Safety Profile and Effectiveness of Dapagliflozin in Pediatric Patients with Chronic Kidney Disease.

INTRODUCTION: Nephroprotection in pediatric chronic kidney disease (CKD) has a major positive impact, both on residual renal function and on quality of life, by delaying the need for renal replacement therapy. To this day, nephroprotective drugs used in children are mainly limited to angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers; interestingly, as suggested by trials conducted in adults with CKD, sodium-glucose cotransporter 2 inhibitors (SGLT2i) might also be beneficial to pediatric patients. However, there are no validated data to this date documenting the effect of SGLT2i in pediatric patients with CKD. METHODS: We present a retrospective single-center study reporting the use of dapagliflozin in pediatric patients with CKD, aiming to evaluate dapagliflozin safety profile as well as its potential for renal protection. Our study describes 7 patients with a mean age of 13.3 years (+/- 7.029) presenting with identified glomerulopathy, leading to CKD and already treated by ACE inhibitors. Patients received a daily dose of dapagliflozin of 5 or 10 mg. RESULTS: Over a period of 15 months, all patients reported the medication as easy to use. After an initial dip, estimated glomerular filtration rate decline slope stabilized in all patients. Urinary albumin-over-creatinine ratio had a strong tendency to decrease after 6 months of treatment (p = 0.0684). Systolic blood pressure also had a tendency to decrease after 6 months of treatment (p = 0.1). No significant side effect was reported by the patients. CONCLUSION: The promising results presented in this study support the use of SGLT2i in pediatric patients with CKD, although larger, randomized controlled trials in pediatric patients are necessary to better characterize their effectiveness in this particular population.

A step-by-step, multidisciplinary strategy to maximize the yield of genetic testing in pediatric patients with chronic kidney diseases.

BACKGROUND: The use of genetic testing in pediatric patients with chronic kidney diseases (CKD) has increased exponentially in the past few years, particularly with the emergence of novel sequencing techniques. However, the genetic yield remains unexpectedly low in nephrology, with an impact on diagnosis, prognosis and treatment. Moreover, the increasing diversity of genetic testing possibilities can be seen as an obstacle by clinicians, in the absence of a strong background in genetics. Here, we propose a step-by-step, multidisciplinary strategy for the diagnostic evaluation of pediatric patients with CKD, and appropriate genetic test selection to maximize the yield of genetic testing. METHODS: A total of 126 pediatric patients were enrolled in a retrospective file analysis. Genetic testing techniques used included phenotype-associated next-generation panel sequencing (N = 41), Sanger and SNaPshot sequencing (N = 3) and/or whole exome sequencing (N = 2). RESULTS: Overall genetic yield reached 63% and genetic testing significantly impacted patient management in 70%. The distribution of kidney diseases among patients was balanced and matched previously described pediatric cohorts in terms of glomerulopathies, tubulopathies and ciliopathies. Genetic analyses led to significant treatment modifications, kidney biopsy sparing and personalized nephroprotection, as well as tailored genetic counseling. Of note, the evaluation of Human Phenotype Ontology term accuracy in the cohort showed that causal mutations were precisely identified in 85% of the patients at most. CONCLUSION: Here we suggest a step-by-step, multidisciplinary strategy to maximize the yield of genetic testing in pediatric patients with CKD. This approach optimizes patient care while avoiding unnecessary treatments or procedures.

Diversity of kidney care referral pathways in national child health systems of 48 European countries.

