Immunoglobulin M nephropathy: Histopathological and clinical characteristics. Case series

La nefropatía por inmunoglobulina M (NIgM) es una glomerulopatía idiopática caracterizada por depósitos mesangiales globales y difusos de IgM. Se realizó un estudio retrospectivo de las características clínicas e histopatológicas de los pacientes con NIgM atendidos en nuestro servicio. De 241 biopsias renales, 21 correspondieron a NIgM (8,7 %). Se incluyeron 18 pacientes (14 de sexo femenino, mediana de edad: 3,08 años). Se excluyó a 1 paciente por enfermedad sistémica asociada y a 2 por seguimiento menor a 1 año. Catorce pacientes se manifestaron con síndrome nefrótico (SN) y 4 con proteinuria aislada o asociada a hematuria. En la microscopia óptica, 13 presentaron hiperplasia mesangial, y 5 esclerosis focal y segmentaria. De los pacientes con SN, 7 fueron corticorresistentes, 4 corticodependientes y 3 presentaban recaídas frecuentes. Todos los pacientes con SN y 1 con proteinuria-hematuria recibieron inmunosupresores; los 18 pacientes recibieron, además, antiproteinúricos. Luego de 5,2 años (2-17,5) de seguimiento, 6 pacientes evolucionaron a enfermedad renal crónica.Immunoglobulin M nephropathy (IgMN) is an idiopathic glomerulopathy characterized by diffuse global mesangial deposits of IgM. We retrospectively studied the clinical and histopathological characteristics of the patients with IgMN seen in our service. Of 241 renal biopsies, 21 corresponded to IgMN (8.7 %). One patient was excluded due to associated systemic disease and 2 due to follow-up less than 1 year, 18 were included (14 girls, median age 3.08 years). Fourteen manifested with nephrotic syndrome (NS) and the remaining with proteinuria (isolated or associated with hematuria). On light microscopy, 13 had hyperplasia with mesangial expansion and 5 had focal and segmental sclerosis. Of the patients with NS, 7 were steroid-resistant, 4 steroid-dependent, and 3 frequent relapsers. All patients with NS and 1 with proteinuria-hematuria received immunosuppressants; the 18 patients also received antiproteinuric drugs. After 5.2 years (2-17.5) of follow-up, 6 patients developed chronic kidney disease.Fil: Meni Battaglia, Luciana. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Balestracci, Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Toledo, Ismael. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Martin, Sandra M.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Careaga, Claudia Mabel. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Gogorza, María C.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Caupolican, Alvarado. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Cao, Gabriel Fernando. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Uncommon Presentation of Atypical Hemolytic Uremic Syndrome : A Case Report

Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and renal damage. Its presentation as nephrotic syndrome (NS) during first year of life is uncommon; we describe a child with clinical and laboratory findings of NS whose renal biopsy revealed thrombotic microangiopathy (TMA). A previously healthy 4-month-old male was admitted with severe dehydration, diarrhea and anuria. Laboratory results showed electrolyte disturbances, increased serum creatinine, anemia without schistocytes, thrombocytosis, normal lactic dehydrogenase (LDH) levels, hypoalbuminemia hypercholesterolemia and decreased C3 levels. After rehydration hematuria and massive proteinuria were also documented and an initial diagnosis of NS of the first year was established. Studies seeking for infectious agents were negative. During hospitalization he continued to be oligo-anuric needing dialysis and a renal biopsy was performed, which showed TMA findings. We here considered the diagnosis of aHUS and started plasma infusions as a bridge until starting eculizumab. After two infusions urine output improved leading to discontinuation dialysis. The diagnoses of STEC infection and thrombocytopenic thrombotic purpura were ruled out. Factor B, H, I and properdin levels were normal. Antibodies against CFH negative were negative. Screening for genes causative of aHUS detected a heterozygous variant in CFHR3 of uncertain significance. On day 20, treatment was switched to eculizumab, which induced a progressive remission of the NS. This case outlines the need for a heightened diagnosis suspicion of this already rare disease since early initiation of eculizumab therapy improves its prognosis

