Search

Objective Pediatric patients spend significant time on maintenance hemodialysis (HD) and traveling. They are often not capable of participating in sports activities. To assess the effects of exercise training during HD on dialysis efficacy in children and adolescents, we set up a multi-center randomized controlled trial (RCT). Methods Patients on HD, age 6 to 18 years, were randomized either to 3× weekly bicycle ergometer training or to no training during HD for 12 weeks. Change in single-pool Kt/V (spKt/V) was the primary outcome parameter. Results We randomized 54 patients of whom 45 qualified (23 in the intervention and 22 in the waiting control group, 14.5 ± 3.01 years, 32 male and 13 female) for the intention-to-treat (ITT) population. Only 26 patients finished study per-protocol (PP). Training was performed for an average of 11.96 weeks (0.14–13.14) at 2.08 ± 0.76 times per week and for a weekly mean of 55.52 ± 27.26 min. Single-pool Kt/V was similar in the intervention compared to the control group (1.70 [0.33] vs. 1.79 [0.55]) at V0 and (1.70 [0.36] vs. 1.71 [0.51]) at V1; secondary endpoints also showed no difference in both ITT and PP analysis. No significant adverse events were reported. No bleeding or needle dislocation occurred in 1670 training sessions. Conclusions Intradialytic bicycle training is safe, but does not improve dialysis efficacy and physical fitness. However, the study can be considered underpowered, particularly because of high dropout rates. Future studies need better strategies to increase motivation and compliance and other more effective/intensive exercise measures should be evaluated. Trial registration The trial was registered in ClinicalTrials.Gov (Clinicaltrials.gov identifier: NCT01561118) on March 22, 2012.

Pediatric patients spend significant time on maintenance hemodialysis (HD) and traveling. They are often not capable of participating in sports activities. To assess the effects of exercise training during HD on dialysis efficacy in children and adolescents, we set up a multi-center randomized controlled trial (RCT).Patients on HD, age 6 to 18 years, were randomized either to 3× weekly bicycle ergometer training or to no training during HD for 12 weeks. Change in single-pool Kt/V (spKt/V) was the primary outcome parameter.We randomized 54 patients of whom 45 qualified (23 in the intervention and 22 in the waiting control group, 14.5 ± 3.01 years, 32 male and 13 female) for the intention-to-treat (ITT) population. Only 26 patients finished study per-protocol (PP). Training was performed for an average of 11.96 weeks (0.14-13.14) at 2.08 ± 0.76 times per week and for a weekly mean of 55.52 ± 27.26 min. Single-pool Kt/V was similar in the intervention compared to the control group (1.70 [0.33] vs. 1.79 [0.55]) at V0 and (1.70 [0.36] vs. 1.71 [0.51]) at V1; secondary endpoints also showed no difference in both ITT and PP analysis. No significant adverse events were reported. No bleeding or needle dislocation occurred in 1670 training sessions.Intradialytic bicycle training is safe, but does not improve dialysis efficacy and physical fitness. However, the study can be considered underpowered, particularly because of high dropout rates. Future studies need better strategies to increase motivation and compliance and other more effective/intensive exercise measures should be evaluated.The trial was registered in ClinicalTrials.Gov ( Clinicaltrials.gov identifier: NCT01561118) on March 22, 2012.

