Kidney Protection Research Articles

Kidney Protection: Strategies for Renal Preservation

Kidney Protection: Strategies for Renal Preservation

Clinical efficacy and safety of Chinese herbal medicine for the treatment of patients with early diabetic nephropathy: A protocol for systematic review and meta-analysis.

Diabetic nephropathy (DN) is among the common and serious complications of diabetes and is also a major cause of end-stage kidney disease. Early DN is also called diabetic microalbumin period, the main treatment is in the control of blood sugar on the basis of kidney protection and urine lowering protein. There are few effective methods of western medicine treatment, and most of them are accompanied by adverse reactions. But some studies have shown that traditional Chinese medicine has achieved the curative effect and has certain superiority. However, there are few systematic reviews on the treatment of traditional Chinese herbal medicine for early DN currently. Therefore, this study conducted a systematic review of clinical efficacy and safety of Chinese herbal medicine for the treatment of patients with early DN, aim to comprehensively analyze the role of traditional Chinese herbal medicine in the treatment of early DN. The protocol of this systematic review and meta-analysis was registered on the INPLASY website (https://inplasy.com/inplasy-2020-4-0139/) and INPLASY registration number is INPLASY202040139. A systematic literature search will be conducted in 3 English database and 4 Chinese databases with a language limitation of English and Chinese. Search for clinical research literature on Chinese herbal medicine treatment of DN published in domestic and foreign biomedical journals. The time is limited from January 2010 to February 2020. We will investigate heterogeneity across studies and publication bias. To assess the risk of bias and quality of the included studies, we will use the Cochrane Collaboration's ROB tool. According to the relevant standards in the Cochrane Intervention System Evaluation Manual, it will be divided into low risk, high risk, and unclear. We will also use the RevMan 5.3 software and Stata 13.0 software for meta-analysis of the effectiveness and symptom scores of DN proteinuria. The ethical considerations are not required because the systematic review is based on published studies. The systematic review and meta-analysis will be published in a peer-reviewed Journal.

Ivabradine Ameliorates Kidney Fibrosis in L-NAME-Induced Hypertension.

Hypertension-induced renal injury is characterized by structural kidney alterations and function deterioration. Therapeutics for kidney protection are limited, thus novel renoprotectives in hypertension are being continuously sought out. Ivabradine, an inhibitor of the If current in the sinoatrial node reducing heart rate (HR), was shown to be of benefit in various cardiovascular pathologies. Yet, data regarding potential renoprotection by ivabradine in hypertension are sparse. Thirty-six adult male Wistar rats were divided into non-diseased controls and rats with NG-nitro-L-arginine methyl ester (L-NAME)-induced hypertension to assess ivabradine's site-specific effect on kidney fibrosis. After 4 weeks of treatment, L-NAME increased the average systolic blood pressure (SBP) (by 27%), decreased glomerular density (by 28%) and increased glomerular tuft area (by 44%). Moreover, L-NAME induced glomerular, tubulointerstitial, and vascular/perivascular fibrosis by enhancing type I collagen volume (16-, 19- and 25-fold, respectively). L-NAME also increased the glomerular type IV collagen volume and the tubular injury score (3- and 8-fold, respectively). Ivabradine decreased average SBP and HR (by 8 and 12%, respectively), increased glomerular density (by 57%) and reduced glomerular tuft area (by 30%). Importantly, ivabradine decreased type I collagen volume at all three of the investigated sites (by 33, 38, and 72%, respectively) and enhanced vascular/perivascular type III collagen volume (by 67%). Furthermore, ivabradine decreased the glomerular type IV collagen volume and the tubular injury score (by 63 and 34%, respectively). We conclude that ivabradine attenuated the alterations of glomerular density and tuft area and modified renal fibrosis in a site-specific manner in L-NAME-hypertension. It is suggested that ivabradine may be renoprotective in hypertensive kidney disease.

Construction and development of FimH lectin domain for rising immune response after injection by uropathogenic E. coli.

