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1.
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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Effects of DPP-4 Inhibitor Linagliptin Versus Sulfonylurea Glimepiride as Add-on to Metformin on Renal Physiology in Overweight Patients With Type 2 Diabetes (RENALIS): A Randomized, Double-Blind Trial.
Muskiet, MHA, Tonneijck, L, Smits, MM, Kramer, MHH, Ouwens, DM, Hartmann, B, Holst, JJ, Touw, DJ, Danser, AHJ, Joles, JA, et al
Diabetes care. 2020;(11):2889-2893
Abstract
OBJECTIVE To compare effects of the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin with those of a sulfonylurea on renal physiology in metformin-treated patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS In this double-blind randomized trial, 46 overweight T2DM patients without renal impairment received once-daily linagliptin (5 mg) or glimepiride (1 mg) for 8 weeks. Fasting glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid clearances. Fractional excretions, urinary damage markers, and circulating DPP-4 substrates (among others, glucagon-like peptide 1 and stromal cell-derived factor-1α [SDF-1α]) were measured. RESULTS HbA1c reductions were similar with linagliptin (-0.45 ± 0.09%) and glimepiride (-0.65 ± 0.10%) after 8 weeks (P = 0.101). Linagliptin versus glimepiride did not affect GFR, ERPF, estimated intrarenal hemodynamics, or damage markers. Only linagliptin increased fractional excretion (FE) of sodium (FENa) and potassium, without affecting FE of lithium. Linagliptin-induced change in FENa correlated with SDF-1α (R = 0.660) but not with other DPP-4 substrates. CONCLUSIONS Linagliptin does not affect fasting renal hemodynamics compared with glimepiride in T2DM patients. DPP-4 inhibition promotes modest natriuresis, possibly mediated by SDF-1α, likely distal to the macula densa.
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Gastrointestinal Absorption and Renal Excretion of Fluoride After Ingestion of a High-Fluoride Dentifrice.
Vale, G, Simões, N, Santana, G, Mota, B, Moura, M
Biological trace element research. 2019;(1):24-29
Abstract
This study aimed to evaluate the gastrointestinal absorption and renal excretion of fluoride after the ingestion of high-fluoride dentifrice. Twelve volunteers participated in this in vivo, crossover, and blinded study. In three experimental phases, the volunteers were randomly assigned to one of three treatment groups, who ingested either the following: distilled and deionized water (control), conventional dentifrice (1100 μg/g), or high-fluoride dentifrice (5000 μg/g). Both dentifrices contained fluoride in the form of NaF/SiO2. To determine the rate of fluoride absorption, non-stimulated saliva was collected for up to 120 min after ingestion and the area under the curve of the salivary fluoride concentration was plotted as a function of time and the maximum concentration determined. All urine produced during the 24 h before and after ingestion was collected, and urinary excretion was calculated from the difference between the urinary fluoride concentrations in the two periods. A specific ion electrode coupled to an ion analyzer was used to measure fluoride concentrations. Statistical analysis was performed by ANOVA followed by Tukey's test with p set at 5%. All measured parameters were highest after the ingestion of the dentifrice with 5000 μg/g (p < 0.001), confirming that this has an increased level of bioavailable fluoride compared with the conventional dentifrice. The high-fluoride dentifrice increases the concentration of salivary fluoride, which may explain its greater anticaries effect. However, it poses a potential risk of causing dental fluorosis and so should not be used by children.
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4.
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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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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Determination of the renal concentration capacity following intravenous administration of dDAVP in healthy humans.
Faerch, M, Schroeder, MK, Mahler, BT, Christensen, JH, Kamperis, K, Rittig, S
Scandinavian journal of clinical and laboratory investigation. 2018;(1-2):114-119
Abstract
The synthetic AVP analogue 1-desamino-8-d-arginine-vasopressin (dDAVP) is used for treatment of polyuric disorders. Lack of commercially available assays limits the usefulness of dDAVP as a diagnostic tool in the assessment of renal concentrating capacity. We aimed to develop a specific radioimmunoassay (RIA) for determination of plasma dDAVP (pdDAVP) in order to investigate the relationship between pdDAVP levels and urine osmolality (Uosm). Further, we aimed to determine the onset, duration, and maximum concentrating capacity following intravenous (i.v.) bolus dDAVP injection. The dDAVP assay was based on a well-established RIA for measurements of AVP. Fourteen healthy subjects (aged 15-18 years) participated. Blood and urine samples were collected prior to and after i.v. bolus of 0.03 µg/kg dDAVP. Diuresis and Uosm was measured for nine hours following dDAVP administration. PdDAVP and Uosm were analyzed.We established a specific RIA for the measurement of pdDAVP. All subjects reached maximal pdDAVP concentration (Cmax) 30 minutes following infusion, and a rise in Uosm after 60 minutes. Maximal Uosm varied between subjects, with no direct correlation to the achieved pdDAVP levels. We found no significant intra-individual variation between two dDAVP infusions and the effect was reproducible in terms of Cmax and maximal Uosm. We characterized the relationship between pdDAVP and Uosm after dDAVP bolus injection in healthy adolescents using our dDAVP assay. Maximal Uosm achieved correlated with the baseline Uosm levels and seemed unrelated to achieved pdDAVP levels. The urine concentrating response was maintained at least eight hours.
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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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Pharmacokinetics of Tecarfarin and Warfarin in Patients with Severe Chronic Kidney Disease.
Albrecht, D, Turakhia, MP, Ries, D, Marbury, T, Smith, W, Dillon, D, Milner, PG, Midei, MG
Thrombosis and haemostasis. 2017;(11):2026-2033
Abstract
Chronic kidney disease (CKD) complicates warfarin anticoagulation partially through its effect on CYP2C9 activity. Tecarfarin, a novel vitamin K antagonist, is not metabolized by CYP2C9. To evaluate the effect of CKD on their metabolism, we measured PK parameters of warfarin and tecarfarin in subjects with and without CKD. CKD subjects with estimated glomerular filtration rate < 30 mL/min not on dialysis (n = 13) were matched to healthy volunteers (HVs) (n = 10). Each subject was randomized to either warfarin 10 mg or tecarfarin 30 mg and was later crossed over to the other drug. PK parameters were measured following each drug. Mean plasma concentrations of (S)-warfarin and (R,S)-warfarin were higher (44 and 27%, respectively) in the subjects with CKD than in the healthy subjects. Both of these values fell outside of the 90% confidence interval of equivalence. For tecarfarin, the difference was less than 15% higher. Elimination half-life (t1/2) increased by 20% for (S)-warfarin and by 8% for (R,S)-warfarin and decreased by 8% for tecarfarin. The mean plasma concentration for tecarfarin's inactive metabolite ATI-5900 increased by approximately eightfold. CKD increased the effect of CYP2C9 genetic variation on (S)-warfarin and (R,S)-warfarin metabolism. Tecarfarin exposure was similar between the HVs and the CKD subjects regardless of CYP2C9 genotype. There were neither serious adverse events (SAEs) nor treatment-emergent adverse events (TEAEs) for any subject in the study. CKD inhibits metabolism of (S)-warfarin and (R,S)-warfarin, but not tecarfarin. The safety of repeated dosing of tecarfarin in CKD patients remains unknown. However, if the PK findings of this single-dose study are present with repeated dosing, tecarfarin may lead to dosing that is more predictable than warfarin in CKD patients who require anticoagulation therapy.