Mycophenolate Mofetil versus Cyclosporin A in Children with Frequently Relapsing Nephrotic Syndrome

The severe side effects of long-term corticosteroid or cyclosporin A (CsA) therapy complicate the treatment of children with frequently relapsing steroid-sensitive nephrotic syndrome (FR-SSNS). We conducted a randomized, multicenter, open-label, crossover study comparing the efficacy and safety of a 1-year treatment with mycophenolate mofetil (MMF; target plasma mycophenolic acid trough level of 1.5–2.5 µg/ml) or CsA (target trough level of 80–100 ng/ml) in 60 pediatric patients with FR-SSNS. We assessed the frequency of relapse as the primary endpoint and evaluated pharmacokinetic profiles (area under the curve [AUC]) after 3 and 6 months of treatment. More relapses per patient per year occurred with MMF than with CsA during the first year (P=0.03), but not during the second year (P=0.14). No relapses occurred in 85% of patients during CsA therapy and in 64% of patients during MMF therapy (P=0.06). However, the time without relapse was significantly longer with CsA than with MMF during the first year (P<0.05), but not during the second year (P=0.36). In post hoc analysis, patients with low mycophenolic acid exposure (AUC <50 µg⋅h/ml) experienced 1.4 relapses per year compared with 0.27 relapses per year in those with high exposure (AUC>50 µg⋅h/ml; P<0.05). There were no significant differences between groups with respect to BP, growth, lipid levels, or adverse events. However, cystatin clearance, estimated GFR, and hemoglobin levels increased significantly with MMF compared with CsA. These results indicate that MMF is inferior to CsA in preventing relapses in pediatric patients with FR-SSNS, but may be a less nephrotoxic treatment option.Idiopathic nephrotic syndrome, the most common form of childhood nephrotic syndrome, is most often associated with renal biopsy findings of minimal glomerular and tubulointerstitial changes (minimal change disease). Most patients respond to therapy with corticosteroids,¹ but about 70% experience a relapsing course.² Approximately 30% develop frequently relapsing steroid-sensitive nephrotic syndrome (FR-SSNS), defined as ≥4 relapses per year.³Although corticosteroids are the mainstay of therapy in pediatric patients with minimal change disease, their repeated use in FR-SSNS results in severe side effects, and other therapeutic options are needed to prevent steroid toxicity.⁴ A 2- to 3-month course of cyclophosphamide or chlorambucil has been shown to produce a longer remission period in many patients⁵; however, these drugs may have serious side effects and their long-term efficacy is limited.^6,7 Levamisole has been shown to reduce the risk of relapse in several small studies, but information is limited regarding long-term efficacy and adverse effects, and the drug is currently not available in most countries. Treatment with cyclosporin A (CsA) is highly effective in maintaining remission in patients with FR-SSNS allowing withdrawal of corticosteroids, but most patients relapse after withdrawal of CsA.⁸ Importantly, prolonged CsA therapy is accompanied by time- and dose-dependent nephrotoxicity.⁹Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is a non-nephrotoxic immunosuppressive drug with inhibitory effects on T and B lymphocytes, cell-surface markers, and cytokine gene expression¹⁰ and has proven efficacy and tolerability in renal allograft recipients. Several small studies with limited statistical power have shown that MMF has steroid-sparing effects and reduces relapse rates in patients with FR-SSNS, albeit with varying efficacy.^11–18We studied efficacy and safety of MMF in patients with FR-SSNS in comparison with CsA in a prospective randomized multicenter open-label crossover trial.     

Molecular karyotyping in patients with mental retardation using 100K single-nucleotide polymorphism arrays

Background

Using array techniques, it was recently shown that about 10% of patients with mental retardation of unknown origin harbour cryptic chromosomal aneusomies. However, data analysis is currently not standardised and little is known about its sensitivity and specificity.

Methods

We have developed an electronic data analysis tool for gene‐mapping SNP arrays, a software tool that we call Copy Number Variation Finder (CNVF). Using CNVF, we analysed 104 unselected patients with mental retardation of unknown origin with a genechip mapping 100K SNP array and established an optimised set of analysis parameters.

Results

We detected deletions as small as 20 kb when covered by at least three single‐nucleotide polymorphisms (SNPs) and duplications as small as 150 kb when covered by at least six SNPs, with only one false‐positive signal in six patients. In 9.1% of patients, we detected apparently disease‐causing or de novo aberrations ranging in size from 0.4 to 14 Mb. Morphological anomalies in patients with de novo aberrations were equal to that of unselected patients when measured with de Vries score.

