Metabolomic assessment of mechanisms underlying anti-renal fibrosis properties of petroleum ether extract from Amygdalus mongolica.

CONTEXT: The petroleum ether extract (PET) of Amygdalus mongolica (Maxim.) Ricker (Rosaceae) has an ameliorative effect on renal fibrosis (RF). OBJECTIVE: To evaluate the antifibrotic effects of A. mongolica seeds PET on RF by serum metabolomics, biochemical and histopathological analyses. MATERIALS AND METHODS: Sixty male Sprague-Dawley rats were randomly divided into the sham-operated, RF model, benazepril hydrochloride-treated model (1.5 mg/kg) and PET-treated (1.75, 1.25, 0.75 g/kg) groups, and the respective drugs were administered intragastrically for 21 days. Biochemical indicators including BUN, Scr, HYP, SOD, and MDA were measured. Haematoxylin and eosin and Masson staining were used for histological examination. The serum metabolomic profiles were determined by UPLC-Q-TOF/MS and metabolism network analysis. Acute toxicity test was performed to validate biosafety. RESULTS: The PET LD50 was >23.9 g/kg in rats. PET significantly alleviated fibrosis by reducing the levels of Scr (from 34.02 to 32.02), HYP (from 403.67 to 303.17) and MDA (from 1.84 to 1.73), and increasing that of SOD (from 256.42 to 271.85). Metabolomic profiling identified 10 potential biomarkers, of which three key markers were significantly associated with RF-related pathways including phenylalanine, tyrosine and tryptophan biosynthesis, amino sugar and nucleotide sugar metabolism and tyrosine metabolism. In addition, three key biomarkers were restored to baseline levels following PET treatment, with the medium dose showing optimal effect. CONCLUSIONS: These findings revealed the mechanism of A. mongolica PET antifibrotic effects for RF rats on metabolic activity and provided the experimental basis for the clinical application.

177Lu-PSMA-617 Therapy in Mice, with or without the Antioxidant α1-Microglobulin (A1M), Including Kidney Damage Assessment Using 99mTc-MAG3 Imaging.

Anti-prostate specific membrane antigen (PSMA) radioligand therapy is promising but not curative in castration resistant prostate cancer. One way to broaden the therapeutic index could be to administer higher doses in combination with radioprotectors, since administered radioactivity is kept low today in order to avoid side-effects from a high absorbed dose to healthy tissue. Here, we investigated the human radical scavenger α1-microglobulin (A1M) together with 177-Lutetium (177Lu) labeled PSMA-617 in preclinical models with respect to therapeutic efficacy and kidney toxicity. Nude mice with subcutaneous LNCaP xenografts were injected with 50 or 100 MBq of [177Lu]Lu-PSMA-617, with or without injections of recombinant A1M (rA1M) (at T = 0 and T = 24 h). Kidney absorbed dose was calculated to 7.36 Gy at 4 days post a 100 MBq injection. Activity distribution was imaged with Single-Photon Emission Computed Tomography (SPECT) at 24 h. Tumor volumes were measured continuously, and kidneys and blood were collected at termination (3-4 days and 3-4 weeks after injections). In a parallel set of experiments, mice were given [177Lu]Lu-PSMA-617 and rA1M as above and dynamic technetium-99m mercaptoacetyltriglycine ([99mTc]Tc-MAG3) SPECT imaging was performed prior to injection, and 3- and 6-months post injection. Blood and urine were continuously sampled. At termination (6 months) the kidneys were resected. Biomarkers of kidney function, expression of stress genes and kidney histopathology were analyzed. [177Lu]Lu-PSMA-617 uptake, in tumors and kidneys, as well as treatment efficacy did not differ between rA1M and vehicle groups. In mice given rA1M, [99mTc]Tc-MAG3 imaging revealed a significantly higher slope of initial uptake at three months compared to mice co-injected with [177Lu]Lu-PSMA-617 and vehicle. Little or no change compared to control was seen in urine albumin, serum/plasma urea levels, RT-qPCR analysis of stress response genes and in the kidney histopathological evaluation. In conclusion, [99mTc]Tc-MAG3 imaging presented itself as a sensitive tool to detect changes in kidney function revealing that administration of rA1M has a potentially positive effect on kidney perfusion and tubular function when combined with [177Lu]Lu-PSMA-617 therapy. Furthermore, we could show that rA1M did not affect anti-PSMA radioligand therapy efficacy.

