Renal Allograft Fibrosis Research Articles

Rapamycin Prevents Interstitial Fibrosis in Renal Allografts through Decreasing Angiogenesis and Inflammation

Rapamycin (RPM) has antiangiogenic and antiproliferative effects on cells. The aim of this study was to evaluate the mechanism of RPM as a novel antifibrotic agent by assessing its effect on interstitial fibrosis (IF). Among 60 renal transplant recipients, group 1 patients ( n = 20) were treated with RPM and group 2 ( n = 40), with cyclosporine. The proportions of infiltrating macrophages and lymphocytes in the interstitium were evaluated in 1-year biopsies. The microvessels were highlightened with CD34. After an initial biopsy, the development of diffuse IF over 18 months was evaluated by follow-up biopsies. The mean microvessel density (MVD) was significantly lower among group 1 (69.3 ± 16) versus group 2 (96.5 ± 30; P < .001). The proportions of macrophages and lymphocytes were lower in group 1 compared to group 2 biopsies ( P < .001 for both). Fourteen (35%) group 2 and only 2 (10%) group 1 cases developed IF over 18 months ( P < .05). The mean MVD in the initial biopsy was 75.6 ± 18 in cases that did not versus 120 ± 28 among those who did develop IF ( P < .001). The amount of interstitial inflammation was greater among patients who did compared with cases who did not develop IF ( P < .01). The overall 1-, 3-, and 5-year graft survival rates for group 1 were 95%, 95%, and 89% versus 95%, 65%, and 45% for group 2 patients, respectively ( P < .001). RPM-treated patients showed a lower incidence of diffuse IF, which can be explained by antiproliferative and antiangiogenic effects of RPM. In conclusion, RPM therapy displayed an independently positive impact on long-term graft survival.

Effects of Silencing Transforming Growth Factor-β1 by RNA Interference Plasmid on Rat Renal Allograft Fibrosis Using Smads Pathway

To evaluate the effects of transforming growth factor (TGF)-β1 RNA interference plasmid on rat renal allograft fibrosis and to explore its mechanisms. A Sprague-Dawley to Wistar rat transplant kidney-sclerosis accelerated model was constructed and transfected with short hairpin RNA-TGF-β1 based on the hydromechanics. Kidney and blood samples were collected at the first, second, and third months after transplantation. Reverse transcriptase-polymerase chain reaction and Western blotting were used to detect the expression of TGF-β1, phosphorylated Smad3/7, E-cadherin, and type I collagen. The fibrosis extent was assessed using Masson staining. The immunohistochemical staining of E-cadherin and α-smooth muscle actin were used to label the tubular epithelial cells and fibroblast, respectively. The blood urea nitrogen and serum creatinine were lower in the plasmid group than in the control groups (P <.05 and P <.01, respectively). The expression of TGF-β1 was significantly inhibited by the plasmid and its target gene type I collagen (P <.05 or P <.01), in which the signal proteins of phosphorylated Smad3 was downregulated and phosphorylated Smad7 was upregulated. Also, the fibrosis of the renal allograft was improved and milder fibrosis was present in the plasmid group. In addition, short hairpin RNA-TGF-β1 plasmid maintained the expression of E-cadherin on tubular epithelial cells, resulting in inhibition of cell transdifferentiation from epithelial cells to fibroblast. Our results suggest that short hairpin RNA-TGF-β1 plasmid could prevent the fibrosis of renal allografts. The mechanism might be associated with its effects of downregulating phosphorylated Smad3 and upregulating phosphorylated Smad7, leading to the suppression of epithelial-myofibroblast transdifferentiation and extracellular matrix synthesis.

