Theresa Kwon

Acute Neurological Involvement in Diarrhea-Associated Hemolytic Uremic Syndrome

BACKGROUND AND OBJECTIVES Neurologic involvement is the most threatening complication of diarrhea-associated hemolytic uremic syndrome (D+HUS). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We report a retrospective multicenter series of 52 patients with severe initial neurologic involvement that occurred in the course of D+HUS. RESULTS Verotoxigenic Escherichia coli infection was documented in 24. All except two patients had acute renal failure that required peritoneal dialysis, hemodialysis, or both techniques. A first group of eight patients remained with normal consciousness; five of them had protracted seizures. A second group of 23 patients had stuporous coma; five of these had protracted severe seizures, and 18 had a neurologic defect including pyramidal syndrome, hemiplegia or hemiparesia, and extrapyramidal syndrome. A third group of 21 patients had severe coma. Plasma exchanges were undertaken in 25 patients, 11 of whom were treated within 24 hours after the first neurologic sign; four died, two survived with severe sequelae, and five were alive without neurologic defect. Magnetic resonance imaging (MRI) for 29 patients showed that (1) every structure of the central nervous system was susceptible to involvement; (2) no correlation seemed to exist between special profile of localization on early MRI and the final prognosis; and (3) MRI did not exhibit any focal lesions in three patients. The overall prognosis of the series was marked by the death of nine patients and severe sequelae in 13. CONCLUSIONS Neurologic involvement is associated with a severe renal disease but does not lead systematically to death or severe disability.

Successful pre-transplant management of a patient with anti-factor H autoantibodies-associated haemolytic uraemic syndrome

Atypical haemolytic uraemic syndrome (aHUS) is known to be associated with mutations involving regulatory proteins of the complement alternative pathway, including factor H (CFH), factor I and MCP, in ∼50% of patients [1,2]. Eight patients have been reported with an acquired CFH deficiency because of the presence of anti-CFH autoantibodies [3,4]. These autoantibodies have been shown to influence the binding of CFH to the C3bBb convertase, thereby compromising CFH activity in vivo [3,4]. We now report the pre-transplant therapeutic management and post-transplant course of one of these patients.

Rituximab in steroid-dependent idiopathic nephrotic syndrome in childhood—follow-up after CD19 recovery

Rituximab (RTX) is a new treatment strategy in high-degree steroid-dependent idiopathic nephrotic syndrome (SDNS) in childhood. Thirty patients (nine girls) with SDNS with steroid side effects and previously treated with immunosuppressive drugs, mostly calcineurin inhibitors, were treated with RTX and included in this non-controlled single-centre study. Patient age at first RTX infusion was 12.9 ± 0.7 years. Our aim was to evaluate disease outcome after a minimum CD19 depletion period of 15 months obtained by repeated RTX infusion. Minimum follow-up after initial CD19 depletion was 24 months. During the RTX treatment period, seven patients had nephrotic syndrome relapses, six among them at the time of an intermittent CD19 recovery and one patient relapsed under CD19 depletion. The risk for these patients to relapse after the RTX treatment period was higher than in those without intermittent relapses. After definitive CD19 recovery over a follow-up of 17.4 ± 1.9 months, 19 patients (63%) did not relapse and 11 (37%) relapsed 4.3 ± 1 months after defininitive CD19 recovery. Among these 11 patients, 6 already had intermittent relapses during the RTX treatment period. Steroid and immunosuppressive treatment could be discontinued in all patients during CD19 depletion and was re-introduced in two after CD19 recovery. Fourteen patients had mostly benign and transitory side effects, which did not require RTX discontinuation. In conclusion, RTX treatment with a 15-month CD19 depletion period induced long-term remission after definitive CD 19 recovery in almost two-thirds the of patients without oral immunosuppressive drugs.

Plasmatherapy in atypical hemolytic uremic syndrome.

