Lifestyle intervention to improve quality of life and prevent weight gain after renal transplantation: Design of the Active Care after Transplantation (ACT) randomized controlled trial.

BACKGROUND: Low physical activity and reduced physical functioning are common after renal transplantation, resulting in a reduced quality of life. Another common post-transplantation complication is poor cardio-metabolic health, which plays a main role in long-term outcomes in renal transplant recipients (RTR). It is increasingly recognized that weight gain in the first year after transplantation, especially an increase in fat mass, is a highly common contributor to cardio-metabolic risk. The aim of this study is to compare the outcomes of usual care to the effects of exercise alone, and exercise combined with dietary counseling, on physical functioning, quality of life and post-transplantation weight gain in RTR. METHODS: The Active Care after Transplantation study is a multicenter randomized controlled trial with three arms in which RTR from 3 Dutch hospitals are randomized within the first year after transplantation to usual care, to exercise intervention (3 months supervised exercise 2 times per week followed by 12 months active follow-up), or to an exercise + diet intervention, consisting of the exercise training with additional dietary counseling (12 sessions over 15 months by a renal dietician). In total, 219 participants (73 per group) will be recruited. The primary outcome is the subdomain physical functioning of quality of life, (SF-36 PF). Secondary outcomes include other evaluations of quality of life (SF-36, KDQOL-SF, EQ-5D), objective measures of physical functioning (aerobic capacity and muscle strength), level of physical activity, gain in adiposity (body fat percentage by bio-electrical impedance assessment, BMI, waist circumference), and cardiometabolic risk factors (blood pressure, lipids, glucose metabolism). Furthermore, data on renal function, medical history, medication, psychological factors (motivation, kinesiophobia, coping style), nutrition knowledge, nutrition intake, nutrition status, fatigue, work participation, process evaluation and cost-effectiveness are collected. DISCUSSION: Evidence on the effectiveness of an exercise intervention, or an exercise + diet intervention on physical functioning, weight gain and cardiometabolic health in RTR is currently lacking. The outcomes of the present study may help to guide future evidence-based lifestyle care after renal transplantation. TRIAL REGISTRATION: Number: NCT01047410 .

Causal path analyses of the association of protein intake with risk of mortality and graft failure in renal transplant recipients.

The effect of a low protein intake on survival in renal transplant recipients (RTR) is unknown. A low protein intake may increase risks of malnutrition, low muscle mass, and death. We aimed to study associations of protein intake with mortality and graft failure and to identify potential intermediate factors. Protein intake was estimated from 24-h urinary urea excretion (24-h UUE). Graft failure was defined as return to dialysis or retransplantation. We used Cox regression analyses to analyze associations with outcome and potential intermediate factors in the causal path. In 604 RTR, mean ± SD 24-h UUE was 380 ± 114 mmol/24-h. During median follow-up for 7.0 yr (interquartile range: 6.2-7.5 yr), 133 RTR died and 53 developed graft failure. In univariate analyses, 24-h UUE was associated with lower risk of mortality (HR [95% CI] = 0.80 [0.69-0.94]) and graft failure (HR [95% CI] = 0.72 [0.56-0.92]). These associations were independent of potential confounders. In causal path analyses, the association of 24-h UUE with mortality disappeared after adjustment for muscle mass. Low protein intake is associated with increased risk of mortality and graft failure in RTR. Causal path analyses reveal that the association with mortality is explained by low muscle mass. These findings suggest that protein intake restriction should not be advised to RTR.

Central body fat distribution associates with unfavorable renal hemodynamics independent of body mass index.

Central distribution of body fat is associated with a higher risk of renal disease, but whether it is the distribution pattern or the overall excess weight that underlies this association is not well understood. Here, we studied the association between waist-to-hip ratio (WHR), which reflects central adiposity, and renal hemodynamics in 315 healthy persons with a mean body mass index (BMI) of 24.9 kg/m(2) and a mean (125)I-iothalamate GFR of 109 ml/min per 1.73 m(2). In multivariate analyses, WHR was associated with lower GFR, lower effective renal plasma flow, and higher filtration fraction, even after adjustment for sex, age, mean arterial pressure, and BMI. Multivariate models produced similar results regardless of whether the hemodynamic measures were indexed to body surface area. Thus, these results suggest that central body fat distribution, independent of BMI, is associated with an unfavorable pattern of renal hemodynamic measures that could underlie the increased renal risk reported in observational studies.

