Increased Plasma Creatinine Research Articles

MO281: Development of an Experimental Model of Haemodynamic Frailty Predisposing to Acute Kidney Injury

Abstract BACKGROUND AND AIMS Frailty is a pre-morbid condition characterized by physiological decline and reduced physiological reserve leading to increased vulnerability to disease, especially common among older adults. Tissue and organ function is underpinned by effective haemodynamic regulation coping with everyday acute challenges and stressors. Impairment of the haemodynamic response may lead to tissue hypoperfusion and subsequent adverse events, such as acute kidney injury (AKI) and others. ‘Haemodynamic frailty’ defines a clinically silent condition characterized by a compromised haemodynamic reserve and impaired adaptive response to supervening circumstances (i.e. stressors such as drugs). Yet, frailty also offers a window of opportunity for disease prevention and health maintenance. Dehydration, hypertension and some drugs are important causes of haemodynamic frailty [1]. In this work, we aimed to develop a pre-clinical model of haemodynamic frailty, based on dehydration and hypertension, predisposing to AKI. METHOD Three-month old male spontaneously hypertensive (SHR) rats were divided into four groups: (1) Control (CT): rats with ad libitum access to drinking water, receiving saline solution (0.9% NaCl, i.p.). (2) Cisplatin (CDDP): rats with ad libitum access to drinking water, receiving a sub nephrotoxic dose of cisplatin (2.5 mg/kg, i.p.). (3) Water deprivation (WD): rats with no access to drinking water during 48 h, receiving saline solution (0.9% NaCl, i.p.). (4) Water deprivation + cisplatin (WD + CDDP): rats with no access to drinking water during the 48 h previous to the cisplatin administration (2.5 mg/kg, i.p.). The dose of cisplatin had proved to be sub-nephrotoxic for normal rats in our previous studies [2]. 24-hour urine and tail vein blood samples were collected at basal state (B), 2 days after water deprivation (D0), and 4 days after cisplatin administration (D4, day of maximum kidney damage). Urine samples were analysed for volume (urinary flow), specific gravity, osmolality, and proteinuria (Bradford method). Haematocrit was calculated from blood samples and plasma was used to determine osmolality, concentration of creatinine (Jaffe reaction) and urea (Jung method). RESULTS SHR rats with 48 hours of water deprivation showed a 10% weight loss, increases in haematocrit and plasma osmolality and a highly concentrated urine (with elevated levels of urine specific gravity and osmolality), which indicates a moderate to severe state of dehydration. No alterations in renal function were observed after water deprivation. Administration of cisplatin triggered significant increases in plasma creatinine, plasma urea and proteinuria, indicative of AKI, only in rats previously deprived of water for 48 h. All the parameters studied remained normal in cisplatin-treated rats without water restriction. Our results suggest that our experimental animal model, based on a combination of hypertension and dehydration, reproduces a state of haemodynamic frailty in which rats become predisposed to undergoing renal failure following exposure to stressors (e.g. a sub-nephrotoxic dose of cisplatin) that are harmless to haemodynamically competent rats. CONCLUSION To our knowledge, this is the first experimental model of haemodynamic frailty predisposing to AKI. This model will allow us to further study mechanisms and biomarkers useful for diagnosis and stratification of haemodynamic frailty in order to develop strategies to prevent undesired health outcomes, including renal damage.

Glutathione peroxidase 4 prevents 12/15 LOX induced renal oxidative cell death and improves renal post Ischemic recovery in Male Spontaneous Hypertensive Rats (SHR)

