Vasodilator reactive oxygen species ameliorate perturbed myocardial oxygen delivery in exercising swine with multiple comorbidities.

Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD) induced systemic inflammation, increased oxidative stress and produced coronary endothelial dysfunction, altering control of coronary microvascular tone via loss of NO bioavailability, which was associated with an increase in circulating endothelin (ET). In the present study, we tested the hypotheses that (1) ROS scavenging and (2) ETA+B-receptor blockade improve myocardial oxygen delivery in the same female swine model. Healthy female swine on normal pig chow served as controls (Normal). Five months after induction of DM (streptozotocin, 3 × 50 mg kg-1 i.v.), hypercholesterolemia (HFD) and CKD (renal embolization), swine were chronically instrumented and studied at rest and during exercise. Sustained hyperglycemia, hypercholesterolemia and renal dysfunction were accompanied by systemic inflammation and oxidative stress. In vivo ROS scavenging (TEMPOL + MPG) reduced myocardial oxygen delivery in DM + HFD + CKD swine, suggestive of a vasodilator influence of endogenous ROS, while it had no effect in Normal swine. In vitro wire myography revealed a vasodilator role for hydrogen peroxide (H2O2) in isolated small coronary artery segments from DM + HFD + CKD, but not Normal swine. Increased catalase activity and ceramide production in left ventricular myocardial tissue of DM + HFD + CKD swine further suggest that increased H2O2 acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ETA+B blockade did not affect myocardial oxygen delivery in Normal or DM + HFD + CKD swine. In conclusion, loss of NO bioavailability due to 5 months exposure to multiple comorbidities is partially compensated by increased H2O2-mediated coronary vasodilation.

Differentiated mouse kidney tubuloids as a novel in vitro model to study collecting duct physiology.

Kidney tubuloids are cell models that are derived from human or mouse renal epithelial cells and show high similarities with their in vivo counterparts. Tubuloids grow polarized in 3D, allow for long-term expansion, and represent multiple segments of the nephron, as shown by their gene expression pattern. In addition, human tubuloids form tight, functional barriers and have been succesfully used for drug testing. Our knowledge of mouse tubuloids, on the other hand, is only minimal. In this study, we further characterized mouse tubuloids and differentiated them towards the collecting duct, which led to a significant upregulation of collecting duct-specific mRNAs of genes and protein expression, including the water channel AQP2 and the sodium channel ENaC. Differentiation resulted in polarized expression of collecting duct water channels AQP2 and AQP3. Also, a physiological response to desmopressin and forskolin stimulation by translocation of AQP2 to the apical membrane was demonstrated. Furthermore, amiloride-sensitive ENaC-mediated sodium uptake was shown in differentiated tubuloids using radioactive tracer sodium. This study demonstrates that mouse tubuloids can be differentiated towards the collecting duct and exhibit collecting duct-specific function. This illustrates the potential use of mouse kidney tubuloids as novel in vitro models to study (patho)physiology of kidney diseases.

Deep learning body-composition analysis of clinically acquired CT-scans estimates creatinine excretion with high accuracy in patients and healthy individuals.

Assessment of daily creatinine production and excretion plays a crucial role in the estimation of renal function. Creatinine excretion is estimated by creatinine excretion equations and implicitly in eGFR equations like MDRD and CKD-EPI. These equations are however unreliable in patients with aberrant body composition. In this study we developed and validated equations estimating creatinine production using deep learning body-composition analysis of clinically acquired CT-scans. We retrospectively included patients in our center that received any CT-scan including the abdomen and had a 24-h urine collection within 2 weeks of the scan (n = 636). To validate the equations in healthy individuals, we included a kidney donor dataset (n = 287). We used a deep learning algorithm to segment muscle and fat at the 3rd lumbar vertebra, calculate surface areas and extract radiomics parameters. Two equations for CT-based estimate of RenAl FuncTion (CRAFT 1 including CT parameters, age, weight, and stature and CRAFT 2 excluding weight and stature) were developed and compared to the Cockcroft-Gault and the Ix equations. CRAFT1 and CRAFT 2 were both unbiased (MPE = 0.18 and 0.16 mmol/day, respectively) and accurate (RMSE = 2.68 and 2.78 mmol/day, respectively) in the patient dataset and were more accurate than the Ix (RMSE = 3.46 mmol/day) and Cockcroft-Gault equation (RMSE = 3.52 mmol/day). In healthy kidney donors, CRAFT 1 and CRAFT 2 remained unbiased (MPE = - 0.71 and - 0.73 mmol/day respectively) and accurate (RMSE = 1.86 and 1.97 mmol/day, respectively). Deep learning-based extraction of body-composition parameters from abdominal CT-scans can be used to reliably estimate creatinine production in both patients as well as healthy individuals. The presented algorithm can improve the estimation of renal function in patients who have recently had a CT scan. The proposed methods provide an improved estimation of renal function that is fully automatic and can be readily implemented in routine clinical practice.

