Definition, diagnosis and clinical management of non-obstructive kidney dysplasia: a consensus statement by the ERKNet Working Group on Kidney Malformations.

Kidney dysplasia is one of the most frequent causes of chronic kidney failure in children. While dysplasia is a histological diagnosis, the term 'kidney dysplasia' is frequently used in daily clinical life without histopathological confirmation. Clinical parameters of kidney dysplasia have not been clearly defined, leading to imprecise communication amongst healthcare professionals and patients. This lack of consensus hampers precise disease understanding and the development of specific therapies. Based on a structured literature search, we here suggest a common basis for clinical, imaging, genetic, pathological and basic science aspects of non-obstructive kidney dysplasia associated with functional kidney impairment. We propose to accept hallmark sonographic findings as surrogate parameters defining a clinical diagnosis of dysplastic kidneys. We suggest differentiated clinical follow-up plans for children with kidney dysplasia and summarize established monogenic causes for non-obstructive kidney dysplasia. Finally, we point out and discuss research gaps in the field.

Long-Term fate of the upper urinary tract and ITS association with continence in exstrophy patients.

INTRODUCTION: Scarce data is available in literature about the upper urinary tract outcomes of patients with Exstrophy-Epispadias Complex (EEC). After bladder closure during childhood, EEC bladders can become hostile to the upper tracts after bladder by exposing them to high pressures, leading to hydronephrosis (HN) and kidney damage. Similarly, vesicoureteral reflux (VUR) may be present and increase the likelihood for pyelonephritis. OBJECTIVE: We sought to assess long-term upper urinary tract outcomes by evaluating renal function, HN and VUR; and to assess if upper urinary tract outcomes are associated with continence status. STUDY DESIGN: A retrospective review of EEC patients having ≥1 surger(y) (ies) at our institution from 1990 until 2019 was performed. Renal function was assessed by evaluating last available estimated glomerular filtration rate (eGFR) and creatinine values. HN was assessed on ultrasound and classified according to the SFU-classification. Patients with recurrent febrile urinary tract infections (UTI) or pyelonephritis underwent a voiding-cystourethrogram (VCUG) assessing VUR, graded following the 'International system of radiographic grading of VUR'. Descriptive and comparative statistical analysis were performed to assess if upper tract outcomes are associated with continence status. RESULTS: Forty-eight patients (75% male) had a median (IQR) follow-up of 18 (10-21) years. The table shows upper tract outcomes for the entire group and stratified by continence status. The median creatinine was 0.6 (0.2-0.9) mg/dL and median eGFR was 108 (72-160) mL/min/1.73 m [2]. In two patients (4.2%), HN (SFU-grade 2) was detected. Thirty-six patients (75%) underwent VCUG, revealing high-grade VUR (stage IV-V) in 8 patients (17%) and low-grade VUR (stage I-III) in 7 patients (15%). Continence was associated with a higher need for VCUG (p = 0.02) and a higher presence of VUR (p = 0.03). DISCUSSION: Renal function in EEC patients and non-EEC patients is comparable when age matched. Only 6% had low-grade HN which was asymptomatic. 17% had high-grade VUR, which is little compared to literature (40-70%). However, results in literature are described in patients with a 'one-stage' bladder closure, whereas some of our patients had a 'two-stage' procedure. A one-stage procedure creates higher bladder pressures resulting in higher VUR-rates. Statistical analysis has showed that continence is associated with a higher prevalence of recurrent febrile UTI's or pyelonephritis and of VUR. CONCLUSIONS: No statistically differences were found between continent and incontinent patients concerning creatinine and eGFR value (p = 0.52 and p = 0.29), nor in the prevalence of hydronephrosis (p = 0.36). However, results of this study suggest that continent patients may portend a higher risk of upper tract deterioration with recurrent febrile UTI's and pyelonephritis due to VUR. Close monitoring of the upper tract status is therefore as important as focus on continence. Large-scale prospective studies defining renal function as well as pyelonephritis rates are needed to optimize the management of the upper tracts in EEC patients.

Pediatric Challenges in Robot-Assisted Kidney Transplantation.

