Targeting the multifaceted neurotoxicity of Alzheimer's disease by tailored functionalisation of the curcumin scaffold.

Simultaneous modulation of multifaceted toxicity arising from neuroinflammation, oxidative stress, and mitochondrial dysfunction represents a valuable therapeutic strategy to tackle Alzheimer's disease. Among the significant hallmarks of the disorder, Aß protein and its aggregation products are well-recognised triggers of the neurotoxic cascade. In this study, by tailored modification of the curcumin-based lead compound 1, we aimed at developing a small library of hybrid compounds targeting Aß protein oligomerisation and the consequent neurotoxic events. Interestingly, from in vitro studies, analogues 3 and 4, bearing a substituted triazole moiety, emerged as multifunctional agents able to counteract Aß aggregation, neuroinflammation and oxidative stress. In vivo proof-of-concept evaluations, performed in a Drosophila oxidative stress model, allowed us to identify compound 4 as a promising lead candidate.

Renal transplantation in children weighing <15 kg: does concomitant lower urinary tract dysfunction influence the outcome?

BACKGROUND: We reviewed our experience with renal transplantation (RTx) in children weighing <15 kg to determine if the presence of lower urinary tract dysfunction (LUTD) influenced the outcome. METHODS: Between 1987 and 2012, 68 RTx were performed in patients weighing less than 15 kg, including 17 with associated LUTD and 51 without. We detailed the lower urinary tract management in these patients, and compared graft survival rates and estimated clearance 12 and 60 months after RTx between groups. RESULTS: None of the patients without LUTD required any lower urinary tract surgery vs 8 out of 17 (47 %) with LUTD (p = 0.0001). The latter included a temporary incontinent urinary diversion in 5 cases (29 %), namely 2 vesicostomies and 3 cutaneous ureterostomies. After comparable follow-ups, there was no difference in patient survival, graft survival, and glomerular filtration rates between groups. CONCLUSIONS: Provided that there is appropriate bladder management, a concomitant LUTD does not adversely influence the outcome of RTx in patients weighing less than 15 kg. However, 50 % of our patients required lower urinary tract reconstruction and, in 30 %, a temporary incontinent urinary diversion was placed at RTx, since lower urinary tract function could not be assessed reliably, the patient was not collaborative enough to be involved in a voiding program, and/or the RTx was prioritized.

Lymphocele after pediatric kidney transplantation: incidence and risk factors.

Lymphocele is a well-known postoperative complication after kidney transplantation. The aim of this study was to analyze time trend incidence, risk factors, and outcome of post-transplant lymphocele in a large pediatric cohort. This is a retrospective single institution review of 241 pediatric kidney transplants performed from 2000 to 2013. Etiology of end-stage renal disease, recipient age and gender, transplant year, BMI percentile for age, type of dialysis, living/non-living related donor, acute rejection, and multiple transplantations were analyzed in association with lymphocele formation. Fourteen of 241 (5.81%) children developed a postoperative lymphocele. There has been a reduction in the incidence of lymphocele after 2006 (3.22% vs. 8.55%, p < 0.05). Significant risk factors for lymphocele were older age (≥11 yr), transplant before 2006, male gender, BMI percentile for age ≥95%, and multiple transplantations (p < 0.05). The one-yr graft survival was significantly reduced in the group with lymphocele compared with control (81.2% vs. 92.51%, p < 0.04). This is the first pediatric report showing the following risk factors associated with post-transplant lymphocele: age ≥11 yr, male gender, BMI for age ≥95%, and multiple transplantations. A lymphocele can contribute to graft loss in the first-year post-transplant.

SIX1 gene: absence of mutations in children with isolated congenital anomalies of kidney and urinary tract.

