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A Model-Based Approach to Assess Unstable Creatinine Clearance in Critically Ill Patients.
Ullah, S, Zoller, M, Jaehde, U, Huseyn-Zada, M, Weig, T, Fuhr, U, Arshad, U, Zander, J, Taubert, M
Clinical pharmacology and therapeutics. 2021;(5):1240-1249
Abstract
Creatinine clearance is an important tool to describe the renal elimination of drugs in pharmacokinetic (PK) evaluations and clinical practice. In critically ill patients, unstable kidney function invalidates the steady-state assumption underlying equations, such as Cockcroft-Gault. Although measured creatinine clearance (mCrCL) is often used in nonsteady-state situations, it assumes that observed data are error-free, neglecting frequently occurring errors in urine collection. In contrast, compartmental nonlinear mixed effects models of creatinine allow to describe dynamic changes in kidney function while explicitly accounting for a residual error associated with observations. Based on 530 serum and 373 urine creatinine observations from 138 critically ill patients, a one-compartment creatinine model with zero-order creatinine generation rate (CGR) and first-order CrCL was evaluated. An autoregressive approach for interoccasion variability provided a distinct model improvement compared to a classical approach (Δ Akaike information criterion (AIC) -49.0). Fat-free mass, plasma urea concentration, age, and liver transplantation were significantly related to CrCL, whereas weight and sex were linked to CGR. The model-based CrCL estimates were superior to standard approaches to estimate CrCL (or glomerular filtration rate) including Cockcroft-Gault, mCrCL, four-variable modification of diet in renal disease (MDRD), six-variable MDRD, and chronic kidney disease epidemiology collaboration as a covariate to describe cefepime and meropenem PKs in terms of objective function value. In conclusion, a dynamic model of creatinine kinetics provides the means to estimate actual CrCL despite dynamic changes in kidney function, and it can easily be incorporated into population PK evaluations.
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Luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, preserves renal function irrespective of acute changes in the estimated glomerular filtration rate in Japanese patients with type 2 diabetes.
Kohagura, K, Yamasaki, H, Takano, H, Ohya, Y, Seino, Y
Hypertension research : official journal of the Japanese Society of Hypertension. 2020;(9):876-883
Abstract
Acute decline in estimated glomerular filtration rate (eGFR), a typical finding after initiating sodium-glucose cotransporter 2 (SGLT2) inhibitors, is associated with maintaining renal function in type 2 diabetes. However, the relationship between the magnitude of acute decline in eGFR and the course of eGFR thereafter is not known. A pooled analysis of four 52-week phase III trials of luseogliflozin 2.5 mg daily (or up to 5 mg daily) in Japanese patients with type 2 diabetes was conducted and stratified according to the tertile of magnitude of acute change in eGFR during the 2 weeks after initiation. The mean age, glycated hemoglobin, eGFR, and urinary albumin were 60 years, 7.8%, 79.6 mL/min/1.73 m2, and 62.7 mg/g Cr, respectively. Acute change in eGFR varied widely between patients (N = 941; mean, -2.3; min, -35.5; max, 27.6). Patients with greater acute decline in eGFR, characterized by higher baseline eGFR and increased diuretic use, showed rapid recovery and maintenance of eGFR thereafter. Higher eGFR, longer duration of diabetes, and higher body mass index and diuretic use were associated with greater acute decline in eGFR. The course of eGFR from 12 to 52 weeks was maintained regardless of acute changes. Although acute changes in eGFR varied widely among patients with type 2 diabetes, the course of eGFR thereafter was stable regardless of the degree of acute changes.
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Serum creatinine and estimated glomerular filtration rates in HIV positive and negative adults in Ethiopia.
Yilma, D, Abdissa, A, Kæstel, P, Tesfaye, M, Olsen, MF, Girma, T, Ritz, C, Friis, H, Andersen, ÅB, Kirk, O
PloS one. 2019;(2):e0211630
Abstract
BACKGROUND Glomerular filtration rate estimating equations using serum creatinine are not validated in most African settings. We compared serum creatinine and estimated glomerular filtration rate (eGFR) in HIV positive and negative adults and assessed the performance of eGFR equations ((Cockcroft and Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)) compared to 24-hour creatinine clearance in HIV positive adults. METHODS Data were collected on demographic, anthropometric, body composition, clinical parameters and serum creatinine in HIV positive and negative adults. 24-hour urine was collected from some of the HIV positive adults who volunteered. Bias was calculated as mean difference between 24-hr creatinine clearance and eGFR (eGFR- 24 hour creatinine clearance) and the accuracy of each eGFR equation was calculated as the percentage of estimates within 30% of creatinine clearance. RESULTS A total of 340 HIV positive and 100 HIV negative adults were included in this study. Creatinine clearance was determined for 46 of HIV positive adults. Serum creatinine increased with increasing age, weight, height, body surface area, fat free mass and grip strength in both HIV positive and negative adults (P<0.05). No difference was observed in eGFR between HIV positive and HIV negative adults. For all eGFR equations, the correlation between eGFR and 24-hr creatinine clearance was 0.45-0.53 and the accuracy within 30% of 24-hr creatinine clearance was 24-46%. Removing ethnic coefficient reduced the bias and improved accuracy of the CKD-EPI and the MDRD estimates. CONCLUSION Ethiopian HIV positive adults in the present study had good kidney function at the initiation of antiretroviral treatment. However, all eGFR equations overestimated 24-hr creatinine clearance in the study population. Creatinine based eGFR equations that accounts for low muscle mass and body surface area are needed.
