BK Polyomavirus in Pediatric Renal Transplantation-What We Know and What We Do Not.

BK polyomavirus (BKPyV) is still a real threat in the management of kidney transplantation. Immunosuppressive treatment disrupts the equilibrium between virus replication and immune response, and uncontrolled BKPyV replication leads to nephropathy (BKPyV nephropathy). The first evidence of BKPyV reactivation in transplant recipients is the detection of viral shedding in urine, which appears in 20% to 60% of patients, followed by BKPyV viremia in 10-20% of kidney transplant recipients. BKPyV nephropathy eventually occurs in 1-10% of this population, mainly within the first 2 years post-transplantation, causing graft loss in about half of those patients. Few data exist regarding the pediatric population and we focus on them. In this paper, we review the existing diagnostic methods and summarize the evidence on the role of BKPyV humoral and cellular immunity in modulating the clinical course of BKPyV infection and as potential predictors of the outcome. We look at the known risk factors for BKPyV nephropathy in the immunosuppressed patient. Finally, we propose a sensible clinical attitude in order to screen and manage BKPyV infection in kidney transplant children.

Relapse rate in children with nephrotic syndrome during the SARS-CoV-2 pandemic.

BACKGROUND: Viral upper respiratory tract infections trigger nephrotic syndrome relapses. Few data exist on the impact of the SARS-CoV-2 pandemic on the risk of relapse in children with idiopathic nephrotic syndrome (INS). METHODS: In a Belgian and Italian cohort of children with INS, we performed a retrospective analysis on the number and duration of relapses observed in 3 different periods in 2020: first COVID period, February 15-May 31; second COVID period, June 1-September 14; third COVID period, September 15-December 31. Relapse rates were compared to those of the previous 5 years (PRECOVID period). For the years 2019 and 2020, all causes and INS relapse-related hospitalizations were recorded. Hospitalizations and deaths due to SARS-CoV-2 infection were also recorded. In the Belgian cohort, SARS-CoV-2 serologies were performed. RESULTS: A total of 218 patients were enrolled, and 29 (13.3%) were diagnosed with new-onset INS during the COVID period. Relapse rates per 1000 person-days were as follows: 3.2 in the PRECOVID period, 2.7 in the first COVID period, 3.3 in the second COVID period, and 3.0 in the third COVID period. The incidence rate ratio for the total COVID period was 0.9 (95%CI 0.76 to 1.06; P = 0.21) as compared to the PRECOVID period. During 2020, both the proportion of patients hospitalized for recurrence (14.2% vs. 7.6% in 2019; P = 0.03) and the rate of hospitalization for recurrence (IRR 1.97 (95%CI 1.35 to 2.88); P = 0.013) were higher compared to 2019. In December 2020, anti-SARS-CoV-2 antibodies were detected in 31% of the Belgian cohort. Patients with positive and negative SARS-CoV-2 serology did not differ significantly in relapse rate (2.4 versus 4.2 per 1000 person-days). The number of new INS cases remained similar between 2020, 2019, and 2018. CONCLUSION: The first year of the SARS-CoV-2 pandemic did not significantly affect the relapse rate in children with INS. No serious infections were reported in this population of immunosuppressed patients. A higher resolution version of the Graphical abstract is available as Supplementary information.

The Struggling Odyssey of Infantile Primary Hyperoxaluria.