Quantitative Benefit-Risk Assessment of P-gp-Mediated Drug-Drug Interactions of Dabigatran Coadministered With Pharmacokinetic Enhancers in Patients With Renal Impairment.

Drug-drug interactions (DDIs) between dabigatran and ritonavir/cobicistat are of major concern in people living with HIV, particularly in those with impaired renal function, because they can result in increased dabigatran exposure and thus an increased risk of major bleeding events. However, the extent of this interaction and subsequent need for dose adjustment in subjects with varying degrees of renal function is currently not yet fully understood. To close this knowledge gap, we conducted an integrated population physiologically-based pharmacokinetic/pharmacodynamic analysis linking changes in dabigatran exposure due to DDIs and varying degrees of renal function to the probability of experiencing an ischemic stroke or major bleeding event within 1 year. The results of our analysis suggest that coadministration of dabigatran etexilate (dabigatran prodrug) and ritonavir/cobicistat should be avoided in subjects with severe renal impairment. A 2-hour dose separation or dabigatran etexilate dose reduction to 110 mg b.i.d. (twice daily) should be considered in subjects with moderate renal impairment when coadministered with ritonavir, while the dabigatran etexilate dose should be further reduced to 75 mg b.i.d. when coadministered with cobicistat. No dabigatran etexilate dose adjustment is needed in subjects with normal renal function receiving ritonavir, but dabigatran etexilate dose reduction to 110 mg b.i.d. should be considered when coadministered with cobicistat.

Physiologically-Based Pharmacokinetic Modeling in Renal and Hepatic Impairment Populations: A Pharmaceutical Industry Perspective.

The predictive performance of physiologically-based pharmacokinetics (PBPK) models for pharmacokinetics (PK) in renal impairment (RI) and hepatic impairment (HI) populations was evaluated using clinical data from 29 compounds with 106 organ impairment study arms were collected from 19 member companies of the International Consortium for Innovation and Quality in Pharmaceutical Development. Fifty RI and 56 HI study arms with varying degrees of organ insufficiency along with control populations were evaluated. For RI, the area under the curve (AUC) ratios of RI to healthy control were predicted within twofold of the observed ratios for > 90% (N = 47/50 arms). For HI, > 70% (N = 43/56 arms) of the hepatically impaired to healthy control AUC ratios were predicted within twofold. Inaccuracies, typically overestimation of AUC ratios, occurred more in moderate and severe HI. PBPK predictions can help determine the need and timing of organ impairment study. It may be suitable for predicting the impact of RI on PK of drugs predominantly cleared by metabolism with varying contribution of renal clearance. PBPK modeling may be used to support mild impairment study waivers or clinical study design.

Assessment of the Protective Effect of Lepidium sativum against Aluminum-Induced Liver and Kidney Effects in Albino Rat.

BACKGROUND AND OBJECTIVES: Environmental pollution with the different Aluminum (Al) containing compounds has been increased. Liver and kidney are two vital organs targeted by Al accumulation. The aim of this study was to assess the possible protective and curative effects of Lepidium sativum Linn (LS) against Al-induced impairment of liver and kidney in albino rat and to explore the mechanism behind this effect. MATERIALS AND METHODS: This experimental animal-based study included fifty albino rats divided into five groups, the control, LS-treated (20 mg/kg), AlCl3-treated (10 mg/kg), AlCl3 then LS, and AlCl3 plus LS-treated, simultaneously for 8 weeks. At the end of the experiment, hepatic and renal functions as well as the biomarkers of antioxidants activities were assessed in the serum. Both liver and kidney were dissected out and histopathologically examined. RESULTS: This study showed that administration of AlCl3 caused a significant (p<0.05) reduction in rats body weight. It significantly increased serum AST, ALT, ALP, bilirubin, urea, and creatinine levels and decreased total protein and albumin. AlCl3 significantly reduced enzymatic (catalase), nonenzymatic (reduced glutathione), and ferric reducing antioxidant power (FRAP) in the serum. Histopathologically, it induced necrosis and degeneration of hepatocytes, glomeruli, and renal tubules. Administration of LS after or along with AlCl3 significantly restored the serum biomarkers of liver and kidney functions to their near-normal levels and had the ability to overcome Al-induced oxidative stress and preserved, to some extent, the normal hepatic and renal structure. The coadministration of LS had a superior effect in alleviating Al-induced changes. CONCLUSION: Exposure to AlCl3 induced a set of functional and structural changes in the liver and kidney of rats evident through both biochemical and histopathological assessment. The antioxidant activity of LS seeds mediated a protective and curative effect of LS against such changes. Further study through a rigorous clinical trial to prove LS activity on human is recommended.