Residual cardiovascular risk reduction guided by lifetime benefit estimation in patients with symptomatic atherosclerotic disease: effectiveness and cost-effectiveness.

AIMS: To determine the (cost)-effectiveness of blood pressure lowering, lipid-lowering, and antithrombotic therapy guided by predicted lifetime benefit compared to risk factor levels in patients with symptomatic atherosclerotic disease. METHODS AND RESULTS: For all patients with symptomatic atherosclerotic disease in the UCC-SMART cohort (1996-2018; n = 7697) two treatment strategies were compared. The lifetime benefit-guided strategy was based on individual estimation of gain in cardiovascular disease (CVD)-free life with the SMART-REACH model. In the risk factor-based strategy, all patients were treated the following: low-density lipoprotein cholesterol (LDL-c) < 1.8 mmol/L, systolic blood pressure <140 mmHg, and antithrombotic medication. Outcomes were evaluated for the total cohort using a microsimulation model. Effectiveness was evaluated as total gain in CVD-free life and events avoided, cost-effectiveness as incremental cost-effectivity ratio (ICER). In comparison to baseline treatment, treatment according to lifetime benefit would lead to an increase of 24 243 CVD-free life years [95% confidence interval (CI) 19 980-29 909] and would avoid 940 (95% CI 742-1140) events in the next 10 years. For risk-factor based treatment, this would be an increase of 18 564 CVD-free life years (95% CI 14 225-20 456) and decrease of 857 (95% CI 661-1057) events. The ICER of lifetime benefit-based treatment with a treatment threshold of ≥1 year additional CVD-free life per therapy was €15 092/QALY gained and of risk factor-based treatment €9933/QALY gained. In a direct comparison, lifetime benefit-based treatment compared to risk factor-based treatment results in 1871 additional QALYs for the price of €36 538/QALY gained. CONCLUSION: Residual risk reduction guided by lifetime benefit estimation results in more CVD-free life years and more CVD events avoided compared to the conventional risk factor-based strategy. Lifetime benefit-based treatment is an effective and potentially cost-effective strategy for reducing residual CVD risk in patients with clinical manifest vascular disease.

GFR estimation is complicated by a high incidence of non-steady-state serum creatinine concentrations at the emergency department.

BACKGROUND: Acquiring a reliable estimate of glomerular filtration rate (eGFR) at the emergency department (ED) is important for clinical management and for dosing renally excreted drugs. However, renal function formulas such as CKD-EPI can give biased results when serum creatinine (SCr) is not in steady-state because the assumption that urinary creatinine excretion is constant is then invalid. We assessed the extent of this by analysing variability in SCr in patients who visited the ED of a tertiary care centre. METHODS: Data from ED visits at the University Medical Centre Utrecht, the Netherlands between 2012 and 2019 were extracted from the Utrecht Patient Oriented Database. Three measurement time points were defined for each visit: last SCr measurement before visit as baseline (SCr-BL), first measurement during visit (SCr-ED) and a subsequent measurement between 6 and 24 hours during admission (SCr-H1). Non-steady-state SCr was defined as exceeding the Reference Change Value (RCV), with 15% decrease or 18% increase between successive SCr measurements. Exceeding the RCV was deemed as a significant change. RESULTS: Of visits where SCr-BL and SCr-ED were measured (N = 47,540), 28.0% showed significant change in SCr. Of 17,928 visits admitted to the hospital with a SCr-H1 after SCr-ED, 27,7% showed significant change. More than half (55%) of the patients with SCr values available at all three timepoints (11,054) showed at least one significant change in SCr over time. CONCLUSION: One third of ED visits preceded and/or followed by creatinine measurement show non-stable serum creatinine concentration. At the ED automatically calculated eGFR should therefore be interpreted with great caution when assessing kidney function.

