Five-year results of a randomized trial comparing de novo sirolimus and cyclosporine in renal transplantation: the SPIESSER study.

Calcineurin inhibitors improve acute rejection rates and short-term graft survival in renal transplantation, but their continuous use may be deleterious. We evaluated the 5-year outcomes of sirolimus (SRL) versus cyclosporine (CsA) immunosuppressive treatment. This observational study was an extension of the SPIESSER study where deceased donor kidney transplant recipients were randomized before transplantation to a SRL- or CsA-based regimen and followed up 1 year. Data from 131 (63 SRL, 68 CsA) out of 133 patients living with a functional graft at 1 year were collected retrospectively at 5 years posttransplant. Seventy percent of CsA patients versus 54% of SRL patients were still on the allocated treatment at 5 years (p = 0.091), most discontinuations in each group being due to safety issues. In intent-to-treat, mean MDRD eGFR was higher with SRL: 54.2 versus 45.3 mL/min with CsA (p = 0.019); SRL advantage was greater in on-treatment analyses. There were no differences for patient survival (p = 0.873), graft survival (p = 0.121) and acute rejection (p = 0.284). Adverse events were more frequent with SRL (80% vs. 60%, p = 0.015). Results confirmed the high SRL discontinuation rate due to adverse events. Nevertheless, a benefit was evidenced on renal function in patients (more than 50%) still on treatment at 5 years.

The influence of cytomegalovirus infections on patient and renal graft outcome: a 3-year, multicenter, observational study (Post-ECTAZ Study).

Cytomegalovirus (CMV) infections posttransplant may increase the risk of acute rejection, graft failure, patient death, opportunistic infections, malignancy, diabetes, and cardiovascular complications. ECTAZ, a multicenter, randomized trial compared safety and efficacy at 12 months (M12) of two doses daclizumab (54 patients, group D) with thymoglobulin (55 patients, group T), plus cyclosporine (CsA), mycophenolate mofetil and steroids in first cadaveric kidney transplant patients. D+/R- patients received oral ganciclovir prophylaxis for 90 days. Post-ECTAZ is a 36-month, multicenter, observational study including recipients who participated in ECTAZ trial. We studied the indirect effects of CMV infections, whether recipients experienced (CMVi+) or not (CMVi-) a CMV infection/syndrome/disease. We compared 49 patients in the group CMVi+ with 54 patients in the group CMVi-. At month 36 (M36), patient survival, graft survival and renal function were comparable. The incidence of biopsy-proven acute rejection was 16.3% in the CMVi+ group versus 24.1% in the CMVi- group (not significant). The incidence of infections was increased in the CMVi+ group (P = .004), but not diabetes, malignancies, and cardiovascular complications. Our study shows at M36 that CMV infection/syndrome/disease episodes were associated with a higher incidence of infections but no difference for other long-term complications. Our data suggest that anti-CMV prophylaxis could decrease the risk for long-term related CMV complications.

Renal transplantation in patients with AA amyloidosis nephropathy: results from a French multicenter study.

Although end-stage renal disease related to AA amyloidosis nephropathy is well characterized, there are limited data concerning patient and graft outcome after renal transplantation. We performed a multicentric retrospective survey to assess the graft and patient survival in 59 renal recipients with AA amyloidosis. The recurrence rate of AA amyloidosis nephropathy was estimated at 14%. The overall, 5- and 10-year patient survival was significantly lower for the AA amyloidosis patients than for a control group of 177 renal transplant recipients (p = 0.0001, 0.028 and 0.013, respectively). In contrast, we did not observe any statistical differences in the 5- and 10- year graft survival censored for death between two groups. AA amyloidosis-transplanted patients exhibited a high proportion of infectious complications after transplantation (73.2%). Causes of death included both acute cardiovascular events and fatal septic complications. Multivariate analysis demonstrated that the recurrence of AA amyloidosis on the graft (adjusted OR = 14.4, p = 0.01) and older recipient age (adjusted OR for a 1-year increase = 1.06, p = 0.03) were significantly associated with risk of death. Finally, patients with AA amyloidosis nephropathy are eligible for renal transplantation but require careful management of both cardiovascular and infectious complications to reduce the high risk of mortality.

