Long-term follow-up including extensive complement analysis of a pediatric C3 glomerulopathy cohort

BACKGROUND: C3 glomerulopathy (C3G) is a rare kidney disorder characterized by predominant glomerular depositions of complement C3. C3G can be subdivided into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). This study describes the long-term follow-up with extensive complement analysis of 29 Dutch children with C3G. METHODS: Twenty-nine C3G patients (19 DDD, 10 C3GN) diagnosed between 1992 and 2014 were included. Clinical and laboratory findings were collected at presentation and during follow-up. Specialized assays were used to detect rare variants in complement genes and measure complement-directed autoantibodies and biomarkers in blood. RESULTS: DDD patients presented with lower estimated glomerular filtration rate (eGFR). C3 nephritic factors (C3NeFs) were detected in 20 patients and remained detectable over time despite immunosuppressive treatment. At presentation, low serum C3 levels were detected in 84% of all patients. During follow-up, in about 50% of patients, all of them C3NeF-positive, C3 levels remained low. Linear mixed model analysis showed that C3GN patients had higher soluble C5b-9 (sC5b-9) and lower properdin levels compared to DDD patients. With a median follow-up of 52 months, an overall benign outcome was observed with only six patients with eGFR below 90 ml/min/1.73 m(2) at last follow-up. CONCLUSIONS: We extensively described clinical and laboratory findings including complement features of an exclusively pediatric C3G cohort. Outcome was relatively benign, persistent low C3 correlated with C3NeF presence, and C3GN was associated with higher sC5b-9 and lower properdin levels. Prospective studies are needed to further elucidate the pathogenic mechanisms underlying C3G and guide personalized medicine with complement therapeutics. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00467-021-05221-6

Improve in-depth immunological risk assessment to optimize genetic-compatibility and clinical outcomes in child and adolescent recipients of parental donor kidney transplants: protocol for the INCEPTION study

Background: Parental donor kidney transplantation is the most common treatment option for children and adoles‑ cents with kidney failure. Emerging data from observational studies have reported improved short- and medium-term allograft outcomes in recipients of paternal compared to maternal donors. The INCEPTION study aims to identify potential diferences in immunological compatibility between maternal and paternal donor kidneys and ascertain how this afects kidney allograft outcomes in children and adolescents with kidney failure. Methods: This longitudinal observational study will recruit kidney transplant recipients aged ≤18 years who have received a parental donor kidney transplant across 4 countries (Australia, New Zealand, United Kingdom and the Netherlands) between 1990 and 2020. High resolution human leukocyte antigen (HLA) typing of both recipients and corresponding parental donors will be undertaken, to provide an in-depth assessment of immunological compat‑ ibility. The primary outcome is a composite of de novo donor-specifc anti-HLA antibody (DSA), biopsy-proven acute rejection or allograft loss up to 60-months post-transplantation. Secondary outcomes are de novo DSA, biopsyproven acute rejection, acute or chronic antibody mediated rejection or Chronic Allograft Damage Index (CADI) score of >1 on allograft biopsy post-transplant, allograft function, proteinuria and allograft loss. Using principal component analysis and Cox proportional hazards regression modelling, we will determine the associations between defned sets of immunological and clinical parameters that may identify risk stratifcation for the primary and secondary outcome measures among young people accepting a parental donor kidney for transplantation. This study design will allow us to specifcally investigate the relative importance of accepting a maternal compared to paternal donor, for families deciding on the best option for donation. Discussion: The INCEPTION study fndings will explore potentially diferential immunological risks of maternal and paternal donor kidneys for transplantation among children and adolescents. Our study will provide the evidence base underpinning the selection of parental donor in order to achieve the best projected long-term kidney transplant and overall health outcomes for children and adolescents, a recognized vulnerable population.Wai H. Lim ... Michael Collins ... et al

Improve in-depth immunological risk assessment to optimize genetic-compatibility and clinical outcomes in child and adolescent recipients of parental donor kidney transplants: protocol for the INCEPTION study

Background: Parental donor kidney transplantation is the most common treatment option for children and adolescents with kidney failure. Emerging data from observational studies have reported improved short- and medium-term allograft outcomes in recipients of paternal compared to maternal donors. The INCEPTION study aims to identify potential differences in immunological compatibility between maternal and paternal donor kidneys and ascertain how this affects kidney allograft outcomes in children and adolescents with kidney failure.Methods: This longitudinal observational study will recruit kidney transplant recipients aged 1 on allograft biopsy post-transplant, allograft function, proteinuria and allograft loss. Using principal component analysis and Cox proportional hazards regression modelling, we will determine the associations between defined sets of immunological and clinical parameters that may identify risk stratification for the primary and secondary outcome measures among young people accepting a parental donor kidney for transplantation. This study design will allow us to specifically investigate the relative importance of accepting a maternal compared to paternal donor, for families deciding on the best option for donation.Discussion: The INCEPTION study findings will explore potentially differential immunological risks of maternal and paternal donor kidneys for transplantation among children and adolescents. Our study will provide the evidence base underpinning the selection of parental donor in order to achieve the best projected long-term kidney transplant and overall health outcomes for children and adolescents, a recognized vulnerable population.Transplantation and autoimmunit

Cytomegalovirus prophylaxis in pediatric kidney transplantation: the Dutch experience.

Item does not contain fulltextMany children receiving a kidney transplant are seronegative for CMV and therefore, highly susceptible to a primary CMV infection. This study aims at evaluating incidence, time of occurrence, and severity of CMV infection in the first year post-transplantation in relation to different types of CMV prophylaxis. Transplantations in three centers in the Netherlands between 1999 and 2010 were included. Retrospective, observational, multicenter study. Clinical data and PCR measurements of CMV were collected. Prophylaxis in high-risk patients (CMV serostatus D+R-) consisted of (val)ganciclovir during three months, or acyclovir plus CMV immunoglobulin at a former stage. Intermediate-risk patients (R+) received (val)acyclovir, or acyclovir plus CMV immunoglobulin at a former stage. Low-risk patients (D-R-) did not receive prophylaxis. Infection was defined as CMV PCR above 50 geq/mL plasma or whole blood, a clinically relevant infection above 1000 geq/mL. One hundred and fifty-nine transplantations were included. CMV infection was documented for 41% of high-risk, 24% of intermediate-risk, and 13% of low-risk patients, in the latter two groups typically during the first three months. The infection rate was highest in the high-risk group after cessation of valganciclovir prophylaxis. Valganciclovir provided better protection than did acyclovir + CMV immunoglobulin. Adding an IL2-receptor blocker to the immunosuppressive regimen did not affect the infection rate. Acute graft rejection was not related with CMV infection. Valganciclovir prophylaxis effectively prevents CMV infection in high-risk pediatric kidney recipients, but only during prophylaxis. Valacyclovir prophylaxis in intermediate-risk patients is less effective.1 september 201

ACCIRT/WRC Newsletter [12 February, 2009]

OBJECTIVE: To explore further the mechanisms leading to immune deficiency in chronic renal failure and the role of dialysis treatment in these mechanisms. DESIGN: Cross-sectional and longitudinal analysis. PATIENTS: We studied 39 children treated with peritoneal dialysis (PD), 23 children treated with hemodialysis (HD), 33 children not yet dialyzed [chronic renal failure (CRF)], and 27 healthy children. Peritoneal cells were also obtained from PD children for analysis. METHODS: White blood cells (WBCs) were isolated from blood and peritoneal dialysis effluent by centrifugation. The number of CD2+, CD4+, and CD8+ T cells, B cells, and natural killer cells were measured by flow cytometry. RESULTS: The total peripheral blood lymphocyte count was lower in PD children (2.6 x 10(9)/L), HD children (2.1 x 10(9)/L), and CRF children (2.0 x 10(9)/L) compared with healthy children (3.1 x 10(9)/L, p <0.05). The B lymphocyte count was also lower in PD children (0.34 x 10(9)/L), HD children (0.22 x 10(9)/L), and CRF children (0.33 x 10(9)/L) compared with healthy children (0.52 x 10(9)/L, p <0.01). Numbers of CD4+ T cells were not different, but numbers of CD8+ T cells were lower in PD children (0.56 x 10(9)/L), HD children (0.63 x 10(9)/L), and CRF children (0.53 x 10(9)/L) compared with healthy children (0.77 x 10(9)/L, p <0.05). The count of natural killer cells was lower in PD children (0.21 x 10(9)/L), HD children (0.17 x 10(9)/L), and CRF children (0.18 x 10(9)/L) compared with healthy children (0.50 x 10(9)/L, p <0.0001). The CD4/CD8 ratio of lymphocytes in peritoneal effluent was 0.8 versus 1.9 in peripheral blood (p <0.001). The CD2/CD19 ratio was not different. The cell subsets remained stable during the first year of PD treatment. The CD2/CD19 ratio in peritoneal effluent was higher in children with a peritonitis incidence > or = 1 per year. CONCLUSIONS: The reduced numbers of B lymphocytes, CD8+ T cells, and natural killer cells found in CRF children, dialyzed or not, may favor the frequent occurrence of infection

Prevention of steroid-induced low bone mineral density * in children with renal diseases: a systematic review.

Item does not contain fulltextBACKGROUND: Children with renal diseases who are treated with glucocorticoids are at increased risk of developing osteoporosis and fractures. However, there is no common strategy for prevention of corticosteroid-induced osteoporosis. The present systematic review was performed to determine whether prevention of bone loss by calcium (Ca), vitamin D (vit D) and/or bisphosphonates is justified, safe and efficacious in children treated with steroids for various renal diseases. METHODS: Data sources: Medline, Embase, Central were searched from 1961 up to 2012. Randomized controlled trials (RCTs) and observational studies concerning children </=18 years with renal diseases requiring steroids were included. RESULTS: The search strategy retrieved 2482 studies. Four RCTs including 166 patients and one observational study including 100 children met our eligibility criteria. One RCT and the observational study concerned treatment with Ca/vit D, one RCT with bisphosphonates and two RCTs with a combination of both therapies. All described a significant improvement in bone mineral density (BMD) in the treatment group compared with the control group. CONCLUSIONS: Ca combined with vit D is recommended to prevent bone disease in children with renal diseases treated with steroids. Because of side effects, bisphosphonates should be reserved for the treatment of severe osteoporosis when Ca and/or vit D supplementation has failed.1 augustus 201