Search

Urinary stone disease (USD) is affecting a greater number of children and low bone mineral density (BMD) and increased skeletal fractures have been demonstrated in stone patients; however, the mechanism(s) driving bone disease remain unclear. This pilot study was undertaken to assess an adolescent kidney stone cohort’s BMD and evaluate for an inverse correlation between BMD and urine concentration of lithogenic minerals and/or inflammatory levels. Prospective case–control study was carried out at a large pediatric center. 15 participants with USD (12–18 years of age, 8 female) were matched by age, sex, and body mass index to 15 controls. Lumbar and total body BMD z-score did not differ between groups. When stone formers were separated by sex, there was a significant difference between male stone formers vs. controls total body BMD z-score (Fig. 1). BMD z-score did not significantly correlate with urine calcium, oxalate, citrate or magnesium. Higher urine IL-13 did significantly correlate with higher total body BMD z-score (r = 0.677, p = 0.018). Total body BMD z-score did significantly correlate with body mass index (BMI) as expected for the control group (r = 0.6321, p = 0.0133). However, this relationship was not present in the USD group (r = − 0.1629, p = 0.5619). This is a small but hypothesis-generating study which demonstrates novel evidence of male-specific low BMD in adolescent stone formers. Furthermore, we demonstrated a positive association between urine IL-13 and total body BMD z-score USD patients as well as a lack of a positive BMD and BMI correlations in stone formers.

The incidence of nephrolithiasis continues to rise. Previously, we showed that a monogenic cause could be detected in 11.4% of individuals with adult-onset nephrolithiasis or nephrocalcinosis and in 16.7-20.8% of individuals with onset before 18 years of age, using gene panel sequencing of 30 genes known to cause nephrolithiasis/nephrocalcinosis. To overcome the limitations of panel sequencing, we utilized whole exome sequencing in 51 families, who presented before age 25 years with at least one renal stone or with a renal ultrasound finding of nephrocalcinosis to identify the underlying molecular genetic cause of disease. In 15 of 51 families, we detected a monogenic causative mutation by whole exome sequencing. A mutation in seven recessive genes ( AGXT, ATP6V1B1, CLDN16, CLDN19, GRHPR, SLC3A1, SLC12A1 ), in one dominant gene ( SLC9A3R1 ), and in one gene ( SLC34A1 ) with both recessive and dominant inheritance was detected. Seven of the 19 different mutations were not previously described as disease-causing. In one family, a causative mutation in one of 117 genes that may represent phenocopies of nephrolithiasis-causing genes was detected. In nine of 15 families, the genetic diagnosis may have specific implications for stone management and prevention. Several factors that correlated with the higher detection rate in our cohort were younger age at onset of nephrolithiasis/nephrocalcinosis, presence of multiple affected members in a family, and presence of consanguinity. Thus, we established whole exome sequencing as an efficient approach toward a molecular genetic diagnosis in individuals with nephrolithiasis/nephrocalcinosis who manifest before age 25 years.

Kidney stones are increasing in the pediatric and adult populations; similarly osteoporosis is increasingly recognized in children. While kidney stone formers are known to suffer from low bone density, metabolic bone patients have not been considered a high risk population for kidney stones. Retrospective chart review of Nationwide Children’s Hospital Metabolic Bone Clinic patients from October 2009–2013. Patients were identified by ICD 9 codes for osteoporosis, osteopenia, low bone density and kidney stones. Only patients with radiologic evidence of both diseases were included.Twenty-six of 889 patients met criteria; this is equivalent to an incidence of 30 per 100,000 patients. Osteoporosis was the most frequent bone diagnosis. Males were the majority (68%). Most common secondary diagnoses: seizure (52%) and cerebral palsy (44%). Treatment: calcium (48%), vitamin D (40%), bisphosphonates (48%). The majority (75%) were non-ambulatory. Most frequent lithogenic medications: Topiramate (42%) and corticosteroids (27%). This is one of the first studies to consider metabolic bone patients as high risk for urinary stone disease. We found a higher rate of kidney stones in pediatric metabolic bone patients compared to data available for the general pediatric kidney stone population. The most common risk factor for bone and stone disease was nonambulatory status. Males were more frequently affected than females; this is the reverse of general adolescent kidney stone population. The predominance of cerebral palsy and seizure patients can be attributed to their frequency of non-ambulatory status and lithogenic medications such as Topiramate.