Angiotensin-2 receptors (AT1-R and AT2-R), new prognostic factors for renal clear-cell carcinoma?

BACKGROUND: The growth factor Angiotensin-2 signals through Angiotensin receptor type 1 (AT1-R) in a broad range of cell types and tumours and through the type-2 receptor (AT2-R) in a more restricted group of cell types. Although numerous forms of cancer have been shown to overexpress AT1-R, expression of AT1-R and AT2-R by human renal clear-cell carcinoma (RCCC) is not well understood. In this study, the expression of both angiotensin receptors was quantified in a retrospective series of RCCC and correlated with prognostic factors. METHODS: Angiotensin receptor type 1 and AT2-R expressions were quantified on tumour tissues by immunohistochemistry (IHC), western blot and quantitative reverse transcriptase PCR (qRT-PCR). IHC results were correlated to Fuhrman's grade and patient progression-free survival (PFS). RESULTS: A total of 84 RCCC were analysed. By IHC, AT1-R and AT2-R were expressed to a greater level in high-grade tumours (AT1-R: P<0.001, AT2-R: P<0.001). Univariate analysis showed a correlation between PFS and AT1-R or AT2-R expression (P=0.001). By multivariate analysis, only AT2-R expression correlated with PFS (HR 1.021, P=0.006) and cancer stage (P<0.001). By western blot, AT1-R and AT1-R were also found to be overexpressed in higher Fuhrman's grade (P<0.01 and P=0.001 respectively). By qRT-PCR, AT1-R but not AT2-R mRNA were downregulated (P=0.001 and P=0.118, respectively). CONCLUSION: Our results show that AT1-R and AT2-R proteins are overexpressed in the most aggressive forms of RCCC and that AT2-R expression correlates with PFS. AT1-R or AT2-R blockage could, therefore, offer novel directions for anti-RCCC therapy.

Optimization of initial tacrolimus dose using pharmacogenetic testing.

Retrospective studies have demonstrated that patients who are expressors of cytochrome P4503A5 (CYP3A5) require a higher tacrolimus dose to achieve a therapeutic trough concentration (C(0)). The aim of this study was to evaluate this effect prospectively by pretransplantation adaptation. We randomly assigned 280 renal transplant recipients to receive tacrolimus either according to CYP3A5 genotype or according to the standard daily regimen. The primary end point was the proportion of patients within the targeted C(0). Secondary end points included the number of dose modifications and the delay in achieving the targeted C(0). In the group receiving the adapted dose, a higher proportion of patients had values within the targeted C(0) at day 3 after initiation of tacrolimus (43.2% vs. 29.1%; P = 0.03); they required fewer dose modifications, and the targeted C(0) was achieved by 75% of these patients more rapidly. The clinical end points were similar in the two groups. Pharmacogenetic adaptation of the daily dose of tacrolimus is associated with improved achievement of the target C(0). Whether this improvement will affect clinical outcomes requires further evaluation.

Interstitial fibrosis quantification in renal transplant recipients randomized to continue cyclosporine or convert to sirolimus.

Conversion from cyclosporine (CsA) to sirolimus at week 12 after kidney transplantation is associated with a significant improvement in renal function. The aim of this analysis was to investigate the effect of this conversion on interstitial fibrosis (IF), a hallmark of chronic allograft injury, in patients taking part in the CONCEPT trial. This multicenter, prospective, trial included 193 renal recipients randomized at week 12 to switch from CsA to sirolimus or to continue CsA, with mycophenolate mofetil. Routine biopsy with automated, quantified assessment of IF by a program of color segmentation was performed at 1 year in 121 patients. At 1 year, renal function was significantly improved in the conversion group as assessed by estimated GFR (MDRD) and measured GFR. Biopsy results, however, showed no between-group difference in percentage of IF. Calculated GFR at 1 year was significantly associated with the percentage of IF (p = 0.004, R(2)= 0.07). By multivariate analysis diabetic patients had more fibrosis than non-diabetic patients. In conclusion, although kidney transplant patients converted from CsA to sirolimus showed significant improvement in renal function, we found no difference of IF on 1-year biopsies.

