Potential cardiovascular risk factors in chronic kidney disease: AGEs, total homocysteine and metabolites, and the C-reactive protein

BACKGROUND: Total homocysteine (tHcy) and advanced glycation end-products (AGEs) are implicated in the pathogenesis of vascular damage. This study aimed to investigate whether elevated serum levels of the AGEs pentosidine, N(epsilon)-carboxymethyllysine (CML) and imidazolone; tHcy, cystathionine, methylmalonic acid (MMA), and 2-methylcitric acid (2-MCA), as well as C-reactive protein (CRP), are related to a higher risk for cardiovascular events. METHODS: A total of 232 patients with chronic kidney diseases (mean age 57.6 +/- 13.1 years, 82 female and 150 male); 99 with chronic renal failure (CRF), 84 maintenance hemodialysis patients and 49 renal transplant recipients were followed for 2 years. The relationship between the parameters of interest, conventional risk factors and elevated levels of CRP with cardiovascular events was tested in all subjects by the Cox proportional hazards model. RESULTS: Mean serum levels of AGEs, tHcy, and of the metabolites were found to be significantly increased in all three groups compared to the healthy subjects (P < 0.01, respectively). Fifty-three cardiovascular events occurred during follow-up; a total of 40 patients died. Final multivariate analysis showed diabetes (RR 2.06, 95% CI 1.17-3.60, P= 0.013), end-stage renal disease (ESRD) (RR 4.88, 95% CI 2.40-9.89, P < 0.001) and elevated CRP levels (RR 2.00, 95% CI 1.11-3.60, P= 0.021) as independent risk factors for cardiovascular events. CONCLUSION: Data from a group consisting of patients with CRF, patients undergoing maintenance hemodialysis treatment, and renal transplant recipients provide evidence that conventional risk factors such as the presence of diabetes, ESRD, as well as elevated levels of the considered risk factor CRP, seem to play a more important role for cardiovascular outcome in patients with chronic kidney disease than elevated levels of AGEs, tHcy, and related metabolites. The evidence suggests that routine CRP measurement can be recommended in cases of chronic renal insufficiency.     

Endothelin-1 in children with chronic renal failure

Endothelin-1 (ET-1) was meansured after extraction from plasma of normal adults (5.9±1.9 pg/ml,n=22), normal children (7.1±1.86 pg/ml,n=29), nonhaemodialysed children with chronic renal failure (CRF) (11.1±1.8 pg/ml),n=10), renal graft recipients (9.5±3.4 pg/ml,n=37), haemodialysed children 24 h after a haemodialysis session (20.02±10.9 pg/ml,n=26) and haemodialysed children before and after a haemodialysis session (15.31±10.6 and 13.8±8.5 respectively,n=14). A sensitive and specific radioimmunoassay was used. ET-1 was significantly higher in non-haemodialysed CRF children and in renal graft recipients than in normal children (P<0.001 andP<0.01, respectively) and significantly higher in haemodialysed children when compared with normal children, non-haemodialysed CRF children and renal graft recipients (P<0.001). ET-1 concentrations were similar in normal children and normal adults. ET-1 was inversely correlated with glomerular filtration rate in non-haemodialysed CRF children (r=–0.39,P<0.01) and positively correlated with extracellular volume in haemodialysed children (r=0.435,P<0.03). After haemodialysis, ET-1 increased in 6 and decreased in 8 of the 14 children studied before and after a haemodialysis session.     

Metabolic outcomes and renal function after simultaneous kidney/pancreas transplantation compared with kidney transplantation alone for type 2 diabetes mellitus patients

In this study, we aimed to compare the metabolic outcomes, renal function, and survival outcomes of simultaneous pancreas and kidney transplantation (SPK) and kidney transplantation alone (KTA) among end-stage kidney disease (ESKD) patients with type II diabetes mellitus (T2DM). Patients with ESKD and T2DM who underwent KTA (n = 85) or SPK (n = 71) in a transplant center were retrospectively reviewed. Metabolic profiles, renal function, and survival outcomes were assessed repeatedly at different follow-up time points. Propensity score procedures were applied to enhance between-group comparability. The levels of renal and metabolic outcomes between SPK and KTA over time were examined and analyzed using mixed-model repeated-measures approaches. The median follow-up period was 1.8 years. Compared with KTA, SPK resulted in superior metabolic outcomes and renal function, with lower levels of glycated hemoglobin (HbA1c; P = 0.0055), fasting blood glucose (P < 0.001), triglyceride (P = 0.015), cholesterol (P = 0.0134), low-density lipoprotein (P = 0.0161), and higher estimated glomerular filtration rate (eGFR; P < 0.001). SPK provided better metabolic outcomes and renal function. The survival outcomes of the recipients and grafts were comparable between the two groups.     

