Association between diabetic status and risk of all-cause and cause-specific mortality on dialysis following first kidney allograft loss.

Background: Diabetes mellitus (DM) is associated with a greater risk of mortality in kidney transplant patients, primarily driven by a greater risk of cardiovascular disease (CVD)-related mortality. However, the associations between diabetes status at time of first allograft loss and mortality on dialysis remain unknown. Methods: All patients with failed first kidney allografts transplanted in Australia and New Zealand between 2000 and 2020 were included. The associations between diabetes status at first allograft loss, all-cause and cause-specific mortality were examined using competing risk analyses, separating patients with diabetes into those with pre-transplant DM or post-transplant diabetes mellitus (PTDM). Results: Of 3782 patients with a median (IQR) follow-up duration of 2.7 (1.1-5.4) years, 539 (14%) and 390 (10%) patients had pre-transplant DM or developed PTDM, respectively. In the follow-up period, 1336 (35%) patients died, with 424 (32%), 264 (20%) and 199 (15%) deaths attributed to CVD, dialysis withdrawal and infection, respectively. Compared to patients without DM, the adjusted subdistribution HRs (95% CI) for pre-transplant DM and PTDM for all-cause mortality on dialysis were 1.47 (1.17-1.84) and 1.47 (1.23-1.76), respectively; for CVD-related mortality were 0.81 (0.51-1.29) and 1.02 (0.70-1.47), respectively; for infection-related mortality were 1.84 (1.02-3.35) and 2.70 (1.73-4.20), respectively; and for dialysis withdrawal-related mortality were 1.71 (1.05-2.77) and 1.51 (1.02-2.22), respectively. Conclusions: Patients with diabetes at the time of kidney allograft loss have a significant survival disadvantage, with the excess mortality risk attributed to infection and dialysis withdrawal.

Donors With a Prior History of Cancer: Factors of Non-Utilization of Kidneys for Transplantation.

Cancer transmission from deceased donors is an exceedingly rare but potentially fatal complication in transplant recipients. We aimed to quantify the likelihood of non-utilization of kidneys for transplantation from donors with a prior cancer history. We included all intended and actual deceased donors in Australia and New Zealand between 1989 and 2017. Association between prior cancer history and non-utilization of donor kidneys was examined using adjusted logistic regression. Of 9,485 deceased donors, 345 (4%) had a prior cancer history. Of 345 donors with a prior cancer history, 197 (57%) were utilized for transplantation. Donor characteristics of age, sex and comorbidities were similar between utilized and non-utilized donors with prior cancer. The time from cancer to organ donation was similar between utilized and non-utilized donors, irrespective of cancer subtypes. Donors with a prior cancer history were less likely to be utilized [adjusted OR (95% CI) 2.29 (1.68-3.13)] than donors without prior cancer. Of all actual donors, the adjusted OR for non-utilization among those with prior cancer was 2.36 (1.58-3.53). Non-melanoma skin cancer was the most frequent prior cancer type for utilized and non-utilized potential donors. Donors with prior cancers were less likely to be utilized for transplantation, with no discernible differences in cancer characteristics between utilized and non-utilized donors.

Kidney Donor Profile Index and allograft outcomes: interactive effects of estimated post-transplant survival score and ischaemic time.

Background: The Kidney Donor Profile Index (KDPI) is routinely reported by the donation agencies in Australia. We determined the association between KDPI and short-term allograft loss and assessed if this association was modified by the estimated post-transplant survival (EPTS) score and total ischaemic time. Methods: Using data from the Australia and New Zealand Dialysis and Transplant Registry, the association between KDPI (in quartiles) and 3-year overall allograft loss was examined using adjusted Cox regression analysis. The interactive effects between KDPI, EPTS score and total ischaemic time on allograft loss were assessed. Results: Of 4006 deceased donor kidney transplant recipients transplanted between 2010 and 2015, 451 (11%) recipients experienced allograft loss within 3 years post-transplant. Compared with recipients of kidneys with a KDPI of 0-25%, recipients who received donor kidneys with a KDPI >75% experienced a 2-fold increased risk of 3-year allograft loss {adjusted hazard ratio [HR] 2.04 [95% confidence interval (CI) 1.53-2.71]}. The adjusted HRs for kidneys with a KDPI of 26-50% and 51-75% were 1.27 (95% CI 0.94-1.71) and 1.31 (95% CI 0.96-1.77), respectively. There were significant interactions between KDPI and EPTS scores (P-value for interaction <.01) and total ischaemic time (P-value for interaction <.01) such that the associations between higher KDPI quartiles and 3-year allograft loss were strongest in recipients with the lowest EPTS scores and longest total ischaemic time. Conclusion: Recipients with higher post-transplant expected survival and transplants with longer total ischaemia who received donor allografts with higher KDPI scores experienced a greater risk of short-term allograft loss compared with those recipients with reduced post-transplant expected survival and with shorter total ischemia.