OBJECTIVE: The aim of the present study was to investigate genetic effects in the formation of congenital lower urinary tract obstruction (LUTO) comprising posterior urethral valves (PUV), urethral atresia, and urethras with variable degrees of stenosis. METHODS: A classic twin study was performed by assessing LUTO twin pairs from the literature. Furthermore, data regarding 3 previously unreported twin pairs with PUV from University of Bonn, Essen and Wroclaws own in-house databases were added. Both pair- and probandwise concordance rates were calculated and compared for monozygotic (MZ) and dizygotic (DZ) twin pairs. RESULTS: The pairwise concordance rates for all LUTO were 53% (95% confidence interval [CI] 32%-73%) and 17% (95% CI 3%-56%) for MZ and DZ twin pairs, respectively (P = .180). The probandwise concordance rates were 69% (95% CI 51%-83%) and 29% (CI 95% 8%-64%) for MZ and DZ twin pairs respectively (P = .084). The MZ/DZ ratios of the pair- and probandwise concordance rates were 3.1 and 2.4, respectively. CONCLUSION: The present study did not show significant differences in comparisons of concordance rates of MZ and DZ twin pairs, probably due to the small number of twin pairs reported. However, the more than 2-fold higher pair- and probandwise concordance rates for MZ versus DZ twin pairs are very suggestive of a contribution of genetic factors to the development of LUTO.

There are currently three distinct autosomal recessive inherited types of primary hyperoxaluria (PH: PHI, PHII, and PHIII), all characterized by the endogenous overproduction of oxalate. The PH type is difficult to differentiate by clinical features alone. In addition to universal general characteristics to all hyperoxaluria subtypes, specific urinary metabolites can be detected: glycolate in PHI, L-glyceric acid in PHII, and hydroxy-oxo-glutarate (HOG) in PHIII. PHIII is considered to be the most benign form and is characterized by severe recurrent urolithiasis in early life, followed by clinical remission in many, but not all patients. We examined urinary HOG (UHOG) excretion as a diagnostic marker and its correlation to progression of the clinical course of PHIII. UHOG was analyzed by combined ion chromatography/mass spectrometry (IC/MS) in urine samples from 30 PHIII and 68 PHI/II patients and 79 non-PH hyperoxaluria patients. Mean UHOG excretion was significantly higher in patients with PHIII than in those with PHI/II and in non-PH patients(51.6 vs. 6.61 vs. 8.36 μmol/1.73 m2/24 h, respectively; p

Item does not contain fulltext BACKGROUND: Primary hyperoxaluria (PH) is characterized by progressive chronic kidney disease (CKD) and systemic oxalate deposition. Myocardial dysfunction might be present early in the course of the disease. However, this hypothesis has not yet been tested in the PH population. Therefore, we aimed to determine whether strain imaging using two-dimensional speckle tracking echocardiography (2D-STE) might detect subclinical myocardial disease in otherwise asymptomatic PH patients. METHODS: Prospective study of pediatric and adolescent PH patients with preserved LV ejection fraction (LV EF) and without renal replacement therapy. Subjects underwent conventional echocardiography and 2D-STE. Global (GLS) and segmental peak systolic LV longitudinal strain (LS) measurements were obtained. Data were compared with age- and gender-matched controls, and Z-scores were calculated as appropriate. RESULTS: Fifteen PH patients (age 14.1 +/- 5.9 years; 13/15 in CKD stages 1-2) were studied. Although LV EF was preserved (63 +/- 6%) in patients, GLS was significantly impaired (GLS - 17.1 +/- 2.2% vs - 22.4 +/- 1.9%, p < 0.001). This was mainly due to decreased LS values in the apical segments (p < 0.05). Echocardiographic indices of ventricular wall thickness were significantly increased in patients compared to controls (all p < 0.03). GLS correlated significantly with Z-scores of diastolic interventricular wall thickness (r = - 0.57, p = 0.025) and moderately with serum creatinine levels (r = 0.53, p = 0.044). No correlation was found between GLS and blood pressure measurements. CONCLUSIONS: Subclinical myocardial disease is already present early in the course of disease in PH patients with preserved LV EF and some degree of renal dysfunction, but without overt systemic oxalosis. Current recommendations to screen only PH patients with advanced CKD for cardiac disease should be revised accordingly.

