Original ArticlesChronic Kidney Disease

Association of Plasma Des-acyl Ghrelin Levels with CKD

Rohit K. Gupta, Tamil Kuppusamy, James T. Patrie, Bruce Gaylinn, Jianhua Liu, Michael O. Thorner and Warren K. Bolton
CJASN July 2013, 8 (7) 1098-1105; DOI: https://doi.org/10.2215/CJN.09170912

Summary

Background and objectives There are no effective therapies for malnutrition in CKD/ESRD patients. This study hypothesized that ghrelin, an endogenous orexigenic hormone, would correlate with renal function and might suggest therapeutic interventions for CKD/ESRD malnutrition.

Design, setting, participants, & measurements Fifty-one CKD and 15 hemodialysis patients were enrolled. Acyl ghrelin (AG) and des-acyl ghrelin (DG) were determined using separate two-site–specific assays. Leptin, insulin, growth hormone, insulin-link growth factor-1, C-reactive protein, TNF-α, and IL-6 were also measured.

Results Univariate correlation analyses showed that CKD stage was highly, positively correlated with the levels of preprandial and postprandial DG and positively correlated with TNF-α, IL-6, leptin, and age. Multivariate partial-correlation analyses showed that CKD was independently associated with the proportion of preprandial and postprandial DG, whereas TNF-α, IL-6, leptin, insulin, and age were not independently associated with either. Geometric mean (GM) preprandial and postprandial AG were comparable between CKD stages ≤2 and >2, whereas GM preprandial DG and postprandial DG were 1.95-fold and 2.17-fold greater, respectively, for CKD stage >2 versus stage ≤2. DG was the dominant form of ghrelin preprandially and postprandially for both CKD stages ≤2 and >2. Dialysis had no effect on AG, but reduced DG by 73% to levels even lower (GM 48.7 pg/ml) than those seen postprandially in CKD stage ≤2 patients (GM 77.0 pg/ml).

Conclusions This study shows a strong and independent correlation of DG with CKD stage. Postprandial suppression of ghrelin is impaired with reduced renal function. Hemodialysis selectively removes DG but not AG.

Introduction

Malnutrition/protein-energy wasting is a major cause of morbidity and mortality for patients suffering from CKD. Approximately 20%–50% of patients with CKD suffer from malnutrition, and 70%–75% of patients with ESRD have protein-energy wasting (1–3).

As patients develop renal failure, they lose their taste for food and decrease nutritional intake (4). Furthermore, increased catabolism or decreased anabolism can lead to cachexia. Hormones such as insulin, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) stimulate protein synthesis, whereas a decrease in these mediators may cause a decline in anabolism resulting in malnutrition. Inflammatory cytokines, such as TNF-α, C-reactive protein (CRP), and IL-6, have been implicated in the increased protein catabolism that characterizes muscle wasting of uremia, and appetite suppression by leptin has also been implicated (5–11).

Ghrelin is an orexigenic hormone that may be involved in the malnutrition of uremia (12–14). It is a 28 amino acid peptide that acts at the GH secretagogue receptor (GHSR) to stimulate appetite, carbohydrate utilization, and GH release. Conflicting reports of the levels of total ghrelin (TG) and acyl ghrelin (AG) in patients with renal dysfunction have been difficult to interpret and reconcile (15–21). Most reports have used single antibody ghrelin assays that recognize an epitope found only on AG or alternatively, an epitope common to both AG and des-acyl ghrelin (DG). Unfortunately, these assays also detect inactive ghrelin fragments. Thus, TG as reported in the literature actually includes AG+DG + ghrelin fragments. We have developed assays to measure full-length AG and DG but not fragments (22,23). We hypothesized that ghrelin levels would correlate with renal function and might suggest therapeutic interventions for CKD/ESRD malnutrition. The purpose of our study was to examine this hypothesis with our assays.

Materials and Methods

Study Participants

There were two groups of patients. Group 1 had CKD not requiring dialysis. Group 2 patients had ESRD and were receiving thrice-weekly hemodialysis. Participants were aged ≥18 years and provided informed consent before enrollment. The study was approved by our institutional review board and complied with the Declaration of Helsinki guidelines.

CKD Patients

Patients seen in our Kidney Center Clinic with CKD from each of the five CKD stages were recruited. The estimated GFR (eGFR) was calculated using the Modified Diet in Renal Disease study equation. Individuals were screened in the clinic and were then screened for inclusion/exclusion. They then were contacted by phone to see if they would be willing to participate. This process was followed until there were 10 individuals in each CKD stage. One individual did not want to participate and then changed their mind. Rather than discourage that individual, we included the patient and one group thus had 11 individuals. Patient characteristics are provided in Table 1. After an overnight fast, plasma samples were obtained at time zero (T=0). The following assays were performed: DG, AG, IL-6, TNFα, GH, insulin, IGF-1, CRP, albumin, and leptin. After the fasting samples were obtained, a standard breakfast was provided. The meal consisted of 55% carbohydrates, 30% fat, and 15% protein. It contained 500 kcal with 500 mg of sodium, 450 mg of potassium, 300 mg of phosphorus, and 240 ml of free fluids. A body mass index was calculated, and a subjective global assessment (SGA) was performed by a licensed nutritionist (6). One hour after completion of the meal (T=1), repeat AG and DG samples were drawn.

