Human papillomavirus-related cancer risk for solid organ transplant recipients during adult life and early prevention strategies during childhood and adolescence.

Malignancies are among the top three causes of patient death in pediatric and adult kidney transplant (KT) recipients. Solid organ transplant (SOT) recipients, including KT individuals, experience more cancer compared with the general population, including human papillomavirus (HPV)-related anogenital and oropharyngeal cancers. This article describes the epidemiology, pathophysiology and natural history of the HPV infection in both the general population and in SOT recipients, as well as its role in the development of HPV-related pre-cancerous lesions and cancers. Emphasis is given to the primary prevention strategy, HPV vaccination in SOT recipients, and its particularities compared with the general population. Secondary prevention strategies in SOT recipients are discussed and compared with the general population, highlighting cervical cancer screening needs within SOT populations. The article emphasizes how these primary and secondary HPV prevention strategies applied during childhood and adolescence by the pediatric transplant professionals, can lower the burden of HPV-related cancers for SOT recipients in subsequent years, during their adult life.

The kidney transplant rate is outpaced by the rate of readmission for complications.

Hospital readmissions experienced by kidney transplant recipients may be secondary to a range of conditions, including infections and rejection episodes. The objective was to identify trends in patients with kidney transplant complications, in regard to hospital discharges, ED visits, and charges over the years available from 1993 to 2015. Using the Healthcare Cost and Utilization Project database, trends were identified in hospitalizations, emergency department visits, and charges from 1993 to 2015 for complications following kidney transplantation. Hospital discharges have significantly increased over time and at a faster rate than the increase in number of kidney transplants performed, while emergency department visits numbers and rates remain unchanged. The type of kidney transplant complications experienced were analyzed by incidence and proportion of total charges. Rejection made up the largest proportion of hospitalizations and of total cost in patients suffering from kidney transplant complications. Improved immunosuppression regimens have resulted in longer allograft survival. We speculate that the overlap between infection and rejection is compounding and contributing to graft injury and thus, it is important to try to prevent and/or properly identify those episodes as well in order to improve graft survival.

COVID-19 in pediatric kidney transplantation: The Improving Renal Outcomes Collaborative.

There are limited data on the impact of COVID-19 in children with a kidney transplant (KT). We conducted a prospective cohort study through the Improving Renal Outcomes Collaborative (IROC) to collect clinical outcome data about COVID-19 in pediatric KT patients. Twenty-two IROC centers that care for 2732 patients submitted testing and outcomes data for 281 patients tested for SARS-CoV-2 by PCR. Testing indications included symptoms and/or potential exposures to COVID-19 (N = 134, 47.7%) and/or testing per hospital policy (N = 154, 54.8%). Overall, 24 (8.5%) patients tested positive, of which 15 (63%) were symptomatic. Of the COVID-19-positive patients, 16 were managed as outpatients, six received non-ICU inpatient care and two were admitted to the ICU. There were no episodes of respiratory failure, allograft loss, or death associated with COVID-19. To estimate incidence, subanalysis was performed for 13 centers that care for 1686 patients that submitted all negative and positive COVID-19 results. Of the 229 tested patients at these 13 centers, 10 (5 asymptomatic) patients tested positive, yielding an overall incidence of 0.6% and an incidence among tested patients of 4.4%. Pediatric KT patients in the United States had a low estimated incidence of COVID-19 disease and excellent short-term outcomes.

Vaccinations in pediatric kidney transplant recipients.

Pediatric kidney transplant (KT) candidates should be fully immunized according to routine childhood schedules using age-appropriate guidelines. Unfortunately, vaccination rates in KT candidates remain suboptimal. With the exception of influenza vaccine, vaccination after transplantation should be delayed 3-6 months to maximize immunogenicity. While most vaccinations in the KT recipient are administered by primary care physicians, there are specific schedule alterations in the cases of influenza, hepatitis B, pneumococcal, and meningococcal vaccinations; consequently, these vaccines are usually administered by transplant physicians. This article will focus on those deviations from the normal vaccine schedule important in the care of pediatric KT recipients. The article will also review human papillomavirus vaccine due to its special importance in cancer prevention. Live vaccines are generally contraindicated in KT recipients. However, we present a brief review of live vaccines in organ transplant recipients, as there is evidence that certain live virus vaccines may be safe and effective in select groups. Lastly, we review vaccination of pediatric KT recipients prior to international travel.