Conclusion

Our standardised CNVF data analysis tool is easy to use and has high sensitivity and specificity. As some genomic regions are covered more densely than others, the genome‐wide resolution of the 100K array is about 400–500 kb for deletions and 900–1000 kb for duplications. The detection rate of about 10% of de novo aberrations is independent of selection of patients for particular features. The incidental finding in two patients of heterozygosity for the 250 kb recurrent deletion at the NPH1 locus, associated with autosomal recessive juvenile nephronophthisis, which was inherited from a healthy parent, highlights the fact that inherited aberrations might be disease‐related even though not causal for mental retardation.     

Wie häufig werden Patienten mit depressiven Störungen in der hausärztlichen Praxis erkannt?

Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz - Hausärzte sind als Primärversorger für Patienten mit depressiven Störungen entscheidende Weichensteller...     

Hematopoietic growth factors for graft failure after bone marrow transplantation: a randomized trial of granulocyte-macrophage colony- stimulating factor (GM-CSF) versus sequential GM-CSF plus granulocyte- CSF

Delay in hematologic recovery after bone marrow transplantation (BMT) can extend and amplify the risks of infection and hemorrhage, compromise patients' survival, and increase the duration and cost of hospitalization. Because current studies suggest that granulocyte- macrophage (GM) colony-stimulating factor (CSF) may potentiate the sensitivity of hematopoietic progenitor cells to G-CSF, we performed a prospective, randomized trial comparing GM-CSF (250 micrograms/m2/d x 14 days) versus sequential GM-CSF x 7 days followed by G-CSF (5 micrograms/kg/d x 7 days) as treatment for primary or secondary graft failure after BMT. Eligibility criteria included failure to achieve a white blood cell (WBC) count > or = 100/microL by day +21 or > or = 300/microL by day +28, no absolute neutrophil count (ANC) > or = 200/microL by day +28, or secondary sustained neutropenia after initial engraftment. Forty-seven patients were enrolled: 23 received GM-CSF (10 unrelated, 8 related allogeneic, and 5 autologous), and 24 received GM- CSF followed by G-CSF (12 unrelated, 7 related allogeneic, and 5 autologous). For patients receiving GM-CSF alone, neutrophil recovery (ANC > or = 500/microL) occurred between 2 and 61 days (median, 8 days) after therapy, while those receiving GM-CSF+G-CSF recovered at a similar rate of 1 to 36 days (median, 6 days; P = .39). Recovery to red blood cell (RBC) transfusion independence was slow, occurring 6 to 250 days (median, 35 days) after enrollment with no significant difference between the two treatment groups (GM-CSF: median, 30 days; GM-CSF+G- CSF; median, 42 days; P = .24). Similarly, platelet transfusion independence was delayed until 4 to 249 days (median, 32 days) after enrollment, with no difference between the two treatment groups (GM- CSF: median, 28 days; GM-CSF+G-CSF: median, 42 days; P = .38). Recovery times were not different between patients with unrelated donors and those with related donors or autologous transplant recipients. Survival at 100 days after enrollment was superior after treatment with GM-CSF alone. Only 1 of 23 patients treated with GM-CSF died versus 7 of 24 treated with GM-CSF+G-CSF who died 16 to 84 days (median, 38 days) after enrollment, yielding Kaplan-Meier 100-day survival estimates of 96% +/- 8% for GM-CSF versus 71% +/- 18% for GM-CSF+G-CSF (P = .026). These data suggest that sequential growth factor therapy with GM-CSF followed by G-CSF offers no advantage over GM-CSF alone in accelerating trilineage hematopoiesis or preventing lethal complications in patients with poor graft function after BMT.(ABSTRACT TRUNCATED AT 400 WORDS)     

Impact of the anesthetic agents ketamine,etomidate, thiopental,and propofol on seizure parameters and seizure quality in electroconvulsive therapy: a retrospective study

In electroconvulsive therapy (ECT), the use of anesthetics without relevant anticonvulsant properties such as ketamine and etomidate may be favorable for seizure quality. Since there is a relative paucity of studies devoted to this issue, our aim was to compare different anesthetics for ECT regarding their impact on seizure quality and different seizure parameters. We retrospectively compared ketamine (n = 912 anesthesias), etomidate (n = 227 anesthesias), thiopental (n = 2,751 anesthesias), and propofol (n = 42 anesthesias) on their influence on general seizure quality and different seizure parameters by multivariate repeated measurement regression analyses. The use of ketamine and etomidate as anesthetics led to seizures that were overall higher in quality and also longer in motor seizure activity when compared to anesthesia with thiopental and propofol. Ketamine was most favorable concerning central inhibitory potential that was indirectly quantified by concordance and postictal suppression. The worst seizure quality was observed with propofol anesthesia; further, this substance had a negative impact on autonomic activation and seizure duration. Based on the data of this retrospective study, the use of ketamine or etomidate as anesthetic in ECT might be advantageous due to the induction of high-quality seizures.     