BACKGROUND: Mutations in human SIX1 gene cause branchiootorenal or branchiootic syndrome. Six1 deficient mice exhibit uni- or bilateral renal hypoplasia or kidney agenesis. Furthermore a lack of Six1 gene in the ureter leads to hydroureter and hydronephrosis. These murine malformations resemble human kidney and urinary tract congenital anomalies (CAKUT), a group of diseases with a diverse anatomical spectrum which includes duplex collecting system as much as urethra kidney and ureteropelvic anomalies. Our study focuses on whether mutations or deletion of this gene may be associated with nonsyndromic CAKUT. METHODS: Fifty unrelated patients (13-21 years) with nonsyndromic CAKUT were retrospectively recruited for SIX1 sequence variations analysis, and compared to three subjects without malformative nephrouropathies (controls). SIX1 coding sequence was screened by high resolution melt analysis (HRMA) and by Sanger direct sequencing. A quantitative comparative real-time polymerase chain reaction (PCR) was later performed in order to detect the presence of SIX1 gene deletion. RESULTS: We did not find significant differences in the HRMA melting curves for each of the SIX1 coding exons between patients and controls, as also confirmed by Sanger direct sequencing. Moreover quantitative comparative real-time PCR for SIX1 and data normalization excluded total SIX1 gene deletion in our patients. CONCLUSIONS: We did not find sequence variations in SIX1 coding regions or complete gene deletion in our CAKUT population. These results suggest that alterations in these sequences are unlikely to be a major cause of nonsyndromic CAKUT. Nevertheless, further studies are necessary to understand if altered SIX1 expression may play a role in human development of kidney and urinary tract congenital anomalies.

Three-yr safety and efficacy of everolimus and low-dose cyclosporine in de novo pediatric kidney transplant patients.

The three yr results of a multicenter trial in de novo pediatric KT treated with a proliferative signal inhibitor and low dose CNI are presented. Thirty-seven children (9.1 ± 5 yr old) received basiliximab, cyclosporine A (CyA C2:1400 ng/mL), (MMF C0:1.5-3 µg/mL), and prednisone. Three wk later everolimus was started (C0:5-10 ng/mL), CyA was reduced (C2:600 ng/mL after 90 days 300 ng/mL), and MMF discontinued. During the three-yr period patient and graft survivals were 96%. One patient died for causes unrelated to the immunosuppression. Cumulative acute rejection rate including protocol and indication biopsies was 21.9%. None of the patients had signs of chronic humoral rejection. Incidence of dnDSA was 5%, 11%, and 22% at one, two, and three yr post-transplant, respectively. Mean glomerular filtration rate measured at one yr and three yr post-transplant was 105.5 ± 31 and 110.7 ± 27 mL/min/1.73 m(2), respectively. A growth velocity of 7.7 ± 6.7 cm/yr was achieved with positive catch-up growth. No malignancy or post-transplant lymphoproliferative diseases were diagnosed. In conclusion, the treatment based on basiliximab induction, everolimus, low-dose cyclosporine, and low-dose prednisone leads to good long-term efficacy in de novo pediatric KT recipients.

Delayed graft function in pediatric deceased donor kidney transplantation: donor-related risk factors and impact on two-yr graft function and survival: a single-center analysis.

There is mounting evidence that the quality of organs from cadaver donors may be influenced by events occurring around the time of brain death. Aim of this present study was to analyze the correlation of DGF with brain-dead donor variables in a single-center pediatric population and to evaluate DGF influence on patients- and grafts outcome. End-points of the study were DGF prevalence, DGF donor-related risk factors, graft function, patient- and graft survival rate, respectively, at six, 12, and 24 months FU. The univariate analysis showed that donor age above 15 yr and vascular cause of donor brain death represented risk factors for DGF. The multivariate analysis confirmed as independent risk factors for DGF donor age >15 yr. At six months FU, DGF showed a negative impact on graft function. In conclusion, among all considered brain-dead donor resuscitation parameters, just non-traumatic cause of death turned out to be of impact for DGF. Donor age >15 yr represented the only independent risk factor for prolonged DGF in our series of children. At two-yr FU, DGF showed a transient negative impact on six-month graft function.

Ureteral complications after renal transplant in children: timing of presentation, and their open and endoscopic management.

