Epigenetic clocks indicate that kidney transplantation and not dialysis mitigate the effects of renal ageing.

BACKGROUND: Chronic kidney disease (CKD) is an age-related disease that displays multiple features of accelerated ageing. It is currently unclear whether the two treatment options for end-stage kidney disease (dialysis and kidney transplantation [KT]) ameliorate the accelerated uremic ageing process. METHODS: Data on clinical variables and blood DNA methylation (DNAm) from CKD stage G3-G5 patients were used to estimate biological age based on blood biomarkers (phenotypic age [PA], n = 333), skin autofluorescence (SAF age, n = 199) and DNAm (Horvath, Hannum and PhenoAge clocks, n = 47). In the DNAm cohort, we also measured the change in biological age 1 year after the KT or initiation of dialysis. Healthy subjects recruited from the general population were included as controls. RESULTS: All three DNAm clocks indicated an increased biological age in CKD G5. However, PA and SAF age tended to produce implausibly large estimates of biological age in CKD G5. By contrast, DNAm age was 4.9 years (p = 0.005) higher in the transplantation group and 5.9 years (p = 0.001) higher in the dialysis group compared to controls. This age acceleration was significantly reduced 1 year after KT, but not after 1 year of dialysis. CONCLUSIONS: Kidney failure patients displayed an increased biological age as estimated by DNAm clocks compared to population-based controls. Our results suggest that KT, but not dialysis, partially reduces the age acceleration.

Fibrates and the risk of cardiovascular outcomes in chronic kidney disease patients.

BACKGROUND AND HYPOTHESIS: The high risk of major adverse cardiovascular events (MACE) in patients with chronic kidney disease (CKD) has been well described. However, the efficacy of fibrates on the risk of MACE in patients with CKD remains unclear. METHODS: We conducted a nested case-control study using data from a large administrative database that included more than 1.5 million Japanese patients. We defined cases as CKD patients with incidences of MACE and matched them with controls based on age, sex, calendar year of cohort entry, and CKD stage. Fibrate exposure timing was categorized as current, recent, or past. A conditional logistic regression analysis was used to investigate the association between fibrate use and the risk of MACE. RESULTS: Our study included 47 490 patients with CKD, with 15 830 MACE identified during a median follow-up of 9.4 months. The number of fibrates used during the study period were 556 (3.5%) in the case group and 1 109 (3.5%) in the control group. Fibrate use was significantly associated with a decreased risk of MACE (odds ratio [OR], 0.84; 95% confidence interval [CI], 0.75 to 0.94), particularly for current (OR, 0.81; 95% CI, 0.68-0.97) and recent use (OR, 0.65; 95% CI, 0.48-0.90). Regarding the class effect of fibrates, pemafibrate use, but not bezafibrate or fenofibrate use, was significantly associated with a decreased risk of MACE (OR, 0.73; 95% CI, 0.528-0.997). CONCLUSION: Recent and current fibrate use, especially pemafibrate use, was associated with a reduced risk of MACE in patients with CKD. This suggests the potential benefits of continuous fibrate therapy and the possible superiority of pemafibrate over other fibrates. However, further investigations in different populations are required to confirm the generalizability of these findings.

α-Blocker Use in Hemodialysis: The Japan Dialysis Outcomes and Practice Patterns Study.

Rationale & Objective: Despite α-blockers' use for hypertension as add-on therapy in patients treated with hemodialysis, scant information is available on their association, particularly with safety, in these patients. Study Design: Prospective cohort study. Setting & Participants: patients treated with hemodialysis and receiving antihypertensive agents in the Japan Dialysis Outcomes and Practice Patterns Study, phases 4-6, were analyzed. Exposure: Primary exposure was the prescription of α-blocking antihypertensive agents at baseline. Outcomes: Incident fractures, falls, and all-cause mortality. Analytical Approach: Multivariable Cox and modified Poisson regression analysis. Results: Of 5,149 patients treated with hemodialysis (mean age, 65 years; 68% men) receiving antihypertensive drugs, 717 (14%) received α-blocking agents. During a mean follow-up period of 2.0 years, 247 fractures, 525 falls, and 498 deaths occurred. Multivariable analysis showed no significant association of α-blocker use and increased risk of fractures (hazard ratio [HR], 0.92 [95% confidence interval {CI}, 0.61-1.38]), falls (HR, 0.94 [95% CI, 0.74-1.20]), or all-cause deaths (HR, 0.87 [95% CI, 0.64-1.20]) compared with α-blocker nonuse. α-Blocker use was, however, significantly associated with a decreased risk of all-cause mortality in the subgroup analysis, for example, patients who were older (HR, 0.71 [95% CI, 0.51-0.99]), were women (HR, 0.68 [95% CI, 0.48-0.95]), or reported a history of cardiovascular disease (HR, 0.67 [95% CI, 0.48-0.95]) or a predialysis blood pressure of ≥140 mm Hg (HR, 0.69 [95% CI, 0.49-0.98]). Limitations: Selection bias cannot be ruled out given the prevalent user analysis. Conclusions: No significant association between α-blocker use and the risk of worse safety-related outcomes was seen, indicating that clinicians may safely prescribe α-blockers to patients receiving hemodialysis who require blood pressure lowering. Plain-Language Summary: α-Blockers have been generally reserved for use as add-on therapy for resistant or refractory hypertension. However, little is known about the safety of α-blockers in patients treated by hemodialysis. We analyzed 5,149 patients receiving hemodialysis in Japan who were receiving antihypertensive drugs from the Japan Dialysis Outcomes and Practice Patterns Study. The results showed no significant increase in the risk of fractures, falls, or deaths for patients using α-blockers compared with those who did not, suggesting that α-blockers may be safely prescribed for patients receiving hemodialysis who need to lower their blood pressure.

