CLINICAL KIDNEY JOURNAL
Clinical Kidney Journal, 2016, vol. 9, no. 3, 359–373 doi: 10.1093/ckj/sfv156 Advance Access Publication Date: 15 March 2016 CKJ Review
CKJ REVIEW
Adipocytokines in renal transplant recipients Kristof Nagy1, Shankar Prasad Nagaraju2, Connie M. Rhee3, Zoltan Mathe1 and Miklos Z. Molnar4 1
Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary, 2Department of Nephrology, Kasturba Medical College, Manipal University, Manipal, India, 3Harold Simmons Center for Chronic Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of California Irvine, Orange, CA, USA and 4Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
Correspondence to: Miklos Z. Molnar; E-mail: [email protected]
Abstract In the last two decades, perceptions about the role of body fat have changed. Adipocytes modulate endocrine and immune homeostasis by synthesizing hundreds of hormones, known as adipocytokines. Many studies have been investigating the influences and effects of these adipocytokines and suggest that they are modulated by the nutritional and immunologic milieu. Kidney transplant recipients (KTRs) are a unique and relevant population in which the function of adipocytokines can be examined, given their altered nutritional and immune status and subsequent dysregulation of adipocytokine metabolism. In this review, we summarize the recent findings about four specific adipocytokines and their respective roles in KTRs. We decided to evaluate the most widely described adipocytokines, including leptin, adiponectin, visfatin and resistin. Increasing evidence suggests that these adipocytokines may lead to cardiovascular events and metabolic changes in the general population and may also increase mortality and graft loss rate in KTRs. In addition, we present findings on the interrelationship between serum adipocytokine levels and nutritional and immunologic status, and mechanisms by which adipocytokines modulate morbidity and outcomes in KTRs. Key words: adiponectin, kidney transplantation, leptin, resistin, visfatin
Introduction of adipocytokines In healthy individuals, the role of adipocytokines on various outcomes has been widely studied. However, little is known about how impaired kidney function and renal replacement therapy modify these associations [1]. For example, few studies have examined the impact of adipocytokines on long-term outcomes, such as graft loss and death, in kidney transplant recipients (KTRs). In Table 1, we summarize all studies investigating the role of adipocytokines in KTR and chronic kidney disease (CKD) patients.
Leptin was first described as a biomarker of obesity two decades ago; it is a 16-kDa peptide product of the obese gene predominantly secreted by white adipose tissue with the primary function of modulating hunger and satiety [72, 73]. Leptin crosses the blood–brain barrier and inhibits neuropeptide Y neurons. I also activates the sympathetic neuron system in the hypothalamus and increases circulating sympathetic hormone levels [74–76]. Leptin acts upon the Ob leptin receptors and activates tyrosine kinase and intracellular pathways [72, 75]. Leptin’s counterpart is adiponectin, which negatively correlates with nutritional parameters, suggesting that higher
Received: November 2, 2015. Accepted: December 18, 2015 © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]
359
CLINICAL KIDNEY JOURNAL
Number of patients
RRT
Findings
Positive correlations
Leptin seems to increase bone mass. Leptin has an effect on lymphoid stem cells. Imbalance between leptin and body weight also persists after renal transplantation Pretransplant leptin levels reduced after transplantation Leptin levels are independently determined by graft function Leptin shows correlation with gender, BMI, insulin and cortisol levels Pretransplant leptin levels reduced after transplantation and was not effected by alimentary intake Pretransplant leptin levels reduced after transplantation Elevated leptin levels not only modulated by BMI Leptin lowers the bone turnover independently from PTH Pretransplant leptin levels reduced after transplantation Leptin correlates with metabolic syndrome
BMI, BMD, z score of BMD CD34/7
(A) Leptin Agras et al. (2005) [2] Agras et al. (2006) [3] Baczkowsk et al. (2000) [4]
41 63 28
Tx. Tx. Tx.
El Haggan et al. (2004) [5] Fonseca et al. (2015) [6] Kagan et al. (2002) [7]
41 40 24
Tx. Tx. Tx.
Kayacan et al. (2003) [8]
34
Tx.
Kokot et al. (1998) [9] Kokot et al. (1999) [10] Kovesdy et al. (2010) [11] Landt et al. (1998) [12] Lee et al. (2010) [13]
40 nd. 978 29 55
Tx Tx Tx Tx Tx.
Lee et al. (2014) [14]
74
Tx.
Malyszko et al. (2005) [15]
27
Tx.
Nicoletto et al. (2012) [16] Rafieian-Kopaei et al. (2013) [17] Souza et al. (2007) [18] (B) Adiponectin Adamczak et al. (2007) [19]
32 72
Tx. Tx
32
Tx.
