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).

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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.

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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
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