Alterations of bone microstructure and strength in end-stage renal failure

Summary: End-stage renal disease (ESRD) patients have a high risk of fractures. We evaluated bone microstructure and finite-element analysis-estimated strength and stiffness in patients with ESRD by high-resolution peripheral computed tomography. We observed an alteration of cortical and trabecular bone microstructure and of bone strength and stiffness in ESRD patients. Introduction: Fragility fractures are common in ESRD patients on dialysis. Alterations of bone microstructure contribute to skeletal fragility, independently of areal bone mineral density. Methods: We compared microstructure and finite-element analysis estimates of strength and stiffness by high-resolution peripheral quantitative computed tomography (HR-pQCT) in 33 ESRD patients on dialysis (17 females and 16 males; mean age, 47.0 ± 12.6years) and 33 age-matched healthy controls. Results: Dialyzed women had lower radius and tibia cortical density with higher radius cortical porosity and lower tibia cortical thickness, compared to controls. Radius trabecular number was lower with higher heterogeneity of the trabecular network. Male patients displayed only a lower radius cortical density. Radius and tibia cortical thickness correlated negatively with bone-specific alkaline phosphatase (BALP). Microstructure did not correlate with parathyroid hormone (PTH) levels. Cortical porosity correlated positively with "Kidney Disease: Improving Global Outcomes” working group PTH level categories (r = 0.36, p < 0.04). BMI correlated positively with trabecular number (r = 0.4, p < 0.02) and negatively with trabecular spacing (r = −0.37, p < 0.03) and trabecular network heterogeneity (r = −0.4, p < 0.02). Biomechanics positively correlated with BMI and negatively with BALP. Conclusion: Cortical and trabecular bone microstructure and calculated bone strength are altered in ESRD patients, predominantly in women. Bone microstructure and biomechanical assessment by HR-pQCT may be of major clinical relevance in the evaluation of bone fragility in ESRD patient

The Swiss Kidney Stone Cohort (SKSC), a longitudinal, multi-centric, observational cohort to study course and causes of kidney stone disease in Switzerland.

Kidney stone disease has a high prevalence worldwide of approximately 10 % of the population and is characterized by a high recurrence rate Kidney stone disease results from a combination of genetic, environmental, and life-style risk factors, and the dissection of these factors is complex. The Swiss Kidney Stone Cohort (SKSC) is an investigator-initiated prospective, multi-centric longitudinal, observational study in patients with kidney stones followed with regular visits over a period of 3 years after inclusion. Ongoing follow-ups by biannual telephone interviews will provide long-term outcome data up to 10 years. SKSC comprises 782 adult patients (age &gt; 18 yrs) with either recurrent stones or a single stone event with at least one risk factor for recurrence. In addition, a control cohort of 207 individuals without kidney stone history and absence of kidney stones on a low-dose CT-scan at enrolment has also been recruited. SKSC includes extensive collections of clinical data, biochemical data in blood and 24 hr urine samples, and genetic data. Biosamples are stored at a dedicated biobank. Information on diet and dietary habits were collected through food frequency questionnaires and standardized recall interviews by trained dieticians with the Globodiet software. SKSC provides an unique opportunity and resource to further study cause and course of kidney disease in a large population with data and samples collected of a homogenous collective of patients throughout the whole Swiss population

Interleukin-10 Mediated Autoregulation of Murine B-1 B-Cells and Its Role in Borrelia hermsii Infection

B cells are typically characterized as positive regulators of the immune response, primarily by producing antibodies. However, recent studies indicate that various subsets of B cells can perform regulatory functions mainly through IL-10 secretion. Here we discovered that peritoneal B-1 (B-1P) cells produce high levels of IL-10 upon stimulation with several Toll-like receptor (TLR) ligands. High levels of IL-10 suppressed B-1P cell proliferation and differentiation response to all TLR ligands studied in an autocrine manner in vitro and in vivo. IL-10 that accumulated in cultures inhibited B-1P cells at second and subsequent cell divisions mainly at the G1/S interphase. IL-10 inhibits TLR induced B-1P cell activation by blocking the classical NF-κB pathway. Co-stimulation with CD40 or BAFF abrogated the IL-10 inhibitory effect on B-1P cells during TLR stimulation. Finally, B-1P cells adoptively transferred from the peritoneal cavity of IL-10−/− mice showed better clearance of Borrelia hermsii than wild-type B-1P cells. This study described a novel autoregulatory property of B-1P cells mediated by B-1P cell derived IL-10, which may affect the function of B-1P cells in infection and autoimmunity

Efficacy of standard and low dose hydrochlorothiazide in the recurrence prevention of calcium nephrolithiasis (NOSTONE trial): protocol for a randomized double-blind placebo-controlled trial.

Nephrolithiasis is a global healthcare problem with a current lifetime risk of 18.8% in men and 9.4% in women. Given the high cost of medical treatments and surgical interventions as well as the morbidity related to symptomatic stone disease, medical prophylaxis for stone recurrence is an attractive approach. Thiazide diuretics have been the cornerstone of pharmacologic metaphylaxis for more than 40 years. However, evidence for benefits and harms of thiazides in the prevention of calcium containing kidney stones in general remains unclear. In addition, the efficacy of the currently employed low dose thiazide regimens to prevent stone recurrence is not known. The NOSTONE trial is an investigator-initiated 3-year prospective, multicenter, double-blind, placebo-controlled trial to assess the efficacy of standard and low dose hydrochlorothiazide treatment in the recurrence prevention of calcium containing kidney stones. We plan to include 416 adult (≥ 18 years) patients with recurrent (≥ 2 stone episodes in the last 10 years) calcium containing kidney stones (containing ≥50% of calcium oxalate, calcium phosphate or a mixture of both). Patients will be randomly allocated to 50 mg or 25 mg or 12.5 mg hydrochlorothiazide or placebo. The primary outcome will be incidence of stone recurrence (a composite of symptomatic or radiologic recurrence). Secondary outcomes will be individual components of the composite primary outcome, safety and tolerability of hydrochlorothiazide treatment, changes in urinary biochemistry elicited by hydrochlorothiazide treatment and impact of baseline disease severity, biochemical abnormalities and stone composition on treatment response. The NOSTONE study will provide long-sought information on the efficacy of hydrochlorothiazide in the recurrence prevention of calcium containing kidney stones. Strengths of the study include the randomized, double-blind and placebo-controlled design, the large amount of patients studied, the employment of high sensitivity and high specificity imaging and the exclusive public funding support. ClinicalTrials.gov, NCT03057431 . Registered on February 20 2017

Loss of &lambda;2&sup3;&sup1;⁵ tarnsgene copy numbers influences the development of B1 cells.

Transgenic L2 mice contain high numbers of the lambda 2(315) immunoglobulin L chain gene in their germ line. They are characterized by an almost complete block in B2 cell development and dominance of B1 cells in their periphery. This was attributed to high transgene expression. Here, we describe a variant of such mice (L2V), which has lost half of the transgene copies. This results in decreased transgene expression. Consequently, such mice display less severe isotype exclusion and an increase in B cells expressing endogenous k light chains. In addition, the B2 cell compartment is enlarged. Nevertheless, L2V mice exhibit phosphatidylcholine (PtC) binding B cells expressing lambda L chains as well as an unaltered number of B1a cells expressing the dominating specificity usually encountered in L2 mice. Since in L2V mice transgene integration and regulation is identical to L2 mice, the correlation of decreased transgene expression and increased presence of B2 cells strongly suggests that high transgene expression is decisive for development of B1 cells in L2 mice