Mycophenolate mofetil in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis: a prospective pharmacokinetics and clinical study.

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) treatment strategy is based on immunosuppressive agents. Little information is available concerning mycophenolic acid (MPA) and the area under the curve (AUC) in patients treated for AAV. We evaluated the variations in pharmacokinetics for MPA in patients with AAV and the relationship between MPA-AUC and markers of the disease. MPA blood concentrations were measured through the enzyme-multiplied immunotechnique (C(0), C(30), C(1), C(2), C(3), C(4), C(6) and C(9)) to determine the AUC. Eighteen patients were included in the study. The median (range) MPA AUC(0-12) was 50·55 (30·9-105·4) mg/h/l. The highest coefficient of determination between MPA AUC and single concentrations was observed with C(3) (P < 0·0001) and C(2) (P < 0·0001) and with C(4) (P < 0·0005) or C(0) (P < 0·001). Using linear regression, the best estimation of MPA AUC was provided by a model including C(30), C(2) and C(4): AUC = 8·5 + 0·77 C(30) + 4·0 C(2) + 1·7 C(4) (P < 0·0001). Moreover, there was a significant relationship between MPA AUC(0-12) and lymphocyte count (P < 0·01), especially CD19 (P < 0·005), CD8 (P < 0·05) and CD56 (P < 0·05). Our results confirm the interindividual variability of MPA AUC in patients treated with MMF in AAV and support a personalized therapy according to blood levels of MPA.

[Guidelines for the management of tuberous sclerosis complex renal disease]. / Atteintes rénales de la sclérose tubéreuse de Bourneville : recommandations de prise en charge.

PURPOSE: To review existing literature and deduce guidelines for the management of renal disease in patients with tuberous sclerosis complex (TSC). PATIENTS: After review of literature, a core panel of five physicians wrote a draft that was evaluated by 14 reviewers who used a 9-level scale (1: total disagreement; 9: total agreement). The guidelines were then reformulated until each item received a median score superior or equal to 8. RESULTS: Forty-eight to 80 % of TSC patients have significant renal involvement including angiomyolipomas (AMLs), cysts, malignant tumors and renal insufficiency. It is recommended to perform an abdominal ultrasound (and serum creatinine if abnormal ultrasound) when TSC is diagnosed. This work-up will be repeated every 3-5years if normal. Associated autosomal dominant polycystic kidney disease must be suspected in case of numerous and large cysts. After the age of 20, follow-up should use computed tomography (CT) or MRI that are more precise than ultrasound for the measurement of AMLs. Biopsy of a renal mass should be discussed in case of calcifications, necrosis or rapid growth. Females with TSC should undergo screening for pulmonary lymphangioleiomyomatosis by CT at the age of 18, and, if negative at the age of 30-40. Acute bleeding should be treated with percutaneous embolization. Asymptomatic angiomyolipomas with several risk factors (size>80mm, predominant vascular component, micro-aneurysms) should undergo prophylactic treatment, if possible using embolization. The role of mTOR inhibitors in the management of angiomyolipomas needs to be defined. CONCLUSION: Standardization of follow-up and treatment is necessary to improve the management of TSC renal involvement.

[Clinical variability and diagnosis steps in childhood mitochondrial disease]. / Variabilité clinique et conduite diagnostique des cytopathies mitochondriales : à propos d'une série de 18 cas pédiatriques.

OBJECTIVES: Mitochondrial respiratory chain deficiencies are known for their high clinical variability. Difficult to diagnose, the prevalence of these diseases is probably underestimated. METHODS: We report 18 children diagnosed with respiratory chain deficiency at the Tours University Hospital over the past 10 years. RESULTS: Three clinical profiles can be distinguished depending on the age at onset of the first symptoms: the neonatal period (4 cases), between 1 month and 2 years of age (10 cases), and after 10 years (4 cases). However, no clinical feature appears specific of any age group. In contrast, respiratory chain analysis on liver biopsy was very informative for all our patients at any age and with any clinical presentation, even with predominant neurological symptoms. CONCLUSIONS: These biochemical analyses support the diagnosis of mitochondrial disorders in view of molecular analysis, which nevertheless frequently remains inconclusive. These investigations should benefit from the new molecular screening technologies based on DNA chips that can identify the genomic mutations responsible for these severe and relatively frequent diseases.