Long-term results of monoclonal anti-Il2-receptor antibody versus polyclonal antilymphocyte antibodies as induction therapy in renal transplantation.

We compared the influence of induction therapy on 5-year patient and graft survival as well as on renal function in 100 kidney graft recipients at low immunological risk treated with antilymphocyte globulin (n = 50) versus anti-IL-2R monoclonal antibody (n = 50) in a prospective multicenter study. Long-term immunosuppressive treatment included cyclosporine, mycophenolate mofetil, and a short course of steroids in all patients. Five year graft (86% vs 86%) and patient (94% vs 94%) survivals were identical in both study arms. Moreover, neither serum creatinine or proteinuria were significantly different between the two groups. Our results showed that the choice of the induction therapy seemed to not have a major impact on long-term outcomes among renal recipients at low immunological risk.

[Epidemiologic description of amyloidosis diagnosed at the University Hospital of Rennes from 1995 to 1999]. / Epidémiologie descriptive des amyloses diagnostiquées au CHU de Rennes de 1995 à 1999.

INTRODUCTION: The frequency of amyloidosis is not well known in France. We compiled a register of amyloidosis diagnosed from 1995 to 1999 in the University Hospital of Rennes. PATIENTS AND METHODS: This retrospective study was performed between 01 January 1995 and 31 december 1999. Diagnosis was assessed on positivity of red Congo by anatomopathology. Immunohistochemistry allowed the definition the type of amyloidosis. Clinical data, staging and outcome of patients were analysed. RESULTS: Forty-three amyloidosis were diagnosed (27 women, 16 men) with an incidence of 8,6 new cases per year. Mean age was 63.7 years. Five diagnosis were realised in 1995, six in 1996, six in 1997, 12 in 1998, 14 in 1999. Twenty amyloidosis were AL type (46.5%), seven AA (16.3%), 1 beta2 microglobulin type, 15 (35%) remained of undetermined type. Thirty-three amyloidosis (77%) were systemic, 10 were localized to one organ (23%). When diagnosis was made, biopsies concerned affected organs in 86% of the cases, accessory sites (labial salivary glands, bone marrow) in only 14% of the cases. Twenty-five patients died (58%). Two deaths were treatment-related, 16 to amyloidois, seven patients died of another complaint. CONCLUSION: Increased incidence of amyloidosis needs to be confirmed. We emphasize the importance of immunohistochemical typing on frozen samples, the value of accessory biopsies and the need for complete extension staging.

Induction versus noninduction in renal transplant recipients with tacrolimus-based immunosuppression.

BACKGROUND: The aim of this study was to compare the efficacy and safety of induction treatment with antithymocyte globulins (ATG) followed by tacrolimus therapy with immediate tacrolimus therapy in renal transplant recipients. METHODS: This 12-month, open, prospective study was conducted in 15 centers in France and 1 center in Belgium; 309 patients were randomized to receive either induction therapy with ATG (n=151) followed by initiation of tacrolimus on day 9 or immediate tacrolimus-based triple therapy (n=158). In both study arms, the initial daily tacrolimus dose was 0.2 mg/kg. Steroid boluses were given in the first 2 days and tapered thereafter from 20 mg/day to 5 mg/day. Azathioprine was administered at 1-2 mg/kg per day. RESULTS: At month 12, biopsy-confirmed acute rejections were reported for 15.2% (induction) and 30.4% (noninduction) of patients (P=0.001). The incidence of steroid-sensitive acute rejections was 7.9% (induction) and 22.2% (noninduction)(P=0.001). Steroid-resistant acute rejections were reported for 8.6% (induction) and 8.9% (noninduction) of patients. A total of nine patients died. Patient survival and graft survival at month 12 was similar in both treatment groups (97.4% vs. 96.8% and 92.1% vs. 91.1%, respectively). Statistically significant differences in the incidence of adverse events were found for cytomegalovirus (CMV) infection (induction, 32.5% vs. noninduction, 19.0%, P=0.009), leukopenia (37.3% vs. 9.5%, P<0.001), fever (25.2% vs. 10.1%, P=0.001), herpes simplex (17.9% vs. 5.7%, P=0.001), and thrombocytopenia (11.3% vs. 3.2%, P=0.007). In the induction group, serum sickness was observed in 10.6% of patients. The incidence of new onset diabetes mellitus was 3.4% (induction) and 4.5% (noninduction). CONCLUSION: Low incidences of acute rejection were found in both treatment arms. Induction treatment with ATG has the advantage of a lower incidence of acute rejection, but it significantly increases adverse events, particularly CMV infection.

