Sustained hypophosphatemia after denosumab in a patient on hemodialysis.

An 81-year-old Caucasian man who had commenced thrice weekly hemodialysis (HD) three months earlier, presented with a hip fracture, two vertebral fractures and a bone mineral density T-score of -3.6. He had received weekly iron sucrose infusions for 6 weeks and alphacalcidol on dialysis days. Although he suffered from coeliac disease and cirrhosis, he was fully ambulatory and well-nourished. He was normocalcaemic with a marginally low plasma phosphate and the PTH was 11.8 pmol/L (<2-times the upper range of the assay). In view of his severe osteoporosis, it was decided to treat him with denosumab (dmab). Laboratory assessment 2 weeks post dmab showed severe hypophosphatemia and hypocalcemia; phosphate 0.11 mmol/L and ionized calcium 0.83 mmol/L, and he was admitted for intravenous phosphate infusion. Three months later he remained on a phosphate supplement. The case illustrates that, in addition to the risks of hypocalcemia in patients with kidney failure and high bone turnover, kidney failure patients without evidence of high bone turnover, can also be at risk of hypocalcemia and severe hypophosphatemia requiring acute hospitalization and phosphate infusion. The potential role of compromised phosphate absorption versus increased deposition will be discussed. We recommend a cautious approach to dmab therapy in patients on dialysis, with evaluation of bone turnover and serum phosphate levels prior to initiation of treatment.

A systematic review for prevention of cisplatin-induced nephrotoxicity using different hydration protocols and meta-analysis for magnesium hydrate supplementation.

BACKGROUND: Nephrotoxicity remains the most serious side effect of cisplatin therapy. Cisplatin-induced nephrotoxicity (CIN) limits the use of this drug and affects up to 20% of patients. Several possible interventions such as magnesium supplementation may prevent CIN. This study aimed to review different types of hydration protocols and we conducted a meta-analysis of magnesium supplementation to understand its effect in protecting against CIN. METHODS: A search of the PubMed, Embase, and Cochrane databases was performed. Trials were eligible if they enrolled patients who received cisplatin and different hydration protocols to prevent CIN. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the efficacy of different protocols. RESULTS: We initially identified 1113 different studies and included 33 of them which met the selection criteria. A meta-analysis of 11 retrospective studies that examined magnesium supplementation during hydration showed that this treatment provided significant protection against CIN (OR = 0.22, 95% CI = 0.14 to 0.35). CONCLUSION: There has been uncertainty regarding the best method to prevent CIN. Our results highlight the potentially protective effect of magnesium supplementation during hydration. This study is registered in PROSPERO, CRD42020212682.

Normal 24-hour urine calcium concentrations after long-term daily oral intake of vitamin D in doses ranging from 5000 to 50,000 international units in 14 adult hospitalized psychiatric patients.

Many controversies exist regarding vitamin D3 supplementation. These include not only diseases that are responsive to vitamin D supplementation, but also the long-term safety of prolonged daily oral vitamin D3 intake above 4000-10,000 International Units (IU). In particular, supplementation levels that do not result in adverse events, and the upper limits of safe serum 25-hydroxyvitamin D (25OHD) concentrations. Adverse reactions reported to occur with excessive vitamin D intake include hypercalcemia, renal failure, calcium crystal formation, undetectable parathyroid hormone concentrations, and hypercalciuria, all of which are reported to be reversible. To address the long-term safety of vitamin D supplementation, we previously reported data from patients in our hospital who have been voluntarily supplemented with vitamin D3 ranging from 5,000 to 10,000 IU/day since July 2011 as a standard of care for the prevention and treatment of vitamin D deficiency. Historically 90% of patients have agreed to daily supplementation, with most taking 10,000 IU/day. These data indicate no evidence for hypercalcemia, renal failure, calcium crystal formation, nephrolithiasis. or undetectable parathyroid hormone concentrations in patients taking 5000 or 10,000 IU/day for extended periods of time. As another measure for potential vitamin D toxicity, we retrospectively assessed 24-hour urine calcium excretion in 14 individuals on long-term daily oral vitamin D intake ranging from 5000 to 50,000 IU/day to further assess the safety of supplementation using these doses. This included patients taking either 5000 (4), 10,000 (9), or 50,000 (1) IU/day. Time on supplementation ranged from 10 to 102 months. A patient taking 400 IU/day and getting frequent sun exposure was also included. All fifteen 24-hour urine calcium measurements were normal. The current findings complement our experience with over 7000 patients in the past 13 years, indicating that prolonged daily oral intake of vitamin D3 ranging from 5000 to 10,000 IU/day is safe.

