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2.
Transplantation ; 99(6): 1178-85, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25539467

ABSTRACT

BACKGROUND: Corticosteroid withdrawal (CW) after pediatric kidney transplantation potentially improves growth while avoiding metabolic and other adverse events. We have recently reported the results of a 196 subject randomized controlled trial comparing early CW (tacrolimus, mycophenolate mofetil (MMF), daclizumab, and corticosteroids until day 4) with tacrolimus, MMF, and corticosteroid continuation (CC). At 6 months, CW subjects showed better growth with no adverse impact on acute rejection or graft survival (Am J Transplant 2010; 10: 828-836). This 2-year investigator-driven follow-up study aimed to determine whether improved growth persisted in the longer term. METHODS: Data regarding growth, graft outcomes and adverse events were collected at 1 year (113 patients) and 2 years (106 patients) after transplantation. The primary endpoint, longitudinal growth calculated as delta height standard deviation score, was analyzed using a mixed model repeated measures model. RESULTS: Corticosteroid withdrawal subjects grew better at 1 year (difference in adjusted mean change, 0.25; 95% confidence interval, 0.10, 0.40; P = 0.001). At 2 years, growth remained numerically better in CW subjects (0.20 (-0.01, 0.41); P = 0.06), and significantly better in prepubertal subjects (0.50 (0.16, 0.84); P = 0.004). Bacterial and viral infection was significantly more common in CW subjects at 1 year only. Corticosteroid withdrawal and CC subjects received similar exposure to both tacrolimus and MMF at 1 and 2 years. No significant difference in patient or graft survival, rejection, estimated glomerular filtration rate, or other adverse events was detected. CONCLUSION: Early CW effectively and safely improves growth up to 2 years after transplantation, particularly in prepubertal children.


Subject(s)
Adrenal Cortex Hormones/administration & dosage , Immunosuppressive Agents/administration & dosage , Kidney Transplantation/methods , Adrenal Cortex Hormones/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Child , Child Development/drug effects , Child, Preschool , Daclizumab , Drug Administration Schedule , Female , Follow-Up Studies , Graft Rejection , Graft Survival/drug effects , Humans , Immunoglobulin G/administration & dosage , Immunosuppressive Agents/adverse effects , Kidney Transplantation/adverse effects , Male , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/analogs & derivatives , Tacrolimus/administration & dosage
3.
Pediatr Nephrol ; 29(9): 1617-24, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24710747

ABSTRACT

BACKGROUND: There is increasing focus on the problems involved in the transition and transfer of young adult patients from paediatric to adult renal units. This situation was addressed by the 2011 International Pediatric Nephrology Association/International Society of Nephrology (IPNA/ISN) Consensus Statement on transition. METHODS: We performed a survey of transition practices of 15 paediatric nephrology units across Europe 2 years after publication of the consensus statement. RESULTS: Two thirds of units were aware of the guidelines, and one third had integrated them into their transition practice. Forty-seven per cent of units transfer five or fewer patients with chronic kidney disease (CKD) stage 5 per year to a median of five adult centres, with higher numbers of CKD stages 2-4 patients. Seventy-three per cent of units were required by the hospital or government to transfer patients by a certain age. Eighty per cent of units commenced transition planning after the patient turned 15 years of age and usually within 1-2 years of the compulsory transfer age. Forty-seven per cent of units used a transition or transfer clinic. Prominent barriers to effective transition were patient and parent attachment to the paediatric unit and difficulty in allowing the young person to perform self-care. CONCLUSIONS: Whereas awareness of the consensus statement is suboptimal, it has had some impact on practice. Adult nephrologists receive transferred patients infrequently, and the process of transition is introduced too late by paediatricians. Government- and hospital-driven age-based transfer policies distract focus from the achievement of competencies in self care. Variable use of transition clinics, written patient information and support groups is probably due to economic and human-resource limitations. The consensus statement provides a standard for evolving and evaluating transition policies jointly agreed upon by paediatric and adult units.


