Incidence of end-stage renal disease after heart transplantation and effect of its treatment on survival

Aims: Many heart transplant recipients will develop end-stage renal disease in the post-operative course. The aim of this study was to identify the long-term incidence of end-stage renal disease, determine its risk factors, and investigate what subsequent therapy was associated with the best survival. Methods and results: A retrospective, single-centre study was performed in all adult heart transplant patients from 1984 to 2016. Risk factors for end-stage renal disease were analysed by means of multivariable regression analysis and survival by means of Kaplan–Meier. Of 685 heart transplant recipients, 71 were excluded: 64 were under 18 years of age and seven were re-transplantations. During a median follow-up of 8.6 years, 121 (19.7%) patients developed end-stage renal disease: 22 received conservative therapy, 80 were treated with dialysis (46 haemodialysis and 34 peritoneal dialysis), and 19 received a kidney transplant. Development of end-stage renal disease (examined as a time-dependent variable) inferred a hazard ratio of 6.45 (95% confidence interval 4.87–8.54, P < 0.001) for mortality. Tacrolimus-based therapy decreased, and acute kidney injury requiring renal replacement therapy increased the risk for end-stage renal disease development (hazard ratio 0.40, 95% confidence interval 0.26–0.62, P < 0.001, and hazard ratio 4.18, 95% confidence interval 2.30–7.59, P < 0.001, respectively). Kidney transplantation was associated with the best median survival compared with dialysis or conservative therapy: 6.4 vs. 2.2 vs. 0.3 years (P < 0.0001), respectively, after end-stage renal disease development. Conclusions: End-stage renal disease is a frequent complication after heart transplant and is associated with poor survival. Kidney transplantation resulted in the longest survival of patients with end-stage renal disease

Lower Intrinsic ADP-Stimulated Mitochondrial Respiration Underlies In Vivo Mitochondrial Dysfunction in Muscle of Male Type 2 Diabetic Patients

OBJECTIVE—A lower in vivo mitochondrial function has been reported in both type 2 diabetic patients and first-degree relatives of type 2 diabetic patients. The nature of this reduction is unknown. Here, we tested the hypothesis that a lower intrinsic mitochondrial respiratory capacity may underlie lower in vivo mitochondrial function observed in diabetic patients

Impact of Continuous Flow Left Ventricular Assist Device Therapy on Chronic Kidney Disease: A Longitudinal Multicenter Study

Background: Many patients undergoing durable left ventricular assist device (LVAD) implantation suffer from chronic kidney disease (CKD). Therefore, we investigated the effect of LVAD support on CKD. Methods: A retrospective multicenter cohort study, including all patients undergoing LVAD (HeartMate II (n = 330), HeartMate 3 (n = 22) and HeartWare (n = 48) implantation. In total, 227 (56.8%) patients were implanted as bridge-to-transplantation; 154 (38.5%) as destination therapy; and 19 (4.7%) as bridge-to-decision. Serum creatinine measurements were collected over a 2-year follow-up period. Patients were stratified based on CKD stage. Results: Overall, 400 patients (mean age 53 ± 14 years, 75% male) were included: 186 (46.5%) patients had CKD stage 1 or 2; 93 (23.3%) had CKD stage 3a; 82 (20.5%) had CKD stage 3b; and 39 (9.8%) had CKD stage 4 or 5 prior to LVAD implantation. During a median follow-up of 179 days (IQR 28–627), 32,629 creatinine measurements were available. Improvement of kidney function was noticed in every preoperative CKD-stage group. Following this improvement, estimated glomerular filtration rates regressed to baseline values for all CKD stages. Patients showing early renal function improvement were younger and in worse preoperative condition. Moreover, survival rates were higher in patients showing early improvement (69% vs 56%, log-rank P = 0.013). Conclusions: Renal function following LVAD implantation is characterized by improvement, steady state and subsequent deterioration. Patients who showed early renal function improvement were in worse preoperative condition, however, and had higher survival rates at 2 years of follow-up

Preoperative right heart hemodynamics predict postoperative acute kidney injury after heart transplantation

Purpose: Acute kidney injury (AKI) frequently occurs after heart transplantation (HTx), but its relation to preoperative right heart hemodynamic (RHH) parameters remains unknown. Therefore, we aimed to determine their predictive properties for postoperative AKI severity within 30 days after HTx. Methods: From 1984 to 2016, all consecutive HTx recipients (n = 595) in our tertiary referral center were included and analyzed for the occurrence of postoperative AKI staged by the kidney disease improving global outcome criteria. The effects of preoperative RHH parameters on postoperative AKI were calculated using logistic regression, and predictive accuracy was assessed using integrated discrimination improvement (IDI), net reclassification improvement (NRI), and area under the receiver operating characteristic curves (AUC). Results: Postoperative AKI occurred in 430 (72%) patients including 278 (47%) stage 1, 66 (11%) stage 2, and 86 (14%) stage 3 cases. Renal replacement therapy (RRT) was administered in 41 (7%) patients. Patients with higher AKI stages had also higher baseline right atrial pressure (RAP; median 7, 7, 8, and in RRT 11 mmHg, p trend = 0.021), RAP-to-pulmonary capillary wedge pressure ratio (median 0.37, 0.36, 0.40, 0.47, p trend = 0.009), and lower pulmonary artery pulsatility index (PAPi) values (median 2.83, 3.17, 2.54, 2.31, p trend = 0.012). Higher RAP and lower PAPi values independently predicted AKI severity [adjusted odds ratio (OR) per doubling of RAP 1.16 (1.02–1.32), p = 0.029; of PAPi 0.85 (0.75–0.96), p = 0.008]. Based on IDI, NRI, and delta AUC, inclusion of these parameters improved the models’ predictive accuracy. Conclusions: Preoperative PAPi and RAP strongly predict the development of AKI early after HTx and can be used as early AKI predictors

