An avoidable cause of thymoglobulin anaphylaxis.

BACKGROUND: Thymoglobulin® (anti-thymocyte globulin [rabbit]) is a purified pasteurised, gamma immune globulin obtained by immunisation of rabbits with human thymocytes. Anaphylactic allergic reactions to a first injection of thymoglobulin are rare. CASE PRESENTATION: We report a case of serious anaphylactic reaction occurring after a first intraoperative injection of thymoglobulin during renal transplantation in a patient with undiagnosed respiratory allergy to rabbit allergens. CONCLUSIONS: This case report reinforces the importance of identifying rabbit allergy by a simple combination of clinical interview followed by confirmatory skin testing or blood tests of all patients prior to injection of thymoglobulin, which is formally contraindicated in patients with a history of hypersensitivity to rabbit proteins.

Are there any additional mechanisms for haemolysis in HELLP syndrome?

HELLP syndrome is a microangiopathy that leads to severe maternal complications. The objective of this study was to identify any additional mechanisms that could have contributed to HELLP syndrome-induced haemolysis. This is a pilot, prospective and observational study that lasted 9months. All patients with HELLP syndrome treated at academic tertiary care women hospital accepted to participate. Sixteen patients were included. In ten patients (63%), schizocytes were detected following a blood smear test. Six patients (38%) were diagnosed with a partial expression deficiency of proteins regulating the complement system (CD 55 or CD 59). In nine patients (56%), an activation of the complement classical pathway was detected. In two patients (13%), an ADAMTS 13 activity below 30% was detected. Three patients (19%) were diagnosed with a folate deficiency and one (6%) with an antiphospholipid syndrome. All patients developed maternal or fetal morbidity including nine (56%) an acute kidney injury. All patients but one had at least one additional mechanism that could contribute to haemolysis, besides a simple physical injury. Larger studies should be promoted to understand haemolysis in HELLP syndrome.

Cardiac troponin-I on diagnosis predicts early death and refractoriness in acquired thrombotic thrombocytopenic purpura. Experience of the French Thrombotic Microangiopathies Reference Center.

BACKGROUND: Cardiac involvement is a major cause of mortality in patients with thrombotic thrombocytopenic purpura (TTP). However, diagnosis remains underestimated and delayed, owing to subclinical injuries. Cardiac troponin-I measurement (cTnI) on admission could improve the early diagnosis of cardiac involvement and have prognostic value. OBJECTIVES: To assess the predictive value of cTnI in patients with TTP for death or refractoriness. PATIENTS/METHODS: The study involved a prospective cohort of adult TTP patients with acquired severe ADAMTS-13 deficiency (< 10%) and included in the registry of the French Reference Center for Thrombotic Microangiopathies. Centralized cTnI measurements were performed on frozen serum on admission. RESULTS: Between January 2003 and December 2011, 133 patients with TTP (mean age, 48 ± 17 years) had available cTnI measurements on admission. Thirty-two patients (24%) had clinical and/or electrocardiogram features. Nineteen (14.3%) had cardiac symptoms, mainly congestive heart failure and myocardial infarction. Electrocardiogram changes, mainly repolarization disorders, were present in 13 cases. An increased cTnI level (> 0.1 µg L(-1) ) was present in 78 patients (59%), of whom 46 (59%) had no clinical cardiac involvement. The main outcomes were death (25%) and refractoriness (17%). Age (P = 0.02) and cTnI level (P = 0.002) showed the greatest impact on survival. A cTnI level of > 0.25 µg L(-1) was the only independent factor in predicting death (odds ratio [OR] 2.87; 95% confidence interval [CI] 1.13-7.22; P = 0.024) and/or refractoriness (OR 3.03; 95% CI 1.27-7.3; P = 0.01). CONCLUSIONS: A CTnI level of > 0.25 µg L(-1) at presentation in patients with TTP appears to be an independent factor associated with a three-fold increase in the risk of death or refractoriness. Therefore, cTnI level should be considered as a prognostic indicator in patients diagnosed with TTP.

[Impact of end-stage renal disease and kidney transplantation on the reproductive system]. / Impact de l'insuffisance rénale chronique et de la greffe rénale sur la fonction reproductive.