Subject(s)
Guideline Adherence/statistics & numerical data , Guideline Adherence/standards , Nephrology/standards , Patient Transfer/standards , Pediatrics/standards , Practice Guidelines as Topic/standards , Adolescent , Adult , Child , Europe , Female , Hospital Units/standards , Hospital Units/statistics & numerical data , Humans , Male , Young Adult
4.
Pediatr Nephrol ; 29(7): 1169-74, 2014 Jul.
Article in English | MEDLINE | ID: mdl-23963710

ABSTRACT

Chronic kidney disease (CKD) and the need for renal replacement therapy (RRT) can place a great strain on the child and family. As well as the medical and nutritional prescription, each child and family requires an individual psychosocial prescription that requires input from multiprofessional team members. The information needs of each child and family need to be constantly evaluated as well as the choice of therapy in relation to social, psychological and economic factors. Many tertiary units lack adequate "time" to deliver such assessments and coordinate the support and respite care for those on long-term dialysis, especially when significant numbers of children are now accepted onto RRT programmes with co-morbidities. National and international standards are needed for the staffing of comprehensive tertiary paediatric renal units as well as studies evaluating supportive care to families.


Subject(s)
Renal Replacement Therapy/psychology , Social Support , Child , Family , Humans , Patient Education as Topic , Respite Care
5.
Pediatr Nephrol ; 28(12): 2361-8, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23843162

ABSTRACT

BACKGROUND: Many factors may impact upon choice of renal replacement therapy (RRT) for children and adolescents, including patient and family choice, patient size and distance from the renal centre as well as logistic issues such as facilities and staffing at the unit. We report a survey of factors influencing treatment choice in 14 European paediatric nephrology units. METHODS: A questionnaire was developed by consensus and completed by 14 members of the European Paediatric Dialysis Working Group on facilities, staffing and family assessments impacting on choice of therapy as well as choice of therapy for 97 patients commencing initial RRT in 2011. RESULTS: All units offered all modalities of RRT, but there were limitations for pre-emptive transplantation (PET) and largely adult surgical dependence for creation of arteriovenous fistulae and transplantation. The average waiting time for a deceased donor kidney was 18.5 (range 3-36) months. Full time dietetic support was available in six of the 14 units. There was no social worker, psychology, play therapy or teaching support in three, two, seven and four units, respectively. Assessment by other members of the multidisciplinary team and home visits before choice of therapy was carried out in 50 % of units, and although all patients were discussed at team meetings, the medical opinion predominated. In terms of types of RRT, 50 % of patients were commenced on chronic peritoneal dialysis (PD), 34 % on haemodialysis (HD) and 16 % underwent pre-emptive transplantation (PET). Chronic PD predominated in patients aged <5 years and HD predominated in those aged >10 years. Patient and family choice and age or size of patient were predominant factors in choice of therapy with a predictable decline in renal function favouring PET and social factors HD. CONCLUSIONS: Chronic peritoneal dialysis predominated as primary choice of RRT, especially in younger children. The PET rates remain low. The influence of surgeons predominanted, and national transplant rules may be significant. Most units had insufficient multiprofessional support, which may impact upon initial choice of therapy as well as sustaining families through RRT.


Subject(s)
Decision Support Techniques , Nephrology/methods , Patient Selection , Practice Patterns, Physicians' , Renal Insufficiency, Chronic/therapy , Renal Replacement Therapy/methods , Adolescent , Age Factors , Child , Child, Preschool , Cooperative Behavior , Europe , Female , Health Care Surveys , Humans , Infant , Interdisciplinary Communication , Male , Nutritionists , Patient Care Team , Patient Preference , Personnel Staffing and Scheduling , Professional-Family Relations , Prognosis , Renal Insufficiency, Chronic/diagnosis , Social Support , Surveys and Questionnaires , Time Factors , Waiting Lists , Workforce
6.
Nephrol Dial Transplant ; 28(7): 1908-14, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23348882

ABSTRACT

BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis (PD) that is associated with significant morbidity and mortality in adults. There are scarce data for children. We performed a 10-year survey to determine the prevalence, risk factors and outcome for EPS in children. METHODS: Chronic PD patients in 14 dialysis units participating in the European Paediatric Dialysis Working Group between January 2001 and December 2010 were included in this study. RESULTS: Twenty-two cases of EPS were reported (prevalence 1.5%; 8.7 per 1000 patient-years on PD). Median PD vintage was 5.9 (1.6-10.2) in EPS and 1.7 (0.7-7.7) years in the remainder of the PD population (P<0.0001). EPS patients had a significantly higher peritonitis rate than non-EPS patients (P=0.2). EPS was diagnosed while the child was on PD in 17 (77%), after conversion to haemodialysis (HD) in 3 and after transplantation in 2. Fifteen of 17 (88%) developed ultrafiltration (UF) failure. The median interval between UF failure and presentation with bowel obstruction was 2.8 (0.02-5.8) months. Twenty (91%) had clinical and radiological signs of bowel obstruction. Enterolysis was performed in 14 and 19 received immunosuppression or tamoxifen. Nine required parenteral nutrition. At final follow-up 4.8 (1.3-8.7) years after EPS diagnosis, 3 patients died, 11 had a functioning transplant and 8 were on HD. CONCLUSIONS: The prevalence of EPS in European children on PD is comparable with that of adult PD patients, but mortality from paediatric EPS is significantly lower. A high index of suspicion is required for the diagnosis of EPS in children with longer dialysis duration, a high peritonitis rate and UF failure.


