IL-33 receptor ST2 deficiency attenuates renal ischaemia-reperfusion injury in euglycaemic, but not streptozotocin-induced hyperglycaemic mice.

AIM: Kidney hypoxia can predispose to the development of acute and chronic renal failure in diabetes. Ischaemia-reperfusion injury (IRI) causes inflammation, and diabetes is known to exacerbate this inflammatory response in the kidney, whereas alarmin IL-33 could act as an innate immune mediator during kidney IRI. Thus, the present study examined the impact of genetic IL-33 receptor ST2 deficiency (ST2-/-) on renal IRI in euglycaemic and hyperglycaemic mice. METHODS: Hyperglycaemia was induced with streptozotocin (STZ) in adult male C57BL/6JRj wild-type (WT) mice and ST2-/- mice. Unilateral renal IRI was achieved 3months after STZ treatment by left kidney nephrectomy (non-ischaemic control kidney) and clamping of the right renal artery for 32min in STZ- and vehicle-treated animals. At 24h after reperfusion, renal function and injury were determined by levels of plasma creatinine, blood urea nitrogen (BUN) and histological tubule scores. Also, in a complementary pilot clinical study, soluble ST2 concentrations were compared in diabetics and non-diabetics. RESULTS: Urinary albumin was significantly increased in STZ-induced hyperglycaemic mice, regardless of genotypic background. At 24h post-ischaemia, plasma creatinine, BUN and tubular injury were significantly reduced in ST2-/- mice compared with vehicle-treated WT mice, but this protective effect was lost in the STZ-induced hyperglycaemic ST2-/- animals. Plasma concentrations of soluble ST2 were significantly greater in type 2 diabetes patients vs non-diabetics. CONCLUSION: Our data suggest that the IL-33/ST2 pathway exerts differential effects depending on the glucose environment, opening-up new avenues for future research on alarmins and diabetes in ischaemia-related diseases.

[Classification and therapeutic management of monoclonal gammopathies of renal significance]. / Classification et prise en charge thérapeutique des gammapathies monoclonales de signification rénale.

Two categories of renal disorders associated with monoclonal gammopathies are to be distinguished, according to the characteristics of the underlying B-cell clone. The first group of renal diseases always occurs in the setting of high tumor mass with production of large amounts of monoclonal immunoglobulins. The main complication is the so-called myeloma cast nephropathy, which almost invariably complicates high tumor mass myeloma. The second group includes all renal disorders caused by a monoclonal immunoglobulin secreted by a nonmalignant B-cell clone, and currently referred as a "monoclonal gammopathy of renal significance (MGRS)". This term was introduced to distinguish monoclonal gammopathies that are responsible for the development of kidney damage from those that are truly benign. The spectrum of renal diseases in MGRS is wide and its classification relies on the localization of renal lesions, either glomerular or tubular, and on the pattern of ultrastructural organization of immunoglobulin deposits. Physicochemical characteristics of the pathogenic monoclonal immunoglobulin are probably involved in their propensity to deposit or precipitate in the kidney, as illustrated by the high rate of recurrence of each specific type after kidney transplantation. Early diagnosis and efficient chemotherapy targeting the causal B-cell clone are mandatory to improve renal prognosis and patient survival.

Kidney graft outcome using an anti-Xa therapeutic strategy in an experimental model of severe ischaemia-reperfusion injury.

