Debbie S. Gipson

Management of Childhood Onset Nephrotic Syndrome

The therapeutic approach to childhood nephrotic syndrome is based on a series of studies that began with an international collaborative effort sponsored by the International Study of Kidney Disease in Children in 1967. The characteristics of children presenting with nephrotic syndrome have changed over recent decades with greater frequency of the challenging condition focal segmental glomerulosclerosis and a greater prevalence of obesity and diabetes mellitus, which may be resistant to glucocorticoids in the former and exacerbated by long-term glucocorticoid therapy in the latter 2 conditions. The Childrens Nephrotic Syndrome Consensus Conference was formed to systematically review the published literature and generate a childrens primary nephrotic syndrome guideline for use in educational, therapeutic, and research venues.

A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis

Primary focal segmental glomerulosclerosis (FSGS) is a disease with poor prognosis and high unmet therapeutic need. Here, we evaluated the safety and pharmacokinetics of single-dose infusions of fresolimumab, a human monoclonal antibody that inactivates all forms of transforming growth factor-β (TGF-β), in a phase I open-label, dose-ranging study. Patients with biopsy-confirmed, treatment-resistant, primary FSGS with a minimum estimated glomerular filtration rate (eGFR) of 25 ml/min per 1.73 m2, and a urine protein to creatinine ratio over 1.8 mg/mg were eligible. All 16 patients completed the study in which each received one of four single-dose levels of fresolimumab (up to 4 mg/kg) and was followed for 112 days. Fresolimumab was well tolerated with pustular rash the only adverse event in two patients. One patient was diagnosed with a histologically confirmed primitive neuroectodermal tumor 2 years after fresolimumab treatment. Consistent with treatment-resistant FSGS, there was a slight decline in eGFR (median decline baseline to final of 5.85 ml/min per 1.73 m2). Proteinuria fluctuated during the study with the median decline from baseline to final in urine protein to creatinine ratio of 1.2 mg/mg with all three Black patients having a mean decline of 3.6 mg/mg. The half-life of fresolimumab was ∼14 days, and the mean dose-normalized Cmax and area under the curve were independent of dose. Thus, single-dose fresolimumab was well tolerated in patients with primary resistant FSGS. Additional evaluation in a larger dose-ranging study is necessary.

Clinical trial of focal segmental glomerulosclerosis in children and young adults

This NIH-funded multicenter randomized study of focal segmental glomerulosclerosis (FSGS) treatment compared the efficacy of a 12-month course of cyclosporine to a combination of oral pulse dexamethasone and mycophenolate mofetil in children and adults with steroid-resistant primary FSGS. Of the 192 patients enrolled, 138 were randomized to cyclosporine (72) or to mycophenolate/dexamethasone (66). The primary analysis compared the levels of an ordinal variable measuring remission during the first year. The odds ratio (0.59) for achieving at least a partial remission with mycophenolate/dexamethasone compared to cyclosporine was not significant. Partial or complete remission was achieved in 22 mycophenolate/dexamethasone- and 33 cyclosporine-treated patients at 12 months. The main secondary outcome, preservation of remission for 26 weeks following cessation of treatment, was not significantly different between these two therapies. During the entire 78 weeks of study, 8 patients treated with cyclosporine and 7 with mycophenolate/dexamethasone died or developed kidney failure. Thus, our study did not find a difference in rates of proteinuria remission following 12 months of cyclosporine compared to mycophenolate/dexamethasone in patients with steroid-resistant FSGS. However, the small sample size might have prevented detection of a moderate treatment effect.

