Ifosfamide-induced renal tubular defects

Unexpected nephrotoxicity has been described in high-dose, bolus ifosfamide (IFF) therapy. Renal injury is not thought to occur in patients receiving fractionated schedules, although microscopic hematuria from bladder irritation is not uncommon. IFF is undergoing trials in patients with malignant lymphomas, gynecologic malignancies, and advanced sarcomas and has shown promising results. This report describes renal abnormalities in four patients with malignant lymphoma receiving single-agent, fractionated IFF and suggests a proximal tubular defect in two patients who were studied in greater detail. These findings suggest an unreported and unique toxicity of IFF when given in smaller, fractionated doses.     

氨磷汀对顺铂肾毒性损伤的保护作用及其机制的研究

目的 观察顺铂的肾毒性损伤部位、形式与肾功能检查结果的相关性,以了解细胞凋亡的发生机制和氨磷汀的保护机制是否与肾组织Fas和FasL表达改变有关。方法 随机将大鼠分成3组,即对照组（生理盐水）、顺铂组（6mg／kg）和氨磷汀组（顺铂6mg／kg＋氨磷汀200mg／kg）,取其血清标本和肾组织,分别做血清BUN、Cr检测和肾组织病理学检查,并用原位缺口末端标记法（TUNEL）做肾组织凋亡细胞检测、Fas和FasL免疫组化染色,再用图像分析软件对其做阳性细胞计数和染色总灰度值测定。结果 顺铂组动物血清BUN、Cr值均明显高于对照组和氨磷汀保护组,3d时,差异已有统计学意义（P〈0．05）;5d时,两者差异分别为P〈0．01和P〈0．05;10d时,恢复正常。顺铂组肾小管上皮细胞坏死和凋亡均很严重,其凋亡细胞计数明显高于对照组和氨磷汀组（P值均〈0．01）,肾组织Fas和FasL表达的总灰度值,明显高于对照组和氨磷汀组（P值均〈0．01）。结论 氨磷汀对顺铂的肾毒性损伤有保护作用,其机制可能与抑制肾组织Fas和FasL的表达有关。     

Amphotericin B-induced nephrotoxicity: a review

Amphotericin B is the gold standard for antifungal treatment for the most severe mycoses. However, adverse effects are common, with nephrotoxicity being the most serious, occurring early in the course of treatment, and usually being reversible in most patients. Tubular damage is a well known problem associated with amphotericin B therapy but acute renal failure is the most serious complication. Recent studies have examined ways to ameliorate the well-known toxicities of amphotericin B. A new approach has been to complex the drug with lipids or entrap it in liposomes. This review will concern amphotericin B-induced nephrotoxicity, whose mechanisms are not completely clear. Nephrotoxicity seems related to direct amphotericin B action on the renal tubules as well as to drug-induced renal vasoconstriction. The main mechanisms of nephrotoxicity suggested in the literature are presented. The clinical picture at different ages (adults, children, newborns), interactions of clinical significance, strategies for prevention of amphotericin B-induced nephrotoxicity are summarized. To provide optimal patient care, it is imperative that the clinician understand the etiology of and the signs and symptoms associated with nephrotoxicity, as well as interventions to prevent nephrotoxicity in patients receiving amphotericin B.     

Hyper-alkalinization without hyper-hydration for the prevention of high-dose methotrexate acute nephrotoxicity in patients with osteosarcoma

Purpose

To evaluate the reliability and renal safety of an original schedule of high-dose methotrexate (HDMTX) administration with hyper-alkalinization, and without hyper-hydration.

Methods

Patients with osteosarcoma received HDMTX (8–12 g/m²) as a 4-h infusion. Hypertonic 8.4% sodium bicarbonate was infused prior to HDMTX, then once daily for 3 days. Methotrexate serum concentrations were measured at hour 4 (Cmax), hour 24, hour 48, and hour 72. Urinary pH was measured on each miction. Serum creatinine was assessed on days 1, 3, and 8.