Early pulse pressure and low-grade proteinuria as independent long-term risk factors for new-onset diabetes mellitus after kidney transplantation.

Risk factors for new-onset diabetes after transplantation (NODAT) need to be assessed in large cohorts. We retrospectively evaluated the impact of early (3 and 6 months after transplantation) proteinuria, urinary albumin excretion (UAE) and arterial pressure on NODAT in 828 Caucasian renal transplant recipients (median follow-up: 5.3 years; 5832 patient-years). The 10- and 20-year incidence of NODAT was 15.0% and 22.0%, respectively. Low-grade (<1 g/day) (HR: 2.04 [1.25-3.33], p = 0.0042) and very low-grade (<0.3 g/day) (HR: 2.21 [1.32-3.70], p = 0.0025) proteinuria were independent risk factors for NODAT. There was a dose-dependent relationship across UAE categories (increasing risk from normoalbuminuria to macroalbuminuria) with NODAT. Tacrolimus, sirolimus and beta-blockers (HR: 1.86 [1.07-3.22], p = 0.0277) were significantly associated with NODAT even after multiple adjustments, but not diuretics, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. Systolic arterial pressure (HR per 10 mmHg: 1.16 [1.03-1.29], p = 0.0126) and pulse pressure (HR: 1.26 [1.12-1.43], p = 0.0002) were associated with NODAT. Only pulse pressure remained significant after adjustments. Patients at highest risks had early proteinuria and pulse pressure >60 mmHg. Early low-grade proteinuria and pulse pressure (in addition to beta-blockers) constitute independent risk factors for NODAT; they may be markers of the metabolic syndrome and/or vascular damage in renal transplant recipients.

Estimation of the glomerular filtration rate through different methods in kidney transplant recipients: correlation with the creatinine clearance measurement.

The measurement of the glomerular filtration rate (GFR) is an important tool for physicians to follow kidney transplant recipients. Indeed, renal function has been shown to be predictive of graft outcome in retrospective studies. Several methods have been proposed to measure GFR. In the present study we evaluated the correlation of GFR between a reference method (calculation through the urine to plasma ratio of creatinine [UV/P] formula) and three estimation equations (Cockcroft and Gault; Nankivell; modification of diet in renal disease) in 81 kidney transplant recipients at 3 and 12 months posttransplantation. We showed a significant correlation between the three predictive formulas and UV/P, but none of the predictive equations showed an excellent correlation. The best correlation between an estimation equation and the UV/P formula was the CG formula. Further studies are required to compare the estimated GFR with better reference methods, such as the use of isotopic markers in kidney graft recipients.

Early proteinuria is a strong indicator of donor renal lesions, ischemia-reperfusion injury and immunological aggression.

BACKGROUND: Early proteinuria is associated with reduced long-term graft survival. However, the determinants and mechanisms of proteinuria early after transplantation have not been identified. METHODS: Parameters associated with proteinuria within the first 3 months following transplantation were retrospectively assessed among 484 renal transplant recipients. RESULTS: Proteinuria was more abundant in patients with a history of two or more rejection episodes (0.42 +/- 0.68 vs 0.18 +/- 0.39 g/d; P = .02). Proteinuria was greater when donor age was 60 or more (OR: 4.43; P = .003), when recipient death was due to cardiovascular causes (OR: 1.98; P = .002), or when cold (OR: 1.77; P = .006) or warm (1.21; P = .09) ischemia times were prolonged. CONCLUSIONS: Proteinuria early after transplantation was related to pretransplant renal lesions, ischemia-reperfusion, and immunologic injuries.

Harvesting organs for paediatric transplantation: medical features.