Long-Term Effect of Denosumab on Bone Disease in Patients with CKD.

BACKGROUND: The effect of long-term denosumab therapy and of denosumab discontinuation on the cortical bone of the hip regions in dialysis patients has not been studied. METHODS: This retrospective study investigated the cortical and trabecular compartments and estimated strength indices of the hip region, obtained using 3D-SHAPER software, after a maximum of 5 years of denosumab therapy in 124 dialysis patients. A Wilcoxon signed-rank test was used to identify the differences in each parameter before and after denosumab initiation. Similarly, we investigated the changes in these parameters after denosumab discontinuation in 11 dialysis patients. RESULTS: Integral and trabecular volumetric bone mineral densities (BMD) were significantly lower at the start of denosumab therapy than those in 1 year before denosumab initiation. After starting denosumab, areal BMD (median change +7.7% [interquartile range (IQR), +4.6 to +10.6]), cortical volumetric BMD (median change +3.4% [IQR, +1.0 to +4.7]), cortical surface BMD (median change +7.1% [IQR, +3.4 to +9.4]), and cortical thickness (median change +3.2% [IQR, +1.8 to +4.9]) showed a significantly higher trend for 3.5 years, which then stabilized at a higher value compared with baseline. A similar trend in the trabecular volumetric BMD (median change +9.8% [IQR, +3.8 to +15.7]) was observed over 2.5 years, with a higher value maintained thereafter. The whole area of the hip region improved after denosumab therapy. Similar trajectories were also found in the estimated strength indices. Conversely, at 1 year after denosumab discontinuation, these 3D parameters and estimated strength indices tended to largely worsen. The lateral aspect of the greater trochanter was the most pronounced location showing volumetric BMD loss. CONCLUSIONS: The BMD of both cortical and trabecular components in the hip region was significantly higher after starting denosumab therapy. However, these measurements exhibited a trend of declining substantially after the discontinuation of denosumab.

Risk factors for blood vessel rupture during vascular access intervention therapy for hemodialysis patients.

Blood vessel rupture is a major complication associated with vascular access intervention therapy (VAIVT). However, information regarding the risk factors for ruptures related to VAIVT is limited. The purpose of this study was to investigate the risk factors for rupture during VAIVT. This was a single-center, retrospective observational study. Demographic, clinical, anatomical, and VAIVT procedure variables were reviewed and analyzed using multivariate logistic regression. The 211 patients included in the study underwent 628 VAIVT procedures from November 2019 to December 2021, and 20 blood vessel ruptures occurred. Patients with ruptures had significantly lower BMI (p = 0.043), shorter access vintage(p = 0.017), underwent VAIVT for the first time (p = 0.006), and had lower blood flow quantity (p = 0.005), lower brachial artery flow volume (p = 0.018), and higher resistance index (p = 0.011). The multivariate logistic regression revealed that receiving VAIVT for the first time (OR 5.95, 95%CI 1.01-34.84; p = 0.048) and high resistance index (OR 1.86, 95%CI 1.01-3.16; p = 0.02) were significantly associated with a high risk for rupture. Furthermore, receiver operating characteristic curve analysis to assess the sensitivity-specificity profiles of the resistance index for ruptures showed that the optimal threshold was 0.70 (sensitivity/specificity, 0.69/0.70). Heightened surveillance during vascular access intervention therapy is warranted, especially in patients undergoing VAIVT for the first time or patients with a high resistance index (> 0.70).

