Johannes Hofer

Extra-renal manifestations of complement-mediated thrombotic microangiopathies

Thrombotic microangiopathies (TMA) are rare but severe disorders, characterized by endothelial cell activation and thrombus formation leading to hemolytic anemia, thrombocytopenia, and organ failure. Complement over activation in combination with defects in its regulation is described in an increasing number of TMA and if primary for the disease denominated as atypical hemolytic-uremic syndrome. Although TMA predominantly affects the renal microvasculature, extra-renal manifestations are observed in 20% of patients including involvement of the central nerve system, cardiovascular system, lungs, skin, skeletal muscle, and gastrointestinal tract. Prompt diagnosis and treatment initiation are therefore crucial for the prognosis of disease acute phase and the long-term outcome. This review summarizes the available evidence on extra-renal TMA manifestations and discusses the role of acute and chronic complement activation by highlighting its complex interaction with inflammation, coagulation, and endothelial homeostasis.

Enterohemorrhagic Escherichia coli O26:H11-Associated Hemolytic Uremic Syndrome: Bacteriology and Clinical Presentation.

Infection by enterohemorrhagic ESCHERICHIA COLI (EHEC) is the most frequent cause of hemolytic uremic syndrome (HUS) in childhood. During a 6-year period, all patients with the clinical diagnosis of HUS were registered in a prospective multicenter study in Austria and Germany. EHEC O26:H11 was the second most frequent detected serotype, accounting for 15.4% of all EHEC isolates. The presence of EHEC O26:H11 was significantly associated with young age at the disease onset ( P < 0.001). Patients infected with this serotype were not different in their clinical presentation than those infected with other serotypes. This study underlines the importance of EHEC serotypes other than O157 in the etiology of HUS and emphasizes the importance of implementation of appropriate diagnostic methods to identify the whole spectrum of EHEC associated with HUS.

Complement factor H-antibody-associated hemolytic uremic syndrome: pathogenesis, clinical presentation, and treatment.

The presence of circulating autoantibodies, primarily to complement factor H antibodies (CFH-Abs) in plasma characterizes the autoimmune form of atypical hemolytic uremic syndrome (aHUS). This acquired form of aHUS defines a distinct subgroup of aHUS patients, which requires diagnostic and treatment approaches in part different from those of the genetically defined forms. The mechanisms leading to CFH-Ab production and disease onset are not completely understood, but CFH-Ab HUS seems to be secondary to a combination of genetic predisposition and environmental factors. Early diagnosis of this specific aHUS entity is important, as prompt induction of plasma exchange and concomitant immunosuppression leads to a favorable outcome. Nevertheless, information on clinical features and outcome in children is limited. Here, we review the literature on the biological and clinical features of CFH-Ab HUS and discuss therapeutic options.

Immunogenicity of meningococcus C vaccination in a patient with atypical hemolytic uremic syndrome (aHUS) on eculizumab therapy

Zlamy M, Hofer J, Elias J, Vogel U, Frosch M, Jungraithmayr T, Zimmerhackl LB, Prelog M. Immunogenicity of meningococcus C vaccination in a patient with atypical hemolytic uremic syndrome (aHUS) on eculizumab therapy. 
Pediatr Transplantation 2011.

Diagnosis and Treatment of the Hemolytic Uremic Syndrome Disease Spectrum in Developing Regions

There has been rapid progress in the understanding of the pathophysiology of the hemolytic uremic syndrome (HUS) disease spectrum; thus, complex diagnostic and therapeutic requirements have emerged in parallel. Current recommendations for diagnosis and therapy were rapidly adapted from the prior skilled scientific groundwork. However, such recommendations can be realized only when highly specialized laboratories and sufficient financial resources are available. Thus, many recommendations are not feasible for patients living and working in developing countries. More than one-third of the worlds population has no access to essential drugs and more than half of this group lives in the poorest regions of Africa and Asia. From this perspective, distinct initial diagnostic and therapeutic recommendations, as well as international cooperations are needed to complete proper diagnostic work-ups in a stringent and cost-efficient manner and to enable patients to be adequately treated with available resources. However, while costs for complement-targeted drugs remain tremendously high, state-of-the-art treatment options remain unavailable for the vast majority of patients in developing areas.