Chronic renal failure leads to many metabolic disorders affecting reproductive function. For men, hypergonadotropic hypogonadism, hyperprolactinemia, spermatic alterations, decreased libido and erectile dysfunction are described. Kidney transplantation improves sperm parameters and hormonal function within 2 years. But sperm alterations may persist with the use of immunosuppressive drugs. In women, hypothalamic-pituitary-ovarian axis dysfunction due to chronic renal failure results in menstrual irregularities, anovulation and infertility. After kidney transplantation, regular menstruations usually start 1 to 12 months after transplantation. Fertility can be restored but luteal insufficiency can persist. Moreover, 4 to 20% of women with renal transplantation suffer from premature ovarian failure syndrome. In some cases, assisted reproductive technologies can be required and imply risks of ovarian hyperstimulation syndrome and must be performed with caution. Pregnancy risks for mother, fetus and transplant are added to assisted reproductive technologies ones. Only 7 authors have described assisted reproductive technologies for patients with kidney transplantation. No cases of haemodialysis patients have been described yet. So, assisted reproductive technologies management requires a multidisciplinary approach with obstetrics, nephrology and reproductive medicine teams' agreement.

Anti-viral therapy in haemodialysed HCV patients: efficacy, tolerance and treatment strategy.

BACKGROUND: In end-stage renal disease (ESRD) patients, hepatitis C virus (HCV) eradication improves patient and graft survival. AIM: To determine optimal use of erythropoietin (EPO) and ribavirin, to compare ribavirin concentrations with those of HCV patients having normal renal function and to evaluate sustained virological response (SVR) in a prospective observatory of ESRD candidates for renal transplantation. METHODS: Thirty-two naïve patients were treated with Peg-IFN-α2a and ribavirin. Two different schedules of ribavirin and EPO administration were used: starting ribavirin at 600mg per week and adapting EPO when haemoglobin (Hb) fell below 10g/dL (adaptive strategy) or starting ribavirin at 1000mg per week while increasing EPO from the start of treatment (preventive strategy). RESULTS: Patients treated with the adaptive strategy had lower median Hb levels (9.6 vs. 10.9g/dL, P=0.02) and more frequent median Hb levels below 10g/dL (58 vs. 5%, P=0.0007) despite lower median ribavirin doses (105 vs. 142mg/day, P<0.0001) than patients treated with the preventive strategy. There was a trend for more frequent transfusion in patients treated with the adaptive strategy than in patients treated with preventive strategy (50 vs. 20%, P=0.08). Compared to patients with normal renal function, ESRD patients had lower ribavirin concentrations during the first month (0.81 vs. 1.7mg/L, P=0.007) and similar concentrations thereafter. SVR was reached in 50%. CONCLUSIONS: Pegylated interferon (Peg-IFN) and an adapted schedule of ribavirin are effective in ESRD patients. Increasing EPO from the start of treatment provides better haematological tolerance. The optimal dosage of ribavirin remains unresolved, in light of frequent side effects.

Long-Term Impact of Cyclosporin Reduction with MMF Treatment in Chronic Allograft Dysfunction: REFERENECE Study 3-Year Follow Up.

Calcineurin inhibitor (CNI) toxicity contributes to chronic allograft nephropathy (CAN). In the 2-year, randomized, study, we showed that 50% cyclosporin (CsA) reduction in combination with mycophenolate mofetil (MMF) treatment improves kidney function without increasing the risk for graft rejection/loss. To investigate the long-term effect of this regimen, we conducted a follow up study in 70 kidney transplant patients until 5 years after REFERENCE initiation. The improvement of kidney function was confirmed in the MMF group but not in the control group (CsA group). Four graft losses occurred, 2 in each group (graft survival in the MMF group 95.8% and 90.9% in control group). One death occurred in the control group. There was no statistically significant difference in the occurrence of serious adverse events or acute graft rejections. A limitation is the weak proportion of patient still remaining within the control group. On the other hand, REFERENCE focuses on the CsA regimen while opinions about the tacrolimus ones are still debated. In conclusion, CsA reduction in the presence of MMF treatment seems to maintain kidney function and is well tolerated in the long term.

Long-term kinetics of a T-lymphocytes subset in kidney transplant recipients: relationship with posttransplant malignancies.

UNLABELLED: Immunosuppression is associated with a high incidence of malignancies among renal transplant patients. In this study, we investigated the relationship between CD4 lymphopenia and the development of posttransplant malignancy (PTM) after induction therapies in renal transplant recipients (RTR). PATIENTS AND METHODS: This retrospective study included 966 RTR who were transplanted between 1993 and 2005 and had a mean follow-up of 83 +/- 46 months. Induction with antithymocyte globulin (ATG) was employed in 747 patients, while remaining 219 recipients received anti-CD25 antibodies. CD4 T-cell counts determined yearly were correlated with the occurrence of PTM. RESULTS: Eighty-five (8.8%) patients developed a PTM: cutaneous neoplasia (n = 33), lymphoma (n = 14), noncutaneous solid cancer (n = 36). Only age was observed to be significantly different among patients with versus without PTM (48 +/- 10 vs 41 +/- 12 years; P < .001). An early CD4 lymphopenia (<300/mm(3)) was frequent after ATG as compared with anti-CD25 induction (69.8% vs 12.1% at 3 months; P < .0001). The proportion of T CD4 lymphopenic patients progressively decreased over time remaining stable at 5- and 10-year follow-ups (12% and 10.8%, respectively). However, CD4 lymphopenia was not associated with a greater incidence of PTM. CONCLUSION: ATG induced CD4 lymphopenia, which persisted in a small proportion of patients in the long term, but did not seem to be correlated with the occurrence of PTM.