Is It Time for a Requiem for Creatine Supplementation-Induced Kidney Failure? A Narrative Review.

Creatine has become one of the most popular dietary supplements among a wide range of healthy and clinical populations. However, its potential adverse effects on kidney health are still a matter of concern. This is a narrative review of the effects of creatine supplementation on kidney function. Despite a few case reports and animal studies suggesting that creatine may impair kidney function, clinical trials with controlled designs do not support this claim. Creatine supplementation may increase serum creatinine (Crn) concentration for some individuals, but it does not necessarily indicate kidney dysfunction, as creatine is spontaneously converted into Crn. Based on studies assessing kidney function using reliable methods, creatine supplements have been shown to be safe for human consumption. Further studies with people who have pre-existing kidney disease remain necessary.

Comparison of the effect of vitamin C and selenium nanoparticles on gentamicin-induced renal impairment in male rats: a biochemical, molecular and histological study.

Renal failure caused by gentamicin is mainly mediated through oxidative damage, inflammation, and apoptosis. Hence, vitamin C and selenium, which have antioxidant, anti-inflammatory, and anti-apoptotic properties, and their nanoparticle forms, which have recently received attention, may reduce gentamicin-induced side effects. Therefore, the aim of this study was to investigate the therapeutic effects of vitamin C and selenium, and their nanoparticles on gentamicin-induced renal damage in male rats. 128 adult male Wistar rats were randomly divided into equal sixteen controlled and treated groups. Serum levels of uric acid, blood urea nitrogen, urea, and creatinine were measured. Renal levels of oxidative parameters such as MDA, SOD, and CAT and inflammatory parameters including IL-1ß, and TNF-α were measured. Renal expression of Nrf2, NF-κB, Bcl-2, caspase-3, BAX and mTORc1 was also evaluated. The results showed that gentamicin causes oxidative damage, inflammation, apoptosis and disruption of autophagy in kidney tissue in a dose-dependent manner. However, treatment with vitamin C, selenium and their nanoparticles could significantly improve these effects. Also, the results showed that the inflammatory and oxidative parameters and the expression of genes involved in them and apoptosis in the gentamicin groups treated with vitamin C nanoparticles and selenium nanoparticles reduced significantly compared to those treated with vitamin C and selenium. It can be concluded that vitamin C, selenium and their nanoparticles can improve gentamicin-induced kidney damage by inhibiting oxidative damage, inflammation and apoptosis-induced by autophagy, and can be a good option for kidney damage caused by gentamicin or as an adjunctive treatment to reduce its side effects.

Practical approaches to improve vancomycin-related patient outcomes in pediatrics- an alternative strategy when AUC/MIC is not feasible.

