Akos Ujszaszi

Elevated Fibroblast Growth Factor 23 is a Risk Factor for Kidney Transplant Loss and Mortality

An increased circulating level of fibroblast growth factor 23 (FGF23) is an independent risk factor for mortality, cardiovascular disease, and progression of chronic kidney disease (CKD), but its role in transplant allograft and patient survival is unknown. We tested the hypothesis that increased FGF23 is an independent risk factor for all-cause mortality and allograft loss in a prospective cohort of 984 stable kidney transplant recipients. At enrollment, estimated GFR (eGFR) was 51 ± 21 ml/min per 1.73 m(2) and median C-terminal FGF23 was 28 RU/ml (interquartile range, 20 to 43 RU/ml). Higher FGF23 levels independently associated with increased risk of the composite outcome of all-cause mortality and allograft loss (full model hazard ratio: 1.46 per SD increase in logFGF23, 95% confidence interval: 1.28 to 1.68, P<0.001). The results were similar for each component of the composite outcome and in all sensitivity analyses, including prespecified analyses of patients with baseline eGFR of 30 to 90 ml/min per 1.73 m(2). In contrast, other measures of phosphorus metabolism, including serum phosphate and parathyroid hormone (PTH) levels, did not consistently associate with outcomes. We conclude that a high (or elevated) FGF23 is an independent risk factor for death and allograft loss in kidney transplant recipients.

Body mass index, waist circumference and mortality in kidney transplant recipients.

Higher body mass index (BMI) appears paradoxically associated with better outcomes in patients with chronic kidney disease. Whereas higher BMI reflects both increased visceral and subcutaneous fat and/or muscle mass, a combined assessment of BMI and waist circumference may enable differentiation of visceral adiposity from muscle and/or nonvisceral fat mass. We examined the association of BMI and waist circumference with all‐cause mortality in a prospective cohort of 993 kidney transplant recipients. Associations were examined in Cox models with adjustment for demographic and comorbid conditions and for inflammatory markers. Unadjusted death hazard ratios (95%CI) associated with one standard deviation higher BMI and waist circumference were 0.94 (0.78, 1.13), p = 0.5 and 1.20 (1.00, 1.45), p = 0.05, respectively. Higher BMI was associated with lower mortality after adjustment for waist circumference (0.48 [0.34, 0.69], p < 0.001), and higher waist circumference was more strongly associated with higher mortality after adjustment for BMI (2.18 [1.55–3.08], p < 0.001). The associations of waist circumference with mortality remained significant after additional multivariable adjustments. Higher BMI and waist circumference display opposite associations with mortality in kidney transplant recipients. Waist circumference appears to be a better prognostic marker for obesity than BMI.

