Evaluation of novel glomerular filtration rate estimation equations in adolescents and young adults with type 1 diabetes.

AIMS: Individuals with type 1 diabetes (T1D) are at an increased risk of chronic kidney disease making estimation of glomerular filtration rate (eGFR) an important component of diabetes care. Which eGFR equation is most appropriate to use in patients with T1D during the transition to adult care is unclear. We, therefore, sought to evaluate the performance of five eGFR equations in adolescents and young adults with T1D. METHODS: Measured iohexol-based glomerular filtration rate was compared to the Chronic Kidney Disease and Epidemiology Collaboration (CKD-EPI) eGFR, Chronic Kidney Disease in Children (CKiD) eGFR, and three recently developed age-adjusted versions of these in 53 patients with T1D and preserved GFR using bias, precision, and accuracy. RESULTS: The best performance was found in the sex-dependent CKiD equation (bias: -0.8, accuracy: 11.8 ml/min/1.73 m2). Bias and accuracy (26.4 and 26.8 ml/min/1.73 m2) were worst in the CKD-EPI equation. Age-dependent adjustment improved performance for this equation (bias: 5.3, accuracy: 13.4 ml/min/1.73 m2), but not for the CKiD equation (bias: 15.5, accuracy: 18.8 ml/min/1.73 m2). CONCLUSION: Age-adjustment improved performance for the CKD-EPI equation, but not for the CKiD equation. The sex-adjusted CKiD equation performed best out of all equations.

Multicentric carpotarsal osteolysis syndrome (MCTO) with generalized high bone turnover and high serum RANKL: Response to denosumab.

MCTO is a rare disorder, caused by mutations in the MafB gene, a negative regulator of receptor activator of nuclear factor-кB ligand (RANKL). Manifestations include carpal and tarsal osteolysis and renal failure. Pathophysiology is poorly understood, and no effective treatment is available. In this case report we describe a patient with MCTO (MafB, mutation c.206C>T, p.Ser69Leu), diagnosed at the age of 5 years. At 7 years, skeletal survey showed diffuse osteopenia. BMD was mildly reduced, and bone turnover markers increased. He was treated with denosumab, a human monoclonal RANKL inhibitor for two years. Each injection was followed by a marked reduction in C-telopeptide (CTX). Following denosumab his BMD and bone symptoms improved and the osteolysis stabilized. At the age of 13 years, osteoporosis was diagnosed using high resolution peripheral quantitative computed tomography (HRpQCT) and serum RANKL was found to be markedly increased. This initial experience suggests that the associated osteoporosis may be ameliorated by denosumab, although further study will be needed to understand the appropriate dose, frequency, and the extent of efficacy. Monitoring of CTX and bone specific alkaline phosphatase will be especially useful in this regard. Further study in other MCTO patients is also needed to determine whether high bone turnover is specific to this mutation or more common than previously appreciated. We propose a model in which osteolysis in this condition is strongly associated with the systemic osteoporosis.

Improvements in peripheral vascular function with vitamin D treatment in deficient adolescents with type 1 diabetes.

BACKGROUND: Vitamin D (VitD) deficiency is prevalent in adolescents with type 1 diabetes (T1D) and is associated with diabetes-related vascular complications in adulthood. The objective of this clinical trial was to assess VitD treatment on endothelial function (EF) and markers of renal inflammation, in this patient group. METHODS: Adolescents with T1D with suboptimal levels of VitD (<37.5 nmol/L) were treated for 12 to 24 weeks with a VitD analog (VitD3 ) at doses of 1000 or 2000 IU daily. The primary end-point assessed the change in reactive hyperemia index (lnRHI), a measure of EF. Secondary end-points included changes in blood pressure, lipid profile, HbA1c and albumin creatinine ratio (ACR). Urinary cytokine/chemokine inflammatory profile was also assessed in a subset of subjects posttreatment. RESULTS: Two hundred and seventy-one subjects were screened for VitD status and 31 VitD deficient subjects with a mean age of 15.7 ± 1.4 years were enrolled and completed the study. Mean 25-OH-VitD levels significantly increased (33.0 ± 12.8 vs 67.0 ± 23.2 nmol/L, P < .01) with a significant improvement in EF following VitD supplementation (lnRHI 0.58 ± 0.20 vs 0.68 ± 0.21, P = .03). VitD supplementation did not significantly impact systolic blood pressure/diastolic blood pressure (SBP/DBP), lipids, HbA1c and ACR and no adverse effects were seen. Several urinary inflammatory cytokines/chemokines: MCP-3 (P < .01), epidermal growth factor (EGF) (P < .01) tumor necrosis factor ß (TNFß) (P = .01), interleukin-10 (IL-10) (P = .01), also significantly decreased post-VitD-treatment. CONCLUSIONS: Treatment with VitD was associated with an improvement in EF and reduced expression of urinary inflammatory markers in adolescents with T1D. This data is suggestive of an additional benefit of VitD supplementation on early markers of microvascular complications.