View this table:
Table 1.

Demographics and patient characteristics for the CKD patients, determined at the prestudy clinic visit

Hemodialysis Patients

Fifteen hemodialysis patients participated. Patients were screened for inclusion and exclusion criteria and then approached about their participation in the study. Patient characteristics are presented in Table 2. Patients arrived at the dialysis center in a fasting state for initial plasma samples (T=0), and then received the standard breakfast and assessment noted above except an SGA was not obtained. Ghrelin levels were measured at 1 hour after the meal (T=1), and dialysis was initiated. A postdialysis ghrelin sample was obtained immediately after each patient received their standard dialysis session (posthemodialysis) (T=4).

View this table:
Table 2.

Demographics and patient characteristics for the 15 hemodialysis patients

Assays for Hormones and Cytokines

The following assays were performed: GH, IGF-1, insulin, hsCRP, IL-6, TNF-α, and leptin. Please see the Supplemental Material for details of the assays.

Assay for Ghrelin

We used two separate two-site sandwich assays, one specific for AG and one for DG. These assays do not measure ghrelin fragments and have superior specificity for AG and DG determination (22,23).

Sample Collection for Ghrelin Assay

Three-milliliter blood samples were collected by syringe and immediately added to chilled EDTA Vacutainer tubes preloaded with aminoethyl-benzenesulfonylfluoride (AEBSF) to give a 4 mM final concentration. The tubes were kept on ice and spun immediately in a chilled centrifuge for 10 minutes to separate the plasma. The plasma supernatant was collected, acidified with 200 μl of 1 N HCI/1000 μl plasma, mixed, and then frozen in aliquots at −20°C.

AG Sandwich Assay

Plates (384-well Maxisorb; Nunc, Roskilde, Denmark) were coated with acyl-specific antiserum at 1 μg/ml overnight. The plate was then blocked, washed, and loaded with 25 μl/well wetting/neutralization buffer (0.5 м phosphate buffer with 1% BSA, pH 7.4) and 25 μl/well ghrelin standards or unknown samples and incubated overnight at 4°C. The washed plate was then incubated for 1 hour with the biotinylated C-terminal ghrelin antiserum in blocking buffer and then for 30 minutes with the streptavidin-poly-HRP80 (RDI Fitzgerald, Concord, MS). Finally, the plate was detected with the florescent substrate Amplex Red (Molecular Probes, Eugene, OR). Fluorescence was read using excitation/emission wavelengths of 535/590 nm (Tecan Genios plate reader; Phenix Research, Hayward, CA). All unknowns were run in duplicate, and all samples for each admission of each individual were run on the same plate. Standards were made up in acid/AEBSF-treated C18 (Empore; 3M, St. Paul, MN) stripped plasma. The assay sensitivity was 6.7 pg/ml with an intra-assay coefficient of variation (CV) of 9.1% at 30 pg/ml, 12.6% at 100 pg/ml, and 16.8% at 300 pg/ml. The inter-assay CV was 17.8% at 50 pg/ml.

DG Sandwich Assay

The protocol for DG assay follows that used for the ghrelin sandwich assay with the substitution of affinity-purified C-terminal ghrelin antiserum for the capture step and biotinylated N-terminal DG-specific monoclonal antiserum as the reporter. All other steps are unchanged. The assay sensitivity was 4.6 pg/ml with an intra-assay CV of 12.5% at 50 pg/ml, 10.7% at 150 pg/ml, and 18.0% at 500 pg/ml. The inter-assay CV was 20.8% at 30 pg/ml.

Statistical Analyses

Patient characteristics were summarized by frequencies and by percentages for categorical variables, and by the median (interquartile range) for continuous variables.

Bivariate correlations were estimated via the nonparametric Spearman rank correlation coefficient (rs). Multivariate partial-correlations were estimated via the nonparametric Spearman rank partial-correlation coefficient (rsp). All tests for bivariate and partial association were two sided and a P≤0.05 decision rule was utilized as the rejection criterion.

Preprandial and postprandial AG as well as DG concentrations were analyzed via repeated-measures ANOVA on the natural logarithmic scale. Comparisons of mean ghrelin concentration were made on logarithmic scale and then converted back to the original scale of measure via the antilog transformation. Hypothesis tests were two sided and a P≤0.05 decision rule was utilized as the rejection criterion. Results are expressed in terms of the geometric mean (GM) and the ratio of GM. Like the arithmetic mean and median, the GM is a statistic that is utilized to estimate the central location of the measurement distribution.

SAS software (version 9.2; SAS Institute Inc., Cary, NC) and Spotfire S Plus software (version 8.2; TIBCO Inc., Seattle, WA) were used to conduct the statistical analyses.

Results

CKD

Patient Characteristics.

There were 10 participants in each of the five CKD categories except for CKD stage 3, which had 11 individuals. Five participants had inadequate samples for the assays; thus, data from 46 individuals were available for analysis. There were 19 men (41%) and 27 women (59%), of whom, 17 were African American (37%) and 29 were Caucasian (63%). Ages ranged from 21 to 82 years (median age 57 years; interquartile range, 40–65 years). There were no differences in body mass index or SGA. There were also no differences in appetite, time or quantity of food consumed at the study session, or evidence of malnutrition (Supplemental Tables 1–3). As selected, the eGFR was lower with the higher stage of CKD.