Circulating suPAR in Two Cohorts of Primary FSGS

Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to primary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the disease. Here, we analyzed circulating suPAR levels in two cohorts of children and adults with biopsy-proven primary FSGS: 70 patients from the North America-based FSGS clinical trial (CT) and 94 patients from PodoNet, the Europe-based consortium studying steroid-resistant nephrotic syndrome. Circulating suPAR levels were elevated in 84.3% and 55.3% of patients with FSGS patients in the CT and PodoNet cohorts, respectively, compared with 6% of controls (P<0.0001); inflammation did not account for this difference. Multiple regression analysis suggested that lower suPAR levels associated with higher estimated GFR, male sex, and treatment with mycophenolate mofetil. In the CT cohort, there was a positive association between the relative reduction of suPAR after 26 weeks of treatment and reduction of proteinuria, with higher odds for complete remission (P=0.04). In the PodoNet cohort, patients with an NPHS2 mutation had higher suPAR levels than those without a mutation. In conclusion, suPAR levels are elevated in geographically and ethnically diverse patients with FSGS and do not reflect a nonspecific proinflammatory milieu. The associations between a change in circulating suPAR with different therapeutic regimens and with remission support the role of suPAR in the pathogenesis of FSGS.

Assessment and treatment of short stature in pediatric patients with chronic kidney disease: a consensus statement

Growth failure is a clinically important issue in children with chronic kidney disease (CKD) and is associated with significant morbidity and mortality. Many factors contribute to impaired growth in these children, including abnormalities in the growth hormone (GH)–insulin-like growth factor-I (IGF-I) axis, malnutrition, acidosis, and renal bone disease. The management of growth failure in children with CKD is complicated by the presence of other disease-related complications requiring medical intervention. Despite evidence of GH efficacy and safety in this population, some practitioners and families have been reluctant to institute GH therapy, citing an unwillingness to comply with daily injections, reimbursement difficulties, or impending renal transplantation. Suboptimal attention to growth failure management may be further compounded by a lack of clinical guidelines for the appropriate assessment and treatment of growth failure in these children. This review of growth failure in children with CKD concludes with an algorithm developed by members of the consensus committee, outlining their recommendations for appropriate steps to improve growth and overall health outcomes in children with CKD.

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.

Health-Related Quality of Life of Children With Mild to Moderate Chronic Kidney Disease

OBJECTIVE: To compare the health-related quality of life (HRQoL) of children with chronic kidney disease (CKD) with healthy children; to evaluate the association between CKD severity and HRQoL; and to identity demographic, socioeconomic, and health-status variables that are associated with impairment in HRQoL in children with mild to moderate CKD. METHODS: This was a cross-sectional assessment of HRQoL in children who were aged 2 to 16 and had mild to moderate CKD using the Pediatric Inventory of Quality of Life Core Scales (PedsQL). Overall HRQoL and PedsQL domain means for parents and youth were compared with previously published norms by using independent sample t tests. Study participants were categorized by kidney disease stage (measured by iohexol-based glomerular filtration rate [iGFR]), and group differences in HRQoL were evaluated by using analysis of variance and Cuzick trend tests. The association between hypothesized predictors of HRQoL and PedsQL scores was evaluated with linear and logistic regression analyses. RESULTS: The study sample comprised 402 participants (mean age: 11 years, 60% male, 70% white, median iGFR: 42.5 mL/min per 1.73 m2, median CKD duration: 7 years). Youth with CKD had significantly lower physical, school, emotional, and social domain scores than healthy youth. iGFR was not associated with HRQoL. Longer disease duration and older age were associated with higher PedsQL scores in the domains of physical, emotional, and social functioning. Older age was associated with lower school domain scores. Maternal education ≥16 years was associated with higher PedsQL scores in the domains of physical, school, and social functioning. Short stature was associated with lower scores in the physical functioning domain. CONCLUSIONS: Children with mild to moderate CKD, in comparison with healthy children, reported poorer overall HRQoL and poorer physical, school, emotional, and social functioning. Early intervention to improve linear growth and to address school functioning difficulties is recommended.

A clinical tool to measure the components of health-care transition from pediatric care to adult care: the UNC TR(x)ANSITION scale.

