Martin Bald

Spontaneous baroreflex sensitivity in children and young adults calculated in the time and frequency domain.

Spontaneous baroreflex receptor sensitivity (BRS) was calculated in 22 healthy normotensive children and young adults (age 14 +/- 5 years) using the sequence technique (time domain) and the alpha-coefficient or the gain of the transfer function between coherent oscillations (frequency domain). BRS estimated by the sequence technique (median: 16.7 ms/mm Hg) was significantly higher than BRS calculated from the gain of the transfer function using all frequencies (median: 13.0 ms/mm Hg; p = 0.009). However, there was a high correlation between these methods (r = 0.92). The reproducibility coefficient (RC) was high for all methods, but the coefficient of variability (VC) was best for the sequence technique and the gain of the transfer function, but significantly worse for the estimates of the alpha-coefficient in the low or high frequency band. The differentiation between increasing or decreasing blood pressure (BP) ramps did not give further information showing the same BRS values. The best BRS estimates will be achieved by using three consecutive beats without lag by the sequence technique and by using only frequencies with a proven correlation of BP and pulse interval (PI) and then calculating the gain of the transfer function using coherent oscillations.

Autonomic blood pressure control in children and adolescents with type 1 diabetes mellitus

Introduction:  Increased daytime blood pressure and reduced nocturnal dipping can already be found in children with type 1 diabetes mellitus. We hypothesized that impaired baroreflex sensitivity can cause this abnormal blood pressure behavior in children and adolescents with type 1 diabetes, reflecting an early stage of diabetic autonomic neuropathy.

Efficacy and Safety of an Everolimus- vs. a Mycophenolate Mofetil-Based Regimen in Pediatric Renal Transplant Recipients.

Introduction Data on the efficacy and safety of everolimus in pediatric renal transplantation compared to other immunosuppressive regimens are scarce. Patients/Methods We therefore performed a multicenter, observational, matched cohort study over 4 years post-transplant in 35 patients on everolimus plus low-dose cyclosporine, who were matched (1:2) with a control group of 70 children receiving a standard-dose calcineurin-inhibitor- and mycophenolate mofetil-based regimen. Results Corticosteroids were withdrawn in 83% in the everolimus vs. 39% in the control group (p<0.001). Patient and graft survival were comparable. The rate of biopsy-proven acute rejection episodes Banff score ≥ IA during the first year post-transplant was 6% in the everolimus vs. 13% in the control group (p = 0.23). The rate of de novo donor-specific HLA antibodies (11% in everolimus, 18% in controls) was comparable (p = 0.55). At 4 years post-transplant, mean eGFR in the everolimus group was 56±33 ml/min per 1.73 m² vs. 63±22 ml/min per 1.73 m² in the control group (p = 0.14). Everolimus therapy was associated with less BK polyomavirus replication (3% vs. 17% in controls; p = 0.04), but with a higher percentage of arterial hypertension and more hyperlipidemia (p<0.001). Conclusion In pediatric renal transplantation, an everolimus-based regimen with low-dose cyclosporine yields comparable four year results as a standard regimen, but with a different side effect profile.

Cytomegalovirus Infection in Pediatric Renal Transplantation and the Impact of Chemoprophylaxis With (Val-)Ganciclovir

Background Cytomegalovirus (CMV) replication and disease, with its associated morbidity and poor transplant outcome, represents a serious threat to transplant recipients. The pediatric kidney transplant population is at a particularly increased risk of CMV infection. Methods We therefore analyzed CMV epidemiology in a large cohort of pediatric renal transplant recipients (n = 242) and assessed the impact of antiviral chemoprophylaxis with valganciclovir (VGCV) or ganciclovir (GCV) on CMV replication and morbidity. Results While antiviral chemoprophylaxis with VGCV or GCV in patients with a high (D+/R−) or intermediate (D+/R+) CMV risk (n = 82) compared to preemptive therapy (n = 47) had no significant effect on the incidence of CMV syndrome or tissue-invasive disease, chemoprophylaxis was associated with a better preservation of transplant function at 3 years posttransplant (loss of estimated glomerular filtration rate in the chemoprophylaxis cohort, 16.0 ± 3.4 vs. 30.1 ± 4.7 mL/min per 1.73 m2 in the preemptive therapy cohort, P < 0.05).CMV replication was associated with a more pronounced decline of graft function (difference in estimated glomerular filtration rate of 9.6 mL/min per 1.73 m2 at 3 years) compared to patients without CMV replication. However, patients undergoing VGCV or GCV chemoprophylaxis had more leukocytopenia. Conclusion Antiviral chemoprophylaxis with VGCV or GCV in recipients with a high or moderate CMV risk is associated with a better preservation of transplant function. Hence, the prevention of CMV replication in this patient population has the potential to improve transplant outcome.

