Reduced Creatinine Clearance Research Articles

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.

The Salutary Effects of Diminazene, Lisinopril or Valsartan on Cisplatin – Induced Acute Kidney Injury in Rats: A Comparative Study

Nephrotoxicity as a cause of acute kidney injury (AKI) induced by cisplatin (CP), limits its usefulness as an anticancer agent. Diminazene, an angiotensin converting enzyme 2 activator, exhibited renoprotective properties on rat models of kidney diseases. This research aims to investigate the salutary effect of diminazene in comparison with lisinopril or valsartan in CP-induced AKI. The first and second groups of rats received oral vehicle (distilled water) for 9 days, and saline injection or intraperitoneal CP (6 mg/kg) on day 6, respectively. Third, fourth, and fifth groups received intraperitoneal injections of CP on day 6 and diminazene (15 mg/kg/day, orally), lisinopril (10 mg/kg/day, orally), or valsartan (30 mg/kg/day, orally), for 9 days, respectively. 24h after the last day of treatment, blood and kidneys were removed under anesthesia for biochemical and histopathological examination. Urine during the last 24 h before sacrificing the rats was also collected. CP significantly increased plasma urea, creatinine, neutrophil gelatinase-associated lipocalin, calcium, phosphorus, and uric acid. It also increased urinary albumin/creatinine ratio, N-Acetyl-β-D-Glucosaminidase/creatinine ratio, and reduced creatinine clearance, as well the plasma concentrations of inflammatory cytokines [plasma tumor necrosis factor–alpha, and interleukin-1beta], and significantly reduced antioxidant indices [catalase, glutathione reductase , and superoxide dismutase]. Histopathologically, CP treatment caused necrosis of renal tubules, tubular casts, shrunken glomeruli, and increased renal fibrosis. Diminazine, lisinopril, and valsartan ameliorated CP-induced biochemical and histopathological changes to a similar extent. The salutary effect of the three drugs used is, at least partially, due to their anti-inflammatory and antioxidant effects. Keywords: Cisplatin • Diminazene • ACE2 activator • Lisinopril • Valsartan • Acute kidney injury

Patients with antiphospholipid syndrome and a first venous or arterial thrombotic event: clinical characteristics, antibody profiles and estimate of the risk of recurrence.

Thrombosis in antiphospholipid syndrome (APS) involves in most cases the venous circulation. Why in some patients thrombotic APS affects the arterial circulation and in particular cerebral circulation is unknown. In previous studies, both patient characteristics and antiphospholipid antibody types and titers have been associated with arterial thrombosis. Aim of this study was to compare the clinical characteristics and laboratory findings of venous and arterial thrombotic APS from a large series of patients. Data were retrieved from the Start 2 antiphospholipid, a multicenter prospective register of long-term collected data from Thrombosis Centers in Italy. Of 167 patients with thrombotic APS, 114 (68 %) had a venous and 53 (32 %) had an arterial event as first clinical manifestation. Several clinical characteristics and risk factors were different among groups in univariate analysis. Using logistic regression analysis, reduced creatinine clearance and hyperlipidemia were independent variable for the occurrence of arterial APS. Notably, no difference in antiphospholipid antibody profiles and aβ2-Glycoprotein I levels were found between groups. A higher adjusted global antiphospholipid syndrome score (aGAPSS) was found in arterial group indicating a possible high recurrence rate in arterial APS. These data have pathophysiological and clinical implication since associated conditions might predispose patients to arterial rather than venous events and call to a close monitoring and treatment of arterial APS due to their increased tendency to recurrence.

Incidence and Predictors of Worsening Renal Function in Edoxaban-Treated Atrial Fibrillation Patients Within ETNA-AF-Europe Registry