228
Tx
Adamczak et al. (2011) [20] Alam et al. (2012) [21]
88 987
Tx Tx
Bayes et al. (2007) [22] Bayes et al. (2005) [23]
68 199
Tx Tx
Canas et al. (2012) [24] Chitalia et al. (2010) [25]
157 43
Tx Tx
Atorvastatin therapy did not modulate ADPN levels ADPN were lower, BMI higher in patients who developed NODAT ADPN has an inverse association with insulin resistance ADPN levels do not predict the CV risk in RTR
Chudek et al. (2003) [26] Chudek et al. (2013) [27] Fonseca et al. (2015) [6] Ho et al. (2015) [28]
44 372 40 69
HD/Tx Tx Tx Tx
Kidney plays an important role in biodegradation of ADPN ACE I/D polymorphism modulates ADPN levels ADPN level is not only modified by early graft function ADPN has negative correlation with arterial stiffness
Leptin was positively associated with peripheral arterial stiffness among renal transplant recipients Leptin is associated with graft function, but not related to BMD and bone metabolism Pretransplant leptin levels reduced after transplantation Leptin levels and duration of kidney transplant shows strong negative correlation Pretransplant leptin levels reduced after transplantation
Negative correlations Lack of correlations
CD34/7/8/4 Cortisol, BMI
Fat mass, CRP Male, DGF Gender, BMI, cortisol, insulin HOMA, fat mass BMI BMI PTH BMI MetSy, waistCX, BMI, fat mass, CRP
Dietary intake Acute rejection
Age vitD Gender
Body mass/fat, creatinine Gender, BF, HOMA Gender
Nutrition, BMD
Duration of kidney Tx
HOMA, fat mass
ADPN levels are higher in RTR than in healthy controls, but lower than in HD patients Role of ADPN in LVH and atherosclerosis cannot be confirmed Elevated levels of ADPN increase mortality
Age, BMI, creatinine GFR
BMI, GFR, HOMA-IR
HDL TNF, BMI, PAPP-A
hsCRP
Female, ACE II genotype Male, DGF
GFR, BMI, abd.circ., CRP HOMA-IR, creatinin Insulin HOMA-R, c-IMT GFR, BMI, Hgb, waist circumference HOMA-IR BMI
CCI
Age, sex
BP, smoking, lipids, DM
Acute rejection DM, smoking, BMI, waist CX, BP, arterial stiffness
| K. Nagy et al.
Author (year)
360
Table 1. Studies evaluating adipocytokines in renal transplant recipients and patients with CKD
CLINICAL KIDNEY JOURNAL
Table 1. Continued
Author (year)
Number of patients
RRT
Findings ADPN level decreases after transplantation and does not predict NODAT Hypoadiponectinemia associated with CVD
Tx
Kaisar et al. (2009) [30]
137
Tx
Kang et al. (2012) [31]
575
Tx
Kulshrestha et al. (2013) [32]
74
Tx
Lee et al. (2011) [33]
55
Tx
Leibowitz et al. (2013) [34]
35
Tx
Malyszko et al. (2005) [35]
82
Tx
Nicoletto et al. (2013) [36] Nishimura et al. (2009) [37]
270 98
Tx Tx
Prasad et al. (2012) [38] Roos et al. (2012) [39] Sethna et al. (2009) [40] Shen et al. (2007) [41]
129 206 33 54
Tx Tx Tx Tx
Shu et al. (2012) [42]
271
Tx
67
Tx
Teplan et al. (2007) [44] Teplan et al. (2008) [45]
68 140
Tx Tx
Yilmaz et al. (2005) [46]
27
Tx
398
Tx
189 40
CKD CKD
246 33
CKD HD
Taherimahmoudi et al. (2010) [43]
Yu et al. (2011) [47] (C) Visfatin Axelsson et al. (2007) [48] Bessa et al. (2010) [49] Carrero et al. (2009) [50] Eleftheriadis et al. (2013) [51]
GFR, BMI, insulin HDL, female
ADIPOQ rs1501299 is associated with PTDM in a sex-specific manner Patients with metabolic syndrome have lower ADPN levels after transplantation Body fat mass is an independent predictor of ADPN levels
Clinical events Fat mass, waist CX, MetSy
ADPN in hypertensive patients is not a predictive factor for CVD ADPN seems to have defense mechanism against endothelial CD146, thrombomodulin, damage creatinine TT genotype of ADPN increases the prevalence of NODAT TAC and ARB modulate ADPN levels and posttransplant ADPN levels correlate with NODAT ADPN level lower in South African population Pretransplant ADPN level predicts higher risk for graft loss Lower ADPN levels associate with higher ambulatory BP ADPN levels are higher in RTR than in healthy controls, but lower than in HD patients (AdipoR1/2) ADPN level is lower in patients with metabolic syndrome, even HDL with lower GFR ADPN levels are higher in RTR than in healthy controls, but lower than in HD patients. ADPN did not decrease immediately after transplantation Immunosuppressive therapy could decrease BMI Leptin In obese RTR, ADMA is increased and ADPN levels are decreased ADMA, hsCRP decreasing instantly after transplantation, not like FMD and ADPN (they change later on) SNP-45/276 of the ADPN gene were significantly associated with an increased risk for NODAT Elevated with higher CKD stages and may predict mortality Visfatin is strongly associated with ED and flow-mediated dilatation Elevated visfatin is associated with anorexia Visfatin is elevated in HD patients and is connected with decreased demands for rHuEpo
