Creatinine Clearance Research Articles

Pharmacokinetics of Piperacillin-Tazobactam in Critically Ill Patients with Open Abdomen and Vacuum-Assisted Wound Closure: Dosing Considerations Using Monte Carlo Simulation.

Open abdomen with vacuum-assisted wound closure therapy (OA/VAC) is frequently used in critically ill patients although the impact of OA/VAC on antibiotics pharmacokinetics (PK) remains unknown. We thus aimed to characterize the PK of piperacillin-tazobactam (PTZ) in critically ill patients with OA/VAC and assess the optimal dosing regimens based on pharmacodynamics (PD) target attainment. Over a 15-month study period, 45 patients with OA/VAC treated with PTZ administered continuously and adapted to 24 h creatinine clearance (CLCR) underwent measurements of free concentrations in their plasma, urine, VAC exudate, and peritoneal fluid. Population PK modeling was performed considering the effect of covariates, and Monte Carlo simulations were employed to determine the probability of target attainment (PTA) for the PK/PD targets (100% fT > 16 mg/L) in the plasma and at the peritoneal site at steady state. Piperacillin concentrations were described using a two-compartment model, with age and total body weight as significant covariates for central volume of distribution (V1) and estimated renal function for clearance (CL). Tazobactam concentrations were described using a two-compartment model with estimated renal function as a significant covariate. The central volume of distributions V1 of piperacillin and tazobactam were 21.2 and 23.2 L, respectively. The VAC-induced peritoneal clearance was negligible compared to renal clearance. Most patients achieved the desirable PK/PD target when using a CLCR-pondered PTZ dosing regimen from 12 g/1.5 g/day to 20 g/2.5 g/day. Despite a wide inter-individual variability, the influence of OA/VAC on piperacillin and tazobactam PK parameters is not straightforward. The use of a CLCR-pondered PTZ dosing regimen from 12 g/1.5 g/day to 20 g/2.5 g/day is needed to reach a PTA > 85%.

Vitamin B1 and calcitriol enhance glibenclamide suppression of diabetic nephropathy: Role of HMGB1/TLR4/NF-κB/TNF-α/Nrf2/α-SMA trajectories

Glibenclamide is one of the most prescribed insulin secretagogues in diabetes due to its low cost, but its efficacy on suppressing diabetic complications is limited. Here, we examine whether addition of either vitamin B1 or calcitriol to glibenclamide could produce more suppression of diabetic nephropathy. Type 2 diabetes was induced by high fructose (10 % in drinking water), high salt (3 % in diet), and high fat diet (25 % in diet) for 3 weeks, followed by single dose of STZ (40 mg/kg, i.p.). Diabetic rats were treated with either glibenclamide (0.6 mg/kg), vitamin B1 (70 mg/kg), glibenclamide/vitamin B1, calcitriol (0.1 μg/kg), or glibenclamide/calcitriol. Addition of either vitamin B1 or calcitriol to glibenclamide therapy enabled more suppression of diabetic nephropathy development as evidenced by more preserved creatinine clearance and less renal damage scores. Combination therapy resulted in mild enhancement in the effect of glibenclamide on glucose tolerance without affecting the area under the curve. Combination therapy was associated with more suppression of inflammatory cascades as evidenced by reducing the expression of high mobility group box-1 (HMGB1), toll-like receptor-4 (TLR4), nuclear factor-kappa B (NF-κB), and tumor necrosis factor-α (TNF-α). In addition, combination therapy enhanced the antioxidant mechanisms as evidenced by increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione content and reducing malondialdehyde and nitric oxide levels. Furthermore, combination therapy provided more suppression of fibrotic pathways as appear from reducing collagen deposition and the expression of α- smooth muscle actin (α-SMA). In conclusion, addition of vitamin B1 or calcitriol to glibenclamide therapy can enhance the therapeutic efficiency of glibenclamide in suppressing diabetic nephropathy progression to the same extend, the protective effect is mediated through modulating HMGB1/TLR4/NF-κB/TNF-α/Nrf2/α-SMA trajectories.

Endovascular Treatment for Transplant Renal Artery Stenosis: 10 Years' Experience from a Single Center.

