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Colonic dialysis can influence gut flora to protect renal function in patients with pre-dialysis chronic kidney disease.
Li, Y, Dai, M, Yan, J, Liu, F, Wang, X, Lin, L, Huang, M, Li, C, Wen, R, Qin, J, et al
Scientific reports. 2021;(1):12773
Abstract
Chronic kidney disease (CKD) is a major public health burden around the world. The gut microbiome may contribute to CKD progression and serve as a promising therapeutic target. Colonic dialysis has long been used in China to help remove gut-derived toxins to delay CKD progression. Since disturbances in the gut biome may influence disease progression, we wondered whether colonic dialysis may mitigate the condition by influencing the biome. We compared the gut microbiota, based on 16S rRNA gene sequencing, in fecal samples of 25 patients with CKD (stages 3-5) who were receiving colonic dialysis(group CD), 25 outpatients with CKD not receiving colonic dialysis(group OP), and 34 healthy subjects(group HS). Richness of gut microbiota was similar between patients on colonic dialysis and healthy subjects, and richness in these two groups was significantly higher than that in patients not on colonic dialysis. Colonic dialysis also altered the profile of microbes in the gut of CKD patients, bringing it closer to the profile in healthy subjects. Colonic dialysis may protect renal function in pre-dialysis CKD by mitigating dysbiosis of gut microbiota.
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Denosumab Improves Glomerular Filtration Rate in Osteoporotic Patients With Normal Kidney Function by Lowering Serum Phosphorus.
Miyaoka, D, Inaba, M, Imanishi, Y, Hayashi, N, Ohara, M, Nagata, Y, Kurajoh, M, Yamada, S, Mori, K, Emoto, M
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2019;(11):2028-2035
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Abstract
Higher serum phosphorus (Pi) increases the risk for chronic kidney disease (CKD). It was reported that a single administration of denosumab or zoledronate significantly suppressed serum Pi levels as well as those of bone resorption markers in serum. Also, previous evidences suggest a link between bone anti-resorptive therapy and vasoprotective/renoprotective effects through mechanisms that remain unexplored. The aim of this study is to assess the renoprotective effect of denosumab and involvement of denosumab-induced reduction in serum Pi in osteoporotic patients. Osteoporotic patients (n = 73) without overt proteinuria in dipstick test results were treated with denosumab (60 mg) every 6 months during the study period (24 months). Estimated glomerular filtration rate based on serum cystatin C (eGFRcys) was used as a filtration marker and tartrate-resistant acid phosphatase-5b (TRACP-5b) as a bone resorption marker. For analysis of non-CKD patients (n = 56), those with eGFRcys <60 mL/min/1.73 m2 were excluded. A single injection of denosumab suppressed serum Pi as well as TRACP-5b during the first 6 months, whereas age-related decline in eGFRcys was significantly reversed, with an increase of 2.75 ± 1.2 mL/min/1.73 m2 after 24 months noted. Multivariate analysis showed that serum Pi reduction following the initial denosumab injection was positively associated with serum TRACP-5b suppression during that same period (β = 0.241, p = 0.049). In addition, a positive association of serum Pi suppression, but not of corrected calcium or TRACP-5b, with eGFRcys increase after 24 months (β = 0.321, p = 0.014) was found after adjustments for gender, age, BMI, antihypertensive drug use, albumin, and eGFRcys. The same was observed in osteoporotic cases restricted to non-CKD patients. In conclusion, serum Pi reduction resulting from phosphorus load decrement from bone induced by denosumab is a determinant for eGFRcys increase. Early introduction of bone antiresorptive therapy can retain glomerular filtration in osteoporosis cases, including non-CKD patients. © 2019 American Society for Bone and Mineral Research.
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Bioelectrical impedance analysis as a nutritional assessment tool in Autosomal Dominant Polycystic Kidney Disease.