BACKGROUND: Deceased after cardiac death donors represent an important source of organs to reduce organ shortage in transplantation. However, these organs are subjected to more ischaemia-reperfusion injury (IRI). Reducing IRI by targeting coagulation is studied here in an experimental model. METHODS: The effect of an anti-Xa compound (fondaparinux) was evaluated using an autotransplanted kidney model in pigs. Kidneys were clamped for 60 min (warm ischaemia) and then preserved for 24 h at 4 °C in University of Wisconsin solution (UW). The anti-Xa compound was injected intravenously before warm ischaemia and used during cold storage, and its effects were compared with those of intravenous injection of unfractionated heparin (UFH) before warm ischaemia and use during cold storage, or use of UW alone during cold storage. RESULTS: At 3 months after transplantation, anti-Xa treatment improved recovery of renal function and chronic serum creatinine levels compared with UW and UFH (mean(s.e.m.) 89(4), 250(4) and 217(8) µmol/l respectively). The anti-Xa treatment also reduced fibrosis, and decreased tissue expression of markers of the epithelial-mesenchymal transition compared with UW and UFH. Cleaved protease-activated receptor 2 was overexpressed in the UW group compared with the anti-Xa and UFH groups. Leucocyte infiltrates were decreased in the anti-Xa group compared with the UW and UFH groups. Macrophage invasion was also decreased by anticoagulation treatment. CONCLUSION: Peritransplant anticoagulation therapy was beneficial to graft outcome, in both the acute and chronic phases. Moreover, specific inhibition of coagulation Xa protease further protected kidney grafts, with better recovery and decreased expression of chronic lesion markers. Surgical relevance The increasing use of marginal donors highlights the importance of organ quality in transplantation. Renal ischaemia-reperfusion injury (IRI), which includes a deleterious activation of coagulation, plays a central role in determining graft quality and outcome. Using an established porcine renal autotransplantation preclinical model with high clinical relevance, the benefits of anticoagulation therapy using an antifactor Xa molecule were evaluated. Peritransplantion anticoagulation treatment, specifically with an anti-Xa compound, protected marginal kidney grafts, improving functional recovery and reducing chronic lesions. This study demonstrates the benefits of anticoagulation therapy at the time of organ collection, particularly for marginal organs, encountered in cases of extended criteria and deceased after circulatory death donors. This anticoagulation strategy could be an important addition to current donor and organ management protocols in order to limit IRI and improve outcome.

Effects of warm ischaemia combined with cold preservation on the hypoxia-inducible factor 1α pathway in an experimental renal autotransplantation model.

BACKGROUND: The increased use of marginal donors highlights the importance of organ quality in transplantation and the identification of prognostic biomarkers. This experimental study investigated modulation of the hypoxia-inducible factor (HIF) 1α pathway in kidney grafts in relation to different degrees of ischaemia. METHODS: In a porcine autotransplantation model, two different kidney graft protocols were compared: standard 24-h cold storage (CS) and 24-h CS preceded by 1 h warm ischaemia (WI + CS). The renal HIF-1α pathway and tubular dedifferentiation were analysed in the early phase of reperfusion and at 3 months. RESULTS: There was a relationship between the degree of ischaemic injury and the outcome of the kidney graft. During the first week of reperfusion, WI + CS grafts showed a higher degree of injury. The observed tubular dedifferentiation was associated with delayed HIF-1α expression, and with loss of its role in transcription. In highly injured kidneys, deregulation of the HIF-1α pathway was also observed in the chronic phase, with reduced production of vascular endothelial growth factor (VEGF) A, and upregulation of VEGF receptor 1 (Flt-1) and thrombospondin 1. In addition, these kidneys displayed altered kidney histology and decreased function. CONCLUSION: The HIF-1α pathway appears to be abolished early in response to severe ischaemia. A high degree of ischaemic injury also results in chronic activation of the HIF-1α pathway, diverting it away from the beneficial activation of angiogenesis. Further studies on the finely tuned balance of signals in this pathway may provide diagnostic biomarkers that can determine organ quality during kidney transplantation. Surgical relevance The increased use of marginal donors has highlighted the importance of organ quality in transplantation. Renal ischaemia-reperfusion injury following transplantation induces graft dysfunction. In a porcine model of renal autotransplantation, the induction of regenerative processes, in response to graded degrees of ischaemia, was studied in the post-transplantation phase. There was early abrogation of the hypoxia-inducible factor (HIF) 1α pathway in response to severe ischaemia. High degrees of ischaemic injury induced chronic activation of the HIF-1α pathway, diverting it from the beneficial activation of angiogenesis. Identification of the mechanisms involved in renal regeneration, such as those related to the HIF-1α pathway, are important as these mechanisms can be used to identify novel therapeutic targets or develop diagnostic biomarkers to determine organ quality early in the transplantation process.

Long-term impact of subclinical inflammation diagnosed by protocol biopsy one year after renal transplantation.

