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Mutations in the N-terminal WD40 domain of coatomer protein complex subunit a (COPA) cause a type I interferonopathy, typically characterized by alveolar hemorrhage, arthritis, and nephritis. We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity. We showed that these CTD COPA mutations disrupt the integrity and the function of coat protein complex I (COPI). In [COPA.sup.R1142X] and [COPA.sup.R1058C] fibroblasts, we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect. The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines, albeit through a distinct molecular mechanism in comparison with mutations in the WD40 domain of COPA. We showed that CTD COPA mutations induce an activation of ER stress and NF-[kappa]B signaling in patient-derived primary cell lines. These results demonstrate the importance of the integrity of the CTD of COPA for COPI function and homeostatic intracellular trafficking, essential to ER homeostasis. CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport, and increased proinflammatory signaling., Introduction The COPA gene encodes coatomer protein complex subunit [alpha] (COPA) (1). COPA was described in 1991 as a coat subunit of Golgi derived non-clathrin-coated vesicles, later termed 'coatomer' (2, [...]

The clinical course of autosomal dominant polycystic kidney disease (ADPKD) starts in childhood. Evidence of the beneficial impact of early nephron-protective strategies and lifestyle modifications on ADPKD prognosis is accumulating. Recent studies have described the association of overweight and obesity with rapid disease progression in adults with ADPKD. Moreover, defective glucose metabolism and metabolic reprogramming have been reported in distinct ADPKD models highlighting these pathways as potential therapeutic targets in ADPKD. Several 'metabolic' approaches are currently under evaluation in adults, including ketogenic diet, food restriction, and metformin therapy. No data are available on the impact of these approaches in childhood thus far. Yet, according to World Health Organization (WHO), we are currently facing a childhood obesity crisis with an increased prevalence of overweight/obesity in the pediatric population associated with a cardio-metabolic risk profile. The present review summarizes the knowledge about the role of glucose metabolism in the pathophysiology of ADPKD and underscores the possible harm of overweight and obesity in ADPKD especially in terms of long-term cardiovascular outcomes and renal prognosis., Author(s): Angélique Dachy [sup.1] [sup.2] [sup.3] , Jean-Paul Decuypere [sup.1] , Rudi Vennekens [sup.4] , François Jouret [sup.3] [sup.5] , Djalila Mekahli [sup.1] [sup.6] Author Affiliations: (1) grid.5596.f, 0000 0001 [...]

Significant progress has been made in understanding the genetic basis of autosomal dominant polycystic kidney disease (ADPKD), quantifying disease manifestations in children, exploring very-early onset ADPKD as well as pharmacological delay of disease progression in adults. At least 20% of children with ADPKD have relevant, yet mainly asymptomatic disease manifestations such as hypertension or proteinuria (in line with findings in adults with ADPKD, where hypertension and cardiovascular damage precede decline in kidney function). We propose an algorithm for work-up and management based on current recommendations that integrates the need to screen regularly for hypertension and proteinuria in offspring of affected parents with different options regarding diagnostic testing, which need to be discussed with the family with regard to ethical and practical aspects. Indications and scope of genetic testing are discussed. Pharmacological management includes renin-angiotensin system blockade as first-line therapy for hypertension and proteinuria. The vasopressin receptor antagonist tolvaptan is licensed for delaying disease progression in adults with ADPKD who are likely to experience kidney failure. A clinical trial in children is currently ongoing; however, valid prediction models to identify children likely to suffer kidney failure are lacking. Non-pharmacological interventions in this population also deserve further study., Author(s): Charlotte Gimpel [sup.1] [sup.2] , Carsten Bergmann [sup.1] [sup.3] , Djalila Mekahli [sup.4] [sup.5] Author Affiliations: (1) grid.5963.9, Department of Internal Medicine IV (Nephrology), Medical Center-University of Freiburg, Faculty [...]