Acute kidney injury (AKI) due to ischemia‐reperfusion (IR) is a serious and frequent complication in hospital setting with high mortality rates. The mechanisms mediating renal IR injury leading to increased risk of later developing cardiovascular and renal diseases in either sex remain poorly understood. Glutathione peroxidase 4 (GPx4) is a negative regulator of 12/15 lipoxygenase (12/15 LOX) and any alteration in 12/15 LOX and GPx4 activity has been reported to contribute to the progression of kidney diseases. The goal of the current study was to test the hypothesis that an imbalance of 12/15 LOX/GPx4 activity in males leads to impaired recovery following IR compared to females. 13‐week‐old male and female SHR were subjected to sham or 30‐minute warm bilateral IR (n=6/group). Additional male SHR were randomized to receive vehicle or the GPx4 activity mimic ebselen (10 mg/kg i.p.; n=5/group) 1 hr prior to sham/IR, 1 day and 3‐day post IR. Blood and urine were collected from all rats 1 and 7 days after IR; kidneys were harvested 7 days post‐IR for biochemical, histological, and Western blot analysis. IR increased plasma creatinine (Pcr) and blood urea nitrogen (BUN) in both male and female SHR compared to respective sham controls at 24 hrs (PIR =0.0001; Psex*IR=0.2). At 7 days post‐IR, Pcr and BUN remained elevated in male SHR but returned to baseline levels in females (Pcr: PIR =0.03; Psex*IR=0.04; BUN: PIR <0.05; Psex*IR=0.05). Histological examination of kidneys 7 days post‐IR showed greater tubular damage (PIR=0.0003, Psex*IR=0.0019) and renal cell death (PIR=0.001; Psex*IR=0.001) in male vs. female SHR. Delayed recovery of renal function in male SHR was associated with activation of renal 12/15 LOX (PIR<0.05; Psex*IR=0.008), reduced renal GPx4 protein expression (PIR=0.05; Psex*IR<0.001), activity (PIR=0.01; Psex*IR=0.0016), and intracellular glutathione (GSH; PIR=0.01; Psex*IR=0.003), and increased lipid peroxidation (PIR=0.008; Psex*IR=0.018) compared to females. Pre‐treatment of male SHR with ebselen significantly reduced 12/15 LOX induced lipid peroxidation (PIR*TxT =0.02), prevented IR‐induced renal cell death (PIR*TxT=0.04) and tubular damage (PIR*TxT=0.02) and improved renal function (Pcr: PIR*TxT =0.027; BUN: PIR*TxT =0.022) compared to vehicle‐treated IR males 7 days post‐IR. In conclusion, our data demonstrate that increased GPx4 activity enhanced renal recovery post‐IR via inhibiting 12/15 LOX induced oxidative renal cell death in male SHR.

The Pathogenesis of Ischemia-Reperfusion Induced Acute Kidney Injury Depends on Renal Neutrophil Recruitment Whereas Sepsis-Induced AKI Does Not.

Acute kidney injury (AKI) may be induced by different causes, including renal ischemia-reperfusion injury and sepsis, which represent the most common reasons for AKI in hospitalized patients. AKI is defined by reduced urine production and/or increased plasma creatinine. However, this definition does not address the molecular mechanisms of different AKI entities, and uncertainties remain regarding distinct pathophysiological events causing kidney injury in the first place. In particular, sepsis-induced AKI is considered not to be associated with leukocyte infiltration into the kidney, but a direct investigation of this process is missing to this date. In this study, we used two murine AKI models induced by either renal ischemia-reperfusion injury (IRI) or cecal ligation and puncture (CLP) to investigate the contribution of neutrophils to tissue injury and kidney function. By using VEC-Y731F mice, in which neutrophil recruitment is impaired, we analyzed the specific contribution of neutrophil recruitment to the pathogenesis of IRI- and CLP-induced AKI. We observed that the degree of renal injury evaluated by plasma creatinine, urinary biomarkers and histological analyses, following IRI-induction was dependent on neutrophil migration into the kidney, whereas the pathogenesis of CLP-induced AKI was independent of neutrophil recruitment. Furthermore, plasma transfer experiments suggest that the pathogenesis of CLP-induced AKI relies on circulating inflammatory mediators. These results extend our knowledge of the AKI pathogenesis and may help in the development of prophylactic and therapeutic treatments for AKI patients.

Effects of exposure of chlorpyrifos-ethyl on metabolism and oxidative damage in rats and their offspring

Chlorpyrifos-ethyl (CE) is one of the most widely used organophosphorus insecticides for industrial, agricultural and public health purposes. The aim of the study was to evaluate the effect of CE exposure via gavage on metabolic and redox status in pregnant, lactating rats and their pups at weaning. The oral administration of this pesticide at doses of 1 mg/kg of body weight No Observed Adverse Effects Level (NOAEL), 5.4mg/kg b.wt (1/25LD50) and 13.5 mg/kg b.wt (1/10LD50) was given 1day/2 to female rats during the entire gestation and lactation period. Plasma biochemical parameters as well as lipid profiles and oxidative stress markers were determined. Oral CE exposure induced an increase in plasma glucose, urea, creatinine and lipid status levels in mothers at parturition (day 0) and at the end of lactation (day21) and in their offspring at weaning (day21). An altered oxidant/antioxidant status marked in mothers treated by the insecticide at day 0 and day 21 and these disturbances were also seen in their offspring. In conclusion, different doses CE exposure induced several metabolic and redox alterations leading to maternal physiological impairments and to offspring metabolic changes. CE should be used with caution especially during pregnancy and lactation period.

Impact of early postoperative creatinine increase on mid-term renal function after cystectomy.