The role of diet and physical activity in post-transplant weight gain after renal transplantation.

BACKGROUND: Long-term survival of renal transplant recipients (RTR) has not improved over the past 20 yr. The question rises to what extent lifestyle factors play a role in post-transplant weight gain and its associated risks after transplantation. METHODS: Twenty-six RTR were measured for body weight, body composition, blood lipids, renal function, dietary intake, and physical activity at six wk, and three, six, and 12 months after transplantation. RESULTS: Weight gain ranged between -2.4 kg and 19.5 kg and was largely due to increase in body fat. RTR who remained body fat stable, showed more daily physical activity (p = 0.014), tended to consume less energy from drinks and dairy (p = 0.054), consumed less mono- and disaccharides (sugars) (p = 0.021) and ate more vegetables (p = 0.043) compared with those who gained body fat. Gain in body fat was strongly related to total cholesterol (r = 0.46, p = 0.017) and triglyceride (r = 0.511, p = 0.011) at one yr after transplantation. CONCLUSIONS: Gain in adiposity after renal transplantation is related to lifestyle factors such as high consumption of energy-rich drinks, high intake of mono- and disaccharides and low daily physical activity. RCTs are needed to investigate potential benefits of lifestyle intervention on long-term morbidity and mortality.

Plasma bilirubin and late graft failure in renal transplant recipients.

Exogenous bilirubin has been shown to protect against oxidative stress in ischemia-reperfusion injury. Oxidative stress has been implicated in the pathophysiology of chronic transplant dysfunction leading to late graft failure after renal transplantation. We prospectively investigated whether high endogenous bilirubin is protective against development of late graft failure in renal transplant recipients (RTR). Baseline data were collected between August 2001 and July 2003 in nonicteric outpatient RTR with a functioning graft for >1 year. At baseline, bilirubin and liver enzymes were measured using routine assays on a Merck Mega analyzer. Graft failure was prospectively recorded until May 19 2009. During follow-up for 7.1 [6.2-7.2] years, 55 RTR developed graft failure. We found that circulating levels of bilirubin are inversely associated with late graft failure in RTR (HR = 0.29 [95% CI: 0.16-0.52], P < 0.001). This association was independent of potential confounders, including creatinine clearance, urinary protein excretion, calcineurin inhibitors, and gender (HR = 0.31 [95% CI: 0.15-0.62] P = 0.001). Our findings are consistent with a protective effect of increased endogenous bilirubin against development of late graft failure in RTR. If our findings are confirmed by other studies, intervention with endogenous or exogenous bilirubin may be of interest for long-term preservation of renal function in RTR.

Smoking is a risk factor for graft failure and mortality after renal transplantation.

BACKGROUND: Smoking in renal transplant recipients (RTR) is an acknowledged cardiovascular risk factor. It is, however, unclear whether smoking also increases the risk of graft failure (GF). METHOD: In this study, we prospectively assessed the association of current smoking versus past and never smoking with GF and mortality in 604 RTR (age 51.5 ± 12.1 years, 55% male). RESULTS: At inclusion, 133 (22%) were current smokers, 255 (42%) were past smokers and 216 (36%) never smoked. During follow-up of 5.3 (4.7-5.7) years, 41 (7%) RTR experienced GF and 95 RTR (16%) died. Current smoking RTR had higher risk for GF compared to never smoking RTR (hazard ratio, HR = 3.3, 95% CI 1.5-7.1, p = 0.002). Past smoking RTR had similar risk of GF as never smoking RTR (HR = 1.1, 95% CI 0.5-2.6, p = 0.7). Current smoking RTR and past smoking RTR were at higher risk for death than never smoking RTR (HR = 2.1, 95% CI 1.1-3.8, p = 0.016, and HR = 2.4, 95% CI 1.4-4.0, p = 0.001, respectively). CONCLUSION: Smoking after renal transplantation is associated with risk for GF and mortality. Since past smoking is a risk factor for mortality but not for GF, smoking cessation may be beneficial to RTR in delaying GF in long term.