BackgroundManaging patients with atrial fibrillation (AF) and worsening renal function (WRF) remains a clinical challenge due to the need of dose adjustment of non-vitamin K antagonist oral anticoagulants. ObjectivesTo determine the incidence of WRF in patients with AF treated with edoxaban, the association of WRF with clinical outcomes, and predictors of WRF and clinical outcomes in these patients. MethodsThis is a subanalysis of the Edoxaban Treatment in routiNe clinical prActice for patients with non-valvular Atrial Fibrillation in Europe study (NCT02944019), an observational study of edoxaban-treated patients with AF. WRF was defined as a ≥25% reduction in creatinine clearance between baseline and 2 years. ResultsOf the 9,054 patients included (69% of the total 13,133 enrolled), most did not experience WRF (90.3%) during the first 2 years of follow-up. WRF occurred in 9.7% of patients. Patients with WRF had significantly higher rates of all-cause death (3.88%/y vs 1.88%/y; P < 0.0001), cardiovascular death (2.09%/y vs 0.92%/y; P < 0.0001), and major bleeding (1.51%/y vs 0.98%/y; P = 0.0463) compared with those without WRF. Rates of intracranial hemorrhage (0.18%/y vs 0.18%/y) and of any stroke/systemic embolic events were low (0.90%/y vs 0.69%/y; P = 0.3161) in both subgroups. The strongest predictors of WRF were a high CHA2DS2-VASc score, high baseline creatinine clearance, low body weight, and older age. Most predictors of WRF were also predictors of clinical outcomes. ConclusionsWRF occurred in approximately 10% of edoxaban-treated AF patients. Rates of death and major bleeding were significantly higher in patients with WRF than without. Stroke events were low in both subgroups.

Dosing and Exposure of Vancomycin With Continuous Infusion: A Retrospective Study.

Vancomycin continuous infusion (CI) has suggested benefits over intermittent infusion: reduced nephrotoxicity, higher target attainment, and simpler therapeutic drug monitoring (TDM). Empiric dosing regimens range from 30-60 mg/kg/day and it is unclear which regimen results in optimal exposure. This study evaluates whether a dosing regimen of 45 mg/kg/day after a 20 mg/kg loading dose for patients with estimated glomerular filtration rate (eGFR) ≥ 50 mL/min results in adequate exposure. We retrospectively analyzed plasma concentrations from patients treated with vancomycin CI as routine clinical care between February and October 2021. Patients under 18 years old, with renal replacement therapy, reduced creatinine clearance (Chronic Kidney Disease Epidemiology Collaboration < 50 mL min/1.73 m2) or outpatient antibiotic therapy were excluded. Dose, renal function, and blood draw procedures were assessed for each measured vancomycin sample. Initially, 121 samples were included. Subsequently, 7 samples, 6 of which with concentrations ≥ 40 mg/L, were verified to be incorrectly drawn and excluded. With doses of 40-50 mg/kg/day concentrations ranged from 18.4-61.0 mg/L. Only 25% were within the target window of 17-25 mg/L and 15% were ≥ 40 mg/L. Supratherapeutic concentrations were observed in 89% of samples from patients dosed 40-60 mg/kg/day with eGFR 50-80 mL/min. Concluding, an empiric dosing regimen of 45 mg/kg results in too high vancomycin exposure and thus we recommend lower doses and differentiation according to renal function. Additionally, when measuring concentrations over 40 mg/L incorrect sampling must be excluded before dose adjustment and the large variability in exposure between patients, warrants the need for swift TDM.

Cardiorenal damages in mice at early phase after intervention induced by angiotensin II, nephrectomy, and salt intake.

The interconnection of heart performance and kidney function plays an important role for maintaining homeostasis through a variety of physiological crosstalk between these organs. It has been suggested that acute or chronic dysfunction in one organ causes dysregulation in another one, like patients with cardiorenal syndrome. Despite its growing recognition as global health issues, still little is known on pathophysiological evaluation between the two organs. Previously, we established a preclinical murine model with cardiac hypertrophy and fibrosis, and impaired kidney function with renal enlargement and increased urinary albumin levels induced by co-treatment with vasopressor angiotensin II (A), unilateral nephrectomy (N), and salt loading (S) (defined as ANS treatment) for 4 weeks. However, how both tissues, heart and kidney, are initially affected by ANS treatment during the progression of tissue damages remains to be determined. Here, at one week after ANS treatment, we found that cardiac function in ANS-treated mice (ANS mice) are sustained despite hypertrophy. On the other hand, kidney dysfunction is evident in ANS mice, associated with high blood pressure, enlarged glomeruli, increased levels of urinary albumin and urinary neutrophil gelatinase-associated lipocalin, and reduced creatinine clearance. Our results suggest that cardiorenal tissues become damaged at one week after ANS treatment and that ANS mice are useful as a model causing transition from early to late-stage damages of cardiorenal tissues.

