Epimeric vitamin D and cardiovascular structure and function in advanced CKD and after kidney transplantation.

BACKGROUND: 25-hydroxyvitamin D can undergo C-3 epimerization to produce 3-epi-25(OH)D3. 3-epi-25(OH)D3 levels decline in chronic kidney disease (CKD), but its role in regulating the cardiovascular system is unknown. Herein, we examined the relationship between 3-epi-25(OH)D3, and cardiovascular functional and structural endpoints in patients with CKD. METHODS: We examined n = 165 patients with advanced CKD from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) study cohort, including those who underwent kidney transplant (KTR, n = 76) and waitlisted patients who did not (NTWC, n = 89). All patients underwent cardiopulmonary exercise testing and echocardiography at baseline, 2 months and 12 months. Serum 3-epi-25(OH)D3 was analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: Patients were stratified into quartiles of baseline 3-epi-25(OH)D3 (Q1: <0.4 ng/mL, n = 51; Q2: 0.4 ng/mL, n = 26; Q3: 0.5-0.7 ng/mL, n = 47; Q4: ≥0.8 ng/mL, n = 41). Patients in Q1 exhibited lower peak oxygen uptake [VO2Peak = 18.4 (16.2-20.8) mL/min/kg] compared with Q4 [20.8 (18.6-23.2) mL/min/kg; P = .009]. Linear mixed regression model showed that 3-epi-25(OH)D3 levels increased in KTR [from 0.47 (0.30) ng/mL to 0.90 (0.45) ng/mL] and declined in NTWC [from 0.61 (0.32) ng/mL to 0.45 (0.29) ng/mL; P < .001]. Serum 3-epi-25(OH)D3 was associated with VO2Peak longitudinally in both groups [KTR: ß (standard error) = 2.53 (0.56), P < .001; NTWC: 2.73 (0.70), P < .001], but was not with left ventricular mass or arterial stiffness. Non-epimeric 25(OH)D3, 24,25(OH)2D3 and the 25(OH)D3:24,25(OH)2D3 ratio were not associated with any cardiovascular outcome (all P > .05). CONCLUSIONS: Changes in 3-epi-25(OH)D3 levels may regulate cardiovascular functional capacity in patients with advanced CKD.

Dynamic Behaviour of Donor Specific Antibodies in the Early Period Following HLA Incompatible Kidney Transplantation.

In HLA-incompatible kidney transplantation, monitoring donor-specific antibodies (DSA) plays a crucial role in providing appropriate treatment and increases kidney survival times. This work aimed to determine if early post-transplant DSA dynamics inform graft outcome over and above other predictive factors. Eighty-eight cases were classified by unsupervised machine learning into five distinct DSA response groups: no response, fast modulation, slow modulation, rise to sustained and sustained. Fast modulation dynamics gave an 80% rate for early acute rejection, whereas the sustained group was associated with the lowest rejection rates (19%). In complete contrast, the five-year graft failure was lowest in the modulation groups (4-7%) and highest in the sustained groups (25-31%). Multivariable analysis showed that a higher pre-treatment DSA level, male gender and absence of early acute rejection were strongly associated with a sustained DSA response. The modulation group had excellent five-year outcomes despite higher rates of early rejection episodes. This work further develops an understanding of post-transplant DSA dynamics and their influence on graft survival following HLA-incompatible kidney transplantation.

C3d-positive donor-specific antibodies have a role in pretransplant risk stratification of cross-match-positive HLA-incompatible renal transplantation: United Kingdom multicentre study.

Anti-HLA-antibody characteristics aid to risk-stratify patients and improve long-term renal graft outcomes. Complement activation by donor-specific antibody (DSA) is an important characteristic that may determine renal allograft outcome. There is heterogeneity in graft outcomes within the moderate to high immunological risk cases (cross-match-positive). We explored the role of C3d-positive DSAs in sub-stratification of cross-match-positive cases and relate to the graft outcomes. We investigated 139 cross-match-positive living-donor renal transplant recipients from four transplant centres in the United Kingdom. C3d assay was performed on serum samples obtained at pretreatment (predesensitization) and Day 14 post-transplant. C3d-positive DSAs were found in 52 (37%) patients at pretreatment and in 37 (27%) patients at Day 14 post-transplant. Median follow-up of patients was 48 months (IQR 20.47-77.57). In the multivariable analysis, pretreatment C3d-positive DSA was independently associated with reduced overall graft survival, the hazard ratio of 3.29 (95% CI 1.37-7.86). The relative risk of death-censored five-year graft failure was 2.83 (95% CI 1.56-5.13). Patients with both pretreatment and Day 14 C3d-positive DSAs had the worst five-year graft survival at 45.5% compared with 87.2% in both pretreatment and Day 14 C3d-negative DSA patients with the relative risk of death-censored five-year graft failure was 4.26 (95% CI 1.79, 10.09). In this multicentre study, we have demonstrated for the first time the utility of C3d analysis as a distinctive biomarker to sub-stratify the risk of poor graft outcome in cross-match-positive living-donor renal transplantation.