Nonsteroidal anti-inflammatory drugs are an important cause of acute kidney injury in children.

OBJECTIVE: To characterize nonsteroidal anti-inflammatory drug (NSAID)-associated acute kidney injury (AKI) in children. STUDY DESIGN: We conducted a retrospective chart review of children diagnosed with AKI through the use of International Classification of Diseases, Ninth Revision diagnosis code 584.5 or 584.9 from January 1999 to June 2010. Medical records were reviewed to confirm the diagnosis of AKI and to quantify NSAID administration. Pediatric RIFLE criteria were used to codify AKI. Patients were not classified as having NSAID-associated AKI if they had a diagnosis explaining AKI or comorbid clinical conditions predisposing to AKI development. RESULTS: Patients (N=1015) were identified through International Classification of Diseases, Ninth Revision screening. Twenty-one children had clinical, laboratory, and radiographic studies suggesting NSAID-associated acute tubular necrosis and 6 had findings suggesting NSAID-associated acute interstitial nephritis, representing 2.7% (27 of 1015) of the total cohort with AKI and 6.6% when excluding complex patients with multifactorial AKI. Children with NSAID-associated AKI had a median (range) age of 14.7 years (0.5-17.7 years); 4 patients (15%) were <5 years old. Fifteen of 20 children (75%) for whom dosing data were available received NSAIDs within recommended dosing limits. Patients<5 years old were more likely to require dialysis (100% vs 0%, P<.001), intensive care unit admission (75% vs 9%, P=.013), and a longer length of stay (median 10 vs 7 days, P=.037). CONCLUSIONS: NSAID-associated AKI accounted for 2.7% of AKI in this pediatric population. AKI typically occurred after the administration of correctly dosed NSAIDs. Young children with NSAID-associated AKI may have increased disease severity.

Prevalence of sleep disturbances in children and adolescents with chronic kidney disease.

Although sleep disorders are common in adults with chronic kidney disease, little is known about the prevalence of sleep problems in children and adolescents with chronic kidney disease and their relationship to health-related quality of life measurements. We performed a clinic-based survey of sleep habits and common symptoms of sleep disturbances in 159 school-aged patients with chronic kidney disease. Three patient groups of chronic kidney disease were assessed: group 1, those not on dialysis and not transplanted; group 2, those on dialysis; and group 3, those with a functioning renal allograft. Four symptom domains for sleep disorders were assessed: excessive daytime sleepiness; sleep disordered breathing; restless legs syndrome symptoms; and insufficient sleep. Patients and the parent-proxy also completed the Pediatric Quality of Life Inventory Version 4.0 Generic Core Scales questionnaire. Ninety-three (93) patients (58.5%) had symptoms of a sleep disturbance. The presence of a sleep disturbance correlated with a decrease in health-related quality of life scores that was independent of the chronic kidney disease study group or estimated glomerular filtration rate. We conclude that sleep disturbances are common throughout the spectrum of chronic kidney disease in children and adolescents and are associated with diminished health-related quality of life scores.

Human papillomavirus infection-related cancer risk for kidney transplant recipients during adult life can be reduced by vaccination during childhood and adolescence.

Malignancies are found between the first three reasons of mortality in pediatric and adult kidney transplant recipients, who overall have disproportionately higher rates of cancer compared to the general population, including human papillomavirus (HPV)-related genital, anal and oropharynx region cancers. Therefore, preventing HPV in this patient population is extremely important. HPV-vaccine was demonstrated to prevent HPV infection in individuals with intact immune systems. In addition, recent data reported less precancerous HPV lesions and cervical cancers with use of HPV vaccine. Since HPV is a sexually transmitted virus that is typically acquired shortly after the onset of sexual activity, it is best to administer the HPV vaccine immunization prior to the onset of sexual activity. This article reviews the epidemiology and pathophysiology of the HPV infection, as well as its role in the development of HPV-related pre-cancerous lesions and cancers in both general population and kidney transplant recipients. The focus is on the most effective primary prophylactic strategy, which is the HPV vaccination. The particularities of HPV vaccination strategies in kidney transplant recipients are compared to the general population. In addition, the article analyzes the various causes of suboptimal HPV immunization rates in kidney transplant candidates and recipients and discusses vaccination optimization strategies that can be applied during childhood and adolescence to reduce the burden of HPV-related disease states and cancer among adult kidney transplant recipients.

