All-cause Mortality In Renal Transplant Recipients Research Articles

N1-Methylnicotinamide: The Mysterious Anti-aging Actor in Renal Transplantation.

The fast global aging of people worldwide is a crucial demographic trend. According to evidence, Americans aged 65 and above will compose 21.6% of the population by 2040. During the aging process, the kidney undergoes gradual functional decrease, which turned out to be a forthcoming problem in clinical practice. Age-related decrease in renal function, evaluated by total glomerular filtration rate (GFR), which has been shown to drop by approximately 5-10% per decade after the age of 35. The sustaining extended period renal homeostasis is the main purpose of any therapeutic options intended for delaying or even reversing the aging kidney. The renal transplant has been regarded as the common alternative for kidney replacement therapy for elderly patients with end-stage renal disease (ESRD). In the last few years, considerable progress has been made to find novel therapeutic options for alleviating renal aging, in particular, calorie restriction and pharmacologic therapy. Nicotinamide N-methyltransferase is an enzyme responsible for generating N1-Methylnicotinamide (MNAM), notorious for its anti-diabetic, anti-thrombotic, and anti-inflammatory activity. MNAM is one of the important factors regarded as in vivo probes for evaluating the activity of some renal drug transporters. Furthermore, it has been shown to have therapeutic potential in the pathogenesis of proximal tubular cell damage and tubulointerstitial fibrosis. In this article, in addition to addressing the role of MNAM in renal function, we also explained its anti-aging effects. We conducted an in-depth investigation of the urinary excretion of MNAM and its metabolites, especially N1-methyl-2-pyridone-5- carboxamide (2py) in RTR. The excretion of MNAM and its metabolite, 2py, was inversely correlated with the risk of all-cause mortality in renal transplant recipients (RTR), independent of possible confounders. Therefore, we have shown that the reason for the lower mortality rate in RTR who had higher urinary excretion of MNAM and 2py may be related to the anti- aging effects of MNAM through transiently generating low levels of reactive oxygen species, stress resistance and the activation of antioxidant defense pathways.

P1653METABOLIC SYNDROME-RELATED DIETARY PATTERN AND RISK FOR MORTALITY IN RENAL TRANSPLANT RECIPIENTS

Abstract Background and Aims The metabolic syndrome (MetS) is an important risk factor for premature mortality in renal transplant recipients (RTR). Diet plays an important role in MetS development. Although an unhealthy diet may affect the long term outcome in RTR, no specific dietary patterns have been established that are linked with MetS in RTR. Reduced rank regression (RRR) has emerged as a method that identifies linear functions of predictor variables (food groups) that explain maximized variation in the response variables (biomarkers). We aim to identify a MetS-related dietary pattern (MetS-DP) in RTR, and to test its association with all-cause mortality. Method We included 432 adult RTR who had a functioning graft ≥1 year and were free of diabetes at baseline. The MetS-DP was constructed at baseline using dietary information derived from a 177-item food frequency questionnaire by reduced rank regression (RRR). In the RRR model, six components of MetS were used as response variable (age- and sex- adjusted waist circumference, systolic blood pressure, diastolic blood pressure, serum triglycerides, HbA1c, and HDL cholesterol), and 48 food groups were made as predictor variables. Using Cox proportional regression, we evaluated the association between the Met-DP score and all-cause mortality in RTR. Results The MetS-DP was characterized by a high intake of fat processed meat and desserts, and a low intake of vegetables, tea, rice, fruits, milk and vegetarian products. During a mean follow-up of 5.2 ±1.2 year, 64 RTRs (14.8%) died. Multivariate analysis showed that RTR in the highest tertile of MetS-DP score had a higher risk of all-cause mortality (hazard ratio [HR]=2.38; 95% confidence interval [CI],1.16-4.91, P=0.018) compared to the lowest tertile, independent of potential confounders. Conclusion The results suggest that the MetS-DP is significantly associated with all-cause mortality in RTR. Dietary measures may be useful to prevent MetS and reduce mortality in RTR.

Urinary Excretion of N1-Methylnicotinamide, as a Biomarker of Niacin Status, and Mortality in Renal Transplant Recipients.

