Oral ghrelin receptor agonist MK-0677 increases serum insulin-like growth factor 1 in hemodialysis patients: a randomized blinded study.

Background: Protein-energy wasting (PEW) in end-stage renal disease (ESRD) patients is associated with increased morbidity and mortality, but options for treatment are limited. Growth hormone (GH) increases insulin-like growth factor 1 (IGF-1), with improved nutritional parameters, but must be given subcutaneously and does not provide normal GH secretion patterns. MK-0677, an oral ghrelin receptor agonist (GRA), maintains normal GH secretion and increases lean body mass in normal subjects; it has not been studied in dialysis patients, an essential step in assessing efficacy and safety prior to clinical trials. Methods: We performed a randomized crossover double-blind study in assessing the effect of MK-0677 versus placebo on IGF-1 levels, the primary outcome, in hemodialysis patients. In total, 26 subjects enrolled and 22 completed the 3-month crossover study. Results: The geometric mean IGF-1 was 1.07-fold greater [95% confidence interval (CI) 0.89-1.27; P = 0.718] after placebo. In patients receiving MK-0677, the geometric mean IGF-1 were 1.76-fold greater (95% CI 1.48-2.10; P < 0.001) following MK-0677. When the data were adjusted for preintervention IGF-1 concentration, the ratio of geometric means (MK-0677 relative to placebo) for the pre- versus postintervention change in the IGF-1 was 1.65 (95% CI 1.33-2.04; P < 0.001). These data demonstrate a 65% greater increase (95% CI 33-104%) in IGF-1 in MK-0677-dosed subjects compared with placebo. There were no serious adverse effects attributable to MK-0677. Conclusions: MK-0677 increased serum IGF-1 levels with minimal adverse effects in hemodialysis subjects. Studies are needed to evaluate whether long-term therapy with MK-0677 improves PEW, lean body mass, physical strength, quality of life and survival in CKD/ESRD patients.

Dependence of Glomerulonephritis Induction on Novel Intraglomerular Alternatively Activated Bone Marrow-Derived Macrophages and Mac-1 and PD-L1 in Lupus-Prone NZM2328 Mice.

Glomerular damage mediated by glomerulus-infiltrating myeloid-derived cells is a key pathogenic event in lupus nephritis (LN), but the process is poorly understood. Confocal microscopy of kidney sections and flow cytometry analysis of glomerular cells from magnetic bead-purified glomeruli have identified glomerulus-infiltrating leukocyte populations in NZM2328 (NZM) lupus-prone mice with spontaneous chronic glomerulonephritis (GN) and anti-glomerular basement membrane-induced nephritis. The occurrence of a major glomerulus-infiltrating CD11b+F4/80-I-A- macrophage population exhibiting the markers programmed death ligand-1 (PD-L1), Mac-2, and macrophage mannose receptor (CD206) and producing Klf4, Il10, Retnla, Tnf, and Il6 mRNA, which are known to be expressed by alternatively activated (M2b) macrophages, correlated with proteinuria status. In NZM mice with spontaneous LN, glomerular macrophage infiltration is predominant. CD11b+F4/80-I-A- intraglomerular macrophages and polymorphonuclear neutrophils (PMN) are important in inducing GN, as anti-CD11b and -ICAM-1 mAb inhibited both proteinuria and macrophage and PMN infiltration. The predominant and high expression of PD-L1 by CD11b+F4/80-I-A- glomerular macrophages in kidneys of mice with GN and the inhibition of proteinuria by anti-PD-L1 mAb supported the pathogenic role of these macrophages but not the PD-L1- PMN in GN development and in inducing podocyte damage. In NZM mice with spontaneous chronic GN and severe proteinuria, few glomerulus-infiltrating PMN were found, leaving macrophages and, to a less extent, dendritic cells as the major infiltrating leukocytes. Taken together, these data support the important pathogenic effect of CD11b+F4/80-I-A- M2b-like glomerulus-infiltrating macrophages in LN and reinforce macrophages as a promising target for GN treatment.

Association of plasma des-acyl ghrelin levels with CKD.

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.

Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria.

BACKGROUND AND OBJECTIVES: This report summarizes the first phase 1 trial treating patients with microalbuminuric diabetic kidney disease (DKD) using FG-3019, a human monoclonal antibody to connective tissue growth factor (CTGF). CTGF is critically involved in processes of progressive fibrosis, including DKD. This phase 1, open-label, dose-escalation trial evaluated safety, pharmacokinetics, and possible therapeutic effects of FG-3019 on albuminuria, proteinuria, and tubular proteins. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: Microalbuminuric subjects (n = 24) with type 2 (79%) or type 1 (21%) diabetes received 3 or 10 mg/kg FG-3019 dosed intravenously every 14 days for four doses. Albuminuria and safety follow-up were to days 62 and 365, respectively. RESULTS: No infusion was interrupted for symptoms, although 5 of 24 subjects had mild infusion-day adverse events thought to be possibly drug-related. No subject developed anti-FG-3019 antibodies. FG-3019 clearance was lower at 10 mg/kg than at 3 mg/kg, suggesting a saturable elimination pathway. Although this study was not designed for efficacy testing, it was notable that urinary albumin/creatinine ratio (ACR) decreased significantly from mean pretreatment ACR of 48 mg/g to mean post-treatment (day 56) ACR of 20 mg/g (P = 0.027) without evidence for a dose-response relationship. CONCLUSIONS: Treatment of microalbuminuric DKD subjects using FG-3019 was well tolerated and associated with a decrease in albuminuria. The data demonstrate a saturable pathway for drug elimination, minimal infusion adverse events, and no significant drug-attributable adverse effects over the year of follow-up. Changes in albuminuria were promising but require validation in a prospective, randomized, blinded study.

Nephrogenic systemic fibrosis: a survey of nephrologists' perceptions and practices.

BACKGROUND AND OBJECTIVES: Nephrogenic systemic fibrosis (NSF) is a disorder that can affect patients with renal dysfunction exposed to a gadolinium-based contrast agent (GBCA). Given the unique role nephrologists play in caring for patients at risk to develop NSF, this study surveyed their perceptions and practices regarding NSF. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: An internet-based, cross-sectional survey of clinical nephrologists in the United States was performed. Perceptions and self-reported practices regarding NSF and local facility policies were assessed concerning GBCA use in renal dysfunction. RESULTS: Of the 2310 eligible nephrologists e-mailed to participate in the survey, 171 (7.4%) responded. Respondents spent 85% of their time in direct patient care and 83% worked in private practice; 59% had cared for a patient with NSF. Although over 90% were aware of the morbidity and mortality associated with NSF, 31% were unaware of an association with specific GBCA brand and 50% believed chronic kidney disease stage 3 patients were at risk to develop NSF. Changes in facility policies concerning GBCA use in renal dysfunction were widespread (>90%). Most nephrologists (56%) felt that enacted policies were appropriate, yet 58% were uncertain if the changes had benefited patients. CONCLUSIONS: These results indicate that nephrologists are generally familiar with the risk factors and consequences of NSF, but their perceptions do not always align with current evidence. Local policy changes in GBCA use are pervasive. Most nephrologists are comfortable with these policy changes but have mixed feelings regarding their effectiveness.

T cells and dendritic cells in glomerular disease: the new glomerulotubular feedback loop.

A newly described glomerulotubular feedback loop may explain the relationship between glomerular damage, epitope spreading, tubulointerstitial nephritis, proteinuria as a progression factor, and the importance of the local milieu in kidney damage. It also opens the horizons for exciting innovative approaches to therapy of both acute and chronic kidney diseases.