Pediatric Patients with Chronic Kidney Disease-Mineral Bone Disorder

Chronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism that has deleterious consequences on skeletal and cardiovascular health. Nowhere is the morbidity of this disorder more telling than in children. During childhood and adolescence, CKD-MBD may result in poor growth and skeletal deformities, while the mineral dysregulation can manifest in cardiovascular disease in early adulthood, a development that places the patients at high risk for severe morbidity and early mortality. Unfortunately, management of CKD-MBD has been less than satisfactory in children despite recent advances and is limited by the lack of evidence-based treatment guidelines. More positive are ongoing research efforts, such as the Chronic Kidney Disease in Children and the Cardiovascular Comorbidity in Children with CKD (4C) studies that are currently providing important insights which should help better elucidate the pathogenesis and progression of mineral dysregulation and its clinical impact in children. Data from these studies and others will undoubtedly also help formulate clinical trials and the generation of evidence-based therapeutic options designed to provide more effective management of CKD-MBD in the pediatric population.     

A program of cell death and extracellular matrix degradation is activated in the amnion before the onset of labor.

Fetal membranes usually rupture during the process of labor. Premature fetal membrane rupture occurs not infrequently and is associated with significant fetal and maternal morbidity. The mechanisms of normal and pathologic fetal membrane rupture are not well understood. We have examined structural and biochemical changes in the rat amnion as labor approaches in order to characterize this process in normal pregnancy. Here we report that before the onset of active labor the amnion epithelial cells undergo apoptotic cell death which encompasses degradation of 28S ribosomal subunit RNA and associated P proteins and fragmentation of nuclear DNA. Concurrent with these cellular changes, the amnion type I collagen matrix is degraded with the accumulation of three-quarter length type I collagen fragments in extraembryonic fluid, characteristic of the cleavage of fibrillar collagen by interstitial collagenase. Western blot and immunohistochemical analyses confirmed that interstitial collagenase protein appears in association with the loss of amnion type I collagen. We conclude that amnion epithelial cells undergo a process of programmed cell death associated with orchestrated extracellular matrix degradation which begins before the onset of active labor. Thus, fetal membrane rupture is likely to be the result of biochemical changes as well as physical forces.     

Time-varying coefficient of determination to quantify the explanatory power of biomarkers on longitudinal GFR among children with chronic kidney disease

Purpose

Coefficients of determination (R²) for continuous longitudinal data are typically reported as time constant, if they are reported at all. The widely used mixed model with random intercepts and slopes yields the total outcome variance as a time-varying function. We propose a generalized and intuitive approach based on this variance function to estimate the time-varying predictive power (R²) of a variable on outcome levels and changes.

Nonlinear Trajectory of GFR in Children before RRT

GFR decline in patients with CKD has been widely approximated using linear models, but this linearity assumption is not well validated. We conducted a matched case-control study in children from the Chronic Kidney Disease in Children (CKiD) cohort ages 1–16 years with mild to moderate CKD to assess whether GFR decline follows a nonlinear trajectory as CKD approaches ESRD. Children (n=125) who initiated RRT (cases) during follow-up were individually matched by CKD stage at baseline and glomerular/nonglomerular diagnosis with children (n=125) who remained RRT-free when the corresponding case initiated RRT (controls). GFR trajectories were compared using log-linear and piecewise log-linear mixed effects models adjusted for baseline characteristics. From study entry to 18 months before RRT, GFR declined 7% faster among cases compared with controls. However, GFR declined 26% faster among cases compared with controls (P<0.001) during the 18 months before RRT. Nonlinearity in the rate of kidney function loss, which was shown in this cohort, may preclude accurate clinical prediction of the timing of RRT and adequate patient preparation. This study should prompt the characterization of predictive factors that may contribute to an acceleration of kidney function decline.GFR is a key measurement of kidney function, and the degree of GFR decline over time is a reflection of the severity of CKD progression. GFR decline has been approximated as linear or log-linear in most analyses of progression, an assumption that has been consistent with available data.^1–4 However, many studies rely on relatively short follow-up periods and few repeated measures. Given the convenience of assuming a linear GFR trajectory, which results from the ease of modeling and interpreting linear slopes, few studies have sought to validate the linearity assumption and explore the possibility of nonlinear GFR decline. However, nonlinearity in GFR decline has been observed in some epidemiologic studies,^5–7 and the implications on the risk for adverse outcomes have generated interest.⁸ A CKD cohort study in France found that about one half of its patients experienced nonlinear GFR decline during the last year before dialysis.⁵ A study by Li et al.⁹ used a flexible approach to model nonlinearity in GFR trajectories. Li et al.⁹ found evidence of nonlinear GFR trajectory behavior in adult patients with CKD, and furthermore, the probability of having nonlinear features in an individual trajectory was associated with known risk factors for CKD progression. O’Hare et al.¹⁰ found several distinct nonlinear patterns of GFR decline in the 2 years before dialysis initiation in Veterans Affairs patients.Clinical strategies and subsequent patient response to care could potentially benefit from new insights into the variable paths of progression in patients with CKD.^10,11 The question of whether characterizing the nonlinearity in the GFR trajectory can assist the identification of risk groups for outcomes, such as ESRD, remains unexplored. The implications on future outcomes of an increased rate of GFR decline could inform clinical decisions about screening frequencies, treatment, or preparation for RRT.The Chronic Kidney Disease in Children (CKiD) study is an ongoing cohort study of children with CKD who, at baseline, had an eGFR between 30 and 90 ml/min per 1.73 m³ and were ages 1–16 years. An end point of the study is RRT defined as transplant or dialysis. To determine whether trajectories of GFR accelerate before RRT, we nested a case-control study, in which cases were children observed to have received RRT and controls were children with CKD who remained RRT-free at the time when the corresponding case initiated RRT.There were 147 children who experienced RRT during follow-up. Each case was matched individually to an eligible control at the time of the case occurrence. The matching factors included baseline CKD stage, glomerular/nonglomerular diagnosis, and, through design, the amount of follow-up time from study entry. Matching was done without replacement, and 22 cases were excluded from the analyses, because no appropriate control was available. We used a random sequence to determine the order of matching. The analysis was, thus, based on 125 matched case-control pairs. Demographic and clinical characteristics of cases and controls at baseline are shown in

