Michelle R. Denburg

Risk of moderate to advanced kidney disease in patients with psoriasis: population based cohort study.

Objective To determine the risk of chronic kidney disease in patients with psoriasis. Design Population based cohort study and nested cross sectional study. Setting Electronic medical records database based in United Kingdom. Participants Cohort study: patients with psoriasis aged 18-90 each matched to up to five patients without psoriasis based on age, practice, and time of visit. Nested study: patients with psoriasis aged 25-64 with confirmed data on psoriasis severity, each matched to up to 10 patients without psoriasis based on age and practice. Main outcome measures Cohort study: incident moderate to advanced (stage 3 through 5) chronic kidney disease. Nested study: baseline prevalence of chronic kidney disease. Results 136 529 patients with mild psoriasis and 7354 patients with severe psoriasis based on treatment patterns were matched to 689 702 unaffected patients. The adjusted hazard ratios (95% confidence intervals) for incident chronic kidney disease were 1.05 (1.02 to 1.07), 0.99 (0.97 to 1.02), and 1.93 (1.79 to 2.08) in the overall, mild, and severe psoriasis groups, respectively. Age was a significant effect modifier in the severe psoriasis group, with age specific adjusted hazard ratios (95% confidence intervals) of 3.82 (3.15 to 4.64) and 2.00 (1.86 to 2.17) for patients aged 30 and 60, respectively. In the nested analysis of 8731 patients with psoriasis with measurements of affected body surface area matched to 87 310 patients without psoriasis, the adjusted odds ratios (95% confidence intervals) for chronic kidney disease were 0.89 (0.72 to 1.10), 1.36 (1.06 to 1.74), and 1.58 (1.07 to 2.34) in the mild, moderate, and severe psoriasis groups, respectively. Conclusions Moderate to severe psoriasis is associated with an increased risk of chronic kidney disease independent of traditional risk factors.

Type 1 Diabetes Is Associated With an Increased Risk of Fracture Across the Life Span: A Population-Based Cohort Study Using The Health Improvement Network (THIN)

OBJECTIVE This study was conducted to determine if type 1 diabetes is associated with an increased risk of fracture across the life span. RESEARCH DESIGN AND METHODS This population-based cohort study used data from The Health Improvement Network (THIN) in the U.K. (data from 1994 to 2012), in which 30,394 participants aged 0–89 years with type 1 diabetes were compared with 303,872 randomly selected age-, sex-, and practice-matched participants without diabetes. Cox regression analysis was used to determine hazard ratios (HRs) for incident fracture in participants with type 1 diabetes. RESULTS A total of 334,266 participants, median age 34 years, were monitored for 1.9 million person-years. HR were lowest in males and females age <20 years, with HR 1.14 (95% CI 1.01–1.29) and 1.35 (95% CI 1.12–1.63), respectively. Risk was highest in men 60–69 years (HR 2.18 [95% CI 1.79–2.65]), and in women 40–49 years (HR 2.03 [95% CI 1.73–2.39]). Lower extremity fractures comprised a higher proportion of incident fractures in participants with versus those without type 1 diabetes (31.1% vs. 25.1% in males, 39.3% vs. 32% in females; P < 0.001). Secondary analyses for incident hip fractures identified the highest HR of 5.64 (95% CI 3.55–8.97) in men 60–69 years and the highest HR of 5.63 (95% CI 2.25–14.11) in women 30–39 years. CONCLUSIONS Type 1 diabetes was associated with increased risk of incident fracture that began in childhood and extended across the life span. Participants with type 1 diabetes sustained a disproportionately greater number of lower extremity fractures. These findings have important public health implications, given the increasing prevalence of type 1 diabetes and the morbidity and mortality associated with hip fractures.