We retrospectively reviewed the records of 24 consecutive patients undergoing treatment for ureteral complications after RTx in the period 2001-2012 to determine the timing of presentation of the complications, and their open or endoscopic management. Three patients (12%) had a necrosis of the transplanted ureter soon after RTx. All required open urinary diversion in a native ureter. Ten cases (42%) developed ureteral obstruction. Time of presentation was variable mainly in relation to the underlying cause. Endoscopic treatment was successful in two cases with urinary stones and open surgery in two with mid-ureteral obstruction. Six patients had VUJ stenosis, three underwent open reimplantation, whereas temporary double-J stent placement was successfully performed in the remainder. Eleven patients (46%) had VUR. It seldom presented in the first year after RTx. Endoscopic treatment was attempted in all and was successful in all the six cases without vs. only one of the five with lower urinary tract pathology (p = 0.01). Endoscopic treatment is an option in patients with VUR in the absence of lower urinary tract pathology. It is an option also for the treatment of stones and can be attempted in case of VUJ stenosis. Ureteral necrosis always requires open treatment.

Plasmapheresis-resistant acute humoral rejection successfully treated with anti-C5 antibody.

Even if kidney graft survival has improved during the last decades, sensitized pediatric patients are an emerging problem. We describe a 17-yr-old male who lost his first graft due to chronic rejection becoming hyperimmunized (CDC PRA 99.61%). A desensitization protocol based on high-dose IVIG, PP, and two Mabthera(®) infusions was performed with minor response (CDC PRA post-desensitization 80%). One month after his second non-living transplant, he developed a biopsy-proven AMR; post-transplant immunological monitoring showed the presence of donor-specific anti-DQ5 antibodies (DSA, MFI 20.000). He received methylprednisolone pulses and 45 PP sessions without clinical response; eculizumab was then used to salvage a kidney undergoing severe PP-resistant rejection. A biopsy performed after the fourth eculizumab infusion showed complete resolution of AMR. Eculizumab infusions were then continued for the first year post-transplantation. Two yr after transplantation, graft function is stable. Anti-C5 therapy may represent an effective therapeutic option in pediatric patients with PP-resistant AMR.

Transplant renal artery stenosis in children: risk factors and outcome after endovascular treatment.

BACKGROUND: Transplant renal artery stenosis (TRAS) is an increasingly recognised cause of post-transplant hypertension. METHODS: We retrospectively analysed 216 paediatric renal recipients transplanted between 2001 and 2011 to assess TRAS prevalence and percutaneous transluminal angioplasty (PTA) efficacy. To assess risk factors, we compared children with TRAS with a propensity score-matched cohort of recipients without TRAS. RESULTS: Of the 216 paediatric patients who were transplanted in the study period, 44 were hypertensive (prevalence 20.3 %) and ten presented with TRAS (prevalence 4.6 %, median age at transplantation 14 years, range 6.78-17.36 years). Hypertensive patients without TRAS were prescribed one to two anti-hypertensive agents, whereas patients with TRAS required one to five medications. In the TRAS group, one recipient presented with vascular complications during surgery, and in three patients the graft had vascular abnormalities. TRAS was detected by Doppler ultrasonography (US) performed due to hypertension in nine of the patients with TRAS, but in the tenth case the TRAS was clinically silent and detected by routine Doppler-US screening. TRAS diagnosis was refined using angio-computed tomography or angio-magnetic resonance imaging. All patients underwent PTA without complications. Significant improvement after PTA was observed in the standard deviation scores for blood pressure [3.2 ± 1.4 (pre-PTA) vs. 1.04 ± 0.8 (post-PTA); p = 0.0006) and graft function [creatinine clearance: 69 ± 17.08 (pre-PTA) vs. 80.7 ± 21.5 ml/min/1.73 m(2) (post-PTA); p = 0.006] We observed no significant differences between the two cohorts for cold ischaemia time, recipient/donor weight ratio, delayed graft function, cytomegalovirus infections and acute rejection episodes. CONCLUSIONS: Our study reports a low but significant TRAS prevalence among the paediatric patients who were transplanted at our centre in the study period and confirms that PTA is an effective and safe therapeutic option in paediatric renal transplant recipients. Known risk factors do not appear to be related to the development of TRAS.

Near-infrared spectroscopy as continuous real-time monitoring for kidney graft perfusion.