The long-term impact of subclinical acute rejection (SCAR) on renal graft function remains poorly understood. Furthermore, the interpretation of borderline lesions is difficult and their incidence is variable. The aim of this study was to analyze the characteristics of subclinical inflammation (SCI) in protocol biopsies performed 1-year after renal transplantation. SCI was defined as the presence of borderline lesions or SCAR according to the Banff 2005 classification. The patients included were a subpopulation of the CONCEPT study in which patients were randomized 3 months after transplantation to receive either sirolimus (SRL) or cyclosporine A (CsA) in combination with mycophenolate mofetil. At 1 year, we observed SCI in 37 of the 121 patients observed with an evaluable biopsy. The incidence was more frequent in the SRL group (SRL 45.2% vs. CsA 15.3%). At 30 months , SCI was associated with a significantly lower level of estimated glomerular filtration rate (mean MDRD 50.8 [±13.3] vs. 57.7 [±16.3] mL/min/1.73 m(2) , p = 0.035). In conclusion, SCI at 1-year posttransplantation is associated with worsening renal function and is more frequent in SRL-treated patients. Therefore, evaluation of SCI may be a valuable tool to allow the optimization of immunosuppressive regimens.

Supplementation with a new therapeutic oxygen carrier reduces chronic fibrosis and organ dysfunction in kidney static preservation.

Static preservation is currently the most widely used organ preservation strategy; however, decreased donor organ quality is impacting outcome negatively. M101 is an O2 carrier with high-oxygen affinity and the capacity to function at low temperatures. We tested the benefits of M101 both in vitro, on cold preserved LLC-PK1, as well as in vivo, in a large white pig kidney autotransplantation model. In vitro, M101 supplementation reduced cold storage-induced cell death. In vivo, early follow-up demonstrated superiority of M101-supplemented solutions, lowering the peak of serum creatinine and increasing the speed of function recovery. On the longer term, supplementation with M101 reduced kidney inflammation levels and maintained structural integrity, particularly with University of Wisconsin (UW). At the end of the 3-month follow-up, M101 supplementation proved beneficial in terms of survival and function, as well as slowing the advance of interstitial fibrosis. We show that addition of M101 to classic organ preservation protocols with UW and Histidine-Tryptophane-Ketoglutarate, the two most widely used solutions worldwide in kidney preservation, provides significant benefits to grafts, both on early function recovery and outcome. Simple supplementation of the solution with M101 is easily translatable to the clinic and shows promises in terms of outcome.

Effect of polyethylene glycol-based preservation solutions on graft injury in experimental kidney transplantation.

BACKGROUND: New preservation solutions are emerging, of various ionic compositions and with hydroxyethyl starch replaced by polymers such as polyethylene glycols (PEGs), offering the potential for 'immunocamouflage'. This experimental study investigated which of three clinically available preservation protocols offered the best graft protection, based on epithelial-to-mesenchymal transition (EMT) and fibrosis. METHODS: Kidneys were preserved for 24 h at 4° C with University of Wisconsin solution (UW)as standard, compared with solutions containing either 1 g/l PEG 35 kDa (Institute Georges Lopez solution, IGL) or 30 g/l PEG 20 kDa (solution de conservation des organes et des tissus, SCOT). Animals were followed for up to 3 months and development of EMT, tubular atrophy and fibrosis was evaluated in comparison with sham-operated animals. RESULTS: Functional recovery was better in the SCOT group compared with the other groups. Chronic fibrosis, EMT and inflammation were observed in the UW and IGL groups, but limited in the SCOT group. Levels of profibrosis markers such as transforming growth factor ß1, plasminogen activator inhibitor 1 and connective tissue growth factor were increased in IGL and UW groups compared with the SCOT group. Hypoxia-inducible factor (HIF) 1α and 2α expression was increased at 3 months in grafts preserved in UW and IGL, but detected transiently on day 14 when SCOT was used. Expression of HIF-regulated genes vascular endothelial growth factor and erythropoietin was increased in UW and IGL groups. CONCLUSION: The choice of colloid and ionic content is paramount in providing long-term protection against chronic graft injury after renal transplantation. Preservation solutions based on PEGs may optimize graft quality.

Heat shock protein gp96 and NAD(P)H oxidase 4 play key roles in Toll-like receptor 4-activated apoptosis during renal ischemia/reperfusion injury.