Background: Primary, secondary and tertiary healthcare services in Europe create complex networks covering pediatric subspecialties, sociology, economics and politics. Two surveys of the European Society for Paediatric Nephrology (ESPN) in 1998 and 2017 revealed substantial disparities of kidney care among European countries. The purpose of the third ESPN survey is to further identify national differences in the conceptualization and organization of European pediatric kidney health care pathways during and outside normal working hours. Methods: In 2020, a questionnaire was sent to one leading pediatric nephrologist from 48 of 53 European countries as defined by the World Health Organization. In order to exemplify care pathways in pediatric primary care nephrology, urinary tract infection (UTI) was chosen. Steroid sensitive nephrotic syndrome (SSNS) was chosen for pediatric rare disease nephrology and acute kidney injury (AKI) was analyzed for pediatric emergency nephrology. Results: The care pathways for European children and young people with urinary tract infections were variable and differed during standard working hours and also during night-time and weekends. During daytime, UTI care pathways included six different types of care givers. There was a shift from primary care services outside standard working hours to general outpatient polyclinic and hospital services. Children with SNSS were followed up by pediatric nephrologists in hospitals in 69% of countries. Patients presenting with community acquired AKI were admitted during regular working hours to secondary or tertiary care hospitals. During nights and weekends, an immediate shift to University Children's Hospitals was observed where treatment was started by intensive care pediatricians and pediatric nephrologists. Conclusion: Gaps and fragmentation of pediatric health services may lead to the risk of delayed or inadequate referral of European children with kidney disease to pediatric nephrologists. The diversity of patient pathways outside of normal working hours was identified as one of the major weaknesses in the service chain.

Conservative management of congenital hepatic hemangioma complicated by ascites.

Involution of a rapidly involuting congenital hemangioma is an unknown cause of neonatal ascites. As involution phase is completed by 14 months after birth, conservative management with diuretics and drainage is possible and may avoid surgical resection.

A Successful Renal Transplant in a Pediatric Patient With Glanzmann Thrombasthenia and Hyperimmunization.

We report the case of a patient with type 2 Glanzmann thrombasthenia who underwent successful kidney transplant with his mother's kidney. He started dialysis at 13 months. The patient had been diagnosed with Glanzmann thrombasthenia at 9 years old, after hemorrhagic shock, during which multiple transfusions were required and hyperimmunization had developed. At 12 years old, he received a kidney transplant. Before transplant, ABO- and HLA-compatible platelet donors were identified and convened to donate forthe surgery and in case of emergency. Bleeding was prevented withprophylacticHLA-matched platelet transfusion and tranexamic acid. After transplant, diuresis started immediately with excellent graft function and no severe bleeding. However, after week 5, several episodes of macroscopic hematuria occurred, with obstruction and anuria. The double J ureteric stent was replaced 4 times in 2 months. Finally, the ureteric stent was removed 9 months later. At 22 months after kidney transplant, the patient has a normal graft function and no further bleeding has occurred, underlying the importance of multidisciplinary management.

Artificial Intelligence in Nephrology: Core Concepts, Clinical Applications, and Perspectives.

Artificial intelligence is playing an increasingly important role in many fields of medicine, assisting physicians in most steps of patient management. In nephrology, artificial intelligence can already be used to improve clinical care, hemodialysis prescriptions, and follow-up of transplant recipients. However, many nephrologists are still unfamiliar with the basic principles of medical artificial intelligence. This review seeks to provide an overview of medical artificial intelligence relevant to the practicing nephrologist, in all fields of nephrology. We define the core concepts of artificial intelligence and machine learning and cover the basics of the functioning of neural networks and deep learning. We also discuss the most recent clinical applications of artificial intelligence in nephrology and medicine; as an example, we describe how artificial intelligence can predict the occurrence of progressive immunoglobulin A nephropathy. Finally, we consider the future of artificial intelligence in clinical nephrology and its impact on medical practice, and conclude with a discussion of the ethical issues that the use of artificial intelligence raises in terms of clinical decision making, physician-patient relationship, patient privacy, and data collection.

Asymptomatic bacteriuria in pediatric kidney transplant recipients: to treat or not to treat? A retrospective study.

