Expanding analytic possibilities in pediatric solid organ transplantation through linkage of administrative and clinical registry databases.

Database linkage is a common strategy to expand analytic possibilities. Our group recently completed a linkage between the SRTR and PHIS databases for pediatric heart transplant recipients. The aim of this project was to expand the linkage between SRTR and PHIS to include liver, kidney, lung, heart-lung, and small bowel transplants. All patients (<21 years) who underwent liver, kidney, lung, heart-lung, or small bowel transplant were identified from the PHIS database using APR-DRG codes (2002-2018). Linkage was performed in a stepwise approach using indirect identifiers. Hospital costs were estimated based on hospital charges and cost-to-charge ratios, inflated to 2018 dollars and described by transplant type. A total of 14 061 patients overlapped between databases. Of these, 13 388 (95.2%) were uniquely linked. Linkage success ranged from 92.6% to 97.8% by organ system. A total of 12 940 (92%) patients had complete cost data. Hospitalization costs were greatest for patients undergoing small bowel transplantation with a median cost of $734 454 (IQR $336 174 - $1 504 167), followed by heart $565 386 (IQR $352 813 - $999 216), heart-lung $471 573 (IQR $328 523 - 992 438), lung $303 536 (IQR $215 383 - $612 749), liver $200 448 (IQR $130 880 - $357 897), and kidney transplant $94 796 (IQR $73 157 -$131 040). We report a robust linkage between the SRTR and PHIS databases, providing an invaluable tool to assess resource utilization in solid organ transplant recipients. Our analysis provides contemporary cost data for pediatric solid organ transplantation from the largest US sample reported to date. It also provides a platform for expanded analyses in the pediatric transplant population.

Urinary apolipoprotein AI in children with kidney disease.

BACKGROUND: Although high-density lipoprotein (HDL) modulates many cell types in the cardiovascular system, little is known about HDL in the kidney. We assessed urinary excretion of apolipoprotein AI (apoAI), the main protein in HDL. METHODS: We enrolled 228 children with various kidney disorders and 40 controls. Urinary apoAI, albumin, and other markers of kidney damage were measured using ELISA, apoAI isoforms with Western blot, and renal biopsies stained for apoAI. RESULTS: Patients followed in nephrology clinic had elevated urinary apoAI vs. controls (median 0.074 µg/mg; interquartile range (IQR) 0.0160-0.560, vs. 0.019 µg/mg; IQR 0.004-0.118, p < 0.001). Patients with tubulopathies, renal dysplasia/congenital anomalies of the kidney and urogenital tract, glomerulonephritis, and nephrotic syndrome (NS) in relapse had the greatest elevations (p ≤ 0.01). Patients with NS in remission, nephrolithiasis, polycystic kidney disease, transplant, or hypertension were not different from controls. Although all NS in relapse had higher apoAI excretion than in remission (0.159 vs. 0.0355 µg/mg, p = 0.01), this was largely driven by patients with focal segmental glomerulosclerosis (FSGS). Many patients, especially with FSGS, had increased urinary apoAI isoforms. Biopsies from FSGS patients showed increased apoAI staining at proximal tubule brush border, compared to diffuse cytoplasmic distribution in minimal change disease. CONCLUSIONS: Children with kidney disease have variably increased urinary apoAI depending on underlying disease. Urine apoAI is particularly elevated in diseases affecting proximal tubules. Kidney disease is also associated with high molecular weight (HMW) apoAI isoforms in urine, especially FSGS. Whether abnormal urinary apoAI is a marker or contributor to renal disease awaits further study.

Extracorporeal membrane oxygenation as a platform for recovery: a case report of a child with pulmonary hemorrhage, refractory hypoxemic respiratory failure, and new onset goodpasture syndrome.

We report a case of a 9-year-old female with acute pulmonary hemorrhage and refractory hypoxemic respiratory failure secondary to Goodpasture syndrome (GS). After failing treatment with high frequency oscillatory ventilation and inhaled nitric oxide, she was successfully managed with venovenous extracorporeal membrane oxygenation (VV ECMO). The patient's weight at the time of cannulation was 31 kg. A 19 French 18 cm (arterial) Biomedicus cannula was inserted in the right internal jugular vein and used as the drain. A 17 French 50 cm (venous) Biomedicus cannula was inserted in the right femoral vein and used as the return. Then the patient was anticoagulated with 100 units/kg of intravenous heparin and the circuit was primed with one unit of packed red blood cells. VV ECMO was performed with an SIII Sorin roller head pump with integrated servo regulator and a Quadrox D Bioline coated oxygenator. Despite systemic anticoagulation with heparin, the patient's pulmonary hemorrhage resolved. Extracorporeal membrane oxygenation served as a platform through which we were able to provide renal replacement therapy and plasmapheresis. The patient was successfully discharged home with normal pulmonary function.