Correlation Analyses.

Univariate correlation analyses showed that CKD stage was positively correlated with preprandial and postprandial DG (rs=0.33 and 0.34, respectively; P=0.03 and 0.02, respectively), but not with preprandial and postprandial AG. CKD stage was also highly, positively correlated with the proportion of preprandial and the proportion of postprandial DG (rs=0.61 and rs=055, respectively; P<0.001 for both). Similarly, univariate correlation analyses showed CKD stage was positively correlated with TNF-α, IL-6, leptin, and age (rs=0.33, 0.40, and 0.41, respectively; P<0.05 for all) (Table 3). Multivariate partial-correlation analyses showed that CKD was independently associated with the proportion of preprandial and postprandial DG (rsp=0.55 and 0.43, respectively; P<0.01 for both), whereas TNF-α, IL-6, leptin, insulin, and age were not independently correlated with either of these two proportions (Table 4). Even with CKD stage removed from the set of partial correlates, TNF-α, IL-6, leptin, insulin, and age were not independently correlated with the proportion of either preprandial or postprandial DG (Supplemental Table 4).

View this table:
Table 3.

Univariate correlations with CKD stage

View this table:
Table 4.

Multivariate correlations of proportion of DG

Repeated-Measures Analyses.

GM preprandial and GM postprandial AG were comparable between CKD stage ≤2 patients and CKD stage >2 patients, whereas GM preprandial DG and GM postprandial DG were 1.95-fold (95% confidence interval [95% CI], 1.16 to 3.26; P=0.01) and 2.17-fold (95% CI, 1.16 to 3.26; P=0.004) greater, respectively, for CKD stage >2 patients compared with CKD stage ≤2 patients. Compared with AG, DG was the dominant preprandial and postprandial ghrelin form for both CKD stage ≤2 patients (P<0.001 for both), and CKD stage >2 patients (P<0.001 for both). GM postprandial DG was reduced by 26% (95% CI, 5% to 43%; P=0.02) and by 18% (95% CI, 1% to 32%; P=0.03), respectively, for CKD stage ≤2 patients and CKD stage >2 patients compared with GM preprandial DG. GM postprandial AG was comparable with GM preprandial AG for both CKD stage ≤2 and CKD stage >2 patients (Figure 1).

Figure 1.
Figure 1.

Geometric mean ghrelin concentration, by CKD stage and by ghrelin form. Circles identify the geometric mean of the measurement distribution and the vertical lines identify the range of the geometric mean 95% confidence interval. Geometric means with dissimilar letters signify that the values are statistically significantly different.

ESRD

The levels of preprandial, postprandial, and postdialysis ghrelin for the ESRD patients are illustrated in Figure 2. There was no decrease in AG postprandially, nor any changes in AG resultant from dialysis. DG actually increased slightly postprandially but the magnitude of the increase was not statistically significant. However, a standard dialysis treatment resulted in a significant decrease in DG of 73% (95% CI, 0.50% to 85%; P<0.001). Dialysis therapy resulted in reduction of DG to levels (GM 48.7 pg/ml; 95% CI, 29.5 to 80.2 pg/ml) even lower than those seen postprandially in CKD stage 1 (n=2 patients; GM 77.0 pg/ml; 95% CI, 51.2 to 117.9 pg/ml). The other correlations in dialysis patients between various significant parameters and ghrelin are presented in Supplemental Table 5. Both preprandial and postprandial DG were negatively correlated with serum albumin levels (rs=−0.64 and −0.59, respectively; P=0.01 and 0.02, respectively) in contrast there was no correlation between AG and serum albumin levels. Preprandial GH correlated negatively with IGF-1, insulin, and leptin (rs=−0.65, −0.71, and −0.67, respectively; P<0.01 for all). IGF-1 correlated with insulin, leptin, and albumin (rs=0.79, 0.59, and 0.65, respectively; P<0.01, 0.02, and 0.01, respectively). Insulin was correlated positively with leptin and albumin (rs=0.81 and 0.59, respectively; P<0.001 and 0.02, respectively). CRP and IL-6 were positively correlated with each other (rs=0.53; P=0.04).

Figure 2.
Figure 2.

Levels of des-acyl ghrelin increased slightly postprandially and were markedly decreased by hemodialysis (P<0.001). Acyl ghrelin decreased slightly after eating but was not affected by hemodialysis. Error bars indicate the SD.

Discussion

Our study examined changes in DG and AG in CKD and ESRD using specific and sensitive assays for these hormones (22,23). We demonstrate that levels of DG but not AG increase with declining eGFR, and that ghrelin metabolism or secretion may be altered by uremia. AG response to feeding was blunted in CKD and absent in ESRD participants, as also reported by others (24,25). These results suggest that AG secretion is within the normal range and its conversion to DG is normal, but DG accumulates as its clearance is progressively decreased with declining eGFR. The increment in DG was tightly linked to the decrease in eGFR so that it correlated with CKD stages 3–5 with high accuracy.

Increased levels of TG with decreasing GFR have been reported by others (15–19,21,26) as well as variable removal by dialysis (16,18,21). Some studies reported a decrease in both AG and DG (16,18) by hemodialysis that would not be expected for AG, which is highly bound to large plasma molecules such as lipoprotein (27,28). Other studies report no change in plasma ghrelin levels with hemodialysis (21). These results differ from those reported here with our ghrelin sandwich assay (22,23,29) and likely reflect the use of different assays with different specificities for the ghrelin molecule, and differences in sample preparation and preservation. The method described in our assay preserves the natural ratio between AG and DG without the confounder of measuring ghrelin fragments.

