 41.9 pg/ml) or CAPD (479.2 ± 47.4 pg/ml) were significantly higher than normal (263.6 ± 20.0 pg/ml), but there was no difference in IL-18 between CRF and CAPD patients. The IL-18 concentration negatively correlated with creatinine clearance (Ccr). However, the duration of dialysis, normalized protein nitrogen appearance, weekly Ccr, and Kt/Vurea were not correlated with plasma IL-18 in CAPD. The plasma IL-18 concentration was positively correlated with TNF-α but not with IL-6 in renal failure patients with or without CAPD. Conclusion: Uremia is the principal origin of increased plasma IL-18 in these patients. Increased IL-18 levels may be associated with Th1 differentiation and elevated TNF-α.

Impact of Religious Activity on Depression and Quality of Life of Chronic Peritoneal Dialysis Patients in Taiwan

BACKGROUND AND PURPOSE Few studies have reported the impact of psychosocial aspects on quality of life (QOL) in peritoneal dialysis (PD) patients. People in Taiwan enjoy freedom of religious beliefs. We evaluated the possible role of religious activity on depression and QOL in PD patients. METHODS Eighty six patients (29 males, 57 females; mean age, 48.3 years) receiving regular PD at National Taiwan University Hospital or Taipei Municipal Jen-Ai Hospital were asked to complete the 10-Question Survey assessing religious activity, the Beck Depression Inventory (BDI) rating severity of depression, and the 36-item Short Form Health Survey Questionnaire (Taiwan Standard Version 1.0) measuring QOL. Patients were categorized into 4 groups according to their religious status, namely: no religious faith; and low, medium, and high religious activity. RESULTS For patients professing a religious faith, lower religious activity was correlated with lower QOL and higher BDI scores. These findings persisted after adjusting for possible confounding roles of gender, age, marital status, education, social activity, time on dialysis, and number of comorbid conditions. For patients having no religious faith, QOL as well as BDI scores were comparable with those of patients having high religious activity. CONCLUSIONS These results suggest that there may be a benefit to a moderate level of religious activity in chronic PD patients in Taiwan, and that such activity is associated with higher QOL and lower BDI scores.

Role of D2 dopamine receptor in adrenal cortical cell proliferation and aldosterone-producing adenoma tumorigenesis

Aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia are the two characteristic types of primary aldosteronism. Dysregulation of adrenal cortical cell proliferation contributes to both diseases. We previously demonstrated that APA expressed less dopamine D2 receptor than the respective non-tumor tissue and might contribute to the overproduction of aldosterone. As activation of D2 receptor inhibits the proliferation of various cells, downregulation of D2 receptor in APA may play a role in the tumorigenesis of APA. In this study, we demonstrate that D2 receptor plays a role in angiotensin II (AII)-stimulated adrenal cortical cell proliferation. The D2 receptor agonist, bromocriptine, inhibited AII-stimulated cell proliferation in primary cultures of the normal human adrenal cortex and APA through attenuating AII-induced phosphorylation of PK-stimulated cyclin D1 protein expression and cell proliferation. D2 receptor also inhibited AII-induced ERK1/2 phosphorylation. Our results demonstrate that, in addition to inhibiting aldosterone synthesis/production, D2 receptor exerts an anti-proliferative effect in adrenal cortical and APA cells by attenuating PKCμ and ERK phosphorylation. The lower level of expression of D2 receptor in APA may augment cell proliferation and plays a crucial role in the tumorigenesis of APA. Our novel finding suggests a new therapeutic target for primary aldosteronism.

Peritoneal Fibrosing Syndrome: Pathogenetic Mechanism and Current Therapeutic Strategies

&NA; Peritoneal dialysis (PD) has been established as a main renal replacement therapy for approximately 20 years. However, long‐term peritoneal exposure to high glucose and other unphysiologic contents in the PD solution may potentiate the development of peritoneal fibrosing syndrome (PFS) in PD patients. PFS is composed of a wide spectrum of peritoneal alterations, which has been observed in PD patients. Molecular studies have shown that the fibrogenic effect of peritoneal mesothelial cells and the accompanying accumulation of extracellular matrix in the peritoneum are key events leading to PFS. In this review, we highlight the impact of PFS and its pathogenetic factors, including bioincompatible PD solution, multidisciplinary inflammatory mediators, and stimulatory cytokines in the peritoneal cavity. Current therapeutic strategies based on both clinical and basic evidence for the prevention or treatment of PFS are also reviewed.

Hydralazine inhibits human peritoneal mesothelial cell proliferation and collagen synthesis

The integrity of the mesothelial layer is essential for both defence and solute transport in continuous ambulatory peritoneal dialysis (CAPD). The human peritoneal mesothelial cell (HPMC) culture has been shown to be a very useful tool to study the peritoneal mesothelial stem cell behaviour. We investigated whether hydralazine, an antihypertensive agent frequently used, might affect HPMC growth and collagen synthesis. HPMCs were cultured from specimens of human omentum by enzymatic disaggregation of omentum. HPMC growth was evaluated by modified methyltetrazolium (MTT) assay. Cell viability was confirmed by trypan blue exclusion and lactate dehydrogenase assay. Collagen synthesis was measured by 3H-proline incorporation into pepsin-resistant, salt-precipitated collagen. Intracellular cAMP levels were measured by enzyme immunoassay. The procollagen alpha 1 (I) mRNA expression was evaluated by Northern blot analysis. Hydralazine inhibited serum-stimulated HPMC growth in a dose-dependent manner. The maximal inhibition was 93% at a concentration of 100 micrograms/ml. Hydralazine inhibited collagen synthesis in confluent mesothelial cells (47% inhibition at a concentration of 100 micrograms/ml). The procollagen alpha 1 (I) mRNA expression was also decreased by hydralazine (about 50% decrease at 100 micrograms/ml). These effects may be due to the phosphodiesterase inhibition property of hydralazine to increase intracellular cAMP levels. These data suggest that the use of hydralazine in CAPD patients may affect peritoneal membrane function and integrity.