Relationship between plasma S-adenosylhomocysteine concentration and glomerular filtration rate in children.

S-Adenosylhomocysteine (SAH) is the metabolic precursor of all the homocysteine (Hcy) produced in the body. It is formed by the enzyme SAH hydrolase in a reversible reaction. In a previous study we have shown that plasma SAH is a more sensitive indicator of the risk for cardiovascular disease, and in a second study involving patients with renal disease, we also showed that it is a more sensitive indicator of renal insufficiency than plasma Hcy. However, in the latter study, the patients with renal disease were older and had a variety of other diseases such as diabetes and primary hypertension, which are associated with vascular disease and which could reduce renal function by involvement of the kidneys. Our objective was to rule out these complicating factors as the cause of the elevated SAH in renal disease and determine whether renal insufficiency alone was the cause of the elevated SAH. We therefore measured SAH, Hcy, folate, and vitamin B12 in 23 patients between the ages of 1 and 18 years with a wide range of renal function, but who had none of these complicating factors. Glomerular filtration rate (GFR) was calculated using serum creatinine according to the Schwartz formula. None of the children were deficient in folate or vitamin B12. After adjusting for age, folate, and vitamin B12, there was a modest and insignificant decrease of 0.033 micromol/L of Hcy associated with an increase of 1 mL/min of GFR (95% confidence interval, -0.066 to 0.0002). However, there was a strong and statistically significant association between log(SAH) and log(GFR): P < .0005, R2 = 0.76. This result suggests that plasma SAH rather than Hcy is the metabolite primarily affected in renal disease. We suggest that plasma Hcy elevations that have been linked to vascular disease may be due to elevated SAH resulting from renal insufficiency.

An infant with Kasabach-Merritt syndrome with associated renal hematoma and intussusception.

A neonate that had a forearm hemangioma, gross hematuria, and a renal parenchymal hematoma was found to have Kasabach-Merritt syndrome. He subsequently returned to our hospital and was found to have an intussusception secondary to an intestinal hemangioma.

Dysfunctional high-density lipoproteins in children with chronic kidney disease.

OBJECTIVES: Our aim was to determine if chronic kidney disease (CKD) occurring in childhood impairs the normally vasoprotective functions of high-density lipoproteins (HDLs). MATERIALS AND METHODS: HDLs were isolated from children with end-stage renal disease on dialysis (ESRD), children with moderate CKD and controls with normal kidney function. Macrophage response to HDLs was studied as expression of inflammatory markers (MCP-1, TNF-α, IL-1ß) and chemotaxis. Human umbilical vein endothelial cells were used for expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin) and adhesion. Cellular proliferation, apoptosis, and necrosis of endothelial cells were measured by MTS/PMS reagent-based assay, flow cytometry, and ELISA. Cholesterol efflux was assessed by gas chromatographic measurements of cholesterol in macrophages exposed to HDLs. RESULTS: Compared with HDL(Control), HDL(CKD) and HDL(ESRD) heightened the cytokine response and disrupted macrophage chemotaxis. HDL(Control) reduced endothelial expression of ICAM-1, VCAM-1, E-selectin, whereas HDL(CKD) and HDL(ESRD) were less effective and showed reduced capacity to protect endothelial cells against monocyte adhesion. Compared with a dramatically enhanced endothelial proliferation following injurious stimulus by HDL(Control), neither HDL(CKD) nor HDL(ESRD) caused proliferative effects. HDLs of all three groups were equally protective against apoptosis assessed by flow cytometry and cleaved caspase-3 activity. Compared to HDL(Control), HDL(CKD) and HDL(ESRD) trended toward reduced capacity as cholesterol acceptors. CONCLUSION: CKD in children impairs HDL function. Even in the absence of long-standing and concomitant risk factors, CKD alters specific HDL functions linked to control of inflammation and endothelial responses.

Clostridium septicum myonecrosis complicating diarrhea-associated hemolytic uremic syndrome.

