Lothar B Zimmerhackl

Publications of Lothar B Zimmerhackl

• Screening for NPHS2 mutations may help predict FSGS recurrence after transplantation.

  Authors: Therese C Jungraithmayr, Katrin Hofer, Pierre Cochat, Gil Chernin, Gerard Cortina, Sonja Fargue, Paul Grimm, Tanja Knueppel, Andreas Kowarsch, Thomas Neuhaus, Philipp Pagel, Karl P Pfeiffer, Franz Schäfer, Ulf Schönermarck, Tomas Seeman, Burkhard Toenshoff, Stefanie Weber, Michelle P Winn, Johannes Zschocke, Lothar B Zimmerhackl

  Journal of the American Society of Nephrology : JASN. 02/2011; 22(3):579-85.

  Steroid-resistant focal segmental glomerulosclerosis (FSGS) often recurs after renal transplantation. In this international survey, we sought to identify genotype-phenotype correlations of recurrentSteroid-resistant focal segmental glomerulosclerosis (FSGS) often recurs after renal transplantation. In this international survey, we sought to identify genotype-phenotype correlations of recurrent FSGS. We surveyed 83 patients with childhood-onset primary FSGS who received at least one renal allograft and analyzed 53 of these patients for NPHS2 mutations. The mean age at diagnosis was 6.7 years, and the mean age at first renal transplantation was 13 years. FSGS recurred in 30 patients (36%) after a median of 13 days (range, 1.5 to 152 days). Twenty-three patients received a second kidney transplant, and FSGS recurred in 11 (48%) after a median of 16 days (range, 2.7 to 66 days). None of the 11 patients with homozygous or compound heterozygous NPHS2 mutations developed recurrent FSGS compared with 45% of patients without mutations. These data suggest that genetic testing for pathogenic mutations may be important for prognosis and treatment of FSGS both before and after transplantation.

• Thrombotic microangiopathy: atypical HUS: current diagnostic and therapeutic approaches.

  Authors: Alejandra Rosales, Magdalena Riedl, Lothar B Zimmerhackl

  Nature reviews. Nephrology. 09/2010; 6(9):504-6.

• A large family with a gain-of-function mutation of complement C3 predisposing to atypical hemolytic uremic syndrome, microhematuria, hypertension and chronic renal failure.

  Authors: Karl Lhotta, Andreas R Janecke, Johanna Scheiring, Barbara Petzlberger, Thomas Giner, Verena Fally, Reinhard Würzner, Lothar B Zimmerhackl, Gert Mayer, Veronique Fremeaux-Bacchi

  Clinical journal of the American Society of Nephrology : CJASN. 08/2009; 4(8):1356-62.

  BACKGROUND AND OBJECTIVES: Atypical hemolytic uremic syndrome (aHUS) is associated with mutations in genes encoding complement-regulatory proteins factor H, I and B and membrane cofactor protein.BACKGROUND AND OBJECTIVES: Atypical hemolytic uremic syndrome (aHUS) is associated with mutations in genes encoding complement-regulatory proteins factor H, I and B and membrane cofactor protein. Recently, heterozygous gain-of-function mutations in the complement C3 gene have been found in patients with aHUS. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A large family with a C3 R570Q mutation is described. Clinical and laboratory findings of carriers of the mutation and unaffected family members are reported. RESULTS: The index patient suffered from recurrent aHUS at age 22 and developed end-stage renal failure. Of 24 family members, nine harbored the C3 R570Q mutation. Carriers showed reduced or borderline C3 levels. Arterial hypertension was found in six family members, microhematuria in five and chronic kidney disease stage 3 in two elderly carrier patients. Despite marked consumption of C3, serum terminal complement complex levels were not elevated in carriers compared with other family members. CONCLUSIONS: The penetrance of the C3 R570Q mutation to induce aHUS is incomplete and lower compared with mutations in other genes predisposing to the disease. The mutation is possibly also associated with hypertension, hematuria and chronic kidney disease, all of which may represent consequences of long-term complement activation in the renal vasculature.

• Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome.

  Authors: Dorothea Orth, Abdul Basit Khan, Asma Naim, Katharina Grif, Jens Brockmeyer, Helge Karch, Michael Joannidis, Simon J Clark, Anthony J Day, Sonja Fidanzi, Heribert Stoiber, Manfred P Dierich, Lothar B Zimmerhackl, Reinhard Würzner

  Journal of immunology (Baltimore, Md. : 1950). 06/2009; 182(10):6394-400.