Transplant renal artery stenosis (TRAS) is a common post-renal transplant complication. Although endovascular treatment is widely used to treat TRAS, previous research has been limited by small sample sizes. This article aimed to present the clinical outcomes of endovascular treatment for TRAS in a large sample. Between January 2010 and December 2019, this study included patients with TRAS who were admitted to our center. All patients' clinical symptoms, comorbidities, imaging data, treatment, and follow-up results were reviewed retrospectively. Seventy two patients participated in this study. The median time between renal transplantation and TRAS was 5.25 months. Out of 72 patients, 55 (76.4%) received balloon dilatation in conjunction with stent deployment, 10 (13.9%) received drug-coated balloon dilatation alone, and 7 (9.7%) received balloon dilatation alone. The median follow-up period was 27 months. Primary patency rates were 100%, 81.8%, 74.5%, 64.6%, and 61.8% at 1, 3, 6, 12, and 24 months. A total of 23 patients were found to have restenosis during follow-up, with 6 (26.1%) requiring reintervention and none remaining restenosis after the second treatment. In the subgroup analysis of the three types of stenosis, patients with transplant renal stenosis at the anastomosis had a significantly higher rate of primary patency. Between endovascular treatments, the primary patency rate, postoperative creatinine clearance, and mean systolic blood pressure did not differ significantly. Endovascular treatment resulted in favorable short-term patency as well as effective relief of renal dysfunction and renal hypertension in TRAS patients.

SS-31 protects diabetic nephropathy progression: A systematic review of in vivo and in vitro studies

Context: Diabetic nephropathy is the leading cause of end-stage renal disease and also death in the world. Administration of Szeto-Schiller-31 (SS-31) as a potential therapeutic candidate that can decrease the renal function damage progressivity in diabetes needs to be comprehensively analyzed. Aims: To assess the protective effects of SS31 against the progressivity of diabetic nephropathy. Methods: This systematic review follows PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines 2020. Searches of databases (Pubmed, Science Direct, Scopus, ProQuest, and Springer) were done on 17 September 2023 in order to find articles related to the animal diabetic model and SS-31 treatment. Manual searches from medRxiv were also conducted to obtain additional evidence. Renal function, histopathology analysis, reactive oxygen species in vivo, and in vitro analysis were described. Results: There were six in vivo studies, each of which discussed the renal function, histopathology, and reactive oxygen species (ROS), and four in vitro studies that discussed ROS. The available data suggested that SS-31 improves kidney function by lowering urinary albumin excretion, proteinuria, serum creatinine, creatinine clearance, and BUN, supported by histopathological improvements. In addition, SS-31 also has the effect of lowering 8-hydroxy-2-deoxyguanosine (8-OHdG) level, malondialdehyde (MDA) level, and nicotinamide adenine dinucleotide phosphate (NADPH) expression. Conclusions: SS31 had a renoprotective effect that could prevent the worsening of renal function in diabetic mice. In addition, the results of histopathology and ROS analysis also support the positive results of SS-31 treatment. Further studies are required to confirm its findings.

Elevated Cystatin C Predicts Higher Mortality in Chronic Heart Failure Independently of Renal Function.

Cystatin C (CysC) is a known prognostic marker in cardiovascular diseases and its role in acute heart failure (HF) has been documented. We prospectively recruited HF patients followed in a HF clinic. Inclusion criteria: HF diagnosed ≥6 months, optimized evidence-based therapy, and ejection fraction <40% (Heart Failure with reduced ejection fraction). Exclusion criteria: renal replacement therapy and hospitalizations or therapeutic adjustments in the previous 2 months. A venous blood sample and 24-hour urine were collected. Follow-up: 5 years; endpoint: all-cause mortality. CysC was measured and creatinine clearance (CrCl) was calculated using 24-hour urine creatinine excretion. A Receiver operating characteristic curve was used to assess association of CysC with 5-year mortality. The prognostic role of CysC was determined using Cox-regression analysis. The multivariate model included CrCl (24-hour urine). We evaluated 215 chronic stable Heart Failure with reduced ejection fraction patients. Mean age was 68 years, 72.1% were male. Median CysC = 1.15 mg/L, creatinine = 1.20 mg/dL, and CrCl = 63.6 mL/min. During follow-up, 103 (47.9%) patients died. The area under the curve for CysC in predicting mortality was 0.77 (0.70-0.83). Best cut-off value for death prediction = 1.00 mg/L with a sensitivity = 83.5%, specificity = 56.2%, positive predictive value = 63.7%, and negative predictive value = 78.7%. Multivariate-adjusted (age-, B-type natriuretic peptide-, evidence-based therapy, New York Heart Association class, and CrCl) 5-year mortality Hazard ratio = 2.40 (95% Confidence interval, 1.25-4.61), P value = 0.008 when CysC ≥1.00 mg/L. Patients with CysC <1.00 mg/L have almost 80% probability of being alive at 5 years; If CysC ≥1.00 mg/L, there is almost 2.5-fold higher death risk independently of B-type natriuretic peptide and CrCl.

Comparison of Angiographic Success and Clinical Outcomes Based on Different Percutaneous Coronary Intervention Techniques.