Latent cytomegalovirus infection is an independent risk factor for late graft failure in renal transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) is a risk factor for rejection and mortality soon after renal transplantation. Little is known about its consequences longer after transplantation. We prospectively investigated whether latent CMV infection is a risk factor for graft failure and mortality long after transplantation. MATERIAL/METHODS: Our study included 606 renal transplant recipients (RTR) with a functioning graft for >1 year. CMV serology was determined using ELISA. RTRs were divided into CMV-seronegative and latent CMV (seropositive + seroconverted). RESULTS: We measured CMV IgG at 6.0 [2.6-11.4] years post-transplant. During follow-up (7.0 [6.2-7.5] years), 54 (9%) RTRs experienced graft failure and 137 (23%) RTRs died. Risk for graft failure and mortality was significantly higher in RTRs with latent CMV compared to CMV-seronegative RTRs (HR=3.1, P=0.005 and HR=2.0, P=0.002, respectively). After adjustment for potential confounders, latent CMV infection remained an independent risk factor for graft failure (HR=4.6, P=0.001), but not for mortality (HR=1.4, P=0.2). CONCLUSIONS: Latent CMV is an independent risk factor for graft failure long after renal transplantation and carries a higher risk for graft failure than for mortality. These findings confirm the notion that latent CMV can be harmful in transplanted kidneys.

Liver Enzymes and the Development of Posttransplantation Diabetes Mellitus in Renal Transplant Recipients.

BACKGROUND: Posttransplantation diabetes mellitus (PTDM) is common in renal transplant recipients (RTR), increasing the risk of graft failure, cardiovascular disease, and mortality. Early detection of a high risk for PTDM is warranted. Because liver function and liver fat are involved, we investigated whether serum liver markers are associated with future PTDM in RTR. METHODS: Between 2001 and 2003, 606 RTR with a functioning allograft beyond the first year after transplantation were included of which 500 participants (56% men; age, 50 ± 12 years) were free of diabetes at baseline and had liver enzyme values (1 missing) available. Serum concentrations of alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase were measured at baseline at 6.0 (6.2-11.5) years posttransplantation. PTDM cases were recorded until April 2012. RESULTS: During median follow-up for 9.6 years (interquartile range [IQR], 6.2-10.2) beyond baseline, 76 (15.2%) patients developed PTDM. Comparing the highest to the lower tertiles, higher liver enzyme activities were significantly related to incident PTDM for ALT (hazard ratio [HR], 2.22; IQR, 1.42-3.48), for GGT (HR, 2.93; IQR, 1.87-4.61), and for alkaline phosphatase (HR, 1.78; IQR, 1.13-2.80). The associations of ALT and GGT with development of PTDM were independent of potential confounders and risk factors, including age, sex, renal function, medication use, lifestyle factors, adiposity, presence of the metabolic syndrome, fasting glucose, HbA1c, proinsulin, and cytomegalovirus status. CONCLUSIONS: Markers for liver function and liver fat in the subclinical range are potential markers for future PTDM, independent of other known risk factors. This may allow for early detection and management of PTDM development.

Physical inactivity: a risk factor and target for intervention in renal care.

Regular physical activity is associated with an increased quality of life and reduced morbidity and mortality in the general population and in patients with chronic kidney disease (CKD). Physical activity, cardiorespiratory fitness, and muscle mass decrease even in the early stages of CKD, and continue to decrease with disease progression; notably, full recovery is generally not achieved with transplantation. The combined effects of uraemia and physical inactivity drive the loss of muscle mass. Regular physical activity benefits cardiometabolic, neuromuscular and cognitive function across all stages of CKD, and therefore provides an approach to address the multimorbidity of the CKD population. Interestingly, maintenance of muscle health is associated with renoprotective effects. Despite evidence of its benefits, physical activity and exercise management are not routinely addressed in the care of these patients. Although studies defining the optimum frequency, duration and intensity of physical activity are lacking, evidence from related fields can guide practical approaches to the care of patients with renal disease. Optimization of metabolic and nutritional status alongside promotion of physical activity is recommended. Behavioural approaches are now recognized as crucial in helping patients to adopt lifestyle changes and might prove valuable in integrating physical activity into renal care.

