Janusz Feber

Hypertension in children: new trends and challenges.

Childhood HTN (hypertension) has become a widely investigated topic within the last decade due to its increasing prevalence. In the present review, we examine new developments and trends that have significantly contributed to aetiology, diagnosis, evaluation and management of childhood HTN. Many recent reports document an increasing prevalence of HTN, mainly essential HTN, in children worldwide. This is probably related to the increase of childhood obesity, although obesity is not the only factor. Evidence has been accumulating to suggest a rather complex interplay between obesity, uric acid level, dietary sodium intake, inflammation, inheritance and other factors, which lead to increased risk of developing HTN in childhood and adulthood. The detection and monitoring of HTN has significantly improved with the use of ABPM (ambulatory blood pressure monitoring), which allows not only for a more accurate classification and staging of HTN, but also for the calculation of more sophisticated parameters such as the AASI (ambulatory arterial stiffness index). Measurement of arterial stiffness enables assessment of arterial dysfunction, which may precede structural vascular changes evaluated by carotid intima media thickness. Sustained HTN eventually leads to end-organ damage [LVH (left ventricular hypertrophy), central nervous system], which in turn increases the risk of cardiovascular morbidity and mortality. New developments in childhood HTN, as outlined in the present review, will hopefully contribute to better screening and management of HTN in children.

Combined liver-kidney transplantation in primary hyperoxaluria type 1

Abstract Primary hyperoxaluria type 1 (PH1) is a rare autosomal recessive disorder characterised by an increased urinary excretion of calcium oxalate, leading to recurrent urolithiasis, nephrocalcinosis and accumulation of insoluble oxalate throughout the body (oxalosis) when the glomerular filtration rate falls to below 40–20 mL/min per 1.73 m2. The disease is due to a functional defect of the liver-specific peroxisomal enzyme alanine: glyoxylate aminotransferase (AGT), the gene of which is located on chromosome 2q37.3. The diagnosis is based on increased urinary oxalate and glycollate, increased plasma oxalate and AGT measurement in a liver biopsy. AGT mistargeting may be investigated by immuno-electron microscopy and DNA analysis. End-stage renal failure is reached by the age of 15 years in 50% of PH1 patients and the overall death rate approximates 30%. The conservative treatment includes high fluid intake, pyridoxine and crystallisation inhibitors. Since the kidney is the main target of the disease, isolated kidney transplantation (Tx) has been proposed in association with vigorous peri-operative haemodialysis in an attempt to clear plasma oxalate at the time of Tx. However, because of a 100% recurrence rate, the average 3-year graft survival is 15%–25% in Europe, with a 5–10-year patient survival rate ranging from 10% to 50%. Since the liver is the only organ responsible for the detoxification of glyoxylate by AGT, deficient host liver removal is the first rationale for enzyme replacement therapy. Subsequent orthotopic liver Tx aims to supply the missing enzyme in its normal cellular and subcellular location and thus can be regarded as a form of gene therapy. Because of the usual spectrum of the disease, isolated liver Tx is limited to selected patients prior to having reached an advanced stage of chronic renal failure. Combined liver-kidney Tx has therefore become a conventional treatment for most PH1 patients: according to the European experience, patient survival approximates 80% at 5 years and 70% at 10 years. In addition, the renal function of survivors remains stable over time, between 40 and 60 mL/min per 1.73 m2 after 5 to 10 years. In addition, liver Tx may allow the reversal of systemic storage disease (i.e. bone, heart, vessels, nerves) and provide valuable quality of life. Whatever the transplant strategy, the outcome is improved when patients are transplanted early in order to limit systemic oxalosis. According to the European experience, it appears that combined liver-kidney Tx is performed in PH1 patients with encouraging results, renal Tx alone has little role in the treatment of this disease, and liver Tx reverses the underlying metabolic defect and its clinical consequences.

