Pediatric urogenital schistosomiasis diagnosed in France.

BACKGROUND: Schistosomiasis affects approximately 230 million people worldwide. There is an increased incidence of schistosomiasis cases in France acquired from outside the country. This increases the risk of schistosomiasis outbreaks as observed in Corsica. Clinicians from non-endemic regions are not accustomed to diagnosing and managing this pathology. The objective of this study is to provide a better description of the clinical and paraclinical characteristics and disease evolution of affected children. METHODS: Through the French Pediatric Nephrology Society and the Pediatric Infectious Pathology Group, we contacted all French pediatric centers that may have treated children with urinary schistosomiasis between 2013 and 2019. Age, sex, comorbidities, and clinical, biological, and radiological data (at discovery and follow-up) were collected retrospectively. RESULTS: A total of 122 patients from 10 different centers were included. The median age was 14 years and the sex ratio M/F was 4:1. Hematuria was present in 82% of the patients while urinary tract abnormality was found in 36% of them. Fourteen patients (11%) displayed complicated forms of urinary schistosomiasis including 10 patients with chronic kidney disease. A total of 110 patients received treatment with praziquantel, which was well-tolerated and led to clinical resolution of symptoms in 98% of cases. CONCLUSION: Patients with schistosomiasis present frequent kidney, urinary, or genital involvement. Systematic screening of patients returning from endemic areas is therefore recommended, especially since treatment with antiparasitic drugs is effective and well-tolerated. Enhancing medical knowledge of this pathology among all practitioners is essential to improve care and outcomes.

Reversed cortico-medullary differentiation in the fetal and neonatal kidneys: an indicator of poor prognosis?

BACKGROUND: Bilateral reversed cortico-medullary differentiation is rarely observed on fetal or neonatal renal ultrasound and is therefore a diagnostic challenge. OBJECTIVE: Our purpose was to widen the differential diagnoses of fetal and neonatal nephropathies introducing reversed cortico-medullary differentiation as a clue either on obstetric US or during follow-up of hyperechoic kidneys in order to improve the management of such rare clinical situations. MATERIALS AND METHODS: We retrospectively reviewed the US images of 11 patients showing bilateral reversed cortico-medullary differentiation on prenatal examination or in which this pattern developed postnatally in the follow-up of fetal hyperechoic kidneys. For each patient, a precise diagnosis was established either on clinical assessment or, when available, on histological or genetic findings. RESULTS: Six fetuses displayed bilateral reversed cortico-medullary differentiation on obstetric examination, and the pattern persisted throughout pregnancy. In the five other fetuses, the kidneys appeared initially homogeneously hyperechoic; this evolved into reversed cortico-medullary differentiation during the third trimester in two cases and shortly after birth in three cases. Two pregnancies were terminated because of estimated poor prognosis. In the nine surviving neonates, four died of renal failure in the post-natal period. The clinical evolution was more favorable in the remaining five newborns. CONCLUSIONS: Six different diagnoses were established in patients presenting with a reversed cortico-medullary differentiation renal pattern. This finding was associated with poor outcome in six cases. An acute prenatal diagnosis of reversed cortico-medullary differentiation improves pre- and postnatal work-up and guides counseling and genetic testing.

Efficacy and Safety of Eculizumab in Pediatric Patients Affected by Shiga Toxin-Related Hemolytic and Uremic Syndrome: A Randomized, Placebo-Controlled Trial.

