Aim We present a paediatric case of successful treatment of an early relapse of atypical haemolytic uraemic (aHUS) syndrome following ABO incompatible (ABOi) living related renal transplant using eculizumab. The female patient presented at 3.8 years of age with clinical aHUS confirmed genetically as complement factor I mutation (heterozygous for CFI c.1216C >T,p.(Arg406Cys) in patient (who had Factor H antibodies) and asymptomatic mother. She was initially treated with forty plasma exchange sessions. Four months after presentation, she commenced peritoneal dialysis converted to home haemodialysis. At 8.8 years of age, a deceased donation after cardiac death en bloc renal transplant failed to perfuse and was removed at the time of transplantation. Methods Prospective case study of paper and electronic records. Results She received an ABOi live related kidney transplant from father at 9.3 years using quadruple immunosuppression (basiliximab, mycophenolate mofetil, tacrolimus, corticosteroids) with B lymphocyte depletion (intravenous rituximab 375 mg/m one month pre-transplantation) with 0% calculated reaction frequency. Recipient and donor (father) blood groups were O and A respectively with anti-A titres of 1 in 128 pre-transplantation. Four sessions of immunoadsorption reduced anti-A titres to 1 in 4 at time of transplant. Six hours post-transplant, she received the first dose of intravenous eculizumab 600 mg as she showed signs of recurrence of aHUS with allograft dysfunction, LDH 1291 U/l, haemoglobin of 83 g/l and thrombocytopenia at 109 × 109/l. LDH rose to maximum value of 3334 U/l on day 2 post transplant with ongoing anaemia and thrombocytopenia (49 g/l and 82 × 109/l respectively) with a second dose of eculizumab administered with good clinical response: reduction in LDH and normalisation of Hb and platelets. Renal allograft function improved at 8 days post-transplant and she continues on regular eculizumab infusions with histopathological evidence of thrombotic microangiopathy. Six weeks post transplant, renal function has stabilised with plasma creatinine of 75–93 μmol/l (eGFR of 45–55 mls/min/1.73 m2), EBV reactivation, BK viraemia, normalisation of LDH 486 U/l, Hb 120 g/l and platelets 353 × 109/l; negative anti-A titres and HLA antibodies Conclusions This is the first report of a paediatric ABOi living related renal transplantation in whom early relapse of a HUS was successfully treated with eculizumab.

In chronic kidney disease (CKD) vascular calcification occurs in response to deranged calcium and phosphate metabolism and is characterized by vascular smooth muscle cell (VSMC) damage and attrition. To gain mechanistic insights into how calcium and phosphate mediate calcification, we used an ex vivo model of human vessel culture. Vessel rings from healthy control subjects did not accumulate calcium with long-term exposure to elevated calcium and/or phosphate. In contrast, vessel rings from patients with CKD accumulated calcium; calcium induced calcification more potently than phosphate (at equivalent calcium-phosphate product). Elevated phosphate increased alkaline phosphatase activity in CKD vessels, but inhibition of alkaline phosphatase with levamisole did not block calcification. Instead, calcification in CKD vessels most strongly associated with VSMC death resulting from calcium- and phosphate-induced apoptosis; treatment with a pan-caspase inhibitor ZVAD ameliorated calcification. Calcification in CKD vessels was also associated with increased deposition of VSMC-derived vesicles. Electron microscopy confirmed increased deposition of vesicles containing crystalline calcium and phosphate in the extracellular matrix of dialysis vessel rings. In contrast, vesicle deposition and calcification did not occur in normal vessel rings, but we observed extensive intracellular mitochondrial damage. Taken together, these data provide evidence that VSMCs undergo adaptive changes, including vesicle release, in response to dysregulated mineral metabolism. These adaptations may initially promote survival but ultimately culminate in VSMC apoptosis and overt calcification, especially with continued exposure to elevated calcium.

