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BACKGROUND: The efficacy of continuous antibiotic prophylaxis in preventing urinary tract infection (UTI) in infants with grade III, IV, or V vesicoureteral reflux is controversial. METHODS: In this investigator-initiated, randomized, open-label trial performed in 39 European centers, we randomly assigned infants 1 to 5 months of age with grade III, IV, or V vesicoureteral reflux and no previous UTIs to receive continuous antibiotic prophylaxis (prophylaxis group) or no treatment (untreated group) for 24 months. The primary outcome was the occurrence of the first UTI during the trial period. Secondary outcomes included new kidney scarring and the estimated glomerular filtration rate (GFR) at 24 months. RESULTS: A total of 292 participants underwent randomization (146 per group). Approximately 75% of the participants were male; the median age was 3 months, and 235 participants (80.5%) had grade IV or V vesicoureteral reflux. In the intention-to-treat analysis, a first UTI occurred in 31 participants (21.2%) in the prophylaxis group and in 52 participants (35.6%) in the untreated group (hazard ratio, 0.55; 95% confidence interval [CI], 0.35 to 0.86; P = 0.008); the number needed to treat for 2 years to prevent one UTI was 7 children (95% CI, 4 to 29). Among untreated participants, 64.4% had no UTI during the trial. The incidence of new kidney scars and the estimated GFR at 24 months did not differ substantially between the two groups. Pseudomonas species, other non-Escherichia coli organisms, and antibiotic resistance were more common in UTI isolates obtained from participants in the prophylaxis group than in isolates obtained from those in the untreated group. Serious adverse events were similar in the two groups. CONCLUSIONS: In infants with grade III, IV, or V vesicoureteral reflux and no previous UTIs, continuous antibiotic prophylaxis provided a small but significant benefit in preventing a first UTI despite an increased occurrence of non-E. coli organisms and antibiotic resistance. (Funded by the Italian Ministry of Health and others; PREDICT ClinicalTrials.gov number, NCT02021006; EudraCT number, 2013-000309-21.).
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Antibacterianos , Profilaxis Antibiótica , Infecciones Urinarias , Reflujo Vesicoureteral , Femenino , Humanos , Lactante , Masculino , Profilaxis Antibiótica/efectos adversos , Profilaxis Antibiótica/métodos , Glomerulonefritis , Análisis de Intención de Tratar , Reflujo Vesicoureteral/complicaciones , Reflujo Vesicoureteral/tratamiento farmacológico , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antibacterianos/uso terapéutico , Infecciones Urinarias/etiología , Infecciones Urinarias/microbiología , Infecciones Urinarias/prevención & control , Farmacorresistencia Bacteriana/efectos de los fármacosRESUMEN
Mutations in genes encoding molecular chaperones can lead to chaperonopathies, but none have so far been identified causing congenital disorders of glycosylation. Here we identified two maternal half-brothers with a novel chaperonopathy, causing impaired protein O-glycosylation. The patients have a decreased activity of T-synthase (C1GALT1), an enzyme that exclusively synthesizes the T-antigen, a ubiquitous O-glycan core structure and precursor for all extended O-glycans. The T-synthase function is dependent on its specific molecular chaperone Cosmc, which is encoded by X-chromosomal C1GALT1C1. Both patients carry the hemizygous variant c.59C>A (p.Ala20Asp; A20D-Cosmc) in C1GALT1C1. They exhibit developmental delay, immunodeficiency, short stature, thrombocytopenia, and acute kidney injury (AKI) resembling atypical hemolytic uremic syndrome. Their heterozygous mother and maternal grandmother show an attenuated phenotype with skewed X-inactivation in blood. AKI in the male patients proved fully responsive to treatment with the complement inhibitor Eculizumab. This germline variant occurs within the transmembrane domain of Cosmc, resulting in dramatically reduced expression of the Cosmc protein. Although A20D-Cosmc is functional, its decreased expression, though in a cell or tissue-specific manner, causes a large reduction of T-synthase protein and activity, which accordingly leads to expression of varied amounts of pathological Tn-antigen (GalNAcα1-O-Ser/Thr/Tyr) on multiple glycoproteins. Transient transfection of patient lymphoblastoid cells with wild-type C1GALT1C1 partially rescued the T-synthase and glycosylation defect. Interestingly, all four affected individuals have high levels of galactose-deficient IgA1 in sera. These results demonstrate that the A20D-Cosmc mutation defines a novel O-glycan chaperonopathy and causes the altered O-glycosylation status in these patients.