ASSOCIATION OF THE MALNUTRITION-INFLAMMATION SCORE WITH CLINICAL OUTCOMES IN KIDNEY TRANSPLANT RECIPIENTS

BACKGROUND The combination of chronic malnutrition and inflammation, often termed malnutrition-inflammation complex syndrome or protein-energy wasting, is common in patients with chronic kidney disease. It is associated with increased mortality in patients on maintenance dialysis therapy. We assessed the association of malnutrition-inflammation score (MIS) with all-cause mortality and death-censored transplant loss or death with a functioning transplant in a sample of kidney transplant recipients. STUDY DESIGN Prospective prevalent cohort study. SETTING & PARTICIPANTS Data from 993 prevalent transplant recipients were analyzed. Sociodemographic parameters, laboratory data, medical and transplant history, comorbid conditions, estimated glomerular filtration rate, and MIS were tabulated at baseline and annually thereafter. PREDICTOR MIS, a 30-point scale expressed per 1 standard deviation (1 SD) unit or categorized as <3 (reference), 3-5, 6-8, and >8. The MIS is derived from 10 components, each with 4 levels of severity from 0 (normal) to 3 (severely abnormal). Higher score reflects more severe degree of malnutrition and inflammation status. OUTCOMES All-cause mortality and death-censored transplant loss or death with a functioning transplant. Association of MIS with total mortality was assessed using time-dependent Cox regression analysis, and the association of MIS with death-censored transplant loss or death with a functioning transplant was assessed using semiparametric competing-risks regression analysis. RESULTS Mean age was 51 ± 13 years, 57% of patients were men, and 21% had diabetes. Percentages of patients in the MIS categories <3, 3-5, 6-8, and >8 were 40%, 32%, 20%, and 8%, respectively. In multivariable time-dependent Cox regression analyses, time-varying MIS score was a significant predictor of all-cause mortality (HR per 1-SD increase, 1.59; 95% CI, 1.37-1.85), death with a functioning transplant (HR per 1-SD increase, 1.48; 95% CI, 1.23-1.78), and death-censored transplant loss (HR per 1-SD increase, 1.34; 95% CI, 1.04-1.71). Compared with MIS <3, HRs for all-cause mortality for MIS of 3-5, 6-8, and >8 were 1.53 (95% CI, 0.74-3.15), 3.66 (95% CI, 1.87-7.14), and 6.82 (95% CI, 3.34-13.91), respectively. LIMITATIONS Single-center study, small number of outcomes. CONCLUSIONS The MIS, a simple tool to assess the presence of malnutrition-inflammation complex syndrome, predicts mortality in kidney transplant recipients.

Evaluation of the Malnutrition-Inflammation Score in Kidney Transplant Recipients

BACKGROUND Chronic protein-energy wasting, termed malnutrition-inflammation complex syndrome, is frequent in patients with chronic kidney disease and is associated with anemia, morbidity, and mortality in patients on maintenance dialysis therapy. The Malnutrition-Inflammation Score (MIS) recently has been developed and validated in dialysis patients. STUDY DESIGN Observational cross-sectional study. SETTING & PARTICIPANTS 993 prevalent kidney transplant recipients. PREDICTOR MIS computed from change in body weight, dietary intake, gastrointestinal symptoms, functional capacity, comorbid conditions, decreased fat store/Systemic Global Assessment, signs of muscle wasting/Systemic Global Assessment, body mass index, serum albumin level, and serum transferrin level. OUTCOMES Markers of inflammation and malnutrition, including serum C-reactive protein, interleukin 6, tumor necrosis factor alpha, serum leptin, prealbumin, body mass index, and abdominal circumference. The relationship was modeled by using structural equation models. RESULTS Mean age was 51 +/- 13 years, 57% were men, and 21% had diabetes. Median time from transplant was 72 months. MIS significantly correlated with abdominal circumference (r = -0.144), serum C-reactive protein level (r = 0.094), serum interleukin 6 level (r = 0.231), and serum tumor necrosis factor alpha level (r = 0.102; P < 0.01 for all). A structural equation model with 2 latent variables (malnutrition and inflammation factor) showed good fit to the observed data. LIMITATIONS Single-center study, lack of information about vascular access, presence of nonfunctioning kidney transplant, relatively high refusal rate. CONCLUSIONS Our results confirm that MIS reflects both energy-protein wasting and inflammation in kidney transplant recipients. This simple instrument appears to be a useful tool to assess the presence of protein-energy wasting in this patient population.

Association between the malnutrition-inflammation score and post-transplant anaemia

BACKGROUND Post-transplant anaemia (PTA) is common and is associated with adverse consequences. The protein-energy wasting (PEW) syndrome is associated with erythropoietin resistance in patients on maintenance dialysis. We assessed the association between PEW and PTA in a large prevalent cohort of stable kidney-transplanted patients. METHODS Data from 942 prevalent kidney-transplanted patients were analysed. Socio-demographic parameters, laboratory results, transplantation-related data and medication were obtained from the charts. Biomarkers reflecting nutritional status and inflammation [serum leptin, albumin, interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and C-reactive protein] were measured. Anthropometric measures and the malnutrition-inflammation score (MIS) were also tabulated. Anaemia was defined according to the guidelines of the American Society of Transplantation. RESULTS Mean age was 51 ± 13 years, 57% were males and 22% had diabetes. The prevalence of PTA was 33%. The haemoglobin (Hb) level significantly and negatively correlated with the MIS (rho = - 0.316), marginally with serum TNF-α (rho = - 0.079) and serum IL-6 (rho = - 0.075) and positively with serum transferrin (r = 0.298), serum albumin (r = 0.274), abdominal circumference (r = 0.254) and serum leptin (rho = - 0.152), P < 0.05 for all. In a multivariable linear regression model, MIS was independently associated with Hb (beta = - 0.118, P = 0.004) in patients with estimated glomerular filtration rate (eGFR) lower than or equal to 60 mL/min/1.73 m(2), but not in patients with higher eGFR. CONCLUSIONS The MIS is independently associated with PTA in the kidney-transplanted population with eGFR lower than or equal to 60 mL/min/1.73 m(2).

