Background
Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, randomized controlled trial was designed to test ...whether the monoclonal antibody rituximab is non-inferior to steroids in maintaining remission in juvenile forms of SDNS and how long remission may last (EudraCT:2008-004486-26).
Methods
We enrolled 30 children 4–15 years who had developed SDNS 6–12 months before and were maintained in remission with low prednisone doses (0.1–0.4 mg/Kg/day). Participants were randomized following a non-inferiority design to continue prednisone alone (n 15, controls) or to add a single intravenous infusion of rituximab (375 mg/m
2
, n 15 intervention). Prednisone was tapered in both arms after 1 month. Children assigned to the control arm were allowed to receive rituximab to treat disease relapse.
Results
Proteinuria increased at 3 months in the prednisone group (from 0.14 to 1.5 g/day) (
p
< 0.001) and remained unchanged in the rituximab group (0.14 g/day). Fourteen children in the control arm relapsed within 6 months. Thirteen children assigned to rituximab (87%) were still in remission at 1 year and 8 (53%) at 4 years. Responses were similar in children of the control group who received rituximab to treat disease relapse. We did not record significant adverse events.
Conclusions
Rituximab was non-inferior to steroids for the treatment of juvenile SDNS. One in two children remains in remission at 4 years following a single infusion of rituximab, without significant adverse events. Further studies are needed to clarify the superiority of rituximab over low-dose corticosteroid as a treatment of SDNS.
Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome, and the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated myeloid-related proteinemia inflammatory ...(PAMI) syndrome are two distinct clinical conditions caused by heterozygous mutations of the
PSTPIP1
gene. While skin and joint involvements are shared by both conditions, PAMI is characterized by hepatosplenomegaly, pancytopenia, and growth failure. Kidney involvement is exceptional in PSTPIP1-mediated disorders. The two missense
PSTPIP1
variants associated with PAMI syndrome are p.E250K and p.E257K. Long-term treatment with interleukin (IL)-1 inhibitors is effective to control inflammatory manifestations and is usually well-tolerated. We report a case of a patient carrying the
PSTPIP1
p.E250K mutation who developed a late-onset kidney involvement despite a long treatment with canakinumab and anakinra. Kidney biopsy showed focal segmental glomerulosclerosis that was treated with tacrolimus (0.1 mg/kg/day in two doses). A literature revision with the aim to assess the proportion and type of kidney involvement in PAMI syndrome revealed that heterogeneous nephropathies may be part of the clinical spectrum. Our study supports the importance of a periodic diagnostic work-up, including kidney laboratory tests and kidney biopsy, in individuals affected with PAMI syndrome. Kidney and liver functions may be impaired regardless of anti-cytokines treatments and additional therapy approaches (i.e., multi-drugs, hematopoietic stem cell transplantation) should be carefully considered.
Antibiotic resistance is an increasing problem, especially in children with urinary tract infections. Rates of drug-specific resistant pathogens were reported, and an easy prediction model to guide ...the clinical decision-making process for antibiotic treatment was proposed. Data on microbiological isolation from urinoculture, between January 2007−December 2018 at Istituto Gaslini, Italy, in patients aged <19 years were extracted. Logistic regression-based prediction scores were calculated. Discrimination was determined by the area under the receiver operating characteristic curve; calibration was assessed by the Hosmer and Lemeshow test and the Spiegelhalterz test. A total of 9449 bacterial strains were isolated in 6207 patients; 27.2% were <6 months old at the first episode. Enterobacteriales (Escherichia coli and other Enterobacteriales) accounted for 80.4% of all isolates. Amoxicillin-clavulanate (AMC) and cefixime (CFI) Enterobacteriales resistance was 32.8% and 13.7%, respectively, and remained quite stable among the different age groups. On the contrary, resistance to ciprofloxacin (CIP) (overall 9.6%) and cotrimoxazole (SXT) (overall 28%) increased with age. After multivariable analysis, resistance to AMC/CFI could be predicted by the following: sex; age at sampling; department of admission; previous number of bacterial pathogens isolated. Resistance to CIP/SXT could be predicted by the same factors, excluding sex. The models achieved very good calibration but moderate discrimination performance. Specific antibiotic resistance among Enterobacteriales could be predicted using the proposed scoring system to guide empirical antibiotic choice. Further studies are needed to validate this tool.