Uropathogenic E. coli is one of the major agents of urinary tract infection. Today, no effective treatment or vaccine against this infection is exist. Accordingly, in the present study, a genetic constrruct for inducing of cellular immune system was designed. At first, fimH gene from E. coli 35218 was amplified using PCR. PCR product inserted into pET23a expression vector and the recombinant vector was analysed by sequencing. The vector was transformed to E. coli strain Origami and the protein was expressed under the 1mM IPTG. FimH was purified with Ni-NTA column and the purified protein was used for immunization of BALB/c. Two weeks after the last injection, lymphocyte proliferation assay was carried out. In addition, IL-4 and IFN-γ cytokines, total antibody serum, IgG1 and IgG2a isotypes were quantified. Finally, protection ability of the vaccine in bladder and kidney infection of mice was evaluated.The results indicated that cellular immune response has a main protective role against UTI and FimH, as a vaccine candidate, significantly increase lymphocyte proliferation, IFN-γ response and total antibody amount. Immunization of mice with FimH conferred effective protection of kidney and bladder against urinary tract infection by uropathogenic E. coli (P< 0.002). It can be concluded that, the current FimH will be valuable for more trying to prepare a new vaccine against UTI.

Chronic kidney disease as a cardiovascular risk factor.

: Chronic kidney disease (CKD) is a public health threat with impact in cardiovascular risk. All forms of cardiovascular disease and mortality are more common in CKD. Treatment of cardiovascular risk factors, hypertension, dyslipidemia and diabetes is essential for cardiovascular and kidney protection. CKD is a marker of high or very high cardiovascular risk and its presence require early treatment and specific goals. Lifestyle is a pivotal factor, stopping smoking, reducing weight in the overweight or obese, starting regular physical exercise and healthy dietary pattern are recommended. Office BP should be lowered towards 130/80 mmHg or even lower if tolerated with sodium restriction and single pill combination, including angiotensin system blocker. Out-of-office BP monitoring, mainly 24-h assessment, is recommended. Diabetes requires treatment from the moment of diagnosis, but prediabetes benefits with lifestyle changes and metformin in patients stage 2 and 3a. iSGLT2 and GLP-1RA are initially recommended in T2D patients with high or very high cardiovascular risk. Concerning dyslipidemia, for patients in stage 4, LDL-C 55 mg/dl or less (1.4 mmol/l) and an LDL-C reduction of 50% or less from baseline is recommended. In stage 3, LDL-C goal is 70 mg/dl or less (1.8 mmol/l) and an LDL-C. reduction of at least 50% from baseline. Statins are the lipid-lowering therapy of choice with or without ezetimibe. Higher doses of statins are required as GFR declines. Available evidence suggests that combined PCSK9 inhibitors with maximally tolerated dose of statins may have an emerging role in treatment of dyslipidemia in CKD patients.

Estimated plasma osmolarity and risk of end-stage kidney disease in patients with IgA nephropathy.

Several experimental studies have indicated that increased plasma osmolarity caused by recurrent dehydration is involved in kidney injury via a mechanism, mediated by vasopressin secretion and activation of the aldose reductase pathway. Epidemiologic evidence linking increased plasma osmolarity and the onset of end-stage kidney disease (ESKD), in patients with primary glomerulonephritis, is lacking. We retrospectively examined 663 patients with IgA nephropathy (IgAN) diagnosed by kidney biopsy and evaluated the association between estimated plasma osmolarity and ESKD prevalence, using a Cox proportional hazards model. During follow-up (median 80.4months; interquartile range 22.2-120.1), 73 patients developed ESKD. In a baseline survey, plasma osmolarity was correlated negatively with the mean value of the estimated glomerular filtration rate, but correlated positively with the mean value of urinary protein excretion, systolic blood pressure, and pathologic severity of extracapillary proliferation, in addition to tissue fibrosis and sclerosis. The incidence rate of ESKD increased linearly with increase in plasma osmolarity (P < 0.05 for trend). In multivariate analyses, plasma osmolarity was an independent risk factor for ESKD (hazard ratio for each increment of 5mOsm/kg in plasma osmolarity 1.56; 95% confidence interval 1.18-2.07) even after adjustment for potential confounders. Increased plasma osmolarity was associated significantly with an increased risk of ESKD in patients with IgAN. Maintenance of plasma osmolarity by appropriate control of the balance between salt and water may contribute to kidney protection.