Uncommon presentation of atypical hemolytic uremic syndrome: A Case Report

Atypical hemolytic uremic syndrome (aHUS) is an ultra‑rare disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and renal damage. Its presentation as nephrotic syndrome (NS) during first year of life is uncommon; we describe a child with clinical and laboratory findings of NS whose renal biopsy revealed thrombotic microangiopathy (TMA). A previously healthy 4‑month‑oldmale was admitted with severe dehydration, diarrhea and anuria. Laboratory results showed electrolyte disturbances, increased serum creatinine, anemia without schistocytes, thrombocytosis, normal lactic dehydrogenase (LDH) levels, hypoalbuminemia hypercholesterolemia and decreased C3 levels.After rehydration hematuria and massive proteinuria were also documented and an initial diagnosisof NS of the first year was established. Studies seeking for infectious agents were negative. Duringhospitalization he continued to be oligo-anuric needing dialysis and a renal biopsy was performed,which showed TMA findings. We here considered the diagnosis of aHUS and started plasmainfusions as a bridge until starting eculizumab. After two infusions urine output improved leading todiscontinuation dialysis. The diagnoses of STEC infection and thrombocytopenic thrombotic purpura were ruled out. Factor B, H, I and properdin levels were normal. Antibodies against CFH negative were negative. Screening for genes causative of aHUS detected a heterozygous variant in CFHR3 of uncertain significance. On day 20, treatment was switched to eculizumab, which induced a progressive remission of the NS. This case outlines the need for a heightened diagnosis suspicion of this already rare disease since early initiation of eculizumab therapy improves its prognosis.Fil: Martin, Sandra M.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Balestracci, Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Puyol, Iris. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Toledo, Ismael. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Cao, Gabriel Fernando. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Arizeta, Gema. Hospital Vall Dhebron; Españ

Postdiarrhoeal haemolytic uraemic syndrome without thrombocytopenia

Background: Thrombocytopenia is a hallmark of postdiarrhoeal haemolytic uraemic syndrome (D+ HUS), although it can be transient and therefore undetected. There is scarce information regarding the prevalence and the course of the disease in children with D+ HUS without thrombocytopenia. Objective: To determine the prevalence of D+ HUS without thrombocytopenia and to describe the clinical characteristics of a series of children with this condition. Patients and methods: The medical records of patients with D+ HUS hospitalised between 2000 and 2016 were reviewed to identify those without thrombocytopenia (>150,000 mm3). Demographic, clinical and laboratory parameters of the selected cases were collected and descriptively analysed. Results: Nine cases (5.6%) without thrombocytopenia were identified among 161 patients hospitalised during the study period. Median age at diagnosis was 17 months (7–32) and median prodromal symptom duration was 15 days (7–21). Eight patients maintained normal urine output while the remaining one required dialysis. No patient presented with severe extrarenal compromise and/or hypertension. Conclusions: The prevalence of non-thrombocytopenic D+ HUS was 5.6% and most cases occurred with mild forms of the disease; however, the need for dialysis in one of them indicated that normalisation of platelet count is not always an accurate marker for disease remittance. Our results also confirm that the time of onset of D+ HUS in patients without thrombocytopenia is usually delayed with respect to the initial intestinal symptoms; thus, heightened diagnostic suspicion is necessary

Eliglustat protects from damage caused by Shiga toxin type 2 in human renal tubular epithelial cells

Shigatoxin-producing Escherichia coli isresponsible for Hemolytic Uremic Syndrome (HUS), a cause of renal failure inchildren. We have previously shown that C-9 and Eliglustat (EG), inhibitors ofglucosylceramide  synthase andglobotriaosylceramide (Gb3), prevent the cytotoxic effects of Shiga toxin type2 (Stx2), in human cortical renal tubular epithelial cells (HRTEC) primarycultures and HK2 cell line. The aim of this work was to evaluate the efficacyof EG, elucidating EG treatments necessary to achieve total protection against Stx2in HRTEC and HK2. Cells were incubated with Stx2 (1 ng/ml, 24 and 72 h) andpre-incubated with or without EG (1-500 nM, 6 and 24 h), followed byco-incubation with same dilutions of EG and Stx2 (24 and 72 h). Total number ofcells stained with Hoechst was counted in microphotographs and compared withcell viability measured by neutral red uptake. Early and late apoptosis andnecrosis was evaluated by annexin V/propidium iodide staining. Tubulogenesis wasevaluated in HRTEC grown on matrigel. Treatment of cells with Stx2significantly decreased cell confluence and viability and the number of cellsattached (p<0.001). In HRTEC, Stx2 increased early and late apoptosis, andnecrosis compared to non-treated cells (p<0.01). Furthermore, Stx2 inhibitedcell aggregation and tubulogenesis on matrigel. HRTEC preincubated with EG (50nM, 24 h or 500 nM, 6 h) totally prevented Stx2 effects on HRTEC measured as cellcount, viability, apoptosis, necrosis and tubulogenesis (p<0.05). Preincubationof HK2 cells with EG (1 nM, 24 h or 10 nM, 6 h) totally prevented Stx2 effectson cell viability and confluence. EG alone did not produce cytotoxic effectsper se. In conclusion, EG protects human renal tubular epithelium against Stx2cytotoxicity being HRTEC more sensitive than HK2. Treatment with EG could be anovel substrate inhibition therapy to neutralize Stx2 action and prevent renal damagein patients with HUS.Fil: Sánchez, Diana Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Fisher Sigel, L. K.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Balestracci, Alejandro. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Ibarra, Cristina Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Amaral, María Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Silberstein, Claudia Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaLXV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LXVIII Reunión Anual de la Sociedad Argentina de Inmunología y Reunión Anual de la Asociación Argentina de FisiologíaArgentinaSociedad argentina de Investigación ClínicaSociedad Argentina de InmunologíaAsociación Argentina de Fisiologí