Ischemia/reperfusion injury (IRI) causes inflammation and cell injury as a result of activating innate immune signaling. Toll-like receptor 4 (TLR4) has a key role in mediating kidney damages during IRI, but the downstream signaling pathway(s) stimulating apoptosis remains debated. In this study we show that TLR4 mediates MyD88-dependent activation of TNF receptor-associated factor 2, apoptosis signal-regulating kinase 1 (ASK1), and Jun N-terminal kinase (JNK) and p38 MAP kinases in ischemic-reperfused kidneys and posthypoxic renal tubule epithelial cells (RTECs). Hypoxia stimulated the expression of the endoplasmic-resident gp96, which co-immunoprecipitated TLR4, whereas silencing gp96 mRNA expression impaired hypoxia-induced apoptosis in TLR4-expressing RTECs. NAD(P)H oxidase 4 (NOX4) was shown to interact with TLR4 and to be required in lipopolysaccharide-induced production of reactive oxygen species (ROS). IRI stimulated the expression of a 28-kDa NOX4 spliced isoform abundantly expressed in wild-type RTECs, which co-immunoprecipitated with TLR4, but not with gp96 in TLR4-deficient RTECs. Silencing NOX4 mRNA expression impaired hypoxia-induced activation of ASK1 and both JNK and p38, leading to the inhibition of ROS production and apoptosis in posthypoxic TLR4-expressing RTECs. These findings show that, concomitantly to the activation of p38, the gp96/TLR4 interaction is required for activation of ASK1/JNK signaling in posthypoxic mouse RTECs, and that the 28-kDa NOX4 has a key role in TLR4-mediated apoptosis during renal IRI.

[Pathologic characteristics of the most frequent peripheral nerve tumors]. / Aspects histopathologiques des principales tumeurs des nerfs périphériques.

Benign tumors of the peripheral nerves come from ectodermic tissues. This chapter describes the most common forms: the schwannomas and the neurofibromas. Schwannomas have two possible patterns of cells: Antoni A and B types. Neurofibromas are most often associated with neurofibromatosis NF1 and may be localized, diffuse, or plexiform. The benign tumor structures account for the fact that they can be removed with or without preserving the concerned nerve. Malignant tumors (malignant peripheral sheath tumors) come from degeneration of neurofibromas in two out of three cases and have a poor prognosis.

Influence of nephron mass and a phosphorylated 38 mitogen-activated protein kinase inhibitor on the development of early and long-term injury after renal warm ischaemia.

BACKGROUND: Renal ischaemia is accompanied by acute and chronic complications. Tumour necrosis factor (TNF) alpha production via p38 mitogen-activated protein kinase (MAPK) is one of the pivotal mechanisms linking ischaemia to inflammation and could be a therapeutic target. FR167653 (FR), an inhibitor of p38 MAPK and TNF-alpha production, may ameliorate renal damage through its effects on TNF-alpha. METHODS: Warm ischaemia (WI) was induced in male pigs by bilateral clamping of the renal pedicle for 60 min or unilateral renal clamping after contralateral nephrectomy. FR was administered before and during WI, and continuously for 3 h during reperfusion in pigs exposed to the same WI conditions. Experimental groups were compared with sham-operated pigs and those subjected to unilateral nephrectomy without renal ischaemia. Renal function, fibrosis and inflammation were evaluated, and expression of monocyte chemoattractant protein 1, transforming growth factor beta and TNF-alpha was determined after 12 weeks. RESULTS: FR significantly reduced renal failure in groups subjected to unilateral nephrectomy and bilateral renal ischaemia. Proteinuria was significantly reduced, and inflammation and expression of proinjury proteins were diminished, accompanied by a reduction in renal fibrosis. CONCLUSION: Control of TNF-alpha production and activity prevents renal damage after prolonged WI.

Acute immuno-allergic interstitial nephritis caused by fluindione.

Fluindione is a vitamin K antagonist that is commonly prescribed for the treatment of cardiovascular disease and venous thromboembolism in France. Bleeding is the most common side effect of fluindione, whereas hypersensitivity reactions are rare. We describe here a patient with acute immuno-allergic interstitial nephritis caused by fluindione. Initial symptoms included fever, eosinophilia, low albuminuria, microscopic hematuria, eosinophiluria and acute renal failure. Kidney biopsy showed severe interstitial nephritis with interstitial edema, inflammatory infiltrates and tubulorrhexis. Fluindione withdrawal and corticosteroid treatment resulted in rapid recovery of renal function. A review of the literature revealed a very low incidence of fluindione-induced interstitial nephritis, with variable renal and extra-renal signs. Early recognition of this rare complication may prevent the development of severe chronic renal injury.

[Regression of primary melanoma with metastases associated with amyopathic dermatomyositis]. / Dermatomyosite amyopathique associée à un mélanome régressif métastasé.

