Case Report: Early acute kidney failure in an 11-year-old boy with Dent disease type 1

Dent disease type 1 (Dent 1) is a rare X-linked genetic condition which impacts kidney function and is caused by pathogenic variants in CLCN5. Affected males typically develop low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and other symptoms. Kidney failure often occurs between the third to fifth decade of life. Here, we report an 11-year-old boy with Dent 1 and a severe kidney disease phenotype. The patient presented with flank pain, nocturnal enuresis, foamy urine, and increased urinary frequency. He was found to have nephrotic-range proteinuria, without hypoalbuminemia, and a significantly decreased estimated glomerular filtration rate at presentation. Further, he did not have hypercalciuria. His family history was remarkable for kidney disease among several relatives including a maternal half-brother and two sons of a maternal great aunt. Due to his symptoms and a strong family history, the patient underwent genetic testing that detected a novel pathogenic variant in CLCN5 [c.791dup (p.Ser265Glnfs*3)]. Given the variability of symptoms among family members and the early onset of severe symptoms in this young patient compared to prior literature, we encourage genetic testing for Dent disease in similarly affected individuals

Pediatric Immunization Practices in Nephrotic Syndrome: An Assessment of Provider and Parental Knowledge

Background: Children with nephrotic syndrome (NS) are at high risk for vaccine-preventable infections due to the immunological effects from the disease and concurrent treatment with immunosuppressive medications. Immunizations in these patients may be deferred due to their immunosuppressive treatment which may increase the risk for vaccine-preventable infections. Immunization practices in children with NS continue to vary among pediatric nephrologists. This raises the question of whether children with NS are receiving the recommended vaccinations at appropriate times. Therefore, it is critical to understand the practices and patient education provided by physicians to patients on the topic of vaccinations. Methods: After informed consent, parents/guardians of 153 pediatric patients (\u3c18 years old) diagnosed with NS from 2005 to 2018 and 50 pediatric nephrologists from 11 participating centers completed anonymous surveys to evaluate immunization practices among pediatric nephrologists, assess the vaccine education provided to families of children with NS, assess the parental knowledge of immunization recommendations, and assess predictors of polysaccharide pneumococcal vaccine adherence. The Advisory Committee on Immunization Practices (ACIP) Immunization 2019 Guideline for those with altered immunocompetence was used to determine accuracy of vaccine knowledge and practices. Results: Forty-four percent of providers self-reported adherence to the ACIP guidelines for inactive vaccines and 22% to the guidelines for live vaccines. Thirty-two percent of parents/guardians reported knowledge that aligned with the ACIP guidelines for inactive vaccines and 1% for live vaccines. Subjects residing in the Midwest and provider recommendations for vaccines were positive predictors of vaccine adherence (p \u3c 0.001 and p 0.02, respectively). Conclusions: Vaccine recommendation by medical providers is paramount in vaccine adherence among pediatric patients with NS. This study identifies potential educational opportunities for medical subspecialty providers and family caregivers about immunization recommendations for immunosuppressed patients

Eculizumab Is an Effective Treatment for Atypical Hemolytic Uremic Syndrome in Patients with or without Identified Genetic Complement Mutations or Complement Factor H Auto-Antibodies.