Reappraisal of putative glyoxalase 1-deficient mouse and dicarbonyl stress on embryonic stem cells in vitro.

Glyoxalase 1 (Glo1) is a cytoplasmic enzyme with a cytoprotective function linked to metabolism of the cytotoxic side product of glycolysis, methylglyoxal (MG). It prevents dicarbonyl stress - the abnormal accumulation of reactive dicarbonyl metabolites, increasing protein and DNA damage. Increased Glo1 expression delays ageing and suppresses carcinogenesis, insulin resistance, cardiovascular disease and vascular complications of diabetes and renal failure. Surprisingly, gene trapping by the International Mouse Knockout Consortium (IMKC) to generate putative Glo1 knockout mice produced a mouse line with the phenotype characterised as normal and healthy. Here, we show that gene trapping mutation was successful, but the presence of Glo1 gene duplication, probably in the embryonic stem cells (ESCs) before gene trapping, maintained wild-type levels of Glo1 expression and activity and sustained the healthy phenotype. In further investigation of the consequences of dicarbonyl stress in ESCs, we found that prolonged exposure of mouse ESCs in culture to high concentrations of MG and/or hypoxia led to low-level increase in Glo1 copy number. In clinical translation, we found a high prevalence of low-level GLO1 copy number increase in renal failure where there is severe dicarbonyl stress. In conclusion, the IMKC Glo1 mutant mouse is not deficient in Glo1 expression through duplication of the Glo1 wild-type allele. Dicarbonyl stress and/or hypoxia induces low-level copy number alternation in ESCs. Similar processes may drive rare GLO1 duplication in health and disease.

The uremic toxin oxythiamine causes functional thiamine deficiency in end-stage renal disease by inhibiting transketolase activity.

Decreased transketolase activity is an unexplained characteristic of patients with end-stage renal disease and is linked to impaired metabolic and immune function. Here we describe the discovery of a link to impaired functional activity of thiamine pyrophosphate cofactor through the presence, accumulation, and pyrophosphorylation of the thiamine antimetabolite oxythiamine in renal failure. Plasma oxythiamine was significantly increased by 4-fold in patients receiving continuous ambulatory peritoneal dialysis and 15-fold in patients receiving hemodialysis immediately before the dialysis session (healthy individuals, 0.18 [0.11-0.22] nM); continuous ambulatory peritoneal dialysis patients, 0.64 [0.48-0.94] nM; and hemodialysis patients (2.73 [1.52-5.76] nM). Oxythiamine was converted to the transketolase inhibitor oxythiamine pyrophosphate. The red blood cell oxythiamine pyrophosphate concentration was significantly increased by 4-fold in hemodialysis (healthy individuals, 15.9 nM and hemodialysis patients, 66.1 nM). This accounted for the significant concomitant 41% loss of transketolase activity (mU/mg hemoglobin) from 0.410 in healthy individuals to 0.240 in hemodialysis patients. This may be corrected by displacement with excess thiamine pyrophosphate and explain lifting of decreased transketolase activity by high-dose thiamine supplementation in previous studies. Oxythiamine is likely of dietary origin through cooking of acidic thiamine-containing foods. Experimentally, trace levels of oxythiamine were not formed from thiamine degradation under physiologic conditions but rather under acidic conditions at 100(°)C. Thus, monitoring of the plasma oxythiamine concentration in renal failure and implementation of high-dose thiamine supplements to counter it may help improve the clinical outcome of patients with renal failure.

Reduced Cardiovascular Reserve in Chronic Kidney Failure: A Matched Cohort Study.