To determine whether early acute kidney injury affects mid-term renal function, to identify risk factors for impaired mid-term renal function, and to highlight the evolution of plasma creatinine and estimated glomerular filtration rate in the first 12 months after cystectomy and urinary diversion. We conducted a single-center retrospective observational cohort study from 2000 to 2019. We included 900 consecutive patients undergoing cystectomy and urinary diversion. Patients with incomplete data and preoperative hemodialysis were excluded. Early acute kidney injury was defined as an increase in plasma creatinine of >50% or >26.5 μmol/L within 24 h after surgery. Multiple linear regression analysis was performed to model the association between risk factors and change in plasma creatinine and estimated glomerular filtration rate at 12 months. Early acute kidney injury was diagnosed in 183/900 patients (20.3%) and was associated with significant mid-term plasma creatinine increase compared to preoperative value (+10.0 μmol/L [95% confidence interval -1.5, 25.0] vs +4.0 μmol/L [-7.0, 13.0]; P < 0.001). Similarly, a significant estimated glomerular filtration rate change was found (-11.2 mL/min [95% confidence interval -19.8, 0.6] vs -4.9 mL/min [-15.6, 5.3]; P < 0.001). In the linear regression model, early acute kidney injury increased creatinine at 12 months by 9.8% (estimated glomerular filtration rate: decrease by 6.2 mL/min), male sex by 12.0%. Limitations include retrospective analysis from prospectively assessed data. Early acute kidney injury resulted in elevated plasma creatinine and decreased estimated glomerular filtration rate values 12 months postoperatively, albeit the clinical relevance remains questionable.

Metabolic transformation of fat in obesity determines the inflammation resolving capacity of splenocardiac and cardiorenal networks in heart failure.

All fats are not created equal, and despite the extensive literature, the effect of fat intake is the most debated question in obesity, cardiovascular, and cardiorenal research. Cellular and molecular mechanisms underlying cardiac dysfunction and consequent heart failure in the setting of obesity are not well understood. Our understanding of how fats are metabolically transformed after nonreperfused myocardial infarction (MI), in particular, is incomplete. Here, using male C57BL/6J mice (2 mo old), we determined the role of omega-6 fatty acids, provided as safflower oil (SO) for 12 wk, followed by supplementation with docosahexaenoic acid (DHA; n-3 fatty acids) for 8 wk before MI. With SO feeding, inflammation resolution was impaired. Specialized proresolving mediators (SPMs) increased in DHA-fed mice to reverse the effects of SO, whereas prostaglandins and thromboxane B2 were reduced in the spleen and amplified multiple resolving mechanisms in heart and kidney post-MI. DHA amplified the number of resolving macrophages and cardiac reparative pathways of the splenocardiac and cardiorenal networks in acute heart failure, with higher Treg cells in chronic heart failure and marked expression of Foxp3+ in the myocardium. Our findings indicate that surplus ingestion of SO intensified systemic, baseline, nonresolving inflammation, and DHA intake dominates splenocardiac resolving phase with the biosynthesis of SPMs and controlled cardiorenal inflammation in heart failure survivor mice.NEW & NOTEWORTHY Chronic and surplus dietary intake of safflower oil (SO) increased plasma creatinine dysregulated post-MI splenocardiac inflammation coincides with the dysfunctional cardiorenal network. In contrast, docosahexaenoic acid (DHA) increases post-MI survival in chronic heart failure. DHA transforms into specialized proresolving mediators (SPMs) and limited proinflammatory prostaglandins and thromboxanes following myocardial infarction (MI). DHA promotes Ly6Clow resolving macrophages and T regulatory cells (Foxp3+) in a splenocardiac manner post-MI.

Renal graft and pregnancy (Literature review)

The article is devoted to a review of the literature, which highlights the issues of maternal and perinatal complications and management of pregnant women who are renal transplant recipients.The risks of the development of hypertensive complications, preeclampsia, infectious complications, gestational diabetes and the risk of the fetus during pregnancy in these women are discussed in details. Pregnancy does not cause graft rejection, but pregestational hypertension, increased plasma creatinine and significant pregestational proteinuria are the risk factors for this complication. Pregnant women with a kidney transplant have a significantly higher risk of fetal growth retardation and premature birth.The article provides recommendations for the optimal period for pregnancy after transplantation which are recommended by various professional medical societies, although there is still no agreement on this issue: the American Society of Transplantation claims that the ideal period is 12-24 months after transplantation, while European best practice guidelines recommends to plan pregnancy no earlier than 2 years after surgery.The observation of pregnant women who are renal transplant recipients should be performed by an obstetrician-gynecologist with experience in high-risk pregnancy together with a transplantologist and perinatologist or neonatologist. All pregnant women who are kidney transplant recipients should be monitored for blood pressure, and aggressive antihypertensive therapy should be prescribed if it increases. It is also necessary to monitor the function of the graft, on suspicion of rejection it is possible to perform ultrasound-controlled kidney biopsy.The principles of immunosuppressive therapy during pregnancy, which includes prednisolone, methylprednisolone, tacrolimus, cyclosporine and azathioprine, and the description the side effects for the mother, the impact on the fetus and breastfeeding of each of the drugs are presented in the article. In the absence of obstetric complications, the optimal method of delivery is spontaneous delivery through the natural birth canal in the term of 38-40 weeks of pregnancy. Breastfeeding is recommended despite immunosuppressive therapy. Breast-feeding should be avoided when such medications as mycophenolate mofetil, sirolimus, everolimus and belatacept are used.Despite the high risk of pregnancy and childbirth, kidney transplant recipients have a good chance of pregnancy outcomes and giving birth to a living child while maintaining their own health. Therefore, motherhood should be encouraged among such women, supported and provided with highly qualified medical care.

