RESUMO
Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below age 30 years. Many monogenic forms have been discovered due to comprehensive genetic testing like exome sequencing. However, disease-causing variants in known disease-associated genes only explain a proportion of cases. Here, we aim to unravel underlying molecular mechanisms of syndromic CAKUT in three unrelated multiplex families with presumed autosomal recessive inheritance. Exome sequencing in the index individuals revealed three different rare homozygous variants in FOXD2, encoding a transcription factor not previously implicated in CAKUT in humans: a frameshift in the Arabic and a missense variant each in the Turkish and the Israeli family with segregation patterns consistent with autosomal recessive inheritance. CRISPR/Cas9-derived Foxd2 knockout mice presented with a bilateral dilated kidney pelvis accompanied by atrophy of the kidney papilla and mandibular, ophthalmologic, and behavioral anomalies, recapitulating the human phenotype. In a complementary approach to study pathomechanisms of FOXD2-dysfunction-mediated developmental kidney defects, we generated CRISPR/Cas9-mediated knockout of Foxd2 in ureteric bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important for kidney/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a shift toward a stromal cell identity. Histology of Foxd2 knockout mouse kidneys confirmed increased fibrosis. Further, genome-wide association studies suggest that FOXD2 could play a role for maintenance of podocyte integrity during adulthood. Thus, our studies help in genetic diagnostics of monogenic CAKUT and in understanding of monogenic and multifactorial kidney diseases.
Assuntos
Estruturas Embrionárias , Fatores de Transcrição Forkhead , Nefropatias , Rim , Néfrons , Sistema Urinário , Anormalidades Urogenitais , Refluxo Vesicoureteral , Adulto , Animais , Humanos , Camundongos , Estudo de Associação Genômica Ampla , Rim/anormalidades , Rim/embriologia , Nefropatias/genética , Camundongos Knockout , Néfrons/embriologia , Fatores de Transcrição/genética , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Fatores de Transcrição Forkhead/deficiência , Fatores de Transcrição Forkhead/metabolismoRESUMO
BACKGROUND/AIMS: Two earthquakes on February 6th, 2023 destroyed ten cities in Türkiye. We report our experience with pediatric victims during these catastrophes, with a focus on crush syndrome related-acute kidney injury (Crush-AKI) and death. METHOD: A web-based software was prepared. Patient demographics, time under rubble (TUR), admission laboratory data, dialysis, and kidney and overall outcomes were asked. RESULTS: 903 injured children (median age: 11.62 years) were evaluated. Mean TUR was 13 h (Interquartile range-IQR: 32.5), max 240 h). 31 of 32 patients with a TUR of >120 h survived. The patient who rescued after ten days survived.Two-thirds of the patients were given 50 mEq/L sodium-bicarbonate in 0.45% sodium-chloride solution on admission day. 58% of patients were given intravenous fluid (IVF) at a volume of 2000-3000 mL/m2 body surface area (BSA), 40% of 3000-4000 mL/m2 BSA, and only 2% of >4000 mL/m2 BSA. 425 patients had surgeries, 48 suffered from major bleeding. Amputations were recorded in 96 patients. Eighty-two and 66 patients required ventilator and inotropic support, respectively.Crush-AKI developed in 314 patients (36% of all patients). 189 patients were dialyzed. Age > 15 years, creatine phosphokinase (CK)≥20 950 U/L, TUR≥10 h, and the first-day IVF volume < 3000-4000 mL/m2 BSA were associated with Crush-AKI development. 22 deaths were recorded, 20 of 22 occurred in patients with Crush-AKI and within the first 4 days of admission. All patients admitted after 7 days survived. CONCLUSIONS: This is the most extensive pediatric kidney disaster data after an earthquake. Serum CK level was significantly associated with Crush-AKI at the levels of >20 950 U/L, but not with death. Adolescent age and initial IVF of less than 3000-4000 mL/m2 BSA were also asscoiated with Crush-AKI. Given that mildly injured victims can survive longer periods in the disaster field, we suggest uninterrupted rescue activity for at least 10 days.
