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PURPOSE: Childhood incontinence is stigmatized and underprioritized, and a basic understanding of its pathogenesis is missing. Our goal was to identify risk-conferring genetic variants in daytime urinary incontinence (DUI). MATERIALS AND METHODS: We conducted a genome-wide association study in the Danish iPSYCH2015 cohort. Cases (3024) were identified through DUI diagnosis codes and redeemed prescriptions for DUI medication in patients aged 5 to 20 years. Controls (30,240), selected from the same sample, were matched to cases on sex and psychiatric diagnoses, if any, and down-sampled to a 1:10 case:control ratio. Replication was performed in the Icelandic deCODE cohort (5475 cases/287,773 controls). Single-nucleotide polymorphism heritability was calculated using the genome-based restricted maximum likelihood method. Cross-trait genetic correlation was estimated using linkage disequilibrium score regression. Polygenic risk scores generated with LDpred2-auto and BOLT-LMM were assessed for association. RESULTS: Variants on chromosome 6 (rs12210989, odds ratio [OR] 1.24, 95% CI 1.17-1.32, P = 3.21 × 10-12) and 20 (rs4809801, OR 1.18, 95% CI 1.11-1.25, P = 3.66 × 10-8) reached genome-wide significance and implicated the PRDM13 and RIPOR3 genes. Chromosome 6 findings were replicated (P = .024, OR 1.09, 95% CI 1.01-1.16). Liability scale heritability ranged from 10.20% (95% CI 6.40%-14.00%) to 15.30% (95% CI 9.66%-20.94%). DUI and nocturnal enuresis showed positive genetic correlation (rg = 1.28 ± 0.38, P = .0007). DUI was associated with attention-deficit/hyperactivity disorder (OR 1.098, 95% CI 1.046-1.152, P < .0001) and BMI (OR 1.129, 95% CI 1.081-1.178, P < .0001) polygenic risk. CONCLUSIONS: Common genetic variants contribute to the risk of childhood DUI, and genes important in neuronal development and detrusor smooth muscle activity were implicated. These findings may help guide identification of new treatment targets.
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Adenine phosphoribosyltransferase (APRT) deficiency is a rare , hereditary disorder characterized by renal excretion of 2,8-dihydroxyadenine (DHA), leading to kidney stone formation and chronic kidney disease (CKD). Treatment with a xanthine oxidoreductase inhibitor, allopurinol or febuxostat, reduces urinary DHA excretion and slows the progression of CKD. The method currently used for therapeutic monitoring of APRT deficiency lacks specificity and thus, a more reliable measurement technique is needed. In this study, an ultra-performance liquid chromatography-tandem mass spectrometry method for simultaneous quantification of DHA, adenine, allopurinol, oxypurinol and febuxostat in human plasma was optimized and validated. Plasma samples were prepared with protein precipitation using acetonitrile followed by evaporation. The chemometric approach design of experiments was implemented to optimize gradient steepness, amount of organic solvent, flow rate, column temperature, cone voltage, desolvation temperature and desolvation flow rate. Experimental screening was conducted using fractional factorial design with addition of complementary experiments at the axial points for optimization of peak area, peak resolution and peak width. The assay was validated according to the US Food and Drug Administration guidelines for bioanalytical method validation over the concentration range of 50 to 5000 ng/mL for DHA, allopurinol and febuxostat, 100 to 5000 ng/mL for adenine and 50 to 12,000 ng/mL for oxypurinol, with r2 ≥ 0.99. The analytical assay achieved acceptable performance of accuracy (-10.8 to 8.3 %) and precision (CV < 15 %). DHA, adenine, allopurinol, oxypurinol and febuxostat were stable in plasma samples after five freeze-thaw cycles at -80 °C and after storage at -80 °C for 12 months. The assay was evaluated for quantification of the five analytes in clinical plasma samples from six APRT deficiency patients and proved to be both efficient and accurate. The proposed assay will be valuable for guiding pharmacotherapy and thereby contribute to improved and more personalized care for patients with APRT deficiency.
