Cyclosporine triggers endoplasmic reticulum stress in endothelial cells: a role for endothelial phenotypic changes and death.

Calcineurin inhibitors cyclosporine and tacrolimus are effective immunosuppressants, but both substances have the same intrinsic nephrotoxic potential that adversely affects allograft survival in renal transplant patients and causes end-stage renal disease in other solid organ or bone marrow transplant recipients. Endothelial cells are the first biological interface between drugs and the kidney, and calcineurin inhibitors may influence endothelial function and viability in a number of ways. Notably, endothelial cells have recently been shown to contribute to the accumulation of interstitial fibroblasts in nonrenal models, through endothelial-to-mesenchymal transition.

[Place of nephrectomy in patients with autosomal dominant polycystic kidney disease waiting for renal transplantation].

Objective: To define the indications, results and place of nephrectomy for autosomal dominant polycystic kidney disease (ADPKD) in relation to renal transplantation.

Material And Methods: Between October 1998 and February 2006, 145 patients with ADPKD were followed in our institution; 38 of them underwent nephrectomy via a subcostal incision, mainly in preparation for renal transplantation. The decision to perform nephrectomy in preparation for renal transplantation was based on clinical examination and CT findings.

Sirolimus interacts with pathways essential for podocyte integrity.

Background: The specific mTor inhibitor sirolimus has been implicated in the pathogenesis of renal glomerular lesions and nephrotic syndrome appearance after transplantation. Podocyte injury and focal segmental glomerulosclerosis have been related to sirolimus therapy in some patients but the pathways underlying these lesions remain hypothetical.

Methods: To go further in the comprehension of these mechanisms, primary cultures of human podocytes were exposed to therapeutic-range concentrations of sirolimus.

Effects of vitamin D supplementation on the calcium-phosphate balance in renal transplant patients.

Low serum levels of 25-hydroxy vitamin D frequently occur after renal transplantation, but few studies have evaluated the effects of normalizing this on serum parathyroid hormone and calcium levels or urinary calcium excretion. To determine this we compared the outcomes of 94 renal transplant patients with low 25-hydroxy vitamin D and normal serum calcium levels who were either treated or not with cholecalciferol every 2 weeks for 2 months (intensive phase) followed by an every other month maintenance phase. The biological characteristics of the two equally divided patient groups did not differ before treatment.

[Proteinuria and renal transplantation].

The occurrence of proteinuria in transplant patients is a marker of poor prognosis. The augmentation of proteinuria is associated with an increased risk of patient death and graft loss. Even a low-level urinary protein excretion (0.

[Interest of screening biopsies in renal transplantation].

Renal biopsy is an invaluable tool used for the monitoring of grafts and the management of their survival. Since 1993, thanks to research on biopsy tissues that enabled to distinguish the different types of rejection and to find markers of reversible or irreversible rejection, a classification of renal lesions has been established to achieve the regularly updated Banff classification. The last in date (2005) has defined the antibody-mediated chronic rejection, forsaken the term "chronic allograft nephropathy" and described a new class with interstitial fibrosis and tubular atrophy (IF/TA).

A simple clinico-histopathological composite scoring system is highly predictive of graft outcomes in marginal donors.

The predictive value of pre-implantation biopsies versus clinical scores has not been studied extensively in marginal donors. Pre-implantation biopsies were performed in 313 kidneys from donors that were > or = 50 years of age (training set, n = 191; validation set, n = 122). The value of the donor clinical parameters and histological results in predicting 1-year estimated glomerular filtration rate (eGFR) <25 mL/min/1.

Cyclosporine-induced endoplasmic reticulum stress triggers tubular phenotypic changes and death.

The molecular mechanisms by which cyclosporine induces chronic nephrotoxicity remain poorly understood. A previous transcriptomic study suggested that cyclosporine might induce endoplasmic reticulum (ER) stress in human tubular cells. The aim of the present study was to characterize the features of tubular ER stress induced by cyclosporine and to investigate its effects on cell differentiation and viability.

Determination of lowest possible creatinine in living-donor kidney renal transplant recipients based on donor kidney function.

Background: The objective of this study was to use information from a donor to establish the lowest possible serum creatinine (SCr) of the recipient as a means of identifying early graft dysfunction.

Methods: We analyzed retrospectively 58 pairs of living donors and recipients. The lowest possible SCr was calculated from four different formulae derived from Cockcroft-Gault formula: Ax(140-recipient age)xrecipient weight/donor GFR (A, women: 1.

Sirolimus early graft nephrotoxicity: clinical and experimental data.

Sirolimus (SRL) is a recently available immunosuppressive agent. SRL, is a macrolide isolated from Streptomyces hydroscopicus that, in complex with its cellular receptor, FK binding protein, potently inhibits downstream signaling by the mammalian target of rapamycin (mTOR). It has been shown to reduce the incidence of acute rejection episode after renal transplantation.