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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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Assessment of pN-GAL as a marker of renal function in elite cyclists during professional competitions.
Andreazzoli, A, Fossati, C, Spaccamiglio, A, Salvo, R, Quaranta, F, Minganti, C, Di Luigi, L, Borrione, P
Journal of biological regulators and homeostatic agents. 2017;(3):829-835
Abstract
Glomerular filtration rate (GFR) has been shown to be lower than physiological values during exercise with a strong negative correlation with exercise intensity. Among new markers of renal function, neutrophil gelatinase-associated lipocalin (NGAL) seems to be very promising. It is an early, sensitive and specific marker of acute kidney injury (AKI) with two isoforms: plasma NGAL (pNGAL) and urinary NGAL (uNGAL). The aim of the present study was to assess acute variations in NGAL plasma levels after performing high endurance physical exercise in a group of professional cyclists during the two major European professional cycling competitions (Giro D’Italia and Tour de France). Eighteen professional cyclistis were recruited for the study. A blood sample was collected during rest (after 8 hours fasting) and immediately after the competition (mountain stages) in order to assess the effect of very intense exercise on kidney function by measuring the variations of pNGAL. We also assessed plasma levels of creatinine, creatine-kinase (CK), LDH, transaminases and electrolytes. The results showed that Creatinine, CK and electrolytes levels remained almost stable between rest and post-competition. The levels of transaminases and NGAL showed a mild increase between rest and post-competition, with a significant difference between the two values only for transaminases (p=0.005). However, post-competition values of all investigated variables remained within the physiological range. The results of the present study suggest that even if NGAL values mildly rose after competition, no kidney injury occurred in these highly trained athletes during mountain stages of professional competitions. Other studies in literature confirmed that high endurance physical exercise seems not to cause renal injury in elite athletes. This is probably due to adaptive mechanisms of renal function and to the adaptation to physical stress gained with training.
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Impact of achieved systolic blood pressure on renal function in hypertensive patients.
Okin, PM, Kjeldsen, SE, Devereux, RB
European heart journal. Quality of care & clinical outcomes. 2016;(4):271-276
Abstract
AIMS: There is strong evidence for the association of high blood pressure (BP) with depressed renal function. Although high BP at baseline is associated with greater progression of chronic kidney disease (CKD), randomized trials in CKD patients have found no significant relationship between more intensive BP control and glomerular filtration rate (GFR) decline. However, the relationship of GFR and change in GFR over time to lower achieved systolic BP (SBP) in hypertensive patients undergoing treatment is unclear. METHODS AND RESULTS Baseline estimated GFR (eGFR) and change in eGFR during follow-up were examined in relation to average on-treatment SBP in 8778 hypertensive patients with ECG left ventricular hypertrophy (LVH) randomly assigned to losartan- or atenolol-based treatment. GFR was estimated using the Modification of Diet in Renal Disease study equation. Patients with average on-treatment SBP ≤130 mmHg (lowest quintile at last measurement) and average SBP between 131 and 141 mmHg were compared with patients with average SBP ≥142 mmHg (median SBP at last measurement). Patients with an average on-treatment SBP ≤130 mmHg had significantly lower baseline eGFR than those with average SBP between 131 and 141 or average SBP ≥142 mmHg (65.5 ± 14.3 vs. 69.3 ± 14.3 vs. 69.0 ± 14.5 mL/min/1.73 m2, P < 0.001 using analysis of covariance adjusting for age, sex, race, randomized treatment, prior antihypertensive treatment, history of diabetes, myocardial infarction, ischaemic heart disease or heart failure, smoking status, baseline serum glucose, total and HDL cholesterol, albuminuria, and baseline LVH by Cornell product and Sokolow-Lyon voltage). However, the decrease in eGFR between baseline and Year 4 was significantly lower among patients with average SBP ≤130 mmHg (-6.3 ± 10.3 vs. -7.9 ± 11.1 vs. -9.2 ± 10.6 mL/min/1.73 m2, P = 0.001 when adjusting for the same variables and for change in Cornell product and Sokolow-Lyon voltage between baseline and Year 4). These differences in eGFR change persisted even after adjusting for baseline eGFR, and there were no significant interactions with randomized treatment, sex, race, or baseline presence of proteinuria. CONCLUSION Lower average on-treatment SBP (≤130 mmHg) was associated with a lower baseline eGFR but with a slower reduction in eGFR during 4-year follow-up in hypertensive patients with ECG LVH, independent of other possible risk factors for decreased GFR. Further study is necessary to determine whether randomized treatment to lower SBP goals is more protective of renal function than treatment to standard SBP goals. CLINICAL TRIAL REGISTRATION http://clinicaltrials.gov/ct/show/NCT00338260?order=1; unique identifier: NCT00338260.