Technique, Safety, and Yield of Bone Biopsies for Histomorphometry in Children.

PURPOSE: To evaluate image-guided bone biopsy for bone histomorphometry to assess osteoporosis in children with respect to safety and yield. MATERIALS AND METHODS: A single-center retrospective review was performed of 79 bone biopsies in 73 patients performed between 2007 and 2015. Biopsies of the iliac bone were performed under general anesthesia, after tetracycline labeling, using a Rochester needle (Medical Innovations International, Inc, Rochester, Minnesota). Ultrasound and fluoroscopic guidance were used in all procedures. Biopsy technique, technical success, safety, and histomorphometry results (complete, incomplete, none) were analyzed. RESULTS: There were 41 male patients (51.8%). Technical success was achieved in 76/79 (96%) procedures. Of 79 biopsies, 75 (95%) were uneventful. Unplanned overnight observation was required in 3 (minor SIR grade B), and prolonged hospital stay owing to hematoma causing nerve compression pain was required in 1 (major SIR grade D). Complete histomorphometric reports were obtained in 69 (87%) procedures, incomplete reports were obtained in 7 (9%), and no reports were obtained in 3(4%). Incomplete reports were insufficient to provide a definitive diagnosis or guide treatment. Histomorphometry impacted subsequent therapy in 69 (87%) biopsies. CONCLUSIONS: Image-guided bone biopsy for osteoporosis using the Rochester needle is a valuable and safe technique for establishing the diagnosis of osteoporosis and directing treatment based on histomorphometry results.

The urinary cytokine/chemokine signature of renal hyperfiltration in adolescents with type 1 diabetes.

OBJECTIVE: Urinary cytokine/chemokine levels are elevated in adults with type 1 diabetes (T1D) exhibiting renal hyperfiltration. Whether this observation extends to adolescents with T1D remains unknown. Our first objective was to determine the relationship between hyperfiltration and urinary cytokines/chemokines in normotensive, normoalbuminuric adolescents with T1D using GFR(cystatin). Our second aim was to determine the relationship between urine and plasma levels of inflammatory biomarkers, to clarify the origin of these factors. METHODS: Urine and serum cytokines/chemokines (Luminex platform) and GFR(cystatin) were measured in normofiltering (n = 111, T1D-N, GFR<135 ml/min/1.73 m(2)) and hyperfiltering (n = 31, T1D-H, GFR ≥ 135 ml/min/1.73 m(2)) adolescents with T1D (ages 10-16), and in age and sex matched healthy control subjects (HC, n = 59). RESULTS: We noted significant step-wise increases in urinary cytokine/chemokine excretion according to filtration status with highest levels in T1D-H, with parallel trends in serum analyte concentrations. After adjusting for serum glucose at the time of sampling, differences in urinary cytokine excretion were not statistically significant. Only serum IL-2 significantly differed between HC and T1D (p = 0.0076). CONCLUSIONS: Hyperfiltration is associated with increased urinary cytokine/chemokine excretion in T1D adolescents, and parallel trends in serum cytokine concentration. The GFR-associated trends in cytokine excretion may be driven by the effects of ambient hyperglycemia. The relationship between hyperfiltration, glycemia, and variations in serum and urine cytokine expression and their impact on future renal and systemic vascular complications requires further study.

A child with autoimmune polyendocrinopathy candidiasis and ectodermal dysplasia treated with immunosuppression: a case report.

