A case of crescentic glomerulonephritis with exacerbation of pre-existing IgA nephropathy after COVID-19.

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.

Artificial Intelligence in Pediatrics: Learning to Walk Together.

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.

Magnetic resonance imaging based kidney volume assessment for risk stratification in pediatric autosomal dominant polycystic kidney disease.

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. 117 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.

Long-term Effects of Kidney Transplantation Compared With Dialysis on Intima-media Thickness in Children-Results From the 4C-T Study.

BACKGROUND: Children requiring kidney replacement therapy experience high burden of cardiovascular (CV) disease leading to increased mortality. Intima-media thickness (IMT) indicating atherosclerosis is a validated surrogate marker for future CV events. METHODS: We investigated the effect of different treatment modalities (dialysis, preemptive kidney transplantation (KTx), late KTx after dialysis) on IMT by multivariable linear mixed-effect modeling. Patients were enrolled in a prospective cohort study. RESULTS: A total of 261 analyzed children had a mean follow-up of 3 y. Children after preemptive and late KTx had lower levels of IMT when compared with dialysis. Using an interaction term, a significant progression of IMT over time was seen during dialysis (ß = 0.0053 mm/y, P   =  0.004). IMT before the start of therapy was the most influential determinant in all models. Low IMT was associated with maintenance steroid treatment after preemptive KTx. High IMT on dialysis was associated with higher systolic blood pressure, lower body mass index, lower serum albumin, and lower bicarbonate. CONCLUSIONS: IMT remained rather stable in children several years after KTx. In contrast, children on dialysis had higher IMT values, which increased over time. In these children, blood pressure control, calorie and protein intake, and acid-base homeostasis seem important. Taken together, children might profit from early transplantation to limit accumulation of CV risk.

Outcome of immunosuppression in children with IgA vasculitis-related nephritis.

BACKGROUND AND HYPOTHESIS: IgA vasculitis with nephritis (IgAVN) is the most common vasculitis in children. Treatment recommendations are, due to a lack of evidence, based on expert opinion resulting in variation. The aim of this study was to describe clinical presentation, treatment and outcome of an extremely large cohort of children with biopsy proven IgAVN to identify prognostic risk factors and signals of treatment efficacy. METHODS: Retrospective data were collected on 1148 children with biopsy proven IgAVN between 2005 and 2019 from 41 international paediatric nephrology centres across 25 countries and analyzed using multivariate analysis. The primary outcome was estimated glomerular filtration rate (eGFR) and persistent proteinuria at last follow up. RESULTS: The median follow up was 3.7 years (IQR 2-6.2). At last follow up, 29% of patients had an eGFR < 90 ml/min/1.73m2, 36% had proteinuria and 3% had chronic kidney disease stage 4-5. Older age, lower eGFR at onset, hypertension and histological features of tubular atrophy and segmental sclerosis were predictors of poor outcome. There was no evidence to support any specific second line immunosuppressive regimen to be superior to others, even when further analysing subgroups of children with reduced kidney function, nephrotic syndrome or hypoalbuminemia at onset. Delayed start of immunosuppressive treatment was associated with a lower eGFR at last follow up. CONCLUSION: In this large retrospective cohort, key features associated with disease outcome are highlighted. Importantly there was no evidence to support that any specific immunosuppressive treatments were superior to others. Further discovery science and well-conducted clinical trials are needed to define accurate treatment and improve outcomes of IgAVN.

Children With Type 1 Spinal Muscular Atrophy Are at Increased Risk for Nephrolithiasis.

