In vitro sensitivity to methyl-prednisolone is associated with clinical response in pediatric idiopathic nephrotic syndrome.

The aim of this study was to evaluate the in vitro steroid sensitivity as a predictor of clinical response to glucocorticoids in childhood idiopathic nephrotic syndrome (INS). Seventy-four patients (median age 4.33, interquartile range [IQR] 2.82-7.23; 63.5% male) were enrolled in a prospective multicenter study: in vitro steroid inhibition of patients' peripheral blood mononuclear cell proliferation was evaluated by [methyl-(3) H] thymidine incorporation assay at disease onset (T0) and after 4 weeks (T4) of treatment. Steroid dependence was associated with increased in vitro sensitivity at T4 assessed both as drug concentration inducing 50% of inhibition (IC50 ; odds ratio [OR] = 0.48, 95% confidence interval [CI] = 0.24-0.85; P = 0.0094) and maximum inhibition at the highest drug concentration (Imax ; OR = 1.13, 95% CI = 1.02-1.31; P = 0.017). IC50 > 4.4 nM and Imax < 92% at T4 were good predictors for optimal clinical response. These results suggest that this test may be useful for predicting the response to glucocorticoid therapy in pediatric INS.

An updated Italian normative dataset for the Stroop color word test (SCWT).

The Stroop color and word test (SCWT) is widely used to evaluate attention, information processing speed, selective attention, and cognitive flexibility. Normative values for the Italian population are available only for selected age groups, or for the short version of the test. The aim of this study was to provide updated normal values for the full version, balancing groups across gender, age decades, and education. Two kinds of indexes were derived from the performance of 192 normal subjects, divided by decade (from 20 to 90) and level of education (4 levels: 3-5; 6-8; 9-13; >13 years). They were (i) the correct answers achieved for each table in the first 30 s (word items, WI; color items, CI; color word items, CWI) and (ii) the total time required for reading the three tables (word time, WT; color time, CT; color word time, CWT). For each index, the regression model was evaluated using age, education, and gender as independent variables. The normative data were then computed following the equivalent scores method. In the regression model, age and education significantly influenced the performance in each of the 6 indexes, whereas gender had no significant effect. This study confirms the effect of age and education on the main indexes of the Stroop test and provides updated normative data for an Italian healthy population, well balanced across age, education, and gender. It will be useful to Italian researchers studying attentional functions in health and disease.

A normative study of the Italian printed word version of the free and cued selective reminding test.

According to the new research criteria for the diagnosis of Alzheimer's disease, episodic memory impairment, not significantly improved by cueing, is the core neuropsychological marker, even at a pre-dementia stage. The FCSRT assesses verbal learning and memory using semantic cues and is widely used in Europe. Standardization values for the Italian population are available for the colored picture version, but not for the 16-item printed word version. In this study, we present age- and education-adjusted normative data for FCSRT-16 obtained using linear regression techniques and generalized linear model, and critical values for classifying sub-test performance into equivalent scores. Six scores were derived from the performance of 194 normal subjects (MMSE score, range 27-30, mean 29.5 ± 0.5) divided per decade (from 20 to 90), per gender and per level of education (4 levels: 3-5, 6-8, 9-13, >13 years): immediate free recall (IFR), immediate total recall (ITR), recognition phase (RP), delayed free recall (DFR), delayed total recall (DTR), Index of Sensitivity of Cueing (ISC), number of intrusions. This study confirms the effect of age and education, but not of gender on immediate and delayed free and cued recall. The Italian version of the FCSRT-16 can be useful for both clinical and research purposes.

Posttransplant de novo donor-specific hla antibodies identify pediatric kidney recipients at risk for late antibody-mediated rejection.

The emerging role of humoral immunity in the pathogenesis of chronic allograft damage has prompted research aimed at assessing the role of anti-HLA antibody (Ab) monitoring as a tool to predict allograft outcome. Data on the natural history of allografts in children developing de novo Ab after transplantation are limited. Utilizing sera collected pretransplant, and serially posttransplant, we retrospectively evaluated 82 consecutive primary pediatric kidney recipients, without pretransplant donor-specific antibodies (DSA), for de novo Ab occurrence, and compared results with clinical-pathologic data. At 4.3-year follow up, 19 patients (23%) developed de novo DSA whereas 24 had de novo non-DSA (NDSA, 29%). DSA appeared at a median time of 24 months after transplantation and were mostly directed to HLA-DQ antigens. Among the 82 patients, eight developed late/chronic active C4d+ antibody-mediated rejection (AMR), and four C4d-negative AMR. Late AMR correlated with DSA (p < 0.01), whose development preceded AMR by 1-year median time. Patients with DSA had a median serum creatinine of 1.44 mg/dL at follow up, significantly higher than NDSA and Ab-negative patients (p < 0.005). In our pediatric cohort, DSA identify patients at risk of renal dysfunction, AMR and graft loss; treatment started at Ab emergence might prevent AMR occurrence and/or progression to graft failure.