High Serum PCSK9 Is Associated With Increased Risk of New-Onset Diabetes After Transplantation in Renal Transplant Recipients.

OBJECTIVE: New-onset diabetes after transplantation (NODAT) is a major complication in renal transplant recipients (RTRs). Cholesterol metabolism has been linked to diabetes development. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is crucial in LDL receptor regulation. Its association with NODAT is unknown. We prospectively determined the association between serum PCSK9 levels and NODAT development and then with all-cause mortality, cardiovascular mortality, and renal graft failure. RESEARCH DESIGN AND METHODS: In a university setting, nondiabetic RTRs recruited between 2001 and 2003 with a functional graft for ≥1 year were eligible. Serum PCSK9 was measured by ELISA. Cox proportional hazards analysis was used to assess the association of PCSK9 with the development of NODAT, all-cause mortality, cardiovascular mortality, and graft failure. RESULTS: In 453 RTRs (age 51 ± 12 years, 56% male; 6.1 [2.7-11.7] years after transplantation), serum PCSK9 was 107.1 ± 43.4 µg/L. During a median follow-up of 10 years, 70 RTRs developed NODAT, 123 died, and 59 developed graft failure. NODAT occurred more frequently in the upper PCSK9 tertile (23%) versus the lowest two PCSK9 tertiles (12%; P < 0.001). In crude Cox regression analyses, PCSK9 was significantly associated with development of NODAT (hazard ratio 1.34 [95% CI 1.10-1.63]) per SD change (P = 0.004). This association remained independent of adjustment for potential confounders, including statin use. PCSK9 was not associated with all-cause mortality, cardiovascular mortality, or graft failure. CONCLUSIONS: Circulating PCSK9 is associated with NODAT in RTRs. The PCSK9 pathway may contribute to the pathogenesis of NODAT.

Vitamin C Depletion and All-Cause Mortality in Renal Transplant Recipients.

Vitamin C may reduce inflammation and is inversely associated with mortality in the general population. We investigated the association of plasma vitamin C with all-cause mortality in renal transplant recipients (RTR); and whether this association would be mediated by inflammatory biomarkers. Vitamin C, high sensitive C-reactive protein (hs-CRP), soluble intercellular cell adhesion molecule 1 (sICAM-1), and soluble vascular cell adhesion molecule 1 (sVCAM-1) were measured in a cohort of 598 RTR. Cox regression analyses were used to analyze the association between vitamin C depletion (≤28 µmol/L; 22% of RTR) and mortality. Mediation analyses were performed according to Preacher and Hayes's procedure. At a median follow-up of 7.0 (6.2-7.5) years, 131 (21%) patients died. Vitamin C depletion was univariately associated with almost two-fold higher risk of mortality (Hazard ratio (HR) 1.95; 95% confidence interval (95%CI) 1.35-2.81, p < 0.001). This association remained independent of potential confounders (HR 1.74; 95%CI 1.18-2.57, p = 0.005). Hs-CRP, sICAM-1, sVCAM-1 and a composite score of inflammatory biomarkers mediated 16, 17, 15, and 32% of the association, respectively. Vitamin C depletion is frequent and independently associated with almost two-fold higher risk of mortality in RTR. It may be hypothesized that the beneficial effect of vitamin C at least partly occurs through decreasing inflammation.

Fear of Movement and Low Self-Efficacy Are Important Barriers in Physical Activity after Renal Transplantation.