TG normally precipitously decreases postprandially, but the DG/AG ratio is maintained (22). In normal individuals, the ratio of DG to AG is approximately 4:1 with 20% AG, and feeding causes a 2- to 5-fold decrease but the ratio is not changed (22). In long-term fasted (>37 hours) normal individuals, the ratio is approximately 12:1 (i.e., greater DG to AG than fed individuals) (22). We found that this relationship is altered in CKD. The DG/AG ratio is similar to that in long-term fasting individuals, and the decrease with feeding is attenuated relative to normal (22). These changes suggest that altered ghrelin metabolism associated with uremia, favoring DG predominance. This was exaggerated in ESRD, in which there was no significant change in either DG or AG postprandially in dialysis patients (Figure 2). Peréz-Fontan et al. and Suneja et al. likewise reported perturbation in the expected responses to feeding in dialysis patients as noted above (24,25)

Ghrelin levels are increased in states of severe malnutrition and decreased in states of satiety (7,30,31). Ghrelin has potent orexigenic activity and induces an increase in food intake, and muscle mass with a positive change in energy uremic balance in rats (32–34). Ghrelin administered to dialysis patients increased appetite and food intake, induced a sustained positive change in energy balance (35,36) and increased food intake in malnourished patients on peritoneal dialysis (35). Thus, a decrease in AG in CKD could theoretically play a role in the malnutrition observed in many of these patients. However, we observed no change in AG levels as eGFR declined.

We did demonstrate that DG increased with decreasing eGFR, as described by others (16,37). DG has been reported to be the “inactive” degradation product of AG but recent studies suggest that DG may itself have pleiotropic biologic activities, including opposing actions to AG (38–43). In normal individuals, DG and AG levels decrease in parallel on feeding, but the ratio of DG/AG remains constant (22). In our studies in CKD, the decrease in postprandial levels was blunted, but the ratio of DG/AG was maintained, and there was actually an increase in DG postprandially in dialysis patients. Others have reported that AG metabolism was altered in dialysis patients, but did not report data on DG (24,25). Our findings suggest that not only is DG increased as eGFR declines, but that abnormalities in the response of the ghrelin axis to feeding occur as CKD develops. Increasing evidence implicates a role of DG in the appetite changes of uremia. Administration of DG to normal animals decreased food intake and gastric emptying (44), and increased anorexigenic transcripts in the hypothalamus (44,45). Mice overexpressing DG had decreased body weight, fat pad mass, and growth. Thus, elevated levels of DG could be involved in the pathogenesis of anorexia of uremia. The reduction in DG by dialysis could play a major role in improving the nutritional status in uremia, and might be further augmented by more frequent or continuous therapies. Of note, transplanted patients have a return of TG levels to normal post-transplant (46).

Inflammatory anorexic cytokines are increased in many patients with CKD. Elevation of serum TNFα, IL-6, CRP, and leptin have all been implicated in the genesis of the cachexia of uremia (8,11,47). Our studies demonstrated higher levels of TNFα, IL-6, and leptin with lower eGFR. After adjusting for CKD, there was no association between DG and the cytokines, suggesting that DG may have an independent role in promoting the malnutrition/protein-energy wasting of CKD and ESRD. AG inhibits leptin and proinflammatory anorectic cytokine expression by monocytes and T cells, including IL-1β, IL-6, and TNF-α in vitro and demonstrates anti-inflammatory effects in a murine endotoxemia model (48). Thus, the increasing DG levels in CKD might oppose the effects of AG cytokine inhibition.

Study Strengths and Limitations

Our study utilized assays for AG and DG with greater sensitivity and specificity than previously available, allowing us to measure DG directly. We confirmed some other studies that examined AG and TG and we discovered that DG was most strongly associated with CKD stage, further clarifying the potential role of the ghrelin system in the malnutrition of CKD. The study was limited by small numbers of participants, single time points for samples, and nonrandomized selection of participants. Other markers of malnutrition in CKD may have a different temporal sequence than ghrelin to support the malnutrition state (e.g., peptide YY or neuropeptide Y) (25,49). However, the focus of our study was ghrelin. We showed for the first time that DG is independently dependent on eGFR and that any relationship to inflammatory cytokines is likely directly related to eGFR rather than due to an interaction with ghrelin.

In conclusion, using sensitive and specific assays for AG and DG, we have demonstrated a tight negative association of DG levels with lower eGFR, impairment of the normal postprandial ghrelin suppression to feeding in CKD and ESRD, and showed that hemodialysis returns DG toward normal. Because orexigenic AG levels were not lower with lower levels of eGFR or decreased by dialysis, a role of DG in the anorexia of uremia is implicated. Additional studies will be required to define the mechanisms of these perturbations of ghrelin and their effect on nutrition and the inflammatory milieu in patients with CKD and ESRD.

Disclosures

None.

Acknowledgments

We appreciate the assistance of Thessa Churillo, nutritionist, and Anita Jacobson, executive secretary.