Results

Twenty-six patients (median age: 18 years, range: 15–25) received a total of 344 cycles of HDMTX, including 16 patients treated in an outpatient basis. Urinary pH remained constantly higher than 7.5 in all patients. Grade 1 creatininemia toxicity was observed in 31 cycles (9%), and grade 2 creatinine toxicity was observed in one patient. No episode of acute severe nephrotoxicity was observed. No significant worsening was observed in serum creatinine and calculated creatinine clearance from baseline to the end of therapy (P = 0.74). The main extra-renal toxicity was alkalinization-related hypokalemia from H48. No re-hospitalization was required.

Conclusion

Hyper-alkalinization appears an efficient and reliable method to prevent the acute renal toxicity of HDMTX and allows its safe administration in the outpatient setting.     

多柔比星心脏毒性机制及防治研究进展

多柔比星(ADM)是一种广谱、高效的蒽环类抗肿瘤药物,长期应用容易导致累积性、不可逆性心脏病变.有关ADM心脏毒性的机制较复杂,主要涉及氧化应激、线粒体病变、心肌细胞凋亡等.近年来一系列减少ADM心脏毒性而不影响其抗肿瘤活性的措施被人们采用.文章就ADM心脏毒性的发病机制及防治措施方面的进展作一综述,期望为改善肿瘤患者的长期生存率提供借鉴.     

Understanding and managing methotrexate nephrotoxicity

Methotrexate (MTX) is one of the most widely used anti-cancer agents, and administration of high-dose methotrexate (HDMTX) followed by leucovorin (LV) rescue is an important component in the treatment of a variety of childhood and adult cancers. HDMTX can be safely administered to patients with normal renal function by the use of alkalinization, hydration, and pharmacokinetically guided LV rescue. Despite these measures, HDMTX-induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma treated on clinical trials. Prompt recognition and treatment of MTX-induced renal dysfunction are essential to prevent potentially life-threatening MTX-associated toxicities, especially myelosuppression, mucositis, and dermatitis. In addition to conventional treatment approaches, dialysis-based methods have been used to remove MTX with limited effectiveness. More recently carboxypeptidase-G(2) (CPDG(2)), a recombinant bacterial enzyme that rapidly hydrolyzes MTX to inactive metabolites, has become available for the treatment of HDMTX-induced renal dysfunction. CPDG(2) administration has been well tolerated and resulted in consistent and rapid reductions in plasma MTX concentrations by a median of 98.7% (range, 84%-99.5%). The early administration of CPDG(2) in addition to LV may be beneficial for patients with MTX-induced renal dysfunction and significantly elevated plasma MTX concentrations.     

Management of nephrotoxicity of chemotherapy and targeted agents: 2020

Nephrotoxic effects of certain chemotherapeutic agents such as cisplatin and ifosfamide has been well documented and these effects are carefully managed by oncologists during their usage. The introduction of targeted agents has added a new challenge to cancer management as their nephrotoxic effects and associated management is in the process of being adopted by oncologists. This work is a compilation of side effects on the renal system due to various chemotherapeutic, immunotherapeutic and targeted agents followed by their recommended management.     

Platinum drugs: Combined anti-lymphoproliferative and nephrotoxicity assay in rats