BACKGROUND: Patients with chronic kidney failure (CKF) experience impaired functional cardiovascular reserve with reduced oxygen consumption at peak exercise (VO(2peak)). No studies have examined whether this is related to impaired cardiovascular compliance as a consequence of loss of adaptive structural alterations, resulting from chronic uremia or hypertension. STUDY DESIGN: Prospective matched-cohort study. SETTING & PARTICIPANTS: We assessed CKF in parallel with patients with essential hypertension but without cardiovascular disease. Patients with CKF were either scheduled for kidney transplantation or transplant waitlisted. 80 patients with CKF and 80 with essential hypertension matched in age, sex, and body mass index were evaluated. 61 patients with CKF (76.3%) were dialysis dependent. PREDICTOR: CKF versus essential hypertension without cardiovascular disease. MEASUREMENTS & OUTCOMES: VO(2peak) was measured during maximal exercise testing. 2-dimensional echocardiography and arterial applanation tonometry were performed prior to exercise testing. To evaluate for the difference in VO(2peak) between study groups, statistically significant predictors of VO(2peak) in multiple regression models were additionally assessed by fitting models comprising the interaction term of patient group with the predictor variable of interest. RESULTS: VO(2peak) was significantly lower in patients with CKF than those with essential hypertension (18.8 vs 24.5 mL/min·kg; P<0.001). Independent predictors of VO(2peak) for CKF included left ventricular (LV) filling pressure (E/mean e'; unstandardized regression coefficient: change in VO(2peak) [in mL/min·kg] per 1-unit change of variable = -5.1) and pulse wave velocity (-4.0); in essential hypertension, these were LV mass index (0.2), LV end-diastolic volume index (0.4), peak heart rate (0.2), and pulse wave velocity (-8.8). The interaction effect of VO(2peak) between patient groups with LV mass index (P<0.001), LV end-diastolic volume index (P<0.001), and peak heart rate (P<0.01) were significantly stronger in the hypertension group, whereby higher values led to greater VO(2peak). LIMITATIONS: Skeletal muscle strength was not assessed. CONCLUSION: This study suggests that maladaptive LV changes, as well as blunted chronotropic response, are important mechanistic factors resulting in reduced cardiovascular reserve in patients with CKF, beyond predominantly vascular changes associated with hypertension.

Subclass analysis of donor HLA-specific IgG in antibody-incompatible renal transplantation reveals a significant association of IgG4 with rejection and graft failure.

Donor HLA-specific antibodies (DSAs) can cause rejection and graft loss after renal transplantation, but their levels measured by the current assays are not fully predictive of outcomes. We investigated whether IgG subclasses of DSA were associated with early rejection and graft failure. DSA levels were determined pretreatment, at the day of peak pan-IgG level and at 30 days post-transplantation in eighty HLA antibody-incompatible kidney transplant recipients using a modified microbead assay. Pretreatment IgG4 levels were predictive of acute antibody-mediated rejection (P = 0.003) in the first 30 days post-transplant. Pre-treatment presence of IgG4 DSA (P = 0.008) and day 30 IgG3 DSA (P = 0.03) was associated with poor graft survival. Multivariate regression analysis showed that in addition to pan-IgG levels, total IgG4 levels were an independent risk factor for early rejection when measured pretreatment, and the presence of pretreatment IgG4 DSA was also an independent risk factor for graft failure. Pretreatment IgG4 DSA levels correlated independently with higher risk of early rejection episodes and medium-term death-censored graft survival. Thus, pretreatment IgG4 DSA may be used as a biomarker to predict and risk stratify cases with higher levels of pan-IgG DSA in HLA antibody-incompatible transplantation. Further investigations are needed to confirm our results.

Exaggerated blood pressure response to dynamic exercise despite chronic refractory hypotension: results of a human case study.

BACKGROUND: Chronic refractory hypotension is a rare but significant mortality risk in renal failure patients. Such aberrant physiology usually deems patient unfit for renal transplant surgery. Exercise stimulates the mechano-chemoreceptors in the skeletal muscle thereby modulating the sympathetic effects on blood pressure regulation. The haemodynamic response to dynamic exercise in such patients has not been previously investigated. We present a case with severe chronic hypotension who underwent exercise testing before and after renal transplantation, with marked differences in blood pressure response to exercise. CASE PRESENTATION: A 40-year old haemodialysis-dependent patient with a 2 year history of refractory hypotension (≤80/50 mmHg) was referred for living donor renal transplantation at our tertiary centre. Each dialysis session was often less than 2 h and 30 min due to symptomatic hypotension. As part of the cardiovascular assessment, she underwent haemodynamic evaluation with cardiopulmonary exercise testing. Blood pressure normalized during unloaded pedalling but was exaggerated at maximal workload whereby it rose from 82/50 mmHg to a peak of 201/120 mmHg. Transthoracic echocardiography, tonometric measure of central vascular compliance and myocardial perfusion scan were normal. She subsequently underwent an antibody-incompatible renal transplantation and was vasopressor reliant for 14 days during the post-operative period. Eight weeks following transplant, resting blood pressure was normal and a physiological exercise-haemodynamic response was observed during a repeat cardiopulmonary exercise testing. CONCLUSION: This case highlights the potential therapeutic role of unloaded leg cycling exercise during dialysis session to correct chronic hypotension, allowing patients to have greater tolerance to fluid shift. It also adds to existing evidence that sympathetic dysfunction is reversible with renal transplant. Furthermore chronic hypotension with preserved exercise-haemodynamic response and cardiovascular reserve should not preclude these patients from renal transplant surgery.