Ryu, H, Park, HC, Kim, H, Heo, J, Kang, E, Hwang, YH, Cho, JY, Lee, KB, Oh, YK, Oh, KH, et al
PloS one. 2019;(4):e0214912
Abstract
OBJECTIVE Autosomal dominant polycystic kidney disease (ADPKD) patients with massive organomegaly suffer from pressure-related complications including malnutrition. In this study, we analyzed the efficacy of segmental bioelectrical impedance analysis (BIA) for objective and quantitative nutritional assessment in ADPKD patients. DESIGN AND METHODS We conducted a cross-sectional study, to evaluate the clinical utility of segmental BIA for assessing the nutritional status of ADPKD patients. BIA measurements was assessed according to modified subjective global assessment (SGA) scores and were compared with data from a healthy population. The association between BIA measurements and the height adjusted kidney and liver volumes (htTKLV), were analyzed. SUBJECTS A total of 288 ADPKD patients, aged ≥ 18 years old, were analyzed. MAIN OUTCOME MEASURES Nutritional status was evaluated with SGA and segmental BIA. The htTKLV were measured in each patients using computed tomonography images. RESULTS Higher ratios of extracellular water to total body water (ECW/TBW) in the whole-body (ECW/TBWWB), trunk (ECW/TBWTR), and lower extremities (ECW/TBWLE) and lower phase angle of lower extremities (PhALE) correlated with lower SGA scores in the ADPKD population and in both gender. The four parameters, ECW/TBWWB, ECW/TBWTR, and ECW/TBWLE of >0.38 and PhALE of <5.8 θ were associated with malnutrition in ADPKD patients. These correlations were preserved in the subgroup analysis for chronic kidney disease stages 1-3A. Compared to healthy populations' data, body fluid parameters and segmental ECW/TBW values, except for the upper extremities (ECW/TBWUE), were greater in ADPKD patients. Increased htTKLV was an independent risk factor for malnutrition in ADPKD. The highest correlation with htTKLV was observed for the ECW/TBWTR (r = 0.466), followed by ECW/TBWWB (r = 0.407), ECW/TBWLE (r = 0.385), PhALE (r = -0.279), and PhATR (r = 0.215). CONCLUSIONS These results demonstrated that segmental BIA parameters of ECW/TBWWB, ECW/TBWTR, ECW/TBWLE and PhALE provide useful information on nutritional status including the impact of organomegaly in ADPKD.
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Randomized Phase II Study Comparing Mannitol with Furosemide for the Prevention of Renal Toxicity Induced by Cisplatin-based Chemotherapy with Short-term Low-volume Hydration in Advanced Non-small Cell Lung Cancer: The OLCSG1406 Study Protocol.
Makimoto, G, Ichihara, E, Hotta, K, Ninomiya, K, Oze, I, Minami, D, Ninomiya, T, Kubo, T, Ohashi, K, Tabata, M, et al
Acta medica Okayama. 2018;(3):319-323
Abstract
Although cisplatin-based chemotherapy shows a survival advantage compared to carboplatin for treating advanced non-small cell lung cancer, high-volume hydration and a long infusion time are necessary to avoid nephrotoxicity, and cisplatin-based chemotherapy has been difficult to administer in outpatient settings. A low-volume hydration method using mannitol or furosemide as forced diuresis was recently introduced, but there are no clear conclusions regarding which agent should be used. We describe our ongoing randomized phase II trial (the OLCSG1406 Study) evaluating the efficacy of forced diuresis. This study will clarify whether mannitol or furosemide is more suitable in cisplatin-based chemotherapy with low-volume hydration.
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Preservation of kidney function in kidney transplant recipients by alkali therapy (Preserve-Transplant Study): rationale and study protocol.