De novo tacrolimus-induced thrombotic microangiopathy in the early stage after renal transplantation successfully treated with conversion to everolimus

BackgroundCalcineurin inhibitor (CNI)-induced thrombotic microangiopathy (TMA) is a rare complication after renal transplantation. It may be difficult to distinguish from CNI toxicity and acute antibody-mediated rejection (AMR). Its clinical presentation may vary from isolated localised forms up to catastrophic systemic presentations.CaseWe report a case of tacrolimus-induced TMA soon after renal transplantation in an 11-year-old boy who received his second renal transplantation. His first graft was lost because of AMR. On day 12 after his second renal transplantation, his renal function started worsening and a kidney biopsy was performed, which showed histopathological signs of TMA. The diagnosis of tacrolimus-induced TMA was established after excluding AMR and other causes of de novo TMA. Genetic complement investigation disclosed two complement factor H risk polymorphisms as possible modifiers of TMA emergence. Treatment was based on replacing tacrolimus with everolimus, with a subsequent normalisation of renal function.ConclusionA prompt diagnosis of de novo TMA by early allograft biopsy is essential for the allograft outcome and genetic investigations for possible complement abnormalities are reasonable, not only for patients with a systemic aspect of their post-transplant TMA. Replacing tacrolimus with everolimus effectively controlled the TMA and stabilised renal function in our patient.

Favorable four‐yr outcome after renal transplantation in a patient with complement factor H antibody and CFHR1/CFHR3 gene mutation‐associated HUS

aHUS is a clinical challenge for successful renal transplantation. Case report: A 14‐yr‐old girl lost her kidneys at the age of 7, due to CFH antibodies and CFH‐related protein (CFHR1/CFHR3) homozygous deletion‐associated aHUS. CFH, CFI, and MCP gene mutations were excluded. The patient was a candidate for renal transplantation despite persistent presence of CFH antibodies (up to 539 AU/mL). Treatment with MMF, IVIG, and repeated PF (n = 8) was introduced while being placed on urgent waiting list. Three years after aHUS onset, the patient underwent the deceased donor renal transplantation “under cover” of PF, as PF was performed directly prior to surgery and, then, PFs were repeated up to overall 14 sessions. Quadruple immunosuppression (basiliximab + tacrolimus + MMF + prednisolone) was used. Moderate symptoms of aHUS (hemolysis, low platelets, and low C3) were present within first seven days post‐transplant and then normalized with PF therapy. The patient remained stable during four yr of further follow‐up after transplantation. Conclusion: Specific pre‐ and post‐transplant management allowed successful renal transplantation in a CFH antibody‐positive patient.

Successful living-related renal transplantation in a patient with factor H antibody-associated atypical hemolytic uremic syndrome.

CFH‐Ab‐associated aHUS requires different diagnostic and therapeutic approaches and then the genetically defined aHUS forms. The risk of post‐transplant recurrence with graft dysfunction in CFH‐Ab aHUS is not well documented. It is suggested that recurrence can be expected if a significant CFH‐Ab load persists at the time of transplantation. A pretransplant procedure to reduce CFH‐Ab titer seems reasonable, but accurate recommendations are lacking. Whether further prophylactic interventions after transplantation are necessary has to be decided on an individual basis. We report the case of a late diagnosed CFH‐Ab HUS with initial ESRD and a successful living‐related renal transplantation over a post‐transplant period of four and a half years on the basis of a prophylactic pretransplant IVIG admission.

Severe visual loss caused by unrecognized malignant hypertension in a 15‐year‐old girl

A 15‐year‐old girl presented with acute bilateral loss of central visual acuity due to hypertensive retinopathy level IV. She was found to have unrecognized malignant arterial hypertension associated with end‐stage renal failure. At the time of diagnosis she also had severe left ventricular hypertrophy (LVH). Hypertension was successfully treated with combined anti‐hypertensive therapy, but renal function did not recover. The patient underwent successful kidney transplant 4 months later and over a period of 20 months hypertensive retinopathy and LVH gradually resolved. This report emphasizes the importance of routine measurement of blood pressure and describes the possible consequences of unrecognized arterial hypertension in children. Early diagnosis and appropriate treatment are necessary to avoid development and progression of target organ damage and promote better long‐term cardiovascular prognosis.

Therapeutic plasma exchange in children: One center's experience

Therapeutic plasma exchange (TPE) has evolved to an accepted therapy for selected indications. However, it is technically challenging in children. Moreover, data on safety and efficacy are mainly derived from adult series. The aim of this study was to review the procedure in the context of clinical indications, effectiveness, and safety.