Donor Hemosiderosis Does Not Affect Liver Function and Regeneration in the Setting of Living Donor Liver Transplantation

Living donor liver transplantation (LDLT) demands a careful assessment of abnormal findings discovered during the evaluation process to determine if there will be any potential risks to the donor or recipient. Varying degrees of elevated hepatic iron levels are not uncommonly seen in otherwise healthy individuals. We questioned whether mild expression of hemosiderin deposition presents a safety concern when considering outcomes of living donation for both the donor and the recipient. We report on three LDLT patients who were found to have low‐ to moderate‐grade hemosiderin deposition on liver biopsy. All other aspects of their evaluation proved satisfactory, and the decision was made to proceed with donation. There were no significant complications in the donors, and all demonstrated complete normalization of liver function postoperatively, with appropriate parenchymal regeneration. The recipients also had unremarkable postoperative recovery. We conclude that these individuals can be considered as potential donors after careful evaluation.     

Effect of cloxacillin prophylaxis on the bacterial flora of craniotomy wounds

During a double-blind placebo-controlled study, the effect of cloxacillin prophylaxis in craniotomies on samples taken for culture from 334 operation wounds in 279 patients was assessed. Patients and operations were equally divided over the cloxacillin and placebo groups. In the cloxacillin group significantly fewer samples contained microorganisms than was the case in the placebo group both just after the incision was made (p less than 0.05) and just before closure of the wound (p less than 0.001). The contaminating bacteria found most frequently were Propionibacterium acnes and Staphylococcus epidermidis. For material collected immediately after the incision, the percentage of cultures positive for S. epidermidis was significantly (p = 0.001) lower in the cloxacillin group than in the placebo group; the percentage of cultures with P. acnes did not differ between the two groups. For samples taken just before the wound was closed, the percentage of cultures with P. acnes or S. epidermidis was significantly (p = 0.008 and 0.003, respectively) lower in the cloxacillin than in the placebo group. In the placebo group neurosurgical infections occurred with P. acnes and/or S. epidermidis as causative microorganisms; in almost all cases those bacteria could be cultured from the edge of the wound. In none of the patients with an infection caused by S. aureus was the bacteria found in the operation area. In 2/6 infections in the cloxacillin group the infecting microorganisms could be cultured from the operation area. These findings support a significant reduction in the infection rate after craniotomy under cloxacillin prophylaxis compared with placebo.     

Recovery from cryptococcemia and the adult respiratory distress syndrome in the acquired immunodeficiency syndrome

We describe a patient who presented with cryptococcosis and the adult respiratory distress syndrome (ARDS) as the initial manifestation of the acquired immunodeficiency syndrome. This patient represents the first reported recovery from ARDS secondary to widespread cryptococcosis. He is currently doing well as an outpatient on maintenance therapy with amphotericin B and azidothymidine.     

Kidney and liver transplantation in children with fibrocystic liver–kidney disease: Data from the US Scientific Registry of Transplant Recipients: 1990–2010

The natural history and survival of children with fibrocystic liver–kidney disease undergoing solid organ transplantation have infrequently been described. We report outcomes in a cohort of US children with fibrocystic liver–kidney disease receiving solid organ transplants over 20 yr. Retrospective cohort study of pediatric transplant recipients with diagnoses of fibrocystic liver–kidney disease from 1/1990 to 3/2010, using data from the SRTR. Subjects were categorized by the first transplanted organ: LT, KT, or SLK. Primary outcomes were death, re‐transplant, transplant of the alternate organ, or initiation of dialysis. Seven hundred and sixteen subjects were transplanted in this period. Median age at first transplant was 9.7 yr. Of the LT, 14 (19%) required a second liver transplant at median of 0.2 yr, and five (7%) required kidney transplant or dialysis at a median of 9.0 yr. Of the KT, 188 (31%) required a second kidney transplant or dialysis at a median of 5.9 yr. Twenty‐nine (5%) subsequently received liver transplant at a median of 6.0 yr. Among patients in this registry, far more children underwent kidney than liver transplants. The risk of subsequently needing transplantation of an alternate organ was low.