Using Collaborative Cross Mouse Population to Fill Data Gaps in Risk Assessment: A Case Study of Population-Based Analysis of Toxicokinetics and Kidney Toxicodynamics of Tetrachloroethylene.

BACKGROUND: Interindividual variability in susceptibility remains poorly characterized for environmental chemicals such as tetrachloroethylene (PERC). Development of population-based experimental models provide a potential approach to fill this critical need in human health risk assessment. OBJECTIVES: In this study, we aimed to better characterize the contribution of glutathione (GSH) conjugation to kidney toxicity of PERC and the degree of associated interindividual toxicokinetic (TK) and toxicodynamic (TD) variability by using the Collaborative Cross (CC) mouse population. METHODS: Male mice from 45 strains were intragastrically dosed with PERC ([Formula: see text]) or vehicle (5% Alkamuls EL-620 in saline), and time-course samples were collected for up to 24 h. Population variability in TK of S-(1,2,2-trichlorovinyl)GSH (TCVG), S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC), and N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine (NAcTCVC) was quantified in serum, liver, and kidney, and analyzed using a toxicokinetic model. Effects of PERC on kidney weight, fatty acid metabolism-associated genes [ Acot1 (Acyl-CoA thioesterase 1), Fabp1 (fatty acid-binding protein 1), and Ehhadh (enoyl-coenzyme A, hydratase/3-hydroxyacyl coenzyme A dehydrogenase)], and a marker of proximal tubular injury [KIM-1 (kidney injury molecule-1)/Hepatitis A virus cellular receptor 1 ( Havcr1)] were evaluated. Finally, quantitative data on interstrain variability in both formation of GSH conjugation metabolites of PERC and its kidney effects was used to calculate adjustment factors for the interindividual variability in both TK and TD. RESULTS: Mice treated with PERC had significantly lower kidney weight, higher kidney-to-body weight (BW) ratio, and higher expression of fatty acid metabolism-associated genes ( Acot1, Fabp1, and Ehhadh) and a marker of proximal tubular injury (KIM-1/ Havcr1). Liver levels of TCVG were significantly correlated with KIM-1/ Havcr1 in kidney, consistent with kidney injury being associated with GSH conjugation. We found that the default uncertainty factor for human variability may be marginally adequate to protect 95%, but not more, of the population for kidney toxicity mediated by PERC. DISCUSSION: Overall, this study demonstrates the utility of the CC mouse population in characterizing metabolism-toxicity interactions and quantifying interindividual variability. Further refinement of the characterization of interindividual variability can be accomplished by incorporating these data into in silico population models both for TK (such as a physiologically based pharmacokinetic model), as well as for toxicodynamic responses. https://doi.org/10.1289/EHP5105.

Optical Metabolic Imaging for Assessment of Radiation-Induced Injury to Rat Kidney and Mitigation by Lisinopril.