The progress in organ transplantation has led to a rise in the demand for organs. Paediatric intensive care units are the main source for obtaining organs. Every "brain dead" patient should be regarded as a potential donor. General contraindications to organ donation are: systemic viral or bacterial infections and extra-cerebral malignancy. They are also organ-specific contraindications. The criteria for the diagnosis of "brain death" have been widely studied and defined. Care of brain dead donors consists of maintenance of cardiac, pulmonary and renal function. Monitoring requires control of central venous and arterial blood pressure, core temperature, urine flow, heart rate and biological data on both urine and blood. A 5% dextrose infusion is maintained with added potassium and sodium chloride according to the urine flow, detectable water loss, and blood and urine composition. Hypotension due to hypovolaemia requires immediate treatment with blood, colloid or albumin infusion. Persistent hypotension with cardiac pump failure is treated with inotropic agents: dopamine and/or dobutamine. Raised urine flow due to diabetes insipidus requires desmopressin (dDAVP). Progress in organ collection requires the consent of the parents and highly motivated medical teams.

Human lymphocyte adhesion to xenogeneic porcine endothelial cells: modulation by human TNF-alpha and involvement of VLA-4 and LFA-1.

Considering that in the allogeneic situation the adhesion of recipient lymphocytes to donor endothelial cells initiates the cellular rejection, we questioned the possible occurrence of a similar process in the xenogeneic situation. The adhesion of human peripheral blood lymphocytes (PBL) to porcine aortic endothelial cells (PAEC) was thus studied in an in vitro porcine-to-human xenogeneic model. It was found that 25.9% of human PBL adhered to resting PAEC. Furthermore, this adhesion increased significantly when the PAEC were stimulated by the human cytokine TNF-alpha (tumor necrosis factor-alpha). The effect of human TNF-alpha was concentration- and time-dependent and was maximal (from 25.9% to 35.6%) with 100 U/ml during 6 h. Moreover, blocking experiments with monoclonal antibody (mAb) demonstrated the role of the PBL adhesion molecules LFA-1 and especially VLA-4. Indeed, an anti-CD11a mAb decreased PBL adhesion to resting PAEC by 17.1% and to TNF-alpha stimulated PAEC by 16.9%, whereas an anti-CD49d mAb decreased dramatically PBL adhesion to resting PAEC by 53.1% and to TNF-alpha stimulated PAEC by 41.0%. Finally, phenotypic analysis of the adherent PBL showed that 50.5% of adherent cells to resting PAEC were NK (natural killer) cells, whereas 50.7% of adherent cells to TNF-alpha stimulated PAEC were T lymphocytes, showing the preferential adhesion of NK cells to resting PAEC, and that the stimulation of the PAEC with human TNF-alpha affects predominantly T lymphocyte adhesion. These results indicate that human PBL could bind to xenogeneic PAEC and that this interaction could be a first step of a xenogeneic cellular rejection.

Evaluation in patients with Alport syndrome of knowledge of the disease and attitudes toward prenatal diagnosis.

Cloning of the COL4A5 gene has now made possible prenatal testing for Alport syndrome with X-linked dominant inheritance. We interviewed 27 females and 24 males with Alport syndrome to evaluate their knowledge of the disease and its transmission, and their attitudes to prenatal testing. Twenty-two males and 8 females were on renal replacement therapy. In all cases transmission was compatible with X-linked disease. Only 59% of the interviewees (74% of women, 42% of men) knew that gender was the major determinant in progression of the disease. Knowledge of the mode of inheritance was adequate in only 25%, in both sexes. Seventy percent of the participants (78% of women, 63% of men) would use prenatal testing. Of the women in favor of prenatal diagnosis, 67% and 39% would terminate pregnancy in the case of an affected male or female fetus, respectively. Of the men in favor of prenatal diagnosis, 53% would consider termination of an affected fetus. In summary, a majority would use prenatal testing, but only one or two thirds of them wished to use selective abortion. As in other inherited disorders, there is a discrepancy between the demand for prenatal diagnosis and the decision to terminate pregnancy. Most of the participants who would terminate a pregnancy had, however, little knowledge of the clinical and genetic aspects of Alport syndrome on which to base such a decision. An important aspect of genetic counselling is to assist consultants in reaching a decision regarding future reproductive behaviour which is appropriate to their situation. This study underlines the need to improve education and counselling to assure appropriate use of prenatal testing.