TNF-α induces Claudin-1 expression in renal tubules in Alport mice.

Claudin-1 (CL-1) is responsible for the paracellular barrier function of glomerular parietal epithelial cells (PEC) in kidneys, but the role of CL-1 in proximal tubules remains to be elucidated. In this study, to evaluate CL-1 as a potential therapeutic drug target for chronic kidney disease, we investigated change of CL-1 expression in the proximal tubules of diseased kidney and elucidated the factors that induced this change. We established Alport mice as a kidney disease model and investigated the expression of CL-1 in diseased kidney using quantitative PCR and immunohistochemistry (IHC). Compared to wild type mice, Alport mice showed significant increases in plasma creatinine, urea nitrogen and urinary albumin excretion. CL-1 mRNA was increased significantly in the kidney cortex and CL-1 was localized on the adjacent cell surfaces of PECs and proximal tubular epithelial cells. The infiltration of inflammatory cells around proximal tubules and a significant increase in TNF-α mRNA were observed in diseased kidneys. To reveal factors that induce CL-1, we analyzed the induction of CL-1 by albumin or tumor necrosis factor (TNF)-α in human proximal tubular cells (RPTEC/TERT1) using quantitative PCR and Western blotting. TNF-α increased CL-1 expression dose-dependently, though albumin did not affect CL-1 expression in RPTEC/TERT1. In addition, both CL-1 and TNF-α expression were significantly increased in UUO mice, which are commonly used as a model of tubulointerstitial inflammation without albuminuria. These results indicate that CL-1 expression is induced by inflammation, not by albuminuria in diseased proximal tubules. Moreover, we examined the localization of CL-1 in the kidney of IgA nephropathy patients by IHC and found CL-1 expression was also elevated in the proximal tubular cells. Taken together, CL-1 expression is increased in the proximal tubular epithelial cells of diseased kidney. Inflammatory cells around the tubular epithelium may produce TNF-α which in turn induces CL-1 expression.

Vascular Endothelial Dysfunction in the Thoracic Aorta of Rats with Ischemic Acute Kidney Injury: Contribution of Indoxyl Sulfate

Chronic kidney disease (CKD) and cardiovascular disease are known to be linked, and the involvement of indoxyl sulfate (IS), a type of uremic toxin, has been suggested as one of the causes. It is known that IS induces vascular dysfunction through overproduction of reactive oxygen species (ROS). On the other hand, the involvement of IS in the vascular dysfunction associated with acute kidney injury (AKI) is not fully understood. Therefore, we investigated this issue using the thoracic aorta of rats with ischemic AKI. Ischemic AKI was induced by occlusion of the left renal artery and vein for 45 min, followed by reperfusion 2 weeks after contralateral nephrectomy. One day after reperfusion, there was marked deterioration in renal function evidenced by an increase in plasma creatinine. Furthermore, blood IS levels increased markedly due to worsening renal function. Seven days and 28 days after reperfusion, blood IS levels decreased with the improvement in renal function. Of note, acetylcholine-induced vasorelaxation deteriorated over time after reperfusion, contradicting the recovery of renal function. In addition, 28 days after reperfusion, we observed a significant increase in ROS production in the vascular tissue. Next, we administered AST-120, a spherical adsorbent charcoal, after reperfusion to assess whether the vascular endothelial dysfunction associated with the ischemic AKI was due to a temporary increase in blood IS levels. AST-120 reduced the temporary increase in blood IS levels after reperfusion without influencing renal function, but did not restore the impaired vascular reactivity. Thus, in ischemic AKI, we confirmed that the vascular endothelial function of the thoracic aorta is impaired even after the recovery of kidney injury, probably with excessive ROS production. IS, which increases from ischemia to early after reperfusion, may not be a major contributor to the vascular dysfunction associated with ischemic AKI.

Dual SGLT1/SGLT2 inhibitor phlorizin reduces glucose transport in experimental peritoneal dialysis.