ABHRAK BHASMA AND SiO2 INFLUENCED FREE RADICAL STATUS IN LIVER AND KIDNEY OF CCl4-INDUCED ACUTELY INTOXICATED MALE ALBINO RAT

Objective: The objective of the study was to study the mechanism of action of abhrak bhasma-mediated liver and kidney protection in CCl4-induced acute hepatotoxicity-induced male albino rats. Action of abhrak bhasma is compared with the action of SiO2 in similar experimental conditions to differentiate the role of silicon.&#x0D; Methods: Male albino rats (Rattus norvegicus) were used for experiments. The acute hepatotoxicity was induced by daily dose of CCl4 (3.0 ml/kg body wt for 7 days consecutive). Concurrent treatment of abhrak bhasma in graded doses (10, 20, 30, and 40 mg) was given for 7 days (PO). SiO2 (10, 20, 30, and 40 mg) in graded doses was also given in independent groups of rats as silica control. Lipid peroxidation (LPO) in liver and kidney was studied by malondialdehyde (MDA) estimations as parameter of toxicity and also to study protection.&#x0D; Results: CCl4-induced hepatotoxicity (MDA levels) is partially managed by low doses of SiO2 but not by high doses. Abhrak bhasma hepatoprotective activities were dose dependent. A 40 mg dose maintained normal levels of LPO. Abhrak bhasma also protected associated renal toxicity.&#x0D; Conclusion: Abhrak bhasma protected CCl4-induced hepatotoxicity and also associated renal toxicity. Silicon from both SiO2 and abhrak bhasma is hepatoprotective in 10 ml doses (10 and 20 mg) but silicon processed in abhrak bhasma by traditional Ayurvedic processes increased its potency and hepatoprotection and added the potency of renal protection.

The Off-Target Effects, Electrolyte and Mineral Disorders of SGLT2i

The sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a relatively new class of antidiabetic drugs that, in addition to emerging as an effective hypoglycemic treatment, have been shown to improve, in several trials, both renal and cardiovascular outcomes. In consideration of the renal site of action and the associated osmotic diuresis, a negative sodium balance has been postulated during SGLT2i administration. Although it is presumable that sodium and water depletion may contribute to some positive actions of SGLT2i, evidence is far from being conclusive and the real physiologic effects of SGLT2i on sodium remain largely unknown. Indeed, no study has yet investigated how SGLT2i change sodium balance in the long term and especially the pathways through which the natriuretic effect is expressed. Furthermore, recently, several experimental studies have identified different pathways, not directly linked to tubular sodium handling, which could contribute to the renal and cardiovascular benefits associated with SGLT2i. These compounds may also modulate urinary chloride, potassium, magnesium, phosphate, and calcium excretion. Some changes in electrolyte homeostasis are transient, whereas others may persist, suggesting that the administration of SGLT2i may affect mineral and electrolyte balances in exposed subjects. This paper will review the evidence of SGLT2i action on sodium transporters, their off-target effects and their potential role on kidney protection as well as their influence on electrolytes and mineral homeostasis.

Decision Algorithm for Prescribing SGLT2 Inhibitors and GLP-1 Receptor Agonists for Diabetic Kidney Disease.

Diabetic kidney disease and its comorbid conditions, including atherosclerotic cardiovascular disease, heart failure, diabetes, and obesity, are interconnected conditions that compound the risk of kidney failure and cardiovascular mortality, and exponentiate health care costs. Sodium glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide 1 receptor agonist (GLP-1 RA) are novel diabetes medications that prevent cardiovascular events and kidney failure. Clinical trials exploring the cardiovascular and kidney outcomes of SGLT2i and GLP-1 RA have fundamentally shifted the treatment paradigm of diabetes. Clinical guidelines for diabetes management recommend a more holistic approach beyond glycemic control and emphasize heart and kidney protection of SGLT2i and GLP-1 RA. However, the adoption of prescribing SGLT2i and GLP-1 RA for patients with diabetes and high cardiovascular and kidney risk has been slow. In this review, we provide a decision-making tool to help clinicians determine when to consider SGLT2i and GLP-1 RA for heart and kidney protection. First, we discuss a comprehensive risk assessment for patients with diabetic kidney disease. We compare the effectiveness of SGLT2i and GLP-1 RA for different risk categories. Then, we present a decision algorithm using cardiovascular and kidney failure risk stratification and the strength of current evidence for the use of SGLT2i and GLP-1 RA. Lastly, we review the adverse effects of SGLT2i and GLP-1 RA and propose mitigation strategies.