BACKGROUND: Anecdotal experience and studies have shown that most pediatric patients fail to reach target therapeutic vancomycin trough levels (VTLs) and required higher total daily doses (TDD). This retrospective study aims to evaluate the frequency of hospitalized children who achieved target VTLs with a vancomycin (VNCO) dosing regimen of 40-60 mg/kg/d q6h and to assess the VNCO-TDD required to attain the target and their effects on clinical outcomes in pediatric patients. METHODS: After ethical approval, patients of 3 month-12 years were evaluated in this chart review study who received ≥ 3 intravenous-VNCO doses and appropriately drawn blood samples of VTLs between October 2019 to June 2020. Data were retrieved for demographic and clinical characteristics, culture reports, VNCO-regimen, subsequent steady-state VTLs, concomitant nephrotoxic medications, and serum creatinine. Clinical pharmacists made interventions in VNCO therapy and higher VNCO-TDD were used. Safety of higher vs standard daily doses and their clinical impact on duration of therapy, hospital stay, and survival were evaluated. RESULTS: A total of 89 (39.1%) patients achieved target VTLs (SD-group). The smallest proportion (18.2%) of 2-6 years patients achieved target VTLs and reported the lowest mean value of 10.1 ± 0.2 mg/L which was a significant difference (p < 0.05) from all subgroups. Subtherapeutic VTLs were observed in 139 (60.9%) cases (HD-group), who received higher VNCO-TDD of 72 ± 8.9 mg/kg/d q6h to achieve the targets. Duration of therapy in culture-proven septic patients was significantly (p = 0.025) longer in SD-group [18.4 ± 12.2 days] than HD-group [15.1 ± 8.9 days]. Nephrotoxicity and electrolyte imbalance were comparable in groups. Length of hospital stay was significantly (p = 0.011) longer [median 22 (range 8-55) days] in SD-group compared to HD-group [median 16 (range 8-37) days]. Number of patients survived in HD-group were significantly (p = 0.008) higher than SD-group [129 (92.8%) vs 75 (84.3%)]. CONCLUSION: Initial Vancomycin doses of 72 ± 8.9 mg/kg/day q6h are required to achieve therapeutic target in 3 months to 12 years patients. High doses are not associated with higher nephrotoxicity than reported with low doses. In addition, efficient pharmacist intervention for the use of higher VNCO-TDD may improve clinical outcomes in terms of duration of therapy, hospital stay, and survival.

Systematic review and meta-analysis of prophylaxis use with intravenous contrast exposure to prevent contrast-induced nephropathy.

PURPOSE: Iodinated radiographic contrast media has been associated with an acute deterioration in renal function, termed contrast induced nephropathy (CIN). This review aims to establish the efficacy of prophylaxis interventions used in adult patients prior to intravenous exposure to iodinated contrast to reduce the risk of CIN. METHODS: An electronic search for published peer-reviewed articles was performed, supplemented with manual review of references from previous systematic reviews and the National Institute for Health and Care Excellence guidelines. Risk of bias was assessed using the Cochrane Collaboration's tool for assessing risk of bias. Random-effect meta-analyses were used to assess CIN incidence, need for kidney replacement therapy (KRT), mortality, fluid overload and persistent kidney dysfunction. RESULTS: 22 studies assessing a range of interventions were included in the qualitative analysis. The incidence of CIN was reduced by the use of N-acetylcysteine compared to a control group of saline (risk difference = -0.07, 95% CI -0.13 to -0.01) but not by sodium bicarbonate compared to control group of saline (risk difference = -0.02, 95% CI -0.04 to 0.01). Published studies give no indication that prophylactic interventions have significant impact on the need for KRT, mortality or persistent renal impairment. CONCLUSION: Evidence for prophylaxis against CIN in patients receiving intravenous iodinated contrast is limited. There was an association with the use of NAC with reduced incidence of CIN following intravenous contrast but there was no impact on other clinical outcomes assessed. The clinical significance of these findings remains unclear and further research focusing on these clinical outcomes is required.

Pharmacological agents for the prevention of colistin-induced nephrotoxicity.

BACKGROUND: Colistin is a polymyxin antibiotic which has been used for treatment of Gram-negative infections, but it was withdrawn due to its nephrotoxicity. However, colistin has gained its popularity in recent years due to the reemergence of multidrug resistant Gram-negative infections and drug-induced toxicity is considered as the main obstacle for using this valuable antibiotic. RESULTS: In total, 30 articles, including 29 animal studies and one clinical trial were included in this study. These compounds, including aged black garlic extract, albumin fragments, alpha lipoic acid, astaxanthin, baicalein, chrysin, cilastatin, colchicine, curcumin, cytochrome c, dexmedetomidine, gelofusine, grape seed proanthocyanidin extract, hesperidin, luteolin, lycopene, melatonin, methionine, N-acetylcysteine, silymarin, taurine, vitamin C, and vitamin E exhibited beneficial effects in most of the published works. CONCLUSIONS: In this review, the authors have attempted to review the available literature on the use of several compounds for prevention or attenuation of colistin-induced nephrotoxicity. Most of the studied compounds were potent antioxidants, and it seems that using antioxidants concomitantly can have a protective effect during the colistin exposure.