Eliglustat prevents Shiga toxin 2 cytotoxic effects in human renal tubular epithelial cells

Background: Shiga toxin-producing Escherichia coli is responsible for post-diarrheal (D+) hemolytic uremic syndrome (HUS), which is a cause of acute renal failure in children. The glycolipid globotriaosylceramide (Gb3) is the main receptor for Shiga toxin (Stx) in kidney target cells. Eliglustat (EG) is a specific and potent inhibitor of glucosylceramide synthase, first step of glycosphingolipid biosynthesis, actually used for the treatment of Gaucher’s disease. The aim of the present work was to evaluate the efficiency of EG in preventing the damage caused by Stx2 in human renal epithelial cells. Methods: Human renal tubular epithelial cell (HRTEC) primary cultures were pre-treated with different dilutions of EG followed by co-incubation with EG and Stx2 at different times, and cell viability, proliferation, apoptosis, tubulogenesis, and Gb3 expression were assessed. Results: In HRTEC, pre-treatments with 50 nmol/L EG for 24 h, or 500 nmol/L EG for 6 h, reduced Gb3 expression and totally prevented the effects of Stx2 on cell viability, proliferation, and apoptosis. EG treatment also allowed the development of tubulogenesis in 3D-HRTEC exposed to Stx2. Conclusions: EG could be a potential therapeutic drug for the prevention of acute kidney injury caused by Stx2. Impact: For the first time, we have demonstrated that Eliglustat prevents Shiga toxin 2 cytotoxic effects on human renal epithelia, by reducing the expression of the toxin receptor globotriaosylceramide.The present work also shows that Eliglustat prevents Shiga toxin 2 effects on tubulogenesis of renal epithelial cells.Eliglustat, actually used for the treatment of patients with Gaucher’s disease, could be a therapeutic strategy to prevent the renal damage caused by Shiga toxin.Fil: Sanchez, Daiana Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Fischer Sigel, Lilian Karina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Balestracci, Alejandro. Hospital de Niños Pedro de Elizalde; ArgentinaFil: Ibarra, Cristina Adriana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Amaral, María Marta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Silberstein, Claudia Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentin

Hyponatremia: a new predictor of mortality in patients with Shiga toxin-producing Escherichia coli hemolytic uremic syndrome

(1) Evaluate mortality rate in patients with Shiga toxin-producing Escherichia coli hemolytic uremic syndrome, (2) determine the leading causes of death, and (3) identify predictors of mortality at hospital admission. We conducted a multicentric, observational, retrospective, cross-sectional study. It included patients under 18 years old with Shiga toxin-producing Escherichia coli hemolytic uremic syndrome hospitalized between January 2005 and June 2016. Clinical and laboratory data were obtained from the Argentine National Epidemiological Surveillance System of Hemolytic Uremic Syndrome. Clinical and laboratory variables were compared between deceased and non-deceased patients. Univariate and multivariate analyses were performed. ROC curves and area under the curve were obtained. Seventeen (3.65%) out of the 466 patients died, being central nervous system involvement the main cause of death. Predictors of death were central nervous system involvement, the number of days since the beginning of diarrhea to hospitalization, hyponatremia, high hemoglobin, high leukocyte counts, and low bicarbonate concentration on admission. In the multivariate analysis, central nervous system involvement, sodium concentration, and hemoglobin were independent predictors. The best cut off for sodium was ≤ 128 meq/l and for hemoglobin ≥ 10.8 g/dl. Mortality was low in children with Shiga toxin-producing Escherichia coli hemolytic uremic syndrome, being central nervous system involvement the main cause of death. The best mortality predictors found were central nervous system involvement, hemoglobin, and sodium concentration. Hyponatremia may be a new Shiga toxin-producing Escherichia coli hemolytic uremic syndrome mortality predictor.Facultad de Ciencias Veterinaria