Subject(s)
Kidney Failure, Chronic/complications , Peritoneal Dialysis/adverse effects , Peritoneal Fibrosis/etiology , Peritonitis/etiology , Adolescent , Adult , Child , Child, Preschool , Europe , Female , Follow-Up Studies , Health Surveys , Humans , Male , Peritoneal Dialysis/mortality , Peritoneal Fibrosis/diagnosis , Peritoneal Fibrosis/mortality , Peritoneal Fibrosis/therapy , Peritonitis/pathology , Prognosis , Risk Factors , Survival Rate , Ultrafiltration , Young Adult
7.
Pediatr Nephrol ; 28(9): 1739-48, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23052647

ABSTRACT

BACKGROUND: To provide recommendations for the care of infants with stage 5 chronic kidney disease (CKD5). SETTING: European Paediatric Dialysis Working Group. DATA SOURCES: Literature on clinical studies involving infants with CKD5 (end stage renal failure) and consensus discussions within the group. RECOMMENDATIONS: There has been an important change in attitudes towards offering RRT (renal replacement therapy) to both newborns and infants as data have accumulated on their improved survival and long-term outcomes. The management of this challenging group of patients differs in a number of ways from that of older children. The authors have summarised the basic recommendations for treating infants with CKD5 in order to support the multidisciplinary teams who endeavour on this difficult task.


Subject(s)
Kidney Failure, Chronic/therapy , Child , Child, Preschool , Counseling , Dialysis Solutions , Humans , Infant , Infant, Newborn , Infections/complications , Infections/therapy , Kidney Failure, Chronic/complications , Kidney Transplantation , Long-Term Care , Nutritional Requirements , Peritoneal Dialysis , Renal Replacement Therapy , Social Support , Urinary Catheterization
8.
Perit Dial Int ; 32(4): 410-8, 2012.
Article in English | MEDLINE | ID: mdl-22859841

ABSTRACT

UNLABELLED: BACKGROUND, OBJECTIVES, AND METHODS: Hospitalization and mortality rates in pediatric dialysis patients remain unacceptably high. Although studies have associated the presence of comorbidities with an increased risk for death in a relatively small number of pediatric dialysis patients, no large-scale study had set out to describe the comorbidities seen in pediatric dialysis patients or to evaluate the impact of those comorbidities on outcomes beyond the newborn period. In the present study, we evaluated the prevalence of comorbidities in a large international cohort of pediatric chronic peritoneal dialysis (CPD) patients from the International Pediatric Peritoneal Dialysis Network registry and began to assess potential associations between those comorbidities and hospitalization rates and mortality. RESULTS: Information on comorbidities was available for 1830 patients 0 - 19 years of age at dialysis initiation. Median age at dialysis initiation was 9.1 years [interquartile range (IQR): 10.9], median follow-up for calculation of hospitalization rates was 15.2 months (range: 0.2 - 80.9 months), and total follow-up time in the registry was 2095 patient-years. At least 1 comorbidity had been reported for 602 of the patients (32.9%), with 283 (15.5%) having cognitive impairment; 230 (12.6%), motor impairment; 167 (9.1%), cardiac abnormality; 76 (4.2%), pulmonary abnormality; 212 (11.6%), ocular abnormality; and 101 (5.5%), hearing impairment. Of the 150 patients (8.2%) that had a defined syndrome, 85% had at least 1 nonrenal comorbidity, and 64% had multiple comorbidities. The presence of at least 1 comorbidity was associated with a higher hospitalization rate [hospital days per 100 observation days: 1.7 (IQR: 5.8) vs 1.2 (IQR: 3.9), p = 0.001] and decreased patient survival (4-year survival rate: 73% vs 90%, p < 0.0001). CONCLUSIONS: Nearly one third of pediatric CPD patients in a large international cohort had at least 1 comorbidity, and multiple comorbidities were frequently reported among patients with a defined syndrome. Preliminary analysis suggests an association between comorbidity and poor outcome in those patients. As this powerful international registry matures, further multivariate analyses will be important to more clearly define the impact of comorbidities on hospitalization rates and mortality in pediatric CPD patients.


