Kuo-How Huang

The MicroRNA Spectrum in 12 Body Fluids

BACKGROUND MicroRNAs (miRNAs) are small, noncoding RNAs that play an important role in regulating various biological processes through their interaction with cellular messenger RNAs. Extracellular miRNAs in serum, plasma, saliva, and urine have recently been shown to be associated with various pathological conditions including cancer. METHODS With the goal of assessing the distribution of miRNAs and demonstrating the potential use of miRNAs as biomarkers, we examined the presence of miRNAs in 12 human body fluids and urine samples from women in different stages of pregnancy or patients with different urothelial cancers. Using quantitative PCR, we conducted a global survey of the miRNA distribution in these fluids. RESULTS miRNAs were present in all fluids tested and showed distinct compositions in different fluid types. Several of the highly abundant miRNAs in these fluids were common among multiple fluid types, and some of the miRNAs were enriched in specific fluids. We also observed distinct miRNA patterns in the urine samples obtained from individuals with different physiopathological conditions. CONCLUSIONS MicroRNAs are ubiquitous in all the body fluid types tested. Fluid type-specific miRNAs may have functional roles associated with the surrounding tissues. In addition, the changes in miRNA spectra observed in the urine samples from patients with different urothelial conditions demonstrates the potential for using concentrations of specific miRNAs in body fluids as biomarkers for detecting and monitoring various physiopathological conditions.

Changing trends of prostate cancer in Asia

Although Asian people have the lowest incidence and mortality rates of prostate cancer in the world, these rates have risen rapidly in the past two decades in most Asian countries. Prostate cancer has become one of the leading male cancers in some Asian countries. In 2000, the age-adjusted incidence was over 10 per 100 000 men in Japan, Taiwan, Singapore, Malaysia, the Philippines and Israel. Although some of the increases may result from enhanced detection, much of the increased incidence may be associated with westernization of the lifestyle, with increasing obesity and increased consumption of fat. The differences in incidences between native Americans and Asian immigrants are getting smaller, reflecting a possible improvement of diagnostic efforts and changes of environmental risk factors in Asian immigrants. Nevertheless, the huge variations in incidences among ethnic groups imply that there are important genetic risk factors. The stage distributions of prostate cancer in Asian populations are still unfavorable compared to those of Western developed countries. However, a trend towards diagnosing cancer with more favorable prognosis is seen in most Asian countries. Both genetic and environmental risk factors responsible for elevated risks in Asian people are being identified, which may help to reduce prostate cancer incidence in a chemopreventive setting.

Stopping smoking might reduce tumour recurrence in nonmuscle-invasive bladder cancer

To evaluate effects of stopping smoking on the outcome of nonmuscle‐invasive bladder cancer, as cigarette smoking is a risk factor for bladder cancer and little is known about whether stopping smoking reduces the risk of recurrence or progression.

Association of Kidney Function With Residual Hypertension After Treatment of Aldosterone-Producing Adenoma

