Creatinine Clearance Research Articles

Pharmacological assessment of delphinidin in counteracting polystyrene microplastic induced renal dysfunction in rats

Polystyrene microplastics (PSMP) are toxic environmental contaminants which can damage various body organs including kidneys. Delphinidin (DEL) is a potential anthocyanidin flavonoid with significant pharmacological benefits. This research was conducted to analyze the protective effect of DEL to avert PSMP prompted renal dysfunction. Rats (n = 24) were divided into 4 separate groups: Control, PSMP (0.01 mgkg−1), PSMP (0.01 mgkg−1) + DEL (25 mgkg−1) and only DEL (25 mgkg−1). Our results showed that PSMP exposure reduced the expressions of Nrf-2 and antioxidant genes while increasing the expression of Keap1. Besides, PSMP intoxication escalated the level of kidney injury markers (urea, KIM-1, creatinine and NGAL) while inducing substantial reduction in the levels of creatinine clearance. Moreover, PSMP significantly reduced the levels of GSH, GST, SOD, HO-1, CAT, GSR, GPx while escalating MDA and ROS. Conversely, inflammatory biomarkers including IL-1β, TNF-α, NF-kB, IL-6 and COX-2 activity were increased due to PSMP intoxication. Our results showed that PSMP administration increased the expressions of Bax and caspase-3 while decreasing the expression of Bcl-2. However, DEL treatment significantly restored the PSMP-induced renal impairments. Therefore, it is suggested that DEL could be used as a therapeutic compound to alleviate PSMP-induced kidney damage in rats, possibly due to its strong pharmacological properties.

Safety and efficacy of apixaban versus warfarin in peritoneal dialysis patients with non-valvular atrial fibrillation: protocol for a prospective, randomised, open-label, blinded endpoint trial (APIDP2)

IntroductionSeveral randomised controlled trials have demonstrated that novel oral anticoagulants are safer compared with vitamin K antagonists for the management of non-valvular atrial fibrillation (NVAF) to prevent thromboembolic events in...

Evaluation of knowledge and attitude concerning augmented renal clearance among physicians and clinical pharmacists in Al-Ain, UAE: A cross-sectional study

Background Kidney function assessment is crucial in critical illness patients and is required before administering renally excreted medication, especially antibiotics and antiepileptics. Conventional clinical practice often focuses on renal impairment with low creatinine clearance (CrCl) and overlooks the augmented renal clearance (ARC), which is defined by (CrCl) more than 130 ml/min. This typical demonstration neglects individuals who experience hyperfunctioning kidneys. Among critically ill patients, the prevalence of (ARC) is approximately 20% to 65% of cases. This study aims to evaluate physicians’ and clinical pharmacists’ knowledge about ARC-associated risk factors, antibiotic regimen modification in ARC patients, and attitudes towards ARC workshops and guidelines in Al-Ain, UAE. Methods A cross-sectional, online self-administered survey-based study was designed to achieve this study’s aim. The questionnaire was constructed on profound literature analysis, validated, and piloted. The survey was emailed to physicians and pharmacists working in two hospitals, private and governmental, and distributed through different social media platforms over three months, December 2022—February 2023. Results Of the 92 complete responses (32 clinical pharmacists, 60 physicians), 57 (61.9%), were aware of ARC, but 72 (78%) demonstrated poor knowledge overall. Clinical pharmacists had a higher mean rank of knowledge than the physician’s group. Meanwhile, 70 (76.1%) participants were unaware of the eGFR threshold to determine ARC. There is a noticeable positive attitude toward seeking more information about antibiotic dose adjustment in ARC patients at 85 (92%) of the respondents. Remarkably, only 28 (30.4%) were directly involved with ARC patients’ treatment plans. Conclusion In conclusion, clinical pharmacists showed better knowledge than physicians. However, overall, the participating healthcare providers lacked knowledge about ARC, so a reliable source of information regarding ARC should be utilized. Future research could explore the implementation of professional development workshops for healthcare providers and national guidelines and then assess their impact on patient outcomes.