Glucose absorption during peritoneal dialysis (PD) is commonly assumed to occur via paracellular pathways. We recently showed that SGLT2 inhibition did not reduce glucose absorption in experimental PD, but the potential role of glucose transport into cells is still unclear. Here we sought to elucidate the effects of phlorizin, a non-selective competitive inhibitor of sodium glucose co-transporters 1 and 2 (SGLT1 and SGLT2), in an experimental rat model of PD. A 120-min PD dwell was performed in 12 anesthetised Sprague-Dawley rats using 1.5% glucose fluid with a fill volume of 20 mL with (n = 6) or without (n = 6) intraperitoneal phlorizin (50 mg/L). Several parameters for peritoneal water and solute transport were monitored during the treatment. Phlorizin markedly increased the urinary excretion of glucose, lowered plasma glucose and increased plasma creatinine after PD. Median glucose diffusion capacity at 60 min was significantly lower (p < 0.05) being 196 µL/min (IQR 178-213) for phlorizin-treated animals compared to 238 µL/min (IQR 233-268) in controls. Median fractional dialysate glucose concentration at 60 min (D/D 0) was significantly higher (p < 0.05) in phlorizin-treated animals being 0.65 (IQR 0.63-0.67) compared to 0.61 (IQR 0.60-0.62) in controls. At 120 min, there was no difference in solute or water transport across the peritoneal membrane. Our findings indicate that a part of glucose absorption during the initial part of the dwell occurs via transport into peritoneal cells.

Analysis of clinical features of patients with type 2 diabetes mellitus with different levels of glomerular filtration rate

Aim to improve the dispensary follow-up of patients with type 2 diabetes (DM) by identifying clinical signs, available during examination in the outpatient clinic, that suggest the development of chronic kidney disease (CKD).&#x0D; Material and methods. A cross-sectional study included a population sample of patients with type 2 diabetes and focused on the clinical indices available during an outpatient consultation. 150 protocols of outpatient consultations were selected using the compliance criteria, including data on 72 clinical indices. The general sample was divided into groups in two ways: by the level of glomerular filtration rate (GFR) and by achieving the goals of glycemic control (calculated parameter delta HbA1c).&#x0D; Results. The following indices differed most significantly in the groups divided by stages of CKD: gender, age, duration of diabetes and insulin therapy, achievement of target values of glycemic control, blood pressure level, comorbid cardiovascular pathology, pulse on the popliteal artery. In patients with preserved GFR and the early stages of CKD, the fact of unsatisfactory glycemic control was associated with an increase in plasma creatinine and a decrease in GFR, higher blood pressure values. In the advanced stages of CKD, the impact of glycemic control on kidney function was practically absent.

Risk factors and implications associated with renal mineralization in chronic kidney disease in cats.

BackgroundNephrocalcinosis is a pathological feature of chronic kidney disease (CKD). Its pathophysiological implications for cats with CKD are unexplored.ObjectivesIdentify nephrocalcinosis risk factors and evaluate its influence on CKD progression and all‐cause mortality.AnimalsFifty‐one euthyroid client‐owned cats with International Renal Interest Society (IRIS) stages 2‐3 azotemic CKD.MethodsRetrospective cohort study. Histopathological kidney sections were assessed for nephrocalcinosis (von Kossa stain). Nephrocalcinosis severity was determined by image analysis (ImageJ). Ordinal logistic regressions were performed to identify nephrocalcinosis risk factors. The influence of nephrocalcinosis on CKD progression and mortality risk were assessed using linear mixed model and Cox regression, respectively. Cats were categorized by their owner‐reported time‐averaged phosphate‐restricted diet (PRD) intake, where PRD comprised ≥50%, 10‐50%, or none of food intake.ResultsNephrocalcinosis was rated as mild‐to‐severe in 78.4% and absent‐to‐minimal in 21.6% of cases. Higher baseline plasma total calcium concentration (tCa; odds ratio [OR] = 3.07 per 1 mg/dL; P = .02) and eating a PRD (10%‐50%: OR = 8.35; P = .01; ≥50%: OR = 5.47; P = .01) were independent nephrocalcinosis risk factors. Cats with absent‐to‐minimal nephrocalcinosis had increasing plasma creatinine (0.250 ± 0.074 mg/dL/month; P = .002), urea (5.06 ± 1.82 mg/dL/month; P = .01), and phosphate (0.233 ± 0.115 mg/dL/month; P = .05) concentrations over a 1‐year period, and had shorter median survival times than cats with mild‐to‐severe nephrocalcinosis.Conclusion and Clinical ImportanceHigher plasma tCa at CKD diagnosis and PRD intake are independently associated with nephrocalcinosis. However, nephrocalcinosis is not associated with rapid CKD progression in cats.

The Allium triquetrum L. Leaves Mitigated Hepatotoxicity and Nephrotoxicity Induced by Lead Acetate in Wistar Rats.