Chronic renal failure in children: an epidemiological survey in Lorraine (France) 1975–1990

A comprehensive investigation in Lorraine from 1975 to 1990 identified 127 children (73 boys, 54 girls) under 16 years with chronic renal failure (CRF). From 1975–1980 to 1985–1990 the mean annual incidence of pre-terminal CRF decreased from 12.7 to 7.5 per million children under 16 years of age. The incidence of end-stage renal disease (ESRD) in children increased from 5.6 to 7.5 per million with a peak of 9.1. The prevalence of preterminal CRF was variable (29.4–54) and the prevalence of ESRD increased from 15.5 to 37.0 per million children. Acquired nephropathies were observed in 30.7% and congenital nephropathies in 68.5%. Although patients with acquired nephropathies had only slightly higher serum creatinine levels, they progressed more rapidly to ESRD than those with congenital disease: mean 1.8 years versus 3.85 years after diagnosis of pre-terminal of CRF (P<0.02). Ten years after onset of pre-terminal CRF, 94% with acquired and 69% of those with congenital nephropathies had started renal replacement therapy (P<0.001). It is unclear whether the decrease in preterminal CRF reflects a reduced number of children with kidney disease reaching CRF or is the result of a real delay in the progression due to better therapeutic management.     

Effect of chronic renal failure and prednisolone on the growth hormone-insulin-like growth factor axis

Abnormalities of the growth hormone (GH)/ insulin-like growth factor (IGF) axis have been reported in children with chronic renal failure (CRF) and post-transplant, and are thought to contribute to poor growth. This study examined the effect of CRF and steroid therapy (given post-transplant and to children with normal renal function) on the GH-IGF axis in children with normal and abnormal growth. Thirty-one children with CRF, ten on dialysis, 26 with renal transplants and ten taking steroid therapy but with normal renal function, were studied. IGF-I, measured by radioimmunoassay, was normal but IGF bioactivity was low in groups with a decreased glomerular filtration rate (P<0.05). Transplanted children growing at a subnormal growth rate had lower IGF bioactivity than those growing at a normal rate (P=0.03), but there was no such difference in bioactivity in children with CRF. There was no correlation between IGF bioactivity and prednisolone treatment. There was no correlation between IGF binding proteins 1, 2 or 3 and growth. Received: 1 August 2000 / Revised: 11 July 2001 / Accepted: 12 July 2001     

Impact of ACE I/D gene polymorphism on congenital renal malformations

To investigate the role of the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism on prevalence and progression of disease in children with chronic renal failure (CRF), we determined the ACE I/D genotype in 95 children with CRF due to renal malformations (hypo- /dysplasia, obstructive uropathy, reflux nephropathy; n=59), other congenital or hereditary diseases (n=23), or acquired glomerular disorders (n=13), who had been followed prospectively over a 2-year period. CRF progression rate was followed in each individual by linear regression analysis of estimates of glomerular filtration rate (GFR) obtained every 2 months. Actuarial renal ’survival’ analysis was performed, using a GFR loss of 10 ml/min per 1.73 m² as a cutoff point. The distribution of the ACE genotype did not differ among the disease groups. There was also no difference in ACE genotype distribution between the patients and a control group of healthy Caucasian children (n=163). Among the children with renal malformations, the 2-year renal survival was significantly lower in those with the DD genotype (61%) than in patients with ID or II genotype (89%, P<0.01). In the other disease groups, the ACE I/D genotype was not predictive of CRF progression. In a multivariate analysis of risk factors, the adverse effect of the DD genotype (risk ratio 10.2, P<0.05) was independent of and additive to those of arterial hypertension (RR 13.2, P<0.001) and gross proteinuria (RR 4.7, P<0.05). We conclude that the ACE DD genotype is a significant risk factor for children with congenital renal malformations to develop progressive CRF. The effect of the ACE polymorphism in this patient group is independent of hypertension and proteinuria. Received: 25 August 2000 / Revised: 10 December 2000 / Accepted: 15 December 2000     