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Lesión Renal Aguda , Chaperonas Moleculares , Masculino , Humanos , Chaperonas Moleculares/metabolismo , Mutación , Polisacáridos/metabolismo , Células Germinativas/metabolismoRESUMEN
BACKGROUND AND HYPOTHESIS: Clinical trials have demonstrated positive cardiovascular and kidney outcomes of sodium-glucose-co-transporter-2 (SGLT2) inhibitors in adult patients with diabetic and other chronic kidney diseases (CKD). Whether benefits extend to children, teenagers, and young adults with early-stage CKD is unknown. For this reason, the DOUBLE PRO-TECT Alport trial (NCT05944016) will study the progression of albuminuria in young patients with Alport syndrome (AS), the most common hereditary CKD, to assess the safety and efficacy of the SGLT2-inhibitor dapagliflozin. Patients living with AS and chronically elevated albuminuria have a high risk of kidney failure before the age of 50 years. METHODS AND RATIONALE: DOUBLE PRO-TECT Alport is a multicenter, randomized, double-blind, placebo-controlled trial (RCT). Participants (aged 10 to 39 years) must have a diagnosis of AS by genetic testing or kidney biopsy, be on a stable (> 3 months) maximum tolerated dose of a renin-angiotensin-system-inhibitor (RASi) and must have a Urinary Albumin to Creatinine Ratio (UACR) of >300 mg/g (pediatric) or >500 mg/g (adult).Eligible participants will be randomly assigned at a 2:1 ratio to 48 weeks of treatment with dapaglifozin 10 mg/day -to- matched placebo. Most participants are expected to be children with a normal glomerular filtration rate (eGFR). In addition to safety, the primary (change in UACR from baseline to Week 48) and key secondary (eGFR change from baseline to Week 52) efficacy outcomes will be analyzed with a mixed model repeated measures approach. Efficacy analyses will be performed primarily in the full analysis set according to the intention-to-treat principle. A sensitivity analysis will be performed using reference-based multiple imputation. CONCLUSION: DOUBLE PRO-TECT Alport will assess whether SGLT2-inhibitors can safely reduce change from baseline in UACR as a marker for progression of CKD in young patients living with AS.
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BACKGROUND: Complement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare chronic kidney diseases with an overall poor prognosis, with approximately 40-50% of patients progressing to kidney failure within 10 years of diagnosis. C3G is characterized by a high rate of disease recurrence in the transplanted kidney. However, there is a lack of published data on clinical outcomes in the pediatric population following transplantation. METHODS: In this multicenter longitudinal cohort study of the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, we compared the post-transplant outcomes of pediatric patients with C3G (n = 17) or IC-MPGN (n = 3) with a matched case-control group (n = 20). RESULTS: Eleven of 20 children (55%) with C3G or IC-MPGN experienced a recurrence within 5 years post-transplant. Patients with C3G or IC-MPGN had a 5-year graft survival of 61.4%, which was significantly (P = 0.029) lower than the 5-year graft survival of 90% in controls; five patients with C3G or IC-MPGN lost their graft due to recurrence during this observation period. Both the 1-year (20%) and the 5-year (42%) rates of biopsy-proven acute rejection episodes were comparable between patients and controls. Complement-targeted therapy with eculizumab, either as prophylaxis or treatment, did not appear to be effective. CONCLUSIONS: These data in pediatric patients with C3G or IC-MPGN show a high risk of post-transplant disease recurrence (55%) and a significantly lower 5-year graft survival compared to matched controls with other primary kidney diseases. These data underscore the need for post-transplant patients for effective and specific therapies that target the underlying disease mechanism.
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BACKGROUND: Infantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder, mostly and often firstly affecting the kidneys, together with impaired disharmonious growth and rickets, eventually resulting in progressive chronic kidney disease (CKD). With the introduction of cysteamine therapy, most pediatric patients reach adulthood with no need for kidney replacement therapy. Still, detailed changes in INC patients' clinical and morphological presentation over the past decades have not yet been thoroughly investigated. METHODS: Two groups with a respective total of 64 children with INC and 302 children with CKD, both treated conservatively and aged 2 to 18 years, were prospectively observed in the time span from 1998 to 2022 with 1186 combined annual clinical and morphological examinations clustered into two measurement periods (1998 to 2015 and ≥ 2016). RESULTS: In INC patients, thoracic proportion indices remained markedly increased, whereas body fat stores remained decreased over the past 25 years (+ 1 vs. below ± 0 z-score, respectively). Their CKD peers presented with overall improved growth, general harmonization of body proportions, and improved body fat stores, while INC patients only presented with an isolated significant increase in leg length over time (∆0.36 z-score). eGFR adjusted for age did not significantly change over the past 25 years in both groups. Alkaline phosphatase (ALP) showed a significant decrease in CKD patients over time, while remaining above normal levels in INC patients. CONCLUSIONS: Disproportionate thoracic shape and impaired body fat stores remain the most characteristic morphological traits in INC patients over the past 25 years, while causal mechanisms remain unclear.
