Ryszard Grenda

Normative values for intima-media thickness and distensibility of large arteries in healthy adolescents.

Objective Sonographic evaluation of arterial wall morphology and elasticity is increasingly accepted as a non-invasive tool in cardiovascular assessment. Several studies suggest that intima–media thickness (IMT) and arterial elasticity indices may sensitively reflect different vasculopathic processes in children. However, normative values and the impact of adolescent growth are largely unknown. Methods We assessed the IMT of the common carotid (cIMT) and femoral arteries (fIMT), carotid elasticity indices and interacting anthropometric factors in 247 healthy subjects aged 10–20 years. Results cIMT, fIMT, incremental elastic modulus (Einc) and circumferential wall stress (CWS) were positively, and distensibility coefficient (DC) inversely, correlated with age, height, body mass index (BMI), systolic blood pressure (BP) and brachial pulse pressure (r = 0.56 to −0.45, P < 0.05 to 0.0001). DC (r = −0.29, P < 0.0001) and stiffness index β (r = 0.25, P < 0.0001), but not Einc, were significantly associated with cIMT independently of age. All vascular parameters showed non-Gaussian distributions. Excessively high IMT was associated with BMI and pulse pressure above the 90th percentile, and elevated Einc with high-normal BMI. Multivariate analysis identified independent positive effects of standardized BMI and brachial pulse pressure on normalized cIMT, negative effects of systolic BP and cIMT on DC, a positive effect of cIMT on stiffness, and positive effects of systolic BP and BMI on Einc and CWS. Conclusions Morphological and functional measures of large arteries should be normalized to take account of changes during adolescence and skewed distributions. Relative body mass, systolic blood pressure and/or pulse pressure are determinants of IMT and elasticity.

Altered morphologic properties of large arteries in children with chronic renal failure and after renal transplantation

Increased intima-media thickness of the carotid arteries (cIMT) has been found in young adults with childhood-onset chronic kidney disease (CKD). The disease stage at which these patients first develop abnormalities of arterial texture is unknown. The objective of this study was to determine the onset and character of arterial changes in children aged 10 to 20 yr with different stages of CKD and to identify risk factors for early arteriopathy. High-resolution ultrasonography was conducted of common cIMT and femoral superficial artery IMT. Fifty-five children with stages 2 to 4 CKD (GFR 51 +/- 31 ml/min per 1.73 m2), 37 on dialysis, and 34 after renal transplantation (Rtx; GFR 73 +/- 31 ml/min per 1.73 m2) were studied. Control subjects were 270 healthy children, matched for age and gender. Compared with control subjects, cIMT, femoral superficial artery IMT (both as absolute values and as SD score of median of normal value), wall cross-sectional area, and lumen cross-sectional area of carotid artery were significantly increased in all patient groups and most markedly abnormal in dialysis patients. cIMT in CKD and Rtx patients was significantly lower in comparison with dialysis patients. cIMT correlated with mean past serum Ca x P product, the cumulative dose of calcium-based phosphate binders, and the time-averaged mean calcitriol dose. The cumulative phosphate binder intake, time-averaged Ca x P product, and young age were independent predictors of an increased cIMT. In children with CKD, thickening of IMT occurs early in the course of disease and is most marked in dialyzed patients. The changes may be partly reversible after Rtx.

Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation.

Abstract 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.

A Randomized Trial to Assess the Impact of Early Steroid Withdrawal on Growth in Pediatric Renal Transplantation: The TWIST Study

Minimizing steroid exposure in pediatric renal transplant recipients can improve linear growth and reduce metabolic disorders. This randomized multicenter study investigated the impact of early steroid withdrawal on mean change in height standard deviation score (SDS) and the safety and efficacy of two immunosuppressive regimens during the first 6 months after transplantation. Children received tacrolimus, MMF, two doses of daclizumab and steroids until day 4 (TAC/MMF/DAC, n=98) or tacrolimus, MMF and standard‐dose steroids (TAC/MMF/STR, n=98). Mean change in height SDS was 0.16 ± 0.32 with TAC/MMF/DAC and 0.03 ± 0.32 with TAC/MMF/STR. The mean treatment group difference was 0.13 (p < 0.005 [95% CI 0.04–0.22]), 0.21 in prepubertal (p = 0.009 [95% CI 0.05–0.36]) and 0.05 in pubertal children (p = ns). Frequency of biopsy‐proven acute rejection was 10.2%, TAC/MMF/DAC, and 7.1%, TAC/MMF/STR. Patient and graft survival and renal function were similar. Significantly greater reductions in total cholesterol and triglycerides but significantly higher incidences of infection and anemia were found with TAC/MMF/DAC (p < 0.05 all comparisons). Early steroid withdrawal significantly aided growth at 6 months more so in prepubertal than pubertal children. This was accompanied by significantly better lipid and glucose metabolism profiles without increases in graft rejection or loss.

