Statin use and incident cardiovascular events in renal transplant recipients

BACKGROUND: Statins achieve potent LDL lowering in the general population leading to a significant cardiovascular (CV) risk reduction. In renal transplant recipients (RTR) statins are included in treatment guidelines, however, conclusive evidence of improved cardiovascular outcomes has not been uniformly provided and concerns have been raised about simultaneous use of statins and the immunosuppressant cyclosporine. This study aimed to elucidate the effect of statins on a compound CV endpoint, comprised of ischaemic CV events and CV mortality in RTR, with subgroup analysis focussing on cyclosporine users. METHOD: 622 included RTR (follow‐up 5.4 years) were matched based on propensity scores and dichotomized by statin use. Survival analysis was conducted. RESULTS: Cox regression showed that statin use was not significantly associated with the compound CV endpoint in a fully adjusted model (HR = 0.81, 95% CI = 0.53‐1.24, P = .33). Subgroup analyses in RTR using cyclosporine revealed a strong positive association of statin use with the CV compound outcome in a fully adjusted model (HR = 6.60, 95% CI 1.75‐24.9, P = .005). Furthermore, statin use was positively correlated with cyclosporine trough levels (correlation coefficient 0.11, P = .04). CONCLUSION: In conclusion, statin use does not significantly decrease incident CV events in an overall RTR cohort, but is independently associated with CV‐specific mortality and events in cyclosporine using RTR, possibly due to a bilateral pharmacological interaction

Remnant lipoprotein cholesterol is associated with incident new onset diabetes after transplantation (NODAT) in renal transplant recipients:results of the TransplantLines Biobank and cohort Studies

BACKGROUND: New onset diabetes after transplantation (NODAT) is a frequent and serious complication of renal transplantation resulting in worse graft and patient outcomes. The pathophysiology of NODAT is incompletely understood, and no prospective biomarkers have been established to predict NODAT risk in renal transplant recipients (RTR). The present work aimed to determine whether remnant lipoprotein (RLP) cholesterol could serve as such a biomarker that would also provide a novel target for therapeutic intervention. METHODS: This longitudinal cohort study included 480 RTR free of diabetes at baseline. 53 patients (11%) were diagnosed with NODAT during a median [interquartile range, IQR] follow-up of 5.2 [4.1–5.8] years. RLP cholesterol was calculated by subtracting HDL and LDL cholesterol from total cholesterol values (all directly measured). RESULTS: Baseline remnant cholesterol values were significantly higher in RTR who subsequently developed NODAT (0.9 [0.5–1.2] mmol/L vs. 0.6 [0.4–0.9] mmol/L, p = 0.001). Kaplan-Meier analysis showed that higher RLP cholesterol values were associated with an increased risk of incident NODAT (log rank test, p < 0.001). Cox regression demonstrated a significant longitudinal association between baseline RLP cholesterol levels and NODAT (HR, 2.27 [1.64–3.14] per 1 SD increase, p < 0.001) that remained after adjusting for plasma glucose and HbA1c (p = 0.002), HDL and LDL cholesterol (p = 0.008) and use of immunosuppressive medication (p < 0.001), among others. Adding baseline remnant cholesterol to the Framingham Diabetes Risk Score significantly improved NODAT prediction (change in C-statistic, p = 0.01). CONCLUSIONS: This study demonstrates that baseline RLP cholesterol levels strongly associate with incident NODAT independent of several other recognized risk factors

Physical Activity and the Development of Post-Transplant Diabetes Mellitus, and Cardiovascular- and All-Cause Mortality in Renal Transplant Recipients