Autosomal dominant polycystic kidney disease (ADPKD) is associated with distinct cytopenias in observational studies; the most consistent and strongest association is seen with alternations in the lymphocytic lineages. Although the underlying mechanism of these associations is unclear, it has been hypothesized to be secondary to sequestration of white blood cells in cystic organs, or related to the uremic environment in chronic kidney disease (CKD). However, since mutations in PKD1 or -2 affect several immunomodulating pathways, cytopenia may well be an unrecognized extrarenal manifestation of ADPKD. Furthermore, many important questions on the clinical implications of this finding and the effect on the disease course in these patients are unanswered. In this review article, we provide an overview of the current evidence on cytopenia in ADPKD and explore the underlying mechanisms of this association and its potential prognostic implications. Based on the current literature, we hypothesize that polycystin deficiency can disturb immune cell homeostasis and that cytopenia is thus an intrinsic feature of ADPKD, related to genetic factors. Taken together, these findings warrant further investigation to establish the exact etiology and role of cytopenia in patients with ADPKD., Author(s): Pieter Schellekens [sup.1] [sup.2] , Willem Roosens [sup.3] , Isabelle Meyts [sup.4] [sup.5] , Rudi Vennekens [sup.6] , Bert Bammens [sup.1] [sup.2] , Djalila Mekahli [sup.3] [sup.7] Author Affiliations: [...]

Background Characterizing the dynamics of serum creatinine concentrations (Scr) and associated creatinine clearance (CLcr) as a measure of kidney function in extremely low birth weight ([less than or equal to] 1000 g; ELBW) neonates remains challenging. Methods We performed a retrospective study that included longitudinal Scr (enzymatic assay) data from 148 ELBW neonates up to 6 weeks after birth. Change of Scr and inter-individual variability was characterized with nonlinear mixed-effect modeling. Key covariates such as gestational age (GA), mode of delivery (MOD), and treatment with ibuprofen or inotropic agents were investigated. Results A total of 2814 Scr concentrations were analyzed. GA was associated with Scr at birth (higher with advancing GA), and GA and MOD showed an association with postnatal maturation of CLcr (faster clearance increase with advancing GA and after C-section). Small CLcr decrease ([less than or equal to] 5%) was quantified during ibuprofen treatment. For a GA of 27 weeks, mean Scr (estimated CLcr) at birth was 0.61 mg/dl (0.23 ml/min), increasing to 0.87 mg/dl (0.27 ml/min) at day three, and decreasing to 0.36 mg/dl (0.67 ml/min) at day 42 after birth. Conclusions We report the first mathematical model able to characterize Scr and CLcr in ELBW neonates during the first 6 weeks of life in a quantitative manner as a function of GA, MOD, and ibuprofen treatment. This model allows the derivation of GA-adjusted reference ranges for ELBW neonates and provides a rationale for normative Scr concentrations, and as such will help clinicians to further optimize monitoring and treatment decisions in this vulnerable patient population., Author(s): Tamara van Donge [sup.1] , Karel Allegaert [sup.2] [sup.3] [sup.4] , Verena Gotta [sup.1] , Anne Smits [sup.2] [sup.5] , Elena Levtchenko [sup.2] [sup.6] , Djalila Mekahli [sup.2] [sup.6] [...]

Prof. Lesley Rees belongs to the women who changed science and has inspired so many young researchers, including myself. These inspiring women deserve more credit and recognition than they get because they serve as a role model for us. Indeed, despite advances towards women empowerment, progress has been slow, and discrepancy persists around the world. Unfortunately, science is not immune to such inequalities, and the voices of female leaders are important in cracking this gender filter. Women represent only a third of researchers globally and often face gender-based discrimination and lack equal opportunities. In this letter, I would like to highlight three astonishing researchers in an effort to underscore the importance of existing women mentorship, while transmitting the pride of the red lipstick rather than the victimization of the red cheeks., Author(s): Djalila Mekahli [sup.1] [sup.2] Author Affiliations: (1) grid.410569.f, 0000 0004 0626 3338, Department of Pediatric Nephrology, University Hospitals Leuven, , Herestraat 49, B-3000, Leuven, Belgium (2) grid.5596.f, 0000 0001 [...]

