Mortality in Children Treated With Maintenance Peritoneal Dialysis: Findings From the International Pediatric Peritoneal Dialysis Network Registry.

RATIONALE & OBJECTIVE: Research on pediatric kidney replacement therapy (KRT) has primarily focused on Europe and North America. In this study, we describe the mortality risk of children treated with maintenance peritoneal dialysis (MPD) in different parts of the world and characterize the associated demographic and macroeconomic factors. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Patients younger than 19 years at inclusion into the International Pediatric Peritoneal Dialysis Network registry, who initiated MPD between 1996 and 2017. EXPOSURE: Region as primary exposure (Asia, Western Europe, Eastern Europe, Latin America, North America, and Oceania). Other demographic, clinical, and macroeconomic (4 income groups based on gross national income) factors also were studied. OUTCOME: All-cause MPD mortality. ANALYTICAL APPROACH: Patients were observed for 3 years, and the mortality rates in different regions and income groups were calculated. Cause-specific hazards models with random effects were fit to calculate the proportional change in variance for factors that could explain variation in mortality rates. RESULTS: A total of 2,956 patients with a median age of 7.8 years at the start of KRT were included. After 3 years, the overall probability of death was 5%, ranging from 2% in North America to 9% in Eastern Europe. Mortality rates were higher in low-income countries than in high-income countries. Income category explained 50.1% of the variance in mortality risk between regions. Other explanatory factors included peritoneal dialysis modality at start (22.5%) and body mass index (11.1%). LIMITATIONS: The interpretation of interregional survival differences as found in this study may be hampered by selection bias. CONCLUSIONS: This study shows that the overall 3-year patient survival on pediatric MPD is high, and that country income is associated with patient survival.

Protein energy wasting; what is it and what can we do to prevent it?

Some children with declining height and BMI SDS fail to respond to optimisation of nutritional intake. As well as poor growth, they have muscle wasting and relative preservation of body fat. This is termed protein energy wasting (PEW). The process results from an interaction of chronic inflammation alongside poor nutritional intake. This review discusses the causes and potential preventative therapies for PEW.

ADCK4-Associated Glomerulopathy Causes Adolescence-Onset FSGS.

Hereditary defects of coenzyme Q10 biosynthesis cause steroid-resistant nephrotic syndrome (SRNS) as part of multiorgan involvement but may also contribute to isolated SRNS. Here, we report 26 patients from 12 families with recessive mutations in ADCK4. Mutation detection rate was 1.9% among 534 consecutively screened cases. Patients with ADCK4 mutations showed a largely renal-limited phenotype, with three subjects exhibiting occasional seizures, one subject exhibiting mild mental retardation, and one subject exhibiting retinitis pigmentosa. ADCK4 nephropathy presented during adolescence (median age, 14.1 years) with nephrotic-range proteinuria in 44% of patients and advanced CKD in 46% of patients at time of diagnosis. Renal biopsy specimens uniformly showed FSGS. Whereas 47% and 36% of patients with mutations in WT1 and NPHS2, respectively, progressed to ESRD before 10 years of age, ESRD occurred almost exclusively in the second decade of life in ADCK4 nephropathy. However, CKD progressed much faster during adolescence in ADCK4 than in WT1 and NPHS2 nephropathy, resulting in similar cumulative ESRD rates (>85% for each disorder) in the third decade of life. In conclusion, ADCK4-related glomerulopathy is an important novel differential diagnosis in adolescents with SRNS/FSGS and/or CKD of unknown origin.

Clinico-pathological correlations of congenital and infantile nephrotic syndrome over twenty years.

