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1.
Br J Haematol ; 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38934404

ABSTRACT

Glomerular hyperfiltration and albuminuria are frequent kidney abnormalities in children with sickle cell anaemia (SCA). However, little is known about their persistence in African SCA children. This prospective study included 600 steady-state SCA children aged 2-18 years from the Democratic Republic of Congo. Participants were genotyped for apolipoprotein L1 (APOL1) risk variants (RVs) and haem oxygenase-1 (HMOX1) GT-dinucleotide repeats. Kidney abnormalities were defined as albuminuria, hyperfiltration or decreased estimated creatinine-based glomerular filtration rate (eGFRcr). At baseline, 247/600 (41.2%) participants presented with kidney abnormalities: 82/592 (13.8%) with albuminuria, 184/587 (31.3%) with hyperfiltration and 15/587 (2.6%) with decreased eGFRcr. After a median follow-up of 5 months, repeated testing was performed in 180/247 (72.9%) available participants. Persistent hyperfiltration and persistent albuminuria (PA) were present in 29.2% (38/130) and 39.7% (23/58) respectively. eGFR normalized in all participants with a baseline decreased eGFRcr. Haemoglobinuria (p = 0.017) and male gender (p = 0.047) were significantly associated with PA and persistent hyperfiltration respectively. APOL1 RVs (G1G1/G2G2/G1G2) were borderline associated with PA (p = 0.075), while HMOX1 long repeat was not associated with any persistent kidney abnormality. This study reveals that a single screening can overestimate the rate of kidney abnormalities in children with SCA and could lead to overtreatment.

2.
Kidney Int Rep ; 9(2): 214-224, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38344731

ABSTRACT

Cystinosis is a rare, inherited, lysosomal storage disorder characterized by the progressive accumulation of intralysosomal cystine and subsequent organ and tissue damage. The kidneys are the first and most severely impacted organ. Although cystinosis was once considered a fatal pediatric disease, patients with cystinosis are living well into adulthood with advances in medical care, including kidney transplant and early and continuous use of cysteamine therapy. This increase in life expectancy has revealed an extrarenal phenotype of cystinosis that emerges in adolescence and adulthood, affecting nearly all body systems, including the endocrine and reproductive systems. As individuals with cystinosis are planning for the future, reproductive health and fertility have become areas of increased focus. This narrative review aims to summarize the current understanding of reproductive health and fertility in patients with cystinosis and discuss practical considerations for monitoring and managing these complications.

3.
Pediatr Nephrol ; 38(8): 2509-2521, 2023 08.
Article in English | MEDLINE | ID: mdl-36472655

ABSTRACT

HIV infection remains one of the leading causes of morbidity and mortality worldwide, especially in children living in resource-limited settings. Although the World Health Organization (WHO) recently recommended antiretroviral therapy (ART) initiation upon diagnosis regardless of the number of CD4, ART access remains limited, especially in children living in sub-Saharan Africa (SSA). HIV-infected children who do not receive appropriate ART are at increased risk of developing HIV-associated nephropathy (HIVAN). Although due to genetic susceptibility, SSA is recognized to be the epicenter of HIVAN, limited information is available regarding the burden of HIVAN in children living in Africa. The present review discusses the information available to date on the prevalence, pathogenesis, risk factors, diagnosis, and management of HIVAN in children, focusing on related challenges in a resource-limited setting.


Subject(s)
AIDS-Associated Nephropathy , HIV Infections , Humans , Child , AIDS-Associated Nephropathy/diagnosis , AIDS-Associated Nephropathy/epidemiology , AIDS-Associated Nephropathy/etiology , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/epidemiology , Resource-Limited Settings , Risk Factors , Africa South of the Sahara/epidemiology
4.
Br J Haematol ; 196(1): 204-214, 2022 01.
Article in English | MEDLINE | ID: mdl-34545573