Introduction Primary percutaneous coronary intervention (PCI) is the standard treatment for patients with ST-segment elevation myocardial infarction (STEMI). Various PCI techniques exist, including balloon angioplasty, bare-metal stents (BMS), drug-eluting stents (DES), thrombus aspiration, direct stenting, rotational atherectomy (Rotablation), and cutting balloon angioplasty. Specific approaches for patients with STEMI and multivessel coronary artery disease may involve: 1) culprit vessel-only (CVO) primary PCI, 2) primary PCI followed by multivessel intervention of additional noninfarct lesions at the same procedure, or 3) CVO primary PCI followed by staged PCI of noninfarct lesions later during the index hospitalization or after discharge. However, their impact on angiographic success and clinical outcomes remains unclear. Methodology A retrospective study (n=90) evaluated the effectiveness of various PCI techniques during primary PCI. Data included demographics, clinical profiles, PCI strategies, and outcomes. Techniques such as thrombus aspiration, direct stenting, balloon angioplasty, and DES deployment were assessed. Descriptive statistics and chi-square tests were employed, with logistic regression for adjustment. Results The comparison of angiographic success and clinical outcomes based on different PCI strategies during primary PCI (n=90) revealed distinct differences. Successful procedures were associated with lower mean values for age (56.00 vs. 60.20), hypertension (165.50 vs. 170.30), weight (74.00 vs. 77.50), BMI, 26.80 vs. 28.70, KILLIP class (1.30 vs. 1.50), ejection fraction (45.80 vs. 47.90), creatinine (0.95 vs. 1.00), creatinine clearance (83.50 vs. 86.70), pulse rate (84.00 vs. 87.50), oxygen saturation (95.80 vs. 94.50), and blood sugar (170.00 vs. 182.00). Risk factors like hypertension (mean = 1.40 vs. 1.60), diabetes (mean = 1.60 vs. 1.70), and hyperlipidemia (mean = 1.85 vs. 1.95) also showed differences between successful and failed procedures. Significant variations were observed across PCI strategies for outcomes including angina within 30 days (Chi square = 18.75, p < 0.001), cerebrovascular accident (CVA, Chi square = 15.42, p = 0.001), acute left ventricular failure (LVF, Chi square = 12.67, p = 0.005), and cardiogenic shock (Chi square = 8.93, p = 0.029). Conclusion Patient demographics and clinical profiles influence PCI success. Techniques such as thrombus aspiration, direct stenting, balloon angioplasty, and DEShave varied impacts on clinical outcomes. While conventional balloon angioplasty remains a viable option, newer techniques such as DES and mechanical thrombectomy demonstrate superior angiographic success rates and improved clinical outcomes, particularly in complex lesion subsets. However, the selection of PCI technique should be guided by careful consideration of patient-specific factors, lesion characteristics, and procedural feasibility.

O39 IMPACT OF UROMODULIN CONCENTRATION ON RENAL AND HAEMODYNAMIC PARAMETERS IN A BLACK AFRICAN COMMUNITY WITH A HIGH PREVALENCE OF HYPERTENSION

Background and Objective: The burden of hypertension (HTN) and related comorbidities disproportionately affects developing countries like South Africa, particularly in urban populations of African ancestry. This demographic exhibits a volume-dependent form of HTN that is resistant to antihypertensive drugs that target the renin-angiotensin-aldosterone system. Renal fluid retention or abnormalities may cause HTN in this group, thus the need to investigate various nephron components for a better understanding. Uromodulin is a potential biomarker for renal function and tubular reserve. However, the relationship with renal function, haemodynamic parameters and HTN in a Black African population is unknown. Therefore, the aim of this study was to explore the relationship between urinary uromodulin concentration and renal as well as haemodynamic parameters in a Black African community with a high prevalence of volume-dependent HTN. Methods: Systemic haemodynamics (central pressures [SphygmoCor] and echocardiographic aortic velocity and diameter measurements in the outflow tract), urinary uromodulin concentrations (ELISA assay) and renal function (creatinine clearance from 24-hour urine collections [n=370]) were determined in a Black African community (n=397). Results: No relationships between urinary uromodulin concentrations and age, body mass index, blood pressure or hypertension were noted. However, urinary uromodulin concentrations were higher in females than males, even after adjusting for several confounders (p=0.0007). Although urinary uromodulin concentrations were unrelated to renal function, an inverse relationship with stroke volume (SV) was observed (p=0.0023). The inverse relationship between SV and urinary uromodulin concentration was independent of confounders and present in hypertensives (p=0.007) but not normotensives (p=0.43). The hypertensives were noted to have a higher SV than the normotensives (p=0.047). Conclusion: In a Black African community sample with a high prevalence of volume-dependent primary hypertension, urinary uromodulin was inversely related to SV, particularly in participants with hypertension. These data suggest the need to investigate the mechanisms linking urinary uromodulin to haemodynamic parameters to identify novel pathways to target for better treatment strategies in hypertension.