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Renal hemodynamic effects of the HMG-CoA reductase inhibitors in autosomal dominant polycystic kidney disease.
Zand, L, Torres, VE, Larson, TS, King, BF, Sethi, S, Bergstralh, EJ, Angioi, A, Fervenza, FC
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2016;(8):1290-5
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BACKGROUND To determine the effect of statins on renal hemodynamics in normal volunteers and those with autosomal dominant polycystic kidney disease either with mild or moderate renal dysfunction. METHODS Thirty-two study subjects were enrolled in this study: 11 normal volunteers, 11 study subjects with autosomal dominant polycystic kidney disease (ADPKD) and mild kidney disease and 10 study subjects with ADPKD and moderate kidney disease. Subjects in each group received simvastatin 40 mg once daily for a period of 4 weeks. Renal blood flow was measured based on para-amino-hippurate (PAH) clearance and with the use of a magnetic resonance (MR) scanner at the beginning and following 4 weeks of therapy with statins. RESULTS At the end of the study, except for the lipid profile, which was significantly lower in all groups, other laboratory results showed no change. Four weeks of therapy with simvastatin resulted in no change in serum creatinine, 24-h urinary protein, sodium, iothalamate clearance, PAH clearance or renal blood flow as measured by MRI or based on PAH clearance. CONCLUSIONS Four weeks of therapy with simvastatin did not change renal blood flow in the study subjects with ADPKD with mild-to-moderate renal dysfunction or in healthy volunteers. CLINICAL TRIAL REGISTRATION NUMBER NCT02511418.
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Prediction of the effect of atrasentan on renal and heart failure outcomes based on short-term changes in multiple risk markers.
Schievink, B, de Zeeuw, D, Smink, PA, Andress, D, Brennan, JJ, Coll, B, Correa-Rotter, R, Hou, FF, Kohan, D, Kitzman, DW, et al
European journal of preventive cardiology. 2016;(7):758-68
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BACKGROUND A recent phase II clinical trial (Reducing Residual Albuminuria in Subjects with Diabetes and Nephropathy with AtRasentan trial and an identical trial in Japan (RADAR/JAPAN)) showed that the endothelin A receptor antagonist atrasentan lowers albuminuria, blood pressure, cholesterol, hemoglobin, and increases body weight in patients with type 2 diabetes and nephropathy. We previously developed an algorithm, the Parameter Response Efficacy (PRE) score, which translates short-term drug effects into predictions of long-term effects on clinical outcomes. DESIGN We used the PRE score on data from the RADAR/JAPAN study to predict the effect of atrasentan on renal and heart failure outcomes. METHODS We performed a post-hoc analysis of the RADAR/JAPAN randomized clinical trials in which 211 patients with type-2 diabetes and nephropathy were randomly assigned to atrasentan 0.75 mg/day, 1.25 mg/day, or placebo. A PRE score was developed in a background set of completed clinical trials using multivariate Cox models. The score was applied to baseline and week-12 risk marker levels of RADAR/JAPAN participants, to predict atrasentan effects on clinical outcomes. Outcomes were defined as doubling serum creatinine or end-stage renal disease and hospitalization for heart failure. RESULTS The PRE score predicted renal risk changes of -23% and -30% for atrasentan 0.75 and 1.25 mg/day, respectively. PRE scores also predicted a small non-significant increase in heart failure risk for atrasentan 0.75 and 1.25 mg/day (+2% vs. +7%). Selecting patients with >30% albuminuria reduction from baseline (responders) improved renal outcome to almost 50% risk reduction, whereas non-responders showed no renal benefit. CONCLUSIONS Based on the RADAR/JAPAN study, with short-term changes in risk markers, atrasentan is expected to decrease renal risk without increased risk of heart failure. Within this population albuminuria responders appear to contribute to the predicted improvements, whereas non-responders showed no benefit. The ongoing hard outcome trial (SONAR) in type 2 diabetic patients with >30% albuminuria reduction to atrasentan will allow us to assess the validity of these predictions.
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Telaprevir enhances ribavirin-induced anaemia through renal function impairment.