Medullary ray injury in renal allografts

Non-immune injury leading to interstitial fibrosis and tubular atrophy (IF/TA) in renal allografts has various etiologies, but pathological means of verification have yet to be developed. Medullary ray injury (MRI) is a pathological feature of many non-immune injuries inducing IF/TA and pathological determination of calcineurin inhibitor (CNI) toxicity proceeding to striped fibrosis. We investigated the contribution of CNI toxicity to MRI and other non-immune etiologies related to IF/TA. In this study MRI is defined as fibrosis and inflammation localized exclusively to the medullary ray. Thirty-six protocol biopsies showing MRI were analyzed and classified histopathologically as following: MRI related to CNI toxicity; chronic obstruction or reflux nephropathy; and acute or chronic pyelonephritis. The etiology of MRI was CNI toxicity (n= 16, 44.4%), chronic obstruction (n= 13, 36.1%), acute or chronic pyelonephritis (n= 2, 5.6%), and other (n= 5, 13.9%). We performed cystography in seven cases of MRI related to chronic obstruction or reflux nephropathy and six cases showing vesicoureteral reflux. The ci+ct score showed significant progression after one year in 30 of the 36 cases (1.53 ± 1.04 vs. 3.03 ± 1.13, P < 0.01). MRI has various etiologies and may also predict changes in urological complications. The classification of MRI may be useful to determine the non-immune etiology leading to IF/TA.

Assessment of renal allograft fibrosis by acoustic radiation force impulse quantification - a pilot study

Chronic allograft nephropathy characterized by interstitial fibrosis and tubular atrophy is a major cause of renal transplant failure. Acoustic radiation force impulse (ARFI) quantification is a promising noninvasive method for assessing tissue stiffness. We evaluated if the method could reveal renal transplant fibrosis. In a prospective study, 30 adult renal transplant recipients were included. ARFI quantification, given as shear wave velocity (SWV), of the renal cortex was performed by two observers. SWV was compared to grade of fibrosis (0-3) in biopsies. The median SWV was 2.8 m/s (range: 1.6-3.6), 2.6 m/s (range: 1.8-3.5) and 2.5 m/s (range: 1.6-3) for grade 0 (n = 12), 1 (n = 10) and grades 2/3 (n = 8) fibrosis respectively. SWV did not differ significantly in transplants without and with fibrosis (grade 0 vs. grade 1, P = 0.53 and grade 0 vs. grades 2/3, P = 0.11). The mean intraobserver coefficient of variation was 22% for observer 1 and 24% for observer 2. Interobserver agreement, expressed as intraclass correlation coefficient was 0.31 (95% CI: -0.03 to 0.60). This study does not support the use of ARFI quantification to assess low-grade fibrosis in renal transplants. ARFI quantification in its present stage of development has also high intra- and interobserver variation in renal transplants.

Early Urinary CCL2 is Associated With the Later Development of Interstitial Fibrosis and Tubular Atrophy in Renal Allografts

Chronic renal allograft injury resulting in progressive interstitial fibrosis and tubular atrophy (IFTA) is a leading cause of graft loss. The goal of this study was to identify early urinary predictors for the subsequent development of IFTA in a prospective cohort of patients (n=111) who underwent serial protocol biopsies at 0, 6, and 24 months. The urinary proteins evaluated were CCL2, CXCL9, CXCL10, and alpha1-microglobulin (alpha1M) using ELISA and immunonephelometry. We first evaluated urines obtained at 1 to 3 months and found that alpha1M and CXCL10 were associated with IFTA at 6 months but not at 24 months. Next, we evaluated urines at 6 months and found that CCL2 was associated with both IFTA and graft dysfunction at 24 months. On univariate analysis, 6-month urinary CCL2 was a risk factor for developing 24-month IFTA, defined as ci+ct score more than 0 (odds ratio 1.045, 95% confidence interval: 1.005-1.084, P=0.028). Furthermore, CCL2 remained an independent predictor of IFTA on multivariate analysis (odds ratio 1.049, 95% confidence interval: 1.006-1.094, P=0.024) when adjusted for donor age, delayed graft function, deceased donation, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker exposure. In comparison, alpha1M, CXCL9, and CXCL10 were not associated with late graft outcomes. This study demonstrates that early urinary CCL2 is an independent predictor for the subsequent development of IFTA at 24 months.