Patients with autosomal or X-linked Alport syndrome (AS) with heterozygous mutations in type IV collagen genes have a 1-20 % risk of progressing to end-stage renal disease during their lifetime. We evaluated the long-term renal outcome of patients at risk of progressive disease (chronic kidney disease stages 1-4) with/without nephroprotective therapy.This was a prospective, non-interventional, observational study which included data from a 4-year follow-up of AS patients with heterozygous mutations whose datasets had been included in an analysis of the 2010 database of the European Alport Registry. Using Kaplan-Meier estimates and logrank tests, we prospectively analyzed the updated datasets of 52 of these patients and 13 new datasets (patients added to the Registry after 2011). The effects of therapy, extrarenal symptoms and inheritance pattern on renal outcome were analyzed.The mean prospective follow-up was 46 ± 10 months, and the mean time on therapy was 8.4 ± 4.4 (median 7; range 2-18) years. The time from the appearance of the first symptom to diagnosis was 8.1 ± 14.2 (range 0-52) years. At the time of starting therapy, 5.4 % of patients had an estimated glomerular filtration rate of60 ml/min, 67.6 % had proteinuria and 27.0 % had microalbuminuria. Therapeutic strategies included angiotensin-converting enzymer inhibitors (97.1 %), angiotensin receptor antagonists (1 patient), dual therapy (11.8 %) and statins (8.8 %). Among patients included in the prospective dataset, prevented the need for dialysis. Among new patients, no patient at risk for renal failure progressed to the next disease stage after 4 years follow-up; three patients even regressed to a lower stage during therapy.Treatment with blockers of the renin-angiotensin-aldosterone system prevents progressive renal failure in AS patients with heterozygous mutations in the genes causing AS. Considerable numbers of aging AS patients on dialysis may have heterozygous mutations in these genes (present in 1 % of total population) as underlying disease. Hence, greater alertness towards timely diagnosis and therapy has the potential to prevent progressive renal failure in most-if not all-AS patients with heterozygous mutations in the causal genes.

Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853(∗)]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage.

The unit of the HOG-creatinine ratio presented in this article is calculated in μmol/mg creatinine instead of the demonstrated unit of μmol/μmol. This applies to the parameter in the text of the article and the labeling of Figs. 1, 2b and 3c.

Background and objectives The Wilms tumor suppressor gene 1 ( WT1 ) plays an essential role in urogenital and kidney development. Genotype/phenotype correlations of WT1 mutations with renal function and proteinuria have been observed in world-wide cohorts with nephrotic syndrome or Wilms tumor (WT). This study analyzed mid-European patients with known constitutional heterozygous mutations in WT1 , including patients without proteinuria or WT. Design, setting, participants & measurements Retrospective analysis of genotype, phenotype, and treatment of 53 patients with WT1 mutation from all pediatric nephrology centers in Germany, Austria, and Switzerland performed from 2010 to 2012. Results Median age was 12.4 (interquartile range [IQR], 6–19) years. Forty-four of 53 (83%) patients had an exon mutation (36 missense, eight truncating), and nine of 53 (17%) had an intronic lysine-threonine-serine (KTS) splice site mutation. Fifty of 53 patients (94%) had proteinuria, which occurred at an earlier age in patients with missense mutations (0.6 [IQR, 0.1–1.5] years) than in those with truncating (9.7 [IQR, 5.7–11.9]; P P= 0.004) mutations. Thirteen of 50 (26%) were treated with steroids and remained irresponsive, while three of five partially responded to cyclosporine A. Seventy-three percent of all patients required RRT, those with missense mutations significantly earlier (at 1.1 [IQR, 0.01–9.3] years) than those with truncating mutations (16.5 [IQR, 16.5–16.8]; P 0.001) and splice site mutations (12.3 [IQR, 7.9–18.2]; P =0.002). Diffuse mesangial sclerosis was restricted to patients with missense mutations, while focal segmental sclerosis occurred in all groups. WT occurred only in patients with exon mutations ( n =19). Fifty of 53 (94%) patients were karyotyped: Thirty-one (62%) had XY and 19 (38%) had XX chromosomes, and 96% of male karyotypes had urogenital malformations. Conclusions Type and location of WT1 mutations have predictive value for the development of proteinuria, renal insufficiency, and WT. XY karyotype was more frequent and associated with urogenital malformations in most cases.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of dialysis-requiring end-stage renal disease in adults and is characterized by the slowly progressing replacement of renal tissue by focal macrocysts. Alport syndrome (AS; hereditary nephritis) is a rare, inherited disorder of the basement membrane associated with hematuria, proteinuria, and loss of kidney function as well as sensorineural hearing loss and ocular abnormalities. Here, we report on a family in which both ADPKD and AS are present. In a male patient, both -ADPKD and AS coincided. This patient shows the very rare coexistence of two severe, inherited renal disorders and illustrates the importance of considering additional diagnoses in the setting of positive family history for a common hereditary disorder. .