  Infections with enterohemorrhagic Escherichia coli (EHEC) are a major cause of hemolytic uremic syndrome (HUS). Shiga toxins (Stxs), especially Stx2, are believed to represent major virulence factorsInfections with enterohemorrhagic Escherichia coli (EHEC) are a major cause of hemolytic uremic syndrome (HUS). Shiga toxins (Stxs), especially Stx2, are believed to represent major virulence factors of EHEC, contributing to HUS pathogenesis. Beside EHEC-associated HUS, there are hereditary atypical forms of HUS, which are mostly caused by mutations of complement regulators. The aim of the present study was to investigate whether or not complement is also involved in the pathogenesis of EHEC-induced typical HUS, by being activated either directly or indirectly by involvement of its inhibitors. Purified Stx2 markedly activated complement via the alternative pathway and was found to bind to factor H (FH), however, only when it was active. No apparent cleavage or destruction of FH was visible, and cofactor activity in fluid phase was unaffected, but clearly delayed for surface-attached FH, where it is essential for host cell protection. Binding studies using FH constructs revealed that Stx2 binds to short consensus repeats (SCRs) 6-8 and SCRs18-20, but not to SCRs16-17, i.e., to regions involved in the surface recognition function of FH. In conclusion, complement, and in particular FH, not only plays an important role in atypical HUS, but most probably also in EHEC-induced HUS.

• Pharmacokinetics and immunodynamics of basiliximab in pediatric renal transplant recipients on mycophenolate mofetil comedication.

  Authors: Britta Höcker, John M Kovarik, Volker Daniel, Gerhard Opelz, Henry Fehrenbach, Martin Holder, Bernd Hoppe, Peter Hoyer, Therese C Jungraithmayr, Sabine Köpf-Shakib, Guido F Laube, Dirk E Müller-Wiefel, Gisela Offner, Christian Plank, Monika Schröder, Lutz T Weber, Lothar B Zimmerhackl, Burkhard Tönshoff

  Transplantation. 12/2008; 86(9):1234-40.

  BACKGROUND: The aim of this substudy within a prospective, multicenter, placebo-controlled trial was to assess the pharmacokinetics and immunodynamics of basiliximab in pediatric renal transplantBACKGROUND: The aim of this substudy within a prospective, multicenter, placebo-controlled trial was to assess the pharmacokinetics and immunodynamics of basiliximab in pediatric renal transplant recipients on comedication with mycophenolate mofetil (MMF). METHODS: Eighty-two patients aged 3 to 18 years, receiving cyclosporine microemulsion, MMF, corticosteroids, and basiliximab or placebo were investigated. Basiliximab serum concentrations were determined by ELISA, CD25+, and CD122+ T lymphocytes by flow cytometry. RESULTS: Basiliximab clearance adjusted to body surface area was significantly (P<0.05) greater in children versus adults, but the relatively higher basiliximab dose given to children yielded similar exposure compared with adolescents. A cross-study comparison revealed that MMF reduced basiliximab clearance and prolonged CD25 saturation duration from approximately 5 weeks in the absence of MMF to 10 weeks in the presence of MMF. Basiliximab led to a marked reduction of CD25+ T-cell fraction during the first 8 to 10 weeks posttransplant, but did not specifically affect CD122+ T cells. The majority of biopsy-proven acute rejection episodes (BPAR) were observed after interleukin (IL) 2-R desaturation, whereas about a quarter of BPARs occurred despite adequate IL2-R blockade. CONCLUSIONS: The currently recommended basiliximab dose for pediatric patients, when used with cyclosporine microemulsion and corticosteroids, yielded adequate drug exposure in children and adolescents also under MMF comedication. The observation that about a quarter of BPARs occurred despite adequate IL2-R blockade suggests that another T-cell activation pathway independent of the IL-2/IL-2R pathway is operative, for example, the IL-15 signaling pathway.

• Efficacy and safety of basiliximab in pediatric renal transplant patients receiving cyclosporine, mycophenolate mofetil, and steroids.

  Authors: Gisela Offner, Burkhard Toenshoff, Britta Höcker, Manuela Krauss, Monika Bulla, Pierre Cochat, Henry Fehrenbach, Wolfgang Fischer, Michel Foulard, Bernd Hoppe [......] Joachim Misselwitz, Carmen Montoya, Dirk E Müller-Wiefel, Thomas J Neuhaus, Lars Pape, Uwe Querfeld, Christian Plank, Dieter Schwarke, Simone Wygoda, Lothar B Zimmerhackl

  Transplantation. 12/2008; 86(9):1241-8.