Secular trends in incidence and seasonal variation of distal radius fracture among children: A nationwide study based on the Swedish National Patient Register 2002-2016.

BACKGROUND AND PURPOSE: Although distal radius fracture (DRF) is the most common fracture type in children, research on its seasonality across different age groups is limited. We investigated secular trends in incidence and seasonal variation of pediatric DRF based on Swedish nationwide population database. PATIENTS AND METHODS: In this observational study, data for all children aged <18 years in Sweden with DRF defined by ICD-codes were analyzed for each month and each year during 2002-2016 using the Swedish National Patient Register. The general population counts for each age and sex-category were acquired to evaluate population at risk for each period. We calculated the age standardized and sex specific annual incidence rates, seasonal incidence rates, and monthly incidence rates and analyzed the seasonal variation in the mechanisms of injury. RESULTS: A total of 155,891 DRF cases were identified. The age standardized and sex specific incidence rate was 531 (95%CI 528-533) per 100,000 patient years at risk. Fracture risk was highest during summer and lowest in the winter. The highest seasonal variation was observed among boys 2- < 5 years. The crude incidence rate and the age-standardized incidence rates in winter significantly decreased between 2002 and 2016 (annual percentage change, -2 %). INTERPRETATION: We found significant seasonal variation in DRF among all age groups in Swedish children. The findings can help in developing strategies to prevent fractures as well as in allocating medical and social resources.

Bilateral renal subcapsular hematoma caused by polyarteritis nodosa: a case report.

Polyarteritis nodosa, which is a systemic vasculitis of small- and medium-sized arteries, can cause arterial aneurysms in various organs, sometimes resulting in aneurysm rupture and hemorrhage. A kidney is one of the major targets of polyarteritis nodosa. Here, we report a 73-year-old woman who presented with sudden-onset high fever, diarrhea, and renal injury with bilateral renal subcapsular hematoma shown on contrast-enhanced computed tomography scan. She did not have trauma and significant medical history other than breast cancer in remission. Serological and immunological tests except for anti-Sjögren's syndrome-A and anti-Sjögren's syndrome-B were all negative. Digital subtraction angiography revealed bilateral intrarenal micro aneurysms, which allowed us to diagnose the patient with polyarteritis nodosa. As continuous monitoring of bilateral intrarenal hematoma by ultrasonography and computed tomography scan did not detect progression of intrarenal hemorrhage and extra renal hematoma, transcatheter arterial embolization and nephrectomy were not performed. Although hemodialysis therapy was required temporarily for acute kidney injury with anuria, her general condition and kidney function remarkably improved after receiving systemic immunosuppressive therapy with corticosteroids and cyclophosphamide. In conclusion, this is a rare case of polyarteritis nodosa manifesting as spontaneous bilateral subcapsular renal hemorrhage with deteriorated renal function, which was successfully treated with immunosuppressive therapy.

Secular trends in hip fracture incidence and subsequent mortality in dialysis patients and the general population in Sweden.

BACKGROUND: Declining trends of hip fracture incidence in dialysis patients were reported from USA and Japan while studies from Europe are lacking. We investigated trends in hip fracture incidence and subsequent mortality in Swedish dialysis patients, comparing with the Swedish general population. METHODS: We used the population-based Swedish national database of fractures and the Swedish National Renal Registry to retrieve data on hip fractures incidence and subsequent mortality for years 2007-2016. Trends for age-standardized hip fracture incidence rate (ASRhip fracture) and age-standardized 30-day (ASMR30day) and 180-day (ASMR180day) post-hip fracture mortality rate in Swedish general population were evaluated by joinpoint regression analysis. Standardized incidence ratios of hip fracture (SIR) and standardized mortality ratios (SMR) were calculated for Swedish dialysis patients. RESULTS: In the general population, ASRhip fracture declined significantly: in women from 2007 and in men from 2009. In dialysis patients, SIR was 3-5 times higher compared to the general population and declined over time in women but not in men. In general population, mortality (ASMR30day and ASMR180day) declined significantly in women and men. In dialysis patients, post-fracture mortality (SMR, mainly for 180-day mortality) remained two-fold higher than in general population with no consistent trend towards improvement. CONCLUSIONS: Hip fracture incidence and subsequent mortality fell among women and men in the Swedish general population. In dialysis patients, hip fracture incidence declined in women but not in men while post-fracture mortality did not improve, and the incidence and subsequent mortality remained 3 to 5-fold and 2-fold higher than in the general population.