Previous studies on renal oligohydramnios (ROH) report highly variable outcome and identify early onset of ROH and presence of extrarenal manifestations as predictors of adverse outcome in most cases. Data on termination of pregnancy (TOP) and associated parental decision-making processes are mostly missing, but context-sensitive for the interpretation of these findings. We provide here a comprehensive analysis on the diagnosis, prenatal decision-making and postnatal clinical course in all pregnancies with ROH at our medical centre over an 8-year period. We report retrospective chart review data on 103 consecutive pregnancies from 2008 to 2015 with a median follow-up of 554 days. After ROH diagnosis, 38 families opted for TOP. This decision was associated with onset of ROH (p

The hereditary kidney disease Alport syndrome (AS) has become a treatable disease: intervention with angiotensin-converting enzyme (ACE)-inhibitors delays end stage renal failure by years. The efficiency of ACE inhibition depends on the onset of therapy-the earlier the better. Therefore, early diagnosis has become increasingly important. To date, robust diagnosis requires renal biopsy and/or expensive genetic analysis, which is mostly performed late after onset of the profound clinical symptoms of this progressive renal disease. Thus, disease biomarkers enabling low-invasive screening are urgently required.Fourteen potential proteomic candidate markers (proteins) identified in a previous study in sera from patients exhibiting manifest AS were evaluated in the plasma, serum, and urine collected from a cohort of 132 subjects, including patients with AS and other nephropathies and healthy controls. Quantitation was performed by immunoassays.The serum and plasma levels of none of the 14 proteins evaluated were significantly different among the three groups and therefore could not be used to discriminate between the groups. In contrast, the levels of various biomarker combinations in the urine were significantly different between AS patients and healthy controls. Importantly, some combinations had the potential to discriminate between AS and other nephropathies.These findings open a window of opportunity for the sensitive and specific early diagnosis of AS. Our results increase the potential for larger scale evaluation of an increased number of patients.

A liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed for simultaneous quantification of mycophenolic acid (MPA) and its phenolic glucuronide (MPAG) in saliva and plasma. Saliva was collected and processed using a standardized commercially available collection device. Sample preparation comprised of protein precipitation with acetonitrile and subsequent centrifugation, followed by evaporation and reconstitution with mobile phase. A labeled isotope of MPA was used as internal standard, and chromatographic separation was achieved on a C18 column with an isocratic flow. LC–MS/MS detection was performed using a triple-stage quadrupole mass spectrometer working in selected reaction monitoring mode with positive electrospray ionization (ESI). The analytes were quantified in a single run within 2 min. For saliva, linearity was demonstrated over the concentration range of 5.0 to 400.0 ng/ml for both MPA and MPAG, and from 0.08 to 20.00 μg/ml for MPA and 0.4 to 100.0 μg/ml for MPAG in plasma. The lower limits of quantification for MPA and MPAG were 0.07 and 0.80 ng/ml in saliva, and 0.002 and 0.009 μg/ml in plasma, respectively. Inter- and intra-day precisions expressed as relative standard deviation (RSD) and accuracies were less than 15%. The recoveries for MPA and MPAG from the collection device's swab were higher than 90%. Sample stability was confirmed for bench times up to 24 h at room temperature. The method was validated according to International Conference on Harmonization (ICH) guidelines Q2 (R1) Validation of Analytical Procedures. The applicability of the method was tested in a renal pediatric patient. Based on a limited sampling strategy, MPA saliva and plasma concentrations were found in good agreement with each other. We suggest that the described method is suitable to analyze saliva and plasma samples of small volumes for therapeutic drug monitoring (TDM) and pharmacokinetic studies in pediatric patients.

