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ABSTRACT: Cardiorenal syndrome is a condition in which a complex interrelationship between cardiac dysfunction and renal dysfunction exists. Despite advances in treatment of both cardiovascular and kidney disease, cardiorenal syndrome remains a major global health problem. Characteristic of the pathophysiology of cardiorenal syndrome is bidirectional cross-talk; mediators/substances activated by the disease state of 1 organ can play a role in worsening dysfunction of the other by exerting their biologically harmful effects, leading to the progression of the syndrome. Accumulation of uremic toxins is a hallmark of renal excretory dysfunction. Removal of some toxins by conventional dialysis is particularly problematic because of their high protein binding. In this review, we demonstrate that protein-bound uremic toxins may play an important role in progression of cardiovascular disease in the setting of chronic kidney disease. The highly protein-bound uremic toxin indoxyl sulfate has emerged as a potent toxin adversely affecting both the kidney and heart. Direct cardiac effects of this toxin have been recently demonstrated both in vitro and in vivo. Specifically, potent fibrogenic and prohypertrophic effects, as well as oxidative stress-inducing effects, appear to play a central role in both renal and cardiac pathology. Many of these adverse effects can be suppressed by use of a gut adsorbent, AST-120. Potential mechanisms underlying indoxyl sulfate-induced cardiorenal fibrosis are discussed. Future research and clinical implications conclude this review.
Circulation Research 11/2012; 111(11):1470-83. · 9.49 Impact Factor
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International journal of cardiology 05/2012; 158(3):457-8. · 7.08 Impact Factor
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ABSTRACT: Progressive decline in renal function coexists with myocardial infarction (MI); however, little is known about its pathophysiology. This study aimed to systematically identify post-MI renal changes (functional, histological, and molecular) over time in a rat MI model and examine potential mechanisms that may underlie these changes. Rats were randomized into three groups: nonoperated, sham, and MI. Cardiac and renal function was assessed before death at 1, 4, 8, 12, and 16 wk with tissues collected for histological, protein, and gene studies. Tail-cuff blood pressure was lower in MI than sham and nonoperated animals only at 1 wk (P < 0.05). Systolic function was reduced (P < 0.0001) while heart/body weight and left ventricle/body weight were significantly greater in MI animals at all time points. Glomerular filtration rate decreased following MI at 1 and 4 wk (P < 0.05) but not at 8 and 12 wk and then deteriorated further at 16 wk (P = 0.052). Increased IL-6 gene and transforming growth factor (TGF)-β protein expression as well as macrophage infiltration in kidney cortex was detected at 1 wk (P < 0.05). Renal cortical interstitial fibrosis was significantly greater in MI animals from 4 wk, while TGF-β bioactivity (phospho-Smad2) was upregulated at all time points. The degree of fibrosis increased and was maximal at 16 wk. In addition, kidney injury molecule-1-positive staining in the tubules was more prominent in MI animals, maximal at 1 wk. In conclusion, renal impairment occurs early post-MI and is associated with hemodynamic and structural changes in the kidney possibly via activation of the Smad2 signaling pathway.