Several animal- and human-derived models are used in autosomal dominant polycystic kidney disease (ADPKD) research to gain insight in the disease mechanism. However, a consistent correlation between animal and human ADPKD models is lacking. Therefore, established human-derived models are relevant to affirm research results and translate findings into a clinical set-up. In this review, we give an extensive overview of the existing human-based cell models. We discuss their source (urine, nephrectomy and stem cell), immortalisation procedures, genetic engineering, kidney segmental origin and characterisation with nephron segment markers. We summarise the most studied pathways and lessons learned from these different ADPKD models. Finally, we issue recommendations for the derivation of human-derived cell lines and for experimental set-ups with these cell lines., Author(s): Caroline Weydert [sup.1] , Jean-Paul Decuypere [sup.1] , Humbert De Smedt [sup.2] , Peter Janssens [sup.1] [sup.3] , Rudi Vennekens [sup.4] , Djalila Mekahli [sup.1] [sup.5] Author Affiliations: (Aff1) [...]

Autosomal dominant polycystic kidney disease (ADPKD), caused by mutations in PKD1 or PKD2 genes, is the most common hereditary renal disease. Renal manifestations of ADPKD are gradual cyst development and kidney enlargement ultimately leading to end-stage renal disease. ADPKD also causes extrarenal manifestations, including endothelial dysfunction and hypertension. Both of these complications are linked with reduced nitric oxide levels related to excessive oxidative stress (OS). OS, defined as disturbances in the prooxidant/antioxidant balance, is harmful to cells due to the excessive generation of highly reactive oxygen and nitrogen free radicals. Next to endothelial dysfunction and hypertension, there is cumulative evidence that OS occurs in the early stages of ADPKD. In the current review, we aim to summarize the cardiovascular complications and the relevance of OS in ADPKD and, more specifically, in the early stages of the disease. First, we will briefly introduce the link between ADPKD and the early cardiovascular complications including hypertension. Secondly, we will describe the potential role of OS in the early stages of ADPKD and its possible importance beyond the chronic kidney disease (CKD) effect. Finally, we will discuss some pharmacological agents capable of reducing reactive oxygen species and OS, which might represent potential treatment targets for ADPKD., Author(s): Asmin Andries [sup.1] , Kristien Daenen [sup.2] [sup.3] , François Jouret [sup.4] [sup.5] , Bert Bammens [sup.2] [sup.3] , Djalila Mekahli [sup.6] [sup.7] , Ann Van Schepdael [sup.1] Author [...]

Oxidative stress (OS), defined as disturbances in the pro-/antioxidant balance, is harmful to cells due to the excessive generation of highly reactive oxygen (ROS) and nitrogen (RNS) species. When the balance is not disturbed, OS has a role in physiological adaptations and signal transduction. However, an excessive amount of ROS and RNS results in the oxidation of biological molecules such as lipids, proteins, and DNA. Oxidative stress has been reported in kidney disease, due to both antioxidant depletions as well as increased ROS production. The kidney is a highly metabolic organ, rich in oxidation reactions in mitochondria, which makes it vulnerable to damage caused by OS, and several studies have shown that OS can accelerate kidney disease progression. Also, in patients at advanced stages of chronic kidney disease (CKD), increased OS is associated with complications such as hypertension, atherosclerosis, inflammation, and anemia. In this review, we aim to describe OS and its influence on CKD progression and its complications. We also discuss the potential role of various antioxidants and pharmacological agents, which may represent potential therapeutic targets to reduce OS in both pediatric and adult CKD patients., Author(s): Kristien Daenen [sup.1] [sup.2] [sup.3] , Asmin Andries [sup.4] , Djalila Mekahli [sup.5] [sup.6] , Ann Van Schepdael [sup.4] , François Jouret [sup.7] [sup.8] , Bert Bammens [sup.1] [sup.2] [...]

Author(s): Angélique Dachy [sup.1] [sup.2] [sup.3] , Jean-Paul Decuypere [sup.1] , Rudi Vennekens [sup.4] , François Jouret [sup.3] [sup.5] , Djalila Mekahli [sup.1] [sup.6] Author Affiliations: (1) grid.5596.f, 0000 0001 [...]