Abstract P131: Effect of uncontrolled systolic blood pressure in hypertensive patients as a risk factor for CIN after coronary angiography with preventative management of CIN : single center prospective study

Background: Contrast induced nephropathy(CIN) is associated with poor outcomes like dialysis and prolonged hospitalization and risk of death. Clinical factor for CIN include advanced age, diabetes (DM), female, heart failure(HF) and hypertension(HTN). Many prophylaxis strategies for CIN(normal saline hydration, N-acetylcysteine, NAHCO3) had been studied and their preventive effects had been known to be no difference. Purpose: We tried to evaluate the effects of uncontrolled systolic blood pressure(defined as SBP&gt;160mmHg) in hypertensive patients as a risk factor for CIN after coronary angiography(CAG) with various preventative management of CIN (normal saline hydration, N-acetylcysteine, NAHCO3). Methods: This study included 41patients who performed CAG combined with various preventative management of CIN in single center. All patients were evaluated with serum creatinine(SCr), creatinine clearance(CrCl) before and after coronary angiography at day0, day1, day2 and day30. Definition of CIN include; SCr increase of ≥0.5 mg/dL, a SCr increase ≥25%, an CrCl decrease of ≥25%, or the composite, occurring 48 to 72 hours after contrast exposure. We also analyzed preexisting renal insufficiency(GFR&lt;60ml/min), DM and HTN, age, sex, anemia, contrast volume and HF which are known risk factors for CIN. Results: 11 of 41 patients developed CIN. There was no statistical differences between the two groups in the aspect of baseline Cr, age, sex, body weight, contrast volume and the prevalence of known risk factor for CIN (DM, HTN, HF and preexisting renal failure). Mean baseline SBP in the CIN group was higher than non-CIN group(166.3±31.9 vs142.4±25.7, P-value=0.018). Among 23 patients with HTN, 11 patients (47.8%) had uncontrolled SBP. The multivariable logistic regression analysis showed that an uncontrolled SBP (odds ratio [OR] 12.63, 95% confidence interval [CI] 1.83-87.07) was the independent risk factor for CIN. Conclusions: CIN associate with variety of short-term and long-term complication after CAG. Hypertension is well known as one of the risk factors for CIN. Even if appropriate preventative management of CIN are taken before and after CAG, uncontrolled SBP in hypertensive patients could increase the risk of CIN.

Abstract P144: Estrogen Worsens Kidney Function in Hypertensive Menopausal Rats

Introduction: Before menopause, women generally have lower rates of hypertension and cardiovascular events compared with men. After menopause, women lose significant cardiovascular and renal protection. Estrogen's effect on kidney function is controversial, with some studies showing protection and others, including ours, indicating long-term estrogen exposure causes renal damage. The relationship between estrogen, hypertension, and kidney function is still not fully understood. Aim: Our aim was to investigate the interaction between hypertension and menopause on kidney function and determine whether the timing of disease initiation, pre- or post-menopause, influences these effects. Methods: Female Long-Evans rats were ovariectomized at 46 weeks of age to simulate menopause and treated with estradiol (E2) or vehicle. Some groups were infused with angiotensin II (Ang; 700ng/kg/min), either 4 weeks before or at the time of ovariectomy. Blood pressure (BP), proteinuria, creatinine clearance, osmolality, glomerular (GLOM) area, GLOM collagen deposition, and GPER and ERα receptor by droplet digital PCR were assessed by two-way ANOVA. Results: BP was higher with Ang (P=0.003) but was not affected by E2 (P=0.85) or timing (P=0.49). E2 significantly increased kidney hypertrophy (P&lt;0.001) independent of Ang (P=0.27), especially when hypertension was initiated at the time of menopause (P&lt;0.001). Both E2 and Ang increased water intake and urine output (P&lt;0.05), especially when hypertension was initiated at the time of menopause. Proteinuria, an indicator of renal damage, was significantly higher with E2 (P=0.03), Ang increased GLOM area (P&lt;0.05) with no effect of E2. There was no change in the urinary osmolality due to either Ang or E2. GLOM collagen deposition was not different between groups. In the renal cortex, E2 decreased ERα mRNA (P&lt;0.01), with no difference in GPER. Conclusion: Although E2 did not affect blood pressure, it worsened the impact of hypertension on kidney function, particularly when started at the time of ovariectomy. This may be due to decreased ERα in the cortex and likely unrelated to damage in the glomerulus. Keywords: Menopause, hypertension, renal damage

Genetically Modified Porcine Kidneys Have Sufficient Tissue Integrity for Use in Pig-to-Human Xenotransplantation.