Sex Disparity in Cause-Specific and All-Cause Mortality Among Incident Dialysis Patients.

RATIONALE & OBJECTIVE: Early mortality rates of female patients receiving dialysis have been, at times, observed to be higher than rates among male patients. The differences in cause-specific mortality between male and female incident dialysis patients with kidney failure are not well understood and were the focus of this study. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Incident patients who had initiated dialysis in Australia and New Zealand in 1998-2018. EXPOSURE: Sex. OUTCOMES: Cause-specific and all-cause mortality while receiving dialysis, censored for kidney transplant. ANALYTICAL APPROACH: Adjusted cause-specific proportional hazards models, focusing on the first 5 years following initiation of dialysis. RESULTS: Among 53,414 patients (20,876 [39%] female) followed for a median period of 2.8 (IQR, 1.3-5.2) years, 27,137 (51%) died, with the predominant cause of death attributed to cardiovascular disease (18%), followed by dialysis withdrawal (16%). Compared with male patients, female patients were more likely to die in the first 5 years after dialysis initiation (adjusted hazard ratio [AHR], 1.08 [95% CI, 1.05-1.11]). Even though female patients experienced a lower risk of cardiovascular disease-related mortality (AHR, 0.93 [95% CI, 0.89-0.98]) than male patients, they experienced a greater risk of infection-related (AHR, 1.20 [95% CI, 1.10-1.32]) and dialysis withdrawal-related (AHR, 1.19 [95% CI, 1.13-1.26]) mortality. LIMITATIONS: Possibility of residual and unmeasured confounders. CONCLUSIONS: Compared with male patients, female patients had a higher risk of all-cause mortality in the first 5 years after dialysis initiation, a difference driven by higher rates of mortality from infections and dialysis withdrawals. These findings may inform the study of sex differences in mortality in other geographic settings.

The incidence of cancer recurrence and new cancer following commencement of dialysis.

Background: Patients with kidney failure have a higher cancer risk compared with the age-matched general population. However, the outcomes of incident dialysis patients with a prior cancer history are unknown. Methods: Using Australia and New Zealand Dialysis and Transplant Registry data (2000-2019), the outcomes and survival probabilities of incident dialysis patients with prior cancers and having experienced a cancer recurrence or having developed a new cancer after dialysis commencement were described. Results: Of 4912 patients with prior cancers before dialysis commencement, 323 (7%) and 343 (7%) patients experienced cancer recurrence or developed new cancers after dialysis initiation, respectively. The median time from dialysis commencement to cancer recurrence was 1.2 years [interquartile range (IQR) 0.5-2.8] and was 2.0 years (IQR 0.7-4.0) for new cancer occurrence. Of those with cancer recurrence, 80% presented with metastatic disease and one in two patients died from cancer, with a median time from cancer recurrence to death of 0.5 years (IQR 0.2-1.7). Of those who developed new cancer, urinary tract and respiratory cancers were the most frequent cancer types, with a median time from new cancer diagnosis to death of 1.3 years (IQR 0.4-3.1). The 3-year survival probabilities on dialysis following cancer recurrence and new cancer were 19% [95% confidence interval (CI) 15-24] and 41% (35-47), respectively. Conclusion: Among incident dialysis patients with a prior cancer history, 14% experienced cancer recurrence or developed a new cancer. Patients who experienced cancer recurrence or developed new cancer have poor outcomes, with ˂50% surviving beyond 3 years. These findings suggest the need to have a greater understanding of the characteristics, cancer screening, treatment responses and reasons for commencing dialysis in patients with kidney failure and prior cancer history, which may help in the shared clinical decision-making process when considering dialysis for these patients.

