Peter F. Hoyer

Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy.

Alport syndrome inevitably leads to end-stage renal disease and there are no therapies known to improve outcome. Here we determined whether angiotensin-converting enzyme inhibitors can delay time to dialysis and improve life expectancy in three generations of Alport families. Patients were categorized by renal function at the initiation of therapy and included 33 with hematuria or microalbuminuria, 115 with proteinuria, 26 with impaired renal function, and 109 untreated relatives. Patients were followed for a period whose mean duration exceeded two decades. Untreated relatives started dialysis at a median age of 22 years. Treatment of those with impaired renal function significantly delayed dialysis to a median age of 25, while treatment of those with proteinuria delayed dialysis to a median age of 40. Significantly, no patient with hematuria or microalbuminuria advanced to renal failure so far. Sibling pairs confirmed these results, showing that earlier therapy in younger patients significantly delayed dialysis by 13 years compared to later or no therapy in older siblings. Therapy significantly improved life expectancy beyond the median age of 55 years of the no-treatment cohort. Thus, Alport syndrome is treatable with angiotensin-converting enzyme inhibition to delay renal failure and therapy improves life expectancy in a time-dependent manner. This supports the need for early diagnosis and early nephroprotective therapy in oligosymptomatic patients.

Neonatal renal venous thrombosis in Germany between 1992 and 1994: epidemiology, treatment and outcome.

Abstract Renal venous thrombosis (RVT) occurs mainly in the neonatal period and bears a dismal prognosis for individual kidney function. There is no generally accepted therapeutic regimen as controlled clinical trials are lacking. Over the last few years, thrombolytic therapy has been successfully employed by single centres. The present study set out to gather up-to-date information on the incidence, therapy and outcome of neonatal RVT as part of a prospective nation wide survey on neonatal thrombosis in Germany to serve as a basis for therapeutic trials in the future. Between 1992 and 1994 the minimum incidence of symptomatic neonatal RVT in Germany was 2.2 per 100,000 live births (95% confidence interval 1.4–3.3). Out of 35 cases, RVT occurred in 15 premature babies (incidence 13 per 100,000 live births (95% confidence interval 5.9–24.8). Ten babies had associated caval occlusion. Therapy was supportive in 8, low dose heparin was used in 14, full heparinization in 9 and thrombolytic therapy in 4 children. On follow-up after a median time of 11.5 months, renal atrophy was present in 26 out of 39 affected kidneys. Conclusion Neonatal renal venous thrombosis still leads to irreversible kidney damage in the majority of cases. Because of the low incidence a multi-national multi-centre therapeutic trial over a long period has to be considered in order to determine the optimal therapeutic approach.

A Novel TRPC6 Mutation That Causes Childhood FSGS

Background TRPC6, encoding a member of the transient receptor potential (TRP) superfamily of ion channels, is a calcium-permeable cation channel, which mediates capacitive calcium entry into the cell. Until today, seven different mutations in TRPC6 have been identified as a cause of autosomal-dominant focal segmental glomerulosclerosis (FSGS) in adults. Methodology/Principal Findings Here we report a novel TRPC6 mutation that leads to early onset FSGS. We identified one family in whom disease segregated with a novel TRPC6 mutation (M132T), that also affected pediatric individuals as early as nine years of age. Twenty-one pedigrees compatible with an autosomal-dominant mode of inheritance and biopsy-proven FSGS were selected from a worldwide cohort of 550 families with steroid resistant nephrotic syndrome (SRNS). Whole cell current recordings of the mutant TRPC6 channel, compared to the wild-type channel, showed a 3 to 5-fold increase in the average out- and inward TRPC6 current amplitude. The mean inward calcium current of M132T was 10-fold larger than that of wild-type TRPC6. Interestingly, M132T mutants also lacked time-dependent inactivation. Generation of a novel double mutant M132T/N143S did not further augment TRPC6 channel activity. Conclusions In summary, our data shows that TRPC6 mediated FSGS can also be found in children. The large increase in channel currents and impaired channel inactivation caused by the M132T mutant leads to an aggressive phenotype that underlines the importance of calcium dose channeled through TRPC6.

Immunosuppression and Renal Outcome in Congenital and Pediatric Steroid-Resistant Nephrotic Syndrome