P0976ALTERED EXPRESSION OF LONG NON-CODING AND MESSENGER RNAS IN DIABETIC NEPHROPATHY FOLLOWING TREATMENT WITH ROSIGLITAZONE

Abstract Background and Aims The value of rosiglitazone (RSG) in the protection of kidneys from diabetic injury was recognized, however, the adverse systemic side effects limit its clinical application. Long noncoding RNAs (lncRNAs) are primarily described as signal molecules since they interact with cellular components, and have been shown to exhibit strong tissue and cell specificity. The aim of this study is to elucidate the novel renoprotective molecular mechanism of RSG and to propose lncRNA targets for diabetic nephropathy treatment, which may provide a new approach to avoid systemic side effects of RSG. Method Db/db mice were treated with RSG as dbR group or vehicle as dbdb group, and db/m mice as control group. Plasma, urine and kidney cortex were collected, and unbiased RNA sequencing of three renal cortical samples from each group was performed. Results Db/db mice developed hyperglycemia, impaired intra-peritoneal glucose tolerance, proteinuria, decreased mitochondrial SOD activity, podocyte impairment, epithelial-mesenchymal transition, glomerulosclerosis and tubulointerstitial fibrosis, however, RSG treatment improved these changes. RNA-seq profiling revealed that the development of DN caused an up-regulation in the expression of 1176 mRNAs and a down-regulation in the expression of 1010 mRNAs (p&amp;lt;0.05) compared to controls, with the expression of 251 mRNAs being returned to normal following treatment with RSG. Further, 88 up-regulated and 68 down-regulated lncRNAs (p&amp;lt;0.05) were identified in db/db mice compared to controls, 10 of which had their normal expression restored following treatment with RSG. Bioinformatic analysis revealed that the primary pathways involved in the pathogenesis of DN, and subsequently in the therapeutic effects of PPARγ, are related to inflammatory and metabolic processes. Six lncRNAs that exhibited opposite expression patterns in dbdb vs. control and dbR vs. dbdb analyses were randomly chosen and qualified by qRT-PCR, including a novel lncRNA and lncRNA-AI838599. From GSEA analysis, three co-expressed mRNAs of lncRNA-AI838599 (Gadd45b, Per1 and Sphk1) were cores enriched in the Hallmark TNFα signaling via NFκb Gene Set (MSigDB). Conclusion RSG treatment can attenuate DN in experimental models through regulation of metabolism and inflammation, and lncRNA-AI838599 emerges as a key rosiglitazone-regulated gene in DN treatment through TNFα-NFκb pathway.

P0529THE DIFFERENCE IN DIETARY RESTRICTION-INDUCED NEPHROPROTECTIVE MECHANISMS IN YOUNG AND OLD ANIMALS

Abstract Background and Aims Acute kidney injury (AKI) is a widespread disease affecting mostly old people. Dietary restriction (DR), based on the reduction of food intake, is believed to be one of the most efficient approaches ameliorating damage in different pathological conditions including age-associated diseases. The aim of the study was to investigate the protective mechanisms of DR in the model of AKI in young and old rats. Method All experiments were made on young (3-4 months) and old (22-24 months) male rats. DR was performed by limiting the amount of food for 35% of the ad libitum (AL) daily intake. Since earlier, we showed ineffectiveness of 4-weeks DR in old rats, in this study we applied 35% DR lasting 8 weeks for old rats and 4 weeks for young rats. During DR, we registered the weight loss and measured the level of adiponectin, as this hormone is closely associated with adipose tissue metabolism. Renal ischemia/reperfusion (I/R) was used as a model of ischemic AKI. I/R was performed by clamping the left renal pedicle for 40 minutes followed by reperfusion with simultaneous contralateral nephrectomy. The severity of AKI was evaluated by measuring blood urea nitrogen (BUN), serum creatinine (SCr) and the levels of protein biomarkers of AKI (NGAL and L-FABP) in urine. Proliferation in kidney epithelium in response to I/R was analyzed by PCNA protein level in kidney tissue. We evaluated the function of mitochondria by measuring TMRE/MitoTracker Green ratio in vital kidney slices; in kidney homogenates, we also analyzed levels of Bcl-XL and Bcl-XS proteins. The production of reactive oxygen species (ROS) was evaluated by staining vital kidney slices with DCF. The content of lipid peroxidation products was measured using Image-iT Lipid Peroxidation Kit, and the level of carbonylated proteins was determined by OxyBlot Protein Oxidation Detection Kit. The activation of autophagic-lysosomal system was estimated by western blotting to LC3 II/LC3 I ratio and LAMP1 level, as well as by staining vital kidney slices with LysoTracker Green probe. Results The body weight of rats during DR dropped as far as 20% by the end of 4 weeks in young rats and 30% by the end of 8 weeks in old rats. Nevertheless, adiponectin concentration elevated during DR only in the serum of young rats. DR strongly influenced mitochondria function, in particular, elevated mitochondrial membrane potential both in kidney cells of young and old rats. DR also resulted in increasing the Bcl-XL level. We revealed the decrease of ROS and lipid peroxidation products in vital kidney slices, but only in kidneys of young rats. However, DR reduced the content of carbonyl groups more than 2 times in animals of both ages. We showed that activation of autophagy in response to DR and I/R occurred only in the kidneys of young rats, indicating deterioration of autophagy signaling in old animals. We also found that 48 h after I/R PCNA level increased 19 times in young kidney, although old rats showed only 4-fold elevation of kidney cells proliferation. Estimation of kidney injury markers (NGAL, L-FABP) in urine revealed that 2-month DR led to some protection in old rats. Nonetheless, despite all positive alterations in kidney tissue of old rats, DR was not able to ameliorate impairment of kidney function after I/R, whereas all young rats showed significant improvement of SCr and BUN levels. Conclusion Short-term DR has a significant nephroprotective effect against renal I/R in young rats. Old animals require longer periods of food restriction, after which some protective alterations are observed. We propose, protection of kidney in old and young rats is implemented through slightly different mechanisms and some of them are missing in old animals.