Artemisia capillaris Thunb. water extract attenuates adriamycin-induced renal injury by regulating apoptosis through the ROS/MAPK axis.

Artemisia capillaris Thunb. is widely used in the treatment of kidney diseases, but the underlying mechanism remain elusive. Therefore, this study aimed to elucidate the mechanism of Artemisia capillaris Thunb. in alleviating renal injury. And renoprotective effects of freeze-dried powder of Artemisia capillaris Thunb. water extract (WAC) were assessed using adriamycin (ADR)-induced renal injury to the NRK-52E cells and ADR-induced renal injury Sprague-Dawley rats (SD rats) models. The results show that WAC could alleviate ADR-induced renal injury in SD rats and the NRK-52E cell line, improved renal function (BUN 9.73 ± 0.35 vs 7.13 ± 0.15, SCR 80.60 ± 1.68 vs 60.50 ± 1.42, ACR 11.50 ± 0.50 vs 8.526 ± 0.15) or cell viability (IC50 = 1.08 µg/ml (ADR), cell viability increase 36.38% ± 6.74% (added 4 mg/ml WAC)), and reduced the apoptosis. Moreover, WAC inhibited the MAPK signal transduction, increased the expression of superoxide dismutase 1 (SOD1), and decreased the production of ROS. The treatment of N-acetylcysteine (NAC, antioxidant) in vitro showed that NAC inhibited apoptosis and alleviated renal injury by inhibiting oxidative stress and reducing the phosphorylation of proteins related to the MAPK signaling pathway. Therefore, these results suggested that WAC can alleviate ADR-induced renal injury and apoptosis by regulating the ROS/MAPK axis and has potential to be used as a renoprotective drug. PRACTICAL APPLICATIONS: Artemisia capillaris Thunb., which is a medicinal and edible plant, is widely used to treat kidney diseases in traditional Chinese medicine. The present research examined the renal protective effect of Artemisia capillaris Thunb. The results show that Artemisia capillaris Thunb. can effectively reduce renal tubular cell apoptosis through the ROS/MAPK axis in vivo and in vitro. In general, Artemisia capillaris Thunb. can be used as a potential herb to attenuate renal injury and further research can be conducted to explore its renoprotective mechanisms.

Antioxidant effect of ascorbic acid against cisplatin-induced nephrotoxicity and P-glycoprotein expression in rats.

Cisplatin (CDDP) is a highly potent anticancer drug that is widely used in the treatment of several cancers. CDDP-induced nephrotoxicity (CIN) is one of the most significant adverse effects, and oxidative stress is thought to be one of the mechanisms underlying CIN. Although there are some studies available on the variability in transporter expression in the kidney after a single CDDP dose, none have reported the change in renal transporter expression after multiple CDDP dose administrations. P-glycoprotein (P-gp), a transporter, is reported to be induced by oxidative stress. Ascorbic acid is a vitamin with antioxidant potential and therefore, may regulate the expression of P-gp transporter and affect CIN. In the present study, our aim was to assess the variability in expression of several renal transporters after multiple CDDP dose administrations and the antioxidant effect of ascorbic acid against transporter expression and CIN. Multiple doses of CDDP affected markers of kidney injury and antioxidants in the kidneys. Also, the expression of P-gp, breast cancer resistance protein, and multidrug resistance-associated protein 4 was upregulated by CDDP. Using a normal kidney cell line, we demonstrated that ascorbic acid attenuated CDDP-induced cytotoxicity due to its high superoxide scavenging ability. CDDP and ascorbic acid were injected into rats once a week for three weeks, and it was observed that co-administration of ascorbic acid attenuated CIN and regulated antioxidant marker. In addition, ascorbic acid reduced P-gp expression, which was upregulated by CDDP. In conclusion, ascorbic acid may attenuate CIN and reverse P-gp-mediated changes in drug pharmacokinetics.

Significant interaction between high-dose methotrexate and high-dose piperacillin-tazobactam causing reversible neurotoxicity and renal failure in an osteosarcoma patient.

