Faculty Bibliography

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10^-11). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10^-15). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

RATIONALE & OBJECTIVE/OBJECTIVE:Remission of proteinuria has been shown to be associated with lower rates of kidney disease progression among people with focal segmental glomerulosclerosis (FSGS). The goal of this study was to evaluate if reductions in proteinuria following treatment are associated with greater kidney survival. STUDY DESIGN/METHODS:Cohort analysis of clinical trial participants SETTING & PARTICIPANTS: Patients with steroid resistant FSGS enrolled in a randomized treatment trial that compared cyclosporine to mycophenolate mofetil plus dexamethasone. PREDICTORS/METHODS:Reduction in proteinuria measured during 26 weeks after initiating treatment OUTCOMES: Repeated measures of estimated glomerular filtration rate (eGFR) and, time to end-stage kidney disease (ESKD) or death assessed between 26 weeks and 54 months after randomization ANALYTIC APPROACH: Multivariable, linear-mixed effects models with subject-specific slope and intercept to estimate the association of change in proteinuria over 26 weeks while receiving treatment with the subsequent slope of change in eGFR. Multivariable, time-varying Cox-proportional hazards models were used to estimate the association of changes in proteinuria with time to ESKD or death. RESULTS:138 of 192 trial participants were included. Changes in proteinuria over 26 weeks were significantly related to eGFR slope. A 1 unit reduction in log-transformed urinary protein:creatinine ratio was associated with a 3.90 ml/year rise in eGFR (95% CI=2.01 to 5.79). This difference remained significant after adjusting for complete remission. There was an analogous relationship between time-varying proteinuria and time to end-stage kidney disease: the HR for ESKD or death per 1 unit reduction in log-transformed urinary protein-creatinine ratio was 0.23 (95% CI=0.12 to 0.44). LIMITATIONS/CONCLUSIONS:Limited to individuals with steroid-resistant FSGS followed for a maximum of five-years. CONCLUSIONS:These findings provide evidence for the benefit of urinary protein reduction in FSGS. Reductions in proteinuria warrant further evaluation as a potential surrogate for preservation of kidney function that may inform the design of future clinical trials.

The causes of kidney disease in pediatric patients are evenly divided between congenital abnormalities of the kidney and urinary tract and acquired disorders. Nearly 10% to 15% of adults in the United States have chronic kidney disease (CKD); there are no comparable data in children. Regardless of patient age, CKD is a systemic problem that affects every organ system, including the lung. We review the tests used to diagnose and evaluate kidney disease and the main clinical syndromes that are likely to be encountered to aid the pulmonology consultant who is asked to evaluate patients with kidney disease.

Background: Sparsentan is a novel Dual Endothelin Angiotensin Receptor Antagonist (DEARA) being investigated for focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN). It is a dual acting, highly selective antagonist of both the endothelin A receptor (ETAR) and the angiotensin II subtype 1 receptor (AT1R). The Phase 2 EPPIK study will examine the long-term antiproteinuric and nephroprotective potential and safety of sparsentan in pediatric patients with FSGS, minimal change disease (MCD), IgAN, IgA vasculitis (IgAV), and Alport syndrome (AS).
Method(s): The global, open-label, single-arm, multicenter study will evaluate the safety, efficacy, and pharmacokinetics (PK) of sparsentan in ~57 patients (aged >=1 to <18 years), including ~30 with FSGS and/or MCD (population 1) and ~27 with IgAN, IgAV, or AS (population 2) over 108 weeks (Figure). See Table for inclusion/exclusion criteria. Sparsentan will be administered in a novel liquid formulation at a dose adjusted to body weight.
Result(s): Primary endpoints include safety (incidence of treatment-emergent adverse events) and change in urine protein/creatinine ratio (UP/C) from baseline over 108 weeks of sparsentan treatment. Secondary endpoints include PK outcomes, change from baseline over 108 weeks in albumin/creatinine ratio and eGFR, and the proportion of patients with FSGS/MCD who achieve partial remission (UP/C <=1.5 g/g and >40% reduction in UP/C).
Conclusion(s): This Phase 2 study will evaluate the long-term safety, antiproteinuric, and nephroprotective effects of sparsentan in pediatric patients