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Adenina Fosforribosiltransferasa/deficiencia , Adenina/análogos & derivados , Alopurinol , Errores Innatos del Metabolismo , Insuficiencia Renal Crónica , Urolitiasis , Humanos , Alopurinol/uso terapéutico , Oxipurinol , Febuxostat , Cromatografía Liquida , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida con Espectrometría de Masas , Adenina/metabolismo , Adenina Fosforribosiltransferasa/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológicoRESUMEN
Background: Primary, secondary and tertiary healthcare services in Europe create complex networks covering pediatric subspecialties, sociology, economics and politics. Two surveys of the European Society for Paediatric Nephrology (ESPN) in 1998 and 2017 revealed substantial disparities of kidney care among European countries. The purpose of the third ESPN survey is to further identify national differences in the conceptualization and organization of European pediatric kidney health care pathways during and outside normal working hours. Methods: In 2020, a questionnaire was sent to one leading pediatric nephrologist from 48 of 53 European countries as defined by the World Health Organization. In order to exemplify care pathways in pediatric primary care nephrology, urinary tract infection (UTI) was chosen. Steroid sensitive nephrotic syndrome (SSNS) was chosen for pediatric rare disease nephrology and acute kidney injury (AKI) was analyzed for pediatric emergency nephrology. Results: The care pathways for European children and young people with urinary tract infections were variable and differed during standard working hours and also during night-time and weekends. During daytime, UTI care pathways included six different types of care givers. There was a shift from primary care services outside standard working hours to general outpatient polyclinic and hospital services. Children with SNSS were followed up by pediatric nephrologists in hospitals in 69% of countries. Patients presenting with community acquired AKI were admitted during regular working hours to secondary or tertiary care hospitals. During nights and weekends, an immediate shift to University Children's Hospitals was observed where treatment was started by intensive care pediatricians and pediatric nephrologists. Conclusion: Gaps and fragmentation of pediatric health services may lead to the risk of delayed or inadequate referral of European children with kidney disease to pediatric nephrologists. The diversity of patient pathways outside of normal working hours was identified as one of the major weaknesses in the service chain.
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BACKGROUND: Many centers accept a minimum body weight of 10 kg as threshold for kidney transplantation (Tx) in children. As solid evidence for clinical outcomes in multinational studies is lacking, we evaluated practices and outcomes in European children weighing below 10 kg at Tx. METHODS: Data were obtained from the European Society of Paediatric Nephrology/European Renal Association and European Dialysis and Transplant Association Registry on all children who started kidney replacement therapy at <2.5 y of age and received a Tx between 2000 and 2016. Weight at Tx was categorized (<10 versus ≥10 kg) and Cox regression analysis was used to evaluate its association with graft survival. RESULTS: One hundred of the 601 children received a Tx below a weight of 10 kg during the study period. Primary renal disease groups were equal, but Tx <10 kg patients had lower pre-Tx weight gain per year (0.2 versus 2.1 kg; P < 0.001) and had a higher preemptive Tx rate (23% versus 7%; P < 0.001). No differences were found for posttransplant estimated glomerular filtration rates trajectories (P = 0.23). The graft failure risk was higher in Tx <10 kg patients at 1 y (graft survival: 90% versus 95%; hazard ratio, 3.84; 95% confidence interval, 1.24-11.84), but not at 5 y (hazard ratio, 1.71; 95% confidence interval, 0.68-4.30). CONCLUSIONS: Despite a lower 1-y graft survival rate, graft function, and survival at 5 y were identical in Tx <10 kg patients when compared with Tx ≥10 kg patients. Our results suggest that early transplantation should be offered to a carefully selected group of patients weighing <10 kg.
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Fallo Renal Crónico , Trasplante de Riñón , Peso Corporal , Niño , Ácido Edético , Supervivencia de Injerto , Humanos , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Sistema de RegistrosRESUMEN
INTRODUCTION: Because of phenotypic overlap between monogenic urinary stone diseases (USD), gene-specific analyses can result in missed diagnoses. We used targeted next generation sequencing (tNGS), including known and candidate monogenic USD genes, to analyze suspected primary hyperoxaluria (PH) or Dent disease (DD) patients genetically unresolved (negative; N) after Sanger analysis of the known genes. Cohorts consisted of 285 PH (PHN) and 59 DD (DDN) families. METHODS: Variants were assessed using disease-specific and population databases plus variant assessment tools and categorized using the American College of Medical Genetics (ACMG) guidelines. Prior Sanger analysis identified 47 novel PH or DD gene pathogenic variants. RESULTS: Screening by tNGS revealed pathogenic variants in 14 known monogenic USD genes, accounting for 45 families (13.1%), 27 biallelic and 18 monoallelic, including 1 family with a copy number variant (CNV). Recurrent genes included the following: SLC34A3 (n = 13), CLDN16 (n = 8), CYP24A1 (n = 4), SLC34A1 (n = 3), SLC4A1 (n = 3), APRT (n = 2), CLDN19 (n = 2), HNF4A1 (n = 2), and KCNJ1 (n = 2), whereas ATP6V1B1, CASR, and SLC12A1 and missed CNVs in the PH genes AGXT and GRHPR accounted for 1 pedigree each. Of the 48 defined pathogenic variants, 27.1% were truncating and 39.6% were novel. Most patients were diagnosed before 18 years of age (76.1%), and 70.3% of biallelic patients were homozygous, mainly from consanguineous families. CONCLUSION: Overall, in patients suspected of DD or PH, 23.9% and 7.3% of cases, respectively, were caused by pathogenic variants in other genes. This study shows the value of a tNGS screening approach to increase the diagnosis of monogenic USD, which can optimize therapies and facilitate enrollment in clinical trials.