Interactions Between Donor Age and 12-Month Estimated Glomerular Filtration Rate on Allograft and Patient Outcomes After Kidney Transplantation.

Reduced estimated glomerular filtration rate (eGFR) at 12-months after kidney transplantation is associated with increased risk of allograft loss, but it is uncertain whether donor age and types modify this relationship. Using Australia and New Zealand registry data, multivariable Cox proportional modelling was used to examine the interactive effects between donor age, types and 12-month eGFR on overall allograft loss. We included 11,095 recipients (4,423 received live-donors). Recipients with lowest 12-month eGFR (<30 ml/min/1.73 m2) experienced the greatest risk of allograft loss, with adjusted HR [95% CI) of 2.65 [2.38-2.95] compared to eGFR of 30-60 ml/min/1.73 m2; whereas the adjusted HR for highest eGFR (>60 ml/min/1.73 m2) was 0.67 [0.62-0.74]. The association of 12-month eGFR and allograft loss was modified by donor age (but not donor types) where a higher risk of allograft loss in recipients with lower compared with higher 12-month eGFR being most pronounced in the younger donor age groups (p < 0.01). Recipients with eGFR <30 ml/min/1.73 m2 12-months after transplantation experienced ≥2.5-fold increased risk of overall allograft loss compared to those with eGFR of >60 ml/min/1.73 m2, and the magnitude of the increased risk is most marked among recipients with younger donors. Careful deliberation of other factors including donor age when considering eGFR as a surrogate for clinical endpoints is warranted.

Socio-economic disparity, access to care and patient-relevant outcomes after kidney allograft failure.

Social disparity is a major impediment to optimal health outcomes after kidney transplantation. In this study, we aimed to define the association between socio-economic status (SES) disparities and patient-relevant outcomes after kidney allograft failure. Using data from the Australia and New Zealand Dialysis and Transplant registry, we included patients with failed first-kidney allografts in Australia between 2005 and 2017. The association between residential postcode-derived SES in quintiles (quintile 1-most disadvantaged areas, quintile 5-most advantaged areas) with uptake of home dialysis (peritoneal or home haemodialysis) within the first 12-months post-allograft failure, repeat transplantation and death on dialysis were examined using competing-risk analysis. Of 2175 patients who had experienced first allograft failure, 417(19%) and 505(23%) patients were of SES quintiles 1 and 5, respectively. Compared to patients of quintile 5, quintile 1 patients were less likely to receive repeat transplants (adjusted subdistributional hazard ratio [SHR] 0.70,95%CI 0.55-0.89) and were more likely to die on dialysis (1.37 [1.04-1.81]), but there was no association with the uptake of home dialysis (1.02 [0.77-1.35]). Low SES may have a negative effect on outcomes post-allograft failure and further research is required into how best to mitigate this. However, small-scale variation within SES cannot be accounted for in this study.

Impact of Pretransplant and New-Onset Diabetes After Transplantation on the Risk of Major Adverse Cardiovascular Events in Kidney Transplant Recipients: A Population-based Cohort Study.