We sought to determine if genetically modified porcine kidneys used for xenotransplantation had sufficient tissue integrity to support long-term function in a human recipient. Kidney transplantation remains the best available treatment for patients with end-stage kidney disease. However, a shortage of available donor human kidneys prevents many patients from achieving the benefits of transplantation. Xenotransplantation is a potential solution to this shortage. Recent pre-clinical human studies have demonstrated kidneys from genetically modified pig donors can be transplanted without hyperacute rejection and are capable of providing creatinine and other solute clearance. It is unknown whether the porcine kidneys would tolerate the relatively higher resting blood pressure in an adult human recipient compared with the pig donor or non-human primate (NHP) recipients used in translational studies. Furthermore, previous experience in NHPs raised concerns about the tissue integrity of the porcine ureter and post-xenotransplant growth of the porcine kidney. Kidneys recovered from porcine donors with 10 gene edits were transplanted into decedent brain-dead recipients who were not eligible for organ donation. Decedents underwent bilateral native nephrectomy before transplant and were followed for 3 to 7 days. Standard induction and maintenance immunosuppression was used as previously reported. Vital signs, including blood pressure, were recorded frequently. Kidney xenografts were assessed daily, serially biopsied, and were measured at implantation and study completion. Three decedents underwent successful xenotransplantation. Subcapsular hematomas developed, requiring incision of the xenograft capsules to prevent Page kidney. Blood pressures were maintained in a physiologic range for adult humans (median arterial pressures (MAP) 108.5mmHg (Interquartile Range (IQR): 97-114mmHg), 74mmHg (IQR: 71-78mmHg), and 95mmHg (IQR: 88-99mmHg, respectively) and no bleeding complications or aneurysm formation was observed. Serial biopsies were taken from the xenografts without apparent loss of tissue integrity despite the lack of a capsule. Ureteroneocystotomies remained intact without evidence of urine leak. Xenograft growth was observed, but plateaued, in 1 decedent with increased volume of the left and right xenografts by 25% and 26%, respectively, and in the context of human growth hormone levels consistently less <0.1ng/ml and insulin-like growth factor 1 levels ranging from 34-50ng/ml. The findings of this study suggest kidneys from 10-gene edited porcine donors have sufficient tissue integrity to tolerate xenotransplantation into a living human recipient. There was no evidence of anastomotic complications, and the xenografts tolerated needle biopsy without issue. Xenograft growth occurred but plateaued by the study end; further observation and investigation will be required to confirm this finding and elucidate underlying mechanisms.

P099 EXERCISE TRAINING FURTHER ATTENUATES BLOOD PRESSURE VARIABILITY AND RENAL DAMAGE IN HYDROCHLOROTHIAZIDE TREATED-HYPERTENSIVE AND POSTMENOPAUSAL RATS

Background and Objective: Considering that blood pressure variability (BPV) has been associated with damage to target organs such as the kidney, this study aimed to investigate the effects of hydrochlorothiazide (HCTZ) combined with exercise training (CET) on BPV, as well as renal tissue morphology, function, inflammation, and oxidative stress. Methods: Female spontaneously hypertensive rats (SHR) were divided into 4 ovariectomized groups (n=5-6/group): sedentary (OS), sedentary + HCTZ (OSH), trained (OT), and trained + HCTZ (OTH). Both HCTZ (3 mg/kg) and CET (3 days/week) were administered for 8 weeks. Blood pressure was directly recorded for BPV analysis. Results: Renal function, morphology, inflammation and oxidative stress were assessed. The OSH, OT, and OTH groups had lower systolic BP (OSH: 189±13; OT: 179±5; OTH: 174±15 mmHg) compared to the OS group (208±15 mmHg). Only the combination of the drug with CET promoted a reduction in BPV variance. The HCTZ-treated groups showed lower plasma creatinine levels and increased creatinine clearance compared to the OS group. Treated groups showed a reduction in fields of 51–100% of interstitial tubule fibrosis when compared to the OS group; and the OTH group also showed reduction in fields in the range of 26–50% vs. other groups. The HCTZ-treated groups showed a reduction in protein oxidation. Renal catalase and IL10/TNF-alpha ratio were increased in the OTH group. Positive correlations were obtained between SBP variance and SBP (r=0.72), plasma creatinine (r=0.58), and levels of TNF-α (r=0.69), hydrogen peroxide (r=0.61), and protein oxidation (r=0.66) in renal tissue. Conclusions: Our results highlight the enhanced efficacy of the combination of HCTZ and CET compared to the use of either drug alone in the model studied. This combination effectively reduced BPV, resulting in beneficial changes in renal inflammatory and redox profiles, inducing morphological and functional benefits in hypertensive ovariectomized rats. Financial support: FAPESP (2022/04050-1), CNPq, CAPES-PROSUP, UNINOVE.

Resveratrol delays the progression of diabetic nephropathy through multiple pathways: A dose-response meta-analysis based on animal models.