Effects of Exercise Training on Mitochondrial Fatty Acid β-Oxidation in the Kidneys of Dahl Salt-Sensitive Rats

Exercise training (Ex) has anti-hypertensive and renal protective effects. In this study, we investigate the effects of Ex on mitochondrial fatty acid metabolism in the kidneys of Dahl salt-sensitive (Dahl-S) rats fed a high-salt (HS) diet. Eight-week-old, male Dahl-S rats were divided into three groups: (1) normal-salt diet, sedentary (NS-Sed), (2) HS diet, sedentary (HS-Sed), and (3) HS-Ex. The NS and HS groups were fed a diet containing 0.6% and 8% NaCl, respectively. The HS-Ex group performed treadmill running for 8 weeks (5 days/week; 60 min/day at 16–20 m/min, 0% gradient). Renal function and the expression of enzymes and regulators of β-oxidation and electron transport chain (ETC) complexes were assessed. HS increased systolic blood pressure and proteinuria, and Ex ameliorated these defects. HS also reduced creatinine clearance, and Ex ameliorated it. HS reduced the renal expression of enzymes of β-oxidation (carnitine palmitoyltransferase type I (CPTI) and acyl-CoA dehydrogenases (CADs)) and the related transcription factors peroxisome proliferator-activated receptor α (PPARα) and PPARγ-coactivator-1α (PGC-1α), and Ex restored this. HS also reduced the renal expression of enzymes in ETC complexes, and Ex restored this expression. Ex ameliorates HS-induced renal damage by upregulating enzymes involved in fatty acid β-oxidation and ETC complexes via increases in PPAR-α and PGC-1α expressions in the kidneys of Dahl-S rats. These results suggest that Ex may have beneficial effects on HS-induced mitochondrial dysfunction in the kidney.

Effects of dexmedetomidine on kidney and brain tissue microcirculation and histology in ovine cardiopulmonary bypass: a randomised controlled trial.

Cardiac surgery requiring cardiopulmonary bypass is associated with postoperative acute kidney injury and neurocognitive disorders, including delirium. Intra-operative inflammation and/or impaired tissue perfusion/oxygenation are thought to be contributors to these outcomes. It has been hypothesised that these problems may be ameliorated by the highly selective α2 -agonist, dexmedetomidine. We tested the effects of dexmedetomidine on renal and cerebral microcirculatory tissue perfusion, oxygenation and histology in a clinically relevant ovine model. Sixteen sheep were studied while conscious, after induction of anaesthesia and during 2 h of cardiopulmonary bypass. Eight sheep were allocated randomly to receive an intravenous infusion of dexmedetomidine (0.4-0.8 μg.kg-1 .h-1 ) from induction of anaesthesia to the end of cardiopulmonary bypass, and eight to receive an equivalent volume of matched placebo (0.9% sodium chloride). Commencement of cardiopulmonary bypass decreased renal medullary tissue oxygenation in the placebo group (mean (95%CI) 5.96 (4.24-7.23) to 1.56 (0.84-2.09) kPa, p = 0.001), with similar hypoxic levels observed in the dexmedetomidine group (6.33 (5.33-7.07) to 1.51 (0.33-2.39) kPa, p = 0.002). While no differences in kidney function (i.e. reduced creatinine clearance) were evident, a greater incidence of histological renal tubular injury was observed in sheep receiving dexmedetomidine (7/8 sheep) compared with placebo (2/8 sheep), p = 0.041. Graded on a semi-quantitative scale (0-3), median (IQR [range]) severity of histological renal tubular injury was higher in the dexmedetomidine group compared with placebo (1.5 (1-2 [0-3]) vs. 0 (0-0.3 [0-1]) respectively, p = 0.013). There was no difference in cerebral tissue microglial activation (neuroinflammation) between the groups. Dexmedetomidine did not reduce renal medullary hypoxia or cerebral neuroinflammation in sheep undergoing cardiopulmonary bypass.

Impact of calcium channel blockers and angiotensin receptor blockers on hematological parameters in type 2 diabetic patients.