The kidney is one of the most radiosensitive organs; it is the primary dose-limiting organ in radiotherapies for upper abdominal cancers. The role of mitochondrial redox state in the development and treatment of renal radiation injury, however, remains ill-defined. This study utilizes 3D optical cryo-imaging to quantify renal mitochondrial bioenergetics dysfunction after 13 Gy leg-out partial body irradiation (PBI). Furthermore, the mitigating effects of lisinopril (lisino), an anti-hypertensive angiotensin converting enzyme inhibitor, is assessed in renal radiation-induced injuries. Around day 150 post-irradiation, kidneys are harvested for cryo-imaging. The 3D images of the metabolic indices (NADH, nicotinamide adenine dinucleotide, and FAD, flavin adenine dinucleotide) are acquired, and the mitochondrial redox states of the irradiated and irradiated + lisino kidneys are quantified by calculating the volumetric mean redox ratio (NADH/FAD). PBI oxidized renal mitochondrial redox state by 78%. The kidneys from the irradiated + lisino rats showed mitigation of mitochondrial redox state by 93% compared to the PBI group. The study provides evidence for an altered bioenergetics and energy metabolism in the rat model of irradiation-induced kidney damage. In addition, the results suggest that lisinopril mitigates irradiation damage by attenuating the oxidation of mitochondria leading to increase redox ratio.

Proteomics for Clinical Assessment of Kidney Disease.

Kidney disease is one of the fastest growing causes of death worldwide, disclosing an unmet clinical need for early diagnosis and optimized risk stratification that allows high risk patient selection for clinical trials and for more intensive nephroprotective interventions in the clinic. The current issue of PROTEOMICS-Clinical Applications contains four manuscripts that explore different aspects of clinical proteomics implementation in the context of acute kidney injury, chronic kidney disease and, more specifically, diabetic kidney disease, and kidney transplantation from a diagnostic and risk stratification point of view. Overall, the evidence discussed suggests that chronic kidney disease is an example where clinical proteomics has become a valuable tool ready for clinical implementation, expected to have a major impact in patient management.

Nephrotoxicity and Kidney Transport Assessment on 3D Perfused Proximal Tubules.

Proximal tubules in the kidney play a crucial role in reabsorbing and eliminating substrates from the body into the urine, leading to high local concentrations of xenobiotics. This makes the proximal tubule a major target for drug toxicity that needs to be evaluated during the drug development process. Here, we describe an advanced in vitro model consisting of fully polarized renal proximal tubular epithelial cells cultured in a microfluidic system. Up to 40 leak-tight tubules were cultured on this platform that provides access to the basolateral as well as the apical side of the epithelial cells. Exposure to the nephrotoxicant cisplatin caused a dose-dependent disruption of the epithelial barrier, a decrease in viability, an increase in effluent LDH activity, and changes in expression of tight-junction marker zona-occludence 1, actin, and DNA-damage marker H2A.X, as detected by immunostaining. Activity and inhibition of the efflux pumps P-glycoprotein (P-gp) and multidrug resistance protein (MRP) were demonstrated using fluorescence-based transporter assays. In addition, the transepithelial transport function from the basolateral to the apical side of the proximal tubule was studied. The apparent permeability of the fluorescent P-gp substrate rhodamine 123 was decreased by 35% by co-incubation with cyclosporin A. Furthermore, the activity of the glucose transporter SGLT2 was demonstrated using the fluorescent glucose analog 6-NBDG which was sensitive to inhibition by phlorizin. Our results demonstrate that we developed a functional 3D perfused proximal tubule model with advanced renal epithelial characteristics that can be used for drug screening studies.

Combining Extracellular miRNA Determination with Microfluidic 3D Cell Cultures for the Assessment of Nephrotoxicity: a Proof of Concept Study.