Introduction: Oxalate overproduction in Primary Hyperoxaluria type I (PH1) leads to progressive renal failure and systemic oxalate deposition. In severe infantile forms of PH1 (IPH1), end-stage renal disease (ESRD) occurs in the first years of life. Usually, the management of these infantile forms is challenging and consists in an intensive dialysis regimen followed by a liver-kidney transplantation (combined or sequential). Methods: Medical records of all infants with IPH1 reaching ESRD within the first year of life, diagnosed and followed between 2005 and 2018 in two pediatric nephrology departments in Brussels and Paris, have been reviewed. Results: Seven patients were included. They reached ESRD at a median age of 3.5 (2-7) months. Dialysis was started at a median age of 4 (2-10 months). Peritoneal dialysis (PD) was the initial treatment for 6 patients and hemodialysis (HD) for one patient. Liver transplantation (LT) was performed in all patients and kidney transplantation (KT) in six of them. A sequential strategy has been chosen in 5 patients, a combined in one. The kidney transplanted as part of the combined strategy was lost. Median age at LT and KT was 25 (10-41) months and 32.5 (26-75) months, respectively. No death occurred in the series. At the end of a median follow-up of 3 years, mean eGFR was 64 ± 29 ml/min/1.73 m2. All patients presented retinal and bone lesions and five patients presented bones fractures. Conclusion: Despite encouraging survival figures, the morbidity in IPH1 patients remains extremely heavy and its management presents a huge challenge. Thanks to the newly developed RNA-interference drug, the future holds brighter prospects.

Case Report: Sustained Efficacy of Lumasiran at 18 Months in Primary Hyperoxaluria Type 1.

Background: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate, ultimately responsible for kidney stones, kidney failure and systemic oxalosis. Lumasiran, is a liver-directed RNA interference therapeutic agent. It has been shown to reduce hepatic oxalate production by targeting glycolate oxidase, and to dramatically reduce oxalate excretion. Care Report: We present the case of a teenager patient affected by PH1, who entered in the lumasiran compassionate use program. The patient had a rapid and sustained decrease in urinary oxalate/creatinine ratio, with a mean reduction after lumasiran administration of about 70%. During the 18 months long follow-up, urinary oxalate remained low, reaching nearly normal values. Plasma oxalate also decreased dramatically. Normal levels were reached immediately after the first dose and remained consistently low thereafter. During the same follow-up period, eGFR remained stable at about 60 ml/min/1.73 m2, but no new kidney stones were observed. Existing kidney stones did not increase in size. The patient did not suffer renal colic events and did not require further urological interventions. Conclusion: In our severely affected PH1 patient, lumasiran proved to be very effective in rapidly and consistently reducing plasma oxalate and urinary excretion to normal and near-normal levels, respectively. In the 18 months long follow-up post-lumasiran, the eGFR remained stable and the patient showed clinical improvements. As far as we know, this report covers the longest observation period after initiation of this novel RNAi therapy.

Rhabdomyolysis and Acute Kidney Injury as Leading COVID-19 Presentation in an Adolescent.

Severe acute respiratory syndrome coronavirus 2, the virus responsible of the current COVID-19 pandemic, has limited impact in the pediatric population. Children are often asymptomatic or present mild flu-like symptoms. We report the case of a COVID-19-infected adolescent presenting severe rhabdomyolysis and acute kidney injury without any fever or respiratory symptoms.

Case Report: Neonatal Unexplained HUS Treated With Complement Inhibitor Eculizumab.

Background: Hemolytic uremic syndrome (HUS) is rare in neonates. It is probably an under-recognized condition in the early postnatal period as it presents similarly to the most common perinatal asphyxia and to differentiate the two conditions is challenging. We describe the clinical presentation of a potential new subtype of neonatal HUS triggered by hypoxic-ischemic event. Our patient was successfully treated by a single dose of Eculizumab as early as at 9 days of life. Case Report: A 35-weeks infant was born with low hemoglobin and subsequently developed respiratory distress, hypotension, and acidosis. Blood transfusion was administered, acidosis corrected, neurological examination remained reassuring. Few hours later he developed renal failure, macroscopic hematuria, hemobilia, thrombocytopenia and coagulopathy refractory to platelet and fresh frozen plasma transfusions. No infection was found. Haptoglobin was non-measurable, and schistocytes present, complement factors C3, C4 and B were low, FBb increased. HUS was suspected. A single dose of Eculizumab™ was administered on day 9 of life. No genetic mutation of atypical HUS was found. He was discharged with improving renal function and developing cholestasis. Conclusion: In neonates with hemolytic anemia, thrombocytopenia, hematuria and renal failure, HUS should be suspected. In neonatal HUS Eculizumab should be considered as first-line therapy and discontinuation can be considered if no genetic mutation is found and clinical condition improves. In very young patients, cholestasis could appear as potential side effect of Eculizumab™.

