The Current Role of Calcineurin Inhibitors in Posttransplant Immunosuppression?

It is important to determine when to use and when to avoid calcineurin inhibitors (CNIs). CNIs are associated with kidney dysfunction in some, but not all, transplant recipients. CNI-sparing protocols have their own drug-specific limitations. Two major clinical series suggest the benefit of routine CNI-sparing approaches, but our review suggests weaknesses in both. Ongoing studies are needed to determine which subgroups of recipients will benefit from CNIs.     

Tacrolimus Exposure and Evolution of Renal Allograft Histology in the First Year After Transplantation

Tacrolimus has a narrow therapeutic window and is characterized by a large inter-individual variability in bioavailability. The impact of tacrolimus exposure on subclinical evolution of graft histology has not been studied in renal recipients. This analysis included 239 protocol biopsies (obtained at implantation, 3 and 12 months) of 120 consecutive kidney recipients treated with tacrolimus, mycophenolate mofetil (MMF) and corticosteroids. Biopsies were scored according to the Banff 2001 criteria and a chronicity score was calculated. Prospective pharmacokinetic data were included in the analysis (5544 tacrolimus predose blood concentrations and tacrolimus AUC(0-12) at 3 and 12 months). Higher donor age and higher number of human leukocyte antigen-DR (HLA-DR) mismatches were independent predictors of subclinical acute rejection at 3 months, present in 8.7% of patients. The number of HLA-DR mismatches was independently associated with biopsy-proven clinical acute rejection. Biopsy-proven acute rejection episodes and low mean tacrolimus exposure were independently associated with higher increase in chronicity scores between 3 and 12 months after transplantation. This observational study suggests that rejection phenomena and immune-mediated mechanisms remain important in the early progression of chronic allograft pathology. Tacrolimus doses or systemic exposure were not associated with lesions of calcineurin inhibitor nephrotoxicity, suggesting that other factors determine susceptibility to tacrolimus nephrotoxicity.     

高渗盐水对顺铂毒性及药物动力学的影响

本文以血清尿素氮及体重做为毒性评价指标,高渗盐水减低了顺铂的毒性。小鼠静注15mg/kg顺铂后,血浆总铂的药物动力学呈三室模型。高渗盐水缩短了血浆总铂的α相半衰期,提高了给药后各时间点血浆超滤铂的浓度,降低了肾脏内给药后2h内的铂浓度,没有明显改变肿瘤内铂浓度的药时曲线下面积。实验表明,高渗盐水提高了顺铂的治疗指数。     

Conversion from Cyclosporine to Tacrolimus Improves Quality-of-Life Indices, Renal Graft Function and Cardiovascular Risk Profile

Long-term use of cyclosporine after renal transplantation results in nephrotoxicity and an increased cardiovascular risk profile. Tacrolimus may be more favorable in this respect. In this randomized controlled study in 124 renal transplant patients, the effects of conversion from cyclosporine to tacrolimus on renal function, cardiovascular risk factors, and perceived side-effects were investigated after a follow-up of 2 years. After conversion from cyclosporine to tacrolimus renal function remained stable, whereas continuation of cyclosporine was accompanied by a rise in serum creatinine from 142 +/- 48 micromol/L to 157 +/- 62 micromol/L (p < 0.05 comparing both groups). Conversion to tacrolimus resulted in a sustained reduction in systolic and diastolic blood pressure, and a sustained improvement in the serum lipid profile, leading to a reduction in the Framingham risk score from 5.7 +/- 4.3 to 4.8 +/- 5.3 (p < 0.05). Finally, conversion to tacrolimus resulted in decreased scores for occurrence of and distress due to side-effects. In conclusion, conversion from cyclosporine to tacrolimus in stable renal transplant patients is beneficial with respect to renal function, cardiovascular risk profile, and side-effects. Therefore, for most renal transplant patients tacrolimus will be the drug of choice when long-term treatment with a calcineurin inhibitor is indicated.     