The aim of this study was to scrutinize the possible mitigating role of leaves' Allium triquetrum L. against the toxicity of lead acetate on liver and kidney markers of Wistar rat. Lead acetate (Pb) and leaves' aqueous extracts (L) were orally administrated for 3 weeks. Rats were divided into the control, Pb group (500 mg/kg body weight/day), positive controls L (2g, 3g, 4g/kg BW/day), along with three combined groups of the same doses (Pb-L1, Pb-L2, Pb-L3). The levels of plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total proteins (TP), albumin (ALB), urea, creatinine (Cr), and uric acid (UA), as well as the hepatic and the renal malondialdehyde (MDA), glutathione (GSH), and glutathione peroxidase (GPx), were estimated. Results exhibited a significant increase in plasma AST, ALT, ALP, urea, creatinine, uric acid, and MDA levels of the Pb group compared to the control, with the exception of TP, ALB, GSH levels, and GPx activities that were significantly diminished, though the co-administration of garlic extracts (Pb-L) revealed a significant decrease in all mentioned markers, excluding the TP, ALB, GSH, and GPx levels. Likewise, Pb caused histological injuries in the hepatic and renal tissues of rats, while the co-administration of leaves' wild garlic has reduced such effect. Thought, the Pb-L has attenuated the Pb-induced toxicity in a dose-dependent manner. In conclusion, the aqueous extracts of A. triquetrum have the potential to alleviate Pb hepatotoxicity and nephrotoxicity through the modulation of most biomarkers in Wistar rat.

Dehydration before Major Urological Surgery and the Perioperative Pattern of Plasma Creatinine: A Prospective Cohort Series

Preoperative dehydration is usually found in 30–50% of surgical patients, but the incidence is unknown in the urologic population. We determined the prevalence of preoperative dehydration in major elective urological surgery and studied its association with postoperative outcome, with special attention to plasma creatinine changes. We recruited 187 patients scheduled for major abdominal urological surgery to participate in a single-center study that used the fluid retention index (FRI), which is a composite index of four urinary biomarkers that correlate with renal water conservation, to assess the presence of dehydration. Secondary outcomes were postoperative nausea and vomiting (PONV), return of gastrointestinal function, in-hospital complications, quality of recovery, and plasma creatinine. The proportion of dehydrated patients at surgery was 20.4%. Dehydration did not correlate with quality of recovery, PONV, or other complications, but dehydrated patients showed later defecation (p = 0.02) and significant elevations of plasma creatinine after surgery. The elevations were also greater when plasma creatinine had increased rather than decreased during the 24 h prior to surgery (p < 0.001). Overall, the increase in plasma creatinine at 6 h after surgery correlated well with elevations on postoperative days one and two. In conclusion, we found preoperative dehydration in one-fifth of the patients. Dehydration was associated with delayed defecation and elevated postoperative plasma creatinine. The preoperative plasma creatinine pattern could independently forecast more pronounced increases during the early postoperative period.

Type 1 diabetes and oxidative stress markers

Oxidative stress is associated with numerous chronic inflammatory diseases. In type 1 diabetes (T1D), oxidative stress is involved in various complications and might be among the probable causes. In this study, we assessed some markers of oxidative stress and their relationship with the course of T1D.Materials and Methods: This study was carried out on 76 patients with T1D (men and women) and 10 healthy controls. The patients underwent biochemical (glycemia, HbA1c, total cholesterol, triglycerides, creatinine, urea and arterial pressure), and oxidative stress markers evaluation: superoxyde dismutase (SOD), catalase (CAT), xanthine oxidase (XO), malondialdehyde (MDA) and reduced glutathione (GSH).Results: Results show a highly significant increase (P≤0.001) in blood sugar, HbA1c, and plasma creatinine and urea levels in diabetic patients compared to controls. Cholesterol levels show no significant difference, while triglyceride values are significantly elevated compared to healthy people. Levels of MDA, a lipid peroxidation product, are significantly elevated compared to control values. Regarding the antioxidant defense system, there was a significant increase (p< 0.05) in SOD and CAT activities and a reduction in the level of GSH. XO was particularly higher in men than in women.Conclusion: The oxidant / antioxidant balance is altered during diabetes. The oxidative stress biomarkers such as MDA and XO in T1D may be a useful tool to monitor progressive complications. These results are preliminary and requires further investigations on a large cohort to assess the potential role of oxidative markers in T1D.

Early type 1 diabetes aggravates renal ischemia/reperfusion-induced acute kidney injury

The present study aimed to investigate the interaction between early diabetes and renal IR-induced AKI and to clarify the mechanisms involved. C57BL/6J mice were assigned to the following groups: (1) sham-operated; (2) renal IR; (3) streptozotocin (STZ—55 mg/kg/day) and sham operation; and (4) STZ and renal IR. On the 12th day after treatments, the animals were subjected to bilateral IR for 30 min followed by reperfusion for 48 h, at which time the animals were euthanized. Renal function was assessed by plasma creatinine and urea levels, as well urinary protein contents. Kidney morphology and gene and protein expression were also evaluated. Compared to the sham group, renal IR increased plasma creatinine, urea and albuminuria levels and decreased Nphs1 mRNA expression and nephrin and WT1 protein staining. Tubular injury was observed with increased Havcr1 and Mki67 mRNA expression accompanied by reduced megalin staining. Renal IR also resulted in increased SQSTM1 protein expression and increased proinflammatory and profibrotic factors mRNA expression. Although STZ treatment resulted in hyperglycemia, it did not induce significant changes in renal function. On the other hand, STZ treatment aggravated renal IR-induced AKI by exacerbating renal dysfunction, glomerular and tubular injury, inflammation, and profibrotic responses. Thus, early diabetes constitutes a relevant risk factor for renal IR-induced AKI.