SIGNIFICANCE STATEMENT: Shiga toxin-related hemolytic uremic syndrome (STEC-HUS) is a serious condition, characterized by multiorgan thrombotic microangiopathy, mainly affecting children. Renal involvement is severe, with approximately half of patients requiring dialysis. So far, no specific treatment has been proven efficient in STEC-HUS. The use of eculizumab, a monoclonal antibody inhibiting terminal complement complex, has demonstrated remarkable success in atypical hemolytic uremic syndrome, but its use in uncontrolled studies to treat STEC-HUS has yielded inconsistent results. In this Phase 3 randomized, placebo-controlled trial in 100 pediatric patients with STEC-HUS, the findings did not show efficacy of eculizumab during the acute phase of the disease. However, the results indicated a reduction of renal sequelae in eculizumab-treated patients at 1-year follow-up. Larger prospective studies would be needed to further explore eculizumab as a potential treatment. BACKGROUND: Shiga toxin-related hemolytic uremic syndrome (STEC-HUS) in children is a severe condition, resulting in approximately 50% of patients requiring RRT. Furthermore, at least 30% of survivors experience kidney sequelae. Recently, activation of the complement alternative pathway has been postulated as a factor in STEC-HUS pathophysiology, leading to compassionate use of eculizumab, a monoclonal antibody inhibiting the terminal complement complex, in affected patients. Given the lack of therapy for STEC-HUS, a controlled study of eculizumab efficacy in treating this condition is a priority. METHODS: We conducted a Phase 3 randomized trial of eculizumab in children with STEC-HUS. Patients were randomly assigned in a 1:1 ratio to receive either eculizumab or placebo during 4 weeks. Follow-up lasted for 1 year. The primary end point was RRT duration <48 hours after randomization. Secondary endpoints included hematologic and extrarenal involvement. RESULTS: Baseline characteristics were similar among the 100 patients who underwent randomization. The rate of RRT <48 hours did not differ significantly between the two groups (48% in the placebo versus 38% in the eculizumab group; P = 0.31) or in the course of ARF. The two groups also exhibited similar hematologic evolution and extrarenal manifestations of STEC-HUS. The proportion of patients experiencing renal sequelae at 1 year was lower in the eculizumab group than in the placebo group (43.48% and 64.44%, respectively, P = 0.04). No safety concern was reported. CONCLUSIONS: In pediatric patients with STEC-HUS, eculizumab treatment does not appear to be associated with improved renal outcome during acute phase of the disease but may reduce long-term kidney sequelae. CLINICAL TRIALS REGISTRATIONS: EUDRACT (2014-001169-28) ClinicalTrials.gov ( NCT02205541 ).

Successful global anti-B-cell strategy with daratumumab in a patient with post-transplant nephrotic syndrome recurrence unresponsive to immunoadsorption and obinutuzumab.

BACKGROUND: Steroid-resistant nephrotic syndrome recurrence post-transplant unresponsive to immunoadsorption is a dilemma, and no reliable treatment strategy has been identified to induce remission so far. CASE PRESENTATION: A 2-year-old girl presented first with idiopathic nephrotic syndrome. She did not reach remission after 30 days of oral steroids and remained resistant to steroid pulses, oral tacrolimus, IV cyclosporine, and to 30 sessions of plasma exchange. Bilateral nephrectomy was performed because of extrarenal complications. Two years later, she received an allograft from a deceased donor and idiopathic nephrotic syndrome relapsed immediately post-transplantation. She did not reach remission after immunosuppressive therapy including tacrolimus, mycophenolate mofetil, methylprednisolone pulses, daily immunoadsorption, and B-cell depletion. She received obinutuzumab 1 g/1.73 m2 injections weekly for 3 weeks and then daratumumab 1 g/1.73 m2 weekly for 4 weeks. One week after the last daratumumab infusion, urine protein/creatinine ratio began to decrease. Proteinuria was negative for the first time at Day 99. Immunoadsorption was stopped 147 days after, and she remained relapse-free at last follow-up (18 months post-transplantation). The treatment was complicated by a pneumocystis jirovecii pneumonia with a favorable outcome and persistent hypogammaglobulinemia. CONCLUSION: A obinutuzumab and daratumumab combination seems to be a promising strategy in post-transplantation SRNS recurrence without response to standard treatment options.

Optimizing COVID-19 Vaccination Strategy in Pediatric Kidney Transplant Recipients: Humoral and Cellular Response to SARS-CoV-2 mRNA Vaccination.

