Oral sitafloxacin vs intravenous ceftriaxone followed by oral cefdinir for acute pyelonephritis and complicated urinary tract infection: a randomized controlled trial.

BACKGROUND: The conventional antibiotic regimen for community-acquired upper urinary tract infections with moderate severity in Thailand is parenteral ceftriaxone (CTRX) for several days followed by oral cephalosporin for 7-14 days. The aim of this study was to compare the efficacy and safety of oral sitafloxacin (STFX) with that of intravenous CTRX followed by oral cefdinir (CFDN) for the therapy of acute pyelonephritis (APN) and complicated urinary tract infection (cUTI). METHODS: This open-label, randomized, controlled, noninferiority clinical trial included patients from nine centers across Thailand. Adult patients with APN or cUTI were randomly assigned to receive 100 mg of oral STFX twice daily for 7-14 days, or 2 g of intravenous CTRX for several days followed by 100 mg of oral CFDN three times per day for another 4-12 days. RESULTS: A total of 289 adult patients with APN or cUTI (141 in the STFX group and 148 in the CTRX/CFDN group) were included in the intent-to-treat (ITT) analysis, and 211 patients (108 in the STFX group and 103 in the CTRX/CFDN group) were included in the per-protocol (PP) analysis. The baseline characteristics of patients in both groups were comparable. The causative pathogen in most patients with APN or cUTI was Escherichia coli. The clinical success rates at the end of treatment revealed the STFX regimen to be noninferior to the CTRX/CFDN regimen (86.6% vs 83.8% for ITT analysis and 97.2% vs 99.0% for PP analysis, respectively). Adverse events with mild-to-moderate severity were similar between groups. CONCLUSION: Oral STFX is noninferior to intravenous CTRX followed by oral CFDN in adult patients with APN and cUTI. Lower rates of resistance compared to CTRX and/or CFDN and oral administration suggest STFX as a more attractive treatment option in this patient population.

Management of metastatic castration-resistant prostate cancer: Insights from urology experts in Thailand.

Treatment options for castration-resistant prostate cancer (CRPC) are available, but clear instructions for the selection of appropriate treatment are lacking. A meeting of urology experts based in Thailand was convened with the following objectives: (1) to reach a consensus and share real-life experiences about how to identify CRPC; (2) to choose the appropriate treatment for CRPC patients; (3) to evaluate disease progression using novel inhibitors of the androgen receptor pathway; (4) to identify the frequency of monitoring disease; and (5) to promote rational use of corticosteroids in CRPC patients. This consensus document can provide guidance to other urologists in Thailand to provide appropriate treatment to metastatic CRPC patients in a timely manner.

Increased oxidative DNA damage seen in renal biopsies adjacent stones in patients with nephrolithiasis.

Urinary excretion of 8-hydroxydeoxyguanosine (8-OHdG), a marker of oxidative DNA damage, is significantly higher in nephrolithiasis patients than in healthy individuals, indicating that these patients have higher degree of oxidative stress. In the present study, we investigated 8-OHdG expression in renal biopsies of patients with nephrolithiasis and in renal tubular cells (HK-2 cells) exposed to calcium oxalate monohydrate (COM). We performed immunohistochemical staining for 8-OHdG in renal biopsies adjacent stones obtained from 28 patients with nephrolithiasis. Controls were noncancerous renal tissues from nephrectomies of patients with renal cancer. 8-OHdG was overexpressed in the nucleus of renal tubular cells in patients with nephrolithiasis compared with controls. Only one nephrolithiasis biopsy was negative for 8-OHdG, whereas in 19 cases 8-OHdG was highly expressed. The level of expression of 8-OHdG among patients with calcium oxalate (mostly mixed with calcium phosphate) and uric acid stones was not significantly different. Increased leukocyte infiltration was observed in renal tissues from patients with nephrolithiasis. Exposure of HK-2 cells to COM caused increased intracellular reactive oxygen species and nuclear expression of 8-OHdG. To our knowledge, this is the first report of increased 8-OHdG expression in renal tubular cells of patients with nephrolithiasis. In vitro, COM crystals were capable of inducing oxidative damage of DNA in the proximal renal tubular cells.

Association between human prothrombin variant (T165M) and kidney stone disease.