Is Venice an ideal habitat for Legionella pneumophila?

INTRODUCTION: Legionella bacterium manifests itself in Legionnaire's disease and Pontiac fever, it is mainly found and transmitted by aerosol produced in cooling towers, water distribution plants and medical equipment, and it affects mainly elder persons in poor health. METHODS: The population of Venice Local Health Unit was divided in two areas of study and the incidence of legionellosis in residents of Venice historical centre (Distretto Sanitario 1) and in residents of the mainland and coastal areas (Distretti Sanitari 2, 3, 4) was calculated. The cases were those notified to the Public Health Unit by law, and the population of residents was that of the eligible for health care in the archives of the Local Health Unit. Only cases of legionellosis in residents who had not travelled in the 10 days previous of the onset of disease, and not related to nosocomial clusters were considered. The standardized incidence ratio was then calculated and confidence interval were defined by Poisson distribution. RESULTS: Given the population of the two areas, 59801 in Distretto Sanitario 1 and 237555 in Distretti 2, 3, 4, the raw incidence of disease is respectively 87 per 100000 and 20 per 100000 in time 2002-2010. The standardized incidence ratio for the population of Distretto Sanitario 1 vs the remaining population is 4.3. DISCUSSION: The difference in risk of getting the disease in this two residential areas geographically very close, is probably related to the different buildings' characteristics, old and difficult to maintain in Venice historical centre.

Antipsychotic utilisation and polypharmacy in Italian residential facilities: a survey.

OBJECTIVE: To evaluate the prescribing practices in psychiatric residential facilities, with particular focus both on the antipsychotic dose and polypharmacy as well as the variation of antipsychotic patterns during a patient's stay within the facilities. METHODS: Fifteen residential facilities of Liguria region in Italy were included. Data were collected through a chart review during a one-day census. Frequency of psychotropic patterns was estimated. Different non-parametric tests were used to analyse the changes in prescription patterns as well as the relationship among antipsychotic dose, the number of antipsychotics and anticholinergic use. RESULTS: The study sample includes 362 patients, 61.9% males. On the census day 77.5% of patients received psychotropic polypharmacy and 57.2% antipsychotic polypharmacy. Antipsychotic polypharmacy was related to the total antipsychotic daily dose and to anticholinergic use. A trend towards an increase of antipsychotic and psychotropic polypharmacy and higher doses of antipsychotics over the period of stay within the facilities was noted. This tendency was related to the length of stay in the facility. CONCLUSIONS: Compared to earlier studies in the same clinical environment a significant increase in the use of psychotropic and antipsychotic polypharmacy was observed. The risk of prescribed polypharmacy seems to be related to time spent in the facility.

Involving patients who attempt suicide in suicide prevention: a focus groups study.

The aim of this study is to gain insight into the individual experiences of patients who attempt suicide in order to better understand the reasons for and emotions behind a suicide attempt, thus also gaining insight, through the patients' own input, into the risk and protective factors which might influence possible repeat attempts and the attitude towards the assistance they receive. Two focus groups were conducted involving 17 participants, all hospitalized at the time of research for attempting suicide. The patients proved themselves competent, even expert in indicating reasons for, risk factors of and prevention strategies for suicide. The main findings suggest that the relational factor represents a key point both as a trigger for the suicide attempt and for promoting the communication of the intent or for preventing a repeat suicide attempt, as interpersonal relationships and an empathic environment were, in essence, what was perceived as therapeutic and protective and enabled the expression of thoughts and self-understanding. Accordingly psychotherapy, non-specific relationship 'monitoring' after discharge and tutored self-help groups have been suggested. Feasibility and implementing methods as well as the role of the nurse for such interventions were discussed.

Schizophrenia trial participation: perceived inclusion barriers and beliefs about antipsychotics.