In this retrospective cohort study, we analyze the early humoral and cellular response in 64 adolescents KTx recipients, after two or three doses of mRNA vaccine BNT162b2 against different variants of COVID-19. After 2 doses, 77.8% % of children with no history of infection had a positive humoral response with a median anti-S IgG level of 1107 (IQR, 593-2,658) BAU/mL. All the patients with a history of infection responded with a higher median IgG level (3,265 (IQR, 1,492-8,178) BAU/mL). In non-responders after 2 doses, 75% responded after a third dose with a median Ab titer at 355 (IQR, 140-3,865 BAU/mL). Neutralizing activity was significantly lower against the delta and the omicron variants compared to the wild-type strain and did not improve after a 3rd dose, while infection did provide higher levels of neutralizations against the variants. T cell specific response correlated with humoral response and no patient displayed a cellular response without a humoral response. Adolescent KTx recipients exhibit a high seroconversion rate after only two doses. A third injection, induces a response in the majority of the non-responders patients but did not counterbalance the strong decrease in neutralizing antibody activities against variants highlighting the need for boosters with specific vaccines.

Outcome of children with IgA vasculitis with nephritis treated with steroids: a matched controlled study.

BACKGROUND: IgA vasculitis (IgAV) is the most common vasculitis in children. IgAV long-term prognosis depends on kidney involvement or IgA vasculitis with nephritis (IgAVN). To date, steroid treatment (oral steroids or methylprednisolone pulses) has not proven to be formally efficient. This study aimed to assess the role of steroids on IgAVN outcome. METHODS: All children with IgAVN diagnosed 2000-2019 in 14 French pediatric nephrology units with minimal follow-up of 6 months were retrospectively included. Outcomes of patients treated with steroids were compared with those of a control group of untreated patients matched for age, sex, proteinuria, eGFR, and histological features. The primary endpoint was IgAVN remission defined as urine protein-to-creatinine ratio < 20 mg/mmol without impaired eGFR one year after disease onset. RESULTS: A total of 359 patients with IgAVN were included with a median follow-up time of 249 days (range 43-809). One hundred eight (30%) patients received oral steroids alone, 207 (51%) patients received three methylprednisolone pulses followed by oral steroids, and 44 patients (12.5%) did not receive steroids. Thirty-two children treated with oral steroids alone were compared with 32 matched control patients who did not receive steroids. One year after disease onset, IgAVN remission proportion was not different between these two groups: 62% versus 68%, respectively. Ninety-three children treated with oral steroids alone were compared with 93 matched patients treated with three methylprednisolone pulses followed by oral corticosteroids. IgAVN remission proportion was not different between these two groups: 77% versus 73%, respectively. CONCLUSION: The benefit of oral steroids alone and methylprednisolone pulses could not be established based on this observational study. Randomized controlled trials are thus required to determine the efficacy of steroids in IgAVN. A higher resolution version of the Graphical abstract is available as Supplementary information.

[Clinical monitoring of children with in utero exposure to angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers]. / Toxicité fœtale et néonatale des inhibiteurs de l'enzyme de conversion et des sartans : quelle surveillance pour les enfants exposés in utero ?

Angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers are widely used to reduce high blood pressure or in other conditions such as congestive heart failure and prevention of diabetic nephropathy. To date, no teratogenic effect has been attributed to them, but in the 2nd and 3rd trimesters of pregnancy, their foetotoxicity is broadly documented: transient oligohydramnios or anamnios, associated to possible neonatal anuria and permanent renal damage, which can lead to intrauterine or neonatal death. Long-term effects among children with in utero exposure are poorly known, but the regression of an oligohydramnios might not always be associated with normal renal function after birth or later in life. This justifies seeking the advice of a pediatric nephrologistto consider the most appropriate monitoring for the child at birth and in the following weeks, and possibly beyond, even in case of normal prenatal ultrasound.

Pediatric ANCA vasculitis: clinical presentation, treatment, and outcomes in a French retrospective study.