Functional cardiovascular reserve predicts survival pre-kidney and post-kidney transplantation.

Exercise intolerance is an important comorbidity in patients with CKD. Anaerobic threshold (AT) determines the upper limits of aerobic exercise and is a measure of cardiovascular reserve. This study investigated the prognostic capacity of AT on survival in patients with advanced CKD and the effect of kidney transplantation on survival in those with reduced cardiovascular reserve. Using cardiopulmonary exercise testing, cardiovascular reserve was evaluated in 240 patients who were waitlisted for kidney transplantation between 2008 and 2010, and patients were followed for ≤5 years. Survival time was the primary endpoint. Cumulative survival for the entire cohort was 72.6% (24 deaths), with cardiovascular events being the most common cause of death (54.2%). According to Kaplan-Meier estimates, patients with AT <40% of predicted peak VO2 had a significantly reduced 5-year cumulative overall survival rate compared with those with AT ≥40% (P<0.001). Regarding the cohort with AT <40%, patients who underwent kidney transplantation (6 deaths) had significantly better survival compared with nontransplanted patients (17 deaths) (hazard ratio, 4.48; 95% confidence interval, 1.78 to 11.38; P=0.002). Survival did not differ significantly among patients with AT ≥40%, with one death in the nontransplanted group and no deaths in the transplanted group. In summary, this is the first prospective study to demonstrate a significant association of AT, as the objective index of cardiovascular reserve, with survival in patients with advanced CKD. High-risk patients with reduced cardiovascular reserve had a better survival rate after receiving a kidney transplant.

Effect of A Reduction in glomerular filtration rate after NEphrectomy on arterial STiffness and central hemodynamics: rationale and design of the EARNEST study.

BACKGROUND: There is strong evidence of an association between chronic kidney disease (CKD) and cardiovascular disease. To date, however, proof that a reduction in glomerular filtration rate (GFR) is a causative factor in cardiovascular disease is lacking. Kidney donors comprise a highly screened population without risk factors such as diabetes and inflammation, which invariably confound the association between CKD and cardiovascular disease. There is strong evidence that increased arterial stiffness and left ventricular hypertrophy and fibrosis, rather than atherosclerotic disease, mediate the adverse cardiovascular effects of CKD. The expanding practice of live kidney donation provides a unique opportunity to study the cardiovascular effects of an isolated reduction in GFR in a prospective fashion. At the same time, the proposed study will address ongoing safety concerns that persist because most longitudinal outcome studies have been undertaken at single centers and compared donor cohorts with an inappropriately selected control group. HYPOTHESES: The reduction in GFR accompanying uninephrectomy causes (1) a pressure-independent increase in aortic stiffness (aortic pulse wave velocity) and (2) an increase in peripheral and central blood pressure. METHODS: This is a prospective, multicenter, longitudinal, parallel group study of 440 living kidney donors and 440 healthy controls. All controls will be eligible for living kidney donation using current UK transplant criteria. Investigations will be performed at baseline and repeated at 12 months in the first instance. These include measurement of arterial stiffness using applanation tonometry to determine pulse wave velocity and pulse wave analysis, office blood pressure, 24-hour ambulatory blood pressure monitoring, and a series of biomarkers for cardiovascular and bone mineral disease. CONCLUSIONS: These data will prove valuable by characterizing the direction of causality between cardiovascular and renal disease. This should help inform whether targeting reduced GFR alongside more traditional cardiovascular risk factors is warranted. In addition, this study will contribute important safety data on living kidney donors by providing a longitudinal assessment of well-validated surrogate markers of cardiovascular disease, namely, blood pressure and arterial stiffness. If any adverse effects are detected, these may be potentially reversed with the early introduction of targeted therapy. This should ensure that kidney donors do not come to long-term harm and thereby preserve the ongoing expansion of the living donor transplant program (NCT01769924).