Sparing effect of peritoneal dialysis vs hemodialysis on BMD changes and its impact on mortality.

INTRODUCTION: Bone loss in end stage renal disease (ESRD) patients associates with fractures, vascular calcification, cardiovascular disease (CVD) and increased mortality. We investigated factors associated with changes of bone mineral density (ΔBMD) during the initial year on dialysis therapy and associations of ΔBMD with subsequent mortality in ESRD patients initiating dialysis. MATERIALS AND METHODS: In 242 ESRD patients (median age 55 years, 61% men) starting dialysis with peritoneal dialysis (PD; n = 138) or hemodialysis (HD; n = 104), whole-body dual-energy X-ray absorptiometry (DXA), body composition, nutritional status and circulating biomarkers were assessed at baseline and 1 year after dialysis start. We used multivariate linear regression analysis to determine factors associated with ΔBMD, and fine and gray competing risk analysis to determine associations of ΔBMD with subsequent mortality risk. RESULTS: BMD decreased significantly in HD patients (significant reductions of BMDtotal and BMDleg, trunk, rib, pelvis and spine) but not in PD patients. HD compared to PD therapy associated with negative changes in BMDtotal (ß=- 0.15), BMDhead (ß=- 0.14), BMDleg (ß=- 0.18) and BMDtrunk (ß=- 0.16). Better preservation of BMD associated with significantly lower all-cause mortality for ΔBMDtotal (sub-hazard ratio, sHR, 0.91), ΔBMDhead (sHR 0.91) and ΔBMDleg (sHR 0.92), while only ΔBMDhead (sHR 0.92) had a beneficial effect on CVD-mortality. CONCLUSIONS: PD had beneficial effect compared with HD on BMD changes during first year of dialysis therapy. Better preservation of BMD, especially in bone sites rich in cortical bone, associated with lower subsequent mortality. BMD in cortical bone may have stronger association with clinical outcome than BMD in trabecular bone.

Bone mineral density and mortality in end-stage renal disease patients.

Osteoporosis characterized by low bone mineral density (BMD) as assessed by dual-energy X-ray absorptiometry (DXA) is common among end-stage renal disease (ESRD) patients and associates with high fracture incidence and high all-cause mortality. This is because chronic kidney disease-mineral bone disorders (CKD-MBDs) promote not only bone disease (osteoporosis and renal dystrophy) but also vascular calcification and cardiovascular disease. The disturbed bone metabolism in ESRD leads to 'loss of cortical bone' with increased cortical porosity and thinning of cortical bone rather than to loss of trabecular bone. Low BMD, especially at cortical-rich bone sites, is closely linked to CKD-MBD, vascular calcification and poor cardiovascular outcomes. These effects appear to be largely mediated by shared mechanistic pathways via the 'bone-vascular axis' through which impaired bone status associates with changes in the vascular wall. Thus, bone is more than just the scaffolding that holds the body together and protects organs from external forces but is-in addition to its physical supportive function-also an active endocrine organ that interacts with the vasculature by paracrine and endocrine factors through pathways including Wnt signalling, osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/RANK ligand system and the Galectin-3/receptor of advanced glycation end products axis. The insight that osteogenesis and vascular calcification share many similarities-and the knowledge that vascular calcification is a cell-mediated active rather than a passive mineralization process-suggest that low BMD and vascular calcification ('vascular ossification') to a large extent represent two sides of the same coin. Here, we briefly review changes of BMD in ESRD as observed using different DXA methods (central and whole-body DXA) at different bone sites for BMD measurements, and summarize recent knowledge regarding the relationships between 'low BMD' and 'fracture incidence, vascular calcification and increased mortality' in ESRD patients, as well as potential 'molecular mechanisms' underlying these associations.

Fractures after kidney transplantation: Incidence, predictors, and association with mortality.