BACKGROUND: Urinary tract infections (UTI) are common infectious complications in kidney transplant recipients (KTR); asymptomatic bacteriuria (AB) is also frequent. It is unclear whether treatment of AB reduces subsequent UTI in KTR; no guideline is available in pediatric KTR. In this retrospective study, we analyzed the incidence of AB in pediatric KTR and the impact of screening and treating AB on the onset of subsequent UTI. METHODS: Thirty-seven pediatric patients were included. Inclusion criteria were the occurrence of one or more episodes of AB between 2 and 24 months post-renal transplantation. Primary outcome was the cumulative incidence of acute pyelonephritis (APN) or lower urinary tract infections (LUTI) occurring between 2 and 24 months post-renal transplantation. RESULTS: Thirty-seven patients presented 171 AB episodes. One hundred sixty-four AB episodes were untreated (95.9%); among them, 150 episodes (91.5%) were not followed by a clinical infection. Ten episodes (6.1%) led to APN, and 4 (2.4%) to LUTI. There were 53 episodes of APN: 10 (18.9%) after untreated AB and 43 (81.1%) de novo. There were 11 episodes of LUTI: 4 (36.4%) after untreated AB and 7 (63.6%) de novo. Multi-drug resistant bacteria were present in 27% of the patients and in 20% of patients with pre-existing uropathy. CONCLUSIONS: Our results are not in favor of systematic treatment of AB in pediatric KTR. Notably, limitation of antibiotic treatment is an urgent and important health issue in this population, in order to reduce multi-drug resistant bacteria emergence.

Effect of different rituximab regimens on B cell depletion and time to relapse in children with steroid-dependent nephrotic syndrome.

BACKGROUND: Several studies have demonstrated that rituximab (RTX) improves relapse-free survival in patients with steroid-dependent nephrotic syndrome (SDNS). However, these studies used various RTX regimens and there are few data comparing these regimens in children with SDNS. In this retrospective study, we assessed the effect of three different initial RTX regimens on both time to B cell reconstitution and to first relapse. METHODS: Sixty-one SDNS patients receiving a first course of RTX were included. Group 1 received one injection of 100 mg/m2, group 2 received one injection of 375 mg/m2, and group 3 received two injections of 375 mg/m2 at day 0 and day 7. Time to B cell reconstitution and time to first relapse and respective risk factors were studied. RESULTS: Median time to B cell reconstitution was 2.5 [1.8-3.5], 5.0 [3.9-6.0], and 6.6 [4.6-7.8] months in groups 1, 2, and 3, respectively. RTX regimen was associated with time to B cell reconstitution (HRs group 2 vs. 3, 4.07 [1.96-8.48]; group 1 vs. 3, 11.13 [4.04-30.67]). One-year relapse-free survival was 50% [58-77], 59% [42-76], and 72% [46-87] in groups 1, 2, and 3, respectively. RTX regimen was associated with risk of relapse (HRs group 2 vs. 3, 1.55 [0.51-4.65]; group 1 vs. 3, 4.98 [1.15-21.60]). CONCLUSIONS: The initial dose of rituximab impacts time to B cell reconstitution and the probability of relapse. Risk of relapse is also associated with patient characteristics, suggesting that RTX regimen could be modified for each patient to balance efficacy, cost, and side effects.

Effect of nonsteroidal anti-inflammatory drugs in children with Bartter syndrome.

BACKGROUND: Bartter syndrome (BS) is a salt-wasting tubulopathy with induced expression of cyclooxygenase-2 in the macula densa, leading to increased prostaglandin production and hyperreninemia. Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in BS; however, there is limited information on the impact of NSAIDs at treatment initiation or the potential utility of plasma renin level to guide therapy in patients with BS. METHODS: We included 19 patients with BS treated with NSAIDs between 1994 and 2016. We assessed serum levels of renin, aldosterone, electrolytes, calcium, phosphorus, vitamin D, and intact parathyroid hormone (iPTH) before and after treatment initiation. We also recorded modifications in sodium and potassium supplements and changes in urine calcium. RESULTS: Median age at diagnosis was 0.9 months [IQR 0-6.9]. Seven patients had BS types 1 or 2, 12 had BS type 3 and two had no mutation identified. There was a trend towards a decrease in sodium chloride supplementation after initiation of NSAIDs. When defining response to treatment based on the normalization of plasma renin level, responders had a greater reduction in their electrolytes supplementation. NSAIDs treatment was associated with a reduction in urine calcium. Before treatment, half of the patients had elevated iPTH, but iPTH normalized following initiation of NSAIDs in all but one patient. CONCLUSIONS: This study confirms that NSAIDs reduce urine wasting of sodium and calcium in patients with BS. Monitoring serum renin levels may be useful to identify the lowest effective dose of NSAIDs that optimizes reduction of urine electrolyte losses.

