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.

Agonists of prostaglandin E2 receptors as potential first in class treatment for nephronophthisis and related ciliopathies.

Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy belonging to the ciliopathy disorders and known as the most common cause of hereditary end-stage renal disease in children. Yet, no curative treatment is available. The major gene, NPHP1, encodes a protein playing key functions at the primary cilium and cellular junctions. Using a medium-throughput drug-screen in NPHP1 knockdown cells, we identified 51 Food and Drug Administration-approved compounds by their ability to alleviate the cellular phenotypes associated with the loss of NPHP1; 11 compounds were further selected for their physicochemical properties. Among those compounds, prostaglandin E1 (PGE1) rescued ciliogenesis defects in immortalized patient NPHP1 urine-derived renal tubular cells, and improved ciliary and kidney phenotypes in our NPH zebrafish and Nphp1 knockout mouse models. Furthermore, Taprenepag, a nonprostanoid prostaglandin E2 receptor agonist, alleviated the severe retinopathy observed in Nphp1−/− mice. Finally, comparative transcriptomics allowed identification of key signaling pathways downstream PGE1, including cell cycle progression, extracellular matrix, adhesion, or actin cytoskeleton organization. In conclusion, using in vitro and in vivo models, we showed that prostaglandin E2 receptor agonists can ameliorate several of the pleotropic phenotypes caused by the absence of NPHP1; this opens their potential as a first therapeutic option for juvenile NPH-associated ciliopathies.

Valganciclovir is not associated with decreased EBV infection rate in pediatric kidney transplantation.

Introduction: Primary infection or reactivation of Epstein-Barr Virus (EBV) is a significant cause of morbidity and mortality in pediatric kidney transplantation. Valganciclovir (VGC) treatment is recommended for prophylaxis of cytomegalovirus infection, but its role for the prevention of EBV infection remains controversial. Patients and methods: All pediatric kidney transplant recipients aged <18 years old were considered for inclusion in this retrospective study. EBV negative recipients with an EBV positive donor (a group at risk of primary infection) or EBV positive recipients (a group at risk of reactivation) were included. Severe infection was defined by post-transplant lymphoproliferative disorder (PTLD), symptomatic EBV infection or by asymptomatic EBV infection with a viral load >4.5 log/ml. Outcomes were compared between patients receiving VGC prophylaxis (group P+) and those not receiving VGC prophylaxis (group P-). Results: A total of 79 patients were included, 57 (72%) in the P+ group and 22 (28%) in the P- group; 25 (31%) were at risk of primary infection and 54 (69%) at risk of reactivation. During the first year post-transplant, the occurrence of severe EBV infection was not different between the P+ group (n = 13, 22.8%) and the P- group (n = 5, 22.7%) (p = 0.99). Among patients at risk of primary infection, the rate of severe EBV infection was not different between the two groups (42.1% in P+ vs. 33.3% in P-). A higher frequency of neutropenia was found in the P+ group (66.6%) than in the P- group (33.4%) (p < 0.01). Conclusion: Our observational study suggests no effect of VGC for the prevention of EBV infection in pediatric kidney transplant recipients, irrespective of their EBV status. Adverse effects revealed an increased risk of neutropenia.

Association of kidney biopsy findings with short- and medium-term outcomes in children with moderate-to-severe IgA vasculitis nephritis.