BACKGROUND: Major fractures (MF) are associated with increased mortality in the general population and represent an even higher risk in patients with chronic kidney disease. We investigated incidence, predictors and clinical outcomes associated with first MF (MFfirst) following kidney transplantation (KT). METHODS: We used the Swedish National Renal Registry of 3992 first KT recipients (2005-2016) (median age 53 years, 65% men) and identified all MFfirst in hip, spine, humerus and forearm following KT. We estimated incidence rates and predictors of MFfirst using flexible parametric hazard models and Fine-Gray analysis accounting for competing risk of death, and risk of all-cause mortality following MFfirst using Cox proportional hazards models with fracture as time-varying exposure. RESULTS: During median follow-up of 4.8 years (IQR 2.2-7.9 years), there were 279 fractures of which 139 were forearm fractures. The crude incidence rate of MFfirst (n = 279) was 13.5/1000 patient-years and that of hip fractures (n = 69) 3.4/1000 patient-years. The multivariate-adjusted fracture incidence rates were highest during the first 6 months following KT, and 86% higher in women than in men. High age, female sex, previous history of MF, diabetes nephropathy, pretransplant dialysis therapy and acute rejection were associated with increased risk for MFfirst, whereas pre-emptive KT was associated with lower risk of MFfirst. Spline curves showed markedly higher impact of higher age on risk of MFfirst in women than in men. MFfirst (n = 279) independently predicted increased all-cause mortality risk (hazard ratio, HR, 1.78(95%CI 1.35-2.36)). Among MFfirst, with humerus fracture as reference, hip fracture (HR, 4.68(95%CI 1.56-14.06)) and spine fracture (HR, 4.02(95%CI 1.19-13.54)), but not forearm fracture (HR, 1.17 (95%CI 0.38-3.53)), were associated with increased all-cause mortality risk. CONCLUSIONS: The initial 6 months following kidney transplantation is a high-risk period for MF. Among MF, hip fracture and spine fracture associate with substantially increased all-cause mortality risk.

Incidence of Fractures Before and After Dialysis Initiation.

Fractures are common in dialysis patients, but little is known about the trajectory of incidence rates of different types of fractures before and after dialysis initiation. To address this, we investigated the incidence of major fractures before and after dialysis initiation. We performed a retrospective statistical analysis using the Swedish Renal Registry of 9041 incident dialysis patients (median age 67 years, 67% men) starting dialysis 2005 through 2015 to identify major fractures (hip, spine, humerus, and forearm) occurring during the dialysis transition period from 1 year before until 1 year after dialysis initiation. Using flexible parametric hazard models and the Fine-Gray model, we estimated adjusted fracture incidence rates and predictors of major fractures. We identified 361 cases with primary diagnosis of major fracture, of which 196 (54%) were hip fractures. The crude incidence rate of major fractures before dialysis initiation was 17 per 1000 patient-years (n = 157) and after dialysis initiation it was 24 per 1000 patient-years (n = 204). The adjusted incidence rate of major fractures began to increase 6 months before dialysis initiation, and then stabilized at a higher rate after 1 year. The adjusted incidence rate of hip fractures started to increase sharply 3 months before dialysis initiation, peaked at initiation, and declined thereafter. In contrast, the adjusted incidence rate of non-hip fractures was stable during the transition period and gradually increased over time. Higher age, female sex, and history of previous major fractures were associated with increased fracture incidence both before and after dialysis initiation. We conclude that the incidence of major fractures, especially hip fractures, start to rise 6 months before initiation of dialysis therapy, indicating that heightened surveillance with implementation of preventive measures to avoid fractures is warranted during the transition period to dialysis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Therapeutic Potential of Thrombomodulin in Renal Fibrosis of Nephrotoxic Serum Nephritis in Wistar-Kyoto Rats.

BACKGROUND: Recombinant human soluble thrombomodulin (rhTM) was approved in 2008 and has been used for treatment of disseminated intravascular coagulation in Japan. The antifibrotic effects of rhTM in acute exacerbation of idiopathic pulmonary fibrosis are well established, but the therapeutic potential of rhTM in renal fibrosis remains poorly understood. METHODS: Nephrotoxic serum nephritis (NTS-N) was induced in 22 female Wistar-Kyoto (WKY) rats on day 0. Rats were administered either rhTM or vehicle intraperitoneally, every day from day 4 to day 55. Rats were sacrificed on day 56 when renal fibrosis was established and renal morphological investigations were performed. In vitro, rat renal fibroblasts (NRK-49F) were pretreated with rhTM or saline, and expression levels of profibrogenic gene induced by thrombin were analyzed by real-time reverse transcription polymerase chain reaction. RESULTS: Compared to WKY-GN-vehicle rats, the body weights of WKY-GN-rhTM rats were significantly greater on day 55. By day 56, rhTM had significantly reduced serum creatinine levels in NTS-N. On the other hand, urinary protein excretion was comparable between the two treatment groups throughout the study. The percentage of Masson trichrome-positive areas in WKY-GN-rhTM rats was significantly lower compared to that in WKY-GN-vehicle rats. Glomerular fibrin deposition was significantly reduced in WKY-GN-rhTM rats. In addition, rhTM significantly reduced the renal cortical mRNA expression levels of TNF-α, Toll-like receptor 4, MYD88, TGF-ß, αSMA, collagen I, collagen III, fibronectin, and protease-activated receptor 1 (PAR1), a thrombin receptor. In vitro, thrombin stimulation of NRK-49F cells significantly enhanced the mRNA expression levels of αSMA and PAR1, and these upregulations were significantly reduced by pretreatment with rhTM. CONCLUSIONS: Administration of rhTM after establishment of crescentic glomerulonephritis (GN) attenuated the subsequent development of renal fibrosis in NTS-N, possibly in part by inhibiting thrombin-mediated fibrogenesis. Our results suggest that rhTM may offer a therapeutic option for limiting the progression of chronic kidney disease in crescentic GN.