BACKGROUND: Pretransplant diabetes and new-onset diabetes after transplant (NODAT) are known risk factors for vascular events after kidney transplantation, but the incidence and magnitude of the risk of major adverse cardiovascular events (MACE) and cardiac deaths remain uncertain in recent era. METHODS: A population cohort study of kidney transplant recipients identified using data from linked administrative healthcare databases from Ontario, Canada. The incidence rates of MACE (expressed as events with 95% confidence interval [95% CI] per 1000 person-years were reported according to diabetes status of pretransplant diabetes, NODAT, or no diabetes. Extended Cox regression model was used to examine the association between diabetes status, MACE, and cardiac death. RESULTS: Of 5248 recipients, 1973 (38%) had pretransplant diabetes, and 799 (15%) developed NODAT with a median follow-up of 5.5 y. The incidence rates (95% CI) of MACE for recipients with pretransplant diabetes, NODAT, and no diabetes between 1 and 3 y posttransplant were 38.1 (32.1-45.3), 12.6 (6.3-25.2), and 11.8 (9.2-15.0) per 1000 person-years, respectively. Compared with recipients with pretransplant diabetes, recipients with NODAT experienced a lower risk of MACE (adjusted hazard ratio, 0.59; 95% CI, 0.47-0.74) but not cardiac death (adjusted hazard ratio, 0.97; 95% CI, 0.61-1.55). The rate of MACE and cardiac death was lowest in patients without diabetes. CONCLUSIONS: Patients with pretransplant diabetes incur the greatest rate of MACE and cardiac deaths after transplantation. Having NODAT also bears high burden of vascular events compared with those without diabetes, but the magnitude of the increased rate remains lower than recipients with pretransplant diabetes.

Global Epidemiology, Health Outcomes, and Treatment Options for Patients With Type 2 Diabetes and Kidney Failure.

The burden of type 2 diabetes and related complications has steadily increased over the last few decades and is one of the foremost global public health threats in the 21st century. Diabetes is one of the leading causes of chronic kidney disease and kidney failure and is an important contributor to the cardiovascular morbidity and mortality in this population. In addition, up to one in three patients who have received kidney transplants develop post-transplant diabetes, but the management of this common complication continues to pose a significant challenge for clinicians. In this review, we will describe the global prevalence and temporal trend of kidney failure attributed to diabetes mellitus in both developing and developed countries. We will examine the survival differences between treated kidney failure patients with and without type 2 diabetes, focusing on the survival differences in those on maintenance dialysis or have received kidney transplants. With the increased availability of novel hypoglycemic agents, we will address the potential impacts of these novel agents in patients with diabetes and kidney failure and in those who have developed post-transplant diabetes.

Effect of the proton-pump Inhibitor pantoprazole on MycoPhenolic ACid exposure in kidney and liver transplant recipienTs (IMPACT study): a randomized trial.

BACKGROUND: Mycophenolic acid (MPA) is widely utilized as an immunosuppressant in kidney and liver transplantation, with reports suggesting an independent relationship between MPA concentrations and adverse allograft outcome. Proton-pump inhibitors (PPIs) may have variable effects on the absorption of different MPA formulations leading to differences in MPA exposure. METHODS: A multicentre, randomized, prospective, double-blind placebo-controlled cross-over study was conducted to determine the effect of the PPI pantoprazole on the MPA and its metabolite MPA-glucuronide (MPA-G) area under the curve (AUC) >12 h (MPA-AUC12 h) in recipients maintained on mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS). We planned a priori to examine separately recipients maintained on MMF and EC-MPS for each pharmacokinetic parameter. The trial (and protocol) was registered with the Australian New Zealand Clinical Trials Registry on 24 March 2011, with the registration number of ACTRN12611000316909 ('IMPACT' study). RESULTS: Of the 45 recipients screened, 40 (19 MMF and 21 EC-MPS) were randomized. The mean (standard deviation) recipient age was 58 (11) years with a median (interquartile range) time post-transplant of 43 (20-132) months. For recipients on MMF, there was a significant reduction in the MPA-AUC12 h [geometric mean (95% confidence interval) placebo: 53.9 (44.0-65.9) mg*h/L versus pantoprazole: 43.8 (35.6-53.4) mg*h/L; P = 0.004] when pantoprazole was co-administered compared with placebo. In contrast, co-administration with pantoprazole significantly increased MPA-AUC12 h [placebo: 36.1 (26.5-49.2) mg*h/L versus pantoprazole: 45.9 (35.5-59.3) mg*h/L; P = 0.023] in those receiving EC-MPS. Pantoprazole had no effect on the pharmacokinetic profiles of MPA-G for either group. CONCLUSIONS: The co-administration of pantoprazole substantially reduced the bioavailability of MPA in patients maintained on MMF and had the opposite effect in patients maintained on EC-MPS, and therefore, clinicians should be cognizant of this drug interaction when prescribing the different MPA formulations.