(1) Background: Little is currently known about the health impacts of daily-life moderate-to-vigorous physical activity (MVPA) in relation to the development of post-transplant diabetes mellitus (PTDM) and the long-term survival of renal transplant recipients (RTRs). (2) Methods: We analyzed self-reported data on MVPA within non-occupational and occupational domains, estimated with the SQUASH questionnaire, from a prospective cohort study of RTRs (n = 650) with a functioning graft exceeding 1 year. PTDM diagnoses were based on plasma glucose levels (>= 126 mg/dL), HbA1c (>= 6.5%), and the use of antidiabetic medication. Mortality data were retrieved from patient files up to the end of September 2015. (3) Results: During a median follow-up period of 5.3 years, 50 patients (10%) developed PTDM and 129 (19.8%) died. Of these deaths, 53 (8.9%) were caused by cardiovascular disease. Cox regression analyses showed that higher MVPA levels among patients were associated with a lower risk of PTDM (hazard ratio (HR); 95% confidence interval (95%CI) = 0.49; 0.25-0.96, p = 0.04), cardiovascular- (0.34; 0.15-0.77, p = 0.01), and all-cause mortality (0.37; 0.24-0.58, p <0.001) compared with No-MVPA patients, independently of age, sex, and kidney function parameters. Associations of MVPA with cardiovascular and all-cause mortality remained significant and materially unchanged following further adjustments made for transplant characteristics, lifestyle factors, metabolic parameters, medication use, and creatinine excretion (muscle mass). However, the association between MVPA and PTDM was no longer significant after we adjusted for metabolic confounders and glucose levels. (4) Conclusion: Higher MVPA levels are associated with long-term health outcomes in RTRs

Urinary Excretion of 6-Sulfatoxymelatonin, the Main Metabolite of Melatonin, and Mortality in Stable Outpatient Renal Transplant Recipients

Melatonin is a multifaceted hormone which rises upon the onset of darkness. Pineal synthesis of melatonin is known to be disturbed in patients with end-stage renal disease, but it is not known if its production is restored to normal after successful renal transplantation. We hypothesized that urinary excretion of 6-sulfatoxymelatonin, the major metabolite of melatonin, is lower in renal transplant recipients (RTRs) compared to healthy controls and that this is associated with excess mortality. Urinary 6-sulfatoxymelatonin was measured via LC-MS/MS in 701 stable outpatient RTRs and 285 healthy controls. Median urinary 6-sulfatoxymelatonin in RTR was 13.2 nmol/24 h, which was 47% lower than in healthy controls. Urinary 6-sufatoxymelatonin appeared undetectable in the majority of 36 RTRs with diabetic nephropathy as primary renal disease. Therefore, this subgroup was excluded from further analyses. Of the remaining 665 RTRs, during 5.4 years of follow-up, 110 RTRs died, of whom 38 died due to a cardiovascular cause. In Cox-regression analyses, urinary 6-sulfatoxymelatonin was significantly associated with all-cause mortality (0.60 (0.44&ndash;0.81), p = 0.001) and cardiovascular mortality (0.49 (0.29&ndash;0.84), p = 0.009), independent of conventional risk factors and kidney function parameters. Based on these results, evaluation and management of melatonin metabolism could be considered for improvement of long-term outcomes in RTRs

Comparative survival of elderly renal transplant recipients with a living donor versus a deceased donor:A retrospective single center observational study

Increasing numbers of elderly (≥65 years) patients are listed for kidney transplantation. This study compares the survival outcome between living (LDK), regularly allocated (ETKAS), and Eurotransplant Senior Program (ESP) donor kidneys in elderly recipients. This is a single-center retrospective cohort study of elderly kidney transplant recipients transplanted between 2005 and 2017. Primary outcome measures were nondeath-censored graft, death-censored graft, and patient survival. In total, 348 patients were transplanted, 109 recipients (31.3%) received an LDK, 100 (28.7%) an ETKAS, and 139 (40%) an ESP kidney. 62.5% were male, and median age was 68 years. LDK recipients had significantly better 5-year nondeath-censored graft survival compared with ETKAS and ESP (resp. 71.0% vs. 66.1% vs. 55.6%, P = 0.047). Death-censored graft survival after 1 year was significantly better in LDK recipients (99.1%) (ETKAS 90.8%; ESP 87.7%, P < 0.001). After 5 years, the difference remained significant (P < 0.001) with little additional graft loss (97.7% vs. 88.1% vs. 85.6). There was no significant difference in patient survival after 5 years (71.7% vs. 67.4% vs 61.9%, P = 0.480). In elderly recipients, the patient survival benefits of an LDK are limited, but there is decreased death-censored graft loss for LDK recipients. Nevertheless, graft survival in ETKAS and ESP remains satisfactory

Using a novel concept to measure outcomes in solid organ recipients provided promising results