Major fractures after initiation of dialysis: Incidence, predictors and association with mortality.

BACKGROUND: Major fractures (MF) are common in dialysis patients. We investigated incidence, predictors and clinical outcomes associated with first MF occurring after initiation of dialysis (MFfirst). METHODS: In Swedish Renal Registry of 9714 incident (2005-2016) dialysis patients (age 68 years, 67% men), we identified all MFfirst in hip, spine, humerus and forearm. Using flexible parametric hazard models and Fine-Gray analysis, we estimated incidence, mortality rates and predictors of MFfirst, and, in time-dependent analysis, risk of all-cause and cardiovascular disease (CVD) mortality following MFfirst. RESULTS: During median follow-up of 2.2 years, the crude incidence rate of MFfirst (n = 835) was 23.7/1000 patient-years and that of hip fractures (n = 470) 13.3/1000 patient-years. The multivariate-adjusted fracture incidence rates increased gradually after dialysis initiation and were 47% higher among women. Female sex, higher age, comorbidity, and previous history of MF (MFprevious) were associated with increased risk for MFfirst, whereas peritoneal dialysis as compared to hemodialysis was associated with decreased risk. The adjusted fracture incidence rate of MFfirst during the first 90 days following dialysis initiation was higher in patients with MFprevious than in those without MFprevious. MFfirst independently predicted increased all-cause (sub-distribution hazard ratio, SHR, 1.67(95%CI 1.47-1.91)) and CVD (SHR 1.49 (95%CI 1.22-1.84)) mortality. Adjusted mortality rate following hip fractures was higher than for other types of MF. Spline curves showed that mortality following MFfirst was highest during the first 6 months of follow-up. CONCLUSIONS: MF are common and associated with increased mortality in incident dialysis patients.

Fractures and their sequelae in non-dialysis-dependent chronic kidney disease: the Stockholm CREAtinine Measurement project.

INTRODUCTION: People undergoing maintenance dialysis are at high risk for fractures, but less is known about fracture incidence and associated outcomes in earlier stages of chronic kidney disease (CKD). METHODS: We conducted an observational analysis from the Stockholm Creatinine Measurement project, a Swedish health care utilization cohort during 2006-11. We identified all adults with confirmed CKD Stages 3-5 and no documented history of fractures and extracted information on comorbid history, ongoing medication, cardiovascular events and death. We studied incidence rates of fractures (overall and by location), with the estimated glomerular filtration rate (eGFR) as time-dependent exposure. We then studied hazard ratios [HRs and 95% confidence intervals (CIs)] for the events of death and major adverse cardiac events (MACE) using Cox regression with fracture as time-varying exposure. RESULTS: We identified 68 764 individuals with confirmed CKD (mean age 79 years, 56% women). During a median follow-up of 2.7 years, 9219 fractures occurred, of which 3105 were hip fractures. A more severe CKD stage was associated with a higher risk of fractures, particularly hip fractures: compared with CKD Stage 3a, the adjusted HR was 1.10 (95% CI 1.02-1.19), 1.32 (1.17-1.49) and 2.47 (1.94-3.15) for CKD Stage 3b, 4 and 5, respectively. Spline curves suggested a linear association with fracture risk with an eGFR <30 mL/min/1.73 m2. Compared with non-fracture periods, incident fracture was associated with a 4-fold increased mortality within 90 days [HR 4.21 (95% CI 3.95-4.49)]. The risk remained elevated beyond 90 days [HR 1.47 (95% CI 1.40-1.54)] and was stronger after hip fractures. Post-fracture MACE risk was also highest in the first 90 days [HR 4.02 (95% CI 3.73-4.33)], particularly after hip fractures, and persisted beyond 90 days [HR 1.20 (95% CI 1.10-1.30)]. CONCLUSION: Our findings highlight the commonness of fractures and the increased risk for subsequent adverse outcomes in CKD patients. These results may inform clinical decisions regarding post-fracture clinical surveillance and fracture prevention strategies.

