Validated SNPs for eGFR and their associations with albuminuria

Albuminuria and reduced glomerular filtration rate are manifestations of chronic kidney disease (CKD) that predict end-stage renal disease, acute kidney injury, cardiovascular disease and death. We hypothesized that SNPs identified in association with the estimated glomerular filtration rate (eGFR) would also be associated with albuminuria. Within the CKDGen Consortium cohort (n= 31 580, European ancestry), we tested 16 eGFR-associated SNPs for association with the urinary albumin-to-creatinine ratio (UACR) and albuminuria [UACR >25 mg/g (women); 17 mg/g (men)]. In parallel, within the CARe Renal Consortium (n= 5569, African ancestry), we tested seven eGFR-associated SNPs for association with the UACR. We used a Bonferroni-corrected P-value of 0.003 (0.05/16) in CKDGen and 0.007 (0.05/7) in CARe. We also assessed whether the 16 eGFR SNPs were associated with the UACR in aggregate using a beta-weighted genotype score. In the CKDGen Consortium, the minor A allele of rs17319721 in the SHROOM3 gene, known to be associated with a lower eGFR, was associated with lower ln(UACR) levels (beta = -0.034, P-value = 0.0002). No additional eGFR-associated SNPs met the Bonferroni-corrected P-value threshold of 0.003 for either UACR or albuminuria. In the CARe Renal Consortium, there were no associations between SNPs and UACR with a P< 0.007. Although we found the genotype score to be associated with albuminuria (P= 0.0006), this result was driven almost entirely by the known SHROOM3 variant, rs17319721. Removal of rs17319721 resulted in a P-value 0.03, indicating a weak residual aggregate signal. No alleles, previously demonstrated to be associated with a lower eGFR, were associated with the UACR or albuminuria, suggesting that there may be distinct genetic components for these traits.     

Determination of the effective dose delivered by image guided radiotherapy in head & neck and breast treatments

Purpose

Image guided radiotherapy (IGRT) improves patient positioning for treatment delivery at the cost of an additional dose. This work aimed to calculate the effective dose (as an indicator of dose) for head & neck (H&N) and breast IGRT treatments by implementing dose calculation models to determine the dose distributions.

Toll-like receptor 2 (TLR2) polymorphisms are associated with reversal reaction in leprosy

BACKGROUND: Leprosy is characterized by a spectrum of clinical manifestations that depend on the type of immune response against the pathogen. Patients may undergo immunological changes known as "reactional states" (reversal reaction and erythema nodosum leprosum) that result in major clinical deterioration. The goal of the present study was to assess the effect of Toll-like receptor 2 (TLR2) polymorphisms on susceptibility to and clinical presentation of leprosy. METHODS: Three polymorphisms in TLR2 (597C-->T, 1350T-->C, and a microsatellite marker) were analyzed in 431 Ethiopian patients with leprosy and 187 control subjects. The polymorphism-associated risk of developing leprosy, lepromatous (vs. tuberculoid) leprosy, and leprosy reactions was assessed by multivariate logistic regression models. RESULTS: The microsatellite and the 597C-->T polymorphisms both influenced susceptibility to reversal reaction. Although the 597T allele had a protective effect (odds ratio [OR], 0.34 [95% confidence interval {CI}, 0.17-0.68]; P= .002 under the dominant model), homozygosity for the 280-bp allelic length of the microsatellite strongly increased the risk of reversal reaction (OR, 5.83 [95% CI, 1.98-17.15]; P= .001 under the recessive model). These associations were consistent among 3 different ethnic groups. CONCLUSIONS: These data suggest a significant role for TLR-2 in the occurrence of leprosy reversal reaction and provide new insights into the immunogenetics of the disease.     

Measurement of glomerular filtration rate in obese patients: pitfalls and potential consequences on drug therapy

Epidemiological studies have shown that obesity is associated with chronic kidney disease and end stage renal disease. These studies have used creatinine derived equations to estimate glomerular filtration rate (GFR) and have indexed GFR to body surface area (BSA). However, the use of equations using creatinine as a surrogate marker of glomerular filtration and the indexation of GFR for BSA can be questioned in the obese population. First, these equations lack precision when they are compared to gold standard GFR measurements such as inulin clearances; secondly, the indexation of GFR for 1.73 m(2) of BSA leads to a systematic underestimation of GFR compared to absolute GFR in obese patients who have BSA that usually exceed 1.73 m(2). Obesity is also associated with pathophysiological changes that can affect the pharmacokinetics of drugs. The effect of obesity on both renal function and drug pharmacokinetics raises the issue of correct drug dosage in obese individuals. This may be particularly relevant for drugs known to have a narrow therapeutic range or excreted by the kidney.     