Subject(s)
Kidney Failure, Chronic/therapy , Peritoneal Dialysis/adverse effects , Adolescent , Child , Child, Preschool , Chronic Disease , Comorbidity , Female , Follow-Up Studies , Hospitalization , Humans , Infant , Kidney Failure, Chronic/epidemiology , Kidney Failure, Chronic/mortality , Male , Peritoneal Dialysis/mortality , Prevalence , Registries , Survival Analysis
9.
Pediatr Nephrol ; 27(8): 1335-40, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22410799

ABSTRACT

BACKGROUND: We report the long-term follow-up of children with antenatally detected unilateral multicystic dysplastic kidney (MCDK) who were followed between 1985 and 2009. METHODS: Involution rates were documented over time based on the initial size of the MCDK, as documented on postnatal ultrasound (USS), as well as long-term complications and renal function. RESULTS: In 323 patients (182 male), 10 % of MCDK had involuted, as evidenced on the first postnatal USS, with survival function analysis showing the probability of complete involution to be 35 % in 249 patients by 2 years of age, 47 % in 180 patients by 5 years of age and 62 % in 94 patients by 10 years of age. There was a significant difference in the involution rates of MCKD at the 10-year follow-up between MCDK with an initial size of >5 cm versus MCDK with an initial size of ≤5 cm (p < 0.0001). No patients in the whole cohort developed sustained hypertension or malignancy during a median follow-up of 10.1 years (range 0.3-15.4 years). Median estimated glomerular filtration rate (eGFR) in 76 patients (7 at 5 years, 69 at 10 years) was 93 ml/min/1.73 m(2) (range 46-175 ml/min/1.73 m(2)), with 40 (53%) having an eGFR of between 90 and 140 ml/min/1.73 m(2). Twenty-three (30 %) of the 76 patients at 10 years had normal eGFR (90-140 ml/min/1.73 m(2)) as well as complete involution of the MCDK, compensatory hypertrophy of the contralateral kidney, no proteinuria and no hypertension. CONCLUSIONS: Larger MCDK at birth are less likely to involute during the first decade of life. However, conservative management remains justified due to the lack of complications. A minority of patients fulfil current criteria for discharge from specialty follow-up at 10 years.


Subject(s)
Multicystic Dysplastic Kidney/complications , Multicystic Dysplastic Kidney/diagnostic imaging , Multicystic Dysplastic Kidney/pathology , Child , Child, Preschool , Female , Humans , Hypertension/epidemiology , Hypertension/etiology , Infant , Infant, Newborn , Kidney Diseases/epidemiology , Kidney Diseases/etiology , Kidney Function Tests , Male , Ultrasonography
10.
Pediatr Nephrol ; 27(6): 999-1004, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22205507

ABSTRACT

BACKGROUND: European and U.S. guidelines emphasise that permanent vascular access in the form of arteriovenous fistulae (AVF) or grafts (AVG) are preferable to central venous catheters (CVC) in paediatric patients on long-term haemodialysis. We report vascular access choice and complication rates in 13 European paediatric nephrology units. METHODS: A survey of units participating in the European Pediatric Dialysis Working Group requesting data on type of vascular access, routine care and complications in patients on chronic haemodialysis between March 2010 and February 2011. RESULTS: Information was complied on 111 patients in 13 participating centres with a median age of 14 (range 0.25-20.2) years. Central venous catheters were used in 67 of 111 (60%) patients, with 42 patients (38%) having an AVF and two patients (2%) having an AVG. Choice of vascular access was significantly related to patient age, with patients with AVF/AVG having a median age of 16 years compared to 12 years for patients with CVCs (p < 0.001). Routine CVC exit site care and catheter lock solution use differed between centres. CVC infections requiring intravenous antibiotics were reported at a rate of 1.9 and exit site infections at a rate of 1.8 episodes/1000 catheter days. Overall infective complications necessitating CVC change occurred at a rate of 0.9 episodes/1000 catheter days. No infective complications were reported in patients with AVF/AVG access. The rate of CVC infections requiring intravenous antibiotics was significantly lower in patients in whom CVC exit sites were cleaned weekly as opposed to every dialysis session (relative risk with every session cleaning vs. weekly cleaning 2.58, 95% confidence interval 1.17-5.69). Catheter malfunction (inadequate blood flow) was a more prevalent complication necessitating 22.4 thrombolytic interventions/1000 catheter days and 2.1 CVC changes/1000 catheter days. CONCLUSIONS: Central venous catheters remain the predominant choice of vascular access in Europe despite problems of malfunction and infection. AVF/AVG were predominantly used in adolescents without reported complications. More regular exit site cleaning may predispose to CVC infection, but this observation requires prospective evaluation.