Summary A 4-day drug schedule was used to explore the efficacy and simultaneous toxicity of cisplatin and 30 other platinum (II) amines given IP to PVGxLew F₁ hybrid rats at cumulative doses of 10–300 mol/kg. Toxic effects monitored were stomach enlargement, kidney hypertrophy with tubular necrosis and proteinuria, evident visceral mucin, and lymphoid involution (thymus, spleen). Immunosuppressive effects were monitored as inhibition of the lymph node hypertrophy induced by grafting PVG spleen cells into each paw of F₁ hybrids. No significant activity/toxicity was observed with platinum-(pyrimidine) blues. N-alkyl derivatives of cisplatin were less active/toxic and some had no immunosuppressant effect, though they are reported as effective antitumour agents (in mice). -Hydroxobridged aminoplatinum (II) dimers were highly toxic, effective immunosuppressants and their toxicity profiles were distinct from the dihalo or diaquo diaminoplatinum species.1,2-Diaminocyclohexane platinum derivatives showed a wide range of potency, all being much less nephrotoxic than cisplatin.Abbreviations used in this paper Cisplatin or cis-DDP cis-diamminodichloroplatinum (II) - BSS balanced salt solution - DACH 1,2-diaminocyclohexane - GvHR local graft-versus-host reaction; en, ethylenediamine - SDS sodium dodecylsulphate - ND not determined     

Fluoroquinolones in pediatrics and their nephrotoxicity in adults: minireview

In recent years there is increasing pressure to use fluoroquinolones in pediatric patients but relatively few data have been published in the literature. Therefore this paper reviews the available information about the pharmacokinetics of fluoroquinolones in children and their use in pediatric urinary tract infections, taking into account their potential as nephrotoxic agents. From the available data it seems reasonable to suggest that there is no risk of quinolone-induced nephrotoxicity and that this class of antibiotics may therefore be considered as potential candidates in urinary tract infections in children. Nevertheless adequate pharmacokinetic investigations and further studies on long-term monitoring for potential toxicity need to be conducted in pediatric populations.     

Renal transport of antibiotics and nephrotoxicity: a review.

The renal excretion of a drug can essentially be divided schematically into three functional processes: glomerular filtration, tubular reabsorption and tubular secretion. When assessing nephrotoxicity, the tubular secretion system, which allows transport of the drug from the blood to the urine via the tubular cells, is particularly important. Historically, two distinct tubular secretion mechanisms have been described for drugs: one via organic cations and the other via organic anions. More recently, a third tubular secretion mechanism has been identified, mediated by P-glycoprotein. In the present review, a number of examples will be given relating to antibiotic-induced kidney damage determined via the tubular reabsorption mechanism (aminoglycosides, amphotericin B) and via the tubular secretion mechanism (cephalosporins, vancomycin), respectively. Drug transport within the tubular cells is the first fundamental stage in the onset of the nephrotoxic process. Knowledge of these concepts is important for the prevention of iatrogenic kidney damage, particularly in patients with underlying disease receiving concomitant treatment with several potentially nephrotoxic molecules.     

Antitumor effectiveness and nephrotoxicity of oxoplatinum

Studies on such transplantable murine tumors as MOPC-21 plasmacytoma and Krebs-2 carcinoma showed oxoplatinum course administration to produce necrosis in solid tumors and pronounced alterations in surviving tumor cells. Single applications of 15 or 20 mg/kg were followed by an increase in the mean survival of Krebs-2 ascites carcinoma--bearing mice by one half. Oxoplatinum--induced changes in the renal tissue ranged from moderate under continuous administration to acute renal failure after high--dose treatment. Such diuretics as diacarb, furosemide and, particularly, mannitol did not interfere with oxoplatinum activity against solid and ascites tumors but assured less pronounced structural disorders in the kidney as compared to oxoplatinum alone.     

肥胖相关肿瘤发生机制和防治研究进展

超重、肥胖是包括心血管疾病、2 型糖尿病和代谢综合征等多种疾病的主要危险因素,并对恶性肿瘤风险和预后产生负面影响。 肥胖已被证明是一些恶性肿瘤的独立危险因素,包括乳腺癌、子宫内膜癌、卵巢癌、胃癌、结直肠癌、肾癌、食管腺癌、胰腺导管腺癌和肝癌等。 但关于肥胖促进肿瘤发生的机制知之甚少,目前主要集中在肥胖后的胰岛素抵抗、脂肪因子失调、性激素失衡、全身炎症、免疫系统变化和肠道菌群失调。 这些机制并不是单独地在起作用,而是以炎症为基础,相互联系、相互促进肿瘤的发生。 肥胖对恶性肿瘤的发展和死亡率的影响,大部分可以通过饮食结构的调整和增加体育锻炼来预防。 以抗炎为基础的药物治疗可作为预防的优先策略,减重手术也为肥胖相关恶性肿瘤的预防和治疗提供更多选择。 本文将综述超重和肥胖促进恶性肿瘤发生、发展的机制,并探讨未来肥胖患者的肿瘤预防和治疗措施。     