BACKGROUND: Nephrotic syndrome (NS) presenting early in life is caused by heterogeneous glomerular diseases. We retrospectively evaluated whether histological diagnosis in children presenting with NS in the first year of life predicts remission or progression to end-stage kidney disease (ESKD). METHODS: This is a single centre retrospective review of all children diagnosed with NS before one year of age between 1990 and 2009. All subjects had a renal biopsy, which was independently blindly reviewed by a single renal pathologist for the purpose of this study. RESULTS: Forty-nine children (25 female) who presented at 0.1-11.6 (median 1.6) months were included with 31 presenting within the first three months of life. Histopathological review diagnostic categories were; 13 Mesangial proliferative glomerulopathy (MesGN), 12 Focal and segmental glomerulosclerosis (FSGS), 11 Finnish type changes, eight Diffuse Mesangial Sclerosis (DMS), three Minimal change disease (MCD) and one each of Dense Deposit Disease (DDD) and Membranous nephropathy. Two children died from haemorrhagic complications of the biopsy. Eight children achieved remission (four MesGN, one Finnish type changes, one FSGS, one MCD and one membranous) with patient and renal survival of 73 % and 43 %, respectively, at follow-up duration of 5-222 (median 73) months (with five lost to follow-up). All children with Finnish-type histopathological changes presented within five months of age. Due to the historical nature of the cohort, genetic testing was only available for 14 children, nine of whom had an identifiable genetic basis (seven NPHS1, one PLCE1 and one ITGA3) with none of these nine children achieving remission. All of them had presented within four months of age and required renal replacement therapy, and two died. CONCLUSIONS: Histopathological findings are varied in children presenting with NS early in life. Whilst groups of histological patterns of disease are associated with differing outcomes, accurate prediction of disease course in a specific case is difficult and more widespread genetic testing may improve the understanding of this group of diseases and their optimal management.

Hemodialysis-induced acute myocardial dyssynchronous impairment in children.

UNLABELLED: In adults, recurrent hemodialysis (HD)-induced cardiac injury results in ischemic myocardial dysfunction. Uremic children, like adults, share the full complement of uremia-related cardiovascular abnormalities but without significant atheromatous coronary artery disease. The aim of this study was, to assess the impact of HD on left ventricular (LV) myocardial function in children. METHOD: We assessed all single-center chronic HD patients (n = 15, range 1-17 years) excluding those with overt cardiac disease. Regional LV function and mechanical synchronicity was measured echographically by two-dimensional segmental longitudinal, circumferential and radial myocardial strain. All patients were assessed pre-dialysis and at the end of dialysis. In addition, we scanned age-matched controls at rest. RESULTS: The peak longitudinal strain was lower in uremic patients compared with controls with a significant fall during HD (mean peak strain -19.9 controls, -17.9 pre-HD, -15.3 end of HD, p < 0.05). Radial strain was lower in uremic patients and increased during HD. Circumferential strain was preserved in uremic patients and fell during HD. Intrasegmental deformation synchronicity was progressively worse pre-dialysis and end of dialysis compared with controls. Intradialytic peak longitudinal strain reduction was significantly associated with systolic blood pressure and ultrafiltrate volume (p < 0.05). CONCLUSION: Uremic children have impaired regional LV function, with a predisposition to longitudinal axis dysfunction and LV mechanical dyssynchrony, both of which are established markers of ischemic injury. This is further evidence for a characteristic cardiovascular phenotype in uremic patients that predisposes them to subclinical demand ischemia during dialysis.

Nephrectomy for the failed renal allograft in children: predictors and outcomes.

BACKGROUND: There are no guidelines for the removal of a failed renal allograft, and its impact on subsequent dialysis and retransplantation has not yet been described. METHODS: We performed a 10-year review of allograft failure to study the factors that determined an outcome of transplant nephrectomy and choice of subsequent renal replacement therapy in children with or without nephrectomy. RESULTS: A total of 34 children developed graft failure over the 10-year study period, of whom 18 (53 %) required transplant nephrectomy. The median graft survival was 1.1 (range 0.2-10.6) versus 7.5 (1.5-15.0) years in the nephrectomy and non-nephrectomy groups, respectively (p = 0.011). Children with graft failure within 1 year of transplantation were four-fold more likely to require transplant nephrectomy than those with graft failure after 1 year (p = 0.04). Renal biopsy performed at ≤ 8 weeks prior to graft loss showed Banff grade II acute rejection in 13 of the 18 children who required subsequent nephrectomy versus three of the 13 children who did not need nephrectomy (p = 0.01). Inflammation (fever, graft tenderness and raised C-reactive protein (CRP) in the 2 weeks preceding graft failure) was seen in 66 % of nephrectomized children, but not in any in the non-nephrectomy group (p = 0.0003 for CRP between groups). Banff II rejection, an inflammatory response and the time post-transplantation significantly and independently predicted the outcome of nephrectomy (p = 0.008, R (2) = 67 %). Human leukocyte antigen (HLA) antibody levels after graft failure were higher in the nephrectomy group (p = 0.0003), but there was no difference between groups in terms of the presence or class of donor-specific antibodies. Of the children with graft failure, 82 % required dialysis (61 % hemodialysis) and 35 % have to date been successfully retransplanted. CONCLUSIONS: Children with Banff II rejection, an inflammatory response and early graft loss are more likely to require transplant nephrectomy. Nephrectomy may be associated with higher circulating HLA antibody levels.

