Clinical and Regulatory Considerations for Central Venous Catheters for Hemodialysis.

Central venous catheters remain a vital option for access for patients receiving maintenance hemodialysis. There are many important and evolving clinical and regulatory considerations for all stakeholders for these devices. Innovation and transparent and comprehensive regulatory review of these devices is essential to stimulate innovation to help promote better outcomes for patients receiving maintenance hemodialysis. A workgroup that included representatives from academia, industry, and the US Food and Drug Administration was convened to identify the major design considerations and clinical and regulatory challenges of central venous catheters for hemodialysis. Our intent is to foster improved understanding of these devices and provide the foundation for strategies to foster innovation of these devices.

Growth and Nutrition in Pediatric Chronic Kidney Disease.

Children with chronic kidney disease (CKD) feature significant challenges to the maintenance of adequate nutrition and linear growth. Moreover, the impaired nutritional state contributes directly to poor growth. Therefore, it is necessary to consider nutritional status in the assessment of etiology and treatment of sub-optimal linear growth. The major causes of poor linear growth including dysregulation of the growth hormone/insulin-like growth factor-I (IGF-I) axis, nutritional deficiency, metabolic acidosis, anemia, renal osteodystrophy/bone mineral disease, and inflammation. This review summarizes the causes and assessment tools of growth and nutrition while providing a summary of state of the art therapies for these co-morbidities of pediatric CKD.

Regulatory Considerations for Hemodiafiltration in the United States.

Online hemodiafiltration provides greater removal of higher molecular weight uremic retention solutes than conventional high-flux hemodialysis. However, online hemodiafiltration is used sparsely in the United States in part because of a paucity of delivery systems cleared for clinical use by the US Food and Drug Administration. Although a pathway for regulatory approval exists in the United States, concerns remain, particularly regarding online production of the large volumes of sterile, nonpyrogenic substitution fluid infused directly into the bloodstream to maintain fluid balance. Clearly defined testing protocols, acceptable to Food and Drug Administration, will be useful to show that an online hemodiafiltration system is capable of routinely achieving a sterility assurance level of 10-6 and nonpyrogenic levels of endotoxin. Large-scale clinical experience has shown that systems providing this level of performance when combined with certain design features, such as redundancy, and an appropriate quality management process can routinely and safely produce substitution fluid for online hemodiafiltration.

FDA Regulatory Perspectives for Studies on Hemodialysis Vascular Access.

In an effort to foster innovation and new product development, the American Society of Nephrology and the US Food and Drug Administration partnered to form the Kidney Health Initiative in 2012. Part of the Kidney Health Initiative's mission is to foster development of therapies by creating a collaborative environment where the US Food and Drug Administration and the greater nephrology community can interact to optimize product evaluation. This particular Kidney Health Initiative project focused on products related to hemodialysis vascular access, with the goal of clarifying appropriate trial end points that could subsequently inform clinical, regulatory, and coverage decisions. Both the lack of common definitions and the lack of consensus on trial end points have been viewed as barriers to innovation in this area. Toward this end, the Kidney Health Initiative convened teams of expert stakeholders to address these issues for each major vascular access category (arteriovenous grafts, arteriovenous fistulas, and central venous catheters), and each team provided recommendations. This commentary provides an overview of the US Food and Drug Administration centers that regulate hemodialysis vascular access and certain laws and regulations that affect these products as well as our perspectives on some of the issues raised and end points proposed by the Kidney Health Initiative teams. The standardized definitions and clinical trial end points proposed by the teams represent an important step forward to improve innovation in this area.

Frequent hemodialysis: history of the modality and assessment of outcomes.

About 660,000 individuals have end-stage renal disease in the USA, the vast majority of whom are receiving standard, in-center, thrice-weekly hemodialysis (HD). The morbidity and mortality among patients receiving standard HD remain unacceptably high. Studies conducted over the past two decades have provided a substantial amount of information on the advantages and drawbacks of providing more frequent HD treatment, either in-center or at home. In this article I summarize these studies, focusing special attention on the randomized, cross-over study assessing outcomes in children who received either frequent, in-center HD or traditional, thrice-weekly, in-center HD performed by Laskin et al. (Pediatr Nephrol doi: 10.1007/s00467-017-3656-x , 2017).