ABSTRACT

Clinical and genetic factors have been reported as influencing the development of sickle cell nephropathy (SCN). However, such data remain limited in the paediatric population. In this cross-sectional study, we enrolled 361 sickle cell disease children from the Democratic Republic of Congo. Participants were genotyped for the beta (ß)-globin gene, apolipoprotein L1 (APOL1) risk variants, and haem oxygenase-1 (HMOX1) GT-dinucleotide repeats. As markers of kidney damage, albuminuria, hyperfiltration and decreased estimated glomerular filtration with creatinine (eGFRcr) were measured. An association of independent clinical and genetic factors with these markers of kidney damage were assessed via regression analysis. Genetic sequencing confirmed sickle cell anaemia in 326 participants. Albuminuria, hyperfiltration and decreased eGFRcr were present in 65 (20%), 52 (16%) and 18 (5·5%) patients, respectively. Regression analysis revealed frequent blood transfusions, indirect bilirubin and male gender as clinical predictors of SCN. APOL1 high-risk genotype (G1/G1, G2/G2 and G1/G2) was significantly associated with albuminuria (P = 0·04) and hyperfiltration (P = 0·001). HMOX1 GT-dinucleotide long repeats were significantly associated with lower eGFRcr. The study revealed a high burden of kidney damage among Congolese children and provided evidence of the possible role of APOL1 and HMOX1 in making children more susceptible to kidney complications.


Subject(s)
Anemia, Sickle Cell/complications , Anemia, Sickle Cell/epidemiology , Black People , Disease Susceptibility , Kidney Diseases/epidemiology , Kidney Diseases/etiology , Adolescent , Anemia, Sickle Cell/diagnosis , Anemia, Sickle Cell/genetics , Apolipoprotein L1/genetics , Child , Child, Preschool , Cross-Sectional Studies , Erythrocyte Indices , Female , Genetic Predisposition to Disease , Genetic Variation , Glomerular Filtration Rate , Heme Oxygenase-1/genetics , Humans , Kidney Diseases/diagnosis , Kidney Function Tests , Male , Mutation , beta-Globins/metabolism
5.
Pediatr Nephrol ; 37(6): 1231-1243, 2022 06.
Article in English | MEDLINE | ID: mdl-34050806

ABSTRACT

The life expectancy of individuals with sickle cell disease has increased over the years, majorly due to an overall improvement in diagnosis and medical care. Nevertheless, this improved longevity has resulted in an increased prevalence of chronic complications such as sickle cell nephropathy (SCN), which poses a challenge to the medical care of the patient, shortening the lifespan of patients by 20-30 years. Clinical presentation of SCN is age-dependent, with kidney dysfunction slowly beginning to develop from childhood, progressing to chronic kidney disease and kidney failure during the third and fourth decades of life. This review explores the epidemiology, pathology, pathophysiology, clinical presentation, and management of SCN by focusing on the pediatric population. It also discusses the factors that can modify SCN susceptibility.


Subject(s)
Anemia, Sickle Cell , Renal Insufficiency, Chronic , Vascular Diseases , Anemia, Sickle Cell/complications , Anemia, Sickle Cell/epidemiology , Anemia, Sickle Cell/therapy , Child , Humans , Prevalence , Renal Insufficiency, Chronic/diagnosis , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/etiology
6.
Cells ; 10(8)2021 07 28.
Article in English | MEDLINE | ID: mdl-34440683