AJP Heart and Circulatory Physiology 02/2012; 302(9):H1884-93. · 3.71 Impact Factor
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ABSTRACT: Cardiovascular death commonly occurs in patients with chronic kidney disease. Indoxyl sulfate (IS), a uremic toxin, has been demonstrated in vitro as a contributory factor in cardiac fibrosis, a typical pathological finding in uremic cardiomyopathy. This study aimed to determine if cardiac fibrosis is reversible by lowering serum IS levels using an oral charcoal adsorbent, AST-120. Subtotal-nephrectomized (5/6-STNx) Sprague-Dawley rats were randomized to receive either AST-120 (AST-120, n=13) or no treatment (vehicle, n=17) for 12 weeks. Sham operated rats (n=12) were used as controls. Early left ventricular (LV) diastolic dysfunction was demonstrated by an increase in peak velocity of atrial filling [A and A' waves] and a decrease of E/A and E'/A' ratios obtained by echocardiography. This was accompanied by a 4.5-fold increase in serum IS (p<0.001) as well as elevated tail-cuff blood pressure (p<0.001) and heart weight (p<0.001). Increased LV fibrosis (p<0.001), gene expression of pro-fibrotic (TGF-β, CTGF) and hypertrophic (ANP, β-MHC and α-skeletal muscle actin) markers, as well as TGF-β and phosphorylated NF-κB protein expression were observed in STNx + vehicle rats. Treatment with AST-120 reduced serum creatinine (by 54%, p<0.05) and urine total protein (by 27%, p<0.05) vs vehicle whilst having no effect on blood pressure (AST-120=227 ± 11 vs vehicle =224 ± 8 mmHg, ns) and heart weight. The increase in serum IS was prevented with AST-120 (by 100%, p<0.001) which was accompanied by reduced LV fibrosis (68%, p<0.01) and TGF-β and phosphorylated NF-κB protein expression (back to sham levels, p<0.05) despite no significant change in LV function. In conclusion, STNx resulted in increased cardiac fibrosis and circulating IS levels. Reduction of IS with AST-120 normalizes cardiac fibrosis, in a blood pressure independent manner.
PLoS ONE 01/2012; 7(7):e41281. · 4.09 Impact Factor
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ABSTRACT: Cardiorenal syndrome (CRS) describes the primary dysfunction in either the kidney or heart that initiates the combined impairment of both organs. The heart and kidney exert reciprocal control of the respective function to maintain constant blood volume and organ perfusion under continuously changing conditions. The pathophysiology of CRS is not fully understood, but appears to be caused by a complex combination of haemodynamic, neurohormonal, immunological and biochemical feedback pathways. Of these pathways, the contributory role of uraemic toxins that accumulate in CRS has been underexplored. One such toxin, namely indoxyl sulphate, has been found to have direct adverse effects on relevant cardiac cells. Early diagnosis by assessing cardiac and renal injury biomarkers may be critical for timely therapeutic intervention. Such therapies are directed at attenuation of neurohormonal activation, control of elevated blood pressure, correction of anaemia and relief of hypervolaemia. Reduction of non-dialysable uraemic toxins is a further potentially beneficial therapeutic strategy.
Clinical and Experimental Pharmacology and Physiology 10/2011; 39(8):692-700. · 1.85 Impact Factor
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ABSTRACT: Indoxyl sulfate (IS) is a uraemic toxin found at high concentration in patients with chronic kidney disease (CKD) co-morbid with chronic heart failure (CHF). The aim of this study was to determine direct effects of IS on cardiac cells as well as the pro-inflammatory effect of IS.
Indoxyl sulfate significantly increased neonatal rat cardiac fibroblast collagen synthesis (by 145.7% vs. control, P < 0.05) and myocyte hypertrophy (by 134.5% vs. control, P < 0.001) as determined by (3)H-proline or (3)H-leucine incorporation, respectively. Indoxyl sulfate stimulated tumour necrosis factor-alpha, interleukin-6 (IL-6), and IL-1beta mRNA expression in THP-1 cells as quantified by RT-PCR. Both p38 (RWJ-67657) and MEK1/2 (U0126) inhibitors suppressed all these effects by IS. Furthermore, western blot analysis showed that IS activated mitogen-activated protein kinase (MAPK) (p38, p42/44) and nuclear factor-kappa B (NFkappaB) pathways. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that IS exerted its effects without affecting cell viability.
This study has, for the first time, demonstrated that IS has pro-fibrotic, pro-hypertrophic, and pro-inflammatory effects, indicating that IS might play an important role in adverse cardiac remodelling mediated via activation of the p38 MAPK, p42/44 MAPK, and NFkappaB pathways. Targeting reduction of IS and/or the pathways it activates may represent a novel therapeutic approach to the management of CHF with concomitant CKD.