Management of anemia in children receiving chronic peritoneal dialysis.

Little information exists regarding the efficacy, modifiers, and outcomes of anemia management in children with CKD or ESRD. We assessed practices, effectors, and outcomes of anemia management in 1394 pediatric patients undergoing peritoneal dialysis (PD) who were prospectively followed in 30 countries. We noted that 25% of patients had hemoglobin levels below target (<10 g/dl or <9.5 g/dl in children older or younger than 2 years, respectively), with significant regional variation; levels were highest in North America and Europe and lowest in Asia and Turkey. Low hemoglobin levels were associated with low urine output, low serum albumin, high parathyroid hormone, high ferritin, and the use of bioincompatible PD fluid. Erythropoiesis-stimulating agents (ESAs) were prescribed to 92% of patients, and neither the type of ESA nor the dosing interval appeared to affect efficacy. The weekly ESA dose inversely correlated with age when scaled to weight but did not correlate with age when normalized to body surface area. ESA sensitivity was positively associated with residual diuresis and serum albumin and inversely associated with serum parathyroid hormone and ferritin. The prevalence of hypertension and left ventricular hypertrophy increased with the degree of anemia. Patient survival was positively associated with achieved hemoglobin and serum albumin and was inversely associated with ESA dose. In conclusion, control of anemia in children receiving long-term PD varies by region. ESA requirements are independent of age when dose is scaled to body surface area, and ESA resistance is associated with inflammation, fluid retention, and hyperparathyroidism. Anemia and high ESA dose requirements independently predict mortality.

Circulating angiopoietin-2 is a marker for early cardiovascular disease in children on chronic dialysis.

Cardiovascular disease (CVD) is increasingly recognised as a complication of childhood chronic kidney disease (CKD) even in the absence of diabetes and hypertension. We hypothesized that an alteration in angiopoietin-1 and -2, growth factors which regulate endothelial and vascular function could be involved. We report that the endothelial survival factor, angiopoietin-1 is low in children with pre-dialysis CKD whereas the pro-inflammatory angiopoietin-2 is elevated in children on dialysis. In dialysis patients, angiopoietin-2 positively correlated with time on dialysis, systolic blood pressure, and carotid artery intima media thickness. Elevated angiopoietin-2 levels in dialysis versus pre-dialysis CKD patients were also associated with an anti-angiogenic (high soluble VEGFR-1 and low VEGF-A) and pro-inflammatory (high urate, E-selectin, P-selectin and VCAM-1) milieu. Ang-2 was immunodetected in arterial biopsy samples whilst the expression of VEGF-A was significantly downregulated in dialysis patients. Serum urate correlated with angiopoietin-2 levels in dialysis patients and addition of uric acid was able to induce rapid release of angiopoietin-2 from cultured endothelial cells. Thus, angiopoietin-2 is a marker for cardiovascular disease in children on chronic dialysis and may act as an anti-angiogenic and pro-inflammatory effector in this context. The possibility that the release of angiopoietin-2 from endothelia is mediated by urate should be explored further.

Nutrition and growth in children with chronic kidney disease.

Poor growth in chronic kidney disease (CKD) is a marker of disease severity and of quality of care. Causes are multifactorial, and include malnutrition, cachexia, hematological factors, endocrine problems and metabolic abnormalities. In this Review, we focus on the impact of inadequate nutrition on growth disturbances in children with CKD, and discuss all aspects of the epidemiology, causes and potential treatments. Regional variations in resources may be a factor that contributes to the observed differences. Successful nutritional management requires a multidisciplinary team that includes not only doctors but also skilled nurses and dieticians. Extremes of body mass index, representing undernutrition and overnutrition, are associated with poor outcomes and should be avoided when designing therapeutic strategies for optimizing nutrition and growth in children with CKD. Improved understanding of the pathophysiology of cachexia and wasting in patients with CKD could lead to the development of novel therapeutic strategies.