Four‐year data after pediatric renal transplantation: A randomized trial of tacrolimus vs. cyclosporin microemulsion

Abstract:  This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with cyclosporin microemulsion (CyA) in pediatric renal recipients. 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 yr) were randomly assigned (1:1) to receive either Tac (n = 103) or CyA (n = 93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection (intent‐to‐treat). Baseline characteristics were comparable between treatment groups. Excluding deceased patients (n = 9) and patients lost to follow‐up (n = 31, mostly transferred to adult care), 95% of 2‐yr data (159 of 167 possible patients), 87% of 3‐yr data (142 of 163) and 73% of 4‐yr data (114 of 156) were retrieved. At 1 yr Tac therapy resulted in a significantly lower incidence of acute rejection (36.9%) compared with CyA (59.1%, p = 0.003). The incidence of corticosteroid‐resistant rejection was also significantly lower with Tac (7.8% vs. 25.8%, p = 0.001). At 4 yr, patient survival was similar (94% vs. 92%, p = 0.86) but graft survival significantly favored Tac (86% vs. 69%; p = 0.025, log‐rank test), respectively. At 1 yr, the mean glomerular filtration rate (GFR) (Schwartz formula, ml/min/1.73 m2) was 64.9 ± 20.7 (n = 84) vs. 57.8 ± 21.9 (n = 77, p = 0.0355), at 2 yr 64.9 ± 19.8 (n = 71) vs. 51.7 ± 20.3 (n = 66, p = 0.0002), at 3 yr 66.7 ± 26.4 (n = 81) vs. 53.0 ± 23.3 (n = 55, p = 0.0022), and at 4 yr 71.5 ± 22.9 (n = 51) vs. 53.0 ± 21.6 (n = 44, p = 0.0001) for Tac vs. CyA, respectively. Cholesterol remained significantly higher with CyA throughout follow‐up. Three patients in each arm developed post‐transplant lymphoproliferative disease. Incidence of insulin‐dependent diabetes mellitus was not different. Tac was significantly more effective than CyA in preventing acute rejection in pediatric renal recipients. Renal function and graft survival were also superior with Tac. Glomerular filtration rate appears to be an useful surrogate marker for long‐term outcome.

Evolution of large-vessel arteriopathy in paediatric patients with chronic kidney disease

UNLABELLED This observational study was designed to verify the hypothesis that the treatment modality significantly affects the evolution of CKD-associated arteriopathy. PATIENTS Paediatric patients (mean age 13.8 +/- 4.2 years) with chronic kidney disease (CKD) stages 3-5, including 24 patients with mean GFR 54 +/- 21 ml/min/1.73 m(2) (CKD group) and 32 patients in end-stage renal disease, of whom 19 received a renal allograft (D-Rtx) and 13 remained on dialysis (D-D). METHODS Sonography of the common carotid artery was performed at baseline and after 12 months. Intima-media thickness (IMT) and the cross-sectional areas of the vessel wall (WCSA) and lumen (LCSA) were measured and normalized to age (SDS). RESULTS At baseline IMT-SDS and WCSA-SDS were increased above normal, and were significantly higher in D than in CKD patients (P < 0.001). IMT-SDS increased over time in CKD and D-D patients (1.4 +/- 1.7 to 2.1 +/- 1.2, P = 0.05). In contrast, IMT-SDS (2.8 +/- 0.6 to 2.0 +/- 0.6, P < 0.005) decreased in those D-Rtx patients who had elevated values prior to transplantation. The total number of patients with elevated cIMT-SDS changed from 7 to 13 in the 24 CKD, from 8 to 11 in the 13 D-D and from 11 to 12 in the 19 D-Rtx patients. While IMT-SDS was independently correlated with blood pressure and serum phosphate in the CKD and D patients, only total dialysis vintage (r = 0.50; P < 0.05) and the IMT-SDS attained at the time of grafting (r = 0.46, P < 0.05) correlated with IMT-SDS 1 year post-Rtx. CONCLUSION While vascular lesions rapidly progress in CKD and D patients, abolition of the uraemic state by Rtx leads to stabilization or partial regression of CKD-associated arteriopathy. Cumulative dialysis duration and the degree of arterial damage prevalent at the time of grafting are the main determinants of persistent arteriopathy 1 year after Rtx.

A prospective, randomized, multicenter trial of tacrolimus-based therapy with or without basiliximab in pediatric renal transplantation.