We report the case of a 19-month-old male child with diarrhea-associated hemolytic uremic syndrome (HUS) who developed swelling of the right arm at the site of a peripherally inserted central venous catheter (PICC), fever, and later, ecchymosis. Wound cultures at the time of surgical debridement grew Clostridium septicum. The child subsequently required amputation of the right arm and prolonged therapy with parenteral penicillin and clindamycin. Clostridium septicum infections in children with HUS have been associated with a high rate of mortality. Along with colon cancer, diarrhea-associated HUS comprises a clinical entity which appears to predispose to atraumatic C. septicum infection, where acidic and anaerobic conditions in the diseased colon favor C. septicum invasion. Though not well recognized among pediatric nephrologists, C. septicum infection constitutes a severe, albeit rare, complication of diarrhea-associated HUS, but one in which a high index of suspicion is warranted as aggressive surgical and antibiotic therapy may be life-saving.

Extra corporeal membrane oxygenation and plasmapheresis for pulmonary hemorrhage in microscopic polyangiitis.

Early initiation of extracorporeal membrane oxygenation to treat acute hypoxemic respiratory failure secondary to massive pulmonary hemorrhage in microscopic polyangiitis in children can be life-saving while awaiting control of the autoimmune disease process by plasmapheresis and immunosuppression.

Angiotensin in atherosclerosis.

PURPOSE OF REVIEW: While it is well established that angiotensin II promotes cardiovascular and renal disorders, recent evidence has indicated a pivotal role in atherosclerotic disease which is distinguished by the central abnormality of lipid accumulation within the vascular wall. RECENT FINDINGS: Studies published in the last year show that angiotensin II activity is increased in atherosclerosis, but even a transient elevation in angiotensin II potentiates the disease. The downstream hormone, aldosterone, has vasculopathic effects in conjunction with, as well as independently of, angiotensin II. The mechanism for angiotensin II injury includes potentiation of damage by known risk factors such as hypertension, hyperlipidemia, diabetes and insulin resistance, falling estrogens and inflammation. In addition, angiotensin II has direct effects on cellular proliferation, hypertrophy, apoptosis, and synthesis/degradation of matrix proteins and collagen that underlie development and progression of atherosclerosis as well as stability of the plaque. Antagonism of angiotensin II actions, therefore, offers the possibility of interfering with these direct and indirect effects and lessening the progression of atherosclerosis, stabilizing vulnerable plaques, and even reversing the disease. SUMMARY: Angiotensin is increased in atherosclerosis, and increased angiotensin II amplifies atherosclerosis by modulating individual risk factors as well as by directly affecting lipid metabolism, the vascular response to lipid accumulation, and plaque stability. Antagonism of angiotensin II actions not only lessens the progression of atherosclerosis, but stabilizes the plaque and may even cause regression of the disease.

Racial and center differences in hemodialysis adequacy in children treated at pediatric centers: a North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) report.

This study assessed hemodialysis adequacy in pediatric centers. Monthly adequacy data were requested in NAPRTCS enrollees on hemodialysis for at least 6 mo. Data forms were returned for 147 children from 32 centers. Data are presented for the 138 children (57% boys, 45% black) that were dialyzed 3 times/wk, representing 2282 patient-months of follow-up. Pre- and postdialysis BUN levels were reported in all children. Kt/V values were reported in 76 children; however, sufficient data were obtained to calculate Kt/V in 129 children. On average, 14.9 Kt/V and 15.2 urea reduction ratio (URR) values were calculated per child. Aggregate dialysis dose was defined as adequate if Kt/V was >1.2 in at least 75% of calculated Kt/V measures within a subject. Mean +/- SD age was 11.3 +/- 3.7 yr (median, 12.0 yr). Hemodialysis dose was variable within subjects (median CV%: URR 8.2, Kt/V 16.9). Aggregate dialysis dose was adequate in 70% of subjects. Multivariate logistic regression showed male gender (OR, 0.41; 95% CI, 0.16 to 0.98), black race (OR, 0.28; 95% CI, 0.11 to 0.67), larger body surface area (fourth versus first quartile: OR, 0.22; 95% CI, 0.05 to 0.80), and absence of reported Kt/V at the treating center (OR, 0.26; 95% CI, 0.10 to 0.62) were significant predictors of inadequate dialysis dose. Age, renal diagnosis, and center size were not associated with adequacy. Racial and gender disparities in hemodialysis dose existed among children at specialized academic pediatric centers and a substantial proportion received inadequate hemodialysis.

