Gilles St-Louis

Increased Risk of Thrombotic Microangiopathy in Patients Receiving a Cyclosporin–Sirolimus Combination

A single‐center cohort study of kidney and kidney–pancreas recipients was conducted to evaluate the association between new immunosuppressive regimens and risk of thrombotic microangiopathy (TMA). From January 1st,1996 to December 31, 2002, 368 patients received a kidney or kidney–pancreas transplant at our center. Four immunosuppressive regimens were evaluated as potential risk factors of TMA: cyclosporin + mycophenolate mofetil (CsA + MMF), cyclosporin + sirolimus (CsA + SRL), tacrolimus + myophenolate mofetil (FK + MMF), and tacrolimus + sirolimus (FK + SRL). Thirteen patients developed biopsy‐proven TMA in the absence of vascular rejection. The incidence of TMA was significantly different in the four immunosuppressive regimens studied (p < 0.001). The incidence of TMA was highest in the CsA + SRL group (20.7%). The relative risk of TMA was 16.1 [95% confidence interval (CI): 4.3–60.8] for patients in the CsA + SRL group as compared with those in the FK + MMF group. We also investigated in vitro the pathophysiological basis of this association. The CsA–SRL combination was found to be the only regimen that concomitantly displayed pro‐necrotic and anti‐angiogenic activities on arterial endothelial cells. We propose that this combination concurs to development of TMA through dual activities on endothelial cell death and repair.

Renal Cell Carcinoma in Kidney Allografts: A Case Series from a Single Center

In kidney transplant recipients, renal cell carcinoma (RCC) occurs either in the native kidney or, less frequently, in the grafted kidney. Here, we report a series of rare cases involving 5 patients from a single center who developed RCC in their grafts. The diagnosis was made serendipitously by ultrasound. The time lapse post‐transplant varied from 4 to 17 years. Surgical treatment consisted of nephron‐sparing surgery (NSS) in four cases and a secondary radical nephrectomy in one case. All tumors were less than 4 cm in diameter. The histopathology was clear cell type in four cases and papillary RCC in one case. Patients treated by NSS retained kidney function for 2 years or more, and none of them presented early neoplasia recurrence. In conclusion, NSS can be performed safely in grafted kidneys to treat incidental RCC. It prevents an immediate return to dialysis for patients.

Inhibition of in vitro immunoglobulin production by rapamycin.

Like FK506, rapamycin, a structural analog of FK506, is a strong immunosuppressant. The immunosuppressive effect of Rapa in in vitro IgG, IgM, and IgA production by human lymphocytes was examined in this study. To inhibit spontaneous or pokeweed mitogenstimulated production of Ig by human peripheral blood lymphocytes, about one thousandfold lower concentrations of Rapa (IC50 = 0.3 nM-2 nM) were required than of cyclosporine (IC50 = 0.3 mUM-2 mUM). T cells were the direct targets of Rapa, because preincubation of T cells with Rapa abolished the T cells helper effect to T-de-pendent Ig production. Rapa also had direct suppressive effect on B cells, since Rapa suppressed IgG production by pure B cells stimulated with IL2 and Staphylococcus aureus Cowan I. Kinetic studies measuring IgG production and cell proliferation revealed that Rapa acted at the activation stage of T and B cells. Exogenous IL2 substantially reversed the inhibitory effect of CsA but not that of Rapa in Ig production. This study is the first report on the strong suppressive effect of Rapa on human humoral immune response with a quantitative comparison with that of CsA. The underlying mechanisms are also explored. The results indicate the potential usefulness of this drug in treatment of presensitized transplantation patients, with whom cytotoxic Ab is a major obstacle to a successful transplantation.

Anti-CD28 antibody- and IL-4-induced human T cell proliferation is sensitive to rapamycin

Rapamycin (RAPA) is a potent immunosuppressant. In this study we investigated the effect of RAPA on T cell proliferation triggered by various stimuli in an in vitro human model. The proliferation of T cells stimulated via an alternative pathway using phorbol myristate acetate (PMA) and anti‐CD28 antibody (αCD28) in the absence of antigen‐presenting cells (APC) was strongly inhibited by RAPA. T cell proliferation provoked via a combination of CD3/TCR and CD28 pathways using anti‐CD3 antibody (αCD3) plus αCD28 was also inhibited by RAPA in the presence of APC. The mitogen (phytohaemagglutinin (PHA) or αCD3)‐induccd up‐regulation of expression of the IL‐2 receptor a chain (IL‐2Rα) and the IL‐4 receptor (IL‐4R) was sensitive to RAPA. This suggests that RAPAs interference with the IL‐2 and IL‐4 autocrine loops during T cell activation might contribute to RAPAs overall immunosuppressive effect. We have further demonstrated in a two‐stage culture system that RAPA strongly inhibited IL‐4‐stimulated proliferation of T cells, the latter being either pretreated with αCD3 in the presence of APC, or with PMA plus αCD28 in the absence of APC. The result suggests that the Ca++ influx during the pretreatment is not obligatory for T cells to achieve IL‐4 responsiveness. The results also indicate that RAPAs antiproliferative effect on IL‐4‐stimulated T cells is not contingent on the various mechanisms of cell priming. Therefore, RAPAs major target is probably at the second stage after the priming. Our study has extended current knowledge about the effect of RAPA on human T cells.

