Mary Waldron

C3 Glomerulopathy: Clinicopathologic Features and Predictors of Outcome

BACKGROUND AND OBJECTIVES The term C3 glomerulopathy describes renal disorders characterized by the presence of glomerular deposits composed of C3 in the absence of significant amounts of Ig. On the basis of electron microscopy appearance, subsets of C3 glomerulopathy include dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The full spectrum of histologic change observed in C3 glomerulopathy has yet to be defined and pathologic predictors of renal outcome within this patient population remain largely unknown. This study thus characterized a large C3 glomerulopathy cohort and identified clinicopathologic predictors of renal outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS All patients with kidney biopsies fulfilling criteria for C3 glomerulopathy from two quaternary renal centers within the United Kingdom and Ireland between 1992 and 2012 were retrospectively reviewed. We recorded histologic, demographic, and clinical data and determined predictors of ESRD using the Cox proportional hazards model. RESULTS Eighty patients with C3 glomerulopathy were identified: 21 with DDD and 59 with C3GN. Patients with DDD were younger, more likely to have low serum C3 levels, and more likely to have crescentic GN than patients with C3GN. Patients with C3GN were older and had more severe arteriolar sclerosis, glomerular sclerosis, and interstitial scarring than patients with DDD. Of 70 patients with available follow-up data, 20 (29%) progressed to ESRD after a median of 28 months. Age >16 years, DDD subtype, and crescentic GN were independent predictors of ESRD within the entire cohort. Renal impairment at presentation predicted ESRD only among patients with DDD. CONCLUSIONS Although detailed serologic and genetic data are lacking, this study nevertheless identifies important clinicopathologic distinctions between patients with DDD and C3GN. These include independent predictors of renal outcome. If replicated in other cohorts, these predictors could be used to stratify patients, enabling application of emerging mechanism-based therapies to patients at high risk for poor renal outcome.

A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome

Genomic disorders affecting the genes encoding factor H (fH) and the 5 factor H related proteins have been described in association with atypical hemolytic uremic syndrome. These include deletions of CFHR3, CFHR1, and CFHR4 in association with fH autoantibodies and the formation of a hybrid CFH/CFHR1 gene. These occur through nonallelic homologous recombination secondary to the presence of large segmental duplications (macrohomology) in this region. Using multiplex ligation-dependent probe amplification to screen for such genomic disorders, we have identified a large atypical hemolytic uremic syndrome family where a deletion has occurred through microhomology-mediated end joining rather than nonallelic homologous recombination. In the 3 affected persons of this family, we have shown that the deletion results in formation of a CFH/CFHR3 gene. We have shown that the protein product of this is a 24 SCR protein that is secreted with normal fluid-phase activity but marked loss of complement regulation at cell surfaces despite increased heparin binding. In this study, we have therefore shown that microhomology in this area of chromosome 1 predisposes to disease associated genomic disorders and that the complement regulatory function of fH at the cell surface is critically dependent on the structural integrity of the whole molecule.

Case Report: Benefits and Challenges of Long-term Eculizumab in Atypical Hemolytic Uremic Syndrome

Atypical hemolytic uremic syndrome (aHUS) is caused by dysregulation of the complement system, leading to complement overactivation. A humanized anti-C5 monoclonal antibody, eculizumab, has been available for the treatment of aHUS since 2011. The long-term safety and efficacy of this novel drug in the pediatric population remain under review. We present a child with a hybrid CFH/CFHR3 gene who, having had multiple disease relapses despite optimal treatment with plasma exchange, commenced eculizumab therapy in August 2010. She remains relapse free in follow-up at 52 months, and treatment has been well tolerated. The risk of meningococcal disease during this treatment is recognized. Despite vaccination against meningococcal disease and appropriate antibiotic prophylaxis, our patient developed meningococcal bacteremia 30 months into treatment. She presented with nonspecific symptoms but recovered without sequelae with appropriate treatment. We recommend that children be vaccinated against invasive meningococcal infection before beginning eculizumab therapy and take appropriate antibiotic prophylaxis during treatment, and we suggest that vaccine responses should be checked and followed annually. Clinicians need to maintain a high index of suspicion for invasive meningococcal disease. Neither vaccination nor antibiotic prophylaxis provides complete protection in patients on eculizumab therapy. The appropriate dosage of eculizumab needed to achieve remission in aHUS in the pediatric population is unknown. Having achieved remission in our patient, we monitor eculizumab and CH50 levels to evaluate ongoing blockade of the terminal complement cascade. Such information may help guide dosing intervals in the future.

