Keisha L. Gibson

End-Stage Renal Disease in African Americans With Lupus Nephritis Is Associated With APOL1

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end‐stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk.

Design of the nephrotic syndrome study network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach

The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multi-center collaborative consortium established to develop a translational research infrastructure for Nephrotic Syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary studies program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis and membranous nephropathy for detailed clinical, histopathologic, and molecular phenotyping at the time of clinically-indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and bi-annually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histologic data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for Nephrotic Syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.

Predictors of Relapse and End Stage Kidney Disease in Proliferative Lupus Nephritis: Focus on Children, Adolescents, and Young Adults

BACKGROUND AND OBJECTIVES The prevalence and significance of remission and relapse in children, adolescents, and young adults with lupus nephritis in the United States are poorly understood. Patterns and predictors of disease progression in a southeastern U.S. pediatric cohort with severe lupus nephritis are presented. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS Individuals age 21 or less with kidney biopsy-proven lupus nephritis followed in the Glomerular Disease Collaborative Network were included. Cox regression models were used to evaluate predictors of relapse and end stage kidney disease (ESKD). RESULTS Seventy-three subjects with a mean age of 15.6 +/- 3.4 yr were included. Five-year kidney survival was 77%. Complete and partial remission rates within 1 yr of induction therapy were 25 and 64%, respectively. Relapse and ESKD rates were similar between complete and partial responders. Relapse occurred in 35% of responders (complete or partial) in 45 +/- 32 mo. Disease relapse was a predictor of ESKD (HR = 10.12, P < 0.0001). Treatment resistance was documented in African Americans more often than non-African Americans (eight versus 0; P = 0.03). ESKD HR associated with treatment resistance was 6.25, P < 0.002. CONCLUSIONS Remission whether complete or partial is associated with improved kidney survival in children with lupus nephritis. Nephritis relapse is a strong predictor of progression to ESKD. Treatment resistance portends a high risk of ESKD and disproportionately affects African American children with lupus nephritis.

Obesity, Albuminuria, and Urinalysis Findings in US Young Adults from the Add Health Wave III Study

BACKGROUND AND OBJECTIVES Obesity has been associated with kidney disease in adults. This study was designed to evaluate the association of obesity with an early marker of kidney disease, albuminuria, among young adults. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Urinalysis (n = 9371), albumin-to-creatinine ratio (n = 4463), and body mass index (kg/m2) were measured in the Add Health Wave III cohort (2001 to 2002), a multiethnic sample of young adults followed for approximately 6 yr. Multivariate logistic regression modeled the association of sex-specific albuminuria with body mass index, adjusted for sample weights, sex, race, ethnicity, and glycosuria. RESULTS Urinalysis revealed that 0.8% had proteinuria, 4.6% had hematuria, 0.2% had combined hematuria and proteinuria, and 1.5% had glycosuria. Albuminuria prevalence was 4.4%. Mean body mass index was higher among those with albuminuria compared with those without. There were no associations between body mass index categories of 25 to < 30 or 30 to < 35 kg/m2 with albuminuria compared with the lowest body mass index (< 25 kg/m2); however, the highest category (> or = 35 kg/m2) was associated with albuminuria, compared with the lowest category (OR = 1.76, 95% CI: 1.02 to 3.04). Glycosuria (OR = 4.0; 95% CI: 1.5 to 11.1, p < 0.01) as well as increasing body mass index during the 6-yr follow-up (OR: 1.07 per unit change in kg/m2; 95% CI: 1.00 to 1.13, p = 0.04) were also associated with albuminuria. CONCLUSIONS Given the increasing prevalence of obesity, the association of albuminuria associated with obesity in young adults is particularly concerning. Obesity may be a target for primary prevention of kidney and cardiovascular disease.

Disease Activity, Proteinuria, and Vitamin D Status in Children with Systemic Lupus Erythematosus and Juvenile Dermatomyositis