The superior question of the systematic literature search is to examine the current status of physical endurance capacity of children, adolescents and young adults with chronic kidney disease (CKD) in relation to healthy control groups as well as to look at the effects of movement and exercise in practical clinical trials. Out of 1 170 key word combinations, the electronic search yielded 49 860 abstracts. After searching the title, the abstract and the whole article, 8 studies remained, matching the preliminary defined analysis criteria. The results of these studies showed a reduced physical capacity of the children and adolescents with CKD compared to healthy controls. Furthermore, the adjustment of the present anemia by EPO led to a positive effect resulting in an improved physical capacity. Statements to the effects of interventions could not be given, since no study had been found in this literature search. In order to yield further knowledge about the specific aspects of physical training in this target group, other in- or outpatient interventions are necessary.

About 150-200 children and adolescents in Germany with end-stage renal disease need a renal replacement therapy. The dialysis treatment is both exhausting and time-consuming. Via a pilot study, we currently examine the feasibility and the tolerance of an intradialytic bicycle ergometer training for children and adolescents on maintenance hemodialysis. We first examine the negative impact of hemodialysis per se on the patient's endurance. Furthermore, we analyze the possible enhancement of endurance and, more importantly, an increase in quality of life by the bicycle ergometer training. Despite the currently small sample size (n = 5, study ongoing), we recognized a trend towards better dialysis efficacy measured as single pool Kt/V. Besides the effects mentioned above, dialysis tolerance seems to be better and the timidity of movement during hemodialysis decreased in both patients and dialysis staff.

Intestinal oxalate absorption is an important part of oxalate metabolism influencing its urinary excretion and its measurement can be a valuable diagnostic tool in hyperoxaluric disorders. In this study, we use [(13)C(2)]oxalate absorption under standardized dietary conditions to assess intestinal oxalate absorption and its impact on urinary oxalate excretion. Tests were conducted in age-matched pediatric patients that included 60 with idiopathic calcium oxalate urolithiasis, 13 with primary hyperoxaluria, and 35 healthy children. In the idiopathic stone formers, median oxalate absorption was significantly higher than that in the controls or in patients with primary disease. From standardized values obtained in control patients, oxalate hyperabsorption was detected in 23 patients with idiopathic disease but not in any patients with primary hyperoxaluria; therefore, a significant correlation between intestinal absorption and urinary excretion was found only in those with the idiopathic disease. We have shown that increased intestinal oxalate absorption is an important risk factor of idiopathic calcium oxalate urolithiasis. In contrast, low intestinal oxalate absorption in patients with primary hyperoxaluria indicates that only foods with excessive oxalate content be restricted from their diet.

Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans, caused by homozygous absence of the survival motor neuron gene 1 (SMN1). SMN2, a copy gene, influences the severity of SMA and may be used in somatic gene therapy of patients with SMA in the future. We present a new, fast, and highly reliable quantitative test, based on real-time LightCycler PCR that amplifies either SMN1 or SMN2. The SMN1 copies were determined and validated in 329 carriers and controls. The specificity of the test is 100%, whereas the sensitivity is 96.2%. The quantitative analysis of SMN2 copies in 375 patients with type I, type II, or type III SMA showed a significant correlation between SMN2 copy number and type of SMA as well as duration of survival. Thus, 80% of patients with type I SMA carry one or two SMN2 copies, and 82% of patients with type II SMA carry three SMN2 copies, whereas 96% of patients with type III SMA carry three or four SMN2 copies. Among 113 patients with type I SMA, 9 with one SMN2 copy lived