Abstract Abstract 2085 Introduction: Atypical hemolytic uremic syndrome (aHUS) is a rare chronic disorder characterized by persistent uncontrolled complement activation that results in life-threatening systemic thrombotic microangiopathy (TMA). In an estimated 50%–70% of patients (pts) with aHUS, uncontrolled complement activation can be attributed to identified genetic mutation(s) in complement regulatory factors and/or the presence of complement factor H auto-antibodies (CFH auto-Abs); newly identified complement mutations continue to be reported in the medical literature. For the 30%–50% of pts who currently have no identified genetic mutation/CFH auto-Abs, the overall risk of end-stage renal disease or death is high and similar to that observed in pts with known genetic mutation(s)/CFH auto-Abs, supporting the need for immediate management of disease in all aHUS pts regardless of mutation/CFH auto-Ab status. Eculizumab, an anti-C5 monoclonal antibody that inhibits terminal complement activation, is the only approved treatment for aHUS. Chronic eculizumab treatment has been proven to inhibit systemic TMA via terminal complement inhibition, improve renal function, and reduce or eliminate the need for plasma exchange/infusion (PE/PI) and dialysis. Furthermore, earlier eculizumab treatment has been associated with greater clinical improvement. The purpose of this analysis was to evaluate the relative efficacy of eculizumab in aHUS pts with or without identified genetic complement mutation(s)/CFH auto-Abs based on data from 3 clinical studies. Methods: This report summarizes a subgroup analysis of efficacy outcomes based on the presence or absence of identified genetic mutation(s)/CFH auto-Abs in 3 aHUS studies: 2 controlled, prospective studies (pts aged ≥12 y), and 1 retrospective study (pts aged &lt;18 y). Results: Across the 3 studies, 24%–41% of pts had no identified genetic complement mutation or detectable CFH auto-Abs. The efficacy of eculizumab was similar regardless of mutation/CFH auto-Ab status (Table). Conclusions: Across 3 studies investigating the efficacy of eculizumab treatment in aHUS pts, our analysis shows that improvements in hematologic, renal, and supportive care interventions (PE/PI, dialysis) outcomes were similar in pts with or without identified genetic complement mutation(s)/CFH auto-Abs. Given that (1) genetic testing often requires several months to complete, (2) uncontrolled complement activation places aHUS pts at risk of life-threatening systemic TMA events and organ damage, and (3) earlier intervention with eculizumab is associated with greater clinical improvement, we conclude that the results of this analysis provide a rationale for initiating eculizumab as first-line therapy at the time of clinical diagnosis of aHUS, without the availability of genetic testing results Disclosures: Goodship: Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Legendre:Alexion Pharmaceuticals: Speakers Bureau. Licht:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Muus:Alexion Pharmaceuticals.: Sat on advisory board of Alexion Pharmaceuticals. Other. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Loirat:Alexion Pharmaceuticals: Coordinator of Alexion trials of eculizumab in atypical HUS for France. Honoraria for conferences. Other. </jats:sec

Pediatric Immunization Practices in Nephrotic Syndrome: An Assessment of Provider and Parental Knowledge

Background:Children with nephrotic syndrome (NS) are at high risk for vaccine-preventable infections due to the immunological effects from the disease and concurrent treatment with immunosuppressive medications. Immunizations in these patients may be deferred due to their immunosuppressive treatment which may increase the risk for vaccine-preventable infections. Immunization practices in children with NS continue to vary among pediatric nephrologists. This raises the question of whether children with NS are receiving the recommended vaccinations at appropriate times. Therefore, it is critical to understand the practices and patient education provided by physicians to patients on the topic of vaccinations.Methods:After informed consent, parents/guardians of 153 pediatric patients (&amp;lt;18 years old) diagnosed with NS from 2005 to 2018 and 50 pediatric nephrologists from 11 participating centers completed anonymous surveys to evaluate immunization practices among pediatric nephrologists, assess the vaccine education provided to families of children with NS, assess the parental knowledge of immunization recommendations, and assess predictors of polysaccharide pneumococcal vaccine adherence. The Advisory Committee on Immunization Practices (ACIP) Immunization 2019 Guideline for those with altered immunocompetence was used to determine accuracy of vaccine knowledge and practices.Results:Forty-four percent of providers self-reported adherence to the ACIP guidelines for inactive vaccines and 22% to the guidelines for live vaccines. Thirty-two percent of parents/guardians reported knowledge that aligned with the ACIP guidelines for inactive vaccines and 1% for live vaccines. Subjects residing in the Midwest and provider recommendations for vaccines were positive predictors of vaccine adherence (p&amp;lt; 0.001 andp0.02, respectively).Conclusions:Vaccine recommendation by medical providers is paramount in vaccine adherence among pediatric patients with NS. This study identifies potential educational opportunities for medical subspecialty providers and family caregivers about immunization recommendations for immunosuppressed patients.</jats:p

Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome

Atypical hemolytic uremic syndrome (aHUS) is caused by alternative complement pathway dysregulation, leading to systemic thrombotic microangiopathy (TMA) and severe end-organ damage. Based on 2 prospective studies in mostly adults and retrospective data in children, eculizumab, a terminal complement inhibitor, is approved for aHUS treatment. Here we prospectively evaluated efficacy and safety of weight-based dosing of eculizumab in eligible pediatric patients with aHUS in an open-label phase II study. The primary end point was complete TMA response by 26 weeks. Twenty-two patients (aged 5 months–17 years) were treated; 16 were newly diagnosed, 12 had no prior plasma exchange/infusion during current TMA symptomatology, 11 received baseline dialysis, and 2 had prior renal transplants. By week 26, 14 achieved a complete TMA response, 18 achieved hematologic normalization, and 16 had 25% or better improvement in serum creatinine. Plasma exchange/infusion was discontinued in all, and 9 of the 11 patients who required dialysis at baseline discontinued, whereas none initiated new dialysis. Eculizumab was well tolerated; no deaths or meningococcal infections occurred. Bone marrow failure, wrist fracture, and acute respiratory failure were reported as unrelated severe adverse events. Thus, our findings establish the efficacy and safety of eculizumab for pediatric patients with aHUS and are consistent with proposed immediate eculizumab initiation following diagnosis in children