Case report: Histoplasmosis presenting as asymptomatic hypercalcemia detected on routine laboratory testing in a pediatric kidney transplant recipient.

Among all infections occurring in pediatric kidney transplant recipients, approximately 1%-5% are fungal. Most fungal infections occur in the first 6 months following kidney transplantation. We present the case of a 15-year-old boy with a history of a kidney transplant 4 years ago, who was found to have asymptomatic moderate hypercalcemia on routine laboratory testing, along with an acute deterioration of his kidney function markers. The cause of his acute kidney injury was likely related to hypercalcemia. An extensive workup for hypercalcemia revealed infection with Histoplasma capsulatum (histoplasmosis) with multiple pulmonary nodules. Hypercalcemia that was initially refractory to medical management resolved after initiating the antifungal treatment. Fungal granulomatous infections such as histoplasmosis should be considered in the differential diagnosis of hypercalcemia in an asymptomatic pediatric kidney transplant recipient.

Pediatric kidney transplant recipients with and without underlying structural kidney disease have a comparable risk of hospitalization associated with urinary tract infections.

Introduction: Urinary tract infections (UTIs) are a common and potentially serious kidney transplant complication. Pediatric kidney transplants are potentially at increased risk for UTIs when structural kidney disease is the underlying end-stage kidney disease (ESKD) etiology. The objective of this manuscript is to determine if children with structural kidney disorders are more prone to UTIs post kidney transplant. Materials and methods: Hospitalizations for pediatric kidney transplant recipients were retrospectively reviewed over a 4-year period for UTIs in the diagnostic codes. The patient's age, sex, graft age, underlying diagnosis for cause of ESKD, symptoms at presentation, urinalysis results, and urine culture results were recorded. UTI rates, febrile UTI rates, and UTI rates in the 1st year post-transplant were compared between children with ESKD due to structural vs. non-structural kidney disease. Results: Overall, 62 of 145 pediatric patients with kidney transplants accounted for 182 hospitalizations for kidney transplant complications over the 4-year study period. UTIs were components of 34% of the hospitalizations. Overall, UTI rates, febrile UTI rates, and UTI rates for the 1st year post kidney transplant were comparable for children with vs. without structural ESKD etiologies. Conclusion: Urinary tract infections are frequent components of hospitalizations for pediatric kidney transplant recipients. Children with and without structural kidney disease as an ESKD etiology have similar UTI rates indicating that UTI susceptibility is primarily due to the transplant process and/or medication regimens. UTIs represent a potentially modifiable risk factor for pediatric kidney transplant complications.

A 25-year experience with pediatric anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (anti-GBM) disease, which is extremely uncommon in children, is characterized by rapidly progressive glomerulonephritis (RPGN) and autoantibodies against GBM collagen. Pulmonary hemorrhage is the third component in Goodpasture Syndrome. Cigarette smoking and exposure to hydrocarbons have been linked to anti-GBM disease in adults, but such an association has not been established in children. We reviewed renal biopsy and autopsy specimens over 25 years from a major tertiary care U.S. children's hospital, diagnosing anti-GBM by clinical RPGN, crescentic glomerulonephritis, and linear immunofluorescence (IF) immunoglobulin G staining in patients under 18 years of age. We identified four patients, with and without pulmonary manifestations. The sole autopsy case showed diagnostic IF despite undetectable serum anti-GBM antibodies and positive testing for serum anti-neutrophil cytoplasmic antibodies (ANCA). Three patients have survived 1-18 years following diagnosis, one of whom is recovering renal function. One adolescent had a history of smoking cigarettes and one had a probable hydrocarbon exposure. Anti-GBM disease is unusual in children, and the relationship to inhaled agents is incompletely understood. Serum anti-GBM antibodies are typically present, but cases with undetectable levels can occur. Some patients are anti-GBM and ANCA positive, with a small subset ANCA-positive, anti-GBM-negative. Ours is the first such described pediatric case.