Plasmatherapy has become empirically first-line treatment in atypical hemolytic uremic syndrome (aHUS), although no prospective controlled trials have been conducted. Patients with mutations that induce complete or partial factor H (FH) quantitative deficiency may be controlled by plasma infusions (PI), but plasma exchanges appear more efficient than PI in patients with mutations that result in a mutant dysfunctional FH in the circulation. Early treatment is crucial. Long-term prophylactic plasmatherapy appears more efficient to prevent end-stage renal disease (ESRD) than plasmatherapy only during relapses. However, the longest follow-up with preserved renal function under plasmatherapy is only 6.5 years. Plasmatherapy does not appear to influence the outcome of aHUS with membrane cofactor protein mutation, and its efficacy in patients with factor I, C3, or factor B mutations is suggested by a few reports. We hope complement blockers will offer patients a better chance to avoid ESRD and provide a better quality of life.

Varicella as a trigger of atypical haemolytic uraemic syndrome associated with complement dysfunction: two cases

We report two cases of children who presented with haemolytic uraemic syndrome following varicella infection. One of them had a membrane cofactor protein mutation, and the other had anti-factor H antibodies. These observations show that infectious agents such as varicella-zoster virus may be the trigger of haemolytic uraemic syndrome in patients with complement dysregulation.

Non-atheromatous arterial stenoses in atypical haemolytic uraemic syndrome associated with complement dysregulation

BACKGROUND A child, who presented atypical haemolytic uraemic syndrome (aHUS) at the age of 1 month, developed cerebral ischaemic events at the age of 10 years. RESULTS Stenoses of both carotid arteries, left subclavian and vertebral arteries, several intracranial, right humeral, several coronary, and all pulmonary arteries were demonstrated. At the age of 13 years, left subclavian and right cervical carotid arteries were occluded. Right carotid recanalization induced intracranial dissection and death. The child had a Lys350Asp factor B mutation. CONCLUSION Arterial steno-occlusive lesions appear as potential complications of dysregulated complement activation in aHUS. Endovascular treatment should be considered cautiously in this setting.

Successful Plasmapheresis for Acute and Severe Unconjugated Hyperbilirubinemia in a Child with Crigler Najjar Type I Syndrome

Crigler-Najjar syndrome type I (CN-I, MIM #218800) is a rare and severe autosomal disorder. It is caused by deficiency of the liver enzyme responsible for bilirubin elimination, the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1; EC 2.4.1.17). Biologically, the disease manifests itself with severe and persistent unconjugated hyperbilirubinemia. Kernicterus is a well-known complication of severe unconjugated hyperbilirubinemia in infants and young children, especially in patients with CN-I.Few articles have shown the efficiency of plasmapheresis for extreme hyperbilirubinemia.In this report, we describe the efficiency of plasmapheresis for a rapid control of acute and severe unconjugated hyperbilirubinemia in a 6-year-old CN-I patient who had previously developed kernicterus in the neonatal period. In spite of intensification of phototherapy, the patient developed severe hyperbilirubinemia (up to 830 μmol/l, with bilirubin/albumin ratio at 1.2). With two plasmapheresis procedures, bilirubin serum concentration decreased to 420 μmol/ and bilirubin/albumin ratio to 0.55. Following the acute episode of very severe unconjugated hyperbilirubinemia, the child recovered and neurological examination was unchanged, thus suggesting that plasmapheresis possibly prevented further worsening of kernicterus.

Value of biomarkers for predicting immunoglobulin A vasculitis nephritis outcome in an adult prospective cohort