The liver and kidneys are often similarly affected by a single disease. This is the case in metabolic, immunological, toxic, and infectious diseases, and in the different congenital malformation syndromes. Also, an enzymatic defect in an otherwise healthy liver or the consequences of advanced liver disease by itself can cause kidney disease as a secondary phenomenon. In this review, we describe numerous pathogenic mechanisms leading to dysfunction or malformations of the liver and kidneys in children. We encourage multidisciplinary management for optimal care. A combined liver-kidney transplantation is sometimes needed., Author(s): Karen Van Hoeve [sup.1] , Djalila Mekahli [sup.1] [sup.2] , Eva Morava [sup.3] , Elena Levtchenko [sup.1] [sup.2] , Peter Witters [sup.2] [sup.3] [sup.4] Author Affiliations: (Aff1) 0000 0004 [...]

Polycystic kidney disease (PKD) encompasses a group of genetic disorders that are common causes of renal failure. The two classic forms of PKD are autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD). Despite their clinical differences, ARPKD and ADPKD share many similarities. Altered intracellular Ca.sup.2+ and increased cyclic adenosine monophosphate (cAMP) concentrations have repetitively been described as central anomalies that may alter signaling pathways leading to cyst formation. The vasopressin V2 receptor (V2R) antagonist tolvaptan lowers cAMP in cystic tissues and slows renal cystic progression and kidney function decline when given over 3 years in adult ADPKD patients. Tolvaptan is currently approved for the treatment of rapidly progressive disease in adult ADPKD patients. On the occasion of the recent initiation of a clinical trial with tolvaptan in pediatric ADPKD patients, we aim to describe the most important aspects in the literature regarding the AVP-cAMP axis and the clinical use of tolvaptan in PKD., Author(s): Peter Janssens [sup.1] [sup.2] , Caroline Weydert [sup.1] , Stephanie De Rechter [sup.1] [sup.3] , Karl Martin Wissing [sup.2] , Max Christoph Liebau [sup.4] [sup.5] [sup.6] , Djalila Mekahli [...]

A Correction to this paper has been published: https://doi.org/10.1007/s00467-021-05207-4, Author(s): Charlotte Gimpel [sup.1] [sup.2] , Carsten Bergmann [sup.1] [sup.3] , Djalila Mekahli [sup.4] [sup.5] Author Affiliations: (1) grid.5963.9, Department of Internal Medicine IV (Nephrology), Medical Center-University of Freiburg, Faculty [...]

Autophagy is the cell biology process in which cytoplasmic components are degraded in lysosomes to maintain cellular homeostasis and energy production. In the healthy kidney, autophagy plays an important role in the homeostasis and viability of renal cells such as podocytes and tubular epithelial cells and of immune cells. Recently, evidence is mounting that (dys)regulation of autophagy is implicated in the pathogenesis of various renal diseases, and might be an attractive target for new renoprotective therapies. In this review, we provide an overview of the role of autophagy in kidney physiology and kidney diseases., Author(s): Stephanie De Rechter[sup.1] [sup.2] , Jean-Paul Decuypere[sup.3] [sup.4] , Ekaterina Ivanova[sup.2] , Lambertus P. van den Heuvel[sup.2] [sup.5] , Humbert De Smedt[sup.6] , Elena Levtchenko[sup.1] [sup.2] , Djalila Mekahli[sup.1] [...]