BACKGROUND: Patient recruitment is the universal rate-limiting factor for randomized controlled trials (RCTs) in all medical specialties. This study examined the opinions on perceived inclusion barriers and beliefs about antipsychotics of a group of psychiatrists participating in a pragmatic RCT on antipsychotic drugs in schizophrenia (the GiSAS trial). METHODS: A survey of all clinicians working in the trial recruiting centers was performed exploring factors associated to the respondents' opinions. RESULTS: Of 465 clinicians, 278 (59.8%) responded to the questionnaire. Respondents (n=278) were mainly influenced by clinical and trial-related barriers (89%). Factors such as work setting and antipsychotic prescription choices appeared to be related to perceived inclusion barriers. Most respondents believed in the superiority of SGAs (62.9%), one-third indicating drug company representatives as the most important source of information; this was related to further optimism towards SGAs. CONCLUSIONS: Respondents were affected mainly by system-related barriers, whereas personal barriers were given less weight. The influence of industry-mediated information could have affected opinions on SGAs and the lack of uncertainty about antipsychotics attitudes towards trial participation.

The role of immunosuppression in malignancies among 351 pediatric renal transplant patients.

The incidence of de novo malignancies over a 38 year experience in 351 children ranging in age from 2 to 18 years was investigated among subjects prescribed various immunosuppressive protocols. There were 14 children (3.98%) who showed de novo malignancies, namely, 4.86 cancers for every 1000 graft-function years (GFYs). Among patients who had grafts functioning for >10 years, 7.4% suffered from cancer. Nine patients survive without a recurrence at a mean of 12.5 +/- 6.6 years including 6 with graft function. Among group I who were treated with pre-calcineurin inhibitor (CNI) therapy 3 (3.8%) children (1 male and 2 females) developed a malignancy at a mean of 15.2 +/- 11.9 years posttransplant (range, 7-35), for 4.65 cancers every 1000 GFYs. Two of them survive with functioning grafts. Among group II, who were treated by CNIs there were 273 children including 24 retransplants. Group II showed 11 malignancies (4.0%), for 5.04 malignancies for every 1000 GFYs. The incidence of cancer was similar in the 2 groups, undergoing different immunosuppressive regimens; however, the malignancies in the CNI- group were more precocious, compared with those of the conventionally-treated cohort.

Pediatric kidney transplantation: a snapshot 10 years later.

Herein we report the outcomes of pediatric kidney recipients who underwent transplantation at least 10 years prior. A cohort of 36 patients (mean age, 26.4+/-6 years) with a mean follow-up time of 14.2+/-4 years was selected for the study. Immunosuppression consisted of cyclosporine and steroids. Actuarial patient and graft survivals 15 years after the transplantation were 97% and 86%, respectively. Only 1 patient died due to a complicated sclerosant peritonitis. Graft function was good with a mean serum creatinine of this selected cohort of 1.5+/-0.6 mg/dL. Eighteen percent were class 1, 33% class 2, and 49% chronic kidney disease. Hypertension was treated in almost 80% of the patients. The majority of patients were smaller than the average population with a final height (between 0 and -2) standard deviation score (HSDS) but only 27% had a severe growth impairment (HSDS>-2). Regarding nutritional status, fewer than 30% were overweight and only 1 patient was obese with a body mass index (BMI) >30. The majority of patients, except 2 mentally retarded individuals, are or have been attending normal school and achieved full-time employment. In conclusion, long-term survivors of a kidney transplant received during childhood reached a high degree of rehabilitation despite a long period of immunosuppression.

Posttransplant recurrence of proteinuria in a case of focal segmental glomerulosclerosis associated with WT1 mutation.

Posttransplant recurrence of inherited focal segmental glomerulosclerosis (FSGS) is still an enigma owing to the evident paradox of the molecular origin of proteinuria. A young girl with FSGS for WT1 mutation (IVS9+4C>T) and Frasier syndrome received a renal transplant at the age of 11 years. After an initial good outcome with recovery of renal function, proteinuria re-appeared after 7 days and steadily increased up to a nephrotic range. Determination of plasma permeability activity showed concomitant high Palb (0.7). At this point, plasmapheresis was started and after nine cycles with 1500 mL exchange and albumin re-infusion, proteinuria decreased to normal range and is still normal after 3 years. This is the first description of posttransplant recurrence of proteinuria in Frasier syndrome that should be included in potential outcome of renal transplant in this category of patients. This observation confirms the concept that recurrence of proteinuria may occur in inherited forms of FSGS so far reported only for patients carrying NPHS2 mutations and reinforces the idea on multifactorial origin of the disease.

Mycophenolate mofetil pharmacokinetic monitoring in pediatric kidney transplant recipients.