Multi-omics integration identifies key upstream regulators of pathomechanisms in hypertrophic cardiomyopathy due to truncating MYBPC3 mutations.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the cardiac muscle, frequently caused by mutations in MYBPC3. However, little is known about the upstream pathways and key regulators causing the disease. Therefore, we employed a multi-omics approach to study the pathomechanisms underlying HCM comparing patient hearts harboring MYBPC3 mutations to control hearts. RESULTS: Using H3K27ac ChIP-seq and RNA-seq we obtained 9310 differentially acetylated regions and 2033 differentially expressed genes, respectively, between 13 HCM and 10 control hearts. We obtained 441 differentially expressed proteins between 11 HCM and 8 control hearts using proteomics. By integrating multi-omics datasets, we identified a set of DNA regions and genes that differentiate HCM from control hearts and 53 protein-coding genes as the major contributors. This comprehensive analysis consistently points toward altered extracellular matrix formation, muscle contraction, and metabolism. Therefore, we studied enriched transcription factor (TF) binding motifs and identified 9 motif-encoded TFs, including KLF15, ETV4, AR, CLOCK, ETS2, GATA5, MEIS1, RXRA, and ZFX. Selected candidates were examined in stem cell-derived cardiomyocytes with and without mutated MYBPC3. Furthermore, we observed an abundance of acetylation signals and transcripts derived from cardiomyocytes compared to non-myocyte populations. CONCLUSIONS: By integrating histone acetylome, transcriptome, and proteome profiles, we identified major effector genes and protein networks that drive the pathological changes in HCM with mutated MYBPC3. Our work identifies 38 highly affected protein-coding genes as potential plasma HCM biomarkers and 9 TFs as potential upstream regulators of these pathomechanisms that may serve as possible therapeutic targets.

The prevalence and incidence of vertebral fractures in end-stage renal disease and the role of parathyroid hormone.

The risk of vertebral fracture is unclear in end-stage renal disease. We report a high vertebral fracture prevalence and incidence in transplantation-eligible patients on dialysis, suggesting that these patients may benefit from radiographic screening for vertebral fractures. Parathyroid hormone had a U-shaped association with vertebral fracture risk. INTRODUCTION: Vertebral fractures are often overlooked, but even undiagnosed vertebral fractures negatively impact physical functioning, quality of life, and mortality. The risk of vertebral fractures in end-stage renal disease (ESRD) patients is unclear, and parathyroid hormone (PTH) might play a role in the development of vertebral fractures. We therefore determined vertebral fracture prevalence and incidence in ESRD patients and assessed associations of vertebral trabecular bone mineral density (BMD) and PTH with vertebral fracture. METHODS: In 146 transplantation-eligible patients on dialysis, we determined vertebral fractures on lateral chest radiographs, which image the thoracic and upper lumbar spine. We determined incident vertebral fractures in 70 patients with follow-up radiographs (23 received a kidney transplant) after median 1.8 years. Vertebral trabecular BMD was measured with computed tomography, and PTH measured with 2-site immunoassays, categorized in tertiles with the middle tertile as reference. We used Poisson regression to assess associations of vertebral trabecular BMD and PTH with vertebral fracture. RESULTS: Mean age of the study population was 52 ± 13 years, and 98 (67%) were male. Median dialysis duration was 26 (IQR 13-55) months. Vertebral fractures were present in 50/146 patients (34%) and incident vertebral fractures occurred in 20/70 patients (29%). Vertebral trabecular BMD was not associated with vertebral fracture prevalence (relative risk 0.97, 95% CI 0.89 to 1.04). For the lowest PTH tertile (< 11 pmol/L), the relative risk of vertebral fracture was greater although not significant (2.28, 95% CI 0.97 to 5.97) and was significantly greater for the highest PTH tertile (≥ 30 pmol/L; 2.82, 95% CI 1.22 to 7.27) after adjustment for potential confounders. CONCLUSIONS: The prevalence and incidence of vertebral fractures is high even in relatively young and healthy ESRD patients. Vertebral trabecular BMD is not associated with vertebral fracture, and the association of PTH with vertebral fracture risk appears U-shaped. Nevertheless, our study did not measure vertebral BMD using DXA and assessed vertebral fractures using lateral chest radiographs and not spine radiographs.

