Protective effect and mechanism of Shenkang injection on adenine-induced chronic renal failure in rats.

PURPOSE: To investigate the protective effects of Shenkang injection (SKI) on adenine-induced chronic renal failure (CRF) in rat. METHODS: Sprague Dawley rats were randomly divided into five groups: control, model, and SKI groups (5, 10, 20 mL/kg). Rats in model and SKI groups were treated with adenine i.g. at a dose of 150 mg/kg every day for 12 weeks to induce CRF. Twelve weeks later, SKI was administered to the rat i.p. for four weeks. The effects of SKI on kidney injury and fibrosis were detected. RESULTS: SKI inhibited the elevation of the urine level of N-acetyl-b-D-glucosaminidase, kidney injury molecule-1, beta-2-microglobulin, urea protein in CRF rats. The serum levels of uric acid and serum creatinine increased and albumin decreased in the model group, which was prevented by SKI. SKI inhibited the release of inflammatory cytokines and increasing the activities of antioxidant enzymes in serum. SKI inhibited the expression of transforming growth factor-ß1, vascular cell adhesion molecule 1, intercellular adhesion molecule 1, collagen I, collagen III, endothelin-1, laminin in kidney of CRF rats. CONCLUSIONS: SKI protected against adenine-induced kidney injury and fibrosis and exerted anti-inflammatory, and antioxidant effects in CRF rats.

Comparative effectiveness of traditional Chinese medicine and angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and sodium glucose cotransporter inhibitors in patients with diabetic kidney disease: A systematic review and network meta-analysis.

Angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and sodium glucose cotransporter inhibitors (SGLT2i) are commonly used to treat diabetic kidney disease (DKD). Currently, increasing evidence also suggests traditional Chinese medicine (TCM) as an effective strategy. We assessed the efficacy of ACEI, ARB, SGLT2i, and TCM on major renal outcomes. We searched the electronic literature published up to March 2021 from CNKI, VIP, WanFang, SinoMed, PubMed, Embase, Cochrane Library, Web of Science, and clinicaltrials.gov; a total of 56 studies and 5464 participants were included. We found that TCM plus ACEI, TCM plus ARB, and TCM alone are very effective treatment methods compared with ACEI, ARB, and the placebo in reducing 24-h urine protein, serum creatinine, and blood urea nitrogen. TCM plus ACEI was the most effective treatment (TCM plus ACEI vs. the placebo in 24-h urine protein [mean difference (MD) - 757.18, 95% confidence interval-1177.41 to - 353.31], serum creatinine [MD - 25.81, 95% confidence interval - 35.51 to - 16.03], and blood urea nitrogen [MD - 3.48, 95% confidence interval - 5.04 to - 1.90]). Although the incidence of end-stage renal disease while receiving an TCM plus ARB compared with a placebo was not statistically significant, the treatment ranking showed this combination therapy to have the greatest probability (72.8%) of reducing end-stage renal disease mortality, followed by SGLT2i (68%). Our analyses showed that combining TCM with conventional treatments for patients with DKD can improve renoprotective effects and superiority, and ACEI plus TCM may be the most effective option for treating DKD.

Juzentaihoto improves adenine-induced chronic renal failure in BALB/c mice via suppression of renal fibrosis and inflammation.

Renal inflammation and fibrosis are observed in underlying diseases associated with the pathological progression of chronic kidney disease (CKD). The inhibition of renal inflammation and fibrosis is one method to suppress the progression of CKD. Juzentaihoto (TJ-48), a Kampo medicine, effectively relieves chronic wasting diseases and fatigue and has been reported to decrease inflammation. In this study, we investigated whether TJ-48 has a renal protective effect and its underlying mechanism in mice with adenine-induced CKD. BALB/c mice were divided into four groups for examination: (1) control, (2) dietary restriction, (3) adenine, and (4) adenine + TJ-48. Biochemical and histological analyses, gene expression analysis, and complete blood counts were performed. TJ-48 treatment decreased tubular damage and fibrosis. TJ-48 also decreased creatinine levels exacerbated by adenine, suppressed the mRNA expression of tumor necrosis factor-α, chemokine ligand 2, transforming growth factor-ß, and kidney injury molecule-1, and decreased the neutrophil/lymphocyte ratio increased by adenine. TJ-48 exerts a renoprotective effect possibly via the suppression of fibrosis and inflammation.