The virtues of vitamin D--but how much is too much?

Vitamin D deficiency is common in healthy adults and children as well as in the chronic kidney disease (CKD) population. What was once a disease of malnourished children in the developing world has re-emerged and reached pandemic proportions. In parallel with this development, there is a growing awareness that vitamin D is not simply a 'calcaemic hormone' but plays an important role in the prevention of cardiovascular disease, infectious and auto-immune conditions, renoprotection, glycaemic control and prevention of some common cancers. Most tissues in the body have a vitamin D receptor and the enzymatic machinery to convert 'nutritional' 25-hydroxyvitamin D to the active form 1,25-dihydroxyvitamin D; it is estimated that 3% of the human genome is regulated by the vitamin D endocrine system. Although there are few well-conducted studies on the benefits of vitamin D therapy, an exuberant use of vitamin D is now seen in the general population and at all stages of CKD. There is emerging evidence that vitamin D may in fact have a therapeutic window, and at least from the effects on the cardiovascular system, more is not necessarily better. In this review, we discuss the role of nutritional vitamin D (ergocalciferol or cholecalciferol) supplementation in CKD patients, interpreting the clinical studies in the light of the vitamin D metabolic pathway and its pluripotent effects. While nutritional vitamin D compounds clearly have numerous beneficial effects, randomised controlled studies are required to determine the effectiveness and optimal dose at different stages of CKD, its concurrent use with activated vitamin D compounds and its safety profile.

Eosinophilic peritonitis in children on chronic peritoneal dialysis.

Eosinophilic peritonitis is a response of the peritoneum to foreign substances. It presents as cloudy dialysate and may be missed because not all laboratories report the eosinophil count, giving only the total number of polymorphonuclear cells. Over a 2-year period, eight children developed 13 episodes of eosinophilic peritonitis. Three episodes were asymptomatic other than cloudy fluid, five followed surgery and two were associated with gastroenteritis. Despite recurrent episodes, there were no adverse outcomes, although a raised peritoneal eosinophil count persisted in most cases. Eosinophilic peritonitis is under-diagnosed and may lead to unnecessary antibiotic therapy.

Chronic mineral dysregulation promotes vascular smooth muscle cell adaptation and extracellular matrix calcification.

In chronic kidney disease (CKD) vascular calcification occurs in response to deranged calcium and phosphate metabolism and is characterized by vascular smooth muscle cell (VSMC) damage and attrition. To gain mechanistic insights into how calcium and phosphate mediate calcification, we used an ex vivo model of human vessel culture. Vessel rings from healthy control subjects did not accumulate calcium with long-term exposure to elevated calcium and/or phosphate. In contrast, vessel rings from patients with CKD accumulated calcium; calcium induced calcification more potently than phosphate (at equivalent calcium-phosphate product). Elevated phosphate increased alkaline phosphatase activity in CKD vessels, but inhibition of alkaline phosphatase with levamisole did not block calcification. Instead, calcification in CKD vessels most strongly associated with VSMC death resulting from calcium- and phosphate-induced apoptosis; treatment with a pan-caspase inhibitor ZVAD ameliorated calcification. Calcification in CKD vessels was also associated with increased deposition of VSMC-derived vesicles. Electron microscopy confirmed increased deposition of vesicles containing crystalline calcium and phosphate in the extracellular matrix of dialysis vessel rings. In contrast, vesicle deposition and calcification did not occur in normal vessel rings, but we observed extensive intracellular mitochondrial damage. Taken together, these data provide evidence that VSMCs undergo adaptive changes, including vesicle release, in response to dysregulated mineral metabolism. These adaptations may initially promote survival but ultimately culminate in VSMC apoptosis and overt calcification, especially with continued exposure to elevated calcium.

Tube feeding in children with chronic kidney disease: technical and practical issues.