Kidney transplantation is universally recognized as the gold standard treatment in patients with End-stage Kidney Disease (ESKD, or according to the latest nomenclature, CKD stage 5). Robot-assisted kidney transplantation (RAKT) is gradually becoming preferred technique in adults, even if applied in very few centra, with potentially improved clinical outcomes compared with open kidney transplantation. To date, only very few RAKT procedures in children have been described. Kidney transplant recipient patients, being immunocompromised, might be at increased risk for perioperative surgical complications, which creates additional challenges in management. Applying techniques of minimally invasive surgery may contribute to the improvement of clinical outcomes for the pediatric transplant patients population and help mitigate the morbidity of KT. However, many challenges remain ahead. Minimally invasive surgery has been consistently shown to produce improved clinical outcomes as compared to open surgery equivalents. Robot-assisted laparoscopic surgery (RALS) has been able to overcome many restrictions of classical laparoscopy, particularly in complex and demanding surgical procedures. Despite the presence of these improvements, many challenges lie ahead in the surgical and technical-material realms, in addition to anesthetic and economic considerations. RALS in children poses additional challenges to both the surgical and anesthesiology team, due to specific characteristics such as a small abdominal cavity and a reduced circulating blood volume. Cost-effectiveness, esthetic and functional wound outcomes, minimal age and weight to undergo RALS and effect of RAKT on graft function are discussed. Although data on RAKT in children is scarce, it is a safe and feasible procedure and results in excellent graft function. It should only be performed by a RAKT team experienced in both RALS and transplantation surgery, fully supported by a pediatric nephrology and anesthesiology team. Further research is necessary to better determine the value of the robotic approach as compared to the laparoscopic and open approach. Cost-effectiveness will remain an important subject of debate and is in need of further evaluation as well.

Single-setting robot-assisted kidney transplantation consecutive to single-port laparoscopic nephrectomy in a child and robot-assisted living-related donor nephrectomy: initial Ghent experience.

INTRODUCTION: Kidney transplantation (KT) is the gold-standard treatment for end-stage renal disease (ESRD) in children. Robot-assisted kidney transplantation (RAKT) in adults is becoming increasingly common with potentially improved morbidity compared with open KT. The study objective was to evaluate feasibility and outcomes of RAKT in children. PATIENTS & METHODS: An 8-years-old boy with ESRD received a kidney transplant from his mother. Simultaneously in two operation theatres, the boy underwent single-port (GelPOINT®) right laparoscopic nephro-ureterectomy (LNU), and his mother underwent robot-assisted left donor nephrectomy (RADN).Two full surgical teams were operating at the same time. Subsequently, the boy underwent RAKT, introducing the graft through the GelPOINT®. RESULTS: Total operative time for LNU, RADN, and RAKT was 180, 140, and 195 min, respectively, with warm, cold, and rewarming ischemia times 1.5, 200, and 47 min, respectively. Blood loss was 300, 20, and 50 cc, respectively. No intraoperative complications were noted. Convalescence of both donor and recipient was uneventful, with good kidney function at 1-year follow-up. CONCLUSION: RAKT in children is technically feasible and safe, resulting in excellent graft function. Concomitant nephrectomy can be done laparoscopically through the single-site GelPOINT®. An experienced RAKT team with the full support of pediatric nephrologists is mandatory.

Intra-patient variability in tacrolimus exposure in pediatric liver transplant recipients: Evolution, risk factors, and impact on patient outcomes.

BACKGROUND: This study aims to investigate the evolution and factors associated with TAC IPV and its impact on patient outcomes in pediatric LT recipients. METHODS: This is a retrospective study including 41 children. The TAC IPV was expressed as the coefficient of variation and was calculated for years 1-5 following LT. The number of missed clinic appointments was used as a surrogate marker for therapy adherence. RESULTS: We identified a decrease in the TAC IPV during the first 3 years after LT (P < 0.01). Serum albumin in the first year (P = 0.03), hematocrit (P = 0.02) and total bilirubin (P = 0.04) in the third year, and therapy adherence (P < 0.01) in the fifth year were associated with TAC IPV. High TAC IPV was associated with biopsy-proven acute allograft rejection (P = 0.04) and the need for biopsy during the first year (P = 0.02). There was a borderline association between TAC IPV and donor-specific antibodies (P = 0.08) and CMV viremia (P = 0.07). High TAC IPV was a predictor of need for liver biopsy and AR with an odds ratio of 1.04 (95% CI 1.0-1.1; P = 0.03) and 1.04 (95% CI 1.0-1.1; P = 0.05), respectively. CONCLUSIONS: Our results highlight the impact of biological factors on TAC IPV during the early LT follow-up and later also therapy adherence. High TAC IPV may be associated with adverse patient outcomes.

