Faculty Bibliography

Background Cardiovascular disease is a major cause of morbidity and mortality in children with chronic kidney disease. We sought to determine the prevalence of cardiovascular risk factors in children with glomerular disease and to describe current practice patterns regarding risk factor identification and management. Methods and Results Seven-hundred sixty-one children aged 0 to 17 years with any of 4 biopsy-confirmed primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy/vasculitis) were enrolled at a median of 16 months from glomerular disease diagnosis in the multicenter prospective Cure Glomerulonephropathy Network study. Prevalence of traditional (hypertension, hypercholesterolemia, and obesity) and novel (proteinuria, prematurity, and passive smoke exposure) cardiovascular risk factors were determined at enrollment and compared across glomerular disease subtypes. Frequency of screening for dyslipidemia and prescribing of lipid-lowering or antihypertensive medications were compared across glomerular disease subtype, steroid exposure, and remission status groups. Compared with the general population, all traditional risk factors were more frequent: among those screened, 21% had hypertension, 51% were overweight or obese, and 71% had dyslipidemia. Children who were not in remission at enrollment were more likely to have hypertension and hypercholesterolemia. Fourteen percent of hypertensive children were not receiving antihypertensives. Only 49% underwent screening for dyslipidemia and only 9% of those with confirmed dyslipidemia received lipid-lowering medications. Conclusions Children with primary glomerular diseases exhibit a high frequency of modifiable cardiovascular risk factors, particularly untreated dyslipidemia. Lipid panels should be routinely measured to better define the burden of dyslipidemia in this population. Current approaches to screening for and treating cardiovascular risk factors are not uniform, highlighting a need for evidence-based, disease-specific guidelines.

There is scant literature describing the effect of glomerular disease on health-related quality of life (HRQOL). The Cure Glomerulonephropathy study (CureGN) is an international longitudinal cohort study of children and adults with four primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy). HRQOL is systematically assessed using items from the Patient-Reported Outcomes Measurement Informative System (PROMIS). We assessed the relationship between HRQOL and demographic and clinical variables in 478 children and 1115 adults at the time of enrollment into CureGN. Domains measured by PROMIS items included global assessments of health, mobility, anxiety, fatigue, and sleep impairment, as well as a derived composite measure incorporating all measured domains. Multivariable models were created that explained 7 to 32% of variance in HRQOL. Patient-reported edema consistently had the strongest and most robust association with each measured domain of HRQOL in multivariable analysis (adjusted β [95% CI] for composite PROMIS score in children, -5.2 [-7.1 to -3.4]; for composite PROMIS score in adults, -6.1 [-7.4 to -4.9]). Female sex, weight (particularly obesity), and estimated glomerular filtration rate were also associated with some, but not all, domains of HRQOL. Primary diagnosis, disease duration, and exposure to immunosuppression were not associated with HRQOL after adjustment. Sensitivity analyses and interaction testing demonstrated no significant association between disease duration or immunosuppression and any measured domain of HRQOL. Thus, patient-reported edema has a consistent negative association with HRQOL in patients with primary glomerular diseases, with substantially greater impact than other demographic and clinical variables.

Objectives/UNASSIGNED:Lupus nephritis (LN) requires renal replacement therapy in 10%-30% of patients. About 30% of these patients receive a kidney transplant. Belatacept is a second-generation, selective, T-cell co-stimulator blocker (inhibits cytotoxic, T-lymphocyte antigen 4, CTLA-4) used as an alternative to calcineurin inhibitors (CNI) for maintenance regimens after kidney transplantation. The pathogenic relevance of CTLA-4 inhibition and the favourable cardiovascular profile of belatacept make it an attractive therapeutic option in systemic lupus erythematosus (SLE). Intravenous administration of belatacept ensures therapeutic adherence. Methods/UNASSIGNED:This retrospective, single-centre study evaluates the outcomes of LN kidney transplant recipients treated with belatacept for reasons not related to SLE at the Columbia University Lupus and Renal Transplant Cohort. Results/UNASSIGNED:Belatacept was started in six patients on CNI regimens at 15.5±17.1 months following transplantation for LN. In five patients, creatinine levels stabilised 6 months after belatacept, one returned to haemodialysis due to CNI toxicity and pyelonephritis and one relisted for a kidney transplant following acute cellular rejection and cortical necrosis. Five patients are followed for extrarenal lupus; no extrarenal manifestations were documented in the other two patients. Data on SLE disease activity pre-belatacept and post-belatacept were available and scored in three patients using the SLE Disease Activity Index Glucocorticosteroid Index (SLEDAI-2KG), which accounts for clinical and laboratory manifestations, as well as steroid dose. Mean SLEDAI-2KG decreased from 13 to 7.6. Conclusion/UNASSIGNED:Belatacept in LN kidney transplant recipients may decrease extrarenal manifestations, attenuate CNI toxicity and stabilise allograft function, providing a better alternative to CNI regimens. Furthermore, these data suggest that belatacept, although initiated for reasons not related to SLE, might have a beneficial effect in SLE.

