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Background Histological findings of kidney involvement have been rarely reported in pediatric patients with SARS-CoV-2 infection. Here, we describe clinical, laboratory, and histological findings of two pediatric cases with almost exclusive kidney involvement by SARS-CoV-2. Results A 10-year-old girl with IgA vasculitis nephritis underwent kidney biopsy, showing diffuse and segmental mesangial-proliferative glomerulonephritis, and steroid therapy was initiated. After the worsening of the clinical picture, including an atypical skin rash, she was diagnosed with SARS-CoV-2. The re-evaluation of initial biopsy showed cytoplasmatic blebs and virus-like particles in tubular cells at electron microscopy. Despite SARS-CoV-2 clearance and the intensification of immunosuppression, no improvement was observed. A second kidney biopsy showed a crescentic glomerulonephritis with sclerosis, while virus-like particles were no longer evident. The second patient was a 12-year-old girl with a 3-week history of weakness and weight loss. Rhinitis was reported the month before. No medications were being taken. Blood and urine analysis revealed elevated serum creatinine, hypouricemia, low molecular weight proteinuria, and glycosuria. A high SARS-CoV-2-IgG titre was detected. Kidney biopsy showed acute tubular-interstitial nephritis. Steroid therapy was started with a complete resolution of kidney involvement. Conclusion We can speculate that in both cases SARS-CoV-2 played a major role as inflammatory trigger of the kidney damage. Therefore, we suggest investigating the potential kidney damage by SARS-CoV-2 in children. Moreover, SARS-CoV-2 can be included among infectious agents responsible for pediatric acute tubular interstitial nephritis.

© 2022 International Society of NephrologyIntroduction: Autosomal recessive polycystic kidney disease (ARPKD) is a rare monogenic disorder characterized by early onset fibrocystic hepatorenal changes. Previous reports have documented pronounced phenotypic variability even among siblings in terms of patient survival. The underlying causes for this clinical variability are incompletely understood. Methods: We present the longitudinal clinical courses of 35 sibling pairs included in the ARPKD registry study ARegPKD, encompassing data on primary manifestation, prenatal and perinatal findings, genetic testing, and family history, including kidney function, liver involvement, and radiological findings. Results: We identified 70 siblings from 35 families with a median age of 0.7 (interquartile range 0.1–6.0) years at initial diagnosis and a median follow-up time of 3.5 (0.2–6.2) years. Data on PKHD1 variants were available for 37 patients from 21 families. There were 8 patients from 7 families who required kidney replacement therapy (KRT) during follow-up. For 44 patients from 26 families, antihypertensive therapy was documented. Furthermore, 37 patients from 24 families had signs of portal hypertension with 9 patients from 6 families having substantial hepatic complications. Interestingly, pronounced variability in the clinical course of functional kidney disease was documented in only 3 sibling pairs. In 17 of 20 families of our cohort of neonatal survivors, siblings had only minor differences of kidney function at a comparable age. Conclusion: In patients surviving the neonatal period, our longitudinal follow-up of 70 ARPKD siblings from 35 families revealed comparable clinical courses of kidney and liver diseases in most families. The data suggest a strong impact of the underlying genotype.