Renal function is independently associated with red cell distribution width in kidney transplant recipients: a potential new auxiliary parameter for the clinical evaluation of patients with chronic kidney disease

Red cell distribution width (RDW), a measure of heterogeneity in the size of circulating erythrocytes, reportedly predicts mortality. Similarly to RDW, impaired renal function is also associated with inflammation and protein‐energy wasting. This study assessed if renal function is associated with RDW independent of relevant confounders in stable kidney transplant recipients. We examined the association between RDW and estimated glomerular filtration rate (eGFR) in a cohort of 723 prevalent kidney transplanted recipients who were not receiving erythropoietin‐stimulating agents. Associations were examined in regression models adjusted for age, sex, comorbidity, blood haemoglobin, iron indices, markers of nutritional status and inflammation, markers of bone and mineral metabolism and the use of immune suppressants. Lower eGFR was significantly associated with higher RDW (r = −0·382, P < 0·001). This association remained highly significant even after multivariate adjustments where 10 ml/min decrease in the eGFR was significantly associated with an increase of the RDW values (B10 ml/min decrease = 0·078; 95% confidence interval: 0·044–0·111). The results were consistent in subgroups of patients with different levels of haemoglobin, chronic kidney disease status and various markers of inflammation and iron status. Lower eGFR is associated with higher RDW, independent of comorbidity, iron deficiency, inflammation and nutritional status in kidney transplant recipients.

Associations between serum leptin level and bone turnover in kidney transplant recipients

BACKGROUND AND OBJECTIVES Obesity is associated with increased parathyroid hormone (PTH) in the general population and in patients with chronic kidney disease (CKD). A direct effect of adipose tissue on bone turnover through leptin production has been suggested, but such an association has not been explored in kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study examined associations of serum leptin with PTH and with biomarkers of bone turnover (serum beta crosslaps [CTX, a marker of bone resorption] and osteocalcin [OC, a marker of bone formation]) in 978 kidney transplant recipients. Associations were examined in multivariable regression models. Path analyses were used to determine if the association of leptin with bone turnover is independent of PTH. RESULTS Higher leptin levels were associated with higher PTH and lower vitamin D levels, and adjustment for vitamin D attenuated the association between leptin and PTH. However, higher leptin was also significantly associated with lower levels of the bone turnover markers: 1 SD higher leptin was associated with 0.13 lower log-OC (-0.17, -0.08, P < 0.001) and 0.030 lower log-CTX (-0.045, -0.016, P < 0.001) after multivariable adjustments. Path analysis indicated that the association of leptin with PTH was mostly mediated through vitamin D, and that the association between leptin and bone turnover was independent of PTH and vitamin D. CONCLUSIONS Elevated leptin level is associated with lower bone turnover independent of its effects on serum PTH in kidney transplant recipients.