Subject(s)
Arteriovenous Shunt, Surgical/trends , Blood Vessel Prosthesis Implantation/trends , Catheterization, Central Venous/trends , Practice Patterns, Physicians'/trends , Renal Dialysis/trends , Adolescent , Age Distribution , Age Factors , Anti-Bacterial Agents/therapeutic use , Arteriovenous Shunt, Surgical/adverse effects , Blood Vessel Prosthesis Implantation/adverse effects , Catheter-Related Infections/epidemiology , Catheter-Related Infections/therapy , Catheterization, Central Venous/adverse effects , Catheterization, Central Venous/instrumentation , Catheters, Indwelling/adverse effects , Catheters, Indwelling/trends , Child , Child, Preschool , Device Removal/trends , Equipment Failure , Europe , Guideline Adherence , Health Care Surveys , Humans , Infant , Patient Selection , Practice Guidelines as Topic , Retrospective Studies , Risk Assessment , Risk Factors , Surgical Wound Infection/epidemiology , Surgical Wound Infection/therapy , Thrombolytic Therapy/trends , Time Factors , Treatment Outcome , Upper Extremity Deep Vein Thrombosis/epidemiology , Upper Extremity Deep Vein Thrombosis/therapy , Young Adult
11.
J Am Soc Nephrol ; 22(12): 2303-12, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22021715

ABSTRACT

Very young children with chronic kidney disease often have difficulty maintaining adequate nutrition, which contributes to the high prevalence of short stature in this population. Characteristics of the dialysis prescription and supplemental feeding via a nasogastric (NG) tube or gastrostomy may improve growth, but this is not well understood. Here, we analyzed data from 153 children in 18 countries who commenced chronic peritoneal dialysis at <24 months of age. From diagnosis to last observation, 57 patients were fed on demand, 54 by NG tube, and 10 by gastrostomy; 26 switched from NG to gastrostomy; and 6 returned from NG to demand feeding. North American and European centers accounted for nearly all feeding by gastrostomy. Standardized body mass index (BMI) uniformly decreased during periods of demand feeding and increased during NG and gastrostomy feeding. Changes in BMI demonstrated significant regional variation: 26% of North American children were obese and 50% of Turkish children were malnourished at last observation (P < 0.005). Body length decreased sharply during the first 6 to 12 months of life and then tended to stabilize. Time fed by gastrostomy significantly associated with higher lengths over time (P < 0.001), but adjustment for baseline length attenuated this effect. In addition, the use of biocompatible peritoneal dialysate and administration of growth hormone independently associated with improved length, even after adjusting for regional factors. In summary, growth and nutritional status vary regionally in very young children treated with chronic peritoneal dialysis. The use of gastrostomy feeding, biocompatible dialysis fluid, and growth hormone therapy associate with improved linear growth.


Subject(s)
Body Size , Feeding Behavior , Peritoneal Dialysis , Female , Humans , Infant , Male , Prospective Studies
12.
Kidney Int ; 80(7): 704-7, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21832978

ABSTRACT

The transfer of young patients from pediatric to adult renal care takes place after a transition process which involves both sides. It is important that it is individualized for each young person, focusing on self-management skills as well as assessing support structures. The consensus statement has been developed by the panel of adult and pediatric nephrologists and endorsed by the councils of both ISN and IPNA. It is hoped that the statement will provide a basis for the development of locally appropriate recommendations for clinical practice.


Subject(s)
Nephrology , Pediatrics , Adolescent , Adult , Child , Continuity of Patient Care , Humans , Renal Insufficiency, Chronic/therapy , Societies, Medical , Young Adult
14.
Pediatr Nephrol ; 26(7): 1163-6, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21424282

ABSTRACT

Karyomegalic interstitial nephropathy has been reported as a rare interstitial nephritis in adult patients. Histology shows atypical epithelial cells and large abnormal hyperchromatic nuclei with irregular outlines. We report 3 adolescent patients who all recovered from their initial treatment for Ewing's sarcoma but developed a tubulopathy attributed to ifosfamide therapy. Renal impairment resulted in biopsy, which showed features of karyomegalic nephropathy in all 3. One patient has progressed to haemodialysis. Recognition of the pathology may be important in similar patients. It is surmised that the unusual histological findings in these patients stem from a common pathogenesis which may be related to chemotherapeutic agent related nuclear damage. At present there is no specific treatment to prevent progressive renal impairment.