BMI, MetSy, IGT, TG, CRP, GFR
BMI, TG BMI, protein Z
HOMA-IR
hsCRP
GFR Graft loss HT HOMA-IR GFR, MetSy, BMI BMI, HOMA-R, GFR
BMI BMI
IL-6, hsCRP, VCAM ICAM, VCAM, CRP, IL-6
GFR FMD, GFR
PEW TSAT, Hgb
TG, Chol, albumin
BMI, leptin DM, BMI, IL-6
Table continues
| 361
57
Negative correlations Lack of correlations
Adipokines in transplant
Idorn et al. (2012) [29]
Positive correlations
CLINICAL KIDNEY JOURNAL
362
Table 1. Continued
Erten et al. (2008) [52] Kato et al. (2009) [53]
Number of patients
RRT
Findings
Positive correlations
Negative correlations Lack of correlations
31/30
HD/CAPD
In CAPD patients, visfatin is higher than in HD/healthy individuals Visfatin shows a strong association with time spent on HD
IL-6, TNF Time on HD, hsCRP
Left ventricular diastolic function Albumin
CAD, hsCRP, BNP, WBC, LDL
GFR, albumin
Proteinuria VCAM, CRP, PTH
GFR GFR, albumin
TG, hsCRP, IL-6, TNF, ICAM, VCAM, CD146, HD vin ED, hsCRP, TG, LDL
GFR GFR, FMD, HDL
ED, hsCRP ED, hsCRP
GFR, FMD GFR, FMD
TNF, IL-6, hsCRP
Albumin
68
HD
Lu et al. (2013) [54]
173
CKD
Mahmood et al. (2010) [55] Malyszko et al. (2009) [56]
50 100
CKD Tx
Malyszko et al. (2010) [57]
75/40
HD/CAPD
Mu et al. (2011) [58]
117
CKD
Yilmaz et al. (2008) [59] Yilmaz et al. (2008) [60]
58 406
Tx CKD
69 100
HD HD
(D) Resistin Akagun et al. (2014) [61] Chung et al. (2012) [62] Dan et al. (2014) [63] Filippidis et al. (2005) [64] Kawamura et al. (2010) [65] Kaynar et al. (2014) [66] Kielstein et al. (2003) [67]
96 33
CKD HD
3192 150 30
CKD Tx HD
Malyszko et al. (2006) [68]
96
Tx
Marouga et al. (2013) [69]
80
CKD
63 231
DBD HD
Oltean et al. (2013) [70] Spoto et al. (2013) [71]
Visfatin level is significantly higher in CAD patients and correlates with E-selectin Higher than in healthy controls. No modulation by DM Higher than in healthy controls
Clearance modulated by RRT type, visfatin could be the link between inflammation and adipocytokines Visfatin may play an important role in uremia-related atherosclerosis Visfatin levels decline after Tx Visfatin is associated with ED independently from inflammation Increased in HD patients with failed renal allografts Low resistin levels independently predict poor hospitalizationfree survival Serum resistin is higher in the CKD population HD does not effect the resistin levels, kidney plays a role in elimination, did not reduce insulin sensitivity Serum resistin is higher in CKD population. Resistin is not elevated in Tx patients Resistin levels depend mainly on GFR and its levels do not modulate insulin sensitivity Kidney function is a major determinant of elevating resistin and inflammation Resistin may be a part of the reverse epidemiology phenomenon of CKD patients High resistin level in DABD causes delayed graft function Resistin predicts death depending on ADPN level
Left ventricular mass index BMI, adiponectin, body fat
DM Gender, comorbidities, medication
Medication
IL-6
hsCRP, TG, HOMA PEW Homocysteine, age
GFR, HDL
hsCRP, IL-6, RBCc, WBC, VCAM TNF, hsCRP
GFR
hsCRP
GFR
BMI, body fat, HOMAR, insulin BMI Insulin, leptin, BMI, waistCX
Alb, GFR, Htc, BMI, leptin, HOMA
HOMA, BMI, cholesterine, leptin
ADPN
Leptin, HOMA
abd.circ., abdominal circumference; ACE, angiotensin-converting enzyme; ADMA, asymmetric dimethylarginine; ADPN, adiponectin; Alb, albumin; ARB, angiotensin receptor blocker; BF, body fat; BMD, bone mineral density; BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; CCI, chronic coronary insufficiency; CKD, chronic kidney disease; CRP, C-reactive protein; CVD, cardiovascular disease; DABD, donation after brain death; DGF, delayed graft function; DM, diabetes mellitus; ED, endothelial dysfunction; FMD, fibromuscular dysplasia; GFR, glomerular filtration rate; HD, hemodialysis; HDL, high density lipoprotein; Hgb, hemoglobin; HOMA, homeostasis model assessment; hsCRP, high-sensitivity C-reactive protein; ICAM, intracellular adhesion molecule; IGT, impaired glucose tolerance; IL, interleukin; LDL, low-density lipoprotein; LVH, left ventricular hypertrophy; MetSy, metabolic syndrome; NODAT, new-onset diabetes after transplantation; PAPP-A, pregnancy-associated plasma protein A; PEW, protein energy wasting; PTH, parathyroid hormone; RBC, red blood cell; RRT, renal replacement therapy; RTR, renal transplant recipients; SNP, single nucleotide polymorphism; TSAT, transferrin saturation; TG, triglyceride; TNF, tumor necrosis factor; Tx, transplantation; vitD, vitamin D; VCAM, vascular cell adhesion molecule; waistCX, waist circumference; WBC, white blood cell.