BACKGROUND: Nephrolithiasis is not a well-documented condition in children with spinal muscular atrophy (SMA). It is possible that this condition was underestimated before the era of nusinersen because of a much shorter life expectancy. We present our observational data on nephrolithiasis and its possible risk factors in children with type 1 SMA. METHODS: We retrospectively reviewed the charts of 20 children with genetically confirmed type 1 SMA. Thirteen patients (aged 9 to 55 months) who underwent urinary tract ultrasonography were included in the study. Medical records were retrospectively reviewed for demographic and clinical characteristics, ultrasound results, and metabolic abnormalities. RESULTS: Seven children (54%) had nephrolithiasis; 5 had multiple stones and two had a single stone. Two patients had microlithiasis (<3 mm), three had a stone in the size of 3 to 5 mm, and one had a stone in the size of more than 8 mm. Two patients with nephrolithiasis had urinary tract abnormalities. Patients with nephrolithiasis were more likely to have a history of urinary tract infections (UTIs) (P = 0.048) and higher urine specific gravity (P = 0.014) than patients without nephrolithiasis. Five of seven children with nephrolithiasis had a urine metabolic evaluation; all had hypercalciuria, three had hyperuricosuria, but none had hyperoxaluria, hypocitraturia, or hypomagnesemia. CONCLUSION: Children with SMA type 1 are at an increased risk for nephrolithiasis. Hypercalciuria and high urine specific gravity appear to be the most common risk factors for the occurrence of nephrolithiasis. In addition, UTI is more common in patients with type 1 SMA with nephrolithiasis.

Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT).

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.

Complement gene mutations in children with C3 glomerulopathy: do they affect the response to mycophenolate mofetil?

BACKGROUND: C3 glomerulopathy (C3G) is a complement-mediated disease. Although genetic studies are not required for diagnosis, they are valuable for treatment planning and prognosis prediction. The aim of this study is to investigate the clinical phenotypes, kidney survival, and response to mycophenolate mofetil (MMF) treatment in pediatric C3G patients with and without mutations in complement-related genes. METHODS: Sixty pediatric C3G patients were included, divided into two groups based on complement-related gene mutations. Demographic and clinical-pathological findings, treatment modalities, and outcome data were compared, and Kaplan-Meier analysis was performed for kidney survival. RESULTS: Out of the 60 patients, 17 had mutations. The most common mutation was in the CFH gene (47%). The mean age at diagnosis was higher in the group with mutation (12.9 ± 3.6 vs. 11.2 ± 4.1 years, p = 0.039). While the patients without mutation most frequently presented with nephritic syndrome (44.2%), the mutation group was most likely to have asymptomatic urinary abnormalities (47.1%, p = 0.043). Serum parameters and histopathological characteristics were similar, but hypoalbuminemia was more common in patients without mutation. During 45-month follow-up,10 patients progressed to chronic kidney disease stage 5 (CKD5), with 4 having genetic mutation. The time to develop CKD5 was longer in the mutation group but not significant. MMF treatment had no effect on progression in either group. CONCLUSIONS: This study is the largest pediatric C3G study examining the relationship between genotype and phenotype. We showed that the mutation group often presented with asymptomatic urinary abnormalities, was diagnosed relatively late but was not different from the without mutation group in terms of MMF treatment response and kidney survival. A higher resolution version of the Graphical abstract is available as Supplementary information.

Stricter Blood Pressure Control Is Associated With Lower Left Ventricular Mass in Children After Kidney Transplantation: A Longitudinal Analysis of the 4C-T Study.

BACKGROUND: We assessed the effect of blood pressure (BP) control on left ventricular mass index (LVMI) and left ventricular hypertrophy (LVH). METHODS: Ninety-six patients (64 males) ≥9 months post-kidney transplantation from the 4C-T (Cardiovascular Comorbidity in Children with Chronic Kidney Disease and Transplantation) study were analyzed longitudinally (mean follow-up, 2.6±1.3 years). Cumulative systolic blood pressure (SBP)/diastolic BP exposure was calculated as a time-averaged area under the curve and categorized: ≤50th, 50th to ≤75th, 75th to ≤90th, and >90th percentile (pct). We performed adjusted linear and logistic mixed models for LVMI and LVH, respectively. RESULTS: At baseline, LVMI was 49.7±12.7g/m2.16 with 64% (n=61) kidney transplantation recipients displaying LVH. Compared with patients with cumulative SBP exposure >90th pct, patients with cumulative SBP of 50th to ≤75th showed a significant LVMI reduction of -5.24g/m2.16 (P=0.007). A similar tendency was seen for cumulative SBP≤50th (ß=-3.70 g/m2.16; P=0.067), but patients with cumulative SBP of 75th to ≤90th pct showed no reduction. A post hoc analysis in patients with cumulative SBP≤75th revealed that median SBP exposure was at 57.5th pct. For cumulative diastolic BP, a significant LVMI reduction was seen in all 3 categories ≤90th pct compared with patients >90th pct. Patients with cumulative SBP of ≤50th or 50th to ≤75th pct showed 79% or 83% lower odds of developing LVH, respectively. Patients with cumulative diastolic BP ≤50th showed a tendency of 82% lower odds for LVH (95% CI, 0.03-1.07). CONCLUSIONS: Stricter BP control led to regression of LVMI and LVH. Our data suggest a BP target below the 60th pct, which needs to be substantiated in a randomized controlled trial.

