Ciclosporin metabolite pattern in blood and urine of kidney graft patients in relation to liver function

Summary Ciclosporin, an immunosuppressant, is metabolized by the liver cytochrome P450 system. Changes in the pattern of its metabolites in blood and urine in patients with disturbed liver function have been studied.Forty seven kidney graft patients receiving 2.9 mg/kg/d ciclosporin b.i.d., and no additional medication that would interfere with ciclosporin metabolism, were allocated to three groups according to liver function: I with normal liver function (n=19), II with elevated liver enzyme activity or bilirubin concentration in serum (n=20), and III with cholestasis (n=8). Ciclosporin and 17 metabolites were determined in blood and 24 h-urine.In blood the trough concentrations of metabolites M19 and M1A were significantly higher in group III than in groups I and II. The total quantity of metabolites excreted in 24 h-urine was significantly different for H230, M4N69 and M1A (group III>I=II). Renal excretion of the daily dose of ciclosporin in patients in group I was 2.7%, group II 3% and group III 5.7%. In group III compared to group I the ciclosporin metabolite pattern was shifted to a relatively higher concentration of M19 in blood and of H 230, M19 and M1A in urine.Since high ciclosporin metabolite concentrations appear to be associated with nephrotoxicity, the metabolite pattern in patients with impaired liver function should be monitored.     

Ciclosporin metabolite pattern in blood and urine of liver graft recipients

Summary The pattern of metabolites of ciclosporin in blood and 24 h-urine of 58 liver graft recipients was routinely monitored by HPLC from transplantation until discharge from hospital. Liver function and ciclosporin metabolite pattern in patients with an uncomplicated clinical course and in those with cholestasis or acute rejection were compared.During cholestasis M19 and M1A, and during acute rejection M19, in blood were significantly elevated compared to the control group. Blood M19 was significantly correlated with bilirubin concentration and -glutamyl transferase activity in serum, and M1A with the serum bilirubin concentration. Analysis of the metabolite pattern over the observation period showed higher concentrations of M19 and M1A in blood from patients with cholestasis and acute rejection than in the control group; concentrations were lower in the rejection group than in the cholestasis group. The metabolite pattern in 24 h-urine showed similar alterations in ciclosporin metabolite pattern to those in blood.Cholestasis and rejection shift the ciclosporin metabolite pattern in blood and urine to higher concentrations of M19 and M1A, whereas the concentrations of other metabolites and ciclosporin were not significantly affected.     

Toxicodynamic effects of ciclosporin are reflected by metabolite profiles in the urine of healthy individuals after a single dose

AIMS

The immunosuppressant ciclosporin is an efficient prophylaxis against transplant organ rejection but its clinical use is limited by its nephrotoxicity. Our previous systematic studies in the rat indicated urine metabolite pattern changes to be sensitive indicators of the negative effects of ciclosporin on the kidney. To translate these results, we conducted an open label, placebo-controlled, crossover study assessing the time-dependent toxicodynamic effects of a single oral ciclosporin dose (5 mg kg⁻¹) on the kidney in 13 healthy individuals.

METHODS

In plasma and urine samples, ciclosporin and 15-F_2t-isoprostane concentrations were assessed using HPLC-MS and metabolite profiles using ¹H-NMR spectroscopy.

RESULTS

The maximum ciclosporin concentrations were 1489 ± 425 ng ml⁻¹ (blood) and 2629 ± 1308 ng ml⁻¹ (urine). The increase in urinary 15-F_2t-isoprostane observed 4 h after administration of ciclosporin indicated an increase in oxidative stress. 15-F_2t-isoprostane concentrations were on average 2.9-fold higher after ciclosporin than after placebo (59.8 ± 31.2 vs. 20.9 ± 19.9 pg mg⁻¹ creatinine, P < 0.02). While there were no conclusive changes in plasma 15-F_2t-isoprostane concentrations or metabolite patterns, non-targeted metabolome analysis using principal components analysis and partial least square fit analysis revealed significant changes in urine metabolites typically associated with negative effects on proximal tubule cells. The major metabolites that differed between the 4 h urine samples after ciclosporin and placebo were citrate, hippurate, lactate, TMAO, creatinine and phenylalanine.

CONCLUSION

Changes in urine metabolite patterns as a molecular marker are sufficiently sensitive for the detection of the negative effects of ciclosporin on the kidney after a single oral dose.     

CYCLOSPORIN NEPHROTOXICITY IN RELATION TO ITS METABOLISM IN PSORIASIS

Cyclosporine (CsA) and some of its metabolites (M9, M17, M18, M21) have been determined by means of an LC-MASS method in eight psoriatic patients developing nephrotoxicity. In comparison with a control group (15 psoriatics who after the same period of time, with the same daily dose, did not develop nephrotoxicity) they showed an increase of CsA metabolites, especially M17. Because M17 blood concentrations in the nephrotoxic group tended to be higher than in the control group from the first week of treatment we suggest that M17 might be considered a marker of ongoing nephrotoxicity.     

Urinary excretion of ciclosporin and 17 of its metabolites in renal allograft recipients

Renal elimination of the immunosuppressant ciclosporin is virtually unknown. Therefore, in 17 renal allograft recipients under steady-state conditions we studied the urinary excretion of ciclosporin and 17 of its metabolites in blood and 24-hour urine. Patients with liver dysfunction or treated with drugs potentially influencing the metabolism and elimination of ciclosporin were excluded from the study. Ciclosporin and its metabolites were measured by HPLC. Metabolite but not ciclosporin excretion was strongly correlated with creatinine clearance. Metabolites 18 and 26 (beta, epsilon-cyclic metabolite) were rarely found in blood but were excreted in considerable amounts in urine. Approximately 3% of the administered dose of ciclosporin per day undergoes renal elimination in unchanged form or as metabolites investigated. The data suggest glomerular filtration of ciclosporin metabolites, a difference in the rate of elimination between ciclosporin and the metabolites and some kind of metabolism or active transport mechanism for metabolites in the kidney.     

Acute nephrotoxicity induced by N-(3,5-dichlorophenyl)-3-hydroxysuccinamic acid in Fischer 344 rats

N-(3,5-Dichlorophenyl)succinimide (NDPS) induces nephrotoxicity via one or more metabolites which arise from oxidation of the succinimide ring. The purpose of this study was to examine the nephrotoxic potential of N-(3,5-dichlorophenyl)-3-hydroxysuccinamic acid (3-NDHSA), a potential metabolite of NDPS and a positional isomer of N-(3,5-dichlorophenyl)-2-hydroxysuccinamic acid (2-NDHSA), a known nephrotoxic metabolite of NDPS. Male Fischer 344 rats were administered a single intraperitoneal injection of 3-NDHSA (0.2 or 0.4 mmol/kg) or sesame oil (2.5 mmol/kg), and renal function was monitored at 24 and 48 h. Both doses of 3-NDHSA induced diuresis, increased proteinuria, glucosuria and hematuria, elevated blood urea nitrogen (BUN) concentrations and kidney weights, decreased organic ion accumulation by renal cortical slices, and induced proximal tubular necrosis. The characteristics of 3-NDHSA-induced nephrotoxicity were identical to NDPS-induced nephropathy, but were evident at lower doses with 3-NDHSA. These results demonstrate that 3-NDHSA is a nephrotoxicant which might contribute to NDPS-induced nephropathy.     

Single dose pharmacokinetics of ciclosporin and its main metabolites after oral ciclosporin as oily solution or capsule

The commercially available oily solution of ciclosporin which has to be suspended before intake is disliked by some patients for bad taste and has a variable bioavailability. In this investigation the oral pharmacokinetics of ciclosporin and its main metabolites 1 and 17 of the oily solution (Sandimmun) and a soft gelatine capsule preparation of ciclosporin were compared in a crossover fashion in 10 kidney allograft recipients. The results demonstrate a bioequivalence of both formulations. In either case metabolite 17 had a significantly longer half-life than either ciclosporin or metabolite 1. At earlier time-points the concentration of ciclosporin could be best correlated with metabolite 1 and at later time-points with metabolite 17. Both metabolites were less correlated with each other in the late absorption phase of ciclosporin.     

环孢素软胶囊在肾移植病人中的应用

目的 :观察环孢素软胶囊 (以下简称环孢素 )应用于肾移植病人的疗效和不良反应。方法 :2 4例入选的肾移植病人 ,男性 15例 ,女性 9例 ,年龄34a±s 6a(18～ 6 5a)。给予环孢素 +硫唑嘌呤 +泼尼松三联用药 ,其中环孢素起始剂量 8mg·kg- 1·d- 1,以后依血浓度 ,肝、肾功能调整给药量 ,硫唑嘌呤为 50～ 70mg·d- 1,泼尼松于术后d3给 80mg·d- 1,以后递减至维持量。所有病人使用环孢素 ,时间最长为 15mo ,观察随访期 12mo± 2mo。结果 :2 4例中仅出现 2例不典型急性排斥反应 ,2例ALT轻度升高 ,8例出现震颤 ,2例出现齿龈增生 ,5例多毛。结论 :环孢素软胶囊对肾移植病人具有免疫抑制作用 ,肝毒性小。     

造血干细胞移植中环孢素血药浓度与其不良反应的相关性研究

目的：介绍环孢素在造血干细胞移植中的应用，研究其血药浓度和药品不良反应（ADR）的相关性。方法：收集23例造血干细胞移植患者使用环孢素后的临床资料，采用荧光偏振免疫法测定环孢素血药浓度，分析其血药浓度和临床表现、生化指标之间的关系。结果：谷浓度（c0）在150-300μg／L范围内未发生排异现象，且肝、肾毒性较小．ADR与血药浓度呈相关性。服药后2h血药浓度（c2）在600-1200μg／L范围内无排异反应发生，但血药浓度与ADR的发生率无相关性。结论：c0在150-300μg／L范围内，环孢素有较好的抗排异效果，且ADR发生率低。监测印对环孢素的安全用药具有重要意义。     

Azathioprine metabolism in kidney transplant recipients

Azathioprine metabolite concentrations were studied in 54 kidney transplant recipients. Thirty-seven of these patients were studied over a 6 month period to investigate the intrapatient variation in metabolite concentrations. All patients had stable functioning grafts and normal peripheral white blood cell counts. The metabolites measured were plasma 6-mercaptopurine and red blood cell 6-thioguanine nucleotide. There was no correlation between azathioprine dose and plasma 6-mercaptopurine concentration but there was a significant correlation between dose and red blood cell 6-thioguanine nucleotide concentration (rs = 0.41, P less than 0.005). The individual transplant recipient showed little variation in metabolite concentrations over several months. Using this group as a control we studied metabolite concentrations in patients with kidney transplants who developed leucopenia. Our preliminary findings indicate that elevated red cell 6-thioguanine nucleotide concentrations, above the control range, can be associated with bone marrow depression.     

Association of Vancomycin Serum Concentrations With Outcomes in Patients With Gram-Positive Bacteremia

We attempted to determine if an association exists between vancomycin serum concentrations resulting from traditional dosing regimens, and efficacy and toxicity outcomes. We reviewed the medical charts of 273 consecutive patients prescribed 273 courses of vancomycin therapy for documented, gram-positive bacteremia. Of the 273 courses of therapy, 45 and 31 patients met all criteria and were evaluated for toxicity and efficacy, respectively. The duration of fever and abnormal white blood cell counts, length of hospital stay, overall mortality, serum creatinine, and serum vancomycin concentrations were evaluated retrospectively. No association between initial peak or trough levels with mortality was noted. However, patients were more likely to become afebrile within 72 hours if peak and trough concentrations were 20 μg/ml or greater and 10 μg/ml or greater, respectively (p<0.01). Patients were also more likely to have their white blood cell count return to normal within 72 hours if trough concentrations were 10 μg/ml or above (p<0.01). No statistically significant correlation between nephrotoxicity and initial serum creatinine, days of hospital stay, or days of vancomycin therapy were found. Serum concentrations of vancomycin, assessed before the development of nephrotoxicity, were significantly higher in patients who became nephrotoxic. Mean (SD) trough concentrations were 23.2 (2.5) μg/ml and 10.2 (3.8) μg/ml in nephrotoxic and nonnephrotoxic patients, respectively. Our results suggest that the commonly accepted therapeutic range for vancomycin trough concentrations (<10 μg/ml) may be too restrictive in patients receiving vancomycin therapy alone.     

Nephrotoxicity of selectively deuterated and methylated analogues of Tris-BP and Bis-BP in the rat

Selectively deuterated and methylated analogues of the flame retardant tris(2,3-dibromopropyl)phosphate (Tris-BP) and its nephrotoxic metabolite bis(2,3-dibromopropyl)phosphate (Bis-BP) were compared to Tris-BP and Bis-BP in inducing acute renal damage in rats. None of the deuterated Tris-BP or Bis-BP analogues significantly altered morphological evidence of nephrotoxicity compared to the protio compounds. On the other hand, some of the selectively methylated analogues were much less nephrotoxic. Although the C1-methyl analogues of both Tris-BP and Bis-BP were as potent nephrotoxicants as Tris-BP and Bis-BP, respectively, neither the C2-methyl nor the C3-methyl analogues were significantly nephrotoxic. Interestingly, whereas the 3,4-dibromobutyl homologue of Tris-BP was not nephrotoxic, the corresponding 3,4-dibromobutyl-Bis homologue was as nephrotoxic as Bis-BP. Additional investigations with treatments that are known to decrease nephrotoxicity caused by several halogenated alkenes, showed that L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) and aminooxyacetic acid were without effects on Tris-BP induced renal damage. Probenecid pretreatment led to a reduction in Tris-BP and Bis-BP tubular necrosis, these effects may be related to inhibition of Bis-BP uptake in the kidney. It appears that the cysteine conjugate beta-lyase pathway is not involved in the generation of nephrotoxic metabolites of Tris-BP.     

万古霉素相关肾毒性危险因素分析

目的：探讨万古霉素相关肾毒性发生的危险因素,并进一步分析万古霉素血药浓度对肾毒性及其发生时间的影响。方法：回顾性分析某院155例使用万古霉素治疗的患者,记录患者基本情况及相关用药情况,采用单因素（t检验,χ²检验）及多因素（COX风险比例模型）对肾毒性危险因素进行分析,采用Kaplan-Meier法分析万古霉素血药浓度与肾毒性的发生时间的关系。结果：单因素分析发现,用药前患者的肌酐、尿素、CrCl、入住ICU、联合应用其他具有肾毒性的药物、万古霉素血药浓度值与万古霉素肾毒性相关。多因素分析显示入住ICU、万古霉素血药浓度是肾毒性发生的独立危险因素,而增加万古霉素监测次数则可降低肾毒性发生的可能。进一步研究发现万古霉素血药浓度不同组之间发生肾毒性的时间有显著差异。结论：入住ICU可能提示患者万古霉素肾毒性发生率增高,临床应用万古霉素应及时监测万古霉素血药浓度并增加监测频次减少相关不良反应的发生。     

Cisplatin nephrotoxicity is mediated by gamma glutamyltranspeptidase, not via a C-S lyase governed biotransformation pathway

Cisplatin exhibits dose-limiting nephrotoxicity in rodents and man. This study investigates the mechanism of cisplatin nephrotoxicity in vivo and in an in vitro model system. Nephrotoxicity was induced in rats (6 mg/kg cisplatin i.p.) and mice (10 mg/kg cisplatin i.p.). Cisplatin administration significantly elevated blood urea nitrogen (BUN) and serum creatinine in male Sprague Dawley rats day 5 post-treatment (BUN Delta+28+/-5 micromol/ml; serum creatinine Delta+108+/-4 nmol/ml, P<0.05) and in male C57BL6 mice day 4 post-treatment (BUN Delta+21+/-4 micromol/ml; serum creatinine Delta+81+/-5 nmol/ml, P<0.05). Nephrotoxicity was confirmed by histological analysis that revealed significant damage to the proximal tubules of cisplatin- versus saline vehicle-treated animals. Inhibition of gamma glutamyltranspeptidase prevented cisplatin nephrotoxicity in Sprague Dawley rats (day 5 BUN Delta+1+/-2 micromol/ml; serum creatinine Delta+8+/-4 nmol/ml) and C57BL6 mice (day 4 BUN Delta+1+/-0.8 micromol/ml; serum creatinine Delta-1+/-2 nmol/ml), but not cellular toxicity in rat proximal tubular (RPT) or human proximal tubular (HPT) cultures. Inhibition of aminopeptidase N (AP-N) or renal dipeptidase (RDP) in male Sprague Dawley rats, or in RPT and HPT cell cultures, did not reduce cisplatin toxicity. In contrast to published findings inhibition of C-S lyase did not prevent the nephrotoxicity of cisplatin in vivo or cellular toxicity in vitro. These data demonstrate that the biotransformation enzymes AP-N, RDP and C-S lyase are not implicated in the metabolism of cisplatin to a nephrotoxic metabolite as has been previously hypothesised. Instead, our data demonstrate that gamma glutamyltranspeptidase is a key enzyme involved in mediating cisplatin nephrotoxicity, which potentially acts to cleave cisplatin-GSH conjugates to a toxic metabolite.     

In situ metabolomics in nephrotoxicity of aristolochic acids based on air flow-assisted desorption electrospray ionization mass spectrometry imaging

Understanding of the nephrotoxicity induced by drug candidates is vital to drug discovery and development. Herein, an in situ metabolomics method based on air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) was established for direct analysis of metabolites in renal tissue sections. This method was subsequently applied to investigate spatially resolved metabolic profile changes in rat kidney after the administration of aristolochic acid I, a known nephrotoxic drug, aimed to discover metabolites associated with nephrotoxicity. As a result, 38 metabolites related to the arginine–creatinine metabolic pathway, the urea cycle, the serine synthesis pathway, metabolism of lipids, choline, histamine, lysine, and adenosine triphosphate were significantly changed in the group treated with aristolochic acid I. These metabolites exhibited a unique distribution in rat kidney and a good spatial match with histopathological renal lesions. This study provides new insights into the mechanisms underlying aristolochic acids nephrotoxicity and demonstrates that AFADESI-MSI-based in situ metabolomics is a promising technique for investigation of the molecular mechanism of drug toxicity.     

A study of the protective effect of chloride salts on cisplatin nephrotoxicity

In rats NaCl and NH4Cl (25 mmoles/kg, p.o.) were found to be equally effective at preventing nephrotoxicity when administered to rats 90 min before cisplatin (5 mg/kg i.p.) but (NH4)2SO4 did not protect. The severity of nephrotoxicity, taken as the maximum elevation in blood urea concentration, showed a high degree of correlation with urinary chloride concentration, but not with urinary pH or volume. Sodium chloride did not protect against nephrotoxicity when administered 3 or 24 hr after cisplatin. Sodium chloride showed protection against nephrotoxicity caused by cisplatin metabolites only at low doses of platinum. For animals pretreated with NaCl (25 mmoles/kg) or water p.o. the urinary excretion of total platinum, cisplatin and six of the seven metabolites separated by hplc was not significantly different between the two treatments during the 0-5-hr period post dosing. However, one metabolite, possibly a nephrotoxic hydrolysis product, was excreted in significantly smaller amounts in the urine of animals pretreated with NaCl (P less than 0.05). Furthermore, in all cisplatin treated animals the amount of this species excreted correlated with the severity of nephrotoxicity. Whilst this suggests that chloride ions may protect against the nephrotoxicity of cisplatin by inhibiting its rate of metabolism this metabolite accounts for only 2.5% of the platinum excreted. Furthermore, the data do not exclude the possibility that NaCl prevents cisplatin-induced nephrotoxicity by preventing renal ischaemia, which may normally follow cisplatin treatment, or that the renal uptake or transport of platinum may be inhibited by NaCl.     

Evaluation of metabolomic profiling against renal toxicity in Sprague–Dawley rats treated with melamine and cyanuric acid

Melamine-induced renal toxicity is associated with crystal formation in the kidney following exposure to melamine and cyanuric acid. However, metabolomic profiling of intact kidney tissue after chronic intake of melamine and cyanuric acid (M?+?CA) mixtures has rarely been studied. The present study investigated the melamine-induced renal toxicity by determining metabolites in the kidney through [¹H]nuclear magnetic resonance. Melamine (63?mg/kg) and cyanuric acid (6.3?mg/kg) were co-administered to rats via oral gavage for 30?days. The mixture of M?+?CA (63/6.3?mg/kg) induced nephrotoxicity, as determined by increased blood urea nitrogen (BUN) and creatinine levels. The kidney weights were significantly increased in the animals treated with M?+?CA (63/6.3?mg/kg). The histological analysis revealed epithelial degeneration and necrotic cell death in the proximal and distal tubules. Furthermore, various metabolites were altered in both renal medullar and cortical tissues. In the medullar tissues, asparagine, choline, creatinine, cysteine, ethanolamine, glucose, isoleucine, glutamine, and myo-inositol levels were elevated, but glucitol, phenylalanine, tyrosine, and sn-glycero-3-levels were reduced. In the cortex, ethanolamine, hypoxanthine, isoleucine and o-phosphoethanolamine levels were increased, whereas formate, glucose, glutathione, threonine, and myo-inositol levels were decreased, suggesting the M?+?CA-induced renal cell injury. These data suggest that a mixture of M?+?CA-induced metabolites may be useful biomarkers for the detection of kidney injury.     

The effect of probenecid on acute N-(3,5-dichlorophenyl)succinimide-induced nephrotoxicity in the Fischer 344 rat

N-(3,5-Dichlorophenyl)succinimide (NDPS), an experimental agricultural fungicide, has been shown to produce selective nephrotoxicity in rats. Previous studies have shown that a metabolite(s) of extrarenal origin contributes to acute NDPS-induced nephrotoxicity. The purpose of this study was to determine if the organic acid transport inhibitor probenecid could modify the renal toxicity produced by NDPS administration. Male Fischer 344 rats were administered a single intraperitoneal (i.p.) injection of probenecid (60, 90 and 120 mg/kg) or 0.9% saline (1.0 ml/kg) followed 30 min later by NDPS (0.4 or 1.0 mmol/kg, i.p.) or sesame oil (2.5 ml/kg, i.p.) Renal function was monitored at 24 h and 48 h. Probenecid (60 mg/kg) did not markedly alter NDPS-induced renal effects on either post-treatment day. However, pretreatment with probenecid (90 or 120 mg/kg) blocked or attenuated the diuresis, increased proteinuria, decreased tetraethylammonium (TEA), uptake, elevation in blood urea nitrogen (BUN) concentration and increased kidney weight produced by NDPS (0.4 mmol/kg) administration. Only increased kidney weight and BUN concentration, and decreased lactate-stimulated p-aminohippurate (PAH) uptake were altered by probenecid (120 mg/kg) pretreatment when NDPS (1.0 mmol/kg) was given. NDPS-induced changes in renal morphology were not prevented by pretreatment with any probenecid dose. These results suggest that at least one nephrotoxic metabolite of NDPS is an organic acid. However, this acidic metabolite might not be the major nephrotoxic metabolite or a precursor to the major nephrotoxic metabolite(s). The identity of these metabolites remains to be determined.     