BACKGROUND: Physical activity (PA) and exercise are commonly used as preventive measures for cardiovascular disease in the general population, and could be effective in the management of post-transplantation cardiovascular risk. PA levels are low after renal transplantation and very few renal transplant recipients (RTR) meet the PA guidelines. Identification of barriers to regular PA is important to identify targets for intervention to improve PA levels after renal transplantation. We investigated fear of movement and physical self-efficacy as barriers to PA in RTR. METHODS: RTR were investigated between 2001-2003. The Tampa Score of Kinesiophobia-Dutch Version (TSK-11) was used to assess fear of movement. Physical self-efficacy was measured with the LIVAS-scale. PA was assessed using validated questionnaires (Tecumseh Occupational Activity Questionnaire and the Minnesota Leisure Time Physical Activity Questionnaire). RESULTS: A total of 487 RTR (age 51±12 years, 55% men) were studied. Median score [interquartile range] on TSK-11 was 22 [17-26]. Low physical self-efficacy (Exp B:0.41[0.31-0.54], p<0.001) and history of myocardial infarction, transient ischemic attack and cerebrovascular accident (Exp B:1.30[1.03-1.63],p = 0.03) were independent determinants for fear of movement. Fear of movement was associated with lower daily PA, occupational, sports and leisure time PA. Mediation-analysis showed that a large part (73%) of the effect of fear of movement on PA was explained by low physical self-efficacy. CONCLUSIONS: This study was the first to examine fear of movement and self-efficacy in relation to PA in RTR. Fear of movement was associated with a low PA level, and the larger part of this relation was mediated by low physical self-efficacy. Both fear of movement and physical self-efficacy level are important targets for intervention during rehabilitation after renal transplantation.

Pancreatic ß-cell dysfunction and risk of new-onset diabetes after kidney transplantation.

OBJECTIVE: Chronic exposure to calcineurin inhibitors and corticosteroids poses renal transplant recipients (RTR) at high risk for development of new-onset diabetes after transplantation (NODAT). Pancreatic ß-cell dysfunction may be crucial to the pathophysiology of NODAT and specific markers for ß-cell dysfunction may have additive value for predicting NODAT in this population. Therefore, we prospectively investigated whether proinsulin, as a marker of pancreatic ß-cell dysfunction, is associated with future development of NODAT and improves prediction of it. RESEARCH DESIGN AND METHODS: All RTR between 2001 and 2003 with a functioning graft for ≥1 year were considered eligible for inclusion, except for subjects with diabetes at baseline who were excluded. We recorded incidence of NODAT until April 2012. RESULTS: A total of 487 RTR (age 50 ± 12 years, 55% men) participated at a median time of 6.0 (interquartile range [IQR], 2.6-11.5) years after transplantation. Median fasting proinsulin levels were 16.6 (IQR, 11.0-24.2) pmol/L. During median follow-up for 10.1 (IQR, 9.1-10.4) years, 42 (35%) RTR had development of NODAT in the highest quartile of the distribution of proinsulin versus 34 (9%) in the lowest three quartiles (P < 0.001). In Cox regression analyses, proinsulin (hazard ratio, 2.29; 95% CI, 1.85-2.83; P < 0.001) was strongly associated with NODAT development. This was independent of age, sex, calcineurine inhibitors, prednisolone use, components of the metabolic syndrome, or homeostasis model assessment. CONCLUSIONS: In conclusion, fasting proinsulin is strongly associated with NODAT development in RTR. Our results highlight the role of ß-cell dysfunction in the pathophysiology of NODAT and indicate the potential value of proinsulin for identification of RTR at increased risk for NODAT.

Impact of depression on long-term outcome after renal transplantation: a prospective cohort study.

BACKGROUND: Renal transplantation is the treatment of choice for end stage renal disease. Although there is more depression in wait-listed versus transplant patients, depression persists after transplantation. We investigated the determinants of depression in renal transplantation recipients (RTRs) and the association with cardiovascular (CV) and all-cause-mortality and graft failure. METHODS: RTR were investigated between 2001 and 2003. Depression was assessed using the Depression Subscale of the Symptom Checklist (SCL-90). Mortality and graft failure were recorded until May 2009. RESULTS: A total of 527 RTR (age, 51±12 years; 55% men) were studied; 31% of the RTR were indicated with depression. Independent variables associated with depression were medically unfit for work, proteinuria, lower physical activity level, and longer dialysis duration. During follow-up for 7.0 (6.2-7.5) years, 114 RTR (59 CV) died. In Cox regression analyses, depression was strongly associated with increased risk for CV (HR=2.12 [1.27-3.53], P=0.004) and all-cause mortality (HR=1.96 [1.36-2.84], P<0.001). Adjustments for confounders did not materially change these associations. The association with graft failure (HR=1.77 [1.01-3.10]. P=0.047) disappeared after adjustment for kidney function (P=0.6). CONCLUSIONS: Although our study has several limitations, including the lack of pretransplant depression status, we identified medically unfit for work, proteinuria, lower physical activity level, and longer dialysis duration as independent variables associated with depression. We furthermore found that depression is associated with CV and all-cause mortality in RTR.

