Sirolimus conversion regimen versus continued calcineurin inhibitors in liver allograft recipients: a randomized trial

A large prospective, open-label, randomized trial evaluated conversion from calcineurin inhibitor (CNI)- to sirolimus (SRL)-based immunosuppression for preservation of renal function in liver transplantation patients. Eligible patients received liver allografts 6-144 months previously and maintenance immunosuppression with CNI (cyclosporine or tacrolimus) since early posttransplantation. In total, 607 patients were randomized (2:1) to abrupt conversion (<24 h) from CNI to SRL (n = 393) or CNI continuation for up to 6 years (n = 214). Between-group changes in baseline-adjusted mean Cockcroft-Gault GFR at month 12 (primary efficacy end point) were not significant. The primary safety end point, noninferiority of cumulative rate of graft loss or death at 12 months, was not met (6.6% vs. 5.6% in the SRL and CNI groups, respectively). Rates of death at 12 months were not significantly different, and no true graft losses (e.g. liver transplantation) were observed during the 12-month period. At 52 weeks, SRL conversion was associated with higher rates of biopsy-confirmed acute rejection (p = 0.02) and discontinuations (p < 0.001), primarily for adverse events. Adverse events were consistent with known safety profiles. In conclusion, liver transplantation patients showed no demonstrable benefit 1 year after conversion from CNI- to SRL-based immunosuppression.     

Melatonin, a pineal secretory product with antioxidant properties, protects against cisplatin-induced nephrotoxicity in rats

In an attempt to define the role of the pineal secretory melatonin and an analogue, 6-hydroxymelatonin (6-OHM), in limiting oxidative stress, the present study investigated the cisplatin (CP)-induced alteration in the renal antioxidant system and nephroprotection with the two indolamines. Melatonin (5 mg/kg), 6-OHM (5 mg/kg), or an equal volume of saline were administered intraperitoneally (i.p.) to male Sprague Dawley rats 30 min prior to an i.p. injection of CP (7 mg/kg). After CP treatment, the animals each received indolamine or saline every day and were sacrificed 3 or 5 days later and plasma as well as kidney were collected. Both plasma creatinine and blood urea nitrogen increased significantly following CP administration alone; these values decreased significantly with melatonin co-treatment of CP-treated rats. In the kidney, CP decreased the levels of GSH (reduced glutathione)/GSSG (oxidized glutathione) ratio, an index directly related to oxidative stress. When animals were treated with melatonin, the reduction in the GSH/GSSG ratio was prevented. Treatment of CP-enhanced lipid peroxidation in the kidney was again prevented in animals treated with melatonin. The activity of the antioxidant enzyme, glutathione peroxidase (GSH-Px), decreased as a result of CP administration, which was restored to control levels with melatonin co-treatment. Upon histological analysis, damage to the proximal tubular cells was seen in the kidneys of CP-treated rats; these changes were prevented by melatonin treatment. 6-OHM has been shown to have some antioxidative capacity, however, the protective effects of 6-OHM against CP-induced nephrotoxicity were less than those of melatonin. The residual platinum concentration in the kidney of melatonin co-treated rats was significantly lower than that of rats treated with CP alone. It is concluded that administration of CP imposes a severe oxidative stress to renal tissue and melatonin confers protection against the oxidative damage associated with CP. This mechanism may be reasonably attributed to its radical scavenging activity, to its GSH-Px activating property, and/or to its regulatory activity for renal function.     