Body growth of children with steroid-resistant nephrotic syndrome

Whilst it is assumed that body growth is retarded in children with steroid-resistant nephrotic syndrome (NS), the degree of growth failure and the pathomechanisms involved are poorly understood. We collected serial growth data in 45 children (24 males) with steroid-resistant NS usually from onset to end-stage renal disease (ESRD) during childhood (n=10) or until final height was attained (n=27). Mean follow-up time was 9 (2–19) years. Mean initial standardized height was –0.3±1.2 standard deviation scores (SDS). Mean final height was +0.4 SDS in males and –1.0 SDS in females (sex difference not significant). In 16 patients with serum creatinine levels consistently <1.2 mg/dl, mean final height SDS was 0.3 SDS higher than that obtained within 6 months of onset. In contrast, 9 children who entered ESRD lost an average of 1.3 SDS from the initial record to ESRD (P=0.017). In prepubertal patients without renal insufficiency, mean height SDS decreased during corticosteroid treatment by 0.3 SDS, followed by a partial catch-up after discontinuation of treatment; the change from initial to final height SDS was inversely correlated with the total prednisone dose given (r=–0.50, P=0.03). In 16 prepubertal children with serial height and serum protein measurements who were off steroids and maintained normal creatinine levels, mean individual albumin concentrations correlated with the change in height SDS per year (r=0.65, P=0.0006) and in boys with final height (r=0.73, P=0.03). In conclusion, growth in steroid-resistant NS depends on the preservation of renal function, the cumulative dose of steroids applied, and the severity of hypoproteinemia. Received: 15 July 1998 / Revised: 30 November 1998 / Accepted: 11 December 1998     

Serum insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 in children with chronic renal failure: relationship to growth and glomerular filtration rate

Growth retardation in children with chronic renal failure (CRF) is partly due to an inhibition of insulin-like growth factor (IGF) activity by an excess of high-affinity IGF-binding proteins (IGFBPs). The aim of this study was to analyze the serum levels and forms of IGFBP-4 and IGFBP-5 in CRF patients using specific, recently developed radioimmunoassays (RIAs) and immunoblot analysis. We examined 89 children [age 11.5 (2.8–19.0) years] with CRF [glomerular filtration rate 26.6 (7.0–67.4) ml/min per 1.73 m²], nine of them with end-stage renal disease undergoing peritoneal dialysis. Serum-immunoreactive IGFBP-4 levels were fourfold increased in CRF (prepubertal 1080±268 ng/ml; pubertal 989±299 ng/ml) compared to healthy prepubertal controls (265±73 ng/ml). In contrast, serum IGFBP-5 levels were not significantly increased neither in prepubertal (361±120 ng/ml vs 282±75 ng/ml in controls) nor pubertal CRF children (478±165 ng/ml vs 491±80 ng/ml in controls). Immunoblot analysis showed the presence of intact as well as fragmented IGFBP-4 and IGFBP-5. Serum IGFBP-4, but not IGFBP-5, levels were inversely correlated with GFR (r=–0.39, P<0.001). In prepuber- tal children, IGFBP-4 levels were inversely correlated with standardized height (r=–0.40; P<0.005). In contrast, IGFBP-5 levels were positively correlated both with standardized height (r=0.32, P<0.02) and baseline height velocity (r=0.45, P<0.005). A 3-month therapy with rhGH stimulated serum IGFBP-5 levels by 43% (P<0.01); there was no consistent effect on IGFBP-4 levels. There was a positive correlation between IGFBP-4 and IGFBP-2 (r=0.46, P<0.001); IGFBP-5 was positively correlated with IGF-I (r=0.59, P<0.001), IGF-II (r=0.42, P<0.001) and IGFBP-3 (r=0.47, P<0.001) and inversely correlated with IGFBP-1 (r=–0.41, P<0.001). In summary, serum IGFBP-4 is fourfold elevated in children with CRF in relation to the degree of renal dysfunction and contributes to the marked increase in IGF-binding capacity in CRF serum. The inverse correlation of serum IGFBP-4 with standardized height is consistent with its role as another inhibitor of the biological action of the IGFs on growth plate cartilage. In contrast, serum IGFBP-5 is not elevated in CRF serum and circulates mainly as proteolysed fragments. The positive correlation of serum IGFBP-5 with growth and its increase during GH therapy indicate that IGFBP-5 is a stimulatory IGFBP in patients with CRF, either by enhancing IGF activity through better presentation of IGF to its receptor or by an IGF-independent effect through activation of a specific, recently described putative IGFBP-5-receptor. Received: 24 September 1999 / Revised: 6 January 2000 / Accepted: 13 January 2000 / Accepted: 13 January 2000     