Wiegand, A, Ritter, A, Graf, N, Arampatzis, S, Sidler, D, Hadaya, K, Müller, TF, Wagner, CA, Wüthrich, RP, Mohebbi, N
BMC nephrology. 2018;(1):177
Abstract
BACKGROUND Graft survival after kidney transplantation has significantly improved within the last decades but there is a substantial number of patients with declining transplant function and graft loss. Over the past years several studies have shown that metabolic acidosis plays an important role in the progression of Chronic Kidney Disease (CKD) and that alkalinizing therapies significantly delayed progression of CKD. Importantly, metabolic acidosis is highly prevalent in renal transplant patients and a recent retrospective study has shown that metabolic acidosis is associated with increased risk of graft loss and patient death in kidney transplant recipients. However, no prospective trial has been initiated yet to test the role of alkali treatment on renal allograft function. METHODS The Preserve-Transplant Study is an investigator-initiated, prospective, patient-blinded, multi-center, randomized, controlled phase-IV trial with two parallel-groups comparing sodium bicarbonate to placebo. The primary objective is to test if alkali treatment will preserve kidney graft function and diminish the progression of CKD in renal transplant patients by assesing the change in eGFR over 2 years from baseline. Additionally we want to investigate the underlying pathomechanisms of nephrotoxicity of metabolic acidosis. DISCUSSION This study has the potential to provide evidence that alkali treatment may slow or reduce the progression towards graft failure and significantly decrease the rate of end stage renal disease (ESRD), thus prolonging long-term graft survival. The implementation of alkali therapy into the drug regimen of kidney transplant recipients would have a favorable risk-benefit ratio since alkali supplements are routinely used in CKD patients and represent a well-tolerated, safe and cost-effective treatment. TRIAL REGISTRATION ClinicalTrials.gov NCT03102996 . Trial registration was completed on April 6, 2017.
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Effects of sildenafil, metformin, and simvastatin on ADH-independent urine concentration in healthy volunteers.
Bech, AP, Wetzels, JFM, Nijenhuis, T
Physiological reports. 2018;(7):e13665
Abstract
Nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by resistance of the kidney to the action of antidiuretic hormone (ADH), resulting in a decrease in the capacity of the kidney to concentrate the urine. NDI can be inherited or acquired due to, for example, chronic lithium therapy. Current treatment options are limited to attempts to lower urine output by a low-solute diet and the use of diuretics or anti-inflammatory drugs. These measures are only partially effective. Recent reports suggested that sildenafil, metformin, and simvastatin might improve ADH-independent urine concentration. If confirmed, this would provide interesting additional therapeutic options for patients with NDI. We, therefore, tested the effect of these drugs on ADH-independent urine concentrating capacity in healthy volunteers. We included 36 healthy volunteers who received sildenafil 20 mg thrice daily, metformin 500 mg thrice daily or simvastatin 40 mg once daily during 1 week. At baseline and at the end of treatment, a water loading test was performed. No significant increase in lowest urine osmolality was seen after the use of metformin or sildenafil (P = 0.66 and P = 0.09 respectively). Lowest urine osmolality increased modestly but significantly after the use of simvastatin (70 mOsm/kg to 85 mOsm/kg, P = 0.05). Our data suggest that only simvastatin has an effect on urine osmolality in healthy volunteers. Validation studies are needed and, most importantly, these drugs should be tested in patients with NDI.
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Acetylator Status Impacts Amifampridine Phosphate (Firdapse™) Pharmacokinetics and Exposure to a Greater Extent Than Renal Function.