Background:
Ureteropelvic junction obstruction (UPJO) is one of the most frequent causes of congenital hydronephrosis. It is essential to distinguish UPJO which needs surgical treatment. fMRU ...combines high quality morphological details of the kidney and excretory pathways with functional data.
Objective
This study aims to introduce a new radiological score based on fMRU findings to be able to differentiate surgical from non-surgical kidneys.
Materials and Methods
We retrospectively selected patients with hydronephrosis due to UPJO who underwent fMRU (January 2009–June 2018). A multidisciplinary team identified a list of fMRU morpho-functional predictive variables to be included in the analysis. To evaluate the role of different independent variables in predicting the outcome, a multivariable logistic regression model has been performed; the outcome variable was the surgical intervention. For each predictive variable, Odds Ratio and 95% Confidence Intervals were calculated. The likelihood ratio test was used to assess the significance of the variables. Using the regression model, we assigned a numerical value to each predictive variable, rounding up the beta-coefficients. The cut-off value of the total score was obtained from the ROC curve analysis.
Results
A total of 192 patients were enrolled, corresponding to 200 pathological kidneys. All of them underwent fMRU; 135 were surgically treated, while 65 underwent ultrasound or MRU follow-up. Predictive variables significantly associated with surgery resulted to be the urographic phase, the presence of abnormal vessels, and a baseline anterior-posterior pelvic diameter >23 mm. Beta coefficients of the logistic regression model were then converted in scores. The ROC curve of the score showed high sensitivity (84.3%) and specificity (81.3%) with a cut-off > 2.5.
Conclusions
We propose a new fMRU score able to identify surgical vs. non-surgical kidneys with UPJO.
Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and ...21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.
Background
Congenital anomalies of the kidney and urinary tract (CAKUT) represent 20–30% of all birth defects and are often associated with extra-renal malformations. We investigated the frequency of ...brain/spine malformations and neurological features in children with CAKUT.
Methods
We reviewed the clinico-radiological and genetic data of 199 out of 1,165 children with CAKUT evaluated from 2006 to 2023 (99 males, mean age at MRI 6.4 years) who underwent brain and/or spine MRI. Patients were grouped according to the type of CAKUT (CAKUT-K involving the kidney and CAKUT-H involving the inferior urinary tract). Group comparisons were performed using
χ
2
and Fisher exact tests.
Results
Brain/spine malformations were observed in 101/199 subjects (50.7%), 8.6% (101/1165) of our CAKUT population, including midbrain-hindbrain anomalies (40/158, 25.3%), commissural malformations (36/158, 22.7%), malformation of cortical development (23/158, 14.5%), Chiari I anomaly (12/199, 6%), cranio-cervical junction malformations (12/199, 6%), vertebral defects (46/94, 48.9%), caudal regression syndrome (29/94, 30.8%), and other spinal dysraphisms (13/94, 13.8%). Brain/spine malformations were more frequent in the CAKUT-K group (62.4%, p < 0.001). Sixty-two subjects (62/199, 31.2%) had developmental delay/intellectual disability. Neurological examination was abnormal in 40/199 (20.1%). Seizures and/or electroencephalographic anomalies were reported in 28/199 (14%) and behavior problems in 19/199 subjects (9%). Developmental delay/intellectual disability was more frequent in kidney dysplasia (65.2%) and agenesis (40.7%) (p = 0.001).
Conclusions
We report a relative high frequency of brain/spine malformations and neurodevelopmental disorders in children with CAKUT who underwent MRI examinations in a tertiary referral center, widening the spectrum of anomalies associated with this condition.
Graphical Abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
Exome sequencing in a family with autosomal dominant congenital urinary tract malformations showed a mutation in dual serine–threonine and tyrosine protein kinase (
DSTYK
), confirmed in other, ...unrelated patients, identifying a major determinant of human urinary tract development.
Congenital malformations of the kidney and urinary tract contribute to 23% of birth defects
1
,
2
and account for 40 to 50% of pediatric cases and 7% of adult cases of end-stage renal disease (ESRD) worldwide.
3
,
4
These disorders are genetically heterogeneous and encompass a wide range of anatomical defects, such as renal agenesis, renal hypodysplasia, ureteropelvic junction obstruction, or vesicoureteral reflux.
5
Mutations in genes that cause syndromic disorders, such as
HNF1B
and
PAX2
mutations, are detected in only 5 to 10% of cases.