Accumulating experimental evidence has shown that resveratrol supplementation is effective for treating diabetic nephropathy (DN) in animal models. In this systematic review and meta-analysis, we assessed the effects and multiple mechanisms of resveratrol in animal models of DN. Before September 2023, preclinical literature was systematically searched and screened across PubMed, Web of Science, EMBASE, and the Cochrane Library. Forty-two studies were included, and the risk of bias tool from SYRCLE was used to assess the methodological quality. Pooled overall effect sizes of the results were generated by STATA 16.0. The overall results provide preliminary evidence that the consumption of resveratrol can significantly reduce the mesangial index, glomerular basement membrane thickness, glomerular hypertrophy, serum creatinine, blood urea nitrogen, 24-h urinary protein, blood glucose, kidney index, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels. In contrast, the levels of albumin and high-density lipoprotein cholesterol are significantly increased. However, resveratrol did not significantly reduce creatinine clearance or glycated hemoglobin levels. Dose-response analysis revealed that resveratrol was most effective at improving kidney function and reducing DN when administered at lower doses of ≤15 mg/kg/day or higher doses of 100-200 mg/kg/day, with significant improvements in biochemical kidney injury markers and a better effect on dysglycemia. The benefits of resveratrol in DN are likely due to its anti-inflammatory, antioxidant, metabolic regulatory, and autophagy-promoting effects. To confirm these findings for clinical use, further large-scale, long-term, high-quality preclinical trials are warranted to accurately assess the anti-DN effects and safety of resveratrol.

240.3: Post-kidney transplant (KTx) with primary allograft function, comparison of Serum creatinine with Serum Cystatin-C, and measured urinary creatinine clearance (mCrCl) with MDRD-4 eGFR and MDRD-4 eGFR eGFRCysC.

240.3: Post-kidney transplant (KTx) with primary allograft function, comparison of Serum creatinine with Serum Cystatin-C, and measured urinary creatinine clearance (mCrCl) with MDRD-4 eGFR and MDRD-4 eGFR eGFRCysC.

Individualized regimen of Posaconazole oral suspension in Chinese HSCT patients based on population pharmacokinetic model

To establish a population pharmacokinetic (PopPK) model of posaconazole suspension in Chinese hematopoietic stem cell transplantation (HSCT) patients and to recommend an optimal dosing regimen. A single-center, retrospective, model-based study was conducted in 62 Chinese patients, including 103 with posaconazole plasma concentrations. PopPK analysis using NONMEM software. A one-compartment model of first-order elimination and absorption was in good agreement with the experimental data. Analysis of covariance showed that body weight (WT), creatinine clearance (CCR), and proton pump inhibitor (PPI) had a significant effect on the pharmacokinetics of posaconazole. The dose simulation results show that patients with CCR ≥ 90 mL/min require at least 3 mg/kg TID and 7 mg/kg BID dosing regimens for prevention and treatment, respectively. However, when combined with PPI, at least 5 mg/kg BID and 5 mg/kg TID dosing regimens are required for prevention and treatment, respectively. Regardless of whether it is used in combination with PPI or not, patients with a CCR of 60–90 mL/min can achieve PTA goals by using a 4 mg/kg BID and 4 mg/kg TID regimen for prevention and treatment, respectively. A dosing regimen of 3 mg/kg BID in patients with a CCR of 30–60 mL/min is sufficient to meet the PTA goal of prophylaxis, and the dose needs to be elevated to 4 mg/kg BID for the treatment of fungal infections, and there is no need to change the dose according to the coadministration of PPI. When the patient's CCR is less than 30 mL/min, whether or not combined with PPI, the administration regimen of 2 mg/kg BID and 3 mg/kg BID can meet the PTA goals for prevention and treatment, respectively.

Risk factors for linezolid - induced haematological toxicity in patients: a retrospective study.

This single-center, observational cohort study aimed to investigate the risk factors associated with linezolid-induced hematological toxicity by analyzing the linezolid trough concentration (Cmin) obtained from patients undergoing treatment between January 2020 and December 2021. A total of 111 eligible individuals were included in the study, of which 47 were diagnosed with linezolid-induced thrombocytopenia and 18 were diagnosed with linezolid-induced hemoglobin decrease. Binary logistic regression analysis revealed that creatinine clearance level (Ccr) < 50 mL/min/1.73 m2 (OR, 5.463; 95% CI, 1.249-23.888, p = 0.024) and Cmin > 7 mg/L (OR, 62.660; 95% CI, 14.293-274.708, p = 0.001) were risk factors associated with linezolid-induced thrombocytopenia. Area under the ROC curve for Cmin was 0.955, with a maximum Youden index of 0.837. The corresponding critical value was 6.94 mg/L (sensitivity 91.5%; specificity 92.2%). Ccr < 50 mL/min/1.73 m2 (OR, 7.282; 95% CI, 1.765-30.048, p = 0.006) and Cmin > 7mg/L (OR, 6.364; 95% CI, 1.937-20.910, p = 0.020) were found to be associated with linezolid-induced hemoglobin reduction. The area under the ROC curve for Cmin was 0.755, Youden index was 0.477 at the maximum, and the corresponding critical value was 7.53 mg/L (sensitivity 77.8%; specificity 69.9%). Renal insufficiency is a related risk factor for linezolid-induced hematological toxicity. Patients receiving linezolid treatment should be closely monitored with blood routine and plasma concentration, particularly in patients with moderate or severe renal insufficiency. The plasma trough concentration of linezolid could be a suitable predictor for linezolid-induced thrombocytopenia and anemia.