INTRODUCTION: Pharmacokinetic interaction of high-dose methotrexate (MTX) and other concomitantly administered renally secreted medicinal products may lead to insufficient methotrexate serum level decrease and significant MTX toxicity. CASE REPORT: We report the case of an 18-year-old male patient treated with high-dose MTX for an osteosarcoma and with high-dose piperacillin-tazobactam at the same time. MTX serum levels were severely elevated 24 hours after the MTX infusion and did not decrease in accordance with the specific calcium folinate rescue protocol. The patient experienced renal failure accompanied by neurological symptoms, most consistent with MTX-related renal and CNS toxicity.Management and outcome: After discontinuation of piperacillin-tazobactam, intensified calcium folinate rescue therapy, and IV hydration, the MTX serum levels decreased appropriately, and toxicity symptoms resolved. DISCUSSION: Severe MTX-related toxicity, caused by drug-drug interaction, suggests that the concomitant use of high-dose MTX and high-dose piperacillin-tazobactam should be avoided generally.

The Toxicity Effect of Echium amoenum on the Liver and Kidney of Mice.

AIMS: The aim of this study was to investigate the toxic effect of Echium amoenum plants on the liver and kidney of the animal model. BACKGROUND: Echium amoenum is one of the medicinal plants containing pyrrolizidine alkaloids with several properties which has widely consumed among different communities. OBJECTIVE: The toxic effects of Echium amoenum on the liver and kidney were investigated in this study. METHODS: Sixty mice were kept for 28 days under the appropriate laboratory conditions. Echium amoenum extract (25, 12.5, 50 mg / kg, ip.) was administered for 28 days. At the end of the experiment, blood samples were drawn and liver and kidneys were removed for evaluating hepatotoxicity and nephrotoxicity of extract. Additionally, experiments were conducted to assay the enzymatic and oxidative activities. RESULTS: There was no significant difference in the levels of copper ion in the liver and kidneys among all groups. There was a significant difference in the levels of lipid peroxidation in the liver of treated groups versus the control group. The significant difference was not observed in the levels of glutathione of the liver of all groups. However, the levels of glutathione of the kidney significantly decreased in the treated groups versus the control group. There was no significant difference in the liver enzymes, including ALP, SGOT, and SGPT, between all groups. This indicates that damage increases with enhancing the time and concentrations of the extract. Biochemical analysis showed the creatinine and urea levels did not change in the treated groups versus the control group. CONCLUSION: According to the present findings, it is suggested that Echium amoenum causes hepatotoxicity and nephrotoxicity effects in dose and time-dependent manner.

Prevention of melamine-induced hepatorenal impairment by an ethanolic extract of Moringa oleifera: Changes in KIM-1, TIMP-1, oxidative stress, apoptosis, and inflammation-related genes.

BACKGROUND/AIMS: Melamine (ML) is a common food adulterant and contaminant. Moringa oleifera is a well-known medicinal plant with many beneficial biological properties. This study investigated the possible prophylactic and therapeutic activity of an ethanolic extract of M. oleifera (MEE) against ML-induced hepatorenal damage. METHOD: Fifty male Sprague Dawley rats were orally administered distilled water, MEE (800 mg/kg bw), ML (700 mg/kg bw), MEE/ML (prophylactically) or MEE+ML (therapeutically). Hepatic aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphate (ALP) in serum were measured. Serum total bilirubin, direct bilirubin, indirect bilirubin, protein, albumin, and globulin contents were also assayed, and urea and creatinine levels were determined. Moreover, antioxidant enzyme activity of glutathione peroxidase (GPx) and catalase (CAT) in serum levels were quantified. Complementary histological and histochemical evaluation of renal and hepatic tissues was conducted, and expression of oxidative stress (GPx and CAT) and apoptosis-related genes, p53 and Bcl-2, in hepatic tissue were assessed. In parallel, transcriptional expression of inflammation and renal injury-related genes, including kidney injury molecule 1 (KIM-1), metallopeptidase inhibitor 1 (TIMP1), and tumor necrosis factor alpha (TNF-α) in the kidney tissue were determined. RESULTS: ML caused significant increases in serum levels of ALT, AST, ALP, total bilirubin, direct bilirubin, indirect bilirubin, urea, and creatinine. Further, ML treated rats showed significant reductions in serum levels of protein, albumin, globulin, GPx, and CAT. Distinct histopathological damage and disturbances in glycogen and DNA content in hepatic and renal tissues of ML treated rats were observed. KIM-1, TIMP-1, and TNF-α gene expression was significantly upregulated in kidney tissue. Also, GPx, CAT, and Bcl-2 genes were significantly downregulated, and p53 was significantly upregulated in liver tissue after ML treatment. MEE significantly counteracted the ML-induced hepatorenal damage primarily for co-exposed rats. CONCLUSION: MEE could be an effective therapeutic supplement for treatment of ML-induced hepato-renal damage, probably via modulating oxidative stress, apoptosis, and inflammation.

