We conducted an open-label, prospective, randomized trial to assess the efficacy and safety of RANKL inhibition with denosumab to prevent the loss of bone mineral density (BMD) in the first year after kidney transplantation. Ninety kidney transplant recipients were randomized 1:1 2 weeks after surgery to receive denosumab (60 mg at baseline and 6 months) or no treatment. After 12 months, total lumbar spine areal BMD (aBMD) increased by 4.6% (95% confidence interval [CI] 3.3-5.9%) in 46 patients in the denosumab group and decreased by À0.5% (95% CI À1.8% to 0.9%) in 44 patients in the control group (betweengroup difference 5.1% [95% CI 3.1-7.0%], p < 0.0001). Denosumab also increased aBMD at the total hip by 1.9% (95% CI, 0.1-3.7%; p = 0.035) over that in the control group at 12 months. High-resolution peripheral quantitative computed tomography in a subgroup of 24 patients showed that denosumab increased volumetric BMD at the distal tibia and radius (all p < 0.05). Biomarkers of bone turnover (C-terminal telopeptide of type I collagen, procollagen type I N-terminal propeptide) markedly decreased with denosumab (all p < 0.0001). Episodes of cystitis and asymptomatic hypocalcemia occurred more often with denosumab, whereas graft function, rate of rejections, and incidence of opportunistic infections were similar. In conclusion, denosumab increased BMD in the first year after kidney transplantation but was associated with more frequent episodes of urinary tract infection.Abbreviations: aBMD and vBMD, areal and volumetric bone mineral density; BSAP, bone-specific alkaline phosphatase; DXA, dual-energy x-ray absorptiometry; HR-pQCT, high-resolution peripheral quantitative computed tomography; P1NP, procollagen type I N-terminal propeptide; b-CTX, C-terminal telopeptide of type I collagen

Progressive renal diseases are characterized by tubulointerstitial inflammatory cell recruitment, tubular atrophy and fibrosis. Various aspects of the recruitment of leukocytes have been extensively studied, but the exit routes (i.e. the lymphatic vessels and their biology) have only recently found attention. Similar to the recruitment of inflammatory cells, the exit is coordinated by an orchestrated interaction of chemotactic cytokines and adhesion molecules. During inflammatory injury, new routes are created by the de novo formation of lymphatic vessels, i.e. neolymphangiogenesis. These newly formed lymphatic vessels help to cope with the increase in interstitial fluid related to inflammation. Here, we review some aspects of lymphatic biology and the current knowledge about lymphatic vessels in renal inflammation.

Background/Aims: Sclerostin is secreted by osteocytes. As a circulating inhibitor of the Wnt-signaling pathway it inhibits bone formation and contributes to the development of osteoporosis. Sclerostin levels are elevated in patients with chronic kidney disease and end-stage renal disease. Since data for patients after kidney transplantation are scarce, we have prospectively measured sclerostin levels before and during the first year after renal transplantation and have examined the association of sclerostin with parameters of bone mineral metabolism and with bone mineral density. Methods: Sclerostin levels were measured by ELISA in 42 consecutive renal transplant recipients before and at defined intervals in the first year after transplantation. Bone mineral density was measured by dual energy X-ray absorptiometry. Results: Pre-transplant serum sclerostin levels were elevated in all patients (61.8 ± 32.3 pmol/l, normal range 20-30 pmol/l). Within 15 days after transplantation and correlating with the improvement of renal function, sclerostin levels dropped to 21.0 ± 14.7 pmol/l and subsequently increased to 23.8 ± 14.9 and 28.0 ± 16.8 pmol/l after 6 and 12 months, respectively (P<0.001). A linear mixed model indicated that pre-transplant sclerostin levels (P<0.001) and time after transplantation (P<0.001) were the most important predictors for the rise of post-transplant sclerostin levels. No correlation was found between post-transplant sclerostin levels and bone mineral density. Conclusions: The rapid reduction of elevated serum sclerostin levels shortly after kidney transplantation parallels the improvement of renal function, but contrasts with the more delayed improvement of hyperparathyroidism. The normalization of both hormones could contribute to improved bone health after renal transplantation.

Abstract

Background

Suspected acute appendicitis is the most frequent cause for emergency operations in visceral surgery worldwide. In approximately twenty percent of all cases however, the diagnosis is incorrect and patients undergo surgery without having acute appendicitis. Operations of bland appendices put patients at risk and entail a serious waste of resources. Several highly accurate tests have been introduced to diagnose acute appendicitis. The false positive rate however, has not changed over the last twenty years. Given the variation that exists in both practice and research, the uncertainty regarding the quality of the underlying evidence, there is a clear need for comprehensive, systematic and quantitative overviews of the diagnostic value of the various tests purported to be predictive of acute appendicitis.

Methods

Literature will be identified searching general bibliographic databases (MEDLINE and EMBASE), specialist computer databases (DARE, Cochrane Database of Systematic Reviews, conference proceedings, MEDION, SCISEARCH, BIOSIS) without language restrictions. We will contact experts and the manufacturers of tests. Hand-searching will complete our searches. Identified articles will be selected according to populations, tests, outcomes and study design. Papers meeting the selection criteria will be appraised to rate their methodological quality. Analysis will include exploration of heterogeneity in results. We will conduct meta-analyses to generate summary estimates of test accuracy measures and summary ROC curves where appropriate. If meta-analysis is considered to be inappropriate, we will describe the identified evidence in the context of appraised quality.

Discussion

These reviews should lead to formulation of recommendations for current practice and future research.