Toxicity of pemetrexed during renal impairment explained-Implications for safe treatment.

Pemetrexed is an important component of first line treatment in patients with non-squamous non-small cell lung cancer. However, a limitation is the contraindication in patients with renal impairment due to hematological toxicity. Currently, it is unknown how to safely dose pemetrexed in these patients. The aim of our study was to elucidate the relationship between pemetrexed exposure and toxicity to support the development of a safe dosing regimen in patients with renal impairment. A population pharmacokinetic/pharmacodynamic analysis was performed based on phase II study results in three patients with renal dysfunction, supplemented with data from 106 patients in early clinical studies. Findings were externally validated with data of different pemetrexed dosing regimens. Alternative dosing regimens were evaluated using the developed model. We found that pemetrexed toxicity was driven by the time above a toxicity threshold concentration. The threshold for vitamin-supplemented patients was 0.110 mg/mL (95% CI: 0.092-0.146 mg/mL). It was observed that in patients with renal impairment (estimated glomerular filtration rate [eGFR]: <45 mL/min) the approved dose of 500 mg/m2 would yield a high probability of severe neutropenia in the range of 51.0% to 92.6%. A pemetrexed dose of 20 mg for patients (eGFR: 20 mL/min) is shown to be neutropenic-equivalent to the approved dose in patients with adequate renal function (eGFR: 90 mL/min), but would result in an approximately 13-fold lower area under the concentration-time curve. The pemetrexed exposure-toxicity relationship is explained by a toxicity threshold and substantially different from previously thought. Without prophylaxis for toxicity, it is unlikely that a therapeutic dose can be safely administered to patients with renal impairment.

Hepatic and cardiovascular safety of acarbose among type 2 diabetes patients with end-stage renal disease: A nationwide population-based longitudinal study.

AIM: To assess the relationship between acarbose and hepatotoxicity, cardiovascular disease (CVD), and mortality among type 2 diabetes (T2D) patients with end-stage renal disease (ESRD). METHODS: 32,531 T2D patients with ESRD were identified from Taiwan's National Health Insurance Research Database in 2000~∼2012 and followed up until 2013. 19.3% of subjects were newly initiated with acarbose during the follow-up. The use of acarbose was quantified as the numbers of the 30-day drug's supplies and dosages (measured by defined daily doses; DDDs), respectively. Time-varying Cox models were applied to evaluate the association of acarbose use with hepatic, cardiovascular and mortality outcomes, with adjustment for patients' demographics, comorbidities, diabetes severity, and co-medications. RESULTS: For each 30-day supply increase in acarbose exposure, the risks of hepatic injury, composite CVD events, and all-cause mortality were significantly lowered by 9% (95% confidence interval: 6-12%), 7% (6-7%) and 7% (7-8%), respectively, while for each 30-day DDD increase in acarbose exposure, the risks for three aforementioned outcomes were significantly reduced by 45% (33-54%), 33% (29-36%) and 35% (32-39%), respectively. In subgroup analyses, the favorable study outcomes of acarbose use were more apparent among patients with more severe diabetes, a longer diabetes duration, or absence of established CVD at baseline. CONCLUSION: Acarbose used in real-world T2D patients with ESRD may have hepatic and cardiovascular safety.

Medicinal plants and renal failure: A case-control study.