European Heart Journal 07/2010; 31(14):1771-9. · 10.48 Impact Factor
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ABSTRACT: Cardiorenal syndrome describes the impairment of renal function and associated diuretic resistance in patients with heart failure and clinically manifest volume overload. The pathophysiology of this syndrome is poorly understood, but appears to be caused by impairment of tubuloglomerular feedback, neurohormonal activation, and other factors and therapies used in the management of heart failure. Early diagnosis of the cardiorenal syndrome by way of markers of renal injury and function is critical for timely interventions that may attenuate progression. Many novel therapies have been evaluated in the cardiorenal syndrome setting, including agents that block key local factors (eg, adenosine A(I) receptor antagonists), improve diuresis, aquaresis, and natriuresis, and augment natural vasodilator mechanisms to improve renal perfusion. Furthermore, device-based approaches such as ultrafiltration may also play an important therapeutic role.
Current Heart Failure Reports 07/2009; 6(2):105-11.
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ABSTRACT: Patients with thalassemia major have inevitably suffered from complications of the disease, due to iron overload. Among such complications, cardiomyopathy is the leading cause of morbidity and mortality (63.6% to 71%). The major causes of death in this group of patients are congestive heart failure and fatal cardiac tachyarrhythmias leading to sudden cardiac death. The free radical-mediated pathway is the principal mechanism of iron toxicity. The consequent series of events caused by iron overload lead to catastrophic cardiac effects. The authors review the electrophysiological and molecular mechanisms, pathophysiology and correlated clinical insight of heart failure and arrhythmias in iron overload thalassemic cardiomyopathy.
The Canadian journal of cardiology 05/2009; 25(4):213-8. · 3.36 Impact Factor
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ABSTRACT: The aims of this study were to determine the prevalence of HPV infection and distribution of HPV genotypes in Northern Thai women and thereby estimate the benefit of administering the HPV vaccine in the population.
Formaldehyde-fixed, paraffin-embedded samples of invasive squamous cell carcinoma from 99 patients were tested for HPV genotypes using the Linear Array HPV Genotyping Test.
HPV was detected in 96/99 (96.9%) cases. Seventy-five (78.1%) cases were single infections and 21 (21.9%) multiple. HPV16 and HPV18 were the most common subtypes, detected in 62/96 (64.4%) cases. HPV52 and HPV58 infections were found in 17/96 (17.7%) cases. Co-infection always involved HPV16. The most common co-infection was HPV16 and 52 (7 cases) but never HPV16 and 18.
Although the prevalence of HPV infection in cervical cancer of Northern Thai women is comparable to the other regions worldwide, the distribution of HPV subtypes differs with lower frequencies of HPV16 and 18, and higher frequencies of HPV52 and 58. Moreover, multiple infections are common. The vaccine against HPV16 and HPV18 can be estimated to prevent approximately two thirds of the cervical cancer cases in Northern Thailand. Although designed for use on unfixed tissue, this study shows that the Linear Array HPV Genotyping Test can be successfully used for HPV genotyping on paraffin-embedded archival tissue. This methodology also provides a means for retrospective studies on serial samples for a greater understanding of HPV genotypes, co-infections, and relationship to cervical cancer.
Gynecologic Oncology 04/2008; 108(3):555-60. · 3.89 Impact Factor
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ABSTRACT: To summarize the epidemiologic features of osteosarcoma.
One hundred and twelve cases of osteosarcoma were collected retrospectively from the Pathology Department of the Chiang Mai University Hospital, Thailand between 1995 and 2005.
From the present study, there were 14 cases in average, annually, since 2002. Seventy-seven percent of cases were from the upper north Thailand, the region serviced by Chiang Mai University Hospital. The male:female ratio was 1.3:1 and 86% of cases occurred within the first three decades of life. The majority of cancer was found in the long bones (83%) and the majority of lesion was around the knee (68%). Conventional and telangiectatic osteosarcoma accounted for 85% and 8% of cases, respectively.