Cotte, L, Barrail-Tran, A, Vincent, C, Valantin, MA, Fournier, I, Lacombe, K, Chevaliez, S, Aboulker, JP, Taburet, AM, Molina, JM, et al
Antiviral therapy. 2015;(5):479-86
Abstract
BACKGROUND Alterations in renal function have been described with telaprevir (TVR). We examined the relationship between ribavirin (RBV) trough concentration (C), estimated glomerular filtration rate (eGFR) and severe anaemia, before and after TVR introduction in HIV-HCV-coinfected patients included in ANRS HC26 TelapreVIH study. METHODS 69 HIV-HCV genotype-1 coinfected patients received 4 weeks of pegylated interferon (PEG-IFN)-α2a/RBV, followed by 12 weeks of TVR/PEG-IFN/RBV, then 32 to 56 weeks of PEG-IFN/RBV. RBV C was determined at week (W)4, W8 and W20/24. eGFR was estimated by the Modification of the Diet in Renal Disease (MDRD) equation. Severe anaemia was defined as haemoglobin <70 g/l, RBV dose reduction, prescription of erythropoietin or blood transfusion. RESULTS 67 patients were analysed. eGFR remained normal between baseline (97.9 ml/min) and W4 (103.4 ml/min), declined to 86.3 ml/min at W8 (P<0.0001), stabilized until W16 and increased back to baseline level at W20 (98.4 ml/min). RBV C increased from 1.88 mg/l at W4 to 2.88 mg/l at W8 (P<0.0001), then decreased to 2.73 mg/l at week 20/24 (P=0.015). An inverse correlation was observed between W8 eGFR and W8 RBV C (r2=0.429; P=0.0005). RBV C≥3 mg/l was observed in 12% of patients at W4, 45% at W8 (P<0.0001) and 38% at W20/24 (P=0.0005). Severe anaemia was observed in 23.9% of patients at W4 and 45.3% at W8. RBV C≥3 mg/l at W8 (OR 7.7 [95% CI 2.2, 27.4]) and baseline haemoglobin <150 g/l (OR 6.4 [1.7, 23.8]) were independently associated with W8 severe anaemia. CONCLUSIONS Association of TVR to PEG-IFN/RBV was associated with a decrease in eGFR and increase in RBV C, leading to severe anaemia in 45% of patients.
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Polymorphisms of the UCP2 Gene Are Associated with Glomerular Filtration Rate in Type 2 Diabetic Patients and with Decreased UCP2 Gene Expression in Human Kidney.
de Souza, BM, Michels, M, Sortica, DA, Bouças, AP, Rheinheimer, J, Buffon, MP, Bauer, AC, Canani, LH, Crispim, D
PloS one. 2015;(7):e0132938
Abstract
INTRODUCTION Uncoupling protein 2 (UCP2) reduces production of reactive oxygen species (ROS) by mitochondria. ROS overproduction is one of the major contributors to the pathogenesis of chronic diabetic complications, such as diabetic kidney disease (DKD). Thus, deleterious polymorphisms in the UCP2 gene are candidate risk factors for DKD. In this study, we investigated whether UCP2 -866G/A, Ala55Val and Ins/Del polymorphisms were associated with DKD in patients with type 2 diabetes mellitus (T2DM), and whether they had an effect on UCP2 gene expression in human kidney tissue biopsies. MATERIALS AND METHODS In a case-control study, frequencies of the UCP2 -866G/A, Ala55Val and Ins/Del polymorphisms as well as frequencies of the haplotypes constituted by them were analyzed in 287 T2DM patients with DKD and 281 T2DM patients without this complication. In a cross-sectional study, UCP2 gene expression was evaluated in 42 kidney biopsy samples stratified according to the presence of the UCP2 mutated -866A/55Val/Ins haplotype. RESULTS In the T2DM group, multivariate logistic regression analysis showed that the -866A/55Val/Ins haplotype was an independent risk factor for DKD (OR = 2.136, 95% CI 1.036-4.404), although neither genotype nor allele frequencies of the individual polymorphisms differed between case and control groups. Interestingly, T2DM patients carrying the mutated haplotype showed decreased estimated glomerular filtration rate (eGFR) when compared to subjects with the reference haplotype (adjusted P= 0.035). In kidney biopsy samples, UCP2 expression was significantly decreased in UCP2 mutated haplotype carriers when compared to kidneys from patients with the reference haplotype (0.32 ± 1.20 vs. 1.85 ± 1.16 n fold change; adjusted P< 0.000001). DISCUSSION Data reported here suggest that the UCP2 -866A/55Val/Ins haplotype is associated with an increased risk for DKD and with a lower eGFR in T2DM patients. Furthermore, this mutated haplotype was associated with decreased UCP2 gene expression in human kidneys.