Antihypertensive medications have been associated with a reduction in hemoglobin (Hb) levels, leading to clinically significant anemia. We aimed to provide valuable insights into the impact of angiotensin receptor blockers (ARBs) and calcium channel blockers (CCBs) on hematological parameters by measuring the levels of erythropoietin (EPO), ferritin, and complete blood count (CBC) in individuals with type 2 diabetes mellitus (T2DM), particularly considering the duration of the antihypertensives use. In addition to comparing their effects on blood pressure, glycemic status, and renal function, a retrospective cohort study was conducted at the consultation unit of Alsalam Teaching Hospital, Mosul, Nineveh Province, between October 2022 and February 2023. A total of 160 participants were enrolled after being fully examined by the consultants to detect their eligibility for inclusion in the study and to rule out any abnormality. They consisted of 40 healthy controls, 30 T2DM patients (T2DM group), 30 T2DM patients with newly diagnosed hypertension (HT) (T2DM+HT group), 30 type 2 diabetic-hypertensives on ARBs (T2DM+HT+ARBs group), and 30 type 2 diabetic-hypertensives on CCBs (T2DM+HT+CCBs group). Five milliliters of blood was drawn from a vein and divided into two parts. Two milliliters was transferred into an anticoagulant tube for the measurement of HbA1c and complete blood picture. Serum was obtained from the remaining blood and used for assessment of ferritin, EPO, FSG, creatinine, urea, and uric acid. Significantly reduced FSG and HbA1c levels were observed in T2DM+HT+CCBs and T2DM+HT+ARBs groups vs T2DM+HT group (p < 0.05). The T2DM+HT+CCBs group had statistically higher urea levels than the T2DM group (p < 0.05). Both CCBs and ARBs use resulted in reduced creatinine clearance (CrCl). T2DM+HT+CCBs group exhibited slightly higher uric acid levels compared to controls (p < 0.05). Prolonged use of CCBs and ARBs led to disturbances in hematological parameters, with CCBs users showing the lowest levels of hemoglobin (Hb), RBCs, and hematocrit (Hct) among the groups. ARBs users displayed the lowest values of EPO and ferritin compared to other patient groups, along with reduced levels of Hb, RBCs, and Hct, albeit slightly higher than CCBs users. Our study highlights the importance of a balanced approach in prescribing ARBs and CCBs to patients with T2DM, given their potential to induce blood abnormalities, particularly with prolonged usage.

Diacerein mitigates adenine-induced chronic kidney disease in rats: Focus on TLR4/MYD88/TRAF6/NF-κB pathway

Chronic kidney disease (CKD) is a serious problem which negatively affects human health. AimsThe purpose of this investigation was to explore the possible beneficial impacts of diacerein on adenine-induced CKD in rats. Main methods32 male Sprague Dawley rats were allocated into 4 groups; normal, diseased (200 mg/kg adenine, orally) and diacerein (25 and 50 mg/kg, orally). Key findingsAdenine produced marked reduction in rats' body weights and a substantial increase in kidney/body weight index. Additionally, adenine significantly increased serum creatinine and BUN levels besides proteinuria levels, and also reduced creatinine clearance. Adenine induced oxidative stress as evidenced by increased MDA content and diminished GSH concentration in renal tissues. These biochemical measurements were confirmed by the morphological and histopathological results. Moreover, adenine revealed substantial elevation in renal level and expression of MYD88, TRAF6 and TNF-α, and renal level of IL-1β in addition to increased expression of TLR4, NF-κB p65 and p-NF-κB p65 while reduced the expression of IκB-α. Diacerein in a dose-dependent manner effectively ameliorated adenine-induced alterations. SignificanceDiacerein could be used as a therapeutic agent to attenuate CKD after further clinical studies.

The efficacy and safety of apixaban: what has changed in 12 years of its use in real clinical practice?

This review examines the position of apixaban among other direct oral anticoagulants in patients with atrial fibrillation (AF) and venous thrombosis in randomized clinical trials and real clinical practice. Since the advent of apixaban, many studies of real clinical practice (RCP) and meta-analyses have appeared. RCP studies have fully confirmed the efficacy and safety of apixaban. Now we have data that au pixaban is equally effective and safe in elderly and senile people and younger patients, as well as in patients with reduced creatinine clearance. The efficacy and safety of apixaban has been confirmed in patients with AF with the presence of diseases of several vascular basins, in patients with AF and angina, including acute coronary syndrome, treated by coronary artery stenting and conservatively. An important property of apixaban is safety, which can be traced in almost all studies, which made it possible to successfully apply it in people with a high risk of bleeding, namely in patients with active cancer and venous thrombosis. Thus, RCP studies in patients with AF, including the elderly and senile patients with chronic kidney disease, many concomitant diseases, as well as patients with VTEC, confirmed the results of randomized clinical trials of apixaban. The drug appears to be an effective and at the same time the safest anticoagulant. The safety image of Apixaban which has become noticeable in all RCTs (in patients with atrial fibrillation, VTEC, including patients with active cancer) was confirmed both in real clinical practice studies and meta-analyses, and allowed it to be successfully used in the category of patients which are at highest risk for bleeding.