COVID-19 associated thrombotic microangiopathy.

A limited number of cases of thrombotic microangiopathy (TMA) have previously been reported in association with COVID-19. Our report describes two cases of TMA associated with COVID-19, one of which was successfully treated with eculizumab. The first case was a 23-month-old girl, and the second case was a 9-month-old boy. PCR tests for SARS-CoV-2 were positive in both cases, and laboratory results showed microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. No known aetiology for TMA was found in either case. Stool tests for Shigatoxin-producing Escherichia coli were negative. Coagulation tests, ADAMTS13 activity, serum complement levels, and homocysteine levels were all within the normal range. No known genetic mutation was found, including mutations of complement, diacylglycerol kinase epsilon, and cobalamin C. In the first case, eculizumab was administered due to persistent haemolysis and prolonged anuria. In conclusion, TMA may be associated with COVID-19 infection. Treatment with eculizumab may be beneficial in selected patients because of the potential activation of the complement system.

A novel homozygous missense variant in TBC1D31 in a consanguineous family with congenital anomalies of the kidney and urinary tract (CAKUT).

Congenital anomalies of the kidney and urinary tract (CAKUT) is the leading cause of chronic kidney disease in the first three decades of life. Until now, more than 180 monogenic causes of isolated or syndromic CAKUT have been described. In addition, copy number variants (CNV) have also been implicated, however, all of these causative factors only explain a small fraction of patients with CAKUT, suggesting that additional yet-to-be-discovered novel genes are present. Herein, we report three siblings (two of them are monozygotic twin) of a consanguineous family with CAKUT. Whole-exome sequencing identified a homozygous variant in TBC1D31. Three dimensional protein modeling as well as molecular dynamics simulations predicted it as pathogenic. We therefore showed for the first time an association between a homozygous TBC1D31 variant with CAKUT in humans, expanding its genetic spectrum.

Implication of FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT).

Background: Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below 30 years of age. Many monogenic forms have been discovered mainly due to comprehensive genetic testing like exome sequencing (ES). However, disease-causing variants in known disease-associated genes still only explain a proportion of cases. Aim of this study was to unravel the underlying molecular mechanism of syndromic CAKUT in two multiplex families with presumed autosomal recessive inheritance. Methods and Results: ES in the index individuals revealed two different rare homozygous variants in FOXD2, a transcription factor not previously implicated in CAKUT in humans: a frameshift in family 1 and a missense variant in family 2 with family segregation patterns consistent with autosomal-recessive inheritance. CRISPR/Cas9-derived Foxd2 knock-out (KO) mice presented with bilateral dilated renal pelvis accompanied by renal papilla atrophy while extrarenal features included mandibular, ophthalmologic, and behavioral anomalies, recapitulating the phenotype of humans with FOXD2 dysfunction. To study the pathomechanism of FOXD2-dysfunction-mediated developmental renal defects, in a complementary approach, we generated CRISPR/Cas9-mediated KO of Foxd2 in ureteric-bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important in renal/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a cell identity shift towards a stromal cell identity. Histology of Foxd2 KO mouse kidneys confirmed increased fibrosis. Further, GWAS data (genome-wide association studies) suggests that FOXD2 could play a role for maintenance of podocyte integrity during adulthood. Conclusions: In summary, our data implicate that FOXD2 dysfunction is a very rare cause of autosomal recessive syndromic CAKUT and suggest disturbances of the PAX2-WNT4 cell signaling axis contribute to this phenotype.

Cardiometabolic Risk Factors in Pediatric Kidney Transplant Recipients.