Phenotypic Spectrum of Children with Nephronophthisis and Related Ciliopathies

BACKGROUND AND OBJECTIVES Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes (NPHP1 to -20) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and detailed characterization of 152 children with a special focus on extrarenal organ involvement and the long-term development of ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We established an online-based registry (www.nephreg.de) to assess the clinical course of patients with nephronophthisis and related ciliopathies on a yearly base. Cross-sectional and longitudinal data were collected. Mean observation time was 7.5±6.1 years. RESULTS In total, 51% of the children presented with isolated nephronophthisis, whereas the other 49% exhibited related ciliopathies. Monogenetic defects were identified in 97 of 152 patients, 89 affecting NPHP genes. Eight patients carried mutations in other genes related to cystic kidney diseases. A homozygous NPHP1 deletion was, by far, the most frequent genetic defect (n=60). We observed a high prevalence of extrarenal manifestations (23% [14 of 60] for the NPHP1 group and 66% [61 of 92] for children without NPHP1). A homozygous NPHP1 deletion not only led to juvenile nephronophthisis but also was able to present as a predominantly neurologic phenotype. However, irrespective of the initial clinical presentation, the kidney function of all patients carrying NPHP1 mutations declined rapidly between the ages of 8 and 16 years, with ESRD at a mean age of 11.4±2.4 years. In contrast within the non-NPHP1 group, there was no uniform pattern regarding the development of ESRD comprising patients with early onset and others preserving normal kidney function until adulthood. CONCLUSIONS Mutations in NPHP genes cause a wide range of ciliopathies with multiorgan involvement and different clinical outcomes.

Impact of Everolimus and Low-Dose Cyclosporin on Cytomegalovirus Replication and Disease in Pediatric Renal Transplantation

In order to investigate the hypothesis that the mammalian target of rapamycin inhibitor everolimus (EVR) shows anticytomegalovirus (CMV) activity in pediatric patients, we analyzed the impact of EVR‐based immunosuppressive therapy on CMV replication and disease in a large cohort (n = 301) of pediatric kidney allograft recipients. The EVR cohort (n = 59), who also received low‐dose cyclosporin, was compared with a control cohort (n = 242), who was administered standard‐dose cyclosporin or tacrolimus and an antimetabolite, mostly mycophenolate mofetil (91.7%). Multivariate analysis revealed an 83% lower risk of CMV replication in the EVR cohort than in the control cohort (p = 0.005). In CMV high‐risk (donor+/recipient−) patients (n = 88), the EVR‐based regimen was associated with a significantly lower rate of CMV disease (0% vs. 14.3%, p = 0.046) than the standard regimen. In patients who had received chemoprophylaxis with (val‐)ganciclovir (n = 63), the CMV‐free survival rates at 1 year and 3 years posttransplant (100%) were significantly (p = 0.015) higher in the EVR cohort (n = 15) than in the control cohort (n = 48; 1 year, 75.0%; 3 years, 63.3%). Our data suggest that in pediatric patients at high risk of CMV, an EVR‐based immunosuppressive regimen is associated with a lower risk of CMV disease than a standard‐dose calcineurin inhibitor–based regimen.

Increased renal echogenicity in a preterm neonate: Question

A 34-year-old otherwise healthy Caucasian female with severe hypertension became pregnant. Because of unknown circumstances her pregnancy was not diagnosed until 26 weeks of gestation. Sonographic examination at that time showed no evidence of oligohydramnion or malformation of the fetus. At 31 weeks of gestation, premature rupture of the membranes occurred and a female newborn was delivered by c-section with a birth weight of 1680 g, a length of 40 cm and a head circumference of 28 cm (all 50th percentile). Histological examination of the placenta revealed signs of chorioamnionitis. The newborn suffered from perinatal asphyxia and primary support included intubation, fluid challenge, and correction of acidosis with bicarbonate. Apgar scores after 5 and 10 min were 4 and 7, respectively. After one dose of surfactant the clinical situation significantly improved and the girl could be extubated on the third day of life. An infection was presumed and antibiotic therapy was initiated. On day 5 a patent ductus arteriosus was diagnosed, but spontaneous closure occurred. There was no decrease in urine output, and blood-pressure readings were within normal limits. Physical examination of the newborn revealed subtle contractions of the extremities and distended cranial sutures, but no further malformations. She seemed hypotonic but there were no clinical or encephalographic signs of seizure activity in the first week of life. Because of pathological abnormalities in a repeat EEG, however, phenobarbital was started and continued for a total of 4 weeks. On day 12, a sonographic examination of the abdomen revealed two kidneys with markedly increased echogenicity and normal size without any cyst formation (Fig. 1). Doppler sonography revealed reduced diastolic blood flow in the renal arteries and an elevated resistance index of 0.83. Because of the echogenic kidneys a diagnostic work-up was started. The girl was healthy, without edema, and had normal urine output and normal blood pressure readings (74– 88 mmHg systolic and 43–62 mmHg diastolic). Laboratory values at initial presentation and during follow-up are shown in the table. Urinalysis revealed up to 5 white blood cells and 3 red blood cells per milliliter, but no significant proteinuria. Urinary calcium and oxalate excretion ratios were in the normal range (Table 1). The answer to this question can be found at http://dx.doi.org/ 10.1007/s00467-005-1938-1