Drug-induced kidney injury is often observed in the clinics and can lead to long-term organ failure. In this work, we evaluated a novel in vitro system that aims at detecting whether compounds can cause renal proximal tubule damage in man. For this, we implemented organotypic cultures of human conditionally immortalized proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC-OAT1) in a three-channel OrganoPlate under microfluidic conditions. Cells were exposed to four known nephrotoxicants (cisplatin, tenofovir, cyclosporine A, and tobramycin). The effect on cell viability and NAG release into the medium was determined. A novel panel of four miRNAs (mir-21, mir-29a, mir-34a, and mir-192) was selected as potential biomarkers of proximal tubule damage. After nephrotoxicant treatment, miRNA levels in culture medium were earlier indicators than cell viability (WST-8 assay) and outperformed NAG for proximal tubule damage. In particular, mir-29a, mir-34a, and mir-192 were highly reproducible between experiments and across compounds, whereas mir-21 showed more variability. Moreover, similar data were obtained in two different laboratories, underlining the reproducibility and technical transferability of the results, a key requirement for the implementation of novel biomarkers. In conclusion, the selected miRNAs behaved like sensitive biomarkers of damage to tubular epithelial cells caused by several nephrotoxicity mechanisms. This biomarker panel, in combination with the 3D cultures of ciPTEC-OAT1 in the OrganoPlate, represents a novel tool for in vitro nephrotoxicity detection. These results pave the way for the application of miRNAs in longitudinal, time-course in vitro toxicity studies.

A Pediatric Case of Well-Functioning Supernumerary Kidney: Relative Renal Function Assessment Using Radionuclide Imaging.

We present an interesting image of a well-functioning supernumerary kidney evaluated with DMSA (dimercaptosuccinic acid) renal scintigraphy in a 14-year-old girl. At 2 years of age, the patient had a diagnosis of supernumerary kidney. She remained asymptomatic up to childhood age, and then a DMSA study was required to guide the following adequate surveillance strategy. DMSA study provided a clear imaging of supernumerary kidney in the left side of the abdomen showing a regular uptake and a normal function in relation to its own size.

Risk Assessment Study of Fluoride Salts: Probability-Impact Matrix of Renal and Hepatic Toxicity Markers.

The present risk assessment study of fluoride salts was conducted by oral administration of three different doses of sodium and potassium fluorides (NaF, KF) and zinc fluoride tetrahydrate (ZnF2 •4H2O) to male Wistar rats. The rats were divided into control and nine experimental groups, to which oral injections of 0.5 mL distilled water and 0.5 mL of fluoride solutions, respectively, were given. The dosage of fluoride compounds was adjusted to contain 2.1 mg (low-dose group, LG), 4.3 mg (mid-dose group, MG), and 5.4 mg fluoride per 200 g rat body weight (high-dose group, HG) corresponding to 5, 10, and 12.5 % of LD50 values for NaF. The 24-h urine volume, N-acetyl-ß-D-glucosaminidase (NAG) and creatinine clearance (Ccr) were measured as markers of possible acute renal impact. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined in serum samples as markers of acute hepatic impact. The levels of serum and urinary fluoride were determined to evaluate fluoride bioavailability. The results reveal that higher doses of NaF, KF, and ZnF2 induced renal damage as indicated by higher urinary NAG (p < 0.05 with ≥90th percentile of control). High doses of ZnF2 also induced a significant Ccr decrease (p < 0.05 with ≤10th percentile of control). Low doses of NaF and mid-doses of ZnF2 induced polyuria (p < 0.05 with ≥90th percentile of control) while medium doses of NaF and low doses of KF also induced liver damage, as indicated by a high level of AST (p < 0.05 with ≥90th percentile of control). These findings suggest that oral administration of fluoride is a potential, dose-dependent risk factor of renal tubular damage.

Current MRI techniques for the assessment of renal disease.

PURPOSE OF REVIEW: Over the past decade, a variety of MRI methods have been developed and applied to many kidney diseases. These MRI techniques show great promise, enabling the noninvasive assessment of renal structure, function and injury in individuals. This review will highlight the current applications of functional MRI techniques for the assessment of renal disease and discuss future directions. RECENT FINDINGS: Many pathological (functional and structural) changes or factors in renal disease can be assessed by advanced MRI techniques. These include renal vascular structure and function (contrast-enhanced MRI, arterial spin labelling), tissue oxygenation (blood oxygen level dependent MRI), renal tissue injury and fibrosis (diffusion or magnetization transfer imaging, magnetic resonance elastography), renal metabolism (chemical exchange saturation transfer, spectroscopic imaging), nephron endowment (cationic-contrast imaging), sodium concentration (23Na-MRI) and molecular events (targeted-contrast imaging). SUMMARY: Current advances in MRI techniques have enabled the noninvasive investigation of renal disease. Further development, evaluation and application of the MRI techniques should facilitate better understanding and assessment of renal disease, and the development of new imaging biomarkers, enabling the intensified treatment of high-risk populations and a more rapid interrogation of novel therapeutic agents and protocols.