Kidney function assessment for eligibility in clinical cancer trials – Data from the European Organisation for Research and Treatment of Cancer

PurposeThere is no consensus on how to estimate kidney function for the assessment of eligibility in clinical cancer trials. Patients and methodsWe recalculated the creatinine clearance (CrCl)/glomerular filtration rate (GFR) at baseline in a total of 1768 patients enrolled in twelve clinical trials using the Cockcroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI 2021) and European Kidney Function Consortium (EKFC) formulas. Patients were classified as having renal impairment (RI; CrCl/GFR <60 mL/min) or no renal impairment (NRI; CrCl/GFR ≥60 mL/min) with each of the four formulas, respectively. Furthermore, we analyzed the number of adverse events (AE) per month under study treatment using measures of central tendency, variability and regression models. ResultsUsing CG, EKFC, MDRD and CKD-EPI 2021, 152 (8 %), 140 (8 %), 110 (6 %), and 61 (4 %) patients had RI respectively. Indeed, 47 (3 %) patients had RI using all 4 formulas, while 158 (9 %) had RI by at least one but not all four methods. CG showed the broadest variability and inconsistencies with other methods. All calculation methods performed similarly for excluding patients at risk of severe AE. EKFC demonstrated superior predictive ability for excluding patients at risk of renal and urinary tract AE. ConclusionThis post hoc analysis highlights the importance of choosing accurate and representative methods for kidney function estimation in clinical cancer trials. CG should be replaced by newer methods. While CKD-EPI 2021 may maximize trial accrual, EKFC should be considered for treatment affecting kidney function.

Study of phenolic compounds of umbellate wintergreen herb and their influence on biochemical indicators of blood and urine in the rat model of chronic kidney disease

Diseases of the kidneys and urinary tract are a common problem in people of all ages. Kidneys filter blood, removing water-soluble waste from the body, maintain water-salt balance, stabilize blood pressure and PH level. Intoxication, hypothermia, injuries and other causes lead to problems with the kidneys - inflammatory disease, urolithiasis, etc. Therefore, the development of effective herbal remedies that affect the etiopathogenic factors of diseases is urgent. The aim. Study of the profile of phenolic compounds of umbellate wintergreen, study of antioxidant and nephroprotective properties of umbellate wintergreen extract on the model of chromate-induced renal failure (chronic kidney disease) in rats. Materials and methods. Phenolic compounds were analyzed by high-performance liquid chromatography (HPLC) using a Waters e2695 Alliance HPLC system in combination with a 2998 PDA detector (Waters, Milford, MA, USA). Study of in vitro antioxidant activity by HPLC method for 50 % extract of umbellate wintergreen herb. A Waters 2695 chromatograph (Waters, USA) equipped with a Waters 996 diode-matrix detector was used. To determine the nephroprotective effect, 60 outbred sexually mature rats (males), divided into six groups, were studied. Based on the results of biochemical studies, creatinine clearance and urea clearance were calculated in experimental animals. Results. 8 phenolic compounds - apigenin, hyperoside, quercitrin, rutin, quercetin, gallic acid, guaiaverine and isoquercetin - were identified and quantified in umbellate wintergreen by HPLC. Based on the results of a preliminary assessment of the antioxidant contribution of individual phenolic compounds to the overall effectiveness of the umbellate wintergreen grass extract, a significant effect of caffeic acid derivatives and quercetin was determined. The use of Chimaphila umbellata extract in experimental animals was marked by the normalization of diuresis, a decrease in the total protein content of urine by 1.8 times. The effect of the use of umbellate wintergreen extract was expected to be dose dependent. Conclusions. The profile of umbellate wintergreen phenolic compounds was investigated by HPLC, and their antioxidant effect was determined. In the conditions of the development of renal failure in rats, the studied extract of Chimaphila umbellata improved the physical condition of the animals, reduced their mortality, improved the excretory function of the kidneys, normalized nitrogen and protein metabolism, contributed to the protection of the structure of the kidney tissue, and therefore had a positive effect on the course of nephropathy

Population pharmacokinetics of oral fosfomycin calcium in healthy women.