Objectives It is known that transition, as a shift of care, marks a vulnerable phase in the adolescents’ lives with an increased risk for non-adherence and allograft failure. Still, the transition process of adolescents and young adults living with a kidney transplant in Germany is not well defined. The present research aims to assess transition-relevant structures for this group of young people. Special attention is paid to the timing of the process. Setting In an observational study, we visited 21 departments of paediatric nephrology in Germany. Participants were doctors (n=19), nurses (n=14) and psychosocial staff (n=16) who were responsible for transition in the relevant centres. Structural elements were surveyed using a short questionnaire. The experiential viewpoint was collected by interviews which were transcribedverbatim before thematic analysis was performed. Results This study highlights that professionals working within paediatric nephrology in Germany are well aware of the importance of successful transition. Key elements of transitional care are well understood and mutually agreed on. Nonetheless, implementation within daily routine seems challenging, and the absence of written, structured procedures may hamper successful transition. Conclusions While professionals aim for an individual timing of transfer based on medical, social, emotional and structural aspects, rigid regulations on transfer age as given by the relevant health authorities add on to the challenge. Trial registration number ISRCTN Registry no 22988897; results (phase I) and pre-results (phase II).

BACKGROUND Paediatric patients on maintenance haemodialysis (HD) often report their own physical fitness to be hampered. Their physical endurance capacity is known to be significantly lower than that of healthy controls. However, physical endurance was up to now only examined on non-HD days. We were interested in the effect of HD on the cardiorespiratory capacity of children and adolescents on maintenance HD. METHODS We therefore examined the endurance capacity by cardiopulmonary exercise testing on a cycle ergospirometer, before and after HD in 14 patients (9 male, 5 female; mean age: 15.1 ± 3.0 years; mean period on HD: 16.3 ± 11.5 months). RESULTS The feasible time spent on the cycle ergospirometer was significantly reduced after dialysis (8.6 ± 3.2 versus 6.4 ± 2.5 min, P < 0.001), also the maximal workload was decreased (95 ± 36 W to 74 ± 29 W, P < 0.003). The starting and recovery heart rates were higher after than before dialysis. The peak oxygen uptake (VO(2) peak, VO(2) peak/kg) was reduced from 1.644 ± 600 to 1.422 ± 450 mL/min (P < 0.02) and from 35 ± 7 to 31 ± 5 mL/min/kg (P < 0.03), respectively. The respiratory exchange ratio as well as the lactate values showed significant differences in varied workload levels (P < 0.05). CONCLUSIONS Paediatric patients on maintenance HD in general have a significantly lower exercise capacity compared to a healthy age-matched population, which is expressed much more after dialysis.

Cystic renal diseases are characterized by intrarenal cysts of different size and number. Further important diagnostic criteria include, e.g., liver fibrosis. The latter represents a significant cause of morbidity and mortality in autosomal-recessive polycystic kidney disease (ARPKD), whereas patients with autosomal-dominant polycystic kidney disease (ADPKD) can develop hepatic cysts without fibrosis. We report the use of transient elastography [FibroScan®, (FS)] for early and noninvasive detection of increased liver stiffness as marker of liver fibrosis. Compared with matched healthy controls, ADPKD patients (n = 7) showed no significant difference in liver stiffness (5.3 kPa vs. 4.5 kPa; ns). ARPKD patients (n = 7) had significantly increased median liver stiffness compared with controls (12.0 kPa vs. 4.5 kPa, p = 0.002) and ADPKD patients (12.0 kPa vs. 5.3 kPa, p = 0.002). Conventional ultrasound revealed evidence of liver fibrosis in only four of seven ARPKD patients (57%) compared with 100% detection by FS. Additional laboratory examinations showed no pathologic liver parameters. In conclusion, our data found FS to be a valuable, sensitive, and noninvasive new tool for early evaluation of liver fibrosis in cystic kidney diseases. This could facilitate diagnosis, monitoring, and management of liver involvement in ARPKD or any other cystic kidney disease.