Scintigraphic assessment of renal function in steel plant workers occupationally exposed to lead.

OBJECTIVES: Occupational exposure to lead may produce kidney damage, but existing data on the dose range associated with nephrotoxicity are inconclusive. We here assessed renal function under conditions of low to moderate lead exposure using renal scintigraphy. METHODS: Fifty-three male foundrymen (exposed group) and fourty male office workers (control group) from a steel plant were included in the study. Glomerular and tubular renal function were assessed by means of (99m)Tc-DTPA and (99m)Tc-EC clearance, respectively. Urinary markers of glomerular dysfunction (albumin) and tubular damage (α1-microglobulin (α1M), ß2-microglobulin (ß2M), retinol-binding protein (RBP), N-acetyl-ß-glucosaminidase (NAG) activity) were determined using latex beads tests or colorimetry. The lead concentration in blood was measured with atomic absorption spectrometry. RESULTS: The blood lead concentrations were 145.8 (121.3-175.3) and 39.3 (35.1-44.1) µg/l (geometric mean, 95(th) CI, p<0.001) in the exposed and control groups, respectively. Subjects exposed to lead presented with increased (99m)Tc-DTPA clearance (158.3 (148.4-168.8) vs. 135.9 (127.9-144.4) ml/min; p<0.01) and urinary albumin excretion (7.61 (6.28-9.22) vs. 4.78 (4.05-5.65) mg/g creatinine; p<0.001). (99m)Tc-EC clearance and excretion of α1M, ß2M, RBP and NAG were not significantly different between the groups. Significant correlations between (99m)Tc-DTPA clearance and blood lead concentrations (r=0.45; p<0.01) and between urinary albumin excretion and blood lead concentrations (r=0.71; p<0.001) were noted. CONCLUSIONS: Use of renal scintigraphy in present study revealed measurable alterations of renal function under the conditions of low-level lead exposure and suggest that increased glomerular filtration may be an early indicator of kidney damage in subjects occupationally exposed to lead.

Vitamin D and proteinuria: a critical review of molecular bases and clinical experience.

Proteinuria is the main predictor of chronic kidney disease progression. Drugs that block the renin-angiotensin-aldosterone (RAA) system reduce proteinuria and slow down the progression of the disease. However, their effect is suboptimal, and residual proteinuria persists as an important predictor of renal impairment. Vitamin D has pleiotropic effects that could have an impact on these parameters. In this study, we critically review the molecular and experimental bases that suggest an antiproteinuric effect of vitamin D receptor (VDR) activation and the available evidence on its antiproteinuric effect in clinical practice. In animal models, we have observed the antiproteinuric effect of VDR activation, which could be due to direct protective action on the podocyte or other pleiotropic effects that slow down RAA system activation, inflammation and fibrosis. Clinical trials have generally been conducted in patients with a vitamin D deficiency or insufficiency and the main trial (VITAL) did not demonstrate that paricalcitol improved the study's primary endpoint (decrease in the urine albumin to creatinine ratio). In this sense, the information available is insufficient to advise the use of native vitamin D or VDR activators as renoprotective antiproteinuric drugs beyond the experimental level. Two Spanish clinical trials and one Italian trial attempted to determine the effect of paricalcitol and vitamin D on residual proteinuria in various clinical circumstances (PALIFE, NEFROVID and PROCEED).

Immunofluorescence with dual microwave retrieval of paraffin-embedded sections in the assessment of human renal biopsy specimens.