Cardiovascular effects of sevelamer in stage 3 CKD.

Serum phosphate independently predicts cardiovascular mortality in the general population and CKD, even when levels are in the normal range. Associations between serum phosphate, arterial stiffness, and left ventricular (LV) mass suggest a possible pathophysiological mechanism, potentially mediated by the phosphaturic hormone fibroblast growth factor-23 (FGF-23). To what extent the phosphate binder sevelamer modulates these effects is not well understood. In this single-center, randomized, double-blind, placebo-controlled trial, we enrolled 120 patients with stage 3 nondiabetic CKD. After a 4-week open-label run-in period, during which time all patients received sevelamer carbonate, we randomly assigned 109 patients to sevelamer (n=55) or placebo (n=54) for an additional 36 weeks. We assessed LV mass and systolic and diastolic function with cardiovascular magnetic resonance imaging and echocardiography, and we assessed arterial stiffness by carotid-femoral pulse wave velocity. The mean age was 55 years, and the mean eGFR was 50 ml/min per 1.73 m(2). After 40 weeks, we found no statistically significant differences between sevelamer and placebo with regard to LV mass, systolic and diastolic function, or pulse wave velocity. Only 56% of subjects took ≥ 80% of prescribed therapy; in this compliant subgroup, treatment with sevelamer associated with lower urinary phosphate excretion and serum FGF-23 but not serum phosphate, klotho, vitamin D, or cardiovascular-related outcomes of interest. In conclusion, this study does not provide evidence that sevelamer carbonate improves LV mass, LV function, or arterial stiffness in stage 3 nondiabetic CKD.

Vascular Klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23.

BACKGROUND: Klotho is known to function as a cofactor for the phosphatonin, fibroblast growth factor (FGF)-23 at the kidney. FGF-23 levels rise in chronic kidney disease (CKD) despite progression of accelerated vascular calcification. There are currently conflicting data on whether FGF-23 may exhibit direct vasculoprotective effects in CKD. METHODS AND RESULTS: In this study, we describe for the first time endogenous Klotho expression in human arteries and human aortic smooth muscle cells. We show that CKD is a state of vascular Klotho deficiency promoted by chronic circulating stress factors, including proinflammatory, uremic, and disordered metabolic conditions. Mechanistic studies demonstrated that Klotho knockdown potentiated the development of accelerated calcification through a Runx2 and myocardin-serum response factor-dependent pathway. Klotho knockdown studies further revealed that vascular cells are a Klotho-dependent target tissue for FGF-23. FGF-23 mediated cellular activation of p-ERK, p-AKT, and cellular proliferative effects, which were abrogated following Klotho knockdown. We next showed that vascular Klotho deficiency driven by procalcific stressors could be restored by vitamin D receptor activators, in vitro and further confirmed using human arterial organ cultures from CKD patients, in vivo. Furthermore, restoration of suppressed Klotho expression by vitamin D receptor activators conferred human aortic smooth muscle cells responsive to FGF-23 signaling and unmasked potential anticalcific effects. CONCLUSIONS: Chronic metabolic stress factors found in CKD promote vascular Klotho deficiency. Mechanistic studies revealed a bifunctional role for local vascular Klotho, first, as an endogenous inhibitor of vascular calcification and, second, as a cofactor required for vascular FGF-23 signaling. Furthermore, vitamin D receptor activators can restore Klotho expression and unmask FGF-23 anticalcific effects.

Efficacy of cinacalcet with low-dose vitamin D in incident haemodialysis subjects with secondary hyperparathyroidism.

