Karel Vondrak

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.

Survival and clinical outcomes of children starting renal replacement therapy in the neonatal period

End-stage renal disease requiring renal replacement therapy (RRT) during the neonatal period is a very rare condition, and little information is available regarding long-term RRT and outcomes. To gain more information, we performed a collaborative study on patient characteristics and treatment outcomes in children who started RRT as neonates during their first month of life between 2000 and 2011 who were prospectively registered in the ESPN/ERA-EDTA, the IPPN (since 2007), the Japanese registry, or the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry. During the first month of life, 264 patients from 32 countries started RRT and were followed for a median of 29 months (interquartile range 11-60 months). Most neonates (242) started on peritoneal dialysis, 21 started on hemodialysis, and 1 patient with a transplant. The most important causes of renal failure were congenital anomalies of the kidney and urinary tract in 141, cystic kidneys in 35, and cortical necrosis in 30. Within 2 years after the start of RRT, 69 children changed dialysis modality and 53 received a renal transplant. After a median of 7 months, 45 children had died, mainly because of infection, resulting in an estimated 2-year survival of 81%, and 5-year survival of 76%. Growth retardation (63%), anemia (55%), and hypertension (57%) were still major problems after 2 years. Thus, relatively good medium-term patient survival may be achieved with RRT started during the neonatal period, but specific therapeutic challenges continue to exist in this age group.

Primary angioplasty in acute myocardial infarction with right bundle branch block: should new onset right bundle branch block be added to future guidelines as an indication for reperfusion therapy?

Aims The current guidelines recommend reperfusion therapy in acute myocardial infarction (AMI) with ST-segment elevation or left bundle branch block (LBBB). Surprisingly, the right bundle branch block (RBBB) is not listed as an indication for reperfusion therapy. This study analysed patients with AMI presenting with RBBB [with or without left anterior hemiblock (LAH) or left posterior hemiblock (LPH)] and compared them with those presenting with LBBB or with other electrocardiographic (ECG) patterns. The aim was to describe angiographic patterns and primary angioplasty use in AMI patients with RBBB. Methods and results A cohort of 6742 patients with AMI admitted to eight participating hospitals was analysed. Baseline clinical characteristics, ECG patterns, coronary angiographic, and echocardiographic data were correlated with the reperfusion therapies used and with in-hospital outcomes. Right bundle branch block was present in 6.3% of AMI patients: 2.8% had RBBB alone, 3.2% had RBBB + LAH, and 0.3% had RBBB + LPH. TIMI flow 0 in the infarct-related artery was present in 51.7% of RBBB patients vs. 39.4% of LBBB patients (P = 0.023). Primary percutaneous coronary intervention (PCI) was performed in 80.1% of RBBB patients vs. 68.3% of LBBB patients (P< 0.001). In-hospital mortality of RBBB patients was similar to LBBB (14.3 vs. 13.1%, P = 0.661). Patients with new or presumably new blocks had the highest (LBBB 15.8% and RBBB 15.4%) incidence of cardiogenic shock from all ECG subgroups. Percutaneous coronary intervention was done more frequently (84.8%) in patients with new or presumably new RBBB when compared with other patients with blocks (old RBBB 66.0%, old LBBB 62.3%, new or presumably new LBBB 73.0%). In-hospital mortality was highest (18.8%) among patients presenting with new or presumably new RBBB, followed by new or presumably new LBBB (13.2%), old LBBB (10.1%), and old RBBB (6.4%). Among 35 patients with acute left main coronary artery occlusion, 26% presented with RBBB (mostly with LAH) on the admission ECG. Conclusion Acute myocardial infarction with RBBB is frequently caused by the complete occlusion of the infarct-related artery and is more frequently treated with primary PCI when compared with AMI + LBBB. In-hospital mortality of patients with AMI and RBBB is highest from all ECG presentations of AMI. Restoration of coronary flow by primary PCI may lead to resolution of the conduction delay on the discharge ECG. Right bundle branch block should strongly be considered for listing in future guidelines as a standard indication for reperfusion therapy, in the same way as LBBB.