2,8-Dihydroxyadenine-induced nephropathy causes hexosylceramide accumulation with increased mTOR signaling, reduced levels of protective SirT3 expression and impaired renal mitochondrial function

AimChronic kidney disease (CKD) is accompanied by increased cardiovascular risk and heart failure (HF). In rodents, 2,8-dihydroxyadenine (DHA)-induced nephropathy is a frequently used CKD model. Cardiac and kidney tubular cells share high energy demand to guarantee constant contractive force of the heart or reabsorption/secretion of primary filtrated molecules and waste products by the kidney. Here we analyze time-dependent mechanisms of kidney damage and cardiac consequences under consideration of energetic pathways with the focus on mitochondrial function and lipid metabolism in mice. Methods and resultsCKD was induced by alternating dietary adenine supplementation (0.2 % or 0.05 % of adenine) in C57BL/6J mice for 9 weeks. Progressive kidney damage led to reduced creatinine clearance, kidney fibrosis and renal inflammation after 3, 6, and 9 weeks. No difference in cardiac function, mitochondrial respiration nor left ventricular fibrosis was observed at any time point. Investigating mechanisms of renal damage, protective SirT3 was decreased in CKD, which contrasted an increase in protein kinase B (AKT) expression, mechanistic target of rapamycin (mTOR) downstream signaling, induction of oxidative and endoplasmic reticulum (ER) stress. This occurred together with impaired renal mitochondrial function and accumulation of hexosylceramides (HexCer) as an established mediator of inflammation and mitochondrial dysfunction in the kidney. Conclusions2,8-DHA-induced CKD results in renal activation of the mTOR downstream signaling, endoplasmic reticulum stress, tubular injury, fibrosis, inflammation, oxidative stress and impaired kidney mitochondrial function in conjunction with renal hexosylceramide accumulation in C57BL/6J mice.

Evaluation of possible palliative role of tamarixetin against cisplatin-induced renal toxicity by modulation of oxidative stress, inflammation and apoptosis in rats

Cisplatin (CP) is a top-notch anti-cancerous agent that is used during the treatments of various types of tumors. Tamarixetin (TM) is a naturally occurring polyphenolic compound with versatile therapeutic and pharmacological abilities. The current investigation was purposed to elucidate the antagonistic effects of TM against CP-prompted renal intoxication. Sprague Dawley rats (n = 48) were separated into 4 equal groups i.e., Group 1st was designated as control group while the 2nd group was treated with CP (10 mg/kg) only, group 3rd received CP (10 mg/kg) + TM (50 mg/kg) and designated as a co-treated group while group 4th was administered with TM (50 mg/kg) only. Our results revealed that treatment of CP reduced the activity of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione-disulfide reductase (GSR), glutathione S-transferase (GST) as well as glutathione (GSH) while elevate ROS and MDA levels. CP administration raised the level of urea, creatinine, KIM1 along with NGAL while significant reduction in creatinine clearance. Whereas, CP treatment substantially elevated the level of caspase-3, caspase- 9 and Bcl-2 associated X protein (Bax) while reducing the level of B cell lymphoma protein 2 (Bcl-2). CP administration significantly elevated the concentration of nuclear factor kappa-B (NF-kB), interleukin 6 (IL-6), interleukin 1 beta (IL-1β) as well as tumor necrosis factor α (TNF-α), and instigated histopathological damages in renal tissues. However, Co-treatment of CP + TM showed palliative effects against CP-induced impairments. The current study manifested that TM is a potential flavonoid that could be used as a therapeutic drug to ameliorate renal damages instigated by CP.

