Hyperkalemia and Hypertension Post Organ Transplantation – A Management Challenge

Potassium is the most important intracellular cation and the kidneys play a pivotal role in potassium homeostasis. Potassium disorder is a common electrolyte abnormality and it increases the risk of death from any cause, particularly cardiovascular events. Hyperkalemia is a common electrolyte abnormality encountered post organ transplantation. The etiology is multifactorial, and includes drugs such as calcineurin inhibitors. In certain regards, the clinical picture of post-transplantation hyperkalemia and hypertension resembles that of Gordon syndrome or familial hyperkalemic hypertension, a disorder characterized by over activity of thiazide-sensitive sodium chloride cotransporter. Effective and safe management of chronic hyperkalemia can be challenging in this special patient population. Despite the significant short-term and long-term side effects, fludrocortisone (a potent synthetic oral mineralocorticoid receptor agonist) has emerged as the default drug of choice for treatment of refractory hyperkalemia in many organ transplant recipients. However, the long-term efficacy and safety of fludrocortisone for management of hyperkalemia in organ transplant recipients remains unknown. This review discusses potassium homeostasis, including the role of the kidneys, and focuses on calcineurin inhibitor-induced hyperkalemia and on the under-appreciated role of thiazide-type diuretic use in management of hyperkalemia and hypertension. We present an illustrative case of post-transplantation hyperkalemia and hypertension with relevant literature.     

Proteomic analysis of pRb loss highlights a signature of decreased mitochondrial oxidative phosphorylation

The retinoblastoma tumor suppressor (pRb) protein associates with chromatin and regulates gene expression. Numerous studies have identified Rb-dependent RNA signatures, but the proteomic effects of Rb loss are largely unexplored. We acutely ablated Rb in adult mice and conducted a quantitative analysis of RNA and proteomic changes in the colon and lungs, where Rbp>KOp> was sufficient or insufficient to induce ectopic proliferation, respectively. As expected, Rbp>KOp> caused similar increases in classic pRb/E2F-regulated transcripts in both tissues, but, unexpectedly, their protein products increased only in the colon, consistent with its increased proliferative index. Thus, these protein changes induced by Rb loss are coupled with proliferation but uncoupled from transcription. The proteomic changes in common between Rbp>KOp> tissues showed a striking decrease in proteins with mitochondrial functions. Accordingly, RB1 inactivation in human cells decreased both mitochondrial mass and oxidative phosphorylation (OXPHOS) function. RBp>KOp> cells showed decreased mitochondrial respiratory capacity and the accumulation of hypopolarized mitochondria. Additionally, RB/Rb loss altered mitochondrial pyruvate oxidation from p>13p>C-glucose through the TCA cycle in mouse tissues and cultured cells. Consequently, RBp>KOp> cells have an enhanced sensitivity to mitochondrial stress conditions. In summary, proteomic analyses provide a new perspective on Rb/RB1 mutation, highlighting the importance of pRb for mitochondrial function and suggesting vulnerabilities for treatment.     

Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women

Previous studies indicate that leptin secretion is regulated by insulin-mediated glucose metabolism. Because fructose, unlike glucose, does not stimulate insulin secretion, we hypothesized that meals high in fructose would result in lower leptin concentrations than meals containing the same amount of glucose. Blood samples were collected every 30-60 min for 24 h from 12 normal-weight women on 2 randomized days during which the subjects consumed three meals containing 55, 30, and 15% of total kilocalories as carbohydrate, fat, and protein, respectively, with 30% of kilocalories as either a fructose-sweetened [high fructose (HFr)] or glucose-sweetened [high glucose (HGl)] beverage. Meals were isocaloric in the two treatments. Postprandial glycemic excursions were reduced by 66 +/- 12%, and insulin responses were 65 +/- 5% lower (both P < 0.001) during HFr consumption. The area under the curve for leptin during the first 12 h (-33 +/- 7%; P < 0.005), the entire 24 h (-21 +/- 8%; P < 0.02), and the diurnal amplitude (peak - nadir) (24 +/- 6%; P < 0.0025) were reduced on the HFr day compared with the HGl day. In addition, circulating levels of the orexigenic gastroenteric hormone, ghrelin, were suppressed by approximately 30% 1-2 h after ingestion of each HGl meal (P < 0.01), but postprandial suppression of ghrelin was significantly less pronounced after HFr meals (P < 0.05 vs. HGl). Consumption of HFr meals produced a rapid and prolonged elevation of plasma triglycerides compared with the HGl day (P < 0.005). Because insulin and leptin, and possibly ghrelin, function as key signals to the central nervous system in the long-term regulation of energy balance, decreases of circulating insulin and leptin and increased ghrelin concentrations, as demonstrated in this study, could lead to increased caloric intake and ultimately contribute to weight gain and obesity during chronic consumption of diets high in fructose.     

The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat

Background and Purpose

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration-dependent mechanical effects of OM in permeabilized cardiomyocyte-sized preparations and single skeletal muscle fibres of Wistar-Kyoto rats under isometric conditions.