Alcohol consumption, new onset of diabetes after transplantation, and all-cause mortality in renal transplant recipients.

BACKGROUND: Renal transplant recipients (RTR) are often advised to refrain from alcohol because of possible interaction with their immunosuppressive medication. Although moderate alcohol consumption is associated with reduced risk of diabetes and mortality in the general population, this is unknown for RTR. Therefore, we investigated the association of alcohol consumption with new onset of diabetes after transplantation (NODAT), mortality, and graft failure in RTR. METHOD: RTR were investigated between 2001 and 2003. Alcohol consumption was assessed by self-report. Mortality and graft failure was recorded until May 2009. RESULTS: Six hundred RTR were studied (age 51 ± 12 years, 55% men). Of these RTR, 48% were abstainers, 38% had light alcohol intake, 13% had moderate intake, and 1% were heavy consumers. Moderate alcohol consumption was associated with a lower risk of developing NODAT over the follow-up period than was abstention (OR = 0.36 [0.2-0.6], P = <0.001). During follow-up for 7.0 years [6.2-7.5 years], 133 recipients died. In Cox regression analyses, moderate alcohol consumption was associated with lower mortality period than was abstention (hazard ratio = 0.40 [0.2-0.8], P = 0.009). Adjustment for confounders, including age and smoking, did not materially change this association. No association was found between alcohol consumption and graft failure. CONCLUSIONS: Moderate alcohol consumption is associated with low prevalence of NODAT and reduced risk for mortality in RTR, in line with findings in the general population. These findings refute the common advice to refrain from alcohol in RTR.

Low physical activity and risk of cardiovascular and all-cause mortality in renal transplant recipients.

BACKGROUND AND OBJECTIVES: 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. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 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. RESULTS: 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. CONCLUSIONS: 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.

Influence of C-reactive protein and urinary protein excretion on prediction of graft failure and mortality by serum albumin in renal transplant recipients.

BACKGROUND: Hypoalbuminemia is an established predictor of poor outcome in renal transplant recipients (RTR). It is considered to reflect inflammation, poor nutritional status, or proteinuria. We explored the roles of high-sensitivity C-reactive protein (hsCRP) and urinary protein excretion in prediction of graft failure and mortality by serum albumin in RTR. METHODS: We included 605 RTR at a median (interquartile range) time of 6.0 years (2.5-11.5 years) after transplantation for baseline measurements. RESULTS: At baseline, urinary protein excretion (beta=-0.242, P<0.0001), hsCRP concentration (beta=-0.207, P<0.0001), recipient age (beta=-0.115, P=0.004), living kidney donor (beta=0.100, P=0.01), and a history of myocardial infarction (beta=-0.084, P=0.03) were independently related to serum albumin. Prospectively, 94 RTR died and 42 had graft failure during 5.3 years (4.7-5.7 years) of follow-up. After adjustment for potential confounders, including hsCRP and urinary protein excretion in Cox-regression analyses, low serum albumin was significantly associated with graft failure (hazard ratio=0.34 [95% confidence interval=0.15-0.76] per g/dL, P=0.008) and mortality (hazard ratio=0.43 [95% confidence interval=0.24-0.78] per g/dL, P=0.005), with significant modification of the effect of serum albumin on graft failure by urinary protein excretion (P=0.003). CONCLUSION: Low serum albumin concentrations predict graft failure and mortality in RTR independent of hsCRP and urinary protein excretion. The effect of serum albumin on graft failure is strongly modified by urinary protein excretion. These results suggest that chronic low-grade inflammation is not an important mechanism underlying inverse associations of serum albumin with graft failure and mortality. They also suggest that proteinuria is involved in the association of low serum albumin with graft failure.