Susan R. Mendley

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 × 108 and 2.32 × 107 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.

Polyomavirus BK versus JC replication and nephropathy in renal transplant recipients: a prospective evaluation.

Background. JC virus (JCV) viruria is more common than BK virus (BKV) viruria in healthy individuals but in kidney transplants (KT), polyomavirus nephropathy (PVAN) is primarily caused by BKV. Few cases of PVAN have been attributed to JCV. Systematic studies on JCV replication in KT are lacking. Methods. Out of a cohort of KT patients screened with urine cytology, patients shedding decoy cells were studied (n=103). Molecular studies demonstrated BKV, JCV, or BKV+JCV shedding in 58 (56.3%), 28 (27.2%), and 17 (16.5%), respectively. Biopsy was performed when decoy cells persisted 2 months or serum creatinine increased >20%. Results. BKV viruria was strongly associated with BKV viremia (93%), PVAN (48%, P=0.01) and graft loss (P=0.03). Higher BKV viremia correlated with graft dysfunction (P=0.01), more advanced histological pattern of PVAN (P<0.0001), and more infected cells in biopsy (P=0.0001). BKV viremia of ≥10,000 copies/mL was significantly associated with histologically confirmed PVAN (P=0.0001). Reduction of immunosuppression lead to disappearance of decoy cells in patients shedding BK (>93%). JCV viruria, was more often asymptomatic (P=0.002) and affected older patients (P=0.02). JCV PVAN was less common (21.4%) and was characterized by sparse cytopathic changes but significant inflammation and fibrosis. JCV viremia was rare (14.2%), transient, and low (mean 2.0E+03/mL). After reduction of immunosuppression decoy cells persisted in >50% of patients with JCV (P=0.0001), but no graft loss occurred. During the period of the current study, the incidence of BKV-PVAN was 5.5% and the incidence of JCV-PVAN was 0.9%. Conclusions. The data point to significant differences of BKV and JCV biology regarding replication and disease in KT patients, with important implications for screening and management.

Health-Related Quality of Life of Children With Mild to Moderate Chronic Kidney Disease

OBJECTIVE: To compare the health-related quality of life (HRQoL) of children with chronic kidney disease (CKD) with healthy children; to evaluate the association between CKD severity and HRQoL; and to identity demographic, socioeconomic, and health-status variables that are associated with impairment in HRQoL in children with mild to moderate CKD. METHODS: This was a cross-sectional assessment of HRQoL in children who were aged 2 to 16 and had mild to moderate CKD using the Pediatric Inventory of Quality of Life Core Scales (PedsQL). Overall HRQoL and PedsQL domain means for parents and youth were compared with previously published norms by using independent sample t tests. Study participants were categorized by kidney disease stage (measured by iohexol-based glomerular filtration rate [iGFR]), and group differences in HRQoL were evaluated by using analysis of variance and Cuzick trend tests. The association between hypothesized predictors of HRQoL and PedsQL scores was evaluated with linear and logistic regression analyses. RESULTS: The study sample comprised 402 participants (mean age: 11 years, 60% male, 70% white, median iGFR: 42.5 mL/min per 1.73 m2, median CKD duration: 7 years). Youth with CKD had significantly lower physical, school, emotional, and social domain scores than healthy youth. iGFR was not associated with HRQoL. Longer disease duration and older age were associated with higher PedsQL scores in the domains of physical, emotional, and social functioning. Older age was associated with lower school domain scores. Maternal education ≥16 years was associated with higher PedsQL scores in the domains of physical, school, and social functioning. Short stature was associated with lower scores in the physical functioning domain. CONCLUSIONS: Children with mild to moderate CKD, in comparison with healthy children, reported poorer overall HRQoL and poorer physical, school, emotional, and social functioning. Early intervention to improve linear growth and to address school functioning difficulties is recommended.

Neurocognitive Functioning of Children and Adolescents with Mild-to-Moderate Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Few data exist on the neurocognitive functioning of children with mild-to-moderate chronic kidney disease (CKD). The primary objectives of this paper are (1) to determine the neurocognitive status in this population and (2) to identify sociodemographic and health-status variables associated with neurocognitive functioning. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a cross-sectional study of 368 children, aged 6 to 16 years, from the Chronic Kidney Disease in Children (CKiD) cohort. Median iGFR was 43 ml/min per 1.73 m(2), and the median duration of CKD was 8.0 years. Approximately 26% had underlying glomerular disease. Measures of intelligence, academic achievement, attention regulation, and executive functioning were obtained at study entry. The prevalence of neurocognitive deficits was determined by comparing participant scores on each measure of neurocognitive functioning with normative data. The association between hypothesized predictors of neurocognitive dysfunction was evaluated using multivariate regression analyses. RESULTS Neurocognitive functioning was within the average range for the entire group; however, 21% to 40% of participants scored at least one SD below the mean on measures of intelligence quotient (IQ), academic achievement, attention regulation, or executive functioning. Higher iohexol-based GFR (iGFR) predicted a lesser risk for poor performance on measures of executive function. Participants having elevated proteinuria (i.e., urine protein/creatinine >2) scored lower on verbal IQ, full-scale IQ, and attention variability than those without elevated proteinuria. CONCLUSIONS Whereas most children with mild-to-moderate CKD have no major neurocognitive deficits, a substantial percentage did show neurocognitive dysfunction that places them at risk for poor long-term educational and occupational outcomes.