Greater Carboxy-Methyl-Lysine Is Associated With Increased Fracture Risk in Type 2 Diabetes

Accumulation of advanced glycation end-products (AGE) in bone alters collagen structure and function. Fluorescent AGEs are associated with fractures but less is known regarding non-fluorescent AGEs. We examined associations of carboxy-methyl-lysine (CML), with incident clinical and prevalent vertebral fractures by type 2 diabetes (T2D) status, in the Health, Aging, and Body Composition cohort of older adults. Incident clinical fractures and baseline vertebral fractures were assessed. Cox regression was used to analyze the associations between serum CML and clinical fracture incidence, and logistic regression for vertebral fracture prevalence. At baseline, mean ± standard deviation (SD) age was 73.7 ± 2.8 and 73.6 ± 2.9 years in T2D (n = 712) and non-diabetes (n = 2332), respectively. Baseline CML levels were higher in T2D than non-diabetes (893 ± 332 versus 771 ± 270 ng/mL, p < 0.0001). In multivariate models, greater CML was associated with higher risk of incident clinical fracture in T2D (hazard ratio [HR] 1.49; 95% confidence interval [CI], 1.24–1.79 per 1-SD increase in log CML) but not in non-diabetes (HR 1.03; 95% CI, 0.94–1.13; p for interaction = 0.001). This association was independent of bone mineral density (BMD), glycated hemoglobin (hemoglobin A1c), weight, weight loss, smoking, cystatin-C, and medication use. CML was not significantly associated with the odds of prevalent vertebral fractures in either group. In conclusion, higher CML levels are associated with increased risk of incident clinical fractures in T2D, independent of BMD. These results implicate CML in the pathogenesis of bone fragility in diabetes. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Coronary artery calcifications in children with end-stage renal disease

Coronary artery calcification (CAC) is common in adults with end-stage renal disease (ESRD), but little is known about the prevalence and the extent of it in children. We used multidetector spiral computed tomography (MDCT), echocardiography, and carotid and brachial high-resolution ultrasonography to screen for the presence and predisposing factors of CAC in 53 children with ESRD [15 hemodialysis (HD) patients, 24 peritoneal dialysis (PD) patients, and 14 renal transplant (rTx) recipients]. CAC was present in 15% of patients (three HD patients, three PD patients, and two rTx). The mean age of the patients with CAC was 16.4 years (range: 11.0–21.2 years), and their median CAC score was 101.3, ranging from 8.5 to 4,322 according to the Agatston method. The patients with CAC had longer duration of total dialysis (P=0.005), had higher time-integrated serum phosphorus (P<0.001), calcium-phosphate (CaxP) product (P=0.012), intact parathyroid hormone (P=0.010), vitamin B₁₂ levels (P=0.010), the amount of cumulative calcium-containing oral phosphate binders (OBPs) (P<0.001), and calcitriol intake (P<0.001), and had lower serum hemoglobin level (P=0.014). Interventricular septum systolic thickness (P=0.033) was significantly higher, relative wall thickness (P=0.062) tended to be higher, and flow-mediated endothelium-dependent dilatations (P=0.071) were lower without reaching statistically significant levels in those with CAC. A stepwise logistic regression analysis revealed that serum phosphorus (P=0.018) and the cumulative exposure to calcium-containing OPBs (P=0.016) were the most significant independent predictors in the development of CAC. These results indicate that even adolescents and children with ESRD may have coronary calcifications. We concluded that impaired divalent ion metabolism is the main factor in the formation of CAC in this age group.     