Haroldsen, PE, Sisic, Z, Datt, J, Musson, DG, Ingenito, G
Clinical therapeutics. 2017;(7):1360-1370
Abstract
PURPOSE The purpose of this study is to evaluate safety, tolerability, and pharmacokinetic (PK) properties of amifampridine phosphate (Firdapse™) and its major inactive 3-N-acetyl metabolite in renally impaired and healthy individuals with slow acetylator (SA) and rapid acetylator (RA) phenotypes. METHODS This was a Phase I, multicenter, open-label study of the PK properties and safety profile of amifampridine phosphate in individuals with normal, mild, moderate, or severely impaired renal function. Amifampridine phosphate was given as a single 10 mg (base equivalent) dose, and the plasma and urine PK properties of amifampridine and its 3-N-acetyl metabolite were determined. The safety profile was evaluated by monitoring adverse events (AEs), clinical laboratory tests, and physical examinations. FINDINGS Amifampridine clearance was predominantly metabolic through N-acetylation, regardless of renal function in both acetylator phenotypes. In individuals with normal renal function, mean renal clearance represented approximately 3% and 18% of the total clearance of amifampridine in RA and SA, respectively. Large differences in amifampridine exposure were observed between acetylation phenotypes across renal function levels. Mean amifampridine exposure values of AUC0-∞ and Cmax were up to 8.8-fold higher in the SA group compared with the RA group across renal function levels. By comparison, mean AUC0-∞ was less affected by renal function within an acetylator group, only 2- to 3-fold higher in individuals with severe renal impairment (RI) compared with those with normal renal function. Exposure to amifampridine in the SA group with normal renal function was higher (AUC0-∞, approximately 1.8-fold; Cmax, approximately 4.1-fold) than the RA group with severe RI. Exposure to the inactive 3-N-acetyl metabolite was higher than amifampridine in both acetylator groups, independent of renal function level. The metabolite is cleared by renal excretion, and exposure was clearly dependent on renal function with 4.0- to 6.8-fold increases in AUC0-∞ from normal to severe RI. No new tolerability findings were observed. IMPLICATIONS A single dose of 10 mg of amifampridine phosphate was well tolerated, independent of renal function and acetylator status. The results indicate that the PK profile of amifampridine is affected by metabolic acetylator phenotype to a greater extent than by renal function level, supporting Firdapse™ administration in individuals with RI in line with current labeling recommendations. Amifampridine should be dosed to effect per the individual patient need, altering administration frequency and dose in normal through severe RI. The therapeutic dose of amifampridine phosphate should be tailored to the individual patient needs by gradual dose titration up to the present maximum recommended dose (60-80 mg/day) or until dose-limiting AEs intervene to avoid overdosing and underdosing. EudraCT identifier: 2013-005349-35.
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Does Nucleos(t)ide Analogues Treatment Affect Renal Function in Chronic Hepatitis B Patients Who Have Already Decreased eGFR? A Longitudinal Study.
Tsai, MC, Chen, CH, Tseng, PL, Hung, CH, Chiu, KW, Chang, KC, Yen, YH, Lin, MT, Hu, TH
PloS one. 2016;(3):e0149761
Abstract
This study aimed to assess the renal function in chronic hepatitis B (CHB) patients who received nucleos(t)ide analogues (NAs) therapy using estimated glomerular filtration rate (eGFR) titer. We performed a longitudinal observational study of 37 tenofovir-, 42 telbivudine-, and 62 entecavir-naïve CHB patients, who had impaired renal function (eGFR, 90-30 ml/min/1.73m2) without history of diabetes, hypertension, and chemotherapy. Calculation and evaluation of eGFR was performed with the Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, and Cockcroft-Gault formula at pretreatment, at baseline, and after the 1st and 2nd year of treatment. The eGFR was significantly increased in patients given telbivudine or entecavir (p = 0.003 and p = 0.012, respectively), but the eGFR was decreased in patients given tenofovir (p = 0.001) after 2 years of treatment. Of all patients, eGFR was stable one year prior to treatment. If we analyzed the renal function by change of chronic kidney disease (CKD) category with a change of 25% of eGFR, the proportion of uncertain drop (drop in CKD category with <25% decrease in eGFR) and certain drop (drop in CKD category with ≧25% decrease in eGFR) in tenofovir group was smaller (5.4%) than those of telbivudine (12.9%) or entecavir (6.5%). Furthermore, telbivudine had the lowest stable rate (76.2%), the highest certain rise rate (9.5%), and certain drop rate (7.1%) compared to the other groups (p = 0.049). In conclusion, in NAs-naïve CHB patients with impaired renal function, telbivudine and entecavir resulted in a significant increase in eGFR while tenofovir resulted in a significant decrease after a 2-year treatment. Interestingly, TDF had the lowest proportion of patients reclassified to certain and uncertain drop groups; in contrast, LdT had a higher proportion in both raise and drop groups. The outcomes of this renal effect remain to be determined.
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Pharmacokinetics of eribulin mesylate in cancer patients with normal and impaired renal function.