Control of hypertension in children after renal transplantation

Abstract: The aim of this cross‐sectional single‐center study was to investigate the efficacy of hypertension control in children who underwent transplantation using ambulatory blood pressure (BP) monitoring, and to determine the risk factors associated with poor control of hypertension. Thirty‐six children fulfilled the inclusion criteria. The mean age was 13.9±4.4 yr; the mean time after renal transplantation was 2.7±2.4 yr (0.5–10.1). Hypertension was defined as a mean ambulatory BP ≥95th centile for healthy children and/or requiring antihypertensive drugs. Hypertension was regarded as controlled if the mean ambulatory BP was <95th centile in children already on antihypertensive drugs, or uncontrolled if the mean ambulatory BP was ≥95th centile in treated children. Hypertension was present in 89% of children. Seventeen children (47%) had controlled hypertension, and 14 (39%) had uncontrolled hypertension. One child (3%) had untreated hypertension, and only four children (11%) showed normal BP without antihypertensive drugs. The efficacy of hypertensive control was 55% (17 of 31 children on antihypertensive drugs had a BP<95th centile), i.e. 45% of treated children still had hypertension. Children with uncontrolled hypertension had significantly higher cyclosporine doses (6.1 vs. 4.3 mg/kg/day, p=0.01) and tacrolimus levels (9.2 vs. 6.1 μg/L, p<0.05), and there was a tendency toward use of lower number of antihypertensive drugs (2.0 vs. 1.5 drugs/patient, p=0.06) and lower use of angiotensin‐converting enzyme (ACE) inhibitors (7 vs. 35%, p=0.09) and diuretics (29 vs. 59%, p=0.14) than in children with controlled hypertension. In conclusion, nearly 90% of our children after renal transplantation are hypertensive and the control of hypertension is unsatisfactorily low. The control of hypertension could be improved by increasing the number of prescribed antihypertensive drugs, especially ACE inhibitors, and diuretics, or by using higher doses of currently used antihypertensives.

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.

Cardiac geometry in children receiving chronic peritoneal dialysis: findings from the International Pediatric Peritoneal Dialysis Network (IPPN) registry.

BACKGROUND AND OBJECTIVES Left ventricular hypertrophy (LVH) is an independent risk factor and an intermediate end point of dialysis-associated cardiovascular comorbidity. We utilized a global pediatric registry to assess the prevalence, incidence, and predictors of LVH as well as its evolution in the longitudinal follow-up in dialyzed children. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Cross-sectional echocardiographic, clinical, and biochemical data were evaluated in 507 children on peritoneal dialysis (PD), and longitudinal data were evaluated in 128 patients. The 95(th) percentile of LV mass index relative to height age was used to define LVH. RESULTS The overall LVH prevalence was 48.1%. In the prospective analysis, the incidence of LVH developing de novo in patients with normal baseline LV mass was 29%, and the incidence of regression from LVH to normal LV mass 40% per year on PD. Transformation to and regression from concentric LV geometry occurred in 36% and 28% of the patients, respectively. Hypertension, high body mass index, use of continuous ambulatory peritoneal dialysis, renal disease other than hypo/dysplasia, and hyperparathyroidism were identified as independent predictors of LVH. The use of renin-angiotensin system (RAS) antagonists and high total fluid output (sum of urine and ultrafiltration) were protective from concentric geometry. The risk of LVH at 1 year was increased by higher systolic BP standard deviation score and reduced in children with renal hypo/dysplasia. CONCLUSIONS Using height-adjusted left ventricular mass index reference data, LVH is highly prevalent but less common than previously diagnosed in children on PD. Renal hypo/dysplasia is protective from LVH, likely because of lower BP and polyuria. Hypertension, fluid overload, and hyperparathyroidism are modifiable determinants of LVH.

Blood Pressure, Renal Function, and Proteinuria in Children with Unilateral Renal Agenesis

Background/Aim: Unilateral renal agenesis (URA) is a model for a reduced nephron number that is believed to be a risk factor for blood pressure (BP) elevation and reduced renal function. The aim of the study was to investigate BP and renal function in children with URA. Methods: Data on children with URA from two pediatric nephrology centers were firstly retrospectively reviewed (renal ultrasound and scintigraphy, clinical BP, creatinine clearance, urinalysis). Children with normal renal ultrasound and scintigraphy were thereafter investigated using ambulatory BP monitoring. Results: Twenty-nine children with URA were investigated – 14 children with an abnormal kidney (mostly scarring) and 15 children with healthy kidneys. Hypertension was diagnosed on the basis of clinical BP in 57% of the children with abnormal kidneys and on the basis of ambulatory BP monitoring in 1 child (7%) with healthy kidneys. The mean ambulatory BP in children with normal kidneys was not significantly different from that in controls. Forty-three percent of the children with abnormal kidneys had a reduced renal function, but none of children with normal kidneys. Conclusions: Children with abnormalities of a solitary kidney have often hypertension, proteinuria, or a reduced renal function. In contrast, children with healthy solitary kidneys have BP and renal function similar to those of healthy children.

Improved control of hypertension in children after renal transplantation: results of a two-yr interventional trial.