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Adenine phosphoribosyltransferase deficiency is a rare, autosomal recessive disorder of purine metabolism that causes nephrolithiasis and progressive chronic kidney disease. The small number of reported cases indicates an extremely low prevalence, although it has been suggested that missed diagnoses may play a role. We assessed the prevalence of APRT deficiency based on the frequency of causally-related APRT sequence variants in a diverse set of large genomic databases. A thorough search was carried out for all APRT variants that have been confirmed as pathogenic under recessive mode of inheritance, and the frequency of the identified variants examined in six population genomic databases: the deCODE genetics database, the UK Biobank, the 100,000 Genomes Project, the Genome Aggregation Database, the Human Genetic Variation Database and the Korean Variant Archive. The estimated frequency of homozygous genotypes was calculated using the Hardy-Weinberg equation. Sixty-two pathogenic APRT variants were identified, including six novel variants. Most common were the missense variants c.407T>C (p.(Met136Thr)) in Japan and c.194A>T (p.(Asp65Val)) in Iceland, as well as the splice-site variant c.400 + 2dup (p.(Ala108Glufs*3)) in the European population. Twenty-nine variants were detected in at least one of the six genomic databases. The highest cumulative minor allele frequency (cMAF) of pathogenic variants outside of Japan and Iceland was observed in the Irish population (0.2%), though no APRT deficiency cases have been reported in Ireland. The large number of cases in Japan and Iceland is consistent with a founder effect in these populations. There is no evidence for widespread underdiagnosis based on the current analysis.
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Adenina Fosforribosiltransferasa/deficiencia , Alelos , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/genética , Urolitiasis/diagnóstico , Urolitiasis/genética , Adenina Fosforribosiltransferasa/genética , Sustitución de Aminoácidos , Bases de Datos Genéticas , Estudios de Asociación Genética/métodos , Genotipo , Humanos , Errores Innatos del Metabolismo/epidemiología , Mutación , Vigilancia de la Población , Sistema de Registros , Urolitiasis/epidemiologíaRESUMEN
We have recently encountered patients incorrectly diagnosed with adenine phosphoribosyltransferase (APRT) deficiency due to misidentification of kidney stones as 2,8-dihydroxyadenine (DHA) stones. The objective of this study was to examine the accuracy of stone analysis for identification of DHA. Medical records of patients referred to the APRT Deficiency Research Program of the Rare Kidney Stone Consortium in 2010-2018 with a diagnosis of APRT deficiency based on kidney stone analysis were reviewed. The diagnosis was verified by measurement of APRT enzyme activity or genetic testing. Attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectra of pure crystalline DHA and a kidney stone obtained from one of the confirmed APRT deficiency cases were generated. The ATR-FTIR spectrum of the kidney stone matched the crystalline DHA spectrum and was used for comparison with available infrared spectra of stone samples from the patients. Of 17 patients referred, 14 had sufficient data available to be included in the study. In all 14 cases, the stone analysis had been performed by FTIR spectroscopy. The diagnosis of APRT deficiency was confirmed in seven cases and rejected in the remaining seven cases. Comparison of the ATR-FTIR spectrum of the DHA stone with the FTIR spectra from three patients who did not have APRT deficiency showed no indication of DHA as a stone component. Misidentification of DHA as a kidney stone component by clinical laboratories appears common among patients referred to our program. Since current clinical protocols used to interpret infrared spectra for stone analysis cannot be considered reliable for the identification of DHA stones, the diagnosis of APRT deficiency must be confirmed by other methods.