ObjectiveCurrent urinary tract infection (UTI) diagnostic strategies that rely on leukocyte esterase have limited accuracy. We performed an aptamer-based proteomics pilot study to identify urine protein levels that could differentiate a culture proven UTI from culture negative samples, regardless of pyuria status.MethodsWe analyzed urine from 16 children with UTIs, 8 children with culture negative pyuria and 8 children with negative urine culture and no pyuria. The urine levels of 1,310 proteins were quantified using the Somascan™ platform and normalized to urine creatinine. Machine learning with support vector machine (SVM)-based feature selection was performed to determine the combination of urine biomarkers that optimized diagnostic accuracy.ResultsEight candidate urine protein biomarkers met filtering criteria. B-cell lymphoma protein, C-X-C motif chemokine 6, C-X-C motif chemokine 13, cathepsin S, heat shock 70kDA protein 1A, mitogen activated protein kinase, protein E7 HPV18 and transgelin. AUCs ranged from 0.91 to 0.95. The best prediction was achieved by the SVMs with radial basis function kernel.ConclusionsBiomarkers panel can be identified by the emerging technologies of aptamer-based proteomics and machine learning that offer the potential to increase UTI diagnostic accuracy, thereby limiting unneeded antibiotics.

This case series describes subclinical development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in some patients and health care workers in a pediatric dialysis unit after contact with a seropositive patient.

BACKGROUND: Urinary stone are increasing in children, primarily during adolescence. Although urinary stones are often viewed in the context of intermittent stone events, increasing evidence indicates that stones are a metabolic process associated with chronic kidney disease and low bone mass. These aforementioned stone associated conditions may have pediatric origins. OBJECTIVE: To compare urine inflammatory markers in otherwise healthy stone forming children versus matched controls. METHODS: Urine samples were collected from 12 adolescents with urinary stones along with 15 controls. The levels of 30 urine cytokines were measured using a Mesoscale 30-Plex Human Cytokine panel and normalized to urine creatinine levels. RESULTS: Macrophage inflammatory protein 1β and Interleukin 13 levels were significantly elevated in the urine of the stone forming adolescents compared to controls. Interleukin 17A was elevated in the urine of controls. CONCLUSIONS: This study indicates that urine levels of cytokines involved in chronic inflammation and fibrosis are elevated urinary stone formers as early as adolescence. Because stone formers are at risk for chronic kidney disease, Macrophage inflammatory protein 1β and Interleukin 13 represent investigative targets.

OBJECTIVES The aim of this study was to examine computed tomography (CT) and ultrasound (US) utilization trends in incident and prevalent pediatric emergency department (ED) urolithiasis patients before and after imaging guideline release. METHODS We reviewed imaging modalities for children with 2 or more ED encounters between January 1, 2006, and September 1, 2013, for urolithiasis using the Pediatric Health Information System database. Z scores compared the proportion of patient encounters receiving CT and US before (January 1, 2006, to December 31, 2010) and after (January 1, 2011, to September 1, 2013) the release of imaging guidelines. McNemar test for paired proportions compared the percentage of US and CT use between initial versus subsequent visits. Piecewise logistic regression was used to determine the probability of US use and CT use over time before and after the implementation of imaging guidance. RESULTS Analysis was completed on 2041 patients with 4930 unique encounters for urolithiasis. During 1758 encounters (35.7%), CT was performed initially. Ultrasound was performed 1585 times (32.2%). Fourteen percent fewer CT procedures were performed during first urolithiasis visits after guideline release (P < 0.01), whereas US use increased by 15% (P < 0.01). Fewer CT procedures were performed at later visits compared with the first (P < 0.05), and US was used more during second or later visits than the first (P < 0.05). CONCLUSIONS Medical providers at large academic pediatric EDs have decreased use of CT and increased use of US over the study time frame to diagnose urolithiasis and are now similar during initial visits (US 36.4% vs CT 36.2%, P = 0.94). Physicians are still more likely to use US as the initial urolithiasis imaging modality during second and later encounters.

