Rebecca L. Ruebner

Complications of Central Venous Catheters Used for the Treatment of Acute Hematogenous Osteomyelitis

OBJECTIVE. To determine the complications and risk factors for complications associated with using central venous catheters (CVCs) for the treatment of acute hematogenous osteomyelitis (AHO). METHODS. We conducted a retrospective cohort study of all patients admitted to the Children’s Hospital of Philadelphia between January 1, 2000, and December 31, 2003, with a diagnosis of AHO. RESULTS. Eighty patients with AHO met inclusion criteria. The median age was 5 years, and 66% of the patients were male. The most commonly affected bones were the femur (25%), tibia (20%), and pelvis (16%). Staphylococcus aureus was the most common organism identified from cultures of bone (67%) and blood (30%). Seventy-five patients (94%) received >2 weeks of intravenous (IV) antibiotic therapy via a CVC and 5 (6%) received <2 weeks of IV antibiotic therapy before conversion to oral therapy for a median of 25 days. None of the patients who switched to oral therapy within 2 weeks was rehospitalized or returned to the emergency department. Of the 75 patients who received >2 weeks of IV therapy, 41% had ≥1 CVC-associated complication. Seventeen patients (23%) had a CVC malfunction or displacement, 8 (11%) had a catheter-associated bloodstream infection, 8 (11%) had fever with negative blood culture results, and 4 (5%) had a local skin infection at the site of catheter insertion. Older age was protective against the development of a CVC-associated complication, whereas the lowest median household income was associated with development of a CVC-associated complication. CONCLUSIONS. Interventions to reduce CVC-associated complications should be developed and evaluated, particularly for young children and those from families with low household incomes. Clinical trials are needed to evaluate the safety and efficacy of oral antibiotic therapy after a short course of IV therapy as an alternative to prolonged IV therapy.

Risk of End‐Stage Renal Disease Among Liver Transplant Recipients With Pretransplant Renal Dysfunction

Guidelines recommend restricting simultaneous liver–kidney (SLK) transplant to candidates with prolonged dialysis or estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 for 90 days. However, few studies exist to support the latter recommendation. Using Scientific Registry of Transplant Recipients and Medicare dialysis data, we assembled a cohort of 4997 liver transplant recipients from February 27, 2002–January 1, 2008. Serial eGFRs were calculated from serum creatinines submitted with MELD reports. We categorized recipients by eGFR patterns in the 90 days pretransplant: Group 1 (eGFR always >30), Group 2 (eGFR fluctuated), Group 3 (eGFR always <30) and Group 4 (short‐term dialysis). For Group 2, we characterized fluctuations in renal function using time‐weighted mean eGFR. Among liver‐alone recipients in Group 3, the rate of end‐stage renal disease (ESRD) by 3 years was 31%, versus <10% for other groups (p < 0.001). In multivariable Cox regression, eGFR Group, diabetes (HR 2.65, p < 0.001) and black race (HR 1.83, p = 0.02) were associated with ESRD. Among liver‐alone recipients in Group 2, only diabetics with time‐weighted mean eGFR <30 had a substantial ESRD risk (25.6%). In summary, among liver transplant candidates not on prolonged dialysis, SLK should be considered for those whose eGFR is always <30 and diabetic candidates whose weighted mean eGFR is <30 for 90 days.

Update on Streptococcus pneumoniae associated hemolytic uremic syndrome.

Purpose of review Streptococcus pneumoniae associated hemolytic uremic syndrome (SpHUS) is defined by the occurrence of acute hemolytic anemia, thrombocytopenia and acute kidney injury in a patient with a S. pneumoniae infection. We review the pathophysiology, clinical course, treatment and prognosis for SpHUS. We also describe an expanded classification system that uses additional diagnostic criteria to identify more patients with a high likelihood of having SpHUS. Recent findings SpHUS often may be underdiagnosed because of overlapping features with disseminated intravascular coagulation (DIC) and the lack of strict diagnostic criteria. The epidemiology has changed with the emergence of different pneumococcal serotypes as newer pneumococcal vaccines have been introduced. Summary SpHUS accounts for 5–15% of all HUS cases. The majority of SpHUS patients have pneumonia and a low mortality rate in contrast to those with meningitis, who have a more severe clinical course. Although the pathogenesis of SpHUS remains unknown, the Thomsen–Friedenreich antigen seems to play a central role. S. pneumoniae produces neuraminidase, thereby exposing the Thomsen–Friedenreich antigen on the surface of cell membranes. Thomsen–Friedenreich antigen exposure can result in hemolysis and direct endothelial injury leading to HUS phenotype. Early identification of these patients is critical so that fresh frozen plasma may be avoided.