The association between chronic kidney disease, falls, and fractures: a systematic review and meta-analysis.

Patients with chronic kidney disease (CKD) are more likely to experience falls and fractures due to renal osteodystrophy and the high prevalence of risk factors for falls. However, it is not well established how great the risk is for falls and fractures for the different stages of CKD compared to the general population. The objective of this systematic review and meta-analysis was to assess whether, and in which degree, CKD was associated with falls and fractures in adults. A systematic search in PubMed, Embase, CINAHL, and The Cochrane Library was performed on 7 September 2018. All retrospective, cross-sectional, and longitudinal studies of adults (18 years of older) that studied the association between CKD, fractures, and falls were included. Additional studies were identified by cross-referencing. A total of 39 publications were included, of which two publications assessed three types of outcome and four publications assessed two types of outcome. Ten studies focused on accidental falling; seventeen studies focused on hip, femur, and pelvis fractures; seven studies focused on vertebral fractures; and thirteen studies focused on any type of fracture without further specification. Generally, the risk of fractures increased when kidney function worsened, with the highest risks in the patients with stage 5 CKD or dialysis. This effect was most pronounced for hip fractures and any type of fractures. Furthermore, results on the association between CKD and accidental falling were contradictory. Compared to the general population, fractures are highly prevalent in patients with CKD. Besides more awareness of timely fracture risk assessment, there also should be more focus on fall prevention.

Thoracic vertebral fractures and hyperkyphosis in elderly patients with end-stage kidney disease; do these patients have different clinical outcomes?

BACKGROUND AND OBJECTIVES: Elderly patients with end-stage kidney disease (ESKD) are at high risk for fractures. However, the prevalence of vertebral fractures and hyperkyphosis is not studied well. This is relevant, because in the general population, both vertebral fractures and hyperkyphosis are associated with poor outcome. Therefore, the primary aim of our study was to assess the prevalence of vertebral fractures and hyperkyphosis in the ESKD population. The secondary aim was to assess if patients with vertebral fractures and/or hyperkyphosis more often have poor outcome after starting dialysis, such as accidental falling, functional decline and mortality compared to the patients without vertebral fractures and/or hyperkyphosis. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: This study included patients ≥65 years with ESKD who were enrolled in the Geriatric assessment in Older patients starting Dialysis (GOLD) study of whom a lateral chest radiograph was available. Chest radiographs were scored independently by two observers for vertebral fractures (Genant ≥1) and hyperkyphosis (≥50 degrees). The relation between vertebral fractures and hyperkyphosis with clinical outcomes (falls, decline in ADL and IADL, mortality) was studied using the Chi-square test. RESULTS: Of the 196 enrolled patients, chest radiographs were available for 160 patients. Mean age was 75.3 (SD ±6.9), and 35% were female. The prevalence of vertebral fractures was 43% and of hyperkyphosis 22%. Patients with hyperkyphosis had a higher one-year mortality compared to patients without hyperkyphosis (20% vs. 8%, p = 0.04). No differences were observed between patients with and without hyperkyphosis, vertebral fractures and the remaining outcomes after six months of follow-up. CONCLUSIONS: In patients ≥65 years old with ESKD starting dialysis, vertebral fractures are highly prevalent. In contrast to the general population, patients with vertebral fractures did experience poor outcome as often as patients without vertebral fractures. Remarkably, patients with hyperkyphosis did have a higher one-year mortality. However, these patients did not experience more functional decline or accidental falls.

Quality of life after the initiation of dialysis or maximal conservative management in elderly patients: a longitudinal analysis of the Geriatric assessment in OLder patients starting Dialysis (GOLD) study.