OBJECTIVE: There is an increased risk of obesity and metabolic syndrome among kidney transplant recipients, which adversely affects cardiovascular and renal outcomes in these patients. The present study aims to investigate the prevalence of metabolic syndrome in pediatric kidney transplant recipients and the associations of metabolic syndrome with cardiovascular disease and graft function. MATERIALS AND METHODS: This cross-sectional, single-center study included 52 kidney transplant recipients (27 males) transplanted before 18 years of age. All subjects underwent a comprehensive assessment that included anthropometric and blood pressure measurements and laboratory tests. Metabolic syndrome was defined based on the recent recommendations of the Pediatric Renal Nutrition Taskforce. Left ventricular hypertrophy was assessed as a risk factor for cardiovascular disease, and estimated glomerular filtration rate was assessed to determine graft function. RESULTS: The median age of patients was 15.9 (13.8;18.4) years, and the median follow-up time was 35.5 (20.0;62;0) months after transplantation. Nineteen patients (36.5%) were obese or overweight, 43 (83%) had hypertension or controlled hypertension, 23 (44%) had dyslipidemia, and 9 (17%) had hyperglycemia. Ten patients (19.2%) were diagnosed with metabolic syndrome. Twenty-eight patients (54%) had left ventricular hypertrophy. The prevalence of left ventricular hypertrophy was higher in patients with metabolic syndrome than in those without metabolic syndrome (90% vs. 45%, P = .014), whereas estimated glomerular filtration rate did not differ between the 2 groups. CONCLUSION: Cardiometabolic risk factors are common in pediatric kidney transplant recipients. Approximately one-fifth of patients have metabolic syndrome, and left ventricular hypertrophy is much more common among patients with metabolic syndrome. However, there is no relationship between metabolic syndrome and graft dysfunction.

Spatial Distribution of Macrophage Subtypes Among Rejection Subtypes in Renal Transplant Biopsies by Dual Immunohistochemistry.

We performed dual immunohistochemistry for CD163/CD34 and CD68/CD34 in 108 renal transplant indication biopsies to investigate the presence and distribution of macrophages in various renal compartments. All Banff scores and diagnoses were revised according to the Banff 2019 classification. CD163 and CD68 positive cell counts (CD163pos and CD68pos) were evaluated in the interstitium, glomerular mesangium, and, within glomerular and peritubular capillaries. The diagnosis was antibody-mediated rejection (ABMR) in 38 (35.2%), T-cell mediated rejection (TCMR) in 24 (22.2%), mixed rejection in 30 (27.8%), and no rejection in 16 (14.8%). Banff lesion scores t , i , and ti were correlated with both CD163 and CD68 interstitial inflammation scores ( r > 0.30; P < 0.05). Glomerular total CD163pos was correlated to Banff lesion scores g and cg ( r > 0.30; P < 0.05). Glomerular total, mesangial, and intracapillary CD68pos were correlated with g ( r > 0.30; P < 0.05). Both glomerular total and peritubular capillary CD68pos were correlated with peritubular capillaritis ( r > 0.30; P < 0.05). Glomerular CD163pos were significantly higher in ABMR compared with no rejection, in mixed rejection compared with no rejection and TCMR. CD163pos in peritubular capillaries was significantly higher in mixed rejection compared with no rejection. Glomerular CD68pos was significantly higher in ABMR compared with no rejection. CD68pos per peritubular capillary was higher in mixed rejection, ABMR, and TCMR compared with no rejection. In conclusion, compared with CD68 positive macrophages, localization of CD163 positive macrophages in various renal compartments seems to be different among rejection subtypes and their glomerular infiltration seems to be more specific for the presence of ABMR component.

Clinical and subclinical acute kidney injury in children with mild-to-moderate COVID-19.