BACKGROUND: Pediatric ANCA vasculitis is a rare group of diseases with a scarcity of data in children. Annual incidence appeared to increase in the last several years, placing higher interest in the clinical and therapeutical outcomes of the disorder. Also, the growing use of rituximab questions the latest outcomes in these diseases. We therefore conducted a retrospective study to better understand the current characteristics, management, and the latest outcomes of the disorder. METHODS: We conducted a 9-year retrospective study of 46 children in 14 different centers across France to describe their clinical and laboratory presentations, therapeutic regimens, and kidney outcome. RESULTS: P-ANCA appeared to be a potential marker for higher relapse risk. Compared to adults, we found that ear-nose-throat presentations were frequent (45.7%) and more severe. Despite an evolution in the treatment management, kidney outcome remained poor with a substantial proportion of chronic kidney disease (54.8% at 1 year). Mortality stays low with 3 patients (6.5%) deceased at the end of our study. CONCLUSION: Clinical presentation was as previously described and time to diagnosis remains long. P-ANCA is a statistically significant marker for increased relapse risk. We observed a modification in the treatment regimens over the past several years with a growing use of rituximab and a decreasing use of cyclophosphamide. Despite these changes, kidney outcome remains poor and prospective studies should be conducted to assess the most appropriate therapeutic modality for each patient. A higher resolution version of the Graphical abstract is available as Supplementary information.

Benefits of BNP/NT-proBNP serum level evaluation for dry weight adjustment in pediatric hemodialysis patients.

BACKGROUND: Dry weight (DW) adjustment in children on hemodialysis (HD) can be challenging. It relies on clinical evaluation and additional supports. Our aim was to study the benefits of cardiac biomarker assessment, in addition to the more commonly used technique, bioimpedance spectroscopy (BIS), and clinical signs for DW prescription in pediatric HD patients. METHOD: Observational study including 41 children on HD in three pediatric HD centers in the Paris region. During one session, BIS was performed before the session and serum levels of BNP and NT-proBNP were analyzed before and after the session. RESULTS: Median pre-dialysis level of BNP was 87 ng/L [24-192] and NT-proBNP 968 ng/L [442-4828]. Cardiac biomarker levels showed positive correlation with the BIS hydration status evaluation (p = 0.004). The most appropriate cutoff for pre-dialysis BNP to detect significant overhydration (OH) was 165 ng/L (sensitivity 0.67, specificity 0.84). Based on the BIS evaluation, only 32% of patients with high blood pressure (BP) had OH, whereas in the normal BP group, 33% had significant OH. CONCLUSIONS: DW prescription for children on HD should not only rely on clinical evaluation, particularly BP, but should also include additional helpful parameters. BIS is well-validated in children, but it has limitations in non-cooperative patients, and its cost can limit its use in some settings. Cardiac biomarkers, especially BNP, were well-correlated to hydration status evaluated by BIS, and thus could add valuable information for individual patient management and DW assessment. A higher resolution version of the Graphical abstract is available as Supplementary information.

Predictive factors for survival in patients with oligohydramnios secondary to antenatal kidney disease.

BACKGROUND: Renal oligohydramnios (ROH) is caused by bilateral congenital abnormalities, either of renal parenchymal or obstructive origin. ROH is a poor prognostic factor of neonatal survival; lung hypoplasia is reported to be the main cause of mortality. We aimed to describe the fetal morbidity and pre- and postnatal mortality in case of ROH due to renal congenital pathologies and to find predictive risk factors for morbidity and mortality. METHODS: All data were collected in Trousseau Hospital in the obstetric, neonatology, and pediatric nephrology units, from 2008 to 2020. RESULTS: We included 66 fetuses with renal parenchymal pathologies posterior urethral valves (PUV) (N = 25), bilateral kidney agenesis (N = 10), hypodysplasia (N = 16), and polycystic kidney disease (N = 10) causing oligohydramnios identified on antenatal ultrasound. Total pre- and postnatal mortality was 76% (50/66). Mortality, excepting termination of pregnancy (TOP), was 65%. The presence of pneumomediastinum and pneumothorax was not different in survivors and non-survivors. Fetuses with kidneys having features of hypodysplasia on ultrasound at T2 and those with oligohydramnios before 32 weeks GA had a higher risk of death. There was a significant difference in plasma creatinine of the surviving patients compared to the deceased patients, from day 3 onwards (183 µmol/L [88; 255] vs. 295 µmol/L [247; 326]; p = 0.038). CONCLUSIONS: The main differences between survivors and non-survivors among patients with "renal oligohydramnios" were oligohydramnios detection before 32 weeks GA, dysplasia detection on the second trimester ultrasound, and increase of serum creatinine from day 3 onwards. A higher resolution version of the Graphical abstract is available as Supplementary information.