This review discusses the indications for enteral feeding in children with chronic kidney disease, the types of feeding tubes that can be used, methods of insertion and their benefits and complications.

A phase I trial of epstein-barr virus gp350 vaccine for children with chronic kidney disease awaiting transplantation.

BACKGROUND.: Vaccination against Epstein-Barr virus (EBV), inducing an antibody response to the envelope glycoprotein gp350, might protect EBV-negative children with chronic kidney disease from lymphoproliferative disease after transplantation. METHODS.: A phase I trial recruited children with chronic kidney disease to two successive cohorts given three injections of 12.5 microg (n=6) and 25 microg (n=10) recombinant gp350/alhydrogel vaccine over 6 to 8 weeks. RESULTS.: One in each cohort acquired wild EBV before the week 28 evaluation. Both doses were similarly immunogenic, inducing an IgG response in all 13 evaluable patients. Neutralizing antibodies were detected in four recipients (1/4 in the 12.5 microg and 3/9 in the 25 microg cohort). Median time from first vaccination to transplantation was 24 weeks. Immune responses declined rapidly and were unlikely to affect posttransplant events. DISCUSSION.: The vaccine was immunogenic but a prolonged vaccine schedule up to time of transplantation or improved adjuvants are required in future trials to reduce posttransplant EBV load and risk of lymphoproliferative disease.

Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) caused by mutations in PKD1 is significantly more severe than PKD2. Typically, ADPKD presents in adulthood but is rarely diagnosed in utero with enlarged, echogenic kidneys. Somatic mutations are thought crucial for cyst development, but gene dosage is also important since animal models with hypomorphic alleles develop cysts, but are viable as homozygotes. We screened for mutations in PKD1 and PKD2 in two consanguineous families and found PKD1 missense variants predicted to be pathogenic. In one family, two siblings homozygous for R3277C developed end stage renal disease at ages 75 and 62 years, while six heterozygotes had few cysts. In the other family, the father and two children with moderate to severe disease were homozygous for N3188S. In both families homozygous disease was associated with small cysts of relatively uniform size while marked cyst heterogeneity is typical of ADPKD. In another family, one patient diagnosed in childhood was found to be a compound heterozygote for the PKD1 variants R3105W and R2765C. All three families had evidence of developmental defects of the collecting system. Three additional ADPKD families with in utero onset had a truncating mutation in trans with either R3277C or R2765C. These cases suggest the presence of incompletely penetrant PKD1 alleles. The alleles alone may result in mild cystic disease; two such alleles cause typical to severe disease; and, in combination with an inactivating allele, are associated with early onset disease. Our study indicates that the dosage of functional PKD1 protein may be critical for cyst initiation.

Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis.

BACKGROUND: Vascular calcification is associated with increased morbidity and mortality in stage V chronic kidney disease, yet its early pathogenesis and initiating mechanisms in vivo remain poorly understood. To address this, we quantified the calcium (Ca) load in arteries from children (10 predialysis, 24 dialysis) and correlated it with clinical, biochemical, and vascular measures. METHODS AND RESULTS: Vessel Ca load was significantly elevated in both predialysis and dialysis and was correlated with the patients' mean serum Ca x phosphate product. However, only dialysis patients showed increased carotid intima-media thickness and increased aortic stiffness, and calcification on computed tomography was present in only the 2 patients with the highest Ca loads. Importantly, predialysis vessels appeared histologically intact, whereas dialysis vessels exhibited evidence of extensive vascular smooth muscle cell (VSMC) loss owing to apoptosis. Dialysis vessels also showed increased alkaline phosphatase activity and Runx2 and osterix expression, indicative of VSMC osteogenic transformation. Deposition of the vesicle membrane marker annexin VI and vesicle component mineralization inhibitors fetuin-A and matrix Gla-protein increased in dialysis vessels and preceded von Kossa positive overt calcification. Electron microscopy showed hydroxyapatite nanocrystals within vesicles released from damaged/dead VSMCs, indicative of their role in initiating calcification. CONCLUSIONS: Taken together, this study shows that Ca accumulation begins predialysis, but it is the induction of VSMC apoptosis in dialysis that is the key event in disabling VSMC defense mechanisms and leading to overt calcification, eventually with clinically detectable vascular damage. Thus the identification of factors that lead to VSMC death in dialysis will be of prime importance in preventing vascular calcification.