Ureteral endometriosis revealed by an acute renal failure.

The authors report a case of an acute renal failure secondary to an obstructive bilateral ureteral endometriosis. They show the limits of the clinical diagnosis as well as the limits of additional explorations and discuss the therapeutic management at the time and in the after effects of the initial acute period.

[Is smoking history a risk factor of arterial hypertension in men?]. / Le tabagisme ancien est-il un facteur de risque d'HTA chez l'homme?

Former smokers exhibit decreased cardiovascular risk as compared to smokers who continue to smoke. However, smoking discontinuation results in weight gain which may be important and influence arterial pressure. From January 1st to June 30th, 1998, 12,417 volunteers (aged 20 to 69) were examined at the "Institut régional pour la santé" (IRSA, Regional Institute for Health), a group of 9 social medical centres in Western and Central France. The subjects were screened for a routine medical and biological check-up provided by their medical insurance. All of the subjects were interviewed by a trained nurse who completed a standardised questionnaire regarding personal medical history, current treatments and lifestyle behaviours (especially alcohol and smoking habits). A physician recorded clinical parameters including age, weight, height, systolic and diastolic arterial pressure. Body mass index (BMI) was calculated. Non smokers and former smokers represented 40.0% and 23.8% of the population respectively. The prevalence of a BMI 27.0 kg/m2 or greater was higher in former smokers than non smokers and current smokers. Systolic and diastolic arterial pressure in former smokers exceeded those of current smokers and non smokers by 4.2/1.1 mmHg and 2.8/1.6 mmHg respectively. Using logistic regression analysis, the relative risk of hypertension in former smokers was 1.24 (CI 95%: 1.10-1.39, p < 0.001) and 1.13 (0.995-1.29, p = 0.055) as compared to non smokers and current smokers, after adjustment for age and alcohol intake. Differences became non significant when BMI was entered in the model. The results of the present study suggest that former smoking status is associated with a higher prevalence of overweight which may cause a higher prevalence of hypertension.

[Microalbuminuria in hypertensive, non-proteinuric renal transplant recipients: role of previous acute rejection episodes and sodium intake]. / Micro-albuminurie chez le transplanté rénal hypertendu non protéinurique: influence des antécédents de rejet aigu et de l'apport sodé.

UNLABELLED: Microalbuminuria (Malb: albuminuria: 30-299 mg/24 h) is associated with many cardiovascular parameters (high systolic (SAP) and diastolic (DAP) arterial pressure, total cholesterol, triglycerides, fasting glucose and body weight, low HDL-cholesterol) and may be a marker of cardiovascular and renal risk in the general population. Whether MAlb could be an integrated marker of cardiovascular and renal risk in transplant recipients is unknown. PATIENTS AND METHODS: 75 hypertensive non-proteinuric renal transplant recipients were selected. Antihypertensive medications were stopped for a month prior to the studies. MAlb (on a 24-hour urine collection), cyclosporine trough levels (CsA-L), fasting glucose and lipids were measured. SAP and DAP were determined with a semi-automatic device. RESULTS: 29 patients (12 W/17M) had normal levels of albuminuria (Nalb: albuminuria < 30 mg/24 h) and 46 had MAlb. As compared to Nalb patients, those with Malb were younger (M +/- SD: 44.3 +/- 13 vs 51.2 +/- 9.7 respectively, p = 0.009), had higher SAP (152 +/- 16 vs 146 +/- 15 mmHg, p = 0.09) et DAP (86 +/- 11 vs 81 +/- 10 mmHg, p = 0.01). No difference in smoking habits, serum creatinine (125 +/- 27 vs 119 +/- 28 mumol/L), total-, HDL- and LDL-cholesterol, triglycerides, fasting glucose, CsA-L (142 +/- 29 vs 144 +/- 26 ng/mL), 24 h-urine urea excretion was observed. History of acute rejection episodes (45.7% vs 17.2%, p = 0.01) was more frequent and 24-hour natriuresis (192 +/- 70 vs 152 +/- 79 mmol/24 h, p < 0.01) was higher in Malb than in Nalb. CONCLUSION: The determinants of microalbuminuria in renal transplant recipients are different from those found in the general population. History of acute rejection episodes was more frequent in renal transplant recipients with Malb than in those with NAlb despite similar renal function, suggesting that Malb may a marker of subclinical renal lesions due to immunological aggression. The relationship between natriuresis and Malb suggests that sodium intake modulates target-organ damage associated with hypertension.