Preemptive Kidney Transplantation Is Associated With Transplantation Outcomes in Children: Results From the French Kidney Replacement Therapy Registry.

BACKGROUND: Kidney transplantation (KT) is the optimal treatment for children with end-stage kidney disease. The aim of this study was to evaluate the impact of preemptive kidney transplantation (PKT) and of pretransplant dialysis duration on graft survival among French pediatric kidney transplant recipients. METHODS: We analyzed all first pediatric kidney-only transplantations performed in France between 1993 and 2012. A Cox multivariable model was used to investigate the association of PKT and pretransplant dialysis time with the hazard of graft failure defined as death, return to dialysis, or retransplant, whichever occurred first. RESULTS: Patients (n = 1911) were included, of which 380 (19.8%) received a PKT. Median time of follow-up was 7.0 y. PKT was associated with a 55% reduction of the hazard of graft failure at any time after KT compared with patients transplanted after dialysis (hazard ratio, 0.45; 95% confidence interval, 0.33-0.62), after adjustment for recipient sex and age, primary kidney disease, donor age and type (living or deceased donor), number of HLA mismatches, cold ischemia time, and year of transplantation. A reduction of the hazard of graft failure was found in PKT whatever the compared duration of dialysis, even when <6 mo and whatever the dialysis modality. Results were similar in multiple sensitivity analyses. CONCLUSIONS: In France, PKT among pediatric patients is associated with a better graft survival when compared with KT after dialysis, even when <6 mo. Based on these findings, we suggest that PKT should be considered as the treatment of choice for children with end-stage kidney disease.

To biopsy or not to biopsy: Henoch-Schönlein nephritis in children, a 5-year follow-up study.

BACKGROUND: The prognosis of Henoch-Schönlein purpura (HSP), IgA vasculitis, depends on kidney involvement. There is no consensus on the initiation of treatment for HSP nephritis (HSPN). Some centres start treatment before performing a kidney biopsy (KB) while in others, treatment is dictated by the importance of the clinical, biological and histological signs. The aim of this study was to evaluate which of these two approaches is associated with a better kidney outcome at 5-year follow-up. METHODS: This multicentre, retrospective, nonrandomised study included children treated for HSPN between 2006 and 2010 in a French paediatric nephrology unit. One group had an early KB at diagnosis (before starting treatment or in the 15 following days). In the second group, initial treatment was decided without performing a KB. RESULTS: Among the 107 children included, 63.5% had an early KB at diagnosis. Follow-up at 5 years was completed in 44 children (28 KB at diagnosis, 16 no KB at diagnosis). Median urine protein/creatinine at 5 years was 2.5 mg/mmol in the early biopsy diagnosis group and 12.5 mg/mmol in the non-biopsy group. An antiproteinuric treatment was given, at 5 years, to 35.7% of the early biopsy at diagnosis children and in 62.5% of the non-biopsied children. CONCLUSIONS: Children with early KB at diagnosis seem to have a better renal outcome at 5 years compared to those without an early biopsy at diagnosis or biopsied later. However, this is a small patient cohort and data are missing. Further work is needed to build consensual guidelines on the management of HSPN in children.

Soluble CD89 is a critical factor for mesangial proliferation in childhood IgA nephropathy.