Long-term in vivo effects of rapamycin on humoral and cellular immune responses in the rat

Rapamycin (RAPA) is a strong immunosuppressant and is able to prevent allograft rejection in animal models. We have demonstrated that RAPA could strongly inhibit in vitro immunoglobulin (Ig) production by human lymphocytes. The present study investigated the long-term in vivo effect of RAPA on humoral and cellular immune responses, and the effect of RAPA on accelerated rejection. It was shown that RAPA strongly inhibited antigen (Ag) specific antibody (AB) production (i.e. cytotoxic Ab to donor lymphocytes and Ab to tetanus toxoid) during the period of drug administration. The accelerated rejection of cardiac allografts in presensitized animals was alleviated by RAPA administration. These results suggest the potential application of RAPA in treatment of presensitized candidates for organ transplantation. A little more than two months after the drug withdrawal, the rats were basically competent in Ab response to further Ag challenges. When tested 4 months after the RAPA-treatment, the rats showed uncompromised cardiac allograft rejection, and the cellular immune response in vitro according to mixed lymphocyte reaction (MLR) and mitogen-stimulated proliferation were not hampered. Such results suggest that the immune system can return to normal status without sequelae after discontinuation of RAPA.

In vitro IgE production by interleukin 4-stimulated human peripheral blood mononuclear cells is suppressed by rapamycin

Rapamycin (RAPA) is a new immunosuppressant which is 50-fold to 100-fold more potent than cyclosporin A (CyA) in inhibiting cellular immune responses and allograft rejection in animal models of organ transplantation. The drugs effect on in vitro IgE synthesis by interleukin (IL)4-stimulated human peripheral blood mononuclear cells was examined and compared with CyAs effect in this study. RAPA was found to be about 100-fold more potent than CyA in inhibiting IgE synthesis. Its inhibitory effect on IgE production was significant if it was added to the culture before Day 6 of a 14-day culture. The suppression was accompanied by the inhibitory effect on cell proliferation and on IgE-binding factor (IgE-BF) production. IL2 was able to partially reverse CyA- but not RAPA-induced inhibition of IgE production. Commercial B cell growth factor (cBCGF) was not able to reverse either RAPA- or CyA-induced suppression of IgE synthesis. The strong inhibitory effect of RAPA in IgE synthesis may be useful in certain clinical applications where overproduction of pathogenic IgE is a key issue. RAPA can also be used as a tool to dissect the regulation of IgE production.

Mycobacterium genavense and chronic intermittent diarrhea in a kidney and pancreas transplant recipient.

deficiency. N Engl J Med 1999; 341: 921. 4. Dionisi-Vici C, Rizzo C, Burlina AB, et al. Inborn errors of metabolism in the Italian pediatric population: a national retrospective survey. J Pediatr 2002; 140: 321. 5. Snodgrass PJ. Biochemical aspects of urea cycle disorders. Pediatrics 1981; 68: 273. 6. Thurlow VR, Asafu-Adjaye M, Agalou S, et al. Fatal ammonia toxicity in an adult due to an undiagnosed urea cycle defect: underrecognition of ornithine transcarbamylase deficiency. Ann Clin Biochem 2010; 47: 279. 7. Rohininath T, Costello DJ, Lynch T, et al. Fatal presentation of ornithine transcarbamylase deficiency in a 62-year-old man and family studies. J Inherit Metab Dis 2004; 27: 285. 8. Lien J, Nyhan WL, Barshop BA. Fatal initial adult-onset presentation of urea cycle defect. Arch Neurol 2007; 64: 1777. 9. Gropman AL, Summar M, Leonard JV. Neurological implications of urea cycle disorders. J Inherit Metab Dis 2007; 30: 865.

Low-dose tacrolimus, trough-monitored mycophenolate mofetil, and planned steroid withdrawal for cadaveric kidney transplantation: a single center experience.

SEVERAL STUDIES have shown excellent graft survival and low rates of acute rejection when tacrolimus (TAC) was combined with a fixed dose of mycophenolate mofetil (MMF) and steroids. Further optimization of MMF using trough mycophenolate acid (MPA) blood levels monitoring may allow the use of lower TAC levels and steroid discontinuation. The current study is a retrospective analysis of our experience with low-dose TAC combined with trough MPA monitoring and steroid withdrawal.

Stabilization of renal function after the first year of follow‐up in kidney transplant recipients treated for significant BK polyomavirus infection or BK polyomavirus‐associated nephropathy

BK polyomavirus virus (BKPyV) screening and immunosuppression reduction effectively prevent graft loss due to BKPyV‐associated nephropathy (BKPVAN) during the first year after transplantation. The aim of our study was to evaluate the impact of this infection during longer follow‐up periods.

Varicella Zoster Virus Vasculopathy After Kidney Transplantation.

CASE 1 A 64-year-old woman developed left lower limb paresis with sciatica 3 weeks after kidney transplantation, complicated by confusion, fever, and generalized zoster rash 2weeks later. Her immunosuppression consisted of tacrolimus, mycophenolate mofetil (MMF), and prednisone without any antiviral prophylaxis (pretransplant serostatus positive for cytomegalovirus IgG, herpes simplex virus 1 IgG, EpsteinBarr virus nuclear antigen IgG, and VZV IgG). She had received an induction with basilixumab, and she never experienced acute rejection. On admission, cerebrospinal fluid (CSF) analysis showed mild pleocytosis with positive VZV using polymerase chain reaction. Brain magnetic resonance imaging (MRI) was normal. The MRI of the lumbar spine showed changes consistent with arachnoiditis. The MMF was discontinued and intravenous acyclovir (10 mg/kg 3 times daily) was started. Twelve days later, confusion worsened. Brain CT demonstrated subarachnoid hemorrhage