Hemolytic Uremic Syndrome Associated With Non-Shigatoxin-producing Infectious Agents: Expanding the Shigatoxin Theory.

Diarrhea-associated hemolytic uremic syndrome (HUS) is usually associated with shigatoxin-producing Escherichia coli or shigella infections. We report 2 cases of HUS, respectively, caused by salmonella and Campylobacter jejuni infections. None of these bacteria produce shigatoxins, and the underlying mechanism of HUS development remains unknown. In streptococcus pneumoniae-associated HUS, bacterial neuraminidase cleaves neuraminic acid and causes exposure of Thomsen-Friedenreich cryptantigen on the cell surface of, for example, erythrocytes, which induces an inflammatory response caused by binding of preformed IgM. Both campylobacter and salmonella bacteria also produce neuraminidase, and HUS development could be explained by a similar mechanism.

Results of a Multicenter Population Pharmacokinetic Study of Ciprofloxacin in Children with Complicated Urinary Tract Infection.

Resistance rates for ciprofloxacin, which is labeled for treating complicated urinary tract infections in children, are rapidly rising. As there is limited knowledge on developmental pharmacology of ciprofloxacin, the primary aim of this study was to develop a population pharmacokinetic model for ciprofloxacin in children treated for complicated urinary tract infections. Children to whom ciprofloxacin was prescribed, intravenous (10 to 15 mg/kg body weight every 12 h) or per os (15 to 20 mg/kg every 12 h), were enrolled. One hundred eight serum and 119 urine samples were obtained during 10 intravenous and 13 oral courses of ciprofloxacin in 22 patients (age range, 0.31 to 15.51 years). A one-compartment model best described our data. Fat-free mass and glomerular filtration rate (estimated by a formula using cystatin C and creatinine), standardized for body surface area, were significant covariates for ciprofloxacin clearance. In our population, ciprofloxacin clearance is 0.16 to 0.43 liter/h/kg of body weight, volume of distribution 0.06 to 2.88 liters/kg, and bioavailability 59.6%. All of our patients had a clinical cure of their infection. Based on target attainment simulations across doses, all children reached the pharmacodynamic target for Enterobacteriaceae, but on average only 53% did for Pseudomonas aeruginosa and 3% for Staphylococcus aureus, at the 15-mg/kg oral dose. For treating urinary tract infections caused by Pseudomonas aeruginosa, oral doses should be at least 20 mg/kg. Furthermore, in our population, fat-free mass and kidney function should be considered, as they prove to be significant covariates for ciprofloxacin clearance and, hence, exposure. (This study has been registered at ClinicalTrials.gov under identifier NCT02598362.).

Epidemiology and outcome of acute kidney injury in children, a single center study.

BACKGROUND: Information on the epidemiology of Acute Kidney Injury (AKI) in children is scarce. We performed a single center retrospective cohort study to analyze the incidence of AKI, the male/female ratio, the underlying etiology, and age at presentation. We also aimed to assess outcome measured by mortality, duration of PICU stay, and development of Chronic Kidney Disease (CKD). METHODS: Records were searched for children presenting with or developing AKI between 1st January 2008 and 1st January 2015. AKI was classified according to the pediatric Rifle criteria while the cause of AKI was defined as the major underlying disease. RESULTS: Of the 28,295 children admitted, 167 episodes of AKI were identified, equaling 5.9 cases per 1000 children. Patients classified as Failure at presentation according to pRifle criteria where significantly more likely to need dialysis (27/50, 54%) compared to those presenting with Injury (12/57, 21.1%) or Risk (6/60, 10 %). Diarrhea-associated Hemolytic Uremic Syndrome (D+HUS) was the most frequent cause (20.3 %) peaking during the summer months, followed by cardiac surgery (13.7%), medication-related nephrotoxicity (13.2%), and acute Glomerulonephritis (12%). The median age of children admitted with AKI was 6.1 years (range 0.1-17) and 50.8% of cases were male. Twenty five (15%) children died while 27 (16.1%) developed CKD. CONCLUSIONS: Pediatric AKI poses a significant problem and strategies aimed at prevention, early detection, treatment, and adequate follow-up are needed. D+HUS is the most common underlying cause and effective surveillance of Enterohemorrhagic E. coli infections in association with additional measures is highly recommended.

Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.

Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1-c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)-both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD.

Pediatric lupus nephritis presenting with terminal renal failure.

A 12-year-old Congolese girl presented with acute renal failure, edema, hypertension, hemoptysis, hematuria, and proteinuria after a history of throat infection. Renal ultrasound showed kidneys of normal size, with increased echogenicity of the cortical parenchyma and decreased corticomedullary differentiation. Other additional investigations showed pancytopenia with decreased complement (low C3 and C4). Antinuclear antibodies were strongly positive, including anti-double stranded DNA. Renal biopsy confirmed severe grade IV lupus nephritis. She was treated with high-dose steroids, mycophenolate mofetil and hydroxychloroquine, in addition to hemodialysis. After one week of intensive treatment, diuresis recovered and dialysis could be stopped after six sessions. We describe an uncommon case of severe lupus nephritis, presenting with terminal renal failure. Since the rarity of this disease presentation, other more common diagnoses have to be considered. Once the diagnosis of lupus nephritis is established, a choice has to be made between the different induction treatment protocols. The patient's ethnic background and other supportive therapies, such as the need for dialysis, can help to make this choice.

Therapeutic plasma exchange in children with acute autoimmune central nervous system disorders.

BACKGROUND: There is a growing evidence for autoimmunity in acute central nervous system (CNS) disorders and treatment with therapeutic plasma exchange (TPE) may be considered. The aim was to share our experience on the clinical application of TPE in these disorders and to present a reproducible protocol which can be used even in small children. METHODS: We present a series of 8 children aged 2-12 years with transverse myelitis, Bickerstaff's brainstem encephalitis, neuromyelitis optica, and acute paraneoplastic or unspecified encephalitis in whom TPE was used as a second-line or rescue treatment. RESULTS: A total of 104 TPE sessions were performed where 80-110 ml/kg of plasma was exchanged using 4% albumin solution and fresh frozen plasma. Six episodes of TPE-related adverse events were documented. Fibrinogen concentrations decreased after the first TPE, whereas platelets decreased gradually. One patient died in the course of the acute illness. Three children achieved a complete resolution of symptoms, 2 children have mild sequelae; whereas 2 children remain paraplegic after a follow-up of 3 to 17 months. CONCLUSIONS: We report 8 children with presumably autoimmune-mediated, acute CNS disorders treated with TPE as a rescue therapy. Although the effect of TPE can only be inferred, 5 children had a good clinical outcome. TPE is feasible even in small children with acute autoimmune CNS disorders.

ARF in children with minimal change nephrotic syndrome may be related to functional changes of the glomerular basal membrane.

BACKGROUND: Acute renal failure (ARF) is a rare complication in children with minimal change nephrotic syndrome (MCNS). Several etiologic factors (renal vein thrombosis, side effect of such drugs as nonsteroidal anti-inflammatory drugs, and infections) have been described, but often such conditions are lacking, and hemodynamic derangements or changes in glomerular permeability are suspected. METHODS: We assessed the role of alterations in renal perfusion and glomerular permeability by measuring clearances of inulin and para-aminohippurate before and during intravenous administration of a 20% albumin solution in patients with MCNS and oliguric ARF (serum creatinine > 1 mg/dL [88 micromol/L], urine output < 0.5 mL/kg body weight/h). RESULTS: Eleven patients aged 2.5 to 15 years with biopsy-proven MCNS were studied. Before albumin administration, all patients had a significantly decreased glomerular filtration rate (GFR), whereas most renal plasma flow (RPF) values were within the normal range. This resulted in a significantly decreased filtration fraction (FF; GFR/RPF x 100), which was extremely low (<7%) in 4 patients. There was a heterogeneous response to albumin administration. Albumin infusion tended to increase RPF, but changes did not reach statistical significance. Some patients showed an increase in glomerular filtration, whereas in others, it decreased. In 7 patients, FF remained unchanged or decreased even further. CONCLUSION: Our data suggest that, although in some patients decreased intravascular volume may contribute to reduced renal function, changes in glomerular permeability may have a major role in ARF occurring in uncomplicated MCNS.