Thurid Ahlenstiel

An Outbreak of Shiga Toxin–Producing Escherichia coli O104:H4 Hemolytic Uremic Syndrome in Germany: Presentation and Short-term Outcome in Children

BACKGROUND In May and June 2011 the largest known outbreak of hemolytic uremic syndrome (HUS) occurred in northern Germany. Because, quite unusually, a large number of adults was affected and the causative Escherichia coli strain, serotype O104:H4, showed an atypical virulence factor pattern, it was speculated that this outbreak was associated with an aggressive course and an unfavorable prognosis also in children. METHODS Retrospective analysis of medical records of 90 children and comparison to previous outbreak and sporadic case series. RESULTS Median age was unusually high (11.5 years) compared with that in historical series. Only 1 patient (1.1%) died in the acute phase. Most patients (67/90 [74%]) received supportive care only. Renal replacement therapy was required in 64 of 90 (71%) of the children. Neurological complications, mainly seizures and altered mental stage, were present in 23 of 90 (26%) patients. Ten patients received plasmapheresis, 6 eculizumab, and 7 a combination of both. After a median follow-up of 4 months, renal function normalized in 85 of 90 (94%) patients, whereas 3 patients had chronic kidney disease stage 3 or 4, and 1 patient (1.1%) still requires dialysis. Complete neurological recovery occurred in 18 of 23 patients. Mild to moderate and major residual neurological changes were present in 3 patients and 1 patient, respectively, although all patients were still improving. CONCLUSIONS E. coli O104:H4 caused the largest HUS outbreak in children reported in detail to date and most patients received supportive treatment only. Initial morbidity, as well as short-term outcome, due to this pathogen, is comparable to previous pediatric series of Shiga toxin-producing E. coli HUS.

Pediatric kidney transplantation followed by de novo therapy with everolimus, low-dose cyclosporine A, and steroid elimination: 3-year data.

Background. Acute rejections and infections continue to cause substantial problems for pediatric kidney transplant (KTX) patients because defining an immunosuppressive protocol capable of preventing both has been challenging. Previously, we initiated a prospective trial to evaluate an immunosuppressive regimen designed to achieve this goal. Herein, we present the results of the 3-year follow-up of this trial. Methods. After KTX, 20 children (median age 12 years, range 1–17 years) received basiliximab, cyclosporine A (CsA) (trough-level=C0 200–250 ng/mL), and prednisolone. Two weeks post-KTX, everolimus (1.6 mg/m2/day) treatment was started (C0 4–6 ng/mL), and the CsA dose was reduced by 50% (C0 75–100 ng/mL, after 6 months: C0 50–75 ng/mL). Prednisolone treatment was gradually withdrawn and was completely stopped at 9 months post-KTX. Results. There was no loss of follow-up and no graft or patient loss during the 3-year period. Indication biopsies showed no acute rejection (Banff ≥IA). One of the patients had signs of chronic humoral rejection. Mean glomerular filtration rate measured at 1 year and 3 years post-KTX was 71±25 and 61±27 mL/min/1.73 m2, respectively. In patients transitioned to adult care, mean glomerular filtration rate at 3 years was 49±13 mL/min/1.73 m2 (P<0.05). No cases of posttransplant lymphoproliferative disorder posttransplant lymphoproliferative disorder or polyoma nephropathy were diagnosed. After 3 years, 17 of 20 patients remained on the original immunosuppressive regimen. Conclusions. A treatment regimen consisting of de novo immunosuppression with basiliximab, CsA, and prednisolone, followed by treatment with everolimus and low-dose CsA combined with steroid withdrawal may be a promising therapy after pediatric KTX.