Childhood IgA nephropathy (IgAN) includes a wide spectrum of clinical presentations, from isolated hematuria to acute nephritis with rapid loss of kidney function. In adults, IgAN is an autoimmune disease and its pathogenesis involves galactose deficient (Gd) IgA1, IgG anti-Gd-IgA1 autoantibodies and the soluble IgA Fc receptor (CD89). However, implication of such factors, notably soluble CD89, in childhood IgAN pathogenesis remains unclear. Here, we studied these biomarkers in a cohort of 67 patients with childhood IgAN and 42 pediatric controls. While Gd-IgA1 was only moderately increased in patient plasma, levels of circulating IgA complexes (soluble CD89-IgA and IgG-IgA) and free soluble CD89 were markedly increased in childhood IgAN. Soluble CD89-IgA1 complexes and free soluble CD89 correlated with proteinuria, as well as histological markers of disease activity: mesangial, endocapillary hypercellularity and cellular crescents. Soluble CD89 was found in patient's urine but not in urine from pediatric controls. Mesangial deposits of soluble CD89 were detected in biopsies from patients with childhood IgAN. Serum chromatographic fractions containing covalently linked soluble CD89-IgA1 complexes or free soluble CD89 from patients induced mesangial cell proliferation in vitro in a soluble CD89-dependent manner. Recombinant soluble CD89 induced mesangial cell proliferation in vitro which was inhibited by free soluble recombinant CD71 (also a mesangial IgA receptor) or mTOR blockers. Interestingly, injection of recombinant soluble CD89 induced marked glomerular proliferation and proteinuria in mice expressing human IgA1. Thus, free and IgA1-complexed soluble CD89 are key players in mesangial proliferation. Hence, our findings suggest that soluble CD89 plays an essential role in childhood IgAN pathogenesis making it a potential biomarker and therapeutic target.

Renal Prognosis in Children With Tubulointerstitial Nephritis and Uveitis Syndrome.

INTRODUCTION: Tubulointerstitial nephritis (TIN) and uveitis (TINU) syndrome is a rare disease. The renal prognosis is generally thought to be better in children with TINU syndrome than in adults. However, data are scarce. We aimed to investigate the long-term renal prognosis in a French cohort of children with TINU syndrome. METHODS: We performed a national retrospective study including 23 French pediatric nephrology centers enrolling patients with TINU syndrome diagnosed between January 2000 and December 2018. RESULTS: A total of 46 patients were included (52% female, median age 13.8 years). At diagnosis of TIN, the median estimated glomerular filtration rate (eGFR) was 30.6 ml/min per 1.73 m2 (4.9-62.8). The median time between diagnosis of uveitis and TIN was 0.4 months (-4.1; +17.1). All patients had anterior uveitis, but 12 (29%) were asymptomatic. Nearly all patients (44 of 46) received steroid treatment, and 12 patients (26%) received a second-line therapy. At last follow-up (median 2.8 years), the median eGFR was 87.5 ml/min per 1.73 m2 (60.3-152.7) and <90 ml/min per 1.73 m2 in 20 patients. CONCLUSION: In our study, nearly half of the patients had renal sequelae at last follow-up. Given the possible progression to chronic kidney disease, long-term monitoring of children with TINU syndrome is mandatory. Approximately a quarter of the children had asymptomatic uveitis suggesting all children presenting with TIN should undergo systematic ophthalmologic screening even in the absence of ocular signs.

Management of IgA Vasculitis with Nephritis.

Immunoglobulin A (IgA) vasculitis (IgAV), previously called Henoch-Schönlein purpura, is characterized by IgA-dominant immune deposits affecting small vessels and often involves the skin, gastrointestinal tract, joints, and kidneys. IgAV is the most common cause of systemic vasculitis in children. The long-term prognosis is dependent on renal involvement: IgAV with nephritis (IgAVN) can progress to renal failure. IgAVN is an inflammatory disease, providing a rationale for the use of corticosteroids. However, data supporting the use of corticosteroids in patients with established IgAVN of any severity remain limited, although most clinicians use them. Even in patients with severe forms of IgAVN, methylprednisolone pulses added to oral corticosteroids appears to improve renal outcomes. Considering the multihit hypothesis for the pathogenesis of IgAVN, involving many other immune agents, there is a strong rationale for the use of other immunosuppressive drugs in patients with IgAVN, including mycophenolic acid, cyclophosphamide, rituximab, calcineurin inhibitors, and complement inhibitors. Thus, these immunosuppressive treatments have also been evaluated in IgAVN, usually in corticosteroid-dependent or corticosteroid-resistant forms and in small retrospective studies. However, their efficacy has not been proven. Thus, the risk of progression to renal failure and the ongoing debate about the best management of IgAVN justifies the interest in investigating and identifying treatments that can potentially preserve renal function in patients with IgAVN. This review reports on the efficacy of the different drugs currently used for the treatment of IgAVN in adults and children.