We previously reported the association between prothrombin (F2), encoding a stone inhibitor protein - urinary prothrombin fragment 1 (UPTF1), and the risk of kidney stone disease in Northeastern Thai patients. To identify specific F2 variation responsible for the kidney stone risk, we conducted sequencing analysis of this gene in a group of the patients with kidney stone disease. Five intronic SNPs (rs2070850, rs2070852, rs1799867, rs2282687, and rs3136516) and one exonic non-synonymous single nucleotide polymorphism (nsSNP; rs5896) were found. The five intronic SNPs have no functional change as predicted by computer programs while the nsSNP rs5896 (c.494 C>T) located in exon 6 results in a substitution of threonine (T) by methionine (M) at the position 165 (T165M). The nsSNP rs5896 was subsequently genotyped in 209 patients and 216 control subjects. Genotypic and allelic frequencies of this nsSNP were analyzed for their association with kidney stone disease. The frequency of CC genotype of rs5896 was significantly lower in the patient group (13.4%) than that in the control group (22.2%) (P = 0.017, OR 0.54, 95% CI 0.32-0.90), and the frequency of C allele was significantly lower in the patient group (36.1%) than that in the control group (45.6%) (P = 0.005, OR 0.68, 95% CI 0.51-0.89). The significant differences of genotype and allele frequencies were maintained only in the female group (P = 0.033 and 0.003, respectively). The effect of amino-acid change on UPTF1 structure was also examined by homologous modeling and in silico mutagenesis. T165 is conserved and T165M substitution will affect hydrogen bond formation with E180. In conclusion, our results indicate that prothrombin variant (T165M) is associated with kidney stone risk in the Northeastern Thai female patients.

Fibrosis and evidence for epithelial-mesenchymal transition in the kidneys of patients with staghorn calculi.

OBJECTIVES: • To quantify fibrotic lesions in renal tissues obtained from patients with large calculi and to evaluate association with renal function. • Presence of epithelial-mesenchymal transition (EMT) in stone-containing renal tissues was investigated. PATIENTS, SUBJECTS AND METHODS: • In all, 50 patients with nephrolithiasis with large calculi and matched healthy controls (37) were recruited. • Plasma creatinine (Cr) and corrected Cr clearance (CCr) were determined in all subjects. • Of the 50 patients, 38 had renal tissue available for histological analysis. Fibrosis was assessed by Masson's trichrome staining. Co-expression of epithelial cytokeratins and mesenchymal markers [α-smooth muscle actin (αSMA) and vimentin] in renal tubular cells was detected by dual immunofluorescence staining. • Expression of fibronectin, transforming growth factor ß1 (TGF-ß1) and CD68 were investigated. RESULTS: • Overall, the kidney function of the patients was significantly reduced, indicated by increased plasma Cr and decreased corrected CCr compared with healthy controls. • Inflammation grading in renal tissues of the patients was correlated with the percentage of the fibrotic area. Renal fibrosis was inversely correlated with renal function. • Cytokeratins co-expressed with αSMA and vimentin were found in nephrolithiatic renal tubular cells, and these cells strongly expressed fibronectin and TGF-ß1. • Infiltration of CD68-positive cells was a common finding in the inflamed renal sections. CONCLUSIONS: • Kidneys of large stone-forming patients had robust signs of inflammation and fibrosis, and there was a close correlation of renal fibrosis with renal dysfunction. • This is the first study to show evidence for renal tubular cells showing signs of EMT in large stone-containing kidneys. Plausibly, TGF-ß1 triggers EMT, which at least in part contributes to large stone-induced renal fibrosis.

Evidence suggesting a genetic contribution to kidney stone in northeastern Thai population.

Genetic factor may play a role in the pathogenesis of kidney stone that is found in the northeastern (NE) Thai population. Herein, we report initial evidence suggesting genetic contribution to the disease in this population. We examined 1,034 subjects including 135 patients with kidney stone, 551 family members, and 348 villagers by radiography of kidney-ureter-bladder (KUB) and other methods, and also analyzed stones removed by surgical operations. One hundred and sixteen of 551 family members (21.05%) and 23 of the 348 villagers (6.61%) were affected with kidney stone. The relative risk (lambda(R)) of the disease among family members was 3.18. Calcium stones (whewellite, dahllite, and weddellite) were observed in about 88% of stones analyzed. Our data indicate familial aggregation of kidney stone in this population supporting that genetic factor should play some role in its pathogenesis. Genetic and genomic studies will be conducted to identify the genes associated with the disease.