6
,
7
Familial forms of nonsyndromic disease have been reported, further supporting genetic determination
8
,
9
; however, owing . . .
Aims
Anti‐CD20 antibodies are increasingly being used to treat idiopathic nephrotic syndrome (INS) in children. While they may allow steroid and calcineurin inhibitor withdrawal, repeated infusions ...of anti‐CD20 antibodies are often required to maintain remission. Data on their potential toxicity in INS are needed, to consider repeated infusions.
Methods
We investigated the side effects associated with the use of rituximab (a chimeric antibody; 130 patients) and ofatumumab (a humanized antibody; 37 patients) in children with INS (steroid‐dependent and steroid/calcineurin inhibitor‐dependent disease) treated at a national referral centre over a 9‐year period (400 treatments; follow‐up 1–9 years).
Results
Infusion reactions were mainly absent in children with steroid‐dependent disease. Rash, dyspnoea, fever, cough and itchy throat (5% and 18% following rituximab and ofatumumab infusion, respectively) were resolved by using premedication with salbutamol. Other short‐term reactions (up to 3 months), including arthritis (2%) and lung injury (1%), were more common with rituximab. Infections were observed 3–9 months following infusion, were similarly common in the two groups and resolved with targeted therapies antibiotic, fluconazole, immunoglobulins (Igs), etc.. The number of circulating CD19/20 cells fell to 0 at month 1 and were reconstituted at month 3; circulating IgG antibodies remained within the normal range for 1 year. Tetanus and hepatitis B virus immunization was not modified by either treatment; Epstein–Barr virus and John Cunningham virus activation markers were occasionally observed.
Conclusion
Overall, the toxicity of anti‐CD20 monoclonal antibodies was limited to post‐infusion side effects in children with more complex disease. The relatively safe profile of anti‐CD20 antibodies supports their use as steroid‐sparing agents in children with INS.
Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) are a major cause of morbidity in children. We measured the risk of progression to end-stage renal disease in 312 patients with CAKUT ...preselected for the presence of anomalies in kidney number or size. A model of dialysis-free survival from birth was established as a function of the renal CAKUT categories of solitary kidney; unilateral and bilateral hypodysplasia; renal hypodysplasia associated with posterior urethral valves; and multicystic and horseshoe kidney. Cox regression analysis took into account the concomitant presence of vesicoureteral reflux, year of diagnosis, and time-varying values of serum creatinine, proteinuria, and hypertension. By 30 years of age, 58 patients had started dialysis, giving a yearly incidence of 0.023 over a combined 2474 patient risk years. The risk for dialysis was significantly higher for patients with a solitary kidney or with renal hypodysplasia associated with posterior urethral valves (hazard ratios of 2.43 and 5.1, respectively) compared to patients with unilateral or bilateral renal hypodysplasia, or multicystic or horseshoe kidney, and was independent of other prognostic factors. Our study shows that sub-clinical defects of the solitary kidney may be responsible for a poorer prognosis compared to more benign forms of CAKUT. Prospective studies are needed to validate these results.
Purpose
To evaluate UDR reliability, sensitivity, specificity and to identify the best treatment basing on UDR among single or double endoscopic injections and ureteral reimplantation.
Methods
Data ...of patients affected by primary VUR and treated by endoscopic injection over a 10 years period were retrospectively analyzed. Two radiologist attributed reflux grade and UDR on voiding cystourethrogram twice and blinded. Follow-up focused on resolution after 1 or 2 endoscopic injections. Relation between UDR, reflux grade and outcomes were analyzed.
Results
Patient enrolled were 198. Low grade VUR was present in 24.8%, grade 3 in 41.6%, grade 4–5 in 33.6%. Resolution after one injection was obtained in 88 patients; among 110 not resolved 104 cases had a second injection. Success after 2 injections was reported in 138 cases. UDR showed a higher reliability compared with reflux grade both in intra than inter-reader measurement (ICC > 90%). Success after 1 or 2 injections was reported for UDR < 0.33 and UDR < 0.47 respectively.
Conclusion
UDR shows to be a more reliable measurement that allows for an objective estimation of VUR severity and prognosis. It represents a quantitative parameter that might be useful to identify patients who may benefit endoscopic or surgical treatment, avoiding unnecessary under or over-treatment.
PDF