BACKGROUND Autonomous secretion of aldosterone in patients with primary aldosteronism increases glomerular filtration rate and causes kidney damage. The influence of a mild decrease in kidney function on residual hypertension after adrenalectomy is unexplored. STUDY DESIGN Nonconcurrent prospective study. SETTING & PARTICIPANTS The study was based on the Taiwan Primary Aldosteronism Investigation (TAIPAI) database. 150 patients (61 men; overall mean age, 47.2 +/- 11.6 years) with a diagnosis of aldosterone-producing adenoma had undergone unilateral adrenalectomy at National Taiwan University Hospital from July 1999 to January 2007. PREDICTOR Presurgery estimated glomerular filtration rate (eGFR). OUTCOMES & MEASUREMENTS Residual hypertension after adrenalectomy, defined either as less than 75% of recorded blood pressure measurements with systolic blood pressure less than 140 mm Hg and diastolic blood pressure less than 90 mm Hg or requiring antihypertensive medications during the first year after surgery. RESULTS Before surgery, 27 (18%), 72 (48%), and 51 (34%) patients had moderately to severely decreased (<60 mL/min/1.73 m(2)), mildly decreased (60 <or= eGFR < 90 mL/min/1.73 m(2)), or nondecreased eGFR (>or=90 mL/min/1.73 m(2)), respectively. After surgery, 16 (59.3%), 29 (40.3%), and 10 (19.3%) patients in each category had postsurgery residual hypertension. Compared with patients without decreased eGFR before surgery, adjusted odds ratios for postsurgery residual hypertension were 2.7 (95% confidence interval, 1.03 to 7.0; P = 0.04) and 2.8 (95% confidence interval, 1.05 to 9.3) for mildly and moderately to severely decreased eGFR, respectively. LIMITATIONS Arbitrary definition for residual hypertension. CONCLUSIONS Two-thirds of patients with aldosterone-producing adenoma were cured of hypertension by means of unilateral adrenalectomy. Kidney function impairment, even mild, appears to be associated with a high incidence of postsurgery residual hypertension.

Major Complications and Associated Risk Factors of Transrectal Ultrasound Guided Prostate Needle Biopsy: A Retrospective Study of 1875 Cases in Taiwan

BACKGROUND/PURPOSE Complications from transrectal ultrasound (TRUS) guided prostate needle biopsy are occasionally encountered in the daily practice of urologists. We tried to determine the associated risk factors of patients who suffered from major complications that required hospitalization after TRUS guided prostate needle biopsies. METHODS We did a retrospective review of 1875 TRUS guided prostate biopsies performed between January 2002 and December 2005. We defined major complications as patients with complications that needed hospitalization. We analyzed the association between biopsy complications and suspected factors, including age, prostate volume, patients underlying disease, selection of prophylactic antibiotics, biopsy core numbers (6, 12, and 15 cores), and antiplatelet/anticoagulant usage. RESULTS There were 124 patients (6.6%) with major complication. These major complications were categorized as acute prostatitis (3.8%), acute urinary retention (2.1%), hematuria (1.9%), rectal bleeding (0.2%), epididymitis (0.2%), sepsis (0.05%), and vasovagal syncope (0.05%). Patients with larger prostate size were noted to have higher risk of developing transient acute prostatitis and acute urinary retention after prostate biopsy. In contrast, age, prophylactic antibiotics (levofloxacin and pipemidic acid), underlying diseases (diabetic mellitus, hypertension, hyperlipidemia, cerebrovascular accident, coronary artery disease), increased biopsy core numbers, and antiplatelet/anticoagulant usage were not associated with major complications after prostate biopsy. CONCLUSION TRUS guided prostate needle biopsy is a safe diagnostic tool in most elderly males with or without systemic underlying disease.

Kidney impairment in primary aldosteronism

BACKGROUND Kidney impairment is noted in primary aldosteronism (PA), and probably initiated by glomerular hyperfiltration. METHODS A prospectively defined survey was conducted on 602 patients who were suspected of PA in the multiple-center Taiwan Primary Aldosteronism Investigation (TAIPAI) database. Estimated glomerular filtration rate (eGFR) was calculated and followed up at 1 yr after treatment. RESULTS The diagnosis of PA was confirmed in 330 patients. Among them 17% of these patients had kidney impairment (eGFR<60 ml/min/1.73 m²). Patients with PA had a higher prevalence of estimated hyperfiltration than those with essential hypertension (EH) (14.5% vs. 7.0%, p=0.005). The eGFR independently predicted PA (OR, 1.017) in the propensity-adjusted multivariate logistic model. In PA, plasma renin activity and lower serum potassium (p=0.018) was correlated with kidney impairment (p=0.001), while this relationship was not significant in patients with EH. Either unilateral adrenalectomy or treatment of spironolactone for PA patients caused a decrease of eGFR (p<0.001). Pre-operative hypokalemia (p=0.013) and the long latency of hypertension (p=0.016) could enhance the significant decrease of eGFR after adrenalectomy. CONCLUSIONS Patients with aldosteronism had relative estimated hyperfiltration than patients with EH. Calculation of eGFR may increase the specificity in identifying patients with PA. Our findings demonstrate the correlation of serum potassium and renin with estimated hyperfiltration in PA and their relationship to kidney damage. These results provide a high priority for future renal protective strategies and methods for the early diagnosis and prompt treatment of PA.