BACKGROUND: Our aim was to identify acute kidney injury (AKI) and subacute kidney injury using both KDIGO criteria and urinary biomarkers in children with mild/moderate COVID-19. METHODS: This cross-sectional study included 71 children who were hospitalized with a diagnosis of COVID-19 from 3 centers in Istanbul and 75 healthy children. We used a combination of functional (serum creatinine) and damage (NGAL, KIM-1, and IL-18) markers for the definition of AKI and subclinical AKI. Clinical and laboratory features were evaluated as predictors of AKI and subclinical AKI. RESULTS: Patients had significantly higher levels of urinary biomarkers and urine albumin-creatinine ratio than healthy controls (p < 0.001). Twelve patients (16.9%) developed AKI based on KDIGO criteria, and 22 patients (31%) had subclinical AKI. AKI group had significantly higher values of neutrophil count on admission than both subclinical AKI and non-AKI groups (p < 0.05 for all). Neutrophil count was independently associated with the presence of AKI (p = 0.014). CONCLUSIONS: This study reveals that even children with a mild or moderate disease course are at risk for AKI. Association between neutrophil count and AKI may point out the role of inflammation in the development of AKI. IMPACT: The key message of our article is that not only children with severe disease but also children with mild or moderate disease have an increased risk for kidney injury due to COVID-19. Urinary biomarkers enable the diagnosis of a significant number of patients with subclinical AKI in patients without elevation in serum creatinine. Our findings reveal that patients with high neutrophil count may be more prone to develop AKI and should be followed up carefully. We conclude that even children with mild or moderate COVID-19 disease courses should be evaluated for AKI and subclinical AKI, which may improve patient outcomes.

Nutritional and Anthropometric Indices in Children Receiving Haemodiafiltration vs Conventional Haemodialysis - The HDF, Heart and Height (3H) Study.

BACKGROUND: The "HDF-Heart-Height" study showed that haemodiafiltration (HDF) is associated with improved growth compared to conventional haemodialysis (HD). We report a post-hoc analysis of this study assessing the effect of extracorporeal dialysis therapies on nutritional indices. METHODS: 107 children were included in the baseline cross-sectional analysis, of whom 79 (43 HD, 36 HDF) completed the 12-month follow-up. Height (Ht), optimal 'dry' weight (Wt), and body mass index (BMI) standard deviations scores (SDS), waist-to-hip ratio, des-acyl ghrelin (DAG), adiponectin, leptin, insulin-like growth factor-1 (IGF-1)-SDS and insulin were measured. RESULTS: The levels of nutritional indices were comparable between HDF and HD patients at baseline and 12-month. On univariable analyses Wt-SDS positively correlated with leptin and IGF-1-SDS, and negatively with DAG, while Ht-SDS of the overall cohort positively correlated with IGF1-SDS and inversely with DAG and adiponectin. On multivariable analyses, higher 12-month Ht-SDS was inversely associated with baseline DAG (beta = -0.13 per 500 higher; 95%CI -0.22, -0.04; P = .004). Higher Wt-SDS at 12-month was positively associated with HDF modality (beta = 0.47 vs HD; 95%CI 0.12-0.83; P = .01) and inversely with baseline DAG (beta = -0.18 per 500 higher; 95%CI -0.32, -0.05; P = .006). Growth Hormone (GH) treated patients receiving HDF had higher annualized increase in Ht SDS compared to those on HD. CONCLUSIONS: In children on HD and HDF both Wt- and Ht-SDS independently correlated with lower baseline levels of the anorexygenic hormone DAG. HDF may attenuate the resistance to GH, but further studies are required to examine the mechanisms linking HDF to improved growth.

A rare cause of nephrotic syndrome-sphingosine-1-phosphate lyase (SGPL1) deficiency: 6 cases and a review of the literature.

BACKGROUND: Recently, recessive mutations in SGPL1 (sphingosine-1-phosphate lyase), which encodes the final enzyme of sphingolipid metabolism, have been reported to cause steroid-resistant nephrotic syndrome, adrenal insufficiency, and many other organ/system involvements. We aimed to determine the clinical and genetic characteristics, and outcomes in patients with SGPL1 mutations. METHODS: The study included 6 patients with bi-allelic SGPL1 mutation. Clinical, genetic, and laboratory characteristics, and outcomes of the patients were evaluated retrospectively. We also reviewed previously reported patients with SGPL1 mutations and compared them to the presented patients. RESULTS: The median age at kidney presentation was 5 months. Four patients (67%) were diagnosed before age 1 year. Kidney biopsy showed focal segmental glomerulosclerosis in 2 patients and diffuse mesangial sclerosis in one patient. Steroids were given to 3 patients, but they did not respond. All 6 patients progressed to chronic kidney disease; 5 required kidney replacement therapy (KRT) at a median age of 6 months. Deceased kidney transplantation was performed in one patient. All 6 patients had adrenal insufficiency, of which 5 were diagnosed at age < 6 months. Three patients had hypothyroidism, 2 had ichthyosis, 4 had immunodeficiency, 5 had neurological findings, and 2 had genitourinary system anomalies. Four patients died at a median age of 30.5 months. Two patients are being followed up with KRT. One patient had a novel mutation. CONCLUSIONS: Patients with SGPL1 mutations have a poor prognosis, and many types of extrarenal organ/system involvement beyond adrenal insufficiency can be seen. Genetic diagnosis of such patients is important for treatment, genetic counseling, and screening for comorbid conditions. A higher resolution version of the Graphical abstract is available as Supplementary information.