BACKGROUND AND OBJECTIVES Mutations in podocyte genes are associated with steroid-resistant nephrotic syndrome (SRNS), mostly affecting younger age groups. To date, it is unclear whether these patients benefit from intensified immunosuppression with cyclosporine A (CsA). The aim of this study was to evaluate the influence of podocyte gene defects in congenital nephrotic syndrome (CNS) and pediatric SRNS on the efficacy of CsA therapy and preservation of renal function. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS Genotyping was performed in 91 CNS/SRNS patients, irrespective of age at manifestation or response to CsA. RESULTS Mutations were identified in 52% of families (11 NPHS1, 17 NPHS2, 11 WT1, 1 LAMB2, 3 TRPC6). Sixty-eight percent of patients with nongenetic SRNS responded to CsA, most of them achieved complete remission. In contrast, none of the patients with genetic CNS/SRNS experienced a complete remission and only two (17%) achieved a partial response, both affected by a WT1 mutation. Preservation of renal function was significantly better in children with nongenetic disease after a mean follow-up time of 8.6 years (ESRD in 29% versus 71%). CONCLUSIONS The mutation detection rate in our population was high (52%). Most patients with genetic CNS/SRNS did not benefit from CsA with significantly lower response rates compared with nongenetic patients and showed rapid progression to end-stage renal failure. These data strongly support the idea not to expose CNS/SRNS patients with inherited defects related to podocyte function to intensified immunosuppression with CsA.

CNS or Bone Marrow Involvement As Risk Factors for Poor Survival in Post-Transplantation Lymphoproliferative Disorders in Children After Solid Organ Transplantation

PURPOSE To identify prognostic factors of survival in pediatric post-transplantation lymphoproliferative disorder (PTLD) after solid organ transplantation. PATIENTS AND METHODS A multicenter, retrospective case analysis of 55 pediatric solid organ graft recipients (kidney, liver, heart/lung) developing PTLD were reported to the German Pediatric-PTLD registry. Patient charts were analyzed for tumor characteristics (histology, immunophenotypes, cytogenetics, Epstein-Barr virus [EBV] detection), stage, treatment, and outcome. Probability of overall and event-free survival was analyzed in defined subgroups using univariate and Cox regression analyses. RESULTS PTLD was diagnosed at a median time of 29 months after organ transplantation, with a significantly shorter lag time in liver (0.83 years) versus heart or renal graft recipients (3.33 and 3.10 years, respectively; P = .001). The 5-year overall and event-free survival was 68% and 59%, respectively, with 59% of patients surviving 10 years. Stage IV disease with bone marrow and/or CNS involvement was associated independently with poor survival (P = .0005). No differences in outcome were observed between early- and late-onset PTLD, monomorphic or polymorphic PTLD, and EBV-positive or EBV-negative PTLD, respectively. Patients with Burkitt or Burkitt-like PTLD and c-myc translocations had short survival (< 1 year). CONCLUSION Stage IV disease is an independent risk factor for poor survival in pediatric PTLD patients. Prospective multicenter trials are needed to delineate additional risk factors and to assess treatment approaches for pediatric PTLD.

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.

Assessment of maximal tubular phosphate reabsorption: comparison of direct measurement with the nomogram of Bijvoet

It is well established that plasma phosphate (Pp) is largely determined by the renal phosphate threshold, which is best described by the maximal rate of tubular phosphate reabsorption divided by the glomerular filtration rate (Tmp/GFR). For its clinical assessment either direct phosphate loading with simultaneous measurement of GFR is performed, or the nomogram described by Walton and Bijvoet is used. In order to test the validity of the two methods, we compared in 20 infants and 31 children the fasting values of phosphate reabsorption [endogenous phosphate reabsorption/inulin clearance (Tp/Cin) and Tp] with those obtained after phosphate loading [maximal phosphate reabsorption (Tmp) and Tmp/Cin], and both with those derived from the nomogram. In addition the fasting Tp/Cin of 50 infants and 143 children could be compared with the nomogram. The results demonstrate that the directly measured Tp/Cin was the same as the directly measured Tmp/Cin and that the measured Tmp/Cin was correctly estimated by the nomogram. However, the comparison of fasting Tp/Cin with nomogram-derived values showed a systematic error, by which the latter values were higher than those measured. The discrepancy was due to the splay of the phosphate titration curve, which was found by Bijvoet when the ratio of phosphate clearance (Cp) corrected for GFR (Cp/GFR) fell below 0.2. The incorporation of this splay in the nomogram could not be confirmed by data measured in our children. It is concluded that fasting Tp is already “maximal” and that, therefore, no phosphate loading is necessary to estimate Tmp. Furthermore, there is no evidence of a major splay, which makes the nomogram incompatible below a Cp/GFR ratio of 0.2. For clinical assessment we recommend use of the formula Tmp/GFR=Pp−(Up×Pcrea/Ucrea) where Pp, Up, Pcrea and Ucrea refer to the plasma and urinary concentration of phosphate and creatinine respectively. This formula can be applied easily without the need to collect timed urinary specimens and is independent of the phosphate load.

Removal of metabolites, cytokines and hepatic growth factors by extracorporeal liver support in children.