Comparison of Two ELISA Methods and Mass Spectrometry for Measurement of Vitamin D‐Binding Protein: Implications for the Assessment of Bioavailable Vitamin D Concentrations Across Genotypes

Studies using vitamin D‐binding protein (DBP) concentrations to estimate free and bioavailable vitamin D have increased dramatically in recent years. Combinations of two single‐nucleotide polymorphisms (SNPs) produce three major DBP isoforms (Gc1f, Gc1s, and Gc2). A recent study showed that DBP concentrations quantified by liquid chromatography–tandem mass spectrometry (LC‐MS/MS) did not differ by race, whereas a widely used monoclonal enzyme‐linked immunosorbent assay (ELISA) quantified DBP differentially by isoform, yielding significantly lower DBP concentrations in black versus white individuals. We compared measurements of serum DBP using a monoclonal ELISA, a polyclonal ELISA, and LC‐MS/MS in 125 participants in the Chronic Renal Insufficiency Cohort (CRIC). Serum free and bioavailable 25OHD were calculated based on DBP concentrations from these three assays in homozygous participants, and race differences were compared. We confirmed that the monoclonal ELISA quantifies DBP differentially by isoform and showed that the polyclonal ELISA is not subject to this bias. Whereas ≤9% of the variability in DBP concentrations quantified using either LC‐MS/MS or the polyclonal ELISA was explained by genotype, 85% of the variability in the monoclonal ELISA‐based measures was explained by genotype. DBP concentrations measured by the monoclonal ELISA were disproportionately lower than LC‐MS/MS‐based results for Gc1f homozygotes (median difference –67%; interquartile range [IQR] –71%, –64%), 95% of whom were black. In contrast, the polyclonal ELISA yielded consistently and similarly higher measurements of DBP than LC‐MS/MS, irrespective of genotype, with a median percent difference of +50% (IQR +33%, +65%). Contrary to findings using the monoclonal ELISA, DBP concentrations did not differ by race, and free and bioavailable 25OHD were significantly lower in black versus white participants based on both the polyclonal ELISA and LC‐MS/MS, consistent with their lower total 25OHD. Future studies of DBP and free or bioavailable vitamin D metabolites should employ DBP assays that are not biased by DBP genotype.

Annual Incidence of Nephrolithiasis among Children and Adults in South Carolina from 1997 to 2012

BACKGROUND AND OBJECTIVES The prevalence of nephrolithiasis in the United States has increased substantially, but recent changes in incidence with respect to age, sex, and race are not well characterized. This study examined temporal trends in the annual incidence and cumulative risk of nephrolithiasis among children and adults living in South Carolina over a 16-year period. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We performed a population-based, repeated cross-sectional study using the US Census and South Carolina Medical Encounter data, which capture all emergency department visits, surgeries, and admissions in the state. The annual incidence of nephrolithiasis in South Carolina from 1997 to 2012 was estimated, and linear mixed models were used to estimate incidence rate ratios for age, sex, and racial groups. The cumulative risk of nephrolithiasis during childhood and over the lifetime was estimated for males and females in 1997 and 2012. RESULTS Among an at-risk population of 4,625,364 people, 152,925 unique patients received emergency, inpatient, or surgical care for nephrolithiasis. Between 1997 and 2012, the mean annual incidence of nephrolithiasis increased 1% annually from 206 to 239 per 100,000 persons. Among age groups, the greatest increase was observed among 15-19 year olds, in whom incidence increased 26% per 5 years (incidence rate ratio, 1.26; 95% confidence interval, 1.22 to 1.29). Adjusting for age and race, incidence increased 15% per 5 years among females (incidence rate ratio, 1.15; 95% confidence interval, 1.14 to 1.16) but remained stable for males. The incidence among blacks increased 15% more per 5 years compared with whites (incidence rate ratio, 1.15; 95% confidence interval, 1.14 to 1.17). These changes in incidence resulted in doubling of the risk of nephrolithiasis during childhood and a 45% increase in the lifetime risk of nephrolithiasis for women over the study period. CONCLUSIONS The incidence of kidney stones has increased among young patients, particularly women, and blacks.

BK Viremia Precedes Hemorrhagic Cystitis in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

