The Effect of a Short Course of Tocolytic Indomethacin on Urinary Biomarkers in Premature Infants.

OBJECTIVE: The aim of this study was to determine the effects of a 2-day prenatal course of indomethacin on the premature kidney as reflected by serum creatinine and urinary biomarkers. STUDY DESIGN: Urine of infants ≤32 weeks was collected for the first 14 days and analyzed for cystatin C, neutrophil gelatinase-associated lipocalin, osteopontin, ß2 microglobulin, epidermal growth factor, uromodulin, and microalbumin. Bivariate analysis compared serum creatinine and biomarkers of exposed (INDO) and unexposed (CONT) subjects. RESULTS: Fifty-seven infants (35 CONT and 22 INDO) were studied. The cohorts were similar in gestational age, birthweight, race, gender, nephrotoxic medication exposure, and Apgar's scores. CONT had more dopamine exposure and included more pre-eclamptic mothers (p = 0.005). No difference in creatinine-based acute kidney injury or the log transformed mean, maximum, and minimum values of urinary biomarkers was detected. CONCLUSION: Our findings suggest that a short course of tocolytic indomethacin does not result in neonatal acute kidney injury. KEY POINTS: · A short prenatal course of indomethacin does not result in neonatal acute kidney injury (AKI).. · Urinary EGF might have a promising role as a more sensitive biomarker for early detection of AKI in premature infants..

Incidence and Risk Factors of Early Onset Neonatal AKI.

BACKGROUND AND OBJECTIVES: Neonatal AKI is associated with poor short- and long-term outcomes. The objective of this study was to describe the risk factors and outcomes of neonatal AKI in the first postnatal week. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The international retrospective observational cohort study, Assessment of Worldwide AKI Epidemiology in Neonates (AWAKEN), included neonates admitted to a neonatal intensive care unit who received at least 48 hours of intravenous fluids. Early AKI was defined by an increase in serum creatinine >0.3 mg/dl or urine output <1 ml/kg per hour on postnatal days 2-7, the neonatal modification of Kidney Disease: Improving Global Outcomes criteria. We assessed risk factors for AKI and associations of AKI with death and duration of hospitalization. RESULTS: Twenty-one percent (449 of 2110) experienced early AKI. Early AKI was associated with higher risk of death (adjusted odds ratio, 2.8; 95% confidence interval, 1.7 to 4.7) and longer duration of hospitalization (parameter estimate: 7.3 days 95% confidence interval, 4.7 to 10.0), adjusting for neonatal and maternal factors along with medication exposures. Factors associated with a higher risk of AKI included: outborn delivery; resuscitation with epinephrine; admission diagnosis of hyperbilirubinemia, inborn errors of metabolism, or surgical need; frequent kidney function surveillance; and admission to a children's hospital. Those factors that were associated with a lower risk included multiple gestations, cesarean section, and exposures to antimicrobials, methylxanthines, diuretics, and vasopressors. Risk factors varied by gestational age strata. CONCLUSIONS: AKI in the first postnatal week is common and associated with death and longer duration of hospitalization. The AWAKEN study demonstrates a number of specific risk factors that should serve as "red flags" for clinicians at the initiation of the neonatal intensive care unit course.

Late onset neonatal acute kidney injury: results from the AWAKEN Study.

BACKGROUND: Most studies of neonatal acute kidney injury (AKI) have focused on the first week following birth. Here, we determined the outcomes and risk factors for late AKI (>7d). METHODS: The international AWAKEN study examined AKI in neonates admitted to an intensive care unit. Late AKI was defined as occurring >7 days after birth according to the KDIGO criteria. Models were constructed to assess the association between late AKI and death or length of stay. Unadjusted and adjusted odds for late AKI were calculated for each perinatal factor. RESULTS: Late AKI occurred in 202/2152 (9%) of enrolled neonates. After adjustment, infants with late AKI had higher odds of death (aOR:2.1, p = 0.02) and longer length of stay (parameter estimate: 21.9, p < 0.001). Risk factors included intubation, oligo- and polyhydramnios, mild-moderate renal anomalies, admission diagnoses of congenital heart disease, necrotizing enterocolitis, surgical need, exposure to diuretics, vasopressors, and NSAIDs, discharge diagnoses of patent ductus arteriosus, necrotizing enterocolitis, sepsis, and urinary tract infection. CONCLUSIONS: Late AKI is common, independently associated with poor short-term outcomes and associated with unique risk factors. These should guide the development of protocols to screen for AKI and research to improve prevention strategies to mitigate the consequences of late AKI.