AIMS: Medicinal plants contain many active constituents that can cause adverse effects on kidneys that are often unrecognized. The aim of our work was to study the association between the regular use of medicinal plants and the risk of chronic renal failure in hospitalized patients in four departments of Mohammed VI University Hospital. MATERIALS AND METHODS: A case-control study was performed from January 2018 to December 2018. The cases were patients with a first-time diagnosis of chronic renal failure and without family history of kidney diseases or pre-existing renal disease. One control was matched to each case for age, gender, date of entry, and history of hypertension or diabetes. RESULTS: 208 patients were recruited. Among 104 cases, 42 patients (40.4%) regularly used medicinal plants compared to 18.3% in the group of controls (OR: 1.3; 95% CI; p < 0.001). Multivariate analysis showed that the regular use of medicinal plants was significantly associated with the risk of chronic renal failure (OR: 3.05; 95% CI; p < 0,001). Also a total of 52 plant species representing 29 plant families were reported in our study. Dominant plant families were represented by the Lamiaceae followed by the Apiaceae. CONCLUSION: Regular use of medicinal plants increases the risk of chronic kidney failure. Therefore, we need active measures to regulate this sector.

Association Between Renin-Angiotensin System Blockade Discontinuation and All-Cause Mortality Among Persons With Low Estimated Glomerular Filtration Rate.

Importance: It is uncertain whether and when angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin II receptor blocker (ARB) treatment should be discontinued in individuals with low estimated glomerular filtration rate (eGFR). Objective: To investigate the association of ACE-I or ARB therapy discontinuation after eGFR decreases to below 30 mL/min/1.73 m2 with the risk of mortality, major adverse cardiovascular events (MACE), and end-stage kidney disease (ESKD). Design, Setting, and Participants: This retrospective, propensity score-matched cohort study included 3909 patients from an integrated health care system that served rural areas of central and northeastern Pennsylvania. Patients who initiated ACE-I or ARB therapy from January 1, 2004, to December 31, 2018, and had an eGFR decrease to below 30 mL/min/1.73 m2 during therapy were enrolled, with follow-up until January 25, 2019. Exposures: Individuals were classified based on whether they discontinued ACE-I or ARB therapy within 6 months after an eGFR decrease to below 30 mL/min/1.73 m2. Main Outcomes and Measures: The association between ACE-I or ARB therapy discontinuation and mortality during the subsequent 5 years was assessed using multivariable Cox proportional hazards regression models, adjusting for patient characteristics at the time of the eGFR decrease in a propensity score-matched sample. Secondary outcomes included MACE and ESKD. Results: Of the 3909 individuals receiving ACE-I or ARB treatment who experienced an eGFR decrease to below 30 mL/min/1.73 m2 (2406 [61.6%] female; mean [SD] age, 73.7 [12.6] years), 1235 discontinued ACE-I or ARB therapy within 6 months after the eGFR decrease and 2674 did not discontinue therapy. A total of 434 patients (35.1%) who discontinued ACE-I or ARB therapy and 786 (29.4%) who did not discontinue therapy died during a median follow-up of 2.9 years (interquartile range, 1.3-5.0 years). In the propensity score-matched sample of 2410 individuals, ACE-I or ARB therapy discontinuation was associated with a higher risk of mortality (hazard ratio [HR], 1.39; 95% CI, 1.20-1.60]) and MACE (HR, 1.37; 95% CI, 1.20-1.56), but no statistically significant difference in the risk of ESKD was found (HR, 1.19; 95% CI, 0.86-1.65). Conclusions and Relevance: The findings suggest that continuing ACE-I or ARB therapy in patients with declining kidney function may be associated with cardiovascular benefit without excessive harm of ESKD.

Herbal Nephropathy.

This column is supplied by Amita Jain, MD, and Juan Jose Olivero, MD. Dr. Jain completed an internal medicine residency at Houston Methodist Hospital in Houston, Texas, and recently joined a primary care practice in Delaware. She earned a Bachelor of Medicine and Surgery (MBBS) degree, with a distinction in microbiology, from Terna Medical College at the Maharashtra University of Health Sciences in Navi Mumbai, India. Before coming to Houston, Dr. Jain completed residency training in internal medicine and allied subspecialties at the Dr. Babasaheb Ambedkar Memorial Hospital in Byculla, Mumbai. Dr. Olivero is a nephrologist at Houston Methodist Hospital and a member of the hospital's Nephrology Training Program. He obtained his medical degree from the University of San Carlos School of Medicine in Guatemala, Central America, and completed his residency and nephrology fellowship at Baylor College of Medicine in Houston, Texas.