Mechanisms for the formation of glycoxidation products in end-stage renal disease

BACKGROUND: Advanced glycation end products (AGEs) accumulate on tissue and plasma proteins in patients with renal failure far in excess of normal aging or diabetes. The aim of these studies was to elucidate the nature of the precursors and the pathways that lead to an accelerated formation of two structurally identified AGEs [pentosidine and Nepsilon(carboxymethyl)lysine (CML)] in the uremic milieu. METHODS: Serum levels of the glycoxidation products, pentosidine and CML, were quantitated by high-performance liquid chromatography in uremic patients treated by dialysis. The formation of early glycation products (as furosine) and late glycoxidation products was modeled in uremic serum and in spent peritoneal dialysate. RESULTS: Clinical factors that affect circulating levels of AGEs included dialysis clearance and dialyzer membrane pore size, but not the presence or absence of diabetes. Both pentosidine and CML form at an accelerated rate in serum from uremic patients. Chelating agents most effectively slow the formation in vitro. In uremic fluids, the primary mechanism of formation of pentosidine is through the Amadori pathway. The primary mechanism of formation of CML is through metal-chelated autoxidation of reducing sugars generating reactive carbonyl precursors. In uremic serum, the presence of an unidentified reactive low molecular weight precursor accelerates the formation of pentosidine. CONCLUSIONS: The formation of the two glycoxidation products, pentosidine and CML, proceeds by different pathways and is enhanced by different precursors in the uremic milieu. The formation of both AGEs is markedly enhanced by metal-catalyzed reactions, evidence for the presence of increased metal-ion mediated oxidant stress in uremia.     

Changes in body composition of children with chronic renal failure on growth hormone

Body composition is altered in children with chronic renal failure (CRF) and contributes to the significant growth failure seen in these children. Recombinant human growth hormone (rhGH) has been used in the past several years to improve the somatic growth of children with CRF. To determine if the growth achieved in these children occurs concomitantly with body compositional changes, seven prepubertal (n=6) and pubertal (n=1) children with chronic renal insufficiency (n=4) and end-stage renal disease (n=3) underwent measurements of total body fat (FM), fat free mass (FFM), bone mineral density (BMD), total bone mineral mass (TBBM), total body water (TBW), and total body potassium (TBK) before and 6 months after initiation of subcutaneous recombinant human growth hormone (rhGH) at 0.35 mg/kg per week. The techniques used included dual- energy X-ray absorptiometry (for measurement of FM, BMD, and TBBM), total body potassium counting (for measurement of TBK), and deuterated water for assessment of TBW. Significant increases in both height and weight were seen following 6 months of rhGH therapy. These increases were accompanied by significant re- ductions in FM (4.4±1.4 kg vs. 3.6±1.2 kg, P=0.002) and percentage fat (18.6±3.9% vs. 14.5±3.4%, P=0.04), while FFM (17.9±3.0 kg vs. 20.7±3.6 kg, P=0.04) increased significantly as did TBBM (776±171 g vs. 844±177 g, P=0.001). Increases in TBK, a measure of body cell mass, were also seen. No difference in total BMD was observed. Thus, growth in CRF is occurring with repletion of the FFM and TBBM compartments. Despite these improvements, no change was observed in the body mass index (BMI). Measurement of BMI alone does not define the compartmental catabolic losses in FFM. Received: 20 September 1999 / Revised: 31 January 2000 / Accepted: 8 February 2000     

Advanced glycation end products and soluble receptor as markers of oxidative stress in children on hemodialysis

Abstract

Background: Advanced glycation end products (AGEs) have biological properties that may contribute to the mortality of children on hemodialysis (HD). This study examines the relationship of LMW fluorescence AGEs, oxidized LDL (ox-LDL), soluble receptor AGE (sRAGE) as markers of oxidative stress in children with end stage renal disease (ESRD) undergoing HD. Method: Thirty children with ESRD undergoing HD, and 30 healthy, age- and sex-matched children were included. Serum levels of LMW fluorescence AGEs, sRAGE, oxidized LDL (ox-LDL), pre- and post-dialysis urea, high-sensitivity C-reactive protein (hs-CRP), hemoglobin (Hb) and serum albumin (ALB), were measured. Results: Abnormal serum inflammatory changes: elevated levels of LMW AGEs, sRAGE, oxLDL, CRP and urea were exhibited in HD children compared with healthy controls; more so in anemic when compared to non-anemic patients. Significant positive correlation was found between serum levels of AGEs and sRAGE. Conclusion: The low molecular weight form of AGEs is associated with oxidative stress in children receiving chronic HD, and may be important in the mechanisms leading to atherosclerosis and inflammation in such patients. LMW AGEs levels showed a negative correlation with sRAGE and both exhibit a significant negative relation to seum urea.     

Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation

This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with the microemulsion formulation of cyclosporin (CyA) in children undergoing renal transplantation. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 years) were randomly assigned (1:1) to receive either Tac (n=103) or CyA microemulsion (n=93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection. Baselinecharacteristics were comparable between treatment groups. Tac therapy resulted in a significantly lower incidence of acute re-jection (36.9%) compared with CyA therapy (59.1%) (P=0.003). The incidence of corticosteroid-resistant rejection was also significantly lower in the Tac group compared with the CyA group (7.8% vs. 25.8%, P=0.001). The differences were also significant for biopsy-confirmed acute rejection (16.5% vs. 39.8%, P<0.001). At 1 year, patient survival was similar (96.1% vs. 96.6%), while 10 grafts were lost in the Tac group compared with 17 graft losses in the CyA group (P=0.06). At 1 year, mean glomerular filtration rate (Schwartz estimate) was significantly higher in the Tac group (62±20 ml/min per 1.73 m², n=84) than in the CyA group (56±21 ml/min per 1.73 m², n=74, P=0.03). The most frequent adverse events during the first 6 months were hypertension (68.9% vs. 61.3%), hypomagnesemia (34.0% vs. 12.9%, P=0.001), and urinary tract infection (29.1% vs. 33.3%). Statistically significant differences (P<0.05) were observed for diarrhea (13.6% vs. 3.2%), hypertrichosis (0.0% vs. 7.5%), flu syndrome (0.0% vs. 5.4%), and gum hyperplasia (0.0% vs. 5.4%). In previously non-diabetic children, the incidence of long-term (>30 days) insulin use was 3.0% (Tac) and 2.2% (CyA). Post-transplant lymphoproliferative disease was observed in 1 patient in the Tac group and 2 patients in the CyA group. In conclusion, Tac was significantly more effective than CyA microemulsion in preventing acute rejection after renal transplantation in a pediatric population. The overall safety profiles of the two regimens were comparable. Received: 1 October 2001 / Revised: 25 October 2001 / Accepted: 15 November 2001     

An analysis of the survival outcomes of simultaneous pancreas and kidney transplantation compared to live donor kidney transplantation in patients with type 1 diabetes: a UK Transplant Registry study

Transplant options for patients with type 1 diabetes and end‐stage renal disease (ESRD) include deceased donor kidney, live donor kidney (LDK) and simultaneous pancreas‐kidney (SPK) transplantation. The aim of this study was to compare outcomes between LDK and SPK for patients with type 1 diabetes and ESRD in the UK. Data on all SPK (n = 1739) and LDK (n = 385) transplants performed between January 2001 and December 2014 were obtained from the UK Transplant Registry. Unadjusted patient and kidney graft survival were calculated using the Kaplan–Meier method. Multivariate analysis of kidney graft and patient survival was performed using Cox proportional hazards regression. There was no significant difference in patient (P = 0.435) or kidney graft survival (P = 0.204) on univariate analysis. On multivariate analysis there was no association between LDK/SPK and patient survival [HR 0.71 (0.47–1.06), P = 0.095]. However, LDK was associated with an overall lower risk for kidney graft failure [HR 0.60 (0.38–0.94), P = 0.025]. SPK recipients with a functioning pancreas graft had significantly better kidney graft and patient survival than LDK recipients or those with a failed pancreas graft. SPK transplantation does not confer an overall survival advantage compared to LDK. However, those SPK recipients with a functioning pancreas have significantly better outcomes.     

