Jan Janda

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.

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.

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.

Residual renal function in children on haemodialysis and peritoneal dialysis therapy

Residual renal function was studied in 28 haemodialysis (HD) and 31 peritoneal dialysis (PD) patients aged 1–20 years observed over 6–43 (median 19) months. After the start of dialysis urine volume (UV) decreased to 57%, 46% and 26% of initial mean values in HD patients after 6, 12 and 24 months, respectively. In PD patients the corresponding figures were 57%, 69% and 62%. Mean UV calculated from all individual mean UV measurements observed was higher in PD than HD patients (954 vs. 537 ml/m2 per 24 h,P<0.01). A better conservation of diuresis in PD patients was also suggested by a significantly longer persistence of a UV greater than 500 ml/m2 per 24 h compared with HD patients. Cox proportional hazard analysis identified dialysis modality and pre-dialysis UV of less than 1,000 ml/m2 per 24 h as the only significant risk factors for UV survival. However, the decline of UV per time was similar in both modes of treatment. No significant changes of glomerular filtration rate were observed during both HD and PD treatment.

Ambulatory blood pressure monitoring in children with unilateral multicystic dysplastic kidney

Abstract Multicystic dysplastic kidney (MCDK) is one of the most common congenital renal anomalies. Arterial hypertension is a potential complication of MCDK. Blood pressure (BP) has so far been measured only casually and the frequency of hypertension has been estimated to be between 0%–8%. Ambulatory blood pressure monitoring (ABPM) provides more precise information on BP than the casual BP measurement. The aim of this study was to investigate the BP profile in children with MCDK using ABPM. A group of 25 children (16 girls), with a mean age of 7.8 years (range 3.8–17.7 years) were investigated. ABPM was performed using the oscillometric SpaceLabs 90207 device. Hypertension was defined as mean systolic and/or diastolic BP during the day and/or in the night exceeding 95th percentile for ABPM. Five (20%) children showed hypertension, two of them had combined daytime and night-time hypertension and three had isolated nocturnal hypertension, although daytime BP was between the 90th–95th percentile in two of them. Children with ultrasonographical and/or laboratory signs of contralateral kidney abnormalities showed a higher incidence of hypertension than those without abnormalities (two of four versus 3 of 21). The mean night-time systolic and diastolic BP of children with MCDK was significantly higher than in healthy children (+0.50 and +0.54 SDS, respectively, P=0.012 and 0.03, respectively). Three of the hypertensive children were already nephrectomised. All five hypertensive children showed ultrasonographical and/or laboratory signs of contralateral kidney abnormalities. Hypertensive children had significantly higher microalbuminuria than normotensive children (6.9 ± 3.2 mg/mmol creatinine versus 1.8 ± 0.7, P=0.03). The nocturnal BP fall (dip) was attenuated in five children, only one of whom was hypertensive. Conclusion Arterial hypertension in children with multicystic dysplastic kidney is seen more often if based on ambulatory blood pressure monitoring than on casual blood pressure recordings. The main risk factor for developing hypertension is contralateral kidney damage. Ambulatory blood pressure monitoring should be performed in children with multicystic dysplastic kidney, especially in those with contralateral kidney abnormalities.

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.

Arterial HTN in children with T1DM--frequent and not easy to diagnose.

Introduction: To evaluate the diagnostic efficacy of the office blood pressure (OBP) and ambulatory blood pressure monitoring (ABPM) in the assessment of hypertension (HTN) in children with diabetes mellitus type 1 (T1DM).

Blockade of Endothelin Receptors Attenuates End-Organ Damage in Homozygous Hypertensive Ren-2 Transgenic Rats