Potential therapeutic effects of Cordyceps cicadae and Paecilomyces cicadae on adenine-induced chronic renal failure in rats and their phytochemical analysis.

BACKGROUND: Natural Cordyceps cicadae (C. cicadae) has been utilized extensively in traditional Chinese medicine to treat chronic renal diseases, heart palpitations, infantile convulsions, and dizziness. However, given its slow growth and immoderate exploitation, C. cicadae resources have been severely depleted. By contrast, Paecilomyces cicadae (P. cicadae), as the anamorph stage of C. cicadae, is easy to cultivate, and this kind of cultivated P. cicadae has good and controllable quality. PURPOSE: This study aimed to compare the therapeutic effects of C. cicadae and P. cicadae on adenine-induced chronic renal failure (CRF) rats. In accordance with the aforementioned studies, our work subsequently analyzed the intrinsic relationships between the efficacy and pharmacodynamic substances of C. cicadae and P. cicadae to conclude whether or not P. cicadae could be used as an alternative to C. cicadae in treating CRF. METHODS: Rats were administered with C. cicadae (1.0 g/kg) or P. cicadae (1.0 g/kg) by gavage for 4 weeks. Furthermore, we applied Fourier transform infrared spectroscopy, gas chromatography-mass spectrometry, liquid chromatography-tandem mass spectrometry, and ultraviolet spectrophotometry to comprehensively detect and analyze the chemical constituent differences from ten batches each of C. cicadae and P. cicadae. RESULTS: This study revealed that both C. cicadae and P. cicadae exerted obvious therapeutic effects on CRF and were more consistent with their chemical compositions. CONCLUSION: P. cicadae can be used as an alternative to C. cicadae for treating CRF to cater to market demands.

Omega-3 polyunsaturated fatty acids alleviate adenine-induced chronic renal failure via regulating ROS production and TGF-ß/SMAD pathway.

OBJECTIVE: To explore the role of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in adenine-induced rat chronic renal failure and its underlying mechanism. MATERIALS AND METHODS: 30 Sprague Dawley (SD) rats were randomly assigned into three groups, namely sham group, adenine induction group (adenine group) and adenine induction + ω-3 PUFAs treatment group (ω-3 PUFAs group), with 10 rats in each group. Serum and kidney samples were collected after rats were sacrificed. Serum levels of Cr (creatinine) and BUN (urea nitrogen) were detected using commercial kits. HE (hematoxylin and eosin) staining was performed to evaluate the pathological changes of kidneys. Levels of oxidative stress indicators in rat kidney homogenate were detected by relative commercial kits, including SOD (superoxide dismutase), GSH (reduced glutathione), CAT (catalase), and T-AOC (total antioxidant capacity). Reactive oxygen species (ROS) production was also detected by immunofluorescence. Protein expressions of nuclear factor E2 related factor 2 (Nrf2) and transforming growth factor-beta (TGF-ß)/SMAD pathway-related genes were detected by Western blot. RESULTS: Serum levels of Cr and BUN in ω-3 PUFAs group were remarkably decreased compared with those of adenine group. Higher contents of SOD, GSH, CAT and T-AOC were observed in ω-3 PUFAs group compared with those of adenine group. Besides, MAD content and ROS production were lower in ω-3 PUFAs group than those of adenine group. Pathological changes of kidneys were alleviated after ω-3 PUFAs treatment. Western blot results demonstrated that ω-3 PUFAs treatment remarkably upregulates Nrf2, HO-1, NQO1, but downregulates relative genes in TGF-ß/SMAD pathway. CONCLUSIONS: ω-3 PUFAs alleviated adenine-induced chronic renal failure through enhancing antioxidant stress and inhibiting inflammatory response via regulating Nrf2 and TGF-ß/SMAD pathway.

Magnesium Citrate Protects Against Vascular Calcification in an Adenine-induced Chronic Renal Failure Rat Model.