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Adenina/análogos & derivados , Cálculos Renales/química , Adenina/análisis , Adenina Fosforribosiltransferasa/deficiencia , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Cálculos Renales/complicaciones , Masculino , Errores Innatos del Metabolismo/complicaciones , Errores Innatos del Metabolismo/diagnóstico , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Urolitiasis/complicaciones , Urolitiasis/diagnóstico , Adulto JovenRESUMEN
OBJECTIVES: To examine the stone recurrence rate among childhood kidney stone formers in the Icelandic population. MATERIALS AND METHODS: We retrospectively examined kidney stone recurrence in a recently reported population-based sample of 190 individuals who experienced their first stone before 18 years of age in the period 1985-2013. Of these 190 individuals, 112 (59%) were females and the median (range) age at the incident stone diagnosis was 15.0 (0.2-17.9) years. Stone recurrence was defined as an acute symptomatic episode with imaging confirmation or self-reported stone passage, new stone detected by imaging in asymptomatic patients, and suspected clinical stone episode without verification. The Kaplan-Meier method was used to assess stone-free survival and the Chi-square, Fisher's exact, Wilcoxon rank-sum and the log-rank tests to compare groups. RESULTS: A total of 68 (35%) individuals experienced a second stone event, 1.7 (0.9-18.9) years after the initial diagnosis. The recurrence rate was 26%, 35%, 41% and 46% after 5, 10, 15 and 20 years of follow-up, respectively. The 5-year recurrence rate increased with time and was 9%, 24% and 37% in the periods 1985-1994, 1995-2004 and 2005-2013, respectively (P = 0.005). No difference in stone recurrence was observed between the sexes (P = 0.23). CONCLUSIONS: In our population-based sample of childhood kidney stone formers, the stone recurrence rate is similar to that reported for adults. The observed rise in stone recurrence with time may be related to closer patient follow-up in recent years or increased stone risk in general.
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Cálculos Renales/epidemiología , Adolescente , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Islandia/epidemiología , Lactante , Masculino , Recurrencia , Estudios Retrospectivos , Factores de TiempoRESUMEN
BACKGROUND: Adenine phosphoribosyltransferase (APRT) deficiency is a rare, hereditary cause of kidney stones and chronic kidney disease (CKD) which is characterized by 2,8-dihydroxyadenine renal parenchymal crystal deposition. The aim of this study was to examine outcomes of kidney transplantation in APRT deficiency patients. METHODS: Included were 13 patients in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, 2 from Westmead Hospital in Sydney, Australia, and 2 from Necker Hospital in Paris, France. The CKD-EPI and CKiD equations were used to calculate glomerular filtration rate estimates. Allograft survival was analyzed employing the Kaplan-Meier method. The Wilcoxon-Mann-Whitney test was used to compare alllograft outcomes according to xanthine oxidoreductase (XOR) inhibitor treatment status at transplantation. RESULTS: Seventeen patients (9 females) received 22 kidney transplants. Age at first transplantation was 47.2 (14.9-67.0) years. Ten patients received XOR inhibitor therapy pretransplant (11 allografts), while 8 patients did not receive such treatment before transplantation (11 allografts). Two-year allograft survival was 91% and 55% in the 2 groups, respectively (P = 0.16). The median (range) estimated glomerular filtration rate at 2 years posttransplant was 61.3 (24.0-90.0) mL/min/1.73 m when XOR inhibitor therapy was initiated before transplantation, and 16.2 (10.0-39.0) mL/min/1.73 m (P = 0.009) when such treatment was not administered pretransplant. CONCLUSIONS: Kidney allograft outcomes are good in APRT deficiency patients beginning XOR inhibitor therapy pretransplant. Delay in such treatment is a major cause of premature graft loss in these patients. Increased awareness among clinicians is imperative, promoting early diagnosis of APRT deficiency and pharmacotherapy initiation before kidney transplantation.
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Adenina Fosforribosiltransferasa/deficiencia , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Errores Innatos del Metabolismo/complicaciones , Urolitiasis/complicaciones , Adolescente , Adulto , Anciano , Alopurinol/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Europa (Continente) , Febuxostat/uso terapéutico , Femenino , Supervivencia de Injerto , Humanos , India , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/etiología , Trasplante de Riñón/efectos adversos , Masculino , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/tratamiento farmacológico , Persona de Mediana Edad , Nueva Gales del Sur , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos , Urolitiasis/diagnóstico , Urolitiasis/tratamiento farmacológico , Xantina Oxidasa/antagonistas & inhibidores , Adulto JovenRESUMEN
BACKGROUND: Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder of adenine metabolism that results in excessive urinary excretion of the poorly soluble 2,8-dihydroxyadenine (DHA), leading to kidney stones and chronic kidney disease. The purpose of this study was to assess urinary DHA excretion in patients with APRT deficiency, heterozygotes and healthy controls, using a recently developed ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) assay. METHODS: Patients enrolled in the APRT Deficiency Registry and Biobank of the Rare Kidney Stone Consortium (http://www.rarekidneystones.org/) who had provided 24-h and first-morning void urine samples for DHA measurement were eligible for the study. Heterozygotes and healthy individuals served as controls. Wilcoxon-Mann-Whitney test was used to compare 24-h urinary DHA excretion between groups. Associations were examined using Spearman's correlation coefficient (rs). RESULTS: The median (range) 24-h urinary DHA excretion was 138 (64-292) mg/24â¯h and the DHA-to-creatinine (DHA/Cr) ratio in the first-morning void samples was 13 (4-37) mg/mmol in APRT deficiency patients who were not receiving xanthine oxidoreductase inhibitor therapy. The 24-h DHA excretion was highly correlated with the DHA/Cr ratio in first-morning void urine samples (rsâ¯=â¯0.84, pâ¯<â¯.001). DHA was detected in all urine samples from untreated patients but not in any specimens from heterozygotes and healthy controls. CONCLUSIONS: High urinary DHA excretion was observed in patients with APRT deficiency, while urine DHA was undetectable in heterozygotes and healthy controls. Our results suggest that the UPLC-MS/MS assay can be used for diagnosis of APRT deficiency.