Measurement and Estimation of Glomerular Filtration Rate in Children.

Rapid, accurate, and precise measures of kidney function are essential for daily management of patients. While plasma and urinary clearances provide the greatest accuracy for assessing glomerular filtration rate (GFR), these are often impractical particularly for the care of children. Serum creatinine, the most commonly used endogenous marker, is simple, convenient, and practical but less accurate because of the influence of non-GFR determinants such as muscle mass, which increases with age in children. GFR estimating equations have been developed for adults and children to improve the accuracy of endogenous biomarkers, such as creatinine and cystatin C, by accounting for some of the non-GFR determinants, thus enhancing the practitioner's ability to assess GFR. In the steady state, when height is used as a surrogate for growth, there is a strong correlation between height/SCr and GFR. Current national guidelines recommend routine reporting of the estimated GFR alongside the serum creatinine value for adults using the Chronic Kidney Disease Epidemiology Collaboration creatinine-based formula and the updated Schwartz "bedside" formula (CKiD 2009) for children.

Acute Kidney Injury in Premature, Very Low-Birth-Weight Infants.

The epidemiology of neonatal acute kidney injury (AKI) is not well established, partly due to lack of a consensus definition. Preterm neonates are likely especially vulnerable to AKI. We performed a retrospective review to assess the incidence of and risk factors for AKI in very low-birth-weight (VLBW), premature infants admitted to a level 4 NICU (2006-2007). AKI was classified using a standardized definition based on changes in serum creatinine (SCr). AKI incidence varied inversely with gestational age (GA): 65% (22-25 weeks), 25% (26-28 weeks), 9% (29-32 weeks) as did severity (p < 0.001). Stage 1 AKI was most common in each cohort. Stages 2 and 3 AKI comprised approximately 60% of AKI in the 22- to 25-week cohort but 20% or less in the older cohorts. By univariate analysis, factors associated with AKI included younger GA, lower BW, lower Apgar scores, hypotension, more frequent treatment with nephrotoxic antimicrobials, longer-duration mechanical ventilation, and higher incidence of patent ductus arteriosus (PDA) requiring treatment. By multiple logistic regression analysis, only GA, hypotension, PDA, and longer duration of mechanical ventilation were independently associated with AKI. AKI was not independently associated with risk of death. Our study suggests that small increases (≥ 0.3 mg/dL) in SCr occur frequently in premature, VLBW infants, and are associated with increased morbidity but not mortality. AKI incidence and severity were highest in the youngest GA cohort. Understanding the epidemiology, risk factors, and impact of neonatal AKI is crucial as long-term premature infant survival continues to improve.

C1q nephropathy in association with Gitelman syndrome: a case report.

There have been rare reports of glomerulopathies developing in patients with Bartter syndrome (BS) and its milder variant, Gitelman syndrome (GS). We present the first case of C1q nephropathy (C1qN) in an African American child with GS. This child was diagnosed with GS at 9 years of age and subsequently developed nephrotic range proteinuria 3 years later. Renal biopsy revealed mesangial hypercellularity and focal segmental glomerulosclerosis (FSGS). The segmental lesions were generally located at the vascular pole. Dominant C1q (2+) staining along with IgG (1-2+) was demonstrated in the mesangium, which correlated with scattered electron dense mesangial deposits demonstrated by electron microscopy. Treatment with an angiotensin-converting enzyme inhibitor led to an improvement in proteinuria to near-normal values (urine protein/creatinine ratio down to 0.5), but the creatinine clearance declined to approximately 58 ml/min/1.73 m(2). This case highlights the possible association between the milder hypokalemic tubulopathy, GS, and glomerular disease, including C1qN. Prompt evaluation of proteinuria with renal biopsy in these patients is recommended to detect significant glomerular pathology. Further research is needed to define risk factors for this complication.