Universal approach to pharmacokinetic monitoring of immunosuppressive agents in children

Abstract: Current data indicate that pharmacokinetic (PK) monitoring of cyclosporin microemulsion (CsA) should be performed using the 2‐h concentration (C2), that tacrolimus (Tac) is commonly monitored using the trough level, and mycophenolate mofetil (MMF) should be monitored using the 1‐h (C1), 2‐h (C2) and 6‐h (C6) concentrations. The three differing time‐point requirements are cumbersome, and we aimed to develop universal guidelines for all three drugs using a large number of full PK profiles in children. One‐hundred and twenty two stable pediatric patients, receiving either CsA (165 PK profiles, 69 patients, 24 with concomitant MMF) or Tac (122 PK profiles, 53 patients, 18 with MMF) were analyzed retrospectively. Pearson r for the CsA C2 was 0.90 [95% confidence interval(CI): 0.86–0.92], for Tac C2 r was 0.86 (95% CI: 0.80–0.90), and for MPA C2 r was 0.77 (95% CI: 0.68–0.83), respectively. For MPA, at least three time‐points are required to accurately estimate the area under the concentration–time curve (AUC), and C1, C2 and C6 serve as best markers. Excellent AUC estimations could be obtained from a limited sampling strategy from C1, C2 and C6 or C0, C1, C2 and C4 with clinically acceptable errors for all three drugs. The AUC can be estimated with great precision by using an identical approach for all three drugs. Target AUCs for a given time‐point after transplantation remain to be established.

Unexpectedly high inter- and intrapatient variability of Ganciclovir levels in children

Abstract:  Few studies report Ganciclovir or Valganciclovir levels in children. Single‐center, retrospective study of all available Ganciclovir levels in transplanted children. Ganciclovir monitoring was performed as previously described [G. Filler (1998); Pediatric Nephrology, 12, 6]. For the normalization of dosing to GFR and target trough levels, we assumed first‐order kinetics. We analyzed 57 Ganciclovir levels in 20 children (mean age 8.6 ± 5.5 yr) treated with intravenous or oral Ganciclovir or oral Valganciclovir. Ganciclovir levels were drawn after IV therapy (n = 9), during oral Ganciclovir (n = 5), or during oral Valganciclovir (n = 15). Oral bioavailability of Valganciclovir was 42.0 ± 21.8%. The dose‐normalized intrapatient Valganciclovir variability was 83%. Mean GFR was 92 ± 22 mL/min/1.73 m2. Mean Ganciclovir concentration at last available measurement was 0.60 ± 0.09 mg/L. While target trough Ganciclovir levels have not been established, possibly subtherapeutic Ganciclovir levels <0.5 mg/L on recommended IV doses were found in eight patients. This subset of patients was significantly younger (4.5 ± 3.1 vs. 11.4 ± 5.0 yr). Levels <0.5 mg/L were found in 24/57 instances and 10 patients subsequently had their dose increased. The last Valganciclovir dose adjusted to a GFR of 100 mL/min/1.73 m2 was 842 ± 323 mg/m2/day. A high proportion of patients had low Ganciclovir levels both on intravenous and oral therapy. The oral bioavailability of Valganciclovir was 42%. Our data suggest substantial inter‐ and intrapatient variability of Ganciclovir levels after pediatric renal transplantation and may support the need for pharmacokinetic monitoring of Ganciclovir and Valganciclovir therapy for the prevention and treatment of CMV disease after pediatric transplantation. It is currently unclear what target trough level would be most suitable.