Etiology and management of dyslipidemia in children with chronic kidney disease and end-stage renal disease.

Lipids are essential components of cell membranes, contributing to cell fuel, myelin formation, subcellular organelle function, and steroid hormone synthesis. Children with chronic kidney disease (CKD) and end-stage renal disease (ESRD) exhibit various co-morbidities, including dyslipidemia. The prevalence of dyslipidemias in children with CKD and ESRD is high, being present in 39-65% of patients. Elevated lipid levels in children without renal disease are a risk factor for cardiovascular disease (CVD), while the risk for CVD in pediatric CKD/ESRD is unclear. The pathogenesis of dyslipidemia in CKD features various factors, including increased levels of triglycerides, triglyceride-rich lipoproteins, apolipoprotein C3 (ApoC-III), decreased levels of cholesterylester transfer protein and high-density lipoproteins, and aberrations in serum very low-density and intermediate-density lipoproteins. If initial risk assessment indicates that a child with advanced CKD has 2 or more co-morbidities for CVD, first-line treatment should consist of non-pharmacologic management such as therapeutic lifestyle changes and dietary counseling. Pharmacologic treatment of dyslipidemia may reduce the incidence of CVD in children with CKD/ESRD, but randomized trials are lacking. Statins are the only class of lipid-lowering drugs currently approved by the U.S. Food and Drug Administration (FDA) for use in the pediatric population. FDA-approved pediatric labeling for these drugs is based on results from placebo-controlled trial results, showing 30-50% reductions in baseline low-density lipoprotein cholesterol. Although statins are generally well tolerated in adults, a spectrum of adverse events has been reported with their use in both the clinical trial and post-marketing settings.

Renal development: a complex process dependent on inductive interaction.

Renal development begins in-utero and continues throughout childhood. Almost one-third of all developmental anomalies include structural or functional abnormalities of the urinary tract. There are three main phases of in-utero renal development: Pronephros, Mesonephros and Metanephros. Within three weeks of gestation, paired pronephri appear. A series of tubules called nephrotomes fuse with the pronephric duct. The pronephros elongates and induces the nearby mesoderm, forming the mesonephric (Woffian) duct. The metanephros is the precursor of the mature kidney that originates from the ureteric bud and the metanephric mesoderm (blastema) by 5 weeks of gestation. The interaction between these two components is a reciprocal process, resulting in the formation of a mature kidney. The ureteric bud forms the major and minor calyces, and the collecting tubules while the metanephrogenic blastema develops into the renal tubules and glomeruli. In humans, all of the nephrons are formed by 32 to 36 weeks of gestation. Simultaneously, the lower urinary tract develops from the vesico urethral canal, ureteric bud and mesonephric duct. In utero, ureters deliver urine from the kidney to the bladder, thereby creating amniotic fluid. Transcription factors, extracellular matrix glycoproteins, signaling molecules and receptors are the key players in normal renal development. Many medications (e.g., aminoglycosides, cyclooxygenase inhibitors, substances that affect the renin-angiotensin aldosterone system) also impact renal development by altering the expression of growth factors, matrix regulators or receptors. Thus, tight regulation and coordinated processes are crucial for normal renal development.

Barriers to medication adherence and its relationship with outcomes in pediatric dialysis patients.