ABSTRACT

Apolipoprotein L1 (APOL1) high-risk genotypes (HRG), G1 and G2, increase the risk of various non-diabetic kidney diseases in the African population. To date, the precise mechanisms by which APOL1 risk variants induce injury on podocytes and other kidney cells remain unclear. Trying to unravel these mechanisms, most studies have used animal or cell models created by gene editing. We developed and characterised conditionally immortalised human podocyte cell lines derived from urine of a donor carrying APOL1 HRG G2/G2. Following induction of APOL1 expression by polyinosinic-polycytidylic acid (poly(I:C)), we assessed functional features of APOL1-induced podocyte dysfunction. As control, APOL1 wild type (G0/G0) podocyte cell line previously generated from a Caucasian donor was used. Upon exposure to poly(I:C), G2/G2 and G0/G0 podocytes upregulated APOL1 expression resulting in podocytes detachment, decreased cells viability and increased apoptosis rate in a genotype-independent manner. Nevertheless, G2/G2 podocyte cell lines exhibited altered features, including upregulation of CD2AP, alteration of cytoskeleton, reduction of autophagic flux and increased permeability in an in vitro model under continuous perfusion. The human APOL1 G2/G2 podocyte cell model is a useful tool for unravelling the mechanisms of APOL1-induced podocyte injury and the cellular functions of APOL1.


Subject(s)
Apolipoprotein L1/metabolism , Models, Biological , Adult , Apolipoprotein L1/genetics , Autophagy/drug effects , Cell Adhesion , Cell Line , Child, Preschool , Cytoskeleton/drug effects , Cytoskeleton/metabolism , Female , Genotype , Humans , Kidney Diseases/metabolism , Kidney Diseases/pathology , Male , Podocytes/cytology , Podocytes/metabolism , Poly I-C/pharmacology , Up-Regulation/drug effects
7.
Trends Mol Med ; 27(7): 673-686, 2021 07.
Article in English | MEDLINE | ID: mdl-33975805

ABSTRACT

Nephropathic cystinosis is a severe, monogenic systemic disorder that presents early in life and leads to progressive organ damage, particularly affecting the kidneys. It is caused by mutations in the CTNS gene, which encodes the lysosomal transporter cystinosin, resulting in intralysosomal accumulation of cystine. Recent studies demonstrated that the loss of cystinosin is associated with disrupted autophagy dynamics, accumulation of distorted mitochondria, and increased oxidative stress, leading to abnormal proliferation and dysfunction of kidney cells. We discuss these molecular mechanisms driving nephropathic cystinosis. Further, we consider how unravelling molecular mechanisms supports the identification and development of new strategies for cystinosis by the use of small molecules, biologicals, and genetic rescue of the disease in vitro and in vivo.


Subject(s)
Amino Acid Transport Systems, Neutral/genetics , Cystinosis/therapy , Genetic Therapy/methods , Mutation , Small Molecule Libraries/therapeutic use , Cystinosis/genetics , Cystinosis/pathology , Humans
8.
Pediatr Nephrol ; 36(4): 777-788, 2021 04.
Article in English | MEDLINE | ID: mdl-32253519

ABSTRACT

Individuals of African origin have an increased risk of developing various progressive chronic kidney diseases (CKD). This risk has been attributed to genetic variants (G1, G2) in apolipoprotein-L1 (APOL1) gene. In the pediatric population, especially in children affected by sickle cell disease (SCD), by human immunodeficiency virus (HIV), or with various glomerular diseases, APOL1 risk variants have been associated with the development of hypertension, albuminuria, and more rapid decline of kidney function. The present review focuses on existing APOL1-related epidemiological data in children with CKD. It also includes data from studies addressing racial disparities in CKD, the APOL1-related innate immunity, and the relationship between APOL1 and CKD and pathogenic pathways mediating APOL1-related kidney injury.


Subject(s)
Apolipoprotein L1 , Renal Insufficiency, Chronic , Albuminuria , Apolipoprotein L1/genetics , Child , Genetic Predisposition to Disease , Humans , Kidney , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/genetics
9.
Kidney Int Rep ; 4(7): 930-938, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31317115