Bone histomorphometry in children prior to commencing renal replacement therapy.

Renal osteodystrophy (ROD) develops early in the course of chronic kidney disease (CKD). With improving patient survival it's importance and relevance has increased. The last published bone biopsy data in children prior to renal replacement therapy (RRT) was in 1982, which demonstrated abnormal histology in all patients with a glomerular filtration rate (GFR) <20 ml/min per 1.73 m(2). Studies investigating the relationship between bone histology and parathyroid hormone levels (PTH) and/or growth in children with CKD are few (seven). These were mostly undertaken in patients already initiated on RRT-dialysis. We investigated the presence of ROD in children at the commencement of RRT and to investigate any relationship between histology, growth and PTH levels. Following double tetracycline labelling, bone biopsies were taken from patients at the time of RRT surgery. Histological classification was based on the newly proposed turnover/mineralisation/volume (TMV) system. Eleven patients underwent bone biopsy. Patients were followed for an average of 1.1 years (0.5-1.8) prior to biopsy over an average of eight clinic visits (3-14), when routine biochemical data were collected. Time-integrated median calcium, phosphate and PTH levels were calculated. PTH levels were within the normal range in two patients with low turnover, 1.1-1.4 times the upper limit of normal (ULN) in three with mixed osteodystrophy and >2.9 times the ULN in four patients with high bone turnover. There was no relationship between bone turnover and growth. The presence of ROD was universal in these children with severe CKD. Low bone turnover was associated with normal-range mean PTH levels, and high bone turnover occurred at lower PTH levels than current guidelines would suggest.

A sporadic case of paraganglioma undetected by urine metabolite screening.

Phaeochromocytoma is a rare cause of hypertension in children, but important to be recognised, as hypertension can be severe and surgery is often curative. Here, we report on a 7-year-old boy with a phaeochromocytoma, who had normal levels of commonly assayed catecholamine metabolites in the urine. Postoperatively, the patient developed renal vein thrombosis. Appropriate screening tests for phaeochromocytomas, peri-operative management, and the high incidence of an underlying genetic basis, even in sporadic cases, are discussed.

The circulating calcification inhibitors, fetuin-A and osteoprotegerin, but not matrix Gla protein, are associated with vascular stiffness and calcification in children on dialysis.

BACKGROUND: Vascular calcification occurs in the majority of patients with chronic kidney disease, but a subset of patients does not develop calcification despite exposure to a similar uraemic environment. Physiological inhibitors of calcification, fetuin-A, osteoprotegerin (OPG) and undercarboxylated-matrix Gla protein (uc-MGP) may play a role in preventing the development and progression of ectopic calcification, but there are scarce and conflicting data from clinical studies. METHODS: We measured fetuin-A, OPG and uc-MGP in 61 children on dialysis and studied their associations with clinical, biochemical and vascular measures. RESULTS: Fetuin-A and OPG were higher and uc-MGP lower in dialysis patients than controls. In controls, fetuin-A and OPG increased with age. Fetuin-A showed an inverse correlation with dialysis vintage (P = 0.0013), time-averaged serum phosphate (P = 0.03) and hs-CRP (P = 0.001). Aortic pulse wave velocity (PWV) and augmentation index showed a negative correlation with fetuin-A while a positive correlation was seen with PWV and OPG. Patients with calcification had lower fetuin-A and higher OPG than those without calcification. On multiple linear regression analysis Fetuin-A independently predicted aortic PWV (P = 0.004, beta = -0.45, model R(2) = 48%) and fetuin-A and OPG predicted cardiac calcification (P = 0.02, beta = -0.29 and P = 0.014, ss = 0.33, respectively, model R(2) = 32%). CONCLUSIONS: This is the first study to define normal levels of the calcification inhibitors in children and show that fetuin-A and OPG are associated with increased vascular stiffness and calcification in children on dialysis. Higher levels of fetuin-A in children suggest a possible protective upregulation of fetuin-A in the early stages of exposure to the pro-calcific and pro-inflammatory uraemic environment.