Bone mineral density at different sites and 5 years mortality in end-stage renal disease patients: A cohort study.

BACKGROUND: Bone disease with osteoporosis and renal osteodystrophy is common in end stage renal disease (ESRD) patients and associates with cardiovascular disease (CVD) and increased morbimortality. We investigated associations of low bone mineral density (BMD) at various bone sites with five year all-cause and CVD mortality in ESRD patients. METHODS: In a post hoc analysis of 426 ESRD patients (median age 56 years, 62% men) starting dialysis, BMD (whole-body dual-energy X-ray absorptiometry, DXA), body composition, nutritional status (subjective global assessment, SGA), handgrip strength (%HGS), Framingham CVD risk score (FRS) and biochemical biomarkers of nutrition and inflammation were assessed. We used the Fine and Gray competing risk regression analysis to assess survival analysis. RESULTS: In multivariate logistic regression analysis, %HGS and intact parathyroid hormone associated with low tertile of: BMDtotal, BMDhead and BMDpelvis, after adjusting for FRS, SGA, %HGS, s-albumin, hsCRP, lean body mass index and year of recruitment. Patients with high FRS had low BMDhead (p<0.001). Low tertile of BMDtotal (sHR, 1.53), BMDhead (sHR 1.54) and BMDpelvis (sHR 1.60) associated with increased all-cause mortality whereas no such associations were found for the trabecular bone rich sites BMD arm, leg, trunk, rib or spine. Low tertile of BMDtotal (sHR 1.94), BMDhead (sHR 1.68), BMDleg (sHR 2.25) and BMDpelvis (sHR 2.45) associated with increased CVD mortality whereas BMD at other sites did not associate with CVD mortality. CONCLUSION: Low head and pelvis BMD, and low total BMD, as assessed by whole-body DXA, were independent predictors of increased risk of all-cause and CVD mortality. Cortical BMD appeared to have stronger association to survival in ESRD than trabecular BMD.

Serum uromodulin is associated with the severity of clinicopathological findings in ANCA-associated glomerulonephritis.

BACKGROUND: Uromodulin (UMOD), also known as Tamm-Horsfall protein, is a kidney-specific protein expressed by epithelial cells lining the thick ascending limb of the loop of Henle. In the current study, we aimed to clarify the clinical significance of UMOD in ANCA-associated glomerulonephritis (AAG). MATERIALS AND METHODS: Sixty-one biopsy-proven AAG patients were included in this study. UMOD was measured using ELISA. The relationships between serum UMOD (sUMOD) levels and various clinicopathological findings were evaluated. RESULTS: AAG was classified into four categories (focal, crescentic, mixed, and sclerotic). In addition, tubulointerstitial lesions were classified as mild, moderate, and severe. The levels of sUMOD and urinary UMOD (uUMOD) were correlated with each other. A negative correlation between sUMOD levels and serum Cr levels, and positive correlation between sUMOD levels and eGFR were found. Patients in the high sUMOD group were associated with low serum Cr levels, focal classification, and mild tubulointerstitial injury compared to the low sUMOD group. Comparing the characteristics among histopathological classes, patients in the focal class had the best renal function and the highest levels of uUMOD/Cr and sUMOD. The focal class had significantly better renal survival compared with the severe histopathological classes (crescentic, mixed, and sclerotic). In univariate logistic regression analyses, prognostic factors for severe histopathological classes were low uUMOD/Cr, high serum Cr, and low sUMOD. Multivariate analyses revealed that low sUMOD predicted severe histopathological classes independent of serum Cr. The mean levels of sUMOD were significantly different between the focal class and severe histopathological classes, with a sensitivity of 70.6% and specificity of 90.0% (cut-off 143 ng/ml, AUC 0.80) by ROC curves. CONCLUSION: Low sUMOD levels were associated with severe clinicopathological findings and might be considered as a risk factor for end stage renal disease in AAG.

Elimination of intravenous alendronate by hemodialysis: A kinetic study.