In a 6‐month, multicenter, randomized, controlled, open‐label, parallel‐group trial, we investigated the efficacy and safety of adding basiliximab to a standard tacrolimus‐based regimen in pediatric renal transplant recipients. Patients <18 years received tacrolimus/azathioprine/steroids (TAS, n = 93) or tacrolimus/azathioprine/steroids/basiliximab (TAS + B, n = 99). Target tacrolimus levels were 10–20 ng/mL between days 0–21 and 5–15 ng/mL thereafter. Steroid dosing was identical in both groups. Basiliximab was administered at 10 mg (patients <40 kg) or 20 mg (patients ≥40 kg) within 4 h of reperfusion; the same dose was repeated on day 4. Biopsy‐proven acute rejection rates were 20.4% (TAS) and 19.2% (TAS + B); steroid‐resistant acute rejection rates were 3.2% and 3.0%, respectively. Patient survival was 100%; graft survival rates were 95% in both arms. The nature and incidence of adverse events were similar in both arms except toxic nephropathy and abdominal pain, which were significantly higher in the TAS + B arm (14.1% vs. 4.3%; p = 0.03 and 11.1% vs. 2.2%; p = 0.02; respectively). Median serum creatinine concentrations at 6 months were 86 μmol/L in the TAS and 91 μmol/L in the TAS + B arm; glomerular filtration rate was 79.4 and 77.6 (mL/min/1.73 m2), respectively. Adding basiliximab to a tacrolimus‐based regimen is safe in pediatric patients, but does not improve clinical efficacy.

Disparities in Policies, Practices and Rates of Pediatric Kidney Transplantation in Europe

We aimed to provide an overview of kidney allocation policies related to children and pediatric kidney transplantation (KTx) practices and rates in Europe, and to study factors associated with KTx rates. A survey was distributed among renal registry representatives in 38 European countries. Additional data were obtained from the ESPN/ERA‐EDTA and ERA‐EDTA registries. Thirty‐two countries (84%) responded. The median incidence rate of pediatric KTx was 5.7 (range 0−13.5) per million children (pmc). A median proportion of 17% (interquartile range 2−29) of KTx was performed preemptively, while the median proportion of living donor KTx was 43% (interquartile range 10−52). The median percentage of children on renal replacement therapy (RRT) with a functioning graft was 62%. The level of pediatric prioritization was associated with a decreased waiting time for deceased donor KTx, an increased pediatric KTx rate, and a lower proportion of living donor KTx. The rates of pediatric KTx, distribution of donor source and time on waiting list vary considerably between European countries. The lack of harmonization in kidney allocation to children raises medical and ethical issues. Harmonization of pediatric allocation policies should be prioritized.

Patient survival and causes of death on hemodialysis and peritoneal dialysis – single-center study

Abstract. Survival and causes of death in children dialyzed in a single center were analyzed. During the last 12 years a chronic dialysis program was introduced in 146 children in our center and 125 of them, eligible for observation, were included in this analysis; 58 patients were on hemodialysis (HD) and 67 on peritoneal dialysis [continuous ambulatory peritoneal dialysis/automated peritoneal dialysis (CAPD/APD)]. Mean age at the start of dialysis was 13.1 years in HD and 9.8 years in CAPD/APD patients. Overall, 16 patients died (12.5%); 6 (10.3%) on HD and 10 (14.9%) on CAPD/APD; 4 HD patients died of hemorrhagic stroke and 2 were killed in road traffic accidents. Of 10 CAPD/APD patients, 7 died of heart failure, ischemic stroke, and/or disseminated thromboembolic disease. Another was killed in a road traffic accident and 2 died during the course of severe infections. The 1-year patient survival rate was 96.6% in HD patients and 95% in CAPD/APD patients, 2-year survival 94% and 93% and 5-year survival 91% and 78%, respectively (P=0.2, NS). In conclusion, the survival rate for HD and CAPD patients is similar, although after 2 years of therapy, it is lower in CAPD patients. The main causes of death are cardiovascular. However, in CAPD/APD patients, heart failure with low cardiac output and thromboembolic complications are major causes of death, and in HD patients the main cause is hemorrhagic stroke.

Successful treatment of a child with fulminant liver failure and coma caused by Amanita phalloides intoxication with albumin dialysis without liver transplantation.

Abstract:  FLF is a life‐threatening disease. Hepatic coma exerts dramatic impact on patient survival. At present, LTx is the treatment modality of choice that provides significant improvement in outcome of most patients with FLF. Multiple attempts have been made to reduce mortality and improve the patients condition. One of the new options is AD – MARS. We present the case of a 11‐yr‐old boy with FLF and hepatic coma who avoided the scheduled LTx because of rapid neurological and biochemical improvement immediately after three MARS sessions.