ABSTRACT

INTRODUCTION: Apolipoprotein-L1 (APOL1) risk variants G1 and G2 increase the risk of chronic kidney disease (CKD), including HIV-related CKD, among African Americans. However, such data from populations living in Africa, especially children, remain limited. Our research aimed to determine the prevalence of APOL1 risk variants and to assess the association between these variants and early-stage CKD in the general pediatric population and HIV-infected children. METHODS: In a cross-sectional study, we enrolled 412 children from the general population and 401 HIV-infected children in Kinshasa, Democratic Republic of Congo (DRC). APOL1 high-risk genotype (HRG) was defined by the presence of 2 risk variants (G1/G1, G2/G2, or G1/G2), and low-risk genotype (LRG) by the presence of 0 or 1 risk variants. The main outcome was elevated albuminuria, defined as a urinary albumin/creatinine ratio ≥30 mg/g. RESULTS: APOL1 sequence analysis revealed that in the general population, 29 of 412 participants (7.0%) carried HRG, 84 of 412 (20.4%) carried the G1/G0 genotype, and 61 of 412 (14.8%) carried the G2/G0 genotype. In HIV-infected children, 23 of 401 (5.7%) carried HRG, and the same trend as in the general population was observed in regard to the prevalence of LRG. Univariate analysis showed that in the general population, 5 of 29 participants (17.2%) carrying HRG had elevated albuminuria, compared with 35 of 383 (9.0%) with LRG (odds ratio [OR] 2.1, 95% confidence interval [CI] 0.6-6.0; P = 0.13). In HIV-infected children, participants who carried APOL1 HRG had almost 22-fold increased odds of albuminuria compared to those with LRG. CONCLUSION: The APOL1 risk variants are prevalent in children living in DRC. HRG carriers have increased odds of early kidney disease, and infection with HIV dramatically increases this probability.

10.
Cells ; 7(9)2018 Sep 01.
Article in English | MEDLINE | ID: mdl-30200518

ABSTRACT

The structural and functional similarity of the larval zebrafish pronephros to the human nephron, together with the recent development of easier and more precise techniques to manipulate the zebrafish genome have motivated many researchers to model human renal diseases in the zebrafish. Over the last few years, great advances have been made, not only in the modeling techniques of genetic diseases in the zebrafish, but also in how to validate and exploit these models, crossing the bridge towards more informative explanations of disease pathophysiology and better designed therapeutic interventions in a cost-effective in vivo system. Here, we review the significant progress in these areas giving special attention to the renal phenotype evaluation techniques. We further discuss the future applications of such models, particularly their role in revealing new genetic diseases of the kidney and their potential use in personalized medicine.

11.
Sci Rep ; 8(1): 5704, 2018 04 09.
Article in English | MEDLINE | ID: mdl-29632324

ABSTRACT

Clinical and fundamental research suggest that altered calcium and cAMP signaling might be the most proximal events in ADPKD pathogenesis. Cells from ADPKD cysts have a reduced resting cytosolic calcium [Ca2+]i and increased cAMP levels. CaSR plays an essential role in regulating calcium homeostasis. Its activation is associated with [Ca2+]i increase and cAMP decrease, making CaSR a possible therapeutic target. Human conditionally immortalized Proximal Tubular Epithelial cells (ciPTEC) with stable knockdown of PKD1 (ciPTEC-PC1KD) and ciPTEC generated from an ADPKD1 patient (ciPTEC-PC1Pt) were used as experimental tools. CaSR functional expression was confirmed by studies showing that the calcimimetic NPS-R568 induced a significant increase in [Ca2+]i in ciPTEC-PC1KD and ciPTEC-PC1Pt. Resting [Ca2+]i were significantly lower in ciPTEC-PC1KD with respect to ciPTECwt, confirming calcium dysregulation. As in native cyst cells, significantly higher cAMP levels and mTOR activity were found in ciPTEC-PC1KD compared to ciPTECwt. Of note, NPS-R568 treatment significantly reduced intracellular cAMP and mTOR activity in ciPTEC-PC1KD and ciPTEC-PC1Pt. To conclude, we demonstrated that selective CaSR activation in human ciPTEC carrying PKD1 mutation increases [Ca2+]i, reduces intracellular cAMP and mTOR activity, reversing the principal dysregulations considered the most proximal events in ADPKD pathogenesis, making CaSR a possible candidate as therapeutic target.