Background: Calcification of renal allografts has been reported in adult kidney transplant (KTx) recipients with a widely differing prevalence (2–60%). Persistent hyperparathyroidism, hypercalcemia and concomitant hypercalciuria were identified as major risk factors. We aimed to determine the prevalence and risk factors for such calcifications in children. Methods: We investigated histological stains of routine graft biopsies from pediatric KTx patients for renal calcifications and determined the urinary excretion of lithogenic (oxalate, calcium) and stone-inhibitory substances (citrate). Results: In our series of transplant patients, tubular calcification was found in 16 of the 36 (44.4%) KTx biopsies by an additional Kossa stain. This transplant calcification was not associated with any singular risk factor and was not correlated to a worse transplant outcome. Conclusion: Although our pediatric findings confirm the reported incidence rates of KTx calcification in adults, we could neither identify hypercalciuria as a risk factor nor confirm any negative influence on graft function. However, long-term studies are clearly needed to prove or disprove a negative impact of calcifications on graft function.

Bodo B Beck, Norbert Laube, Sandra Habbig, Markus Feldkotter, Jochen WU Fries and Bernd Hoppe Division of Pediatric Nephrology, Department of Pediatrics, University Hospital Cologne, Cologne, Germany; Division of Experimental Urology, Department of Urology, University of Bonn, Bonn, Germany and Department of Pathology, University Hospital Cologne, Cologne, Germany Correspondence: B Hoppe, University Children’s Hospital Cologne, Division of Pediatric Nephrology, Kerpenerstrasse 62, Cologne D-50924, Germany. E-mail: behoppe@t-online.de