Current treatment of atypical hemolytic uremic syndrome

Tremendous advances have been made in understanding the pathogenesis of atypical Hemolytic Uremic Syndrome (aHUS), an extremely rare disease. Insights into the molecular biology of aHUS resulted in rapid advances in treatment with eculizumab (Soliris(®), Alexion Pharmaceuticals Inc.). Historically, aHUS was associated with very high rates of mortality and morbidity. Prior therapies included plasma therapy and/or liver transplantation. Although often life saving, these were imperfect and had many complications. We review the conditions included under the rubric of aHUS: S. pneumoniae HUS (SpHUS), inborn errors of metabolism, and disorders of complement regulation, emphasizing their differences and similarities. We focus on the clinical features, diagnosis, and pathogenesis, and treatment of aHUS that results from mutations in genes encoding alternative complement regulators, SpHUS and HUS associated with inborn errors of metabolism. Mutations in complement genes, or antibodies to their protein products, result in unregulated activity of the alternate complement pathway, endothelial injury, and thrombotic microangiopathy (TMA). Eculizumab is a humanized monoclonal antibody that inhibits the production of the terminal complement components C5a and the membrane attack complex (C5b-9) by binding to complement protein C5a. This blocks the proinflammatory and cytolytic effects of terminal complement activation. Eculizumab use has been reported in many case reports, and retrospective and prospective clinical trials in aHUS. There have been few serious side effects and no reports of tachphylaxis or drug resistance. The results are very encouraging and eculizumab is now recognized as the treatment of choice for aHUS.

Neurocognitive Dysfunction in Children, Adolescents, and Young Adults With CKD.

BACKGROUND Neurocognitive dysfunction is a known complication in children with chronic kidney disease (CKD). However, less is known about putative mechanisms or modifiable risk factors. The objective of this study was to characterize and determine risk factors for cognitive dysfunction in children, adolescents, and young adults with CKD compared with controls. STUDY DESIGN Cross-sectional study. SETTING & PARTICIPANTS The Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults With Chronic Kidney Disease (NiCK) Study included 90 individuals aged 8 to 25 years with CKD compared with 70 controls. PREDICTORS CKD versus control, estimated glomerular filtration rate (eGFR), ambulatory blood pressure. OUTCOMES Performance on neurocognitive assessment with relevant tests grouped into 11 domains defined a priori by expert opinion. Results of tests were converted to age-normalized z scores. MEASUREMENTS Each neurocognitive domain was analyzed through linear regression, adjusting for eGFR and demographic and clinical variables. For domains defined by multiple tests, the median z score of tests in that domain was used. RESULTS We found significantly poorer performance in multiple areas of neurocognitive function among individuals with CKD compared with controls. Particular deficits were seen in domains related to attention, memory, and inhibitory control. Adjusted for demographic and clinical factors, we found lower performance in multiple domains with decreasing eGFRs (attention: β=0.053, P=0.02; visual spatial: β=0.062, P=0.02; and visual working memory: β=0.069, P=0.04). Increased diastolic load and decreased diastolic nocturnal dipping on ambulatory blood pressure monitoring were independently associated with impairments in neurocognitive performance. LIMITATIONS Unable to assess changes in neurocognitive function over time, and neurocognitive tests were grouped into predetermined neurocognitive domains. CONCLUSIONS Lower eGFR in children, adolescents, and young adults is associated with poorer neurocognitive performance, particularly in areas of attention, memory, and inhibitory control. Hypertension identified on ambulatory blood pressure monitoring may be an important risk factor, illustrating that neurocognitive function is an area of target-organ damage in CKD.

Assessment of Kidney Function in Survivors Following Fontan Palliation

OBJECTIVE The Fontan operation is a palliative procedure for congenital single ventricle heart disease. Long-term kidney function in this cohort is not well-known. Our aim was to evaluate renal function in long-term survivors post-Fontan palliation, and we hypothesize that this cohort will have a higher prevalence of chronic kidney disease (CKD) compared to controls. DESIGN We performed a retrospective cohort study of 68 subjects evaluated through the Single Ventricle Survivorship Program at the Childrens Hospital of Philadelphia between July 2010 and December 2014 compared to 70 healthy children similar in age and sex. Primary outcome was CKD, defined as estimated glomerular filtration rate (eGFR) <90 mL/min/1.73 m2 using creatinine and cystatin C-based estimating equations. Secondary outcomes included proteinuria and elevated intact parathyroid hormone. RESULTS The Fontan cohort included 68 subjects with median age 13 years (IQR 9.0, 17.3) who were median 11.1 years (IQR 6.5, 15.7) post-Fontan palliation. This cohort was compared to 70 healthy individuals (median age 15.5 years (IQR 12.5, 18.3). Although median eGFRs were comparable: 102.6 vs. 101.9 mL/min/1.73 m2 (P = .89) in Fontan vs. healthy subjects <18 years of age (Full CKiD equation), and 128.5 vs. 129.7 mL/min/1.73 m2 (P = .56) in Fontan vs. healthy subjects ≥18 years of age (CKD-EPI creatinine and cystatin formula); 10% of Fontan subjects had an eGFR<90 mL/min/1.73 m2 . Median intact parathyroid hormone level was higher at 59.4 pg/mL (IQR 43.0, 83.1) in the Fontan group compared to 23.4 pg/mL (IQR 16.7, 30.0) in controls (P ≤ .001). Proteinuria was present in 10% of the Fontan group compared to 4.7% in controls (P = .27). CONCLUSION Ten percent of long-term survivors post-Fontan palliation had eGFR <90 ml/min/1.73 m2 , and higher median parathyroid hormone levels compared to controls. Taken together, these measures may indicate early kidney disease. Future studies will focus on longitudinal assessment of kidney function and evaluation of risk factors for CKD post-Fontan palliation.