Circulating calcification inhibitors and vascular properties in children after renal transplantation

Pediatric transplant patients are known to have vascular abnormalities. The calcification inhibitors matrix Gla protein (MGP) and fetuin-A play an important role in the pathophysiology of vascular calcification. In the cross-sectional study reported here, we examined the circulating levels of fetuin-A and MGP in children after renal transplantation compared to healthy children and the association of these factors with vascular properties of the carotid artery. Levels of MGP and fetuin-A together with vascular properties of the carotid artery were determined in 29 pediatric renal transplant recipients and 54 healthy controls. The level of fetuin-A was decreased in the transplant group relative to the control group (P = 0.005), whereas the level of MGP (both non-phosphorylated MGP and non-carboxylated MGP) did not differ between groups. The intima-media thickness (P < 0.001) and the elasticity (P = 0.002) of the carotid artery were significantly increased in children after renal transplantation compared to healthy children. No associations between vascular parameters and calcification inhibitors were found in either group. Circulating levels of MGP and fetuin-A could not be identified as independent predictors of vascular stiffness or other carotid artery parameters in pediatric renal transplant recipients. Future prospective studies in pediatric ESRD and transplant patients are needed to learn more about the role of calcification inhibitors in relation to the prevention of vascular damage.     

Endothelin and cardiovascular remodelling in end-stage renal disease

Background. Plasma endothelin (ET) is elevated in end-stage renal disease (ESRD), but the origin and consequences of this increase remain unclear. In the present study we analysed the relationships between plasma ET levels and cardiovascular alterations in ESRD. Methods and results. Common carotid artery (CCA) intima-media thickness (IMT) and diameter, atherosclerotic plaque occurrence, and left ventricular (LV) geometry and function were determined by ultrasound imaging in 76 haemodialysis patients and in 57 age-, sex-, and blood pressure-matched controls. Arterial stiffness was evaluated via carotid-femoral pulse wave velocity (CF-PWV), forearm post-ischaemic vasodilation was measured by venous plethysmography, and plasma ET levels were determined using a specific immunoenzymoassay. Compared with controls, ESRD patients had elevated plasma ET levels (1.6±1.4 vs 4.6±3.8 pg/ml; P<0.001), increased LV mass (P<0.001), increased CCA-IMT (P<0.001), a higher prevalence of atherosclerotic plaques (P<0.001) and increased CF-PWV (P<0.01). Plasma ET levels correlation positively with LV outflow velocity integral (r=0.57; P<0.0001), stroke index (P<0.01), and baseline forearm blood flow (P<0.001) which were all significantly higher in ESRD patients than in controls (P<0.01). After adjustment for age, blood pressure, haemoglobin levels, gender and body dimensions, plasma ET levels were significantly correlated to LV mass (r=0.46; P<0.001), CCA-IMT and CCA intima -media cross-sectional area (r=0.41; P<0.001), and CF-PWV (p<0.05). Post-ischaemic forearm vasodilation was decreased in ESRD (85±31 vs 119±28%; P<0.001) and there was a negative correlation between post-ischaemic flow recovery and ET levels (r=-0.49; P<0.001). In ESRD patients, plasma ET levels were positively and independently correlated with the prevalence of CCA atherosclerotic plaque (P<0.01). Conclusions. These results indicate that the increased plasma ET levels in ESRD patients are associated with left ventricular hypertrophy and arterial intima-media thickening, suggesting that increased ET concentrations in ESRD patients may be of pathophysiological significance in the process of cardiovascular remodelling.     

Serum levels of total homocysteine,homocysteine metabolites and of advanced glycation end-products (AGEs) in patients after renal transplantation

AIMS: Hyperhomocysteinemia has been described as an independent risk factor for cardiovascular diseases (CVD) influencing patient outcome. Advanced glycation end-products (AGEs) are involved in the pathogenesis of vascular damage in uremia. This study was undertaken to assess whether high serum levels of total homocysteine (tHcy) with its metabolites methylmalonic acid (MMA), methylcitric acid (MCA) and cystathionine (CYSTA) as well as elevated serum concentrations of the AGEs pentosidine and Nepsilon-carboxymethyllysine (CML) are independent risk factors for CVD, left ventricular hypertrophy (LVH) or hypertension as well as kidney dysfunction in renal transplant recipients (RTR). METHODS: Serum levels of tHCy, MMA, MCA and CYSTA were measured by a gas chromatographic-mass spectrometric assay, pentosidine by HPLC and CML using an ELISA assay. RESULTS: All measured parameters were significantly higher in RTRs than in healthy subjects (p < 0.0001). The levels of pentosidine and CML as well as of tHcy and its metabolites correlated significantly with each other, but not with those ofMMA and CYSTA. Significant correlations were also found between pentosidine and tHcy, MMA or MCA as well as between CML, MMA and MCA, respectively. Acute or chronic rejection did not influence these values. No significant differences were observed between patients with or without CVD or with hypertension. In RTRs with LVH, only the tHcy levels were significantly higher than in those RTRs without LVH (p = 0.006). Logistic regression analysis revealed an independent influence of tHcy on the presence of LVH. CONCLUSION: These results may indicate an association between high tHcy values and LVH. Further investigation is needed to determine whether a reduction of tHcy and Hcy metabolites and/or AGE serum concentrations would significantly improve patient outcome after undergoing renal transplantation.     