RESUMO
BACKGROUND: Primary hyperoxaluria type 1 (PH1) is characterized by increased endogenous oxalate production and deposition as calcium oxalate crystals. The main manifestations are nephrocalcinosis/nephrolithiasis, causing impaired kidney function. We aimed to evaluate the clinical characteristics and overall outcomes of paediatric PH1 patients in Turkey. METHODS: This is a nationwide, multicentre, retrospective study evaluating all available paediatric PH1 patients from 15 different paediatric nephrology centres in Turkey. Detailed patient data was collected which included demographic, clinical and laboratory features. Patients were classified according to their age and characteristics at presentation: patients presenting in the first year of life with nephrocalcinosis/nephrolithiasis (infantile oxalosis, Group 1), cases with recurrent nephrolithiasis diagnosed during childhood (childhood-onset PH1, Group 2), and asymptomatic children diagnosed with family screening (Group 3). RESULTS: Forty-eight patients had a mutation consistent with PH1. The most common mutation was c.971_972delTG (25%). Infantile oxalosis patients had more advanced chronic kidney disease (CKD) or kidney failure necessitating dialysis (76.9% vs. 45.5%). These patients had much worse clinical course and mortality rates seemed to be higher (23.1% vs. 13.6%). Patients with fatal outcomes were the ones with significant comorbidities, especially with cardiovascular involvement. Patients in Group 3 were followed with better outcomes, with no kidney failure or mortality. CONCLUSION: PH1 is not an isolated kidney disease but a systemic disease. Family screening helps to preserve kidney function and prevent systemic complications. Despite all efforts made with traditional treatment methods including transplantation, our results show devastating outcomes or mortality.
Assuntos
Hiperoxalúria Primária , Hiperoxalúria , Falência Renal Crônica , Nefrocalcinose , Nefrolitíase , Insuficiência Renal , Humanos , Criança , Nefrocalcinose/diagnóstico , Nefrocalcinose/epidemiologia , Nefrocalcinose/etiologia , Estudos Retrospectivos , Falência Renal Crônica/complicações , Diálise Renal/efeitos adversos , Hiperoxalúria Primária/complicações , Hiperoxalúria Primária/diagnóstico , Hiperoxalúria Primária/genética , Nefrolitíase/complicações , Nefrolitíase/diagnóstico , Nefrolitíase/genética , Hiperoxalúria/complicaçõesRESUMO
In this era of rapidly advancing technology, artificial intelligence (AI) has emerged as a transformative force, even being called the Fourth Industrial Revolution, along with gene editing and robotics. While it has undoubtedly become an increasingly important part of our daily lives, it must be recognized that it is not an additional tool, but rather a complex concept that poses a variety of challenges. AI, with considerable potential, has found its place in both medical care and clinical research. Within the vast field of pediatrics, it stands out as a particularly promising advancement. As pediatricians, we are indeed witnessing the impactful integration of AI-based applications into our daily clinical practice and research efforts. These tools are being used for simple to more complex tasks such as diagnosing clinically challenging conditions, predicting disease outcomes, creating treatment plans, educating both patients and healthcare professionals, and generating accurate medical records or scientific papers. In conclusion, the multifaceted applications of AI in pediatrics will increase efficiency and improve the quality of healthcare and research. However, there are certain risks and threats accompanying this advancement including the biases that may contribute to health disparities and, inaccuracies. Therefore, it is crucial to recognize and address the technical, ethical, and legal challenges as well as explore the benefits in both clinical and research fields.
RESUMO
BACKGROUND: Relapses or new-onset IgA nephropathy (IgAN) have been documented in patients after vaccination against SARS-CoV-2; however, only one adult patient has been reported in whom pre-existing IgAN worsened during coronavirus disease 2019 (COVID-19). CASE: We present the first pediatric case with biopsy-proven IgAN and genetically confirmed Alport syndrome, who developed end-stage kidney disease after an exacerbation of IgAN associated with COVID-19. The patient`s basal serum creatinine was 0.7-0.9 mg/dL before infection. He had not been vaccinated against COVID-19. He was admitted to the hospital with edema, hypertension, an elevated serum creatinine of 4.7 mg/ dL, and massive proteinuria. Three months before admission, he had been admitted to another hospital with COVID -19 and an elevated serum creatinine (1.9 mg/dL), but no biopsy had been performed at that time. The kidney biopsy revealed IgAN with 50% fibrocellular crescents with sclerosed glomeruli, tubular atrophy, and interstitial fibrosis. His serum creatinine did not decrease even after five administrations of pulse steroids, and hemodialysis was initiated. CONCLUSION: In conclusion, COVID -19 may pose a high risk for exacerbation of pre-existing glomerular disease. It is therefore necessary to closely monitor the kidney function of patients with underlying glomerulonephritis during and after COVID-19 and consider an early biopsy if serum creatinine does not return to baseline levels. In addition, this case report highlights the clinical importance of the co-occurence of IgAN and Alport syndrome.