Clinical Outcome of Children With Antenatally Diagnosed Hydronephrosis.

Fetal renal pelvis dilation is a common condition, which is observed in 1-4. 5% of pregnancies. In many cases, this finding resolves spontaneously. However, sometimes it may be a signal of significant urinary tract pathologies. The main abnormalities found after birth are uretero-pelvic junction stenosis, primary vesicoureteral reflux, megaureter, duplex kidneys, and posterior urethral valves, with uretero-pelvic junction stenosis and primary vesicoureteral reflux accounting for most of the cases. Diagnosis, management, and prognosis at short and longer term of these conditions will be reviewed in this article.

Prospective Cohort Study Investigating the Safety and Efficacy of Ambulatory Treatment With Oral Cefuroxime-Axetil in Febrile Children With Urinary Tract Infection.

Aims: To assess the safety and efficacy of ambulatory oral cefuroxime-axetil treatment in children presenting with first febrile urinary tract infection (UTI) in terms of resolution of fever, antibiotics tolerance, bacterial resistance, and loss to ambulatory follow-up. Methods: Two-year prospective single-center evaluation of the local protocol of oral ambulatory treatment of children presenting first febrile urinary tract infection (UTI). Results: From October 2013 to October 2015, 82 children were treated ambulatory with oral cefuroxime-axetil. The median age was 8 months. When analyzing those 82 children treated orally, 51 (62%) completed oral treatment, 14 (17%) missed their scheduled follow-up visits (3 patients at day 2 and 11 patients at week 2), and 17 (21%) were switched to IV therapy for the following reasons: vomiting in 9, persistent fever in 5, antibiotic resistance in 2 and bacteremia in 1. Six children (8%) presented recurrent UTI after a median of 5 months of follow-up. Conclusions: This 2-year evaluation suggests that oral treatment with cefuroxime-axetil in febrile UTI is feasible but should be implemented with caution. Home-treated children require reevaluation during treatment since 21% of our cohort had to be temporarily switched to parenteral therapy and 17% did not attend scheduled follow-up visits during oral treatment.

Outcomes of kidney transplantations in children weighing 15 kilograms or less: a retrospective cohort study.

Kidney transplantation (KT) is often delayed in small children because of fear of postoperative complications. We report early- and long-term outcomes in children transplanted at ≤15 kg in the two largest Belgian pediatric transplant centers. Outcomes before (period 1) and since the introduction of basiliximab and mycophenolate-mofetil in 2000 (period 2) were compared. Seventy-two KTs were realized between 1978 and 2016: 38 in period 1 and 34 in period 2. Organs came from deceased donors in 48 (67%) cases. Surgical complications occurred in 25 KTs (35%) with no significant difference between the two periods. At least one acute rejection (AR) occurred in 24 (33%) KTs with significantly less patients experiencing AR during period 2: 53% and 12% in period 1 and, period 2 respectively (P < 0.001). Graft survival free of AR improved significantly in period 2 compared with period 1: 97% vs. 50% at 1 year; 87% vs. 50% at 10 years post-KT (P = 0.003). Graft survival tended to increase over time (period 1: 74% and 63% at 1 and 5 years; period 2: 94% and 86% at 1 and 5 years; P = 0.07), as well as patient survival. Kidney transplantation in children ≤15 kg remains a challenging procedure with 35% of surgical complications. However, outcomes improved and are nowadays excellent in terms of prevention of AR, patient and graft survival.

Early-onset of ADCK4 glomerulopathy with renal failure: a case report.