Recent studies stress the importance of antimicrobial peptides in protecting the urinary tract from infection. Previously, we have shown that ribonuclease 7 (RNase 7) is a potent antimicrobial peptide that has a broad-spectrum antimicrobial activity against uropathogenic bacteria. The urothelium of the lower urinary tract and intercalated cells of the kidney produce RNase 7, but regulation of its antimicrobial activity has not been well defined. Here, we characterize the expression of an endogenous inhibitor, ribonuclease inhibitor (RI), in the urinary tract and evaluate its effect on the antimicrobial activity of RNase 7. Using RNA isolated from non-infected human bladder and kidney tissue, quantitative real-time polymerase chain reaction showed that RNH1, the gene encoding RI, is constitutively expressed throughout the urinary tract. With pyelonephritis, RNH1 expression and RI peptide production significantly decrease. Immunostaining localized RI production to the umbrella cells of the bladder and intercalated cells of the renal collecting tubule. In vitro assays showed that RI bound to RNase 7 and suppressed its antimicrobial activity by blocking its ability to bind the cell wall of uropathogenic bacteria. Thus, these results demonstrate a new immunomodulatory role for RI and identified a unique regulatory pathway that may affect how RNase 7 maintains urinary tract sterility.

Diabetes mellitus is a systemic disease associated with a deficiency of insulin production or action. Diabetic patients have an increased susceptibility to infection with the urinary tract being the most common site of infection. Recent studies suggest that Ribonuclease 7 (RNase 7) is a potent antimicrobial peptide that plays an important role in protecting the urinary tract from bacterial insult. The impact of diabetes on RNase 7 expression and function are unknown. Here, we investigate the effects of insulin on RNase 7. Using human urine specimens, we measured urinary RNase 7 concentrations in healthy control patients and insulin-deficient type 1 diabetics before and after starting insulin therapy. Compared to controls, diabetic patients had suppressed urinary RNase 7 concentrations, which increased with insulin. Using primary human urothelial cells, we explored the mechanisms by which insulin induces RNase 7. Insulin induces RNase 7 production via the phosphatidylinositide 3-kinase signaling pathway (PI3K/AKT) to shield urothelial cells from uropathogenic E. coli. In contrast, we show that uropathogenic E. coli suppresses PI3K/AKT and RNase 7. Together, these results indicate that insulin and PI3K/AKT signaling are essential for RNase 7 expression. They also suggest that increased infection risks in diabetic patients may be secondary to suppressed RNase 7 production. These data may provide unique insight into novel UTI therapeutic strategies in at risk populations.

Calcium nephrolithiasis in children is increasing in prevalence and tends to be recurrent. Although children have a lower incidence of nephrolithiasis than adults, its etiology in children is less well understood; hence treatments targeted for adults may not be optimal in children. To better understand metabolic abnormalities in stone forming children, we compared chemical measurements and the crystallization properties of 24-hour urine collections from 129 stone formers matched to 105 non-stone forming siblings and 183 normal, healthy children with no family history of stones; all aged 6 to 17 years. The principal risk factor for calcium stone formation was hypercalciuria. Stone formers have strikingly higher calcium excretion along with high supersaturation for calcium oxalate and calcium phosphate, and a reduced distance between the upper limit of metastability and supersaturation for calcium phosphate, indicating increased risk of calcium phosphate crystallization. Other differences in urine chemistry that exist between adult stone formers and normal individuals such as hyperoxaluria, hypocitraturia, abnormal urine pH and low urine volume were not found in these children. Hence, hypercalciuria and a reduction in the gap between calcium phosphate upper limit of metastability and supersaturation are crucial determinants of stone risk. This highlights the importance of managing hypercalciuria in children with calcium stones.