Subject(s)
Antineoplastic Agents, Alkylating/adverse effects , Cell Nucleus Shape/drug effects , Epithelial Cells/drug effects , Ifosfamide/adverse effects , Kidney Tubules/drug effects , Nephritis, Interstitial/chemically induced , Sarcoma, Ewing/drug therapy , Adolescent , Biopsy , Chronic Disease , Disease Progression , Epithelial Cells/pathology , Fatal Outcome , Female , Humans , Kidney Tubules/pathology , Male , Nephritis, Interstitial/pathology , Nephritis, Interstitial/therapy , Renal Dialysis , Treatment Outcome
15.
Pediatr Nephrol ; 26(5): 767-73, 2011 May.
Article in English | MEDLINE | ID: mdl-21327779

ABSTRACT

Chronic kidney disease (CKD) would be expected to impact upon the quality of life (QoL) of children and young people; therefore, it is important that they are given the means to express their opinions about how they perceive their own QoL. We used the Generic Children's Quality of Life Measure (GCQ) in 225 paediatric renal patients (118 male, mean age 13.6 years, range 6.2-18.9 years) from seven UK centres. Of these, 47 were on dialysis (23 on haemodialysis), 128 were post-transplant (47 pre-emptive) and 49 had advanced CKD. A comparison between the 124 renal patients (65 male, mean age 11.2 years) in the same age range as the general population (6-14 years) showed a higher GCQ QoL score for the renal patients (p = 0.02). Analysis of the whole group of renal patients (n = 225) revealed no significant difference between the mean GCQ scores of participants in various treatment modalities (p = 0.26) and no significant differences between gender (p = 0.90) and age group (p = 0.44). The results indicate that young people can perceive their QoL as good despite living with what others may perceive as severe limitations. This may seem counter-intuitive, but QoL is a subjective measure and thus may be difficult to predict from observable limitations (health status). The GCQ is an ideal measure for use in annual departmental audits of generic paediatric QoL and may help to individualise the work of psychosocial teams with each patient.


Subject(s)
Kidney Failure, Chronic/complications , Kidney Failure, Chronic/psychology , Quality of Life , Adolescent , Child , Cross-Sectional Studies , Female , Humans , Male , Self Report , Surveys and Questionnaires , Young Adult
16.
Am J Pathol ; 177(3): 1534-48, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20639457

ABSTRACT

Integrin alpha3beta1 is a major receptor for laminin. The expression levels of laminins-8 and -10 in the basement membrane surrounding blood vessels are known to change during tumor angiogenesis. Although some studies have suggested that certain ligands of alpha3beta1 can affect angiogenesis either positively or negatively, either a direct in vivo role for alpha3beta1 in this process or its mechanism of action in endothelial cells during angiogenesis is still unknown. Because the global genetic ablation of alpha3-integrin results in an early lethal phenotype, we have generated conditional-knockout mice where alpha3 is deleted specifically in endothelial cells (ec-alpha3-/-). Here we show that ec-alpha3-/- mice are viable, fertile, and display enhanced tumor growth, elevated tumor angiogenesis, augmented hypoxia-induced retinal angiogenesis, and increased vascular endothelial growth factor (VEGF)-mediated neovascularization ex vivo and in vivo. Furthermore, our data provide a novel method by which an integrin may regulate angiogenesis. We show that alpha3beta1 is a positive regulator of endothelial-VEGF and that, surprisingly, the VEGF produced by endothelial cells can actually repress VEGF-receptor 2 (Flk-1) expression. These data, therefore, identify directly that endothelial alpha3beta1 negatively regulates pathological angiogenesis and implicate an unexpected role for low levels of endothelial-VEGF as an activator of neovascularization.