Intra-individual variation of cystatin C and creatinine in pediatric solid organ transplant recipients

Abstract:  There is controversy about the feasibility of cystatin C (CysC) as a marker of glomerular filtration rate (GFR) post‐transplant (Tx). We studied intra‐patient variability of CysC in comparison with serum creatinine (SCr) in 20 children (11 males, mean age 11.5 ± 6.4 yr) with solid organ transplants (14 kidney, four liver, and two combined liver + kidney transplants). The mean age at Tx was 7.0 ± 5.6 yr. A total of 178 simultaneous SCr and CysC measurements (median 8 per patient) were analyzed. In addition, GFR was calculated using the Schwartz and a novel CysC‐based formula. Intra‐individual coefficient of variations (CV) was calculated as ratio of standard deviation over mean. The mean CV was significantly lower for SCr (7.71 ± 4.16%) when compared with CysC (10.27 ± 4.87, p = 0.04), but was no longer significantly different when excluding patients with a bladder augment. The CV of the GFR estimated by Schwartz formula (7.44 ± 3.77) was significantly lower than GFR calculated from CysC (12.52 ± 7.37), p = 0.001. The mean ratio between the Schwartz GFR and the GFR calculated from CysC was 102.6 ± 12.8%, not significantly different from 100% (p = 0.3796). The only potential confounding factors to explain increased CV after Tx were gender and bladder augmentation, whereas calcineurin inhibitors or steroids did not influence CV. With the limitation of a small number of subjects, our data suggest that the CysC and the CysC‐calculated GFR is equivalent but not better than SCr and Schwartz formula. We therefore conclude that measurement of CysC can be used for longitudinal intra‐individual follow‐up of renal function post‐Tx.

Adding Sirolimus to Tacrolimus-Based Immunosuppression in Pediatric Renal Transplant Recipients Reduces Tacrolimus Exposure

In adult renal recipients, coadministration of tacrolimus (TAC) and sirolimus (SIR) results in reduced exposure to TAC at SIR doses of 2 mg/day. Eight pediatric renal recipients (median age at transplant 2.0 years, range: 1.2–12.9 years) were converted to TAC‐ and SIR‐based immunosuppression as a rescue therapy. All patients had biopsy‐proven chronic allograft nephropathy. TAC levels were measured using a commercially available EMIT assay and SIR levels with a newly developed assay based on the LC‐MS MS technology. SIR was started at 0.13 ± 0.05 mg/kg/day (3.51 ± 1.26 mg/m2/day) in two divided doses. TAC was given at 0.14 ± 0.09 mg/kg/day, resulting in a trough level of 6.3 ± 2.5 ng/mL. After the addition of SIR, the median dose required to keep TAC blood trough concentrations within the target range increased by 71.2% (range: 21.9–245.4%), dose‐normalized TAC exposure (AUC) decreased to 67.1% and the dose‐normalized Cmax, a surrogate for absorption rate, to 53.8% (both geometric means) while terminal half‐life (t1/2), a pharmacokinetic parameter characterizing systemic elimination, remained unchanged (p < 0.93). Adding SIR to TAC‐based immunosuppression in young pediatric renal transplant recipients results in a significant decrease of TAC exposure. TAC trough levels should be monitored frequently.

Body composition in children with renal disease: use of dual energy X-ray absorptiometry

Dual energy X-ray absorptiometry (DEXA) is a non-invasive accurate method which estimates bone mineral content and density (BMD), as well as fat (FM) and lean (LM) body mass. This method was used in control children in order to establish normal values for BMD of lumbar spine and whole body composition {logistic curves, general equation E=k+K/[1+αexp(-βA)]}. In children with chronic renal failure (CRF), LM correlated with the urinary excretion of creatinine (r=0.97,P=0.0001) independently from glomerular filtration rate. However, the assessment of LM by DEXA must take into account the hydration level, since there is a positive correlation between fluid loss and reduction in LM in children on hemodialysis (r=0.98,P=0.0001). After renal transplantation, a significant loss of BMD (median −9.2%), was observed at 6 months which returned to 95% of pretransplant values by the end of the 1 st year. Maximal changes in LM and FM occurred during the first 3 months (−7.8% and +7.2%, respectively) and may be due to steroids; these should be influenced by physical activity since FM correlated inversely with maximal oxygen consumption (r=0.69P=0.0001). Recombinant growth hormone treatment could also increase LM and decrease FM, as shown in 9 patients. DEXA appears therefore to be a reliable method for evaluating therapeutic interventions affecting nutritional status in children with CRF.

