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Lofaro D.,Kidney and Transplantation Research Center | van Stralen K.J.,University of Amsterdam | Jager K.J.,University of Amsterdam
Pediatric Nephrology | Year: 2016

Background: Pediatric renal replacement therapy (RRT) patients surviving long-term are at a much higher risk of mortality compared with the age-matched general population. Recently, we demonstrated a transition from cardiovascular disease to infection as the main cause of death in a long-term follow-up study of pediatric RRT. Here, we explore the burden of infections requiring hospitalization over 30 years of follow-up on RRT. Methods: The cohort comprised all 234 Dutch patients on RRT under 15 years of age between 1972 and1992. We analyzed infection-related hospitalizations during the period 1980–2010. We evaluated the Hospital Admission Rate (HAR) per patient-years (py) and infectious over non-infectious HAR ratio (HARR). Results: The HAR decreased significantly over time for all patients. The rate of hemodialysis-related infections decreased between 1980 and 1999, but stabilized during 2000–2010, whereas peritoneal dialysis-related infections decreased progressively. Transplantation-related infections did not change, except for urinary tract infections (UTIs), which increased significantly from 3.3/100 py [95%CI 3.2–3.4] in 1980–1989 to 4.4/100 py [4.2–4.5] in 2000–2010 (p <0.001). The contribution of infection to HAR increased significantly in transplanted patients (HARR: 1980–1989: 0.25 [0.2–0.3]; 2000–2010: 1.0 [0.79–1.27], p <0.001). Conclusions: Our findings indicate a relative increase in infections requiring hospitalization over time in patients starting RRT during the pediatric age, especially severe UTIs in transplantation. More attention paid to urological abnormalities in cases of recurrent UTI and tailored adjustment of immunosuppression may reduce risk in these patients. © 2015, The Author(s).

Lofaro D.,Kidney and Transplantation Research Center | Lofaro D.,University of Calabria | Jager K.J.,University of Amsterdam | Abu-Hanna A.,University of Amsterdam | And 9 more authors.
Nephrology Dialysis Transplantation | Year: 2016

Background. Identification of patient groups by risk of renal graft loss might be helpful for accurate patient counselling and clinical decision-making. Survival tree models are an alternative statistical approach to identify subgroups, offering cut-off points for covariates and an easy-to-interpret representation. Methods. Within the European Society of Pediatric Nephrology/ European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry data we identified paediatric patient groups with specific profiles for 5-year renal graft survival. Two analyses were performed, including (i) parameters known at time of transplantation and (ii) additional clinical measurements obtained early after transplantation. The identified subgroups were added as covariates in two survival models. The prognostic performance of the models was tested and compared with conventional Cox regression analyses. Results. The first analysis included 5275 paediatric renal transplants. The best 5-year graft survival (90.4%) was found among patients who received a renal graft as a pre-emptive transplantation or after short-term dialysis (< 45 days), whereas graft survival was poorest (51.7%) in adolescents transplanted after long-term dialysis (> 2.2 years). The Cox model including both pre-transplant factors and tree subgroups had a significantly better predictive performance than conventional Cox regression (P < 0.001). In the analysis including clinical factors, graft survival ranged from 97.3% [younger patients with estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 and dialysis < 20 months] to 34.7% (adolescents with eGFR < 60 mL/min/1.73 m2 and dialysis > 20 months). Also in this case combining tree findings and clinical factors improved the predictive performance as compared with conventional Cox model models (P < 0.0001). Conclusions. In conclusion, we demonstrated the tree model to be an accurate and attractive tool to predict graft failure for patients with specific characteristics. This may aid the evaluation of individual graft prognosis and thereby the design of measures to improve graft survival in the poor prognosis groups. © The Author 2015.

Gigliotti P.,Kidney and Transplantation Research Center | Lofaro D.,Kidney and Transplantation Research Center | Leone F.,Kidney and Transplantation Research Center | Papalia T.,Kidney and Transplantation Research Center | And 10 more authors.
Journal of Nephrology | Year: 2016

Subclinical rejection (SCR) has been variably associated with reduced graft survival, development and progression of interstitial fibrosis/tubular atrophy and chronic allograft nephropathy, but data are controversial concerning SCR treatment in terms of graft survival improvement. In this single-center retrospective study, we enrolled 174 adult kidney transplant recipients with a protocol biopsy performed at 30 days after transplantation to evaluate the incidence rate and risk factors for early SCR and its impact on 10-year graft survival. Five patients showed primary non function and were excluded. Among 159/169 (94.08 %) patients with stable graft function who underwent protocol biopsy, 17 (10.7 %) showed signs of SCR and were treated with low-dose intravenous (i.v.) steroids. Ten patients showed functional impairment, 8 (4.73 %) resulting as acute rejection. At multivariate analysis, donor age [odds ratio (OR) 1.04, 95 % confidence interval (CI) 1.01–1.09], and delayed graft function (DGF) (OR 1.08, 95 % CI 1.03–1.12) were significantly associated with SCR. The 10-year graft survival rate in the SCR group was similar to that in the normal-findings group (76.5 vs. 74.9 % respectively; p = 0.61). At multivariate Cox regression, acute [hazard ratio (HR) 5.22, 95 % CI 1.70–16.01], but not sub-clinical, rejection was independently associated with long-term graft failure. In conclusion, early protocol biopsy is a useful and safe tool to detect early SCR which seems not to affect the long-term survival. We suggest that this could be, probably, linked to early SCR treatment with low dose i.v. steroids. © 2015, Italian Society of Nephrology.