Aristolochic acid-induced upper tract urothelial carcinoma in Taiwan: clinical characteristics and outcomes.

Aristolochic acid (AA), a component of all Aristolochia‐based herbal medicines, is a potent nephrotoxin and human carcinogen associated with upper urinary tract urothelial carcinoma (UUC). To investigate the clinical and pathological characteristics of AA‐induced UUC, this study included 152 UUC patients, 93 of whom had been exposed to AA based on the presence of aristolactam‐DNA adducts in the renal cortex. Gene sequencing was used to identify tumors with A:T‐to‐T:A transversions in TP53, a mutational signature associated with AA. Cases with both aristolactam‐DNA adducts and A:T‐to‐T:A transversions in TP53 were defined as AA‐UUC, whereas patients lacking both of these biomarkers were classified as non‐AA‐UUC. Cases with either biomarker were classified as possible‐AA‐UUC. Forty (26%), 60 (40%), and 52 (34%) patients were classified as AA‐UUC, possible‐AA‐UUC and non‐AA‐UUC, respectively. AA‐UUC patients were younger (median ages: 64, 68, 68 years, respectively; p=0.189), predominately female (65%, 42%, 35%, respectively; p=0.011), had more end‐stage renal disease (28%, 10%, 12%, respectively; p=0.055), and were infrequent smokers (5%, 22%, 33%, respectively; p=0.07) compared to possible‐AA‐UUC and non‐AA‐UUC patients. All 14 patients who developed contralateral UUC had aristolactam‐DNA adducts; ten of these also had signature mutations. The contralateral UUC‐free survival period was shorter in AA‐UUC compared to possible‐ or non‐AA‐UUC (p=0.019 and 0.002, respectively), whereas no differences among groups were observed for bladder cancer recurrence. In conclusion, AA‐UUC patients tend to be younger and female, and have more advanced renal disease. Notably, AA exposure was associated with an increased risk for developing synchronous bilateral and metachronous contralateral UUC.

Primary Aldosteronism: Diagnostic Accuracy of the Losartan and Captopril Tests

BACKGROUND To assess whether angiotensin-II receptor blockers (ARBs) offer any additional advantage in confirming the diagnosis of primary aldosteronism (PA) and their use in the differentiation of PA subtypes. METHODS A prospective, cohort, head-to-head study was conducted between July 2003 and July 2006. A total of 135 patients received captopril and losartan tests to confirm the diagnosis of PA in the TAIPAI (Taiwan Primary Aldosteronism Investigation) intervention. RESULTS In total, 71 patients were diagnosed with PA. The area under the receiver-operating characteristic (ROC) curve of the postcaptopril plasma aldosterone concentration (PAC) was significantly less than that of the postlosartan PAC (0.744 vs. 0.829, P = 0.038). Using an aldosterone-renin ratio (ARR, ng/dl per ng/ml/h) >35 with a PAC >10 ng/dl, the specificity was 89.1% vs. 93.8% and the sensitivity was 66.2% vs. 84.5 % for the captopril test vs. the losartan test, respectively. With respect to the losartan test, the accuracy was 88.9%, the agreement was good (k = 0.778), and there was no disagreement with the McNemar test (P = 0.118). Losartan had the advantage of a better negative predictive value to exclude PA when patients were referred with a serum potassium (SK) level <3.8 mmol/l. When a postlosartan ARR >60 was the cutoff value, the positive predictive value was 82% with a negative predictive value of 57% in distinguishing aldosterone-producing adenomas (APAs) from idiopathic hyperaldosteronism (IHA). CONCLUSIONS The postlosartan ARR and PAC were shown to have better accuracy for the diagnosis of PA than the captopril test. With a postlosartan ARR >60, APAs can be adequately differentiated from IHA.