Assessing the initial severity of immunoglobulin A vasculitis nephritis (IgAV-N) is important due to its determining effect on kidney management and outcomes. This paper describes a multicentre paediatric cohort of IgAV-N patients and discusses relationships among clinical presentation, histological features, and kidney outcome. We retrospectively studied a cohort of 170 children with biopsy-proven IgAV-N, diagnosed between 2007 and 2017. One-quarter of the cohort (27%) presented with initial nephrotic syndrome (NS). Kidney biopsy revealed International Study of Kidney Disease (ISKDC) grade II or grade III in 83% of cases. Endocapillary proliferation was observed in 73% of patients, and chronic lesions were observed in 25%. Data analysis showed a significant association between NS at onset and endocapillary proliferation and cellular crescents. After a median follow-up of 21 months (IQR 12-39), 30% of patients had persistent proteinuria or decreased eGFR. At the end of follow-up, kidney impairment was more often observed in patients with NS at onset and those with cellular crescents and chronic lesions on initial kidney biopsy.Conclusion: This study highlights the relationship between the clinical and histological presentation of IgAV-N and the factors that affect kidney outcome. The ISKDC classification may be improved by including lesions that are more discriminating for disease severity and prognosis. What is Known: • Nephrotic syndrome (NS) or kidney failure at diagnosis and cellular crescents in more than 50% of the glomeruli are recognized as risk factors for poor kidney outcome in immunoglobulin A vasculitis nephritis (IgAV-N). • The reference histological classification of the International Study of Kidney Disease in Children (ISKDC) is primarily based on the presence and number of affected glomeruli (mesangial proliferation, cellular crescents). The updated Oxford classification, which emphasizes tubular atrophy and interstitial fibrosis, is also used to group pathological features of IgAV-N. Both classifications have limitations. What is New: • Medical treatment should not be postponed in patients with IgAV-N and NS until after biopsy, as NS at diagnosis is associated with initial histological severity and poorer kidney outcome. This proposal needs to be verified in further studies. • Endocapillary proliferation is associated with the initial severity of IgAV-N at diagnosis, while chronic glomerular changes and interstitial fibrosis are associated with poorer short- and medium-term kidney outcomes.

Aetiology, course and treatment of acute tubulointerstitial nephritis in paediatric patients: a cross-sectional web-based survey.

BACKGROUND: Acute tubulointerstitial nephritis (TIN) is a significant cause of acute renal failure in paediatric and adult patients. There are no large paediatric series focusing on the aetiology, treatment and courses of acute TIN. PATIENTS, DESIGN AND SETTING: We collected retrospective clinical data from paediatric patients with acute biopsy-proven TIN by means of an online survey. Members of four professional societies were invited to participate. RESULTS: Thirty-nine physicians from 18 countries responded. 171 patients with acute TIN were included (54% female, median age 12 years). The most frequent causes were tubulointerstitial nephritis and uveitis syndrome in 31% and drug-induced TIN in 30% (the majority of these caused by non-steroidal anti-inflammatory drugs). In 28% of patients, no initiating noxae were identified (idiopathic TIN). Median estimated glomerular filtration rate (eGFR) rose significantly from 31 at time of renal biopsy to 86 mL/min/1.73 m2 3-6 months later (p<0.001). After 3-6 months, eGFR normalised in 41% of patients (eGFR ≥90 mL/min/1.73 m2), with only 3% having severe or end-stage impairment of renal function (<30 mL/min/1.73 m2). 80% of patients received corticosteroid therapy. Median eGFR after 3-6 months did not differ between steroid-treated and steroid-untreated patients. Other immunosuppressants were used in 18% (n=31) of patients, 21 of whom received mycophenolate mofetil. CONCLUSIONS: Despite different aetiologies, acute paediatric TIN had a favourable outcome overall with 88% of patients showing no or mild impairment of eGFR after 3-6 months. Prospective randomised controlled trials are needed to evaluate the efficacy of glucocorticoid treatment in paediatric patients with acute TIN.

Mycophenolic acid area under the concentration-time curve is associated with therapeutic response in childhood-onset lupus nephritis.

BACKGROUND: Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is widely used in lupus nephritis treatment. Therapeutic drug monitoring of adults suggests that area under the concentration-time curve (AUC) of MPA (MPA-AUC) is associated with clinical outcomes, but childhood data are scarce. METHODS: Retrospective study of 27 children with biopsy-proven lupus nephritis treated with MMF between 2008 and 2016. In 25 children, MPA-AUC was performed within 6 months after kidney biopsy and MMF initiation. Treatment response at 6 months was defined as normal or improved GFR by 25% compared with baseline, 50% reduction of proteinuria to < 0.5 g/day or 50 mg/mmol, and no hematuria. RESULTS: A total of 62 MPA-AUC were analyzed in 27 patients. Overall median was 44 mg h/L (interquartile range [IQR] 33-54). Individual dose adaptation was required in 32 cases (52%) to achieve target AUC of 30-60 mg h/L. At 6 months, 14/25 patients were defined as responders (56%, median MPA-AUC 49 mg h/L (40-59)) and 11/25 as non-responders (44%, 29 mg h/L (24-38)). Patients with MPA-AUC levels > 45, 30-45, and < 30 mg h/L had 6-month response rates of 89% (8/9), 60% (6/10), and 0% (0/6), respectively. In a logistic regression model adjusted for age, sex, lupus nephritis classification, and time since MMF initiation, an MPA-AUC > 45 mg h/L was significantly associated with therapeutic response (OR 3.6, 95% CI 2.4-9.5, p = 0.03). CONCLUSIONS: Therapeutic drug monitoring leading to individualized dosing may improve efficacy of MMF. MPA-AUC > 45 mg h/L is associated with better response rate and may be considered as a target value in pediatric lupus nephritis.