The impact of short stature on health-related quality of life in children with chronic kidney disease

OBJECTIVES To compare the health-related quality of life (HRQoL) of children with chronic kidney disease (CKD) and short stature (SS) with that of children with CKD and normal height (NH), to evaluate the impact of catch-up growth and growth hormone (GH) use on HRQoL, and to describe the concordance of perceptions of HRQoL between children with SS and NH and their parents. STUDY DESIGN Four hundred eighty-three children and/or parents enrolled in the multicenter Chronic Kidney Disease in Children study who had completed the Pediatric Quality of Life Inventory (Version 4.0) on at least 2 Chronic Kidney Disease in Children study visits composed this substudy population. Participants were dichotomized into NH or SS groups. The demographic characteristics that varied at baseline (sex, glomerular filtration rate, and parent education) were controlled for in the main analysis evaluating the impact of catch-up growth and use of GH on HRQoL. RESULTS Multivariate modeling (controlling for confounding variables) revealed a significant association between both catch-up growth and GH use on parent-proxy reports of child physical functioning (P < .05) and social functioning (P < .05). Older children with CKD (15-17 years old) had significantly higher ratings than their parents on the Pediatric Quality of Life Inventory Physical, Emotional, Social, and School Functioning scales compared with younger children (8-14 years old). CONCLUSION The finding that height gains and GH use are associated with increases in physical and social functioning by parent report provides additional support for interventions to improve height in children with CKD. The importance of evaluating both the parent and child perceptions of HRQoL is supported by our results.

Casual Blood Pressure and Neurocognitive Function in Children with Chronic Kidney Disease: A Report of the Children with Chronic Kidney Disease Cohort Study

BACKGROUND AND OBJECTIVES Children with chronic kidney disease (CKD) are at risk for cognitive dysfunction, and over half have hypertension. Data on the potential contribution of hypertension to CKD-associated neurocognitive deficits in children are limited. Our objective was to determine whether children with CKD and elevated BP (EBP) had decreased performance on neurocognitive testing compared with children with CKD and normal BP. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a cross-sectional analysis of the relation between auscultatory BP and neurocognitive test performance in children 6 to 17 years enrolled in the Chronic Kidney Disease in Children (CKiD) project. RESULTS Of 383 subjects, 132 (34%) had EBP (systolic BP and/or diastolic BP ≥90(th) percentile). Subjects with EBP had lower mean (SD) scores on Wechsler Abbreviated Scales of Intelligence (WASI) Performance IQ than those with normal BP (normal BP versus EBP, 96.1 (16.7) versus 92.4 (14.9), P = 0.03) and WASI Full Scale IQ (97.0 (16.2) versus 93.4 (16.5), P = 0.04). BP index (subjects BP/95(th) percentile BP) correlated inversely with Performance IQ score (systolic, r = -0.13, P = 0.01; diastolic, r = -0.19, P < 0.001). On multivariate analysis, the association between lower Performance IQ score and increased BP remained significant after controlling for demographic and disease-related variables (EBP, β = -3.7, 95% confidence interval [CI]: -7.3 to -0.06; systolic BP index, β = -1.16 to 95% CI: -2.1, -0.21; diastolic BP index, β = -1.17, 95% CI: -1.8 to -0.55). CONCLUSIONS Higher BP was independently associated with decreased WASI Performance IQ scores in children with mild-to-moderate CKD.

Use of opportunistic clinical data and a population pharmacokinetic model to support dosing of clindamycin for premature infants to adolescents.

Clindamycin is commonly prescribed to treat children with skin and skin‐structure infections (including those caused by community‐acquired methicillin‐resistant Staphylococcus aureus (CA‐MRSA)), yet little is known about its pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving i.v. clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA‐MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. A one‐compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (l/h) = 13.7 × (weight/70)0.75 × (PMA3.1/(43.63.1 + PMA3.1)); V (l) = 61.8 × (weight/70). Maturation reached 50% of adult CL values at ~44 weeks PMA. Our findings support age‐based dosing.

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.

Duration of chronic kidney disease reduces attention and executive function in pediatric patients

Chronic kidney disease (CKD) in childhood is associated with neurocognitive deficits. Affected children show worse performance on tests of intelligence than their unaffected siblings and skew toward the lower end of the normal range. Here we further assessed this association in 340 pediatric patients (ages 6 to 21) with mild-moderate CKD in The Chronic Kidney Disease in Childhood cohort from 48 pediatric centers in North America. Participants underwent a battery of age-appropriate tests including Conner’s Continuous Performance Test-II (CPT-II), Delis- Kaplan Executive Function System Tower task, and the Digit Span Backwards task from the age-appropriate Wechsler Intelligence Scale. Test performance was compared across the range of estimated GFR and duration of CKD with relevant covariates including maternal education, household income, IQ, blood pressure and preterm birth. Among the 340 patients, 35% had poor performance (below the mean by1.5 or more standard deviations) on at least one test of executive function. By univariate nonparametric comparison and multiple logistic regression, longer duration of CKD was associated with increased odds ratio for poor performance on the CPT-II Errors of Commission, a test of attention regulation and inhibitory control. Thus, in a population with mild to moderate CKD, the duration of disease rather than estimated GFR was associated with impaired attention regulation and inhibitory control.

Kidney epithelial cells release growth factors in response to extracellular signals

The growth of nontransformed monkey kidney epithelial cells in culture appears to be regulated by the interplay of positive and negative autocrine growth factors. Reduction of the potassium or sodium concentration of the medium induces rapid release of novel growth-promoting activities, whereas addition of the mitogen adenosine diphosphate stimulates the appearance of a platelet-derived growth factor-like protein which could function in a paracrine manner. These observations suggest that autocrine and paracrine growth factors could play an important role in physiological and pathological states in the kidney.