Apolipoprotein(a) Kinetics in Statin-Treated Patients With Elevated Plasma Lipoprotein(a) Concentration.

BACKGROUND: Lipoprotein(a) [Lp(a)] is a low-density lipoprotein‒like particle containing apolipoprotein(a) [apo(a)]. Patients with elevated Lp(a), even when treated with statins, are at increased risk of cardiovascular disease. We investigated the kinetic basis for elevated Lp(a) in these patients. OBJECTIVES: Apo(a) production rate (PR) and fractional catabolic rate (FCR) were compared between statin-treated patients with and without elevated Lp(a). METHODS: The kinetics of apo(a) were investigated in 14 patients with elevated Lp(a) and 15 patients with normal Lp(a) levels matched for age, sex, and body mass index using stable isotope techniques and compartmental modeling. All 29 patients were on background statin treatment. Plasma apo(a) concentration was measured using liquid chromatography-mass spectrometry. RESULTS: The plasma concentration and PR of apo(a) were significantly higher in patients with elevated Lp(a) than in patients with normal Lp(a) concentration (all P < 0.01). The FCR of apo(a) was not significantly different between the groups. In univariate analysis, plasma concentration of apo(a) was significantly associated with apo(a) PR in both patient groups (r = 0.699 and r = 0.949, respectively; all P < 0.01). There was no significant association between plasma apo(a) concentration and FCR in either of the groups (r = 0.160 and r = -0.137, respectively). CONCLUSION: Elevated plasma Lp(a) concentration is a consequence of increased hepatic production of Lp(a) particles in these patients. Our findings provide a kinetic rationale for the use of therapies that target the synthesis of apo(a) and production of Lp(a) particles in patients with elevated Lp(a).

Fractional turnover of apolipoprotein(a) and apolipoprotein B-100 within plasma lipoprotein(a) particles in statin-treated patients with elevated and normal Lp(a) concentration.

CONTEXT: Lipoprotein(a) [Lp(a)] is a highly atherogenic lipoprotein characterized by apolipoprotein(a) [apo(a)] covalently bounded to apoB-100 (apoB). However, the metabolism of apo(a) and apoB within plasma Lp(a) particles in patients on statins remains unclear. METHODS: The kinetics of Lp(a)-apo(a) and Lp(a)-apoB were determined in 20 patients with elevated Lp(a) (≥0.8 g/L; n = 10) and normal Lp(a) (≤0.3 g/L; n = 10) using stable isotope techniques and compartmental modeling. Plasma apo(a) concentration was measured using liquid chromatography-mass spectrometry. All patients were on statin therapy and were studied in the fasting state. RESULTS: The fractional catabolic rate (FCR) of Lp(a)-apo(a) was not significantly different from that of Lp(a)-apoB in statin-treated patients with elevated or normal Lp(a) (P > 0.05 in both). Lp(a)-apo(a) FCR was significantly correlated with Lp(a)-apoB in patients with elevated and normal Lp(a) concentrations (r = 0.970 and r = 0.979, respectively; all P < 0.001) with Lin's concordance test showing substantial agreement between the FCRs of Lp(a)-apo(a) and Lp(a)-apoB in patients with elevated and normal Lp(a) concentrations (rc = 0.978 and rc = 0.966, respectively). CONCLUSION: Our data indicate that the apo(a) and apoB proteins within Lp(a) particles have similar FCR and are therefore tightly coupled as an Lp(a) holoparticle in statin-treated patients with elevated and normal Lp(a) concentrations.

Association Between Plasma Neutrophil Gelatinase-Associated Lipocalin and Cardiac Disease Hospitalizations and Deaths in Older Women.