The role of bile acid retention and a common polymorphism in the ABCB11 gene as host factors affecting antiviral treatment response in chronic hepatitis C

Summary. The outcome of hepatitis C virus (HCV) infection and the likelihood of a sustained virological response (SVR) to antiviral therapy depends on both viral and host characteristics. In vitro studies demonstrated that bile acids (BA) interfere with antiviral interferon effects. We investigate the influence of plasma BA concentrations and an ABCB11 polymorphism associated with lower transporter expression on viral load and SVR. Four hundred and fifty‐one Caucasian HCV‐patients treated with PEG‐interferon and ribavirin were included in the study. ABCB11 1331T>C was genotyped, and plasma BA levels were determined. The 1331C allele was slightly overrepresented in HCV‐patients compared to controls. In HCV‐patients, a significant difference between patients achieving SVR vs non‐SVR was observed for HCV‐2/3 (5 vs 9 μm ; P = 0.0001), while median BA levels in HCV‐1 were marginally elevated. Normal BA levels <8 μm were significantly associated with SVR (58.3%vs 36.3%; OR 2.48; P = 0.0001). This difference was significant for HCV‐2/3 (90.7%vs 67.6%; P = 0.002) but marginal in HCV‐1 (38.7%vs 27.8%; P = 0.058). SVR rates were equivalent between ABCB11 genotypes for HCV‐1, but increased for HCV‐2/3 (TT 100%vs CC 78%; OR 2.01; P = 0.043). IL28B genotype had no influence on these associations. No correlation between BA levels and HCV RNA was detected for any HCV genotype. The higher allelic frequency of ABCB11 1331C in HCV‐patients compared to controls may indirectly link increased BA to HCV chronicity. Our data support a role for BA as host factor affecting therapy response in HCV‐2/3 patients, whereas a weaker association was found for HCV‐1.     

3D dose reconstruction for narrow beams using ion chamber array measurements

3D dose reconstruction is a verification of the delivered absorbed dose. Our aim was to describe and evaluate a 3D dose reconstruction method applied to phantoms in the context of narrow beams. A solid water phantom and a phantom containing a bone-equivalent material were irradiated on a 6 MV linac. The transmitted dose was measured by using one array of a 2D ion chamber detector. The dose reconstruction was obtained by an iterative algorithm. A phantom set-up error and organ interfraction motion were simulated to test the algorithm sensitivity.In all configurations convergence was obtained within three iterations. A local reconstructed dose agreement of at least 3% / 3 mm with respect to the planned dose was obtained, except in a few points of the penumbra. The reconstructed primary fluences were consistent with the planned ones, which validates the whole reconstruction process. The results validate our method in a simple geometry and for narrow beams. The method is sensitive to a set-up error of a heterogeneous phantom and interfraction heterogeneous organ motion.     

Activity measurements of 18F and 90Y with commercial radionuclide calibrators for nuclear medicine in Switzerland

The activity of radiopharmaceuticals in nuclear medicine is measured before patient injection with radionuclide calibrators. In Switzerland, the general requirements for quality controls are defined in a federal ordinance and a directive of the Federal Office of Metrology (METAS) which require each instrument to be verified. A set of three gamma sources (Co-57, Cs-137 and Co-60) is used to verify the response of radionuclide calibrators in the gamma energy range of their use. A beta source, a mixture of ⁹⁰Sr and ⁹⁰Y in secular equilibrium, is used as well. Manufacturers are responsible for the calibration factors. The main goal of the study was to monitor the validity of the calibration factors by using two sources: a ⁹⁰Sr/⁹⁰Y source and a ¹⁸F source. The three types of commercial radionuclide calibrators tested do not have a calibration factor for the mixture but only for ⁹⁰Y. Activity measurements of a ⁹⁰Sr/⁹⁰Y source with the ⁹⁰Y calibration factor are performed in order to correct for the extra-contribution of ⁹⁰Sr. The value of the correction factor was found to be 1.113 whereas Monte Carlo simulations of the radionuclide calibrators estimate the correction factor to be 1.117. Measurements with ¹⁸F sources in a specific geometry are also performed. Since this radionuclide is widely used in Swiss hospitals equipped with PET and PET-CT, the metrology of the ¹⁸F is very important. The ¹⁸F response normalized to the ¹³⁷Cs response shows that the difference with a reference value does not exceed 3% for the three types of radionuclide calibrators.     

CT radiation dose in children: a survey to establish age-based diagnostic reference levels in Switzerland

This work aimed at assessing the doses delivered in Switzerland to paediatric patients during computed tomography (CT) examinations of the brain, chest and abdomen, and at establishing diagnostic reference levels (DRLs) for various age groups. Forms were sent to the ten centres performing CT on children, addressing the demographics, the indication and the scanning parameters: number of series, kilovoltage, tube current, rotation time, reconstruction slice thickness and pitch, volume CT dose index (CTDI(vol)) and dose length product (DLP). Per age group, the proposed DRLs for brain, chest and abdomen are, respectively, in terms of CTDI(vol): 20, 30, 40, 60 mGy; 5, 8, 10, 12 mGy; 7, 9, 13, 16 mGy; and in terms of DLP: 270, 420, 560, 1,000 mGy cm; 110, 200, 220, 460 mGy cm; 130, 300, 380, 500 mGy cm. An optimisation process should be initiated to reduce the spread in dose recorded in this study. A major element of this process should be the use of DRLs.     

Normal and stenotic renal arteries: experimental balloon-expandable intraluminal stenting

Elastic recoil of the vessel wall is a common cause of failure of percutaneous transluminal angioplasty in renal arteries. To oppose such recoil, balloon-expandable metal stents were implanted in artificially stenotic renal arteries in pigs and normal renal arteries in dogs and pigs. The stents were then examined angiographically and histologically at regular intervals. All stents were completely covered with endothelialized neointima in 3 weeks. There was no difference in intimal thickness between the stenotic and nonstenotic renal arteries. A large stent diameter and a large open or nonmetal surface may cause less intimal hyperplasia, but nonturbulent, fast arterial flow is probably the most important factor in ensuring long-term patency of the vessel.