Primary aldosteronism: changes in cystatin C-based kidney filtration, proteinuria, and renal duplex indices with treatment.

Objectives To obtain information about the effect of prolonged aldosterone excess on kidney function. Methods We determined kidney function changes defined by cystatin C-based estimations of glomerular filtration rate (CysC-GFR). Pretreatment proteinuria and intrarenal Doppler velocimetric indices in primary aldosteronism were examined and followed after adrenalectomy or spironolactone treatment. Results This prospective, multicenter study included 130 primary aldosteronism patients (56 men; age, 49.9 ± 13.4 years: 100 with adenoma and 30 with idiopathic hyperaldosteronism) and 73 essential hypertension patients (36 men; age, 51.4 ± 14.8 years) as controls. Patients with primary aldosteronism had higher CysC-GFR (P < 0.05) and heavier proteinuria (0.042) than those with essential hypertension. With primary aldosteronism, a higher aldosterone–renin ratio (odds ratio, OR = 7.85, P = 0.008) was independently related to pretreatment CysC-GFR. The factors related to pretreatment proteinuria included CysC-GFR (OR, −0.006, P = 0.001), plasma aldosterone concentration (OR, 0.004, P = 0.002), and duration of hypertension (OR, 0.016, P = 0.032). Duration of hypertension was also independently correlated with the pretreatment resistive index among primary aldosteronism patients (OR, 0.004, P = 0.035). CysC-GFR (all, P < 0.05), proteinuria (P < 0.001), and resistive index (P < 0.001) decreased 1 year after adrenalectomy but not with spironolactone treatment. Conclusion Our data suggest that prolonged hyperaldosteronism will cause relative kidney hyperfiltration and reversible intrarenal vascular structural changes, which disguise the consequent renal injury, including declining GFR and proteinuria. Adrenalectomy and spironolactone treatment exert different clinical impacts toward kidney damage even with a similar blood pressure-lowering effect.

Protective Role of AMP-Activated Protein Kinase-Evoked Autophagy on an In Vitro Model of Ischemia/Reperfusion-Induced Renal Tubular Cell Injury

Ischemia/reperfusion (I/R) injury is a common cause of injury to target organs such as brain, heart, and kidneys. Renal injury from I/R, which may occur in renal transplantation, surgery, trauma, or sepsis, is known to be an important cause of acute kidney injury. The detailed molecular mechanism of renal I/R injury is still not fully clear. Here, we investigate the role of AMP-activated protein kinase (AMPK)-evoked autophagy in the renal proximal tubular cell death in an in vitro I/R injury model. To mimic in vivo renal I/R injury, LLC-PK1 cells, a renal tubular cell line derived from pig kidney, were treated with antimycin A and 2-deoxyglucose to mimic ischemia injury followed by reperfusion with growth medium. This I/R injury model markedly induced apoptosis and autophagy in LLC-PK1 cells in a time-dependent manner. Autophagy inhibitor 3-methyladenine (3MA) significantly enhanced I/R injury-induced apoptosis. I/R could also up-regulate the phosphorylation of AMPK and down-regulate the phosphorylation of mammalian target of rapamycin (mTOR). Cells transfected with small hairpin RNA (shRNA) for AMPK significantly increased the phosphorylation of mTOR as well as decreased the induction of autophagy followed by enhancing cell apoptosis during I/R. Moreover, the mTOR inhibitor RAD001 significantly enhanced autophagy and attenuated cell apoptosis during I/R. Taken together, these findings suggest that autophagy induction protects renal tubular cell injury via an AMPK-regulated mTOR pathway in an in vitro I/R injury model. AMPK-evoked autophagy may be as a potential target for therapeutic intervention in I/R renal injury.