Background Neutrophil gelatinase-associated lipocalin ( NGAL ) or lipocalin 2 may promote atherosclerosis and plaque instability leading to increased risk of cardiac events. We investigated the relationships between plasma NGAL , cardiovascular disease biomarkers, and long-term cardiac events. Methods and Results The study population consisted of 1131 ambulant older white women (mean age 75 years) without clinical coronary heart disease ( CHD ) and measures of plasma NGAL in the Perth Longitudinal Study of Ageing Women with 14.5-year CHD and heart failure hospitalizations or death (events) captured using linked records. Over 14.5 years, 256 women had CHD events, while 118 had heart failure events. Per SD increase in log-transformed NGAL there was a 35% to 37% increase in relative hazards for CHD and heart failure events in unadjusted analyses, which remained significant after adjustment for conventional risk factors for CHD events (hazard ratio 1.29, 95% CI 1.13-1.48, P<0.001) but not heart failure ( P>0.05). Women in the highest 2 quartiles of NGAL had higher relative hazards for CHD events compared with women in the lowest quartile hazard ratio 1.61, 95% CI 1.08-2.39, P=0.019 and hazard ratio 1.97, 95% CI 1.33-3.93, P=0.001, respectively. These associations were independent of high-sensitivity cardiac troponin I, homocysteine, and estimated renal function. NGAL correctly reclassified 1 in 4 women who sustained a CHD event up in risk and 1 in 10 women without CHD events down in risk. Conclusions NGAL was associated with increased risk of long-term CHD events, independent of conventional risk factors and biomarkers. These findings provide mechanistic insight into the role of NGAL with cardiac events.

Lipoprotein (a) and Low-density lipoprotein apolipoprotein B metabolism following apheresis in patients with elevated lipoprotein(a) and coronary artery disease.

BACKGROUND: Lipoprotein apheresis effectively lowers lipoprotein(a) [Lp(a)] and low-density lipoprotein (LDL) by approximately 60%-70%. The rebound of LDL and Lp(a) particle concentrations following lipoprotein apheresis allows the determination of fractional catabolic rate (FCR) and hence production rate (PR) during non-steady state conditions. We aimed to investigate the kinetics of Lp(a) and LDL apolipoprotein B-100 (apoB) particles in patients with elevated Lp(a) and coronary artery disease undergoing regular apheresis. PATIENTS AND METHODS: A cross-sectional study was carried out in 13 patients with elevated Lp(a) concentration (>500 mg/L) and coronary artery disease. Lp(a) and LDL-apoB metabolic parameters, including FCR and PR were derived by the fit of a compartment model to the Lp(a) and LDL-apoB concentration data following lipoprotein apheresis. RESULTS: The FCR of Lp(a) was significantly lower than that of LDL-apoB (0.39 [0.31, 0.49] vs 0.57 [0.46, 0.71] pools/day, P = 0.03) with no significant differences in the corresponding PR (14.80 [11.34, 19.32] vs 15.73 [11.93, 20.75] mg/kg/day, P = 0.80). No significant associations were observed between the FCR and PR of Lp(a) and LDL-apoB. CONCLUSIONS: In patients with elevated Lp(a), the fractional catabolism of Lp(a) is slower than that of LDL-apoB particles, implying that different metabolic pathways are involved in the catabolism of these lipoproteins. These findings have implications for new therapies for lowering apolipoprotein(a) and apoB to prevent atherosclerotic cardiovascular disease.

Lipoprotein(a) and apolipoprotein(a) isoform size: Associations with angiographic extent and severity of coronary artery disease, and carotid artery plaque.

BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is an emerging genetic risk factor for cardiovascular disease (CVD). We examined whether plasma Lp(a) concentration and apolipoprotein(a) [apo(a)] isoform size are associated with extent and severity of coronary artery disease (CAD), and the presence of carotid artery plaque. METHODS: We included in our study male participants (n = 263) from a cohort with angiographically defined premature CAD (Carotid Ultrasound in Patients with Ischemic Heart Disease). The angiographic extent and severity of CAD were determined by the modified Gensini and Coronary Artery Stenosis≥20% (CAGE) scores. Carotid artery plaque was assessed by bilateral carotid B-mode ultrasound. Apo(a) isoform size was determined by LPA Kringle IV-2 copy number (KIV-2 CN). RESULTS: Lp(a) concentration, but not KIV-2 CN, was positively associated with the Gensini score. The association remained significant following adjustment for conventional CVD risk factors (all p < 0.05). Lp(a) concentration and elevated Lp(a) [≥50 mg/dL] were positively associated with the CAGE≥20 score, independent of conventional CVD risk factors. KIV-2 C N Q1 (lowest KIV-2 CN quartile) was associated with CAGE≥20 score and KIV-2 CN, with the CAGE≥20 score in those without diabetes. In multivariate models that included phenotypic familial hypercholesterolemia or low-density lipoprotein cholesterol, Lp(a) concentration, but not KIV-2 CN, was independently associated with the Gensini and CAGE≥20 scores. No significant associations between Lp(a) concentration and KIV-2 CN with carotid artery plaque were observed. CONCLUSIONS: Lp(a) concentration, but not apo(a) isoform size, is independently associated with angiographic extent and severity of CAD. Neither Lp(a) nor apo(a) isoform size is associated with carotid artery plaque.