BACKGROUND: Medication adherence is a major factor determining outcome in children with chronic disease. Children with end-stage renal disease are challenged with requirements for renal replacement therapy in addition to complicated medication regimens. METHODS: We assessed barriers to medication adherence in 22 pediatric patients receiving chronic dialysis [63.6 % hemodialysis (HD), 36.4 % peritoneal dialysis (PD); age 15.9 ± 0.7 years, dialysis vintage 31.6 ± 6.5 months]. Adherence was assessed by a 16-question survey with a maximum score (difficulty) of 64. RESULTS: The overall mean adherence score was 30.9 ± 2.4 (range 16-49; median 27.5). There was a trend for lower adherence scores in patients on HD (27.5 ± 2.9) compared to those on PD (36.8 ± 3.7) (p = 0.06). Compared to HD patients, the mean score/question was significantly higher in PD patients (1.7 ± 0.2 vs. 2.4 ± 0.2, respectively; p = 0.006). Of the 16 questions, HD and PD patients gave a mean response of ≤1.2 for five and zero questions, respectively. Neither gender, age nor dialysis vintage was related to adherence scores. There was also a trend for adherence scores to be higher in females (35.6 ± 3.7) than in males (27.5 ± 2.9) (p = 0.1), but this difference did not reach statistical significance. Markers of mineral bone disease were similar in HD and PD patients. Among all targets in HD and PD patients combined, there was no relationship between adherence scores and number of targets reached (r = -0.09, p = 0.7). CONCLUSION: There are many barriers to medication adherence in pediatric patients receiving dialysis. In our patient group the difficulties were more evident in patients receiving PD than in those receiving HD.

High serum phosphorus and FGF 23 levels are associated with progression of coronary calcifications.

BACKGROUND: Coronary calcifications (CC) portend increased mortality in adults receiving hemodialysis (HD), however the risk factors associated with CC progression are not well known in pediatric patients. Our previous cross-sectional studies demonstrated high CC prevalence (31 %) in pediatric patients, which were significantly associated with high serum phosphorus (P), fibroblast growth factor 23 (FGF) levels, dialysis vintage, and low cholesterol. The current study was undertaken to determine and elucidate CC progression in pediatric HD patients. METHODS: A 1-year prospective longitudinal study of 16 pediatric patients (ten male; mean age, 16.9 ± 3 years; range, 10.1-20.4 years) receiving chronic HD was conducted. RESULTS: CC were observed in five of 16 (31.3 %) patients on baseline computed tomogram (CT) scan; 14/16 patients underwent 1-year CT. All patients with initial CC who completed CT at 1 year (3/5) progressed; one patient had new CC and none of the patients had resolved CC. Mean Agatston score increased from 23.4 ± 18.06 HU (baseline) to 169 ± 298.9 HU. Patients with CC progression had higher mean serum P (8.6 ± 1.8 mg/dl vs. 6.3 ± 1.1 mg/dl, p = 0.015) and FGF 23 levels (3,994 ± 860.5 pg/ml vs. 2,327 ± 1,206.4 pg/ml, p = 0.028). Serum P and FGF 23 levels were positively correlated with final Agatston scores (R = 0.65, p = 0.01 for serum P and R = 0.54, p = 0.045 for FGF 23) and change in Agatston scores (R = 0.65, p = 0.01 for serum P and R = 0.52, p = 0.048 for FGF 23). CONCLUSIONS: Our study shows that CC is progressive in pediatric patients receiving HD and that increased serum P and FGF 23 levels are associated with this progression.

Management of anemia with erythropoietic-stimulating agents in children with chronic kidney disease.

Anemia management is an important component of the care provided to children with chronic kidney disease (CKD) and influences both morbidity and mortality risk. The introduction of recombinant human erythropoietin to the treatment regimen three decades ago revolutionized the therapy and significantly decreased the need for repeated blood transfusions and exposure to associated risks. Recent data on the efficacy and complications associated with erythropoietic-stimulating agent (ESA) usage has, however, prompted a reassessment of treatment-related recommendations. This review will address these recommendations, in addition to describing pediatric outcomes associated with current ESAs and presenting information on alternative ESAs, many of which will likely soon be incorporated into clinical practice.

Comparative clinical outcomes between pediatric and young adult dialysis patients.

Published data on the comparative achievement of The Kidney Disease Dialysis Outcome Quality Initiative (KDOQI) recommended clinical performance targets between children and young adults on dialysis are scarce. To characterize the achievement of KDOQI targets among children (<18 years) and young adults (18-24 years) with prevalent end stage renal disease (ESRD), we performed a cross-sectional analysis of data collected by the Mid-Atlantic Renal Coalition, in conjunction with the 2007 and 2008 ESRD Clinical Performance Measures Projects. Data on all enrolled pediatric dialysis patients, categorized into three age groups (0-8, 9-12, 13-17 years), and on a random sample of 5% of patients ≥ 18 years in ESRD Network 5 were examined for two study periods: hemodialysis (HD) data were collected from October to December 2006 and from October to December 2007 and peritoneal dialysis (PD) data were collected from October 2006 to March 2007 and from October 2007 to March 2008. In total, 114 unique patients were enrolled the study, of whom 41.2% (47/114) were on HD and 58.8% (67/114) on PD. Compared to the pediatric patients, young adults were less likely to achieve the KDOQI recommended serum phosphorus levels and serum calcium × phosphorus product values, with less than one-quarter demonstrating values at or below each goal. Multivariate analysis revealed that both young adults and 13- to 17-year-olds were less likely to achieve target values for phosphorus [young adults: odds ratio (OR) 0.04, 95% confidence interval (95% CI) 0.01-0.19, p < 0.001; 13- to 17-year-olds: OR 0.17, 95% CI 0.04-0.77, p = 0.02] and calcium × phosphorus product (young adults: OR 0.01, 95% CI 0.002-0.09, p < 0.001; 13- to 17-year-olds: OR 0.09, 95% CI 0.02-0.56, p = 0.01) than younger children. In summary, there are significant differences in clinical indices between pediatric and young adult ESRD patients.

Serum uric acid is associated with high blood pressure in pediatric hemodialysis patients.

Serum uric acid (UA) is positively associated with hypertension (HTN). HTN is common in pediatric patients receiving hemodialysis (HD) and peritoneal dialysis (PD). We assessed the relationship between UA and BP in 63 pediatric dialysis patients by measuring pre-treatment UA levels and BP in HD patients and in-center UA levels and blood pressure (BP) in PD patients. UA levels were similar in both groups [6.8 ± 0.2 (HD) vs. 6.5 ± 0.3 (PD), p = 0.6]. Pre-treatment systolic BP percentile was associated with a high UA level [91.9 ± 2.3 (>6.0 mg/dL) vs. 79.3 ± 5.8 mm Hg (≤6.0 mg/dL), p = 0.01] in HD patients only. There was a negative relationship between UA and dialysis vintage (r = -0.31, p = 0.01). In both groups, there was no relationship between UA and Kt/V. In HD patients, fluid overload was unrelated to UA level [4.2 ± 0.6% (≤6.0 mg/dL) vs. 4.3 ± 0.3% (>6.0 mg/dL), p = 0.9]. Moreover, pre-HD treatment systolic BP percentile correlated with UA (beta 0.36, p = 0.02) independent of volume. UA levels were higher in patients receiving anti-hypertensive medications [6.3 ± 0.2 (No Meds] vs 7.0 ± 0.2 (BP Meds) mg/dL, p= 0.01]. Finally, there was no relationship between serum UA and normalized protein catabolic rate (r = 0.14; p = 0.4). In summary, serum UA impacts BP in pediatric HD patients, independent of volume, nutritional and weight status.

Elevated FGF 23 and phosphorus are associated with coronary calcification in hemodialysis patients.

Increased mortality of adult chronic hemodialysis (HD) patients is associated with coronary calcifications (CC), increased serum phosphorus (P), use of calcium (Ca)-containing P-binders, and vitamin D deficiency. Serum concentration of fibroblast growth factor 23 (FGF 23) is markedly elevated in adults receiving dialysis and is independently associated with increased mortality. Although coronary calcifications have been described in pediatric and adult HD patients, no significant association between serum FGF 23 and CC has been reported. In our study, 5/16 patients had CC. Patients with CC were older, had longer dialysis vintage and higher serum P. Serum Ca, total PTH, elemental Ca intake, and calcitriol doses were not different for CC patients. Serum FGF 23 levels were markedly elevated in all patients (mean 4,024, range 874-8,253), but significantly higher in patients with CC (4,247 ± 10,35 vs 2,427 ± 11,92, p = 0.01) and positively correlated with Agatston calcification score (r = 0.69, p = 0.003) and serum P (r = 0.49, p = 0.05). Using multivariate analysis, serum FGF 23 and serum P remained the most significant factors associated with Agatston score. This study confirms the occurrence of CC in pediatric HD patients and is the first to show a significant association between CC and elevated serum FGF 23 in children.

Malnutrition-inflammation-coronary calcification in pediatric patients receiving chronic hemodialysis.

Malnutrition, inflammation, and renal osteodystrophy parameters with resultant coronary calcification (CC) are associated with increased cardiovascular mortality in adults. Previous pediatric studies demonstrated CC in children but none assessed for an association between inflammation, malnutrition, renal osteodystrophy, and CC. To assess CC, ultrafast computerized tomogram was obtained for 16 pediatric patients (6 females; median age 17.2 years; range 9.1-21.2 years) receiving hemodialysis for >/=2 months. Inflammation was assessed by serum IL-6, IL-8, and C-reactive protein levels on the day of the computerized tomogram scan; nutrition parameters included serum albumin, cholesterol, the body mass index standard deviation score, and normalized protein catabolic rate. Renal osteodystrophy parameters included time-averaged serum calcium, phosphorus, total PTH, and calcitriol/calcium dose. Patients received hemodialysis thrice-weekly; mean single pool Kt/V 1.48+/-0.13; and mean normalized protein catabolic rate 1.27+/-0.17 g/kg/day. Five of 16 patients had CC. Patients with CC were older (19.1+/-2.1 vs. 15.4+/-3.1 months; P=0.03), had longer dialysis vintage (49.4+/-15.3 vs. 17.2+/-10.5 months, P=0.0002), lower serum cholesterol (122+/-17.7 vs. 160.4+/-10.6 mg/dL, P=0.02), and higher phosphorus (9.05+/-1.2 vs. 6.1+/-0.96 mg/dL, P=0.0001). Mean serum albumin and normalized protein catabolic rate did not differ for patients with CC. All patients had elevated IL-6 and IL-8 levels compared with healthy norms; the mean IL-6, IL-8, and C-reactive protein levels were not different in patients with CC. Coronary calcification was prevalent in older children receiving maintenance hemodialysis with a longer dialysis vintage. Worse renal osteodystrophy control and malnutrition (low cholesterol) may contribute to CC development.

Cause and outcome of central venous catheter infections in paediatric haemodialysis patients.

BACKGROUND: Paediatric patients with end-stage renal disease often receive haemodialysis (HD) via a central venous catheter (CVC). The most common problem with CVC is infection. METHODS: We assessed infection rates and subsequent outcome in paediatric chronic HD patients receiving dialysis via a CVC. RESULTS: Over a 3-year period, there were 28 episodes of infection in 17 patients. The overall rate of infection was 13.7 infections/100 catheter months. Among all catheters, catheter survival was 4.5 ± 0.8 months and similar in infected versus uninfected catheters. Among the 28 infections, there were 43 organisms captured. The most common organisms were Gram-positive, comprising 79% of all species. Among Gram-positive organisms, all coagulase-negative and -positive organisms were sensitive to vancomycin while all enterococci were sensitive to vancomycin. The majority of Gram-negative organisms were sensitive to aminoglycosides or cephalosporins. Among infected catheters, the rate of thrombosis was 1 event/1.7 catheter months; in uninfected catheters, the overall prevalence and rate of thrombosis was similar (1 event/1.6 catheter months). Thirty-nine percent of infections resulted in catheter loss within the subsequent 2 months, the most common reason being catheter occlusion. Multiple organisms/episode were more common in patients who required catheter replacement (46%) than in those who had salvage of the catheter (25%). CONCLUSIONS: In summary, HD catheter infection rates are high, while thrombosis rates are similar in infected and uninfected catheters. Infection with Gram-positive organisms was most common. The vast majority of CVC infections are cleared by antibiotics, although catheter loss is not uncommon even after clearance of the organism.

Outcome of accidental peritoneal dialysis catheter holes or tip exposure.

Pediatric peritoneal dialysis (PD) patients are at risk for acute peritonitis. One risk factor is accidental exposure of the catheter to a non-sterile surface. We studied catheter exposures in 17 pediatric patients receiving PD who developed 16 holes and 12 other accidental exposures. The rate of exposures was 3.7 events/100 patient-months. After exposure, the mean counts (+ or - standard error) of white blood cells (WBC), red blood cells, and neutrophils were 39.8 + or - 19.3, 9.5 + or - 7.1, and 24.2 + or - 5.3/mm(3), respectively. There was a trend towards higher peritoneal fluid WBC in patients with holes than in those with exposures (60.1 + or - 34.8 vs. 15.4 + or - 5.1/mm(3), respectively; p = 0.2). The initial peritoneal fluid WBC count was significantly higher if there was a positive culture than a negative culture (165.0 + or - 132.6 vs. 20.3 + or - 6.4/mm(3), respectively; p = 0.01). The percentage of neutrophils was higher in patients with a positive culture than in those with a negative culture (54.7 + or - 14.1 vs. 19.1 + or - 4.9%, respectively; p = 0.01). Of the 28 patients, 27 received a single dose of intravenous antibiotics, as per the protocol at that time. Among those treated, 7% developed a positive culture (all staphylococcal species) while 93% had a negative culture. We conclude that following accidental exposure of the peritoneal dialysis catheter: (1) the prevalence of peritonitis is low; (2) measuring peritoneal fluid WBC provides treatment guidance; (3) if treatment is initiated, it should be applied intraperitoneally and include activity against Gram-positive organisms.

Anti-erythropoietin antibodies followed by endogenous erythropoietin production in a dialysis patient.

We present a case of a young girl with end-stage renal disease secondary to anti-glomerular basement membrane disease who was receiving maintenance peritoneal dialysis and developed pure red cell aplasia secondary to anti-erythropoietin (EPO) antibodies. This occurred 13 months after the initiation of EPO alfa therapy for anemia. Initially, the patient required intermittent red blood cell transfusions. After immunosuppressive therapy had been initiated with corticosteroids and cyclosporine, the EPO antibody levels decreased precipitously, associated with an increased level of endogenous EPO production. For the following 6 months, the patient maintained adequate (>10 g/dL) hemoglobin levels and did not require red cell transfusions.

Non-infected hemodialysis catheters are associated with increased inflammation compared to arteriovenous fistulas.

Although hemodialysis catheters predispose to infection which, in turn, causes inflammation, we studied whether they induce inflammation independent of infection. We compared the level of the inflammatory marker C-reactive protein (CRP) in maintenance hemodialysis patients, comparing those dialyzed using a non-infected catheter to those using arteriovenous fistulas. All incident patients had catheters and fistula placement at dialysis initiation. In 35 patients the fistulas matured, the catheters were removed and the patients were evaluated at 6 months (catheter-fistula). These results were compared to 15 patients in whom the fistula did not mature and catheter use persisted for 6 months (catheter-catheter). There was a significant 82% reduction in the CRP level in the catheter-fistula group but a 16% increase in the catheter-catheter group at 6 months. The changes in CRP did not differ by gender, diabetes status, or by race, and was not correlated with a change in phosphorus, age, or urea reduction ratio at 1 month following hemodialysis initiation. Decreased CRP was associated with increased hemoglobin and albumin. Patients with persistent fistula use from dialysis initiation through 6 months had consistently low CRP levels over that time period. Our study shows that catheters might contribute to increased inflammation independent of infection, and supports avoidance of catheters and a timely conversion to fistulas with catheter removal.