OBJECTIVE To evaluate relationships among vitamin D, proteinuria, and disease activity in pediatric systemic lupus erythematosus (SLE) and juvenile dermatomyositis (JDM). STUDY DESIGN Multiple linear regression was used to associate subject-reported race, sunscreen use, and vitamin D intake with physician-assessed disease activity and serum 25-hydroxyvitamin D (25[OH]D) in 58 subjects with pediatric SLE (n=37) or JDM (n=21). Serum 25(OH)D was correlated with urinary vitamin D binding protein/creatinine ratio (DBP/C) and other indicators of proteinuria. RESULTS Serum 25(OH)D levels in subjects with SLE were inversely associated with the natural log of urinary DBP/C (r=-0.63, P<.001) and urine protein to creatinine ratio (r=-0.60, P<.001), with an adjusted mean 10.9-ng/mL (95% CI, 5.1-16.8) decrease in 25(OH)D for those with proteinuria. Excluding subjects with proteinuria, serum 25(OH)D levels were inversely associated with disease activity in JDM, but not in SLE. Overall, 66% of all subjects were taking concurrent corticosteroids, but this was not associated with 25(OH)D levels. CONCLUSIONS Low serum 25(OH)D in patients with SLE is associated with proteinuria and urinary DBP. Vitamin D deficiency is associated with disease activity in patients with JDM and SLE; this relationship in SLE may be confounded by proteinuria.

Therapeutic approach to FSGS in children

Therapy of primary focal segmental glomerulosclerosis (FSGS) in children incorporates conservative management and immunosuppression regimens to control proteinuria and preserve kidney function. In long-term cohort studies in adults and children with primary FSGS, renal survival has been directly associated with degree of proteinuria control. This educational article reviews the current therapeutic approach toward children with primary FSGS.

Cognitive Pharmacy Services at a Pediatric Nephrology and Hypertension Clinic

Purpose: Pediatric patients require special attention from pediatric pharmacists. This is particularly true for pediatric patients with chronic kidney disease (CKD) as the number of their medications and the complexity of their treatment increase with disease progression. However, there is paucity of information describing pediatric cognitive pharmacy services in this setting. The objective of this study is to identify the potential roles of a clinical pharmacist as a provider in a pediatric nephrology and hypertension clinic. Methods: Pediatric patients (≤18 years of age) who chronically took at least one medication were consecutively enrolled at the University of North Carolina (UNC) Pediatric Nephrology and Hypertension Clinic from 1 August 2007 to 15 April 2008. Demographic information and the interventions performed during the clinic visit by a clinical pharmacist were examined. Results: Three hundred and seventy-four visits made in 283 participants were evaluated. The mean (SD) number of cognitive pharmacy interventions per patient was 2.3 (1.0) on the first visit, with medication counseling and verification of current medications comprising the most common activity (85%). The mean (SD) number of medications per patient was 5.7 (4.8) and of medications counseled per visit was 4.0 (3.4). Medication adherence was investigated in 141 (38%) visits. Pretransplant education on medications was performed in 3% of the patients. Discrepancies of medications were discovered in 12 of the 374 visits. Conclusion: Pediatric cognitive pharmacy services to patients at the UNC pediatric nephrology clinic were feasible, which improved the quality of services and promoted better outcomes for these complex patients.

Complete Remission in the Nephrotic Syndrome Study Network

BACKGROUND AND OBJECTIVES This analysis from the Nephrotic Syndrome Study Network (NEPTUNE) assessed the phenotypic and pathology characteristics of proteinuric patients undergoing kidney biopsy and defined the frequency and factors associated with complete proteinuria remission (CRever). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We enrolled adults and children with proteinuria ≥0.5 g/d at the time of first clinically indicated renal biopsy at 21 sites in North America from April 2010 to June 2014 into a prospective cohort study. NEPTUNE central pathologists assigned participants to minimal-change disease (MCD), FSGS, membranous nephropathy, or other glomerulopathy cohorts. Outcome measures for this analysis were (1) CRever with urine protein-to-creatinine ratio (UPC) <0.3 g/g with preserved native kidney function and (2) ESRD. Continuous variables are reported as median and interquartile range (IQR; 25th, 75th percentile). Cox proportional hazards modeling was used to assess factors associated with CRever. RESULTS We enrolled 441 patients: 116 (27%) had MCD, 142 (32%) had FSGS, 66 (15%) had membranous nephropathy, and 117 (27%) had other glomerulopathy. The baseline UPC was 4.1 g/g (IQR, 1.9, 7.7) and the eGFR was 81 ml/min per 1.73 m(2) (IQR, 50, 105). Median duration of observation was 19 months (IQR, 11, 30). CRever occurred in 46% of patients, and 4.6% progressed to ESRD. Multivariate analysis demonstrated that higher prebiopsy proteinuria (hazard ratio, 0.3; 95% confidence interval, 0.2 to 0.5) and pathology diagnosis (FSGS versus MCD; hazard ratio, 0.2; 95% confidence interval, 0.1 to 0.5) were inversely associated with CRever. The effect of immunosuppressive therapy on remission varied by pathology diagnosis. CONCLUSIONS In NEPTUNE, the high frequency of other pathology in proteinuric patients affirms the value of the diagnostic kidney biopsy. Clinical factors, including level of proteinuria before biopsy, pathology diagnosis, and immunosuppression, are associated with complete remission.