Artificial intelligence outperforms experienced nephrologists to assess dry weight in pediatric patients on chronic hemodialysis.

BACKGROUND: Dry weight is the lowest weight patients on hemodialysis can tolerate; correct dry weight estimation is necessary to minimize morbi-mortality, but is difficult to achieve. Here, we used artificial intelligence to improve the accuracy of dry weight assessment in hemodialysis patients. METHODS/RESULTS: We designed a neural network which used bio-impedancemetry, blood volume monitoring, and blood pressure values as inputs; output was artificial intelligence dry weight. Fourteen pediatric patients were switched from nephrologist to artificial intelligence dry weight. Artificial intelligence dry weight was higher (28.6%), lower (50%), or identical to nephrologist dry weight. Mean difference between artificial intelligence and nephrologist dry weights was 0.497 kg (- 1.33 to + 1.29 kg). In patients for whom artificial intelligence dry weight was lower than nephrologist dry weight, systolic blood pressure significantly decreased after dry weight decrease to artificial intelligence dry weight (77th to 60th percentile, p = 0.022); anti-hypertensive treatments were successfully decreased or discontinued in 28.7% of cases. In patients for whom artificial intelligence dry weight was higher than nephrologist dry weight, no hypertension was observed after dry weight increase to artificial intelligence dry weight; when present, symptoms of dry weight underestimation receded. CONCLUSIONS: Neural network predictions outperformed those of experienced nephrologists in most cases, proving artificial intelligence is a powerful tool for predicting dry weight in hemodialysis patients.

Combination therapy of rituximab and mycophenolate mofetil in childhood lupus nephritis.

BACKGROUND: In clinical trials, the addition of rituximab (RTX) to the combination therapeutic regimen of mycophenolate mofetil (MMF) and corticosteroids failed to improve outcome in lupus nephritis (LN). However, recent data suggest that RTX may have steroid-sparing beneficial effects with an efficacy similar to that of conventional regimens. We report our experience with RTX in the treatment of children with LN. METHODS: Patients treated with RTX for first occurrence of LN class III to V were enrolled in the study. Treatment consisted of methylprednisolone pulse (500 mg/m2) followed by RTX (1000 mg/1.73 m2) at days 1 and 15, and MMF (1200 mg/m2/day). Prednisolone tapering and withdrawal was left to the physician's discretion. Complete remission (CR) was defined as a urine protein-to-creatinine ratio (U Pr/Cr) of <5 mg/mg and normal serum creatinine, and partial remission (PR) as a U Pr/Cr of <30 mg/mg and a <15% rise in serum creatinine over baseline. RESULTS: Twelve patients were included in the study, with median follow-up of 23.7 [interquartile range (IQR) 12.8-33.5] months. Median age of the patients was 13.6 [12.3-15.1] years, median proteinuria was 32 [19-67] mg/mg and median estimated glomerular filtration rate was 76.1 [59.3-97.7] mL/min/1.73 m2. Median CD20 depletion duration was 10 [6.8-11.0] months. Prednisolone was rapidly tapered, with median dose of 0.3 [0.15-0.41], 0.10 [0.09-0.16] and 0.0 [0.0-0.04] mg/kg/day at 3, 6 and 12 months respectively. At 3 months, three and seven patients achieved CR and PR, respectively; at 6 and 12 months all patients achieved remission (9 CR, 3 PR) and none relapsed during follow-up. Five infectious complications were observed, including three varicella-zoster virus (VZV) infections. CONCLUSIONS: In our pediatric patients with LN, therapy with RTX + MMF combined with a rapid decrease in steroid appears to have been an efficacious treatment for severe LN but was associated with high rate of VZV infection. The potential of RTX to allow complete steroid avoidance warrants further investigation in children.

Hypernatremia and acute pancreatitis in chronic kidney disease: back to the salt mines. Questions.