Experimental Approaches

Cap>2+p>-dependent active force production (F_active), its Cap>2+p> sensitivity (pCa₅₀), the kinetic characteristics of Cap>2+p>-regulated activation and relaxation, and Cap>2+p>-independent passive force (F_passive) were monitored in Triton X-100-skinned preparations with and without OM (3nM-10 &amp;#x003bc;M).

Key Results

In permeabilized cardiomyocytes, OM increased the Cap>2+p> sensitivity of force production (&amp;#x00394;pCa₅₀: 0.11 or 0.34 at 0.1 or 1&amp;#x02009;&amp;#x003bc;M respectively). The concentration&amp;#x02013;response relationship of the Cap>2+p> sensitization was bell-shaped, with maximal effects at 0.3&amp;#x02013;1&amp;#x02009;&amp;#x003bc;M OM (EC₅₀: 0.08 &amp;#x000b1; 0.01&amp;#x02009;&amp;#x003bc;M). The kinetics of force development and relaxation slowed progressively with increasing OM concentration. Moreover, OM increased F_passive in the cardiomyocytes with an apparent EC₅₀ value of 0.26 &amp;#x000b1; 0.11&amp;#x02009;&amp;#x003bc;M. OM-evoked effects in the diaphragm muscle fibres with intrinsically slow kinetics were largely similar to those in cardiomyocytes, while they were less apparent in muscle fibres with fast kinetics.

Conclusions and Implications

OM acted as a Cap>2+p>-sensitizing agent with a downstream mechanism of action in both cardiomyocytes and diaphragm muscle fibres. The mechanism of action of OM is connected to slowed activation&amp;#x02013;relaxation kinetics and at higher OM concentrations increased F_passive production.     

Examination of left ventricular contractile reserve by Doppler myocardial imaging in patients with dilated cardiomyopathy

Detection of left ventricular contractile reserve by means of dobutamine stress echocardiography is a well known technique. The aim of the present study was to detect velocity changes during the administration of dobutamine, to establish if Doppler myocardial imaging is a suitable method for determining left ventricular contractile reserve, and to determine if the technique provides more information than traditional stress echocardiography. Twenty-five patients (all males; mean age, 53.4 years) were examined for a clinical diagnosis of idiopathic dilated cardiomyopathy with a poor left ventricular systolic function (ejection fraction less than 30%). Doses of 5-10 and 20 mg/kg/min dobutamine were administered and elevated at 4-minute intervals. Ejection fraction was calculated using the Simpson rule. The peak systolic and the early and late diastolic velocities were measured in the basal segment of the septum and the inferior wall at baseline and at full dose of dobutamine. Results indicated that peak systolic velocity increased significantly, both in the septum (0.11±0.03 vs. 0.20±0.05 m/sec; p=0.001) and in the inferior wall (0.10±0.05 vs. 0.17±0.06 m/sec; p=0.03). Late diastolic velocities also increased significantly, both in the septum (0.17±0.05 vs. 0.22±0.07 m/sec; p=0.01) and in the inferior wall (0.18±0.08 vs.0.21±0.02 m/sec; p=0.01). There was a significant linear correlation between the relative increases in basal ejection fraction value and in peak systolic velocity upon dobutamine stimulation. Patients were divided into responders and nonresponders based on responses in either ejection fraction (25% relative increase) or peak systolic velocity (5 cm/s increase). This study concludes that 1) Doppler myocardial imaging is an adequate and simple technique to examine left ventricular contractile reserve; and 2) measurement of peak systolic velocity during dobutamine stimulation seems to be a simple and good indicator of left ventricular contractile reserve. (c)2001 CHF, Inc.     

Sensitivity and specificity of the fine needle aspiration biopsy of the thyroid: clinical point of view

INTRODUCTION: The rates of sensitivity and specificity of fine needle aspiration biopsy (FNAB) for the diagnosis of thyroid malignancy differ considerably among various reported series. These values are influenced by three factors: (a) whether only clearly positive and negative results are considered, or whether the commonly encountered 10-20% of indeterminate/suspicious ones are included; (b) whether adenomas are considered as neoplasms in one group with carcinomas; and (c) whether only histologically proven cases are used in calculations or whether patients with benign clinical follow-up are included. AIM: The aim of the study was to evaluate the sensitivity and specificity of FNABs performed at this institution in the last 7 years from the clinical point of view, considering only benign vs. suspicious/malignant FNAB results (indicating surgery), and benign (including adenomas) vs. malignant definitive histology. STUDY DESIGN: Retrospective study comparing pre-operative FNAB results with definitive histological examination after operation. PATIENTS: A total of 2492 FNABs were performed in 2100 patients (1875 women and 225 men); their ages ranged from 9 to 85 years, with a median of 46 years. Clinical diagnosis was multinodular goitre in 1330, single nodule in 591, Hashimoto's thyroiditis in 147 and subacute thyroiditis in 32 cases. In 148 instances, the nodule was cystic. A history of previous treatment for carcinoma of the thyroid was present in 12 patients. Five hundred and thirty-six patients subsequently underwent thyroid surgery. STATISTICS: The values of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy were calculated. RESULTS: The sensitivity was 86%, specificity 74%, PPV 34%, NPV 97% and diagnostic accuracy 75%. CONCLUSIONS: The specificity and positive predictive value are low when fine needle aspiration biopsy results are divided into two categories only (these being indication for surgery or not), and when only suspicious/malignant fine needle aspiration biopsies with subsequent malignant histology are considered to be true positive. Nevertheless, the ability to discriminate 11.7% of patients with a 34% probability of malignancy (suspicious/malignant cytology) from 81.2% of patients (benign cytology) with a probability of only 3% is very helpful.     