Tan, AR, Sarantopoulos, J, Lee, L, Reyderman, L, He, Y, Olivo, M, Goel, S
Cancer chemotherapy and pharmacology. 2015;(5):1051-61
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Abstract
PURPOSE To evaluate the effect of renal impairment on eribulin mesylate pharmacokinetics following a single dose in adults with advanced solid tumors. METHODS Patients were grouped by renal function: moderate impairment (creatinine clearance [CrCl] 30-50 mL/min), severe impairment (CrCl 15-29 mL/min), or normal (CrCl ≥80 mL/min). During each 21-day cycle, eribulin mesylate doses (days 1 and 8) were administered intravenously: moderate, 1.1 mg/m(2) (except cycle 1 day 1, 1.4 mg/m(2)); severe, 0.7 mg/m(2); normal, 1.4 mg/m(2). RESULTS Nineteen patients were enrolled (normal, n = 6; moderate, n = 7; severe, n = 6). Renal impairment was associated with an increased mean dose-normalized area under the concentration-time curve (ratios for moderate/normal and severe/normal: 1.49; 90 % confidence interval [CI] 0.9, 2.45). CrCl and renal function correlated positively, with a numerically small slope (0.0184; 90 % CI -0.00254, 0.0394). A simulated dose reduction to eribulin 1.1 mg/m(2) in patients with moderate or severe renal impairment achieved the same exposure as 1.4 mg/m(2) in those with normal renal function. All groups had similar toxicity profiles, with no unexpected adverse events. CONCLUSIONS Renal impairment decreased eribulin clearance and increased exposure. Pharmacokinetic evaluation supports an eribulin dose reduction to 1.1 mg/m(2) in patients with moderate or severe renal impairment. CLINICALTRIALS. GOV IDENTIFIER NCT01418677.
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Characterization of renal biomarkers for use in clinical trials: biomarker evaluation in healthy volunteers.
Brott, DA, Adler, SH, Arani, R, Lovick, SC, Pinches, M, Furlong, ST
Drug design, development and therapy. 2014;:227-37
Abstract
BACKGROUND Several preclinical urinary biomarkers have been qualified and accepted by the health authorities (US Food and Drug Administration, European Medicines Agency, and Pharmaceuticals and Medical Devices Agency) for detecting drug-induced kidney injury during preclinical toxicologic testing. Validated human assays for many of these biomarkers have become commercially available, and this study was designed to characterize some of the novel clinical renal biomarkers. The objective of this study was to evaluate clinical renal biomarkers in a typical Phase I healthy volunteer population to determine confidence intervals (pilot reference intervals), intersubject and intrasubject variability, effects of food intake, effect of sex, and vendor assay comparisons. METHODS Spot urine samples from 20 male and 19 female healthy volunteers collected on multiple days were analyzed using single analyte and multiplex assays. The following analytes were measured: α-1-microglobulin, β-2-microglobulin, calbindin, clusterin, connective tissue growth factor, creatinine, cystatin C, glutathione S-transferase-α, kidney injury marker-1, microalbumin, N-acetyl-β-(D) glucosaminidase, neutrophil gelatinase-associated lipocalin, osteopontin, Tamm-Horsfall urinary glycoprotein, tissue inhibitor of metalloproteinase 1, trefoil factor 3, and vascular endothelial growth factor. RESULTS Confidence intervals were determined from the single analyte and multiplex assays. Intersubject and intrasubject variability ranged from 38% to 299% and from 29% to 82% for biomarker concentration, and from 24% to 331% and from 10% to 67% for biomarker concentration normalized to creatinine, respectively. There was no major effect of food intake or sex. Single analyte and multiplex assays correlated with r (2)≥0.700 for five of six biomarkers when evaluating biomarker concentration, but for only two biomarkers when evaluating concentration normalized to creatinine. CONCLUSION Confidence intervals as well as intersubject and intrasubject variability were determined for novel clinical renal biomarkers/assays, which should be considered for evaluation in the next steps of the qualification process.