Long-echo time MR spectroscopy for skeletal muscle acetylcarnitine detection

Animal models suggest that acetylcarnitine production is essential for maintaining metabolic flexibility and insulin sensitivity. Because methods to detect acetylcarnitine involve biopsy of the tissue of noninvasive alternatives to measure acetylcarnitine concentrations could facilitate our understanding of its physiological relevance in humans. investigated the use of long-echo time (TE) proton magnetic resonance spectroscopy (1H-MRS) to measure skeletal muscle acetylcarnitine on a clinical 3T scanner. We applied long-TE 1H-MRS to measure endurance-trained athletes, lean and obese sedentary subjects, and type diabetes mellitus (T2DM) patients to cover a wide spectrum in insulin sensitivity. A long-TE 1H-MRS protocol was implemented for successful of skeletal muscle acetylcarnitine in these individuals. There were differences in insulin sensitivity, as measured by hyperinsulinemic- clamp, and skeletal muscle mitochondrial function, as measured by (31P-MRS), across groups. Insulin sensitivity and mitochondrial function highest in trained athletes and lowest in T2DM patients. Skeletal muscle acetylcarnitine concentration showed a reciprocal distribution, with acetylcarnitine concentration correlating with mean insulin sensitivity group. These results demonstrate that measuring acetylcarnitine with 1H-MRS is feasible on clinical MR scanners and support the T2DM patients are characterized by a decreased formation of possibly underlying decreased insulin sensitivity

Evidence for a Direct Effect of the NAD +

Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD(+)) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD(+) precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 +/- 1.1 years, BMI 33.4 +/- 0.8 kg/m(2)) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 +/- 44 vs. 1,135 +/- 97 mol/L for placebo vs. acipimox, P < 0.01) owing to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene sets and a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. Further studies in C2C12 myotubes confirmed a direct effect of acipimox on NAD(+) levels, mitonuclear protein imbalance, and mitochondrial oxidative capacity. To the best of our knowledge, this study is the first to demonstrate that NAD(+) boosters can also directly affect skeletal muscle mitochondrial function in humans

Adaptations in mitochondrial function parallel, but fail to rescue, the transition to severe hyperglycemia and hyperinsulinemia : a study in zucker diabetic fatty rats

Cross-sectional human studies have associated mitochondrial dysfunction to type 2 diabetes. We chose Zucker diabetic fatty (ZDF) rats as a model of progressive insulin resistance to examine whether intrinsic mitochondrial defects are required for development of type 2 diabetes. Muscle mitochondrial function was examined in 6-, 12-, and 19-week-old ZDF (fa/fa) and fa/+ control rats (n = 8-10 per group) using respirometry with pyruvate, glutamate, and palmitoyl-CoA as substrates. Six-week-old normoglycemic-hyperinsulinemic fa/fa rats had reduced mitochondrial fat oxidative capacity. Adenosine diphosphate (ADP)-driven state 3 and carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP)-stimulated state uncoupled (state u) respiration on palmitoyl-CoA were lower compared to controls (62.3 ± 9.5 vs. 119.1 ± 13.8 and 87.8 ± 13.3 vs. 141.9 ± 14.3 nmol O2/mg/min.). Pyruvate oxidation in 6-week-old fa/fa rats was similar to controls. Remarkably, reduced fat oxidative capacity in 6-week-old fa/fa rats was compensated for by an adaptive increase in intrinsic mitochondrial function at week 12, which could not be maintained toward week 19 (140.9 ± 11.2 and 57.7 ± 9.8 nmol O2/mg/min, weeks 12 and 19, respectively), whereas hyperglycemia had developed (13.5 ± 0.6 and 16.1 ± 0.3 mmol/l, weeks 12 and 19, respectively). This mitochondrial adaptation failed to rescue the progressive development of insulin resistance in fa/fa rats. The transition of prediabetes state toward advanced hyperglycemia and hyperinsulinemia was accompanied by a blunted increase in uncoupling protein-3 (UCP3). Thus, in ZDF rats insulin resistance develops progressively in the absence of mitochondrial dysfunction. In fact, improved mitochondrial capacity in hyperinsulinemic hyperglycemic rats does not rescue the progression toward advanced stages of insulin resistance