BACKGROUND: Maximal conservative management (MCM) may be an appropriate alternative option for dialysis in some elderly patients with end-stage kidney disease (ESKD). Evidence about the impact of dialysis or MCM on quality of life (QoL) in older patients is sparse. In the GOLD (Geriatric assessment in OLder patients starting Dialysis) Study the trajectory of QoL was assessed in patients starting dialysis or MCM. METHODS: Patients ≥65 years old were included just prior to dialysis initiation or after decision for MCM. Baseline data included demographics, frailty as measured with a geriatric assessment, comorbidity (CIRS-G) and QoL, measured with the EQ-5D-3 L (EQ-5D Index and overall self-rated health). Six months follow-up data included QoL, hospitalizations and mortality. Change of QoL was assed with paired t-tests. Cox-regression was used to assess survival of MCM and dialysis patients. RESULTS: The cohort comprised 192 dialysis and 89 MCM patients. The MCM patients were older (mean age 82 ± 6 vs. 75 ± 7 years, p <  0.01) and mean kidney function was better (eGFR 11.5 ± 4.0 vs. 8.0 ± 2.9 ml/min/1.73m2, p <  0.01). Baseline QoL did not differ significantly between the groups. After six months, EQ-5D Index did not improve significantly in the dialysis group with mean ± standard error (SE) 0.026 ± 0.014 (p = 0.10; not clinically relevant), but a small but clinically relevant decline was seen in the conservative group: 0.047 ± 0.022 (p < 0.01; between group difference p < 0.01). Hospitalization occurred in 50% of dialysis patients vs. 24% of conservative patients (p < 0.01). In patients over 80 years old, no survival benefit could be found for dialysis patients starting dialysis vs. MCM. CONCLUSION: A small decline of QoL was found for conservative patients, while QoL did not change in dialysis patients. However, hospitalization rate was higher in patients starting dialysis. In patients over 80 years, no survival benefit was found.

Mortality due to bleeding, myocardial infarction and stroke in dialysis patients.

Essentials Mortality due to bleeding vs. arterial thrombosis in dialysis patients is unknown. We compared death causes of 201 918 dialysis patients with the general population. Dialysis was associated with increased mortality risks of bleeding and arterial thrombosis. Clinicians should be aware of the increased bleeding and thrombosis risks. SUMMARY: Background Dialysis has been associated with both bleeding and thrombotic events. However, there is limited information on bleeding as a cause of death versus arterial thrombosis as a cause of death. Objectives To investigate the occurrence of bleeding, myocardial infarction and stroke as causes of death in the dialysis population as compared with the general population. Methods We included 201 918 patients from 11 countries providing data to the ERA-EDTA Registry who started dialysis treatment between 1994 and 2011, and followed them for 3 years. Age-standardized and sex-standardized mortality rate ratios for bleeding, myocardial infarction and stroke as causes of death were calculated in dialysis patients as compared with the European general population. Associations between potential risk factors and these causes of death in dialysis patients were investigated by calculating hazard ratios (HRs) with 95% confidence intervals (CIs) by the use of Cox proportional-hazards regression. Results As compared with the general population, the age-standardized and sex-standardized mortality rate ratios in dialysis patients were 12.8 (95% CI 11.9-13.7) for bleeding as a cause of death (6.2 per 1000 person-years among dialysis patients versus 0.3 per 1000 person-years in the general population), 13.4 (95% CI 13.0-13.9) for myocardial infarction (22.5 versus 0.9 per 1000 person-years), and 12.4 (95% CI 11.9-12.9) for stroke (14.3 versus 0.7 per 1000 person-years). Conclusion Dialysis patients have highly increased risks of death caused by bleeding and arterial thrombosis as compared with the general population. Clinicians should be aware of the increased mortality risks caused by these conditions.

Mesenchymal Stromal Cell Characteristics and Regenerative Potential in Cardiovascular Disease: Implications for Cellular Therapy.

Administration of mesenchymal stromal cells (MSCs) is a promising strategy to treat cardiovascular disease (CVD). As progenitor cells may be negatively affected by both age and comorbidity, characterization of MSC function is important to guide decisions regarding use of allogeneic or autologous cells. Definitive answers on which factors affect MSC function can also aid in selecting which MSC donors would yield the most therapeutically efficacious MSCs. Here we provide a narrative review of MSC function in CVD based on a systematic search. A total of 41 studies examining CVD-related MSC (dys)function were identified. These data show that MSC characteristics and regenerative potential are often affected by CVD. However, studies presented conflicting results, and directed assessment of MSC parameters relevant to regenerative medicine applications was lacking in many studies. The predictive ability of in vitro assays for in vivo efficacy was rarely assessed. There was no correlation between quality of study reporting and study findings. Age mismatch was also not associated with study findings or effect size. Future research should focus on assays that assess regenerative potential in MSCs and parameters that relate to clinical success.

Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant.

The presence of donor-specific anti-HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long-term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement-dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10-year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10-year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10-year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence.

Chronic kidney disease and bleeding risk in patients at high cardiovascular risk: a cohort study.

Essentials The association between chronic kidney disease and bleeding is unknown. We followed 10 347 subjects at high cardiovascular risk for bleeding events. Chronic kidney disease was associated with a 1.5-fold increased bleeding risk. Especially albuminuria rather than decreased kidney function was associated with bleeding events. SUMMARY: Background There are indications that patients with chronic kidney disease have an increased bleeding risk. Objectives To investigate the association between chronic kidney disease and bleeding in patients at high cardiovascular risk. Methods We included 10 347 subjects referred to the University Medical Center Utrecht (the Netherlands) from September 1996 to February 2015 for an outpatient visit with classic risk factors for arterial disease or with symptomatic arterial disease (Second Manifestation of Arterial disease [SMART] cohort). Patients were staged according to the KDIGO guidelines, on the basis of estimated glomerular filtration rate (eGFR) and albuminuria, and were followed for the occurrence of major hemorrhagic events until March 2015. Hazard ratios (HRs) with 95% confidence intervals (CIs) for bleeding were calculated with Cox proportional hazards analyses. Results The incidence rate for bleeding in subjects with chronic kidney disease was 8.0 per 1000 person-years and that for subjects without chronic kidney disease was 3.5 per 1000 person-years. Patients with chronic kidney disease (n = 2443) had a 1.5-fold (95% CI 1.2-1.9) increased risk of bleeding as compared with subjects without chronic kidney disease (n = 7904) after adjustment. Subjects with an eGFR of < 45 mL min-1  1.73 m-2 with albuminuria had a 3.5-fold (95% CI 2.3-5.3) increased bleeding risk, whereas an eGFR of < 45 mL min-1  1.73 m-2 without albuminuria was not associated with an increased bleeding risk (HR 1.3, 95% CI 0.7-2.5). Conclusion Chronic kidney disease is a risk factor for bleeding in patients with classic risk factors for arterial disease or with symptomatic arterial disease, especially in the presence of albuminuria.

Quality of life as indicator of poor outcome in hemodialysis: relation with mortality in different age groups.

BACKGROUND: Physical, cognitive and psychosocial functioning are frequently impaired in dialysis patients and impairment in these domains relates to poor outcome. The aim of this analysis was to compare the prevalence of impairment as measured by the Kidney Disease Quality of Life- Short Form (KDQOL-SF) subscales between the different age categories and to assess whether the association of these subscales with mortality differs between younger and older dialysis patients. METHODS: This study included data from 714 prevalent hemodialysis patients, from 26 centres, who were enrolled in the CONvective TRAnsport STudy (CONTRAST NCT00205556, 09-12-2005). Baseline HRQOL domains were evaluated for patients <65 years, 65-74 years and over 75 years. Multivariable Cox proportional hazards analyses were performed to assess the relation between the separate domains and 2-year mortality. RESULTS: Emotional health was higher in patients over the age of 75 compared to younger patients (mean level 71, 73 and 77 for increasing age categories respectively, p = 0.02), whilst physical functioning was significantly lower in older patients (mean level 60, 48 and 40, p < 0.01). A low level of physical functioning (Hazard Ratio (HR) 1.72 [95%Confidence Interval (CI) 1.02-2.73]), emotional health (HR 1.85 [95% 1.30-2.63]), and social functioning (HR 1.59 [95% CI 1.12-2.26]), was individually associated with an increased 2-year mortality within the whole population. The absence of effect modification suggests no evidence for different relations within the older age groups. CONCLUSIONS: In dialysis patients, older age is associated with lower levels of physical functioning, whilst the level of emotional health is not associated with age. KDQOL-SF domains physical functioning, emotional health and social functioning are independently associated with mortality in prevalent younger and older hemodialysis patients.