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Adenina Fosforribosiltransferasa/deficiencia , Adenina/análogos & derivados , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/orina , Urolitiasis/diagnóstico , Urolitiasis/orina , Adenina/orina , Adenina Fosforribosiltransferasa/orina , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Cromatografía Liquida , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sistema de Registros , Espectrometría de Masas en Tándem , Adulto JovenRESUMEN
BACKGROUND: There is no consensus regarding the timing of dialysis therapy initiation for end-stage kidney disease (ESKD) in children. As studies investigating the association between timing of dialysis initiation and clinical outcomes are lacking, we aimed to study this relationship in a cohort of European children who started maintenance dialysis treatment. METHODS: We used data on 2963 children from 21 different countries included in the European Society of Pediatric Nephrology/European Renal Association-European Dialysis and Transplant Association Registry who started renal replacement therapy before 18 years of age between 2000 and 2014. We compared two groups according to the estimated glomerular filtration rate (eGFR) at start: eGFR ≥8 mL/min/1.73 m2 (early starters) and eGFR <8 mL/min/1.73 m2 (late starters). The primary outcomes were patient survival and access to transplantation. Secondary outcomes were growth and cardiovascular risk factors. Sensitivity analyses were performed to account for selection- and lead time-bias. RESULTS: The median eGFR at the start of dialysis was 6.1 for late versus 10.5 mL/min/1.73 m2 for early starters. Early starters were older [median: 11.0, interquartile range (IQR): 5.7-14.5 versus 9.4, IQR: 2.6-14.1 years]. There were no differences observed between the two groups in mortality and access to transplantation at 1, 2 and 5 years of follow-up. One-year evolution of height standard deviation scores was similar among the groups, whereas hypertension was more prevalent among late initiators. Sensitivity analyses resulted in similar findings. CONCLUSIONS: We found no evidence for a clinically relevant benefit of early start of dialysis in children with ESKD. Presence of cardiovascular risk factors, such as high blood pressure, should be taken into account when deciding to initiate or postpone dialysis in children with ESKD, as this affects the survival.
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Accesibilidad a los Servicios de Salud , Fallo Renal Crónico/mortalidad , Trasplante de Riñón/mortalidad , Sistema de Registros/estadística & datos numéricos , Diálisis Renal/mortalidad , Tiempo de Tratamiento , Adolescente , Niño , Preescolar , Estudios de Cohortes , Femenino , Tasa de Filtración Glomerular , Humanos , Lactante , Recién Nacido , Fallo Renal Crónico/terapia , Masculino , Tasa de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Kidney stone disease is a common disorder in Western countries that is associated with significant suffering, morbidity, and cost for the healthcare system. Numerous studies have demonstrated familial aggregation of nephrolithiasis and a twin study estimated the heritability to be 56%. Over the past decade, genome-wide association studies have uncovered several sequence variants that confer increased risk of common complex kidney stone disease. The first reported variants were observed at the CLDN14 locus in the Icelandic population. This finding has since been replicated in other populations. The CLDN14 gene is expressed in tight junctions of the thick ascending limb of the loop of Henle, where the protein is believed to play a role in regulation of calcium transport. More recent studies have uncovered variants at the ALPL, SLC34A1, CASR, and TRPV5 loci, the first two genes playing a role in renal handling of phosphate, while the latter two are involved in calcium homeostasis. Although genetic data have provided insights into the molecular basis of kidney stone disease, much remains to be learned about the contribution of genetic factors to stone formation. Nevertheless, the progress made in recent years indicates that exciting times lie ahead in genetic research on kidney stone disease.