Clinical manifestations of autosomal recessive polycystic kidney disease (ARPKD): kidney-related and non-kidney-related phenotypes

Autosomal recessive polycystic kidney disease (ARPKD), although less frequent than the dominant form, is a common, inherited ciliopathy of childhood that is caused by mutations in the PKHD1-gene on chromosome 6. The characteristic dilatation of the renal collecting ducts starts in utero and can present at any stage from infancy to adulthood. Renal insufficiency may already begin in utero and may lead to early abortion or oligohydramnios and lung hypoplasia in the newborn. However, there are also affected children who have no evidence of renal dysfunction in utero and who are born with normal renal function. Up to 30 % of patients die in the perinatal period, and those surviving the neonatal period reach end stage renal disease (ESRD) in infancy, early childhood or adolescence. In contrast, some affected patients have been diagnosed as adults with renal function ranging from normal to moderate renal insufficiency to ESRD. The clinical spectrum of ARPKD is broader than previously recognized. While bilateral renal enlargement with microcystic dilatation is the predominant clinical feature, arterial hypertension, intrahepatic biliary dysgenesis remain important manifestations that affect approximately 45 % of infants. All patients with ARPKD develop clinical findings of congenital hepatic fibrosis (CHF); however, non-obstructive dilation of the intrahepatic bile ducts in the liver (Caroli’s disease) is seen at the histological level in only a subset of patients. Cholangitis and variceal bleeding, sequelae of portal hypertension, are life-threatening complications that may occur more often in advanced cases of liver disease. In this review we focus on common and uncommon kidney-related and non-kidney-related phenotypes. Clinical management of ARPKD patients should include consideration of potential problems related to these manifestations.     

Subnormothermic machine perfusion for preservation of porcine kidneys in a donation after circulatory death model

Machine perfusion for preservation led to compelling success for the outcome of renal transplantation. Further refinements of methods to decrease preservation injury remain an issue of high interest. This study investigates functional and morphological aspects of kidneys preserved by subnormothermic (20 °C) machine perfusion (SNTM) compared with oxygenated hypothermic machine perfusion (HMPox) and cold storage (CS) in a donation after circulatory death (DCD) model. After 30 min of warm ischaemia, porcine kidneys were randomly assigned to preservation for 7 h by CS, HMPox or SNTM. Afterwards, kidneys were reperfused for 2 h with autologous blood in vitro for assessment of function and integrity. Application of SNTM for preservation led to significantly higher blood flow and urine output compared with both other groups. SNTM led to a twofold increased creatinine clearance compared with HMPox and 10‐fold increased creatinine clearance compared with CS. Structural integrity was best preserved by SNTM. In conclusion, this is the first study on SNTM for kidneys from DCD donors. SNTM seems to be a promising preservation method with the potential to improve functional parameters of kidneys during reperfusion.     

Liver transplantation for acute liver failure: are there thresholds not to be crossed?

Factors predicting survival after liver transplantation (LT) for irreversible acute liver failure (ALF) are rare. The aim of this study was to identify prognostic preoperative factors of patients with ALF that predict mortality after LT to avoid futile transplantation. From chart review, we identified 57 patients receiving transplants for ALF from 12/2000 to 09/2010. Recipient and donor data were analyzed and correlated with in‐hospital mortality and patient survival by univariable/multivariable logistic regression and Cox proportional hazards. The survival rates at 30 days and 12 months were 77.2% and 64.9%, respectively. The in‐hospital mortality rate was 29.8%. Follow‐up of patients discharged from the hospital alive showed 30‐day and 12‐month survivals of 100% and 92.5%, respectively. Multivariable analysis of factors known preoperatively showed that the lowest pH of the recipient before LT (P = 0.03) was independently associated with in‐hospital mortality, and the recipient's BMI (P = 0.03) and the lowest pH before LT (P = 0.03) were independently associated with patient survival. A pH of 7.26 was the calculated cutoff (ROC) for increased in‐hospital mortality. Donor factors did not affect patient survival. Patients with ALF and a pH ≤ 7.26 have the worst outcome after liver transplantation. Therefore, emergency liver transplantation should be critically discussed for each individual.