INTRODUCTION: Common features of autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia include candidiasis, hypoparathyroidism and hypoadrenalism. The initial manifestation of autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia may be autoimmune hepatitis, keratoconjunctivitis, frequent fever with or without a rash, chronic diarrhea, or different combinations of these with or without oral candidiasis. CASE PRESENTATION: We discuss a profoundly affected 2.9-year-old Caucasian girl of Western European descent with a dramatic response to immunosuppression (initially azathioprine and oral steroids, and then subsequently mycophenolate mofetil monotherapy). At four years of follow-up, her response to mycophenolate mofetil is excellent. CONCLUSION: The clinical features of autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia may continue for years before some of the more common components appear. In such cases, it may be life-saving to diagnose autoimmune polyendocrinopathy-candidiasis-ectodermal dysplasia and commence therapy with immunosuppressive agents. The response of our patient to immunosuppression with mycophenolate mofetil has been dramatic. It is possible that other patients with this condition might also benefit from immunosuppression.

Hyperfiltration and effect of nitric oxide inhibition on renal and endothelial function in humans with uncomplicated type 1 diabetes mellitus.

Studies of experimental diabetes mellitus (DM) suggest that increased nitric oxide (NO) bioactivity contributes to renal hyperfiltration. However, the role of NO in mediating hyperfiltration has not been fully elucidated in humans. Our aim was to examine the effect of NO synthase inhibition on renal and peripheral vascular function in normotensive subjects with uncomplicated type 1 DM. Renal function and brachial artery flow-mediated vasodilatation (FMD) were measured before and after an intravenous infusion of the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester (l-NMMA) in 21 healthy control and 37 type 1 DM patients. Measurements in DM participants were made under clamped euglycemic conditions. The effect of l-NMMA on circulating and urinary NO metabolites (NO(x)) and cGMP and on urinary prostanoids was also determined. Baseline characteristics were similar in the two groups. For analysis, the DM patients were divided into those with hyperfiltration (DM-H, n = 18) and normal glomerular filtration rate (GFR) levels (DM-N, n = 19). Baseline urine NO(x) and cGMP were highest in DM-H. l-NMMA led to a decline in GFR in DM-H (152 ± 16 to 140 ± 11 ml·min(-1)·1.73 m(-2)) but not DM-N or healthy control participants. The decline in effective renal plasma flow in response to l-NMMA (806 ± 112 to 539 ± 80 ml·min(-1)·1.73 m(-2)) in DM-H was also exaggerated compared with the other groups (repeated measures ANOVA, P < 0.05), along with declines in urinary NO(x) metabolites and cGMP. Baseline FMD was lowest in DM-H compared with the other groups and did not change in response to l-NMMA. l-NMMA reduced FMD and plasma markers of NO bioactivity in the healthy control and DM-N groups. In patients with uncomplicated type 1 DM, renal hyperfiltration is associated with increased NO bioactivity in the kidney and reduced NO bioactivity in the systemic circulation, suggesting a paradoxical state of high renal and low systemic vascular NO bioactivity.

Ability of Cystatin C to detect changes in glomerular filtration rate after ACE inhibition in patients with uncomplicated type 1 diabetes.

Although it is known that glomerular filtration rate (GFR) declines in response to angiotensin converting enzyme (ACE) inhibition, recent observations using GFR(CYSTATIN C) have shown a paradoxical increase calling into question its validity. In this descriptive study, we aimed to reconcile this observation by simultaneously measuring GFR(CYSTATIN C), GFR(CREATININE), and gold standard GFR(INULIN) responses to ACE inhibition. Adolescents with type 1 diabetes and hyperfiltration (n = 9, GFR(INULIN) ≥ 135 mL/min/1.73 m(2)) or normofiltration (n = 11) were studied during clamped euglycemia at baseline and after 3-week enalapril therapy. In hyperfilterers, the anticipated GFR(INULIN) decline before and after enalapril was observed (174 ± 29 mL/min/1.73 m(2) to 140 ± 26 mL/min/1.73 m(2), P = .01). Although GFR(CYSTATIN C) equations tended to underestimate while GFR(CREATININE) equations tended to overestimate baseline GFR(INULIN) in hyperfilterers, both approaches generally reflected declining GFR(INULIN) responses to enalapril. Normofilterers demonstrated a trend toward rising GFR(INULIN) in response to enalapril (112 ± 16 mL/min/1.73 m(2) to 119 ± 27 mL/min/1.73 m(2), P = .35). Although all estimating equations tended to overestimate baseline GFR(INULIN), they generally reflected the rising trend in GFR(INULIN) in response to enalapril in normofilterers. Although GFR(INULIN) declines in response to enalapril among hyperfilterers, we confirm the previous observation that it demonstrates a trend to rising among normofilterers. These group trends are both reflected by cystatin C- and creatinine-based estimates.