BACKGROUND:Discard rate of Public Health Service Increased Risk (PHS-IR) organs is high despite the absence of worse kidney transplant outcomes. METHODS:We conducted a retrospective, single-center study of PHS-IR kidney offers made to kidney transplant-only potential recipients from 6/2004 to 5/2015. Overall mortality and transplant outcomes between potential recipients were stratified by response to PHS-IR kidney offers. Cox regression and Kaplan-Meier analyses of mortality and allograft failure were performed. RESULTS:A total of 2423 potential recipients were offered a PHS-IR kidney, with 1502 transplanted, with or without a PHS-IR kidney. Predictors of accepting a PHS-IR kidney included higher Estimated Post Transplant Survival (EPTS) score, prior kidney transplant, and lower educational achievement on multivariable analysis (P = 0.025, P = 0.004, P = 0.023). A positive response to a PHS-IR kidney was associated with lower risk of mortality (3.63% vs 11.6%; aHR 0.467, P = 0.0008). PHS-IR kidney recipients had decreased risk of allograft loss compared to non-PHS-IR recipients (P = 0.007), though mortality outcomes were not significantly different based on PHS-IR status (P = 0.38). No transmission of HIV, HBV, or HCV occurred from PHS-IR kidney donors in this cohort. CONCLUSIONS:Efforts must be made to increase awareness of the beneficial outcomes of PHS-IR organs to maximize appropriate donor allocation.

PURPOSE OF REVIEW/OBJECTIVE:Advances in technology to assess immunologic risk in solid organ transplant offer an opportunity to optimize the approach to pediatric deceased donor kidney transplant in the setting of a new allocation system in the United States. RECENT FINDINGS/RESULTS:Degree of human leukocyte antigen (HLA) mismatch, class II HLA mismatch, unacceptable antigens and donor-specific antibody (DSA) detected by solid-phase assays, and epitope matching pretransplant affect pediatric kidney transplant outcomes. Detection of de novo DSAs (dnDSAs) posttransplant has been associated with increased risk of acute rejection and worse allograft function. Development of dnDSA occurs in recipients with greater epitope mismatching. SUMMARY/CONCLUSIONS:Improved long-term outcomes may be anticipated in pediatric kidney transplant recipients by incorporating extended HLA mismatch information and updating the clinical approach to donor kidney matching using available technology to identify clinically relevant immunologic risk.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Use of small changes in serum creatinine to diagnose AKI allows for earlier detection but may increase diagnostic false-positive rates because of inherent laboratory and biologic variabilities of creatinine. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:We examined serum creatinine measurement characteristics in a prospective observational clinical reference cohort of 2267 adult patients with AKI by Kidney Disease Improving Global Outcomes creatinine criteria and used these data to create a simulation cohort to model AKI false-positive rates. We simulated up to seven successive blood draws on an equal population of hypothetical patients with unchanging true serum creatinine values. Error terms generated from laboratory and biologic variabilities were added to each simulated patient's true serum creatinine value to obtain the simulated measured serum creatinine for each blood draw. We determined the proportion of patients who would be erroneously diagnosed with AKI by Kidney Disease Improving Global Outcomes creatinine criteria. RESULTS:Within the clinical cohort, 75.0% of patients received four serum creatinine draws within at least one 48-hour period during hospitalization. After four simulated creatinine measurements that accounted for laboratory variability calculated from assay characteristics and 4.4% of biologic variability determined from the clinical cohort and publicly available data, the overall false-positive rate for AKI diagnosis was 8.0% (interquartile range =7.9%-8.1%), whereas patients with true serum creatinine ≥1.5 mg/dl (representing 21% of the clinical cohort) had a false-positive AKI diagnosis rate of 30.5% (interquartile range =30.1%-30.9%) versus 2.0% (interquartile range =1.9%-2.1%) in patients with true serum creatinine values <1.5 mg/dl (P<0.001). CONCLUSIONS:Use of small serum creatinine changes to diagnose AKI is limited by high false-positive rates caused by inherent variability of serum creatinine at higher baseline values, potentially misclassifying patients with CKD in AKI studies.