To the Editor:Drs. Ogino and Wilson (2002xSMN dosage analysis and risk assessment for spinal muscular atrophy. Ogino, S and Wilson, RB. Am J Hum Genet. 2002; 70: 1598–1599Abstract | Full Text | Full Text PDF | Scopus (14)See all References2002 [in this issue]) raised some issues regarding our paper on quantitative testing of SMN1 and SMN2 in spinal muscular atrophy (SMA) (Feldkotter et al. 2002xQuantitative analysis of SMN1 and SMN2 based on real-time LightCycler PCR: fast and highly reliable heterozygosity testing and prediction of severity of spinal muscular atrophy. Feldkotter, M, Wirth, R, Schwarzer, V, and Wirth, B. Am J Hum Genet. 2002; 70: 358–368Abstract | Full Text | Full Text PDF | PubMed | Scopus (467)See all References2002). First, they raised some ethical issues regarding the testing of unaffected children for SMA. We are also aware of the controversial aspects of such testing and, in general, agree with Drs. Ogino and Wilson: the identification, at birth, of homozygous absence of SMN1 in children, followed by the quantitative analysis of SMN2, should be offered as a prognostic tool only when a therapy for SMA is available. In this case, a newborn screening (similar to that in phenylketonuria) could—and possibly should—be considered. Since several drugs that up-regulate full-length SMN2 have been found (Andreassi et al. 2001xAclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients. Andreassi, C, Jarecki, J, Zhou, J, Coovert, DD, Monani, UR, Chen, X, Whitney, M, Pollok, B, Zhang, M, Androphy, E, and Burghes, AH. Hum Mol Genet. 2001; 10: 2841–2849Crossref | PubMedSee all References2001; Chang et al. 2001xTreatment of spinal muscular atrophy by sodium butyrate. Chang, JG, Hsieh-Li, HM, Jong, YJ, Wang, NM, Tsai, CH, and Li, H. Proc Natl Acad Sci USA. 2001; 98: 9808–9813Crossref | PubMed | Scopus (291)See all References2001) and since the identification of many more is in progress, the development of a therapy for SMA seems likely to become a reality in the near future. Therefore, the development of a highly sensitive and fast method to determine the number of SMN2 copies will be an essential prerequisite before starting a therapy. Furthermore, the identification, immediately after birth, of children who carry homozygous absence of SMN1 will be equally essential, to start the therapy before the motor neurons are degenerated. On the basis of the number of SMN2 copies, the dosage and starting-point of a therapy may significantly vary.Since an efficient therapy has to be started early, we calculated the posterior probability that a child with an SMN1 deletion would develop type I, type II, or type III SMA, under the assumption that the analysis is done immediately after birth. As a consequence, we have used a Bayesian-type analysis that is based on the odds ratios and a priori probabilities as chosen.We reevaluated the sensitivity calculations, and we agree with Drs. Ogino and Wilson that the sensitivity of the test, for the detection of an SMA carrier from the general population without family history, is 95.9% (i.e., 1-0.024+0.017), since 2.4% of carriers have two SMN1 copies per chromosome and 1.7% carry intragenic SMN1 mutations. Therefore, there is a posterior probability of ∼1:850 (i.e., [4.1/100]×[1/35]) that a person from the general population who carries two SMN1 copies is an SMA carrier. The carrier frequency of 1:35 is based on the results presented in our previous article (Feldkotter et al. 2002xQuantitative analysis of SMN1 and SMN2 based on real-time LightCycler PCR: fast and highly reliable heterozygosity testing and prediction of severity of spinal muscular atrophy. Feldkotter, M, Wirth, R, Schwarzer, V, and Wirth, B. Am J Hum Genet. 2002; 70: 358–368Abstract | Full Text | Full Text PDF | PubMed | Scopus (467)See all References2002). The sensitivity of the test for the detection of an SMA carrier from a family with an affected patient who carries a homozygous absence of SMN1 is 97.6% (i.e., 1-0.024).With reference to the primers designed to detect either SMN1 or SMN2, the test is based on two nucleotide differences in exon 7 and in intron 7 (position +100). This implies that converted SMN genes may amplify with a decreased efficiency. At this point, it is important to mention that, in the large majority (42/44 [∼95%]) of converted SMN genes, the complete gene, except for the region containing the nucleotide difference in exon 8, is converted (Hahnen et al. 1996xHybrid survival motor neuron genes in patients with autosomal recessive spinal muscular atrophy: new insights into molecular mechanisms responsible for the disease. Hahnen, E, Schonling, J, Rudnik-Schoneborn, S, Zerres, K, and Wirth, B. Am J Hum Genet. 1996; 59: 1057–1065PubMedSee all References1996). This means that, for most converted SMN genes, the two primers that we have applied lie in either SMN1 or SMN2 only and will not hamper the efficiency of the PCR. Additionally, the analysis of 20 patients with only homozygous absence of SMN1 exon 7 showed identical number of SMN2 copies analyzed with both methods—multiplex competitive PCR (Wirth et al. 1999xQuantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implication for genetic counseling. Wirth, B, Herz, M, Wetter, A, Moskau, S, Hahnen, E, Rudnik-Schoneborn, S, Wienker, T, and Zerres, K. Am J Hum Genet. 1999; 64: 1340–1356Abstract | Full Text | Full Text PDF | PubMed | Scopus (216)See all References1999) and LightCycler PCR (Feldkotter et al. 2002xQuantitative analysis of SMN1 and SMN2 based on real-time LightCycler PCR: fast and highly reliable heterozygosity testing and prediction of severity of spinal muscular atrophy. Feldkotter, M, Wirth, R, Schwarzer, V, and Wirth, B. Am J Hum Genet. 2002; 70: 358–368Abstract | Full Text | Full Text PDF | PubMed | Scopus (467)See all References2002). Nevertheless, the efficiency of the PCR may be reduced for those rarely observed SMN genes in which the breakpoint lies between the two primers used in the LightCycler PCR.