496-P: Risk Factors for Incident CKD in Prediabetes

The magnitude of risk for chronic kidney disease (CKD) in prediabetes is unclear. The study aim was to determine CKD incidence and risk factors in patients with prediabetes from the CURE-CKD registry of electronic health record data from &amp;gt;2.6 million patients with or at-risk for CKD. Adults with prediabetes were identified by established criteria for %A1C, random and fasting blood glycemia, and administrative codes. CKD was defined by estimated glomerular filtration rate (eGFR) &amp;lt;60 mL/min/1.73m2 or urine albumin-to-creatinine ratio &amp;gt;30 mg/g based upon two or more measurements &amp;gt;90 days apart and administrative codes. Cox proportional hazards regression was used to predict incident CKD. From 2006 to 2017, there were 544,253 patients with prediabetes and no CKD. Baseline A1C was 5.9±0.3% (mean±SD) and eGFR was 90.7±16.8 mL/min/1.73 m2. Notable medication use was: NSAIDs n=110,964 (20%), PPIs n=49,916 (9%), and ACEi/ARB n=63,738 (12%). Incident CKD occurred (n=59,583) at a rate of 25.2/1,000 person-years with mean time to CKD of 2.9 years. Older age, female gender, Hispanic/Latinx, Black, Native Hawaiian and Other Pacific Islander race/ethnicity, lower eGFR, PPI and ACEi/ARB use were associated with higher hazards of CKD in prediabetes (Table 1). Incident CKD is common in prediabetes with risk factors similar to those in diabetes. CKD screening and detection with a focus on kidney protection may offer novel opportunities to reduce CKD risk in prediabetes. Disclosure K.A. Hennessey: None. K.B. Daratha: None. R.Z. Alicic: None. C. Jones: None. J.J. Neumiller: None. O. Duru: None. S. Nicholas: Speaker’s Bureau; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; Centers for Disease Control and Prevention, George Institute for Global Health, Goldfinch Bio, Inc., National Institutes of Health. S.M. McPherson: None. K.C. Norris: None. K.R. Tuttle: Consultant; Self; AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Gilead Sciences, Inc., Goldfinch Bio, Novo Nordisk Inc.