End-Stage Kidney Disease After Pediatric Nonrenal Solid Organ Transplantation

OBJECTIVES: Adult solid organ transplant (SOT) recipients commonly develop advanced kidney disease; however, the burden of end-stage kidney disease (ESKD) in children after SOT is not well-described. The objectives of this study were to determine the incidence of ESKD after pediatric SOT and the relative risk by SOT type. METHODS: Retrospective multicenter cohort study of children, ages ≤18 years, who received SOTs from 1990 through 2010 using Scientific Registry of Transplant Recipients data linked to the US Renal Data System. We performed a competing risks analysis to determine cumulative incidence of ESKD (chronic dialysis or kidney transplant), treating death as a competing risk, and fit a multivariable Cox regression model to assess hazard of ESKD by organ type. RESULTS: The cohort included 16 604 pediatric SOT recipients (54% liver, 34% heart, 6% lung, 6% intestine, and 1% heart–lung). During a median follow-up of 6.2 years (interquartile range 2.2–12.1), 426 (3%) children developed ESKD. Compared with liver transplant recipients, in whom the incidence of ESKD was 2.1 cases per 1000 person-years, in adjusted analyses the highest risk of ESKD was among intestinal (hazard ratio [HR] 7.37, P < .001), followed by lung (HR 5.79, P < .001) and heart transplant recipients (HR 1.79, P < .001). CONCLUSIONS: In a 20-year national cohort of pediatric SOT recipients, the risk of ESKD was highest among intestinal and lung transplant recipients. The burden of earlier stages of chronic kidney disease is probably much higher; modifiable risk factors should be targeted to prevent progressive kidney damage in this high-risk population.

Risk Factors for End-Stage Kidney Disease After Pediatric Liver Transplantation

Adult liver transplant (LT) recipients commonly develop advanced kidney disease. However, burden of end‐stage kidney disease (ESKD) after pediatric LT has not been well‐described. We performed a retrospective cohort study of pediatric LTs in the United States from 1990 to 2010. Multivariable Cox regression models were fit to determine risk factors for ESKD and death. Eight thousand nine hundred seventy six children received LTs. During median follow‐up of 7.8 years, 2005 (22%) subjects died (mortality rate 26.1 cases/1000 person‐years); 167 (2%) developed ESKD (incidence rate 2.2 cases/1000 person‐years). Risk factors for ESKD included older age at LT (highest risk age >15 vs. < 5 years, HR = 4.94, p < 0.001), hepatitis C (HR 2.79, p = 0.004), liver re‐transplant (HR 2.67, p < 0.001), eGFR pre‐LT < 60 versus ≥ 60 (HR 2.37, p < 0.001), hepatitis B (HR 2.25, p = 0.027), black race (HR 1.46, p = 0.046), and male sex (HR 1.44, p = 0.022). LT recipients with ESKD had increased risk of mortality (HR 2.37, p < 0.001). Among pediatric LT recipients, rate of ESKD was lower than among adults and far exceeded by rate of death, however follow‐up time in this study may underestimate lifetime burden of ESKD. Although uncommon, ESKD was highly associated with mortality. Pediatric LT recipients should be routinely monitored for kidney disease, particularly those at highest risk of ESKD.

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.

Nephrotic syndrome associated with tyrosine kinase inhibitors for pediatric malignancy: case series and review of the literature

BackgroundTyrosine kinase (TK) inhibitors are increasingly being used to treat a variety of pediatric malignancies. Reports in adult patients describe a range of effects of TK inhibitors on the kidney, including hypertension, proteinuria, acute kidney injury, and thrombotic microangiopathy (TMA); however, there are only a few reports of TK-inhibitor-associated nephrotic syndrome.MethodsWe report four pediatric patients with various malignancies (chronic myelogenous leukemia, acute lymphoblastic leukemia, and glioma/renal cell carcinoma) who developed nephrotic syndrome during treatment with TK inhibitors (imatinib, sunitinib, dasatinib, and quizartinib). One of the four patients also had clinical features of TMA.ResultsThree of the four patients achieved complete remission of nephrotic syndrome with discontinuation of the TK inhibitor and have had no additional nephrotic syndrome relapses to date. The temporal relationship of nephrotic syndrome onset to TK-inhibitor therapy and resolution of nephrotic syndrome with cessation of therapy strongly imply an association in these patients.ConclusionsTK inhibitors are important therapies in pediatric cancer, and their use is expanding. Nephrotic syndrome with or without features of TMA is a potential complication of these therapies in children.