BACKGROUND:Acute kidney injury often goes unrecognised in its early stages when effective treatment options might be available. We aimed to determine whether an automated electronic alert for acute kidney injury would reduce the severity of such injury and improve clinical outcomes in patients in hospital. METHODS:In this investigator-masked, parallel-group, randomised controlled trial, patients were recruited from the hospital of the University of Pennsylvania in Philadelphia, PA, USA. Eligible participants were adults aged 18 years or older who were in hospital with stage 1 or greater acute kidney injury as defined by Kidney Disease Improving Global Outcomes creatinine-based criteria. Exclusion criteria were initial hospital creatinine 4·0 mg/dL (to convert to μmol/L, multiply by 88·4) or greater, fewer than two creatinine values measured, inability to determine the covering provider, admission to hospice or the observation unit, previous randomisation, or end-stage renal disease. Patients were randomly assigned (1:1) via a computer-generated sequence to receive an acute kidney injury alert (a text-based alert sent to the covering provider and unit pharmacist indicating new acute kidney injury) or usual care, stratified by medical versus surgical admission and intensive care unit versus non-intensive care unit location in blocks of 4-8 participants. The primary outcome was a composite of relative maximum change in creatinine, dialysis, and death at 7 days after randomisation. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01862419. FINDINGS/RESULTS:Between Sept 17, 2013, and April 14, 2014, 23,664 patients were screened. 1201 eligible participants were assigned to the acute kidney injury alert group and 1192 were assigned to the usual care group. Composite relative maximum change in creatinine, dialysis, and death at 7 days did not differ between the alert group and the usual care group (p=0·88), or within any of the four randomisation strata (all p>0·05). At 7 days after randomisation, median maximum relative change in creatinine concentrations was 0·0% (IQR 0·0-18·4) in the alert group and 0·6% (0·0-17·5) in the usual care group (p=0·81); 87 (7·2%) patients in the alert group and 70 (5·9%) patients in usual care group had received dialysis (odds ratio 1·25 [95% CI 0·90-1·74]; p=0·18); and 71 (5·9%) patients in the alert group and 61 (5·1%) patients in the usual care group had died (1·16 [0·81-1·68]; p=0·40). INTERPRETATION/CONCLUSIONS:An electronic alert system for acute kidney injury did not improve clinical outcomes among patients in hospital. FUNDING/BACKGROUND:Penn Center for Healthcare Improvement and Patient Safety.

BACKGROUND:Acute rejection associated with medication nonadherence is a major cause of allograft loss in pediatric kidney transplant patients. There is currently no reliable method to detect medication nonadherence and prevent allograft rejection. METHODS:In 46 pediatric patients who underwent renal transplantation between 2002 and 2003, the variation of serum drug levels was studied as a potential objective tool to monitor medication nonadherence. Tacrolimus (TAC) and mycophenolic acid (MPA) trough levels were measured from 1 to 12 months posttransplant, and standard deviation (SD) and percent coefficient of variation (CV%) were calculated. Because SD increased as mean trough levels rose, CV% (CV%=SD/mean multiplied by 100%) was used to eliminate this confounding effect. RESULTS:Ten of 46 patients had biopsy-proven rejection. The median TAC CV% was 53.4% in patients with biopsy-proven rejection, which was significantly higher than 30% in those without rejection (P=0.005). Median MPA CV% was 51.9% in patients without rejection and 45.1% in patients with rejection (P=NS). High TAC CV% correlated with increased risk for rejection, whereas MPA CV% did not. CONCLUSION/CONCLUSIONS:The TAC CV% seems to be a useful and superior marker, compared with SD alone, for assessing medication nonadherence and the possibility of allograft rejection in pediatric renal transplantation.

BACKGROUND:Malaria is the leading cause of morbidity and mortality in children younger than 5 years old and pregnant women in sub-Saharan Africa. Insecticide-treated nets (ITNs) reduce clinical malaria by more than 50% and all cause mortality in young children by 15% to 30%. However, use of these nets is poor across sub-Saharan Africa, limiting the potential impact of this effective tool in the fight against malaria. OBJECTIVE:We sought to improve the use of ITNs using a community-created and -implemented approach, and measure the change in ITN use over the year after implementation. METHODS:Using a community-based participatory research approach, we created and implemented an intervention to improve ITN use in a rural village. Our intervention involved providing hands-on instructions and assistance in hanging of nets, in-home small group education, and monthly follow-up by trained community members. ITN use was measured for all individuals in a subset of the community (61 households, 759 individuals) at baseline and at 6 months and 1 year after distribution. RESULTS:Rates of individual usage increased significantly from 29% at baseline to 88.7% (p < .001) at 6 months and to 96.6% (p < .001) at 12 months. For children under age 5, usage rates increased from 46% at baseline to 95.7% (p < .001) at 6 months and 95.4% (p < .001) at 12 months. CONCLUSION/CONCLUSIONS:Our study demonstrates that rapidly achieving and sustaining almost universal ITN usage rates is possible using a community-based approach. Closing the gap between ITN ownership and use will help communities to realize the full potential of ITNs in the prevention of malaria.

The polycystic kidney disease (PKD1) gene-encoded protein, polycystin-1, is developmentally regulated, with highest expression levels seen in normal developing kidneys, where it is distributed in a punctate pattern at the basal surface of ureteric bud epithelia. Overexpression in ureteric epithelial cell membranes of an inhibitory pMyr-GFP-PKD1 fusion protein via a retroviral (VVC) delivery system and microinjection into the ureteric bud lumen of embryonic day 11 mouse metanephric kidneys resulted in disrupted branching morphogenesis. Using confocal quantitative analysis, significant reductions were measured in the numbers of ureteric bud branch points and tips, as well as in the total ureteric bud length, volume and area, while significant increases were seen as dilations of the terminal branches, where significant increases in outer diameter and volumes were measured. Microinjection of an activating 5TM-GFP-PKD1 fusion protein had an opposite effect and showed significant increases in ureteric bud length and area. These are the first studies to experimentally manipulate polycystin-1 expression by transduction in the embryonic mouse kidney and suggest that polycystin-1 plays a critical role in the regulation of epithelial morphogenesis during renal development.