467-P: Brown Fat Original Mir-30b Targeting Renal RUNX1 to Improve Diabetic Nephropathy

It has been verified that adipose tissue was the major source of circulating microRNAs (miRNA), which could target downstream genes in distant organs such as liver. Here we show that brown adipose tissue (BAT) transplantation from healthy mice donor could reactivate endogenous BAT activity of diabetic mice induced by high fat diet (HFD) and streptozotocin (STZ) injection. BAT activation increased circulating miR-30b level and significantly improved diabetic nephropathy. In vitro, miR-30b was significantly downregulated by TGF β1 in HK-2 cells. In vivo, agomiR-30b was directly administered to the BAT of diabetic mice (0.25nmol/g body weight) twice per week for 4 consecutive weeks. Over-expressing miR-30b markedly decreased fibronectin expression, coupled with downregulated Runt-related transcription factor 1(Runx1) and snail family zinc finger 1 (Snail1) in the kidney of diabetic mice, while silencing of miR-30b displayed the opposite features. Next, knockdown or overpression of Runx1 both in vitro by using siRUNX1 or pCMV-RUNX1, and in vivo by AAV-U6-shRunx1 or AAV-EF1a-Runx1 respectively, could mimic the above phenotype of miR-30b mimic and inhibitor treatment respectively. Moreover, Runx1 promoted TGFβ1-induced fibrosis through upregulating PI3K pathway. These results suggest that BAT transplantation ameliorates diabetic nephropathy in mice through reactivating endogenous BAT and increasing circulating miR-30b level, which subsequently target renal Runx1 and Snail1, to improve renal fibrosis. BAT-original miRNAs might be a promising target for kidney protection in diabetes mellitus. Disclosure M. Guan: None. Funding National Natural Science Foundation of China (81870612, 81628004, 31400992, 81470047); Guangdong Science and Technology Project (2019A1515011997)

P0620OXIDANT-INDUCED RENAL PRECONDITIONING BIOMARKERS FOR AKI PREVENTION WITH RBT-1

Abstract Background and Aims Ischemic preconditioning has shown tissue protective effects in various organs including kidneys in animal models. However, the translation of these findings to human acute kidney injury (AKI) has not been successful, at least partly because of difficulty in simulating an ischemic state, as attempted by remote ischemic preconditioning (RIPC). RBT-1 is a novel therapeutic composed of SnPP (tin protoporphyrin) and FeS (iron sucrose) and was designed to induce non-ischemic, oxidant renal preconditioning to prevent AKI. It has shown efficacy in various models of AKI: glycerol-induced (rhabdomyolysis), maleate (ATP depletion), ischemia/reperfusion (I/R), and post-AKI progression to CKD (long-term progression). This study investigated the mechanism of action of RBT-1 in mice, and its translation to the clinical setting. Method Male CD-1 mice were pretreated with control or RBT-1 for 18 hours; animals were then sacrificed for assessment of biomarkers of cytoprotection. Nrf2-/- mice were treated for 18 hours with RBT-1 prior to indication of ischemia/reperfusion (I/R); AKI was assessed by blood urea nitrogen (BUN) and plasma creatinine (PCr). Patients with CKD (Stage 3 and 4) were enrolled in Phase 1 studies of FeS and SnPP and cytoprotective biomarkers were assessed. Results In mice, RBT-1 significantly increased several Nrf2-dependent antioxidant, anti-inflammatory genes, such as HO-1, NQO1, SRXN1, and GCLC. RBT-1 also increased cytoprotective heavy chain ferritin (Fhc) levels. Nrf2-/- mice were resistant to RBT-1-mediated protection against AKI. At baseline, CKD patients had elevated plasma HO-1 and urinary NQO1 levels. Ferritin and hemopexin levels were also elevated at baseline. RBT-1 components were shown to further increase HO-1, NQO1, ferritin, and hemopexin in patients with CKD. Conclusion RBT-1 represents a novel therapeutic approach for the prevention of AKI. It mediates kidney protection by upregulating antioxidant and anti-inflammatory genes. Translation of RBT-1-mediated upregulation of cytoprotective markers has been demonstrated in the clinic in patients with CKD. These data, along with the broad range of RBT-1 activity previously shown in various models of AKI, highlight the potential of RBT-1 in AKI and suggest oxidant-induced renal preconditioning may be protective in preventing AKI.