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Cistinosis , Insuficiencia Renal Crónica , Terapia de Reemplazo Renal , Humanos , Niño , Cistinosis/terapia , Cistinosis/patología , Cistinosis/diagnóstico , Cistinosis/complicaciones , Masculino , Adolescente , Femenino , Preescolar , Insuficiencia Renal Crónica/terapia , Insuficiencia Renal Crónica/patología , Terapia de Reemplazo Renal/estadística & datos numéricos , Terapia de Reemplazo Renal/métodos , Estudios Prospectivos , Riñón/patología , Progresión de la Enfermedad , Cisteamina/uso terapéutico , Cisteamina/administración & dosificaciónRESUMEN
OBJECTIVES: Oral microbiome plays a crucial role in the incidence and development of oral diseases. An altered intestinal microbiome has been reported in adults with chronic kidney disease (CKD). This study aimed to characterize the tongue microbiome of young patients with CKD compared to their healthy mothers to identify the influence of CKD-associated factors on resilient tongue ecosystem. MATERIAL AND METHODS: Thirty patients with CKD (mean age, 14.2 years; 16 males and 14 females) and generalized gingivitis were included in the study. Swabs of the posterior tongue were collected from the patients and 21 mothers (mean age 40.8 years). Next-generation sequencing of 16S rDNA genes was employed to quantitatively characterize microbial communities. RESULTS: The bacterial communities were similar in terms of richness and diversity between patients and mothers (p > 0.05). In patients with CKD, 5 core phyla, 20 core genera, and 12 core species were identified. CONCLUSIONS: The tongue microbiome of the study participants showed no relevant CKD-associated differences compared to their mothers and appears to be a highly preserved niche in the oral cavity. Differences observed in the abundance of individual species in this study could be attributed to the age rather than CKD, even after a mean disease duration of 11 years. CLINICAL RELEVANCE: CKD and its associated metabolic changes appear to have no detectable impact on the resilient tongue microbiome observed in young patients.
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Gingivitis , Microbiota , Insuficiencia Renal Crónica , Adulto , Femenino , Masculino , Humanos , Adolescente , LenguaRESUMEN
While 44-83% of children with steroid-resistant nephrotic syndrome (SRNS) without a proven genetic cause respond to treatment with a calcineurin inhibitor (CNI), current guidelines recommend against the use of immunosuppression in monogenic SRNS. This is despite existing evidence suggesting that remission with CNI treatment is possible and can improve prognosis in some cases of monogenic SRNS. Herein, our retrospective study assessed response frequency, predictors of response and kidney function outcomes among children with monogenic SRNS treated with a CNI for at least three months. Data from 203 cases (age 0-18 years) were collected from 37 pediatric nephrology centers. Variant pathogenicity was reviewed by a geneticist, and 122 patients with a pathogenic and 19 with a possible pathogenic genotype were included in the analysis. After six months of treatment and at last visit, 27.6% and 22.5% of all patients respectively, demonstrated partial or full response. Achievement of at least partial response at six months of treatment conferred a significant reduction in kidney failure risk at last follow-up compared to no response (hazard ratio [95% confidence interval] 0.25, [0.10-0.62]). Moreover, risk of kidney failure was significantly lower when only those with a follow-up longer than two years were considered (hazard ratio 0.35, [0.14-0.91]). Higher serum albumin level at CNI initiation was the only factor related to increased likelihood of significant remission at six months (odds ratio [95% confidence interval] 1.16, [1.08-1.24]). Thus, our findings justify a treatment trial with a CNI also in children with monogenic SRNS.
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Síndrome Nefrótico , Podocitos , Insuficiencia Renal , Niño , Humanos , Recién Nacido , Lactante , Preescolar , Adolescente , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/genética , Síndrome Nefrótico/patología , Inhibidores de la Calcineurina/efectos adversos , Inmunosupresores/efectos adversos , Estudios Retrospectivos , Podocitos/patología , Insuficiencia Renal/inducido químicamenteRESUMEN
Familial hypercholesterolemia (FH) is an inherited metabolic defect leading to increased total cholesterol and low-density cholesterol (LDL) from birth onwards. Homozygous FH, presenting with clear clinical features, has a prevalence of ~ 1 per million. Prevalence of heterozygous FH is 1/500 European population. Atherosclerotic burden depends on the degree and duration of high LDL exposure. In severe cases, early detection is critical, and aggressive lipid-lowering therapies should begin in early childhood to reduce coronary heart disease risk. Pediatric therapeutic concepts correspond to adults and are orientated at LDL plasma concentration. Mean LDL plasma target value during treatment is < 135 mg/dL. Medication in childhood consists of ezetemibe, statins, resins, and PCSK-9 inhibitors, with consideration for age restrictions. Only a minority achieve the treatment target with drug therapy alone. Therapeutic apheresis for the treatment of hypercholesterolemia selectively removes lipoproteins from blood (lipid apheresis (LA)). LA has a long tradition in adult medicine and is also safely used in children by a variety of methods, if customized to special pediatric needs. LA reduces cholesterol levels independently of residual LDL-receptor function and not only achieves reduction or disappearance of xanthomas but also inhibits progression of or mitigates aortic valve stenosis and supravalvular aortic stenosis as well as coronary artery and other atherosclerotic lesions. Cardiovascular prognosis of patients with otherwise untreatable FH depends largely on timely use of LA. Taking into account LA as a lifelong treatment, starting early in childhood, it is important to accommodate therapy modalities, such as treatment frequency and point of time, into the life of the individual.
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Eliminación de Componentes Sanguíneos , Hiperlipoproteinemia Tipo II , Adulto , Humanos , Preescolar , Niño , Eliminación de Componentes Sanguíneos/métodos , Lipoproteínas , Vasos Coronarios , ColesterolRESUMEN
In recent years, migration and the social changes associated with it have increasingly become the focus of scientific interest. The diversity of cultures in hospitals poses a major challenge. Medical teams are often confronted with language barriers and different concepts of illness, health, and healing. The field is wide, and in addition to foreign language skills, primarily human skills such as self-awareness, communication, and empathy are demanded. Religion also plays a role in medical care for patients with a foreign cultural background. This work is intended to provide an overview of the scientifically based necessary skills in dealing with this patient clientele and to give an insight into the personal experiences of the authors. After many years of dealing with intercultural care of patients, this experience has shown one thing above all: Sometimes, it is beyond language and just needs humanity.
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Comunicación , Competencia Cultural , HumanosRESUMEN
BACKGROUND: Data on humoral immune response to standard COVID-19 vaccination are scarce in adolescent patients and lacking for children below 12 years of age with chronic kidney disease including kidney transplant recipients. METHODS: We therefore investigated in this retrospective two-center study (DRKS00024668; registered 23.03.2021) the humoral immune response to a standard two-dose mRNA vaccine regimen in 123 CKD patients aged 5-30 years. A live-virus assay was used to assess the serum neutralizing activity against the SARS-CoV-2 omicron (BA.1) variant. RESULTS: Children aged 5-11 years had a comparable rate and degree of immune response to adolescents despite lower vaccine doses (10 µg vs. 30 µg BNT162b2). Treatment with two (odds ratio 9.24) or three or more (odds ratio 17.07) immunosuppressants was an independent risk factor for nonresponse. The immune response differed significantly among three patient cohorts: 48 of 77 (62.3%) kidney transplant recipients, 21 of 26 (80.8%) patients on immunosuppressive therapy, and 19 of 20 (95.0%) patients with chronic kidney disease without immunosuppressive therapy responded. In the kidney transplant recipients, immunosuppressive regimens comprising mycophenolate mofetil, an eGFR of < 60 mL/min/1.73 m2, and female sex were independent risk factors for nonresponse. Two of 18 (11.1%) and 8 of 16 (50.0%) patients with an anti-S1-RBD IgG of 100-1411 and > 1411 BAU/mL, respectively, showed a neutralization activity against the omicron variant. CONCLUSION: A standard mRNA vaccine regimen in immunosuppressed children and adolescents with kidney disease elicits an attenuated humoral immune response with effective live virus neutralization against the omicron variant in approximately 10% of the patients, underlying the need for omicron-adapted vaccination. A higher resolution version of the Graphical abstract is available as Supplementary information.
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COVID-19 , Inmunidad Humoral , Adolescente , Humanos , Niño , Femenino , Adulto Joven , Vacuna BNT162 , COVID-19/prevención & control , Vacunas contra la COVID-19 , Estudios Retrospectivos , SARS-CoV-2 , Vacunación , Inmunosupresores/uso terapéutico , ARN Mensajero , Anticuerpos AntiviralesRESUMEN
BACKGROUND: Randomized controlled trials in pediatric kidney transplantation are hampered by low incidence and prevalence of kidney failure in children. Real-World Data from patient registries could facilitate the conduct of clinical trials by substituting a control cohort. However, the emulation of a control cohort by registry data in pediatric kidney transplantation has not been investigated so far. METHODS: In this multicenter comparative analysis, we emulated the control cohort (n = 54) of an RCT in pediatric kidney transplant patients (CRADLE trial; ClinicalTrials.gov NCT01544491) with data derived from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, using the same inclusion and exclusion criteria (CERTAIN cohort, n = 554). RESULTS: Most baseline patient and transplant characteristics were well comparable between both cohorts. At year 1 posttransplant, a composite efficacy failure end point comprising biopsy-proven acute rejection, graft loss or death (5.8% ± 3.3% vs. 7.5% ± 1.1%, P = 0.33), and kidney function (72.5 ± 24.9 vs. 77.3 ± 24.2 mL/min/1.73 m2 P = 0.19) did not differ significantly between CRADLE and CERTAIN. Furthermore, the incidence and severity of BPAR (5.6% vs. 7.8%), the degree of proteinuria (20.2 ± 13.9 vs. 30.6 ± 58.4 g/mol, P = 0.15), and the key safety parameters such as occurrence of urinary tract infections (24.1% vs. 15.5%, P = 0.10) were well comparable. CONCLUSIONS: In conclusion, usage of Real-World Data from patient registries such as CERTAIN to emulate the control cohort of an RCT is feasible and could facilitate the conduct of clinical trials in pediatric kidney transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Trasplante de Riñón , Niño , Humanos , Trasplante de Riñón/efectos adversos , Rechazo de Injerto/epidemiología , Rechazo de Injerto/prevención & control , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto , Sistema de Registros , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Infantile nephropathic cystinosis (INC) is a systemic lysosomal storage disease causing intracellular cystine accumulation, resulting in renal Fanconi syndrome, progressive kidney disease (CKD), rickets, malnutrition, and myopathy. An INC-specific disproportionately diminished trunk length compared to leg length poses questions regarding the functionality of the trunk. METHODS: Thus, we prospectively investigated thoracic dimensions and proportions, as well as their clinical determinants in 44 pediatric patients with INC with CKD stages 1-5 and 97 age-matched patients with CKD of other etiology between the ages of 2-17 years. A total of 92 and 221 annual measurements of patients with INC and CKD, respectively, were performed, and associations between anthropometric and clinical parameters were assessed using linear mixed-effects models. RESULTS: Patients with INC exhibited altered chest dimensions that were distinct from CKD controls, characterized by markedly increased chest depth to height and chest depth to chest width ratio z-scores (> 1.0), while those of patients with CKD were only mildly affected (z-score within ± 1.0). Ratio z-scores differed significantly between both patient groups from 2-6 years of age onward. The degree of chest disproportion in INC patients was significantly associated with both the degree of CKD and tubular dysfunction (e.g., low serum phosphate and bicarbonate) across three different age groups (2-6, 7-12, and 13-17 years). CONCLUSION: Our data show an INC-specific alteration in thoracic shape from early childhood onward, which is distinct from CKD of other etiologies, suggesting early childhood subclinical changes of the musculoskeletal unit of the thoracic cage, which are associated with kidney function. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Cistinosis , Síndrome de Fanconi , Insuficiencia Renal Crónica , Humanos , Niño , Preescolar , Adolescente , Cistinosis/complicaciones , Riñón , Síndrome de Fanconi/complicaciones , Insuficiencia Renal Crónica/complicacionesRESUMEN
The aim of this retrospective analysis was to provide information on how infections with respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) differ in symptoms, clinical course, outcome, and utilization of hospital care. We investigated 748 polymerase chain reaction results from symptomatic children aged 0-4 years in Cologne, Germany. One hundred sixty-nine patients tested positive for RSV (22.6%) and 24 children for SARS-CoV-2 (3.2%). Symptomatic patients with RSV infection were hospitalized significantly longer. RSV-positive patients needed oxygen supplementation significantly more often as well as high-flow therapy. With regard to care efforts, RSV-infected patients put higher pressure on the hospital and utilized more hospital resources.
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COVID-19 , Infecciones por Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Infecciones del Sistema Respiratorio , Humanos , Niño , Lactante , Estudios Retrospectivos , Hospitalización , COVID-19/epidemiología , SARS-CoV-2 , Virus Sincitial Respiratorio Humano/genética , Alemania/epidemiología , MorbilidadRESUMEN
Children with infantile nephropathic cystinosis (INC), an inherited lysosomal storage disease resulting in cystine accumulation in all body cells, are prone to progressive chronic kidney disease (CKD), impaired growth and reduced weight gain; however, systematic anthropometric analyses are lacking. In this prospective multicenter study we investigated linear growth, body proportion, body mass index (BMI), upper arm fat area (UFA) and biochemical parameters in 43 pediatric INC patients with CKD stages 1 to 5 and 49 age-matched CKD controls, with 193 annual measurements. INC patients showed more impaired height than CKD controls (-1.8 vs -0.7 z-score; P < .001), despite adequate cysteamine therapy, treatment for Fanconi syndrome and more frequent use of growth hormone. Only the youngest INC patients shared the same body pattern with CKD controls characterized by preferential impairment of leg length and rather preserved trunk length. In late-prepuberty, body pattern changed only in INC patients due to improved leg growth and more impaired trunk length. Mean UFA z-score in INC patients was slightly reduced in early childhood and progressively decreased thereafter reaching -0.8 z-score in adolescence, while CKD controls showed a steady increase in standardized BMI and UFA especially during adolescent age. Menarche in female INC patients was significantly delayed compared to CKD controls. Our data indicate that with age and progression of disease, pediatric INC patients undergo unique changes of body growth and fat stores that are distinct from those with CKD stemming from other causes, suggesting other factors apart from CKD to contribute to this development. Pediatric patients with infantile nephropathic cystinosis display more severe impaired linear growth than other peer CKD patients, despite of cysteamine treatment, supplementation for Fanconi syndrome, and more frequent use of growth hormone, with a distinct change of body proportions and overall lower body fat.
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Cistinosis , Síndrome de Fanconi , Insuficiencia Renal Crónica , Tejido Adiposo , Adolescente , Brazo , Niño , Preescolar , Cisteamina/uso terapéutico , Cistinosis/tratamiento farmacológico , Síndrome de Fanconi/tratamiento farmacológico , Femenino , Hormona del Crecimiento/uso terapéutico , Humanos , Masculino , Estudios ProspectivosRESUMEN
PURPOSE OF REVIEW: The purpose of this update is to summarize current knowledge on the pathophysiology of immunglobulin A (IgA) vasculitis nephritis (IgAVN) as well as to critically review evidence for established therapeutic regimes and available biomarkers. An additional purpose is to raise the discussion what could be done to further improve our understanding of IgAVN, identify patients at risk for adverse outcome and increase the evidence for therapy recommendations. RECENT FINDINGS: Clinical and experimental studies have established the concept of a multilevel pathogenesis. Toll-like-receptor activation, B cell proliferation, micro-RNAs and complement activation have been identified or confirmed as potential therapeutic targets which can modify the course of the disease. Currently, kidney injury molecule-1, monocyte chemotactic protein-1, N-acetyl-ß-glucosaminidase, and angiotensinogen are the most promising urinary biomarkers for early diagnosis of renal involvement in IgA vasculitis. SUMMARY: Close surveillance of all IgAV patients for renal involvement is recommended. Given the multilevel pathogenesis, early treatment of even mild cases should be initiated. Further therapeutic options should be considered in case first-line therapy (mostly corticosteroids) has no effect. The evidence supporting current therapeutic regimes is predominantly based on expert opinion. Prospective studies are needed and should involve substances inhibiting B cell proliferation and complement activation.
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Vasculitis por IgA , Enfermedades Renales , Nefritis , Biomarcadores , Femenino , Humanos , Vasculitis por IgA/diagnóstico , Vasculitis por IgA/tratamiento farmacológico , Inmunoglobulina A , Masculino , Nefritis/etiologíaRESUMEN
BACKGROUND: Asymptomatic hyperuricemia is frequently observed in pediatric kidney transplant recipients; symptomatic hyperuricemia, however, is a rare complication. Only few data are available in this patient population. We, therefore, investigated the prevalence of hyperuricemia and its association with kidney transplant function and blood pressure in a multicenter cohort of pediatric kidney transplant recipients. METHODS: This is a retrospective, observational multicenter registry study. All pediatric kidney transplant recipients in the CERTAIN database with at least one documented serum uric acid level and a follow-up of 5 years posttransplant were eligible. We identified 151 patients with 395 measurements of serum uric acid. We calculated the prevalence of hyperuricemia, analyzed potential risk factors and clinical consequences such as elevated blood pressure and reduced estimated glomerular filtration rate (eGFR). Statistical analysis was performed using IBM SPSS Statistics 26. RESULTS: One hundred and ten of 395 (27.8%) serum uric acid levels were above 416 µmol/L (7.0 mg/dL), defined as the upper limit of normal. Univariate analysis showed a significant (p = .026) inverse association of serum uric acid with eGFR overtime. There was no significant association of serum uric acid concentrations with body mass index (z-score), blood pressure (z-score), or sex. No episodes of gout were documented. CONCLUSION: This study shows that hyperuricemia is present in a considerable number of patients sometime after pediatric kidney transplantation and is associated with lower eGFR. Whether hyperuricemia contributes to faster decline of graft function or to the overall cardiovascular risk of these patients remains to be elucidated.
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Hiperuricemia , Trasplante de Riñón , Niño , Tasa de Filtración Glomerular/fisiología , Humanos , Hiperuricemia/complicaciones , Hiperuricemia/diagnóstico , Hiperuricemia/epidemiología , Trasplante de Riñón/efectos adversos , Prevalencia , Sistema de Registros , Factores de Riesgo , Ácido ÚricoRESUMEN
BACKGROUND: Preexistent LUTD are considered a hostile environment, which might negatively impact KTx survival. In such cases, surgical reconstruction of the bladder is required. However, there is still disagreement on the optimal timing of the reconstruction procedure. METHODS: This is a multicenter analysis of data from the CERTAIN Registry. Included were 62 children aged 8.18 ± 4.90 years, with LUTD. Study endpoints were the duration of initial posttransplant hospitalization, febrile UTIs, and a composite failure endpoint comprising decline of eGFR, graft loss, or death up to 5 years posttransplant. Outcome was compared to matched controls without bladder dysfunction. RESULTS: Forty-one patients (66.1%) underwent pretransplant and 14 patients (22.6%) posttransplant reconstruction. Bladder augmentation was performed more frequently in the pretransplant (61%) than in the posttransplant group (21%, p = .013). Outcome in the pre- and posttransplant groups and in the subgroups of patients on pretransplant PD with major bladder surgery either pre- (n = 14) or posttransplant (n = 7) was comparable. Outcomes of the main study cohort and the matched control cohort (n = 119) were comparable during the first 4 years posttransplant; at year 5, there were more events of transplant dysfunction in the study cohort with LUTD than in controls (p = .03). CONCLUSIONS: This multicenter analysis of the current practice of LUTD reconstruction in pediatric KTx recipients shows that pre- or posttransplant surgical reconstruction of the lower urinary tract is associated with a comparable 5-year outcome.
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Trasplante de Riñón , Infecciones Urinarias , Niño , Estudios de Cohortes , Supervivencia de Injerto , Humanos , Receptores de Trasplantes , Vejiga Urinaria/cirugía , Infecciones Urinarias/etiologíaRESUMEN
BACKGROUND: Chronic kidney disease (CKD) still leads to high mortality rates, mainly due to cardiovascular disease. One important influencing factor is persisting low-grade chronic inflammation partly maintained by gingivitis that favors transient bacteremia during daily activities such as toothbrushing. METHODS: To examine whether intensive dental prophylaxis can restore oral health, reduce the prevalence of bacteremia and degree of systemic inflammation indicated by CRP levels, we conducted this pilot study examining 30 CKD patients aged 6-26 years, 15 receiving intensive prophylaxis (IP), 15 receiving treatment as usual (TAU) serving as control group. There were three appointments for examination, each 10 ± 1 weeks apart (at baseline, after intervention periods one and two, when TAU also received IP, and the IP group stopped prophylaxis). RESULTS: The gingival index (GI) in the IP group decreased by 90% (GI 0.09; p=0.001), resulting in almost healthy gingiva. There was no significant change in CRP or prevalence of bacteremia. General prevalence of bacteremia after toothbrushing was 9.5% affecting 7 (26%) of the participants. In three participants, bacteremia dissolved after IP, in one after TAU. Two patients developed bacteremia ≥ 10 weeks after ending IP. We identified eight different bacterial species. CONCLUSIONS: We were able to show that IP can effectively treat gingivitis. It might be a promising approach to reduce systemic inflammation and subsequently lower premature cardiovascular disease, despite the lack of statistical significance. Future research requires a larger patient cohort to enable matched treatment groups with long-term follow-up and molecular detection methods for bacteremia. A higher resolution version of the Graphical abstract is available as Supplementary information.