#3950 EFFECT OF DEHYDRATION, HYPERTENSION, RENAL MASS REDUCTION AND AGE ON TRIPLE WHAMMY-ACUTE KIDNEY INJURY

Abstract Background and Aims Renin-angiotensin system inhibitors, diuretics and non-steroidal anti-inflammatory drugs (NSAIDs) is known as Triple Whammy (TW), a common combination used in hypertensive patients suffering from pain or inflammation; this combination of drugs can cause in some cases acute kidney injury (AKI). The renal outcome of the TW therapy seems to be influenced by additional factors, as the incidence of TW-induced AKI ranges from &amp;lt;1% to up to 22% depending on the study. The incidence of TW-AKI is higher among older adults, therefore age and other clinical conditions such as dehydration could be associated with TW-AKI. Furthermore, loss of functional nephrons in chronic kidney disease is a risk or predisposing factor for new AKI episodes. Consequently, the aim of our study was to analyse in vivo the influence of dehydration, age, renal mass reduction and hypertension (HTA) in TW therapy-induced AKI. Method Five experimental groups were subjected to TW therapy: (1) control group (3 months old Wistar rats); (2) dehydrated rats (3 months old Wistar rats with 60-70% water restriction); (3) aged rats (16 month old Wistar rats); (4) renal mass reduction (RMR) rats (3 months old Wistar rats with a 5/6 reduction of renal mass one month before the experiment); and (5) 3 months old spontaneously hypertensive rats). All rats received antihypertensive double therapy with Trandolapril in water and Furosemide i.p. for 4 days, and then a triple therapy for 2 days with Trandolapril and Ibuprofen in drinking water and Furosemide i.p. Blood and urine samples were collected at baseline (B), after 4 days of double therapy (day 4) and two days after triple therapy (day 6). Renal outcomes of the TW therapy were analysed by plasma creatinine, creatinine clearance, plasma urea and proteinuria. Results Risk factors such as dehydration or the loss of nephrons significantly increase plasma creatinine and urea and reduce creatinine clearance at day 6 compared to 3 months old Wistar rats without risk factors. Creatinine clearance is significantly reduced at day 4 in RMR and dehydration groups. Also, the RMR group shows at baseline and day 4 decreased creatinine clearance and increased plasma creatinine and urea than 3 months old Wistar rats. Proteinuria values are within normal ranges (&amp;lt; 10mg/day) in all experimental groups. Conclusion Renal mass reduction and dehydration are important risk factors in the development of AKI after TW therapy, while hypertension and age do not seem to influence renal outcomes. The knowledge of the specific conditions and the different factors that increase the risk of developing AKI in patients undergoing TW therapy will help us to stratify these patients based on their individual risk and to apply in each case the appropriate individualized treatment. This research was funded by grants from Instituto de Salud Carlos III (ISCIII) PI21/00548 and PI21/01226 co-funded by the European Union and Red de Investigación Renal RICORS2040 (Kidney Disease), RD21/0005/0004 co-funded by the European Union – NextGenerationEU, Mecanismo para la Recuperación y la Resiliencia (MRR). Eva M. Baranda-Alonso is recipient of a predoctoral fellowship from the Junta de Castilla y Leon (Spain) and the European Social Fund from the European Commission.Noelia Diaz-Morales is recipient of a Juan de la Cierva-Formación postdoctoral contract (FJC2020-043205-I) funded by MCIN/AEI/10.13039/501100011033 and European Union “NextGenerationEU/PRTR”.

Vitamin D and calcium co-therapy mitigates pre-established cadmium nephropathy by regulating renal calcium homeostatic molecules and improving anti-oxidative and anti-inflammatory activities in rat

BackgroundCadmium (Cd) is a major environmental pollutant and chronic toxicity could induce nephropathy by increasing renal oxidative stress and inflammation. Although vitamin D (VD) and calcium (Ca) prophylactic treatments attenuated Cd-induced cell injury, none of the prior studies measure their renoprotective effects against pre-established Cd-nephropathy. AimsTo measure the alleviating effects of VD and/or Ca single and dual therapies against pre-established nephrotoxicity induced by chronic Cd toxicity prior to treatment initiation. MethodsForty male adult rats were allocated into: negative controls (NC), positive controls (PC), Ca, VD and VC groups. The study lasted for eight weeks and all animals, except the NC, received CdCl2 in drinking water (44 mg/L) throughout the study. Ca (100 mg/kg) and/or VD (350 IU/kg) were given (five times/week) during the last four weeks to the designated groups. Subsequently, the expression of transforming growth factor-β (TGF-β1), inducible nitric oxide synthase (iNOS), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), VD synthesising (Cyp27b1) and catabolizing (Cyp24a1) enzymes with VD receptor (VDR) and binding protein (VDBP) was measured in renal tissues. Similarly, renal expression of Ca voltage-dependent channels (CaV1.1/CaV3.1), store-operated channels (RyR1/ITPR1), and binding proteins (CAM/CAMKIIA/S100A1/S100B) were measured. Serum markers of renal function alongside several markers of oxidative stress (MDA/H2O2/GSH/GPx/CAT) and inflammation (IL-6/TNF-α/IL-10) together with renal cell apoptosis and expression of caspase-3 were also measured. ResultsThe PC group exhibited hypovitaminosis D, hypocalcaemia, hypercalciuria, proteinuria, reduced creatinine clearance, and increased renal apoptosis/necrosis with higher caspase-3 expression. Markers of renal tissue damage (TGF-β1/iNOS/NGAL/KIM-1), oxidative stress (MDA/H2O2), and inflammation (TNF-α/IL-1β/IL-6) increased, whilst the antioxidants (GSH/GPx/CAT) and IL-10 decreased, in the PC group. The PC renal tissues also showed abnormal expression of Cyp27b1, Cyp24a1, VDR, and VDBP, alongside Ca-membranous (CaV1.1/CaV3.1) and store-operated channels (RyR1/ITPR1) and cytosolic Ca-binding proteins (CAM/CAMKIIA/S100A1/S100B). Although VD was superior to Ca monotherapy, their combination revealed the best mitigation effects by attenuating serum and renal tissue Cd concentrations, inflammation and oxidative stress, alongside modulating the expression of VD/Ca-molecules. ConclusionsThis study is the first to show improved alleviations against Cd-nephropathy by co-supplementing VD and Ca, possibly by better regulation of Ca-dependent anti-oxidative and anti-inflammatory actions.