Objectives: Efforts to evaluate the health of solid organ transplant recipients are hampered by the lack of adequate patient-reported outcome measures (PROMs) targeting this group. We developed the Transplant ePROM (TXP), which is based on a novel measurement model and administered through a mobile application to fill this gap. The main objective of this article is to elucidate how we derived the weights for different items, and to report initial empirical results. Study design and setting: The nine health items in the TXP were fatigue, skin, worry, self-reliance, activities, weight, sexuality, stooling, and memory. Via an online survey solid organ recipient participating in the TransplantLines Biobank and Cohort study (NCT03272841) were asked to describe and then compare their own health state with six other health states. Coefficients for item levels were obtained using a conditional logit model. Results: A total of 232 solid organ transplant recipients (mean age: 54 years) participated. The majority (106) were kidney recipients, followed by lung, liver, and heart recipients. Fatigue was the most frequent complaint (54%). The strongest negative coefficients were found for activities and worry, followed by self-reliance and memory. Conclusion: A set of coefficients and values were developed for TXP. The TXP score approximated an optimal health state for the majority of respondents and recipients of different organs reported comparable health states. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/

Malnutrition according to GLIM criteria in stable renal transplant recipients:Reduced muscle mass as predominant phenotypic criterion

Background & aims: Malnutrition has a negative impact on quality of life and survival in renal transplant recipients (RTR). Therefore, malnutrition detection is important in RTR, but this may be hampered by concomitant presence of weight gain and overweight. Recently, the Global Leadership Initiative on Malnutrition (GLIM) developed a set of diagnostic criteria for malnutrition. We aimed to assess the prevalence of malnutrition according to the GLIM criteria and the distribution of phenotypic criteria in RTR. Additionally, we examined the potential value of 24-h urinary creatinine excretion rate (CER) as alternative measure for the criterion reduced muscle mass. Methods: We used data from stable outpatient RTR included in the TransplantLines Cohort and Biobank Study (NCT02811835). Presence of weight loss and reduced intake or assimilation were derived from Patient-Generated Subjective Global Assessment (PG-SGA) item scores. Reduced muscle mass was assessed by multi-frequency bio-electrical impedance analysis (MF-BIA) and defined as an appendicular skeletal muscle mass index (ASMI) < 7 kg/m(2) for men and 5 mg/L. Malnutrition was defined as presence of at least one phenotypic (weight loss and/or low BMI and/or reduced muscle mass) and one etiologic criterion (reduced intake/assimilation and/or disease burden/inflammation). Results: We included 599 RTR (55 +/- 13 years old, 62% male, BMI 27.2 +/- 4.7 kg/m(2)) at a median of 3.1 years after transplantation. According to GLIM criteria, 14% was malnourished, of which 91% met the phenotypic criterion for reduced muscle mass. Similar results were found by using CHI as measure for muscle mass (13% malnutrition of which 79% with reduced muscle mass). Conclusions: Malnutrition is present in one in 7 stable RTR, with reduced muscle mass as the predominant phenotypic criterion. Assessment of nutritional status, most importantly muscle status, is warranted in routine care, to prevent malnutrition in RTR from remaining undetected and untreated. The diagnostic value of 24-h urinary CER in this regard requires further investigation. (C) 2020 The Author(s). Published by Elsevier Ltd

Plasma neutrophil gelatinase-associated lipocalin and kidney graft outcome

BACKGROUND: Plasma neutrophil gelatinase-associated lipocalin (pNGAL) has been investigated extensively in acute kidney injury. This study investigated its pathophysiological significance and utility as marker for graft failure and mortality in stable kidney transplant recipients (KTR). METHODS: Baseline pNGAL was measured in 698 KTR (58% male, age 53 ± 13 years, estimated glomerular filtration rate 52.4 ± 20.4 mL/min/1.73 m(2)) at median 5.4 (interquartile range 1.8–12.0) years after transplantation, enrolled in the prospective TransplantLines Food and Nutrition Biobank and Cohort Study. RESULTS: pNGAL concentrations were higher in males, younger patients, patients with a deceased-donor kidney and higher serum creatinine. Independent of these, pNGAL was positively associated with urinary protein excretion, systemic inflammation parameters and calcineurin inhibitor use. During median follow-up of 5.3 (4.5–6.0) years, death-censored graft failure rates were 3.9%, 7.3% and 25.0% across increasing tertiles of pNGAL (P(log-rank) < 0.001). Cox-regression analyses showed no independent associations of pNGAL with mortality, but strong associations with graft failure (hazard ratio, per doubling 4.16; 95% confidence interval 3.03–5.71; P < 0.001), which remained independent of adjustment for confounders. These associations were present only in patients with pre-existent proteinuria and poor kidney function. CONCLUSIONS: pNGAL is associated with parameters of kidney graft damage and with graft failure. The latter association is particularly present in KTR with pre-existent poor kidney function and proteinuria. Trial Registration: ClinicalTrials.gov NCT02811835