| K. Nagy et al.
Author (year)
CLINICAL KIDNEY JOURNAL
Adipokines in transplant
adiponectin levels are observed in healthy individuals. It is a 30kDa plasma protein synthetized within adipose tissue, and it circulates in the blood as low and high molecular weight isoforms [78]. It activates the downstream signaling pathways through the AdipoR1 receptor, found in kidney cells and skeletal muscle, as well as the AdipoR2 receptor, located in the liver. In the general population, it is considered to be an anti-inflammatory adipocytokine that improves insulin sensitivity and offers cardioprotective benefits [79]. One of the largest adipocytokines is visfatin (52 kDa), which is largely synthesized and secreted by granulocytes and has recently been found to be an insulin sensitizer [56, 80]. Interestingly, endothelial cells within the uremic milieu have also been found to secrete visfatin [81]. While the exact pathways and functions of visfatin are still under investigation, it most likely activates insulin-like receptors and the tyrosine kinase pathway and has insulin-like, pro-inflammatory and anti-apoptopic actions [56, 80]. Resistin is another adipocytokine with metabolic functions and is known to cause insulin resistance. It is a 12.5-kDa cysteine-rich protein that is synthesized in different isoforms by macrophages [82–85]. It acts as a pro-inflammatory factor that increases the production of inflammatory cytokines and elevates the expression of cell adhesion molecules. While its exact biologic functions are still being elucidated, higher resistin levels have been associated with chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, and resistin may play a role in the pathophysiology of atherosclerosis and endothelial cell injury [86, 87].
| 363
There are other adipocytokines, such as apelin, chemerin and omentin, that will not be discussed in detail in this article. These hormones have been recently discovered, and they are primarily expressed in visceral adipose tissue. For example, apelin synthesis is upregulated by nutritional and inflammatory markers, and it is negatively correlated with endothelial dysfunction [88]. In KTRs, lower apelin levels were associated with underlying cardiovascular disease (CVD) [89]. Moreover, lower apelin levels were observed and were found to be associated with endothelial damage and inflammation [89]. In addition, chemerin affects adipocyte differentiation and insulin signaling, and, despite positive correlations with inflammatory parameters and dyslipidemia, elevated levels have been associated with a survival advantage in dialysis patients [90]. Lastly, omentin’s gene locus has been linked to diabetes and it is negatively correlated with inflammatory and nutritional parameters and positively correlated with plasma adiponectin levels, suggesting a protective role [91, 92]. Less is known about adipocytokines’ functions and associations with outcomes within KTRs. To better inform the field, we analyzed these associations using one of the largest prevalent KTR cohorts (MINIT-HU) with measured adipocytokines [93–98]. In this study, we collected sociodemographic information, clinical parameters, medical and transplant history and laboratory data from 993 prevalent KTRs who were followed within a single ambulatory transplant clinic at the Department of Transplantation and Surgery, Faculty of Medicine, Semmelweis University in Budapest, Hungary, during the period of 31 December 2006– 31 December 2007 [93–98]. Table 2 shows the correlations of the measured adipocytokines in this population, which will be discussed later in this article.