The authors have summarized some epidemiologic features of osteosarcoma. The authors found the relatively high frequency of telangiectatic osteosarcoma around the upper part of north Thailand These results give an initial picture to the national health provider section for planning personnel, medical and supportive equipment, and funding for the care of osteosarcoma patients. Nationwide co-operation in registering osteosarcoma patients would provide more complete data on this tumor in Thailand and promote the establishment of standardized treatment protocols.
Journal of the Medical Association of Thailand = Chotmaihet thangphaet 08/2007; 90(7):1400-5.
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ABSTRACT: The aim of the present study was to determine the spectrum, frequency and demographics of bone tumors.
A retrospective study of the 1,001 bone tumor specimens from the files at the Pathology Department of the Chiang Mai University Hospital, Thailand from 2000 to 2004.
From the study, 41 were non-neoplastic mass lesions, and 960 were neoplastic, with 856 (89%) as primary and 104 (11%) as metastatic tumors. In the primary tumor group, 654 (76%) cases were of hematologic origin, and 202 (24%) were non-hematologic. The most common benign bone tumors were giant cell tumor (n = 37), osteochondroma (n = 25), and chondroma (n = 15). The most common malignant bone tumors were lymphoma-leukemia (n = 583), metastatic malignancy (n = 104), plasma cell myeloma (n = 71), and osteosarcoma (n = 58).
The present study showed a higher frequency of osteosarcoma (68%), lower frequencies of chondrosarcoma (12%) and Ewing sarcoma (4%) among primary non-hematologic malignant bone tumors when compared with similar studies based on Western patients. Whether these differences reflect differences in the ethnic population or in practice patterns remains to be determined
Journal of the Medical Association of Thailand = Chotmaihet thangphaet 07/2006; 89(6):780-7.
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ABSTRACT: Limb loss has a devastating effect on patients. To know the underlying causes of limb amputation would be helpful in planning public health strategies in the country. The objectives of this study are (1) to identify the primary causes and the feature of limb amputations in the setting of a university hospital, and (2) to study the time trends of the causes of limb amputation over a period of 5 years.
The clinical and pathological data from 216 amputated limbs submitted to the Pathology Department of Chiang Mai University Hospital from 2000 to 2004 were reviewed.
Of these, 188 cases were first time amputations, and 28 cases were repeat amputations. The 188 first amputated specimens included 23 upper limbs (12%) and 165 lower limbs (88%), from 115 male (61%) and 73 female (39%) patients. Dysvascular (46%), tumor-related (36%), and infection-related (10%) amputations were the three most common scenarios. The rate of amputation was high in 2004 (32%) owing to an unexpected increase in the numbers of dysvascular amputation. Atherosclerosis accounted for at least 52% of dysvascular amputations. The leading cause of tumor-related amputations was sarcoma (72%), almost half of which were osteosarcomas. The major cause of lower limb amputation was dysvascular (51%) whereas that of upper limb amputation was tumor related (61%). Subgroup analysis of the major limb amputations revealed that 44% were tumor related, 39% were dysvascular, and 8% were infection-related causes. The proportion of major limb losses in the tumor-related group (87%, 59/68) was significantly higher than those in the dysvascular group (62%, 53/86) (P = 0.001). In addition, the proportion of upper limb losses in the tumor-related group (21%, 14/68) was significantly greater than those in the dysvascular group (2%, 2/86), (P < 0.001). The causes of 28 repeat amputations were similar, i.e., dysvascular (61%), tumor related (29%), and infectious related (7%).
(1) Atherosclerosis, a potentially preventable disease is responsible for the great proportion of limb losses in Northern Thailand; (2) the numbers of dysvascular amputation seem to be increasing; (3) tumor, especially sarcoma, is the most common cause of major limb amputations as well as upper limb loss.
Archives of Orthopaedic and Trauma Surgery 12/2005; 125(10):701-5. · 1.37 Impact Factor