Siblings with pediatric sodium chlorite toxicity causing methemoglobinemia, renal failure and hemolytic anemia.

INTRODUCTION: Over the past decade, Miracle Mineral Solution (sodium chlorite) has been promoted as a cure-all for many conditions. CASE REPORT: A 9-year-old boy presented with his brother after they accidentally ingested a small amount of undiluted 22.4% sodium chlorite. Symptoms included nausea, vomiting, diarrhea, and dyspnea. Oxygen saturation remained 71% despite supplemental oxygen (15L/min). The patient was noted to have dark chocolate-appearing blood, minimal urine output, diffuse pallor and cyanosis. He developed methemoglobinemia, renal failure requiring renal replacement therapy and hemolysis requiring blood transfusion. DISCUSSION: These are the 7th and 8th reported cases of sodium chlorite toxicity by ingestion and the second and third in children. Takeaway for Physicians: Miracle Mineral Solution is a commonly purchased potentially lethal compound that can cause methemoglobinemia with respiratory failure, hemolytic anemia requiring transfusion and renal failure requiring dialysis.

Nephroprotective Role of Zhibai Dihuang Wan in Aristolochic Acid-Intoxicated Zebrafish.

Zhibai Dihuang Wan (ZDW) is an eight-herbal formula of traditional Chinese medicine. Clinically, it regulated immune activity and was used to treat diabetes and renal disease. In this study, we aimed to explore the nephroprotective effect of ZDW in an aristolochic acid- (AA-) intoxicated zebrafish model. We used a green fluorescent kidney transgenic zebrafish to evaluate the nephroprotective effects of ZDW by recording subtle changes in the kidney. Our results demonstrated that ZDW treatment can attenuate AA-induced kidney malformations (60% for AA-treated, 47% for pretreatment with ZDW, and 17% for cotreatment ZDW with AA, n = 50). Furthermore, we found that the expression levels of tnfα and mpo were decreased either in pretreatment or cotreatment groups. In conclusion, our findings revealed that AA-induced nephrotoxicities can be attenuated by ZDW. Therefore, we believe that zebrafish represent an efficient model for screening AA-protective Chinese medicine.

Ameliorative effect of phosphodiesterase 4 and 5 inhibitors in deoxycorticosterone acetate-salt hypertensive uni-nephrectomized KKAy mice.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Hypertension increases kidney stress, which deteriorates function, and leads to peripheral renal vascular resistance. Long-term hypoperfusion promotes interstitial fibrosis and glomerular sclerosis, resulting in nephrosclerosis. Although hypertension and DN are frequent ESRD complications, relevant animal models remain unavailable. We generated a deoxycorticosterone acetate (DOCA)-salt hypertensive uni-nephrectomized (UNx) KKAy mouse model demonstrating hypertension, hyperglycemia, cardiac hypertrophy, kidney failure, increased urinary albumin creatinine ratio (UACR), and increased renal PDE4D and cardiac PDE5A mRNA levels. We hypothesized that the novel PDE4 selective inhibitor, compound A, and PDE5 inhibitor, sildenafil, exhibit nephroprotective, and cardioprotective effects in this new model. Compound A, sildenafil, and the angiotensin II receptor blocker, irbesartan, significantly reduced ventricular hypertrophy and pleural effusion volume. Meanwhile, compound A and sildenafil significantly suppressed the UACR, urinary kidney injury molecule-1, and monocyte chemoattractant protein-1 levels, as well as that of renal pro-fibrotic marker mRNAs, including collagen 1A1, fibronectin, and transforming growth factor-beta (TGF-ß). Moreover, compound A significantly suppressed TGF-ß-induced pro-fibrotic mRNA expression in vitro in all major kidney lesions, including within the glomerular mesangial region, podocytes, and epithelial region. Hence, PDE4 and PDE5 inhibitors may be promising treatments, in combination with irbesartan, for DN with hypertension as they demonstrate complementary mechanisms.