Kidney dysfunction and short term all-cause mortality after transcatheter aortic valve implantation

BackgroundAcute kidney injury (AKI) after transcatheter aortic valve implantation (TAVI) has been associated with worse outcomes. However, the impact on outcome of AKI in TAVI-patients is not well established. MethodsInoperable patients with severe aortic stenosis (AS) undergoing TAVI in 2010-2018 were enrolled in this study. AKI and chronic kidney disease (CKD) were defined according to KDIGO guidelines. Patients were divided in two groups according to post-procedural AKI development. The primary endpoint was 30-day all-cause mortality across the two groups. ResultsA total of 373 patients (mean age 82.3 ± 6) were analyzed. Compared to non-AKI patients, those who developed AKI, were treated more frequently with trans-apical TAVI (66% vs 35%, p<0.01), with greater amount of contrast medium (200.6 vs 170.4 ml, p=0.02) and in presence of clinically significant peripheral artery disease (PAD, 33% vs 21%, p=0.04). Trans-apical access (OR 3.24, 95% CI 1.76-5.60, p<0.01) was associated with a 3-fold risk of AKI. After adjustment for age, Society of Thoracic Surgery risk score (STS), PAD, access type, EF and contrast medium amount, patients with AKI presented an increased risk of 30-day all-cause mortality (HR=1.25, 95%CI 1.09-1.69, p=0.008). Patients with CKD IV and V, who developed AKI, presented a 9-fold 30-day mortality risk (HR=9.71, 95% CI 2.40-39.2, p=0.001). ConclusionIn our analysis, AKI was a strong predictor of 30-day all-cause mortality. Particularly, patients with severe CKD with AKI showed the highest 30-day mortality risk. Thus, this group of patients might benefit from closer monitoring and specific kidney protection therapies.

Mediators of the effects of canagliflozin on kidney protection in patients with type 2 diabetes

Canagliflozin reduced kidney disease progression in participants with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. This analysis explored potential mediators of the effects of canagliflozin on kidney outcomes. The percent mediating effect of 18 biomarkers indicative of disease was determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the average post-randomization level of each biomarker. Multivariable analyses assessed the joint effects of biomarkers that mediated most strongly in univariable analyses. The kidney outcome was defined as a composite of 40% estimated glomerular filtration rate decline, end-stage kidney disease, or death due to kidney disease. Nine biomarkers (systolic blood pressure [8.9% of effect explained], urinary albumin:creatinine ratio [UACR; 23.9%], gamma glutamyltransferase [4.1%], hematocrit [51.1%], hemoglobin [41.3%], serum albumin [19.5%], erythrocytes [56.7%], serum urate [35.4%], and urine pH [7.5%]) individually mediated the effect of canagliflozin on the kidney outcome. In a parsimonious multivariable model, erythrocyte concentration, serum urate, and systolic blood pressure maximized cumulative mediation (115%). Mediating effects of UACR, but not other mediators, were highly dependent upon the baseline level of UACR: UACR mediated 42% and 7% of the effect in those with baseline UACR 30 mg/g or more and under 30 mg/g, respectively. The identified mediators support existing hypothesized mechanisms for the prevention of kidney outcomes with sodium glucose co-transporter 2 inhibitors. Thus, the disparity in mediating effects across baseline UACR subgroups suggests that the mechanism for kidney protection with canagliflozin may vary across patient subgroups.

Nephrotoxicity/renal failure after therapy with 90Yttrium- and 177Lutetium-radiolabeled somatostatin analogs in different types of neuroendocrine tumors: a systematic review.

Data regarding the nephrotoxicity of the peptide receptor radionuclide therapy (PRRT) with Yttrium- and Lutetium-radiolabeled somatostatin analogs (RSA) are inconclusive. We aimed to evaluate the short- and long-term nephrotoxicity following PRRT usage in patients with all types of neuroendocrine tumors (NETs). A systematic review of observational studies reporting data about nephrotoxicity after treatment with Yttrium and Lutetium RSA was performed. Data on serum creatinine, creatinine clearance, glomerular filtration rate (GFR) and need for renal replacement therapy were compiled. We included patients with progressive, inoperable symptomatic G1, G2 and G3 different types of NETs. After searching in three electronic databases PubMed, Scopus and the Cochrane Library, from 1 January 1978 to November 2018, data were extracted and summarized using a random-effects model. The final analysis included 34 studies, comprising 5386 participants, enrolling patients with G1, G2, G3 NETs and a follow-up from 12 up to 191 months. Compared with renal function before treatment, measured/estimated glomerular filtration rate (m/eGFR) values changed after PRRT, with a mean annual decrease following PRRT between 2 and 4 mL/min/1.73 m suggesting different grades of nephrotoxicity after PRRT. When compared, Y-RSA and the Y-RSA-Lu-RSA combination are associated with a higher m/eGFR decline compared to Lu-RSA alone. PRRT can be followed by potentially serious long-term nephrotoxicity, despite kidney protection. The use of the quantified renal function combined with a long follow-up period and personalized dosimetry-based PRRT can reduce nephrotoxicity, in order to use the whole PRRT potential in the management of NETs.