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Sitios Genéticos/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Cálculos Renales/genética , Fosfatasa Alcalina/genética , Alelos , Claudinas/genética , Humanos , Polimorfismo de Nucleótido Simple , Receptores Sensibles al Calcio/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/genética , Canales Catiónicos TRPV/genéticaRESUMEN
BACKGROUND: Adenine phosphoribosyltransferase (APRT) deficiency is a hereditary purine metabolism disorder that causes kidney stones and chronic kidney disease (CKD). The purpose of this study was to examine the course of APRT deficiency in patients who presented in childhood. METHODS: The disease course of 21 (35%) patients in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, who presented with manifestations of APRT deficiency and/or were diagnosed with the disorder before the age of 18 years, was studied. The effect of pharmacotherapy on renal manifestations and outcomes was thoroughly assessed. RESULTS: Fourteen children were placed on allopurinol, 100 (25-200) mg/day, at the age of 2.6 (0.6-16.5) years. Six of these patients had experienced kidney stone events and three had developed acute kidney injury (AKI) prior to allopurinol treatment. During 18.9 (1.7-31.5) years of pharmacotherapy, stones occurred in two patients and AKI in three. Six adult patients started allopurinol treatment, 200 (100-300) mg/day, at age 29.8 (20.5-42.4) years. Five of these patients had experienced 28 stone episodes and AKI had occurred in two. Stone recurrence occurred in four patients and AKI in two during 11.2 (4.2-19.6) years of allopurinol therapy. Lack of adherence and insufficient dosing contributed to stone recurrence and AKI during pharmacotherapy. At latest follow-up, estimated glomerular filtration rate (eGFR) was 114 (70-163) and 62 (10-103) mL/min/1.73 m2 in those who initiated treatment as children and adults, respectively. All three patients with CKD stages 3-5 at the last follow-up were adults when pharmacotherapy was initiated. CONCLUSION: Timely diagnosis and treatment of APRT deficiency decreases renal complications and preserves kidney function.
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Lesión Renal Aguda/epidemiología , Adenina Fosforribosiltransferasa/deficiencia , Alopurinol/uso terapéutico , Cálculos Renales/epidemiología , Errores Innatos del Metabolismo/complicaciones , Insuficiencia Renal Crónica/epidemiología , Urolitiasis/complicaciones , Lesión Renal Aguda/etiología , Lesión Renal Aguda/fisiopatología , Adenina/análogos & derivados , Adenina/química , Adenina/metabolismo , Adenina Fosforribosiltransferasa/genética , Adenina Fosforribosiltransferasa/metabolismo , Adolescente , Adulto , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular/fisiología , Humanos , Lactante , Riñón/fisiopatología , Cálculos Renales/química , Cálculos Renales/diagnóstico , Cálculos Renales/etiología , Masculino , Errores Innatos del Metabolismo/tratamiento farmacológico , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Recurrencia , Sistema de Registros/estadística & datos numéricos , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/fisiopatología , Urolitiasis/tratamiento farmacológico , Urolitiasis/genética , Urolitiasis/metabolismo , Xantina Deshidrogenasa/antagonistas & inhibidores , Xantina Deshidrogenasa/metabolismo , Adulto JovenRESUMEN
BACKGROUND: An increase in the incidence of kidney stone disease has been reported for all age groups worldwide. To examine this trend, we conducted a nationwide study of the epidemiology of kidney stones in Icelandic children and adolescents over a 30-year period. METHODS: Computerized databases of all major hospitals and medical imaging centers in Iceland were searched for International Classification of Diseases and radiologic and surgical procedure codes indicative of kidney stones in patients aged < 18 years, followed by a thorough medical record review. Age-adjusted incidence was calculated for the time intervals 1985-1989, 1990-1994, 1995-1999, 2000-2004, 2005-2009, and 2010-2013. Time trends in stone incidence were assessed by Poisson regression. The prevalence of stone disease for the years 1999-2013 was also determined. RESULTS: Almost all the 190 patients (97%) that we identified had symptomatic stones, and acute flank or abdominal pain and hematuria were the most common presenting features. The total annual incidence of kidney stones increased from 3.7/100,000 in the first 5-year interval to 11.0/100,000 during the years 1995-2004 (p < 0.001) and decreased thereafter to 8.7/100,000 in 2010-2013 (p = 0.63). The incidence rise was highest in girls aged 13-17 years, in whom it rose from 9.8/100,000 in 1985-1989 to 39.2/100,000 in 2010-2013 (p < 0.001), resulting in an overall female predominance in this age group. The mean annual prevalence of stone disease in 1999-2013 was 48/100,000 for boys and 52/100,000 for girls. CONCLUSION: We found a significant increase in the incidence of childhood kidney stone disease, driven by a dramatic increase of stone frequency in teenage females which is poorly understood and warrants further study.