BACKGROUND: Treatment with cinacalcet improves the control of secondary hyperparathyroidism (SHPT) and the achievement of calcium and phosphorus targets. Most data come from subjects receiving cinacalcet after several years of dialysis treatment. We therefore compared the efficacy of treatment with cinacalcet and low doses of active vitamin D to flexible doses of active vitamin D alone for the management of SHPT in patients recently initiating haemodialysis. METHODS: This open-label trial randomized subjects (n = 309) with parathyroid hormone (PTH) >300 pg/mL on dialysis for 3-12 months to either cinacalcet with low-dose active vitamin D, if prescribed (cinacalcet); or usual care without cinacalcet (control). Randomized subjects were stratified by PTH at screening (300-450, >450-600, >600 pg/mL) and by the use of active vitamin D at enrolment. Treatment duration was 12 months, with primary efficacy endpoint (mean PTH reduction ≥ 30% from baseline) assessed at 6 months. RESULTS: The mean [standard deviation (SD)] haemodialysis vintage at enrolment was 7.2 (2.7) months; 53% of subjects were not receiving active vitamin D at enrolment. There was a significant difference in the achievement of the primary endpoint (≥ 30% PTH reduction at 6 months) between cinacalcet-treated subjects and controls in both the entire cohort (63 versus 38%; n = 304; P < 0.0001) and the subgroup of subjects not receiving active vitamin D at enrolment (70 versus 44%; n = 161; P < 0.01). Hypocalcaemia and gastrointestinal adverse events were more commonly observed in cinacalcet-treated subjects. CONCLUSIONS: These results indicate that cinacalcet with low-dose active vitamin D, if prescribed, provides a more effective treatment approach than usual care without cinacalcet for SHPT in incident haemodialysis patients, even in relatively treatment-naive patients.

Vitamin D reduces left atrial volume in patients with left ventricular hypertrophy and chronic kidney disease.

BACKGROUND: Left atrial enlargement, a sensitive integrator of left ventricular diastolic function, is associated with increased cardiovascular morbidity and mortality. Vitamin D is linked to lower cardiovascular morbidity, possibly modifying cardiac structure and function; however, firm evidence is lacking. We assessed the effect of an activated vitamin D analog on left atrial volume index (LAVi) in a post hoc analysis of the PRIMO trial (clinicaltrials.gov: NCT00497146). METHODS AND RESULTS: One hundred ninety-six patients with chronic kidney disease (estimated glomerular filtration rate 15-60 mL/min per 1.73 m(2)), mild to moderate left ventricular hypertrophy, and preserved ejection fraction were randomly assigned to 2 µg of oral paricalcitol or matching placebo for 48 weeks. Two-dimensional echocardiography was obtained at baseline and at 24 and 48 weeks after initiation of therapy. Over the study period, there was a significant decrease in LAVi (-2.79 mL/m(2), 95% CI -4.00 to -1.59 mL/m(2)) in the paricalcitol group compared with the placebo group (-0.70 mL/m(2) [95% CI -1.93 to 0.53 mL/m(2)], P = .002). Paricalcitol also attenuated the rise in levels of brain natriuretic peptide (10.8% in paricalcitol vs 21.3% in placebo, P = .02). For the entire population, the change in brain natriuretic peptide correlated with change in LAVi (r = 0.17, P = .03). CONCLUSIONS: Forty-eight weeks of therapy with an active vitamin D analog reduces LAVi and attenuates the rise of BNP. In a population where only few therapies alter cardiovascular related morbidity and mortality, these post hoc results warrant further confirmation.

Rapid resolution of severe sustained low blood pressure in haemodialysis patients after successful renal transplantation.

BACKGROUND: Low blood pressure occurring in the absence of volume depletion, anti-hypertensive medication, heart failure or cortisol deficiency occurs in ~5-10% of haemodialysis patients, and can result in serious complications. The pathophysiology of this syndrome is poorly understood. METHODS: We describe eight cases with dialysis-associated hypotension who underwent renal transplantation. Four patients were severely hypotensive with a systolic blood pressure (SBP) <100 mmHg before and during dialysis, and four had a SBP usually <100 mmHg during dialysis, but usually >100 mmHg between sessions. All had donor-specific human leukocyte antigen antibodies. Six patients underwent pre-transplant plasmapheresis, which was curtailed in two because of further falls in blood pressure. Two patients experienced clotting of their arteriovenous fistula. In one patient cryofiltration was used, which was tolerated without severe falls in the BP. The remaining patient, who had hypotension-associated retinal vein thrombosis before transplant, was supported with an epinephrine infusion and did not receive plasmapheresis. RESULTS: Post-transplant, the first patient did not receive pressor therapy and died from bowel ischaemia. The other seven patients were supported with inotropes on critical care. The administration of steroids did not reverse hypotension. The mean pre-treatment SBP was 96 mmHg (range 71-110, SEM 5.0). After inotropes were withdrawn and graft function was established, the mean SBP was 127 mmHg (range 113-149, SEM 4.9) (P < 0.01). CONCLUSIONS: Renal transplantation was performed successfully and safely in patients when pressor therapy was used to treat severe dialysis-associated hypotension and, moreover, the blood pressure normalized rapidly after graft function was established.

Vitamin D therapy and cardiac structure and function in patients with chronic kidney disease: the PRIMO randomized controlled trial.