Salt, but not protein intake, is associated with accelerated disease progression in autosomal dominant polycystic kidney disease

In autosomal dominant polycystic kidney disease (ADPKD), there are only scarce data on the effect of salt and protein intake on disease progression. Here we studied association of these dietary factors with the rate of disease progression in ADPKD, and what the mediating factors are by analyzing an observational cohort of 589 patients with ADPKD. Salt and protein intake were estimated from 24-hour urine samples and the plasma copeptin concentration measured as a surrogate for vasopressin. The association of dietary intake with annual change in the estimated glomerular filtration rate (eGFR) and height adjusted total kidney volume (htTKV) growth was analyzed with mixed models. In case of significant associations, mediation analyses were performed to elucidate potential mechanisms. These patients (59% female) had a mean baseline age of 47, eGFR 64 mL/min/1.73m2 and the median htTKV was 880 mL. The mean estimated salt intake was 9.1 g/day and protein intake 84 g/day. During a median follow-up of 4.0 years, eGFR was assessed a median of six times and 24-hour urine was collected a median of five times. Salt intake was significantly associated with annual change in eGFR of -0.11 (95% confidence interval (0.20 - - 0.02) mL/min/1.73m2 per gram of salt, whereas protein intake was not (-0.00001 (-0.01 - 0.01) mL/min/1.73m2 per gram of protein. The effect of salt intake on eGFR slope was significantly mediated by plasma copeptin (crude analysis: 77% mediation, and, adjusted analysis: 45% mediation), but not by systolic blood pressure. Thus, higher salt, but not higher protein intake may be detrimental in ADPKD. The substantial mediation by plasma copeptin suggests that this effect is primarily a consequence of a salt-induced rise in vasopressin

Protein Intake, Fatigue and Quality of Life in Stable Outpatient Kidney Transplant Recipients

Fatigue is a frequent complaint in kidney transplant recipients (KTR), often accompanied by poor quality of life (QoL). The role of nutrition as determinant of fatigue in KTR is largely unexplored. The aims of this study are to examine the association of protein intake with fatigue and QoL in KTR and to identify other determinants of fatigue. This cross-sectional study is part of the TransplantLines Cohort and Biobank Study (NCT03272841). Protein intake was calculated from urinary urea nitrogen (UUN) in 24-h urine samples. Fatigue was assessed by the Checklist Individual Strength (CIS) questionnaire; moderate and severe fatigue were defined as a CIS score of 20–34 and ≥ 35, respectively. QoL was assessed with the RAND-36-Item Health Survey (RAND-36). Associations of protein intake with fatigue and QoL were analyzed using multinomial logistic and linear regression analyses. We included 730 stable outpatient KTR (median age 58 year [IQR 48–65], 57% male) with a mean protein intake of 82.2 ± 21.3 g/d. Moderate and severe fatigue were present in 254 (35%) and 245 (34%) of KTR. Higher protein intake was significantly associated with lower risk of moderate fatigue (OR 0.89 per 10 g/d; 95%CI 0.83–0.98, p = 0.01), severe fatigue (OR 0.85; 95%CI 0.78–0.92, p < 0.001) and was associated with higher physical component summary score of QoL (β 0.74 per 10 g/d; 95%CI 0.39–1.09, p < 0.001). Higher BMI, a history of dialysis, glomerulonephritis as primary kidney disease and a history of combined organ transplantation were also associated with severe fatigue. In conclusion, amongst the potential modifiable factors of fatigue, higher protein intake is independently associated with lower risk of moderate and severe fatigue and with better QoL in KTR. These findings underline the need to incorporate nutritional assessment in the diagnostic work-up of fatigue. Intervention studies are needed to assess the benefits and safety of higher protein intake in KTR