The Effect of the Extra Virgin Olive Oil Minor Phenolic Compound 3',4'-Dihydroxyphenylglycol in Experimental Diabetic Kidney Disease.

The aim of this study was to analyze the possible nephroprotective effect of 3',4'-dihydroxyphenylglycol (DHPG), a polyphenolic compound of extra virgin olive oil (EVOO), on renal lesions in an experimental model of type 1 diabetes. Rats were distributed as follows: healthy normoglycemic rats (NDR), diabetic rats treated with saline (DR), and DR treated with 0.5 mg/kg/day or 1 mg/kg/day of DHPG. DR showed a significantly higher serum and renal oxidative and nitrosative stress profile than NDR, as well as reduced prostacyclin production and renal damage (defined as urinary protein excretion, reduced creatinine clearance, increased glomerular volume, and increased glomerulosclerosis index). DHPG reduced the oxidative and nitrosative stress and increased prostacyclin production (a 59.2% reduction in DR and 34.7-7.8% reduction in DHPG-treated rats), as well as 38-56% reduction in urinary protein excretion and 22-46% reduction in glomerular morphological parameters (after the treatment with 0.5 or 1 mg/kg/day, respectively). Conclusions: DHPG administration to type 1-like diabetic rats exerts a nephroprotective effect probably due to the sum of its antioxidant (Pearson's coefficient 0.68-0.74), antinitrosative (Pearson's coefficient 0.83), and prostacyclin production regulator (Pearson's coefficient 0.75) effects.

Ameliorative effect of lycopene alone and in combination with co-enzyme Q10 in streptozotocin-induced diabetic nephropathy in experimental rats

Diabetic nephropathy (DN) has become an utmost reason for long-standing renal dysfunction and end-stage renal disease globally. Oxidative stress induced by persistent hyperglycemia is considered a fundamental element in the evolution of DN. The goal of this research was to discover the outcome of appendages of natural antioxidants such as lycopene and co-enzyme Q10 (CoQ10) in DN rats and to observe the preventive effects in DN. A diabetes model was developed in a Wistar strain of male rats (200–250 g) by subcutaneous injection of streptozotocin (55 mg/kg). Development of nephropathy was assessed by renal function tests including blood glucose, creatinine, albumin, total protein, total bilirubin, uric acid, total cholesterol, triglycerides, and CRP level. Oxidative stress markers such as LPO and GSH content and activity of membrane-bound Na+/K+ ATPases were measured in kidney homogenate. Renal damage was assessed by performing a histopathological analysis. DN rats showed a significant elevation in creatinine, albumin, total protein, total bilirubin, uric acid, total cholesterol, triglycerides, CRP, and LPO levels whereas a significant reduction in creatinine clearance and GSH level. Treatment with antioxidants such as lycopene (5 mg/kg/p.o.) and CoQ10 (10 mg/kg/p.o.) along with their combination for 4 weeks notably altered the level of renal function biomarkers and oxidative stress markers. These antioxidants and their combination also protected the kidney from abnormal morphological changes. The present findings suggest that the combined administration of lycopene and CoQ10, which are antioxidants, exhibits synergistic effects in mitigating renal injury by reducing hyperglycemia, oxidative stress markers, and histopathological alterations.

Effect of tenofovir containing ART on renal function in patients with moderate/severe reduced creatinine clearance at baseline: A retrospective study at two referral hospitals in Namibia.