BK virus is associated with hemorrhagic cystitis after hematopoietic stem cell transplantation (HSCT), although evidence supporting a causal relationship remains limited. Although BK viruria is common after HSCT, BK viremia may better predict clinically significant cystitis, similar to its predictive value for nephropathy after kidney transplantation. We hypothesized that BK viremia would precede hemorrhagic cystitis in a cohort of 88 consecutive children prospectively enrolled to originally study thrombotic microangiopathy in the first 100 days after allogeneic HSCT. Cox regression models with time-varying covariates assessed the association between different BK viremia cutoffs and the development of hemorrhagic cystitis, defined as at least macroscopic hematuria. Subjects with a peak plasma BK viral load 1 to 9999 copies/mL had an adjusted hazard ratio of 4.2 (95% confidence interval (CI), 1.3 to 13.7) for the development of hemorrhagic cystitis. Those with peak BK viremia >100,000 copies/mL had an adjusted hazard ratio of 116.8 (95% CI, 12 to 1136) for cystitis. Other independent risk factors for hemorrhagic cystitis included age >7 years and HHV-6 viremia. Neither graft-versus-host disease nor achieving engraftment increased the risk for cystitis. If therapeutic strategies are found to be effective, these observations may support screening for BK viremia after HSCT, as currently recommended for other DNA viruses.

Mineral metabolism and cortical volumetric bone mineral density in childhood chronic kidney disease.

CONTEXT The relationships among cortical volumetric bone mineral density (CortBMD) and comprehensive measures of mineral metabolism have not been addressed in chronic kidney disease (CKD). OBJECTIVE The aim of the study was to identify the determinants of CortBMD in childhood CKD. A secondary objective was to assess whether CortBMD was associated with subsequent fracture. DESIGN AND PARTICIPANTS This prospective cohort study included 171 children, adolescents, and young adults (aged 5-21 years) with CKD stages 2-5D at enrollment and 89 1 year later. OUTCOMES Serum measures included vitamin D [25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25(OH)₂D), 24,25-dihydroxyvitamin D], vitamin D-binding protein, intact PTH, fibroblast growth factor 23, calcium, and phosphorus. Tibia quantitative computed tomography measures of CortBMD were expressed as sex-, race-, and age-specific Z-scores based on 675 controls. Multivariable linear regression identified the independent correlates of CortBMD Z-scores and the change in CortBMD Z-scores. RESULTS Lower calcium (β = .31/1 mg/dL, P = .01) and 25(OH)D (β = .18/10 ng/mL, P = .04) and higher PTH (β = -.02/10%, P = .002) and 1,25(OH)₂D (β = -.07/10%, P < .001) were independently associated with lower CortBMD Z-scores at baseline. The correlations of total, free, and bioavailable 25(OH)D with CortBMD did not differ. Higher baseline 1,25(OH)₂D (P < .05) and greater increases in PTH (P < .001) were associated with greater declines in CortBMD Z-scores. Greater increases in calcium concentrations were associated with greater increases in CortBMD Z-scores in growing children (interaction P = .009). The hazard ratio for fracture was 1.75 (95% confidence interval 1.15-2.67; P = .009) per SD lower baseline CortBMD. CONCLUSIONS Greater PTH and 1,25(OH)₂D and lower calcium concentrations were independently associated with baseline and progressive cortical deficits in childhood CKD. Lower CortBMD Z-score was associated with increased fracture risk.

Validation of The Health Improvement Network (THIN) Database for Epidemiologic Studies of Chronic Kidney Disease

Chronic kidney disease (CKD) is a prevalent and important outcome and covariate in pharmacoepidemiology. The Health Improvement Network (THIN) in the UK represents a unique resource for population‐based studies of CKD. We compiled a valid list of Read codes to identify subjects with moderate to advanced CKD.

Vitamin D deficiency is common in children and adolescents with chronic kidney disease

Here we determined if vitamin D deficiency is more common in children with chronic kidney disease compared to healthy children. In addition, we sought to identify disease-specific risk factors for this deficiency, as well as its metabolic consequences. We found that nearly half of 182 patients (ages 5 to 21) with kidney disease (stages 2 to 5) and a third of age-matched 276 healthy children were 25-hydroxyvitamin D deficient (<20 ng/ml). The risk of deficiency was significantly greater in advanced disease. Focal segmental glomerulosclerosis and low albumin were significantly associated with lower 25-hydroxyvitamin D, which, in turn, was associated with significantly higher intact parathyroid hormone levels. We found that 25-hydroxyvitamin D levels were positively associated with 1,25-dihydroxyvitamin D, the relationship being greatest in advanced disease (significant interaction), and inversely related to those of inflammatory markers C-reactive protein and IL-6. The association with C-reactive protein persisted when adjusted for the severity of kidney disease. Thus, lower 25-hydroxyvitamin D may contribute to hyperparathyroidism, inflammation, and lower 1,25-dihydroxyvitamin D in children and adolescents, especially those with advanced kidney disease.