Workshop on Late Renal Allograft Dysfunction

Despite continued improvement in incidence of acute immune injury and short-term graft survival, late allograft dysfunction remains a significant problem in the renal transplant population. Recent reports suggest that rates of renal function decline are quite varied in the overall recipient population, and that individual rates for many recipients may not change substantially over time. Moreover, analyses also reveal distinct predictive factors for both early and late functional decline. Long-term outcome studies for renal transplantation, however, might be significantly limited by incomplete data sets for assessing clinical endpoints. In view of the heterogeneous factors that may cause progressive allograft injury, more routine biopsy sampling would allow a more complete characterization of induced injuries. Elucidating mechanisms of renal fibrosis in response to injury, in experimental systems and humans, is also an important goal in better understanding chronic allograft damage. Regulation of cell senescence genes and epithelial to mesenchymal transition, studied in other models of renal fibrosis, are likely relevant to studies of renal allograft dysfunction. Recent technical advances in analyzing biological samples may play a pivotal role in identifying and validating surrogate markers of allograft function for future interventional trials in transplantation.     

Mycophenolate Mofetil Is Associated with Altered Expression of Chronic Renal Transplant Histology

Mycophenolate mofetil (MMF) reduces acute rejection in controlled trials of kidney transplantation and is associated with better registry graft survival. Recent experimental studies have demonstrated additional antifibrotic properties of MMF, however, human histological data are lacking. We evaluated sequential prospective protocol kidney biopsies from two historical cohorts treated with cyclosporine (CSA)-based triple therapy including prednisolone and either MMF (n = 25) or azathioprine (AZA, n = 25). Biopsies (n = 360) were taken from euglycemic kidney-pancreas transplant recipients. Histology was independently assessed by the Banff schema and electron microscopic morphometry. MMF reduced acute rejection and OKT3 use (p < 0.05) compared with AZA. MMF therapy was associated with limited chronic interstitial fibrosis, striped fibrosis and periglomerular fibrosis (p < 0.05-0.001), mesangial matrix accumulation (p < 0.01), chronic glomerulopathy scores (p < 0.05) and glomerulosclerosis (p < 0.05). MMF was associated with delayed expression of CSA nephrotoxicity, reduced arteriolar hyalinosis, striped fibrosis and tubular microcalcification (p < 0.05-0.001). The beneficial effects of MMF remained in recipients without acute rejection. Retrospective analysis shows that MMF therapy was associated with substantially reduced fibrosis in the glomerular, microvascular and interstitial compartments, and a delayed expression of CSA nephrotoxicity. These outcomes may be due to a limitation of immune-mediated injury and suggest a direct effect of reduced fibrogenesis.     

冬虫夏草对大鼠小剂量环孢素A慢性肾毒性保护作用的实验研究

为进一步探讨冬虫夏草对环孢素Ａ慢性肾毒性的保护作用和机制，将ＳＤ大鼠分为两组：ＣｓＡ大鼠分为两组：ＣｓＡ组和ＣｓＡ＋冬虫夏草组，实验３个组。结果显示：在实验不同时期冬虫夏草组大鼠血Ｃｒ，ＢＵＮ及血清Ｎａ＾＋，Ｋ＾＋均较对照组为低，实验第３月冬虫夏草组鼠血清血管紧张素Ⅱ（ＡＴ－Ⅱ）水平低于对照组；实验不同阶段尿ＥＧＦ排出量亦较对照组为低；肾组织病理形态改变较对照组明显为轻。本实验证明冬虫夏草对ＣｓＡ     

Use of gene chip technology for the characterisation of the regulation of renal transport processes and of nephrotoxicity in rats

Gene expression profiling using microarrays (rat-specific array RG-U34A, Affymetrix, U.S.A.) was employed for the investigation of: (1) hormonal regulation of renal function and (2) nephrotoxicity. For this purpose about 8,800 genes were analysed in kidney and, additionally, in liver tissue.