Targeting multiple pathways reduces renal and cardiac fibrosis in rats with subtotal nephrectomy followed by coronary ligation.

AIM: Multiple interacting pathways contribute to progression of renal and cardiac damage in chronic kidney disease followed by chronic heart failure (renocardiac syndrome). We hypothesized that simultaneous pharmacological modulation of critical pathways implicated in renocardiac syndrome would effectively reduce fibrosis in and preserve function of heart and kidney. METHODS: Rats were subjected to subtotal nephrectomy followed 9 weeks later by coronary artery ligation. From week 11 until week 16, rats received vehicle or losartan, or a combination of the NF-kB inhibitor PDTC, the NO donor molsidomine and superoxide dismutase mimetic tempol, or a combination of all four of these plus metoprolol together. At week 16, renal and cardiac structure, function and gene expression were assessed. RESULTS: Individual and combined treatments were similarly effective in limiting cardiac fibrosis and further decline in systolic function. Combined treatment with all five drugs reduced renal fibrosis and CTGF gene expression more effectively than other strategies. Combining all five drugs reduced heart rate, inotropy and mean arterial pressure (MAP). CONCLUSION: Thus, in our model of chronic renocardiac syndrome, combined treatments similarly decreased cardiac fibrosis and stabilized systolic function as losartan alone, perhaps suggesting a dominant role for a single factor such as angiotensin II type 1 (AT1) receptor activation or inflammation in the network of aberrant systems in the heart. However, tubulointerstitial fibrosis was most effectively reduced by a five-drug regimen, pointing to additive effects of multiple pathophysiological pathways in the kidney.

High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury.

PURPOSE: Lung transplant recipients often develop acute kidney injury (AKI) evolving into chronic kidney disease (CKD). The immunosuppressant tacrolimus might be associated with the emergence of AKI. We analyzed the development and recovery of kidney injury after lung transplantation and related AKI to whole-blood tacrolimus trough concentrations and other factors causing kidney injury. METHODS: We retrospectively studied kidney injury in 186 lung-transplantation patients at the UMC Utrecht between 2001 and 2011. Kidney function and whole-blood tacrolimus trough concentrations were determined from day 1 to 14 and at 1, 3, 6, and 12 months postoperative. Systemic inflammatory response syndrome (SIRS), septic shock, and nephrotoxic medications were evaluated as covariates for AKI. We analyzed liver injury and drug-drug interactions. RESULTS: AKI was present in 85 (46%) patients. Tacrolimus concentrations were supra-therapeutic in 135 of 186 patients (73%). AKI in the first week after transplantation was related to supra-therapeutic tacrolimus concentrations (OR 1.55; 95% CI 1.06-2.27), ≥3 other nephrotoxic drugs (OR 1.96; 95% CI 1.02-3.77), infection (OR 2.48; 95% CI 1.31-4.70), and cystic fibrosis (OR 2.17; 95% CI 1.16-4.06). Recovery rate of AKI was lower than expected (19%), and the cumulative incidence of severe CKD at 1 year was 15%. CONCLUSIONS: After lung transplantation, AKI is common and often evolves into severe CKD, which is a known cause of morbidity and mortality. Supra-therapeutic whole-blood tacrolimus trough concentrations are related to the early onset of AKI. Conscientious targeting tacrolimus blood concentrations might be vital in the early phase after lung transplantation. What is known about this subject? • Lung transplant recipients often develop acute kidney injury evolving into chronic kidney disease increasing both morbidity and mortality. • To date, the pathophysiology of kidney injury after lung transplantation has not been fully elucidated. • The immunosuppressant tacrolimus is difficult to dose, especially in the unstable clinical setting, and is nephrotoxic. WHAT THIS STUDY ADDS: • For the first time, supra-therapeutic whole-blood tacrolimus trough concentrations are related to the emergence of acute kidney injury in the first days after lung transplantation. • Supra-therapeutic whole-blood tacrolimus trough concentrations often occur early after lung transplantation. • AKI after lung transplantation shows low recovery rates.