BACKGROUND: Acute pancreatitis can be a life-threatening complication in patients with chronic kidney disease (CKD), especially in kidney transplant recipients. CASE DIAGNOSIS/TREATMENT: The patient was 7 years old when he received renal transplantation for CKD secondary to posterior urethral valves. Two years later, he presented with severe necrotizing pancreatitis (Ranson's score 5, Balthazar's score 8). Viral and genetic testing came back negative; pancreatitis was attributed to the patient's treatments (prednisone, trimethoprim-sulfamethoxazole, and everolimus). Twenty days later, necrotized pancreatic cysts had formed. Two drains were surgically inserted into the abdomen, and continuous cyst lavage was started with normal saline solution. Two days later, blood tests revealed severe hypernatremia and hypokalemia. We suspected unwanted peritoneal dialysis had occurred because of the high sodium chloride content and the absence of potassium in the normal saline solution being used for cyst lavage. We switched to a peritoneal dialysis solution for the lavage, leading to complete correction of hydroelectrolytic disorders. CONCLUSION: Acute pancreatitis is a frequent and potentially severe complication in CKD patients. It should be suspected in the presence of nonspecific symptoms, such as abdominal pain or vomiting. Rigorous monitoring of electrolytes is also mandatory for managing CKD patients with acute pancreatitis.

Fluid status evaluation by inferior vena cava diameter and bioimpedance spectroscopy in pediatric chronic hemodialysis.

BACKGROUND: Evaluation of patient's dry weight remains challenging in chronic hemodialysis (HD) especially in children. Inferior Vena Cava (IVC) measurement was reported useful to assess fluid overload both in adults and children. METHODS: We performed a monocentric prospective study to evaluate the relation between predialytic IVC diameter measurements and hydration status evaluated by physicians and bioimpedance spectroscopy (BIS) and between IVC measurements and persistent hypertension. RESULTS: Forty-eight HD sessions in 16 patients were analyzed. According to physicians, patients were overhydrated in 84.5% of dialysis sessions, 20.8% according to BIS, and 0%, 4.1% and 20.8% according to IVC inspiratory, expiratory and collapsibility index reference curves respectively. There was no correlation between relative overhydration evaluated by BIS and IVC measurements z-scores (p = 0.20). Patients whose blood pressure normalized after HD had a more dilated maximal IVC diameter before dialysis session than patients with persistent hypertension (median - 0.07SD [-0.8; 0.88] versus -1.61SD [-2.18; -0.74] (p = 0.03)) with an optimal cut-off of -0.5 SD. CONCLUSIONS: In our study, IVC measurement is not reliable to assess fluid overload in children on HD and was not correlated with extracellular fluid volume assessed by BIS measurements. However, IVC measurements might be of interest in differentiating volume-dependant hypertension from volume-independant hypertension.

Mutations in GREB1L Cause Bilateral Kidney Agenesis in Humans and Mice.

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute a major cause of chronic kidney disease in children and 20% of prenatally detected anomalies. CAKUT encompass a spectrum of developmental kidney defects, including renal agenesis, hypoplasia, and cystic and non-cystic dysplasia. More than 50 genes have been reported as mutated in CAKUT-affected case subjects. However, the pathophysiological mechanisms leading to bilateral kidney agenesis (BKA) remain largely elusive. Whole-exome or targeted exome sequencing of 183 unrelated familial and/or severe CAKUT-affected case subjects, including 54 fetuses with BKA, led to the identification of 16 heterozygous variants in GREB1L (growth regulation by estrogen in breast cancer 1-like), a gene reported as a target of retinoic acid signaling. Four loss-of-function and 12 damaging missense variants, 14 being absent from GnomAD, were identified. Twelve of them were present in familial or simplex BKA-affected case subjects. Female BKA-affected fetuses also displayed uterus agenesis. We demonstrated a significant association between GREB1L variants and BKA. By in situ hybridization, we showed expression of Greb1l in the nephrogenic zone in developing mouse kidney. We generated a Greb1l knock-out mouse model by CRISPR-Cas9. Analysis at E13.5 revealed lack of kidneys and genital tract anomalies in male and female Greb1l-/- embryos and a slight decrease in ureteric bud branching in Greb1l+/- embryos. We showed that Greb1l invalidation in mIMCD3 cells affected tubulomorphogenesis in 3D-collagen culture, a phenotype rescued by expression of the wild-type human protein. This demonstrates that GREB1L plays a major role in early metanephros and genital development in mice and humans.