In the last 10 years, the incidence of kidney stones has increased in the pediatric population, and this rise has been paralleled by a significant increase in pediatric obesity rates in the USA. The purpose of this study was to evaluate percentage body fat (%BF) measured by dual energy X-ray absorptiometry (DXA) in hypercalciuric children with and without kidney stones. A retrospective chart review was performed on children with idiopathic hypercalciuria based on a 24-h urine calcium excretion of4 mg/kg/day or200 mg/day who had undergone DXA scanning. Patients were then classified by sex and by %BF (3 categories; normal:27% girls,21% boys; at risk for obesity: 27-36% girls, 21-30% boys; obese:36% girls,30% boys). The 2003-2004 NHANES data were used as a control. Fifty patients (24 males) were analyzed, of whom 26% were assessed as having a normal %BF, 44% as being at risk for obesity, and 30% as being obese. Children with an increased %BF had a significantly higher occurrence of kidney stones (p = 0.03) than those with a normal %BF. No significant differences were noted in 24-h urine chemistries between the groups. In conclusion, an increased %BF was associated with an increased occurrence of kidney stones in children with idiopathic hypercalciuria.

This study evaluates the impact of pediatric uninary tract infection (UTI)s on the economy and inpatient healthcare utilization in the USA. A retrospective analysis of patient demographics and hospital economics was performed on children less than 18 years of age admitted with a UTI between 2000 and 2006 using the Healthcare Cost and Utilization Project Kids’ Inpatient Database. Our results were stratified as follows. Hospital admissions—nearly 50,000 children/year were admitted with a UTI. Pediatric UTIs represented 1.8% of all pediatric hospitalizations. Seventy-three percent of patients were female and 40% were under 1 year of age. Payer information—from 2000 to 2006, pediatric insurance coverage shifted from the private sector to the public sector. Hospital cost—in 2000, estimated hospital costs for UTIs were $2,858 per hospitalization and rose to $3,838 by 2006. Mean hospital charges increased from $6,279 to $10,489 per stay. By 2006, aggregate hospital charges exceeded $520 million. Our results indicate that UTIs are among the most common pediatric admission diagnoses. Hospitalization is more common in females and younger children. Since 2000, hospital charges for UTIs increased disproportionately to hospital costs. Over time, more children hospitalized with a UTI depend on public agencies to cover healthcare expense. More efforts are needed to evaluate cost-effective strategies for evaluation and treatment of UTIs.

Summary Purpose The metabolic evaluation of children with nephrolithiasis begins with a 24-h urine collection. For adults, the diagnostic yield increases with consecutive collections; however, little is known regarding the variability of multiple 24-h studies in the pediatric population. We sought to evaluate the variability of consecutive 24-h urine collection in children through a multi-institutional study hypothesizing that compared with a single collection, consecutive 24-h urine collections would reveal a greater degree of clinically useful information in the evaluation of children at risk for nephrolithiasis. Materials and methods Including data from six institutions, we identified children less than 18 years of age considered at risk for recurrent nephrolithiasis, undergoing metabolic evaluation. We evaluated a subset of patients performing two collections with urine creatinine varying by 10% or less during a 7-day period. Discordance between repeat collections based on normative urine chemistry values was evaluated. Results A total of 733 children met inclusion criteria, and in over a third both urine calcium and urine volume differed by 30% or more between samples. Urine oxalate demonstrated greater variation between collections in children p = 0.030) while variation in other parameters did not differ by age. Discordance between repeat samples based on normative values was most common for urine oxalate (22.5%) and the derived relative supersaturation ratios for both calcium phosphate (25.1%) and calcium oxalate (20.5%). The proportion of discordant samples, based on normative thresholds, as well as variability greater ≥30% and 50%, respectively, are shown in the table. Conclusions Our analysis indicates that stone risk in as many as one in four children may be misclassified if normative values of only a single 24-h urine are used. In light of these findings, repeat 24-h urine collections prior to targeted intervention to modify stone risk are advised to increase diagnostic yield in children at risk for nephrolithiasis. Table . Percent variability and discordant samples (based on normative thresholds) for urinary parameters in consecutive 24-h urine studies in children. Parameter Percent variability Discordant samples ≥30% ≥50% Calcium ( N , %) 219 (34.2) 102 (15.9) 88 (13.1) Oxalate ( N , %) 94 (23.3) 28 (6.9) 104 (22.5) Citrate ( N , %) 92 (16.6) 22 (4.0) 42 (8.2) SS CaOx ( N , %) N/A N/A 138 (20.5) SS CaPhos ( N , %) N/A N/A 169 (25.1) Volume 269 (36.8) 89 (12.2) N/A