Table 2. Correlations in 988 renal transplant recipients Leptin Correlation coefficient Demographic data Age Charlson comorbidity index ESRD time Kidney-related parameters eGFR Inflammatory markers TNF-α CRP IL-6 Nutritional parameters BMI Abdominal circumference HDL cholesterol LDL cholesterol Cholesterol Adipocytokines Leptin Resistin Adiponectin Transplantation-related data Cold ischemic time PRA mean HLA mismatch
Adiponectin
P-value
Correlation coefficient
Resistin
P-value
Correlation coefficient
P-value
0.08 0.03 −0.02
0.02 0.43 0.58
0.08 0.13 0.09
Clinical Kidney Journal, 2016, vol. 9, no. 3, 359–373 doi: 10.1093/ckj/sfv156 Advance Access Publication Date: 15 March 2016 CKJ Review
CKJ REVIEW
Adipocytokines in renal transplant recipients Kristof Nagy1, Shankar Prasad Nagaraju2, Connie M. Rhee3, Zoltan Mathe1 and Miklos Z. Molnar4 1
Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary, 2Department of Nephrology, Kasturba Medical College, Manipal University, Manipal, India, 3Harold Simmons Center for Chronic Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of California Irvine, Orange, CA, USA and 4Division of Nephrology, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
Correspondence to: Miklos Z. Molnar; E-mail: [email protected]
Abstract In the last two decades, perceptions about the role of body fat have changed. Adipocytes modulate endocrine and immune homeostasis by synthesizing hundreds of hormones, known as adipocytokines. Many studies have been investigating the influences and effects of these adipocytokines and suggest that they are modulated by the nutritional and immunologic milieu. Kidney transplant recipients (KTRs) are a unique and relevant population in which the function of adipocytokines can be examined, given their altered nutritional and immune status and subsequent dysregulation of adipocytokine metabolism. In this review, we summarize the recent findings about four specific adipocytokines and their respective roles in KTRs. We decided to evaluate the most widely described adipocytokines, including leptin, adiponectin, visfatin and resistin. Increasing evidence suggests that these adipocytokines may lead to cardiovascular events and metabolic changes in the general population and may also increase mortality and graft loss rate in KTRs. In addition, we present findings on the interrelationship between serum adipocytokine levels and nutritional and immunologic status, and mechanisms by which adipocytokines modulate morbidity and outcomes in KTRs. Key words: adiponectin, kidney transplantation, leptin, resistin, visfatin
Introduction of adipocytokines In healthy individuals, the role of adipocytokines on various outcomes has been widely studied. However, little is known about how impaired kidney function and renal replacement therapy modify these associations [1]. For example, few studies have examined the impact of adipocytokines on long-term outcomes, such as graft loss and death, in kidney transplant recipients (KTRs). In Table 1, we summarize all studies investigating the role of adipocytokines in KTR and chronic kidney disease (CKD) patients.
Leptin was first described as a biomarker of obesity two decades ago; it is a 16-kDa peptide product of the obese gene predominantly secreted by white adipose tissue with the primary function of modulating hunger and satiety [72, 73]. Leptin crosses the blood–brain barrier and inhibits neuropeptide Y neurons. I also activates the sympathetic neuron system in the hypothalamus and increases circulating sympathetic hormone levels [74–76]. Leptin acts upon the Ob leptin receptors and activates tyrosine kinase and intracellular pathways [72, 75]. Leptin’s counterpart is adiponectin, which negatively correlates with nutritional parameters, suggesting that higher
Received: November 2, 2015. Accepted: December 18, 2015 © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]
359
CLINICAL KIDNEY JOURNAL
Number of patients
RRT
Findings
Positive correlations
Leptin seems to increase bone mass. Leptin has an effect on lymphoid stem cells. Imbalance between leptin and body weight also persists after renal transplantation Pretransplant leptin levels reduced after transplantation Leptin levels are independently determined by graft function Leptin shows correlation with gender, BMI, insulin and cortisol levels Pretransplant leptin levels reduced after transplantation and was not effected by alimentary intake Pretransplant leptin levels reduced after transplantation Elevated leptin levels not only modulated by BMI Leptin lowers the bone turnover independently from PTH Pretransplant leptin levels reduced after transplantation Leptin correlates with metabolic syndrome
BMI, BMD, z score of BMD CD34/7
(A) Leptin Agras et al. (2005) [2] Agras et al. (2006) [3] Baczkowsk et al. (2000) [4]
41 63 28
Tx. Tx. Tx.
El Haggan et al. (2004) [5] Fonseca et al. (2015) [6] Kagan et al. (2002) [7]
41 40 24
Tx. Tx. Tx.
Kayacan et al. (2003) [8]
34
Tx.
Kokot et al. (1998) [9] Kokot et al. (1999) [10] Kovesdy et al. (2010) [11] Landt et al. (1998) [12] Lee et al. (2010) [13]
40 nd. 978 29 55
Tx Tx Tx Tx Tx.
Lee et al. (2014) [14]
74
Tx.
Malyszko et al. (2005) [15]
27
Tx.
Nicoletto et al. (2012) [16] Rafieian-Kopaei et al. (2013) [17] Souza et al. (2007) [18] (B) Adiponectin Adamczak et al. (2007) [19]
32 72
Tx. Tx
32
Tx.