[Weaning from corticosteroid therapy after kidney transplantation]. / Sevrage de la corticothérapie après transplantation rénale.

For years, the numerous side effects of long term steroid administration have motivated their elimination from the immunosuppressive regimen in renal transplantation. However until the 90's, steroid withdrawal induced an increase in the incidence of acute rejection episodes, and some studies described a significant risk of graft loss. New immunosuppressive drugs (tacrolimus, mycophenolate and mTOR inhibitors) have led to reevaluate steroid discontinuation. Recent trials with these drugs have shown that late steroid withdrawal (3 months post-transplant) was no more associated with a higher risk of acute rejection or graft loss. Some studies have demonstrated an improvement in the cardiovascular risk factors and a decreased incidence of infections and osteoporosis. Its positive impact on patient survival remains to be confirmed in long term follow-up studies.

[Immunosuppressive strategies and chronic graft dysfunction in kidney transplantation]. / Stratégies immunosuppressives et dysfonction chronique du greffon en transplantation rénale.

Chronic graft dysfunction is a major cause of return to dialysis. In the majority of cases, it is correlated with histological signs of cellular and/or humoral rejection, the nephrotoxicity of anticalcineurins, or nonspecific lesions of interstitial fibrosis and tubular atrophy. Although the incidence of acute rejection has considerably decreased, renal toxicity of the calcineurin inhibitors remains problematic. In cases of established nephrotoxicity, the use of non-nephrotoxic immunosuppressors such as mycophenolic acid or the proliferation signal inhibitors makes it possible to reduce or even stop the anticalcineurins. In prevention of anticalcineurin nephrotoxicity, many attempts to minimize or wean patients from them have shown that improvement in renal function is only obtained at the cost of an increase in the incidence of acute rejection. This makes it necessary to select patients who may benefit from anticalcineurin-sparing treatment, based on clinical, histological, and biological markers. Finally, long-term follow-up is also fundamental in order to validate the positive impact on renal function of this strategy in terms of graft survival.

Impact of cyclosporine reduction with MMF: a randomized trial in chronic allograft dysfunction. The 'reference' study.

Long-term use of calcineurine inhibitors (CNIs) may contribute to the development of chronic allograft dysfunction (CAD). We investigate the impact of the introduction of MMF combined with cyclosporine (CsA) 50% dose reduction. An open, randomized, controlled, multicenter, prospective study was conducted in 103 patients, receiving a CsA-based therapy with a serum creatinine between 1.7-3.4 mg/dL, more than 1 year after transplantation. They were randomized to receive MMF with half dose of CsA (MMF group) or to continue their maintenance CsA dose (control group). A total of 96 weeks after randomization, the evolution of renal function assessed by regression line analysis of 1/SeCr improved in the MMF group (positive slope) vs. the control group (negative slope), 4.2 x 10(-4) vs. -3.0 x 10(-4), respectively (p < 0.001). Concurrently, the absolute renal function improved significantly in the MMF group. No episode of biopsy-proven acute rejection occurred. One patient in each group lost his graft because of biopsy-proven chronic allograft nephropathy. There was a significant decrease of triglycerides level in the MMF group. Anemia and diarrhea were statistically more frequent in the MMF group. In CAD, the reduction of CsA in the presence of MMF results in significant improvement in renal function during a 2-year follow-up.

Changes in growth factor and cytokine mRNA levels after hepatectomy in rat with CCl(4)-induced cirrhosis.