BACKGROUND: Hypomagnesemia was identified as a strong risk factor for cardiovascular disease in patients with chronic renal failure (CRF). However, the effects of magnesium (Mg) on vascular calcification (VC) have not been fully elucidated. Thus, we aim to determine the effects of Mg citrate (MgCit) on VC in CRF rats. METHODS: Rats were divided into 5 groups: group 1 (normal diet), group 2 (normal diet with MgCit), group 3 (the VC model of CRF induced by 0.75% adenine and 0.9% phosphorus diet from day 1 to day 28), group 4 (group 3 treated with low-dose MgCit from day 1 to day 42), and group 5 (same as group 3 except the high-dose MgCit). All rats were killed at day 43 with collection of blood and aortas. Then, serum biochemical parameters, VC-related staining, calcium and P contents, alkaline phosphatase contents and activity, expression of alpha smooth muscle actin, and runt-related transcription factor 2 (RUNX2) in aortas were assessed. RESULTS: Group 3 had extensive VC. The VC degree decreased in groups 4 and 5 in a dose-depended manner with reduced calcium content, P levels, alkaline phosphatase content and activity, and protein levels of RUNX2 and increased protein levels of alpha smooth muscle actin in aortas. CONCLUSIONS: MgCit exerted a protective role in VC in adenine-induced CRF rats; thus, it may be a potential drug for the prevention of VC in patients with CRF.

Garlic (Allium sativum) exhibits a cardioprotective effect in experimental chronic renal failure rat model by reducing oxidative stress and controlling cardiac Na+/K+-ATPase activity and Ca2+ levels.

Gentamicin (GNT)-induced nephrotoxicity culminates into renal failure with a possible cardiovascular impact. Garlic extract (GE) is a cardiovascular protectant with limited mechanistic data. Therefore, we assessed the disturbance in specific cardiac parameters and the potential protective effect of GE supplementation against them in a rat model of GNT-induced chronic renal failure (CRF). Adult male rats (n = 24) were randomly assigned into four groups (n = 6 each): normal controls (CON), garlic extract controls (GE; 250 mg kg-1, orally), GNT-induced CRF (GNT; 100 mg kg-1, i.p.), and GNT + GE (GNT and GE in the same previous doses) groups. GNT and GE were given daily for 3 weeks. Animals co-treated with GNT and GE exhibited improved renal functions, body weight (BW), and heart weight (HW)/BW ratio; declined blood pressure; lowered plasma levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and total peroxides (TP); and elevated total antioxidant capacity (TAC) levels. Moreover, the heart tissue contained raised levels of TAC and Na+/K+-ATPase activity and lowered levels of TP and Ca2+. Findings provide evidence that administration of GE in experimental CRF model helped protect the heart through reducing oxidative stress and controlling cardiac Na+/K+-ATPase activity and Ca2+ levels.

Update of aristolochic acid nephropathy in Korea.

BACKGROUND/AIMS: The true incidence of aristolochic acid nephropathy (AAN) is thought to be underestimated because numerous ingredients known or suspected to contain aristolochic acid (AA) are used in traditional medicine in Korea. METHODS: We collected data on cases of AAN since 1996 via a database in Korea. We evaluated the year of AAN development, route to obtaining AA-containing herbal medicine, gender, reason for taking AA-containing herbal medicine, clinical manifestations, histological findings, phytochemical analysis, and prognosis of patients with AAN. RESULTS: Data on 16 cases of AAN were collected. Thirteen cases developed AAN before and three cases after the prohibition of AA-containing herbal medicine by the Korea Food and Drug Administration. Patients were prescribed AA-containing herbal medicine from oriental clinics or had purchased it from traditional markets. AAN was distributed in all age groups. Young females were most commonly exposed to AA-containing herbal medicine for slimming purposes and postpartum health promotion, while older adults took AA-containing compounds for the treatment of chronic diseases. The most common symptoms presented at hospitalization were nausea and vomiting, and acute kidney injury was accompanied by Fanconi syndrome in almost half of the patients. Phytochemical analysis of AA in herbal medicine was available in six cases. Progression to end stage renal disease (ESRD) was observed in seven patients (43.8%), and five patients (31.3%) had progressed to ESRD within 6 months of diagnosis. CONCLUSION: Our report shows that patients were still exposed to AA-containing herbal medicine and that there is a possibility of underdiagnosis of AAN in Korea. A stronger national supervision system of herbal ingredients and remedies in oriental medicine is needed to prevent AAN.