BACKGROUND: Near-infrared spectroscopy (NIRS) is a non-invasive technique designed to study regional oxygenation (rSO(2)) by measuring the absorption of chromophores. This study investigated the role of NIRS in the real-time monitoring of kidney graft perfusion for 72 h post-transplantation. METHODS: Consecutive children undergoing living related donor (LRD) or deceased donor (DD) kidney transplantation (KTP) were prospectively enrolled between April 2010 and August 2011. Renal rSO(2) values were registered continuously for 3 days and correlated with hourly urine output, serum creatinine, and urinary neutrophil gelatinase-associated lipocalin (u-NGAL). RESULTS: Twenty-four children were included, 6 underwent LRD and 18 DD KTP. Median age was 12.5 years (interquartile range [IQR] 3.5-16.6) and median body weight was 37 kg (IQR 13-49.7). Four patients experienced delayed graft function (DGF). Renal Doppler ultrasound showed normal vascularization patterns in all children. Median basal renal rSO(2) value was 68.8 % (IQR 59.3-76.2), significantly lower than the end-of-period result (83.6 %; IQR 79.2-90.4; p < 0.0001). Renal rSO(2) values showed significant correlation with serum creatinine (rs = -0.62; p < 0.05) and estimated glomerular filtration rate (eGFR) (rs = 0.64; p < 0.05). No correlation was shown between rSO(2) and diuresis. Increased rSO(2) was also found in patients who experienced DGF. u-NGAL exhibited a trend toward a decrease from baseline in both DD and LRD KTPs, with a strong negative correlation with rSO(2). CONCLUSIONS: rSO(2) assessed by NIRS strongly correlates with common markers of kidney graft function and perfusion, allowing continuous real-time monitoring of blood flow in renal grafts.

Lower urinary tract symptoms (LUTS) after renal transplant in non-urologic anuric patients.

We assessed LUTS at least 12 months after RTx in patients without evidence of lower urinary tract dysfunction (non-urologic) that had been anuric for at least six months before RTx. No bladder recycling was performed before RTx. LUTS were evaluated using a questionnaire. Clinical records were also reviewed. LUTS in anuric patients were compared with those in non-anuric patients. Fourteen anuric patients fulfilled the inclusion criteria. Median age at RTx was 11 (5-21) yr, median duration of anuria before RTx 24 (7-46) months, and median post-RTx follow-up 2.7 (1.9-10.2) yr. Daytime symptoms were exceptional. Nocturia was the most common symptom (10 patients). Only one patient reported symptoms to affect her quality of life. One patient experienced a febrile UTI and none graft failure. LUTS (nocturia) proved unrelated to duration of anuria, length of follow-up, and presence of (nocturnal) polyuria. LUTS were not statistically different in patients anuric and non-anuric before RTx. Non-urologic patients suffer from long-term storage symptoms, particularly nocturia. LUTS, however, do not seem to increase the risks of urinary infections or graft failure and appear to occur irrespective of the presence of anuria before RTx. Bladder recycling before RTx seems unnecessary.

Detection of viral DNA in kidney graft preservation and washing solutions is predictive of posttransplant infections in pediatric recipients.

BACKGROUND: In pediatric kidney transplant recipients, viral infections occur soon after transplant and may be transmitted from the graft. METHODS: This study of 75 pediatric kidney transplants investigated whether genome sequences of parvovirus B19, Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), and BK polyomavirus (BKV) could be detected in kidney graft samples (graft biopsy samples and preservation and washing solutions) collected before implantation and whether their presence was a risk factor for infections in the recipient. RESULTS: B19 DNA was detected in approximately 30% of graft biopsy samples, preservation solutions, and washing solutions; EBV DNA was detected in approximately 20% of preservation and washing solutions but rarely in biopsy samples; and HCMV DNA and BKV DNA were rarely detected in graft biopsy samples. Seronegative recipients of B19 DNA-positive and EBV DNA-positive grafts had a significantly higher risk of infection during the early posttransplant period than did recipients of negative grafts. In particular, none of the B19-seronegative recipients of B19 DNA-negative grafts experienced infection soon after transplant, whereas most recipients of B19 DNA-positive grafts experienced infection within the first month after transplant. CONCLUSIONS: Molecular testing of donor grafts for viruses that infect circulating and resident cells in the graft-such as B19 in the kidney-could be useful (in association with donor/recipient serostatus) for identifying recipients at high risk for posttransplant infections.