  BACKGROUND: Basiliximab, a monoclonal CD25 antibody has proofed effective in reducing acute rejection episodes in adults in various immunosuppressive regimens. The effect of basiliximab in theBACKGROUND: Basiliximab, a monoclonal CD25 antibody has proofed effective in reducing acute rejection episodes in adults in various immunosuppressive regimens. The effect of basiliximab in the pediatric population is controversial. METHODS: In a 12-month, double-blind, placebo-controlled trial, renal transplant patients aged 1 to 18 years were randomized to basiliximab or placebo with cyclosporine microemulsion, mycophenolate mofetil, and corticosteroids. The intent-to-treat population comprised 192 patients (100 basiliximab and 92 placebo). RESULTS: The primary efficacy endpoint, time to first biopsy-proven acute rejection episode, or treatment failure by month 6, occurred in 16.7% of basiliximab-treated patients and 21.7% of placebo-treated patients (Kaplan-Meier estimates; hazard ratio 0.72, two-sided 90% confidence interval 0.416-1.26, n.s.). The rate and severity of subclinical rejections in protocol biopsies performed at 6 months posttransplant was higher in the basiliximab group (25.0%) than in the placebo group (11.7%). Patient and death-censored graft survival at 12 months was 97% and 99%, respectively, in the basiliximab cohort, and 100% and 99% among placebo-treated patients (n.s.). Renal function was similar in both treatment groups, and there were no significant between-treatment differences in the incidence of adverse events or infections. CONCLUSIONS: Addition of basiliximab induction to a regimen of cyclosporine microemulsion, mycophenolate mofetil, and steroids resulted in a numerically lower but not significant incidence of biopsy-proven acute rejection versus placebo and excellent graft and patient survival at 1 year in pediatric renal transplant recipients. Whether this numerical difference is a true therapeutic benefit in view of the higher rate and severity of subclinical rejections in the basiliximab group in the protocol biopsy will be investigated in a long-term follow-up study.

• Five-year outcome in pediatric patients with mycophenolate mofetil-based renal transplantation.

  Authors: Therese C Jungraithmayr, Silke Wiesmayr, Astrid Staskewitz, Günter Kirste, Monika Bulla, Henry Fehrenbach, Jürgen Dippell, Christel Greiner, Martin Griebel, Udo Helmchen, Günter Klaus, Heinz E Leichter, Michael J Mihatsch, Dietrich V Michalk, Joachim Misselwitz, Christian Plank, Burkhard Tönshoff, Lutz T Weber, Lothar B Zimmerhackl

  Transplantation. 04/2007; 83(7):900-5.

  BACKGROUND: Mycophenolate mofetil (MMF) based immunosuppression after renal transplantation has proven to be safe and beneficial for children and adolescents. However, long-term analysis, inBACKGROUND: Mycophenolate mofetil (MMF) based immunosuppression after renal transplantation has proven to be safe and beneficial for children and adolescents. However, long-term analysis, in particular of pediatric patients, is scarce. PATIENTS: Data of 140 patients receiving MMF versus azathioprine (AZA) in combination with cyclosporine A (CsA) and prednisone without induction were analyzed with a main focus on survival and renal function in long-term follow-up. RESULTS: After 5 years of follow-up, 44 MMF and 20 AZA patients were still on study. Graft survival of intent to treat (ITT) groups was 90.7% for MMF and 68.5% for AZA patients (P<0.001). Cumulative rejection free survival was 51.2% in MMF versus 37.0% in AZA patients (P<0.05). In association with early acute rejections (ARE), projected half-life was 14.4/4.5 years in patients with and 18.7/14.5 years without rejection in the MMF/AZA group, respectively. CONCLUSIONS: MMF based protocols improved long-term graft survival without an increase in side effects. Early ARE were associated with worse half-life of the graft, although more stressed in the AZA group. Thus, to improve quality of life in children for very long-term outcome, ARE should be further decreased and renal function should be better preserved.

• Shiga toxin-mediated hemolytic uremic syndrome: time to change the diagnostic paradigm?

  Authors: Martina Bielaszewska, Robin Köck, Alexander W Friedrich, Christof von Eiff, Lothar B Zimmerhackl, Helge Karch, Alexander Mellmann

  PLoS ONE. 02/2007; 2(10):e1024.

  BACKGROUND: Hemolytic uremic syndrome (HUS) is caused by enterohemorrhagic Escherichia coli (EHEC) which possess genes encoding Shiga toxin (stx), the major virulence factor, and adhesin intiminBACKGROUND: Hemolytic uremic syndrome (HUS) is caused by enterohemorrhagic Escherichia coli (EHEC) which possess genes encoding Shiga toxin (stx), the major virulence factor, and adhesin intimin (eae). However, the frequency of stx-negative/eae-positive E. coli in stools of HUS patients and the clinical significance of such strains are unknown. METHODOLOGY/PRINCIPAL FINDINGS: Between 1996 and 2006, we sought stx-negative/eae-positive E. coli in stools of HUS patients using colony blot hybridization with the eae probe and compared the isolates to EHEC causing HUS. stx-negative/eae-positive E. coli were isolated as the only pathogens from stools of 43 (5.5%) of 787 HUS patients; additional 440 (55.9%) patients excreted EHEC. The majority (90.7%) of the stx-negative/eae-positive isolates belonged to serotypes O26:H11/NM (nonmotile), O103:H2/NM, O145:H28/NM, and O157:H7/NM, which were also the most frequent serotypes identified among EHEC. The stx-negative isolates shared non-stx virulence and fitness genes with EHEC of the corresponding serotypes and clustered with them into the same clonal complexes in multilocus sequence typing, demonstrating their close relatedness to EHEC. CONCLUSIONS/SIGNIFICANCE: At the time of microbiological analysis, approximately 5% of HUS patients shed no longer the causative EHEC, but do excrete stx-negative derivatives of EHEC that lost stx during infection. In such patients, the EHEC etiology of HUS is missed using current methods detecting solely stx or Shiga toxin; this can hamper epidemiological investigations and lead to inappropriate clinical management. While maintaining the paradigm that HUS is triggered by Shiga toxin, our data demonstrate the necessity of considering genetic changes of the pathogen during infection to adapt appropriately diagnostic strategies.

• New aspects in the pathogenesis of enteropathic hemolytic uremic syndrome.

  Authors: Helge Karch, Alexander W Friedrich, Angela Gerber, Lothar B Zimmerhackl, M Alexander Schmidt, Martina Bielaszewska

  Seminars in thrombosis and hemostasis. 04/2006; 32(2):105-12.

  Shiga toxin (Stx) subtyping suggests that the clinical outcome of infections caused by Shiga toxin-producing ESCHERICHIA COLI (STEC) depends, in large part, on the STX genotype of the infectingShiga toxin (Stx) subtyping suggests that the clinical outcome of infections caused by Shiga toxin-producing ESCHERICHIA COLI (STEC) depends, in large part, on the STX genotype of the infecting strain. Whereas the presence of the STX2 or STX2C genotype is associated with the ability of STEC to cause the hemolytic uremic syndrome (HUS), strains possessing STX2D or STX2E have been isolated from patients with less severe disease. In addition to the type of Stx, the level of Stx production might be critical for the pathogenicity of STEC. Control of Stx expression appears to be at the level of transcription. Injury to microvascular endothelial cells is the key event underlying the pathogenesis of HUS. We could show that in addition to Stx, STEC also produces other putative virulence factors, such as cytolethal distending toxin, which can contribute to the endothelial injury by interference with the cell cycle, which results in inhibition of cell proliferation and finally cell death.

• Enterohemorrhagic Escherichia coli in human infection: in vivo evolution of a bacterial pathogen.

  Authors: Alexander Mellmann, Martina Bielaszewska, Lothar B Zimmerhackl, Rita Prager, Dag Harmsen, Helmut Tschäpe, Helge Karch

  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 10/2005; 41(6):785-92.

  BACKGROUND: Enterohemorrhagic Escherichia coli (EHEC) cause most cases of the hemolytic uremic syndrome (HUS) worldwide. To investigate genetic changes in EHEC during the course of human infection,BACKGROUND: Enterohemorrhagic Escherichia coli (EHEC) cause most cases of the hemolytic uremic syndrome (HUS) worldwide. To investigate genetic changes in EHEC during the course of human infection, we analyzed consecutive stool samples and shed isolates from patients with HUS, focusing on the genes encoding Shiga toxin (stx) and intimin (eae). METHODS: Sequential stool samples from 210 patients with HUS were investigated for the persistence of E. coli strains harboring stx and/or eae. Initial stool samples were collected during the acute phase of HUS, and subsequent stool samples were collected 3-16 days later (median interval, 8 days). RESULTS: Organisms that were stx and eae positive (stx+/eae+ strains; n=137) or stx negative and eae positive (stx-/eae+ strains; n=5) were detected in the initial stool samples from 142 patients. Subsequently, the proportion of those who shed stx+/eae+ strains decreased to 13 of 210 patients, whereas the proportion of those who shed strains that were stx-/eae+ increased to 12 of 210 patients. Seven patients who initially excreted strains that were stx+/eae+ shed, at second analysis, stx-/eae+ strains of the same serotypes; they had no free fecal Shiga toxin at follow-up. Comparison of the initial and follow-up isolates from these patients with use of molecular-epidemiological methods revealed loss of stx genes and genomic rearrangement. CONCLUSIONS: We demonstrate the loss of a critical bacterial virulence factor from pathogens during very brief intervals in the human host. These genetic changes have evolutionary, diagnostic, and clinical implications. Generation of stx- mutants might contribute to subclonal evolution and evolutionary success.

• Complete remission of post-transplant FSGS recurrence by long-term plasmapheresis.

  Authors: Karsten Häffner, Lothar B Zimmerhackl, Christian von Schnakenburg, Matthias Brandis, Martin Pohl

  Pediatric nephrology (Berlin, Germany). 08/2005; 20(7):994-7.

  Focal segmental glomerulosclerosis (FSGS) is known to recur in approximately 30% of renal allografts with graft loss in about half of these cases. The exact etiology remains unclear, though aFocal segmental glomerulosclerosis (FSGS) is known to recur in approximately 30% of renal allografts with graft loss in about half of these cases. The exact etiology remains unclear, though a putative circulating permeability factor or loss of inhibitory substances is being discussed. Different therapeutic approaches have been used. We report on a 10-year-old Arabian boy with a recurrence of FSGS immediately after transplantation. In addition to intensifying immunosuppressive therapy with high-dose cyclosporin A and cyclophosphamide, plasmapheresis was initiated and remission was achieved after 8 months. Three weeks after cessation of plasmapheresis a relapse occurred. Plasmapheresis was resumed and remission was achieved again after four additional sessions. The interval between plasmapheresis treatments was then gradually increased and fourteen months after transplantation plasmapheresis was stopped again. Since then (1.5 years after cessation of treatment) the patient has been in complete remission without any further episode of proteinuria. In conclusion, complete and sustained remission with stable renal function was achieved in our patient by long-term plasmapheresis in combination with intensified immunosuppression. Therefore, continuation of plasmapheresis treatment should be considered even in the situation of initial non-response.

• Primary focal segmental glomerulosclerosis--long-term outcome after pediatric renal transplantation.

  Authors: Therese C Jungraithmayr, Monika Bulla, Jürgen Dippell, Christel Greiner, Martin Griebel, Heinz E Leichter, Christian Plank, Burkhard Tönshoff, Lutz T Weber, Lothar B Zimmerhackl

  Pediatric transplantation. 05/2005; 9(2):226-31.

  Recurrence of the primary disease is a significant issue in pediatric renal transplantation (RTx). According to data reported by the North American Pediatric Renal Transplantation Cooperative Study,Recurrence of the primary disease is a significant issue in pediatric renal transplantation (RTx). According to data reported by the North American Pediatric Renal Transplantation Cooperative Study, patients with focal segmental glomerulosclerosis (FSGS) as primary renal disease have a recurrence rate of 30% after the first RTx. The relative risk of an early graft loss because of recurrent disease is increased to 1.6-3.1 in pediatric patients with FSGS. In a German open multicenter study, which was initiated to investigate mycophenolate mofetil (MMF) after pediatric RTx [Transplantation 2001:71:638, Transplantation 2003:75:454], patients with FSGS were evaluated for recurrence rate, risk factors for recurrence, long-term graft function, glomerular filtration rate and transplant survival. All patients received immunosuppression with MMF, cyclosporine A and prednisone without induction therapy. Renal function and survival data for FSGS patients were compared with the results of patients with other primary renal diseases within the same study population. Among 86 patients transplanted between 1996 and 1999 eight patients suffered from FSGS as primary disease. Recurrence was diagnosed in two of the eight patients. One out of these two patients lost his graft as a result of recurrence. Risk factors such as time between diagnosis and end stage renal disease (ESRD) and age at onset did not predict recurrence. A three-year patient survival in the FSGS group was 100%, graft survival 87% vs. 97% in the non-FSGS group. Acute rejections occurred in three out of eight FSGS patients and in 37 out of 78 among the non-FSGS group. Long-term renal function, calculated using mathematical modeling based on glomerular filtration rate (GFR) data during 3 yr after RTx, was similar in FSGS patients - including a patient who had recurrence with a functioning graft - and those without FSGS. In patients with FSGS, recurring disease after RTx remains an important cause of graft loss (one of two patients in this population) even under modern immunosuppressants. Nevertheless, the immunosuppressive regimen used was associated with a similar graft survival rate and long-term renal function of FSGS patients compared with patients with other primary diseases.

• Teratocarcinosarcoma of the oral cavity.

  Authors: Roman Crazzolara, Wolfgang Puelacher, Milomir Ninkovic, Bettina Zelger, Wolfgang Buchberger, Bernhard Meister, Lothar B Zimmerhackl, Andreas Klein-Franke

  Pediatric blood & cancer. 12/2004; 43(6):687-91.

  Teratocarcinosarcoma (TCS) is a very rare and aggressive neoplasm characterized by teratoma and carcinosarcoma components. The authors report on a case of TCS in the oral cavity of a child. RapidTeratocarcinosarcoma (TCS) is a very rare and aggressive neoplasm characterized by teratoma and carcinosarcoma components. The authors report on a case of TCS in the oral cavity of a child. Rapid growth and extensive local destruction were prominent features prior to treatment. Histologic examination revealed various tissue elements, such as epithelial, mesenchymal, and neuroectodermal components. Chemotherapy was effective in reducing tumor mass, followed by partial anterior mandibulectomy and reconstruction with composite microvascular tissue transfer. The approach allowed radical resection of the tumor and functional reconstruction with excellent aesthetic results.

• Cyclosporin A absorption profiles in pediatric renal transplant recipients predict the risk of acute rejection.

  Authors: Lutz T Weber, Victor W Armstrong, Maria Shipkova, Reinhard Feneberg, Manfred Wiesel, Otto Mehls, Lothar B Zimmerhackl, Michael Oellerich, Burkhard Tönshoff

  Therapeutic drug monitoring. 08/2004; 26(4):415-24.

  The current focus of cyclosporin A (CsA) monitoring in adult transplantation for optimized immunosuppression is on the early portion of the CsA area under the concentration-time curve (AUC),The current focus of cyclosporin A (CsA) monitoring in adult transplantation for optimized immunosuppression is on the early portion of the CsA area under the concentration-time curve (AUC), particularly in the first 4 hours postdose, designated as AUC(0-4), and on the blood concentration 2 hours postdose (C2) as a highly predictive marker for AUC(0-4). Because data in pediatric patients are scarce, full-time (12 hours) and absorption profiles of CsA were analyzed in relation to CsA effectiveness in 61 pediatric renal transplant recipients aged 3.2 to 17.4 years on an immunosuppressive triple regimen with CsA, mycophenolate mofetil, and methylprednisolone. CsA dosing was based on body surface area and adjusted to CsA trough levels. Pharmacokinetic (PK) profiles were obtained 1 and 3 weeks (initial period) and 3 and 6 months posttransplant (stable period). Patients with an AUC(0-4) < 4400 microg x h/L at both PK sampling periods in the first 3 weeks posttransplant had an adjusted relative risk of 48.4% to suffer an acute rejection episode (ARE), whereas in patients with at least 1 AUC0-4 above this threshold, the adjusted relative risk for an ARE was only 13.1% (P < 0.02). The single PK parameters C0 or C2 did not discriminate between patients with and without acute rejection. The PK parameters C1.25 (r2 = 0.64) or C2 (r2 = 0.60) showed a stronger relationship to the absorption profile (AUC(0-4)) than C0 (r2 = 0.15). An abbreviated profile consisting of the PK variables C(0.5;2) or C(0;0.5;2) showed the closest correlation to the absorption profile (r2 = 0.89) and the lowest percentage prediction error. These data indicate that absorption profiling in pediatric renal transplant recipients has the potential to optimize immunosuppressive therapy with CsA.

• Successful (?) therapy of hemolytic-uremic syndrome with factor H abnormality.

  Authors: Angela Gerber, Antje H Kirchhoff-Moradpour, Silke Obieglo, Matthias Brandis, Michael Kirschfink, Peter F Zipfel, Judith A Goodship, Lothar B Zimmerhackl

  Pediatric nephrology (Berlin, Germany). 10/2003; 18(9):952-5.

  We report a patient with continuously recurring hemolytic-uremic syndrome due to factor H deficiency. First at the age of 3 months he showed signs of hemolytic anemia, thrombocytopenia and renalWe report a patient with continuously recurring hemolytic-uremic syndrome due to factor H deficiency. First at the age of 3 months he showed signs of hemolytic anemia, thrombocytopenia and renal insufficiency, often recurring concomitantly with respiratory tract infections, despite weekly to twice weekly plasma substitution (20 ml/kg body weight). Now at the age of 3.5 years glomerular filtration rate is approximately 50 ml/min/1.73 m(2) and psychomotoric development is normal. Since factor H is mainly synthesized in the liver, hepatic transplantation has been proposed as curative treatment. Before justification of liver transplantation as the ultimate treatment for these patients, an international registry should be developed to optimize and standardize therapeutic alternatives.