This work was performed through the Nephrology Clinical Research Center and the University of Virginia General Clinical Research Center (M01 RR0874) and by grants from the National Institutes of Health (R01DK076095 and R21DK077372).

Footnotes

  • Received September 6, 2012.
  • Accepted January 29, 2013.

References

  1. ↵
    1. Ikizler TA
    : Nutrition, inflammation and chronic kidney disease. Curr Opin Nephrol Hypertens 17: 162–167, 2008pmid:18277149
    OpenUrlCrossRefPubMed
    1. Muscaritoli M,
    2. Molfino A,
    3. Bollea MR,
    4. Rossi Fanelli F
    : Malnutrition and wasting in renal disease. Curr Opin Clin Nutr Metab Care 12: 378–383, 2009pmid:19474712
    OpenUrlCrossRefPubMed
  3. ↵
    1. Fouque D,
    2. Pelletier S,
    3. Mafra D,
    4. Chauveau P
    : Nutrition and chronic kidney disease. Kidney Int 80: 348–357, 2011pmid:21562470
    OpenUrlCrossRefPubMed
  4. ↵
    1. Bossola M,
    2. Tazza L,
    3. Giungi S,
    4. Luciani G
    : Anorexia in hemodialysis patients: An update. Kidney Int 70: 417–422, 2006pmid:16775598
    OpenUrlCrossRefPubMed
  5. ↵
    1. Stenvinkel P,
    2. Pecoits-Filho R,
    3. Lindholm B
    : Leptin, ghrelin, and proinflammatory cytokines: Compounds with nutritional impact in chronic kidney disease? Adv Ren Replace Ther 10: 332–345, 2003pmid:14681862
    OpenUrlCrossRefPubMed
  6. ↵
    1. Steiber AL,
    2. Kalantar-Zadeh K,
    3. Secker D,
    4. McCarthy M,
    5. Sehgal A,
    6. McCann L
    : Subjective global assessment in chronic kidney disease: A review. J Ren Nutr 14: 191–200, 2004
    OpenUrlCrossRefPubMed
  7. ↵
    1. Bologa RM,
    2. Levine DM,
    3. Parker TS,
    4. Cheigh JS,
    5. Serur D,
    6. Stenzel KH,
    7. Rubin AL
    : Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients. Am J Kidney Dis 32: 107–114, 1998pmid:9669431
    OpenUrlCrossRefPubMed
  8. ↵
    1. Rao M,
    2. Guo D,
    3. Perianayagam MC,
    4. Tighiouart H,
    5. Jaber BL,
    6. Pereira BJ,
    7. Balakrishnan VS
    : Plasma interleukin-6 predicts cardiovascular mortality in hemodialysis patients. Am J Kidney Dis 45: 324–333, 2005pmid:15685511
    OpenUrlCrossRefPubMed
    1. Kaizu Y,
    2. Ohkawa S,
    3. Odamaki M,
    4. Ikegaya N,
    5. Hibi I,
    6. Miyaji K,
    7. Kumagai H
    : Association between inflammatory mediators and muscle mass in long-term hemodialysis patients. Am J Kidney Dis 42: 295–302, 2003pmid:12900811
    OpenUrlCrossRefPubMed
    1. Honda H,
    2. Qureshi AR,
    3. Heimbürger O,
    4. Barany P,
    5. Wang K,
    6. Pecoits-Filho R,
    7. Stenvinkel P,
    8. Lindholm B
    : Serum albumin, C-reactive protein, interleukin 6, and fetuin a as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD. Am J Kidney Dis 47: 139–148, 2006pmid:16377395
    OpenUrlCrossRefPubMed
  11. ↵
    1. Barreto DV,
    2. Barreto FC,
    3. Liabeuf S,
    4. Temmar M,
    5. Lemke HD,
    6. Tribouilloy C,
    7. Choukroun G,
    8. Vanholder R,
    9. Massy ZA
    ; European Uremic Toxin Work Group (EUTox): Plasma interleukin-6 is independently associated with mortality in both hemodialysis and pre-dialysis patients with chronic kidney disease. Kidney Int 77: 550–556, 2010pmid:20016471
    OpenUrlCrossRefPubMed
  12. ↵
    1. Kojima M,
    2. Hosoda H,
    3. Date Y,
    4. Nakazato M,
    5. Matsuo H,
    6. Kangawa K
    : Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402: 656–660, 1999pmid:10604470
    OpenUrlCrossRefPubMed
    1. Kojima M,
    2. Kangawa K
    : Ghrelin: Structure and function. Physiol Rev 85: 495–522, 2005pmid:15788704
    OpenUrlCrossRefPubMed
  14. ↵
    1. Date Y,
    2. Kojima M,
    3. Hosoda H,
    4. Sawaguchi A,
    5. Mondal MS,
    6. Suganuma T,
    7. Matsukura S,
    8. Kangawa K,
    9. Nakazato M
    : Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 141: 4255–4261, 2000pmid:11089560
    OpenUrlCrossRefPubMed
  15. ↵
    1. Pérez-Fontán M,
    2. Cordido F,
    3. Rodríguez-Carmona A,
    4. Peteiro J,
    5. García-Naveiro R,
    6. García-Buela J