BACKGROUND: We present a rare early presentation of a ADCK4-related glomerulopathy. This case is of interest as potentially treatable if genetic results are timely obtained. CASE PRESENTATION: We report the case of a 5-year-old boy who was identified with significant proteinuria by a urinary routine screening program for school children. Physical examination revealed dysplastic ears and abnormal folded pinna. Albumin level was 41 g/L (39-53 g/L), and urine proteins/creatinine ratio was 2.6 g/g. Renal ultrasound showed enlarged kidneys and perimedullary hyperechogenicity. Treatment by angiotensin-converting-enzyme inhibitor was not beneficial. Renal biopsy showed signs of focal segmental glomerulosclerosis. After 4 years of follow-up, he developed a clinical nephrotic syndrome and no response to prednisone and other immunosuppressive agents was obtained. Within 6 months, he was in end-stage-renal-failure (ESRF) and hemodialysis was started. He was transplanted at 10 years with his mother's kidney. Genes known to be responsible in steroid-resistant nephrotic syndromes were tested. Our patient is compound heterozygous for two mutations in the aarF domain-containing-kinase 4 (ADCK4) gene. ADCK4 gene is one of the genes involved in coenzyme Q10 (CoQ10) biosynthesis, is located in chromosome 19q13.2 and expressed in podocytes. ADCK4 mutations show a largely renal-limited phenotype. The nephropathy usually presents during adolescence, fast evolves towards ESRF, and may be treatable by CoQ10 supplementation if started early in the disease. Our patient presented nephrotic range proteinuria at 5 years, and he reached ESRF at 10 years. CONCLUSION: ADCK4-related glomerulopathy is an important novel and potentially treatable cause of isolated nephropathy not only in adolescents, but also in children in their first decade of life. Discovery of important proteinuria in an asymptomatic child should prompt early genetic investigations.

Eculizumab in anti-factor h antibodies associated with atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening multisystemic condition often leading to end-stage renal failure. It results from an increased activation of the alternative pathway of the complement system due to mutations of genes coding for inhibitors of this pathway or from autoantibodies directed against them. Eculizumab is a monoclonal antibody directed against complement component C5 and inhibiting the activation of the effector limb of the complement system. Its efficacy has already been demonstrated in aHUS. The present article reports for the first time the use of eculizumab in a patient presenting with aHUS associated with circulating anti-complement Factor H autoantibodies and complicated by cardiac and neurologic symptoms. Our observation highlights the efficacy of eculizumab in this form of aHUS not only on renal symptoms but also on the extrarenal symptoms. It also suggests that eculizumab should be used very promptly after aHUS presentation to prevent life-threatening complications and to reduce the risk of chronic disabilities. To obtain a complete inhibition of the effector limb activation, the advised dosage must be respected. After this initial therapy in the autoimmune aHUS form, a long-term immunosuppressive treatment should be considered, to prevent relapses by reducing anti-complement Factor H autoantibody plasma levels.

Adiponectin gene polymorphisms and their effect on the risk of myocardial infarction and type 2 diabetes: an association study in an Italian population.

OBJECTIVE: While many studies have shown an association between the gene coding for adiponectin (ADIPOQ) and adiponectin levels, much more controversy surrounds its association with metabolic traits such as insulin resistance, obesity and type 2 diabetes. Furthermore, very few studies have looked into the relations between ADIPOQ variants and risk of cardiovascular disease. The present study assessed the influence of four common ADIPOQ Single Nucleotide Polymorphisms (SNPs), rs17300539 (-11391G→A), rs266729 (-11377C→G), rs2241766 (+45T→G) and rs1501299 (+276G→T) on the risk of myocardial infarction and type 2 diabetes. METHODS: and RESULTS: A large genetic association case-control study was conducted in 2008 Italians, including patients with myocardial infarction, type 2 diabetes, or both, and a reference group of healthy controls. Homozygotes TT for the rs1501299 (+276) had half the risk of either myocardial infarction alone or in association with type 2 diabetes when compared to the carriers of the G allele (OR = 0.58, p =0.01, and OR = 0.55, p =0.006 respectively). SNPs rs17300539 (-11391), rs266729 (-11377) and rs2241766 (+45) showed no significant association with any of the three case groups. CONCLUSIONS: These results suggest that homozygotes TT for the adiponectin polymorphism rs1501299 (+276) are protected from the risk of myocardial infarction.