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Dolor Abdominal/epidemiología , Dolor Agudo/epidemiología , Dolor en el Flanco/epidemiología , Hematuria/epidemiología , Cálculos Renales/epidemiología , Dolor Abdominal/etiología , Dolor Agudo/etiología , Adolescente , Niño , Preescolar , Femenino , Dolor en el Flanco/etiología , Hematuria/etiología , Humanos , Islandia/epidemiología , Incidencia , Cálculos Renales/complicaciones , Masculino , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Factores SexualesRESUMEN
INTRODUCTION: Adenine phosphoribosyltransferase (APRT) deficiency is a rare, but significant, cause of kidney stones and progressive chronic kidney disease. The optimal treatment has not been established. The purpose of this pilot study was to compare the effect of the xanthine oxidoreductase inhibitors allopurinol and febuxostat on urinary 2,8-dihydroxyadenine (DHA) excretion in APRT deficiency patients. MATERIALS AND METHODS: Patients listed in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, currently receiving allopurinol therapy, were invited to participate. The trial endpoint was the 24-h urinary DHA excretion following treatment with allopurinol (400mg/day) and febuxostat (80mg/day). Urinary DHA was measured using a novel ultra-performance liquid chromatography - electrospray tandem mass spectrometry assay. RESULTS: Eight of the 10 patients invited completed the study. The median (range) 24-h urinary DHA excretion was 116 (75-289) mg at baseline, and 45 (13-112) mg after 14days of allopurinol therapy (P=0.036). At the end of the febuxostat treatment period, 4 patients had urinary DHA below detectable limits (<20ng/mL) compared with none of the participants following allopurinol treatment (P=0.036). The other 4 participants had a median 24-h urinary DHA excretion of 13.2 (10.0-13.4) mg at the completion of febuxostat therapy (P=0.036). CONCLUSION: Urinary DHA excretion in APRT deficiency patients decreased with conventional doses of both allopurinol and febuxostat. Febuxostat was, however, significantly more efficacious than allopurinol in reducing DHA excretion in the prescribed doses. This finding, which may translate into improved outcomes of patients with APRT deficiency, should be confirmed in a larger sample.
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Adenina Fosforribosiltransferasa/deficiencia , Adenina/análogos & derivados , Alopurinol/uso terapéutico , Febuxostat/uso terapéutico , Errores Innatos del Metabolismo/tratamiento farmacológico , Urolitiasis/tratamiento farmacológico , Adenina/orina , Adulto , Anciano , Estudios Cruzados , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Islandia , Cálculos Renales/etiología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Sistema de Registros , Resultado del TratamientoRESUMEN
Adenine phosphoribosyltransferase (APRT) deficiency is a hereditary disorder that leads to excessive urinary excretion of 2,8-dihydroxyadenine (DHA), causing nephrolithiasis and chronic kidney disease. Treatment with allopurinol or febuxostat reduces DHA production and attenuates the renal manifestations. Assessment of DHA crystalluria by urine microscopy is used for therapeutic monitoring, but lacks sensitivity. We report a high-throughput assay based on ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) for quantification of urinary DHA. The UPLC-MS/MS assay was optimized by a chemometric approach for absolute quantification of DHA, utilizing isotopically labeled DHA as an internal standard. Experimental screening was conducted with D-optimal design and optimization of the DHA response was performed with central composite face design and related to the peak area of DHA using partial least square regression. Acceptable precision and accuracy of the DHA concentration were obtained over a calibration range of 100 to 5000ng/mL on three different days. The intra- and inter-day accuracy and precision coefficients of variation were well within ±15% for quality control samples analyzed in replicates of six at three concentration levels. Absolute quantification of DHA in urine samples from patients with APRT deficiency was achieved wihtin 6.5min. Measurement of DHA in 24h urine samples from three patients with APRT deficiency, diluted 1:15 (v/v) with 10mM ammonium hydroxide (NH4OH), yielded a concentration of 3021, 5860 and 10563ng/mL and 24h excretion of 816, 1327 and 1649mg, respectively. A rapid and robust UPLC-MS/MS assay for absolute quantification of DHA in urine was successfully developed. We believe this method will greatly facilitate diagnosis and management of patients with APRT deficiency.