Kaposi sarcoma in transplantation.

Kaposi sarcoma (KS) is a multicentric neoplasm of lymphatic endothelium derived cells infected with Kaposi's human herpesvirus 8 (HHV8). Post-transplant KS can lead to multifocal, progressive (florid) lesions with frequent primary involvement of the oral mucosa and dissemination to the viscera. KS prevalence after organ transplantation varies greatly depending on the prevalence of HHV8 infection in the general population.

mToR inhibitors-induced proteinuria: mechanisms, significance, and management.

Massive urinary protein excretion has been observed after conversion from calcineurin inhibitors to mammalian target of rapamycin (mToR) inhibitors, especially sirolimus, in renal transplant recipients with chronic allograft nephropathy. Because proteinuria is a major predictive factor of poor transplantation outcome, many studies focused on this adverse event during the past years. Whether proteinuria was due to sirolimus or only a consequence of calcineurin inhibitors withdrawal remained unsolved until high range proteinuria has been observed during sirolimus therapy in islet transplantation and in patients who received sirolimus de novo.

Autophagy protects renal tubular cells against cyclosporine toxicity.

A major side effect of the powerful immunosuppressive drug cyclosporine (CsA) is the development of a chronic nephrotoxicity whose mechanisms are not fully understood. Recent data suggest that tubular cells play a central role in the pathogenesis of chronic nephropathies. We have shown that CsA is responsible for endoplasmic reticulum (ER) stress in tubular cells.

Impact of protein deficiency on venous ulcer healing.

Objective: The prevalence of protein deficiency and its impact on wound healing is not known for leg ulcers. The aim of this study was to determine the prevalence of protein deficiency in outpatients presenting with leg ulcers and the parameter's prognostic value for wound outcome.

Design Of Study: Prospective controlled observational study.

Complement mutation-associated de novo thrombotic microangiopathy following kidney transplantation.

Mutations in one or more genes encoding complement-regulatory proteins predispose to atypical hemolytic uremic syndrome (aHUS) and its recurrence following kidney transplantation. We evaluated plasma complement level and performed a screening for mutations in genes encoding complement Factors H and I (CFH, CFI) and membrane cofactor protein (MCP) in 24 kidney transplant recipients experiencing de novo thrombotic microangiopathy (TMA). Six patients presented with low C3 and/or low Factor B levels suggestive complement alternative pathway.

B cell survival in intragraft tertiary lymphoid organs after rituximab therapy.

Background: Rituximab is emerging as a potent therapeutic option in chronic inflammatory diseases associated with a prominent humoral component. Recent studies have demonstrated that chronic inflammatory infiltrate organize progressively themselves into ectopic lymphoid tissues (tertiary lymphoid organs; TLOs) supporting a local humoral immune response. In the present study, we evaluated the impact of rituximab therapy on TLOs associated with chronic active antibody-mediated rejection, a prototypic humoral chronic inflammatory condition.

High-dosage intravenous immunoglobulin-associated macrovacuoles are associated with chronic tubulointerstitial lesion worsening in renal transplant recipients.

Background And Objectives: Intravenous immunoglobulins (IVIg) may induce acute renal failure associated with tubular vacuolization. Although the use of IVIg is increasing in kidney transplantation, their impact on graft histology and function remains unknown.

Design, Setting, Participants, & Measurements: Twenty-seven kidney transplant recipients who had high immunologic risk and were treated with four courses of IVIg after transplantation were studied retrospectively at a transplant center, and findings were compared with those of 27 control subjects.

Hydrolysis of coagulation factors by circulating IgG is associated with a reduced risk for chronic allograft nephropathy in renal transplanted patients.

Chronic allograft nephropathy (CAN), a major cause of late allograft failure, is characterized by a progressive decline in graft function correlated with tissue destruction. Uncontrolled activation of the coagulation cascade by the stressed endothelium of the graft is thought to play an important role in the pathophysiology of CAN. In this study, we demonstrate that circulating IgG from renal-transplanted patients are endowed with hydrolytic properties toward coagulation factors VIII and IX, but fail to hydrolyze factor VII and prothrombin.

Sirolimus may reduce fertility in male renal transplant recipients.

Assessment of sex hormones in organ transplant recipients suggests that sirolimus may impair testicular function. The aim of this study was to evaluate the frequency and severity of sirolimus-associated alterations in sperm parameters and their impact on fathered pregnancy rate. An observational study was carried out in male patients aged 20-40 years who received a kidney transplant during 1995-2005.

[Immunosuppression in kidney transplantation].

Kidney transplantation has become the treatment of choice in end-stage chronic renal failure since it significantly improves both the quality of life and the life duration of affected patients, when compared with dialysis. Some of these better results that were observed over the last thirty years are obviously due to significant improvements in the quality of immunosuppression. In the first part of this chapter, the allo-immune response is schematically described regarding the various signals.

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.