Quantitative trait genetic linkage analysis of body mass index in familial coronary artery disease.

OBJECTIVE: Body mass index (BMI) is one of the most reproducible and commonly used proxies for obesity and is known to be influenced by many environmental causes as well as genetic factors. Identification of susceptibility genes for BMI regulation has been difficult. Reasons for these inconclusive results are both methodological and related to obesity aetiology. A genome-wide linkage analysis was performed to localise Quantitative trait loci influencing BMI in a large cohort collected in the PROCARDIS coronary heart disease study consisting of 1,812 informative families. METHODS: Multipoint linkage analysis for BMI was conducted using both a variance component approach and a model-free regression method, and the resulting LOD scores were compared. RESULTS: The strongest evidence for linkage was detected on chromosomes 13 (LOD 1.6). Other regions showing a LOD score greater than 1 were observed on chromosomes 3, 5, 11, 12 and 15. These results were mainly confirmed by the three different approaches used in the analysis. CONCLUSION: Our study did not find any locus with strongly supporting evidence for linkage to BMI even in such a large sample. Our results confirm the substantial genetic heterogeneity influencing BMI regulation that has emerged from the majority of genome scans so far published.

Meta-analysis of genome-wide linkage studies in BMI and obesity.

OBJECTIVE: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis. RESEARCH METHODS AND PROCEDURES: We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome-wide logarithm of the odds (LOD) scores, non-parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI-defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry. RESULTS: Bins at chromosome 13q13.2- q33.1, 12q23-q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3-22.3 were also observed for BMI-defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1-qter and 12p11.21-q23 (p < 0.01). CONCLUSION: Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further.

Apolipoprotein E polymorphisms influence effect of pravastatin on survival after myocardial infarction in a Mediterranean population: the GISSI-Prevenzione study.

AIMS: Controversy exists with regard to the influence of APOE polymorphisms on coronary heart disease development and on the efficacy of statin treatment. we investigated the relationship between apoe, mortality and the response to treatment in Mediterranean myocardial infarction (mi) survivors. METHODS AND RESULTS: We analysed 3304 Italian patients with MI randomized to pravastatin or no treatment in the GISSI-Prevenzione study, with a mean follow-up time of 23.0 +/- 6.7 months (median 24.3 months). Mortality curves were calculated using Kaplan-Meier method, and differences in survival were tested using the log-rank test. There were 109 deaths during follow-up. Patients treated with pravastatin showed a significant decrease in mortality compared with non-treated patients (HR 0.67, 95% confidence interval 0.45-0.97, P = 0.038). Among the 3304 patients, 554 (16.8%) were epsilon4 carriers and 2750 (83.2%) were non-epsilon4 carriers. No significant difference in terms of mortality was observed between the epsilon4 and the non-epsilon4 carriers (3.61% vs. 3.24%, P = 0.67). However, although in non-epsilon4 carriers no significant difference in mortality was observed between patients treated with pravastatin and non-treated (2.81% vs. 3.67%, P = 0.21), among the epsilon4 carriers a significant reduction in mortality was observed in patients treated compared with non-treated (1.85% vs. 5.28%, P = 0.023). CONCLUSION: We found that epsilon4 allele is a determinant of pravastatin response in terms of survival. Though in the entire population investigated,we found a beneficial effect of pravastatin in terms of survival, only the epsilon4 carriers seemed to have gained a significant benefit from this treatment. We suggest that the effect of statins is of particular interest in this fraction of the population. Genetic markers can help in identifying patients that benefit more from statin treatment.

Multiple QTL influence the serum Lp(a) concentration: a genome-wide linkage screen in the PROCARDIS study.