Differential Expression of Proteoglycans in Tissue Remodeling and Lymphangiogenesis after Experimental Renal Transplantation in Rats

BackgroundChronic transplant dysfunction explains the majority of late renal allograft loss and is accompanied by extensive tissue remodeling leading to transplant vasculopathy, glomerulosclerosis and interstitial fibrosis. Matrix proteoglycans mediate cell-cell and cell-matrix interactions and play key roles in tissue remodeling. The aim of this study was to characterize differential heparan sulfate proteoglycan and chondroitin sulfate proteoglycan expression in transplant vasculopathy, glomerulosclerosis and interstitial fibrosis in renal allografts with chronic transplant dysfunction.MethodsRenal allografts were transplanted in the Dark Agouti-to-Wistar Furth rat strain combination. Dark Agouti-to-Dark Agouti isografts and non-transplanted Dark Agouti kidneys served as controls. Allograft and isograft recipients were sacrificed 66 and 81 days (mean) after transplantation, respectively. Heparan sulfate proteoglycan (collXVIII, perlecan and agrin) and chondroitin sulfate proteoglycan (versican) expression, as well as CD31 and LYVE-1 (vascular and lymphatic endothelium, respectively) expression were (semi-) quantitatively analyzed using immunofluorescence.FindingsArteries with transplant vasculopathy and sclerotic glomeruli in allografts displayed pronounced neo-expression of collXVIII and perlecan. In contrast, in interstitial fibrosis expression of the chondroitin sulfate proteoglycan versican dominated. In the cortical tubular basement membranes in both iso- and allografts, induction of collXVIII was detected. Allografts presented extensive lymphangiogenesis (p<0.01 compared to isografts and non-transplanted controls), which was associated with induced perlecan expression underneath the lymphatic endothelium (p<0.05 and p<0.01 compared to isografts and non-transplanted controls, respectively). Both the magnitude of lymphangiogenesis and perlecan expression correlated with severity of interstitial fibrosis and impaired graft function.InterpretationOur results reveal that changes in the extent of expression and the type of proteoglycans being expressed are tightly associated with tissue remodeling after renal transplantation. Therefore, proteoglycans might be potential targets for clinical intervention in renal chronic transplant dysfunction.

Noninvasive evaluation of renal allograft fibrosis by transient elastography - a pilot study

Chronic allograft injury (CAI) is the most common cause of graft failure after the first year of transplantation. To date, only protocol biopsies can reveal subclinical disease. Transient elastography (TE) is a novel noninvasive technique that has demonstrated high reliability in the assessment of liver fibrosis. This study evaluates the feasibility of TE for the assessment of renal allograft fibrosis. Fifty-seven patients underwent TE by the FibroScan device. Biopsies were performed in 20 patients. Measurement of parenchymal stiffness by TE was successful in 55 of 57 patients (96.5%). Stiffness was significantly correlated to the extent of interstitial fibrosis (Pearson r: 0.67, P: 0.002, R(2): 0.45) and inversely related to estimated glomerular filtration rate (eGFR) (Pearson r: -0.47, P: 0.0003, R(2): 0.22). Stiffness values of patients with an eGFR >50 ml/min were significantly lower than in patients with an eGFR < or = 50 ml/min (22.2 +/- 11.0 vs. 37.1 +/- 14.2 kPa, P: 0.0005). The stiffness values of CAI Banff grades 0-1 differed significantly from grade 2 (P: 0.008) and grade 3 (P: 0.046). Parenchymal stiffness measured by TE reflects interstitial fibrosis in kidney allografts. A longitudinal assessment of parenchymal stiffness might be a powerful tool to identify patients with CAI who benefit from biopsy and consequent adaptation of the immunosuppressive regime.

Hepatic Stellate Cells in Hepatitis C Patients: Relationship With the Development of Interstitial Fibrosis in Renal Allografts