Rare Collagenous Heterozygote Variants in Children With IgA Nephropathy.

INTRODUCTION: Childhood IgA nephropathy (cIgAN) is a primary glomerulonephritis clinically characterized by microscopic hematuria and proteinuria, the presence of which may potentially overlap with Alport syndrome. Interestingly, earlier studies suggested that familial IgAN could be linked to the chromosome 2q36 region, also the coding region for collagen type 4 alpha 3/4 (COL4A3/A4). METHODS: To investigate a possible relationship or phenocopy between Alport syndrome and cIgAN, COL4A3, COL4A4, and COL4A5 exons were sequenced in 36 cIgAN patients. Clinical data and treatment were collected retrospectively. COL4A3/A4/A5 variants were classified according to American College of Medical Genetics and the Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: Four of 36 cIgAN patients were affected by ACMG class 4/5 COL4A3 heterozygous variants (COL4A3-cIgAN). We found no COL4A4 or COL4A5 variant. Despite having rare and deleterious COL4A3 variants, 3 of 4 COL4A3-cIgAN children developed clinical and biologic features of active IgAN rather than Alport syndrome. Response to intensive immunosuppressive treatment was favorable, leading to a reduction of endocapillary and extracapillary proliferation lesions. High levels of immune immunoglobulin G and A (IgG/IgA) complexes, reduction of proteinuria, and gradual stabilization of estimated glomerular filtration rate (eGFR) argued against Alport syndrome. Nevertheless, COL4A3-cIgAN patients seemed predisposed to a more serious IgAN presentation compared with the non‒COL4A3-cIgAN group, with more glomerulosclerosis and a lower eGFR over time. One of the 4 patients underwent kidney transplant with subsequent IgAN recurrence. CONCLUSIONS: Predisposition factors for developing serious cIgAN flare-up should be considered for cIgAN with COL4A3 pathologic heterozygous variants. COL4A3 variants, usually responsible for Alport syndrome in adults, should not automatically exclude an immunosuppressive regimen in cIgAN. Moreover, evidence of an ACMG class 4/5 COL4A3 variant in early-stage cIgAN could be a helpful tool for stratifying severity of cIgAN beyond the Oxford classification.

Procalcitonin serum levels in stage 5 chronic kidney disease children on hemodialysis.

BACKGROUND: Infections are responsible for morbidity and mortality in children on hemodialysis (HD). Procalcitonin (PCT) is rarely used in this population, even though it is an efficient biomarker of infection and sepsis. Our aim was to study PCT baseline level in uninfected children with stage 5 chronic kidney disease (CKD 5) on HD, and determine how to use it in this population. METHODS: Prospective observational study including 40 uninfected children on classical HD or hemodiafiltration (HDF) in three pediatric HD centers in the Paris region. PCT was monitored before and after three consecutive sessions within 1 week. RESULTS: Median pre-dialysis PCT was 0.60 ng/mL [0.36-1.15], median post-dialysis PCT was 0.23 ng/mL [0.10-0.47], PCT reduction rate was 59.8% [37.5-75.8]. Seventy percent of pre-dialysis PCT were <1 ng/mL. Anuric patients had higher pre-dialysis PCT than those with residual urine output (0.70 [0.42-1.30] vs. 0.48 [0.30-0.93] ng/mL, p=0.01). HDF was more efficient than HD to clear PCT during sessions (reduction rate 75% [67-80] vs. 37 [31-50]), p<0.001). CONCLUSION: PCT levels in pediatric HD patients without infection are higher than normal, but this increase is relatively moderate compared to massive increases of PCT in children with bacterial infections on HD. If PCT is measured after dialysis sessions, the specific technique-dependent reduction rates should be taken into consideration. Moderately increased PCT levels around 2 ng/ml should be interpreted with caution; however, higher PCT serum levels can be used to motivate rapid start of antibiotic treatment in pediatric HD patients.