Canonical Wnt signaling activity contributes to physiological and adaptive bone mineralization and is an essential player in bone remodeling. Sclerostin is a prototypic soluble canonical Wnt signaling pathway inhibitor that is produced in osteocytes and blocks osteoblast differentiation and function. Therefore, sclerostin is a potent inhibitor of bone formation and mineralization. Accordingly, rodent sclerostin-deficiency models exhibit a strong bone phenotype. Moreover, blocking sclerostin represents a promising treatment perspective against osteoporosis. Beyond the bone field novel data definitely associate Wnt signaling in general and sclerostin in particular with ectopic extraosseous mineralization processes, as is evident in cardiovascular calcification or calciphylaxis. Uremia is characterized by parallel occurrence of disordered bone mineralization and accelerated cardiovascular calcification (chronic kidney disease - mineral and bone disorder, CKD-MBD), linking skeletal and cardiovascular disease-the so-called bone-vascular calcification paradox. In consequence, sclerostin may qualify as an emerging player in CKD-MBD. We present a stepwise review approach regarding the rapidly evolving field sclerostin participation in CKD-MBD. Starting from data originating in the classical bone field we look separately at three major areas of CKD-MBD: disturbed mineral metabolism, renal osteodystrophy, and uremic cardiovascular disease. Our review is intended to help the nephrologist revise the potential importance of sclerostin in CKD by focusing on how sclerostin research is gradually evolving from the classical osteoporosis niche into the area of CKD-MBD. In particular, we integrate the limited amount of available data in the context of pediatric nephrology., Author(s): Vincent M. Brandenburg[sup.1] , Patrick D'Haese[sup.2] , Annika Deck[sup.1] , Djalila Mekahli[sup.3] , Bjorn Meijers[sup.4] , Ellen Neven[sup.2] , Pieter Evenepoel[sup.4] Author Affiliations: (1) Department of Cardiology, University Hospital [...]

Renal lesions represent the second most significant cause of morbidity and mortality in patients with tuberous sclerosis complex (TSC). Recent advances in the understanding of the pathophysiology of TSC have led to the exploration of new potential therapeutic targets. Clinical trials with mammalian target of rapamycin (mTOR) inhibitors have demonstrated promising results for several indications, such as renal angiomyolipoma, subependymal giant cell astrocytoma, lymphangioleiomyomatosis and facial angiofibromas. Currently, there is a scarcity of natural history data and randomized, placebo-controlled clinical trials on TSC. Recently, however, recommendations for the diagnostic criteria, surveillance, and management of TSC patients have been updated. This review focuses on these novel recommendations and highlights the need for multidisciplinary follow-up of this multi-systemic disease., Author(s): Liesbeth De Waele[sup.1] [sup.2] , Lieven Lagae[sup.1] [sup.2] , Djalila Mekahli[sup.2] [sup.3] Author Affiliations: (1) Department of Pediatric Neurology, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium (2) Department [...]

Background The health related quality of life (HRQoL) of young adults treated for chronic kidney disease (CKD) stage 4/5 from infancy is unknown. Methods A HRQoL questionnaire was sent to all 41 patients aged >16 years from a previously characterised cohort of infants with CKD stage 4/5 born between 1986 and 1997. Patient scores were compared with a previously reported cohort of patients who needed renal replacement therapy (RRT) in mid childhood and in the normal population. Results All patients (11 women) completed the questionnaire at a median (range) age of 19.2 (16.3-23.4) years. At the time of the survey, 5 (12.5%) were on dialysis, 35 (85.5%) had a functioning kidney transplant, one (2%) was still conservatively treated and 22 (54%) had comorbidities; 68% were either studying or in paid employment, with 17% actively seeking employment. Although patients described a lower HRQoL than a healthy, age-matched UK group, in some aspects, scores were comparable with patients needing RRT in later childhood. Lower scores were associated with comorbidities, dialysis at last follow-up, more than one treatment modality change and short stature. Conclusions Our survey demonstrates very encouraging results for long-term HRQoL of infants with severe CKD and highlights the negative impact of comorbidities. These data will help clinicians to counsel and inform families. Keywords Chronic kidney disease (CKD) * Infants * Dialysis * Transplantation * Quality of life, Introduction Although infants have been accepted into renal replacement therapy (RRT) programmes since the 1980s, the subject is one of continuing debate: Some nephrologists believe treatment is unjustified due to [...]

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of kidney failure. It is a systemic disorder, not only affecting the kidneys, but also associated with cyst formation in other organs such as the liver, spleen, pancreas, and seminal vesicles. Other extra-renal symptoms may consist of intracranial arterial aneurysms, cardiac valvular defects, abdominal and inguinal hernias and colonic diverticulosis. Very little is known regarding bone involvement in ADPKD; however, recent evidence has revealed the potential role of fibroblast growth factor 23 (FGF23). FGF23 is an endocrine fibroblast growth factor acting in the kidney as a phosphaturic hormone and a suppressor of active vitamin D with key effects on the bone/kidney/parathyroid axis, and has been shown to increase in patients with ADPKD, even with normal renal function. The aim of this review is to provide an overview of bone and mineral abnormalities found in experimental models and in patients with ADPKD, and to discuss the possible role of FGF23 in this disease. Keywords ADPKD * FGF23 * Bone * Primary cilia, Introduction Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal disease in humans and affects more than 1 in 400 to 1,000 live births [...]

