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Summary: Background: Globally, 85% of acute kidney injury (AKI) cases occur in low-and-middle-income countries. There is limited information on persistent kidney disease (acute kidney disease [AKD]) following severe malaria-associated AKI. Methods: Between March 28, 2014, and April 18, 2017, 598 children with severe malaria and 118 community children were enrolled in a two-site prospective cohort study in Uganda and followed up for 12 months. The Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used to define AKI (primary exposure) and AKD at 1-month follow-up (primary outcome). Plasma neutrophil gelatinase-associated lipocalin (NGAL) was assessed as a structural biomarker of AKI. Findings: The prevalence of AKI was 45·3% with 21·5% of children having unresolved AKI at 24 h. AKI was more common in Eastern Uganda. In-hospital mortality increased across AKI stages from 1·8% in children without AKI to 26·5% with Stage 3 AKI (p

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.

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.

Objective To characterize the clinical course after cutaneous vesicostomy (CV) in megabladder ( mgb −/− ) mice with functional urinary bladder obstruction. Materials and Methods A total of 45 mgb −/− male mice underwent CV at a median age of 25 days. The 34 mice that survived >3 days after CV were evaluated by serial observation and renal ultrasonography. The moribund mice were killed. The urinary bladders and kidneys were analyzed by histopathologic analysis, and urine biochemical studies were performed. Results At a median duration of 11 weeks after CV, 35% of mgb −/− male mice (12 of 34) had become moribund with pelvic masses, which were identified as bladder stones at necropsy. The urine pH was alkaline, and microscopic examination demonstrated struvite crystals. The urine samples contained Gram-positive cocci, and the urine cultures were polymicrobial. The stone composition was chiefly struvite (88%-94%) admixed with calcium phosphate. In 40% of cases (2 of 5), retained intravesical polypropylene suture was identified as the presumed nidus. No stones were detected in >100 male mice before CV or in 25 cases when CV was performed using polydioxanone suture. The kidneys from 33% of the mice (4/12) with bladder stones contained staghorn calculi. The histopathologic findings from the mice with struvite stones demonstrated active cystitis, pyelitis, and chronic pyelonephritis. Conclusion These findings attest to the importance of the nidus in lithogenesis and provide a novel murine model for struvite urolithiasis and chronic infection of the diverted urinary tract.

The mechanisms that maintain sterility in the urinary tract are incompletely understood; however, recent studies stress the importance of antimicrobial peptides in protecting the urinary tract from infection. Ribonuclease 7 (RNase 7), a potent antimicrobial peptide contributing to urinary tract sterility, is expressed by intercalated cells in the renal collecting tubules and is present in the urine at levels sufficient to kill bacteria at baseline. Here, we characterize the expression and function of RNase 7 in the human urinary tract during infection. Both quantitative real-time PCR and enzyme-linked immunosorbant assays demonstrated increases in RNASE7 expression in the kidney along with kidney and urinary RNase 7 peptide concentrations with infection. While immunostaining localized RNase 7 production to the intercalated cells of the collecting tubule during sterility, its expression during pyelonephritis was found to increase throughout the nephron but not in glomeruli or the interstitium. Recombinant RNase 7 exhibited antimicrobial activity against uropathogens at low micromolar concentrations by disrupting the microbial membrane as determined by atomic force microscopy. Thus, RNase 7 expression is increased in the urinary tract with infection and has antibacterial activity against uropathogens at micromolar concentrations.

Congenital obstructive uropathy (COU) is a leading cause of pediatric chronic kidney disease (CKD). Urinary tract infections (UTIs) pose a risk for ascending infections and CKD in patients with COU. We evaluated the impact of comorbid UTIs on hospital charges and length of stay (LOS) for pediatric COU discharges.The study sample (n = 2832) was drawn from the 2003 and 2006 US Healthcare Cost and Utilization Project Kids' Inpatient Database. Data were analyzed using logistic and linear regression.Comorbid UTIs complicated 6.7% of COU discharges, and were most common in patients with posterior urethral valves (15.7% of discharges). Comorbid UTIs increased mean charges by $7910 (95% confidence interval (CI) $4770-$11,040; p 0.001) and prolonged mean LOS by 2.66 days (95% CI 2.03-3.29; p 0.001) compared to COU discharges without UTI. After controlling for LOS, charges for COU with a secondary diagnosis of UTI were no longer significantly higher. Mean charges in inflation-adjusted dollars increased by $2710, a 15.8% increase unexplained by covariate diagnoses and procedures.Comorbid UTIs contribute significantly to inpatient charges for COU, by prolonging LOS.

Although the urinary tract is constantly challenged by microbial invasion, it remains free from colonization. Although little is known about how the urinary tract maintains sterility, the presence of antimicrobial peptides (AMPs) in the urine suggests that they may play a role in its protection from infection. Ribonuclease 7 (RNase 7) is a potent AMP that was first identified in the skin. Here, we characterize the expression and relevance of RNase 7 in the human kidney and urinary tract. Using RNA isolated from healthy human tissue, we performed quantitative real-time PCR and found basal RNASE7 expression in kidney and bladder tissue. Immunohistochemical and immunofluorescent analysis localized RNase 7 to the urothelium of the bladder, ureter, and the intercalated cells of the collecting tubules. In control urine samples from healthy individuals, the concentration of RNase 7 was found to be in the low micromolar range; very abundant for an AMP. Antibacterial neutralization assays showed that urinary RNase 7 has potent antimicrobial properties against Gram-negative and Gram-positive uropathogenic bacteria. Thus, RNase 7 is expressed in the human kidney and urinary tract and it may have an important antimicrobial role in maintaining tract sterility.

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