Management of pediatric dialysis and kidney transplant patients after natural or man-made disasters.

Pediatric patients on kidney replacement therapy (KRT) are among the most vulnerable during large-scale disasters, either natural or man-made. Hemodialysis (HD) treatments may be impossible because of structural damage and/or shortage of medical supplies, clean water, electricity, and healthcare professionals. Lack of peritoneal dialysis (PD) solutions and increased risk of infectious/non-infectious complications may make PD therapy challenging. Non-availability of immunosuppressants and increased risk of infections may result in graft loss and deaths of kidney transplant recipients. Measures to mitigate these risks must be considered before, during, and after the disaster including training of staff and patients/caregivers to cope with medical and logistic problems. Soon after a disaster, if the possibility of performing HD or PD is uncertain, patients should be directed to other centers, or the duration and/or number of HD sessions or the PD prescription adapted. In kidney transplant recipients, switching among immunosuppressants should be considered in case of non-availability of the medications. Post-disaster interventions target treating neglected physical and mental problems and also improving social challenges. All problems experienced by pediatric KRT patients living in the affected area are applicable to displaced patients who may also face extra risks during their travel and also at their destination. The need for additional local, national, and international help and support of non-governmental organizations must be anticipated and sought in a timely manner.

Humoral and cellular immune response to SARS-CoV-2 mRNA BNT162b2 vaccine in pediatric kidney transplant recipients compared with dialysis patients and healthy children.

BACKGROUND: Compared with the general population, the immune response to COVID-19 mRNA vaccines is lower in adult kidney transplant recipients (KTRs). However, data is limited for pediatric KTRs. In this study, we aimed to assess humoral and cellular immune responses to the COVID-19 mRNA vaccine in pediatric KTRs. METHODS: This multicenter, prospective, case-control study included 63 KTRs (37 male, aged 12-21 years), 19 dialysis patients, and 19 controls. Humoral (anti-SARS-CoV2 IgG, neutralizing Ab (nAb)) and cellular (interferon-gamma release assay (IGRA)) immune responses were assessed at least one month after two doses of BNT162b2 mRNA vaccine. RESULTS: Among COVID-19 naïve KTRs (n = 46), 76.1% tested positive for anti-SARS-CoV-2 IgG, 54.3% for nAb, and 63% for IGRA. Serum levels of anti-SARS-CoV-2 IgG and nAb activity were significantly lower in KTRs compared to dialysis and control groups (p < 0.05 for all). Seropositivity in KTRs was independently associated with shorter transplant duration (p = 0.005), and higher eGFR (p = 0.007). IGRA titer was significantly lower than dialysis patients (p = 0.009). Twenty (43.4%) KTRs were positive for all immune parameters. Only four of 11 seronegative KTRs were IGRA-positive. COVID-19 recovered KTRs had significantly higher anti-SARS-CoV-2 IgG and nAb activity levels than COVID-19 naïve KTRs (p = 0.018 and p = 0.007, respectively). CONCLUSIONS: The humoral and cellular immune responses to SARS-CoV-2 mRNA BNT162b2 vaccine are lower in pediatric KTRs compared to dialysis patients. Further prospective studies are required to demonstrate the clinical efficacy of the mRNA vaccine in KTRs. This prospective study was registered in ClinicalTrials.gov (NCT05465863, registered retrospectively at 20.07.2022). A higher resolution version of the Graphical abstract is available as Supplementary information.