Toxicity of Herbs, Vitamins, and Supplements.

In the United States, the Food and Drug Administration regulates the efficacy and safety of pharmaceutical drugs. This government agency was formed in direct response to a mass poisoning and more than 100 deaths from kidney failure due to a medicinal toxic alcohol exposure. In contrast, the Food and Drug Administration also regulates the use of vitamins, minerals, herbs, or botanicals as dietary supplements, banning specific medical claims but requiring no documentation of efficacy. Safety of dietary supplements is only ensured through reporting of adverse events and rarely through intervention. Consumers should be aware that supplements may in fact contain actual pharmaceuticals or nothing of value and have significant toxic potential. Toxicity due to Chinese herbal medicines, aristolochic acid, amygdalin, hypervitaminosis D, and heavy metal contamination is reviewed.

Red orange and lemon extract prevents the renal toxicity induced by ochratoxin A in rats.

In this work, we investigated the effects of red orange and lemon extract (RLE) on ochratoxin A (OTA)-induced nephrotoxicity. In particular, we analyzed the change in renal function and oxidative stress in Sprague-Dawley rats treated with OTA (0.5 mg/kg body weight, b.w.) and with RLE (90 mg/kg b.w.) by oral administration. After OTA treatment, we found alterations of biochemical and oxidative stress parameters in the kidney, related to a severe decrease of glomerular filtration rate. The RLE treatment normalized the activity of antioxidant enzymes and prevented the glomerular hyperfiltration. Histopathological examinations revealed glomerular damages and kidney cortex fibrosis in OTA-rats, while we observed less severe fibrosis in OTA plus RLE group. Then, we demonstrated that oxidative stress could be the cause of OTA renal injury and that RLE reduces this effect.

Key role of organic cation transporter 2 for the nephrotoxicity effect of triptolide in rheumatoid arthritis.

Tripterygium wilfordii Hook. F. (TwHF), a traditional Chinese Medicine, is effective in treating rheumatoid arthritis (RA), but its severe nephrotoxicity limits its extensive application. The nephrotoxic mechanism of Triptolide (TP), the main pharmacological and toxic component of TwHF, has not been fully revealed. This study was designed to explore the nephrotoxicity of TP in the RA state and the potential molecular mechanism. A rat collagen-induced arthritis (CIA) model was constructed and administered with TP for 28 days in vivo. Results showed that the kidney injury induced by TP was aggravated in the CIA state, the concentration of TP in the renal cortex was higher than that of the medulla after TP administration in the CIA rats, and the expression of organic cation transporter 2 (Oct2) in kidney was up-regulated under CIA condition. Besides, rat kidney slice study demonstrated that TP was transported by Oct2 and this was confirmed by transient silencing and overexpression of OCT2 in HEK-293T cells. Furthermore, cytoinflammatory models on HK-2 and HEK-293T cell lines were constructed by exposure of TNF-α or IL-1ß to further explore the TP's renal toxicity. Results suggested that TNF-α exposure aggravated TP's toxicity and up-regulated the protein expression of OCT2 in both cell lines. TNF-α treatment also increased the function of OCT2 and finally OCT2 silencing confirmed OCT2 mediated nephrotoxicity of TP in HEK-293T cells. In summary, the exposure of TNF-α in RA state induced the expression of OCT2, which transported more TP into kidney cortex, subsequently exacerbated the kidney injury.