CONTEXT: Vitamin D is associated with decreased cardiovascular-related morbidity and mortality, possibly by modifying cardiac structure and function, yet firm evidence for either remains lacking. OBJECTIVE: To determine the effects of an active vitamin D compound, paricalcitol, on left ventricular mass over 48 weeks in patients with an estimated glomerular filtration rate of 15 to 60 mL/min/1.73 m(2). DESIGN, SETTING, AND PARTICIPANTS: Multinational, double-blind, randomized placebo-controlled trial among 227 patients with chronic kidney disease, mild to moderate left ventricular hypertrophy, and preserved left ventricular ejection fraction, conducted in 11 countries from July 2008 through September 2010. INTERVENTION: Participants were randomly assigned to receive oral paricalcitol, 2 µg/d (n =115), or matching placebo (n = 112). MAIN OUTCOME MEASURES: Change in left ventricular mass index over 48 weeks by cardiovascular magnetic resonance imaging. Secondary end points included echocardiographic changes in left ventricular diastolic function. RESULTS: Treatment with paricalcitol reduced parathyroid hormone levels within 4 weeks and maintained levels within the normal range throughout the study duration. At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m(2.7) [95% CI, -0.14 to 0.83 g/m(2.7)] vs placebo group, -0.07 g/m(2.7) [95% CI, -0.55 to 0.42 g/m(2.7)]). Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, -0.01 cm/s [95% CI, -0.63 to 0.60 cm/s] vs placebo group, -0.30 cm/s [95% CI, -0.93 to 0.34 cm/s]) also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group. CONCLUSION: Forty-eight week therapy with paricalcitol did not alter left ventricular mass index or improve certain measures of diastolic dysfunction in patients with chronic kidney disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00497146.

FGF23 and Cardiovascular Structure and Function in Advanced Chronic Kidney Disease.

Background: Fibroblast growth factor 23 (FGF23) is a bone-derived phosphatonin that is elevated in chronic kidney disease (CKD) and has been implicated in the development of cardiovascular disease. It is unknown whether elevated FGF23 in CKD is associated with impaired cardiovascular functional capacity, as assessed by maximum exercise oxygen consumption (VO2Max). We sought to determine whether FGF23 is associated with cardiovascular functional capacity in patients with advanced CKD and after improvement of VO2Max by kidney transplantation. Methods: We performed secondary analysis of 235 patients from the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) cohort, which recruited patients with stage 5 CKD who underwent kidney transplantation or were waitlisted and hypertensive controls. All patients underwent cardiopulmonary exercise testing (CPET) and echocardiography and were followed longitudinally for 1 year after study enrollment. Results: Patients across FGF23 quartiles differed in BMI (P=0.004) and mean arterial pressure (P<0.001) but did not significantly differ in sex (P=0.5) or age (P=0.08) compared with patients with lower levels of FGF23. Patients with higher FGF23 levels had impaired VO2Max (Q1: 24.2±4.8 ml/min per kilogram; Q4: 18.6±5.2 ml/min per kilogram; P<0.001), greater left ventricular mass index (LVMI; P<0.001), reduced HR at peak exercise (P<0.001), and maximal workload (P<0.001). Kidney transplantation conferred a significant decline in FGF23 at 2 months (P<0.001) before improvement in VO2Max at 1 year (P=0.008). Multivariable regression modeling revealed that changes in FGF23 was significantly associated with VO2Max in advanced CKD (P<0.001) and after improvement after kidney transplantation (P=0.006). FGF23 was associated with LVMI before kidney transplantation (P=0.003), however this association was lost after adjustment for dialysis status (P=0.4). FGF23 was not associated with LVMI after kidney transplantation in all models. Conclusions: FGF23 levels are associated with alterations in cardiovascular functional capacity in advanced CKD and after kidney transplantation. FGF23 is only associated with structural cardiac adaptations in advanced CKD but this was modified by dialysis status, and was not associated after kidney transplantation.

Initiation of Dialysis Is Associated With Impaired Cardiovascular Functional Capacity.