Background The role of calcium oxalate crystals and deposits in UTI pathogenesis has not been established. The objectives of this study were to identify bacteria present in pediatric urolithiasis and, using in vitro and in vivo models, to determine the relevance of calcium oxalate deposits during experimental pyelonephritis. Methods Pediatric kidney stones and urine were collected and both cultured and sequenced for bacteria. Bacterial adhesion to calcium oxalate was compared. Murine kidney calcium oxalate deposits were induced by intraperitoneal glyoxalate injection and kidneys were transurethrally inoculated with uropathogenic Escherichia coli to induce pyelonephritis Results E. coli of the family Enterobacteriaceae was identified in patients by calcium oxalate stone culture. Additionally Enterobacteriaceae DNA was sequenced from multiple calcium oxalate kidney stones. E. coli selectively aggregated on and around calcium oxalate monohydrate crystals. Mice inoculated with glyoxalate and uropathogenic E. coli had higher bacterial burdens, increased kidney calcium oxalate deposits and an increased kidney innate immune response compared to mice with only calcium oxalate deposits or only pyelonephritis. Conclusions In a murine model, the presence of calcium oxalate deposits increases pyelonephritis risk, likely due to preferential aggregation of bacteria on and around calcium oxalate crystals. When both calcium oxalate deposits and uropathogenic bacteria were present, calcium oxalate deposit number increased along with renal gene transcription of inner stone core matrix proteins increased. Therefore renal calcium oxalate deposits may be a modifiable risk factor for infections of the kidney and urinary tract. Furthermore, bacteria may be present in calcium oxalate deposits and potentially contribute to calcium oxalate renal disease.

The goal of this study was to examine national trends in hospitalization, emergency department (ED) utilization, secondary diagnoses, and charges associated with pediatric urolithiasis. Data were evaluated from the Kids’ Inpatient Database of the Healthcare Costs and Utilization Project (HCUP) database from 1997 to 2012 and the HCUP National ED Sample from 2006 to 2011. Pediatric nephrolithiasis discharges increased by 18 %, while ureterolithiasis discharges decreased by 17 %. Hospital charges increased by 20 % when accounting for inflation, despite an overall decrease in discharges by 2.5 %. Female patients and those aged 15–17 years were more commonly affected. Pediatric ED visits increased by 9 %. The most common secondary diagnoses during 2003–2009 were urinary tract infections (UTI) (13 %), asthma (9 %), epilepsy (4 %), and paralysis (4 %). Decreased hospitalizations and increased ED visits indicate a shift to outpatient care. Inpatient health care charges associated with pediatric urolithiasis continue to rise. Comorbidities include UTI, asthma, epilepsy, attention deficit hyperactivity disorder (ADHD), and mood disorders. Because of the significant health care burden and the increased risk to children of developing long-term sequelae there is a strong need for increased research into the mechanism of this systemic inflammatory disease and improved therapeutic targets.

Prior cross-sectional studies have demonstrated an association between hypercalciuria and low bone mineral density (BMD) in children and adults. However, the natural history of BMD in children with hypercalciuria and its response to therapy has not been evaluated. The objective of this retrospective study was to determine the change over time in lumbar (L1 - L4) BMD Z-score measured on sequential DXA scans in 19 children with hypercalciuria treated with dietary recommendations without (n = 12, Group A) and with citrate (n = 7, Group B). The mean lumbar bone density Z-score/year decreased in Group A (-0.11 ±/0.41) indicating that children with hypercalciuria lose L1 - L4 BMD over time. In contrast, the L1 - L4 BMD Zscore/ year increased in Group B (0.19 ± 0.38) suggesting that pharmacologic therapy may reverse this trend. Similarly 75% of patients in Group A, but only 29% patients in Group B had a decrease in L1 - L4 BMD. There was a definite, although not significant, trend towards improved mean bone mineral density Z-score per year and a lower percentage of patients with a decreased Z-score in hypercalciuric children treated with potassium citrate. Our findings suggest the possibility that dietary recommendations alone is not adequate as the bone mineral density of children with hypercalciuria will decrease over time, potentially increasing the risk for osteoporosis as an adult.