毒鼠强中毒致肾毒性损伤的临床特征

目的 :观察毒鼠强的肾毒性及其临床特征。　 方法 :经口中毒的 71例毒鼠强受害者均来自南京汤山集体中毒事件。其中男性 4 0例 ,女性 31例 ,平均年龄为 4～ 79(2 9 9± 16 1)岁。观察毒鼠强中毒患者的蛋白尿、血尿、糖尿、氨基酸尿、尿酸排泄、血肌酐 (SCr)以及视黄醇结合蛋白 (RBP)、N 乙酰 β D氨基葡萄苷酶 (NAG酶 )、尿C3 、α2 巨球蛋白 (α2 MG)的变化 ,同时对尿蛋白进行电泳分析。　 结果 :① 2 7例 (38% )患者出现蛋白尿 ,平均 (2 13± 1 5 6 )g/ 2 4h ,8例 (11 3% )尿蛋白 >2g/ 2 4h。小分子蛋白尿组占 (38 2± 14 7) %。② 2 9例 (4 9 1% )伴有血尿 ;③尿酸排泄和RBP、NAG酶、尿C3 、α2 MG水平异常增高的发生率分别为 17%、5 2 1%、73 2 %、2 5 %和 31%。 9例(12 7% )患者伴有SCr(192± 86 ) μmol/L和尿素氮 (13 2± 10 1)mmol/L显著增高 ;④ 18(2 5 4 % )例患者伴有肾性糖尿 ,12例 (16 9% )患者出现氨基酸尿、其中 8例 (11 3% )既有糖尿又有氨基酸尿 ,呈范可尼综合征样改变 ;⑤呼吸衰竭患者有更严重的肾小管和肾功能的损伤 (P <0 0 5 )。所有肾脏损伤指标在 2～ 3周均恢复正常。⑥相关分析提示肾脏损伤与中毒患者肝脏和心脏损伤显著相关 (P <0 0 5 )。　 结论 :毒鼠强有明显     

Challenges and considerations in diagnosing the kidney disease in deteriorating graft function

Despite significant reductions in acute‐rejection rates with the introduction of calcineurin inhibitor (CNI)‐based immunosuppressive therapy, improvements in long‐term graft survival in renal transplantation have been mixed. Improving long‐term graft survival continues to present a major challenge in the management of kidney‐transplant patients. CNIs are a key component of immunosuppressive therapy, and chronic CNI toxicity has been widely thought to be a major factor in late graft failure. However, recent studies examining the causes of late graft failure in detail have challenged this view, highlighting the importance of antibody‐mediated rejection and other factors. In addition, the diagnosis of CNI nephrotoxicity represents a challenge to clinicians, with the potential for over‐diagnosis and an inappropriate reduction in immunosuppressive therapy. When graft function is deteriorating, accurately determining the cause of the kidney disease is essential for effective long‐term management of the patient. Diagnosis requires a thorough clinical investigation, and in the majority of cases a specific cause can be identified.     

Evaluation of biochemical effects of Casuarina equisetifolia extract on gentamicin-induced nephrotoxicity and oxidative stress in rats. Phytochemical analysis

Nephrotoxicity is defined as renal dysfunction that arises as result of exposure to external agents such as drugs and environmental chemicals. The present work was undertaken to carry out the phytochemical study and nephroprotective activity of methanolic extract of Casuarina equisetifolia leaves in gentamicin-induced nephrotoxicity in Wistar rats. Flavonoids and phenolic acids were identified and quantified using high performance liquid chromatography. Subcutaneous injection of rats with gentamicin (80 mg/kg body weight/day) for six consecutive days induced marked acute renal toxicity, manifested by a significant increase in serum urea, creatinine and uric acid levels, along with a significant depletion of serum potassium level, compared to normal controls. Also oxidative stress was noticed in renal tissue as evidenced by a significant decrease in glutathione level, superoxide dismutase, glutathione-S-transferase activities, also a significant increase in malondialdehyde and nitric oxide levels when compared to control group. Administration of plant extract at a dose of 300 mg/kg once daily for 4 weeks restored normal renal functions and attenuated oxidative stress. In conclusion, Casuarina equisetifolia leaves extract ameliorates gentamicin-induced nephrotoxicity and oxidative damage by scavenging oxygen free radicals, decreasing lipid peroxidation and improving intracellular antioxidant defense, thus extract may be used as nephroprotective agent.     

The Assessment of Subclinical Ifosfamide-Induced Renal Tubular Toxicity Using Urinary Excretion of Retinol-Binding Protein

The excretion of retinol-binding protein in early morning urine samples, expressed as a ratio to urinary creatinine (RBPCR), was used as a measure of proximal renal tubular toxicity in children during or after treatment with ifosfamide-containing chemotherapy. The results showed a progressive increase in renal tubular leak after exposure to ifosfamide that persisted after treatment. The toxic effect appeared to be greatest in younger children and at least partly dose-dependent, although partially reversible after each course of chemotherapy. However, few patients had related symptoms and none experienced major metabolic difficulty.     