Protection against renal ischemia and reperfusion injury by short-term time-restricted feeding involves the mitochondrial unfolded protein response

Food restriction improves metabolic health and increases resistance to stress in experimental animals. However, most studies have focused on long-term dietary restriction protocols consisting of several weeks or months of limited food ingestion. Here it was investigated the impact of 2-h time-restricted feeding (TRF) for one week on stress resistance in a rat model of kidney injury induced by ischemia and reperfusion (IR). At baseline, TRF reduced blood glucose, increased β-hydroxybutyrate and improved body composition in male Wistar rats. Importantly, implementing the one-week TRF schedule before ischemia significantly improved renal function, suppressed tubular injury, prevented the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and inhibited the development of interstitial fibrosis. These benefits were related to increased antioxidant protection, reduction in dynamin-related protein 1 (DRP1)-mediated mitochondrial fragmentation and modulation of the mitochondrial unfolded protein response (UPRmt). Specifically, preoperative TRF boosted the activation of the UPRmt in the acute phase after renal IR while promoted its resolution at the stage of fibrosis. Our study indicates that dietary preconditioning by short-term TRF improves the outcome of renal IR injury, and suggests that an optimal intervention that promotes kidney protection may not necessarily require adherence to restrictive diets for prolonged periods of time.

Potency of Sunkist Orange (Citrus sinensisL. Osbeck) against Kidney Histology of White Wistar Rats Induced by Gentamicin

About 1.7%-58% of all cases of acute kidney failure are caused by gentamicin nephrotoxicity and consequently increasing urea and creatinine levels in the blood which are indications of damage to function. Oranges contain secondary metabolites such as flavonoids, alkaloids, coumarin, limonoid, keratinoid and essential oil that have pharmacological activities such as antioxidants, anti-inflammatory, anti-cancer, and also nephroprotector. The purpose of this study is to evaluate the nephroprotective activity of Citrus sinensis peel ethanol extract (EEKJS) on rats induced by gentamicin. Rats were induced using gentamicin at a dose of 80 mg/kgBW intraperitoneally on the 7th day after induced at a dose of 50 mg/kgBW, 100 mg/kgBW, and 200 mg/kgBW for 7 days. The results obtained from the ethanol extract of Citrus sinensis peel gave nephroprotective with the lowest serum creatinine and urea levels at a dose of 200 mg/kgBW which was 0.4±0.02 mg/dl and 43.33 ± 2.51 mg/dl and difference significantly (p&lt;0.05) with a positive control group which was only induced by gentamicin and histopathological results showed significant cell damage in the positive control group that was only induced by gentamicin, and in the 50 mg/kgBW dose group, 100 mg/kgBW, 200 mg/kgBW had cell repair after gentamicin induction. Citrus sinensis are highly recommended to be a food supplement for kidney protection.

Protection of the transplant kidney during cold perfusion with doxycycline: proteomic analysis in a rat model

BackgroundIt has been previously shown that doxycycline (Doxy) protects the kidney from preservation injury by inhibition of matrix metalloproteinase. However, the precise molecular mechanism involved in this protection from injury is not known. We used a pharmaco-proteomics approach to identify potential molecular targets associated with kidney preservation injury.MethodsRat kidneys were cold perfused with or without doxycycline (Doxy) for 22 h. Kidneys perfusates were analyzed for the presence of injury markers such as lactate dehydrogenase (LDH), and neutrophil-gelatinase associated lipocalin (NGAL). Proteins extracted from kidney tissue were analyzed by 2-dimensional gel electrophoresis. Proteins of interest were identified by mass spectrometry.ResultsTriosephosphate isomerase, PGM, dihydropteridine reductase-2, pyridine nucleotide-disulfide oxidoreductase, phosphotriesterase-related protein, and aminoacylase-1A were not affected by cold perfusion. Perfusion with Doxy increased their levels. N(G),N(G)-dimethylarginine dimethylaminohydrolase and phosphoglycerate kinase 1 were decreased after cold perfusion. Perfusion with Doxy led to an increase in their levels.ConclusionsThis study revealed specific metabolic enzymes involved in preservation injury and in the mechanism whereby Doxy protects the kidney against injury during cold perfusion.