Dyslipidemia after pediatric renal transplantation—The impact of immunosuppressive regimens

Dyslipidemia contributes to cardiovascular morbidity and mortality in pediatric transplant recipients. Data on prevalence and risk factors in pediatric cohorts are, however, scarce. We therefore determined the prevalence of dyslipidemia in 386 pediatric renal transplant recipients enrolled in the CERTAIN registry. Data were obtained before and during the first year after RTx to analyze possible non‐modifiable and modifiable risk factors. The prevalence of dyslipidemia was 95% before engraftment and 88% at 1 year post‐transplant. Low estimated glomerular filtration rate at 1 year post‐transplant was associated with elevated serum triglyceride levels. The use of TAC and of MPA was associated with significantly lower concentrations of all lipid parameters compared to regimens containing CsA and mTORi. Immunosuppressive regimens consisting of CsA, MPA, and steroids as well as of CsA, mTORi, and steroids were associated with a three‐ and 25‐fold (P<.001) increased risk of having more than one pathologic lipid parameter as compared to the use of TAC, MPA, and steroids. Thus, amelioration of the cardiovascular risk profile after pediatric RTx may be attained by adaption of the immunosuppressive regimen according to the individual risk profile.

Dent disease with compound heterozygous mutations leading to severe chronic renal failure in a female patient

We read with interest the paper of Godefroid and Proesmans [1] about a girl with rickets and nephrocalcinosis. Dent disease was discussed as a possible cause of the girl0s renal phosphate wasting disorder. However, Dent disease seemed unlikely because the patient is female and has a severe form of nephrocalcinosis and reduced glomerular filtration rate (GFR). Dent disease is an X-linked tubular syndrome caused by mutations in the renal chloride channel CLCN-5. The gene is located on chromosome Xp11.22 [2]. Clinical symptoms are low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, and renal failure. Patients may also suffer from rickets and other features of the renal Fanconi syndrome [3]. Females are considered only as carriers of mutations, with less-marked clinical manifestations. We are following a family with Dent disease in which we have identified a hemizygous mutation in an 11.5year-old boy and a compound heterozygous status in his 40-year-old mother (manuscript in preparation). The boy presented at the age of 2.5 years with failure to thrive. Diagnostic investigation revealed Fanconi syndrome. Secondary causes were ruled out and he was treated symptomatically. Since he developed decreased renal function with hypercalciuria and low-molecular weight proteinuria, the diagnosis of Dent disease was considered and subsequently confirmed by molecular analysis. Presently he is stable with a creatinine of 1.1 mg/dl (GFR 70 ml/min per 1.73 m2). The mother has chronic renal failure (creatinine 4.7 mg/dl, GFR 17 ml/min per 1.73 m2) with hypercalciuria and nephrocalcinosis as well as short stature. The parents are non-consanguineous and all other family members (great-grandmother, grandparents, father, and one sister) are unaffected. Our analysis shows that females are not only carriers of mutations of Dent disease but can also be compound heterozygous/homozygous with typical clinical symptoms. As the mother of our patient has chronic renal failure and hypercalciuria with nephrocalcinosis from early childhood (similar to the reported case [1]), Dent disease could be present in this female. Molecular analysis is necessary to verify the diagnosis.

Increased renal echogenicity in a preterm neonate: Answer

2. The mother was hypertensive prior to pregnancy. After repeated questioning, she stated that she was on antihypertensive medication (ebrantil 60 mg/day, hydrochlorothiazide 12.5 mg/day and candesartan 8 mg/day) until her pregnancy was diagnosed at 26 weeks gestation 3. The most likely diagnosis is kidneys with tubular dysplasia due to exposure to candesartan during pregnancy 4. The long-term follow-up of this patient should include monitoring of growth and development, surveillance of blood pressure, renal function tests and urinalysis, as well as ultrasound studies to evaluate kidney growth Commentary