Metabolism and proteomics of large and small dense LDL in combined hyperlipidemia: effects of rosuvastatin.

Small dense LDL (sdLDL) has been reported to be more atherogenic than large buoyant LDL (lbLDL). We examined the metabolism and protein composition of sdLDL and lbLDL in six subjects with combined hyperlipidemia on placebo and rosuvastatin 40 mg/day. ApoB-100 kinetics in triglyceride-rich lipoproteins (TRLs), lbLDL (density [d] = 1.019-1.044 g/ml), and sdLDL (d = 1.044-1.063 g/ml) were determined in the fed state by using stable isotope tracers, mass spectrometry, and compartmental modeling. Compared with placebo, rosuvastatin decreased LDL cholesterol and apoB-100 levels in TRL, lbLDL, and sdLDL by significantly increasing the fractional catabolic rate of apoB-100 (TRL, +45%; lbLDL, +131%; and sdLDL, +97%), without a change in production. On placebo, 25% of TRL apoB-100 was catabolized directly, 37% was converted to lbLDL, and 38% went directly to sdLDL; rosuvastatin did not alter these distributions. During both phases, sdLDL apoB-100 was catabolized more slowly than lbLDL apoB-100 (P < 0.01). Proteomic analysis indicated that rosuvastatin decreased apoC-III and apoM content within the density range of lbLDL (P < 0.05). In our view, sdLDL is more atherogenic than lbLDL because of its longer plasma residence time, potentially resulting in more particle oxidation, modification, and reduction in size, with increased arterial wall uptake. Rosuvastatin enhances the catabolism of apoB-100 in both lbLDL and sdLDL.

Triglyceride-rich lipoprotein metabolism in women: roles of apoC-II and apoC-III.

BACKGROUND: Experimental data suggest that apolipoprotein (apo) C-II and C-III regulate triglyceride-rich lipoprotein (TRL) metabolism, but there are limited studies in humans. We investigated the metabolic associations of TRLs with apoC-II and apoC-III concentrations and kinetics in women. MATERIAL AND METHODS: The kinetics of plasma apoC-II, apoC-III and very low-density lipoprotein (VLDL) apoB-100 and triglycerides were measured in the postabsorptive state using stable isotopic techniques and compartmental modelling in 60 women with wide-ranging body mass index (19·5-32·9 kg/m(2) ). RESULTS: Plasma apoC-II and apoC-III concentrations were positively associated with the concentrations of plasma triglycerides, VLDL1 - and VLDL2 -apoB-100 and triglyceride (all P < 0·05). ApoC-II production rate (PR) was positively associated with VLDL1 -apoB-100 concentration, VLDL1 triglyceride concentration and VLDL1 triglyceride PR, while apoC-II fractional catabolic rate (FCR) was positively associated with VLDL1 triglyceride FCR (all P < 0·05). No significant associations were observed between apoC-II and VLDL2 apoB-100 or triglyceride kinetics. ApoC-III PR, but not FCR, was positively associated with VLDL1 triglyceride, and VLDL2 -apoB-100 and triglyceride concentrations (all P < 0·05). No significant associations were observed between apoC-III and VLDL-apoB-100 and triglyceride kinetics. In multivariable analysis, including homoeostasis model assessment score, menopausal status and obesity, apoC-II concentration was significantly associated with plasma triglyceride, VLDL1 -apoB-100 and VLDL1 triglyceride concentrations and PR. Using the same multivariable analysis, apoC-III was significantly associated with plasma triglyceride and VLDL1 - and VLDL2 -apoB-100 and triglyceride concentrations and FCR. CONCLUSIONS: In women, plasma apoC-II and apoC-III concentrations are regulated by their respective PR and are significant, independent determinants of the kinetics and plasma concentrations of TRLs.