Renal transplant recipients (RTR) commonly suffer from vitamin B6 deficiency and its functional consequences add to an association with poor long-term outcome. It is unknown whether niacin status is affected in RTR and, if so, whether this affects clinical outcomes, as vitamin B6 is a cofactor in nicotinamide biosynthesis. We compared 24-h urinary excretion of N1-methylnicotinamide (N1-MN) as a biomarker of niacin status in RTR with that in healthy controls, in relation to dietary intake of tryptophan and niacin as well as vitamin B6 status, and investigated whether niacin status is associated with the risk of premature all-cause mortality in RTR. In a prospective cohort of 660 stable RTR with a median follow-up of 5.4 (4.7–6.1) years and 275 healthy kidney donors, 24-h urinary excretion of N1-MN was measured with liquid chromatography-tandem mass spectrometry LC-MS/MS. Dietary intake was assessed by food frequency questionnaires. Prospective associations of N1-MN excretion with mortality were investigated by Cox regression analyses. Median N1-MN excretion was 22.0 (15.8–31.8) μmol/day in RTR, compared to 41.1 (31.6–57.2) μmol/day in healthy kidney donors (p < 0.001). This difference was independent of dietary intake of tryptophan (1059 ± 271 and 1089 ± 308 mg/day; p = 0.19), niacin (17.9 ± 5.2 and 19.2 ± 6.2 mg/day; p < 0.001), plasma vitamin B6 (29.0 (17.5–49.5), and 42.0 (29.8–60.3) nmol/L; p < 0.001), respectively. N1-MN excretion was inversely associated with the risk of all-cause mortality in RTR (HR 0.57; 95% CI 0.45–0.71; p < 0.001), independent of potential confounders. RTR excrete less N1-MN in 24-h urine than healthy controls, and our data suggest that this difference cannot be attributed to lower dietary intake of tryptophan and niacin, nor vitamin B6 status. Importantly, lower 24-h urinary excretion of N1-MN is independently associated with a higher risk of premature all-cause mortality in RTR.

Fish Intake, Circulating Mercury and Mortality in Renal Transplant Recipients.

Marine-derived omega-3 polyunsaturated fatty acids (n-3 PUFAs) are inversely associated with cardiovascular and all-cause mortality in renal transplant recipients (RTRs). Recommendations to increase marine-derived n-3 PUFAs by increasing fish intake may have a drawback in concomitant stimulation of mercury intake, which could lead to higher circulating mercury concentrations and mitigation of otherwise beneficial effects of n-3 PUFAs. We aimed to monitor circulating mercury concentrations, and to prospectively evaluate whether it counteracts the potential association between fish intake and cardiovascular and all-cause mortality in a cohort of RTRs (n = 604, 53 ± 13 years-old, 57% men) with long-term follow-up (median of 5.4 years; 121 deaths). Circulating mercury concentration (median 0.30 (IQR 0.14–0.63) µg/L) positively associated with fish intake (std. β = 0.21, p < 0.001). Multivariable-adjusted Cox-proportional hazards regression analyses showed that prior to, and after additional adjustment for circulating mercury concentrations, fish intake was inversely associated with both cardiovascular (HR 0.75, 95% CI 0.58–0.96; and, HR 0.75, 95% CI 0.58–0.97, respectively) and all-cause mortality (HR 0.84, 95% CI 0.72–0.97; and, HR 0.86, 95% CI 0.74–0.99, respectively). Secondary analyses accounting for marine-derived n-3 PUFAs intake revealed associations of similar magnitude. In conclusion, we found no evidence of a counteracting effect conferred by circulating mercury concentrations on the associations between fish and marine-derived n-3 PUFAs intake and the risks of cardiovascular and all-cause mortality in RTRs.

Iron deficiency, anemia, and mortality in renal transplant recipients.

Anemia, iron deficiency anemia (IDA), and iron deficiency (ID) are highly prevalent in renal transplant recipients (RTR). Anemia is associated with poor outcome, but the role of ID is unknown. Therefore, we aimed to investigate the association of ID, irrespective of anemia, with all-cause mortality in RTR. Cox regression analyses were used to investigate prospective associations. In 700 RTR, prevalences of anemia, IDA, and ID were 34%, 13%, and 30%, respectively. During follow-up for 3.1 (2.7-3.9) years, 81 (12%) RTR died. In univariable analysis, anemia [HR, 1.72 (95%CI: 1.11-2.66), P = 0.02], IDA [2.44 (1.48-4.01), P < 0.001], and ID [2.04 (1.31-3.16), P = 0.001] were all associated with all-cause mortality. In multivariable analysis, the association of anemia with mortality became weaker after adjustment for ID [1.52 (0.97-2.39), P = 0.07] and disappeared after adjustment for proteinuria and eGFR [1.09 (0.67-1.78), P = 0.73]. The association of IDA with mortality attenuated after adjustment for potential confounders. In contrast, the association of ID with mortality remained independent of potential confounders, including anemia [1.77 (1.13-2.78), P = 0.01]. In conclusion, ID is highly prevalent among RTR and is associated with an increased risk of mortality, independent of anemia. As ID is a modifiable factor, correction of ID could be a target to improve survival.

The predictive value of the antioxidative function of HDL for cardiovascular disease and graft failure in renal transplant recipients

BackgroundProtection of low-density lipoproteins (LDL) against oxidative modification is a key anti-atherosclerotic property of high-density lipoproteins (HDL). This study evaluated the predictive value of the HDL antioxidative function for cardiovascular mortality, all-cause mortality and chronic graft failure in renal transplant recipients (RTR). MethodsThe capacity of HDL to inhibit native LDL oxidation was determined in vitro in a prospective cohort of renal transplant recipients (RTR, n = 495, median follow-up 7.0 years). ResultsThe HDL antioxidative functionality was significantly higher in patients experiencing graft failure (57.4 ± 9.7%) than in those without (54.2 ± 11.3%; P = 0.039), while there were no differences for cardiovascular and all-cause mortality. Specifically glomerular filtration rate (P = 0.001) and C-reactive protein levels (P = 0.006) associated independently with antioxidative functionality in multivariate linear regression analyses. Cox regression analysis demonstrated a significant relationship between antioxidative functionality of HDL and graft failure in age-adjusted analyses, but significance was lost following adjustment for baseline kidney function and inflammatory load. No significant association was found between HDL antioxidative functionality and cardiovascular and all-cause mortality. ConclusionThis study demonstrates that the antioxidative function of HDL (i) does not predict cardiovascular or all-cause mortality in RTR, but (ii) conceivably contributes to the development of graft failure, however, not independent of baseline kidney function and inflammatory load.