This open-label, longitudinal, long-term study of de novo pediatric renal transplant recipients was designed to investigate the pharmacokinetics (PK) of mycophenolic acid (MPA) and its possible interaction with cyclosporine (CsA). Thirty-four children on an immunosuppressive regimen of CsA, prednisone, and mycophenolate mofetil (MMF, 300-400 mg/m2 twice daily) were investigated at 6, 30, 180, and 360 days after transplantation. Considerable interindividual variability in the areas under the concentration curve (AUC(0-12)) of MPA was observed during the follow-up, although the dose of MMF remained the same over the same time. Predose levels (C0) increased significantly during the first 6 months after transplantation: C0 at 6 and 180 days after transplantation was 0.8 +/- 0.6 and 1.9 +/- 1.1 microg/mL (P < .0001). A significant time-dependent increase in the AUC of MPA was also observed during the first 6 posttransplant months: AUC(0-12) at 6 and 180 days after transplantation was 23.3 +/- 10.8 and 40 +/- 11.6 mg*h/L (P = .003). MPA concentrations 3 and 4 hours after MMF intake were the individual time points that best correlated with the full MPA AUC (r = 0.8 and 0.79; P < .001). The abbreviated MPA AUC (0-4 hours) correlated reasonably with the full AUC (r = 0.87; P < .001). Finally, a significant reduction in CsA dose during the first 6 posttransplant months (P < .001) matched the significant increases in both MPA C0 and full MPA AUC, thus demonstrating the interaction of the 2 immunosuppressive drugs. These observations suggest the need for therapeutic drug monitoring when adjusting the dose of MMF in children.

C2 is an age-independent parameter for optimal cyclosporine exposure in long-term kidney transplant recipients.

The argument for therapeutic drug monitoring (TDM) of cyclosporine (Cya) has been discussed for the last two decades. So far, a generalized consensus has been reached for TDM of Cya microemulsion in adult transplant recipients, being Cya blood levels obtained 2 hours after the administration (C2), the most reliable in reflecting the overall Cya exposure. However, clear guidelines are not available for the pediatric population because of the distinct metabolism of the drug in this patient population. Therefore, adult data do not necessarily apply to children. In this retrospective analysis, the authors sought to define a universal parameter for pharmacokinetic clinical monitoring of Cya in long-term kidney transplant recipients, regardless of their age. Lower C2 levels were observed in all patients, adult and pediatric, who eventually developed chronic allograft dysfunction (CRAD) compared with patients who maintained stable kidney function throughout the entire follow-up (pediatric CRAD, 933 +/- 455 ng/mL; vs Stable, 1236 +/- 347 ng/mL, P = .0001; and adult CRAD, 781 +/- 518 ng/mL; vs Stable, 1088 +/- 452 ng/mL, P = .009). On the other hand, the risk of Cya underexposure was not highlighted by trough level monitoring (C0) because all patients have been maintained steadily on therapeutical C0 levels for the entire follow-up. In conclusion, for Cya maintenance therapy, C2 appears to be a superior strategy to C0 monitoring in both adult and pediatric kidney transplant recipients.

Conversion from tacrolimus to cyclosporine for a non-dose-dependent tacrolimus-induced toxicity, a pediatric kidney transplant recipient case report.

Tacrolimus-induced toxicity is considered a dose-related side effect largely due to a direct action of this potent calcineurin inhibitor on its targets including the kidney and the pancreas. This paper describes a case of tacrolimus systemic toxicity that appeared in a pediatric kidney transplant recipient who received a low drug dose. The kidney biopsy was a crucial aid toward the correct diagnosis, which reversed upon conversion to cyclosporine-based immunosuppression. A review of the literature suggests a chance of systemic toxicity even when the patient is maintained on therapeutic levels of tacrolimus. Because idiosyncratic reactions to the drug have not yet been postulated, we conclude that this suspicion may be addressed by a safe conversion to cyclosporine in pediatric patients.

Cyclosporine monitoring in stable, long-term, pediatric kidney transplant recipients: the value of C2 determination.

Although a generalized consensus has been reached for therapeutic drug monitoring of cyclosporine microemulsion in adult transplant patients, clear guidelines are recently not available for the pediatric population. In this retrospective analysis of pharmacokinetic data obtained from stable, long-term, pediatric kidney transplant recipients, we sought to define a possible approach to manage cyclosporine therapy in a pediatric setting. The 2-hour postdose cyclosporine blood concentration, C(2), rather than trough levels, was the best single time point predictor of the area under the concentration curve. We concluded that therapeutic drug monitoring of cyclosporine-based immunosuppressive regimens should be tailored based on C(2) determinations for pediatric kidney transplant recipients.