Association between obesity and the severity of ambulatory hypertension in children and adolescents

The goal of our study was to analyze the association between obesity and the severity of ambulatory hypertension in obese children. A total of 109 patients with primary obesity ages 7 to 18 years (mean ± SD age 14.1 ± 3.1) were enrolled. Patients were divided into three groups according to body mass index (BMI) Z-scores: group 1 (n = 27): BMI >1.65 and < 3.28 standard deviation scores (SDS); group 2 (n = 55): BMI >3.29 and <4.91 SDS; group 3 (n = 27): BMI >4.92 SDS. Definition and staging of ambulatory hypertension was based on blood pressure (BP) levels and BP load, obtained from ambulatory BP monitoring (ABPM). Only 24% had ambulatory normotension, 25% had ambulatory prehypertension, 3% had hypertension, and 48% had severe ambulatory hypertension. The severity of hypertension increased significantly with the degree of obesity (P = .0027). Daytime systolic, diastolic, and mean arterial BPs increased significantly with increased BMI, whereas the nighttime pressure remained elevated regardless of the degree of obesity. Isolated nighttime hypertension was observed in 25% of patients and 38% were classified as nondippers. Almost 50% of children with obesity and hypertension detected on ABPM suffer from severe ambulatory hypertension. BMI is associated with the severity of ambulatory hypertension and the increase of daytime BP.

Clinical practice guidelines for pediatric peritoneal dialysis.

Peritoneal dialysis (PD) continues to be an important modality of treatment for children with end-stage renal disease. The Canadian Association of Pediatric Nephrologists recognized the need nationally to review the literature on the delivery of PD in children to provide optimal standardized care. This resulted in the development of the Canadian Clinical Practice Guidelines for pediatric PD. Clinical practice guidelines are a useful adjunct to clinical care. The present review includes recommendations for catheter placement and types, requirement for prophylactic omentectomy, initiation and adequacy of dialysis, PD prescription, and solute clearance. It provides physicians with updated evidence-based recommendations that include consideration towards practicality with the major goal of improved and standardized patient care.

Complications of chronic kidney disease in children post‐renal transplantation – A single center experience

Abstract:  Similar to adults, CKD may persist after pediatric RTx. Clinical and laboratory parameters were analyzed retrospectively in 23 RTx recipients (13 males, age 11.9 ± 5.2 yr), initially treated with prednisone, calcineurin inhibitor (TAC = 18, cyclosporine neoral = 5), and MMF at four months post‐RTx (T1) and at 3.4 ± 2.8 yr post‐RTx (T2). Mean (±s.d.) cystatin C GFR (mL/min/1.73 m2) was 72 ± 19 at T1 and 70 ± 22 at T2 (NS). At T2, CKD stage I was present in five patients (22%), stage II in eight patients (35%), and stage III in 10 patients (43%). At T2, calcineurin inhibitors were utilized in 19, MMF in 13, and SIR in 13 patients. The prevalence of hypertension was 69% at T1 and 87% at T2 (p = NS). Anemia was diagnosed in 61% at T1 and 69% at T2 with average therapeutic MMF (2.78 ± 1.3 mg/mL) and SIR (7.62 ± 2.3 mg/mL) trough levels. Hypercholesterolemia was detected in 44.0% at T1 and 47% at T2. Bone disease was diagnosed in 26.0% at T1 and 21.7% at T2. Mean height Z‐scores were −1.0 ± 1.2 (T1) and −1.0 ± 1.59 (T2, NS), with 21% at T1 and 30% at T2 below two SDS. We observed suboptimal growth, hypertension, hypercholesterolemia, bone disease, and anemia in a significant proportion of transplanted children.