Glucocorticoid effects on changes in bone mineral density and cortical structure in childhood nephrotic syndrome.

The impact of glucocorticoids (GC) on skeletal development has not been established. The objective of this study was to examine changes in volumetric bone mineral density (vBMD) and cortical structure over 1 year in childhood nephrotic syndrome (NS) and to identify associations with concurrent GC exposure and growth. Fifty‐six NS participants, aged 5 to 21 years, were enrolled a median of 4.3 (0.5 to 8.1) years after diagnosis. Tibia peripheral quantitative computed tomography (pQCT) scans were obtained at enrollment and 6 and 12 months later. Sex, race, and age‐specific Z‐scores were generated for trabecular vBMD (TrabBMD‐Z), cortical vBMD (CortBMD‐Z), and cortical area (CortArea‐Z) based on >650 reference participants. CortArea‐Z was further adjusted for tibia length‐for‐age Z‐score. Quasi‐least squares regression was used to identify determinants of changes in pQCT Z‐scores. At enrollment, mean TrabBMD‐Z (−0.54 ± 1.32) was significantly lower (p = 0.0001) and CortBMD‐Z (0.73 ± 1.16, p < 0.0001) and CortArea‐Z (0.27 ± 0.91, p = 0.03) significantly greater in NS versus reference participants, as previously described. Forty‐eight (86%) participants were treated with GC over the study interval (median dose 0.29 mg/kg/day). On average, TrabBMD‐Z and CortBMD‐Z did not change significantly over the study interval; however, CortArea‐Z decreased (p = 0.003). Greater GC dose (p < 0.001), lesser increases in tibia length (p < 0.001), and lesser increases in CortArea‐Z (p = 0.003) were independently associated with greater increases in CortBMD‐Z. Greater increases in tibia length were associated with greater declines in CortArea‐Z (p < 0.01); this association was absent in reference participants (interaction p < 0.02). In conclusion, GC therapy was associated with increases in CortBMD‐Z, potentially related to suppressed bone formation and greater secondary mineralization. Conversely, greater growth and expansion of CortArea‐Z (ie, new bone formation) were associated with declines in CortBMD‐Z. Greater linear growth was associated with impaired expansion of cortical area in NS. Studies are needed to determine the fracture implications of these findings.

Improvements in Bone Density and Structure during Anti-TNF-α Therapy in Pediatric Crohn's Disease.

CONTEXT Pediatric Crohns Disease (CD) is associated with deficits in trabecular bone mineral density (BMD) and cortical structure, potentially related to TNF-α effects to decrease bone formation and promote bone resorption. OBJECTIVE This study aimed to examine changes in bone density and structure in children and adolescents with CD following initiation of anti-TNF-α therapy. DESIGN AND PARTICIPANTS Participants (n = 74; age 5-21 years) with CD completed a 12-month prospective cohort study. MAIN OUTCOME MEASURES Tibia peripheral quantitative computed tomography scans were obtained at initiation of anti-TNF-α therapy and 12 months later. Musculoskeletal outcomes were expressed as sex-and race-specific z scores relative to age, based on >650 reference participants. RESULTS At baseline, CD participants had lower height, trabecular BMD, cortical area (due to smaller periosteal and larger endocortical circumferences), and muscle area z scores, compared with reference participants (all P < .01). Pediatric CD activity index decreased during the 10-week induction (P < .001), in association with subsequent gains in height, trabecular BMD, cortical area (due to recovery of endocortical bone), and muscle area z scores over 12 months (height P < .05; others P < .001). Bone-specific alkaline phosphatase levels, a biomarker of bone formation, increased a median of 75% (P < .001) during induction with associated 12-month improvements in trabecular BMD and cortical area z scores (both P < .001). Younger age was associated with greater increases in trabecular BMD z scores (P < .001) and greater linear growth with greater recovery of cortical area (P < .001). CONCLUSIONS Anti-TNF-α therapy was associated with improvements in trabecular BMD and cortical structure. Improvements were greater in younger and growing participants, suggesting a window of opportunity for treatment of bone deficits.