Asunto(s)
Bacteriemia , Enfermedades Cardiovasculares , Gingivitis , Insuficiencia Renal Crónica , Adolescente , Bacteriemia/epidemiología , Bacteriemia/etiología , Bacteriemia/prevención & control , Niño , Profilaxis Dental , Femenino , Gingivitis/epidemiología , Gingivitis/etiología , Gingivitis/prevención & control , Humanos , Masculino , Proyectos Piloto , Insuficiencia Renal Crónica/complicaciones , Cepillado Dental/métodos , Adulto JovenRESUMEN
BACKGROUND: Pharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after transplantation. Virus-specific T cells correlate with both virus-specific and general cellular immune defense. Additional steering of immunosuppressive therapy by virus-specific T cell levels might optimize dosing of immunosuppressants. METHODS: In a multicenter, randomized, controlled trial, we randomized 64 pediatric kidney recipients to a control group with trough-level monitoring of immunosuppressants or to an intervention group with additional steering of immunosuppressive therapy by levels of virus-specific T cells (quantified by cytokine flow cytometry). Both groups received immunosuppression with cyclosporin A and everolimus in the same target range of trough levels. Primary end point was eGFR 2 years after transplantation. RESULTS: In the primary analysis, we detected no difference in eGFR for the intervention and control groups 2 years after transplantation, although baseline eGFR 1 month after transplantation was lower in the intervention group versus the control group. Compared with controls, patients in the intervention group received significantly lower daily doses of everolimus and nonsignificantly lower doses of cyclosporin A, resulting in significantly lower trough levels of everolimus (3.5 versus 4.5 µg/L, P<0.001) and cyclosporin A (47.4 versus 64.1 µg/L, P<0.001). Only 20% of patients in the intervention group versus 47% in the control group received glucocorticoids 2 years after transplantation (P=0.04). The groups had similar numbers of donor-specific antibodies and serious adverse events. CONCLUSIONS: Steering immunosuppressive therapy by virus-specific T cell levels in addition to pharmacokinetic monitoring seems safe, results in a similar eGFR, and personalizes immunosuppressive therapy by lowering exposure to immunosuppressive drugs, likely resulting in lower drug costs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: IVIST trial, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2009-012436-32 and ISRCTN89806912.
Asunto(s)
Ciclosporina/administración & dosificación , Everolimus/administración & dosificación , Rechazo de Injerto/prevención & control , Inmunosupresores/administración & dosificación , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Adolescente , Recuento de Linfocito CD4 , Niño , Preescolar , Esquema de Medicación , Monitoreo de Drogas , Femenino , Rechazo de Injerto/sangre , Rechazo de Injerto/diagnóstico , Humanos , Lactante , Fallo Renal Crónico/sangre , Fallo Renal Crónico/etiología , MasculinoRESUMEN
Autosomal recessive polycystic kidney disease (ARPKD) is a severe disease of early childhood that is clinically characterized by fibrocystic changes of the kidneys and the liver. The main cause of ARPKD are variants in the PKHD1 gene encoding the large transmembrane protein fibrocystin. The mechanisms underlying the observed clinical heterogeneity in ARPKD remain incompletely understood, partly due to the fact that genotype-phenotype correlations have been limited to the association of biallelic null variants in PKHD1 with the most severe phenotypes. In this observational study we analyzed a deep clinical dataset of 304 patients with ARPKD from two independent cohorts and identified novel genotype-phenotype correlations during childhood and adolescence. Biallelic null variants frequently show severe courses. Additionally, our data suggest that the affected region in PKHD1 is important in determining the phenotype. Patients with two missense variants affecting amino acids 709-1837 of fibrocystin or a missense variant in this region and a null variant less frequently developed chronic kidney failure, and patients with missense variants affecting amino acids 1838-2624 showed better hepatic outcome. Variants affecting amino acids 2625-4074 of fibrocystin were associated with poorer hepatic outcome. Thus, our data expand the understanding of genotype-phenotype correlations in pediatric ARPKD patients and can lay the foundation for more precise and personalized counselling and treatment approaches.