[Renal transplantation in the pediatric age]. / Trapianto renale in età pediatrica.

Renal transplantation is the optimal and preferred treatment for children with end-stage renal disease. Pediatric kidney transplantation results have improved significantly over the years and the actuarial survival of the children with renal transplantation has become excellent. These improvements are due to many factors, including better immunosuppressive regimens and therefore a decrease in acute rejection episodes and possible improvement of graft survival. The concentration of care in specialized pediatric transplantation centers allowed the improvement of kidney transplants also in children less than 6 years old. The same success is not always achieved in infants. The selection of the donor is another important factor. The survival rate of renal transplantation is better in case of living-related donors. Renal transplants performed from cadaveric donors <6 years of age have an actuarial survival lower than renal transplants from cadaver donors >6 years of age. Owing to the limited members of cadaveric kidneys available for transplants, also the donors <6 years old are sometimes a valuable resource. As far as HLA-matching and its relationship with renal transplant outcome is concerned, there are conflicting data, but important registers on adults and children show the positive relationship between histocompatibility matching and graft outcome. A major distinguishing feature of pediatric from adult renal recipients is the need for children to grow. It is well known that chronic renal insufficiency involves a growth failure. A functioning transplant may improve the growth, but a catch-up growth is rarely achieved. To overcome this problem many techniques, such as alternate-day steroid therapy, discontinuation of prednisone, the use of recombinant growth hormone, have been adopted. As to social rehabilitation, transplanted children attend the school and work more than dialyzed ones.

Lipid profile during rhGH therapy in pediatric renal transplant patients.

To evaluate the effect of recombinant human growth hormone (rhGH) treatment on the lipid profile of pediatric renal transplant patients, we studied nine children treated with rhGH for 1 yr and a control group of 12 untreated patients matched in terms of age, renal transplant function and post-transplant follow-up. The levels of lipoprotein (a [Lp(a)], cholesterol, triglycerides, apolipoprotein A (APO A) and apolipoprotein B (APO B), and the APO B/APO A ratio, were determined at baseline and after 6 and 12 months of follow-up. RhGH therapy had no effect on cholesterol, triglycerides or apolipoproteins. Mean serum Lp(a) levels increased from 6.7 +/- 5.7 mg/dL at baseline to 11.8 +/- 10.7 after 6 months (p = 0.018) and 13.6 +/- 15.1 after 12 months of rhGH treatment (p = 0.04), but did not change in the control group. Lp(a) is a risk factor for cardiovascular morbidity, and increased Lp(a) levels may be a side-effect of rhGH treatment in renal transplant patients. Although long-term follow-up of a large number of patients is needed to establish the duration and extent of the effects of rhGH treatment on Lp(a) levels in transplanted children, serum Lp(a) levels should be carefully monitored in those receiving rhGH therapy.

L-arginine supplementation in young renal allograft recipients with chronic transplant dysfunction.

AIMS: L-arginine (LA), the precursor of nitric oxide (NO), was suggested to be beneficial in many forms of renal disease: hypertension, ureteral obstructive nephropathy and cyclosporin A (CsA) nephrotoxicity. METHODS: Thus, we investigated the effects of LA supplementation on renal function, proteinuria and blood pressure (BP) in young renal allograft recipients with chronic renal transplant dysfunction treated with CsA. Eleven CsA-treated renal allograft recipients with chronic transplant dysfunction, aged 11-22 years, were randomly assigned to a 6-week treatment period with placebo (P), followed by 2 subsequent 6-week periods with LA supplementation (0.1 g/kg body weight/day) or a 6-week treatment period with LA, followed by 2 subsequent 6-week periods with P. At the end of each treatment period 24-hour BP recordings were made, and GFR (Inutest), RPF (PAH clearance) and the urinary excretion of protein, albumin, nitrate, cGMP and urea were evaluated. RESULTS: In comparison to placebo, LA treatment did not significantly change GFR, RPF, proteinuria and albuminuria, mean systolic or diastolic BP. The urinary excretion of urea and NO3 increased after LA supplementation (uUrea: LA 26.3 +/- 4.6 compared to P 23.5 +/- 4.7 g/day/1.73 m3, p < 0.05, uNO3: LA 514 +/- 152 compared to P 95 +/- 41 mM/day/1.73 m3, p < 0.05), whereas urinary excretion of cGMP remained unchanged. CONCLUSION: LA supplementation did not improve renal function and did not decrease proteinuria in CsA-treated renal allograft recipients with chronic transplant dysfunction possibly because of inhibition of NO-cGMP forming mechanism.