Influenza vaccine after pediatric kidney transplant: a Midwest Pediatric Nephrology Consortium study.

The main aim of this study was to compare the response to trivalent inactivated influenza vaccine in children who received a kidney transplant and were on steroid-free versus steroid-based immunosuppression. Groups: 1. Kidney transplant recipients on steroid-free immunosuppression (n=27); 2. Kidney transplant recipients on steroid-based immunosuppression (n=39); 3. Healthy controls (n=21). Hemagglutination inhibition titers against 2007-2008 A/H1N1 and A/H3N2 and B strains were measured before and 8 weeks postvaccination. Postvaccination geometric mean titers to A/H1N1 were significantly lower among both transplant groups than controls (p=0.025 and 0.015, respectively). Postvaccination titers to H3N2 and B strains were not statistically different between groups. Proportions of participants developing seroprotection were not different among groups. Both kidney transplant groups seroconverted less than controls for A/H1N1 (p=0.0002) and were no different from controls for B. For A/H3N2, the steroid-free group had the weakest seroconversion (p=0.008), possibly due to mycophenolate-enhanced exposure and a younger age. Overall, children after kidney transplantation demonstrated a good serologic response to the inactivated influenza vaccine although somewhat lower than controls. Steroid-free immunosuppression did not seem to present an advantage in antibody response. Data on inactivated influenza vaccine safety and efficacy was collected and demonstrated absence of acute rejection or laboratory-proven influenza for 6 months postvaccination.

Coronavirus disease 2019 (COVID-19) in two pediatric patients with kidney disease on chronic immunosuppression: A case series.

Coronavirus disease 2019 (COVID-19) is a highly infectious disease caused by the severe acute respiratory syndrome coronavirus 2 virus (SARS-CoV-2). While children appear to experience less severe disease than adults, those with underlying conditions such as kidney disease may be more susceptible to infection. Limited data are present for children with kidney disease, and there are limited prior reports of pediatric hemodialysis patients with COVID-19. This report describes the mild clinical disease course of COVID-19 in two pediatric patients with chronic kidney disease, one on hemodialysis and both on chronic immunosuppression. We review treatment in these patients, as well as our measures to reduce transmission among our hemodialysis patients and staff.

Assessment of Seroconversion to SARS-CoV-2 in a Cohort of Pediatric Kidney Transplant Recipients.

Background: The occurrence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated coronavirus disease 2019 (COVID-19) have profoundly affected adult kidney disease patients. In contrast, pediatric solid organ transplant recipients, including pediatric kidney transplant (KT) recipients, do not seem to be at particularly higher risk for SARS-CoV-2 infection or for severe COVID-19 disease. This patient population might be protected by certain mechanisms, such as the immunosuppressive medications with their anti-inflammatory properties or simply being well-versed in self-protection techniques. Assessing SARS-CoV-2 antibody serologies could potentially help understand why this patient population is apparently spared from severe SARS-CoV-2 clinical courses. Objective: To examine SARS-CoV-2 serologic status in a cohort of pediatric KT recipients. Methods: SARS-CoV-2 anti-spike IgG and IgM antibodies were measured by three different methods in pediatric KT recipients coming for routine clinic visits immediately post-confinement in May-June of 2020. The patients were considered seroconverted if SARS-CoV-2 antibodies were positive by 2/3 methods and weak positive/indeterminate if positive by 1/3. Results: Thirty-one patients were evaluated (about 1/3 of our institution's pediatric KT population). One patient seroconverted, while three were considered weak positive/indeterminate. None were symptomatic and none had nasopharyngeal PCR confirmed SARS-CoV-2 disease. Conclusions: Seroconversion to SARS-CoV-2 was rare in this population and likely reflects the social distancing practiced by these patients. The results will serve as a foundation for a future longitudinal study to evaluate the long-term emergence and persistence of antibodies in this population and may inform studies of response to a future vaccine.

Human Papillomavirus Vaccination in Male and Female Adolescents Before and After Kidney Transplantation: A Pediatric Nephrology Research Consortium Study.