外源性野生型p53基因对人肺癌细胞生长的抑制

目的观察外源性野生型ｐ５３基因对有ｐ５３基因突变的人肺癌细胞系生长的影响。方法用多聚酶链反应单链构象多态性及ＤＮＡ测序，选择ｐ５３基因突变的人肺巨细胞癌系８０１Ｄ为受体细胞。构建野生型ｐ５３表达质粒ＰＺＩＰｎｅｏＳＶｐ５３。用基因枪介导外源基因。建立转染细胞系８０１Ｄｐ５３。用聚合酶链反应检测外源基因，观察转染细胞恶性生长的变化。结果转染细胞系８０１Ｄｐ５３体外长期传代有ｎｅｏ基因及外源ｐ５３基因存在，转染细胞生长明显受到抑制，克隆形成抑制率达９６％，裸鼠异种移植致瘤性降低，肿瘤生长明显缓慢。结论外源性野生型ｐ５３经基因枪导入有ｐ５３基因突变的人肺癌细胞后可长期存在于转染细胞中，且明显抑制转染细胞的恶性生长     

Decreased frequency of HLA-B35 in patients with gastric MALT lymphoma

Persistent infection with Helicobacter pylori has been shown to be strongly associated with the development of low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, the prevalence of H. pylori infection exceeds the incidence of MALT lymphoma by far. This discrepancy might at least partially be explained on a genomic basis of the host. To evaluate the association between HLA type and MALT lymphoma, we investigated 46 patients with MALT lymphoma recruited in a prospective multicenter study from October 1998 to March 2001. Over 13,000 voluntary stem cell donors from over 40 German blood banks represented the control group. Exploratory statistical analysis using Fishers exact test showed significantly decreased frequency of HLA-B35 in the MALT lymphoma group compared to the control group. Our data suggest a negative association between HLA-B35 and MALT lymphoma; however, larger studies are necessary to confirm a protective role of this HLA antigen.     

Cytokine profile and insulin antibody IgG subclasses in patients with recent onset Type 1 diabetes treated with oral insulin

Aims/hypothesis Tolerance to orally administered antigens may be generated through the induction of T helper cell type 2 and 3 (Th2/Th3) regulatory cells. We previously reported that treatment of recent onset Type 1 diabetes with oral insulin had no effect on residual beta cell function. The aim of this study was to evaluate whether this treatment produces a deviation in the immune response, with polarisation of the cytokine pattern and the induction of a Th2-like antibody response.Methods Mononuclear cells were collected from a total of 20 patients with Type 1 diabetes before and after 12 months of treatment with oral insulin (n=11) or placebo (n=9). Following stimulation of the cells with insulin or phytohaemagglutinin, levels of Th2 and Th3 cytokines (including TGF-, IFN-, IL-4 and IL-5) in the culture supernatants were assessed by ELISA. In addition, levels of total and specific insulin antibody IgG subclasses were measured by radioimmunoassay in serum samples drawn from 33 patients with Type 1 diabetes before and after 3, 6 and 12 months of therapy with oral insulin (n=18) or placebo (n=15).Results After 12 months of treatment, the release of TGF- was significantly higher in patients who received oral insulin compared with those who received placebo (p=0.025 and p=0.006 for lymphocytes challenged with insulin and phytohaemagglutinin respectively). The two groups had similar levels of IL-4 and IL-5 both at baseline and after 12 months of treatment. The release of IFN- was markedly reduced in patients treated with oral insulin compared with those who received placebo at the 12-month follow-up. Circulating levels of IgG1 and IgG3 subclasses directed against insulin were significantly lower in the oral insulin group than in the placebo group after 12 months of treatment (p=0.05 for IgG1 and p=0.014 for IgG3).Conclusions/interpretation The increased TGF- release observed in patients treated with oral insulin suggests that a regulatory response can be induced in vivo by this treatment. The lower levels of insulin antibody IgG1 and IgG3 subclasses present in patients exposed to oral insulin are consistent with a Th2 deviation of the immune response. The failure of oral insulin treatment to provide any measurable clinical benefit may be due to the timing of treatment initiation.