Fosfomycin is an antibiotic extensively used to treat uncomplicated urinary tract infections in women, and it is available in different salts and formulations. The European Medicines Agency (EMA) recommends further studies to characterize the pharmacokinetics of fosfomycin calcium for oral administration and to justify its dosage recommendation. A population pharmacokinetic model of fosfomycin calcium was developed after oral administration to healthy women. A clinical trial (a randomized, open-label, bioavailability study of single and multiple doses of 1000 mg capsules, single dose of 500 mg capsule and single dose of 250 mg/5 mL suspension of oral fosfomycin calcium under fasted conditions in healthy women volunteers, Code: PD7522.22, EudraCT: 2020-001664-28) was carried out at the Clinical Trial Unit, Araba University Hospital (Vitoria-Gasteiz, Spain). Twenty-four healthy women were included in the study, and plasma samples were collected at different times over a period of 24 h. The concentration-time data of fosfomycin in plasma were modelled by a population approach using a nonlinear mixed-effects modelling implemented by NONMEM 7.4 (ICON Clinical Research LLC, North Wales, PA, USA). The pharmacokinetics of fosfomycin was best described by a two-compartment model. Creatinine clearance and body weight were identified as covariates for fosfomycin clearance and volume of distribution, respectively. This study provides relevant information on the pharmacokinetic profile of fosfomycin in women after oral administration as calcium salt. This population model may be very useful for establishing dosage recommendations of fosfomycin calcium to treat urinary tract infections in women.

Exploring the efficacy of structured nursing via web-based interaction platforms in sustaining hemodialysis patients.

Discussed based on the network interactive platform of structured care for patients with chronic renal failure (CRF) in the process of hemodialysis. This study seeks to elucidate the application value of structured nursing, deployed through network interaction platforms, in sustaining patients undergoing maintenance hemodialysis. A total of 62 patients diagnosed with Chronic Renal Failure (CRF) between April 2022 and August 2023 were randomly allocated into two distinct care groups: conventional and structured nursing care based on a web-interactive platform. Both cohorts were comparatively analyzed with respect to psychological states, quality of life within therapeutic interventions, and relationships with complications. Renal function indicators, including Creatinine Clearance (Ccr), Serum Creatinine (SCr), and Blood Urea Nitrogen (BUN), were subjected to Pearson analysis to appraise their predictive value in prognostication, while Receiver Operating Characteristic (ROC) curve analysis was constructed to further discern their diagnostic precision. Post-intervention, notable improvements were observed in the emotional states of patients in both cohorts, with the structured care group exhibiting significantly lower Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) scores (p< 0.05). Furthermore, patients under the web-interactive structured nursing regimen demonstrated superior overall adherence, a reduced incidence rate of complications, and markedly higher scores in quality of life assessments compared to those under conventional care (p< 0.05). The derived cut-off values for Ccr, SCr, and BUN were 32.5 ml/min, 251.5 umol/L, and 14.5 mmol/L, respectively, with sensitivities and specificities pegged at 0.645% and 0.645% for Ccr, 0.774% and 0.548% for SCr, and 0.774% and 0.774% for BUN. The corresponding areas under the ROC curve (AUC) for each parameter were 0.816, 0.653, and 0.856, respectively. Comprehensive hemodialysis care for patients with chronic renal failure can improve self-care ability to improve quality of life and reduce the incidence of complications, which has great potential for clinical progress and is worthy of further research.

Impact of device variability and protocol differences on kidney function during normothermic machine perfusion: A comparative study using porcine and human kidneys.

A growing interest in renal normothermic machine perfusion (NMP) has resulted in more clinically available perfusion devices. While all perfusion systems have the same aim, there are significant differences in their circuits, pumps, sensors, and software. Therefore, our objective was to assess the impact of different perfusion protocols and devices on kidney function and perfusion parameters during NMP. Porcine kidneys were subjected to 30 min of warm ischemia, 24 h of static cold storage, and subsequently perfused for 6 h using (1) the Kidney Assist (KA) machine with a pressure of 75 mm Hg, (2) the KA device incorporating several adjustments and a pressure of 85 mm Hg (modified KA), or (3) the Perlife (PL) perfusion device (n = 4). Consecutively, discarded human kidneys were perfused using the KA or modified KA (n = 3) protocol. The PL group quickly reached the device's upper flow limit and consequently received a significantly lower pressure compared to the KA groups. The arterial pO2 was significantly lower in the PL group. Yet, hemoglobin concentration increased over time, and oxygen consumption was significantly higher compared to the KA groups. Fractional sodium excretion was significantly lower in the PL group. Tissue ATP levels, urine production, and creatinine clearance rates did not differ between groups. In human kidneys, the modified KA group showed significantly lower vascular resistance, higher oxygen delivery, and lower levels of lactate in the perfusate compared to the KA group. This study shows that perfusion characteristics and kidney function are significantly influenced by the perfusion protocol and the device and its settings during normothermic machine perfusion and therefore should be interpreted with caution.