Vizza D.,Kidney and Transplantation Research Center | Perri A.,Kidney and Transplantation Research Center | Lofaro D.,Kidney and Transplantation Research Center | Toteda G.,Kidney and Transplantation Research Center | And 5 more authors.
PLoS ONE | Year: 2013

Nerve growth factor is a neurotrophin that promotes cell growth, differentiation, survival and death through two different receptors: TrkA NTR and p75NTR. Nerve growth factor serum concentrations increase during many inflammatory and autoimmune diseases, glomerulonephritis, chronic kidney disease, end-stage renal disease and, particularly, in renal transplant. Considering that nerve growth factor exerts beneficial effects in the treatment of major central and peripheral neurodegenerative diseases, skin and corneal ulcers, we asked whether nerve growth factor could also exert a role in Cyclosporine A-induced graft nephrotoxicity. Our hypothesis was raised from basic evidence indicating that Cyclosporine A-inhibition of calcineurin-NFAT pathway increases nerve growth factor expression levels. Therefore, we investigated the involvement of nerve growth factor and its receptors in the damage exerted by Cyclosporine A in tubular renal cells, HK-2. Our results showed that in HK-2 cells combined treatment with Cyclosporine A + nerve growth factor induced a significant reduction in cell vitality concomitant with a downregulation of Cyclin D1 and up-regulation of p21 levels respect to cells treated with Cyclosporine A alone. Moreover functional experiments showed that the co-treatment significantly up-regulated human p21promoter activity by involvement of the Sp1 transcription factor, whose nuclear content was negatively regulated by activated NFATc1. In addition we observed that the combined exposure to Cyclosporine A + nerve growth factor promoted an upregulation of p75 NTR and its target genes, p53 and BAD leading to the activation of intrinsic apoptosis. Finally, the chemical inhibition of p75NTR down-regulated the intrinsic apoptotic signal. We describe two new mechanisms by which nerve growth factor promotes growth arrest and apoptosis in tubular renal cells exposed to Cyclosporine A. © 2013 Vizza et al.

Leone F.,Kidney and Transplantation Research Center | Lofaro D.,Kidney and Transplantation Research Center | Gigliotti P.,Kidney and Transplantation Research Center | Perri A.,Kidney and Transplantation Research Center | And 6 more authors.
Journal of Nephrology | Year: 2014

Background: Data on serum soluble Klotho levels in chronic kidney disease are contradictory and even less is known after renal transplantation. Experimental studies demonstrated that recombinant human erythropoietin (rhEPO) treatment mitigates Klotho reduction caused by renal damage. Therefore, this study aimed to determine serum Klotho levels in a cohort of kidney transplant recipients (KTR) and to evaluate whether rhEPO treatment can modulate, in vivo and in vitro, soluble Klotho.Results: Serum Klotho levels in KTR were significantly higher than in HS (0.68 vs. 0.37, p = 0.002) and significantly associated with estimated glomerular filtration rate (r = −0.378, p = 0.003) and fibroblast growth factor 23 (r = −0.307, p < 0.0001). After 5 weeks of rhEPO discontinuation, treated KTR showed a sharper reduction of Klotho levels than controls (−0.56 vs. −0.11 ng/ml, p < 0.0001). In HK-2 cells CyA treatment induced a Klotho down-regulation that was mitigated by rhEPO pre-treatment. In the same experimental conditions, our results revealed that cells treated with CyA + rhEPO secreted higher soluble Klotho levels than those exposed to CyA or rhEPO alone.Conclusions: Our results demonstrate that KTR have higher serum Klotho levels than HS and that rhEPO treatment modulates these concentrations, suggesting a link between rhEPO and soluble Klotho in KTR.Methods: 117 KTR and 22 healthy subjects (HS) were enrolled. In 17 KTR, rhEPO was discontinued for 5 weeks and Klotho levels were compared to 34 propensity score-matched controls. Moreover, we evaluated Klotho mRNA expression and protein secretion in HK-2 tubular cells treated with cyclosporin A (CyA) and rhEPO, alone or in combination. © 2014, Italian Society of Nephrology.

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