Ad 1.) Kidney functions develop during postnatal life. Thus, in vivo transport and accumulation of p-aminohippurate (PAH) was investigated on renal cortical slices (RCS) from 10- and 55-day-old rats. The animals were treated with dexamethasone (DEXA; 60 μg/100 g b.wt./day) for 3 days, which caused a significant reduction in the accumulation of PAH in 10-day-old rats (42 ± 5% whereas it was only slightly reduced in 55-day-old rats (70 ± 8%). To further clarify the regulation of renal function by DEXA, results were compared with those obtained previously after in vitro stimulation with DEXA. RCS were incubated for 24 hours in DEXA-containing medium (10⁻⁹ M). Under these conditions DEXA significantly increased the PAH uptake capacity in RCS obtained from 10- and 55-day-old rats up to 126 and 136%, respectively. Thus a stimulation of tubular transport capacity is possible in vitro. The effect of DEXA treatment on the gene expression of the kidney (in vivo) was moderate. Focussing especially on transporters, ion channels, ATPases, glucuronyltransferases, glutathione-S-transferase and cytochrome P450, the expression of only few genes were significantly changed (3 to 50-fold up- or down-regulation). Moreover, distinct age differences were found after in vivo administration of DEXA. The investigation of in vitro effects of DEXA is currently been performed.

Ad 2.) The kidney is threatened by nephrotoxins because of its ability to accumulate them. We used a single administration of uranyl nitrate (UN; 0.5 mg/100 g b.wt.) as a model for chronic renal failure (CRF). Clearance experiments were performed 10 weeks after UN administration (maximal symptoms of CRF) in adult female rats. As expected, UN induced interstitial cicatrices with reduced GFR and diminished PAH transport capacity. Despite the impressive morphological and functional changes in the kidney after exposure to UN, the gene expression profiles in the kidneys were only minimally affected: we found significantly changed expression levels for only 20 genes (5 genes were up-regulated [e.g. transgelin], 15 down-regulated [among these the Na-K-Cl-symporter, insulin-like growth factor, kallikrein, and ornithine decarboxylase). The lack of agreement between gene expression data and the nephrotoxic effects of UN can probably be explained by the long time interval between dosing and the assessment of the effect. The results confirm that primary genomic responses are likely to be strongest transiently after exposure and then decrease in intensity.     

Interferon-gamma (IFN-gamma) and IL-4 expressed during mercury-induced membranous nephropathy are toxic for cultured podocytes.

The subepithelial immune deposits of Dorus Zadel Black (DZB) rats with mercury-induced membranous nephropathy consist of autoantibodies directed to laminin P1 and of complement. The animals develop massive proteinuria within 10-14 days which is associated with obliteration of foot processes of glomerular visceral epithelial cells (GVEC), or podocytes. Previous studies indicate that these autoantibodies are probably not the sole mediator of proteinuria and GVEC damage. In this study we investigated whether circulating or macrophage-derived cytokines can contribute to the GVEC changes as detected in vivo. In vivo at the height of the proteinuria, increased intraglomerular IFN-gamma immunoreactivity was found. In diseased rats a five-fold increase in intraglomerular macrophages was found, but we could not detect intraglomerular IFN-alpha, IFN-beta, IL-1 beta or tumour necrosis factor-alpha (TNF-alpha) by using immunohistology. Subsequently, we exposed cultured GVEC to these cytokines to investigate their cytotoxic effects on several physiological and structural parameters. IFN-gamma and IL-4 were the only cytokines that exerted toxic effects, resulting in a rapidly decreased transepithelial resistance of confluent monolayers, which was closely associated with altered immunoreactivity of the tight junction protein ZO-1. IL-4 also affected vimentin and laminin immunoreactivity. IFN-gamma and IL-4 only interfered with monolayer integrity when added to the basolateral side of the GVEC, indicating specific (receptor-mediated) effects. Only IL-4 decreased the viability of the cells, and treated monolayers demonstrated an increased passage of the 44-kD protein horseradish peroxidase. From our experiments we concluded that IFN-gamma subtly affected monolayer integrity at the level of the tight junctions, and that IL-4 additionally induced cell death. We hypothesize that the toxic effects of the cytokines IFN-gamma and IL-4 as seen with cultured podocytes are necessary together with the autoantibodies, for the ultimate induction of proteinuria in mercury nephropathy in the DZB rat.     

Action of cisplatin and cycloplatam on the rat kidney

Laboratory of Evolution of the Kidney and Water and Salt Metabolism, I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Academy of Sciences of the USSR, Leningrad. All-Union Oncologic Scientific Center, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR, I. P. Ashmarin.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 108, No. 7, pp. 52–54, July, 1989.