Prescription of tenofovir disoproxil fumarate (TDF) for patients with baseline creatinine clearances (CrCl) <60mL/min is said to increase risk of further decline in CrCl. Study objectives were to assess incidence of improvement and predictors thereof; to assess incidence of decline and transition to lower stages of CrCl; and comparison of declines between patients with a baseline CrCl<60mL/min (group-I) and≥60mL/min (group-II). The study was retrospective, included patients 16yrs or older who received TDF-containing ART. Improvement and decline were defined as≥25% increase or decrease in CrCl, respectively. Binary logistic regression was performed to identify predictors of improvement. Groups I and II had 2862 and 7526 patients, respectively. In group-I, improvement in CrCl was observed in 40.1% (n=1146), and was associated with stage IV of CrCl (adjusted Odds Ratio [aOR]=13.4 [95% CI: 6.7 - 26.9, P<.001]); male gender (aHR=1.8 [95% CI: 1.5 - 2.2, P<.001]); and a poor HIV-status (aHR=1.2 [95% CI: 1.0 - 1.4], P=.033). In group-I and group-II, respectively, decline occurred in 2.3% and 13.0%, (P<.001); transition to lower stages occurred in 1.0% and 25.2% (P<.001); and migration to stage IV CrCl occurred in 1.0% and 0.5% (P<.001). Improvement was more likely than decline in group-I patients. Although, group-I patients were more likely to experience new onset severe reduced CrCl than group-II patients, the proportions were extremely low. TDF should not be withheld from HIV-positive patients with a baseline CrCl<60mL/min.

Sesamol Attenuates Renal Inflammation and Arrests Reactive-Oxygen-Species-Mediated IL-1β Secretion via the HO-1-Induced Inhibition of the IKKα/NFκB Pathway In Vivo and In Vitro.

Chronic nephritis leads to irreversible renal fibrosis, ultimately leading to chronic kidney disease (CKD) and death. Macrophage infiltration and interleukin 1β (IL-1β) upregulation are involved in inflammation-mediated renal fibrosis and CKD. Sesamol (SM), which is extracted from sesame seeds, has antioxidant and anti-inflammatory properties. We aimed to explore whether SM mitigates macrophage-mediated renal inflammation and its underlying mechanisms. ApoE-/- mice were subjected to 5/6 nephrectomy (5/6 Nx) with or without the oral gavage of SM for eight weeks. Blood and urine samples and all the kidney remnants were collected for analysis. Additionally, THP-1 cells were used to explore the mechanism through which SM attenuates renal inflammation. Compared with the sham group, the 5/6 Nx ApoE-/- mice exhibited a significant increase in the macrophage infiltration of the kidneys (nephritis), upregulation of IL-1β, generation of reactive oxygen species, reduced creatinine clearance, and renal fibrosis. However, the administration of SM significantly alleviated these effects. SM suppressed the H2O2-induced secretion of IL-1β from the THP-1 cells via the heme oxygenase-1-induced inhibition of the IKKα-NF-κB pathway. SM attenuated renal inflammation and arrested macrophage accumulation by inhibiting IKKα, revealing a novel mechanism of the therapeutic effects of SM on renal injury and offering a potential approach to CKD treatment.

Seasonal variation of lupus nephritis in a cohort of Egyptian patients

IntroductionSystemic lupus erythematosus is an autoimmune multisystem disease; renal affection is one of its most common manifestations. The effect of environmental factors on lupus nephritis flares is not fully understood.MethodsThis is a retrospective study that included 200 patients with lupus nephritis flares. All patients had confirmed diagnosis of lupus nephritis on histopathological examination. Lupus nephritis flares were defined by either (1) nephritic flare: defined as increased proteinuria or serum creatinine concentration; abnormal urinary sediment or a reduction in creatinine clearance, or (2) proteinuria flare defined as persistent increase in proteinuria > 0.5–1.0 g/day after achieving complete remission; doubling to > 1 g/day after achieving partial remission. The time of renal flare (month of the year) was recorded to determine the effect of seasonal variation on lupus nephritis flares.ResultsThe median age for the patients was 33 years (IQR = 13); 92% of patients were females. The median duration of lupus was 7 years (IQR = 6). The median serum creatinine was 1.4 mg/dl, median serum urea level was 32, and median UPCR was 2.4 gm/dl. The highest incidence of flares occurred in June (14%) and July (12.5%) (p = 0.003).ConclusionSeasonal pattern of LN flare was observed in our study in Egyptian cohort of patients, with most flares observed during meteorological summertime. Larger studies are needed to confirm this seasonal pattern.Key Points• Flares of lupus nephritis are common in patients with systemic lupus erythromatosus.• A seasonal pattern of flares of lupus nephritis was observed in our study. This seasonal pattern has been observed by previous studies in variable ethnicities and variable climatic circumstances.