Douglas M. Silverstein

Inflammation in chronic kidney disease: role in the progression of renal and cardiovascular disease

Inflammation is the response of the vasculature or tissues to various stimuli. An acute and chronic pro-inflammatory state exists in patients with chronic kidney disease (CKD), contributing substantially to morbidity and mortality. There are many mediators of inflammation in adults with CKD and end-stage kidney disease (ESKD), including hypoalbuminemia/malnutrition, atherosclerosis, advanced oxidation protein products, the peroxisome proliferators-activated receptor, leptin, the thiobarbituric acid reactive system, asymmetric dimethyl arginine, iron, fetuin-A, and cytokines. Inflammation contributes to the progression of CKD by inducing the release of cytokines and the increased production and activity of adhesion molecules, which together contribute to T cell adhesion and migration into the interstitium, subsequently attracting pro-fibrotic factors. Inflammation in CKD also causes mortality from cardiovascular disease by contributing to the development of vascular calcifications and endothelial dysfunction. Similar to the situation in adults, cardiovascular disease in pediatric CKD is linked to inflammation: abnormal left ventricular wall geometry is positively associated with markers of inflammation. This review focuses on traditional and novel mediators of inflammation in CKD and ESKD, and the deleterious effect inflammation has on the progression of renal and cardiovascular disease.

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.

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.

Acute and chronic inflammation in pediatric patients receiving hemodialysis.

OBJECTIVES To assess chronic and acute inflammation in children receiving maintenance hemodialysis. STUDY DESIGN To assess markers of acute inflammation, serum levels (ELISA) of the cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-10, and IL-6, 3 to 5 mL of serum was obtained from 13 pediatric patients (mean patient weight, 37.0+/-15.2 kg; mean age, 14.6+/-4.6 years) before and 30 minutes and 24 hours after a routine midweek hemodialysis treatment session. Chronic inflammation was assessed by serum C-reactive protein (CRP) levels. RESULTS Early-response cytokines TNF-alpha at 30 minutes (5.84+/-0.94 to 9.67+/-0.92 pg/mL; P=.002) and 24 hours (5.84+/-0.94 to 9.54+/-1.05 pg/mL; P=.008) and IL-1beta at 30 minutes (17.19+/-2.00 to 26.17+/-1.12 pg/mL; P=.001) and 24 hours (17.19+/-2.00 to 23.01+/-1.13 pg/mL; P=.02) increased significantly after hemodialysis. Later-response cytokines IL-10 and IL-6 activation was not significant. CRP levels were elevated in 10 of 13 patients (mean, 14.7+/-9.5mg/L; range, 7.2-38.8 mg/L) and correlated with dialysis vintage. Baseline IL-6 and IL-10 levels correlated with dialysis vintage and correlated negatively with eqKt/V. CONCLUSIONS We observed a chronic inflammatory state in pediatric hemodialysis patients not related to the hemodialysis treatment but rather dialysis vintage and hemodialysis adequacy. We suggest that either more frequent dialysis or enhanced cytokine clearance may ameliorate the chronic inflammatory state observed in pediatric patients receiving hemodialysis.

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.

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.

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

BackgroundCoronary 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.MethodsA 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.ResultsCC 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).ConclusionsOur 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.

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.

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.

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 (± standard error) of white blood cells (WBC), red blood cells, and neutrophils were 39.8 ± 19.3, 9.5 ± 7.1, and 24.2 ± 5.3/mm3, respectively. There was a trend towards higher peritoneal fluid WBC in patients with holes than in those with exposures (60.1 ± 34.8 vs. 15.4 ± 5.1/mm3, 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 ± 132.6 vs. 20.3 ± 6.4/mm3, 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 ± 14.1 vs. 19.1 ± 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.