Preoperative Concentrated Urine Increases the Incidence of Plasma Creatinine Elevation After Major Surgery.

Background: Postoperative elevation of plasma creatinine is a frequent complication to major surgery. A rise by 50% fulfills the criterion for Acute Kidney Injury. We studied the relationship between concentrated urine before surgery, which is usually a sign of chronically low intake of water, and the perioperative change in plasma creatinine.Methods: The creatinine concentration was measured in plasma and urine just before and at 6 h, 1 day, and 2 days after major abdominal surgery in a consecutive series of 181 patients. Receiver operating curve analysis was used to find the optimal cut-off to separate concentrated from diluted urine.Results: Urine creatinine of 11.3 mmol/L before the surgery started was exceeded in one third of the patients and associated with greater increase in plasma creatinine at 6 h (median 21 vs. 10%) and at 1 day postoperatively (21 vs. 7%; P < 0.0001). Elevation of plasma creatinine of >25% occurred in 41% and 19% in those with high and low urine creatinine, respectively (P < 0.001) and an increase by >50% in 16% and 10% (P = 0.27). Patients with high urine creatinine before surgery failed to further concentrate their urine during the perioperative period, which is normally associated with intensified renal fluid conservation.Conclusion: High urinary concentration of creatinine before surgery should be considered as a risk factor for postoperative elevation of plasma creatinine. The mechanism is probably that the renal threshold is then more easily reached.

Preservation of renal endothelial integrity and reduction of renal edema by aprotinin does not preserve renal perfusion and function following experimental cardiopulmonary bypass

BackgroundAcute kidney injury is a severe complication following cardiopulmonary bypass (CPB) and is associated with capillary leakage and microcirculatory perfusion disturbances. CPB-induced thrombin release results in capillary hyperpermeability via activation of protease-activated receptor 1 (PAR1). We investigated whether aprotinin, which is thought to prevent thrombin from activating PAR1, preserves renal endothelial structure, reduces renal edema and preserves renal perfusion and reduces renal injury following CPB.MethodsRats were subjected to CPB after treatment with 33.000 KIU/kg aprotinin (n = 15) or PBS (n = 15) as control. A secondary dose of 33.000 KIU/kg aprotinin was given 60 min after initiation of CPB. Cremaster and renal microcirculatory perfusion were assessed using intravital microscopy and contrast echography before CPB and 10 and 60 min after weaning from CPB. Renal edema was determined by wet/dry weight ratio and renal endothelial structure by electron microscopy. Renal PAR1 gene and protein expression and markers of renal injury were determined.ResultsCPB reduced cremaster microcirculatory perfusion by 2.5-fold (15 (10–16) to 6 (2–10) perfused microvessels, p < 0.0001) and renal perfusion by 1.6-fold (202 (67–599) to 129 (31–292) au/sec, p = 0.03) in control animals. Both did not restore 60 min post-CPB. This was paralleled by increased plasma creatinine (p < 0.01), neutrophil gelatinase-associated lipocalin (NGAL; p = 0.003) and kidney injury molecule-1 (KIM-1; p < 0.01). Aprotinin treatment preserved cremaster microcirculatory perfusion following CPB (12 (7–15) vs. 6 (2–10) perfused microvessels, p = 0.002), but not renal perfusion (96 (35–313) vs. 129 (31–292) au/s, p > 0.9) compared to untreated rats. Aprotinin treatment reduced endothelial gap formation (0.5 ± 0.5 vs. 3.1 ± 1.4 gaps, p < 0.0001), kidney wet/dry weight ratio (4.6 ± 0.2 vs. 4.4 ± 0.2, p = 0.046), and fluid requirements (3.9 ± 3.3 vs. 7.5 ± 3.0 ml, p = 0.006) compared to untreated rats. In addition, aprotinin treatment reduced tubulointerstitial neutrophil influx by 1.7-fold compared to untreated rats (30.7 ± 22.1 vs. 53.2 ± 17.2 neutrophil influx/section, p = 0.009). No differences were observed in renal PAR1 expression and plasma creatinine, NGAL or KIM-1 between groups.ConclusionsAprotinin did not improve renal perfusion nor reduce renal injury during the first hour following experimental CPB despite preservation of renal endothelial integrity and reduction of renal edema.

Hypercholesterolemia in Progressive Renal Failure Is Associated with Changes in Hepatic Heparan Sulfate - PCSK9 Interaction.