Background. Hyperkalemia, due to its effect on cardiac conductivity, is a potentially life-threatening electrolyte abnormality. Multiple therapeutic agents may be used alone or in combination for its prompt management. Methods. We report on the safety and efficacy of continuous infusion of a solution containing fixed concentrations of calcium gluconate, insulin, dextrose and sodium acetate (HyperK-Cocktail) for the treatment of hyperkalemia. This solution is prepared at our institution and is infused parenterally until the plasma potassium level stabilizes. Twentyone consecutive hyperkalemic patients managed with HyperK-Cocktail on 23 occasions are reported. Results. None of the subjects had intravenous extravasation injuries, hypernatremia, hypocalcemia, hypercalcemia or alkalosis during HyperK-Cocktail infusion. Transient hyperglycemia developed in nine subjects and hypoglycemia in one subject. The decrease in serum potassium was similar in the initial hour when compared to prior studies using a beta-agonist and/or insulin and glucose; a larger decrease was present from 2 to 8 h with the HyperKCocktail. The plasma potassium decreased by a mean of 1.0, 1.7, 2.1 and 2.1 mmol/L at 1, 2, 4 and 8 h, respectively. The mean serum potassium at hours 1–8 was significantly lower than the initial level. Conclusion. The results of our study demonstrated that HyperK-Cocktail is a safe and effective combination therapy for children with hyperkalemia.

This study evaluates the impact of vesicoureteral reflux (VUR) on the economy and inpatient healthcare utilization in the USA. A retrospective analysis was performed on children ≤ 18 years of age, hospitalized with the principal discharge diagnosis of VUR between 2000 and 2006, using the Healthcare Cost and Utilization Project Kids' Inpatient Database. The results are stratified as follows. First, by hospitalizations: between 2000 and 2006, 6,655 ± 720 (standard error) children/year were hospitalized with VUR. Since 2003, both the length of each hospitalization and the number of hospitalizations have decreased. Second, by related procedures/diagnoses: ureteral reimplantation was the most common procedure, accounting for 89% of hospitalizations. Congenital genitourinary anomalies, disorders of the kidney/ureter/bladder, and urinary tract infections (UTI) were the most common related diagnoses. Thirdly, by hospital economics: since 2000, hospital charges for VUR increased despite decreased lengths of hospitalization. By 2006, hospital charges rose to $18,798/hospitalization, and aggregate national charges exceeded $100 million. Our results indicate that fewer children with VUR are requiring inpatient management. Children with VUR are often hospitalized for ureteral reimplantation or the management of related diagnoses. Since 2000, hospital charges for inpatient VUR management have increased. More efforts are needed to evaluate cost-effective strategies for the evaluation and management of VUR.

A novel COL4A5 mutation causes rapid progression to end-stage renal disease in males, despite the absence of clinical and biopsy findings associated with Alport syndrome. Affected males have proteinuria, variable hematuria, and an early progression to end-stage renal disease. Renal biopsy findings include global and segmental glomerulosclerosis, mesangial hypercellularity and basement membrane immune complex deposition. Exon sequencing of the COL4A5 locus identified a thymine to guanine transversion at nucleotide 665, resulting in a phenylalanine to cysteine missense mutation at codon 222. The phenylalanine at position 222 is absolutely conserved among vertebrates. This mutation was confirmed in 4 affected males and 4 female obligate carriers, but was absent in 6 asymptomatic male family members and 198 unrelated individuals. Immunostaining for α5(IV) collagen in renal biopsies from affected males was normal. This mutation, in a non-collagenous interruption associated with severe renal disease, provides evidence for the importance of this structural motif and suggests the range of phenotypes associated with COL4A5 mutations is more diverse than previously realized. Hence, COL4A5 mutation analysis should be considered when glomerulonephritis presents in an X-linked inheritance pattern, even with a presentation distinct from Alport syndrome.

We describe two brothers with severe combined immunodeficiency, who presented with systemic granulomatous disease, with granulomatous interstitial nephritis as the main feature, several years following bone marrow transplantation. Neither brother had an apparent drug-induced, infectious disease or autoimmune source for the granulomatous interstitial nephritis. Both patients’ renal function improved following treatment with corticosteroids. This report implicates granulomatous interstitial nephritis as a complication of bone marrow transplantation for severe combined immunodeficiency.