Objective: To describe the development of the University of North Carolina (UNC) TRxANSITION Scale that measures the health-care transition and self-management skills by youth with chronic health conditions. Methods: Item and scale development of the UNC TRxANSITION Scale was informed by two theoretical models, available literature, and expert opinion interviews and feedback from youth with chronic conditions, their parents, and interdisciplinary collaboration. Through an iterative process, three versions of the scale were piloted on a total of 185 adolescents and emerging adults with different chronic illnesses. This clinically administered scale relies on a semi-structured interview format of the patient and does not rely solely on patient report, but is verified with information from the medical record to validate responses. Results: Following the item development and the three iterations of the scale, version 3 was examined in a more intensive fashion. The current version of the UNC TRxANSITION Scale comprises 33 items scattered across the following 10 domains: Type of illness, Rx=medications, Adherence, Nutrition, Self-management, Informed-reproduction, Trade/school, Insurance, Ongoing support, and New health providers. It requires approximately 7–8 min to administer. With a sample of 128 adolescents and young adults, ranging in age from 12 to 20, inter-rater reliability was strong (r = 0.71) and item-total correlation scores were moderate to high. Content and construct validity were satisfactory, and the overall score was sensitive to advancing age. The univariate linear regression yielded a beta coefficient of 1.08 (p < 0.0001), indicating that the total score increased with advancing age. Specifically, there was about a one point increase in the total score for each year of age. Conclusion: The UNC TRxANSITION Scale is a disease-neutral tool that can be used in the clinical setting. Initial findings suggest that it is a reliable and valid tool that has the potential to measure health-care transition skill mastery and knowledge in a multidimensional fashion.

A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease

It has been suggested that soluble urokinase receptor (suPAR) is a causative circulating factor for and a biomarker of focal and segmental glomerulosclerosis (FSGS). Here we undertook validation of these assumptions in both mouse and human models. Injection of recombinant suPAR in wild-type mice did not induce proteinuria within 24 hours. Moreover, a disease phenotype was not seen in an inducible transgenic mouse model that maintained elevated suPAR concentrations for 6 weeks. Plasma and urine suPAR concentrations were evaluated as clinical biomarkers in 241 patients with glomerular disease from the prospective, longitudinal multi-center observational NEPTUNE cohort. The serum suPAR concentration at baseline inversely correlated with estimated glomerular filtration rate (eGFR) and the urine suPAR/creatinine ratio positively correlated with the urine protein/creatinine ratio. After adjusting for eGFR and urine protein, neither the serum nor urine suPAR level was an independent predictor of FSGS histopathology. A multivariable mixed-effects model of longitudinal data evaluated the association between the change in serum suPAR concentration from baseline with eGFR. After adjusting for baseline suPAR concentration, age, gender, proteinuria and time, the change in suPAR from baseline was associated with eGFR, but this association was not different for patients with FSGS as compared to other diagnoses. Thus, these results do not support a pathological role for suPAR in FSGS.

Urine Podocyte mRNAs, Proteinuria, and Progression in Human Glomerular Diseases

Model systems demonstrate that progression to ESRD is driven by progressive podocyte depletion (the podocyte depletion hypothesis) and can be noninvasively monitored through measurement of urine pellet podocyte mRNAs. To test these concepts in humans, we analyzed urine pellet mRNAs from 358 adult and pediatric kidney clinic patients and 291 controls (n=1143 samples). Compared with controls, urine podocyte mRNAs increased 79-fold (P<0.001) in patients with biopsy-proven glomerular disease and a 50% decrease in kidney function or progression to ESRD. An independent cohort of patients with Alport syndrome had a 23-fold increase in urinary podocyte mRNAs (P<0.001 compared with controls). Urinary podocyte mRNAs increased during active disease but returned to baseline on disease remission. Furthermore, urine podocyte mRNAs increased in all categories of glomerular disease evaluated, but levels ranged from high to normal, consistent with individual patient variability in the risk for progression. In contrast, urine podocyte mRNAs did not increase in polycystic kidney disease. The association between proteinuria and podocyturia varied markedly by glomerular disease type: a high correlation in minimal-change disease and a low correlation in membranous nephropathy. These data support the podocyte depletion hypothesis as the mechanism driving progression in all human glomerular diseases, suggest that urine pellet podocyte mRNAs could be useful for monitoring risk for progression and response to treatment, and provide novel insights into glomerular disease pathophysiology.