Background: The goal of the treatment of Alport syndrome (AS) is to delay the progression of kidney damage. The current standard of care is the use of Renin Angiotensin Aldosterone System (RAAS) blockers: angiotensin-converting enzyme inhibition (ACEi), angiotensin receptor blockade, and, recently, spironolactone (SP). Aim of the study: the purpose of this retrospective study is to evaluate the efficacy (reduction of proteinuria and changes of glomerular function) and safety of a sequential introduction of RAAS blockers up to a triple RAAS blockade in pediatric proteinuric patients with AS. Methods: in this retrospective study (1995 to 2019), we evaluated proteinuria values in AS patients, during the 12 months following the beginning of a new RAAS blocker, up to a triple blockade. ACEi was always the first line of treatment, then ARB and SP were sequentially added if uPCR increased by 50% from the basal level in 2 consecutive samples during a 3-months observation period, or when uPCR ratio was &gt, 2 mg/mg. Results: 26 patients (mean age at treatment onset was 10.55 ± 5.02 years) were enrolled. All patients were on ACEi, 14/26 were started on a second drug (6/14 ARB, 8/14 SP) after a mean time of 2.2 ± 1.7 years, 7/26 were on triple RAAS blockade after a further period of 5.5 ± 2.3 years from the introduction of a second drug. Repeated Measure Anova analysis of log-transformed data shows that the reduction of uPCR values after Time 0 from the introduction of the first, second and third drug is highly significant in all three cases (p values = 0.0016, 0.003, and 0.014, respectively). No significant changes in eGFR were recorded in any group, apart from a 15-year-old boy with X-linked AS, who developed kidney failure. One patient developed mild hyperkaliemia, and one gynecomastia and symptomatic hypotension. No life-threatening events were recorded. Conclusions: double and triple RAAS blockade is an effective and safe strategy to reduce proteinuria in children with AS. Nevertheless, we suggest monitoring eGFR and Kaliemia during follow-up.

Autosomal recessive polycystic kidney disease (ARPKD) is a severe disease of early childhood that is clinically characterized by fibrocystic changes of the kidneys and the liver. The main cause of ARPKD are variants in the PKHD1 gene encoding the large transmembrane protein fibrocystin. The mechanisms underlying the observed clinical heterogeneity in ARPKD remain incompletely understood, partly due to the fact that genotype-phenotype correlations have been limited to the association of biallelic null variants in PKHD1 with the most severe phenotypes. In this observational study we analyzed a deep clinical dataset of 304 patients with ARPKD from two independent cohorts and identified novel genotype-phenotype correlations during childhood and adolescence. Biallelic null variants frequently show severe courses. Additionally, our data suggest that the affected region in PKHD1 is important in determining the phenotype. Patients with two missense variants affecting amino acids 709-1837 of fibrocystin or a missense variant in this region and a null variant less frequently developed chronic kidney failure, and patients with missense variants affecting amino acids 1838-2624 showed better hepatic outcome. Variants affecting amino acids 2625-4074 of fibrocystin were associated with poorer hepatic outcome. Thus, our data expand the understanding of genotype-phenotype correlations in pediatric ARPKD patients and can lay the foundation for more precise and personalized counselling and treatment approaches. German Society for Pediatric Nephrology (GPN); ESCAPE Network; European Society for Paediatric Nephrology (ESPN); German PKD foundation; Koeln Fortune program; GEROK program of the Medical Faculty of University of Cologne; Marga and Walter Boll-Foundation; German Federal Ministry of Research and Education (BMBF)Federal Ministry of Education & Research (BMBF) [01GM1515, 01GM1903]; working group CAKUT of the ESPN; working group Inherited Kidney Diseases of the ESPN We thank the German Society for Pediatric Nephrology (GPN) and the ESCAPE Network for their support. We thank Mr Mathias Burgmaier (Aachen) and Mr Samuel Kilian (Heidelberg) for support in conducting statistical analysis. ML was supported by grants of the GPN, the European Society for Paediatric Nephrology (ESPN), the German PKD foundation, the Koeln Fortune program, the GEROK program of the Medical Faculty of University of Cologne, and the Marga and Walter Boll-Foundation. FS, CB, and ML are supported by the German Federal Ministry of Research and Education (BMBF grant 01GM1515 and 01GM1903). KB was supported by the Koeln Fortune program and the GEROK program of the Medical Faculty of University of Cologne, as well as the Marga and Walter Boll-Foundation. This work was generated within the European Reference Network for Rare Kidney Disorders (ERKNet). The work was supported by the working groups CAKUT and Inherited Kidney Diseases of the ESPN.