    : Plasma ghrelin levels in patients undergoing haemodialysis and peritoneal dialysis. Nephrol Dial Transplant 19: 2095–2100, 2004pmid:15187192
    OpenUrlCrossRefPubMed
  16. ↵
    1. Yoshimoto A,
    2. Mori K,
    3. Sugawara A,
    4. Mukoyama M,
    5. Yahata K,
    6. Suganami T,
    7. Takaya K,
    8. Hosoda H,
    9. Kojima M,
    10. Kangawa K,
    11. Nakao K
    : Plasma ghrelin and desacyl ghrelin concentrations in renal failure. J Am Soc Nephrol 13: 2748–2752, 2002pmid:12397045
    OpenUrlAbstract/FREE Full Text
    1. Aguilera A,
    2. Cirugeda A,
    3. Amair R,
    4. Sansone G,
    5. Alegre L,
    6. Codoceo R,
    7. Bajo MA,
    8. del Peso G,
    9. Díez JJ,
    10. Sánchez-Tomero JA,
    11. Selgas R
    : Ghrelin plasma levels and appetite in peritoneal dialysis patients. Adv Perit Dial 20: 194–199, 2004pmid:15384825
    OpenUrlPubMed
  18. ↵
    1. Jarkovská Z,
    2. Hodková M,
    3. Sazamová M,
    4. Rosická M,
    5. Dusilová-Sulková S,
    6. Marek J,
    7. Justová V,
    8. Lacinová Z,
    9. Haluzík M,
    10. Haas T,
    11. Krsek M
    : Plasma levels of active and total ghrelin in renal failure: A relationship with GH/IGF-I axis. Growth Horm IGF Res 15: 369–376, 2005pmid:16198134
    OpenUrlCrossRefPubMed
  19. ↵
    1. Jarkovská Z,
    2. Rosická M,
    3. Krsek M,
    4. Sulková S,
    5. Haluzík M,
    6. Justová V,
    7. Lacinová Z,
    8. Marek J
    : Plasma ghrelin levels in patients with end-stage renal disease. Physiol Res 54: 403–408, 2005pmid:15588149
    OpenUrlPubMed
    1. Iglesias P,
    2. Díez JJ,
    3. Fernández-Reyes MJ,
    4. Codoceo R,
    5. Alvarez-Fidalgo P,
    6. Bajo MA,
    7. Aguilera A,
    8. Selgas R
    : Serum ghrelin concentrations in patients with chronic renal failure undergoing dialysis. Clin Endocrinol (Oxf) 64: 68–73, 2006pmid:16402931
    OpenUrlCrossRefPubMed
  21. ↵
    1. Rodriguez Ayala E,
    2. Pecoits-Filho R,
    3. Heimbürger O,
    4. Lindholm B,
    5. Nordfors L,
    6. Stenvinkel P
    : Associations between plasma ghrelin levels and body composition in end-stage renal disease: A longitudinal study. Nephrol Dial Transplant 19: 421–426, 2004pmid:14736968
    OpenUrlCrossRefPubMed
  22. ↵
    1. Liu J,
    2. Prudom CE,
    3. Nass R,
    4. Pezzoli SS,
    5. Oliveri MC,
    6. Johnson ML,
    7. Veldhuis P,
    8. Gordon DA,
    9. Howard AD,
    10. Witcher DR,
    11. Geysen HM,
    12. Gaylinn BD,
    13. Thorner MO
    : Novel ghrelin assays provide evidence for independent regulation of ghrelin acylation and secretion in healthy young men. J Clin Endocrinol Metab 93: 1980–1987, 2008pmid:18349056
    OpenUrlCrossRefPubMed
  23. ↵
    1. Prudom C,
    2. Liu J,
    3. Patrie J,
    4. Gaylinn BD,
    5. Foster-Schubert KE,
    6. Cummings DE,
    7. Thorner MO,
    8. Geysen HM
    : Comparison of competitive radioimmunoassays and two-site sandwich assays for the measurement and interpretation of plasma ghrelin levels. J Clin Endocrinol Metab 95: 2351–2358, 2010pmid:20194708
    OpenUrlCrossRefPubMed
  24. ↵
    1. Pérez-Fontán M,
    2. Cordido F,
    3. Rodríguez-Carmona A,
    4. García-Naveiro R,
    5. Isidro ML,
    6. Villaverde P,
    7. García-Buela J
    : Acute plasma ghrelin and leptin responses to oral feeding or intraperitoneal hypertonic glucose-based dialysate in patients with chronic renal failure. Kidney Int 68: 2877–2885, 2005pmid:16316365
    OpenUrlCrossRefPubMed
  25. ↵
    1. Suneja M,
    2. Murry DJ,
    3. Stokes JB,
    4. Lim VS
    : Hormonal regulation of energy-protein homeostasis in hemodialysis patients: An anorexigenic profile that may predispose to adverse cardiovascular outcomes. Am J Physiol Endocrinol Metab 300: E55–E64, 2011pmid:20959536
    OpenUrlCrossRefPubMed
  26. ↵
    1. Ozkaya O,
    2. Buyan N,
    3. Bideci A,
    4. Gonen S,
    5. Ortac E,
    6. Fidan K,
    7. Cinaz P,
    8. Söylemezoğlu O
    : Osteoprotegerin and RANKL serum levels and their relationship with serum ghrelin in children with chronic renal failure and on dialysis. Nephron Clin Pract 105: c153–c158, 2007pmid:17259742
    OpenUrlCrossRefPubMed
  27. ↵
    1. Beaumont NJ,
    2. Skinner VO,
