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1.
J Pediatr Urol ; 17(3): 387.e1-387.e7, 2021 06.
Article in English | MEDLINE | ID: mdl-33762156

ABSTRACT

INTRODUCTION/OBJECTIVE: 24-h urine collections are recommended for motivated first-time stone formers. Given that children have a lifetime potential for recurrences, metabolic work-up has been recommended. 24-hour urine collections can be problematic, especially in children. We sought to study the benefits of 24-h urine collections in children with stones. STUDY DESIGN: We performed a single center, retrospective chart review of the most recent pediatric nephrolithiasis patients under age 18 at our center who supplied their first 24-h urine collection. We assessed whether 24-h urine results led to a change in management and if those patients were adherent to the recommendations. RESULTS: Seventy pediatric nephrolithiasis patients who had 24-h urine collection were reviewed. Recommendations other than standard dietary and fluid intake changes were made in 8/70 (11%). A low citrate/calcium ratio (327 vs. 525, p < 0.03) and whether the test was ordered by nephrology vs. urology (26% vs. 2%, p < 0.003) were predictive of an additional recommendation. Of the 8 patients who had changes recommended only 1/8 completed a repeat 24-h urine collection, 3/8 never returned for followed up and 2/8 stopped the medicines prior to follow up. There was no difference in early stone recurrence rates, 55% of the studies were incorrectly collected, and total costs are estimated at $9800. DISCUSSION: Our study aimed to evaluate the impact and value of 24-h urine collection in first time pediatric stone formers. We found that 24-h urine collections altered management from standard dietary recommendations in only 11% of cases. These collections were fraught with challenges - 55% of our samples appeared to be incorrectly collected, there was at least one abnormality noted in 100% of collections, these tests are expensive, and patients were poorly compliant with recommendations based on test results. Additionally, changes made based on the 24-h urine results seemed to vary depending on who evaluated the test results. Among cases in which changes were made, nephrologists made alterations at a far greater rate than urologists did. We do acknowledge there are several limitations to our study. First, this is a retrospective chart review. Second, for the urology patients, we were only able to review patient records that were available due to a transition from one electronic medical record to another, resulting in a loss of some earlier patient records. We highly doubt that those records we could not review were significantly different than those we did review. Third, this is a single center design and includes the practice patterns of the providers here. We acknowledge that our local practice patterns may or may not be reflective of national practice patterns, however, most clinicians are likely faced with similar interpretation issues and poor rates of compliance and could benefit from guidelines. CONCLUSION: 24-h urine collection for first time pediatric stone formers is expensive, difficult to accomplish and infrequently leads to treatment changes. Our data suggest it adds little for most children with stones and may be better reserved for those children with recurrent stone disease.


Subject(s)
Kidney Calculi , Urine Specimen Collection , Adolescent , Child , Citric Acid , Humans , Kidney Calculi/diagnosis , Recurrence , Retrospective Studies , Risk Factors
2.
Pediatr Nephrol ; 27(11): 2081-2090, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22907601

ABSTRACT

BACKGROUND: Mutations in the K(+) channel KCNJ10 (Kir4.1) cause an autosomal recessive syndrome featuring seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME). Kir4.1 localizes to the basolateral membrane of the renal distal convoluted tubule, and its loss of function mimics renal features of Gitelman syndrome, with hypokalemic alkalosis, hypomagnesemia, and hypocalciuria. Presentation early in life due to seizures provides an opportunity to investigate the development of the electrolyte defect with age. METHODS: We used DNA sequencing, electrophysiology, confocal imaging, and biochemistry to identify a new KCNJ10 mutation in a previously unreported family and determine its impact on channel function. We examined medical records to follow the development of electrolyte disorders with age. RESULTS: The four affected members were all homozygous for a novel T57I mutation that confers biochemical loss-of-function. Electrolytes in affected children were normal in the first years of life but showed significant worsening with age, resulting in clinically significant defects at age 5-8 years. Similar findings were seen in other SeSAME patients. CONCLUSIONS: These findings provide evidence for a delayed activity of salt reabsorption by the distal convoluted tubule and suggest an explanation for the delayed clinical presentation of subjects with Gitelman syndrome.


Subject(s)
Hearing Loss, Sensorineural/metabolism , Intellectual Disability/metabolism , Kidney Tubules, Distal/metabolism , Potassium Channels, Inwardly Rectifying/metabolism , Seizures/metabolism , Absorption , Age Factors , Biomarkers/blood , Child , DNA Mutational Analysis , Electrolytes/blood , Female , Genetic Predisposition to Disease , HEK293 Cells , Hearing Loss, Sensorineural/genetics , Hearing Loss, Sensorineural/therapy , Homozygote , Humans , Infant , Intellectual Disability/genetics , Intellectual Disability/therapy , Male , Membrane Potentials , Microscopy, Confocal , Mutation , Pedigree , Phenotype , Potassium Channels, Inwardly Rectifying/genetics , Predictive Value of Tests , Seizures/genetics , Seizures/therapy , Transfection
3.
Mol Immunol ; 45(9): 2667-77, 2008 May.
Article in English | MEDLINE | ID: mdl-18308397