Asunto(s)
Adenina Fosforribosiltransferasa/deficiencia , Adenina/análogos & derivados , Cromatografía Líquida de Alta Presión/métodos , Errores Innatos del Metabolismo/orina , Espectrometría de Masas en Tándem/métodos , Urolitiasis/orina , Adenina/orina , Adenina Fosforribosiltransferasa/orina , Adulto , Humanos , Límite de Detección , Errores Innatos del Metabolismo/diagnóstico , Urinálisis/métodos , Urolitiasis/diagnósticoRESUMEN
BACKGROUND: The choice for either kidney or combined liver-kidney transplantation in young people with kidney failure and liver fibrosis due to autosomal recessive polycystic kidney disease (ARPKD) can be challenging. We aimed to analyze the characteristics and outcomes of transplantation type in these children, adolescents, and young adults. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: We derived data for children, adolescents, and young adults with ARPKD with either kidney or combined liver-kidney transplants for 1995 to 2012 from the ESPN/ERA-EDTA Registry, a European pediatric renal registry collecting data from 36 European countries. FACTOR: Liver transplantation. OUTCOMES & MEASUREMENTS: Transplantation and patient survival. RESULTS: 202 patients with ARPKD aged 19 years or younger underwent transplantation after a median of 0.4 (IQR, 0.0-1.4) years on dialysis therapy at a median age of 9.0 (IQR, 4.1-13.7) years. 32 (15.8%) underwent combined liver-kidney transplantation, 163 (80.7%) underwent kidney transplantation, and 7 (3.5%) were excluded because transplantation type was unknown. Age- and sex-adjusted 5-year patient survival posttransplantation was 95.5% (95% CI, 92.4%-98.8%) overall: 97.4% (95% CI, 94.9%-100.0%) for patients with kidney transplantation in contrast to 87.0% (95% CI, 75.8%-99.8%) with combined liver-kidney transplantation. The age- and sex-adjusted risk for death after combined liver-kidney transplantation was 6.7-fold (95% CI, 1.8- to 25.4-fold) greater than after kidney transplantation (P=0.005). Five-year death-censored kidney transplant survival following combined liver-kidney and kidney transplantation was similar (92.1% vs 85.9%; P=0.4). LIMITATIONS: No data for liver disease of kidney therapy recipients. CONCLUSIONS: Combined liver-kidney transplantation in ARPKD is associated with increased mortality compared to kidney transplantation in our large observational study and was not associated with improved 5-year kidney transplant survival. Long-term follow-up of both kidney and liver involvement are needed to better delineate the optimal transplantation strategy.
Asunto(s)
Trasplante de Riñón , Cirrosis Hepática/etiología , Cirrosis Hepática/cirugía , Trasplante de Hígado , Riñón Poliquístico Autosómico Recesivo/complicaciones , Insuficiencia Renal/etiología , Insuficiencia Renal/cirugía , Adolescente , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Lactante , Cirrosis Hepática/mortalidad , Masculino , Riñón Poliquístico Autosómico Recesivo/mortalidad , Sistema de Registros , Insuficiencia Renal/mortalidad , Sociedades Médicas , Análisis de SupervivenciaRESUMEN
BACKGROUND: Adenine phosphoribosyltransferase (APRT) deficiency is a purine metabolism disorder causing kidney stones and chronic kidney disease (CKD). The course of nephrolithiasis and CKD has not been well characterized. The objective of this study was to examine long-term kidney outcomes in patients with APRT deficiency. STUDY DESIGN: An observational cohort study. SETTING & PARTICIPANTS: All patients enrolled in the APRT Deficiency Registry of the Rare Kidney Stone Consortium. OUTCOMES: Kidney stones, acute kidney injury (AKI), stage of CKD, end-stage renal disease, estimated glomerular filtration rate (eGFR), and changes in eGFR. MEASUREMENTS: Serum creatinine and eGFR calculated using creatinine-based equations. RESULTS: Of 53 patients, 30 (57%) were females and median age at diagnosis was 37.0 (range, 0.6-67.9) years. Median duration of follow-up was 10.3 (range, 0.0-31.5) years. At diagnosis, kidney stones had developed in 29 (55%) patients and 20 (38%) had CKD stages 3 to 5, including 11 (21%) patients with stage 5. At latest follow-up, 33 (62%) patients had experienced kidney stones; 18 (34%), AKI; and 22 (42%), CKD stages 3 to 5. Of 14 (26%) patients with stage 5 CKD, 12 had initiated renal replacement therapy. Kidney stones recurred in 18 of 33 (55%) patients. The median eGFR slope was -0.38 (range, -21.99 to 1.42) mL/min/1.73m(2) per year in patients receiving treatment with an xanthine dehydrogenase inhibitor and -5.74 (range, -75.8 to -0.10) mL/min/1.73m(2) per year in those not treated prior to the development of stage 5 CKD (P=0.001). LIMITATIONS: Use of observational registry data. CONCLUSIONS: Progressive CKD and AKI episodes are major features of APRT deficiency, whereas nephrolithiasis is the most common presentation. Advanced CKD without a history of kidney stones is more prevalent than previously reported. Our data suggest that timely therapy may retard CKD progression.