    3. Tan TM,
    4. Ramesh BS,
    5. Byrne DJ,
    6. MacColl GS,
    7. Keen JN,
    8. Bouloux PM,
    9. Mikhailidis DP,
    10. Bruckdorfer KR,
    11. Vanderpump MP,
    12. Srai KS
    : Ghrelin can bind to a species of high density lipoprotein associated with paraoxonase. J Biol Chem 278: 8877–8880, 2003pmid:12531885
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Patterson M,
    2. Murphy KG,
    3. le Roux CW,
    4. Ghatei MA,
    5. Bloom SR
    : Characterization of ghrelin-like immunoreactivity in human plasma. J Clin Endocrinol Metab 90: 2205–2211, 2005pmid:15657369
    OpenUrlCrossRefPubMed
  29. ↵
    1. Akamizu T,
    2. Shinomiya T,
    3. Irako T,
    4. Fukunaga M,
    5. Nakai Y,
    6. Nakai Y,
    7. Kangawa K
    : Separate measurement of plasma levels of acylated and desacyl ghrelin in healthy subjects using a new direct ELISA assay. J Clin Endocrinol Metab 90: 6–9, 2005pmid:15483072
    OpenUrlCrossRefPubMed
  30. ↵
    1. Lowrie EG,
    2. Lew NL
    : Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 15: 458–482, 1990pmid:2333868
    OpenUrlCrossRefPubMed
  31. ↵
    1. Stenvinkel P,
    2. Heimbürger O,
    3. Paultre F,
    4. Diczfalusy U,
    5. Wang T,
    6. Berglund L,
    7. Jogestrand T
    : Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 55: 1899–1911, 1999pmid:10231453
    OpenUrlCrossRefPubMed
  32. ↵
    1. Levey AS,
    2. Bosch JP,
    3. Lewis JB,
    4. Greene T,
    5. Rogers N,
    6. Roth D
    ; Modification of Diet in Renal Disease Study Group: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Ann Intern Med 130: 461–470, 1999pmid:10075613
    OpenUrlCrossRefPubMed
    1. Deboer MD,
    2. Zhu X,
    3. Levasseur PR,
    4. Inui A,
    5. Hu Z,
    6. Han G,
    7. Mitch WE,
    8. Taylor JE,
    9. Halem HA,
    10. Dong JZ,
    11. Datta R,
    12. Culler MD,
    13. Marks DL
    : Ghrelin treatment of chronic kidney disease: improvements in lean body mass and cytokine profile. Endocrinology 149: 827–835, 2008pmid:18039782
    OpenUrlCrossRefPubMed
  34. ↵
    1. Barazzoni R,
    2. Zhu X,
    3. Deboer M,
    4. Datta R,
    5. Culler MD,
    6. Zanetti M,
    7. Guarnieri G,
    8. Marks DL
    : Combined effects of ghrelin and higher food intake enhance skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rats with chronic kidney disease. Kidney Int 77: 23–28, 2010pmid:19890275
    OpenUrlCrossRefPubMed
  35. ↵
    1. Wynne K,
    2. Giannitsopoulou K,
    3. Small CJ,
    4. Patterson M,
    5. Frost G,
    6. Ghatei MA,
    7. Brown EA,
    8. Bloom SR,
    9. Choi P
    : Subcutaneous ghrelin enhances acute food intake in malnourished patients who receive maintenance peritoneal dialysis: A randomized, placebo-controlled trial. J Am Soc Nephrol 16: 2111–2118, 2005pmid:15888560
    OpenUrlAbstract/FREE Full Text
  36. ↵
    1. Ashby DR,
    2. Ford HE,
    3. Wynne KJ,
    4. Wren AM,
    5. Murphy KG,
    6. Busbridge M,
    7. Brown EA,
    8. Taube DHGMA,
    9. Ghatei MA,
    10. Tam FW,
    11. Bloom SR,
    12. Choi P
    : Sustained appetite improvement in malnourished dialysis patients by daily ghrelin treatment. Kidney Int 76: 199–206, 2009pmid:19387475
    OpenUrlCrossRefPubMed
  37. ↵
    1. Muscaritoli M,
    2. Molfino A,
    3. Chiappini MG,
    4. Laviano A,
    5. Ammann T,
    6. Spinsanti P,
    7. Melchiorri D,
    8. Inui A,
    9. Alegiani F,
    10. Rossi Fanelli F
    : Anorexia in hemodialysis patients: The possible role of des-acyl ghrelin. Am J Nephrol 27: 360–365, 2007pmid:17556836
    OpenUrlCrossRefPubMed
  38. ↵
    1. Kirk SE,
    2. Gertz BJ,
    3. Schneider SH,
    4. Hartman ML,
    5. Pezzoli SS,
    6. Wittreich JM,
    7. Krupa DA,
    8. Seibold JR,
    9. Thorner MO
    : Effect of obesity and feeding on the growth hormone (GH) response to the GH secretagogue L-692,429 in young men [Abstract. J Clin Endocrinol Metab 82: 1154–1159, 1997pmid:9100588
    OpenUrlCrossRefPubMed
    1. Chapman IM,
    2. Pescovitz OH,
    3. Murphy G,
    4. Treep T,
    5. Cerchio KA,
    6. Krupa D,
    7. Gertz B,
    8. Polvino WJ,
    9. Skiles EH,