A De Novo Deletion in the Regulators of Complement Activation Cluster Producing a Hybrid Complement Factor H/Complement Factor H–Related 3 Gene in Atypical Hemolytic Uremic Syndrome

The regulators of complement activation cluster at chromosome 1q32 contains the complement factor H (CFH) and five complement factor H-related (CFHR) genes. This area of the genome arose from several large genomic duplications, and these low-copy repeats can cause genome instability in this region. Genomic disorders affecting these genes have been described in atypical hemolytic uremic syndrome, arising commonly through nonallelic homologous recombination. We describe a novel CFH/CFHR3 hybrid gene secondary to a de novo 6.3-kb deletion that arose through microhomology-mediated end joining rather than nonallelic homologous recombination. We confirmed a transcript from this hybrid gene and showed a secreted protein product that lacks the recognition domain of factor H and exhibits impaired cell surface complement regulation. The fact that the formation of this hybrid gene arose as a de novo event suggests that this cluster is a dynamic area of the genome in which additional genomic disorders may arise.

Broadening the phenotype associated with mutations in UPF3B: Two further cases with renal dysplasia and variable developmental delay

We present two brothers with mutations in UPF3B, an X-linked intellectual disability gene. Our family consists of two affected brothers and a carrier mother. Both affected brothers had renal dysplasia. A maternal uncle died from a congenital heart defect at 4 months. The two boys had variable degrees of developmental delay. One had macrocephaly, significant expressive speech delay and constipation. The other brother had normocephaly, obsessional tendencies and was diagnosed with high functioning autism. The phenotypically normal mother had 100% skewed X-inactivation. Our cases expand the phenotype seen with UPF3B mutations and highlight the variability within families.

Cyanide poisoning in the post-transplantation patient—a cautionary tale

There have been few reported cases of cyanide toxicity following treatment with sodium nitroprusside. We report on the case of a paediatric patient who had received sodium nitroprusside for intractable hypertension in the post-operative period, resulting in cyanide toxicity. Treatment with sodium thiosulphate, sodium nitrate and haemodialysis resulted in the elimination of cyanide from the circulation. The patient made a full recovery with no neurological sequelae.

Tinzaparin is safe and effective in the management of hemodialysis catheter thrombosis.

Children on hemodialysis are at increased risk of thrombosis, especially when dialyzed via a central venous catheter (CVC); there are limited published data regarding the safety and efficacy of tinzaparin in this group. We conducted a retrospective chart review of all children in the National Pediatric Hemodialysis Centre for Ireland diagnosed with a CVC thrombus and treated with subcutaneous tinzaparin over a 10 year period. Seven children were treated with subcutaneous tinzaparin for 10 CVC thrombi. Tinzaparin was commenced at 175 IU/kg/day and the dose was titrated by measuring anti-factor Xa levels, aiming for levels of 0.3–1.0 IU/ml. Treatment was continued until resolution of the CVC thrombus. Restoration of normal flows during dialysis occurred within 3 days in all patients. There were no episodes of bleeding and all children tolerated the treatment well.

Pediatric Renal Transplantation in a Highly Sensitised Child—8 Years On

Highly sensitised children have markedly reduced chances of receiving a successful deceased donor renal transplant, increased risk of rejection, and decreased graft survival. There is limited experience with the long-term followup of children who have undergone desensitization. Following 2 failed transplants, our patient was highly sensitised. She had some immunological response to intravenous immunoglobulin (IVIg) but this was not sustained. We developed a protocol involving sequential therapies with rituximab, IVIg, and plasma exchange. Immunosuppressant therapy at transplantation consisted of basiliximab, tacrolimus, mycophenolate mofetil, and steroids. At the time of transplantation, historical crossmatch was ignored. Current CDC crossmatch was negative, but T and B cell flow crossmatch was positive, due to donor-specific HLA Class I antibodies. Further plasma exchange and immunoglobulin therapy were given pre- and postoperatively. Our patient received a deceased donor-kidney-bearing HLA antigens to which she originally had antibodies, which would have precluded transplant. The graft kidney continues to function well 8 years posttransplant.

Clinical Relapses of Atypical HUS on Eculizumab: Clinical Gap for Monitoring and Individualised Therapy

Atypical hemolytic uremic syndrome (aHUS) is caused by dysregulation of the complement system. A humanised anti-C5 monoclonal antibody (eculizumab) is available for the treatment of aHUS. We present the first description of atypical HUS in a child with a coexistent diagnosis of a POL-III leukodystrophy. On standard eculizumab dosing regime, there was evidence of ongoing C5 cleavage and clinical relapses when immunologically challenged. Eculizumab is an effective therapy for aHUS, but the recommended doses may not be adequate for all patients, highlighting the need for ongoing efforts to develop a strategy for monitoring of treatment efficacy and potential individualisation of therapy.

A rare cause of hypercalcemia: Answers

2) Sarcoidosis. His symptoms of polyuria and polydipsia result from decreased concentrating ability, which occurs secondary to any cause of hypercalcemia. 3) The patient had a raised serum angiotensin-converting enzyme level at 225 U/L and biopsy of one of the enlarged inguinal lymph nodes revealed multiple noncaseating epithelioid cell granulomata (Fig. 1a and b). 4) Initial saline hyperhydrationwith 0.9%NaCl and diuresis with frusemide failed to significantly reduce the total serum and ionized calcium levels over 48 h. Commencement of steroid treatment (prednisolone 2 mg/kg/day) led to a progressive fall in calcium levels; normalizing after 11 days of treatment.