Background Henoch-Schönlein purpura, more recently renamed immunoglobulin A vasculitis (IgAV), is a systemic vasculitis characterized by IgA deposits. The current markers used to assess IgAV inaccurately evaluate the risk of nephritis occurrence and its long-term outcomes. The current study assessed biomarkers of nephritis outcomes. Methods This French multicentre prospective study enrolled 85 adult patients at the time of disease onset. Patients were assessed for clinical and biological parameters and re-examined after 1 year. Immunoglobulins, cytokines, IgA glycosylation, IgA complexes and neutrophil gelatinase-associated lipocalin (NGAL) concentrations were assessed in blood and urine. Results We identified 60 patients with IgAV-related nephritis (IgAV-N) and 25 patients without nephritis (IgAV-woN). At the time of inclusion (Day 1), the serum levels of galactose-deficient IgA1 (Gd-IgA1) and urinary concentrations of IgA, IgG, IgM, NGAL, interleukin (IL)-1β, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were higher in the IgAV-N patients than in the IgAV-woN patients (P < 0.005 for all comparisons). After follow-up (1 year), 22 patients showed a poor outcome. Among the tested markers, urine IgA at disease onset adequately reclassified the risk of poor outcome over conventional clinical factors, including estimated glomerular filtration rate, proteinuria and age (continuous net reclassification improvement = 0.72, P = 0.001; integrated discrimination improvement = 0.13, P = 0.009) in IgAV patients. Conclusions Taken together, these results showed that serum Gd-IgA1 and urinary IgA, IgG, IgM, NGAL, IL-1β, IL-6, IL-8, IL-10, IgA-IgG and IgA-sCD89 complexes were associated with nephritis in IgAV patients. Urinary IgA level may improve patient risk stratification for poor outcome.

Clinical and Genetic Spectrum of Bartter Syndrome Type 3

Bartter syndrome type 3 is a clinically heterogeneous hereditary salt-losing tubulopathy caused by mutations of the chloride voltage-gated channel Kb gene (CLCNKB), which encodes the ClC-Kb chloride channel involved in NaCl reabsorption in the renal tubule. To study phenotype/genotype correlations, we performed genetic analyses by direct sequencing and multiplex ligation-dependent probe amplification and retrospectively analyzed medical charts for 115 patients with CLCNKB mutations. Functional analyses were performed in Xenopus laevis oocytes for eight missense and two nonsense mutations. We detected 60 mutations, including 27 previously unreported mutations. Among patients, 29.5% had a phenotype of ante/neonatal Bartter syndrome (polyhydramnios or diagnosis in the first month of life), 44.5% had classic Bartter syndrome (diagnosis during childhood, hypercalciuria, and/or polyuria), and 26.0% had Gitelman-like syndrome (fortuitous discovery of hypokalemia with hypomagnesemia and/or hypocalciuria in childhood or adulthood). Nine of the ten mutations expressed in vitro decreased or abolished chloride conductance. Severe (large deletions, frameshift, nonsense, and essential splicing) and missense mutations resulting in poor residual conductance were associated with younger age at diagnosis. Electrolyte supplements and indomethacin were used frequently to induce catch-up growth, with few adverse effects. After a median follow-up of 8 (range, 1-41) years in 77 patients, chronic renal failure was detected in 19 patients (25%): one required hemodialysis and four underwent renal transplant. In summary, we report a genotype/phenotype correlation for Bartter syndrome type 3: complete loss-of-function mutations associated with younger age at diagnosis, and CKD was observed in all phenotypes.

Fluid status evaluation by inferior vena cava diameter and bioimpedance spectroscopy in pediatric chronic hemodialysis

BackgroundEvaluation of patient’s dry weight remains challenging in chronic hemodialysis (HD) especially in children. Inferior Vena Cava (IVC) measurement was reported useful to assess fluid overload both in adults and children.MethodsWe performed a monocentric prospective study to evaluate the relation between predialytic IVC diameter measurements and hydration status evaluated by physicians and bioimpedance spectroscopy (BIS) and between IVC measurements and persistent hypertension.ResultsForty-eight HD sessions in 16 patients were analyzed. According to physicians, patients were overhydrated in 84.5% of dialysis sessions, 20.8% according to BIS, and 0%, 4.1% and 20.8% according to IVC inspiratory, expiratory and collapsibility index reference curves respectively. There was no correlation between relative overhydration evaluated by BIS and IVC measurements z-scores (p = 0.20). Patients whose blood pressure normalized after HD had a more dilated maximal IVC diameter before dialysis session than patients with persistent hypertension (median − 0.07SD [−0.8; 0.88] versus −1.61SD [−2.18; −0.74] (p = 0.03)) with an optimal cut-off of −0.5 SD.ConclusionsIn our study, IVC measurement is not reliable to assess fluid overload in children on HD and was not correlated with extracellular fluid volume assessed by BIS measurements. However, IVC measurements might be of interest in differentiating volume-dependant hypertension from volume-independant hypertension.