APOL1-Associated glomerular disease among African-American children: A collaboration of the chronic kidney disease in children (CKiD) and nephrotic syndrome study network (NEPTUNE) cohorts

Background Individuals of African ancestry harboring two variant alleles within apolipoprotein L1 ( APOL1 ) are classified with a high-risk (HR) genotype. Adults with an HR genotype have increased risk of focal segmental glomerulosclerosis and chronic kidney disease compared with those with a low-risk (LR) genotype (0 or 1 variants). The role of APOL1 risk genotypes in children with glomerular disease is less well known. Methods This study characterized 104 African-American children with a glomerular disease by APOL1 genotype in two cohorts: the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE). Results Among these subjects, 46% had an HR genotype with a similar age at cohort enrollment. For APOL1 HR children, the median age of disease onset was older (CKiD: 4.5 versus 11.5 years for LR versus HR; NEPTUNE: 11 versus 14 years for LR versus HR, respectively) and preterm birth was more common [CKiD: 27 versus 4%; NEPTUNE: 26 versus 12%; combined odds ratio 4.6 (95% confidence interval: 1.4, 15.5)]. Within studies, HR children had lower initial estimated glomerular filtration rate (eGFR) (CKiD: 53 versus 69 mL/min/1.73 m 2 ; NEPTUNE: 74 versus 94 mL/min/1.73 m 2 ). Longitudinal eGFR decline was faster among HR children versus LR (CKiD: -18 versus -8% per year; NEPTUNE: -13 versus -3% per year). Conclusions Children with an HR genotype in CKiD and NEPTUNE seem to have a more aggressive form of glomerular disease, in part due to a higher prevalence of focal segmental glomerulosclerosis. These consistent findings across independent cohorts suggest a common natural history for children with APOL1 -associated glomerular disease. Further study is needed to determine the generalizability of these findings.

Corticosteroid Therapy for Henoch Schönlein Purpura

Weiss et al’s1 meta-analysis concludes that several weeks of corticosteroid use decreases the risk of longterm renal disease in children presenting with Henoch Schonlein purpura (HSP). They base this conclusion on a combined odds ratio ([OR]: 0.43; 95% confidence interval (CI): [0.19 – 0.96]) of 3 placebo-controlled or prospective trials. We disagree with their conclusion on the basis of selection bias in the studies reported, differences in duration of follow-up, as well as new data from a prospective study presented by Dudley et al2 at the 2007 American Society of Nephrology meeting that reported no differences in development of renal disease between those receiving prednisolone and placebo (OR: 1.32; 95% CI: [0.59 –2.94]). Extrapolating the results of the analyzed trials to the practice of the primary care pediatrician may not be wise, because the children reported were either hospitalized for HSP or presented to a tertiary care level emergency department. It is reasonable to assume that they, on average, were sicker and may have had more severe involvement than the child with HSP presenting to a primary care practice. Methodologic issues that raise concern about the validity of Weiss et al’s1 meta-analysis include differences in treatment regimens and follow-up duration. Follow-up periods for each study were quite different with Ronkainen et al3 who reported 6 months of follow-up compared with 1 year for the Mollica et al4 and Huber et al5 trials. Also, the Mollica et al4 study, which was designed as an incidence trial compared with the prevalence design of the other 3 studies, included 2 patients who developed renal disease 1 year after their HSP diagnosis but are not taken into account by Weiss et al1 in their metanalysis. If we exclude Mollica et al4 from the meta-analysis and add the Dudley et al2 study, we measure a new combined OR: 0.89; 95% CI (0.52–1.54). However, if the Dudley et al and Mollica et al2,4 studies are included, we measure a combined OR: 0.77; 95% CI (0.44 –1.39) (Fig 1). Both of the combined OR reported indicate a trend toward supporting steroids in patients with HSP, but neither are statistically significant because the CIs cross the null. Weiss et al1 in their sensitivity analysis for future studies estimate that 5%–20% of untreated patients with HSP will develop persistent renal involvement. This is a large overestimate because long-term studies of unselected patients with HSP show less than a 2% prevalence of persistent renal involvement.6 The relatively small subgroup of HSP patients who may benefit from corticosteroids includes those who present with renal involvement and probably those with severe abdominal symptoms requiring medical attention.4,6,7 In summary, we feel the data does not currently exist, however, to recommend the routine use of corticosteroids to prevent renal disease in children with uncomplicated HSP, and that if steroids are to be used for these children, it should be only in the context of a controlled trial.