Effects of extended-release niacin on the postprandial metabolism of Lp(a) and ApoB-100-containing lipoproteins in statin-treated men with type 2 diabetes mellitus.

OBJECTIVE: The effects of extended-release niacin (ERN; 1-2 g/d) on the metabolism of lipoprotein(a) (Lp(a)) and apolipoprotein (apo) B-100-containing lipoproteins were investigated in 11 statin-treated white men with type 2 diabetes mellitus in a randomized, crossover trial of 12-weeks duration. APPROACH AND RESULTS: The kinetics of Lp(a) and very low-density lipoprotein (VLDL), intermediate-density lipoprotein, and low-density lipoprotein (LDL) apoB-100 were determined following a standardized oral fat load (87% fat) using intravenous administration of D3-leucine, gas chromatography-mass spectrometry, and compartmental modeling. ERN significantly decreased fasting plasma total cholesterol, LDL cholesterol, and triglyceride concentrations. These effects were achieved without significant changes in body weight or insulin resistance. ERN significantly decreased plasma Lp(a) concentration (-26.5%) and the production rates of apo(a) (-41.5%) and Lp(a)-apoB-100 (-32.1%); the effect was greater in individuals with elevated Lp(a) concentration. ERN significantly decreased VLDL (-58.7%), intermediate-density lipoprotein (-33.6%), and LDL (-18.3%) apoB-100 concentrations and the corresponding production rates (VLDL, -49.8%; intermediate-density lipoprotein, -44.7%; LDL, -46.1%). The number of VLDL apoB-100 particles secreted increased in response to the oral fat load. Despite this, total VLDL apoB-100 production over the 10-hour postprandial period was significantly decreased with ERN (-21.9%). CONCLUSIONS: In statin-treated men with type 2 diabetes mellitus, ERN decreased plasma Lp(a) concentrations by decreasing the production of apo(a) and Lp(a)-apoB-100. ERN also decreased the concentrations of apoB-100-containing lipoproteins by decreasing VLDL production and the transport of these particles down the VLDL to LDL cascade. Our study provides further mechanistic insights into the lipid-regulating effects of ERN.

Metabolism of apolipoprotein A-II containing triglyceride rich ApoB lipoproteins in humans.

OBJECTIVE: To characterize human triglyceride-rich lipoproteins (TRL) with and without apoA-II and to study their metabolism in vivo. METHODS: Plasma from 11 participants on a controlled diet given a bolus infusion of [D5]l-phenylalanine to label apoB was combined into four pools and applied to anti-apoA-II immunoaffinity columns. Fractions with and without apoA-II were separated into VLDL and IDL by ultracentrifugation; lipids and apolipoproteins were measured. For kinetic measurements, apoB was isolated and hydrolyzed to the constituent amino acids. Tracer enrichment was measured by GCMS. Metabolic rates were determined by SAAM-II. RESULTS: VLDL and IDL with apoA-II comprised 7% and 9% of total VLDL and IDL apoB respectively. VLDL with apoA-II was enriched in apoC-III, apoE, and cholesterol compared to VLDL without apoA-II. Mean apoB FCR of VLDL with apoA-II was significantly lower than for VLDL without apoA-II (2.80 ± 0.96 pools/day v.s. 5.09 ± 1.69 pools/day, P = 0.009). A higher percentage of VLDL with apoA-II was converted to IDL than was cleared from circulation, compared to VLDL without apoA-II (96 ± 8% vs. 45 ± 22%; P = 0.007). The rate constants for conversion of VLDL to IDL were similar for VLDL with and without apoA-II. Thus, a very low rate constant for clearance accounted for the lower FCR of VLDL with apoA-II. CONCLUSION: VLDL with apoA-II represents a small pool of VLDL particles that has a slow FCR and is predominantly converted to IDL rather than cleared from the circulation.