Renoprotective effect of Chinese chive polysaccharides in adenine-induced chronic renal failure.

In this work, we investigated the effect of Chinese chive polysaccharides (CCP) on renal function in mice with adenine-induced chronic renal failure (CRF). Results exhibited that adenine treatment caused serious renal pathological damages and elevation of serum creatinine and blood urea nitrogen of mice. However, these changes could be significantly reversed by the administration of CCP in a dose-dependent manner. When CCP dosage reached 200mg/kg/day, the area of renal pathological damage was decreased by 59.2%, and the levels of serum creatinine and blood urea nitrogen were decreased by 23.9% and 34.7% compared to those of model group. Moreover, it was found that renal oxidative damage, inflammation and fibrosis of adenine-induced CRF mice could also be significantly inhibited by CCP. These results suggested that CCP could improve the kidney functions of adenine-induced CRF mice and the renoprotective effect might be associated with its antioxidant, anti-inflammatory and anti-fibrosis activities.

Zhen-wu-tang ameliorates adenine-induced chronic renal failure in rats: regulation of the canonical Wnt4/beta-catenin signaling in the kidneys.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhen-wu-tang (ZWT), composed of Radix Aconiti lateralis, Rhizoma Atractylodis macrocephalae, Poria, Radix Paeoniae alba and ginger, is a classic Chinese herbal formula for the treatment of chronic kidney diseases that may cause chronic renal failure (CRF). AIM OF THE STUDY: To better understand its clinical use, this study investigated the effects and underlying mechanisms of action of ZWT on CRF. MATERIALS AND METHODS: CRF was induced by adenine. ZWT was given via an oral gavage method. The serum biochemical parameters were measured enzymatically or by ELISA. The kidneys were examined pathohistologically. The gene expression was analyzed by real time PCR and Western blot. RESULTS: Similar to the positive control losartan, ZWT extract inhibited adenine-induced increase in serum concentrations of creatinine, BUN and advanced oxidation protein products in rats. These effects were accompanied by attenuation of proteinuria and renal pathological changes and suppression of renal mRNA and protein overexpression of Collagen IV and fibronectin, two of the key components of fibrosis. Mechanistically, renal mRNA and protein expression of Wnt4, a Wnt signaling ligand, was increased in the adenine-treated group, compared to the vehicle-treated control. Consistently, Wnt4 downstream genes beta-catenin and Axin were also overexpressed. Treatment with ZWT extract and losartan suppressed adenine-stimulated overexpression of these mRNAs and proteins. CONCLUSIONS: The present results demonstrate that ZWT extract ameliorates adenine-induced CRF in rats by regulation of the canonical Wnt4/beta-catenin signaling in the kidneys. Our findings provide new insight into the underlying renoprotective mechanisms of the ancient formula.