BACKGROUND: Dermatomyositis is a rare and serious inflammatory connective tissue disease characterized by a typical cutaneous rash and myopathy. Amyopathic dermatomyositis is a particular form of dermatomyositis involving only cutaneous signs and without myopathy present for over 2 years. PATIENTS AND METHODS: A 48 year-old woman presented with a 3-year history of cutaneous rash without myopathy characteristic of amyopathic dermatomyositis. Clinical examination revealed extensive axillary adenopathy, histological examination of which suggested secondary melanoma. The patient reported a black nevus in the axillary area that had disappeared 1 year earlier. Curettage of the lymph node was negative and the patient was treated with interferon (3M 3 times a week). Regression of the cutaneous signs was noted. DISCUSSION: The data, there have been no other reports of paraneoplastic amyopathic dermatomyositis associated with regression of primary melanoma. The literature contains few reports of dermatomyositis associated with melanoma. Amyopathic dermatomyositis may be associated with malignancy.

Protective effect of PEG 35,000 Da on renal cells: paradoxical activation of JNK signaling pathway during cold storage.

Polyethylene glycol (PEG), a high-molecular weight colloid, is added to preservation solutions in order to decrease cold- and ischemia-induced injuries of the grafted organ. We evaluated on LLC-PK1, a porcine proximal tubular epithelial cell line (1) the efficiency of several commercial preservation solutions (University of Wisconsin, Euro-Collins, Celsior, SCOT, IGL-1), and (2) whether adding PEG (400-35,000 Da) in a simple extracellular-type buffer modified cell integrity and mitogen-activated protein kinase (MAPK) signaling pathways. SCOT was the most efficient commercial solution. Moreover, only PEG 35,000 Da totally preserved cell viability, induced a decrease on reactive oxygen species production and a decrease on p38-MAPK activation. Furthermore PEG 35,000 Da stimulated c-Jun N-terminal kinase (JNK). However, the inhibition of JNK pathway, with the specific SP600125 inhibitor, in the presence of PEG 35,000 Da did not affect cell survival. We also confirmed on whole pig kidney the protective effect of PEG 35,000 Da on cold-induced tubular injuries. This study confirms PEG antioxidative properties, but we demonstrate that its effect on JNK signaling pathway had also a paradoxical effect on cell death. This sheds a new light on PEG effects during cell preservation, independently from the classical immuno-camouflaging hypothesis.

Paranasal sinus fungus ball: epidemiology, clinical features and diagnosis. A retrospective analysis of 173 cases from a single medical center in France, 1989-2002.

Over the last decade, we have observed a high frequency of Aspergillus rhinosinusitis in french medical centers. The epidemiological data, clinical presentations, radiology, mycology and histology results of 173 consecutive patients with paranasal sinus fungus balls who were admitted from 1989 to 2002 have been reviewed. The most common symptoms included purulent nasal discharges and nasal obstructions, with the maxillary sinus being the most common site of infection (152 cases, 87.8%). Computed tomography scans (CT scan) were performed in 92% (159/173) of the cases and heterogeneous opacities were observed in 132 patients (83%). Histology examinations were performed in all cases and proved positive in 162 patients. Fungi were recovered, mainly Aspergillus fumigatus, from samples of 50 patients, while specimens from the remaining 123 patients were negative. Since no specific clinical sign could be found, a diagnosis of fungus ball is frequently made after a long term symptomatic period. CT scan findings of metallic or calcified densities within an opacified sinus cavity are highly suggestive of a fungus ball, but mycological and histological studies are essential to confirm the diagnosis. Treatment consisted of functional endonasal sinus surgery and was successful in 172 out of 173 cases.

Proximal tubular dysfunction in primary Sjögren's syndrome: a clinicopathological study of 2 cases.