Mycoplasma hominis septic arthritis in a pediatric renal transplant recipient: case report and review of the literature.

Septic arthritis (SA) typically occurs in young children, often from Staphylococcus. With chronic immunosuppression, however, pathogens may be atypical. A 15-year-old African-American female developed Mycoplasma hominis SA in her right hip 2 months following cadaveric renal transplant (Tx). Her presentation was subtle and indolent, without fever or leukocytosis. Although reported in adult Tx recipients, M. hominis infections have not been described in pediatric recipients. Early immunosuppression (basiliximab, prednisone, tacrolimus, mycophenolate mofetil and Thymoglobulin) may have increased her susceptibility to M. hominis. Optimal therapy for M. hominis SA is not well established and relapses occur. This patient underwent joint incision and drainage, treatment for 8 weeks with doxycycline and levofloxacin guided by in vitro sensitivities, and a reduction in immunosuppression. She has been free of ongoing infection for 3 years with stable graft function (Cr 1.1 mg/dL) on moderate immunosuppression with prednisone, tacrolimus and MMF.

Histological patterns of polyomavirus nephropathy: correlation with graft outcome and viral load.

Polyomavirus-associated nephropathy (PVAN) is a significant cause of allograft loss. The diagnosis requires allograft biopsy, but the impact of the histological features on diagnosis and outcome has not been described. We studied the distribution and extent of PVAN in 90 patients. Viral cytopathic changes, tubular atrophy/fibrosis and inflammation were semi-quantitatively scored and classified into histological patterns. The histological findings were correlated with viruria, viremia and graft survival. PVAN lesions were random, (multi-)focal and affected both cortex and medulla. Areas with PVAN coexisted with areas of unaffected parenchyma. In 36.5% (15/41) of biopsies with multiple tissue cores, discordant findings with PVAN-positive and -negative cores were observed. However, all patients with PVAN had decoy cells in urine as well as significant viruria and viremia (mean of 2.5 x 10(8) and 2.32 x 10(7) viral copies, respectively). Biopsies showing lesser degrees of renal scarring at the time of diagnosis were associated with, more likely, resolution of the infection, in response to decrease of immunosuppression (p = 0.001). More advanced tubulointerstitial atrophy, active inflammation and higher creatinine level at diagnosis correlated with worse graft outcome (p = 0.0002, 0.0001 and 0.0006). Due to the focal nature of PVAN, correlation of biopsy results with viruria and viremia are required for diagnosis.

Acid incubation reverses the polarity of intercalated cell transporters, an effect mediated by hensin.

Metabolic acidosis causes a reversal of polarity of HCO(3)(-) flux in the cortical collecting duct (CCD). In CCDs incubated in vitro in acid media, beta-intercalated (HCO(3)(-)-secreting) cells are remodeled to functionally resemble alpha-intercalated (H(+)-secreting) cells. A similar remodeling of beta-intercalated cells, in which the polarity of H(+) pumps and Cl(-)/HCO(3)(-) exchangers is reversed, occurs in cell culture and requires the deposition of polymerized hensin in the ECM. CCDs maintained 3 h at low pH ex vivo display a reversal of HCO(3)(-) flux that is quantitatively similar to an effect previously observed in acid-treated rabbits in vivo. We followed intracellular pH in the same beta-intercalated cells before and after acid incubation and found that apical Cl/HCO(3) exchange was abolished following acid incubation. Some cells also developed basolateral Cl(-)/HCO(3)(-) exchange, indicating a reversal of intercalated cell polarity. This adaptation required intact microtubules and microfilaments, as well as new protein synthesis, and was associated with decreased size of the apical surface of beta-intercalated cells. Addition of anti-hensin antibodies prevented the acid-induced changes in apical and basolateral Cl(-)/HCO(3)(-) exchange observed in the same cells and the corresponding suppression of HCO(3)(-) secretion. Acid loading also promoted hensin deposition in the ECM underneath adapting beta-intercalated cells. Hence, the adaptive conversion of beta-intercalated cells to alpha-intercalated cells during acid incubation depends upon ECM-associated hensin.