Long-term kidney and liver outcome in 50 children with autosomal recessive polycystic kidney disease.

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) is a rare ciliopathy characterized by congenital hepatic fibrosis and cystic kidney disease. Lack of data about long-term follow-up makes it difficult to discuss timing and type of organ transplantation. Our objectives were to evaluate long-term evolution and indications for transplantation, from birth to adulthood. METHODS: Neonatal survivors and patients diagnosed in postnatal period with ARPKD between 1985 January and 2017 December from 3 French pediatric centers were retrospectively enrolled in the study. RESULTS: Fifty patients with mean follow-up 12.5 ± 1 years were enrolled. ARPKD was diagnosed before birth in 24%, and at mean age 1.8 years in others. Thirty-three patients were < 1 year of age at first symptoms, which were mostly kidney-related. These most often presented high blood pressure during follow-up. Portal hypertension was diagnosed in 29 patients (58%), 4 of them with bleeding from esophageal varices. Eight patients presented cholangitis (> 3 episodes in three children). Liver function was normal in all patients. Nine children received a kidney transplant without liver complications. A 20-year-old patient received a combined liver-kidney transplant (CLKT) for recurrent cholangitis, and a 15-year-old boy an isolated liver transplant for uncontrollable variceal bleeding despite portosystemic shunt. CONCLUSIONS: Long-term outcome in patients with ARPKD is heterogeneous, and in this cohort did not depend on age at diagnosis except for blood pressure. Few patients required liver transplantation. Indications for liver or combined liver-kidney transplantation were limited to recurrent cholangitis or uncontrollable portal hypertension. Liver complications after kidney transplantation were not significant.

Bi-allelic mutations in renin-angiotensin system genes, associated with renal tubular dysgenesis, can also present as a progressive chronic kidney disease.

BACKGROUND: Bi-allelic loss of function variations in genes encoding proteins of the renin-angiotensin system (AGT, ACE, REN, AGTR1) are associated with autosomal recessive renal tubular dysgenesis, a severe disease characterized by the absence of differentiated proximal tubules leading to fetal anuria and neonatal end-stage renal disease. CASE-DIAGNOSIS/TREATMENT: We identified bi-allelic loss of function mutations in ACE, the gene encoding angiotensin-converting enzyme, in 3 unrelated cases displaying progressive chronic renal failure, whose DNAs had been sent for suspicion of juvenile hyperuricemic nephropathy, nephronophthisis, and cystic renal disease, respectively. In all cases, patients were affected with anemia whose severity was unexpected regarding the level of renal failure and with important polyuro-polydipsia. CONCLUSIONS: Bi-allelic loss of function mutation of ACE can have atypical and sometimes late presentation with chronic renal failure, anemia (out of proportion with the level of renal failure), and polyuro-polydipsia. These data illustrate the usefulness of next generation sequencing and "agnostic" approaches to elucidate cases with chronic kidney disease of unknown etiology and to broaden the spectrum of phenotypes of monogenic renal diseases. It also raises the question of genetic modifiers involved in the variation of the phenotypes associated with these mutations.

Consensus recommendations for diagnosis, management and treatment of Fabry disease in paediatric patients.