Assuntos
COVID-19 , Glomerulonefrite por IGA , Glomerulonefrite , Nefrite Hereditária , Masculino , Adulto , Humanos , Criança , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/diagnóstico , Nefrite Hereditária/complicações , Creatinina , COVID-19/complicações , SARS-CoV-2 , Doença AgudaRESUMO
Introduction: In the pediatric context, most children with autosomal dominant polycystic kidney disease (ADPKD) maintain a normal glomerular filtration rate (GFR) despite underlying structural kidney damage, highlighting the critical need for early intervention and predictive markers. Due to the inverse relationship between kidney volume and kidney function, risk assessments have been presented on the basis of kidney volume. The aim of this study was to use magnetic resonance imaging (MRI)-based kidney volume assessment for risk stratification in pediatric ADPKD and to investigate clinical and genetic differences among risk groups. Methods: This multicenter, cross-sectional, and case-control study included 75 genetically confirmed pediatric ADPKD patients (5-18 years) and 27 controls. Kidney function was assessed by eGFR calculated from serum creatinine and cystatin C using the CKiD-U25 equation. Blood pressure was assessed by both office and 24-hour ambulatory measurements. Kidney volume was calculated from MRI using the stereological method. Total kidney volume was adjusted for the height (htTKV). Patients were stratified from A to E classes according to the Leuven Imaging Classification (LIC) using MRI-derived htTKV. Results: Median (Q1-Q3) age of the patients was 6.0 (2.0-10.0) years, 56% were male. There were no differences in sex, age, height-SDS, or GFR between the patient and control groups. Of the patients, 89% had PKD1 and 11% had PKD2 mutations. Non-missense mutations were 73% in PKD1 and 75% in PKD2. Twenty patients (27%) had hypertension based on ABPM. Median htTKV of the patients was significantly higher than controls (141 vs. 117â ml/m, p = 0.0003). LIC stratification revealed Classes A (38.7%), B (28%), C (24%), and D + E (9.3%). All children in class D + E and 94% in class C had PKD1 variants. Class D + E patients had significantly higher blood pressure values and hypertension compared to other classes (p > 0.05 for all). Discussion: This study distinguishes itself by using MRI-based measurements of kidney volume to stratify pediatric ADPKD patients into specific risk groups. It is important to note that PKD1 mutation and elevated blood pressure were higher in the high-risk groups stratified by age and kidney volume. Our results need to be confirmed in further studies.
RESUMO
BACKGROUND: Kidney transplantation (KTx) from small donors is associated with inferior graft survival in registry studies, whereas single-center studies show favorable results. METHODS: We compared 175 pediatric KTx from small donors ≤20 kg (SDKTx) with 170 age-matched recipients from adult donors (ADKTx) from 20 centers within the Cooperative European Paediatric Renal Transplant Initiative registry. Graft survival and estimated glomerular filtration rate (eGFR) were analyzed by Cox regression and mixed models. Detailed data on surgical and medical management were tested for association with graft survival. RESULTS: One-year graft survival was lower after SDKTx compared with ADKTx (90.9% versus 96.5%; odds ratio of graft loss, 2.92; 95% confidence interval [CI], 1.10-7.80; P â =â 0.032), but 5-y graft survival was comparable (90.9% versus 92.7%; adjusted hazard ratio of graft loss 1.9; 95% CI, 0.85-4.25; P â =â 0.119). SDKTx recipients had an annual eGFR increase of 8.7â ±â 6.2 mL/min/1.73 m² compared with a decrease of 6.9â ±â 5.7 mL/min/1.73 m² in ADKTx recipients resulting in a superior 5-y eGFR (80.5â ±â 25.5 in SDKTx versus 65.7â ±â 23.1 mL/min/1.73 m² in ADKTx; P â =â 0.008). At 3 y posttransplant, eGFR after single SDKTx was lower than after en bloc SDKTx (86.6â ±â 20.4 versus 104.6â ±â 35.9; P â =â 0.043) but superior to ADKTx (68.1â ±â 23.9 mL/min/1.73 m²). Single-kidney SDKTx recipients had a lower rate of hypertension at 3 y than ADKTx recipients (40.0% versus 64.7%; P â =â 0.008). CONCLUSIONS: Compared with ADKTx, 5-y graft function is superior in SDKTx and graft survival is similar, even when performed as single KTx. Utilizing small donor organs, preferably as single kidneys in experienced centers, is a viable option to increase the donor pool for pediatric recipients.