Association of Serum Phosphorus Level With Anemia in Kidney Transplant Recipients

Background. Anemia and mineral and bone disorders (MBD) are both important and common complications in kidney transplant recipients. Studies in patients with chronic kidney disease indicated a possible independent association of higher serum phosphorus with anemia, but similar associations have not been examined in kidney transplant recipients. We hypothesized that higher serum phosphorus is associated with anemia independent of other components of MBD. Methods. We examined the association of serum phosphorus with hemoglobin level and the prevalence of anemia in a prevalent cohort of 992 kidney transplant recipients in a single outpatient transplant center. Associations were examined in linear and logistic regression models with adjustment for demographic and comorbid conditions for various known risk factors of anemia, including measures of iron deficiency, inflammation, and components of MBD including serum levels of 25(OH) vitamin D, parathyroid hormone, and fibroblast growth factor 23. Results. In multivariable adjusted regression models, a 1 standard deviation (0.8 mg/dL) higher serum phosphorus level was associated with 0.26 g/dL lower blood hemoglobin concentration (95% confidence intervals −0.36 to −0.15, P<0.001) and with an odds ratio for anemia of 1.77 (95% confidence intervals 1.33–2.37, P<0.001). These associations were consistent across the entire spectrum of the physiologic serum phosphorus concentration and were more accentuated in patients with lower estimated glomerular filtration rate. Conclusions. Higher serum phosphorus is independently associated with anemia in kidney transplant recipients.

Association between lunar phase and sleep characteristics.

OBJECTIVES Popular belief holds that the lunar cycle affects human physiology, behavior, and health, including sleep. To date, only a few and conflicting analyses have been published about the association between lunar phases and sleep. Our aim was to analyze the relationship between lunar phases and sleep characteristics. METHODS In this retrospective, cross-sectional analysis, data from 319 patients who had been referred for sleep study were included. Individuals with apnea-hypopnea index ≥ 15/h were excluded. Socio-demographic parameters were recorded. All participants underwent one-night standard polysomnography. Associations between lunar cycle (new moon, full moon and alternate moon) and sleep parameters were examined in unadjusted and adjusted models. RESULTS Fifty-seven percent of patients were males. Mean age for men was 45 ± 14 years and 51 ± 12 years for women. In total, 224 persons had their sleep study done during alternate moon, 47 during full moon, and 48 during new moon. Full moon was associated with lower sleep efficiency [median (%) (IQR): new moon 82 (18), full moon 74 (19), alternate moon 82 (15); P < 0.001], less deep sleep [median (%) (IQR): new moon 9 (9), full moon 6 (4), alternate moon 11 (9); P < 0.001], and increased REM latency [median (min) (IQR): new moon 98 (74), full moon 137 (152), alternate moon 97 (76); P < 0.001], even after adjustment for several covariables. CONCLUSION The results are consistent with a recent report and the widely held belief that sleep characteristics may be associated with the full moon.

Serum erythropoietin level and mortality in kidney transplant recipients

BACKGROUND AND OBJECTIVES Posttransplant anemia is frequently reported in kidney transplant recipients and is associated with worsened patient survival. Similar to high erythropoiesis-stimulating agent requirements, resistance to endogenous erythropoietin may be associated with worse clinical outcomes in patients with ESRD. We examined the association between serum erythropoietin levels and mortality among kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We collected sociodemographic, clinical, medical, and transplant history and laboratory data at baseline in 886 prevalent kidney transplant recipients (mean age 51 ± 13 [SD] years, 60% men, 21% diabetics). A solid-phase chemiluminescent immunometric assay was used to measure serum erythropoietin. Cox proportional hazards regression was used to model the association between baseline serum erythropoietin levels and all-cause mortality risk. RESULTS During the median 39-month follow-up, 99 subjects died. The median serum erythropoietin level was 10.85 U/L and hemoglobin was 137 ± 16 g/L. Mortality rates were significantly higher in patients with higher erythropoietin levels (crude mortality rates in the highest to lowest erythropoietin tertiles were 51.7, 35.5, and 24.0 per 1000 patient-years, respectively [P = 0.008]). In unadjusted and also in adjusted Cox models each SD higher serum erythropoietin level significantly predicted all-cause mortality: HR(1SD increase) 1.22 and 1.28, respectively. In adjusted Cox models each SD higher serum erythropoietin/blood hemoglobin ratio also significantly predicted all-cause mortality: HR(1SD increase) 1.32. Serum erythropoietin predicted mortality in all analyzed subgroups. CONCLUSIONS In this sample of prevalent kidney transplant recipients, higher serum erythropoietin levels were associated with increased mortality.