To document trends and covariates of creatinemia (Scr) in extremely low birth weight (ELBW, < 1,000 g) neonates, maternal characteristics [betamethasone, premature preterm rupture of membranes (PPROM), pre-eclampsia, maternal Scr], characteristics at delivery [gestational age (GA), birth weight (BW), small for GA (SGA), Apgar, intubation] and during neonatal stay [ventilation, oxygen, parenteral nutrition, ibuprofen, steroids, intraventricular hemorrhage, retinopathy of prematurity (ROP), phototherapy] were linked with Scr observations. Data were reported by median and range or incidence. Characteristics in ELBW neonates with raised peak Scr (>P75) were compared to controls (P75 (112.3 µmol/l), Scr remained elevated until day 28. Mothers of cases received less betamethasone, neonates had a lower GA, lower BW, lower Apgar, and needed more often intubation. Postnatal ventilation, oxygen, parenteral nutrition, ibuprofen, steroids, ROP, and intraventricular hemorrhage were different. GA and ventilation or Apgar were independent factors for raised peak Scr. ELBW neonates display trends similar to heavier neonates, but peak Scr is higher, and the subsequent decrease slower. Raised creatinemia in ELBW neonates reflects immaturity (GA) and morbidity (ventilation, Apgar). Keywords ELBW neonates * Creatinemia * Renal clearance * Ibuprofen * Raised creatinemia, Introduction The recognition of acute renal failure (ARF) in preterm neonates is of relevance to adapt medical treatment during neonatal stay [1-5]. In addition, there are reports on the association [...]

Autosomal dominant polycystic kidney disease (ADPKD) in children is sometimes considered to be a benign condition, with morbidity manifesting in adulthood. Therefore, diagnostic screening of children at risk is controversial. The aim of our study was to to compare the manifestations of ADPKD in children diagnosed by postnatal ultrasound (US) screening versus those presenting with symptoms. This was a retrospective chart review of children with ADPKD assessed in a single centre between 1987 and 2007. Age and reason for diagnosis were noted, and children were separated into two groups: (1) those diagnosed on the basis of family-based screening; (2) those presenting with a symptom. The two groups were compared for renal size, number of cysts, estimated glomerular filtration rate (eGFR), the presence of hypertension and microalbuminuria. In the 47 children with ADPKD (21 females) from 33 families who satisfied the enrollment criteria, mean (standard deviation) age at referral and last follow-up was 7.2 (4.4) and 12.9 (5.1) years, respectively, and the mean follow-up duration was 5.7 (3.6) years. Diagnosis was based on postnatal US screening in 31 children, whereas 16 were diagnosed after presenting with symptoms. The proportions of children with nephromegaly, hypertension, micro albuminuria and decreased eGFR, respectively, were similar in both groups. Based on these results, we conclude that renal-related morbidities, including hypertension and microalbuminia, do occur in children with ADPKD and at a similar frequency in those diagnosed after presenting with symptoms and those diagnosed upon postnatal screening. We suggest that at-risk children should have regular checks to detect hypertension. Moreover, affected children may benefit from novel therapies to minimize cystic disease progression. Keywords Autosomal dominant polycystic kidney disease * Microalbuminuria * Chronic kidney disease * Hypertension * Screening * Children * Nephromegaly, Introduction Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder, with an incidence of 1:400-1000, characterised by progressive growth of renal cysts manifested by nephromegaly, often leading to [...]

Sirs, BK-virus nephropathy (BKN) is an important cause of graft dysfunction in kidney transplant recipients. Severe allograft dysfunction and graft loss are well-known complications [1-3]. However, pancytopenia caused by an [...]