Immunofluorescence of frozen tissue sections (IF-F) is a classic technique for renal immunopathologic examination. However, it has certain disadvantages, such as diffuse antigen distribution and few or even no glomeruli in the section. We developed a new technique of immunofluorescence staining using dual microwave retrieval in paraffin-embedded renal tissue sections (IF-DMP) and compared IF-DMP with IF-F in 406 renal biopsy samples. IF-DMP detected significantly more glomeruli than did IF-F (P< .001). There was no significant difference for the specificity and sensitivity in the detection of immunoglobulins, complements, κ, and λ between IF-F and IF-DMP. Concordant observations were 98% for all immunofluorescence, complements, κ, and λ staining and 100% for immunoglobulin staining. Both techniques were completely accurate in confirming diagnoses of various glomerular diseases. IF-DMP provided clearer images of tissue structure and more precise localization of antigens, and it is a suitable alternative for traditional IF-F in clinical renal immunopathologic diagnosis.

[Kidney and bone update : the 5-year history and future of CKD-MBD. Pharmacoeconomics in the field of CKD-MBD].

Pharmacoeconomics (PE) , which contributes to the decisions on the population rather than the patient level such as policy making, provides us with the cost and value of a given drug. Recent Japanese PE studies in the field of CKD-MBD are reviewed in this manuscript. Lanthnum carbonate is not cost effective as a first-line phosphate binder, while cost effective as a second-line drug added on conventional treatments for those with serum phosphate >6.0 mg/dL, as shown in incremental cost-effectiveness ratio (ICER) of $34,896. Cinacalcet hydrochloride was found to be cost effective only for those who cannot undergo parathyroidectomy. Taking these findings into account, when cinacalcet have to be used, we should give priority to calcium containing phosphate binders rather than expensive sevelamer or lanthanum from the viewpoint of the medical cost. Moreover, the doses of cinacalcet should be minimized by administering inexpensive vitamin D concomitantly.

Hydration status assessment by multi-frequency bioimpedance in patients with advanced chronic kidney disease.

INTRODUCTION: Body composition assessment has the potential to improve the care of patients with chronic kidney disease (CKD). Whole-body multiple-frequency bioimpedance spectroscopy (BIS) appears to be a useful and appropriate technique for assessing hydration status and body composition in CKD patients. OBJECTIVE: The aims of this study were to determine the hydration status by BIS in patients with advanced CKD, and to analyse the association of body fluid status with common clinical and biochemical characteristics. The prognostic value of the phase angle at 50 KHz (PA) was also evaluated. PATIENTS AND METHODS: The study group consisted of 175 patients (66 ± 14 year, 77 females) with eGFR < 40 ml/min not yet on dialysis. Body composition was assessed by BIS (BCM, Fresenius). Hydration status was expressed as a percentage of the total body water (TBW). Patients were prospectively followed-up for a median of 481 days, and the main determinants of mortality were estimated by Cox regression analysis. RESULTS: The majority of patients (85%) showed a hydration status within ± 5% TBW. Patients with oedemas or uncontrolled arterial hypertension showed mean estimate fluid overload significantly higher than that of the other study patients. Fluid overload was negatively associated with serum albumin levels, body mass index and urinary sodium/potassium ratio; and positively with male gender and diabetes. During the follow-up period, 16 patients died (9%). The main determinants of mortality adjusted for other potential covariates were: Davies comorbidity index (HR = 4.304; P = .001), and PA (per each °; HR = 0.491; P = .026). CONCLUSIONS: BIS may help identify changes in hydration status in CKD patients not fully appreciated by clinical or biochemical assessment. PA was a significant predictor of mortality in these patients.

[Level of evidence for therapeutic drug monitoring of fluconazole]. / Niveau de preuve du suivi thérapeutique pharmacologique du fluconazole.

Fluconazole is a recommended treatment option for the treatment of invasive candidiasis. Fluconazole is active against most pathogenic Candida spp. except C. kruzei and C. glabrata. Fluconazole is orally well absorbed. Its volume of distribution is reported to be 0.7-1.0 L/kg and it is weakly bound to plasma proteins. The majority of fluconazole dose is excreted via the kidneys. Usually, fluconazole pharmacokinetics display moderate inter-individual variability. However, in presence of renal dysfunction or in pediatrics patients, fluconazole pharmacokinetics might be difficult to predict. Concentration-efficacy relationships are demonstrated whereas concentration-toxicity relationships are sparse. As a consequence, therapeutic drug monitoring is not routinely recommended but can be useful in certain situations.