Abstract:  Hypertension is a frequent complication in children after renal transplantation and the control of post‐transplant hypertension is unsatisfactorily low. The aim of this prospective interventional study was to improve the control of hypertension in children after renal transplantation. Thirty‐six children fulfilled the inclusion criteria (≥6 months after transplantation and no acute rejection in the last three months). BP was measured using ABPM. Hypertension was defined as mean ambulatory BP ≥95th‐centile for healthy children and/or using antihypertensive drugs. The study intervention consisted of using intensified antihypertensive drug therapy – in children with uncontrolled hypertension (i.e., mean ambulatory BP was ≥95th centile in treated children), antihypertensive therapy was intensified by adding new antihypertensive drugs to reach goal BP <95th centile. ABPM was repeated after 12 and 24 months. Daytime BP did not change significantly after 12 or 24 months. Night‐time BP decreased from 1.57 ± 1.33 to 0.88 ± 0.84 SDS for systolic and from 1.10 ± 1.51 to 0.35 ± 1.18 SDS for diastolic BP after 24 months (p < 0.05). The number of antihypertensive drugs increased from 2.1 ± 0.9 to 2.7 ± 0.8 drugs per patient (p < 0.05), this was especially seen with the use of ACE‐inhibitors (increase from 19% to 40% of children, p < 0.05). In conclusion, this interventional trial demonstrated that, in children after renal transplantation, the control of hypertension, especially at night‐time, can be improved by increasing the number of antihypertensive drugs, especially ACE‐inhibitors.

Determinants of eGFR at start of renal replacement therapy in paediatric patients

BACKGROUND Few studies have investigated the determinants of glomerular filtration rate (GFR) in paediatric patients starting on dialysis or with a transplant. METHODS Data were collected as part of the European Society of Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association registry from 14 European countries and referred to incident paediatric patients starting on renal replacement therapy (RRT) between 2002 and 2007 under the age of 18 years. Estimated glomerular filtration rate (eGFR) was calculated using the Schwartz formula. Data were adjusted for age, gender, treatment modality at start, primary cause of renal failure (PRD) and regions in Europe (eGFR(adj)). RESULTS Median eGFR in the 938 patients starting RRT was 10.4 mL/min/1.73 m(2) (5th and 95th percentile: 4.0-26.9). Twenty-six patients (2.8%), mainly infants with Finnish-type nephropathy, started with eGFR levels >50 mL/min/1.73 m(2). Younger age, female gender, starting on dialysis and having a short time between the first visit to a paediatric nephrologist (PN) and start of RRT were associated with lower eGFR at start of RRT. Gender differences were only present during adolescent age and disappeared when using the same K value for both genders. The various PRDs showed large differences in the rate of decline in eGFR between the first visit to a PN and start of RRT; however, this did not result in differences in eGFR(adj) at start of RRT. CONCLUSIONS The main determinants of eGFR at start of RRT were age, gender, treatment modality at start, and the time between the first visit to a PN and start of RRT. Research is needed to determine the consequences of these differences.

Corticosteroid-Free Kidney Transplantation Improves Growth: 2-Year Follow-up of the TWIST Randomized Controlled Trial.

Background Corticosteroid withdrawal (CW) after pediatric kidney transplantation potentially improves growth while avoiding metabolic and other adverse events. We have recently reported the results of a 196 subject randomized controlled trial comparing early CW (tacrolimus, mycophenolate mofetil (MMF), daclizumab, and corticosteroids until day 4) with tacrolimus, MMF, and corticosteroid continuation (CC). At 6 months, CW subjects showed better growth with no adverse impact on acute rejection or graft survival (Am J Transplant 2010; 10: 828–836). This 2-year investigator-driven follow-up study aimed to determine whether improved growth persisted in the longer term. Methods Data regarding growth, graft outcomes and adverse events were collected at 1 year (113 patients) and 2 years (106 patients) after transplantation. The primary endpoint, longitudinal growth calculated as delta height standard deviation score, was analyzed using a mixed model repeated measures model. Results Corticosteroid withdrawal subjects grew better at 1 year (difference in adjusted mean change, 0.25; 95% confidence interval, 0.10, 0.40; P = 0.001). At 2 years, growth remained numerically better in CW subjects (0.20 (−0.01, 0.41); P = 0.06), and significantly better in prepubertal subjects (0.50 (0.16, 0.84); P = 0.004). Bacterial and viral infection was significantly more common in CW subjects at 1 year only. Corticosteroid withdrawal and CC subjects received similar exposure to both tacrolimus and MMF at 1 and 2 years. No significant difference in patient or graft survival, rejection, estimated glomerular filtration rate, or other adverse events was detected. Conclusion Early CW effectively and safely improves growth up to 2 years after transplantation, particularly in prepubertal children.