Fabry disease (FD), a rare X-linked disease, can be treated with bi-monthly infusion of enzyme replacement therapy (ERT) to replace deficient α-galactosidase A (AGAL-A). ERT reduces symptoms, improves quality of life (QoL), and improves clinical signs and biochemical markers. ERT initiation in childhood could slow or stop progressive organ damage. Preventative treatment of FD from childhood is thought to avoid organ damage in later life, prompting a French expert working group to collaborate and produce recommendations for treating and monitoring children with FD. Organ involvement should be assessed by age 5 for asymptomatic boys (age 12-15 for asymptomatic girls), and immediately for children diagnosed via symptoms. The renal, cardiac, nervous and gastrointestinal systems should be assessed, as well as bone, skin, eyes, hearing, and QoL. The plasma biomarker globotriaosylsphingosine is also useful. ERT should be considered for symptomatic boys and girls with neuropathic pain, pathological albuminuria (≥3 mg/mmol creatinine), severe GI involvement and abdominal pain or cardiac involvement. ERT should be considered for asymptomatic boys from the age of 7. Organ involvement should be treated as needed. Early diagnosis and management of FD represents a promising strategy to reduce organ damage, morbidity and premature mortality in adulthood.

[Proteinuria in pediatrics: from screening to diagnosis and monitoring of kidney disease]. / Protéinurie en pédiatrie : du dépistage au diagnostic et suivi de maladie rénale.

The incidental finding of a proteinuria is a common cause of consultation in pediatric nephrology. Although it is transient in most cases, it may also be indicative of a kidney disease. For this reason, a moderate proteinuria in children should not be overlooked. Moreover, as well as in adults, proteinuria is an essential marker in the monitoring of chronic renal disease in pediatric patients. We propose to review the physiopathology of proteinuria, the screening modalities and how to deal with proteinuria in pediatric.

Toxocara canis infection: Unusual trigger of systemic lupus erythematosus.

Infection by Toxocara canis can cause systemic vasculitis. We report here a unique case of systemic lupus erythematosus (SLE) triggered by T. canis infection. An 8-year-old girl was treated with albendazole therapy for common toxocariasis, but she developed two weeks later, asthenia, fever, infiltrated maculopapular eruption of the face, peripheral vascular disease with necrosis of the fingers and inflammatory anemia with proteinuria. Anti-nuclear, anti-DNA and anti-Sm antibodies positivity, together with minimal change nephritis with mesangial exclusive IgM deposit on renal biopsy and clinical relapse after initially successful steroid therapy, led to the diagnosis of SLE. T. canis infection can trigger systemic lupus but must also be ruled out of the differential diagnosis given its association with autoimmunity.

Albuminuria induces a proinflammatory and profibrotic response in cortical collecting ducts via the 24p3 receptor.

Albuminuria is strongly associated with progressive kidney tubulo-interstitial damage and chronic kidney disease (CKD) progression. In proteinuric nephropathies, albumin reabsorption by the proximal tubule is saturated and the distal nephron is exposed to high concentrations of luminal albumin that may produce adverse effects. Since proximal tubular cells exposed to albuminuria exhibit a proinflammatory and profibrotic response, we assessed the effect of albuminuria in the collecting duct (CD). With the use of kidney sections and isolated cortical CDs (CCDs) from puromycin-aminonucleoside-induced nephrotic rats (PAN rats) exhibiting proteinuria, immunofluorescence microscopy revealed internalized albumin in CD cells. In these proteinuric rats, increased expression levels of cytokines and profibrotic signaling markers were detected in isolated CCDs and bands of inflammatory fibrosis could be observed around CDs. Albumin endocytosis was confirmed by FITC-albumin uptake in cultured murine CCD (mCCDcl1) cells. Exposure of mCCDcl1 cells to albumin induced NF-κB activation as assessed by luciferase reporter gene assay, nuclear translocation of NF-κB p65 subunit, and increased NF-κB target gene expression. Moreover, albuminuria-like condition results in transforming growth factor-ß1 (TGF-ß1) overexpression and the upregulation of profibrotic signaling markers such as Snail or vimentin via an autocrine mechanism. In mCCDcl1 cells, neutrophil gelatinase-associated lipocalin (NGAL)/lipocalin-2/24p3 receptor (24p3R) mediates albumin endocytosis as well as activation of NF-κB and TGF-ß1 signaling pathways. Therefore, CD may play a key role in initiation and/or progression of inflammation and fibrosis in response to proteinuria.