Background: Molecular Adsorbents Recirculating System (MARS)-mini has recently been approved and applied in children with hepatic failure. However, its indication, efficacy and capability to induce liver regeneration remain unclear. The aim of our pilot study in children was to analyse the impact of MARS on markers of detoxification and regeneration. Methods: In children with fulminant Wilsons disease and bridged with MARSmini for liver transplantation, we analyzed toxic metabolites (bile acids, bilirubin, lactate, ammonia, tryptophan and copper), regulators of the inflammatory cascade [nitrate, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), methionine, cystine and hyaluronic acid] and hepatic growth factors [hepatocyte growth factor (HGF), epidermal growth factor (EGF), transforming growth factor-β1 (TGF-β1), cortisol, corticosteroid-binding globulin (CBG), insulin-like growth factor-1 (IGF-1), angiogenin, vascular endothelial growth factor (VEGF), IL-6 and TNF-α] from blood, albumin circuit and haemodialysate from four applications. Results: In all four applications, transfer of toxic metabolites (6/6) and inflammatory mediators (6/6), but also of hepatic growth factors (9/10), into the albumin circuit of MARS was consistently detected. Corresponding blood levels were decreased for 3/6 metabolites, 3/6 inflammatory mediators and 1/10 growth factors and increased for 1/10 growth factors. Bridging for liver transplantation was successful with MARS. Conclusions: In our prospective study, substantial extraction of albumin-bound and water-soluble candidate substances was detected with variable effect on respective blood levels. Notably, essential factors inducing liver regeneration were simultaneously removed. These data provide a basis for evaluation of liver restoration and efficacy of liver support in children with liver failure to devise a collaborative, multicentre trial.

Practical aspects in the use of cyclosporin in paediatric nephrology

Many factors must be considered for the effective and safe use of cyclosporin A (CsA) in paediatric nephrology. Detailed knowledge of the variable bioavailability, tissue distribution, and metabolism, as well as causes which lead to their alteration are necessary. Factors which affect the activity of the mixed function oxidase system cytochrome P-450 must be considered, i. e. liver dysfunction and many drugs. Precise knowledge of the CsA determination method and the spectrum of metabolites is essential. In children with renal transplants, a body surface area-related dose will better meet the dose requirements than a body weight related-dose. For drug level monitoring whole blood rather than plasma should be used, and the parent drug level should be the main determinant; elevated metabolite levels may be important in suspected nephrotoxicity or liver dysfunction. Pharmacokinetic profiles are necessary to discover absorption problems or increased CsA clearance rates which necessitate shorter dosing intervals. In children with steroid-dependent minimal change nephrotic syndrome, remission without steroids is maintained as long as CsA is given. The appropriate starting dosage is 150 mg/m2 per day; trough level monitoring is mandatory to prevent nephrotoxicity and to confirm adequate immunosuppressive drug levels which should be 80–160 ng/ml (parent drug level). Although the benefit of CsA has been reported in some cases of lupus erythematosus, its use should be restricted to severe cases only until its efficacy and safety has been confirmed in controlled trials.

Everolimus in pediatric de nova renal transplant patients1

Background. The steady-state pharmacokinetics of everolimus were longitudinally assessed in pediatric de novo kidney allograft recipients during a 6-month period. Methods. Nineteen patients received everolimus 0.8 mg/m2 (maximum 1.5 mg) twice daily as a dispersible tablet in water in addition to cyclosporine and corticosteroids. Everolimus and cyclosporine trough concentrations were obtained on days 3, 5, 6, and 7 and at months 1, 2, 3, and 6; an everolimus pharmacokinetic profile was obtained on day 7 and month 3. Results. There were 9 boys and 10 girls with a median age of 9.9 (range, 1–16) years. Steady-state pharmacokinetic parameters were as follows (median, range): Cmin (trough level), 4.7 (2.3- 9.5) ng/mL; peak concentration, 13.5 (5.9–22.2) ng/mL; area under the concentration-time curve (AUC), 77 (53–147) ng·hr/mL; and apparent oral clearance, 10.2 (5.5–15.6) L/hr/m2. Clearance (unadjusted for demographic factors) was positively correlated with age (r =0.66), body surface area (r =0.68), and weight (r =0.67). There were no trends in Cmin or AUC versus patient age when everolimus was dosed on a mg/m2 basis. Everolimus Cmin were stable over time with median values of 3.9, 3.4, and 3.1 ng/mL at months 1, 3, and 6, respectively. Intra- and interpatient variability in AUC was 29% and 35%, similar to that in adults. During the observation period, eight patients maintained stable AUCs and nine patients had increases or decreases, generally between 30% and 50% compared with the AUC at week 1. The concurrent median cyclosporine Cmin were generally at the lower end of conventional target ranges: 156, 83, and 69 ng/mL at months 1, 3, and 6, respectively. There were no graft losses and only three mild or moderate, reversible rejection episodes occurred. Everolimus was generally safe and well tolerated. Conclusions. These data support the use of body surface area-adjusted dosing for everolimus in pediatric patients. Although exposure is generally stable over time with moderate variability in AUC, therapeutic monitoring would be a helpful adjunct for individualizing everolimus exposure, assessing regimen adherence, and adjusting doses as the child matures.