Background: Kidney transplant (KT) recipients have higher incidence of malignancies, including Human Papillomavirus (HPV)-associated cancers. Thus, HPV vaccines may have an important role in preventing HPV-related disease in this population; however, immunogenicity and safety data are lacking. Objective: To examine the immunological response and tolerability to HPV vaccination in pediatric KT recipients compared to future KT candidates. Methods: The quadrivalent HPV vaccine was administered to girls and boys age 9-18 recruited from seven centers part of the Pediatric Nephrology Research Consortium. Subjects were recruited for three groups: (1) CKD: chronic kidney disease stages 3, 4, and 5 not on dialysis; (2) Dialysis; (3) KT recipients. The outcome consisted of antibody concentrations against HPV 6, 11, 16, and 18. Geometric mean titers (GMTs) and seroconversion rates were compared. Vaccine tolerability was assessed. Results: Sixty-five participants were recruited: 18 in the CKD, 18 in the dialysis, and 29 into the KT groups. KT patients had significantly lower GMTs after vaccination for all serotypes. The percentages of subjects who reached seroconversion were overall lower for the KT group, reaching statistical significance for HPV 6, 11, and 18. Comparing immunosuppressed subjects (anyone taking immunosuppression medications, whether KT recipient or not) with the non-immunosuppressed participants, the former had significantly lower GMTs for all the HPV serotypes and lower seroconversion rates for HPV 6, 11, and 18. KT females had higher GMTs and seroconversion rates for certain serotypes. There were no adverse events in either group. Conclusions: HPV vaccine was well-tolerated in this population. Pediatric KT recipients had in general lower GMTs and seroconversion rates compared to their peers with CKD or on dialysis. Immunosuppression played a role in the lack of seroconversion. Our results emphasize the importance of advocating for HPV vaccination prior to KT and acknowledge its safety post transplantation. Future studies are needed to investigate the effect of a supplemental dose of HPV vaccine in KT recipients who do not seroconvert and to evaluate the long-term persistence of antibodies post-KT.

Evaluation of T2Candida Panel for detection of Candida in peritoneal dialysates.

Fungal peritonitis in the peritoneal dialysis population is difficult to diagnose promptly due to the inherently slow cultivation-based methods currently required for identification of peritonitis pathogens. Because of the moderate risk for severe complications, the need for rapid diagnostics is considerable. One possible solution to this unmet need is the T2Candida Panel, a new technology designed to detect the most common pathogenic Candida spp. directly from whole blood specimens in as little as a few hours. We hypothesized that this technology could be applied to the detection of Candida in peritoneal dialysate, a matrix not currently approved by the Food and Drug Administration for testing by this system. Remnant dialysate samples from three healthy (noninfected) pediatric peritoneal dialysis patients were spiked with Candida glabrata, serially diluted, and tested in triplicate with unaltered dialysate specimens. The assay detected C. glabrata in 100% of spiked dialysate samples across the full spectrum of dilutions tested, and no assay inhibition or cross-reactivity was noted. These findings suggest one of possibly more applications of this technology. The positive clinical implications of this test will continue to be realized as its use is validated in peritoneal dialysate and other patient specimen types.

The Improving Renal Outcomes Collaborative: Blood Pressure Measurement in Transplant Recipients.

BACKGROUND AND OBJECTIVES: Hypertension is highly prevalent in pediatric kidney transplant recipients and contributes to cardiovascular death and graft loss. Improper blood pressure (BP) measurement limits the ability to control hypertension in this population. Here, we report multicenter efforts from the Improving Renal Outcomes Collaborative (IROC) to standardize and improve appropriate BP measurement in transplant patients. METHODS: Seventeen centers participated in structured quality improvement activities facilitated by IROC, including formal training in quality improvement methods. The primary outcome measure was the proportion of transplant clinic visits with appropriate BP measurement according to published guidelines. Prospective data were analyzed over a 12-week pre-intervention period and a 20-week active intervention period for each center and then aggregated as of the program-specific start date. We used control charts to quantify improvements across IROC centers. We applied thematic analysis to identify patterns and common themes of successful interventions. RESULTS: We analyzed data from 5392 clinic visits. At baseline, BP was measured and documented appropriately at 11% of visits. Center-specific interventions for improving BP measurement included educating clinic staff, assigning specific team member roles, and creating BP tracking tools and alerts. Appropriate BP measurement improved throughout the 20-week active intervention period to 78% of visits. CONCLUSIONS: We standardized appropriate BP measurement across 17 pediatric transplant centers using the infrastructure of the IROC learning health system and substantially improved the rate of appropriate measurement over 20 weeks. Accurate BP assessment will allow further interventions to reduce complications of hypertension in pediatric kidney transplant recipients.