Background: Hematuria is associated with the incidence and progression of CKD. The study aims were to assess the prevalence of hematuria in a large cohort of proteinuric glomerular disease and assess the association between hematuria and kidney-related outcomes.
Method(s): Hematuria was assessed at first reported study urinalysis in patients with MN, MCD, and FSGS in NEPTUNE and CureGN cohorts with >24 months of followup. Hematuria was defined as small, moderate, or large blood on urinary dipstick and no hematuria was negative or trace blood. Multivariable Cox proportional hazards models were fit for time to composite outcome (ESKD or 40% decline in GFR and eGFR <60) and proteinuria remission (UPCR <0.3 mg/mg).
Result(s): 1,108 adults and children were included. 412 (37%) patients had FSGS, 389 (36%) had MCD, and 307 (28%) had MN. 745 (67%) participants were positive for hematuria at first urinalysis. Those who had hematuria vs. those without at first urinalysis were more likely to have an underlying diagnosis of MN (37% vs 23%), be older (34 vs 25 years), have shorter time since biopsy (128 vs 315 days) and higher UPCR (3.6 vs 0.8). Patients with hematuria had higher rates of the composite outcome and lower rates of complete remission (Figure 1). After adjusting for diagnosis, age, sex, UPCR, eGFR, time since biopsy, and cohort, hematuria was associated with a higher hazard of reaching the composite outcome (HR 1.39 [1.05, 1.84], p-value 0.02) and lower hazard of reaching proteinuria remission (HR 0.71 [0.55-0.91], p-value 0.006).
Conclusion(s): Hematuria is prevalent among patients with podocytopathic disease not classically considered nephritic. There was an independent association between hematuria and worse kidney related outcomes. The underlying mechanisms warrants further investigation and include genetic predisposition, structural alterations in the glomerular basement membrane, and tubular toxicity from heme pigment. (Figure Presented)

There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.

BACKGROUND:Exposure to environmental chemicals may be a modifiable risk factor for progression of chronic kidney disease (CKD). The purpose of this study was to examine the impact of serially assessed exposure to bisphenol A (BPA) and phthalates on measures of kidney function, tubular injury, and oxidative stress over time in a cohort of children with CKD. METHODS AND FINDINGS/RESULTS:Samples were collected between 2005 and 2015 from 618 children and adolescents enrolled in the Chronic Kidney Disease in Children study, an observational cohort study of pediatric CKD patients from the US and Canada. Most study participants were male (63.8%) and white (58.3%), and participants had a median age of 11.0 years (interquartile range 7.6 to 14.6) at the baseline visit. In urine samples collected serially over an average of 3.0 years (standard deviation [SD] 1.6), concentrations of BPA, phthalic acid (PA), and phthalate metabolites were measured as well as biomarkers of tubular injury (kidney injury molecule-1 [KIM-1] and neutrophil gelatinase-associated lipocalin [NGAL]) and oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG] and F2-isoprostane). Clinical renal function measures included estimated glomerular filtration rate (eGFR), proteinuria, and blood pressure. Linear mixed models were fit to estimate the associations between urinary concentrations of 6 chemical exposure measures (i.e., BPA, PA, and 4 phthalate metabolite groups) and clinical renal outcomes and urinary concentrations of KIM-1, NGAL, 8-OHdG, and F2-isoprostane controlling for sex, age, race/ethnicity, glomerular status, birth weight, premature birth, angiotensin-converting enzyme inhibitor use, angiotensin receptor blocker use, BMI z-score for age and sex, and urinary creatinine. Urinary concentrations of BPA, PA, and phthalate metabolites were positively associated with urinary KIM-1, NGAL, 8-OHdG, and F2-isoprostane levels over time. For example, a 1-SD increase in ∑di-n-octyl phthalate metabolites was associated with increases in NGAL (β = 0.13 [95% CI: 0.05, 0.21], p = 0.001), KIM-1 (β = 0.30 [95% CI: 0.21, 0.40], p < 0.001), 8-OHdG (β = 0.10 [95% CI: 0.06, 0.13], p < 0.001), and F2-isoprostane (β = 0.13 [95% CI: 0.01, 0.25], p = 0.04) over time. BPA and phthalate metabolites were not associated with eGFR, proteinuria, or blood pressure, but PA was associated with lower eGFR over time. For a 1-SD increase in ln-transformed PA, there was an average decrease in eGFR of 0.38 ml/min/1.73 m2 (95% CI: -0.75, -0.01; p = 0.04). Limitations of this study included utilization of spot urine samples for exposure assessment of non-persistent compounds and lack of specific information on potential sources of exposure. CONCLUSIONS:Although BPA and phthalate metabolites were not associated with clinical renal endpoints such as eGFR or proteinuria, there was a consistent pattern of increased tubular injury and oxidative stress over time, which have been shown to affect renal function in the long term. This raises concerns about the potential for clinically significant changes in renal function in relation to exposure to common environmental toxicants at current levels.