Complement Polymorphisms in Kidney Transplantation: Critical in Graft Rejection?

The complement system, as part of the innate immune system, plays an important role in renal transplantation. Complement is involved in the protection against foreign organisms and clearance of apoptotic cells but can also cause injury to the renal allograft, for instance, via antibody binding or in ischemia-reperfusion injury. Numerous polymorphisms in complement factors have been identified thus far; some of them result in different functionalities or alter complement levels. In this review, we provide an overview of the literature on the role of complement polymorphisms in renal transplantation. Furthermore, we discuss functional complement polymorphisms that have not yet been investigated in kidney transplantation. By investigating multiple polymorphisms both in donor and recipient at the same time, a complotype can be constructed. Because the combination of multiple polymorphisms is likely to have a greater impact than a single one, this could provide valuable prognostic information.

Quality of Life After Treatment with Autologous Bone Marrow Derived Cells in No Option Severe Limb Ischemia.

OBJECTIVE: Quality of life (QoL) is an important outcome in evaluating treatment effect in severe limb ischemia. The randomized, double blind, placebo controlled JUVENTAS trial, investigating the effect of bone marrow derived mononuclear cell (BMMNC) administration in no option severe limb ischemia, showed an improved QoL at 6 months compared with baseline in both the treatment and placebo groups. The aim of the present study was to evaluate whether the improved QoL persisted beyond 6 months' follow up, whether this differed in both trial arms, and if major amputation influenced QoL. METHODS: Short form 36 (SF-36) and EuroQol 5D (EQ5D), including the EQ Visual Analogue Scale (EQ-VAS), questionnaires were sent to JUVENTAS trial participants. In the JUVENTAS trial, a norm based scoring method was applied to report the results of the SF-36. The results of the long-term follow up were compared with baseline and 6 month follow up and the results of both trial arms were compared, as were the results of patients with and without amputation. RESULTS: One hundred and nine patients (86.5% of surviving patients) responded to the questionnaires. Median follow up after inclusion was 33 months (interquartile range [IQR] 21.2-50.6) for the BMMNC and 36 months (IQR 21.4-50.9) for the placebo group. The improvement in QoL at 6 months persisted in both arms at a median follow up of 35 months. The long-term QoL did not differ between the BMMNC and placebo group in any of the SF-36 or EQ5D domains. Patients with and without a major amputation had similar QoL scores. CONCLUSIONS: The increased QoL in patients with no option severe limb ischemia persisted until 3 years after inclusion, but did not differ between the BMMNC and placebo arms or between patients with and without a major amputation.

Bone Marrow derived Cell Therapy in Critical Limb Ischemia: A Meta-analysis of Randomized Placebo Controlled Trials.

OBJECTIVE/BACKGROUND: Critical limb ischemia (CLI) is the most advanced stage of peripheral artery disease (PAD), and many patients with CLI are not eligible for conventional revascularization. In the last decade, cell based therapies have been explored as an alternative treatment option for CLI. A meta-analysis was conducted of randomized placebo controlled trials investigating bone marrow (BM) derived cell therapy in patients with CLI. METHODS: The MEDLINE, Embase, and the Cochrane Controlled Trials Register databases were systematically searched, and all included studies were critically appraised by two independent reviewers. The meta-analysis was performed using a random effects model. RESULTS: Ten studies, totaling 499 patients, were included in this meta-analysis. No significant differences were observed in major amputation rates (relative risk [RR] 0.91; 95% confidence interval [CI] 0.65-1.27), survival (RR 1.00; 95% CI 0.95-1.06), and amputation free survival (RR 1.03; 95% CI 0.86-1.23) between the cell treated and placebo treated patients. The ankle brachial index (mean difference 0.11; 95% CI 0.07-0.16), transcutaneous oxygen measurements (mean difference 11.88; 95% CI 2.73-21.02), and pain score (mean difference -0.72; 95% CI -1.37 to -0.07) were significantly better in the treatment group than in the placebo group. CONCLUSIONS: This meta-analysis of placebo controlled trials showed no advantage of stem cell therapy on the primary outcome measures of amputation, survival, and amputation free survival in patients with CLI. The potential benefit of more sophisticated cell based strategies should be explored in future randomized placebo controlled trials.