Infants With Congenital Adrenal Hyperplasia Are at Risk for Hypercalcemia, Hypercalciuria, and Nephrocalcinosis.

CONTEXT: Hypercalcemia is reported as a rare finding in adrenal insufficiency, but is not well described in congenital adrenal hyperplasia (CAH). METHODS: A retrospective chart review was conducted of patients with CAH diagnosed before the age of 2 years who had at least one recorded serum calcium measurement. Data from birth to 6 years of age were reviewed. RESULTS: Of the 40 patients who met inclusion criteria, 33 (82.5%) had at least one elevated calcium concentration and 21 (53%) had two or more elevated calcium concentrations. Of the 126 elevated serum calcium concentrations, the median was 10.9 mg/dL (range, 10.6 to 14.2 mg/dL). Median age at the last elevated calcium measurement was 5 months (range, 0.3 to 46 months). Serum calcium concentration was inversely related to age (r = -0.124; P = 0.004). Overall, calcium level positively correlated with 17-hydroxyprogesterone (17OHP) concentration (r = 0.170; P = 0.003), and this remained significant after adjusting for age (P < 0.05). However, patients had hypercalcemia with both high and low 17OHP concentrations. Serum calcium concentration also was positively related to glucocorticoid (r = 0.196; P = 0.012) and fludrocortisone (r = 0.229; P = 0.003) doses, and remained significant after age adjustment. Only seven patients were evaluated for hypercalciuria. Of these, six had at least one period of documented hypercalciuria. Three patients had nephrocalcinosis on renal ultrasound. CONCLUSION: Children with CAH are at risk for developing hypercalcemia, hypercalciuria, and nephrocalcinosis. Further studies are needed to determine the broader prevalence and the etiology of hypercalcemia in CAH.

Immunogenicity of Augmented Compared With Standard Dose Hepatitis B Vaccine in Pediatric Patients on Dialysis: a Midwest Pediatric Nephrology Consortium Study.

BACKGROUND AND OBJECTIVES: Patients on maintenance dialysis have a higher risk of unresponsiveness to hepatitis B vaccination and loss of hepatitis B immunity. Adult guidelines recommend augmented dosing (40 mcg/dose), resulting in improved response in adults. We sought to determine whether children on dialysis mount a similar antibody response when given standard or augmented dosing of hepatitis B vaccine. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a retrospective review of patients on dialysis aged <19 years from May 1, 2008 to May 1, 2013 at 12 pediatric dialysis units. Hepatitis B surface antibody (HBsAb) titers ≥10 mIU/ml were defined as protective. RESULTS: A total of 187 out of 417 patients received one or more hepatitis B vaccine boosters. The median age was 13 years; the cohort was 57% boys and 59% white. Booster dose or HBsAb titers were missing in 17 patients. Conversion to protective HBsAb titers was achieved in 135 out of 170 patients (79%) after their first single-dose booster or multidose booster series. In patients receiving a single-dose booster, the response rate was 53% (nine out of 17) after a 10 mcg dose, 86% (65 out of 76) after a 20 mcg dose, and 65% (17 out of 26) after a 40 mcg hepatitis B vaccine dose. In patients receiving a multidose booster series, the response rate was 95% (19 out of 20) after a 10 mcg/dose series, 83% (20 out of 24) after a 20 mcg/dose series, and 71% (five out of seven) after a 40 mcg/dose series. Patients receiving a multidose booster series had a response rate of 86% (44 out of 51), compared with 76% (91 out of 119) in patients receiving a single-dose booster (P=0.21). Twenty-seven patients received more than one single-dose booster or multidose series, and 26 out of 27 (96%) eventually gained immunity after receiving one to three additional single-dose boosters or multidose booster series. CONCLUSIONS: There was no clear gradient of increasing seroconversion rate with increasing vaccine dose in this cohort of pediatric patients on dialysis.