Eculizumab Inhibits Thrombotic Microangiopathy and Improves Renal Function in Pediatric Patients with Atypical Hemolytic Uremic Syndrome: 1-Year Update

Abstract Introduction: Atypical hemolytic uremic syndrome (aHUS) is a progressive, life-threatening disease of uncontrolled and chronic complement activation, leading to systemic thrombotic microangiopathy (TMA) and severe end-organ damage. Prior to an effective pharmacologic treatment, and despite intensive management with plasma exchange/plasma infusion, up to 25% of children died during the initial presentation, and up to 48% reached end-stage renal disease or died 5 years after disease onset. In a prospective study of children and adolescents with aHUS, eculizumab (ECU), a terminal complement inhibitor, was shown to inhibit TMA and improve hematologic outcomes and renal function by 26 weeks. Here, we report 1-year data from this prospective trial. Methods: This was an open-label, single-arm, Phase 2 trial of ECU in pediatric patients (pts) with aHUS. Inclusion criteria included platelet count less than the lower limit of normal (LLN) at screening and at baseline (BL), lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal (ULN) at the start of the current manifestation, and elevated serum creatinine (SCr) at screening. An identified complement abnormality was not required. Pts with STEC-HUS (Shiga toxin + E. coli) or severe ADAMTS13 deficiency (&lt;5%) were excluded. The primary endpoint was the proportion of pts who achieved complete TMA response, defined as hematologic normalization (platelet count ≥150x109/L; LDH ≤ULN), and improvement of renal function (≥25% decrease in SCr from BL, confirmed by ≥2 consecutive measurements obtained ≥4 weeks apart). Dosing was based on weight cohorts, and the regimen was designed with investigators and regulatory agencies to ensure that ≥95% of pts had complete and sustained terminal complement inhibition (defined as &gt;80% inhibition in a hemolytic assay), including in times of increased complement activity (eg, infection or surgery). Results: 22 pts (aged 1 month to 17 years) were enrolled and 19 completed 26 weeks of treatment. The median time from the current manifestation to enrollment was 0.20 months (range, 0.03–4.26). At the 1-year update, the mean (SD) treatment duration was 12.5 (6.38) months, with a median (range) of 12.6 (0.0–24.5) months. At week 26, 14 pts (64%) achieved the primary endpoint of complete TMA response (Table), and that number increased to 15 (68%) at 1 year. Platelet levels (Fig 1) and estimated glomerular filtration rate (eGFR) (Fig 2) increased significantly from BL through the 26-week study period, and those gains were maintained or further improved at 1 year. Nine of 11 pts (82%) on dialysis at BL discontinued dialysis, and all remained dialysis-free at 1 year. 11 pts not on dialysis at BL also remained dialysis-free at 1 year. Quality of life significantly improved. ECU was well tolerated and there were no meningococcal infections or deaths. Conclusions: Longer-term analysis at 1 year further demonstrates the safety and efficacy of ongoing ECU therapy in pediatric aHUS pts. It is interesting to note that renal function, as represented by eGFR, further increased between weeks 26 and 1 year: this highlights the need to pursue ECU treatment over the long term. These findings show that treatment with ECU results in life-altering outcomes, in stark contrast to the natural history of the disease. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Greenbaum: Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ardissino:Alexion Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Al-Akash:Alexion Pharmaceuticals: Honoraria, Speakers Bureau. Lieberman:Alexion Pharmaceuticals: Honoraria, Speakers Bureau; Questcor: Honoraria, Speakers Bureau. Rees:Alexion Pharmaceuticals: Honoraria. van de Kar:Alexion Pharmaceuticals: Member of International Advisory Board of aHUS Other. Vande Walle:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ogawa:Alexion Pharmaceuticals: Employment. Bedrosian:Alexion Pharmceuticals: Employment. Licht:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Achillon Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. </jats:sec