Protective effects of Salvia miltiorrhiza on adenine-induced chronic renal failure by regulating the metabolic profiling and modulating the NADPH oxidase/ROS/ERK and TGF-ß/Smad signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Chronic renal failure (CRF) is defined as a progressive and irreversible loss of renal function and associated with inflammation and oxidative stress. Salvia miltiorrhiza (SM) is an important Chinese herb used in traditional Chinese medicine for treating cardiovascular diseases. The previous studies showed the SM exhibited significant protective effects on CRF. In this present study, the metabolic profiling changes and action mechanism of SM on CRF were explored. AIMS OF THE STUDY: The aims of this study were to illustrate the metabolic profiling changes of adenine induced CRF and analyze the protective effects and action mechanisms of SM ethanol extract (SMEE) and water extract (SMWE). MATERIALS AND METHODS: The animals were divided into normal group, CRF model group, Huangkui capsule-treated group, SMEE-treated group and SMWE-treated group. The UPLC-QTOFMS coupled with multivariate statistical methods were used to explore the changes of metabolic profile in plasma, urine and renal tissue from CRF rats simultaneously after treatment with SMEE and SMWE. Hematoxylin eosin (HE) staining and Masson staining were applied to observe pathological changes in renal tissue. Biochemical indicators including serum urea nitrogen (BUN), urine protein (UP) and serum creatinine (Scr) were measured according to the manufacturer's instructions of kits. Furthermore, HK-2 cell damaged model induced by ISF was established to access the protective effects and action mechanism. The dichlorodihydrofluorescein diacetate (DCFH-DA) assay was used to determine the reactive oxygen species (ROS) and Western blot was applied to analyze the expression of pathogenesis-related proteins in different groups. RESULTS: The results showed that the ethanol extract (SMEE) and water extract (SMWE) of SM significantly inhibited the elevation of serum creatinine (Scr), blood urea nitrogen (BUN), urine protein (UP) and indoxyl sulfate (ISF) in adenine-induced CRF rats, especially SMEE exhibited more significant effects. Moreover, SM extracts obviously improved the symptoms of glomerular and tubular atrophy, focal calcium deposits, interstitial fibrosis, interstitial inflammation, and renal tissues. By metabolomics analysis, fifty-nine metabolites (thirteen in plasma, twenty-seven in urine and nineteen in kidney tissue) were up-regulated or down-regulated and contributed to CRF progress. After treatment of SM extracts, the altered metabolites were restored back to normal level. These potential biomarkers underpinning the metabolic pathways are including phenylalanine metabolism, pyrimidine metabolism, purine metabolism and tryptophan metabolism. Furthermore, SM extracts prevent epithelial-mesenchymal transition (EMT) of human renal tubular epithelial (HK-2) cell by inhibiting NADPH oxidase/ROS/ERK and TGF-ß/Smad signaling pathways. CONCLUSIONS: SMEE and SMWE can significantly alleviate adenine-induced CRF via regulation of the metabolic profiling and modulation of NADPH oxidase/ROS/ERK and TGF-ß/Smad signaling pathways, which provided important supports for the development of protective agent of SM for CRF.

Antiretroviral therapy as a risk factor for chronic kidney disease: Results from traditional regression modeling and causal approach in a large observational study.

OBJECTIVE: We investigated whether patients receiving selected antiretroviral combinations had a higher risk of chronic kidney disease (CKD) using traditional regression modeling and a causal approach in a large prospective cohort. PATIENTS AND METHODS: For the purpose of this study, we selected 6301 patients who (i) started their first antiretroviral regimen after 1st January 2004, (ii) had at least one serum creatinine measurement within 6 months before ART initiation (study entry), and (iii) had at least two measurements after study entry. Baseline eGFR was defined from the last serum creatinine measurement before study entry. All eGFR values were calculated using the Modification of Diet and Renal Disease (MDRD) equation. Both traditional Cox proportional hazards model and Cox marginal structural models were applied. Distinct coding for antiretroviral therapy exposure were investigated as well as double robust estimators. RESULTS: Overall we showed that patients receiving tenofovir (TDF) with a ritonavir boosted protease inhibitor (rbPI) exhibited a higher risk of CKD compared with patients who received TDF with a non-nucleosidic reverse transcriptase inhibitor (NNRTI). Such an increased risk was observed considering both initial and current regimens. Our analysis revealed a clinician-driven switch away from TDF among persons experiencing a decline in renal function while receiving this drug. CONCLUSION: Our results show that combination of TDF and boosted protease inhibitor is associated with a higher CKD risk than TDF and a NNRTI.

Quercetin Attenuates Vascular Calcification through Suppressed Oxidative Stress in Adenine-Induced Chronic Renal Failure Rats.