The serum concentration of lipoprotein Lp (a) is known to be highly heritable and associated with cardiovascular risk. A genome-wide variance component linkage analysis was performed to localise quantitative trait loci (QTLs) influencing Lp(a) levels in a large cohort collected in the PROCARDIS coronary heart disease study. Highly significant linkage was detected at the previously described LP(a) locus on chromosome 6q27 (LOD 108). Taking into account the effect of the locus detected on chromosome 6, a highly significant LOD score was detected on chromosome 13q22-31 (LOD 7.0). Another significant region of linkage was observed on chromosomes 11p14-15 (LOD 3.5). The significant peak at 13q22-31 shows an essential overlap with a locus modulating cholesterol in familial hypercholesterolemia. If the gene underlying these loci is the same, it will be a promising candidate target for manipulating LDL-cholesterol and Lp(a). We also detected linkage at a previously identified locus influencing Lp(a) on chromosome 1q23 (LOD 1.5). Our findings provide new and confirmatory information about genomic regions involved in the quantitative variation of Lp(a) and serve as a basis for further studies of candidate genes in these regions.

Meta-analysis of 4 coronary heart disease genome-wide linkage studies confirms a susceptibility locus on chromosome 3q.

OBJECTIVE: In coronary heart disease (CHD), 4 independent, genome-wide screens have now been published on Finnish, Mauritian, European, and Australian families. Results from these studies are inconclusive. We performed a meta-analysis to identify genetic regions that show evidence for susceptibility genes across studies. METHODS AND RESULTS: The rank-based genome-scan meta-analysis (GSMA) method was applied to the 4 CHD genome-wide linkage studies. The strongest evidence for linkage was found on chromosomes 3q26-27 (P=0.0001) and 2q34-37 (P=0.009). Analysis weighted by study size confirmed linkage in these regions (3q26-27, P=0.0002; 2q34-37, P=0.014). CONCLUSIONS: The genetic regions 3q26-27 and 2q34-37 might contain susceptibility genes for CHD. Linkage to the 3q26-qter region has previously been shown in type 2 diabetes mellitus, metabolic syndrome, cholesterol concentration in LDL size fractions, and renal function in hypertensive subjects. The 2q34-37 region lies close to the type 2 diabetes NIDDM1 locus. Both of these regions harbor several candidate genes involved in the homeostasis of glucose and lipid metabolism. These results are particularly intriguing, given the growing evidence of an association between CHD risk and metabolic abnormalities, such as insulin resistance, type 2 diabetes, abdominal obesity, and dyslipidemia.

APO B gene polymorphisms and coronary artery disease: a meta-analysis.

BACKGROUND: The APO B gene is characterised by numerous polymorphic sites, three of which (XbaI, EcoRI, SpIns/Del) are related to levels of total cholesterol (TC), low-density lipoproteins, apo B and tryglicerides, and to coronary artery disease (CAD) and/or myocardial infarction (MI). Moreover, conflicting results emerge from literature. To assess how each polymorphism of the APO B gene was associated with CAD and MI risk, we carried out a meta-analysis of all published studies. METHODS AND RESULTS: Thirty case-control studies were considered, for a total of 6077, 3870 and 11616 individuals, respectively, for XbaI, EcoRI and SpIns/Del polymorphisms. For each polymorphism we calculated the risk of CAD/MI on the overall sample and for large and small studies separately. No evidence of increased risk emerged for XbaI polymorphism. Whereas, positive associations were detected for EcoRI, SpIns/Del and risk of CAD and MI, with odds ratio (OR) of 1.73 (95% CI, 1.19-2.50) and 1.19 (95% CI, 1.05-1.35) for carriers of AA and DD, respectively. CONCLUSIONS: Despite the small size of most studies and the incomplete understanding of the effects of these polymorphisms on lipid metabolism and on final clinical implications, the findings suggest that EcoRI and SpIns/Del polymorphisms significantly increase the risk of CAD and MI. Despite the rarity of the allelic variant of EcoRI polymorphism, its presence is strongly related to the occurrence of CAD/MI. Moreover, there is a high consistency between small and large studies. The results on SpIns/Del polymorphism seem the most interesting and reliable, considering both the number of subjects analysed and the consistency of the evidence of its effect on lipid levels. These results need to be confirmed by larger and appropriately powered studies.