Dyslipidemia is an important risk factor in CKD. The liver clears triglyceride-rich lipoproteins (TRL) via LDL receptor (LDLR), LDLR-related protein-1 (LRP-1), and heparan sulfate proteoglycans (HSPGs), mostly syndecan-1. HSPGs also facilitate LDLR degradation by proprotein convertase subtilisin/kexin type 9 (PCSK9). Progressive renal failure affects the structure and activity of hepatic lipoprotein receptors, PCSK9, and plasma cholesterol. Uninephrectomy- and aging-induced CKD in normotensive Wistar rats and hypertensive Munich-Wistar-Frömter (MWF) rats. Compared with 22-week-old sex- and strain-matched rats, 48-week-old uninephrectomized Wistar-CKD and MWF-CKD rats showed proteinuria, increased plasma creatinine, and hypercholesterolemia (all P<0.05), which were most apparent in hypertensive MWF-CKD rats. Hepatic PCSK9 expression increased in both CKD groups (P<0.05), with unusual sinusoidal localization, which was not seen in 22-week-old rats. Heparan sulfate (HS) disaccharide analysis, staining with anti-HS mAbs, and mRNA expression of HS polymerase exostosin-1 (Ext-1), revealed elongated HS chains in both CKD groups. Solid-phase competition assays showed that the PCSK9 interaction with heparin-albumin (HS-proteoglycan analogue) was critically dependent on polysaccharide chain length. VLDL binding to HS from CKD livers was reduced (P<0.05). Proteinuria and plasma creatinine strongly associated with plasma cholesterol, PCSK9, and HS changes. Progressive CKD induces hepatic HS elongation, leading to increased interaction with PCSK9. This might reduce hepatic lipoprotein uptake and thereby induce dyslipidemia in CKD. Therefore, PCSK9/HS may be a novel target to control dyslipidemia.

MO654REAL LIFE EXPERIENCE AFTER 20 MONTHS USING SGLT2 INHIBITORS

Abstract Background and Aims Diabetic kidney disease (DKD) develops in almost half of diabetic patients and is the leading cause of chronic kidney disease (CKD). SGLT2 inhibitors (SGLT2i) have consistently shown to confer kidney protection in patients with type 2 diabetes (T2D). The recent KDIGO guidelines suggest their use as a first line medication along with metformin. After the study CREDENCE was published, in mid-2019, DKD patients at the Nephrology outpatient department of the Hospital of Braga were started on SGLT2i. We aimed at assessing these patients’ clinical and laboratory data after the introduction of the new drug. Method We collected data on age, gender, weight, blood pressure (BP) values, the use of renin-angiotension-aldosterone system inhibitors (RAASi), kidney function, glycated hemoglobin (HbA1c), glycosuria, proteinuria and albuminuria at baseline and during the two next patient assessments. Data was analyzed using SPSS®. Results Twenty-nine DKD patients who started SGLT2i between May 2019 and August 2020 were followed. Mean age was 71.2±13.5 years, 22 patients were male and their mean weight was 86.9±13.9 kg. They had had T2D for a mean of 15.9±10.3 years and a significant percent had end organ damage: 34% had diabetic retinopathy, 24% complaints suggestive of neuropathy, 51% had documented heart failure and 27% had cerebral vascular disease. Most were hypertensive with a mean BP of 156±19/83±11mmHg and 72.4% were taking RAASi. One third were treated with insulin. Most patients were started on canagliflozin (n=28) and one patient started empagliflozin. After starting the drug, patients were evaluated at a mean time of 141±55 days and had a second reevaluation at a mean time of 254±72 days. On the first evaluation they showed a significant reduction in the mean systolic BP to 140±15.1mmHg (p=0.001). Glycated hemoglobin decreased from a mean of 7.4±1.3% to 7.1±1.1% although this difference was not significant (p=0.4). Protein-creatinine urinary ratio was significantly reduced from a median value of 1.48 (IQR 0.24-1.85) to 0.93 (IQR 0.40-1.56). Mean serum creatinine increased significantly from baseline until the first evaluation at 1.96±0.49 to 2.27±0.66mg/dL (p=0.00) but remained stable on the second evaluation (2.29±0.79mg/dL). Seventy percent of the patients developed significant glycosuria (urinary concentration &amp;gt;500mg/dL) after starting SGLT2i. When asked about adherence, most non-glycosuric patients admitted not having started the drug. Conclusion Despite having a weak effect in the reduction of HbA1c, SGLT2i are an exciting drug for kidney protection in DKD. Patient adherence is easy to assess based on glycosuria. In our experience and based on this criterion drug compliance was acceptable (at least 70%) and we were able to reinforce instructions among non-compliant patients. Some of the benefits of SGLT2i were evident soon after they were started such as the improvement in BP and proteinuria. The initial increase in plasma creatinine was expected due to reduction in intraglomerular pressure and hyperfiltration and was noticeable only on the first assessment. We expect to continue SGLT2i use DKD patients.