Background/Aims: A growing body of evidence suggests that the interplay between the endothelin (ET) and the renin-angiotensin systems (RAS) plays an important role in the development of the malignant phase of hypertension. The present study was performed to evaluate the role of an interaction between ET and RAS in the development of hypertension and hypertension-associated end-organ damage in homozygous male transgenic rats harboring the mouse Ren-2 renin gene (TGRs) under conditions of normal-salt (NS, 0.45% NaCl) and high-salt (HS, 2% NaCl) intake. Methods: Twenty-eight-day-old homozygous male TGRs and age-matched transgene-negative male normotensive Hannover Sprague-Dawley (HanSD) rats were randomly assigned to groups with NS or HS intake. Nonselective ETA/B receptor blockade was achieved with bosentan (100 mg/kg/day). Systolic blood pressure (BP) was measured in conscious animals by tail plethysmography. Rats were placed into metabolic cages to determine proteinuria and clearance of endogenous creatinine. At the end of the experiment the final arterial BP was measured directly in anesthetized rats. Kidneys were taken for morphological examination. Results: All male HanSD fed either the NS or HS diet exhibited a 100% survival rate until 180 days of age (end of experiment). The survival rate in untreated homozygous male TGRs fed the NS diet was 41%, which was markedly improved by treatment with bosentan to 88%. The HS diet reduced the survival rate in homozygous male TGRs to 10%. The survival rate in homozygous male TGRs on the HS diet was significantly improved by bosentan to 69%. Treatment with bosentan did not influence either the course of hypertension or the final levels of BP in any of the experimental groups of HanSD rats or TGRs. Although the ET-1 content in the renal cortex did not differ between HanSD rats and TGRs, ET-1 in the left heart ventricle of TGRs fed the HS diet was significantly higher compared with all other groups. Administration of bosentan to homozygous male TGRs fed either the NS or HS diet markedly reduced proteinuria, glomerulosclerosis and attenuated the development of cardiac hypertrophy compared with untreated TGR. Conclusions: Our data show that nonselective ETA/B receptor blockade markedly improves the survival rate and ameliorates end-organ damage in homozygous male TGRs without significantly lowering BP.

Enterohemorrhagic Escherichia coli as Causes of Hemolytic Uremic Syndrome in the Czech Republic

Background Enterohemorrhagic Escherichia coli (EHEC) cause diarrhea-associated hemolytic uremic syndrome (D+ HUS) worldwide, but no systematic study of EHEC as the causative agents of HUS was performed in the Czech Republic. We analyzed stools of all patients with D+ HUS in the Czech Republic between 1998 and 2012 for evidence of EHEC infection. We determined virulence profiles, phenotypes, antimicrobial susceptibilities and phylogeny of the EHEC isolates. Methodology/Principal Findings Virulence loci were identified using PCR, phenotypes and antimicrobial susceptibilities were determined using standard procedures, and phylogeny was assessed using multilocus sequence typing. During the 15-year period, EHEC were isolated from stools of 39 (69.4%) of 56 patients. The strains belonged to serotypes [fliC types] O157:H7/NM[fliC H7] (50% of which were sorbitol-fermenting; SF), O26:H11/NM[fliC H11], O55:NM[fliC H7], O111:NM[fliC H8], O145:H28[fliC H28], O172:NM[fliC H25], and Orough:NM[fliC H25]. O26:H11/NM[fliC H11] was the most common serotype associated with HUS (41% isolates). Five stx genotypes were identified, the most frequent being stx 2a (71.1% isolates). Most strains contained EHEC-hlyA encoding EHEC hemolysin, and a subset (all SF O157:NM and one O157:H7) harbored cdt-V encoding cytolethal distending toxin. espPα encoding serine protease EspPα was found in EHEC O157:H7, O26:H11/NM, and O145:H28, whereas O172:NM and Orough:NM strains contained espPγ. All isolates contained eae encoding adhesin intimin, which belonged to subtypes β (O26), γ (O55, O145, O157), γ2/θ (O111), and ε (O172, Orough). Loci encoding other adhesins (efa1, lpfA O26, lpfA O157OI-141, lpfA O157OI-154, iha) were usually associated with particular serotypes. Phylogenetic analysis demonstrated nine sequence types (STs) which correlated with serotypes. Of these, two STs (ST660 and ST1595) were not found in HUS-associated EHEC before. Conclusions/Significance EHEC strains, including O157:H7 and non-O157:H7, are frequent causes of D+ HUS in the Czech Republic. Identification of unusual EHEC serotypes/STs causing HUS calls for establishment of an European collection of HUS-associated EHEC, enabling to study properties and evolution of these important pathogens.

Urinary transforming growth factor-β1 in children with obstructive uropathy.

Aim:  Obstructive uropathies (OU) in childhood constitute one of the major causes of chronic renal insufficiency. Transforming growth factor‐β1 (TGF‐β1) is considered to be the major fibrogenic growth factor. The aim of the present study was to investigate urinary TGF‐β1 levels in children with obstructive and non‐obstructive uropathies (NOU).