Decline in renal function following thoracic organ transplantation in children.

Heart and/or lung transplantation are life-saving treatments for end-stage cardiopulmonary disease; however, chronic renal failure may develop. The impact of thoracic organ transplant on renal function in infants and children is not well characterized. This retrospective cohort study evaluated renal function following thoracic organ transplantation in 46 children (32 heart, 9 lung, 5 heart-lung; median age 4.1 years) with at least 12 months of follow-up. Glomerular filtration rate (GFR, ml/min/1.73 m2) was estimated by the Schwartz formula throughout and each GFR estimate was converted to per cent normal for age (GFR%). Changes in renal function following transplantation were analyzed using longitudinal mixed-effects linear regression models. GFR% decreased following thoracic organ transplantation (p <0.001). Younger age at transplant was associated with a greater decline in GFR% (p <0.01). The decline in GFR% persisted after adjustment for nutritional status with body mass index or weight-for-length z-scores. The prevalence of renal insufficiency (GFR% <75) increased from 22% at transplant to 55% and 85% at 1 and 5 years post transplant, respectively, while 15% had a GFR% <50 at 5 years post transplantation. Higher tacrolimus trough levels over the first 6 months correlated with a lower GFR% (p <0.01). Renal function declined significantly following thoracic organ transplantation.

Serum cardiac troponin and subclinical cardiac status in pediatric chronic renal failure.

BACKGROUND: Patients with uremia often have elevated serum cardiac troponin T (cTnT) even without clinical heart damage. Pediatric patients are ideal for studies of the relationship between uremia and heart disease because they are unlikely to have cardiac risk factors other than uremia. OBJECTIVE: To determine the relationship between uremia and cTnT levels. DESIGN: Echocardiograms and blood chemistry results were obtained from 50 pediatric patients with chronic renal failure and without clinical heart disease. Levels of cTnT were tested for correlation with cardiac dysfunction. In multivariate analysis, biochemical aspects of renal disease and its treatment were tested for correlation with cardiac dysfunction. RESULTS: Forty-nine patients had cardiovascular abnormalities, including increased left ventricular function and mass, elevated heart rate and blood pressure, and reduced LV afterload. LV contractility was inversely correlated with cTnT level (r = -0.36). Higher cTnT also correlated with higher serum creatine kinase-MB mass, lower serum parathyroid hormone, higher blood urea nitrogen and bicarbonate levels, and the use of diuretics, but not with higher cardiac troponin I. Left ventricular contractility was inversely related to serum creatinine, phosphorus, and the use of beta-blockers. CONCLUSIONS: Elevated cTnT levels are not artifactual, but are genuine indicators of cardiomyocyte damage. Cardiac damage, indicated by either elevated cTnT or low LV contractility, is related to uremia, deranged calcium and phosphorus metabolism, and bicarbonate levels. Serum cTnT and LV contractility identify subclinical cardiac damage that could be treated to hopefully reduce cardiovascular morbidity and mortality in this high-risk population.

Pharmacokinetics of darbepoetin alfa in pediatric patients with chronic kidney disease.

Darbepoetin alfa is a novel erythropoiesis-stimulating protein with a two- to threefold longer half-life than recombinant human erythropoietin (epoetin) in adult patients with chronic kidney disease (CKD). This randomized, open-label, crossover study was conducted to determine the pharmacokinetic profile of darbepoetin alfa in pediatric patients with CKD. Twelve patients 3-16 years of age with CKD were randomized and received a single 0.5 micro g/kg dose of darbepoetin alfa administered intravenously (IV) or subcutaneously (SC). After a 14- to 16-day washout period, patients received an identical dose of darbepoetin alfa by the alternate route. After IV administration, the mean clearance of darbepoetin alfa was 2.3 ml/h per kg, with a mean terminal half-life of 22.1 h. After SC administration, absorption was rate limiting, with a mean terminal half-life of 42.8 h and a mean bioavailability of 54%. Comparison of these results with those from a previous study of darbepoetin alfa in adult patients indicated that the disposition of darbepoetin alfa administered IV or SC is similar in adult and pediatric patients, although absorption may be slightly more rapid in pediatric patients after SC dosing. The mean terminal half-life of darbepoetin alfa in this study was approximately two- to fourfold longer than that previously reported for epoetin in pediatric patients.