228
Tx
Adamczak et al. (2011) [20] Alam et al. (2012) [21]
88 987
Tx Tx
Bayes et al. (2007) [22] Bayes et al. (2005) [23]
68 199
Tx Tx
Canas et al. (2012) [24] Chitalia et al. (2010) [25]
157 43
Tx Tx
Atorvastatin therapy did not modulate ADPN levels ADPN were lower, BMI higher in patients who developed NODAT ADPN has an inverse association with insulin resistance ADPN levels do not predict the CV risk in RTR
Chudek et al. (2003) [26] Chudek et al. (2013) [27] Fonseca et al. (2015) [6] Ho et al. (2015) [28]
44 372 40 69
HD/Tx Tx Tx Tx
Kidney plays an important role in biodegradation of ADPN ACE I/D polymorphism modulates ADPN levels ADPN level is not only modified by early graft function ADPN has negative correlation with arterial stiffness
Leptin was positively associated with peripheral arterial stiffness among renal transplant recipients Leptin is associated with graft function, but not related to BMD and bone metabolism Pretransplant leptin levels reduced after transplantation Leptin levels and duration of kidney transplant shows strong negative correlation Pretransplant leptin levels reduced after transplantation
Negative correlations Lack of correlations
CD34/7/8/4 Cortisol, BMI
Fat mass, CRP Male, DGF Gender, BMI, cortisol, insulin HOMA, fat mass BMI BMI PTH BMI MetSy, waistCX, BMI, fat mass, CRP
Dietary intake Acute rejection
Age vitD Gender
Body mass/fat, creatinine Gender, BF, HOMA Gender
Nutrition, BMD
Duration of kidney Tx
HOMA, fat mass
ADPN levels are higher in RTR than in healthy controls, but lower than in HD patients Role of ADPN in LVH and atherosclerosis cannot be confirmed Elevated levels of ADPN increase mortality
Age, BMI, creatinine GFR
BMI, GFR, HOMA-IR
HDL TNF, BMI, PAPP-A
hsCRP
Female, ACE II genotype Male, DGF
GFR, BMI, abd.circ., CRP HOMA-IR, creatinin Insulin HOMA-R, c-IMT GFR, BMI, Hgb, waist circumference HOMA-IR BMI
CCI
Age, sex
BP, smoking, lipids, DM
Acute rejection DM, smoking, BMI, waist CX, BP, arterial stiffness
| K. Nagy et al.
Author (year)
360
Table 1. Studies evaluating adipocytokines in renal transplant recipients and patients with CKD
CLINICAL KIDNEY JOURNAL
Table 1. Continued
Author (year)
Number of patients
RRT
Findings ADPN level decreases after transplantation and does not predict NODAT Hypoadiponectinemia associated with CVD
Tx
Kaisar et al. (2009) [30]
137
Tx
Kang et al. (2012) [31]
575
Tx
Kulshrestha et al. (2013) [32]
74
Tx
Lee et al. (2011) [33]
55
Tx
Leibowitz et al. (2013) [34]
35
Tx
Malyszko et al. (2005) [35]
82
Tx
Nicoletto et al. (2013) [36] Nishimura et al. (2009) [37]
270 98
Tx Tx
Prasad et al. (2012) [38] Roos et al. (2012) [39] Sethna et al. (2009) [40] Shen et al. (2007) [41]
129 206 33 54
Tx Tx Tx Tx
Shu et al. (2012) [42]
271
Tx
67
Tx
Teplan et al. (2007) [44] Teplan et al. (2008) [45]
68 140
Tx Tx
Yilmaz et al. (2005) [46]
27
Tx
398
Tx
189 40
CKD CKD
246 33
CKD HD
Taherimahmoudi et al. (2010) [43]
Yu et al. (2011) [47] (C) Visfatin Axelsson et al. (2007) [48] Bessa et al. (2010) [49] Carrero et al. (2009) [50] Eleftheriadis et al. (2013) [51]
GFR, BMI, insulin HDL, female
ADIPOQ rs1501299 is associated with PTDM in a sex-specific manner Patients with metabolic syndrome have lower ADPN levels after transplantation Body fat mass is an independent predictor of ADPN levels
Clinical events Fat mass, waist CX, MetSy
ADPN in hypertensive patients is not a predictive factor for CVD ADPN seems to have defense mechanism against endothelial CD146, thrombomodulin, damage creatinine TT genotype of ADPN increases the prevalence of NODAT TAC and ARB modulate ADPN levels and posttransplant ADPN levels correlate with NODAT ADPN level lower in South African population Pretransplant ADPN level predicts higher risk for graft loss Lower ADPN levels associate with higher ambulatory BP ADPN levels are higher in RTR than in healthy controls, but lower than in HD patients (AdipoR1/2) ADPN level is lower in patients with metabolic syndrome, even HDL with lower GFR ADPN levels are higher in RTR than in healthy controls, but lower than in HD patients. ADPN did not decrease immediately after transplantation Immunosuppressive therapy could decrease BMI Leptin In obese RTR, ADMA is increased and ADPN levels are decreased ADMA, hsCRP decreasing instantly after transplantation, not like FMD and ADPN (they change later on) SNP-45/276 of the ADPN gene were significantly associated with an increased risk for NODAT Elevated with higher CKD stages and may predict mortality Visfatin is strongly associated with ED and flow-mediated dilatation Elevated visfatin is associated with anorexia Visfatin is elevated in HD patients and is connected with decreased demands for rHuEpo