[Natural history of vascular ports for hemodialysis after renal transplantation]. / Histoire naturelle des abords vasculaires pour l'hémodialyse après transplantation rénale.

INTRODUCTION: The objective of this study was to assess the long-term outcome of AV shunts in renal transplant recipients, to discuss mechanisms affecting their functioning and the surgical strategy designed to optimally preserve the venous capital in the hypothesis of a return to dialysis. MATERIALS AND METHODS: 160 renal transplant recipients, with a mean age of 47 years, were reviewed. AV shunts were performed at the wrist in 95% of cases and in the cubital fossa in 13% of cases. The AV shunt had been performed an average of 29 months before renal transplantation. RESULTS: 62% of AV shunts were considered to be functional with a mean follow-up of 69 months after transplantation and 95 months after creation. The intraoperative and early and late postoperative thrombosis rates were 6%, 7.5% and 17%, respectively. The AV shunt was subsequently closed in 12 patients (7.5%). CONCLUSION: Native distal AV shunts, although not used after renal transplantation, have a prolonged survival. The main risk is thrombosis which can be prevented intraoperative and perioperatively. These results encourage a conservative attitude to all well tolerated AV shunts.

[Economic contribution of mofetil mycofenolate as preventive immunosuppressive treatment after renal transplantation from cadaver]. / Apport économique du mycophénolate mofétil comme traitement immunosuppresseur prophylactique après transplantation rénale de cadavre.

OBJECTIVES: The economic impact resulting from the clinical consequences of immunosuppressive strategy using mycophenolate mofetil in new renal transplant recipients was conducted considering the viewpoint of the health insurance system. METHODS: The analysis was based on the results of three controlled randomized double-blind clinical trials comparing mycophenolate mofetil with placebo or azathioprine in 1003 out of 1493 included patients respectively. Health care costs associated with each event were determined by 7 French experts in renal transplantation working in six different hospitals. Direct cumulative costs for each strategy were compared. RESULTS: The studies demonstrated a difference in the incidence of acute rejection and treatment failures whatever the cause. The three trials showed that, compared with current strategies, use of mycophynolate mofetil in the immunosuppression protocol generated a 19 to 38% cost reduction during the 6 months after transplantation. Cost reduction resulted from lower incidence of acute rejection and the subsequent nephrectomics and dialysis sessions. The sensitivity analysis on the most important cost factors-cost of hospitalization per day and number of hospitalization days-confirmed strength of the results. CONCLUSION: Use of mycophenolate mofetil in the immunosuppressive prophylaxis protocol after renal transplantation allows a reduction in the direct costs during the 6 months following transplantation.

["De novo" cancer after organ transplantation]. / Les cancers "de Novo" après transplantation d'organe.