[Arterial hypertension due to mercury poisoning: diagnostic value of captopril]. / Hypertension artérielle par intoxication au mercure: intérêt diagnostique du captopril.

BACKGROUND: Mercury poisoning is a rare cause of hypertension in children. Urinary excretion sometimes remains low despite severe clinical intoxication. CASE REPORT: A 32 month-old girl was admitted with hypertension, tachycardia, apathy, irritability and excessive sweating. Erythromelalgia and neurologic symptoms permitted the diagnosis of acrodynia. Urine mercury remained normal until chelation. Captopril significantly increased urine mercury concentration but failed to improve clinical manifestations. Clinical improvement required infusions of BAL for 5 days then oral dimercaptosuccinic acid for 3 months. Metal vapors originated from the mercury which spilled from a broken thermometer onto the carpet. COMMENTS: Low basal urine mercury could be associated with real mercury poisoning. Small amounts of metal mercury held in a thermometer could produce a high level of mercury vapor leading to intoxication in young children. The binding capacity of metal ions by captopril could be used to increase urine mercury output. Nevertheless, captopril therapy fails to improve acrodynia. Total elimination of mercury requires long-term therapy with BAL or dimercaptosuccinic acid. CONCLUSIONS: An unexpected mode of intoxication and low basal urine mercury are not decisive arguments against mercury poisoning, which is the only cause of acrodynia.

[Idiopathic nephrosis (minimal glomerular lesions, segmental and focal hyalinosis)]. / La néphrose idiopathique (lésions glomérulaires minimes, hyalinose segmentaire et focale).

Idiopathic nephrosis, the most common cause of nephrotic syndrome, is histologically defined by minimal glomerular changes, diffuse mesangial proliferation or focal and segmental glomerulosclerosis. The response to corticosteroids carries greater prognostic weight than the histological features seen on the initial renal biopsy. The severity of the condition lies in the risk of relapses which occurs in more than half of cases when steroid dosage is decreased (steroid dependency), then requiring, in case of steroid toxicity, the use of alkylating agents or, more recently, cyclosporine. In 10% of the cases, nephrosis is steroid resistant and the severity of the disease lies in the risk of developing end stage renal failure which occurs in nearly one half of those cases.

Kidney damage due to tuberous sclerosis complex: management recommendations.

OBJECTIVE: To deduce recommendations from the literature on the management of kidney damage caused by tuberous sclerosis complex (TSC). MATERIAL AND METHODS: Five practitioners have written up recommendations after reviewing the literature. They were evaluated by 14 experts using a 9 level scale (1: complete disagreement; 9: complete agreement), then reworded until each item received a median score of greater than or equal to 8. RESULTS: Forty-eight to 80% of patients with TSC have kidney disease with the presence of angiomyolipomas (AML), cysts, cancers and/or progression towards renal insufficiency. An abdominal ultrasound (and serum creatinine level if there is an abnormality) is recommended as soon as the TSC is diagnosed. The evaluation should be repeated every 3 to 5 years if it is normal. Numerous and voluminous cysts are suggestive of associated polycystosis. After 20 years of age, the monitoring should be based on CT scan or MRI, which are more precise in the monitoring of AML. The biopsy of a renal mass should be discussed if there are calcifications, central necrosis or rapid growth. Lymphangioleiomyomatosis should be screened for in women via pulmonary CT scan at 18 and 30 to 40 years of age. Haemorrhagic rupture of an AML should be treated in first-line by embolisation. Asymptomatic AMLs that cumulate risk factors for bleeding (size >80 mm, predominant vascular contingent, micro-aneurisms) should be preventively treated, if possible by embolisation. The role of mTOR inhibitors remains to be defined. CONCLUSION: Monitoring and a standardised treatment are necessary to improve the treatment of renal damage caused by TSC.