    10. Pezzoli SS,
    11. Thorner MO
    : Oral administration of growth hormone (GH) releasing peptide-mimetic MK-677 stimulates the GH/insulin-like growth factor-I axis in selected GH-deficient adults. J Clin Endocrinol Metab 82: 3455–3463, 1997pmid:9329386
    OpenUrlCrossRefPubMed
    1. Murphy MG,
    2. Bach MA,
    3. Plotkin D,
    4. Bolognese J,
    5. Ng J,
    6. Krupa D,
    7. Cerchio K,
    8. Gertz BJ
    : Oral administration of the growth hormone secretagogue MK-677 increases markers of bone turnover in healthy and functionally impaired elderly adults. The MK-677 Study Group. J Bone Miner Res 14: 1182–1188, 1999pmid:10404019
    OpenUrlCrossRefPubMed
    1. Murphy MG,
    2. Plunkett LM,
    3. Gertz BJ,
    4. He W,
    5. Wittreich J,
    6. Polvino WM,
    7. Clemmons DR
    : MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. J Clin Endocrinol Metab 83: 320–325, 1998pmid:9467534
    OpenUrlCrossRefPubMed
    1. Bresciani E,
    2. Nass R,
    3. Torsello A,
    4. Gaylinn B,
    5. Avallone R,
    6. Locatelli V,
    7. Thorner MO,
    8. Müller EE
    : Hexarelin modulates the expression of growth hormone secretagogue receptor type 1a mRNA at hypothalamic and pituitary sites. Neuroendocrinology 80: 52–59, 2004pmid:15361691
    OpenUrlCrossRefPubMed
  43. ↵
    1. Iglesias P,
    2. Díez JJ,
    3. Fernández-Reyes MJ,
    4. Aguilera A,
    5. Burgués S,
    6. Martínez-Ara J,
    7. Miguel JL,
    8. Gómez-Pan A,
    9. Selgas R
    : Recombinant human growth hormone therapy in malnourished dialysis patients: A randomized controlled study. Am J Kidney Dis 32: 454–463, 1998pmid:9740162
    OpenUrlCrossRefPubMed
  44. ↵
    1. Asakawa A,
    2. Inui A,
    3. Fujimiya M,
    4. Sakamaki R,
    5. Shinfuku N,
    6. Ueta Y,
    7. Meguid MM,
    8. Kasuga M
    : Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin. Gut 54: 18–24, 2005
    OpenUrlAbstract/FREE Full Text
  45. ↵
    1. Chen C-Y,
    2. Inui A,
    3. Asakawa A,
    4. Fujino K,
    5. Kato I,
    6. Chen C-C,
    7. Ueno N,
    8. Fujimiya M
    : Des-acyl ghrelin acts by CRF type 2 receptors to disrupt fasted stomach motility in conscious rats. Gastroenterology 129: 8–25, 2005pmid:16012930
    OpenUrlCrossRefPubMed
  46. ↵
    1. Arbeiter AK,
    2. Büscher R,
    3. Petersenn S,
    4. Hauffa BP,
    5. Mann K,
    6. Hoyer PF
    : Ghrelin and other appetite-regulating hormones in paediatric patients with chronic renal failure during dialysis and following kidney transplantation. Nephrol Dial Transplant 24: 643–646, 2009pmid:18809976
    OpenUrlCrossRefPubMed
  47. ↵
    1. Bossola M,
    2. Muscaritoli M,
    3. Valenza V,
    4. Panocchia N,
    5. Tazza L,
    6. Cascino A,
    7. Laviano A,
    8. Liberatori M,
    9. Lodovica Moussier M,
    10. Rossi Fanelli F,
    11. Luciani G
    : Anorexia and serum leptin levels in hemodialysis patients. Nephron Clin Pract 97: c76–c82, 2004pmid:15292683
    OpenUrlCrossRefPubMed
  48. ↵
    1. Dixit VD,
    2. Schaffer EM,
    3. Pyle RS,
    4. Collins GD,
    5. Sakthivel SK,
    6. Palaniappan R,
    7. Lillard JW Jr.,
    8. Taub DD
    : Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest 114: 57–66, 2004pmid:15232612
    OpenUrlCrossRefPubMed
  49. ↵
    1. Pérez-Fontán M,
    2. Cordido F,
    3. Rodríguez-Carmona A,
    4. Penín M,
    5. Díaz-Cambre H,
    6. López-Muñiz A,
    7. Sangiao-Alvarellos S,
    8. García-Buela J
    : Short-term regulation of peptide YY secretion by a mixed meal or peritoneal glucose-based dialysate in patients with chronic renal failure. Nephrol Dial Transplant 23: 3696–3703, 2008pmid:18503008
    OpenUrlCrossRefPubMed
View Abstract
Back to top

In this issue

View Selected Citations (0)
Print
Download PDF
Email Article
Citation Tools
Request Permissions
Association of Plasma Des-acyl Ghrelin Levels with CKD
Rohit K. Gupta, Tamil Kuppusamy, James T. Patrie, Bruce Gaylinn, Jianhua Liu, Michael O. Thorner, Warren K. Bolton
CJASN Jul 2013, 8 (7) 1098-1105; DOI: 10.2215/CJN.09170912
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Jump to section