• Hemolytic-uremic syndrome associated with enterohemorrhagic Escherichia coli O26:H infection and consumption of unpasteurized cow's milk.

  Authors: Franz Allerberger, Alexander W Friedrich, Katharina Grif, Manfred P Dierich, Hans Jürgen Dornbusch, Cristoph J Mache, Edith Nachbaur, Michael Freilinger, Petra Rieck, Martin Wagner, Alfredo Caprioli, Helge Karch, Lothar B Zimmerhackl

  International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 04/2003; 7(1):42-5.

  BACKGROUND: Enterohemorrhagic Escherichia coli (EHEC) O26 has emerged as a significant cause of hemolytic-uremic syndrome (HUS). The source and the vehicle of contamination with EHEC O26 are notBACKGROUND: Enterohemorrhagic Escherichia coli (EHEC) O26 has emerged as a significant cause of hemolytic-uremic syndrome (HUS). The source and the vehicle of contamination with EHEC O26 are not often identified. We report two Austrian cases of HUS due to E. coli O26:H- affecting an 11-month-old boy and a 28-month-old girl in which transmission through unpasteurized cow's milk was positively identified. METHODS AND RESULTS: Using automated ribotyping and pulsed-field gel electrophoresis (PFGE), the isolates (which yielded the virulence genes stx2, eae, and hly) were indistinguishable from each other. An epidemiologic investigation revealed that the children had stayed in the same hotel. Both patients had consumed unpasteurized cow's milk from the breakfast buffet. Fecal samples were taken from the cows of the farm producing the incriminating milk, and one of three cattle EHEC O26:H- isolates had a PFGE pattern indistinguishable from that of the patients' strains. CONCLUSIONS: These two cases of E. coli O26 infection illustrate the hazards associated with the consumption of raw milk, and underline the importance of microbiological diagnostic approaches able to detect sorbitol-fermenting, non-O157 EHEC.

• Pediatric renal transplantation with mycophenolate mofetil-based immunosuppression without induction: results after three years.

  Authors: Therese Jungraithmayr, Astrid Staskewitz, Günter Kirste, Michael Böswald, Monika Bulla, Rainer Burghard, Jürgen Dippell, Christel Greiner, Udo Helmchen, Bernd Klare [......] Heinz E Leichter, Michael J Mihatsch, Dietrich V Michalk, Joachim Misselwitz, Christian Plank, Uwe Querfeld, Lutz T Weber, Manfred Wiesel, Burkhard Tönshoff, Lothar B Zimmerhackl

  Transplantation. 02/2003; 75(4):454-61.

  BACKGROUND: Mycophenolate mofetil (MMF)-based immunosuppression has reduced the acute rejection rate in adults and in children in the early posttransplantation period. Three-year posttransplantationBACKGROUND: Mycophenolate mofetil (MMF)-based immunosuppression has reduced the acute rejection rate in adults and in children in the early posttransplantation period. Three-year posttransplantation results have been reported for adults but not for children thus far. In the present open-labeled study, patients 18 years old and younger were evaluated prospectively for up to 3 years after renal transplantation (RTX). METHODS: Eighty-six patients receiving MMF in combination with cyclosporine and prednisone without induction were evaluated for patient survival, transplant survival, renal function, arterial blood pressure, adverse events, and opportunistic infections. These patients were compared with a historic control group (n=54) receiving azathioprine (AZA) instead of MMF. RESULTS: Patient survival after 3 years was 98.8% in the MMF group and 94.4% in the AZA group (NS). Intent-to-treat analysis of graft survival demonstrated superiority for MMF (98% vs. 80%; P<0.001). Cumulative acute rejection episodes occurred in 47% of patients in the MMF group versus 61% in the AZA group (P<0.05). Renal function was not significantly different, neither after 3 years nor in the long-term calculation. Antihypertensive medication was administered to 73% to 84% of patients, similar in both groups. Opportunistic infections were recorded only for MMF. Infection rates were comparable to those reported in adults. CONCLUSIONS: These results suggest that MMF is safe and beneficial as a longer term maintenance immunosuppressive drug in children and adolescents.

• Clinical course and the role of shiga toxin-producing Escherichia coli infection in the hemolytic-uremic syndrome in pediatric patients, 1997-2000, in Germany and Austria: a prospective study.

  Authors: Angela Gerber, Helge Karch, Franz Allerberger, Hege M Verweyen, Lothar B Zimmerhackl

  The Journal of infectious diseases. 09/2002; 186(4):493-500.

  Hemolytic-uremic syndrome (HUS) is mainly associated with foodborne infections by Shiga toxin-producing Escherichia coli (STEC). From January 1997 through December 2000, 394 children with HUS wereHemolytic-uremic syndrome (HUS) is mainly associated with foodborne infections by Shiga toxin-producing Escherichia coli (STEC). From January 1997 through December 2000, 394 children with HUS were evaluated in a prospective multicenter surveillance study in Germany and Austria (incidences, 0.7/100,000 and 0.4/100,000 children <15 years old, respectively). Blood leukocytosis was associated with increased detection of STEC in stool cultures (P<.01) and a more severe disease course. Risk of death was associated with cerebral involvement (P<.01). Most strikingly, non-O157:H7 STEC were detected in 43% of stool cultures of patients with HUS: O26 was detected in 15%, sorbitol-fermenting O157:H(-) in 10%, O145 in 9%, O103 in 3%, and O111 in 43%. Patients with O157:H7 serotypes required dialysis for a longer time and had bloody diarrhea detected more frequently, compared with patients with non-O157:H7 serotypes (P<.05). This large study in children with HUS underlines the rising importance of non-O157:H7 serotypes, and, despite increased public awareness, the number of patients remained unchanged.

• The pharmacokinetic-pharmacodynamic relationship for total and free mycophenolic Acid in pediatric renal transplant recipients: a report of the german study group on mycophenolate mofetil therapy.

  Authors: Lutz T Weber, Maria Shipkova, Victor W Armstrong, Natalie Wagner, Ekkehard Schütz, Otto Mehls, Lothar B Zimmerhackl, Michael Oellerich, Burkhard Tönshoff

  Journal of the American Society of Nephrology : JASN. 04/2002; 13(3):759-68.

  It is currently being debated whether pharmacokinetic monitoring of mycophenolic acid (MPA), the active constituent of mycophenolate mofetil (MMF), can optimize MMF therapy after organIt is currently being debated whether pharmacokinetic monitoring of mycophenolic acid (MPA), the active constituent of mycophenolate mofetil (MMF), can optimize MMF therapy after organ transplantation. This open-label longitudinal study in pediatric renal transplant recipients was designed to investigate the pharmacokinetic (PK)/pharmacodynamic relationship of total and free MPA and to establish PK values for the assessment of an individual's MPA PK parameters. Fifty-four children, aged 2.2 to 17.8 yr, on an immunosuppressive triple regimen consisting of cyclosporin A, prednisone, and MMF (600 mg/m(2) body surface area twice daily) were investigated 1 wk and 3 wk (initial phase) and 3 mo and 6 mo (stable phase) after renal transplantation. MPA was measured by reverse phase HPLC, free MPA by HPLC after separation by ultrafiltration. There was an association between the risk of acute rejection episodes and MPA-AUC(0-12) values or MPA predose levels; by receiver operating characteristic analysis, an AUC(0-12) of 33.8 mg x h/L in the initial phase posttransplant had a diagnostic sensitivity of 75% and a diagnostic specificity of 64% for discrimination of patients with acute rejections. The respective discrimination threshold for the MPA predose concentration was 1.2 mg/L with a sensitivity of 83% and a specificity of 64%. In contrast, high free, but not total, MPA-AUC(0-12) values were associated with an increased risk of the MMF-related side effects leukopenia and/or infections. These data indicate that therapeutic drug monitoring of MPA has the potential for optimization of MMF efficacy in this patient population by steering patients away from the low values of MPA PK variables that are associated with an increased rejection risk. For the assessment of the toxic risk of MMF regarding leukopenia and/or infections, measurement of free MPA appears to be more appropriate.

• Hemolytic uremic syndrome due to an altered factor H triggered by neonatal pertussis.

  Authors: Reinhard Berner, Martin F Krause, Nader Gordjani, Peter F Zipfel, Norbert Boehm, Marcus Krueger, Matthias Brandis, Lothar B Zimmerhackl

  Pediatric nephrology (Berlin, Germany). 04/2002; 17(3):190-2.

  We report on a previously healthy newborn suffering from severe Bordetella pertussis infection who developed hemolytic uremic syndrome (HUS) a few weeks after the onset of whooping cough, with aWe report on a previously healthy newborn suffering from severe Bordetella pertussis infection who developed hemolytic uremic syndrome (HUS) a few weeks after the onset of whooping cough, with a fatal outcome. A factor H protein with abnormal mobility was found in the serum of the patient as analyzed by Western blotting, indicating that B. pertussis infection might have triggered HUS in a genetically predisposed patient.