ABSTRACT

The immediate early (IE) proteins of human cytomegalovirus (hCMV) have diverse roles in directing viral and host cell transcription. Among these is the ability of IE2 to induce transcription of the IL1B gene that codes for IL-1beta in monocytes. This function is partially explained by interaction between IE2 and the host cell transcription factor Spi-1/PU.1 (Spi-1). We now show that maximal IE2 function also depends on productive interactions localizing to two C/EBP sites on the IL1B promoter suggesting either bi- or tri-molecular interactions between IE2, Spi-1 and C/EBPbeta at two different locations on the promoter. The IE2 interaction region on Spi-1 was previously mapped to the DNA-binding ETS domain and overlaps the region of Spi-1 that interacts with the transcription factor C/EBPbeta, a factor known to be critical for the induction of IL1B in response to Toll/IL-1 receptor (TIR) family signal transduction. The Spi-1 interacting region of IE2 maps to amino acids 315-328, a sequence that also interacts with the bZIP domain of C/EBPbeta. An expression vector coding for amino acids 291-364 of IE2 can suppress LPS induction of a co-transfected IL1B enhancer-promoter fragment in a monocyte cell line. This inhibition is likely the result of competition between Spi-1 and C/EBPbeta, thus blunting gene induction.


Subject(s)
Cytomegalovirus/metabolism , Immediate-Early Proteins/metabolism , Interleukin-1beta/genetics , Trans-Activators/metabolism , Transcription, Genetic , CCAAT-Enhancer-Binding Protein-beta/chemistry , CCAAT-Enhancer-Binding Protein-beta/metabolism , Cell Line , Cytomegalovirus/immunology , HeLa Cells , Humans , Immediate-Early Proteins/chemistry , Interleukin-1beta/immunology , Interleukin-1beta/metabolism , Peptides/chemistry , Peptides/immunology , Peptides/metabolism , Promoter Regions, Genetic , Protein Structure, Tertiary , Proto-Oncogene Proteins/chemistry , Proto-Oncogene Proteins/metabolism , Trans-Activators/chemistry , Transfection
4.
J Biol Chem ; 280(50): 41421-8, 2005 Dec 16.
Article in English | MEDLINE | ID: mdl-16223730

ABSTRACT

The DNA-binding ETS transcription factor Spi-1/PU.1 is of central importance in determining the myeloid-erythroid developmental switch and is required for monocyte and osteoclast differentiation. Many monocyte genes are dependent upon this factor, including the gene that codes for interleukin-1beta. It has long been known that the conserved ETS DNA-binding domain of Spi-1/PU.1 functionally cooperates via direct association with a diverse collection of DNA-binding proteins, including members of the basic leucine zipper domain (bZIP) family. However, the molecular basis for this interaction has long been elusive. Using a combination of approaches, we have mapped a single residue on the surface of the ETS domain critical for protein tethering by the C/EBPbeta carboxyl-terminal bZIP domain. This residue is also important for nuclear localization and DNA binding. In addition, dependence upon the leucine zipper suggests a novel mode for both protein-DNA interaction and functional cooperativity.


Subject(s)
Basic-Leucine Zipper Transcription Factors/chemistry , DNA/chemistry , Escherichia coli/metabolism , Arginine/chemistry , Blotting, Western , CCAAT-Enhancer-Binding Protein-beta/chemistry , Cations , Cell Nucleus/metabolism , Dose-Response Relationship, Drug , Genetic Vectors , Glutathione Transferase/metabolism , HeLa Cells , Humans , Interleukin-1/metabolism , Luciferases/metabolism , Models, Biological , Models, Genetic , Models, Molecular , Monocytes/metabolism , Plasmids/metabolism , Promoter Regions, Genetic , Protein Binding , Protein Conformation , Protein Structure, Secondary , Protein Structure, Tertiary , Proteins/chemistry , Proto-Oncogene Proteins/chemistry , Trans-Activators/chemistry , Transcriptional Activation
5.
Pediatr Nephrol ; 17(5): 386-9, 2002 May.
Article in English | MEDLINE | ID: mdl-12042901

ABSTRACT

Following an uneventful full-term pregnancy, a 3-day-old girl presented with a focal seizure. Serological evaluation revealed hypomagnesemia and hypocalcemia. Renal ultrasonography performed because of hematuria showed bilateral nephrolithiasis. Renal wasting of calcium and magnesium was detected and urine citrate excretion was low. The hypocalcemia was refractory to calcium therapy, but responded briskly to magnesium supplementation. After 8 weeks of treatment with magnesium and calcium supplementation plus potassium citrate, the hypomagnesemia and hypocalcemia normalized spontaneously, as did the urinary calcium, magnesium, and citrate excretion. We speculate that our patient had a transient tubular defect in the thick ascending loop of Henle.


Subject(s)
Calcium/metabolism , Kidney Calculi/metabolism , Kidney/metabolism , Magnesium/metabolism , Calcium/therapeutic use , Female , Humans , Hypocalcemia/drug therapy , Hypocalcemia/etiology , Infant, Newborn , Kidney Calculi/complications , Kidney Calculi/diagnostic imaging , Magnesium/therapeutic use , Potassium Citrate/therapeutic use , Remission, Spontaneous , Ultrasonography
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