Subject(s)
Calcium/metabolism , Kidney Tubules, Proximal/metabolism , Polycystic Kidney, Autosomal Dominant/metabolism , Receptors, Calcium-Sensing/metabolism , TRPP Cation Channels/genetics , Cells, Cultured , Cyclic AMP/metabolism , Cytosol/metabolism , Gene Knockdown Techniques , Humans , Kidney Tubules, Proximal/cytology , Mutation , Phenethylamines/pharmacology , Propylamines/pharmacology , TOR Serine-Threonine Kinases/metabolism
12.
JIMD Rep ; 38: 1-6, 2018.
Article in English | MEDLINE | ID: mdl-28405942

ABSTRACT

Cystinosis is a rare autosomal recessive lysosomal storage disease characterized by multi-organ cystine accumulation, leading to renal failure and extra-renal organ dysfunction. Azoospermia of unknown origin is the main cause of infertility in all male cystinosis patients. Although spermatogenesis has shown to be intact at the testicular level in some patients, no male cystinosis patient has been reported yet to have successfully induced conception.We present the first successful conception ever reported, induced by a 27-year-old male renal transplant infantile nephropathic cystinosis patient through percutaneous epididymal sperm aspiration (PESA) followed by intracytoplasmatic sperm injection (ICSI). After 36 weeks and 6 days of an uncomplicated pregnancy, a dichorial diamniotic (DCDA) twin was born with an appropriate weight for gestational age and in an apparently healthy status. Moreover, we demonstrate that the sperm of epididymal origin in selected male cystinosis patients can be viable for inducing successful conception.Our observation opens a new perspective in life for many male cystinosis patients whom nowadays have become adults, by showing that despite azoospermia fathering a child can be realized. In addition, our findings raise questions about the possibility of sperm cryopreservation at a young age in these patients.

13.
Carbohydr Res ; 439: 9-15, 2017 Feb 01.
Article in English | MEDLINE | ID: mdl-28033491

ABSTRACT

Cystinosis is a genetic disorder caused by malfunction of cystinosin and is characterized by accumulation of cystine. Cysteamine, the medication used in cystinosis, causes halitosis resulting in poor patient compliance. Halitosis is mainly caused by the formation of dimethylsulfide as the final product in the cysteamine metabolism pathway. We have synthesized carbohydrate-cysteamine thiazolidines, and hypothesized that the hydrolytic breakdown of cysteamine-thiazolidines can result in free cysteamine being released in target organs. To examine our hypothesis, we tested these analogs in vitro in patient-derived fibroblasts. Cystinotic fibroblasts were treated with different concentrations of arabinose-cysteamine, glucose-cysteamine and maltose-cysteamine. We demonstrated that the analogs break down into cysteamine extracellularly and might therefore not be fully taken up by the cells under the form of the pro-drug. Potential modifications of the analogs that enable their intracellular rather than extracellular breakdown, is necessary to pursue the potential of these analogs as pro-drugs.


Subject(s)
Cysteamine/chemistry , Extracellular Space/chemistry , Fibroblasts/metabolism , Prodrugs/chemical synthesis , Thiazolidines/chemical synthesis , Arabinose/chemistry , Biotransformation , Cysteamine/metabolism , Cysteamine/pharmacology , Cystine Depleting Agents/metabolism , Cystine Depleting Agents/pharmacology , Cystinosis/metabolism , Cystinosis/pathology , Drug Design , Extracellular Space/metabolism , Fibroblasts/drug effects , Glucose/chemistry , Humans , Hydrolysis , Lactose/chemistry , Molecular Structure , Primary Cell Culture , Prodrugs/pharmacology , Ribose/chemistry , Sulfides/metabolism , Thiazolidines/pharmacology
14.
Cell Calcium ; 60(4): 282-7, 2016 10.
Article in English | MEDLINE | ID: mdl-27451386