From March 1972 to 1st of January 1996, 804 kidney, liver and pancreas transplants were performed in 690 patients. 39 post transplant cancers occurred in 27 patients. 21 skin tumors (15 squamous cell carcinoma, 4 basocellular carcinomas, 1 squamous carcinoma, 1 melanoma), 4 squamous cancers (anus, esophagus, tongue, and parotid), 4 post-transplant lymphoproliferative disorders, 1 non-Hodgkin's lymphoma T, 4 gynecological tumors (breast, ovarian peritoneal carcinomatosis, 2 uterine cervix cancers), 4 miscellaneous tumors (larynx, right colon, brain, prostate, own kidney). 14 patients died (14/27: 52%). Post transplant de novo cancers are a major risk in transplant patients These cancers are mainly represented by skin tumors and lymphomas. Skin cancers are mainly spinocellular and occur in the areas which are exposed to the sun. Post transplant lymphoproliferative disorders are very close to Burkitt's lymphoma, they produced B lymphocyte proliferation due to the reduction of the control of T lymphocytes and induced by Epstein-Barr virus. They can disappear with the diminution of immunosuppression.

[Calcified intertrigo, a rare cause of cutaneous calcinosis]. / Intertrigo calcifie une forme rare de calcinose cutanee.

INTRODUCTION: Calcinosis cutis is classically described in patients presenting chronic renal failure with secondary hyperparathyroidism. There are three clinical types described in the literature: cutaneous necrosis (secondary to vascular calcification), panniculitis with calcification of the adipose tissue and necrosis of the skin and dermo-hypodermic calcinosis without necrosis usually called metastatic calcinosis. The latter can affect all tissues but skin involvement is rare. CASE REPORT: A case of calcinosis cutis is presented in a 50 years old woman with moderate secondary hyperparathyroidism and chronic renal failure caused by renal amyloidosis. She was referred by the renal unit to our service for erythematous, woody-hard, infiltrated plaques with petechial purpura satellite lesions, involving the flexural areas, that appeared within a few weeks. DISCUSSION: This observation is original by the topography of the cutaneous lesions the involvement of the fexural areas is unusual and by the histologic aspect of pseudoxanthome elastic-like. We must notice that the hyperparathyroidism had always been very moderate (normal parathormonemia) compared to the rapid development of an important dermic calcinosis.

Gastrointestinal surgical emergencies following kidney transplantation.

This study reports major gastrointestinal complications in a group of 416 patients following kidney transplantation. Three hundred and ninety-nine patients received a cadaveric kidney while the other 17 received a living related organ. The immunosuppressive regimen changed somewhat during the course of the study but included azathioprine, prednisolone, antilymphocyte globulin, and cyclosporin. Perforations occurred in the colon (n = 6), small bowel (n = 4), duodenum (n = 2), stomach (n = 1), and esophagus (n = 1). There were five cases of acute pancreatitis, four of upper gastrointestinal and two of lower intestinal hemorrhage, two of acute appendicitis, one of acute cholecystitis, one postoperative mesenteric infarction, and two small bowel obstructions. Fifty percent of the complications occurred while patients were being given high-dose immunosuppression to manage either the early postoperative period or episodes of acute rejection. Ten percent of the complications had an iatrogenic cause. Of the 31 patients affected, 10 (30%) died as a direct result of their gastrointestinal complication. This high mortality appears to be related to the effects of the immunosuppression and the associated response to sepsis. Reduction of these complications can be achieved by improved surgical management, preventive measures, prompt diagnosis, and a reduced immunosuppressive protocol.

[Neurotoxicity of acyclovir in peritoneal dialysis apropos of 1 case]. / Neurotoxicité de l'aciclovir chez le dialysé péritonéal à propos d'un cas.

We report a case of reversible myoclonic encephalopathy which appeared after intravenous acyclovir treatment in a patient in CAPD for which pharmacological dosages have been made in serum, peritoneal dialysate and cerebrospinal fluid (CSF). Encephalopathy appeared after two intravenous doses of 7.33 mg/kg (doses higher than recommended), administered on admission and 16 hours later. Pharmacological dosages indicated that acyclovir peritoneal clearance was negligible, and that acyclovir persisted a long time in plasma and CSF. Neurological symptoms persisted although serum concentrations returned to normal value. The diagnostic value of pharmacological dosages in serum and CSF is discussed. In addition, neurological symptoms disappeared following two consecutive hemodialysis procedures. Hence we suggest that hemodialysis could be used for drug removal in case of acyclovir overdose in CAPD patients.