Estimation of renal function immediately after cessation of continuous renal replacement therapy at the ICU

Estimating glomerular filtration (eGFR) after Continuous Renal Replacement Therapy (CRRT) is important to guide drug dosing and to assess the need to re-initiate CRRT. Standard eGFR equations cannot be applied as these patients neither have steady-state serum creatinine concentration nor average muscle mass. In this study we evaluate the combination of dynamic renal function with CT-scan based correction for aberrant muscle mass to estimate renal function immediately after CRRT cessation. We prospectively included 31 patients admitted to an academic intensive care unit (ICU) with a total of 37 CRRT cessations and measured serum creatinine before cessation (T1), directly (T2) and 5 h (T3) after cessation and the following two days when eGFR stabilized (T4, T5). We used the dynamic creatinine clearance calculation (D3C) equation to calculate eGFR (D3CGFR) and creatinine clearance (D3Ccreat) between T2-T3. D3Ccreat was corrected for aberrant muscle mass when a CT-scan was available using the CRAFT equation. We compared D3CGFR to stabilized CKD-EPI at T5 and D3CCreat to 4-h urinary creatinine clearance (4-h uCrCl) between T2-T3. We retrospectively validated these results in a larger retrospective cohort (NICE database; 1856 patients, 2064 cessations). The D3CGFR was comparable to observed stabilized CKD-EPI at T5 in the prospective cohort (MPE = − 1.6 ml/min/1.73 m2, p30 = 76%) and in the retrospective NICE-database (MPE = 3.2 ml/min/1.73 m2, p30 = 80%). In the prospective cohort, the D3CCreat had poor accuracy compared to 4-h uCrCl (MPE = 17 ml/min/1.73 m2, p30 = 24%). In a subset of patients (n = 13) where CT-scans were available, combination of CRAFT and D3CCreat improved bias and accuracy (MPE = 8 ml/min/1.73 m2, RMSE = 18 ml/min/1.73 m2) versus D3CCreat alone (MPE = 18 ml/min/1.73 m2, RMSE = 32 ml/min/1.73 m2). The D3CGFR improves assessment of eGFR in ICU patients immediately after CRRT cessation. Although the D3CCreat had poor association with underlying creatinine clearance, inclusion of CT derived biometric parameters in the dynamic renal function algorithm further improved the performance, stressing the role of muscle mass integration into renal function equations in critically ill patients.

ThP6.13 - A closed loop clinical audit on adherence of weight-based and renal function-adjusted venous thromboprophylaxis prescribing to local guidelines in emergency general surgical patients

Abstract Aims to audit adherence of venous thromboembolism (VTE) prophylaxis according to local trust guidelines in a single-centre emergency general surgery department, adjusting doses based on weight and renal function (creatinine clearance). Following initial audit of practice, intervention to improve local practice was implemented with informative posters and teaching sessions, aiming to improve overall adherence to guidelines and limit risk of complications from incorrect dosing. Methods A two-cycle snapshot audit of VTE prophylaxis prescribing was conducted in a district general hospital emergency general surgery department against local guidelines concerning VTE prophylaxis. All current inpatients admitted under general surgery were included in the study reviewing baseline characteristics including age, weight, and creatinine clearance. Results The first cycle audited the adherence of departmental practice against guidelines in 57 inpatients. 49 (86.0%) were prescribed VTE prophylaxis in accordance with local guidelines. Of the 8 patients who did not adhere to guidelines, 5 (62.5%) had no VTE prophylaxis prescribed, while 3 (37.5%) had incorrect doses prescribed for their weight or renal function. The second cycle audited 43 inpatients. 39 (90.7%) adhered to guidelines. All re-audited patients had the correct VTE prophylaxis prescribed, although there was no VTE prophylaxis prescribed in 4 (9.3%) patients. There were no bleeding or thromboembolic complication in any patients over the course of admission in both cycles of this audit. Conclusion Adherence to local guidelines concerning VTE prophylaxis was increased following intervention. This eliminated VTE prophylaxis prescribing errors, although did not improve the amount of VTE prophylaxis prescription omissions.

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.