Increased risk of all-cause mortality and renal graft loss in stable renal transplant recipients with hyperparathyroidism.

Hyperparathyroidism is reported in 10% to 66% of renal transplant recipients (RTR). The influence of persisting hyperparathyroidism on long-term clinical outcomes in RTR has not been examined in a large prospective study. We investigated the association between baseline parathyroid hormone (PTH) levels and major cardiovascular events, renal graft loss, and all-cause mortality by Cox Proportional Hazard survival analyses in 1840 stable RTR derived from the Assessment of LEscol in Renal Transplantation trial. Patients were recruited in a mean of 5.1 years after transplantation, and follow-up time was 6 to 7 years. Significant associations between PTH and all 3 outcomes were found in univariate analyses. When adjusting for a range of plausible confounders, including measures of renal function and serum mineral levels, PTH remained significantly associated with all-cause mortality (4% increased risk per 10 units; P=0.004), and with graft loss (6% increased risk per 10 units; P<0.001), but not with major cardiovascular events. Parathyroid hormone above the upper limit of normal (65 pg/mL) indicated a 46% (P=0.006) higher risk of death and an 85% higher risk of graft loss (P<0.001) compared with low/normal values. Hyperparathyroidism is an independent, potentially remediable, risk factor for renal graft loss and all-cause mortality in RTR.

Low Physical Activity and Risk of Cardiovascular and All-Cause Mortality in Renal Transplant Recipients

Low physical activity (PA) is a risk factor for mortality in the general population. This is largely unexplored in renal transplant recipients (RTRs). We studied whether PA is associated with cardiovascular and all-cause mortality in a prospective cohort of RTR. Between 2001 and 2003, 540 RTRs were studied (age, 51 ± 12 years; 54% male). PA was assessed using validated questionnaires (Tecumseh Occupational Activity Questionnaire and the Minnesota Leisure Time Physical Activity Questionnaire). Cardiovascular and all-cause mortality were recorded until August 2007. Independent of age, PA was inversely associated with metabolic syndrome, history of cardiovascular disease, fasting insulin, and triglyceride concentration, and positively associated with kidney function and 24-hour urinary creatinine excretion (i.e., muscle mass). During follow-up for 5.3 years (range, 4.7 to 5.7 years), 81 RTRs died, with 37 cardiovascular deaths. Cardiovascular mortality was 11.7, 7.2, and 1.7%, respectively, according to gender-stratified tertiles of PA (P=0.001). All-cause mortality was 24.4, 15.0, and 5.6% according to these tertiles (P<0.001). In Cox regression analyses, adjustment for potential confounders including history of cardiovascular disease, muscle mass, and traditional risk factors for cardiovascular disease did not materially change these associations. Low PA is strongly associated with increased risk for cardiovascular and all-cause mortality in RTRs. Intervention studies are necessary to investigate whether PA improves long-term survival after renal transplantation.

Renal transplant dysfunction—importance quantified in comparison with traditional risk factors for cardiovascular disease and mortality

Renal transplant recipients (RTR) mainly die of premature cardiovascular disease. Traditional cardiovascular disease risk factors are prevalent in RTR. Additionally, non-traditional risk factors seem to contribute to the high risk. The impact of renal dysfunction was compared with traditional risk factors for cardiovascular morbidity and mortality in 1052 placebo-treated patients of the ALERT trial. All patients were on cyclosporine-based immunosuppressive therapy, follow-up was 5-6 years and captured endpoints included cardiac death, non-cardiovascular death, all-cause mortality, major adverse cardiac event (MACE), non-fatal myocardial infarction (MI) and stroke. A calculated 84 micromol/l increase in serum creatinine was needed to double the risk for cardiac death, an increase of 104 micromol/l to double the risk for non-cardiovascular death and an increase of 92 micromol/l to double the risk for all-cause mortality. MACE risk was doubled if serum creatinine was elevated by 141 micromol/l, age was increased by 23 years, or LDL-cholesterol by 2 mmol/l. Diabetes increased the incidences of cardiac death, all-cause mortality, MACE, stroke and non-fatal MI. A serum creatinine increase of approximately 130 micromol/l, or approximately 20 years increase in age was calculated as similar in risk for cardiac death, all-cause mortality and MACE, and comparable to risk of diabetes in RTR. An increase in serum creatinine of 80-100 micromol/l doubles the risk for cardiac death, non-cardiovascular death and all-cause mortality in RTR. An increase of 130 micromol/l in serum creatinine or approximately 20 years increase in age is comparable to risk of diabetes.