Factor H (CFH) autoantibodies are associated with atypical hemolytic uremic syndrome (aHUS). Peritransplantation plasma exchange therapy and intensification of immunosuppression, with adjuvant use of anti-CD20 monoclonal antibodies has recently been advocated for cases of CFH-autoantibody associated aHUS. In this report, we describe successful deceased donor renal transplantation in a case of CFH-autoantibody associated aHUS with combined CFHR1 and 3 deficiency in addition to the CFH sequence variant, (cG2850T, pGln950His). CFH-autoantibodies were detected 2 weeks prior to transplantation. Disease recurrence was not observed using basiliximab, an IL2-receptor antagonist and high-dose corticosteroids with mycophenolate mofetil. Adjuvant therapies such as Rituximab nor intensification of plasma therapy were employed. Consequently, careful consideration needs to be given to the use of additional immunosuppression in certain cases of CFH-autoantibody associated aHUS. Serial measurement of CFH-autoantibodies is required in the immediate pre- and posttransplantation period to further clarify their role as a factor in the recurrence of aHUS posttransplantation. Furthermore, delineation of the functional significance of CFH-autoantibodies is warranted in individual cases.

Mutations in hepatocyte nuclear factor 1B (HNF1B), which is a transcription factor expressed in tissues including renal epithelia, associate with abnormal renal development. While studying renal phenotypes of children with HNF1B mutations, we identified a teenager who presented with tetany and hypomagnesemia. We retrospectively reviewed radiographic and laboratory data for all patients from a single center who had been screened for an HNF1B mutation. We found heterozygous mutations in 21 (23%) of 91 cases of renal malformation. All mutation carriers had abnormal fetal renal ultrasonography. Plasma magnesium levels were available for 66 patients with chronic kidney disease (stages 1 to 3). Striking, 44% (eight of 18) of mutation carriers had hypomagnesemia (<1.58 mg/dl) compared with 2% (one of 48) of those without mutations (P < 0.0001). The median plasma magnesium was significantly lower among mutation carriers than those without mutations (1.68 versus 2.02 mg/dl; P < 0.0001). Because hypermagnesuria and hypocalciuria accompanied the hypomagnesemia, we analyzed genes associated with hypermagnesuria and detected highly conserved HNF1 recognition sites in FXYD2, a gene that can cause autosomal dominant hypomagnesemia and hypocalciuria when mutated. Using a luciferase reporter assay, we demonstrated HNF1B-mediated transactivation of FXYD2. These results extend the phenotype of HNF1B mutations to include hypomagnesemia. HNF1B regulates transcription of FXYD2, which participates in the tubular handling of Mg(2+), thus describing a role for HNF1B not only in nephrogenesis but also in the maintenance of tubular function.

42nd Annual Scientific Meeting of the European Society for Paediatric Nephrology A Joint Meeting with the Renal Association 2-5 September 2009, University of Birmingham, UK Pediatr Nephrol (2009) 24:1777–1899 DOI 10.1007/s00467-009-1250-6

The aim of this study was to determine whether CNIs can be safely withdrawn in paediatric patients with declining renal allograft function receiving MMF and corticosteroids for long-term immunosuppression following renal transplantation. We performed a retrospective review of paediatric renal transplant recipients who received MMF with corticosteroids at least three months after transplantation with or without CNI in a single centre. Thirty-eight children (71% male), mean age 7.2 +/- 3.7 yr received MMF and corticosteroids, with 29 (76%) receiving a CNI. Mean follow-up was 59.2 +/- 42 months post-MMF commencement and 109 +/- 98.8 months post-transplantation. Patient and renal allograft survival were 100% and 94%, respectively. There was a significant improvement in eGFR after MMF introduction both in children on a CNI and those where the CNI was withdrawn, with stabilisation of eGFR after two yr. There was no significant difference in the number of acute rejection episodes prior to or following introduction of MMF between the groups. MMF in combination with corticosteroids is a safe and effective immunosuppressive regimen in paediatric renal transplantation. Complete withdrawal of CNIs after conversion to MMF should be considered in all patients, to preserve renal function as evidenced by improved eGFR.