Cirrhotic liver is considered to regenerate less actively than normal liver after hepatic resection. However, the mechanisms responsible for this impaired regeneration and the cross talk of implicated factors still remain unclear. In the present study, mRNA levels for cyclins, growth factors, and cytokines were quantitatively assessed by a RT-PCR method at different times after hepatectomy in order to determine the relationships between these factors and the impaired regenerative process observed in cirrhotic liver. In our model of CCl(4)-induced cirrhosis, mRNA levels for cyclins and thymidine kinase provide evidence for the impaired and delayed hepatic regeneration. Moreover, we observed a significant decrease in interleukin (IL)-6 and tumor necrosis factor-alpha mRNA and a significant increase for IL-1beta mRNA. No significant change of hepatocyte growth factor (HGF) mRNA level was detected, contrasting with the decrease both at mRNA and protein levels in the expression of the c-Met/HGF receptor. Therefore, the impaired regeneration of the cirrhotic liver is associated not only with a lowered level of signals that normally promote liver growth but also with a strong decrease in c-Met receptor despite a normal expression of its specific ligand.

[Bartter's syndromes]. / Les syndromes de Bartter.

Bartter syndromes are defined as a family of inherited recessive autosomal tubulopathies. They are characterized by hypochloremia, hypokalemia, metabolic alkalosis associated with potassium renal leakage and normal blood pressure despite increased plasma renin activity. Three forms of the disease are identified as followed: 1) Gitelman syndrome or hypocalciuria hypomagnesemia syndrome is a mild form often discovered in childhood or teenagers in reason of tetany. It is an homogeneous disorder related to mutations of the genes encoding the thiazide-sensitive Na-Cl cotransporter located in the distal convoluted tubule. 2) Antenatal Bartter syndrome with hypercalciuria and nephrocalcinosis or hyperprostaglandin E syndrome is a severe form, often revealed by hydramnios, prematurity and growth delay. It is related to mutations of two types of genes encoding for transporters of Henle's loop: the bumetanide-sensitive cotransporter Na-K-2Cl (NKCC2) [type I] or the inwardly-rectifying potassium channel (ROMK) [type II]. 3) the classical form or type III Bartter syndrome, often revealed by dehydration in the first year of life, is associated with hypomagnesemia in 20% of cases and normal or increased calciuria. This form is related to mutations of CLCNKB gene encoding for a chloride channel in Henle's loop. This classification, in part related to the demonstration of mutations in the genes encoding for tubular chloride or potassium channels, does not fit all cases, overlapping syndromes are frequent. Moreover some endocrinological (diabetes) and neurological (deafness) abnormalities are sometimes associated with Bartter syndromes. Both phenotypic and genetic approach must help to the diagnosis of these tubulopathies.

[Granulomatous interstitial nephritis with acute renal insufficiency, a potential complication of intravesicular bcg therapy]. / Néphrite interstitielle granulomateuse avec insuffisance rénale aiguë, une complication potentielle de la BCGthérapie intravésicale.

Intravesical Bacillus Calmette-Guerin has proved to be the most effective treatment of superficial bladder carcinoma. This therapy may induce a renal failure of variable severity, sometimes associated with multiple organ failure. Renal prognosis of this complication is not well defined. We report on a 68 year-old male patient who developed granulomatous hepatitis and acute tubulo-interstitial nephritis with mononuclear infiltrates containing numerous epithelioid cells, following the third course of intravesical BCG. Eleven cases of renal impairment due to intravesical BCG have been previously described, as part of a systemic disease in seven patients. The potential pathophysiological mechanisms of this rare complication are precised.

The invasion of the rabbit intestinal tract by Eimeria intestinalis sporozoites.

To follow the route of migration of Eimeria intestinalis sporozoites from the excystation stage to their development in the epithelial cells of the ileum, we inoculated sporocysts into the duodenum of coccidia-free rabbits and euthanized the animals at 10 min to 12 h post-inoculation. Excystation occurred at less than 10 min after the experimental infection. The sporozoites penetrated into the epithelium of the duodenum at as early as 10 min post-inoculation; 6 h later, the number of sporozoites had dramatically decreased in the duodenal mucosa, with a corresponding increase being noted in the ileal mucosa. These findings suggest that sporozoites invade the duodenal epithelium and migrate to the ileum by an as yet unknown nonlumenal tissue route.

Eimeria sp. from the rabbit (Oryctolagus cuniculus): pathogenicity and immunogenicity of Eimeria intestinalis.

The pathogenicity and immunogenicity of Eimeria intestinalis was evaluated in SPF rabbits. The animals were given immunizing doses of 6, 6 x 10(2), 6 x 10(3), and 6 x 10(4) sporulated oocysts and were challenged with 3 x 10(3) oocysts. The criteria analysed were the daily weight gain and the oocyst output. This study showed that E. intestinalis had strong immunogenicity, as the inoculation of 6 oocysts was sufficient to minimize the clinical expression of the disease following the challenge and to reduce the oocyst output by about 60%. The immunity towards the excretion of oocysts and the illness was absolute in animals inoculated with 600 or more oocysts. Moreover, this protection seemed to be efficient at least 8 weeks after the challenge. The present results also confirm the pathogenicity of E. intestinalis, although the occurrence of diarrhoea may be irregular, and emphasize the fact that the capacity of this Eimeria for multiplication is not a criterion for clinical diagnosis of the disease.