Subject(s)
Endothelial Cells/metabolism , Endothelium, Vascular/metabolism , Hypoxia/metabolism , Integrin alpha3beta1/metabolism , Neovascularization, Pathologic/metabolism , Vascular Endothelial Growth Factor A/metabolism , Animals , Blotting, Western , Endothelial Cells/pathology , Endothelium, Vascular/pathology , Female , Flow Cytometry , Hypoxia/genetics , Hypoxia/pathology , Immunohistochemistry , Integrin alpha3beta1/genetics , Male , Mice , Mice, Knockout , Neoplasm Transplantation , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Polymerase Chain Reaction , Vascular Endothelial Growth Factor Receptor-2/metabolism
17.
Saudi J Kidney Dis Transpl ; 21(4): 778-83, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20587895

ABSTRACT

Glomerular diseases are a common cause of chronic kidney disease (CKD) in many countries. The pattern of glomerular diseases has been reported in adult Sudanese patients but there has been no previous study on Sudanese children. The aim of this study is to describe the pattern of glomerular diseases in Sudanese children from a clinico-pathological perspective. We retrospectively reviewed the clinical records of 321 children seen with nephritis/nephrosis at the Pediatric Nephrology Unit, Soba University Hospital and Dr. Salma Dialysis and Kidney Transplantation Centre, Khartoum, Sudan during the period from 2002 to 2007. Biopsies were studied with light microscopy and immuno-histochemistry with electron microscopy performed abroad in selected patients (predominantly Alport's). The mean age of the 321 study children was 8.71 years (range 2 months-16 yrs) of whom, 188 were males (60.2%). The most common presentation was with the nephrotic syndrome, seen in 202 patients (62.9%). The most common glomerular disease encountered was minimal change disease, seen in 96 children (29.9%), followed by post-infectious GN in 78 (24.3%) and focal and segmental glomerulosclerosis, seen in 44 patients (13.7%). Membranoproliferative GN (MPGN) was seen in 43 patients (13.4%) while mesangioproliferative GN was seen in 24 (7.5%). Systemic lupus erythematosus (SLE) was the most common secondary glomerular disease accounting for 16 patients (4.9%). HBsAg was positive in 10 patients and the most common associated lesion was MPGN (60%). Histopathology enabled us to change the therapy in 55.3% of the patients. Our study suggests that the pattern of GN in our cohort of patients is comparable with reports from other parts of the world with a high prevalence of post-infectious GN. Renal biopsies have an important part in planning therapy and management. Also, the importance of establishing a Sudanese renal registry including pediatric patients is stressed.


Subject(s)
Glomerulonephritis, Membranoproliferative/epidemiology , Kidney Glomerulus/pathology , Adult , Child , Female , Glomerulonephritis, Membranoproliferative/pathology , Humans , Male , Nephrotic Syndrome/epidemiology , Nephrotic Syndrome/pathology , Registries , Sudan/epidemiology
18.
Nature ; 465(7299): 813-7, 2010 Jun 10.
Article in English | MEDLINE | ID: mdl-20535211

ABSTRACT

Down's syndrome (DS) is a genetic disorder caused by full or partial trisomy of human chromosome 21 and presents with many clinical phenotypes including a reduced incidence of solid tumours. Recent work with the Ts65Dn model of DS, which has orthologues of about 50% of the genes on chromosome 21 (Hsa21), has indicated that three copies of the ETS2 (ref. 3) or DS candidate region 1 (DSCR1) genes (a previously known suppressor of angiogenesis) is sufficient to inhibit tumour growth. Here we use the Tc1 transchromosomic mouse model of DS to dissect the contribution of extra copies of genes on Hsa21 to tumour angiogenesis. This mouse expresses roughly 81% of Hsa21 genes but not the human DSCR1 region. We transplanted B16F0 and Lewis lung carcinoma tumour cells into Tc1 mice and showed that growth of these tumours was substantially reduced compared with wild-type littermate controls. Furthermore, tumour angiogenesis was significantly repressed in Tc1 mice. In particular, in vitro and in vivo angiogenic responses to vascular endothelial growth factor (VEGF) were inhibited. Examination of the genes on the segment of Hsa21 in Tc1 mice identified putative anti-angiogenic genes (ADAMTS1and ERG) and novel endothelial cell-specific genes, never previously shown to be involved in angiogenesis (JAM-B and PTTG1IP), that, when overexpressed, are responsible for inhibiting angiogenic responses to VEGF. Three copies of these genes within the stromal compartment reduced tumour angiogenesis, explaining the reduced tumour growth in DS. Furthermore, we expect that, in addition to the candidate genes that we show to be involved in the repression of angiogenesis, the Tc1 mouse model of DS will permit the identification of other endothelium-specific anti-angiogenic targets relevant to a broad spectrum of cancer patients.