INTRODUCTION: The potential utility of intravenous alendronate for the treatment of osteoporosis in hemodialysis patients was recently reported. However, the pharmacokinetics of intravenous alendronate in patients on hemodialysis is not clear. METHODS: Six hemodialysis patients (mean age, 80.5 years) with osteoporosis who had received intravenous alendronate prior to the study were enrolled. The participants received a 30-min infusion of 900-µg alendronate intravenously at the beginning of the dialysis session. The blood flow rate (Qb) and dialysate flow rate (Qd) were set at 200 mL/min and 500 mL/min, respectively. All patients used the same dialyzer (1.5-m2 polysulfone membrane). At the completion of administration, plasma and dialysate samples were collected, and alendronate concentrations were determined using metal-free high-performance liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS). RESULTS: The plasma arterial alendronate concentration was 150.9 ± 46.09 ng/mL. It decreased through the dialyzer to 76.1 ± 34.1 ng/mL (venous alendronate concentration). Mean alendronate clearance was 113.9 ± 25.6 mL/min. Mean alendronate removal by hemodialysis, measured by the difference in arterial-venous concentrations, was 51.8%. CONCLUSIONS: Fifty percent of intravenous alendronate was removed by hemodialysis, which is nearly equal to elimination of alendronate in patients with normal renal function. The elimination by hemodialysis would decrease the risk of excessive accumulation in bone. UMIN 000027182.

Effects of Denosumab and Alendronate on Bone Health and Vascular Function in Hemodialysis Patients: A Randomized, Controlled Trial.

Mineral and bone disorders including osteoporosis are common in dialysis patients and contribute to increased morbimortality. However, whether denosumab and alendronate are effective and safe treatments in hemodialysis patients is not known. Thus, we conducted a prospective, three-center study of 48 hemodialysis patients who were diagnosed as having osteoporosis and had not received anti-osteoporotic agents previously. Participants were randomized to either denosumab or intravenous alendronate, and all subjects received elemental calcium and calcitriol during the initial 2 weeks. The primary endpoint was the percent change in lumbar spine bone mineral density (LSBMD) at 12 months of treatment. The secondary endpoints included the following: change in BMD at other sites; change of serum bone turnover markers (BTM), coronary artery calcium score (CACS), ankle-brachial pressure index (ABI), brachial-ankle pulse wave velocity (baPWV), flow mediated dilation (FMD), and intima-media thickness at the carotid artery (CA-IMT); change from day 0 to day 14 in serum levels of Ca and P; time course of serum calcium (Ca), phosphorus (P), and intact parathyroid hormone (i-PTH); new fractures; and adverse events. Initial supplementation with elemental calcium and calcitriol markedly ameliorated the decrease of serum corrected calcium (cCa) levels induced by denosumab during the first 2 weeks, whereas serum cCa levels in the alendronate group were increased. Denosumab and alendronate markedly decreased serum levels of BTM and increased LSBMD at 12 months compared with baseline. However, no significant differences were found in the changes in LSBMD between the two groups. The serum cCa, P, and i-PTH levels in the two groups were maintained within the appropriate range. In contrast to the anti-osteoporotic effects, no significant differences after 12 months of treatment were found in the CACS, CA-IMT, ABI, baPWV, and FMD compared with pretreatment in both groups. Denosumab and alendronate treatment improved LSBMD, reduced BTM, and appeared to be safe in hemodialysis patients with osteoporosis. © 2019 American Society for Bone and Mineral Research.

Recombinant human soluble thrombomodulin attenuates anti-glomerular basement membrane glomerulonephritis in Wistar-Kyoto rats through anti-inflammatory effects.

BACKGROUND: Since recombinant human soluble thrombomodulin (RH-TM) has anti-inflammatory properties through neutralizing high-mobility group box 1 protein (HMGB1), the protective effects of RH-TM were examined in anti-glomerular basement membrane (GBM) glomerulonephritis (GN) in Wistar-Kyoto rats. METHODS: Rats were injected with nephrotoxic serum (NTS) to induce anti-GBM GN on Day 0, and were given either RH-TM or vehicle from Day 0 to Day 6. Rats were sacrificed 7 days after NTS injection. RESULTS: RH-TM-treated rats had decreased proteinuria and serum creatinine level. RH-TM significantly reduced the percentage of glomeruli with crescentic features and fibrinoid necrosis. In addition, RH-TM-treated rats had significantly reduced glomerular ED1+ macrophage accumulation as well as reduced renal cortical proinflammatory cytokine expression. Furthermore, RH-TM had a potent effect in reducing intercellular adhesion molecule-1 (ICAM-1) expression in kidneys and urine. RH-TM significantly reduced renal cortical mRNA levels for toll-like receptor -2 and -4, known as receptors for HMGB1, and their downstream adopter protein, myeloid differentiation primary respond protein 88 (MyD88). CONCLUSIONS: We showed for the first time that anti-inflammatory effects, which were characterized by reduced glomerular macrophage influx concomitant with a marked reduction in proinflammatory cytokines, were involved in the mechanism of attenuating experimental anti-GBM GN by RH-TM. The observed effects might be attributable to the downregulation of ICAM-1 by reducing the HMGB1/TLR/MyD88 signaling pathway.