Reversal of loss of glomerular filtration rate in children with transplant nephropathy after switch to everolimus and low‐dose cyclosporine A

Abstract:   Until now there have been no good therapeutic options in children with biopsy‐proven transplant nephropathy (TN) and loss of glomerular filtration rate (GFR) while receiving cyclosporine A (CsA), mycophenolate mofetil (MMF) and prednisolone (Pred). In 13 kidney transplanted children (mean age 13 yr, SD 4) with CsA/MMF/Pred immunosuppression, renal biopsy revealed significant TN. MMF was discontinued, CsA dose was reduced to 50% and Everolimus was started (1.6 mg/m2/day). Pred was stopped in 10 of 13 patients. The mean GFR was 55 mL/min/1.73 m2 (SD 24) one yr before switch, 45 mL/min/1.73 m2 (SD 16, p < 0.05) at the time of switch and 47 mL/min/1.73 m2 (SD 18, p < 0.05) 12 months later. There were no severe side‐effects or acute rejections. Lactate dehydrogenase, cholesterol, creatine kinase, and U‐albumin/creatinine ratio did not increase significantly. After six months, the mean certican‐C0 level was 4.0 μg/L (SD 1.5) and mean CsA‐C0 level was 52 ng/mL (SD 23). The GFR of transplanted kidneys in children with TN improved by changing immunosuppression from CsA/MMF/Pred to everolimus and low‐dose CsA.

Protocol biopsy‐driven interventions after pediatric renal transplantation

Kanzelmeyer NK, Ahlenstiel T, Drube J, Froede K, Kreuzer M, Broecker V, Ehrich JHH, Melk A, Pape L. Protocol biopsy‐driven interventions after pediatric renal transplantation.
Pediatr Transplantation 2010: 14:1012–1018

Different models of transition to adult care after pediatric kidney transplantation: a comparative study.

Transition from pediatric to adult care is a critical and difficult step for young people with transplants and for the multidisciplinary team involved. In our retrospective study, we investigated the clinical course in a two‐yr period of transition. Data from 66 teenagers were collected one yr before and after their transfer to three different adult care settings: (i) a specialized transition clinic, (ii) a general transplantation clinic, and (iii) a nephrologist. Patient survival rate was 100%. Three patients developed graft loss. GFR development was comparable in the three settings (ΔGFR 1.4 ± 8.7 vs. 3.1 ± 10.6 vs. 0.8 ± 4.4 mL/min/1.73 m2, p = ns). Immunosuppressive therapy was stable in setting 1, whereas the number of changes increased in setting 2 and even more in setting 3. The percentage of patients with steroids increased from 36% to 38% and 52% in settings 1–3. Patient satisfaction was highest in setting 1 (100% vs. 64% and 78%, p < 0.05). Setting 1 was associated with fewer changes in therapy (13% vs. 91% and 45%, p < 0.05). The use of a specialized transition clinic is associated with fewer changes in medication and care and a higher level of patient satisfaction. This was not associated with a lower increase in GFR one yr after transition. Long‐term results are awaited.

Improved gastrointestinal symptom burden after conversion from mycophenolate mofetil to enteric‐coated mycophenolate sodium in kidney transplanted children

Abstract:  It has been shown in adult kidney transplant recipients that a conversion from MMF to EC‐MPS significantly reduced the GI related symptom burden. No such study exists on children with GI problems while receiving MMF therapy. Ten paediatric kidney transplant recipients (mean age 14.5 yr, s.d. 4.5) receiving triple immunosuppression (Cyclosporin A or Tacrolimus + MMF + Prednisolone) with severe GI symptoms were converted to an equimolar dose of EC‐MPS. The GSRS was completed before and at four wk after the switch, and GFR was determined for a mean period of six months. Values were compared by the paired t‐test. Mean GSRS improved significantly after the switch to EC‐MPS in all but one patient, from 2.1 (s.d. 0.9) to 1.1 (s.d. 0.6). The differences could be found in all four subscales. Graft function did not change after conversion to EC‐MPS. In children with moderate or severe GI symptoms while receiving MMF, conversion to EC‐MPS led to significantly reduced GI symptoms.

mTOR inhibitors in pediatric kidney transplantation

The mammalian target of the rapamycin (mTOR) inhibitors sirolimus and everolimus are increasingly being used in pediatric kidney transplantation in different combinations and doses. Several studies have shown beneficial effects of using mTOR inhibitors in children after pediatric renal transplantation. A switch to a low-dose calcineurin inhibitor (CNI) and mTOR inhibitor has been proven to stabilize the glomerular filtration rate. Additionally, de novo studies using a low-dose CNI and an mTOR inhibitor have shown good graft survival and a low number of rejections. Side effects of mTOR inhibitors, such as hyperlipidemia, wound healing problems, and proteinuria, mainly occur if high doses are given and if treatment is not combined with a CNI. Lower doses of mTOR inhibitors do not result in growth impairment or reduced testosterone levels. Treatment with mTOR inhibitors is also associated with a lower number of viral infections, especially cytomegalovirus. Due to their antiproliferative effect, mTOR inhibitors could theoretically reduce the risk of post-transplant lymphoproliferative disease. mTOR inhibitors, especially in combination with low-dose CNIs, can safely be used in children after kidney transplantation as de novo therapy or for conversion from CNI- and mycophenolate mofetil-based regimens.