BACKGROUND:It is important to monitor the scope of clinical research of all types, to involve participants of all ages and subgroups in studies that are appropriate to their condition, and to ensure equal access and broad validity of the findings. OBJECTIVE:We conducted a review of clinical research performed at New York University with the following objectives: (1) to determine the utility of institutional administrative data to characterize clinical research activity; (2) to assess the inclusion of special populations; and (3) to determine if the type, initiation, and completion of the study differed by age. METHODS:Data for all studies that were institutional review board-approved between January 1, 2014, and November 2, 2016, were obtained from the research navigator system, which was launched in November 2013. One module provided details about the study protocol, and another module provided the characteristics of individual participants. Research studies were classified as observational or interventional. Descriptive statistics were used to assess the characteristics of clinical studies across the lifespan, by type, and over time. RESULTS:A total of 22%-24% of studies included children (minimum age <18 years) and 4%-5% focused exclusively on pediatrics. Similarly, 64%-72% of studies included older patients (maximum age >65 years) but only 5%-12% focused exclusively on geriatrics. Approximately 85% of the studies included both male and female participants. Of the remaining studies, those open only to girls or women were approximately 3 times as common as those confined to boys or men. A total of 56%-58% of projects focused on nonvulnerable patients. Among the special populations studied, children (12%-15%) were the most common. Noninterventional trial types included research on human data sets (24%), observational research (22%), survey research (16%), and biospecimen research (8%). The percentage of projects designed to test an intervention in a vulnerable population increased from 17% in 2014 to 21% in 2015. CONCLUSIONS:Pediatric participants were the special population that was most often studied based on the number of registered projects that included children and adolescents. However, they were much less likely to be successfully enrolled in research studies compared with adults older than 65 years. Only 20% of the studies were interventional, and 20%-35% of participants in this category were from vulnerable populations. More studies are exclusively devoted to women's health issues compared with men's health issues.

BACKGROUND:Glomerulosclerosis represents the final stage of glomerular injury during the course of kidney disease and can represent a primary disturbance in disorders like focal segmental glomerulosclerosis or a secondary response to tubulointerstitial disease. Overall, primary focal glomerulosclerosis (FSGS), the focus of this review, accounts for 10-20% of patients of all ages who progress to end stage kidney disease. There are no FDA approved therapeutic options that effectively prevent or delay the onset of kidney failure. AREAS COVERED/UNASSIGNED:Current immunosuppressive therapy and conservative management including inhibitors of the renin-angiotensin-aldosterone axis and sodium-glucose cotransporter are reviewed. Focal segmental glomerulosclerosis is now recognized to represent a heterogeneous entity with multiple underlying disease mechanisms. Therefore, novel approaches targeting the podocyte cytoskeleton, immunological, inflammatory, hemodynamic and metabolic pathways are highlighted. EXPERT OPINION/UNASSIGNED:A number of factors that are driving the development of drugs to treat focal segmental glomerulosclerosis in particular and glomerulosclerosis in general including growing awareness of the burden of chronic kidney disease, improved scientific understanding of the mechanism of injury, the development of non-invasive profiles to identify subgroups of patients with discrete mechanisms of glomerular injury.

Background/UNASSIGNED:Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS). Methods/UNASSIGNED:FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied. Results/UNASSIGNED: 0.03). Conclusions/UNASSIGNED:PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes.