Klaus Arbeiter

Strict blood-pressure control and progression of renal failure in children.

BACKGROUND Although inhibition of the renin-angiotensin system delays the progression of renal failure in adults with chronic kidney disease, the blood-pressure target for optimal renal protection is controversial. We assessed the long-term renoprotective effect of intensified blood-pressure control among children who were receiving a fixed high dose of an angiotensin-converting-enzyme (ACE) inhibitor. METHODS After a 6-month run-in period, 385 children, 3 to 18 years of age, with chronic kidney disease (glomerular filtration rate of 15 to 80 ml per minute per 1.73 m(2) of body-surface area) received ramipril at a dose of 6 mg per square meter of body-surface area per day. Patients were randomly assigned to intensified blood-pressure control (with a target 24-hour mean arterial pressure below the 50th percentile) or conventional blood-pressure control (mean arterial pressure in the 50th to 95th percentile), achieved by the addition of antihypertensive therapy that does not target the renin-angiotensin system; patients were followed for 5 years. The primary end point was the time to a decline of 50% in the glomerular filtration rate or progression to end-stage renal disease. Secondary end points included changes in blood pressure, glomerular filtration rate, and urinary protein excretion. RESULTS A total of 29.9% of the patients in the group that received intensified blood-pressure control reached the primary end point, as assessed by means of a Kaplan-Meier analysis, as compared with 41.7% in the group that received conventional blood-pressure control (hazard ratio, 0.65; confidence interval, 0.44 to 0.94; P=0.02). The two groups did not differ significantly with respect to the type or incidence of adverse events or the cumulative rates of withdrawal from the study (28.0% vs. 26.5%). Proteinuria gradually rebounded during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood-pressure control. Achievement of blood-pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of renal disease. CONCLUSIONS Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition. (ClinicalTrials.gov number, NCT00221845.)

Improved Acidosis Correction and Recovery of Mesothelial Cell Mass with Neutral-pH Bicarbonate Dialysis Solution among Children Undergoing Automated Peritoneal Dialysis

Acid-base balance and peritoneal membrane longevity are of utmost relevance for pediatric patients undergoing peritoneal dialysis (PD). PD fluids with neutral pH and reduced glucose degradation product contents are considered more biocompatible, because they preserve peritoneal cell functions in vitro. To investigate the clinical effects of a novel PD fluid buffered with 34 mM pure bicarbonate at neutral pH, a randomized, prospective, crossover comparison with conventional, acidic, 35 mM lactate PD fluid was performed for two consecutive 12-wk periods with 28 children (age, 6 mo to 15 yr) undergoing automated PD (APD). Blood bicarbonate levels and arterial pH were significantly higher after 3 mo of bicarbonate PD (24.6 +/- 2.3 mM and 7.43 +/- 0.06, respectively), compared with lactate PD (22.8 +/- 3.9 mM and 7.38 +/- 0.05, respectively; P < 0.05). This effect was reversible among patients who returned from bicarbonate to lactate fluid. Low initial pH and young patient age independently predicted increased blood pH during bicarbonate APD. Peritoneal equilibration tests revealed subtle changes in solute transport, with a less steep creatinine equilibration curve during bicarbonate dialysis, suggesting reduced peritoneal vasodilation. The peritoneal release of carcinogen antigen-125 increased twofold during bicarbonate APD (29 +/- 15 versus 15 +/- 8 U/ml per 4 h, P < 0.01), which is consistent with recovery of the mesothelial cell layer. This effect was fully reversed when the patients returned to lactate fluid. Effluent carcinogen antigen-125 levels were inversely correlated with peritoneal glucose exposure during lactate but not bicarbonate APD, indicating improved in vivo mesothelial cell tolerance of high-dose glucose with the neutral-pH PD fluid with reduced glucose degradation product content. Among children undergoing APD, neutral-pH, bicarbonate-buffered PD fluid provides more effective correction of metabolic acidosis and better preservation of peritoneal cell mass than do conventional, acidic, lactate-based fluids.

B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ.

Primary B-cell disorders comprise a heterogeneous group of inherited immunodeficiencies, often associated with autoimmunity causing significant morbidity. The underlying genetic etiology remains elusive in the majority of patients. In this study, we investigated a patient from a consanguineous family suffering from recurrent infections and severe lupuslike autoimmunity. Immunophenotyping revealed progressive decrease of CD19(+) B cells, a defective class switch indicated by low numbers of IgM- and IgG-memory B cells, as well as increased numbers of CD21(low) B cells. Combined homozygosity mapping and exome sequencing identified a biallelic splice-site mutation in protein C kinase δ (PRKCD), causing the absence of the corresponding protein product. Consequently, phosphorylation of myristoylated alanine-rich C kinase substrate was decreased, and mRNA levels of nuclear factor interleukin (IL)-6 and IL-6 were increased. Our study uncovers human PRKCD deficiency as a novel cause of common variable immunodeficiency-like B-cell deficiency with severe autoimmunity.

Superior consistency of ambulatory blood pressure monitoring in children: implications for clinical trials.

Background Casual office blood pressure (CBP) measurements are still standard in antihypertensive drug trials. In pediatric hypertensive trials, ethical considerations, very low disease prevalence and the marked impact of white-coat hypertension create the need for very sensitive and reproducible techniques of BP assessment. We hypothesized that ambulatory BP monitoring (ABPM) may identify treatment effects more sensitively than CBP and thereby reduce sample sizes required in pediatric antihypertensive trials. Methods Standard deviations (SDs) were used to assess population variability of CBP and ABPM at baseline and after 6 months standardized antihypertensive treatment from a trial investigating the BP-lowering effect of ramipril in children with chronic kidney disease. Results In 157 hypertensive children, ramipril had a similar mean BP-lowering effect on clinic and ambulatory 24-h BP for systolic (−10 vs. −11 mmHg, P = NS) and diastolic values (−9 vs. −11 mmHg, P = NS). However, the SDs of the CBP responses were up to 39% larger than those of ABPM (SBP 15.5 vs. 9.4; DBP 13.8 vs. 8.8; both P < 0.0001). Using power analysis, we demonstrate that, depending on the magnitude of the expected antihypertensive effect and trial design, the utilization of ABPM in antihypertensive drug efficacy studies allows reduction of sample sizes by 57–75%. This reduction of cohort size with ABPM is substantially greater than previously observed for adults. Conclusion The primary use of ABPM can substantially reduce the number of children put at potential risk in blinded antihypertensive drug trials by up to three quarters.

Risk factors for peritonitis in pediatric peritoneal dialysis: a single-center study.

Recent US registry data and a European multicenter study described increased risk of peritonitis in young children on peritoneal dialysis (PD). No underlying age-specific risk factors could be defined in these reports. Therefore, we analyzed risk factors for peritonitis in children treated by PD as primary renal replacement therapy at the Kinderdialyse, Vienna, and particularly searched for age-specific aspects. Thirty children (15 boys, mean age 4.6 years) received PD [21 automated peritoneal dialysis (APD), nine continuous ambulatory peritoneal dialysis (CAPD)] for 13 months (3–49 months). During the total observation period of 395 dialysis months, 27 peritonitis episodes were diagnosed (1:14.6 months or 0.82/patient per year). Of our population, 43% remained peritonitis free; seven patients suffered from more than one peritonitis episode. Ten potential risk factors [age, gender, PD modality, duration of PD, exit-site status, urine volume, residual glomerular filtration rate (GFR), Kt/V, normalized protein catabolic rate (nPCR), albumin] and four indices of peritonitis outcome (peritonitis incidence, peritonitis burden, risk of suffering more than one episode of peritonitis and chance of staying free from peritonitis) were analyzed. Our study identified six risk factors in univariate analysis, namely age, APD treatment, exit-site infections, low urinary volume, low residual GFR and low nPCR, which were significantly correlated with two or more of the outcome indices. Multivariate analysis identified exit-site infection and residual urine volume as strong independent predictors. In summary, our study identified several age-dependent and age-independent risk factors for peritonitis in pediatric PD. These data demonstrate that the risk for peritonitis in small children is not pre-determined but might be open to therapeutic interventions, such as optimizing exit-site care, dialysis prescription and nutrition management.

Reproducible erythroid aplasia caused by mycophenolate mofetil

Abstract Anemia secondary to mycophenolate mofetil (MMF) was recently described in experimental animals. A clinical association between MMF and anemia has been observed, but there are no proven reports. We describe a girl with chronic graft failure who developed erythroid aplasia under immunosuppression with MMF. She showed prompt resolution when MMF was discontinued and a recurrence of this clinical course when MMF was restarted. As re-challenge with a medication is the most definitive approach for showing a direct relationship between the drug and the side effect, this case clearly demonstrates that MMF can cause erythroid aplasia.

Urinary heat shock protein-72 excretion in clinical and experimental renal ischemia

Abstract.Renal ischemia not only causes injury but also induces repair mechanisms, such as the cellular induction of the 72-kilodalton heat shock protein HSP-72. The aim of this study was to determine whether HSP-72 is excreted in urine after ischemic renal injury. The first urine of six pediatric allograft recipients was examined for proteinuria and urinary HSP-72 excretion. Sprague-Dawley rats were treated with renal ischemia or hyperthermia and renal cortex and urinary HSP-72 levels were determined. HSP-72 was excreted in the first urine of renal allografts. In rats, renal HSP-72 was induced both by renal ischemia or hyperthermia. However, only renal ischemia resulted in urinary excretion of HSP-72. Urinary excretion of HSP-72 indicates an increased renal stress response and loss of tubular cell integrity after clinical and experimental renal ischemia.

Conversion from calcineurin inhibitor to sirolimus in pediatric chronic allograft nephropathy

Abstract:  CAN is a major cause for allograft loss in renal transplantation. Sirolimus was recently introduced as a potent non‐nephrotoxic alternative to CNIs. In the present study, effects of a conversion protocol were investigated in pediatric CAN with declining GFR, defined by a Schwartz formula clearance below 60 mL/1.73 m2/min, steadily increasing SCr and allograft biopsy. In eight children with a median age of 12.8 yr, sirolimus was started at median 32 months after transplantation with a loading dose of 0.24 mg/kgBW, followed by 0.2 mg/kgBW/day, aimed at trough levels of 15–20 ng/mL. CNIs were reduced to 50% at start of sirolimus and discontinued at median seven days when target levels of sirolimus were reached. Following conversion, changes of GFR significantly stabilized (−2.9 vs. +0.4 mL/min/1.73 m2/month, p = 0.025). Individual GFR increased in five of eight patients (p = 0.026), only one child exhibited unaltered progression of graft failure. In the responders, mean SCr improved by 0.3 mg/dL (p = 0.043). Effects were not dependent on GFR at conversion, nor time post‐transplantation. Blood pressure, hematological parameters and proteinuria remained stable during the observation period, serum lipids transiently increased. About half of the children suffered from infectious complications. No child had to be taken off sirolimus; there was no graft loss during the observation period. In conclusion, conversion from CNIs to sirolimus is an effective protocol with tolerable side effects to stabilize renal graft function for at least one yr in the majority of children with biopsy proven CAN.

Urinary tract infections beyond the early post-transplant period in pediatric renal graft recipients

ZusammenfassungHintergrundHarnwegsinfekte sind eine häufige bakterielle Komplikation nach Nierentransplantation bei Erwachsenen und Kindern. Es existieren jedoch nur wenige Daten bei pädiatrischen Patienten in der Frühphase nach Nierentransplantation. Ziel dieser Studie war es, Häufigkeit, Risikofaktoren und Einfluss auf die Kurzzeit Transplantatfunktion von Harnwegsinfekten in der späteren Phase nach Nierentransplantation zu untersuchen.Patienten und MethodenIm Zeitraum von 1997 bis 2000 wurden 47 Kinder, die 58 Transplantate erhielten, untersucht. Sie waren zum Zeitpunkt der Analyse seit 3,5 Jahren transplantiert. Die Definition eines Harnwegsinfektes war eine signifikante Bakteriurie (>105 Keime/ml) und Symptome.Ergebnisse15 (32%) von den 47 Patienten hatten 1 bis 7 Harnwegsinfekte im Untersuchungszeitraum. Insgesamt wurden in den 3 Jahren 35 Harnwegsinfekte dokumentiert. Das mediane Alter bei Diagnose war 5,5 Jahre (1,8–24,2 Jahre). Geschlecht, Organquelle, Immunsuppression und Grundkrankheit hatten keinen Einfluss auf die Häufigkeit der Harnwegsinfekte. Während der Infektion kam es zu einem signifikantem Kreatininanstieg, während das C-reaktive Protein nicht anstieg.SchlussfolgerungUnsere Ergebnisse zeigen, dass Harnwegsinfekte auch nach der Frühphase nach Nierentransplantation ein häufiges aber meist harmloses Ereignis sind. Um Fragen über die Langzeitfolgen dieser Infekte auf die Transplantatfunktion zu beantworten, sind ausgedehntere Untersuchungen notwendig.SummaryBackgroundUrinary tract infection is a frequent bacterial complication after renal transplantation in adults and children, however there are only very limited data on children beyond the early post-transplant period. In this study we investigated urinary tract infections in pediatric outpatients who had received transplants more than six months previously. Incidence, risk factors and impact on short-term graft function were analyzed.Methods47 children who had received a total of 58 allografts were analyzed between 1997 and 2000. At the time of analysis they had had their transplants for an average of 3.5 years (range 0.5–9.4). Urinary tract infection was defined as the presence of both significant bacteriuria (>105 CFU/ml) and symptoms.ResultsOf the 47 patients, 15 (32%) had from 1 to 7 urinary tract infections each. In total 35 infections were recorded. Median age at urinary tract infection was 5.5 years (range 1.8–24.2). Gender, donor source, immunosuppression and underlying disease (urologic vs. nonurologic) did not influence the incidence of urinary tract infection. Creatinine but not C-reactive protein rose significantly during the infection.ConclusionsOur data suggest that urinary tract infection remains a frequent but mostly benign complication in the pediatric transplant population, even beyond the early post-transplant period. More extended studies are needed to assess the long-term effects on graft function.

Age‐Related Penetrance of Hereditary Atypical Hemolytic Uremic Syndrome

Hereditary atypical hemolytic uremic syndrome (aHUS), a dramatic disease frequently leading to dialysis, is associated with germline mutations of the CFH, CD46, or CFI genes. After identification of the mutation in an affected aHUS patient, single‐site gene testing of relatives is the preventive care perspective. However, clinical data for family counselling are scarce.