The kidney is often the target of immune system dysregulation in the context of primary or systemic disease. In particular, the glomerulus represents the anatomical entity most frequently involved, generally as the expression of inflammatory cell invasion or circulant or in situ immune-complex deposition. Glomerulonephritis is the most common clinical and pathological manifestation of this involvement. There are no universally accepted classifications for glomerulonephritis. However, recent advances in our understanding of the pathophysiological mechanisms suggest the assessment of immunological features, biomarkers, and genetic analysis. At the same time, more accurate and targeted therapies have been developed. Data on pediatric glomerulonephritis are scarce and often derived from adult studies. In this review, we update the current understanding of the etiologic events and genetic factors involved in the pathogenesis of pediatric immunologically mediated primitive forms of glomerulonephritis, together with the clinical spectrum and prognosis. Possible new therapeutic targets are also briefly discussed.

Alport syndrome (AS) is an inherited progressive renal disease caused by mutations in COL4A3, COL4A4, and COL4A5 genes. Despite simultaneous screening of these genes being widely available, mutation detection still remains incomplete in a non-marginal portion of patients. Here, we applied whole-exome sequencing (WES) in 3 Italian families negative after candidate-gene analyses. In Family 1, we identified a novel heterozygous intronic variant (c.2245-40A>G) -outside the conventionally screened candidate region for diagnosis- potentially disrupting COL4A5 exon29 splicing. Using a minigene-based approach in HEK293 cells we demonstrated that this variant abolishes exon29 branch site, causing exon skipping. Moreover, skewed X-inactivation of the c.2245-40A>G allele correlated with disease severity in heterozygous females. In Family 2, WES highlighted a novel COL4A5 hemizygous missense mutation (p.Gly491Asp), which segregates with the phenotype and impacts on a highly-conserved residue. Finally, in Family 3, we detected a homozygous 24-bp in-frame deletion in COL4A3 exon1 (NM_000091.4:c.30_53del:p.Val11_Leu18del or c.40_63del24:p.Leu14_Leu21del), which is ambiguously annotated in databases, although it corresponds to a recurrent AS mutation. Functional analyses showed that this deletion disrupts COL4A3 signal peptide, possibly altering protein secretion. In conclusion, WES -together with functional studies- was fundamental for molecular diagnosis in 3 AS families, highlighting pathogenic variants that escaped previous screenings.

The aim of this trial was to compare the safety and efficacy of homotoxicological remedies versus placebo and versus desmopressin (dDAVP) in the treatment of monosymptomatic nocturnal enuresis (MNE). We conducted a randomised, double-blind, double-dummy, controlled trial in which 151 children with MNE were randomly assigned to receive oral homotoxicological remedies (n = 50), dDAVP (n = 50) or placebo (n = 51). The primary outcomes were: the reduction of wet nights per week after 3 months of therapy; the evaluation of the numbers and percentages of non-responders and responders; the number of children relapsing after initial response and the number of children attaining 14 consecutive dry nights during the treatment. The secondary outcome was the detection of adverse effects. Baseline clinical characteristics were similar in the three groups of patients. After the 3 months of therapy there was a significant difference between the three groups (P < 0.001) in the mean number of wet nights per week. The daily dose of dDAVP produced a statistically significant decrease (62.9%) in wet nights compared to placebo (2.4%) (P < 0.001) and compared to homotoxicological remedies (30.0%) (P < 0.001). There was a significant decrease in wet nights among the group treated with homotoxicological medications if compared with placebo (P < 0.001). The full response achieved with homotoxicological remedies (20%) was superior if compared with placebo (0%) (P < 0.001). Homotoxicology was superior to placebo (P < 0.001) with regard to the number of children attaining 14 consecutive dry nights during treatment. Our study demonstrates that homotoxicology is safe and effective when compared with placebo, even if it is significantly less effective than dDAVP in this clinical condition.