ABSTRACT

Nephropathic cystinosis is an autosomal recessive lysosomal storage disorder caused by loss-of-function mutations in the CTNS gene coding for the lysosomal cystine transporter, cystinosin. Recent studies have demonstrated that, apart from cystine accumulation in the lysosomes, cystinosin-deficient cells, especially renal proximal tubular epithelial cells are characterized by abnormal vesicle trafficking and endocytosis, possible lysosomal dysfunction and perturbed intracellular signalling cascades. It is therefore possible that Ca(2+) signalling is disturbed in cystinosis, as it has been demonstrated for other disorders associated with lysosomal dysfunction, such as Gaucher, Niemann-Pick type C and Alzheimer's diseases. In this study we investigated ATP-induced, IP3-induced and lysosomal Ca(2+) release in human proximal tubular epithelial cells derived from control and cystinotic patients. No major dysregulation of intracellular Ca(2+) dynamics was found, although ATP-induced Ca(2+) release appeared slightly sensitized in cystinotic cells compared to control cells. Hence, these subtle changes in Ca(2+) signals elicited by agonists may contribute to the pathogenesis of the disease.


Subject(s)
Amino Acid Transport Systems, Neutral/metabolism , Calcium Signaling , Calcium/metabolism , Epithelial Cells/metabolism , Kidney Tubules, Proximal/metabolism , Amino Acid Transport Systems, Neutral/deficiency , Amino Acid Transport Systems, Neutral/genetics , Cells, Cultured , Cystinosis/metabolism , Cystinosis/pathology , Humans
15.
Kidney Int ; 89(6): 1192-203, 2016 06.
Article in English | MEDLINE | ID: mdl-27181776

ABSTRACT

Nephropathic cystinosis is an autosomal recessive metabolic, lifelong disease characterized by lysosomal cystine accumulation throughout the body that commonly presents in infancy with a renal Fanconi syndrome and, if untreated, leads to end-stage kidney disease (ESKD) in the later childhood years. The molecular basis is due to mutations in CTNS, the gene encoding for the lysosomal cystine-proton cotransporter, cystinosin. During adolescence and adulthood, extrarenal manifestations of cystinosis develop and require multidisciplinary care. Despite substantial improvement in prognosis due to cystine-depleting therapy with cysteamine, no cure of the disease is currently available. Kidney Disease: Improving Global Outcomes (KDIGO) convened a Controversies Conference on cystinosis to review the state-of-the-art knowledge and to address areas of controversies in pathophysiology, diagnostics, monitoring, and treatment in different age groups. More importantly, promising areas of investigation that may lead to optimal outcomes for patients afflicted with this lifelong, systemic disease were discussed with a research agenda proposed for the future.


Subject(s)
Amino Acid Transport Systems, Neutral/genetics , Cysteamine/therapeutic use , Cystine Depleting Agents/therapeutic use , Cystine/metabolism , Cystinosis/etiology , Rare Diseases/etiology , Adolescent , Adult , Age Factors , Child , Congresses as Topic , Cysteamine/adverse effects , Cystine Depleting Agents/adverse effects , Cystinosis/complications , Cystinosis/diagnosis , Cystinosis/therapy , Fanconi Syndrome/complications , Fanconi Syndrome/drug therapy , Genetic Testing , Genetic Therapy , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation , Humans , Immunosuppression Therapy/adverse effects , Infant , Kidney Failure, Chronic/etiology , Kidney Transplantation/adverse effects , Lysosomes/metabolism , Mutation , Rare Diseases/complications , Rare Diseases/diagnosis , Rare Diseases/therapy , Renal Dialysis
16.
Kidney Int ; 89(5): 1037-1048, 2016 May.
Article in English | MEDLINE | ID: mdl-27083281