BMI, MetSy, IGT, TG, CRP, GFR
BMI, TG BMI, protein Z
HOMA-IR
hsCRP
GFR Graft loss HT HOMA-IR GFR, MetSy, BMI BMI, HOMA-R, GFR
BMI BMI
IL-6, hsCRP, VCAM ICAM, VCAM, CRP, IL-6
GFR FMD, GFR
PEW TSAT, Hgb
TG, Chol, albumin
BMI, leptin DM, BMI, IL-6
Table continues
| 361
57
Negative correlations Lack of correlations
Adipokines in transplant
Idorn et al. (2012) [29]
Positive correlations
CLINICAL KIDNEY JOURNAL
362
Table 1. Continued
Erten et al. (2008) [52] Kato et al. (2009) [53]
Number of patients
RRT
Findings
Positive correlations
Negative correlations Lack of correlations
31/30
HD/CAPD
In CAPD patients, visfatin is higher than in HD/healthy individuals Visfatin shows a strong association with time spent on HD
IL-6, TNF Time on HD, hsCRP
Left ventricular diastolic function Albumin
CAD, hsCRP, BNP, WBC, LDL
GFR, albumin
Proteinuria VCAM, CRP, PTH
GFR GFR, albumin
TG, hsCRP, IL-6, TNF, ICAM, VCAM, CD146, HD vin ED, hsCRP, TG, LDL
GFR GFR, FMD, HDL
ED, hsCRP ED, hsCRP
GFR, FMD GFR, FMD
TNF, IL-6, hsCRP
Albumin
68
HD
Lu et al. (2013) [54]
173
CKD
Mahmood et al. (2010) [55] Malyszko et al. (2009) [56]
50 100
CKD Tx
Malyszko et al. (2010) [57]
75/40
HD/CAPD
Mu et al. (2011) [58]
117
CKD
Yilmaz et al. (2008) [59] Yilmaz et al. (2008) [60]
58 406
Tx CKD
69 100
HD HD
(D) Resistin Akagun et al. (2014) [61] Chung et al. (2012) [62] Dan et al. (2014) [63] Filippidis et al. (2005) [64] Kawamura et al. (2010) [65] Kaynar et al. (2014) [66] Kielstein et al. (2003) [67]
96 33
CKD HD
3192 150 30
CKD Tx HD
Malyszko et al. (2006) [68]
96
Tx
Marouga et al. (2013) [69]
80
CKD
63 231
DBD HD
Oltean et al. (2013) [70] Spoto et al. (2013) [71]
Visfatin level is significantly higher in CAD patients and correlates with E-selectin Higher than in healthy controls. No modulation by DM Higher than in healthy controls
Clearance modulated by RRT type, visfatin could be the link between inflammation and adipocytokines Visfatin may play an important role in uremia-related atherosclerosis Visfatin levels decline after Tx Visfatin is associated with ED independently from inflammation Increased in HD patients with failed renal allografts Low resistin levels independently predict poor hospitalizationfree survival Serum resistin is higher in the CKD population HD does not effect the resistin levels, kidney plays a role in elimination, did not reduce insulin sensitivity Serum resistin is higher in CKD population. Resistin is not elevated in Tx patients Resistin levels depend mainly on GFR and its levels do not modulate insulin sensitivity Kidney function is a major determinant of elevating resistin and inflammation Resistin may be a part of the reverse epidemiology phenomenon of CKD patients High resistin level in DABD causes delayed graft function Resistin predicts death depending on ADPN level
Left ventricular mass index BMI, adiponectin, body fat
DM Gender, comorbidities, medication
Medication
IL-6
hsCRP, TG, HOMA PEW Homocysteine, age
GFR, HDL
hsCRP, IL-6, RBCc, WBC, VCAM TNF, hsCRP
GFR
hsCRP
GFR
BMI, body fat, HOMAR, insulin BMI Insulin, leptin, BMI, waistCX
Alb, GFR, Htc, BMI, leptin, HOMA
HOMA, BMI, cholesterine, leptin
ADPN
Leptin, HOMA
abd.circ., abdominal circumference; ACE, angiotensin-converting enzyme; ADMA, asymmetric dimethylarginine; ADPN, adiponectin; Alb, albumin; ARB, angiotensin receptor blocker; BF, body fat; BMD, bone mineral density; BMI, body mass index; BP, blood pressure; CAD, coronary artery disease; CCI, chronic coronary insufficiency; CKD, chronic kidney disease; CRP, C-reactive protein; CVD, cardiovascular disease; DABD, donation after brain death; DGF, delayed graft function; DM, diabetes mellitus; ED, endothelial dysfunction; FMD, fibromuscular dysplasia; GFR, glomerular filtration rate; HD, hemodialysis; HDL, high density lipoprotein; Hgb, hemoglobin; HOMA, homeostasis model assessment; hsCRP, high-sensitivity C-reactive protein; ICAM, intracellular adhesion molecule; IGT, impaired glucose tolerance; IL, interleukin; LDL, low-density lipoprotein; LVH, left ventricular hypertrophy; MetSy, metabolic syndrome; NODAT, new-onset diabetes after transplantation; PAPP-A, pregnancy-associated plasma protein A; PEW, protein energy wasting; PTH, parathyroid hormone; RBC, red blood cell; RRT, renal replacement therapy; RTR, renal transplant recipients; SNP, single nucleotide polymorphism; TSAT, transferrin saturation; TG, triglyceride; TNF, tumor necrosis factor; Tx, transplantation; vitD, vitamin D; VCAM, vascular cell adhesion molecule; waistCX, waist circumference; WBC, white blood cell.