Nephrotoxicity induced by N-(3,5-dichlorophenyl)-3-hydroxysuccinamic acid in male and female Fischer 344 rats

The agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) is a more potent nephrotoxicant in female rats than in males. Similarly, nephrotoxicant NDPS metabolites studied to date in male and female rats have also demonstrated gender differences, being twice as potent as nephrotoxicants in females as in males. The purpose of this study was to examine the nephrotoxic potential of N-(3,5-dichlorophenyl)-3-hydroxysuccinimide (3-NDHSA) in male and female Fisher 344 rats to determine if gender differences in nephrotoxic potential also exist for this metabolite. Rats (four per group) were administered a single intraperitoneal (i.p.) injection of 3-NDHSA (0.1, 0.2 or 0.4 mmol kg(-1)) or vehicle, and renal function was monitored at 24 and 48 h. 3-NDHSA 0.1 mmol kg(-1) did not induce nephrotoxicity in male or female rats. In male rats, 3-NDHSA 0.2 mmol kg(-1) induced mild nephrotoxicity seen as diuresis and transient, mild proteinuria. However, 3-NDHSA 0.4 mmol kg(-1) induced marked nephrotoxicity. In female rats, 3-NDHSA 0.2 mmol kg(-1) induced mild nephrotoxicity, as evidenced by transient diuresis and proteinuria. As in males, 3-NDHSA 0.4 mmol kg(-1) induced marked nephrotoxicity. These results indicate that, unlike NDPS and other nephrotoxic NDPS metabolites, 3-NDHSA does not exhibit gender differences in nephrotoxic potential. In addition, in comparison with NDPS and other nephrotoxic NDPS metabolites, 3-NDHSA is a less potent nephrotoxicant that NDHS or 2-NDHSA and similar to NDPS in nephrotoxic potential in male rats.     

Blood cyclosporin concentrations but not doses correlate with acute changes in renal function following heart and heart-lung transplantation.

The relationship between changes in cyclosporin (CyA) dose or CyA blood concentration and the reciprocal creatinine concentration was investigated by cross-correlation analysis over the first 3 postoperative months in 32 consecutive heart and heart-lung recipients. Exploratory analysis suggested that early changes in renal function, probably attributable to recovery from preoperative cardiac failure, obscured later underlying correlations. Therefore, all data up to the first nadir in plasma creatinine following transplantation were excluded from the analysis. Five-day mean CyA doses or blood concentrations were cross-correlated with 5-day mean reciprocal creatinine concentrations measured either in the same 5-day period or with the creatinine measured up to two 5-day periods later. Although a significant correlation was found between CyA dose and blood concentration (the 95% confidence interval of the population correlation coefficient did not overlap zero), there was no relationship between dose and changes in renal function. The blood CyA concentration, however, correlated significantly with the reciprocal creatinine concentration measured in the same 5-day period and was also predictive of changes in creatinine measured in the subsequent 5-day period. Thus, a major criterion for therapeutic drug monitoring had been fulfilled: CyA dosage adjustment based on blood CyA concentrations, as the intermediate therapeutic end point, is helpful in the management of acute nephrotoxicity in heart and heart-lung transplant recipients because of the lack of a dose-effect relationship. Regular CyA monitoring and appropriate dosage adjustment is essential for the management of acute nephrotoxicity in the first 3 months following heart or heart-lung transplantation.