ABO-incompatible kidney transplantation of an 8-yr-old girl with donor/recipient-constellation A1B/B

Abstract: Background: Antigen‐specific immunoadsorption combined with rituximab offers the possibility for ABO‐incompatible kidney transplantation without splenectomy.

Longitudinal growth on an everolimus- versus an MMF-based steroid-free immunosuppressive regimen in paediatric renal transplant recipients

Concerns have been raised that mammalian target of rapamycin inhibitors in pediatric transplant recipients might interfere with longitudinal bone growth by inhibition of growth factor signaling and growth plate chondrocyte proliferation. We therefore undertook a prospective nested, case‐control study on longitudinal growth over 2 years in steroid‐free pediatric renal transplant recipients. Fourteen patients on a steroid‐free maintenance immunosuppressive regimen consisting of low‐dose everolimus (EVR) in conjunction with low‐dose cyclosporine (CsA) were compared to a matched cohort of 14 steroid‐free patients on a standard dose mycophenolate mofetil (MMF) regimen in conjunction with a standard dose calcineurin inhibitor (CNI). The mean change in height standard deviation (SD) score in the first study year was 0.31 ± 0.71 SD score in the EVR group compared to 0.31 ± 0.64 SD score in the MMF group (P = 0.20). For the entire study period of 2 years, the change in height SD score in the EVR group was 0.43 ± 0.81 SDS compared to 0.75 ± 0.85 SDS in the MMF group (P = 0.32). The percentage of prepubertal patients experiencing catch‐up growth, defined as an increase in height SD score ≥0.5 in 2 years, was similar in the EVR group (5/8, 65%) and the MMF group (6/8, 75%; P = 1.00). Longitudinal growth over 2 years in steroid‐free pediatric patients on low‐dose EVR and CsA is not different to that of a matched steroid‐free control group on an immunosuppressive regimen with standard‐dose CNI and MMF. Hence, low‐dose EVR does not appear to negatively impact short‐term growth in pediatric renal transplant recipients.

Glomerular mRNA expression of prothrombotic and antithrombotic factors in renal transplants with thrombotic microangiopathy.

Background Thrombotic microangiopathy (TMA) in renal transplants (rTx-TMA) is a serious complication and is usually either recurrent TMA (RecTMA) due to humoral rejection (HR-TMA) or due to calcineurin inhibitor toxicity (CNI-TMA). Although the triggers are known, our knowledge about the thrombogenic transcriptome changes in the microvessels is rudimentary. Methods We examined the expression of several prothrombotic and antithrombotic genes in 25 biopsies with rTx-TMA (6 RecTMA, 9 HR-TMA, and 10 CNI-TMA) and 8 controls. RNA from microdissected glomeruli of paraffin-embedded tissue was isolated and mRNA transcripts were quantified with real-time polymerase chain reaction after preamplification. Results were correlated with clinicopathologic parameters. Results Glomerular mRNA expression of KLF2, KLF4, and tPA was lower and that of PAI-1 was higher in rTx-TMA than in the controls. Glomerular mRNA expression of KLF2 and KLF4 correlated with that of tPA and inversely with that of PAI-1 in rTx-TMA. The mRNA expression of complement regulators CD46 and CD59 were higher in rTx-TMA than in the controls. Only in HR-TMA were glomerular ADAMTS13 and CD55 down-regulated. Conclusions The glomerular capillary bed seems to contribute to all subtypes of rTx-TMA by down-regulation of the endothelial transcription factors KLF2 and KLF4, indicating dedifferentiation with subsequent up-regulation of PAI-1 and down-regulation of tPA, resulting in inhibition of local fibrinolysis. Decreased glomerular expression of ADAMTS13 and CD55 could be an additional pathway toward microthrombosis exclusively in HR-TMA.