Subject(s)
Carcinoma, Lewis Lung/blood supply , Disease Models, Animal , Down Syndrome/genetics , Gene Dosage/genetics , Melanoma, Experimental/blood supply , Neovascularization, Pathologic/genetics , ADAM Proteins/genetics , ADAM Proteins/metabolism , ADAMTS1 Protein , Animals , Carcinoma, Lewis Lung/complications , Carcinoma, Lewis Lung/genetics , Carcinoma, Lewis Lung/pathology , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Adhesion Molecules/antagonists & inhibitors , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Chromosomes, Mammalian/genetics , Down Syndrome/complications , Down Syndrome/physiopathology , Female , Humans , Immunoglobulins/genetics , Immunoglobulins/metabolism , Intracellular Signaling Peptides and Proteins , Male , Melanoma, Experimental/complications , Melanoma, Experimental/genetics , Melanoma, Experimental/pathology , Mice , Neoplasm Transplantation , Neovascularization, Pathologic/pathology , Oncogene Proteins/genetics , Oncogene Proteins/metabolism , Proto-Oncogene Protein c-ets-2/genetics , Proto-Oncogene Protein c-ets-2/metabolism , Transcription Factors , Transcriptional Regulator ERG , Trisomy/genetics , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/pharmacology , Vascular Endothelial Growth Factor Receptor-2/metabolism
19.
Clin J Am Soc Nephrol ; 5(6): 1041-6, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20430942

ABSTRACT

BACKGROUND AND OBJECTIVES: The International Pediatric Peritonitis Registry (IPPR) was established to collect prospective data regarding peritoneal dialysis (PD)-associated peritonitis in children. In this report, we present the IPPR results that pertain to relapsing peritonitis (RP). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was an online, prospective entry into the IPPR of data that pertain to peritonitis cases by participating centers. RESULTS: Of 490 episodes of nonfungal peritonitis, 52 (11%) were followed by a relapse. There was no significant difference between RP and non-RP in distribution of causative organisms and antibiotic sensitivities. Initial empiric therapy-ceftazidime with either first-generation cephalosporin or glycopeptide (vancomycin or teicoplanin)-was not associated with relapse. Switching to monotherapy with a first-generation cephalosporin on the basis of culture results was associated with higher relapse rate (23%) than other final antibiotic therapies (0 to 9%). Culture-negative RP was less likely to have a satisfactory early treatment response than non-RP (82 versus 98%). Young age, single-cuff catheter, downward-pointing exit site, and chronic systemic antibiotic prophylaxis were additional independent risk factors for RP in the multivariate analysis. Compared with non-RP, RP was associated with a lower rate of full functional recovery (73 versus 91%), higher ultrafiltration problems (14 versus 2%), and higher rate of permanent PD discontinuation (17 versus 7%). CONCLUSIONS: This is the largest multicenter, prospective study to date to examine RP in children. In addition, this is the first report in the literature to examine specifically the relationship of postempiric antibiotic treatment regimens to the subsequent risk for relapse.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Catheter-Related Infections/drug therapy , Catheters, Indwelling/adverse effects , Peritoneal Dialysis/adverse effects , Peritonitis/drug therapy , Adolescent , Age Factors , Anti-Bacterial Agents/adverse effects , Antibiotic Prophylaxis/adverse effects , Catheter-Related Infections/metabolism , Chi-Square Distribution , Child , Child, Preschool , Drug Therapy, Combination , Europe , Female , Humans , Infant , Logistic Models , Male , Odds Ratio , Peritoneal Dialysis/instrumentation , Peritonitis/microbiology , Peritonitis/prevention & control , Prospective Studies , Registries , Republic of Korea , Risk Assessment , Risk Factors , Secondary Prevention , Treatment Outcome , United States , Young Adult
20.
Clin Med (Lond) ; 10(1): 30-3, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20408302

ABSTRACT

Clinical ethics committees (CECs) are increasing in number in the UK and have mostly developed in response to local interest, as opposed to being mandated as in the USA. However, there is no regulatory framework for UK CECs with no defined educational requirements or specification of core competencies for their members. The UK Clinical Ethics Network has consulted extensively with its members to set out, for the first time in the UK, the core competencies necessary for the provision of clinical ethics support. Recommendations for educational and membership requirements for CECs have also been made. Given the appropriate resources the standards proposed can be appropriately evaluated and are consistent with principles of ethical governance.


Subject(s)
Clinical Competence , Ethics Committees, Clinical , Ethics, Medical/education , Humans , United Kingdom , United States
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