The aim of this study was twofold; first, we evaluated the influence of hepatitis C virus (HCV) and iron deposition on hepatic stellate cells (HSCs), and second, we determined the influence of HSCs on the development of interstitial fibrosis (IF) in renal allografts. Thirty chronic HCV positive patients bearing renal allografts underwent liver biopsies, which were scored for iron deposition and the number of HSCs. We evaluated the density of tumor necrosis factor-alpha (TNF-alpha) in liver biopsies and the expression of transforming growth factor-beta (TGF-beta) on tubules of renal allografts from the same patients. We examined the development of IF in renal allografts at 12 and 24 months after the reference biopsy. The density of HSCs was significantly greater among patients with compared with those without iron deposits (P < .01). TNF-alpha expression was localized mainly to liver sinusoidal cells; in some cases, it was also expressed in hepatocytes. Patients with higher-grade TNF-alpha expression in the liver showed higher-grade alpha-smooth muscle antibody (alpha-SMA)-positive HSCs (P < .001). In parallel, an increasing amount of HSCs in the liver increased the incidence of IF in the renal allograft at 12 (P < .01) and 24 (P < .01) months after the reference biopsy. In addition, the expression of TGF-beta on renal allograft tubules were increased with greater grades of alpha-SMA-positive HSCs in liver (P < .01). In conclusion, HCV infection seemed to trigger the development of IF in renal allografts by augmenting TGF-beta secretion through activation of HSC.

Expression of Transforming Growth Factor-β1 and Hypoxia-Inducible Factor-1α in Renal Transplantation

Chronic allograft nephropathy (CAN) includes pathologic changes of interstitial fibrosis, tubular atrophy, and fibrous intimal thickening. Transforming growth factor (TGF)-β1 is a fibrogenic cytokine involved in renal allograft fibrosis. Hypoxia-inducible factor (HIF)-1α is induced as an adaptive response to hypoxia triggering the production of fibrogenic cytokines such as TGF-β1. Between January 1995 and February 2005, we performed 71 renal allograft biopsies in 61 recipients. Immunohistochemical studies were performed with an immunoperoxidase technique using as the primary antibody either a rabbit anti-human TGF-β1 polyclonal or a mouse anti-human HIF-1α monoclonal reagent. The glomerular TGF-β1 expression in recipients diagnosed with glomerulonephritis was significantly greater than other pathologic groups ( P < .05), and the glomerular TGF-β1 expression in the heavy proteinuria group (≥2.5 g/d) was significantly greater than the low proteinuria group (<1.0 g/d; P < .05). The tubular and interstitial TGF-β1 and HIF-1α expressions in CAN were greater than in other groups ( P < .05). The tubular TGF-β1 expression among the graft loss group was significantly greater than the graft function group ( P < .05).

Early Epithelial Phenotypic Changes Predict Graft Fibrosis

Chronic allograft nephropathy accounts for the loss of approximately 40% of allografts at 10 yr. Currently, no biomarker is available to detect interstitial fibrosis and tubular atrophy in the renal graft at an early stage, when intervention may be beneficial. Because tubular epithelial cells have been shown to exhibit phenotypic changes suggestive of epithelial-to-mesenchymal transition, we studied whether these changes predict the progression of fibrosis in the allograft. Eighty-three kidney transplant recipients who had undergone a protocol graft biopsy at both 3 and 12 mo after transplantation were enrolled. De novo vimentin expression and translocation of beta-catenin into the cytoplasm of tubular cells were detected on the first biopsy by immunohistochemistry. Patients with expression of these markers in >or=10% of tubules at 3 mo had a higher interstitial fibrosis score at 1 yr and a greater progression of this score between 3 and 12 mo. The intensity of these phenotypic changes positively and significantly correlated with the progression of fibrosis, and multivariate analysis showed that their presence was an independent risk factor for this progression. In addition, the presence of early phenotypic changes was associated with poorer graft function 18 mo after transplantation. In conclusion, early phenotypic changes indicative of epithelial-to-mesenchymal transition predict the progression toward interstitial fibrosis in human renal allografts.

Influence of Pretransplant IFN-Alpha Therapy on Interstitial Fibrosis in Renal Allografts with Hepatitis C Virus Infection