Enzymuria in carboplatin nephrotoxicity

Urinary excretion of N-acetyl-beta-glucosaminidase (NAG) is an early marker of nephrotoxicity. NAG activity was assayed by the fluorimetric method of Leaback and Walker in 17 patients treated (22 courses) with carboplatin (CBDCA, 220-550 mg/m2) before infusion and 24, 48, 72 and 96 h after. Increased excretion of NAG, a sensitive index of renal tubular damage, was observed following 10 of the 22 courses. A transient increase in plasma creatinine and/or abnormal proteinuria was observed in 6 cases. Impaired renal function prior to therapy seems to be a predisposing factor to the nephrotoxicity.     

A proposed mechanism of tamoxifen in breast cancer prevention

Recent clinical trials suggest that tamoxifen (TAM) is a preventive agent for breast cancer, however, the mechanism is unknown. Previously, we found that both 17beta-estradiol (E2) and estrone (E1) could be activated by epoxidation resulting in their ability to bind to DNA, forming DNA adducts both in vitro and in vivo, and to inhibit nuclear DNA-dependent RNA synthesis. Since epoxidation is required for the activation of many well-known chemical carcinogens including benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene, aflatoxins, etc., we proposed that estrogen epoxidation is the underlying mechanism for the initiation of breast cancer (Carcinogenesis 17 (1996) 1957). Here, we report that TAM is able to dramatically inhibit the formation of E2 and E1 epoxides as measured by both the loss of their ability to inhibit nuclear DNA-dependent RNA synthesis and to bind to nuclear DNA. These findings suggest that the breast cancer preventive effect of TAM may be through a competitive epoxidation inhibition mechanism that prevents the formation of E2 and E1 epoxides and consequently, the initiation of breast cancer.     

Inhibition of protein farnesyltransferase: a possible mechanism of tumor prevention by dehydroepiandrosterone sulfate

Dehydroepiandrosterone sulfate (DHEAS) is the most abundantadrenal steroid with apparent anticarcinogenic properties. Givenour recent ohservation of the dehydroepiandrosterone-medlatedinhibition of protein isoprenylation and the fact that 99% ofthe circulating dehydroepiandrosterone is sulfated, with lessthan 1% representing the free steroid, we investigated the effectsof DHEAS on post-translational isoprenylation of proteins. Wehere report that exposure of HT-29 SF human colonic adenocarcinomacells to DHEAS inhibited the incorporation of [³H]mevalonateinto cellular proteins in a dose-dependent manner when endogenousmevalonate synthesis was blocked by lovastatin. Interestingly,significant inhibition was observed at concentrations of DHEASwhich are comparable to peak serum levels of this steroid occurringin the second decade of life. Immunoprecipitation revealed thatisoprenylation of p21^ras was also suppressed in DHEAS treatedHT-29 SF cells. In a cell-free system, DHEAS inhibited the farnesylationof a biotinylated decapeptide corresponding to the C-terminusof K-ras by 50% at a concentration of 100 µM. This suggeststhat DHEAS inhibits isoprenylation of cellular proteins, includingp21^ras at a point in the mevalonate pathway distal to 3-hydroxy-3-methylglutaryl-CoAreductase and that the DHEAS mediated suppression of proteinfarnesylation may largely be due to inhibition at the levelof protein farnesyltransferase. Thus, these findings may providea plausible explanation for the antitumor activity of DHEAS.