ABSTRACT

The involvement of the glomerulus in the pathogenesis of cystinosis, caused by loss-of-function mutations in cystinosin (CTNS, 17p13), is a matter of controversy. Although patients with cystinosis demonstrate glomerular lesions and high-molecular-weight proteinuria starting from an early age, a mouse model of cystinosis develops only signs of proximal tubular dysfunction. Here we studied podocyte damage in patients with cystinosis by analyzing urinary podocyte excretion and by in vitro studies of podocytes deficient in cystinosin. Urine from patients with cystinosis presented a significantly higher amount of podocytes compared with controls. In culture, cystinotic podocytes accumulated cystine compatible with cystinosin deficiency. The expression of podocyte specific genes CD2AP, podocalyxin, and synaptopodin and of the WT1 protein was evident in all cell lines. Conditionally immortalized podocyte lines of 2 patients with different CTNS mutations had altered cytoskeleton, impaired cell adhesion sites, and increased individual cell motility. Moreover, these cells showed enhanced phosphorylation of both Akt1 and Akt2 (isoforms of protein kinase B). Inhibition of Akt by a specific inhibitor (Akti inhibitor 1/2) resulted in normalization of the hypermotile phenotype. Thus, our study extends the list of genetic disorders causing podocyte damage and provides the evidence of altered cell signaling cascades resulting in impaired cell adhesion and enhanced cell motility in cystinosis.


Subject(s)
Amino Acid Transport Systems, Neutral/metabolism , Cell Movement , Cystinosis/metabolism , Podocytes/metabolism , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adolescent , Amino Acid Transport Systems, Neutral/deficiency , Amino Acid Transport Systems, Neutral/genetics , Case-Control Studies , Cell Adhesion , Cell Line , Cell Movement/drug effects , Child , Child, Preschool , Cystinosis/genetics , Cystinosis/pathology , Cystinosis/urine , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , Cytoskeleton/metabolism , Down-Regulation , Female , Genetic Predisposition to Disease , Humans , Male , Mutation , Phenotype , Phosphorylation , Podocytes/drug effects , Podocytes/pathology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , Sialoglycoproteins/genetics , Sialoglycoproteins/metabolism , Signal Transduction , Urine/cytology , WT1 Proteins/genetics , WT1 Proteins/metabolism , Young Adult
17.
J Inherit Metab Dis ; 39(3): 457-464, 2016 05.
Article in English | MEDLINE | ID: mdl-26909499

ABSTRACT

Lysosomes play a central role in regulating autophagy via activation of mammalian target of rapamycin complex 1 (mTORC1). We examined mTORC1 signalling in the lysosomal storage disease nephropathic cystinosis (MIM 219800), in which accumulation of autophagy markers has been previously demonstrated. Cystinosis is caused by mutations in the lysosomal cystine transporter cystinosin and initially affects kidney proximal tubules causing renal Fanconi syndrome, followed by a gradual development of end-stage renal disease and extrarenal complications. Using proximal tubular kidney cells obtained from healthy donors and from cystinotic patients, we demonstrate that cystinosin deficiency is associated with a perturbed mTORC1 signalling, delayed reactivation of mTORC1 after starvation and abnormal lysosomal retention of mTOR during starvation. These effects could not be reversed by treatment with cystine-depleting drug cysteamine. Altered mTORC1 signalling can contribute to the development of proximal tubular dysfunction in cystinosis and points to new possibilities in therapeutic intervention through modulation of mTORC-dependent signalling cascades.


Subject(s)
Cystinosis/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , Signal Transduction/physiology , Amino Acid Transport Systems, Neutral/metabolism , Autophagy/physiology , Cells, Cultured , Cysteamine/metabolism , Cystinosis/pathology , Fanconi Syndrome/metabolism , Fanconi Syndrome/pathology , Humans , Kidney Failure, Chronic/metabolism , Kidney Failure, Chronic/pathology , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/pathology , Lysosomes/metabolism
18.
Enzyme Res ; 2016: 2682680, 2016.
Article in English | MEDLINE | ID: mdl-26881065

ABSTRACT

Chitotriosidase enzyme (EC: 3.2.1.14) is the major active chitinase in the human body. It is produced mainly by activated macrophages, in which its expression is regulated by multiple intrinsic and extrinsic signals. Chitotriosidase was confirmed as essential element in the innate immunity against chitin containing organisms such as fungi and protozoa; however, its immunomodulatory effects extend far beyond innate immunity. In the current review, we will try to explore the expanding spectrum of immunological roles played by chitotriosidase enzyme in human health and disease and will discuss its up-to-date clinical value.