The aim of this study is to identify the influence of chronic HCV infection on development of interstitial fibrosis (IF) in renal allografts and evaluate if pretransplant interferon-alpha (IFN-alpha) therapy has an effect on IF. The development of IF and graft outcome were compared between anti-HCV positive (n = 28) and anti-HCV negative (n = 30) recipients. The influence of IFN-alpha therapy on IF and graft survival was compared between anti-HCV positive recipients who received pre-transplant IFN-alpha therapy (n = 15, group 1) and anti-HCV positive recipients who did not receive IFN-alpha therapy (n = 13, group 2). Recipients with anti-HCV antibodies had higher incidences of IF and shorter graft survival than did recipients without anti-HCV antibodies (p < 0.05 for both). Development of IF was higher in group 2 recipients, and patients in group 1 had longer graft survivals (p < 0.05 for both). Patients with positive HCV-RNA had higher grades of tubular TGF-beta1 expression than did patients with negative HCV-RNA (p < 0.05). Expression of tubular TGF-beta1 was lower in group 1 patients when compared with group 2 patients (p < 0.001). In conclusion, we suggested that HCV infection may have a triggering effect on the development of IF in renal allografts by augmenting renal expression of TGF-beta1.

Does Colchicine Have an Antifibrotic Effect on Development of Interstitial Fibrosis in Renal Allografts of Recipients With Familial Mediterranean Fever?

Colchicine, which has been reported to inhibit fibrosis, has been successfully used to treat fibrotic disorders, such as liver cirrhosis, scleroderma, and idiopathic pulmonary fibrosis. We hypothesized that besides its ability to prevent amyloid deposition, colchicine may prevent the development of interstitial fibrosis (IF) in amyloidosis patients who had undergone renal transplantation. We evaluated the influence of colchicine therapy on the development of IF in 25 patients with systemic amyloidosis secondary to familial Mediterranean fever (group 1). Twenty-five nonamyloidotic patients who did not receive colchicine therapy served as controls (group 2). The incidences of recurrence and development of IF in the first, second, and third years after transplantation were evaluated from follow-up allograft biopsies. Only four patients showed amyloid recurrence in their renal allografts. IF developed in 44% (11/25) of group 1 patients and 80% (20/25) of group 2 patients during the 36 months posttransplantation ( P < .01). Development of IF in the first, second, and third years posttransplantation was significantly greater among group 2 recipients than group 1 recipients ( P < .01). The overall 1-, 2-, and 3-year graft survival rates for group 1 recipients were 96%, 92%, and 80%, and those for group 2 recipients were 96%, 88%, and 60%, respectively. Our results support the thesis that colchicine therapy may help prevent the development of interstitial fibrosis in renal allografts.

Vascular Endothelial Growth Factor Expression and Cyclosporine Toxicity in Renal Allograft Rejection

The aim of this study was to evaluate the influence of vascular endothelial growth factor (VEGF) on renal function and on development of interstitial fibrosis (IF) in renal allografts. Tubular and interstitial expressions of VEGF and TNF-alpha, and density of macrophages in the interstitium were examined in 92 patients with nonrejected kidneys, acute rejection (AR), chronic allograft nephropathy (CAN), borderline changes (BC) and acute cyclosporin A (CsA) toxicity. Follow-up biopsy specimens from patients with AR and BC were evaluated for development of IF. A significant difference in tubular and interstitial VEGF expressions was found between patients with AR, BC, CAN and CsA toxicity (p < 0.001). Macrophage infiltration was positively correlated with VEGF and TNF-alpha expressions (p < 0.001). VEGF expression increased with increasing expression of TNF-alpha (p < 0.001). Renal function in first 6 months after initial biopsy was better in patients with marked tubular VEGF expression (p < 0.01); however, in follow-up, development of IF and graft loss was found earlier in these patients (p < 0.01 and p < 0.05, respectively). Increased renal VEGF expression has protective properties immediately following renal allograft but allows for increased risk of early IF, and therefore poor graft outcome in the long term.

Fibrosis and matrix metalloproteinases in rat renal allografts

The temporal activity and gene expression of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMP) were investigated in a rat model of chronic allograft nephropathy. Gelatinolytic activity of MMP-2 and -9 were demonstrated by zymography, and MMP-2,-9 and TIMP-3 mRNA by in situ hybridization. The generation of fibrosis was determined as total collagen content/DNA. Significantly more latent and active MMP-2, as well as latent MMP-9, were seen in allografts than in autografts. Intense MMP-2 mRNA expression was demonstrated in the allografts during the first 20 days after transplantation, located mainly in the interstitium of the kidney. In addition, some tubular cells expressed MMP-2 mRNA. After day 20, MMP-2 gene expression was faint. MMP-9 mRNA expression in allografts was located mainly in the glomerulus. TIMP-3 mRNA expression was downregulated in allografts. MMP-2, MMP-9 and TIMP-3 seem to play a critical role in the development of fibrosis in the renal allograft.

The novel antifibrotic agent pirfenidone attenuates the profibrotic environment generated by calcineurin inhibitors in the rat salt-depletion model

Calcineurin inhibitors (CNIs) promote fibrosis in renal allografts by altering the dynamics of extracellular matrix (ECM) turnover. Graft structure is changed and functional disturbance may follow. This study examined the effects of an antifibrotic agent, pirfenidone, on functional, structural, and molecular markers of fibrosis in a rat model. Cyclosporine or tacrolimus were administered to salt-depleted rats, with or without varying doses of pirfenidone. Both CNIs increased serum creatinine, and pirfenidone attenuated this functional disturbance. No changes in urinary protein excretion or graft histology were observed, suggesting structural and functional alterations can be dissociated. Messenger RNA expression of pro- and antifibrotic genes affecting ECM was estimated with semiquantitative RT-PCR. Cyclosporine-induced increases in collagen III mRNA expression were attenuated by pirfenidone (500 mg/kg/d), and increases in TIMP-1 expression were reversed by all doses of pirfenidone. Matrix metalloproteinase-2 expression was decreased by cyclosporine; all doses of pirfenidone significantly reversed this effect. Tacrolimus alone decreased TGF-β and TIMP-1 expression, suggesting some antifibrotic action; addition of pirfenidone had no further effect. The mechanism of action of pirfenidone is reversal of some CNI-induced changes in fibrotic gene expression. It also attenuates creatinine rise in salt-depleted rats in this model of CNI-induced nephrotoxicity.

Comparison of renal allograft fibrosis after transplantation from heart-beating and non-heart-beating donors

Renal transplants from non-heart-beating donors (NHBDs) yield acceptable function and allograft survival rates in the medium term. However, the long-term results are less certain and there is a paucity of information relating to the development of chronic allograft nephropathy. The aim of this study was to compare allograft fibrosis in kidneys transplanted from NHBDs and conventional heart-beating donors (HBDs). A series of 37 NHBD and 75 HBD renal transplants were studied. Protocol renal transplant biopsies were performed at 6 and 12 months after transplantation. Biopsy sections were stained with Sirius red to demonstrate interstitial extracellular matrix. Renal allograft fibrosis was quantified using a computerized image analysis system. The mean first warm ischaemia time for kidneys from NHBDs was 24 min. A significant delay in graft function occurred in eight of 75 recipients in the HBD group and 31 of 37 in the NHBD group (P < 0.001). There were no significant differences in the level of allograft fibrosis between the two groups at any time point. Despite high rates of delayed graft function secondary to a prolonged warm ischaemia time, NHBD kidneys do not appear to be more susceptible to the development of renal allograft fibrosis. This study supports the growing body of evidence that kidneys from NHBDs are an acceptable alternative to those from HBDs.

Transplant: immunology and treatment of rejection

Transplant: immunology and treatment of rejection

Relationships Between HLA‐A, ‐B, ‐DQ and ‐DR Antigens and Interstitial Fibrosis in Renal Allografts

Although renal transplant recipients tend to exhibit similar clinical and immunological changes over time, some allograft biopsies show early IF. To evaluate the relationship between HLA antigens and IF in renal allografts, we reviewed for HLA‐A, ‐B, ‐DQ, and ‐DR antigens in 88 renal transplant recipients. For each antigen type, we determined the numbers of patients who did and did not possess the antigen. We then determined the mean time to onset of IF for each of these two groups, and statistically compared the means. In the second part of the analysis, we divided the 88 patients into those who did and did not show IF at 6 months posttransplantation, and then calculated the prevalence of each antigen type in the IF (+) and IF (−) groups. This same procedure was repeated with the patients grouped according to presence of IF at 12 months posttransplantation. The patient groups with HLA‐B8, ‐B27, ‐DQ2, ‐DQ5, ‐DQ6, ‐DQ7, ‐DR4, ‐DR13, and ‐DR15, respectively, had significantly shorter times to IF onset after transplantation than the corresponding groups without these antigens (p < 0.05). The groups that were IF (+) at 6 and 12 months posttransplantation had significantly higher frequencies of HLA‐B8, ‐B27, ‐DQ2, and ‐DR4 than the corresponding IF (−) groups at these two time points (p < 0.05). The results indicated that any kidney recipient with these antigens is predisposed to developing diffuse IF in their graft relatively soon after transplantation. We conclude that although there are multiple etiological agents in the pathogenesis of interstitial fibrosis, one cannot exclude an HLA association in these cases.