Enhanced plasma levels of advanced glycation end products (AGE) and pro-inflammatory cytokines in children/adolescents with chronic renal insufficiency and after renal replacement therapy by dialysis and transplantation--are they inter-related?

AIMS: Advanced glycation end products (AGEs) are formed by non-enzymatic glycation or glycoxidation. After their interaction with specific receptors, they may induce expression of various proinflammatory cytokines. AGEs were shown to accumulate with advanced age, in diabetes mellitus and, in particular, in patients with chronic renal failure. In contrast to numerous investigations in adults, there are no data on plasma levels of AGEs in children with chronic renal insufficiency (CRI) and after renal replacement therapy. To elucidate the specific role of renal impairment for the formation of AGEs, these data become especially interesting by exclusion of the age-dependent modulatory effects occurring in adults. Therefore, we investigated the concentrations of fluorescent (FL) AGEs, carboxymethyllysine (CML) and markers of inflammation (CRP, IL-6, TNF-alpha) in children/adolescents with chronic renal insufficiency (CRI) and on renal replacement therapy with maintenance dialysis (D) or renal transplantation (TX). PATIENTS: Eleven CRI patients on conservative treatment (CRI, age: mean 12.6, median 12.80, SD 5.8 +/- 1.7 years, serum creatinine: 205.7, 157.5, 58.0 micromol/l, respectively), 10 patients on D (13.6, 13.0, 5.4 years, and 698.2, 633.8, 296.1 micromol/l, respectively) and 9 patients after TX (15.9, 16.0, 3.4 years, and 115.9, 128.0, 35.1 micromol/l, respectively) were included. METHODS: Plasma levels of CML, TNF-alpha, and IL-6 were determined by ELISA, FL-AGEs spectrofluorimetrically (lambda(ex)/lambda(em): 370/440 nm). RESULTS: FL-AGEs and CML levels were increased in all 3 groups with the highest levels in the D patients, a successful renal transplantation did not lead to normalization of plasma AGEs. The mean CRP and IL-6 concentrations were marginally elevated, and no significance among groups was revealed. TNF-alpha was noticeably elevated in all groups, with the highest values in CRI and TX patients, while in the dialysis patients the rise was less pronounced. Stepwise multiple regression did not reveal any correlation between AGEs and proinflammatory parameters, even after exclusion of the TX group from analysis. CONCLUSIONS: In children with CRI and on maintenance dialysis therapy, plasma AGE levels are markedly increased. After renal transplantation, AGE levels decrease without normalization. Proinflammatory parameters (except for TNF-alpha) are only mildly to moderately elevated. No association between AGE levels and data characterizing a proinflammatory state was revealed.     

High plasma pentosidine level is accompanied with cardiovascular events in hemodialysis patients

Background

Cardiovascular disease is a major complication in patients with end-stage renal disease (ESRD). The accumulation of advanced glycation end products (AGEs) is facilitated in these patients. The aim of this study was to investigate the relationship between circulating AGEs and cardiovascular events in hemodialysis patients.

Methods

The plasma level of pentosidine, a well-defined AGEs, was measured in 110 hemodialysis patients who were prospectively followed for 90?months. The relationship between plasma pentosidine level and cardiovascular events was assessed using Kaplan-Meier and Cox regression analysis.

Results

Thirty-nine cardiovascular events (14 coronary heart disease and 25 strokes) occurred during the follow-up period. Multivariable Cox proportional hazard analysis showed that plasma pentosidine levels (HR 1.040, 95% CI 1.022–1.058, p?p?p?Conclusion The plasma pentosidine level predicts cardiovascular events in hemodialysis patients. The effects of lowering circulating AGE levels on cardiovascular events should be examined in ESRD patients.