BACKGROUND: This study investigated whether quercetin could alleviate vascular calcification in experimental chronic renal failure rats induced by adenine. METHODS: 32 adult male Wistar rats were randomly divided into 4 groups fed normal diet, normal diet with quercetin supplementation (25 mg/kg·BW/d), 0.75% adenine diet, or adenine diet with quercetin supplementation. All rats were sacrificed after 6 weeks of intervention. Serum renal functions biomarkers and oxidative stress biomarkers were measured and status of vascular calcification in aorta was assessed. Furthermore, the induced nitric oxide synthase (iNOS)/p38 mitogen activated protein kinase (p38MAPK) pathway was determined to explore the potential mechanism. RESULTS: Adenine successfully induced renal failure and vascular calcification in rat model. Quercetin supplementation reversed unfavorable changes of phosphorous, uric acid (UA) and creatinine levels, malonaldehyde (MDA) content, and superoxide dismutase (SOD) activity in serum and the increases of calcium and alkaline phosphatase (ALP) activity in the aorta (P < 0.05) and attenuated calcification and calcium accumulation in the medial layer of vasculature in histopathology. Western blot analysis showed that iNOS/p38MAPK pathway was normalized by the quercetin supplementation. CONCLUSIONS: Quercetin exerted a protective effect on vascular calcification in adenine-induced chronic renal failure rats, possibly through the modulation of oxidative stress and iNOs/p38MAPK pathway.

PA21, a novel phosphate binder, improves renal osteodystrophy in rats with chronic renal failure.

The effects of PA21, a novel iron-based and non-calcium-based phosphate binder, on hyperphosphatemia and its accompanying bone abnormality in chronic kidney disease-mineral and bone disorder (CKD-MBD) were evaluated. Rats with adenine-induced chronic renal failure (CRF) were prepared by feeding them an adenine-containing diet for four weeks. They were also freely fed a diet that contained PA21 (0.5, 1.5, and 5%), sevelamer hydrochloride (0.6 and 2%) or lanthanum carbonate hydrate (0.6 and 2%) for four weeks. Blood biochemical parameters were measured and bone histomorphometry was performed for femurs, which were isolated after drug treatment. Serum phosphorus and parathyroid hormone (PTH) levels were higher in the CRF rats. Administration of phosphate binders for four weeks decreased serum phosphorus and PTH levels in a dose-dependent manner and there were significant decreases in the AUC0-28 day of these parameters in 5% PA21, 2% sevelamer hydrochloride, and 2% lanthanum carbonate hydrate groups compared with that in the CRF control group. Moreover, osteoid volume improved significantly in 5% of the PA21 group, and fibrosis volume and cortical porosity were ameliorated in 5% PA21, 2% sevelamer hydrochloride, and 2% lanthanum carbonate hydrate groups. These results suggest that PA21 is effective against hyperphosphatemia, secondary hyperparathyroidism, and bone abnormalities in CKD-MBD as sevelamer hydrochloride and lanthanum carbonate hydrate are, and that PA21 is a new potential alternative to phosphate binders.

Use of cinacalcet for the management of hyperparathyroidism in patients with different degrees of renal failure.

BACKGROUND: The effects of cinacalcet in persistent and/or hypercalcaemia-associated secondary hyperparathyroidism (SHPT) have been described in patients on dialysis. OBJECTIVES: To evaluate the efficacy and safety of cinacalcet in SHPT not on dialysis and its effects on bone turnover markers. METHODS: Non-randomised, longitudinal, observational, analytical study of patients with chronic kidney disease (CKD) and SHPT (PTH> 80 pg/mL) as well as normo- or hypercalcaemia (≥8.5mg/dL), treated with cinacalcet. RESULTS: Mean cinacalcet dose was 30mg/day in 66.7%. We studied 15 patients (10 women), aged 66.0±17.93years. The aetiology was unknown in 20% of cases. Sociodemographic variables and renal function parameters were recorded. We compared values at baseline as well as after 6 and 12 months. Calcium (10.3±0.55 vs. 9.4±1.04) and iPTH (392.4±317.65 vs. 141.8±59.26) levels decreased. Increased levels of phosphorus (3.7±1.06 vs. 3.9±0.85) and ß-CTX (884.2±797.22 vs. 1053.6±999.00) were detected, although there were no significant changes in GFR, urinary calcium or other bone markers. Two patients withdrew from the study (gastrointestinal intolerance and parathyroidectomy, respectively). CONCLUSIONS: Cinacalcet at low doses is effective in the management of SHPT in CKD patients who are not on dialysis. Its use reduces iPTH and calcaemia, without causing serious side effects or significant changes in renal function.