Randomized clinical trial of the effect of microemulsion cyclosporin and tacrolimus on renal allograft fibrosis

The aim of this study was to compare the effect of Neoral cyclosporin- and tacrolimus-based therapy on the development of renal allograft fibrosis (chronic allograft nephropathy; CAN) in a prospective randomized trial. A total of 102 patients undergoing renal transplantation were randomized to immunosuppression with either microemulsion cyclosporin (Neoral; 15 mg per kg per day adjusted to whole-blood trough concentrations of 200-300 ng/ml) or tacrolimus (0.2 mg per kg per day adjusted to whole-blood trough levels of 8-15 ng/ml) in conjunction with steroids, or at a lower dose (7 mg per kg per day and 0.1 mg per kg per day respectively) with the addition of azathioprine for non-heart-beating renal transplant recipients. Renal transplant interstitial fibrosis was quantified using computerized histomorphometric measurement of picrosirius red-stained 1-year protocol renal transplant biopsies. Levels of interstitial fibrosis were compared in relation to observed efficacy and toxicity profiles of the two drugs. There was a significant increase in allograft interstitial fibrosis in the patients treated with Neoral compared with those given tacrolimus. There was no significant difference in the demographic characteristics between the patient groups or in the incidence of acute rejection (Neoral 36 per cent versus tacrolimus 35 per cent) or steroid-resistant rejection (both 10 per cent) between the two drugs. There was a higher incidence of insulin resistance in the tacrolimus group (post-transplant diabetes mellitus, glucose tolerance testing) but this was not statistically significant. Neoral was associated with a significant increase in total cholesterol (P = 0.030) and low-density lipoprotein (P = 0.021) levels, which persisted throughout the study period. Despite equivalent efficacy and pretransplantation risk factors for CAN, Neoral was associated with increased allograft fibrosis and significantly higher serum low-density lipoprotein cholesterol levels compared with tacrolimus.

Primary immunosuppression with tacrolimus is associated with a reduction in renal allograft fibrosis compared with neoral therapy

Kidney disease after transplantation of a nonrenal organ has been described to be the result of the nephrotoxicity from the commonly used calcineurin-inhibitors as well as other factors. The aim of this study was to evaluate renal function and potential risk factors for the development of chronic renal failure among nonrenal organ recipients.We designed a single-center retrospective study including all 165 of our cardiac and liver recipients between February 1998 and October 2003, collecting clinical, analytic, and therapeutic data. We excluded double transplants and patients with survival less than 6 months. Creatinine clearance was calculated according to the Cockcroft-Gault and the Levey Modification of Diet in Renal Disease (MDRD)-5 equations.Although 165 patients received a cardiac or liver transplantation, 17 died in the first 6 months and three were double transplants; therefore we analyzed 145 patients: 107 (74%) cardiac transplantations and 38 (26%) liver transplantations. There were 106 male and 39 female recipients. The mean age (±SD) at the time of transplantation was 54 ± 10 years and the mean follow-up was 2.9 ± 1.7 years. Urinanalysis before transplantation was only performed in 33 patients (22.8%) including three (2.1%) who had proteinuria.Serum creatinine increased until 12 months after transplantation (P < .001), then it recovered its average level. Creatinine clearance calculated using the aforementioned equations showed a similar pattern, with a progressive decline to 12 months (P < .05), with eventual stabilization or even improvement.The factors that we observed to increase the risk of renal damage were age, female sex, obesity, and the presence of proteinuria prior to transplantation. There was a good correlation (r = 0.96) between cyclosporine but not tacrolimus trough levels and serum creatinine at 48 hours after transplantation.