| K. Nagy et al.
Author (year)
CLINICAL KIDNEY JOURNAL
Adipokines in transplant
adiponectin levels are observed in healthy individuals. It is a 30kDa plasma protein synthetized within adipose tissue, and it circulates in the blood as low and high molecular weight isoforms [78]. It activates the downstream signaling pathways through the AdipoR1 receptor, found in kidney cells and skeletal muscle, as well as the AdipoR2 receptor, located in the liver. In the general population, it is considered to be an anti-inflammatory adipocytokine that improves insulin sensitivity and offers cardioprotective benefits [79]. One of the largest adipocytokines is visfatin (52 kDa), which is largely synthesized and secreted by granulocytes and has recently been found to be an insulin sensitizer [56, 80]. Interestingly, endothelial cells within the uremic milieu have also been found to secrete visfatin [81]. While the exact pathways and functions of visfatin are still under investigation, it most likely activates insulin-like receptors and the tyrosine kinase pathway and has insulin-like, pro-inflammatory and anti-apoptopic actions [56, 80]. Resistin is another adipocytokine with metabolic functions and is known to cause insulin resistance. It is a 12.5-kDa cysteine-rich protein that is synthesized in different isoforms by macrophages [82–85]. It acts as a pro-inflammatory factor that increases the production of inflammatory cytokines and elevates the expression of cell adhesion molecules. While its exact biologic functions are still being elucidated, higher resistin levels have been associated with chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, and resistin may play a role in the pathophysiology of atherosclerosis and endothelial cell injury [86, 87].
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There are other adipocytokines, such as apelin, chemerin and omentin, that will not be discussed in detail in this article. These hormones have been recently discovered, and they are primarily expressed in visceral adipose tissue. For example, apelin synthesis is upregulated by nutritional and inflammatory markers, and it is negatively correlated with endothelial dysfunction [88]. In KTRs, lower apelin levels were associated with underlying cardiovascular disease (CVD) [89]. Moreover, lower apelin levels were observed and were found to be associated with endothelial damage and inflammation [89]. In addition, chemerin affects adipocyte differentiation and insulin signaling, and, despite positive correlations with inflammatory parameters and dyslipidemia, elevated levels have been associated with a survival advantage in dialysis patients [90]. Lastly, omentin’s gene locus has been linked to diabetes and it is negatively correlated with inflammatory and nutritional parameters and positively correlated with plasma adiponectin levels, suggesting a protective role [91, 92]. Less is known about adipocytokines’ functions and associations with outcomes within KTRs. To better inform the field, we analyzed these associations using one of the largest prevalent KTR cohorts (MINIT-HU) with measured adipocytokines [93–98]. In this study, we collected sociodemographic information, clinical parameters, medical and transplant history and laboratory data from 993 prevalent KTRs who were followed within a single ambulatory transplant clinic at the Department of Transplantation and Surgery, Faculty of Medicine, Semmelweis University in Budapest, Hungary, during the period of 31 December 2006– 31 December 2007 [93–98]. Table 2 shows the correlations of the measured adipocytokines in this population, which will be discussed later in this article.
Table 2. Correlations in 988 renal transplant recipients Leptin Correlation coefficient Demographic data Age Charlson comorbidity index ESRD time Kidney-related parameters eGFR Inflammatory markers TNF-α CRP IL-6 Nutritional parameters BMI Abdominal circumference HDL cholesterol LDL cholesterol Cholesterol Adipocytokines Leptin Resistin Adiponectin Transplantation-related data Cold ischemic time PRA mean HLA mismatch
Adiponectin
P-value
Correlation coefficient
Resistin
P-value
Correlation coefficient
P-value
0.08 0.03 −0.02
0.02 0.43 0.58
0.08 0.13 0.09