Evaluation of serum cystatin C levels and 99mTechnetium-mercaptoacetyltriglycine-3 renal scintigraphy for the early detection of cisplatin-induced renal toxicity in cancer patients

SUMMARY: Cisplatin has a broad-spectrum antineoplastic activity. Nephrotoxicity is a prominent component of the toxicity profile of cisplatin-based chemotherapy. In recent years, several reports have confirmed that cystatin C (cys-C) demonstrates a better correlation with the glomerular filtration rate than with serum creatinine. Scintigraphic techniques are also widely used in evaluating renal function. In the present study, serum cys-C, serum creatinine concentrations and ^99mTechnetium-mercaptoacetyltriglycine-3 (^99mTc-MAG-3) scintigraphy were studied in 22 cisplatin-naive cancer patients, 3 days before and 24 h after the first cycle of cisplatin-based chemotherapy. Serum cystatin C and creatinine levels increased in cancer patients after chemotherapy (creatinine: from 68 ± 12 to 72 ± 17 nmol/L; cystatin-C: from 0.064 ± 0.025 to 0.072 ± 0.033 jimol/L), but these differences were not statistically significant (P>0.05). Semiquantitative variables of ^99mTc-MAG-S scintigraphy significantly elevated after chemotherapy (T½*: from 10.27 ± 5.00to 16.17 ± 9.40 min, R20/max*: from 0.40 ± 0.12 to 0.67+0.45, Tmax**: from 5.40 ± 4.01 to 7.59 ± 5.30 min; * P <0.001, ** P <0.01, respectively). These results suggest that MAG-3 scintigraphy is a highly sensitive method in the early detection of cisplatin-induced nephrotoxicity. Serum cystatin C doesn't seem to play a role in the early detection of cisplatin-induced nephrotoxicity. As a result, MAG-3 scintigraphy may be used in selected patients who have a predisposition for renal toxicity.     

Effect of aminoglycoside therapy on renal function in fullterm infants

The effect of aminoglycosides on renal function was evaluated in 30 fullterm infants who were treated within 24 h of birth with either amikacin (10 infants, group A), gentamicin (9 infants, group B), or netilmicin (10 infants, group C). Renal function was assessed before, during, and 48 h after discontinuation of therapy by measuring the plasma creatinine concentration (PCr), the fractional excretion of sodium (FENa), potassium, magnesium, phosphate (FEP), uric acid, and the urinary excretion of calcium (UCA/UCr ratio) immediately before (trough) and after (peak) the infusion of the aminoglycosides. The results were compared with 10 control newborns who did not receive antibiotics. Significant alterations in renal function were observed only during therapy with gentamicin (group B). These consisted of a sustained elevation of FENa and UCa/UCr ratio throughout therapy, a latent increase in FEP on the 7th day (P <0.05), and lack of the normal postnatal decline of PCr in 3 of 9 infants (P <0.01). These abnormalities persisted up to 2 days after discontinuation of therapy. Therapeutic doses of gentamicin may result in significant electrolyte disturbances in sick fullterm infants. Received May 23, 1995; received in revised form and accepted May 23, 1996     

铬作业工人尿γ—谷氨酰移换酶活性的研究

本文对47名铬作业工人的肾功能状况进行了研究。结果表明γ-GT活性增加是反映铬中毒性肾损害的敏感指标之一。尿γ-GT活性与尿铬、尿蛋白和β_2-MG含量呈显著性相关。因此,尿γ-GT活性检测可作为铬性肾损害的监测指标。     

A well-meant present from a friend.

Case A 70-year-old female was admitted to hospital because of a generalweakness and a high creatinine level. On admission she was hypotensive(105/55 mmHg) and complained of chronic back pains. During theweeks preceding the hospitalization she was taking fosinopril10 mg qd, amitryptiline 50 mg qd and paracetamol as required(not >1000 mg per day). She had raised urea (35.1 mmol/l),creatinine (889 µmol/l), potassium