Selection and characterization of a precocious line of Eimeria intestinalis, an intestinal rabbit coccidium.

A precocious line of Eimeria intestinalis was obtained by selection for early development of oocysts in rabbits and after six consecutive passages in animals. This line (EiP) was derived from a wild strain (EiO) isolated in 1975 from the caecal content of a rabbit with coccidiosis. The prepatent period of the EiP strain was reduced from 215 h to less than 144 h, the result being that the oocyst sporulation time was the same for both lines. The excreted and unsporulated oocysts had exactly the same shape, but microscopical examination of the sporulated oocysts showed a marked difference between EiP and EiO strains. A huge refractile globule was located in each of two sporocysts of the precocious line, whereas no refractile globule was seen in the other two. The EiP line had a reproductive potential much lower (1000 times) than that of its parent strain EiO and, as judged by the weight gain, mortality and lesions that also occurred in the jejunum and above all in the ileum, its pathogenicity was substantially reduced.

[Changes in plasma parameters in rabbit does as a function of their physiological state and feed rationing]. / Evolution de paramètres plasmatiques chez des lapines reproductrices en fonction de l'état physiologique et du rationnement alimentaire.

We followed the evolution of hematocrit and of plasma Na, K, Cl, total protein, creatinine, Pi, alkaline phosphatases, triglycerides, cholesterol, glucose and GPT. The amount of feed given to the rabbit does was restricted to 75 percent of the quantity eaten ad libitum, in similar conditions to those of intensive breeding. This had a slight effect on the values obtained for plasmatic components in healthy rabbits. This was not dependent on the timing of blood collection, nor on the physiological state of the animal. The changes in biochemical composition of the plasma due to pregnancy in healthy rabbit does are: a fall in total plasma protein and cholesterol levels, alkaline phosphatases activity, hematocrit, and a rise followed by a marked fall in plasma triglycerides level. During lactation, these levels return progressively to the values obtained in non-pregnant, non-lactating rabbits.

[The pathology of ther reproducing female rabbit: a comparative, descriptive study of morbidity phenomena observed during the reproduction o purebred strains of rabbit]. / Pathologie des lapines reproductrices: étude descriptive comparative des phénomènes morbides observés lors de la reproduction de deux souches pures de lapin.

We analysed the working life of purebred New Zealand, and Californian rabbit breeding does kept in identical conditions. Our study notes the health of the does as well as various factors affecting the survival rate of baby rabbits until weaning. After the first six months of rearing the productivity and the health of the two breeds were very different. The Californian females came through their first two gestations and lactations very well but more than half of them showed signs of respiratory ailments, and many had to be eliminated. Their first two litters were characterised by a low number of baby rabbits weaned as well as a large number of whole litters dead before weaning. The females of the New Zealand breed were in good health but then died suddenly at the end of gestation or in the middle of lactation; the surviving females raised practically their whole litter until weaning. The loss of animals is numerically fairly similar in the two breeds but takes on different farms. This comparative study of the elimination of the does, of their mortality, or of that of the baby rabbits during lactation leads us to the hypothesis that these three phenomena are probably different manifestations of the same pathological phenomena occurring early on, probably from the first gestation onwards.

[Pathology among breeding does. Evolution of several plasma parameters among primiparous rabbit does]. / Pathologie des reproductrices. Evolution de quelques paramètres plasmatiques chez des lapines primipares.

One of the most important limiting factors of rabbit production is reproductive pathology. This pathology has two aspects: livestock reduction (elimination and death of rabbit does) and mortality of young rabbits before weaning. We studied alterations of hematocrit and of plasma Na, K, Ca, Mg, Pi, total proteins, prolactin, during gestation and lactation of primiparous rabbit does. In females which were going to die the first results showed a fall in plasma NaK, Ca concentrations and a rise in plasma Mg. We think that these alterations are only consequences of anterior metabolic alterations and are indicators or secondary causes of the animal's proximate death. We noticed a deep fall in plasma prolactin concentration before death; its signification is discussed. In the females which did not wean their whole litter, average prolacting levels during gestation and at the beginning of lactation were lower than in females weaning their whole litter. These first results would confirm the hypothesis that youngs' mortality is a pathology linked with dams' state.