19.
Acta Clin Belg ; 71(3): 131-7, 2016 Jun.
Article in English | MEDLINE | ID: mdl-25560059

ABSTRACT

Cystinosis is a rare, autosomal recessive inherited lysosomal storage disease. It is the most frequent and potentially treatable cause of the inherited renal Fanconi syndrome. If left untreated, renal function rapidly deteriorates towards end-stage renal disease by the end of the first decade of life. Due to its rarity and non-specific presentation, the entity is often not promptly recognized resulting in delayed diagnosis. Two major milestones in cystinosis management, cystine-depleting therapy with cysteamine and renal allograft transplantation, have had a considerable impact on the natural history and prognosis of cystinosis patients. However, due to its significant side effects and a strict 6-hourly dosing regimen, non-adherence to the immediate release of cysteamine bitartrate formulation (Cystagon®) is a major issue that might affect long-term outcome. Recently, a new twice-daily administered delayed-release enteric-coated formula of cysteamine bitartrate (Procysbi(TM)) has been approved by the European Medical Agency for the treatment of cystinosis, and has been shown to be safe and effective. This delayed-release cysteamine has the potential to improve compliance and hence prognosis, through its better dosing regimen, positive impact on quality of life and possibly less side-effects, and is now tested in an ongoing long-term clinical trial. Longer survival of patients with cystinosis makes transition from pediatric to adult-oriented care another challenge in cystinosis management and requires an extended multidisciplinary approach.


Subject(s)
Cystinosis , Child , Child, Preschool , Cysteamine , Fanconi Syndrome , Humans , Infant , Kidney Transplantation
20.
Pediatr Nephrol ; 30(8): 1349-60, 2015 Aug.
Article in English | MEDLINE | ID: mdl-25956701

ABSTRACT

BACKGROUND: Cystinosis is a rare, inherited autosomal recessive disease caused by the accumulation of free cystine in lysosomes. It is treated by the administration of cysteamine, which should be monitored by trough white blood cell (WBC) cystine measurements to ensure effective treatment. CASE-DIAGNOSIS/TREATMENT: The index case had an older brother who had previously been diagnosed with cystinosis, allowing early diagnosis of the index case at the age of 5 months. Cysteamine therapy was started at the age of 3 years; however, monitoring of WBC cystine levels did not occur on a regular basis during most of his life. Growth retardation improved after correction of electrolyte disturbances, the initiation of cysteamine therapy and treatment with recombinant human growth hormone. Renal replacement therapy was started at the age of 11 years, and renal transplantation was performed at the age of 12 years. Extra-renal cystine accumulation caused multiple endocrinopathies (including adrenal insufficiency, hypothyroidism and primary hypogonadism), neurological symptoms, pancytopenia owing to splenomegaly and portal hypertension due to nodular regenerative hyperplasia, aggravated by splenic vein thrombosis and partial portal vein thrombosis. The patient died of diffuse intra-abdominal bleeding caused by severe portal hypertension. CONCLUSION: Cysteamine treatment should be started as early as possible, and dosage should be monitored and adapted based on trough WBC cystine levels. RELEVANT INTERNATIONAL GUIDELINE: Emma F et al. (2014) Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant 29:iv87-iv94.


Subject(s)
Cysteamine/administration & dosage , Cystinosis/drug therapy , Cystinosis/physiopathology , Adolescent , Adult , Child , Child, Preschool , Cystinosis/complications , Disease Management , Fatal Outcome , Humans , Infant , Infant, Newborn , Kidney Transplantation , Male , Nephrology , Pediatrics , Pedigree , Renal Insufficiency/etiology , Renal Insufficiency/surgery , Young Adult
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