Tubulointerstitial nephritis is the most common renal complication in primary Sjögren's syndrome (SS). It is usually associated with symptoms of distal tubular dysfunction, type I (distal) renal tubular acidosis (RTA) and nephrogenic diabetes insipidus. Proximal tubular abnormalities are considered to be less frequent, and Fanconi's syndrome has been only exceptionally reported in patients with SS. We describe 2 patients with primary SS, characterized by xerostomia, dry eyes, extensive lymphocytic infiltrate on salivary gland biopsy, positive tests for anti-SSA/SSB antibodies and/or antinuclear antibodies, who presented in renal failure with proteinuria, microscopic hematuria and type I RTA. Further studies revealed proximal tubular dysfunction, including renal glucosuria, generalized aminoaciduria, phosphaturia, uricosuria, together with proximal (type II) RTA in 1 case. Neither of these patients had Bence Jones proteinuria or monoclonal gammopathy. Kidney biopsy showed focal proximal tubulitis, associated with proximal tubular cell atrophy and dedifferentiation, and diffuse interstitial nephritis with fibrosis. No significant glomerular or peritubular deposits of immunoglobulin light or heavy chain were observed. These findings demonstrate that diffuse, distal and proximal, tubular dysfunction may occur in patients with SS and interstitial nephritis. Lymphocytic infiltration of proximal tubular cells is probably involved in the pathogenesis of Fanconi's syndrome in SS. However, the mechanisms involved in the alteration of sodium-dependent apical transports remain to be elucidated.

[Simultaneous occlusion of the abdominal aorta and both internal carotid arteries as the presenting symptoms of left atrial myxoma]. / Occlusions simultanées de l'aorte abdominale et des deux artères carotides internes révélant un myxome de l'oreillette gauche.

Myxoma is a benign tumour but which has redoubtable embolic complications. When situated in the left atrium, the emboli obstruct, in the majority of cases, the cerebral arteries, occasionally the visceral or coronary arteries, and, very rarely, the aorta. In this case, the authors report an atypical presentation with ischaemia of the lower half of the body, associated with pulmonary oedema and deep coma. The left atrial myxoma was responsible for complete and simultaneous obstruction of the internal carotid arteries and the infra-renal abdominal aorta. This report illustrates the fact that myxoma can be responsible for massive, life-threatening, embolisation.

Protective effect of polyethylene glycol against prolonged cold ischemia and reperfusion injury: study in the isolated perfused rat kidney.

The purpose of this study was to evaluate an intracellular solution with polyethylene glycol (PEG, molecular weight 20,000) as an impermeant, compared with University of Wisconsin (UW) and Euro-Collins (EC) solutions, after a 48-h cold storage (CS). The normothermic isolated perfused rat kidney (IPK) technique was used to assess renal function after CS. Five groups were studied: a control group (immediately reperfused, n = 10); one that received EC (n = 16); one that received UW (n = 16); and two that each received an intracellular (IC) solution, one with PEG (ICPEG, n = 16) and one without PEG (IC, n = 16). The perfusion flow rate was significantly greater in the PEG group and correlated with less significant cellular and interstitial edema and lower renal vascular resistance than in the IC, EC, and UW groups. Glomerular filtration rate was significantly higher in the PEG group during reperfusion than in the IC, EC, and UW groups. Proximal tubular functions were more efficient with PEG: fractional sodium reabsorption and total sodium reabsorption were significantly greater during reperfusion in the PEG group than in the IC, EC, and UW groups. Of greater interest is the protective effect of PEG on lipid peroxidation, which reflects ischemia/reperfusion damage. The second major effect is the dramatic ATP restoration during reperfusion, which outlines the preservation of oxidative phosphorylation after preservation by ICPEG. These results are supported by histological studies, particularly concerning brush border and mitochondrial preservation. Our results indicate that PEG is promising for cold ischemia and reperfusion injury protection.

[Effect of preservation of the kidney on the long-term function following autotransplantation]. / Influence de la conservation d'un rein sur son devenir fonctionnel à long terme dans un modèle d'autotransplantation.

The consequences of ischaemia-reperfusion injury from kidney recipients on delayed graft function and graft survival still remain a matter of debate. Using an autotransplanted pig kidney model, the influence of trimetazidine added to two standard preservation solutions (Euro-Collins and University of Wisconsin) was studied. The renal parameters were analysed over a period of 12 weeks after transplantation. The degree of interstitial fibrosis, and the number of CD4, CD8 and macrophage positive cells were analysed at 2, 4-5 and 11-12 weeks after the transplantation. Glomerular filtration and sodium reabsorption were significantly more improved after cold-flush and preservation with trimetazidine-supplemented solutions than with trimetazidine-free solutions. The cytoprotective action of trimetazidine also reduced interstitial fibrosis and the number of infiltrating CD4 and CD8-positive cells. These results indicate that the condition of cold preservation may influence long-term kidney graft functions and that trimetazidine reduces to a certain extent the degree of interstitial fibrosis.