Background The transition to dialysis period carries a substantial increased cardiovascular risk in patients with chronic kidney disease. Despite this, alterations in cardiovascular functional capacity during this transition are largely unknown. The present study therefore sought to assess ventilatory exercise response measures in patients within 1 year of initiating dialysis. Methods and Results We conducted a cross-sectional study of 241 patients with chronic kidney disease stage 5 from the CAPER (Cardiopulmonary Exercise Testing in Renal Failure) study and from the intradialytic low-frequency electrical muscle stimulation pilot randomized controlled trial cohorts. Patients underwent cardiopulmonary exercise testing and echocardiography. Of the 241 patients (age, 48.9 [15.0] years; 154 [63.9%] men), 42 were predialytic (mean estimated glomerular filtration rate, 14 mL·min-1·1.73 m-2), 54 had a dialysis vintage ≤12 months, and 145 had a dialysis vintage >12 months. Dialysis vintage ≤12 months exhibited a significantly impaired cardiovascular functional capacity, as assessed by oxygen uptake at peak exercise (18.7 [5.8] mL·min-1·kg-1) compared with predialysis (22.7 [5.2] mL·min-1·kg-1; P<0.001). Dialysis vintage ≤12 months also exhibited reduced peak workload, impaired peak heart rate, reduced circulatory power, and increased left ventricular mass index (P<0.05 for all) compared with predialysis. After excluding those with prior kidney transplant, dialysis vintage >12 months exhibited a lower oxygen uptake at peak exercise (17.0 [4.9] mL·min-1·kg-1) compared with dialysis vintage ≤12 months (18.9 [5.9] mL·min-1·kg-1; P=0.033). Conclusions Initiating dialysis is associated with a significant impairment in oxygen uptake at peak exercise and overall decrements in ventilatory and hemodynamic exercise responses that predispose patients to functional dependence. The magnitude of these changes is comparable to the differences between low-risk New York Heart Association class I and higher-risk New York Heart Association class II to IV heart failure.

Myocardial Cytoskeletal Adaptations in Advanced Kidney Disease.

Background The myocardial cytoskeleton functions as the fundamental framework critical for organelle function, bioenergetics and myocardial remodeling. To date, impairment of the myocardial cytoskeleton occurring in the failing heart in patients with advanced chronic kidney disease has been largely undescribed. Methods and Results We conducted a 3-arm cross-sectional cohort study of explanted human heart tissues from patients who are dependent on hemodialysis (n=19), hypertension (n=10) with preserved renal function, and healthy controls (n=21). Left ventricular tissues were subjected to pathologic examination and next-generation RNA sequencing. Mechanistic and interference RNA studies utilizing in vitro human cardiac fibroblast models were performed. Left ventricular tissues from patients undergoing hemodialysis exhibited increased myocardial wall thickness and significantly greater fibrosis compared with hypertension patients (P<0.05) and control (P<0.01). Transcriptomic analysis revealed that the focal adhesion pathway was significantly enriched in hearts from patients undergoing hemodialysis. Hearts from patients undergoing hemodialysis exhibited dysregulated components of the focal adhesion pathway including reduced ß-actin (P<0.01), ß-tubulin (P<0.01), vimentin (P<0.05), and increased expression of vinculin (P<0.05) compared with controls. Cytoskeletal adaptations in hearts from the hemodialysis group were associated with impaired mitochondrial bioenergetics, including dysregulated mitochondrial dynamics and fusion, and loss of cell survival pathways. Mechanistic studies revealed that cytoskeletal changes can be driven by uremic and metabolic abnormalities of chronic kidney disease, in vitro. Furthermore, focal adhesion kinase silencing via interference RNA suppressed major cytoskeletal proteins synergistically with mineral stressors found in chronic kidney disease in vitro. Conclusions Myocardial failure in advanced chronic kidney disease is characterized by impairment of the cytoskeleton involving disruption of the focal adhesion pathway, mitochondrial failure, and loss of cell survival pathways.

New vitamin D analogs and changing therapeutic paradigms.

Vitamin D compounds have been used successfully to treat secondary hyperparathyroidism for almost three decades. Side effects of increased levels of serum calcium and phosphate and potential complications have increasingly been recognized as problematic, and this has become an even more difficult clinical challenge with the desire to capitalize on some of the pleiotropic effects of vitamin D. Nonclassical nuclear vitamin D receptor (VDR) effects on the cardiovascular system, kidneys, and immune system, with the prospect of improved patient survival, have moved to center stage. Selective vitamin D compounds with minimal effects on mineral metabolism and with maximal cardiovascular and renal benefits are now needed. New vitamin D compounds already in clinical use, which have an improved side-effect profile and differential nonclassical effects compared with calcitriol, are limited to the three licensed pharmaceuticals--paricalcitol, 22-oxacalcitriol, and doxercalciferol. Other compounds are under early development and it is anticipated that these novel therapeutic concepts will result in new vitamin D therapies that will help to reduce the high mortality rate patients with kidney disease experience.